One-Pot Synthesis of Benzimidazo[2,1-b]thiazoline Derivatives through an Addition/Cyclization/Oxidative Coupling Reaction

Article abstract of DOI:10.1021/acs.joc.0c01137

A novel and efficient approach to the synthesis of benzimidazo[2,1-b]thiazoline derivatives has been developed through an addition/cyclization/intramolecular oxidative C-H functionalization process. A variety of alkylene benzimidazo[2,1-b] thiazolines were conveniently assembled from the reaction of aryl isothiocyanate and propargylic amine in the presence of Cu(OAc)2 and PIFA at room temperature. The product could be further converted to substituted benzimidazo[2,1-b]thiazole derivatives.

Full text of DOI:10.1021/acs.joc.0c01137

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Note
One-Pot Synthesis of Benzimidazo[2,1-b]thiazoline Derivatives
through An Addition/Cyclization/Oxidative Coupling Reaction
Haofeng Wang, Xin Wu, Luyu Wang, Erfei Li, Xiaoyu Li, Tao
Tong, Honglan Kang, Jian-Wu Xie, Guodong Shen, and Xin Lv
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01137 • Publication Date (Web): 20 Aug 2020
Downloaded from pubs.acs.org on August 20, 2020
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One-Pot Synthesis of Benzimidazo[2,1-b]thiazoline Derivatives
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through An Addition/Cyclization/Oxidative Coupling Reaction
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Haofeng Wang,a# Xin Wu,a# Luyu Wang,a# Erfei Li, Xiaoyu Li,a Tao Tong,a Honglan Kang,a
Jianwu Xie,a Guodong Shenb and Xin Lv*a
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aKey Laboratory of the Ministry of Education for Advanced Catalysis Materials, College of
Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, People’s Republic of
China. Email: lvxin@zjnu.cn
bSchool of Chemistry and Chemical Engineering, Shandong Provincial Key Laboratory of
Chemical Energy Storage and Novel Cell Technology, Liaocheng University, Liaocheng 252059,
Shandong, People’s Republic of China.
N
NCS
+
S
R3
R2
R1
Cu(OAc)2 (0.5 mol%)
MeCN, rt, 10 h
Ar
Ar
N
NH2
R2 R3
then PIFA (1.6 eq)
R1
rt, 5 h
Abstract:
A
novel and efficient approach to the synthesis of
benzimidazo[2,1-b]thiazoline derivatives has been developed through an
addition/cyclization/intramolecular oxidative C-H functionalization process. A variety
of alkylene benzimidazo[2,1-b]thiazolines were conveniently assembled from the
reaction of aryl isothiocyanate and propargylic amine in the presence of Cu(OAc)2
and PIFA at room temperature. The product could be further converted to substituted
benzimidazo[2,1-b]thiazole derivatives.
Nitrogen-containing heterocycle scaffolds wildly exist in a variety of natural products,
pharmaceuticals, and agrochemicals.1 Among them, benzimidazo[2,1-b]thiazoles have
attracted great attention because many of these N-heterocycles could be employed as
anti-microbial,2 anti-cancer,3 anti-inflammatory,4 and anti-virus5 agents. As a class of
benzimidazo[2,1-b]thiazole derivatives, many alkylene benzimidazo[2,1-b]thiazolines
possess biological and pharmaceutical activities. For example, it is claimed that some
2-substituted thiazolo[3,2-a]benzimidazol-3-ones (Figure 1, A) have antitrichinellosis
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activity.6 Certain benzylidene benzimidazo[2,1-b]thiazolinones (B) were studied as
anti-fungal agents;7 several thiazolobenzimidazole derivatives (C) exhibit lipid
7
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9
peroxidation
inhibition
effects;8
and
some
substituted
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benzimidazo[2,1-b]thiazolinones (D) might have anti-diabetic activity.9
N
R
N
S
NH
S
N
N
R
O
O
A
(
B
)
(
)
N
S
Ar
O
O
N
N
S
O
O
N
S
C
(
)
D
(
)
Figure 1. Some alkylene benzimidazo[2,1-b]thiazolines with biological activities
General routes to benzimidazo[2,1-b]thiazoles involves the reactions of
benzimidazole-2-thiols with α-halo carbonyl propargyl
compounds,4,8
bromides/tosylates,10 or active alkynes.11 Chen and coworkers developed a
copper-catalyzed synthesis of benzimidazothiazoles through 1,2-aminothiolation of
1,1-dibromoalkenes.12 Shen group found that benzimidazothiazoles could be
synthesized through a Cu-catalyzed coupling reactions of trans-1,2-diiodoalkenes
with benzimidazole-2-thiols.13 Su et al and Sun et al respectively reported the
Cu-mediated assembly of benzimidazothiazoles via 1,2-aminothiolation of terminal
alkynes.14
Hajra
and
coworkers
developed
the
synthesis
of
benzimidazo[2,1-b]thiazoles by Cu-catalyzed thioamination of nitroalkene.15 The
reaction of 2-aminothiazole with o-haloarylboronic acid or quinone is an alternative
route to benzimidazo[2,1-b]thiazoles.16 However, these methods may have some
shortcomings such as the requirements of special starting materials (such as
benzimidazole-2-thiols or 2-aminothiazoles) and/or relatively vigorous conditions
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(such as high temperatures). Moreover, till now facile and selective access to
2-alkylene benzimidazo[2,1-b]thiazolines have been rarely documented.7-8,11,17-18
These heterocycles were synthesized from the reactions of 2-mercaptobenzimidazoles,
chloroacetic acids and aryl aldehydes.7-8,17 The reactions between
N-(3-prop-2-yn-1-yl)-o-phenylenediamines and carbon disulfide/phenyl isothiocyante
also provided the formation of 2-benzylidene benzimidazo[2,1-b]thiazolines.18
However, the application scope may also be restricted since benzimidazole-2-thiols or
N-(prop-2-yn-1-yl)-o-phenylenediamines need to be prepared beforehand and
rigorous reaction conditions are employed (use of excess strong acids/bases at
relatively high temperatures). Therefore, developing more convenient and versatile
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one-pot
synthetic
approaches
to
the
assembly
of
2-alkylene
benzimidazo[2,1-b]thiazoline derivatives under milder conditions are still highly
desired. In continuation of our ongoing efforts to developing novel one-pot
multi-bond forming reactions for the assembly of heterocycles,19 and to overcome the
inherent issues of the previously documented methods to the relevant heterocycles,
herein we studied
a
novel and mild synthesis of 2-alkylene
benzimidazo[2,1-b]thiazolines through an addition/cyclization/intramolecular
oxidative coupling reaction of aryl isothiocyanate and propargylic amine in the
presence of a copper(II) catalyst and a hypervalent iodine reagent. Comparing with
the previous protocols, the present method facilely generates a wide variety of
2-alkylene benzimidazo[2,1-b]thiazolines under milder conditions from easily
accessible starting materials.
