Facile preparation of 3-substituted benzisothiazoles from o-mercaptoacylphenones

Article abstract of DOI:10.1021/ol9028447

(Chemical Equetion Presentation) A synthesis of 3-substituted benzisothiazoles starting from readily available o-mercaptoacylphenones is presented. The key cyclization step features a mild S-nitrosation and its succeeding intramolecular aza-Wittig reactio

Full text of DOI:10.1021/ol9028447

ORGANIC
LETTERS
2010
Vol. 12, No. 4
752-754
Facile Preparation of 3-Substituted
Benzisothiazoles from
o-Mercaptoacylphenones
Nelmi O. Devarie-Baez and Ming Xian*
Department of Chemistry, Washington State UniVersity, Pullman, Washington 99164
mxian@wsu.edu
Received December 9, 2009
ABSTRACT
A synthesis of 3-substituted benzisothiazoles starting from readily available o-mercaptoacylphenones is presented. The key cyclization step
features a mild S-nitrosation and its succeeding intramolecular aza-Wittig reaction leading to the construction of the title compounds.
Benzisothiazole is a unique heterocyclic structure that has
been visualized as an important pharmacophore of some
bioactive molecules. These molecules have been reported
to possess many interesting biological activities such as
antibacterial,1 anti-HIV,2 antiproliferative activities of B-
lymphoblastic leukemia cells,2 and others.3 As an example,
Ziprasidone, which contains a key benzisothiazole subunit,
is an FDA-approved antipsychotic drug for the treatment of
schizophrenia.4 Due to the importance of this scaffold in drug
discovery, the synthesis of benzisothiazoles has received
considerable attention from organic chemists. Currently, most
of the methods to access benzisothiazoles rely on multistep
chemical manipulations.5 Only a few single flask strategies
have been developed and the range of the substrates is
limited.6
organophosphines reacted with S-nitrosothiols to form azay-
lide intermediates under very mild conditions. These reactive
intermediates could undergo intramolecular reactions with
different electrophiles attached on the phosphine substrates,
leading to the formation of different final products. With this
information in mind, we proposed a new synthesis of
3-substituted benzisothiazoles from readily available o-
mercaptoacylphenones. As shown in Scheme 1, nitrosation
Scheme 1. Proposed Synthesis of Benzisothiazoles
In our recent efforts to develop chemical probes for the
detection of protein S-nitrosation,7 it was noticed that
(1) Zani, F.; Vicini, P. Arch. Pharm. Pharm. Med. Chem. 1998, 331,
219.
(2) Vicini, P.; Geronikaki, M. I.; Bernadetta, B.; Poni, G.; Cabras, C. A.;
La Colla, P. Bioorg. Med. Chem. 2003, 11, 4785.
(3) (a) Genokaki, A.; Eleftheuriou, P.; Vicini, P.; Alam, I.; Dixit, A.;
Saxena, A. K. J. Med. Chem. 2008, 51, 5221. (b) Morini, G.; Poli, E.;
Comini, M.; Menozzi, A.; Pozzoli, C. Arch. Pharm. Res. 2005, 28, 1317.
(4) (a) Seeger, T. F.; Seymour, P. A.; Schmidt, A. W.; Zorn, S. H.;
Shulz, D. W.; Lebel, L. A.; McLean, S.; Guanowsky, V.; Howard, H. R.;
Lowe, J. A., III; Heym, J. J. Pharmacol. Exp. Ther. 1995, 275, 101. (b)
Prakash, C. Drug Metab. Dispos. 1997, 25, 897. (c) Walinsky, S. W.; Fox,
D. E.; Lambert, J. F.; Sinay, T. G. Org. Proc. Res. DeV. 1999, 3, 126.
of the o-mercaptoacylphenone starting material should
provide the corresponding S-nitroso derivative 1. It is well-
known that S-nitroso compounds are unstable species and
their purification/isolation is always problematic.8 Therefore,
10.1021/ol9028447  2010 American Chemical Society
Published on Web 01/15/2010

