Product Class 16: Benzisothiazoles

11.16 Product Class 16:
Benzisothiazoles
D. W. Brown and M. Sainsbury
General Introduction
Benzisothiazoles have a much longer history than isothiazoles and 2,1-benzisothiazole
was first synthesized in 1898. Saccharin, the best-known 1,2-benzisothiazole derivative,
was first prepared in 1879.
Two isomeric forms of benzisothiazole are known, depending on the position of the
ring fusion. Benz[d]isothiazole is better known as 1,2-benzisothiazole (1) and benz[c]isothiazole
as 2,1-benzisothiazole (2) (Scheme 1). 2,3-Dihydro-1,2-benzisothiazole (3) is also
described as 1,2-benzisothiazoline, and 1,3-dihydro-2,1-benzisothiazole (4) as 2,1-benzisothiazoline.
It is noteworthy that in 1,3-dihydro-2,1-benzisothiazoles the ortho-quinone
system is lost and the carbocycle becomes benzenoid.
Scheme 1 Nomenclature of Benzisothiazoles
4
3
5
N 2
6
S
7 1
1 1,2-benzisothiazole
NH
S
3 2,3-dihydro-1,2-benzisothiazole
4
3
5
S 2
6
N
7 1
2 2,1-benzisothiazole
S
N
H
4 1,3-dihydro-2,1-benzisothiazole
Both compounds are well represented and their chemistry is regularly reviewed, most recently
by Chapman and Peart in Comprehensive Heterocyclic Chemistry II [1] and by Schulze
(the authors acknowledge the fact that this chapter is based upon this earlier contribution)
in Houben±Weyl. [2] Other information on these compounds is available annually in
Progress in Heterocyclic Chemistry. Aspects of the aromaticity of isothiazoles in general is
covered by Simkin, Minkin, and Glukhovtsev in Advances in Heterocyclic Chemistry. [3]
The main interest in benzisothiazoles over the years has been the sweet taste of the
compound saccharin, 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (5). Five hundred times
sweeter than sugar in dilute solution, saccharin has been the subject of many patents
and also much development work aimed at reducing its metallic aftertaste. [4] In addition
2-alkylsaccharins show a wide range of biological activity (see Section 11.16.1.3.2.1.1) and
some 2-alkanoic acid derivatives exhibit antimicrobial action. [5] Other benzisothiazoles
have pharmacological importance and value as agrochemicals. For example, ipsapirone
(6) is an axiolytic serotonin receptor agonist and probenazole (7) is used against rice blast
fungus (Scheme 2).
573
for references see p 622

574 Science of Synthesis 11.16 Benzisothiazoles
Scheme 2 Some Commercially Important Benzisothiazoles
O
NH
S
O O
5 saccharin
11.16.1 Product Subclass 1:
1,2-Benzisothiazoles
O
N
S
O O
N
( )4
6 ipsapirone
N
N
N
O
N
S
O O
7 probenazole
1,2-Benzisothiazole (1), which smells of almonds, exists as a low-melting, pale yellow
solid (mp378C; bp2208C). Bond lengths and internal bond angles for 1,2-benzisothiazole-3-acetic
acid [6] are shown in Scheme 3.
141
Scheme 3 Bond Lengths (pm) and Angles (8) for 1,2-Benzisothiazole-3-acetic Acid [6]
138
137
140
141
144
172
131
N
S
168
bond lengths
CO 2H CO 2H
120
122
119
120
115
N
S
121
117 94
111.5
internal bond angles
In the 1 H NMR spectra of 1,2-benzisothiazoles the H3 signal normally occurs at d 8.2±8.8:
thus, for 5,6-dimethoxy-1,2-benzisothiazole H3 resonates at d 8.7. For the same compound
the chemical shifts of H4 and H7 are d 7.3 and 7.4, respectively. [7] The chemical
shifts of the benzenoid resonances are, as might be anticipated, influenced by the nature
of the substituents in that ring and, for example, in the spectrum of 5-acetoxy-3-methyl-
1,2-benzisothiazole the resonance of H4 is at d 8.6, while those of H6 and H7 are at ca. d
8.1. [8]
13 C NMR signals for C3 of 3-alkyl-1,2-benzisothiazoles occur at d 161±165, the resonance
of C3a is normally found at d 128±130 and that of C7a is at d 148±153 in
CDCl 3. [8,11] The resonance positions of these signals are almost the same in 1,2-benzisothiazole
1-oxides, and even in 1,1-dioxides the only obvious change is an upfield shift of
about 10 ppm in the resonance position of C7a (in DMSO). [11]
Benzisothiazoles are soluble in organic solvents, but insoluble in water. They dissolve
in aqueous acid forming salts.
3-Methyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (8) is a nonplanar and flexible
molecule. X-ray studies show that it exists as two crystallographically distinct conformers,
in which the pyramidal nitrogen lies above the plane of the ring by either 3 pm or
51 pm. The N-H and C-Me bonds are arranged in a cis configuration (Scheme 4), allowing
the lone pair of the nitrogen atom to bisect the angle between the S-O bonds. [12]

11.16.1 1,2-Benzisothiazoles 575
Scheme 4 Conformation of 3-Methyl-2,3-dihydro-1,2benzisothiazole
1,1-Dioxide [12]
H
N
S
O
O
8
•
Reactivity: The attachment of a benzene ring to the isothiazole nucleus has the effect of
directing most electrophilic substitution reactions into the carbocycle at C4. Although the
nature of substituents already in the benzenoid ring influences the position of attack,
electrophilic nitration and halogenation reactions are important for the synthesis of the
corresponding nitro- and halo-1,2-benzisothiazoles (see Section 11.16.1.3.1.1).
N-Alkylation of 1,2-benzisothiazoles can be achieved by treatment with triethyloxonium
tetrafluoroborate, [13] or with dimethyl sulfate [14] in contact with perchloric acid. [15,16]
The salts formed are unstable to strong heat and, for example, if 3-chloro-2-ethyl-1,2-benzisothiazolium
chloride (9) is distilled, chloroethane is lost and 3-chloro-1,2-benzisothiazole
(10) is obtained in 78% yield (Scheme 5). [17]
Scheme 5 Thermal Decomposition of 3-Chloro-2-ethyl-1,2-benzisothiazolium Chloride [17]
Cl
+
NEt
S Cl
9
−
distillation
− EtCl
78%
For the synthesis of 2-alkylsaccharins see Section 11.16.1.3.2.1.1.
Some nucleophilic reagents (sodium methoxide, sodium cyanide, butyllithium, thiols,
and some tertiary bases) react with 1,2-benzisothiazoles, or 3-halo-1,2-benzisothiazoles,
and cause ring opening. For example, 1,2-benzisothiazole (1) is cleaved by treatment
with sodium methoxide to sodium 2-cyanobenzenethiolate (Scheme 6). [18±20]
10
Cl
N
S
Scheme 6 RingOpeningof 1,2-Benzisothiazole with Sodium Methoxide [18±20]
1
N
S
NaOMe, MeOH
When 3-chloro-1,2-benzisothiazole (11) is treated with sodium cyanide in acetone the
reaction gives bis(2-cyanophenyl) disulfide (12) [21] and 2-thiocyanatobenzonitrile (13) in
yields of 22 and 62%, respectively, together with a smaller amount of 2-acetylbenzo[b]thiophen-3-amine
(14) (6%) (Scheme 7). [22] The reaction between 11 and sodium benzenethiolate
at 408C gives bis(2-cyanophenyl) disulfide (12) in about 50% yield, plus diphenyl disulfide
and a smaller amount of 2-cyanophenyl phenyl disulfide. [21±27] A similar result is noted
when copper(I) cyanide replaces sodium cyanide, but now 3-chloro-1,2-benzisothiazole
(11) gives bis(2-cyanophenyl) disulfide (12) as the main product (80%). 3-Chloro-1,2-benzisothiazole
(11) reacts with butyllithium at ±78 8C in diethyl ether to give 2-(butylsulfanyl)benzonitrile
(15) in 90% yield (Scheme 7). [18±26]
CN
SNa
for references see p 622

576 Science of Synthesis 11.16 Benzisothiazoles
Scheme 7 Reaction of 3-Chloro-1,2-benzisothiazole [18±27]
11
Cl
N
S
NaX
CN
S
S
NC
12
13
CN
+ +
Reagent Yield (%) Ref
12 13 14
NaCN, acetone 22 62 6 [21,22]
a [21±27]
NaSPh, 40 8C 50
a Diphenyl disulfide and 2-cyanophenyl phenyl disulfide are also formed.
11
Cl
N
S
BuLi, Et 2O, −78 o C
Reaction of 3-bromoisothiazolo[5,4-b]pyridine (16) [25] with piperidine gives 2-(piperidinosulfanyl)pyridine-3-carbonitrile
(17) (Scheme 8). [28]
15
CN
SBu
SCN
Scheme 8 Reaction of 3-Bromoisothiazolo[5,4-b]pyridine with Piperidine [28]
N
16
Br
N
S
piperidine
83%
N
Fortunately, some reactions with alkoxides, amines, and enolates can be mediated so that
ring scission does not occur and this allows the synthesis of many derivatives through
nucleophilic substitution (see Section 11.16.1.3.1.2).
1,2-Benzisothiazolium salts 18 (R 2 = H) or 3-amino-1,2-benzisothiazolium salts 18
(R 2 = NHEt) behave in a similar fashion and, for example, with aqueous sodium hydroxide
and sodium acetate afford the appropriate bis[2-(iminomethyl)aryl] disulfides 19, [29±31]
whereas 3-aryl-1,2-benzisothiazolium salts 18 (R 2 = aryl) react with aqueous sodium
hydroxide or concentrated ammonia to give 2-(sulfanylamino)benzophenones 20
(Scheme 9). [29,32]
CN
S N
17
14
S
NH 2
Ac

11.16.1 1,2-Benzisothiazoles 577
Scheme 9 Reactions of 1,2-Benzisothiazolium Salts [29±32]
R 3
18
R 2
NR
S
1
+
X −
2 M NaOH
NaOAc
R 2 = H, NHEt
2 M NaOH
or NH3
R 2 = aryl
With zinc and hydrochloric acid, hydrazine and diisopropylamine, or nitrous acid,
3-chloro-1,2-benzisothiazole (11) undergoes ring scission to bis(2-cyanophenyl) disulfide
(12) in over 90% yield, [33] thus relating the results of these reactions to those between
3-chloro-1,2-benzisothiazole and cyanide, benzenethiolate, and butyllithium (Scheme 7).
11.16.1.1 Synthesis by Ring-Closure Reactions
11.16.1.1.1 By Formation of Two C-C Bonds
The benzene ring of 3-substituted 1,2-benzisothiazoles can be supplied by the cycloaddition
of benzyne and a symmetrically substituted 1,2,5-thiadiazole 21 (Scheme 10). [10,67±69]
An adduct 22 is formed which then eliminates a nitrile to form the benzisothiazole 23.
This method probably has little synthetic value as yields are low. For example, when the
thiadiazoles 21 (R 1 = H, Me, CN, or Cl) are the starting materials the yields are 25, 31, 36,
and 35%, respectively. [10]
R 3
R 3
R 2
20
NR 1
S
S
R 2
NR
19
1
COR 2
S
NHR 1
Scheme 10 Synthesis of 1,2-Benzisothiazoles by the Addition of Benzyne to
1,2,5-Diazathiazoles [10]
+
R 1 R 1
N
S
21
N
−
N
R 1
S
+
N
11.16.1.1.2 By Formation of One S-N or One N-C Bond
22
R 1
R 3
− R 1 CN
23
R 1
N
S
R1 = H 25%
R1 = Me 31%
R1 = CN 36%
R1 = Cl 35%
Many useful methods for the synthesis of 1,2-benzisothiazoles depend on the formation
of the S-N bond as the last step. Essentially these methods differ only in the selection of
the starting material. Also included in this section are syntheses that probably involve
N-C bond formation as the last step. There are two reasons for this merger: firstly the
starting materials are often very similar and secondly there is possible ambiguity concerning
the precise reaction mechanisms.
for references see p 622

578 Science of Synthesis 11.16 Benzisothiazoles
11.16.1.1.2.1 Method 1:
From Thiols, Disulfides, and Related Compounds
One of the early approaches to the synthesis of benzisothiazoles depends on the oxidative
cyclization of 2-(aminomethyl)benzenethiols with iodine or bromine, [34] or with alkaline
potassium ferricyanide. [35] It seems likely that a disulfide, or an equivalent, is an intermediate
in these reactions and in acidic medium disulfides can be isolated as their ammonium
salts. In alkaline solution, however, the reactions proceed to give the 1,2-benzisothiazoles.
Thus, iodine and potassium iodide in aqueous sodium hydroxide oxidize 2-(aminomethyl)-5-methylbenzenethiol
(24) [34,35] to 5-methyl-1,2-benzisothiazole (26) in 89% yield,
possibly via 25 (Scheme 11). [34]
Scheme 11 Synthesis of 5-Methyl-1,2-benzisothiazole from 2-(Aminomethyl)-
5-methylbenzenethiol [34]
24
SH
NH2
I2, KI
0.5 M NaOH
NH2
S
S
H2N 25
N
S
26 89%
Indeed, diaryl disulfides are commonly presynthesized and then used as the starting materials.
Often the nitrogen-bearing substituent is either a cyanide or an amide and, if a halogen
is used as the oxidant, the product contains a halogen atom at C3. For example,
chlorine in dimethylformamide leads to the production of 3-chloro-1,2-benzisothiazole
(11) in 36% yield from bis(2-cyanophenyl) disulfide (12), [36] probably via the sulfenyl
chloride 27 (Scheme 12).
Scheme 12 Synthesis of 3-Chloro-1,2-benzisothiazole from Bis(2-cyanophenyl) Disulfide [36]
CN
S
12
S
NC
Cl 2, DMF, 17 h
27
CN
SCl
11 36%
Not surprisingly, similar constructions of 3-bromoisothiazolo[5,4-b]pyridine (16) utilize
2-sulfanylpyridine-3-carbonitrile (28) or bis(3-cyano-2-pyridyl) disulfide (29) (Scheme 13).
If 29 is the starting material, bromine in boiling chloroform is used, rather than chlorine,
to effect the cyclization and C3 halogenation. The yield is higher (86 versus 68%) if the
2-sulfanylpyridine 28 is the starting material as opposed to the dipyridyl disulfide 29. [28]
In this case bromine in acetic acid/ethyl acetate is the reagent, and the reaction mixture
is worked upby the addition of aqueous ammonia at 408C.
Cl
N
S

11.16.1 1,2-Benzisothiazoles 579
Scheme 13 Synthesis of 3-Bromoisothiazolo[5,4-b]pyridine from 2-Sulfanylpyridine-3-carbonitrile
or Bis(3-cyano-2-pyridyl) Disulfide [28]
N
N
28
CN
SH
CN
S
29
S N
NC
1. AcOH, EtOAc, reflux
2. Br2
3. 10% NH4OH, 40 oC Br 2, CHCl3
86%
68%
Bis[2-(arylimino)aryl] disulfides can also be ring closed, and when, for example,
bis[4-nitro-2-(4-tolyliminomethyl)phenyl] disulfide (30) is treated with chlorine in chloroform
it gives 5-nitro-2-(4-tolyl)-1,2-benzisothiazolium chloride (31) in 67% yield (Scheme
14). [29]
Scheme 14 Synthesis of 5-Nitro-2-(4-tolyl)-1,2-benzisothiazolium Chloride from
Bis[4-nitro-2-(4-tolyliminomethyl)phenyl] Disulfide [29]
O 2N
N-4-Tol
S
S
4-TolN
30
NO 2
N
Cl2, CHCl3, heat, 10 min
67%
16
Br
N
S
O 2N
31
+
N-4-Tol
S
Cl −
Bis[2-(aminocarbonyl)aryl] disulfides 32 afford 3-chloro-1,2-benzisothiazolium chlorides
33 when treated with phosphorus pentachloride (Scheme 15). [17] In this way 3-chloro-2methyl-1,2-benzisothiazolium
chloride (33, R 1 = Me; R 2 = H) is generated in 90% yield
from bis[2-(methylaminocarbonyl)phenyl] disulfide (32, R 1 = Me; R 2 = H).
for references see p 622

