InCl3/MeSO3H catalysed addition reactions of pyrrole to N-sulfonylimines

Article abstract of DOI:10.3184/174751912X13399309115414

The addition reaction of pyrrole to N-sulfonylimines has been shown to proceed in the presence of a catalytic amount of InCl₃ and MeSO ₃H, to give pyrrole sulfonamides in medium to excellent yields.

Full text of DOI:10.3184/174751912X13399309115414

478 RESEARCH PAPER
AUGUST, 478–479
JOURNAL OF CHEMICAL RESEARCH 2012
InCl3/MeSO3H catalysed addition reactions of pyrrole to N-sulfonylimines
Dong-Mei Cui*, Ai-Qing Bao, Guan-Ming Zhu, Ao-Xue Wu and Wei-Bo Jin
College of Pharmaceutical Science, Zhejiang University ofTechnology, Hangzhou 310014, P. R. China
The addition reaction of pyrrole to N-sulfonylimines has been shown to proceed in the presence of a catalytic amount
of InCl3 and MeSO3H, to give pyrrole sulfonamides in medium to excellent yields.
Keywords: addition reaction, pyrrole, N-sulfonylimines, catalysts, indium(III) chloride
Pyrroles form the starting materials and intermediates in many
important natural product and drug syntheses.1–10 As a result,
their synthesis is an important industrial and synthetic goal.
The common methods reported for the synthesis of aminoal-
kylated pyrrole derivatives involves the Mannich reaction of
formaldehyde with an amine and the reactions of pyrroles with
imines.11–14 Despite significant advances, several drawbacks
remain associated with such reactions, including the use
stoichiometric amounts of the catalyst, byproducts, and low
yields. Recently, Unaleroglu reported the use of Cu(OTf)2
as a catalyst for the addition of pyrrole to N-tosyl imines.15,16
Here we report that InCl3–proton acid systems can serve
as catalysts to promote the addition reactions of pyrrole to
N-sulfonylimines.
Our initial explorations focused on the reaction of pyrrole
(1a) (0.2 mmol) with N-benzylidene-4-methylbenzenesulfon-
amide (2a) (0.4 mmol) in the presence of a catalytic amount
of InCl3 (10 mol %) and methanesulfonic acid (MeSO3H)
(20 mol%) in THF (3 mL) at 0 °C for 8 h. This proceeded
efficiently to form the addition product 3a in 62% yield
(Scheme 1, Table 1, entry 2). Investigation of the starting mate-
rial stoichiometries revealed that a slight excess of N-sulfonyl
imine (2 equiv.) was necessary to drive the reaction to full
conversion (Table 1, entries 2 and 3). Only a trace of 3a was
formed at room temperature (Table 1, entry 1). Different
solvents were screened, and THF was found to be the best
(Table 1, entries 3–6). Decreasing the amount of InCl3 or
MeSO3H resulted in lower yields (entries 7 and 8). Using either
InCl3 or MeSO3H alone gave lower yields (entries 9 and 10).
These results indicated that both InCl3 and MeSO3H played
a crucial role in this addition reaction. Other acid catalysts,
such as trifluoromethanesulfonic acid and sulfuric acid were
ineffective.
In conclusion, we have demonstrated an efficient InCl3/
MeSO3H-catalysed addition reaction of pyrrole to N-sulfony-
limines to produce pyrrole derivatives under mild conditions
with perfect regioselectivity. Further efforts to expand the
scope of the chemistry and studies of the detailed mechanism
are currently under way in our laboratories.
Experimental
Under otherwise noted, materials were obtained from commercial
suppliers and were used without further purification. N-sulfonylimi-
nes were prepared by the procedures in the literature. TLC was per-
formed using silica gel 60 F254 and visualised using UV light. Column
1
chromatography was performed with silica gel (mesh 300–400). H
NMR and 13C NMR spectra were recorded on a Bruker Avance
500 MHz spectrometer in CDCl3 with Me4Si as an internal standard.
Data were reported as follows: chemical shift in ppm (δ), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, br = broad and m =
multiplet), coupling constant in (Hz) and integration. IR spectra were
obtained on 370 FT-IR spectrometer; absorptions were reported in
cm−1. Mass spectra (MS) and high resolution mass spectra (HRMS)
were obtained from the Zhejiang University of Technology Mass
Spectrometry Facility.
