Umpolung reactivity

Special Topic 27/02/09 Anne Fournier

The synthetic problem

Heteroatoms impose an alternating acceptor and donor reactivity pattern
d0 X a1 d2
3

X = halogen, O, N

d = donor (-)
a d4 a
5

a = acceptor (+)

An odd number of carbons between functional groups

X a1 d2 X a1 d2 a3 a1 d4 d2
X

1,3-disubstitution
a1 a3 d2 d4

An even number of carbons between functional groups

X

X d
4

a3 d4 d2

a1

a1 d2

a3

d2

a1

a3

a1

d4
X
X

d2

a3 d4

1,2-disubstitution

d a d4
3

a d2

a d2

a3

a1

a
X

a1 d2

1,4-disubstitution

Definition
Umpolung is any process by which donor and acceptor reactivity of an atom are interchanged (reversal in polarity).
d0 X a
1

a0 X

Umpolung
a d
2 3

a5

d1 a2

d3

d5 a4

usual reactivity: C2n= donor, C2n+1= acceptor

Umpolung reactivity: 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. 3

Seebach ACIEE 1979, 239

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

"usual" reaction polarity

umpolung reaction polarity

O acyl bonding
acyl transfer reaction Friedel-Craft reaction

Nu

O E R R' alpha bonding

enolate anion alkylation aldol and Claisen reactions

O Nu R R'

R' beta bonding

conjugate additions Michael reactions

R'

Nu

Carbonyl Umpolung
Carbonyl Umpolung intermediates
O _ _ R + + R' Application Strategy carbonyls vs. acyl anions enolates vs. a-electrophiles Michael acceptors vs. homoenolates

umpolung reaction polarity

O R

..

_ acyl anion

d1 synthon O Nu R R' R + a2 synthon -electrophile O

R'

.. homoenolate
R E R d3 synthon

Carbonyl Umpolung
Masked Acyl Anion Equivalents

1a. Benzoin Condensation: Cyanide ion Catalyzed Addition

O

_ CN
Ar H

OH

..

_
CN

Ar

Nucleophilic attack of cyanide

Deprotonation (umpolung)

Ar

..

CN

cyanohydrin
O

Acyl anion equivalent

a1 d1
Ar OH

Ar

Must use aromatic or heteroaromatic aldehydes; aliphatic aldehydes tend to undergo an aldol condensation Cannot selectivity cross couple of two different aldehydes
OH

Ar

Addition of aldehyde

O Ar

O R Ar OH

Ar Ar NC O

1,2-substitution

Ar

Benzoin

Regeneration of catalyst _ _ CN

NC OH

Proton transfer

..

Lapworth JACS 1903, 995.

Carbonyl Umpolung
Masked Acyl Anion Equivalents

1b. Cyanide ion Catalyzed Cross Silyl-Benzoin Reaction

O O O O R2 R1 R1 OSiR3 OH R1

M-CN
R1 SiR3 R2 H

18-Crown-6 Not observed

Only product
O OSiR3

[1,2]-Brook
CN

R3Si R1

Rearrangement

R1

.. _

CN

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

Carbonyl Umpolung
Masked Acyl Anion Equivalents

2. N-Heterocyclic Carbenes Catalyzed Acyloin Formation

O R1 R2 R2 N R H N R1 O R2 R1 R1

R1 R2 N H R3 S

..

Base -H
R3

umpolung

OH

R2

OH

..

..

R3

R3

R3

Breslow intermediate Acyl anion equivalent

thiazolium salts

ylides or nucleophilic carbenes

O R2 R4 R N

R1 O R2 N

R1 OH

R OH acyloin R3 S R4 OH R3 S R4

R O R4

Effective for aliphatic and (hetero)aromatic aldehydes Applicable to acylsilanes

(a) Breslow JACS 1958,3719. (b) Enders Acc. Chem. Res. 2004, 534.

Carbonyl Umpolung
Masked Acyl Anion Equivalents

3. Recent Progress in Asymmetric Benzoin Reactions

O O

cat. (10mol%) KOtBu (10mol%)

Ar H Ar

Ar

8-83%
OH

ee = 80-95%
Ph N O
cat.

N N tBu

Ar = Ph, m-Me-Ph, p-Me-Ph, p-MeO-Ph, m-Cl-Ph, p-F-Ph, p-Cl-Ph, p-Br-Ph, o-Furyl, o-Naphtyl

Triazolium salt

Enders ACIEE, 2002, 1743

Carbonyl Umpolung
Masked Acyl Anion Equivalents

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

General reaction

O R3 R1 X R2

R4 R5

R4 R5

Nuc. cat. polar solvent

R1 R2 R3 O

1,4-disubstitution

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

O R4 R2 R5

d1
R1

R3

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

O O OMe

Aromatic substrates

5
H R1 X CO2R2

cat. (20mol%), KHMDS (20mol%) xylenes, rt, 24h. 63-95%

6
R
1

CO2R2 N N N BF4

7 8
X

ee = 82-97% R1 = 6-Me, 8-Me, 8-MeO R2 = Me, Et X = O, S, NMe, CH2

O cat.

Aliphatic substrates
O CO2Et O

cat. (20mol%), KHMDS (20mol%) xylenes, 25C, 24h. 81% ee = 95%

CO2Et Bn cat. N

N N

BF4
Ph

Enantioselective intramolecular Stetter reaction

Rovis JACS, 2002, 10298

11

Carbonyl Umpolung
Masked Acyl Anion Equivalents

5b. Quaternary Stereocenters via Asymmetric Stetter

Aromatic substrates
O O EWG

cat. (20mol%), Et3N (2eq.) PhMe, 25C, 24h.

