Synthesis of Mannich type products via a three-component coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2005.01.118

The reactions of alkyl nitriles, acetyl chloride, aldehydes and β-ketoesters or simple ketones was studied for the one-pot synthesis of β-acetamido carbonyl compounds. It was observed that the reaction proceeds in the absence of Lewis acids. However, a Le

Full text of DOI:10.1016/j.tetlet.2005.01.118

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2137–2140
Synthesis of Mannich type products via a three-component
coupling reaction
Ghanshyam Pandey, Ravi P. Singh, Ashish Garg and Vinod K. Singh*
Department of Chemistry, Institute of Technology, Kanpur 208016, India
Received 22 September 2004; revised 11January 2005; accepted 21January 2005
Abstract—The reactions of alkyl nitriles, acetyl chloride, aldehydes and b-ketoesters or simple ketones was studied for the one-pot
synthesis of b-acetamido carbonyl compounds. It was observed that the reaction proceeds in the absence of Lewis acids. However, a
Lewis acid catalyzes the reaction and several were tested. It was found that whereas Cu(OTf)2 is suitable for the coupling of b-keto-
esters with aldehydes, Sc(OTf)3 is the best for ketones. A possible mechanism is proposed based on the isolation and characteriza-
tion of an intermediate.
Ó 2005 Elsevier Ltd. All rights reserved.
One-pot transformations, particularly multi-component
reactions (MCR)1 are of current interest to organic
chemists. Since the first MCR reported in 1850 by Strec-
ker,2 this methodology has emerged as an efficient and
powerful tool in modern synthetic organic chemistry
allowing the facile creation of several new bonds in a
one-pot transformation. Very recently, transition metal
catalyzed MCR reactions of aldehydes, ketones and
amines (Mannich reactions) were reported.3 Recently,
we reported cycloaddition reactions of aziridines and
azetidines with nitriles, which were proposed to proceed
in a Ritter fashion.4 Based on this assumption, it can be
Table 1. Effect of Lewis acid on the three-component coupling to give b-acetamido-carbonyl compounds
AcHN
Ph
O
AcHN
Ph
O
Lewis acid, CH3CN,
AcCl, rt, 30 h
MeO2CCH2COCH3
or
PhCHO
+
or
CH3
Ph
PhCOCH3
COOMe
A
B
Entry
Lewis acid
Isolated yield (%)
A
B
1Nil
2
5
301
Zn(OTf)2 (10 mol %)
Bi(OTf)3 (10 mol %)
Sn(OTf)3 (10 mol %)
Sc(OTf)3 (10 mol %)
Cu(OTf)2 (10 mol %)
Yb(OTf)3 (10 mol %)
BF3ÆOEt2 (100 mol %)
BF3ÆOEt2 (10 mol %)
CuCl2 (100 mol %)
BiCl3 (100 mol %)
20
44
36
47
65
—
—
—
—
—
—
—
—
60
69
68
82
64
75
78
48
79
77
77
59
19
3
4
5
6
7
8
9
10
11
12
13
14
LaCl3 (100 mol %)
LiClO4 (100 mol %)
InCl3 (100 mol %)
*
Corresponding author. Fax: +91512 2597436; e-mail: vinodks@iitk.ac.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.118

