68 Chem. Soc. Rev., 2012, 41, 68–78 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Soc. Rev., 2012, 41, 68–78

The Baylis–Hillman reaction: a novel concept for creativity in chemistry

Deevi Basavaiah* and Gorre Veeraraghavaiah

Received 29th June 2011

DOI: 10.1039/c1cs15174f

This tutorial review highlights the way in which the Baylis–Hillman reaction has been increasingly

attracting the attention of synthetic and medicinal chemists; it not only helps in originating new

ideas to create novel methodologies and molecules but also offers intellectual challenges to

understand and address the present day needs in the areas of organic and medicinal chemistry.

1. Introduction

Creativity originates from thinking which, in fact, is the origin

of every man-made event. Every idea (either good or bad)

generates from the concept of our thinking. Perception of an

object differs from mind to mind depending on the existing

knowledge and familiarity levels of that particular mind. Very

often the difference in the pattern of thinking is so much as

zero to millions. Let us consider the simple example shown in

Fig. 1. How do people think about this Fig. 1? A mathe-

matician may treat that it is a rhombus while a chemist would

probably say that it is a cyclobutane ring. A common man

may assume that it is just a four-line boundary whereas a

bridge player may think that it is a diamond, one of the

four suits of the playing cards (which is treated as above clubs

but below spades and hearts in playing cards language).

Thus, even though the object is the same, the way of under-

standing differs from person to person depending on their

familiarity, knowledge and interest levels. Similarly different

perceptions prevail in the case of chemistry also.w

2. Creativity and proximity

2.1. Molecules with one functional group

Bond forming and bond cleavage reactions essentially involving

carbon are the most fundamental components in the ocean of

organic chemistry. In these reactions, functional groups are the

key players.1,2 The most important functional groups in organic

chemistry are carbonyl (keto, aldehyde, acid, ester, amide etc.),

alkene, alkyne, hydroxy, amino, cyano, and nitro groups.

School of Chemistry, University of Hyderabad, Hyderabad-500 046,India. E-mail: dbsc@uohyd.ernet.in; Fax: +91-40-23012460

Deevi Basavaiah

Deevi Basavaiah was born inValiveru, a village near Tenali,India. He obtained PhDdegree from the BanarasHindu University, India, in1979 under the supervision ofProfessor Gurbakhsh Singh.He then worked in theresearch group of ProfessorH. C. Brown, Purdue Univer-sity, USA, as a post-doctoralfellow for three years. In 1984he joined as a faculty memberin the School of Chemistry,University of Hyderabad,India, where he is currently

Professor. The main objective of his research is the developmentof the Baylis–Hillman reaction as a useful and powerfulsynthetic tool in organic synthesis and his research group hasbeen working towards this direction for the last 27 years. Chiralcatalysis is another important area of his research interest.

Gorre Veeraraghavaiah

Gorre Veeraraghavaiah wasborn in 1983 in Rajavolu, avillage in CherukupalleMandal, Guntur (Dist.),Andhra Pradesh, India. Aftercompletion of graduationfrom the Acharya NagarjunaUniversity, Guntur, he joinedas a post-graduate student in2005 in School of Chemistry,University of Hyderabad,Hyderabad, and obtained hisMSc (Chemistry) degree in2007. Presently he is workingtowards PhD degree in theUniversity of Hyderabad on

the development of the Baylis–Hillman reaction and its syntheticapplications under the supervision of Professor Basavaiah.

w Since there is a limit on the number of references, only essentialreferences have been selected and several leading references could notbe cited. The references, which appeared in earlier reviews4–14 (exceptthe very relevant ones), are also not cited

Chem Soc Rev Dynamic Article Links

www.rsc.org/csr TUTORIAL REVIEW

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online / Journal Homepage / Table of Contents for this issue

