Azetidin 2-methylene

Highly electrophilic P-lactams such as 36 and 38 have been shown to react with stabilised phosphoranes to yield azetidin-2-methylenes 37 and 39 [30] respectively (Scheme 13). However this reaction did not occur with less reactive P-lactams e.g. monocyclic P-lactams or cephem derivatives. The olefins 37 and 39 can be used as protected P-lactams they are much more stable to basic and nucleophilic conditions, and they readily regenerate P-lactams by ozonolysis [30]. The de-esterification of 37 and 39 by conventional methods gave the acids (R = H) which are very weak antibacterial agents or P-lactamase inhibitors. 

Corey s ylide (1), as the methylene transfer reagent, has been utilized in ring expansion of epoxide 75 and arizidine 77 to provide the corresponding oxetane 76 and azetidine 78, respectively. 

Axenrod and co-workers reported a synthesis of TNAZ (18) starting from 3-amino-l,2-propanediol (28). Treatment of (28) with two equivalents of p-toluenesulfonyl chloride in the presence of pyridine yields the ditosylate (29), which on further protection as a TBS derivative, followed by treatment with lithium hydride in THF, induces ring closure to the azetidine (31) in excellent yield. Removal of the TBS protecting group from (31) with acetic acid at elevated temperature is followed by oxidation of the alcohol (32) to the ketone (33). Treatment of the ketone (33) with hydroxylamine hydrochloride in aqueous sodium acetate yields the oxime (34). The synthesis of TNAZ (18) is completed on treatment of the oxime (34) with pure nitric acid in methylene chloride, a reaction leading to oxidation-nitration of the oxime group to em-dinitro functionality and nitrolysis of the A-tosyl bond. This synthesis provides TNAZ in yields of 17-21 % over the seven steps. 

Calculations at the MP2(Full)/6-31++G(d,p)//MP2(Full)/6-31+G(d) level of theory were used to investigate the SN reactions between ammonia and aziridine, aze-tidine, methylethylamine, and four fluorinated derivatives of aziridine.52 The results show that aziridine and azetidine have strain energies of 27.3 and 25.2 kcalmol-1, respectively, and that as a consequence they react 7.76 x 1023 and 2.30 x 1017 times faster with ammonia than does the methylene group of methylethylamine. However, even after subtracting the effect due to the release of ring strain, aziridine still reacts much faster than the other two substrates. This is because the electrostatic attraction of the charges in the product-like dipolar transition state are much greater for aziridine. 

Several H and 13C NMR data of azetidines and azetidin-3-ones have been reported. A significant variation is observed in geminal coupling constants of the methylene group attached to nitrogen of different classes of azetidines. The substituents at the nitrogen atom and the conformations of the compounds appear to affect the J values. 

The reaction of iV-benzylidene l-methoxyaniline with the lithium enolate derived from ethyl 3-ferrocenylpropanoate 472 provided an easy access to azetidin-2-ones 473 and 474 with ferrocene tethered to the C-3 position through a methylene group (Equation 192) <2001JOC8920>. However, the azetidin-2-one 475, formed in the reaction of an enolate with the imine of ferrocene carbaldehyde, furnished an amide 476 by N(l)-C(4) cleavage (Scheme 66). 

Substituted azetidine 2-phosphonic acids 4 were prepared in enantiopure form via N-alkylation of the starting P-amino alcohols with a methylene phosphonate moiety, followed by sequential chlorination and stereoselective 4-exo-tet ring closure <02TL4633>. 

Amino-3-methoxy-2-(3-pyridyl-methylen-amino)-E15/2, 1809 [(NC)2CH-NH2 + R-CHO] Azetidin 3-Azido-4-(4-methyl-phenyl)-2-oxo- E16b, 371 (Nj-C-CO-Cl + Imin) Furazan 4-(Anilinomethylen-amino)-3-methyl- E8c, 673 (NH2 -> N=CH —NH —Ar) Hydrazin l,2-Bis-[2-pyrrylme-thylen]- -1-oxid X/2, 121 1 H-(Imidazo 1,2-a]-l,3,5-benzotriaze-pin), 10-Hydroxy-2,3-dihydro E9d, 476 [1 -(2-NH2 — Ar) — 2-imino — imidazolidin/COCl2) Imidazo[4,5-f indazol 5,6-Dimethyl-... 