580 Science of Synthesis 11.16 Benzisothiazoles
Scheme 15 Synthesis of 3-Chloro-1,2-benzisothiazolium Chlorides from
Bis[2-(aminocarbonyl)aryl] Disulfides [17]
R 2
O
NR
S
1
S +
Cl −
PCl5, dry benzene
80 o Cl
C, 30−45 min
R3 NHR1 R
S
1HN O
R2 32
R 1 R 2 R 3 Yield (%) of 33 Ref
Me H H 90 [17]
Et H H ± [17]
Et 5-Cl 6-Cl ± [17]
Et 5-OMe 6-OMe ± [17]
CH 2CH=CH 2 H H ± [17]
Ph H H ± [17]
morpholino H H ± [17]
Some aminocarbonyl- 34 (X = O), aminothiocarbonyl- 34 (X = S), or carbamimidoyl-substituted
34 (X = NEt) aryl disulfides cyclize to give 3-substituted 1,2-benzisothiazoles 35 in
methanol solution, but these are accompanied by 2-sulfanylbenzamide 36 (X = O), 2-sulfanylbenzenecarbothioamide
36 (X = S), or N,N-diethyl-2-sulfanylbenzimidamide 36
(X = NEt), as appropriate, in solution (Scheme 16). In addition, these products are in equilibrium
with the starting materials and the disulfides 34 are favored when acids are present.
[37]
Scheme 16 Equilibrium between Bisaryl, Disulfides and 3-Substituted
1,2-Benzisothiazoles and 2-Sulfanylbenzamides, -benzothioamides, or benzimidamides [37]
X
NHEt
S
S
EtHN
X
34
X = O, S, NEt
MeOH
The nitrogen-bearing component in cyclizations of this type need not be a secondary
amine and pyrido[1,2-b][1,2]benzisothiazolium tetrafluoroborates 38 can be synthesized
by the oxidative cyclization of 2-(2-sulfanylphenyl)pyridines 37 in the presence of
N-chlorosuccinimide with the addition of silver tetrafluoroborate (Scheme 17). [38] In this
way 2-nitropyrido[1,2-b][1,2]benzisothiazolium tetrafluoroborate (38, R 1 =NO 2) is obtained
in 60% yield and the 2-cyano analogue 38 (R 1 = CN) in 57% yield.
35
XH
N
S
+
33
X
36
SH
NHEt

Scheme 17 Synthesis of Pyrido[1,2-b][1,2]benzisothiazolium Tetrafluoroborates from
2-(2-Sulfanylphenyl)pyridines [38]
R 1
N
1. NCS, benzene, N 2, 0−10 o C, 15 min
2. AgBF 4
SH
R
37 38
1 = CN 57%
R1 = NO2 60%
3-Chloro-1,2-benzisothiazole (11); Typical Procedure: [36]
Cl 2 was passed for a few minutes into DMF (50 mL) and to this soln bis(2-cyanophenyl) disulfide
(12; 5.6 g, 21 mmol) was added. The resulting mixture was stirred for 17 h, then Cl 2
was passed through the mixture for a few minutes and stirring was continued for 4 h. The
mixture was poured into ice water and extracted with Et 2O. The Et 2O extract was washed
with H 2O, dried, and concentrated; the residue was crystallized (EtOH/H 2O); yield: 2.5 g
(36%); mp41±458C.
3-Bromoisothiazolo[5,4-b]pyridine (16): [28]
2-Sulfanylpyridine-3-carbonitrile (28; 10 mmol) was suspended in AcOH/EtOAc (20±30 mL)
and heated to reflux. Br 2 (1±3 mL) was added to the mixture at reflux. After 1 h, the mixture
was filtered, the residue washed with AcOH/EtOAc and then dissolved or suspended
in EtOH (30±40 mL). This soln/suspension was made alkaline at 408C by addition of 10%
NH 3 soln. The product was precipitated by the addition of H 2O and crystallized (EtOH or
EtOH/H 2O); yield: 40±81%.
5-Methyl-1,2-benzisothiazole (26); Typical Procedure: [34]
To a stirred suspension of 2-(aminomethyl)-5-methylbenzenethiol (24; 3.06 g, 20 mmol) in
0.5 M NaOH (400 mL) was added dropwise over 0.75 h a soln of I 2 (10.2 g) and KI (25 g) in
H 2O (150 mL). A very strong almond odor was produced. The precipitate was collected by
filtration, giving small colorless plates (MeOH/H 2O); yield: 2.6 g (87%); mp848C.
3-Chloro-2-methyl-1,2-benzisothiazolium Chloride (33,R 1 = Me; R 2 = H);
Typical Procedure: [17]
A suspension of bis[2-(methylaminocarbonyl)phenyl] disulfide (32, R 1 = Me; R 2 = H; 33.2 g,
0.1 mol) and PCl 5 (62.4 g, 0.3 mol) in dry benzene (200 mL) was rapidly stirred and heated
to reflux. The frothing was controlled by regular removal of the heat source. After 30±
45 min, the vigorous frothing subsided and the mixture was maintained at steady reflux.
On cooling, the mixture was filtered and the residue washed with benzene and dried under
vacuum; crude yield: 40 g (90%); mp1648C (dec) (1,2-dichlorobenzene).
11.16.1.1.2.2 Method 2:
From Oximes
11.16.1 1,2-Benzisothiazoles 581
One versatile approach to 1,2-benzisothiazoles 40 is the cyclization of the oximes of 2-(alkylsulfanyl)benzaldehydes
or alkyl (or aryl) 2-(alkylsulfanyl)phenyl ketones 39 (Scheme
18). In these cases the S-alkyl substituent group(methyl or, more commonly, tert-butyl)
is lost in the reaction. [39±47] Cyclization is normally achieved using acetic anhydride in pyridine,
or polyphosphoric acid as the reagents.
R 1
N
+
S
BF 4 −
for references see p 622

582 Science of Synthesis 11.16 Benzisothiazoles
Scheme 18 Synthesis of 1,2-Benzisothiazoles from the Oximes of 2-Sulfanylbenzaldehydes
or Alkyl (or Aryl) 2-(Alkylsulfanyl)phenyl Ketones [39±47]
R 2
39
R 1
SR 3
NOR 4
Ac2O, py
or PPA
R 2
R 1 R 2 R 3 R 4 Reaction Conditions Yield (%)
of 40
H H t-Bu H PPA 71 [39]
H H t-Bu Bz 1008C, 0.5 h; MeOH, reflux, 1 h 90 [40]
H 7-NO 2 t-Bu H PPA, 100 8C, 0.5 h 75 [41]
Me H Me H Ac 2O, pyridine 95 [42,43]
Me H Me 4-O 2NC 6H 4CO Ac 2O, pyridine 66 [44]
Me H Me Bz Cl 2CHCHCl 2, reflux, 3 h 60 [43,44]
Me H Me 4-MeC 6H 4SO 2 Cl 2CHCHCl 2, reflux, 3 h 32 [43,44]
Me 6-Me Me H Ac 2O, pyridine 88 [45]
Me 5-Me Me H Ac 2O, pyridine 90 [42]
Me 7-Ac Me H Ac 2O, pyridine 43 [46]
Me 5-SMe Me H Ac 2O, pyridine 92 [47]
Me 6-SMe Me H Ac 2O, pyridine 89 [47]
Et 5-Me Me H Ac 2O, pyridine 76 [42]
(CH 2) 2CO 2Et 5-Me Me H Ac 2O, pyridine 83 [42]
Ph H Me Bz Ac 2O, pyridine 93 [42]
Ph H t-Bu H MeOH, reflux, 10 h 82 [40]
Ph 5-Me Me H Ac 2O, pyridine 94 [42]
2-pyridyl H t-Bu Bz 1,2-dichlorobenzene, 160 8C, 20 h 66 [40]
In the case of acid-promoted ring closures with 2-sulfanylacetophenone oximes 39
(R 1 = Me), however, Beckmann rearrangements can occur. [48] For this reason thermal
methods of cyclization are recommended and the solvents now used range from methanol
to 1,2-dichlorobenzene [40] or 1,1,2,2-tetrachloroethane. [43] Nevertheless, benzo[1,2-d:5,4-d¢]diisothiazoles
42 (R 1 = H or Me) are synthesized in 68 [39] and 84% [47] yields,
respectively, from the bisoximes 41 of 1,3-diacyl-4,6-bis(tert-butylsulfanyl)benzenes with
polyphosphoric acid (Scheme 19).
40
R 1
N
S
Scheme 19 Synthesis of Benzo[1,2-d:5,4-d']diisothiazoles [39,47]
HON
R 1
Bu t S
41
R 1
SBu t
NOH
PPA, 20 o C, 24 h
R1 = H 68%
R1 = Me 84%
R 1
N
S
42
R 1
N
S
Ref

11.16.1 1,2-Benzisothiazoles 583
This last route has been applied to the syntheses of many benzisothiazolo heterocycles
simply by selecting the appropriate oximino derivative of a sulfanylheteroarene as the
starting material. For example, isothiazolo[5,4-b]quinoline (44) can be obtained in 50%
yield from 2-thioxo-1,2-dihydroquinoline-3-carbaldehyde oxime (43) by reaction with
acetic anhydride in acetic acid at reflux, [24] and ethyl thieno[3,2-d]isothiazole-5-carboxylate
(46) is produced in 74% yield when ethyl 4-(hydroxyiminomethyl)-5-sulfanylthiophene-2-carboxylate
(45) is treated similarly (Scheme 20). [49]
Scheme 20 Synthesis of Isothiazolo[5,4-b]quinoline [24] or Ethyl Thieno[3,2-d]isothiazole-5-carboxylate
[49]
N
H
43
45
S
NOH
NOH
EtO2C S
SH
Ac 2O, AcOH, reflux
50%
DMSO, 170 o C, 5 min
74%
EtO2C
Benzo[1,2-d:5,4-d¢]diisothiazoles (42,R 1 = H); Typical Procedure: [39]
4,6-Bis[tert-butylsulfanyl]benzene-1,3-dicarbaldehyde dioxime (41, R 1 = H; 0.7 g, 2 mmol)
and PPA (25 g) were stirred together at 208C for 24 h, diluted with AcOH and heated under
reflux for 1 h. The cooled soln was filtered and the residue washed with H 2O, dried, and
subjected to chromatography (alumina, toluene). The product was crystallized (toluene)
as cream-colored crystals; yield: 0.27 g (68%); mp215.5±2168C.
Ethyl Thieno[3,2-d]isothiazole-5-carboxylate (46): [49]
Ethyl 4-(hydroxyiminomethyl)-5-sulfanylthiophene-2-carboxylate (45; 10 g, 43 mmol) was
added portionwise over 5 min to stirred DMSO at 1708C. The mixture was then poured
onto crushed ice (500 g). Extraction with Et 2O gave pale yellow plates; yield: 6.8 g (74%);
mp97±988C (MeOH).
11.16.1.1.2.3 Method 3:
From (Aminosulfanyl)arenes
Other more versatile routes to 1,2-benzisothiazoles take advantage of the intramolecular
cyclization of (aminosulfanyl)arenes bearing an unsaturated ortho substituent, such as a
cyano or carbonyl group. For example, the 2-(aminosulfanyl)benzonitriles 48 are generated
in situ by the action of chloroamine on the appropriate sodium 2-cyanobenzenethiolate
47 (X = SNa). [41,50] The cyanobenzenethiolate starting materials are generally obtained
by reacting the corresponding aryl bromides 47 (X = Br) with sodium hydrogen sulfide.
Such a construction is thus very similar to that used to generate monocyclic isothiazoles.
Here it can be used to synthesize 7-nitro-1,2-benzisothiazol-3-amine (49, R 1 =NO 2) in 78%
yield, and its 7-chloro- and 7-methoxy- analogues 49 (R 1 =ClorR 1 = OMe, respectively) in
62 and 73% yields, respectively (Scheme 21). [41] Note, the mechanism of this last reaction
may place it in the N-C bonding category, rather than the S-N one; this conclusion may
also apply to some other procedures listed here for convenience.
N
44
S
46
N
S
N
S
for references see p 622

584 Science of Synthesis 11.16 Benzisothiazoles
Scheme 21 Synthesis of 1,2-Benzisothiazol-3-amines from
2-(Aminosulfanyl)benzonitriles [41,50]
R 1
47
CN
X
1. NaSH
2. NH2Cl −5 to 10 oC R 1
48
CN
SNH 2
49
R 1
NH2
N
S
R1 = 7-NO2 78%
R1 = 7-Cl 62%
R1 = 7-OMe 73%
1,2-Benzisothiazoles without an amino groupat C3 can also be synthesized if sodium
2-formylbenzenethiolates replace sodium 2-cyanobenzenethiolates as the starting materials.
[41] As an illustration, 7-chloro-1,2-benzisothiazole (52, R 1 = Cl) is formed from 2,3-dichlorobenzaldehyde
(50, R 1 = Cl) via sodium 2-chloro-6-formylbenzenethiolate (51,
R 1 = Cl) in an overall yield of 57% (Scheme 22). [41]
Scheme 22 Synthesis of 7-Substituted 1,2-Benzisothiazoles from Sodium
2-Formylbenzenethiolates [41]
CHO
NaSH, HMPA
120 oC CHO
Cl
SNa
R
50
51
1 R1 1. NH3 2. NaOCl
−5 to 0 oC, 1 h
52
R 1
N
S
R 1 = Cl 57%
R 1 = OMe 70%
Chloroamine can sometimes give rise to side reactions and disulfides can be formed, but
2-sulfanylpyridine-3-carbonitriles 53 can be converted into the 2-(aminosulfanyl)pyridine-3-carbonitriles
54 by the action of hydroxylamine-O-sulfonic acid. In aqueous solution
at pH 7 these intermediates then cyclize to isothiazolo[5,4-b]pyridin-3-amines 55 in
good yields (Scheme 23). For example, 4,6-dimethylisothiazolo[5,4-b]pyridin-3-amine (55,
R 1 =R 2 = Me) is obtained in 72% yield from 4,6-dimethyl-2-sulfanylpyridine-3-carbonitrile
(53, R 1 =R 2 = Me). [51]
Scheme 23 Synthesis of Isothiazolo[5,4-b]pyridin-3-amines from
2-(Aminosulfanyl)pyridine-3-carbonitriles [51]
R 2
R 1
N
53
CN
SH
1. NaOH
2. NH2OSO3H 2-Acylbenzenesulfenyl halides 56 are also used as starting materials and when these are
treated with ammonia they give the corresponding 1,2-benzisothiazoles 57 or, if a primary
amine is the reagent, 1,2-benzisothiazolium salts 58 (Scheme 24). [29] For example,
2-formyl-5-nitrobenzenesulfenyl bromide (56, R 1 = H) gives 6-nitro-1,2-benzisothiazole
(57, R 1 = H) in 95% yield, whereas 2-benzoyl-5-nitrobenzenesulfenyl bromide (56, R 1 = Ph)
affords 6-nitro-2,3-diphenyl-1,2-benzisothiazolium bromide (58, R 1 = Ph) after treatment
with aniline and then concentrated hydrobromic acid. [29]
R 2
R 1
N
54
CN
SNH2
NaOEt
R 2
R 1
N
55
NH 2
N
S

