Efficient one-pot synthesis of benzo[e]pyrazolo- [1,5-c][1,3]thiazine derivatives under copper-catalyzed conditions

Article abstract of DOI:10.3987/COM-16-13477

An efficient method has been developed for the synthesis of benzo[e]pyrazolo[1,5-c][1,3]thiazines via one-pot two-step reactions of readily available substituted 1-(2-halophenyl)-3- Akylprop-2-yn-1-ones, hydrazine hydrochloride and β-oxodithioesters under mild conditions, and the corresponding benzo[e]pyrazolo[1,5-c][1,3]thiazines were obtained in good to excellent yields. The novel method affords a new strategy for the construction of diverse and useful poly N,S-heterocyclic compounds.

Full text of DOI:10.3987/COM-16-13477

HETEROCYCLES, Vol. 92, No. 7, 2016
1215
HETEROCYCLES, Vol. 92, No. 7, 2016, pp. 1215 - 1223. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 5th April, 2016, Accepted, 20th April, 2016, Published online, 28th April, 2016
DOI: 10.3987/COM-16-13477
EFFICIENT ONE-POT SYNTHESIS OF BENZO[e]PYRAZOLO-
[1,5-c][1,3]THIAZINE DERIVATIVES UNDER COPPER-CATALYZED
CONDITIONS
Jiyang Jie, Haoyi Li, Meihui Piao, and Xiaobo Yang*
College of Chemistry & Chemical Engineering, Shenyang Normal University,
Shenyang, Liaoning, 110034, China. E-mail: bxy1223@gmail.com
Abstract – An efficient method has been developed for the synthesis of
benzo[e]pyrazolo[1,5-c][1,3]thiazines via one-pot two-step reactions of readily
available substituted 1-(2-halophenyl)-3-akylprop-2-yn-1-ones, hydrazine
hydrochloride and β-oxodithioesters under mild conditions, and the corresponding
benzo[e]pyrazolo[1,5-c][1,3]thiazines were obtained in good to excellent yields.
The novel method affords a new strategy for the construction of diverse and
useful poly N,S-heterocyclic compounds.
INTRODUCTION
N-Heterocycles and S-heterocycles play the key roles in pharmaceutical and agrochemical industries.1,2
Pyrazoles represent an important structural motif frequently found in man-made biologically active
compounds such as celecoxib, fipronil, lonazolac, viagra, although they are rarely found in natural
products.3 Thiazine derivatives show various biological and medical functions.4 For example, they exhibit
antibacterial,5 anntimalarial,6 antiretroviral activities,7 and some of them are investigated as cell growth
inhibitors,8 promising inhibitors of nitric oxide synthase,9 endogenous natriuretic factors.10 However,
methods for the synthesis of pyrazolothiazines are very limited.11 Additionally, dithioester was a good
partner when some S-heterocycles were synthesized.12 So, it provides us opportunities for developing
novel procedures for the synthesis of this kind of derivatives.
In our previous works, we successfully employed 1-(2-halophenyl)-3-arylprop-2-yn-1-ones, hydrazine
hydrochloride and other nitrogen sources to construct N-fused heterocycles under mild copper-catalyzed
conditions (Scheme 1).13-15 And we found that pyrazoles could be easily constructed by
1-(2-halophenyl)-3-arylprop-2-yn-1-ones and hydrazine hydrochloride. Following this strategy, we herein
wish to report a convenient and efficient one-pot synthesis of pyrazolothiazines under copper-catalyzed
conditions.

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HETEROCYCLES, Vol. 92, No. 7, 2016
R2
N
R2
N
N
N
R1
R1
R3
N
NH2
H2N
NH
EWG
NC
O
[Cu]
EWG
R3
[Cu]
(b)
(a)
R1
H2N NH2
•
HCl
R2
X
R2
N
[Cu]
[Cu]
R2
N
NH2
R3 CO2H
O
S
this work
R1
R3
SMe
N
R1
N
R3
N
S
R3
O
(d)
(c)
Scheme 1. Strategies for constructing heterocycles using 1-(2-halophenyl)-3-arylprop-2-yn-1-ones and
hydrazine hydrochloride
RESULTS AND DISCUSSION
Initially the reaction of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1a), hydrazine hydrochloride and
methyl 3-(4-chlorophenyl)-3-oxopropanedithioate (2b) was chosen as the model to optimize reaction
conditions including copper-catalysts, ligands, bases, solvents and temperature under nitrogen atmosphere.
As shown in Table 1, the reaction of the three components is a one-pot two-step process: coupling of 1a
o
with hydrazine hydrochloride in MeCN first led to intermediate I in the presence of Cs2CO3 at 80 C for
12 h, and then treatment of Ia with 2b provided the target product (3e) under copper catalysis for 24 h
(see Schemes 2 and 3). First, four ligands (20 mol% amount relative to 1a) were screened applying 10
mol% of CuI as the catalyst, Cs2CO3 as the base, MeCN as the solvent under nitrogen atmosphere (entries
o
o
1-4), the reaction was performed at 80 C for the first step and at 100 C for the second step, and the
highest yield (89%) was obtained in the absence of ligand (entry 4). When CuBr (entry 5) and Cu(OAc)2
(entry 6) were used as the catalysts, and low yields were obtained. No desired product was observed
without copper catalyst (entry 7). Other bases were also examined (entries 8-10), and they showed the
inferior results. DMF, DMSO, 1,4-dioxane and toluene were used as the solvents (entries 11-14), and they
were inferior to MeCN (entry 4). Lower reactivity was observed when temperature was decreased to 80
oC (entry 15). When the amount of 2b was decreased to 1.5 eq. (relative to 1a), a lower yield was

