Bromodimethylsulfonium bromide catalyzed three-component Mannich-type reactions

Article abstract of DOI:10.1002/ejoc.200700643

Bromodimethylsulfonium bromide catalyzes Mannich-type reactions of a variety of aldimines, generated in situ from aldehydes and anilines, with enolizable ketones or diethyl malonate in three-component reactions to afford the corresponding β-amino carbonyl compounds. The salient features of this protocol are: shorter reaction times, simplicity of the procedure, good to excellent yields, avoidance of aqueous workup and column-chromatographic separations, and high stereoselectivities. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700643

FULL PAPER
DOI: 10.1002/ejoc.200700643
Bromodimethylsulfonium Bromide Catalyzed Three-Component Mannich-Type
Reactions
Abu T. Khan,*[a] Tasneem Parvin,[a] and Lokman H. Choudhury[b]
Keywords: β-Amino carbonyl compounds / Aldehydes / Amines / Bromodimethylsulfonium bromide
Bromodimethylsulfonium bromide catalyzes Mannich-type
reactions of a variety of aldimines, generated in situ from al-
procedure, good to excellent yields, avoidance of aqueous
workup and column-chromatographic separations, and high
dehydes and anilines, with enolizable ketones or diethyl ma- stereoselectivities.
lonate in three-component reactions to afford the corre-
sponding β-amino carbonyl compounds. The salient features
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
of this protocol are: shorter reaction times, simplicity of the
Germany, 2008)
and using directly carbonyl compounds as nucleophiles was
introduced.
Introduction
Owing to the importance of β-amino carbonyl com-
pounds, numerous methods for the synthesis of these com-
pounds either by indirect-type or direct-type Mannich reac-
tions have been reported over the years. Recently, direct-
type Mannich reactions of aldehydes, enolizable ketones or
diethyl malonate, and arylamines in the presence of various
catalysts such as NbCl5,[5] Zn(OTf)2,[6] silica sulfuric acid,[7]
Yb(OPf)3,[8] [NaBArF4],[9] ZrOCl2·8H2O,[10] etc. have been
reported. Although these methodologies are useful, most of
the methods still encounter some limitations, such as
requirements for expensive catalysts or longer reaction
times. It is thus evident that there remains a wide scope for
the development of clean and efficient methodologies for
the preparation of β-amino carbonyl compounds through a
convenient and environmentally friendly method.
Bromodimethylsulfonium bromide (BDMS) is a readily
accessible, cheap, and highly effective reagent,[11] as well as
a catalyst for various organic transformations.[12] Recently,
Das et al. reported the efficiency of bromodimethylsulfon-
ium bromide in one-pot multicomponent syntheses of
homoallylic amines.[13] In addition, very recently we have
demonstrated the virtue of this catalyst for Michael ad-
ditions of amines to electron-deficient alkenes.[12a] In con-
tinuation of our work on the development of new synthetic
methodologies,[14] we sought to explore the advantages of
this reagent further for other important transformations.
Here we report a simple and effective methodology for one-
pot, three-component, Mannich-type reactions of aromatic
aldehydes, aromatic amines, and enolizable ketones or di-
ethyl malonates in the presence of BDMS as a catalyst as
shown in Scheme 1.
Multicomponent reactions (MCRs) are of increasing im-
portance in organic and medicinal chemistry, as high de-
grees of molecular diversity can be introduced in these reac-
tions in a very fast, efficient, and timesaving manner, and
without the isolation of any intermediates. As a result, con-
siderable attention has been paid to the development of new
and improved one-pot multicomponent reactions in recent
years.[1]
A Mannich-type reaction is a multicomponent reaction
of a non-enolizable aldehyde, a primary or secondary
amine, and an enolizable carbonyl compound to afford the
corresponding β-amino carbonyl compound.[2] These β-
amino carbonyl compounds are important synthetic inter-
mediates for various pharmaceuticals and natural prod-
ucts[3] and have found wide application in organic synthesis.
