1

The Morita-Baylis-Hillman Reaction

Stephen Goble

Organic Super-Group Meeting Literature Presentation

November 19, 2003

Leading References: Drewes, S. E. et. al. 1988. Tetrahedron. 4653-4670.Basavaiah, D. et. al. 1996. Tetrahedron. 8001-8062.Langer, P. 2000. Angew. Chem. Int. Ed. 39(17) 3049-3052.

2

ContentsI Introduction

II Scope & Limitations

III Asymmetric Morita-Baylis-Hillman Reactions

IV Recent Applications

V Problem Set

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• Morita, K., Suzuki, Z., and H. Hirose. 1968. Bull. Chem. Soc. Jpn. 41, 2815.

• Proposed Mechanism:

• Low Conversions (<23%); Negligible Utility.

• With PPh3 (1 Eq), the Wittig product predominates.

Introduction: Morita - First Nucleophilic Triggered Acrylic α-Substitution

CN CN

P+

Cy

CyCy

-

PCy3

R

HO CNR

O

PCy

CyCy

HCN

R

OH

CN PCy3 (cat)

R H

O+ CN

R

OH

120 C 2 h

4

Introduction: Baylis & Hillman Patents

German Patent DE-B 2,155,113 (1972) & US Patent 3,743,669 (1973) – To M. E. Hillman and A. B. Baylis (Celanese Corporation – North Plainfield, NJ)

Claims: Method for the preparation of acrylic compounds from the reaction between α,β-unsaturated carboxylic acid derivatives and aldehydes in the presence of a sterically unhindered tertiary amine catalyst.

• High Conversions & Yields

• Versatile: Broad substrate/catalyst tolerance; Broad Temperature Range (0-200 C), but very slow at RT (days).

• No Journal Publications; First Prominent Journal Citation Appeared in 1982

O

R2H

OH

HR2+

3o amine

O

R1 R1

O

5

Introduction: Morita-Baylis-Hillman ReactionGeneral Form:

3 Essential components: An activated alkene, an electrophileand a nucleophilic trigger (catalyst)

Most effective catalysts are nucleophilic un-hindered tertiary amine such as DABCO, Pyrrocoline, and Quinuclidine

NN

NN

EWG+

X

R2R1

EWGX

R2

R1Catalyst

• C-C Bond forming reaction w/ mild conditions.

• Wide range of substrates (electrophiles and alkenes).

• Atom economical.

• Synthetically useful products.

Some Advantages to the MBH:

6

Introduction: Mechanism

NN N

N+

R

O

R

O-

O

R' H

NN+

R

OO-

H

Michael Addition"Nucleophilic Trigger" Aldol Condensation

R

OOH

HHR' R'

Proton Transfer-Elimination

RDS

Mechanism consists of 3 Steps:

1. Michael addition of the nucleophilic trigger catalyst to the activated alkene.

2. Quenching the Zwitterionic adduct with an electrophile.

3. Proton transfer and elimination of the catalyst.

**Since the electrophilic quench is RDS, rate enhancement can beachieved by stabilizing the Zwitterion or by activating the aldehyde

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Scope & Limitations: The Alkene• MBH reaction tolerates a wide range of activated alkenes:

Reaction with aldehydes at atmospheric pressure with DABCO catalyst:

X

X = COR1 X = CO2R1

X = CN

X = SO2R1

X = SO3R1

X = PO(OR1)2

X =EWG

X = CHO

OH

R

SOH

R

CNOH

R

OH

ROH

R

POH

R

EWGOH

RO

H

O

OOR1

SOH

R

O

OR1

O

OR1

O

R1

O

OR1OR1

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Scope & Limitations: The Alkene

O

R2H

OH

HR2+

O

R1 R1

O

R3 R3

~10k Bar

DABCO

O

OCH2OH8

O

OCH2OH8

DABCO

6 days

OH

O

OCH3

8O

OCH38

DABCO

12 days

OH

• Sterics: Hindered β-substituted derivatives require higher pressures: (Hill, J. S. and N. S. Isaacs. 1988. J. Chem. Res. 330):

• Hydrogen bonding groups increase reaction rates (Ameer, F. et. al. 1988. Synth. Comm. 18, 495; Drewes, S. E. et. al. 1988. Synth. Comm. 18, 1565):

• Example:

• Explanation: Stabilization of the adduct (i) and/or activation of the aldehyde.

