Synthesis of 2-Imidazolines via Palladium-Catalyzed Cyclization Reaction of 2,3-Allenyl Amines and Aryl Iodides

Article abstract of DOI:10.1055/s-0037-1610742

An effective method for the synthesis of polysubstituted 2-imidazoline derivatives via palladium-catalyzed cyclization of 2,3-allenyl amines with aryl iodides is described. This pure domino process allows the formation of new carbon-carbon and carbon-nitrogen bonds in a single synthetic operation.

Full text of DOI:10.1055/s-0037-1610742

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–H
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A
en
Y. Liu et al.
Paper
Synthesis
Synthesis of 2-Imidazolines via Palladium-Catalyzed Cyclization
Reaction of 2,3-Allenyl Amines and Aryl Iodides
Yue Liu
Cheng Zhang
Ts
R1
NTs
Pd(PPh3)4
N
R1I
Xiaoxia Liang
Xianzhong Zeng
Rongmei Lu
Zixuan Fang
Shaoyu Wang
Yanjun Liu
+
K2CO3/THF
R2
N
H
R2
N
19 examples: 48–78%
* Low toxicity
* form C–C and C–N
* Readily available substrates
Jinxing Hu*
0
0
0
0-0
0
0
1-
7
1
7
3-0
5
9
4
School of Pharmacy, Weifang Medical University,
Weifang, 261053, P. R. of China
jinxinghu2013@wfmc.edu.cn
Received: 30.09.2019
Accepted after revision: 17.12.2019
Published online: 09.01.2020
palladium-catalyzed functionalization of allenes to synthe-
size imidazolines remains extremely challenging. Inspired
by our group’s reported synthesis of imidazolidines deriva-
tives via Pd-catalyzed cyclization reaction,15 in this article
we describe the application of a Pd-catalyzed cyclization
reaction to synthesize polysubstituted 2-imidazoline deriv-
atives from 2,3-allenyl amines and aryl iodides (Scheme 1,
Eq 4).
DOI: 10.1055/s-0037-1610742; Art ID: ss-2019-h0558-op
Abstract An effective method for the synthesis of polysubstituted 2-
imidazoline derivatives via palladium-catalyzed cyclization of 2,3-allenyl
amines with aryl iodides is described. This pure domino process allows
the formation of new carbon–carbon and carbon–nitrogen bonds in a
single synthetic operation.
Initially, we investigated the cyclization reaction of N-
(buta-2,3-dien-1-yl)-N'-tosylbenzimidamide (1a) and iodo-
benzene (2a), using Pd(PPh3)4 as the catalyst and K2CO3 as
the base, to obtain 2-imidazoline 3aa with a isolated yield
of 61% (Table 1, entry 1). Subsequently, the effects of palla-
dium catalysts were examined; thus, Pd(OAc)2,
Pd(PPh3)2Cl2, Pd(CF3COO)2 and Pd(dppf)Cl2, were examined,
but the yields were slightly lower (entries 2–5). Our re-
search confirmed that the reaction did not proceed without
Pd catalyst (entry 6). The influence of the solvent and tem-
perature were then studied (entries 7–11 and 17), and THF
was determined to be the most suitable solvent for the
Key words allenes, amines, cyclization, imidazoline, palladium
2-Imidazoline heterocyclic compounds have high me-
dicinal value and a variety of catalytic applications in biolo-
gy. Indeed, anti-hypertensive,1 antihyperglycemic,2 anti-
depressive,3 antihypercholesterolemic,4 and anti-inflamma-
tory5 activities have been reported for these compounds.
Illustrative examples include P2X7 ion channel blocker I for
treating inflammation conditions,6 estrogen receptor mod-
ulator II for oncology applications,7 proteasome inhibitor III
for multiple myeloma,8 and nutlin-3 (IV),9 which disrupts
oncogenic p53-mdm2 protein–protein interactions (Figure
1).
OH
The group of Shunsuke Chiba explored a new strategy of
organic catalysis to synthesize 2-imidazolines with
Cu(OAc)2 as a catalyst in the presence of K3PO4 and
PhI(OAc)2 (Scheme 1, Eq. 1).10 The authors subsequently re-
ported a copper-catalyzed synthesis of 2-imidazolines
through amination with amidoximes (Scheme 1, Eq. 2).11
Zhou’s group reported a convenient method for the synthe-
sis of a variety of imidazolines and tetrahydropyrimidines
by lanthanide-catalyzed direct cycloamidination of amino-
alkenes and nitriles (Scheme 1, Eq. 3).12
HO
Cl
N
Cl
N
N
H
Cl HN
II
I
O
H
Cl
Cl
O
N
N
N
NH
Ph
N
N
OMe
MeO
COOEt
N
O
In recent years, the synthesis of various heterocyclic
compounds from functionalized allenes has attracted the
interest of many scientists.13–16 Among the approaches,
III
IV
Figure 1 Examples of biologically active 2-imidazolines
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Liu et al.
