Synthesis of functionalized 2-aminopyrroles by lewis acid catalyzed ring-opening of 1,1,2,3-tetrasubstituted cyclopropanes with arylamines

Article abstract of DOI:10.1002/cjoc.201200229

Under the catalysis of Lewis acid Co(ClO₄)₂ the reaction of the sterically hindered 1,1,2,3-tetrasubstituted cyclopropanes with arylamines in refluxing THF gave the functionalized 2-aminopyrroles with sequential ring-opening of cyclo

Full text of DOI:10.1002/cjoc.201200229

FULL PAPER
DOI: 10.1002/cjoc.201200229
Synthesis of Functionalized 2-Aminopyrroles by Lewis Acid
Catalyzed Ring-opening of 1,1,2,3-Tetrasubstituted
Cyclopropanes with Arylamines
Han, Ying(韩莹)
Fu, Qin(府琴)
Tang, Wanquan(唐万荃)
Yan, Chaoguo*(颜朝国)
College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu 225002, China
Under the catalysis of Lewis acid Co(ClO4)2 the reaction of the sterically hindered 1,1,2,3-tetrasubstituted
cyclopropanes with arylamines in refluxing THF gave the functionalized 2-aminopyrroles with sequential
ring-opening of cyclopropane, nucleophilic substitution, nucleophilic addition of cyano group and recyclization
processes.
Keywords cyclopropane, pyrrole, ring-opening reaction, catalysis, domino reaction
Introduction
cyclopropane directly, while it firstly decomposed to
aldehyde and amine, and then the generated amine at-
tacked the cyclopropyl ring to finish the reaction. Thus
it is logical to examine the reactivity of amine with
sterically hindered polysusbstituted cyclopropanes and
to explore the generality and scope of this domino reac-
tion. Herein we wish to report the results on the ring-
opening reactions of 1,1,2,3-tetrasubstituted cyclopro-
panes with aromatic amines under Lewis acid catalysis
and the syntheses of the functionalized 2-aminopyrrole
deivatives.
The ring-opening reactions of functionalized cyclo-
propane have proven to be very valuable tool in syn-
thetic organic chemistry.[1,2] The presence of both elec-
tron-donating groups and electron-withdrawing groups
in cyclopropane core produces a synergistic electron
‘push-pull’ relationship and thus increases the reactivity
of cyclopropane.[3,4] Although the ring-opening reac-
tions of activated cyclopropane derivatives with nucleo-
philes, double bonds, triple bonds and 1,3-dipoles are
well established,[5-9] most of the reported works were
focused on using donor-acceptor cyclopropanes having
at least one unsubstituted methylene unit in order to
avoid sterically hindrance and to finish the ring-opening
of cyclopropyl moiety in mild condition.[10-15] The reac-
tivity of the sterically hindered polysusbstituted cyclo-
propanes, in which no unsubstituted methylene unit ex-
ists, was rarely investigated.[16-20] Our group recently
found that Lewis acid catalyzed reactions of 1,1-di-
cyano-2,3-diarylcyclopropanes with aromatic imines
give the novel polysubstituted pyrrole-3-carbonitriles
bearing an 2-arylideneimino group (Scheme 1).[21] Even
there have been several reports about Lewis acid-cata-
lyzed reactions of imines with the activated cyclopro-
pane to form pyrrolidine derivatives.[22-26] In our reac-
tion the combination of ring-opening of cyclopropane
with addition of cyano group produced new reaction
pattern. This protocol not only provids an effective
methodology for the preparation of functionalized pyr-
roles, but also opens a broad way for employing the
sterically hindered cyclopropane to develop new ring-
opening reaction. The investigation of reaction mecha-
nism indicated that the aromatic imine did not react with
Scheme 1 Reaction of cyclopropane with aromatic imine
R2
R1
CN
Co(ClO4)2
+
N
CN
THF
O2N
R3
R3
R1
N
N
R2
CN
O2N
*
E-mail: cgyan@yzu.edu.cn
Received March 8, 2012; accepted May 15, 2012.
Chin. J. Chem. 2012, 30, 1867—1872
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1867

Han et al.
FULL PAPER
Experimental
Anal. calcd for C25H20N4O2: C 73.51, H 4.94, N 13.72;
found C 73.36, H 5.30, N 13.61. MS (ESI－ ) m/z:
407.33.
All reactions were monitored by TLC. Melting
points were taken on a hot-plate microscope apparatus.
IR spectra were obtained on a Bruker Tensor 27 spec-
trometer (KBr disc). NMR spectra were recorded with a
Bruker AV-600 spectrometer with DMSO-d6 as solvent
and TMS as internal standard (600 and 150 MHz for 1H
and 13C NMR spectra, respectively). Elemental analyses
were obtained on Thermo Flash 2000 instrument.
