Amidation of carboxylic acids with

There are several different routes to carboxamides. Usually a carboxyhc acid is converted to a more reactive intermediate, e.g. an acid chloride, which is then reacted with an amine. For practical reasons it is preferable to form the reactive intermediate in situ. We have found that arylboronic acids bearing electron-withdrawing aromatic groups, e.g. 3,4,5-trifluorophenylboronic acid, 3,4,5-F3C( H2B(OH)2, and 3,5-bis(tri-fluoromethyl)phenylboronic acid, 3,5-(CF3)2C6H3B(OH)2, act as highly efficient catalysts in the amidation of carboxylic acids with amines [167]. The catalysts are useful in the reaction of primary and secondary amines with a variety of carboxylic acids (Eq. 114). 

Litjens MJJ, Straathof AJJ, Jongejan JA, Heijnen JJ (1999) Synthesis of primary amides by lipase-catalyzed amidation of carboxylic acids with ammonium salts in an organic solvent. Chem Commun 1255 -1256... 

Ishihara and Yamamoto et al. have found that arylboronic acids bearing electron-withdrawing aromatic groups, e.g. 3,4,5-F3CgH2B(OH)2 and 3,5-(CF3)2CgH3B(OH)2, act as highly efficient catalysts in the amidation of carboxylic acids with amines [10]. 

Although, the enzymatic reaction of esters with amines or ammonia have been well documented, the corresponding aminolysis with carboxylic acids are rarer, because of the tendency of the reactants to form unreactive salts. For this reason some different strategies have been used to avoid this problem. Normally, this reaction has been used for the preparation of amides of industrial interest, for instance, one of the most important amides used in the polymer industry like oleamide has been produced by enzymatic amidation of oleic acid with ammonia and CALB in different organic solvents [10]. 

This lactamization process can be promoted by enzymes such as pancreatic porcine lipase. Reduction of co-azido carboxylic acids leads to macrocyclic lactams. Although treatment of carboxylic acids with amines does not directly give amides, the reaction can be made to proceed in good yield at room temperature or... 

N-Silylated peptide esters are acylated by the acid chloride of N-Cbo-glycine to N-acylated peptide bonds [11]. Likewise, acid chlorides, prepared by treatment of carboxylic acids with oxalyl chloride, react with HMDS 2 at 24°C in CH2CI2 to give Me3SiCl 14 and primary amides in 50-92% yield [12]. Free amino acids such as L-phenylalanine or /5-alanine are silylated by Me2SiCl2 48 in pyridine to 0,N-protected and activated cyclic intermediates, which are not isolated but reacted in situ with three equivalents of benzylamine to give, after 16 h and subsequent chro-... 

One of the most important characteristics of IL is its wide temperature range for the liquid phase with no vapor pressure, so next we tested the lipase-catalyzed reaction under reduced pressure. It is known that usual methyl esters are not suitable for lipase-catalyzed transesterification as acyl donors because reverse reaction with produced methanol takes place. However, we can avoid such difficulty when the reaction is carried out under reduced pressure even if methyl esters are used as the acyl donor, because the produced methanol is removed immediately from the reaction mixture and thus the reaction equilibrium goes through to produce the desired product. To realize this idea, proper choice of the acyl donor ester was very important. The desired reaction was accomplished using methyl phenylth-ioacetate as acyl donor. Various methyl esters can also be used as acyl donor for these reactions methyl nonanoate was also recommended and efficient optical resolution was accomplished. Using our system, we demonstrated the completely recyclable use of lipase. The transesterification took place smoothly under reduced pressure at 10 Torr at 40°C when 0.5 equivalent of methyl phenylthioacetate was used as acyl donor, and we were able to obtain this compound in optically pure form. Five repetitions of this process showed no drop in the reaction rate (Fig. 4). Recently Kato reported nice additional examples of lipase-catalyzed reaction based on the same idea that CAL-B-catalyzed esterification or amidation of carboxylic acid was accomplished under reduced pressure conditions. ... 

Reaction of carboxylic acids with the amino groups of glycine (Huang and Collins 1962) or taurine (Figure 2.19) (James and Bend 1976) to form the amides. 

Similarly, hydrolysis of tertiary amides of carboxylic acids is usually slow under conventional conditions. Hydrolysis of a morpholide occurred in only 48% yield with 2M HC1 at reflux after 4h, yet proceeded in 70% yield after only 10 min at 200 °C in the MBR (Scheme 2.2) [26]. The convenience of operation and the rapid throughput enabled preparation of multiple batches of the corresponding acid in a few hours. 