HETEROCYCLES, Vol. 92, No. 7, 2016
1217
obtained (entry 16).
Table 1. Copper-catalyzed synthesis of 1-(4-chlorophenyl)-2-(2-phenyl-5H-benzo[e]pyrazolo-
[1,5-c][1,3]thiazin-5-ylidene)ethan-1-one
(3e)
(1a),
via
one-pot
hydrazine
two
hydrochloride
step
reaction
and
of
methyl
1-(2-bromophenyl)-3-phenylprop-2-yn-1-one
3-(4-chlorophenyl)-3-oxopropanedithioate (2b): optimization of conditionsa
H2N NH2
•
HCl
i
base, solvent
80 oC, 12 h
O
Ph
N
S
Cl
N
Ph
O
S
Br
1a
ii
SMe
O
2b
cat., ligand,
Cl
3e
base, solvent, temp,
N2, 24 h
temp.
(oC)c
2b
yield
(%)b
entry
cat.
ligand
base
solvent
(eq.)d
1
2
CuI
CuI
L-proline
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOAc
K3PO4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.5
43
55
86
89
43
41
0
DMEDA
3
CuI
1,10-phen
4
CuI
CuBr
Cu(OAc)2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
5
6
7
8
CuI
37
34
trace
68
29
21
39
52
66
9
CuI
10
11
12
13
14
15
16
CuI
NaOEt
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuI
DMSO
dioxane
toluene
MeCN
MeCN
CuI
CuI
CuI
CuI
100
a
Reaction conditions: (1a) (0.25 mmol), hydrazine hydrochloride (0.375 mmol), (2b) (0.625 mmol),
catalyst (0.025 mmol), ligand (0.05 mmol), base (0.75 mmol), solvent (2 mL), under nitrogen atmosphere.
Reaction time (12 h for the first step; 24 h for the second step). b Isolated yield from 1a to 3e. c For the
second step. d Relative to 1a.

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As shown in Table 2, the substrate scope of the one-pot two-step reactions was investigated, and the
examined substrates provided moderate to good yields. For compound 1, the substrates with
electron-withdrawing groups showed higher reactivity than those with electron-donating groups. The
substrate with a C–Cl bond, 1-(2-chlorophenyl)-3-phenylprop-2-yn-1-one, also gave the target product
(3a) in 73% yield. For substrate 2, substituents bearing either electron-withdrawing or electron-donating
groups gave good yields. Interestingly, no extra ligand and additive were required in the reactions above.
The reactions could tolerate some functional groups in the substrates including ether (3d, 3j, 3m-p), C–Cl
bond (3e, 3k), C–F bond (3q, 3r), CF3 (3f, 3l, 3p, 3r). In addition, we cannot get the desire product when
R2 are alkyl groups.
Table 2. One-pot two-step synthesis of benzo[e]pyrazolo[1,5-c][1,3]thiazine derivatives under
copper-catalyzed conditionsa
R2
H N NH
2
•
HCl
i
2
Cs2CO3, MeCN,
80 oC, 12 h
O
N
N
O
R1
R1
R2
O
S
S
ii
X
X=Cl, Br
1
R3
SMe
R3
2
3
CuI, Cs2CO3, MeCN,
100 oC, N2, 24 h
3, yieldb
Ph
N
Ph
N
Ph
N
O
N
N
N
S
S
S
O
O
3a 91% (X=Br)
3c 76%
3b 72%
73% (X=Cl)
Ph
Ph
N
Ph
N
N
N
N
S
N
S
S
O
O
O
OMe
Cl
CF3
3d 65%
3e 89%
3f 67%

HETEROCYCLES, Vol. 92, No. 7, 2016
1219
Ph
Ph
N
Ph
N
N
N
N
O
N
O
S
S
S
O
3h 82%
3i 91%
3g 64%
Ph
Ph
N
Ph
N
N
N
N
S
N
S
S
O
O
O
OMe
Cl
CF3
3j 73%
3k 72%
3l 94%
Ph
N
Ph
Ph
N
N
MeO
MeO
MeO
N
O
N
S
N
S
S
O
O
3n 53%
3o 56%
3m 95%
Ph
Ph
Ph
N
N
N
N
MeO
F
F
N
N
O
S
S
S
O
O
CF3
CF3
3p 94%
3q 89%
3r 87%
Ph(p-Me)
N
N
O
S
3s 89%
a Reaction conditions: substituted 1-(2-bromophenyl)-3-alkylprop-2-yn-1-one (1) (0.25 mmol), hydrazine
hydrochloride (0.375 mmol), β-oxodithioesters (2) (0.625 mmol), CuI (0.025 mmol), Cs2CO3 (0.75
o
mmol), MeCN (2 mL) 100 C (for the second step), under nitrogen atmosphere. Reaction time (12 h for
the first step; 24 h for the second step). b Isolated yield from 1 to 3.

