Advanced Organic Reactions 2000 - Warren

SELECTIVITY 1
SELECTIVITY
Science 1983, 219, 245
Chemoselectivity
preferential reactivity of one functional group (FG) over another
- Chemoselective reduction of C=C over C=O:

O H2, O
Pd/C
- Chemoselective reduction of C=O over C=C:

O OH O
NaBH4
+
O OH
NaBH4, CeCl3
only
- Epoxidation:
MCPBA
+
OH OH OH
O O
(2 : 1)
VO(acac)2,
tBuOOH
exclusively
OH OH
O
Regioselectivity
- Hydration of C=C:
1) B2H6
2) H2O2, NaOH OH
R
R OH
R
1) Hg(OAc)2, H2O
2) NaBH4
- Friedel-Crafts Reaction:
O
RCOCl,
AlCl3 R
+ R
O
O
RCOCl,
SiMe3 AlCl3 R
SELECTIVITY 2
- Diels-Alder Reaction:
R O R O R
+ +
O
major minor
O R O
R R
+ +
O
major minor
O O
O O OAc O O OAc
H H
O OAc O OAc O OAc

Raney Ni, H2
O O SPh O O SPh O O
H H H
Change in mechanism:
SPh
PhSH, H+
R
SPh
R
PhSH, (PhCO2)2
Stereochemistry:
Relative stereochemistry: Stereochemical relationship between two or more stereogenic centers
within a molecule
H H H H
HO OH
enantiomers
cholesterol same relative stereochemistry
syn: on the same side ( cis)

anti: on the opposite side (trans)
- differences in relative stereochemistry lead to diastereomers.

Diastereomers= stereoisomers which are not mirror images; usually have different physical
properties
SELECTIVITY 3
Absolute Stereochemistry: Absolute stereochemical assignment of each stereocenter (R vs S)
Cahn-Ingold-Prelog Convention (sequence rules)
- differences in absolute stereochemistry (of all stereocenters within the molecule) leads to
enantiomers.
- Reactions can "create" stereocenters

O MeMgBr HO CH3
Ph H Ph H
MeMgBr
H 3C OH
Ph H
O enantiomers
Ph (racemic product)
H
HO CH3
Ph H
MeMgBr
Diastereomeric transition states- not necessarily equal in energy

Me Me Me Me
N O N
Ph O H
O Zn Zn
O
CH3 CH3 CH3 CH3
H Ph
Zn Zn
H 3C H 3C
HO CH3 HO CH3
Ph H H Ph
Diastereoselectivity
CH3MgBr
CH3 + CH3
Ph Ph
Ph CHO
HO H H OH
syn anti
Diastereomers
Cram Model (Cram's Rule): empirical

O
O O
M S
M H 3C H
R S Nu
CH3MgBr CH3MgBr
L
favored
R H
L Ph
SELECTIVITY 4
Felkin-Ahn Model
O M S O
L Nu L
Nu
S M R
R
favored disfavored
Chelation Control Mode

M
OR
O
O
HO M
OR CH3MgBr S
R CH3MgBr
S M Nu
S M R OR
favored
R
HO
TBSO MgBr TBSO
O
H O relative stereochemical control
H O
OBn OBn
Stereospecific
Stereochemictry of the product is related to the reactant in a mechanistically defined manner; no
other stereochemical outcome is mechanistically possible.
i.e.; SN2 reaction- inversion of configuration is required
Br2 H Br
H 3C
meso
H
Br CH3
Br2 CH3 Br Br CH3

H H
H
+ H
Br CH3 CH3 Br
enantiomers (racemic)
Stereoselective
When more than one stereochemical outcome is possible, but one is formed in excess (even if that
excess is 100:0).
CH3 H
H2, Pd/C H H
H + CH3
H H
α-pinene only isomer not observed
O O O O O O
LDA, CH3I
N O N O + N O Diastereoselective
Enantiospecific
S S S
(96 : 4)
Diasteromers
OXIDATIONS 5
Oxidations
Carey & Sundberg: Chapter 12 problems: 1a,c,e,g,n,o,q; 2a,b,c,f,g,j,k; 5; 9 a,c,d,e,f,l,m,n; 13
Smith: Chapter 3 March: Chapter 19
I. Metal Based Reagents

1. Chromium Reagents
2. Manganese Rgts.
3. Silver
4. Ruthenium
5. other metals
II Non-Metal Based Reagents
1. Activated DMSO
2. Peroxides and Peracids
3. Oxygen/ ozone
4. others
III. Epoxidations
Metal Based Reagents
Chromium Reagents
- Cr(VI) based
- exact stucture depends on solvent and pH
- Mechanism: formation of chromate ester intermediate
Westheimer et al. Chem Rev. 1949, 45, 419 JACS 1951, 73, 65.
HO
HCrO4 - O- R
R Cr
R2CH-OH C O O-
O + HCrO3- + H+
H+ R R
H
+ H2O
Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7)

J. Chem. Soc. 1946 39
Org. Syn. Col. Vol. V, 1973, 310.
- CrO3 + H2O → H2CrO4 (aqueous solution)
K2Cr2O7 + K2SO4
- Cr(VI) → Cr(III)
(black) (green)
- 2°- alcohols are oxidized to ketones

Jones
reagent R
R2CH-OH O
acetone R
- saturated 1° alcohols are oxidized to carboxylic acids.

Jones Jones
reagent O HO OH O
hydration reagent
RCH2-OH
acetone R H R H acetone R OH
- Acidic media!! Not a good method for H+ sensitive groups and compounds
OXIDATIONS 6
1) Jones, SePh
SePh acetone
CO 2CH 3
OH 2) CH2N2
Me 3Si Me 3Si
JACS 1982, 104, 5558
H17C 8 H17C 8
O O
OH O
Jones
O acetone O
JACS 1975, 97, 2870
O O
Collins Oxidation (CrO3•2pyridine)

TL 1969, 3363
- CrO3 (anhydrous) + pyridine (anhydrous) → CrO 3•2pyridine↓
- 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH 2Cl2)
without over-oxidation
- Collins reagent can be prepared and isolated or generated in situ. Isolation of the reagent
often leads to improved yields.
- Useful for the oxidation of H+ sensitive cmpds.
- not particularly basic or acidic
- must use a large excess of the rgt.
CrO3•(C 5H5N)2 H
OH CH 2Cl 2 JACS 1969, 91, 44318.
O
ArO O
ArO O
O
O
CrO3 catalyzed (1-2 mol % oxidation with NaIO6 (2.5 equiv) as the reozidant in wet aceteonitrile.
oxidized primary alcohols to carboxylic acids.
Tetrahedron Lett. 1998, 39, 5323.
Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation)

TL 1975 2647
Synthesis 1982, 245 (review)
CrO3 + 6M HCl + pyridine → pyH+CrO3 Cl- ↓
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc
PCC, CH 2Cl 2
OHC
HO JACS 1977, 99, 3864.
O
O
PCC, CH 2Cl 2
CHO
O
O OH TL, 1975, 2647
OXIDATIONS 7
- Oxidative Rearrangements
Me OH
Me
PCC, CH 2Cl 2
JOC 1977, 42, 682
O
Me
Me
PCC, CH 2Cl 2
JOC 1976, 41, 380
OH O
- Oxidation of Active Methylene Groups
PCC, CH 2Cl 2
O O O
JOC 1984, 49, 1647
PCC, CH 2Cl 2
O O
- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole

JOC 1984, 49, 550.
NH NH
N N
- selective oxidation of allylic alcohols
OH
OH
PCC, CH 2Cl 2
H H 3,5-dimethyl
pyrazole H H
HO
O
(87%)
Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)

TL 1979, 399
- Na2Cr2O7•2H2O + HCl + pyridine → (C5H5N)2CrO7 ↓
PDC PDC
CHO CH 2Cl 2 DMF CO 2H
OH
1° alcohol
-allylic alcohols are oxidized to α,β-unsaturated aldehydes

OXIDATIONS 8
- Supported Reagents Comprehensive Organic Synthesis 1991, 7, 839.
PCC on alumina : Synthesis 1980, 223.
- improved yields due to simplified work-up.
PCC on polyvinylpyridine : JOC, 1978, 43, 2618.
CH 2 CH CH 2 CH R2CH-OH R2C=O CH 2 CH
cross-link CrO3, HCl partially
spent
N N N N reagent
Cr(VI)O3 •HCl Cr(III)
to remove Cr(III)
1) HCl wash
2) KOH wash
3) H2O wash
CrO3/Et2O/CH2Cl2/Celite
Synthesis 1979, 815.
- CrO3 in non-aqueous media does not oxidized alcohols
- CrO3 in 1:3 Et2O/CH2Cl2/celite will oxidized alcohols to ketone and aldehydes
C 8H17 C 8H17
CrO3
Et2O/CH 2Cl 2/celite
(69%)
HO O Synthesis 1979, 815
H2CrO7 on Silica
- 10% CrO3 to SiO2
- 2-3g H2CrO3/SiO2 to mole of R-OH
- ether is the solvent of choice
Manganese Reagents
Potassium Permanganate KMnO4/18-Crown-6 (purple benzene)
JACS 1972 94, 4024.
O
O O
K+ MnO 4-
O O
O
- 1° alcohols and aldehydes are oxidized to carboxylic acids

- 1:1 dicyclohexyl-18-C-6 and KMnO4 in benzene at 25°C gives a clear purple solution as high
as 0.06M in KMnO4.
O
JACS 1972, 94, 4024

CO 2H
CHO
Synthesis 1984, 43
CL 1979, 443
CHO
OXIDATIONS 9
Sodium Permanganate
TL 1981, 1655
- heterogeneous reaction in benzene
- 1° alcohols are oxidized to acids
- 2° alcohols are oxidized to ketones
- multiple bonds are not oxidized
Barium Permanganate (BaMnO4)
TL 1978, 839.
- Oxidation if 1° and 2° alcohols to aldehydes and ketones- No over oxidation
- Multiple bonds are not oxidized
- similar in reactivity to MnO2
Barium Manganate
BCSJ 1983, 56, 914
Manganese Dioxide
Review: Synthesis 1976, 65, 133
- Selective oxidation of α,β-unsatutrated (allylic, benzylic, acetylenic) alcohols.
- Activity of MnO2 depends on method of preparation and choice of solvent
- cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double
bond.
OH OH
HO HO
MnO 2, CHCl3
(62%) J. Chem. Soc. 1953, 2189

JACS 1955, 77, 4145.
HO O
- oxidation of 1° allylic alcohols to α,β-unsaturated esters

MnO2,
OH ROH, NaCN
CO 2R
OH CO 2Me
MnO 2, Hexanes JACS1968, 90, 5616. 5618
MeOH, NaCN
Manganese (III) Acetate α-hydroxylation of enones

Synthesis 1990, 1119 TL 1984 25, 5839
O O
Mn(OAc)3, AcOH AcO
Ruthenium Reagents
Ruthenium Tetroxide
- effective for the conversion of 1° alcohols to RCO2H and 2° alcohols to ketones
- oxidizes multiple bonds and 1,2-diols.
OXIDATIONS 10
RuO4, NaIO4 CO 2H
Ph OH Ph
O CCl 4, H2O, CH3CN O
JOC 1981, 46, 3936
OH
RuO4, NaIO4
Ph OH Ph CO 2H
CCl 4, H2O, CH3CN
H CH 3 H CH 3 94%ee
96% ee
HO
RuO2, NaIO4 O
TL 1970, 4003
CCl 4, H2O
O O
O O
Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-)

Aldrichimica Acta 1990, 23, 13.
Synthesis 1994, 639
- mild oxidation of alcohols to ketones and aldehydes without over oxidation
OH O
TPAP
MeO 2C MeO 2C
OSiMe 2tBu O OSiMe 2tBu
N+ TL 1989, 30, 433

-O Me
(Ph3P)4RuO2Cl3 RuO2(bipy)Cl2
- oxidizes a wide range of 1°- and 2°-alcohols to aldehydes and ketones without oxidation of
multiple bonds.
OH
CHO
CHO
OH JCS P1 1984, 681.
H H
Ba[Ru(OH)2O3]
-oxidizes only the most reactive alcohols (benzylic and allylic)
(Ph3P)3RuCl2 + Me3SiO-OSiMe3
- oxidation of benzylic and allylic alcohols TL 1983, 24, 2185.
Silver Reagents
Ag2CO3 ( Fetizon Oxidation) also Ag2CO3/celite Synthesis 1979, 401
- oxidation of only the most reactive hydroxyl
O O
OH Ag 2CO 3 O
OH OH JACS 1981, 103, 1864.

mechanism: TL 1972, 4445.
O
O OH Ag 2CO 3, C 6H6 O
OH O
O O
OXIDATIONS 11
- Oxidation of 2° alcohol over a 1° alcohol
OH Ag2CO3, Celite OH
JCS,CC 1969, 1102
OH (80%) O
Silver Oxide (AgO2)
- mild oxidation of aldehyde to carboxylic acids
AgO 2, NaOH RCO 2H
RCHO
CO 2H
CHO AgO 2
JACS 1982, 104, 5557
Ph
Ph
Prevost Reaction Ag(PhCO2)2, I2

Ag(PhCO 2)2, I2 AcO OAc
AcOH
Ag(PhCO 2)2, I2 AcO OH
AcOH, H 2O
Other Metal Based Oxidations

Osmium Tetroxide OsO 4
review: Chem. Rev. 1980, 80, 187.
-cis hydroxylation of olefins
old mechanism:
OsO 4, NMO O O OH
Os
O O OH
osmate ester
intermediate cis stereochemistry
- use of R 3N-O as a reoxidant

TL 1976, 1973.
OsO 4, NMO O OH
O
O OH
O OH
OH
TL 1983, 24, 2943, 3947
Stereoselectivity: OsO 4
R2 R3 HO H
OsO 4, NMO R2 HO
R4 R3
RO H RO H R4
OXIDATIONS 12
- new mechanism: reaction is accelerated in the presences of an 3° amine
R1 R1
O
O O R1 R3N R2
R2 O
Os R2 O
O Os Os O
O O [2+2] O
O O NR3
[O]
[3+2] R1 OsO2
[O]
R2
O hydrolysis R1 R2
O
Os O
O + OsO4
O HO OH
- Oxidative cleavage of olefins to carboxylic acids.
JOC 1956, 21, 478.
- Oxidative cleavage of olefins to ketones & aldehydes.
OH
CHO
OH O
OsO 4, NMO NaIO4 CHO H2O
O OH O O
O O
O O
O O
OAc OAc
OAc
JACS 1984, 105, 6755.
Substrate directed hydroxylations: Chem. Rev. 1993, 93, 1307

-by hydroxyl groups
HO HO
OsO4,
O HO HO
pyridine
O + O
HO
HO HO
3:1
HO
OsO4, HO
O pyridine O
TMSO
TMSO
HO CH3 HO CH3 OH HO CH3 OH

OsO4, Et2O
OH + OH
CH3 CH3 (86 : 14) CH3
- by amides
AcO AcO
OH
MeS MeS
OsO4
OH
HN HN
O O
OAc OAc
OXIDATIONS 13
- by sulfoxides
•• O OMe •• O OMe OH
S OsO4 S
OH
(2 : 1)
••
O OAc
••
1) OsO4 O
S 2) Ac2O S
HN O AcO HN O
(20 : 1)
- by sulfoximines
O O
Ph S Ph S O
OH OH
MeN OsO4, R3NO MeN ∆ OH
OH
OH OH
CH3
Raney nickel
H 3C OH
OH
OH
CH3
- By nitro groups
PhO2S N
PhO2S N 1) OsO4 NHR
+ N
N NHR 2) acetone, H O2N
O2N N N
N N O O
N
N HO N NHR
HO N NHR
N N
N N O O
- OsO4 bis-hydroxylation favors electon rich C=C.

OsO4
X + X
X OH OH
OH OH
X= OH 80 : 20 (directing effect ?)
= OMe 98 : 2
= OAc 99 : 1
= NHSO2R 60 : 40 (directing effect ?)
- Ligand effect:
OsO4
X + OH
OH K3Fe(CN)6, K2CO3 OH OH
MeSO2NH2, tBuOH/H2O OH OH
OsO4 (no ligand) 4:1

Quinuclidine 9:1
DHQD-PHAL > 49 : 1
OXIDATIONS 14
Sharpless Asymmetric Dihydroxylation (AD) Chem. Rev. 1994, 94, 2483.
- Ligand pair are really diastereomers!!
dihydroquinidine ester
N
"HO OH" Ar
H
H OR'
R3 R3 OH
R2 0.2-0.4% OsO4
R2 80-95 % yield
R1 20-80 % ee
acetone, H 2O, MNO
R1 OH
H OR'
"HO OH" Ar
MeO
N Ar =
dihydroquinine ester
N
R'= p-chlorobenzoyl
Mechanism of AD:
L
HO OH
O
O O
H 2O Os
O O
O
O O
Os
O O
First Cycle Second Cycle
(high enantioselectivity) [O] (low enantioselectivity) [O]
O
O
O Os
O O
O
L Os
O O
L
O
O O
Os
O O
O
R 3N HO OH
H 2O, L
- K3Fe(CN)6 as a reoxidant gives higher ee's- eliminates second cycle
TL 1990, 31, 2999.
- Sulfonamide effect: addition of MeSO2NH2 enhances hydrolysis of Os(VI) glycolate
(accelerates reaction)
- New phthalazine (PHAL) ligand's give higher ee's
N Et
Et N
Et N Et
N N
N N N
O O
H H O O
OMe H H
MeO
MeO OMe
N N
N N
(DHQD)2-PHAL (DHQ)2-PHAL
JOC 1992, 57, 2768.
OXIDATIONS 15
- Other second generation ligands
N Et Et
Et Ph N N
O O N O
H H H
MeO N N OMe O OMe
Ph
N N N
PYR IND
Proposed catalyst structure:

"Bystander
quinoline
O Os Asymmetric
O H N (side wall)
MeO N Binding
O Os Cleft
O
N
H
H N
N N
O N
O
Phthalazine
OMe Floor
N
OMe
OMe
Corey Model: JACS 1996, 118, 319 O N

Enzyme like binding pocket; O
O
[3+2] addition of OsO4 to olefin. Os O N H
N O N N
O O N
DHQL
Rs RM RL large and flat,

i.e Aromatics work particularly well
RL H
DHQ
OXIDATIONS 16
Olefin Preferred Ligand ee's
R1 PYR, PHAL 30 - 97 %
R2
R1 PHAL 70 - 97 %
R1
IND 20 - 80 %
R2
R2
R1 PHAL 90 - 99.8 %
R2
R3
R1 PHAL 90 - 99 %
H
R2
R3 PHAL, PYR 20 - 97 %
R1
+ MeSO2NH2
R4
"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant

AD-mix α (DHQ)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4 (0.4 MOL % Os to C=C)
AD-mix β (DHQD)2PHAL, K 3Fe(CN)6, K2CO3, K2OsO4
O
HO
O
Campthothecin
N
N
O
OMe OMe OMe

AD
N O (DHQD)2PYR N O N O
94 % ee OH O
OH OH
- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)

H Ph
Ph H olefins with axial
dissymmetry
tBu tBu
H H
Ph Ph
AD mix α Ph OH
OH
30% conversion
OH H
+ +
Ph OH
tBu H tBu
tBu (4 : 1) tBu
enriched
OXIDATIONS 17
Asymmetric Aminohydroxylation TL 1998, 39, 2507; ACIEE 1996, 25, 2818, 2813,
preparation of α-aminoalcohols from olefin. Syn addition as with the dihydroxylation
regiochemistry can be a problem
O O
Cl OH
Ph O N CO2Me
Na Ph O NH Ph
CO2Me +
Ph CO2Me N O Ph
K2OsO6H4 (cat) Ph
Ligand OH O
Ligand= PHAL 4:1
AQN 1:4
Molybdenum Reagents
MoOPH [MoO5•pyridine (HMPA)]
JOC 1978, 43, 188.
- α-hydroxylation of ketone, ester and lactone enolates.
O O
O- O O THF, -78°C
+ Mo R'
R' O R
R O
L L OH
Palladium Reagents
Pd(0) catalyzed Dehydrogenation (oxidation) of Allyl Carbonates (Tsuji Oxidation)
Tetrahedron 1986, 42, 4361
O
R O 2 CO R R R
OH Pd(0)
H O O O Pd O
H - CO 2 H
R Pd(OAc) 2, R - R
R
CH 3CN, 80° C TL 1984, 25, 2791
HO
H HO
OH O CO H
2 OH
Pd2(DBA) 3•CHCl 3, JACS 1989, 111, 8039.

H O OH
CH 3CN, 80° C H O O
Oxidation of silylenol ethers and enol carbonates to enones

O OTMS Pd(OAc) 2, O
CH 3CN
O O Pd(OAc) 2, O
CH 3CN
OTIPS O
(NH 4)2Ce(NO 3)6
DMF, 0°C
Ph Ph TL 1995, 36, 3985
OXIDATIONS 18
Oppenauer Oxidation Synthesis 1994, 1007 Organic reactions 1951, 6, 207
OiPr R1R2CHOH OiPr O
+O Al H +O Al + Al(OiPr)3
OiPr (CH3)2C=O R1 R2
R1 O OiPr
R2
Nickel Peroxide
Chem Rev. 1975, 75, 491
Thallium Nitrate (TNN, Tl(NO 3)3•3H2O
Pure Appl. Chem. 1875, 43, 463.
Lead Tetraacetrate Pb(OAc)4 Oxidations in Organic Chemistry (D), 1982, pp 1-145.
Non-Metal Based Reagents

Activated DMSO Review: Synthesis 1981, 165; 1990, 857. Organic Reactions 1990, 39, 297
Me Me
Me E Nu: +
S+ O- + E S+ O Nu S + E-O
Me Me Me
E= (CF3CO)2O, SOCl2, (COCl)2, Cl2, (CH3CO)2O, TsCl, MeCl, SO3/pyridine, F 3CSO2H,
PO5, H3PO4, Br2
Nu:= R-OH, Ph-OH, R-NH2, RC=NOH, enols
Swern Oxidation
- trifluoroacetic anhydride can be used as the activating agent for DMSO
O
Me Me Me
(COCl) 2 Cl -CO, -CO 2
S + O- S+ O Cl - S + Cl
CH 2Cl 2, -78°C Me
Me Me O
R Me
R2CH-OH Me R Et3N: R
S+ O O + S
Me R Me
H
B:
O O
Cl
DMSO, (COCl) 2
TL 1988, 29, 49.
CH 2Cl 2, Et3N
OH O
Moffatt Oxidation (DMSO/DCC) JACS 1965, 87, 5661, 5670.
Me C 6H11 Me R
S + O- CF 3CO 2H, R R
Me NH S+ O
Pyridine R2CH-OH O
Me S +
O C Me
H
+ N R
Me
C 6H11 N C N C 6H11 C 6H11 B:
CHO
OH DCC/ DMSO
JACS 1978, 100, 5565
CO 2Me CO 2Me
CF 3CO 2H,
O Pyridine O
S S
SO3/Pyridine JACS 1967, 89, 5505.

CO 2Me CO 2Me
HO OH HO H
H
SO 3, pyridine,
DMSO, CH 2Cl 2 CONH 2
CONH 2
JACS 1989, 111, 8039.
O
H OH H
HO
OXIDATIONS 19
Corey-Kim Oxidation (DMS/NCS) JACS 1972, 94, 7586.
O
Me Me
S: + N Cl S + Cl
Me Me
O
N-Chlorosuccinimide
(NCS)
Oxygen & Ozone
Singlet Oxygen Acc. Chem. Res. 1980, 13, 419 Tetrahedron 1981, 37, 1825
•• •• hν
••
••
•O O • O O
•• ••
••
••
triplet singlet
H "ene" reaction H Ph3P:

O
O O OH
O
Tetrahedron 1981, 1825
1) O2, hν, Ph2CO HO

2) reduction
Ozone Comprehensive Organic Synthesis 1991, 7, 541

O O
O 3, CH 2Cl 2 O O Ph3P: O + O
-78°C O O NaBH 4
H
Jones OH
RCOOH
Other Oxidations
Mukaiyama Oxidation BCSJ 1977, 50, 2773
O
N N
N N
R PrMgBr R R
O
CH OH CH O MgBr O
R THF R
R
OH
OHC
Cl CH 3 O Cl CH 3 O
O O
MeO NH MeO NH
O N N N N O
OEt OEt
O O
tBuMgBr, THF
SEt (70%) SEt
SEt SEt
MeO MeO
JACS 1979, 101, 7104

OXIDATIONS 20
OH O
tBuMgBr, THF
O
N N
N N
O O O
Dess-Martin Periodinane JOC 1983, 48, 4155. JACS 1992, 113, 7277.
- oxidation conducted in CHCl3, CH3CN or CH2Cl2
- excellent reagent for hindered alcohols
- very mild
AcO OAc OAc
I R I
••
R2CH-OH
OAc O + O + 2 AcOH
O
R
O O
Dess-Martin O
HO JOC 1991, 56, 6264
(99%)
RO
RO
Chlorite Ion
-oxidation of α,β-unsaturated aldehydes to α,β−unsaturated acids.
NaClO 2, - HClO2
NaH2PO 4
tBuOH, H 2O OBn OBn
OBn
OH
CHO H CO 2H
-O-Cl-O
Selenium Dioxide
- Similar to singlet oxygen (allylic oxidation)
1) SeO2
2) NaBH 4
OAc
OAc
OH
Phenyl Selenium Chloride
O O Ph O
OLi
SePh Se
PhSeCl H2O 2 - PhSeOH
O-
THF
H
- PhS-SPh will do similar chemistry however a sulfoxide elimination is less facile than a
selenoxide elinimation.
Peroxides & Peracids

- R3N: → R3N-O
- sulfides → sulfoxides → sulfones
-Baeyer-Villiger Oxidation- oxidation of ketones to esters and lactones via oxygen insertion
Organic Reactions 1993, 43, 251 Comprehensive Organic Synthesis 1991, vol 7, 671.
OXIDATIONS 21
m-Chloroperbenzoic Acid, Peracetic Acid, Hydrogen peroxide
O H O H
O O 2N O
O O
Cl NO 2
H
O O
O
R1 C R2
R1 R2 R2 + ArCO2H
O R1 O
O
O Ar
HO O Ar
O
- Concerted R-migration and O-O bond breaking. No loss of stereochemistry
- Migratory aptitude roughly follows the ability of the group to stabilize positive charge:
3° > 2° > benzyl = phenyl > 1° >> methyl
JACS 1971, 93, 1491
O O
HO
O
O mCPBA O CO2H
CHO
O O HO CO2H
O HO OH
PGE1
O
O
CH3 mCPBA O Tetrahedron Lett. 1977, 2173
Tetrahedron Lett. 1978, 1385
(80 %) CH3
CH3
CH3
Oxone (postassium peroxymonosulfate) Tetrahedron 1997, 54, 401

oxone
RCHO RCOOH
acetone (aq)
Oxaziridines
reviews: Tetrahedron 1989, 45, 5703; Chem. Rev. 1992, 92, 919
O
R3
N C
R R2
- hydroxylation of enolates
O
_
O O R O
Base R'
R R _ R + PhSO2N=CHPh
R' R' R'
O NSO2Ph
O Ph HO
Ph
N
PhSO2
O By-product
_ supresed by using
O R
R' bulkier oxaziradine
R + PhSO2N=CHPh such as camphor
R' oxaziradine
Ph NHSO2Ph
OXIDATIONS 22
Asymmetric hydroxylations
O
O
MeO 2C NaN(SiMe3)2, THF HO
MeO 2C Tetrahedron 1991, 47, 173
OMe
OMe
N (67% ee)
Ar SO 2 O
MeO O MeO O O OH O
KN(SiMe3)2 OH
CO2Me CO2Me OH
OH
MeO N MeO MeO O OH OH

SO2 O
(>95% ee)
- hydroxylation of organometallics
R-Li or R-Mg → R-OH JACS 1979, 101, 1044
- Asymmetric oxidation of sulfides to chiral sulfoxides.