Synthesis of 2-substituted pyrroles 3a–i; general procedure
The pyrrole (0.2 mmol) was added to a mixture of N-sulfonylimine
(0.4 mmol), InCl3 (0.02 mmol), and MeSO3H (0.04 mol) in anhydrous
THF (3 mL) under N2. The mixture was then stirred at 0 °C for 3–6 h.
The mixture was quenched with saturated solution of NaHCO3 and
then extracted with dichloromethane (20 mL × 3). The organic layer
was washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel) to
yield the product in an analytically pure form.
4-Methyl-N-(phenyl(1H-pyrrol-2-yl)methyl)benzenesulfonamide
1
(3a): M.p. 130–131 °C (lit.15 132–133 °C); H NMR (500 MHz,
CDCl3): δ 8.59 (br, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.21–7.19 (m, 3H),
7.15–7.09 (m, 4H), 6.701–6.70 (m, 1H), 6.02–6.01 (m, 1H), 5.60–5.59
(m, 1H), 5.54 (d, J = 8.1 Hz, 1H), 5.37 (d, J = 8.1 Hz, 1H), 2.36
(s, 3H).
N-((4-Fluorophenyl)(1H-pyrrol-2-yl)methyl)-4-methylbenzenesul-
fonamide (3b):15 1H NMR (500 MHz, CDCl3): δ 8.59 (br, 1H), 7.55
(d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.10–7.06 (m, 2H),
6.91–6.85 (m, 2H), 6.72–6.70 (m, 1H), 6.02 (dd, J = 6.0, 2.8 Hz, 1H),
5.58–5.56 (m, 1H), 5.54 (d, J = 8.1 Hz, 1H), 5.40 (d, J = 8.1 Hz, 1H),
2.38 (s, 3H).
N-((4-Chlorophenyl)(1H-pyrrol-2-yl)methyl)-4-methylbenzenesul-
fonamide (3c): M.p. 114–115 °C (lit.16 115–116 °C); 1H NMR
(500 MHz, CDCl3): δ 8.58 (br, 1H), 7.4 (d, J = 8.5 Hz, 2H), 7.17–7.15
(m, 4H), 7.04 (d, J = 8.5 Hz, 2H), 6.72–6.70 (m, 1H), 6.03–6.02 (m,
1H), 5.57–5.54 (m, 1H), 5.53 (d, J = 8.1 Hz, 1H), 5.37 (d, J = 8.1 Hz,
1H), 2.39 (s, 3H).
To further assess the scope of this process, we have exam-
ined the addition reaction of pyrrole to different N-sulfony-
limines using the optimised reaction conditions as described in
entry 3 of Table 1. The results are summarised in Table 2 and
Scheme 1. Tosylimines with an electron-withdrawing group on
the benzene ring all gave good yields (entries 2–5). In sharp
contrast, where there was an electron-donating substituent on
the aromatic ring, the corresponding adduct 3f was obtained in
37% yield (entry 6). Under the same reaction conditions, the
addition reaction of pyrrole to other N-sulfonylimines took
place smoothly to afford the corresponding addition products
3g–i with 55–67% yield (entries 7–9).
N-((4-Bromophenyl)(1H-pyrrol-2-yl)methyl)-4-methylbenzenesul-
fonamide (3d): M.p. 118–119 °C (lit.16 116–117 °C); 1H NMR
(500 MHz, CDCl3): δ 8.55 (br, 1H), 7.53 (d, J = 9.0 Hz, 2H), 7.32 (d,
J = 9.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H),
6.73–6.71 (m, 1H), 6.02 (dd, J = 6.0, 2.8 Hz, 1H), 5.58–5.56 (m, 1H),
5.52 (d, J = 8.1 Hz, 1H), 5.31 (d, J = 8.1 Hz, 1H), 2.03 (s, 3H).
4-Methyl-N-((4-nitrophenyl)(1H-pyrrol-2-yl)methyl)benzenesulfon
amide (3e): M.p. 150–151 °C (lit.15 153–154 °C); 1H NMR (500 MHz,
CDCl3): δ 8.52 (br, 1H), 8.07 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.5 Hz,
2H), 7.35 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 6.76–6.75 (m,
1H), 6.04 (dd, J = 6.0, 2.8 Hz, 1H), 5.68 (d, J = 7.9 Hz, 1H), 5.55–5.54
(m, 1H), 5.36–5.34 (d, J = 7.9 Hz, 1H), 2.38 (s, 3H).