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N
Related previous methods:
S
R
R
S
N
I
CuI/1,10-phen, I2
K2CO3, 80 °C, 17 h
N
N
S
N
I
N
or
N
R
Ref. 12
(R)Ar
Ref. 13
Ref. 14a
H(R)
CuI/1,10-phen
K2CO3
110 °C, 15 h
Br
Ar(H)
S
R
Br
CuI/DMEDA, TBAF
65°C, 24 h
N
H
R
N
CuI/2,9-(iPr)2phen, I2
SH
N
OTs
S
N
R
K2CO3, 40 °C, 17 h
Ref. 10a
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N
NO2
R
Ref. 14b
R
N
R
S
Ar
Ref. 15
CuI, Cs2CO3
110°C, 15 h
Cu(OAc)2 H2O
80°C, 8 h
Ar
N
CuCl (2 eq), ICy HCl (2 eq)
TEA, 100°C, 24 h
R
N
R
N
S
Limited to the synthesis of 6-
hydroxy substituted products
N
Ref. 16a
I
Ref. 16b
N
S
N
S
O
O
S
(HO)2B
N
R
25-51% yields
NH2
R
R
Cu(OAc)2, Cs2CO3
120°C, 24 h
AcOH, HCl
N
HO
2 related examples
One-pot multi-bond formation
This work:
N
S
R3
Cu(OAc)2
(0.5 mol%)
R2
NCS
Ar
Ar
N
NH2
+
R2 R3
R1
then PIFA
R1
Easily accessible substrates
A variety of 2-alkylene benzimidazothiazolines were conveniently generated
Room temperature
Scheme 1. Synthesis of benzimidazo[2,1-b]thiazole derivatives
To search for the feasibility of the hypothesized one-pot synthesis, we
commenced our study with the reaction between phenyl isothiocyanate (1a) and
propargylamine (2a) in the presence of 1 mol% CuI and 2 equiv of iodobenzene
diacetate (PIDA) at rt for 10 h and then at 80 ºC for 5 h. To our delight, the desired
product 2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole 3a was isolated in
42% yield (Table 1, entry 1). Its structure was unambiguously confirmed by X-ray
diffraction analysis.20 Different Cu catalysts were screened and Cu(OAc)2 was
identified as the optimal catalyst (entries 1-4). A Ag catalyst was also tested and it
was inferior to Cu(OAc)2 (entry 5). Interestingly, when the catalyst loading was
reduced to 0.5 mol%, the yield was increased to 60% (entry 6). However, further
decreasing the amount of the catalyst led to a lower efficiency (entry 7). A slightly
higher yield could be obtained when the mixture was heated at 70 ºC for the late stage
(entry 8). The isolated yield was increased to 70% when the temperature was
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Table 1. Optimization of the Reaction Conditionsa
5
6
7
N
N
NCS
Catalyst
Solvent, rt, 10 h
S
NH2
+
8
9
then oxidant
temp., 5 h
1a
3a
2a
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Entry
1
Catalyst
CuI
Solv.
MeCN
MeCN
Oxid.
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
I2
T (℃)
80
80
80
80
80
80
80
70
65
55
65
65
65
65
65
Yieldb
42%
2
CuBr
33%
3
Cu(OAc)2 MeCN
51%
4
Cu(OTf)2
AgOTf
MeCN
MeCN
50%
5
48%
6
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
60%c
55%d
62%c
70%c
53%c
45%c
tracec
tracec
tracec
tracec
7
8
9
10
11
12
13
14
15
Cu(OAc)2
Cu(OAc)2
THF
DMF
Cu(OAc)2 DMSO
Cu(OAc)2 dioxane
Cu(OAc)2 MeCN
/CuIe
f
16
17
18
19
20
21
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
Cu(OAc)2 MeCN
O2
65
65
65
rt
tracec
tracec
67%c
IBX
PIFA
PIFA
PIFA
PIFA
76%c
rt
76%c,g
70%c,h
rt
aReaction conditions: phenyl isothiocyanate 1a (0.5 mmol),
propargylamine 2a (0.51 mmol, 1.02 eq), catalyst (1.0 mol%), in solvent (5
mL), under nitrogen, at rt for 10 h. Then an oxidant (1.0 mmol, 2.0 eq) was
added, and the mixture was stirred at the indicated temperature for further
b
c
d
5 h. Isolated yield. 0.5 mol% of Cu(II) catalyst was utilized. 0.2 mol%
of Cu catalyst was utilized. e The ratio of Cu(OAc)2 and CuI was 1:1. f O2
balloon was used. g1.6 eq of PIFA was used. h1.2 equiv of PIFA was used.
decreased to 65 ºC (entry 9). However, further decreasing the temperature resulted in
a lower yield (entry 10). Other solvents including THF, DMF, DMSO, and dioxane
were also tested, and MeCN gave the best result (compare entry 9 with entries 11-14).
Other oxidative systems such as Cu(OAc)2/CuI/I2, Cu(OAc)2/O2 and IBX were
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unsuitable for this one-pot transformation (entries 15-17). However, switching the
oxidant to PIFA afforded 67% yield of 3a (entry 18). Notably, a good yield was
achieved when the reaction was performed at room temperature (entry 19). Finally,
different amounts of the hypervalent iodine reagent were also evaluated, indicating
that 1.6 equiv of PIFA was appropriate for the reaction (entries 19-21).
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Having established the optimal set of reaction conditions, we proceeded to
examine the scope of isothiocyanates and propargylamines. The results are
summarized in Table 2. The reactions of a range of aryl isothiocyantes 1 were
investigated. It was found that aryl isothiocyanate bearing various substitution
patterns afforded moderate to good yields of the desired tricyclic products (the
synthesis of 3a-3i). Both electron-donating (p-Me, p-nBu, o-Me, 2,4-diMe and
p-MeO) and electron-withdrawing (p-Cl, o-Cl and 2,4-diCl) groups on the aromatic
ring of the isothiocyanates were well tolerated under these reaction conditions. The
yield was slightly decreased when a substituent was introduced at the ortho-position
of the phenyl ring (the synthesis of 3d, 3g or 3h). The reaction of the isothiocyanate
with a β-naphthalenyl substituent furnished the desired tetracyclic product in a
moderate yield (the synthesis of 3j). The substrates bearing the functional groups such
as phenylethynyl and cyanomethyl also smoothly participated in this one-pot
transformation to give moderate yields of the desired products (the synthesis of 3k
and 3l). When an m-substituted phenyl isothiocyanate was employed as the substrate,
a mixture of two regioisomers was isolated (the synthesis of 3m + 3m’).
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Next, we studied the generality of the one-pot transformation by using
propargylic amines with different substituents. Moderate to good yields of the desired
benzimidazothiazolines could be generated when α-monosubstituted or
α-disubstituted propargylic amines were employed (the synthesis of 3n-3u). It is
noteworthy that spirocyclic benzimidazothiazoline derivatives was successfully
constructed when 1-ethynylcyclohexanamine was utilized (the synthesis of 3s-3u).