This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 68–78 69

Each functional group in its own right plays a specific role in

organic chemistry. Let us take the case of the carbonyl group:

it can be reduced to alcohol, transformed into lactones, can

undergo nucleophilic addition reactions, and can stabilize

carbanion (Scheme 1A); also it can undergo a diverse range of

other reactions. Similarly alkene can be reduced to alkane,

converted into diol, epoxide, transformed into two carbonyl

compounds (Scheme 1B) etc.Now consider the hydroxyl group:

it can be oxidized to aldehyde (in the case of primary alcohol) or

ketone (in the case of secondary alcohol), can be converted into

alkene, alkane, or halide (Scheme 1C).1,2

2.2. Molecules with two functional groups: power of proximity

Proximity is yet another important component not only in real

life but also in chemistry. If a molecule contains two functional

groups several atoms apart they (functional groups) can only

exhibit their individual properties. But when they are in

proximity, while keeping their individual reactivities fairly

intact they can also show additional and quite different

properties. Let us consider a compound having ketone and

alkene in close combination: it can undergo different reactions

such as Diels–Alder reaction and Michael reaction in addition

to their own individual reactions (Scheme 2A).1,2 In the case of

a molecule containing alkene and alcohol in proximity, it can

generate a carbonium ion more easily than alcohol or alkene

and also can be an excellent substrate for Johnson–Claisen

rearrangement (Scheme 2B).1,2 Thus proximity of two func-

tional groups in a molecule plays a unique role since such

compounds offer different reactions otherwise not shown by

the individual groups.

2.3. Molecules with three functional groups

Let us now consider molecules containing three functional

groups (ketone, alkene and hydroxyl) in proximity. In an

acyclic system it appears that there is a possibility of four

general structures (Fig. 2) [such as (1) alkene in the middle

(here two possibilities) (2) keto group in the middle, (3) hydroxyl

group in the middle]. In the case of a cyclic system one can notice

that there are several possibilities. Some of the important

structures (CS1–17) are presented in Fig. 2. If we generalize

Fig. 1 Variation in thinking and mindset about an object.

Scheme 1 Molecules with one functional group and their properties.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

70 Chem. Soc. Rev., 2012, 41, 68–78 This journal is c The Royal Society of Chemistry 2012

the structures AcS1 it will lead to the more general structures

GAcS. Let us focus only on general structures GAcS and

CS5–7—their synthesis, chemistry, applications and also

challenges involved in these endeavors. A careful observation

of these molecules indicates that these are nothing but the

Baylis–Hillman adducts (Fig. 3).3–14 The major objective of

writing this mini review is to summarize and discuss briefly the

growth of the Baylis–Hillman (BH) reaction, influence of

proximity of the functional groups in BH-adducts (GAcS and

CS5–7) leading to unlimited synthetic applications and what

makes this reaction to become an inspiring concept of creativity

in chemistry.

3. The Baylis–Hillman (BH) reaction3–14

3.1. Background

It is very appropriate to mention briefly the background

history for this fascinating reaction. In the year 1963 Rauhut

and Currier reported the dimerization of alkyl acrylates under

the catalytic influence of trialkylphosphine to produce the

corresponding dialkyl 2-methyleneglutarate derivatives.3a

Morita and coworkers in the year 1968 described the reaction

of various aldehydes with acrylates or acrylonitrile under

the influence of tricyclohexylphosphine as a catalyst to

provide 2-methylene-3-hydroxy alkanoates (or alkanenitriles)

(Scheme 3).3b,c In the year 1972, Baylis and Hillman in their

German patent reported an amine catalyzed coupling of

various activated alkenes with aldehydes to produce a variety

of densely functionalized molecules.3d,e This reaction is now

referred to as the Baylis–Hillman reaction. This is essentially a

three component reaction well equipped with large variations

of parameters providing a huge reservoir of diverse classes of

densely functionalized molecules (Scheme 4).3–14 This reaction

is also known as the Morita–Baylis–Hillman (MBH) reaction.

The main features of this fascinating reaction are given below.

Scheme 2 Influence of proximity of functional groups in molecules.

Fig. 2 Possible structures of molecules with three (different) func-

tional groups in proximity.

Fig. 3 The Baylis–Hillman adducts.

