Synthesis of 2,3,4-trisubstituted pyrroles via a facile reaction of vinyl azides and tosylmethyl isocyanide

Article abstract of DOI:10.1139/v11-150

A facile synthesis of polysubstituted pyrroles from tosylmethyl isocyanide (TOSMIC) and readily synthesized vinyl azides was developed. The reaction proceeded under mild conditions in the presence of base. 2-Tosyl-substituted pyrroles were obtained in moderate to good isolated yields. Additionally, a base-initiated one-pot pyrrole synthesis also was developed using carboxaldehydes, ethyl 2-azidoacetate, and TOSMIC.

Full text of DOI:10.1139/v11-150

214
Synthesis of 2,3,4-trisubstituted pyrroles via a
facile reaction of vinyl azides and tosylmethyl
isocyanide
Wenteng Chen, Jiaan Shao, Zhi Li, Marc A. Giulianotti, and Yongping Yu
Abstract: A facile synthesis of polysubstituted pyrroles from tosylmethyl isocyanide (TOSMIC) and readily synthesized vi-
nyl azides was developed. The reaction proceeded under mild conditions in the presence of base. 2-Tosyl-substituted pyr-
roles were obtained in moderate to good isolated yields. Additionally, a base-initiated one-pot pyrrole synthesis also was
developed using carboxaldehydes, ethyl 2-azidoacetate, and TOSMIC.
Key words: vinyl azides, 2,3,4-trisubstituted pyrroles, cyclization reaction, nucleophilic reaction, multicomponent reaction.
Résumé : On a développé une méthode facile de synthèse de pyrroles polysubstitués à partir de l’isocyanure de tosylméthyle
(ICTOSM) et d’azotures de vinyles facilement accessibles. La réaction s’effectue dans des conditions douces, en pré-
sence d’une base. On a obtenu des 2-tosylpyrroles substitués avec des rendements en produits isolés allant de modérés
à bons. De plus, on a mis au point une synthèse monotope de pyrroles initiée par une base et impliquant des carboxal-
déhydes, du 2-azidoacétate d’éthyle et de l’isocyanure de tosylméthyle.
Mots‐clés : azotures de vinyle, pyrroles 2,3,4-trisubstitués, réaction de cyclisation, réaction nucléophile, réaction à plusieurs
composants.
[Traduit par la Rédaction]
thesis from tosylmethyl isocyanide (TOSMIC) and vinyl
azides, furnishing 2,3,4-trisubstituted pyrroles in the presence
of base. In the previous studies, the azide group of vinyl
azides lost nitrogen and incorporated the nitrogen atom into
a newly formed molecule. In this report, however, the azide
group of vinyl azides serves as a leaving group, which is cru-
cial for the final aromatization of the intermediate to the final
products. Meanwhile, in the Van Leusen synthesis, pyrroles
are formed via elimination of sulfinic acid from the inter-
mediate cycloadducts. Therefore, the present work would be
a good addition to the synthetic application of Van Leusen’s
reagent. Moreover, previous reports on the use of vinyl
azides as reaction partners for the preparation of 2-tosyl-
substituted pyrroles are rare.
Introduction
Substituted pyrroles are important heterocycles that are
present as the core scaffolds in many natural products1 and
are reported to contribute to a wide spectrum of biological
activities.2 Thus, pyrroles are interesting synthetic targets for
obtaining biologically active compounds. Over the past deca-
des, a number of classical and new multicomponent reactions
(MCRs) have been reported for the preparation of pyrroles,
including the Hantzsch reaction,3 the Paal–Knorr cyclization
reaction of 1,4-dicarbonyl compounds and amines,4 transi-
tion-metal-based strategies,5 the Van Leusen cyclization,6
and other cyclizations.7–11 Despite the numerous approaches
for the synthesis of pyrroles that have been developed so far,
it is still challenging to prepare structurally diverse pyrroles
from readily available building blocks.
Vinyl azide is a pivotal three-atom synthon for the forma-
tion of nitrogen-containing heterocycles (azaheterocycles).
