Pyrimidines quaternization

Substituted pyrimidine Quaternizing reagent Position of quaternization Principal Subsidiary product product Reference... 

Considerable rate enhancements are observed upon quaternization of the pyrimidine ring, due to its electron-deficiency. Heating of the l-ethyl-2-(pent-4-yn-l-yl)-5-phenylpyrimidinium tetrafluoroborate (X = CH2) at 180°C for 15 min ( ) gave in a more or less quantitative yield 1-ethyl-6,7-dihydro-3-phenyl-5//-l-pyridinium salt (X = CH2) (90T595) (Scheme 36). A similar reaction was also observed with the 2-(butynylthio)pyrimidinium salt (X = S). 

Whereas in all previously mentioned inverse cycloaddition reactions [h]-fused pyrido annelated systems are formed, some reactions are described which lead to [c]-pyridine annelated bicyclic systems. 5-(Butynylthio)pyrimidines (R = Ph, NHCOCH3) give on heating at 180°C in nitrobenzene 5-R-2,3-dihydrothieno[2,3-c]pyridines (89T803). 5-Propynyloxymethylpyrimidines also readily undergo cycloaddition into l,3-dihydrofuro[3,4-c]pyridines (89T5151) (Scheme 39). Considerable rate enhancements were observed with quaternized pyrimidinium salts. Whereas... 

The reaction of 2-aminopyridine with 2-chloropyridine 102 furnishes pyrido[l,2- 3,2- ]pyrimidine derivative 104 in good yield (Scheme 10) <1998T5775, 2003CHE328>. The first step is quaternization with the formation of salt 103. Then 103 undergoes intramolecular cyclization with participation of cyano and amino groups. 

Dihydro-2//-pyrido[l,2-a]pyrimidines were quaternized with alkyl halides or benzyl chloride.188,189,193... 

Thienopyrimidyl-2-thioacetamido)cephalosporanic acid derivatives 170 were prepared by reaction of the appropriate 7/3-chloroacetamidoceph-alosporanic acids 169 with the thieno[2,3-d]pyrimidine potassium salts 168 (87PHA160). The 4-methylthio group of quaternized thieno[2,3-d]pyrimi-dine 172 was displaced by the 3-aminomethyl group of cephalosporins 171 to afford cephalosporin derivatives 173 (89AUP584898). 

The aza substituent constants (vide supra) reflect the fact that electron-withdrawing annular nitrogens decrease the reactivity of any other ring nitrogen in the order ortho meta < para. For this reason, pyrazines should quaternize more readily than pyrimidines and pyridazines, and all three diazines should react faster than triazines. When the diazines are included in a Hammett plot for the methylation of substituted pyridines (p = —2.3), the positive deviations showed that they were all more reactive than indicated by their pK values. Relative rates compared with pyridine were pyridazine, 0.25 pyrimidine, 0.044 and pyrazine, 0.036 (72JA2765). Pyridazine in particular appears to be much more reactive than one would expect. (See Section III, A below). 

The isomer ratios estimated for a series of pyrazines, pyridazines, and pyrimidines are in good agreement with experiment (72T1983) they provide not only reasonable predictions of isomer ratios of quaternization products but also a method for rectifying many of the previously contradictory statements in the literature. 

Reactions of this type are easy if the amino group is quaternized as in, for example, l-(4-pyridyl)pyridinium chloride 767, which gives pyridine and 4-substituted pyridines 768 [Y = Cl, Br (with PX5) Y = SH, SR (with SH, SR) Y = NH2, NHR (with NH3, NH2R)]. Similarly, NMeJ groups in pyrimidines undergo nucleophilic displacement. 

Chloropyrimidine is aminated with alcoholic ammonia at 130° while 4-chloro-2-methyl- and 4-chloro-6-methyl-pyrimidine 3deld the corresponding 4-amino derivatives at 100°. 4-Aminopyrimi-dine is not prepared fix>m the chloro analog because of facile self-quaternization (see Section III, B, 2 for comments on factors involved) of the latter. 

Quaternization of the pyrimidine ring of quinazolines enhances its reactivity toward nucleophiles. This reactivity has been used to advantage for preparing 1,2,3,4-tetrahydro derivatives. Methylation of 4-phenylquinazoline occurred at N-1 and N-3 (7 1) and was the first example in which it was shown that alkylating at two different sites in quinazolines was possible. The l-methyl(and 3-methyl)quinazolinium salt that was formed was reduced with sodium borohydride to l-methyl(and 3-methyl)-4-phenyl-l,2,3,4-tetra-hydroquinazoline. Potassium permanganate oxidized the latter compound to l-methyl-4-phenylquinazolin-2(lH)-one. 

Nevertheless, the 9-methyl derivative of 71 failed to produce a quaternary salt because of the steric hindrance effect of the methyl group, as did 2-methyl-3-nitro-4-oxo-4//-pyrido[l,2- ]pyrimidine because of the electron deficiency of the ring. When the pyridopyrimidine bore a substituent containing a nitrogen atom more basic than N-1, the quaternization occurred in that side cliain. ... 

Uracil nucleosides react with 1-methylimidazole in the presence of phosphoryl chloride to give 4-substituted pyrimidin-2-(l/()-one nucleosides via quaternized imidazole species <85CPB2575>. Quaternary salts are believed to be intermediates in the thermal isomerization of 5- to 4-nitroimidazoles in the presence of catalytic quantities of iodomethane (Scheme 12) <88TL536i>. There is a similar transposition of l,2-dimethylimidazole-5-nitrile. 

Ammonia itself adds across the N —C6 azomethine bond in highly electrophilic pyrimidines, for example, in 5-nitropyrimidine or quaternized pyrimidines. Other nucleophiles for additions are the... 

Pyrimidine reacts with trimethylsilyl cyanide and benzoyl chloride with aluminum chloride as catalyst, to give the Reissert-type compound (366) <81JHC443>. The intermediate acylpyrimidinium cation (367) adds a soft nucleophile such as the silyl ether of acetophenone, and the adduct rapidly undergoes a second A-quaternization to (368) with a subsequent nucleophilic attack to form (369) (Scheme 61). The reactive intermediate can also be trapped by reactions with heteronucleophiles <88JCS(P1)725>. Intramolecular nucleophilic addition is shown in the formation of the spiran derivative (370) <92JOC2526>. 

Two publications have appeared on the use of n.m.r. to determine the site of protonation (or protonation ratios) in pyrimidines. Three-bond coupling, e.g. decreases markedly across quaternized nitrogen, as shown... 

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