Efficient synthesis of 1,2-benzisothiazoles from: O -haloarylamidines and elemental sulfur via N-S/C-S bond formation under transition-metal-free conditions

Article abstract of DOI:10.1039/c7gc03599c

An efficient method for the synthesis of 1,2-benzisothiazoles from amidines and elemental sulfur via N-S/C-S bond formation under transition-metal-free conditions is described. This reaction is performed smoothly under simple conditions to give the corresponding products in good to high yields with good functional group tolerance.

Full text of DOI:10.1039/c7gc03599c

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Efficient synthesis of 1,2-benzisothiazoles from o-haloarylamidi-
nes and elemental sulfur via N-S/C-S bond formation under tra-
nsition-metal-free conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Hao Xie,a Guozheng Li,a Feng Zhang,b,* Fuhong Xiao,a GuoꢀJun Denga,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient method for the synthesis of 1,2-benzisothiazoles from methyl thiosalicylates via SꢀN bond formation process
from amidines and elemental sulfur via N-S/C-S bond formation (between SH and NH groups) using hypervalent iodine reagent
under transition-metal-free conditions is described. The reaction PIFA [(phenyliodine(III)bis(trifluoroacetate)] as the oxidant.11
performed smoothly under simple conditions to give the Recently, Yadav and coꢀworkers developed
a substrate
corresponding products in good to high yields with good controlled synthesis of benzisothiazole derivatives from 2ꢀ
functional group tolerance.
aminoꢀ
sulfur source.12 However, this method is mainly suitable for the
preparation of 3ꢀsubstituted benzo[ ]isothiazole which is
isomer of 1,2ꢀbenzoisothiazole (benzo[ ]isothiazole). General
synthetic route for various substituted 1,2ꢀbenzoisothiazole
preparation under simple and mild reaction conditions is highly
desirable.
N'ꢀarylꢀbenzohydrazides using Lawesson's reagent as the
Benzothiazole and benzisothiazole derivatives are privileged
motif frequently found in natural products, pharmaceuticals,
and many other biologically active products.1 For example,
benzisothiazole derivatives have shown a diverse range of
biological and pharmacological activities such as antiꢀ
metalloproteinases (MMPs),2 antiproliferative,3 antimicrobial,4
c
d
antiꢀinflammatory
and
antibacterial.5
Therefore,
the
Thermolysis reaction
R
development of efficient methods for facile construction of
benzothiazole and benzisothiazole derivatives attracted
considerable interest. However, comparing with the numerous
synthetic methods for benzothiazole derivatives,6 efficient
procedures for benzisothiazole synthesis are much less
developed. The benzisothiazole core skeleton could be prepared
in relative low yield from 2,2'ꢀdisulfanediyldibenzamide using
lithium aluminium tetrahydride as the reducing agent.7
Thermolysis reaction of hydroxylamine derivatives provided
the corresponding benzisothiazole derivatives in moderate to
good yields (Fig.1, a).8 Similarly, flash vacuum pyrolysis (FVP)
R
O
thermolysis
N
R1
R2
(a)
(b)
(c)
N
S
S
S
R1 = t-C4H9 or i-C3H7
With ammonia
R
S
NH3
N
R
N
Cl
- 2HCl
Cl
o
of oxime ethers at 650 C also afforded 1,2ꢀbenzisothiazoles as
This work: via S-N/C-N bond for mation
the major products.9 However, the highly functionalized
starting materials need several steps to prepare and the substrate
scope is very limited. When treatment of 3ꢀchloroꢀ1,2ꢀ
benzisothiazolium chlorides with NH3, 3ꢀarylaminoꢀ1,2ꢀ
benzisothiazoles could be achieved as the major products (Fig.1,
b).10 A series of benzisothiazolone derivatives were synthesized
NR1R2
NR1R2
S8, K3PO4
air
NH
N
S
X
37 examples
yields up to 97%
transition-metal-free
X = F, Cl or Br
Fig. 1 Various synthesis of 1,2ꢀbenzisothiazoles.
a.Key Laboratory for Green Organic Synthesis and Application of Hunan Province,
Key Laboratory of Environmentally Friendly Chemistry and Application of
Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan
411105, China. E-mail: gjdeng@xtu.edu.cn.
