Pyridine Boronic Acids

Durham E-Theses
Functionalised Pyridyl- and Pyrimidyl- Boronic acids

and derived new Biheteroaryls
Smith, Amy Elizabeth
How to cite:
Smith, Amy Elizabeth (2005) Functionalised Pyridyl- and Pyrimidyl- Boronic acids and derived new
Biheteroaryls, Durham theses, Durham University. Available at Durham E-Theses Online:
http://etheses.dur.ac.uk/2751/
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University of Durham
A Thesis Entitled
Functionalised Pyridyl- and Pyrimidyl- Boronic Acids and

Derived New Biheteroaryls
Submitted by
Amy Elizabeth Smith, B.Sc. (Hons)
(Ustinov College)
Department of Chemistry
A Candidate for the Degree of Doctor of Philosophy 2005
The copyright of this thesis rests wnh the
author or the university to which was
submitted. No quotation from It, or
Information derived from It may be published
wHhout the prior written consent of the author
or university, and any Information derived
from should be acknowledged.
2 NOV 2008
ACKNOWLEDGEMENTS
I w o u l d like to thank m y academic supervisor Prof. M . R. Bryce and m y
industrial
supervisor M r . B. Tarbit for their invaluable help and support throughout this project.
Thanks also go to the EPSRC and Seal Sands Chemicals for f u n d i n g , and to the members
o f the Bryce research group past and present for m a k i n g me feel part o f the team.
This research w o u l d not have been possible w i t h o u t the help o f the technical staff, namely:
Dr A l a n K e n w r i g h t , M r Ian M c K e a g and M r s Catherine Heffernan ( N M R ) ; D r M i k e Jones
and M i s s Lara Turner (mass spectrometry); M r s Jarika Dostal (elemental analysis); Dr
A n d r e i Batsanov ( X - r a y crystallography), M r M a l c o l m Richardson and M r Peter Coyne
(glassblowing); M r T o n y Baxter and M r s Elizabeth W o o d (stores) and all the other people
w h o I have w o r k e d and studied w i t h the chemistry department and at Seal Sands
Chemicals.
1 w o u l d also like to thank all the friends I made d u r i n g m y time at D u r h a m , in particular

D a v i d H a i g h , Rachel Roberts, Rachel Slater, and Lucy Wheatley for their support w h i c h
came in every f o r m fr study nights to pub nights.
Finally I w o u l d like to thank m y f a m i l y , especially my mam and dad for their c o n t i n u i n g

love, patience and support throughout m y time at university, and Ian for making D u r h a m a
very special place filled w i t h the best memories.
MEMORANDUM
The w o r k presented w i t h i n this thesis was carried out at the University o f Durham between
October 2002 and September 2005.
The thesis is the w o r k o f the author, except where
acknowledged by reference and has not been submitted for any other degree.
The
copyright o f this thesis lies solely w i t h the author and no quotation f r o m it should be
published w i t h o u t
prior w r i t t e n consent and information derived
from
it should
be
acknowledged.
Part o f this w o r k has been the subject o f the f o l l o w i n g publications:
A . E. T h o m p s o n , G. Hughes, A . . Batsanov, M . R. Bryce, p. R. Parry, and B. Tarbit; J.
Org. Chem. 2005, 70, 388.
A . E. T h o m p s o n , A . . Batsanov, M . R. Bryce, N . Saygili, p. R. Parry, and B. Tarbit,
Telrahedro,
2005, 7 , 5 1 3 1 ,
and has been presented at:
Seal Sands Chemistry Day, Ramside Hall 2004
Durham
University
Chemistry
Department
D u r h a m 2005
Seal Sands Chemistry Day, W y n y a r d 2006
III
Final
Year
Postgraduate
Symposium,
ABBREVIATIONS
DMF
Dimethylformamide
THF
Tetrahydrofuran
N M R
Nuclear Magnetic Resonance
TMEDA
MA^,jV',^'-Tetramethyl-l,2-ethylenediamine
DMSO
Dimethylsulfoxide
HPLC
H i g h Pressure L i q u i d Chromatography
nOe
nuclear Overhauser effect
D C M
Dichloromethane
DPA
Diisopropylamine
L D A
Lithium Diisopropylamide
TLC
T h i n Layer Chromatography
dba
dibenzylideneacetone
dppf
diphenylphospliinoferrocene
cyclohexyl
Triisopropylborate
TMB
Trimethylborate
TBB
Tributylborate
/7-BLIL
DoM
directed (/?o-metallation
DMGs
directing metallating groups
LTMP
L i t h i u m 2,2,6,6-tetramethylpiperidide
DME
dimethylether
ROESY
Rotating frame Overhauser Enhancement Spectroscopy
COSY
Correlation Spectroscopy
IV
HSQC
Heteronuclear Single Quantum Coherence
HMBC
Heteronuclear M u l t i p l e Bond Correlation
EtOAc
Ethyl acetate
STATEMENT OF COPYRIGHT
N o part o f this thesis may be reproduced by any means, nor transmitted, nor translated into
any machine language w i t h o u t the written permission o f the author.
ABSTRACT
The
novel
substituted
pyridylboronic
dimethoxy-3-pyridylboronic
difluoro-3-pyridylboronic
acid
acid
acids 2 - e t h o x y - 3 - p y r i d y l b o r o n i c
acid
103, 2,6-
146, 2 , 3 - d i m e t h o x y - 4 - p y r i d y l b o r o n i c
acid
158, 2,6-
225, 2 , 6 - d i c h l o r o - 3 - p y r i d y l b o r o n i c
acid
230 and 2,3-
d i c h l o r o - 4 - p y r i d y l b o r o n i c acid 238 have been synthesised, and the synthesis o f existing

alkoxy
pyridylboronic
pyridylboronic
acids
2-methoxy-5-pyridylboronic
acid 43 has been optimized
pyrimidylboronic
acids
and scaled
2-chloro-5-pyrimidylboronic
p y r i m i d y l b o r o n i c acid 2 2 1 have been syntliesised.
acid
40 and
up.
The novel
acid
244
and
2-methoxy-3substituted
2-amino-5-
A l l o f the above mentioned boronic
acids were shown to undergo palladium-catalysed Suzuki cross-coupling reactions w i t h a

variety o f heteroaryl halides to yield novel heteroarylpyridine derivatives.
B(0H)2
B(0H)2
B(0H)2
N
MeO
OEt
,OMe
N
OMe
B(0H)2
OMe
146
103
B(0H)2
N
230
B(0H)2
B(0H)2
(0)2
CI^N
43
244
221
A range o f halogenated aromatics and heteroaromatics bearing primary amine groups have
been shown to be suitable substrates for S u z i i k i - M i y a u r a cross-coupling reactions w i t h
arylboronic acids and p y r i d y l b o r o n i c acids under standard conditions, w i t h o u t the need for
protection/deprotection
steps.
New
amino-SLibstituted
arylpyridines,
bipyridines,
pyrazinopyridines, indolinopyridines, carbazolopyridines and indolopyridines have thereby

been
obtained.
One
derivative
was
further
VI
functionalised
via
diazotisation.
PAGE N U M B E R
Acknowledgements
11
Memorandum
Abbreviations
IV
Abstract
VI
Contents
VII
1.0
2.0
Introduction
1.1
Synthesis o f A r y l and Heteroarylboronic A c i d s
1.2
Application o f Boronic Acids
22
1.3
Conclusion
37
A l k o x y b o r o n i c acids: Scale-up o f e x i s t i n g p r e p a r a t i o n s a n d the synthesis o f new

examples
2.1
Introduction
2.2
Large-scale Syntheses o f Previously Published

Alkoxy-substituted P y r i d y l b o r o n i c A c i d s
44
2.3
Novel Alkoxypyridylboronic Acids
46
2.3.1
2-Ethoxy"3-pyridylboronic Acid
46
2.3.2
2,6-Dimethoxy3-pyridylboronic A c i d
56
3-D^^
59
2.3.3
2.4
3,0
44
Acid
Conclusion
60
A m i n e Substituted Couplings and A m i n e Substituted Boronic acid

3.1
Introduction
63
3.2
z L i k i - M i y a u r a Cross-Couplings w i t h a Partner Bearing a

Primary A m i n e Group
64
3.3
Transformation o f 184 via Diazotization
81
3.4
2-Amino-5-pyrimidylboronic Acid
82
3.5
Conclusion
86
VII
4.0
5.0
Synthesis a n d A p p l i c a t i o n o f N o v e l H a l o p y r i d y l b o r o n i c A c i d s
4.1
Introduction
89
4.2
2,6Ditoro3-pyridylboronic A c i d
89
4.3
2,6-Dichloro-3pyridylboronic A c i d
92
4.4
2,3-Dichloro4-pyridylboronic A c i d
100
4.5
2-Chloro-5-pyrimidylboronic Acid
103
4.6
Conclusion
107
E x p e r i m e n t a l Procedures
5.1
General Methods
108
5.1.1
General Procedure for all the Cross-Coupling Reactions
109
5.2
Experimental Procedures o f Chapter 2
109
5.3
120
5.4
138
Chapter 1
Introduction
I n t r o d u c t i o n to A p p l i c a t i o n o f B o r o n i c A c i d s
1.0
Introduction
F u n c t i o n a l i s e d a r y l and heteroaryl systems are i m p o r t a n t synthetic templates f o r

industries such as agrochemicals, fine chemicals and pharmaceuticals.
Small m u l t i -
substituted r i n g systems m a y be incorporated i n t o larger systems b y u t i l i s i n g substituted

b o r o n i c acid moieties i n S u z u k i - M i y a u r a cross-coupling reactions.
I t is therefore
i m p e r a t i v e that n e w l y f u n c t i o n a l i s e d b o r o n i c acid r i n g systems are developed.
These
systems m u s t also cross-couple successfully w i t h a range o f halogenated partners i n

order to satisfy the need f o r b u i l d i n g b l o c k s f o r the next generation o f i n d u s t r i a l
products.
I n this first chapter the literature methods used to synthesise heteroaryl b o r o n i c
acids are discussed i n detail.
I n a d d i t i o n to this, the p a l l a d i u m catalysed S u z u k i -
M i y a u r a c r o s s - c o u p l i n g reactions o f these b o r o n c o n t a i n i n g species are also r e v i e w e d .

T h e f o l l o w i n g chapters encompass the syntheses o f heteroaryl b o r o n i c acids
c o n t a i n i n g a l k o x y , a m i n e and halogen substituents, respectively.
successful large-scale (ca.
F u r t h e r m o r e , the
100 g) syntheses o f several a l k o x y - s u b s t i t u t e d heteroaryl
b o r o n i c acids are also reported.
T h e later p a r t o f each chapter explores the S u z u k i -
M i y a u r a reactions o f each n o v e l class o f b o r o n i c acids w i t h various c r o s s - c o u p l i n g

partners.
Chapter 3 examines i n detail the S u z u k i - M i y a u r a cross-coupling reactions o f a
range o f heteroaryl and a r y l halides bearing a m i n e groups w i t h a range o f a r y l and
heteroaryl b o r o n i c acids.
1.1
Synthesis o f A r y l a n d H e t e r o a t y l b o r o n i c A c i d s
T h e m a i n m e t h o d used i n the syntheses o f b o r o n i c acids is the reaction o f an

o r g a n o m e t a l l i c reagent w i t h an electrophile, i n this case a t r i a l k y l b o r a t e such as
triisopropylborate (TPB).*
T h i s route is also useful f o r the syntheses o f boronate
esters.^ T h e reaction o f a n o r g a n o m e t a l l i c reagent, such as " b u t y l l i t h i u m ( - B u L i ) w i t h

an a r y l h a l i d e f o r m s the o r g a n o l i t h i u m reagent.^
T h e subsequent a d d i t i o n o f
an
e l e c t r o p h i l i c borate species a l l o w s the f o r m a t i o n o f a c a r b o n - b o r o n b o n d . T h e b o r o n i c

a c i d can t h e n be generated b y a c i d i f i c a t i o n o f the reaction m i x t u r e . P y r i d i n e undergoes
e l e c t r o p h i l i c substitution w i t h d i f f i c u l t y for t w o reasons; p y r i d i n e and electrophiles tend

t o f o r m p y r i d i n i u m cations, thereby m a k i n g e l e c t r o p h i l i c substitution at a carbon even
m o r e d i f f i c u l t ^ , and secondly the electrophilic s u b s t i t i o n o f p y r i d i n e is a selective
reaciiorr
(Scheme 1.1a) w h i c h n o r m a l l y occurs at the C-3 p o s i t i o n w h e r e the least
destabilising intermediate i s .
5
2-Position
3-Position
4-Position
S c h e m e L l a : E l e c t r o p h i l i c Substitution o f P y r i d i n e at the 2- 3- and 4-positions.
T h e o r g a n o m e t a l l i c reagents used are either G r i g n a r d 6 or o r g a n o l i t h i u m species^.
Both
reagents are f o r m e d b y a d d i n g the corresponding a l k y l - or a r y l h a l i d e to the appropriate

m e t a l and they c o n t a i n a m e t a l - c a r b o n b o n d w h i c h is h i g h l y polarised.
A
G r i g n a r d reagent ( R - M g - X , where X
is b r o m i n e , c h l o r i n e or i o d i n e ) is
generated b y the o x i d a t i v e i n s e r t i o n , or a d d i t i o n , o f m a g n e s i u m i n t o a carbon-halogen

bond/
H o w e v e r , G r i g n a r d reagents react w i t h water and o x y g e n , so they require
anhydrous c o n d i t i o n s and are i n general neither isolated n o r stored, but are generated
and reacted in situr
T h e m a g n e s i u m a t o m acts as a L e w i s acid due to its e m p t y 3p
o r b i t a l w h i c h accepts a lone pair o f electrons f r o m the solvent.
T h e order o f halide
a c t i v i t y is I > B r > C I , a l t h o u g h a r y l chlorides require the use o f T H F or another higher

b o i l i n g solvent instead o f the usual ether.
D u e t o the p o o r r e a c t i v i t y o f some organic
halides, m o d i f i c a t i o n s such as the use o f higher reaction temperatures, catalysts and

activated m a g n e s i u m have been used to f o r m G r i g n a r d reagents.^
M a g n e s i u m can be
activated b y a n u m b e r o f d i f f e r e n t methods. I o d i n e - a c t i v a t e d m a g n e s i u m turnings m a y
form m a g n e s i u m i o d i d e w h i c h is m o r e soluble and reactive t h a n m a g n e s i u m alone.

E n t r a i n m e n t is the use o f catalytic amounts o f a l o w e r but m o r e reactive a l k y l halide,
e.g. 1 , 2 - d i b r o m o e t h a n e , to initiate the G r i g n a r d reaction. A l s o u s i n g finely p o w d e r e d
m a g n e s i u m w i t h increased surface area facilitates the G r i g n a r d reagent f o r m a t i o n . ^
G r i g n a r d reagents can also be generated b y h a l o g e n - m a g n e s i u m exchange, n o r m a l l y
using i o d o p y r i d i n e s w h i c h are expensive.^
U s i n g b r o m o - and c M o r o p y r i d i n e s is
reported i n m a g n e s i u m exchange/^"^* but an attempt b y C a i ei ai to synthesise 3p y r i d y l b o r o n i c acid u s i n g this m e t h o d gave a p o o r y i e l d o f the desired p r o d u c t (36%).^^
L i t h i u m reagents are generated b y either m e t a l - h y d r o g e n exchange or m e t a l halogen exchange.
T h e f o r m e r can be achieved u s i n g / 7 - B u L i or
d i i s o p r o p y l a m i d e ( L D A ) . First d e p r o t o n a t i o n occurs, the ease o f w h i c h depends u p o n
the a c i d i t y o f the h y d r o g e n t o be r e m o v e d and the s t a b i l i t y o f the c a r b a n i o n produced/*^
E l e c t r o n - d e f i c i e n t s i x - m e m b e r e d aromatic heterocycles, such as p y r i d i n e , can be
deprotonated w i t h l i t h i u m amides w h e r e as a l k y l l i t h i u m s prefer a d d i t i o n t o the e l e c t r o n deficient r i n g over d e p r o t o n a t i o n . ^ M e t a l - h y d r o g e n exchange is f a c i l i t a t e d b y the
presence o f certain f u n c i o n a l g r o u p s ; this process is t e r m e d directed o r / o - m e t a l l a t i o n
( D o M ) . I t is possible to achieve clean m e t a l l a t i o n w i t h a l k y l l i t h i u m s f o r m a n y d i r e c t i n g
m e t a l l a t i n g groups ( D M G s ) such as O R , N H C O R , C O N H R , where the D M G cannot
undergo h a l o g e n exchange. F o r substrates c a r r y i n g substituents w h i c h can undergo
halogen-metal exchange, such as I, B r , , F, the harder and less basic L D A ( p K a 35.7)
and L T M P ( l i t h i u m 2 , 2 5 6 , 6 - t e t r a m e t h y l p i p e r i d i d e , p K a 3 7 . 3 ) can u s u a l l y be r e l i e d u p o n
for deprotonation.
T h e regioselective D o M effect can be rationalised i n terms o f
k i n e t i c or t h e r m o d y n a m i c c o n t r o l o f the reaction. There are three m a i n factors that
affect D o M : the i n d u c t i v e e l e c t r o n - w i t h d r a w i n g effect o f the D M G ; the strength o f
c o o r d i n a t i o n b e t w e e n the h e t e r o a t o m c o n t a i n i n g the D M G and the m e t a l , and the
electronic r e p u l s i o n between the c a r b a n i o n and the lone pair o f the n i t r o g e n i n the r i n g .
W h e n m e t a l amides are used, the reaction is n o r m a l l y t h e r m o d y n a m i c a l l y c o n t r o l l e d
(Scheme 1.1b). T h e D o M observed is a result o f the stabilisation f r o m the chelation o f
the metal w i t h the D M G (a) and the i n d u c t i v e e f f e c t o f the D M G (b) and the
dstabilisation b y the r e p u l s i o n between the carbanion and the lone pair o n the n i t r o g e n
( c ) . A s a result, the f o r m a t i o n o f the p y r i d i n e 3- and 4 - carbanion is m o r e favourable
than the f o r m a t i o n o f the 2 - c a r b a n i o n .
Li
DMG
DMG
(b)
(a)
(c)
BR
DMG
(d)
Scheme L i b :
(e)
D o M effects under t h e r m o d y n a m i c c o n t r o l (a), ( b ) , (c) and k i n e t i c
c o n t r o l ( d ) and (e).
W h e n a l k y l l i t h i u m s are used at l o w temperatures the reaction n o r m a l l y proceeds under

k i n e t i c c o n t r o l , w h e r e the i n d u c t i v e m e c h a n i s m ( d ) and c h e l a t i o n i n the t r a n s i t i o n state
(e) direct the reaction (Scheme 1.1b). T h e c o o r d i n a t i o n o f the D M G to the metal a l l o w s
disaggregation o f the m e t a l l a t i n g agent, r e i n f o r c i n g the e l e c t r o n - w i t h d r a w i n g effect o f
the D M G and increasing the p r o x i m i t y effect o f the a l k y l l i t h i u m . T h e p y r i d y l n i t r o g e n
can p r o m o t e deprotonation at C " 2 via c o o r d i n a t i o n w i t h a base w h e n a strong D M G is
absent. I n such cases it is i m p o r t a n t to use a chelating solvent, such as T H F , to stop this
occurring.
D u e to the a d d i t i o n p r o b l e m s associated w i t h the treatment o f electron-deficient
s i x - m e m b e r e d rings w i t h a l k y l l i t h i u m s , the simplest w a y to produce
species is b y h a l o g e n - l i t h i u m exchange.
T h e disadvantage o f this route is the greater
expense o f the starting halo-substituted r i n g systems.

n o r m a l l y achieved b y using -BuLi
pyridyllithium
M e t a l - h a l o g e n exchange is
because the b y - p r o d u c t - b u t y l b r o m i d e
rarely
interferes w i t h subsequent steps i n the reaction. M e t a l - h a l o g e n exchange is e x t r e m e l y

e x o t h e r m i c , therefore, l o w temperature and s l o w rate o f a d d i t i o n o f - B u L i are needed
to a v o i d side-reactions o c c u r r i n g , such as d e p r o t o n a t i o n , a d d i t i o n o f the substrate,
e l i m i n a t i o n o f l i t h i u m b r o m i d e , b r o m i n e m i g r a t i o n ( " d a n c e " ) or even r i n g o p e n i n g
reactions.
A
catalysed
d i f f e r e n t r o u t e is available t o synthesise b o r o n i c esters, n a m e l y

borylation
o f alkenes, alkyne
and
organic
electrophiles
with
metaldiboron
c o m p o u n d s or pinacolborane.'^ T h i s route has been investigated i n the last f e w years

and extended to cross-coupling reactions o f b o r a t i n g agents, most c o m m o n l y
b i s ( p i n a c o l a t o ) d i b o r o n or pinacolborane,'^ w i t h a r y l and v i n y l halides or triflates and
a l l y l c h l o r i d e s o r acetates t o y i e l d a r y l - , v i n y l - , and allylboronates i n h i g h y i e l d s i n the
presence o f a base and a p a l l a d i u m catalyst. T h i s route has advantages over t r a d i t i o n a l
methods, f o r e x a m p l e , the p r o t e c t i o n o f f u n c t i o n a l groups sensitive to o r g a n o m e t a l l i c
reagents is not required. M o r e o v e r , it is a one-step procedure f o r the synthesis o f
o r g a n o b o r o n i c esters f r o m organic electrophiles. A weaker base, f o r e x a m p l e K O A c , is
the m o s t e f f i c i e n t f o r a r y l iodides and b r o m i d e s because stronger bases, such as K3PO4
and K 2 C O 3 , p r o m o t e the further c o u p l i n g o f arylboronates w i t h the haloarenes, r e s u l t i n g
i n a substantial a m o u n t o f the s y m m e t r i c a l b i a r y l / ^ T h e boronic esters obtained can
t h e n be used i n the same manner as other b o r o n i c esters and acids i n S u z u k i - M i y a u r a
c o u p l i n g reactions w i t h halide c o m p o u n d s or they can be deprotected to produce the
corresponding b o r o n i c acids.
For examples 2 , 4 - d i m e t h o x y - 5 - p y r i m i d y l b o r o n i c acid
was synthesised via cedranediolborane b e i n g cross-coupled w i t h the c o r r e s p o n d i n g a r y l
iodide and t h e n a deprotection step."^*^
2Pyridylboronic esters, k n o w n t o be
troublesome, have been generated b y cross-coupling 2 - b r o m o p y r i d i n e s
with
b i s ( p i n a c o l a t o ) d i b o r o n i n the presence o f a base and catalyst. D e p e n d i n g o n the reaction
c o n d i t i o n s used, v a r y i n g amounts o f protodeboronated products were observed. I t was
stated that due to the i n s t a b i l i t y o f the esters, they were reacted in p r o d u c i n g a
nearly statistical m i x t u r e o f h o m o - and cross-coupled products.^*
W h y m a k e b o r o n i c acids?
Many
phenylboronic
acids possessing
ftinctionality
such as a m i n o - , halo-,
f o r m y l - , c y a n o - , a c e t y l - , a l k y l - and t r i ( a l k y l s i l y l ) - s u b s t i t u e n t s are n o w
available.
syntheses
There are also a n u m b e r o f h e t e r o c y c l i c b o r o n i c acids available, the

of
functionalities.
syntheses
commercially
of
some
have
been reported,
but
they
do
not
possess
such
diverse
H e t e r o c y c l i c b o r o n i c acids are valued f o r their i m p o r t a n t role i n the

bi(hetero)aryls
via
Suzuki-Miyaura
cross-coupling.
Many
natural
products^^ and m o d e m pharmaceuticals^^ c o n t a i n at least one heterocycle and thus using

b o r o n i c acids f o r the syntheses o f novel analogues f o r h i g h t h r o u g h - p u t screening has
intensified.
These
biaryl
also
have
applications
in
materials
science^"^
and
supramolecular chemistry.^''
A n example is the synthesis o f a m o d e m pharmaceutical
n a m e l y nemertelline,^^ the n e u r o t o x i n isolated

Suzuki-Miyaura
cross-coupling
reactions
p r o v i d e an e f f i c i e n t t w o - s t e p r a p i d
f r o m a H o p l o n e m e r t i n e sea w o r m .
p e r f o r m ed
on
h a l o p y r id y l b o r o n i c
synthesis o f n e m e r t e l l i n e , compared
acid s
to the other
routes, w h e r e a m i n i m u m o f five steps are r e q u i r e d .

B o r o n i c acid s have also recently been investigated f o r other uses, f o r e x a m p l e ,
fluorescent
sensors c o n t a i n i n g b o r o n i c a c i d
moieties have been synthesised
for non
invasive and continuous glucose m o n i t o r i n g ? ^
P y r i d y l b o r o n i c acids
U n t i l 2 0 0 2 , there was o n l y v e r y
l i m i t ed
literature o n p y r i d y l b o r o n i c
syntheses w i t h 3- and 4 - p y r i d y l b o r o n i c acid s first reported i n 1965.^
acid
3 - P y r id y l b o r o n i c
acid (3) was obtained i n a 2 8 % y i e l d via a G r i g n a r d reaction, w h e r e as 4 - p y r i d y l b o r o n i c

acid (6) w a s generated via the o r g a n o l i t h i u m d e r i v a t i v e i n a 2 0 % y i e l d (Scheme 1.1c).
MgBr
(0)2
1. Mg, THF
1. TBB
2. 22
. HCl
28%
Li
1. -BuLi, EiO
N 2. ()
AcOH
reflux
()
S c h e m e l . l c : Syntheses o f 3- and 4 - P y r i d y l b o r o n i c acids.^
20%
T h e l o w yields reflect the d i f f i c u l t y i n i s o l a t i n g the products, w h i c h was suggested to be

due to the amphoteric nature o f 3 - p y r i d y l b o r o n i c a c i d at p H 7, where i t c o u l d exist
p r e d o m i n a n t l y as the z w i t t e r i o n i c p y r i d i n i u m boronate ( 7 ) .
T h e presence o f the
z w i t t e r i o n i c structure was not supported b y any characterisation data.2 T h e h y d r o p h i l i c
nature o f b o t h isomers 3 and 6 was also stated to hinder their i s o l a t i o n f r o m the
aqueous phase.
T h e isolated c o m p o u n d s w e r e not f u l l y characterised; o n l y their
nitrogen content was g i v e n as evidence o f p u r i t y . T h e l o w y i e l d s , tedious w o r k u p and
extreme reaction c o n d i t i o n s needed, f o r the preparation makes this m e t h o d unattractive
f o r large-scale i n d u s t r i a l use. M o r e recently, n e w i m p r o v e d syntheses have been
published.
H a l a z y et al. synthesised 4 - p y r i d y l b o r o n i c acid ( 6 ) i n 6 5 % y i e l d via
h a l o g e n - l i t h i u m exchange f r o m 4 - b r o m o p y r i d i n e (9) (Scheme l . l d ) . ^ ^
(0)2
1. -BuLi/EtsO
2. (0')
3. HCl
NaOH
65%
N
6
S c h e m e l . l d : 4 - P y r i d v l b o r o n i c acid synthesis."^
Coudret also developed a route to 6, h o w e v e r , using 4 - i o d o p y r i d i n e that was converted

to the b o r o n i c acid and then i m m e d i a t e l y protected as the p i n a c o l borate (12) (Scheme
1 .le).^^ T h e resulting 4 - p y r i d y l p i n a c o l y l b o r o n i c ester (12) was obtained i n a 7 4 % y i e l d .
NH2
^
1. HCI/NaNOs
2. Kl/acetone
10
70%
1. -BLi/EtzO
2. ()
,
74%
3. Pinacol/AcO H
"
S c h e m e l . l e : 4 - P y r i d y l b o r o n i c acid synthesis
12
28
I n 2 0 0 2 , C a i et al. p u b l i s h e d the use o f a l i t h i u m - h a l o g e n exchange to produce 3p y r i d y l l i t h i u m f r o m 3 - b r o m o p y r i d i n e . ' ^ The p y r i d y l l i t h i u m species was t h e n reacted
w i t h a variety o f b u i l d i n g b l o c k s in situ, e.g. w i t h T P B t o g i v e 3 - p y r i d y l b o r o n i c acid (3)
i n 8 7 % y i e l d . Cai et al. noted that the isolated p r o d u c t was a m i x t u r e o f free boronic
acid and anhydride (13) based o n c , H , N analysis. C a i et al. then studied the order o f
a d d i t i o n o f the various reagents^^ and stated that sequential a d d i t i o n produced poor
yields ( 2 0 - 3 0 % ) . A " r e v e r s e " a d d i t i o n procedure ( 3 - b r o m o p y r i d i n e added t o - B u L i
f o l l o w e d b y the a d d i t i o n o f T P B ) gave better yields but had to be carried o u t at l o w
temperatures. H o w e v e r , i n order to achieve consistent h i g h yields an " situ" procedure
was r e q u i r e d ; the -BuLi
w a s added to a s o l u t i o n o f 3 - b r o m o p y r i d i n e and T P B ,
f o l l o w e d b y an aqueous w o r k up.
T h i s approach is reported to be tolerant o f
temperature g i v i n g the best y i e l d s ( 9 0 - 9 5 % ) at - 4 0 and y i e l d i n g 8 0 % even at 0 .
T h i s procedure a l l o w e d the synthesis o f 19.6 g o f 3 - p y r i d y l b o r o x i n e ( 1 3 ) , u s i n g the
same l i t h i u m - h a l o g e n exchange to o b t a i n the 3pyridylboronic a c i d , and t h e n a further
c y c l i s a t i o n step.
T h e characterisation o f the anhydride (13) was d i f f i c u l t due to the
presence o f v a r y i n g amounts o f hydrates, so it was converted to the p i n a c o l ester (14),
i n 8 1 % y i e l d , w h i c h was then f u l l y characterised. Cai extended the in situ procedure to
a n u m b e r o f other heterocyclic b o r o n i c acids i n c l u d i n g 5 - p y r i m i d y l b o r o n i c acid, 3q u i n o l y l b o r o n i c acid and 3 - t h i e n y l b o r o n i c acid.^^
Pinacol
Toluene
Reflux
13
14
S c h e m e l . l f : 3 - P y r i d y l b o r o x i n and p i n a c o l ester synthesis o f Cai et al.^^
I n 2 0 0 5 , C a i et al.
p u b l i s h e d w o r k o n a k i l o g r a m scale u t i l i s i n g the same procedure,^"
and also coupled the b o r o n i c ester ( 1 4 ) w i t h 3 - b r o m o q u i n o l i n e to o b t a i n 3 - p y r i d i n - 3 ylquinoline in 87% yield.
Dreos et al. p u b l i s h e d the synthesis o f " a l m o s t p u r e " 4 - p y r i d y l b o r o n i c acid (6)

via the p r e v i o u s l y described reverse a d d i t i o n procedure, a l t h o u g h it was o n l y i n a 3 4 %
y i e l d ; f u l l analysis o f the c o m p o u n d was g i v e n . ^ ' It was c l a i m e d that l o w e r yields were
obtained w h e n the reaction w a s carried out at - 6 0 due to cleophilic additions to
the 4 - b r o m o p y r i d i n e o c c u r r i n g c o m p e t i t i v e l y w i t h the halogen metal exchange reaction
and the l o w r e a c t i v i t y o f 4 - p y r i d y l l i t h i u m towards t r i m e t h o x y b o r a n e . T o overcome this
p r o b l e m the reaction was carried out at - 1 1 0 and N,
','-tetramethyl-1,2ethylenediamine ( T M E D A ) was added as an a c t i v a t i n g agent.
T h e salt o f 2 - p y r i d y l l i t h i u m borate has been isolated as a stable compound,^^ but

the synthesis o f 2 - p y r i d y l b o r o n i c acid ( 1 5 ) , u n t i l recently, has remained e l u s i v e . T h e
proposed reason b e h i n d the failure o f this synthesis was that the p y r i d y l b o r o n i c acid
underwent protodeboronation?'*
It was observed by F ischer et al. that the 3- and 4 -
p y r i d y l b o r o n i c acids, u p o n u v
i r r a d i a t i o n i n neutral and s l i g h t l y basic c o n d i t i o n s ,
decompose to produce p y r i d i n e (16) and boric acid (17).
T h e proposed deprotonation
o f the 2 - p y r i d y l b o r o n i c acid (15) is a Sel substitution reaction, w h i c h is k n o w n to occur

w i t h p y r i d i n e and p y r i d i n i u m ions (Scheme l . l g ) . It was also observed that a l t h o u g h 3and 4 - p y r i d y l b o r o n i c acids w e r e t h e r m a l l y stable, they decomposed u p o n treatment w i t h
m e t h y l 10(6.*
+ HBO
S c h e m e l . l g : D e c o m p o s i t i o n o f 2 - p y r i d y l b o r o n i c acid
34
T h e first c l a i m o f the synthesis o f 2 - p y r i d y l b o r o m c acid was b y M a t o n d o et al. w h o i n

2002 described the c o u p l i n g o f 2 - p y r i d y l b o r o n i c
amongst couplings o f other b o r o n i c acids.^^
acid (15) w i t h
2-bromopyridine,
T h e synthesis and characterisation o f the
c o u p l i n g products were detailed but the synthesis o f 15 was not. M a t o n d o ' s subsequent
w o r k , described the synthesis o f a n e w f a m i l y o f azaheteroarylboronic acids i n g o o d
yields
(62-75%)
by
trimethylsilylborate.^^
transmetallation
between
Grignard
azine
reagents
and
(ris-
T h i s procedure gave the parent heterocyclic b o r o n i c acids such
as 2 - p y r i d y l b o r o n i c a c i d ( 1 5 ) , 3 - p y r i d y l b o r o n i c a c i d (3), 5 - p y r i m i d y l b o r o n i c acid (18)

and q u i n o l i n y l - 3 - b o r o n i c acid ( 1 9 ) and t w o substituted derivatives, n a m e l y 6 - m e t h y l (20) and 6 - b r o m o - 2 p y r i d y l b o r o n i c acid (21) (Scheme l . l h ) . It is n o t e w o r t h y that the
w o r k - u p had to be carried out at no higher than 20 and at a p H between 6-7 or
deboronation o f the p r o d u c t occurred.
i, ,
x'^^
IvJ
N'
B(0H)2
Br
R = H,
R = H,
R = H,
X = CH,
X = CH,
x = ;
R = C4H4,
X = CH,
R = 6-Me,
R = 6-Br,
X = CH,
X = CH,
2- B(OH)2
3- B(OH)2
5-B(OH)2
3-B(OH)2
2-B(OH)2
2-B(OH)2
15
18
19
20
21
S c h e m e l . l h : ( i ) ' P r M g C l , 20 2 h; ( ) [ ( ) 8 ] , o to R T , 24 h; ( )
H C l / H 2 0 ( 6 < p H < 7 ) , O to R T .
3 6
M a t o n d o et al. also p u b l i s h e d the syntheses o f the n o v e l
3-alkoxy-2-pyridylboronic
acids c o n t a i n i n g linear a l k o x y or p e r f l u o r o a l k o x y chains w i t h carbon atoms { =

6,8,10,12 and 18). T h e yields ranged f r o m 60 to 7 5 % a l t h o u g h it was stated that higher
yields m a y have been obtained had it not been f o r d i f f i c u l t i e s w i t h p r o d u c t extraction
and purification.^^
A t the outset o f the present w o r k Rault et al. p u b l i s h e d the syntheses o f a
n u m b e r o f h a l o p y r i d y l b o r o n i c acids and esters.^^' ^^^*
The
6-halo-3-pyridylboronic
acids (Scheme l . l i ; c o m p o u n d s 2 2 - 2 4 ) were prepared, o n a m u l t i - g r a m scale, u s i n g

halogen-metal
exchange
from
the
corresponding
2,5-dihalopyridines.
substituted p y r i d i n e starting materials gave m u c h greater yields i n
Bromine
metal-halogen
exchange and subsequent b o r o n i c acid f o r m a t i o n than the c o r r e s p o n d i n g c h l o r o - ,

and
iodo-
derivatives.
unsuccessful
from
both
The
synthesis
of
6-iodo-3-pyridylboronic
5-bromo-2-iodopyridine
acid
and 2 , 5 - d i i o d o p y r i d i n e .
fluoro
(25)
The
was
2-
substituted boronic acids were n o t obtained, even w h e n u s i n g c o n d i t i o n s that selectively

lithiated i n the 2-.^
o f these compounds.''^
electron-rich,
or
It was suggested that this was due to the k n o w n i n s t a b i l i t y
T h e b o r o n i c acids were c o u p l e d w i t h sterically hindered,
electron-poor
phenylhalides
under
standard
Suzuki-Miyaura
c o n d i t i o n s , a l t h o u g h o n l y three examples were reported.
10
^^B(0H)2
X = Br = 75%
22
X = = 87% 2 3
x =
76% 2 4
x =
0%
25
S c h e m e l . l i 6 - H a l o - 3 - p y r i d y l b o r o n i c acids.""
Rault et al. p u b l i s h e d the syntheses o f 2 - , 4 - and 5 - h a l o - 3 - p y r i d y l b o r o n i c acids

