Optional synthesis of 2- OR 5-substituted 3-bromopyrroles via bromine-lithium exchange of N-benzenesulfonyl-2,4-dibromopyrrole

Article abstract of DOI:10.3987/COM-12-S(N)81

The regioselective bromine-lithium exchange of N-benzenesulfonyl-2,4- dibromopyrrole (6) with n-BuLi followed by treatment with various electrophiles gave 5-substituted 3-bromopyrroles (5) in excellent yields. In contrast, the sequential treatment of 6 wi

Full text of DOI:10.3987/COM-12-S(N)81

HETEROCYCLES, Vol. 86, No. 2, 2012
1261
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1261 - 1273. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2012, Accepted, 14th August, 2012, Published online, 21st August, 2012
DOI: 10.3987/COM-12-S(N)81
OPTIONAL
SYNTHESIS
OF
2-
OR
5-SUBSTITUTED
3-BROMOPYRROLES VIA BROMINE–LITHIUM EXCHANGE OF
N-BENZENESULFONYL-2,4-DIBROMOPYRROLE
Tsutomu Fukuda and Masatomo Iwao*
Division of Chemistry and Materials Science, Graduate School of Engineering,
Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan; E-mail:
iwao@nagasaki-u.ac.jp
Abstract
–
The
regioselective
bromine–lithium
exchange
of
N-benzenesulfonyl-2,4-dibromopyrrole (6) with n-BuLi followed by treatment
with various electrophiles gave 5-substituted 3-bromopyrroles (5) in excellent
yields. In contrast, the sequential treatment of 6 with n-BuLi and
diisopropylamine followed by quenching with electrophiles produced
regioisomeric 2-substituted 3-bromopyrroles (3) selectively. The latter reaction
can be rationalized by the rapid equilibration of the C-5 lithio species (4) to the
more stable C-2 lithio species (2) in the presence of diisopropylamine.
INTRODUCTION
The directed lithiation1 of N-protected pyrroles followed by reaction with electrophiles has frequently
been employed in the synthesis of 2-substituted pyrroles.2 During our investigation of the directed
lithiation of N-benzenesulfonyl-3-bromopyrrole (1),3 we encountered an interesting phenomenon
involving a dynamic equilibrium between C-2 and C-5 lithio species (Scheme 1).3b Thus, the treatment of
1 with lithium diisopropylamide regioselectively generated C-2 lithio species (2). When 2 was treated
with reactive electrophiles such as methyl chloroformate and chlorotrimethylsilane, 2-substituted
3-bromopyrroles (3) were obtained in good yields. On the other hand, when 2 was treated with less
reactive electrophiles such as dimethylcarbamoyl chloride and chlorotriisopropylsilane, unexpected
5-substituted 3-bromopyrroles (5) were produced. The electrophile-controlled regioselective
functionalization of 2 was rationalized by a dynamic equilibrium between the C-2 lithio species (2) and
C-5 lithio species (4).
This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
Br
Br
Br
3
LDA, THF
–78 °C, 1 h
4
reactive electrophiles
5
2
Li
E
N
N
N
SO2Ph
2
SO2Ph
SO2Ph
1
3
dynamic equilibrium
Br
Br
less reactive electrophiles
Li
E
N
N
SO2Ph
4
SO2Ph
5
Scheme 1
From a practical viewpoint, the reactions shown in Scheme 1 are useful for the synthesis of 2-substituted
3-bromopyrroles (3). However, they are impractical for the synthesis of 5-substituted 3-bromopyrroles (5)
because of the limited number of suitable electrophiles. In the previous Letter,3b we described briefly that
the lithio species (4) can be generated alternatively by the selective bromine!lithium exchange of
N-benzenesulfonyl-2,4-dibromopyrrole (6). In addition, we also indicated that the C-5 lithio species (4)
thus generated could rearrange to the more stable C-2 lithio species (2) in the presence of
diisopropylamine.4 In this paper, we describe the application of these reactions for the practical synthesis
of 5 and 3.
RESULTS AND DISCUSSION
The synthesis of N-benzenesulfonyl-2,4-dibromopyrrole (6) is shown in Scheme 2.
N-Benzenesulfonylpyrrole (7) was brominated with 2.6 equiv of NBS to give
N-benzenesulfonyl-2,5-dibromopyrrole (8). Reaction of this compound with a catalytic amount of
trifluoromethanesulfonic acid followed by treatment with triethylamine provided 6 in 84% yield.
Br
1. TfOH (0.2 equiv)
toluene, 0 °C, 1 h
NBS (2.6 equiv)
Br
Br
Br
N
N
N
DMF, rt, 0.5 h
(68%)
2. Et3N (2.2 equiv)
rt, 24 h
(84%)
SO2Ph
SO2Ph
SO2Ph
7
8
6
Scheme 2

