Novel alternative for the N-S bond formation and its application to the synthesis of benzisothiazol-3-ones

Article abstract of DOI:10.1021/ol061867q

(Chemical Equation Presented) The synthesis of a series of benzisothiazolone derivatives starting from the readily available methyl thiosalicylate is presented. The key cyclization step features the formation of a N-acylnitrenium ion, generated by the hypervalent iodine reagent PIFA, and its succeeding intramolecular trapping by the thiole moiety leading to the construction of the title compounds by formation of a new N-S bond.

Full text of DOI:10.1021/ol061867q

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4811-4813
Novel Alternative for the N−S Bond
Formation and Its Application to the
Synthesis of Benzisothiazol-3-ones
Arkaitz Correa, Imanol Tellitu,* Esther Dom´ınguez,* and Raul SanMartin
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencia y Tecnolog´ıa,
Euskal Herriko Unibertsitatea, P.O. Box 644, 48080 Bilbao, Spain
imanol.tellitu@ehu.es
Received July 28, 2006
ABSTRACT
The synthesis of a series of benzisothiazolone derivatives starting from the readily available methyl thiosalicylate is presented. The key
cyclization step features the formation of a N-acylnitrenium ion, generated by the hypervalent iodine reagent PIFA, and its succeeding
intramolecular trapping by the thiole moiety leading to the construction of the title compounds by formation of a new N−S bond.
The continuous demand for highly efficient and environ-
mentally benign synthesis of fine chemicals has encouraged
the development of mild, safe, and highly chemoselective
oxidizers. In this field, hypervalent iodine reagents constitute
a paramount family of compounds which have received a
great deal of attention due to their ready availability, low
toxicity, easy handling, and reactivity similar to that of heavy
metal reagents. Thus, their efficient use in metal-free
transformations relies not only on the extremely mild reaction
conditions required but also on their ability to oxidize
chemoselectively a wide range of functionalities such as
alcohols, amines, sulfides, and carbonyl compounds, among
others.1 In particular, our attention has been caught by the
ability of the hypervalent iodine reagent [phenyliodine(III)-
bis(trifluoroacetate)] (PIFA) to oxidize conveniently substi-
tuted amides to the corresponding N-acylnitrenium ions,2
which are powerful electrophiles that easily undergo in-
tramolecular heterocyclization reactions, as depicted in
Scheme 1. Thus, by employing this simple strategy, a wide
Scheme 1. General PIFA-Mediated Amidation Process
variety of appealing N-heterocycles via C-N bond formation
have been achieved.3
To expand the chemistry of nitrenium ions as useful
synthetic intermediates in organic synthesis,4 we have
(3) See, for example: (a) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 3,
1053. (b) Serna, S.; Tellitu, I.; Dom´ınguez, E.; Moreno, I.; SanMartin, R.
Tetrahedron Lett. 2003, 44, 3483. (c) Wardrop, D. J.; Burge, M. S. Chem.
Commun. 2004, 1230. (d) Correa, A.; Tellitu, I.; Dom´ınguez, E.; Moreno,
I.; SanMartin, R. J. Org. Chem. 2005, 70, 2256. (e) Serna, S.; Tellitu, I.;
Dom´ınguez, E.; Moreno, I.; SanMartin, R. Org. Lett. 2005, 7, 3073.
(4) For some reviews on the chemistry of nitrenium ions, see: (a)
Abramovitch, R. A.; Jeyaraman, R. In Azides and Nitrenes: ReactiVity and
Utility; Scriven, E. F. V., Eds.; Academic Press: Orlando, 1984; p 297. (b)
Falvey, D. E. In ReactiVe Intermediate Chemistry; Moss, R. A., Platz, M.
S., Jones, M., Eds.; Wiley-Interscience: Hoboken, NJ, 2004; p 594. (c)
Borodkin, G. I.; Shubin, V. G. Russ. J. Org. Chem. 2005, 41, 473.
(1) For recent reviews on the synthetic applications of polyvalent iodine
reagents, see: (a) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102,
2523. (b) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (c) Wirth, T. Top.
Curr. Chem. 2003, 224, 1. (d) Tohma, H.; Kita, Y. AdV. Synth. Catal. 2004,
346, 111. (e) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893. (f) Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656.
(2) This ability was first reported in 1990; see: Kikugawa, Y.; Kawase,
M. Chem. Lett. 1990, 581.
10.1021/ol061867q CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/15/2006

