Umpolung reactivity

Special Topic 27/02/09

Anne Fournier

1
The synthetic problem
Heteroatoms impose an alternating acceptor and donor reactivity pattern
d0 X X = halogen, O, N
d = donor (-)
a1 3
a 5
a a = acceptor (+)
d2 d4

An odd number of carbons between functional groups

X X X X

1,3-disubstitution
a1 a1 a1
a3 a1 a3
d2 d2 d4 d2 d2 d4

An even number of carbons between functional groups

X X X
4
d d2
a3 a1 1,2-disubstitution
a3 a1 a1 a3 a1 a3
d4 d2 d2 d4 d2 d4
X

X X X
4 2
d d 1,4-disubstitution
3 1 a1 a3 a1 a1
a a 3
a a3
d4 d2 d2 d2
X
2
 Definition
Umpolung is any process by which donor and acceptor
reactivity of an atom are interchanged (reversal in polarity).

d0 X a0 X
Umpolung
1
a a3 d1
4
a5 d3 d5
2 d
d a2 a4

« usual » reactivity: Umpolung reactivity:

C2n= donor, C2n+1= acceptor C2n= acceptor, C2n+1= donor

Reactivity enables us to construct new bonds which are difficult to construct or cannot be
achieved by « usual » reactivity, particulary the construction of 1,2 or 1,4-difunctionality.

Seebach ACIEE 1979, 239 3

 Carbonyl Umpolung
Patterns of Carbonyl Reactivity
O
O
_
+ _ R'
R'
+ R
R _ _ + +

"usual" reaction polarity umpolung reaction polarity

O O

acyl transfer reaction

acyl bonding Friedel-Craft reaction
R Nu R E

O O

E enolate anion alkylation Nu

R alpha bonding aldol and Claisen reactions R

R' R'

O R' O R'

conjugate additions
beta bonding Michael reactions
R Nu R E
4
Carbonyl Umpolung
Carbonyl Umpolung intermediates
O Application Strategy
_
_ R' carbonyls vs. acyl anions
R enolates vs. a-electrophiles
+ + Michael acceptors vs. homoenolates
umpolung reaction polarity

O
O
_
.. acyl anion
R
R E
d1 synthon

O
O
Nu
R + -electrophile
R
R' a2 synthon

O R' O
_
.. homoenolate
R E R
d3 synthon 5
 Carbonyl Umpolung
Masked Acyl Anion Equivalents
 1a. Benzoin Condensation: Cyanide ion Catalyzed Addition
O OH
_ O
CN

..
_
Ar H
..
Ar CN Deprotonation Ar CN
Nucleophilic attack
of cyanide H (umpolung)
Acyl anion equivalent
cyanohydrin

O O
Ar
a1
d1 • Must use aromatic or heteroaromatic aldehydes; aliphatic
Ar aldehydes tend to undergo an aldol condensation Ar H
OH

• Cannot selectivity cross couple of two different aldehydes Addition of aldehyde

OH
O O

Ar
Ar R
Ar
Ar Ar
1,2-substitution NC
Regeneration NC Proton transfer
of catalyst O
OH OH
_
_ CN
..

Benzoin

Lapworth JACS 1903, 995. 6

 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 1b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction

O O
O O
R2 R1
M-CN
R1 R1
R1 SiR3 R2 H 18-Crown-6
OSiR3 OH

Only product Not observed

O OSiR3
[1,2]-Brook
.._
R3Si CN Rearrangement R1 CN
R1
Acyl anion equivalent

Kinetic control, regiosepecific, (but need to make acyl silane), lower yields often result
from aliphatic aldehydes (improvement with La(CN)3 catalyst)
Johnson JACS 2005, 1833 7
 Carbonyl Umpolung
Masked Acyl Anion Equivalents
 2. N-Heterocyclic Carbenes Catalyzed Acyloin Formation

O
R1 R1 R1
R1 R1
R2 R2 R2

..
R2 R2 O N OH N OH
N N N umpolung
R H
Base

..
..

H
-H S R S R S R
S S R3 R3 R3
R3 R3
Breslow intermediate
thiazolium salts ylides or nucleophilic carbenes

Acyl anion equivalent

R1 R1
O
R2 R2
N O N OH
R4
R
R R O
S S
OH R3 R3
R4 OH R4 O
acyloin R4 H

Effective for aliphatic and (hetero)aromatic aldehydes

(a) Breslow JACS 1958,3719.
Applicable to acylsilanes (b) Enders Acc. Chem. Res. 2004, 534. 8
 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 3. Recent Progress in Asymmetric Benzoin Reactions

O O
cat. (10mol%)
KOtBu (10mol%) Ar
Ar H Ar
8-83%
OH

ee = 80-95%
Ph
N N Ar = Ph, m-Me-Ph,
p-Me-Ph, p-MeO-Ph,
O N m-Cl-Ph, p-F-Ph,
p-Cl-Ph, p-Br-Ph,
o-Furyl, o-Naphtyl
cat. tBu

Triazolium salt

Enders ACIEE, 2002, 1743

9
 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 4. Stetter Reaction: Generation of 1,4-dicarbonyls