O

O

N+

OH

n(i)

O

O-

N+ (ii)OR

H OH

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Scope & Limitations: The Electrophile• Most common electrophiles for atmospheric pressure reactions:

• Aldehydes, α-keto-esters, fluorinated ketones, aldimines.

• Ketones are inert at atmospheric pressure. High pressures are required (Hill, J. S. and N. S. Isaacs. 1986. Tetrahedron Lett. 27 (41) 5007-5010).

• In the absence of a good electrophile the alkene can dimerize (Basavaiah, D. et. al. 1987. Tetrahedron Lett. 28, 4591):

• 1,4-Addition electrophiles (Hwu, J. R. et. al. 1992. Tetrahedron Lett. 33, 6469):

O

RR

OR

O

2 R = alkyl, aryl

ODBU

DMI185 C

EWG+

OEWG

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Scope & Limitations: The Catalyst• Un-hindered – nucleophilic catalysts are preferred.

• Basicity of the Catalyst: Reaction rates generally increase with increased basicity (Hine, J. and Y. J. Chen. 1987. J. Org. Chem. 52. 2091-2094)

• Hydrogen bonding catalysts increase reaction rates:

3-quinuclidinole stabilizes the Zwitterionic intermediate by H-bonding (Drewes, S. E. et. al. 1988. Synth Comm. 18, 1565-1568)

• Lanthanide lewis acid triflates (i.e. La(OTf)3) accelerate the reaction up to 5-fold (Aggarwal, V. K. et. al. 1998. J. Org. Chem. 63, 7183-7189) – also stabilizes zwitterion and/or activates aldehyde.

• DBU was recently found to be a superior catalyst (10-fold rate enhancement observed vs. 3-QDL) (Aggarwal, V. K. et. al. 1999. Chem. Comm.2311-2312). – hindered and non-nucleophilic.

Stabilization of Zwitterion

NOH

NO

3-QuinuclidineOMe

O-H

NN+

OMe

O-

N+N

OMe

O-

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Scope & Limitations: Reaction Conditions• Reaction Pressure: (Hill, J. S. and N. S. Isaacs. 1986. Tetrahedron Lett. 27 (41) 5007-5010)

• High pressures Increase rates of reaction (volume of activation = -70 cm3/mol).

• Making a wider variety of substrates available (β-substituted and electron poor alkenes; ketones as electrophiles).

• The reaction gives better yields with less reactive catalysts (triethylamine over DABCO) at high pressures.

• Solvent effects:

• Hydrogen bonding increases the rate of the reaction (Ameer, F. et. al. 1988. Synth. Comm. 18, 495).

• Significant rate enhancements seen with methanol and water as additives or solvents (Auge, J. et. al. 1994. Tetrahedron Lett. 35(43) 7947-7948).

• Temperature – highly substrate dependent. Microwave utilization can shorten times from days to minutes (Kundu, M.K. et. al. 1994. Synlett. 444)

CNOH

5 days

1 atm O+ DABCO +

CN 5 kbar

5 min

CNOH

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Intramolecular Morita-Baylis-Hillman

• Activated alkene and electrophile in the same molecule:

• Few amine catalyzed examples (Drewes, S. E. et. al. 1993. Synth. Comm. 23, 2807):

• Phosphine catalysis gives the desired MBH product (Roth, F. et. al. 1992. Tetrahedron Lett. 33, 1045):

O O O O

DABCO

DCM

O OH

O O

OH

minor

O O

N+

N

Cl-

majornone

+ +

O O

OEt PBu3OH

OEt

O

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Intramolecular Morita-Baylis-Hillman

• Secondary Amines Catalyze Intramolecular MBH (Black, G. P. et. al. 1997. Tetrahedron Lett. 38(49) 8561-8564):

OO

Ph Ph

O OH

Ph

O OH

N

1,4 addition

and aldol

elimination

addition

• Conditions: catalyst (30%), CDCl3, 7 days

• Catalysts: Various cyclic secondary amines including piperidine, piperazine, pyrrolydine.

