Synthesis of 3-Substituted Aryl[4,5]isothiazoles through an All-Heteroatom Wittig-Equivalent Process

Article abstract of DOI:10.1021/acs.orglett.6b01338

Extending the previous use of tert-butyl sulfoxide as the sulfinyl source, intramolecular sulfinylation of sulfonamides was successfully performed. The resulting sulfinimides were not isolated and instead were believed to go through an all-heteroatom Witt

Full text of DOI:10.1021/acs.orglett.6b01338

Letter
pubs.acs.org/OrgLett
Synthesis of 3‑Substituted Aryl[4,5]isothiazoles through an All-
Heteroatom Wittig-Equivalent Process
†
†
‡
,†
Fanghui Xu, Yuan Chen, Erkang Fan, and Zhihua Sun*
†College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620,
China
‡
Department of Biochemistry, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States
*
S Supporting Information
ABSTRACT: Extending the previous use of tert-butyl sulfoxide as the sulfinyl source,
intramolecular sulfinylation of sulfonamides was successfully performed. The resulting
sulfinimides were not isolated and instead were believed to go through an all-heteroatom
Wittig-equivalent process to eventually afford aryl[4,5]isothiazoles in high yields.
sothiazole is an important structural scaffold in medicinal
Scheme 1. Formation of Aryl[4,5]isothiazole
I
chemistry. A primary example is the benzisothiazole group in
the U.S. Food and Drug Administration-approved drug
lurasidone, which can be used to treat adults with schizophrenia
1
and bipolar 1 depression. Other isothiazole-containing
compounds have been studied in a variety of drug development
2
projects. Traditionally, the synthesis of aryl-fused isothiazoles
3
requires multiple manipulations of the S or N sources, and
protocols that employ direct ring formation using readily
4
available starting materials are limited. Two recent reports of
benzisothiazole synthesis are notable improvements in the field:
a cyclization method starting from o-mercaptoacylphenones
5
a
through S-nitrosation followed by an aza-Wittig procedure5
b
and direct ring fusion through aryne and 1,2,5-thiadiazoles.
Here we present another efficient synthesis of aryl-fused
isothiazoles using tert-butyl sulfoxide and tert-butylsulfinamide
as the S and N sources, respectively.
We recently reported a mild and general procedure for the
synthesis of sulfoxides, sulfinic acid esters, and sulfonamides
that uses tert-butyl sulfoxides as the sulfinyl source through
activation by N-bromosuccinimide (NBS) and acetic acid at
6
room temperature. To expand the application of this
procedure, we utilized it for the synthesis of chiral 2,3-
dihydrobenzisothiazole-1-oxide 4 (Scheme 1) from the starting
material, 3, which is readily accessible from ortho metalation o7f
aryl sulfoxides 1 and asymmetric addition to imines 2.
However, upon treatment of 3a (R = none, R = Ph in
The formation of 5 from 4 may be explained by a process
equivalent to an aza-Wittig reaction through the loss of tert-
butylsulfinic acid (Scheme 1). Such an all-heteroatom Wittig
1
2
Scheme 1; also see Table 1) with NBS and acetic acid, the
corresponding compound 4 was not isolated. Instead, the
corresponding isothiazole 5a (Table 1) was obtained.
Received: May 9, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01338
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Exploration of Optimal Conditions for Activation of
the tert-Butyl Sulfinyl Group
support an all-heteroatom Wittig-equivalent process for the
formation of 5.
The transformation of 3a to 5a was then optimized with
regard to reagent ratio, acid used, and solvent. The results are
summarized in Table 1. While the use of 1.2 equiv of acetic acid
gave a good yield (75%; Table 1, entry 1), increasing the
amount of acid to 1.5 equiv produced a better yield (82%;
Table 1, entry 2), while using 2.0 equiv of acid gave no furthe6r
improvement. Similar to the results in our previous report,
