Facile synthesis of 2,3-disubstituted pyrroles from 2-substituted 1-pyrrolines

Article abstract of DOI:10.3987/COM-12-12457

2-Substituted-1-pyrrolines react with various arylaldehyde acetals in the presence of a Lewis acid and base to give 2-substituted 3-arylmethylidene-1- pyrrolines, which are transformed to 2,3-disubstituted pyrroles by base-catalyzed double-bond isomerization.

Full text of DOI:10.3987/COM-12-12457

HETEROCYCLES, Vol. 85, No. 5, 2012
1187
HETEROCYCLES, Vol. 85, No. 5, 2012, pp. 1187 - 1195. © 2012ꢀ The Japan Institute of Heterocyclic Chemistry
Received, 27th February, 2012, Accepted, 26th March, 2012, Published online, 3rd April, 2011
DOI: 10.3987/COM-12-12457
FACILE SYNTHESIS OF 2,3-DISUBSTITUTED PYRROLES FROM
2-SUBSTITUTED 1-PYRROLINES
Yurie Fujiwara,a Mitsunori Oda,a,* Taku Shoji,a Takako Abe,b and
Shigeyasu Kurodab
a Department of Chemistry, Faculty of Science, Shinshu University, Asahi 3-1-1,
Matsumoto, Nagano, 390-8621 Japan, bGraduate School of Science and
Engineering, Faculty of Nano and Functional Materials Science, University of
Toyama,
Gofuku
3190,
Toyama,
930-8555
Japan,
e-mail:
mituoda@shinshu-u.ac.jp
Abstract – 2-Substituted-1-pyrrolines react with various arylaldehyde acetals in
the presence of Lewis acid and base to give 2-substituted
a
3-arylmethylidene-1-pyrrolines, which are transformed to 2,3-disubstituted
pyrroles by base-catalyzed double-bond isomerization.
Pyrrole derivatives are an important family of compounds especially because of their significance in the
synthesis of natural products and pharmaceuticals.1 In addition to reliable classical methods such as the
Knorr,2 Paal–Knorr,3 and Hantzsch syntheses,4 synthetic methodologies for pyrroles have been
continuously developed.5 Although the development of nitrogen-containing five-membered rings is a
recent topic of interest, synthetic routes for pyrroles by inexpensive or easily available hydrogenated
materials such as pyrrolines and pyrrolidines are also still
R
!
important.6 Previously, we reported the synthesis of
2
R CHO
N
N
1,3-disubstituted pyrroles 1 simply by heating pyrrolidine
(2) and aldehydes 3 without any catalyst in a pressure
vessel, as shown in Scheme 1.7 In this paper, we describe a
new facile synthesis of 2,3-disubstituted pyrroles 4 from
2-substituted 1-pyrrolines 5 with acetals 6 by a two-step
sequence, which involves an aldol-type condensation
followed by base-catalyzed double-bond isomerization.
H
R
2
3
1
R
OR'
R CH
Y
Y
N
N
H
OR'
5
6
4
Scheme 1

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HETEROCYCLES, Vol. 85, No. 5, 2012
Ph
For the first step, we found that a conventional
aldol-type condensation8 of 2-phenyl-1-pyrroline (5a)9
with benz-aldehyde under continuous azeotropic
distillation of water provided 3-benzylidene-2-phenyl-
1-pyrroline (7a) in 73% yield.10,11 However, it took a
very long time (175 h) to complete the reaction (Scheme 2).
H+, – H2O
Ph CHO
Ph
N
Ph–H
175 h
Ph
N
5a
7a
Scheme 2
Table 1. Lewis acid- and triethyamine-assisted aldol
condensation of 5a in refluxing acetonitrile
Table 2. TiCl4- and triethyamine-assisted aldol condensation
of 2-substituted 1-pyrroline
Ph
Ar
OMe
OR
Lewis acid
TlCl4 (3.0 eq)
Ph CH
Ph
Ar CH
Y
N
Ph
Et3N (3.0 eq)
N
Y
OMe
Et3N (3.0 eq)
MeCN
N
N
OR
MeCN
5a
6a
7a
7
5
6 (2.0 eq)
entry
yield of 7a (%)a
reaction conditions
product
(yield:%)
reaction
time
entry
Y
Ar
R
30 b
75 b
81
BF3·Et2O (3.0 eq), 6a (1.5 eq), 22 h
TiCl4 (3.0 eq), 6a (1.5 eq), 22 h
TiCl4 (3.0 eq), 6a (2.0 eq), 18 h
1
2
3
1
2
3
7a (74)
7b (70)
Ph
Ph
Ph
Et
25 h
22 h
p-Br-C6H4
Me
7c (41)
Ph
o-Me-C6H4
Me
29 h
TMSOTf (4.0 eq), 6a (1.5 eq), 23 h
SnCl4 (3.0 eq), 6a (2.0 eq), 23 h
4
5
65
48
4
7d (36)
7e (39)
7f (79)
7g (57)
7h (12)
7i (0)
Ph
Ph
1-naphthyl
2-thienyl
Ph
Me
Me
Me
Me
Me
Me
27 h
26 h
24 h
24 h
26 h
26 h
5
6
7
8
9
a Isolated yield. b Some recovery of 5a was observed.
