Tert-amino effect-promoted rearrangement of aryl isothiocyanate: A versatile approach to benzimidazothiazepines and benzimidazothioethers

Article abstract of DOI:10.1021/acs.joc.0c01806

A general and practical approach to benzimidazothiazepine and benzimidazothioether derivatives via an intramolecular nucleophilic addition/ring expansion rearrangement of aryl isothiocyanates promoted by the tert-amino effect has been developed. This reaction is catalyzed by low-cost camphorsulfonic acid and tolerates a broad substrate scope with complete atom economy. Structurally intriguing benzimidazothiazepine and benzimidazothioether products could be easily obtained by a simple operation in good to excellent yield (up to 98%).

Full text of DOI:10.1021/acs.joc.0c01806

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Article
tert-Amino Effect-Promoted Rearrangement of Aryl Isothiocyanate: A
Versatile Approach to Benzimidazothiazepines and Benzimidazothioethers
Xinyu Geng, Siyuan Liu, Wenyao Wang, Jingping Qu, and Baomin Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01806 • Publication Date (Web): 02 Sep 2020
Downloaded from pubs.acs.org on September 2, 2020
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tert-Amino Effect-Promoted Rearrangement of Aryl
Isothiocyanate: A Versatile Approach to
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Benzimidazothiazepines and Benzimidazothioethers
Xinyu Geng,a Siyuan Liu,a,b Wenyao Wang,a Jingping Qu,a and Baomin Wang*a,c
a State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering,
Dalian University of Technology, Dalian 116024, P. R. China * Email: bmwang@dlut.edu.cn
b Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Pharmaceutical
Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, P. R. China
c Ningbo Institute of Dalian University of Technology, Ningbo 315016, P. R. China
N
NCS
N
N
R1
20 mol% CSA
xylene, 140 o
R3
S
R3
S
R3
R2
N
R1
or
N
C
R2
 Novel tert-amino effect-promoted rearrangement
22 examples, up to 98% yield
 Complete atom economy
 Wide substrate scope
 Readily available substrates
 Low-cost catalyst
ABSTRACT: A general and practical approach to benzimidazothiazepine and benzimidazothioether derivatives via
an intramolecular nucleophilic addition/ring expansion rearrangement of aryl isothiocyanates promoted by the tert-
amino effect has been developed. This reaction is catalyzed by low-cost camphorsulfonic acid and tolerates a broad
substrate scope with complete atom economy. Structurally intriguing benzimidazothiazepine and benzimidazothioether
products could be easily obtained by a simple operation in good to excellent yield (up to 98%).
INTRODUCTION
Among the multitude of nitrogen-containing heterocyclic compounds, benzimidazoles and thiazepines are prominent
as they often exhibit broad ranges of biological activities. Benzimidazoles, which is present in a diverse array of
antitumor, antimalarial, anti-inflammatory, antiviral, antifungal and other therapeutical agents,1 have been attracting
continuous attention in the fields of organic and medicinal chemistry (Figure 1). On the other hand, N,S-containing
seven-membered thiazepines constitute another important class of structural cores commonly found in pharmaceutical
products, and have garnered extensive interest due to their impressive performance in the therapy of cancer, psychosis,
viral infection, heart disease, etc. (Figure 1).2 Despite the extensive research of synthetic routes to these two
motifs,2b,3,4 methods for the construction of the structure hybrid together with the diversity of the fused structure per se,
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especially the benzimidazo[1,3]thiazepine, remain extremely rare. To the best of our knowledge, only two reports
involving the preparation of benzimidazo[1,3]thiazepine were documented.5 As shown in Scheme 1a, this heterocycle
was reported to be obtained through the alkylative annulation between 2-benzimidazolinethione and 1,4-dibromobutane.
However, both reports suffer from severe limit in the product diversity with only one example being reported (Scheme
1a). Therefore, the development of novel and efficient methods for access to benzimidazo[1,3]thiazepines with broad
diversity is desirable for potential medicinal exploitation.
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N
N
S
N
N
HN
OMe
N
H
N
N
MeO
COOH
O
S
O
N
N
N
N
CN
CF3
Cl
antimalarial
GABAA agonist
O
antiulcer
anti-inflammatory
bezimidazole
H
N
S
N
R1
S
N
F
N
N
N
N
S
S
N
O
N
I
antitumor
N
this work
antipsychotic
antiviral
thiazepine
Figure 1. Selected examples of bioactive benzimidazoles and thiazepines, and the structure hybrid.
Scheme 1. tert-Amino effect-promoted rearrangement and the construction of benzimidazo[1,3]thiazepines
Previous Work:
a) Construction of benzimidazo[1,3]thiazepine via alkylative annulation
H
Br
N
N
N
Br
5a
Suri,
1983
Kim, 1989 5b
S
S
N
H
base
only 1 example
b) tert-Amino effect reactions involving 1,n-hydride transfer/cyclization processes:
types 1-3 reactions according to Meth-Cohn's classification of t-amino effect reactions 6b
R3
H
R3
H
Our group 8d, 8f, 8i
Y
X
Y
X
R3
R2
8c
Acid catalyst
1,n-HT
X
Xiao
, 2019
Akiyama
Y
R2
H
or
8e
, 2018
N
N
8g
N
R1
R3
Mori
, 2018
R1
R1
......
X = C, N; Y = C, N, O, ...
c) This Work:
tandem intramolecular nucleophilic addition/ring expansion rearrangement
promoted by tert-amino effect (type 4 reaction of Meth-Cohn's classification 6b
)
N
N
NCS
N
N
20 mol% CSA
xylene, 140 o
R3
S
R3
S
R3
R2
N
R1
or
C
R2
R1
22 examples, up to 98% yield
Molecular rearrangement facilitated by the tert-amino effect, a term coined by Meth-Cohn and Suschitzky in 1972,6
is an efficient synthetic tool for the construction of nitrogen-containing heterocyclic compounds.7 Particularly, tert-
amino effect promoted 1,n-hydride transfer/cyclization processes, referred to as types 1-3 reactions of t-amino effect
according to Meth-Cohn’s classification,6b are the most concerned reactions owing to their high efficiency and
remarkable step/atom economy, which have attracted considerable interest due to their reliable capability (Scheme
1b).8 Strategies based on these reactions have been adapted to synthesize complicated pharmaceutical and natural
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molecules such as deoxyvasicinone,9 rutaecarpine,9 PUN-286607,10 cryptaustoline.11 In sharp contrast to the enormous
efforts devoted to the development of tert-amino effect promoted reactions involving hydride transfer processes, much
less attention was paid to other types of transformations mediated by the tert-amino effect,6b,12 especially those leading
to the construction of novel heterocyclic systems while not involving hydride shifts, such as those reacting at the
tertiary nitrogen center without hydride transfer event, classified as type 4 reactions by Meth-Cohn.6b
As part of our interest in developing new efficient synthetic approaches to pharmaceutically relevant nitrogen
heterocycles, we recently reported facile construction of benzoazepine and diazepine structures and other heterocycles
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through tert-amino effect-assisted 1,5-hydride transfer/cyclization processes by introducing new hydride acceptor
8d,f,i
moieties.
