Amidation of carboxylic acids

Several important generalizations emerge from the study of the boric acid catalyzed amidation of carboxylic acids and amines. 

To carry out the enzymatic amidation of carboxylic acids, normally two strategies are considered the use of ionic liquids or the removal of water from the reaction media at high temperature or reduced pressure. For instance, one of the first examples of the use of ionic liquids in biocatalysis has been the preparation of octanamide from octanoic acid as starting material and ammonia in the presence of CALB (Scheme 7.3) [11]. 

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. ... 

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. 

Apart from aryl esters and amides of carboxylic acids, aryl carbonates, and carbamates, other types of organic compound have been reported to undergo PFR. They include oxalates, formiates, sulfonates, sulfonamides, thioesters, selenoesters, and telluroesters. 

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. 

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

This purely ionic class of compounds has several members they are prepared from amides of carboxylic acids and PhI(OMe)(OTs) in acetonitrile, at room temperature as N-phenyliodonio amide tosylates (Scheme 21) [66]. 

Fig. 6.21. In situ activation of a carboxylic acid—i.e., the side chain carboxyl group of protected L-aspartic acid—as the mixed anhydride (B) and its aminolysis to a Weinreb amide. How this Weinreb amide acylates an organolithium compound is shown in Figure 6.44. The acylation of an H nucleophile by a second Weinreb amide is presented in Figure 6.42 and the acylation of a di(ketone enolate) by a third Weinreb amide in Figure 13.64. Figure 6.50 also shows how Weinreb amides of carboxylic acids can be obtained by C,C bond formation.

Fig. 7.1 Survey of the mutual interconversion of carboxylic acid derivatives, especially primary amides of carboxylic acids, and nitriles.

Rayle HL, Fellmeth L. Development of a process for triazine-promoted amidation of carboxylic acids. Org. Process 36. Res. Dev. 1999 3 172-176. 

BF3 Et20 is effective in the direct amidation of carboxylic acids to form carboxamides (Eq. 88) [144]. The reaction is accelerated by bases and by the azeotropic removal of water. 

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). 

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, ... 

Sulfonamides are hydrolyzed more slowly than amides of carboxylic acids examination of the structures involved shows us what probably underlies this difference. Nucleophilic attack on a trigonal acyl carbon (Sec. 20.4) is relatively unhindered it involves the temporary attachment of a fourth group, the nucleophilic reagent. Nucleophilic attack on tetrahedral sulfonyl sulfur is relatively hindered it involves the temporary attachment of a /// group. The tetrahedral... 

Problem 23.7 (a) Although amides of carboxylic acids are very weakly acidic (Ka = 10" to 10" 5), they are still enormously more acidic than ammonia Ka = 10" 33) or amines, RNH2. Account in detail for this. 

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. 

Bellas, D., Hrdlovic, P. Photochemical rearrangement of aryl, vinyl, and substituted vinyl esters and amides of carboxylic acids. Chem. Rev. 1967, 67, 599-609. 

Amidase Cleavage of amides of carboxylic acids Methotrexate... 

Primary amides of carboxylic acids are easily converted in humans to the corresponding acid (e.g. depamide, progabide)... 

The enzymatic ammoniolysis of carboxylic esters and amidation of carboxylic acids. 

Amidation of carboxylic acids. Boron trifluoride etherate has been used as a reagent for reaction of carboxylic acids with primary or secondary amines to form amides. The reaction is accelerated by bases (triethylamine, DBU) and by azeotropic removal of the water formed. The reaction is conducted in refluxing benzene or toluene. Yields are generally in the range of 50-85%. 

Primary amides of carboxylic acids are easily converted to the corresponding acid (e.g. depamide, progabide) in humans and can thus be used in prodrug design. Amides of ketoprofen-derived arylacetic acids possess a therapeutic index one order of magnitude greater than that of indomethacin. ... 

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