JACS 1987, 109, 3370.
Synlett, 1990, 643.
Remote Oxidation (functionalization) Comprehensive Organic Synthesis 1991, 7, 39.

Barton Reaction
NOCl, CH2Cl2
pyridine hν
- NO
OH O • O
NO • OH
H •
•NO JACS 1975, 97, 430
OH OH
NO N N
HO perhydrohistricotoxin
ketone C5H11
oxidation state
Epoxidations
Peroxides & Peracids
- olefins → epoxides Tetrahedron 1976, 32, 2855
- α,β-unsaturated ketones, aldehydes and ester → α,β-epoxy- ketones, aldehydes and esters
(under basic conditions).
O O
tBuOOH
triton B, C6H6
O JACS 1958, 80, 3845
(CH 2)n (CH 2)n
OXIDATIONS 23
CO 2Me O CO 2Me
mCPBA, NaHPO3
TL 1988, 23, 2793
O O
H H
O O
Henbest Epoxidation- epoxidation directed by a polar group

OH OH OH
mCPBA
O + O
10:1 diastereoselection
OAc OAc OH
mCPBA
O + O
1:4 diastereoselection
O O
Ph NH
Ph NH
mCPBA "highly selective"
O
Ar
O O
H proposed transition state:
O -OH directs the epoxidation
H
O
- for acyclic systems, the Henbest epoxidation is often less selective
Rubottom Oxidation: JOC 1978, 43, 1588

O OTMS TMSO O
O H2O
LDA, TMSCl OH
mCPBA
Sharpless Epoxidation tBuOOH w/ VO(acac)2, Mo(CO)6 or Ti(OR) 4

Reviews: Comprehensive Organic Synthesis 1991, vol 7, 389-438
Asymmetric Synthesis 1985, vol. 15, 247-308
Synthesis, 1986, 89. Org. React. 1996, 48, 1-299.
Aldrichimica Acta 1979, 12, 63
review on transition mediated epoxidations: Chem. Rev. 1989, 89, 431.
- Regioselective epoxidation of allylic and homo-allylic alcohols
- will not epoxidize isolated double bonds
- epoxidation occurs stereoselectively w/ respect to the alcohol.
OXIDATIONS 24
- Catalysts: VO(acac)2; Mo(CO)6; Ti(OiPr)4
- Oxidant: tBuOOH; PhC(CH3)2OOH
VO(acac)2
tBuOOH
OH OH
O
OH OH
O
(CH2)n (CH2)n
ring size VO(acac)2 MoO2(acac)2 mCPBA

5 >99% -- 84
6 >99 98 95
7 >99 95 61
8 97 42 <1
9 91 3 <1
Acyclic Systems:
tBu
O R1
L M
L R3 Rt
1,3-interaction O
O
R3 Rc
Rt
R2 O
R1 Rc O
A1,2-strain
M
O
R2 L
A1,3-strain L
Major influences:
A1,2-Strain between Rg and R1 (Rg and R2)
A1,3 -strain between R2 and Rc (R1 and Rc)
1,3-interactions between L and R1 (L and R2)
VO(acac)2,
tBuOOH
O
+ O
OH OH OH
(4 : 1)
tBu
CH3 H L O
H M
H O O L O
M L O H
L H 3C
O H
tBu
H
OXIDATIONS 25
VO(acac)2,
tBuOOH
O
+ O
OH OH OH
(19 : 1)
tBu H
O H 3C H
L
M H
L O H 3C O O
H 3C O H M L
H H L
O
tBu
CH3
SiMe3 SiMe3 SiMe3

VO(acac)2,
tBuOOH
O
+ O
OH OH OH
(> 99 : 1)
- Careful conformational analysis of acyclic systems is needed.
Homoallylic Systems
L
L
V OtBu
O O O
OH OH
dominent stereocontrol element
Titanium Catalyst structure:

RO2C
OR OR
RO CO2R
Ti O O
Ti
O O O OR
O OR
OR
CO2R CO2R
OR O OR O
RO CO2R RO CO2R
Ti O O O
Ti Ti Ti O
CO2R
O O O O O CO2R
O O O
O O
tBu tBu
OR OR
Disfavored Favored
OXIDATIONS 26
Asymmetric Epoxidation
tBuOOH, Ti(OiPr), (+) or (-) Diethyl Tartrate, 3Å molecular sieves
Empirical Rule
R1
R2 (+)- DET epoxidation from the bottom
(-)- DET epoxidation from the top
R3 OH
Catalytic system: addition of molecular sieves to "soak" up any water with 3A sieves, 5-10 mol %
catalyst is used.
Preparation of Allylic Alcohols:
[(CH3)2CHCH2]2AlH Na (MeOCH2CH2O)2AlH2
CO2R'
R (DIBAL) R OH
(REDAL)
R CHO R C C CH2OH
R R
[(CH3)2CHCH2]2AlH
CO2R' H2, Lindlar's Catalyst
OH
"In situ" derivatization of water soluble epoxy-alcohol

(-)-DIPT
O
OH
(R)-glycidol
OH water soluble
O
OH
(+)-DIPT
(S)-glycidol
O
O O
O S NO2 organic soluble
OH
O
Alkoxide opening of epoxy-alcohol product

reduced by use of Ti(OtBu)4 and catalytic conditions
O- O
O OH
OH OH
R from R
Ti(OiPr)4
Stoicheometric vs Catalytic epoxidation:

(+)-DET
Ti(OiPr)4
tBuOOH
O
OH OH
stoicheometric: 85% ee
catalytic (6-7 mol %) 47% yield >95% ee
in situ deriv. with PNB 78% yield 92 % ee >98 %ee after 1 recrystallization
(+)-DET
R Ti(OiPr)4 R
tBuOOH
O
OH OH
yields: 50 - 100 %
ee: > 95%
OXIDATIONS 27
Ring Opening of Epoxy-Alcohols
REDAL OH
R OH
O 1,3-Diol
AE
R OH R OH
R OH
DIBAL
OH
1,2-Diol
Two dimensional amplification

OH OH OH
(+)-DIPT, Ti(OiPr)4,
tBuOOH, 3A sieves +
(90 % ee)
O O
OH OH
OH 95 : 5
major minor
major minor major minor
95 : 5 95 : 5
OH OH
O O OH
O
O O
OH OH O
OH
90 % meso 0.25 %
(>99.5 % ee) 9.75%
Kinetic Resolution of Allylic Alcohols

(+)-DIPT, Ti(OiPr)4,
OH tBuOOH, 3A sieves O
OH + OH
R R R
CO2R
OR
O H
RO CO2R
Ti O
Ti O
O O O CO2R
O
O
tBu
OR
OXIDATIONS 28
R3 R4 kinetic resolution R3 R4 R3 R4
-20 °C, 0.5 - 6 days O
R2
OH
R2
OH + R2
OH
R1 R1 R1
40 - 50 % yield 40 - 50 % yield
> 99 % ee high ee
Reiterative Approach to the Synthesis of Carbohydrate

OR OR (+)-DET, Ti(OiPr)4,
OR (MeO)2P(O)CH2CO2Me DIBAL tBuOOH, 3A sieves
CHO NaH
OH
CO2Me
OR OR OR OR
HO-
OH OH acetone, H+ O mCPBA, Ac2O
O -
O
OH PhS
HO O Pummerer
SPh SPh
PhS-
CHO
OR OR OR
HO H
O O O
DIBAL HO H
OAc O HO H
O O CHO O
HO H
SPh O CHO CH2OH
L-glucose
Jacobsen Aysmmetric Epoxidation

JACS 1990, 112, 2801; JACS 1991, 113, 7063; JOC 1991, 56, 2296.
- Reaction works best for cis C=C conjugated to an aromatic ring
H H H H
N N NaOCl N N
Mn Mn
O Cl O O O
O
tBu tBu tBu tBu
O 5 mol % Cat. ,NaOCl, O

H2O, CH2Cl2
(98% ee)
O
86% ee
Methyltrioxoruthenium (MTO) Ru(VII)

Sharpless et al. JACS 1997, 117, 7863, 11536.
0.5 mol % MTO Ru (VII),
Ph pyridine, CH2Cl2 Ph
O
1.5 eq. 30% H2O2 (aq.)
OXIDATIONS 29
Oxaziridines
- Asymmetric epoxidation of olefins Tetrahedron 1989 45 5703
CH3
O2 O
Ph * N S N *
C6F5
Ph *
Dioxiranes (Murray's Reagent) Reviews: Chem. Rev. 1989, 89, 1187; ACR 1989, 27, 205
Org. Syn. 1996, 74, 91
KHSO 5 O
O
"oxone" O
- epoxidation of olefins
OTBS O
OTBS
O
TBSO O TBSO O JOC 1990, 55, 2411
TBSO CH 2Cl 2, acetone TBSO
(100%) O
- Asymmetric epoxidation JACS 1996, 118, 491.

- oxidation of sulfides to sulfoxides and sulfones
- oxidation of amines to amine-N-oxides
- oxidation of aldehydes to carboxylic acids
- hydroxylation of enolates
1) LDA
2) Cp 2TiCl2 OH
H JOC 1994, 59, 2358

O 3) O
O O
- bis-trifluoromethyldioxirane, much more reactive
JACS 1991, 113, 2205.
F3C O
F3C O
- oxidation of alcohols to carbonyl compounds. 1° alcohols give a mixture of aldehydes and

carboxylic acids.
- Insertion into 3° C-H bonds to give R3C-OH
DCC-H2O2 JOC 1998, 63, 2564

R O
N H O
H2O2, MeOH R
R N C N R R + H C H
H C O N N
N O
R R
R
REDUCTIONS 30
Carey & Sundberg Chapter 5 problems: 1a,b,c,d,f,h,j; 2; 3a-g, n,o; 4b,j,k,l; 9; 11;
Smith: Chapter 4 March: Chapter 19
Reductions
1. Hydrogenation
2. Boron Reagents
3. Aluminium Reagents
4. Tin Hydrides
5. Silanes
6. Dissolving Metal Reductions
Hydrogenations
Heterogeneous Catalytic Hydrogenation
Transition metals absorbed onto a solid support
metal: Pd, Pt, Ni, Rh
support: Carbon, alumina, silica
solvent: EtOH, EtOAc, Et2O, hexanes, etc.
- Reduction of olefins & acetylenes to saturated hydrocarbons.

- Sensitive to steric effects and choice of solvent
- Polar functional groups, i.e. hydroxyls, can sometimes direct the delivery of H2.
- Cis addition of H2.
R1 R1 H2, Pd/C H H
R1 R1
R2 R2 R2 R2
- Catalyst can be "poisoned"
- Directed heterogeneous hydrogenation
O O
H
H2, Pd/C
O O
MeO OH MeO OH
O H2, Pd/C H O
O O
MeO CO2Me MeO CO2M2
(86 : 14)
Lindlar Catalyst ( Pd/ BaSO4/ quinoline)- partially poisoned to reduce activity; will only
reduce the most reactive functional groups.
acetylenes + H2, Pd/BaSO4/ quinoline → cis olefins (Lindlar Reduction)

Acid Chlorides + H2, Pd/BaSO4 → Aldehydes (Rosemund Reduction)
Org. Rxn. 1948, 4, 362
H2, Pd/BaSO4, Quinoline SiMe 3

R SiMe 3
TL 1976, 1539
R
O O
H2, Pd/BaSO4, pyridine
CO 2Me CO 2Me
JOC 1982, 47, 4254
REDUCTIONS 31
H2, Lindlar Catalyst
CH 2Cl 2: MeOH: Quinoline
HO OH
(90:9.5:0.5)
8π e- JACS 1982, 104, 5555

conrotatory 6π e-
disrotatory H
H
HO OH
HO OH HO OH H
Ease of Reduction: (taken from H.O. House Modern Synthetic Reactions, 2nd edition)
R COCl R CHO
R NO 2 R NH 2
R R' R R'
R CHO R CH 2-OH
R CH CH R' R CH 2 CH 2 R'
O HO H
R R' R R'
R Ar CH 3 + HO R
Ar O
R C N R CH 2 NH 2
O
R CH 2-OH + HO R'
R OR'
O
CH 2 R'
R' R N
R N
R'
R'
requires high
temperature & pressure
R CO 2- Na+ no reaction
Raney Nickel Desulfuriztion ,

Reviews: Org. Rxn. 1962, 12, 356; Chem. Rev. 1962, 62, 347.
R R S Raney Nickel R H
O (CH 2)n
R R S R H
REDUCTIONS 32
O O O O O O
HO HO
Raney Nickel
JOC 1987, 52, 3346
EtOH
S H H
(74%)
Homogeneous Catalytic Hydrogenation

- catalyst is soluble in the reaction medium
- catalyst not "poisoned" by sulfur
- very sensitive to steric effects
- terminal olefins faster than internal; cis olefins faster than trans
R
R R
> > > R > >> R
R R R R R R
R R
R
- (Ph3P)3RhCl (Wilkinson's Catalyst); [R3P Ir(COD)py]+ PF6- (Crabtree's Catalyst)
OH (Ph3P)3RhCl, H2
OH
JOC 1992, 57, 2767
C 6H6
(92%)
Directed Hydrogenation
Review: Angew. Chem. Int. Ed. Engl. 1987, 26 , 190
- Diasterocontrolled hydrogenation of allylic alcohols directed by the -OH group
- +
O K
O- K+
PPh3
(Ph3P)3RhCl, H2 O PPh3
Rh H
H
H
MeO
MeO
Ph Ph
P P(C 6H11)3
BF4- Ir +
Rh+ PF6 -
N
P
Ph Ph
Brown's Catalyst
(Crabtree's Ctalyst)
JACS 1983, 105 , 1072
Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than
isolated double bonds
MeO2C
MeO2C
OH
OH
REDUCTIONS 33
mechanism:
OH +
L + H2 + L
M L S M
M
L L S L O
H
lose
reductive H2
elimination (oxidative
H addition)
H OH
migratory H +
HO
H insertion H
M M
L L S L L O
H
Diastereoselective Hydrogenation: since -OH directs the H2, there is a possibility for control of
stereochemistry
- sensitive to: H2 pressure
catalyst conc.
substrate conc.
solvent.
Regioselective Hydrogenation- allylic and homoallylic alcohols are hydrogenated faster than
isolated double bonds
HO HO
"Ir"
(20 mol %)
O O (24 : 1)
H
Brown's Catalyst
JACS 1984, 106, 3866
OH H2 (640 psi), CH2Cl 2 OH
H
OMe OMe OMe

OMe
H
Me Brown's Catalyst
Me
TL 1987, 28 , 3659
H2 (1000 psi)
O O
OH OH
Selectivity is often higher with lower catalyst concentration:

20 mol % 2.5 mol %
OH OH Catalyst Catalyst
50 : 1 150 : 1
OH OH
33 : 1 52 : 1
REDUCTIONS 34
Olefin Isomerization:
CH3
(3 : 1)
OH OH
olefin
isomerization
major
product
OH O
- Conducting the hydrogenation at high H 2 pressures supresses olefin isomerization and often
gives higher diastereoselectivity.
Other Lewis basic groups can direct the hydrogenation. (Ir seems to be superior to Rh for
these cases)
OMe CO2Me
OMe CO2Me
+
Ir
99 : 1 Ir+ > 99 : 1
Rh+ 32 : 1
O O
CO2H CO2H
> 99 : 1 Ir+ 7 : 1
Rh+ 1 : 1
O O
O N O N O
O
1:1 130 : 1
Acyclic Examples
Me
OH Rh+ (2 mol %)
CH 3
H2 (15 psi) JCSCC 1982, 348
Me OH
(97:3)
L
H
L M O
OH
H
Ph Ph
H anti
H 3C H
CH3 1,2-strain OH
H
H Ph syn
Ph
H
L M O
H
L
REDUCTIONS 35
L
H
L M O
OH
R3 favored
R2
H R3 R1 syn
R1 H
OH R2
R3 R1
R2
H R1 disfavored OH
R3 anti
R2 R3 R1
H 1,2-strain
R2
L M O
H
L
- Supression of olefin isomerization is critical for acyclic stereocontrol !

L
H
L M O
OH OH
R2
R2 R1 CH3
H R2 R1 anti
CH3 R1 H
R2
olefin
isomerization
OH L OH
H
L M O syn
R2 R1 R2 R1
H R2
CH2R2
H
R1 H
- Rh+ catalyst is more selective than Ir + for acyclic stereoselection.
Acyclic homoallylic systems:

HO
R1 R3
R2
relative
stereochemistry
is critical
A 1,3-strain
A
E L R3 L
O M E
L O M
R2 H 1,2-strain R2 L
H
R3
REDUCTIONS 36
OH Rh+ (20 mol %) OH
H2 (15 psi)
OBz OBz
TBSO TBSO 32 : 1
Tetrahedron Lett. 1985, 26, 6005

OH Rh+ (20 mol %)
OH
H2 (15 psi)
OBz OBz
TBSO TBSO 8:1
Asymmetric Homogeneous Hydrogenation

- Chiral ligands for homogeneous hydrogenation of olefins and ketones
H
O PPh2 PPh2 PPh2
P PPh2
MeO OMe PPh2 PPh2
O PPh2 PPh2
P H
DIOP CHIRAPHOS R= -CH3 PROPHOS
= -Ph PHENPHOS DBPP
= -C6H11 CYCPHOS
DIPAMP
PPh2 Ph2P NMe2

PPh2 X PPh2
PPh2 PPh2 Fe
PPh2 PPh2 N
PPh2 CO2tBu PPh2
X= CH2 DPCP
NORPHOS CAMPHOS X= N-R PYRPHOS BPPM PPPFA
P PPh2
PPh2
PPh2
PPh2
P
DUPHOS DIPHEMP BINAP
CO 2H Rh (I) L*, H2 CO 2H
Ph Ph
HN Ph ACR 1983, 16, 106.
HN Ph
O (95% ee) O
CO 2Me CO 2H
NHAc NH 2
O HO
O OH
L-DOPA
DIOP 85% ee
DIPAMP 96% ee
PPPFA 93% ee
BINAP 100% ee
NORPHOS 95% ee
BPPM 91% ee
REDUCTIONS 37
General Mechanism: J. Halpern Science 1982, 217, 401 Asymmetric Synthesis 1985, vol 5, 41.
CO2Me Ph
Ph
P S NHAc P
Rh Rh CO2Me
NH
P S P
(fast equilibrium) O
CH3
rate H2
CO2Me limiting (slow)
Ph
NHAc
Ph Ph
H
H S P
P Rh CO2Me
Rh CO2Me H NH
(fast) P
P NH
O O
S
CH3
CH3
Detailed Mechanism:
P S CO2Me
Rh + Ph
*
P S NHAc
MeO2C NH HN CO2Me
P P
* Rh Ph Ph Rh *
P CH3 H 3C P
O O
major complex minor complex
H2 H2
(slow) (slow)
MeO2C CO2Me
NH NH
H H
H H
Rh Ph Ph Rh
P CH3 H 3C P
O O
* P P *
S S
CH3 CH3
O O
NH HN P
P S S
Rh Rh *
*
H H
CO2Me MeO2C
P P
Ph Ph
H
H MeO2C N CH3
H 3C N CO2Me
O
O Ph
Ph
(S)
(R)
Major product
Minor product
REDUCTIONS 38
+
MeO2C
H NH
H
Rh Ph
P CH3
O
* P
Free Energy
CO2Me +
NH
H
H
Ph Rh
HN CO2Me + H 3C
O
P
P *
P
Ph Rh *
H 3C P
O
minor complex
MeO2C NH +
P
* Rh Ph
P CH3
O
major complex
Reaction Coordinate
Ph Ph
O
P O
Ru
P O
O ACR 1990, 23, 345.
Ph Ph
BINAP
O O O O
(BINAP)RuAc2, (BINAP)RuAc2,
H2 (100 atm) R H2 (100 atm) R
O O O O
50 °C, CH2Cl 2 50 °C, CH2Cl 2
(94 % ee) (95 - 98 % ee)
Ru(AcO)2(BINAP),
CO 2H H2 (135 atm), MeOH CO 2H
MeO (97% ee) 97 % ee

MeO
(S)-naproxen
MeO MeO MeO
(BINAP)RuAc2,
NAc H2 (4 atm) NAc NH
MeO MeO MeO
OMe OMe OMe
OMe (95 - 100 % ee) OMe OMe

Tetrahydropapaverine
Directed Asymmetric Hydrogenation
(BINAP)Ru (II), H2
OH OH CHO
(96 - 99 % ee)
OH OH
HO
J. Am. Chem. Soc. 1987, 109, 1596

O
Vitamin E
REDUCTIONS 39
Kinetic Resolution by Directed Hydrogenation
MeO Ph Rh+ CF 3SO 3-

P P
Ph OMe
H2 (15 psi), L*Rh+

CO 2Me CO 2Me
MeO 2C 0 °C MeO 2C
R (~60% conversion) R
R= Et > 96 % ee
Ph 82 %
OMe 93 %
Hydrogenation of Carbonyls
1,3-diketones:
O O OH O O OH
R1 R2 R1 R2 R1 R2
Ru (II)
O O H2 (700 psi) OH OH OH OH
+
R1 R2 R1 R2 R1 R2
anti syn
R1= -CH3 R2= -CH3 anti : syn= 99 : 1
-CH3 -CH2CH3 16 : 1 (90 % ee)
-CH2CH3 -iPr 32 : 1
-CH2CH3 -CH2CH3 49 : 1
O O H2 O OH Directed OH OH
Reduction
R1 R2 R1 R2 R1 R2
H
M O
H R2
O R1 O R1
R2 H
M O
H
anti syn
Ru2Cl 4(BINAP) OH
O Et3N, H2 (100 atm)
MeO 2C JACS 1988, 110 , 6210
MeO 2C
(98% ee)
Decarbonylations
O (Ph3P)3RhCl O (Ph3P)3RhCl
R H R Cl
R H - CO R Cl - CO
REDUCTIONS 40
OHC
(Ph3P)3RhCl
Fe Fe Fe
PhCH 3, ∆ Fe JOC 1990, 55, 3688
Diimide HN=NH
Review: Organic Reactions 1991, 40J. Chem. Ed. 1965, 254
- Only reduces double bonds
- Syn addition of H 2
- will selectivley reduce the more strained double bond
- Unstable reagent which is generated in situ
K+O2C-N=N-CO2K+ + AcOH → H-N=N-H
H2N-NH2 + Cu2+ + H2O2 → H-N=N-H
HN=NH
ACIEE 1965, 271
(76%)
O O
+-
CO 2MeK O 2C N N CO 2- K+ CO 2Me
JACS 1986, 108 , 5908
AcOH, MeOH
NO 2 NO 2
(95%)
HN hν (254 nm) NH
S + COS + CO
HN NH
O
O S O
N N
H H TL 1993, 34, 4137
hν, 16 hr
(96%)
Metal Hydrides
Review on Metal Hydride Selectivity: Chem Soc Rev. 1976, 5 , 23
Comprehensive Organic Synthesis 1991, vol 8, 1.
Boron Hydrides Review: Chem. Rev. 1986, 86 , 763.
NaBH4 reduces ketones and aldehydes
LiBH4 reduces ketones, aldehydes, esters and epoxides. THF soluble
LiBH4/TMSCl stronger reducing agent. ACIEE 1989, 28, 218.
Zn(BH4)2 reduces ketones and aldehydes
R4N BH4 organic soluble (CH2Cl2) borohydrides. Synth Commun. 1990, 20, 907
LiEt3BH reduces ketones, aldehydes, esters, epoxides and R-X
Li s-Bu3BH reduces ketones, aldehydes, esters and epoxides (hindered borohydride)
Na(CN)NH3 reduces iminium ions, ketones and aldehydes
Na(AcO)3BH reduces ketones and aldehydes (less reactive)
NaBH2S3 reduces ketones and aldehydes
REDUCTIONS 41
Sodium Borohydride NaBH4
- reduces aldehydes and ketones to alcohols
- does not react with acids, esters, lactones, epoxides or nitriles.
- Additives can increase reactivity.
Sodium Cyanoborohydride Na (CN)BH3

Reviews: Synthesis 1975, 136; OPPI 1979, 11 , 201
- less reactive than NaBH4
- used in reductive aminations (Borch Reduction)
Na(CN)BH3 reduces iminium ions much more quickly than ketones or aldehydes
R"-2NH, MeOH,
R R R' R H
AcO - NH4+ , pH~ 8 Na(CN)BH3
O N+ R'
R R R' R N
R'
O
R"-2NH, MeOH, JACS 1971, 93 , 2897
CHO AcO- NH4+
N
H
N Na(CN)BH3
N
- Related to Eschweiler-Clark Reaction

H2CO, HCO 2H
R Me
R NH 2 N
or H
H2CO, H2/Pd
- Reduction of tosylhydrazones gives saturated hydrocarbon

O
H H
1) TsNHNH 2, H+
2) Na(CN)BH3
TL 1978, 1991
H (90%) H
HO HO
1) TsNHNH 2, H+
O 2) Na(CN)BH3
(100%) JOC 1977, 42 , 3157
- migration of the olefin occurs w/ α,β-unsaturated ketones

O
JACS 1978, 100 , 7352
(75%)
- Epoxide opening
O
NaBH3CN,
OH BF3•OEt2, THF OH
JOC 1994, 59, 4004
HO
REDUCTIONS 42
NaBH2S3 Lalancette Reduction Synthesis 1972, 526 Can. J. Chem. 1970, 48 , 735.
NaBH4/ NiCl 2 Chem. Pharm. Bull. 1981, 29 , 1159; Chem. Ber. 1984, 117 , 856.
Ar-NO2 → Ar-NH2
Ar-NO → Ar- NH2
R2C=N-OH → R2CH-NH2
NaBH4 / TiCl 4
Synthesis 1980, 695.
R-COOH → R-CH2-OH
R-COOR' → R-CH2-OH
R-CN → R-CH2-NH2
R-CONH2 → R-CH2-NH2
R2C=N-OH → R2CH-NH2
R-SO2-R' → R-S-R'
NaBH4 / CeCl 3 Luche Reduction

reduced α,β-unsaturated ketones in a 1,2-fashion
OH O OH O
NaBH 4/ CeCl3 NaBH 4
R R R + R
R R R R R R
R R H
JCSCC 1978, 601
JACS 1978, 100 , 2226
O OH
CO 2Me NaBH 4/ CeCl3 CO 2Me

C 5H11 MeOH C 5H11
OH OH
- selective reduction of ketones in the presence of aldehydes.

