Azines, alkylation

Reactions of iV -alkylated or arylated azinium compounds with nucleophiles proceed more readily than those of the parent, uncation-ized azines, and the ring tends to open. The iV -substituent may bring into play an accelerative effect from the London forces of attraction. Increased displaceability of the substituent in iV -alkyl-azinium compounds has been noted for 2-halopyridinium (87) 1-haloisoquinolinium, 4-halopyrimidinium, 4-methoxypyrid-inium (88), 4-phenoxy- and 4-acetamido-quinazolinium (89), 3-methylthiopyridazinium, and 2-car boxymethylthiopyrimidi-nium salts (90). The latter was prepared in situ from the iV -alkyl-pyrimidine-2-thione. The activation can be effectively transmitted to... 

Arylthio but not 2-arylthio groups in quinazolines can be replaced with hydroxide ion or alkylamines. 4-Alkylthio-2-alkyl (or aryl)-quinazolines are readily alkoxylated (65°, 1 hr, 80-90% yield) at the 4-position. Arylthio and alkylthio groups have been found to be poorer leaving groups than chloro in several azines. 

Amination of the deactivated carbanion of 4-benzylpyridine formed with excess sodamide presumably proceeds because the strong indirect deactivation is overcome by electrophilic attack by Na+ at the partially anionic azine-nitrogen and by concerted nucleophilic attack by H2N at the 2-position via a 6-membered cyclic transition state (75). However, in simple nucleophilic displacement a carbanion will be more deactivating than the corresponding alkyl group, as is true in general for anionic substituents and their non-ionic counterparts. 

Alkyl-8H-7-aryl-l,2,4-triazino[3,4-3]-[l,3,4]thiadiazine-4-oncs 19 have been prepared from the reactions of tri-azines 30 with various phenacyl bromides. The intermediates 31 formed in such reactions underwent loss of HzO to form 19 (Scheme 2) <2003CHE809>. 

Multiple alkylations of azines can be achieved using a rhodium catalyst along with a phosphine ligand. Electron-rich azines give better results (Equation (101)).95... 

The formation of a second ring, based on the generation of a six-membered carbanion followed by alkylation with a difunctional electrophile and further cyclization, was also exploited in the synthesis of hexahydropyrrolo[l,2-tf]pyr-azine-l,4-dione 235 starting from alkoxycarbonyl piperazine-2,5-dione 233. When the key precursor was treated with 2equiv of NaH and 1,3-dibromopropane, the bicyclic compound 234 was obtained in acceptable yield and further transformed into compound 235 by deprotection and decarboxylation (Scheme 30) <2005T8722>. 

Compounds which are of interest in this context include 4-oxadiazolylpyrid-azines (35, R = cyclopropyl, Et) [117], 6-aryloxy-2-hydroxyalkyI-3(27/)-pyri-dazinones [118], 3-halo-6-hydrazinopyridazines of type (36, R = substituted amino) [119], Ar-2-isoxazolylmethyl-substituted 3-iminopyridazines (37) [ 120], carbamates derived from 3,6-bis(hydroxymethyl)-4-pyridazinones (38, R = alkyl, Ph) [121], and iminodihydropyridazine derivatives (39, R1 = acyl R2 = H,MeS R3 = aryl) [122, 123]. In Hungary, antidepressant activity has been observed with some 3,6-disubstituted pyridazines of type (40) [124]. 

Quatemized azines and azoles have also been investigated as potential phase-transfer catalysts. 1-Alkyl-2- and 4-dialkylaminopyridinium salts [38, 39] have... 

N-dealkylation results from an alkyl substitution on an aromatic molecule, which is one of the first places where microorganisms initiate catabolic transformation of atrazine, a xenobiotic molecule (Fig. 15.2). It is a typical example of a reaction leading to transformation of pesticides like phenyl ureas, acylanihdes, carbamates, s-tri-azines, and dinitranilines. The enzyme mediating the reaction is a mixed-function oxidase, requiring a reduced nicotinamide nucleotide as an H donor. 

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