4- azetidin-2-one

N-Inversion in azetidine and azetidin-2-one is rapid, even at —77 and -40 °C, respectively (B-73NMR144). Again, halo substituents on nitrogen drastically slow the inversion rate, so that Af-chloro-2-methylazetidine can be separated into two diastereomers (b-77SH(1)54). Substituent effects on N-inversion are much the same as in the aziridines Af-aryl and N- acyl... 

In view of the uneven attention which azetidines, azetines and azetes have received and because of their lack of chemical similarity, they are treated separately in this chapter. Furthermore, because of the considerable literature on azetidin-2-ones, these have been dealt with in their own right, rather than as derivatives of azetidine. 

There are few examples of formation of simple azetidines from [2 + 2] fragments, although this type of approach is important for certain azetidine derivatives, e.g. azetidin-2-ones (see Section 5.09.3). Nitrogen analogues of the Paterno-Buchi route to oxetanes are rare an example involves the photoaddition of 3-ethoxyisoindolone (37) to the enol ether (38) (75JA7288, 72CC1144). 

S.09.3 AZETIDIN-2-ONES AND RELATED AZETIDINE DERIVATIVES 5.09.3.1 Structure... 

Azetidin-2-one (SO) is a hydrolytically sensitive, colourless solid, m.p. 73-74 °C (75LA2195). Other simple azetidin-2-ones are usually low-melting solids or oils (74LA539) icf. Table 3). 

Table 3 Physical Properties of Some Azetidin-2-ones...

The most informative feature of the IR spectra of azetidin-2-ones is generally the /3-lactam carbonyl absorption, the frequency of which is affected by substitution and by fusion of the ring (c/. Table 3). Thus, IR spectra of simple monocyclic /3-lactams generally have absorption maxima in the region 1730-1760 cm while the fused 2- and 3-cephem systems (60) and (61) show IR maxima in the regions 1772-1784 and 1782-1792 cm S respectively (b-72MI50900 p. 318). 

IR spectra of systems related to /3-lactams show the expected trends in the frequency of the carbonyl absorption, where present. For example, the presence of an exocyclic double bond at C-4 in an azetidin-2-one raises the value of vc=o considerably. Thus the 4-thioxoazetidin-2-one (62 Z=S) and the derived 4-alkylidene systems (62 Z = CR R ) exhibit /3-lactam carbonyl absorptions at 1835 and 1800-1810 cm respectively (80JOC1477, 80JOC1481), while the 4-iminoazetidin-2-ones (63) have vc=o at 1800-1825 cm (81CC41). Additional spectral data for these and similar systems may be found in the references in Table 5. 

Azetidin-2-ones are the most extensively studied derivatives of azetidine, largely as a result of the discovery of the antibacterial properties of penicillins, cephalosporins and... 

Despite the strained nature of the azetidin-2-one system, a surprising number of transformations in which the /3-lactam is preserved can be carried out, and some of these will be dealt with in subsequent sections. The highly hindered /3-lactam l-benzyl-3,3,4-triphenyl-azetidin-2-one is claimed to be stable towards hydrochloric acid, sodium and potassium hydroxides, LAH and phenylmagnesium bromide (80IJC(B)702). 

Irradiation of the A-bromo- or N- chloro-azetidin-2-ones (71) in the presence of alkenes, alkynes or radical donors induces rearrangement to the /3-haloalkyl isocyanates (72) via a... 

O-Alkylation of A-unsubstituted /3-lactams to give the corresponding 2-alkoxy-l- etines can be achieved by reaction of the azetidin-2-ones with hard electrophiles (trialkyloxonium tetrafluoroborates) followed by treatment with base (cf. Section 5.09.4.3.1) (67JHC619, 69LA(725)124). In contrast, reaction of the A-unsubstituted azetidin-2-ones (73) or their derived anions with a variety of softer electrophiles results in A-substitution, and some representative reactions are illustrated in Scheme 7. 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

Azetidin-2-ones are also cleaved by amines and other nucleophiles (75S547 p. 579). In some cases other heterocycles are produced (cf. Section 5.09.3.2.6). 

Ring expansions of suitable /3-lactams can also be achieved on treatment with base rearrangement of the Af-substituted azetidin-2-ones (133) occurs in the presence of LDA to give (134) (72JA9261). Aminolysis of the /3-lactam epoxide (135) and the aldehyde (137) affords (136) and (138) respectively (81JHC1239). 

A number of azetidine derivatives related to azetidin-2-ones are known (Table 5 see Section 5.09.3.3.5). For many of these, minimal studies of reactivity have appeared. The information available, however, suggests that their reactivity is fairly predictable. This is Illustrated for a few specific examples Table 5 gives leading references for other systems. 

Azetidin-2-one formation by N—C(4) ring closure has also been observed in the irradiation of cfs-a-phenylcinnamides (143) in degassed benzene. Both cis and trans lactams are formed (68JA2333). 

There appear to be few examples of the formation of azetidin-2-ones by closure of the C(2) —C(3) bond. One reaction which fits into this category involves reaction of the iron carbonyl lactone complexes (144) with an amine to give the allyl complexes (145) which on oxidation are converted in high yield to 3-vinyl-/3-lactams (146) (80CC297). 

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... 

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. 

O-Alkylation of the readily available iV-unsubstituted azetidin-2-ones (/3-lactams) constitutes a versatile route to 2-alkoxy-l-azetines (cf. Section 5.09.3.2.3). Thus treatment of the /3-lactams (266) with trialkyloxonium tetrafluoroborates followed by basification affords the 2-alkoxy-l-azetines (267) in moderate yields (67JHC619,69LA(725)124). Similar treatment of the azetidine-2-thiones (268) (available from thiation of the corresponding /3-lactams with phosphorus pentasulfide) affords the analogous 2-ethylthio-1-azetines (269) (67JHC619), which are generally more stable than their 2-alkoxy analogues. 

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