ZnCl2-Catalyzed [3 + 2] Cycloaddition of Benzimidates and 2 H-Azirines for the Synthesis of Imidazoles

Article abstract of DOI:10.1021/acs.joc.8b02437

ZnCl₂-catalyzed [3 + 2] cycloaddition reaction of benzimidates and 2H-azirines has been developed. This convenient method allowed the efficient construction of a series of multisubstituted imidazoles in moderate to good yields under mild reaction conditions. This transformation exhibits good reactivity and high functional group tolerance.

Full text of DOI:10.1021/acs.joc.8b02437

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Note
ZnCl2-Catalyzed [3+2] Cycloaddition of Benzimidates
and 2H-Azirines for the Synthesis of Imidazoles
Shoujie Shi, Kang Xu, Cheng Jiang, and Zhenhua DING
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02437 • Publication Date (Web): 05 Nov 2018
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ZnCl2-Catalyzed [3+2] Cycloaddition of Benzimidates and 2H-Azir-
ines for the Synthesis of Imidazoles
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Shoujie Shi, Kang Xu, Cheng Jiang, Zhenhua Ding*
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School
of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Supporting Information Placeholder
ABSTRACT: ZnCl2-catalyed [3+2] cycloaddition reaction of benzimidates and 2H-azirines has been developed. This convenient
method allowed the efficient construction of a serious of multi-substituted imidazoles in moderate to good yields under mild reaction
conditions. This transformation exhibits good reactivity and high functional group tolerance.
2H-Azirine ring systems represent a highly important class of
compounds found in natural products and biological active
compounds.1 Because of their high ring strain, 2H-azirines are
also used as valuable building blocks in organic synthesis in the
preparation of various N-heterocycles.2,3 For example, the pyr-
idines (Scheme 1a) synthesis via an Au-catalyzed ring-expan-
sion of 2-propargyl 2H-azirine have been developed by Gagosz
and co-workers.4 The pyrroles (Scheme 1b)5 and pyrazines
(Scheme 1c)6 synthesis from 2H-azirines catalyzed by Rh and
Cu, respectively, have been reported by Park group. Synthesis
of substituted imidazoles from 2H-azirine have also been inves-
tigated,7 Leonard and co-worker reported the reaction of 2H-
azirine and CH3CN in the presence of HClO4 to form imidazo-
lium salt (Scheme 1d).7a Although much progress have been
achieved in this area,8-11 the development of new catalytic sys-
tem for the construction of N-heterocycles using 2H-azirine as
substrate under mild reaction conditions is still desirable. In this
paper, we report a novel ZnCl2-catalyzed [3+2] cycloaddition
reaction between benzimidates12 and 2H-azirines for the syn-
thesis of substituted imidzoles (Scheme 1e).
We commenced our investigation with the optimization stud-
ies on the [3+2] cycloaddition of ethyl benzimidate 1a and 3-
(4-bromophenyl)-2H-azirine 2a (Table 1). The reaction pro-
vided expected product 3aa in 67% yield in the presence of 10
o
mol% ZnCl2 in dichloromethane (DCE) at 80 C (entry 1).
Scheme 1. Synthesis of N-Heterocycles from 2H-Azirines
Other Lewis acid such as AlCl3, CoBr2, FeCl2 and FeCl3 also
promoted this reaction, but with lower yields (entries 2-5). The
reaction did not take place without Lewis acid catalyst (entry
6). The slight lower yields were obtained when using toluene or
tetrahydrofuran (THF) as solvents (entries 7-8), while the reac-
tion did not occur at all when methanol was employed (entry 9).
The product yield was further improved to 74% when CH3CN7a
was used instead of dichloromethane (entry 10). The use of
lower temperature (60 oC or 25 oC) resulted in lower yields of
3aa (entries 11-12), while higher temperature (100 oC) did not
increase the product yield (entry 13). The reaction didn’t occur
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when HCl was used instead of ZnCl2 (entry 14). The gram scale
Page 2 of 7
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reaction was performed and the product was obtained in 78%
2
yield (entry 15).
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Table 1. Optimization of Reaction Conditionsa
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entry
Lewis
acid
solvent
T
Yieldb
(%)
(oC)
1
ZnCl2
AlCl3
CoBr2
FeCl2
FeCl3
-
DCE
80
80
80
80
80
80
80
80
80
80
60
25
100
80
80
67
26
60
46
49
nr
2
DCE
3
DCE
4
DCE
5
DCE
6
DCE
7
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
HCl
toluene
THF
66
59
nr
8
9
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10
11
12
13
14
15
74
68
49
72
nr
a Reactions were carried out under atmosphere on a 0.3 mmol
scale in solvent (1.5 mL). b Isolated yields.
ZnCl2
78c
a Reactions were carried out under atmosphere on a 0.3 mmol
scale in solvent (1.5 mL). Isolated yields. nr = no reaction.
The reaction was performed in 5 mmol scale.
The present reaction was applicable to a variety of 2H-azir-
ines 2, as illustrated in Scheme 3. 3-Aryl-2H-azirine derivatives
participated in this reaction and afforded the corresponding cy-
cloaddition products 3aa-3ah in moderate to good yields. The
substrates bearing bromo and chloro groups gave the products
3aa and 3ac, respectively, in 74% and 75% yields. The structure
of 3aa was confirmed by X-ray crystal structure analysis.13 The
reaction proceeded well when the substrates bore electron-with-
drawing groups such as fluoro and nitro groups afforded the
products (3ac and 3ad) in good yields (87% and 82%). On the
other hand, the reaction became sluggish with methyl, methoxy
group and provided the products (3ae and 3af) in ca. 50% yield.