p-MeO-C6H4
p-Me2N-C6H4
t-Bu
Ph
Then, we examined reactions with benzaldehyde
dimethyl acetal assisted by a Lewis acid and
triethyamine12 (Table 1). The results indicate that
Ph
MeO2C
Ph
the yield depends on the Lewis acid used. Among the Lewis acids used, TiCl4 was the most effective,
giving the most satisfactory yield of 7a (Table 1, entry 3). This reaction proceeded much faster than the
conventional method.
Several 2-substituted 1-pyrrolines were subjected to condensation with some acetals under these
conditions. The results are summarized in Table 2. Benzaldehyde diethyl acetal reacted similarly, but the
reaction proceeded slightly slower, giving 7a in a similar yield (Table 2, entry 1). Various dimethyl
acetals such as p-bromobenzaldehyde, o-methylbenzaldehyde, 1-naphthylcarbaldehyde, and
2-thienylcarbaldehyde dimethyl acetals react with 5a to give 7b–7e (Table 2, entry 2–5), respectively, and
the yield mainly depends on the structure of the aryl group. Using alkanal dimethyl acetals, such as
acetaldehyde and propanal dimethyl acetals, did not form the expected condensation products. None of
the dimethyl ketals – acetone, benzophenone, acetophenone, and cyclohexane dimethyl ketals – react with
5a under these conditions. Reactions of other 2-(substituted phenyl)-1-pyrrolines with 6a provide
satisfactory yields of 7f–g (Table 2, entries 6 and 7, respectively). However, 7h was obtained in low yield

HETEROCYCLES, Vol. 85, No. 5, 2012
1189
(Table 2, entry 8) probably because
of the sterically bulky t-Bu group.
Moreover, 2-(methoxycarbonyl)-1-
pyrroline was found to be inactive
under these conditions (Table 2,
entry 9). We propose the following
reaction mechanism, shown in
Scheme 3, to explain the change of
product yields. A reaction of TiCl4
4
Ar CH(OMe)2
Y
N
TiCl4
TiCl4
Ar
H
+
C OMe
8
NEt3
Ar
Ar
OMe
– MeOH
H
H
Y
Y
N
Y
N
Y
N
N
–
TiCl4
TiCl4
9
7
10
Scheme 3. Proposed mechanism for condensation
and triethylamine with 4 produces the enamine 9, which then reacts with the methyloxonium ion 8
generated in situ to yield the adduct 10.13 The elimination of methanol subsequently forms the final
product 7. The reason why alkanal dimethyl acetals does not give the expected product may be ascribed
to that the methyloxonium ion derived from alkanal dimethyl acetals undergoes elimination of proton to
give the corresponding methylvinyl ether, which is observed in the crude reaction mixture accompanied
with the starting material 4.