Although the ability of microwaves (MW) to heat water and other polar materials has been known for half a century or more, it was not until 1986 that two groups of researchers independently reported the application of MW heating to organic synthesis. Gedye et al. [1] found that several organic reactions in polar solvents could be performed rapidly and conveniently in closed Teflon vessels in a domestic MW oven. These reactions included the hydrolysis of amides and esters to carboxylic acids, esterification of carboxylic acids with alcohols, oxidation of alkyl benzenes to aromatic carboxylic acids and the conversion of alkyl halides to ethers. 

N-Tosyl amides and lactams.2 DCC in combination with 4-pyrrolidinopyri-dine (4-PPy) effects condensation of carboxylic acids with secondary sulfonamides to provide N-tosyl amides in 75-90% yield. The intramolecular version of this reaction provides 4-, 5-, and 6-membered N-tosyl lactams in 60-90% yield. 

Formylation and Acylation of Organic Compounds with Substituted Amides of Carboxylic Acids V. I. Minkin and G. N. Dorofeenko, Russ. Chem. Rev. (Engl. Transl.), 1960, 29,599-618. 

Acyl chlorides. Acyl chlorides are formed rapidly by reaction of carboxylic acids with SOCl2 and pyridine in CH2C12 at 25°. The dicyclohexylammonium salts of carboxylic acids react particularly rapidly (ca. 1 minute). The acid chlorides prepared in situ in this way react with amines in the presence of DMAP or DBU to form amides in >85% yield. This SOCl2-Py method is also useful for peptide synthesis with slight racemization. 

This section deals with the coordination chemistry of amides of carboxylic acids, predominantly formamide, acetamide and their -substituted derivatives. Lactams are also mentioned briefly. 

Conversions of carboxylic acids to ketones are typically performed in stepwise fashion6 via intermediates such as acid chlorides,7 anhydrides,8 thioesters,9 or N-alkoxy amides,16 or by the direct reaction of carboxylic acids with lithium reagents.11 In this latter method trimethylsiiyl chloride has been shown to be an effective reagent for trapping the tetrahedral alkoxide intermediates and for quenching excess organolithium reagent. 

Acyl chlorides are reactive compounds used to make esters and amides. They are derivatives of carboxylic acids with the -OH replaced by -Cl, and are too reactive to be found in nature. 

The familiar substitution reactions of derivatives of carboxylic acids with basic reagents illustrate nucleophihc substitution at aliphatic sp carbons. (Substitution reactions of carboxylic acids, and their derivatives, with acidic reagents are covered in Chapter 4.) The mechanisms of these reactions involve two steps (1) addition of the nucleophile to the carbonyl group and (2) elimination of some other group attached to that carbon. Common examples include the basic hydrolysis and aminolysis of acid chlorides, anhydrides, esters, and amides. 

Sn[N(TMS)2l2, A, A -carbonyldiimidazole (110, p. 1418), which behaves as in reaction 16-63, POCl3, °" TiCl4, ° molecular sieves,Lawesson s reagent (p. 1278), ° and (MeO)2POCl. ° Certain dicarboxylic acids form amides simply on treatment with primary aromatic amines. In these cases, the cyclic anhydride is an intermediate and is the species actually attacked by the amine. Carboxylic acids can also be converted to amides by heating with amides of carboxylic acids (exchange),sulfonic acids, or phosphoric acids, for example, ... 

The selective removal of the acetyl group in t e final step is consistent with the general observation that amides of carboxylic acids are more easily hydrolyzed than amides of sulfonic acids. 

Amides are difficult to prepare by direct reaction of carboxylic acids with amines because amines are bases that convert acidic carboxyl groups into their carboxylate anions. Since the carboxylate anion has a negative charge, it is no longer likely to be attacked by a nucleophile. We ll see a better method for making amides from acids in Section 26.10 in connection with the synthesis of proteins from amino acids. 

Activation of carboxylic acids with carbonyldiimidazole (equation 12) and subsequent reaction with amines gives amides and peptides in good yield. " Through the same intermediate, the activation also occurs with the more stable AA -oxalyldiimidazole and the mixture of triphenyl phosphite and imidazole. "... 

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