11.16.1 1,2-Benzisothiazoles 585
Scheme 24 Synthesis of 6-Nitro-1,2-benzisothiazoles and 6-Nitro-1,2-benzisothiazolium
Bromides from 2-Acyl-5-nitrobenzenesulfenyl Bromides [29]
O 2N
56
R 1
SBr
O
concd NH3
benzene, reflux
R 1 = H 95%
1. PhNH2
benzene, reflux
2. HBr
R 1 = Ph
O 2N
57
O 2N
58
R 1
N
S
R 1
+
NPh
S
Br −
In a specific procedure selective nucleophilic displacement of a fluorine atom from the 4-
(2,4-difluorobenzoyl) piperidine-1-carbaldehyde 59 by potassium phenylmethanethiolate
gives the corresponding benzyl sulfide 60. Treatment of this product with thionyl
chloride yields a sulfanyl chloride that is cyclized by a reaction with ammonia to give
6-fluoro-3-(1-formylpiperidin-4-yl)-1,2-benzisothiazole (61), a potential antipsychotic
agent (Scheme 25); the overall yield is ~35%. [52]
Scheme 25 Synthesis of 6-Fluoro-3-(formylpiperidin-4-yl)-1,2-benzisothiazole from
4-(2,4-Difluorobenzoyl) Piperidine-1-carbaldehyde [52]
F
59
CHO CHO
N
N
F
O
t-BuOK, BnSH
THF
F
60
O
SBn
1. SOCl 2, CH 2Cl 2
2. NH3, EtOH
F
N
S
61 ~35%
CHO
N
7-Nitro-1,2-benzisothiazole-3-amine (49,R 1 = 7-NO 2); Typical Procedure: [41]
A mixture of 2-bromo-3-nitrobenzonitrile (47, X = Br; R 1 = 6-NO 2; 1.0 g, 4.4 mmol), NaSH
(0.4 g, 7.7 mmol) and acetone (25 mL) was stirred under N 2 for 6 h and the acetone then
evaporated. The residue was treated with H 2O (25 mL) and to this was added dropwise dil
NH 3 soln (d 0.89, 7 mL) and 5% NaOCl (6 mL). After 1 h, the mixture was extracted with
Et 2O and the extracts dried and evaporated. The residue was crystallized (acetone/H 2O)
giving yellow needles; yield: 0.67 g (78%); mp247±2488C.
7-Chloro-1,2-benzisothiazole (52, R 1 = Cl); Typical Procedure: [41]
2,3-Dichlorobenzaldehyde (50, R 1 = Cl; 3.5 g, 20 mmol), NaSH (0.7 g, 13 mmol), and HMPA
(20 mL, 11.5 mmol) were heated together under N 2 at 120 8C for 24 h and then poured into
H 2O. The thiol was extracted with Et 2O and then from the organic solvent into 3% NaOH
(20 mL) as its sodium salt. This alkaline soln was treated successively with aq dil NH 3 (d
0.89, 20 mL) and 5% aq NaOCl (18 mL), the latter added dropwise at ±5±08C. After 1 h, the
product was obtained by Et 2O extraction; yield: 1.93 g (57%); mp49±50 8C.
7-Methoxy-1,2-benzisothiazole (52, R 1 = OMe) was similarly prepared; yield: 70%; bp
135±1388C/7 Torr.
for references see p 622

586 Science of Synthesis 11.16 Benzisothiazoles
4,6-Dimethylisothiazolo[5,4-b]pyridin-3-amine (55,R 1 =R 2 = Me) From 4,6-Dimethyl-2-sulfanylpyridine-3-carbonitrile
(53,R 1 =R 2 = Me); Typical Procedure: [51]
4,6-Dimethyl-2-sulfanylpyridine-3-carbonitrile (53,R 1 =R 2 = Me; 1.64 g, 10 mmol) was added
to a soln of NaOH (0.8 g, 20 mmol) in EtOH (20 mL) and the clear soln shaken with a
soln of hydroxylamine-O-sulfonic acid (1.2 g, 10 mmol) in H 2O (20 mL) that had just previously
been neutralized with KHCO 3 (~1.5 g). After 15 min the mixture was diluted with
H 2O and filtered. The residue was crystallized (benzene); yield: 1.3 g (72%); mp181±1838C.
4,6-Dimethylisothiazolo[5,4-b]pyridin-3-amine (55,R 1 =R 2 = Me) From 2-(Aminosulfanyl)-
4,6-dimethylpyridine-3-carbonitrile (54,R 1 =R 2 = Me); Typical Procedure: [51]
2-(Aminosulfanyl)-4,6-dimethylpyridine-3-carbonitrile (54, R 1 =R 2 = Me; 1.79 g, 10 mmol)
was heated under reflux for 80 min in a soln of sodium (0.23 g, 10 mmol) in abs EtOH
(20 mL). On cooling, H 2O was stirred into the mixture which was then filtered; yield:
1.6 g (88%).
11.16.1.1.2.4 Method 4:
From Disulfides
Bis(2-acetyl-4-methylphenyl) disulfide (62) reacts with ammonia and silver nitrate at 50 8C
to give a 30% yield of 3,5-dimethyl-1,2-benzisothiazole (64) within 5 minutes, [53] probably
via the 2-(aminosulfanyl)acetophenone 63 (Scheme 26).
Scheme 26 Synthesis of a 3,5-Methyl-1,2-benzisothiazole from a Bis(2-acylphenyl)
Disulfide [53]
Ac
S
S
Ac
NH 3, AgNO 3, MeOH
50 o C, 5 min
62 63
It may well be that the reactions of 2-halobenzaldehydes 65 (R 1 = H) and 2-halobenzophenones
65 (R 1 = aryl) with sulfur and ammonia to give 1,2-benzisothiazoles 66 follow
mechanistically related pathways (Scheme 27). Quite often the recommended protocol
demands moderately high temperatures (80±1608C) within an autoclave. [18,54±56] This is
one of the easiest approaches to 1,2-benzisothiazoles and it has been used repeatedly.
The method also lends itself to the synthesis of polycyclic analogues if the benzene
ring of the starting material is replaced by a naphthyl, an anthracenyl, [18,55] or a 1,8-naphthyrin
[56] unit.
30%
Ac
SNH2
64
N
S

11.16.1 1,2-Benzisothiazoles 587
Scheme 27 Synthesis of 1,2-Benzisothiazoles from 2-Halobenzaldehydes
or 2-Halobenzophenones [18,41,55]
R 2
65
R 1
Cl
O
S8, NH3, autoclave
80−160 o C, 6−8 h
65−85%
R 2
66
R 1
N
S
R 1 R 2 Reaction Conditions Yield (%) Ref
H 3-Cl MeOCH 2CH 2OH, 160 8C, 6 h 46 [41]
H 6-Cl MeOCH 2CH 2OH, 160 8C, 6 h 75±80 [18]
H 4-NMe 2 MeOH, 160 8C, 6 h 76 [18,55]
H 4-NEt 2 MeOH, 80 8C, 6 h 72 [18,55]
H 5-NO 2 MeOH, 80 8C, 10 h 90 [18,55]
Ph H MeOCH 2CH 2OH, 160 8C, 6 h 70±85 [18]
Ph 6-Cl MeOCH 2CH 2OH, 160 8C, 6 h 70±85 [18]
Ph 5-NO 2 MeOH, 80 8C, 6 h 80±95 [18]
4-Tol H MeOCH 2CH 2OH, 160 8C, 6 h 89 [18]
4-Tol 5-Cl MeOCH 2CH 2OH, 160 8C, 6 h 75±95 [18]
4-Et 2NC 6H 4 H MeOCH 2CH 2OH, 160 8C, 6 h 75±85 [18]
3-O 2NC 6H 4 5-Cl MeOCH 2CH 2OH, 160 8C, 6 h 75±85 [18]
2-thienyl 5-NO 2 MeOH, 80 8C, 6 h 80±95 [18]
Benzothiazoles 66 Using Methanol as the Solvent; General Procedure: [18]
A 2-chlorobenzaldehyde or a 2-chlorobenzophenone (0.1 mol) was heated in an autoclave
with an equimolar quantity of sulfur in MeOH (300 mL) containing NH 3 (50 g) for 6 h or
8 h, respectively, at 808C. The solvent was evaporated and the residue distilled through a
Vigreux column; yield: 65±80%.
Benzothiazoles 66 Using 2-Methoxyethanol as the Solvent; General Procedure: [18]
The 2-chlorobenzaldehyde or the 2-chlorobenzophenone (0.2 mol) and an equimolar
quantity of sulfur were heated in an autoclave in 2-methoxyethanol (500 mL) containing
NH 3 (100 g) at 1608C for 6 h. For the aldehydes the solvent was largely evaporated, and the
residue treated with H 2O (500 mL) and extracted with CH 2Cl 2 (3 î 200 mL). The combined
organic extracts were dried, the solvent evaporated, and the residue crystallized. In the
case of the ketones the reaction solvent was completely removed by distillation and the
residue distilled through a Vigreux column; yield: 70±85%.
11.16.1.1.2.5 Method 5:
From 2-Acylbenzenesulfonamides or 2-(Sulfinyl)benzamides
Saccharin (5) is still prepared by the original route, namely the oxidative cyclization of
toluene-2-sulfonamide (67) (Scheme 28). The only variation in this synthesis is the choice
of the oxidant, typically potassium permanganate or chromic acid; yields are generally
high (80±95%). [56,57] Anodic oxidation is also employed. [58]
for references see p 622

588 Science of Synthesis 11.16 Benzisothiazoles
Scheme 28 Synthesis of Saccharin by Oxidation of Toluene-2-sulfonamide [56,57]
NH2 S
O O
67
[O]
80−95%
NH
S
O O
N-Alkyl- and N-arylsaccharins 69 are readily synthesized from 2-(aminosulfonyl)benzoyl
chlorides 68 and primary amines (Scheme 29). [59±61]
Scheme 29 Synthesis of N-Alkyl- and N-Arylsaccharins from 2-(Aminosulfonyl)benzoyl
Chlorides and Primary Amines [59±61]
O
NH2 S
O O
68
Cl
R 1 NH2
5
69
O
O
NHR
S
1
O O
A modern variant embodies a two-stepprocess from N,N-diethylbenzamides 70. [62,63] Ortho-lithiation
by sec-butyllithium in the presence of N,N,N¢,N¢-tetramethylethylenediamine,
followed by an oxidative amination of the intermediate lithium sulfinate with
hydroxylamine-O-sulfonic acid [62] gives (aminosulfonyl)benzamides 71 that are cyclized
to saccharins 72 in excellent yields by treatment with hot acetic acid (Scheme 30).
Scheme 30 Synthesis of Saccharins from N,N-Diethylbenzamides [62,63]
R 1
70
O
NEt2
s-BuLi, TMEDA
NH2OSO3H
R 1
O
NEt2
NH2
S
O O
71
AcOH
heat
R 1
O
NH
S
O
72
O
The pyridosaccharin 75 is prepared by ortho-lithiation of N-tert-butylpyridine-3-sulfonamide
(73) with lithium diisopropylamide, followed by entrapment of the anion with carbon
dioxide and cyclodehydration of the product 74 with polyphosphoric acid (Scheme
31). The N-tert-butyl groupis lost in this last step, but is retained if the reagent used in
the final step is phosphoryl chloride. [64]
Scheme 31 Synthesis of Isothiazolo[5,4-c]pyridine-3(2H)-one 1,1-Dioxide [64]
N
NHBu
S
t
O O
73
1. LDA (2 equiv)
2. CO2 3. H +
N
CO 2H
NHBu
S
t
O O
74
PPA
N
75
O
NH
S
O O
A method for the preparation of 1,2-benzisothiazol-3(2H)-ones 77 involves the cyclization
of the benzyl sulfoxides 76 on treatment with trichloroacetic anhydride (Scheme 32). [65]
The method has applicability for the synthesis of substituted 1,2-benzisothiazol-3(2H)ones
in general. [66]

11.16.1 1,2-Benzisothiazoles 589
Using this approach, 2-phenyl-1,2-benzisothiazol-3(2H)-one and 2-(3,4,5-trimethoxyphenyl)-1,2-benzisothiazol-3(2H)-one
are synthesized from the appropriate benzyl sulfoxides
in 75 and 79% yields, respectively. [65]
Scheme 32 Synthesis of 2-Aryl-1,2-benzisothiazol-3(2H)-ones
O
NHR 1
S(O)Bn
(CCl3CO)2O, CH2Cl2
− BnOCOCCl3
R 1 = Ph 75%
R
76 77
1 = 3,4,5-(MeO) 3C6H2 79%
11.16.1.1.3 By Formation of One S-C Bond
O
NR
S
1
Syntheses that have the formation of an S-C(Ar) bond as the ultimate stepare uncommon,
although it is known that aryllithiums, formed from the aryl bromides 78, and
chlorobis(h 5 -cyclopentadienyl)methylzirconium complexes afford zirconocene complexes,
which on reaction with nitriles form zirconocene complexes 79. These, on treatment
with disulfur dichloride, form 1,2-benzisothiazoles 80 (Scheme 33). Yields range
from poor (25%) in the case of 7-methoxy-3-methyl-1,2-benzisothiazole (81, R 1 = Me;
R 2 = OMe), to good (83%) for 3-methyl-1,2-benzisothiazole (84, R 1 = Me; R 2 = H). Although
anhydrous conditions are necessary, the method does have the advantage that the aryl
bromides are readily available. [9]
Scheme 33 Synthesis of 1,2-Benzisothiazoles from Aryl Bromides [9]
R 1
78
Br
1. t-BuLi, −78 oC 2. ZrMe(Cp) 2Cl
3. MeCN, 80 oC, 16 h
N
Zr
Cp
1 Cp
R
79
S2Cl2
20 o C, 18 h
R 1
N
S
80 R 1 = H 83%
R 1 = OMe 25%
In a second synthesis of this type, benzophenones 81 afford N-chlorosulfonylimines 82 as
transient intermediates. When treated with chlorosulfonyl isocyanate in boiling nitrobenzene
these cyclize to 3-aryl-1,2-benzisothiazole 1,1-dioxides 83, but only in low (28±
31%) yields (Scheme 34). [70]
for references see p 622