Then, the second step, which is the base-catalyzed double-bond isomerization of pyrroline 7 to the
corresponding pyrrole 4, was examined. The results under various conditions with several bases are
Table 4. t-BuOK-catalyzed double-bond isomerization of 7
Table 3. Base-catalyzed double-bond isomerization of 7a
Ar
Ar
Ph
Ph
t-BuOK (0.5 eq)
base
Y
Y
DMSO, rt
N
N
Ph
Ph
solvent
H
N
N
H
7
4
7a
4a
product
(yield:%)
reaction
time
entry
Y
Ar
yield of
4a (%)
entry
reaction conditions
1
2
3
4b (89)
4c (73)
Ph
Ph
p-Br-C6H4
o-MeC6H4
3 h
5 h
(i-Pr)2NEt (3.0 eq), toluene, 110˚C, 12 h
DBN (1.0 eq), MeCN, 85˚C, 10 h
t-BuOK (1.0 eq), t-BuOH, 100˚C, 8 h
t-BuOK (0.8 eq), DMSO, rt, 4 h
1
2
3
4
5
6
trace
4
4d (76)
4e (96)
4f (84)
4g (46)
4h (31)
Ph
Ph
1-naphthyl
2-thienyl
Ph
7 h
6 h
6 h
5 h
6 h
67
37
94
17
4
p-MeO-C6H4
p-Me2N-C6H4
t-Bu
5
6
7
t-BuOK (0.5 eq), DMSO, rt, 8 h
Ph
t-BuOK (0.1 eq), DMSO, 60˚C, 4 h
Ph
shown in Table 3. t-BuOK in DMSO worked efficiently as a catalyst for double-bond isomerization to
give 4a in high yield (Table 3, entry 5), though the reactions at elevated temperatures and with a larger
amount of the t-BuOK resulted in lower yields (Table 3, entries 4 and 6, respectively). Under optimal

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HETEROCYCLES, Vol. 85, No. 5, 2012
conditions with t-BuOK/DMSO, other pyrrolines 7 were also converted to the corresponding pyrroles in
good-to-high yields (Table 4, entry 1–5). However, compounds with the strong electron-donating groups
at the 2 position in 7 gave 4 in low yields (Table 4, entries 6 and 7). Therefore, the isomerization must
proceed through repeated deprotonation and protonation steps. The electron-donating groups may reduce
the acidity of the C–H bonds of the tetrahedral carbons of 7, and consequently decrease the yield of these
reactions.
We have demonstrated transformation of 2-substituted 1-pyrrolines to 2,3-disubstituted pyrroles in two
steps, which involve condensation with acetals assisted by a combination of TiCl4 and triethylamine,
followed by the double-bond isomerization catalyzed by t-BuOK in DMSO. Although limited acetals can
be employed in the condensation step, the reactions were completed in a reasonably short time. The
results suggest a new facile synthetic method for 2,3-disubstituted pyrroles, which can be applied to the
synthesis of bioactive compounds such as pharmaceuticals.
EXPERIMENTAL
Melting points were measured on a Yanaco MP-3. IR spectra were recorded on JEOL Diamond-20 and
JASCO FT/IR-4100 spectrometers. UV spectra were measured on a Shimadzu UV-2550 spectrometer. 1H
and 13C-NMR spectra were recorded with tetramethylsilane as internal standard on JEOL !400 and
ECA500 NMR instruments. Mass spectra were measured on a JMS-700 mass spectrometer. Column
chromatography was done with Silica gel 60N from Kanto Chem., Inc. Trimethylsilyl triflate, titanium
tetrachloride, stannic tetrachloride, benzaldehyde acetals, t-BuOK, and borontrifluoride-ether complex
were purchased from Tokyo Kasei Industrial Co. 2-Phenyl- and 2-(4-methoxyphenyl)-1-pyrrolines were
synthesized from N-vinylpyrrolidin-2-one by the method of Sorgi et al.9f 2-(4-Dimethylaminophenyl)-,
and 4-t-butyl-1-pyrrolines were prepared from 2-methoxy-1-pyrroline according to a literature
procedure.9d
3-Benzylidene-2-phenyl-1-pyrroline (7a) from 5a and benzaldehyde
A mixture of 5a (1.06 g, 7.27 mM), benzaldehyde (0.763 g, 7.19 mM), p-toluenesulfonic acid (72 mg,
0.42 mM) in 50 mL of benzene was charged in a 100-mL flask, which was connected with a Dean-Stark
trap to remove water continuously. The mixture was refluxed on an oil bath for 175 h to completion of the
reaction. The resulted mixture was washed with a saturated aqueous NaHCO3 solution (100 mL) and
brine, and then, was dried over MgSO4. After evaporation of the solvent, the residue was purified by
silica gel column chromatography to give 1.31 g (73% yield) of 7a as colorless needles. Mp 110–112 ˚C
(lit., 110–111˚C10a and 108–109˚C10b). 1H NMR (CDCl3) " = 3.09 (dt, J = 5.6, 3.2 Hz, 2H), 4.22 (t, J = 5.6

HETEROCYCLES, Vol. 85, No. 5, 2012
1191
Hz, 2H), 6.84 (t, J = 3.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.2 Hz,
13
2H), 7.44–7.49 (m, 3H), 7.65 (m, 2H) ppm; C NMR (CDCl3) " = 30.9, 59.6, 127.89, 127.93, 128.47,
128.58, 128.8, 128.9, 129.6, 134.5, 134.0, 142.1, 175.0 ppm.