The classical Mannich reaction has some limitations,
such as requirements for harsh reaction conditions and long
reaction times. In addition, indirect-type[4] Mannich reac-
tions using preformed electrophiles such as imines and
stable nucleophiles such as enolates or enol ethers suffer
from the drawback of the necessity for the isolation and
purification of the preformed intermediates. Therefore, a
modified and improved methodology, known as the direct-
type Mannich reaction, in the presence of various catalysts
[a] Department of Chemistry, Indian Institute of Technology
Guwahati,
Guwahati 781039, India
E-mail: atk@iitg.ernet.in
[b] Department of Basic Sciences and Social Sciences, North-
Eastern Hill University,
Shillong 793022, India
834
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 834–839

Three-Component Mannich-Type Reactions
Scheme 1.
ketones on treatment with aniline and acetophenone sepa-
rately under the same experimental conditions. We believe
that the nitro-substituted aldehydes prefer the aldol reac-
tion followed by subsequent dehydration rather than in situ
aldimine formation and subsequent nucleophilic addition.
Next, terephthalaldehyde was treated with 2 equiv. of ani-
line and acetophenone to afford a bis product as shown in
Table 1 (Entry 14).
Next, to generalize the method, aliphatic aldehydes such
as acetaldehyde were treated with aniline and acetophenone
under the same experimental conditions. After 12 h of stir-
ring, we were unable to obtain the desired Mannich prod-
ucts. Similarly, the combination of an aliphatic amine such
as butylamine with benzaldehyde and acetophenone under
the same experimental conditions was not successful even
after prolonged stirring. Likewise, the reaction of an ali-
phatic ketone such as acetone was also not applicable for a
Mannich-type reaction with benzaldehyde and aniline un-
der the given experimental conditions. Next, in an attempt
to check the applicability of benzylamine, we were unsuc-
cessful in achieving the desired β-amino ketone. From these
studies we have established that our new method is a selec-
tive procedure for Mannich-type reactions of aromatic alde-
hydes, amines, and ketones.
Results and Discussion
Initially, the three-component Mannich-type reaction of
benzaldehyde (2.0 mmol), aniline (2.0 mmol), and aceto-
phenone (2.0 mmol) in the presence of bromodimethylsul-
fonium bromide as a catalyst was examined. Interestingly,
we observed that 10 mol-% of bromodimethylsulfonium
bromide is sufficient to catalyze the three-component, one-
pot reaction in a very good yield within 30 min. In the ab-
sence of the catalyst the reaction failed to provide the de-
sired product even after 48 h of stirring. Interestingly, this
protocol offers a wealth of advantages over the indirect
methods, since there is no need for the preparation of silyl
enol ethers or preformed imines. In the screening of dif-
ferent solvents to find the most suitable solvent for this
transformation, ethanol was found to be superior to other
solvents such as THF, toluene, 1,4-dioxane, and CH2Cl2 in
terms both of reaction time and of yields obtained. Encour-
aged by this result, we examined the scope of this protocol
by using various electron-withdrawing aromatic aldehydes
and amines. It is interesting to note that the pure products
of all these reactions can be obtained just by recrystallisation
of the crude materials from ethanol, avoiding aqueous
workup and tedious column-chromatographic separation.
Next, benzaldehyde was treated individually with a vari-
ety of aromatic amines such as 3-chloro-, 2-nitro-, or 4-
nitroaniline in combination with acetophenone, which pro-
vided very good to excellent yields within 30 min to 1 h
(Table 1, Entries 2–4). It is gratifying to mention that this
method does not suffer from any steric effects for ortho-
substituted amines such as 2-nitroaniline as reported for
other recent methods.[5] Similarly 4-ethylaniline provided
the desired β-amino ketone with good yields (Table 1, En-
try 5).
After that, to extend the preparative utility and general-
ity of this multicomponent reaction, benzaldehyde and 4-
chlorobenzaldehyde were treated individually with aniline
and 3-chloroaniline in combination with other enolizable
carbonyl compounds such as cyclohexanone or diethyl ma-
lonate under the same experimental conditions, as shown in
Scheme 2.