Paper
Synthesis
viding the possibility of further conversion. It is worth not-
ing that when the phenyl ring was substituted with 2-thie-
nyl (3al, 78%), the yield of the reaction increased. In addi-
tion to aryl iodides, we also tested aliphatic iodides, such as
methyl iodide and n-butyl iodide (3am), but did not obtain
the corresponding product.
previous work
PhI(OAc)2, Cu(OAc)2
K3PO4
N
(1)
(2)
N
N
DMF, rt
NH
We then investigated the Pd-catalyzed cyclization reac-
tion using iodobenzene (2a) and different 2,3-allenyl
amines 1 under the standard conditions (Scheme 3). Irre-
spective of whether electron-withdrawing or electron-do-
nating substituents were present, the corresponding com-
pounds were obtained in moderate yield. In general, elec-
tron-donating substituents on the phenyl ring, such as
methoxyl (3ba), tended to reduce the yield, whereas elec-
tron-withdrawing substituents such as halogen (3ca–da) or
CF3 (3fa), enhanced the yield. The reaction with the aryl
group having a sensitive ester group also proceeded
smoothly, and the desired product 3ea was obtained in 65%
yield. In addition, 2-thienyl-substituted and 1-iodonaph-
thalene-substituted 2,3-allenyl amine were also tested on
the reaction and the expected products 3ga and 3ha were
R3
N
R4
OAc
N
CuI, K3PO4
N
R4
R1
N
toluene, 100 °C
R1
R2 R3
R2
R2
Ln[N(SiMe3)2]3 (5 mol%)
toluene, rt to 80 °C, 3–24 h
R
N
R3
H
N
R3
N
R1
(3)
X
RCN
R1
X
R2
x = 1, 2
this work
Ts
N
Pd(PPh3)4
NTs
(4)
+
PhI
N
K2CO3/THF
N
H
Table 1 Optimization of Reaction Conditionsa
Scheme 1 Selected synthetic methods for 2-imidazolines
Ts
NTs
N
cat.
N
H
+
PhI
N
reaction. To further improve the efficiency of the reaction, a
range of bases were investigated (entries 12–16). During
screening, neither weaker (entries 12–13) nor stronger base
(entries 14–16) produced more of the desired target com-
pound 3aa. Accordingly, it was established that the opti-
mized reaction conditions were 1a (1.0 equiv) and 2a (1.2
equiv) with K2CO3 (3.0 equiv) in THF at 85 °C using
[Pd(PPh3)4] (5 mol%) as catalyst.
After establishing appropriate reaction conditions, we
further explored the scope of the method. The results of the
coupling–cyclization of 1a with various aryl iodides 2 are
summarized in Scheme 2. We found that aryl iodides are
good model coupling partners, which can produce the de-
sired products in moderate to good yields. Herein, we spe-
cifically describe the effect of different substituents on the
phenyl ring on the reaction.
Generally, electron-donating substituents on the phenyl
ring, such as methoxy (Scheme 2, 3ab–ac) and methyl
groups (3ad–af), increased the yield, while electron-with-
drawing substituents, such as halides (3ag–ai), reduced the
yield. The reaction with the aryl iodide of carbonyl group
also proceeded smoothly, and the desired product 3aj was
obtained in 61% yield, indicating that the conversion was
not affected by the COCH3 group. It was also found that
even with a strong electron-withdrawing substituent (CF3)
on the aromatic ring, the reaction proceeded smoothly to
give the desired product (3ak). We also found that the dif-
ferent positions of the substitution on the aromatic ring
had only a slight effect on the reaction (3ab–af), thus pro-
base
1a
2a
3aa
Entry
Cat
Base
K2CO3
Solvent
Yield (%)b
1
2
Pd(PPh3)4
Pd(OAc)2
THF
61
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CsF
THF
46
3
Pd(PPh3)2Cl2
Pd(CF3COO)2
Pd(dppf)Cl2
–
THF
43
4
THF
50
5
THF
52
6
THF
n.d.c
trace
35
7
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
DCM
toluene
dioxane
DMF
H2O
8
9
55
10
11
12
13
14
15
16
17
37
28
THF
31
Cs2CO3
t-BuOLi
NaOH
NaH
THF
42
THF
25
THF
n.d.c
23
THF
K2CO3
THFd
65
a Reaction conditions: Under a N2 atmosphere, 1a (0.25 mmol, in 3 mL
THF), PhI (1.2 equiv), base (3.0 equiv), and [Pd0] (5 mol%) at reflux.
b Isolated yield.
c n.d.= not detected.
