Synthesis of polyfunctional imidazoles from vinyl azides and amidine along with NHBoc as a leaving group

Article abstract of DOI:10.1016/j.tet.2019.04.008

An efficient method for the synthesis of polyfunctional imidazoles from vinyl azides and amidine has been developed. Starting from vinyl azide and amidine, this transformation proceeds without any additives and the obtained imidazoles can be decorated with ester functional group that is a promising site for further modification.

Full text of DOI:10.1016/j.tet.2019.04.008

Accepted Manuscript
Synthesis of polyfunctional imidazoles from vinyl azides and amidine along with
NHBoc as a leaving group
Pai Tang, Di Ke, Jiaan Shao, Wenteng Chen, Yongping Yu
PII:
S0040-4020(19)30398-9
https://doi.org/10.1016/j.tet.2019.04.008
TET 30253
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 February 2019
Revised Date: 15 March 2019
Accepted Date: 2 April 2019
Please cite this article as: Tang P, Ke D, Shao J, Chen W, Yu Y, Synthesis of polyfunctional imidazoles
from vinyl azides and amidine along with NHBoc as a leaving group, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.04.008.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Synthesis of polyfunctional imidazoles from
vinyl azides and amidine along with NHBoc
as a leaving group
Leave this area blank for abstract info.
Pai Tang, a Di Ke, a Jiaan Shao,b Wenteng Chen,*,a Yongping Yu *,a
a College of Pharmaceutical Science, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China
b Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P. R. China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of polyfunctional imidazoles from vinyl azides and amidine along with
NHBoc as a leaving group
,a
,a
Pai Tang, a Di Ke, a Jiaan Shao, b Wenteng Chen, Yongping Yu
a College of Pharmaceutical Science, Zhejiang University, Hangzhou, Zhejiang 310058, P. R. China
b Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, Zhejiang 310018, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient method for the synthesis of polyfunctional imidazoles from vinyl azides and
amidine has been developed. Starting from vinyl azide and amidine, this transformation
proceeds without any additives and the obtained imidazoles can be decorated with ester
functional group that is a promising site for further modification.
Available online
2019 Elsevier Ltd. All rights reserved.
Keywords:
Vinyl azides
Amidines
Polyfunctional imidazoles
Leaving group
———
Corresponding author. Tel.: +86-571-88208450; fax: +86-571-88208450; e-mail: wentengchen@zju.edu.cn
Corresponding author. Tel.: +86-571-88208452; fax: +86-571-88208452; e-mail: yyu@zju.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
1. Introduction
2. Results and discussion
Imidazoles are of highly importance in natural products and
Initially, vinyl azide 1d and benzamidine 2a were selected to
optimize the reaction conditions (Table 1). It was found that the
desired imidazole 3d was obtained with the yield of 49% in
MeCN at 80 oC (Table 1, entry 1). However, additives (Et3N and
K2CO3) were not favour for this transformation (Table 1, entries
2-3). Only a trace of the 3d was obtained in the presence of Et3N
and the reaction failed to proceed when K2CO3 was used as the
additive. This is much different from our previous work.3a
pharmaceuticals. Compounds with the imidazole core possess
1a
various biological activities, such as antitumor,
antimicrobials1b-1d and antioxidants. 1e And the substituents on the
imidazole ring have a huge impact on the chemical and biological
properties of the resultant molecules.1f-1g Therefore, some
strategies have been developed for the synthesis of
polyfunctional imidazoles, such as C−H amination of N-Alkyl
2a
enamines,
ZnCl2 catalyzed [3
+
2] cycloaddition of
Table 1. Optimization of the reaction conditions a
2b
benzimidates and 2H-azirines,
copper-mediated three-
2c
component reaction of ketones, aldehydes, and Me3SiN3 and et
al. Despite enormous attentions have been focused on effective
construction of polyfunctional imidazoles, the universal
biological activities make the pursue of new approaches from
easily available reagents for the synthesis of imidazoles.