The results are summarized in Table 2. Interestingly, the
reactions of cyclohexanone with benzaldehyde or 4-chloro-
benzaldehyde exhibit good diastereoselectivity and provide
the anti isomers as the major products (Table 2, Entries 1–
3). A similar diastereoselectivity was also observed by
Hashemi and his group.[10] The anti/syn ratios were deter-
Next, aldehydes substituted with electron-withdrawing
groups, such as 3-bromo- and 4-chlorobenzaldehyde, were
treated separately with a variety of aromatic amines in com-
bination with acetophenone under the same experimental
conditions, and the corresponding desired products were
isolated in very good yields without any difficulty (En-
tries 6–13). It is worth mentioning that nitro aldehydes such
1
mined by H NMR spectroscopy. To confirm the anti con-
figurations of these products unambiguously, compound 5b
was recrystallised from ethanol and a single-crystal XRD
as 4-nitrobenzaldehyde and 3-nitrobenzaldehyde provided was performed. The ORTEP plot of the product, showing
the corresponding chalcones instead of the desired β-amino the anti configuration, is depicted in Figure 1. The unit cell
Eur. J. Org. Chem. 2008, 834–839
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
835

A. T. Khan, T. Parvin, L. H. Choudhury
FULL PAPER
Table 1. Three-component bromodimethylsulfonium bromide catalyzed direct Mannich-type reactions of various aromatic aldehydes,
amines, and ketones.
[a] All the products were fully characterized by the usual spectroscopic techniques. [b] Isolated yield.
Scheme 2.
consists of four molecules, and they exhibit intermolecular
hydrogen bonding between the C=O group of one molecule
Figure 1. ORTEP plot of 5b showing anti configuration.
and the N–H group of another.
Likewise, diethyl malonate also reacted under the same ethyl ester of the β-amino acid (Table 2, Entries 4–5) in
experimental conditions and provided the corresponding good yields (Scheme 3).
836
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 834–839

Three-Component Mannich-Type Reactions
Table 2. BDMS-catalyzed multicomponent reactions of aromatic aldehydes, amines, and either cyclohexanone or diethyl malonate.
Entry
R
RЈ
Product[a]
Time
Yield[b] (%)
anti/syn[c]
1
2
3
4
5
H
H
4-Cl
H
H
5a
5b
5c
6a
6b
15 min
15 min
20 min
6 h
86[6]
92[7]
88
98:2
98:2
99:1
–
3-Cl
3-Cl
H
92[6]
94
H
3-Cl
7 h
–
[a] All the products were fully characterized by usual spectroscopic techniques. [b] Isolated yields. [c] Ratios were determined by 1H NMR
spectroscopy.
Table 3. Comparison of the catalytic activity of BDMS with those of different catalysts for the Mannich reaction of benzaldehyde, aniline,
and acetophenone.
Run
Catalyst
Reaction conditions
Reaction time
Yield (%)[a]
1
2
3
4
5
6
7
no catalyst
FeCl3
NbCl5
EtOH, room temp.
EtOH, room temp.
EtOH, room temp.
PhCH3/C6F5CF3
EtOH, room temp.
H2O, 30 °C
48 h
24 h
12 h
12 h
12 h
48 h
30 min
n.r.
n.r.[6]
95[6]
98[9]
92[8]
81[10]
96
Yb(OPf)3
silica sulfuric acid
[NaBArF
BDMS
]
4
EtOH, room temp.
[a] Corresponding reference; n.r. = no reaction.
with its simultaneous transformation into Me2SO and HBr.
The nucleophilic additions of enolizable ketones into these
imines in the presence of HBr, followed by hydrolysis, af-
forded β-amino carbonyl compounds. The reaction between
Me2SO and HBr then regenerated the bromodimethylsul-
fonium bromide catalyst (Scheme 4).
Scheme 3. syn and anti isomers of product 5b.
Conclusions
We have demonstrated the efficacy and generality of bro-
modimethylsulfonium bromide as a versatile catalyst for the
synthesis of β-amino carbonyl compounds through the
Mannich-type reactions of a variety of aldimines, generated
in situ from aldehydes and anilines, with enolizable ketones
or diethyl malonate. The salient features of this protocol
are: (a) the simplicity of the procedure, (b) the ready ac-
cessibility of the catalyst and its cost effectiveness, (c) the
avoidance of column chromatography, and (d) high yields
and good diastereoselectivities.
It is worth mentioning that this method is faster, more
cost-effective, and simpler than most of the existing meth-
ods. The efficacy and generality of the catalyst bromodime-
thylsulfonium bromide can be gauged by comparison
(Table 3). For this comparison the reaction of acetophe-
none, benzaldehyde, and aniline was chosen as a model re-
action, and comparison was carried out on the basis of re-
action conditions, reaction time, and percentage yields ob-
tained.