( c o m p o u n d s 2 6 - 3 0 ) via halogen-metal exchange u s i n g - B u L i or via directed
ortho-
l i t h i a t i o n ( h y d r o g e n - m e t a l exchange) u s i n g L D A . ' ' ^ F i v e n o v e l p y r i d y l b o r o n i c acids

were thereby obtained (Scheme l . l j ) .
achieved
using
halogen-metal
T h e highest yields (compounds 26 and 2 7 ) were
exchange
from
the
corresponding
dihalopyridine.
H o w e v e r , starting f r o m 3 - b r o m o - 4 - c h l o r o p y r i d i n e gave c o m p o u n d 29 i n o n l y 2 5 %
yield,
compared
chloropyridine.
to
43%
when
carrying
out
directed
or//?o-lithiation
on
4-
It was concluded that no one m e t h o d gave h i g h e r y i e l d s f o r a l l
compounds.
-^B(0H)2
/^B(0H)2
Br.^,.^B(0H)2
x = Br = 60%
X = = 66%
x = F = 63%
26
27
28
43%
71%
29
30
S c h e m e l . l j : 2 - , 4 - , and 5 - H a l o - 3 - p y r i d y l b o r o n i c acids
42
T h e b o r o n i c acids were also c o u p l e d w i t h sterically hindered, electron-rich, or electronpoor
phenylhalides
under
standard
Suzuki-Miyaura
conditions,
again o n l y
three
Rault et al. p u b l i s h e d the synthesis o f 2- and 3 - - 4 - p y r i d y l b o r o n i c
acids
examples o f these were reported.
( c o m p o u n d s 31-36).*^
halogen-metal
The 2-halo-4-pyridylboromc
exchange, using - B u L i ,
acids were synthesised via
i n g o o d yields.
H o w e v e r , the
3-halo-4-
p y r i d y l b o r o n i c acids w e r e produced via directed or/?o-metallation i n l o w e r yields. T w o

cross-coupling examples were reported o n this occasion.
11
B(0H)2
B(0H)2
x = Br = 6 8 %
= Br = 32%
X = CI = 38%
31
X = = 6 4 % 3 2
X = F = 64% 3 3
34
35
X = F = 4 6 % 36
S c h e m e l . l k : 2 - and 3 - H a l o - 4 - p y r i d y l b o r o n i c acids. 43
T h e second report o f a 2 - p y r i d y l b o r o n i c acid synthesis b y R a u l t et al. (Scheme 1.11)33

comprised
the
synthesis,
purification,
some
X-ray
r e a c t i v i t y o f the n e w 5- a n d 6 - h a l o - 2 - p y r i d y l b o r o n i c
crystallographic
acids. N o
data
and
difficulties
the
i n the
syntheses o f these c o m p o u n d s w e r e noted and it was c l a i m e d that they were stable to

storage at < 5 .
p y r i d y l b o r o n i c acid.
T h e o n l y stated p r o b l e m was i n the synthesis o f
5-bromo-2-
2 , 5 - D i b r o m o p y r i d i n e c o u l d not be selectively l i t h i a t e d at the 2 -
p o s i t i o n , and a l l attempted reactions resulted i n 6 - b r o m o - 3 - p y r i d y l b o r o n i c acid.
Almost
f u l l characterisation was g i v e n f o r c o m p o u n d s 3 7 to 3 9 (no 1 C N M R ) , but an X - r a y

3
crystal structure o f the c o r r e s p o n d i n g p i n a c o l ester o f c o m p o u n d 3 7 was c o n c l u s i v e

p r o o f that the c o m p o u n d h a d been obtained.^^
x = Br = 55%
X = CI = 45%
37
38
X'^N^B(0H)2
x = CI = 36%
39
^^N'^B(0H)2
S c h e m e l . l l : 2 - and 3 - H a l o - 6 - p y r i d y l b o r o n i c acids.
C o m p o u n d s 3 7 a n d 3 9 w e r e c o u p l e d under standard S u z u k i - M i y a u r a c o n d i t i o n s
moderate y i e l d w i t h t w o substituted iodobenzenes and bromobenzene.
in
Interestingly,
c o m p o u n d 37 d i d n o t react as b o t h the b o r o n i c a c i d and the h a l i d e , and o n l y the desired

raonocoupled
p r o d u c t was isolated.
Earlier w o r k i n our laboratory established routes to n o v e l p y r i d y l b o r o n i c acids

w i t h halo and/or m e t h o x y f u n c t i o n a l i t y w h i c h was supported b y the f i r s t X - r a y crystal
structures o f p y r i d y l b o r o n i c acid d e r i v a t i v e s /
2-Bromo-5-pyridylboronic acid (22), 2-
- 5 - p y r i d y l b o r o n i c a c i d ( 2 3 ) , 2 - m e t h o x y - 5 - p y r i d y l b o r o n i c a c i d ( 4 0 ) and 5 - c h l o r o 2-methoxy-4-pyridylboronic
acid (41) were synthesised via
halogen-metal
exchange
u s i n g - B u L i (Scheme 1.1m).
12
B(0H)2
79%
61%
65%
X = Br
X = OMe
22
23
40
48%
Me
41
Scheme l . l m : Pyridylboronic acid derivatives/
The X - r a y crystal structures o f 22 and 23 (22 is s h o w n i n F igure 1.1a) c o n f i r m the

presence o f the free b o r o n i c a c i d w h i c h is extensively h y d r o g e n bonded. T h e b o r o n i c
acids w e r e cross-coupled under S u z u k i - M i y a u r a conditions w i t h a w i d e range
heteroaryl
bromides,
including
quinolines,
pyrimidine,
pyridines,
pyrazines
of
and
thiazoles to produce a n e w b i h e t e r o a r y l l i b r a r y c o n t a i n i n g 2 1 c o m p o u n d s .
Figure
l.la:
)0C
XRay strucre o f 2 - b r o m o - 5 - p y r i d y l b o r o n i c
acid ( 2 2 ) , at
120
K.
Dashed lines are h y d r o g e n bonds.
C o n t r a r y to the couplings carried out b y R a u l t , i n our laboratory, c o u p l i n g o f c o m p o u n d

2 2 consistently gave m u l t i c o m p o n e n t p r o d u c t m i x t u r e s ( T L C evidence) f r o m w h i c h
o n l y l o w yields (10 3 2 % ) o f b i ( h e t e r o a r y l ) products were isolated. Further details o f
these S u z u k i - M i y a u r a c o u p l i n g s w i l l be discussed i n part 2 o f this i n t r o d u c t i o n (1.2).
B r y c e ei al, p u b l i s h e d m o r e h a l o - and a l k o x y - substituted p y r i d y l b o r o n i c acids
in
2003
(Scheme
1.1).*^
2-Fluoro-5-pyridylboronic
acid
(24),
3-bromo-5"
p y r i d y l b o r o n i c acid ( 3 0 ) and 2 - e t h o x y - 5 - p y r i d y l b o r o n i c
acid ( 4 2 ) w e r e synthesised
using
with
metal-halogen
exchange
followed
by
reaction
TPB.
2Methoxy-3-
p y r i d y l b o r o n i c acid (43), 3-bromo6-methoxy"4-pyridylboronic acid (44) and 3 - b r o m o 6-ethoxy-4pyridylboronic
acid
(45)
were
synthesised
using
metal-hydrogen
exchange."*^
13
x =F
x =H
X = OEt
Y=H
Y = Br
Y=H
51%
74%
61%
24
30
42
B(0H)2
B(0H)2
OMe
13%
R = Me
R = Et
43
39%
23%
44
45
S c h e m e l . l n : P y r i d y l b o r o n i c acids.47
Each b o r o n i c a c i d was c o u p l e d w i t h 3 - b r o m o q u i n o l i n e , to c o n f i r m their s u i t a b i l i t y as a

cross-coupling partner
for
Suzuki-Miyaura
reactions, to a f f o r d the
corresponding
p y r i d y l q u i n o l i n e products. D e r i v a t i v e 3 0 c o u p l e d i n a v e r y l o w y i e l d ( 8 % ) and this was

due to the f o r m a t i o n o f numerous other products ( T L C evidence) that p r o b a b l y arose
f r o m further c o u p l i n g s o f the reactive b r o m i n e substituent o n 30. It is n o t e w o r t h y that
no such further c o u p l i n g s were observed w i t h 44 and 45, presumably due to the steric
effect o f the h e t e r o c y c l i c substituent adjacent t o the b r o m i n e .
The synthesis o f 5 - b r o m o - 2 - f l u o r o - 3 - p y r i d y l b o r o n i c
p u b l i s h e d b y Gallagher et al.
fluoropyridine
acid (47) i n 80 % , was
i n 2002, 8 b y directed o r r / o - l i t h i a t i o n o f 5 - b r o m o - 2 4
(46) f o l l o w e d b y reaction w i t h t r i m e t h y l b o r a t e .
The Suzuki-Miyaura
reactions o f 47 w i t h a range o f a r y l iodides gave 3-monosubstituted

fluoropyridines
5-bromo-2-
(48) i n excellent yields. S u z u k i - M i y a u r a cross-coupling reactions o f 47
w i t h aryl b r o m i d e s w e r e unsuccessful.
Gallagher et al. then carried out a second
S u z u k i - M i y a u r a c r o s s - c o u p l i n g reaction u t i l i s i n g the b r o m o substituent o n 48 w i t h a r y l

and heteroaryl b o r o n i c acids to generate 3,5-disubstituted 2 - f l u o r o p y r i d i n e s ( 4 9 ) , w h i c h
i n t u r n were converted to the c o r r e s p o n d i n g p y r i d o n e s (50) (Scheme l . l o ) .
14
B(0H)2
S c h e m e l . l o P y r i d o n e synthesis. 48
Pyridylboronic
acids
are occasionally
mentioned
i n other
66,^^ f o r
example, Peukert et al. detailed the S u z u k i c o u p l i n g o f 3/err-butyl ethylcarbamate-4p y r i d y l b o r o n i c acid and l - ( 2 " b r o m o p h e n y l ) - 2 - m e t h o x y e t h a n o n e as one step i n a m u l t i
stage synthesis o f a pharmaceutical.
T h e synthesis a n d i s o l a t i o n o f the p r o d u c t w a s
detailed, h o w e v e r , no characterisation data w e r e g i v e n and it w a s stated t o have been

used i n its crude f o r m w i t h no p u r i f i c a t i o n .
P y r i m i d y l b o r o n i c acids
Substituted p y r i m i d y l b o r o n i c acids were first isolated b y L i a o et al. d u r i n g the

syntheses o f a n t i - t u m o u r reagents, b y l i t h i a t i n g p y r i m i d y l ethers a n d reacting in situ
w i t h t r i m e t h y l b o r a t e o r tributylborate.^^ Some o f the resulting b o r o n i c acids w e r e
unstable and thus converted to 5"Uracilboronic acid by a catalytic
process.
hydrognation
A t t e m p t e d couplings between halogenated u r a c i l and appropriate b o r o n i c
acids, i n the hope
o f achieving
nucleoside
syntheses, w e r e
unsuccessful.
The
p y r i m i d y l b o r o n i c acids d i d couple w i t h -electron d e f i c i e n t heterocyclic halides i n g o o d

yields.
T h e parent p y r i m i d i n - 5 - y l b o r o n i c acid ( 5 1 ) w a s first synthesised i n 1986 b y
G r o n o w i t z et al. i n a 5 2 % y i e l d via h a l o g e n - l i t h i u m exchange and then an in situ

quench using t r i b u t y l b o r a t e ( T B B ) . ' F u l l characterisation o f 5 1 was g i v e n . I n 1997, i n
5
15
Introduction to Application o f Boronic Acids
a study into the synthesis o f n o v e l potent i n o s i t o l monophosphate i n h i b i t o r s , 5 1 was

c o u p l e d t o a number o f t r o p o l o n e derivatives i n modest yields (Scheme l . l p ) .
B(0H)2
OMe
30%
OMe
N
51
B(0H)2
0.
OMe
.OMe
37%
OMe
OMe
51
S c h e m e l . l p : C o u p l i n g s o f b o r o n i c acids w i t h t r o p o l o n e derivatives.^'
M a t o n d o et ai
p u b l i s h e d the detailed synthesis of
51 i n 7 2 % y i e l d by a trans
m e t a l l a t i o n between G r i g n a r d azine reagent and /rz.y-trimethylsilylborate, f o l l o w e d b y

an aqueous w o r k u p . 36
reagents was c r u c i a l ? ^
Cai also obtained 51 stating that the order o f a d d i t i o n of

I n their hands, a sequential a d d i t i o n procedure y i e l d e d the
p r o d u c t i n o n l y 2 8 % y i e l d , whereas an "in situ q u e n c h " (the borate being present d u r i n g

the h a l o g e n - l i t h i u m exchange) gave 5 1 i n a m u c h higher y i e l d o f 7 6 % .
I n our laboratory i n 2 0 0 4 , the detailed synthesis o f 51 was investigated.
hands b o t h literature routes gave an i m p u r e p r o d u c t (by
30%).
I n our
N M R ) i n l o w yields ( <
A m o d i f i e d synthesis ( s t i l l using an " situ q u e n c h " ) r e p r o d u c i b l y and cleanly
gave 51 i n 1 - 10 g batches. T h e route was extended to the synthesis o f 2 - m e t h o x y - 5 p y r i m i d y l b o r o n i c acid (52).^ C o m p o u n d 5 1 , obtained b y this route, was isolated as an
air-stable h e m i - h y d r a t e as c o n f i r m e d b y its X - r a y crystal structure.
B o t h 51 and 52
w e r e coupled under S u z u k i - M i y a u r a c o n d i t i o n s to produce a range o f biheteroaryls and,

i n one e x a m p l e , a t w o f o l d reaction gave 4 , 6 - d i ( p y r i m i d i n - 5 - y l ) p y r i m i d i n e .
Y i e l d s were
l o w w h e n c o u p l i n g 2 - b r o m o p y r i m i d i n e w i t h 5 1 and 52 (9 and 4 % , respectively) and 5 1

w i t h 3 - b r o m o q u i n o l i n e ( 1 8 % ) . U s i n g 2 - c h l o r o p y r i m i d i n e instead o f 2 - b r o m o p y r i m i d i n e
increased the yields to 3 4 % and 5 0 % , respectively.
16
(0)2
Meo
51
.(0)2
52
c h e m e l . l q : P y r i m i d y l b o r o n i c acids. 52
Other Nitrogen-Containing Heterocyclic Boronic Acids

Pyrrole
In
1 9 9 1 , the
first
report o f a p y r r o l y l b o r o n i c
p y r r o l y l b o r o n i c acid b y Schlter et al.
acid appeared,^^ n a m e l y
2-
P y r r o l e c o u l d be lithiated d i r e c t l y or c o u l d
tert-
undergo metal-halogen exchange, w h e n the n i t r o g e n a t o m was protected b y

b u t o x y c a r b o n y l ( B o c ) , t r i i s o p r o p y l s i l y l ( T I P S ) or p h e n y l s u l p h o n y l groups.
Schlter et
al. used r e r / - b u t o x y c a r b o n y l i n t h e i r synthesis o f j V - ( B o c ) - 2 - p y r r o l y l b o r o n i c acid ( 5 3 ) i n

4 0 % y i e l d . U n f o r t u n a t e l y , 53 c o u l d not be used i n any S u z u k i - M i y a u r a cross-coupling
reactions as it was susceptible to d e b o r o n a t i o n , and h o m o c o u p l i n g to give p r o d u c t (54)
w h e n heated (Scheme l . l r ) .
Boc
(0)2
Boc
40%
53
54
S c h e m e l . l r : i V - ( B o c ) - p y r r o l e - 2 - b o r o n i c acid ( 5 3 ) and h o m o c o u p l e d p r o d u c t ( 5 4 ) .
53
7 V - ( B o c ) - 5 - ( p e n t - 4 - e n y l ) - 2 - p y r r o l y l b o r o n i c acid (55) was p r o d u c e d b y F urstner et al. i n

the synthesis o f a potent c y t o t o x i c p r o d i g i o s i n a l k a l o i d , via directed o r / o - m e t a l l a t i o n
o f J-BOC protected 2 - ( p e n t - 4 - e n y l ) p y n O e .
T h e a i m was to cross-couple 55 w i t h a
triflate (56) (Scheme 1.1).^ T h e diene ( 5 7 ) produced u n d e r w e n t further t r a n s f o r m a t i o n

f i n a l l y to produce the desired p r o d u c t n o n y l p r o d i g i o s i n ( 5 8 ) . It was again observed that
2 - p y r r o l y l b o r o n i c acid w a s unstable and u n d e r w e n t p r o t o d e b o r o n a t i o n d u r i n g attempts
to couple it.
17
,/
Boc
B(0H)2
TfO
55
56
OMe
57
58
OMe
OMe
S c h e m e 1.1 N o n y l p r o d i g i o s i n (58) synthesis 54
K e t c h a et ai
discovered that 1 - ( p h e n y l s u l f o n y l ) p y r r o l e c o m p e t i t i v e l y
desulfonylated
w h e n a t t e m p t i n g to lithiate at the C-2 p o s i t i o n and f o r this reason the b o r o n i c acid was

obtained i n o n l y 8 % y i e l d . H o w e v e r , S u z u k i - M i y a u r a reactions o f the b o r o n i c acid t o o k
place i n y i e l d s o f 3 9 - 9 1 % , w i t h o u t d e b o r o n a t i o n occurring.^
M u c h o w s k i et al
p u b l i s h e d the o n l y synthesis o f 3 - p y r r o l y l b o r o n i c a c i d u s i n g
a triisopropylsilyl protecting group.
T h e protected p y r r o l e first u n d e r w e n t selective
i o d i n a t i o n at C-3 then m e t a l - h a l o g e n exchange u s i n g - B u L i , to produce the b o r o n i c

acid i n 4 3 % y i e l d .
Indole
I n d o l e b o r o n i c acids are k n o w n to possess sugar b i n d i n g properties, and the

i n d o l e m o t i f is an integral part o f a w i d e v a r i e t y o f natural properties.
The f o l l o w i n g
p r o t e c t i n g groups have been used p r i o r to m a k i n g the b o r o n i c a c i d : j V - t o s y l , - ,
18
N-Boc, N-Me, N-OMe, TBS and TV-potassio salt. Johnson et . 6 p u b l i s h e d the

synthesis o f 2 - i n d o l y l b o r o n i c acid using '^- protected indole i n 6 5 % overall y i e l d ;
the b o r o n i c acid (59) w a s then c o u p l e d under S u z u k i - M i y a u r a conditions w i t h a range
o f a r y l halides, but o n l y l o w y i e l d s o f products (60) were obtained and this was
explained by steric hindrance and preferential h o m o c o u p l i n g . A s i g n i f i c a n t a m o u n t o f
h o m o c o u p l e d b o r o n i c acid (61) was obtained.
5
Ar-X
(H0)2B
Pd(0)
Bo
59
60
61
S c h e m e l . l t : Cross- and h o m o - c o u p l i n g o f j V - B o c - 2 - i n d o l y l b o r o n i c a c i d (59). 56
I s h i k u r a et al. studied a range o f TV-substituted i n d o l - 2 - y l b o r o n a t e s and f o u n d

that the reaction yields (0 - 8 0 % ) w h e n the b o r o n i c acids were c o u p l e d w i t h a r y l - , 2 and 3 - p y r i d y l and 3-thienyl groups depended o n the p r o t e c t i n g g r o u p e.g. 1 5 % f o r
to ~ 8 0 % for M e . "
T h e ease o f the synthesis o f 3 - i n d o l y l b o r o n i c acid seems to be i n f l u e n c e d by the
p r o t e c t i n g g r o u p , w i t h silicon-based groups being f a v o u r e d .
indolylboronic
T h e synthesis o f 3-
acid u s i n g a p h e n y l s u l p h o n y l p r o t e c t i n g g r o u p must take place at
b e l o w - 1 0 0 , or rearrangement to the m o r e stable 2 - l i t h i o derivative

occur.^^
I f a d i f f e r e n t p r o t e c t i n g g r o u p , such as TBS, is used the reaction is m u c h
less temperature sensitive; this p r o t e c t i n g g r o u p is used i n the synthesis o f the

a n t i v i r a l / a n t i t u m o u r b i s ( i n d o y l ) i m i d a z o l e d e r i v a t i v e topsentin.^^
T h e l i t h i a t i o n was
carried out at - 7 8 and no isomerisation was observed, the b o r o n i c acid was used
w i t h o u t p u r i f i c a t i o n , so therefore, a y i e l d was not recorded.
^-TIPS is another
p r o t e c t i n g group that has a stabilising i n f l u e n c e o n the boronic acid.
T h e A'^-TIPS-B-
b r o m o i n d o l e (62) was converted to the A'^-TIPS-S-indolylboronic acid (63) i n an o v e r a l l

yield 86%.^^
19
Introduction to Application o f Boronic Acids
(H0)2B
1. BuLi, THF, -60c
NBS, THF
86%
-78c
2. ()
TIPS
TIPS
TIPS
3. aq NH4CI
62
63
S c h e m e l . l u : Synthesis o f # - T I P S - 3 - i n d o l y l b o r o n i c acid (63)
60
The o n l y syntheses p u b l i s h e d f o r 5-, 6- and 7 - i n d o l y l b o r o n i c acids have used the

7V-potassio-salt p r o t e c t i n g g r o u p , ^ ' '
6 2
and moderate y i e l d s ( - 4 4 % ) were obtained.
was established that a h a l o g e n - l i t h i u m exchange takes place w i t h o u t

o c c u r r i n g at the C-2 p o s i t i o n .
It
metallation
T h e o n l y i m i d a z o l y l b o r o n i c acid synthesis^^ to be
p u b l i s h e d utilises a 1,2-protected i m i d a z o l e ( 6 4 ) (Scheme l . l v ) .
N o y i e l d was quoted
as the crude b o r o n i c acid ( 6 5 ) w a s reacted i n S u z u k i - M i y a u r a c o u p l i n g reactions w h e r e

o n l y a 7 % y i e l d o f ( 6 6 ) was obtained. T h e author stated that the i n s t a b i l i t y o f 65 was
responsible f o r the l o w c o u p l i n g y i e l d s and n o t the i n e f f i c i e n c y o f the c o u p l i n g reaction
themselves. N o evidence to support this statement was g i v e n .
II
1. ()
nBuLi
SPh
SPh
(0)2'
2.
-^^
SPh
SEM
SEM
65
PhS
SEM
7%
66
S c h e m e l . l v : Synthesis o f I m i d a z o l y l b o r o n i c a c i d (65)
63
20
Q u i n o l i n y l b o r o n i c acids
T h e syntheses o f 8 - q u i n o l i n y l b o r o n i c
acid^^ have been reported. 8 - Q u i n o l y l b o r o n i c
acid^'* and
2-11-3-
a c i d was obtained i n 7 9 % y i e l d and
Letsinger et al. f a i l e d to synthesise any other isomers and proposed that i t was the o n l y
isomer achievable due to the need to facilitate the metal-halogen exchange b y the
c o o r d i n a t i o n o f the rt-BuLi w i t h the heterocyclic n i t r o g e n a t o m . Recently, the synthesis
o f 2 - c h l o r o q u i n o l y l - 3 - b o r o n i c acid ( 8 5 % ) was p u b l i s h e d b y a D o M reaction due to the
c h l o r i n e i n the - . "
There are also a n u m b e r o f sulphur and o x y g e n heterocyclic b o r o n i c
acids
k n o w n but despite m a n y attempted syntheses t h i a z o l y l , o x a z o l y l , and p y r a z i n y l b o r o n i c

acids r e m a i n u n k n o w n .
21
Introduction to A p p l i c a t i o n o f Boronic A c i d s
1.2
Application of Boronic Acids
Boronic acids have a number o f advantages over o r g a n o l i t h i u m , organomagnesium

and other organometallic reagents.
They are generally innocuous, air-, moisture- and
temperature-stable, unlike m a n y other organoboron compounds e.g. .
The m a i n
application for boronic acids, amongst others, is the synthesis o f biaryl by transition metal
catalysed
cross-coupling reactions.
The biaryl
unit
is present
in several types
of
compounds o f current interest i n c l u d i n g natural products, polymers, advanced materials,

l i q u i d crystals and molecules o f medicinal interest.
There are a number o f c o m m o n l y used catalytic methods in biaryl synthesis for
example; K u m a d a , N e g i s h i , Stille and S u z u k i - M i y a u r a reactions. These reactions prepare
both symmetrical and unsymmetrical biaryl and invariably proceed using either nickel or
palladium catalysts. In 1972, K u m a d a , Tamao and C o r r i u reported independently that the
reaction o f organomagnesium reagents w i t h alkenyl or aryl halides could be catalysed by
N i ( I I ) complexe.^^ The c o u p l i n g o f a Grignard reagent ( A r ' M g X ) w i t h a l k y l , v i n y l or aryl
halides under Ni-catalysis provides an economical transformation.
disadvantages,
the
reaction
is
limited
to
halide
partners
that
H o w e v e r , there are
do
not
react
with
organomagnesium compounds and the polar nature o f the Grignard reagent precludes the
use o f several types o f functional groups in the c o u p l i n g partner such as aldehydes, ketones,
esters and nitro groups.^^ The advantage o f this reaction is the direct c o u p l i n g o f Grignard
reagents, w h i c h avoids additional reaction steps such as the conversion o f Grignard
reagents to zinc compounds for the starting materials i n the Negishi coupling.^^
An
example is in the industrial-scale production o f styrene derivatives, and the K u m a d a

c o u p l i n g is generally the method o f choice for the low-cost synthesis o f unsymmetrical
biaryl.
The Negishi c o u p l i n g , first published in 1977, was the first reaction that allowed the
preparation o f unsymmetrical biaryl in good yields. The versatile n i c k e l - or p a l l a d i u m catalysed coupling o f organozinc compounds w i t h various halides ( a r y l , v i n y l , benzyl, or
a l l y l ) has broad scope and is not restricted to the formation o f biaryl. U n l i k e the K u m a d a
22
Introduction to A p p l i c a t i o n o f B o r o n i c A c i d s
reaction, functional groups are tolerated in the c o u p l i n g partner. A r y l m a g n e s i u m and

arylzinc reagents are precursors to biaryl in the K u m a d a and N e g i s h i reactions,
respectively. A r y l l i t h i u m s are not generally used due to their h i g h l y polar and basic nature.
There are, however, some isolated examples w h i c h have been successful. The Stille
C o u p l i n g is a versatile cc bond f o r m i n g reaction between stannanes (Ar^SnRs, R = M e ,
B u ) and halides, w i t h very few limitations on the R-groups. Well-elaborated methods a l l o w
the preparation o f d i f f e r e n t products f r o m all o f the combinations o f halides and stannanes.
The m a i n drawback is the t o x i c i t y o f the t i n compounds and their l o w polarity, w h i c h
makes them p o o r l y s d ^
in water. Stannanes are stable, but boronic acids and their
derivatives undergo m u c h the same chemistry in the S u z u k i - M i y a u r a c o u p l i n g (see b e l o w ) ,
w i t h o u t the drawbacks o f using t i n compounds.
The palladium catalysed reaction o f a boronic acid [ ' ( 0 ) 2 ] w i t h an aryl hal ide
( A r ^ X ) is a general method for the f o r m a t i o n o f carbon-carbon bonds. Since the late 1990
this type o f reaction has been called Suzuki c o u p l i n g , Suzuki reaction or S u z u k i - M i y a u r a
c o u p l i n g . The reaction is extremely versatile due to the availability o f the reagents and the
m i l d reaction conditions.
The reaction is unaffected by the presence o f water, tolerates a
broad range o f functional groups, generally proceeds regio- and stereo-selectively and the
inorganic by-product is non-toxic and easily removed.^^
Due to the extensive synthetic possibilities using S u z u k i - M i y a u r a couplings, the
parameters o f the reaction and the mechanism are constantly under investigation.
Mechanism
The cross-coupling reactions o f organoboron compounds f o l l o w a similar catalytic

cycle to that o f other m a i n metal reagents, i n v o l v i n g : (a) o x i d a t i v e addition o f organic
halide
or
other
electrophiles
to
palladium(O)
complex
yielding
R^-Pd"X;
transmetallation between R I - P d - X and R 2 - B w i t h the aid o f base; and (c)
(b)
reductive
e l i m i n a t i o n o f R^-R^ to regenerate the palladium(O) c o m p l e x . Water and base are necessary

to activate the boronic acid."^^
The c o u p l i n g reaction o f 3 - b r o m o p y n d i n e and a phenyl
boronic acid has been analysed using electrospray ionisation mass spectrometry ( E S I -
23
M ) 7 ^ F r o m this study it was concluded that the reaction m i x t u r e contained t w o key

intermediates ( I and I I ) as shown in scheme 1.2a.
Reductive Elimination \
^ \
Oxidative Addition
Ar^(L2)Pd(ll)X
ArVLoPdrlIlAr^
Transmeta at on
XB(0H)2
2()2 + base
Scheme 1.2a: Studies o f mechanism by Canary et al . 70
Other studies, i n c l u d i n g that o f Suzuki et al . have shown the formation o f three

intermediates d u r i n g the coupling o f 1 -alkenyl halide and 1-alkenylboron compounds. The
generally accepted catalytic mechanism is depicted in Scheme 1.2b7^
^
Reductive Elimination \
-2
1
LPd(0)L--^
\
Aripd(ll)(L2)Ar2
Oxidative Addition
Ar^Pd(ll){L2)X
HQ OR
.b;
HO
OH
NaOR
Transmetalation
2^
Ar^Pd(ll)(L2)OR
Ligand Exchange
NaX
OH
Scheme 1.2b: Catalytic Mechanism for S u z u k i - M i y a u r a Cross-Coupling Reaction.
24
A l t h o u g h the t w o steps o f oxidative addition and reductive e l i m i n a t i o n are reasonably w e l l

understood, less is k n o w n about the transmetallation process. O x i d a t i v e addition o f the
halide to the palladium(O) complex forms an organopalladium halide (Scheme 1.2c).
Ar-X
Ar
/
Pd
Pd(0)
Ar-Pd-X
Scheme l , 2 c : Oxidative addition step.
T h i s step is generally accepted to be rate-determining,^^ although it has been shown b y

Smith et al . that when using an aryl iodide, instead o f an aryl bromide or chloride, the
transmetallation step is rate determining.^^ Recent literature has shown that the oxidative
addition o f chloro-, b r o m o - and iodoarenes to a bisphosphine palladium(O)
(containing hindered ligands) occurs via three different mechanisms7^
complex
A d d i t i o n o f Phi
occurs by the associative displacement o f a phosphine, PhBr by rate-limiting dissociation o f

a phosphine and that o f PhCI occurs by a reversible dissociation o f a phosphine, f o l l o w e d
by r a t e - l i m i t i n g oxidative addition.
N e x t is the transmetallation step where t w o alternative processes are hypothesised.
A v a i l a b l e i n f o r m a t i o n indicates that there are several processes for transferring the organic
group onto the organopalladium halide ( 6 8 ) / ^ The addition o f sodium hydroxide and other
bases exerts a remarkable accelerating effect on the transmetallation between 68 and
organoboronic acids.
Quarternization o f the boron atom w i t h a negatively charged base
enhances the cleophilicity o f the organic group on the boronic acid for alkylation o f 68.
S i m i l a r l y a hydroxyboronate anion (67), w h i c h exists in e q u i l i b r i u m w i t h the free boronic
acid, could alkylate A r ^ - P d - X (Scheme 1.2d).
Phenylboronic acid has a p K a o f
8.8
therefore the concentration o f hydroxyboronate an ions w i l l increase at p H 9 and above.

The rate o f the c o u p l i n g reaction o f phenylboronic
acid and 3-iodobenzoic
significantly increased upon raising the p H f r o m 8 to 10. 3

7
acid is
H o w e v e r , the rate is retarded
25
above p H 11. K i n e t i c studies using N M R spectroscopy also support this mechanism by

showing the f o r m a t i o n o f the hydroxyboronate anion7^
OH
2()2
Aripd(L2)X
68
HO
R2
2^()-
Ar2pd(L2)Ar^
67
Scheme 1.2d Transmetal lation step.
An
alternative
process
is
transmetallation
to
an
alkoxo-,
hydroxo-,
acetoxo-,
or
(acetylacetoxo)palladium(ll) complex (69), f o r m e d by the in situ ligand exchange between

A r ' - P d - X (68) and a base ( R O ) (Scheme 1.2e). This species is more electrophilic than the
organopalladium halide c o m p l e x (68) due to the P d - 0 bond being more polar than the P d - X
bond.
These complexes undergo transmetallation w i t h o u t the aid o f base.
The reaction
may i n v o l v e the rate determining coordination o f the RO" ligand to the boron atom via a
transition state depicted as 70.
The h i g h basicity o f the Pd(0) species and the h i g h
o x o p h i l i c i t y o f the boron centre are the reasons for the strong reactivity o f the R O - P d
complexes. This latter scheme is generally accepted to be the mechanism due to Suzuki et
al. s h o w i n g the f o r m a t i o n o f A r ' P d ( I I ) O R .
RO
Aripd(L2)X
68
2();
Aripd(L2)OR
69
Ar2pd(L2)Ar
Ar^-Pd
71
70
Scheme 1.2e: Transmetallation step.
A s the organopalladium species w i t h t w o aryl units (71) attached are unstable, the
biaryl (72) is produced and the palladium(O) c o m p l e x (73) is regenerated,.
26
Aii
Ar
Ar^-Ar^
Pd
2
r2
72
+ L2Pd(0)
73
Scheme 1.2f: Reductive E l i m i n a t i o n Step
For a h o m o c o u p l i n g reaction o f a boronic acid to proceed there needs to be a step replacing

the aryl group f r o m the c o u p l i n g partner ( r ' ) w i t h that f r o m the boronic acid ( A r ^ ) .
Proposed
mechanisms
for
homocoupling
involve
two
transmetallations
stages/'*'
7 5
Yoshida et al. proposed the catalytic cycle in Scheme 1.2g as it is k n o w n that oxygen
readily reacts w i t h palladium(O) to a f f o r d p a l l a d i u m ( I I ) peroxide.
Oxidative cyclisation
o.
Pd(0)
RoBO
Ar-Ar
RzB-OO-BR
Reductive E l i m i n a t i o n
Scheme 1.2g: Proposed pathway o f h o m o c o u p l i n g74
In this cycle a three-membered p a l l a d i u m ( I I ) peroxide complex is formed by oxidative

cyclization o f molecular oxygen w i t h the palladium(O) complex.
Subsequently a double
transmetallation o f the organic m o i e t y attached to the boronic acid to the p a l l a d i u m ( I I ) ,
27
^ I ntroduction to A p p l i c a t i o n o f B o r o n i c A c i d s
w i t h the aid o f base gives diorganopalladium and boron peroxide. Reductive e l i m i n a t i o n o f

the h o m c o u p l i n g product regenerates the palladium(O) complex.
The S u z u k i - M i y a u r a reaction can be carried out using a variety o f catalysts, bases
and solvents, where their combinations significantly affect the yields and selectivity o f the
products.
H o w e v e r , the influence o f the parameters depends upon the nature o f the
substrate and for this reason, in this chapter^ o n l y the most relevant literature w i l l be
reported.
Catalysts and L igands
1()4 s a c o m m o n l y used catalyst for S u z u k i - M i y a u r a reactions; however, it is

air sensitive so alternative species have been investigated.^
Ideay, a universal catalyst
w o u l d satisfy the diverse requirements o f every different S u z u k i - M i y a u r a c o u p l i n g and

obtain a high y i e l d using l o w loading. T o date this has not been realised, but a number o f
research groups have reported different catalysts/catalytic systems relevant to heterocyclic
boronic acid couplings.
Suzuki-Miyaura
The use o f b u l k y trialkylphosphine ligands is thought to assist in
cross-couplings
by
stabilising
and p r o m o t i n g the generation
o f the
unsaturated Pd(0) and P d ( I I ) intermediates and thereby enhancing the catalytic a c t i v i t y o f

Pd complexes in c o u p l i n g reactions^ ^
B u c h w a l d et al. reported a number o f different
ligands, some for use in r o o m temperature couplings, and some for extremely l o w loadings
o f catalyst (0.000001 m o l
heterocyclic boronic acids.
T h e y have however, o n l y published one example using

In 2004, they reported a catalyst system that enabled the
c o u p l i n g o f both electron-rich and electron-poor heteroaryl boronic acids w i t h hindered aryl

halides and a variety o f heteroaryl halides at exceptionally l o w l o a d i n g s / ^
T h e catalyst
system, 2 - ( 2 ' , 6 ' - d i m e t h o x y b i p h e n y l ) - d i c y c l o h e x y l p h o s p h i n e , SPhos (74) and Pd2dba3 (dba

= dibenzylideneacetone) was used to cross-couple 3 - p y n d y l b o r o n i c acid w i t h a range o f
aryl halides in isolated yields o f 81 loadings
of
3 % 7^
Aryl
9 6 % , reactions times o f 15 24 h and catalyst

couplings
carried
out
using
2-(2',4',6'-
triisopropylbiphenyl)diphenylphosphine (75) were not as high y i e l d i n g ; this was claimed to

be due to the importance o f ligand b u l k and electron-donating a b i l i t y in the high activity o f
28
catalysts. Interestingly, it was found that w h e n aryl bromides became too hindered (three tB u groups) the desired c o u p l i n g product was not obtained.
Scheme 1.2 Ligands investigated by B u c h w a l d et al.
M a n y phosphines are sensitive to air and moisture and can undergo conversion to
other species, for example, phosphine oxide species.
For this reason and economical and
environmental reasons, especially f r o m an industrial perspective, n e w recyclable catalytic

systems are being sought. L i et al
reported the P d ( 0 A c ) 2 / D A B C O (trimethylenediamine)
catalytic system for use in S u z u k i - M i y a u r a cross-coupling reactions.^*^ This system can be

recovered and recycled f i v e times w i t h o u t any loss o f catalytic a c t i v i t y ; the system is,
however, l i m i t e d to a r y l iodides and bromides. Capretta et al used a catalytic system based
upon Pd2dba3.CHC3 on a
l,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6"phosphaadamantane
f r a m e w o r k for solid-phase S u z u k i - M i y a u r a cross-couplings o f a r y l halides w i t h a r y l and

t h i e n y l b o r o n i c acids.^^
The reactions proceed at r o o m temperature w i t h l o w p a l l a d i u m
loadings (2 m o l % ) g i v i n g moderate to h i g h conversions (42 - 100%). A l t e r n a t i v e l y , the

catalyst can be p o l y m e r supported.
Le D r i a n et ai
reported the same product yields f r o m
the S u z u k i - M i y a u r a cross-coupling o f phenylboronic acid and bromoaromatic compounds

using a p o l y m e r supported catalyst or " f r e e " catalyst.^"^ Recovery and reuse o f the catalyst
was stated to be straightforward and only 0 , 6 % o f the initial palladium content was lost
d u r i n g the reaction.
W i l l i a m s et al
using reverse-phase
glass beads in aqueous
carried out S u z u k i - M i y a u r a cross-coupling reactions

media.^^
The beads were coated
with
1()4, w h i c h is assumed to be still m o b i l e o n the surface, and the reaction occurs at the
interface. 3 m o l % 1()4 on p o l y m e r beads was used to couple a r y l boronic acids w i t h
29
heteroaryl iodides and bromides to afford the desired products in moderate to excellent
yields ( 4 7 - 100%).
The advances catalytic systems have enabled S u z u k i - M i y a u r a reactions to be
carried out at a range o f temperatures, some even at r o o m temperature, e.g. the synthesis o f
76 - 80 using hindered aryl bromides (Scheme 1.21).*" The concentration o f base used made
no difference to the yields obtained.
B(0H)2
4^
Pd(0Ac)2, RT
, THF, 15 min
76 R u
77 Rl = CN
R2 = H
R CH
R =H
R3=H
R2=H
80 R] -
R =
1
R2= H
R =H
3
95%
92%
90%
96%
84%
R =
2
Scheme 1.2i S u z u k i - M i y a u r a cross-coupling reactions 84
H a l o partners: I, B r , , F
A range o f halo partners can be used in S u z u k i - M i y a u r a cross-coupling reactions.