A typical procedure of Lewis acid ad triethylamine-assisted condensation of 2-substituted
1-pyrrolines with dialkoxymethylarenes
To a solution of 5 (1.00 mM), triethylamine (417 µL, 3.00 mM), dimethyl acetal (2.00 mM) in solvent (10
mL) at 0 ˚C was added dropwise Lewis acid (3.00 mM). Then, the mixture was heated in an oil bath
under nitrogen atmosphere using a balloon. The reaction was monitored by TLC analysis and the resulted
reaction mixture was poured into a saturated aqueous NaHCO3 solution (50 mL). The solids formed were
removed by filtration and the filtrate was extracted three times with 20 mL of chloroform. The combined
organic layer was washed with brine and was dried over MgSO4. The solvent was removed and the
residue was purified by silica gel chromatography to give the product.
3-(4-Bromobenzylidene)-2-phenyl-1-pyrroline (7b); Brown needles, mp 83–86 ˚C. 1H NMR (CDCl3) " =
3.03 (dt, J = 5.8, 2.8 Hz, 2H), 4.23 (t, J = 5.8 Hz, 2H), 6.76 (t, J = 2.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H),
7.46–7.52 (m, 5H), 7.62–7.64 (m, 2H) ppm; 13C NMR (CDCl3) " = 30.9, 59.7, 121.8, 126.5, 128.5, 128.7,
129.7, 130.3, 131.7, 134.3, 136.0, 142.8, 174.8 ppm; UV (EtOH) !max = 227 (log# = 4.03), 235 (4.01),
252sh (4.02), 287sh (4.40), 295 (4.19), 300 (4.48), 312 (4.35) nm; MS (70 eV): m/z (rel int) 313 (M+, 98),
312(58), 311 (M+, 100), 310 (40), 285 (11), 283 (12), 232 (18), 231 (14), 230 (13), 204 (18), 203 (21),
202 (14), 156 (25), 129 (47), 128 (32), 127 (14), 117 (47), 101 (11), 91 (16), 77 (21). Anal. Calcd for
C17H14BrN: C, 65.40; H, 4.52; N, 4.49%. Found C, 65.24; H, 4.62; N, 4.33%.
1
3-(2-Methybenzylidene)-2-phenyl-1-pyrroline (7c); Brown solids, mp 80–84 ˚C. H NMR (CDCl3) " =
2.21 (s, 3H), 2.98 (dt, J = 6.3, 2.8 Hz, 2H), 4.15 (t, J = 6.3 Hz, 2H), 6.98 (t, J = 2.8 Hz, 1H), 7.17–7.24 (m,
13
3H), 7.44–7.48 (m, 4H), 7.66–7.70 (m, 2H) ppm; C NMR (CDCl3) " = 20.0, 30.6, 59.1, 125.5, 125.8,
127.3, 127.8, 128.4, 128.7, 129.6, 130.2, 134.4, 135.9, 136.9, 142.5, 174.6 ppm; UV (EtOH) !max = 229
(log# = 4.03), 236 (4.03), 248 (4.01), 287sh (4.18), 295 (4.19), 318sh (3.83) nm; MS (70 eV): m/z (rel int)
247 (M+, 100), 246 (41), 232 (20), 219 (11), 156 (18), 129 (33), 128 (22), 117 (26), 116(10), 115 (18), 91
(11), 77 (14). HRMS m/z Calcd for C18H17N(M+) 247.1361, found: 247.1356.