Especially, it has been reported that vinyl azide was em-
ployed with various transition metals in pyrrole synthesis.9
Recently, we studied the base initial synthesis of polysubsti-
tuted pyrrolo[1,2-a]pyrazine using vinyl azides as the starting
material.12 As part of our ongoing studies on synthetic appli-
cations of vinyl azides, we present a facile and general syn-
Results and discussion
The reaction of vinyl azide 1a, derived from benzaldehyde,
with TOSMIC was selected as a prototype reaction (Table 1)
for the identification of the optimal reaction conditions for
this synthesis. No reaction was observed when base was ab-
sent (Table 1, entry 1), but the transformation occurred in the
presence of a variety of bases at room temperature to form 3a
as the major product (Table 1). Screening of the bases revealed
Received 28 May 2011. Accepted 8 September 2011. Published at www.nrcresearchpress.com/cjc on 22 December 2011.
W. Chen, J. Shao, and Z. Li. Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.
R. China.
M.A. Giulianotti. Torrey Pines Institute for Molecular Studies, 11350 Village Parkway, Port St. Lucie, FL 34987, USA.
Y. Yu. Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.R. China; Torrey Pines
Institute for Molecular Studies, 11350 Village Parkway, Port St. Lucie, FL 34987, USA.
Corresponding author: Yongping Yu (e-mail: yyu@zju.edu.cn).
Can. J. Chem. 90: 214–221 (2012)
doi:10.1139/V11-150
Published by NRC Research Press

Chen et al.
215
Table 1. Optimization of reaction conditions.
COOEt
COOEt
base
+
TOSMIC
N3
solvent , temperature
Ts
N
H
graphic 1a
2
3a
Entry
1
2
3
4
5
6
7
Base
—
DBU
t-BuOK
Cs2CO3
K2CO3
NaH
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
t (°C)
25
25
25
25
25
25
25
25
Yield (%)a
n.r.
24
30
46
26
51
Trace
n.r.
NaH
NaH
8
THF
9
NaH
DCM
25
n.r.
10
11
NaH
NaH
Dioxane
CH3CN
25
40
n.r.
35
Note: n.r, no result; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene. Reaction conditions: vinyl azide (0.2 mmol, 1.0
equiv), tosylmethyl isocyanide (TOSMIC, 0.4 mmol, 2.0 equiv), base (0.5 mmol, 2.5 equiv), 2 mL solvent, 24 h,
room temperature.
aIsolated yield.
that NaH was the most efficient base (Table 1, entries 2–
11). When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a
strong base, was employed, the desired product 3a was ob-
tained with a yield of 24% (Table 1, entry 2). When the
base was changed to Cs2CO3, the yield of 3a was 46% (Ta-
ble 1, entry 4). Other inorganic bases, such as t-BuOK and
K2CO3 gave the product in low yields (Table 1, entries 3
and 5). Optimization of the solvent showed that acetonitrile
(Table 1, entry 6) was superior to other solvents (Table 1,
entries 6–10). This reaction was also tested at a higher tem-
perature, but with a decrease in the yield (Table 1, entry
11). Based on this initial study, the optimal conditions
were obtained in acetonitrile at room temperature when
NaH was employed as a base (51%; Table 1, entry 6).
With the optimized reaction condition in hand, this meth-
odology was evaluated using different substituted vinyl
azides (1) with TOSMIC (2; Table 2). The vinyl azides (Ta-
ble 2, entries 1–10) were readily prepared from the corre-
sponding aromatic carboxaldehydes with ethyl 2-azidoacetate
via a Knoevenagel condensation.9 Additional vinyl azides
(Table 2, entries 11–14) were prepared from the correspond-
ing olefins by successive reaction with bromine then with so-
dium azide.13
As presented in Table 2, various substituted vinyl azides
with TOSMIC worked well to provide the corresponding pyr-
roles in moderate to good isolated yields. The reaction could
tolerate an array of R1 substituents in the vinyl azides such as
aryl, H, and the furyl moiety (Table 2). Vinyl azides bearing
an electron-withdrawing group on the aryl ring gave good
yields (62%–86%; Table 2, entries 4–9). The case is illus-
trated in Table 2, entry 8, where the vinyl azide with a NO2
substituent at the aryl group gave a good isolated yield
(86%). The influence of R2 substituents in this reaction is also
illustrated in Table 2 (entries 11–14). When an arylcarbonyl
group occurred at the a-position of the vinyl azide, it lead
to a sharp decrease in the yield (<45%; Table 2, entries
11–14), compared with entry 4 (75%; Table 2). The a-N-
morpholinylcarbonyl-substituted vinyl azide greatly favored
this process, providing the corresponding product in higher
yield (94%; Table 2, entry 12).
a-Azidostyrene (Table 2, entry 11) was detrimental to the
desired transformation, most probably because of its rela-
tively low electron-withdrawing properties.
