An interrupted Pummerer reaction induced by hypervalent iodine(III) reagent: Facile synthesis of 2-aryl-1,2-benzisothiazol-3(2H)-ones

Article abstract of DOI:10.3987/com-01-9214

Treatment of N-aryl-2-(benzylthio)benzamides with phenyliodine(III) bis(trifluoroacetate) containing trifluoroacetic acid resulted in an interrupted Pummerer-type reaction to give 2-aryl-1,2-benzisothiazol-3(2H)-ones rather than the normal Pummerer-type p

Full text of DOI:10.3987/com-01-9214

HETEROCYCLES, Vol. 55, No. 7, 2001, pp. 1231 - 1235, Received, 2nd April, 2001
AN INTERRUPTED PUMMERER REACTION INDUCED BY
HYPERVALENT IODINE(III) REAGENT : FACILE SYNTHESIS OF 2-
ARYL-1,2-BENZISOTHIAZOL-3(2H)-ONES
Huey-Min Wang,a Hsin-Yu Huang,b Iou-Jiun Kangb, and Ling-Ching Chen*b
a Chung Hwa College of Medical Technology, Tainan, Taiwan 717, R.O.C.
b
Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University,
Kaohsiung, Taiwan 807, R.O.C.
Abstract⎯Treatment of N-aryl-2-(benzylthio)benzamides with phenyliodine(III)
bis(trifluoroacetate) containing trifluoroacetic acid resulted in an interrupted
Pummerer-type reaction to give 2-aryl-1,2-benzisothiazol-3(2H)-ones rather than
the normal Pummerer-type products.
The Pummerer reaction of sulfoxides normally proceeds via an activated sulfoxide (1) and then a
thionium ion (2) which reacts with a nucleophile at carbon to afford an α-substituted sulfide.1 In an
interrupted Pummerer reaction, the tricoordinate sulfur intermediate (1) undergoes reaction with a
nucleophile at sulfur leading to unexpected product (Scheme I ). 2
O
OCOCF3
TFAA or
OCOCF3
S
S
other
electrophilic
reagent
+
1
Nu
+
S
Nu
CH
CF3CO2H Pummerer
S CH
+
2
1
Nu
S
Nu
Nu
Interrupted
OCOCF3
OCOCF3
+
S
+
Pummerer
Scheme I
2-Aryl-1,2-benzisothiazol-3(2H)-ones have received much attention because of their antibacterial and

antifungal properties.3-6 The methods used for their synthesis involve the reaction of 2-
(chlorothio)benzoyl chloride with appropriate amines,4 cyclization of 2-carbamoylbenzenesulfenyl
halides with amines,5 reaction of bis(2-carbamoylphenyl) disulfides with thionyl chloride,6 catalytic
cyclization of N-substituted 2-(methoxycarbonyl)benzenesulfenamides by a strong base,7 and cyclization
of sulfoxide substrates acting as sulfenyl halide equivalents.8 Nevertheless, it is desirable to develop a
convenient and useful procedure for the preparation of 2-aryl-1,2-benzisothiazol-3(2H)-ones.
Recently, hypervalent iodine reagents have been used extensively in organic synthesis due to their low
toxicity, ready availability and easy handling. As a continuation of our studies concerning hypervalent
iodine(III) chemistry,9 we have reported a Pummerer-type reaction that provides a very simple and
convenient procedure for the preparation of 4H-pyrrolo[2,1-c][1,4]benzothiazines by treatment of α-
acyl sulfides with phenyliodine(III) bis(trifluoroacetate) (PIFA).10 We report here an interrupted
Pummerer-type reaction of sulfides using PIFA, which has been applied to prepare 2-aryl-1,2-
benzisothiazole-3(2H)-ones via intramolecular N-S bond formation.
The requisite N-aryl-2-(benzylthio)benzamides (4) were readily prepared from 2-(benzylthio)benzoic
acid (3) with NCS/Ph3P-complex followed by treatment with appropriate arylamines .11 Treatment of 4
with PIFA containing trifluoroacetic acid (TFA) in CH2Cl2 caused cyclization to give 2-aryl-1,2-
benzisothiazol-3(2H)-ones (5) in moderate yields.12 Under these conditions no sulfoxides and normal
Pummerer-type products were obtained (Scheme II).
O
O
O
OH
NHR
Ph
A
B
NR
S
Ph
S
S
3
4
5
complex / RNH2
Reagents : A) NCS / Ph3P
B) PIFA TFA / CH2Cl2
Scheme II
The results are given in Table 1. It was observed that electron-rich aromatic substituents on the nitrogen
led to improved yields of cyclization with sulfides (4c-e) (Table 1, Runs 3~5). Conversely, electron-
deficient substituents hindered the reactions of the N-(4-ethoxycarbonylphenyl) substrate (4g) and N-(4-
cyanophenyl) substrate (4h) to give the corresponding cyclization products in only 35 and 32 % yields,
respectively (Table 1, Runs 7 and 8). Moreover, the N-(4-nitrophenyl) substrate (4i) proved unreactive

(Run 9).
Table 1. Yields of 2-Aryl-1,2-benzisothiazol-3(2H)-ones (5) in the Reaction of
Sulfides 4 with PIFA
Run
substrate
R
substrate
Yield / %
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
CH2Ph
4-MeOC6H4
3,5-(MeO)2C6H3
72
75
80
71
76
64
35
32
0
3,4,5-(MeO)3C6H2
ClC H
4-
4-
4-
6
4
EtO2CC6H4
NCC6H4
4- O2NC6H4
A machanistic sequence for 1,2-benzisothiazol-3(2H)-one ring formation using PIFA is shown in
Scheme III. The cyclization from 4 to 5 is assumed to proceed through an interrupted Pummerer-type
reaction intermediate (7) which would be formed by attack of PIFA on the sulfur atom of 4, followed by
simultaneous elimination of the iodobenzene and trifluoroacetic acid from the resultant sulfonium salt
(6). Apparently, without the electron withdrawing group on the carbon alpha to the sulfide group,
trifluoroacetate ion is not basic enough to generate the thionium ion.
O
O
NHR
Ph
PIFA
NHR
+
S
S
Ph
OCOCF3
_
PhI
CF3CO2H
4
I
Ph
OCOCF3
6
O
O
NR
NR
+
_
S
S
OCOCF3
PhCH2OCOCF3
5
Ph
7
Scheme III

In summary, our results herein demonstrate that the use of a combined reagent PIFA-TFA in CH2Cl2 is a
convenient and useful method for the interrupted Pummerer-type reaction of sulfides to prepare 2-aryl-
1,2-benzisothiazol-3(2H)-ones.
ACKNOWLEDGEMENT
We gratefully acknowledge the National Council Science of Republic of China for financial support of
this work. (Grant No. 89-2113-M-037-018)
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12. General procedure for the preparation of 5 : A solution of N-aryl-2-(benzylthio)benzamides (4) (1
mmol) in CH2Cl2 (5 mL) was added dropwise to a solution of the mixture of PIFA (1.25 mmol) and
TFA (2 mmol) in CH2Cl2 (2 mL) at 0 ˚C and the mixture was stirred at the same temperature for 1
h. Then the mixture was refluxed for 2 h to complete the reaction. The resultant mixture was
quenched with water and extracted with CH2Cl2. The extract was dried (MgSO4) and concentrated
under reduced pressure and the residue was purified by chromatography on a silica gel column,
eluting with hexane-chloroform to give 5.