1
3-(1-Naphthylmethylidene)-2-phenyl-1-pyrroline (7d); Brown microcrystals, mp 119–120 ˚C. H NMR
(CDCl3) " = 3.00 (dt, J = 6.3, 2.5 Hz, 2H), 4.16 (t, J = 6.3 Hz, 2H), 7.46 (t, J = 2.5 Hz, 1H), 7.43–7.52 (m,
6H), 7.63 (d, J = 7.5 Hz, 1H), 7.76–7.81 (m, 3H), 7.85 (dt, J = 8.0, 2.0 Hz, 2H) ppm; 13C NMR (CDCl3) "
= 31.0, 59.0, 123.9, 124.5, 125.2, 125.5, 125.9, 126.2, 128.3, 128.5, 128.6, 128.8, 129.8, 131.5, 133.6,
134.0, 134.3, 144.1, 174.2 ppm; UV (EtOH) !max = 225 (log# = 4.52), 267sh (3.98), 319sh (4.13), 326
(4.13), 346sh (3.91), 393sh (2.56) nm; MS (70 eV): m/z (rel int) 283 (M+, 100), 282 (50), 180 (13), 179

1192
HETEROCYCLES, Vol. 85, No. 5, 2012
(22), 178 (14), 118 (11), 117 (22). HRMS m/z Calcd for C21H17N(M+) 283.1361, found: 283.1360.
1
2-Phenyl-3-(2-thienylmethylidene)-1-pyrroline (7e); Brown microcrystals, mp 95–96 ˚C. H NMR
(CDCl3) " = 3.02 (dt, J = 6.0, 2.8 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 7.05 (t, J = 2.8 Hz, 1H), 7.08 (dd, J =
5.0, 3.5 Hz, 1H), 7.12 (d, J = 3.5 Hz, 1H), 7.39 (d, J = 5.0 Hz, 1H), 7.45–7.48 (m, 3H), 7.59–7.62 (m, 2H)
ppm; 13C NMR (CDCl3) " = 31.1, 59.7, 120.3, 126.8, 127.5, 128.4, 128.5, 128.9, 129.5, 134.4, 140.0,
141.6, 174.2 ppm; UV (EtOH) !max = 254 (log# = 3.91), 316 (4.39), 329sh (4.33), 377 (2.29) nm. MS (70
eV): m/z (rel int) 239 (M+, 100), 238 (53), 211 (21), 135 (12), 117 (18), 77 (11). HRMS m/z Calcd for
C15H13NS(M+) 239.0769, found: 239.0772.
1
3-Benzylidene-2-(4-methoxyphenyl)-1-pyrroline (7f); Brown prisms, mp 142–144 ˚C. H NMR (CDCl3)
" = 3.06 (dt, J = 5.6, 2.8 Hz, 2H), 3.86 (s, 3H), 4.18 (t, J = 5.6 Hz, 2H), 6.86 (t, J = 2.8 Hz, 1H), 6.99 (dt,
J = 8.8, 2.8 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.41 (m, 4H), 7.63 (dt, J = 8.8, 2.8 Hz, 2H) ppm; 13C NMR
(CDCl3) " = 31.1, 55.4, 59.3, 113.9, 126.9, 127.5, 127.8, 128.6, 128.9, 130.2, 137.1, 142.2, 160.8, 174.3
ppm; UV (EtOH) !max = 222 (log# = 4.16), 224sh (4.15), 230sh (4.06), 282sh (4.36), 290sh (4.37), 304sh
(4.22) nm; MS (70 eV): m/z (rel int) 263 (M+, 100), 262 (42), 232 (37), 186 (12), 147 (19), 129 (12). Anal.
Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32%. Found C, 82.14; H, 6.45; N, 5.22%.
3-Benzylidene-2-(4-dimethylaminophenyl)-1-pyrroline (7g); Brown microcrystals, mp 125–126 ˚C. 1H
NMR (CDCl3) " = 3.03 (s, 6H), 3.04 (dt, J = 5.8, 3.0 Hz, 2H), 4.14 (t, J = 5.8 Hz, 2H), 6.77 (d, J = 8.7 Hz,
2H), 6.94 (t, J = 3.0 Hz, 1H), 7.27 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.3 Hz, 2H), 7.43 (d, J = 7.3 Hz, 2H),
13
7.60 (d, J = 8.7 Hz, 2H) ppm; C NMR (CDCl3) " = 31.4, 40.5, 59.1, 111.8, 122.0, 127.5, 127.7, 128.6,
129.0, 130.1, 137.5, 142.5, 151.5, 174.4 ppm; UV (EtOH) !max = 223 (log# = 4.08), 232sh (4.01), 270sh
(4.39), 293 (4.45), 306 (4.35), 328 (3.96) nm; MS (70 eV): m/z (rel int) 276 (M+, 100), 275 (46), 248 (22),
199 (14), 138 (12), 129 (11), 128 (11), 114 (12). Anal. Calcd for C19H20N2·0.2H2O: C, 81.51; H, 7.34; N,
10.01%. Found C, 81.60; H, 7.44; N, 10.22%.
