L,3-Diazetidin-2-ones

Carbonyl-substituted isocyanates have been reported to add [2 + 2] to carbodiimides, although in one case the reported 4-imino-l,3-diazetidin-2-one (64AP623) was reassigned an oxadiazine structure (72BCJ1534). It is clear that the initially formed [2 + 2] kinetically favored adducts are thermally unstable and ultimately form more stable [4 + 2] products, oxadiazines (Scheme 13) (79BSF(2)499). 

Desiraju et at. have prepared some mono and bicyclic-l,3-diazetidine-2-ones with a view to study them as aza analogues of /3-lactams and to evaluate their biological activities. The X-ray structure of azacarbapenam 35 and azacarbacepham 36 suggests is that the structural requirement for the biological activities of /3-lactams is met. Aza-/3-lactam analogue 37 was also crystallized and an X-ray analysis was carried out <1998J(P1)2597>. Only limited X-ray studies have been reported for aza-/3-lactams. 

Alkoxy-l,3-diazetidin-2-one ring from 0-alkyllactims and isocyanates... 

While l,3-diazetidine-2,4-diones are well known and readily prepared by dimerization (vide infra), very few closures from ureas are documented. One simple dialkyl derivative stable enough to be isolated is illustrated in Scheme 60. Smaller alkyl groups like isopropyl are much less stable (71JOC3056). 

Cyclohexylamine is reported to react with formaldehyde giving a 60% yield of 1,3-diazetidine. One additional example reports a photochemical closure of iV-cyclohexylben-zaldehydeimine (68JA1666). An excellent review covers much of the earlier work on dimerizations of isocyanates (69ACR186). Aromatic isocyanates readily dimerize to uretidinediones (l,3-diazetidine-2,4-diones) when catalyzed by trialkyl phosphites or pyridine presumably by a dipolar intermediate AH = 2.1 to 4.2 kJ mol-1, AS = -251 to -293 JK-1 mol- (Scheme 86) (66JA3582, 76JGU799). 

Each vibrational mode was assigned to one of the six types of motion predicted by theoretical analysis (C=0, stretch, N-C stretch, N-Cl stretch, N-C-N bend, N-Cl bend, and C=0 bend). The vibrational frequencies of 1,3-dichloro-l,3-diazetidine-2,4-dione 45 were calculated at Hatree-Fock level, DFT (B3LYP) level, and MP-2 level of theory using a standard 6-311G basis set. For N-C stretching modes all operators except E have a trace of zero. 

The dimerization of aryl isocyanates to l,3-diarylazetidin-2,4-diones is one of the classical methods for the synthesis of 1,3-diazetidinones. In 1993 trimerization of phenyl isocyanate catalyzed by a fluoride ion was also reported, and a small amount of l,3-diazetidin-2,4-dione was obtained at room temperature <1993JOC1932>. 

The reaction of carbodiimides with alkyl- or arylisocyanates proceeds exclusively across the C=N bond of the isocyanates to give 2-imino-l,3-diazetidine-4-ones 209 as evidenced by degradation studies In the case of N-alkyl-N -arylcarbodiimides the reaction proceeds... 

Startg. O-alkyllactim allowed to react at room temp, with p-nitrophenyl isocyanate 2-methoxy-2,3-pentamethylene-l-(4-nitrophenyl)-l,3-diazetidin-4-one. Y 87%. F.e. s. U.Kraatz, Tetrah. Let. 1973, 1219. 

A new synthesis of 6-arylamino-2-heteroarylimino-l,2-dihydro-l,3,5-triazines from 2,4-bis-(heteroarylimino)-l,3-diazetidines and amidines has been developed by Molina et al. The formation of the triazines was explained as an initial addition of the imino nitrogen of the amidine to the exocyclic C=N bond, followed by formation of an open chain intermediate. This intermediate cyclized, followed by elimination of 4-amino-6-methyl-3-methylthio-l,2,4-triazin-5(47/)-one to give the triazine product (Scheme 62) <87S150>. 1,3,5-Triazines (207) and (208) have been prepared from 2-acylimino-l,3-thiazetidines (204) by treatment with iso thioureas or guanidines respectively (Scheme 63) <91JHC177>. 

The Wittig-type reactions of iminophosphoranes with isocyanates and related compounds have also been extensively used in heterocyclic synthesis. Examples include the preparations of the mesoionic [l,3,4]thiadiazolo[2,3-c][l,2,4]triazines (210) from (209), 0 bicyclic guanidines, e.g. (212), from (211), naphthypyridines (215), (216), and (217) from (213) and (214), 2 pyrido[l,2-f]pyrimido-[4,5-d)pyrimidines (218), 7H-pyrido-[4,3-c]- (219) and 10H-pyrido[3,4-b]- (220) carbazoles, tricyclic fused 2,4-diimino-l,3-diazetidines (222) from the bisiminophosphorane (221), benzotriazepines (225) from (223) and (224), 6 and mesoionic thiazolo-[2,3-b]-1,3,4-thiadiazoles (227) and N,N-bisheteroarylamines from the iminophosphorane (226), derived from 3-amino-4-phenylthiazole-2(3H)-thione. The carbodiimides (229), prepared from the iminophosphorane (228), can be converted into quinolines or a-carboline derivatives depending on the nature of the isocyanate used in the reaction with (228) and the reactions of iminophosphoranes (230) and (231) with aryl and styryl isocyanates provide one-pot syntheses of quinoline, a-carboline, and quinindoline derivatives. 9... 

In the presence of ethyl chloroformate or hydrogen chloride in toluene, 2-acylated 1-(diphenyl-methyl)-l,2-diazetidin-3-ones (321) undergo a novel ring expansion to 4/7-l,3,4-oxadiazin-6(5 -ones (322) in excellent yields (Equation (21)) <84JOC2204>. 

Special ring-openings are [2+2] cycloreversions (oxetan-2-ones, 1,2-dioxetanes, l,2-dioxetan-3-ones, 1,2-diazetidines, l,2-diazetidin-3-ones) and valence isomerizations (1,2-dithiete, 1,2-dihydro-1,2-diazete). 

Oxetan-2-ones, azetidin-2-ones and l,2-diazetidin-3-ones are more reactive than five- and six-membered homologues. They are attacked by nucleophiles on the C-atom of the carbonyl group. Ring-opening occurs to give y-substituted carboxylic acids or carboxylic acid derivatives. 

Dihydro-3-oxo-lH-imidazo[l,2-a]bcnzimidazoles from l-apyl-2-cyano-l,2-diazetidin-4-ones... 

Disubstituted hydrazines and semicarbazones react with a-haloacyl halides under two-phase catalytic conditions to produce l,2-diazetidin-3-ones (20-85%) [35], whereas (3-haloacyl halides react with hydrazines to form pyrazolin-3-ones (ca. 30%). 

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