A-Methoxylation amides

Oxidation of Ai,Ai-dialkylamides in MeOH normally gives a-methoxylated amides in high yields. The reaction also works well for Ai-formyl-2,2-dimethylazetidine, (6a), but in the absence of the methyl groups, (6b), the primary product undergoes EGA-catalyzed... 

Fig. 26 B3LYP/6-31G geometries for (a) ground state of A,-l ormyloxy-A,-methoxyform-amide 40 and transition states for migration of (b) formyloxyl and (c,d) methoxyl groups.

In addition to elimination reactions, the methoxylated amide products from electrolysis reactions have been treated with a variety of nucleophiles [47]. In recent studies, these efforts have been utilized to expand the chiral pool of starting materials available to synthetic chemists. For example, consider the reactions illustrated in Scheme 23 [52, 53]. In these efforts, Steckhan and coworkers have used the oxidation reaction to make a stable -a-methoxy amide that... 

Scheme 29 Regioselective N-a-methoxylation of amides using an electroauxiliary.

Using an identical process, the pipecolic acid derivative (112) was converted into a bicyclic amide derivative as shown in Scheme 36. In this case, the methoxylated amide proved to be unstable in the crude electrolysis reaction and was taken directly into the cyclization-ozonolysis sequence. A 74% yield of the bicyclic ketone was obtained over three steps. Compound (114) was converted into A58365B demonstrating that the anodic oxidation reaction allowed for rapid access to both natural products. 

Much of the recent work on the use of anodic amide oxidation reactions has focused on the utility of these reactions for functionalizing amino acids and for synthesizing peptide mimetics [13]. For example, in work related to the cyclization strategy outlined in Scheme 3, the anodic amide oxidation reaction has been used to construct a pair of angiotensin-converting enzyme inhibitors [14]. The retrosynthetic analysis for this route is outlined in Scheme 4. In this work, the anodic oxidation reaction was used to functionalize either a proline or a pipercolic add derivative and then the resulting methoxylated amide used to construct the bicyclic core of the desired inhibitor. A similar approach has recently been utilized to construct 6,5-bicyclic lactam building blocks for... 

Titanium chloride catalysed cyclisation of the methoxylated amide 17 is highly dependent upon the nature of the substituent R <99TL7939>. If R = Me cyclisation to the 6,6 system 18 occurs, but the merest hint of an electron withdrawing character results in a different path for the reaction ending in the formation of the 7,6 system 9 (Scheme 3). 

Figure 7.23 Influence of low-methoxyl amidated pectin on microstructure of caseinate gels acidified with giucono-8-lactone. The images show the gels (2 wt%) after 6 hours of acidification to pH = 4.0 for different added polysaccharide concentrations (wt%) (a) 0 (b) 0.1 (c) 0.4 (d) 0.8. Scale bar = 10 pm. Reproduced from (Matia-Merino et al., 2004) with permission.

A number of related couplings have been reported during the synthesis of the alkaloid ( )-cryptopleurine149 and also intramolecular coupling of diaryl amides to dibenzazepine and dibenzazodne structures.150 A versatile method for the preparation of tetrahydroquinolines and jololidines has been developed.151 The method involves the anodic oxidation of AT,AT-dimethyl-aniline in methanol to afford a-methoxylated or a, a -dimethoxylated compounds and subsequent treatment of products with Lewis acids in the presence of olefins. 

Especially the a-methoxylation or acetoxylation of amides like A-acyl and N-alkoxycarbonyl derivatives of amines, amino acids, and peptides leads to the synthetically very useful N,0-acetals, which are powerful amidoalkylation reagents [26] ... 

The reaction mechanism of the a-methoxylation or a-acetoxylation of amides and carbamates" has been shown to involve direct one-electron removal from the lone pair electrons of the nitrogen atom in the initial step when inert supporting electrolytes are used. 

In the amidoalkylation, however, the preparation of the starting a-methoxyamides is often difficult since the reaction of aldehydes higher than formaldehyde is not necessarily successful, and even when formaldehyde is employed the yields and purities of the a-methoxyamides are not always satisfactory. On the other hand, the anodic a-methoxylation of amides and carbamates generally allows the synthesis of a-methoxyamides (carbamates) which caimot be prepared by the method describe by equation (50). 

Since anodically prepared a-formyloxy-A / -dimethylformamide has successfully been used as an electrophilic reagent, and it has been found that the a-methoxylation of the carbamates of a variety of higher aliphatic amines and alicyclic amines can be readily performed, extensive studies have been carried out to utilize the anodically synthesized a-methoxy- or a-acyloxy-amides and -carbamates as electrophiles in organic synthesis. One example is shown in equation (51). ... 

The methoxylation of A-ethyl carboxamides has been studied especially intensively, as the produced A-(a-methoxyethyl)amides may be transformed to the technically interesting vinyl amides by methanol elimination [209]. Glassy carbon anodes together with graphite or steel cathodes and tetramethylammonium methyl sulfate as conducting salt proved to be the best conditions. Alternatively, the SPE cell using Nafion as polyelectrolyte is practicable [218,219]. 

The acyloxylation of A -alkylsubstituted amides has received considerable attention [70,75,118], from both the mechanistic and the preparative points of view. In electrolytes containing alkali metal carboxylates the direct mechanisms probably operates, whereas in the case where a nitrate salt is the supporting electrolyte an indirect mechanism involving hydrogen abstraction from the A -alkyl group by anodically generated NO3 is indicated. The same mechanistic problem is encountered in side-chain acetoxylation of alkylaromatic compounds in the presence of N03 [123,152,153]. The method for large-scale substitution into A -formyl derivatives, which works so well for methoxylation, fails when applied to acetoxylation, probably because of the acid sensitivity of the products [80]. 

Functionalization of amines via the o-aminobenzamides. Diazotization of the amide and CuCl-promoted decomposition of the diazonium salt in the presence of MeOH result in a-methoxylation of the amide. 

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