Aliphatic carboxamides

Kovalenko, A. L . Serov, Y. V and Tsclin-.skii. I. V Aminoalkylation of lower aliphatic carboxamides by N-mcthylene-ten-butyl-aminc, Zh. Org. Khim., 26, 1240, 1990 Chem. Abstn. 11.1, 211357. 1990. 

Cooper G. and Cronin J. R. (1995) Einear and cyclic aliphatic carboxamides of the Murchison meteorite hydrolyzable derivatives of amino acids and other carboxylic acids. Geochim. Cosmochim. Acta 59, 1003-1015. 

Hydroxy(tosyloxy)iodobenzene (HTIB 30) is another hypervalent organoiodine compound which acts as a Hofmann reagent, converting aliphatic carboxamides to alkylammonium tosylates in refluxing acetonitrile (equation 23). 

A very mild procedure for the Hofmann rearrangement of aromatic and aliphatic carboxamides 409 is based on the use of (tosylimino)phenyl-X. -iodane, PhINTs, as the oxidant (Scheme 3.165) [506]. Owing to the mild reaction conditions, this method is particularly useful for the Hofmann rearrangement of substituted benzamides 409 (R = aryl), which usually afford complex reaction mixtures with other hypervalent iodine oxidants. The mild reaction conditions and high selectivity in the reaction of carboxamides with PhINTs allow the isolation of the initially formed labile isocyanates 410, or their subsequent conversion into stable carbamates 411 by treatment with alcohols. Based on the previously reported mechanistic studies of the Hofmann rearrangement using other hypervalent iodine reagents [489,490,496], it is assumed that the reaction... 

Aliphatic and aromatic carboxamides, with the exception of p-nitrobenzamide, are dehydrated in this way in high yield. Acid-labile protective groups such as tetra-hydropyranyl and tert-butyldimethylsilyl ether and base-sensitive compounds are not attacked. A,A -Sulfinyldi-1,2,4-triazole, easily prepared from thionylchloride and triazole [THF, (C2H5)3N, 0 °C, 1 h] in 85-95% yield, was used without further purification. 

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2.5-/ra//.v-2.5-diphenylpyrrolidine-derived acrylamide and cinnamamide 399, efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides 400 in highly regio- and stereoselectivity (Scheme 1.47). Acid hydrolysis of these products affords enantiopure 4,5-dihydroisoxazole-5-carboxylic acids 401 (443). 

CARBONYLATION REACTIONS LEADING TO ALIPHATIC CARBOXYLIC ACIDS, ESTERS, LACTONES AND CARBOXAMIDES... 

Because of partial deactivation of many catalysts by aliphatic amines, less nucleophilic derivatives such as carboxamides or carbamates are usually used as substrates for carbene N-H insertion. 

Numerous methods to prepare individual classes of aliphatic diazo compounds have been extensively developed. The major strategies for their synthesis involve the alkaline cleavage of N-alkyl-N-nitroso-ureas, -carboxamides and -sulfonamides, dehydrogenation of hydrazones, as well as diazo group transfer from sulfonyl and related azides to active methylene compounds, and electrophilic diazoalkane substitution reactions. These synthetic methods have been comprehensively reviewed (15,16). Useful information on the preparation of selected diazo compounds can be found elsewhere (6,17). 

When an amino group is adjacent to a carboxamide group, annulation usually leads to a pyrrolo[2,3-r/ pyrimidin-4-one 164. Such is the case when 163 is allowed to react with aliphatic carboxylic esters (Equation 61) <1996H(42)691>. 

The Ni(II) complex of the hexaaza macrocyclic ligand 1 is reported to show a high activity for the electrocatalytic reduction of C02 to CO when a rotating copper disc electrode is used (85). In addition, water-soluble Niu-azacyclam complexes, 3a-3g, where R = carboxamide or sulfonamide, either aliphatic or aromatic, are found to be active in the electrocatalytic reduction of C02 at a mercury cathode. The efficiency is comparable to that of [Ni(cyclam)]2+ (14). 