A r y l triflates are also sometimes used, but are base sensitive and thermally labile.
Mild
reaction conditions have been developed for the c o u p l i n g o f arylboronic acids w i t h triflates
using efficient catalysts and weak non-aqueous bases in polar solvents.
To
prevent
premature catalyst decomposition and/or to promote cross-coupling, an alkati metal halide

may also be added. A n investigation by M a r t i n et al. to extend the reaction f r o m electronr i c h aryl triflates to less reactive aryl sulphonates and aryl chlorides discovered that
alternative sulphonate
leaving groups were active in these reactions.
Although
aryl
mesylates, benzenesulphonates and tosylates are m u c h less expensive than triflates, they are
inactive towards p a l l a d i u m catalysts.^^'^^
It has been shown that, due to the d i f f e r i n g
reactivities o f iodo-, b r o m o - and chloro-aryls, selective c o u p l i n g can be achieved under the

S u z u k i - M i y a u r a reaction conditions.*^ A l t h o u g h chloro-compounds are often cheaper and
30
more readily available than the corresponding i o d o - or bromo-analogues, the reaction is

more d i f f i c u l t w h e n is the leaving group because higher energies are needed for the
oxidative addition o f the chloro-compound to the palladiu(0) c o m p l e x . A r y l chlorides
as c o u p l i n g partners participate in S u z u k i - M i y a u r a c o u p l i n g reactions more readily i f used
in conjunction w i t h electron-deficient groups. For these reasons, bromides and iodides are
traditionally the aryl halides used. A r y l chlorides were, u n t i ! recently, not used as they
were k n o w n to be a lot less reactive and in many cases unreactive.^^ Over the last f e w
years, however, n e w catalytic systems have been developed for unreactive chlorides. I n
1998, Fu et al reported the use o f Pd2(dba)3 and P ( ^ B u ) as a catalytic system to crosscouple a w i d e range o f aryl chlorides in good yields (82 9 2 % ) (Scheme 1.2j).^' They
observed no c o u p l i n g i n the absence o f a phosphine and lower yields using phosphines
other than ()
T h e phosphine was used in high loading ( 3 . 6 % ) and electronw i t h d r a w i n g groups were present to activate the aryl chlorides.
Pd2(dba)3
P(r-Bu)3
CI
X
X = COMe, Me,
OMe. NH2
(H0)2B
CS2CO3
QP _
Me, OMe
82-92%
djoixane
80-90C
Scheme 1.2j: S u z u k i - M i y a u r a cross c o u p l i n g o f aryl chlorides 91
Fu et al . then extended this system to a range o f aryl iodides, aryl bromides and activated
chlorides (j.e. heteroaryl chlorides and aryl chlorides that bear an electron w i t h d r a w i n g
group) at r o o m temperature.^^
T h e y stated that CsF was an effective alternative base to
CS2CO3. T h e ratio o f phosphine t o catalyst was f o u n d t o be an important parameter: a 1:1

ratio furnished a very active catalytic system, whereas a 2:1 ratio produced extremely s l o w
reactions.
given.
Pd2(dba)3 was stated to be superior to P d ( 0 A c ) 2 , although no evidence was
Chloro-substituted p y r i d i n e and thiophenes were coupled at r o o m temperature and
31
this was related to their ability
to bind to p a l l a d i u m
through nitrogen
or
sulphur,
respectively.
In 2 0 0 1 , triarylphosphine derivative (81), Pd2(dba)3 and P d ( 0 A c ) 2 were shown to be
successful in c o u p l i n g a range o f sterically-demanding and
electronically-deactivated
substrates.^^ I ncluded was the example o f 2-chloropyridine (82) and phenylboronic acid
(83) at r o o m temperature p r o d u c i n g 2-phenylpyridine (84) in 9 3 % yield (Scheme 1.2k).
TMS
5% Pd(0Ac)2
6% 81
()8
93%
342
toluene
r.t
81
82
83
84
Scheme 1.2k: S u z u k i - M i y a u r a cross c o u p l i n g o f aryl chlorides 93
B e d f o r d et al . published the first c o u p l i n g o f aryl chlorides (both electron-rich and

electron-poor) under aerobic .^*
The number o f complexes derived f r o m d i - or
t r i - a l k y i substituted phosphine ligands was l i m i t e d due to their laborious synthesis, w h i c h is

reflected in their high c o m m e r c i a ! cost compared to the more c o m m o n cataiysts.
deduced
that
an
ideal
catalyst
for
use
with
aryl
chlorides
should
They
contain
tricyclohexylphosphine, w h i c h is easy to synthesise f r o m cheap, c o m m e r c i a l l y available

materials,
is
easy
to
handle
and
shows
good
activity
at
low
loadings.
T r i c y c l o h e x y l p h o s p h i n e adducts o f p a l l a d i u m complexes w i t h /-metallated A'^-donor

ligands, e.g. 85, showed high activity. C o m p l e x 85 was synthesised f r o m the c o m m e r c i a l l y
available TV.A'-dimethylbenzylamine.
b r i e f investigation o f solvents and bases to
optimise the c o u p l i n g conditions showed that the catalyst activity was greatly affected by
reaction conditions and w o r k e d best using dioxane and CS2CO3 w i t h a 0.01 m o l % catalyst
loading.
Pd-TFA
Scheme 1.21: C o m p l e x 85 94
32
In 2 0 0 3 , W i d d o w s o n and W i l h e l m published the first Suzuki couplings on aryl
fluorides.
H o w e v e r , a nitro group in the 2-position o f the fluoroarene was essential for the reaction to
occur. I t was stated that the nitro group facilitated by coordinating w i t h the palladium atom
o f the catalyst. These authors f o u n d that w h e n attempting to couple fluoroarenes w i t h other
groups e.g. C O O M e , and F in the 2-posistion, no product could be detected.^^
C h o i c e o f Base
Cross-coupling reactions o f organoboronic acids and organic halides require the

presence o f a negatively charged base, such as an aqueous solution o f sodium or potassium
carbonate, phosphate or hydroxide.
A l t h o u g h , i n general, aqueous s o d i u m carbonate is
used as a base in S u z u k i - M i y a u r a cross-coupling reactions, there are other used in the

literature for example; Ba(0H)2,^^ K 2 C O 3 ,
68
and CS2CO3. V a r i o u s groups c l a i m that w h i l s t
investigating a range o f couplings in certain conditions certain bases are best, but no
systematic study has been carried out. I n 1996, Chan et al ?^
stated that the type o f base
had a remarkable accelerating effect upon the rate o f c o u p l i n g o f sterically b u l k y boronic

acids w i t h halopyridines in d i m e t h y l ether ( D M E ) (Scheme 1.2m).
OMe
Pd(PPh3)4, N2,
OMe
DME, reflux,
2.0 eq. base
86
87
88
89
= R2
= H, X = Br
R = Me,
= H, X = Br
= R2 = (CH)4, x =
91
R' = Me,R2 = H
= R2 = ( C H ) 4
Scheme
1 . 2 m : Couplings used in investigations
into accelerating effects o f different
bases^^
33
In D M E , using their standard base (aq. N a O H ) l o w yields o f the desired products were
obtained or no coupling was observed (90 = 2 6 % , 91 and 92 = 0 % ) , after 90 h. B y
increasing the base strength f r o m using N a O H or NaOCsHs to t-BuOK, the yields increased
w i t h shorter reaction times ( 4 1 0 h). Using / - B u O K high yields were obtained o f 90, 91
and 92 (86, 83 and 7 7 % , respectively). Chan et al. also reported the synthesis o f 86 and
mentioned that D M E was used as a solvent for the coupling reactions to suppress
deboronation o f 86. 8
9
M i c r o w a v e Reactions
Microwave-assisted
S u z u k i - M i y a u r a reactions
have been carried out
using a
number o f polar solvents, for example water,'*^' 1 e t h y l e n e g l y c o l ' ' and D M F ' O
which
efficiently absorb microwaves. These conditions significantly decrease the amount o f t i m e

needed to carry out a coupling,'^^ and can increase the efficiency o f ligandless catalysts^^
M i s c e l l a n e o u s examples o f S u z u k i - M i y a u r a reactions
A f e w instances are n o w given in w h i c h the S u z u k i - M i y a u r a cross coupling reaction

has facilitated the synthesis o f a number o f important molecules. -Substituted porphyrins
are o f continuous interest due to their biological properties. -Brominated porphyrins are
easily
obtained
from
the
controlled
bromination
of
porphyrins,
and
derived
tetraphenylporphyrins 93 have been obtained in high yields (Scheme 1.2).^

Ph
Ph
Ph
(0)2, Pd(PPh3)4
Ar
67-88%
Br
K2CO3, toluene
110
Ph
93
Scheme 1.2n: Synthesis o f 11-1-11-118
90
34
The
couplings.
field
o f non-linear optics has also advanced due t o S u z u k i - M i y a u r a cross-
F e w 1,8-di(hetero)arylnaphthalenes, used in this field, were k n o w n due t o the
lack o f general synthetic methods.

using t w o S u z u k i - M i y a u r a
Grahn et al. developed a process for their production
cross-coupling
reactions.
This
work
showed that
nitro-
substituents o n the h a l o - c o u p l i n g partner were tolerated w h e n phenyl boronic acids were

60.'^
Suzuki-Miyaura
coupings
o f 5-halopyrazine
with
arylboronic
acids
have
s i m p l i f i e d the syntheses o f arylpyrazines ( 9 4 ) , w h i c h are b u i l d i n g blocks f o r luminescent

imidazopyrazine.
Using
l,4-bis(diphenylphosphine)butane
catalyst gave excellent yields (Scheme 1.2)."^
palladium(II)
chloride
as a
The p r i m a r y amine substituent o n the
c o u p l i n g partner was tolerated i n this reaction.
4()2
aq.
Toluene
Reflux, 7
Pd(clppb)C2
N./NH2
Me
94
Scheme 1.2 Example o f the synthesis o f arylpyrazines. 105
H i g h l y functionalised and sterically hindered c o u p l i n g partners can be tolerated in

couplings w i t h phenylboronic acids and functionalised phenylboronic acids'"^ as illustrated
in the syntheses o f pyridazinone derivatives 95 and 96 b y R ' k y e k et al.
1()4
...N
N
RB(0H)2, 2M
H:3
95 R = CeHs
86%
96 R = 3-(4) 78%
t o l u e n e , r e f l u x , 15h
Scheme 1.2p Synthesis o f 95 and 96 106
35
T h o m p s o n et al . published the c o u p l i n g o f 4 - p y r i d y l b o r o n i c acid to produce the

f u l l y substituted 2 - ( 4 ' - p y r i d y l ) p y r i d i n e (97), showing that sterically hindered reagents
containing m e t h y l , m e t h o x y and n i t r i l e groups can undergo c o u p l i n g reactions (Scheme
1.2q).^^^ The source or synthesis o f 6 was not noted in the p u b l i c a t i o n .
()2
H3C0
CH
Pd(dppf)(0Ac)2
NC
22%
N'
6
Scheme 1.2q: S u z u k i - M i y a u r a cross c o u p l i n g reactions 107
I n 2004, Rault et al . extended his cross-coupling to non halo aromatics and

published the S u z u k i - M i y a u r a cross c o u p l i n g o f 23 w i t h tert-huXy 3,4-dihydro-6-iodo-2methyl-4-oxopyridine 1 ( 2 / i ) - c a r b o x y l a t e (98) to give 99 in an 8 0 % y i e l d (Scheme 1.2r).^^
-^B(0H)2
cr
N
N
23
Cl
99
Scheme 1.2r: 2 - C h l o r o - 5 - p y r i d y l b o r o n i c acid S u z u k i - M i y a u r a cross coupling^^ ( i )

Reagents and conditions; N a H C O s , ()4, D M E / H 2 O , 6 h, reflux.
36
1.3
Conclusions
A w i d e variety o f heterocyclic boronic acids are available and their cross-coupling

reactions have established that they are extremely versatile reagents for organic syntheses.
The parameters o f the S u z u k i - M i y a u r a reaction are under constant investigation and
m o d i f i c a t i o n to meet the demands o f the modern chemical industry.
These important
considerations led us to consider larger-scale syntheses (up to 100 g batches) o f new and
existing
pyridylboronic
acids
and
their
subsequent
Suzuki-Miyaura
cross-coupling
reactions (up to 5 g batches).

A t the outset o f the w o r k described in this thesis the versatility and scope o f the
S u z u k i - M i y a u r a cross-coupling had not been explored for systems where both the boronic
acid and the c o u p l i n g partner were heteroaromatics.
A l s o no systematic study had
addressed the effect o f specific substituents upon each o f the c o u p l i n g partners. This has
led us to synthesise new functionalised p y r i d y l - and p y r i m i d y l - boronic acids, and t o couple
them w i t h a large range o f substituted partners in order to produce some heterobiaryl
systems,
which
would
be
very
difficult
to
obtain
by
other
routes.
37
R. C h i n c h i l l a , c. Najera, and M . Y u s , Chem. Rev., 2 0 0 4 , 1 0 4 , 2667.

E. T y r r e l l and p. Brookes, Synthesis, 2003, 469.
G. Solomons and c. Fryhle, O r g a n i c Chemistry 7th E d i t i o n ' , W i l e y , N e w Y o r k ,
2000.
M . B. Smith and J. M a r c h , 'March's Advanced Organic Chemistry 5th E d i t i o n ' ,
ley-interscience, N e w York, 2001.
J. A . Joule, and K. M i l l s , 'Heterocyclic Chemistry 4th E d i t i o n ' , B l a c k w e l l Science
L t d . Cambridge, 2000.
F. c. Fischer and E. Hvinga, Recueil,
1965, 84, 439.
P. R. Parry, . W a n g , . s. Batsanov, M . R. Bryce, and . Tarbit, J. Org.
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43
Chapter 2
Alkoxyboronic acids: Scale-up of existing

preparations and the synthesis of new
examples
A l k o x y b o r o n i c acids: Scale-up o f existing preparations and the synthesis o f new examples
2.0
Chapter 2
2.1
Introduction
A t the beginning o f this project very little had been published on the syntheses o f
p y r i d y l b o r o n i c acids, and larger-scale syntheses (>ca. 10 g batches) had not been reported.
T o extend the w o r k already published in our group on small-scale (1 g) synthesis o f various
alkoxy-substituted
methodology.
pyridylboronic
acids,'' 2 w e
turned
our
attention
to
larger
scale
These investigations were important in assisting in the ultimate industrial
aim o f c a r r y i n g out the syntheses on plant scale. Our i n i t i a l aim was to produce ca. 100 g
batches o f the k n o w n alkoxy-substituted p y r i d y l b o r o n i c acids 40 and 43.
We
later
extended the chemistry to produce novel p y r i d y l b o r o n i c acids.
2.2
Large-scaie
Syntheses
of
Previously
Published
Alkoxy-sustituted
Pyridylboronic Acids.
B r y c e et al.
previously published small-scale syntheses (250-350 m g batches) o f 2 -
m e t h o x y - 5 - p y r i d y l b o r o n i c acid (40) and 2 - m e t h o x y - 3 - p y r i d y l b o r o n i c acid (43) in 6 5 % and

1 3 % yields, respectively.
T h e starting materials were readily available in large quantities,
and the syntheses c o u l d be carried out at relatively h i g h temperatures (-20

w o u l d be achievable i n industry.
C o m p o u n d 40 was synthesised via
exchange o f 2 - m e t h o x y - 5 - b r o m o p y r i d i n e
which
lithium-halogen
(100), at - 7 8 4 (or - 2 0 ^"C) and subsequent
reaction w i t h the electrophile T P B (Scheme 2.2a).
B(0H)2
MeO
Scheme 2.2a: 2 - M e t h o x y - 5 - p y r i d y l b o r o n i c acid synthesis. Reagents and C o n d i t i o n s : ( i ) nB u L i , , -78 c, ( ) 1. T P B , -78

( 2. aqueous w o r k - u p .
44
C o m i n and K i l l p a c k published the lithiation o f 2-, 3- and 4 - m e t h o x y p y r i d i n e using

m e s i t y l l i t h i u m and interest grew when Queguiner et al. established methodology for the
or/o-lithiation o f 2 - m e t h o x y p y r i d i n e using L D A at 0 . 4 ' C o m p o u n d 43 was thus
synthesised via the directed o-//7o-metallation o f 2 - m e t h o x y p y r i d i n e (101) (Scheme 2.2b).
5
()
(i)
N
OMe
OMe
101
8
N
OMe
43
Scheme 2.2b: 2 - M e t h o x y - 3 - p y r i d y l b o r o n i c acid synthesis. Reagents and Conditions: ( i )

L D A , T H F , ( i i ) 1. T M B , 2. aqueous work-up.^
C o m m e r c i a l l y purchased l i t h i u m diisopropylamide ( L D A ) was added to 101 in T H F at 0

^C, f o l l o w e d by the addition o f trimethylborate ( T M B ) and an aqueous w o r k up. The use o f
T M B instead o f T P B as the electrophile was to m i n i m i s e steric hindrance.
The initial a i m was to increase the small-scale y i e l d o f 43. A repeat o f the synthesis
o f 43 using d i i s o p r o p y l a m i n e ( D P A ) and - B u L i t o produce L D A in situ,
followed by
dropwise addition o f 101 to this m i x t u r e afforded an increased y i e l d o f 7 0 % f r o m 13%.

A p p l y i n g these small-scale procedures to a 50 g scale resulted in impure 40 and 43.
A f t e r m u c h experimentation, w e optimised procedures to a f f o r d ca. 75 g batches o f
analytically pure 40 and 43 i n 6 5 % and 5 8 % yields, respectively. These scaled-up reactions
are not a straightforward extrapolation o f the procedures used i n the small-scale reactions.
I n particular, additional
f i l t r a t i o n and washing were needed on scale-up to
remove
unreacted starting material and inorganic salts before isolation o f the product could occur
easily. Moreover, the p H needed to be precisely controlled at this stage ( p H 10) and d u r i n g
acidification w h i c h induces precipitation o f the pure product ( p H 4 and 6, for 40 and 43
respectively). The greater amounts o f 40 and 43 prompted us to attempt crystal g r o w t h ,
w h i c h had previously been unsuccessftil.^ Crystals o f 40 were g r o w n over 10 months f r o m
a water/ethanol m i x t u r e and the structure was solved by D r . A Batsanov (Figure 2.2a).
45
N(1B)
F i g u r e 2.2a: X - r a y crystal structure o f 40. Dashed lines are hydrogen bonds.
The X - r a y crystal structure o f 40 provided further p r o o f that the free boronic acid had been
obtained and not the anhydride. Extensive hydrogen b o n d i n g is present (intermolecular O H . . . . N and dimer f o r m a t i o n ) and is similar to that found in the X - r a y crystal structures o f
22 and 23 previously published.^
H o w e v e r , the packing diagram showed that, due to the
presence o f the m e t h o x y group, the crystals o f 40 do not pack together as closely as 22 and
23. The attempted crystal g r o w t h o f 43 was unfortunately unsuccessful.
2.3
Novel Alkoxypyridylboronic Acids
2.3.1
2-Ethoxy-3-pyridylboronic Acid
Due to successful scale up o f 40 and 43 we attempted to extend the synthesis to new

a l k o x y p y r i d y l b o r o n i c acids.
2 - E t h o x y p y r i d i n e 102 is cheap and readily available f r o m
commercial suppliers and w i t h the idea that the ethoxy group may increase solubility o f the
corresponding boronic a c i d , this was our next target.
The synthesis o f 103 was readily
achieved by a directed or/Ao-metalation reaction^ o f 102 ( L D A
in T H F ) f o l l o w e d b y
addition o f triisopropylborate and an aqueous w o r k u p . T h e i n i t i a l attempts were carried out

at 0
using the same protocol as that used for 2 - m e t h o x y - 3 - p y r i d y l b o r o n i c acid (43).
was shown that using D P A
and - B u L i , or c o m m e r c i a l l y
available L D A
It
made no
difference to the y i e l d . W e repeated the synthesis at a range o f temperatures, w h i l s t other
46
factors, i.e. solvent and reagent quantities, remained the same f o r each experiment.
2.3.1a shows the results f r o m these experiments.
Entry
T e m p . I
Y i e l d I %a
-78
55
-50
70
-20
42
35
a identification and p u r i t y o f the products ( > 9 8 % pure i n all cases) established b y

spectra.
Table
NMR
T a b l e 2.3.1a: Results f r o m the syntheses o f 103 at v a r y i n g temperatures (conditions stated

in Scheme 2.3.1a).
T h i s procedure, using the o p t i m u m temperature o f - 50 , was scaled-up to give ca. 70 g

batches o f analytically-pure 103 (Scheme 2.3.1a) in 4 8 % y i e l d .
following
attractive
decomposition
after
features:
(i)
18 months
it
is
stable
storage), ( )
at
room
C o m p o u n d 103 has the
temperature
as predicted, the
(no
observable
hydrophobic
ethoxy
substituent ensures good s o l u b i l i t y o f 103 in organic solvents w h i c h makes extraction f r o m

the aqueous phase easier than for most other p y r i d y l b o r o n i c acid derivatives w e have
studied and ( ) for cross-coupled products the 2-ethoxy group leads to sterically-induced
t w i s t i n g o f the b i a r y l system (peri-interactions) and hence increased s o l u b i l i t y , w h i c h
assists chromatographic separation f r o m any m i n o r byproducts.
(i), ()
N'
102
OEt
B(0H)2
OEt
103
Scheme 2.3.1a: 2 - E t h o x y - 3 - p y r i d y l b o r o n i c acid (103) synthesis. Reagents and conditions:

( i ) L D A , T H F , - 50 " , ( i i ) triisopropylborate, aqueous w o r k u p .
47
A l k o x y b o r o n i c acids: Scale-up o f existing preparations and the synthesis o f n e w examples
'
0(3)
PK
F i g u r e 2.3.1a: X - R a y structure o f 103 s h o w i n g thermal ellipsoids ( 5 0 % p r o b a b i l i t y ) and
hydrogen bonds. S y m m e t r y transformations: (i) X+Vi, '/-, z - ' / ; ( ) - / , '/-, z+'/.
The X - r a y crystal structure o f 103, solved by D r A . Batsanov,
shows a nearly
planar conformation o f the molecule, stabilised by an intramolecular 0 -
hydrogen
bond w h i c h forms a geometrically favourable six-membered r i n g (Figure 2.3.1a), w h i l e the

other h y d r o x y l group forms an intermolecular 0 - bond l i n k i n g the molecules into an
infinite chain. This structure is unusual as arylboronic acids (like carboxylic acids) t y p i c a l l y
f o r m H-bonded dimers in crystals (see Figure 2.1a);'' * this does not occur w i t h comp ound
103.
Suzuki
cross-coup ling
reactions
of
103
were
carried
out
with
a range
of
aryl/heteroaryl halides 104-112 under standard conditions [(()22, dioxane, r e f l u x ]

to yield products 1 1 3 - 1 2 1 , respectively. The results are collated i n Table 2.3.1.b.
48
T a b l e 2.3.1b. 103 + R - X
113-121
Boronic
Isolated yield
Entry
R-X
Product
Acid
(%)
N M e
r
NÔMe
103
Br
82
N
104
GEt
N
N.
N
103
Br
90
N
105
OEt
103
89
106
NO,
NH,
103
74
Br
OEt
OEt
107
Me
103
/NH2
75
Br
108
49
\ ^ N ^ N . M e
Mev^N^^Me
103
109
78
OEt
M e
CL M e
90
103
( f r o m 110a)
110
N'
ÔEt
( f r o m 110b)
a = Br
b = Cl
103
71
N OEt
111
103
68
N
OEt
112
T a b l e 2.3.1b
S u z u k i - M i y a u r a cross-coupling o f 103.
(i) Reagents and conditions:
Pd(PPh3)2C2, 1,4-dioxane, (1 M ) , r e f l u x , 24 h; for 110a, 20 , 16 h; for 110b, 60

, 15 m i n .
The reactions are h i g h - y i e l d i n g w i t h a variety o f halogenated c o u p l i n g partners (viz.

p y r i d y l , p y r i m i d y l , p y r a z y l and p h e n y l derivatives). The reaction is versatile w i t h respect
to functional group tolerance (viz. n i t r o , amine, amide, ester and t r i f l u o r o m e t h y l ) thereby
a l l o w i n g access to highly-functionalised 2-ethoxy-3-aryI/heteroaryl-pyridine
w h i c h are attractive as candidates for pharmaceutical and agrochemical uses.
derivatives,
The h i g h -
y i e l d i n g reactions in the presence o f a p r i m a r y amine substient (entries 4 , 5 and 7) are
50
notable, as protection o f the amino group was previously generally considered to be

necessary for Suzuki reactions (see chapter 3 ) .
9
Substrates 104-112 gave the optimized y i e l d o f products after 24 at r e f l u x , as

j u d g e d b y T L C and N M R m o n i t o r i n g o f the reaction m i x t u r e . Reagent 110a is a notable
exception. A h i g h y i e l d o f product 119 ( 7 8 % ) was obtained after o n l y 15 minutes r e f l u x ;
the y i e l d decreased after 2 and 8 to 4 0 % and 12%, respectively; w i t h 24 r e f l u x an
intractable green product was obtained. Indeed, the reaction o f 103 w i t h 110a at 20 for
16 gave 119 i n 9 0 % y i e l d . The chloro-analogue 110b was also very reactive: 6 2 % y i e l d
o f 119 was obtained after o n l y a 15 minutes reaction t i m e at 60 . R e f l u x i n g analytically
pure c o m p o u n d 119 in dioxane in the presence o f base led to the decomposition o f 119 to
y i e l d an insoluble green solid w h i c h accounted for the reduced isolated y i e l d o f 119 at
longer reaction times. The reasons f o r the increased reactivity o f 110a and 110b, compared
to 104-109 and 111-112, were investigated. Some relevant literature and model reactions,
as described b e l o w .
Cross-coupling reactions o f organoboronic acids and organic halides require the
presence o f a negatively charged base, such as an aqueous solution o f sodium or potassium
carbonate, phosphate or h y d r o x i d e .
The d i f f i c u l t i e s that can be encountered d u r i n g a
reaction in a basic solution are side reactions, such as the saponification o f esters,
racemization
compounds.'
of
optically
active
compounds,
or
Aldol
condensations
of
carbonyl
T h e literature precedents are that esters can remain intact d u r i n g S u z u k i -
M i y a u r a cross c o u p l i n g s . " ^
For example, Beeby et al. published the cross c o u p l i n g o f
methyl 2-bromobenzoate (122), where the m e t h y l ester group is ortho
to the halide, w i t h
phenylboronic acid in 6 2 % y i e l d at r e f l u x for 4 in the presence o f aqueous sodium

carbonate (Scheme 2 . 3 . I b ) . ^ '
Br
B{OHb
x^'x^ji
122
83
Scheme 2.3.1b: Reagents and Conditions; 0.2 m o l % 123, 1 M N a z C O j , T H F , 60 c . ^ '
51
S u z u k i - M i y a u r a cross-coupling reactions where the a r y l - X species contains both amine and

ketone functionalities have also been published by Jones et al. (Scheme 2.3.1c).
The
reacting hal ide is Ortho to a nitrogen and meta to the m e t h y l ester group. This c o u p l i n g
took place over 3-48 h to give the products shown in h i g h yields ( 8 2 - 9 6 % ) ? ^
ArB(0H)2
126
127
128
129
130
131
Scheme
2.3.1c:
Reagents
and
Conditions;
Ar
Ar
Ar
Ar
Ar
Ar
=
=
=
=
=
=
4-4
2-naphthyl
4-4
4-4
2-thienyl
l,4-bis(diphenylphosphino)butane,
b i s ( b e n z o n i t r i l e ) p a l l a d i u m ( I I ) dichloride, 1 M N a i C O s , toluene, r e f l u x .
T h o m p s o n et al.
published the cross c o u p l i n g o f areneboronic
22
acids w i t h
6-halo-2-
aminopyrazinoate esters in the presence o f triethylamine and a range o f p a l l a d i u m catalysts

i n D M F at 90 for 12 h (Scheme 2.3.Id).^^ This first proved that 110a c o u l d be used in
S u z u k i - M i y a u r a cross c o u p l i n g reactions.
Br"
CeHs
N'
110a
Me
Scheme 2.3.1d: Reagents and C o n d i t i o n s ; ( i ) 1()4, 83, D M F , E t j N , 90 12 23
H o w e v e r , ester groups have been f o u n d to be problematic for some S u z u k i - M i y a u r a cross

c o u p l i n g reactions.'^' IS
Y o s h i d a et al. published base-free reaction conditions for the
h o m o - c o u p l i n g o f arylboronic esters, stating that it was possible to couple arylboronic
52
esters bearing base-sensitive functional groups, namely m e t h y l ester groups. T h e y showed

that arylboronic esters bearing e l e c t r o n - w i t h d r a w i n g groups or an electron-donating group
at the para position afforded the homocoupled-product in excellent yields ( 8 7 - 9 9 % ) .
H o w e v e r , even in the base-free conditions, the h o m o c o u p l i n g o f 4 - m e t h y l ester
phenylboronic ester (133) Qjara- m e t h y l ester group to the reacting site), and other base
sensitive groups, was carried out at a l o w e r temperature o f 60 (all other couplings were
carried out at 80 ). The reason for the lower temperature was not explained in the paper.
The homo-coupled product (134) was obtained in 5 1 % y i e l d after 72 at 60 (Scheme
2.3.le).
134
Scheme 2.3. Reagents and C o n d i t i o n s ; 3 m o l % P d ( 0 A c ) 2 , 4.5 m o l % DPPP, D M S O , 60
"
Zhang
and L e i
published
the
homo-coupling
o f arylboronic
acids
initiated
by
the
transmetallation o f p a l l a d i u m enolates.'^ This was discovered w h i l s t attempting to couple

a-bromophenylacetate (135) and 3,5-dimethylphenyl boronic acid (136). They were unable
to couple the ester to obtain the expected product (137) and obtained o n l y the h o m o coupled product (138) (Scheme 2 . 3 . I f ) .
In the absence o f an -bromo ester no c o u p l i n g
product could be obtained. Interestingly, w h e n c o u p l i n g 136 and ethyl - b r o m o acetate the

h o m o - c o u p l i n g and cross-coupling reaction compete and both products are obtained.
53
OMe
OMe
Scheme 2.3.1f: Reagents and Conditions; Pd2(dba)3.CHC3, r a c - B I N A P , CS2CO3, dioxane,

100
17
Our investigation into the stability and reactivity o f 110a in S u z u k i - M i y a u r a crossc o u p l i n g reactions is detailed in Table 2.3.1c.
W e considered that 110a m i g h t be h i g h l y
reactive w i t h all p y r i d y l b o r o n i c acids, but c o u p l i n g reactions w i t h 40 and 43 showed that

this was not the case. The anomalously high reactivity o f 103 may be due to the increased
solubility o f 103, a f f o r d i n g faster reaction rates at lower temperatures.
ester in conjunction w i t h a nitrogen or tho
The meta m e t h y l
to the reacting b r o m i d e may assist w i t h the
coordination o f the p a l l a d i u m catalyst thereby accelerating oxidative addition. The reason

for the lower reactivity o f 139 (entry 1) is at present not fiiUy understood and m a y be due to
absence o f the or tho
nitrogen.
Entries 2 and 3 show that (predictably) there is no steric
interference f r o m the reacting ester.
54
T a b l e 2.3.1c.
Entry
Boronic A c i d + R-X
Boronic
Acid
141-143
R-X
Product
Isolated y i e l d
(%)
67
103
Et
(21
43
77
OMe
140
40
79
MeO
140
T a b l e 2.3.1c:
N
143
Reagents and conditions: (()22, 1,4-dioxane, (1 M ) , reflux,
15 m i n , r o o m temp, 19 h).
Compounds 139 and 140 are stable at r e f l u x in both neat dioxane, and in dioxane w i t h
(1()22
solid.
H o w e v e r , r e f l u x i n g in dioxane w i t h 1 M resulted in an intractable
This leads us t o believe that a heat-induced, base-initiated polymerasation.
Due to
the S u z u k i - M i y a u r a cross c o u p l i n g reactions that T h o m p s o n et al. published (Scheme

2.3. I d ) the base-initiated reaction must o n l y occur in the presence o f selected bases.
55
2.3.2
2,6-Dimethoxy-3-pyridyIboronic Acid
The metal lation o f 2,6-dimethoxypyridine (144)^ ^^ was published by Khanapure et
al. and unlike 2 - m e t h o x y p y r i d i n e (101), no additional compounds were observed w h e n 144

was treated w i t h rt-BuLi (Scheme 2.3.2a).
^ ^ ^ 2 0 U e
(i), (), ()
Meo
OMe
MeO
144
OMe
145
Scheme 2.3.2a: 2 , 6 - D i m e t h o x y - 3 - ( m e t h o x y m e t h y l ) p y r i d i n e (145) synthesis. Reagents and

Conditions: (i) - B u L i , T H F , 10 , 30 m i n , ( i i ) , ( i i i ) hydrolysis.^"*
W e therefore applied the methodology developed for the synthesis o f 2-ethoxy-3p y r i d y l b o r o n i c acid (103) to 2,6-dimethoxvpyridine (144).
A c c o r d i n g l y , 146 was readily
obtained by the directed or/o-metallation reaction^ o f 144 ( L D A T H F ) f o l l o w e d by the

addition o f triisopropylborate and an aqueous w o r k u p (Scheme 2.3.2b).
(i), (ii). ()
MeO
OMe
MeO
(144)
OMe
(146)
Scheme 2.3.2b: 2 , 6 - D i m e t h o x y - 3 - p y r i d y l b o r o n i c
Conditions: (i) D P A , - B u L i , THF,
^^^B((DH)2
acid (146) synthesis.
Reagents and
-10 m i n , (ii) 147, -78 , h (iii) and
aqueous w o r k - u p .
Crystals o f 146 grew over 4 months from a water/ethanol m i x t u r e and the X - r a y

structure, w h i c h was solved by D r . A Batsanov, is shown in figure 2.3.2a.
56
cm
0(3)
C(4)
F i g u r e 2,3.2a: X - r a y crystal structure o f 146 (dashed lines are H-bonds).
The X - r a y crystal structure o f 146 provided p r o o f that the free boronic acid had
been obtained and not the anhydride, i.e. the b o r o x i n . The X - r a y crystal structure o f 146,
showed a H-bonded dimer, like the X - r a y crystal structures o f 22 and 23 (figure
previously published^ and the structure o f 40 (figure 2.2a).
A n intramolecular
1.1a)
O-H-
hydrogen b o n d w h i c h f o r m s a geometrically favourable six-membered r i n g (Figure 2.3.2a)

is also observed.
The i n i t i a l reactions (1-5 g scale) were carried out at - 78 , although the reaction
was successful at - 10 on scale up (100 g) to obtain a 4 5 % y i e l d o f 146. It was s h o w n ,
on a 1 g scale, that using D P A
and - B u L i gave a higher yield ( 8 2 % ) than using
commercial L D A ( 5 2 % ) . S u z u k i - M i y a u r a cross-coupling reactions o f 146 were carried out

w i t h 147, 110a and 148 under standard conditions [()22, dioxane, r e f l u x ] to y i e l d
products 149-152, respectively, in good yields. The results are collated in Table 2.3.2a.
T a b l e 2.3.2a
B o r o n i c A c i d + R-X
149-152
Boronic
Isolated y i e l d
Entry
R-X
Product
Acid
(%)
146
83
147
,N^NH2
146
B r - ^ N ^
74
110a
^
146
150
NH2
75
Br'
148
158
Br'
N' Y \
110
86
152
T a b l e 2.3.2:
S u z u k i - M i y a u r a cross-coupling o f 146 and 158. ( ) Reagents and conditions:
Pd(PPh3)2C2, 1,4-dioxane, N a z C O j (1 M) r e f l u x , 24 h; for 110a 15 m i n .
58
A l k o x y b o r o n i c acids: Scale-Up o f existing preparations and the synthesis o f n e w examples
2.3.3
2,3-Dimethoxy-4-pyridylboronic Acid
It is k n o w n that lithiation at C 4 o f 2,3-dimethoxypyridine (153) proceeds using 2

equivalents o f - B u L i at 0 to produce 154 - 157 (Scheme 2.3.3a)?^
It was stated that no
lithiation was observed when 153 was treated w i t h 2.2 equiv o f - B u L i at -70 .
Using
1.2 equivalents o f / j - B u L i at 0 gave o n l y a very poor metal lati on y i e l d (5-15 % ) . It was

stated that this was due to 1 equivalent o f the base being entirely chelated by the t w o
methoxy groups and/or the nitrogen atom o f the p y r i d i n e .
OMe
N
OMe
(i), (), ()
OMe
OMe
154 3) E = D
153
156 ) E = CH(OH)Ph
157 d') E = OH
Scheme 2.3.3a: 156 a-d synthesis. Reagents and Conditions: (i) 2 eq. - B u L i , T H F , 0 ,
1 h, ( i i ) E+, ( i i i ) hydrolysis ( 6 0 - 9 9 % ) ? ^
T h i s may be the reason w e f o u n d that the synthesis o f 2 , 3 - d i m e t h o x y - 4 - p y r i d y l b o r o n i c acid

(158)
was
not
readily
achieved
d i m e t h o x y p y r i d i n e (153).
by
the
directed
o/-Ao-metallation
reaction
of
2,3-
D u e to the h i g h cost and l i m i t e d a v a i l a b i l i t y o f 153, the
synthesis o f 158 was o n l y attempted once.
W e f o l l o w e d the methodology developed f o r
the synthesis o f 2 , 6 - d i m e t h o x y - 3 - p y r i d y l b o r o n i c acid (146) apart from using T M B instead

o f T P B to l i m i t the effects o f steric hindrance (Scheme 2.3.3b).
59
B(0H)2
OMe
153
Scheme 2.3.3b
OMe
158
2,3-Dimethoxy-4-pyridylboronic
acid (158) synthesis.
Reagents and
Conditions: (i) D P A , - B u L , T H F , -10 m i n , ( i i ) 153, -78 ( i i i ) T M B and

aqueous w o r k - u p .
One equivalent o f - B u L i was used, as using t w o equivalents for the synthesis o f other 2,3disubstituted-4-pyridylboronic acid had been found to not increase the y i e l d (see Chapter
4).
158 was thereby synthesised in 1 2 % y i e l d w h i c h meant there was o n l y a l i m i t e d
quantity for use in further reactions.
For this reason only one cross-coupling was carried
out w i t h 110a as the c o u p l i n g partner, this halide was chosen as the product w o u l d be a
very h i g h l y functionalised biheteroaryl (152) (Entry 4, Table 2.3.2a) w h i c h was obtained
86% yield.
2.4
Conclusion
A range o f novel a l k o x y - and diaikoxy-substituted p y r i d y l b o r o n i c acids have been
synthesized and the synthesis o f existing boronic acids have been o p t i m i z e d and scaled up.
These have been shown to serve as versatile compounds for the preparation o f h i g h l y functional ised aryl/heteroaryl-pyridine libraries.
60
P. R. Parry, c . W a n g , A . . Batsanov, M . R. B r y c e , and B. Tarbit, J. Org.