1
3-Benzylidene-2-t-butyl-1-pyrroline (7h);A brown oil. H NMR (CDCl3) " = 1.41 (s, 9H), 2.90 (dt, J =
5.8, 3.0 Hz, 2H), 3.95 (t, J = 5.8 Hz, 2H), 7.04 (t, J = 3.0 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5
Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H) ppm; 13C NMR (CDCl3) " = 29.5, 31.8, 36.2, 58.0, 126.7, 127.6, 128.6,
129.0, 137.6, 141.0, 181.0 ppm; UV (EtOH) !max = 277 (log# = 4.28), 286 (4.31), 303 (4.09), 330 (2.91)
nm; MS (70 eV): m/z (rel int) 213 (M+, 62), 212 (55), 198 (100), 188 (14), 172 (10), 171 (38), 170 (47),
155 (17), 136 (22), 116 (16), 115 (33), 105 (21), 91 (19). HRMS m/z Calcd for C15H19N(M+) 213.1518,
found: 213.1507.
A typical procedure of t-BuOK-catalyzed double-bond isomerization of 7 to 4
A mixture of 7 (0.500 mmol), t-BuOK (33 mg, 0.50 mmol) in DMSO (2 mL) was stirred at room
temperature under argon atmosphere for 3–7 h. The reaction mixture was poured into cold water and was

HETEROCYCLES, Vol. 85, No. 5, 2012
1193
neutralized by 0.1 N HCl, and then extracted with Et2O (15 mL x 3). The combined organic layer was
washed with brine and was dried over MgSO4. After removal of the solvent, the residue was purified by
silica gel chromatography to give the product. Analytical samples were obtained by recrystallization from
EtOAc-hexane. These pyrroles were colorless or creamy white just after chromatographic purification.
However, the samples were colorized during the recrystallization, as often seen in other pyrroles.
3-Benzyl-2-phenylpyrrole (4a); Purple prisms, mp 107–108 ˚C. 1H NMR (CDCl3) " = 4.01 (s, 2H), 6.09 (t,
J = 2.8 Hz, 1H), 6.80 (t, J = 2.8 Hz, 1H), 7. 12 (tt, J = 7.2, 1.2 Hz, 1H), 7.22-7.30 (m, 5H), 7.34-7.39 (m,
4H), 8.16 (s, 1H) ppm; 13C NMR (CDCl3) " = 32.6, 111.6, 117.8, 119.3, 125.7, 126.5, 126.8, 128.4, 128.6,
128.8, 129.0, 133.4, 142.3 ppm; IR (KBr) $max = 3404vs, 3396vs, 761s, 710s, 694s cm–1; UV (EtOH) !max
= 206 (log# = 4.57), 287 (4.17) nm; MS (70 eV): m/z (rel int) 233 (M+, 100), 232 (44), 156 (96), 154 (12),
128 (11). Anal. Calcd for C17H15N: C, 87.52; H, 6.48; N, 6.00%. Found C, 87.33; H, 6.49; N, 5.92%.
3-(4-Bromobenzyl)-2-phenylpyrrole (4b); Red needles, mp 55–58 ˚C. 1H NMR (CDCl3) " = 3.95 (s, 2H),
6.07 (t, J = 2.4 Hz, 1H), 6.82 (t, J = 2.4 Hz, 1H), 7. 09 (d, J = 8.4 Hz, 2H), 7.34-7.40 (m, 7H), 8.19 (s, 1H)
13
ppm; C NMR (CDCl3) " = 32.0, 111.5, 117.9, 118.6, 119.5, 126.6, 126.8, 128.9, 129.1, 130.3, 131.4,
133.3, 141.3 ppm; IR (KBr) $max = 3388vs, 1485s, 1011s, 772s, 734s cm–1; UV (EtOH) !max = 202 (log# =
4.52), 221sh (4.27), 284 (4.15) nm; MS (70 eV): m/z (rel int) 313 (M+, 98), 311 (M+, 100), 232 (19), 230
(13), 156 (100), 154 (17), 128 (13). Anal. Calcd for C17H14BrN: C, 65.40; H, 4.52; N, 4.49%. Found C,
65.42; H, 4.62; N, 4.41%.