R X EWG

55-96%

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

O O

F F N N N

F F F BF4

Aliphatic substrates
O

cat.
R EWG

cat. (20mol%), KHMDS PhMe, 25C, 24h. 63-90% ee = 84-99% R = Me, n-Bu
R EWG

Rovis JACS, 2004, 8876

12

Carbonyl Umpolung
Masked Acyl Anion Equivalents

6. Metallophosphites as Umpolung Catalyst: The Enantioselective Cross Silyl Benzoin Reaction

Ar Me O Ar O O P Me O O Ar H R2 Ar R1 OSiEt3 O H O O

Ar = 2-FPh

(5-20mol%)
R2

R1

SiEt3

n-BuLi (5-20mol%) THF, 0.5h. 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 HS R H SH

BuLi THF, -30C

E+

Cleavage
R E

Lewis Acid (cat.)

Li

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

Cl O

[Cp2ZrHCl]
R R

ZrCp2

CO
R ZrCp2 Cl

Acyl anion equivalent (Acyzirconocene chloride)

R'CHO Lewis acid R' = alkyl, alkenyl

O R'

R''X PdCl2(PPh3)2 R''X = phenyl, benzyl, allyl halides, acid chlorides, allyl acetates
O

(a) Hanzawa ACIEE 1998, 1696 (a) Hanzawa TL 1998, 6249 (a) Guan Curr. Org. Chem. 2008, 1406

R''

-ketol

OH

ketone or -diketone

16

Carbonyl Umpolung
Unmasked Acyl Anion Equivalents

Zirconium mediated or catalysed Umpolung reactions

O R4 R1

ZrCp2Cl

R3 R2

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

Pd(OAc)2 (10mol%) BF3.OEt2 (1eq) Et2O-THF

R4

R1 R3 O R

R4

R1

R3 OH

O R2 R O R2

(a) Hanzawa TL 1998, 8141 (b) Hanzawa ACIEE, 1999, 2395 (c) Hanzawa T 2002, 8141

1,2-addition

1,4-addition (generation of 1,4-dicarbonyls)

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 or Hell-Volhardt-Zelinski reaction

+
R' X -

Nu X = Cl, Br or I

R R' Nu

-Electrophile equivalent
O CO2Et

1. CH3COCH2Cl

NaCH(CO2Et)2

CO2Et

2.

2 BrCH(CO2Et)2

Na2CO3

(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) 2,6-lutidine, RT 15-20mA, 2,2F/mole
TBSO O

TBSO O

OSiR3 R2 R1

porous C anode 15-20 mA

R1

OSiR3

MeO

R2
O

TsOH, RT

CH2Cl2/CH3OH 0.4M LiClO4

very reactive
O

O H

OH TBSO O

Allicacol A

Moller JACS 2003, 36

20

Carbonyl Umpolung
Homoenolate Equivalents

1. The Tautomerism Problem

Enolates
M O M O

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

Homoenolates
O M O M

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

21

Carbonyl Umpolung
Homoenolate Equivalents

2. The Acetal Approach

Br O O M

M
O O

1. RX 2. H3O+

Homoenolate equivalent

Synthesis of enantiopure 4-substituted quinolizidines

Ph O (CH2)3MgBr O N CH3 O
O N Ph OH CH3

H2, Pd/C aq. HCl 66%

H

CH3

69%
O

Bosch JOC 2003, 1919

22

Carbonyl Umpolung
Homoenolate Equivalents

3. Silyl Enol Ethers of Ketones

OM M OSiR3 M OSiR3

R''X
R' R3Si R' R' R''

R'

SiR3

M = Li or MgBr

Homoenolate equivalent
Kuwajima Chem. Comm. 1979, 708

Synthesis of ()--Araneosene
MeOO2C Br O OTBS Li Br MeOO2C O

4 steps

TBS

THF, -78C, 2h 82%

TAS-F, THF-DMF -35C to 0C, 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 RO OTMS OR TiCl4

TiCl4 CH2Cl2 R = Et, Me, iPr

TiCl3
Cl TMSO

- TMSCl
O O O

R'COR''
O

TiCl3

or/and
RO

R' R'' RO

R' R''

OH

-hydroxyesters

Homoenolate equivalent
(a) Nakamura, Kuwajima JACS 1977, 7360 (b) Nakamura, Kuwajima JACS 1986, 3745

lactones

24

Carbonyl Umpolung
Homoenolate Equivalents

4b. Zinc Homoenolates: Preparation

O OR

Cyclopropane Ring Opening

OTMS

2
OR

ZnCl2 Et2O
O Zn

2 TMSCl OEt2

RO

Nakamura, Organometallics, 1985, 641

Direct Oxidative Addition

O I

Zn-Cu Benzene/DMA 60C, 3-4h

EtO

ZnI

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
O Zn

RO

OEt2

Cu(I), HMPA, THF

RO

Kuwajima JACS 1984, 3368

Catalytic Homo-Reformatsky Reactions

O OTMS

1.2 eq
OEt

RCHO

cat. ZnX2 CH2Cl2, RT

EtO

OTMS
Nakamura, Kuwajima JACS 1987, 8056

26

Carbonyl Umpolung
Homoenolate Equivalents

4b. Zinc Homoenolates: Reactivity

Palladium Coupling Reactions

OR1

0.5 eq
O Zn O R2 R O
1

O O

5mol% PdCl2(PPh3)2
Cl

R2 R1O O
Nakamura JOC, 1987, 8056

Et2O, RT

27

Thank you for your attention

28