2 0 0 2 , 67, 7 5 4 1 .
Chem.,
P. R. Parry, M . R. B r y c e , and B. Tarbit, Synthesis, 2003, 1035.

P. Parry, ' N e w Pyridylboronic A c i d s and their Cross-Coupling Reactions', Ph.D.
Thesis, D u r h a m , 2003.
Y . Fort, P. Gros, and G. Queguiner, Tetrahedron,
1995, 36, 4 7 9 1 .
D . L. C o m i n and M . o . K i l l p a c k , J. Org. Chem., 1990, 55, 69.

F. M o n g i n and G. Queguiner, Tetrahedron,
2 0 0 1 , 57, 4059.
A . E. T h o m p s o n , A . . Batsanov, p. R. Parry, N . Saygili, M . R. B r y c e , and B.

Tarbit, Tetrahedron, 2005, 6 1 , 5 1 3 1 .
8
V . R. Pedireddi and N . SeethaLekshmi, Tetrahedron.
. Caron, . . Massett, D. E. B o g l e , M . J. Castaldi, and T . F. Braish, Org. Pro. Res.

Dev., 200], 5, 254.
10
. M . Echavarren, D. J. Cardenas, . M i y a u r a , T . . M i t c h e l l , . E. D e n m a r k , R. F.
Sweis, S. Brase, . d. Meijere, J. Ma rsden, M . M . Ha ley, I. M a r e k , N . C h i n k o v , D.
Banon-Tenne, J.-E. B c k v a l l , u. K a zm a ier, M . Pohlma n, J. T s u j i , T. M a n d a i , p.
K n c h e l , M . I. Ca la za , E. H u p e , I. Sa pountzis, N . G o m m e r m a n n , L. Jia ng, . L.
B u c h w a l d , V . Sniekus, E. J.-G. A n e t i l , E.-i. N e g i s h i , . Z e n g , . T a n , M . Q i a n , Q.
H u , and . H uang, 'Metal-Catalyzed Cross-Coupling Reactions', ed. A . d. M e i j e r e
and F. Diederich, W i l e y - V C H , 2004.
Lett., 2004, 45, 1903.
. D. Walker, T . E. Barder, J. R. M a r t i n e l l i , and . L. B u c h w a l d , Angew.

Ed., 2004, 43, 1871.
12
F. Y . K w o n g , W . H . L a m , . .
Commun., 2004, 1922.
13
H . C h a u m e i l , . Signorella, and c . L e D r i a n , Tetrahedron,
14
F. Y . K w o n g , K.
2336.
15
Chem.,
Int.
Y u e n g , . . Chan, and . s. . Chan, Chem.
2000, 56, 9655.
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5553.
16
. P. Stanforth, Tetrahedron,
17
X . Z h a n g and A . L e i , Tetrahedron
1998, 54, 2 6 3 .
Lett., 2 0 0 2 , 43, 2525.
61
18
H . Yoshida, Y . Y a m a r y o , J. Ohshita, and A . K u n a i , Tetrahedron

1541.
19
. Peukert, J. Brendel, . Pirard, A . B r u g g e m a n n , p. B e l o w , H . - W . K l e e m a n n ,

H e m m e r l e , and . Schmidt, J. Med. Chem., 2003, 46, 486.
20
. - . Shieh and J. . Carlson, J. Org. Chem., 1992, 57, 379.
21
. Beeby, . B e t t i n g t o n , I. J. . Fairlamb, . E. Goeta , . R. K a p d i , E. . N i e m e l ,

and . L. T h o m p s o n , New. J. Chem., 2004, 28, 600.
22
23
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2052.
24
. P. Khanapure and E. R. B l e h l , Heterocycles,
25
D. P. Curran, D . B o m , .-. , and .
26
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6173.
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Chem.,
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62
Chapter
Amine Substituted Couplings and Amine

Substituted Boronic acid
A m i n e Substituted C o u p l i n g Substrates and an A m i n e Substituted B o r o n i c acid
3.0
Chapter 3
3.1
Introduction
A t the beginning o f this project there were publications stating that S u z u k i - M i y a u r a
cross-coupling reactions c o u l d not be carried out w i t h compounds bearing labile protons

(especially
primary
amines,
protection/deprotection
carboxylic
acids
and
steps were necessary. ^
alcohols)
A l i et al.
attempted S u z u k i - M i y a u r a cross-coupling reactions w i t h
and
thereby
additional
obtained no product
2-chloropyridine-3-carboxamide
and 5 - c h l o r o p y r i d i n - 2 ( l / / ) - o n e and similar reactions o f 2 - c h l o r o - 3 - h y d r o x y p y r i d i n e

o n l y a very l o w y i e l d ( 1 5 % ) o f cross-coupled p r o d u c t ^
from
gave
3-Iodoanthranilic acid failed to
react w i t h a range o f arylboronic acids.^ M o r e recently, Caron et al. reported that the
attempted
cross-coupling
reaction
between
a m i n o p y r i d i n e (159) was unsuccessful.'
phenylboronic
acid
(83)
and
2-chloro-3-
H o w e v e r , w h e n the a m i n o p y r i d i n e was
first
protected as the acetamide (160), the c o u p l i n g proceeded e f f i c i e n t l y in an 8 6 % y i e l d

(Scheme 3.1a).
^ N H
(i
NH
62/
%CI
159
NH
86%
160
Scheme . :
^^<^^^
90%
161
ph
162
Synthesis o f 2 - p h e n y l - 3 - a m i n o p y r i d i n e (162). Reagents and C o n d i t i o n s ; (i)
A c C l , E t j N , CH2CI2; ( ) a, 83, 22
(aq.), E t O H , 3, 1()4, ( ) b M e O H , H C l ;
() HCl.'
It should be noted that d u r i n g the course o f our w o r k M e i e r et al. reported successful

Suzuki
coupling
reactions
of
unprotected
bromopyridylcarboxylic
acids
with
4-
63
f o r m y l p h e n y l b o r o n i c acid.^ There are only isolated examples in the literature o f successful

reactions the presence o f an NH2 group, and many o f these are l o w yielding.^ ''*
One
example, viz. the preparation o f 164, was published previously by our group, in 2 6 % y i e l d ,
but at the t i m e its significance was not appreciated (Scheme 3.1b).'^
B(0H)2
MeO
MeO
163
164
Scheme 3.1b S u z u k i - M i y a u r a cross-coupling in the presence o f an amine group. Reagents

and conditions; 1()4, D M F , 1 M 23,
80 , 65 h . '
Prior to our w o r k no systematic study using the same catalyst and reaction conditions w h i l e
v a r y i n g the a m i n o - c o n t a i n i n g substrate and the arylboronic acids was available. Therefore,
w e decided to carry this out and this w o r k is discussed in the f o l l o w i n g section. "
3.2
Suzuki-Miyaura Cross-Couplings w i t h a Partner Bearing a P r i m a r y
Amine
Group
Initially
pyridylboronic
we
utilized
acids (43)
syntheses (Chapter 2 ) .
the
2methoxy-5-pyridyIboronic
(40)
and
in these reactions as w e had successfully
2-methoxy-3-
scaled up
their
In addition to this, there is widespread interest in p y r i d y l b o r o n i c
acid derivatives and their derived libraries o f aryl/heteroarylpyridines.'^' I

7
2 8
Examples o f
reactions using other boronic acids were carried out for comparison (Chart 3.2a).
64
B(0H)2
B(0H)2
B(0H)2
B(0H)2
MeO
MeO
165
C h a r t 3.2a; Structures o f boronic acids used in this study
T h e standard reagents and conditions used f o r most o f these S u z u k i - M i y a u r a crosscoupling
reactions
were
aqueous
sodium
carbonate
as
base
and
bis(triphenylphosphino)palladium dichloride as catalyst in 1,4-dioxane at 95 , although

other conditions were used (Table 3.2a). The results clearly show that many reactions
proceed in moderate or h i g h yields in the presence o f a p r i m a r y amine group, thereby
directly a f f o r d i n g novel amino-substituted biaryl/heteroaryl systems w i t h o u t the need for
protection/deprotection steps. The table has been split into sections to a l l o w several trends
to be discussed.
T a b l e 3.2a.
Entry
Boronic Acid + R-X

Boronic
Acid
-* 173-183
R-X
Product
Isolated yield
(%)
40
81
167
MeO
40
78
168
MeO
65
40
80
169
MeO
N
175
40
77
176
MeO
40
82
159
177
H,N
43
69
159
OMe
HoN
80
165
159
MeO'
179
HoN
166
70
159
83
86
159
181
66
10
40
40*
171
VNH,
40
11
182
-^^^ 7NH,
172
40*
183
* problems w i t h isolation caused a s l i g h t l y lower y i e l d o f isolated product.
Table
3.2a:
Suzuki-Miyaura
cross-coupling
reactions.
Reagents
and
conditions:
Pd(PPh3)2C2, 1,4-dioxane, N a j C O j aq (1 M) r e f l u x , 28 h.
Entries 1-4 show that the position o f the b r o m i n e on the r i n g relative to the amine
substituent made no difference to the reactivity, whether on a phenyl or p y r i d y l r i n g (yields
77-81%).
- D e f i c i e n t heteroaryl chlorides are k n o w n to be reactive partners in Suzuki
reactions,'*' 12 but c o m p a r i n g entries 4 and 11 shows that, under these conditions, c h l o r o c o u p l i n g partners are s i g n i f i c a n t l y less reactive than the equivalent bromo-partner (40 and
7 7 % yields, respectively). It is k n o w n that Suzuki M i y a u r a cross-couplings o f arylboronic
acids
and
less-reactive
(electron-rich)
chloroaromatics
proceed
in
the
presence
of
'/[02(0)] (dba = dibenzylideneacetone) under conditions where [Pd2(dba)3] alone is

ineffective. Indeed, w e have shown that product yields using 2 , 3 - d i c h l o r o - 4 - p y r i d y l b o r o n i c
acid
and 2 , 6 - d i c h l o r o - 3 - p y r i d y l b o r o n i c
acid w i t h
3-bromoquinoline,
are
significantly
increased using '/(1()22 compared t o 1()22 alone (see Chapter 4 ) .

H o w e v e r , the addition o f ' (10 m o l % ) to the reaction mixtures in entries 10 and 11
had no effect on these selected l o w e r - y i e l d i n g reactions in Table 3.2a.
A comparison o f
entries 5, 10 and 11 shows that 3 - a m i n o - 2 - c h l o r o p y r i d i n e (159) is a more reactive substrate

than the 4 - a m i n o - and 5-amino- isomers 171 and 172, respectively.
Indeed, 159 also
reacted w i t h the 4 - m e t h o x y p h e n y l - (165) and p h e n y l - (83) boronic acids to give the

expected cross-coupled products (179 and 181) in 80 and 8 6 % yields, respectively (Entries
7 and 9 ) . The lower y i e l d obtained f r o m reacting 159 w i t h 2 - m e t h o x y p h e n y l b o r o n i c acid
67
(166) ( E n t r y 8) and 2 - m e t h o x y - 3 - p y r i d y l b o r o n i c acid (43) ( E n t r y 6) is presumably due to

steric hindrance. The increased reactivity o f 159 is presumed to be due to the a m i n o
group's a b i l i t y to coordinate w i t h the p a l l a d i u m atom o f the catalyst (possibly w i t h
displacement o f a ligand), and the high y i e l d w i t h 159 is ascribed to steric factors in
the complexed intermediate facilitating the displacement o f the or//?o-halogen.
This
concept o f coordination has been noted several publications to be discussed below.
hatan et al. stated that the coordination o f the nitrogen to p a l l a d i u m is the key step in
efficient reactions o f 2 - p y r i d y l esters w i t h phenylboronic acids.^^ T o date, W i d d o w s o n and
W i l h e l m published the o n l y examples o f S u z u k i - M i y a u r a cross c o u p l i n g using
uncomplexed fluoroarenes as the reactive partner (Scheme 3.2).^* The reaction tolerated a
w i d e range o f boronic acids, however, a nitro group ortho to the fluorine was essential for
the reaction to occur. The 2-nitro group is required to assist oxidative addition o f the
palladium into the C-F bond b y both electron w i t h d r a w i n g effects and, more importantly,
by coordinating the p a l l a d i u m atom. Schrter et al. reported that cross-couplings show a
h i g h regioselectivity at the C-2 position on a number o f r i n g systems {e.g. thiophenes,
benzothiophenes, fiirans, benzofiirans, pyrroles).^'
Pd2(dba)3
(H0)2B
R = , Me,
OMe, NO2
Y = , NH2,
Mes, OMe,
H, -Bu, Cl
22-85%
CS2CO3
DME, 16 h,
r
Scheme 3.2a: S u z u k i - M i y a u r a cross-couplings o f
fluoroarenes
30
A l i et al. stated that 2,5-dichloropyridine underwent selective cross-coupling at the C-2

position and suggested that this may be due to coordination o f the p a l l a d i u m to the pyridine
\\0%
Fu et al. f o u n d that c h l o r o - substituted pyridines had the potential to bind to the
68
p a l l a d i u m t h r o u g h the nitrogen and were therefore suitable substrates for room-temperature

S u z u k i - M i y a u r a cross-coupling reactions.'" I n their hands 2-chloropyridine coupled w i t h
83 in a higher y i e l d o f 9 7 % than 3-chloropyridine ( 7 7 % ) .
The reactions o f the substrates detailed in entries 5 and 10 were also carried out on 5
g scales; products 177 and 182 were obtained in 80 and 6 0 % yields, respectively.
The
increased y i e l d o f 6 0 % was due to less material being lost d u r i n g isolation o f the product.
T a b l e 3.2b.
Boronic Acid + R-X
184-194
Boronic
Entry
Isolated y i e l d
R-X
Product
Acid
(%)
N
12
N^NH2
NH2
40
69
MeO
N ^NH,
13
43
75
OMe
N
14
NO2
NH2
165
75
MeO
186
N^NH2
15
166
69
OMe
NO2
69
Amine Substituted Coupling Substrates and an Amine Substituted Boronic acid
N^NHz
16
83
80
107
17
40
188
Br^J>NHC(0)Me M e O - {
N
-(0)
81
109
HgC^N
18
40
NH2
Br
73
108
Meo
.2
19
43
75
108
^
20
165
NH2
'l
65
108
^^
21
166
75
108
,^ . N H
22
83
68
108
Table 3.2b:
194
Suzuki-Miyaura cross-coupling reactions.
Pd(PPh3)2C2, 1,4-dioxane, 23
Reagents and conditions: (i)
(1 M), reflux, 8 h.
70
Entries
12-22, using
substrates
107-109, demonstrate that
more
highly-
functional ised amino-substituted bipyridines can also be obtained in synthetically viable

yields.
The conditions of the reaction shown in entry 12 were varied to establish the
optimum mol% of catalyst, amount of base and reaction time needed. The reaction was
repeated using three different molar ratios of catalyst while keeping all the other parameters
the same. The results which are shown in Table 3.2c, established that when using
(1()22 for these couplings 5 mol% is required and that there is no advantage in using
more than this.
Reaction No.
M o l % Pd(PPh3)2Cl2
Isolated yield (%)"
37
69
10
67
.r^
-,
.-
..
NMR determined identification and purity of the products.
Table 3.2c: Results from the formation of 184 with varying molar ratios of catalyst.
The re action was the n re pe ate d using 5 mol% catalyst but varying the re action time ; the
results are shown in Table 3.2d. No incre ase in yield was observed after 8 h. The reaction
was also carried out for 8 h, using 5 mol% catalyst and varying the base (, K2CO3,
CS2CO3
and ). Yie lds we re found to be independent of the base use d (yields 67-
69%).
Reaction No.
Time (h)
Isolated yield (%)"
32
69
12
64
24
61
71
48
66
65
68
a 'H NMR determined identification and purity of the products (>98% pure in all cases).
Table 3.2d: Results for the formation of 184, for varying times (h).
Protection of amine 108 was carried out using a modification of the procedure of
Wright et .32 to give the analytically-pure acetamide derivative 109 in 93% yield. Entry
17 shows that 109 reacted in a similarly high yield to the free amine (Entry 18).
Table 3.2e.
Entry
23
Boronic Acid + R-X
Boronic
Acid
R-X
Product
yield (%)
40
60
163
24
Isolated
43
163
198
70
N^NH2
25
166
71
163
26
83
68
163
201
72
27
165
69
Me
163
202
28
23
BrH5j|yNH2
62
163
H,N
29
40
Br
CF,
84
195
N^NH2
30
40
Br"
^Br
196
76*
Meo
205
NH2
-'
31
40
35
197
Me
206
* Reaction was repeated using 1.2 equiv of 40.
Table 3.2e:
Pd(PPh3)2C2, 1,4-dioxane,
23
aq (1 M) reflux, 8 h.
The reactions were extended using 2-amino-5-bromopyrazine 163 which reacted in

moderate yield with the boronic acids 40, 43,165 166, 83 and 23 (entries 23-28) to provide
novel pyrazinylpyridine derivatives 198-203. Entry 28 establishes that 2-chloro-5pyridylboronic acid 23 shows comparable reactivity to the methoxy analogues 40 and 43.
73
Entries 30 and 31 extend the scope of the reaction and involve two-fold crosscouplings with the dihalo derivatives 196 and 197 to yield products 205 and 206,
respectively. When compound 40 was used in 1.2 equivalents in the reaction with 196, the
yield of compound 205 was reduced to 32% and a trace amount (<1% yield) of monocoupled product was also isolated, but not obtained analytically pure. We are confident
based on 'H NMR, ' C NMR, gCOSY, ROES Y, NOESY, gHSQC and gHMBC data that
the mono-substituted product was that derived from the Suzuki cross-coupling ortho to the
amine, i.e., 5-bromo-3-(6methoxypyridin-3-yl)pyridin-2-amine (207).
3
Z %0-S-^^^
Figure 3.2a: Formula and nomenclature for 5-bromo-3-(6-methoxypyridin-3-yl)pyridin-2amine (207)
This would be consistent with concept of the free amine group coordinating to the
palladium atom of the catalyst.
For ease of discussion for the spectra below the
nomenclature shown above (Figure 3.2a) will be used and the peaks will be labelled as
shown below (Figure 3.2b).
74
OCH
D
NH2
ppm
Figure 3.2b: 'H NMR spectrum of 207 in d-DMSO.
From the NMR spectrum the amine and methoxy group protons can be easily
assigned. The NMR solvent DMSO peak can be seen at 2.5 ppm and a H2O peak can be
seen at 3.3 ppm. The methoxy group protons are next ftirthest up field as they are
aliphatic protons attac hed to a carbon that is attac hed to an oxygen at 3.85 ppm. The
amine group has a characteristic broad peak at ~ 6.5 ppm. The remaining 5 peaks (Labelled
A-E from left to right for ease of discussion) can be assigned to the protons attached
directly to the two rings (V - ). The ' C NMR spectrum shows the correct number of
3
carbons (11), supporting the monocoupled product structure (with a trace of impurity at
127 and 129).
75
1
160
140
120
100 90
80
70
60
so
ppm
Figure 3.2c: ' C NMR spectrum of 207 in d-DMSO (peaks at 40 ppm)

3
Ippm)
Fl ppm
Figure 3.2d: ROESY (Rotating frame Overhauser Enhancement Spectroscopy) spectrum of

207
76
'ii[iiiFim[niiini|iin|iiMiin[iiii|mi|i
8.6
8.2
7.8
7.0
6.6
Fl (ppm)
Figure 3.2e: COSY (Correlation Spectroscopy) spectrum of 207
The observed responses from protons V to z seen in ROESY and COSY NMR
spectra tell us that the proton that gives rise to peak couples with the protons that give
rise to peaks A, and E. Therefore, peaks A, and E are observed from 3 protons on one
ring system (V, and X). The coupling constants (larger from protons V and ) establish
that peak A relates to proton X, peak relates to proton and peak E relates to proton V.
Peaks and D relate to protons Y and z due to the electronegativity of the nitrogen
adjacent carbon 1 (see Figure 3.2a), proton Y is observed further downfield; therefore, Y
relates to peak and z to D. No response can be seen in the ROESY or COSY NMR
spectra from protons z and Y this could be due to the bulky amine group restricting
rotation of the molecule. If the other mono coupled isomer had been formed, observable
coupling between protons Y and X and Y and would be predicted to be seen in the
ROESY spectrum.
77
-2
<)
2-_
5-
S-
9]
cppm)
Figure 3.2f: Part of HSQC (Heteronuclear Single Quantum Coherence) spectrum of 207
A H SQC spectrum shows which proton is directly attached to which carbon,

therefore the proton peaks relating to; the carbon that is attached to the bromine (2 or 4) and
the carbon that is attached to the amine group (5) were identified, as neither carbons couple
to any protons.
78
(ppm)
6.6
170
160
150
140
130
120
110
PI (ppm)
Figure 3.2g: Part of
(H eteronuclear Multiple Bond Correlation) spectrum of 207
The HMBC allows the peak relating to the carbon attached to the amine group to be
identified, therefore the other carbon, of the two identified by the H SQC, is the one
attached to the bromine. That carbon attached to the bromine has long-range coupling with
the protons that give rise to peaks and D (protons Y and z respectively). The long-range
coupling with proton Y confirms the structure in Figure 3.2a. If the cross-coupling reaction
had occurred at the carbon which is para
to the amine group, this coupling in the H MBC
spectrum between the carbon attached to the bromine and proton Y should not be
observable, as it would be a 4-bond coupling.
79
Table 3.2f.
Entry
Boronic Acid + R-X

Boronic
R-X
Acid
Isolated yield
Product
(%)
MeO
32
(from 208a)
40
208
(from 208b)
a X = Br
bX = I
213
MeO
33
40
22
209
214
MeO
34
40
52
210
215
MeO
35
CHO
40
54
211
N.
36
43
Br'
.NH2
82*
110a
80
37
40
B r ^ " ^
82
212
218
Table 3.2f
Pd(PPh3)2C2, 1,4-dioxane,
23
aq (1 M), reflux, 24. *15 min, reflux.
Entry 32 suggests there is no significant difference in reactivity between 5-bromoand 5-iodo-indole under these conditions. However, we cannot generalise, as no other
examples were tried. Entries 32 - 35 show that reactions using indole, 2,3-dihydroindole
and carbazole derivatives also gave the expected products in moderate yields. Entry 37 was
carried out to show that these conditions are not confined to free amine groups, but that
hydroxy! groups (which also have labile hydrogens) could also be coupled with 40 in high
yields.
3.3
Transformation of 182 via Diazotization

The amine group in the above compounds is a possible site for further reactions, e.g.
diazotization.^^ Diazonium salts can react with a number of different cleophiles to form
a range of products.
Diazotization of 2(6-methoxypyridin-3-yl)pyridin-4-amine 182
following the standard procedure used previously in our group on other molecules (Scheme
.)/^ gave the expected product 219 in 32% yield where the amino group was replaced
with a bromine. A second product 220 was isolated in 30% yield, and 32% of the starting
material was also recovered. Structure 220 had an amine group and a bromine group
attached this was supported by a combination of mass spectra, elemental analysis, NMR
and " NMR spectroscopic data.
81
220
N
OMe
182
OMe
219
Scheme 3.3a: Diazotization of 182. Reagents and Conditions: (i) HBr, NaNCb, NaOH
- I ...II.
8.5
8.0
NH2

7.5
7.0
6.
6.0
5.5
JL_
5.0
4.5
ppm
Figure 3.3: NMR spectrum of 220 in de-acetone
'H NMR spectra of the second product (220) showed 5 aromatic protons (labelled A to E
from left to right for ease of discussion) and the broad singlet at 5.8 ppm from the amine
protons. The J values and splitting of the peaks confirm that the protons resulting peaks
A, and E are on one ring system, and those resulting peaks and E are on adjacent
carbons.
The two singlets (B and D) relate to two protons on another ring system.
Therefore only five protons are present and the amine group (peak at -5.9 ppm). From this
it was concluded that a proton had been displaced by a bromine.
82
160
150
140
130
120
110
100
90
80
70
ppm
Figure 3.3b: ' C NMR spectrum of 220 in d-acetone

3
The 1 C NMR spectrum (Figure 3.3b) shows 11 carbons as expected if the bromine had
3
displaced any proton. Replacing a proton with a bromine causes an upfield shift of the
carbon to which it is attached by ca. 6 ppm.
3.4
35
2-Amino-5-pyrimidylboronic Acid Synthesis

To
date, there
have
been
several
reports
regarding
the
syntheses
of
aminophenylboronic acids^^ but no amine-substituted heterocyclic boronic acids have been

described.
After our success with the synthesis of various
amine-substituted
bi(hetero)aryls, we turned to an amine-substituted heterocyclic boronic acid, with the view

to synthesising a bi(hetero)aryl with amine group() on either or both rings.
Our target, 2-amino-5-pyrimidylboronic acid, was chosen for two reasons: (i) the
starting material, 2-amino-5-bromopyrimidine (148), was readily available and () we had
recently successfully synthesised pyrimidylboronic acids (see chapter 4). Compound 148
allowed only one site for halogen-lithium exchange, as the DoM methodology could further
complicate the reaction. The reactive lithio-species then reacted with the already present
borate. As previous work in our group on the synthesis of other pyrimidylboronic acids,^^
had employed the "reverse addition route" instead of the sequential addition route, this was
attempted first.
We recognized that the acidic amino hydrogens of 148 could be problematic under
strongly basic conditions; nonetheless, the synthesis was attempted on unprotected 148
83
(Scheme 3.4a) using a range of equivalents of lithium, on a 2 g scale, as shown below in

Table 3.4a.
-Br
H2N
N'
(i)
()
-B(0H)2
H2N
148
221
Scheme 3.4a: 2-Amino-5-pyrimidylboronic acid synthesis. Reagents and Conditions: (i)

TPB, THF, -78 , -BuLi, (ii) Aqueous work-up.
Reaction No.
Equiv. -BuLi used
Isolated Yield of 221 (%)"
1.2
12
2.5
46
5.0
45
10.0
a 'H NMR determined identification and purity of the products.

Table 3.4a: Results for the formation of 221 using varing equivalents of rt-BuLi.
The results show that the desired product was obtained in a synthetically-useful yield, and
there is no advantage in using more than 2.5 equiv. of n-BuLi. As far as we are aware this
is the first reported example of lithium-halogen exchange on 148.
Two examples of Suzuki-Miyaura c ross-c oupling reactions of 221 were carried out
with 147 and 163 under standard c onditions [()22, dioxane, reflux] to yield
products 222 and 223, respectively, in moderate yields (Table 3.5).
84
Table 3.4b.
Entry
221 + R-X
Boronic
222 and 223

R-X
Product
Acid
Isolated yield
(%)
221
60
147
H2N
N
222
N- ^ N H ,
221
Br" N '
163
Table 3.4b:
40
,
223
Suzuki-Miyaura cross-coupling of 221.
Pd(PPh3)2C2, 1,4-dioxane, NajCOj aq (1 M) reflux, 24 h.
The versatility of the reactions with respect to functional group tolerance (viz. nitro,
amide, ester and trifluoromethyl) needs further investigation. This would allow access to
highly-functionalised pyrimidine derivatives, which are attractive drug and agrochemical
candidates.
85
A m i n e Substituted C o u p l i n g Substrates and an A m i n e Substituted Boronic acid
35
Conclusion
range o f halogenated aromatics and heteroaromatics bearing p r i m a r y
groups have been shown to be suitable substrates for S u z u k i - M i y a u r a
amine
cross-coupling
reactions w i t h arylboronic acids and p y r i d y l b o r o n i c acids under standard conditions,

w i t h o u t the need for protection/deprotection steps. N e w amino-substituted arylpyridines,
bipyridines, pyrazinopyridines, indolinopyridines, carbazolopyridines and indolopyridines
have thereby been obtained.
Since our publication on this work,^^ another group has
published different cross-couplings in the presence o f p r i m a r y amine g r o u p s . I n
this
w o r k , Itoh et al. also showed that 3amino-2-chloropyndine (159) is more reactive in

S u z u k i - M i y a u r a cross-coupling reactions than other isomers (171 and 172).^^
The first amino-heterocyclic boronic acid, namely
2-aminO"5"pyridimidylboronic
acid (221), has been successfully synthesised in moderate y i e l d .
S u z u k i - M i y a u r a cross-
c o u p l i n g reactions have been earned out using 2 2 1 to synthesise novel p y r a z i n o p y r i m i d i n e

and quinolinopyriidine derivatives. This paves the w a y f o r the synthesis o f other
heterocyclic
boronic
acids
bearing
free
amine
substituents.
86
. Caron, . S. Massett, D. E. B o g l e , M . J. Castaldi, and T. F. Braish, Org. Pro. Res.

Dev., 2 0 0 1 , 5, 254.
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V . L i s o w s k i , M . Robba, and . Rault, J. Org. Chem., 2000, 65, 4193.

P. Meier, . Legraverant, . M u l l e r , and J. Schaub, Synthesis, 2003, 5 5 1 .
.
Tarbit,
G.
Cooke,
Vanderstraeten, Tetrahedron,
8
9
IO
12
13
14
15
Augier
de
Crmiers, V .
M.
Roteilo, and
p.
E.
2 0 0 1 , 57, 2787.
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J. . M i l l e r and R. p. Farrell, Tetrahedron
1996, 509.
Lett., 1998 39, 6 4 4 1 .
G. . Fu, . F. L i t t k e , and c . D a i , J. Am. Chem. Soc, 2000, 122, 4020.

J. . Daab and F. Bracher, Monatshefte fur Chemie., 2003, 134, 573.
R. K. A r v e l a and N . E. Leadbeater, Org. Lett., 2005, 7 , 2 1 0 1 .
L. L i u , Y . Zhang, and Y . W a n g , J. Org. Chem., 2005, 70, 6122.
F. Bracher and J. . Daab, Eur. J. Org. Chem., 2 0 0 2 , 2288.
P. R. Parry, . W a n g , . . Batsanov, M . R. B r y c e , and . Tarbit, J. Org.
Chem.,
2002, 67, 7 5 4 1 .
16
. E. T h o m p s o n , G . H ughes, . s . Batsanov, M . R. B r y c e , p. R. Parry, and B.

Tarbit, J. Org. Chem., 2005, 70, 388.
17
J. Sopkova de O l i v e i r a Santos, A . B o u i l l o n , J.-C. Lancelot, and . Rault, Acta
Cryst., 2003, 59, 596.

8
N . L e f l e m m e , p. Dallemagne, and . Rault, Tetrahedron,
2004, 60, 4 8 6 1 .
J.-C. Lancelot, A . B o u i l l o n , A . . V o i s i n , and . Rault, Tetrahedron,

19
2005, 6 1 ,
1417.
. B o u i l l o n , . . V o i s i n , . Robie, J.-C. Lancelot, V . C o l l o t , and . Rault, J. Org.
20
Chem., 2003, 68, 10178.

. B o u i l l o n , J.-C. Lancelot, J. Sopkova de O l i v e i r a Santos, V . C o l l o t , p. B o v y , and
21
. Rault, Tetrahedron,
2003, 59, 10043.
87
22
A . B o u i l l o n , J.-C. Lancelot, V . Col lot, p. B o v y , and . Rault, Tetrahedron,

58, 4369.
2002,
23
A . B o u i l l o n , J.-C. Lancelot, V . C o l l o t , p. B o v y , and . Rault, Tetrahedron,
2002,
58, 3323.
24
2002,
58, 2885.
25
B. Abarca, R. Ballesteros, F. Blanco, . B o u i l l o n , V . C o l l o t , J.-R. D o m i n g u e z , J.-C.

Lancelot, and . Rault, Tetrahedron,
2004, 60, 4887.
26
P. R. Parry, M . R. B r y c e , and B. Tarbit, Synthesis, 2003, 1035.
27
N . S a y g i l i , A . . Batsanov, and M . R. Bryce, Org. Biomol.
28
E. T y r r e l l and p. Brookes, Synthesis, 2003, 469.
29
H. Tatamidani, F. K a k i u c h i , and N . Chatani, Org. Lett., 2004, 6, 3597.
D. A . W i d d o w s o n and R. W i l h e l m , Chem. Comm., 2003, 578.
31
. Schroter, . Stock, and T . Bach, Tetrahedron,
32
Chem., 2004, 2, 852.
2005, 6 1 , 2245.
S. W . W r i g h t , D. L. H ageman, and L. D. M c C l u r e , J. Heterocy cl.
Chem., 1998, 35,
719.
33
M . . Smith and J. M a r c h , 'March's A d v a n c e d Organic Chemistry 5th Edition',

W i ley-intersc ience, N e w Y o r k , 2 0 0 1 .
34
M . B r y c e , . W a n g , M . K i l i z i r a k i , H . M a c B r i d e , L. E. H o r s b u r g h , A . K. Sheridan,
A . M o n k m a n , and 1. D. . Samuel, Adv. Mater.,
35
2 0 0 0 , 1 2 , 217.
H.-O. K a l i n o w s k i , . Berger, and . B r a u n , 'Carbon-13 N M R Spectroscoy', John

W i l e y & Sons, N e w Y o r k , 1988.
36
. Scherer, . M e u d t , . Lehnemann, . K a l i n i n , and V . Sniekus, Int. A p p i .