On the basis of the results presented above, we propose the
following possible mechanism for this reaction, as shown in
Scheme 1. First, it is expected to involve a Michael addition
of TOSMIC 2 to the vinyl azides 1, followed by an intramo-
lecular cyclization reaction. The desired product 3 is gener-
ated via intramolecular proton transfer and the elimination of
–
the N3 group.
Multicomponent reactions have a couple of distinct advan-
tages.14 In this report, a one-pot three-component process
was also investigated, where a mixture of 3-nitrobenzalde-
hyde and ethyl 2-azidoacetate was stirred under the Knoeve-
nagel condensation conditions using NaH as the base for 2 h
at –15 °C, followed by addition of TOSMIC. The reaction
mixture was then stirred at room temperature (rt) for 24 h to
give the desired product 3h (Scheme 2) with a total yield of
54%.
Conclusions
In conclusion, we have developed an efficient approach for
the generation of 2,3,4-trisubstituted pyrroles in moderate to
good yields. This reaction was realized through a domino
process from TOSMIC and readily available vinyl azides. Ex-
pansion of the method to a one-pot, three-component proto-
col to generate pyrrole 3h from commercially available
aromatic carboxaldehyde, ethyl 2-azidoacetate, and TOSMIC
Published by NRC Research Press

216
Can. J. Chem. Vol. 90, 2012
Table 2. Cyclization of tosylmethyl isocyanide (TOSMIC) with various vinyl azides.
R1
R2
R2
R1
NaH (2.5 equiv)
CH3CN, rt
+ TOSMIC
N3
Ts
N
H
3
1
2
Yield
(%)a
51
Entry
1
Substrate
Product
1a
3a
3b
2
3
1b
1c
42
3c
50
75
4
1d
3d
5
6
1e
1f
3e
3f
78
64
7
1g
3g
62
Published by NRC Research Press

Chen et al.
217
Table 2 (concluded).
R1
R2
R2
R1
NaH (2.5 equiv)
CH3CN, rt
+ TOSMIC
N3
Ts
N
H
3
1
2
Yield
(%)a
Entry
8
Substrate
Product
1h
3h
3i
86
9
1i
72
10
11
1j
3j
46
1k
3k
n.r.
12
13
1l
3l
94
45
1m
3m
14
1n
3n
36
O
N3
Br
Note: n.r., no result. Reactions were performed in anhydrous CH3CN at room temperature with 2.0 equiv of TOSMIC 2
under an N2 atmosphere.
Published by NRC Research Press

218
Can. J. Chem. Vol. 90, 2012
Scheme 1. Proposed mechanism for the synthesis of pyrroles.
R1
R2
R2
R1
+
TOSMIC
N3
Ts
N
H
3
1
2
R2
R1
Base
N
Ts
-N3
Ts
NC
N3
R2
N3
R1
R1
Ts
R2
NC
R2
N
R1
Ts
N3
Scheme 2. One-pot three-component synthesis of polysubstituted pyrroles.
NO2
NO2
O
NaH, CH3CN
+
N3
TOSMIC
+
COOEt
EtO
-15 °C to rt, 24 h
CHO
Ts
N
H
3h
also was accomplished. The domino process includes a
Knoevenagel condensation, a Michael addition, and intramo-
lecular cycloaddition.
General procedure A for the synthesis of 3
A mixture of vinyl azide 1 (1.0 mmol), TOSMIC 2
(2.0 mmol), and NaH (2.5 mmol) was stirred in anhydrous
CH3CN (2 mL) at rt under nitrogen for 24 h. The reaction
mixture was quenched with water (10 mL) and then extracted
three times with EtOAc (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried over MgSO4,
and concentrated. The crude product was purified by chroma-
tography (silica gel; petroleum ether:ethyl acetate = 3:1) to
afford 3 and was crystallized from a mixture of EtOAc with
hexanes.
