Amide methanolysis

Hopper CR, Schowen RL, Venkatasubban KS, Jayaraman H. Proton inventories of transition states for solvation catalysis and proton-transfer catalysis. Decomposition of the tetrahedral intermediate in amide methanolysis. J Hm Chem Soc. 1973 95 3280— 3283. 

These authors also reported that /V-acyloxy-/V-alkoxyamides did not undergo methanolysis under the same conditions but treatment of /V-acctoxy-/V-ethoxybenz-amide 25a in more forcing conditions with NaOMe in DME afforded a mixture of ethyl and methylbenzoate, 97 and 98 (Scheme 20). They attributed the formation of the former to a HERON reaction and methyl benzoate to the direct attack of methoxide at the amide carbonyl. 

The same authors <2000J(P1)3584> studied the reactivity of 2 toward benzenediazonium (chloride or tetrafluoro-borate) salts. No diazo coupling took place under neutral or slightly acidic conditions. However, under basic conditions (NaOH in H20/MeOH), a mixture of 62 and 63 was obtained. This result clearly indicates that the diazo coupling takes place through the anion of 62 which arises from the base-catalyzed methanolysis of amide 2 in which the pyrrole ring is obviously not nucleophilic enough. 

Methanolysis of 696 followed by reaction with iodine, leads to syn y-hydrox-ylation relative to the amide group. Further, deiodination and subsequent hydrolysis affords the y-hydroxy-oc-amino acid derivative 698. This interesting reaction sequence opens the way for the synthesis of hydroxy substituted constrained phenylalanines with defined stereochemistry (Scheme 7.219). 

The methanolysis of amides of N,N-di(2-picolyl)amine (Scheme 12) also illustrates the leaving group effect.216 Addition of the p-nitrophenyl derivative to a hot solution of CuCl2 in methanol... 

The results in Table 2.4 are also relevant to preparative scale reactions. Adapting the definition of selectivities (Equation 2.10) for the reaction shown in Scheme 2.21 by rearranging Equation 2.14 gives a definition of S for competing methanolysis and aminolysis (Equation 2.17). Although the molar concentration of methanol in almost pure solvent is high (24.7 M), the major product is amide even when the concentration of m-nitroaniline is only 10-2 M (Table 2.4), and S is calculated from Equation 2.17 to be over 8000 very high yields are predicted for reactions in more concentrated solutions of m-nitroaniline. In contrast, under the same conditions, the less basic amine o-nitroaniline has an S value of only 6 [44] ... 

Figure 5-72. The methanolysis of the amide 5.34 is almost instantaneous in the presence of cop-per(n) chloride. It is likely that the reaction involves attack by a co-ordinated methanol molecule.

Formamidines such as 81 may be lithiated with s-BuLi or r-BuLi and give stabilised organolithiums 82 which react with a wide range of electrophiles. Cleavage is much easier than cleavages in the amide series acidic methanolysis gives a secondary amine 83 while hydride reduction gives a tertiary amine 84.57... 

The insertion of isocyanates, isolelectronic with C02, proceeded more cleanly. Isocyanates (RNCO) with bulky R groups inserted exclusively into the Zr-C bond (Table 5) methanolysis resulted in a-amino amides 32 [21]. 

Hydrolysis of lactams. The N-Boc derivatives of lactams are hydrolyzed to Boc derivatives of w-amino acids by treatment with LiOH (3 equiv.) in aqueous THF at 25° in 85-95% yield. Treatment with NaOCH-, in t H,OH at 0° affords the esters of these products. The same reactions are useful for hvdrolysis or methanolysis of secondary amides. ... 

Methanolysis of metal-carbon bonded amides yields NHji... 

Yet further violations of the rule that phosphetans undergo substitution with retention of configuration have come to light. The phosphetan amides (111), normally resistant to hydrochloric, sulphuric, and trifluoroacetic acids, do, however, undergo methanolysis in the presence of BF3, when considerable inversion of configuration occurs at phosphorus. ... 

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