Some functional groups such as formyl group could be tolerated
in this reaction conditions and gave the annulation product 3ah
in 46% yield. The 2,3-di-substituted 2H-azirines also under-
went cycloaddition reaction to generate tri-substituted imidaz-
oles. When 2H-azirine 2i was employed, the reaction proceeded
well and afforded the imidazole products 3ai and 3ai’ with 2.5:1
ratio in 71%. A thienyl-substituted 2H-azirine 2j also under-
went the reaction with modest reactivity (3aj). Ethyl 3-phenyl-
2H-azirine-2-carboxylate 3k reacted with benzimidate 1a to
provide products 3ak and 3ak’ with 1:1 ratio in moderate yield.
When a fluoro was introduced to para position of benzene ring
of the 2H-azirine, the products ratio was 1.4:1 with 52% yield
(3al). The symmetric 2,3-diphenyl-2H-azirine also participated
in this annulation reaction and afforded the corresponding prod-
uct 3am in 78% yield.
b
c
After screening the reaction conditions, we examined the
substrate scope of benzimidates 1 (Scheme 2). Benzimidates
bearing electron-donating groups such as methoxy, methyl
groups participated in this reaction well, and provided the cor-
responding products in 79-86% yields (3ba, 3ca, 3da). The
electron-withdrawing group nitro and CF3 could be tolerated in
the reaction conditions with moderate product yields (3ea and
3fa). Halogen substituents such as bromo, chloro and fluoro are
tolerated well in the reaction conditions, the desired products
were obtained in good yields (3ga, 3ha, 3ia). The reaction pro-
ceeded well when an acetyl group at the meta position of ben-
zimidate and gave the product 3ja in 66% yield. The 2-naph-
thimidate substrate also underwent this reaction with good re-
activity (3ka). A 4-phenyl substituted benzimidate underwent
the cycloaddition reaction of 2a as smoothly as model substrate
and afforded the expected product in 70% yield (3la). The reac-
tion also proceeded well when indole-4-carbimidate was used
as substrate and provided imidazolyl substituted indole in good
yield (3ma). Furan-2-carbimidate and thiophene-2-carbimidate
underwent the reaction well and afforded the corresponding im-
idazole in moderate yields (3na and 3oa). When the imidate
with a benzyl substituent at 2-position, the reaction proceeded
and gave the desired product 3pa in73% yield.
Scheme 3. Scope of 2H-Azirinesa,b
Scheme 2. Scope of benzimidatesa,b
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In summary, we have developed a ZnCl2-catalyzed [3+2] cy-
cloaddition reaction of benzimidates and 2H-azirines for the
synthesis of substituted imidazoles. The reaction exhibits excel-
lent reactivity, good functional group tolerance and moderate to
good yields. Ongoing effort in our laboratory will explore the
cycloaddition reaction to construct other heterocycles catalyzed
by Lewis acid.
a Reactions were carried out under atmosphere on a 0.3 mmol
scale in solvent (1.5 mL). b Isolated yields.
EXPERIMENTAL SECTION
We then performed the reaction with addition of 1 equivalent
of 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) and product
3aa was obtained in 71% (Scheme 4a). This experiment ex-
cluded the possibility of free radical reaction mechanism. Based
on the previous reports and our data, we proposed the reaction
mechanism of this transformation (Scheme 4b). First, in the
presence of ZnCl2, the cationic azirine complex I was formed.
Then complex I undergoes nucleophilic attack by benzimidate
1a to generate intermediate II. A subsequent ring opening and
intramolecular nucleophilic attack of the N to the carbocation
and OEt as a leaving group to form the five membered ring in-
termediate III. Finally, the elimination of ZnCl2 catalyst to af-
ford the imidazole product 3aa and finish the catalytic cycle.
General Experimental Methods. Unless otherwise noted, all
chemicals were purchased from commercial suppliers and used
without further purification. All reactions were performed by
standard Schlenk techniques in oven-dried reaction vessels un-
der air. Flash column chromatography was carried out using
commercially available 300-400 mesh under pressure unless
1
otherwise indicated. H and 13C nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker AV-300 (300 MHz)
NMR spectrometer. 1H and 13C{1H } NMR spectra are reported
in parts per million (ppm) downfield from an internal standard,
tetramethylsilane (0 ppm), and DMSO-d6 (δ H = 2.50 ppm; δ C
= 39.51 ppm), respectively. Infrared (IR) spectra were recorded
using a thin film supported on KBr disks. High Resolution Mass
measurement was performed on Agilent QTOF 6520 mass
spectrometer with electron spray ionization (ESI) as the ion
source. Anhydrous acetonitrile (MeCN) was distilled and stored
over molecular sieves. Benzimidate derivatives 1 were prepared
by following the same procedure as described in the literature.14
2H-azirines 2 were prepared by known procedure.15
Scheme 4. Proposed Mechanism
General Procedure for ZnCl2-Catalyzed [3+2] Cycloaddi-
tion Reaction of Benzimidate and 2H-azirines. An oven-
dried Schlenk tube equipped with a magnetic stir bar was
charged with ZnCl2 (4.1 mg, 0.03 mmol, 10 mol %), benzimi-
date 1 (0.3 mmol, 1.0 equiv.), 2H-azirine 2 (0.36 mmol, 1.2
equiv). 1.5 mL CH3CN were successively added and then
stirred at 80 °C for 12 h. The reaction mixture was allowed to
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cool down to room temperature and quenched with H2O (2 mL
1H NMR (300 MHz, DMSO-d6) δ 13.03 (s, 1H), 8.21 (d, J =
8.2 Hz, 2H), 7.90 (s, 1H), 7.84 (d, J = 8.5 Hz, 4H), 7.58 (d, J =
8.4 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 145.2,
1
2
3
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× 1) and extracted with ethyl acetate (5 mL × 3). The combined
organic layer was dried over Na2SO4, filtered, and concentrated.