Experimental section
General methods
All solvents were purified according to standard methods
prior to use. Reactions were run under an atmosphere of ni-
trogen unless mentioned otherwise. Purifications of the reac-
tion products were carried out by chromatography using
silica gel (200–300 mesh). Melting points were recorded on
a BÜCHI B-540 melting point apparatus. Infrared spectra
were recorded on an FTIR spectrophotometer. NMR spectra
General procedure B for the one-pot synthesis of 3h
A mixture of 3-nitrobenzaldehyde (1.0 mmol), ethyl 2-azi-
doacetate (5.0 mmol), and NaH (5.0 mmol) was stirred in an-
hydrous CH3CN (5 mL) at –15 °C under nitrogen for 2 h. A
solution of TOSMIC (3.0 mmol) and NaH (3.0 mmol) in an-
hydrous CH3CN was then added into this mixture. The reac-
tion was stirred at –15 °C to rt for 24 h. After the completion
of the reaction, the resulting solution was quenched with sa-
turated NH4Cl solution (10 mL) and then extracted three
times with EtOAc (3 × 10 mL). The combined organic ex-
tracts were washed with brine (10 mL), dried over MgSO4,
1
were recorded for H NMR at 500 MHz and for 13C NMR
1
at 125 MHz. For H NMR, tetramethylsilane (TMS) served
as the internal standard (d = 0) and data are reported as fol-
lows: chemical shift, integration, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, and m = multiplet), and
coupling constant(s) in Hz. For 13C NMR, TMS (d = 0) or
CDCl3 (d = 77.26) was used as the internal standard and
spectra were obtained with complete proton decoupling. LC–
MS and HRMS data were obtained using ESI ionization.
Published by NRC Research Press

Chen et al.
219
and concentrated. The crude product was purified by chroma-
tography (silica gel; petroleum ether:ethyl acetate = 3:1) to
afford 3h and was crystallized from a mixture of EtOAc
with hexanes.
8.5 Hz), 7.59 (1H, s), 9.87 (1H, brs). 13C NMR (125 MHz,
CDCl3) d: 14.2, 21.8, 60.3, 118.0, 122.4, 126.3, 127.5,
128.0, 129.3, 129.7, 130.5, 130.7, 132.5, 138.0, 144.8,
163.3. LC–MS (ESI) m/z [M + H]+: 448.2. HRMS (EI) m/z
calcd for C20H18NO4SBr (M)+: 447.0140; found: 447.0147.
Ethyl 4-phenyl-5-tosyl-1H-pyrrole-3-carboxylate (3a)
Treatment of 1a (217 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3a (188 mg, 51%)
as a pale yellow solid (EtOAc/hexane); mp 168–170 °C. IR
Ethyl 4-(2-bromophenyl)-5-tosyl-1H-pyrrole-3-carboxylate
(3e)
Treatment of 1e (296 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3e (350 mg, 78%)
as an off-white solid (EtOAc/hexane); mp 179–181 °C. IR
(KBr, cm–1) n: 3450, 3219, 2982, 1690, 763. 1H NMR
(500 MHz, CDCl3) d: 1.01 (3H, t, J = 7.0 Hz), 2.38 (3H, s),
4.00–4.11 (2H, m), 7.11 (2H, d, J = 8.5 Hz), 7.21–7.24 (1H,
m), 7.28–7.32 (3H, m), 7.34–7.37 (1H, m), 7.45 (1H, d, J =
7.0 Hz), 7.61 (1H, d, J = 3.5 Hz), 9.92 (1H, brs). 13C NMR
(125 MHz, CDCl3) d: 14.0, 21.8, 60.2, 118.8, 125.3, 125.9,
126.7, 127.7, 128.7, 129.6, 129.7, 131.9, 132.8, 133.1,
137.4, 144.7, 163.3. LC–MS (ESI) m/z [M + H]+: 448.2.
HRMS (EI) m/z calcd for C20H18NO4SBr (M)+: 447.0140;
found: 447.0139.
1
(KBr, cm–1) n: 3451, 3234, 2986, 1684, 770, 698, 661. H
NMR (500 MHz, CDCl3) d: 1.07 (3H, t, J = 7.0 Hz), 2.34
(3H, s), 4.08 (2H, q, J = 7.0 Hz), 7.07 (2H, d, J = 8.0 Hz),
7.14 (2H, d, J = 7.5 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.30 (2H,
t, J = 7.5 Hz), 7.34 (1H, d, J = 7.0 Hz), 7.58 (1H, d, J =
2.0 Hz), 10.07 (1H, brs). 13C NMR (125 MHz, CDCl3) d:
14.1, 21.7, 60.2, 117.9, 126.4, 127.4, 127.7, 128.0, 130.0,
130.7, 130.8, 131.5, 138.2, 144.4, 163.5. LC–MS (ESI) m/z
[M + H]+: 370.3. HRMS (EI) m/z calcd for C20H19NO4S
(M)+: 369.1035; found: 369.1033.