590 Science of Synthesis 11.16 Benzisothiazoles
Scheme 34 Synthesis of 3-Aryl-1,2-benzisothiazoles from Benzophenones [70]
R 1
81
R 2
O
R 1 = H, Me, OMe; R 2 = Me, Cl
ClSO2NCO
PhNO2
130 o C, 2 h
28−31%
R 1
82
R 2
N
SO2Cl
R 1
83
N
S
O O
Finally, the ortho-lithiation of an arene can be used in a synthesis of 1,2-benzisothiazole
1,1-dioxides. For example the treatment of N-acetyl-2-chlorobenzenesulfonamide (84,
R 1 = Me) with two equivalents of lithium diisopropylamide leads to a dilithio derivative
85, which then cyclizes to 3-methyl-1,2-benzisothiazole 1,1-dioxide (86, R 1 = Me) in 69%
yield (Scheme 35). Other examples, such as 3-isopropyl-1,2-benzisothiazole 1,1-dioxide
(86, R 1 = iPr) and 3-phenyl-1,2-benzisothiazole 1,1-dioxide (86, R 1 = Ph), are similarly obtained
from the appropriate N-acyl-2-chlorobenzenesulfonamides in 58 and 86% yields, respectively.
[71]
Scheme 35 Synthesis of 3-Substituted 1,2-Benzisothiazole 1,1-Dioxides [71]
Cl
S
H
N R
84
1
O O
O
LDA (2 equiv)
THF
11.16.1.2 Synthesis by Ring Transformation
Li
S
N R
O O
85
1
OLi
86
R 2
R 1
N
S
O O
R 1 = Me 69%
R 1 = iPr 58%
R 1 = Ph 86%
Although placed here as a separate section, many of these reactions probably serve only
to generate intermediates from which the isothiazole ring arises by familiar bond forming
reactions.
Benzo[b]thiophene-2,3-dione (87) and ammonia are likely to react and yield a (2-sulfanylphenyl)methylimine,
which in contact with hydrogen peroxide cyclizes oxidatively
to 1,2-benzisothiazole-3-carboxamide (88) in 66% yield (Scheme 36). [72,73] Hydrolysis to
1,2-benzisothiazole-3-carboxylic acid (89) can be effected without isolating the amide if
the reaction mixture is heated with aqueous sodium hydroxide. [73]

11.16.1 1,2-Benzisothiazoles 591
Scheme 36 Synthesis of 1,2-Benzisothiazole-3-carboxamide or 1,2-Benzisothiazole-
3-carboxylic Acid [72,73]
87
S
O
O
aq NH 3
CONH2
SH
NH
H2O 2
2 M NaOH
reflux, 15 min
88 66%
CONH 2
N
S
89 85%
The same procedure can be adopted to synthesize naphtho[1,2-d]isothiazole-3-carboxamide
(91a), naphtho[2,3-d]isothiazole-3-carboxamide (91b), and naphtho[2,1-d]isothiazole-3-carboxamide
(91c) from the appropriate naphthothiophenediones 90 (Scheme
37). [72±74]
Scheme 37 Synthesis of Naphthoisothiazole-3-carboxamides [72±74]
R 2
R 3
R 1
R 4
90
S
O
O
1. aq NH3 2. 30% H2O2 R 2
R 3
R 1
R 4
CONH2
N
S
91a R1 ,R2 =
b R1 = R4 = H; R2 ,R3 =
c R1 = R2 = H; R3 ,R4 (CH CH)2; R
=
3 = R4 = H
(CH CH) 2
(CH CH)2
Benzothiophen-3(2H)-ones 92, or their tautomers, undergo S-amination when reacted
with O-mesitylsulfonylhydroxylamine and the products 93 ring open on basification to
afford sulfanamides 94, these then recyclize to 3-alkenyl-1,2-benzisothiazoles 95 (Scheme
38). Whereas this approach works well when the substrate is 92 (R 1 = Me) and gives 3-isopropenyl-1,2-benzisothiazole
(95,R 1 = Me) in 82% yield, unfortunately, for 2-methyl-2-phenylbenzothiophen-3(2H)-one
(92, R 1 = Ph), 4-phenyl-2,3,4,5-tetrahydro-1,2-benzothiazepin-4-one
(96) is also a major product (38% yield). This last compound arises through an
intramolecular Michael reaction. [75±77]
CO2H
N
S
for references see p 622

592 Science of Synthesis 11.16 Benzisothiazoles
Scheme 38 Synthesis of 3-Alkenyl-1,2-benzisothiazoles from Benzothiophen-
3(2H)-ones [75±77]
92
S
O
R 1
MesSO2ONH2
CH2Cl2, 0 o C
O
94
SNH2
R 1
93
O
+
S
NH 2
R 1
NaOH
95
N
S
R 1
+
O
S NH
A very similar procedure replaces benzothiophen-3(2H)-ones with 2,3-dihydro-4H-benzothiopyran-4-ones
97. Under similar reaction conditions these afford the S-amino derivatives
98, which when heated with 10% aqueous sodium hydroxide ring open and recyclize
to yield 3-alkenyl-1,2-benzisothiazoles 99 (Scheme 39). [75±78] For simple derivatives such as
3-vinyl-1,2-benzisothiazole (99, R 1 =R 2 = H), 5-methyl-3-vinyl-1,2-benzisothiazole (99,
R 1 =H; R 2 = Me), and 3-prop-1-enyl-1,2-benzisothiazole (99, R 1 = Me; R 2 = H) the yields are
42, 35, and 63%, respectively. [75,77]
Scheme 39 Synthesis of 3-Alkenyl-1,2-benzisothiazoles from 2,3-Dihydro-4Hbenzothiopyran-4-ones
[75±78]
R 2
97
O
S
R 1
MesSO 2ONH 2
CH2Cl2, 20 o C, 1 h
R 2
98
O
10% NaOH
20 oC, 10 min
+
S
NH2 R 1
R 2
99
96
N
S
Ph
R 1
R1 = R2 = H 42%
R1 = H; R2 = Me 35%
R1 = Me; R2 = H 63%
The conversion of N-acetyl-3H-1,2-benzodithiol-3-imines 100 into 3-acetamido-1,2-benzisothiazoles
102 by the action of hydroxylamine also has parallels with work described
earlier. S-Amination with the formation of an intermediate N-hydroxysulfanamide 101
is a likely first step. [71] Hydrolysis to the corresponding 1,2-benzisothiazol-3-amine 103
can be effected in high yield by treatment with hydrochloric acid (Scheme 40). Although
the yield of 3-acetamido-1,2-benzisothiazole (102, R 1 = H) from N-acetyl-1,2-benzodithiol-
3-imine (100, R 1 = H) is only 50±62%, that of 3-acetamido-5-chloro-1,2-benzisothiazole
(102,R 1 = 5-Cl) from N-acetyl-5-chloro-1,2-benzodithiol-3-imine (100,R 1 = 5-Cl) is much improved
at 81%. [69]

11.16.1 1,2-Benzisothiazoles 593
Scheme 40 Synthesis of 3-Acetamido-1,2-benzisothiazoles and 1,2-Benzisothiazol-
3-amines [69,71]
R 1
100
NAc
S
S
NH2OH, NaOAc 3H2O
EtOH, reflux, 1.5h
R 1
NHAc
N
S
102 R 1 = H 50−62%
R 1 = 5-Cl 81%
R 1
101
concd HCl
reflux, 1 h
NAc
SH
NHOH
S
R 1
103
NH 2 HCl
N
S
R1 = H 88%
R1 = 5-Cl 81%
Another synthesis, this time of 1,2-benzisothiazole-3-acetic acids 105, depends on the reactions
of 4-hydroxy-2H-thiobenzopyran-2-ones 104 with hydroxylamine (Scheme 41). [79]
The reaction may also be related mechanistically to the previous examples.
Scheme 41 Synthesis of 1,2-Benzisothiazole-3-acetic Acids [79]
R 1
S
104
OH
O
NH 2OH
R1 = H 35%
R1 = 5-Cl 50%
R1 = 5-NO2 30%
However, an approach to 5,6-dialkoxy-3-aryl-1,2-benzisothiazoles 109 that requires the
sodium periodate cleavage of 6,7-dialkoxy-4-aryl-2H-1,3-benzothiazines 106 is likely to involve
the initial formation of an S-oxide 107. This then ring opens to an N-formylimine
108 and eliminates formic acid to provide the 3-aryl-1,2-benzisothiazole 109 (Scheme
42). [80]
R 1
N
S
105
CO 2H
for references see p 622

594 Science of Synthesis 11.16 Benzisothiazoles
Scheme 42 Synthesis of 5,6-Dialkoxy-3-aryl-1,2-benzisothiazoles from 6,7-Dialkoxy-
4-aryl-2H-1,3-benzothiazines [80]
R 1 O
R 1 O
106
Ar 1
S
N
R 1 O
R 1 O
NaIO 4, H 2O
MeOH, 48 h
Ar 1
S
O
107
N
R 1 O
Ar 1
OH R SOH
1O − HCO 2H
R 1 Ar 1 Yield (%) of 109 Ref
Me Ph 55 [80]
Et Ph 58 [80]
Me 4-Tol 40 [80]
Me 4-ClC 6H 4 55 [80]
108
R 1 O
R 1 O
NCHO
1,2-Benzisothiazole-3-carboxamide (88); Typical Procedure: [73]
A cooled soln of benzo[b]thiophene-2,3-dione (87; 4.9 g, 0.03 mol) in concd aq NH 3 was
treated dropwise with H 2O 2 (10 mL). The rapidly formed, colorless precipitate was collected
and crystallized (H 2O); yield: 3.5 g (66%); mp1348C.
1,2-Benzisothiazole-3-carboxylic Acid (89): [73]
The above procedure was followed. The product 88 (3.5 g) was then heated with 2 M NaOH
soln (40 mL) for about 15 min, during which time the evolution of NH 3 was clearly detectable.
The solid obtained by acidification of the cooled mixture was crystallized (H 2O);
yield: 3.0 g (85%); mp1438C.
3-Acetamido-1,2-benzisothiazole (102, R 1 = H); Typical Procedure: [69]
N-Acetyl-3H-1,2-benzodithiol-3-imine (100, R 1 = H; 20.9 g, 0.1 mol) was added to a soln of
hydroxylamine hydrochloride (13.9 g, 0.2 mol) and NaOAc·3H 2O (27.2 g, 0.2 mol) in EtOH
(500 mL). The mixture was heated under reflux for 1.5 h. After cooling, the mixture was
filtered from NaCl and sulfur, and the filtrate evaporated under vacuum. The residual yellow
syrupcrystallized on scratching, giving yellow prisms (EtOH); yield: 10±12 g (50±62%);
mp162 8C.
1,2-Benzisothiazol-3-amine Hydrochloride (103, R 1 = H); Typical Procedure: [69]
3-Acetamido-1,2-benzisothiazole was heated under reflux in concd HCl (200 mL) for 1 h.
The mixture was filtered while hot and, on cooling, deposited crystals of 3-amino-1,2benzisothiazolium
hydrochloride as colorless needles. A second fraction was isolated by
109
Ar 1
N
S

11.16.1 1,2-Benzisothiazoles 595
concentration of the mother liquor and was crystallized (H 2O); combined yield: 17.1 g
(88%); sublimed at 2448C.
6-Chloro-1,2-benzisothiazol-3-amine (103, R 1 = 6-Cl) was similarly prepared from
3-acetamido-6-chloro-1,2-benzisothiazole; yield: 81%; sublimed at 205 8C.
3-Aryl-1,2-benzothiazoles 109; General Procedure: [80]
To a soln of 6,7-dialkoxy-4-phenyl-2H-1,3-benzothiazine 106 (5 mmol) in MeOH (50 mL)
was added a soln of NaIO 4 (2.14 g, 10 mmol) in H 2O (20 mL) and the mixture was stirred
for 48 h. The mixture was filtered, the residue washed with H 2O, and the product crystallized
(MeOH); yield: 40±58%.
11.16.1.3 Synthesis by Substituent Modification
11.16.1.3.1 Substitution of Existing Substituents
11.16.1.3.1.1 Electrophilic Substitution
Nitration of 1,2-benzisothiazole (1) gives a mixture of 5- and 7-nitro-1,2-benzisothiazoles
(110 and 111, respectively). [22,29,81±84] The nitration of 3,5-dimethyl-1,2-benzisothiazole
(112) is more easily controlled and gives 3,5-dimethyl-4-nitro-1,2-benzisothiazole (113)
in 81% yield (Scheme 43). [82]
Scheme 43 Nitration of 1,2-Benzisothiazoles [22,29,81±84]
1
N
S
112
N
S
NaNO 3, H 2SO 4
0 o C
KNO 3, concd H 2SO 4
0−5 o C, 1.25 h
81%
O 2N
There are many other examples that illustrate the use of halogenation and nitration reactions
for the synthesis of substituted 1,2-benzisothiazoles 114±116 from the parent heterocycles
(Scheme 44).
Scheme 44 Synthesis of 1,2-Benzisothiazoles by Electrophilic Substitution [22,29,45,81,82]
R 2
R 1
N
S
Cl2, AcOH
R 2
114
110
NO2
N
S
113
R 1
N
S
+
N
S
R 1 R 2 Yield (%) of 114 Ref
H OH 92 [29]
Me NH 2 81 [82]
Ph OH 88 [29]
Cl
NO 2
111
N
S
for references see p 622

596 Science of Synthesis 11.16 Benzisothiazoles
R 1
R N
S
2 R2 Br
115
R 1 R 2 Reagent Position of Bromination Yield (%) of 115 Ref
H 4-Cl/7-NH 2 Br 2, CHCl 3 6-Br 83 [81]
H 5-OH Br 2, AcOH 4-Br 93 [29]
Me H Br 2, AcOH 7-Br + 5-Br 37 [82]
Me H Br 2,Ag 2SO 4,H 2SO 4 7-Br + 5-Br 32 [82]
Me 4-Br Br 2,Ag 2SO 4,H 2SO 4 7-Br 96 [82]
Me 5-OH Br 2, CHCl 3 4-Br 95 [82]
Ph 5-OH Br 2, AcOH 4-Br 10 [29]
R 1
R N
S
2 R2 O2N R 1 R 2 Reagents Position of Nitration Yield (%) of 116 Ref
H 4-Cl HNO 3,H 2SO 4 7-NO 2 77 [22]
H 5-OH HNO 3, AcOH 4-NO 2 72 [29]
Me 5-Me HNO 3,H 2SO 4 4-NO 2 91 [45]
Me 6-Me HNO 3,H 2SO 4 7-NO 2 89 [45]
Me 4-Br HNO 3,H 2SO 4 7-NO 2 + 5-NO 2 42 + 41 [82]
Me 5-OH HNO 3, AcOH 4-NO 2 72 [82]
Me 5-OMe KNO 3,H 2SO 4 4-NO 2 93 [82]
Me 5-NHAc KNO 3,H 2SO 4 4-NO 2 60 [29]
Me 5-Br KNO 3,H 2SO 4 4-NO 2 81 [82]
Ph 5-OH HNO 3, AcOH 4-NO 2 73 [29]
Ph 5-NHAc HNO 3, AcOH 4-NO 2 63 [29]
However, there are limited representatives of direct acylation reactions, and Vilsmeier±
Haack reactions on 3-methyl-1,2-benzisothiazoles 117 result in ring opening, followed
by recyclization to produce N 2 -benzo[b]thiophen-3-yl-N 1 ,N 1 -dimethylformimidamide 118
and 3-(formylamino)benzo[b]thiophenes 119 (Scheme 45). [44,82,85]
116
R 1
N
S
R 1
N
S