Scheme 1
* Correspondent. E-mail: cuidongmei@zjut.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 479
Table 1 The reaction of pyrrole (1a) with 2a with InCl3a
Entry
InCl3 /mol%
MeSO3H /mol%
Ratio (1a:2a)
Solvent
Temp./°C
Yield of 3a /%b
1
2
10
10
10
10
10
10
5
10
10
–
20
20
20
20
20
20
20
10
–
1:1
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
THF
THF
rt
0
0
0
0
0
0
0
0
0
Trace
28
3
THF
62
4
Toluene
CH2Cl2
Dioxane
THF
0
0
5
6
Trace
48
7
8
THF
54
9
THF
25
10
20
THF
8
a The reactions were performed with 1a (0.2 mmol), 2a (0.2–0.4 mmol), InCl3 (0–10 mol%), and MeSO3H (0–20 mol%) in solvent
(3 mL) for 8 h.
b Isolated yield.
Table 2 InCl3 / MeSO3H catalysed reaction of pyrrole with
N-sulfonyl iminesa
2H), 7.48 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.12 (d, J =
7.6 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.69–6.68 (m, 1H), 6.00 (dd,
J = 6.0, 2.8 Hz, 1H), 5.75–5.73 (m, 1H), 5.58–5.56 (m, 2H).
N-((4-Bromophenyl)(1H-pyrrol-2-yl)methyl)benzenesulfonamide
(3i): M.p. 123–124 °C; 1H NMR (500 MHz, CDCl3): δ 8.65 (br, 1H),
7.60 (d, J = 8.5 Hz, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz,
2H), 7.26 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 7.5 Hz, 2H), 6.67–6.66 (m,
1H), 6.00–5.96 (m, 1H), 5.80–5.79 (d, J = 8.5 Hz, 1H), 5.55 (d, J =
8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 139.9, 139.5, 132.7,
131.6, 129.8, 129.1, 129.0, 127.0, 122.0, 119.0, 108.4, 108.3, 55.4; IR
(KBr, cm−1): 3418.3, 1636.6, 1384.2, 1324.1, 1159.6, 750.0, 723.3,
686.7, 589.8, 556.2 cm−1; Mass spectrum (ESI) m/z (rel, int,%) 413
(M+ Na, 95), 391 (21), 393 (18), 414 (15.5), 415 (100), 416 (16.4).
HRMS (ESI): m/z Calcd for C17H15BrN2NaO2S: 412.9936; found:
412.9935.
Entry R1
R2
Time/h Imine Yield/%b
1
2
3
4
5
6
7
8
9
C6H5
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
4-CH3-C6H4
8
8
6
6
4
4
4
4
4
3a
3b
3c
3d
3e
3f
3g
3h
3i
62
76
59
71
82
37
55
67
62
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-NO2-C6H4 4-CH3-C6H4
4-tBu-C6H4
C6H5
4-CH3-C6H4
C6H5
C6H5
C6H5
4-Cl-C6H4
4-Br-C6H4
a The reactions were performed with 1a (0.2 mmol), 2 (0.4 mmol),
InCl3 (10 mol%), and MeSO3H (20 mol%) at 0 °C in THF (3 mL).
b Isolated yield.
This work was partially supported by the Zhejiang Science
Foundation (No. Y4100558).)
N-((4-Tert-butylphenyl)(1H-pyrrol-2-yl)methyl)-4-methylbenzene-
sulfonamide (3f): 1H NMR (500 MHz, CDCl3): δ 8.62 (br, 1H), 7.51
(d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H),
7.01 (d, J = 8.5 Hz, 2H), 6.81–6.66 (m, 1H), 6.01 (dd, J = 5.9, 2.8 Hz,
1H), 5.65–5.63 (m, 1H), 5.54 (d, J = 8.0 Hz, 1H), 5.41 (d, J = 8.0 Hz,
1H), 2.34 (s, 3H), 1.25 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 150.9,
143.1, 137.2, 135.5, 130.8, 129.4, 127.2, 127.0, 125.3, 118.5, 108.2,
107.9, 55.7, 34.5, 31.3, 21.5; IR (KBr, cm−1): 3414.4, 2963.3, 1793.6,
1560.3, 1508.3, 1458.4, 1384.3, 1326.1, 1266.2, 1159.7, 1092.5,
1027.8, 924.5, 845.6, 812.6, 747.3, 704.2, 665.3, 579.5 cm−1; Mass
spectrum (ESI) m/z (rel, int,%) 405.1 (M+ Na, 100), 212.1 (5.7), 308.1
(34.4), 615.1 (22.3), 787.3(10.8). HRMS (ESI) for C22H26N2NaO2S:
Calcd: 405.1620; found 405.1613.
