Advanced organic reactions

174 Pages·1983·1.24 MB·English

by  Stuart W.

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
NaBH
4
+
O OH
NaBH , CeCl
4 3
only
- Epoxidation:
MCPBA
+
OH OH OH
O O
(2 : 1)
VO(acac) ,
2
tBuOOH
exclusively
OH OH
O
Regioselectivity
- Hydration of C=C:
1) B H
2 6
2) H O , NaOH OH
2 2
R
R OH
R
1) Hg(OAc) , H O
2 2
2) NaBH
4
- Friedel-Crafts Reaction:
O
RCOCl,
AlCl3 R +
R
O
O
RCOCl,
SiMe
3 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, H
2
+
O H O SPh O H O SPh O H O
Change in mechanism:
SPh
PhSH, H+
R
R
SPh
R
PhSH, (PhCO )
22
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 CH
3
Ph H Ph H
MeMgBr
H C OH
3
Ph H
O enantiomers
Ph (racemic product)
H
HO CH
3
Ph H
MeMgBr
Diastereomeric transition states- not necessarily equal in energy
Me Me Me Me
N
O Zn O Ph ON Zn O H
CH3 CH3 H CH3 CH3Ph
Zn Zn
H C
3 H C
3
HO CH3 HO CH3
Ph H H Ph
Diastereoselectivity
CH MgBr
3
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 H3C H
R S Nu
CH3MgBr CH3MgBr
L
favored
R H
L
Ph
SELECTIVITY 4
Felkin-Ahn Model
O M S O
L Nu Nu L
R S M R
favored disfavored
Chelation Control Mode
M
OR
O
O
HO M
OR S
R CH3MgBr CH3MgBr
S M S M NuR OR
favored
R
HO
TBSO MgBr TBSO
O
relative stereochemical control
H O 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 C H Br
3
meso
H
Br CH
3
Br2 CH3 Br Br CH3
H + H
H H
Br CH CH Br
3 3
enantiomers (racemic)
Stereoselective
When more than one stereochemical outcome is possible, but one is formed in excess (even if that
excess is 100:0).
CH3H H H
H , Pd/C
2
H + CH
3
H H
a -pinene only isomer not observed
O O O O O O
LDA, CH I
3
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
R2CH-OH HCHr+O4- RR C O Cr OO-- RR O + HCrO3- + H+
H
+ H O
2
Jones Reagent (H CrO , H Cr O , K Cr O )
2 4 2 2 7 2 2 7
J. Chem. Soc. 1946 39
Org. Syn. Col. Vol. V, 1973, 310.
- CrO + H O fi H CrO (aqueous solution)
3 2 2 4
K Cr O + K SO
2 2 7 2 4
- Cr(VI) fi 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.
Jreoangeesnt O hydration HO OH Jreoangeesnt O
RCH -OH
2
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 CH
2 3
OH 2) CH N
2 2
Me Si Me Si
3 3
JACS 1982, 104, 5558
H C H C
17 8O 17 8O
OH O
Jones
O acetone O
JACS 1975, 97, 2870
O O
Collins Oxidation (CrO •2pyridine)
3
TL 1969, 3363
- CrO (anhydrous) + pyridine (anhydrous) fi CrO •2pyridinefl
3 3
- 1° and 2° alcohols are oxidized to aldehydes and ketones in non-aqueous solution (CH Cl )
2 2
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•(C5H5N)2 H
OH CH2Cl2 O JACS 1969, 91, 44318.
ArO O
ArO O
O
O
CrO catalyzed (1-2 mol % oxidation with NaIO (2.5 equiv) as the reozidant in wet aceteonitrile.
3 6
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 fi pyH+CrO Cl- fl
3
- Reagent can be used in close to stoichiometric amounts w/ substrate
- PCC is slighly acidic but can be buffered w/ NaOAc
PCC, CH Cl
2 2
OHC
HO JACS 1977, 99, 3864.
O
O
PCC, CH Cl
2 2
CHO
O
O OH TL, 1975, 2647
OXIDATIONS 7
- Oxidative Rearrangements
Me OH
Me
PCC, CH Cl
2 2 JOC 1977, 42, 682
O
Me
Me
PCC, CH Cl
2 2 JOC 1976, 41, 380
OH
O
- Oxidation of Active Methylene Groups
PCC, CH Cl
2 2
O O O
JOC 1984, 49, 1647
PCC, CH Cl
2 2