2005, US 2005/0038287.
37
T. Itoh and T. Mase, Tetrahedron
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88
Chapter 4
Synthesis and Application of Novel

Halopyridylboronic Acids
Synthesis and A p p l i c a t i o n o f N o v e l H a l o p y r i d y l b o r o n i c A c i d s
4.0
Synthesis a n d A p p l i c a t i o n o f N o v e l H a l o p y r i d y l b o r o n i c A c i d s
4.1
Introduction
A t the outset o f this project there was one publication i n the literature o f a
d i h a l o p y r i d y l b o r o n i c a d d . i A s stated in Chapter 1, Gallagher et al. had prepared 5-bromo2"fluoro-3-pyridylboronic
fluoropyridine
acid (47) in 8 0 % y i e l d by a D o M reaction o f 5-bromo-2
(46), f o l l o w e d by reaction w i t h trimethylborate and described a sequence
leading to 3,5-disubstituted 2-fluoropyridine w h i c h were converted into the corresponding

2-pyridone derivatives (Scheme l , l o ) .
I n 2002, Rault et al. published the synthesis and S u z u k i - M i y a u r a cross c o u p l i n g o f a
number o f c h l o r o p y r i d y l b o r o n i c acids; 2-chlorO"3-pyridylboronic acid (27) and 2"Chloro-5p y r i d y l b o r o n i c acid (23) w i t h 2-bromobenzonitrile in 57 and 7 2 % yields r e s p e c t i v e l y / and
4-chloro-3-pyridylboronic
acid (29) w i t h 4-bromotoluene
characterisation o f the coupled products was g i v e n .
in 5 4 % y i e l d , although
It was our a i m to synthesise a series o f d i h a l o p y r i d y l b o r o n i c

methodology.
no
acids v i a
DoM
D o M methodology does not require brominated starting materials and
therefore cheaper and more readily available reagents can be used w h i c h makes the
procedure more c o m m e r c i a l l y viable on an industrial scale.
W e later extended the
chemistry to produce a h a l o p y r i m i d y l b o r o n i c acid by using h a l o g e n - l i t h i u m exchange

methodology.
4.2
2,6"DifluorO"3"pyridyIboronic Acid
F o l l o w i n g the successful synthesis o f 2 , 6 " d i m e t h o x y - 3 - p y r i d y l b o r o n i c acid (146),

w e applied the methodology to 2 , 6 - d i f l u o r o - 3 " p y r i d y l b o r o n i c
acid (225) w h i c h
was
expected to be readily accessible b y a D o M reaction^* o f 2 2 4 ( L D A i n T H F ) f o l l o w e d by the

addition o f triisopropylborate and an aqueous w o r k u p .
The initial attempts using an
aqueous w o r k u p were unsuccessful, upon acidification o f the aqueous layer to p H 6 no

solid precipitated even after prolonged stirring (24 h).
The aqueous layer was further
89
acidified to p H 1 but still no precipitate f o r m e d . T L C analysis o f the aqueous layer showed

a base line spot characteristic o f a boronic acid.
Extraction w i t h ethyl acetate and
recrystallisation gave product 225 in 6 8 % y i e l d . U s i n g T M B instead o f T P B gave a similar
y i e l d ( 7 0 % ) . H o w e v e r , the y i e l d o f 225 increased to 8 2 % w h e n D P A and - B u L i were used
to generate L D A instead o f using c o m m e r c i a l L D A (Scheme 4.2a). The reaction was
scaled-up to give 50 g o f 225 in 3 4 % unoptimised y i e l d .
B(0H)2
(i), (), ()
Scheme
4.2a:
2,6-Difluoro-3-pyridylboronic
acid
(225)
synthesis.
Reagents
and
C o n d i t i o n s : (i) D P A , - B u L i , T H F , -10 m i n , ( i i ) 2 , 6 - d i m e t h o x y p y r i d i n e , -78 3 h

( i i i ) T P B and aqueous w o r k - u p ( i n c l u d i n g ethyl acetate extractions).
S u z u k i - M i y a u r a cross-coupling reactions o f 225 were carried out w i t h a range o f

aryl/heteroaryl halides 147, 110a and 148 under our standard conditions [(1()22,
d i o x a n e , r e f l u x ] to y i e l d products 226-228, respectively. T h e results are collated in Table
4.2a.
T a b l e 4.2a.
Entry
225 + R-X
Boronic
Acid
226-228
R-X
Product
Isolated y i e l d
(%)
81
225
84a
147
226
90
N^NHz
225
82
110a
227
N N H 2
NyNH2
225
69
Br
148
Table
4.2a
Suzuki-Miyaura
Pd(PPh3)2C2, 1,4-dioxane, 23
cross-couplings
o f 225
(i)
Reagents
and
conditions:
(1 M) r e f l u x , 24 h; for 110a 15 m i n . (a 10 m o l % 'BU3P)
Bromo-heteroaryls bearing p r i m a r y amine groups have been shown to be suitable

substrates
for
pyridylboronic
Suzuki-Miyaura
acids
under
cross-coupling
standard
reactions
conditions,
with
arylboronic
without
the
acids
need
and
for
protection/deprotection steps (see Chapter 3 ) . Compounds 147 and 148 coupled w i t h 225
i n h i g h yields and new amino-substituted p y r i m i d o p y r i d i n e s , q u i n o l i n o p y r i d i n e s ,
thereby been obtained.
have
The reaction was extended to couple 110a to show its versatility
w i t h respect to functional group tolerance (ester) thereby a l l o w i n g access to a h i g h l y functionalised 2 , 6 - d i f l u o r o - 3 - p y r a z i n o p y r i d i n e derivative. Substrates 147 and 148 gave the
o p t i m i z e d y i e l d o f products after 24 h at reflux, as j u d g e d by T L C and N M R m o n i t o r i n g
o f the reaction m i x t u r e .
Reagent 110a is a notable exception, as previously discussed. A
h i g h y i e l d o f product 227 ( 8 2 % ) was obtained after o n l y 15 minutes r e f l u x . Products 226,

227, 228 are attractive as candidates for pharmaceutical and agrochemical uses.
91
4.3
2,6-DichIoro-3-pyridylboronic Acid
S u z u k i - M i y a u r a reactions on chloro-aryls are w e l l k n o w n in the literature.^"^

(after
completion
phenylboronic
o f our
acid
work)
with
Itoh and
Mase
amine-substituted
In 2005
published the cross-couplings
heteroaryl
chlorides.
of
Substituted
chloropyrimidines and 2-chIoropyridines reacted w i t h phenylboronic acid in moderate to

good yields (68 9 3 % ) . * In 2004, G o n g et al. reported that in r e f l u x i n g dioxane the amine
group o n various halo-substituted phenyls reacted w i t h various heteroaryl chlorides b y
cleophilic heteroaromatic substitution (Scheme 4.3a).
NN
AR
^^N
p^
AR
/l
Scheme 4.3a Intermediates in the synthesis o f 2,4-diamino-A^4,6"diarylpyrimidines^

Reagents and conditions; ( i ) reflux dioxane.
In
our
laboratory,
the
mono-chloropyridylboronic
acids,
namely
2"Chloro-5-
p y r i d y l b o r o n i c acid (23) and 5chloro-2-methoxy-4-pyndylboronic acid (41), had been

shown
to couple
in moderate yields
with
both electron-rich
and
electron-deficient
heteroaryl bromides.'*^
A s the synthesis o f 2 , 6 - d i f l u o r o - 3 " p y r i d y l b o r o n i c
acid (225) was successful, we
applied analogous D o M methodology to 2,6-dichloropyridine (229) and 2,6dichloro-3p y r i d y l b o r o n i c acid (230) was thereby readily obtained in 7 0 - 7 5 % yields (Scheme 4.3b) on
2.5 g 5 g and 10 g scale s re actions.
Various parame te rs and conditions o f the synthe sis
were change d to e xamine the ir e ffe ct o n the product y i e l d . U s i n g comme rcial L D A , inste ad
o f L D A forme d in situ ( D P A and - B u L i ) de cre ase d the y i e l d to 5 0 % . U s i n g cone . H C l in
the aque ous w o r k up ste p, inste ad o f HBr de cre ase d the y i e l d to 51 % . U s i n g comme rcial
L D A and H C l in the same re action furthe r de cre ase d the y i e l d to 3 4 % . S t i m n g for > 1 h
92
after the addition o f the borate, d i d not increase the yield above 7 3 % .
A d d i n g the
triisopropylborate at the start o f the reaction (reverse addition method) lowered the y i e l d to
4 2 % . A n unoptimised scale-up o f the synthesis using L D A formed situ and H B r , w h i c h
had given 230 in 7 3 % y i e l d on 10 g scale, was used to synthesise 70 g o f 230 but it required
an additional recrystallisation f r o m toluene to obtain pure product in 2 2 % y i e l d .
Scheme
4.3b:
(), ()
2,6-Dichloro3-pyridylboronic
acid
(230)
synthesis.
Reagents
and
C o n d i t i o n s : (i) D P A , - B u L i , T H F , -10 m i n , ( i i ) 2,6-dichloropyridine, -78 h

( i i i ) and aqueous w o r k - u p .
Crystals o f 230 grew over a number o f months f r o m a water/ethanol m i x t u r e and the

xray structure, w h i c h was solved b y D r . A Batsanov, is shown in figure 4.3a.
F i g u r e 4.3a: X - r a y crystal structure o f 230-0.511 (dashed lines are H-bonds).
The X-ray crystal structure o f 230 shows a hemi-hydrate and provided p r o o f that the
free boronic acid had been obtained and not the anhydride, i.e. the b o r o x i n .
Hydrogen
b o n d i n g is present between the water molecule, and the p y r i d y l N ( l ) and 0 ( 2 ' ) o f the
boronic acid group. U n l i k e the X - r a y crystal structures o f 22 and 23 previously p u b l i s h e d "
93
and the structure o f 40 (figure 2.1a) no H-bonded dimer was observed for 230. The lack o f
dimer is presumably due to preferred H-bonding to O H o f water than to the O H o f the
boronic acid.
The crystals o f 230 were g r o w n f r o m the 70 g scale synthesis and an unexpected

byproduct co-crystallised along w i t h 230. The X - r a y analysis established the b i p y r i d y l
structure 2 3 1 shown in figure 4.3b. There was no evidence to suggest this byproduct was
present in any other samples and therefore we considered that its mechanism o f f o r m a t i o n
c o u l d be explained by either: (i) oxygen being present d u r i n g the large-scale synthesis; ( )
an i m p u r i t y in the starting material 2 2 9 ; ( ) or h o m o c o u p l i n g o f 230 occurring d u r i n g
crystallisation. T o test these possibilities, the synthesis o f 230 was carried out in the
presence o f oxygen (flask was not evacuated to remove oxygen at the start o f the
experiment) and a lower yield o f 230 ( 15%) was obtained but 2 3 1 was not present in the
product isolated ( and ' ^ c N M R ) .
H o m o c o u p l i n g o f the boronic acid was u n l i k e l y , due
to no catalyst or base being present and to date no examples o f Suzuki c o u p l i n g w i t h o u t

catalyst or base are k n o w n .
Therefore, it was concluded that 231 was probably already
present as an i m p u r i t y in the starting material or was derived f r o m an i m p u r i t y ; however,

there was no sample remaining o f this batch o f starting material, so we c o u l d not prove its
o r i g i n conclusively.
F i g u r e 4.3b: X - r a y crystal structure o f 2 3 1 .
94
S u z u k i - M i y a u r a cross-coupling reactions o f 230 were carried out w i t h 147 and 148

under our standard conditions [Pd(PPh3)2C2, dioxane, r e f l u x ] to y i e l d products 232 and
233, respectively. Due to the l o w yields o f the desired c o u p l i n g products, other conditions
were investigated and the results are collated i n Table 4.3b. W e d r e w o n the w o r k o f Fu et
al. w h o reported 02(0)/'
as a catalyst for cross-coupling a w i d e range o f aryl
halides w i t h arylboronic acids in very good yields ( 7 5 - 9 5 % ) . ' ^
The catalyst
system
produced b i a r y l w i t h a range o f substituents ( N H 2 , O M e , C O M e , M e ) and was extended to

couple aryl boron acids w i t h chloropyridines.
A range o f phosphanes and bases were
used in couplings; using 'BU3P w i t h either P d ( 0 A c ) 2 or 1()22 in the presence o f

CS2CO3 or gave slightly increased yields ( 5 4 - 5 7 % ) . ' ^
a-h
T a b l e 4.3a.
230 + R - X
232 o r 233
B o r o n ic
Entry
R-X
Isolated
Product
Conditions
Acid
y i e l d (%)
36
54
56
57
55
38
24
30
2
3
4
230
5
N^CI
147
232
N./NH2
230
Br
148
46
N
Cl
95
T a b l e 4.3a:
Reagents and conditions:
Pd(PPh3)2C2, 1,4-dioxane, N a j C O j (1 M ) , r e f l u x , 65 h, (b) ()22, ',

dioxane, 23
(a)
1,4-
(1 M ) , reflux, 65 h, () ()22, ', 1,4-dioxane , CS2CO3 (1 M ) ,
r e f l u x , 65 h, ( d ) P d ( 0 A c ) 2 , ', 1,4-dioxane , NjCOy
(1 M ) , r e f l u x , 65 h, (e ) P d ( 0 A c ) 2 ,
'BU3P, 1,4-dioxane , CS2CO3 (1 M ) , re flux, 65 h, ( f ) (()22, 1,4-dioxane, N a j C O j (1

M ) , reux, 8 h, (g) Pd(PPh3)2C2, 1,4-dioxane, N a z C O j (1 M ) , 150 , 5 m i n @ 150 , (h)
Pd(PPh3)2C2, 1,4-dioxane, (1 M ) , 150 20 m i n @ 150 .
Entry 2 - 5 shows that changing the aqueous base f r o m sodium carbonate to cesium
carbonate had no effect on the y i e l d . A d d i n g 'BU3P 1 increased the y i e l d o f the coupled
2
product (cf. entry 1 - 2 ) . Changing the catalyst to f r o m Pd(PPh3)2C2 to P d ( 0 A c ) 2 made no

difference to the y i e l d (entries 2 and 4 ) .
Previously in our hands, 2-chloro-5pyridylboronic acid (23) had coupled w i t h 3b r o m o q u i n o l i n e (147) in 5 5 % y i e l d (scheme 4.3c).
The same reaction carried out using
conditions a and b o f table 4.3a gave 58 and 7 1 % yields o f 234, respectively, demonstrating
a modest increase in y i e l d w i t h added '.
B(OH 2
Br
(!)
Scheme 4.3c
Suzuki c o u p l i n g o f 23.
Reagents and conditions; (i) ()4, D M F ,
N a a C O a i l M ) , 80 " C .
As
previously
discussed
(Chapters
and
3)
other
reactions,
especially
h o m o c o u p l i n g o f the boronic acid, can occur w i t h halogen-substituted boronic acids under

Suzuki conditions.
from
the
A l t h o u g h no homocoupled products were isolated, 236 was isolated
cross-coupling
o f 2,6-dichloro-3-pyridylboronic
acid
(230)
and
3-amino-2-
96
c h l o r o p y r i d i n e (159) (Scheme 4.3d). Product 236 was obtained in 3 2 % y i e l d along w i t h ca

1 5 % y i e l d o f the expected coupled product, but 235 was not obtained analytically pure.
Cyclisation had occurred w i t h the amino group o f 235 attacking C2 (attached to the
c h l o r i n e ) ; base present in the reaction m i x t u r e then removes a proton f r o m the positively
charged nitrogen. Overall this gives c o m p o u n d 236 and a molecule o f h y d r o c h l o r i c acid.
2
N
230
()
Cl
C l ^ N ^ C I
159
235
236
Scheme 4 . 3 d : Suzuki c o u p l i n g o f 230 and 159. Reagents and conditions; ( i ) ()22,

', 1,4-dioxane, (1 M ) , r e f l u x , 65 h,
T h i s structure o f 236 was supported by mass spectra, ' H
NMR,
' C NMR,
3
gCOSY,
R O E S Y , g H S Q C and g H M B C data (Figs 4.3c 4.3).
"1
F i g u r e 4.3c:
N M R spectrum of 236 in d-DMSO.
97
The ' H N M R spectrum showed five aromatic protons ( F i g . 4.3c) w i t h no broad singlet f r o m
a free amine group. A singlet at 12.23 p p m w i t h an integral o f one proton was assigned to
the N H o f 236.
'SS
'
'a
-is
lio
1(5
'i
F i g u r e 4 . 3 d : ' C N M R spectrum o f 236.

3
The 1 C N M R spectrum showed 10 carbons as expected for 236 ( F i g 4.3d).

3
F i g u r e 4.3e: R O E S Y spectrum o f 236.
The R O E S Y spectrum c o n f i r m e d that the protons producing the t w o doublets at 8.6 and
7.3 p p m are on adjacent carbons, and the quartet at 7.5 p p m is f r o m a proton on the carbon
adjacent to both carbons that carry protons, causing the doublet o f doublets at 7.9 and 8.5
ppm.
Overall this c o n f i r m s that on one ring system t w o protons are present and on the
other r i n g system three protons are present.
98
8-6
8.4
8.0
7.
7.6
7.4
T.2
FZ (PPm
F i g u r e 4.3f: C O S Y spectrum o f 236.
T h e C O S Y spectrum further supported a structure w i t h t w o separate r i n g systems and no

interaction is observed between the t w o r i n g systems grouped previously by the R O E s Y
spectrum.
si
F i g u r e 4.3g: H S Q C spectrum o f 236.
99
The H S Q C spectrum assigned the carbons to w h i c h each o f the five aromatics protons are
attached, and identified those carbons not bearing protons.
(PP4
F i g u r e 4.3: H M B C spectrum o f 236.
The H M B C spectrum identified w h i c h carbons the five aromatic protons couple

through 2 or 3 bonds.
with
Quaternary carbons can sometimes be observed by this technique.
Taken together, all the data points unambiguously to structure 236.
4.4
2,3-Dichloro-4-pyridylboronic Acid
The D o M methodology used for 2 , 6 - d i c h l o r O " 3 - p y n d y l b o r o n i c acid (230) was applied

to 2,3-dichloropyridine (237). Reaction o f 237 [ L D A (1.1 equiv.) in T H F ] f o l l o w e d by the
addition o f triisopropylborate and an aqueous w o r k u p gave 238 in o n l y 4 0 % y i e l d on 2.5 15 g scales o f product.
U s i n g D P A and - B u L i , instead o f commercial L D A , gave a
disappointing 30 % y i e l d . L i t h i a t i o n o f 237 c o u l d occur at both C ( 4 ) and C ( 6 ) and using 2

equivalents o f L D A increased the y i e l d o f 238 to 5 6 % (Scheme 4.4a) suggesting that the
lower than expected y i e l d was, indeed, at least partly due to both positions l i t h i a t i n g .
If
lithiation had occurred at C 6 the derived boronic acid w o u l d deboronate, so the 5 6 % y i e l d

suggests lithiation at C 4 is preferred.
Interestingly, when H C l was used in the aqueous
100
w o r k u p instead o f H B r , 238 deboronated and o n l y starting material (237) was obtained,

even when the aqueous w o r k up was carried out at 0 . A n unoptimised scale-up o f the
synthesis detailed in Scheme 4.4a gave a 70 g batch o f pure 253, in a lower y i e l d o f 2 2 %
after recrystallisation f r o m toluene.
B(0H)2
V ^ '
Scheme
4.4a:
(i). (), ()
^ " ^ '
N^CI
"^N^CI
237
238
2,3-DichIoro-4-pyridy!boronic
acid
(238)
synthesis.
Reagents
and
Conditions: (i) 2.0 equiv. L D A , T H F , -10 , m i n , ( i i ) 2 , 3 - d i c h l o r o p y n d i n e , -78 , 3

( i i i ) T P B and aqueous w o r k - u p .
Crystals o f 238 were g r o w n over a number o f months f r o m a water/ethanol m i x t u r e

and the structure was solved b y Dr. A Batsanov. The X - r a y crystal structure o f 238 is
shown in figure 4.4a.
i ^ . . . . . , - o ( 2 i
Odi
Cl(21
N(11
ICIfl)
F i g u r e 4.4a: X - r a y crystal structure o f 238. Dashed lines are H-bonds.
101
Similar to the structures o f 40 23 and 230 the free boronic acid was observed and not the
anhydride. Extensive intermolecular hydrogen bonding is present. N o intermolecular dimer
f o r m a t i o n between t w o boronic acid moieties was observed.
Cross-coupling reactions o f 238 w i t h 147, 148, 1 and 239 under our standard
conditions [0()22, dioxane, r e f l u x ] yielded products 240-242, respectively.
the
disappointing
yields
of
the
desired
coupling
products,
other
Due to
conditions
were
investigated; the results are collated in Table 4.4a.
T a b l e 4.4a.
Entry
238 + R - X
Boronic
a-f
R-X
Acid
240-242
Product
Isolated
y i e l d (%)
2
3
Conditions
238
34
48
54
54
56
57
NyNH2
238
42
Br
148
241

1=41
238
l X = Br
239 = 50
239 = I
242
T a b l e 4.4a:
Reagents and conditions:
Pd(PPh3)2C2, 1,4-dioxane, N a j C O j (1 M ) , r e f l u x , 65 h, (b) 1()22, ',
(a)
1,4-
102
dioxane, N a z C O j (1 M ) , r e f l u x , 65 h (c) ()22, ', 1,4-dioxane, CS2CO3 (1 M ) ,

reflux, 65 h (d) P d ( 0 A c ) 2 , 'BU3P, l,4dioxane, Na2C03 (1 M ) , r e f l u x , 65 h, (e) P d ( 0 A c ) 2 ,
'BU3P, 1,4-dioxane, CS2CO3 (1 M ) , reflux, 65 h (f) 1()22, 1,4-dioxane, N a j C O j (1
M) reflux, 8 h.
Similar trends can be seen as previously described for reactions o f

p y r i d y l b o r o n i c acid 230 (Table 4.3a).
2,6-dichloro-3-
The addition o f a ligand to the standard reaction
conditions increased the y i e l d o f 240 f r o m 34 to 5 4 % (Entry 1 and 3). E n t r y 8 shows that

using iodoaryl c o u p l i n g partners increased the y i e l d slightly compared to the bromo
analogue.
4.5
2-Chloro-5-pyrimidylboronic Acid
2 - C h l o r o - 5 - p y r i m i d y l b o r o n i c acid (244) was an attractive target for comparison w i t h

2 2 1 and the d i c h l o r o p y r i d y l b o r o n i c acids (230 and 238).
The initial synthesis o f 244
f o l l o w i n g the route for 2 2 1 produced impure 244. H o w e v e r , the halogen-lithium exchange

o f 243 ( - B u L i in T H F / toluene) in the presence o f triisopropylborate and then an aqueous
w o r k u p gave pure 244 8 5 % y i e l d . A sequential addition method (adding the T P B after
the lithiation) gave 244 in a lower y i e l d o f 15%.
N - ^ ^ ^
(i), ()
N-^BiOHb
ClA
243
Scheme
4.5a:
2-Chloro-5-pyrimidylboronic
244
acid
(244)
synthesis.
Reagents
and
Conditions: (i) - B u L i , T P B , -78 , toluene:THF ( ) aqueous w o r k - u p .
Crystals o f 244 were g r o w n over a t w o months f r o m a water/ethanol m i x t u r e and

the structure was solved by D r . A Batsanov. The X - r a y crystal structure o f 244 is shown in
figure 4.5a.
103
F i g u r e 4.5a: X - r a y crystal structure o f 244. Dashed lines are H-bonds.
S i m i l a r to the structures o f 40, 23 and 230 the free boronic acid was observed and not the
anhydride.
Extensive intermolecular hydrogen b o n d i n g is present but no intermolecular
d i m e r f o r m a t i o n between t w o boronic acid moieties was observed.

Cross-coupling reactions o f 244 w i t h 147 [()22, dioxane, r e f l u x ]
gave
product 245 in only 2 1 % y i e l d . A d d i t i o n o f tributylphosphine increased the y i e l d to 4 7 %

(Table 4.5a; entry 2 ) , so this ligand was also used in the reactions i n entries 3 and 4.
procedures gave novel functionalised heteroaryl-pyrimidines
These
245-247 in moderate and
synthetically-viable yields ( 4 5 - 4 8 % ) .
a-b
T a b l e 4.5a.
Entry
244 + R - X
Boronic
Acid
R-X
245-247
Product
Conditions
Isolated
y i e l d (%)
21
244
147
47
104
245
244
48
148
246
244
45
NHo
NH2
247
T a b l e 4.5a;
Pd(PPh3)2Cl2, 1,4-dioxane, 23
Reagents and conditions: (a)
(1 M ) , r e f l u x , 65 h, (b) ()22, ',
1,4-
dioxane, (1 M ) , r e f l u x , 65 h; for 110a 15 m i n .
D u r i n g the course o f our w o r k Rault et al. published syntheses o f 2,6-dichloro-3p y r i d y l b o r o n i c acid 230, and 2,5-dichloro-4-pyridylboronic acid in 80 and 5 6 % yields,
respectively, also using D o M 61>.*
N o cross-coupling reactions were reported;
hydroxydeboronation in the presence o f hydrogen peroxide yielded 248 (Scheme 4.5b).
-B(OH)2
cr
N ' CI
80% C I - ^ N ^ C I
229
230
99%
C'^N^CI
248
Scheme 4.5b: Recent synthesis o f 230. * Reagents and conditions (a) L D A , T P B , - 80 ,

T H F (b) aq. H2O2, CH2CI2, rt, 20 h.
105
4.6
Conclusion
A range o f novel halo substituted p y r i d y l b o r o n i c acids and a p y r i m i d y l boronic acid have

been synthesized and the syntheses o f 230 and 237 have been scaled up to produce 50 g
quantities.
These compounds serve as versatile reagents for the production o f h i g h l y -
functionalised a r y l / h e t e r o a r y l - p y r i d y l / p y r i m i d y l
libraries.
A n added advantage o f these
reactions is that the products obtained are able to undergo further functionalisation.
For
instance, the compounds that contain a amine group can be employed in a diazotisation
reaction
A n example s h o w i n g the possibility o f such a reaction was highlighted in the
previous chapter. Furthermore the compounds that contain a chloro can be employed as the
halo substrate for
ftirther
cross-coupling reactions, w h i c h can then lead to numerous
possibilities for fijrther functionalisation.
106
Synthesis and A p p l i c a t i o n f N o v e l H a l o p y r i d y l b o r o n i c A c i d s
T. G allagher and A . Sutherland, J. Org. Chem., 2 0 0 3 , 68, 3352.

2002,
58, 2885.
2002,
58, 3323.
G. Queguiner and F. M o n g i n , Tetrahedron,
2 0 0 1 , 57, 4059.
R. K. A r v e l a and N . E. Leadbeater, Org. Lett,
2005, 7 , 2 1 0 1 .
N . M . A l i , A . M c K i l l o p , M . B. M i t c h e l l , R. A . Rebelo, and p. J. W a l l b a n k ,
Tetrahedron,
1992, 48, 8117.
c. B a i l l i e , L. Z h a n g , and J. X i a o , J. Org. Chem., 2004, 69, 7779.

8
T . Itoh and T. Mase, Tetrahedron
B. G o n g , F. H o n g , c. K o h m , . Jenkins, J. T u l i n s k y , R. Bhatt, p. de V r i e s , J.
Singer, and P. K l e i n , Bioorg.
10
Lett., 2005, 46, 3573.

w.
Med. Chem. Lett., 2 0 0 4 , 14, 2303.
P. R. Parry, c, W a n g , A . . Batsanov, M . R. B r y c e , and B. Tarbit, J. Org.
Chem.,
2002, 67, 7 5 4 1 .
P. R. Parry, M . R. B r y c e , and B. Tarbit, Synthesis, 2 0 0 3 , 1035.
12
G. c. F u , A . F. L i t t k e , and c. D a i , J. Am. Chem. Soc, 2000, 122, 4020.
13
G. . F u and . F. L i t t k e , Angew.
14
J.-C. Lancelot, A . B o u i l l o n , A . . V o i s i n , and s . Rault, Tetrahedron,
Chem. Int. Ed., 1998, 37, 3387.

2005, 6 1 ,
1417.
107
Chapter 5
Experimental Procedures
5.0
T h i s chapter describes the experimental procedures and analytical data for each o f the novel
compounds presented in this thesis. This chapter also includes the experimental procedures
for compounds w h i c h are already k n o w n in the literature that were used during the course
o f this w o r k .
5.1
General Methods
A l l reactions that required inert or dry atmosphere were carried out under a blanket
o f argon, w h i c h was dried by passage through a c o l u m n o f phosphorus pentoxide.
All
reagents employed were o f standard reagent grade and purchased f r o m A l d r i c h , Lancaster,

or F l u o r o c h e m , or supplied by Seal Sands Chemicals, and were used as supplied unless
otherwise stated. The f o l l o w i n g solvents were dried and distilled immediately prior to use:
diethyl ether and toluene, over sodium metal; T H F , over potassium metal; D M F , dried by
standing over 4 molecular sieves for at least 48 h. A l l other solvents in this w o r k were
used w i t h o u t prior p u r i f i c a t i o n . C o l u m n chromatography was carried out o n silica (40-60
mesh).
N M R spectra were recorded on a Varian U n i t y 300 M H z , a Varian V X R 400
M H z or a Varian Inova 500 spectrometer at 500 M H z using deuteriated solvent as lock.
Chemical shifts are quoted i n p p m , relative to tetramethylsilane ( T M S ) , using T M S or the
residual solvent as internal reference,
N M R spectra were recorded using broad band
decoupling on a V a r i a n U n i t y 2 0 0 , 250 or 300 spectrometer at 50, 63 or 75
MHz,
respectively, or a Varian V X R 400 or V a r i a n Inova 500 spectrometer at 100 M H z and 125

M H z , respectively.
T h e f o l l o w i n g abbreviations are used in l i s t i n g N M R spectra: =
singlet, d = doublet, = triplet, q = quartet, br broad.

Electron Impact ( E I ) mass spectra were recorded on a Micromass
Autospec
spectrometer operating at 70 e V w i t h the ionisation mode as indicated. Electro Spray (ES)

mass spectra were recorded on a M i c r o m a s s L C T mass spectrometer.
108
Experimental
Procedures
Elemental anaiyses were obtained o n an Exeter A n a l y t i c a l Inc. C E - 4 4 0 elemental

analyser.
M e l t i n g points were recorded on a Stuart Scientific S M P 3 m e l t i n g point apparatus
and are uncorrected.
5.1.1
G e n e r a l P r o c e d u r e f o r aU t h e C r o s s - C o u p l i n g R e a c t i o n s
T h e boronic acid (1.0 equiv.) the arylhalide (0.9 equiv.) and ()22 (ca. 5 m o l % )
were sequentially added to degassed 1,4-dioxane and the m i x t u r e was stirred at 20 for 30
min. Degassed aqueous Na2C03 solution (1 M 3.0 equiv.) was added and the reaction
m i x t u r e was heated under argon at r e f l u x for the t i m e specified. The solvent was removed
in vacuo
then ethyl acetate was added and the organic layer was washed w i t h brine,
separated, and dried over M g S 0 4 , The m i x t u r e was p u r i f i e d by chromatography on a silica

gel c o l u m n . O n some occasions additional recrystallisation was necessary to remove traces
of
30 w h i c h co-eluted w i t h the desired
5.2
product.
Experimental Procedures of Chapter 2
2 - M e t h o x y - 5 - p y r i d y I b o r o n i c a c i d (40)
Ql^g
I
2
T o a solution o f 5 - b r o m o - 2 - m e t h o x y p y r i d i n e (100) (100 cm^, 773

m m o l ) in anhydrous ether (500 c m ) at 78 c, - B u L i (1.6 M in
3
hexane, 580 c m , 928 m m o l ) was added dropwise. The reaction was
stirred for 1 h at 78 then triisopropylborate (360 cm 1.56 m o l ) was added q u i c k l y .

3
T h e reaction m i x t u r e was stirred at - 7 8 f o r another 1 h then quenched w i t h water (1.0

dm^) and a l l o w e d to w a r m to r o o m temperature w i t h stirring overnight.
The organic
solvent was evaporated vacuo and the remaining aqueous layer was taken to p H 10 ( w i t h
5 % N a O H ) , and was washed w i t h d i e t h y l ether (3
400
crrH) to remove unreacted starting
material. The aqueous layer was then acidified to p H 4 ( w i t h 4 8 % H B r ) to precipitate 40 as

w h i t e solid (70.0 g 65 % ) , analytically pure and spectroscopically identical w i t h the sample
described previously.^
109
2 - M e t h o x y - 3 - p y r i d y l b o r o n i c a c i d (43)
g^Q_j
T o a solution o f diisopropylamine (142 c m \ 1.01 m o l ) in anhydrous T H F
^^
(1.0 d m ) at 0 , - B u L i (2.5 M in hexane, 424 c m , 1.06 m o l ) was added
v^N
dropwise. The reaction was stirred for 1 h at 0 then 2 - m e t h o x y p y r i d i n e
(101) (96 cm^, 920 m m o l ) in anhydrous T H F (500 cm^) was added dropwise. The reaction
was stirred for 1 h at 0 then triisopropylborate (254 c m , 1.10 m o l ) was added s l o w l y .
3
The reaction m i x t u r e was stirred at 0 for another 0.5 h then quenched w i t h water (500
cm^) and a l l o w e d to w a r m to r o o m temperature w i t h stirring overnight.
The organic
solvent was evaporated in vacuo and the remaining aqueous layer was adjusted t o p H 10
( w i t h 5 % N a O H : on some occasions this addition o f N a O H was not necessary) and then
filtered. The filtrate was washed w i t h d i e t h y l ether (3 X
500 cm^) to remove unreacted
starting material. The aqueous layer was then acidified to p H 6 ( w i t h 4 8 % H B r ) to

precipitate 43 as w h i t e solid (80.7 g, 58 % ) , analytically pure and spectroscopically
identical w i t h the sample described previously.^
2 - E t h o x y - 3 - p y r i d y l b o r o n i c a c i d (103)
B(OH)
P r o c e d u r e A : T o a solution o f diisopropylamine (5.9 c m , 41.69 m m o l ) i n
.^''-'^^*
anhydrous T H F (50 c m ) a t - 1 0 , - B u L i (2.5 M in hexane, 17.4 c m , 43.59

3
m m o l ) was added dropwise. The reaction was stirred for 0.5 h at -10 then
cooled to -50 .
2 - E t h o x y p y r i d i n e (102) (4.5 c m , 37.9 m m o l ) in anhydrous T H F (10

3
cm^) was added dropwise. The reaction was stirred for 1 h at -50 then triisopropylborate
(10.5 c m , 45.5 m m o l ) was added s l o w l y .
3
The reaction m i x t u r e was stirred at -50 for
another 1 h then a l l o w e d to w a r m to -10 and quenched w i t h water (50 cm^). The

reaction was left at r o o m temperature w i t h stirring overnight.
The organic solvent was
evaporated in vacuo and the remaining aqueous layer, p H 10 was filtered. The filtrate was
washed w i t h diethyl ether (2 X 50 cm^). The aqueous layer was then acidified to p H 4 ( w i t h
4 8 % H B r ) to give 103 as a white solid (4.4 g, 7 0 % ) , m p 103.0-103.8 ; ' H N M R (400
M H z , acetone-de) 8 . 1 6 ( 1 , d d , J = 2.0 H z , J=
H z ) , 7.83 ( 2 H , ), 6.94 ( I H , d d , J = 4.8 H z , J=
4.8 H z ) , 7.87 (1H d d , J = 2 . 0 H z , J=
7.0
7.0 H z ) , 4.33 (2 q, y = 6 . 8 H z ) , 1.31 ( 3 H ,
110
, J = 6.8 H z ) ; ' C N M R (100 M H z , acetone-de) 166.0, 148.4, 144.8, 116.9, 61.2, 14.5;
3
MS (EI ) m/z 166.9 (+ 100%). A n a l . Caled, for C7H10BNO3: , 50.35; , 6.04; , 8.39.
Found: , 50.32; , 5.92; , 8.34%.
P r o c e d u r e : F o l l o w i n g procedure A , diisopropylamine (96.7 g, 0.96 m o l ) in anhydrous

T H F (500 cm^), - B u L i (2.5 M in hexane, 400 c m , 1.00 m o l ) , 2-ethoxypyridine (102)
3
(107 g, 0.87 m o l ) and triisopropylborate (196 g, 1.04 m o l ) were used.
A f t e r quenching
w i t h water the reaction was left at room temperature w i t h stirring overnight.

layer was discarded and the aqueous layer, p H 10, was then
filtered.
The organic
T h e filtrate was
washed w i t h diethyl ether (200 c m ) until no starting material was detected in the ether
3
washings by tic. The aqueous layer was then acidified to p H 7 ( w i t h 4 8 % H B r ) to give 103
as an analytically-pure o f f - w h i t e solid (69.7 g, 48 % ) spectroscopically identical w i t h the
sample from Procedure A .
2 , 6 - D i m e t h o x y - 3 - p y r i d y l b o r o n i c a c i d (146)
To
\
IV
a solution
o f diisopropylamine
(6.5
cm^, 46.45
mmol)
in
anhydrous T H F (100 c m at - 10 - B u L i (2.5 M in hexane, 20.0
c m , 50 m m o l ) was added dropwise. The reaction was stirred for 0.5

3
h at 0 and was then cooled t o -78 before 2 , 6 - d i m e t h o x y p y r i d i n e (144) (56 c m ^ 42

mmol)
was
added dropwise.
The
reaction
was
stirred
for
3 h at
-78
then
triisopropylborate (6.2 cm^, 54 m m o l ) was added s l o w l y . The reaction m i x t u r e was stirred

at -78 for another 1 h, then quenched w i t h water (100 cm^) and allowed to w a r m to
r o o m temperature w i t h stirring overnight.
and then
filtered.
The
filtrate
The organic solvent was evaporated in vacuo
was washed w i t h diethyl ether (3 X 50 c m ) to remove