HETEROCYCLES, Vol. 86, No. 2, 2012
1263
N-Benzenesulfonyl-2,4-dibromopyrrole (6) thus synthesized was treated with 1.1 equiv of n-BuLi in THF
at !78 °C for 0.5 h, and the resulting C-5 lithio species (4) was reacted with 1.8 equiv of an appropriate
electrophile under conditions A (!78 °C, 1 h) or B (!78 °C, 1 h ! 0 °C, 1 h). After the usual work-up,
the product was isolated by column chromatography. As shown in Table 1, various 5-substituted
3-bromopyrroles (5) were obtained in excellent yields.
Table 1. Bromine–lithium exchange of 6 followed by reactions with electrophiles
Br
Br
Br
electrophilea
conditionsb
n-BuLi (1.1 equiv)
Br
�i
E
N
N
N
THF
–78 °C, 0.5 h
SO2Ph
SO2Ph
SO2Ph
4
5
6
entry
electrophilea
ClCO2Me
conditionsb
product
E
yield (%)c
1
2
A
A
A
A
A
A
A
A
A
B
5a
5b
5c
5d
5e
5f
CO2Me
TMS
SPh
I
97
93
92
97
89
73
78
80
50
82
TMS-Cl
3
PhSSPh
4
ICH2CH2I
5
p-MeOC6H4CHO
HCO2Et
CH(OH)(C6H4OMe-p)
CHO
6
7
p-MeOC6H4COCl
TIPS-OTf
5g
5h
5i
COC6H4OMe-p
TIPS
8
9
t-BuNCO
CONHt-Bu
CONHt-Bu
10
t-BuNCO
5i
a Electrophile (1.8 equiv) was added as a THF solution.
b A: !78 °C, 1 h; B: !78 °C, 1 h ! 0 °C, 1 h.
c Isolated yield.
Next, the reaction conditions for the amine-mediated rearrangement of the C-5 lithio species (4) to the
C-2 lithio species (2) were investigated (Table 2). To this end, the C-5 lithio species (4) was treated with
1.0 equiv of a secondary amine in THF under conditions A (!78 °C, 1 h ! 0 °C, 0.5 h) and then reacted
with 1.8 equiv of methyl chloroformate, and the products were analyzed. The use of dimethylamine or
diethylamine did not produce the desired product (3a) but provided the corresponding
benzenesulfonamides (9 or 10) by the nucleophilic attack of the in situ generated lithium amides on the
substrate (entries 1 and 2). When diisopropylamine was used for the reaction, a 97:3 mixture of 3a and 5a
was obtained in 95% yield (entry 3). On the other hand, in the reactions with more bulky

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HETEROCYCLES, Vol. 86, No. 2, 2012
2,2,6,6-tetramethylpiperidine (TMP) or N-t-butyl-N-tritylamine (TBTA),5 C-2 selectivity was decreased
(entries 4 and 5). The amines, especially TBTA, may not be efficiently incorporated in the dynamic
equilibrium because of their much lower kinetic acidities. To improve the C-2 selectivity of the products,
longer reaction times (entries 6 and 7) and an increased amount of diisopropylamine (entry 8) were also
tested, but regioselectivity was not improved (entries 6–8). The reaction conditions shown in entry 3 were
estimated to be the most optimal.
Table 2. Examination of reaction conditions for the generation of 2
Br
Br
n-BuLi (1.1 equiv)
Br
�i
N
N
THF
–78 °C, 0.5 h
SO2Ph
SO2Ph
4
6
aminea
conditionsb
Br
CO2Me
Br
Br
�i
ClCO2Mec
–78 °C, 1 h
+
MeO2C
N
N
N
SO2Ph
SO2Ph
SO2Ph
2
3a
5a
entry
aminea
conditionsb
yield (%)d
ratio (3a:5a)e
g
1
2
3
4
5
6
7
8
Me2NHf
A
A
A
A
A
B
C
A
–
–
–
h
Et2NH
–
i-Pr2NH
TMP
95
86
80
86
74
89
97:3
93:7
41:59
97:3
97:3
97:3
TBTAi
i-Pr2NH
i-Pr2NH
i-Pr2NHj
a Amine (1.0 equiv) was added as a neat liquid unless otherwise mentioned.
b A: !78 °C, 1 h ! 0 °C, 0.5 h; B: !78 °C, 1 h ! 0 °C, 1 h; C: !78 °C, 1 h ! 0 °C, 3 h.
c Methyl chloroformate (1.8 equiv) was added as a THF solution.
d Isolated yield.
e Determined by 1H NMR analysis (400 MHz).
f Dimethylamine was added as a 2.0 M solution in THF.
g N,N-Dimethylbenzenesulfonamide (9) was obtained in 86% yield.
h N,N-Diethylbenzenesulfonamide (10) was obtained in 89% yield.
i N-t-Butyl-N-tritylamine (TBTA) was added as a 0.5 M solution in THF.
j 1.5 equiv of diisopropylamine.