Considering the medicinal significance of benzimidazole and thiazepine frameworks, we hypothesized
that new reaction design by installing an isothiocyanato group into the ortho position of aryl tertiary amines may
provide access to these target structures through an unprecedented intramolecular addition/ring expansion
rearrangement process, which could be classified as type 4 reaction of tert-amino effect6b (Scheme 1c). Herein, we
report our efforts toward realization of this hypothesis.
RESULTS AND DISCUSSION
Initially, 1-(2-isothiocyanatophenyl)pyrrolidine (1a) was selected as a model substrate for optimization of the
reaction conditions (Table 1). With xylene as the solvent under reflux, the catalyst was first investigated. The outcome
showed that no reaction occurred in the absence of any catalyst (entry 1). But to our delight, when Sc(OTf)3 was used
as a Lewis acid catalyst, the desired benzimidazothiazepine product 2a was obtained in 67% yield (entry 2), whose
structure was unambiguously determined by single crystal X-ray analysis.13 Inspired by this result, we further screened
a variety of other metal triflates, but none performed better than the original Sc(OTf)3 (entries 3-8).
Table 1. Screening of optimal reaction conditions for 2aa
NCS
N
cat. solvent
S
T o
C
N
N
2a
1a
Entry
Catalyst
---
Solvent
xylene
xylene
xylene
xylene
T (oC) t (h) Yield (%)b
1
2
3
4
5
6
7
8
9
140
140
140
140
140
140
140
140
140
12
8
0
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
67
58
37
0
15
8
Mg(OTf)2 xylene
24
20
20
20
36
Ni(OTf)2
La(OTf)3
Zn(OTf)2
ZnCl2
xylene
xylene
xylene
xylene
33
47
27
5
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22d
23e
24f
25g
26h
FeCl3
BF3·Et2O
TfOH
TsOH
CSA
TFA
xylene
xylene
xylene
xylene
xylene
xylene
xylene
EtOH
140
140
140
140
140
140
140
80
18
18
4.5
4.5
6
22
74
62
74
92
14
54
25
10
71
40
32
90
91
78
71
85
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0.5
24
11
24
36
8
DPPc
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CSA
CSA
DCE
80
1,4-dioxane
MeCN
THF
80
80
60
xylene
xylene
xylene
xylene
xylene
140
140
140
140
140
12
4
4
4
a
o
b
Reactions were carried out with 1 (0.2 mmol) and cat. (0.04 mmol, 0.2 equiv) in xylene (0.1 mol/L) at 140 C.
Isolated yield. c Diphenyl phosphate. d The loading of catalyst was 0.1 equiv. e The loading of catalyst was 0.05 equiv. f
The reactant concentration was 0.2 mol/L. g The reactant concentration was 0.05 mol/L. h Use microwave.
Then we tested some non-triflate Lewis acids (entries 9-11), and found that BF3·Et2O could improve the yield to
74%. Afterwards, we turned our attention to Brønsted acids (entries 12-16). Gratifyingly, the yield was improved to 92%
with the catalysis of camphorsulfonic acid (CSA); meanwhile, the reaction time was shortened to 6 h (entry 14). Then
with CSA as the catalyst, the effect of solvent was examined (entries 17-21). While 1,4-dioxane proved to be a suitable
o
reaction medium affording 71% product yield at 80 C, other solvents such as ethanol, 1,2-dichoroethane (DCE),
acetonitrile and THF worked poorly. Afterwards, we attempted to vary the catalyst and reactant concentration (entries
22-25). However these changes caused either reduction of product yield or prolonged reaction time. It is worth noting
that the use of microwave instead of traditional heating could also lead to the formation of product 2a in 85% yield
within 4 h (entry 26). Finally, we confirmed the optimal conditions to be 20 mol% of CSA as the catalyst, xylene as
the solvent, 0.1 mol/L as the reactant concentration, and 140 oC as the reaction temperature (entry 14)
With the optimized reaction conditions in hand, we next explored the substrate scope of this reaction. In general, this
transformation tolerates a broad range of substrates, and a diverse array of benzimidazo[1,3]thiazepines could be
produced. Isothiocyanates with various electron-withdrawing (halogen, trifluoromethyl) and electron-donating groups
(methyl, methoxy, amine) on the phenyl ring reacted smoothly to afford the target products 2b−2o in good to high
yields (60-98%) (Scheme 2). Notably, substrates bearing an electron-withdrawing group generally showed good
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reaction efficiency, probably because of the enhanced electrophilicity of the isothiocyanate moiety resulting from the
electron-withdrawing effect. In addition, when a phenyl group was introduced to the 5/6-position of the substrate, the
desired products 2k and 2l were successfully formed in 81% and 73% yields, respectively. To enhance the generality of
this method, disubstituted substrates were employed to the reaction, and as expected, the corresponding disubstituted
products 2p and 2q were formed in 82% and 85% yields, respectively. Remarkably, other than aromatic isothiocyanate
substrates, heteroarene could also be tolerated. For example, 3-isothiocyanato-2-(pyrrolidin-1-yl)pyridine was smoothly
converted into the corresponding product 2r in 77% yield.
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Scheme 2. Substrate scopea,b
.
N
N
NCS
R1
S
CSA, xylene
140 o
R3
R2
N
R1
C
1
2
N
N
N
N
N
N
S
S
S
S
N
N
2a
, 6 h, 92%
2b
, 3 h, 73%
2c
2d
, 4 h, 65%
, 1 h, 64%
F
F
N
Cl
N
N
N
S
S
S
S
N
N
N
Cl
N
2e
, 1.5 h, 60%
2f
2g
2k
2o
, 4 h, 98%
, 4 h, 85%
2h
, 2.5 h, 69%
Br
N
N
N
Ph
N
N
S
N
S
S
S
N
Br
N
Ph
2i
2j, 4 h, 92%
, 3 h, 73%
N
, 4 h, 94%
2l
, 3 h, 81%
F3C
N
N
N
N
S
S
S
S
N
N
N
N
MeO
Cl
2p
, 5 h, 82%
, 5 h, 69%
2n
, 36 h, 63%
2m
2q
, 3.5 h, 98%
F
N
N
S
N
N
S
N
N
S
N
S
N
Br
N
2t
24 h, 30%
2s
4 h, 80%
, 2 h, 85%
2r
, 16 h, 77%
N
S
N
N
N
S
2v
, 4 h, 92%
2u
, 5 h, 88%
a
o
b
Reactions were carried out with 1 (0.2 mmol) and CSA (0.04 mmol, 0.2 equiv) in xylene (0.1 mol/L) at 140 C.
Isolated yield.