d Reaction carried out in a tube with a screw cap in 85 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

C
Y. Liu et al.
Paper
Synthesis
Ts
NTs
N
Ar
[Pd(PPh3)4] (5 mol%)
N
+
ArI
N
K2CO3 (3.0 equiv)
THF, 85 °C, 24 h
H
1a
2
3
O
Ts
N
Ts
N
Ts
N
O
N
N
N
3aa, 65%
3ab, 73%
3ac, 70%
Ts
N
Ts
N
Ts
N
N
N
N
3ad, 70%
3ae, 75%
3af, 68%
Ts
N
Ts
N
Br
F
Ts
N
Cl
N
F
N
N
3ag, 60%
3ah, 63%
3ai, 53%
Ts
N
Ts
N
Ts
N
S
N
CF3
N
N
O
3aj, 61%
3ak, 46%
3al, 78%
Ts
N
R1
N
3am, trace
R1= Methyl, 1-Butyl
Scheme 2 Substrate scope of aryl iodides. Reagents and conditions: 1a (0.22 mmol, in 3 mL THF), Pd(PPh3)4 (5 mol%), 2 (1.2 equiv), K2CO3 (3.0 equiv),
N2 atmosphere. Isolated yields given.
obtained in 56% and 48% yields, respectively. Aliphatic-sub-
stituted 2,3-allenyl amine was not suitable for this process
and the corresponding imidazoline 3ia was not obtained.
This indicated that aliphatic-substituted allenyl amines are
not good coupling partners.
To investigate the mechanism of the cyclization reac-
tion, we conducted a number of control experiments. When
a radical scavenger (TEMPO or BHT) was added to the reac-
tion system under the standard conditions, the reaction still
proceeded smoothly (Scheme 4, Eq. 1 and Eq. 2) to give the
product. These results indicate that the reaction does not
proceed via a radical mechanism.
First, oxidative addition of the aryl iodide to Pd0 affords
aryl-Pd species A, which adds to the central carbon of al-
lene moiety to provide -allyl species B. The intermediate B
under base conditions then affords the intermediate C. Fi-
nally, intermediate C undergoes intramolecular nucleophil-
ic attack of the nitrogen atom to afford the product 3, there-
by releasing the active catalytic species.
In summary, we have developed an efficient method to
synthesize polysubstituted 2-imidazoline derivatives. The
reaction has a good tolerance range and provides a synthet-
ic route to important heterocyclic compounds, thereby pro-
moting the development of catalysis of allenes. Further re-
search on allene chemistry to extend the range of hetero-
cyclic chemistry is ongoing in our laboratory.
Pd0-catalyzed cyclization reactions of functionalized al-
lenes leading to heterocyclic compounds has been studied
extensively.13–16 In some of these reactions, the allylpalladi-
um intermediate was captured by intramolecular nucleop-
hiles and formed the target product.15,16 In this reaction, the
sulfonyl group is a slightly stronger electron-withdrawing
group, which can generate a nitrogen anion under base
conditions, followed by intramolecular nucleophilic attack.
Therefore, based on experimental results and on previous
reports,13–16 a reaction mechanism is proposed in Scheme 5.
Unless otherwise indicated, all commercial reagents and solvents
were used without additional purification. Reactions were monitored
by thin-layer chromatography (TLC) on silica plates (GF-254) and vi-
sualized under UV light. The melting point was measured on an WRS-1C
melting point (Shanghai ShenGuang Instrument Co., Ltd.) apparatus
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

D
Y. Liu et al.
Paper
Synthesis
[Pd(PPh3)4] (5 mol%)
Ts
N
NTs
PhI
+
R2
Ph
K2CO3 (3.0 equiv)
THF, 85 °C, 24 h
R2
N
H
N
1
2a
3
Ts
Ts
N
Ts
F
N
Br
N
O
N
N
N
Cl
3ba, 59%
3ca, 71%
3da, 68%
O
O
Ts
N
Ts
N
Ts
N
S
F3C
N
N
N
3ea, 65%
3fa, 76%
3ga, 56%
Ts
N
Ts
N
N
N
3ha, 48%
3ia, trace
Scheme 3 Substrate scope of 2,3-allenyl amine. Reagents and conditions: 1 (0.22 mmol, in 3 mL THF), Pd(PPh3)4 (5 mol%), 2a (1.2 equiv), K2CO3
(3.0 equiv), N2 atmosphere. Isolated yields given.
