Ynamines in Synthesis

IBS
Baran Seminar
January 23, 2008
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

General Outline - More reactive than their counterparts the ynol ethers due to lack of electronegative O atom
- Usually colorless liquids (sometime solids) that are usually moisture sensitive
I - Ynamines - A Brief History - Very reactive species in general, but usually thermally stable
II - General Reactivity - Ynamides retain stability but reactivity is attenuated
III - Preparation of Ynamines - Reactivity as a function of N substitution: alkyl > morpholino > aryl/alkyl > bisaryl > (CF3)2
IV - Ynamine Methodologies - Reactivity as a function of C substitution: H > alkyl > aryl > Si > COOR
V - Ynamines in Total Synthesis
III - Preparation of Ynamines
Three methods to prepare ynamines: A) Elimination B) Substitution C) Isomerization
I - Ynamines - A Brief History Also, ynamides are sometimes more easily prepared (D)
-First report of an Ynamine in 1892 by J. Bode (Liebigs Ann. Chem. 267, 268) A - Ynamines by Elimination
-Other reports in 1943 and 1951 - From chloroenamines (Neuenschwander, Helv. Chim Acta 82, 326):
-In 1958, all previous reports had been proven false, and Zaugg et. al reported an Cl
accidental synthesis of an ynamine (JOC 23 1389): n-BuLi
NEt2 Ph NEt2
Ph
S NaH, HCONMe2 S
Cl Cl N Cl
X=
2eq BuLi SnR3
N N Cl Bu3SnCl
N N
H Br NMe2 X NEt2
Cl Cl
54%
Cl NEt2
Me
- From amide chlorides (Viehe, ACIE 5, 584):
-In 1960, Wolf and Kowtz cast doubt on Zaugg's report, and claimed the first ynamine for R NR*2
themselves (Liebigs Ann. Chem. 638 33): O COCl2 Cl Cl LiNR22
+
R R
Ph Li + Cl NEt2 Ph NEt2 NR12 NR12 NR*2
1.7%
-However, in 1965 Dumont reproduced Zaugg's work and proved the 1958 ynamine Ph
-First general method of synthesis by Viehe in 1963 (ACIE 2, 477) - From carbazoles and trichloroethylenes (Chrzaszcz, B.S.C. Belg. 104, 117): NR*2
-Since this date, ynamines have been extensively studied and reviewed:
- Viehe - ACIEE 6, 767 X X X
- Viehe - Chemistry of Acetylenes, Marcel Dekker: NY, 1969; Ch. 12, pp 861-912
- Ficini - T 32, 448 Cl
- Pitacco - The Chemistry of Funcitonal Groups John Wiley & Sons: NY, Ch 15, pp Mg, THF
623-713 TEBACl, NaOH
- Collard-Motte - Top. Curr. Chem. 130, p 89 HN Cl N N
- Himbert - Methoden Der Organischen Chemie (Houben-Weyl)Georg Thieme: 55 - 87%
Cl Cl
Stuttgart, pp. 3267
- Hsung - T 57, 7575 Cl
77%
II - General Reactivity
R1 If R = H R1 X X X
R2N R1 R2N N (same method also works to make N-ethynylpyrrole)
- "push-pull" enamines from vinyligous amides (Dell, J.C.S. Perkin Trans. 1, 3055)
R1 Nu: E+ R1 Br
Br2, Et3N t-BuOK, THF O
R2N A A+B- B- A+ R2N A R2N O R2N O R2N
R2N R1 DCM 15 - 69%
B B R1
R1 R1
1
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

