Lactams, reaction with hydrazoic acid

Finally, the Eschenmoser-Claisen rearrangement has found appUcations in drug synthesis. Mulzer s synthesis of the antidepressant (J )-rolipram serves as an example (Scheme 7.36) [84]. Rearrangement of chiral cinnamyl alcohol 104 gave unsaturated amide 105 with Uttle erosion of optical purity. Ozonolysis and reduction afforded alcohol 106 and set the stage for a subsequent Mitsunobu reaction with hydrazoic acid. Reduction of the azide function followed by intramolecular transamidation gave y-lactam 107, which was converted into (R)-rolipram in two straightforward steps. 

The Schmidt reaction of cyclic ketones with hydrazoic acid affords convenient access to ring-expanded N-unsub-stituted lactams but extension of this process to alkyl azides to provide Aralkyl lactams is capricious in nature. A protocol... 

Reactions of cyclopropanones with nucleophiles frequently lead to ring enlargement reactions since the formation of four-membered rings from the reactive intermediates is accompanied by a considerable reduction in strain energy. Thus, 2 reacts with diazomethane to form cyclobutanone96>, with hydrazoic acid to form (3-lactam 76,89) and, under special conditions, with amines and hydroxyl amine derivatives to form N-sub-stituted (3-lactams 87> (Scheme 24). 

An unusual Schmidt reaction has been observed with ketone (56) <95H(40)223>. When the reaction is carried out using hydroxylamine 0-sulfonic acid/formic acid, the expected ring expansion to the tetrahydropyridinones occurs. With hydrazoic acid, however, the unexpected 1,3-diazepine system is obtained (58). This observation is rationalized by the intermediate (57), formed by addition of hydrazoic acid to the initially formed lactam, which then undergoes a Huisgen rearrangement. 

The Schmidt reaction of carboxylic acids with hydrazoic acid has the advantage over Curtius rearrangement that it is only one step from the acid to the amine, but the conditions are more drastic (usually sulphuric acid plus sodium azide). Under these harsh conditions, the isocyanate intermediate is rarely isolated. For these reasons, the Curtius rearrangement is frequently employed to convert acids to amines. The Schmidt reaction of ketones with hydrazoic acid is a powerful method for the synthesis of amides and lactams. TTiis process is somewhat related to the Beckmann rearrangement of oximes however, the Schmidt reaction is more succinct, allowing the conversion of ketones to amides in a single operation. Considering its widespread... 

The Schmidt reaction of ketones with hydrazoic acid requires the presence of an acid catalyst. Sulfuric acid is the most common catalyst, but Lewis acids have also been utilized. Hydrazoic acid is usually made in situ by treatment of sodium azide with sulphiuic acid. The strongly acidic conditions can bring about decomposition of acid-sensitive substrates and result in undesired by-products. However, the Schmidt reaction can be conducted under mild conditions. For example, various ketones are converted to the corresponding amides or lactams using trimethylsilyl azide or sodium azide in the presence of FeClj in dichloroethane at room temperature. ... 

Reaction of hydrazoic acid with the monoaryl sulphoxides (345) affords benzothiazine oxides (346) and benzothiadiazepine oxides (347), and the same reagent converts the diaryl sulphoxides (348) into the benzothiadiazine oxides (349), which undergo a base-catalysed rearrangement to (350), cf. (228) - (229a). JV-5-Alkylation of the latter occurs on treatment with sodamide and alkyl halides, and reduction of the lactam moiety is brought about by LiAlH4. ... 

The Schmidt reaction with the dienone 11/102 (Scheme 11/15) yields the 1,4-thiazepine, 11/103. Treatment of its dihydroderivate, II/104, gives exclusively the enlargement product 11/105, in which the methylene group migrated [82]. A similar reaction can be observed if the synthetic ergot alkaloid precursors of type 11/106 are treated with in situ generated hydrazoic acid. Again no trace of the isomeric lactam can be observed [83]. 

As noted above, reactions of cyclopropanones with nucleophiles may yield intermediates such as vinyl cyclopropanols which are readily converted to cyclobutanones through carbinyl cations . In like manner, generation of electron-deficient nitrogen species may lead to the formation of ) -lactams by related ring enlargement Hydrazoic acid, amines and hydroxylamine derivatives have all been used in this context as shown in Scheme 12. These reactions are summarized in the examples outlined below. 

Besides inorganic azides or hydrazoic acid, quaternary ammonium azides are also suitable sources of azide for addition across cyclopropanones. However, as indicated above, the azide adducts suffer from ring expansion, especially when elevated temperatures are employed. The reaction of ran5-2,3-di-fert-butylcyclopropanone (8) with tetraethylammonium azide in refluxing chloroform effected ring expansion to yield the -lactam 9. ... 

Lactam of 16-Aminohexadecanolc Acid from Cyclohexadecanone. To a stirred mixture of 50 cc. of concentrated sulfuric acid and 150 cc. of benzene, cooled in an ice bath, is added a solution of 15.3 g. (0.0643 mole) of cyclohexadecanone and 2.9 g. (0.0674 mole) of hydrazoic add in 150 cc. of benzene., After fifteen minutes, ice is added to the reaction mixture, and the benzene layer is separated and washed with a dilute sodium hydroxide solution. The product obtained by concentration of the benzene layer can be purified by distillation (b.p. 171-178°/ mm.), and crystallization of the distillate from acetone. The yield of pure lactam, melting at 125-126°, is 14 g. (86%). 

Benzoic acid, aniline, and several tetrazole derivatives also have been isolated as by-products of this reaction. Essentially the same reaction products have been obtained from phenylglyoxylic anhydride. Hydrazoic add reacts with cyclic ketones in the same way as with open-chain ketones, yielding cyclic amides (lactams) by ring enlargement. ... 

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