Ring contraction lactams

Depending on their structural details, bicyclic amidines and amidinium salts hydrolyzed by K0H/H20 give ring-enlarged or ring-contracted lactams when hydrolyzed by K0H/H20 [8]. 

The reaction sequence is successful because reverse, ring-contraction reactions are unlikely and because only the final product contains a secondary lactam group, which is depro-tonated under the reaction conditions. 

Several ring contraction routes to /3-lactams have been developed. One of the most important is the photochemical Wolff rearrangement of 3-diazopyrrolidine-2,4-diones (178), which provides a general route to 3-carboxyazetidin-2-ones (179). Lack of stereoselectivity is a problem, but facile epimerization is possible because of the electron withdrawing 3-substituent (78T1731). 

A variety of mono- and bi-cyclic /3-lactams have also been prepared by oxidative ring contraction of pyrrolidine-2,3-diones (180) (75JOC2356), and by the photolysis of pyrazolidin-3-ones (181) (78T1731, 75JOC3510, 75JOC3502, 75CC725). 

A third approach to 3-amino-/3-lactams is by Curtius rearrangement of the corresponding acyl azides. These are readily prepared from r-butyl carbazides, available via photochemical ring contraction of 3-diazopyrrolidine-2,4-diones in the presence of f-butyl carbazate (c/. Section 5.09.3.3.2). Thus treatment of (201) with trifluoroacetic acid followed by diazotiz-ation gives the acyl azide (202) which, in thermolysis in benzene and subsequent interception of the resulting isocyanate with r-butanol, yields the protected 3-amino-/3-lactam (203) (73JCS(P1)2907). 

In analogy to Edstrom s experiments, the nine- and ten- membered ring lactams underwent regio and stereoselective transannular ring contractions to give the corresponding indolizidinones and quinolizidinones, respectively (vide supra Scheme 56) (Table 21) [61]. 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

Diastereoselective intramolecular 1,3-dipolar cycloadditions of alkylidene-cyclopropyl nitrones provide spirocyclopropylisoxazolidines. These compounds have been shown to undergo either thermally induced ring expansion to octahydro[l]pyrindin-4-ones or to acid induced ring contraction into fS-lactams with concomitant loss of ethylene (Scheme 2.218) (710-716). Use of chiral auxiliaries, that is (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles (715). 

When acted upon by phosphorous acid, the polymethylenediamides (60) afford the novel diphosphonic acids (61),53 while lactams are converted into the related compounds (63).64 The pyrrol idonebis(phosphonic acid) (62) is evidently obtained by ring contraction of the acid (61 n = 2).55... 

The diverse chemistry of carbenes is beyond the scope of this account, but a few typical reactions are shown here to illustrate the usefulness of the photochemical generation of these reactive species. A carbene can insert into a C—H bond, and this finds application in the reaction of an a-diazoamide to produce a P-lactam (5.29). Carbenes derived from o-diazoketones can rearrange to ketenes, and thus a route is opened up to ring-contraction for making more highly strained systems <5.301. Carbenes also react with alkenes, often by cycloaddition to yield cyclopropanes in a process that can be very efficient (5.31) and highly stereoselective (5.321. 

Many photo-induced ring contractions are known. An illustrative example is the isomerization of tetrahydrothiin-4-one into a zwitterion before loss of ethylene (Scheme 30) (70JOC584) pyrazolidinones give (3-lactams (Section 3A2.3.3). 

A new /3-lactam synthesis has been devised which relies on the formal ring contraction of the A3-pyrrolinone (271), readily prepared from commercially available mucochloric... 

Rezaie and Bremner reported the synthesis of tricyclic 1,4-thiazepines by ring contraction. OT-Cyclophane lactam 237 was treated with Ar-bromosuccinimide and azoisobutyronitrile to yield 47% of dihydroindole derivative 238, as the major product next to side products 239-242 (Scheme 42). The same reaction condition was applied for the ester derivative of 237 (X = COOCH3>, but with longer reaction time. This resulted in indole analogues 240-242 (X = COOCH3) without the formation of dihydroindole derivatives. Bromination on the aromatic ring was observed prior to the intramolecular cyclization. The exact mechanism has not been resolved, but a possible reaction sequence could be... 

Aminothiocarboxylic acids react with aldehydes and 3-dimethylamino-2-isocyanoacrylic acid methyl ester following the pathway described for /7-aminoacids, affording, after ring contraction of the seven-membered intermediate 87, Michael-type cyclization and /7-elimination, /7-lactam 88 equipped with a thiazole... 

The array of dienophiles amenable to these hetero Diels-Alder reactions is not limited to enol ethers and enamines since allylsilanes and simple alkenes have also been successfully employed [370, 371]. More recently, it has been shown that methoxy allenes such as 4-41 undergo formation of 6H-l,2-oxazines 4-43 upon cycloaddition to nitrosoalkenes such as 4-34 and subsequent tauto-merisation of the intermediate exo-methylene compound 4-42 (Fig. 4-9) [372, 373]. In these studies, 4-43 proved to be a versatile synthetical intermediate allowing oxidative demethylation or reductive removal of the methoxy group as well as nucleophilic substitutions after the generation of an azapyrylium ion [372 - 374]. Furthermore, ring contraction reactions of these oxazines leading to pyrroles [373] and y-lactames [375] are known. 

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