HPLC/MS were measured at Fennigan LCQ Deca XP
MAX instrument. The substituted cyclopropanes were
synthesized by our previous reported method.[27]
Arylamines and other reagents are commercial reagents
and used as received. Solvents were purified by stan-
dard techniques.
2-Amino-5-p-t-butylphenyl-1-p-methylphenyl-4-p-
nitrophenylpyrrole-3-carbonitrile (3c) Yellow solid,
1
yield 68%, m.p. 280—282 ℃; H NMR (600 MHz,
CDCl3) δ: 8.08 (d, J＝8.7 Hz, 2H, ArH), 7.42 (d, J＝8.7
Hz, 2H, ArH), 7.19 (d, J＝7.8 Hz, 2H, ArH), 7.12 (d,
J＝7.8 Hz, 2H, ArH), 7.03 (d, J＝7.8 Hz, 2H, ArH),
6.82 (d, J＝7.8 Hz, 2H, ArH), 2.37 (s, 3H, CH3), 1.23 (s,
9H, C(CH3)3); 13C NMR (150 MHz, CDCl3) δ: 150.0,
145.1, 139.6, 138.3, 131.2, 130.7, 130.6, 129.4, 129.3,
128.6, 128.3, 127.0, 125.8, 124.3, 122.6, 119.0, 33.6,
30.2, 20.2; IR (KBr) ν: 3433 (s), 3337 (m), 2960 (w),
2205 (m), 1637 (m), 1561 (w), 1512 (s), 1342 (s), 1265
(w), 1106 (w), 831 (m) cm － 1. Anal. calcd for
C28H26N4O2: C 74.65, H 5.82, N 12.44; found C 74.53,
H 6.25, N 12.07. MS (ESI＋) m/z: 450.47.
General procedure for the preparation of polysub-
stituted 2-aminopyrroles via reactions of cyclopro-
panes with arylamines
2-Amino-5-p-bromophenyl-1-p-methylphenyl-4-p-
nitrophenylpyrrole-3-carbonitrile (3d) Yellow solid,
A mixture of 1,1-dicyano-2,3-diarylcyclopropane
(2.0 mmol) and arylamine (2.0 mmol) and Co(ClO4)2
(0.2 mmol) in 20 mL THF was refluxed for about 36 h
(TLC analysis). After cooling the reaction was
quenched with water and extracted with methylene di-
chloride. The solvent was evaporated under reduced
pressure. The residue was purified by thin-layer chro-
matography (SiO2) with light petroleum and ethyl ace-
tate (V/V＝3/1) as developing reagent to give the pure
product for analysis.
1
yield 80%, m.p. 221—222 ℃. H NMR (600 MHz,
CDCl3) δ: 8.12 (d, J＝8.8 Hz, 2H, ArH), 7.41 (d, J＝8.8
Hz, 2H, ArH), 7.25 (d, J＝8.5 Hz, 2H, ArH), 7.22 (d,
J＝8.5 Hz, 2H, ArH), 7.03 (d, J＝8.2 Hz, 2H, ArH),
6.76 (d, J＝8.2 Hz, 2H, ArH), 2.38 (s, 3H, CH3); 13C
NMR (150 MHz, CDCl3) δ: 146.6, 145.3, 139.1, 138.8,
136.1, 131.2, 130.9, 130.8, 130.7, 130.5, 129.9, 129.8,
129.7, 129.5, 128.5, 128.0, 126.9, 126.8, 124.2, 122.8,
122.0, 121.2, 118.5, 20.2; IR (KBr) ν: 3447 (w), 3332
(m), 3229 (w), 2202 (m), 1631 (m), 1557 (m), 1513 (s),
2-Amino-5-p-methoxyphenyl-1-p-methylphenyl-4-
p-nitrophenylpyrrole-3-carbonitrile (3a)
－
1
1340 (s), 1170 (w), 1108 (m), 1014 (w), 824 (m) cm .
Anal calcd for C24H17BrN4O2: C 60.90, H 3.62, N 11.84;
found C 60.72, H 3.70, N 11.47. MS (ESI－ ) m/z:
472.73.
Yellow
1
solid, yield 63%, m.p. 203—204 ℃; H NMR (600
MHz, CDCl3) δ: 8.09 (d, J＝8.4 Hz, 2H, ArH), 7.41 (d,
J＝8.4 Hz, 2H, ArH), 7.19 (d, J＝8.4 Hz, 2H, ArH),
7.02 (d, J＝8.4 Hz, 2H, ArH), 6.82 (d, J＝7.8 Hz, 2H,
ArH), 6.66 (d, J＝7.8 Hz, 2H, ArH), 4.16 (bs, 2H, NH2),
3.73 (s, 3H, OCH3), 2.36 (s, 3H, CH3); 13C NMR (150
MHz, CDCl3) δ: 159.2, 147.3, 146.0, 142.5, 140.6,
139.4, 132.2, 132.1, 130.5, 129.2, 128.0, 126.9, 123.6,
122.1, 118.2, 114.0, 55.1, 21.2; IR (KBr) ν: 3429 (m),
3325 (m), 3226 (w), 2928 (w), 2200 (m), 1631 (m),
1561 (m), 1509 (s), 1334 (s), 1248 (m), 1178 (w), 1106
(m), 1032 (w), 840 (m) cm － 1. Anal. calcd for
C25H20N4O3: C 70.74, H 4.75, N 13.20; found C 70.58,
H 5.19, N 12.86. MS (ESI－) m/z: 423.60.