The crude mixture was purified by flash column chromatog-
raphy (ethyl acetate/hexane) on silica gel and afforded corre-
sponding imidazole 3.
2
134.5, 131.9, 128.6 (q, JC-H= 31.8 Hz), 128.0, 126.9, 126.5,
126.3, 126.2, 125.9, 122.9, 119.8; IR (KBr) νmax = 3421, 3193,
2924, 2849, 1620, 1442, 1327, 1167, 1124, 1065, 1026, 1009,
849, 823, 504 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C16H11BrF3N2: 367.0058, Found: 367.0047.
5-(4-Bromophenyl)-2-phenyl-1H-imidazole (3aa): A white
solid; m.p. 169-171°C; Yield: 67 mg, 74%; 1H NMR (300 MHz,
DMSO-d6) δ 12.76 (s, 1H), 8.04 (d, J = 7.6 Hz, 2H), 7.85 (d, J
= 8.0 Hz, 3H), 7.63 – 7.53 (m, 2H), 7.52 – 7.43 (m, 2H), 7.41 –
7.32 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 146.6,
140.4, 134.4, 131.8, 130.9, 129.2, 128.7, 126.8, 125.5, 119.4,
115.4; IR (KBr) νmax = 3421, 3168, 2926, 2843, 1658, 1485,
1458, 1301, 1140, 1069, 1051, 1025, 1007, 941, 830, 775, 694,
510 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for C15H12BrN2:
299.0184, Found: 299.0180.
2,5-Bis(4-bromophenyl)-1H-imidazole (3ga): A white solid;
1
9
m.p. 203-205°C; Yield: 64 mg, 66%; H NMR (300 MHz,
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DMSO-d6) δ 12.83 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.90 – 7.75
(m, 3H), 7.68 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 145.6, 132.1, 131.8,
130.0, 127.3, 126.8, 121.8, 119.7; IR (KBr) νmax = 3449, 3231,
2922, 2850, 1647, 1482, 1431, 1291, 1152, 1072, 1009, 943,
829, 780, 725, 503 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C15H11Br2N2: 376.9289, Found: 376.9288.
5-(4-Bromophenyl)-2-(4-methoxyphenyl)-1H-imidazole
(3ba): A white solid; m.p. 197-198°C; Yield: 78 mg, 79%; 1H
NMR (300 MHz, DMSO-d6) δ 7.97 (d, J = 8.7 Hz, 2H), 7.82
(d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.05
(d, J = 8.8 Hz, 2H), 3.81 (s, 3H); 13C{1H} NMR (75 MHz,
DMSO-d6) δ 159.9, 146.9, 131.8, 127.0, 126.8, 123.7, 119.3,
114.6, 55.7; IR (KBr) νmax = 3434, 2922, 2850, 2357, 1649,
1611, 1542, 1492, 1402, 1256, 1174, 1114, 1028, 1007, 938,
836, 774, 736, 617, 567, 505 cm-1;HRMS (ESI) m/z [M+H]+:
Calcd for C16H14BrN2O: 329.0290, Found: 329.0285.
5-(4-Bromophenyl)-2-(4-chlorophenyl)-1H-imidazole
(3ha): A yellow solid; m.p. 198-200°C; Yield: 71 mg, 71%; 1H
NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.02 (d, J = 8.3
Hz, 2H), 7.91 – 7.78 (m, 3H), 7.63 – 7.47 (m, 4H); 13C{1H}
NMR (75 MHz, DMSO-d6) δ 133.3, 131.9, 129.7, 129.4, 128.8,
127.4, 127.2, 127.0, 126.8; IR (KBr) νmax = 3434, 3178, 2922,
2851, 2353, 1655, 1596, 1483, 1399, 1271, 1092, 1069, 1009,
944, 833, 762, 731, 501 cm-1; HRMS (ESI) m/z [M+H]+: Calcd
for C15H11BrClN2: 332.9794, Found: 332.9794.