- "push-pull" ynamines from trichloroenamines and acid chlorides (pp. 1 Neueschwander ref.): From tertiary amines and haloalkynes (Viehe, ACIEE 3, 582)
O NR3
Cl BuLi, Et2O; R1(O)Cl Ph X Ph NR3 Ph NR2
NR2 40h, 55 ºC X– - RX
NR2 X = Cl or Br
Cl R1 C - Ynamines by Isomerization
Cl Principle:
X NR2
- From esters and lithioaminals (Katritzky, JOC 62, 4142): NR2 base
R1 R1 NR2
When R = aryl, this can be done with KOH in DMSO R1
N For R = alkyl:
Li NR2 Al2O3, KNH2, 50 - 80 ºC
N NR2
R1
O ; N NNHTs N 60 - 90% R1
N
N 6 eq. BuLi D - Special Syntheses of Ynamides
R OMe N R From chiral enamides (Hsung OL 1, 1237)
TsNHNH2, -78 to rt
TsOH, PhH N 42% O O O
N R
X NBS or Br2, heat X KOtBu X
- From benzotriazoloketones (Katritzky, OL 2, 3789): N N N R
a) Tf2O, 2,6-Lut 67 - 85% 40 - 88%
> 88% R R R
R
N N R1 R1 Br R1
NaOMe, MeCN X = O, NMe, CH2
~ 8:1 E/Z
O N N or NaOH/THF N N R = Ph or pentyl
> 90% R1= iPr or Ph
B - Ynamines by Substitution Tosylynamides from 2º tosylamines (Brückner, Synlett 2000, 1402)
Nucleophilic substitution on haloalkynes by metal amides R Ts R Ts R Ts R Ts
-More facile on fluoroalkynes than chloroalkynes (different mechanisms) N formylation N PPh3, CCl4, THF N BuLi N
LiNR2 H 85 - 99%
H F Li NR2 Cl
O
LiNR2 Cl
A X A NR2
usually > 60% Alkynyl isocyanates from alkynylacids
A = vinyl, phenyl, EWG; X = Cl, sometimes even OMe 1) (COCl)2
- A can be alkyl (even tBu), but heat and very polar solvents required R COOH R NCO
Most recently, X can be –(–I–Ph)+ –OTf, Prepared from stannyl alkynes and Stang's 2) NaN3, heat
reagent, >15 examples (Stang, JACS 115, 2590)
Acetyl bromides and amides (Hsung, JOC 71, 4170; Danheiser OL 5, 4011)
-these alkynes are so reactive that often a lithium amide is not necessary, just base.
H CuX, base R
Chiral TMS ynamines from dichloroacetylene (Pericas, JOC 65, 7291)
N R1 Br R1 N
X OMe Ph EWG R rt to 75 ºC
Cl 1) R2NH, Et2O, -70 to reflux NR2 EWG
2) 2 eq BuLi, -70 to -10 ºC Finally, from terminal alkynes and "amides" (Stahl, JACS 130, 833)
HNR2 = NH NH NH
3) TMSCl, -10 to rt R
H 20% CuCl2, 2eq py. R2
70 - 96% + N R N
Cl TMS R1 R2
X Ph 2eq Na2CO3, 1atm O2
toluene, 70 ºC
R1
X = OR, H
2
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

IV - Ynamine Methodologies - Ynamines react with acidic CH's (see Ficini Review):
A - Addition Reactions Et2N
B - "Cycloadditions"
1. - [2 + 1] Me
2. - [2 + 2] Et2N Me H3O+, heat O
3. - [4 + 2] O O Et
4. - [3 + n] R
C - Functioalizations R O R O
O
A - Addition Reactions
-Electron-rich ynamines react readily with water:
O CO2Me CO2Me
H2O Et2N Me
R2N R1 R1 Et
R2N
-This has been taken advantage of in anhydride synthesis and peptide coupling:
NEt2
O Et2N Ph O O
96+% Et2N Me H2O
R OH R O R
R = alk or Ar
O O O O O
O H
NH2 + R2N R2 N R Et2N O
R OH
R1 R1 O - Reaction with anhydrides:
Very careful reagent control needed to achieve high yields. See reviews for details.
Me
-Ynamines react with allylic and propargylic alcohols to give 4-alkenyl amides: Et2N O O
TFAA
R1 Et2N Me
R2N R1 LA
R2N O CF3 CF3
OH
O - Reginato studied ynamine umpolung chemistry (TL 34, 3311):
- Hsung applied this stereoselectively with ynamides (OL 4, 1383): 1. TMS2CuCNLi2
THF/HMPA, -23 ºC TMS E
O O Ph2N H
R1 O 2. Electrophile
X OH X R1 72 - 92% NPh2
N Alk N - Himbert's push-pull ynamines can be ozonized to give 1,2,3-triones (Synthesis 1998, 1718):
PNBSA (0.2 eq)
70-80 ºC O O
Ph Ph Alk O O3, DCM, -50 ºC
>80% de
Ph Ph PhMeN PhMeN R
- and with propargylic alcohols (T 62, 3928) R 42 - 93%
O O O
OH - Katrinsky created a homologation sequence for acid chlorides (OL 2, 3789):
O
X X
N O N N
N Alk 1. TsOH
PNBSA (0.1 eq) R N OH
80-85 ºC R Cl 2. -OH, TBAF R
Ph modest yields and de's Ph Alk 45 - 98%
Ph O
Ph
3
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

