Azetidinone expansion

The literature on fused-ring azetidines and azetidinones has virtually exploded in the last 15 years. A major factor in the expansion of research in this area has been the discovery... 

While these rearrangements are used most often to prepare large rings, the expansion of cyclopropanone to azetidinones is also practical (Scheme 24 CHEC 5.09.3.3.3). 

Treatment of the /3-lactam, 3,3-dimethoxy-l-p-methoxyphenyl-4-p-methoxyphenyliminomethyl-2-azetidinone (3, R = H), with stannous chloride in dichloromethane for 20 h gave 1,4-bisf/ -methoxyphenyl)-2,3(l//,4//)-pyrazine-dione (5, R = H) in 95% yield by ring expansion via the acetal (4) 874 the 4-methy-lated substrate (3, R = Me) likewise gave 1,4-bisf p-methoxyphenyl)-5,6-dimcthyl-2,3(lH,4tf)-pyrazinedione (5, R = Me) (99%).874 cf-1740... 

There have also been a few examples of ring expansions involving azetines. One such instance, which follows a pericyclic mechanism, is the thermolysis of 4-cyano-l-t-octyl-3-t-octylamino-2-t-octyliminoazetine (160), producing the 4-amino-5-cyanoimidazole (Scheme 89). Such azetine species have been implicated as intermediates in the photolysis of enaminonitriles to imidazoles (Section 4.08.1.1.1 Scheme 17). In strongly basic medium the azetidinone (161), which possesses a lactam group, is ring expanded to the 4H-imidazolinone (163), probably via the anionic acylic species (162 Scheme 89) <80AHC(27)241>. 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

Later, /J-lactams have been obtained by regiospecific metal-catalyzed ring expansion of aziridines. Treatment of A -t ri-butyl-2-phenylaziridine (252) with carbon monoxide in benzene, employing chlorodicarbonylrhodium(I) dimer as the catalyst at 90°C and 20 atm, produced the azetidinone 253 in quantitative yield. Several other )S-lactams were also synthesized from the corresponding aziridine derivatives by the application of this method, and it was noted that this reaction was completely regiospecific. The possible reaction mechanism for the formation of fi-btciams is outlined in Scheme 47. 

The Buchwald group reported an interesting copper-catalyzed lactam /V-arylation/ ring-expansion cascade wherein compound 669 reacted with 2-azetidinone 670 in the presence of Cul and K2C03 to give 671 in 96% yield (Scheme 110) (04JA3529). 

Several substituted fi-lactams and benzyl amine derivatives participated in this coupling reaction, though the ring expansion was slower when /V-substituted benzyl amines were used. Exposure of the intermediate /V-aryl lactam to AcOH in THF, however, overcame the sluggish transamidation. In some examples, the addition of N,N -dimethylethylene-diamine facilitated the reaction, though it was not required in all cases. Phenethyl amine 672 reacted with azetidinone 670 to give 673 in 78% yield. 

Alper and Hamel have reported an interesting case of Pd-catalyzed CO insertion reaction, involving ring expansion of aziridines to azetidinones (Scheme 47). It seems reasonable to assume that the reaction is initiated by oxidative addition of Pd(0) across the strained C—N bond, as shown below,... 

The iron(III) chloride-catalyzed ring expansion reaction of 2-azetidinone-tethered alkynols and allenols provides pyrroles or y-lactones, respectively (Scheme 4-351). The proposed mechanism for the pyrrole formation includes a Meyer-Schuster rearrangement of the propargyl alcohol to the corresponding allenyl alcohol, P-lactam ring opening, tautomerization of the allenyl alcohol to the a,P-unsaturated carbonyl compound, and cyclization by attack of the amino group to the ketone under dehydration. ... 

Scheme 4-351. Iron-catalyzed ring expansion of 2-azetidinone-tethered alkynols and allenols.

---