11.16.1 1,2-Benzisothiazoles 597
Scheme 45 Vilsmeier±Haack Reactions of 3-Methyl-1,2-benzisothiazoles [44,82,85]
R 1
R 1 = OMe, Br
117
N
S
POCl3, DMF
100 o C, 5 h
R 1
S
N
118
NMe 2
+
R 1
119
S
NHCHO
On the other hand, Friedel±Crafts acetylation of 4-methyl-6-(methylsulfanyl)-1,2-benzisothiazole
(120) with acetyl chloride and aluminum trichloride in boiling dichloromethane
gives 7-acetyl-4-methyl-6-(methylsulfanyl)-1,2-benzisothiazole (121), but only in 40% yield
(Scheme 46). [14,47]
Scheme 46 Friedel±Crafts Acylation of 4-Methyl-6-(methylsulfanyl)-
1,2-benzisothiazole [14,47]
MeS
120
N
S
AcCl, AlCl3
CH2Cl2, 4 h reflux
40%
5-Bromo-3-methyl-4-nitro-1,2-benzothiazole (116,R 1 = Me; R 2 = 5-Br; Nitration
Position = 4-NO 2); Typical Procedure: [82]
5-Bromo-3-methyl-1,2-benzothiazole (1.14 g, 5 mmol) was added to a stirred soln of KNO 3
(0.55 g, 5.2 mmol) in concd H 2SO 4 (10 mL) at 0±5 8C over 1.25 h. The mixture was stirred for
a further 2 h at 0±5 8C and 18 h at 208C. It was then poured onto ice and extracted with
EtOAc to give the product as yellow needles; yield: 1.1 g (81%); mp 104±105 8C (EtOAc).
11.16.1.3.1.2 Nucleophilic Substitution
Despite the fact that reactions of 1,2-benzisothiazoles with some hard nucleophiles can
cause ring opening (see Section 11.16.1), it is possible to replace successfully the
3-chlorine atom of 3-chloro-1,2-benzisothiazoles 122 with ammonia, some amines, [22]
metal alkoxides, [21,22,91] and enolates. [92] This is a useful synthetic procedure and a series
of 3-substituted 1,2-benzisothiazoles 123 results (Scheme 47).
MeS
Ac
121
N
S
for references see p 622

598 Science of Synthesis 11.16 Benzisothiazoles
Scheme 47 Synthesis of 3-Substituted 1,2-Benzisothiazoles by Nucleophilic
Substitution of 3-Chloro-1,2-benzisothiazoles [21,22,91,92]
R 1
122
Cl
N
S
Nu −
− Cl
R 1
123
R 1 Reagent Nu Yield (%) of 123 Ref
Nu
N
S
H CH 2(CO 2Et) 2 CH(CO 2Et) 2 46 [92]
H CH 2(CN)CO 2Et CH(CN)CO 2Et 70 [92]
H NaOEt, EtOH OEt 92 [21]
H NaO(CH 2) 2NMe 2 O(CH 2) 2NMe 2 ± [91]
H H 2N(CH 2) 2NH 2 NH(CH 2) 2NMe 2 ± [91]
4-Me NaO(CH 2) 2NEt 2 O(CH 2) 2NEt 2 ± [91]
4-Cl NaOMe, MeOH, 608C, 5 h OMe 75 [22]
4-Cl NH 3,H 2NCHO, 130±140 8C NH 2 90 [22]
4-Cl MeNH 2 NHMe ± [22]
4-Cl morpholine morpholino ± [22]
4-Cl H 2NCHO NHCHO ± [22]
4,5-Cl 2 NH 3,H 2NCHO, 130±140 8C NH 2 ± [22]
4,5-Cl 2 NaOMe, MeOH, 608C, 5 h OMe 75 [22]
It is also possible to treat 3-chloro-1,2-benzisothiazolium salts in the same way and, for
example, when 3-chloro-2-ethyl-1,2-benzisothiazolium chloride (124) is heated with
phenols 125 (X = O) or benzenethiols 125 (X = S) these substrates afford the corresponding
aryl ethers or sulfides 126. The reactions with phenols can be complicated by coupling
through the para position, leading to 3-(4-hydroxyphenyl)-1,2-benzisothiazoles 127
(Scheme 48). [93]
Similar thermally induced reactions occur with aromatic amines, such as N-methylaniline.
Here 3-[4-(methylamino)phenyl]-1,2-benzisothiazole (128, R 1 =H; R 2 = Me) is
formed from 3-chloro-2-ethyl-1,2-benzisothiazolium chloride (124). N,N-Dialkylanilines
and N-(pyrrolidin-1-yl)aniline also give rise to analogous compounds in 56±70% yield. [32]

11.16.1 1,2-Benzisothiazoles 599
Scheme 48 Reaction of 3-Chloro-2-ethyl-1,2-benzisothiazolium Chloride
with Phenols and Benzenethiols [93] or N-Substituted Anilines [32]
124
Cl
+
NEt
S
Cl −
Cl
+
NEt
S
Cl
124
−
+
+
R 1
XH
125
NR 1 R 2
reflux, high bp solvent
(e.g., 1,2-dichlorobenzene)
− EtCl
Et3N, 1,2-dichlorobenzene
180 oC, 1 h
− EtCl
50−70%
X
N
S
126 X = O, S
R 1
+
N
S
128
N
S
OH
127 when X = O
NR 1 R 2
Ammonia also combines with 3-chloro-1,2-benzisothiazolium chlorides 129 to afford
1,2-benzisothiazol-3-amines 130, but here ring opening occurs since there is an exchange
of nitrogen substituents. [17,30,94] Primary amines show the same reactivity, affording an
equilibrium mixture of imines 131 and 132 (Scheme 49). [30]
Scheme 49 Reaction of 3-Chloro-1,2-benzisothiazolium Chlorides with Ammonia [17,30,94]
and Primary Amines [30]
NHR 1
N
S
130
NH3
Cl
NR
S
1
+
Cl
129
−
R 2 NH 2
NR 2
NR
S
1
131
NR 1
NR
S
2
132
It is worth noting that hydrolysis of 3-chloro-1,2-benzisothiazolium salts 33 is a useful approach
to 1,2-benzisothiazol-3(2H)-ones 133 (Scheme 50). [17]
R 1
for references see p 622

600 Science of Synthesis 11.16 Benzisothiazoles
Scheme 50 Hydrolysis of 3-Chloro-1,2-benzisothiazolium Salts
To Give 1,2-Benzisothiazol-3(2H)-ones [17]
R 2
33
Cl
NR
S
1
Cl −
+
H 2O
R 2
133
O
NR
S
1
4-Chloro-3-methoxy-1,2-benzisothiazole (123, R 1 = 4-Cl; Nu = OMe); Typical Procedure: [22]
3,4-Dichloro-1,2-benzisothiazole (41 g, 0.2 mol) was stirred in 30% NaOMe in MeOH
(100 mL) for 5 h at 608C. After cooling to about 108C the mixture was filtered and the residue
washed with chloride-free H 2O and crystallized (EtOAc); yield: 30 g (75%); mp1128C.
4-Chloro-1,2-benzisothiazol-3-amine (123,R 1 = 4-Cl; Nu = NH 2); Typical Procedure: [22]
3,4-Dichloro-1,2-benzisothiazole (123 g, 0.6 mol), NH 3 (35 g, 2.1 mol) and formamide
(300 g) were heated together at 130±1408C for 0.5 h in a pressure vessel, during which
time the pressure fell from 8 to 3 atm. After cooling and the release of pressure the mixture
was filtered, and the residue washed with H 2O and dried; yield: 100 g (90%); mp
1628C.
3-(4-Aminophenyl)-1,2-benzisothiazoles 128; General Procedure: [32]
The substituted aniline (100 mmol) was dissolved in 1,2-dichlorobenzene (150 mL) containing
Et 3N (20 g, 200 mmol) and to this stirred soln was added 3-chloro-2-ethyl-1,2-benzothiazolium
chloride. The mixture was heated to 180 8C for 1 h, the solvent distilled under
reduced pressure and the residue treated with H 2O (500 mL). The soln was made alkaline
with concd NaOH and extracted with Et 2O. The dried, combined extracts were evaporated
and the residue distilled under reduced pressure; yield: 50±70%.
11.16.1.3.2 Addition Reactions
11.16.1.3.2.1 Addition of Organic Groups
11.16.1.3.2.1.1 Method 1:
Alkylation of Saccharins
For the alkylation of aromatic benzisothiazoles see Section 11.16.1.
Saccharins 134 are readily N-alkylated and many derivatives are claimed to show biological
activity (see Section 11.16.1). For example, 2-(chloromethyl) derivatives 136 are obtained
by reacting saccharins 134 with chloromethyl phenyl sulfide to give the sulfides
135 and then treating these compounds with sulfuryl chloride. The 2-(chloromethyl)saccharins
136 can be converted into 2-[(arylcarbonyloxy)methyl]saccharins 137 by further
reaction with benzoic acid (Scheme 51). Compounds of this type, e.g. 137 (R 1 = iPr;
R 2 = OMe), are of particular interest because they act as human leukocyte elastase (HLE)
inhibitors. [62,86,87] The HLE inhibitory activity of these derivatives is based on the propensity
of bionucleophiles (Nu ± ) to attack the lactam carbonyl of the saccharin and induce the
loss of a carboxylate anion, leading to a sulfanylimine (137 ® 138). [88,89]

Scheme 51 Synthesis of N-Alkylated Saccharins as HLE Inhibitors and Their Reaction with
Bionucleophiles [62,86±89]
R 2
R 1
134
O
NH
S
O O
Ar 1 CO 2H
PhSCH 2Cl
toluene
reflux
11.16.1.3.2.2 Addition of Heteroatoms
11.16.1.3.2.2.1 Method 1:
Oxidation
11.16.1 1,2-Benzisothiazoles 601
R 2
R 2
R 1
O
R 1
N
S
O
137
O
O
N
S
O
135
O
OCOAr 1
SO2Cl2
CH2Cl2
N
R S
2
R1 O
O O
SPh Cl
Nu −
− Ar 1 CO2 −
R 2
136
R 1
O
S
138
N
Nu
O O
1,2-Benzisothiazole 1-oxides can be synthesized from 1,2-benzisothiazoles by reaction
with nitric acid generated in situ from potassium nitrate and sulfuric acid. In the case of
3-(substituted)-1,2-benzisothiazoles 139, the yields of the corresponding 1-oxide 140 so
formed do not exceed 47% (Scheme 52). [31]
Oxidation with other reagents, for example hydrogen peroxide or peracids, allows
the formation of 1,2-benzisothiazole 1,1-dioxides 141, but the yields are unpredictable.
[31,32,44,80]
Scheme 52 Synthesis of 1,2-Benzisothiazole 1-Oxides and 1,1-Dioxides [31,32,44,80]
R 2
139
R 1
N
S
R 1
[O]
R 2
R N
[O]
S
2 R2 R 1
N
S
O
140
R 1
N
S
O
O
141
R 1 R 2 Oxidant Yield (%) of 141 Ref
Me H H 2O 2 41 [44]
Ph 5,6-(OMe) 2 H 2O 2 53 [80]
4-MeNHC 6H 4 H perphthalic acid 39 [32]
NHEt H H 2O 2 42 [31]
for references see p 622

602 Science of Synthesis 11.16 Benzisothiazoles
Although 3-chloroperoxybenzoic acid is a suitable oxidant for the formation of 1,2-benzisothiazole
1,1-dioxides, over-reaction is possible and the oxaziridine 143 is formed from
3-methyl-1,2-benzisothiazole 142 in >90% (Scheme 53). [90]
Scheme 53 Epoxidation of 3-Methyl-1,2-benzisothiazole 1,1-Dioxide [90]
142
N
S
MCPBA, CH2Cl2 K2CO3
>90%
O
N
S
O O
In addition, there is a problem if the carbocycle already contains a hydroxy group, as for
6,7-dichloro-1,2-benzisothiazol-5-ol (144), because oxidation even with dilute nitric acid
in acetic acid causes the formation of 6,7-dichloro-1,2-benzisothiazole-4,5-dione (145) in
70% yield (Scheme 54). [29]
143
Scheme 54 Oxidation of 6,7-Dichloro-1,2-benzisothiazol-5-ol [29]
HO
Cl
Cl
144
N
S
aq HNO3
AcOH
70%
In the case of 1,2-benzisothiazol-3-amines 146, a reaction with hydrogen peroxide in
acetic acid gives the 1,1-dioxide 147, but the yield in this reaction can be severely diminished
by ring opening (Scheme 55). This unwanted reaction leads to 2-carbamimidoylbenzenesulfonic
acids 148. [31]
O
Cl
O
Cl
145
N
S
Scheme 55 Synthesis of 1,2-Benzisothiazol-3-amine 1,1-Dioxides [31]
146
NHR 1
N
S
30% H 2O 2, AcOH
N
S
O O
147
NHR 1
+
NHR 1
NH
SO 3H
148 major product
This reaction does not occur for 3-unsubstituted 1,2-benzisothiazoles 149 and here hydrogen
peroxide in acetic acid at 808C gives 4-chlorosaccharins 150 (Scheme 56). For the synthesis
of the 4,5-dichlorosaccharin 150 (R 1 = Cl) and the 5-bromo-4-chlorosaccharin 150
(R 1 = Br) the yields are 95%. [22]
Scheme 56 Synthesis of 4-Chlorosaccharins [22]
R 1
Cl
149
N
S
H2O2, AcOH
80 oC, 20 min
R1 = Cl 95%
R1 = Br 95%
R 1
Cl
O
NH
S
O
150
O

11.16.2 2,1-Benzisothiazoles 603
11.16.2 Product Subclass 2:
2,1-Benzisothiazoles
2,1-Benzisothiazole (2) is a pale yellow liquid, bp 2428C/748 Torr, 708C/0.5 Torr. It can be
represented by the resonance forms shown in Scheme 57. [8,95]
Scheme 57 2,1-Benzisothiazole Resonance Contributors [8,95]
2
S
N
S
N
+
−
S
N
+
−
The molecule is planar and an X-ray crystal structure analysis of 5-chloro-2,1-benzoisothiazole
shows that the S-N bond is short (1.54 ä), with an N-S-C3 bond angle of only
988. [96] The parent heterocycle is only slightly less basic than isothiazole (pKa ±0.51). [97]
Ultraviolet absorption maxima are exhibited by 2,1-benzisothiazole at l max (EtOH)
(log e) 221 (4.21), 288 (3.88), 298 (3.96), and 315 (sh) nm (3.60), [98] and in the 1 H NMR spectrum
(neat) H3 resonates as a double doublet of doublets at d 9.06 (J 3,7 = 0.94 Hz,
J 3,4 = 0.38 Hz, J 3,5 = 0.18 Hz). The other protons resonate at d 7.78 (H7), 7.63 (H4), 7.31 (H6),
and 7.09 (H5). [8,96] The chemical shift of the H3 resonance is dependant on the nature of
the substituents in the carbocycle, for example the presence of a chlorine atom at C4
causes a shift to d 9.33, whereas a nitro groupat this site is responsible for a further downfield
shift of the H3 signal to d 10.05. [98±100]
These data, and also those from the 13 C NMR spectrum, [101,102] tend to confirm the
1,2-quinonoid structure of the parent bicyclic compound, and this is supported by ab initio
calculations and photoelectron spectroscopy. [103]
2,1-Benzisothiazol-3-ol (151, R 1 =H) [104±108] exists in solution preferentially as
2,1-benzisothiazol-3(1H)-one (152, R 1 = H) and exhibits an electronic spectrum [l max
(EtOH) (log e) 230 (4.22), 243 (3.96), 353 nm (3.69)] that is very similar to that of the 1-methyl
derivative 152 (R 1 = Me). [104,105] The benefit gained from the presence of a benzene ring
system is, however, offset in the 3-imino analogue 154, which favors the ortho-quinonoid
tautomer 2,1-benzisothiazol-3-amine (153) [l max (EtOH) (log e) 230 (4.49), 286 (3.41),
373 nm (3.81)] (Scheme 58). [109]
Scheme 58 Tautomerism in 2,1-Benzisothiazol-3-ol and -3-amines
151
153
OR 1
S
N
NH2
S
N
O
S
N
R1 152
154
Reactivity: The bromination of 2,1-benzisothiazole with bromine in sulfuric acid containing
silver sulfate is an nonspecific reaction and a mixture of 5-bromo- (155) (31%), 7-bromo-
(156) (31%), and 4,7-dibromo-2,1-benzisothiazole (157) (10%) is produced (Scheme
59). [99] Similar results are noted for nitration with nitric acid and sulfuric acid and here
the products are 4-nitro- (17%), 5-nitro- (57%), and 7-nitro-2,1-benzisothiazoles (26%). [99] Be-
NH
S
N
H
S
N
for references see p 622

