Amidation regeneration

On treatment with gaseous HBr in organic solvents, N-nitros-amides regenerate the parent amide (equation 3) in quantitative yield (7f ) This implies that N-nitrosamide formation is reversible and explains why it is beneficial to add one mole of base... 

The reductive cyclization of the 2-nitrodihydrocinnamoyl group has found application for the protection of alcohols and amines using sodium phosphinate or cyclohexene as the hydrogen donor. - The hydrogen transfer reduction of both esters and amides regenerates the alcohols or amines under mild conditions (equation 12). 

From a historical perspective, the a-(dialkylamino)nitrile anions were the first acyl anion equivalents to undergo systematic investigation. More recent studies indicate that anions of a-(dialkylamino)nitriles derived from aliphatic, aromatic or heteroaromatic aldehydes intercept an array of electrophiles including alkyl halides, alkyl sulfonates, epoxides, aldehydes, ketones, acyl chlorides, chloroformates, unsaturated ketones, unsaturated esters and unsaturated nitriles. Aminonitriles are readily prepared and their anions are formed with a variety of bases such as sodium methoxide, KOH in alcohol, NaH, LDA, PhLi, sodium amide, 70% NaOH and potassium amide. Regeneration of the carbonyl group can be achieved... 

Acid or base hydrolysis of acid chlorides, acid anhydrides, esters, or amides regenerates the parent carboxylic acid. 

Lauramide has been prepared by passing ammonia gas through lauric acid in the presence of metallic oxides, specifically a complex mixture of Si02—AI2O2—Fe202—CaO—SO in the ratio of 24 16 3 47 10. The oxides, which are hydrated during amidation, can be regenerated by calcination (12,13). 

Imides (e.g. phthalimide) can be purified by conversion to their potassium salts by reaction in ethanol with ethanolic potassium hydroxide. Hie imides are regenerated when the salts are hydrolysed with dilute acid. Like amides, imides readily crystallise from alcohols and, in some cases (e.g. quinolinic imide), from glacial acetic acid. 

This amide is readily prepared from the acid chloride (Pyr, rt, 1 h, 77-86% yield) or the acid (DCC, DMAP, CH2CI2, rt, 1 h, 88% yield). Treatment of the amide with camphorsulfonic acid forms an A-acylindole. The acid can be regenerated from the A-acylindole by Li0H/H202/THF/H20 or NaOH/MeOH. Alternatively, it can be transesterified with MeOH/TEA, converted to an amide, by heating with an amine or converted to an aldehyde by DIB AH (62-85% yield). ... 

Raston has reported an acid-catalyzed Friedel-Crafts reaction [89] in which compounds such as 3,4-dimethoxyphenylmethanol were cyclized to cyclotriveratrylene (Scheme 5.1-57). The reactions were carried out in tributylhexylammonium bis(tri-fluoromethanesulfonyl)amide [NBu3(QHi3)][(CF3S02)2N] with phosphoric or p-toluenesulfonic acid catalysts. The product was isolated by dissolving the ionic liq-uid/catalyst in methanol and filtering off the cyclotriveratrylene product as white crystals. Evaporation of the methanol allowed the ionic liquid and catalyst to be regenerated. 

When a carbonyl group is bonded to a substituent group that can potentially depart as a Lewis base, addition of a nucleophile to the carbonyl carbon leads to elimination and the regeneration of a carbon-oxygen double bond. Esters undergo hydrolysis with alkali hydroxides to form alkali metal salts of carboxylic acids and alcohols. Amides undergo hydrolysis with mineral acids to form carboxylic acids and amine salts. Carbamates undergo alkaline hydrolysis to form amines, carbon dioxide, and alcohols. 

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

This novel resin-bound CHD derivative was then utilized in the preparation of an amide library under microwave irradiation. Reaction of the starting resin-bound CHD with an acyl or aroyl chloride yields an enol ester, which, upon treatment with amines, leads to the corresponding amide, thus regenerating the CHD. This demonstrates the feasibility of using the CHD resin as a capture and release reagent for the synthesis of amides. The resin capture/release methodology [126] aids in the removal of impurities and facilitates product purification. 

The quest for a solvent-free deprotection procedure has led to the use of relatively benign reagent, ammonium persulfate on silica, for regeneration of carbonyl compounds (Scheme 6.10) [48]. Neat oximes are simply mixed with solid supported reagent and the contents are irradiated in a MW oven to regenerate free aldehydes or ketones in a process that is applicable to both, aldoximes and ketoximes. The critical role of surface needs to be emphasized since the same reagent supported on clay surface delivers predominantly the Beckmann rearrangement products, the amides [49]. 

From all the above observations, it was concluded that, for diphosphine chelate complexes, the hydrogenation stage occurs after alkene association thus, the unsaturated pathway depicted in Scheme 1.21 was proposed [31 a, c, 74]. The monohydrido-alkyl complex is formed by addition of dihydrogen to the en-amide complex, followed by transfer of a single hydride. Reductive elimination of the product regenerates the active catalysts and restarts the cycle. The monohydrido-alkyl intermediate was also observed and characterized spectroscopically [31c, 75], but the catalyst-substrate-dihydrido complex was not detected. 

Serine peptidases can hydrolyze both esters and amides, but there are marked differences in the kinetics of hydrolysis of the two types of substrates as monitored in vitro. Thus, the hydrolysis of 4-nitrophenyl acetate by a-chy-motrypsin occurs in two distinct phases [7] [22-24]. When large amounts of enzyme are used, there is an initial rapid burst in the production of 4-nitro-phenol, followed by its formation at a much slower steady-state rate (Fig. 3.7). It was shown that the initial burst of 4-nitrophenol corresponds to the formation of the acyl-enzyme complex (acylation step). The slower steady-state production of 4-nitrophenol corresponds to the hydrolysis of the acetyl-enzyme complex, regenerating the free enzyme. This second step, called deacylation, is much slower than the first, so that it determines the overall rate of ester hydrolysis. The rate of the deacylation step in ester hydrolysis is pH-dependent and can be slowed to such an extent that, at low pH, the acyl-enzyme complex can be isolated. 

Warsinsky R, Steckhan E (1995) Oxidative free radical additions of a-nitro amides to alkenes and alkynes mediated by electrochemically regenerable manganew (HI) acetate. In Torii S (ed) Novel trends in electroorganic synthesis, Kodansha, Tokyo, pg 135 J. Chem. Soc. Perkin Trans 1 (1994) 1994 2027... 

Figure 1.31 illustrates a mechanism proposed for this hydrogenation. The titanocene hydride 31A is expected to be a catalytic species. The imine substrate is inserted into the Ti—H bond of 31A with a 1,2-fashion to form a titanocene amide complex 31B. Then the hydrogenolysis of 31B through a a-bond metathesis produces the amine product with regeneration of 31A. The enantioface selection... 

From a simplified scheme of reduction of the amide function it can be seen that the first stage is formation of an intermediate with oxygen and nitrogen atoms linked to an sp carbon. Such compounds tend to regenerate the original sp system by elimination of ammonia or an amine. Thus an aldehyde is formed and may be isolated, or reduced to an alcohol. Alternatively the product is an amine resulting from direct hydrogenolysis of the sp intermediate. 

When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction conditions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62% yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-tive protonation event. With this evidence in hand, the proposed mechanism begins with carbene addition to the a-reducible aldehyde followed by formation of activated car-boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In turn, intermediate XLin then undergoes nucleophilic attack by the amine and releases the co-catalyst back into the catalytic cycle. 

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