Abstract
The synthesis of 4-alkoxy-1H-2,1-benzothiazine 2,2-dioxide derivatives was achieved through an unexpected base-mediated cyclization of N-benzoyl-N-methylsulfonylanthranilates. A reaction mechanism involving the sulfene species has been postulated. The obtained 4-alkoxy derivatives can be further functionalized at the N-1 position allowing unsymmetrically N,Odisubstituted 1H-2,1-benzothiazines 2,2-dioxide to be prepared.
Highlights
As part of our on-going research program aimed at identifying new anti-HCV agents,[1] we were interested in synthesizing 1-benzoyl-6-(2-bromophenoxy)-1H-2,1-benzothiazin-4(3H)-one 2,2dioxide derivative 1 (Scheme 1).The 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide nucleus has been definitely less explored, both in terms of chemical space[2] and biological relevance, with respect to its positional isomer 2H-1,2-benzothiazin-4(3H)-one 2,2-dioxide, whose scaffold characterizes very successful compounds such as the non-steroidal anti-inflammatory “oxicams”.The synthetic route to obtain the 1H-2,1-benzothiazine-4(3H)-one 2,2-dioxide skeleton was first reported simultaneously by two different groups, Loev and co-workers[3] and Rossi and coworkers.[4]
An improved 3-step synthesis was developed by Lombardino which entails the base-mediated cyclization of a N-alkyl-N-(methylsulfonyl)anthranilate, prepared from the coupling of an anthranilate and methanesulfonyl chloride (MsCl), followed by N-alkylation of the resulting sulfonamide.[5]
The reaction of N-(methylsulfonyl)anthranilate 4a with benzoyl chloride and NaH in dry THF gave the N-benzoyl-N-(methylsulfonyl)anthranilate 5a. When this key intermediate 5a was submitted to the cyclization step by treatment with NaH in dry DMF, the desired cyclization product 1 was not obtained while 6-(2-bromophenoxy)-4-methoxy-1H-2,1benzothiazine 2,2-dioxide 7a was formed as the major reaction product (40% yield) together with N-benzoylanthranilate 9a (20% yield)
Summary
As part of our on-going research program aimed at identifying new anti-HCV agents,[1] we were interested in synthesizing 1-benzoyl-6-(2-bromophenoxy)-1H-2,1-benzothiazin-4(3H)-one 2,2dioxide derivative 1 (Scheme 1).The 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide nucleus has been definitely less explored, both in terms of chemical space[2] and biological relevance, with respect to its positional isomer 2H-1,2-benzothiazin-4(3H)-one 2,2-dioxide, whose scaffold characterizes very successful compounds such as the non-steroidal anti-inflammatory “oxicams”.The synthetic route to obtain the 1H-2,1-benzothiazine-4(3H)-one 2,2-dioxide skeleton was first reported simultaneously by two different groups, Loev and co-workers[3] and Rossi and coworkers.[4]. The structure of 4-methoxy derivative 7a was assigned only by NMR experiments since it was not possible to obtain this compound in a suitable crystal form for X-ray analysis. In order to evaluate the reaction reproducibility and to exclude any influence of the 2-bromophenoxy substituent on the reaction trend, the cyclization was repeated using both unsubstituted methyl and ethyl N-benzoyl-N(methylsulfonyl)anthranilate, 6a and 6b respectively; again 4-alkoxy 2,1-benzothiazines 8a (36%) and 8b (33%) were obtained together with N-benzoylanthranilate 10a10 (20%) and 10b11 (25%).
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