Sulfur powder is an important, cheap and easy to handle
sulfur source.13 Therefore, It is the most direct way to construct
sulfurꢀcontaining heterocycles with sulfur powder as the sulfur
source via CꢀS bond formation process.14 Very recently, the
Nguyen group,15 we16 and others17 developed various methods
b.College of Science, Hunan Agricultural University, Changsha, 410128, China. E-
mail: zhangf@iccas.ac.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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for construction of sulfurꢀcontaining heterocycles under metalꢀ temperature both decreased the reaction yield (entries 12 and
free conditions using elemental sulfur as the sulfur source. 13). Finally, the reaction yield could be slightly improved by
Since benzisothiazole derivatives are very prominent prolonging the reaction time to 48 h (entry 14). No desired
biologically active compounds and there is lack of effective product was observed when Na2S·9H2O was used (entry 15).
synthetic method for preparation of them, we herein report a
Table 2. Substrate scope with respect to substituents on aniline
general synthesis of 3ꢀarylaminoꢀ1,2ꢀbenzisothiazoles using
amidines and elemental sulfur as the starting materials (Fig. 1,
c). The reaction could be realized in oneꢀpot via SꢀN/CꢀS bond
formation under transitionꢀmetalꢀfree conditions.
ringa
R1
HN
R1
HN
NH
Table 1 Optimization of the reaction conditionsa
K3PO4
+
N
S8
air, 36 h
Ph
S
Cl
HN
Ph
HN
1
2
NH
base
R 2a, R = H, 83%
2c, R = Et, 72%
2e, R = OMe, 92%
2g, R = OCF3, 60%
2i, R = Cl, 67%
+
2b, R = Me, 63%
2d, R = t-Bu, 94%
2f, R = OEt, 73%
2h, R = F, 65%
N
S8
HN
S
Cl
1a
2a
N
S
Yield (%)b
Entry
1
Base
Solvent
2j, R = Br, 65%
2k, R = Ph, 80%
2l, R = 2-Naphthyl, 67%
Cs2CO3
K2CO3
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
36
40
37
28
68
60
46
2
3
4
2m, R = Me, 54%
2n, R = Et, 81%
2o, R = Cl, 45%
HN
HN
R
KH2PO4
K3PO4
K3PO4
K3PO4
N
N
S
S
5
6
7
2p, 66%
OMe
OMe
DMF
HN
OMe
OMe
HN
8
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMAc
62
71
80
78
55
63
HN
N
9
DMSO/ toluene (1:1)
OMe
N
S
N
10
11
12c
13d
DMSO/ toluene (1:2)
DMSO/ toluene (1:3)
S
S
2q, 77%
2r, 88%
2s, 52%
DMSO/ toluene (1:2)
DMSO/ toluene (1:2)
DMSO/ toluene (1:2)
DMSO/ toluene (1:2)
a Reaction conditions: 1 (0.2 mmol), S8 (5 equiv), K3PO4 (0.4 mmol),
DMSO/toluene (1:2, 0.6 mL), under air at 135 oC for 36 h.
14e
15f
K3PO4
82
With the optimized reaction conditions established, we next
probed the scope and generality of this reaction by changing
trace
a Reaction conditions: 1a (0.2 mmol), S8 (32.0 mg, 5 equiv), base (2
equiv), solvent (0.6 mL), under air at 135 oC for 36 h. b GC Yield. c
S8 (2 equiv). d 120 oC. e 48 h. f Na2S 9H2O (0.4 mmol) in stead of
S8.
substituents on
Nꢀphenyl ring (Table 2). In general, substrates
with electronꢀdonating groups at the para position could
smoothly react with sulfur powder to give the corresponding
products in good to high yields. Especially when tertꢀbutyl and
methoxy group were presented, the corresponding products 2d
and 2e were obtained in 94% and 92% yield, respectively.