N
Ar
NTs
Ts
standard conditions
TEMPO (2 equiv)
Ar
N
N
Ph
N
H
(1)
(2)
+
+
Ph
PhI
Ph
Ts
2
N
ArI
3
Pd(0)
1a
2a
3aa, 63%
D
Ts
N
NTs
standard conditions
BHT (2 equiv)
NTs
[Pd]
I
PhI
Ph
Ph
Ph
N
H
Ar
Ar
N
A
N
Ar
N
H
1
N
1a
2a
3aa, 60%
Ar
Ts
PdX
Scheme 4 Experiments for mechanistic study
H
N
Ar
C
N
base
N
Ar
with the thermometer unadjusted. 1H and 13C NMR spectra were ac-
quired on a Bruker Avance III 400 MHz spectrometer with DMSO-d6
as the solvent and tetramethylsilane (TMS) as the internal standard.
HRMS was carried out by ESI on a TOF mass analyzer. The reagents
aryl Iodides (2a–m), Pd(PPh3)4, were commercially obtained.
Ts
[Pd]
Ar
HN
Ar
I
Ts
Pd
I
B
Scheme 5 Proposed mechanism
Typical Procedure
2,3-Allenyl amine 1a (50 mg, 0.22 mmol) and iodobenzene 2a (38 mg,
0.26 mmol, 1.2 equiv) were added consecutively to a sealed tube
charged with a mixture of potassium carbonate (64 mg, 0.66 mmol,
3.0 equiv), and [Pd(PPh3)4] (8.9 mg, 0.011 mmol, 5 mol%) in THF (3
mL) under an argon atmosphere. The resulting mixture was stirred at
85 °C for 24 h and the progress of the reaction was monitored by TLC.
Upon completion, H2O (8 mL) was added and the solution was ex-
tracted with CH2Cl2. After evaporation of the solvent, the crude prod-
uct was added to silica gel and the mixture was purified by silica gel
column chromatography (PE/EtOAc = 4:1) to afford the desired prod-
uct 3aa.
2-Phenyl-5-(1-phenylvinyl)-1-tosyl-4,5-dihydro-1H-imidazole
(3aa)
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 4:1) to afford
3aa.
Yield: 40 mg (65%); light-yellow solid; mp 80.2–81.3 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.82–7.26 (m, 13 H), 5.59 (s, 2 H),
5.43 (d, J = 7.5 Hz, 1 H), 3.68 (dd, J = 16.5, 9.4 Hz, 1 H), 3.46 (d, J =
16.5 Hz, 1 H), 2.41 (s, 3 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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Y. Liu et al.
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Synthesis
13C NMR (100 MHz, DMSO-d6):  = 158.72, 146.57, 145.31, 137.18,
135.20, 131.97, 131.57, 130.73, 130.55, 129.72, 129.26, 128.29,
127.63, 121.98, 113.72, 63.10, 60.76, 21.56.
HRMS (ESI-Q-TOF): m/z[M + Na]+ calcd for C24H22N2O2S: 425.1402;
found: 425.1460
2-Phenyl-5-(1-(m-tolyl)vinyl)-1-tosyl-4,5-dihydro-1H-imidazole
(3ae)
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ae.
Yield: 48 mg (75%); light-yellow solid; mp 96.1–97.2 °C.
5-(1-(4-Methoxyphenyl)vinyl)-2-phenyl-1-tosyl-4,5-dihydro-1H-
imidazole (3ab)
1H NMR (400 MHz, DMSO-d6):  = 7.64 (d, J = 7.2 Hz, 2 H), 7.56 (d, J =
8.1 Hz, 3 H), 7.44 (m, 4 H), 7.28 (dd, J = 15.3, 7.6 Hz, 3 H), 7.17 (d, J =
6.7 Hz, 1 H), 5.52 (d, J = 5.3 Hz, 2 H), 5.43 (d, J = 8.0 Hz, 1 H), 3.69 (dd,
J = 16.2, 9.5 Hz, 1 H), 3.45 (dd, J = 16.2, 2.6 Hz, 1 H), 2.41 (s, 3 H), 2.33
(s, 3 H).
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 4:1) to afford
3ab.
13C NMR (100 MHz, DMSO-d6):  = 158.72, 147.72, 145.27, 138.28,
137.97, 135.29, 131.55, 130.82, 130.56, 129.70, 129.32, 128.98,
128.29, 127.67, 127.63, 124.18, 112.68, 63.35, 60.88, 21.56, 21.51.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H24N2O2S: 439.1558;
found: 439.1522.
Yield: 48 mg (73%); light-yellow solid; mp 155.3–156.1 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.64 (d, J = 7.4 Hz, 2 H), 7.55 (d, J =
7.9 Hz, 3 H), 7.44 (m, 6 H), 6.96 (d, J = 8.5 Hz, 2 H), 5.46 (d, J = 8.2 Hz,
2 H), 5.40 (d, J = 8.0 Hz, 1 H), 3.78 (s, 3 H), 3.67 (dd, J = 16.3, 9.5 Hz,
1 H), 3.43 (dd, J = 16.3, 2.2 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 159.70, 158.78, 146.86, 145.27,
135.26, 131.56, 130.85, 130.57, 130.12, 129.72, 128.31, 128.22,
127.63, 114.50, 110.90, 63.21, 60.95, 55.64, 21.56.