changing the acid or solvent in every case produced lower
product yields than the acetic acid/CH Cl combination (Table
reagent ratio
yield of 5a
entry
acid
solvent
CH Cl
(3a/NBS/acid)
(%)
2
2
1
2
3
4
5
6
7
8
9
AcOH
AcOH
AcOH
1.0/2.0/1.2
1.0/2.0/1.5
1.0/2.0/2.0
1.0/2.0/1.5
1.0/2.0/1.5
1.0/2.0/1.5
1.0/2.0/1.5
1.0/2.0/1.5
1.0/2.0/1.5
75
2
2
1, entries 4−9).
CH Cl
82
2
2
2
2
2
2
With the optimized reaction conditions in hand, a collection
of starting materials 3 bearing various functional groups were
subjected to the NBS/acetic acid/CH Cl protocol to produce
CH Cl
81
2
PhCO H
CH Cl
71
2
2
2
2
TsOH
TFA
CH Cl
31
2
5
. As shown in Scheme 3, the 3-position of the final
CH Cl
45
2
aryl[4,5]isothiazole 5 can contain a wide range of aromatic
groups (with additional electron-donating or -withdrawing
substitutions) or alkyl groups (5o−q). For the fused aromatic
portion, substituted benzene, naphthalene, or pyridine
derivatives were obtained (5d−k).
AcOH
AcOH
AcOH
toluene
THF
20
none
47
DMF
8
process has been reported before. This mechanism is
supported by the fact that after the completion of reaction,
a
1
Scheme 3. Additional Examples of Isothiazole Synthesis
the H NMR spectrum of the reaction mixture indicated the
presence of 1 equiv of tert-butyl protons (the tert-butyl group of
the sulfoxide was released from the reaction as isobutene). This
suggests that the tert-butylsulfinyl group attached to the
nitrogen atom was retained during the reaction and did not
go through NBC/acid activation to release isobutene.
To provide further evidence of the Wittig-like reaction
pathway, we reasoned that replacing the sulfinyl group in 4 with
a sulfonyl group should slow the conversion of the intermediate
to 5 and thus might allow isolation of the sulfonamide
equivalent of 4. Indeed, as shown in Scheme 2, when p-
Scheme 2. Additional Evidence for the Reaction Pathway
Using a Sulfonyl Derivative
toluenesulfonyl-protected 6 was treated with NBS and acetic
acid, both cyclized 7 (equivalent to 4) and the further-
transformed benzisothiazole 5a were isolated in 92% total yield
with a 7:5a ratio of 72:28. In addition, p-toluenesulfonic acid
could be detected and isolated from the reaction. The direct
conversion of 7 to 5a was possible by heating, which also
afforded p-toluenesulfonic acid. All of these observations
a
Reaction conditions: a mixture of 3 (0.5 mmol), NBS (1.0 mmol),
AcOH (0.75 mmol), and CH Cl2 (2 mL) was stirred at room
temperature for 20 min under a nitrogen atmosphere.
2
B
DOI: 10.1021/acs.orglett.6b01338
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In summary, we have demonstrated an efficient protocol for
the synthesis of aryl[4,5]isothiazoles. The key reaction step
utilizes NBS/acid activation of aryl tert-butyl sulfoxides to allow
cyclization by an ortho-placed sulfinamidomethyl group
followed by spontaneous transformation to the isothiazole.
This new procedure should complement existing methods for
accessing this important molecular scaffold in biological and
medicinal chemistry. In addition, our experimental evidence
strongly supports an all-heteroatom Wittig-equivalent trans-
formation process for the formation of the final products. This
transformation may be considered for use in other functional
group manipulations.
(6) Wei, J.; Sun, Z. Org. Lett. 2015, 17, 5396.
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P. J. Org. Chem. 2006, 71, 2609.
(
(
8) Schwo
̈
bel, A.; Kresze, G.; Perez, M. A. Liebigs Ann. Chem. 1985,
1
985, 72.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01338.
Procedures and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sungaris@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors are grateful for financial support from the Shanghai
Municipal Education Commission (14ZZ159).
■
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DOI: 10.1021/acs.orglett.6b01338
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