Carboxamides from acid anhydrides

Carboxamides form rather unstable 1 1 adducts with HFA insertion into one N—H bond occurring as with urea 202). Addition of another molecule of HFA can only be effected by salt formation with pyridine. The addition is reversible. A stable product 125a is obtained from urea in the presence of acetic acid anhydride 257). Thiourea forms the corresponding oxadiazin-thione 125b with HFA (257). 

Hydrolysis of acid chlorides, acid anhydrides, esters and carboxamides leads to the carboxylic acid, although these compounds are often derived from a carboxylic acid group in the first place (Scheme 5.5). Nitriles are usually derived from amines via diazotization and reaction with copper(I) cyanide (see Chapter 8) and so the hydrolysis of a nitrile group is of more value. In all cases, alkaline hydrolysis gives the salt of the acid, from which the free acid is obtained by addition of mineral acid. 

Adducts (6) and (7) from amides and chlorophosphoric acid aiyl esters or dichlorophosphoric acid aryl esters respectively are well known. - The adducts are formed in a 1 1 ratio. They have been applied to the synthesis of mixed anhydrides from diarylphosphoric acids and carboxylic acids, as well as mixed substituted esters of pyrophosphoric acid. The adduct formation between primary or secondary carboxamides and dichlorophosphates has been used to prepare nitriles and isonitriles respectively. The adduct from DMF and phenyldichlorophosphate is a useful reagent for the preparation of carboxylic acid esters from the corresponding acids and alcohols, 3-lactams from imines and carboxylic acids," carboxylic acid anhydrides, carboxylic acid esters and thiol esters. Adducts of amides with ester amides or diamides of chlorophosphoric acid have been studied. ... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Substituted and /V,7V-disubstituted 4-oxo-4//-pyrido[l,2-a]pyrimi-dine-3-carboxamides and -3-acetamides 428 (n = 0,1) were prepared from the corresponding carboxylic acid 427 when the carboxylic acids were reacted first with methyl chloroformate in the presence of triethylamine in chloroform at -20°C, after which the mixed anhydrides were treated with an amine at - 10°C overnight (89EUP326981). 

Treatment of the sulfinamide anhydride, prepared from anthranilic acid and thionyl chloride, with carboxamides and thiocarboxamides 1 affords quinazolin-4(3//)-ones 2. Thiocarbox-amides, being much more easily dissolved than carboxamides in nonprotic solvents such as benzene, are more suitable as starting materials. This approach has been used by Kametani et al. in the synthesis of the quinazoline alkaloids glomerine, homoglomerine, chrysoginc, and glycosminine. " ... 

Carboxamides of the tricyclic compounds 244 (n = 1, R = CONH2) and 389 (w = 1, R = CONH2) were obtained from the appropriate esters or from carboxylic acids with ammonia, via mixed anhydrides. N-Substi-tuted carboxamides of the pyrido[l,2-fl]quinazolinones 211 (R = CONHR ) were prepared directly from the corresponding acids with amines in the presence of diphenylphosphoryl azide and triethylamine in dimethyl-formamide at — S C " or were obtained from esters with amines. ... 

Amide formation. Carboxamides including peptides are S3mthesized from carboxylic acids and aUcyl azides, after converting the acids into mixed anhydrides and then selenocarboxylates. Treatment of the mixed anhydrides with a suspension of freshly prepared from LAH and Se completes the first stage of the transformation. 

The JV-unsubstituted carboxamide 95 (R=H) can be prepared if the ester 90 is allowed to stand for about a week at room temperature in methanol containing 25% ammonia [58,112], A-Substituted derivatives of 95 were prepared from Boc- or Z-protected amino acids with mixed anhydride methods, using isobutyl chloroformate and the corresponding amine [78, 84, 113-115]. 

Preparation of aziridine-2-carboxamides via aminolyses of mixed anhydrides formed from potassium salts of the corresponding acids... 

Some reviews on the preparation of cyanides from aldoximes [1045, 1046] and from carboxamides [1047,1048] are available. Often used dehydration reagents are acetic anhydride for aldoximes and phosphorus pentoxide for carboxamides. In the following sections, dehydration reactions affording cyanides are described with various dehydration reagents, classified into acidic and basic reagents. 

Biological tests show that 3-carboxamide (251), compared with cephalothin, displays equal Staphylococcus activity but is less active against other bacteria (Table XXVII). Other 3-carboxamides were prepared from the 3-carboxylic acid chlorides or mixed anhydrides (U.S. Patent 3,953,436). The 3-nitrone derivative was also used to prepare various five-membered heterocyclic rings at C-3 via 1,3-dipolar cycloaddition reaction with various dipolarophiles. In general, these derivatives showed considerable loss in biological activity (Spry, 1975a,b). 

However, the use of phenyl )V-phenylphosphoramidochloridate as a condensing agent for carboxylic acids and amines yields carboxamides in a one-step method (eq 7). The amide (12) is prepared from the carboxylic acid, 2 equiv of triethylamine, 1 equiv of amine, and 1 equiv of reagent (1) and isolated by filtration or evaporation of solvent and washing with water. Once again, a mixed anhydride intermediate (13) is presumed, which results from nucleophilic attack by the carboxylate anion on the phosphorus atom with elimination of a chloride ion a further nucleophilic attack by the amine on the carbonyl group of (13) and breakdown of the complex yields the amide (12) and phenyl Af-phenylphosphoramidate (14) which can be recycled to (1) by reaction with phosphorus pentachloride. 

---