Entry
1
Additive
—
R
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOH
T (oC)
80
Yield(%)b
49
Vinyl azide is a well-developed three-atom synthon and plays
a significant role in the construction of aza-heterocycles in recent
years. Our group and others have developed a range of strategies
for the aza-heterocycles synthesis including 4-aminopyridines, 3a
polyfunctional anilines, 3b polyfunctional pyrazoles, 3c pyrrolo [1,
2-α] pyrazine, 3d thiazoles3e and others.3f -3j
Boc
Boc
Boc
Boc
Boc
2
Et3N
K2CO3
—
80
trace
n.r
3
80
4
100
120
60
62
5
—
81
6
—
21
Boc
Boc
7
—
25
n.r
8
—
80
n.r
Boc
Boc
Boc
Boc
9
—
DMF
80
21
10
11
12
13
14
—
Toluene
1,4-Dioxane
DCE
80
19
—
80
53
—
80
71
Boc
CBz
MeCN
MeCN
MeCN
120
120
120
68
—
—
—
Ts
H
10
15
n.r
a
Unless otherwise noted, the reactions were carried out with vinyl
azide 1a (0.3 mmol) and amidine 2 (0.3 mmol) heating in solvent (1.0
mL) in the presence or absence of the additive (0.1 mmol) for 12 h
(sealed tubes). b Isolated yields.
Scheme 1. The reactivity between vinyl azides and amidines
Previously, we have developed an approach for the synthesis
of 5-aminopyrimidines from a-azidovinyl ketones and amidines.4
In this work, the intramolecular Michael addition of amidine to
the azidovinyl ketone occurred in the presence of K2CO3.The N3
group was not involved in the formation of pyrimidine ring and
transferred to amino group. Others also reported the synthesis of
disubstituted imidazoles from vinyl azides and amidine with the
addition of DBU.5 The reaction undergoes cyclization by the loss
of N2 of vinyl azides and a subsequent elimination of ammonia
giving the desired product. And the β-position substitution of
vinyl azides did not tolerate in this reaction. For further
understanding the promising chemical reactivity of vinyl azides,
we study the possible reaction between vinyl azides (bearing with
an ester group at the R2 position) and amidine. Surprising, the
reaction gave the formation of polyfunctional imidazoles as the
major product and the N3 group did involve in the formation of
imidazole ring along with the leaving of NH-Boc. Moreover, the
affording imidazoles possess the functional group ester that
would be capable for further modification with diverse biological
activities (Scheme 1). 1h
And the reaction temperature is another important factor for
this reaction. The reaction yields would be increased to 81%
when the reaction was performed in a seal tube at 120 C (Table
o
1, entry 5), while the reaction did not proceeded well when the
reaction temperature lowered to 60 oC and 25 oC (Table 1, entries
6-7). Furthermore, the reaction solvents including EtOH, DMF,
toluene, 1, 4-dioxane and DCE were screened (Table 1, entries 8-
12). And MeCN shows the best one with the highest yield of
81%. As the proposed mechanism, we also tested the leaving
capability of other substitutions, including NHCBz and NHTs
(Table 1, entries 13-14). The reaction could be proceed although
with a lower reaction yield, 68% and 10% respectively. The
reaction failed to proceed when benzamidine was used as
substrate, thus indicating the importance of NH2 protection
(Table 1, entry 15). In all, we have obtained the optimized
reaction conditions in MeCN at 120 oC without any additives.
Next, the generality of the synthesis of polyfunctional
imidazoles was explored using a series of vinyl azides 1 and

3
NHBoc-amidines
2
. As shown in table 2, various substituted
To validate the process for scale-up studies, we performed
ACCEPTED MANUSCRIPT
vinyl azides worked well to provide the corresponding
imidazoles in moderate to excellent yields. The steric and
electronegativity effects were also investigated.
the reaction of 1a with 2a under optimal conditions and obtained
the corresponding product 3a in 59% yield (Scheme 2). This
study indicates the feasibility of the method for industrial
production.
Table 2. Substrate scope of vinyl azides and NHBoc-amidine
a
NH
NHBoc
H
N
R2
R1
R2
MeCN
R1
+
120 oC, 12 h
N3
R
R
N
2
1
3
Scheme 2. Gram scale preparation
To gain insight into the reaction mechanism for the
formation of 3a, we conducted the control experiments using
3b (78%)
3c (79%)
3f (n.r)
3a (81%)
3d (70%)
2
H
-aziridine in the replacement of vinyl azide 1a
3). The formation of 2 -aziridines from thermolysis of vinyl
azides has been reported before.6 As expected, the reaction
of 2 -aziridine and 2a went smoothly to give the desired
(Scheme
H
H
product 3a with 83% yield.
