The document summarizes the Baylis-Hillman reaction, which is a carbon-carbon bond forming reaction between an activated alkene and an aldehyde or carbon electrophile catalyzed by a nucleophilic catalyst. The reaction produces densely functionalized products. Key advantages of the reaction include its atom economy, ability to generate chiral centers for asymmetric synthesis, and potential for further functionalization of products. Examples are given of the reaction being used in the synthesis of drugs such as pregabalin and sampatrilat. Mechanisms and strategies to improve the reaction are also discussed.
2. Introduction
Two most fundamental reactions in synthetic organic chemistry
functional group transformations
Carbon-carbon bond formation
Friedel-Crafts reaction
Grignard reaction
Diels-Alder reaction
Wittig reaction
Heck reaction
Suzuki coupling
Grubb’s RCM
Some C-C bond forming reactions are-
Morita-Baylis-Hillman Aldol reaction Reformatsky reaction Claisen
rearrangements
O
Aldol
1,2-Addition
1,4-addition
Baylis Hillman
Diels-Alder
Five possible ways of constructing C-C bonds with MVK
3
3. Baylis-Hilman reaction
It is a carbon-carbon bond forming reaction between the a-position
of an
activated alkene and an aldehyde or a carbon electrophile in
presence of a nucleophilic catalyst such as tertiary amine and
phosphine gives a densely functionalized product, if aldehyde as
the electrophile is used
functionalized allyl alcohol will the product.
This reaction is also known as the Morita-Baylis-Hillman reaction or
MBH.
DABCO (1,4-Diazabicyclo[2,2,2]octane) is one of the most frequently
used
tertiary amine catalyst for this reaction. In addition nucleophilic amines
such as DMAP (4-Dimethylamino pyridine) and DBU (1,8-Diazabicyclo
[5,4,0]undec-7-ene) as well as phosphines have been found to
successfully
catalyze this reaction.
4.
5.
6.
7. Advantages
1) It is an atom economic coupling reaction of easily prepared starting
material.
2) Reaction of a pro-chiral electrophile generates a chiral centre
therefore an asymmetric synthesis is possible.
3) Reaction products usually contain multiple functionalities in
proximity so that a varity of further transformations are possible.
4) It can employ a nucleophilic organocatalytic system without the use
of heavy metal under mild conditions.
8. Limitations
Because of there is a great extent of variability in reaction
substrates, it is
often challenging to develop reaction conditions suitable for certain
combination of substrates. The MBH reaction of an aryl vinyl ketone
with
an aldehyde is not straightforward, since the reactive aryl vinyl
ketones
readily adds first to another molecule of aryl vinyl ketone via Michael
addition, then the adduct adds to the aldehyde to form a double MBH
adduct.
9.
10.
11.
12.
13.
14. 28
Hill, J. S.; Isaacs, N. S.; J. Phys. Org. Chem. 1990, 3, 285
Hill and Isaacs Mechanism
Based on pressure dependence, rate, and kinetic isotope effect
(KIE) data.
ESMS and Tandem mass spectrometry.
No α-proton cleavage occurs in the rate-determining step (RDS).
Addition of the enolate to the aldehyde was the RDS.
Ph
R3N
OMe
O O
R3N
OMe
O
OMe
O
Ph OMe
OH O
NR3
Proposed RDS
Int 1
Int 2 Ph H
O
15. Robiette, R.; Aggarwal, V. K.; Harvey, J. N.; J. Am. Chem. Soc., 2007, 129, 15513
Mechanism of MBH reaction –
based on computational
method
O
OMe
Alcohol catalyzed TS 1
NMe3
O
OMe
O
Ph
O
H
OMe
Me3N
Int 2
O
3
Me N
Ph
O OMe
H
O
Ph
Hemi 1
O
OMe
Ph
Me3N
O H
O
Ph
RDS
TS3-hemi
O
Me N
Ph
O OMe
OH
Ph
3
Hemi 2
O O
Ph O
Ph
O
Ph
O OMe
OH
Ph
Hemi 3
Non-alcohol catalyzed
O
Ph
O
H
OMe
MeOH
Me3N
Int 2 -MeOH
TS 2-MeOH
Ph
O
Me3N
HOMe
Me N
COOMe
O
Ph
H
O
Me
H
3
TS3-MeOH
RDS
Ph O
OH OMe
HOMe
Me3N
Int-MeOH
OH OMe
O
Ph
29
PhCHO
PhCHO
Int.1
16. Hindered bases with high pKa
Higher the pKa of the conjugate acid of the amine higher the rate of reaction.
(leading to increased concentrations of the intermediate ammonium enolate)
e.g.; Quinuclidine (highest pKa), DBU.
Improvement of reaction rate
Important landmarks
Hydrogen-bonding additives or solvents
help the proton-transfer step.
e.g.; MeOH/t-BuOH/H2O
Lewis acids with alcohol-based ligands
The Lewis acid-alcohol complex results in increased acidity of the
OH groups, which promotes proton-transfer events.