Scheme 3 Earlier work of Rauhut–Currier and Morita.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 68–78 71

3.2. Atom economy, organo-catalysis, and operational

simplicity

This is generally an atom economy carbon–carbon bond

forming reaction involving the coupling of the a-position of

activated alkenes with carbon electrophiles under the influence

of a catalyst or a catalytic system. When the activated alkenes

themselves act as electrophiles, Michael type dimers are

produced in an atom economy process.15 This reaction is

indeed one of the best and well known examples for organo-

catalysis (and thus for green chemistry) when amines or

phosphines are used as catalysts. BH-reactions involving allyl

halides as electrophiles provide useful classes of functionalized

1,4-pentadienes.16 However, these reactions involve the loss

of a halide group and thus do not fall in the category of

atom-economy reactions. Most of the BH-reactions are

operationally simple.

3.3. Huge reservoir of densely functionalized molecules3–14

The starting materials i.e., activated alkenes and electrophiles

are abundantly available or easily prepared. There is also a

pool of catalysts. A variety of tertiary amines (such as

DABCO, DBU, DMAP, TMG), phosphines (like tricyclo-

hexyl, tributyl, triphenyl phosphines), and chalcogenides

in combination with Lewis acids have been meticulously

employed as catalysts. It is also interesting to note that some

Lewis acids mediate a number of BH-reactions. In fact, a huge

reservoir of diverse classes of densely functionalized molecules

has been prepared using appropriate selection of essential

components. It is indeed very attractive and challenging

to discover or uncover new activated alke(y)nes and electro-

philes as such efforts will produce various classes of new

multi-functional molecules. A possible list of some of the most

attractive and challenging activated alkenes and electrophiles

that are not yet well explored is presented in Fig. 4 and

Scheme 5 respectively. It will be fascinating to examine the

appropriate combination of some of the catalysts and also

discover various new catalysts to accelerate the rate of the

reactions. Thus this reaction offers an unlimited scope for

planning and designing different combinations of activated

alkenes, electrophiles and catalysts to obtain many more

classes of multi-functional molecules.

3.4. Opportunities in obtaining enantiomerically pure densely

functionalized molecules3–14

3.4.1. Chiral activated alkenes, electrophiles and catalysts.

The Baylis–Hillman reaction creates a chiral center in the case

of prochiral electrophiles thereby providing a provision to

Scheme 4 The BH-reaction: a tool for the generation of a huge reservoir of densely functionalized molecules.

Fig. 4 Potential activated alkenes: challenges ahead.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

72 Chem. Soc. Rev., 2012, 41, 68–78 This journal is c The Royal Society of Chemistry 2012

synthesize enantiomerically pure/enriched multifunctional

molecules. Thus this reaction offers challenges in designing

appropriate chiral activated alkenes, electrophiles, catalysts or

any chiral medium for obtaining a large variety of enantio-

merically pure compounds. Several chiral activated alkenes

and electrophiles have been prepared and successfully

employed in a number of asymmetric BH-reactions.5,8–14 It

will be still desirable and useful to understand and explore the

applicability of several new chiral activated alkenes and

electrophiles as such endeavors will throw light towards under-

standing the profile of this reaction. However, the scope and

applications of chiral activated alkenes and electrophiles

are limited as they cannot offer solutions for many problems

in asymmetric BH reactions. Therefore the real attraction

lies in the development of chiral catalysts, that is, in the

design, synthesis, and exploration of their applications. In

fact, a number of chiral catalysts have been designed and

systematically used in different asymmetric BH-reactions.

Representative classes of chiral activated alkenes, electrophiles

and catalysts that are well studied are presented in Fig. 5.17–30

Although considerable success has been achieved in the

asymmetric version of the BH reaction using chiral catalysts

we feel that this aspect is still at the initial stages as applica-

tions of these catalysts are limited to certain substrates only.

Thus there is a serious need to develop new catalysts that

would accommodate many more substrates in order to obtain

several classes of enantiomerically pure molecules. In this

connection we believe that chiral carbenes will offer a lot of

promise as catalysts in addressing many unsolved problems

and widening the scope of the asymmetric BH-reaction.29 It is

therefore a challenge to design appropriate chiral carbenes and

examine their potential as catalysts in BH reactions in the

years to come.

3.4.2. Asymmetric Baylis–Hillman reaction: unexplored

aspect. Asymmetric BH-reactions (intermolecular system)

can in principle have two directions, that is, Path A and Path B

(Scheme 6). Chemists have already made considerable efforts

and achieved reasonable success towards understanding

Path A.5,8–14 However Path B is not yet all explored and

remains almost untouched so far. Therefore it is desirable to

examine this aspect.