Next, variation of the tertiary amine moiety was examined to further expand the structure diversity of the thiazepine
product. Notably, octahydroisoindole- and isoindoline-derived substrates could be employed in this reaction. The
former was efficiently converted to a four-ring-fused product 2s in 80% yield, though the latter gave the corresponding
product 2t in a relatively low yield of 30% within 24 h, probably due to the relatively more rigid structure of the
isoindoline which may hinder the intramolecular addition to the isothiocyanate fragment.
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Finally, to our delight, tertiary acyclic amine modified substrates were also suitable for this reaction, as exemplified
by the conversion of substrates 1u and 1v to benzimidazothioethers 2u and 2v in high yields (88% and 92%,
respectively).
7
8
9
Based on the experimental results, a plausible mechanism of this unique tert-amino effect-promoted rearrangement
involving two possible pathways was proposed. Specifically, activation of the isothiocyanate by proton facilitates the
intramolecular addition of the tertiary amine to the isothiocyanate to form the quaternary ammonium intermediate II,
which is followed by a ring expansion rearrangement to afford the desired product (path A, Scheme 3). Alternatively,
the pyrrolidinium ring in II may be opened by the sulfonate of CSA generating an alkyl sulfonate intermediate III,
which is subsequently attacked by the thiourea sulfur to give the thiazepine product via a 7-exo-tet cyclization process
(path B, Scheme 3).
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Scheme 3. Proposed mechanism for the rearrangement reaction
N
N
NCS
N
S
O
O
S
H
2a
1a
HO
H
R
H
N
H
H
N
S
N
N
C
S
S
N
O
O
R
N
S
II
O
III
I
path A
H
path B
N
S
O
O
N
S
O
R
II
Scheme 4. i) gram scale synthesis of 2a; ii) transformation of the product 2a
NCS
N
i)
CSA, xylene
S
140 o
C
N
N
1a
, 5 mmol
2a,
4.5 h, 77%, 778 mg
N
N
O
ii)
N
N
O
oxone
S
S
EtOH, H2O, r.t.
2a
3a,
95%
To demonstrate the practical utility, we scaled up the reaction. The desired product 2a was synthesized on 5 mmol
scale with a 77% yield. To further exploit the potential of these products, a derivatization was conducted. Considering
the unique biological activity of arylsulfones and its wide application,14 the representative sulfide 2a was subjected to
oxidation with oxone as the oxidant, and the thiazepine-dioxide 3a was obtained in 95% yield (Scheme 4).
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CONCLUSION
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In summary, we have developed a novel and efficient reaction for the construction of benzimidazothiazepines and
benzimidazothioethers via a tert-amino effect-promoted rearrangement of isothiocyanate derivatives. The reaction is
wide in scopes with complete atom economy, and the desired product could be prepared on gram scale. It is worth
noting that the final product can be readily converted into the benzimidazothiazepine dioxides species by simple
oxidation. In addition, this reaction extended the concept of tert-amino effect reactions reacting at the tertiary nitrogen
center while without hydride transfer event. Studies directed towards exploration into the bioactivities of the
structurally intriguing heterocyclic products and development of other tert-amino effect-promoted rearrangement
processes are underway in our laboratories.
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EXPERIMENTAL SECTION
General Information. Unless otherwise noted, materials were purchased from commercial suppliers and used
1
without further purification. Column chromatography was performed on silica gel (200~300 mesh). All H NMR
spectra were recorded on a Bruker AvanceⅡ 400 MHz or Varian DLG 400 MHz, 13C NMR spectra were recorded on a
Bruker Avance Ⅱ 101 MHz or Varian DLG 101 MHz, 19F NMR were recorded on a Varian DLG 377 MHz with
1
chemical shifts reported as ppm (in CDCl3, TMS as an internal standard). Data for H NMR are recorded as follows:
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad singlet, dd = double
doublet, coupling constants in Hz, integration). HRMS (ESI) was obtained with an HRMS/MS instrument (LTQ
Orbitrap XL TM).
General procedure for the synthesis of reactant 1:
H
NCS
Fe, AcOH
EtOH, H2O
5
N
NO2
F
NH2
NO2
R1
R2
Et3N, CS2, THF
R3
R3
R3
R3
R2
N
R1
R2
R2
reflux
Boc2O, DMAP
r.t
K2CO3, DMSO
120 oC
N
N
R1
R1
(i)
(ii)
4
(iii)
1
6
7
Unless otherwise noted, the reactant 1 was synthesized through the following steps:
(i). 2-Fluoro nitrobenzene 4 (15 mmol) and K2CO3 (22.5 mmol, 1.5 equiv) were added into DMSO (15 mL), then
amine 5 (15 mmol, 1.0 equiv) was added under stirring. After the addition was finished, the reaction was heated to 120
oC in oil bath. After the reaction was complete (monitored by TLC), the mixture was cooled to room temperature,
quenched with water and extracted with ethyl acetate, and the organic phase was washed with brine. The organic phase
was then dried over Na2SO4, filtered and the solvent was evaporated under vacuum to give the product 6. Compound 6
was used to next step without further purification.
(ii). Crude product 6 (1 equiv), iron powder (5 equiv), AcOH (1.5 equiv) was added to 90% alcohol solution (37.5
mL). The mixture was heated to reflux by oil bath and reaction was monitored by TLC. After the starting material was
completely consumed, the reaction mixture was cooled, quenched with water and then filtered. The filtrate was
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extracted with ethyl acetate, and the organic phase was washed with brine, dried over Na2SO4, filtered. The solvent was
4
5
evaporated under vacuum to give the product 7, which was used to next step without further purification.
(iii). Crude product 7 (1 equiv) was dissolved in dry THF (30 mL), then added Et3N (1.5 equiv), CS2 (10 equiv),
stirred at room temperature for 1 h. Then Boc2O (1.1 equiv) was added dropwise, and stirred continuously over 2 h.
Afterwards, catalytic amount of DMAP (5–10 mol %) in THF (5 mL) was added dropwise. The reaction was stirred
overnight at room temperature, and then quenched with water. The mixture was extracted with ethyl acetate, and the
organic phase was washed with brine. The organic phase was separated and evaporated under vacuum. The residue was
purified by column chromatography on silica gel to give the product 1.
6
7
8
9
10
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1-(2-isothiocyanatophenyl)pyrrolidine (1a)
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Light yellow liquid (1.85 g, 60% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); H NMR (400
MHz, CDCl3) δ 7.19 – 7.14 (m, 1H), 7.13 – 7.08 (m, 1H), 6.70 – 6.63 (m, 2H), 3.47 – 3.42 (m, 4H), 1.99 – 1.94 (m,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.6, 129.4, 128.3, 117.6, 116.8, 115.2, 50.1, 25.7. HRMS (ESI) m/z: [M +
H]+ Calcd for C11H12N2S 205.0794; Found 205.0794.