2-Phenyl-5-(1-(o-tolyl)vinyl)-1-tosyl-4,5-dihydro-1H-imidazole
(3af)
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H24N2O3S: 455.1508;
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
found: 455.1560.
3af.
5-(1-(2-Methoxyphenyl)vinyl)-2-phenyl-1-tosyl-4,5-dihydro-1H-
Yield: 43 mg (68%); light-yellow solid; mp 151.2–152.1 °C.
imidazole (3ac)
1H NMR (400 MHz, DMSO-d6):  = 7.60 (d, J = 7.2 Hz, 2 H), 7.53 (dd, J =
15.9, 7.9 Hz, 3 H), 7.43 (dd, J = 19.7, 7.8 Hz, 4 H), 7.20 (m, 4 H), 5.66 (s,
1 H), 5.12 (d, J = 8.7 Hz, 1 H), 5.08 (s, 1 H), 3.60 (dd, J = 16.2, 2.0 Hz,
1 H), 3.33 (m, 1 H), 2.39 (s, 3 H), 2.33 (s, 3 H).
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ac.
13C NMR (100 MHz, DMSO-d6):  = 158.80, 147.89, 145.28, 138.76,
135.99, 135.16, 131.57, 130.84, 130.70, 130.63, 129.72, 129.43,
128.26, 128.19, 127.48, 126.06, 115.16, 64.66, 59.54, 21.54, 20.01.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H24N2O2S: 439.1558;
found: 439.1577.
Yield: 46 mg (70%); light-yellow solid; mp 154.9–155.6 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.68 (d, J = 7.2 Hz, 2 H), 7.58–7.41
(m, 7 H), 7.33 (t, J = 7.4 Hz, 1 H), 7.16 (d, J = 7.1 Hz, 1 H), 7.06–6.92 (m,
2 H), 5.55 (s, 1 H), 5.43–5.34 (m, 1 H), 5.18 (s, 1 H), 3.81 (s, 3 H), 3.51–
3.44 (m, 1 H), 3.30–3.20 (m, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 156.68, 147.17, 145.25, 135.13,
131.52, 131.24, 131.05, 130.63, 130.07, 129.64, 128.34, 127.89,
127.48, 121.17, 114.53, 111.92, 63.13, 60.00, 55.99, 21.57.
5-(1-(4-Fluorophenyl)vinyl)-2-phenyl-1-tosyl-4,5-dihydro-1H-im-
idazole (3ag)
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H24N2O3S: 455.1508;
found: 455.1568.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 4:1) to afford
3ag.
2-Phenyl-5-(1-(p-tolyl)vinyl)-1-tosyl-4,5-dihydro-1H-imidazole
Yield: 39 mg (60%); light-yellow solid; mp 117.2–118.3 °C.
(3ad)
1H NMR (400 MHz, DMSO-d6):  = 7.63 (d, J = 7.2 Hz, 2 H), 7.56 (d, J =
7.8 Hz, 5 H), 7.44 (m, 4 H), 7.24 (t, J = 8.6 Hz, 2 H), 5.54 (d, J = 5.9 Hz,
2 H), 5.43 (d, J = 8.0 Hz, 1 H), 3.69 (dd, J = 16.1, 9.5 Hz, 1 H), 3.46 (m,
1 H), 2.41 (s, 3 H).
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ad.
13C NMR (100 MHz, DMSO-d6):  = 163.70, 161.26, 158.73, 146.60,
145.30, 135.23, 134.38, 131.57, 130.77, 130.56, 129.72, 129.28,
129.20, 128.29, 127.65, 116.02, 115.81, 113.07, 63.28, 60.78, 21.55.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C24H21FN2O2S: 443.1308;
found: 443.1336.
Yield: 45 mg (70%); light-yellow solid; mp 140.1–141.4 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.64 (d, J = 6.9 Hz, 2 H), 7.55 (d, J =
7.0 Hz, 3 H), 7.51–7.30 (m, 7 H), 7.21 (d, J = 7.0 Hz, 2 H), 5.51 (d, J =
6.7 Hz, 2 H), 5.41 (d, J = 7.7 Hz, 1 H), 3.67 (dd, J = 16.7, 9.6 Hz, 1 H),
3.42 (d, J = 16.7 Hz, 1 H), 2.41 (s, 3 H), 2.32 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 158.76, 147.28, 145.27, 138.07,
135.25, 134.99, 131.57, 130.57, 129.70, 128.30, 127.62, 126.87,
111.82, 63.21, 60.89, 21.56, 21.17.
5-(1-(4-Chlorophenyl)vinyl)-2-phenyl-1-tosyl-4,5-dihydro-1H-im-
idazole (3ah)
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H24N2O2S: 439.1558;
found: 439.1530.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 4:1) to afford
3ah.
