Synthesis of Novel Dispiro 1,4-Benzothiazine Hybrid Heterocycles Through 1,3-Dipolar Cycloaddition

Abstract The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of acenaphthylene-1,2-dione or isatins and α-amino acids to (E)-methyl/ethyl 2-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-2-ylidene)acetate led to the stereoselective formation of novel dispiro 1,4-benzothiazine hybrid heterocycles in good yields. GRAPHICAL ABSTRACT


INTRODUCTION
1,3-Dipolar cycloadditions have been a subject of intensive research in organic synthesis in view of their enormous synthetic applications. [1] In particular, the cycloaddition of nonstabilized azomethine ylides generated in situ from the decarboxylative condensation of α-amino acids and nonenolizable 1,2-diketones to exocyclic olefins constitute one of the most convergent approaches for the construction of novel dispiro oxindole or acenaphthene-pyrrolidine, pyrrolizine, pyrrolothiazole, or octahydroindolizine hybrid heterocycles. [2] Spiro oxindoles are present in many natural products such as coerulescine, horsfiline, and elacomine, which are endowed with a wide range of biological activities. [3] Furthermore, compounds containing the spiro pyrrolidine motif exhibit significant biological activities such as anticonvulsant, [4] potential antileukaemic, [5] local anaesthetic, [6] and antiviral [7] activities.
On the other hand, 1,4-benzothiazines [8] form a significant class of heterocycles possessing a wide spectrum of biological activities such as analgesic, [9] anticancer, [10] antifungal, [11] antibacterial, [12] antitubercular, [13] antithyroid, [14] and calcium antagonist [15] activities. These heterocycles form the core of antibiotic and cholesterol-lowering drugs. [16] In addition, 1,4-benzothiazines are also known for their applications as dyes, photographic developers, and ultraviolet absorbers. [17] The importance of spiro compounds and 1,4-benzothiazines prompted us to construct novel hybrids comprising these motifs. In this context, the present work discloses the outcome of 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the decarboxylative condensation of various α-amino acids with acenaphthenequinone or isatins to 1,4-benzothiazine dipolarophiles comprising an excocyclic alkene. Acenaphthenequinone, though less explored in terms of biological activity, is a versatile precursor for azomethine ylide cycloaddition as it reacts with α-amino acids generating reactive 1,3-dipoles. The present work also pertains to our continuous effort in the synthesis of novel dispiro hybrid heterocycles employing 1,3-dipolar cycloaddition reactions. [18]
Subsequently, the 1,3-dipolar cycloaddition of azomethine ylides generated in situ from the reaction of sarcosine 5, phenylglycine 6, proline 7, or 1,3-thiazolane-4carboxylic acid 8 with acenaphthenequinone 4 to the dipolarophiles 3a and 3b afforded novel dispiro 1,4-benzothiazine hybrid heterocycles 9-12 (Scheme 2). The cycloadditions were effected by heating an equimolar mixture of the reactants to reflux in ethanol on a water bath. After the reaction was complete as evident from thin-layer chromatography (TLC), the reaction mixture was poured into ice water and the resultant solid was subjected to column chromatography to obtain the pure product.
The reaction proceeds via the generation of azomethine ylide A in situ from the decarboxylative condensation of acenaphthenequinone 4 and α-amino acids, which then reacts with the exocyclic dipolarophiles 3 to afford the dispiro hybrid heterocycles 9-12 (Scheme 3). It is well known that the azomethine ylide exists in resonance forms A and B, either of which can react with the dipolarophile 3 to afford the respective isomers (Scheme 3). However, this cycloaddition occurs selectively involving the dipolarophile A, leading to the formation of 9. The other isomer 9′ arising from the cycloadditon of dipole B is not obtained in the course of the reaction, which may presumably be attributed to the steric factors. This selectivity is also apparent form the 1 H NMR spectrum of the product 9, wherein three triplets due to H-4′ and H-5′ are observed in the range 3-4 ppm. If the other isomer 9′ was formed, a singlet would have been expected due to H-3′ instead of a triplet. In addition, this cycloaddition reaction occurs stereoselectively, resulting in the exclusive formation of one diastereomer in all the cases 9-12, although up to four new contiguous stereo centers are generated during the course of the cycloaddition in a single step.
