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Chapter III
3-1
Review on aza-Michael addition reaction
Introduction
Organic chemistry is an innovative science and the glory of organic
chemistry continues to improve after each discovery. One of such path
breaking discovery was Michael reaction1 which involved a base promoted
addition of various active methylene compounds to electron deficient alkenes.
In the initial stages, although the reaction was accomplished mostly with
carbon nucleophiles2, the attention was then focused on the use of various other
nucleophiles3 like N (aza-Michael), S (thia-Michael) to design C-N and C-S
bond, respectively. The role of aza-Michael reaction in the synthesis of
pharmacologically important family of β-amino carbonyl compounds and its
derivatives is well documented in the literature4. Over the last few years there
has been increasing interest in the synthesis of such pharmacologically
important compounds by reaction of a variety of nitrogen nucleophiles with a
range of Michael acceptors employing efficient catalytic systems. Various
strategies of aza-Michael reaction have also been proved useful in the synthesis
of core intermediates of many natural products5.
Over the past several years tremendous progress has been achieved by
employing new nitrogen nucleophiles and suitable acceptors as well as more
efficient catalytic systems for this important transformation. In the following,
we have taken a brief account of aza-Michael addition reaction with special
emphasis on the development of the new catalysts.
3-2
Catalysts for aza-Michael addition reaction
Catalysis is one of the most intensely studied and pursued in both the
chemical engineering and applied chemistry. Indeed, it is more so now because
the use of catalysis for environmental management, abatement and to the
world’s economic advancement is becoming more crucial. Indeed, the
advancement of catalysis is the cornerstone of both economic and
environmental sustainability of the world. Today the study of catalytic activity
- 111 -
Chapter III
Review on aza-Michael addition reaction
of catalysts on the design of chemicals and the chemical reactions puts catalysis
at the heart of synthetic methodologies. This review gives an overview of
catalysis with emphasis on how the field of catalysis can contribute to azaMichael addition reaction. The subsequent section follows proposed ideas of
new synthetic methodologies for aza-Michael addition reaction.
3-2a. Metal and metal salt catalyzed aza-Michael addition
Metal and metal salts catalysis has emerged with great activity over
homogenous catalytic system. It plays important advantages of easy
availability, inexpensiveness and ease of separability. Consequently, a variety
of metal and metal salts have been disclosed for aza-Michael addition reaction.
In 1994, K. Utimoto et al.6 have described highly productive method for
conjugate addition catalyzed by oxophilic lanthanide (III) salts. After screening
variety of lanthanide salts using a range of solvents, Utimoto et al. inferred
lanthanide triflates to be promising catalysts for aza-Michael addition reaction
however, for the reason undisclosed, author have established general protocol
using Ytterbium triflate as a catalyst which is relatively expensive compared
to other lanthanide triflates. The method was further extended to yield optically
active β-lactams (Scheme 1).
CO2Et
+
PhCH2NH2
Yb(OTf)310 mol%
NHCH2Ph
CO2Et
rt, 6 hr, THF
Scheme 1
β−lactum
Owing to the unique properties of high catalytic activity coupled with
stability as well as easy recoverability from water, indium trichloride7 has
been extensively used in aza-Michael addition of primary as well as secondary
amines to α-β unsaturated ethylenic compounds (Scheme 2). The noteworthy
feature of the present protocol is, with the methyl acrylate higher percentage of
- 112 -
Chapter III
Review on aza-Michael addition reaction
bisalkylation product was observed while only selective aromatic amines give
good yield of Michael addition product in water at room temperature.
R1
NH
+
R1
InCl3 20 mol %
X
R2
N
X
R2
rt, H2O
X = -CN, -COOCH3
X
N
+
R1
R2 = H
Scheme 2
Both the triflates of lanthanides and the salts of indium are relatively
expensive. In another approach, Kawatsura et al. screened various transition
metal salts as well as transition metal organometallic complexes8. Amongst
various organometallic complexes screened, only those with Pd (II), Rh (II) Ru
(III) and Ir (III) were found to be effective irrespective of the substitution
pattern at the Michael acceptors which is followed by attack of nucleophiles
(Scheme 3).
R1
R2
R1
Pd (II) / Rh (II) / Ru (III) / Ir (III)
+
R2
HNHRR'
Organomettallic complexes
EWG
RR'N
EWG
R1, R2 = Me, H
EWG = -CN, -COOR
Scheme 3
Unlike conventional organometaliic complexes, ferrocenyl Ni (II)
complexes9 has been demonstrated to be highly efficient catalyst in addition of
aromatic amines to conjugated alkenes (Scheme 4).