Yield: 42 mg (63%); light-yellow solid; mp 130.1–131.2 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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Y. Liu et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6):  = 7.63 (d, J = 7.3 Hz, 2 H), 7.54 (t, J =
7.0 Hz, 5 H), 7.44 (m, 6 H), 5.59 (s, 2 H), 5.44 (d, J = 9.5 Hz, 1 H), 3.69
(dd, J = 16.2, 9.5 Hz, 1 H), 3.46 (d, J = 16.2 Hz, 1 H), 2.41 (s, 3 H).
2-Phenyl-5-(1-(thiophen-2-yl)vinyl)-1-tosyl-4,5-dihydro-1H-imid-
azole (3al)
Prepared according to the General Procedure; the crude material was
13C NMR (100 MHz, DMSO-d6):  = 158.72, 146.49, 145.32, 136.78,
135.20, 133.35, 131.59, 130.73, 130.56, 129.73, 129.06, 128.97,
128.30, 127.65, 113.68, 63.12, 60.76, 21.56.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C24H21ClN2O2S: 459.1012;
found: 459.1055.
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3al.
Yield: 49 mg (78%); light-yellow solid; mp 131.2–132.1 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.91 (s, 1 H), 7.67 (d, J = 8.0 Hz,
2 H), 7.42 (tt, J = 18.0, 8.7 Hz, 7 H), 7.20 (d, J = 2.7 Hz, 1 H), 6.70 (s,
1 H), 5.51 (s, 2 H), 5.38 (s, 1 H), 3.73 (dd, J = 16.3, 9.4 Hz, 1 H), 3.43 (d,
J = 9.4 Hz, 1 H), 2.40 (s, 3 H).
5-(1-(3-Bromo-4-chlorophenyl)vinyl)-2-phenyl-1-tosyl-4,5-di-
hydro-1H-imidazole (3ai)
13C NMR (100 MHz, DMSO-d6):  = 149.29, 146.93, 146.51, 145.33,
143.97, 137.69, 135.38, 130.60, 129.14, 128.71, 127.66, 126.97,
116.96, 112.70, 112.23, 63.15, 60.48, 21.55.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ai.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C22H20N2O2S2: 431.0966;
Yield: 37 mg (53%); light-yellow solid; mp 114.2–115.1 °C.
found: 431.0924.
1H NMR (400 MHz, DMSO-d6):  = 7.74 (dd, J = 6.9, 1.5 Hz, 1 H), 7.56
(m, 6 H), 7.43 (m, 5 H), 5.61 (s, 2 H), 5.48 (d, J = 9.5 Hz, 1 H), 3.71 (dd,
J = 16.3, 9.5 Hz, 1 H), 3.50 (dd, J = 16.3, 2.6 Hz, 1 H), 2.41 (s, 3 H).
2-(4-Methoxyphenyl)-5-(1-phenylvinyl)-1-tosyl-4,5-dihydro-1H-
imidazole (3ba)
13C NMR (100 MHz, DMSO-d6):  = 158.61, 145.70, 145.32, 135.27,
131.60, 130.67, 130.52, 129.71, 129.28, 128.29, 127.69, 117.58,
117.37, 114.68, 63.18, 60.60, 40.60, 40.39, 40.19, 39.98, 39.77, 39.56,
39.35, 21.56.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd forC24H20ClFN2O2S: 477.0918;
found: 477.0946.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 4:1) to afford
3ba.
Yield: 39 mg (59%); light-yellow solid; mp 59.2–60.5 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.63 (d, J = 8.7 Hz, 2 H), 7.56 (d, J =
8.2 Hz, 2 H), 7.48 (d, J = 7.1 Hz, 2 H), 7.39 (m, 5 H), 7.01 (d, J = 8.7 Hz,
2 H), 5.53 (d, J = 7.9 Hz, 2 H), 5.41 (d, J = 8.1 Hz, 1 H), 3.84 (s, 3 H), 3.56
(dd, J = 16.0, 9.3 Hz, 1 H), 3.41 (d, J = 2.4 Hz, 1 H), 2.41 (s, 3 H).
1-(4-(1-(2-Phenyl-1-tosyl-4,5-dihydro-1H-imidazol-5-yl)-
vinyl)phenyl)ethan-1-one (3aj)
13C NMR (100 MHz, DMSO-d6):  = 163.27, 160.79, 145.76, 145.03,
144.97, 138.97, 134.65, 134.55, 134.34, 134.30, 132.92, 132.88,
132.79, 131.59, 130.50, 130.37, 129.00, 128.63, 128.13, 127.67,
117.91, 116.84, 116.59, 115.27, 115.05, 72.99, 61.88, 51.90, 21.65,
21.62.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H24N2O3S:455.1508;
found: 455.1546.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3aj.