3
unreacted starting material. The aqueous layer was then acidified to p H 6 ( w i t h 4 8 % H B r )

t o precipitate 146 as w h i t e solid (6.3 g, 82 %) m p 108.2-109.1 ; N M R (400 M H z ,
D M S 0 - d 6 ) 7.86 ( H , d, J =
3.86 (,
8.0 H z ) , 7.53 (2H ), 6.36 ( H , d, J =
8.0 H z ) , 3.89 ( 3 H , ),
s); " N M R (100 M H z , D M S O - d ) 166.85, 164.65, 148.60, 101.62, 53.67,
111
53.57. M S (EI) m/z 183.0 (+, 100%). A n a l . Caled, f o r C7H10BNO4: , 45.95; , 5.51; N,
7.66. F o u n d : , 45.46; , 5.34; N , 7.79%.
Procedure
anhydrous
: F o l l o w i n g procedure A , diisopropylamine
T H F (500 c m ^ ) , - B u L i
(2.5 M
(106.3
cm^, 0.76 m o l ) in
hexane, 312 c m , 0.78 m o l ) , 2,63
d i m e t h o x y p y r i d i n e (144) (107 g , 0.69 m o l ) and triisopropylborate (196 g, 0.86 m o l ) were

added at - 1 0 . T h e filtrate was washed w i t h diethyl ether (250 c m ) u n t i l no starting
3
material was detected in the ether washings by t i c . The aqueous layer was then acidified to
p H 6 ( w i t h 4 8 % H B r ) to give 146 as an analytically-pure o f f - w h i t e solid (57.2 g , 45 % )
spectroscopically identical w i t h the sample f r o m Procedure A .
2 , 3 - D i m e t h o x y - 4 - p y r i d y I b o r o n i c a c i d (158)
T o a solution o f diisopropylamine (2.6 c m \ 18.5 m m o l ) in anhydrous T H F
OMe
(50 c m ) at - 1 0 , - B u L i (2.5 M in hexane, 8 c m , 20 m m o l ) was added

dropwise. The reaction was stirred f o r 0.5 h at 0 and was then cooled t o 3
78 before 2 , 3 - d i m e t h o x y p y r i d i n e ( 1 5 3 ) (2 c m ^ 16.8 m m o l ) i n anhydrous

T H F (10 cm^) was added dropwise.
The reaction was stirred f o r 3 h at -78 then
t r i m e t h y l borate (2.5 c m , 21.5 m m o l ) was added s l o w l y . T h e reaction m i x t u r e was stirred

3
at -78 f o r another 1 h, then quenched w i t h water (50 cm^) and allowed to w a r m to r o o m

temperature w i t h stirring overnight. The organic solvent was evaporated vacuo and then
filtered. The filtrate was washed w i t h diethyl ether (2 X 50 c m ) to remove unreacted
3
starting material. T h e aqueous layer was then acidified to p H 2 ( w i t h 4 8 % H B r ) to

precipitate 158 as w h i t e solid (0.3 g, 12 %) m p 125.8-126.5 ; ' H N M R (400 M H z ,
D M S O - d e ) 7.85 ( I H , d , J=
8.0 H z ) , 7.54 (2 ), 6.35 ( H , d, J = 8.0 H z ) , 3.89 ( 3 H , s),
3.85 ( 3 H , ); ' C N M R (100 M H z , D M S O - d e ) 166.48, 164.25, 148.15, 101.28, 53.19,

3
53.12. M S (ES+) m/z 182.0 (+, 100%). A n a l . Caled, f o r C7H10BNO4: , 45.95; , 5 . 5 1 ;

, 7.66. F o u n d : , 45.96; , 5.07; N 6.60%.
112
5-(2-Ethoxy-3-pyridyl)-2-methoxypyrimidine ( )
Boronic

N
N'
OB
acid
103
(284
mg,
1.7
mmol),
5-bromo-2-
m e t h o x y p y r i m i d i n e (104) (283 m g , 1.5 m m o l ) , 1()22 (59.6

m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and NaaCOj (1 M , 4 c m ) ;
3
reaction t i m e 24 h; eluent EtOAc:hexane (1:2 v / v ) , gave 113 as a
w h i t e solid (284 m g , 8 2 % ) m p 70.9-71.6 ; N M R (400 M H z , acetone-de) 8.79 ( 2 ,

), 8.17 ( H , d d , J = 1.6 H z , J = 4.8 H z ) , 7.82 ( H , dd, = 1.6 H z , J = 7.2 H z ) , 7.06 ( H ,
dd, J = 4.8 H z , J = 7.2 H z ) , 4.42 ( 2 , q, J = 7.2 H z ) , 3.98 ( 3 H , s), 1.34 ( , , J = 7.2 H z ) ;
' C N M R (100 M H z , C D C b ) 164.70, 160.42, 158.80, 146.80, 137.38, 124.10, 117.69,
3
116.91, 9 6 . 1 1 , 61.99, 54.82, 14.57; M S ( E I ) m/z 231.1 (+ 100%). A n a l . Caled, for

C12H13N3O2: , 62.33; H , 5.67; N, 18.17. Found: , 62.42; , 5.74; N , 17.93%.
5 - ( 2 - E t h o x y - 3 - p y r i d y l ) p y r i i n i d i n e (114)
N
B o r o n i c acid 103 (284 m g , 1.7 m m o l ) , 5 - b r o m o p y r i m i d i n e (105) (239 m g ,

j
1.5 m m o l ) , ()22 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane ( 1 c m ) and

3
NaaCOa (1 M , 4 c m ) ; reaction t i m e 24 h; eluent EtOAc:hexane (1:1 v / v ) ,

3
gave 114 as a w h i t e solid (271 m g , 9 0 % ) m p 119.0-119.8 ;
NMR
(400 M H z , acetone-d) 9.10 ( , ), 9.01 (2 s), 8.23 ( H , d d , y = 1.6 H z , J = 4.8 H z ) ,

7.89 ( H , d d , J = 1.6 H z , J= 8.0 H z ) , 7.11 ( H , d d , J = 5.2 H z , J= 7.6 H z ) , 4.43 ( 2 , q, J =
7.2 H z ) , 1.34 ( , , = 6.8 H z ) ; 1 C N M R (100 M H z , CDCI3) 160.5, 157.3, 156.4,
3
147.7, 138.0, 130.6, 117.5, 117.0, 96.2, 62.2, 14.6; M S ( E I ) m/z 201.1 (+ 100%). A n a l .
Caled, for C i H , 1N3O: , 65.66; , 5 . 5 1 ; , 20.88. Found: , 65.46; , 5 . 5 1 ; N , 20.63%.
2 - ( 2 - E t h o x y - 3 - p y r i d y l ) p y r i n i i d i n e (115)
B o r o n i c acid 103 (284 m g , 1.7 m m o l ) , 2-bromopyrmdine (106) (239 m g ,
1.5 m m o l ) , ()22 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and
3
N,
OEt
^ (1 M , 4 c m ) ; reaction t i m e 24 h; eluent EtOAc:hexane (1:2 v / v ) ,

3
gave 115 as a colourless viscous o i l (268 m g , 8 9 % ) ; ' H N M R (200 M H z , CDCI3) 8.68
113
Experimental
( 2 , d,J=
Procedures
4.8 H z ) , 8.11 ( , d, J = 4.8 H z ) , 7.94 ( H , d, J = 7 . 3 H z ) , 7.03 ( H , , J = 4 . 8
H z ) , 6.83 ( I H , dd, J = 5.1 H z , J=
7.2 H z ) , 4.37 ( 2 H , q, J = 7.0 H z ) , 1.23 ( 3 H , \, J = 7.0
H z ) ; ' C N M R (100 M H z , CDCI3) 164.5, 161.1, 156.8 ( 2 C ) , 148.0, 140.1, 122.3, 118.7,
116.3, 62.0 14.2; H R M S ( E l ) caled for C i H i i N a O ( M " ) 2 0 1 . 0 9 1 2 1 , found 201.09133.
3
2 ' - E t h o x y - 5 - n i t r o - [ 3 , 3 ' ] b i p y r i d i n y l - 6 - y l a m i n e (116)

Boronic
,NH2
^
acid
103
(284
mg,
1.7
mmol),
5-bromo-2-amino-3-
nitropyridine (107) (327 m g , 1.5 m m o l ) , ()22 (59.6 m g , 0.085

m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e
3
24 h; eluent E t O A c , gave 116 as a yel l o w solid (289 m g , 7 4 % ) m p

193.0-193.9
( ' H N M R (400 M H z , D M S O - d ) 8.65 ( 2 , d d , J =
2.0 H z , J=
16.0 H z ) , 8.15 ( H , dd, J = 2 . 0 H z , J=
4.8 H z ) , 8.03 ( 2 , br s, N H 2 ) , 7.90 ( H ,
dd, J = 2.0 Hz, J = 4 . 8 H z ) , 7.07 ( I H , dd, J = 4 . 8 H z , J=
7.6 H z ) , 4.37 ( 2 H , ,=
7.2 H z ) ,
1.31 ( 3 H , t, J = 7.2 H z ) ; ' C N M R (100 M H z , D M S O - d ) 159.7, 156.0, 152.7, 146.0,

3
137.9, 134.2, 126.2, 120.5, 118.7, 117.4, 61.5, 14.3; M S ( E l ) m/z 260.0 (+,
100%). A n a l .
Caled, f o r 2,240: , 55.38; , 4.65; , 21.53. Found: , 55.12; , 4 . 5 8 ; , . 3 6 % .
5 - ( 2 - E t h o x y p y r i d i n - 3 - y l ) - 6 - m e t h y l p y r i d i n - 2 - a m i n e (117)
^NH2
Bofoi'c
acid
103
(284
mg,
1.7
mmol),
6-amino-3-bromo-2-
m e t h y l p y r i d i n e (108) (281 m g , 1.5 m m o l ) , ()22 (59.6 m g ,

0.085 m m o l ) ,
1,4-dioxane
(10 c m ) and (1 M , 4 c m ) ;
3
reaction t i m e 24 h; eluent E t O A c , gave 117 as a crystalline solid (258
mg, 7 5 % ) mp 138.6-139.0 ; N M R (400 M H z , DMSO-de) 8.10 ( H , d d , y = 2.0 H z ,

J= 4.8 H z ) , 7.47 ( H , d d , J = 2.0 Uz,J=
7.2 H z ) , 7.12 ( H , d, J=
8.4 H z ) , 6.99 ( H , dd J
= 4.8 H z , J = 7.2 H z ) , 6.30 ( H , d, J = 8.4 H z ) , 5.88 ( 2 , br s N H 2 ) , 4.29 ( 2 H , , J = 7.2

H z ) , 2.05 ( ), 1.22 ( , X,J=
7.2 H z ) ; ' C N M R (100 M H z , D M S O - d ) 160.2, 158.5,

3
153.6, 145.3, 139.6, 139.0, 123.3, 119.0, 116.8, 104.9, 60.9, 22.3, 14.5; M S ( E I ) m/z 229.1
14
(+, 100%). A n a l . Caled, for : , 68.10; 6.59; N , 18.23. Found: , 67.85; ,

6.54; N , 17.96%.
7 V - ( 2 ' - E t h o x y - 2 - m e t h y l - [ 3 , 3 ' ] b i p y r i d i n y l - 6 - y l ) - a c e t a m i d e (118)

N
If
Me
pyridin-2-yl)-acetamide
\
,
^ ^ " " * ^ acid 103 (284 m g , 1.7 m

mm
mooll)),, A^-(5-bromo-6-methyl(109)'
(334
mg,
1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane

1,4
(10 c m ) and
3
(1 M , 4 c m ) ; reaction t i m e 24 h; e e n t E t O A c , gave 118
OEt
as a crystalline solid (317 m g , 7 8 % ) m p 147.7-148.6 ; N M R (400 M H z , D M S O - d )

10.50 ( H , br , NH) 8.17 ( H , ,J=
( H , d d , J = 2 . 0 H z , J=
H z ) , 4.31 ( 2 H ,
q, J =
2.0 H z , J = 4 . 8 H z ) , 7.94 ( H , d, J=
7.2 H z ) , 7.51 ( I H , d,J=
8.4 H z ) , 7.57
8.4 H z ) , 7.04 ( I H , d d , J = 4.8 H z , y = 7.2
7.2 H z ) , 2.20 (3H ), 2.08 ( , ), 1.20 ( , t,J=
7.2 H z ) ; ' C N M R
3
(100 M H z , D M S O - d e ) 169.2, 160.0, 154.3, 150.7, 146.3, ! 3 9 . 7 , 139.6, 126.7, 122.0,

116.9, 110.4, 6 1 . 1 , 23.3, 2 2 . 1 , 14.4; M S ( E I ) m/z 271.0 (M+ 100%). A n a l . Caled, f o r
C i s H n N j O a : , 66.40; , 6.32; , 15.49. Found: , 66.18; , 6.25; , 1 5 . 3 1 % .
M e t h y l 2 - a m i n o - 5 - ( 2 - e t h o x y - 3 - p y r i d y l ) - 3 - p y r a z i n o a t e (119)
B o r o n i c acid 103 (284 m g , 1.7 m m o l ) , 3-amino-6-bromopyrazine-2carboxylic
^^^
"^
OEt
acid
methyl
ester
Pd(PPh3)2C2 (59.6 m g , 0.085
(llOa)^
mmol),
(345
mg,
1,4-dioxane
1.5
mmol),
(10 c m )
3
and
(1 M , 4 c m ) ; reaction time 16 h at 20 ; eluent E t O A c , gave

3
119 as a yellow solid (440 mg, 9 0 % ) mp 156.6-157.0 ;
NMR
( 4 0 0 M H z , D M S O - d e ) 8.89 ( I H , ), 8.17 ( , d d , J = 2 . 0 H z , J = 4 . 8 H z ) , 8.12 ( H , d d , J

= 2.0 H z , J= 7.6 H z ) , 7.46 (2 br , NH2) 7.11 ( H , ,=
4.8 H z , J= 7.6 H z ) , 4.41 ( 2 H ,
7.2 H z ) , 3.87 ( 3 H , ), 1.35 ( , , J = 7.2 H z ) ' C N M R (100 M H z , D M S O - d )

3
166.3, 159.8, 154.3, 148.0, 146.5, 138.0, 136.7, 122.4, 119.3, 117.4, 61.6, 52.2, 14.4; M S
(EI) m/z 274.0
(+, 100%).
A n a l . Caled, for ,440:
56.93; 5.14; N 20.43.
F o u n d : , 56.63; , 4.97; N 2 0 . 3 3 % .
115
W h e n the reaction was carried out at reflux for 15 m i n , product 119 (321 m g , 7 8 % yield)
was obtained.
A comparable reaction w i t h 3-amino-6-chloropyrazine-2-carboxylic
acid m e t h y l ester
1 1 0 b 15 m i n at 60 , gave 119 in 6 2 % yield.

3
3 - ( 2 - A m i n o - 4 - t r i f l u o r o m e t h y l b e n z e n e ) - 2 - e t h o x y p y r i d i n e (120)
Boronic
acid
103
(284
mg,
1.7
mmol),
2-bromo-5-
3 (trifluoromethyOaniline (111) (360 mg, 1.5 mmol), 1()22 (59.6
2 \
mg, 0.085 m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4 c m ) ;

3
OEt
reaction t i m e 24 h; eluent D C M , gave 120 as a clear b r o w n o i l (300
mg, 7 1 % ) ; N M R (400 M H z , acetone-d) 8.27 ( H , d d , J = 2.0 H z , J = 3.2 H z ) , 7.70

( I H , dd, J = 2 . 0 H z , J = 5.2 H z ) , 7.26 ( H , d, J = 7.8 H z ) , 7.20 ( H , ), 7.12 ( H , d d , J =
2.0 H z , J= 4.8 H z ) , 7.04 ( H , d , J = 7.8 H z ) , 4.90 ( 2 H , t, ), 4.48 (2H q , J = 7 . 2 H z ) , 1.36
( 3 H , t, J= 7.2 H z ) ; ' C N M R (100 M H z , acetone-d) 166.3, 147.5, 140.8, 132.4, 130.9 ( q ,
3
= 3 2 H z ) , 125.5 (q, J = 2 7 0 H z ) , 122.2, 117.8, 113.5, 112.2, 62.2, 14.8; H R M S ( E I ) caled

for C M H I S F N S O ( M + ) 282.09800, found 282.09820.
4 - ( 2 - e t h o x y p y r i d i n - 3 - y I ) - 3 - ( t r i f l u o r o m e t h y l ) a n i l i n e (121)
NH 2
Boronic
acid
103
(trifluoromethyl)aniline
(284
mg,
1.7
(112) (360 m g ,
mmol),
4-bromo-3-
1.5 m m o l ) , 1()22
(59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4

3
cm^); reaction t i m e 24 h; eluent D C M , gave 121 as a clear o i l (288

m g , 6 8 % ) ; N M R (400 M H z , acetone-d) 8.23 (2 m ) , 7.55 ( 2 , d d , J = 2 . 0 H z , J =
7.2 H z ) , 7.18 ( H , d , J = 2 . 0 H z ) , 5.27 ( 2 , ), 4.69 ( 2 , , J = 7 . 2 H z ) , 1.30 ( , , J = 7 . 2
H z ) ; ' C N M R (100 M H z , acetone-d) 161.6, 148.9, 146.6, 140.0, 133.5, 129.5 (q, J =
3
116
29.2 H z ) , 126.5, 123.8 (,J=

250 H z ) , 120.7, 117.4, 116.5, 111.7, 61.6, 14.5; H R M S ( E I )
calcd for C14H13F3N2O ( M 282.09800, found 282.09812.
M e t h y l 5 - ( 2 - e t h o x y p y r i d i n - 3 - y l ) p y r i d i n e - 3 - c a r b o x y l a t e (141)
J^N^
B o r o n i c acid 103 (284 m g , 1.7 m m o l ) , methyl 5-bromopyridine-3carboxylate (139) (324 m g , 1.5 m m o l ) , 1()22 (59.6 m g ,
0.085 m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4 c m ) ;
OEt
reaction t i m e 15 m i n ; eluent E t O A c gave 141 as a y e l l o w solid (260

m g , 6 7 % ) m p 69.2-70.3 ; N M R (400 M H z , D M S O - d ) 9.05 ( H , d, J = 2.0 H z ) ,
8.99 ( H , d , J = 2.0 H z ) , 8.42 ( H , t, J = 2.0 H z ) , 8.26 ( H , d d , J = 4.8 H z , J = 2 . 0 H z ) ,
7.92 ( H , d d , = 7.2 H z , J= 2.0 H z ) , 7.15 ( I H , d d , J = 4.8 H z , J = 7 . 2 H z ) , 4.37 ( 2 H , q , y =
7.2 H z ) , 3.90 ( 3 H , ), 1.34 ( 3 H , , J = 7.2 H z ) ; ' C N M R (100 M H z , D M S O - d e ) 164.56,
3
160.16, 153.28, 148.63, 147.13, 139.25, 136.60, 131.97, 125.40, 119.30, 117.67, 61.26,
53.49, 14.01; M S ( E l ) m/z 258.0 (M+ 100%). A n a l . Calcd. for C14H14N2O3: , 6 5 . 1 1 ;
5.46; , 10.85. Found: , 64.96; , 5.36; , 11.10%.
M e t h y l 3 - ( 2 - m e t h o x y p y r i d i n - 3 - y l ) b e n z o a t e (142)
B o r o n i c acid 43 (260 m g , 1.7 m m o l ) , methyl
3-bromobenzoate
(140) (323 m g , 1.5 m m o l ) , ()22 (59.6 m g , 0.085 m m o l ) ,

1,4-dioxane (10 c m ) and (1 M , 4 c m ) ; reaction time 15
3
N'
m i n ; eluent E t O A c gave 142 as clear y e l l o w crystals (280 m g , 7 7 % )
m p 76.2-77.1 ( f r o m toluene:hexane); ' H N M R (400 M H z , acetone-d) 8.19 ( 2 , m ) ,

7.99 ( H , m ) , 7.84 ( H , m ) , 7.77 ( H , d d , J = 7.2 H z , J = 2 . 0 H z ) , 7.57 ( H , , =
7.09 ( H , ,=
7.2 H z , J = 0.8 H z ) , 3.92 (,
7.2 H z ) ,
), 3.90 ( , s); 1 N M R (100 M H z ,

3
acetone-d6) 166.87, 161.26, 147.04, 139.33, 137.91, 134.33, 130, 9 1 , 130.54, 129.10,
128.87, 123.83, 118.00, 53.49, 52.18; M S ( E S + ) m/z 243.0 (+,
C14H13NO3: ,
69.12; , 5.39;
, 5.76.
Found:
100%). A n a l . Calcd. for
, 68.70; , 5.34; ,
5.47%.
117
M e t h y l 3 - ( 6 - m e t h o x y p y r i d i n - 3 - y l ) b e n z o a t e (143)
^ B o r o n i c
' \
MeO-^N^
acid
40
(260
mg,
1.7
mmol),
methyl
3-
bromobenzoate (140) (323 m g , 1.5 m m o l ) , 1()22 (59.6
m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4

3
cm^); reaction t i m e 15 m i n ; eluent E t O A c gave 143 as a grey solid (289 m g , 7 9 % ) m p 89.290.5 ; N M R (400 M H z , D M S O - d ) 8.49 ( H , d, J = 1.6 H z ) , 8.14 ( H , t, 7 =
H z ) , 8.03 ( H , dd,J=
8.8 H z , J = 1.6 H z ) , 7.93 ( 2 H , m ) , 7.60 ( H , t,J=
1.6
8.0 H z ) , 6.91 ( H ,
d , J = 8.8 H z ) , 3.89 ( 3 H , ), 3.87 (,); ' C N M R (100 M H z , D M S O - d e ) 166.02, 163.33,

3
144.85, 137.63, 131.09, 130.40, 129.47, 128.93, 128.27, 127.91, 126.72, 110.66, 53.26,
52.71; M S (ES+) m/z 244.1
(+, 100%).
A n a l . Caled, for C14H13NO3:
69.12;
, 5.39;
, 5.76. F o u n d : , 69.40; 5.39; N 5.85%.
3 - ( 2 , 6 - D i m e t h o x y p y r i d i n - 3 - y l ) q u i n o l i n e (149)
B o r o n i c acid 146 (311 m g , 1.7 m m o l ) , 3-bromoquinoline
(147)
(312 m g , 1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) , 1,4-
dioxane (10 cm^) and N a i C O s (1 M , 4 cm^); reaction t i m e 24 ;

eluent D C M : E t O A c (1:1 v / v ) gave 149 as an o f f w h i t e solid
(333 m g , 8 3 % ) m p 98.0-98.7 ; ' H N M R (400 M H z , D M S O - d e ) 9.06 ( I H , d, J = 2.0
H z ) , 8.42 ( , d,J=
J=
2.0 H z ) , 8.02 ( H , d, J= 8.0 H z ) , 7.97 ( H , d, J= 8.0 H z ) , 7.91 ( H , t,
8.0 H z ) , 7.73 ( H , t, J=
8.0 H z ) , 7.60 ( H , t, J= 8.0 H z ) , 6.55 ( H , d, J= 8.0 H z ) , 3.94
( , ), 3.91 ( , s); ' C N M R (100 M H z , D M S O - d ) 162.38, 159.15, 151.09, 146.17,

3
142.24, 134.47, 129.50, 129.31, 128.59, 128.15, 127.51, 126.79, 111.68, 101.86, 53.48,
53.46; M S ( E I ) m/z 266.1 ( ^ , 100%). A n a l . Caled, for CÛO , 72.16; , 5.30; ,
10.52. F o u n d : , 71.67; , 5.28; , 10.50%.
M e t h y l 3 - a i n i n o - 6 - ( 2 , 6 - d i m e t h o x y p y r i d i n 3 - y l ) p y r a z i n e - 2 - c a r b o x y l a t e (150)
^
B o r o n i c acid 146 (311 m g , 1.7 m m o l ) , m e t h y l 3-amino-6bromopyrazine-2-carboxylate (110a) (348 m g , 1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m )

3
Meo
118
and (1 M , 4 c m ^ ) ; reaction t i m e 15 m i n ; eluent E t O A c gave 150 as a yel l o w

needles (320 m g , 7 4 % ) m p 191.8-192.3 ( f r o m toluene); N M R (400 M H z , D M S O - d )
8.79 ( H , ), 8.08 ( H , d, J = 8.0 H z ) , 7.36 ( 2 , br s NH2), 6.54 ( I H , d,J= 8.0 H z ) , 3.98
( 3 H , ), 3.91 ( 3 H ), 3.87 ( 3 H ); ' C N M R (100 M H z , D M S O - d ) 166.52, 162.16,
158.90, 154.04, 147.70, 141.16, 137.12, 122.01, 110.96, 102.02, 53.49, 53.49, 52.22; M S
3
( E I ) m/z 291.2 (+, 100%). A n a l . Caled, for C13H 14N4O4: , 53.79; , 4.86; , 19.30.
Found: , 53.64; , 4 . 8 1 ; 19.07%.
5 - ( 2 , 6 - D i m e t h o x y p y r i d i n - 3 - y l ) p y r i m i d i n - 2 - a m i n e (151)
Boronic
2
acid
146
(311
mg,
b r o m o p y r i m i d i n e (148) (261 m g ,
1.7
mmol),
2-amino-5-
1.5 m m o l ) , (1()22
(59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and N a j C O s (1

3
MeO^^N'^ÔMe
M , 4 c m ) ; reaction t i m e 65 h; eluent E t O A c gave 151 as a pale

3
y e l l o w solid (261 m g , 7 5 % ) m p 201.2-202.5 ( f r o m toluene);

D M S O - d ) 8.36 ( 2 ), 7.70 ( H , d,J=
N M R (400 M H z ,
8.0 H z ) , 6.67 ( 2 , s), 6.45 ( H , d,J=
8.0 H z ) ,
3.89 ( 3 H , s), 3.88 ( 3 H ); ' C N M R (100 M H z , D M S O - de) 162.21, 161.57, 158.67,

3
157.22, 140.51, 118.31, 109.84, 101.35, 53.28, 53.24; M S (ES+) m/z 233.1 (+ 100%).
A n a l . Caled, for C , i H i 2 N 4 0 2 : , 56.89; , 5 . 2 1 ; , 24.12. F o u n d : , 57.18; , 5 . 2 ! ; ,
24.08%.
M e t h y l 3 - a n i i n o - 6 - ( 2 , 3 - d i m e t h o x y p y r i d i n - 4 - y l ) p y r a z i n e - 2 - c a r b o x y l a t e (152)
Boronic
acid
158
(311
mg,
bromopyrazine-2-carboxylate
1.7
(110a)
mmol),
(348
methyl
3-amino-6-
mg,
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane
1.5
mmol),
(10 c m ) and
3
(1 M , 4 c m ) ; reaction t i m e 15 m i n ; eluent E t O A c g ave 152

3
'^-ÔMe
as y e l l o w crystals (375 m g , 8 6 % ) m p 195.6-196.1 ( f r o m toluene);
N M R (400 M H z , D M S O - d e ) 8.79 ( H , ), 7.94 ( H , d ) , 7.60
( 2 , br s), 7.31 ( H , d, J = 5.2 H z ) , 3.94 ( 3 H , ), 3.88 ( , s), 3.76 ( ); ' C N M R (100

3
M H z , D M S O - d ) 166.16, 157.89, 154.76, 148.29, 140.58, 140.41,
136.87,
135.89,
119
122.58, 116.55, 60.136, 53.43, 52.26; H R M S ( E I ) caled f o r C,3H i4N404 (+) 290.10150,
found 290.10148.
5.3
Experimental Procedures of Chapter 3
2 - A m i n o - 5 - p y r i m i d y l b o r o n i c acid (221)
T o a solution o f 2 - a m i n o - 5 - b r o m o p y r i m i d i n e
^^^^
H2N
)2
N'
(148) (1.74 g 10
m m o l ) and triisopropylborate (2.9 c m \ 12 m m o l ) in anhydrous T H F

(50 c m ) at 78 , - B u L i (2.5 M in hexane, 10 c m , 25 m m o l ) was
3
added dropwise over 1 h. T h e reaction was stirred f o r 3.5 h at - 7 8 , then a l l o w e d to

w a r m t o - 2 0 and quenched w i t h water (50 ) before being stirred f o r 30 m i n . T h e
organic solvent was evaporated in vacuo
remove inorganic salts.
and the remaining aqueous layer
filtered
to
The filtrate was washed w i t h d i e t h y l ether (3 X 50 cm^) t o remove
unreacted starting material and the aqueous layer filtered to remove inorganic salts. The
filtrate was then acidified to p H 6 ( w i t h 4 8 % H B r ) to precipitate 2 2 1 as a w h i t e solid (640
m g , 46 %) m p > 300 ; N M R (400 M H z , DMSO-de) 8.49 ( 2 , ), 7.96 ( 2 , br s);

' C N M R (100 M H z , D M S O - d ) 164.11, 163.89. A n a l . Caled, f o r C4H6BN3O2: , 34.58;
3
4.35; , 30.25. F o u n d :
, 34.46; , 4.34; , 30.37%.
2 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - p h e n y l a m i n e (173)
H2N B o r o n i c acid 40 (258 m g , 1.7 m m o l ) , 2-bromoaniline (167) (258 m g ,
J
1.5 m m o l ) , ([]22 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10

c m ) and (1 M , 4 c m ) ; reaction t i m e 65 h; eluent E t O A c ,
3
Me
gave 173 as a w h i t e solid (243 m g , 8 1 % ) m p 66.8-67.5 ( f r o m
toluene); ' H N M R (400 M H z , acetone-d) 8.22 ( H , d , J = 2 . 0 H z ) , 7.78 ( H , d d , J = 8.8

H z , J = 2.8 H z ) , 7.13 ( H , m ) , 7.05 ( H , d d , J = 8.2 H z , J = 1.2 H z ) , 6.86 ( 2 , d, J =
8.0Hz), 6.74 ( I H, m ) , 4.50 (2H br , NH2), 3.96 ( , s, 0CH3); 1 C N M R (100 M H z ,

3
acetone-d) 163.75, 147.34, 146.17, 140.14, 130.92, 129.54, 129.26, 123.81, 118.12,
116.12, 111.10, 53.33; M S ( E I ) m/z 200.1 (+,
100%). A n a l . Caled, f o r C12H12N2O: ,
71.98; 6.04; , 13.99. F o u n d : , 71.76; , 6.08; , 13.85%.
120
3- ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - p h e n y I a m i n e (174)
H2
B o r o n i c acid 40 (258 m g , 1.7 m m o l ) , 3-bromoaniIine (168) (158 m g ,

1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10
cm^) and
MeO'^N^
(1 M ,
4 cm^); reaction t i m e
65
h;
eluent
D C M . E t O A c (4:1 v / v ) gave 174 as a b r o w n solid (234 m g , 7 8 % ) m p
65.2-66.3 ( f r o m toluene:hexane); N M R (400 M H z , acetone-de) 8.39 ( H , d, J = 2.4

H z ) , 7.90 ( H , d d , J = 8 . 4 H z , J= 2.4 H z ) , 7.18 ( H , , J = 7 . 6 H z ) , 6.95 ( H , ,J=
2.0 H z ) ,
6.85 ( 2 m ) , 6.71 ( H , m ) , 4.77 ( 2 br s NH2), 3.95 ( , , ) ; ' C N M R (100 M H z ,

3
acetone-d6) 145.54, 145.28, 137.92, 130.18, 121.49, 119.05, 117.99, 115.58, 114.08,
112.94, 111.08, 53.37; M S (EI) m/z 199.1 (+ 100%). A n a l . Caled, for C12H12N2O: ,
71.98; , 6.04; , 13.99. Found: , 71.48; , 6.02; , 13.99%.
4- ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - p h e n y I a m i n e (175)
B o r o n i c acid 40 (258 m g , 1.7 m m o l ) , 4-bromoaniline (169)
'NH
(258 m g , 1.5 m m o l ) , (()22 (59.6 m g , 0.085 m m o l ) , 1,4dioxane (10 cm^) and (1 M , 4 cm^); reaction t i m e 65 h;
MeO'
N'
eluent D C M , gave 175 as a dark b r o w n solid (240 m g , 8 0 % ) ,
m p 100.4-101.6 ; N M R (200 M H z , acetone-de) 8.35 ( H , ,J=
2.6 H z ) 7.87 ( H ,
dd, J = 8.6 H z , J = 2 . 0 H z ) , 7.37 ( 2 , d d , J = 8.9 H z , J = 2.3 H z ) , 6.81 ( , m ) , 4.81 ( 2 ,

br s), 3.94 ( , s, OCH});
' C N M R (100 M H z , acetone-d) 163.34, 148.80, 148.76,

3
144.34, 137.18, 131.15, 127.79, 126.59, 115.42, 115.33, 111.00, 53.26; M S (El) m/z 200.1
(+ 100%). A n a l Caled, for C n H ^ N z O : , 71.98; , 6.04; , 13.99. Found: , 72.10; ,
6.10; 13.79%.
6 ' - M e t h o x y - [ 3 , 3 ' ] b i p y r i d i n y l - 6 - y I a i n i n e (176)
Meo-
Boronic
acid
40
(258
mg,
1.7
mmol),
2-amino-5-
^^^^NH2
b r o m o p y r i d i n e (170) (260 m g ,
(59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 cm^) and N a j C O j (1
1.5 m m o l ) , (()22
M , 4 c m ) ; reaction t i m e 65 . Y i e l d e d 176 as o f f w h i t e needles (232 m g , 7 7 % ) m p 155.23
121
156.1 ; ' H N M R (400 M H z , acetone-d) 8.37 ( H , d, J =2.4 H z ) , 8.27 ( H , d, J = 2 . 4

H z ) , 7.89 ( H , d d , J = 2 . 4 H z , J= 8.4 H z ) , 7.70 ( 1 H d d , J = 2 . 4 H z , J = 8.4 H z ) , 6.84 ( I H ,
d , y = 8.4 Hz ) , 6.67 ( l H, d , J= 8.4 Hz ) , 5.56 ( 2 H, br s NH2), 3.94 (3H, s 0CH3); ' C N M R

3
(100 M H z , acetone-d6) 163.74, 159.90, 146.51, 144.44, 137.22, 35.98 128.56, 123.06,
111.25, 53.34; M S ( E I ) m/z 201.1 (+ 100%). A n a l . Caled, for C11H11N3O: , 65.66; ,
5 . 5 1 ; N , 20.88. Found: , 65.90; , 5 . 5 1 ; N , 21.10%.
6 ' - M e t h o x y - [ 2 , 3 ' ] b i p y r i d i n y l - 3 - y l a m i n e (177)

H2N
Boronic acid 40 (258 m g , 1.7 m m o l ) , 3-amino-2-chloropyridine
1^60-)>{~)
~ I
(159) (261 m g , 1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) ,
1,4-dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e 65

3
h; eluent D C M : E t O A c (4:1 v / v ) gave 177 as a b r o w n crystalline solid (247 m g , 8 2 % ) m p

84.0-84.4 ; ' H N M R (300 M H z , acetone-d) 8.55 ( H , ), 8.03 ( 2 , m ) , 7.23 ( H , d , J
= 7.8 H z ) , 7.09 ( H , m ) , 6.87 ( H , d, J=
8.4 H z ) , 4.80 ( 2 H br s, NH2), 3.97 ( 3 H , , ) ;
' ^ c N M R (100 M H z , acetone-de) 164.12, 147.34, 142.51, 142.03, 139.72, 139.57, 129.42,
123.66, 123.07, 110.87, 53.40; M S
( E I ) m/z 201.2 ( + ,
100%).
A n a l . Caled, for
C i i H i i N j O : , 65.66; , 5 . 5 1 ; , 20.88. F o u n d : , 65.39; , 5.54; , 2 0 . 7 2 % .
W h e n the reaction was carried out on 5 g scale, product 177 (4.10 g 8 0 % yield) was
obtained.
2'-Methoxy-[2,3'lbipyriinyI-3-ylamine(178)
H j N ^ ^
Boronic
acid 43
(258
mg,
1.7
mmol),
159
(261
mg,
1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and N a z C O j (1

3
M , 4 c m ) ; reaction t i m e 65 h; eluent D C M , yielded 178 as a pale y e l l o w

3
powder (207 m g , 6 9 % ) m p 184.1-185.2 ( f r o m toluene); ' H N M R (400

M H z , acetone-d) 8.21 ( , d d , J = 5 . 0 H z , J = 1.6 H z ) , 7.95 ( 1 , d d , J = 4.4 H z , J = 1.6
H z ) , 7.70 ( H , d d , J = 7.2 H z , J = 2.0 H z ) , 7.14 ( I H , m ) , 7.07 ( 2 m ) , 4.56 ( 2 , br s,
NH2), 3.91 ( , , ) ; ' C N M R (125 M H z , D M S O - d ) 160.38, 146.49, 142.65,
3
122
Experimental
Procedures
140.39, 140.23, 137.17, 123.31, 122.32, 121.40, 117.16, 53.16; M S ( E I ) m/z 201.0 (M+
100%). A n a l . Calcd. f o r : , 65.66; , 5 . 5 1 ; N , 20.88.
5.50; N , 20.43%.
3-Amino-2-(4-methoxyphenyI)pyridine
Found: , 65.83; ,
(179)
Boronic acid 165 (260 m g , 1.7 m m o l ) , 159 ( 2 6 1 m g , 1.5 m m o l ) ,

H'N
Pd(PPh3)2C2 (59.6 m g , 0.085
mmol),
1,4-dioxane
(10 c m ) and
3
Na2C03 (1 M , 4 c m " ) ; reaction t i m e 65 h ; eluent E t O A c yielded 179

M e O ' ^ ^
as a b r o w n crystalline solid ( 2 4 0 m g , 8 0 % ) m p 99.2-100.1 ;
N M R (500 M H z , acetone-de) 7.96 ( H , d d , J = 6.0 H z , J = 3 . 5 H z ) , 7.66 ( 2 , d d , J = 9 . 0

H z , J = 5.0 Hz ) , 7.13 ( H , d d , J = 9.0 H z , J = 6.0 H z ) , 7.0 ( , m ) , 4.63 ( 2 , br s, NH2),
3.82 ( , s, 0CH3); ' C N M R (100 M H z , acetone-d) 163.22, 148.03, 142.24, 133.96,
3
133.35, 131.33, 126.13, 125.75, 125.58, 117.35, 116.67, 58.30; M S ( E I ) m/z 200.1 ( + ,
7 8 % ) , 199.0
100%).
H R M S Calcd. f o r C i z H n N z O : 199.08714
(M+-1), found:
199.08710.
3-Amino-2-(2-methoxyphenyl)pyridine
Boronic
N^^^
acid
(180)
166 ( 2 6 0 m g , 1.7 m m o l ) ,
159 (261 m g , 1.5 m m o l ) ,
p j ^ p p ^ ^ ^ ^ ^ ^ ( 5 9 6 m g , 0.085 m m o l ) , 1,4-dioxane ( 1 0 c m ) and NazCOa ( 1

3
M 4 cm^); reaction time 65 h; eluent E t O A c yielded 180 as a b r o w n

OMe
crystalline solid (210 m g , 7 0 % ) m p 99.2-100.1 ( f r o m toluene); N M R
(400 M H z , acetone-d) 7.94 ( H , d d , J= 4.4 H z , J= 1.2 H z ) , 7.38 ( H , m ) , 7.30 ( H , d d ,
J=
7.2 H z , J = 2.0 H z ) , 7.10 ( 2 , m ) , 7.05 ( 2 m ) , 4.40 ( 2 , br , N H a ) , 3.82 ( , s,
03); ' C N M R (125 M H z , acetone-d) 157.52, 144.39,

3
143.26,
138.89,
132.41,
130.13, 129.47, 123.53, 22.13, 121.50, 111.97, 55.74; M S ( E I ) m/z 200.1 ( + , 100%).
A n a l . Calcd. f o r : , 71.98; , 6.04; , 13.99.
F o u n d : , 71.69; , 6.01; ,
13.79%.
123
3 - A m i n o - 2 - p h e n y l p y r i d i n e (181)
Boronic
acid 83 (207 m g ,
1.7 m m o l ) , 159 (193
mg,
1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and N a a C O j

3
N^
(1 M , 4 ); reaction t i m e 65 ; eluent E t O A c yielded 181 a pale b r o w n
crystalline solid (219 m g , 86%) analytically pure and spectroscopically identical w i t h the
sample described p r e v i o u s l y /
2 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) p y r i d i n - 4 - a m i n e (182)
B o r o n i c acid 40 (258 m g , 1.7 m m o l ) , 4-amino-2-chloropyridine
(171) (261 m g ,
NH2
mmol),
1.5
1,4-dioxane
m m o l ) , (1()22 (59.6 m g ,
(10 c m ) and
(1 M ,
0.085
4 cm );
3
reaction time 65 h; eluent E t O A c , yielded 182 as a pale b r o w n crystalline solid (120 m g ,

4 0 % ) m p 148.9-149.6 ( f r o m toluene and hexane); ' H N M R (400 M H z , acetone-d)
8.75 ( H , ), 8.24 ( H , d, J=
8.8 H z ) , 8.14 ( H , d, J = 5.2 H z ) , 7.08 ( H , ), 6.80 ( H ,
m ) , 6.54 ( H , dd J= 5.6 Hz , J = 2.4 Hz ) , 5.62 ( 2 H , br s), 3.92 (, s, 03); 1 N M R

3
(100 M H z , acetone-d) 167.76, 158.68, 158.32, 153.40, 148.66, 140.54, 132.80, 133.64,
111.45, 108.10, 56.33; M S ( E I ) m/z 201.1 (+ 100%).
A n a l , caled f o r d i H u N j O ; ,
65.66; , 5 . 5 1 ; , 20.86. Found: , 65.58; , 5.42; , 20.98%.
W h e n the reaction was carried out on 5 g scale, product 182 (3.08 g, 6 0 % yield) was
obtained.
6 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) p y r i d i n - 3 - a m i n e (183)
Boronic
^J>~NH2
acid
40
(258
mg,
1.7
chloropyridine (172) (261
mg,
1.5
mmol),
5-amino-2-
m m o l ) , ()22
(59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and (1

3
M , 4 c m ^ ) ; reaction t i m e 65 h; eluent E t O A c , g ave 183 as a pale b r o w n crystalline solid

(120 m g , 4 0 % ) m p 147.0-147.7 ( f r o m toluene); H N M R (500 M H z , acetone-d) 8.75
( H , d , J = 2 . 5 H z ) , 8.27 ( H , d d , J = 8 . 5 Hz, J =2.5
H z ) , 8.17 ( H , d , J = 2 . 5 H z ) , 7.63
124
( H , d , J = 8.5 H z ) , 7.15 ( H , dd, J = 8.5 H z , J = 2.5 H z ) , 6.82 ( H , d , J=
8.5 H z ) , 5.03
( 2 H , br ), 3.95 ( , s ) ; 1 N M R (100 M Hz , acetone-de) 167.14, 147.56, 147.38,

146.78, 140.38, 139.73, 132.91, 124.76, 123.20, 113.85, 56.36; M S ( E I ) m/z 201.1 ( + ,
3
100%). A n a l . Caled for C i i H n N s O ; , 65.66; 5 . 5 1 ; , 20.86.