HETEROCYCLES, Vol. 86, No. 2, 2012
1265
After obtaining the optimized conditions for generating the C-2 lithio species (2), we performed
functionalization. The lithio species (2) was reacted with 1.8 equiv of an appropriate electrophile under
conditions A (!78 °C, 1 h) or B (!78 °C, 1 h ! 0 °C, 3 h). As shown in Table 3, highly regioselective
2-substituted 3-bromopyrroles (3) were obtained in good yields. Pure 2-substituted
N-benzenesulfonyl-3-bromopyrroles (3) were readily obtained by column chromatography or
recrystallization.
Table 3. Synthesis of 2-substituted 3-bromopyrroles (3)
Br
Br
Br
Br
1. n-BuLi (1.1 equiv), THF
–78 °C, 0.5 h
electrophilea
conditionsb
+
E
E
Br
�i
N
N
N
N
2. i-Pr2NH (1.0 equiv)
–78 °C, 1 h ! 0 °C, 0.5 h
SO2Ph
SO2Ph
SO2Ph
SO2Ph
2
3
5
6
entry
electrophilea
ClCO2Me
TMS-Cl
conditionsb product
E
yield (%)c ratio (3:5)d
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
B
B
B
3a
3b
3c
3d
3e
3f
CO2Me
95
91
94
97
92
67
74
72
91
97:3
97:3
98:2
97:3
97:3
97:3
97:3
97:3
97:3
TMS
PhSSPh
SPh
I
ICH2CH2I
(p-MeOC6H4)CHO
HCO2Et
CH(OH)(C6H4OMe-p)
CHO
(p-MeOC6H4)COCl
TIPS-OTf
3g
3h
3i
COC6H4OMe-p
TIPS
t-BuNCO
CONHt-Bu
a Electrophile (1.8 equiv) was added as a THF solution.
b A: !78 °C, 1 h; B: !78 °C, 1 h ! 0 °C, 1 h.
c Isolated yield.
d Determined by 1H NMR analysis (400 MHz).
In conclusion, we have developed an efficient procedure to produce 5- or 2-substituted
N-benzenesulfonyl-3-bromopyrroles using N-benzenesulfonyl-2,4-dibromopyrrole (6) as a common
starting material. The lithio species (4) generated by the selective bromine–lithium exchange of
N-benzenesulfonyl-2,4-dibromopyrrole (6) was quenched with a number of electrophiles to give C-5
functionalized 3-bromopyrroles (5) in excellent yields. Moreover, quenching the lithio species (4) after
diisopropylamine-mediated isomerization produced the C-2 functionalized product (3) with excellent
selectivity. The reactions described in this paper could aid the synthesis of more complex pyrrole

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HETEROCYCLES, Vol. 86, No. 2, 2012
derivatives because further regioselective functionalization of the pyrrole ring is possible at the bromine
positions.6,7
EXPERIMENTAL
Melting points were determined using a Yanagimoto micro melting point apparatus and are uncorrected.
IR spectra were obtained using a Thermo Nicolet Nexus 670 NT FT-IR instrument and are reported in
terms of wave number (cm!1). NMR spectra were recorded on a JEOL JNM-AL400 instrument (400 MHz
1
13
1
for H and 100 MHz for C) using tetramethylsilane as an internal standard (! 0.0). Data for H NMR
spectra are reported as follows: chemical shift (! ppm), multiplicity, coupling constant (Hz), and
13
integration. Data for C NMR spectra are reported in terms of chemical shift. High-resolution mass
spectra were recorded on a JEOL JMS-700N spectrometer. Elemental analysis was performed for C, H,
and N using a Perkin Elmer 2400II instrument. Column chromatography was conducted using silica gel
60 N, 63–210 µm (Kanto Chemical Co., Inc.). n-Butyllithium was used after titration with
2,5-dimethoxybenzyl alcohol. Solvents were dried and distilled by standard methods if necessary.ꢀ
N-Benzenesulfonyl-2,4-dibromopyrrole (6)
A solution of NBS (13.9 g, 78.0 mmol) in DMF (30 mL) was added dropwise to a solution of
N-benzenesulfonylpyrrole (7)3a (6.22 g, 30.0 mmol) in DMF (60 mL) at room temperature, and the
mixture was stirred for 0.5 h. The solution was quenched with 10% aq. Na2SO3 and the product was
extracted with EtOAc. The extract was washed with water and brine, then dried over Na2SO4, and
evaporated. The residue was purified by column chromatography using silica gel 60 N (hexane–EtOAc =
5:1) to give the colorless solid N-benzenesulfonyl-2,5-dibromopyrrole (8) (7.49 g, 68%). This compound
was partially unstable and was used for the next reaction without further purification. Mp
1
102.5–104.5 °C; IR (KBr): 1448, 1385, 1196, 1141, 1096 cm!1; H NMR (400 MHz, CDCl3): ! 6.31 (s,
13
2H), 7.53–7.59 (m, 2H), 7.64–7.69 (m, 1H), 8.02–8.06 (m, 2H); C NMR (100 MHz, CDCl3): ! 101.8,
118.9, 127.7, 129.4, 134.5, 138.3. Anal. Calcd for C10H7Br2NO2S: C, 32.90; H, 1.93; N, 3.84. Found: C,
32.96; H, 1.67; N, 3.64.
Under an argon atmosphere, neat liquid trifluoromethanesulfonic acid (354 µL, 4.00 mmol) was added to
a solution of 8 (7.30 g, 20.0 mmol) in toluene (1.00 L) at 0 °C. The mixture was stirred for 1 h at 0 °C.
Triethylamine (6.1 mL, 44.0 mmol) was then added to the solution and the mixture was allowed to warm
to room temperature. The solution was stirred for 24 h, washed with sat. aq. NaHCO3 and brine, dried
over Na2SO4, and evaporated. The residue was purified by column chromatography using silica gel 60 N
(hexane–toluene = 2:1) to give the colorless solid 6 (6.16 g, 84%). Recrystallization from Et2O –pentane