2-Amino-1,5-di(p-methylphenyl)-4-p-nitrophenyl-
pyrole-3-carbonitrile (3b) Yellow solid, yield 71%,
m.p. 214—216 ℃; 1H NMR (600 MHz, CDCl3) δ: 8.08
(d, J＝8.8 Hz, 2H, ArH), 7.41 (d, J＝8.8 Hz, 2H, ArH),
7.19 (d, J＝8.1 Hz, 2H, ArH), 7.03 (d, J＝8.1 Hz, 2H,
ArH), 6.92 (d, J＝7.9 Hz, 2H, ArH), 6.79 (d, J＝7.9 Hz,
2H, ArH), 3.73 (d, J＝7.0 Hz, 1H, NH), 3.71 (d, J＝7.0
Hz, 1H, NH), 2.36 (s, 3H, CH3), 2.25 (s, 3H, CH3); 13C
NMR (150 MHz, CDCl3) δ: 147.3, 146.0, 140.6, 139.4,
137.8, 132.1, 130.6, 130.5, 129.3, 129.2, 128.0, 127.0,
126.9, 123.6, 118.6, 117.4, 212 (2C); IR (KBr) ν: 3451
(w), 3338 (m), 2198 (m), 2611 (m), 1557 (m), 1508 (s),
2-Amino-1,5-di(p-methoxyphenyl)-4-p-nitrophe-
nyl pyrrole-3-carbonitrile (3e) Yellow solid, yield
59%, m.p. 216—218 ℃; 1H NMR (600 MHz, CDCl3) δ:
8.08 (d, J＝8.9 Hz, 2H, ArH), 7.42 (d, J＝8.9 Hz, 2H,
ArH), 7.08 (d, J＝8.8 Hz, 2H, ArH), 6.93 (d, J＝8.8 Hz,
2H, ArH), 6.89 (d, J＝8.9 Hz, 2H, ArH), 6.79 (d, J＝8.8
Hz, 2H, ArH), 3.81 (s, 3H, OCH3), 3.73 (s, 3H, OCH3);
13C NMR (150 MHz, CDCl3) δ: 159.9, 147.5, 146.0,
140.7, 137.8, 130.7, 130.4, 129.5, 129.3, 129.2, 129.1,
127.2, 127.1, 127.0, 123.6, 123.3, 118.5, 115.3, 115.0,
55.6, 55.5; IR (KBr) ν: 3425 (m), 3329 (m), 3231 (w),
2922 (w), 2200 (m), 1634 (m), 1559 (m), 1509 (s), 1334
－
1
(s), 1247 (m), 1107 (m), 1027 (w), 833 (m) cm . Anal.
calcd for C24H20N4O4: C 68.17, H 4.58, N 12.72; found
C 67.78, H 4.88, N 12.45. MS (ESI＋) m/z: 441.45.
2-Amino-1-p-methoxyphenyl-4-p-nitrophenyl-5-
phenylpyrrole-3-carbonitrile (3f) Yellow solid, yield
76%, m.p. 190—192 ℃; 1H NMR (600 MHz, CDCl3) δ:
8.07 (d, J＝8.4 Hz, 2H, ArH), 7.42 (d, J＝8.4 Hz, 2H,
ArH), 7.17 (t, J＝7.1 Hz, 1H, ArH), 7.12 (t, J＝7.1 Hz,
2H, ArH), 7.08 (d, J＝8.5 Hz, 2H, ArH), 6.92 (d, J＝7.3
Hz, 2H, ArH), 6.88 (d, J＝8.4 Hz, 2H, ArH), 3.80 (s,
3H, OCH3); 13C NMR (150 MHz, CDCl3) δ: 159.9,
146.1, 140.4, 132.4, 130.8, 130.5, 130.0, 129.4, 129.3
－
1
1338 (s), 1176 (w), 1107 (m), 822 (w), 750 (w) cm .