2138
G. Pandey et al. / Tetrahedron Letters 46 (2005) 2137–2140
envisioned that Mannich-type products (retron: N–C–
C–CO) can be obtained if the amine is replaced by an
acetyl source (acetyl chloride or acetic anhydride) and
the intermediate adds to the alkyl nitrile in a Ritter fash-
ion. In this letter, we disclose our results based on the
above concept.
aldehyde and acetyl chloride were stirred at room
temperature in acetonitrile for 30 h, b-acetamido car-
bonyl compounds were obtained in 15–30% yields. The
reaction was more efficient in the presence of a Lewis
acid. Thus, a variety of Lewis acids were screened and
the results are summarized in Table 1. It was observed
that where Cu(OTf)2 returned a high yield for the cou-
pling of an aldehyde with a b-ketoester, acetophenone
was coupled more efficiently with similar aldehydes
We observed that when a mixture of an enolizable
ketone (a b-ketoester or a simple aryl alkyl ketone),
Table 2. Three-component coupling route to (b-acetamido ketoesters in the presence of Cu(OTf)2
O
AcHN
O
AcHN
O
O
O
Cu(OTf)2 (10 mol%)
CH3CN, AcCl, rt, 30 h
MeO
H
OMe
OMe
+
+
O
O
R
R
syn
R
anti
Entry
1
b-Acetamido ketoester
Yielda,b (%)
65
syn/anti c
Entry
b-Acetamido ketoester
Yielda,b (%)
syn/anti c
Me
Me
CO2Me
CO2Me
44/56
10
54
67/33
AcHN
O
AcHN
O
Me
CO2Me
O
CO2Me
O
Me
2
3
73
70
1
49/511
60/40
60
49
50/50
18/82
Me
AcHN
Me
AcHN
NO2
CO2Me
O
CO2Me
O
12
13
14
15
16
17
18
Me
F
AcHN
AcHN
O2N
CO2Me
O
CO2Me
O
4
5
6
7
8
9
70
68
72
63
55
68
47/53
14/86
48/52
33/67
60/40
62/38
43
30
62
33
58
35
47/53
35/65
49/51
52/48
50/50
45/55
AcHN
AcHN
AcHN
Cl
Cl
CO2Me
O
CO2Me
O
NHAc
F
F
CO2Me
O
CO2Me
O
Br
Cl
AcHN
Me
AcHN
OMe
Me
CO2Me
CO2Me
AcHN
O
AcHN
O
F
CO2Me
O
F
CO2Me
O
MeO
MeO
AcHN
AcHN
OMe
OMe
CO2Me
O
CO2Me
AcHN
AcHN
O
a Yields are reported after aqueous work-up.
b The product was obtained as a mixture of diastereomers.
c Ratio obtained from 1H NMR of the crude reaction mixture.

G. Pandey et al. / Tetrahedron Letters 46 (2005) 2137–2140
2139
using Sc(OTf)3. When compared to the literature proce-
dure,5 that is, harsh reaction conditions (high tempera-
ture) and long reaction times (5 d) with CoCl2 as a
catalyst, our procedure appeared to be simple and effi-
cient.6 The reaction was extended to a variety of alde-
hydes with b-ketoesters using Cu(OTf)2 as catalyst and
the results are summarized in Table 2. In all cases mix-
tures of syn- and anti-diastereomers were obtained,7
whilst the diastereoselectivity depended upon the nature
of the reactants. For example, 4-chlorobenzaldehyde
and 3-nitrobenzaldehyde gave products where the syn/
anti ratio was reasonably good (Table 2, entries 5 and
12) whereas other aldehydes gave poor diastereo-
selectivity.
The three-component coupling reaction was extended to
ketones and the results are summarized in Table 3. In
most cases, high yields of product were obtained. The
reaction was not clean with aliphatic aldehydes. Simi-
larly, acyclic aliphatic ketones gave unsatisfactory
a
Table 3. Three-component coupling route to b-acetamido ketones in the presence of Sc(OTf)3
O
AcHN
O
Sc(OTf)3 (10 mol%)
RCN, AcCl, rt, 30 h
H
Ar
ArCOCH3
+
R
R
Entry
1
b-Acetamido ketone
Isolated yield (%)
82
Entry
11
b-Acetamido ketone
OMe
Isolated yield (%)
98
Ph
Ph
AcHN
O
AcHN
O
O
NO2
OH
Cl
Ph
2
3
4
5
80
85
76
84
12
13
14
15
95
86
90
93
Ph
Me
AcHN
AcHN
O
AcHN
Ph
Ph
O
AcHN
O
O
F
Ph
Ph
AcHN
O
AcHN
Cl
Ph
Ph
Ph
EtCONH
O
AcHN
O
Cl
Ph
Ph
6
7
90
67
16
17
60
74
Ph
Ph
n-PrCONH
O
AcHN
Br
O
Ph
Ph
PhCONH
O
AcHN
O
O
OMe
Ph
87b
Ph
8
82
18
Ph
AcNH
O
AcHN
MeO
Cl
Ph
9
85
32
19
20
85c
Ph
AcNH
O
AcHN
O
NHAc
MeO
Ph
10
Ph
75d
AcNH
O
O
a RCN was used as solvent; for entries 1–14 and for entries 18–20, MeCN was used; for entry 15, n-propionitrile was used; for entry 16,
n-butyronitrile was used; benzoyl nitrite was used for entry 17.
b The major compound was shown to be anti with a ratio of 32:68.
c The major compound was shown to be anti with a ratio of 10:90.
d The major compound was shown to be anti with a ratio of 35:65.