3e (63%)
3g (72%)
3j (62%)
3h (trace)
3k (43%)
3n (67%)
3i (60%)
3l (52%)
3o (76%)
Scheme 3. Control reaction9
3m (51%)
3p (43%)
3s (70%)
Based on these observations, a possible mechanism for
the formation of
conditions, vinyl azides was first transformed into the
corresponding 2 -aziridines by an elimination of N2. The
imino carbon of 2 -aziridine undergoes nucleophilic attack
by NHBoc-amidine to generate intermediate . A
3 is proposed in Scheme 4. Under thermal
EtOOC
NH
MeO
MeO
N
H
OMe
H
3q (49%)
3t (58%)
3r (45%)
2
I
subsequent intramolecular nucleophilic attack occurred by
the loss of BocNH2. Finally, the strained three-membered
ring of intermediate II is opened to obtain the imidazole 3.
3u (61%)
a Reaction conditions: vinyl azides 1 (1.0 mmol), NHBoc-amidine 2 (1.0
mmol) in MeCN (2 mL) heated in a sealed tube (120 °C, 12 h). Yields
shown are those of the isolated products.
Vinyl azides with either aryl or alkyl substituents could work
well in the reaction conditions in moderate to good yields. And
electron-donating groups (Me and OEt) and electron-
withdrawing groups (Br, CN and CF3) on aryl ring of R1 are well
tolerated in the transformation. It seems that strong electron-
withdrawing group such as NO2 may have detrimental effect on
the formation of unstable intermediate (3h). The heterocyclic
substitutions on R1 were also tolerated in the reaction though
with lower yields. For example, furyl (3k), thienyl (3l) and
pyridyl (3m) substitutions affords the desired imidazoles with the
yields of 43%, 52% and 51%, respectively. Moreover, the scopes
of NHBoc-amidine 2 were also investigated. It was found that
either electron-donating (Me) or electron-withdrawing (Cl) group
on aryl ring of R, is compatible. The desired products were
obtained as expected (3o-3u) with isolated yields of 43-76%.
Scheme 4. A possible reaction mechanism
Conclusions
In conclusion, we have demonstrated an efficient method
for the synthesis of 2, 4, 5-trisubstituted imidazoles from
vinyl azides and NHBoc-amidines without any additives. This
transformation involved a thermolysis formation of aziridine
from vinyl azides and a leaving of NHBoc group. Moreover, the
method could easily construct an imidazole scaffold bearing the

4
Tetrahedron
functional ester group that would be capable for further
(ESI): m/z calcd for (C20H20N2O3+H) +: 337.1552; found:
ACCEPTED MANUSCRIPT
modification.
337.1552.
4. Experiment sections
4.1 General Information:
4.2.4. Ethyl
carboxylate (3d)
4-(4-bromophenyl)-2-phenyl-1H-imidazole-5-
o
1
White solid, 259 mg, yield: 70%. m.p.: 158.0-159.3 C. H
NMR (500 MHz, CDCl3) δ 10.33 (s, 1H), 7.97 (d, J = 6.3 Hz,
2H), 7.88 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.50 –
7.43 (m, 3H), 4.35 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 160.5, 148.2, 147.3, 132.5, 131.3,
131.2, 130.3, 129.2, 128.9, 126.3, 122.9, 118.9, 61.6, 14.50.
HRMS (ESI): m/z calcd for (C18H15BrN2O2+H) +: 371.0395;
found: 371.0398.
Unless otherwise noted, all reagents were obtained from
commercial suppliers and used without any purification. All
solvents were purified according to standard methods prior to use.
Purifications of reaction products were carried out by
chromatography using silica gel (200-300 mesh). Melting points
were recorded on a melting point apparatus. NMR spectra were
recorded for 1H NMR at 500 MHz and for 13C NMR at 125 MHz.