The reactions with α,γ-disubstituted propargylamines also smoothly delivered the
desired disubstituted 2-methylene benzimidazothiazolines 3v-3x.
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Table 2. One-Pot Synthesis of 2-Alkylene Benzimidazo[2,1-b]thiazoline Derivatives
N
S
N
R3
Cu(OAc)2 (0.5 mol%)
MeCN, rt, 10 h
R1
R2
NCS
Ar
Ar
NH2
+
R2 R3
then PIFA (1.6 eq)
rt, 5 h
R1
2
3
1
Me
N
N
N
N
N
N
N
S
S
S
N
S
Me
3a, 76% (70%)c
3b, 75%
3c, 73%
3d, 68%
Cl
Cl
Me
N
N
N
N
N
N
S
N
S
S
S
S
N
Cl
Cl
Me
3h, 66%
3g, 63%
3e, 71%
3f, 73%
N
N
N
N
N
N
S
S
NC
S
N
N
MeO
R
Ph
3i, 67%
3j, 48%
3k, 54%
3l, 56%
S
N
S
N
N
S
N
N
S
N
N
N
Ph
R'
Ph
R = i-Pr, R' = H
or R = H, R' = i-Pr
3m+3m', 75% (65:35)d
3o, 67%
3p, 74%
3n, 76%
S
N
S
N
S
N
S
N
N
N
N
N
Me
3t, 80%
3q, 65%
3r, 70%
3s, 72%
N
S
N
N
N
S
N
S
N
S
N
N
Bu-n
Ph
Bu-n
Bu-n
C6H13-n
Ph
Cl
3u, 69%
3w, 52%
3x, 57%
3v, 75%
a Reaction conditions: aryl isothiocyanate 1 (0.5 mmol), propargylamine 2 (0.51 mmol, 1.02 eq), Cu(OAc)2
(0.5 mol%), in MeCN (5 mL), under N2, at rt for 10 h. Then PIFA (0.8 mmol, 1.6 eq) was added, and the
mixture was stirred at rt for further 5 h. b Isolated yield. c The yield of a reaction on 5 mmol scale was given in
d
the parentheses. For details, see the Experimental Section. The molecular ratio determined approximately
by1H NMR was given in the parentheses.
It is noteworthy that 2-alkylene benzimidazothiazoline-type product was
obtained exclusively in each case, and no benzimidazothiazole that derived from the
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prototropic migration was observed under these conditions. Therefore, this
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transformation provides
a
highly selective assembly of 2-alkylene
8
9
benzimidazo[2,1-b]thiazoline derivatives under very mild conditions.
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A representative large-scale one-pot reaction was also carried out (Table 2, the
synthesis of 3a). The reaction proceeded smoothly on 5 mmol scale and gave the
desired product in a good yield despite the requirement of longer reaction time.
To probe the pathway of this transformation, two control experiments were
performed (Scheme 2). The reaction of phenyl isothiocyanate (1a) and
propargylamine (2a) under the catalysis of Cu(OAc)2 (0.5 mol%) at rt afforded an
excellent yield of the thiazolidine-type intermediate 5a or its isomer (eq 1). We failed
to isolate the thiourea-type intermediate 4a derived from the simple nucleophilic
addition since the intermediate seemed to be unstable under these conditions. In the
presence of PIFA (1.6 eq), the thiazolidine-type intermediate was smoothly converted
to the product 3a at rt (eq 2).
H
Cu(OAc)2
(0.5 mol%)
N
NCS
+
N
H
H
NH2
N
N
eq 1
eq 2
S
Ph
MeCN, rt
10 h
S
1a
5a
2a
4a (unstable)
91% yield
H
N
N
S
N
N
PIFA (1.6 eq), MeCN, rt, 5 h
S
5a
3a 80% yield
Scheme 2 Two control experiments
Based on the above observation and the related reports21, a probable pathway for
the one-pot synthesis of 2-alkylene benzimidazo[2,1-b]thiazolines is depicted in
Scheme 3. First, the nucleophilic addition of propargylamine 2 to isothiocyanate 1 led
to the formation of N-proparyl thiourea-type intermediate 4. Under the catalysis of
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Cu(II), an intramolecular 5-exo-dig cyclization afforded the corresponding
intermediate 5 . 5 was converted to the final 2-alkylene benzimidazo[2,1-b]thiazoline
3 through an intramolecular oxidative coupling process in the presence of a
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hypervalent iodine reagent such as PIFA (possibly via intermediates II, III and IV).
R1
R3
NCS
+
H
R2
H
N
N
Cu(II)
Nucleophilic
Addition
Ar
NH2
R2
R3
Ar
N
S
R1
2
4
1
Ar NH
Ar
R2
R3
N
H
N
R2
R3
Cu(II)
H
N
NH
R2 PIFA
R3 - TFA
5-exo-dig
S
S
Ar
Ar
Cyclization
- Cu(II)
S
R1
S
R1
R1
5a
(such as
R1
)
5
I
R1
R1
N
S
S
N
- H+
- PhI
- TFA
R3
N
N
N
H
R2
3
N
2
I
R2
R3 R
R3
Ph
R
OCOCF3 II
IV
III
R
Intramolecular Oxidative C-H Functionalization
Scheme 3 The proposed pathway for the one-pot synthesis
N
S
N
6a
DBU
DCM, rt
N
96% yield
N
S
N
1) Br2-AcOH
R2
S
2) NHR1R2
N
N
3a
R1
, 66% yield
7
MeCN, 80°C
NR1R2 = NEt2
1) Br2
AcOH
7a
NaH, THF 80°C
2) PhOH
N
7b
, 58% yield
, 72% yield
7c
N
N
S
O
N
8a
, 52% yield
Scheme 4 The synthetic application
In order to demonstrate the synthetic utility of this method, product 3a was
further elaborated as depicted in Scheme 4. In the presence of DBU, 3a was
quantitatively converted to its isomer 6a. Subsequently treated by bromine and
reacted with a secondary aliphatic amine, benzimidazo[2,1-b]thiazol-2-yl amine 7
could
be
conveniently
generated
starting
from
this
molecule.
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2-(Phenoxymethyl)benzimidazo[2,1-b]thiazole 8a was successfully assembled after
being treated with bromine-AcOH and phenol/NaH.
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In conclusion, we have developed a novel and efficient strategy for the synthesis
of benzimidazo[2,1-b]thiazoline derivatives. Catalyzed by Cu(II) (0.5 mol%) and in
the presence of PIFA, a variety of alkylene benzimidazo[2,1-b]thiazolines were easily
generated via an intermolecular addition/cyclization/intramolecular oxidative
coupling process at room temperature. A broad range of aryl isothiocyanates and
propargylic amines are compatible under these mild conditions. Furthermore, the
obtained products could be further derived to corresponding substituted
benzimidazo[2,1-b]thiazoles conveniently. This modular and practical synthetic
protocol will enable the synthesis of related N-heterocyclic molecules of biological
and medicinal use.
