Azetidines preparation

While these rearrangements are used most often to prepare large rings, it should be noted that the expansion of cyclopropane derivatives to azetidines is also practical (Scheme 6 Section 5.09.3.3.3.a). 

Azetidine was first prepared in low yield and impure form in 1888 by treatment of 3-bromopropylamine with base (1888CB2669). Various modifications of the standard cyclization procedures have been reported (79CRV331), but by far the most efficient synthesis to date, which utilizes only readily available materials, is that outlined in Scheme 6. 

A number of 2-acylazetidines have been prepared by reaction of 1,3-dihaloacyl compounds with amino derivatives (Section 5.09.2.3.l(m)). This is illustrated for azetidine 2-carboxylic acid (56), the only known naturally occurring azetidine. Ring expansion of activated aziridines (43) and contraction of 4-oxazolines (55) has also found limited use (Section 5.09.2.3.2(f) and Hi)). 

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

Af-Halogeno-, fV-nitroso- and hence fV-amino-azetidines have been prepared from azetidines by reaction with positive halogen reagents and nitrosating agents, respectively (Section 5.09.2.2.3). 

It is often necessary to prepare /3-lactams with particular substituents at N-1, C-3 and C-4, e.g. in the preparation of fused /3-lactams from monocyclic precursors. For reasons of space it is not possible to give an exhaustive list of the variously substituted /3-lactams available however, Table 4 summarizes the most general routes to /3-lactams bearing particular substituents at C-3 and C-4. -Substitution of azetidin-2-ones has already been dealt with cf. Section 5.09.3.2.3). N-Unsubstituted /3-lactams and protected 3-amino-/3-lactams are particularly important synthetic intermediates and methods of preparing these are discussed below. 

AT-Unsubstituted azetidin-2-ones are versatile intermediates in the preparation of a variety of novel /3-lactam containing systems. They are usually made either by reductive dechlorosulfonylation of alkene/chlorosulfonyl isocyanate cycloadducts cf. Section 5.09.3.3.2), which... 

The methods of preparation of azetidine derivatives with exocyclic unsaturation, other than azetidin-2-ones, are summarized in Table 5. 

The secondary amines used in the preparation of enamines have been primarily simple dialkylamines or cyclic amines of five- or higher-membered rings. Azetidine (4) yields a stable enamine with cyclopentanone (28). No simple enamines formed by condensation of ethylenimine (5) or a substituted ethylenimine with an aldehyde or ketone have been reported. 

The preparation of isothiazolidin-3-one 5-oxide and 5,5-dioxide derivatives of azetidin-3-ones was described (99EUP100069), starting from penicillanic acid sulfoxide amides in the presence of halogenating agents in anhydrous inert solvents or even without them. Through rearrangement and oxidation with conventional methods, compounds 73 could be obtained. For some derivatives the usefulness, as intermediates for the preparation of novel p-lactam analogs or active substances in formulations for antimicrobial therapy, is claimed. 

Enantiopure 3-phenyl-2-cyanoazetidines (S)-238 and (K)-238, which are epimeric at C2, are prepared in high yields from (K)-phenylglycinol. A one-pot sequence, including addition of organohthium or allyhnagne-sium bromide to the cyano group and in situ reduction of the resulting imine with sodium borohydride, allowed for the preparation of 2-(l-aminoalkyl)azetidines, which were then protected as N-Boc derivatives (R,S)-239 and (S,it)-239 [112] (Scheme 36). Complete anti diastereoselectivity (dr more than 95 5 by NMR) was observed in both cases. The same sequence... 

On the other hand, other chiral dirhodium(II) tetracarboxylate catalysts based on azetidine- and aziridine-2-carboxylic acids have been prepared by Zwanenburg et al. and submitted to the cyclopropanation of styrene with... 

P-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiAlhL is a powerful method for the synthesis of stereodefined aziridines and azetidines <06OL1101>. However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cw-disubstituted pyrrolidines and piperidines 32 <060L1105>. During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of a peptide-... 

The enantioselective preparation of trans-2,4-disubstituted azetidines 4 by treatment of 3 with methanesulfonyl chloride and triethylamine followed by benzylamine at 45 °C has been reported. A-Arylation of the debenzylated 4 has given 5 in yields of 32-96% by use of rac-Binap and moderate reaction temperatures to suppress racemization of the amines . Azetidines can also be formed from certain oxetanes (see 4.2.3) and from P-Iactams (see 4.3 and 4.6) <99JOC9596>. 

Correspondingly, 4-acetoxy-2-azetidin-one (102) was prepared from 4-carboxy-2-azetidinone (101) by a non-Kolbe reaction (Eq. 13) [123],... 

Derivatives of azetidine were prepared from a-, /3-, or y-AA. L-Threonine was transformed in eight steps into 4... 

A number of nitramine-nitrate explosives have been prepared by Millar and co-workers from the action of dinitrogen pentoxide on aziridines and azetidines (Section 5.8). Millar and co-workers used their aziridine ring-opening nitration methodology (Section 5.8.1) to synthesize the high performance melt-castable nitramine-nitrate explosive known as Tris-X... 

Tetrahydro-2-pyrimidinone 951 derivatives are produced by the palladium-catalyzed reaction between 2-vinyl-azetidines 950 and isocyanates, while tetrahydro-2-pyrimidinimines 952 can be prepared under similar conditions using diarylcarbodiimides <2001SL914>. 

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