Scheme 5 Potential electrophiles: future challenges.

Fig. 5 The asymmetric Baylis–Hillman reaction: a representative set of examples of chiral activated alkenes, electrophiles and catalysts that are

well explored in the literature.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 68–78 73

3.5. Intramolecular Baylis–Hillman reaction and its

asymmetric version5,10,11

If a substrate contains activated alkene and electrophilic

components in appropriate positions there is a possibility

of performing the intramolecular Baylis–Hillman reaction.

Thus, this reaction offers opportunities to design various

substrates for performing the intramolecular Baylis–Hillman

reaction that would lead to the formation of a number

of functionalized carbocyclic and heterocyclic molecules.

Achieving its asymmetric version is yet another attractive

endeavor that needs to be addressed. Some of the important

examples that are reported in the literature are described in

Scheme 7.31–35

3.5.1. Challenges ahead: multi (intramolecular) BH-

reactions. We believe that one of the future directions will be

the design of appropriate substrates for multi intramolecular

BH-reactions (including the combination of BH and

Rauhut–Currier reactions) and their asymmetric versions

using suitable chiral catalysts. Two such possible strategies

are presented in Scheme 8.

4. Single component Baylis–Hillman reaction

The literature records some examples that describe the BH-

reaction of substrates containing two essential components.36,37

It is more appropriate to present here one such example, that is,

pyridine-2-carboxaldehyde as a substrate in this category as it

contains the electrophile and catalyst components leading to the

formation of indolizine derivatives (Scheme 9).36 It will be

intellectually exciting to discover BH-reactions with molecules

containing all the three essential components, as these (single

component) reactions not only provide the opportunity to

design such substrates but also offer challenges in understand-

ing the scope of this methodology. A possible example of a

single component substrate which contains all the three essential

components leading to the formation of tetracyclic molecules is

presented in Scheme 10.

5. Applications of Baylis–Hillman adducts5–14

This reaction produces densely functionalized molecules

containing at least three functional groups, in proximity for

appropriate use in various organic reactions and transforma-

tions. Different perspectives (looking at these molecules)

about these densely functionalized molecules are pictorially

presented in Fig. 6. Chemists have systematically explored the

applications in all these directions and developed several

methodologies and strategies for obtaining carbocyclic/

heterocyclic/trisubstituted alkenes (Fig. 7).38–52 In fact several

Scheme 6 The asymmetric BH-reaction: enormous scope for expansion.

Scheme 7 The intramolecular BH-reaction: known examples.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

74 Chem. Soc. Rev., 2012, 41, 68–78 This journal is c The Royal Society of Chemistry 2012

bioactive and natural products have been synthesized using

the Baylis–Hillman adducts (Fig. 8).20,53–63 Although BH-

adducts (acetates/bromides) have been extensively employed

in a multitude of synthetic transformations, it looks to us that

the power of proximity of functional groups in BH-adducts

is not yet well understood/explored. Thus we believe that

these adducts still offer enormous scope for developing and

even discovering many new transformations and strategies

in synthetic organic chemistry leading to the production of

medicinally relevant compounds and even to certain important

medicines.

6. Mechanism5,9a,10,64

Understanding the mechanism of the Baylis–Hillman reaction

is indeed an intellectually exciting area by itself. This is

because of large variations of parameters such as diversity in

the selection of activated alkenes, electrophiles and catalysts.

Another important factor is the reaction conditions such as

solvent or additives that influence the rate of the reaction.

There are in fact several elegant publications on the mecha-

nistic studies of the reaction.64 But so far there is no clear

understanding about the rate determining step, and also

transition states (either C–C bond formation or proton migra-

tion or release of catalyst or the presence of any new inter-

mediate). Based on the available reports and evidence it is

believed that in most of the BH-reactions the first step involves

the Michael addition of catalyst (amine, phosphine, chalco-

gene, Lewis acid) to activated alkene to provide the zwitter-

ionic enolate which will then react with a carbonyl compound

(such as aldehyde, ketone, a-keto ester etc.) constructing a

C–C bond in aldol fashion (proof provided by mass spectral

studies by Coelho and coworkers in the case of DABCO as

a catalyst and methyl acrylate as an activated alkene)64g

producing multi functional molecules in an atom-economy

process (Scheme 11).