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Experimental Section
General Information.
All one-pot reactions were carried out in an over dried Schlenk tube equipped with a
magnetic stir bar under N2 atmosphere. The solvents MeCN, DMF, and DMSO were
distilled from CaH2. THF and dioxane were distilled from Na. Substrates
isothiocyanates 122 and primary propargylamines 223 were commercially available or
prepared according to the known literatures. All other reagents were obtained from
commercial sources and utilized without further purification, if not stated otherwise.
The heat source of all reactions that require heating is an oil bath. The NMR spectra
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were recorded in CDCl3 or d6-DMSO on a 400 or 600 MHz instrument with TMS as
internal standard. Chemical shifts (δ) were reported in ppm with respect to TMS. Data
are represented as follows: chemical shift, multiplicity (s = singlet, d =doublet, t =
triplet, q = quartet, m = multiplet, b = broad), coupling constant (J, Hz) and
integration. TLC was carried out with 0.2 mm thick silica gel plates (GF254).
Visualization was accomplished by UV light. The chromatographic columns were
hand packed with silica gel 60 (160-200 mesh). HRMS analyses were carried out
using a TOF-MS instrument with an ESI source.
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General
Procedure
for
the
One-Pot
Synthesis
of
Alkylene
Benzimidazo[2,1-b]thiazolines 3. An oven-dried Schlenk tube was charged with a
magnetic stir bar and Cu(OAc)2 (0.0025 mmol, 0.5 mol%). The tube was capped, and
then evacuated and backfilled with nitrogen (3 times). A solution of propargylamine 2
(0.51 mmol, 1.02 eq) in MeCN (2.5 mL) was added via syringe under nitrogen at
room temperature. The mixture was stirred for 10 min. Then a solution of aryl
isothiocyanate 1 (0.5 mmol, 1 eq) in MeCN (2.5 mL) was added slowly via syringe
(for about 20 min), and the mixture was stirred at rt for about 10 h. Then PIFA (0.8
mmol, 1.6 eq) were added under the protection of nitrogen. The tube was sealed
immediately and the mixture was stirred at rt for 5 h. The mixture was diluted with
DCM (10 mL), and washed with sat. NaHCO3 (15 mL). The aqueous layer was
extracted with DCM (10 mL × 3). The organic layers were combined, dried over
anhydrous Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel using petrol/AcOEt as eluent to afford product 3.
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Procedure for the One-Pot Synthesis of Alkylene Benzimidazo[2,1-b]thiazoline
3a on A Larger Scale. An oven-dried two-necked flask was charged with a magnetic
stir bar and Cu(OAc)2 (0.025 mmol, 0.5 mol%). The tube was capped, and then
evacuated and backfilled with nitrogen (3 times). A solution of propargylamine 2 (5.1
mmol, 1.02 eq) in MeCN (25 mL) was added via syringe under nitrogen at room
temperature. The mixture was stirred for 10 min. Then a solution of
phenylisothiocyanate 1a (5.0 mmol, 1 eq) in MeCN (25 mL) was added slowly via
syringe (for about 20 min), and the mixture was stirred at rt for about 12 h. Then
PIFA (8.0 mmol, 1.6 eq) were added under the protection of nitrogen. The tube was
sealed immediately and the mixture was stirred at rt for 20 h. The mixture was diluted
with DCM (100 mL), and washed with sat. NaHCO3 (75 × 2 mL). The aqueous layer
was extracted with DCM (100 mL × 3). The organic layers were combined, dried over
anhydrous Na2SO4 and concentrated. The residue was purified by column
chromatography on silica gel using petrol/AcOEt as eluent to afford product 3a as a
yellow solid (0.656 g, 70% yield).
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2-Methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3a)24: yellow solid (72
mg, 76% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.19); mp 162 – 164 °C; 1H NMR
(600 MHz, CDCl3) δ 7.67 – 7.61 (m , 1H), 7.23 – 7.17 (m, 3H), 5.54 (dd, J = 4.8, 2.4
Hz, 1H), 5.44 (dd, J = 5.2, 2.6 Hz, 1H), 4.96 (t, J = 2.4 Hz, 2H); 13C{1H} NMR (151
MHz, CDCl3) δ 156.2, 148.2, 141.5, 133.6, 122.3, 122.2, 119.1, 109.5, 108.8, 49.4;
HRMS (ESI) m/z: [M + H]+ calcd for C10H9N2S 189.0481; found 189.0488.
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6-Methyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole
(3b): yellow
6
7
8
9
solid (76 mg, 75% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.21); mp 181.5 – 183
°C; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H),
6.93 (s, 1H), 5.49 (dd, J = 4.6, 2.3 Hz, 1H), 5.40 (dd, J = 5.2, 2.6 Hz, 1H), 4.83 (t, J =
2.4 Hz, 2H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.3, 146.1, 141.5,
133.6, 132.2, 123.4, 118.5, 109.3, 108.9, 49.1, 21.7; HRMS (ESI) m/z: [M + H]+
calcd for C11H11N2S 203.0637; found 203.0645.
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6-Butyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3c): Light yellow
solid (89 mg, 73% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.48); mp 105 – 107 °C;
1H NMR (600 MHz, CDCl3) δ 7.51 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.97
(s, 1H), 5.51 – 5.48 (m, 1H), 5.42 – 5.38 (m, 1H), 4.88 (t, J = 2.1 Hz, 2H), 2.71 – 2.66
(m, 2H), 1.65 – 1.59 (m, 2H), 1.39 – 1.33 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (151 MHz, CDCl3) δ 155.4, 146.3, 141.5, 137.4, 133.6, 122.9, 118.5, 109.3,
108.3, 49.2, 35.9, 34.3, 22.4, 14.1; HRMS (ESI) m/z: [M + H]+ calcd for C14H17N2S
245.1107; found 245.1109.
8-Methyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole
(3d):
Light
yellow solid (69 mg, 68% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.45); mp 119.5
– 121 °C; 1H NMR (600 MHz, CDCl3) δ 7.06 (t, J = 7.6 Hz, 1H), 7.02 – 6.96 (m, 2H),
5.51 – 5.48 (m, 1H), 5.40 (dd, J = 4.9, 2.4 Hz, 1H), 4.87 (t, J = 2.2 Hz, 2H), 2.60 (s,
13
3H); C{1H} NMR (151 MHz, CDCl3) δ 155.1, 147.2, 141.5, 133.1, 128.9, 122.7,
122.1, 109.3, 106.3, 49.3, 16.7; HRMS (ESI) m/z: [M + H]+ calcd for C11H11N2S
203.0637; found 203.0638.
