Carboxylic acid amide halides

Alkylmagnesium halide Carboxylic acid amides from esters Bodroux reaction... 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

This latter thought has an important consequence if compounds with C=0 double bonds are sorted in decreasing order of resonance stabilization of their C=0 group they are at the same time sorted according to their increasing propensity to enolization. So as the resonance stabilization of the C=0 double bond decreases from 22 kcal/mol to somewhere near zero in the order carboxylic acid amide > carboxylic acid ester/carboxylic acid > ketone > aldehyde > carboxylic acid chloride/-bromide, the enol content increases in this same order (Figure 12.2). These circumstances immediately explain why no enol reactions whatsoever are known of carboxylic acid amides, virtually none of normal carboxylic acid esters/carboxylic acids, but are commonly encountered with ketones, aldehydes and carboxylic acid halides. 

It reduces esters or lactones selectively in the presence of several other functional groups such as carboxylic acids, amides, nitriles, and halides. Simple amides are not reduced, but tertiary amides are reduced to the corresponding tertiary amines. LiB(C2H5)3H or 9-BBN reduces tertiary amides to the corresponding alcohols. 

Carboxylic acid amide functionalised imidazolium salts can be reacted with group 10 halides directly in the presence of an inorganic base (e.g. K COj) to form homoleptic complexes (see Figure 4.41) [122]. Interestingly, the carbene units are cis to each other and not trans as would be expected (see Figures 4.30 and 4.38). The cis complexation is not aided by hydrogen bonding as the carboxylic acid amide functionality loses its proton upon complexation to nickel. 

The sulfmylation of esters, - lactones, carboxylic acids, > amides and lactams may be effected by reacticm of the corresptHiding lithium enolates in THF at -78 to 0 C with dimethyl or difdie-nyl disulfides, or, less conunmily, with methyl or fdienyl sulfmyl halides. The enolates of ketones, however, are insufficioitly nucleq diilic to react with dialkyl sulfides unless HMPA is added to the re-acticm mixture, although they do react smoothly with diaryl sulfides. This difference allows the selective sulfenylation of esters in the presence of ketones (entry 5, Table 3). ... 

Cyanoborohydride and its modified reagents have been used for reductive dehalogenations. Thus, the combination of sodium or tetrabutylammonium cyanoborohydride, sodium or potassium 9-cyano-9-hydro-9-borabicyclo[3.3.1]nonanate [9-BBNCN] (2) or polymeric cyanoborane (3) in HMPA furnishes an efficient and mild system for the reduction of alkyl halides. The reagents are selective in that other functional groups, including ester, carboxylic acid, amide, cyano, alkene, nitro, sulfone, ketone, aldehyde and epoxide, are essentially inert under the reduction conditions thus, the reduction procedure is attractive for synthetic schemes which demand minimum damage to sensitive portions of the molecule. 

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

From formylation reactions of CH-acidic compounds, which take place if mixtures of carboxylic acid amides and anhydrides are used as formylating agents, it was concluded that the latter compounds form similar adducts to those from amides and acid halides. ... 

A complication can occur when an aliphatic carboxylic acid amide is converted to the corresponding imidoyl halide, because isomerization to the corresponding enamine (IX) occurs. The generated enamine undergoes rapid reaction with the imidoyl halide to form the condensation product X. 

If the imidoyl halides are generated from N,N -disubstituted carboxylic acid amides, or from tetrasubstituted ureas, only iminium salts are formed. 

The reaction of substituted carboxylic acid amides with a variety of halogenating agents, such as phosphorus pentachloride, phosphorus penta-bromide, thionyl chloride, and carbonyl chloride, produces imidoyl halides or iminium halides, depending upon the structure of the amide. For example, a monosubstituted carboxylic acid amide can react with carbonyl chloride to produce the imidoyl chloride I, or its hydrochloride II, if R is aliphatic. 

In many instances, however, it is possible to purify imidoyl halides by vacuum distillation. If the compounds are thermally sensitive, purification can be conducted by solution in nonpolar organic solvents, in which the polar by-products, as well as products formed by self-condensation, are less soluble, or completely insoluble. While it is often difficult to establish melting points, because recrystallization and thereby exposure to moisture results in partial conversion to the corresponding carboxylic acid amides, identification by infrared spectroscopy is a good analytical tool. The characteristic spectral feature of the imidoyl halides is the C=N double bond absorption which occurs at 1650-1689 cm in imidoyl chlorides (see Table V). 

The reaction of iminium chloride with alcohols affords imidoyl ester hydrochlorides LXXXVI as intermediates, which eliminate alkyl halides upon heating, thereby regenerating the corresponding carboxylic acid amide... 

Carboxylic acid amides by Grignard synthesis with addition of 1 C-atom from halides... 

Alkyl and aryl magnesium halides react with isocyanates to give the substituted carboxylic acid amides 263 after hydrolysis . 

The suffixes for carboxylic acids, amides, acid anhydrides, and acyl halides are, respectively, -oic acid, -amide, -oic anhydride, and -oyl chloride. 

Halomethyl deri atiYes of carboxylic acid amides are obtained by the joint reaction of formaldehyde and a hydrogen halide vith amides having the type fomiula RCOXHR in which R and R represent aliphatic and cA cioaiipliatic hydrocarbon radicals . These products haA e the. structure, RCOX R CHsX, in which X represents a halogen atom. 

---