R1
NH2
R1
R2
R'''
R
+
EWG
R''
1-5 mol % catalyst
R'
R1, R2 = H, Me
EWG = -CN, -COOR
R, R', R'', R''' = H, Me, CF3, OMe
Scheme 4
- 113 -
HN
R2
EWG
R'''
R
R''
R'
Chapter III
Review on aza-Michael addition reaction
The utility of Bi(NO3)2, as a metal salt catalyst is well established in
various organic transformations and Banik et al.10 have established a general
and solvent-free protocol for carbon as well as aza-Michael addition to various
enones using bismuth nitrate as an inexpensive although non reusable catalyst
(Scheme 5).
O
O
R
R1
+
Bi(NO)3
HN
R1
R'
R2
R2
N
R
R'
Scheme 5
In search for a cheaper metal catalyst Xu et al. have reported the use of
Cu(I) catalyst11a for the addition of secondary as well as primary amines to
various conjugated alkenes (Scheme 6). Subsequently, Xu et al. also disclosed
the catalytic activity of other transition metal salts viz. iron Chloride,
chromium chloride and stannous chloride11b etc. (Scheme 7). Using copper
salts although they were not successful in using aromatic amines as
nucleophiles, using the aforementioned salts, weakly nucleophilic aromatic
amines underwent aza-Michael addition smoothly with a range of Michael
acceptors, except α-β unsaturated-N-acyloxyzolidone.
O
Hexahydropyridine
OEt
N
OEt
Copper/ rt / H2O
O
Scheme 6
O
EtO
+
H 2N
O
Catalyst
H2O, rt
Scheme 7
- 114 -
EtO
N
Chapter III
Review on aza-Michael addition reaction
To address the issue of failure of aromatic amines to undergo azaMichael reaction, Reboule et al. then demonstrated the utility of samarium
iodide12 as catalyst and depending upon amine to substrate ratio, mixture of βamino N-acyloxazolidones and β-amino amides were obtained (Scheme 8).
O
R
O
N
NHAr O
O
+
ArNH2
O
NHAr O
10% SmI2(THF)2
R
CH2Cl2, rt,48 hr
N
O
+
R
N
H
R = CO2Et, CH3, C3H7, H
Scheme 8
The use of ceric ammonium salts (especially nitrate over to sulfate) in a variety
of organic transformations is well documented in the literature. So it was not at
all surprising that one stems out to try ceric ammonium nitrate (CAN) for the
aza-Michael reaction. In fact the use of cericammonium nitrate (CAN) in azaMichael reaction was reported by Adapa et al.13 as well as Duan et al.14 almost
simultaneously. Various primary aliphatic as well as secondary amines
including piperazines were demonstrated to undergo aza-Michael addition
reaction (Scheme 9). The main difference between the two protocols is the use of
ultrasonic waves (Duan et al) to improve yield and to achieve the
transformation in less time (Scheme 10).
R
CAN, (3 mol %)
+
NH
EWG
R
H2O, rt
R'
EWG
N
R'
EWG = -CN, COMe, CO2Et, COOMe, CONH2
Scheme 9
H
N
R
R1
+
R1
CAN
EWG
(((
EWG = -CN, COMe, CO2Et, COOMe, CONH2
Scheme 10
- 115 -
R
N
EWG
Ar
Chapter III
Review on aza-Michael addition reaction
The use of ytterbium triflate in promoting aza-Michael reaction was
demonstrated almost a decade ago. However, higher cost of ytterbium triflate
was the major limiting factor for the choice of this catalyst. The issue of the
cost of this lanthanide triflate has recently been circumvented by Bhanage et
al.15 They have reported the use of yttrium nitrate hexahydrate, especially in
addition of aromatic as well as heterocyclic amines to various conjugated
alkenes at ambient temperature under solvent free condition in excellent yields
(Scheme 11).
R
NH
+
R
Y(NO3)3.6H2O
N
EWG
EWG
Solvent-free, rt
X
X
R = H, CH3 EWG = COOMe, CONH2, CN, COOBu
X = Me, OMe, Cl, Br, CF3
Scheme 11
3-2b. Solid acid catalyzed aza-Michael addition reaction
Bronsted as well as Lewis acids are well known for their catalytic
activity to promote innumerable organic reactions. As a mild Lewis acid,
moisture and air sensitive zirconium oxychloride16 adds as a new catalyst for
conjugate addition of amines to α-β unsaturated ketones under solvent-free
condition but at elevated temperature (Scheme 12).