1
3-(2-Methylbenzyl)-2-phenylpyrrole (4c); Brown microcrystals, mp 132–133 ˚C. H NMR (CDCl3) " =
2.24 (s, 3H), 3.94 (s, 2H), 5.98 (t, J = 3.0 Hz, 1H), 6.79 (t, J = 3.0 Hz, 1H), 7.10–7.16 (m, 4H), 7.24 (m,
1H), 7.34–7.38 (m, 4H), 8.18 (s, 1H) ppm; 13C NMR (CDCl3) " = 19.7, 30.5, 111.7, 117.8, 118.9, 125.98,
126.03, 126.5, 126.7, 128.9, 129.0, 130.0, 133.6, 136.4, 140.4, 144.0 ppm; IR (ATR) $max = 3380s, 763s,
731vs, 694s cm–1; UV (EtOH) !max = 286 (log# = 4.15) nm; MS (70 eV): m/z (rel int) 247 (M+, 100), 246
(21), 232 (11), 156 (40), 143 (68). HRMS m/z Calcd for C18H17N(M+) 247.1361, found: 247.1356.
3-(1-Naphthylmethy)-2-phenylpyrrole (4d); Brown microcrystals, mp 124–126 ˚C. 1H NMR (CDCl3) " =
4.44 (s, 2H), 6.01 (t, J = 2.9 Hz, 1H), 6.80 (t, J = 2.9 Hz, 1H), 7.24 (tt, J = 7.2, 1.2 Hz, 1H), 7.31 (dd, J =
6.8, 1.2 Hz, 1H), 7.33–7.37 (m, 2H), 7.39–7.41 (m, 2H), 7.44–7.47 (m, 3H), 7.73 (d, J = 8.0 Hz, 1H),
13
7.86 (dd, J = 7.5, 2.0 Hz, 1H), 8.01 (dd, J = 7.5, 2.0 Hz, 1H), 8.23 (s, 1H) ppm; C NMR (CDCl3) " =
30.0, 111.8, 117.8, 118.7, 124.0, 125.4, 125.7, 125.8, 126.0, 126.4, 126.6 (2C), 128.6, 128.85, 128.90,
132.1, 133.4, 133.7, 137.9 ppm; IR (ATR) $max = 3437vs, 803s, 783vs, 767vs, 696s cm–1; UV (EtOH) !max
= 273sh (log# = 4.23), 283 (4.32), 295sh (4.24) nm; MS (70 eV): m/z (rel int) 283 (M+, 100), 282 (51),
155 (48). HRMS m/z Calcd for C21H17N(M+) 283.1361, found: 283.1357.
2-Phenyl-3-(2-thienylmethy)pyrrole (4e); Brown microcrystals, mp 75–76 ˚C. 1H NMR (CDCl3) " = 4.15
(d, J = 1.0 Hz, 2H), 6.22 (t, J = 3.0 Hz, 1H), 6.81-6.83 (m, 2H), 6.92 (dd, J = 5.0, 3.5 Hz, 1H), 7.12 (dd, J

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= 5.0, 1.0 Hz, 1H), 7.27 (tt, J = 7.2, 1.2 Hz, 1H), 7.37–7.41 (m, 4H), 8.16 (s, 1H) ppm; 13C NMR (CDCl3)
" = 27.1, 111.3, 117.7, 118.9, 123.2, 124.3, 126.6, 126.7, 126.9, 128.8, 128.9, 133.1, 146.1 ppm; IR
(ATR) $max = 3406s, 3397s, 763s, 690vs cm–1; UV (EtOH) !max = 227 (log# = 4.13), 284 (4.14) nm; MS
(70 eV): m/z (rel int) 239 (M+, 100), 238 (75), 162 (12), 154 (14). HRMS m/z Calcd for C15H13NS(M+)
239.0769, found: 239.0773.
1
3-Benzyl-2-(4-methoxyphenyl)pyrrole (4f); Blue needles, mp 78–79 ˚C. H NMR (CDCl3) " = 3.81 (s,
2H), 3.96 (s, 3H), 6.08 (t, J = 2.8 Hz, 1H), 6.77 (t, J = 2.8 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.16–7.31 (m,
7H), 8.08 (s, 1H) ppm; 13C NMR (CDCl3) " = 32.0, 55.3, 111.3, 114.2, 117.1, 118.4, 125.7, 126.2, 128.3,
128.3, 128.5, 128.9, 142.5, 158.4 ppm; IR (KBr) $max = 3359s, 3345s, 1509vs, 1254s, 1030s, 708s cm–1;
UV (EtOH) !max = 268sh (log# = 4.19), 276 (4.23) nm; MS (70 eV): m/z (rel int) 263 (M+, 100), 262 (32),
248 (8), 218 (5), 186 (57). Anal. Calcd for C18H17NO·0.05H2O: C, 81.82; H, 6.52; N, 5.30%. Found C,
81.74; H, 6.39; N, 5.30%.