- Ynamines can be used to "enaminate" indoles at C3 (Y. Zhang, T 62, 3917) 2. [2 + 2] Cycloadditions
Alk - Enamines react with CO2 to give highly reactive ketene-amides (Ficini review)
R2N R1
10% Tf2NH O NR2
+ R2N Alk DCM, -35 ºC Z H
NR2
N
H
74 - 90% R1 O
O O
N CO2
H R1 R1 O
R2N R1 R2N
- Internal capture can yield nitrogen heterocycles (Ficini Review) R2N

NH2
R2N Alk N NR2 O R2N R1
O
CO2R
Alk R1 R1
OH
- Reaction with phosgene or thiophosgene yields a useful synthon (Ficini Review): R2N O NR2
O
- Similarly, reaction with ketones and LA give vinylamides (or imides, for ynamides):
X Cl Cl
Cl Cl Nu: R1 R1
X pyridines O
R2N R1 R2N O oxazoles
etc. O NR2 O NR2
R1
B - "Cycloadditions"
1. [2 + 1] Cycloadditions
X
- Ynamines can react with Rhodium carbenoids to cyclopropenate (Pirrung, TL 35, 6229)
O X X
O O
- This effectively accomplishes a 2-carbon homologation/functionalization of ketones
N2 alkynyl pyrrole Hsung recently applied this intramolecularly to ynamides and called it "yne-carbonyl
N 40% N metathesis" (OL 8, 231)
Rh(OAc)2
O O O
O O
- Ynamides react with DMDO to make reactive oxirenes (Hsung, OL ASAP, DOI: ol703083k) BF3OEt2 (cat) O
O O
N DCM, rt N
n
n 33-88%
Ph ketones, heterocycles, Ph
O maleimides tolerated
- Reactions with aryl isocyanates yield quinolones (Ficini Review, 1468)
O NR2
R2N R1 R1 R1
+

NCO N NR2 N O
H H
favored in polar solvent favored in non-polar solvent
4
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

- Reactions with cyclohexenones achieve stereoselectivity with an equatorial methyl! O O H O

O O
H NEt2 Ts N Ts N Ts N
DEAP
Bn 89% Bn 70% H Bn 57%
- Finally, two-carbon oxidative homologation of aldehydes (Hsung, OL 1, 1237)
Me Me Me
H
80 - 100% trans O >10 examples
- When reacted with cyclopentenone, selectivity of the R1 group is achieved:
R H O O
O O O LiOH
O N Me O N HO
1. DEAP cat BF3•OEt2 90%
O O -78 to rt
2. workup + > 20:1 E:Z Me R Me R
NEt2 OH 58 - 91%
H H
Me Me 3. [4 + 2] Cycloadditions
neutral or basic workup acidic workup - Much better than vinyl ketenes for making pyranes from MVK (Ficini Review)
- A tribute to MRL's demolished shin: Gold cycloisomerizations (Cossy, ACIEE 45, 6726) O NEt2
Me NEt2 Me O NEt2
TsN O
AuCl, DCM TsHN
MeO2C
65% Me O Me
among other examples MeO2C - Complex bicyclic enamines are accessed easily (TL 1976 1025)
> 95:5 dr!! CO2Me CO2Me
OH CO2Me
TsN Ts DEAP 80 ºC NEt2
AuCl, DCM N CHO NEt2
Ph - ethylene
61%
among other examples Me
Me
- Ring expansions of cyclic imines (Viehe, ACIE 5, 585): H3O+; NaBH4
- and pyridines: CO2Me
BF3•OEt2 Ph
O NEt2
Ph NEt2 DEAP
N N NEt2
N O N H
35 ºC Me HO
N R R Me
N
NEt2 - Nitro groups react readily with ynamines to give oxazoloisoxazoles (Nesi, T 55 13809)
Ph Ph Ph
- Pauson-Khand chemistry can be used on ynamides (Witulski ACIE 37, 489) O N N
DEAP
NO2
Ts
Co2(CO)8 (OC)4Co Co(CO)4 alkene, TMANO O 52 - 63% O N
rt to 40 ºC Ts
N N R = H or Ester O
Ts N -stable under CO >95:5 dr R R
Bn Bn Bn
atm, chromatograhable Me CONEt2
5
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