O
RNH2
R1
NHR
ZrOCl2 .8H2O
+
R2
50 oC
R1
O
R2
Scheme 12
Lithium perchlorate is a well known Lewis acid and its use in azaMichael reaction of primary aliphatic as well as secondary amines with a
variety of Michael acceptors was demonstrated by Saidi et al.17 The noteworthy
- 116 -
Chapter III
Review on aza-Michael addition reaction
feature of this catalyst is, under kinetically controlled condition, conventional
Michael addition product results while under thermodynamic control
nucleophilic attack at carbonyl carbon of esters yields corresponding amide as
the sole product (Scheme 13).
R
R'
+
R1R2NH
R'
Solid LiClO4
R1R2N
rt, 1-4 hr
X
X
R
R = H, Ph; R' = CH3; X = CN, CONH2, COONH2, COOMe, COMe
Ph
+
Solid LiClO4
NH
COOMe
N
60 oC, 3hr
Ph
O
Scheme 13
Naturally occurring clays do possess both, Bronsted as well as Lewis
acidity and Bedekar et al. reported clay catalyzed addition of secondary amines
to conjugated alkenes18 (Scheme 14). However, the essentiality of organic
solvent as well as high temperature appears to be the major limiting factor.
CO2Me
N
H2N
NH
N
H2N
N
CO2Me
Clay, EDC, Reflux
Scheme 14
Like clays, the use of silica gel to promote aza-Michael reaction was
reported by two different groups viz. Basu et al.19 and L. You et al.20 (Scheme
15) Elevated temperature as well as long reaction times are the drawbacks of
these protocols.
R1
N
H
Silica gel
+
R2
R3
40-70 oC
1-12 hr
R1 = R2 = H, alkyl, aryl
R3 =COOEt, CN
R1
Scheme 15
- 117 -
R2
N
R3
Chapter III
Review on aza-Michael addition reaction
The use of Amberlyst-15 as a solid acid catalyst in aza-Michael reaction
has been reported again by two different groups viz. Das et al21 (Scheme 16) and
Esteves et al22 (Scheme 17) with the only difference that, Stevens et al have used
netherto unexplored vinyl sulfones as a Michael acceptors.
R
R1
+
NH
R2
R1
Amberlist 15
X
R2
rt, 10-30 min
R
N
X
R'
R'
X = COOMe, CN, COMe
Scheme 16
R1
R1
NH
O
R2
O
S
R
O
Amberlist 15, rt
R
N
S
R2
O
R = Me / p-H2NC6H4
Scheme 17
Heteropoly acids (HPAs), apart from their high acidity (Bronsted)
acidity offer advantages such as of reusability, environmental compatibility,
non toxicity and operational simplicity. Chen et al.23 have recently reported the
use of 12-tungustophosphoric acid in water medium to promote conjugate
addition of aliphatic as well as aromatic amines to α-β unsaturated esters and
nitriles at room temperature (Scheme 18).
R2
NH
R1
+
R3
H3PW12O40 (1 mol %)
H2O, rt
R1 = Bn, alkyl, aryl; R2 = H, alkyl; R3 = COOMe, CN
Scheme 18
- 118 -
R2
N
R1
R3
Chapter III
Review on aza-Michael addition reaction
Kotsuki et al.24 have reported the use of p-toluenesulphonic acids to
promote the aza-Michael reaction between conjugated enones and ureas under
high pressure conditions (Scheme 19).
O
O
O
+
H 2N
R
or
H2 N
N
H
R
Acid catalyst
High pressure
O
O
O
N
H
O
or
R
N
H
N
H
Scheme 19
As an inorganic solid acid, the use of sulfated zirconia to promote azaMichael reaction of α-β unsaturated ketone with a range of amines has been
demonstrated by Reddy et al.25 (Scheme 20).
R4
R1
NH
R2
SO4- / ZrO2
+
R1
R3
N
EWG
rt, 15-120 min
R3
EWG
R2
R4
Scheme 20
3-2c. Solid supported heterogeneous catalysts
Heterogeneous catalysts conventionally offer the prime advantage of
high catalytic activity due to improved surface area, reusability, easier
separation from the reaction mixture, (availing the isolation of product easier,)
etc. Taking clues from earlier reports on use of indium chloride to promote azaMichael reaction, Kantam et al.26 have reported recently polyaniline
supported indium chloride as a heterogeneous and reusable catalyst to
promote the conjugate addition of primary aliphatic as well as secondary
amines to conjugate alkenes (Scheme 21). Typically, with the use of excess of
Michael acceptors, bis-Michael addition product results. However, with
aromatic amines, corresponding Michael addition products result only in
moderate yields.