recently reported the first successful intramolecular reaction
of these electrophilic intermediates with amine functionalities
(Nu ) NR, Scheme 1) developing a novel versatile method
for the construction of new N-N linkages.5 Thus, in
connection with this previous work and following with our
research on the synthesis of highly valuable heterocycles
through oxidative processes mediated by the environmentally
friendly reagent PIFA, we report here a novel approach
toward the synthesis of benzisothiazol-3-one derivatives of
type 1. This novel approach (see Scheme 2) features the
an AlMe3-promoted aminolysis protocol10 on commercially
available methyl thiosalicylate (3), as outlined in Table 1.
Next, on the basis of our previous experience and to optimize
the experimental conditions for the proposed cyclization step,
we selected para-methoxyphenylamide 2a as a model system
that could guarantee the stability of the corresponding
N-acylnitrenium intermediate.11 Thus, we briefly examined
its behavior under the action of PIFA using different solvents
(trifluoroethanol, CH2Cl2, acetonitrile, and toluene), temper-
atures (from 0 to 60 °C), and additives (TFA and BF3‚OEt2)
to conclude that the optimal results were obtained when
amide 2a was treated with PIFA (0.01 M) in CH2Cl2 at 0
°C in the presence of TFA (3.0 equiv) thus leading to
benzisothiazolone 1a in 78% yield.
Scheme 2. Proposed Strategy for the Synthesis of
Benzisothiazolones 1
Having established an optimal protocol for the key
cyclization step and with the aim to determine its scope with
respect to the amide motif, we analyzed the influence of the
nature of this functionality on the efficiency of the cyclization
step. Thus, when amides 2a-j were treated with the easy-
to-handle reagent PIFA under the optimized reaction condi-
tions, the effectiveness of the proposed cyclization proved
to be suitable for N-arylamides 2a-g yielding the corre-
sponding benzisothiazolones 1a-g in good yields (see Table
1). Consequently, these results suggest that activated (2a,c),
nonactivated (2b,d), and moderately deactivated (2e,f) aryl
rings, as well as the methoxypyridyl system (2g), are able
to stabilize the N-acylnitrenium intermediate and, therefore,
to accomplish successfully the scheduled cyclization. To our
delight, alkylamides 2h and 2j also rendered successfully
the corresponding benzisothiazolones 1h and 1j, respectively.
Thus, although the previously reported oxidative process for
the construction of N-N linkages by employing amine
moieties as the nucleophilic counterpart of the reaction
proved to be restricted to aromatic amides,5 the presented
process can be efficiently extended to certain alkyl amides.12
Finally, we find no apparent explanation for the fact that
although a wide range of experimental conditions were tested
on amide 2i they all failed to afford the desired heterocycle,
leading, in all cases, to a complex mixture of products.
In summary, we have developed a new and efficient
synthetic protocol for the preparation of benzisothiazol-3-
one derivatives of type 1 based on an oxidative cyclization
approach mediated by the hypervalent iodine reagent PIFA.
PIFA-mediated oxidation of properly substituted amides 2
and the subsequent trapping of the so-obtained N-centered
electrophilic species by the thiole moiety to form a new N-S
bond.
Benzisothiazol-3-ones are of widespread interest because
of their effective antifungal, antibacterial, and antipsychotic
properties.6 Furthermore, it has been shown that certain
benzisothiazolone compounds also possess anti-HIV activity.7
As a result, a number of routes leading to the target
compounds have been described in the literature, but although
they have been proven to be useful protocols, some of them
are of limited use because they require the employment of
highly toxic and corrosive agents such as chlorine gas.8
Therefore, the development of a chlorine-free synthetic
protocol would be rather desirable, and in this context, we
envisaged that the employment of PIFA would be of high
practical value.9
Our synthetic study started by an effective preparation of
the required 2-mercaptoamide derivatives 2a-j following