O OH
CO 2Me NaBH 4/ CeCl3 CO 2Me
EtOH, H2O
CHO CHO
O
CeCl 3 1) NaBH 4, CeCl3
H2O R 2) work-up
OH JACS 1979, 101 , 5848
OH
O CHO OH CHO
NaBH 4/ CeCl3
EtOH, H2O
(78%)
REDUCTIONS 43
Zinc Borohydride Zn(BH4)2 Synlett 1993, 885.
ZnCl2 (ether) + NaBH 4 → Zn(BH4)2
- Ether solution of Zn(BH4)2 is neutral- good for base sensitive compounds
- Chelation contol model
Zn
RO
O H
O OH
OR H B
R1 OR
H H R1
R2
R1 H R2
R2
Zn(BH4)2,
Et2O, 0°C OH
OH
O OH
H-
H TL 1983, 24 , 2653, 2657, 2661
Me O
O
R Zn
Na + (AcO)3BH , Me4N + (AcO)3BH

Review: OPPI 1985, 17 , 317
- used in Borch reductive amination TL 1990, 31 , 5595; Synlett 1990, 537
- selective reduction of aldehydes in the presence of ketones
O Bu4N (AcO) 3BH O
C 6H6, ↑↓
OH
CHO
(77%)
TL 1983, 24 , 4287
AcO OAc
O Bu4N (AcO) 3BH B
H
CHO C 6H6, ↑↓ O O
OH
Ph
Ph OH
Ph
-hydroxyl-directed reduction of ketones

TL 1983, 24 , 273; TL 1984, 25 , 5449
OH O O Me OH OH O Me
Me4N (AcO) 3BH, Ph
Ph
N CH 3CN, AcOH, −40°C N
Me Me O Me Me O TL 1986, 27 , 5939
O O JACS 1988, 110 , 3560
(98:2)
H OAc H OAc
O B R B
R O OAc R O OAc
H H
R O
major minor
OH O
OH OH
Na+ BH(OAc)3
50 : 1
REDUCTIONS 44
OH O O OH OH O OH OH OH
Na+ BH(OAc)3 Na+ BH(OAc)3
CO2R CO2R CO2R
HO
OBn OBn
BnO BnO Me
MeO
OBn OBn O
Me4N (AcO) 3BH,

OH
CH 3CN, AcOH, −40°C O
Me Me
O
MeO O MeO O N O
OH Me
O
O
Me Me O OH
OH OH HO
Me OH
FK-506
TL 1989, 30 , 1037
(Ph3P)2Cu BH4
reduction of acid chlorides to aldehydes JOC 1989, 45, 3449
reduction of alkyl and aryl azides to amines J. Chem. Res. (S) 1981, 17
R4N BH4 organic soluble borohydride (CH2Cl2)

R4N= BnEt3N or Bu4N Heterocylces 1980, 14, 1437, 1441
reduction of amides to amines
reduction of nitriles to amines
BnEt3N BH4 / Me 3SiCl

reduction of carbolxylic acids to alcohols Synth. Commun. 1990, 20, 907
LiBH4/ Me 3SiCl ACIEE 1989, 28, 218.
Alkyl Borohydrides
Selectrides
M + HB M + = Li (L-selectride)
LS-selectride
K (K-selectride) Li + HB
3 3
- hindered reducing agent

increased selectivity based on steric considerations
CO 2H CO 2H
O OH
L-selectride
THF
JACS 1971, 93, 1491
R R
HO HO
OH OH
REDUCTIONS 45
- selective 1,4-reductions of α,β-unsaturated carbonyl cmpds.
JOC 1975, 40 , 146; JOC 1976, 41 , 2194
O O
K-selectride, THF
(99%)
- 1,4-reduction generates an enolate which can be subsequently alkylated.

O O
a) K-selectride, THF
b) Br
K+ HBPh3
Syn. Comm. 1988, 18 , 89.
- even greater 1,4-selectivity
Li + HBEt3 (Super Hydride)
- very reactive hydride source
- reduces ketones, aldehydes, esters, epoxides and C-X (alkyl halides and sulfonates)
O HO
Li Et3BH, THF
HCA 1983, 66 , 760
HO H HO H
HO
HO
CH 3
OH 1) TsCl, pyridine
2) Li Et3BH, THF HCA 1988, 71 , 872
HO
HO H
H
Boranes
Hydroboration
B 2H6 H2O 2, NaOH
B H HO H
B 2H6 R R' R R'

H3O +
R R'
B H H H
B 2H6 R H2O 2, NaOH

R H B R-CH 2CHO
H
- BH3 reduces carboxylic acids to 1° alcohols in the presence of esters, nitro and cyano groups.
- BH3 reduces amides to amines
HO 2C HO
BH 3•SMe 2
O O THF
O O
- Boranes also reduce ketones and aldehydes to the corresponding alcohols.
REDUCTIONS 46
Hindered Boranes
Disiamyl Borane (Sia2BH) B

H
Thexyl Borane B
H
H
B
9-BNN =
B
H B
H
O
Catecholborane BH
O
BH BH
Pinylborane
2 2
B B
Alpine Borane H
BCl BCl
IPC 2BCl (DIP-Cl)
2
2
B
Borolane H
Ph Ph
Oxazaborolidine O
N B
H
Asymmetric Reduction of Unsymmetrical Ketones Using Chiral Boron Reagents

Review: Synthesis 1992, 605.
Alpine Borane Midland Reduction

JACS 1979, 111 , 2352; JACS 1980, 112 , 867
review: Chem. Rev. 1989, 89 , 1553.
O alpine-borane OH
THF, 0°C Tetrahedron 1984, 40 , 1371
(94% ee)
REDUCTIONS 47
B B
H
9-BBN = B
B
α-pinene 9-BBN
B OH
Mechanism: H O
RL Rs RL
Rs
- works best for aryl- and acetylenic ketones

- because of steric hindrance, alpine-borane is fairly unreactive
Chloro Diisopinylcamphenylborane (DIP-Cl, Ipc2BCl) H.C. Brown

Review: ACR 1992, 25 , 16. Aldrichimica Acta 1994, 27 (2), 43
BCl
2
- Cl increases the Lewis acidity of boron making it a more reactive reagent
- saturated ketones are reduced to chiral alcohols with varying degrees of ee.
O OH
I Ipc2B-Cl, I
CO2tBu CO2tBu
THF
JOC 1992, 57, 7044
PrO PrO
OMe OMe (90 % ee)
Borolane (Masamune's Reagent)

JACS 1986, 108 , 7404; JACS 1985, 107, 4549
B
H
B
O H OH
MeSO 3H, pentane (80% ee)

Asymmetric Hydroboration:
a) B
H
b) H2O 2, NaOH (99.5% ee)
OH
(99.5% ee)
REDUCTIONS 48
Oxazaborolidine (Corey)
JACS 1987, 109 , 7925; TL 1990, 31, 611l ; TL 1992, 33 , 4141
Ph Ph Ph Ph
O O + BH3
N B N B
H CH 3
Catalytic
O OH
R R
> 90 % ee
O OH
92 % ee
O OH
86 % ee
I I
O OH
93 % ee
Ph Ph
O O OH
N B
Me
BH 3•THF, -0°C TL 1988, 29 , 6409
(90% ee)
CF 3
O OH
O
• HCl
Cl Cl CH 3
N
H
94 % ee
Fluoxetine (Prozac)
O O
O O
90 : 10
BzO BzO
O OH
Aluminium Hydrides
1. LiAlH 4
2. AlH3
3. Li (tBuO)3AlH
4. (iBu)2AlH DIBAL-H
5. Na (MeOCH2CH2O)2AlH2 REDAL
REDUCTIONS 49
Lithium Aluminium Hydride LiAlH4 (LAH) Chem. Rev. 1986, 86, 763 Org. Rxn. 1951, 6, 469.
- very powerful reducing agent
- used as a suspension in ether or THF
- Reduces carbonyl, carboxylic acids and esters to alcohols
- Reduces nitrile, amides and aryl nitro groups to amines
- opens epoxides
- reduces C-X bonds to C-H
- reduces acetylenic alcohols trans-allylic alcohols
LAH
OH
R OH
R
LAH, THF NH 2
H2N N H2N N
H NH 2 H
(62%)
NH 2
Lindlar/ H2
H2N N
H
O HO
CO 2Me
OH
LAH, THF, ↑↓
TL 1988, 29 , 2793.
(100%)
O H O H
O O
BINAL-H (Noyori)
- Chiral aluminium hydride for the asymmetric reduction of prochiral ketones
1) LiAlH4
OH 2) ROH O H
Al Li +
OH O OR
R= Me, Et, CF 3CH 2-
BINOL BINAL-H
O
O O BINAL-H,THF
Tetrahedron 1990, 46 , 4809
-100 to -78°C
HO (94% ee)
Intermediate for 3-Component Coupling Strategy to Prostaglandins
I
O
Li+ O -
CO 2Me
RO Li+ RCu
RO OTBS
OTBS
O
O CO 2Me CO 2H
HO OH
RO OTBS PGE 2
REDUCTIONS 50
Alane AlH3
LiAlH 4 + AlCl3 → AlH3
- superior to LAH for the 1,2-reduction of α,β-unsaturated carbonyls to allylic alcohols
OMe
O 1) AlH3, ether, 0°C HO
O 2) H3O + O
Ph Me JACS 1989, 111 , 6649
O
O Me OH
O
Diisobutyl Aluminium Hydride DIBAL or DIBAL-H

Al
H
- Reduces ketones and aldehydes to alcohols
- reduces lactones to hemi-acetals
Al OH
O O
work up CHO
DIBAL O
O O OH
(CH 2)n (CH 2)n
(CH 2)n (CH 2)n
(stable complex) lactol
- reduces esters to alcohols

- under carefully controlled reactions conditions, will partially reduce an ester to an aldehyde
Al if complex
O
DIBAL is unstable fast
R CO 2Me R C OMe R CHO R CH 2 OH
H
if complex
is stable
R CHO
O OBn
O OBn O O H
DIBAL, CH 2Cl 2 HO O
O
HO OBn
OH OBn O HO OH
HO
OH
JACS 1990, 112 , 9648
OBn OBn
CO 2iPr DIBAL, CH 2Cl 2 CHO
iPrO2C OHC
OBn OBn
O O
TMS-Cl, Et3N DiBAl-H O
TL 1998, 39, 909
R OH CH2Cl2 R OSiMe3 CH2Cl2, -78°C
R H
Reduction of O-Methyl hydroxamic acids
O R'-M O O
OMe DIBAL or LAH TL 1981, 22 , 3815
R R' R N R H
Me
REDUCTIONS 51
Sodium Bis(2-Methoxyethoxy)Aluminium Hydride REDAL
Organic Reactions 1988, 36, 249 Organic Reactions 1985, 36, 1.
MeO O H
Na+ Al
MeO O
H
- "Chelation" directed opening fo allylic epoxides
OH
REDAL O DIBAL-H R OH TL 1982, 23 , 2719
R OH R OH
OH
1,3-diol 1,2-diol
Sharpless OH
epoxidation O REDAL JOC 1988, 53 , 4081
Ph OH Ph OH
DME Ph OH
OH
OH +
O
LiAlH4 2 : 98
AlH3 95 : 5
OH
O
OH OH + OH
BnO BnO BnO
OH
REDAL 150 : 1
DIBAL 1 : 13
O
OH
OH Me
Me O OH
HO OH
HO O OH OH OH OH O OH
Me Me Me
Me
O O sugar
Me
O O Me O O sugar
OH
Amphotericin B NH 2 Me
HO
Erythromycin A
Lithium Tri(t-Butoxy)aluminium Hydride Li+ (tBuO)3AlH
- hindered aluminium hydride, will only react with the most reactive FG's
O Li(tBuO)3AlH O
R Cl R H
Cl Me
O
N+
Me Li(tBuO)3AlH O
H Me TL 1983, 24 , 1543
R-CO 2H R O
pyridine, -30°C N+ CuI (cat), -78°C R H
H Me
Meerwein-Ponndorf-Verley Reduction: opposite of Oppenauer oxidation

Synthesis 1994, 1007 Organic Reactions 1944, 2, 178
O O
H H
Al(O-Pr)3, iPrOH
O O
O AcHN O AcHN
O OH
REDUCTIONS 52
Asymmetric M-P-V Reduction
Bn
Ph Ph
N
X O O Sm O
X OH
I JACS 1993, 115, 9800
iPrOH, THF
X= H, Cl, OMe
yield: 83-100 %
96% ee
Dissolving Metal Reductions

Birch Reductions reduction of aromatic rings Organic Reactions 1976, 23, 1.
Tetrahedron 1986, 42, 6354. Comprehensice Organic Synthesis 1991, vol. 8, 107.
- Li, Na or K metal in liquid ammonia
H H H H
M, NH3 _•
•
R R R R
H H H
- position of the double bond in the final product is dependent of the nature of the substituent
R R R
R= ERG R= EWG
- ketones and nitro groups are also reduced but esters and nitrile are not.
- α,β-unsaturated carbonyl cmpds are reduced in a 1,4-fashion to give an enolate which can be
subsequently used to trap electrophiles
Me Me
Me K, NH3, Me Me
Me MeOH, -78°C O
O HO JOC 1991, 56 , 6255
HO
O O (92%) O OH
Me Me
O O O O
a) Li, NH3, tBuOH
b) CH 2O JOC 1984, 59 , 3685
O O
HO
Other Metals
- Mg
Mg, MeOH X- CN, CO2R, CONR'2
X X
H
H
Mg, MeOH
TL 1987, 28 , 5287
EtO2C (98%)
EtO2C
- Zn reduction of α-halocarbonyls
O O
Zn, PhH, Me
Br DMSO, MeI JACS 1967, 89, 5727
REDUCTIONS 53
Cl X Y Zn, AcOH
Zn
O R-OH R CH CH R'
R X= Cl, Br, I
R R' Y= X, OH
O
"Copper Hydrides"
LAH or DIBAL-H + MeCu → "CuH"
- selective 1,4-reduction of α,β-unsaturated ketones (even hindered enones)
O O
1) MeCu, DIBAL,
HMPA, THF, -50°C JOC 1987,52 , 439
2) MeLi
3) Br
O O
MeCu, DIBAL, HMPA

THF, -50°C JOC 1986,51 , 537
H H (85%) H H
O O
H
[(Ph3P)CuH]6 Stryker Reagent

JACS 1988, 110 , 291 ; TL 1988, 29 , 3749
- 1,4-reduction of α,β-unsaturated ketones and esters; saturated ketones are not reduced
- halides and sulfonates are not reduced
- 1,4-reduction gives an intermediate enolate which can be trapped with electrophiles.
O Br O
[(Ph3P)CuH] 6, THF
TL 1990, 31 , 3237
Silyl Hydrides
- Hydrosilylation
Et3SiH + (Ph3P)3RhCl (cat)
- selective 1,4-reduction of enones, 1,2-reduction of saturated ketones to alchohols.
Et3SiH,
O (Ph3P)3RhCl (cat) O SiEt3 H3O + O
TL 1972, 5085
J. Organomet. Chem. 1975, 94 , 449
O OSi(iPr)3
iPr3SiH, Et2O
O O
JOC 1994, 59, 2287
Si O Pt
O O
2 2 (87%)
- Buchwald Reduction
JACS 1991, 113 , 5093
- catalytic reagent prepared from Cp2TiCl2 + nBuLi and stoichometric (Et)3SiH in THF will
reduce ester, ketones and aldehydes to alcohols under very mild conditions.
- α,b− unsaturated esters are reduced to allylic alcohols
- free hydroxyl groups, aliphatic halides and epoxides are not reduced
REDUCTIONS 54
Clemmensen Reduction Organic Reactions 1975, 22, 401
Comprehensive Organic Synthesis 1991, vol 8, 307.
- reduction of ketones to saturated hydrocarbons
Zn(Hg), HCl H
O
H
Wolff-Kishner Reduction Organic Reactions 1948, 4, 378

Comprehensive Organic Synthesis 1991, vol. 8, 327.
- reduction of ketones to saturated hydrocarbons

H2N-NH2, KOH H
O
H
Radical Deoxygenation
Review: Tetrahedron 1983, 39 , 2609 Chem. Rev. 1989, 89, 1413.
Comprehensive Organic Synthesis 1991, vol. 8, 811
W. B. Motherwell, D. Crich Free Radical Chain Reactions in Organic Synthesis
(Academic Press: 1992)
- free radical reduction of halide, thio ethers, xanthates, thionocarbanates by a radical chain
mechanism.
nBu3Sn-H, AIBN
Ph-CH3 ↑↓
R3C-X R3C-H N N
S CN CN
S S
AIBN
X= -Cl, -Br, -I, -SPh, O Ph , O SMe , O N N
Barton-McCombie Reduction
JCS P1 1975, 1574
R3C-X → R3C-H X= -OC(=S)-SMe, -OC(=S)-Im, -OC(=S)Ph
O
O
O O
O NaH, imidazole, O O nBu3SnH, AIBN
O O PhCH3, reflux O
THF, CS2, MeI O O
O O
O (85%)
HO O
SMe
S
Xanthate
R R R
Cl
nBu3SnH, AIBN
a) Ph NMe2 , THF
+ PhCH3, reflux
S
b) H2S, pyridine (73%)
HO (90%) Ph O
Thionobenzoates
S
N N Ph O nBu3SnH, AIBN Ph O
Ph O O O O O
O O N N O PhCH3, reflux
HO N N AcHN (57%) AcHN
AcHN (CH2Cl)2 OBn OBn
OBn 59% S
Thiocarbonyl Imidazolides
REDUCTIONS 55
- Cyclic Thionocarbonates: deoxygenation of 1,2- and 1,3-diols to alcohols
S
OH S
N N nBu3SnH, AIBN
O HO
HO O N N O PhCH3, reflux O
O JCS P1 1977, 1718
MeO MeO MeO
MeO MeO (61%) MeO
OMe OMe OMe
- Thionocarbonate Modification (Robbins)

JACS 1981, 103 , 932; JACS 1983, 105 , 4059.
iPr O O B PhOC(S)Cl, iPr O B nBu3SnH, AIBN iPr O O B

pyridine, DMAP O
Si Si PhCH3, reflux Si
iPr iPr iPr
O > 90% O (58-78%) O
Si O OH Si O O OPh Si O
iPr iPr iPr iPr iPr iPr
S
S
OAr O
O nBu3SnH, CH3
O
AIBN, PhCH3 O O
O O Tetrahedron 1991, 47, 8969
88-91% O
O O
O
Ar= 2,4,6-trichlorophenyl, Best method for deoxygenation

4-fluorophenyl of primary alcohols
- N-Phenyl Thionocarbamates Tetrahedron 1994, 34, 10193.

iPr O O U PhNCS iPr O O U (TMS)3SiH, AIBN iPr O U
Si Si O
iPr NaH, THF iPr PhH, reflux Si
S S iPr
O O O
(78%) (93%)
Si O O Si O O Si O
iPr iPr NHPh iPr iPr NHPh iPr iPr
Thiocarbamates
- Methyl oxylates
O OAc
O OAc O OAc
MeO2CCOCl nBu3SnH, AIBN
THF OC PhCH3, reflux
OC OC
O
HO CO2Me
CO2Me MeO2C O CO2Me
Methyl Oxylate Esters
- Water Soluble Tin Hydride: [MeO(CH2)2O(CH2)3]3SnH / 4,4'-Azo(bis-4-cyanovaleric acid)

TL 1990, 31 , 2957
- Silyl Hydride Radical Reducing Agents
- replacement for nBu3SnH
(Me3Si)3SiH Chem Rev. 1995, 95, 1229.
JOC 1991, 56 , 678; JOC 1988, 53 , 3641; JACS 1987, 109 , 5267
Ph2SiH2 / Et3B / Air
TL 1990, 31 , 4681; TL 1991, 32 , 2569
- hypophosphorous acid as radical chain carrier
JOC 1993, 58, 6838
REDUCTIONS 56
- Photosensitized electron transfer deoxygenation of m-trifluoromethylbenzoates
JACS 1986, 108, 3115, JOC 1996, 61, 6092, JOC 1997, 62, 8257
iPr O U
O N-methylcarbazole,
Si
iPr hν, iPrOH, H2O iPr O O U
O Si
Si O O (85%) iPr
O
iPr iPr CF3 Si O
O
iPr iPr
Dissolving Metal : JACS 1972, 94, 5098

O
P(NMe2)2
OH O
nBuLi, Li, EtNH2,
(Me2N)2P(O)Cl THF, tBuOH CH3
O O O
O H O H O H
Radical Decarboxylation: Barton esters

Aldrichimica Acta 1987, 20 (2), 35
N hn or ∆ S nBu3SnH, ∆
O R H
R N - CO2
S O R
Radical Deamination
Comprehensive Organic Synthesis 1991, vol. 8, 811
Reduction of Nitroalkanes JOC 1998, 63, 5296
NO2
O Bu3SnH, PhSiH3 O
initiator, PhCH3 (reflux)
O O
(75%)
PROTECTING GROUPS 57
Carey & Sundberg Chapter 13.1 problems # 1; 2; 3a, b, c ;
Smith: Chapter 7
Protecting Groups
T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd edition) J.
Wiley & Sons, 1991.
P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994
1. Hydroxyl groups
2 Ketones and aldehydes
3. Amines
4. Carboxylic Acids
- Protect functional groups which may be incompatible with a set of reaction

conditions
- 2 step process- must be efficient
- Selectivity a. selective protection
b. selective deprotection
Hydroxyl Protecting Groups
Ethers
Methyl ethers
R-OH → R-OMe difficult to remove except for on phenols
Formation: - CH2N2, silica or HBF4

- NaH, MeI, THF
Cleavage: - AlBr3, EtSH
- PhSe -
- Ph2P -
- Me3SiI
OMe OH
O O
AlBr3, EtSH
TL 1987, 28 , 3659
O O
OBz OBz
Methoxymethyl ether MOM

R-OH → R-OCH2OMe stable to base and mild acid
Formation: - MeOCH2Cl, NaH, THF

- MeOCH2Cl, CH2Cl2, iPr2EtN
Cleavage - Me2BBr2 TL 1983, 24 , 3969
Methoxyethoxymethyl ethers (MEM)
R-OH → R-OCH2OCH2CH2OMe stable to base and mild acid
Formation: - MeOCH2CH2OCH2Cl, NaH, THF

- MeOCH2CH2OCH2Cl, CH2Cl2, iPr2EtN TL 1976, 809
Cleavage - Lewis acids such as ZnBr2, TiCl4, Me2BBr2
S
B Cl HO
MEM-O TL 1983, 24 , 3965, 3969
S
O-Si(Ph)2tBu O-Si(Ph)2tBu
C5H11 O C5H11 O
- can also be cleaved in the presence of THP ethers
Methyl Thiomethyl Ethers (MTM)

R-OH → R-OCH2SMe Stable to base and mild acid
Formation: - MeSCH2Cl, NaH, THF

Cleavage: - HgCl2, CH3CN/H2O
- AgNO3, THF, H2O, base
Benzyloxymethyl Ethers (BOM)

R-OH → R-OCH2OCH2Ph Stable to acid and base
Formation: - PhOCH2CH2Cl, CH2Cl2, iPr2EtN

Cleavage: - H2/ PtO2
- Na/ NH3, EtOH
Tetrahydropyranyl Ether (THP)
O
R-OH +
H , PhH R O O Stable to base, acid labile
Formation - DHP (dihydropyran), pTSA, PhH

Cleavage: - AcOH, THF, H2O
- Amberlyst H-15, MeOH
Ethoxyethyl ethers (EE)

JACS 1979, 101 , 7104; JACS 1974, 96 , 4745.
O
R-OH
H+ R O O (R-OEE) base stable, acid labile
Benzyl Ethers (R-OBn)

R-OH → R-OCH2Ph stable to acid and base
Formation: - KH, THF, PhCH2Cl

- PhCH2OC(=NH)CCl3, F3CSO3H JCS P1 1985, 2247
Cleavage: - H2 / PtO2
- Li / NH3
2-Napthylmethyl Ethers (NAP) JOC 1998, 63, 4172
formation: 2-chloromethylnapthalene, KH
cleavage: hydrogenolysis
OH O ONAP H2, Pd/C OH O OH
BnO BnO
(86%)
p- Methoxybenzyl Ethers (PMB)

Formation: - KH, THF, p-MeOPhCH2Cl
- p-MeOPhCH2OC(=NH)CCl3, F3CSO3H TL 1988, 29 , 4139
Cleavage: - H2 / PtO2
- Li / NH3
- DDQ
- Ce(NH4)2(NO3)6 (CAN)
- e-
o-Nitrobenzyl ethers
Review: Synthesis 1980, 1; Organic Photochemistry, 1987, 9 , 225
NaH, THF O 2N
R-OH
Cl O
R
NO 2
Cleavage: - photolysis at 320 nm

HO NO 2
HO
O hν, 320 nm,
O pyrex, H2O OH
HO O
HO
JOC 1972, 37 , 2281, 2282.
HO
OH HO
OH
p-Nitrobenzyl Ether TL 1990, 31 , 389

-selective removal with DDQ, hydrogenolysis or elctrochemically
9-Phenylxanthyl- (pixyl, px) TL 1998, 39, 1653

Formation: Ph Cl Ph OR
pyridine
ROH +
O O
Removal: Ph
Ph OR OH
hν (300 nm)
ROH +
O CH3CN,H 2O O
Trityl Ethers -CPh3 = Tr

R-OH → R-OCPh3 - selective for 1° alcohols
- removed with mild acid; base stable
formation: - Ph3C-Cl, pyridine, DMAP
- Ph3C + BF4-
Cleavage: - mild acid
Methoxytrityl Ethers
JACS 1962, 84 , 430
- methoxy group(s) make it easier to remove
R1
(p-Methoxyphenyl)diphenylmethyl ether
4'-methoxytrityl MMTr-OR
Di-(p-methoxyphenyl)phenylmethyl ether
R2 C O R 4',4'-dimethoxytrityl DMTr-OR
Tri-(p-methoxyphenyl)methyl ether
4',4',4'-trimethoxytrityl TMTr-OR
R3
Tr-OR < MMTr-OR < DMTr-OR << TMTr-OR

O O
HN HN
R O 80% AcOH (aq)

O N HO O N
O 20°C O
HO OH HO OH
R = Tr 48 hr.
R= MMTr 2 hr.
R= DMTr 15 min.
R= TMTr 1 min. (too labile to be useful)
Oligonucleotide Synthesis (phosphoramidite method - Lessinger)

Review: Tetrahedron 1992, 48 , 2223
S S S
OH O O O O
I I I
L OH L O Si (CH 2)3 NH 2 L O Si (CH 2)3 N C (CH 2)2 C OH
I I I H
C OH C O C O
A A A
DMTrO B
O HO B
S O O
I O
Cl 3CCOOH
L O Si (CH 2)3 N C (CH 2)2 C O
I H
O
C O S O
A
DMTrO B' DMTrO B'

DMTrO B'
O O
O
O N (iPr)2 O O -
P Base O O
P CN P
O O
CN B O B
O O
coupling
S O S O
DMTrO B' HO B'
O O
Repeat Cycle
I2, H2O O O- Cl 3CCOOH O O-
P P -
O- O
O B O B
O O
S O S O
Silyl Ethers Synthesis 1985, 817 Synthesis 1993, 11 Synthesis 1996, 1031
R-OH → R-O-SiR3
formation: - R3Si-Cl, pyridine, DMAP
- R3Si-Cl, CH2Cl2 (DMF, CH3CN), imidazole, DMAP
- R3Si-OTf, iPr2EtN, CH2Cl2
Trimethylsilyl ethers Me3Si-OR TMS-OR

- very acid and water labile
- useful for transiant protection
Triethylsilyl ethers Et3Si-OR TES-OR

- considerably more stable that TMS
- can be selectively removed in the presence of more robust silyl ethers with with F - or
mild acid
O
TESO H2O/ACOH/THF OH
(3:5:11), 15 hr O Liebigs Ann. Chem. 1986, 1281
OTBS (97%)
OTBS
Triisopropylsilyl ethers iPr3Si-OR TIPS-OR

- more stabile to hydrolysis than TMS
Phenyldimethylsilyl ethers
J. Org. Chem. 1987, 52 , 165
t-Butyldimethylsilyl Ether tBuMe 2Si-OR TBS-OR TBDMS-OR