The catalyst bromodimethylsulfonium bromide is an in-
expensive reagent. We believe that BDMS catalyzes these
conversions through the rapid formation of imines, along
Experimental Section
General: Melting points were recorded with a Büchi B-545 melting
point apparatus. IR spectra were recorded in KBr with a Nicolet
Impact 410 spectrophotometer. 1H and 13C NMR spectra were re-
corded with a Varian 400 MHz spectrometer in CDCl3 with TMS
as internal reference. Elemental analyses were carried out with a
Perkin–Elmer 2400 automatic C,H,N,S analyzer. The XRD was
performed with a Bruker Nonius Smart Apex II single-crystal X-
ray diffractometer. CCDC-665099 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Preparation of Bromodimethylsulfonium Bromide (BDMS):[15] Di-
methyl sulfide (1.83 mL, 25 mmol) was added to dry dichlorometh-
ane (5 mL) in a 150 mL standard joint conical flask. Then, bromine
Scheme 4. Plausible mechanistic illustration of BDMS-catalyzed
Mannich-type reactions.
Eur. J. Org. Chem. 2008, 834–839
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
837

A. T. Khan, T. Parvin, L. H. Choudhury
FULL PAPER
(1.3 mL, 25 mmol) was dissolved in dry dichloromethane (5 mL) 128.3, 128.5, 128.8, 128.9, 133.5, 133.8, 136.7, 143.2, 144.9,
and added slowly to the above solution at ice-bath temperature
over a period of 5 min. During the addition, light orange crystals
of bromodimethylsulfonium bromide began to separate. After the
addition of bromine was complete, the crystals of bromodimethyl-
sulfonium bromide were collected by filtration. The solid material
was then washed with dry hexane and dried under vacuum. The
crystalline product (4.3 g) was obtained in 77% yield, m.p. 80 °C.
198.4 ppm. IR (KBr): ν = 3400, 1679 cm–1. C H NO (329.44): C
83.86, H 7.04, N 4.25; found C 83.60, H 7.11, N 4.38.
˜
23 23
3-(4-Chlorophenyl)-3-[(3-chlorophenyl)amino]-1-phenylpropan-1-one
1
(4g): Yield: 0.726 g, 98%. White solid, m.p. 117–118 °C. H NMR
(400 MHz, CDCl3): δ = 3.42–3.46 (m, 2 H), 4.71 (br. s, 1 H), 4.93–
4.96 (m, 1 H), 6.40 (d, J = 8.4 Hz, 1 H), 6.51 (s, 1 H), 6.64 (d, J =
8.0 Hz, 1 H), 6.99 (t, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 2 H),
7.36 (d, J = 8.4 Hz, 2 H), 7.46 (t, J = 7.2 Hz, 2 H), 7.58 (t, J =
8.4 Hz, 1 H), 7.89 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): 46.4, 54.4, 112.4, 114.0, 118.4, 128.2, 128.6, 129.3, 129.5,
130.6, 133.6, 134.2, 135.3, 136.9, 141.4, 148.4, 198.2 ppm. IR
General Reaction Procedure: Bromodimethylsulfonium bromide
(0.2 mmol) was added to a mixture of benzaldehyde (2 mmol), ani-
line (2 mmol), and acetophenone (2 mmol), and the reaction mix-
ture was stirred at room temperature. The progress of the reaction
was monitored by TLC. After completion of the reaction, the crude
solid was just filtered off and washed with a hexane/ethanol (80:20)
mixture. The solid residue was then dissolved in hot ethanol and
was recrystallized to provide the pure product. The pure product
was characterized by conventional spectroscopic methods, and its
data were compared with those reported.[4]
(KBr): ν = 3376, 1684 cm–1. C H Cl NO (370.28): C 68.12, H
˜
21 17
2
4.63, N 3.78; found C 67.90, H 4.57, N 3.69.
