Investigation of ring transformations of diaryl-β-lactams condensed with 1,3-benzothiazines

Reactions of derivatives of the isoquinoline analog trans -2,2a-diaryl-2,2a-dihydro-5,6-dimethoxy-1 H ,8 H -azeto[2,1-b ][1,3]benzothiazin-1-one were studied under basic conditions. Their treatment with sodium methoxide in methanol resulted first in alcoholysis of the β-lactam ring, followed by opening of the thiazine ring and oxidation of the thiol moiety to disulfide. Thus, the corresponding β-amino acid derivatives, disulfides of N -( ortho -mercaptobenzyl)- substituted diaryl-3-aminoacrylic acid methyl esters, were obtained in good yields. The structures of the new molecules were proved by means of NMR and IR spectroscopy. Geometric isomerism investigations indicated the presence of the Z forms of the acrylic acid moiety.

As concerns the mechanism (Scheme 1), the first step in this reaction is most probably alcoholysis of the β-lactam ring 14 of 13, resulting in diphenyl ester 14.The thiazine ring of 14 can be further transformed to the corresponding chain intermediate 15.This latter imine 15 converts to an enamine, providing an acrylic acid derivative 16, which is followed by oxidation to disulfide 17 by air.The IR, 1 H-and 13 C-NMR spectral data (Tables 1 and 2) furnish unambiguous proof of the presumed structures of the new compounds 13b-f and 17a-f.Merely the following comments are necessary.
The presence of the azetidinone ring in compounds of type 13 is obvious from the νC=O IR band in the expected interval, 16a 1762-1777 cm -1 , and the carbon line with chemical shifts 169.0-170.1 ppm, also in accordance with the literature data.17a The assignment of the carbon line and the position of the oxo group are confirmed by the cross peaks with the methylene hydrogens H's in the 2D-HMBC spectra.
The H-2 chemical shifts of 13d and 13e are higher (4.90 and 5.08 ppm) than those of 13b,c,f (4.81-4.84ppm) due to the ortho substituent on the benzene ring attached to C-2′.As a consequence of the steric hindrance between the two aromatic rings (on C-2 and C-2′) the C-2 substituent is forced into an orientation in which H-2 is coplanar with the benzene ring on C-2.The parallel orientation of the benzene rings on C-2 and C-2′ and their position cis to the azetidinone ring are confirmed by the mutual anisotropic effects on the aromatic H's, as described earlier for 13a. 15As a consequence, the chemical shifts of the H's mentioned above are ~7 ppm for the cis isomers, while for the trans counterparts they are downfield-shifted by 0.55-0.70ppm.

MeO
Since the signals of the aromatic H's appear in the interval 6.78-7.16 in the spectra of 13b-f (except for that on the C-2 nitro-substituted ring on C-2′ in 13e, where the -I effect of the nitro group results in a significant downfield shift), the cis position of the two benzene rings is obvious.
Further proof is given by the lines of the unsaturated carbons between the NH and the ester groups (C-2: 159.8-163.8ppm and C-2′: 97.2-99.6 ppm) and the NH signal in the IR (3285-3290 cm -1 ) and in the 1 H-NMR spectrum (9.56-9.65 ppm), and also the couplings of the H's in the CH2NH moiety, resulting in doublet and triplet splits, respectively, of the CH2 and NH signals.Due to free rotation around the S-S and C-N bonds the methylene H's are chemically equivalent in the compounds of type 17 in contrast with 13b-f.The only exception is 17e, in which the ortho-nitro substituent hinders this motion and the methylene H's become nonequivalent in this crowded molecule.
It should be noted that 17b is poorly soluble in CDCl3 and we measured the NMR spectra in DMSO-d6.In this solution, a better-soluble contamination gives well-identifiable signals in the 1 H-NMR spectrum.

Experimental Section
General.Melting points were determined on a Kofler micro melting apparatus and are uncorrected.Elemental analyses were performed with a Perkin-Elmer 2400 CHNS elemental analyzer.The mass spectra were recorded in the interval 200-2200 m/z on an Agilent 1100 LCMSD trap instrument equipped with an electrospray source.Merck Kieselgel 60F254 plates were used for TLC, and Merck Silica gel 60 (0.063-0.100) for column chromatography.Substituted phenylacetyl chloride derivatives were purchased from Aldrich.1,3-Benzothiazines 12a-f 19 and β-lactam 13a 15 were prepared earlier.
The 1 H-and 13 C-NMR spectra were recorded in CDCl3 solution in 5-mm tubes at room temperature, on a Bruker DRX 500 spectrometer at 500 ( 1 H) and 126 ( 13 C) MHz, with the deuterium signal of the solvent as the lock and TMS as internal standard.The standard Bruker micro program NOEMULT.AU to generate NOE was used with a selective preirradiation time.DEPT spectra were run in a standard manner, using only the Θ = 135º pulse to separate CH/CH3 and CH2 lines phased "up" and "down", respectively.The 2D-HSC and HMBC spectra were obtained by using the standard Bruker pulse programs.
General procedure for diaryl β-lactam derivatives (13b-f) 1,3-Benzothiazines 12b-f (5 mmol) were dissolved in toluene (30 ml), followed by addition of the appropriate substituted phenylacetyl chloride (5 mmol).The mixture was refluxed, and a solution of triethylamine (0.50 g, 5 mmol) in toluene (30 ml) was added dropwise, with stirring, during 1 h.The crystalline triethylamine hydrochloride was removed by filtration, the toluene solution was evaporated and the residue was crystallized and recrystallized from ethanol to obtain white crystals.General procedure for 3-aminoacrylic acid derivatives (17a-f) Azeto-1,3-thiazines 13a-f (2.8 mmol) were dissolved in dry methanol (100 ml).To this stirred solution, sodium methoxide (300 mg, 5.6 mmol) was added and the reaction mixture was stirred under reflux for 2 h.After evaporation to 30 ml, the solution was left to stand overnight at room temperature.The crystals that separated out were filtered off and recrystallized from methanol to give 3-aminoacrylic acid derivatives 17a-f as white crystalline products.