JACS 1972, 94 , 6190
- Stable to base and mild acid
- under controlled condition is selective for 1° alcohols
t-butyldimethylsilyl triflate tBuMe 2Si-OTf TL 1981, 22 , 3455

- very reactive silylating reagent, will silylate 2° alcohols
cleavage:
- acid
- F- (HF, nBu4NF, CsF, KF)
TBSO
HO
CO2Me HF, CH3CN
CO2Me
(70%)
O OTBS
O HO JCS Perkin Trans. 1 1981, 2055
t-Butyldiphenylsilyl Ether tBuPh2Si-OR TBDPS-OR ∑-OR

- stable to acid and base
- selective for 1° alcohols
- Me3Si- and iPr 3Si groups can be selectively removed in the presence of TBS or TBDPS
groups.
- TBS can be selectively removed in the presence of TBDPS by acid hydrolysis.
TL 1989, 30 , 19
cleavage - F-
- Fluoride sources: - nBu 4NF (basic reagent)
- HF / H2O /CH3CN TL 1979, 3981.
- HF•pyridine Synthesis 1986, 453
- SiF4. CH2Cl2 TL 1992, 33 , 2289
Me
OH
O Si tBu
Me JOC 1981, 46 ,1506
AcOH / THF/ H2O TL 1989, 30 , 19.
Ph
Ph O Si tBu
O Si tBu
Ph
Ph
Me Me
tBu Si tBu Si
O O
Me Me
OTHP OH
PPTS / EtOH
JACS 1984, 106 , 3748
Esters
R-OH → R-O2CR'
Formation: - "activated acid", base, solvent, (DMAP)
Activated Acids Chem. Soc. Rev. 1983, 12, 129 Angew. Chem. Int. Ed. Engl. 1978, 17, 569.
RCO2H → "activated acid" → carboxylic acid derivative (ester, amide, etc.)
Acid Chlorides
O O
O O N N +
R N R N
R OH R Cl +
N N
acyl pyridinium ion

(more reactive)
1. SOCl2
2. PCl5
3. (COCl)2
Anhydrides
O O O
2 P2O 5
R OH R O R
Activating Agents:
Carbonyl Diimidazole
O
O
O NH
R N
+ N N + CO + N
R OH N N N
Acyl Imidazole
Dicyclohexylcarbodiimide
C 6H11
O
O NH O O
R O C Nu: +C 6H11 C 6H11
+ N C N N N
R OH N R Nu H H
C 6H11
Ketene formation is a common side reaction- scambling of chiral centers

C 6H11
O
NH
R
O C R
C O
H N
C 6H11 "ketene"
Hydroxybenzotriazole (HOBT) - reduces ketene formation

C 6H11
O N O
NH N
+ N
R O C R O N N
N
N
OH
C 6H11
N-Hydroxysuccinimide (NHS)
O
C 6H11
O O O
NH HO N
R O C +
R O N
N O
C 6H11 O
2,2'-Dipyridyl Disulfide (Aldrithiol, Corey Reagent)

Aldrichimica Acta 1971, 4 , 33
O Ph3P: O
+ + + Ph3P=O
R OH N S S N R S N N SH
Mukaiyama's Reagent (2-Chloro-1-methyl pyridinium Iodide or 2-Fluoro-1-

methyl pyridinium p-toulenesulfonate)
Aldrichimica Acta 1987, 20 , 54
Chem. Lett. 1975, 1045; 1159; 1976, 49; 1977, 575
O O
TsO - I-
+ + +
R OH F N R O N
Me Me
Acetates
R-OH → R-O2CCH3
- stable to acid and mild base
- not compatable with strong base or strong nucleophiles such as organometallic
reagents
Formation: - acetic anhydride, pyridine
- acetyl chloride, pyridine
Cleavage: - K2CO3, MeOH, reflux
- KCN, EtOH, reflux
- NH3, MeOH
- LiOH, THF, H2O
- enzymatic hydrolysis (Lipase) Org. Rxns. 1989, 37, 1.
OAc OAc
Porcine Pancreatic
Lipase
TL 1988, 30 , 6189
OAc OH (96% ee)
Chloroacetates
- can be selectively cleaved with Zn dust or thiourea.
O Me
Me
Cl O OR
O O OR
HO
AcO H2NNHCOSH AcO JCS CC 1987, 1026
Me O
Me O
O
OAc O
OAc
O
Cl O HO
Cl OH
O
O
Trifluoroacetates
Formation: - with trifluoroacetic anhydride or trifluoroacetyl chloride
Cleavage: - K2CO3, MeOH
Pivaloate (t-butyl ester)

- Fairly selective for primary alcohols
Formation: - tbutylacetyl chloride or t-butylacetic anhydride
Cleavage: - removed with mild base
Benzoate (Bz)
- more stable to hydrolysis than acetates.
Formation: - benzoyl chloride, benzoic anhydride, benzoyl cyanide (TL 1971, 185) ,
benzoyl tetrazole (TL 1997, 38, 8811)
Cleavage: - mild base
- KCN, MeOH, reflux
1,2 and 1,3- Diols Synthesis 1981, 501 Chem. Rev. 1974, 74, 581
R2
O R2 R3
OH
R3
R1 O O
R
H+ , -H2O
OH R R1
Isopropylidenes (acetonides)
H+ Me Me
OH
R1 O O
R acetone or
OH MeO OMe OMe R
or R1
- in competition between 1,2- and 1,3-diols, 1,2-acetonide formation is usually favored

- cleaved with mild aqueous acid
Cycloalkylidene Ketals
- Cyclopentylidene are slightly easier to cleave than acetonides
- Cyclohexylidenes are slightly harder to cleave than acetonides
O
MeO OMe
OH (CH 2)n -or- (CH 2)n (CH 2)n

R1 O O
R
OH H+ , -H2O
R R1
Benzylidene Acetals
PhCHO Ph
OH -or-
R1 PhCH(OMe)2 O O
R
+
OH H , -H2O
R R1
- in competition between 1,2- and 1,3-diols, 1,3-benzylidene formation for is usually

favored
- benzylidenes can be removed by acid hydrolysis or hydrogenolysis
- benzylidene are usually hydrogenolyzed more slowly than benzyl ethers or olefins.
p-Methoxybenzylidenes
- hydrolyzed about 10X faster than regular benzylidenes
- Can be oxidatively removed with Ce(NH 4)2(NO3)6 (CAN)
OMe
OBn Ce(NH 4)2(NO3)6 OBn
BnO O CH 3CN, H2O BnO OH
O (95%) OH
MeO O MeO O
Other Reactions of Benzylidenes

- Reaction with NBS (Hanessian Reaction)
H
O
Ph O NBS, CCl 4 Br
O O
HO Ph O O Org. Syn. 1987, 65, 243
HO
HO
OMe HO
OMe
- if benzylidene of a 1° alcohol, then 1° bromide
- Reductive Cleavage
Ph
Na(CN)BH3,
TiCl4,CH 3CN OH
O O
CO 2Me
MeO 2C Synthesis 1988, 373.
MeO 2C CO 2Me OBn
O TMS-CN O
O Ph OH
BF3•OEt2 Tetrahedron 1985, 41, 3867
O O Ph
MeO O MeO O
H CN
Ph
O O BnO OH
DIBAL-H
TL 1988, 29 , 4085
O O
OMe OMe
Carbonates
O
OH
R1 (Im)2CO O O
R
OH R R1
- stable to acid; removed with base

- more difficult to hydrolyze than esters
Di-t-Butylsilylene (DTBS) TL 1981, 22 , 4999
- used for 1,3- and 1,4-diols; 1,2-diols are rapidly hydrolyzed
- cleaved with fluoride (HF, CH 3CN -or- Bu4NF -or- HF•pyridine)
- will not fuctionalize a 3°-alcohol
(t-Bu)2SiCl 2, Et3N O tBu
OH CH 3CN, HOBT
Si
OH O tBu
1,3-(1,1,3,3)-tetraisopropyldisiloxanylidene (TIPDS) TL 1988, 29 , 1561

- specific for 1,3- and 1,4-diols
- cleaved with fluoride or TMS-I
O O
HN HN
iPr2Si(Cl)-O-Si(Cl)iPr2 O O N
HO O N pyridine Si
O O
O
HO OH Si O OH
Ketones and Aldehydes

- ketones and aldehydes are protected as cyclic and acyclic ketals and acetals
- Stable to base; removed with H3O+
R R
MeOH, H+ OMe
O
R1 OMe
R1
(CH 2OH)2, H+
R O
PhH, -H2O
TL 1980, 21 , 1357
-or- R1 O
(CH2OSiMe 3)2,
TMS-OTf, CH2Cl 2 1,3-dioxolanes
CH 2(CH 2OH)2, R O
H+ , PhH, -H2O
R1 O
1,3-dioxanes
Cleavage rate of substituted 1,3-dioxanes:
Chem. Rev. 1967, 67 , 427.
R O R O R O
> >>
R1 O R1 O R1 O
- Ketal formation of α,β-unsaturated carbonyls are usually slower than for the
saturated case.
O O O
CH 2(CH 2OH)2,
H+ , PhH, -H2O
O O
Fluoride cleavable ketal:
O
O
LiBF4
O O
O TL 1997, 38, 1873
(88%)
O O
Me3Si
Base cleavable ketal:

HO SO2Ph SO2Ph
O
DBU, CH2Cl 2 O
OH
O O TL 1998, 39, 2401
R1 R2
pTSA, C6H6 R1 R2
R1 R2
Carboxylic Acids Tetrahedron 1980, 36, 2409. Tetrahedron 1993, 49, 3691
Nucelophilic Ester Cleavage: Organic Reactions 1976, 24, 187.
Esters
Alkyl Esters
formation: - Fisher esterification (RCOOH +R'OH + H+)
- Acid Chloride + R-OH, pyridine
- t-butyl esters: isobutylene and acid
- methyl esters: diazomethane
Cleavage: - LiOH, THF, H2O
- enzymatic hydrolysis Org. Rxns. 1989, 37, 1.
- t-butyl esters are cleaved with aqueous acid
- Bu 2SnO, PhH, reflux (TL 1991, 32, 4239)
OH Pig Liver Esterase OH
pH 6.8 buffer
MeO 2C CO 2Me MeO 2C CO 2H
O
Bu2SnO, PhH, ↑↓ O
R OR' TL 1991, 32, 4239

R OH
R= Me, Et, tBu
9-Fluorenylmethyl Esters (Fm)

TL 1983, 24 , 281
- cleaved with mild base (Et2NH, piperidine)
DCC
RCO 2H +
O
OH
R O
2-Trimethylsilyl)ethoxymethyl Ester (SEM)
HCA 1977, 60 , 2711.
- Cleaved with Bu 4NF in DMF
DCC R O O
RCO 2H + HO O SiMe 3
SiMe 3
O
- Cleaved with MgBr2•OEt2 TL 1991, 32, 3099.
2-(Trimethylsilyl)ethyl Esters
JACS 1984, 106 , 3030
- cleaved with Fluoride ion
DCC
RCO 2H + HO R O
SiMe 3 SiMe 3
O
Haloesters
- cleaved with Zn(0) dust or electrochemically
DCC
RCO 2H + HO CCl 3 R O CCl 3
Benzyl Esters
RCO2H + PhCH2OH → RCO2Bn
Formation: - DCC
- Acid chloride and benzyl alcohol
Cleavage: - Hydrogenolysis
- Na, NH3
Diphenylmethyl Esters
DCC
RCO 2H + HO R O
CHPh 2 CHPh 2
O
Cleavage: - mild H3O+

- H2, Pd/C
- BF3•OEt2
o-Nitrobenzyl Esters
- selective removed by photolysis
Orthoesters Synthesis 1974, 153 Chem. Soc. Rev. 1987, 75
TL 1983, 24 , 5571
O O
BF 3•OEt2 O
RCOCl +
R O R
O
OH O O
- Stable to base; cleaved with mild acid

Amines
Carbamates
9-Fluorenylmethyl Carbamate (Fmoc)
Acc. Chem. Res. 1987, 20 , 401
- Cleaved with mild base such as piperidine, morpholine or dicyclohexylamine
NaHCO 3
H2O, dioxane
R2NH +
O O
Cl O R2N O
2,2,2-Trichloroethyl Carbamate
O O
R2NH, pyridine
R
Cl 3C O Cl Cl 3C O N
R
- Cleaved with zinc dust or electrochemically.
O
S Te Te S
N O CCl 3 NH
TL 1986, 27 , 4687
EtO2C NaBH 4 EtO2C
S S
2-Trimethylsilylethyl Carbamate (Teoc)
- cleaved with fluoride ion.
O O
O
Me 3Si Me 3Si R
O O N + R2NH O N
R
O
SiMe 3
OH
OTBS Cl
O O H O
Cl MeO N
O Bu4NF, THF CH 3
MeO N H
CH 3 (100%) OEt
H O
OEt SEt
O
SEt SEt
SEt
JACS 1979, 101 7104
t-Butyl Carbamate (BOC)

O O
O
tBuO O OtBu
R2NH R2N OtBu
Cleavage: - with strong protic acid (3M HCl, CF3COOH)

- TMS-I
O
B Cl
- O TL 1985, 26 , 1411
Allyl Carbamate (Alloc) TL 1986, 27 , 3753

O O
O
O O O
R2NH R2N O
- removed with Pd(0) and a reducing agent (Bu3SnH, Et 3SiH, HCO2H)
HN O 1) Pd(OAc) 2, Et3N, Et3SiH NH 2

2) H3O +
TL 1986, 27 , 3753
CO 2Me CO 2Me
Benzyl Carbanate (Cbz)

O
O
BnO Cl
R2NH R2N O Ph
Cleavage: - Hydrogenolysis
- PdCl 2, Et3SiH
- TMS-I
- BBr3
- hν (254 nm)
- Na/ NH3
m-Nitrophenyl Carbamate
JOC 1974, 39 , 192
O NO 2
R2N O
- removed by photolysis
Amides
Formamides
- removed with strong acid
HCO 2Et O
R2NH +
R2N H
Acetamides
- removed with strong acid
Ac2O O
R2NH +
R2N CH 3
Trifluoroacetamides
Cleavage: - base (K2CO3, MeOH, reflux)
- NH3, MeOH
O
(CF3CO) 2O
R2NH +
R2N CF 3
Sulfonamides
p-Toluenesulfonyl (Ts)
pTsCl, pyridine
R2NH R2N SO 2
Cleavage: - Strong acid
- sodium Naphthalide
- Na(Hg)
Ts Ts Na(Hg), MeOH
Na2HPO 4 H H
N N N N
JOC 1989, 54 , 2992
(65%)
N N
Ts H
Trifluoromethanesulfonyl
Tf Tf
N N NH HN
Na, NH3
JOC 1992, 33, 5505
N N NH HN
Tf Tf
Trimethylsilylethanesulfonamide (SES)
TL 1986, 54 , 2990; JOC 1988, 53, 4143
- removed with CsF, DMF, 95°C
SO 2Cl
Me 3Si R2N SiMe 3
R2NH S
Et3N, DMF O O
tert-Butylsulfonyl (Bus) JOC 1997, 62, 8604

mCPBA
tBuSOCl, -or- CF3SO3H,
Et3N, CH2Cl2 O RuCl3, NaIO4 CH2Cl2, anisole
R-NH2 S R2N SO2tBu R-NH2
R 2N tBu
C-C BOND FORMATION 72
Carbon- Carbon Bond Formation
1. Alkylation of enolates, enamines and hydrazones
C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4)
Smith: Chapt. 9
2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6)
3. Umpolung Smith: Chapt. 8.6
4. Organometallic Reagents
C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2
Smith: Chapt. 8
5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op
Smith Chapt. 11.12, 11.13
Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99.
- α-deprotonation of a ketone, aldehyde or ester by treatment with a strong non-
nucleophillic base.
- carbonyl group stabilizes the resulting negative charge.
O O O-
B:
H H - H
R R R
H
H H H
- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater
(lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3)
O
MeO- pKa = 15 unfavorable enolate
pKa = 20 concentration
H 3C CH3 tBuO- pKa = 19
O O more favorable
H 3C CH2 OEt
pKa = 10 enolate concentration
- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2,

Na CH2S(O)CH3
Enolate Formation:
- H+ Catalyzed (thermodynamic)
O
OH
H+
- Base induced (thermodynamic or kinetic)

O O- +
:B B:H
H
Regioselective Enolate Formation Tetrahedron 1976, 32, 2979.

- Kinetic enolate- deprotonation of the most accessable proton (relative rates of
deprotonation). Reaction done under essentially irreversible conditions.
O O - Li+
LDA, THF, -78°C
typical conditions: strong hindered (non-nucleophilic) base such as LDA
R2NH pKa= ~30
Li
N
Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be
problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)
O O
OR' LDA, THF, -78°C

N
R E+
R
O O- Li+
N
OR' Li R
OR'
R THF, -78°C
- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate:

more highly substituted C=C of the enol form
O - K+ O O - K+
tBuO- K+, tBuOH
kinetic thermodynamic
typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate

formation. Enolate in small concentration (pKa of ROH= 15-18 range)
- note: the kinetic and thermodynamic enolate in some cases may be the same
- for α,β-unsaturated ketones
O
thermodynamic kinetic
site site
Trapping of Kinetic Enolates

- enol acetates
1) NaH, DME
2) Ac2O Ph
Ph Ph + O
O kinetic O
O
O isolatable
separate & purify
CH3Li, THF CH3Li, THF
Regiochemically
Ph Ph
pure enolates
O- Li+ O- Li+
- silyl enolethers Synthesis 1977, 91. Acc. Chem. Res. 1985, 18, 181.
1) LDA
2) Me3SiCl Ph
Ph Ph + OTMS
O kinetic OTMS
isolatable
separate & purify
CH3Li, THF CH3Li, THF

-or-
Bu4NF -or- TiCl4
Geometrically Ph Ph
pure enolates O- M+ O- M+
- tetraalkylammonium enolates- "naked" enolates

- TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc.
- Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl
enol ether
- From Enones
1) MeLi
1) Li, NH3
2) TMS-Cl 2) E+
O TMSO O
H H
E
OSiMe3 O OSiMe3
TMS-Cl, Et3N TMS-OTf

Et3N
O OSiMe3
Li, NH3, tBuOH
TMS-Cl
- From conjugate (1,4-) additions

O
O- Li+ O
(CH3)2CuLi E+ E
Trap or use directly
- From reduction of α-halo carbonyls

O
Zn or Mg O- M+
Br
Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides)

Comprehensive Organic Synthesis 1991, vol. 3, 1.
1° alkyl halides, allylic and benzylic halides work well
2° alkyl halides can be troublesome
3° alkyl halides don't work
O O
a) LDA, THF, -78°C Me
b) MeI
- Rate of alkylation is increased in more polar solvents (or addition of additive)

O O O O
NMe2
(Me2N)3P O S
R NMe2 H 3C CH3 CH3N CH3N NCH3
HMPA R= H DMF Me2N
DMSO
R-CH3 DMA
TMEDA
Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry
X
C
180 °
M+ -O
Alkylation of 4-t-butylcyclohexanone:
O O
E
R
R
equitorial anchor
E H
A E
H tBu
A favored Chair
tBu R
O
R
B O- M+
H
E O
tBu Twist Boat
B R
E
on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This
approach leads directly into a chair-like product. "Equitorial apprach leads to a higher
energy twist-boat conformation.
Alkylation of α,β-unsaturated carbonyls

O- M+ O
R1 R2 E
R1 R2
O Kinetic H E H
R1 R2
H H O- M+ O
E
R1 R2 R1 R2
H H E
Thermodynamic
Stork-Danheiser Enone Transposition:
- overall γ-alkylation of an α,β-unsaturated ketone
O O
LDA HO CH3 CH3
+
PhCH2OCH2Cl CH3Li H3O
PhO PhO PhO
OMe OMe OMe O
J. Org. Chem. 1995, 60, 7837.
Chiral enolates- Chiral auxilaries.

D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23.
Asymmetric Synthesis 1984, 3, 1.
- N-Acyl oxazolidinones
O O
H 2N OH
R
N O
Me Ph
Me Ph norephedrine
O O
R H 2N OH
N O
valinol
O O O O
O
R LDA, THF R LiOH, H2O, THF R
N O N O
OH
Et-I
Me Ph Me Ph Complimentary Methods
major product for enantiospecific alkylations
(96:4)
O O O
O O Diastereoselectivity: 92 - 98 %
R LDA, THF
N O R
N O
LiOH, H2O, THF R for most alkyl halides
OH
Et-I
major product
(96:4)
Enolate Oxidation Chem. Rev. 1992, 92, 919.

O O O O
NaN(SiMe3)2, R
R THF, -78°C
N O N O
O OH
N (88 - 98 % de)
Ph SO2Ph
1) HO-
O O
2) CH2N2 O
LDA, THF R
N O 3) TFA
R
O Boc N 4) Raney Ni OMe
N OtBu NH2
tBuO N HN (94 - 98 % de)
O Boc
Bu Bu
O O B O O
R Bu2BOTf, Et3N O O NBS N3-
N O R
R N O
N O
Br
Ph
Ph
Ph
O O
1) LiOH O
R 2) H2, Pd/C
N O R
OH
N3
NH2
Ph D- amino acids
O O O O
R KN(SiMe3)2, THF R
N O N O
N3
SO2N3
Ph Ph
Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969.

diastereoselectivities on the order of 50 : 1
SO2Ph
R
N Ar
Ar N O R
O SO2Ph
R O O N
O
O SO2N(C6H11)2 S O
O2
R
H
LDA, NBS H
Et2Cu•BF3 H
O O
O
Br HO
O O NH2
SO2N(C6H11)2 SO2N(C6H11)2 O
SO2N(C6H11)2 O
Asymmetric Acetate Aldol

O S O
TIPSO O
1) Br H
N O J. Am. Chem. Soc. 1998, 120, 591
Sn(OTf)2, CH2Cl 2, Br NH2 J. Org. Chem. 1986, 51, 2391
R3N, -40°C
2) TIPS-OTf, pyridine 85 %, 19:1 de
3) NH3
Chiral lithium amide basess

CH3 CH3
Ph N OMe
MeO MeO
Li
CO2Et THF, -78°C O

(CH3)2C=O
OMe OMe O
(72% ee)
H
N Ph OTMS
O But H N Ph
N
N O Li
Li N
THF, HMPA (97 % ee)
TMSCl N tBu
tBu Me
Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations

OTMS tBu-Cl, TiCl4, O
CH3
CH2Cl2, -40°C note: alkylation with a
C(CH3)3 3° alkyl halide
(79%)
ACIEE1978, 17, 48
SPh O SPh O TL 1979, 1427
OTMS
Raney Ni
R Cl R R
TiCl4, CH2Cl2, -40°C (95 %)
(78%)
Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363.

- Advantages: mono-alkylation, usually gives product from kinetic enolization
O O
N N can not become coplanar
"Kinetic" "Thermodynamic"
O O
O
O +
••
N N N O
H R-I H2O
R E
H+, (-H2O)
enamine
-Chiral enamines
O
N
E
Imines Isoelectronic with ketones

Me
Ph O
Li
OMe Ph O E = -CH3, -Et, Pr,
N N 1) E
PhCH2-, allyl-
LDA, THF, -20°C 2) H3O+ E
ee 87 - 99 %
Hydrazones isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503
N N
O N N
N
-N
Me2N-NH2 LDA, THF
-
+
H , (-H2O)
N
N O
E+ hydrolysis
E E
- Hydrazone anions are more reactive than the corresponding ketone or aldehyde
enolate.
- Drawback: can be difficult to hydrolyze.
- Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders
"Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983)
OMe MeO
N N
NH2 H 2N
SAMP RAMP
N N
LDA O3 O
N OMe N OMe
H
I OTBS
(95 % de) TBSO

TBSO
1) LDA
N 2) Ts-CH3, THF
N -95 - -20 °C O
OMe 3) MeI, 2N HCl
CH3
(100 % ee)
Me
O
Li •• MeO
R1 N N R1 N N
E (C,C) R2 R2 H
H Z (C,N)
E
Aldol Condensation Comprehensive Organic Synthesis 1991, 2, 133, 181.

O a) LDA, THF, -78°C O OH β-hydroxyl aldehyde
b R'CHO (aldol)
R
H H R'
R
- The effects of the counterion on the reactivity of the enolates can be important
Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers
- The aldol reaction is an equilibrium which can be "driven" to completion.
M
O- M+ O O O OH
work-up
R + RCHO H H R'
R'
R' R
R
In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+
counterions will stabilize the intermediate β-alkoxycarbonyl and push the equillibrium
towards products. (JACS 1973, 95, 3310)
O- M+ O OH
PhCHO, THF Ph M= Li 16% yield

M= MgBr 93% yield
- Dehydration of the intermediate β-alkoxy- or β-hydroxy ketone can also serve to drive
the reaction to the right.
O O
O
tBuO- Na +, tBuOH
JACS 1979, 101 , 1330
O O
H H
O O
Enolate Geometry
- two possible enolate geometries
O O - Li+ O - Li+
LDA, THF, -78°C H
+
H
E - enolate Z - enolate
- enolate geometry plays a major role in stereoselection.

OM O OH
Z -enolate
R2 R3CHO erythro
1 1 3
R R R (syn)
H R2
E -enolate OM O OH
R3CHO threo
H
R
1
R 1
R 3 (anti)
R2 R
2
- Zimmerman-Traxler Transition State : Ivanov condensation

JACS 1957, 79 , 1920.
+
O MgBr H Br
O O
- - + Mg
Ph H + PHCHCO2 MgBr Ph
Ph OMgBr
H
"pericyclic" T.S.
Analysis of Z-enolate stereoselectivity
R2 R2
R3 R2 O M O O
O O R3 O OH
R3 M M
O R1 R3
H H
H H R1
H R1 H R2
R1
erythro (syn)
favored
R2 H R2 O M R2
O O O O O OH
H M H M
O
H R1 R3
H H R3
R3 R1 R3 R1 R2
R1
threo (anti)
disfavored
Analysis of E-enolate stereoselectivity

H
H R3 H O M O O
3 O OH
O O R M
R3 M O
R2 R1 R3
R2 R2 H R1
H
H R1 R1 R2
threo (anti)
favored
H H
O O H H O M O O
H M H M
O OH
2 O R2
R R1 R3
R1 R2 R3 R3 R1
R3
R1 erthro (syn) R2
disfavored
Analysis of Boat Transition State for Z-Enolates

R2 R3
O O O
M O HO
R3 H
O M
R1 R3 R2
H
H R1 R2
H R1
Favored Chair
Boat
H
R2 O
O O O HO R3
M O M
H R2
R1 R3 staggered
H R2
R3 R1 H R1
Boat: R1-R2
Disfavored Chair 1,3-interaction is gone
Analysis of Boat Transition State for E-Enolates
H R3
O O O
M O HO
R3 H
O M
R2 R1 R3 H
H R1 R2
R2 R1
Favored Chair
Boat
H
H O
O O O HO
M R3
H O M
R1 R3 H
staggered
R2 R2
R3 R1 R1
R2
Disfavored Chair Boat: R1-R2
1,3-interaction is gone
Summary of Aldol Transition State Analysis:

1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates
usually give a higher degree of stereoselection than E-enolates.
2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic
aldol reactions.
3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic
diastereoselection.
O- M+ O HO
Path A
R2
R1 R1 R3
H Path R2
B
O- M+ O HO
H
R1 R1 R3
Path A
R2 R2
When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent
steric influence then path B proceeds.
4. The Zimmerman-Traxler like transition state model can involve either a chair or boat
geometry.
Noyori "Open" Transition State for non-Chelation Control Aldols

Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+
- Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols
regardless of enolate geometry.
Z- Enolates:
R1 O-
R1 O-
R1 O-
O HO
Favored R3 H
H R2 R3 H R1 R3
R3 H H R2
H R2 R2
O O
O
Syn Aldol
Favored
R1 O-
R1 O-
R1 O-
O HO
Disfavored H R3
H R2 H H R R2 R1 R3
H R3 3
H R2 R2
O O
O
Disfavored Anti Aldol
E- Enolate:
- - O R1
O R1 - R1
O O HO
favored R3 H
H R2 H R1 R3
R3 H R2
R3 H R2
H R2
O O
O Syn Aldol
favored
-
-
O R1 -
O R1
O R1 O HO
disfavored H R3
H R2 H H R3 R2 R1 R3
H R3
H R2 R2
O O
O
disfavored Anti Aldol
NMR Stereochemical Assignment.