• Best conversion and yields with piperidine (93% (55%))

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E/Z Selectivity in the Baylis-Hillman

• When the alkene is β-substituted the product is a mixture of E/Z isomers:

• Because the first step is reversible, the SM will be equilibrated prior to the reaction:

• Solvent Effects vs. Pressure:• E/Z ratio (RT/1 atm)(crotonaldehyde/benzaldehyde/DABCO):

neat = 1; THF = 1.3; CHCl3 = 1.5; MeCN = 3; MeOH = 4• Higher pressures enhance this ratio dramatically for less polar solvents, and neat reactions (p = 15 kbar)

neat = 13; THF = 12; CHCl3 = 25; MeCN = 7; MeOH = 4

CNCNH

HN+

N

HH

CNN+

N

CN

Rozendaal, E. Van et. al. 1993. Tetrahedron. 49(31) 6931-6936.

• Catalyst Effects:

• Decreased basicity of the base leads to increased E/Z ratios:

triethylamine = 4; quinuclidine = 2; DABCO = 1

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Proposed Explanation of pressure effects (MM2):

Rozendaal, E. Van et. al. 1993. Tetrahedron.49(31) 6931-6936.

6 and 7 have similar energies – should generate equal amounts of 8and 9

10 is ~4 kcal lower in E than 11

E1cB mechanism is favored by high pressures

Protic solvents would suppress the proton shift from 8/9 to 10/11 by competition

CNH

HN+

N

HH

CNN+

N

rotation

CNH

HN+

N

HH

CNN+

N

PhCHO PhCHO

CH(O-)Ph CH(O-)Ph

CH(O-)PhH

CNN+

N

H CNH

CH(O-)PhN+

N

H

rotationrotation

NR3

E2

NR3

E2

CN

CH(OH)PhH

H3CCH(OH)Ph

CNH

H3C

E1cB E1cB

6 7

8 9

89

CHC(OH)PhH

HN+

N10

CHC(OH)PhH

HN+

N11

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Asymmetric Morita-Baylis-Hillman Reactions

• Chiral Auxiliaries on the acrylate at atmospheric pressure:

• Menthyl acrylates: poor d.e. at 1 atm (Brown, J. M. et. al. 1986. Tetrahedron Lett. 27(28) 3307-3310):

• Oppolzer’s Auxiliary: up to 70% d.e. at 1 atm (Basavaiah, D. et. al. 1990. Tetrahedron Lett. 31(11) 1621-1624):

O

O

+ H

O

O

O OHDABCO

20 C 7 d*

58:42 diasteromer mix

H

O DABCO

20 C 7 dO

SO2NCy2O

+ O

SO2NCy2O OH

*

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• Chiral Auxiliaries on the acrylate at elevated and lowered pressures (Gilbert, A. et. al. 1991. Tetrahedron: Asymmetry. 2(10) 969-972)

Asymmetric Morita-Baylis-Hillman Reactions

• Using (-) menthyl and (-) bornyl chiral auxiliaries were employed to give elevated d.e. in most cases.

• Highly substrate dependent

• Leahy’s Sultame improvement (Brzezinski, L. J. et. al. 1997. J. Am. Chem. Soc. 119, 4317-4318):

• ~15 equivalents of aldehyde

• α-branched aldehydes give poor yields

N

SO O

O

RCHO, DABCO

DCM 0 CO

O

O

R R

R = alkyl, aryl

O

O

O

MeOH, CSA

(85%)MeO2C

OH

Rh(I) H2

(85%)MeO2C

OH

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Asymmetric Morita-Baylis-Hillman Reactions

Explanation of diastereoselectivity:

Preferential re (α) face addition to the favored rotamer (9) accounts for the selectivity – si (β) face is blocked by the sulfonyl oxygens.