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G. Pandey et al. / Tetrahedron Letters 46 (2005) 2137–2140
+
LA
H
R
C
N
O
O
MeCOCl
RCN
MeOCO
Ph
O
H
O
Ph
Ph
Ph
Ph
Ph
2
Ph
1
H2O
ROCNH
Ph
O
3
Scheme 1. Proposed reaction mechanism.
results, however, cyclohexanone gave a 32% yield of the
product (Table 3, entry 10). The reaction proceeded well
with nitriles such as propionitrile (entry 15), butyro-
nitrile (entry 16) and phenyl nitrile (entry 17). The
reactions of propiophenone proceeded in good yield
and good diastereoselectivity (Table 3, entries 18–20).
References and notes
1. For reviews, see: (a) Montgomery, J. Acc. Chem. Res. 2000,
33, 467; (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed.
2000, 39, 3168; (c) Terret, N. K.; Gardner, M.; Gordon, D.
W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135;
(d) Armstrong, R. W.; Combs, A. W.; Templest, P. A.;
Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123;
(e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555; (f) Ellman, J. A. Acc. Chem. Res. 1996, 29, 132.
2. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
3. Xu, Li.-W.; Xia, C.-G.; Li, L. J. Org. Chem. 2004, 69,
8482.
4. (a) Prasad, B. A. B.; Pandey, G.; Singh, V. K. Tetrahedron
Lett. 2004, 45, 1137; (b) Prasad, B. A. B.; Bisai, A.; Singh,
V. K. Org. Lett. 2004, 6, 4829.
The mechanism may involve the enolic form of the ke-
tone which attacks the activated aldehyde to provide a
b-acetoxy ketone 1 (Scheme 1). The acetate group of 1
is displaced by the nucleophilic nitrogen of the nitrile
to provide a stable carbocation 2 that reacts in a Ritter
fashion with water to provide the Mannich type product
3. The intermediacy of 1 was confirmed by its isolation
and characterization (1H and 13C NMR). In a separate
experiment, the acetate 1 could be converted to the final
product by treatment with acetonitrile.
5. (a) Rao, I. N.; Prabhakaran, E. N.; Das, S. K.; Iqbal, J. J.
Org. Chem. 2003, 68, 4079; (b) Bahulayan, D.; Das, S. K.;
Iqbal, J. J. Org. Chem. 2004, 68, 5735.
6. General experimental procedure: To a stirred suspension of
Cu(OTf)2 in dry alkyl or phenyl nitrile (5 mL) were added
an aldehyde (1mmol), methylacetoacetate/ketone (1mmol)
and acetyl chloride (1.1 mmol). The reaction mixture was
stirred at ambient temperature for 30 h. The solvent was
removed under reduced pressure to afford a residue which
was taken into ethyl acetate, washed with water, saturated
sodium bicarbonate solution, and brine. The organic layer
was dried over anhydrous Na2SO4 and filtered. The filtrate
was evaporated under reduced pressure and the residue was
purified over silica gel to afford the b-acetamido ketones
(Tables 2 and 3).
In conclusion, we have reported an efficient and im-
proved three-component coupling reaction for the syn-
thesis of b-acetamide carbonyl compounds (Mannich-
type products). The method offers several advantages
such as high yields, short reaction times and tolerance
to a wide variety of reactants.
Acknowledgements
1
V.K.S. thanks the Department of Science and Technol-
ogy, India for a research grant. G.P., A.G. and R.P.S.
thank CSIR for research fellowships.
7. The ratio of syn/anti diastereomers was determined by H
NMR based on the coupling constants between the methine
protons.