3-(4-Chlorophenyl)-3-[(2-nitrophenyl)amino]-1-phenylpropan-1-one
(4h): Yield: 0.663 g, 87%. Yellow solid, m.p. 92–93 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.48 (dd, J = 4.4 Hz, J = 16.8 Hz, 1 H),
3.62 (dd, J = 6.4 Hz, J = 16.4 Hz, 1 H), 5.29–5.33 (m, 1 H), 6.64
(t, J = 8.8 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 7.28–7.32 (m, 3 H),
7.36 (d, J = 7.6 Hz, 2 H), 7.44 (t, J = 8.0 Hz, 2 H), 7.56 (t, J =
7.2 Hz, 1 H), 7.89 (d, J = 7.2 Hz, 2 H), 8.14 (d, J = 8.8 Hz, 1 H),
8.57 (d, J = 5.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
46.7, 53.1, 115.0, 116.4, 127.0, 128.0, 128.3, 129.0, 129.4, 132.7,
3-[(3-Chlorophenyl)amino]-1,3-diphenylpropan-1-one (4b): Yield:
1
0.658 g, 98%. White solid, m.p. 140–141 °C. H NMR (400 MHz,
CDCl3): δ = 3.42 (dd, J = 7.2 Hz, J = 16.4 Hz, 1 H), 3.50 (dd, J =
4.8 Hz, J = 16.0 Hz, 1 H), 4.71 (br. s, 1 H), 4.97 (t, J = 6.0 Hz 1
H), 6.42 (d, J = 8.0 Hz, 1 H), 6.54 (s, 1 H), 6.62 (d, J = 7.6 Hz, 1
H), 6.98 (t, J = 8.0 Hz, 1 H), 7.27 (d, J = 7.2 Hz, 1 H), 7.34 (t, J
= 7.2 Hz, 2 H), 7.41–7.47 (m, 4 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.90
(d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 45.9,
54.5, 111.8, 113.5, 117.5, 126.1, 127.4, 128.0, 128.6, 128.8, 129.9,
133.7, 134.0, 136.4, 136.5, 140.3, 144.2, 196.5 ppm. IR (KBr): ν =
˜
3376, 1685, 1591, 1297 cm–1. C21H17ClN2O3 (380.83): C 66.23, H
4.50, N 7.36; found C 66.32, H 4.42, N 7.25.
133.4, 134.6, 136.4, 142.1, 148.0, 197.9 ppm. IR (KBr): ν = 3372,
˜
3-(4-Chlorophenyl)-3-[(4-nitrophenyl)amino]-1-phenylpropan-1-one
(4i): Yield: 0.739 g, 97%. Yellow solid, m.p. 150–151 °C (ref.[16] m.p.
149–150 °C). 1H NMR (400 MHz, CDCl3): δ = 3.52 (d, J = 6.4 Hz,
2 H), 5.07 (q, J = 6.0 Hz, 1 H), 5.56 (d, J = 6.0 Hz, 1 H), 6.50 (d,
J = 9.2 Hz, 2 H), 7.30–7.35 (m, 4 H), 7.47 (t, J = 8.0 Hz, 2 H),
7.60 (t, J = 7.6 Hz, 1 H), 7.89 (d, J = 7.6 Hz, 2 H), 8.01 (d, J =
9.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 45.5, 53.7,
112.4, 126.4, 127.8, 128.3, 129.0, 129.4, 133.7, 134.1, 136.3, 138.6,
1686 cm–1. C21H18ClNO (335.83): C 75.11, H 5.40, N 4.17; found
C 75.28, H 5.43, N 4.07.
1,3-Diphenyl-3-[(2-nitrophenyl)amino]propan-1-one (4c): Yield:
1
0.610 g, 88%. Yellow solid, m.p. 100–101 °C. H NMR (400 MHz,
CDCl3): δ = 3.52 (dd, J = 5.2 Hz, J = 17.2 Hz, 1 H), 3.66 (dd, J =
7.6 Hz, J = 17.2 Hz, 1 H), 5.33–5.39 (m, 1 H), 6.63 (t, J = 7.2 Hz,
1 H), 6.80 (d, J = 8.0 Hz, 1 H), 7.29–7.37 (m, 4 H), 7.43–7.48 (m,
4 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.92 (d, J = 7.2 Hz, 2 H), 8.16 (d,
J = 7.2 Hz, 1 H), 8.63 (br. s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 47.2, 54.0, 115.5, 116.5, 126.8, 127.3, 128.3, 128.7,
129.3, 129.6, 133.0, 134.1, 136.7, 136.9, 142.0, 144.8, 197.2 ppm.
139.9, 152.2, 197.7 ppm. IR (KBr): ν = 3375, 1685, 1593, 1296
˜
cm–1. C21H17ClN2O3 (380.83): C 66.23, H 4.50, N 7.36; found C
66.31, H 4.46, N 7.27.