Halogen functional groups such as OCF3, fluoro, chloro and
bromo were compatible under the standard reaction conditions
We initiated our studies by choosing 2ꢀchloroꢀNꢀ
phenylbenzimidamide (1a) as a model substrate to get the
optimized reaction conditions, and the selected results are
summarized in Table 1. When the reaction mixture in DMSO
was stirred at 135 °C for 36 h in the presence of Cs2CO3, the
desired product 3ꢀphenylaminoꢀ1,2ꢀbenzisothiazole (2a) was
observed in 36% yield (entry 1). To improve the reaction yield,
various inorganic bases were screened (entries 2ꢀ5). Among
them, K3PO4 showed the best efficiency for this kind of
transformation. Although other single organic solvent did not
give better yield, the use of mixed solvent system of DMSO
with PhMe profoundly enhanced the reaction efficiency (entries
9ꢀ11) and the desired product 2a could be obtained in 80%
yield when DMSO/PhMe (v:v = 1:2) was used as the solvent
system. Decreasing the amount of sulfur powder or reaction
(
2gꢀ2j). Substrates with aromatic substituents on the phenyl
ring such as phenyl and 2ꢀnaphthyl also smoothly react with
sulfur powder to give the corresponding products 2k and 2l in
80% and 67% yields, respectively. In addition, the position of
substituents on the phenyl ring slightly affected the reaction
yields (2n and 2o). The desired product 2p was obtained in
66% yield even the bulky methyl group was located at the ortho
position. It is worth noting that multiꢀsubstituted substrates also
could smoothly react with sulfur powder to give the
corresponding products in moderate to good yields (2qꢀ2s).
2 | J. Name., 2012, 00, 1-3
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Table 3 Substrate scope with respect to substituents on amidine
moietya
Table 4 Substrate scope with respect to various halogen leaving
groups and heteroaromatic substratesa
3ꢀAminoꢀ1,2ꢀbenzisothiazole (2ac) is very important and
versatile building block in organic synthesis. With 3ꢀaminoꢀ1,2ꢀ
benzisothiazole in hand, late modifications were conducted to
convert 2ac into other functionalized compounds. A Bocꢀ
protected
successfully achieved in 82% yield (Scheme 1, 4a). Similarly,
ꢀtosylation also could be smoothly proceeded using
tosylchloride as the reactant. When phthalic anhydride was
3ꢀaminoꢀ1,2ꢀbenzisothiazole
derivative
was
N
Furthermore, various amidines derived from substituted 2ꢀ used, the corresponding product was obtained in 94% yield. To
chlorobenzonitriles were also tested (Table 3). We were our delight, 3ꢀaminoꢀ1,2ꢀbenzisothiazole could smoothly react
surprised to find that no desired product 2t was obtained when with BocꢀAlaꢀOH in the presence of 2,4,6ꢀTripropylꢀ
2ꢀchloroꢀ6ꢀmethylꢀ
Nꢀphenylbenzimidamide (1t) was employed. 1,3,5,2,4,6ꢀTrioxatriphosphorinaneꢀ2,4,6ꢀTrioxide (T3P) to
Moderate yield was obtained when 2ꢀchloroꢀ3ꢀmethylꢀ
N
ꢀ
give the benzisothiazolylꢀprotected amino acid derivative (4d)
phenylbenzimidamide (1v) was used. Better yield was achieved in 70% yield.
when the methyl substituent is far away from the chloro or
amidine group (2u). In addition, halogen substituents such as
fluoro, chloro, bromo and CF3 were all compatible. The desired
product 2z and 2aa were obtained in 96% and 97% yields,
Ts
NHBoc
N
Ts
N
N
S
S
respectively. The position of substituents significantly affected
4a
4b
the reaction yield (2y vs 2z
Finally, the optimized conditions were successfully applied
to other ꢀhalo amidines (Table 4). Halogens such as F, Cl and
Br were all good leaving groups to provide the same product 2a
in high yield. In addition, 3ꢀaminoꢀ1,2ꢀbenzisothiazole (2ac
, 2aa vs 2ab).