N

SO O

O

R

DABCON

SO O

O-

N+R3

N

SO O

O-

+R3N

RCHO

RCHO

RCHO RCHO

addition to

re-face

H

H

OR

O- N+R3

XcNXcN R

O-O

NR3

XcN

O

O

-O R

R

N+R3 O

O

O R

N+R3

R

O

O

O RR

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Asymmetric Morita-Baylis-Hillman Reactions• Chiral Electrophiles:

• Initial Attempts (Drewes, S. E. et. al. 1988. Synth Comm. 18, 1565-1568):

• Increased pressures has shown no improvement in d.e. (Gilbert, A. et. al. 1991. Tetrahedron: Asymmetry. 2(10) 969-972)

• Better results have been seen with chiral amino aldehydes (Manickum, T. et. al. 1993. Synth. Comm. 23, 183):

Up to 76% d.e. observed

CHO

OCH2OMe+

O

RDABCO

or 3-HQ

R

O

MeOCH2O

OH

R

O

MeOCH2O

OH+

70 30:

CHO

NR2+

O

MeODABCO

or 3-HQ

OMe

O

R2N

OH

OMe

O

R2N

OH+

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• Chiral Electrophiles (con’t):

• Chromium tricarbonyl complexes (Kundig, E. P. et. al. 1993. Tetrahedron Lett. 34, 7049):

Asymmetric Morita-Baylis-Hillman Reactions

>99% e.e. after decomplexation

+EWGO

HR

Cr(CO)3

DABCO

Cr(CO)3

R

EWG

HOH

>95% d.e.

+CNH

RCr(CO)3

DABCO

Cr(CO)3

R

NC

NHTsH

>95% d.e.

NTs

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Asymmetric Morita-Baylis-Hillman Reactions• Chiral Catalysts:

• Early Attempts (Basavaiah, D. et. al. 1996. Tetrahedron. 8001-8062):

• C-2 symmetric DABCO derivatives (Oishi, T. et. al. 1992. Tetrahedron Lett. 33, 639):

Quinidine =

N

O

O

N

H

H

O

H+

CN Quinidine CNOH

20% ee

O2N

CHOO

+

O2N

OOH*

up to 47% ee

Catalyst

THF, 5 K Bar

Catalysts:NN

RO

RO

NN

Ph

PhNN

PhPh

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Asymmetric Morita-Baylis-Hillman Reactions• Improved Chiral Catalysts (Barrett, A. G. M. et. al. 1998. Chem. Commun.2533-2534):

• 30-75% e.e. with a variety of substrates

• Explanation:

Less sterically hindered!

O2N

CHOO

+

O2N

OOH

10 mol%

N

HO

O2N

N+ OHM

O-

H

R O

vs N+ OHM

O-

O

R H

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Asymmetric Morita-Baylis-Hillman Reactions• Cinchona alkaloid catalysts (Iywabuchi, Y. 1999. J. Am. Chem. Soc. 121, 10219-10220):

• Highly reactive alkene makes the reaction possible at -55 ºC.

• 90-99% e.e. with variety of electrophiles (including α-branched)

major minor

N

OH

N

OH

+

O

O CF3

CF3

N

OH

N

OH

O-

OR'

RCHO RCHO

N

O

N+

OH

O

OR'

OH

HR

N

O

N+

OH

O

OR'

OH

HR

R

O

OCH(CF3)2

OH

R

O

OCH(CF3)2

OH

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Recent Applications of the Morita-Baylis-Hillman Reaction

• Asymmetric MBH Catalyzed by Chiral Brønsted Acids: (McDougal, N. T. and S. E. Schaus. 2003. J. Am. Chem. Soc. 125, 12094-12095)

X

OHOH

X

X = H, Br, Ph,

H3C

CH3

H3C

CH3

CH3 CF3

CF3

, ,

R

O

H+

O10% cat

Et3PTHF-10 C

R

OOH

80-96% ee on a variety of aldehydes

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Recent Applications of the MBH Reaction

• Phosphine Catalyzed β-Hydration Reactions (Stewart, I. C., R. G. Bergman, and F. D. Toste. 2003. J. Am. Chem. Soc. 125. 8696-8697)

R1

EWG5% PMe3

ROH R1

EWG

OR

EWG = CO2Et, COMe, CO2Me, CNR1 = Me, H. Does not work with PhROH = H2O, MeOH, iPrOH, PhOH

O

R3+P

O-

PR3

RO-H

RO-

R3+P

O

+

O

R3+P

O

RO

O-RO-H

O

RO

Proposed Mechanism:

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Recent Applications of the MBH Reaction• Intramolecular MBH with high Regioselectivity (Frank, S., Megott, D. and W. Roush. 2002. J. Am. Chem. Soc. 124(11) 2404-2405):

CORCOR' catalyst

CORCOR'

1-2 1-2

• Catalysts: PMe3, PBu3

• Solvent: MeCN, tert-amyl alcohol

• Regioselectivity: Cyclization occurs almost exclusively from the ketone/aldehyde (R = alkyl, H) to the ester (R’ = O-alkyl).