Ethyl 4-(4-methoxyphenyl)-5-tosyl-1H-pyrrole-3-
carboxylate (3b)
Ethyl 4-(4-fluorophenyl)-5-tosyl-1H-pyrrole-3-carboxylate
(3f)
Treatment of 1b (247 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3b (168 mg, 42%)
as a pale yellow solid (EtOAc/hexane); mp 140–142 °C. IR
Treatment of 1f (235 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3f (248 mg, 64%)
as a pale yellow solid (EtOAc/hexane); mp 183–185 °C. IR
1
(KBr, cm–1) n: 3451, 3236, 2987, 1674, 807, 768. H NMR
(500 MHz, CDCl3) d: 1.12 (3H, t, J = 7.0 Hz), 2.35 (3H, s),
3.86 (3H, s), 4.10 (2H, q, J = 7.0 Hz), 6.86 (2H, d, J =
8.5 Hz), 7.08–7.11 (4H, m), 7.28 (2H, d, J = 8.5 Hz), 7.56
(1H, d, J = 3 Hz), 10.13 (1H, brs). 13C NMR (125 MHz,
CDCl3) d: 14.1, 21.5, 55.3, 59.9, 112.8, 117.6, 123.4, 126.4,
127.2, 127.4, 129.4, 130.7, 131.8, 138.1, 144.2, 159.3, 163.4.
LC–MS (ESI) m/z [M + H]+: 400.4. HRMS (EI) m/z calcd
for C21H21NO5S (M)+: 399.1140; found: 399.1137.
1
(KBr, cm–1) n: 3451, 3220, 2986, 1686, 808, 781. H NMR
(500 MHz, CDCl3) d: 1.10 (3H, t, J = 7.0 Hz), 2.36 (3H, s),
4.09 (2H, q, J = 7.0 Hz), 6.98–7.02 (2H, m), 7.10–7.14 (4H,
m), 7.26–7.29 (2H, m), 7.59 (1H, s), 10.08 (1H, brs). 13C
NMR (125 MHz, CDCl3) d: 14.2, 21.8, 60.3, 114.5 (d, J =
21 Hz), 118.0, 126.5, 127.4, 127.9, 129.6, 129.7, 132.8 (d,
J = 8 Hz), 138.1, 144.7, 162.8 (d, J = 245 Hz), 163.4. LC–
MS (ESI) m/z [M + H]+: 388.3. HRMS (EI) m/z calcd for
C20H18NO4FS (M)+: 387.0941; found: 387.0938.
Ethyl 4-(benzo[d][1,3]dioxol-5-yl)-5-tosyl-1H-pyrrole-3-
carboxylate (3c)
Ethyl 4-(3, 4-dichlorophenyl)-5-tosyl-1H-pyrrole-3-
carboxylate (3g)
Treatment of 1c (261 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3c (207 mg, 50%)
as a pale yellow solid (EtOAc/hexane); mp 173–175 °C. IR
Treatment of 1g (286 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3g (272 mg, 62%)
as a pale yellow solid (EtOAc/hexane); mp 191–193 °C. IR
1
(KBr, cm–1) n: 3450, 3270, 2924, 1692, 810, 771. H NMR
(500 MHz, CDCl3) d: 1.14 (3H, t, J = 7.0 Hz), 2.37 (3H, s),
4.11 (2H, q, J = 7.0 Hz), 5.98 (2H, s), 6.57 (1H, d, J =
1.5 Hz), 6.62 (1H, dd, J1 = 1.5 Hz, J2 = 8.0 Hz), 6.76 (1H,
d, J = 8.0 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J =
8.5 Hz), 7.56 (d, 1H, J = 3.5 Hz), 10.11 (1H, brs). 13C
NMR (125 MHz, CDCl3) d: 14.3, 21.8, 60.2, 101.2, 107.5,
111.3, 117.9, 124.4, 124.9, 126.5, 127.5, 127.8, 129.6,
130.4, 138.2, 144.6, 146.9, 147.4, 163.4. LC–MS (ESI) m/z
[M + H]+: 414.3. HRMS (EI) m/z calcd for C21H19NO6S
(M)+: 413.0933; found: 413.0935.