b)
a)
c)
NH2
N
o
S
Me
HN
)
d)
NHBoc
O
was obtained when 2ꢀhalo benzimidamides were used as the
substrates. Bromo is the best leaving group to give the desired
product in 93% yield. A 5 mmol scale experiment showed that
high yield could be achieved under the given reaction
conditions. This method provided an efficient approach for 3ꢀ
aminoꢀ1,2ꢀbenzisothiazoles which is a versatile and useful
functional molecule. However, much lower yield was obtained
N
O
O
N
N
4c
4d
S
S
a Reaction conditions: a) Boc2O, Et3N, CH2Cl2, R.T., 24 h, 82%;
b) TsCl, Et3N, CH2Cl2, R.T., 24 h, 73%; c) Phthalic anhydride,
[bmim][PF6], 135 oC, 24 h, 94%; d) Boc-Ala-OH, T3P (1.43 M in
DMF), Et3N, CH2Cl2, R.T., 24 h, 70%.
when 2ꢀchloroꢀNꢀmethylꢀNꢀphenylbenzimidamide (1ad) was
used and the corresponding product 2ad was obtained in 33% Scheme 1 Late modification of 3ꢀaminoꢀ1,2ꢀbenzisothiazolea
yield. In addition, when nitrogenꢀcontaining heteroaromatic
To understand the mechanism of the reaction, we performed
some control experiments under modified conditions (Scheme
compounds were used as the substrates, the corresponding
products 2ae 2ag were obtained in high yields.
ꢀ
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2). Good yields still could be obtained in the presence of radical tolerated in this reaction system. The resulting sulfurꢀcontaining
scavengers such as TEMPO, BHT and DBE (Scheme 2, a). compounds could be transformed to useful organic synthons.
Thus, a radical process could be excluded for this kind of We expect that these studies will provide new methods to
transformations. Intermolecular competition experiment using a access functionalized benzisothiazoles with versatile uses in
methyl and
a trifluoromethyl substituted amidines was organic synthesis and medicinal applications.
conducted under the standard reaction conditions (Scheme 2,
b). Better reaction yield was obtained when an electronꢀ
withdrawing substituent was presented (21% vs 12% yield).
This means the CꢀS bond formation prefers a nucleophilic
substitution process.
Conflicts of interest
The authors declare no competing financial interest.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21572194, 21502160, 21372187), the
Collaborative Innovation Center of New Chemical
Technologies for Environmental Benignity and Efficient
Resource Utilization, the Hunan Provincial Innovative
Foundation for Postgraduate (CX2017B301).
Notes and references
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Based on the aforementioned studies and some related
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benzisothiazoles through SꢀN/CꢀS formation between 2ꢀhalo
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Scheme 3. Proposed mechanism
In summary, we have developed a novel approach for the
synthesis of 3ꢀarylaminoꢀ1,2ꢀbenzisothiazoles from amidines
and elemental sulfur under transitionꢀmetalꢀfree conditions. The
new strategy required only cheap reagents, such as K3PO4 and
air, and a variety of useful functional groups were well
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Green Chemistry
Page 6 of 6
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DOI: 10.1039/C7GC03599C
Efficient synthesis of 1,2-benzisothiazoles from o-haloarylamidines
and elemental sulfur via N-S/C-S bond formation under
transition-metal-free conditions
Hao Xie, Guozheng Li, Feng Zhang,* Fuhong Xiao, Guo-Jun Deng*
R1
R2
R1
R2
N
N
K3PO4
air
S
NH
+
N
S
X
34 examples
yields up to 97%
X = F, Cl or Br
tr ansition-metal-fr ee
Facile synthesis of 1,2-benzisothiazoles from amidines and elemental sulfur via
N-S/C-S bond formation under transition-metal-free conditions has been developed
with good tolerance of a broad range of functional groups.