5-(4-Bromophenyl)-2-(m-tolyl)-1H-imidazole (3ca): A white
5-(4-Bromophenyl)-2-(4-fluorophenyl)-1H-imidazole (3ia):
1
1
solid; Yield: 78 mg, 81%; H NMR (300 MHz, DMSO-d6) δ
A yellow solid; Yield: 69 mg, 73%; H NMR (300 MHz,
12.70 (s, 1H), 7.99 – 7.71 (m, 5H), 7.58 (d, J = 7.6 Hz, 2H),
7.40 – 7.32 (m, 1H), 7.19 (d, J = 6.8 Hz, 1H), 2.39 (s, 3H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 146.9, 138.4, 131.9,
130.9, 129.4, 129.1, 126.8, 126.1, 122.7, 119.4, 21.6; IR (KBr)
νmax = 3426, 3154, 2921, 2852, 1660, 1612, 1483, 1401, 1324,
1138, 1069, 1008, 943, 830, 791, 726, 690, 503 cm-1; HRMS
(ESI) m/z [M+H]+: Calcd for C16H14BrN2: 313.0340, Found:
313.0339.
DMSO-d6) δ 12.75 (s, 1H), 8.20 – 7.98 (m, 2H), 7.96 – 7.73
(m, 3H), 7.68 –7.50 (m, 2H), 7.43 – 7.23 (m, 2H); 13C{1H}
NMR (75 MHz, DMSO-d6) δ 162.6 (d, 1JC-F= 245.4 Hz), 145.8,
3
140.4, 134.4, 131.8, 127.6 (d, JC-F= 3.4 Hz), 126.8, 119.4,
116.2 (d, 2JC-F= 21.9 Hz), 115.4; IR (KBr) νmax = 3421, 2921,
2851, 1612, 1503, 1444, 1400, 1247, 1147, 1072, 1008, 964,
833, 769, 739, 615, 532 cm-1; HRMS (ESI) m/z [M+H]+: Calcd
for C15H11BrFN2: 317.0090, Found: 317.0088.
5-(4-Bromophenyl)-2-(3,5-dimethylphenyl)-1H-imidazole
(3da): A white solid; m.p. 197-199°C; Yield: 86 mg, 86%; 1H
NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 7.83 (d, J = 7.8
Hz, 2H), 7.77 (s, 1H), 7.66 (s, 2H), 7.57 (d, J = 7.4 Hz, 2H),
6.99 (s, 1H), 2.34 (s, 6H); 13C{1H} NMR (75 MHz, DMSOd6)
δ 147.0, 138.2, 131.8, 130.8, 130.2, 127.5, 127.0, 126.8, 126.2,
123.3, 119.4, 21.5; IR (KBr) νmax = 3447, 3197, 2920, 2843,
1654, 1605, 1478, 1402, 1025, 1007, 852, 827, 766, 732, 688,
507 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for C17H16BrN2:
327.0497, Found: 327.0498.
1-(3-(5-(4-Bromophenyl)-1H-imidazol-2-yl)phenyl)etha-
none (3ja): A white solid; m.p. 223-224°C; Yield: 68 mg, 66%;
1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.59 (s, 1H),
8.27 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.81 (dd, J =
24.7, 8.2 Hz, 3H), 7.64 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 8.4 Hz,
2H), 2.66 (s, 3H). 13C{1H} NMR (75 MHz, DMSO-d6) δ 198.3,
137.8, 131.9, 131.3, 129.8, 129.7, 128.4, 126.9, 124.9, 27.3; IR
(KBr) νmax = 3428, 3202, 2919, 2851, 1663, 1473, 1445, 1404,
1260, 1139, 1024, 1007, 943, 834, 754, 727, 683, 595 cm-1;
HRMS (ESI) m/z [M+H]+: Calcd for C17H13BrN2O: 341.0290,
Found: 341.0285.
5-(4-Bromophenyl)-2-(4-nitrophenyl)-1H-imidazole (3ea):
A yellow solid; m.p. 206-207°C; Yield: 56 mg, 54%; 1H NMR
(300 MHz, DMSO-d6) δ 13.18 (s, 1H), 8.33 (d, J = 8.9 Hz, 2H),
8.27 – 8.18 (m, 2H), 7.99 (s, 1H), 7.89 – 7.80 (m, 2H), 7.58 (d,
J = 8.5 Hz, 2H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 147.1,
144.6, 141.7, 136.7, 134.0, 132.0, 127.1, 126.1, 124.8, 120.0,
117.4; IR (KBr) νmax = 3401, 3178, 2923, 2852, 1646, 1603,
1508, 1482, 1402, 1339, 1152, 1109, 1069, 1008, 854, 833, 767,
717, 501 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C15H11BrN3O2: 344.0035, Found:. 344.0034.
5-(4-Bromophenyl)-2-(naphthalen-2-yl)-1H-imidazole
(3ka): A gray solid; m.p. 206-207°C; Yield: 78 mg, 74%; H
1
NMR (300 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.55 (s, 1H), 8.21
(d, J = 8.5 Hz, 1H), 8.05 – 7.86 (m, 6H), 7.64 – 7.50 (m, 4H);
13C{1H} NMR (75 MHz, DMSO-d6) δ 133.5, 133.2, 131.9,
128.8, 128.6, 128.4, 128.2, 127.2, 126.9, 124.0, 123.8; IR (KBr)
νmax = 3533, 3229, 3193, 2920, 2850, 2616, 2360, 1657, 1598,
1478, 1410, 1292, 1149, 1132, 1070, 1006, 950, 864, 825, 751,
489 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for C19H14BrN2:
349.0340, Found: 349.0338.