1868
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1867—1872

Lewis Acid Catalyzed Ring-opening of 1,1,2,3-Tetrasubstituted Cyclopropanes with Arylamines
(2C), 128.7, 128.5, 127.9, 127.5, 127.1, 126.9, 123.7,
123.3, 118.8, 115.4, 115.0, 55.5; IR (KBr) ν: 3419 (m),
3223 (w), 2205 (m), 1632 (m), 1557 (m), 1511 (s), 1340
(s), 1249 (m), 1177 (w), 1109 (w), 1029 (w), 846 (m),
703 (w) cm . Anal. calcd for C24H18N4O3: C 70.23, H
4.42, N 13.65; found C 79.42, H 4.64, N 13.38. MS
(ESI－) m/z: 409.60.
ArH), 7.04 (t, J＝7.3 Hz, 1H, ArH), 6.96 (t, J＝7.8 Hz,
2H, ArH), 6.86 (d, J＝7.8 Hz, 2H, ArH), 4.07 (bs, 2H,
NH2); 13C NMR (150 MHz, CDCl3) δ: 147.9, 146.2,
140.3, 134.3, 131.0, 130.5, 130.3, 129.9, 129.3, 128.7,
128.3, 128.2, 128.0, 127.9, 127.7, 127.3, 125.3, 123.7,
122.3, 119.5; IR (KBr) ν: 3411 (w), 3359 (w), 3228 (w),
3059 (w), 2202 (m), 1600 (m), 1560 (m), 1508 (m),
1337 (s), 1108 (m), 854 (w) cm－1. Anal. calcd for
C27H18N4O2: C 75.34, H 4.21, N 13.02; found C 75.27,
H 4.50, N 12.75. MS (ESI＋) m/z: 431.05.
－
1
2-Amino-1-p-chlorophenyl-5-p-methylphenyl-4-p-
nitrophenylpyrrole-3-carbonitrile (3g) Yellow solid,
1
yield 66%, m.p. 226—228 ℃; H NMR (600 MHz,
CDCl3) δ: 8.08 (d, J＝8.6 Hz, 2H, ArH), 7.41 (d, J＝8.6
Hz, 2H, ArH), 7.37 (d, J＝8.5 Hz, 2H, ArH), 7.11 (d,
J＝8.5 Hz, 2H, ArH), 6.95 (d, J＝7.8 Hz, 2H, ArH),
6.78 (d, J＝7.8 Hz, 2H, ArH), 4.23 (bs, 2H, NH2), 2.27
(s, 3H, CH3); 13C NMR (150 MHz, CDCl3) δ: 146.9,
146.2, 140.2, 138.2, 135.3, 133.4, 130.6, 130.1, 129.6,
129.4, 129.3 (3C), 129.0, 126.6, 123.7, 119.0, 21.2; IR
(KBr) ν: 3428 (m), 3316 (m), 3226 (m), 2206 (m), 1635
(m), 1561 (m), 1505 (s), 1340 (s), 1103 (m), 835 (m)
2-Amino-1,5-di(p-methylphenyl)-4-phenacylpyr-
role-3-carbonitrile (4a) Light yellow solid, yield
74%, m.p. 204 — 206 ℃ ; 1H NMR (600 MHz,
DMSO-d6) δ: 7.18—6.93 (m, 7H, ArH), 6.48 (s, 4H,
ArH), 5.64 (s, 2H, ArH), 3.10 (s, 2H, NH2), 2.04 (s, 3H,
CH3), 1.79 (s, 3H, CH3); 13C NMR (150 MHz,
DMSO-d6) δ: 190.1, 149.2, 136.7, 131.9, 131.6, 130.5,
129.9, 128.9, 128.6, 128.5, 127.9, 127.6, 126.9, 20.6,
20.5; IR (KBr) ν: 3353 (m), 3196 (s), 2216 (s), 1614 (s),
1571 (s), 1514 (m), 1495 (m), 1469 (m), 1396 (m), 1352
(w), 1289 (m), 1190 (s), 1076 (m), 1020 (w), 928 (s),
－
1
cm . Anal. calcd for C24H17ClN4O2: C 67.21, H 4.00,
N 13.06; found C 66.85, H 4.47, N 12.73. MS (ESI＋)
m/z: 429.33.
－
1
811 (s) cm . Anal. calcd for C26H21N3O: C 79.77, H
5.41, N 10.73; found C 79.52, H 5.65, N 10.80. MS
(ESI＋) m/z: 392.59.