- Boger studied DA's with tetrazines approaching Ningalin D and Purpurone(JOC 68, 3593)
C - Functionalizations
O Ar O Ar Ar - Ynamines can make kinetic anions:
O
NEt2 NEt2 R2N BuLi or LHMDS R2N
N N DEAP N Zn, HOAc X = R3Si or H
N
N N N R2N X R2N
rt
100% Me Me
- "push-pull" ynamines react with hydrazines to give pyrazoles (Zakhartsova, IVVZKKT 41, 28)
O
O Ar O Ar Ar O H2N-NHR1 Me2N NR1 R NR1
4. [3 + n] Cycloadditions Me2N
N N
- "click" like chemistry in 1963 (Huisgen, ACIE 2, 565) R ? yield?
O NMe2
NEt2 R moderate selectivity
Ph O - Brandsma studied the bis-functionalization of ethynylpyrrole (Russ. JOC 32, 1164)
N3
Et2N Ph
N
71% N N
Ph 2 eq n-BuLi
N N E1 OR... with
N X
- similarly, nitrone 1,3-dipoles give isoxazolines (Viehe ACIE 5, 585) E1 = BuI, DMF, TMSCl E = elemental
E2 = H or TMSCl S, Se, or Te
-78 to rt X = S, Se, or Te
O- N 45 - 49%
Ph N 33 to 78%
N Me Me
89% E2
Ph O - Sn and Zn ynamines can be made and used in couplings (Helv. Chim. Acta 83, 641)
Ph N
ZnCl2 or
Ph ClSnBu3 X O
R2N R2N M O
- "push pull" ynamines can give isoxazoles and pyrazoles (Sukhova JOC 29, 1028 and 30, 49) Pd(PPh3)4
THF R2N
NEt2
- Bicyclic aniline derivs. were synthesized by Ranier and Imbriglio (JOC 65, 7272; OL 1, 2037)
O 27% TMS
Fe(CO)5,
PhCNO or
N O TMS PhMe, 100 ºC TMS [O] then E
Et2N O n n dienophile n
O Ph
TsN TsN O TsN
O
N Ar TMS TMS (H)
N N Ar (OC)3Fe R1
H N (H) TMS
Cl O 33 - 48% - Witulski used yne-ynamines in [2+2+2] rxns do make indolines (Synlett 2000 1723)
NEt2
H R Ph
Ph Grubb's or Wilkenson's
TsN
TsN H PhMe
54 - 70% R
Grubbs selective for meta
Wilk's selective for ortho

6
 Baran Group Meeting
I.B. Seiple
Ynamines in Synthesis 1/23/2008

V - Ynamines in Total Synthesis 2004 - Hsung - Desbromoarborescidines A and C (OL 7, 1047)

1994 - Boger's synthesis of bleomycin A2 (JACS 116, 5619) - Keteniminium Pictet–Spengler cyclization
- Report #2 in a series - synthesis of the pyrimidine metal binding domain
NMe
NTs 15% PNBSA
PhMe, 70 ºC NTs 8 steps H

67% N
N 4
H N
H BnO
BnO
4 HO

2006 - Cossy's Heck–Suzuki–Miyaura to lennoxamine (TL 47, 767)

Br O 1. SOCl2, reflux
N 2. Et3N, DMAP, rt
OMe N Br OMe OMe
H2N
MeO CO2H MeO CO2H
O OMe
aq. NaOH, rt
100% Br
MeO OMe MeO OMe
OMe O KHMDS, PhMe, then OMe O
TfO
Bn2N MeO MeO
CO2Et CO2Et N I SiMe3 N
1. H Ph
N N Me N N 1. NaBH4, EtOH, 5 ºC
6d, 70% Br 2. TBAF, 90% Br

EtO2C N CO2Et dioxane, 101 ºC

95 - 98% H2N CO2Et
2. MnO2, 83%
H
2. TfOH, DCM; 75% Me TfO O B(OH)2
Sn
MeO OMe
NHBoc OMe O
O N O O
NHBoc CONH2 O 1. H2, cat Pd/C (80%)
MeS Pd(OAc)2 (5%) MeO 2. H2SO4 (60%)
H2N N N
O
N N CONH2 N N PPh3 (10%)
Me Ph 77%
98 - 100% Ar
H2N CO2Et H2N CO2Et
THF, 0 ºC, 12h, 85% OMe O OMe O
Me Me
O MeO MeO
Xc H2N O H2N O N N
H NHBoc H 1. H2, cat Pd/C (65%)
N 1. Bu3SnH (89 - 95%) N
MeS CONH2 2. NH3•EtOH (80 - 85%)
3. LiOH (90 - 96%) NH2
N N N N
4. HCl•EtOAc (100%) lennoxamine
O O
H2N CO2Et H2N CO2H
Me O O
7