General reaction

R4 O R4
O

R3 R5 Nuc. cat. R5 1,4-disubstitution

R1
R1 X polar solvent
R2 O R2 R3 O

X = H or SiR3
Nuc. cat. = CN- or NHCs

R4
O

R2 R5
d1 3
R1 a

R3 O

Scope includes unsaturated esters, nitriles, ketones and aldehydes

(a) Stetter ACIEE 1976, 639.
(b) Scheidt JACS 2004, 126, 2314 10
 Carbonyl Umpolung
Masked Acyl Anion Equivalents
 5a. Recent Advancements in Asymmetric Stetter Reactions
Aromatic substrates

O
O
OMe
5
H cat. (20mol%), KHMDS (20mol%) 6
CO2R2
R1 xylenes, rt, 24h. 1
R
N BF4
X CO2R2 63-95% 7 N
X
8 N

ee = 82-97% O

R1 = 6-Me, 8-Me, 8-MeO cat.

R2 = Me, Et
X = O, S, NMe, CH2

Aliphatic substrates

O O

cat. (20mol%), KHMDS (20mol%) CO2Et N

CO2Et xylenes, 25°C, 24h.
Bn
N BF4
N
cat. Ph
81%

ee = 95%
11
Enantioselective intramolecular Stetter reaction Rovis JACS, 2002, 10298
 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 5b. Quaternary Stereocenters via Asymmetric Stetter

Aromatic substrates
O
O
EWG
cat. (20mol%), Et3N (2eq.)
PhMe, 25°C, 24h.
R
55-96% EWG
X R X

ee = 89-99% F
F
X = O, S, CH2
F
R = Et, Me, Ph F

F
Opposite N N
stereochemistry
Aliphatic substrates N BF4

O
O
O
cat.
cat. (20mol%), KHMDS
R
PhMe, 25°C, 24h. R
EWG EWG
63-90%

ee = 84-99%
Rovis JACS, 2004, 8876
R = Me, n-Bu 12
 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 6. Metallophosphites as Umpolung Catalyst: The Enantioselective

Cross Silyl Benzoin Reaction

Ar Ar

O O
Me
O
P Ar = 2-FPh
H
Me O O
O
O O (5-20mol%)
Ar Ar
R2
R1
R1 SiEt3 H R2 n-BuLi (5-20mol%)
THF, 0.5h.
OSiEt3
65-88%
41-91% ee

Johnson JACS 2004, 3070

13
 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 7a. Anions of 1,3-Dithianes (Corey-Seebach reaction)

O
O Cleavage
S S BuLi S S E+ S S
HS SH
R E
Lewis Acid (cat.) THF, -30°C R Li
R H R H R E

Acyl Anion equivalent

• Usually formed from corresponding aldehydes by thioacetalization

• R = primary, secondary and tertiary alkyl, allyl, benzyl, aryl, and O-containing groups
• Biggest drawback: removal of dithiane
1. HgCl2, H2SO4, H2O 2. NaIO4 or m-CPBA 3. MeX (X = I, OTs,…)

(a) Corey, Seebach ACIEE 1965 1075

(b) Corey, Seebach ACIEE 1965 1077 14
 Carbonyl Umpolung
Masked Acyl Anion Equivalents

 7b. Anions of 1,3-Dithianes (Corey-Seebach reaction)

15
 Carbonyl Umpolung
Unmasked Acyl Anion Equivalents
 Zirconium mediated or catalysed Umpolung reactions
O
Cl

[Cp2ZrHCl] CO
ZrCp2
R R ZrCp2
R

Cl

Acyl anion equivalent

(Acyzirconocene chloride)

R'CHO R''X
Lewis acid PdCl2(PPh3)2
R' = alkyl, alkenyl R''X = phenyl, benzyl, allyl halides,
acid chlorides, allyl acetates

O
O

R'
R
(a) Hanzawa ACIEE 1998, 1696 R R''

(a) Hanzawa TL 1998, 6249 OH

-ketol ketone or -diketone
(a) Guan Curr. Org. Chem. 2008, 1406 16
 Carbonyl Umpolung
Unmasked Acyl Anion Equivalents
 Zirconium mediated or catalysed Umpolung reactions
O R4 R1

R ZrCp2Cl R3 O

R2

Pd(OAc)2 (5mol%) Pd(OAc)2 (10mol%)

monophosphine (10mol%) BF3.OEt2 (1eq)
toluene Et2O-THF

R4 R1 R1
R3 R4

O R
R3 O
OH
(a) Hanzawa TL 1998, 8141 R2 R O R2

(b) Hanzawa ACIEE, 1999, 2395 1,2-addition 1,4-addition (generation of 1,4-dicarbonyls)

(c) Hanzawa T 2002, 8141 17
 Carbonyl Umpolung
Acyl Anion Equivalents
 A Summary (Acyl anions are the most sought umpolung reagents)
Masked Acyl Anion Equivalents

 1,3-Dithianes (stoichiometric synthesis, pre-functionalization)

