2-azetidinones amides

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

The electrophilicity of alane is the basis for its selective reaction with the amide group. Alane is also useful for reducing azetidinones to azetidines. Most nucleophilic hydride reducing agents lead to ring-opened products. DiBAlH, A1H2C1, and A1HC12 can also reduce azetinones to azetidines.100... 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

Photosensitized decomposition of oxime oxalyl amides proceeded via carbamoyl radicals which underwent A-exo cyclizations forming four-membered /3-lactams as main products. Irradiation of solution of oxime derivative 22 and 4-methoxyacetophenone (MAP) in toluene at 100 °C with a 400 W UV lamp led to azetidinone 23 in 3 1 ratio of diastereoisomers (equation 10) . ... 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

This procedure illustrates a general method for preparing aliphatic and, in certain cases, aromatic /3-lactarns containing a free NH group and substituted in either the 4 position or in both the-3 and 4 positions of the 2-azetidinone ring. The major byproduct of the cycloaddition step is a /3,7-unsaturated carbox-amide-N-sulfonyl chloride which, in the case of certain aromatic olefins, may predominate. Reactions of both /3-lactam-N-sulfonyl chlorides and the /3,y-unsaturated carboxamide-N-sulfonyl chlorides have been tabulated.3... 

Appropriately substituted hydroxy amides and ureas can be used instead of diamines. Thus, acid-catalyzed cyclocondensation of iV-carbamoyl prolinols 137 (R1 = H, (CH2)3) (Scheme 27) with aldehydes RCHO (R = Ph, 2-MeOC6H4, 2-naphthyl, etc.) stereoselectively afforded a series of pyrroldine-fused oxadiazepinones 46 (Scheme 5) <1990CPB2627, 1990H(30)287, 1996LA927>. Similar heterocyclization of 4-(2-hydroxyethylthio)-2-azetidinone with acetone dimethyl acetal was used in the synthesis of azetidinone-fused oxathiazepanes of type 33 (X = S) (Figure 4) <1980JA2039>. 

The amidic proton of the same azetidinone has been silylated in a classical way, almost quantitatively, using chlorosilane/triethylamine mixture at 0 °c.122a... 

The X-ray structural analysis of (65) reveals some interesting features. The length ofthe C—N amide bond is 1.482 A compared to 1.41 A in an azetidinone. In addition the nitrogen has a tetrahedral structure, it is even more tetrahedral than ammonia. These parameters indicate that the conceivable azacyclobutadiene structure (66) does not contribute to (65), apparently as a consequence of an antiaromatic destabilization of (66) 217). 

Some reactions of munchnones occur via acylamino ketenes, the covalent valence tautomers of the betaines. The ketenes are intermediates in the thermolysis (see Scheme 22) and in the formation of azetidinones from imines (equation 69) they are thought to be involved in the aminolysis of the mesoionic compounds, which results in amides of a-acylamino acids, and in the formation of the benzodioxin (247) by the combined action of acetic anhydride and tetrachloro-o-benzoquinone on Af-benzoylalanine (equation 70). 

An efficient use of triphosgene, as an acid activator, for the synthesis of substituted 2-azetidinones via ketene-imine cycloaddition reaction using various acids and imines has been achieved <02T2215>. Novel routes to monocyclic (3-lactams 13 and 14 through the photochemical decomposition of oxime oxalate amides <02CC2086> and a-oxoamides <02OL1443> have also been described. 

On account of its relevance to penicillin chemistry, a great deal of work has been carried out on -lactams, but only a flavor of that chemistry can be included here. The reaction of 2-azetidinones (-lactams) with nucleophilic reagents is accompanied by acylnitrogen fission, as is normal for amides (cf. 63 64), e.g., propiolactam yields -alanine (H2NCH2CH2C02H) on hydrolysis. 

A variation of the cross-coupling protocol involving the ring opening of 4-alkenyl-2-azetidinones to yield amides has been recently reported (equation 23). Differently substituted aryl- and vinylmercurials effect the transformation in good yields and stereoselectively. ... 

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