Synthesis of New Bis ( spiro-β-lactams ) via Interaction of Methyl 1-Bromocycloalcanecarboxylates with Zinc and N , N 9-Bis ( arylmethylidene ) benzidines

Interaction of the Reformatsky reagents, prepared from methyl 1-bromocyclopentane-1-carboxylate or methyl 1bromocyclohexane-1-carboxylate, with N,N′-bis(arylmethylidene)benzidines has given rise to a set of intermediates as a result of nucleophilic addition to the C�N group of a substrate. Further intramolecular attack of the amide nitrogen atom onto the ester carbonyl group is responsible for the ring closure, which affords two series of spirocompounds: 2,2′-([1,1′-biphenyl]-4,4′-diyl) bis(3-aryl-2-azaspiro[3.4]octan-1-one) or 2,2′-([1,1′-biphenyl]-4,4′-diyl)bis(3-aryl-2-azaspiro[3.5]nonan-1-ones).

Generally, the interaction of aromatic aldehyde phenylhydrazones (except furfural phenylhydrazone) with carbocyclic Reformatsky reagents afforded various spiroazetidinone derivatives (3-aryl-2-phenylaminospiro [3.5] nonan-1-ones), but not the pyrazolone ones (Scheme 3).Formation of the azetidinones in this case occurs despite the fact that the five-membered ring formation is energetically more favorable if compared with the four-membered ring formation [37].
In our previous study, we have shown that the Reformatsky reagents derived from methyl 1-bromocycloalkanecarboxylates react with the aromatic aldehyde azines to form, as in the previous cases, bis(spiroazetidinones) [35].

General.
e IR spectra were recorded on a PerkinElmer Spectrum Two FTIR spectrometer using Nujol lms of samples.

General Procedure for the Bis(spiroazetidinones) 6 and 7
Synthesis.
e mixture of zinc (3.0 g, 46 mmol), methyl 1bromocycloalkanecarboxylate (12 mmol), HgCl 2 (5 mg), and N,N′-bis(arylmethylidene)benzidine 3 (5 mmol) in dry toluene (20 mL) with 2 mL of HMPA was heated for 4 h under re ux and then cooled down, decanted from the zinc excess, and treated with 5% acetic acid.Organic layer was separated, and the aqueous layer was twice extracted with ethyl acetate.
e combined organic layers were dried over Na 2 SO 4 and then concentrated.

Results and Discussion
ere have been established that the Reformatsky reagents, prepared from α-bromoesters (1 or 2) and zinc, react with bis(azomethynes) (3a-k) via addition to the C�N bond of the substrate molecule to yield the intermediates 4a-i or 5a-k (Scheme 4), which further through spontaneous cyclization followed by elimination of bromozincmethylate has  -k).e synthesized compounds (6a-i and 7a-k) were obtained in 54-84% yields as white or slightly colored (light yellow or beige) solids which melt with decomposition.In all cases, compounds containing a cyclohexane ring were obtained with better yield than the analogous compounds with a cyclopentane ring. is is probably due to the fact that the spirostructure, consisting of four-membered and vemembered cycles, is more strained if compared with the spirostructure, consisting of four-membered and sixmembered cycles.Analogous results were observed in the synthesis of similar spiro-β-lactams [50] and in the synthesis of some carbocyclic spirosystems [51].
e in uence of a substituent in the benzene ring of the arylmethylidene moiety is not clearly visible probably due to the fact that the rst stage of the reaction (nucleophilic addition of the Reformatsky reagent) is promoted by electron-withdrawing substituents which increase a partial positive charge on the carbon atom of the bis(azomethyne) C N group, while as the second stage (nucleophilic attack of the nitrogen atom on the carbonyl carbon atom leading to cyclization) is promoted by electrondonating substituents, which increase the nucleophilicity of the nitrogen atom in the intermediates ( 4 and 5).
e structure of bis(spiroazetidinones) (6a-i and 7a-k) was con rmed by elemental analyses and IR and 1 H-NMR, 13 C-NMR, and 19 F-NMR (6f and 7f ) NMR spectra.e IR spectra of 6a-i and 7a-k contain the absorption bands typical for stretching vibrations of β-lactam carbonyl groups (1746-1729 cm −1 ).e presence of the only one set of signals in the 1 H-NMR spectra of 6a-i and 7a-k (CDCl 3 ) indicates that, in solution, these compounds exist as a single diastereoisomer.A. Jarrahpour et al. have also reported about presence of only one set of signals in the 1 H-NMR spectra of bis(spiroazetidinones) they obtained [49].
e most characteristic feature of the 1 H-NMR spectra is the presence of singlet signals in the region δ 4.68-5.31ppm corresponding to protons of the CH group of the lactam cycle.
e most characteristic feature of the 13  Study of the antinociceptive activity of the synthesized compounds 7c-h with the help of the hot-plate test [52] has demonstrated that these compounds exhibit an activity greater than that of metamizole sodium, but less than that of ortophen.Antinociceptive activity study was carried out by R. R. Makhmudov, PhD, the associate professor, the head of the Research Laboratory of Biologically Active Compounds of PSU.