5-(4-Bromophenyl)-2-(4-(trifluoromethyl)phenyl)-1H-imid-
azole (3fa): A white solid; m.p. 190-191°C; Yield: 69 mg, 63%;
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2-([1,1'-Biphenyl]-4-yl)-5-(4-bromophenyl)-1H-imidazole
HRMS (ESI) m/z [M+H]+: Calcd for C15H12ClN2: 255.0689,
Found: 255.0688.
(3la): A yellow solid; m.p. 251-253°C; Yield: 80 mg, 70%; 1H
NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.13 (d, J = 8.3
Hz, 2H), 7.88 (d, J = 8.2 Hz, 3H), 7.79 (d, J = 8.4 Hz, 2H), 7.73
(d, J = 7.3 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.48 (t, J = 7.5 Hz,
2H), 7.38 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ
133.5, 133.2, 131.9, 128.8, 128.6, 128.4, 128.2, 127.2, 126.9,
126.8, 124.0, 123.8; IR (KBr) νmax = 3414, 2921, 2851, 1646,
1483, 1422, 1401, 1128, 1107, 1079, 1067, 1007, 942, 837, 767,
732, 690, 561, 504 cm-1;HRMS (ESI) m/z [M+H]+: Calcd for
C21H16BrN2: 375.0497, Found: 375.0498.
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5-(4-Fluorophenyl)-2-phenyl-1H-imidazole (3ac): A green
solid; m.p. 169-170°C; Yield: 63 mg, 87%; 1H NMR (300 MHz,
DMSO-d6) δ 12.69 (s, 1H), 8.02 (d, J = 7.4 Hz, 2H), 7.90 (dd,
J = 8.4, 5.7 Hz, 2H), 7.75 (s, 1H), 7.53 – 7.43 (m, 2H), 7.41 –
7.32 (m, 1H), 7.23 (t, J = 8.8 Hz, 2H); 13C{1H} NMR (75 MHz,
1
DMSO-d6) δ 161.4 (d, JC-F = 242.4 Hz), 146.4, 131.0, 129.2,
3
2
128.6, 126.7 (d, JC-F = 7.9 Hz), 125.4, 115.8 (d, JC-F = 21.7
Hz); IR (KBr) νmax = 3445, 3144, 2923, 2843, 2360, 1658,
1607, 1566, 1497, 1462, 1459, 1402, 1232, 1156, 1025, 838,
774, 693, 602, 513 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C15H12FN2: 239.0985, Found: 239.0982.
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4-(5-(4-Bromophenyl)-1H-imidazol-2-yl)-1-methyl-1H-in-
dole (3ma): A yellow solid; Yield: 82 mg, 77%; 1H NMR (300
MHz, DMSO-d6) δ 12.64 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.83
(s, 1H), 7.65 (d, J = 7.2 Hz, 1H), 7.62 – 7.58 (m, 2H), 7.49 –
7.42 (m, 3H), 7.29 – 7.22 (m, 1H), 3.83 (s, 3H); 13C{1H} NMR
(75 MHz, DMSO-d6) δ 147.5, 137.7, 131.9, 130.6, 126.8,
125.4, 122.5, 121.3, 119.3, 116.9, 110.5, 102.7, 33.1; IR (KBr)
νmax = 3398, 3132, 2922, 2849, 2360, 1901, 1723, 1657, 1598,
1512, 1485, 1449, 1417, 1333, 1286, 1119, 1065, 1018, 1006,
943, 831, 752, 509 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C18H15BrN3: 352.0449, Found: 352.0450.
5-(4-Nitrophenyl)-2-phenyl-1H-imidazole (3ad): A yellow
solid; m.p. 178-179°C; Yield: 66 mg, 82%; 1H NMR (300 MHz,
DMSO-d6) δ 13.00 (s, 1H), 8.25 (d, J = 8.9 Hz, 2H), 8.11 (d, J
= 8.4 Hz, 3H), 8.05 (d, J = 7.5 Hz, 2H), 7.54 – 7.45 (m, 2H),
7.43 – 7.35 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ
147.5, 145.7, 141.8, 139.6, 130.5, 129.3, 129.1, 125.6, 125.2,
124.6, 118.5; IR (KBr) νmax = 3519, 3108, 2923, 2852, 2363,
1655, 1600, 1511, 1330, 1182, 1143, 1111, 858, 788, 752, 713,
689, 486 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C15H12N3O2: 266.0930, Found: 266.0928.
5-(4-Bromophenyl)-2-(furan-2-yl)-1H-imidazole (3na): A
1
yellow solid; m.p. 209-210°C; Yeild: 49mg, 56%; H NMR
2-Phenyl-5-(p-tolyl)-1H-imidazole (3ae): A white solid; m.p.
(300 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.78 (d, J = 6.6 Hz, 4H),
7.55 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 3.2 Hz, 1H), 6.68-6.58 (m,
1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 145.8, 142.9,
131.4, 126.3, 119.0, 111.8, 107.0; IR (KBr) νmax = 3414, 3229,
2923, 2852, 1637, 1618, 1521, 1483, 1475, 1400, 1289, 1173,
1150, 1108, 1070, 1019, 1006, 983, 890, 813, 765, 731, 640,
596, 501 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C13H10BrN2O: 288.9977, Found: 288.9973.