- 119 -
R
Chapter III
Review on aza-Michael addition reaction
R1
+
N
EWG
H
R2
EWG
PANI-In (10 mol %)
R1
Water
N
R2
EWG
R1
N
H
R1
H
N
Monoadduct
PANI-In (10 mol %)
+
EWG
H
EWG
Water
R1
N
EWG
Scheme 21
Bisadduct
To circumvent the high cost of indium chloride, quite recently Saidi et
al.27 have reported the use of silica supported aluminium chloride as an
efficient catalyst to promote aza-michael reaction of both secondary as well as
aromatic amines with a variety of Michael acceptors (Scheme 22).
PhNH2
Solid supported
AlCl3
OMe
+
Ph
O
H
N
OMe
60 oC, 4 hr, Quant.
O
Scheme 22
CeCl3.7H2O-NaI system supported on SiO2 has been found to be one
of the efficient and easily separable catalysts in Michael addition of secondary
amines to α-β unsaturated enones28 (Scheme 23). Surprisingly, cerium chloride
alone is unable to promote this reaction suggesting that during the preparation
of the catalyst halide exchange reaction might be taking place and cerium
iodide (?) is a true catalyst in this reaction.
R1
OR
NH
+
R2
O
OR
CeCl3.7H2O-NaI
CH3CN, Reflux
R1 / R2 = PhCH2, n-C4H9
Scheme 23
- 120 -
N
R1
O
R2
Chapter III
Review on aza-Michael addition reaction
Misra et al29a in 2007 have reported silica supported perchloric acid
while Sing et al.29b have reported silica impregnated perchloric acid for azaMichael addition of a series of secondary amines (Scheme 24). Primary amines
were also effectively added to electron deficient alkene to furnish
corresponding Michael addition product in moderate to satisfactory yield.
Chaudhary et al.30 reports phosphate impregnated titania as a new catalyst to
promote the same reactions (Scheme 25).
R1
NH
X
+
HClO4 / SiO2
R1
MW 540 W, 2-7 min
R2
X
N
R2
Scheme 24
R4
R3
Phosphate impregnated
titania
R1
NH
+
R1
X
X
rt
R2
R2
R4
R3
X = COOMe, CN, COMe, CONH2
Scheme 25
Very recently, Guo et al.31 have reported the use of silica sulphuric
acid as a highly efficient catalyst for Michael addition of secondary amines and
aliphatic as well as aromatic amines on selective Michael acceptors (Scheme 26).
Satisfactory results have been obtained within short reaction times. However,
the authors have not extended reaction with Michael acceptors like conjugated
nitriles, esters, amides, etc.
- 121 -
Chapter III
Review on aza-Michael addition reaction
NH2
O
NH
or
+
R
S
O
O
SSA, rt, 30 min
Solvent -free
O
S
O
N
H
or
O
R
N
O
S
O
Scheme 26
3-2d. Organocatalytic aza-Michael addition reaction
During the last decade, organocatalysis has been one of the most
rapidly growing and competitive field in catalytic systems. It offers several
advantages such as, mild reaction conditions, operational simplicity and easily
accessible catalytic system.
Many of the Bronsted acid catalysts discussed earlier are capable to
promote aza-Michael addition with secondary amines or primary aliphatic
amines which are sufficiently nucleophilic and they either fail or furnish azaMichael addition products with weakly nucleophilic aromatic amines.
However, Amore et al.32 have developed acetic acid mediated microwave
assisted protocol to promote addition of aromatic amines to a range of
conjugated alkenes (Scheme 27). The striking feature of the protocol is the
temperature (200 oC) of the reaction mixture at which both the starting
materials are expected to boil off.
H
N
O
NH2
Microwave, 200 oC
+
OMe
O
AcOH, 20 Min.
R
R
Scheme 27
- 122 -
OMe
Chapter III
Review on aza-Michael addition reaction
Like heterogeneous solid acid catalyst, the use of polyvinyl pyridine
(Scheme 28) as well as borax (Scheme 29) to promote the aza-Michael reaction
has been reported by two different research groups, viz. Samant et al. 33 and
Chaudhuri et al.34
N
N
PVP
+
COOMe
H
rt
COOMe
Scheme 28
R1
NH
R1
Borax 10 mol %
+
EWG
R2
rt, Water
1.5 - 8 hr / 25 - 92 %
EWG
N
R2
EWG = CO2Me, CN, CONH2, COMe, COPh
Scheme 29
Biomolecular modeling of organic chemical reactions involves
cyclodextrins as supramolecular catalysts. Like enzymes, cyclodextrins show
reversible formation of host guest complexes without covalent bonding.