5.53; , 2 1 . 1 8 % .
Found: , 65.63; ,
5 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - 3 - n i t r o p y r i d i n - 2 - a i n i n e (184)
B o r o n i c acid 40 ( 2 5 8 m g , 1.7 m m o l ) , 2 - a m i n o - 5 - b r o m o - 3 "2
2
MeO' N '
nitropyridine (107) (327 m g , 1.5 m m o l ) , ()22 (59.6

m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and
3
(1 M , 4
c m ) ; reaction t i m e 65 h; eluent D C M : E t O A c (3:2 v / v ) gave

3
184 as an orange solid (253 m g , 6 9 % ) m p 228.9-229.5 ; ' N M R (400 M H z , D M S O - d )

8.81 ( , d , J = 2 . 4 H z ) , 8.61 ( IH , d , J= 2.4 H z ) , 8.56 ( IH , d , J= 2.4 H z ) , 8.10 ( I H , d d ,
J = 8.4 H z , J = 2.4 H z ) , 8.07 ( 2 H , br , N H z ) 6.95 ( H , d d , J = 8.4 H z , y = 0.8 H z ) , 3.38
( , , ) ; '^ N M R (100 M Hz , D M S O - d e ) 163.99, 155.21, 153.78, 145.21, 138.11,
132.48, 127.60, 126.03, 122.80, 111.66, 54.27; MS (EI) m/z 246.0 (+, 100%).
Anal.
Caled. f o r C i i H i o N 4 0 3 : , 53.66; , 4.09; , 22.75. Found: , 53.18; , 4.09; , 21.69%.
5 - ( 2 - M e t h o x y p y r i d i n - 3 - y I ) - 3 - n i t r o p y r i d i n - 2 - a m i n e (185)
Boronic acid 43 (258 m g , 1.7 m m o l ) , 107 (327 m g , 1.5 m m o l ) ,
NH
OMe
NO2
Pd(PPh3)2C2 (98 m g , 0.085 m m o l ) , 1,4-dioxane
(10 c m ) and
3
(1 M , 4 cm^); reaction t i m e 65 h; eluent D C M : E t O A c (4:1
v / v ) gave 185 as a y e l l o w solid (277 m g , 7 5 % ) , m p 222.1-223.2 ; N M R (400 M H z ,

D M S O - d ) 8.63 ( H , d , J= 2.0 H z ) , 8.56 ( H , d , J= 2.0 H z ) , 8.18 ( H , d d , J= 4.8 H z , J
= 2.0 H z ) , 8.06 ( 2 , br
NH2), 7.89 {IH, d d , J = 7.2 Hz , J = 2.0 H z ) , 7.10 ( I H, d d , J= 7.2
H z , J = 4.8 H z ) 3.90 ( 3 H , , ) ; ' C N M R (100 M H z , D M S O - d ) 160.76, 156.85,

3
153.47, 146.75, 138.82, 134.90, 126.81, 121.15, 119.62, 118.36, 54.20; M S ( E I ) m/z 246.0
( + , 100%). A n a l . Caled, f o r 4 0 : , 53.75; 4.09; , 22.75. F o u n d : , 53.45;
, 4.09; , 22.66%.
125
5 - ( 4 - M e t h o x y p h e n y l ) - 3 - n i t r o p y r i d i n - 2 - a m i n e (186)
N

Pd(PPh3)2C2 (98 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and
3
"^
Meo
(1 M , 4 c m ) ; reaction time 65 h; eluent D C M , yielded

3
186 as an orange solid (276 m g , 7 5 % ) , m p 182.1-182.9
( f r o m toluene); N M R (400 M H z , acetone-d) 8.68 ( H , d, J =2.4
H z ) , 8.55 (,
d,J =
2.4 H z ) , 7.63 ( 2 , d, J = 8.8 H z ), 7.49 ( 2 , br s, NH2), 7.04 ( 2 , d, J = 8.8 H z ) , 3.84 ( ,

s, 0CH 3); ' C N M R (125 M H z , D M S O - d ) 158.95, 154.20, 152.51, 130.95, 127.86,
3
127.23, 126.60, 124.68, 114.53, 5 5 . 2 1 ; M S ( E I ) m/z 245.0 (+ 100%). A n a l . Caled, for

C i i H i i N j O j : , 58.77; , 4.52; , !7.13. F o u n d : , 58.42; , 4.46; , 16.75%.
5 - ( 2 - m e t h o x y p h e n y I ) - 3 - n i t r o p y r i d i n - 2 - a m i n e (187)
B o r o n i c acid 166 (258 m g , 1.7 m m o l ) , 107 (327 m g , 1.5 m m o l ) ,
/~NH
~
OMe
NO2
Pd(PPh3)2C2 (98 m g , 0.085 m m o l ) , 1,4-dioxane
(10 c m )
3
and
NaaCOa (1 M , 4 cm^); reaction t i m e 65 h; eluent E t O A c , gave 187
as a mustard-yellow solid (254 m g , 6 9 % ) , m p 164.0-165.0 c;

acetone-d) 8.68 ( H , d, J =2.4
H z ) , 8.55 ( H , d,J=
N M R (400 M H z ,
2.4 H z ) , 7.63 ( 2 H , ,J=
8.8 H z ),
7.49 (2H br , NH2), 7.04 ( 2 H , d, J = 8.8 H z ) , 3.84 ( , s, ) ; ' C N M R (125 M H z ,

3
D M S O - d ) 158.95, 154.20, 152.51, 130.95, 127.86, 127.23, 126.60, 124.68, 114.53,

5 5 . 2 1 ; M S ( E I ) m/z 245.0 (+ 100%). A n a l . Caled, for C12H11N3O3: , 58.77; , 4.52; N ,
17.13. Found: , 58.82; , 4.52; N , 17.17%.
2 - A m i n o - 3 - n i t r o - 5 - p h e n y l p y r d i n e (188)
=.
=1
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and

3
^^^
Na2C03 (1 M , 4 c m ) ; reaction t i m e 65 h; eluent D C M : E t O A c (4:1

3
v / v ) yielded 188 as a y e l l o w solid (257 m g , 8 0 % ) analytically pure and spectroscopically

identical w i t h the sample described previously.^
126
A ' - [ 5 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - 6 ' - m e t h y l p y r i d i n - 2 - y l ] a c e t a m i d e (189)

B o r o n i c acid 40 (258 m g , 1.7 m m o l ) ,
^^/j^^NHC(0)Me
Me^N
methylpyridin-2-yl)acetamide
(109)
N-(5-bromo-6(334 m g , 1.5
m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) ,
1,4-
dioxane (10 ) and (1 M , 4 ); reaction t i m e 8 ; eluent E t O A c gave 189 as a

w h i t e solid (310 m g , 8 1 % ) m p 142.6-143.1 ; N M R (400 M H z , D M S O - d ) 10.50
( H , br s, N H ) , 8.11 ( I H , d d , J = 2 . 4 Hz, J = 0.8 H z ) , 7.93 ( H , d,J=
8.8 H z ) , 7.69 ( H ,
d d , J = 8.8 H z , J= 2.4 H z ) , 7.54 ( H , d , J = 8.8 H z ) , 6.83 ( H , d d , y = 8.8 H z , J= 0.8 H z ) ,

3.83 ( , ), 2.31 ( , s), 2.04 ( , s); ' C N M R (100 M H z , D M S O - d ) 170.0, 163.4,
3
154.4, 151.4, 147.2, 140.5, 140.1, 128.9, 128.7, 111.4, 110.7, 53.9, 24.5, 23.2; M S ( E I ) m/z
257.1 ( + , 100%). A n a l . Calcd. f o r C H H I J N J O J : , 65.35; , 5.88; , 16.33. F o u n d : ,
65.28; , 5.82; , 16.32%.
6'-Methoxy-2-methyl-[3,3']bipyridinyl-4-ylamine(190)
H3C
||1
^^^ acid 40 (258 m g , 1.7 m m o l ) , 2 - a m i n o - 5 - b r o m o - 6 m e t h y l p y r i d i n e (108) ( 2 8 1 m g , 1.5 m m o l ) , 0()22 (59.6
23
(1 M , 4
c m ^ ) ; reaction t i m e 65 h; eluent D C M : E t O A c (1:4 v / v )
yielded
m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and

3
190 as o f f - w h i t e needles (235 m g , 7 3 % ) m p 181.7-182.1 ( f r o m toluene); N M R (400

M H z , acetone-d) 8.10 ( , d, J = 2.4 H z ) , 7.65 ( H , d d , J = 8.4 H z , J = 2.4 H z ) , 7.28.
( H , d , J= 8.4 H z ) , 6.83 ( H , d , J= 8.4 H z ) , 6.49 ( H , ,=
8.4 H z ) , 5.41 ( 2 , br , NH2),
3.95 ( , s, 03), 2.87 ( , s, ) ; ' C N M R (100 M H z , acetone-d) 163.50, 159.27,

3
154.42, 147.33, 140.35, 139.49, 130.50, 122.40, 110.61, 106.10, 53.32, 23.08; M S ( E I ) m/z
215.1 (+ 100%). A n a l . Calcd. f o r C i z H u N s O : , 66.96; , 6.09; , 19.52. F o u n d : ,
66.74; , 6.03; , 19.44%.
127
2'-Methoxy-2-methyl-[3,3']bipyridinyl-4-ylamine(191)
HsC^N^NHz
Boronic acid 43 (258 m g , 1.7 m m o l ) , 108 ( 2 8 1 m g , 1.5 m m o l ) ,

Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) ,
1,4-dioxane
(10 c m ) and
3
Na2C03 (1 M , 4 c m ) ; reaction time 65 h; eluent D C M : E t O A c (1:4

3
v / v ) yielded 191 as o f f - w h i t e needles (241 m g , 7 5 % ) m p 151.2-151.9

c ; ' H N M R (500 M Hz , acetone-d) 7.08 ( H , d , J= 3.5 H z ) , 7.43 ( H , d d , J = 7.0 H z , J
= 1.5 H z ) , 7.12 ( H , d, J= 8.0 H z ) , 6.94 ( H , m ) , 6.49 ( H , d , J= 8.4 H z ) , 6.37 ( H , d , J =
8.0 H z ) , 5.40 (2H br s, NH2), 3.80 ( 3 H, s OCH3), 2.04 ( 3 H, s, CH3); ' C N M R (125 M Hz ,
3
acetone-de) 161.87, 159.27, 154.91, 146.27, 140.00, 139.75, 124.34, 120.83, 117.43,
105.57, 53.22, 22.55; M S ( E I ) m/z 215.0 (+, 100%).
A n a l . Caled, for C12H13N3O: ,
66.96; , 6.09; N 19.52. F o u n d : , 66.66; , 6.12; , 19.10%.
2 - A i i i i n o - 6 - m e t h y l - 5 - ( 4 - m e t h o x y p h e n y l ) p y r i d i n e (192)
HC
3
^ ^ " " ^ acid 165 (258 m g , 1.7 m m o l ) , 108 (281 m g , 1.5 m m o l ) ,
H
N
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , l,4-doxane (10 c m ) and

3
(1 M , 4 c m ) ; reaction t i m e 65 h; eluent D C M : E t O A c
3
^^"
(3:7 / ) yielded 192 as o f f - w h i t e needles (207 m g , 6 5 % ) m p
160.1-160.9 ( f r o m toluene); ' H N M R (400 M H z , acetone-d) 7.20 ( , d, J = 8.8 H z ) ,

6.94 ( 2 , d, J= 8.8 H z ) , 6.42 ( H , d , J= 8.0 H z ) , 5.35 ( 2 H , br s, NH2), 3.81 ( , , ) ,
2.37 ( , s, ) ; ' C N M R ( 1 0 0 M H z , acetone-d) 159.09, 158.72, 153.81, 139.39,
3
133.86, 130.84, 125.85, 114.17, 105.95, 55.25, 23.07; MS (EI) m/z 214.1 ( + , 100%).
A n a l . Caled, f o r C13H14N2O: , 72.87; , 6.59; , 13.07. F o u n d : , 72.72; , 6.53; ,
12.73%.
2 - A m i n o - 6 - m e t h y I - 5 - ( 2 - m e t h o x y p h e n y l ) p y r i d i n e (193)
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) ,
1,4-dioxane
(10 cm^) and
OM"
128
(1 M , 4 c m ) ; reaction t i m e 65 h; eluent D C M : E t O A c (1:4 v / v ) yielded 193 as an

o f f - w h i t e powder (241 m g , 7 5 % ) m p 158.7-159.2 ( f r o m toluene); ' H N M R (400 M H z ,
acetone-d) 7.09 ( H , d,J= 8.4 H z ) , 7.05 ( H , dd,J=
7.4 H z , J= 2.0 H z ) , 7.00 ( H , d, J
= 8.4 H z ) , 6.93 ( H , t,J=
7.4 H z ) , 7.27 ( H , m ) , 6.36 ( H , d, J = 8 . 4 H z ) , 5.26 ( 2 br s,
3
NH2), 3.71 ( , , ) , 2.04 ( , , ) ; ' C N M R (125 M H z , D M S O - d e ) 158.24,

156.47, 153.56, 139.04, 130.96, 129.21, 128.37, 120.85, 120.34, 111.09, 104.83, 55.14
3
22.29; M S ( E I ) m/z 214.0 (+ 100%). A n a l . Caled, for C u H u N s O : , 72.87; , 6.59; ,

13.07. Found: , 73.04; , 6.60; , 12.62%.
2 - A m i n o - 5 - p h e n y l - 6 - m e t h y l p y r i d i n e (194)
H3C
^f~%^f~\-f^H2

3
(1 M , 4 c m ) ; reaction t i m e 65 h; eluent E t O A c yielded

3
194 w h i t e crystalline solid (188 m g , 6 8 % ) m p 117.2-118.4 ( f r o m toluene:hexane);

N M R (400 M H z , acetone-de) 7.43 ( 2 , m ) , 7.33 ( , m ) , 7.28 ( H , d,J=
( , d, J=
8.4 H z ) , 6.49
8.4 H z ) , 5.44 (2 br , NH2), 2.30 ( , s, ) ; ' C N M R (100 M H z , acetone3
de) 162.00, 156.84, 144.76, 142.39, 132.86, 131.83, 129.97, 129.18, 109.01, 26.09; M S
( E I ) m/z 184.1 (+ 100%). A n a l , caled for Ci2H,2N2
, 78.23; ,
6.57;
15.21. Found:
, 78.27; , 6.63; , 1 5 . 5 1 % .
5 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - p y r a z i n - 2 - y l a i n i n e (198)
\^
Boronic
acid
^^^)>NH2
40
(258
mg,
bromopyrazine
1.7
mmol),
2-amino-5-
(261 m g , 1.5 m m o l ) , 1
(59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and N a j C O a (1

3
M , 4 cm^); reaction t i m e 65 h; eluent E t O A c gave 198 as a b r o w n crystalline solid (182 m g ,

6 0 % ) , m p 166.1-166.6 ( f r o m toluene); ' H N M R (400 M H z , acetone-d) 8.75 ( H , d d ,
J= 2.6 H z , J= 0.6 H z ) , 8.50 ( I H , d, J = 1.6 H z ) , 8.24 ( I H , d d , J = 8.6 H z , J = 2.6 H z ) , 8.09

( I H , d, J = 1.2 H z ) , 6.86 ( I H , d d , J = 8.4 H z , J = 0 . 8 H z ) , 5.98 ( 2 H , br ), 3.96 ( , s); ' C
3
N M R (100 M H z , acetone-d); 164.36, 155.54, 144.29, 139.25, 138.97, 136.41, 132.23,
129
127.60, 111.11, 5 3 . 4 1 ; M S ( E I ) m/z 202.1 (+ 100%). A n a l . Calcd f o r C,oH ioN40: ,

59.40; , 4.98; N , 2 7 . 7 1 . Found: , 59.16; , 4.98; N , 2 7 . 6 9 % .
5 - ( 2 - M e t h o x y p y r i d i n - 3 - y l ) - p y r a z i n - 2 - y l a m i n e (199)
,^^^
pj^ppj^^^^^^ (59.6 m g , 0.085
mmol),
1,4-dioxane
(10 c m ) and
3
(1 M , 4 c m ) ; reaction t i m e 65 h; eluent E t O A c , gave 199 as

OMe
a o f f w h i t e powder (213 m g , 7 0 % ) , m p 134.7-135.2 ( f r o m
toluene); ' H N M R (500 M H z , acetone-d) 8.70 ( , d , J = 1.5 H z ) , 8.26 ( IH , d d , y = 9.5

H z , J = 5.5 H z ) , 8.11 ( IH , d d , J = 6.5 H z , J = 3 . 0 H z ) , 8.08 ( IH , d , J = 1.0 H z ) , 7.04 ( IH ,
dd, J = 12.0 H z , J= 2.5 H z ) , 6.02 ( 2 H , br ), 4.00 ( , s); ' C N M R (125 M H z , acetone-d)
3
163.97, 158.19, 149.16, 146.28, 141.00, 140.64, 135.29, 124.32, 120.84, 56.37; M S ( E I )
m/z 202.1 (M+ 100%). H R M S Calcd f o r C,oHioN40: 202.08546 ( M + ) , f o u n d : 202.08550.
5 - ( 2 - M e t h o x y p h e n y i ) - D y r a z i n - 2 - y l a m i n e (200)
2
N
Pd(PPh3)4 (98 m g , 0.085 m m o l ) , T H F (10 c m ) and

3
c m ^ ) ; reaction t i m e 65 h.
(1 M , 4
Purified by c o l u m n chromatography and
recrystallised using toluene to y i e l d 2 0 0 as a beige solid ( 2 1 4 m g ,

7 1 % ) , m p 99.8-100.2 ; N M R (400 M H z , acetone-d) 8.60 ( H , ,J=
( H , ,J=
1.2 H z ) , 7.85 ( H , d d , J=
1.6 H z ) , 8.11
1.8 H z , J= 7.8 H z ) , 7.34 ( H , m ) 7.13 ( H , d , J= 8.4
H z ) , 7.10 ( H , m ) 5.80 ( 2 H br , NH2), 3.93 ( , , ) ; ' C H M R (125 M Hz , acetone3
de) 157.40, 154.85, 143.71, 139.90, 131.98 130.45, 129.45, 127.32, 121.30, 112.09,
55.62; M S ( E I ) m/z 200.8 (+,
100%). A n a l . Calcd f o r C i H u N j O : , 65.66; , 5 . 5 1 ; N
20.88. F o u n d : , 65.38; , 5.47; 20.58%.
5 - P h e n y l p y r a z i n - 2 - a m i n e (201)
2
Pd(PPh3)2C2 (59.6 m g , 0.085
mmol),
1,4-dioxane
(10 c m ) and
3
130
(1 M , 4 cm^); reaction t i m e 8 h; eluent E t O A c , gave 2 0 1 as a yel l o w powder (174

m g , 6 8 % ) , analytically pure and spectroscopically identical w i t h the sample described
previously.^
5 - ( 4 - M e t h o x y p h e n y l ) p y r a z i n - 2 - a m i n e (202)
^NH2
B o r o n i c acid 165 (258 m g , 1.7 m m o l ) , 163(261 m g , 1.5 m m o l ) ,

, \
Meo
^
NaaCOs (1 M , 4 c m " ) ; reaction t i m e 8 h ; eluent E t O A c , gave

202 as a b r o w n needles (208 m g , 6 9 % ) , analytically pure and
spectroscopically identical w i t h the sample described p r e v i o u s l y /
5 - ( 6 - C h I o r o p y r i d i n - 3 - y l ) p y r i m i d i n - 2 - a i n i n e (203)
B o r o n i c acid 23^ (267 m g , 1.7 m m o l ) , 163 (261 m g , 1.5
NH2
m m o l ) , Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10

c m ) and N a i C O s (1 M , 4 c m ) ; reaction t i m e 65 h; eluent
3
DCM:Et20 (1:2 v / v ) gave 203 as an o f f - w h i t e solid (193 m g , 6 2 % ) , m p 205.5-205.8
(
N M R (300 M H z , acetone-d) 8.99 ( H , d , J = 2.4 H z ) , 8.63 ( , d , J= 1.2 Hz ) , 8.38 ( H ,
d d , J= 8.4 H z , J= 2.7 H z ) , 8.13 ( H , ,J=
1.5 H z ) , 7.54 ( H , d , J = 8 . 4 H z ) , 6.02 ( 2 , br
, N H j ) ; ' C N M R (100 M H z , acetone-d) 156.28, 150.41, 147.04, 140.16, 137.49,

3
136.10, 133.23, 132.63, 124.77; M S ( E I ) m/z 205.9 (+ 100%).
A n a l . Caled, f o r
C9H7CIN4: , 52.31; , 3.41; , 27.11. Found: , 51.99; , 3.33; , 26.67%.
2 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) - 5 - ( t r i f l u o r o m e t h y l ) - p h e n y l a i n i n e (204)
_ ^
B o r o n i c acid 4 0 (258 m g , 1.7 m m o l ) , 1 - a m i n o - 2 - b r o m o - 5 (trifluoromethyl)benzene
N=/
"
(195) (360 m g ,
1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane ( 1 0 c m )

3
and (1 M , 4 03); reaction t i m e 8 h; eluent E t O A c gave 204 as a w h i t e crystalline

solid (337 mg, 8 4 % ) mp 63.9-64.2 ; N M R ( 4 0 0 M H z , D M S O - d ) 8.16 ( H , d d , J =
2.4 Hz,J=
1.0 H z ) , 7.71 ( I H , d d , y = 8.8 H z , J= 2.4 H z ) , 7.06 ( 2 H , m), 6.85 (2H m) 5.31
( 2 H , , N H ) , 3.85 ( 3 H , , ) ; ' C N M R (100 M Hz , D M S O - d ) 162.9, 146.6, 146.4,

2
131
139.5, 131.1, 129.1 (J = 30.9 H z ) , 127.5, 125.9, 112.3, 111.1, 110.6, 53.2; M S ( E I ) m/z
268.2 (+, 100%). A n a l . Caled, for : , 5 8 . 2 1 ; , 4.13; N , 10.44. F o u n d : ,

5 8 . 0 1 ; H , 4.24; N , 10.47%.
3.5- B i s ( 6 - m e t h o x y p y r i d n - 3 - y l ) p y r i d i n - 2 - a m i n e (205)
Boronic acid 40 (550 m g , 3.6 m m o l ) , 2-amino-3,5
N. ^ N H ,
dibromopyridine
(196)
(378
mg,
1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10

N'
c m ) and (1 M , 4 c m ) ; reaction time 8 h;

3
eluent E t O A c gave 205 as a w h i t e crystalline solid (350 m g , 7 6 % ) m p 144.0-144.5 ;

N M R (400 M H z , acetone-de) 8.42 ( H , d d , J = 2.4 H z , J=
0.8 H z ) , 8.30 ( H , d d , J = 2 . 4
H z , J = 0.8 H z ) , 8.28 ( H , d, J = 2.4 H z ) , 7.94 ( H , d d , J = 8.8 H z , J = 2 . 4 H z ) , 7.85 ( H ,

dd, J=
8.8 H z , J=
2.4 H z ) , 7.64 ( H , d, J = 2.4 H z ) , 6.87 ( 2 H , dd, J=
8.8 H z , J=
0.8 H z ) ,
6.83 ( H , d d , J = 8.8 H z , J = 0 . 8 H z ) , 5.49 (2 s, N H 2 ) , 3.93 ( , , ) , 3.90 ( , s,

0 3 ) ; ' C N M R (100 M H z , acetone-d)
3
164.0, 163.7, 157.0, 147.3, 145.6, 144.4,
139.8, 137.2, 135.3, 127.9, 127.7, 124.0, 118.3, 111.2, 111.1, 53.7 ( 2 C ) ; M S ( E I ) m/z 308.3
(+ 100%). A n a l . Caled, for C17H16N4O2: , 66.22; , 5.23; , 18.17. F o u n d : , 6 6 . 0 1 ;
, 5.32; , 18.02%.
W h e n boronic acid 40 (1.2 equiv.) was used in this reaction, the y i e l d o f c o m p o u n d 205
was reduced to 3 2 % , and a trace amount ( < 1 % yield) o f mono-coupled product was
isolated, but not obtained analytically pure.
4.6- B i s ( 6 - m e t h o x y p y r i d i n - 3 - y l ) p y r i n i i d i n - 2 - a i n i n e (206)
Boronic acid 40 (550 m g , 3.6 m m o l ) , 2-amino-3,5dichloropyrimidine
(202)
(247
mg,
1.5
mmol),
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4-dioxane (10

c m ) and (1 M , 4 c m ) ; reaction t i m e 8 h; f r o m
3
OMe
toluene gave 206 as a green crystalline solid (163 m g ,
3 5 % ) m p 226.3-227.0 ; N M R (400 M H z , D M S O - d ) 8.98 ( 2 , ,=
2.4 H z ) , 8.42
132
( 2 , d d , J = 8 . 8 H z , J = 2 . 4 H z ) , 7.68 ( H , ), 6.91 (2 d d , J = 8 . 8 H z , J = 1.0 H z ) , 6.73

(2 s N H 2 ) , 3.89 [ 6 , s, ()2]; ' C N M R (100 M H z , D M S O - d e ) 165.7, 164.5 ( 2 C ) ,
3
163.3 ( 2 C ) , 147.1 ( 2 , 138.3 ( 2 C ) , 127.3 ( 2 C ) , 111.1 (2C) 110.1, 54.3 ( 2 ; M S ( E I ) m/z

309.3 ( M + , 100%). A n a l . Caled, for C e H i s N s O : : , 62.13; , 4.89; , 22.64. F o u n d : ,
62.20; , 4.89; , 2 2 . 3 5 % .
5-(6---3-)-1-(213)
Boronic acid 40 (258 m g , 1.7 m m o l ) , 5-bromoindole (208a) (294
mg,
1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) ,
1,4-
dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e 65 h.
Y i e l d e d 213 as an o f f - w h i t e w a x y solid (150 m g , 4 5 % ) , m p
94.3-97.7 , N M R (400 M H z , acetone-de) 10.37 ( H , br , N H ) , 8.29 ( H , d , J = 2.4

H z ) , 7.98 ( H , d d , J = 2.6 H z , J = 8.6 H z ) , 7.84 ( H , m ) , 7.56 ( H , dd, J = 0 . 8 H z , J = 8.4
H z ) 7.42 ( 2 H , m ) , 6.87 ( I H , d d , J = 0.8 H z , J=
8.4 H z ) , 6.58 ( H , m ) , 3.79 ( 3 H , , ) ;
'^c N M R (125 M H z , acetone-d) 163.41, 145.17, 138.05, 136.38, 132.10, 129.55, 129.39,
126.18, 120.99, 118.75, 112.34, 110.88, 102.43, 53.19; M S ( E I ) m/z 224.0 (+ 100%).
A n a l . Caled, for ^ : , 74.88; , 5.39; , 12.49. F o u n d : , 74.39; , 5.46; ,
12.46%.
5-(6-Methoxy-pyridin-3-yl)-m-indole(213)
Boronic acid 40 (258 m g , 1.7 m m o l ) , 5-iodoindole (208b) (364.6
mg,
1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) ,
1,4-
dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e 65 h.

3
Y i e l d e d 213 as an o f f - w h i t e w a x y solid (121 m g , 3 6 % ) , m p

98.2-98.8 , analytically pure and spectroscopically identical w i t h the sample described
previously.
133
5-(6-Methoxy-pyridin-3-yl)-2,3,dihydro-lH-indoIe(214)
MeO-^ ^ \
Boronic acid 40 (258 m g , 1.7 m m o l ) , 5-bromoindoline (209)
"
(297 m g , 1.5 m m o l ) , Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , 1,4,
dioxane (10 c m ) and Na2C03 (1 M , 4 c m ) ; reaction t i m e 65 h.