1
(KBr, cm–1) n: 3451, 3237, 2924, 1686, 770, 672. H NMR
(500 MHz, CDCl3) d: 1.11 (3H, t, J = 7.0 Hz), 2.39 (3H, s),
4.10 (2H, q, J = 7.0 Hz), 7.03 (1H, s), 7.07 (1H, d, J =
8.0 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.33 (2H, d, J = 8.0 Hz),
7.40 (1H, d, J = 8.0 Hz), 7.60 (1H, s). 13C NMR (125 MHz,
CDCl3) d: 14.2, 21.8, 60.4, 118.0, 126.3, 127.6, 128.5, 129.5,
129.8, 130.3, 131.5, 131.6, 132.3, 132.4, 137.8, 145.1, 163.1.
LC–MS (ESI) m/z [M + H]+: 438.2. HRMS (EI) m/z calcd
for C20H17NO4SCl2 (M)+: 437.0255; found: 437.0258.
Ethyl 4-(4-bromophenyl)-5-tosyl-1H-pyrrole-3-carboxylate
(3d)
Ethyl 4-(3-nitrophenyl)-5-tosyl-1H-pyrrole-3-carboxylate
(3h)
Treatment of 1d (296 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3d (336 mg, 75%)
as a pale yellow solid (EtOAc/hexane); mp 185–187 °C. IR
Treatment of 1h (262 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure B gave 3h (356 mg, 86%)
as a pale yellow solid (EtOAc/hexane); mp 161–163 °C. IR
1
1
(KBr, cm–1) n: 3450, 3223, 2924, 1685, 818, 778. H NMR
(KBr, cm–1) n: 3451, 3250, 2984, 1689, 810, 737. H NMR
(500 MHz, CDCl3) d: 1.11 (3H, t, J = 7.0 Hz), 2.37 (3H, s),
4.09 (2H, q, J = 7.0 Hz), 7.02 (2H, d, J = 8.5 Hz), 7.12 (2H,
d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz), 7.44 (2H, d, J =
(500 MHz, CDCl3) d: 1.07 (3H, t, J = 7.0 Hz), 2.36 (3H, s),
4.08 (2H, q, J = 7.0 Hz), 7.13 (2H, d, J = 8.0 Hz), 7.32 (2H,
d, J = 8 Hz), 7.54 (1H, t, J = 8.0 Hz), 7.62–7.64 (2H, m),
Published by NRC Research Press

220
Can. J. Chem. Vol. 90, 2012
7.78 (1H, s), 8.22 (1H, d, J = 8.0 Hz). 13C NMR (125 MHz,
CDCl3) d: 14.2, 21.7, 60.5, 118.0, 122.9, 125.6, 126.7, 127.4,
127.7, 128.5, 129.9, 133.5, 137.2, 137.9, 145.3, 147.5, 163.1.
LC–MS (ESI) m/z [M + H]+: 415.3. HRMS (EI) m/z calcd
for C20H18N2O6S (M)+: 414.0886; found: 414.0889.
calcd for C24H17NO3SClBr (M)+: 512.9801; found:
512.9807.
(4-(4-Bromophenyl)-5-tosyl-1H-pyrrol-3-yl)(p-tolyl)
methanone (3n)
Treatment of 1n (342 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3n (178 mg, 36%)
as a yellow solid (EtOAc/hexane); mp 180–182 °C. IR (KBr,
Ethyl 4-(4-(methylsulfonyl)phenyl)-5-tosyl-1H-pyrrole-3-
carboxylate (3i)
1
cm–1) n: 3451, 1645. H NMR (500 MHz, CDCl3) d: 2.35
Treatment of 1i (295 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3i (322 mg, 72%)
as a pale yellow solid (EtOAc/hexane); mp 180–182 °C. IR
(KBr, cm–1) n: 3452, 3266, 2986, 1684, 771. 1H NMR
(500 MHz, CDCl3) d: 1.11 (3H, t, J = 7.0 Hz), 2.36 (3H, s),
3.12 (3H, s), 4.10 (2H, q, J = 7.0 Hz), 7.11 (2H, d, J =
8.0 Hz), 7.27–7.28 (2H, m), 7.38 (2H, d, J = 8.0 Hz), 7.64
(1H, s), 7.88 (2H, d, J = 8.5 Hz). 13C NMR (125 MHz,
CDCl3) d: 14.2, 21.8, 44.8, 60.5, 117.8, 126.4, 126.5, 127.4,
128.3, 128.5, 129.8, 131.9, 137.8, 140.0, 145.1, 163.1. LC–
MS (ESI) m/z [M + H]+: 448.3. HRMS (EI) m/z calcd for
C21H21NO6S2 (M)+: 447.0810; found: m/z: 447.0815.