2-Amino-1-p-chlorophenyl-5-m-chlorophenyl-4-p-
nitrophenylpyrrole-3-carbonitrile (3h) Yellow solid,
1
yield 55%, m.p. 197—198 ℃; H NMR (600 MHz,
2-Amino-5-p-chlorophenyl-1-p-methylphenyl-4-
phenacylpyrrole-3-carbonitrile (4b) Light yellow
CDCl3) δ: 8.13 (d, J＝7.6 Hz, 2H, ArH), 7.42 (s, 3H,
ArH), 7.19 (d, J＝7.8 Hz, 1H, ArH), 7.13—7.08 (m, 3H,
ArH), 6.89 (s, 1H, ArH), 6.79 (d, J＝7.3 Hz, 1H, ArH);
13C NMR (150 MHz, CDCl3) δ: 147.3, 146.5, 139.5,
135.7, 134.5, 132.9, 131.4, 130.6, 130.4, 129.9, 129.5,
129.4 (2C), 128.9, 128.4, 124.6, 123.9, 123.6, 120.2,
58.5, 18.4; IR (KBr) ν: 3417 (s), 3324 (s), 3226 (m),
2201 (m), 1712 (m), 1637 (m), 1596 (m), 1559 (m),
1497 (w), 1339 (s), 1227 (w), 1096 (w), 1014 (w), 834
1
solid, yield 70%, m.p. 276—278 ℃; H NMR (600
MHz, CDCl3) δ: 7.63 (d, J＝7.2 Hz, 2H, ArH), 7.35 (s,
1H, ArH), 7.20 (s, 4H, ArH), 7.02 (d, J＝8.4 Hz, 2H,
ArH), 6.92 (d, J＝9.0 Hz, 2H, ArH), 6.81 (d, J＝8.4 Hz,
2H, ArH), 4.25 (s, 2H, NH2), 2.36 (s, 3H, CH3); 13C
NMR (150 MHz, CDCl3) δ: 190.3, 139.9, 137.9, 134.0,
132.2, 131.9, 130.7, 129.5, 128.0, 127.9, 127.8, 100.0,
21.2; IR (KBr) ν: 3315 (w), 3228 (w), 2211 (s), 1624 (s),
1569 (s), 1538 (m), 1514 (m), 1477 (m), 1398 (s), 1354
(s), 1266 (m), 1175 (m), 1085 (m), 926 (s), 818 (m)
－
1
(w) cm . Anal. calcd for C23H14Cl2N4O2: C 61.49, H
3.14, N 12.47; found C 61.35, H 3.52, N 12.27. MS
(ESI－) m/z: 449.29.
－
1
cm . Anal. calcd for C25H18ClN3O: C 72.90, H 4.40, N
10.20; found C 72.66, H 4.81, N 10.46. MS (ESI＋) m/z:
412.64.
2-Amino-1-phenylmethyl-5-p-methylphenyl-4-p-
nitrophenylpyrrole-3-carbonitrile (3i) Yellow solid,
1
yield 50%, m.p. 208—210 ℃; H NMR (600 MHz,
2-Amino-1-p-methylphenyl-4-phenacyl-5-phenyl-
pyrrole-3-carbonitrile (4c) Light yellow solid, yield
60%, m.p. 216—218 ℃; 1H NMR (600 MHz, CDCl3) δ:
7.60 (d, J＝7.2 Hz, 2H, ArH), 7.33 (s, 1H, ArH), 7.28 (d,
J＝7.8 Hz, 1H, ArH), 7.18 (d, J＝8.4 Hz, 2H, ArH),
7.13 (b, 2H, ArH), 7.03 (d, J＝8.4 Hz, 2H, ArH), 6.98 (s,
1H, ArH), 6.92 (b, 2H, ArH), 6.86 (d, J＝7.2 Hz, 2H,
ArH), 4.25 (s, 2H, NH2), 2.34 (s, 3H, CH3); 13C NMR
(150 MHz, CDCl3) δ: 190.5, 147.3, 139.6, 138.0, 132.9,
131.9, 131.7, 130.8, 130.5, 129.5, 128.0, 127.8, 127.6,
120.4, 21.2; IR (KBr) ν: 3057 (m), 3029 (m), 2924 (m),
2209 (s), 1624 (w), 1538 (m), 1512 (m), 1473 (m), 1394
CDCl3) δ: 8.05 (d, J＝8.6 Hz, 2H, ArH), 7.38 (t, J＝8.5
Hz, 4H, ArH), 7.33 (t, J＝7.3 Hz, 1H, ArH), 7.12 (d,
J＝7.8 Hz, 2H, ArH), 7.07 (d, J＝7.8 Hz, 2H, ArH),
7.03 (d, J＝7.8 Hz, 2H, ArH), 4.91 (s, 2H, CH2), 3.96 (s,
2H, NH2), 2.35 (s, 3H, CH3); 13C NMR (150 MHz,
CDCl3) δ: 150.5, 149.9, 144.4, 143.1, 139.6, 134.9,
134.8, 133.9, 133.6, 133.4, 132.9, 132.2, 131.7, 130.9,
129.8, 129.5, 127.9, 127.6, 122.6, 118.7, 51.0, 25.3; IR
(KBr) ν: 3447 (w), 3356 (m), 2200 (m), 1628 (m), 1557
(m), 1512 (s), 1342 (s), 1110 (w), 864 (w), 746 (w)
－
1
cm . Anal calcd for C25H20N4O2: C 73.51, H 4.94, N
13.72; found C 73.26, H 5.29, N 13.64. MS (ESI－) m/z:
407.47.