Surendra et al.35 have reported the catalytic activity of β-cyclodextrin for aza
Michael addition reaction in aqueous medium (Scheme 30). This methodology
permits the use of amines of almost every class as Michael donors.
R1
NH
R2
+
R3
β -CD / H2O
R1
N
R3
R2
Scheme 30
3-2e. Ionic Liquids
Until recently, most of the organic reactions were carried out in
molecular solvents. However, in the last decade, ionic liquids have emerged as
novel reaction media to promote a variety of organic transformations.
- 123 -
Chapter III
Review on aza-Michael addition reaction
Yadav et al.36 have reported the use of both hydrophilic (1-butyl-3-
methyl imidazolium tetrafluroborate) as well as hydrophobic (1-butyl-3methyl imidazolium hexafluorophosphate) ionic liquids to promote azaMichael reaction (Scheme 31). Although the reaction medium is reusable, the
advantage of its use over to other conventional solvents is definitely
questionable because the time required for the reaction is too long.
R1
[bmim]PF6 / [bmim]BF4
NH
+
R1
rt
R2
EWG
N
EWG
R2
EWG =CN, COCH3, CO2Et, CO2Me, COPh
Scheme 31
After this first report, Xu et al.37 have reported the use of simple
quaternary ammonium salt for the same purpose (Scheme 32). Commercial
availability as well as high yield are the prime advantages of quaternary
ammonium salts. The report also shows the catalytic activity of hydrophilic
ionic liquid [bmim]BF4. The only limitation with the present protocol is the
reaction fails with aromatic amines.
O
OEt
Catalyst
+
N
H2O/rt/7hr
COOEt
+
N
NH2
COOEt
EtOOC
NH
R2
R2
R1
R1
EWG
+
N
Ionic liquid
R3
H2O / rt
EWG
R3
EWG = CN, COOEt, COOCH3, COCH3
Scheme 32
To overcome this incompleteness, recently, Xu et al.38 reported basic
ionic liquid [Emim]OH as a catalyst and green solvent for conjugate addition
- 124 -
Chapter III
Review on aza-Michael addition reaction
of aromatic amines to α-β unsaturated ketones (Scheme 33). The protocol shows
less reactivity towards α-β unsaturated ester.
O
O
R1
+
[Emim]OH
ArNH2
R1
solvent free, rt
ArNH
R2
R2
O
O
Cat. [Emim]OH
+
ArNH2
Solvent free, rt
n
n
NHAr
Scheme 33
Based upon similar philosophy Xu et al.39 has also reported the use of
[bmim]OH as a reusable, basic ionic liquid to promote the same reactions
(Scheme 34).
R4
R1
NH
R2
[bmim]OH
+
R1
R3
N
EWG
rt, 10-20 min
R3
EWG
R2
R4
EWG = CN, COCH3, CO2CH3
Scheme 34
For the same reaction, Ying et.al. have recently reported both, DBUderived and DBU-based task specific ionic liquids. Firstly, they reported
[DBU][Ac] as a efficient catalytic system for the solvent free conjugate
addition of secondary amines to α-β unsaturated ester, nitrile and amide40
(Scheme 35) in excellent yields and in acceptable results for the weak
nucleophiles like aromatic amines.
Later on, they described [DBU][Lac] as a better catalyst compared to
[DBU][Ac] while examining the catalytic activity towards addition of primary
aromatic amines41 (Scheme 36) to various α-β unsaturated ketones.
- 125 -
Chapter III
Review on aza-Michael addition reaction
O
O
Bn2NH +
[DBU][Ac]
O
rt
Bn
O
N
Bn
Scheme 35
O
O
NH2 +
[DBU][Lac]
R2
R2
R1
Solvent free, rt
R1
R3
R3
Scheme 36
3-2f. Solvent promoted aza-Michael addition reaction
Reaction media plays important role in organic synthetic chemistry.
The medium considered for reaction should include the advantage of
recyclability or easy removal with energy conservation. It should have much of
catalytic activity to promote the reaction. Most of the solvents can be easily
removed by water solubility should be extensively employed for green context.