(3H, s), 2.36 (3H, s), 7.05 (2H, d, J = 8.5 Hz), 7.10–7.14
(4H, m), 7.31 (2H, d, J = 8.5 Hz), 7.35–7.36 (3H, m), 7.58
(2H, d, J = 8.0 Hz), 10.05 (1H, brs). 13C NMR (125 MHz,
CDCl3) d: 21.8, 122.4, 125.7, 126.7, 127.4, 128.0, 129.1,
129.4, 129.7, 130.5, 130.9, 132.5, 135.9, 138.0, 143.5,
144.8, 190.3. LC–MS (ESI) m/z [M + H]+: 494.3. HRMS
(EI) m/z calcd for C25H20NO3SBr (M)+: 493.0347; found:
493.0343.
Supplementary data
Supplementary data (including experimental procedures,
1
characterization data, and copies of H and 13C NMR spectra
Ethyl 4-(furan-2-yl)-5-tosyl-1H-pyrrole-3-carboxylate (3j)
Treatment of 1j (207 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3j (165 mg, 46%)
as a yellow solid (EtOAc/hexane); mp 209–211 °C. IR (KBr,
cm–1) n: 3451, 3225, 2988, 1685. 1H NMR (500 MHz,
CDCl3) d: 1.10 (3H, t, J = 7.0 Hz), 2.36 (3H, s), 4.09 (2H,
q, J = 7.0 Hz), 6.99–7.02 (2H, m), 7.10 (2H, d, J = 8.0 Hz),
7.12–7.14 (1H, m), 7.26 (2H, d, J = 8.0 Hz), 7.59 (1H, s),
9.80 (1H, brs). 13C NMR (125 MHz, CDCl3) d: 14.2, 21.8,
60.3, 114.4, 114.6, 118.1, 126.2, 127.5, 128.1, 129.6, 132.5,
132.6, 138.1, 144.7, 163.4. LC–MS (ESI) m/z [M + H]+:
360.2. HRMS (EI) m/z calcd for C18H17NO5S (M)+:
359.0827; found: 359.0826.
for all products) are available with the article through the
journal Web site at http://nrcresearchpress.com/doi/suppl/
10.1139/v11-150.
Acknowledgements
We thank the National Natural Science Foundation of
China (Grant Nos. 30772652 and 90813026) and the Na-
tional Key Tech Project for Major Creation of New Drugs
(Grant No. 2009ZX09501-010).
References
(1) (a) Larionov, O. V.; de Meijere, A. Angew. Chem. Int. Ed.
2005, 44 (35), 5664. doi:10.1002/anie.200502140; (b) Smith,
N. D.; Huang, D.; Cosford, N. D. P. Org. Lett. 2002, 4 (20),
3537. doi:10.1021/ol0267073.
Morpholino(5-tosyl-1H-pyrrol-3-yl)methanone (3l)
Treatment of 1l (182 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3l (314 mg, 94%)
as an off-white solid (EtOAc/hexane); mp 202–204 °C. IR
(KBr, cm–1) n: 3451, 3238, 2998, 1625. 1H NMR
(500 MHz, DMSO-d6) d: 2.37 (3H, s), 3.57 (8H, m), 6.96
(1H, d, J = 1.0 Hz), 7.41–7.43 (3H, m), 7.83 (2H, d, J =
8.5 Hz), 12.77 (1H, brs). 13C NMR (125 MHz, DMSO-d6)
d: 21.5, 66.7, 115.6, 119.7, 127.2, 127.3, 129.3, 130.5,
139.5, 144.5, 164.2. LC–MS (ESI) m/z [M + H]+: 335.3.
HRMS (EI) m/z calcd for C16H18N2O4S (M)+: 334.0987;
found: 334.0978.
(2) (a) Silvestri, R.; La Regina, G.; De Martino, G.; Artico, M.;
Befani, O.; Palumbo, M.; Agostinelli, E.; Turini, P. J. Med.
