Diazines alkylation

Diazine alkyl groups, with the exception of those at the 5-position of pyrimidine, can undergo condensation reactions that utilise a side-chain carbanion produced by removal of a proton. As in pyridine chemistry, formation of these anions is made possible by delocalisation of the charge onto one (or more) of the ring nitrogen atoms. 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

Diazines are generally resistant to electrophilic attack on carbon, and, as for pyridine, addition on nitrogen is observed. Alkyl halides give mono-quaternary salts di-quatemary salts are not formed under normal conditions. Of conrse, if the diazine ring carries a snbstitnent that makes the starting... 

While 1,2-diazinones usually give N-alkylation, O-alkylation can be achieved by first transforming them into the trimethylsilyloxy-l,2-diazines or silver salts <1996CHEC-II(6)1>. This approach has been used by El Ashry to attach sugar moieties to the oxygen atom of phthalazin-l(2//)-one <2003CAR2291 >. 

Alkyl halides react with diazines less readily than with pyridines. All the diazines are, nevertheless, more reactive toward methyl iodide than predicted by their pKa values and the Bronsted relationship. The significant although modest rate enhancements found are considered to arise from interactions between the two lone pairs on the nitrogen atoms this interaction is largest in pyridazine. Use of oxonium ions can convert the diazines into diquatemary salts. Quinoxalines and phenazines similarly yield diquatemary salts under forcing conditions. 

Diazines other than diketopiperazines can also be prepared on insoluble supports (Table 15.31 see also Figure 3.13 [382]). Most strategies are based on intramolecular nucleophilic substitutions or acylations. Several examples of the solid-phase preparation of quinoxalinones have been reported. In most cases, the compounds have been prepared from support-bound 2-fluoronitrobenzenes according to the strategies outlined in Figure 15.18. Alternatively, a-amino acid esters bound to polystyrene as IV-benzyl derivatives can be N-arylated with 2-fluoronitrobenzene. Reduction of the resulting 2-nitroaniline leads to the formation of quinoxalinones [383]. 1,4-Diazines have been chemically modified by N- or C-alkylation on insoluble supports (Entries 9 and 10, Table 15.31). 

The monocyclic diazines, triazines, and tetrazines are all theoretically subject to electrophilic attack at one or more of their annular nitrogen atoms by protons alkylating, acylating, and aminating reagents and peracids. Coordination with metals could also be classified under this heading. 

Alkyl-2-(fV-cyanoimino)thiazolidine 1-oxides 684 undergo a ring-enlargement process in the presence of trifluoro-acetic anhydride to afford 5,6-dihydro-2//-l-thia-2,4-diazin-3(4//)-ones 685 (Scheme 297). Initial reaction of 684 with the anhydride leads to open-chain imidate 686, intramolecular displacement of trifluoroacetate gives 4//-l-thia-2,4-diazine 687, which finally hydrolyzes to the isolated product 685 (Scheme 297) <1997SL316, CHEC-III(9.05.10)334>. 

E8b, 621 (5-H - 5-Alkyl) l-Alkyl-5-(3-guanidino-ureido)-3-methyl-4-nitroso- (Hydro-4-methyl-benzolsulfonat) E8b, 562 (3-CHj — 1-R — 6-oxo —1,6-H2 — [Pg.62]

With azines the situation is varied. In the radical cations of pyridine and diazines the semi-occupied orbital is largely confined to the nn orbital(s) (see Scheme 2, structure 2), while the radical cation is of the n type with monoazanaphthalenes, -phenanthrenes and -anthracenes. The situation might change with substitution. As an example, alkylpyridine radical cations are of the n type, like the parent compound, whereas for the 2,5-dimethyl, 2-chloro, and 2-bromo derivatives the structure is of the n type [13]. Likewise, with benzo[c]cinnoline the parent compound and its alkyl derivatives give an n radical cation, but with some dimethoxy derivatives a n structure is found [14] and a switch from n to 7t structure occurs also in passing from 1,2,4,5-tetrazine to its 3,6-diamino derivatives [15]. 

The diazines react with alkyl halides to give mono-quaternary salts, though somewhat less readily than comparable pyridines. Dialkylation cannot be achieved with simple alkyl halides, however the more reactive trialkyloxonium tetrafluoroborates do convert aU three systems into di-quatemary salts. ... 

Unsymmetrically substituted diazines can give rise to two isomeric quaternary salts. Substituents influence the orientation mainly by steric and inductive, rather than mesomeric effects. For example, 3-methylpyridazine alkylates mainly at N-1, even though N-2 is the more electron-rich site. Again, quater-nisation of 3-methoxy-6-methylpyridazine takes place adjacent to the methyl substituent, at N-1, although mesomeric release would have been expected to favour attack at N-2. ... 

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