Synthesis of 4H-3-aryl-2-cyano-1,4-benzothiazine 1,1-dioxides for antiviral studies

Introduction

The 3,4-dihydrobenzothiazine 1,1-dioxides 1a–b (Figure 1) have previously been shown by us to have good activity against human beta-herpes viruses, including human cytomegalovirus (HCMV) and human herpes virus 6 (HHV-6) and 7 (HHV-7) [1], [2]. In the case of HHV-6, these compounds act by inhibiting the viral helicase enzyme [3]. To date, however, the benzothiazine analogues 2a,b have not been described in the literature. Synthesis of compounds 2a,b as potential antiviral agents is described in this report.

Figure 1

Structures of 1,4-benzothiazine derivatives 1 and 2.

Unsaturated 1,4-benzothiazines have a rich history of biological activity [4] and thus new methods for preparation of this class of compounds often appear in the literature [5], [6], [7]. Recently, at least three different ring-forming syntheses of analogs of sulfone derivatives 2 without the cyano substituent at the 2-position have been published [8], [9], [10]. While a cyano group could conceivably be added to the 2-position of this core structure to give target compounds 2, this would seem to be a difficult task and was thus not pursued. Alternatively, compounds 2 could in principle be prepared by dehydrogenation of compounds 1. Unfortunately, our initial attempts of this one step conversion using oxidizing reagents such as NBS (N-bromosuccinimide) were not successful. We thus turned our attention to development of a ring-forming synthesis of compounds 2 that would give the 2-cyano-substituted thiazine directly. Herein, we wish to describe this synthesis and characterization of novel 1,4-benzothiazines 2a,b.

Results and discussion

One of the previously described approaches to the 2-unsubstituted analogs of 2 involves condensation of an in situ formed amine group with a pendant aryl ketone (which is linked to an ortho-sulfonyl group) to directly provide the unsaturated thiazine ring [8]. We thus envisioned that the cyano-substituted ring system 2 might similarly be prepared starting with an aryl ketone intermediate that has the requisite cyano group already in place. This successful approach is shown in Scheme 1.

Scheme 1

Synthesis of target compounds 2a,b and benzamide by products 5a,b.

To begin, known 1-(cyanomethyl)sulfonyl-2-nitrobenzene (3) [11] was allowed to react with benzoyl chlorides in the presence of triethylamine in acetonitrile to give aryl ketone intermediates 4a,b in good yields (73%–91%) following purification by column chromatography. Subsequent treatment of these intermediate products with iron powder in acetic acid, conditions similar to that used to prepare compounds 1 [1], [11], gave the desired 2-cyano-substituted compounds 2a,b via the cyclodehydration reaction. Interestingly, the non-cyclized benzamides 5a,b were also obtained as major byproducts in this reaction, apparently by a competing acyl group transfer to the in situ generated amine group (likely facilitated by the presence of the cyano group which makes the methylsulfonyl moiety a good leaving group for acyl substitution). After purification by column chromatography, target compounds 2a,b were obtained in modest yields of 22% and 18%, respectively. The unexpected benzamides 5a,b were obtained in slightly higher yields of 24% and 30%. On the basis of TLC analysis of an extract from the iron reduction mixture, no other mobile products were observed after the starting ketone 4 was consumed. Despite the low yield of the target compounds 2a,b, sufficient quantities for antiviral studies were prepared.

All new compounds prepared in this study were characterized by IR and NMR spectral analysis. Intermediate products 4a,b appear to exist as mixtures of keto and enol forms based on the presence of both a relatively weak carbonyl absorbance in the IR spectrum at ~1700 cm⁻¹ and a broad (and also weak) absorbance at ~3500 cm⁻¹ which is assigned to the OH group of the enol tautomer. This suggestion is fully supported by analysis of the ¹H NMR and ¹³C NMR spectra for 4a. Interestingly, the ¹³C NMR spectrum of 4b is consistent with the presence of a single tautomer. For both compounds, a strong signal at ~185 ppm (for a carbonyl carbon) indicates the keto form as the major tautomer. These IR and NMR data are in full agreement with previously reported analysis of an analog of 4a,b which lacks the nitro and halogen substituents [12].

IR analysis of target compounds 2a,b and benzamide byproducts 5a,b was more routine. The conjugated cyano group of 2a,b shows a strong absorbance at ~2200 cm⁻¹, while the absorbance for the non-conjugated cyano group of benzamides 5a,b is less intense and shifted to a slightly higher wavenumber (~2250 cm⁻¹), as expected. Each compound gives an NH stretching band in the 3200–3300 cm⁻¹ region, while benzamides 5a,b also show a carbonyl absorbance at ~1665 cm⁻¹. The ¹H NMR and ¹³C NMR spectra for products 2a,b and 5a,b, as well as the combustion analysis results, are also consistent with the assigned structures.

Conclusions

The 2-cyano-1,4-benzothiazines 2a,b were prepared by a two-step route that involves a reductive cyclodehydration reaction to give the unsaturated 1,4-thiazine ring directly. The yields are modest (18%–22%) due to the formation of non-cyclized benzamides 5a-b as unexpected byproducts. Nonetheless, these benzothiazines were prepared in sufficient quantities and are currently undergoing biological screening to determine their antiviral activity.

Experimental

¹H NMR and ¹³C NMR spectra were recorded in DMSO-d₆ at 300 MHz and 75 MHz, respectively, using a Bruker Avance instrument. IR spectra were recorded for neat compounds using ATR. Acetonitrile and triethylamine were distilled from CaH₂. Melting points were recorded in open glass capillaries and are uncorrected. Elemental analyses were performed by Atlantic Microlab, Norcross, GA.