－
1
(m), 1071 (m), 925 (s), 836 (m), 811 (m) cm . Anal.
calcd for C25H19N3O: C 79.55, H 5.07, N 10.13; found
C 79.22, H 5.42, N 9.84. MS (ESI＋) m/z: 378.30.
2-Amino-1-p-naphthyl-4-p-nitrophenyl-5-phenyl-
pyrrole-3-carbonitrile (3j) Yellow solid, yield 82%,
m.p. 214—216 ℃; 1H NMR (600 MHz, CDCl3) δ: 8.11
(d, J＝8.6 Hz, 2H, ArH), 7.91 (d, J＝8.0 Hz, 2H, ArH),
7.61—7.55 (m, 3H, ArH), 7.49 (d, J＝8.6 Hz, 2H, ArH),
7.45 (t, J＝7.5 Hz, 1H, ArH), 7.34 (d, J＝7.2 Hz, 1H,
2-Amino-5-p-fluorophenyl-1-p-methylphenyl-4-
phenacylpyrrole-3-carbonitrile (4d) Light yellow
1
solid, yield 75%, m.p. 265—267 ℃; H NMR (600
MHz, DMSO-d6) δ: 7.62 (d, J＝7.2 Hz, 2H, ArH), 7.33
(s, 1H, ArH), 7.19 (m, 4H, ArH), 7.02 (d, J＝8.4 Hz, 2H,
Chin. J. Chem. 2012, 30, 1867—1872
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1869

Han et al.
FULL PAPER
ArH), 6.86 (s, 2H, ArH), 6.64 (s, 2H, ArH), 4.23 (b, 2H,
NH2), 2.36 (s, 3H, CH3); 13C NMR (150 MHz,
DMSO-d6) δ: 189.9, 160.4, 149.4, 138.5, 138.1, 133.0,
132.9, 131.5, 130.0, 128.9, 127.6, 126.3, 119.7, 116.5,
114.3, 114.1, 20.6; IR (KBr) ν: 3226 (m), 3193 (m),
2214 (s), 1642 (m), 1610 (m), 1570 (m), 1515 (m), 1469
(m), 1257 (m), 1189 (s), 1074 (m), 930 (s), 848 (m)
cm . Anal. calcd for C25H19FN3O: C 75.93, H 4.59, N
10.63; found C 79.78, H 4.61, N 10.27. MS (ESI＋) m/z:
397.04.
the presence of Co(ClO4)2 (0.2 mmol) as catalyst was
heated to reflux for about 36 h. After work up, the de-
sired funationalized 2-aminopyrrole 3a was obtained in
63% yield. The structure of 3a is very similar to the re-
lated reaction product of imine with cyclopropane,[21]
which clearly indicated that arylamine could replace
imine as a nucleophilic reagent to cause the ring-open-
ing of polysubstituted cyclopropane. Then the generality
of the reaction was evaluated using various arylamines
and 1,1-dicyano-2,3-diaryl cyclopropanes. The results
of the reaction were listed in Table 1. 1,1-Dicyano-2,3-
diarylcyclopropanes having different kinds of groups
such as alkyl, alkoxyl, chloro and bromo substituted
phenyl groups were used in reactions, from which
polysubstituted 2-aminopyrroles 3a—3o were obtained
in good yields (55% — 82%). On the other hand
arylamines bearing electron-donating alkyl, methoxyl
groups gave relatively higher yields of product than that
of p-chloroaniline. Under this reaction conditions
m-nitro- and p-nitroanilines did not show any reactivity
and no desired products were separated from their reac-
tions, which might be due to the much weak nucleo-
philic ability of nitroaniline. Benzylamine and
α-naphthylamine also gave satisfactory yields of prod-
ucts (Table1, Entries 9—10). The structures of the pre-
pared functionalized 2-aminopyrroles 3a—3j were fully
－
1
2-Amino-5-p-fluorophenyl-1-p-methylphenyl-4-
(piperidine-4-carbonyl)pyrrole-3-carbonitrile
(4e)
1
Light yellow solid, yield 77%; m.p. 235—236 ℃; H
NMR (600 MHz, CDCl3) δ: 7.21 (s, 2H, ArH), 7.03 (s,
4H, ArH), 6.86 (s, 2H, ArH), 3.61 (s, 2H, NCH2), 3.23
(s, 2H, NCH2), 2.37 (s, 3H, CH3), 1.51 (b, 4H, 2CH2),
1.25—1.12 (m, 2H, CH2); IR (KBr) ν: 3437 (m), 3314
(w), 2935 (w), 2205 (m), 1623 (s), 1558 (m), 1505 (m),
－
1
1443 (m), 1228 (w), 847 (w) cm . Anal. calcd for
C24H23FN4O: C 71.62, H 5.76, N 13.92; found C 71.52,
H 6.17, N 13.66.