 Cyanohydrin derivatives (stoichiometric synthesis, pre-functionalization)
 Isonitriles, Nitronates anions, t-Butyl hydrazones, Vinyl thioether anions,…
 Metal cyanides (catalytic formation, direct)
 Nucleophilic carbenes (catalytic formation, direct)
 Metallophosphites (catalytic formation, direct)

Unmasked Acyl Anion Equivalents

 Acylzirconocene chloride
18
 Carbonyl Umpolung
-Electrophile Equivalents

 1. -Halo Carbonyl Substitution

O O
-halogenation of ketones
R + Nu R
or R' R'
X = Cl, Br or I
Hell-Volhardt-Zelinski reaction X - Nu

-Electrophile equivalent

O CO2Et

1. CH3COCH2Cl NaCH(CO2Et)2 CO2Et

Na2CO3
2. 2 BrCH(CO2Et)2 (EtO2C)2C=C(CO2Et)2

19
 Carbonyl Umpolung
-Electrophile Equivalents
 2. Anodic Oxidation of Silyl Enol Ethers
Anodic oxidative cyclization

O
OTBS
H
RVC anode
carbon cathode
0.4 M LiClO4

MeOH/CH2Cl2 (1:4)
TBSO
TBSO 2,6-lutidine, RT O
O 15-20mA, 2,2F/mole

MeO
OSiR3
OSiR3 porous C anode
15-20 mA
R2
R1
. R2
TsOH, RT

R1 O
CH2Cl2/CH3OH
0.4M LiClO4 O
very reactive H

O
OH

TBSO
O
O

Allicacol A
Moller JACS 2003, 36

20
 Carbonyl Umpolung
Homoenolate Equivalents

 1. The Tautomerism Problem

• Enolates
M

O
O • tautomerism is generally not a problem
because oxyanionic tautomer still acts as
M carbon nucleophile

• Homoenolates

O
M • tautomerism is a much larger problem
O M because it is often irreversible and
oxyanioic tautomer rarely acts as a
carbon nucleophile

21
 Carbonyl Umpolung
Homoenolate Equivalents

 2. The Acetal Approach

M
Br R
M 1. RX

O O O O 2. H3O+
O

Homoenolate equivalent

Synthesis of enantiopure 4-substituted quinolizidines

Ph
O Ph
OH
(CH2)3MgBr
O H2, Pd/C
N CH3 O N CH3
O aq. HCl N CH3

69% 66% H
O

Bosch JOC 2003, 1919

22
 Carbonyl Umpolung
Homoenolate Equivalents

 3. Silyl Enol Ethers of Ketones

O OM OSiR3 M OSiR3

M R''X
R' SiR3 R' R' R' R''
M = Li or MgBr R3Si
Homoenolate equivalent

Kuwajima Chem. Comm. 1979, 708

Synthesis of ()-δ-Araneosene

MeOO2C

Br Br O

OTBS 4 steps
O MeOO2C
Li

TBS THF, -78°C, 2h TAS-F, THF-DMF

82% -35°C to 0°C, 3h
90%

Corey Org. Lett. 2002, 2441

23
 Carbonyl Umpolung
Homoenolate Equivalents
 4a. Cyclopropane Ring Opening : Titanium Homoenolates
Homoaldols Reactions of Titanium Homoenolates

RO OTMS OR TiCl4
RO OTMS
TiCl4 TiCl3

CH2Cl2 Cl TMSO

R = Et, Me, iPr

- TMSCl

O
O
O TiCl3
R'COR''
or/and R'
O
RO
RO
R''
R' OH
R''
Homoenolate equivalent
-hydroxyesters
lactones (a) Nakamura, Kuwajima JACS 1977, 7360
24
(b) Nakamura, Kuwajima JACS 1986, 3745
 Carbonyl Umpolung
Homoenolate Equivalents

 4b. Zinc Homoenolates: Preparation

• Cyclopropane Ring Opening
O OR

OTMS

2 ZnCl2
2 TMSCl
Et2O O Zn OEt2
OR

RO

Nakamura, Organometallics, 1985, 641

• Direct Oxidative Addition

O I O ZnI
Zn-Cu

Benzene/DMA
EtO 60°C, 3-4h EtO

Yoshida, TL, 1985, 5559

25
 Carbonyl Umpolung
Homoenolate Equivalents

 4b. Zinc Homoenolates: Reactivity

• Copper-Catalyzed Conjugate Additions

O OR

O
O
OTMS
2 TMSCl RO
O Zn OEt2
Cu(I), HMPA, THF

RO
Kuwajima JACS 1984, 3368

• Catalytic Homo-Reformatsky Reactions

O

OTMS cat. ZnX2 R

1.2 eq RCHO
EtO
OEt CH2Cl2, RT
OTMS
Nakamura, Kuwajima JACS 1987, 8056 26
 Carbonyl Umpolung
Homoenolate Equivalents

 4b. Zinc Homoenolates: Reactivity

• Palladium Coupling Reactions

OR1
O
0.5 eq O
O Zn O 5mol% PdCl2(PPh3)2 R2
R1O
R2 Cl Et2O, RT
R1O O

Nakamura JOC, 1987, 8056

27
 Thank you
for
your attention

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