3-(4-Chlorophenyl)-3-[(4-ethylphenyl)amino]-1-phenylpropan-1-one
(4j): Yield: 0.691 g, 95%. White solid, m.p. 91–92 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.12 (t, J = 7.6 Hz, 3 H), 2.47 (q, J =
7.6 Hz, 2 H), 3.47 (d, J = 7.2 Hz, 2 H), 4.71(br. s, 1 H), 4.92 (t, J
= 6.8 Hz, 1 H), 6.51 (d, J = 8.4 Hz, 2 H), 6.92 (d, J = 8.4 Hz, 2
H), 7.26 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.43 (t, J
= 7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 16.0, 28.1, 46.1, 55.2,
114.8, 128.2, 128.4, 128.7, 128.9, 129.1, 133.2, 133.8, 134.8, 136.6,
IR (KBr): ν = 3370, 1685, 1592, 1352 cm–1. C H N O (346.38):
˜
21 18
2
3
C 72.82, H 5.24, N 8.09; found C 72.93, H 5.20, N 7.94.
1,3-Diphenyl-3-[(4-nitrophenyl)amino]propan-1-one (4d): Yield:
0.658 g, 95%. Yellow solid, m.p. 177–178 °C (ref.[16] m.p. 179–
1
180 °C). H NMR (400 MHz, CDCl3): δ = 3.53 (d, J = 6.8 Hz, 2
H), 5.10 (t, J = 6.0 Hz, 1 H), 5.58 (br. s, 1 H), 6.52 (d, J = 9.2 Hz,
2 H), 7.28 (d, J = 7.2 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 7.38 (t,
J = 7.2 Hz, 3 H), 7.46 (t, J = 7.6 Hz, 2 H), 7.59 (t, J = 7.2 Hz, 1
H), 7.89 (d, J = 7.2 Hz, 2 H), 8.00 (d, J = 9.2 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 46.0, 55.0, 101.9, 112.9, 126.7, 128.5,
128.7, 129.3, 129.7, 134.4, 136.9, 139.1, 141.6, 152.6, 198.4 ppm.
141.3, 143.9, 198.0 ppm. IR (KBr): ν = 3400, 1680 cm–1
.
˜
C23H22ClNO (363.89): C 75.92, H 6.09, N 3.85; found C 75.71, H
6.12, N 3.96.
IR (KBr): ν = 3371, 1685, 1590, 1350 cm–1. C H N O (346.38):
˜
21 18
2
3
3-(3-Bromophenyl)-1-phenyl-3-(phenylamino)propan-1-one (4k):
Yield: 0.685 g, 90 %. Light blue solid, m.p. 95–96 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.47–3.50 (m, 2 H), 4.68 (br. s, 1 H), 4.94–
4.97 (m, 1 H), 6.58 (d, J = 7.6 Hz, 2 H), 6.72 (t, J = 7.2 Hz, 1 H),
7.11 (t, J = 7.2 Hz, 2 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.37 (d, J =
7.6 Hz, 1 H), 7.41 (d, J = 7.6 Hz, 1 H), 7.46 (t, J = 7.2 Hz, 2 H),
7.58 (t, J = 7.2 Hz, 1 H), 7.60 (s, 1 H), 7.91 (d, J = 7.2 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): 46.2, 55.0, 114.4, 118.7, 123.2,
C 72.82, H 5.24, N 8.09; found C 72.65, H 5.16, N 8.19.
3-[(4-Ethylphenyl)amino]-1,3-diphenylpropan-1-one (4e): Yield:
1
0.639 g, 97%. White solid, m.p. 126–127 °C. H NMR (400 MHz,
CDCl3): δ = 1.13 (t, J = 7.6 Hz, 3 H), 2.48 (q, J = 7.6 Hz, 2 H),
3.42 (dd, J = 7.6 Hz, J = 16.4 Hz, 1 H), 3.51 (dd, J = 5.2 Hz, J =
16.4 Hz, 1 H), 4.60 (br. s,1 H), 4.97 (dd, J = 5.2 Hz, J = 7.6 Hz 1
H), 6.51 (d, J = 8.4 Hz, 2 H), 6.93 (d, J = 8.4 Hz, 2 H), 7.23 (t, J
= 7.2 Hz, 1 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.42–7.46 (m, 4 H), 7.56 125.4, 128.4, 129.0, 129.4, 129.8, 130.6, 130.8, 133.8, 134.9, 145.4,
(t, J = 7.2 Hz, 1 H), 7.91 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.0, 28.0, 46.4, 55.2, 114.2, 126.6, 127.4,
146.4, 197.9 ppm. IR (KBr): ν = 3380, 1681 cm–1. C H BrNO
(380.28): C 66.33, H 4.77, N 3.68; found C 66.42, H 4.70, N 3.59.