The structures of all the dispiro 1,4-benzothiazine hybrid heterocycles 9-12 were elucidated with the help of one-and two-dimensional NMR spectroscopy. As a representative case the 1 H and 13 C chemical shift assignment of 12b are discussed. In the 1 H NMR spectrum of 12b, a triplet and a quartet at 1.28 and 4.23 ppm (J ¼ 7.2 Hz) can be readily assigned to the protons of the ÀOEt group. The correlation spectroscopy (C,HÀCOSY) correlation of these protons assigns the carbon signals at 13.3 and 60.5 ppm to ÀCH 3 and ÀCH 2 carbons respectively. Further, the heteronuclear multiple-bond correlations (HMBC) of the -CH 2 protons assign the signal at 167.8 ppm to the carboxylate carbon. A doublet at 4.59 ppm with J value 10.2 Hz can be assigned to H-7′ on the basis of its multiplicity. This proton shows C, HÀCOSY correlation with a carbon signal at 51.6 ppm, assigning it to 7′ÀC. From the HMBC correlation of H-7′ the 3-C amide carbonyl carbon appears at 161.7 ppm. Further, H-7′ has a H,H-COSY correlation with a multiplet at 4.84-4.87 ppm, which can be assigned to H-7a′. The C,H-COSY correlation of H-7a′ assigns the carbon signal at 66.9 ppm to 7a′-C. It is evident from the H,H-COSY correlation of H-7a′ that the doublets of doublets at 3.11 and 3.33 ppm (J ¼ 11.1, 6.3 Hz) are due to 1′-CH 2 and from the C,H-COSY spectrum it is clear that 1′-CH 2 carbon appears at 35.0 ppm. The two doublets at 3.42 and 3.78 ppm with J ¼ 8.7 Hz, which can be assigned to 3′-CH 2 protons, show (i) C,H-COSY correlation with a carbon signal at 50.5 ppm due to 3′-C and (ii) HMBC correlation with one of the spiro carbons 5′-C at 79.6 ppm, thereby assigning the carbon signal at 63.0 to the other spiro carbon 6′-C. The NH of the 1,4-benzothiazine ring appears as a singlet at 9.74 ppm and shows HMBC correlation with the 2-C spiro carbon at 63.0 ppm. The doublet at 5.89 ppm (J ¼ 7.8 Hz) and the triplet at 6.70 ppm (J ¼ 7.8 Hz) can be assigned to H-5 and H-7 respectively on the basis of the shielding effect of NH through resonance. The H,H-COSY correlations of these protons assign the triplet and doublet at 6.79 and 7.08 ppm (J ¼ 7.5 Hz) to 6-C and 8-C respectively, whereas the C,H-COSY correlations assigns the carbon signals at 115.2, 122.3, 126.9, and 127.6 ppm to 5-C to 8-C respectively. The two doublets observed at 7.26 ppm (J ¼ 6.9 Hz) and 7.91 ppm (J ¼ 7.2 Hz) can be assigned to 8 00 -and 3 00 -CH protons respectively from the fact that the former shows HMBC correlation with the C-1″ carbonyl carbon at 200.1 ppm and the latter shows with the spiro carbon 5′-C at 79.6 ppm. Further, from the H,H-COSY correlation the triplets at 7.61 ppm (J ¼ 8.1 Hz) and 7.46 ppm (J ¼ 7.5 Hz) are due to 4″-and 7″-CH protons and the doublets at 7.83 ppm (J ¼ 8.4 Hz) and 7.98 ppm (J ¼ 6.9 Hz) are due to 5″-and 6″-CH protons respectively. The C, H-COSY correlations of these protons assign the carbon signals at 126.4, 125.0, 130.5, 126.8, and 119.4 ppm to 3″-C to 8″-C carbons respectively. The 1 H and 13 C chemical shifts of 12b are shown in Fig. 1. The structure of 12b elucidated from NMR spectroscopy was further confirmed from single-crystal x-ray studies. The ORTEP diagram shown in Fig. 2 [20] reveals that the 7′-H and 8′-H are trans and the two carbonyls attached to C-5′ and C-2 are also trans. Similarly, by straightforward considerations the 1 H and 13 C chemical shift assignments for all the other dispiro 1,4-benzothiazine hybrid heterocycles 9-12 were done and the data are given in the experimental section.
Then the cycloaddition of azomethine ylides generated in situ from the reaction of α-amino acids and isatins 13 to these dipolarophiles 3 was investigated with a view to synthesize novel dispiro oxindole-1,4-benzothiazine hybrid heterocycles [14][15][16] (Scheme 4). The reaction under similar conditions afforded excellent yields of the products. However, the reaction failed to occur in the case of proline. The structure of these compounds was elucidated with one-and two-dimensional NMR spectroscopy as done for these cases. As a representative example, the 1 H and 13 C NMR chemical shifts of 14b are shown in Fig. 3.

CONCLUSIONS
The 1,3-dipolar cycloaddition of unstabilized azomethine ylides generated in situ from the decarboxylative condensation of acenaphthylene-1,2-dione/isatins and α-amino acids to (E)-ethyl/methyl 2-(3-oxo-3,4-dihydro-2H-benzo [b][1,4]thiazin-2-ylidene)acetate resulted in the formation of novel dispiro 1,4-benzothiazine hybrid heterocycles. These cycloadditions proceeded stereoselectively, affording a single isomer of the product in excellent yields. The structure of all the dispiro heterocycles was elucidated with the help of one-and two-dimensional NMR spectroscopy. The prominent advantages of this reaction include a facile one-pot, three-component protocol, formation of two C-C and one C-N bonds in a single step, and generation of four new contiguous stereo centers.

SUPPLEMENTARY INFORMATION
Full experimental detail, characterization data for all compounds, and copies of 1 H and 13 C NMR spectra for this article can be accessed on the publisher's website.