(5) Correa, A.; Tellitu, I.; Dom´ınguez, E.; SanMartin, R. J. Org. Chem.
2006, 71, 3501. To the best of our knowledge, this is the only report in
which a non-carbon species has been used as the nucleophilic counterpart
of this amidation process.
(6) For some selected monographs, see: (a) Pain, D. L.; Peart, B. J.;
Wooldridge, K. R. H. ComprehensiVe Heterocyclic Chemistry; Potts, K.
T., Ed.; Pergamon: Oxford, 1984; Vol. 6, p 175. (b) Chapman, R. F.; Peart,
B. J. ComprehensiVe Heterocyclic Chemistry II; Shinkai, I., Ed.; Perga-
mon: Oxford, 1996; Vol. 3, p 371.
(7) Rice, W. G.; Supko, J. G.; Malspeis, L.; Buckheit, R. W.; Clanton,
D.; Bu, M.; Graham, L.; Schaffer, C. A.; Turpin, J. A.; Domagala, J.;
Gogliotti, R.; Bader, J. P.; Halliday, S. M.; Coren, L.; Sowder, R. C.; Arthur,
L. O.; Henderson, L. E. Science 1995, 270, 1194.
(10) (a) Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun. 1982,
12, 989. (b) Novak, A.; Humphreys, L. D.; Walker, M. D.; Woodward, S.
Tetrahedron Lett. 2006, 47, 5767-5769.
(11) When nitrenium ions are stabilized by the electron-donating effect
of a proper neighboring group (such as aryl, alkoxy, or nitrogen groups),
they exhibit a sufficiently long life to undergo further organic reactions:
(a) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J. L.
Tetrahedron 1987, 43, 2577. (b) Kikugawa, Y.; Nagashima, A.; Sakamoto,
T.; Miyazama, E.; Shiiya, M. J. Org. Chem. 2003, 68, 6739. (c) Falvey, D.
E.; Kung, A. C. J. Org. Chem. 2005, 70, 3127.
(12) Computational calculations on alkylnitrenium ions show that there
is substantial hyperconjugation from the vicinal σ bonds of the N-alkyl
substituent. (a) Glover, S. A.; Scott, A. P. Tetrahedron 1989, 45, 1763. (b)
Cramer, C. J.; Dulles, F. J.; Falvey, D. E. J. Am. Chem. Soc. 1994, 116,
9787. Apart from these theoretical studies, no other synthetic application
of alkylnitrenium intermediates can be found in the literature, as far as we
know. However, because of the low stabilization of deficient nitrogen species
that a methyl group would produce, an alternative formation of an
intermediate of type ArCON(Me)-IPh(OCOCF3) that reacts intramolecu-
larly with the thiole group followed by reductive elimination of iodobenzene
cannot be ruled out.
(8) (a) Davis, M. AdV. Heterocycl. Chem. 1972, 14, 58. (b) Baggaley,
K. H.; English, P. D.; Jennings, L. J. A.; Morgan, B.; Nunn, B.; Tyrrell, A.
W. R. J. Med. Chem. 1985, 28, 1661.
(9) Some selected examples of chlorine-free synthesis by employing (a)
a PIFA-mediated Pummerer-type reaction of sulfides: Wang, H.-M.; Huang,
H.-Y.; Kang, I.-J.; Chen, L.-C. Heterocycles 2001, 55, 1231. (b) An
amidation-cyclization process of 2,2′-dithiobenzoates: Jin, C. K.; Moon,
J.-K.; Lee, W. S.; Nam, K. S. Synlett 2003, 1967. (c) A transamination of
sulfenamides: Shimizu, M.; Takeda, A.; Fukazawa, H.; Abe, Y.; Shibuya,
I. Heterocycles 2003, 60, 1855. (d) An amidation-cyclization process of
2,2′-dithiobenzamides: Sano, T.; Takagi, T.; Gama, Y.; Shibuya, I.; Shimizu,
M. Synthesis 2004, 1585.
4812
Org. Lett., Vol. 8, No. 21, 2006

Table 1. Synthesis of Benzisothiazolones 1a-j from Amides 2a-j
a Isolated yields after purification by crystallization from Et2O. b Isolated yields after purification by column chromatography.
The benefits from the use of such an innocuous oxidizer are
clear in terms of lack of toxicity, safety, cost, and availability,
properties that make this iodine reagent a rather useful tool
in organic synthesis. In addition, our approach features the
first successful intramolecular trapping of N-acylnitrenium
ions by a thiole functionality developing a novel and easy
method for the construction of N-S linkages.
Spanish Ministry of Science and Technology (CTQ 2004-
03706/BQU) is gratefully acknowledged. A.C. thanks the
Basque Government for a predoctoral scholarship.
Supporting Information Available: Experimental details
for compounds 2a-j and 1a-j and 1H NMR and 13C NMR
spectra of all new compounds are included. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the University
of the Basque Country (9/UPV 41.310-13656/2001) and the
OL061867Q
Org. Lett., Vol. 8, No. 21, 2006
4813