˜
21 18
838
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 834–839

Three-Component Mannich-Type Reactions
3-(3-Bromophenyl)-3-[(4-nitrophenyl)amino]-1-phenylpropan-1-one
(4l): Yield: 0.757 g, 89%. Light yellow solid, m.p. 159–160 °C. H
Acknowledgments
1
NMR (400 MHz, CDCl3): δ = 3.48 (d, J = 6.0 Hz, 2 H), 5.02 (q,
J = 6.0 Hz, 1 H), 5.48 (d, J = 6.4 Hz, 1 H), 6.48 (d, J = 9.2 Hz, 2
H), 7.18 (t, J = 8.0 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.37 (d, J
= 8.0 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.51 (s, 1 H), 7.57 (t, J =
7.2 Hz, 1 H), 7.87 (d, J = 7.2 Hz, 2 H), 7.99 (d, J = 9.2 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): 45.5, 53.8, 112.3, 123.3, 125.0,
126.3, 128.2. 128.9, 129.3, 130.8, 131.2, 134.0, 136.1, 138.7, 143.8,
T. P. is thankful to the Indian Institute of Technology Guwahati
(IITG) for her research fellowship. The authors are grateful to the
Director, IITG for providing the general research facilities to carry
out this work. We are thankful to the Department of Science and
Technology for providing the XRD facility under the FIST pro-
gramme to the Department of Chemistry. A. T. K. is also grateful
to Prof. Dr. R. R. Schmidt, Universität Konstanz, and to the Alex-
ander von Humboldt Foundation for providing a short-term fel-
lowship in Germany. We are thankful to the referees for their valu-
able comments.
152.0, 197.4 ppm. IR (KBr): ν = 3380, 1685, 1598, 1337 cm–1
.
˜
C21H17BrN2O3 (425.28): C 59.31, H 4.03, N 6.59; found C 59.10,
H 4.08, N 6.50.
3-(3-Bromophenyl)-3-[(4-ethylphenyl)amino]-1-phenylpropan-1-one
(4m): Yield: 0.751 g, 92 %. White solid, 119–120 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.11 (t, J = 7.6 Hz, 3 H), 2.46 (q, J =
7.6 Hz, 2 H), 3.35 (dd, J = 7.6 Hz, J = 16.4 Hz, 1 H), 3.44 (dd, J
= 5.2 Hz, J = 16.0 Hz, 1 H), 4.40 (br. s, 1 H), 4.88 (dd, J = 5.2, J
= 7.2 Hz, 1 H), 6.45 (d, J = 8.4 Hz, 2 H), 6.91 (d, J = 8. 4 Hz, 2
H), 7.15 (t, J = 7.6 Hz, 1 H), 7.32–7.36 (m, 2 H), 7.43 (t, J =
7.6 Hz, 2 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.57 (s, 1 H), 7.88 (d, J =
7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.0, 28.0,
46.4, 54.7, 114.1, 123.1, 125.3, 128.3, 128.6, 128.9, 129.6, 130.5,
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130.6, 133.7, 134.0, 136.6, 144.8, 146.1, 197.9 ppm. IR (KBr): ν =
˜
3401, 1680 cm–1. C23H22BrNO (408.34): C 67.65, H 5.43, N 3.43;
found C 67.50, H 5.39, N 3.58.
1,4-Bis[3-oxo-3-phenyl-1-(phenylamino)propyl]benzene (4n): Yield:
0.934 g, 89 %. Light green solid, m.p. 128–129 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.43 (d, J = 6.0 Hz, 4 H), 4.70 (br. s, 2 H),
4.96 (t, J = 5.6 Hz, 2 H), 6.55 (d, J = 6.8 Hz, 4 H), 6.67 (t, J =
6.8 Hz, 2 H), 7.08 (t, J = 6.8 Hz, 4 H), 7.38 (s, 4 H), 7.42 (t, J =
7.2 Hz, 4 H), 7.53 (t, J = 8.0 Hz, 2 H), 7.87 (d, J = 7.2 Hz, 4 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 46.1, 54.9, 114.2, 118.3,
121.2, 127.2, 128.4, 128.9, 129.3, 133.7, 136.8, 142.1, 143.8, 146.8,
[6] Y.-Y. Yang, W.-G. Shou, Y.-G. Wang, Tetrahedron 2006, 62,
10079–10086.