Thus, according to environmental impact the reaction media can be recycled
with efficient number of cycles, non inflammable, high polarity for
homogeneity and also with low vapour pressure. Various reaction media like
supercritical fluids, fluorous based systems, ionic liquids and water have been
extensively used in organic transformations.
The Michael addition of anilines to electron deficient olefins proceeds
easily in water, trifluoroethanol and hexafluoroisopropanol without any
assisting agent42 (Scheme 37). Moreover, according to the nature of the solvent
and that of the electrophile, the selectivity of the reaction can be finely tuned to
afford mono-or bis-addition products, or even quinolines, in a one pot fashion.
De. et al. has extensively studied the effect of polar protic solvents in 1,4
addition of anilines on to Michael acceptors.
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Chapter III
Review on aza-Michael addition reaction
NH2
HN
R1
R1
R1
N
N
Water or TFE or HFIP
+
R
or
or
20 oC or heat
O
R
R
R
R1 = CH2-CH2-CO-CH3
R1
R1
HN
NH2
N
R1
Water or HFIP
+
CO2Me
or
heat
R
R
R
R1 = CH2-CH2-CO-CH3
Scheme 37
Kumar et al.43 described the use of inexpensive and nontoxic
polyethylene glycol (400) as the reaction medium of aza-Michael reaction of
amines as well as monoalkylated piperazine derivatives with electron deficient
alkenes (Scheme 38).
R
N
N
H +
EWG
PEG / rt
R
N
N
EWG
EWG = CN, COCH3, COOCH3
Scheme 38
Today the point of view of researchers continues with the green
chemical concept. The choice of solvent is the heart of the chemical reaction
and should be parallel with the reactivity as well as green nature of solvent.
Various reactions have been carried out in aqueous media due to its
environmental acceptability, abundance and low cost. Ranu et al have reported
rate accelerated aza-Michael reaction in water44a (Scheme 39). Surprising thing
is that scientist himself has reported the same protocol44b operable at elevated
temperature and the report was not so far extended to generalization. The latest
report shows the aza-Michael addition over α-β unsaturated esters, nitriles,
ketones and amides.
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Chapter III
Review on aza-Michael addition reaction
R1
R1
NH
+
R2
H2O
R2
X
rt
X
N
R1, R2 = H / Alkyl; X = CO2R, COR, CONH2, CN
Scheme 39
3-3
Application of aza-Michael reaction
Aza-Michael addition reaction has been extensively studied using a
variety of catalysts as well as solvents as summarized earlier and various
researchers have also reported the utility of aza Michael addition towards the
synthesis of various pharmacological active compounds45 as well as natural
products46 like colchicine, podophylotoxin and combretastatine A-4, etc.
Noteworthy applications of intramolecular aza-Michael addition lies in the
synthesis of
6,7,2’,3’,4’-substituted-1,2,3,4-tetrahydro-2-phenylquinolone
which shows potent cytotoxic and antitubuline effects.
Verma et al. have reported microwave assisted isomerisation of 2’amino chalcone on clay48 (Scheme 40.1). Microwave heating is used for
induction of the reaction under dry condition with salient features of rapid
reaction rate and cleaner reactions. Various 2’-aminochalcones have been used.
The isolated yield was 70-80%.
O
O
Reaction condition
R2
NH2
R1
R2
N
H
Scheme and reaction conditions
40.1 K-10, Clay, Micrwave.
40.2 InCl3-SiO2, Microwave.
40.3 Silica gel supported TaBr5, 140-150oC
40.4 Allumina / Silica gel supported CeCl3.7H2O-NaI, 70oC
40.5 SbCl3, acetonitrile, 55oC
- 128 -
R1
Chapter III
Review on aza-Michael addition reaction
Subsequently, Perumal et al.49 reported indium trichloride supported
on silica gel to effect the same transformations using microwave dielectric
heating technique in almost same yields (Scheme 40.2).
Later on, two more procedures for intramolecular aza-Michael reaction
were reported. Van Lier et al. reported tantalum pentabromide adsorbed on
silica gel as a lewis acid catalyst (Scheme 40.3). in this protocol, instead of
microwave dielectric heating reaction was carried out under conventional
heating50.
Later on, alumina supported cerium chloride heptahydrate-sodium
iodide51 was reported to be relatively less expensive catalyst for the synthesis
of targeted dihydroquinilines in improved yields (Scheme 40.4).
For developing both the solution phase reaction as well as solid
supported reactions, Bhattacharya et al.52 have reported antimony trichloride
as a effective catalyst for isomerization of 2’-amino chalcones. The catalyst is
effective in cost, handling and yield of the product (Scheme 40.5).
