Lactams carboxylic acid azides

In synthetic target molecules esters, lactones, amides, and lactams are the most common carboxylic acid derivatives. In order to synthesize them from carboxylic acids one has generally to produce an activated acid derivative, and an enormous variety of activating reagents is known, mostly developed for peptide syntheses (M. Bodanszky, 1976). In actual syntheses of complex esters and amides, however, only a small selection of these remedies is used, and we shall mention only generally applicable methods. The classic means of activating carboxyl groups arc the acyl azide method of Curtius and the acyl chloride method of Emil Fischer. 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

Diphenylphosphoryl azide (DPPA) 58 was first introduced as a reagent for peptide synthesis by Yamada in 197233 and has been widely used since it gives good yields and very little racemization. It may also be used to bring about a modified Curtius reaction in which a carboxylic acid, R CC H and an alcohol, R2OH, react in the presence of triethylamine to afford the carbamate R1 NHCO2R2.33 In Protocol 15, the use of DPPA to form a macrocyclic lactam 61 is illustrated. The 82% yield of the product using this method should be compared with the value of 24% for reaction of the bis(acid chloride) of 59 with the diamine 60. 

Dehydration. This reagent is useful for synthesis of acyl azides from carboxylic acids, NaCN, and pyridine, with tetrabutylammomum bromide as catalyst (75-95% yield). In combination with pyridine, it effects dehydration of oximes to nitriles in 80-90% yield, P-Lactams can be prepared directly in 40-75 )t yield from carboxylic acids and imines with the reagent (1 equiv,) and triethylamine (excess). In general, a mixture of cis- and rra/j5-azetidinones is formed. 

Thionyl chloride forms a fairly stable primary adduct (15) with DMF, which has been isolated. On heating it decomposes to SO2 and NA -dimethylformamide chloride (equation 4). Treatment of the adduct (15) with carboxylic acids affords iminium salts (16 equation S) in which the carboxylic acid function is strongly activated, e.g. for amide formation. With imines -lactams are formed, sodium azide is converted to acyl azides. ... 

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... 

A soln. of cis-3-benzamidopyrrolid-2-one-4-carboxylic acid hydrazide in 3%-HCl cooled and treated with 10%-NaNO2-soln., the resulting azide (Y ca. 100%) treated with dioxane and heated 1 hr. on a water bath cis-l-benzoyl-4-amino-methylimidazolid-2-one-5-carboxylic acid lactam (Y 77.6%).—The trans-isomer undergoes normal Gurtius degradation. J. Sicher et al.. Coll. 24, 3719 (1959). 

The reactions of HN3 with cyclic alcohols to yield mixtures of ketones, amines, and products with an enlarged ring are catalyzed by H2SO4 [1]. Tertiary alcohols are converted to azides in the presence of acid [12] or TiCU [13]. Aldehydes and ketones with HN3 undergo a Schmidt-type reaction by liberating N2 and inserting NH In the presence of H or Lewis acids [14]. Ketones yield secondary amides and, in the case of cyclic ketones, lactames. Aldehydes are converted to nitriles or N-formylamines. Tetrazole derivatives result with excess HN3 [1, 15]. However, a-azido ethers are obtained from aldehydes and HN3 in the presence of alcohols by catalysis of TiC [16]. Carboxylic acids and anhydrides form amines, N2, and CO2 in Schmidt reactions with HN3. Intermediates are carbamic acids which form by insertion of NH into the R-COOH bond [1, 14]. High yields result for acids of arenes [17]. 

In general, ketones are preferentially attacked by hydrazoic acid when both ketonic and carboxylic groups are present in the same molecule (c/. conversion of 152 to 153 in Scheme 28). Thus, treatment of the ketophenolic acid (159) with sodium azide in phosphoric acid chemo- and regio-selectively gives the lactam-lactone (160) as the sole product (equation 47). "... 

Esterification at room temp, with tetrachloroaluminic acid ether complex has been described The alcoholysis of a-mono-alkylacetoacetates to the corresponding esters and alkyl acetates has been accomplished with excellent yields A new modification of the Curtius degradation avoids the prepn. of acid chlorides by using in their place carboxylic alkoxyformic anhydrides intermediates well-known in peptide chemistry. Among recent developments in this latter field are the use of mixed anhydrides prepared with diphenylketene an improved peptide synthesis via azides prepared with nitrosyl chloride or butyl nitrite instead of aq. sodium nitrite and a rapid synthesis directly from acid hydrazides with N-bromosuccinimide Oligopeptides and /5-lactams have been synthesized from simple starting materials and isonitriles,... 

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