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HETEROCYCLES, Vol. 92, No. 7, 2016
As shown in Scheme 2, we attempted two control experiments in order to explore the copper-catalyzed
one-pot two-step reaction mechanism. Coupling of 1-(2-bromo-5-methoxyphenyl)-
3-phenylprop-2-yn-1-one (1c) with hydrazine hydrochloride in the presence of Cs2CO3 led to
5-(2-bromo-5-methoxyphenyl)-3-phenyl-1H-pyrazole in 89% yield (Ia) (Scheme 2A), whose structure
was confirmed by NMR and MS. Copper-catalyzed reaction of Ia with methyl
3-oxo-3-phenylpropanedithioate (2a) provided product 3m in 91% yield under the standard condition
(Scheme 2B). Therefore, a possible mechanism on the copper-catalyzed three-component reactions of
substituted 1-(2-bromophenyl)-3-phenylprop-2-yn-1-ones, hydrazine hydrochloride and β-oxodithioesters
leading to benzo[e]pyrazolo[1,5-c][1,3]thiazine derivatives (3) is proposed in Scheme 3. First, coupling of
substituted 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (1) with hydrazine hydrochloride provides I in
the presence of base (Cs2CO3). Copper-catalyzed coupling of I with β-oxodithioesters (S-arylation) gives
II, intramolecular nucleophilic substitution reaction in II leads to the target product (3).
In summary, we have developed a convenient and efficient copper-catalyzed method for the synthesis of
benzo[e]pyrazolo[1,5-c][1,3]thiazine derivatives from the readily available starting materials. The
reactions were performed under mild conditions, and no extra ligand and additive were required. In
addition, pyrazoles were not pre-synthesized. This convenient and economical approach to
benzo[e]pyrazolo[1,5-c][1,3]thiazine derivatives is expected to find wide application in academic and
industrial research.
Ph
O
N
MeO
MeO
N
(A)
Cs2CO3, MeCN
80 oC, 12 h
H
H2N NH2
•
HCl
+
Ph
Br
Br
1c
Ia
89% yield
Ph
Ph
N
CuI, Cs2CO3,
MeCN
MeO
N
S
O
N
MeO
N
(B)
O
100 oC, N2,
24 h
H
+
H2CS
Ph
S
Br
2a
Ia
Ph
3m
91% yield
Scheme 2. (A) Coupling of 1-(2-bromo-5-methoxyphenyl)-3-phenylprop-2-yn-1-one (1c) with hydrazine
hydrochloride leading to 5-(2-bromo-5-methoxyphenyl)-3-phenyl-1H-pyrazole (Ia).
(B) Copper-catalyzed reaction of Ia with methyl 3-oxo-3-phenylpropanedithioate (2a) leading
to 3m

HETEROCYCLES, Vol. 92, No. 7, 2016
1221
R2
N
O
R1
Cs2CO3
N
R2
H2N NH2
•
HCl
R1
+
H
Br
Br
1
I
R2
N
R2
R3
SMe
N
N
R1
N
O
H
R1
2
SMe
O
S
S
copper-catalyzed
S-arylation
S
R3
O
R3
II
3
Scheme 3. Possible mechanism for synthesis of benzo[e]pyrazolo[1,5-c][1,3]thiazine derivatives (3)
EXPERIMENTAL
All reactions were carried out under nitrogen atmosphere. Proton and carbon magnetic resonance spectra
13
(1H NMR and C NMR) were recorded using tetramethylsilane (TMS) in the solvent of CDCl3 as the
internal standard (1H NMR: TMS at 0.00 ppm, CDCl3 at 7.26 ppm; 13C NMR: CDCl3 at 77.0 ppm).
General procedure for synthesis of compounds 3a-s.
Substituted 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one (0.25 mmol), hydrazine hydrochloride (0.5
mmol), Cs2CO3 (0.5 mmol, 163 mg), dried MeCN (3 mL) were added to a 25 mL t-shaped tube with a
magnetic stirrer under nitrogen atmosphere. The mixture was allowed to stir under nitrogen atmosphere at
80 oC for 12 h. After cooled to room temperature, β-oxodithioester (0.625 mmol), Cs2CO3 (0.25 mmol, 82
mg), CuI (0.025 mmol, 5 mg) were added to this 25 mL t-shaped tube with a magnetic stirrer under
nitrogen atmosphere. The mixture was allowed to stir under nitrogen atmosphere at 100 oC for 24 h. After
cooled to room temperature, the resulting solution was concentrated via rotary evaporation, and the
residue was purified by column chromatography on silica gel to provide the desired product (3a-s).
ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (21402126), Natural
Science Foundation of Liaoning Province (20141090), the Program for Excellent Talents in University of
Liaoning Province (LJQ2014121), Doctoral Fund of Shenyang Normal University, Director Fund of
Ecological and Environmental Research Centre of Shenyang Normal University (EERC-G-201403).
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