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Chapter III
3-4
Review on aza-Michael addition reaction
Concluding remarks
Last few years have witnessed tremendous achievements in the field of
catalytic aza-Michael additions. The reaction has great potential in organic
synthesis, primarily because of the ubiquitous presence of β-amino acids or
alcohols in many natural products as partial structures or in designed hybrid
scaffolds containing β-amino acids/alcohols, due to their role played in
bioprocesses as isosteres of α-amino acids. Although there is still no any report
for “universal” catalyst (and will probably never be one) for all types of
nucleophiles and Michael acceptors, in this chapter an impressive number of
highly efficient systems has been compiled by us. By this compilation we are
inspired to contribute towards aza-Michael addition, which is developing in
multitude.
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Chapter III
3-5
References
1.
(a) Michael, A.
Review on aza-Michael addition reaction
J. Prakt. Chem. 1887, 3 , 349.
(b) Michael, A.
Am. Chem. J. 1887, 9, 112.
2.
For review: Bergmann, E. D.; Ginsburg, D.; Pappo, R.
Org. React. 1959, 10, 179.
3
Perlmutter, P.
Conjugate Addition Reaction in Organic Synthesis
Pergamon Press. Oxford. 1992.
4
(a) Reviews: Liu, M.; Sibi, M. P.
Tetrahedron. 2002, 58, 7991.
(b) Vicario, J. L.; Badia, D.; Carrillo, L.
Org. Prep. Proc. Int. 2005, 37, 513.
(c) Xu, L.-W.; Xia, C.-G.
Eur. J. Org. Chem. 2005, 633.
5
(a) Arend, M.; Westermann, B.; Risch, N.
Angew. Chem. Int. Ed. 1998, 37, 1045.
(b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jaspers, C. P.
J. Am. Chem. Soc. 1998, 120, 6615.
6
Matsubara, S.; Yoshioka, M.; Utimoto, K.
Chemistry Letters. 1994, 827.
7
Loh, T.-P.; Wei, L.-L.
Synlett. 1998, 975.
8
kawatsura, M.; Hartwig, J. F.
Organometallics. 2001, 20, 1960.
9
Fadini, L.; Togni, A.
Chem. Commun. 2003, 30, 30.
10
Srivastava, N.; Banik, B. K.
J. Org. Chem. 2003, 68, 2109.
- 131 -
Chapter III
11
Review on aza-Michael addition reaction
(a) Xu, L.-W.; Li, J.-W.; Xia, C.-G.; Zhou, S.-L.; Hu, X.-X.
Synlett. 2003, 15, 2425.
(b) Xu, L.-W.; Li, L.; Xia, C.-G.
Helv. Chim. Acta. 2004, 87, 1522.
12
Reboule, I.; Gil, R.; Colline, J.
Tetrahedron Lett. 2005, 46, 7761.
13
Varala, R.; Sreelatha, N.; Adapa, S. R.
Synlett. 2006, 10, 1549.
14
Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y.
Tetrahedron Lett. 2006, 47, 5433.
15
Bhanushali, M. J.; Nandurkar, N. S.; Jagtap, S. R.; Bhanage, B. M.
Catal. Commun. 2008, 9, 1189.
16
Firauzabadi, H.; Iranpoor, N.; Jafarpour, M.; Ghaderi, A.
J. Mol. Cat. A: Chemical. 2006, 252, 150.
17
Azizi, N.; Saidi, M. R.
Tetrahedron. 2004, 60, 383.
18
Shaikh, N. S.; Deshpande, V. H.; Bedekar, A. V.
Tetrahedron. 2001, 57, 9045.
19
Basu, B.; Das, P.; Hossain, I.
Synlett. 2004, 14, 2630.
20
You, L.; Feng, S.; An, R.; Wang, X.; Bai, D.
Tetrahedron Lett. 2008, 49, 5147.
21
Das, B.; Chaudhury, N.
J. Mol. Cat A: Chemical. 2007, 263, 212.
22
Esteves, A. P.; Silva, M. E.; Rodrigues, L. M.; Ana, M. F.; Campos, O.;
Hrdina, R.
Tetrahedron Lett. 2007, 48, 9040.
23
Chen, X.; She, J.; Shang, Z.; Wu, J.; Zhang, P.
Synthesis. 2008, 24, 3931.
24
Azad, S.; Kobayashi, T.; Nakano, K.; Ichikawa,Y.; Kotsuki, H.
Tetrahedron Lett. 2009, 50, 48.