the application of S-nitroso compounds in organic synthesis
is very rare.9 However, in our hypothesis, these S-nitroso
intermediates were not necessary to isolate. We expected to
treat them immediately with the phosphine substrates after
their formation. As such, an azaylide intermediate 2 should
be formed. Finally, an intramolecular aza-Wittig reaction
should occur to furnish the desired benzisothiazole 5.7a,b
The preparation of the o-mercaptoacylphenone starting
material was straightforward (Scheme 2): deprotonation of
led to decomposition. To convert the unstable S-nitroso
intermediates to azaylide intermediates, phosphine substrates
such as PPh3 were added directly into the reaction mixture.
As expected, the HCl/NaNO2 condition led to the oxidation
of phosphine substrates completely, which suggests this is
not suitable for this one-step strategy. We found that alkyl
nitrites are quite safe for PPh3. No significant oxidation of
PPh3 by alkyl nitrites was observed after 1 h at rt (monitored
by TLC and 31P NMR). Therefore, we next explored alkyl
nitrite-mediated benzisothiazole formation using 7a as the
model substrate.
With use of THF as the reaction solvent, different
commercially available alkyl nitrites including EtONO,
t-BuONO, and i-pentylONO were evaluated (Table 1).
Scheme 2. Preparation of o-Mercaptoacylphenones
Table 1. Exploration of Alkyl Nitrites and Solvents
the thiosalysilic acid 6 in THF under refluxing conditions
and subsequent treatment with a series of organolithiums at
room temperature resulted in the corresponding o-mercap-
toacylphenones 7 in good yields (see the Supporting Infor-
mation for details).
entry
RONO
EtONO
solvent
yield of 5a (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
dioxane
DMF
CHCl3
CH2Cl2
benzene
toluene
0
33
70
35
60
58
65
56
48
Upon the production of 7, the conditions of S-nitrosation
were studied (Scheme 3). When 7 was treated with either
t-BuONO
i-PentylONO
i-PentylONO
i-PentylONO
i-PentylONO
i-PentylONO
i-PentylONO
i-PentylONO
Scheme 3. Study of Nitrosation
Given the instability of S-nitroso compounds, the nitro-
sation step and subsequent azaylide formation with PPh3
were carried out at 0 °C. Interestingly, EtONO did not
lead to any detectable benzisothiazole formation, while
t-BuONO provided the desired product 5a in a moderate
yield (33%). Isopentyl nitrite (i-pentylONO) proved to be
the best reagent, which furnished 5a in very good yield
(70%). We carefully studied the effect of temperature on
the process and found that 0 °C was the optimal condition.
HCl/NaNO2 or alkyl nitrites, the two most commonly used
nitrosation conditions, we observed immediate formation of
S-nitroso compounds at both rt and 0 °C, by the characteristic
deep red color. Attempts to isolate the S-nitroso compounds
Table 2. The Effects of Phosphine Substrates
(5) (a) McKinnon, D. M.; Lee, K. R. Can. J. Chem. 1988, 66, 1405. (b)
Pedras, M.; Soledade, C.; Suchy, M. Bioorg. Med. Chem. 2006, 14, 714.
(c) Fink, D. M.; Scrupczewski, J. T. Tetrahedron Lett. 1993, 34, 6525.
(6) (a) Creed, T.; Leardini, R.; McNab, H.; Nanni, D.; Nicolson, I. S.;
Reed, D. J. Chem. Soc., Perkin Trans. 1 2001, 1079. (b) Wirschun, W. G.;
Hitzler, M. G.; Jochims, J. C.; Groth, U. HelV. Chim. Acta 2002, 85, 2627.
(7) (a) Wang, H.; Xian, M. Angew. Chem., Int. Ed. 2008, 47, 6598. (b)
Zhang, J.; Wang, H.; Xian, M. Org. Lett. 2009, 11, 477. (c) Zhang, J.;
Wang, H.; Xian, M. J. Am. Chem. Soc. 2009, 131, 3854. (d) Wang, H.;
Zhang, J.; Xian, M. J. Am. Chem. Soc. 2009, 131, 13238.
entry
PR3
PBu3
P(OEt)3
PPh3
2-PyP(Ph)2
n-BuPPh2
EtPPh2
yield of 5a (%)
1
2
3
4
5
6
19
47
70
48
71
80
(8) For selected reviews on S-nitrosothiols, see: (a) Williams, D. L. H.
Acc. Chem. Res. 1999, 32, 869. (b) Al-Sadoni, H. H.; Ferro, A. Curr. Med.
Chem. 2004, 11, 2679. (c) Wang, P.; Xian, M.; Tang, X.; Wu, X.; Wen,
Z.; Cai, T.; Janczuk, A. J. Chem. ReV. 2002, 102, 1091. (d) Oae, S.;
Shinhama, K. Org. Prep. Proc. Int. 1983, 15, 165.
Org. Lett., Vol. 12, No. 4, 2010
753

