Azetidin-2-imines

The synthesis of imino-penam and -cephem derivatives has also been investigated using the [2 + 2] cycloaddition of ketenimines to Schiff bases as the key-step [24]. N-(aryl) and N-(alkyl)ketenimines are not electrophilic enough to react with Schiff bases. On the other hand, iV-(tosyl)ketenimines 25 were susceptible to nucleophilic attack by imines (Scheme 9). They were readily generated in situ from the corresponding sulphimides 23. The a-bromo-iminium bromide intermediates 24 reacted with Schiff bases and triethylamine to give JV-(tosyl)azetidin-2-imines 26. 

This one-pot procedure was successfully applied to the preparation of various functionalised monocyclic azetidin-2-imines [24] (Scheme 10). 

As an substitute for ketenes, keteniminium cations can also react with imines to afford /3-lactams. It has been found that ketoketenes give better yields of cycloadducts than do ketene iminium salts, whereas aldoketene iminium salts prevail in corresponding aldoketenes in respective reactions. In addition, ketenimines bearing an electron-withdrawing group (e.g., tosyl, cyano) on the nitrogen atom can react with imines to furnish azetidin-2-imines. ... 

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. 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

The reactions of ketenes or ketene equivalents with imines, discussed above, all involve the imine acting as nucleophile. Azetidin-2-ones can also be produced by nucleophilic attack of enolate anions derived from the acetic acid derivative on the electrophilic carbon of the imine followed by cyclization. The reaction of Reformatsky reagents, for example... 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

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... 

The direct, stereoselective conversion of alkynes to A-sulfonylazetidin-2-imines 16 by the initial reaction of copper(l) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated A-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of A-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been... 

As mentioned in chapter 4.2.3, aliphatic imines are photochemically rather unreactive. When the C—N double bond is conjugated to an electron withdrawing group (e.g. carbonyl group), as in O-alkyl derivatives of succinimide and phthalimide, the reactivity increases and azetidines are obtained in cycloadditions to olefins486). A somehow similar example is the photoaddition of a 6-azauracil derivative to 2,3-dimethyl-2-butene... 

Lithium ester enolate addition to imines has been used for the construction of optically active p-lactams, e.g. 64 and the lithium enolates have been found to be superior to other metal derivatives for both yields and diastereoselectivity in some cases <00H(53)1479>. Immobilized lithium ester enolates have been utilized for the first time <00OL907> and soluble polymer supported imines were used to obtain N-unsubstituted azetidin-2-ones under mild conditions <00CEJ193>. Both lithium and titanium enolates have been employed to obtain cholesterol absorption inhibitors <99TA4841>. Lithium ynolates 65 add to imines to provide P-lactams in good to excellent yield <00TL5943>. 

The [2 + 2]-cycloaddition reactions of l,3-di-tert-butylallene-l,3-dicarbonitrile (go) with imines afford azetidines [60]. The nitrogen atom of the imine was attached to the central carbon atom of the allene to give 2-methyleneazetidines. 

A new electrolysis system comprising two metal redox couples, Bi(0)/Bi(III) and A1(0)/A1(III), has been shown to be effective for electroreductive Barbier-type allylation of imines [533]. The electrode surface structure has been correlated with the activity towards the electroreduction of hydrogen peroxide for Bi monolayers on Au(III) [578], Electroreductive cycliza-tion of the 4-(phenylsulfonylthio)azetidin-2-one derivative (502) as well as the allenecarboxylate (505) leading to the corresponding cycKzed compounds (504) and (506) has been achieved with the aid of bimetallic metal salt/metal redox systems, for example, BiCh/Sn and BiCh /Zn (Scheme 175) [579]. The electrolysis of (502) is carried out in a DMF-BiCh/Py-(Sn/Sn) system in an undivided cell by changing the current direction every 30 s, giving the product (504)in 67% yield. 

Terminal alkynes readily react with coordinatively unsaturated transition metal complexes to yield vinylidene complexes. If the vinylidene complex is sufficiently electrophilic, nucleophiles such as amides, alcohols or water can add to the a-carbon atom to yield heteroatom-substituted carbene complexes (Figure 2.10) [129 -135]. If the nucleophile is bound to the alkyne, intramolecular addition to the intermediate vinylidene will lead to the formation of heterocyclic carbene complexes [136-141]. Vinylidene complexes can further undergo [2 -i- 2] cycloadditions with imines, forming azetidin-2-ylidene complexes [142,143]. Cycloaddition to azines leads to the formation of pyrazolidin-3-ylidene complexes [143] (Table 2.7). 

The thermodynamics and shock-tube kinetics of pyrolysis of azetidine, in argon at high dilution, have been compared with those for trimethylene oxide, sulfide and imine. ... 

Cationic polymerization of 4-membered imines (IUPAC azetidines) generally follows the same patterns as the aziridines [Matyjaszewski, 1984a,b Muhlbach and Schulz, 1988]. Imines are generally unreactive toward anionic polymerization presumably because of the instability of an amine anion (which would constitute the propagating species). The exception occurs with V-acylaziridines as a result of the electron deficiency of the nitrogen coupled with the highly strained 3-membered ring. 

Azetidin-2-ones with general strueture (299) have been synthesized from the reaetion of 5-aminotetrazole with amino aeid esters <84TL91l) and from addition of glyeine enolates to N-(tetrazol-5-yl)imines <84TL3849>. A number of these eompounds displayed moderate to potent... 

A number of cycloadditions of imines or imino compounds with a variety of alkenes, including allenes (88HCA1025), vinyl ethers (88TL547), methyl acrylate (86ZOR636), ketene acetals (87JOC365) and electrophilic alkenes (85T1953), afford functionalized azetidines. 

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