- 132 -
Chapter III
25
Review on aza-Michael addition reaction
Reddy, B. M.; Patil, M. K.; Reddy, B. T.
Catal. Lett. 2008, 126, 413.
26
Kantam, M. L.; Roy, M.; Roy, S.; Subhas, M. S.; Sreedhar, B.; Choudury,
B.; Rajib Lal De, M.
J. Mol. Cat A: Chemica, 2007, 265, 244.
27
Saidi, M. R.; Pourshojaei, Y.; Aryansab, F.
Synth. commun. 2009, 39, 1109.
28
Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torregiani, E.
J. Org. Chem. 2001, 66, 9052.
29
(a) Mukherjee, C.; Misra, A. K.
Lett. In Org. Chem. 2007, 4, 54.
(b) Singh, S. P.; Vijaya Kumar, T.; Chandrashekaram, M.; Giribabu, L.;
Yella Reddy, P.
Synth. commun. 2009, 39, 3982.
30
Nath, J.; Chauduri, M K.
Catalysis Letters. 2009.
31
Wang, Y.; Yuan, Y.-Q.; Guo, S.-R.
Molecules, 2009, 14, 4779.
32
Amore, K. M.; Leadbeater, N. E.; Miller, T. A.; Schmink, J. R.
Tetrahedron Lett. 2006, 47, 8583.
33
Raje, V. P.; Bhat, R. P.; Samant, S. D.
Synlett. 2006, 16, 2676.
34
Hussain, S.; Bhardwaj, S. K.; Chaudhuri, M. K.; Kalita, H.
Eur. J. Org. Chem. 2007, 374.
35
Surendra, K.; Shrilakshmi krishnaveni, N.; Sridhar, R.; Ramarao, K.
Tetrahedron Lett. 2006, 47, 2125.
36
Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V.
Chemistry Letters. 2003, 32(11), 988.
37
Xu, L.-W.; Li, J.-W.; Zhou, S.-L.; Xia, C.-G.
New J. Chem. 2004, 28, 183.
38
Yang, L.; Xu, L.-W.; Zhou, W.; Li, L.; Xia, C. G.
- 133 -
Chapter III
Review on aza-Michael addition reaction
Tetrahedron Lett. 2006, 47, 7723.
39
Xu, J.-M.; Wu, Q.; Zhang, Q.-Y.; Zhang, F.; Lin, X.-F.
Eur. J. Org. Chem. 2007, 1798.
40
Ying, A.-G.; Liu, L.; Wu, G.-F.; Chen, G.; Chen, X.-Z.; Ye, W.-D.
Tetrahedron Lett. 2009, 50, 1653.
41
Ying, A.-G.; Wang, L.-M.; Deng, H.-X.; Chen, J.-H.; Chen, X.-Z.; Ye,
W.-D.
Arkivok, 2009, Xi, 288.
42
De, K.; Legros, J.; Crouse, B.; Daniele, B.-D.
J. Org Chem. 2009, 74, 6260.
43
Kumar, R.; Chaudhary, P.; Nimesh, S.; Chandra, R.
Green Chemistry. 2006, 8, 356.
44
(a) Ranu, B. C.; Banerjee, S.
Tetrahedron Lett. 2007, 48, 141
(b) Ranu, B. C.; Dey, S. S.; Hajra, A.
Arkivoc, 2002, vii, 76.
45
Kalinin, V. N.; Shostakovski, M. V.; Ponomaryov, A.B.
Tetrahedron Lett. 1992, 33, 373.
46
(a) Singh, O. V.; Kapil, R. S.
Synth. Commun. 1993, 2, 277.
(b) Prakash, O.; Kumar, D.; Saini, R. K.; Singh, S. P.
Synth. commun. 1994, 24, 2167.
47
Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S.-C.;
Hamel, E.; Hackl, T.; Lee, K.-H.
J. Med. Chem. 1998, 41, 1155.
48
Varma, R. S.; Saini; R. k.
Synlett. 1997, 857.
49
Hemanth Kumar, K.; Muralidharan, D.; Perumal, P. T.
Synthesis, 2004, 1, 0063.
50
Ahmed, N.; Van Lier, J. E.
Tetrahedron Lett. 2006, 47, 2725.
- 134 -
Chapter III
51
Review on aza-Michael addition reaction
Ahmed, N.; Van Lier, J. E.
Tetrahedron Lett. 2007, 48, 13.
52
Bhattacharya, R. N.; Kundu, P.; Maiti, G.
Synth commun. 2010, 40, 476.
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