Study of the transamidative ring expansion of N-ω-halogenoalkyl-β-lactams of alkyl chain lengths 2–12 in liquid ammonia and other liquid amines: syntheses of 7-, 8- and 9-membered 1,5-diaza cyclic ketones, including routes to (±)-dihydroperiphylline and (±)-celabenzine

Abstract

N-(3-Halogenopropyl) -4-phenylazetidin-2-ones undergo amination in liquid ammonia followed by transamidative ring expansion to give the eight-membered 4-phenyl-l,5-diazacyclooctan-2-one in excellent yield. Ring expansion of the amines in liquid ammonia is found to be much more effective than in hydrocarbon solvents. Formation of 7-, 8-, and 9-membered azalactams from the requisite o-halogenoalkyl-p-lactams is an excellent synthetic process, though it is not applicable to 10membered rings. In the cases of rings of 13-, 15-and 17-members, although amination and apparent expansion takes place, the large rings appear not to be stable to ammonia and the final products are acyclic amides. N -[4-Halogenobut-2(Z) -enyl] -4-phenylazetidin-2-one satisfactorily forms a 9-membered (Z)-olefinic azalactam. but the (€)-isomer gives an acyclic amino amide. By using alkyl-substituted p-lactam side-chains, C-substituted medium rings can be obtained; the relative instability of N-acyl j3-lactams to ammonia, however, leads to acylamino amides rather than expanded rings.Employing ethylamine in place of ammonia, it is shown that N-ethylated azalactams are formed satisfactorily, and using allylamine, N-ally1 medium rings capable of further elaboration are obtained. The chemistry of these systems is discussed. Using transamidation in liquid ammonia, a short synthesis of the 9-membered spermidine alkaloid ( k )-dihydroperiphylline is reported. Synthesis of key intermediates, whose transformation into the 13-membered alkaloids of the celabenzine group has already been effected, has been carried out.X-Ray single-crystal structure determinations for 4-phenyl-l,5-diazacyclononan-2-one, trans-4phenyl-8-methyl-1,5-diazacyclooctan -2-one and (Z) -4-phenyl-1,5-diazacyclonon-7-en-2-0ne are reported, and comment is made on certain conformational features.

Ring-Enlargement and Ring-Opening Reactions of 1,2-Thiazetidin-3-one 1,1-Dioxides with Ammonia and Primary Amines as Nucleophiles

“…In this reaction, proceeding via an eight-membered intermediate, a higher energy barrier had to be overcome; the necessary energy could not be supplied just by opening of the four-membered oxosulfonamide ring. It is worth mentioning that the analogous transamidation with a b-lactam could not be performed even at higher temperature [16]. The spectral data of 23 fully supported the tenmembered structure.…”

“…In several cases, base-induced transamidations via a seven-membered cyclic intermediate have been investigated, but the results were mainly negative [13] [15]. Scheme 6 Begley et al [16] reported on transamidation reactions with N-(aminoalkyl)-substituted b-lactams, substances with a structure similar to that of the compounds we were interested in. The reactions occurred smoothly via five-or six-membered intermediate.…”

“…Both reactions were carried out at room temperature in benzylamine as the solvent. The isolated products were Nbenzyl-2-(cyclohexylsulfamoyl)-2-methylpropanamide (15) and N-benzyl-2-(isobutylsulfamoyl)-2-methylpropanamide (16).…”

Reactivity of β-Lactamido N-Sulfonyl Radicals

“…When submitted to standard radical conditions (tributyltin hydride, cat. AIBN in refluxing benzene), phenyl derivative 1a 14 led to the corresponding desulfonylated amide. However, when the same reaction was carried out without AIBN, the same product was obtained.…”

β-Lactams fromD-Erythrose-Derived Imines: A Convenient Synthesis of 2,3-Diamino-2,3-dideoxy-D-mannonic-Acid Derivatives

“…Nocardicins, however, do not undergo ring opening with aqueous hydroxylamine [97], and monocyclic, N-unprotected b-lactams were stable in boiling liquid NH 3 [98]. Aminolysis of monocyclic Nalkyl b-lactams requires a large excess of NH 3 and long reaction times at elevated temperature and pressure [93] [99], while the analogous ring opening of N-unprotected monocyclic b-lactams has not been reported to date ( [98], for a nucleophilic opening of a N-Boc b-lactam by aqueous NH 3 , see [100]). …”