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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.
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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
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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:
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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
12
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%))
14
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
15
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
16
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
*
17
• 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
18
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
19
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+
20
• 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
21
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
22
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
23
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
24
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
25
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:
26
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).
27
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
29
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.