1-(2-isothiocyanato-4-methylphenyl)pyrrolidine (1b)
Yellow oil (2.15 g, 66% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); 1H NMR (400 MHz, CDCl3)
δ 6.92 (s, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 8.8 Hz, 1H), 3.37 – 3.27 (m, 4H), 2.14 (s, 3H), 1.93 – 1.84 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 142.8, 129.4, 129.1, 127.5, 117.0, 115.3, 50.3, 25.5, 19.9. HRMS (ESI) m/z: [M +
H]+ Calcd for C12H15N2S 219.0950; found 219.0953.
1-(2-isothiocyanato-5-methylphenyl)pyrrolidine (1c)
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Yellow solid (2.80 g, 85% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 56.1 – 58.0 C; H
NMR (400 MHz, CDCl3) δ 7.09 – 7.03 (m, 1H), 6.51 – 6.45 (m, 2H), 3.49 – 3.38 (m, 4H), 2.27 (s, 3H), 2.01 – 1.91 (m,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.4, 138.5, 129.2, 118.6, 115.6, 114.2, 50.1, 25.7, 21.7. HRMS (ESI) m/z:
[M + H]+ Calcd for C12H15N2S 219.0950; Found 219.0944.
1-(2-isothiocyanato-6-methylphenyl)pyrrolidine (1d)
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Yellow liquid (2.07 g, 63% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); H NMR (400 MHz,
CDCl3) δ 7.10 – 7.06 (m, 1H), 7.04 – 6.95 (m, 2H), 3.27 – 3.18 (m, 4H), 2.27 (s, 3H), 2.12 – 1.96 (m, 4H). 13C{1H}
NMR (101 MHz, CDCl3) δ 144.5, 139.0, 131.8, 130.0, 125.2, 124.0, 51.1, 26.2, 18.6. HRMS (ESI) m/z: [M + H]+
Calcd for C12H15N2S 219.0950; Found 219.0946.
1-(4-fluoro-2-isothiocyanatophenyl)pyrrolidine (1e)
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Yellow liquid (1.47 g, 44% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); H NMR (400 MHz,
CDCl3) δ 6.91 (dd, J = 8.5, 3.0 Hz, 1H), 6.86 (ddd, J = 9.1, 7.7, 3.0 Hz, 1H), 6.65 (dd, J = 9.2, 5.1 Hz, 1H), 3.41 – 3.32
(m, 4H), 2.01 – 1.93 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.9 (d, J = 238.8 Hz), 141.9 (d, J = 2.2 Hz), 134.8,
118.2, 116.1 (d, J = 8.3 Hz), 115.4 (d, J = 5.9 Hz), 115.2 (d, J = 2.7 Hz), 50.5, 25.5. 19F NMR (377 MHz, CDCl3) δ -
125.86 (td, J = 8.1, 5.1 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for C11H12FN2S 223.0700; Found 223.0693.
1-(3-fluoro-2-isothiocyanatophenyl)pyrrolidine (1f)
Yellow solid (0.60 g, 18% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 29.6 – 31.0 oC; 1H
NMR (400 MHz, CDCl3) δ 7.00 (q, J = 7.9 Hz, 1H), 6.46 (t, J = 8.7 Hz, 1H), 6.38 (d, J = 8.7 Hz, 1H), 3.60 – 3.42 (m,
4H), 2.06 – 1.90 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 161.4 (d, J = 250.1 Hz), 145.1 (d, J = 1.5 Hz), 138.6,
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127.8 (d, J = 10.4 Hz), 110.1 (d, J = 2.9 Hz), 103.5 (d, J = 20.1 Hz), 50.1, 25.7. 19F NMR (377 MHz, CDCl3) δ -118.79
(t, J = 7.8 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for C11H12FN2S 223.0700; Found 223.0691.
1-(5-chloro-2-isothiocyanatophenyl)pyrrolidine (1g)
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Light yellow solid (1.96 g, 55% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 55.7 – 56.9 oC;
1H NMR (400 MHz, CDCl3) δ 7.12 – 7.01 (m, 1H), 6.64 – 6.58 (m, 2H), 3.49 – 3.42 (m, 4H), 2.01 – 1.94 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 145.0, 133.8, 130.3, 117.3, 115.1, 114.9, 50.1, 25.7. HRMS (ESI) m/z: [M + H]+
Calcd for C11H12ClN2S 239.0404; Found 239.0402.
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1-(4-chloro-2-isothiocyanatophenyl)pyrrolidine (1h)
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White solid (0.92 g, 26% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 81.3 – 82.7 C; H
NMR (400 MHz, CDCl3) δ 7.15 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 9.0, 2.5 Hz, 1H), 6.59 (d, J = 8.9 Hz, 1H), 3.46 –
3.38 (m, 4H), 2.01 – 1.93 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.1, 128.7, 128.2, 121.5, 117.4, 116.0, 50.2,
25.6. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12ClN2S 239.0404; Found 239.0401.
1-(5-bromo-2-isothiocyanatophenyl)pyrrolidine (1i)
Light yellow solid (1.48 g, 35% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 54.1 – 55.9 oC;
1H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 8.8 Hz, 1H), 6.82 – 6.71 (m, 2H), 3.66 – 3.37 (m, 4H), 2.19 – 1.99 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 145.1, 130.5, 121.9, 120.2, 117.8, 115.6, 50.1, 25.7. HRMS (ESI) m/z: [M + H]+
Calcd for C11H12BrN2S 282.9899; Found 282.9904.
1-(4-bromo-2-isothiocyanatophenyl)pyrrolidine (1j)
Light yellow solid (1.81 g, 43% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 112.1 – 113.2
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oC; H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 6.53 (d, J = 8.9 Hz, 1H),
3.45 – 3.40 (m, 4H), 2.00 – 1.94 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.4, 131.5, 131.0, 117.7, 116.4, 107.9,
50.2, 25.6. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12BrN2S 282.9899; Found 282.9902.
1-(4-isothiocyanato-[1,1'-biphenyl]-3-yl)pyrrolidine (1k)
Yellow liquid (2.58 g, 62% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); 1H NMR (400 MHz,
CDCl3) δ 7.60 – 7.54 (m, 2H), 7.49 – 7.41 (m, 2H), 7.40 – 7.34 (m, 1H), 7.29 – 7.22 (m, 1H), 6.94 – 6.86 (m, 2H), 3.59
– 3.49 (m, 4H), 2.06 – 1.97 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.7, 141.3, 140.8, 133.5, 129.8, 129.4,
128.8, 127.7, 127.1, 121.3, 116.7, 115.9, 113.8, 50.2, 25.7. HRMS (ESI) m/z: [M + H]+ Calcd for C17H17N2S 281.1107;
Found 281.1108.