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5,7-Dimethyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3e): Light
yellow solid (77 mg, 71% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.39); mp 196 –
198 °C; 1H NMR (600 MHz, CDCl3) δ 7.22 (s, 1H), 6.72 (s, 1H), 5.51 – 5.45 (m, 1H),
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5.41 – 5.35 (m, 1H), 5.12 – 5.05 (m, 2H), 2.48 (s, 3H), 2.38 (s, 3H); C{1H} NMR
(151 MHz, CDCl3) δ 155.9, 148.5, 141.9, 131.9, 131.3, 125.0, 119.0, 116.7, 108.9,
51.5, 21.5, 16.9; HRMS (ESI) m/z: [M + H]+ calcd for C12H13N2S 217.0794; found
217.0795.
6-Chloro-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3f): yellow
solid (81 mg, 73% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.23); mp 203 – 204.5
°C; 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.49 (m, 1H), 7.17 – 7.15 (m, 2H), 5.55 (dd,
J = 4.7, 2.3 Hz, 1H), 5.45 (dd, J = 7.8, 2.6 Hz, 1H), 4.92 (t, J = 2.4 Hz, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ 157.1, 146.8, 140.8, 134.0, 128.0, 122.7, 119.8, 110.0,
109.0, 49.3; HRMS (ESI) m/z: [M + H]+ calcd for C10H8ClN2S 223.0091 (35Cl);
found 223.0102.
7-Chloro-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3g): Light
yellow solid (70 mg, 63% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.34); mp 145 –
147 °C; 1H NMR (600 MHz, CDCl3) δ 7.15 (d, J = 7.6 Hz, 1H), 7.09 – 6.95 (m, 2H),
5.54 – 5.50 (m, 1H), 5.43 – 5.38 (m, 1H), 4.91 – 4.87 (m, 2H); C{1H} NMR (151
13
MHz, CDCl3) δ 157.1, 144.9, 140.8, 134.3, 123.3, 122.7, 122.2, 110.0, 107.5, 49.5;
HRMS (ESI) m/z: [M + H]+ calcd for C10H8ClN2S 223.0091 (35Cl); found 223.0094.
6,8-Dichloro-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3h) ： Light
yellow solid (85 mg, 66% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.41); mp 194.5
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– 196.3 °C; 1H NMR (600 MHz, CDCl3) δ 7.19 (s, 1H), 7.05 (s, 1H), 5.57 – 5.54 (m,
6
7
13
1H), 5.47 – 5.43 (m, 1H), 4.93 – 4.90 (m, 2H); C{1H} NMR (151 MHz, CDCl3) δ
8
9
158.0, 143.8, 140.3, 134.3, 128.0, 123.8, 122.6, 110.4, 107.9, 49.5; HRMS (ESI) m/z:
[M + H]+ calcd for C10H7Cl2N2S 256.9702 (35Cl, 35Cl); found 256.9704.
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6-Methoxy-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3i): yellow
solid (73 mg, 67% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.1); mp 156.5 – 158.5
°C; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 1H), 6.82 (dd, J = 8.8, 2.4 Hz,
1H), 6.69 (d, J = 2.3 Hz, 1H), 5.52 (dd, J = 4.5, 2.2 Hz, 1H), 5.43 (dd, J = 5.0, 2.5 Hz,
1H), 4.91 (t, J = 2.3 Hz, 2H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.2,
154.7, 142.6, 141.6, 134.1, 119.5, 110.3, 109.3, 93.6, 56.1, 49.2; HRMS (ESI) m/z:
[M + H]+ calcd for C11H11N2OS 219.0587; found 219.0591.
9-Methylene-9,10-dihydronaphtho[2',1':4,5]imidazo[2,1-b]thiazole (3j): Red brown
solid (57 mg, 48% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.43); mp 152 – 154 °C;
1H NMR (600 MHz, CDCl3) δ 7.79 – 7.74 (m, 3H), 7.73 – 7.68 (m, 1H), 7.44 (t, J =
7.4 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 5.26 – 5.22 (m, 1H), 5.16 – 5.12 (m, 1H), 4.64
(s, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 146.4, 140.3, 134.2, 130.5, 129.1, 127.8,
127.5, 126.5, 124.7, 121.6, 116.9, 104.6, 100.1, 48.9; HRMS (ESI) m/z: [M + H]+
calcd for C14H11N2S 239.0637; found 239.0640.
2-Methylene-6-(phenylethynyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole
(3k):
white solid (78 mg, 54% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.39); mp 215 –
216 °C; 1H NMR (600 MHz, CDCl3) δ 7.58 (d, J = 8.3 Hz, 1H), 7.55 – 7.51 (m, 2H),
7.41 – 7.37 (m, 2H), 7.37 – 7.31 (m, 3H), 5.57 – 5.54 (m, 1H), 5.47 – 5.44 (m, 1H),
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4.95 (s, 2H); C{1H} NMR (151 MHz, CDCl3) δ 157.7, 148.3, 141.1, 133.4, 131.6,
128.5, 128.3, 126.3, 123.5, 119.1, 117.0, 112.0, 109.9, 90.1, 88.8, 49.4; HRMS (ESI)
m/z: [M + H]+ calcd for C18H13N2S: 289.0794; found 289.0792.
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2-(2-Methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazol-6-yl)acetonitrile
(3l):
white solid (64 mg, 56% yield) (petroleum ether/EtOAc = 2:1, Rf = 0.23); mp 167 –
168 °C; 1H NMR (600 MHz, CDCl3) δ 7.60 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 7.09 (d,
J = 7.0 Hz, 1H), 5.58 (dd, J = 4.8, 2.3 Hz, 1H), 5.47 (dd, J = 5.2, 2.6 Hz, 1H), 4.98 (t,
J = 2.3 Hz, 2H), 3.87 (s, 2H); 13C{1H} NMR (151 MHz, CDCl3) δ 161.5, 147.9, 141.0,
133.9, 123.9, 122.2, 119.6, 118.3, 110.0, 108.3, 49.4, 23.9; HRMS (ESI) m/z: [M +
H]+ calcd for C12H10N3S: 228.0590; found 228.0589.
The mixture of 7-isopropyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole
(3m) and 5-isopropyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole
1
(3m’). Mole ratio ≈ 65:35 (approximately determined by H NMR). Light yellow
solid (86 mg, 75% in total) (petroleum ether/EtOAc = 5:1, Rf = 0.26); mp 106 – 108
°C; Major: 1H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 7.9 Hz, 1H), 7.08 – 7.04 (m,
2H), 5.53 – 5.50 (m, 1H), 5.20 – 5.15 (m, 2H), 4.87 – 4.85 (m, 1H), 3.39 – 3.32 (m,
1H), 1.34 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (151 MHz, CDCl3) δ 156.2, 148.2,
1
143.2, 131.1, 122.4, 118.3, 116.6, 108.9, 108.3, 51.9, 28.3, 24.0. Minor: H NMR
(600 MHz, CDCl3) δ 7.48 (s, 1H), 7.18 – 7.12 (m, 2H), 5.49 – 5.47 (m, 1H), 5.41 –
5.36 (m, 3H), 3.03 – 2.97 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (151 MHz,
CDCl3) δ 155.9, 148.3, 141.5, 141.4, 131.8, 131.7, 121.0, 116.3, 109.3, 49.2, 34.2,
24.6.