Yield: 42 mg (61%); light-yellow solid; mp 157.1–158.3 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.97 (d, J = 8.1 Hz, 2 H), 7.65 (m,
4 H), 7.56 (d, J = 8.0 Hz, 3 H), 7.44 (dd, J = 21.1, 7.7 Hz, 4 H), 5.71 (s,
1 H), 5.67 (s, 1 H), 5.50 (d, J = 7.1 Hz, 1 H), 3.72 (dd, J = 16.2, 9.6 Hz,
1 H), 3.46 (dd, J = 16.2, 2.3 Hz, 1 H), 2.60 (s, 3 H), 2.41 (s, 3 H).
2-(4-Bromophenyl)-5-(1-phenylvinyl)-1-tosyl-4,5-dihydro-1H-im-
idazole (3ca)
13C NMR (100 MHz, DMSO-d6):  = 197.95, 158.75, 146.89, 145.35,
142.45, 136.73, 135.18, 131.62, 130.71, 130.58, 129.74, 128.99,
128.32, 127.67, 127.37, 114.89, 63.07, 60.83, 27.26, 21.57.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ca.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C26H24N2O3S: 467.1508;
Yield: 52 mg (71%); light-yellow solid; mp 131.7–132.6 °C.
found: 467.1562.
1H NMR (400 MHz, DMSO-d6):  = 7.59 (m, 7 H), 7.44 (m, 6 H), 5.59 (d,
J = 3.1 Hz, 2 H), 5.42 (d, J = 7.7 Hz, 1 H), 3.68 (dd, J = 16.2, 9.5 Hz, 1 H),
3.46 (dd, J = 16.2, 2.6 Hz, 1 H), 2.41 (s, 3 H).
2-Phenyl-1-tosyl-5-(1-(4-(trifluoromethyl)phenyl)vinyl)-4,5-di-
hydro-1H-imidazole (3ak)
13C NMR (100 MHz, DMSO-d6):  = 144.93, 144.85, 144.79, 143.47,
138.75, 134.19, 133.66, 130.52, 130.41, 128.96, 128.53, 128.22,
127.99, 127.90, 127.80, 127.08, 116.71, 73.56, 62.45, 52.59, 21.60,
21.58.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C24H21BrN2O2S: 503.0507,
505.0487; found: 503.0545, 505.0495.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 4:1) to afford
3ak.
Yield: 33 mg (46%); light-yellow solid; mp 110.5–111.3 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.75 (q, J = 8.4 Hz, 4 H), 7.58 (m,
6 H), 7.44 (dd, J = 19.9, 7.8 Hz, 4 H), 5.68 (d, J = 5.6 Hz, 2 H), 5.48 (m,
1 H), 3.71 (dd, J = 16.3, 9.5 Hz, 1 H), 3.49 (dd, J = 16.3, 2.6 Hz, 1 H),
2.41 (s, 3 H).
2-(3-Chloro-4-fluorophenyl)-5-(1-phenylvinyl)-1-tosyl-4,5-dihy-
dro-1H-imidazole (3da)
13C NMR (100 MHz, DMSO-d6):  = 157.47, 145.51, 140.86, 137.03,
136.03, 134.88, 130.76, 130.33, 129.68, 129.48, 129.30, 128.86,
128.55, 127.69, 126.96, 125.15, 67.60, 60.31, 21.56.
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3da.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H21F3N2O2S: 493.1276;
Yield: 47 mg (68%); colorless oil.
found: 493.1210.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

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Y. Liu et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6):  = 7.74 (dd, J = 7.0, 1.6 Hz, 1 H), 7.55
(ddd, J = 10.6, 9.7, 4.9 Hz, 6 H), 7.43 (m, 5 H), 5.60 (s, 2 H), 5.48 (d, J =
8.1 Hz, 1 H), 3.71 (dd, J = 16.3, 9.5 Hz, 1 H), 3.50 (dd, J = 16.3, 2.6 Hz,
1 H), 2.41 (s, 3 H).
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C22H20N2O2S2: 431.0966;
found: 431.0910.
2-(Naphthalen-1-yl)-5-(1-phenylvinyl)-1-tosyl-4,5-dihydro-1H-
13C NMR (100 MHz, DMSO-d6):  = 158.61, 156.25, 145.70, 145.31,
135.91, 135.28, 131.58, 130.68, 130.52, 129.70, 129.28, 128.28,
128.10, 128.03, 127.69, 120.33, 120.15, 117.57, 117.36, 114.67, 63.18,
60.60, 21.56.
imidazole (3ha)
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 6:1) to afford
3ha.
HRMS (ESI-Q-TOF): m/z [M
+
Na]+ calcd for C24H20ClFN2O2S:
Yield: 33 mg (48%); light-yellow solid; mp 159.3–160.2 °C.