1-(3-isothiocyanato-[1,1'-biphenyl]-4-yl)pyrrolidine (1l)
Yellow solid (3.36 g, 80% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), 96.6 – 98.5 oC; 1H NMR
(400 MHz, CDCl3) δ 7.66 – 7.13 (m, 7H), 6.80 – 6.65 (m, 1H), 3.50 (s, 4H), 1.99 (s, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 143.6, 139.5, 130.6, 128.8, 127.7, 126.8, 126.8, 126.2, 116.9, 115.5, 50.2, 25.7. HRMS (ESI) m/z: [M + H]+
Calcd for C17H17N2S 281.1107; Found 281.1107.
1-(2-isothiocyanato-4-(trifluoromethyl)phenyl)pyrrolidine (1m)
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Colorless liquid (1.07 g, 26% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); H NMR (400 MHz,
CDCl3) δ 7.40 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.9, 2.2 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 3.57 – 3.51 (m, 4H), 2.04 –
1.96 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 145.8, 134.4, 127.0 (q, J = 3.9 Hz), 125.0 (q, J = 3.7 Hz), 124.0 (q, J
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= 271.7 Hz), 118.8 (q, J = 33.5 Hz), 115.6, 114.7, 50.1, 25.7. 19F NMR (470 MHz, CDCl3) δ -61.38 (s). HRMS (ESI)
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m/z: [M + H]+ Calcd for C12H12F3N2S 273.0668; Found 273.0667.
1,1'-(4-isothiocyanato-1,3-phenylene)dipyrrolidine (1n)
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White solid (0.91 g, 22% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 94.1 – 95.7 C; H
NMR (400 MHz, CDCl3) δ 7.03 (d, J = 8.7 Hz, 1H), 5.94 (dd, J = 8.7, 2.5 Hz, 1H), 5.74 (d, J = 2.5 Hz, 1H), 3.50 –
3.40 (m, 4H), 3.33 – 3.24 (m, 4H), 2.09 – 1.90 (m, 8H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.8, 145.9, 130.2, 105.4,
102.4, 96.9, 50.1, 47.6, 25.6, 25.5. HRMS (ESI) m/z: [M + H]+ Calcd for C15H20N3S 274.1372; Found 274.1368.
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1-(2-isothiocyanato-5-methoxyphenyl)pyrrolidine (1o)
Light yellow solid (3.05 g, 87% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 73.9 – 75.1 oC;
1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.7 Hz, 1H), 6.23 (dd, J = 8.7, 2.7 Hz, 1H), 6.17 (d, J = 2.7 Hz, 1H), 3.77 (s,
3H), 3.49 – 3.38 (m, 4H), 2.03 – 1.92 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.5, 145.7, 130.4, 110.0, 102.9,
100.7, 55.4, 50.1, 25.7. HRMS (ESI) m/z: [M + H]+ Calcd for C12H15N2OS 235.0900; Found 235.0893.
1-(5-chloro-2-isothiocyanato-4-methylphenyl)pyrrolidine (1p)
Light yellow solid (2.51 g, 66% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 50.0 – 52.5 oC;
1H NMR (400 MHz, CDCl3) δ 7.01 (s, 1H), 6.66 (s, 1H), 3.43 – 3.37 (m, 4H), 2.22 (s, 3H), 2.00 – 1.94 (m, 4H).
13C{1H} NMR (101 MHz, CDCl3) δ 143.4, 133.9, 130.8, 125.0, 115.5, 115.4, 50.2, 25.6, 18.7. HRMS (ESI) m/z: [M
+ H]+ Calcd for C12H14ClN2S 253.0561; Found 253.0559.
1-(5-bromo-4-fluoro-2-isothiocyanatophenyl)pyrrolidine (1q)
Light yellow solid (2.34 g, 52% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 43.1 – 44.1 oC;
1H NMR (400 MHz, CDCl3) δ 6.96 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 6.4 Hz, 1H), 3.42 – 3.32 (m, 4H), 2.03 – 1.92 (m,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 150.9 (d, J = 239.7 Hz), 142.2, 119.0, 117.0, 116.1 (d, J = 25.7 Hz), 108.6 (d,
J = 21.4 Hz), 50.5, 25.5. 19F NMR (377 MHz, CDCl3) δ -120.74 (t, J = 7.4 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for
C11H11BrFN2S 300.9805; Found 300.9798.
3-isothiocyanato-2-(pyrrolidin-1-yl)pyridine (1r)
Brown oil (0.90 g, 29% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); 1H NMR (400 MHz, CDCl3)
δ 8.04 (dd, J = 4.8, 1.7 Hz, 1H), 7.38 (dd, J = 7.6, 1.7 Hz, 1H), 6.54 (dd, J = 7.7, 4.8 Hz, 1H), 3.71 – 3.66 (m, 4H), 1.99
– 1.94 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.9, 146.6, 136.7, 112.1, 111.9, 49.0, 25.7. HRMS (ESI) m/z:
[M + H]+ Calcd for C10H12N3S 206.0746; Found 206.0742.
(cis)-2-(2-isothiocyanatophenyl)octahydro-1H-isoindole (1s)
Yellow oil (2.75 g, 71% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); 1H NMR (400 MHz, CDCl3)
δ 7.15 (dd, J = 8.1, 1.7 Hz, 1H), 7.12 – 7.06 (m, 1H), 6.66 – 6.59 (m, 2H), 3.52 – 3.45 (m, 2H), 3.41 – 3.35 (m, 2H),
2.33 – 2.24 (m, 2H), 1.66 – 1.34 (m, 8H). 13C{1H} NMR (101 MHz, CDCl3) δ 144.7, 129.6, 128.3, 116.9, 115.8, 114.5,
54.0, 37.2, 26.0, 22.9. HRMS (ESI) m/z: [M + H]+ Calcd for C15H19N2S 259.1263; Found 259.1256.
2-(2-isothiocyanatophenyl)isoindoline (1t)
Yellow solid (0.83 g, 22% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 111.2 – 113.8 oC; 1H
NMR (400 MHz, CDCl3) δ 7.36 – 7.29 (m, 4H), 7.28 – 7.23 (m, 1H), 7.22 – 7.16 (m, 1H), 6.79 – 6.71 (m, 2H), 4.90 (s,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 142.6, 137.1, 130.5, 128.6, 127.4, 122.4, 118.0, 116.1, 115.4, 55.8. HRMS
(ESI) m/z: [M + H]+ Calcd for C15H13N2S 253.0794; Found 253.0790.
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2-isothiocyanato-N,N-dimethylaniline (1u)
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Colorless oil (0.81 g, 30% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant); H NMR (400 MHz,
CDCl3) δ 7.23 – 7.13 (m, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 2.84 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 149.7, 128.0, 127.3, 124.1, 121.8, 118.8, 43.4. HRMS (ESI) m/z: [M + H]+ Calcd for C9H11N2S 179.0637;
Found 179.0639.