In the case of allyl halides as electrophiles, the first step

might involve the formation of a quaternary salt and then the

zwitterionic enolate A generated from activated alkene might

react with this salt to provide the required pentadienes

(Scheme 12).16 When the activated alkenes act as electrophiles,

the zwitterion A adds on to the activated alkene in 1,4-fashion

producing the Michael type dimers.5,11,15 It is interesting

and desirable to understand the transition states and rate

Scheme 8 The intramolecular multi-BH-reactions: future projections.

Scheme 9 Electrophile induced BH-reaction: synthesis of indolizines.

Scheme 10 Single component BH-reactions: future challenges.

Fig. 6 BH-adducts: different perceptions.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 68–78 75

Fig. 7 Applications of BH-adducts: various synthetic transformations.

Fig. 8 Applications of Baylis–Hillman (BH) adducts: synthesis of natural products and bio-active molecules.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

76 Chem. Soc. Rev., 2012, 41, 68–78 This journal is c The Royal Society of Chemistry 2012

determining steps in these reactions (Scheme 12). Considering

the fact that there are variations of parameters in performing

the BH-reaction it is quite clear that a number of mechanistic

pathways are possible depending on the substrates and condi-

tions. It is indeed a challenge to understand and propose

appropriate mechanistic pathway(s) for a given system of the

BH-reaction.

7. The factors that decide growth of a reaction:

standing of the Baylis–Hillman reaction

In science the most important thing is the identification of

research area that should involve creativity and intellectual

challenges finally leading to the applications to human well-

being. In the case of synthetic chemistry discovery of new

and truly useful carbon–carbon bond forming reactions

undoubtedly represents one such area of research. It is equally

important to recognize any C–C bond forming reaction which

is known, but buried in the literature and to bring the same

from an unknown status to the limelight of high applicability.

In the case of C–C bond forming reactions there are certain

factors that influence the growth of the reaction. Some of

these factors might be: (1) abundance and easy accessibility of

starting materials in general and scope for creativity in design-

ing new substrates for growth and diversification of the

reaction, (2) operational simplicity–organocatalysis–atom-

economy–green chemistry, (3) functional group attraction

for developing carbon assemblies, (4) stereochemical and

mechanistic challenges, (5) provision for intramolecular

version, and (6) the products with unlimited source of applica-

tions and opportunities for creativity and diversity in plan-

ning, design and synthesis. The Baylis–Hillman reaction is

one such reaction that is well equipped with all these require-

ments (Fig. 9) grown from an unknown patent level to high

Scheme 11 Various parameters that made the BH-reaction mechanism interesting.5,10,13

Scheme 12 Parameters that influence the mechanism of the BH-reaction.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 68–78 77

popularity and applicability. Another elegant aspect in science

is the art of creativity that can address the present day needs.

From this brief review it is quite evident that the Baylis–

Hillman reaction has already attained the status as a novel

concept for creativity in chemistry.

8. Conclusions

Considering the way in which the Baylis–Hillman reaction has

been progressing we envision that this reaction will continue

to grow to further heights. In conclusion, we have briefly

presented the highlights of the BH reaction in this review and

also predict many more brilliant and important contributions

from this reaction to chemistry/medicinal chemistry leading

towards human well being in the years to come.

Abbreviations

AcS acyclic system

CS cyclic system

DABCO 1,4-diazabicyclo(2.2.2)octane

DBU 1,8-diazabicyclo(5.4.0)undec-7-ene

DMAP 4-(dimethylamino)pyridine

EWG & EWG1 electron withdrawing group

GAcS general acyclic system

JC Johnson–Claisen

LA Lewis acid

Ms methanesulfonyl

MVK methyl vinyl ketone

NMI N-methylimidazole

PMP p-methoxyphenyl

Tf trifluoromethanesulfonyl

TMG tetramethylguanidine

TS transition state

Ts p-toluenesulfonyl

Acknowledgements

We thank DST (New Delhi) for financial support. We thank

UGC (New Delhi) for recognizing the School of Chemistry as

a ‘‘Center for Advanced Studies in Chemistry’’ and providing

some instrumental facilities. GV thanks CSIR (New Delhi) for

his research fellowship.