This procedure illustrates a general method for preparing aliphatic and, in certain cases, aromatic /3-lactarns containing a free NH group and substituted in either the 4 position or in both the-3 and 4 positions of the 2-azetidinone ring. The major byproduct of the cycloaddition step is a /3,7-unsaturated carbox-amide-N-sulfonyl chloride which, in the case of certain aromatic olefins, may predominate. Reactions of both /3-lactam-N-sulfonyl chlorides and the /3,y-unsaturated carboxamide-N-sulfonyl chlorides have been tabulated.3... 

A number of studies have also been made of the hydrolysis of nitriles in the coordination sphere of cobalt(III). Pinnell et al.3 4 found that benzonitrile and 3- and 4-cyanophenol coordinated to pentaamminecobalt(III) are hydrolyzed in basic solution to the corresponding N-bonded carboxamide (equation 22). The reaction is first order in hydroxide ion and first order in the complex with koH= 18.8M 1s 1 at 25.6 °C for the benzonitrile derivative. As fc0H for the base hydrolysis of benzonitrile is 8.2 x 10-6 M-1 s at 25.6 °C, the rate acceleration is ca. 2.3 x 106-fold. The product of hydrolysis is converted to [(NH3)5CoNH2COPh]3+ in acidic solution and the pJC of the protonated complex is 1.65 at 25 °C. Similar effects have been observed with aliphatic nitriles.315 Thus, base hydrolysis of acetonitrile to acetamide is promoted by a factor of 2 x 106 on coordination to [Co(NH3)5]3+. 

With some exceptions, BTI is considered to be the best choice for the Hofmann type degradation of carboxamides to primary amines. Generally, treatment of an aliphatic primary carboxamide with BTI in aqueous acetonitrile (at an acidic pH 1-3), followed by addition of hydrochloric acid delivers the corresponding amine hydrochloride in excellent yield. 

A one-pot synthesis of 3,5-disubstituted 7-hydroxy-3//-l,2,3-triazolo[4,5-d]pyrimidines (130) has been carried out by using benzyl azide, cyano-acetamide, ethyl or methyl esters of the appropriate carboxylic acid, and sodium ethoxide as catalyst. The reaction proceeds via a 5-amino-l-benzyltriazole-4-carboxamide intermediate (85JHC1607). 7-Amino-3H-l,2,3-triazolo[4,5-d]pyrimidines 133 (R2 = H) were prepared starting from benzyl azide, malononitrile, and an aliphatic or aromatic nitrile, or by reaction of 130 with phosphorus oxychloride followed by amination. Compound 132 was formed in most reactions from two molecules of the 5-amino-4-cyano-l-benzyltriazole intermediate by an intermolecular nucleophilic at-... 

Nitriles. Aliphatic and aromatic amides (carboxamides) are dehydrated by HMPT at 220-240° to give nitriles in good yield. A phosphorodiamidate derivative (a) was. suggested as an intermediate. 

Figure 2 The structures of ceramide 1, a schematic structure of ceramide that illustrates the sites at which structural modifications may be introduced by chemical synthesis, and the structure of a representative ceramide found in human skin (2). Structural changes in the ceramide molecule have been introduced at many sites. Alterations include the configuration at C-2 and C-3 the lengths of the fatty amide chain and of the aliphatic chain attached to C-5 the positions of the unsaturation and the secondary hydroxy group the replacement of the hydroxyl groups with other atoms (hydrogen or fluorine) or functionalities (methoxy, methylthio, and keto) the incorporation of aromatic, heteroaromatic, and other rings in place of the alkenyl side chain of the sphingoid base and the replacement of the carbonyl group of the carboxamide group. In addition, the 2-amino-1,3-diol functionalities have been incorporated into cyclic structures.

Both aliphatic and aromatic esters may be converted to amides by electrochemical reduction of the ester in the presence of an amine in a divided cell as in Eq. (23) [95]. This reaction is not formally a reduction, but the reaction does not occur without passage of current. The mechanism is likely formation of an anion radical with abstracts a proton from ammonia to form amide ion. The amide ion subsequently displaces alkoxide in a chain reaction to form carboxamide. 

The Haller-Bauer reaction is applied to nonenolizable ketones which react with fresh sodium amide to form amides (equation 44). Cleavage of aliphatic or alicyclic phenyl ketones to produce tertiary carboxamides is the most useful. With equivalent amounts of l,4-diazabicyclo[2.2.2]octane (DABCO) the reaction proceeds under milder conditions. ... 

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