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3-Hexyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3n): Yellow oil
6
7
1
(103 mg, 76% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.59); H NMR (600 MHz,
8
9
CDCl3) δ 7.63 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.20 – 7.13 (m, 2H), 5.44
– 5.42 (m, 1H), 5.41 – 5.38 (m, 1H), 5.23 – 5.18 (m, 1H), 2.23 – 2.17 (m, 1H), 1.93 –
1.87 (m, 1H), 1.43 – 1.35 (m, 1H), 1.23 – 1.13 (m, 6H), 1.07 – 1.00 (m, 1H), 0.80 (t, J
= 7.0 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 155.3, 148.3, 146.1, 133.0, 122.0,
121.9, 119.1, 109.0, 108.8, 61.5, 34.6, 31.5, 28.9, 22.7, 22.5, 14.0; HRMS (ESI) m/z:
[M + H]+ calcd for C16H21N2S 273.1420; found 273.1422.
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2-Methylene-3-phenethyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3o): yellow
solid (98 mg, 67% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.27); mp 83.5 – 84.5
°C; 1H NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 7.5, 1.6 Hz, 1H), 7.29 – 7.16 (m, 6H),
7.08 (d, J = 7.1 Hz, 2H), 5.59 – 5.54 (m, 1H), 5.53 – 5.50 (m, 1H), 5.33 – 5.27 (m,
1H), 2.80 – 2.71 (m, 1H), 2.63 – 2.54 (m, 1H), 2.43 – 2.35 (m, 1H), 2.32 – 2.22 (m,
13
1H); C{1H} NMR (100 MHz, CDCl3) δ 155.2, 148.3, 145.8, 140.2, 132.8, 128.6,
128.2, 126.3, 122.2, 122.1, 119.2, 109.4, 108.7, 61.0, 36.2, 29.0; HRMS (ESI) m/z:
[M + H]+ calcd for C18H17N2S 293.1107; found 293.1112.
2-Methylene-3-(3-phenylpropyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3p):
yellow solid (113 mg, 74% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.28); mp 91 –
92.5 °C; 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 1H), 7.26 – 7.13 (m, 6H),
7.05 (d, J = 7.3 Hz, 2H), 5.45 – 5.38 (m, 2H), 5.27 – 5.21 (m , 1H), 2.61 – 2.53 (m,
2H), 2.31 – 2.24 (m, 1H), 1.99 – 1.93 (m, 1H), 1.81 – 1.73 (m, 1H), 1.46 – 1.38 (m,
13
1H); C{1H} NMR (151 MHz, CDCl3) δ 155.3, 148.4, 146.0, 141.1, 133.0, 128.5,
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128.4, 126.1, 122.1, 122.0, 119.2, 109.2, 108.8, 61.4, 35.2, 33.8, 24.1; HRMS (ESI)
m/z: [M + H]+ calcd for C19H19N2S 307.1263; found 307.1260.
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2-Methylene-3-phenyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3q): yellow
solid (86 mg, 65% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.27); mp 121.5 – 123
°C; 1H NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.42 – 7.37 (m, 3H), 7.33
– 7.28 (m, 2H), 7.15 (t, J = 7.4 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.68 (d, J = 8.0 Hz,
1H), 6.01 (d, J = 2.2 Hz, 1H), 5.45 – 5.40 (m, 1H), 5.27 – 5.22 (m, 1H); 13C{1H}
NMR (151 MHz, CDCl3) δ 155.2, 148.5, 146.8, 137.4, 133.2, 130.1, 129.4, 127.3,
122.2, 122.0, 119.1, 111.4, 109.4, 65.5; HRMS (ESI) m/z: [M + H]+ calcd for
C16H13N2S 265.0794; found 265.0781.
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3,3-Dimethyl-2-methylene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3r): Brown
oil (76 mg, 70% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.3); 1H NMR (400 MHz,
CDCl3) δ 7.66 – 7.61 (m, 1H), 7.38 – 7.33 (m, 1H), 7.22 – 7.12 (m, 2H), 5.40 (d, J =
2.9 Hz, 1H), 5.32 (d, J = 2.9 Hz, 1H), 1.81 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3)
δ 152.9, 152.4, 148.7, 132.3, 121.9, 121.6, 119.2, 108.6, 107.1, 65.3, 27.9; HRMS
(ESI) m/z: [M + H]+ calcd for C12H13N2S 217.0794; found 217.0799.
3-Methylene-2H-spiro[benzo[4,5]imidazo[2,1-b]thiazole-3,1'-cyclohexane]
(3s):
yellow solid (92 mg, 72% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.0.35); mp 99 –
100.5 °C; 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz,
1H), 7.20 – 7.13 (m, 2H), 5.74 (d, J = 2.9 Hz, 1H), 5.36 (d, J = 2.9 Hz, 1H), 2.40 (td,
J = 13.7, 4.9 Hz, 2H), 2.13 – 2.09 (m, 2H), 1.93 – 1.75 (m, 5H), 1.49 – 1.41 (m, 1H);
13C{1H} NMR (151 MHz, CDCl3) δ 153.3, 151.1, 148.9, 132.2, 121.8, 121.4, 119.3,
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109.9, 109.2, 67.1, 34.0, 24.4, 21.7; HRMS (ESI) m/z: [M + H]+ calcd for C15H17N2S
257.1107; found 257.1113.
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6-Methyl-2-methylene-2H-spiro[benzo[4,5]imidazo[2,1-b]thiazole-3,1'-cyclohexane]
(3t): Light yellow oil (108 mg, 80% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.46);
1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 1H), 7.22 (s, 1H), 7.01 (d, J = 8.0
Hz, 1H), 5.74 (d, J = 1.6 Hz, 1H), 5.35 (d, J = 1.7 Hz, 1H), 2.47 (s, 3H), 2.40 (td, J =
13.6, 4.4 Hz, 2H), 2.14 – 2.08 (m, 2H), 1.95 – 1.77 (m, 5H), 1.53 – 1.44 (m, 1H);
13C{1H} NMR (151 MHz, CDCl3) δ 152.6, 151.3, 147.0, 132.4, 131.2, 123.2, 118.8,
109.8, 109.4, 67.0, 33.9, 24.5, 21.9, 21.7; HRMS (ESI) m/z: [M + H]+ calcd for
C16H19N2S 271.1263; found 271.1269.