For 1H NMR, tetramethylsilane (TMS) served as internal
standard (δ=0) and data are reported as follows: chemical shift,
integration, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), and coupling constant(s) in Hz. For 13C
NMR, TMS (δ=0) or CDCl3 (δ=77.26) was used as internal
standard and spectra were obtained with complete proton
decoupling. HPLC analysis and the HRMS of all biologically
evaluated compounds was confirmed on a Agilent 1290 HPLC-
6224 Time of Fight Mass Spectrometer using PhenomenexLuna
5ꢀ C18, 100 Å, 150 × 4.60 mm 5 micron column at a flow rate of
0.5 mL/min using liner gradients buffer B in A (B: CH3OH
containing 0.1 % formic acid, A: H2O containing 0.1% formic
acid). Mobile phase B was increased linearly from 5% to 95%
over 7 min and 95% over the next 2 min, after which the column
was equilibrated to 5% for 1 min. The starting material 1 and 2
were prepared according to literature methods.7, 8
4.2.5.
Ethyl
4-(3-bromophenyl)-2-phenyl-1H-imidazole-5-
carboxylate (3e)
o
1
White solid, 233 mg, yield: 63%. m.p.: 140.7-142.6 C. H
NMR (500 MHz, CDCl3) δ 10.32 (s, 1H), 8.16 (t, J = 1.7 Hz,
1H), 7.99 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.95-7.92
(m, 1H), 7.52 – 7.45 (m, 4H), 7.30 (t, J = 7.9 Hz, 1H), 4.37 (q, J
= 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 160.6, 148.3, 146.7, 135.6, 132.7, 131.6, 130.3, 129.6,
129.3, 128.9, 128.3, 126.3, 122.0, 119.3, 61.7, 14.4. HRMS
(ESI): m/z calcd for (C18H15BrN2O2+H) +: 371.0395; found:
371.0398.
4.2.6.
Ethyl
4-(4-cyanophenyl)-2-phenyl-1H-imidazole-5-
carboxylate (3g)
o
1
White solid, 228mg, yield: 72%. m.p.: 148.2-146.9 C. H
NMR (500 MHz, CDCl3) δ 10.34 (s, 1H), 8.16 (d, J = 8.3 Hz,
2H), 8.05 – 7.95 (m, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.53-7.43 (m,
3H), 4.38 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 160.1, 148.4, 146.2, 138.1, 131.9, 130.6,
130.2, 129.3, 128.7, 126.3, 119.8, 119.3, 111.9, 61.8, 14.5.
HRMS (ESI): m/z calcd for (C19H15N3O2+H) +: 318.1243; found:
318.1247.
4.2 General Procedure for the Synthesis of 3
A mixture of vinyl azide 1 (1.0 mmol) and NHBoc-amidine
2
(1.0 mmol, 1.0 equiv.) was stirred in MeCN (2 mL) in a sealed
o
tube at 120 C (the temperature of oil bath) for 12.0 h. The
reaction mixture was quenched with water (25 mL), and then
extracted three times with EtOAc. The combined organic layer
was collected and washed with brine, dried over MgSO4 and
concentrated. The crude product was purified by chromatography
using PE / EtOAc to afford 3a-3u.
4.2.7. Ethyl 2-phenyl-4-(3, 4, 5-trimethoxyphenyl)-1H-imidazole-
5-carboxylate (3i)
o
1
4.2.1. Ethyl 2, 4-diphenyl-1H-imidazole-5-carboxylate (3a)
White solid, 229 mg, yield: 60%. m.p.: 203.2-204.8 C. H
NMR (500 MHz, CDCl3) δ 10.06 (s, 1H), 7.98 (d, J = 7.0 Hz,
2H), 7.56 – 7.44 (m, 3H), 7.38 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H),
3.93 (s, 6H), 3.89 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 160.2, 152.9, 148.4, 147.6, 138.7, 130.3, 129.2,
129.0, 127.7, 126.2, 118.5, 106.9, 61.3, 61.2, 56.4. 14.7. HRMS
(ESI): m/z calcd for (C21H22N2O5+H) +: 383.1607; found:
383.1606.
o
1
White solid, 237 mg, yield: 81%. m.p.: 156.2-159.1 C. H
NMR (500 MHz, CDCl3) δ 10.26 (s, 1H), 7.97 (s, 4H), 7.56 –
7.32 (m, 6H), 4.34 (q, J = 7.0 Hz, 2H), 1.32 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 160.5, 148.6, 133.6, 130.2, 129.7, 129.2,
128.7, 128.0, 126.3, 118.8, 61.4, 14.5. HRMS (ESI): m/z calcd
for (C18H16N2O2+H) +:293.1290; found: 293.1291.