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N,N-diethyl-2-isothiocyanatoaniline (1v)
Yellow solid (1.70 g, 55% yield in 3 steps, ethyl acetate/petroleum ether = 1/50 as eluant), mp: 34.8 – 38.1 oC; 1H
NMR (400 MHz, CDCl3) δ 7.22 – 7.14 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 3.19 (q, J = 7.1 Hz,
4H), 1.03 (t, J = 7.2 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 146.3, 129.6, 127.1, 125.9, 123.5, 122.0, 47.8, 11.8.
HRMS (ESI) m/z: [M + H]+ Calcd for C11H15N2S 207.0950; Found 207.0944.
General procedure for the synthesis of product 2:
Compound 1 (0.2 mmol, 1 equiv) was dissolved in 2 mL xylene, then the catalyst (0.04 mmol, 0.2 equiv) was added.
The solution was stirred at 140 oC by oil bath, and monitored by TLC. After the reaction was finished, the mixture was
cooled to room temperature, and purified by column chromatography on silica gel to give the product 2.
General Procedure for Gram-scale reaction:
Compound 1a (5 mmol, 1 equiv) was dissolved in 50 mL xylene, and then the catalyst (1 mmol, 0.2 equiv) was
o
added. The solution was stirred at 140 C by oil bath, and monitored by TLC. After the reaction was finished, the
mixture was cooled to room temperature, and the solvent was removed through vacuum distillation. The residue was
purified by column chromatography on silica gel to give the product 2a (778 mg, 3.8 mmol).
2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2a)
White solid (41.2 mg, 92% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 133.5 – 135.0 oC; 1H NMR
(400 MHz, CDCl3) δ 7.82 – 7.68 (m, 1H), 7.35 – 7.19 (m, 3H), 4.41 – 4.29 (m, 2H), 2.98 – 2.84 (m, 2H), 2.33 – 2.19
(m, 2H), 2.00 – 1.94 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.5, 142.9, 136.4, 122.7, 122.1, 119.6, 108.9, 44.5,
32.7, 31.9, 27.9. HRMS (ESI) m/z: [M + H]+ Calcd for C11H13N2S 205.0794; Found 205.0790.
9-methyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2b)
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Yellow solid (47.9 mg, 73% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 115.5 – 116.9; H NMR
(400 MHz, CDCl3) δ 7.49 (s, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.32 – 4.26 (m, 2H), 2.90 – 2.82
(m, 2H), 2.46 (s, 3H), 2.25 – 2.17 (m, 2H), 1.92 – 1.84 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.2, 143.2,
134.5, 131.8, 124.2, 119.3, 108.4, 44.5, 32.7, 32.0, 28.0, 21.5. HRMS (ESI) m/z: [M + H]+ Calcd for C12H15N2S
219.0950; Found 219.0947.
8-methyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2c)
White solid (28.2 mg, 65% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 138.6 – 140.4 oC; 1H NMR
(400 MHz, CDCl3) δ 7.58 (d, J = 8.1 Hz, 1H), 7.11 – 7.03 (m, J = 8.7 Hz, 2H), 4.36 – 4.25 (m, 2H), 2.92 – 2.80 (m,
2H), 2.49 (s, 3H), 2.27 – 2.16 (m, 2H), 1.93 – 1.83 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 150.8, 141.0, 136.6,
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132.8, 123.7, 119.1, 108.9, 44.4, 32.8, 32.0, 28.0, 21.9. HRMS (ESI) m/z: [M + H]+ Calcd for C12H15N2S 219.0950;
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7-methyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2d)
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White solid (28.0 mg, 64% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 138.6 – 140.1 oC; 1H NMR
(400 MHz, CDCl3) δ 7.57 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 4.70 – 4.57 (m, 2H),
2.96 – 2.83 (m, 2H), 2.67 (s, 3H), 2.22 – 2.11 (m, 2H), 1.99 – 1.89 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ
152.2, 143.2, 135.0, 125.6, 122.1, 120.3, 117.8, 45.6, 32.7, 30.7, 28.1, 19.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C12H15N2S 219.0950; Found: 219.0945.
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9-fluoro-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2e)
Yellow solid (26.7 mg, 60% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 155.6 – 158.3 oC; 1H NMR
(400 MHz, CDCl3) δ 7.37 (d, J = 9.2 Hz, 1H), 7.21 – 7.15 (m, 1H), 7.02 (t, J = 9.2 Hz, 1H), 4.37 – 4.25 (m, 2H), 2.97 –
2.83 (m, 2H), 2.30 – 2.18 (m, 2H), 1.97 – 1.86 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.3 (d, J = 237.8 Hz),
153.1, 143.1 (d, J = 12.6 Hz), 133.0, 111.0 (d, J = 26.3 Hz), 109.2 (d, J = 10.2 Hz), 105.3 (d, J = 24.1 Hz), 44.9, 32.6,
31.9, 27.8. 19F NMR (377 MHz, CDCl3) δ -121.09 (td, J = 9.2, 4.2 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for
C11H12FN2S 223.0700; Found 223.0698.
10-fluoro-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2f)
White solid (43.4 mg, 98% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 165.6 – 167.1 oC; 1H NMR
(400 MHz, CDCl3) δ 7.22 – 7.13 (m, J = 8.1, 4.6 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.91 (t, J = 9.2 Hz, 1H), 4.36 – 4.28
(m, 2H), 2.93 – 2.85 (m, 2H), 2.29 – 2.17 (m, 2H), 1.97 – 1.86 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.4 (d, J
= 253.7 Hz), 152.1, 139.2 (d, J = 8.7 Hz), 131.6 (d, J = 17.0 Hz), 123.1 (d, J = 7.3 Hz), 107.6 (d, J = 17.5 Hz), 105.1 (d,
J = 4.0 Hz), 45.0, 32.6, 31.8, 27.8. 19F NMR (377 MHz, CDCl3) δ -128.01 (dd, J = 10.2, 4.7 Hz). HRMS (ESI) m/z:
[M + H]+ Calcd for C11H12FN2S 223.0700; Found 223.0700.
8-chloro-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2g)
Light yellow solid (40.5 mg, 85% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 180.2 – 183.7 oC; 1H
NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 7.19 (d, J = 8.6 Hz, 1H), 4.33 – 4.19 (m, 2H), 2.94 –
2.82 (m, 2H), 2.28 – 2.16 (m, 2H), 1.95 – 1.83 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.5, 141.4, 136.9, 128.7,
122.8, 120.4, 109.1, 44.8, 32.7, 31.8, 27.9. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12ClN2S 239.0404; Found:
239.0399.
9-chloro-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2h)
Light yellow solid (32.7 mg, 69% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 154.0 – 156.0 oC; 1H
NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.20 (q, J = 8.7 Hz, 2H), 4.34 – 4.27 (m, 2H), 2.94 – 2.86 (m, 2H), 2.29 – 2.18
(m, 2H), 1.97 – 1.85 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.1, 143.5, 135.0, 127.8, 123.2, 119.3, 109.7, 44.8,
32.6, 31.8, 27.8. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12ClN2S 239.0404; Found 239.0401.