Coupling constants (J) are a weighted average of various conformations.
H
O O
HB Syn Aldol
R1 R3 JAB = 2 - 6 Hz
R2 HA
60 ° 60 °
HA HA HA
O HB HB R3 R3 OH
H
O R1 O
R2 R2 R2
R1 R3 O O R1 HB
H
non H-bonded
H
O OH
B Anti Aldol
R1 R3 JAB = 1 - 10 Hz
R2 HA
60 ° 60 °
HA HA HA
O R3 R3 HB HB OH
H
O R1 O
R2 R2 R2
R1 HB O O R1 R3
H
non H-bonded
Boron Enolates: Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1;
Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3.
- Alkali & alkaline earth metal enolates tend to be aggregates- complicates
stereoselection models.
- Boron enolates are monomeric and homogeneous
- B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C
bonds (more covalent character)- therefore tighter more organized transition state.
Generation of Boron Enolates:
O R2B-X OBR2
X= OTf, I
R= Bu, 9-BBN
iPrEtN
R3N: H _ OBL2
+ BL2OTf R2
R1 O R1
H R2
Z-enolate
R3N: H _ OBEt2
+ BL2OTf
R1 O R1
R2 H R2
E-enolate
O
R 3B OBR2
OSiMe3 OBR2
R2B-X
+ Me3 Si-X
O R' 3B OBR'2
N2 R' Hooz Reaction
R R
Diastereoselective Aldol Condensation with Boron Enolates

O OBEt2 O OBEt2
RCHO
Ph Ph Ph R
pure
Z-enolate 100% Syn Aldol
OBEt2 O OH
R3CHO generally
R2 R1 R3 > 95 : 5
R1 syn : anti
Z-enolate R2
OBEt2 O OH
R3CHO generally
R1 R3 ~ 75 : 25
R1 anti : syn
R2 R2
E-enolate
Asymmetric Aldol Condansations with Chiral Auxilaries-

D.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115.
- Li+ enolates give poor selectivity (1:1)
- Boron and tin enolates give much improved selectivity
Bu Bu
O O B OH O O
Bu2BOTf, O - O +
Me EtNiPr2 , -78° RCHO
N O R N O
N O
Me
> 99:1 erythro

O O
1) Bu2BOTf, OH
Me EtNiPr2 , -78° O
N O
2) RCHO R X
Ph Me
L L H L L L L
B
_ + B
_ B +
O O R O O O _ O
+ O O
N O N O R N O
RCHO
H L L L L
B B +
R O _ O O _ O
+
N R N
O O
O O
preferred conformation
R2 R2
R3
O O
H H
L O R3 L O R3
B B
N N
H
L O L
O
O O
Favored Disfavored
O O OH O O OH
O N R3 O N R3
R2 R2
Oppolzer Sultam
L 2B OH
O O O
R2 R2 R3CHO
N N N R3
S S S R2
O2 O2 O2
1) LDA
2) Bu3SnCl
R3
Sn OH
O R3CHO O
R2
O N R3
N
S R2
S
O2
O
Chiral Boron
O BOTf OH O OH O
StBu Ph StBu + Ph StBu
iPrEt2N,
PhCHO,-78°C
when large, 1 : 33
higher E-enolate (> 99 % ee)
selectivity
Ph Ph
O ArO2SN NSO2Ar OH O
B OH O
R Br
SPh Ph SPh + Ph SPh
iPrEt2N, R R
PhCHO,-78°C > 95 : 5
(> 95 % ee)
• In general, syn aldol products are achievable with high selectivity, anti aldols are
more difficult
Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors.

Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with
aldehydes: proceeds via "open" transition state to give anti aldols starting from either
E- or Z- enolates.
RCHO, TiCl4, OH OH
OSiMe3 CH2Cl2, -78°C
CO2Et + CO2Et
R R
OEt CH3 CH3
R= iPr (anti : syn) = 100 : 0

C6H11 94 : 6
Ph 75 : 25
RCHO, TiCl4, OH
OSiMe3 OH
CH2Cl2, -78°C
CO2Et + CO2Et
R R
OEt CH3 CH3
R= iPr (anti : syn) = 52 : 48

C6H11 63 : 37
Ph 67 : 33
Asymmetric Mukiayama Aldol:

RCHO, TiCl4, OH O OH O
Ph O
CH2Cl2, -78°C
R Rc +
OSiMe3 R Rc
H 3C NMe2
(90-94% de)
syn : anti = 85 : 15
selectivity insenstivie to enolate geometry
Ph iPrCHO, TiCl4, O HO
N SO Ph CH2Cl2, -78°C 96 % de
2 Rc anti : syn = 93 : 7
O OSitBuMe2 CH3
RCHO, TiCl4, O HO
CH2Cl2, -78°C + Syn product
O Rc
CH3
OSitBuMe2
SO2N(C6H11)2
E-Enolate
R= Ph % de= 90 anti : syn = 91 : 19
nPr 85 94 : 6
iPr 85 98 : 2
Z-Enolate
R= iPr % de= 87 anti : syn = 97 : 7
Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals:
OSiMe3 O OH
TiCl4 or SnCl4 Mukaiyama-Johnson Aldol
R
RCHO or RCH(OR')2
via Ti or Sn enolate
CH2Cl2, -78°C
O O
TiCl4, CHCl2, -78 °C

O O
O HO
O O
O
OTMS
+
O
O Cl4Ti O
Cl4Ti O+ OSiMe3
OTMS TiCl4,
(CH3)2C(OEt)2 O OEt
Ph (78 %) Ph
Fluoride promoted alkylation of silyl enol ethers Acc. Chem. Res. 1985, 18, 181
OSiMe3 O
nBu4NF, THF, MeI

Meyer's Oxazolines:
1) RCHO
O (ipc)2BOtf 2) 3N H2SO4 H 3C H 3C
iPrEt2N, Et2O O 3) CH2N2
N R + R
CO2Me CO2Me
N (~ 30%)
OH OH
(ipc)2B
Ester R= nPr %ee (anti) = 77 anti : syn = 91 : 9
equiv.
C6H11 84 95 : 5
tBu 79 94 : 6
Anti-Aldols by Indirect Methods:

SePh
O 1) (C5H7)2BOTf 1) HF
R3N OTBS 2) [O] CO2Me
PhSe C6H11
R R
C6H11 3) NaIO4 CO2Me R
2) RCHO
OTBS 4) CH2N2
HO O HO
HO
chiral syn
auxillary aldol
1) TBS-Cl CH3 CH3

2) DiBAl-H O3 Anti Aldol
R R Product
3) TsCl CHO
4) Ba(CN)BH3 OTBS OTBS
CO2Me O OH
1) LDA, THF, 1) HIO6
-78 °C O 2) CH2N2 MeO2C
N R
2) RCHO CH3
N R
CH3 Anti Aldol
MOMO O HO
N CH3 syn : anti

O O O O KBEt3H, Et2O, 1 : 99
MOMO -78 °C
MeO 1) LDA, THF, CH3
N -78 °C N CH3 OMOM
2) RCOCl CH3
O
OMOM MOMO O HO
MeO
Zn(BH4)2 N CH3 syn : anti
97 : 3
CH3
OMOM
Syn Aldols by Indirect Methods:
O O
1) LDA, THF, O O O O O OH
-78 °C Zn(BH4)2
O N
O N R O N R
2) RCOCl syn : anti = 100 : 1
CH3 CH3
Aldol Strategy to Erythromycin:
O
9
10
8 4 3 2 1
11 7
12
OH 6
CO2H Erythromycin
15 5
seco acid
13 O 4
OH OH OH O OH OH
14 1 3
O 2
OH
[O] [O]
syn
Erythromycin aldol 3
aglycone
CHO CO2H
OH O OH OH
syn syn
aldol 4 aldol 1
CHO + CHO +
CHO CO2H
O OH
syn
aldol 2
CHO +
CHO
O
OH OH O OH OH
1
HO2C
3 5 9 11 13
1) Zn(BH3)2
O O LDA, O O O TiCl4, iPr 2EtN, O O O OH 2) (H3C)2C(OMe)2
CH3CH 2COCl CH2Cl2 CSA
O N O N 1 O N 5
83%, (96:4) (100%)
Ph CHO
Ph 90% (> 99:1) Ph
O 1) 9-BBN, THF O O O O
O O O
2) Swern oxid.
CHO
O N O N
3 5 73% (85:15)
Ph Ph
1) Na BH(OAc)3
O OH OTBS
O O O O OH 2) TBS-OTf, 2,6-lutidine
O O Sn(OTf)2, 3) AlMe3, (MeO)MeNH•HCl MeO
Et3N, CH2Cl2 N
O N O N 9 11 13
CH3CH 2CHO 72% (>99:1) CH3
84% (> 96:4)

Ph Ph
O OH OTBS 1) PMBC(NH)CCl3 PMBO
TfOH TMSO OTBS
EtMgBr
11 13 2) (PhMe2Si)2NLi,
86% 8 TMS-Cl
48 %
X X
L
H3C H
H O O O OH L O
Sn H CH3
O L Ti
X R H
L O O
CH3 CH3 L Disfavored
H O
CH3 H
CH3 anti-syn CH3
X CH3
H L X
H3C J. Am. Chem. Soc.
O CH3 O O OH O 1990,112, 866
Sn L
H H
O X R Ti L
H
O L CH3 CH3 O
H O L
H3C H
Disfavored anti-syn
CH3 H3C
CH3
PMBO PMBO
O O O O BF3•OEt2, O O O O OH O OTBS
TMSO OTBS
CH 2Cl2, -78 °C
CHO
O N 3 5 7 + 11 13 83% (95:5)
O N
3 5 7 9 11 13
8
p-MeOC 6H4
Ph Ph
O O O O OH O O OTBS
1) Zn(BH3)2 1) NaH, CS2, MeI
2) DDQ 2) nBu3SnH, AIBN
O N
95% 70%
Ph
p-MeOC 6H4 p-MeOC 6H4
Cl3C6H2COCl
O O O O O O OTBS 1) LiOOH O O O O O OH
2) TBAF
iPr2EtN, DMAP
O N HO
63% 13 (86%
Ph p-MeOC 6H4 O
O 9
10 9 1) Pd(OH)2, iPrOH
11
8 2) PCC
11 7 3) 1M HCl, THF OH
O 5
12 6
5 58 % 13 O OH
13 O O 1 3
4
1 3 O OH
O 2 O
Michael Addition
- 1,4-addition of an enolate to an α,β-unsaturated carbonyl to give 1,5-dicarbonyl
compounds
O O O
- +
O M
R Ph
Ph
R
Organometallic Reagents
Grignard reagents:
O
Mg(0) OH
R-Br R-MgBr
THF R
O
O
OH
often a mixture of
+
R-MgBr R 1,2- and 1,4-addition
THF
R
O
OH
R-MgBr R 1,2-addition
THF, CeCl3
O O
R-MgBr 1,4-addition
CuI,THF, -78C
R
Organolithium reagents
- usually gives 1,2-addition products
- alkyllithium are prepared from lithium metal and the corresponding alkyl halide
- vinyl or aryl- lithium are prepared by metal-halogen exchange from the
corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or t-
butyllithium.
Li(0)
R-Br R-Li
Et2 O
X Li
nBu-Li
X= Br, I, Bu3Sn
Et2 O
Organocuprates
Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1.
- selective 1,4-addition to α,β-unsaturated carbonyls
CuI, THF
2 R-Li R2CuLi
O O
R2CuLi
- curprate "wastes" one R group- use non transferable ligand

MeO
_
Cu MeO
Cu R Li+
R-Li
non-transferable
ligand
Other non transferable ligands
_ _ _ _
+ +
Bu3P Cu R Li Me2S Cu R Li+ NC Cu R Li F3B Cu R Li+
2-
+ Mixed Higher Order Cuprate

Cu R 2Li
S B. Lipshutz Tetrahedron 1984, 40 , 5005
CN Synthesis 1987, 325.
Addition to Acetals Tetrahedron Asymmtetry 1990, 1, 477.

n-C6 H13 CH3 1) PCC
O R (n-C6H13)2CuLi
2 NaOEt n-C6 H13 CH3
H3C TL 1984, 25, 3087
BF3•OEt 2 O
O OH
R OH
Chiral axulliary is destroyed 99 % ee
LA
LA O
O O
R O CH3 H
R O
R O
H CH3
Nu: H
Nu
TMS
O 1) TiCl4
JACS 1984, 106, 7588
O 2) [O]
3) TsOH OH
98 % ee
Stereoselective Addition to Aldehydes

- Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes
may be stereoselective.
- Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828.
empirical rule
O - OH
M M
1) "R2 - "
S R1 S
R 1
* 2) "H + " R 2
L L
O OH
M S M S
L R1 R2 -
R
1
R
2
L
- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61.

based on ab initio calculations of preferred geometry of aldehyde which considers the
trajectory of the in coming nucleophile (Dunitz-Burgi trajectory).
O O
S
M vs.
L
L R2 - R2 -
1
S M 1
R R
better worse
- Chelation Control Model- "Anti-Cram" selectivity
- When L is a group capable
+
of chelating a counterion such as alkoxide groups
M OH
O S
2 M
OR' R
1
R1 R
*
M OR' "Anti-Cram" Selectivity
S
M+
OR'
O OR' HO R2
R2 -
M S
M S R1
1
R
Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239.
i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic)
O O
usually
- +
R R
Benzoin Condensation Comprehensive Organic Synthesis 1991, 1, 541.
KCN O- OH HO O- -O OH O OH
PhCHO
PhCHO
H
Ph CN Ph - CN Ph Ph Ph Ph Ph Ph
CN CN
Cyanohydrin anion Benzoin
Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions
NH2 H
NH2 _
+ +
N N S
N N S
H 3C N OPO3PO3
H 3C H 3C N OPO3PO3
H 3C
Thiamin pyrophosphate
H 2C OH
CHO H 2C OH
O
H OH O CHO
thiamin-PP HO H
H OH + H OH H OH
+
H OH
H OH H OH H 2C OPO3
H OH
H 2C OPO3 H 2C OPO3
H OH
glyceraldehyde-3-P
D-ribose-5-P D-ribulose-5-P (C3 aldose) H 2C OPO3
(C5 aldose) (C5 ketose)
sedohepulose-7-P
(C7 ketose)
Trimethylsilycyanohydrins
O TMS-CN TMSO CN TMSO CN acyl anion
LDA, THF
R H R
_ equivalent
R H
NC O
OMs
NaHMDS, OEE
THF, -60°C CSA, tBuOH
CN Tetrahedron Lett. 1997, 38, 7471
(72%)
OEE O
O O O
O O
Dithianes
B:, THF R'-I Hg(II) O

S S S S S S
R - R R'
R H R R'
Aldehyde Hydrazones
H B:
N tBu N tBu
N O
N E+
R E R E
R H H
Heteroatom Stabilized Anions (Dithiane anion is an example)

Sulfones
O R'
_ OH R' OH
Ph R'
Al(Hg)
Ph LDA, THF R' R' R'
R S R S
Ph
O O O O R S R
O O
Sulfoxides
O R'
_ OH
R' OH
Ph Ph R' R' R' Raney Ni
LDA, THF R S R'
R S Ph
O R S
O
R
O
Epoxide Opening Asymmetric Synthesis 1984, 5, 216.
Basic (SN2) Condition
Nu:
R R Nu
Steric Approach Control
O HO
Acid (SN1-like) Condition
R Nu: attachs site that best
R OH
O+ stabilizes a carbocation
Nu Nu
H
OH
O
OH OH + OH
BnO BnO BnO TL 1983, 24, 1377
OH
Me2CuLi 6:1
AlMe3 1:5
OH
Me3Al
O JACS 1981, 103, 7520
S S
_ OH S JOC 1974, 3645
O
S
O
OH
S S + S S
_ Ph
Ph (69 %)
1) TBS-Cl O OH
2) MeI, CaCO 3, H+
Ph Tetrahedron Lett. 1992, 33, 931
Cyclic Sulfites and Sulfates (epoxide equivalents) Synthesis 1992, 1035.

O O O
OH S S
SOCl2, Et3N O O RuCl3, NaIO4 O O
R2
R1
R1 R2 R1 R2
OH
sulfite sulfate
O O O -
S S
H2O HO H
O O Nu: O H
R2 R2
R1 R2 R1 Nu R1 Nu
H2O
O O O
O-
S O S
O O Nu: Nu: H H
O H
Nu2 R
R1 R2 R1
R2 R1 Nu1 2
Nu
CO2Me
MeO2C CO2Me
O SO2
CO2Me
R2
R1 R1 R2
O NaH
O
O SO2 OTBS
1) H2, Rh
1) (CH3)2CuLi 2) HF
CO2Me O carpenter Bee
CO2Me
pheromone
O 2) TBS-Cl
CH3
OBn MeO OMe

OMe OBn
OMe H
O SO2 N OMe 1) Ac2O
H3C OMe NCH3 2) HCl
∆
O
MeO OH
MeO
OBn
meso OBn
HO OBn OBn
MeO OMe MeO OMe
NCH3 NCH3
BnO BnO
OAc
Irreversible Payne Rearrangement

OH
O
OH
O
O SO2
Bu 4NF OH
OTBS
O O
Payne Rearrangement of 2,3-epoxyalcohols Aldrichimica Acta 1983, 16, 60
Sigmatropic Rearrangements Asymmetric Synthesis 1984, 3, 503.

Nomenclature:
2 3 R 2 3 R
1 1
σ bond ∆ σ bond
[3,3]-rearrangement
that breaks that forms
1 3 R 1 3 R
2 2
3 3
2 4 2 4
∆
1 1 5 [1,5]-Hydogen migration
R H 5 R H
1 1
σ bond σ bond
that breaks that forms
3,3-sigmatropic Rearrangements
Cope Rearrangemets- requires high temperatures Organic Reaction 1975, 22, 1
∆
R R
Chair transition state:
CH3 CH3 Z
220 °C
H 3C H H 3C
H E
E,Z (99.7 %) E,E (0.3 %) Z,Z (0 %)
CH3
H
H 3C HH
H 3C
CH3
H
CH3 Z
E
H 3C
H 3C
E Z
H 3C
E,Z (0 %) E,E (90 %) Z,Z (10 %)
"Chirality Transfer"
H
Ph R E S
Ph CH3
CH3
CH3 (87 %)
Diastereomers
Ph
Ph Z
H 3C
H 3C CH3
R R
E H (13 %)
CH3
R R
Ph E
Z Ph H
CH3
CH3
Diastereomers
Ph
Ph Z
H 3C
H
H 3C R
S
Z CH3
- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower
temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43,
93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.
OMe O
OH
KH, DME, 110°C
OMe
KH
OH
O- O
Ring expansion to medium sized rings
OH O
KH, ∆
9-membered
ring
Claisen Rearrangements - allyl vinyl ether to an γ,δ-unsaturated carbonyl

Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis
1991, 5, 827.
∆
O O
O
OH CHO
O
220 °C
Hg(OAc)2 JACS 1979, 101 , 1330

O
O H O
H H
O
O O
Chair Transition State for Claisen

E-olefin
R O O
R
H X X
X=H E/Z = 90 : 10
X= OEt, NMe2, etc E/Z = > 99 : 1
R O X 1,3-diaxial
interaction Z-olefin
R X R
X
H
O
O
new stereogenic
centers
R O
old stereogenic O
center H X R
X
- Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over
non-enzymatic reaction
CO2H HO2C CO2H
Chorismate
mutase O J. Knowles
JACS 1987, 109, 5008, 5013
O CO2H
OH OH
Chorismate Prephenate
- Claisen rearrangement usually proceed by a chair-like T.S.

H HO2C H
HO2C H O H
O Chair
CO2H
T.S
OH OH
Opposite
H stereochemistry
H H CO2H
CO2H Boat
O H
CO2H T.S O
CO2H
OH OH
OH OH OH
+
O O
J. Org. Chem. 1976, 41, 3497, 3512 +
J. Org. Chem. 1978, 43, 3435
O
R R
O
H H
O
s CH3 R H
O
R s
H CH3
CH3 O
CH3 OH CH3 OH
CH3 O CH3 CH3

CO2R
H
CH3 OH CH3 OH
Tocopherol
94 - 99 % ee
hydrophobically accelerated Claisen - JOC 1989, 54, 5849

Johnson ortho-ester Claisen:
EtO OEt OEt OEt
OH O ∆ O [3.3]
H3C-C(OEt)3 O
H+ - EtOH
Ireland ester-enolate Claisen. Aldrichimica Acta 1993, 26, 17.

OTMS
O OH
LDA, THF
TMS-Cl O [3.3]
O O
O
OBn LDA, THF Me
O TMS-Cl
CO2H JOC 1983, 48, 5221
Me
Me Me
OBn
Eschenmoser
NMe2
R
EtO OEt O ∆ O
OH
BF3 NMe2 NMe2
R R
"Chirality Transfer"
R R
R aldehyde
O N
N N O oxidation state
Ph O
Ph Ph
R= Et, Bn, iPr, tBu (86 - 96 % de)
[2,3]-Sigmatropic Rearrangement Comprehensive Organic Synthesis 1991, 6, 873.

Z H H
H H E
:X Y X Y:
R Y: R :X Y
X
R R
R1
R R1 R
X Y:
H Y
:X
-Wittig Rearrangement Organic Reactions 1995, 46, 105 Synthesis 1991, 594.
_
O base
HO
BuLi _
O SnR3 O
TBDPSO KH, 18-C-6, TBDPSO TBDPSO
Me3SnCH2I nBuLi
H H H
MeO O MeO O MeO O
OH O O
J. Am. Chem. Soc.
SnMe3 Li 1997, 119, 10935
TBDPSO
TBDPSO
H +
H
MeO O
MeO O
OH
(58%) (42%)
CH3 H3C CH3

H3C Ph
O
_
OH (87 %)
H Ph
CH3 CH3
CH3 (13 %)
H _ H3C
O Ph Ph OH
Sulfoxide Rearrangement
R R
S S (MeO) 3P
O
-
O HO
O O
CO2Et CO2Et
(MeO) 3P
S
Ph HO
O-
Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23,
876; ; Chem. Rev. 1992, 28, 1021.
H H
- Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl)

R R
H
O O
H
H
OH
CHO
Et2AlCl JOC 1992, 57, 2766
CH2Cl2 -78°C
O O
Ph Ph
O OH
O O 99.8 % de
H SnCl4
O
Ph
OH
O
SnCl4 + syn isomer
H3C
(94 : 6)
O
TiCl2
O
O OH Tetrahedron Lett.
(97% ee)
+ 1997, 38, 6513
H CO2Me CO2Me
OH
O OH
+ +
PhS PhS CO2Me
R H CO2Me CO2Me
PhS R
R
(9 : 1)
anti (99 % ee) syn (90 % ee)
- Metallo-ene Reaction Angew. Chem. Int. Ed. Engl. 1989, 28, 38

CH3 CH3
C6H13 C6H13
H2O
C6H13
CH3 H 3C (10 %)
ClMg
C6H13 C6H13
Cl MgCl H2O
H 3C
H 3C H 3C
ClMg (> 1%)
intramolecular
BrMg
+ (11 : 1)
+
MgBr
BrMg
CH3
1) Mg(0), Et2 )
1) Li 2) 60 °C MgCl
CHO 2) SOCl2 MgCl

Cl
CH3 CH3
O Cl 1) Mg(0), Et2 )
SOCl2 2) 60 °C
OH
CH3 CH3
MgCl O2
H H
MgCl OH
1) PCC CH3 H3C

4) KOH
2) MeLi 5) H2
3) O3 CHO 6) Ph3 P=CH2
H
H
O Capnellene
Synthesis of Phyllanthocin A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269.
O O O O
1) LAH
(Me3Si)2 NLi 2) BnBr
O N O N
Br
Ph CH3 Ph CH3
BnO
1) O3
2) H2, Lindlar's BnO MeAlCl
CHO
BnO 1) MEM-Cl
H 2) O3
BnO BnO
CH3
O H
OH CHO
OMEM
O O O
O
1) ZnCl2 O
1) BnO +
- O
2) H O
O BnO (CH3 )2S(O)CH 2-
2) H3O + O
MEMO O
3) Swern
O CH 1) DBU
O O 1) LDA, TMSCl O 3
2) H2, Pd/C
2) BnMe3 NF, MeI
O O
BnO BnO 3) RuO4
O O
O O
O
O CH3 O CH3
O Ph Phyllanthocin
O MeO2C O
HO2C
O
C=C BOND FORMATION 103
C=C Bond Formation C&S Chapt. 2 # 5,6,8,9,12
1. Aldol Condensation
2. Wittig Reaction (Smith, Ch. 8.8.A)
3. Peterson Olefination
4. Julia-Lythgoe Olefination
5. Carbonyl Coupling Reactions (McMurry Reaction) (Smith Ch. 13.7.F)
6. Tebbe Reagent
7. Shapiro and Related Reaction
8. β−Elimination and Dehydration
9. From Diols and Epoxides
10 From Acetylenes
11. From Other Alkenes-Transition Metal Catalyzed Cross-Coupling and Olefin
Metathesis
Aldol Condensation -Aldol condensation initially give β-hydroxy ketones which under
certain conditions readily eliminated to give α,β-unsaturated carbonyls.
OMe OMe
LDA, THF, -78°C
Tetrahedron
O O 1984, 40, 4741
O O
CHO
OMe OR O OMe OR O
-78C → RT
Robinson Annulation : Sequential Michael addition/aldol condensation between

a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-1-
one
JOC 1984, 49 , 3685 Synthesis 1976, 777.
O O
O
L-proline O
O
Weiland-Mischeler Ketone
(chiral starting material)
Mannich Reaction - α,β-unsaturated carbonyls (α-methylene carbonyls)
H2C=O, Me2NH•HCl
O
O
Me
H 2C N Cl-
+ Me
Mannich Reaction
Wittig Reaction review: Chem. Rev. 1989, 89, 863.

mechanism and stereochemistry: Topic in Stereochemistry 1994, 21, 1
- reaction of phosphonium ylide with aldehydes, ketones and lactols to give
olefins
strong _
Ph3P + base +
R X R PPh3 R PPh3 R PPh3
-
X ylide phosphorane
O
+
Ph3P O - Ph3P O - Ph3P=O
R1 R2 R2
R
R R
R R1 2 R R1 2 R1
betaine oxaphosphetane
- Olefin Geometry
O
L S
Z- olefin
Ph3P
L S
L S
E- Olefin
Ph3P
S L
- With "non-stabilized" ylides the Wittig Reaction gives predominantly Z-olefins.
Seebach et al JACS
-
O
O
O S L L S
S L S L
L S L S
PPh3 + PPh3
+ PPh3 +
O O PPh3
L S - Ph3P=O S S
Ph3P L S
L S L L
L S Z-olefins
- "Stabilized ylides" give predominantly E-olefins

O
_ S
+ L S
Ph3P CO2Me CO2Me
L
- Betaine formation is reversible and the reaction becomes under thermodynamic

control to give the most stable product.
- There is NO evidence for a betaine intermediate.
- Vedejs Model:
R
O
Pukered (cis)
Ph H Cis oxaphosphetane
R
Ph P (kinetically favored)
H
Ph
H R
Ph R
Planar (trans)
Ph P H Trans oxaphosphetane
O (thermodynamically favored)
Ph
Phosphonate Modification (Horner-Wadsworth-Emmons)

_
R X (EtO)3P R P(OEt)2 R P(OEt)2
Arbazov Reaction O O
- R is usually restricted to EWG such as CO2H, CO2Me, CN, SO2Ph etc. and the
olefin geometry is usually E.
- Still Modification TL 1983, 24, 4405.