Received 15 March 2012; accepted 23 May 2012
Paper 1201213 doi: 10.3184/174751912X13399309115414
Published online: 8 August 2012
References
1
2
B. Carte, and D.J. Faulkner, J. Org. Chem., 1983, 48, 2314.
M. Biava, G.C. Porretta, D. Deidda, R. Pompei, A. Tafi, and F. Manetti,
Bioorg. Med. Chem., 2003, 11, 515.
3
4
5
B.H. Lipshutz, Chem. Rev., 1986, 86, 795.
C.Y. Leon and B. Ganem, Tetrahedron, 1997, 53, 7731.
J.T. Gupton, K.E. Krumpe, B.S. Burnham, K.A. Dwornik, S.A. Petrich,
K.X. Du, M.A. Bruce, P. Vu, M. Vargas, K.M. Keertikar, K.N. Hosein,
C.R. Jones and J.A. Sikorski, Tetrahedron 1998, 54, 5075.
D.L. Boger, C.W. Boyce, M.A. Labroli, C.A. Sehon and Q. Jin, J. Am.
Chem. Soc., 1999, 121, 54.
N-(Phenyl(1H-pyrrol-2-yl)methyl)benzenesulfonamide (3g): M.p.
1
128–129 °C; H NMR (500 MHz, CDCl3): δ 8.56 (br, 1H), 7.65(d,
6
7
J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 8.0 Hz, 2H),
7.22–7.16 (m, 3H), 7.08 (dd, J = 8.0, 2 Hz, 2H), 6.70–6.68 (m, 1H),
6.01 (dd, J = 6.0, 2.8 Hz, 1H), 5.81–5.79 (m, 2H), 5.55 (d, J = 8.0 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ 140.0, 138.4, 132.6, 130.5,
128.9, 128.6, 128.0, 127.3, 127.1, 118.7, 108.3, 108.2, 55.9; IR (KBr,
cm−1): 3453.0, 1636.8, 1384.1, 1158.8, 1091.7, 913.1, 743.2, 554.4
cm−1; Mass spectrum (ESI) m/z (rel, int,%) 313.1 (M+ H, 2.2), 335.1
(M+ Na, 1.1), 83.1 (12), 130.2 (0.7), 139.1 (100), 156.1 (4.1),
246.1(1.1). HRMS (ESI) for C17H16N2NaO2S: Calcd: 335.0831; found
335.0830.
W. Herz, K. Dittmerand and S.J. Cristol, J. Am. Chem. Soc., 1947, 69,
1698.
8
9
W. Herz, and J.L. Rogers, J. Am. Chem. Soc., 1951, 73, 4921.
O. Okitsu, R. Suzuki, and S. Kobayashi, J. Org. Chem., 2001, 66, 809.
10 S. Kobayashi, I. Hachiya, S. Suzuki and M. Moriwaki, Tetrahedron Lett.,
1996, 37, 2809.
11 W. Herz, K. Dittmer and S.J. Cristol, J. Am. Chem. Soc., 1947, 69, 1698.
12 W. Herz and J.L. Rogers, J. Am. Chem. Soc., 1951, 73, 4921.
13 O. Okitsu, R. Suzuki and S. Kobayashi, J. Org. Chem., 2001, 66, 809.
14 S. Kobayashi, I. Hachiya, S. Suzuki and M. Moriwaki, Tetrahedron Lett.,
1996, 37, 2809.
N-((4-Chlorophenyl)(1H-pyrrol-2-yl)methyl)benzenesulfonamide
15 B. Temelli and C. Unaleroglu, Tetrahedron Lett., 2005, 46, 7941.
16 B. Temelli and C. Unaleroglu, Tetrahedron, 2006, 62, 10130.
(3h):16 1H NMR (500 MHz, CDCl3): δ 8.65 (br, 1H), 7.63 (d, J = 8.0 Hz,

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.