8-bromo-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2i)
Orange solid (79.4 mg, 94% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 194.9 – 197.0 oC; 1H NMR
(400 MHz, CDCl3) δ 7.56 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 4.36 – 4.22 (m, 2H), 2.97 – 2.83
(m, 2H), 2.29 – 2.18 (m, 2H), 1.96 – 1.85 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.5, 141.8, 137.3, 125.5,
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120.7, 116.2, 112.1, 44.8, 32.6, 31.8, 27.8. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12BrN2S 282.9899; Found
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282.9896.
9-bromo-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2j)
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Light yellow solid (77.9 mg, 92% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 150.8 – 152.0 oC; 1H
NMR (400 MHz, CDCl3) δ 7.82 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.6, 1.9 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 4.33 –
4.22 (m, 2H), 2.95 – 2.82 (m, 2H), 2.28 – 2.18 (m, 2H), 1.95 – 1.85 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.9,
144.0, 135.4, 125.7, 122.2, 115.1, 110.1, 44.8, 32.6, 31.8, 27.8. HRMS (ESI) m/z: [M + H]+ Calcd for C11H12BrN2S
282.9899; Found 282.9897.
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8-phenyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2k)
Yellow solid (60.8 mg, 73% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 151.7 – 153.6 oC; 1H NMR
(400 MHz, CDCl3) δ 7.76 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.7 Hz, 2H), 7.52 – 7.41 (m, 4H), 7.34 (t, J = 7.5 Hz, 1H),
4.44 – 4.30 (m, 2H), 2.96 – 2.83 (m, 2H), 2.29 – 2.17 (m, 2H), 1.97 – 1.86 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ 152.1, 142.4, 141.7, 136.9, 136.6, 128.8, 127.5, 127.0, 122.1, 119.7, 107.5, 44.6, 32.8, 31.9, 28.0. HRMS (ESI) m/z:
[M + H]+ Calcd for C17H17N2S 281.1107; Found 281.1104.
9-phenyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2l)
Yellow solid (67.9 mg, 81% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 171.1 – 173.3 oC; 1H NMR
(400 MHz, CDCl3) δ 7.92 (s, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.37 –
7.27 (m, 2H), 4.42 – 4.23 (m, 2H), 2.96 – 2.80 (m, 2H), 2.27 – 2.16 (m, 2H), 1.95 – 1.84 (m, 2H). 13C{1H} NMR (101
MHz, CDCl3) δ 152.2, 143.4, 141.7, 135.9, 135.9, 128.8, 127.4, 126.8, 122.6, 118.0, 109.1, 44.7, 32.7, 31.9, 28.0.
HRMS (ESI) m/z: [M + H]+ Calcd for C17H17N2S 281.1107; Found 281.1104.
9-(trifluoromethyl)-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2m)
White solid (54.5 mg, 98% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 132.1 – 135.6 oC; 1H NMR
(400 MHz, CDCl3) δ 7.97 (s, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 4.40 – 4.30 (m, 2H), 2.97 – 2.87
(m, 2H), 2.30 – 2.19 (m, 2H), 1.98 – 1.89 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 154.0, 142.2, 138.2, 124.7 (q, J
= 272.7 Hz), 124.7 (q, J = 32.3 Hz), 119.6 (q, J = 3.6 Hz), 117.2 (q, J = 4.4 Hz), 109.3, 44.9, 32.6, 31.7, 27.8. 19F NMR
(377 MHz, CDCl3) δ -60.67 (s). HRMS (ESI) m/z: [M + H]+ Calcd for C12H12F3N2S 273.0668; Found 273.0669.
8-(pyrrolidin-1-yl)-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2n)
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Yellow oil (34.2 mg, 63% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 144.0 – 147.4 C; H NMR
(400 MHz, CDCl3) δ 7.53 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 8.8, 2.1 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 4.28 – 4.20 (m,
2H), 3.37 – 3.27 (m, 4H), 2.87 – 2.78 (m, 2H), 2.19 (p, J = 5.8 Hz, 2H), 2.07 – 1.98 (m, 4H), 1.91 – 1.80 (m, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 147.7, 145.4, 137.8, 134.4, 119.8, 109.4, 89.9, 48.3, 44.1, 33.1, 32.1, 28.1, 25.5.
HRMS (ESI) m/z: [M + H]+ Calcd for C15H20N3S 274.1372; Found 274.1365.
8-methoxy-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2o)
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White solid (32.2 mg, 69% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 193.4 – 194.7 C; H NMR
(400 MHz, CDCl3) δ 7.58 (d, J = 8.8 Hz, 1H), 6.88 (dd, J = 8.7, 2.4 Hz, 1H), 6.73 (s, 1H), 4.32 – 4.22 (m, 2H), 3.86 (s,
3H), 2.94 – 2.83 (m, 2H), 2.27 – 2.16 (m, 2H), 1.94 – 1.83 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.8, 150.0,
137.4, 137.0, 120.1, 111.4, 92.7, 55.9, 44.4, 32.9, 32.0, 28.0. HRMS (ESI) m/z: [M + H]+ Calcd for C12H15N2OS
235.0900; Found 235.0897.
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8-chloro-9-methyl-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2p)
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White solid (41.1 mg, 82% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 186.4 – 187.9 oC; 1H NMR
(400 MHz, CDCl3) δ 7.53 (s, 1H), 7.28 (s, 1H), 4.30 – 4.20 (m, 2H), 2.92 – 2.84 (m, 2H), 2.46 (s, 3H), 2.29 – 2.19 (m,
2H), 1.94 – 1.83 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 152.2, 141.8, 135.4, 129.9, 129.4, 120.7, 109.2, 44.8,
32.7, 31.9, 27.9, 20.5. HRMS (ESI) m/z: [M + H]+ Calcd for C12H14ClN2S 253.0561; Found 253.0559.
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8-bromo-9-fluoro-2,3,4,5-tetrahydrobenzo[4,5]imidazo[2,1-b][1,3]thiazepine (2q)
White solid (51.3 mg, 85% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 201.7 – 203.2 oC; 1H NMR
(400 MHz, CDCl3) δ 7.46 (t, J = 8.1 Hz, 2H), 4.37 – 4.22 (m, 2H), 2.98 – 2.84 (m, 2H), 2.31 – 2.20 (m, 2H), 1.98 –
1.87 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.2 (d, J = 239.5 Hz), 153.9, 142.2 (d, J = 11.2 Hz), 133.6, 112.8,
106.1 (d, J = 25.2 Hz), 104.2 (d, J = 24.7 Hz), 42.1, 32.6, 31.8. 27.7. 19F NMR (377 MHz, CDCl3) δ -114.63 (dd, J =
8.8, 5.6 Hz). HRMS (ESI) m/z: [M + H]+ Calcd for C11H11BrFN2S 300.9805; Found 300.9805.