4.2.2. Ethyl 2-phenyl-4-(p-tolyl)-1H-imidazole-5-carboxylate
(3b)
4.2.8.
Ethyl
2-phenyl-4-(3-(trifluoromethyl)
phenyl)-1H-
imidazole-5-carboxylate (3j)
o
1
White solid, 239 mg, yield: 78%. m.p.: 229.2-230.4 C. H
NMR (500 MHz, CDCl3) δ 10.21 (s, 1H), 7.96 (s, 2H), 7.87 (s,
2H), 7.44 (s, 3H), 7.22 (d, J = 7.5 Hz, 2H), 4.34 (q, J = 7.0 Hz,
2H), 2.39 (s, 3H), 1.33 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 160.7, 147.9, 138.7, 130.0, 129.5, 129.3, 129.2, 128.8,
126.2, 61.2, 21.6, 14.5. HRMS (ESI): m/z calcd for
(C19H18N2O2+H) +: 307.1447; found: 307.1447.
o
1
White solid, 223 mg, yield: 62%. m.p.: 189.3-191.4 C. H
NMR (500 MHz, CDCl3) δ 10.55 (s, 1H), 8.26 (s, 1H), 8.17 (d, J
= 7.7 Hz, 1H), 8.09 – 7.95 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.55
(t, J = 7.8 Hz, 1H), 7.52-7.39 (m, 3H), 4.36 (q, J = 7.1 Hz, 2H),
1.32 (t, J = 7.1 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 160.7,
148.5, 146.7, 132.9, 130.4, 129.2, 128.9, 128.6, 126.7, 126.7,
126.4, 125.3, 125.3, 119.4, 61.8, 14.3. HRMS (ESI): m/z calcd
for (C19H15F3N2O2+H) +: 361.1164; found: 361.1168.
4.2.3.
Ethyl
4-(4-ethoxyphenyl)-2-phenyl-1H-imidazole-5-
carboxylate (3c)
4.2.9. Ethyl 4-(furan-2-yl)-2-phenyl-1H-imidazole-5-carboxylate
(3k)
o
1
White solid, 299 mg, yield: 89%. m.p.: 176.3-177.2 C. H
NMR (500 MHz, CDCl3) δ 10.23 (s, 1H), 7.95 (d, J = 5.4 Hz,
4H), 7.43 (s, 3H), 6.92 (s, 2H), 4.33 (dd, J = 8.2, 3.4 Hz, 2H),
4.07 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H), 1.32 (t, J = 6.7
Hz, 3H). 13C NMR (125 MHz, CDCl3) δ159.6, 147.7, 130.9,
130.0, 129.3, 129.1, 126.2, 114.2, 63.7, 61.1, 15.1, 14.5. HRMS
o
Pale yellow solid, 121 mg, yield: 43%. m.p.: 221.7-224.9 C.
1H NMR (500 MHz, CDCl3) δ 10.16 (s, 1H), 8.00 (s, 1H), 7.95
(s, 1H), 7.58 (s, 1H), 7.50 – 7.35 (m, 4H), 6.54 (s, 1H), 4.49 –
4.37 (m, 2H), 1.43 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,

5
CDCl3) δ 159.8, 143.1, 142.6, 130.3, 129.8, 129.1, 126.3, 125.9,
4.2.16. Ethyl 2-(p-tolyl)-4-(3, 4, 5-trimethoxyphenyl)-1H-
imidazole-5-carboxylate (3r)
ACCEPTED MANUSCRIPT
113.2, 112.8, 112.1, 111.7, 61.4, 14.6. HRMS (ESI): m/z calcd
for (C16H14N2O3+H) +: 283.1083; found: 283.1083.
o
1
White solid, 178 mg, yield: 45%. m.p.: 220.3-221.4 C. H
NMR (500 MHz, CDCl3) δ 10.23 (s, 1H), 7.88 (d, J = 7.7 Hz,
2H), 7.34 (s, 2H), 7.27 (s, 1H), 7.26 (s, 1H), 4.35 (q, J = 7.1 Hz,
2H), 3.92 (s, 6H), 3.88 (s, 3H), 2.40 (s, 3H), 1.33 (t, J = 7.0 Hz,
3H). 13C NMR (125 MHz, CDCl3) δ 160.5, 152.9, 148.3, 147.9,
140.5, 138.6, 129.9, 129.7, 129.0, 126.2, 118.2, 106.9, 61.3, 61.1,
4.2.10.