(CF3CH2O)2P CO2Me
O
- CF3CH2O- groups make the betaine less stable, giving more Z-olefin.
O
Me3Si CHO (CF3CH2O)2P CO2Me Me3Si JACS 1988,
- + CO2Me 110, 2248
(Me3Si)2N K , THF,
18-C-6 Z:E = 25:1
Peterson Olefination review: Synthesis 1984, 384 Organic Reactions 1990, 38 1.

-
O
O
R1 R2
LDA, THF Me3Si CO2Me R1 R2
Me3Si CO2Me Me3Si
_
Silicon can stabilize MeO2C H
an α- negative charge
O
R1 usually a mixture
R1 R2 - Me3Si-O of E and Z olefins
Me3Si R2 CO2Me
MeO2C H
Julia-Lythgoe Olefination TL 1973, 4833 Tetrahedron 1987, 43, 1027
SO2Ph OH
PhO2S 1) MsCl, Et N OTBS
LDA, THF, -78°C OTBS 2) Na(Hg),3MeOH
mixture TL 1991,
CHO of olefins 32, 495
TBSO
R
R R
O
O O
H O
1) tBuLi, THF,
O O
HMPA, -78°C
O OBz 2) Na(Hg) NaHPO4
THF, MeOH, -40°C
OBz O O
+
OSitBuPh2 HO
OSitBuPh2 HO
HO
PhO2S
O
O
O
OH
OH
OH
Milbemycin α1
OR SmI2,
HMPA/THF O OTBDPS
OTBDPS Synlett 1994, 859
O
SO2Ph R= H, Ac O 75 % yield
O E:Z = 3 : 1
Ramberg-Backlund Rearrangement
Br
1) Na2S•Al2O3
OSiPh2tBu 2) mCPBA O OSiPh2tBu SOCl2
S
OSiPh2tBu O OSiPh2tBu
Br
Cl
O MeLi, THF O OR - SO2 OR
OR
S S
O OR O OR OR
thiiarane dioxide
JACS 1992, 114, 7360
Carbonyl Coupling Reactions (McMurry Reaction)

Reviews: Chem. Rev. 1989, 89, 1513.
- reductive coupling of carbonyls with low valent transition metals, Ti(0)
or Ti(II), to give olefins
O R1 R1 R1 R2 usually a mixture
"low-valent Ti" +
of E and Z olefins
R1 R2 R2 R2 R2 R1
excellent method for the preparation of strained (highly substituted) olefins

- Intramolecular coupling gives cyclic olefins
CHO
"low-valent Ti" JACS 1984, 106, 723
CHO
OMe OMe
TiCl4, Zn,
pyridine Tetrahedron Lett. 1993, 34, 7005
OMe (86 %) OMe

OHC
O OH OH
Tebbe Reagent Cp2Ti(CH2)ClAlMe2

- methylenation of ketones and lactones. The later gives cyclic enol ethers.
H2
Cp C
O Ti AlMe2
O O
Cp Cl 200 °C
O
- Cp2TiMe2 will also do the methylenation chemistry

JACS 1990, 112, 6393.
Shapiro and Related Reactions Organic Reactions 1990, 39, 1 : 1976, 23, 405
- Reaction of a tosylhydrazone with a strong base to give an olefin.
_
_
NNHTs N N N
N Ts _ E
Et Et Et - N2 Et
2 eq. nBuLi E+ Et
_
THF
Me Me Me Me Me
Bamford-Stevens Reaction- initial conversion of a tosylhydrazone to a diazo

intermediate
H H H
R1 R3 R1 R3 R1 R3
base
R2 R2 R2
NNHTs N Ts +N
N _
_ N
a: aprotic- decomposition of the diazo intermediate under aprotic conditions

gives and olefin through a carbene intermediate.
H
R1 H
R3 - N2 R1
R2 R1 R3
R2 R3
+N •• R2
_
N
Carbene
b. protic- decomposition of the diazo intermediate under protic conditions an
olefin through a carbonium ion intermediate.
H H
R1 R3 R1 R3 H
R2 H+ R2 - N2 + R1
H R1 R3 -H
+N + N R2 R3
_ + H R2
N N
β- Eliminations
Anti Eliminations
- elimination of HX from vicinal saturated carbon centers to give a olefin,
usually base promoted.
- base promoted E2- type elimination proceeds through an anti-periplanar
transition state.
B:
H
R1 R2 R1 R2
R3 R4 R3 R4
- typical bases: NaOMe, tBuOK, DBU, DBN, DABCO, etc.
N N N
N N
N
DBN DBU DABCO

- X: -Br, -I, -Cl, -OR, epoxides
O O
O B: OH
R R
N
O OH BCSJ 1979, 52, 1705
R R' AlEt2 R JACS 1979, 101, 2738
- or - R'
"unactivated" TMS-OTf, DBU
Syn Elimination
- often an intramolecular process
H
R1 R2
R1 R2 O O
X X= Se S
R3 R4 Ph Ph
R3 R4
Cope Elimination- elimination of R2NOH from an amine oxide

OLI + O O
Me2N=CH2 I - O- O
NMe2 mCPBA N
THF, -78°C Me2 - Me2NOH
THF
O O NMe2
1) Me2CuLi JACS 1977,
99 , 944
+ Tetrahedron
2) Me2N=CH2 1977, 35 , 613
CF3CO2-
Selenoxide Elimination Organic Reactions 1993, 44, 1.

O
N SePh R
JACS 1979,
R' Bu3P: O R
R' mCPBA H
R' - ArSeOH R'
R R 101, 3704
- or - SeAr Se
OH
NO2 O SeAr
SeCN
H 3C O H 3C PhSeO2H, H 3C O H 3C
O O
PhH, 60 °C JOC 1995, 60, 7224
H3CHN N N H3CHN N N JCS P1 1985, 1865
Ph (82%) Ph
O O
Dehydration of Alcohols
- alcohols can be dehydrated with protic acid to give olefins via an E 1
mechanism.
- other reactions dehydrate alcohols under milder conditions by first converting
them into a better leaving group, i.e. POCl3/ pyridine, P2O5
Martin sulfurane; Ph2S[OCPh(CF3)2]2 JACS, 1972, 94, 4997 dehydration
occurs under very mild, neutral conditions, usually gives the most stable olefin
OH
MSDA, CH2Cl2
JACS 1989,
BzO BzO 111 , 278
H H
Burgess Reagent (inner salt) JOC, 1973, 38, 26 occurs vis a syn elimination
_ +
MeO2CNSO2NEt3
MeO2C
_ + - N SO2
H R3
MeO2CNSO2NEt3 R1 R4
R4 H O
R1 PhH, reflux
R2 OH R1 R4 R2 R3
R2 R3
Olefins from Vicinal Diols

Corey-Winter Reaction JACS 1963, 85, 2677; TL 1982, 1979; TL 1978, 737
S
OH
Im2C=S O O R3P:
R'
R
R R'
OH R R'
- vic-diols can be converted to olefins with K2WCl6 JCSCC 1972, 370; JACS
1972, 94, 6538
- This reaction worked best with more highly substituted diols and give
predominantly syn elimination.
- Low valent titanium; McMurry carbonyl coupling is believed to go through
the vic-diol. vic-diols are smoothly converted to the corresponding olefins under
these conditions. JOC 1976, 41 , 896
Olefins from Epoxides

O Ph2P - HO H R2 MeI HO H R2
R1 H
R1 H PPh2 R1 H PPh2Me
H R2 +
+
PPh2Me R1 R2
HO -Ph2MeP=O
"inversion "
R2 H of R groups
H H
R1 H
NCSe Se -
-
O NC-Se - O H R2
-
OR H NCOR H
R1 H 2 2
R1 H SeCN
H R2 H R1 H
R1
NCO H R2 H R2 R1 H
R1 H "retention"
R1 H Se -
Se of R groups
H R2
From Acetylenes
- Hydrogenation with Lindlar's catalyst gives cis-olefins
Co2(CO)8 H2, Rh
R R' R R'
R R'
Co2(CO)6
Bu3SnH
H SnBu3
R R'
From Other Olefins

Sigmatropic Rearrangements
- transposition of double bonds
Birch Reduction Tetrahedron 1989, 45, 1579

OMe OMe O
H3O+
Olefin Isomerization- a variety of transition metal (RhCl3•H2O) catalyst will

isomerize doubles bonds to more thermodynamically favorable configurations
(i.e. more substituted, trans, conjugated)
RhCl3•3H2O
JOC 1987,
EtOH 52 , 2875
OH OH
Cl Cl
Ti
+ JACS 1992
114 , 2276
up to 80% ee
Olefin Inversion Tetrahedron 1980, 557

- Conversion of cis to trans olefins
- Conversion of trans to cis- olefins
R R' hν, PhSSPh R
R'
OH
OH
I2, CH2Cl2
CO2Me HO
CO2Me
C5H11 OH
C5H11 OH
OH JACS, 1984, 107, xxxx
Transition Metal Catralyzed Cross-Coupling Reactions

Coupling of Vinyl Phosphonates and Triflates to Organometallic Reagents
- vinyl phosphates review: Synthesis 1992, 333.
O OP(OEt)2
Li, NH3,
R2CuLi tBuOH
R R
O O
O
(EtO)2PCl R2CuLi
O OP(OEt)2 R
- preparation of enol triflates Synthesis 1997, 735

O
OTf
LDA, THF, -78°C
kinetic
product
Tf2NPh
O Tf2O, CH2Cl2 OTf

thermodynamic
product
tBu N tBu
- reaction with cuprates. Acc. Chem. Res. 1988, 25, 47

OTf Ph
Ph2 CuLi TL 1980,
21 , 4313
tBu tBu
- palladium (0) catlyzed cross-coupling of vinyl or aryl halides or triflates with

organostannanes (Stille Reaction)
Angew. Chem. Int. Ed. Engl. 1986, 25, 508.; Organic Reactions 1997, 50, 1-652
O SnMe3
O
1)LDA, Tf2NPh
JOC 1986,
O 2) Pd(PPh3)4
O 51 , 3405
OH
OTBS Bu3Sn
I Bu Sn I
3 O OH
O O J. Am. Chem. Soc.
OH
1998, 120, 3935
HO
TBSO
HO Bu3Sn
TBSO I
(-)-Macrolactin A
BOMe
TESO 1) O3, Me 2S
TBSO OH 1) HF, MeCN
CHO 1) 2) allyl bromide, Zn 2) Me4NBH(OAc)3
2
MgBr 3) Dess-Martin 3) TBSCl, imidazole

Periodinane (76%)
2) TESOTf, 2,6-lutidine (70%)
(52%)
a) nBu3SnH,
TESO TESO O3, NaBH4 TESO OTES (Ph3P)2PdCl2 TESO OTES
(77%) OH b) I2 I OH
(83%
OH I
OPiv 1) Dess-Martin
Periodinane
OPiv 2) Ph3P+CH2I, I- OH
Bu3Sn NaHMDS
TBSO TBSO
3) DIBAL
PdCl2(MeCN)2 TBSO (50%) TBSO
I
TESO TESO TESO
Bu3SnCHBr2, CrCl2 CO2H
CHO SnBu3
(42%) PdCl2(MeCN)2
(65%) CO2H
Bu3SnH, AIBN TESO I
(38%) Bu3Sn
CO2H
TESO
OH
Ph3P, DEAD
Bu3Sn +
TESO
CO2H (50%)
TESO
TESO OH
Bu3Sn
I 1) Pd2(dba)3
O O iPr2NEt O O
2) TBAF
(35%) HO
TESO
HO
TESO (-)-Macrolactin A
palladium (0) catalyzed carbonylations- coupling of a vinyl triflate with a

organostanane to give α,b-unsaturated ketones.
O
OTf
Me3SnPh Ph JACS 1994,
106 , 7500
But Pd(0), CO tBu
Nickel (II) Catalyzed Cross-Coupling with Grignard Reagents (Kumada

Reaction): Pure Appl. Chem. 1980, 52, 669 Bull Chem. Soc. Jpn. 1976, 49, 1958
R-MgBr
(dppp)NiCl2
X R R= alkyl, vinyl or aryl
Aryl or vinyl halide or triflate
AcO
Br OMe Br HO
Ni Ni OMe
1)
Br
Tetrahedron Lett.
(2 equiv), 65 °C 1998, 39, 2537, 2947,
N OAc
H N OH
2) LiAlH4 , Et2 O H
(72%)
(±)-Neocarazostatin B
Olefin Metathesis Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
olefin
metathesis R2
R1 + R2 R1
catalyst
catalyst
Ring-Opening Metathesis
(CH 2)n Polymerization (ROMP)
(CH 2)n
n
catalyst Ring-Closing Metathesis

(CH 2)n
(RCM)
(CH 2)n
Metathesis Catalysts:
(C6H11)3P Ph (C6H11)3P
iPr iPr Cl Ph
Cl
H3C N Ru Ph Ru
F3C O Mo Cl Cl
F3C O Ph (C6H11)3P (C6H11)3P
F3C
F3C CH3
Schrock' s Catalyst Grubbs' Catalyst
Mechanism:
R2
R1 + [M] R1 [M]
R1
[M] R2 [M]
R1 +
R2
C≡C BOND FORMATION 115
C≡C Bond Formation
1. From other acetylenes

2. From carbonyls
3. From olefins
4. From Strained Rings
5. Eschenmosher Fragmentation
6. Allenes
From Other Acetylenes

- The proton of terminal acetylenes is acidic (pKa= 25), thus they can be
deprotonated to give acetylide anions which can undergo substitution reactions
with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes.
R R1
R1-X
O
OH
R _ R2 R3
R H R
R
M+ R2 3
Et2AlCl
OH
R
- Since the acetylenic proton is acidic, it often needs to be protected as a

trialkylsilyl derivative. It is conveniently deprotected with fluoride ion.
B:, R3SiCl F-
R H R SiR3 R H
Acetylide anions and organoboranes
_ R3B _ I2 JOC 1974, 39 , 731

R1 Li+ R1 BR3 Li+ R1 R JACS, 1973, 95 , 3080
Palladium Coupling Reactions:

O O
O O
JACS 1990,
Cl Cl
iPr3Si SnBu3 112, 1607
(Ph3P)4Pd
iPr3Si SiiPr3
OTBS
OTBS CO2Me
CO2Me Br C5H11
OTBS
OTBS OTBS
Pd(Ph3P)4, CuI
iPr2NH, PhH
TBSO C5H11 JACS 1985,

107, 7515
OH
HO
CO2H
OH
Copper Coupling- 1,3-diynes

Cu(OAc)2 Adv. Org. Chem.
R1 + R2 R1 R1 1963,4 , 63
Nicholas Reaction
- acetylenes as their Co2(CO)8 complex can stabilize an α-positive charge,
which can subsequently be trapped with nucleophiles.
OR4 (CO)6Co2 OR4 (CO)6Co2
Co2(CO)8 +
R1 R1 R1
R2 R2 R
R3 R3 R3 2
oxidative Nu
Nu: (CO)6Co2 Nu decomplexation
R1 R1
R2 R2
R3 R3
CO2Me CO2Me CO2Me

N Tf2O, CH2Cl2, N N
MeNO2, -10°C I2
JCSCC 1991, 544
TBSO O O
(OC)6Co2
tBu N tBu
HO
Co2(CO)6
Co2(CO)6-acetylene deocomplexation: JOC 1997, 62, 9380
From Aldehydes and Ketones
R R'
R'-X
P3P, CBr4 Br 2 eq. nBuLi ClCO2Et
R R _ Li+
RCHO R CO2Et
Br H2O
R H
Br2C a) nBuLi,
OSitBuPh2 THF, -78°C MeO2C
OHC OSitBuPh2 CBr4, Ph3P OSitBuPh2
b) ClCO2Me
OSitBuPh2
OHC OSitBuPh2 OSitBuPh2
Br2C MeO2C
JACS 1992, 114 , 7360
- by conversion of ketones to gem-dihalides followed by elimination

O Cl
PCl5 Cl Cl tBuOK
R' tBuOK
R' R' R R'
R R - HCl R - HCl
- by conversion of ketones to enol phosphates followed by elimination

P(O)(OEt)2 LiNH , NH JOC 1987,
O LDA, (EtO)2P(O)Cl O 2 3
52 , 4885
R R'
R' R'
R R
- Insertion reaction of a vinyl carbene (terminal acetylenes)

N2
O +
••
N2CHP(O)(OMe)2 C -N2 C
R R' JOC 1982,
R R' 47 , 1837
tBuOK R R' R R'
O
Me3Si N2
_
THF, Synlett 1994, 107
-78°C → RT
Via Elimination Reactions of Vinyl Halides

- Treatment of vinyl halides with strong base gives acetylenes.
X
R' Base
R R R'
H - HX
X= Cl, Br, I, OTf, O3SR, OP(O)R2 Base= LDA; tBuOK; NaNH2, DBU
- Addition of Grignard reagents to 1,1-difluoroethylene yields an acetylide anion

which can be subsequently trapped with electrophiles.
H2C=CF2 E+
_ TL 1982, 23 , 4325
R-MgX R R E JOC 1976, 41 , 1487
Strained Rings Topics in Current Chemistry 1983, 109, 189.

- Cyclopropenones and cyclobutendiones can be photolyzed or thermolyzed
(FVP) to give acetylenes.
O O
hν (209 nm) C
- CO - CO JACS 1973,
O 95 , 6134
8 °K
O C
O Benzyne
1) 370 °C
2) 12°K ACIEE 1988,27 , 398
O
- CO JACS 1991, 113 , 6943
R1
R2
FVP
R1 R2 +
(retro- D-A)
CL 1982, 1241
Eschenmoser Fragmentation
Ph
O N Ph R
N Base
R R -or- HCA 1972,
heat O 55 , 1276
O
R' R' R'
HN NH2
iPr iPr
O O
O tBuOOH,
triton B, C6H6
O iPr JOC 1992, 57, 7052
AcOH, CH2Cl2
Allenes Tetrahedron 1984, 40, 2805

- from dihalocyclopropanes
R Br R R R'
_ H
••
Br Br R H
R' R' R'
- From SN2' Reactions

Nu: X Nu H
R
R' R R'
- from sigmatropic rearrangements from propargyl sulfoxides and phosphine

oxides.
Ph
Ph O
OH Ph2PCl, Et3N :P R' TL 1990, 31 , 2907
O Ph2P JACS 1990, 112 , 7825
R
R' R R H
R'
FUNCTIONAL GROUP INTERCONVERSIONS 119
Functional Group Interconversions
C&S Chapter 3 #1; 2; 4a,b, e; 5a, b, d; 6a,b,c,d; 8
1 sulfonates
2 halides
3 nitriles
4 azides
5 amines
6 esters and lactones
7 amides and lactams
Sulfonate Esters
- reaction of an alcohols (1° or 2°) with a sulfonyl chloride
R'SO2Cl O R'= CH3 mesylate
R OH R O S R'
O CF3 triflate
sulfonate ester
CH3 tosylate
- sulfonate esters are very good leaving groups. Elimination is often a

competing side reaction
Halides
- halides are good leaving groups with the order of reactivity in SN2 reactions
being I>Br>Cl. Halides are less reactive than sulfonate esters, however
elimination as a competing side reaction is also reduced.
- sulfonate esters can be converted to halides with the sodium halide in acetone
at reflux. Chlorides are also converted to either bromides or iodides in the same
fashion (Finkelstein Reaction).
O
X-
R O S R' R X X= Cl, Br, I
O
NaI, acetone
reflux
R Cl R I
- conversion of hydroxyl groups to halides: Organic Reactions 1983, 29, 1

R OH R X
- R-OH to R-Cl
- SOCl2
- Ph3P, CCl4
- Ph3P, Cl2
- Ph3P, Cl3CCOCCl3
- R-OH to R-Br
- PBr3, pyridine
- Ph3P, CBr4
- Ph3P, Br2
- R-OH to R-I
- Ph3P, DEAD, MeI
Nitriles
- displacement of halides or sulfonates with cyanide anion
KCN, 18-C-6
R X DMSO
R C N
- dehydration of amides
O
R C N
R NH2
- POCl3, pyridine
- TsCl, pyridine
- P2O5
- SOCl2
- Reaction of esters and lactones with dimethylaluminium amide

TL 1979, 4907
Me H 3C
Me2AlNH2 OH
O JOC 1987, 52, 1309
NC
Ar
O Ar
- Dehydration of oximes
OH
H2NOH•HCl N
P2O5
R CHO R C N
R H
- Oxidation of hydrazones
O
O
N C Tetrahedron Lett.
NMe2 (97%) 1998, 39, 2009
N
- Reduced to aldehydes with DIBAL.

DIBAL
RC≡N RCHO
Azides
- displacement of halides and sulfonates with azide anion
LDA, THF O
O NaN3 O
NBS
O O O
Br
SO2N(C6H11)2 SO2N(C6H11)2 SO2N(C6H11)2 N3
O O
TL 1986, 27, 831
O HO
NH2 NH2
SO2N(C6H11)2
- activation of the alcohol
+ + R N3 +
R OH +
N F N OR N O
Me Me Me
TsO -
+
EtO2C PPh3
Ph3P, NaN3
R OH + EtO2C N N CO2Et N N
_ CO2Et
DEAD
activated alcohol
+
R-OH R N3 +
R O PPh3 Ph3P=O
JOC 1993, 58, 5886
HO N3
O
(PhO)2P(O)-N3 P(OPh)2 SN2
O + -
DBU, PhCH3 + DBU-H + N3 (91 %) O
O
(99.6 % ee) Ar (97.5 % ee)
- Photolyzed to aldehydes
Amines
- Gabriel Synthesis
O O
R X H2NNH2
N - K+ N R R NH2
O O
- reduction of nitro groups
R NO2 R NH2
H2, Pd/C
Al(Hg), H2O
NaBH4
LiAlH 4
Zn, Sn or Fe and HCl
H2NNH2
sodium dithionite
- reduction of nitriles
R C N R CH2 NH2
H2, PtO 2/C
B2H6
NaBH4
LiAlH 4
AlH3
Li, NH3
- reduction of azides
R N3 R NH2
H2, Pd/C
B2H6
NaBH4
LiAlH 4
Zn, HCl
(RO)3P
Ph3P
thiols
- reduction of oximes (from aldehydes and ketones)

OH
N NH2
R R' R R'
H2, Pd/C
Raney nickel
NaBH4, TiCl4
LiAlH 4
Na(Hg), AcOH
- reduction of amides
O
R'
R' R N
R N
R'' R''
H2, Pd/C
B2H6
NaBH4, TiCl4
LiBH4
LiAlH 4
AlH3
- Curtius rearrangement
O O O
NaN3 •• ∆ ••
••
R Cl R N N N R N
••
••
+ - N2
nitrene
R N O H2O
R NH2
isocyanate
- reductive aminations of aldehydes and ketones

- Borsch Reaction
- Eschweiler-Clark Reaction
- alkylation of sulfonamides
Tf Tf Tf
N HN K2CO3, DMF N N NH HN
Tf 110°C Na, NH3 TL 1992, 33 , 5505
Tf
N HN Br N N NH HN
Tf Br Tf Tf
cyclam
- transaminiation
O N Ph N Ph NH2
PhCH2NH2 Can. J. Chem.
tBuOK H3O +
H+ 1970, 48, 570
Esters and Lactones

- Reaction of alcohols with "activated acids"
- Baeyer-Villigar Reaction Organic Reactions 1993, 43, 251
- Pd(0) catalyzed carboylation of enol triflates
OTf CO, DMF CO2R
Pd(0), ROH TL 1985, 26 , 1109
- Arndt-Eistert Reaction Angew. Chem. Int. Ed. Engl. 1975, 15, 32.
O O O
CH2 N2 hν
N2 ••
R Cl Et2 O R ROH R CH
diazo ketone
Wolff R O
Rearrangement C O R'OH
R
H OR'
ketene
O TsN3, Et3N O
CO2Me N2
R R
- Diazoalkanes: carbene precursors

1) NH2NH2
2) Pb(OAc)4, DMF
R-CHO R-N2 JOC 1995, 60, 4725
R3N
H 2N
N TsN3 N2
R R R R
- Halo Lactonizations review: Tetrahedron 1990, 46 , 3321

I
+ I
I2-KI
CO2H O O
H2O, NaHCO3
H
O O
Pd(OAc)2
(5 mol %)
CO2H O JOC 1993, 58, 5298
DMSO, air O
(86%)
- Selenolactonization
PhSe
O PhSeCl, CH2Cl2 O H 2O 2 O
O JACS 1985,
O
107 , 1148
OH
- Mitsunobu Reaction Synthesis 1981 , 1; Organic Reactions, 1991, 42, 335

Mechanism: JACS 1988, 110 , 6487
O
OH DEAD, Ph3P O R'' Inversion of alcohol

stereochemistry
R R' R''CO2H R R'
Amides and Lactams

- reaction of an "activated acid" with amines
- Beckman Rearrangement Organic Reactions 1988, 35, 1
OH
O N PCl5 O
R R' R R' R NR'

- Schmidt rearrangement
O O
HN3
R R' H+ R NR'
- others
O NR2
OTf CO, DMF
Pd(0), R2NH
TL 1985, 26 , 1109
O OH
O
O
PhCH2NH2 N Ph TL 1977, 4171
AlMe3 H
OTHP OTHP
-Weinreb amide Tetrahedron Lett. 1981, 22, 3815

DIBAL O
O O
H3CNH(OCH3) •HCl R H
OCH3
R OR' R N
AlMe3 O
CH3
R1-M R R1
THREE-MEMBERED RING FORMATION 125
3 Membered Rings
1. epoxides
a. peracids, hydroperoxides and dioxiranes
b. transition metal catalyzed epoxidations
c. halohydrins
d. Darzen's condensation
e. sulfur ylides
2. cyclopropanes
a. Simmons-Smith reactions
b. diazo compounds
c. sulfur ylides
d. S N2 displacements
3. aziridines
a. nitrenes
b. SN2 displacements
Epoxides
- peracid, hydroperoxide and dioxirane oxidation of alkenes
- transition metal catalyzed epoxidation of alkenes

- Sharpless epoxidation
- Metal oxo reagents (Jacobsen's reagent)
- from halohydrins
Br
NBS, H2O base
OH O
bromohydrin
- Darzen's Condensation
O O-
R
B: _ R R' O
R' CO2Et R CO2Et
BrCH2CO2Et BrCHCO2Et
R'
Br
- sulfur ylides Chem. Rev. 1997,97, 2421.
O O
+ +
Me S + Ph S CH2- _ SPh2
Me2SCH2-
Me CH2- NMe2
Trost
Corey Johnson
sulfoximine
- dimethylsulfoxonium methylide and dimethylsulfonium methylide