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6-Chloro-2-methylene-2H-spiro[benzo[4,5]imidazo[2,1-b]thiazole-3,1'-cyclohexane]
(3u): yellow solid (100 mg, 69% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.51); mp
121 – 122.5 °C; 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.6 Hz, 1H), 7.39 (d, J =
1.3 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 5.74 (d, J = 2.6 Hz, 1H), 5.35 (d, J = 2.6 Hz,
1H), 2.30 (td, J = 13.7, 4.6 Hz, 2H), 2.11 – 2.06 (m, 2H), 1.93 – 1.85 (m, 3H), 1.81 –
1.73 (m, 2H), 1.48 – 1.40 (m, 1H); 13C{1H} NMR (151 MHz, CDCl3) δ 154.2, 150.5,
147.5, 132.6, 127.0, 122.3, 119.8, 110.3, 109.3, 67.2, 33.9, 24.3, 21.5; HRMS (ESI)
m/z: [M + H]+ calcd for C15H16ClN2S 291.0717 (35Cl); found 291.0725.
2-Pentylidene-3-phenethyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3v): Light
yellow oily liquid (131 mg, 75% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.48); 1H
NMR (600 MHz, CDCl3) δ 7.68 (d, J = 7.9 Hz, 1H), 7.27 – 7.16 (m, 6H), 7.11 – 7.02
(m, 2H), 5.88 – 5.80 (m, 1H), 5.32 – 5.17 (m, 1H), 2.72 (td, J = 13.4, 5.2 Hz, 1H),
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2.58 – 2.51 (m, 1H), 2.43 – 2.36 (m, 1H), 2.30 – 2.11 (m, 3H), 1.62 – 1.50 (m, 2H),
1.47 – 1.40 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ
155.4, 148.4, 140.4, 136.8, 132.9, 128.5, 128.2, 126.2, 125.0, 122.0, 121.9, 119.1,
108.7, 60.4, 36.6, 31.1, 30.9, 29.1, 22.3, 14.0; HRMS (ESI) m/z: [M + H]+ calcd for
C22H25N2S 349.1733; found 349.1738.
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2-Pentylidene-3-(3-phenylpropyl)-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3w):
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yellow oily liquid (95 mg, 52% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.36); H
NMR (600 MHz, CDCl3) δ 7.70 – 7.62 (m, 1H), 7.23 (t, J = 7.4 Hz, 2H), 7.21 – 7.19
(m, 1H), 7.18 – 7.17 (m, 1H), 7.16 – 7.12 (m, 2H), 7.09 – 7.02 (m, 2H), 5.69 (td, J =
7.2, 1.4 Hz, 1H), 5.25 – 5.17 (m, 1H), 2.56 (t, J = 7.4 Hz, 2H), 2.27 – 2.20 (m, 1H),
2.19 – 2.07 (m, 2H), 1.95 – 1.88 (m, 1H), 1.78 – 1.70 (m, 1H), 1.48 – 1.34 (m, 5H),
0.95 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ 155.6, 148.4, 141.3,
136.9, 133.0, 128.5, 128.4, 126.1, 124.8, 122.0, 121.9, 119.2, 108.8, 60.8, 35.3, 34.2,
31.1, 30.9, 24.2, 22.4, 14.0; HRMS (ESI) m/z: [M + H]+ calcd for C23H27N2S:
363.1889; found 363.1888.
3-Hexyl-2-pentylidene-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazole (3x): yellow oily
1
liquid (94 mg, 57% yield) (petroleum ether/EtOAc = 5:1, Rf = 0.48); H NMR (600
MHz, CDCl3) δ 7.64 (d, J = 7.8 Hz, 1H), 7.27 – 7.25 (m, 1H), 7.21 – 7.12 (m, 2H),
5.81 – 5.67 (m, 1H), 5.28 – 5.16 (m, 1H), 2.23 – 2.10 (m, 3H), 1.94 – 1.84 (m, 1H),
1.50 – 1.44 (m, 2H), 1.41 – 1.34 (m, 3H), 1.25 – 1.15 (m, 6H), 1.08 – 1.01 (m, 1H),
0.93 (t, J = 7.3 Hz, 3H), 0.82 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (151 MHz, CDCl3) δ
155.6, 148.5, 137.2, 133.1, 124.7, 122.0, 121.8, 119.2, 108.9, 61.1, 35.1, 31.6, 31.1,
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31.0, 29.1, 22.9, 22.6, 22.4, 14.07, 13.98; HRMS (ESI) m/z: [M + H]+ calcd for
C20H29N2S: 329.2046; found 329.2045.
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Procedure for the Synthesis of the Intermediate 5a. An oven-dried Schlenk tube
was charged with a magnetic stir bar and Cu(OAc)2 (0.0025 mmol, 0.5 mol%). The
tube was capped, and then evacuated and backfilled with nitrogen (3 times). A
solution of propargylamine 2a (0.51 mmol, 1.02 eq) in MeCN (2.5 mL) was added via
syringe under nitrogen at room temperature. The mixture was stirred for 10 min. Then
a solution of phenyl isothiocyanate 1a (0.5 mmol, 1 eq) in MeCN (2.5 mL) was added
slowly via syringe (for about 20 min), and the mixture was stirred at rt for about 10 h.
The mixture was diluted with DCM (10 mL), and washed with sat. NaHCO3 (15 mL).
The aqueous layer was extracted with DCM (10 mL × 3). The organic layers were
combined, dried over anhydrous Na2SO4 and concentrated. The residue was purified
by column chromatography on silica gel using petrol/AcOEt as eluent to afford
intermediate 5a.
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5-Methylene-N-phenyl-4,5-dihydrothiazol-2-amine 5a.25 Yellow solid (87 mg, 91%
yield) (petroleum ether/EtOAc = 5:1, Rf = 0.44); mp 101 – 102.5 °C (lit.23 mp 104 –
108 °C); 1H NMR (600 MHz, CDCl3) δ 7.29 (t, J = 7.8 Hz, 2H), 7.15 (d, J = 8.1 Hz,
2H), 7.07 (t, J = 7.4 Hz, 1H), 5.20 – 5.18 (m, 1H), 5.12 (dd, J = 4.0, 2.2 Hz, 1H), 4.57
13
– 4.53 (m, 2H) (the signal of NH is missing); C{1H} NMR (151 MHz, CDCl3) δ
159.4, 145.7, 143.9, 129.1, 123.6, 121.3, 104.2, 58.4.
Procedure for the Synthesis of Benzimidazo[2,1-b]thiazole 6a. DBU (0.2 mmol) in
DCM (2 mL) was added dropwise to a solution of product 3a (0.5 mmol) in DCM (3
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mL) at 0 ºC. Then the mixture was stirred at rt for about 5 h. After evaporation of the
solvent, the residue was purified by column chromatography on silica gel using
petrol/AcOEt as eluent to afford product 6a.