seemed to dominate the second step and led to lower yield
of the product. We also studied the solvent effects on this
reaction. As shown in Table 1, most of the solvents, i.e.,
dioxane, DMF, CH2Cl2, benzene, etc., proved to be
efficient for this transformation and furnished the desired
product in good yields. However, THF seemed to be the
most effective choice.
Table 3. One-Pot Synthesis of 3-Substituted Benzisothiazoles
Although PPh3 showed good reactivity in this synthesis,
we wondered if a better phosphine substrate could be
identified. Therefore, a series of phosphine reagents were
examined (Table 2). Trialkylphosphine reagents such as
PBu3 (entry 1) turned out to be ineffective for this reaction
while P(OEt)3 resulted in the formation of 5a in a moderate
yield. Triphenylphosphine derivatives such as 2-PyPPh2
and n-BuPPh2 produced the product in moderate to good
yields (entries 4 and 5). Interestingly, when EtPPh2 was
used, the highest yield of 5a was obtained (entry 6).
With the optimized conditions/reagents in hand, the
benzisothiazole synthesis was tested with a series of
o-mercaptoacylphenones (7a-h, Table 3). In all cases,
the desired products were obtained in good yields. A
typical procedure is as follows: compound 7 was dissolved
in THF at 0 °C and was treated with i-pentylONO (3
equiv). The reaction was continued for 5 min at 0 °C.
Then, a solution of EtPPh2 (2.1 equiv) in THF was added
quickly to the reaction and the mixture was allowed to
stir for 10 min at 0 °C and 50 min at rt. The desired
product was obtained by flash column chromatography.
In conclusion, a facile synthesis of 3-substituted ben-
zisothiazoles from o-mercaptoacylphenones has been
developed. We demonstrated that S-nitrosothiols, albeit
unstable, could be useful synthetic intermediates. Further
expansion of the utility of S-nitrosothiols in organic
synthesis is ongoing in our laboratory.
Acknowledgment. We thank NSF CAREER Award
(CHE-0844931) for financial support. We also thank Prof.
P. Garner and Prof. R. Ronald (Washington State University)
for helpful discussions.
Supporting Information Available: Synthetic procedures,
spectroscopic data, and experimental procedures. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
OL9028447
At lower temperature such as -20 °C, longer reaction
times were needed for the nitrosation step, which resulted
in a decrease of yield. At higher temperatures, like 20
°C, the decomposition of the S-nitroso intermediate
(9) Examples are: (a) Carevo, M.; Motherwell, W. B.; Potier, P.
Tetrahedron Lett. 2001, 42, 4377. (b) Carevo, M.; Motherwell, W. B.; Potier,
P.; Weibel, J.-M. Chem. Commun. 2002, 2394. (c) Shinhama, K.; Kim,
Y. H.; Oae, S. Bull. Chem. Soc. Jpn. 1980, 53, 1771.
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