Aza-trieyclo 3.3.2.0J ]-deca-2,6,9-trien 9-Methoxy- E17b, 1219 (Lactam - Ester-imid) 3H-Azepin 2-Butyloxy- E9d, 158 (02N — Ar + RjP/R-OH) Azetidin l-Cyclohexyl-3-methylen-2-oxo- E16b, 136 (aus HO —A — CO-NHR)... 

Azetidin l-Benzyl-3-methylen-2-thiono- E16b, 907 (=0 - =S) 1,3-Benzothiazol... 

Azetidines. N-Arylsulfonyl-2-phenylazetidines (2) can be prepared from N-arylsulfonyl-2-phenylaziridines (I) by methylene transfer from dimethyloxo-sulfonium methylide. 

Cp2TiMe2 is a suitable reagent for the methylenation of heteroatom-substituted carbonyl compounds in the reactions with a- and /3-lactams (Scheme 522). It reacts with l-aryl-2-azetidinones with the formation of methylene azetidine compounds. Analogous reactions with aziridinines afford methylene aziridine compounds.1339... 

A highly efficient cyclization of 2-chloro-4-sulfonamino-l-alkenes to 2-methylene-azetidines provides an avenue to P-lactams, e.g., on ozonolysis of the products. Pertinent to cyclization of bromoallyl bromohomoallyl carbinols is the chemo/regioselectivity. It is actually dependent on the nature of the promoter, Cul or Pd(OAc)2. ... 

As shown in Scheme 4, a new approach to 3-methylene-azetidin-2-ones has been described. The reaction of the acrylamide (16) with n-butyl-lithium, followed by the addition of toluene-4-sulphonyl chloride, gives the azetidinone (17), in 60% yield. In the same paper it is reported that lithium phenylethynolate reacts with imines (in a highly stereoselective manner) to form azetidinones, in a promising new approach to functionalized azetidinones. 

A new method for the preparation of 3-methylene-azetidine-2-one using 2,4,6-tri-isopropylbenzenesulfonylhydrazone has recently been reported by Barrett and coworkers63. The a-lithioacrylate 137 is generated on treatment of the 2,4,6-tri-isopropylbenzenesulfonylhydrazone of an a-keto amide (136) with excess of buLi in DME. The reactions of 137 with aldehydes give 3-hydroxy-2-(methylene)alkanamides 138, which on treatment with tosyl chloride in THF give the 3-methylene-/Mactams 139 in good yields (equation 76)63. 

Isocyanides readily undergo cycloaddition reactions, and these are very valuable in the formation of heterocyclic rings. Reaction of j5-nitrostyrene with an alkyl isocyanide gives a hydroxy indole (146). Reaction proceeds even more readily between tosylmethyl isocyanide (147), in which the methylene is activated, and aryldiazonium compounds. With ketenes, isocyanides give imino lactones. However, with r-butylcyanoketene, the reaction follows a different pathway involving the carbonyl bond of the ketene, to yield 148. A [1 + 3] cycloaddition of an isocyanide to a 1,3-dipole has been used to prepare azetidines. The method has been used for synthesis of a number of azetidines . 

Nitrato-N-nitramines. A soln. of startg. aziridine in methylene chloride treated with 1.25 eqs. N2O5 at -10 to —5° for 0.5 to 1 h - product. Y 70%. Reaction is only applicable with strained N-heterocyclics (aziridines, azetidines). F.e.s. P. Golding et al., Tetrahedron Letters 29, 2735-6 (1988). 

Four-membered Rings.— This Section will include examples of /3-lactam synthesis since these molecules serve as interesting intermediates for the preparation of antibiotics, both natural and synthetic, and as fascinating molecules in their own right. Methylene transfer for conversion of aziridines into azetidines has been little explored. The reaction of dimethyloxosulphonium methylide with... 

Some work published by Barrett and his group, related to that mentioned earlier, describes how 3-methylene-azetidin-2-ones (73) may be formed from l-lithio-oxy-l-lithio-aminoallene derivatives (72) by reaction with aldehydes followed by manipulation as shown in Scheme 6. 

Wassermann has reported (19—21) the synthesis of ( )-3-ANA by way of the P-lactam (25). Various methods were used to prepare (25), such as cyclopropane ring expansion of (24), cyclisation of (26) or acylation of the azetidine carboxylate (27). In another approach (22) the a-methylene P-lactam (28) has also been elaborated to 3-ANA via the use of (29). 

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