Azaheterocycle methylation

V-methyltransferase, active toward histamine and the catechol neurotransmitters, e.g., norepinephrine, is even more restrictive than COMT in terms of the metabolism of exogenous compounds. A class of compounds that does appear to be susceptible to N-methylation are azaheterocycles, particularly those that contain pyridine as part of the... 

Crooks PA, Godin CS, Damani LA, et al. Formation of quaternary amines by N-methylation of azaheterocycles with homogeneous amine N-methyltransferases. Biochem Pharmacol 1988 37(9) 1673-1677. 

Other examples of (trialkylsilyl)azaheterocyclic systems where direct reaction has resulted in ipso substitution of the silyl group include 2-pyridyl [69JHC433 72JOM(38)29 76JOM(104)153], 2-benzothiazolyl (71JHC257 73CB594 85TL5477), l-methyl-2-imidazolyl and 1-methyl-... 

Palladium-catalyzed cross-coupling reactions are not restricted to stannane derivatives, however, and other azaheterocyclic carbanion derivatives to have been investigated include l-methyl-2-pyrrolylmagnesium bromide and l-methyl-2-pyrrolylzinc chloride (81TL5319), l-methyl-2-indolymagnesium bromide (81TL5319), l-substituted-2- and 5-imidazolyl-... 

Other azaheterocyclic borates to have been similarly utilized include the 3-quinoline, 4-isoquinoline, l-methyl-2-pyrrole, and 1-methyl 2- and... 

N-methyl-a-nilroacrylamide 46 to afford polyfunctionalized pyridones 12 in reactions with 1,3-dicarbonyl compounds 19 in the presence of piperidine. As a result, versatile azaheterocyclic compounds can be easily prepared from pyridone 1 and pyrimidinone 3, and the synthetic utility of the RTF reaction has been considerably improved. 

No major improvement of photodurability was observed on going from the five- to the six-membered ring azaheterocyclic spiropyrans.32 In the piperidine series, a methyl group at C3 diminishes photostability by a factor of, 2 (Table 12, 142 vs. 144). The introduction of electron-acceptor atoms such as sulfur and oxygen at the position 3 to the nitrogen atom of the azaheterocycle results in a decrease of the photostability of the modified spiropyran. On the other hand, the indoline series compounds are more photostable than the pyrrolidinospiropyrans. As noted previously, electron-donor groups (e.g., CH3) on the azaheterocyclic moiety increase photostability. 

Comparatively little Is known about the species distribution of the various methylation reactions. Catechol and N-metlqrlatlons apparently occur throughout the Mammalia (46) In the case of azaheterocycle pyridine there occurred at 10 fold variation In the extent of methylation (48), from the rabbit and cat which are extensive methylators (up to 50Z of the dose), to rat, mouse and man. In which methylation only accounts for 2-lOZ of an administered dose. It Is well known that the 0-methylatlon of 4-hydroxy-3,5-dllodobenzolc acid Is far more extensive In primate species than non-prlmate mammals (52). 

In addition to metabolizing some aldehydes, aldehyde oxidase also oxidizes a variety of azaheterocycles but not thia- or oxaheterocycles. Of the various purine nucleosides metabolized by aldehyde oxidase, the 2-hydroxy- and 2-amino derivatives are more efficiently metabolized, and for the N -substituents, the typical order of preference is the acyclic nucleosides is as follows 9-[(hydroxy-alkyloxy)methyl]-purines) > 2 -deoxyribofuranosyl > ribofuranosyl > arabinofuranosyl > H. The kinetic rate constants for purine analogues revealed that the pyrimidine portion of the purine ring system is more important for substrate affinity than the imidazole portion. Aldehyde oxidase is inhibited by potassium cyanide and menadione (synthetic vitamin K). 

In pursuit of an energy efficient set of conditions suited for process-scale chemistiy, O Brien, Blakemore et al. have also shown that asymmetric alpha-lithiation of N-Boc pyrrolidine as well as other azaheterocycles can he carried out at temperatures up to —20 °C when short reaction times (2-20 min) are maintained/" In the case of N-Boc-pyrrolidine specifically, it vras shown that hy using a (-l-)-sparteine surrogate (+)-2, the asymmetric lithiation and trapping with dimethyl sulfate can he achieved at —30°C providing the alpha-methylated product in 55% yield and 84% ee (Scheme 11.30) when a lithiation time of 2 minutes was used. 

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