HETEROCYCLES, Vol. 86, No. 2, 2012
1267
1
gave colorless granules. Mp 87–88 °C; IR (KBr): 1445, 1379, 1187, 1136, 1091 cm!1; H NMR (400
MHz, CDCl3): ! 6.29 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.53–7.59 (m, 2H), 7.65–7.71 (m, 1H),
7.93–7.97 (m, 2H); 13C NMR (100 MHz, CDCl3): ! 100.6, 100.8, 120.0, 123.2, 128.0, 129.5, 134.7, 137.5.
Anal. Calcd for C10H7Br2NO2S: C, 32.90; H, 1.93; N, 3.84. Found: C, 32.81; H, 1.69; N, 3.53.
Bromine–lithium exchange of N-benzenesulfonyl-2,4-dibromopyrrole (6) followed by reactions with
electrophiles (Table 1)
General procedure
Under an argon atmosphere, a hexane solution of n-butyllithium (1.60 M, 688 µL, 1.10 mmol) was added
dropwise to a solution of 6 (365 mg, 1.00 mmol) in THF (5.0 mL) at !78 °C. After stirring for 30 min, a
solution of an appropriate electrophile (1.80 mmol) in THF (2.0 mL) was added dropwise and the mixture
was treated under the conditions described in Table 1 (A: !78 °C, 1 h; B: !78 °C, 1 h ! 0 °C, 1 h). The
reaction mixture was quenched with sat. aq. NH4Cl, allowed to warm to room temperature, and
evaporated. The products were extracted with Et2O and the extract was washed with water and brine,
dried over Na2SO4, and evaporated. The residue was purified by column chromatography using silica gel
60 N to give 5.
Methyl N-benzenesulfonyl-4-bromopyrrole-2-carboxylate (5a)
Methyl chloroformate (138 µL, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (toluene), 5a was obtained as colorless solid (332 mg, 97%). Recrystallization from
Et2O–hexane gave colorless prisms. Physical and spectroscopic data of this compound were reported
previously.3b
N-Benzenesulfonyl-4-bromo-2-(trimethylsilyl)pyrrole (5b)
Chlorotrimethylsilane (228 µL, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1), 5b was obtained as colorless oil (332 mg, 93%). IR (KBr): 1371,
1176, 1132, 1076, 846 cm–1; 1H NMR (400 MHz, CDCl3): ! 0.29 (s, 9H), 6.51 (d, J = 1.6 Hz, 1H), 7.39 (d,
J = 1.6 Hz, 1H), 7.47–7.53 (m, 2H), 7.57–7.64 (m, 1H), 7.64–7.69 (m, 2H); 13C NMR (100 MHz, CDCl3):
! 0.0, 102.3, 125.7, 126.2, 127.5, 129.4, 133.8, 137.8, 139.6; HRFABMS m/z. Calcd for C13H17BrNO2SSi
[(M+H)+]: 357.9933. Found: 357.9921.
N-Benzenesulfonyl-4-bromo-2-(phenylthio)pyrrole (5c)
Diphenyl disulfide (393 mg, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1), 5c was obtained as pale purple oil (361 mg, 92%). IR (KBr): 1378,