(Corey's reagent) review: Tetrahedron 1987, 43 , 2609.
O
O -
DMSO, NaH O SMe2 O
R R' R R' R R'
- cyclopropyldiphenylsulfonium ylide (Trost's reagent) ACR 1974, 7, 85.
+ O
O _ SPh2 -
O SPh2 O BF3
R'
R R' R R' R R'
R
- sulfoximine ylides (Johnson's reagent) ACR 1973, 6 , 341

O
O Ph S CH2-
O
NMe2
R R' R R'
Cyclopropanes
- Simmons-Smith Reaction Org. Reactions 1973, 20, 1.
ZnCu + CH2I2 ICH2ZnI
- polar groups (-OH, -NR2- CO2R) can direct the cyclopropanation

OH OH
ZnCu, CH2I2 JACS 1979, 101 , 2139
- sulfur ylides
O O
O
Me2S CH2- Tetrahedron
1987, 43 , 2609
O _
Ph S
Ph Ph Ph ACR 1973,
NMe2 Ph 6 , 341
O
O
- diazo alkanes and diazo carbonyls Synthesis 1972, 351; 1985, 569
- cyclopropanation with diazoalkanes; olefin requires at least on electron
withdrawing group.
CO2Me N N CO2Me
CO2Me
MeO2C MeO2C JACS 1975,
CH2N2 MeO2C hν
97 , 6075
(MeO)2HC (MeO)2HC (MeO)2HC
- diazoketones; photochemical or metal catalyzed decomposition of

diazoketones to carbenes followed by cyclopropanation of olefins.
Org. Rxns. 1979, 26, 361; Tetrahedron 1981, 37, 2407
N2 CuSO4 , ∆ JACS 1970, 92 , 3429

JACS 1969, 91 , 4318
O O
O Rh2(OAc)2 O
Ph O Ph O JACS 1993, 115, 9468
O O
Ph 91 % yield
N2 O O
Ph 89 % de
Asymmetric cyclopropanation: Doyle, Chem Rev. 1998, 98, 911

Aldrichimica Acta 1997, 30, 107
O
O
CO2Et
CO2Et TsN3 , Et3N
N2
C5H11 C5H11
O
O - SPh
CO2Et JACS 1977,
CO2Et 99, 1940
C5H11
C5H11
SPh
- SN2 Reactions
O DBU O
JACS 1978,
O O O O 99 , 1940
Br CO2Et CO2Et
- Electrophillic Cyclopropanes review: ACR 1979, 12 , 66

in many ways, cyclopropanes react silmilarly to double bonds
- homo-1,4-addition
CO2R Nu CO2R
ACR 1979,12 , 66
Nu: CO2R CO2R
Nu:= malonate anion, amines, thiolate anion, enamines, cuprates

(usually requires double activation of cyclopropane)
Me
H
MeO2C Me2CuLi MeO2C
O O TL 1976, 3875
- hydrogenation
O
CO2Me CO2Me ArCO3H, CO2Me
CH2I2, Zn-Cu Na2HPO4
H H H
O
H2, PtO2, CO2Me
TL 1982, 23 , 1871
AcOH
- hydrolysis
OH OH OH
CH2I2, Zn-Cu +
H , MeOH JACS 1967
89 , 2507
OMe MeO O
Aziridines
Ts
R2 Cu(acac)2
N
J. Org. Chem. .1991, 56, 6744
R1 R3 PhN=ITs R2
R1 R3
FOUR-MEMBERED RING FORMATION 129
4 Membered Rings
1. cyclobutanes & cyclobutenes

2. oxatanes
Cyclobutanes
- [2+2] cycloadditions
- photochemical cycloadditions (2πs +2πs)
Acc. Chem. Res. 1968, 1, 50; Synthesis 1970, 287; Acc. Chem. Res. 1971, 4, 41;
Organic Photochemistry 1981, 5, 123; Angew. Chem. Int. Ed. Engl. 1982, 21, 820;
Acc. Chem. Res. 1982, 15, 135; Organic Photochemistry 1989, 10, 1
Organic Reactions 1993, 44, 297
- for synthetic purposes, cyclic α,β-unsaturated carbonyl are the most
useful.
intersystem
crossing 3
E 1
E* E*
- symmetry requirements
*
hν
2πs + 2πs O O
~ 340 nm
HOMO
LUMO
- enones with olefins
O O O O O
CH2 hν JCSCC
+ + + 1966, 423
CH2
(90%) O
O O O
H
hν E.J. Corey
+ JACS 1963,
+
85 , 362
H
Caryophellene
Base
Hot Ground State?
O O O
H
hν H2C=CH2
isomerization
cis
2πs + 2πa ring-fusion
thermal cyclization H
CH3 H2C=CH2 CH3

hν, CH2Cl2
JACS 1986,
N N 108 , 306
CH3 O
CH3 HO
H H CH3
O Ph CH3 O grandisol
O O
O H H
+ JACS 1984
106 , 4038
hν
H H
2:1
- enones with acetylenes

O
O hν O O O
JACS 1982
104, 5070
- DeMayo Reaction
CO2Me
O O H
O pTSA, MeOH
hν, pyrex O reflux JACS 1986,
O O 108 , 6425
O
H
O
R
O R hν O
R
O O
H MeO2C
O O 70-80 % de
favored O O
H H H H
O
O controls O O
hν H 3C
conformation O H 3C
O O O
O H H
H 3C CH3 CH3
O CH3
CH3 O
H H
controls disfavored
addition O TL 1993, 34, 1425
H 3C
O
H
H 3C
- Photochemistry of Ketones (Norrish Type I and II reactions)

H H
O O• Norrish I O
cleavage
• •
hν •
254, 307 nm
Norrish II
cleavage
•
HO OH OH
Yang
reaction •
+
- filtering photchemical reaction to prevent Norrish reactions

quartz 180 nm
Vycor 200 nm
Pyrex 280 nm
Uranium glass 320 nm
- Yang Reaction
MOMO MOMO
O
hν (254 nm) OH JACS 1987,
C6H6 109 , 3017
CH3 SEMO CH3
SEMO
- thermal cycloadditons (2πa + 2πs)

- symmetry requirements
2πa + 2πs O HOMO
LUMO
- ketenes
O
∆ H
O O
H
O
Et3N
Cl O
H
O
Zn
Cl O
Cl
O
hν R
N2 O
R H
- thermal cyclization of ketene with olefins

Tetrahedron 1986, 42, 2587; 1981, 37, 2949; Organic Reactions 1994, 45, 159.
LUMO
of ketene
2πa
py O
pz
HOMO
of olefin
2πs
Cl O
O
O
Ph CH3 Cl
CCl3 Cl CH2N2 Cl
CH3
O CH3 Cl
O Zn-Cu, Et2O CH3
CH3 R*O Ar
Ph
JACS 1987,
109 , 4753
O H
H 3C 1) H 3C
N+ JACS 1982, 104, 2920
N+ H 3C
H 3C 2) H2O
H
OMe OMe
-reaction of ketene with enamines

H
NR2 O O
H
NR2
O O
NR2
R'
R'
- reaction of ketene with imines to give β-lactams (Staudinger Reaction)

H
R O
N
H
NR
O
O O
O CH2Cl2 O R
O
R H -78°C → 0°C H
N O N R
O + N
N N Ph
Ph O Bn Ph NBn
H Bn O
(90-96 % de)
- reaction of difluorodihaloethylene with olefins
Organic Reactions 1962, 12, 1
F X
F2C=CX2
R F X
X= F, Cl
R
- reaction of difluorodihaloethylene with acetylenes- biradical mechanism

F X O O
F2C=CX2 hydrolysis
R F X
X= F, Cl
R R
- SN2 Reaction
O
O
KH, DMSO JACS 1980,
102 , 1404
OTs
CN CN
O _ JACS 1974, 96,
HO OH
OR OR 5268, 5272
Grandisol
- acyloin reaction Organic Reactions 1976, 23, 259

OTMS O
CO2Me Na, TMS-Cl
(CH2)n (CH2)n F-
(CH2)n
CO2Me
OTMS OH
R CO2Me R O
R CO2Me R OH
- benzocyclobutanes ACIEE 1984, 23, 539; Synthesis 1978, 793

O O O O
benzocyclobutane o-quinodimethane O
- cyclotrimerization of 1,5-diyenes with an acetylenes

SiMe3 SiMe3 Me3Si
CpCo(CO)2 Me3Si
- sulfur ylides
+ O
O _ SPh2
O BF3
R R'
R'
R R' R
Oxatanes Organic Photochemistry 1981, 5, 1

- [2+2] cycloaddition (Paterno-Buchi Reaction)
O O
hν R
R R'
R'
O O
hν (254 nm) R
R R'
R'
O hν O
O TL 1975
Me2C CMe2 O 1001
O O
- SN2 reaction
OH NBS O
SiMe3 JCSCC 1979, 421
SiMe3
Br
OH
CO2Me Tf2O, CH2Cl2 CO2Me TL 1980,21 , 445

O
HO C5H11 C5H11
OTBS OH
OH
Br Br
CO2Me (MeO)3P, DEAD CO2Me JACS 1984,
O
HO C5H11 C5H11 107 , 6372
O O
OH OH
- sulfur ylides
O -
O
O O
H2C_ S Me NTs JACS 1979,
S 101 , 6135
NTs CH3
O
β-Lactones
O O- O O
R1 LDA, THF O JOC 1991,
R2 SPh R4 SPh
O 56 , 1176
R3 R1 R4
H R2 R1
R3 R4 R2 R3
OH DEAD, Ph3P
O R2CuLi CO2H
O O R JACS 1987,
BnO N CO2H BnO NH 109 , 4649
H BnO N O
H
O
O 1) MgBr2•OEt2 OBn
OBn O 2) KF, H2O, CH3CN O
O
+ TL 1995, 36, 4159
H
H SiMe3 96 % de
BALDWIN'S RULES FOR RING CLOSURE 135
Baldwin's Rules (Suggestions) for Ring Closure
JOC 1977, 42 , 3846
JCSCC 1976, 734, 736, 738
Approach Vector Analysis

- for an SN2 displacement at a tetrahedral center, the approach vector of the
entering nucleophile is 180° from the departing leaving group
Nu: Nu L Nu :L
L
- for the addition of a nucleophile to an Sp2 center, the nucleophile approaches

perpendicular to the π-system.
Nu
Nu
Nomenclature
1. indicate ring size being formed
3 membered ring = 3
4 membered ring = 4
etc.
2. indicate geometry of electrophilic atom

if Y= Sp3 center; then Tet (tetrahedral)
if Y= Sp2 center; then Trig (trigonal)
if Y= Sp center; then Dig (digonal)
Z
Y
X:
3. indicate where displaced electrons end up

- if the displaced electron pair ends up out side the ring being formed;
then Exo
- if the displaced electron pair ends up within the ring being formed;
then Endo
Z Z
Y Y
X: X:
Exo Endo
4. Ring forming reaction is designated as Favored or Disfavored
disfavored does not imply the reaction can't or won't occur- it only means
the reaction is more difficult than favored reactions.
Rules (Suggestions) for Ring Closure
- All Exo-Tet reactions are favored
X: X: X: X:
Y Z X: Y Z Y Y Y
Z Z Z
3- 4- 5- 6- 7-
- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -
- 5-Endo-Tet and 6-Endo-Tet are disfavored
Z Z
Y
Y
X:
X:
5- 6-
- - - - -Disfavored- - - - -
- All Exo-Trig reactions are favored
X: X: X:
X: Y Z X: Y Z Y Y Y
Z Z Z
3- 4- 5- 6- 7-
- - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - -
- 3-Endo-Trig, 4-Endo-Trig and 5-Endo-Trig are disfavored; 6-Endo-Trig, 7-

Endo-Trig, etc. are favored
Z Z
Z Z Y
X: Y Y X: Z
X: Y X:
X: Y
3- 4- 5- 6- 7-
- - - - - - - - - - - - -Disfavored- - - - - - - - - - - - - - - - - -Favored- - - - - -
- 3-Exo-Dig and 4-Exo-Dig are disfavored; 5-Exo-Dig, 6-Exo-Dig, 7-Exo-Dig, etc.
are favored
X: X: X: Y X: X:
Y Y Y
Z Y
Z Z Z Z
3- 4- 5- 6- 7-
- - - - - -Disfavored- - - - - - - - - - - - - - - - - - -Favored- - - - - - - - - - - -
- All Endo-Dig are favored
Z Z
Y
Z Z Y X: Z
X: Y
Y X: Y
X: X:
3- 4- 5- 6- 7-
- - - - - - - - - - - - - - - - - - - - - - - - - - --Favored- - - - - - - - - - - - - - - - - - - - - - - - - - - - -
EXCEPTION:
There are many !!! (see March p 212-214)
FIVE-MEMBERED RING FORMATION 138
5 Membered Rings
HO O
CO2H CO2H
HO OH HO OH
PGF2α PGE2
Me H Me
Me
Me
Me
Me Me
Me
Hirsutene Modhephane Isocumene
1. Intramolecular SN2 Reactions

2. Intramolecular Aldol Condensation and Michael Addition
3. Intramolecular Wittig Olefination
4. Ring Expansion and Contraction Reactions
a. 3 → 5
b. 4 → 5
c. 6 → 5
5. 1,3-Dipolar additions
6. Nazarov Cyclization
7. Arene-Olefin Photocyclization
8. Radical Cyclizations
9. Others
Synthesis 1973, 397; ACIEE 1982, 21 , 480;
Intramolecular SN2 Reaction 5-exo-tet: favored

O
LDA JCSCC 1973, 233

O
Br
O
O O
CO2Me
CO2Me
Br
CN CN OH
JACS 1974, 96 , 5268
O
O Cl
O JACS 1979,
101 , 5081
RO2C RO2C CO2R
CO2R Cl
O O
NaH, DMSO
JCSCC 1979, 817
TsO
Intramolecular Aldol Condensation 5-exo-trig: favored

intramolecular aldol condensation of 1,4-diketones
O O
R
R
O
R'
R'
O O
CH3
CH3 TL 1982,
O 29, 2237
CH3
CH3
Br Br
O
NaOMe, MeOH
O JACS 1980,
102 , 4262
O CO2Me
CO2Me
O O
NaOH JOC 1983,
O O 48 , 1217
O
Intramolecular Michael Addition 5-exo-tet: favored

Organic Reactions 1995, 47, 315-552
O
O JACS 1979,
101 , 7107
MeO2C O O
Intramolecular Wittig Olefination Tetrahedron 1980, 36, 1717
O O
O 1) (MeO) 2P(O)CH2 - P(OMe)2
O
2) Collins O
C5H11
THPO
OTHP C5H11
THPO
OTHP JOC 1981, 46 , 1954
O CO2H
base
C5H11
THPO
OTHP C5H11
HO
OH
Ring Expansion Reactions

- 3 → 5: Vinyl Cyclopropane Rearrangement Organic Reactions 1985, 33, 247.
O _
SPh2 OTMS
O
O O
H O
H H
O O O
TMSO
JACS 1979, 101 , 1328

O
H
O
- 4 → 5: Reaction of cyclobutanones with Diazomethane

Cl Me Me
Cl
CH2N2
Me
O
O
O TL 1980,
Me Me Me 21 , 3059
Cl
CH2N2 O
Cl
Cl
Cl
Cl O O
Cl
Cl
CH3 CH2N2 Cl
O CH3 CH3
O CH3
Ph JACS 1987,109 , 4752

Ph
Ring Contraction Reactions
- 6 → 5: Favorskii Reaction Organic Reactions 1960, 11 , 261
O _
O OH -
O OH
CO2H
Cl _
1,3-Dipolar Addition to Olefins 1,3-Dipolar Cycloaddition Chemistry , vol 1 & 2 (A.

Padwa ed.) (Wiley, NY 1984); ACIEE 1977, 16 , 10. Chem Rev. 1998, 98, 863.
1,3-Dipole (4π)
+ LUMO
_
b
a c
4πs + 2πs Alkene (2π)

HOMO
- trimethylenemethane (TMM) ACIEE 1986, 25 , 1. Synlett 1992, 107.

high
temperature •
•
TMM
CO2Me
MeO2C MeO2C CO2Me
H CH3
∆, MeCN • •
N •
-N2
N
• H
JACS 1981,
103 , 2744
note: TMM usually reacts poorly w/ electron defficient olefins

_
Pd(0)
Me3Si OAc +
PdLn
O O
Me3Si OAc H
O O
TL 1986, 27 , 4137
Pd(0), 80°C
MeO2C CO2Me
Ni(COD)2, 35 °C ACIEE 1985, 24 , 316

TL 1983, 24 , 5847
CO2Me CO2Me
- α,α'-dihaloketones
O
O OFeLn
Fe(CO)9 Ar ACR 1979, 12 , 61
+
Br Br Ar
- nitrones ACR 1979, 12 , 396; Organic Reactions, 1988, 36 , 1
O- O
+N R2 R1 N
R1
R2 R3
R3
Nitrone
JACS 1964,
O 86 , 3756
- O N
N
Me O OH
N Me2N
O MeNHOH, Me 1) MeI Me
2) H2, Pd/C JOC 1984,
EtONa 49 , 5021
H H H H H
MeO2C MeO2C Bn
NH Bn NH
N N
O- O JACS 1983,
S S 104 , 6460
C 4H 9
C 4H 9
- nitrile oxides
O O + O
-
N N O O OH
N H2
ArNCO JACS 1992,
104 , 4023
CO2Et CO2Et CO2Et CO2Et
O O OH O O 1) DHP, PPTS OTHP 1) Swern

Bu 2BOTf, iPr 2EtN, CH2 Cl2, ↑↓ 2) NH2OH•HCl
N O CH2 Cl2, -78°C 2) LAH AcONa, MeOH
N O
O CH3 (60%) (89%)
OH
H
Ph Ph
(99%)
OTHP OTHP
OTHP
NaOCl, H2 O, + _ H2, Raney Ni, H2 O,
CH2 Cl2 N O MeOH, B(OMe)3
THPO
N (88%) O
N (88%)
OH O OH
OTHP O O
1) PPTS, EtOH, ↑↓
1) TBS-Cl, DMF, HF•pyridine,
2) (CH3 )2C(OMe)2 ,
imidazole CH3 CN, pyridine
OH PPTS Cassiol
2) nBuLi, THF
TL 1996, 37, 9292
3) Swern (73%)
Bu3Sn
O (48%)
TBSO O TBSO O OH
O HO
(80%)
O O OH
OTBS OTBS OTBS
LAH
TL 1993, 34, 3017
N + O N NH2
O _ OH
Arene -Olefin Photocyclization Organic Photochemistry 1989, 10 , 357

- the photochemistry of benzene is dominated by the singlet state
1 *
hν
hν * OAc
OAc
*
JACS 1982,
Me2CuLi O
O 104 , 5805
JCSCC, 1986 247
Me
1) FVP
* 2) H2, Pd/C
*
hν
isocume
+ +
*
Tetrahedron
1981,37 , 4445
*
hν * *
OMe
OMe
JACS 1981,
103 , 688
OMe
cedrane
* HO
AcO hν AcO * H+
H
TL 1982, 23 , 3983
TL 1983, 24 , 5325
Intramolecular Photochemical [2+2]
"Rule of Five"
O O
hν
O O
O O JOC 1975, 40 , 2702
JOC 1979, 44 , 1380
hν
O
O
Nazarov Cyclization review: Synthesis 1983, 429 Organic Reaction 1994, 45, 1
- cyclization of allyl vinyl or divinyl ketones
O O
H3PO4/HCO2H
O
O
H3PO4/HCO2H
- 1,4-hydroxy-acetylenes
H2SO4, MeOH JOC 1989,

HO
OH H H 54 , 3449
O
OH OH
- Silicon-Directed Nazarov
O O
Tetreahedron
FeCl3 1986, 42 , 2821
SiMe3
Me Me
- Tin -directed Nazarov TL 1986, 27 , 5947
Radical Cyclization
B. Giese Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds
(Pergamon Press; NY) 1986; Bull. Soc. Chim. Fr. 1990, 127 , 675; Tetrahedron 1981, 37 ,
3073; Tetrahedron 1987, 43, 3541; Advances in Free Radical Chemistry 1990, 1, 121.
Organic Reactions 1996, 48, 301-856.
Radical Addition to multiple bonds:

1. Free radical addition is a two stage process involving an addition step followed by an
atom transfer step.
2. In general, the preferred regioselectivity of the addition is in a manor to give the
most stable radical (thermodynamic control)
Advantages of free radical reactions:
1. non-polar, little or no solvent effect
2. highly reactive- good for hindered or strained sysntems
3. insensitive to acidic protons in the substrates (i.e. hydroxyl groups do not
necessarily need to be protected
Mechanism of radical chain reactions

1. initiation
2. propagation
3. termination (bad)
Formation of carbon centered radicals:

tin hydride reduction of
alkyl, vinyl and aryl halides,
alcohol derivatives:
xanthates, thionocarbonate, thiocarbonylimidazolides
organosselenium & boron compounds
carboxylic acid derivatives (Barton esters)
reduction of organomercurials
thermolysis of organolead compounds
thermolysis or photolysis of azoalkanes.
Radical Ring Closure

For irreversible ring closure reaction, the kinetic product will predominate.
Both the 5-exo-trig and 6-endo trip are favored reactions, with the 6 exo-trig mode
producing the most stable radical. However, the 5-exo-trig is about 50 time faster
• •
k1,5 • k1,6
kinetically thermodynamically
favored favored
•
• 3-exo-trig
• + vs
100 : 0 4-endo-trig
• •
• 4-exo-trig
+
vs
100 : 0 5-endo-trig
•
•
• 5-exo-trig
+ vs
98:2 6-endo-trig
•
• •
+ 6-exo-trig
vs
85:15 7-endo-trig
•
• •
7-exo-trig
+ vs
8-endo-trig
100 : 0
• •
and
radicals open up fast and are not synthetically useful;
often used as probes for radical reaction
Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization
•
•
•
+
48:1
•
•
•
+
>200:1
•
•
•
+
2:3
•
•
•
+
< 1:100
Stereochemistry of 5-hexenyl radical cyclization

1-, or 3-substitued 5-hexenyl radicals give cis disubstituted cyclopentanes
2-, or 4-substituted 5-hexenyl radicals give trans disubstitued cyclopentanes
2 Bu3SnH H
Br R R
•
+
R H R
65 : 35
prefered transition state
R
• R R R
Br H +
3
H 75 : 25
H
4
Br R +
•
R H
R 83 : 17 R
R
Bu3SnH R
Br • +
1 H
R 73 : 27 R
Br
nBuSnH, JACS 1983,
AIBN 105 , 3720
OH OH CN
CN
Bu3SnH,
AIBN JACS 1990,
112, 5601
CO2Me
Br CO2Me
Br OH
Si H Si
H2O2 H
O Bu3SnH O
OH
THPO THPO THPO
multiple cyclizations: D. Curran Advances in Free Radical Chemistry 1990, 1, 121.

OTBS
O OAc
1) NaBH4, CeCl3 1) LDA, THF
2) Ac2O, Et3N O 70 °C
2) TBSCl O
OTBS
PhSe
PhSeCl, CH2Cl2 O H2O2 O THPO CuSMe2 Li+
O O
THPO 1) PPTS, EtOH I 1) Me3Si Li

2) LAH
(1.0 equiv)
CO2H
3) (CF3SO2)2O I
pyridine 2) CsF
4) Bu4NI, PhH
Me
I • H
Bu3SnH, AIBN JACS 1985,
PhH, reflux 107 , 1148
H H
(±)-hirsutene
CH3MgBr, HO 1) I2 O
O O 2) DBU O
CuBr•SMe2 O
O O MgBr
CuBr•SMe2, THF
O 1) LAH
O 2) CH3SO2Cl CO2Me 1) CH3MgBr
HO
O 3) NaI (excess) Br
4) Li 2) Me3SiBr
5) CrO3, H2SO4, H2O
H H
Bu3SnH, AIBN •
PhH, reflux (±)-capnellene
Tetrahedron Lett.
1985, 41, 3943
H 3C H
O O Me O
nBuSnH, O
AIBN JACS 1986,
108, 1106
Me Me
Me
Br
OH
CHO H O JACS 1988,
O SmI2, THF 110 , 5064
O O
H
radical trapping
OEt
I
O OEt OEt
nBuSnH, O tBuNC O
AIBN JACS 1986,
108 , 6384
RO • CN
RO RO
can also be trapped with acrylate esters or acrylonitrile.
OEt OEt O OEt OEt

I Me3Si
nBuSnH, O C5H11 O 140° O
O
AIBN
SiMe3 Brook
rearrangement
• C5H11 C5H11
RO RO RO RO
O OTMS
OEt
Pd(OAc)2, 1) (S)-BINAL-H HO 1) Wittig HO
CH3 CN O 2) HCl, H2O, THF CHO 2) deprotect CO2H
C5H11
C5H11
RO HO
RO OH (+)-PGF2α
O
Paulson-Khand Reaction Tetrahedron 1985, 41 , 5855; Organic Reactions 1991, 40 , 1.

O O
R R' R'' R R
R'' Organometallics
+
Co2(CO)6 1982, 1 , 1560
R' R' R''
Co2(CO)8, NMO JOC 1992,

57 , 5277
O O O O
Cp2TiCl2, Ph
EtO2C CO2Et EtMgBr, CO CO2Et
O JOC 1992,
Ph 57 , 5803
CO2Et
Ring-Closing Metathesis Tetrahedron 1998, 54, 4413, Acc. Chem. Res. 1995, 25, 446.
P(C6H11)3
Cl Ph
O OH O O Ru
O Bu2BOTf, Cl
CH2Cl 2, -78°C N O P(C6H11)3
N O
CHO (97%)
(82 %)
Ph Ph
OH O O
LiBH4, OH
THF, MeOH J. Org. Chem. 1996, 61, 4192
N O
OH
(78%)
Ph
Diazoketones Tetrahedron 1981, 37 , 2407; Organic Reactions 1979, 26 , 361

O O
R1 N2 BF3 R1
TL 1975, 4225
R2 R2
FVP of Acetylenic Ketones

O O O
R1 R1
FVP R3 R1 R3 TL 1986,
27 , 19
R3
R2 H R2 H •• R2
6-MEMBERED RING FORMATION 150
Six Membered Rings
1. Diels-Alder Reaction
2. o-Quinodimethanes
3. Intramolecular ene reaction
4. Cation olefin cyclizations
5. Robinson annulation
Diels-Alder Reaction
ACIEE 1984, 23 , 876; ACIEE 1977, 16 , 10; Organic Reactions 1984, 32 , 1
W. Carruthers Cycloadditions Reactions in Organic Synthesis (Pergamon Press, Oxford) 1990
- reaction of a 1,3-diene with an olefin to give a cyclohexene.