Notes and references

1 (a) M. B. Smith and J. March, March’s Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6th edn, Wiley,New York, 2007; (b) F. A. Carey and R. J. Sundberg, AdvancedOrganic Chemistry, Parts A & B, 5th edn, Springer, New York,2007.

2 (a) R. C. Larock, Comprehensive Organic Transformations: a guideto functional group transformations, VCH, New York, 1989;(b) Comprehensive Organic Synthesis, ed. B. M. Trost andI. Fleming, Pergamon Press, New York, 1991, vol. 1–9.

3 (a) M. M. Rauhut and H. Currier, American Cyanamide Co.U. S. Patent, 1963, 3074999. Chem. Abstr., 1963, 58, 11224a;(b) K. Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn.,1968, 41, 2815; (c) K. Morita and T. Kobayashi, Bull. Chem.Soc. Jpn., 1969, 42, 2732; (d) A. B. Baylis and M. E. D. Hillman,German patent 2155113, 1972, Chem. Abstr., 1972, 77, 34174q;(e) M. E. D. Hillman and A. B. Baylis, U. S. Patent, 3,743,669,1973.

4 M. Shi, F. Wang, M.-X. Zhao and Y. Wei, Chemistry of theMorita–Baylis–Hillman Reaction, RSC Catalysis Series, 2011.

5 D. Basavaiah, B. S. Reddy and S. S. Badsara, Chem. Rev., 2010,110, 5447.

6 V. Declerck, J. Martinez and F. Lamaty, Chem. Rev., 2009, 109, 1.7 V. Singh and S. Batra, Tetrahedron, 2008, 64, 4511.8 Y.-L. Shi and M. Shi, Org. Biomol. Chem., 2007, 5, 1499.9 (a) Y. Wei and M. Shi, Acc. Chem. Res., 2010, 43, 1005;(b) G. Masson, C. Housseman and J. Zhu, Angew. Chem., Int. Ed.,2007, 46, 4614; (c) P. Langer, Angew. Chem., Int. Ed., 2000, 39,3049.

10 D. Basavaiah, K. V. Rao and R. J. Reddy, Chem. Soc. Rev., 2007,36, 1581.

11 D. Basavaiah, A. J. Rao and T. Satyanarayana, Chem. Rev., 2003,103, 811.

Fig. 9 Important features: standing of the BH reaction.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online

78 Chem. Soc. Rev., 2012, 41, 68–78 This journal is c The Royal Society of Chemistry 2012

12 E. Ciganek, in Organic Reactions, ed. L. A. Paquette, Wiley,New York, 1997, vol. 51, p. 201.

13 D. Basavaiah, P. D. Rao and R. S. Hyma, Tetrahedron, 1996,52, 8001.

14 S. E. Drewes and G. H. P. Roos, Tetrahedron, 1988, 44, 4653.15 D. Basavaiah, V. V. L. Gowriswari and T. K. Bharathi,

Tetrahedron Lett., 1987, 28, 4591.16 (a) D. Basavaiah, N. Kumaragurubaran and D. S. Sharada,

Tetrahedron Lett., 2001, 42, 85; (b) D. Basavaiah, D. S. Sharada,N. Kumaragurubaran and R. M. Reddy, J. Org. Chem., 2002,67, 7135.

17 P. R. Krishna, P. S. Reddy, M. Narsingam, B. Sateesh andG. N. Sastry, Synlett, 2006, 595.

18 D. Basavaiah, V. V. L. Gowriswari, P. K. S. Sarma and P. D. Rao,Tetrahedron Lett., 1990, 31, 1621.

19 K. He, Z. Zhou, G. Zhao and C. Tang, Heteroat. Chem., 2006,17, 317.

20 L. J. Brzezinski, S. Rafel and J. W. Leahy, J. Am. Chem. Soc.,1997, 119, 4317.

21 A. Lu, X. Xu, P. Gao, Z. Zhou, H. Song and C. Tang,Tetrahedron: Asymmetry, 2008, 19, 1886.

22 B. Alcaide, P. Almendros, C. Aragoncillo and R. Rodriguez-Acebes, J. Org. Chem., 2004, 69, 826.

23 E. P. Kundig, L. H. Xu, P. Romanens and G. Bernardinelli,Tetrahedron Lett., 1993, 34, 7049.

24 J.-F. Pan and K. Chen, Tetrahedron Lett., 2004, 45, 2541.25 (a) Y. Iwabuchi, M. Nakatani, N. Yokoyama and S. Hatakeyama,