Ethyl
2-phenyl-4-(thiophen-2-yl)-1H-imidazole-5-
carboxylate (3l)
o
1
White solid, 156 mg, yield: 52%. m.p.: 148.6-149.7 C. H
NMR (500 MHz, CDCl3) δ 10.19 (s, 1H), 8.10 (s, 1H), 7.97 (d, J
= 6.6 Hz, 2H), 7.50-7.38 (m, 3H), 7.39 (dd, J = 5.1, 1.0 Hz, 1H),
7.12 (dd, J = 5.0, 3.8 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J
= 7.1 Hz, 3H).13C NMR (125 MHz, CDCl3) δ 160.4, 147.9,
142.6, 136.6, 130.3, 129.2, 128.8, 128.5, 127.7, 127.2, 126.4,
117.3, 61.5, 14.7. HRMS (ESI): m/z calcd for (C16H14N2O2S+H)
+:299.0854; found: 299.0855.
+
56.4, 21.7, 14.7. HRMS (ESI): m/z calcd for (C22H24N2O5+H) :
397.1763; found: 397.1763.
4.2.17. Ethyl 2, 4-di-p-tolyl-1H-imidazole-5-carboxylate (3s)
o
1
White solid, 224 mg, yield: 70%. m.p.: 228.8-230.4 C. H
NMR (500 MHz, CDCl3) δ 10.13 (s, 1H), 7.84 (d, J = 7.1 Hz,
4H), 7.26 – 7.09 (m, 4H), 4.33 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H),
2.39 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 160.5, 148.3, 140.2, 138.6, 129.8, 129.5, 128.8, 126.4,
126.1, 61.2, 21.7, 21.6, 14.50. HRMS (ESI): m/z calcd for
(C20H20N2O2+H) +: 321.1603; found: 321.1600.
4.2.11.
Ethyl
2-phenyl-4-(pyridin-2-yl)-1H-imidazole-5-
carboxylate (3m)
o
1
White solid, 149 mg, yield: 51%. m.p.: 204.4-205.2 C. H
NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 8.86 (d, J = 7.6 Hz,
1H), 8.53 (s, 1H), 7.96 (d, J = 6.8 Hz, 2H), 7.80 (t, J = 7.4 Hz,
1H), 7.44 – 7.38 (m, 3H), 7.26 – 7.17 (m, 1H), 4.48 (d, J = 6.8
Hz, 2H), 1.46 (t, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
164.1, 148.8, 147.2, 146.5, 137.4, 136.5, 130.6, 129.9, 129.1,
126.2, 124.5, 123.6, 61.4, 14.6. HRMS (ESI): m/z calcd for
(C17H15N3O2+H) +: 294.1243; found: 294.1245.
4.2.18.
Ethyl
2-(4-chlorophenyl)-4-phenyl-1H-imidazole-5-
carboxylate (3t)
o
1
White solid, 189 mg, yield: 58%. m.p.: 182.9-184.0 C. H
NMR (500 MHz, CDCl3) δ 10.57 (s, 1H), 7.92 (s, 3H), 7.79 –
7.25 (m, 6H), 4.32 (d, J = 6.0 Hz, 2H), 1.30 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 160.8, 148.7, 147.1, 136.2, 133.4, 129.7,
129.4, 128.8, 128.1, 127.6, 119.0, 61.5, 14.3. HRMS (ESI): m/z
calcd for (C18H15ClN2O2+H) +: 327.0900; found: 327.0903.
