Synthesis of 1,3-thiazines by a three-component reaction and their transformations into β-lactam-condensed 1,3-thiazine and 1,4-thiazepine derivatives

GRAPHICAL ABSTRACT ABSTRACT Variously substituted 1,3-thiazines have been prepared by a three-component reaction involving a thioamide, an aldehyde, and an alkene. Two diastereomeric thiazines were transformed by stereoselective Staudinger reaction into the corresponding chloro-β-lactam-condensed-1,3-thiazines, and one of them was rearranged in basic media to afford a highly substituted 1,4-thiazepine. Several of the obtained compounds (six 1,3-thiazines and one β-lactam-condensed-1,3-thiazine) were analyzed by X-ray crystallography, which enabled to assign their spatial arrangement and stereochemistry.

the approach of the alkene (endo or exo), two diastereoisomers can be obtained.
We found that the use of BF 3 .OEt 2 as Lewis acid (in the presence of a water-adsorbent agent MgSO 4 ) was better than trifluoroacetic acid (TFA) or p-toluenesulfonic acid (PTSA) as Brønsted acid (Entries 1-4). In these conditions, the conversion into 1,3-thiazine 1a was almost total, and the 1:1 mixture of endo/exo adducts was separable by column chromatography on silica gel. However, the reaction time was too long (5 days). Finally, the use of microwave activation 5 (entries 5-7) was very efficient, reducing the reaction time to 10 min.
With these optimized conditions (40 W, 150°C, in 1,2dichloroethene, DCE), we examined the scope and limitations of this reaction. First, the aromatic aldehyde partner was varied ( Figure 1, 1b-1f). Whatever the aldehyde was used, total conversions were obtained in all the cases, yields were good to excellent and the two diastereoisomers endo/exo (ratios varying from 1:1 to 1:0.5) were separated by column chromatography on silica gel. No reaction occurred with aliphatic aldehydes (isobutyralde- hyde or trimethylacetaldehyde), ferrocenecarboxaldehyde, and ethylglyoxalate.
Then, the nature of the alkene was examined (Figure 1, 1g-k). Thiazines derived from aliphatic acyclic alkenes were isolated with good yields. Interestingly, the formation of the styrene adduct (1h) was highly endo-selective (endo/exo 1:0.2) probably due to favorable secondary orbital interactions. However, when the reaction was performed with trans-anethole, an inseparable mixture of 3 diastereoisomers (1i) was obtained: the endo and exo adducts (respectively, 56% and 34%), and the epimer at C 5 (1i-epi) as minor compound (10%). The cyclohexene adduct (1j) was obtained as a 1:1.6 endo/exo mixture, whereas the norbornene adduct (1k) was formed with a total exo-selectivity, as a single isomer, in 78% yield. The relative stereochemistry was unambiguously assigned by X-ray crystallography for 1j-exo and 1k-exo. By using ethyl acrylate and ethyl vinyl ether as the alkene partners, the desired adducts could not be obtained.
Finally, the thioamide partner was also varied ( Figure 2). Thioacetamide or thioformamide 6 were used instead of the thiobenzamide. Seven expected thiazines (1l-1r) were obtained in good yields and for each type of alkene, the ratio endo/exo was similar to those obtained previously. The use of thioformamide led in moderate yield (38%) to the corresponding 2-H-1,3-thiazine 1r, which represents a possible carbene precursor. 7 Four of the obtained compounds (1n-endo, 1o-exo, 1q-exo, and 1r-exo) were analyzed by X-ray crystallography, which enabled to assign their spatial arrangement and stereochemistry.
The cis spatial arrangement between Ph and Cl groups is coherent with the 1,3-benzothiazine series and was confirmed by the X-ray analysis of 2a (Figure 3). It is interesting to note the planar geometry of the nitrogen atom and the boat-like conformation of the thiazine ring with the butyl and phenyl groups in pseudo-equatorial positions and almost in the same plane.
We next attempted the transformation of β-lactam derivative 2a into the corresponding 1,4-thiazepine, using t-BuOK as the base, in methanol (Scheme 4). 2d-f After 4 h at rt, compound 3a was isolated in 52% yield. The first step of this process is probably the methanolysis of the β-lactam ring, furnishing the αchloro-ester. After cyclization into an episulfonium salt, then elimination of HCl, the seven-membered ring is obtained. 2g The desmotrope form of 3a, the corresponding imine, was not observed compared to the benzothiazepine series. In summary, 18 variously substituted 1,3-thiazines have been synthesized by an efficient three-component reaction. Starting from 2,4-diphenyl-6-butyl-1,3-thiazine, the Staudinger reaction provided stereoselectively the corresponding β-lactam, which was then transformed into a highly functionalized 1,4thiazine. Biological tests are currently in progress to evaluate the inhibitory effect of the prepared compounds against metallo-βlactamases.

Experimental
Spectroscopy: 1 H and 13 C NMR spectra were recorded with a Bruker DRX 400 MHz or a Bruker DRX 500 MHz spectrometer. Samples were dissolved in an appropriate deuterated solvent (CDCl 3 , acetone-d 6 , D 2 O, DMSO-d 6 ). The chemical shifts (δ) are expressed in ppm relative to internal tetramethylsilane for 1 H and 13 C nucleus, and coupling constants are indicated in Hz. Abbreviations for signal coupling are as follows: s = singlet; d = doublet; dd = doublet of doublets; t = triplet; q = quartet; quin = quintet; m = multiplet; br = broad signal. To assign the signals to the different proton and carbon atoms, as well as the relative stereochemistry of the cycloadducts, additional 2D NMR experiments (COSY, HSQC, HMBC) and NOESY experiments were performed. Mass spectra were obtained on a GC/MS Saturn 2000 spectrometer. High-resolution mass spectra (HRMS) were performed on Q-TOF Micro WATERS by electrospray ionization (ESI). Infrared (IR) spectra were recorded with a Perkin Elmer 16 PC FT-IR spectrometer. Chromatography: Thin Layer Chromatography (TLC) was run on pre-coated Scheme  aluminum plates of silica gel 60 F-254 (Merck). Flash chromatography was performed on silica gel column (Merck silica gel, 40-63 µm) using air pressure. Microwave irradiation was carried out with microwave oven Discover® LabMate System from CEM, using 10 mL pressurized vials. Elemental analysis was obtained from Thermoquest NA 2500 CHNS-O instrument. Melting points were determined using an Electrothermal IA9000 capillary apparatus. X-ray diffraction experiments were performed with graphite-monochromatized MoK α radiation on a Bruker Nonius APEX-II Kappa CCD area detector diffractometer. Additional X-ray structural details are provided in the Supplemental Materials.