J. Am. Chem. Soc., 1999, 121, 10219; (b) For the recent applicationof this catalyst see: X.-Y. Guan, Y. Wei andM. Shi, Chem.–Eur. J.,2010, 16, 13617.

26 Y.-H. Liu, L.-H. Chen and M. Shi, Adv. Synth. Catal., 2006,348, 973.

27 K. Yuan, L. Zhang, H.-L. Song, Y. Hu and X.-Y.Wu, TetrahedronLett., 2008, 49, 6262.

28 N. T. McDougal and S. E. Schaus, J. Am. Chem. Soc., 2003,125, 12094.

29 L. He, Y.-R. Zhang, X.-L. Huang and S. Ye, Synthesis, 2008,2825.

30 B. K. Senapati, G.-S. Hwang, S. Lee and D. H. Ryu,Angew. Chem., Int. Ed., 2009, 48, 4398.

31 J. E. Yeo, X. Yang, H. J. Kim and S. Koo, Chem. Commun., 2004,236.

32 P. M. Brown, N. Kappel, P. J. Murphy, S. J. Coles andM. B. Hursthouse, Tetrahedron, 2007, 63, 1100.

33 M. E. Krafft, K. A. Seibert, T. F. N. Haxell and C. Hirosawa,Chem. Commun., 2005, 5772.

34 M. E. Krafft and J. A. Wright, Chem. Commun., 2006, 2977.35 S.-H. Chen, B.-C. Hong, C.-F. Su and S. Sarshar, Tetrahedron

Lett., 2005, 46, 8899.36 D. Basavaiah and A. J. Rao, Chem. Commun., 2003, 604.37 H. Kinoshita, T. Osamura, S. Kinoshita, T. Iwamura,

S.-i. Watanabe, T. Kataoka, G. Tanabe and O. Muraoka,J. Org. Chem., 2003, 68, 7532.

38 (a) S. E. Drewes, N. D. Emslie, N. Karodia and G. Loizou, Synth.Commun., 1990, 20, 1437; (b) D. Basavaiah and S. Pandiaraju,Tetrahedron Lett., 1995, 36, 757; (c) D. Basavaiah, S. Pandiarajuand M. Krishnamacharyulu, Synlett, 1996, 747.

39 D. Basavaiah and P. K. S. Sarma, J. Chem. Soc., Chem. Commun.,1992, 955.

40 D. Basavaiah, M. Krishnamacharyulu, R. S. Hyma andS. Pandiaraju, Tetrahedron Lett., 1997, 38, 2141.

41 S. Matsumoto, Y. Okubo and K. Mikami, J. Am. Chem. Soc.,1998, 120, 4015.

42 D. Basavaiah and T. Satyanarayana, Org. Lett., 2001, 3, 3619.43 H. Cao, T. O. Vieira and H. Alper, Org. Lett., 2011, 13, 11.44 E. S. Kim, K. H. Kim, S. Park and J. N. Kim, Tetrahedron Lett.,

2010, 51, 4648.45 S. Hutait and S. Batra, Tetrahedron Lett., 2010, 51, 5781.46 W. Zhong, W. Ma and Y. Liu, Tetrahedron, 2011, 67, 3509.47 P. Wasnaire, M. Wiaux, R. Touillaux and I. E. Marko,

Tetrahedron Lett., 2006, 47, 985.48 Y. Du, J. Feng and X. Lu, Org. Lett., 2005, 7, 1987.49 S. Gowrisankar, K. Y. Lee, C. G. Lee and J. N. Kim, Tetrahedron