2-Amino-5-p-fluorophenyl-1-p-methylphenyl-4-
(morpholine-4-carbonyl)pyrrole-3-carbonitrile (4f)
1
Light yellow solid, yield 68%, m.p. 202 ℃; H NMR
(600 MHz, CDCl3) δ: 7.21 (d, J＝7.9 Hz, 2H, ArH),
7.02 (q, J＝8.6 Hz, 4H, ArH), 6.88 (t, J＝8.6 Hz, 2H,
ArH), 3.64—3.25 (m, 10H, NH2, 2CH2CH2), 2.37 (s,
3H, CH3); 13C NMR (150 MHz, CDCl3) δ: 164.1, 163.0,
161.3, 147.0, 139.6, 131.8, 131.2, 131.1, 130.7, 127.8,
125.9, 125.2, 115.8, 115.7, 115.6, 115.5, 72.8, 64.4,
58.4, 21.2, 18.4; IR (KBr) ν: 3414 (m), 3319 (s), 2855
(m), 2209 (s), 1609 (s), 1505 (s), 1477 (m), 1363 (w),
1
characterized by H and 13C NMR, MS, IR spectra, and
were further confirmed by single-crystal studies per-
formed for the representative compounds 3a (Figure 1)
and 3g (Figure 2).
Table 1 Synthesis of polysubstituted 2-aminopyrroles 3a—3j
－
1
1270 (m), 1231 (m), 1115 (m), 852 (m), 805 (m) cm .
Anal. calcd for C23H21FN4O2: C 68.30, H 5.23, N 13.85;
found C 68.12, H 5.37, N 13.50. MS (ESI＋ ) m/z:
405.87.
Ar'
Ar
Ar
N
Co(ClO4)2
NH2
CN
Ar'NH2
THF
CN
CN
2-Amino-5-p-bromophenyl-1-p-methylphenyl-4-
(morpholine-4-carbonyl)pyrrole-3-carbonitrile (4g)
O2N
O2N
1
Light yellow solid, yield 54%, m.p. 286—288 ℃; H
Entry Comp.
Ar
Ar'
Yield/%
63
NMR (600 MHz, DMSO-d6) δ: 7.57 (d, J＝8.6 Hz, 2H,
ArH), 7.44 (d, J＝8.6 Hz, 2H, ArH), 7.18—7.11 (m, 4H,
ArH), 3.72—3.32 (m, 10H, NH2, CH2CH2), 2.25 (s, 3H,
CH3); 13C NMR (150 MHz, DMSO-d6) δ: 167.9, 167.5,
165.4, 140.8, 140.0, 139.9, 139.5, 136.2, 136.1, 134.8,
134.6, 134.5, 128.5, 126.8, 126.7, 121.0, 70.7, 69.5,
58.8, 52.3, 50.5, 25.6; IR (KBr) ν: 3449 (m), 3310 (s),
2173 (s), 1655 (s), 1628 (s), 1541 (s), 1489 (m), 1439
(m), 1396 (w), 1274 (m), 1219 (m), 1116 (m), 1074 (m),
1011 (m), 969 (m), 825 (m) cm－1. Anal. calcd for
C23H21BrN4O2: C 59.36, H 4.55, N 12.04; found C
59.27, H 4.80, N 11.75. MS (ESI＋) m/z: 466.84.
1
2
3a
3b
3c
3d
3e
3f
p-CH3OC6H4
p-CH3C6H4
p-(CH3)3CC6H4
p-BrC6H4
p-CH3C6H4
p-CH3C6H4,
p-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
p-CH3OC6H4
p-ClC6H4
71
3
68
4
80
5
p-CH3OC6H4
C6H5
59
6
76
7
3g
3h
3i
p-CH3C6H4
m-ClC6H4
p-CH3C6H4
C6H5
66
8
p-ClC6H4
55
9
C6H5CH2
50
10
3j
α-C10H7
82
Results and Discussion
To extend the utility of this reaction, the reactivity of
other polysubstituted cyclopropanes was also explored.
Under similar reaction conditions 1,1-dicyanocyclo-
proanes with phenacyl group (Table 2, Entries 1—4),
piperidine-4-carbonyl and morphine-4-carnonyl groups
According to the previously established reactions for
the reactions of imines with polysubstituted cyclopro-
panes,[21] a THF solution of 1,1-dicyano-2,3-diaryl-
cyclopropane (2.0 mmol) and p-toluidine (2.0 mmol) in
1870
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1867—1872

Lewis Acid Catalyzed Ring-opening of 1,1,2,3-Tetrasubstituted Cyclopropanes with Arylamines
Table 2 Synthesis of polysubstituted 2-aminopyrroles 4a—4g
Ar
Co(ClO4)2
THF, reflux
Ar
E
N
+
CN
CN
NH2
O
O
NH2
E
CN
Entry Compd
Ar
E
Yield/%
74
1
2
3
4
5
6
7
p-CH3C6H4
p-ClC6H4
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4f
70
C6H5
60
p-FC6H4
p-FC6H4
p-FC6H4
p-BrC6H4
C6H5
75
Figure 1 Molecular structure of compound 3b.