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Recent Applications of the MBH Reaction• Intramolecular Cycloisomerization of Bis-enones (Wang, L.., Luis, A., Agapiou, K., Jang, H. and M. J. Krische. 2002. J. Am. Chem. Soc. 124(11) 2402-2403):

• Wide range of 5 and 6 membered ring substrates with yields of 70-90%.

• Polar solvents accelerate rates but increase oligomerization.

• For mono-enone/mono-enoate compounds a single product is obtained.

• Electronic > Steric for selectivity.

H3C

O O

OEtOBn

OBn OBn

cat. Bu3P

22 examples

OBn

OBn

OBn

OEt

O

O

O R2O

R1

nBu3P

O R2O-

R1

n

O R2O

R1

n

Bu3+P

-O R2O

R1

nBu3+P

28

Problem Set

Problem 1: Michael Krische recently published a paper on the transformation below. A) Propose a mechanism for this reaction. B) Suggest a reason why the yields are lower when the carbonate (92%) is replaced with an acetate (67%).

Bradley G. Jellerichs, Jong-Rock Kong, and Michael J. Krische. J. Am. Chem. Soc. 2003. 125. 7758-7759.

OCO2CH3O

RBu3P (100 mol%)

(Ph3P)4Pd (1 mol%)tBuOH (0.1 M), 60 C

O

R

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Krische’s Proposal: Concomitant activation of latent nucleophilic and electrophilic partners.

OCO2CH3O

RBu3P (100 mol%)

(Ph3P)4Pd (1 mol%)tBuOH (0.1 M), 60 C

O

R

Bu3PLnPd

CO2-OCH3

-OCH3

Bu3PLnPdHOCH3

O

R[Pd]

Bu3+P Bu3

+P

R

O[Pd]

Bradley G. Jellerichs, Jong-Rock Kong, and Michael J. Krische. J. Am. Chem. Soc. 2003. 125. 7758-7759.

30

Problem Set

Problem 2: Kwon recently published a novel and efficient method for the synthesis of functionalized tetrahydropyridines. Provide a rational mechanism for this transformation.

Xue-Feng Zhu, Jie Lan, and Ohyun Kwon. J. Am. Chem. Soc. 2003. 125. 4716-4717.

NTs

+ CO2Et20 mol% PBu3

DCM, RT

N [Ar, H]

CO2Et

Ts[Ar, H]

31

Kwon suggests the following…

CO2Et

H

PBu3

P+Bu3

CO2EtP+Bu3

CO2Et

NTs

N

CO2Et

Ts

P+Bu3

N

CO2Et

Ts

P+Bu3

N H

CO2Et

Ts

Xue-Feng Zhu, Jie Lan, and Ohyun Kwon. J. Am. Chem. Soc. 2003. 125. 4716-4717.

32

Problem Set

Problem 3: Earlier this year, Krische published a diastereoselective synthesis of diquinanes from acyclic precursors that is catalyzed by tributylphosphine. Once again, propose a catalytic cycle.

Jian-Cheng Wang, Sze-Sze Ng, and Michael J. Krische. J. Am. Chem. Soc. 2003. 125. 3682-3683.

X

O R2O

R1 Bu3P (10 mol%)

heat

H

H

R1

O OR2

33

Proposed Catalytic Cycle:

X

O R2O

R1 Bu3P (10 mol%)

heat

H

H

R1

O OR2

Bu3PBu3P

X

O R2

O

R1

Bu3+P

X

R2

O

R1

Bu3+P

[3+2]H

H

R1

O OR2

Bu3+P

Jian-Cheng Wang, Sze-Sze Ng, and Michael J. Krische. J. Am. Chem. Soc. 2003. 125. 3682-3683.