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HETEROCYCLES, Vol. 86, No. 2, 2012
1
1188, 1135, 728 cm–1; H NMR (400 MHz, CDCl3): ! 6.49 (d, J = 2.0 Hz, 1H), 6.88–6.92 (m, 2H),
7.07–7.16 (m, 3H), 7.34–7.40 (m, 2H), 7.48–7.53 (m, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.88–7.92 (m, 2H);
13C NMR (100 MHz, CDCl3): ! 100.0, 122.1, 125.2, 126.3, 126.6, 127.2, 128.1, 128.9, 129.1, 134.2,
136.2, 137.5; HRFABMS m/z. Calcd for C16H12BrNO2S2 (M+): 392.9493. Found: 392.9522.
N-Benzenesulfonyl-4-bromo-2-iodopyrrole (5d)
1,2-Diiodoethane (507 mg, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1), 5d was obtained as colorless solid (398 mg, 97%). Recrystallization
from Et2O–pentane gave colorless granules. Mp 87.0–88.0 °C; IR (KBr): 1377, 1184, 1134, 609 cm–1; 1H
NMR (400 MHz, CDCl3): ! 6.50 (d, J = 1.9 Hz, 1H), 7.53–7.59 (m, 2H), 7.60 (d, J = 1.9 Hz, 1H),
7.64–7.70 (m, 1H), 7.93–7.97 (m, 2H); 13C NMR (100 MHz, CDCl3): ! 64.2, 102.5, 125.6, 128.1, 128.2,
129.4, 134.6, 137.6. Anal. Calcd for C10H7BrINO2S: C, 29.15; H, 1.71; N, 3.40. Found: C, 29.13; H, 1.33;
N, 3.32.
N-Benzenesulfonyl-4-bromo-2-("-hydroxy-4-methoxybenzyl)pyrrole (5e)
p-Methoxybenzaldehyde (219 µL, 1.80 mmol) was reacted under the conditions A. After
chromatographic purification (toluene to toluene–EtOAc = 5:1), 5e was obtained as pale purple oil (375
mg, 89%). IR (KBr): 3421, 1512, 1372, 1251, 1175 cm–1; C NMR (100 MHz, CDCl3): ! 55.3, 67.7,
13
100.9, 113.7, 117.6, 122.4, 126.8, 127.9, 129.5, 132.3, 134.2, 138.5, 139.1, 159.4; HRFABMS m/z. Calcd
for C18H16BrNO4S (M+): 420.9983. Found: 420.9990.
N-Benzenesulfonyl-4-bromopyrrole-2-carbaldehyde (5f)
Ethyl formate (145 µL, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1 to toluene), 5f was obtained as pale brown solid (229 mg, 73%).
Recrystallization from Et2O–hexane gave pale brown needles. The spectroscopic data are identical with
those previously reported.3b
N-Benzenesulfonyl-4-bromo-2-(4-methoxybenzoyl)pyrrole (5g)
p-Methoxybenzoyl chloride (307 mg, 1.80 mmol) was reacted under the conditions A. After
chromatographic purification (toluene), 5g was obtained as pale yellow oil (330 mg, 78%). IR (KBr):
1650, 1600, 1376, 1257, 1173 cm–1; 1H NMR (400 MHz, CDCl3): ! 3.87 (s, 3H), 6.62 (d, J = 1.8 Hz, 1H),
6.91–6.96 (m, 2H), 7.56–7.62 (m, 2H), 7.64–7.70 (m, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.81–7.85 (m, 2H),
13
8.11–8.15 (m, 2H); C NMR (100 MHz, CDCl3): ! 55.6, 99.4, 113.7, 124.3, 126.9, 128.4, 129.0, 129.9,
132.3, 133.3, 134.2, 138.8, 163.9, 182.8; HRFABMS m/z. Calcd for C18H15BrNO4S [(M+H)+]: 419.9905.

HETEROCYCLES, Vol. 86, No. 2, 2012
1269
Found: 419.9898.
N-Benzenesulfonyl-4-bromo-2-(triisopropylsilyl)pyrrole (5h)
Triisopropylsilyl trifluoromethanesulfonate (484 µL, 1.80 mmol) was reacted under the conditions A.
After chromatographic purification (hexane–toluene = 2:1), 5h was obtained as colorless solid (355 mg,
80%). Recrystallization from MeOH gave colorless plates. The spectroscopic data are identical with those
previously reported.3b
N-tert-Butyl-1-benzenesulfonyl-4-bromopyrrole-2-carboxamide (5i)
tert-Butyl isocyanate (206 µL, 1.80 mmol) was reacted under the conditions B. After chromatographic
purification using different solvent systems (hexane–toluene = 1:1 and toluene–EtOAc = 10:1), 5i was
obtained as colorless solid (316 mg, 82%). Recrystallization from Et2O–hexane gave colorless needles.
1
Mp 81.5–83.0 °C; IR (KBr): 3275, 1665, 1643, 1560, 1379, 1143 cm–1; H NMR (400 MHz, CDCl3): !
1.42 (s, 9H), 6.09 (br s, 1H), 6.53 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.51–7.57 (m, 2H),
13
7.61–7.67 (m, 1H), 8.00–8.04 (m, 2H); C NMR (100 MHz, CDCl3): ! 28.5, 52.1, 99.9, 119.0, 123.7,
128.1, 129.2, 131.9, 134.5, 137.9, 158.7. Anal. Calcd for C15H17BrN2O3S: C, 46.76; H, 4.45; N, 7.27.
Found: C, 46.79; H, 4.18; N, 7.27.
Examination of reaction conditions for the generation of 2 (Table 2)
General procedure
Under an argon atmosphere, a hexane solution of n-butyllithium (1.60 M, 689 µL, 1.10 mmol) was added
dropwise to a solution of 6 (365 mg, 1.00 mmol) in THF (5.0 mL) at !78 °C. After stirring for 30 min, an
appropriate secondary amine (1.00 mmol or 1.50 mmol) was added as a neat liquid or a THF solution,
and the mixture was reacted under the conditions described in Table 2 (A: !78 °C, 1 h ! 0 °C, 0.5 h; B:
!78 °C, 1 h ! 0 °C, 1 h; C: !78 °C, 1 h ! 0 °C, 3 h). After the reaction mixture was recooled to !78 °C,
a solution of methyl chloroformate (138 µL, 1.80 mmol) in THF (2.0 mL) was added dropwise and the
mixture was stirred for 1 h at !78 °C. The reaction mixture was quenched with sat. aq. NH4Cl, allowed to
warm to room temperature, and evaporated. The products were extracted with Et2O and the extract was
washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by column
chromatography using silica gel 60N (hexane–toluene = 1:1 to toluene) to give a mixture of the colorless
solids 3a and 5a. The regioisomeric ratio was determined by integration of the 1H NMR absorption of the
methyl protons for each regioisomer (! Me of 3a: 3.80; ! Me of 5a: 3.73).
N,N-Dimethylbenzenesulfonamide (9)