Lett., 2004, 45, 6141.50 D. Basavaiah, S. Roy and U. Das, Tetrahedron, 2010, 66, 5612.51 J. N. Kim, Y. J. Im, J. H. Gong and K. Y. Lee, Tetrahedron Lett.,

2001, 42, 4195.52 T. Gendrineau, J.-P. Genet and S. Darses, Org. Lett., 2010,

12, 308.53 Y. Iura, T. Sugahara and K. Ogasawara, Org. Lett., 2001, 3, 291.54 D. Basavaiah, B. Devendar, K. Aravindu and A. Veerendhar,

Chem.–Eur. J., 2010, 16, 2031.55 B. M. Trost, O. R. Thiel and H.-C. Tsui, J. Am. Chem. Soc., 2002,

124, 11616.56 A. Weichert and H. M. R. Hoffmann, J. Org. Chem., 1991,

56, 4098.57 (a) ‘‘Pregabalin’’ Pfizer, Drugs of Future 2002, 27, 426;

(b) Pregabalin is presently an anticonvulsant drug used for neuro-pathic pain (Pfizer)—From Wikipedia, the free encyclopedia(http://en.wikipedia.org/wiki/Pregabalin).

58 M. P. Feltrin and W. P. Almeida, Synth. Commun., 2003, 33, 1141.59 P. Webber and M. J. Krische, J. Org. Chem., 2008, 73, 9379.60 D. Basavaiah, P. K. S. Sarma and S. Pandiaraju, Tetrahedron

Lett., 1994, 35, 4227.61 (a) P. J. Dunn, Abstracts of papers, 223rd ACS National Meeting,

Orlando, FL, United States, April 7–11, 2002; (b) P. J. Dunn,Pfizer Global Research and Development, Sandwich, Kent, UK,personal communication; (c) Sampatrilat is a dual inhibitor ofneutral endopeptidase (NEP) and angiotensin convertingenzyme (ACE) (under development by Pfizer and Shire for possibletreatment of hypertension).

62 Y. Iwabuchi, M. Furukawa, T. Esumi and S. Hatakeyama, Chem.Commun., 2001, 2030.

63 G. W. Amarante, M. Cavallaro and F. Coelho, Tetrahedron Lett.,2010, 51, 2597.

64 (a) T. Regiani, V. G. Santos, M. N. Godoi, B. G. Vaz,M. N. Eberlin and F. Coelho, Chem. Commun., 2011, 47, 6593;(b) C. Patel and R. B. Sunoj, J. Org. Chem., 2010, 75, 359;(c) D. Roy and R. B. Sunoj, Org. Lett., 2007, 9, 4873;(d) R. Robiette, V. K. Aggarwal and J. N. Harvey, J. Am. Chem.Soc., 2007, 129, 15513; (e) K. E. Price, S. J. Broadwater,B. J. Walker and D. T. McQuade, J. Org. Chem., 2005, 70, 3980;(f) V. K. Aggarwal, S. Y. Fulford and G. C. Lloyd-Jones, Angew.Chem., Int. Ed., 2005, 44, 1706; (g) L. S. Santos, C. H. Pavam,W. P. Almeida, F. Coelho andM. N. Eberlin,Angew. Chem., Int. Ed.,2004, 43, 4330; (h) G. Li, J. Gao, H.-X. Wei and M. Enright,Org. Lett., 2000, 2, 617; (i) T. Kataoka, H. Kinoshita, T. Iwama,S.-i. Tsujiyama, T. Iwamura, S.-i. Watanabe, O. Muraoka andG. Tanabe, Tetrahedron, 2000, 56, 4725; (j) Y. Fort, M. C. Bertheand P. Caubere, Tetrahedron, 1992, 48, 6371; (k) M. L. Bode andP. T. Kaye, Tetrahedron Lett., 1991, 32, 5611; (l) J. S. Hill andN. S. Isaacs, J. Phys. Org. Chem., 1990, 3, 285.

Dow

nloa

ded

by U

nive

rsity

of

Oxf

ord

on 0

9 D

ecem

ber

2011

Publ

ishe

d on

06

Sept

embe

r 20

11 o

n ht

tp://

pubs

.rsc

.org

| do

i:10.

1039

/C1C

S151

74F

View Online