1
168-170°C; Yield: 35 mg, 50%; H NMR (300 MHz, DMSO-
d6) δ 12.61 (s, 1H), 8.03 (d, J = 7.4 Hz, 2H), 7.76 (d, J = 8.0
Hz, 2H), 7.66 (s, 1H), 7.52 – 7.43 (m, 2H), 7.40 – 7.32 (m, 1H),
7.23 – 7.16 (m, 2H), 2.31 (s, 3H); 13C{1H} NMR (75 MHz,
DMSO-d6) δ 146.3, 135.9, 131.1, 129.6, 129.2, 128.5, 125.4,
124.8, 21.3; IR (KBr) νmax = 3424, 3162, 2921, 2849, 2259,
1655, 1607, 1499, 1459, 1405, 1298, 1179, 1143, 1045, 1025,
1006, 822, 774, 693, 507 cm-1; HRMS (ESI) m/z [M+H]+: Calcd
for C16H15N2: 235.1235, Found: 235.1230.
5-(4-Bromophenyl)-2-(thiophen-2-yl)-1H-imidazole (3oa):
A white solide; m.p. 212-213°C; Yeild: 55mg, 60%; 1H NMR
(300 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.77 (d, J = 6.9 Hz, 1H),
7.59 – 7.50 (m, 2H), 7.17 – 7.09 (m, 1H); 13C{1H} NMR (75
MHz, DMSO-d6) δ 142.6, 140.1, 134.5, 134.1, 131.8, 128.3,
126.8, 126.6, 124.4, 119.4, 114.9; IR (KBr) νmax = 3552, 3475,
3414, 3110, 2921, 1640, 1617, 1496, 1476, 1419, 1227, 1139,
1084, 1064, 1008, 947, 930, 847, 830, 781, 726, 698, 624, 502,
481 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for C13H10BrN2S:
304.9748, Found: 304.9746.
5-(4-Methoxyphenyl)-2-phenyl-1H-imidazole (3af): A yel-
low solid. Yield: 33 mg, 43%; 1H NMR (300 MHz, DMSO-d6)
δ 8.01 (d, J = 7.4 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.59 (s, 1H),
7.51 – 7.43 (m, 2H), 7.40 – 7.31 (m, 1H), 6.97 (d, J = 8.8 Hz,
2H), 3.78 (s, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 158.5,
146.2, 131.1, 129.2, 128.5, 126.2, 125.3, 114.4, 55.5; IR (KBr)
νmax = 3392, 3162, 2921, 2843, 1604, 1499, 1460, 1247, 1178,
1027, 833, 774, 708, 693, 610, 524 cm-1; HRMS (ESI) m/z
[M+H]+: Calcd for C16H15N2O: 251.1184, Found: 251.1184.
2-Benzyl-5-(4-bromophenyl)-1H-imidazole (3pa): A yellow
oil; Yeild: 69mg, 73%; 1H NMR (300 MHz, DMSO-d6) δ 12.05
(s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.55 – 7.45 (m, 3H), 7.33 –
7.15 (m, 5H), 4.00 (s, 2H); 13C{1H} NMR (75 MHz, DMSO-
d6) δ 147.7, 138.9, 131.7, 128.9, 128.8, 126.7, 126.5, 118.9,
34.7; IR (KBr) νmax = 3413, 3137, 2923, 2853, 2360, 2342,
1637, 1617, 1535, 1493, 1477, 1454, 1399, 1135, 1069, 1008,
952, 829, 772, 726, 693, 506 cm-1; HRMS (ESI) m/z [M+H]+:
Calcd for C16H14BrN2: 313.0340, Found: 313.0336.
2,5-Diphenyl-1H-imidazole (3ag): A white solid; Yield: 31
mg, 47%; 1H NMR (300 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.03
(d, J = 7.3 Hz, 2H), 7.87 (d, J = 7.3 Hz, 2H), 7.73 (s, 1H), 7.53
– 7.44 (m, 2H), 7.43 – 7.34 (m, 3H), 7.27 – 7.19 (m, 1H); 13C{1H}
NMR (75 MHz, DMSO-d6) δ 146.5, 131.1, 129.2, 129.0, 128.6,
128.4, 126.8, 125.4, 125.1, 125.0, 124.9; IR (KBr) νmax = 3463,
3144, 2923, 2852, 1646, 1606, 1488, 1459, 1401, 1143, 1072,
1024, 1006, 822, 773, 757, 692, 501 cm-1; HRMS (ESI) m/z
[M+H]+: Calcd for C15H13N2: 221.1079, Found: 221.1077.
