Direct amide formation

Although there are several reports in the literature on boron-mediated amide formations, the boron reagents had to be used in stoichiometric amounts.1-4-5-6-7-8-9 Recently, Yamamoto et al. presented the first truly catalytic method allowing for a direct amide formation from free carboxylic acids and amines as the reaction partners.10-1112 Best results were obtained by using phenylboronic acids bearing electron withdrawing substituents in the meta- and/or para-positions such as 3,4,5-trifluorophenylboronic acid or 3,5-bis(trifluoromethyl)boronic acid as the catalysts. 

Direct amide formation in aqueous solution between carboxylic acids and amines can occur and the rates are first order in the anion of the acid and the basic form of the amine (Eq. 9.12).23 The second-order rate constant is independent of the acidity of the medium. The condensation reaction of glycine to form di- and triglycine occurs in aqueous solution... 

Amination of ketene has been studied by ab initio methods.Reactions of ammonia, its dimer, and its (mono)hydrate with ketene have been calculated and compared with earlier smdies of ammonia (at lower levels of theory), of water, and of water dimer. In general, the results favour initial addition of ammonia to the C=0 bond (giving the enol amide), as against addition to the C=C bond (which gives the amide directly). Amide formation is compared with the corresponding hydration reaction where enol acid and acid are the alternative immediate products. Most of the reactions, i.e. both additions and tautomerizations, are suggested to involve cyclic six-membered transition states. 

All of the Amathia brominated amides are presumably biosynthesised from amino acids by similar pathways in the related bryozoans. The amathamides are amides derived formally by reaction of 2-(2,4-dlbromo-5-methoxyphenyl)ethanamlne, 68, with proline followed variously by introduction of a double bond, or methyl, methoxy or bromine substituents. The A. convoluta metabolites 70-74, and 75 from A. alternata are all also derived formally from 2-(2,4-dibromo-5-methoxy-phenyDethanamlne, 68—either by direct amide formation with tyrosine, or by having an additional aminopropyl group which is then... 

Direct Amidation. Formation of polyamides by condensation of amine and carboxyl groups is illustrated by... 

Figure 4. Direct amide formation by DMAP polymer via mixed anhydride fonnation.

Certain combinations of carboxylic acid and amine when heated in a non-protic solvent such as toluene form the corresponding amide. Most often, however, such a combination simply yields the inert ammonium carboxylate, RC02 R NH3+. Now a mechanism for direct amide formation, supported by NMR and DFT studies, has been proposed in which the dimeric form of the acid (1) reacts with an amine (2) to yield, via the transition state (3), the neutral tetrahedral intermediate (4) which collapses to the amide (5) (Scheme 1). ... 

Houlding T, Tchabanenko K, Rahman MdT, Rebrov EV. Direct amide formation using radiofrequency heating. Org. Biomol. Chem. 2013 11(25) 4171 177. 

Interestingly, it is evident that the reactivity of boric acid is better at high temperatures, and it declines at lower reaction temperatures. Subsequently, a wide variety of boron-based reagents, such as catechol and arylboronic acid-based catalysts, have been developed for direct amide formation. The enhancement of the Lewis acidity of boron has been proven to enhance catalytic activity e.g. chlorocatechol derivative 9 or 10), as in eqn (13.2). ... 

The industrial application of catalytic direct amide formation is still little explored and the eurrent proeesses are still unoptimised. Moreover, due to the high tolerance to water, aeids or bases, boron-based catalysts could be considered one of the most potentially interesting areas of research in the arena of direct amidation used in pharmaceuticals and fine chemicals. Clear steps have been followed so far by the scientific community in this direction for amide transformation, especially with boron-based eatalysts, and a renaissance in this area has already been triggered. 

B. M. Monks and A. Whiting, Direct amide formation avoiding poor atom economy reagents. Sustainable Catalysis published by Wilq and Sons, Inc., Hoboken, New Jersey, 2013, pp. 89-110. 

Charville H, Jackson D, Hodges G, Whiting A (2010) The thermal and boron-catalysed direct amide formation reactions mechanistically understudied yet important processes. Chem Commun 46(11) 1813-1823... 

In the alternate approach, the amide formation is performed on para-nitrobenzenesulfonyl chloride (91). Reduction by either chemical or catalytic methods affords directly the desired product (90). ... 

Attempts have been made to incorporate functional groups into the phosphonates in zinc phosphonate structures. Zn(03P(CH2)2C02H) H20 was reacted with aromatic amines but no amide formation was observed. However, Zn(03P(CH2)2C0NHC6H5) could be synthesized directly from zinc nitrate, (2-carboxyethyl)phosphonic acid, and aniline in a one-step procedure.406... 

The synthesis of polyamides follows a different route from that of polyesters. Although several different polymerization reactions are possible, polyamides are usually produced either by direct amidation of a diacid with a diamine or the self-amidation of an amino acid. The polymerization of amino acids is not as useful because of a greater tendency toward cycliza-tion (Sec. 2-5b). Ring-opening polymerization of lactams is also employed to synthesize polyamides (Chap. 7). Poly(hexamethylene adipamde) [IUPAC poly(iminohexanedioylimi-nohexane-l,6-diyl) or poly(iminoadipoyliminohexane-l,6-diyl)], also referred to as nylon 6/6, is synthesized from hexamethylene diamine and adipic acid [Zimmerman, 1988 Zimmerman and Kohan, 2001]. A stoichiometric balance of amine and carboxyl groups is readily obtained by the preliminary formation of a 1 1 ammonium salt (XU ) in aqueous solution at a concentration of 50%. The salt is often referred to as a nylon salt. Stoichiometric... 

With the (S)-PGA enamine-amide route, sitagliptin was prepared in 65% overall yield from 2,4,5-trifluorophenylacetic acid (9) in 4 chemical steps [18]. Two addi-honal crystallization steps are required for enanhomeric purity upgrade and final salt formation. The (S)-PGA enamine-amide hydrogenahon approach eliminated the ester hydrolysis and amide formation steps of the (S)-PGA enamine-ester route by incorporating the newly developed Meldrum s acid chemistry, which enabled direct amidahon with triazole 3. 

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