7,8,9,10-tetrahydropyrido[3',2':4,5]imidazo[2,1-b][1,3]thiazepine (2r)
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White solid (31.7 mg, 77% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 95.1 – 96.3 C; H NMR
(400 MHz, CDCl3) δ 8.38 – 8.26 (m, 1H), 7.95 (dd, J = 8.1, 2.4 Hz, 1H), 7.24 – 7.13 (m, 1H), 4.63 – 4.43 (m, 2H), 3.02
– 2.84 (m, 2H), 2.32 – 2.20 (m, 2H), 1.99 – 1.84 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.8, 148.5, 143.6,
135.2, 126.8, 118.4, 42.9, 32.8, 32.1, 28.0. HRMS (ESI) m/z: [M + H]+ Calcd for C10H12N3S 206.0746; Found
206.0745.
(cis)-7,7a,8,9,10,11,11a,12-octahydrobenzo[e]benzo[4,5]imidazo[2,1-b][1,3]thiazepine (2s)
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Colorless oil (41.3 mg, 80% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant); H NMR (400 MHz, CDCl3) δ
7.71 (d, J = 7.4 Hz, 1H), 7.26 – 7.16 (m, 3H), 4.47 – 4.15 (m, 2H), 3.08 (t, J = 12.5 Hz, 1H), 2.72 (s, 1H), 2.42 – 2.25
(m, 1H), 2.19 – 2.03 (m, 1H), 1.81 (s, 1H), 1.72 – 1.28 (m, 7H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.5, 142.9,
136.9, 122.7, 122.1, 119.6, 109.0, 53.5, 48.2, 41.3, 37.9, 33.2, 31.0, 25.2, 21.2. HRMS (ESI) m/z: [M + H]+ Calcd for
C15H19N2S 259.1263; Found 259.1261.
7,12-dihydrobenzo[e]benzo[4,5]imidazo[2,1-b][1,3]thiazepine (2t)
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Yellow oil (15.6 mg, 30% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant), mp: 157.7 – 160.0 C; H NMR
(400 MHz, CDCl3) δ 7.57 (d, J = 7.8 Hz, 1H), 7.42 – 7.31 (m, 4H), 7.31 – 7.27 (m, 1H), 7.25 – 7.16 (m, 2H), 5.31 (s,
2H), 4.35 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 142.6, 137.8, 135.6, 134.1, 129.9, 129.3, 128.7, 128.6,
122.2, 121.8, 118.3, 107.9, 46.8, 31.9. HRMS (ESI) m/z: [M + H]+ Calcd for C15H13N2S 253.0794; Found 253.0789.
3-methyl-2-(methylthio)-3H-imidazo[4,5-b]pyridine (2u)
Brown oil (31.3 mg, 88% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant); 1H NMR (400 MHz, CDCl3) δ 7.74
– 7.67 (m, 1H), 7.27 – 7.20 (m, 3H), 3.67 (s, 3H), 2.82 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.2, 143.3, 136.8,
121.8, 121.8, 118.0, 108.3, 29.9, 14.7. HRMS (ESI) m/z: [M + H]+ Calcd for C9H11N2S 179.0637; Found 179.0636.
1-ethyl-2-(ethylthio)-1H-benzo[d]imidazole (2v)
Light red liquid (38.1 mg, 92% yield, ethyl acetate/petroleum ether = 1/2.5 as eluant); 1H NMR (400 MHz, CDCl3) δ
7.80 – 7.64 (m, 1H), 7.32 – 7.18 (m, 3H), 4.16 (q, J = 7.3 Hz, 2H), 3.42 (q, J = 7.4 Hz, 2H), 1.49 (t, J = 7.4 Hz, 3H),
1.40 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 151.5, 143.7, 135.6, 121.7, 121.6, 118.2, 108.5, 38.8, 26.8,
14.9, 14.5. HRMS (ESI) m/z: [M + H]+ Calcd for C11H15N2S 207.0950; Found 207.0944.
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General procedure for the synthesis of product 3a:
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Compound 2a (40.8 mg, 0.2 mmol) was dissolved in ethanol/water mixture (EtOH:H2O = 2:1, 2 mL). Then oxone
was added (492.8 mg, 0.8 mmol, 4.0 eq) and the mixture was stirred at room temperature overnight. After the reaction
was finished, the mixture was diluted with water and saturated aqueous NaHCO3 was added. The aqueous phase was
then extracted with ethyl acetate and the organic phase was washed with brine, dried over Na2SO4 and evaporated to
dryness. The crude product was purified by chromatography on silica gel to give the product 3a (44.7 mg, 95% yield).
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White solid (44.5 mg, 95 % yield, ethyl acetate/petroleum ether = 1:1 as eluant), mp: 218.5 – 220.8 C; H NMR
(400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 1H), 7.50 – 7.34 (m, 3H), 4.62 – 4.46 (m, 2H), 3.47 – 3.30 (m, 2H), 2.43 –
2.33 (m, 2H), 2.08 – 1.96 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.0, 140.8, 135.4, 126.1, 123.9, 122.3, 110.2,
54.1, 44.4, 28.0, 23.9. HRMS (ESI) m/z: [M + H]+ Calcd for C11H13N2O2S 237.0692; Found 237.0690.
General procedure for crystal analysis of product 2a:
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Compound 2a (40.8 mg, 0.2 mmol) was dissolved in 1.0 mL dry xylene at 50 C and filtered with membrane filter.
Then after 6 hour’s standing at 0 oC, single crystals of compound 2a suitable for X-ray analysis were obtained from the
solution as white needles. Single-crystal X-ray diffraction study were carried out on a Brüker SMART APEX CCD
diffractometer with graphite-monochromated Mo Kα radiation (λ = 0.71073 Å).
ACKNOWLEDGMENTS
We thank the Fundamental Research Funds for the Central Universities (No. DUT18LAB16) for support of this
work. We gratefully thank Professor Erick M. Carreira at ETH Zürich for suggestions on the reaction mechanism.
Supporting Information. 1H and 13 C NMR spectra of all products and X-ray crystallographic data for compound 2a
(PDF) and X-ray crystal details for 2a (CIF).
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Jain, K. S.; Shah, A. K. 1,5-Benzothiazepine, a versatile pharmacophore: a review. Eur. J. Med. Chem. 2008, 43, 2279-
2290; (b) Martínez, W. R.; Militão, G. C. G.; da Silva, T. G.; Silva, R. O.; Menezes, P. H. Synthesis of novel [3,1]-
benzothiazepine and [3,1]-benzoxazepine derivatives with antitumoral activity. RSC Adv. 2014, 4, 14715-14718; (c)
Campiani, G.; Butini, S.; Fattorusso, C.; Catalanotti, B.; Gemma, S.; Nacci, V.; Morelli, E.; Cagnotto, A.; Mereghetti,
I.; Mennini, T.; Carli, M.; Minetti, P.; Di Cesare, M. A.; Mastroianni, D.; Scafetta, N.; Galletti, B.; Stasi, M. A.;
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