5-(4-Chlorophenyl)-2-phenyl-1H-imidazole (3ab): A green
solid; m.p. 156-158°C; Yield: 58 mg, 75%; 1H NMR (300 MHz,
DMSO-d6) δ 12.75 (s, 1H), 8.03 (d, J = 7.5 Hz, 2H), 7.90 (d, J
= 8.2 Hz, 2H), 7.84 (s, 1H), 7.54 – 7.41 (m, 4H), 7.40 – 7.34
(m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 146.6, 140.4,
134.1, 130.9, 129.2, 128.9, 128.7, 126.5, 125.4, 115.4; IR (KBr)
νmax = 3428, 3138, 2920, 2843, 1648, 1486, 1458, 1410, 1295,
1091, 1026, 1011, 941, 827, 781, 709, 695, 582, 514, 501 cm-1;
4-(2-Phenyl-1H-imidazol-5-yl)benzaldehyde (3ah): A yellow
solid, m.p. 168-169°C; Yield: 35 mg, 46%; 1H NMR (300 MHz,
DMSO-d6) δ 12.93 (s, 1H), 9.98 (s, 1H), 8.18 – 7.99 (m, 5H),
7.94 (d, J = 8.2 Hz, 2H), 7.56 – 7.44 (m, 2H), 7.44 – 7.35 (m,
1H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 192.7, 147.1,
141.1, 140.4, 134.5, 130.7, 130.6, 129.3, 128.9, 125.6, 125.1,
117.6; IR (KBr) νmax = 3455, 3324, 3287, 2921, 2850, 1683,
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1601, 1458, 1424, 1395, 1303, 1215, 1165, 1127, 1026, 943,
115.4, 115.1, 115.0, 114.8, 60.9, 60.0, 14.61, 14.56. IR (KBr)
νmax = 3452, 3074, 2922, 2851, 1710, 1607, 1533, 1503, 1485,
1474, 1381, 1316, 1230, 1158, 1130, 1023, 965, 842, 789, 715,
703 cm-1; HRMS (ESI) m/z[M+H]+: Calcd for C18H16FN2O2:
311.1196, Found: 311.1188.
834, 775, 698, 649, 507 cm-1; HRMS (ESI) m/z [M+H]+: Calcd
for C16H13N2O: 249.1028, Found: 249.1025.
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Ethyl 5-methyl-2-phenyl-1H-imidazole-4-carboxylate (3ai):
Obtained as a 2.5:1 mixture with its regioisomer ethyl 4-methyl-
2-phenyl-1H-imidazole-5-carboxylate (3ai’); A white solid;
2,4,5-Triphenyl-1H-imidazole(3am): A white solid; m.p. 274-
275°C; Yield: 70 mg, 78%; 1H NMR (300 MHz, DMSO-d6) δ
12.74 (s, 1H), 8.13 (d, J = 7.3 Hz, 2H), 7.56 (d, J = 7.2 Hz, 4H),
7.49 (t, J = 7.5 Hz, 2H), 7.44 – 7.23 (m, 7H); 13C{1H} NMR (75
MHz, DMSO-d6) δ 146.0, 130.8, 129.2, 128.9, 128.7, 128.6-
127.1(m), 125.7; IR (KBr) νmax = 3434, 3037, 2963, 2920,
2851, 2363, 1600, 1488, 1460, 1460, 1396, 1127, 1070, 1027,
965, 915, 840, 765, 736, 697, 495 cm-1; HRMS (ESI)
m/z[M+H]+: Calcd for C21H17N2: 297.1392, Found: 297.1383.
1
m.p. 197-198°C; Yield: 50 mg, 71%; H NMR (400 MHz,
DMSO-d6) δ 12.99 (s, 1H, 3ai’), 12.85 (s, 1H, 3ai), 8.12 (d, J
= 6.6 Hz, 2H, 3ai’), 7.93 (d, J = 7.5 Hz, 2H, 3ai), 7.50 – 7.36
(m, 3H, 3ai and 3ai’), 4.30 – 4.21 (m, 2H, 3ai and 3ai’) 2.51 (s,
3H, 3ai), 2.42 (s, 3H, 3ai’), 1.31 – 1.27 (m, 3H, 3ai and 3ai’);
13C{1H} NMR (100 MHz, DMSO-d6) δ 163.8, 160.8, 147.8,
146.6, 144.8, 137.1, 130.3, 129.6, 129.3, 129.1, 128.9, 126.6,
125.5, 60.4, 59.9, 59.7, 15.1, 14.9, 11.6; IR (KBr) νmax = 3466,
2978, 2345, 1707, 1597, 1535, 1491, 1458, 1400, 1320, 1213,
1112, 1100, 1024, 972, 783, 708, 618, 465 cm-1; HRMS (ESI)
m/z [M+H]+: Calcd for C13H15N2O2: 231.1134, Found:
231.1131.
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ASSOCIATED CONTENT
Supporting Information
tert-Butyl-2-phenyl-5-(thiophen-2-yl)-1H-imidazole-4-car-
1
boxylate (3aj): A yellow solid; Yield: 32 mg, 32%; H NMR
The Supporting Information is available free of charge on the ACS
Publications website.
(300 MHz, DMSO-d6) δ 12.97 (s, 1H), 8.16 (d, J = 6.6 Hz, 2H),
8.04 – 7.99 (m, 1H), 7.60 – 7.56 (m, 1H), 7.54 – 7.46 (m, 3H),
7.15 (dd, J = 5.0, 3.8 Hz, 1H), 1.61 (s, 9H); 13C{1H} NMR (75
MHz, DMSO-d6) δ 159.8, 147.9, 140.8, 137.3, 130.1, 129.4,
129.1, 127.9, 127.9, 127.3, 127.0, 119.3, 82.3, 28.5; IR (KBr)
νmax = 3439, 3071, 2977, 2926, 2851, 1700, 1563, 1506, 1480,
1453, 1433, 1393, 1367, 1300, 1170, 1111, 1047, 1021, 847,
780, 694 cm-1; HRMS (ESI) m/z [M+H]+: Calcd for
C18H19N2O2S: 327.1167, Found: 327.1167.