30
17. 31
XH
Y
`R
R
*
Three functional groups
Via the functional group manipulation develop opportunities in organic synthesis
Chiral center
For asymmetric version offers
challenge to develop efficient catalyst
Intra-molecular version
Offers challenges to design and synthesize novel class of substrates with
several combinations of activated olefinic and electrophilic groups thereby
leading to develop various cyclic frameworks of synthetic importance
X= O, NR
Y= Electron withdrawing group
Offers challenge to develop
novel activated alkenes,
electrophiles
and catalyst
18. 32
Pfizer, Pregabalin, Drugs Future, 2002, 27, 426
Me
H
Me
O
NC
+
DBU, DBP Me
Me
NC
OH
Me
Me
NC
OAc
Py
OEt
NC
Me
O
Me
KOH
O K
NC
Me
O
Me
O t-BuNH3
NC
O
Me
Me
HCl
t-BuNH2
Pd(OAc)2
Ph3P
CO, EtOH
Chiral (R,R)-Rh catalyst
H2
Chiral (R,R)-Rh catalyst
H2
NC NC O K
O
Me
Me
O
Me
Me
O t-BuNH3
sponge Ni catalyst
KOH, H2
OH
H2N
Me
O
Me
Pregabalin (Lyrica)
Used in: Fibromyalagia
spinal cord injury
Neuropathic pain
Baylis Hillman reaction
AcCl,/ Ac2O
(S)-3-(aminomethyl)-5-methylhexanoic acid
Synthesis for Pregabalin
19. Dunn, et al; Organic Process Research & Development, 2003, 3
73
,244
Synthesis of Sampatrilat
CO2But
+
O 3-Quinuclidinol (0.25 eq)
H2O, CH3CN,
HO
CO2But
Cl 2
CO But
2
SOCl (0.88eq)
Et3N (1.02eq)
Py (0.1 eq)
Ph
Et3N, 81%
N Ph
H
(S,S)
(0.66 eq)
H H
(1.6eq)
2
N
Ph
ButO C
Ph
CO2H
(1.1 eq)
LDA (2.2 eq)
THF -30 to 20 OC
CO2H
N
Ph
Ph
ButO2C
de > 98%
NH
CO2H
OH
HO2C
HN
NHSO2Me
O
H2N
O
Sampatrilat
Baylis Hillman Reaction
Vasopeptidase inhibitor
Inhibits the angiotensin
converting enzyme (ACE)
20. O
H
O N CHO MeOOC
+
O
H OH
O N COOMe
DABCO
88%
O
H
O N COOMe
DEAD, Ph3P
AcOH, THF
77%
COOMe
OAc OAc
Dry HCl
Et2O
99%
H3N
Cl
O N
H
O
N
N Ph
COOH
O
DCC, HOBT, DMAP, CHCl3, 79%
O N
H
O
N
O
N PhO
N
H
OMe
O
OAc
Baylis Hillman Reaction
Potential Antimalarial Therapeutic Agents
The antimalarial efficacy of compound is comparable to that of chloroquine with
IC50 6-8ng/mL against D-6
34
Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A.J.; J. Med. Chem. 2002, 45, 3491
Synthesis of Novel Pyrimidinyl Peptidomimetics
21. N
O
R1HN CHO
N Ph
+
COOMe DABCO
N
O
R1HN
N Ph
OH
COOMe
Baylis Hillman reaction
DEAD, Ph3P
4-(NO2)PhCOOH or
PhCOOH or
CH3COOH
N
O
R1HN
N Ph
COOMe
OR2 R1 = PhCH2OCO, R2 = 4-(NO2)PhCO
R1 = PhCH2OCO, R2 = PhCO
R1 = PhCH2OCO, R2 = CH3CO
Anti-malarial compound
35
Zhu, S.; Hudson, T.H.; Kyle, D.E.; Lin, A. J. J. Med. Chem. 2002, 45, 3491
Antimalarial Therapeutic Agents
22. H3C
O O
H
+
OCH3
OCH3
DABCO, 7 days, rt
90%
O
HO
NBS, (CH3)2S,
OoC to rt, 24 h, 92%
O
OCH3
Br
COOH
LiAlH4, THF
OH
CH2OH
CH3I, acetone
reflux 6h
50%
CH2OH
OCH3
K2CO3, 95%
CHO
OCH3
PCC, CH2Cl2
1.5 h, rt,90%
H
H
O Sn, (CH3CH2)2O, HOAc,
O
p-(TsOH), C6H6, reflux
9h, 70%
OCH3
Baylis Hillman reaction
36
J. Bermejo et al, J. Med. Chem. 2002, 45, 2358
Synthesis of Antiproliferative Agent
23. Simplicity of this reaction in the easy construction of the carbon-
carbon bond.
Conclusions
Morita Baylis Hillman adduct is an excellent source for various
stereochemical transformation methodologies.
Several natural products and biologically active molecules have also
been synthesized using Morita Baylis Hillman strategy.
37
25. References
1. Baylis, A. B.; Hillman, M. E. D. Ger. Pat. 2,155,113, (1972). Both Anthony B.
Baylis
and Melville E. D. Hillman were chemists at Celanese Corp. USA.
2. Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001-8062.
(Review).
3. Ciganek, E. Org. React. 1997, 51, 201-350. (Review).
4. Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem.
Soc.
2002, 124, 24022403.
5. Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404-
2405.
6. Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230-
6231.
7. Krishna, P. R.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45, 4773-
4775.
8. Sagar, R,; Pant, C. S.; Pathak, R.; Shaw, A. K. Tetrahedron 2004, 60, 11399-
11406.
9. Mi, X.; Luo, S.; Cheng, J.-P. J. Org. Chem. 2005, 70, 2338-2341.
10. Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680-3681.
11. Price, K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7,
147150. A novel mechanism involving a hemiacetal intermediate is proposed.
12. Limberakis, C. Morita–Baylis–Hillman Reaction. In Name Reactions for