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A THF solution of dimethyamine (2.0 M, 500 µL, 1.00 mmol) was reacted under the conditions A. After
chromatographic purification using different solvent systems (hexane–toluene = 1:1 and toluene–EtOAc
= 5:1), 9 was obtained as yellow oil (160 mg, 86%). IR (KBr): 1446, 1339, 1167, 954, 738 cm–1; 1H NMR
13
(400 MHz, CDCl3): ! 2.71 (s, 6H), 7.53–7.59 (m, 2H), 7.59–7.65 (m, 1H), 7.76–7.80 (m, 2H); C NMR
(100 MHz, CDCl3): ! 37.9, 127.7, 129.0, 132.8, 135.4. HREIMS m/z. Calcd for C8H11NO2S (M+):
185.0510. Found: 185.0483. These spectroscopic data are identical with those previously reported.8
N,N-Diethylbenzenesulfonamide (10)
Diethyamine (103 µL, 1.00 mmol) was reacted under the conditions A. After chromatographic
purification using different solvent systems (hexane–toluene = 1:1 and toluene–EtOAc = 5:1), 10 was
obtained as yellow oil (190 mg, 89%). IR (KBr): 1446, 1333, 1155, 1017, 732 cm–1; 1H NMR (400 MHz,
CDCl3): ! 1.12 (t, J = 7.2 Hz, 6H), 3.24 (q, J = 7.2 Hz, 4H), 7.47–7.52 (m, 2H), 7.53–7.58 (m, 1H),
13
7.79–7.83 (m, 2H); C NMR (100 MHz, CDCl3): ! 14.1, 42.0, 126.9, 129.0, 132.3, 140.3. HRFABMS
m/z. Calcd for C10H16NO2S [(M+H)+]: 214.0902. Found: 214.0910. These spectroscopic data are identical
with those previously reported.9
Synthesis of 2-substituted 3-bromopyrroles (3) (Table 3)
General procedure
Under an argon atmosphere, a hexane solution of n-butyllithium (1.60 M, 688 µL, 1.10 mmol) was added
dropwise to a solution of 6 (365 mg, 1.00 mmol) in THF (5 mL) at !78 °C. After stirring for 30 min, neat
liquid diisopropylamine (140 µL, 1.00 mmol) was added. After stirring for 1 h at !78 °C, the mixture was
allowed to warm to 0 °C, stirred for 0.5 h at 0 °C, and then recooled to !78 °C. A solution of an
appropriate electrophile (1.8 mmol) in THF (2.0 mL) was added dropwise and the mixture was treated
under the conditions described in Table 3 (A: !78 °C, 1 h; B: !78 °C, 1 h ! 0 °C, 1 h). The reaction
mixture was quenched with sat. aq. NH4Cl, allowed to warm to room temperature, and evaporated. The
products were extracted with Et2O and the extract was washed with water and brine, dried over Na2SO4,
and evaporated. The residue was purified by column chromatography using silica gel 60 N to give a
97:3–98:2 mixture of 3 and 5.
Methyl N-benzenesulfonyl-3-bromopyrrole-2-carboxylate (3a)
Methyl chloroformate (138 µL, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1 to toluene), a 97:3 mixture of 3a and 5a was obtained as colorless
solid (327 mg, 95%). Physical and spectroscopic data of this compound were reported previously.3b