Chem. 2003, 46 (6), 917. doi:10.1021/jm0256124; (b)
Kemnitzer, W.; Drewe, J.; Jiang, S.; Zhang, H.; Crogan-
Grundy, C.; Labreque, D.; Bubenick, M.; Attardo, G.; Denis,
R.; Lamothe, S.; Gourdeau, H.; Tseng, B.; Kasibhatla, S.; Cai,
S. X. J. Med. Chem. 2008, 51 (3), 417. doi:10.1021/
jm7010657; (c) Pacorel, B.; Leung, S. C.; Stachulski, A. V.;
Davies, J.; Vivas, L.; Lander, H.; Ward, S. A.; Kaiser, M.;
Brun, R.; O’Neill, P. M. J. Med. Chem. 2010, 53 (2), 633.
doi:10.1021/jm901216v; (d) Plitt, P.; Gross, D. E.; Lynch, V.
M.; Sessler, J. L. Chemistry 2007, 13 (5), 1374. doi:10.1002/
chem.200601514.
(4-(4-Bromophenyl)-5-tosyl-1H-pyrrol-3-yl)(4-
chlorophenyl)methanone (3m)
(3) Palacios, F.; Aparicio, D.; de los Santos, J. M.; Vicario, J.
Tetrahedron 2001, 57 (10), 1961. doi:10.1016/S0040-4020(01)
00033-3.
Treatment of 1m (363 mg, 1.0 mmol) with 2 (390 mg,
2.0 mmol) by General procedure A gave 3m (232 mg, 45%)
as an off-white solid (EtOAc/hexane); mp 225–227 °C. IR
(4) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6 (14), 2465.
doi:10.1021/ol049044t.
(5) Balme, G. Angew. Chem. Int. Ed. 2004, 43 (46), 6238. doi:10.
1002/anie.200461073.
(6) (a) Baxendale, I. R.; Buckle, C. D.; Ley, S. V.; Tamborini, L.
Synthesis 2009, 2009 (9), 1485. doi:10.1055/s-0028-1087991;
(b) van Leusen, D.; van Echten, E.; van Leusen, A. M. J. Org.
Chem. 1992, 57 (8), 2245. doi:10.1021/jo00034a011; (c) van
Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen,
1
(KBr, cm–1) n: 3451, 1650. H NMR (500 MHz, CDCl3) d:
2.36 (3H, s), 7.03–7.04 (2H, m), 7.11 (2H, d, J = 8.0 Hz),
7.29–7.30 (2H, m), 7.30–7.32 (4H, m), 7.36–7.37 (3H, m),
7.60–7.62 (2H, m). 13C NMR (125 MHz, CDCl3) d: 21.8,
122.6, 125.2, 126.9, 127.4, 128.5, 128.8, 129.3, 129.8,
130.3, 130.9, 131.0, 132.4, 136.9, 137.8, 139.0, 145.0,
189.3. LC–MS (ESI) m/z [M + H]+: 514.2. HRMS (EI) m/z
Published by NRC Research Press

Chen et al.
D. Tetrahedron Lett. 1972, 13 (52), 5337. doi:10.1016/S0040-
4039(01)85244-8.
(7) Robinson, G. M.; Robinson, R. J. Chem. Soc. Trans. 1918,
113, 639. doi:10.1039/ct9181300639.
(8) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001, 66 (12),
4427. doi:10.1021/jo001714v.
221
1016/S0040-4039(01)85244-8; (b) ten Have, R.; Leusink, F.
R.; van Leusen, A. M. Synthesis 1996, 1996 (7), 871. doi:10.
1055/s-1996-4306; (c) Dijkstra, H. P.; ten Have, R.; van
Leusen, A. M. J. Org. Chem. 1998, 63 (16), 5332. doi:10.
1021/jo972216y.
(12) Chen, W.; Hu, M.; Wu, J.; Zou, H.; Yu, Y. Org. Lett. 2010, 12
(9) (a) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org.
Lett. 2008, 10 (2), 313. doi:10.1021/ol702727j; (b) Wang, Y.-F.;
Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett. 2008, 10
(21), 5019. doi:10.1021/ol802120u.
(10) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J. Org.
Chem. 2005, 2005 (24), 5277. doi:10.1002/ejoc.200500387.
(11) (a) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van
Leusen, D. Tetrahedron Lett. 1972, 13 (52), 5337. doi:10.
(17), 3863. doi:10.1021/ol101538x.
(13) Gilchrist, T. L.; Mendonca, R. ARKIVOC 2000, 1, 769.
(14) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39 (18),
3168. doi:10.1002/1521-3773(20000915)39:18<3168::AID-
ANIE3168>3.0.CO;2-U; (b) Ruijter, E.; Scheffelaar, R.;
Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50 (28), 6234.
doi:10.1002/anie.201006515.
Published by NRC Research Press