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2-Methylbenzo[4,5]imidazo[2,1-b]thiazole (6a).16a Light yellow solid (90 mg, 96%
yield) (petroleum ether/EtOAc = 3:1, Rf = 0.27); mp 160.5 – 162 °C (lit.16a mp 156 –
159 °C); 1H NMR (600 MHz, CDCl3) δ 7.73 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 7.9 Hz,
1H), 7.29 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.18 (t, J = 7.5 Hz, 1H), 2.35 (s, 3H);
13C{1H} NMR (151 MHz, CDCl3) δ 156.5, 147.5, 129.5, 124.6, 123.0, 120.7, 119.0,
113.8, 110.0, 14.1.
General Procedure for the Synthesis of Benzimidazo[2,1-b]thiazolylmethyl
Amine Derivatives 7. An oven-dried flask equipped with a condenser was charged
with a magnetic stir bar, 3a (1.0 mmol) and glacial acetic acid (2 mL). The flask was
capped. Then a solution of bromine (176 mg, 1.1 mmol) in acetic acid (2 mL) was
added dropwise via syringe at rt. The mixture was stirred at 80 °C for about 2 h. The
reaction was quenched by the addition of sat. NaHCO3 solution, and the mixture was
extracted with DCM (5 mL × 3). The solid was washed with water, dried, and was
utilized for the next step without further purification.
An oven-dried Schlenk tube was charged with a magnetic stir bar and the above
bromide (53 mg, 0.2 mmol). Then the tube was capped, and then evacuated and
backfilled with nitrogen (3 times). MeCN (1 mL) was added via syringe at rt. The
reaction mixture was stirred for about 10 min at rt, and then a solution of amine (0.6
mmol, 3 eq) in MeCN (1 mL) was added dropwise. After being stirred at room
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temperature for about 3 h, the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel (petroleum ether/EtOAc, 10:1) to
give product 7.
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N-(Benzo[4,5]imidazo[2,1-b]thiazol-2-ylmethyl)-N-ethylethanamine
(7a):
Light
yellow solid (34 mg, 66% yield) (petroleum ether/EtOAc = 3:1, Rf = 0.1); mp 78.5 –
80.5 °C; 1H NMR (600 MHz, CDCl3) δ 7.75 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 8.0 Hz,
1H), 7.53 (s, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 3.72 (s, 2H), 2.61
13
(q, J = 7.1 Hz, 4H), 1.07 (t, J = 7.1 Hz, 6H); C{1H} NMR (151 MHz, CDCl3) δ
157.0, 147.7, 130.7, 129.6, 123.2, 120.8, 119.2, 114.0, 110.1, 50.9, 46.7, 11.9; HRMS
(ESI) m/z: [M + H]+ calcd for C14H18N3S 260.1216; found 260.1217.
2-(Pyrrolidin-1-ylmethyl)benzo[4,5]imidazo[2,1-b]thiazole (7b): Yellow oil (30 mg,
58% yield)(petroleum ether/EtOAc = 4:1, Rf = 0.4). 1H NMR (600 MHz, d6-DMSO) δ
8.36 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.6 Hz,
1H), 7.26 (d, J = 7.6 Hz, 1H), 3.80 (s, 2H), 2.60 – 2.54 (m, 4H), 1.77 – 1.72 (m, 4H).
13C{1H} NMR (151 MHz, d6-DMSO) δ 156.3, 147.5, 129.9, 129.1, 123.4, 121.1,
118.8, 116.4, 111.7, 53.8, 52.9, 23.7. HRMS (ESI) m/z: [M + H]+ calcd for C14H16N3S
258.1059; found: 258.1060.
2-(Piperidin-1-ylmethyl)benzo[4,5]imidazo[2,1-b]thiazole (7c). Yellow oil (39 mg,
1
72% yield)(petroleum ether/EtOAc = 1:1, Rf = 0.4). H NMR (600 MHz, CDCl3) δ
7.76 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.33 (t, J = 7.5 Hz,
1H), 7.22 (t, J = 7.4 Hz, 1H), 3.60 (s, 2H), 2.55 – 2.40 (m, 4H), 1.63 – 1.57 (m, 4H),
13
1.49 – 1.41 (m, 2H). C{1H} NMR (151 MHz, CDCl3) δ 157.1, 147.8, 129.6, 129.4,
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123.3, 120.9, 119.3, 114.3, 110.1, 56.6, 54.5, 26.0 24.3. HRMS (ESI) m/z: [M + H]+
calcd for C15H18N3S 272.1216; found: 272.1219.
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General Procedure for the Synthesis of Benzimidazo[2,1-b]thiazolylmethyl
Amine Derivatives 8a. An oven-dried Schlenk tube was charged with a magnetic stir
bar and phenol (19 mg, 0.2 mmol). The tube was capped, and then evacuated and
backfilled with nitrogen (3 times). Anhydrous THF (2 mL) was added via syringe.
The reaction mixture was stirred for about 10 min at rt, and then sodium hydride (240
mg, 10 mmol) was added immediately under the protection of nitrogen. The tube was
capped again and the mixture was stirred at rt for about 1 h. After that, a solution of
the above bromide (53 mg, 0.2 mmol) in anhydrous THF (1 mL) was added dropwise.
After being stirred at rt for 16 h, the solvent was removed in vacuo, and the residue
was dissolved in DCM (20 mL), washed with brine (5 mL × 2), and dried over
anhydrous Na2SO4. The solvent was removed in vacuo. The residue was purified by
column chromatography on silica gel (petroleum ether/EtOAc, 10:1) to give product
as a yellow solid.
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3-(Phenoxymethyl)benzo[4,5]imidazo[2,1-b]thiazole (8a). Yellow solid (29 mg, 52%
1
yield)(petroleum ether/EtOAc = 2:1, Rf = 0.4); mp 158 – 158.5 ℃. H NMR (600
MHz, CDCl3) δ 7.80 (d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.40 –
13
7.32 (m, 3H), 7.28 (d, J = 7.7 Hz, 1H), 7.07 – 6.95 (m, 3H), 5.20 (s, 2H). C{1H}
NMR (151 MHz, CDCl3) δ 157.8, 156.7, 133.2, 129.9, 128.5, 125.2, 123.8, 122.2,
121.4, 119.5, 116.2, 115.3, 110.3, 64.1. HRMS (ESI) m/z: [M + H]+ calcd for
C16H13N2OS 281.0743; found: 281.0744.
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Supporting Information Available. Copies of 1H NMR and 13C NMR spectra for the
products (3), the derivatives (6a, 7 and 8a) and key intermediate (5a), and
crystallographic information for of 3a. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Acknowledgments
We are grateful to the Natural Science Foundation of Zhejiang Province (No.
LY16B020003) and the National Natural Science Foundation of China (NSFC, No.
21202152) for financial support.
References and notes:
1. For selected reviews, see: (a) Hu, D. X.; Withall, D. M.; Challis, G. L.; Thomson, R. J.
Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products. Chem. Rev.
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