HETEROCYCLES, Vol. 86, No. 2, 2012
1271
N-Benzenesulfonyl-3-bromo-2-(trimethylsilyl)pyrrole (3b)
Chlorotrimethylsilane (228 µL, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 3:1 – 1:1), a 97:3 mixture of 3b and 5b was obtained as colorless solid
(326 mg, 91%). Physical and spectroscopic data of this compound were reported previously.3b
N-Benzenesulfonyl-3-bromo-2-(phenylthio)pyrrole (3c)
Diphenyl disulfide (393 mg, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1), a 98:2 mixture of 3c and 5c was obtained as colorless solid (372 mg,
94%). Physical and spectroscopic data of this compound were reported previously.3b
N-Benzenesulfonyl-3-bromo-2-iodopyrrole (3d)
1,2-Diiodoethane (507 mg, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification over Silica Gel 60N (hexane–toluene = 1:1), a 97:3 mixture of 3d and 5d was obtained as
colorless solid (401 mg, 97%). Physical and spectroscopic data of this compound were reported
previously.3b
N-Benzenesulfonyl-3-bromo-2-("-hydroxy-4-methoxybenzyl)pyrrole (3e)
p-Methoxybenzaldehyde (219 µL mg, 1.80 mmol) was reacted under the conditions A. After
chromatographic purification (toluene to toluene–EtOAc = 10:1), a 97:3 mixture of 3e and 5e was
obtained as colorless solid (599 mg, 84%). Physical and spectroscopic data of this compound were
reported previously.3b
N-Benzenesulfonyl-3-bromopyrrole-2-carbaldehyde (3f)
Ethyl formate (145 µL, 1.80 mmol) was reacted under the conditions A. After chromatographic
purification (hexane–toluene = 1:1 to toluene), a 97:3 mixture of 3f and 5f was obtained as colorless solid
(210 mg, 67%). Physical and spectroscopic data of this compound were reported previously.3b
N-Benzenesulfonyl-3-bromo-2-(4-methoxybenzoyl)pyrrole (3g)
p-Methoxybenzoyl chloride (307 mg, 1.80 mmol) was reacted under the conditions B. After
chromatographic purification (hexane–toluene = 1:1–1:2 to toluene), a 97:3 mixture of 3g and 5g was
obtained as colorless solid (309 mg, 74%). Physical and spectroscopic data of this compound were
reported previously.3b
N-Benzenesulfonyl-3-bromo-2-(triisopropylsilyl)pyrrole (3h)

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Chlorotriisopropylsilane (484 µL, 1.80 mmol) under the conditions B. After chromatographic purification
(hexane–toluene = 1:1), a 97:3 mixture of 3h and 5h was obtained as colorless solid (319 mg, 72%).
Physical and spectroscopic data of this compound were reported previously.3b
N-tert-Butyl-1-benzenesulfonyl-3-bromopyrrole-2-carboxamide (3i)
tert-Butyl isocyanate (206 µL, 1.80 mmol) was reacted under the conditions B. After chromatographic
purification using different solvent systems (hexane–toluene = 1:1, toluene, and toluene–EtOAc = 10:1), a
97:3 mixture of 3i and 5i was obtained as colorless solid (351 mg, 91%). Physical and spectroscopic data
of this compound were reported previously.3b
REFERENCES AND NOTES
1. For reviews, see: (a) V. Snieckus, Chem. Rev., 1990, 90, 879; (b) G. W. Rewcastle and A. R.
Katritzky, Adv. Heterocycl. Chem., 1993, 56, 155; (c) M. Gray, M. Tinkl, and V. Snieckus,
'Comprehensive Organometallic Chemistry II,' Vol. 11, ed. by A. McKillop, Pergamon, Oxford,
1995, Chapter 1; (d) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, and S. Thayumanavan, Acc.
Chem. Res., 1996, 29, 552; (e) J. Clayden, 'Organolithiums: Selectivity for Synthesis,' Pergamon,
Oxford, 2002; (f) M. C. Whisler, S. MacNeil, V. Snieckus, and P. Beak, Angew. Chem. Int. Ed.,
2004, 43, 2206.
2. (a) I. Hasan, E. R. Lin, L.-C. C. Marinelli, F. W. Fowler, and A. B. Levy, J. Org. Chem., 1981, 46,
157; (b) G. R. Martinez, P. A. Grieco, and C. V. Srinivasan, J. Org. Chem., 1981, 46, 3760; (c) M. P.
Edwards, S. V. Ley, S. G. Lister, and B. D. Palmer, J. Chem. Soc., Chem. Commun., 1983, 630; (d) J.
M. Muchowski and D. R. Solas, J. Org Chem., 1984, 49, 203; (e) M. P. Edwards, A. M. Doherty, S.
V. Ley, and H. M. Organ, Tetrahedron, 1986, 42, 3723; (f) L. S. Liebeskind, S. Iyer, and C. F.
Jewell, J. Org. Chem., 1986, 51, 3065; (g) A. R. Katritzky and K. Akutagawa, Org. Prep. Proc. Int.,
1988, 20, 585; (h) S. Martina, V. Enkelmann, G. Wegner, and A.-D. Schlüter, Synthesis, 1991, 613;
(i) M. Gharpure, A. Stoller, F. Bellamy, G. Firnau, and V. Snieckus, Synthesis, 1991, 1079; (j) L.
Groenendaal, M. E. Van Loo, J. A. J. M. Vekemans, and E. W. Meijer, Synth. Commun., 1995, 25,
1589; (k) M. Lautens and E. Fillion, J. Org. Chem., 1997, 62, 4418; (l) T. V. Hughes and M. P. Cava,
J. Org. Chem., 1999, 64, 313; (m) N. Basari", #. Marini", and M. $indler-Kulyk, Tetrahedron Lett.,
2003, 44, 7337; (n) A. Fensome, R. Bender, R. Chopra, J. Cohen, M. A. Collins, V. Hudak, K.
Malakian, S. Lockhead, A. Olland, K. Svenson, E. A. Terefenko, R. J. Unwalla, J. M. Wilhelm, S.
Wolfrom, Y. Zhu, Z. Zhang, P. Zhang, R. C. Winneker, and J. Wrobel, J. Med. Chem., 2005, 48,
5092; (o) M. F. Semmelhack, A. Chlenov, and D. M. Ho, J. Am. Chem. Soc., 2005, 127, 7759; (p) H.
Salman, Y. Abraham, S. Tal, S. Meltzman, M. Kapon, N. Tessler, S. Speiser, and Y. Eichen, Eur. J.

