940
Table 2. Synthesis of substituted pyrrole derivatives28
The reactions were also scrutinized in different solvents
O
O
O
such as CH3CN, THF, DMF, and MeOH using 1 equivalent of
nitromethane at room temperature using 10 mol % BDMS as
catalyst, and it afforded lower yields as well as required longer
reaction times. It is noteworthy to mention that nitromethane acts
as reagent-cum-solvent in the present protocol. The isolated
Ar
RO
Me
R1NH2
2
Me
OR
10 mol% BDMS
1
H
N
R1
room temperature
MeNO2
4
ArCHO
3
1
5
product 5a was characterized from H NMR in which the H-5
Time Yield
/h /%b
proton appears at ¤ 6.56 ppm as a singlet whereas the C-5 carbon
signal comes at ¤ 110.9 ppm.
S.No Aldehyde (3)
R (1) R1 (2) Producta (5)
After optimization, the reactions were examined with
methyl acetoacetate (1a), benzylamine (2a) and with various
aromatic aldehydes such as 4-chlorobenzaldehyde, benzalde-
hyde, furan-2-carbaldehyde in nitromethane (4) in the presence
of 10 mol % BDMS at room temperature and the desired
products 5b-5d were isolated in 68-72% yields (Table 2,
Entries 2-4). Similarly, 4-methylbenzylamine (2b), methyl
acetoacetate (1a), and 4-chlorobenzaldehyde afforded the de-
sired product 5e in 75% yield (Table 2, Entry 5) under identical
reaction conditions.
The scope of the present protocol was further examined by
carrying out reactions with methyl acetoacetate (1a) and (R)-
(+)-¡-methylbenzylamine (2c) with various aromatic aldehydes
having substituents Me, OMe, NO2, Br, and F in the aromatic
ring under similar reaction conditions and the products 5f-5k
were obtained in good yields (Table 2, Entries 6-11). Likewise,
a reaction with 2-naphthaldehyde, methyl acetoacetate (1a), (R)-
(+)-¡-methylbenzylamine (2c), and nitromethane under identi-
cal reaction conditions provided the desired product 5l in 62%
yield (Table 2, Entry 12). In addition, a wide variety of ¢-keto
esters such as ethyl acetoacetate (1b), allyl acetoacetate (1c), and
t-butyl acetoacetate (1d) and different aromatic aldehydes such
as 4-fluorobenzaldehyde, 3-hydroxybenzaldehyde, and 4-bro-
mobenzaldehyde were treated with (R)-(+)-¡-methylbenzyl-
amine (2c) and nitromethane under similar reaction conditions,
respectively, and the desired products 5m-5p were obtained in
good yields (Table 2, Entries 13-16). Similarly, methyl aceto-
acetate (1a) or ethyl acetoacetate (1b), (S)-(¹)-¡-methylbenzyl-
amine (2d), nitromethane reacted with various aromatic alde-
hydes having substituents such as Cl, Me, OH, OMe, NO2, and
F on the aromatic ring under similar reaction conditions and
the required products 5q-5w were isolated in 58-78% yield
(Table 2, Entries 17-23).
1
2
3
4
5
6
7
8
9
4-F-C6H4
4-Cl-C6H4
C6H5
2-Furanyl
4-Cl-C6H4
C6H5
4-Me-C6H4
4-OMe-C6H4
4-NO2-C6H4
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1a
1b
1b
2a
2a
2a
2a
2b
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2c
2d
2d
2d
2d
2d
2d
2d
2e
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
7
8
9
8
7
5
5
7
8
6
5
8
5
8
6
7
5
5
8
8
8
5
6
9
78
72
70
68
75
76
80
68
70
78
82
62
75
60
67
65
78
76
60
58
67
68
62
62
10 4-Br-C6H4
11 4-F-C6H4
12 2-Naphthyl
13 4-F-C6H4
14 3-OH-C6H4
15 4-Br-C6H4
16 4-Br-C6H4
17 4-Cl-C6H4
18 4-Me-C6H4
19 3-OH-C6H4
20 2,4-Di-OMe-C6H3 1b
5t
21 2-NO2-C6H4
22 2-F-C6H4
23 3-F-C6H4
24 4-Cl-C6H4
1b
1b
1b
1a
5u
5v
5w
5x
aAll the reactions were performed using ¢-keto ester (1 mmol),
benzylamine or substituted benzylamine (1 mmol), and alde-
hyde (1 mmol) in nitromethane (1 mL) with BDMS (10 mol %)
b
at room temperature. Isolated yield.
Furthermore, the reaction was also examined with cyclo-
hexylamine (2e), methyl acetoacetate (1a), and 4-chlorobenzal-
dehyde in the presence of 10 mol % BDMS at room temperature,
and it gave the product 5x in 62% yield. All the products were
1
characterized by IR, H and 13C NMR spectra as well as their
elemental analyses. The structure of the product 5n29 was further
confirmed by single-crystal XRD and the ORTEP diagram of
5n and their intermolecular H-bonding interaction through
O-H£O bonds (H£O = 0.821 ¡, O£O = 2.823 ¡, <O-
H£O = 172.64°) is shown in Figure 2.
(a)
(b)
Figure 2. (a) ORTEP diagram of 5n. (b) Intermolecular
H-bonding interactions (CCDC no. is 848584).
The formation of products 5 may be proposed as follows: ¢-
Keto ester on reaction with bromodimethylsulfonium bromide
gives the intermediate A and HBr in the reaction medium. Then
the liberated HBr catalyzes the formation of enamino ester C
from ¢-keto ester and benzylamine. At the same time, carbanion
B is generated from nitromethane 4 in the presence of benzyl-
amine 2, which reacts instantly with an aromatic aldehyde 3 to
form nitrostyrene D. Subsequently, the enamino ester C reacts
with nitrostyrene D to form Michael adduct E, which undergoes
tautomerization into F. Finally, it gives the intermediate G on
cyclization, which is converted into the desired product 5 with
the elimination of H3NO2 as shown in Scheme 2.
In conclusion, we have devised a simple and efficient
synthetic protocol for the synthesis of substituted pyrrole
derivatives using ¢-keto esters, benzylamines, aromatic alde-
Chem. Lett. 2013, 42, 939-941
© 2013 The Chemical Society of Japan
Bagdi, Prasanta Ray