1H and 13C NMR spectra for all the products (PDF)
X-ray crystallographic data for 3aa (CIF)
AUTHOR INFORMATION
Corresponding Author
*zhding@cpu.edu.cn
Notes
The authors declare no competing financial interest.
Ethyl-2,5-diphenyl-1H-imidazole-4-carboxylate (3ak): Ob-
tained as a 1:1 mixture with its regioisomer Ethyl-2,4-diphenyl-
1H-imidazole-5-carboxylate (3ak’); A yellow solid; m.p. 167-
169°C; Yield: 37 mg, 41%; 1H NMR (300 MHz, DMSO-d6) δ
13.23 (s, 1H, 3ak), 13.09 (s, 1H, 3ak’), 8.21 (d, J = 6.5 Hz, 1H,
3ak and 3ak’), 8.08 (d, J = 6.8 Hz, 1H, 3ak and 3ak’ ), 7.91 (d,
J = 6.4 Hz, 1H, 3ak and 3ak’), 7.73 – 7.66 (m, 1H, 3ak and
3ak’), 7.54 – 7.36 (m, 6H, 3ak and 3ak’), 4.34 – 4.15 (m, 2H,
3ak and 3ak’), 1.31 – 1.15 (m, 3H, 3ak and 3ak’); 13C{1H}
NMR (75 MHz, DMSO-d6) δ 165.71, 163.34, 160.41, 148.31,
147.45, 146.3, 130.1, 129.7, 129.2, 129.0, 128.3, 128.1, 126.9,
126.1, 119.3, 60.8, 60.0, 14.6; IR (KBr) νmax = 3428, 2921,
2850, 2357, 1712, 1531, 1487, 1474, 1381, 1311, 1258, 1265,
1235, 1129, 1023, 997, 966, 780, 762, 717, 693 cm-1; HRMS
(ESI) m/z [M+H]+: Calcd for C18H17N2O2: 293.1290, Found:
293.1290.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation of
China (NSFC 81602952), the Natural Science Foundation of
Jiangsu Province (BK20160748), the Project Program of Jiangsu
Key Laboratory of Drug Design and Optimization, China Pharma-
ceutical University (2018KFKT-3) is acknowledged.
REFERENCES
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Heterogeneous Terminal alogenation from the Marine Sponge Dysidea
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A Review. Org. Prep. Proced. Int. 2002, 34, 219-269. (c) Balme, G.
Pyrrole Syntheses by Multicomponent Coupling Reactions. Angew.
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M. S. Recent Advances in 2H-Azirine Chemistry. Tetrahedron 2013,
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Ethyl-5-(4-fluorophenyl)-2-phenyl-1H-imidazole-4-carbox-
ylate (3al): Obtained as a 1.4:1 mixture with its regioisomer
Ethyl-4-(4-fluorophenyl)-2-phenyl-1H-imidazole-5-carbox-
ylate (3al’); A white solid; m.p. 206-207°C; Yield: 49 mg, 52%;
1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H, 3al), 13.09 (s,
1H, 3al’), 8.20 (d, J = 6.6 Hz, 2H, 3al), 8.07 (d, J = 7.3 Hz, 2H,
3al’), 7.97 (dd, J = 8.7, 5.8 Hz, 2H, 3al), 7.75 (dd, J = 8.6, 5.6
Hz, 2H, 3al’), 7.55 – 7.40 (m, 5H, 3al), 7.41 – 7.22 (m, 5H,
3al’), 4.30 (q, J = 7.1 Hz, 2H, 3al), 4.20 (q, J = 7.1 Hz, 2H,
3al’), 1.28 (t, J = 7.1 Hz, 3H, 3al), 1.21 (t, J = 7.0 Hz, 3H, 3al’);
2
13C{1H} NMR (75 MHz, DMSO-d6) δ 164.2 (d, JC-F = 22.2
2
Hz), 163.3, 161.0 (d, JC-F = 21.6 Hz), 160.0, 148.3, 146.4,
(3) For recent contributions, see: (a) Xuan, J.; Xia, X.-D.; Zeng, T.-
T.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Visible-Light-In-
duced Formal [3+2] Cycloaddition for Pyrrole Synthesis under Metal-
146.3, 137.7, 132.4 (d, 3JC-F = 8.3 Hz), 131.7 (d, 3JC-F = 8.3 Hz),
4
130.7 (d, JC-F = 3.0 Hz), 130.1, 130.0, 129.7, 129.4, 129.23,
4
129.15, 128.9, 126.9, 126.4 (d, JC-F = 3.3 Hz), 126.1, 119.3,
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The Journal of Organic Chemistry
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ines and Enamides for the Synthesis of Pyrroles. Org. Lett. 2018, 20,
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Loh, T.-P. Transition-Metal-Free Synthesis of Substituted Pyridines
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Mueller, J. O.; Schmidt, F. G.; Blinco, J. P.; Barner-Kowollik, C. Vis-
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2H‑Azirines and Aldehydes. Org. Lett. 2015, 17, 4070-4073. (d) Jin,
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(13) Crystallographic data for 3aa has been deposited with the Cam-
bridge Crystallographic Data Centre as deposition numbers CCDC
1861288. Detailed information can be found in the Supporting Infor-
mation.
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