477.0918; found: 477.0978.
1H NMR (400 MHz, DMSO-d6):  = 8.09 (d, J = 8.1 Hz, 1 H), 7.97 (d, J =
7.9 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.59 (p, J = 6.7 Hz, 2 H), 7.50 (t, J =
7.2 Hz, 6 H), 7.44–7.35 (m, 5 H), 5.88 (s, 1 H), 5.25 (d, J = 14.1 Hz, 2 H),
3.68 (dd, J = 16.3, 1.8 Hz, 1 H), 3.38 (d, J = 16.3 Hz, 1 H), 2.37 (s, 3 H).
4-(5-(1-Phenylvinyl)-1-tosyl-4,5-dihydro-1H-imidazol-2-yl)phe-
nyl acetate (3ea)
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ea.
13C NMR (100 MHz, DMSO-d6):  = 158.69, 146.76, 145.34, 135.05,
133.73, 131.51, 130.78, 130.66, 129.68, 128.80, 128.60, 128.19,
127.45, 126.96, 126.53, 125.80, 125.67, 116.79, 65.24, 59.56, 21.54.
Yield: 46 mg (65%); light-yellow solid; mp 117.1–118.0 °C.
HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C28H24N2O2S: 475.1558;
1H NMR (400 MHz, DMSO-d6):  = 7.97 (d, J = 8.3 Hz, 2 H), 7.65 (dd, J =
13.7, 7.8 Hz, 4 H), 7.56 (d, J = 8.1 Hz, 3 H), 7.44 (m, 4 H), 5.69 (d, J =
12.7 Hz, 2 H), 5.50 (d, J = 7.9 Hz, 1 H), 3.87 (s, 3 H), 3.74 (dd, J = 16.2,
7.1 Hz, 1 H), 3.48 (dd, J = 16.2, 2.7 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 166.36, 158.72, 146.84, 145.34,
142.60, 138.15, 135.19, 131.61, 131.42, 130.69, 130.57, 129.89,
129.74, 129.60, 128.31, 127.66, 127.47, 115.00, 67.26, 63.08, 52.69,
21.56.
found: 475.1510.
Funding Information
This work was financially supported by the National Natural Science
Foundation of China (Grant No. 81903469), the Natural Science Foun-
dation of Shandong Province (ZR2019BB016), and Weifang Science
and Technology Development Plan Project (2019GX029).
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HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C26H24N2O4S: 483.1457;
found: 483.1413.
Supporting Information
5-(1-Phenylvinyl)-1-tosyl-2-(4-(trifluoromethyl)phenyl)-4,5-di-
hydro-1H-imidazole (3fa)
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610742.
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Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 3:1) to afford
3fa.
References
Yield: 55 mg (76%); light-yellow solid; mp 123.6–124.4 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.94 (s, 2 H), 7.72 (m, 2 H), 7.52 (m,
4 H), 7.39 (m, 5 H), 5.55 (s, 2 H), 5.51 (m, 1 H), 3.83 (dd, J = 16.4,
9.7 Hz, 1 H), 3.56 (dd, J = 16.4, 2.9 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 157.49, 147.63, 145.58, 137.91,
135.07, 133.68, 131.61, 130.66, 129.79, 129.09, 128.70, 127.61,
127.13, 113.13, 63.63, 61.28, 21.53.
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HRMS (ESI-Q-TOF): m/z [M + Na]+ calcd for C25H21F3N2O2S: 493.1276;
found: 493.1230.
5-(1-Phenylvinyl)-2-(thiophen-2-yl)-1-tosyl-4,5-dihydro-1H-imid-
azole (3ga)
Prepared according to the General Procedure; the crude material was
purified by flash column chromatography (PE/EtOAc = 5:1) to afford
3ga.
Yield: 35 mg (56%); light-yellow solid; mp 105.8–106.6 °C.
1H NMR (400 MHz, DMSO-d6):  = 7.63 (m, 2 H), 7.54 (m, 4 H), 7.44
(m, 4 H), 7.26 (dd, J = 3.6, 1.0 Hz, 1 H), 7.10 (dd, J = 5.1, 3.7 Hz, 1 H),
5.56 (s, 1 H), 5.43 (s, 1 H), 5.37 (dd, J = 9.7, 3.4 Hz, 1 H), 3.89 (dd, J =
16.3, 9.7 Hz, 1 H), 3.57 (dd, J = 16.3, 3.4 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 158.66, 145.36, 141.58, 140.90,
135.09, 131.57, 130.57, 129.74, 128.42, 128.30, 127.67, 126.65,
125.59, 111.11, 63.26, 61.33, 21.57.
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H

H
Y. Liu et al.
Paper
Synthesis
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–H