3-Benzyl-2-(4-dimethylaminophenyl)pyrrole (4g); Blue microcrystals, mp 108–111 ˚C. 1H NMR (CDCl3)
" = 2.95 (s, 6H), 3.96 (s, 2H), 6.05 (t, J = 2.5 Hz, 1H), 6.73–6.75 (m, 3H), 7.16 (t, J = 7.0 Hz, 1H),
7.22–7.28 (m, 6H), 8.04 (s, 1H) ppm; 13C NMR (CDCl3) " = 41.6, 48.0, 104.4, 105.7, 108.8, 109.7, 113.0,
116.0, 117.9, 118.1, 118.4, 119.2, 129.7, 135.0 ppm; UV (EtOH) !max = 291 (log# = 4.33) nm; IR (ATR)
$
max = 3390s, 3348s, 1617s, 1520vs, 820s, 707s cm–1; MS (70 eV): m/z (rel int) 276 (M+, 100), 199 (48),
185 (34), 155 (10), 138 (16), 137 (17), 84 (11). Anal. Calcd for C19H20N2·0.1H2O: C, 82.04; H, 7.32; N,
10.07%. Found C, 82.07; H, 7.33; N, 9.93%.
3-Benzyl-2-t-butylpyrrole (4h); A brown oil. 1H NMR (CDCl3) " = 1.34 (s, 9H), 3.99 (s, 2H), 5.88 (t, J =
3.0 Hz, 1H), 6.56 (t, J = 3.0 Hz, 1H), 7.13-7.19 (m, 3H), 7.23-7.27 (m, 2H), 7.91 (s, 1H) ppm; 13C NMR
(CDCl3) " = 30.6, 32.4, 33.6, 112.0, 113.9, 116.3, 125.6, 128.2, 128.7, 135.3, 142.9 ppm; IR (ATR) $max
=
3455s, 3423s, 2959vs, 2906s, 1494s, 1453s, 726vs, 709vs cm–1; UV (EtOH) !max = 262 (log# = 2.97), 270
(2.86) nm; MS (70 eV): m/z (rel int) 213 (M+, 89), 248 (22), 198 (100), 188 (18), 173 (11), 131 (12), 120
(43), 115 (14), 91 (62). HRMS m/z Calcd for C15H19N(M+) 213.1518, found : 213.1511.
REFERENCES AND NOTES
1. R. J. Sundberg, In Comprehensive Heterocyclic Chemistry, Vol. 2; ed. by A. R. Katritzky, C. W.
Rees, and E. F. V. Scriven; Pergamon, Oxford, 1996, pp.119–206.
2. L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635.
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2391.
4. A. Hantzsch, Ber. Dtsch. Chem. Ges., 1890, 23, 1474.
5. For recent examples, see the following; a) O. A. Attansai, G. Favi, F. Mantellini, G. Moscatelli, and

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S. Santeusanio, J. Org. Chem., 2011, 76, 2860; b) H.-Y. Wang, D. S. Mueller, R. M. Sachwani, R.
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10. Dannhardt et al. obtained 7a by reaction of 5 with 1,4-diphenyl-2,3-diazabutadiene in 26 % yield.
The extension of the method was not reported; a) G. Dannhardt and R. Obergrusberger, Arch. Pharm.
(Weinheim), 1981, 314, 811. For previous other synthesis of 7a, see; b) S. Sugawara and S. Uchida,
Tetrahedron, 1959, 5, 48.
11. The configuration of the phenyl group of the benzylidene moiety in 7a was not previously discussed.
We tentatively assigned the (E)-configuration as depicted in Scheme 2 because of inherent instabilily
of the (Z)-isomer by two phenyl groups closely located to each other. PM3 calculations indicate that
the (E)-isomer is more stable than the (Z)-isomer by 3.82 kcal/mol in heat of formation.
12. Under conditions with either a Lewis acid or triethylamine, no condensation product was observed.
The alkylation of 7a at the 3 position with alkyl halide under conditions using a strong base, such as
LDA, was reported; G. Dannhardt and R. Obergrusgerger, Arch. Pharm. (Weinheim), 1979, 312,
498.
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