Amide synthesis from acid chlorides

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Conductivity measurements have revealed that DMF and carboxylic acid chlorides form salt-like adducts (22) in an equilibrium reaction (equation 12). Such adducts can be prepared either from DMF and acid halides (chlorides and bromides) or from chloromethyleneiminium salts and salts of carboxylic acids. Acyloxyiminium salts (23) can be prepared in the pure state by reacting acid amides with carboxylic acid chlorides in the presence of silver trifluoromethanesulfonate (equation 13). Salts of type (24 equation 14) are regarded as being intermediates in the synthesis of ketones from carboxylic acids and Grignard reagents in the presence of a-chloroenamines as well as in the preparation of acyl halides (F, Cl, Br, I) by action of a-haloenamines on carboxylic acids. ... 

Formation of anhydride succeeds with Ni catalysts even at lower temperatures (230 to 250 °C) than the synthesis of propionic acid from ethylene. Thiolcarboxylic acid esters are obtained analogously by addition of thiols instead of carboxylic acids (2). Olefins, carbon monoxide and amines react to give saturated carboxylic acid amides (3) and acid chlorides are formed from hydrogen chloride and carbon monoxide in the presence of noble metal catalysts of the 8th group of the periodic table of the elements (4). 

Further examples of the synthesis of amines from acid chlorides, aziridines, aldehydes,and amides, a new synthesis of a-aminoamidines, and a total synthesis of the naturally occurring polyamine thermospermine have been reported. ... 

Although a few methods for the direct conversion of acids into nitriles are kno vn, the most popular still proceed via dehydration of the corresponding amides. A new, mild, one-pot method to effect the acid-to-nitrile conversion in high yield involves the use of mixed sulphonic-carboxylic anhydrides (Scheme 23) the method, however, is not applicable to acids containing —NHa, — NHR, —OH, or —SH groups. In a similar vein, a new and efficient one-pot synthesis of nitriles from acid chlorides is mediated by sulphonamide at 120 °C. ... 

Amines and ammonia are good nucleophiles and are rather hard to displace, once a tetrahedral intermediate has been formed. The synthesis of amides from acid chlorides and amines has been widely applied (Figure 15.27). Notice in the second example that it is the nitrogen rather than the oxygen of the amino alcohol that acts as the nucleophile, and in the third example that the acid chloride is more reactive toward substitution than the aliphatic bromide. 

Cefpimizole (51) appears to be less active in vitro than cefotaxime and cefoperazone and to have a somewhat narrower activity spectrum although some strains of Pseudomonas are susceptible. It is not orally active, but its performance in vivo appears superior to what would be expected from its in vitro data. Its synthesis begins by acylation of cephaloglycin (48) with the bis acid chloride of imidazole-4,5-dicarboxylic acid (49) to give amide 50. The acetyl moiety at C-3 of this intermediate is displaced with 4-pyridineethanesulfonic acid and sodium iodide to give cef-pimazole (51) [16]. 

Synthesis of amides from amines and acid chlorides Glass DCM 77 EOF... 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

One synthesis pathway for preparation of nonionic surfactants containing an amide bond from a fatty acid chloride and tetra(ethylene glycol) is illustrated in Fig. 12 [39]. 

Imidazo[4,5- ]pyridines can be synthesized by a large number of routes, from which condensation of the appropriate carboxylic acid or acid chloride with the corresponding diaminopyridine, sometimes requiring cyclization of the intermediate amide with strong acid, appears to be the most widely used method <1996CHEC-II(7)283>. A recent example has been reported for the synthesis of pyridoimidazole C-nucleosides, and although the yield in this particular case was low, no epimerization at the C-1 stereocenter was observed (Equation 29) <2003TL5807>. 

In one synthesis of this drug, L-proline (11-2) is acylated with the acid chloride (11-1) obtained from the addition of hydrogen chloride to the double bond in methacrylic acid followed by reaction with thionyl chloride to give amide (11-3) as a mixture of diastereomers. The pure 2S isomer is then isolated from the mixture by fractionation as the dicyclohexylamine salt. Treatment of that compound with ammonium hydrosulfide leads to the displacement of chlorine by a thiol group and the formation of captopril (11-4) [13]. 

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