N(CH2)5
N(CH2)4O
N(CH2)4O
77
68
54
4g
the 2-aminopyrrole (3) as the separated product 3. In
this reaction mechanism a sequential process of ring-
opening of cyclopropane, nucleophilic substitution, ad-
dition to cyano group and recyclization are observed.
Scheme 2 The formation mechanism of 2-aminopyrrole
Ar'
Ar
Ar
Ar
Z
NH
Co(ClO4)2
CN
CN
+
NH2Ar'
N
CN
CN
-
C
Figure 2 Molecular structure of compound 3g.
Z
Z
NC
(Table 2, Entries 5—7) reacted smoothly with p-tolui-
dine to give the more functionalized 2-aminopyrrole
derivatives 4a—4g in good yields (Table 2). These re-
sults showed that this reaction is quite general and has a
very broad substrate scope. It should be pointed out that
there is no any ring-opening product observed when the
polysubstituted cycloproanes in which one cyano group
is replaced by an ester group were used in this reaction.
The exact reasons of this are not very clear at present
and more detailed works should be made in future.
1
(A)
(B)
Ar'
Ar'
N
Ar'
N
Ar
Ar
Ar
N
O
NH
NH2
NH2
Z
Z
Z
CN
(C)
CN
CN
(D)
3
To explain the formation mechanism of functional-
ized 2-aminopyrroles, we proposed a plausible reaction
mechanism (Scheme 2) based on our previously estab-
lished mechanism for the reaction of cyclopropanes
with aromatic imine.[21] Firstly the cyclopropane ring
underwent a heterolytic ring-cleavage to give a 1,3-
zwitterionic intermediate (A) due to the combinatorial
activation of aryl groups and two stronger electron-
withdrawing cyano groups in cyclopropane 1 and the
catalysis of Lewis acid Co(ClO4)2. Secondly the nucleo-
philic amine attracks the carbocation in intermediate (A)
to give an adduct intermediate (B). Thirdly the intra-
molecular addition of the amino group to one of cyano
group results in a ring intermediate (C), from which
2-aminodihydropyrrole (D) was formed by the imine-
enamine tautomerization. At last, 2-aminodihydropyr-
role (D) was dehydrogenated by heating in air to give
Conclusions
In conclusion an efficient synthetic procedure for the
functinalized 2-aminopyrroles was established by Lewis
acid catalyzed ring-opening reaction of the sterically
hindered cyclopropanes with arylamines. This protocol
has advantages of mild reaction conditions, easily ac-
cessible starting material and easy purification of the
products, which makes it a useful and attractive method
for the synthesis of the polysubstituted pyrroles and also
opens a brand way for employing the sterically hindered
cyclopropane to design new ring-opening reaction. The
potential uses of the reaction in synthetic and medicinal
chemistry might be quite significant. Further expansion
of the reaction scope and synthetic applications of this
methodology are in progress in our laboratory.
Chin. J. Chem. 2012, 30, 1867—1872
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1871

Han et al.
FULL PAPER
[11] Du, D.; Wang, Z. W. Tetrahedron Lett. 2008, 49, 956.
Acknowledgement
[12] Chagarovskiy, A. O.; Budynina, E. M.; Ivanova, O. A.; Grishin, Y.
K.; Trushkov, I. V.; Verteletskii, P. V. Tetrahedron 2009, 65, 5385.
[13] Sanders, S. D.; Ruiz-Olalla, A.; Johnson, J. S. Chem. Commun. 2009,
5135.
This work was financially supported by the National
Natural Science Foundation of China (Grant No.
21172189) and the Priority Academic Program Devel-
opment of Jiangsu Higher Education Institutions.
[14] Gopinath, P.; Chandrasekaran, S. J. Org. Chem. 2011, 76, 700.
[15] Pohlhaus, P. D.; Johnson, J. S. J. Org. Chem. 2005, 70, 1057.
[16] Xu, W.; Ghiviriga, I.; Chen, Q. Y.; Dolber, W. R. J. Fluorine Chem.
2010, 131, 958.
Supplementary Information
[17] Oudeyer, S.; Le´onel, E.; Paugam, J. P.; Nédélec, J. V. Tetrahedron
2003, 59, 1073.
Single crystal data for compounds 3b (CCDC
865228) and 3g (CCDC 865229) have been deposited in
the Cambridge Crystallographic Data Center.
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(Zhao, X.)
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1867—1872