- thermal symmetry allowed pericyclic reaction
- diene must reaction is an s-cis conformation
- highly stereocontrolled process- geometry of starting material is preserved in the
product
- possible control of 4 contiguous stereocenters in one step
B B A B A
X Y X Y
A Y X
+ +
A Y X
X Y X Y
B B A B A
- Alder Endo Rule: In order to maximize secondary orbital interactions, the endo TS is
favored in the D-A rxn. Tetrahedron 1983, 39, 2095
X Y B A
X Y X
B Y
A
Y
A
X
B B A
O
O exo O
minor
O O
H
H
O
H
endo H
O major
O O O O
O
Orientation Rules
X X X
Y Y
+ +
Y
major minor
X Y X X Y
+ +
Y
major minor
- when both the diene and dienophile are "unactivated" the D-A rxn is sluggish
- D-A rxns with electron rich dienes and electron defficient dienophiles work the best.
Some electron deficient dienophiles are quinones, maleic ahydride, nitroalkenes, α,β-
unsaturated ketones, esters and nitriles.
- D-A rxns with electron deficient dienes and electron rich dienophiles also work well.
These are refered to as reverse demand D-A rxns.
- D-A rxns are sensitive to steric effects of the dienephiles, particularly at the 1- and 2-
postions. Steric bulk at the 1-position may prevent approach of the dienophile while steric
bulk at the 2-position may prevent the diene from adopting the s-cis conformation.
- The D-A rxn is promoted by Lewis acids (TiCl4, BF3 AlCl3, AlEt2Cl, SnCl4,...)
- The D-A rxn is promoted by high pressure (1 kbar ~ 14200 psi) Synthesis 1985, 1.
O
OMe
OMe 5 Kbar Me
O JACS 1986,
+ 108 , 3040
Me
O
O
NHBOC NHBOC
NHBOC H H
20 kbars, 50°C Synthesis
+ H +
O O 1986, 928
Eu(fod)3
O
OMe OMe OMe
- The D-A rxn is usually insenstive to solvent effects, except for water. ACR 1991, 24 , 159
O
isooctane O
+
+ krel=1
O H
endo exo JACS 1980, 102 , 7816
4:1 TL 1983, 24 , 1901
TL 1984 , 25 , 1239
H2O 20 : 1
krel= 700
CO2- Na+ CO2H CO2H

JOC 1984, 49 , 5257
CHO OHC H H JOC 1985, 50 , 1309
+
OHC
H2O
(70%) (15%)
- The mechanism of the D-A rxn is believed to be a one-step, concerted, non-synchronous

process.
- concerted- bond making and bond breaking processes take place in a single kinetic step
(no dip in the transition state)
- synchronous- bond making and bond breaking take place at the same time and to the
same extent.
M.J.S. Dewar JACS
+ 1984, 104 , 203, 209.
- study of secondary D-isotope effects have indicated a highly symmetrical T.S.

D D
H H
k1 D D
+
H H
JACS 1972,
D D 94 , 1168
D D
k2 D D
+
D D
Diels Alder Reactions:
O O
H MeO2C CHO
PhH, reflux
O H MeO2C OAc
O CO2H
OMe
HO2C
MeO
N N Tetrahedron
H 1958, 2 , 1
H
MeO2C O2CAr
reserpine OMe
H H CH3 trans
CHO
H H
+ O
H
O CHO
NHCO2Bn trans BnO2CHN
BnO2CHN
NHCO2Bn
JACS 1978,
100 , 5179
N
H
pumiliotoxin C
MeO OMe
O
R
+ O
O R O
MeO2C MeO2C
CO2Me R O
MeO2C
PhS SPh
PhS
SPh
MeO OMe
O
O
JACS 1986,
O 108 , 5908
Compactin
OMe OMe
R R
R
ACR 1981,
+ 14 , 400
Me3SiO Me3Si-O O
Danishefsky's
Diene
OMe OH
O
CO2Me
MeO2C H
O
+ H
O
Me3SiO O
H O
Vernolepin
Hetero Diels-Alder Reactions

- Heterodienophiles
OMe
CO2Bn PhH, reflux CO2Bn
N N JACS 1982,
+ 102 , 1428
Me3SiO EtO2C O CO2Et
O
CO2Me HO TL 1987,
Me3SiO PhH, 5°C
28 , 813
+ HO
N N OH
Ts TsN H
CO2Me
CH(OMe)2 CH(OMe)2 OAc

O AcO OH
O TL 1985
+ N 27 , 4727
CO2Bn N NAc
CO2Bn AcO
CH3 CH3 CH3
Me Me
Me O Me O Me NHTs TL 1983,
S
+ S Me 24 , 987
NTs Me
Me NTs Me
Me
Me Me
S Tetrahedron,
S
S Ph 1983, 39 , 1487
Ph S Ph H
Ph
O
O 1) MgBr2
OMe 2) H3O+
H O JACS 1985,
+ 107 , 1256
Me3SiO OBn O
OBn
OMe
OMe O OMe
HF, Me JACS 1985,
Yb(fod)3 Me
Ar Pyridine O 107 , 6647
O
+ H
Ar
Ar O
Me Me3SiO
Me3SiO
Me Me
Me Me
O C3F7
M
O O
C3F7 O M
3
3
M(fod)3 M(hfc)3
- Heterodienes
H H
H O O O O O
O
+ ACIEE 1983,
+ 22 , 887
MeO2C MeO2C MeO2C
H endo: exo H
OAc AcO AcO
1:2
Me O OEt EtO O Me HO O Me
+ ACR 1986,
19 , 250
PhS OH
endo:exo SPh
OAc 10 : 1 OAc OH
OR'
O O OR' O OMe
O RO RO JACS 1987,
N O RO 109 , 285
N
+ N
O RO N RO NHAc
RO
OR CO2R' OR
OR' OR
∆ JOC 1985,
N 50 , 2719
N N
AcO O O
O
Intramolecular Diels-Alder Reactions (IDA)

- Type I IDA rxns
Fused bicyclc
Bridged Bicyclic
- Generally, for E-dienes, the fused product is observed unless the connecting chain is
very long. For Z-dienes, either the fused or bicyclic products are possible.
- Type II IDA rxns: gives bridgehead olefin
395°C JACS 1982,

104 , 5708, 5715
O
O
O O
O
185°C O
JACS 1987,
EtO2C O 109 , 447
EtO2C
EtO2C CO2Et
AcO O
OH
NHBz O
155°C Ph ACIEE 1983,

O
24 , 419
OH
H O
OH
O BzO AcO
O
Taxol
- IDA reactions to give fused 6•5 (hydroindene) and 6•6 (hydronaphthalene) ring
systems are usually favorable reactions.
R' R'
R R
n= 1 or 2
(CH2)n (CH2)n
- Intramolecular D-A rxns that give medium sized rings (7,8,9, 10) are much less
favorable.
- Intramolecular D-A rxn which form large rings are often favorable reactions with the
diene and olefin portions act as if they were seperate molecules
O
H
H O
H
O O O
+ JACS 1980,
H +
H H 102 , 1390
O O O
O O O O
O O O O
endo exo
6.2 : 6.8 : 1 (77% combined yield)
- Preference for endo or exo transition state depends on the substituition of the diene,
dieneophile and connecting chain.
- For intramolecular D-A rxns, geometric constraints can now reverse the normal
regiochemistry of the addition as compared to the intermolecular rxn.
+
CO2R' CO2R'
R R
CO2R'
CO2R'
- for intramolecular D-A reactions, we will use endo and exo to described the
disposition of the connecting chain
R R'
R' H
R
(CH2)n
R'
H
R (CH2)n
(CH2)n endo
R R'
R' H
R
(CH2)n
(CH2)n H
exo
- Lewis acids can greatly effect the endo/exo ratio of IDA reactions especially when the
olefin portion is E. The effects for Z-olefins is much more subtle
MeO2C
MeO2C MeO2C
H H
+
JACS 1982,
104 , 2269
H H
150°C 75 : 25 (75% combined yield)

(RO)2AlCl2, rt 100 : 0 (72% combined yield)
CO2Me MeO2C
MeO2C
H H
+
H H
180°C 75 : 25 (74% combined yield)

EtAlCl2, rt 63 : 37 (60% combined yield)
- the effect of substituents on the connectinng chain can influence the stereochemical
course of the IDA reaction
HN
O
HN JOC 1981,
EtAlCl2 H 46 , 1509
MeO2C
O
rt
MeO2C
H
R
O R R R
O
H
H
Intramolecular Diels-Alder Reactions:

CO2Me
MeO2C
H JOC 1981,
130°C TBSO 46 , 1506
TBSO
O O
O O TL 1973,
150°C
4477
OTBS OTBS
CF3CO2H H JACS 1981,

H 103 , 4948
H H
O
OTBS TBSO CO2Me

CO2Me H
EtAlCl2 JOC 1982,
47 , 180
Asymmetric Diels-Alder Reactions

- Chiral Auxillaries Chem. Rev. 1992, 92 , 953; Tetrahedron 1987, 43 , 1969
OAc OAc O
HO CO2H
O M OH
BF3•OEt2, -40°C JOC 1983, 48, 1137
O + JOC 1983, 43, 4441
H HO ACIEE 1985, 24, 1
H
OH
OAc OAc
>98% d.e. (-)- Shikimic Acid
O
TiCl4, 0°C TL 1984,
+ 25 , 2191
O O
O R*
O
O (97:3)
O X ∆ = 4.5 %ee
CO2R* TiCl4= 78% ee
O
iBu2AlCl= 90% ee
O CO2R*
O
O O
O O
Ph
O Ph + + JOC 1989,
OR* Ph
54 , 2209
O Ph O OR*
18 : 82
w/ BF3•OEt2 92 : 8 d.e > 95%
O
O
Ar Et2AlCl
O + R* Chem Lett. 1989, 2149
O
CH2Cl2, -80°C
OTMS
O up to 70% d.e.
Ph Ph
H PhCHO O O
O OR* + OR* JACS 1986, 108, 7060
Eu(hfc)3
Me OTMS O Me O Me
8 : 92
CH3 O
O O
R* O
Ph SnCl4, -78C O N R*
O N + PhMgBr O N R* OH
H O N
S O S O S
O R R Ph
97% d.e. R R
JCSCC , 1985 , 1449

TL 1986, 27 , 1853
O
Tetrahedron
O (iPrO)2TiCl2, 1987, 43 , 1969
H
H O CH2Cl2, 0°C
H CO2R*
O O
SO2
N X endo/exo= 86:4 TL 1989,
98% de 30 , 6963
EtAlCl2, -78°C
Oppolzer Auxillary
O
O O
O
Evan's auxillaries R N O
R N O
Me Ph
+
O O
CO2R*
Me2AlCl CO2R*
N O endo (major) endo
CO2R*
CO2R*+
exo exo
1 equiv Me2AlCl 2 equiv. Me2AlCl
endo/exo 20:1 60:1
endo A/ endoB 4:1 20:1
k(rel) 1 100
_
Me2AlCl2
_
Me2ClAl +
O O O + Al
O O O O Al
Me2AlCl Me2AlCl
N O N O O
N O N
H
O
O O O
OH JACS 1984, 106, 4261
R N O R*
JACS 1988, 110 , 1238
EtAlCl2, -100°C
Ph (R)-(+)-α-terpineol
O O O O
R* R*
O N H H
Me2AlCl
+
Ph Me TL 1984 , 25 , 4071
JACS 1988, 110 , 1238
H H
15 : 85
O O
O N
Me2AlCl 95 : 5
Ph
- Chiral Dienes
O
Ph
O
OMe CHO OHC OMe BF3•OEt2, -20°C 4:1
O BF3•OEt2, -78°C 94:6
Ph
O
π-stacking
MeO arrangement O
O OH Ph
OMe H O O OH
O O H
+ OMe
Ph O
O
O H
approach of O
dienophile only product
- Chiral Catalysts Chem. Rev. 1992, 92 , 1007; Synthesis 1991, 1; OPPI 1994, 26, 129-
158
OH
CHO CHO JCSCC

+ 1979, 437
EtAlCl2, -78°C 72% (ee)
OtBu
Me Eu(hfc)3, -10°C O TL 1983,
+ PhCHO 24 , 3451
TMSO O Ph
Me Me
Ph Ph
Ph O OH
Me O OH
O O
Ph Ph CL 1986, 1967
+ O N
N O (iPrO)2TiCl2 O
O
O
Ph Ph O
Ph O OH O N
O O
Me O OH H
N O Ph Ph
O 70% yield
(iPrO)2TiCl2 95% ee
O O (30 mol % catalyst) O H
Ph
O O
OH
OH
JACS 1986,
+ 108 , 3510
Ph
OH O OAc BH3, -78°C OH O OAc (98%)
Ts
N
Et B
O N
Br CHO O H CHO JACS 1992,
+ 114 , 8290
-78°C Br
(> 99% ee)
H
N
O
O
Br CHO CHO H
+ N B Bu N
Ts
Br
CH2Cl2, -78 °C,
Br 16 hrs Br
Br (81%, 99% ee) O H
O
N B O
OC Ts
OH
O HO
approach of diene
CO2H
Br Gibberellic Acid
H
N
OTBS H 3C 1) NaBH4
O OTBS O
2) DDQ
CHO H O O JACS 1994, 116, 3611
-
3) F
+ N B H
Ts 4) HCl
O CH2Cl2, PhCH3 CHO

O OH
-78 °C, 42 hrs HO
O
(83%, 97% ee) O OH
Cassiol
Ketene Equivalents in the D-A reaction

- ketenes undergo thermal [2+2] cycloaddition with dienes to give vinyl cyclobutanones.
- 2-chloroacrylonitrile as a ketene equiv. for D-A rxns.
Cl KOH, tBuOH
AcO Cl CN 70 °C O
+ AcO CN HO
Nature (London) 1994, 367, 630
ACIEE 1995, 34, 2079
ortho-Quinodimathanes Synthesis 1978, 793; Tetrahedron 1987, 43 , 2873

R R
R
R
benzocyclobutane o-quinodimethane
O O
OTMS
1) LiNH2, NH3, THF
MgBr Me3Si SiMe3
CuI, TMS-Cl CpCo(CO)2

I
O O
O
170 °C
H
Me3Si Me3Si
Me3Si
H H H H
Me3Si Me3Si
Me3Si
1) CF3CO2H, CCl4, -30°C H ACIEE 1984, 23 , 539

2) Pb(O2CCF3)4 JACS 1977, 99 , 5483
H H JACS 1979, 101 , 215
HO JACS 1980, 102 , 241
Estrone
O
O
HN
HN JACS 1971,
155 °C
93 , 3836
H
Me Me
O O
N N
155 °C
ACIEE 1971, 11 , 1031
O O
Me Me
O O
N N
155 °C ACIEE 1971, 11 , 1031
N N
OMe OMe
Me Me
O
O N
N ACIEE 1971, 11 , 1031
180 °C
NH
N
Photoenolization Tetrahedron 1976, 22, 405

R R R
R OH
•
O hν O• MeO2C CO2Me CO2Me
OH
H H
CO2Me
R R R R
O O
O -H2O
R
R OH O
CO2Me
O
CO2Me
R O R
Intramolecular Ene Reactions ACIEE 1984, 23 , 876, Synthesis 1991, 1

H
SnCl4
JOC 1985,
CHO 50, 4144
OH
H
Me2AlCl JACS 1991,

113 , 2071
H OH
BnO CHO
OBn
Binaphthol Tetrahedron Lett. 1985, 26, 5535

CHO
Me2Zn OH
90% ee)
Polyene Cyclization
+ +
Terpene Biosynthesis
terpenes C 10 geraniol
sesquiterpenes C 15 farnesol
diterpenes C 20 geranylgeraniol
steroids C 30 squalene
- isoprene- basic building block
OPP
isoprene unit
isopentyl-PP
OPP
OPP
OPP
geraniol-PP (C10) Farnesyl-PP (C15) geranylgeraniol-PP (C20)

squalene (C30)
O
HO2C
Camphor α-Cedrane Abietic Acid
Biosynthesis of camphor:
+
OPP O
+
Biosynthesis of cedrane:
OPP H
+
+
Stork-Eschenmoser Hypothesis- Olefin Geometry is preserved in the cyclization reaction, i.e.

trans olefin leads to a trans fused ring jucntion
A. Eschenmoser HCA 1955, 38, 1890; G. Stork JACS 1955, 77, 5068
Me Me Me
Me Me
+ Me
R Me Me
R
H H
H H
Biosynthesis of Abietic acid:
OPP OPP
+ OPP
+ H
H
H H
+
H
+
H
H
H H H
H HO2C
-Steroid Biosynthesis:
H H+
squalene squalene H
epoxidase cyclase + H
squalene
H H
+O HO HO
H H
Protosterol
H squalene oxide
H
+
H
H H H
H
H H H
HO HO HO
H H
Lanosterol Cholesterol
- Polyene cyclization in synthesis ACR 1968, 1, 1; Bioorg. Chem. 1976, 5, 51; Asymmetric
Synthesis 1984, 3, 341-409; ACIEE 1976, 15, 9
SnCl4
CH3NO2, 0°C
H
E.E. van Tamelen
(8%)
JACS 1972, 94 , 8229
H
O HO
H δ- Amyrin
OH
CHO
SnCl4 JACS 1974,
PhH, rt H
96 , 3333
(38%)
MeO MeO
SnCl4 H W.S. Johnson

pentane JACS 1974, 96, 3979
H H
(27%)
O O H
O
HO
CO2Me CO2Me
1) Hg(O2CCF3)2 O
OPO(OEt)2 2) NaCl JACS 1980,
102 , 7612
ClHg
H
Robinson Annulation Synthesis 1976, 777; Tetrahedron 1976, 32, 3.

O
acid or base O
O
(thermodynamic
conditions)
- unfavorable equillibium for the Michael addition under kinetic conditions
-O O
-
O base
(kinetic conditions)
- stabilizing the resulting enolate of the Michael Addition product can shift the
equilibrium as in the case of the vinyl silane shown below
O
Me3Si Me3Si
- O
O -
O O
base
(kinetic conditions)
OR OR OR
a) MeLi
JACS 1974,
b) O O O 96 , 6181
O Me3SiO Me3Si
H H
O
O
c) MeONa O
- Methyl Vinyl Ketone equivalents

I
mCPBA H+
+ -
O
O O
Me3Si Me3Si O
Me3Si
Aldol
JACS 1974,
O O O 96 , 3862
O
+ -
O O O O
O
O
Intramolecular Aldol Condensation of 1,5-Diketones

6-exo-trig; favored process
O
R' O
base R'
- H2O
R
R O
- DeMayo reaction to 1,5-diketones

O
O O
H
O O DIBAL-H
hν
O O
H 3C O
Intramolecular Alkylations (SN2 reaction)
Radical Cyclizations
Acyloin Reaction
Birch Reduction Organic Reactions 1992, 42, 1.
Aromatic Substitution (Carey & Sundberg, Chapter 11)
Intramolecular Wittig Reaction
Sigmatropic Rearrangements
Medium Sized Rings
7-Membered Rings
[4+2] cycloadditions
- [4+2] cycloadditions between dienes and allylcations leads to cycloheptadienes
review: ACIEE 1984, 23 , 1; ACIEE 1973, 12 , 819
+ + +
I CF3CO2Ag ACIEE 1973, 12, 819

+ ACIEE 1984, 23, 1
-78°C
Me
ZnCl2, -30°C
ACIEE 1982,
+
21, 442
+
H H
F3CCO2
SiMe3 SiMe3
O O
OTMS
+ JACS 1982,
104 , 1330
ZnCl2
Br
OMe O O
O O + O
O O O
+ O
O
O O JACS 1979, 101, 226

mCPBA
O
HO
- Noyori [4+2] cycloaddition of α,α'-dibromoketones and dienes

review: ACR 1979, 12 , 61
O Fe2(CO)9 O
-or- OM
R R ACR 1979, 61
R R Zn-Cu R R
Organic Reactions
+ 1983, 29, 163
Br Br
O O O
Br Br Fe2(CO)9 Br Br Zn
O O O
Br Br
CO2Me
O N
MeO2C
Br Br 1) N JACS 1978, 100 , 1786
Br Br Fe2(CO)9
2) Zn O
OMe O O
O O + O
O O O
+ O
O
O O
mCPBA JACS 1979, 101, 226
O
HO
O O
1) O 1) H2, Pd/C OH
Me Me O
2) CF3CO3H JACS 1972, 94, 3940
O JOC 1976, 41, 2075
Br Br Fe2(CO)9 O
O H H
O CO2H
O O Me Me Me
O 1) CF3CO3H
OH
2) LDA, MeI JCSCC 1985, 55
O
O OBn Me OBn OH OH OBn
O
O
- [4+2] cycloaddition between pentadienyl cations and olefins
+ + +
O OH
HO - O
∆ O Tetrahedron 1966, 22, 2387
+ O
JOC 1987, 52, 759
O O
O
MeO OMe
OMe
SnCl4 JACS 1977, 99, 8073
JACS 1979, 101, 6767
JACS 1981, 103, 2718
OMe
O O
Seven-Membered Rings from Funnctionalization of Tropone

Organic Reactions 1997, 49, 331-425
O O-
O
Cl
R R
JOC 1988, 53, 4596
JACS 1987, 109, 3147
O
- [6+4] cycloadditions of tropones with dienes

[6+4]
O
150°C JACS 1986, 108, 4655
O
JOC 1986, 51, 2400
(88%)
HO HO
HO OH
Ingenol
- [4+2] cycloaddition between tropone and olefins

O
O
[4+2]
150°C
(81%)
Radical Ring Expansion Reactions

- one carbon ring expansions
O O O
Br •
nBu3SnH,
NaH, CH2Br2 CO2Me AIBN CO2Me
CO2Me
(CH2)n (CH2)n (CH2)n

n = 1,2,3
O O
•O nBu3SnH JACS 1987,109, 3493
CO2Me JACS 1987,109 , 6548
(CH2)n •
(CH2)n (CH2)n
CO2Me CO2Me
O O O
Bu3SnLi
CH3 •
BrCH2SePh SePh
SnBu3 SnBu3
O Tetrahedron 1991, 47, 6795
•O
+ Bu3Sn•
SnBu3
- more than one carbon expansion

O X O
R
(CH2)n
(CH2)n Tetrahedron 1989, 45, 909
SnBu3
R
X= I, SePh
n= 1,2
Br Br Bu3SnH, AIBN,
+ C6H6, reflux JOC 1992, 57, 7163
O O
O
Eight-Membered Rings review:Tetrahedron 1992, 48 , 5757.

[4+4] Cycloaddition of Dienes
Ni(COD)2, Ph3P MeO2C JACS 1986,

MeO2C
108 , 4678
MeO2C 60°C MeO2C
O O
O
O O
O
JACS 1988,
Ni(COD)2, Ph3P
H 110 , 5904
60°C H
O
Asteriscanolide
Carbonyl Coupling Reactions

- Acyloin Reaction
CO2Me O
Na JACS 1971,
93 , 1673
CO2Me OH
- McMurry Reaction
R R
CO2Et Ti (0)
O
O
CHO OHC
TiCl3, Zn-Cu
JACS 1986,
H H 108 , 3513
Aldol-like Condensations
O
TiCl4 O
O OH JCSCC 1983, 703
OTMS O
SiMe3 SiMe3
R Lewis Acid R
JACS 1986,
O 108 , 3516
(CH2)n O OMe (CH2)n O
n= 1,2
Me3Si Cl Cl
Me3Si Cl
SnCl4
OTs
O OTs O
tBuPh2SiO O
tBuPh2SiO JACS 1988,
OEt Laurenyne 110 , 2248
TiCl4
JOC 1988,
53 , 50
O SiMe3 O
Pinocol Rearrangement
O
Me3SiO SnCl4 Me3SiO
+ JACS 1989,
OMe 111 , 1514
OMe
OMe H
OMe
Tiffeneu-Demyanov Ring Expansion

- one carbon ring expansion for virtually any size ring
N2
O HO NH2 O H O
1) Me3SiCN JOC 1980,
2) LAH HONO 45 , 185
- also see Beckman and Schmidt rearrangements as a one atom ring expansion
for the conversion of cyclic ketones to lactams.
DeMayo Reaction
O
O O O
hν O O
+
OAc
AcO
O
JCSCC 1984, 1695
O O
O
CO2Me
O O H
O pTSA, MeOH
hν, pyrex O reflux JACS 1986,
O O 108 , 6425
O
H
Ring Expansion/Contraction via Sigmatropic Rearrangements

- Cope Rearrangement
O
O
SMe TL 1991,
55°C
32 , 6969
O
O
O O
- Anion Accelerated Cope

KH, 18-C-6
115°C O JACS 1989,
111, 8284
OH O
OCOCH2OH
Pleuromutilin
- Claisen Rearrangement
O
O
Tebbe
reagent O 185°C
O H TL 1990,
31 , 6799
- Ester Enolate Claisen- 4 carbon ring contractions

O
1) LDA, TBS-Cl
2) 110°C CO2H
O
JACS 1982, 104 , 4030
MOMO MOMO
1) LDA, TBS-Cl
H 2) 110°C JOC 1988, 53 , 4141
O
H
O H CO2TBS

Advanced Organic Reactions 2000 - Warren

Enviado por

Dados do documento

Descrição original:

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Advanced Organic Reactions 2000 - Warren

Enviado por

Direitos autorais:

Formatos disponíveis

SELECTIVITY 1

- Chemoselective reduction of C=C over C=O:

- Chemoselective reduction of C=O over C=C:

O OAc O OAc O OAc

syn: on the same side ( cis)

- differences in relative stereochemistry lead to diastereomers.

- Reactions can "create" stereocenters

Diastereomeric transition states- not necessarily equal in energy

Cram Model (Cram's Rule): empirical

Chelation Control Mode

Br2 CH3 Br Br CH3

α-pinene only isomer not observed

I. Metal Based Reagents

Metal Based Reagents

Jones Reagent (H 2CrO4, H2Cr2O7, K2Cr2O7)

- 2°- alcohols are oxidized to ketones

- saturated 1° alcohols are oxidized to carboxylic acids.

Collins Oxidation (CrO3•2pyridine)

Pyridinium Chlorochromate (PCC, Corey-Suggs Oxidation)

- Oxidation of Active Methylene Groups

- PCC/Pyrazole PCC/ 3,5-Dimethylpyrazole

- selective oxidation of allylic alcohols

Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)

-allylic alcohols are oxidized to α,β-unsaturated aldehydes

HO O Synthesis 1979, 815

- 1° alcohols and aldehydes are oxidized to carboxylic acids

JACS 1972, 94, 4024

(62%) J. Chem. Soc. 1953, 2189

- oxidation of 1° allylic alcohols to α,β-unsaturated esters

Manganese (III) Acetate α-hydroxylation of enones

Tetra-n-propylammonium Perruthenate (TPAP, nPr4N+ RuO4-)

N+ TL 1989, 30, 433

OH OH JACS 1981, 103, 1864.

JACS 1982, 104, 5557

Prevost Reaction Ag(PhCO2)2, I2

Ag(PhCO 2)2, I2 AcO OH

Other Metal Based Oxidations

- use of R 3N-O as a reoxidant

Substrate directed hydroxylations: Chem. Rev. 1993, 93, 1307

HO CH3 HO CH3 OH HO CH3 OH

CH3 CH3 (86 : 14) CH3

- OsO4 bis-hydroxylation favors electon rich C=C.

OsO4 (no ligand) 4:1

Proposed catalyst structure:

Corey Model: JACS 1996, 118, 319 O N

Rs RM RL large and flat,

"AD-mixes" commercially available pre-mix solutions of Os, ligand and reoxidant

OMe OMe OMe

- Kinetic resolution (not as good as Sharpless asymmetric epoxidation)

Pd2(DBA) 3•CHCl 3, JACS 1989, 111, 8039.

Oxidation of silylenol ethers and enol carbonates to enones

Non-Metal Based Reagents

SO3/Pyridine JACS 1967, 89, 5505.

H "ene" reaction H Ph3P:

1) O2, hν, Ph2CO HO

Ozone Comprehensive Organic Synthesis 1991, 7, 541

JACS 1979, 101, 7104

Peroxides & Peracids

Oxone (postassium peroxymonosulfate) Tetrahedron 1997, 54, 401

MeO 2C Tetrahedron 1991, 47, 173

MeO N MeO MeO O OH OH

- Asymmetric oxidation of sulfides to chiral sulfoxides.

Remote Oxidation (functionalization) Comprehensive Organic Synthesis 1991, 7, 39.