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Tetrahedron 2007, 63, 2404–2408.
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9257–9259.
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Eur. J. Org. Chem. 2006, 5152–5157.
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A. Ali, P. Goswami, L. H. Choudhury, J. Org. Chem. 2006, 71,
8961–8963; c) B. Das, M. Krishnaiah, V. Katta, Tetrahedron
Lett. 2006, 47, 4457–4460.
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dron Lett. 2007, 48, 3805–3808; b) A. T. Khan, S. Islam, A.
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239, 158–165; c) A. T. Khan, P. R. Sahu, A. Majee, J. Mol.
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Ghosh, S. Islam, Eur. J. Org. Chem. 2004, 2002–2009; e) B.
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63, 5593–5601; b) A. T. Khan, L. H. Choudhury, T. Parvin, A.
Ali, Tetrahedron Lett. 2006, 47, 8137–8141.
198.6 ppm. IR (KBr): ν = 3447, 1680 cm–1. C H N O (524.66):
˜
36 32
2
2
C 82.41, H 6.15, N 5.34; found C 82.63, H 6.08, N 5.23.
2-{(4-Chlorophenyl)[(3-chlorophenyl)amino]methyl}cyclohexanone
(5c): Yield: 0.613 g, 88%. Light brown solid, m.p. 154–155 °C. Data
for the major isomer (anti): 1H NMR (400 MHz, CDCl3): δ = 1.69–
1.79 (m, 3 H), 1.90–1.99 (m, 3 H), 2.31–2.41 (m, 2 H), 2.72–2.76
(m, 1 H), 4.52 (d, J = 6.0 Hz, 1 H), 4.90 (br. s, 1 H), 6.38 (d, J =
8.4 Hz, 1 H), 6.48 (s, 1 H), 6.61 (d, J = 7.2 Hz, 1 H), 6.97 (t, J =
8.0 Hz, 1 H), 7.29 (s, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 24.3, 28.0, 32.0, 42.4, 57.3, 57.7, 112.0, 113.5, 117.8, 128.7, 128.9,
130.3, 133.1, 135.0, 140.0, 148.4, 212.5 ppm. IR (KBr): ν = 3339,
˜
1706 cm–1. C19H19Cl2NO (348.27): C 65.53, H 5.50, N 4.02; found
C 65.34, H 5.43, N 3.90.
Diethyl 2-{[(3-Chlorophenyl)amino](phenyl)methyl}malonate (6b):
Yield: 0.707 g, 94 %. White solid, m.p. 111–112 °C. 1H NMR
(400 MHz, CDCl3): δ = 1.13 (t, J = 7.2 Hz, 3 H), 1.17 (t, J =
7.2 Hz, 3 H), 3.88 (d, J = 5.2 Hz, 1 H), 4.11 (q, J = 7.2 Hz, 2 H),
4.15 (q, J = 7.2 Hz, 2 H), 5.18 (d, J = 5.6 Hz, 1 H), 5.56 (br. s, 1
H), 6.47 (d, J = 8.8 Hz, 1 H), 6.58 (s, 1 H), 6.62 (d, J = 8.8 Hz, 1
H), 6.99 (t, J = 8.8 Hz, 1 H), 7.26–7.35 (m, 5 H) ppm. 13C NMR
(100 MHz, CDCl3): 13.7, 13.9, 56.7, 57.8, 61.5, 61.9, 111.8, 113.3,
117.6, 126.5, 127.7, 128.6, 130.0, 134.9, 139.0, 147.8, 167.0,
[15] G. A. Olah, Y. D. Vankar, M. Arvanaghi, G. K. Surya Prakash,
Synthesis 1979, 720.
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168.0 ppm. IR (KBr): ν = 3370, 1752 cm–1. C H ClNO (375.85):
˜
Received: July 12, 2007
20 22
4
C 63.91, H 5.90, N 3.73; found C 63.71, H 5.83, N 3.61.
Published Online: December 12, 2007
Eur. J. Org. Chem. 2008, 834–839
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
839