604 Science of Synthesis 11.16 Benzisothiazoles
cause of this lack of specificity, [104,110,111] direct electrophilic substitution reactions of
2,1-benzisothiazoles are normally of little synthetic value.
Scheme 59 Bromination of 2,1-Benzisothiazole [99]
2
S
N
Br2, H2SO4
Ag2SO4
Br
155 31%
S
N
+
Br
156 31%
S
N
+
Br
Br
157 10%
N-Alkylation occurs with alkyl halides (R 1 X) giving salts 158 in which the benzenoid ring
is restored. [112±120] These are quite stable under anhydrous conditions and many have been
synthesized (see Section 11.16.2.3.2.1), but on heating with sodium hydrogen carbonate,
with tertiary amines, or with acids, these undergo ring scission, affording 2-aminobenzaldehydes
159 and, through dismutation, 2,1-benzisothiazole-3(1H)-thiones 160. [116,121] A
similar reaction takes place when 2,1-benzisothiazole is reacted with ethyl chloroformate
in tetrahydrofuran and water. Here the initial product is presumably the salt 161, which
adds water and ring opens to ethyl N-(2-formylphenyl)carbamate (162) (Scheme 60). [116]
Scheme 60 N-Alkylation of 2,1-Benzisothiazole and the Hydrolytic RingOpeningof
1-Alkyl-2,1-benzisothiazolium Salts [112,116,121]
2
R 1 = Me, Bn, CH 2CO 2H
2
S
N
S
N
R 1 X
ClCO 2Et
H 2O, THF
reflux, 3 h
158
S
N
+
R1 X −
161
S
N
+
Cl −
CO 2Et
HCl, NaHCO 3, Et 3N, or py
159
CHO
NHR 1
+
162
S
N
160
CHO
N
H
S
S
N
H
CO2Et
2,1-Benzisothiazolamines can be diazotized by treatment with nitrous acid and the products
behave as typical arenediazonium salts. From these salts a range of useful derivatives
is obtained (see Section 11.16.2.3.1.2.2.2)
Although Raney nickel reduction of 3-methyl-2,1-benzisothiazole (163,R 1 = Me) causes
desulfurization and ring opening to give 1-(2-aminophenyl)ethanone (164, R 1 = Me) [122]
under mild conditions, 3-aryl-2,1-benzisothiazoles 164 (R 1 = aryl) undergo further reduction
to give the appropriate 2-benzylanilines 165 (R 1 = aryl) (Scheme 61). [123,124]

11.16.2 2,1-Benzisothiazoles 605
Scheme 61 Reductive RingOpeningof 3-Substituted 2,1-Benzisothiazoles [122,123,124]
S
N
Raney Ni
benzene, 60
163
o 1 R
R R1
C
O
NH2 NH2
164
165
1
− S
[H]
Treatment with hydrazines (R 1 NHNH 2) also causes the elimination of sulfur, but in this
case the reagent is incorporated in the product so that 2-aminophenylhydrazones 166
are generated (Scheme 62); with hydrazine hydrate, 166 (R 1 = H) is formed in 23% yield. [125]
Scheme 62 Reaction of 2,1-Benzisothiazole with Hydrazines [125]
2
S
N
R1NHNH2 − S
R1 = H 23%
NH2 166
NNHR 1
Triethyl phosphite and aqueous sodium hydrogen sulfite both effect desulfurization and
in the latter case 2,1-benzisothiazol-3-amine (153) affords 2-(2-aminophenyl)quinazolin-4ol
(167) in 66% yield, but only after 60 hours at reflux (Scheme 63). [126]
Scheme 63 Reaction of 2,1-Benzisothiazol-3-amine with Sodium Hydrogen Sulfite [126]
153
NH 2
S
N
aq NaHSO 3, reflux, 60 h
− S
66%
The ortho-quinoid character of 2,1-benzisothiazoles indicates that they should undergo
cycloaddition reactions with dienophiles, such as maleic anhydride [127] and diethyl acetylenedicarboxylate,
[95] but the reactions require strenuous conditions and the expected adducts
are unstable. For example, 2,1-benzisothiazole (163, R 1 = H) and 3-methyl-2,1-benzisothiazole
(163, R 1 = Me) combine with dimethyl acetylenedicarboxylate over extremely
long reaction times (90 8C for 240 hours), giving very low yields of the appropriate dimethyl
quinoline-2,3-dicarboxylates 168 (R 1 = H or Me) (Scheme 64). [95]
OH
N
N
167
NH 2
Scheme 64 Cycloaddition of 2,1-Benzisothiazole and 3-Methyl-2,1benzisothiazole
with Dimethyl Acetylenedicarboxylate [95]
163
R 1
S
N
MeO2C
R1 = H 5%
R1 = Me 23%
CO2Me
R 1
N
168
CO2Me
CO 2Me
The reactivity of the 2,1-benzisothiazole system as a diene is finely balanced and for
2,1-benzisothiazol-3-amine (153) potential dienophiles may react instead as electrophiles.
These may combine either with the 3-amino groupor with the nitrogen atom of the heterocycle.
In the latter event sulfur is lost and the heterocycle is cleaved. With maleic an-
for references see p 622

606 Science of Synthesis 11.16 Benzisothiazoles
hydride, for example, acylation at the 3-amino position occurs, affording a quantitative
yield of N-(3-carboxyprop-2-enoyl)-2,1-benzisothiazol-3-amine (169). [127] In contrast, the
site of reactivity is switched to N1 when dimethyl acetylenedicarboxylate is the reagent
and after heating it and 2,1-benzisothiazol-3-amine (153) together at 100 8C for 24 hours
dimethyl (Z)-2-(2-cyanoanilino)but-2-enedioate (171) is produced in 56% yield, presumably
via the initial adduct 170 (Scheme 65). [95]
Scheme 65 Reactions of 2,1-Benzisothiazol-3-amine with Maleic Anhydride and
Dimethyl Acetylenedicarboxylate [95,127]
153
153
NH2
S
N
NH2
S
N
O
O
O,
heat
100%
HN
S
N
169
MeO2C CO2Me
100 o NH
C, 24 h
S
95% N
MeO 2C
O
170
CO2H
H
CO 2Me
MeO 2C
CN
NH
171
56%
H
CO2Me
With benzyne, 2,1-benzisothiazole (2) gives acridine (173) in low yield (5%). Presumably
here adduct 172 is formed as an intermediate, but with 2,1-benzisothiazol-3-amine both
N1 and the 3-amino group are phenylated, resulting in the formation of 3-anilino-1-phenyl-1,3-dihydro-2,1-benzisothiazole
(174) in 49% yield, together with a minor amount (5%)
of 2-anilinobenzonitrile (175) (Scheme 66). [128]
Scheme 66 Reactions of 2,1-Benzisothiazole and 2,1-Benzisothiazol-3-amine with
Benzyne [128]
2
153
S
N
NH 2
S
N
S
N
172
NHPh
S
N
Ph
174 49%
+
− S
5%
175 5%
NHPh
CN
N
173

11.16.2 2,1-Benzisothiazoles 607
11.16.2.1 Synthesis by Ring-Closure Reactions
11.16.2.1.1 By Formation of One S-N Bond
11.16.2.1.1.1 Method 1:
From 2-Nitrophenylmethanethiols or 2-Nitrobenzenecarbothioamides
2,1-Benzisothiazole (2) was first synthesized over 100 years ago by the reductive cyclization
of either 2-nitrophenylmethanethiol (176, R 1 = H), [129] or S-2-nitrobenzyl thiocarbamate
(176, R 1 = CONH 2), with tin(II) chloride in hydrochloric acid (Scheme 67); [130] the
yield in the first procedure was 31%.
Scheme 67 Original Synthesis of 2,1-Benzisothiazole through the
Reduction of 2-Nitrophenylmethanethiols [129,130]
NO2 176
SR 1
SnCl2, HCl
R 1 = H 31%
The reduction of 2-nitrobenzenecarbothioamides 177 with tin(II) chloride is a more modern
development of the original protocol and this method has been employed to synthesize
a number of 2,1-benzisothiazol-3-amines 178 (Scheme 68). [112,131,132] However, yields
vary widely depending on the nature of the amino substituent without an obvious reason:
3-pyrrolidin-1-yl-2,1-benzisothiazole (178, R 1 =H; NR 2 2 = pyrrolidin-1-yl) is formed in 72%
yield (as the hydrochloride), whereas N,N-dimethyl-2,1-benzisothiazol-3-amine (178,
R 1 =H;NR 2 2 = NMe 2)is generated in only 24% yield from the corresponding benzenecarbothioamide.
[118]
2
S
N
Scheme 68 Synthesis of 2,1-Benzisothiazol-3-amines from
2-Nitrobenzenecarbothioamides [112,118,131,132]
R 1
177
NR 2 2
S
NO 2
SnCl 2, concd HCl
R 1
178
NR 2 2
S
N
R 1 NR 2 2 Yield (%) of 178 Ref
H NMe 2 24 [112]
H pyrrolidin-1-yl 72 [112]
H piperidino 40 [132]
6-Cl NMe 2 92 [112]
6-Cl morpholino 33 [112]
N,N-Dimethyl-2,1-benzisothiazol-3-amine (178,R 1 =H;NR 2 2 =NMe 2); Typical Procedure: [112]
To a suspension of finely divided N,N-dimethyl-2-nitrobenzenecarbothioamide (177,
R 1 =H;NR 2 2 = NMe 2; 105 g, 0.5 mol) in concd HCl (1 L) at 258C was added dropwise, with
vigorous stirring, a mixture of SnCl 2 ·2H 2O (248 g, 1.1 mol) in concd HCl (250 mL). The mixture
was then stirred at 508C for 3 h. After cooling in ice, the mixture was filtered and the
tin complex residue washed with benzene (CAUTION: carcinogen). This solid was suspend-
for references see p 622

608 Science of Synthesis 11.16 Benzisothiazoles
ed in a mixture of benzene (1 L) and H 2O (500 mL) and excess 50% NaOH was added, keeping
the temperature below 208C. The benzene soln was separated, washed with H 2O and
concentrated. On cooling a yellow crystalline solid was obtained that could be recrystallized
(H 2OorEt 2O); yield: 21.4 g (24%); mp120±1218C.
11.16.2.1.1.2 Method 2:
From 2-Aminophenylmethanethiols or 2-Aminobenzenecarbothioamides
A complementary approach is to oxidize 2-aminophenylmethanethiols, but although the
oxidation of 2-aminophenylmethanethiol (179) with iodine in 2 M sodium hydroxide at
pH 13.5 gives 2,1-benzisothiazole (2) in 60% yield (Scheme 69), the product is contaminated
with upto 10% of bis(2-aminobenzyl) disulfide (180). [34]
Scheme 69 Synthesis of 2,1-Benzisothiazole from 2-Aminophenylmethanethiol [34]
NH2 179
SH
I2, KI
2 M NaOH
pH 13.5
2 60%
S
N
+
S S
H 2N
NH2 180 10%
The formation of disulfides is precluded when 2-aminobenzenecarbothioamides 181 are
oxidized and this now forms a versatile route to 2,1-benzisothiazol-3-amines 182 (Scheme
70). The oxidants are normally hydrogen peroxide in pyridine, or acetic acid, [112,133,134] although
bromine in acetic acid is also used. [135]
Scheme 70 Synthesis of 2,1-Benzisothiazol-3-amines from
2-Aminobenzenecarbothioamides [112,133±135]
R 1
R 2
R
181
3
NHR 4
S
NH2
R 1
R 2
R3 182
NHR 4
S
N
R 1 R 2 R 3 R 4 Oxidant Yield (%) of 182 Ref
H H H H H2O2, pyridine 62 [112]
H H H Me H2O2, pyridine 46 [112]
H H H Et H2O2, pyridine 52 [112,133±135]
H H CF3H H2O2, pyridine ± [133,134]
H Me H Et H2O2, pyridine 60 [112]
H Cl H H H2O2, pyridine 87 [112]
Br H H Me H2O2, pyridine 30 [112]
Br H Br H Br2, AcOH 92 [135]
OMe H OMe Et H2O2, AcOH 58 [112]
OMe OMe H Et H2O2, AcOH 62 [112]
NO2 H H H H2O2, AcOH 90 [135]

11.16.2 2,1-Benzisothiazoles 609
This approach is also applicable to the synthesis of naphtho[1,2-c]isothiazol-3-amine (184)
from 1-aminonaphthalene-2-carbothioamide (183), but fails in the case of the linear isomer
186 (from 185), probably because such a doubly quinonoid product is inherently unstable
(Scheme 71). [136]
Scheme 71 Synthesis of Naphtho[1,2-c]isothiazol-3-amine [136]
183
185
NH2
S
NH2
NH2
S
NH2
30% H2O2, MeOH
py, 20 o C, 8 h
94%
It is commonplace to prepare the starting 2-aminobenzenecarbothioamides 188 (X,
Y = Ph) by reacting the corresponding 2-aminobenzonitriles 187 (X, Y = Ph) with hydrogen
sulfide, and an analogous preparation of 2-aminoheteroarenecarbothioamides 188 (X,
Y = heteroarene) starting from 2-cyanoheteroarylamines 187 (X, Y = heteroarene) provides
wide access to isothiazol-3-amines 189 fused to many five- and six-membered heterocycles
(Scheme 72). [137±147]
184
186
NH2
S
N
NH2
S
N
Scheme 72 Synthesis of Fused Heteroaryl Isothiazol-3-amines [137±148]
NC
H 2N
187
X
Y
H2S S
H 2N
NH2
188
X
Y
As an example, isothiazolo[3,4-b]pyridin-3-amine (191) is formed in 80% overall yield from
2-aminopyridine-3-carbothioamide (190) using hydrogen peroxide in pyridine as the oxidant.
[137] Similarly, thieno[2,3-c]isothiazol-3-amine (193) is obtained in 68% yield from
2-aminothiophene-3-carbothioamide (192), again using hydrogen peroxide in pyridine
as the oxidizing agent (Scheme 73). [148] Many other five- and six-membered ring-fused isothiazoles
have also been prepared by this route. [8,142±152]
[O]
H2N
X
189
Scheme 73 Synthesis of Isothiazolo[3,4-b]pyridin-3-amine and
Thieno[2,3-c]isothiazol-3-amine [137,148]
N
190
NH2
S
NH 2
30% H 2O 2, py, 20 o C, 10 min
80%
N
191
NH2
S
N
S
N
Y
for references see p 622