3
Y i e l d e d 2 1 4 as a green o i l (75 m g , 2 2 % ) ; N M R ( 4 0 0 M H z ,
acetone-d) 8.43 ( H , s), 7.93 ( H , d d , J = 8.4 H z , y = 2.4 H z ) , 7.43 ( H , s), 7.31 ( H , d, y

= 8.4 H z ) , 6.89 ( H , d, J = 8.4 H z ) , 6.75 ( H , d, J = 8.4 H z ) , 5.08 ( H , br ,
NH)
4.02 ( 3 H ,
, ) , 3.67 ( 2 , , J = 8.4 H z ) , 3.13 ( 2 , , = 8.4 H z ) ; I C N M R (100 M H z , acetone3
d 6 ) 145.27, 144.40, 138.16, 137.30, 126.15, 123.20, 121.07, 118.85, 112.39, 110.91,
109.47, 102.44, 53.22, 47.57; MS ( E I ) m/z 225.8 (+, 100%).
3 - ( 6 - M e t h o x y - p y r i d i n - 3 - y l ) - 9 / r - c a r b a z o l e (215)
l^gQ
^
LJ
B o r o n i c acid 40 (258 m g , 1.7 m m o l ) , 3--9-21

(210) (369.2 m g , 1.5 m m o l ) , 1()22 (59.6 m g , 0.085
m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4 c m ) ;

3
reaction t i m e 65 h. Y i e l d e d 215 as a w h i t e powder (215 m g ,
5 2 % ) m p 188.1-189.5 ; N M R ( 4 0 0 M H z , acetone-d) 10.47 ( H , br s, NH) 8.57

( I H , d d , J = 2 . 4 H z , J = 0 . 8 H z ) , 8.44 ( H , m ) , 8.25 ( H , d , J = 3.6 H z ) , 8.08 ( H , d d , J =
8.4 H z , J = 2 . 4 H z ) , 7.70 ( H , m ) , 7.64 ( H , m ) , 7.58 ( H , m ) , 7.46 ( H , m ) , 7.25 ( H , m ) ,
6.91 ( H , d d , J= 8.4 H z , J = 0.8 H z ) , 3.99 ( s, ) ; ' C N M R (100 M H z , acetone-d)
3
163.66, 145.34, 141.24, 140.18, 138.12, 131.70, 129.39, 126.50, 125.12, 124.45, 123.75,
120.91,
119.60,
118.72,
111.99,
111.64,
111.09, 53.32; H R M S
(EI)
caled f o r
CsHhNzO
2 7 4 . 1 1 0 6 1 ; Found 274.11055.
5-(6-Methoxy-pyridin-3-yl)-l-indoIe-3-carbaldehyde(216)
MeO
B o r o n i c acid 4 0 (258 m g , 1.7 m m o l ) ,

j
5-bromoindole-3-
p^^
carboxaldehyde ( 2 1 1 ) (336 m g , 1.5 m m o l ) , 1()22
(59.6 m g , 0.085 m m o l ) , l,4-dioxane ( 1 0 c m ) and NzCO
(1
M , 4 c m ^ ) ; reaction t i m e 65 h. Yielded 216 as a w h i t e powder
(204 m g , 5 4 % ) m p 224.8-225.2 ; ' N M R (400 M H z , acetone-d) 10.11 ( H , s, NH)
134
8.49 ( 2 , d d , J = 2.4 H z , J = 8.4 H z ) , 8.29 ( H , ), 8.03 ( H , dd,J=
2.4 Hz, J = 8.4 H z ) ,
7.68 ( H , d d , J = 8.4 Hz,J=

0.8 H z ) , 7.59 ( H , d d , J = 2 . 4 H z , J= 8.4 H z ) , 6.92 ( I H , dd J
= 0.8 Uz,J=
8.4 H z ) , 3.98 ( 3 H , s, 0 C H 3 ) ; ' C N M R (100 M H z , acetone-d) 185.21,
163.99, 145.61, 138.52, 138.40, 133.02, 131.60, 126.05, 123.52, 120.01, 119.91, 113.42,
3
111.27 53.42; H R M S ( E I ) caled f o r C15H12N2O2 252.26798; Found 2 5 1 . 2 6 5 2 1 .
M e t h y l 3 - a m i n o - 6 - ( 2 - m e t h o x y p y r i d i n 3 - y I ) p y r a z i n e - 2 - c a r b o x y I a t e (217)
Boronic
acid
43
(260
mg,
N
> r
OMe
1.7
mmol),
110a
(348
methyl
mg,
3-amino-61.5
mmol),

3
(1 M , 4 c m ) ; reaction t i m e 15 m i n ; eluent E t O A c gave 217

3
as a y e l l o w s o l i d (320 m g , 8 2 % ) m p 185.3-186.0 ( f r o m toluene); ' H N M R (400 M H z ,

D M S 0 - d 6 ) 8.84 ( I H , ), 8.20 ( H , dd, J = 4 . 8
H z , J=
2.0 H z ) , 8.11 ( H , d d , J = 7.6 H z , J
= 2.0 H z ) , 7.48 ( 2 , br , [ ) , 7.14 ( H , d d , J = 7.6 H z , J = 4.8 H z ) , 3.96
(, s),
3.87
( , s); "^ N M R (100 M H z , D M S O - d ) 166.40, 160.15, 154.49, 148.19, 146.54, 138.13,

136.63, 122.46, 119.49, 117.65, 53.52, 52.28; M S (ES+) m/z 261.1 (+,
Caled. f o r C , 2 H , 2 N 4 0 3 :
c,
55.38; H , 4.65; N ,
21.53.
F ound:
100%).
, 55.02; , 4 . 4 1 ; ,
Anal.
21.23%.
4 - ( 6 - M e t h o x y p y r i d i n - 3 - y l ) p h e n o l (218)
B o r o n i c acid 40 (260 m g , 1.7 m m o l ) , 4-bromophenol (212)
(259 m g , 1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) ,
1,4-dioxane (10 c m ) and (1 M , 4 c m ) ; reaction
3
Mecr " N "
t i m e 8 h; eluent E t O A c . D C M (4:1 v / v ) gave 218 as peach
needles (249 m g , 8 2 % ) m p 166.9-167.9 ; N M R (400 M H z , acetone-d) 8.50 ( H , ),

8.34 ( I H , ,=
2.8 H z , = 0.8 H z ) , 7.85 ( I H , d d , y = 8 . 8 H z , J = 2 . 8 H z ) , 7.45 ( 2 H , m ) ,
6.93 ( 2 H , m ) , 6.79 ( I H , d d , J = 8.8 H z , J = 0.8 H z ) , 3.90 (3H s); ' C N M R (100 M H z ,

3
acetone-d) 163.6, 157.7, 144.7, 137.5, 130.5, 129.6, 128.2, 116.4, 111.0, 53.2; M S (EI)
m/z 201.0 (+,
100%). A n a l . Caled, for 12I,N02 , 71.63; , 5 . 5 1 ; , 6.96. Found: ,
7 1 . 6 1 ; H , 5 . 5 1 ; N , 6.96%.
135
Diazotisation^
2-(6-Methoxypyridin-3-yl)pyridin-4-atnine
(182)
(500
mg,
2.48
mmol)
was
suspended in 4 8 % h y d r o b r o m i c acid (2.5 cm^) and the m i x t u r e sonicated for 10 m i n then

cooled to -5 " C . To this solution, maintained at -5 , a solution o f sodium nitrite (520 m g )
in water (0.5 c m ) was added dropwise w i t h vigorous stirring over 0.5 h. The m i x t u r e was
3
then allowed to w a r m up to room temperature and stirred for an additional 1 h.
Sodium
hydroxide solution ( 5 % aqueous) was then added carefully to adjust the p H to ca. 10 before
being extracted w i t h D C M (50 cm^).
The extract was dried over magnesium sulphate,
evaporated and the solid p u r i f i e d by c o l u m n chromatography (eluent E t O A c ) .
Two
products were obtained along w i t h unreacted 182, in the f o l l o w i n g order o f e l u t i o n .
4 - B r o m o - 2 - ( 6 - m e t h o x y p y r i d i n - 3 - y l ) p y r i d i n e (219)
219 a w h i t e solid (210 m g , 3 2 % ) m p 70.0-71.0 ;
Br
N M R (400
M H z , acetone-d) 8.90 ( H , d d , J = 2.4 H z , J = 0.8 H z ) , 8.51 ( H ,
dd, J = 5.2 H z , J = 0.4 H z ) , 8.38 ( H , dd, J = 8.8 Hz, J = 2.4 H z ) ,

NÔMe
8-12 ( H , dd, J = 2 . 0 H z , J = 0 . 4 H z ) , 7.53 ( , dd,J=
5.2 H z , J =
2.0 H z ) , 6.87 ( I H , dd, J = 8.8 H z , J = 0.8 H z ) , 3.95 ( 3 H , ); ' C N M R (100 M H z , acetone3
d) 165.72, 157.00, 151.42, 146.71, 137.97, 133.80, 127.85, 125.84, 123.28, 111.27,
53.69; H R M S ( E I ) caled f o r C H B r N i O (+) 263.98983, f o u n d 263.98955.
220 ( u n k n o w n s t r u c t u r e )
220 colourless needles (208 mg, 30%) mp 177.0-178.0 ; N M R (400 M H z , acetone-d)

8.72 ( H ,
dd, J = 2.4 H z , J= 0.4 H z ) , 8.34 ( H , ), 8.23 ( , dd, J = 8.8 H z , J = 2 . 4 H z ) ,
7.26 ( H , s), 6.81 ( H ,
dd, J = 8.8 H z , J = 0.8 H z ) , 5.88 (2 br ), 3.92 ( ); ' C N M R

3
(100 M H z , acetone-d) 165.19, 154.54, 152.56, 151.71, 145.88, 137.62, 128.90, 110.95,
105.96,
105.40, 53.52; H R M S
( E I ) caled for C i H i o B r N j O
(+)
279.00072,
found
279.00100.
136
2 - ( 6 - M e t h o x y p y r i d i n - 3 - y I ) p y r i d i n - 4 - a m i n e (182)
(210 m g , 3 2 % ) o f the starting material spectroscopically identical to
previously described.
OMe
- ( Q u i n o l i n - 3 - y l ) p y r i m i d i n - 2 - a m i n e (222)
N
B o r o n i c acid 2 2 1 (236 m g , 1.7 m m o l ) , 3-brom oquinoline (147)

J

H^N
(312 m g , 1.5 m m o l ) , (()22 (59.6 m g , 0.085 m m o l ) , 1,4

,
dioxane (10 c m ) and (1 M , 4 c m ) ; eluent E t O A c gave
222 as a pale y e l l o w solid (200 m g , 6 0 % ) m p 265.9-266.9
( f r o m toluene: hexane); N M R (400 M H z , D M S O - d ) 9.21 ( H , d, J = 2.8 H z ) , 8.79

( 2 , ), 8.59 ( H , d,J=
( H , t,J=
2.0 H z ) , 8.02 ( H , d, J = 8.0 H z ) , 7.98 ( H , d,J=
8.0 H z ) , 7.64 ( H , t,J=
8.0 H z ) , 7.72
7.2 H z ) , 6.94 ( 2 H , br s); ' C N M R (100 M H z , D M S O 3
de) 163.15, 156.42, 148.43, 146.47, 150.71, 129.13, 128.66 128.36, 128.04, 127.71,
126.97, 119.18; M S (ES+) m/z 223.
(+, 100%).
A n a l . Caled, for
C13H10N4: , 70.26; ,
4.54; , 2 5 . 2 1 . F o u n d : , 70.02; , 4 . 4 1 ; , 25.23%.
5 - ( 2 - A m i n o p y r i m i d i n - 5 - y I ) p y r a z i n - 2 - a i n i n e (223)
Boronic
2
acid
221
(236
mg,
1.7
mmol),
2-amino-5-
bromopyrazine (163) (261 m g , 1.5 m m o l ) , (()22 (59.6

3
cm^); eluent E t O A c gave 223 as a pale y e l l o w solid (113 m g ,

40%)
mp 32.4-1^
(from toluene); N M R (400 M H z , D M S O - d e ) 8.71 ( H , s),
8.47 ( , ), 8.38 ( H , d, J = 1.6 H z ) , 7.90 ( H , d, J=
1.6 H z ) , 6.74 ( 2 H , ), 6.46 (2 s);
''c N M R (100 M H z , D M S O - d ) 162.82, 154.66, 154.62, 137.32, 136.09, 131.42, 128.85,

128.16; M S (ES+) miz 188.1 (+ 100%). A n a l . Caled, for CgHgN: , 51.06; , 4.28; ,
44.66. F o u n d : , 51.02;
, 4 . 4 1 ; , 44.23%.
137
Experimental
5.4
Procedures
Experimental Procedure of Chapter 4
2 , 6 - D i f l u o r o - 3 - p y r i d y l b o r o n i c a c i d (225)
B(0H)2
T o a solution o f diisopropylamine (6.5 c m , 47.7 m m o l ) in anhydrous

3
ether (50 c m ) at 0 , " - B u L i (2.5 M in hexane, 20 c m , 52.1 m m o l )

3
"
was added dropwise. T h e reaction was stirred for 0.5 h at 0 and was
then cooled to -78 before 2 , 6 - d i f l u o r o p y r i d i n e (224) (5.0 g , 43.4 m m o l ) was added

dropwise. The reaction was stirred f o r 3 h at -78 then triisopropylborate (15 c m , 65.0
3
m m o l ) was added s l o w l y . T h e reaction m i x t u r e was stirred at -78 for another 0.5 h, then
quenched w i t h water ( 5 0 cm^) and allowed t o w a r m to r o o m temperature w i t h stirring
overnight. T h e organic solvent was evaporated in vacuo and washed w i t h d i e t h y l ether (3 X
50 cm^) to remove unreacted starting material. The aqueous layer was then acidified t o p H
6 ( w i t h 4 8 % H B r ) and then extracted w i t h ethyl acetate (3 X 50 cm^). T h e organic layer
was reduced in vacuo and the crude product recrystallised from toluene to give 2 2 5 as a
white solid (5.6 g, 82 % ) , m p 136.7-137.2 ; N M R (400 M H z , DMSO-d) 8.28 ( ,

q, = 8.4 H z ) , 7.47 ( 2 , s), 7.03 ( H , d , J = 8.4 H z ) ; ' C N M R (100 M H z , D M S O - d )
3
164.58 ( 1 , d d , J = 178.4 H z , J =13.6 H z ) , 162.14 ( 1 , d d , J = 178.4 H z , J =13.6 H z ) ,

153.02, 106.59 ( 1 , d d , J = 32.4 H z , J =5.4 H z ) . A n a l . Caled, f o r C5H4BF2NO2: , 37.79;
H , 2.54; N , 8 . 8 1 . F o u n d : , 37.92; , 2.34; N , 8.67%.
2 , 6 - D i c h l o r o - 3 - p y r i d y l b o r o n i c a c i d (230)
^.^,.
T o a solution o f diisopropylamine (5.2 c m ^ 37.2 m m o l ) i n anhydrous

T H F ( 5 0 c m ) at 0 , " - B u L i (2.5 M i n hexane, 15.2 c m , 38.0 m o l )
3
e'
ei
was added dropwise. T h e reaction was stirred for 0.5 h at 0 "C and was
then cooled t o - 7 8 before 2,6-dichloropyridine ( 2 2 9 ) (5.0 g 33.8 m m o l ) i n anhydrous

T H F (25 cm^) was added dropwise.
The reaction was stirred for 3 h at -78 then
triisopropylborate (9.3 c m ^ , 40.5 m m o l ) w a s added s l o w l y .
T h e reaction m i x t u r e was
stirred at -78 f o r another 1 h, then quenched w i t h water (50 ) and allowed to w a r m to

r o o m temperature w i t h stirring overnight.
and then
filtered.
T h e organic solvent was evaporated vacuo
T h e filtrate was washed w i t h d i e t h y l ether (3 X 50 c m ) to remove

3
138
unreacted starting material. The aqueous layer was then acidified to p H 6 ( w i t h 4 8 % H B r )

to precipitate 230 as w h i t e solid (4.7 g 7 3 % ) , m p 155.2-156.0 ; N M R (400 M H z ,
D M S O - d ) 7.88 ( H , d , J =8.0 H z ) , 7.48 ( H , d, J =8.0 H z ) ; 1 C N M R (100 M H z ,
3
D M S O - d e ) 151.50, 149.12, 146.25, 122.80. A n a l . Caled, for
C5H4BCI2NO2: , 3 1 . 3 1 ; ,
2.10; , 7.30. F o u n d : , 31.11; , 2.05; , 7.40%. Recrystallisation o f the product f r o m

toluene increased the m e l t i n g point to 275.1-276.3 . T h i s is assumed to be due to the
f o r m a t i o n o f the anhydride although N M R was inconclusive.
2 , 6 - d c h l o r o - 3 - ( 2 , 6 - d c h l o r o p y r i d n - 3 - y I ) p y r i d D e (231)
CI\^N^CI
2 3 1 cocrystallised w i t h 230 f r o m a reaction that had been carried

out to obtain 70 g o f product.
2 , 3 - D i c h l o r o - 4 - p y r i d y i b o r o n i c a c i d (238)
g^QI^^^
T o a solution o f diisopropylamine (5.2 cm^, 37.2 m m o l ) in anhydrous T H F (50
J^Y^CI
c m ) at 0 , - B u L i (2.5 M in hexane, 15.2 c m , 38.0 m m o l ) was added
\êi
dropwise. The reaction was stirred f o r 0.5 at 0 and was then cooled to -78
before 2,3-dichloropyridine (237) (5.0 g 33.8 m m o l ) in anhydrous T H F (25 cm^) was

added dropwise. The reaction was stirred for 3 h at -78 then tri sopropyl borate (9.3 c m ,
3
40.5 m m o l ) was added s l o w l y . The reaction m i x t u r e was stirred at -78 for another 1 h,
then quenched w i t h water ( 5 0 cm^) and a l l o w e d t o w a r m to r o o m temperature w i t h stirring
overnight. The organic solvent was evaporated in vacuo and then filtered. The filtrate was
washed w i t h diethyl ether (3 X 25 cm^) to remove unreacted starting material. The aqueous
layer was then acidified t o p H 6 ( w i t h 4 8 % H B r ) to precipitate 2 3 8 as w h i t e solid (3.6 g,
5 6 % ) , m p 140.2-141.0 ; ' H N M R (400 M H z , D M S O - d ) 8.30 ( H , d , J = 4 . 4 H z ) , 7.41
( H , d, J = 4.4 H z ) ; ' C N M R (100 M H z , D M S O - d ) 147.36, 146.86, 130.94, 126.80.
3
MS ( E I ) m/z 190.8 (+, 100%). A n a l . Caled, for C5H4BCI2NO2:
7.30.
F ound:
, 30.71; ,
3 1 . 3 1 ; , 2.10; ,
1.94; , 6.90%.
139
Experimental
Procedures
2- C h l o r o - 5 - p y r i m i d y l b o r o n i c a c i d (244)
/\.(0)2
T o a solution o f 5 - b r o mo - 2 - c h l o r o p y r i mi d i n e (243) (2.5 g 13.0 m m o l )

and triisopropylborate (4.2 c m ^ , 18.2 m m o l ) i n anhydrous T H F (20
c m ) and toluene (5 c m ) at 78 , - B u L i (2.5 M in hexane, 6.2 c m ,

3
15.6 m m o l ) was added dropwise.
The reaction was stirred for 4 h at 78 then the
reaction m i x t u r e was then quenched w i t h water (40 ) and allowed to w a r m to room

temperature w i t h stirring overnight. The organic solvent was evaporated in vacuo and the
remaining aqueous layer was washed w i t h d i e t h y l ether (3 X 10 cm^) t o remove unreacted
starting material.
The aqueous layer was then acidified to p H 5 ( w i t h 4 8 % H B r ) to
precipitate 244 as w h i t e solid (1.75 g, 85 %) m p . 200 (dec); ' H N M R (400 M H z ,

D M S O - d e ) 8.87 ( 2 H , ) ; ' C N M R ( 1 0 0 M H z , D M S O - d ) 165.33, 161.77. M S ( E I ) m/z
3
157.8 (+ 100%). A n a l . Caled, for C4H4BCIN2O2: , 30.34; , 2.55; , 17.69. F o u n d : ,

30.62; , 1.94; , 17.10%.
3- ( 2 , 6 - D i f l u o r o p y r i d i n - 3 - y l ) q u i n o l i n e (226)
B o r o n i c acid 2 2 5 (270 m g , 1.7 m m o l ) , 3-bromoquinoline (147)

(312 m g , 1.5 m m o l ) , ()22 (59.6 m g , 0.085 m m o l ) , 1,4dioxane ( 1 0 c m ) and Na2C03 (1 M , 4 c m ) ; reaction t i m e 2 4 h ;
3
eluent D C M : E t O A c (1:1 v / v ) gave 2 2 6 as a w h i t e solid (303 m g ,
84%) m p 155.5-156.2 ; N M R (400 M H z , D M S O - d ) 9.10 ( H , , J = 2 . 0 H z ) , 8.61

( H , s), 8.54 ( H , q , J = 10.0 Hz,J=
H z ) , 7.67 ( , t,J=
8.0 H z ) , 8.06 ( 2 , , J = 8.0 H z ) , 7.82 ( H , , J = 8 . 0
8.0 H z ) , 7.38 ( I H , d d , 7 = 8.0 H z , J = 2 . 4 H z ) ; ' C N M R (100 M H z ,

3
D M S O - d ) 160.13 ( d d , J = 244 H z , J = 14.5 H z ) , 157.37 ( d d , J = 244 H z , J = 14.5

H z ) , 150.04 id,J=
8.0 H z ) , 147.04 ( d , J= 8.0 H z ) , 146.95 ( d , J= 6.2 H z ) , 135.82 ( d , J =
3.4 H z ) , 130.40, 128.72, 128.48, 127.33, 127.13, 125.63 ( d , J=
4.9 H z ) , 117.31 ( d d , J =
25.6 Hz, J =5.4 H z ) , 107.58 (dd, J= 3 4 . 3 H z , J= 5.7 H z ) ; M S ( E l ) m/z 242.1 ( M + , 100%).

A n a l . Caled, f o r C n H g F j N j : , 69.19; , 3 . 2 2 ; N , u.57.
F o u n d : , 69.19; , 3.22; N ,
11.35%.
140
M e t h y l 3 - a m i n o - 6 - ( 2 , 6 - d i f l u o r o p y r i d i n 3 - y l ) p y r a z i n e - 2 - c a r b o x y l a t e (227)
Boronic
Q
acid 225 (270 m g , 1.7 m m o l ) , methyl
\
(110a)
(348
mg,
3-amino-61.5
mmol),

3
(1 M , 4 cm^); reaction t i m e 15 m i n ; eluent E t O A c gave

227 as a y e l l o w p o w d e r (327 m g , 8 2 % ) m p 201.8-202.3 ( f r o m toluene); ' H N M R (400
M H z , D M S O - d e ) 8.68 ( H , d,J=
2.4 H z ) , 8.52 ( H , ,=
8.0 H z ) , 7.63 ( 2 , br , N b b ) ,
7.32 ( , d d , J = 8.0 H z , J = 2.4 H z ) , 3.88 ( , s); "
N M R (100 M H z , D M S O - d e )
166.01, 154.72, 147.36, 147.26, 145.53, 133.33, 122.79, 107.63, 107.31, 107.23, 52.29;
M S (ES+) m/z 267.0 (+ 100%). A n a l . Caled, f o r C,iH8F2N402: , 49.63; , 3.03; ,
21.05. F o u n d : , 49.46; , 2.76; , 2 0 . 9 5 % .
5 - ( 2 , 6 - D i f l u o r o p y r i d i n - 3 - y l ) p y r i m i d i n - 2 - a m i n e (228)
NH2
i g
Boronic
acid
225
(270
mg,
1.7
-amin
mmol),
b r o m o p y r i m i d i n e (148) (261 m g , 1.5 m m o l ) , (()22 (59.6

m g , 0.085 m m o l ) , 1,4-dioxane (10 c m ) and 23
3
reaction t i m e 24 h; eluent E t O A c
(1 M , 4 c m ) ;
3
gave 228 as a w h i t e solid (215
mg, 6 9 % ) mp 221.1-222.0 (from toluene); N M R (400 M H z , acetone-d) 8.51 ( 2 ,

d,J=
1.6 H z ) , 8 . 2 8 ( 1 , dt, J = 8.0 H z , J = 1.6 H z ) , 7.18 ( I H , d d , J = 8 . 0 H z , J = 2 . 8 H z ) ,
6.33 ( 2 H , ); ' C N M R (100 M H z , acetone-d) 164.20, 160.90 {d,J=

3
194.5 H z , J = 11.1
H z ) , 158.38 ( d d , J = 194.5 H z , J = 11.1 H z ) , 158.34 ( d , J = 2.6 H z ) , 145.55 (dd, J = 6 . 4 H z ,
J=
3.8 H z ) ; M S ( E S + ) m/z 208.2 (M+ 100%). A n a l . Caled, f o r C9H6F 2N4: , 51.93;
2.91; , 26.91. F ound: , 52.06; , 3.03; , 27.01%.
3 - ( 2 , 6 - D i c h l o r o p y r i d m - 3 - y ! ) q u i n o l i n e (232)
B o r o n i c acid 230 (326 m g , 1.7 m m o l ) , 3-bromoquinoline (147)
(312 m g , 1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) , tri-t-
butylphosphine (30 m g , 0.15 m m o l ) , 1,4-dioxane (10 c m ) and
c\^-^r^c\
(1 M , 4 c m ) ; reaction t i m e 24 h ; eluent D C M : E t O A c
3
(1:1 v / v ) gave 232 as a w h i t e solid (235 m g , 5 7 % ) m p 162.2-163.0 ( f r o m toluene); ' H
141
N M R (400 M H z , acetone-de) 9.03 ( H , d,J=
2.0 H z ) , 8.48 ( H , ,J=
2.0 H z ) , 8.13 ( ,
), 8 . 1 1 ( , ), 8.05 ( H , d, J = 8.0 H z ) , 7.84 ( H , t, J = 8.0 H z ) , 7.68 (2H m); ' C N M R

(100 M H z , D M S O - d e ) 150.39, 148.53, 147.75, 146.93, 143.82, 136.51, 132.60, 130.53,
3
129.06, 128.75, 128.49, 127.36, 126.92, 124.09; M S ( E I ) m/z 274.0 (+ 100%).
Anal.
Caled, for CllHgCbNz: , 61.12; , 2.93; , 10.18. Found: , 60.79; , 2.92; , 10.09%.
5 - ( 2 , 6 - D i c h l o r o p y r i d n - 3 - y l ) p y r i i n i d i n - 2 - a m i n e (233)
N_
Boronic
2
acid
230
(326
mg,
1.7
mmol),
2-amino-5-
b r o m o p y r i m i d i n e (148) (261 m g , 1.5 m m o l ) , !()22 (59.6

m g , 0.085 m m o l ) , tri-t-butylphosphine (30 m g , 0.15 m m o l ) , 1,4-
N ' CI
dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e 24 h;

3
eluent E t O A c gave 233 as a pale y e l l o w solid (166 m g , 4 6 % ) mp 245.2-245.9 ( f r o m
toluene); N M R (400 M H z , D M S O - d ) 8.38 ( 2 , ), 7.99 ( H , d, J= 8.0 H z ) , 7.65 ( H ,

d, J = 8.0 H z ) , 7.00 ( 2 H , s); ' C N M R (100 M H z , D M S O - d e ) 163.04, 158.09, 147.56,
3
147.48, 142.80, 130.89, 123.98, 1 I 8 . 0 1 ; M S (ES+) m/z 240.0 (+, 100%). A n a l . Caled, for
C9H6CI2N4: , 44.84; , 2.51; , 23.24. F ound: , 44.76; , 2.52; , 22.88%.
2 - ( 2 , 6 - D i c h l o r o p y r i d i n 3 - y l ) p y r i d i n - 3 - a n i n e (235)
B o r o n i c acid 230 (326 m g , 1.7 m m o l ) , 2-chloro-3-aminopyridine (159)
(193 m g ,
1.5 m m o l ) , Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , tri-t-
butylphosphine (30 mg, 0.15 mmol), 1,4-dioxane (10 cm^) and Na2C03
C|Z
( 1 M 4 c m ) ; reaction t i m e 24 ; eluent E t O A c gave 235 as a w h i t e
solid (ca 54 m g , 1 5 % ) ; N M R (400 M H z , acetone-d) 7.90 ( 2 , m ) , 7.67 ( H , m ) ,

7.14 ( H , m), 5.23 (2 s); ' C N M R (100 M H z , D M S O - d ) 143.8, 143.6, 138.8, 138.3,
3
129.5, 125.0, 124., 124.3, 122.7, 122.2.
f o l l o w e d by 236 as a w h i t e solid (98 mg, 3 2 % ) mp dec 310 ; ' H

N M R (400 M H z , D M S O - d ) 12.2 ( , ), 8.58 ( , d d , J = 8.8 H z ,
^
J = 0 . 8 H z ) , 7.93 ( I H , d d , J = 8.0 H z , J = 1.6 H z ) , 7.49 ( I H , d d , J =
142
8.0 H z , J = 4 . 8 H z ) , 7.35 ( H , d, J = 8.0 H z ) ; ' C N M R (100 M H z , D M S O - d e ) 151.92,

148.91, 143.56, 139.18, 133.31, 132.30, 122.27, 119.77, 116.35, 113.99; M S ( E S + ) m/z
204.1 (+, 100%). H R M S Caled for : 203.62774 (+), f o u n d : 203.62780.
3
3 - ( 2 , 3 - D i c h I o r o p y r i d i n - 4 - y l ) q u i n o l i n e (240)
B o r o n i c acid 237 (326 m g , 1.7 m m o l ) , 3-bromoquinoIine (147) (312
mg,
1.5
mmol),
(1()22
(59.6
mg,
0.085
butylphosphine (30 m g , 0.15 m m o l ) , 1,4-dioxane
mmol),
tr-t-
(10 cm^) and
(1 M , 4 cm^); reaction t i m e 24 h; eluent D C M : E t O A c (3:7

v / v ) gave 240 as a w h i t e solid (236 m g , 5 7 % ) mp 162.2-163.0 ;
N M R (400 M H z , acetone-d) 9.03 ( H , d, J = 2 . 0 H z ) , 8.60 ( H , d, J = 2.0 H z ) , 8.52 ( H ,

d, 7 = 4.8 H z ) , 8.10 ( 2 H , t, / = 8.0 H z ) , 7.87 ( H , t, J=
8.0 H z ) , 7.71 ( 2 H , m ) ; ' C N M R

3
(100 M H z , D M S O - d ) 149.76, 149.04, 147.71, 147.69, 147.18, 136.46, 130.86, 129.39,

128.78, 128.67, 128.04, 127.48, !26.77, 125.85; MS (EI) m/z 274.0 (+, 100%).
Anal.
Caled, for C,4H8C2N2: , 61.12; , 2.93; , 10.18. F o u n d : , 60.94; , 2.75; , 9.89%.
5 - ( 2 , 3 - D i c h l o r o p y r i d i n - 4 - y l ) p y r i n i d i n - 2 - a m i n e (241)
N^NH2
,
B o r o n i c acid 237 (326 m g , 1.7 m m o l ) , 2 - a m i n o - 5 - b r o m o p y r i m i d i n e

(148) (261 m g , 1.5 m m o l ) , ()22 (59.6 m g , 0.085 m m o l ) , t r i t-butylphosphine (30 m g , 0.15 m m o l ) , 1,4-dioxane (10 cm^) and
(1 M , 4 cm^); reaction t i m e 24 h; eluent E t O A c gave 2 4 1 as
a y e l l o w solid (151 m g , 4 2 % ) m p 197.5-198.9 ( f r o m toluene); N M R (400 M H z ,

acetone-d) 8.49 ( 2 , s), 8.38 ( H , d, J = 4.8 H z ) , 7.49 ( H , d, J = 4 . 8 H z ) , 6.46 (2 s);
' C N M R (100
3
M H z , D M S O - d ) 163.28,
124.67, 118.35; M S ( E S + ) m/z 240.0 (+,
1 5 8 . 1 , 149.02, 147.50,
145.91, 127.323,
100%). A n a l . Caled, for C9H6CI2N4: , 44.84;
, 2.51; , 23.24. F o u n d : , 44.76; , 2.52; , 22.68%.
143
3 - ( 2 , 3 - D i c h l o r o p y r i d i n - 4 - y I ) p y r i d i n e (242)
B o r o n i c acid 237 (326 m g , 1.7 m m o l ) , 3-bromopyridine (1) (237 m g , 1.5
m m o l ) , Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , tri-t-butylphosphine ( m g ,
0.15 m m o l ) , 1,4-dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e
3
24 h; eluent E t O A c gave 242 as a o f f w h i t e solid (138 m g , 4 1 % ) m p 192.2-
193.0 (from hexane); N M R (500 M H z , acetone-de) 8.72 ( , s),

8.69 ( H , d, J = 5.0 H z ) , 8.48 ( H , ,J=
5.0 H z ) , 7.99 ( I H , d,J=
8.0 H z ) , 7.57 ( 2 , m ) ;
'^ N M R (100 M H z , D M S O - d ) 150.16, 148.98, 147.64, 147.61, 136.61, 132.14, ! 2 7 . 8 8 ,

125.53, 123.44; M S ( E I ) m/z 224.0 (+,
100%). A n a l . Caled, for : , 53.36; ,
2.69; , 12.45. Found: , 53.72; , 2.92; , 12.09%.
W h e n the reaction was repeated using 3-iodopyridine (239) (169 m g , 5 0 % ) , 242 was
obtained.
3 - ( 2 - C h l o r o p y r i m i d i - - y l ) q u i n o l i n e (245)
N
B o r o n i c acid 244 (269 m g , 1.7 m m o l ) , 3-bromoquinoline (147)
(312 m g , 1.5 m m o l ) , 1()22 (59.6 m g , 0.085 m m o l ) , 1,4-
dioxane (10 cm^) and Na2C03 (1 M, 4 cm^); reaction time 24 ;

eluent E t O A c gave 245 as a w h i t e solid (170 m g , 4 7 % ) m p 214.3215.2 ; N M R (400 M H z , D M S O - d ) 9.34 (,
), 8.86 ( H , d , J = 2.0 H z ) , 8.07
( 2 , d d , J = 8.4 H z ) , 7.84 ( I H , t, J = 8.4 H z ) , 7.69 ( I H , t, J = 8.4 H z ) ; ' C N M R (100 M H z ,

3
D M S O - d e ) 159.47, 158.51, 148.85, 147.37, 134.22, 130.58, 129.87, !28.82, 128.55,

127.51, 127.25, 125.73; M S ( E I ) m/z 240.9 ( M + , 100%). A n a l . Caled, for C o H g C l N a :
c,
64.61; H , 3.34; N , 17.39. F o u n d : c , 64.36; H , 3 . 3 6 ; N , 17.10%.
5 - ( 2 - c h l o r o p y r i m i d i n - 5 - y l ) p y r i i n i d i n - 2 - a m i n e (246)
|yj
MU
j"
Boronic
acid
244
(269
mg,
1.7
mmol),
2-amino-5-
b r o m o p y r i m i d i n e (148) (261 m g , 1.5 m m o l ) , Pd(PPh3)2C2 (59.6

m g , 0.085 m m o l ) , tri-t-butylphosphine (30 m g , 0.15 m m o l ) , 1,4-
144
dioxane (10 c m ) and (1 M , 4 c m ) ; reaction t i m e 24 h; eluent E t O A c gave 246 as

3
a white solid (140 m g , 4 5 % ) m p 196.8-197.2 ; N M R (400 M H z , D M S O - d ) 9,12

( 2 , ), 8.75 ( 2 , ), 7.10 ( 2 , ); ' C N M R (100 M H z , D M S O - d f i ) 163.5, 158.3 156.4,
3
156.3, 128.3, 114.8; M S ( E I ) m/z 207.03 (+,
100%).
A n a l . Caled, for C u H g C l N s :
46.28; , 2 . 9 1 ; , 33.73. F o u n d : , 46.02; 2.99; , 33.29%.
M e t h y l 3 - a i n i n o - 6 - ( 2 - c h l o r o p y r i n i i d i - - y l ) p y r a z i n e - 2 - c a r b o x y I a t e (247)
Boronic acid 244 (269 m g , 1.7 m m o l ) , m e t h y l
o
(110a)
(348
mg,
3-amino-61.5
mmol),
a^
Pd(PPh3)2C2 (59.6 m g , 0.085 m m o l ) , tri-t-buty!phosphine (30
N^"NH2

3
cm^); reaction t i m e 2 4 h; eluent E t O A c gave 247 as a y e l l o w s o l i d (191 m g , 4 8 % ) dec 230

; N M R (400 M H z , D M S O - d ) 9.21 ( 2 , ), 8.96 ( H , ), 7.65 ( 2 , s), 3.85 ( , );
1 C N M R (100 M H z , D M S O - d ) 165.9, 159.0, 156.6, 155.3, 145.8, 128.8, 99.5; M S ( E I )
3
m/z 266.0
(+, 100%).
A n a l . Caled, for CloHgClNsOz:
, 45.21; , 3.04; N 26.36.
F ound:
, 45.68; , 3.33; , 2 6 . 6 2 % .
145
P. R. Parry, . W a n g , . . Batsanov, M . R. B r y c e , and . Tarbit, J. Org.

2002, 67, 7 5 4 1 .
Chem.,
P. R. Parry, M. R. B r y c e , and . Tarbit, Syn thesis, 2003, 1035.

R. . EUingson and R. L. H e n r y , J. Am. Chem. Soc,
1949, 7 1 , 2798.
T . Tsuyoshi and N . M a y u m i , J. Org. Chem., 2003, 68, 9412.

R. Troschutz and . Karger, J. Heterocycl.
Chem., 1997, 34 1147.
T . Itoh, . Maeda, T. Wada, . T o m i m o t o , and T . Mase, Tetrahedron
Lett., 2002,
43, 9287.
J.-F. Cavalier, M . B u r t o n , F . Dussart, . M a r c h a n d , J.-F . Rees, and J. M a r c h a n d Brynaert, Bioorg.
Med. Chem., 2 0 0 1 , 9, 1037.
M . Bryce, . W a n g , M . K i l i z i r a k i , H . M a c B r i d e , L. E. H o r s b u r g h , A . K. Sheridan,
A . M o n k m a n , and I. D . . Samuel, Adv. Mater.,
2000,12 217.
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Pyridine Boronic Acids

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Durham E-Theses

Functionalised Pyridyl- and Pyrimidyl- Boronic acids

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a link is made to the metadata record in Durham E-Theses

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Functionalised Pyridyl- and Pyrimidyl- Boronic Acids and

Amy Elizabeth Smith, B.Sc. (Hons)

I w o u l d like to thank m y academic supervisor Prof. M . R. Bryce and m y

1 w o u l d also like to thank all the friends I made d u r i n g m y time at D u r h a m , in particular

Finally I w o u l d like to thank m y f a m i l y , especially my mam and dad for their c o n t i n u i n g

The thesis is the w o r k o f the author, except where

prior w r i t t e n consent and information derived

Part o f this w o r k has been the subject o f the f o l l o w i n g publications:

A . E. T h o m p s o n , G. Hughes, A . . Batsanov, M . R. Bryce, p. R. Parry, and B. Tarbit; J.

Org. Chem. 2005, 70, 388.

A . E. T h o m p s o n , A . . Batsanov, M . R. Bryce, N . Saygili, p. R. Parry, and B. Tarbit,

and has been presented at:

Seal Sands Chemistry Day, Ramside Hall 2004

Seal Sands Chemistry Day, W y n y a r d 2006

Nuclear Magnetic Resonance

nuclear Overhauser effect

directing metallating groups

Rotating frame Overhauser Enhancement Spectroscopy

Heteronuclear Single Quantum Coherence

Heteronuclear M u l t i p l e Bond Correlation

230 and 2,3-

d i c h l o r o - 4 - p y r i d y l b o r o n i c acid 238 have been synthesised, and the synthesis o f existing

acid 43 has been optimized

p y r i m i d y l b o r o n i c acid 2 2 1 have been syntliesised.

A l l o f the above mentioned boronic

acids were shown to undergo palladium-catalysed Suzuki cross-coupling reactions w i t h a

pyrazinopyridines, indolinopyridines, carbazolopyridines and indolopyridines have thereby

Synthesis o f A r y l and Heteroarylboronic A c i d s

Application o f Boronic Acids

A l k o x y b o r o n i c acids: Scale-up o f e x i s t i n g p r e p a r a t i o n s a n d the synthesis o f new

Large-scale Syntheses o f Previously Published

Novel Alkoxypyridylboronic Acids

A m i n e Substituted Couplings and A m i n e Substituted Boronic acid

z L i k i - M i y a u r a Cross-Couplings w i t h a Partner Bearing a

Transformation o f 184 via Diazotization

General Procedure for all the Cross-Coupling Reactions

Experimental Procedures o f Chapter 2

Experimental Procedures o f Chapter 3

Experimental Procedures o f Chapter 4

F u n c t i o n a l i s e d a r y l and heteroaryl systems are i m p o r t a n t synthetic templates f o r

substituted r i n g systems m a y be incorporated i n t o larger systems b y u t i l i s i n g substituted

i m p e r a t i v e that n e w l y f u n c t i o n a l i s e d b o r o n i c acid r i n g systems are developed.

systems m u s t also cross-couple successfully w i t h a range o f halogenated partners i n

I n a d d i t i o n to this, the p a l l a d i u m catalysed S u z u k i -

M i y a u r a c r o s s - c o u p l i n g reactions o f these b o r o n c o n t a i n i n g species are also r e v i e w e d .

100 g) syntheses o f several a l k o x y - s u b s t i t u t e d heteroaryl

b o r o n i c acids are also reported.

T h e later p a r t o f each chapter explores the S u z u k i -

M i y a u r a reactions o f each n o v e l class o f b o r o n i c acids w i t h various c r o s s - c o u p l i n g

T h e m a i n m e t h o d used i n the syntheses o f b o r o n i c acids is the reaction o f an

T h i s route is also useful f o r the syntheses o f boronate

esters.^ T h e reaction o f a n o r g a n o m e t a l l i c reagent, such as " b u t y l l i t h i u m ( - B u L i ) w i t h

e l e c t r o p h i l i c borate species a l l o w s the f o r m a t i o n o f a c a r b o n - b o r o n b o n d . T h e b o r o n i c

e l e c t r o p h i l i c substitution w i t h d i f f i c u l t y for t w o reasons; p y r i d i n e and electrophiles tend

S c h e m e L l a : E l e c t r o p h i l i c Substitution o f P y r i d i n e at the 2- 3- and 4-positions.

T h e o r g a n o m e t a l l i c reagents used are either G r i g n a r d 6 or o r g a n o l i t h i u m species^.

reagents are f o r m e d b y a d d i n g the corresponding a l k y l - or a r y l h a l i d e to the appropriate

generated b y the o x i d a t i v e i n s e r t i o n , or a d d i t i o n , o f m a g n e s i u m i n t o a carbon-halogen