Imine with diketene

Cycloaddition of chiral imines with diketene allows one to gain access to chiral lactams. An interesting example of this is the reaction of lactate-derived imine 573 with diketene, which produces a 7.3 1 mixture of 574 and 575 [117]. Chromatographic separation of the major isomer furnishes 574 with an enantiomeric excess of 96%. 

When diethyl malonate is the diketone component, the ester (135) is first formed, which then cyclizes to the expected (136). Reaction of (131) with diketene gives a mixture of (137) and (138), the latter on acid cyclization also yields (134). This rearrangement is by a 1,3-shift of the acetoacetyl group to give the transient imine followed by cyclization. Similar rearrangements are known. Compound (139), the 7-one isomer of (134), is obtained from the reaction of (131) with a-bromocrotonic acid (76JHC291). 

Atnino groups are converted into pyrazole rings on heating the compound with a methyl ketone under acidic conditions an intermediate imine may be involved. 1-Aminopyridinium iodide reacts with diketene to give the aceto-acetylimino ylide which cyclizes under the influence of a base. 

Cycloaddition of phthalimidoketene with imine 18 also gives a single cis-fi-lactam 19 indicating that the presence of the oxygen in a ring is not necessary for stereoselective cycloaddition63. Cycloaddition of chiral imine 20 with diketene as an acetylketene equivalent under carefully optimized conditions gives a 15 1 mixture of the fr n.r-/ -lactam 21 and the tra s-disubstituted diastereomer 2267. 

Diketene reacts with imines to give l,3-oxa2inones (16) (105). This reaction has been used in the synthesis of the tranquili2er Keta2olam... 

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

Ethyl lactate has also been used to synthesize the important 4-acetoxyazetidinone intermediate, crucial to numerous car-bapenem syntheses. The key step in its use was the diketene addition to the (5)-lactaldehyde imine, which in the best case proceeded in 67% yield with a 10 1 ratio of diastereomers (eq 13). ... 

The N -substituted N-imines can be prepared by the reaction of the N-aminoazonium salts, in the presence or absence of base, with anhydrides or acyl halides,8,13-17,20,21,45,46 diketene,47 diethyl malonate,48 sulfonyl chloride,8,15,49,50 /i-halovinyl ketones and esters,51-54 diethyl ethoxymeth-ylenemalonate and related compounds,53,55-57 isocyanates,17,58 thioiso-cyanates,17,58 imidoyl chlorides and imidates,59,60 nitro acetate,8,61 and active halobenzenes.62,63 Some representative pyridine -(substituted imines) prepared in this way are shown in Scheme 1. 

The allene PrCH=C=CHCH2NH2 isomerizes to the 3-pyrroline (122) under the influence of silver tetrafluoroborate. Photolysis of aroyl azides in the presence of diketen (123) yields the hydroxy-pyrrolinones (124).AT-Ray analysis has shown that the adduct of the imine Pr"CH=NPr to N-phenylmaleimide has structure (125). Treatment of dichloromaleimide with ethoxycarbonyl-methylenetriphenylphosphorane affords the Wittig product (126). The formation of the pyrrolidinone (128) in the thermolysis of the iV-cyclohexenylacryl-amide (127) represents an intramolecular ene-reaction (see arrows). The perfluoropyrrolidinone (130) results from the reaction of the cyclobutane (129) with potassium fluoride. Pyrrolidinols (131) are obtained in moderate yields by photochemical cyclization of the amides ArCOCH2CH2NBzCH2Ph. ... 

The same author [63] reported the synthesis of 1 (3-methylcarbapenem intermediates such as 111 (Scheme 16), employing chiral imines prepared from (S)-methyl 3-hydroxy-2-methylpropionaldehyde and p-anisidine or DAM-NH2. The reaction of diketene 98 with these imines in the presence of imidazole produced a diastereomeric mixture of P-lactams 107 and 108 in a variable ratio. These authors found that the best results in terms of chemical yield and stereoselectivity could be obtained when the [2 + 2] cycloaddition reaction was performed on imines derived from DAM-NH2 toluene as solvent and using 4-methylimidazole instead of imidazole. Under these conditions the P-lactam 108b was obtained in 49% yield and the ratio of isomers 107b/108b was 1 15. 

Diketene can be used as a masked acetylketene, and reaction with chiral imines, in the presence of imidazole as the catalyst, gives rise to the formation of acetyl substituted azetidinones 250 ... 

In the reaction of diketene with A-di-p-anisylmethyl substituted imine mixtures of the two 3-acetyl-/3-lactams are formed in a ratio of 7 1... 

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