4.2.12. Ethyl 2-phenyl-4-propyl-1H-imidazole-5-carboxylate (3n)
o
1
White solid, 173 mg, yield: 67%. m.p.: 167.5-169.1 C. H
NMR (500 MHz, CDCl3) δ 7.92 (d, J = 5.9 Hz, 2H), 7.36 (s, 3H),
4.51 – 4.21 (m, 2H), 2.89 (t, J = 7.0 Hz, 2H), 1.48 – 1.12 (m,
5H), 1.00 – 0.79 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 164.9,
147.2, 129.6, 129.5, 129.0, 126.1, 61.4, 60.8, 29.9, 23.2, 14.6,
4.2.19. Ethyl 2-(4-chlorophenyl)-4-(p-tolyl)-1H-imidazole-5-
carboxylate (3u)
o
1
White solid, 208 mg, yield: 61%. m.p.: 190.5-191.3 C. H
NMR (500 MHz, CDCl3) δ 10.52 (s, 1H), 7.90 (s, 2H), 7.81 (s,
2H), 7.40 (s, 2H), 7.20 (s, 2H), 4.30 (s, 2H), 2.38 (s, 3H), 1.30 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 161.1, 147.0, 138.6, 136.0,
130.9, 129.8, 129.4, 129.3, 128.8, 128.2, 127.7, 127.5, 126.1,
61.3, 21.6, 14.4. HRMS (ESI): m/z calcd for (C19H17ClN2O2+H)
+:341.1057; found: 341.1056.
+
14.1. HRMS (ESI): m/z calcd for (C15H18N2O2+H) :259.1447;
found: 259.1444.
4.2.13. Ethyl 4-phenyl-2-(p-tolyl)-1H-imidazole-5-carboxylate
(3o)
o
1
White solid, 233 mg, yield: 76%. m.p.: 203.2-203.9 C. H
NMR (500 MHz, CDCl3) δ 10.14 (s, 1H), 7.96 (s, 2H), 7.85 (s,
2H), 7.39 (m, 3H), 7.26 (s, 2H), 4.34 (q, J =7.0 Hz, 2H), 2.40 (s,
3H), 1.32 (t, J = 6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
160.7, 148.3, 140.3, 129.9, 129.6, 128.7, 128.1, 126.4, 126.1,
+
61.2, 21.7, 14.5. HRMS (ESI): m/z calcd for (C19H18N2O2+H) :
307.1447; found: 307.1446.
Acknowledgments
4.2.14. Ethyl 4-(4-bromophenyl)-2-(p-tolyl)-1H-imidazole-5-
carboxylate (3p)
This work was supported from the National Key R&D
Program of China (No.2017YFE0102200), National Natural
Science Foundation of China (No. 81673291), and Arthritis &
Chronic Pain Research Institute, USA to Y. Yu; Natural
Sciences Foundation of Zhejiang Province (No. LY18H300001)
to W. Chen.
o
1
White solid, 165 mg, yield: 43%. m.p.: 181.2-182.4 C. H
NMR (500 MHz, CDCl3) δ 10.14 (s, 1H), 7.85 (d, J = 8.0 Hz,
4H), 7.54 (d, J = 8.5 Hz, 2H), 7.28 (s, 1H), 7.26 (s, 1H), 4.35 (q,
J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 161.4, 148.2, 147.4, 140.6, 131.3, 131.2,
129.9, 126.2, 126.1, 122.9, 61.4, 21.7, 14.5. HRMS (ESI): m/z
calcd for (C19H17BrN2O2+H) +:385.0555; found: 385.0552.
Supporting Information
1
Supplementary data (characterization data, and copies of H
and 13C NMR spectra for all products) associated with this article
can be found in the online version, at http://dx.doi.org/
4.2.15.
Ethyl
4-(pyridin-2-yl)-2-(p-tolyl)-1H-imidazole-5-
carboxylate (3q)
o
1
White solid, 150 mg, yield: 49%. m.p.:175.3-177.3 C. H
NMR (500 MHz, CDCl3) δ 11.45 (s, 1H), 8.84 (s, 1H), 8.53 (s,
1H), 7.85 (d, J = 7.9 Hz, 2H), 7.80-7.77 (m, 1H), 7.22 (t, J = 6.4
Hz, 3H), 4.46 (d, J = 5.4 Hz, 2H), 2.36 (s, 3H), 1.44 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 164.1, 148.8, 147.4, 146.7, 140.0,
137.3, 129.7, 126.3, 126.1, 124.5, 123.5, 61.4, 21.6, 14.6. HRMS
(ESI): m/z calcd for (C18H17N3O2+H) +: 308.1399; found:
308.1396.
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1
9． 2H-azirine (A), Yellow oil; H NMR (500 MHz, CDCl3) δ 7.35-7.30
(m, 3H), 7.15 – 7.13 (m, 2H), 4.51-4.46 (m, 2H), 3.47 (s, 1H), 1.42 (t, J
= 7.1 Hz, 3H).