HETEROCYCLES, Vol. 86, No. 2, 2012
1273
Org. Chem., 2005, 2207; (q) S. E. Denmark and J. D. Baird, Org. Lett., 2006, 8, 793; (r) M. L.
Meketa and S. M. Weinreb, Org. Lett., 2006, 8, 1443; (s) L. Diab, T. $mejkal, J. Geier, and B. Breit,
Angew. Chem. Int. Ed., 2009, 48, 8022; (t) D. M. Knapp, E. P. Gillis, and M. D. Burke, J. Am. Chem.
Soc., 2009, 131, 6961; (u) M. Haberberger, E. Irran, and S. Enthaler, Eur. J. Inorg. Chem., 2011,
2797; (v) L. Melzig, A. Metzger, and P. Knochel, Chem. Eur. J., 2011, 17, 2948.
3. (a) T. Ohta, T. Fukuda, F. Ishibashi, and M. Iwao, J. Org. Chem., 2009, 74, 8143; (b) T. Fukuda, T.
Ohta, E. Sudo, and M. Iwao, Org. Lett., 2010, 12, 2734.
4. A C-5 to C-2 rearrangement of the lithiated N-benzenesulfonyl-3-(1-hydroxypropyl)pyrrole has been
reported, see: N. V. Moskalev and G. W. Gribble, Tetrahedron Lett., 2002, 43, 197. We thank
Professor Gribble for this information.
5. J. Busch-Petersen and E. J. Corey, Tetrahedron Lett., 2000, 41, 2515.
6. (a) Y. Zhao, M. Helliwell, and J. A. Joule, ARKIVOC, 2000, iii, 360; (b) L. Ghosez, C. Franc, F.
Denonne, C. Cuisinier, and R. Touillaux, Can. J. Chem., 2001, 79, 1827; (c) J. Nobuhiro, M.
Hirayama, T. Choshi, K. Kamoshita, S. Maruyama, Y. Sukenaga, T. Ishizu, H. Fujioka, and S.
Hibino, Heterocycles, 2006, 70, 491; (d) D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil, Z. Huo,
and Y. Yamamoto, J. Am. Chem. Soc., 2008, 130, 15720; (e) A. A. Kanakis and V. Sarli, Org. Lett.,
2010, 12, 4872; (f) K. Yoshida, K. Hayashi, and A. Yanagisawa, Org. Lett., 2011, 13, 4762.
7. (a) J. K. Laha, C. Muthiah, M. Taniguchi, B. E. McDowell, M. Ptaszek, and J. S. Lindsey, J. Org.
Chem., 2006, 71, 4092; (b) I. Islam, G. Brown, J. Bryant, P. Hrvatin, M. J. Kochanny, G. B. Phillips,
S. Yuan, M. Adler, M. Whitlow, D. Lentz, M. A. Polokoff, J. Wu, J. Shen, J. Walters, E. Ho, B.
Subramanyam, D. Zhu, R. I. Feldman, and D. O. Arnaiz, Bioorg. Med. Chem. Lett., 2007, 17, 3819.
8. C. J. Chapman, C. G. Frost, and M. F. Mahon, Dalton Trans., 2006, 2251.
9. (a) K. Bahrami, M. M. Khodaei, and M. Soheilizad, J. Org. Chem., 2009, 74, 9287; (b) C. Schneider,
E. Broda, and V. Snieckus, Org. Lett., 2011, 13, 3588.