O 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 Cl
2 2
H H 3,5-dimethyl
pyrazole H H
HO
O
(87%)
Pyridinium Dichromate (PDC, Corey-Schmidt Oxidation)
TL 1979, 399
- Na Cr O •2H O + HCl + pyridine fi (C H N) CrO fl
2 2 7 2 5 5 2 7
PDC PDC
CHO CH2Cl2 OH DMF CO2H
1° alcohol
-allylic alcohols are oxidized to a,b -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.
CH2CH CH2CH R2CH-OH R2C=O CH2CH
cross-link CrO , HCl
3 partially
spent
N N N N reagent
Cr(VI)O •HCl Cr(III)
3
to remove Cr(III)
1) HCl wash
2) KOH wash
3) H2O wash
CrO /Et O/CH Cl /Celite
3 2 2 2
Synthesis 1979, 815.
- CrO in non-aqueous media does not oxidized alcohols
3
- CrO in 1:3 Et O/CH Cl /celite will oxidized alcohols to ketone and aldehydes
3 2 2 2
C8H17 C8H17
CrO
3
Et O/CH Cl /celite
2 2 2
(69%)
HO O Synthesis 1979, 815
H CrO on Silica
2 7
- 10% CrO to SiO
3 2
- 2-3g H CrO /SiO to mole of R-OH
2 3 2
- ether is the solvent of choice
Manganese Reagents
Potassium Permanganate KMnO /18-Crown-6 (purple benzene)
4
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 KMnO in benzene at 25°C gives a clear purple solution as high
4
as 0.06M in KMnO .
4
O
JACS 1972, 94, 4024
CO H
2
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 (BaMnO )
4
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 MnO
2
Barium Manganate
BCSJ 1983, 56, 914
Manganese Dioxide
Review: Synthesis 1976, 65, 133
- Selective oxidation of a,b -unsatutrated (allylic, benzylic, acetylenic) alcohols.
- Activity of MnO depends on method of preparation and choice of solvent
2
- cis & trans allylic alcohols are oxidized at the same rate without isomerization of the double
bond.
OH
OH
HO
HO
MnO , CHCl
2 3
(62%) J. Chem. Soc. 1953, 2189
JACS 1955, 77, 4145.
O
HO
- oxidation of 1° allylic alcohols to a,b -unsaturated esters
MnO ,
2
ROH, NaCN
OH
CO R
2
OH
CO Me
2 JACS1968, 90, 5616. 5618
MnO , Hexanes
2
MeOH, NaCN
Manganese (III) Acetate a -hydroxylation of enones
Synthesis 1990, 1119 TL 1984 25, 5839
O O
Mn(OAc) , AcOH AcO
3
Ruthenium Reagents
Ruthenium Tetroxide
- effective for the conversion of 1° alcohols to RCO H and 2° alcohols to ketones
2
- oxidizes multiple bonds and 1,2-diols.
OXIDATIONS 10
Ph OH RuO4, NaIO4 Ph CO2H
O CCl , H O, CH CN O
4 2 3 JOC 1981, 46, 3936
OH
RuO , NaIO
4 4
Ph OH Ph CO H
2
CCl , H O, CH CN
4 2 3
H CH3 96% ee H CH3 94%ee
HO
RuO , NaIO O
2 4
TL 1970, 4003
CCl , H O
O 4 2
O
O
O
Tetra-n-propylammonium Perruthenate (TPAP, nPr N+ RuO -)
4 4
Aldrichimica Acta 1990, 23, 13.
Synthesis 1994, 639
- mild oxidation of alcohols to ketones and aldehydes without over oxidation
OH O
TPAP
MeO2C OSiMe2tBu O MeO2C OSiMe2tBu
N+ TL 1989, 30, 433
-O Me
(Ph P) RuO Cl RuO (bipy)Cl
3 4 2 3 2 2
- 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) O ]
2 3
-oxidizes only the most reactive alcohols (benzylic and allylic)
(Ph P) RuCl + Me SiO-OSiMe
3 3 2 3 3
- oxidation of benzylic and allylic alcohols TL 1983, 24, 2185.
Silver Reagents
Ag CO ( Fetizon Oxidation) also Ag CO /celite Synthesis 1979, 401
2 3 2 3
- oxidation of only the most reactive hydroxyl
O O
OH Ag2CO3 O
OH OH JACS 1981, 103, 1864.
mechanism: TL 1972, 4445.
O
O OH Ag CO , C H O
2 3 6 6
O
OH
O O