610 Science of Synthesis 11.16 Benzisothiazoles
H 2N
S
S
NH2
192
1. 30% H2O2, py, MeOH, 40−50 o C, then 20 o C
2. 2 M HCl
3. 0.89 M NH3 68%
N-Ethyl-2,1-benzisothiazol-3-amine (182, R 1 =R 2 =R 3 =H;R 4 = Et);
Typical Procedure: [112,133±135]
A soln of 30% H 2O 2 (36 mL, 0.32 mol) was added dropwise to a stirred soln of 2-(ethylamino)benzenecarbothioamide
(54 g, 0.3 mol) in pyridine (100 mL) at 35 8C. The mixture was
allowed to stand for 16 h then filtered. The yellow crystalline solid residue was washed
with H 2O and then recrystallized (EtOH); yield: 28 g (52%); mp195±1968C.
Isothiazolo[3,4-b]pyridin-3-amine (191); Typical Procedure: [137]
2-Aminopyridine-3-carbothioamide (190; 4.6 g, 30 mmol) was dissolved in pyridine
(10 mL) and stirred at 358C while 30% H 2O 2 (3.6 mL) was slowly added. A yellow solid was
deposited and this, after further stirring for 10 min at 35 8C and standing at rt for 16 h, was
collected by filtration, washed with H 2O, dried, and crystallized (EtOH) as fine needles;
yield: 3.6 g (80%); mp203.5±204.58C.
Thieno[2,3-c]isothiazol-3-amine (193): [148]
2-Aminothiophene-3-carbothioamide (192; 3.1 g, 20 mmol) was dissolved by warming it
in a soln of MeOH (150 mL) and pyridine (1.6 g, 20 mmol) To the well-stirred soln at 408C
was added 30% H 2O 2 (3.6 mL) dropwise such that the temperature did not exceed 508C.
The mixture was stirred for a further 1 h at 20 8C and poured into ice-cold concd HCl
(50 mL), producing a solid hydrochloride. The free base was obtained by treatment of
this with NH 3 soln (0.89 M NH 3/H 2O 1:1) followed by extraction with Et 2O; yield: 2.2 g
(68%); mp138±1408C (EtOH, darkens in air).
11.16.2.1.1.3 Method 3:
From Isatoic Anhydride
2,1-Benzisothiazol-3(1H)-ones 196 are synthesized from 2H-3,1-benzoxazine-2,4(1H)-diones
194 by reaction with sodium or potassium hydrogen sulfides and oxidation of the intermediate
2-aminobenzenecarbothioates 195 with either hydrogen peroxide or iodine
(Scheme 74); yields range from 28 to 90%. [104±108]
Scheme 74 Synthesis of 2,1-Benzisothiazol-3(1H)-ones from 2H-3,1-Benzoxazine-2,4(1H)diones
[104±108]
R 2
M = Na, K
R 1
N O
O
194
O
MSH
R 2
O
195
NHR 1
SM
S
193
H2O2 or I2 28−90%
NH2
S
N
R 2
196
O
S
N
R1

11.16.2 2,1-Benzisothiazoles 611
11.16.2.1.1.4 Method 4:
From 2-Methylanilines
On the face of it, a synthesis of 2,1-benzisothiazoles starting from such readily available
materials as 2-methylanilines and thionyl chloride should be very attractive, but even in a
high boiling solvent, such as mesitylene, xylene, or bromobenzene, such a reaction takes
a long time and the yields are modest. [98,127,153,154]
For example, when 5-methoxy-2,1-benzisothiazole (199,R 1 =H;R 2 = 5-OMe) is formed
from 4-methoxy-2-methylaniline (197, R 1 =H; R 2 = 4-OMe), via the sulfine 198 (R 1 =H;
R 2 = 4-OMe), by treatment with thionyl chloride the yield is only 56% (Scheme 75). [127] In
addition, side reactions, such as chlorination in the rings, are a potential problem. [153]
Thus, a similar reaction of 2-methylaniline (197, R 1 =R 2 = H) with thionyl chloride at
145±1508C affords 3-chloro-2,1-benzisothiazole as the main product in 17% yield, rather
than the parent heterocycle. [153]
Despite these difficulties this approach has been used to prepare 6-bromo-2,1-benzisothiazole
(199,R 1 =H;R 2 = 6-Br) in 42% yield from 5-bromo-2-methylaniline (197,R 1 =H;
R 2 = 5-Br), and 4-methyl-2,1-benzisothiazole (199,R 1 =H;R 2 = 4-Me) is obtained from 2,3-dimethylaniline
(197,R 1 =H;R 2 = 3-Me) in 28% yield. [98]
Scheme 75 Synthesis of 2,1-Benzisothiazoles from 2-Methylanilines [98,127,153,155]
R 2
197
R 1
NH 2
SOCl2, xylene
reflux, 24−48 h
R 2
R 1
S
O
R
198 199
3
N
− SO2 S
O
R 1 R 2 R 3 Yield (%) of 199 Ref
H 4-OMe 5-OMe 56 [127]
H 5-Br 6-Br 42 [98]
H 3-Me 4-Me 28 [98]
Ph H H 93 [155]
Although naphtho[c]isothiazole cannot be synthesized in this way, naphtho[2,1-c]isothiazole
(201) (31%) and naphtho[1,2-c]isothiazole (203) (7%) can be produced from the appropriate
2-methylarylamines 200 and 202, respectively, although the reaction times are
24 hours (Scheme 76). In the reaction of 202 some 5-chloronaphtho[1,2-c]isothiazole (204)
is also formed. [155]
Scheme 76 Syntheses of Naphtho[2,1-c]isothiazole and Naphtho[1,2-c]isothiazole [155]
SOCl2 xylene
reflux, 24 h
31%
NH2 200 201
S
N
R 1
S
N
for references see p 622

612 Science of Synthesis 11.16 Benzisothiazoles
NH 2
SOCl2 xylene
reflux, 24 h
202 203 7%
S +
N
Homologues of 2-methylaniline can also be employed, but in the case of 2-ethylaniline
(205) treatment with thionyl chloride in xylene at reflux leads not only to 2,1-benzisothiazole-3-carboxylic
acid (206) in 30% yield but also to N-(2-ethylphenyl)-2,1-benzisothiazole-3-carboxamide
(207) (11%) and 3-(4-ethyl-1,3-benzisothiazol-2-yl)-2,1-benzisothiazole
(208) (4%) (Scheme 77). [156]
Scheme 77 Synthesis of 2,1-Benzisothiazole-3-carboxylic Acid from 2-Ethylaniline [156]
Et
NH2
205
1. SOCl2, xylene, reflux, 24 h
2. 2 M NaOH, pH 7, 12 h
3. SOCl2, 12 h
4. 2.5 M NaOH, steam distillation
206 30%
CO 2H
S
N
+
O H N
Cl
S
N
207 11%
Et
204
+
S
N
S
S
N
N
208 4%
Instead of thionyl chloride, N-sulfinylmethanesulfonamide (from methanesulfonamide
and thionyl chloride) and N-sulfinyl-4-toluenesulfonamide have been recommended as
reagents. 2,1-Benzisothiazole (210, R 1 =R 3 = H) itself can be synthesized in ~60% yield by
treating 2-methylaniline (209, R 1 =R 2 = H) in benzene with N-sulfinylmethanesulfonamide.
[100] The reaction mechanism is probably very similar to that described in Scheme
75, since N-sulfinylanilines 210 can be used as the substrates in place of the 2-methylanilines.
If used these afford the sulfines 211, which then cyclize with the loss of sulfur dioxide
to give the 2,1-benzisothiazoles 212. A series of such compounds synthesized by this
method is given in Scheme 78 using either 2-methylanilines or N-sulfinylanilines as the
starting compounds. [100]
Et

11.16.2 2,1-Benzisothiazoles 613
Scheme 78 Synthesis of 2,1-Benzisothiazoles from 2-Methylanilines and
N-Sulfinylanilines [100]
R 2
209
MsN S O
benzene, py, 0 o R
C
1−72 h, reflux
1 R1 NH 2
R 2
R 2
210
NSO
R 1
211
S
NSO
O
MsN S O
Substrate Reflux (h) Product Yield (%) Ref
R1 R2 R1 R3 209 H H 16 H H 27 [100]
210 H H 18 H H 60 [100]
210 H 4-Me 65 H 5-Me 70 [100]
210 H 3-CO2Me 45 H 4-CO2Me 65 [100]
210 H 5-CN 43 H 6-CN 85 [100]
209 H 4-Cl 65 H 5-Cl 89 [100]
209 H 6-Cl 64 H 7-Cl 84 [100]
210 H 6-Cl 19 H 7-Cl 87 [100]
209 H 4-OMe 65 H 5-OMe 88 [100]
210 H 4-OMe 60 H 5-OMe 77 [100]
209 H 5-NO2 65 H 6-NO2 85 [100]
209 Me H 65 Me H 6 [100]
210 Me H 1 Me H 55 [100]
210 Ph Ph 3.5 Ph Ph 11 [100]
6-Bromo-2,1-benzisothiazole (199,R 1 =H;R 3 = 6-Br); Typical Procedure: [98]
Thionyl chloride (8 mL, 100 mmol) was slowly added dropwise to a soln of 5-bromo-2methylaniline
(197, R 1 =H; R 2 = 5-Br; 5.8 g, 31 mmol) in xylene (15 mL). After a vigorous
reaction a yellow solid separated and the mixture was heated under reflux for 24 h. A
further quantity of thionyl chloride (8 mL, 100 mmol) was then added, followed by a second
period of heating for 24 h under reflux. On cooling concd HCl (50 mL) was added and
SO 2 evolved. After vigorously stirring for 0.5 h, the mixture was filtered [the residue was
extracted with boiling H 2O, giving 5-bromo-2-methylaniline hydrochloride; yield: 2.6 g
(39%); sublimed at 2468C] and the aqueous layer separated, washed with petroleum ether
and diluted with H 2O (250 mL). The solid that separated was collected and crystallized
(MeOH), giving long, colorless needles; yield: 2.7 g (42%); mp818C.
2,1-Benzisothiazole-3-carboxylic Acid (206): [156]
Thionyl chloride (36 g, 0.3 mol) was added dropwise to a stirred, cooled soln of 2-ethylaniline
(205; 12.1 g, 0.1 mol) in xylene (50 mL). The mixture was heated under reflux and the
− SO2
R 3
212
R 1
S
N
for references see p 622

614 Science of Synthesis 11.16 Benzisothiazoles
sulfur dioxide and hydrogen chloride produced were neutralized by passing into
2 M NaOH. At the end of 12 h, a further portion of thionyl chloride (22 mL, 0.3 mol) was
introduced dropwise and the mixture heated as before for a further 12 h. After addition
of H 2O (200 mL) and 2.5 M NaOH (400 mL) the mixture was subjected to a steam distillation
procedure (~300 mL distillate). The alkaline residue was treated with decolorizing
charcoal (1 g), filtered, acidified with AcOH, and the resulting crystals collected by filtration;
yield: 5.3 g (30%); mp2128C.
2,1-Benzisothiazole (212,R 1 =R 3 = H) from 2-Methylaniline (209,R 1 =R 2 = H) or 2-Methyl-Nsulfinylaniline
(210,R 1 =R 2 = H); Typical Procedure: [100]
To a soln of 2-methylaniline (209, R 1 =R 2 = H; 7.5 g, 70 mmol) in dry benzene (30 mL)
cooled in an ice bath, or to a soln of 2-methyl-N-sulfinylaniline (210, R 1 =R 2 = H; 10.7 g,
70 mmol) in dry benzene (30 mL) at 208C, was added N-sulfinylmethanesulfonamide
(15.5 g, 0.11 mol when 210 was used; 29.6 g, 0.21 mol when 209 was used) in dry benzene
(30 mL). To the stirred, cooled (ice bath) mixture was added a soln of dry pyridine (7.9 g,
0.10 mol) in dry benzene (20 mL). At the end of the exothermic reaction a colorless solid
was produced that dissolved after 20 min of the subsequent 18 h (when 210 was used, 16 h
when 209 was used) period of heating under reflux (with the exclusion of moisture). The
pyridine and benzene were distilled under reduced pressure and the cooled residue treated
carefully with H 2O (35 mL). After 0.5 h at 20 8C, this was extracted with CHCl 3, the extract
dried and the solvent evaporated under reduced pressure. The dark oily residue was
distilled, giving a yellow oil (6 g, from 209) bp50±608C/0.4 Torr, which was purified by the
addition of H 2O (20 mL), acidification to pH 4 with 5% HCl and extraction with CHCl 3. The
dried extracts were distilled, giving a pale yellow oil; yield: 5.7 g (60%, from 210). When
substrate 209 (R 1 =R 2 = H) (10.7 g) is used 2,1-benzisothiazole (2.6 g) is obtained in 27%
yield; bp608C/0.6 Torr.
11.16.2.1.1.5 Method 5:
From Bis(2-aminophenyl)methane
Another related synthesis is that of 3-(2-aminophenyl)-2,1-benzisothiazole (214,
R 1 =R 2 = H) from bis(2-aminophenyl)methane (213, R 1 =R 2 = H) by treatment with N-sulfinylmethanesulfonamide
in boiling pyridine and benzene for 48 hours; [157,158] the yield
is only 21% and the product is tautomeric with the tetracyclic isomer 215 (R 1 =R 2 =H)
(Scheme 79). In other examples, such as 3-(2-amino-4-bromophenyl)-6-bromo-2,1-benzisothiazole
(214, R 1 =H; R 2 = Br) and 3-(2-amino-5-methylphenyl)-5-methyl-2,1-benzisothiazole
(214, R 1 = Me; R 2 = H), the yields from the appropriate bis(2-aminophenyl)methanes
are higher: 43 and 55%, respectively. [158]

11.16.2 2,1-Benzisothiazoles 615
Scheme 79 Synthesis of 3-(2-Aminophenyl)-2,1-benzisothiazoles [157,158]
R 1
R 1
R 2
R 2 NH 2
213
NH2
R 1
R 2
MsN S O
R 1 = R 2 = H 21%
R 1 = H; R 2 = Br 43%
R 1 = Me; R 2 = H 59%
R 1
214
S
N
R 2
NH2 R 1
R 2
R 1
S
N
H
215
NH
In a similar manner benzo[1,2-c:4,3-c¢]diisothiazole (217) is prepared in 41% yield by treating
2,3-dimethylbenzene-1,4-diamine (216) with two molecular equivalents of N-sulfinylmethanesulfonamide
(Scheme 80). [110]
Scheme 80 Synthesis of Benzo[1,2-c:4,3-c¢]diisothiazole [110]
H 2N
216
NH 2
MsN S O
41%
11.16.2.2 Synthesis by Ring Transformation
11.16.2.2.1 From 2,1-Benzisoxazoles
Rather than reduce 2-nitrophenylmethanethiols or 2-nitrobenzylthiocarbamates directly
to 2,1-benzisothiazoles there are a few syntheses in which 2-nitroacetophenones 218 are
reduced first to give 2,1-benzisoxazoles 219, and then these products are heated with
phosphorus pentasulfide and an organic base such as imidazole or pyridine at reflux to
insert the sulfur atom and form the heterocycles 220 (Scheme 81). This has some practical
advantages over the older routes since the starting materials are readily available and
easily handled.
In the case of 5-chloro-3-phenyl-2,1-benzisothiazole (220, R 1 = Ph; R 3 = 5-Cl) the yield
for the sulfurization stepfrom 5-chloro-3-phenyl-2,1-benzisoxazole (219, R 1 = Ph; R 3 =5-
Cl) is 54%. [113] 7-Acetyl-3-methyl-2,1-benzisothiazole (220, R 1 = Me; R 3 = 7-Ac) is similarly
prepared from 7-acetyl-3-methyl-2,1-benzisoxazole (219, R 1 = Me; R 3 = 7-Ac) in 75%
yield. [159]
N
S
217
S
N
R 2
for references see p 622

616 Science of Synthesis 11.16 Benzisothiazoles
Scheme 81 Synthesis of 2,1-Benzisothiazoles from 2,1-Benzisoxazoles [113,159]
R 2
218
R 1
O
NO 2
R3 SnCl2, HCl P4S10 O
N
219
R 1 R 2 R 3 Conditions Yield (%) of 220 Ref
Ph H H imidazole, 120 8C, 15 min 31 [113]
Ph 4-Cl 5-Cl imidazole, 120 8C, 15 min 54 [113]
4-ClC 6H 4 4-Cl 5-Cl imidazole, 120 8C, 15 min ± [113]
Me 6-Ac 7-Ac pyridine, reflux 75 [159]
OMe 6-CS 2Me 7-CS 2Me pyridine, reflux 7 [159]
5-Chloro-3-phenyl-2,1-benzisothiazole (220, R 1 = Ph; R 3 = 5-Cl); Typical Procedure: [113]
5-Chloro-3-phenyl-2,1-benzisoxazole (219, R 1 = Ph; R 3 = 5-Cl; 16.3 g, 71 mmol), P 4S 10 (49 g,
0.11 mol) and imidazole (25 g, 0.37 mol) were vigorously stirred together at 120 8C for
15 min. The dark, oily mixture was partitioned between 10% aq NaOH and EtOAc. The
EtOAc extracts were washed with H 2O, dried (MgSO 4), and evaporated under reduced pressure.
The residual oil was treated with concd HCl and the insoluble portion separated by
filtration. The filtrate was poured into H 2O and stored in a refrigerator, where crystallization
took place; yield: 9.6 g (54%); mp 86±88 8C (aq EtOH).
7-Acetyl-3-methyl-2,1-benzisothiazole (220,R 1 = Me; R 3 = 7-Ac); Typical Procedure: [159]
7-Acetyl-3-methyl-2,1-benzisoxazole (219;R 1 = Me; R 3 = 7-Ac; 5 g, 29 mmol) was heated under
reflux in pyridine (80 mL) with P 4S 10 (8 g) for 8 h. The cooled soln was poured into H 2O
and extracted with CHCl 3 (3 î 50 mL). The combined extracts were washed with H 2O
(5 î 20 mL), dried, and the solvent removed under reduced pressure. The residual yellow
oil crystallized on standing and was purified by chromatography (CHCl 3) to give the product
as yellow crystals; yield: 4.1 g (75%); mp79 8C.
In a similar way methyl 3-methoxy-2,1-benzisoxazole-7-carboxylate was obtained
from dimethyl 2-nitroisophthalate in three steps (reduction to the amine, oxidative ring
closure and esterification). It was converted into methyl 3-methoxy-2,1-benzisothiazole-7carbodithioate
by thiation with P 4S 10; yield: 7%; mp128±1298C. Also isolated was the hydrolysis
product, 3-methoxy-2,1-benzisothiazole-7-carbothioic acid (0.5%).
11.16.2.3 Synthesis by Substituent Modification
11.16.2.3.1 Substitution of Existing Substituents
11.16.2.3.1.1 Of Hydrogen
Direct lithiation of 2,1-benzisothiazole occurs on reaction with butyllithium in tetrahydrofuran
and the product, 2,1-benzisothiazol-3-yllithium (221), may then be reacted
in situ with iodomethane to give 3-methyl-2,1-benzisothiazole (222) in 44% yield (Scheme
82). [100]
R 1
R 3
220
R 1
S
N

11.16.2 2,1-Benzisothiazoles 617
Scheme 82 Synthesis of 3-Methyl-2,1-benzisothiazole via
2,1-Benzisothiazol-3-yllithium [100]
2
S
N
BuLi, THF
221
Li
S
N
MeI, 20 o C, 1 h
222 44%
A further application is the formation of 5,7-di-tert-butyl-2,1-benzisothiazol-3-amine (224)
through the reaction of 5,7-di-tert-butyl-2,1-benzisothiazol-3-yllithium (223) with trimethylsilylmethyl
azide, followed by treatment with aqueous acid (Scheme 83). [100,160]
Scheme 83 Synthesis of 5,7-Di-tert-butyl-2,1-benzisothiazol-3-amine [100,160]
Bu t
Bu t
223
Li
S
N
11.16.2.3.1.2 Of Heteroatoms
1. TMSCH2N3
2. H +
11.16.2.3.1.2.1 Electrophilic Substitution
1-Alkyl-3-chloro-2,1-benzisothiazolium chlorides 225 are strongly electrophilic and combine
with N,N-dimethylaniline at 208C, over 12 hours, to afford highly colored 1-alkyl-3-
[4-(dimethylamino)phenyl]-2,1-benzisothiazolium salts 226 (isolated as the perchlorates)
(Scheme 84). [108] For the 1-methyl compound (226, R 1 = Me) the yield is 60% and for the
benzyl analogue (226, R 1 = Bn) the yield is 83%.
Bu t
Scheme 84 Synthesis of 1-Alkyl-3-[4-(dimethylamino)phenyl]-2,1-benzisothiazolium
Perchlorates [108]
225
Cl
S
N
+
R1 Cl−
+ NMe 2
Bu t
224
1. MeCN
2. NaClO4 R 1 = Bn 83%
R 1 = Me 60%
NH 2
S
N
NMe 2
S
N
S
N
+
R1 ClO4 −
226
1-Alkyl-5-chloro-3-phenyl-2,1-benzisothiazolium tetrafluoroborates 227 react with secondary
amines to form the corresponding 1,3-dihydrobenzothiazol-3-amines 228, but if
primary amines are used then the adducts 229 suffer the loss of sulfur and concomitant
ring opening to yield [2-(alkylamino)phenyl](phenyl)methanones 231, after hydrolysis of
the intermediate arylimines 230 (Scheme 85). [113]
for references see p 622

618 Science of Synthesis 11.16 Benzisothiazoles
Scheme 85 Reaction of 1-Alkyl-5-chloro-3-phenyl-2,1-benzisothiazolium
Tetrafluoroborates with Amines [113]
Cl
Cl
227
227
S
N
+
Ph
R1 BF4 − S
N
R1 R2 2NH
R1 = Me; NR2 2 = morpholino 50%
R1 = Et; NR2 NR
2 = NMe2 90%
2 Cl
Ph
2
Ph
S
N
+
R1 BF4 −
R 2 NH2
Cl
Cl
230
Ph
NR 2
NHR 1
229
Ph
S
N
R1 NHR 2
− R 2 NH2
Although these examples are of limited synthetic value, a related process is the addition
of ethyl glycinate, in the presence of 2-methylimidazole at 160 8C, to 5-chloro-1-methyl-3phenyl-2,1-benzisothiazolium
tetrafluoroborate (227, R 1 = Me). This leads to the formation
of the well-known tranquilizer valium (7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one, 233) through the ring expansion of the adduct 232 (Scheme
86). [113]
Scheme 86 Synthesis of Valium [113]
Cl
227
Ph
S
N
+
BF
−
4
H2NCH2CO2Et
2-methylimidazole
160 oC Ph
Me Me
Cl
S
N
232
H
N
H2O
CO 2Et
Enolates from 1,3-dicarbonyl compounds, for example diethyl malonate or ethyl benzoylacetate,
also react with 2,1-benzisothiazolium salts 234, enabling access to the corresponding
3-methylene-1,3-dihydro-2,1-benzisothiazoles 235 (R 2 =CO 2Et or Bz) (Scheme
87). For diethyl malonate, however, the product, 3-[bis(ethoxycarbonyl)methylene]-2,1benzisothiazole,
is accompanied by 2-(methylamino)benzaldehyde. [137]
228
− S
Cl
Cl
47%
231
Ph
233
N
Me
Ph
O
NHR 1
N
O

11.16.2 2,1-Benzisothiazoles 619
Scheme 87 Synthesis of 3-Methylene-1,3-dihydro-2,1-benzisothiazoles [137]
R 1
S
N
+
BF4 −
Me
234 R 1 = H, SMe
R2 −
CHCO2Et
R 2 = CO2Et 28%
11.16.2.3.1.2.2 Nucleophilic Substitution
11.16.2.3.1.2.2.1 From 3-Chloro-2,1-benzisothiazoles
235
R 2
S
N
Me
CO2Et
3-Chloro-2,1-benzisothiazoles 236 (normally available from the 3-hydroxy analogues by
reaction with phosphoryl chloride) are potentially useful sources of other 3-substituted
2,1-benzisothiazoles 237. For example, 3-chloro-2,1-benzisothiazole (236, R 1 = H) reacts
with sodium alkoxides, sodium enolates, sodium alkanethiolates, and secondary amines
to form 3-alkoxy-, [104,105,120,132] 3-alkyl-, [120] 3-(alkylsulfanyl)-, [104] and 3-amino-substituted
[104,112,120] 2,1-benzisothiazoles, respectively (Scheme 88). Generally the yields are good
(70±90%), but when sodium cyanide is used as the nucleophilic reagent 3-chloro-2,1-benzisothiazole
affords only a 38% yield of the 3-cyano derivative 237 (R 2 = CN). [153,161]
Scheme 88 Synthesis of 3-Substituted 2,1-Benzisothiazoles
from 3-Chloro-2,1-benzisothiazoles [104,112,120,132,153,161]
R 1
236
Cl
S
N
R2Na, MeOH, reflux
or R2H R 1
237
R 2
S
N
Nucleophile R 1 R 2 Yield (%) of 237 Ref
NaCH 2CO 2Et H CH 2CO 2Et 79 [120]
NaCN H CN 38 [153,161]
NaOMe H OMe 77 [104,105,132]
NaSEt H SEt 92 [104]
Me 2NH H NMe 2 75 [112,120]
pyrrolidine H pyrrolidin-1-yl 91 [102,104]
H 2O 5-Cl OH 92 [120]
NaOEt 5-Cl OEt 75 [120]
NaSPh 5-Cl SPh 70 [120]
Unfortunately, Grignard reagents may cause reductive dechlorination so that with methylmagnesium
bromide, for example, 3-chloro-2,1-benzisothiazole gives a 1:3 mixture of
3-methyl-2,1-benzisothiazole and 2,1-benzisothiazole. [153]
3-Chloro-2,1-benzisothiazole (236,R 1 = H); Typical Procedure: [104]
POCl 3 (5 mL, 55 mmol) was carefully added to a soln of 2,1-benzisothiazol-3-ol (5 g, 33 mol)
in pyridine (2.5 mL). The red soln was heated at 130±1408C for 1 h, then cooled and cau-
for references see p 622

620 Science of Synthesis 11.16 Benzisothiazoles
tiously poured into ice water. The mixture was extracted with Et 2O, the extracts washed
with H 2O, dried (MgSO 4), and evaporated. The residue was distilled under reduced pressure
giving a yellow oil; yield: 3.5 g (63%); bp65 8C/0.2 Torr.
3-Methoxy-2,1-benzisothiazole (237, R 1 =H;R 2 = OMe); Typical Procedure: [104]
A soln of 3-chloro-1,2-benzisothiazole (236, R 1 = H; 2 g, 11.8 mmol) and NaOMe (1 g,
18.5 mmol) in MeOH (20 mL) was heated under reflux for 2.5 h and then poured into
H 2O. The mixture was extracted with Et 2O, the extracts dried (MgSO 4), and the solvent
evaporated under reduced pressure. A yellow, solid residue was obtained; crude yield:
1.8 g (92%). This was distilled to give yellow crystals; bp93±94 8C/0.2 Torr; mp56±59.58C
(sinters at 508C).
11.16.2.3.1.2.2.2 Method 2:
From 2,1-Benzisothiazole 3-Diazonium Salts
2,1-benzisothiazole (153) can be diazotized by treatment with nitrous
acid [114,115,139,140,162±164] and under Sandmeyer conditions in the presence of copper(I) bromide
to give the diazonium salts 238, which may then be converted into the 3-bromo-
2,1-benzisothiazole (239). Similar reaction conditions afford 3-nitro- and 3-iodo-2,1-benzisothiazoles,
but generally yields are only moderate (30±50%). [109] Such diazonium salts
also react with azide ion to form 3-azido-2,1-benzisothiazoles, and in the case of 3-azido-
7-(trifluoromethyl)-2,1-benzisothiazole (241) the yield from 7-(trifluoromethyl)-2,1-benzisothiazol-3-amine
(240) is as high as 65% (Scheme 89). [165]
Scheme 89 Synthesis of 3-Bromo- and 3-Azido-7-(trifluoromethyl)-
2,1-benzisothiazoles [109,165]
NH2
S
N
153
CF3 240
NH 2
S
N
11.16.2.3.2 Addition Reactions
11.16.2.3.2.1 Method 1:
N-Alkylation
NaNO 2, 2 M HCl
1. NaNO2, HCl
2. NaN3 65%
CF3 241
S
N
238
N2 + Cl −
N 3
S
N
Cu2Br2 30%
Br
S
N
239
The quaternary salts 243 used as the substrates in various reactions (Sections
11.16.2.3.1.2.1 and 11.16.2.3.1.2.2) are available from the parent 2,1-benzisothiazoles
242 through alkylation with a variety of alkylating agents, including alkyl halides,
[8,105,120,127] dimethyl sulfate, [8,122±125,128] Meerwein's salts (e.g., triethyloxonium tetrafluoroborate),
[121] and methyl tosylate. [124] A list of compounds synthesized in this way is
given in Scheme 90. [120,121,124,126]

11.16.2 2,1-Benzisothiazoles 621
Scheme 90 Synthesis of 1-Substituted 2,1-Benzisothiazolium Iodides [112,113,116,118,120]
R
S
N
1
R3 R2 1. R4X, 115−120 oC, 1−42 h
2. NaI
242
R 2
R 3
243
R 1
S
N
+
I −
R4 R 1 R 2 R 3 R 4 R 4 X Time (h) Yield (%) of 243 Ref
H H H Me Me 2SO 4 1 ~100 [116]
H H H CH 2CO 2Et BrCH 2CO 2Et 2 ~100 [116]
H H H (CH 2) 3 a Br(CH 2) 3Br 22 ~100 [116]
H H H (CH 2) 4 b Br(CH 2) 4Br 42 ~100 [116]
H H Cl Me TsOMe 4 ~100 [116]
H H Cl Bn BnBr 4 ~100 [116]
H Cl H Bn BnBr 4 ~100 [116]
H NO 2 H Me TsOMe 4 ~100 [116]
Me H H Me FSO 2OMe ± 83 [118]
Ph Cl H Et (EtO) 3CH c 1 d 57 [113]
Ph Cl H Et (EtO) 3CH e 8 37 [113]
Cl H H Me Me 2SO 4 28 f 84 [120]
OMe H H Me Me 2SO 4 0.5 f 59 [120]
NH 2 H H Me MeI 3 88 [120]
NHEt OMe OMe Me MeI 3 78 [112]
NMe 2 H Cl Me MeI 3 92 [112]
a The product was the 1,3-bis(2,1-benzolium-1-yl)propane diiodide.
b The product was the 1,4-bis(2,1-benzolium-1-yl)butane diiodide.
c SbCl5 is used in place of NaI.
d Reaction is carried out a 20 8C.
e BF3 is used in place of NaI.
f Reaction is carried out at 50 8C.
N-Alkyl-2,1-benzisothiazolium salts 243; General Procedure: [116]
2,1-Benzisothiazole 242 (0.10 mol) and Me 2SO 4, alkyl bromide, or methyl 4-toluenesulfonate
(0.11 mol) were heated together at 115±1208C for 1 to 42 h. The crude product was
formed in quantitative yield as colorless crystals or as oils. Treatment of the oily salts
with an excess of sat. aq NaI gave the orange, crystalline, quaternary salts. The salts were
recrystallized (EtOH containing 5% H 2O).
for references see p 622

622 Science of Synthesis 11.16 Benzisothiazoles
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