Displacement pyrimidine

Nitrogen nucleophiles used to diplace the 3 -acetoxy group include substituted pyridines, quinolines, pyrimidines, triazoles, pyrazoles, azide, and even aniline and methylaniline if the pH is controlled at 7.5. Sulfur nucleophiles include aLkylthiols, thiosulfate, thio and dithio acids, carbamates and carbonates, thioureas, thioamides, and most importandy, from a biological viewpoint, heterocycHc thiols. The yields of the displacement reactions vary widely. Two general approaches for improving 3 -acetoxy displacement have been reported. One approach involves initial, or in situ conversion of the acetoxy moiety to a more facile leaving group. The other approach utilizes Lewis or Brmnsted acid activation (87). 

The ease of displacing a chloro, bromo or iodo substituent in comparable pyrimidines by aminolysis is disappointingly similar. Using 2-halogeno-4,6-dimethyl- and 4-halogeno-... 

Imidazo[l,2-c]pyrimidine, 2,5,7-trichloro-nucleophilic displacement reactions, 5, 627 Imi dazo[ 1,2-a]pyrimidines pK, 3, 338 reactivity, 5, 627 synthesis, 5, 647 Imidazo[ 1,2-c]pyrimidines reactions, 5, 627 structure, 5, 610 synthesis, 5, 648-649 lmidazo[ 1,5-a]pyrimidines reactions, 5, 628 synthesis, 5, 649 lmidazo[l,5-6]pyrimidines synthesis, 5, 649-650 Imidazopyrrolopyridines bromination, 4, 506 lmidazo[4,5-6]quinoxaline nomenclature, 1, 22... 

Pyrimidine, I-alkyl-2-methyltetrahydro-C-thioacylation, 4, 807 Pyrimidine, 4-alkylsulfinyl-nucleophilie displaeement reaetions, 3, 97 Pyrimidine, 6-alkylsulfinyl-nucleophilic displacement reactions, 3, 97 Pyrimidine, 2-alkylsulfonyl-nueleophilie displaeement reactions, 3, 97 Pyrimidine, 4-alkylsulfonyl-nucleophilic displacement reactions, 3, 97 Pyrimidine, 6-alkylsulfonyl-nucleophilie displaeement reactions, 3, 97 Pyrimidine, alkylthio-dealkylation, 3, 95 desulfurization, 3, 95 oxidation, 3, 96 synthesis, 3, 135, 136 Pyrimidine, 2-alkylthio-aminolysis, 3, 96 hydrolysis, 3, 95 Prineipal Synthesis, 3, 136 Pyrimidine, 4-alkylthio-aminolysis, 3, 96 hydrolysis, 3, 95 Pyrimidine, 6-alkylthio-aminolysis, 3, 96 hydrolysis, 3, 95 Pyrimidine, 4-allenyloxy-rearrangement, 3, 93 Pyrimidine, 4-allyloxy-2-phenyl-rearrangement, 3, 93 Pyrimidine, 4-allynyloxy-rearrangement, 3, 93 Pyrimidine, 4-anilino-2,5,6-trifluoro-NMR, 3, 63 Pyrimidine, 2-aryl-pyrroleaeetic aeid from, 4, 152 Pyrimidine, arylazo-synthesis, 3, 131 Pyrimidine, 4-arylazo-reduetion, 3, 88... 

Pyrimidines have also served as electrophiles in crown synthesis from this group. 4,6-Dichloropyrimidine reacts with diethylene glycol and sodium hydride in anhydrous xylene solution to form the 20-crown-6 derivative as well as the other products shown in Eq. (3.48). Note that a closely related displacement on sy/rr-trichlorotriazine has been reported by Montanari in the formation of polypode molecules (see Eq. 7.5). 

A large number of nucleophilic substitution reactions involving interconversions of pyridopyrimidines have been reported, the majority of which involve substituents in the pyrimidine ring. This subject has been reviewed previously in an earlier volume in this series which dealt with the theoretical aspects of nucleophilic re-activiti in azines, and so only a summary of the nucelophilic displacements of the substituent groups will be given here. In general, nucleophilic substitutions occur most readily at the 4-position of pyrido-... 

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... 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

Alkylthio, arylthio, and thioxo. The thioxo group in pyrimidine-2,4-dithione can be displaced by amines, ammonia, and amine acetates, and this amination is specific for the 4-position in pyrimidines and quinazolines. 2-Substitution fails even when a 5-substituent (cf. 134) sterically prevents reaction of a secondary amine at the 4-position. Acid hydrolysis of pyrimidine-2,4-dithione is selective at the 4-position. 2-Amination of 2-thiobarbituric acid and its /S-methyl derivative has been reported. Under more basic conditions, anionization of thioxo compounds decreases the reactivity 2-thiouracil is less reactive toward hot alkali than is the iS-methyl analog. Hydrazine has been reported to replace (95°, 6 hr, 65% 3deld) the 2-thioxo group in 5-hexyl-6-methyl-2-thiouracil. Ortho and para mercapto- or thio- azines are actually in the thione form. ... 

Sulfonate and sulfamoyl. A nitrile group is introduced into the 3- or 4-position of pyridine and into the 2- or 4-position of pyrimidine by displacement of a sulfonate group with potassium cyanide. Amines, water, or hydrazine displace 2- or 4-sulfonate groups from pyridine derivatives. 4-Quinolinylsulfonates (139)... 

The 0X0 group facilitates reaction relative to H, CH3, or NH2 substituents on pyrimidines in the displacement of mercapto, arylthio, or amino groups by amines. The 2-thioxo group is reactive toward... 

Triazanaphthalene (449) is the most unstable of the pyrido-pyrimidines to ring-degradation at pH 2 or pH 7.7 The 4-oxo derivative was converted into the 4-thioxo compound via nucleophilic displacement of the acyloxy intermediate formed with phosphorus pentasulfide. The 4-carboxymethylthio-pyridopyrimidine underwent some substitution by hydroxide ion but primarily gave the ring-opening reaction, which is facilitated by resonance activation of the 2-position by the 6-aza moiety. 

OKO-l,3,7-triazanaphthalene (450) forms acyloxy derivatives in situ with phosphorus oxychloride and pentasulfide which undergo nucleophilic displacement with chloride ion and with a complex sulfide ion, respectively, to form the 4-chloro and 4-thioxo derivatives. The 4-carboxymethylthio compoimd failed to undergo the ring-opening reaction (see below) characteristic of more activated azino- and diazino-pyrimidines, but it did yield about 10% of the 4-0X0 displacement product. 

Only a few displacements involving mono-substituted compounds are known. 4-Chloropyrido[2,3-d]pyrimidine reacts readily (96°, 30 min) with aqueous aniline, hydrazine, or ammonia and with diethylamine (0°, 16 hr). In contrast to the 1,3,6-isomers, the 4-oxo and 2,4-dioxo derivatives are readily converted into chloro and thioxo derivatives by phosphorus oxychloride and pentasul-... 

Reaction of 5-chloro-l,2,4-triazolo[l,5-c]pyrimidines (165) with sodium hydroxide, thiourea, or hydrazine hydrate (79AJC1585) or with sodium azide (85EUP152841) also caused the displacement of the chlorine atom to... 

Reaction of 1,3-propanediamine and a mixture of a and isomers of 5-bromo-5-deoxy-D-xylofuranose in H2O for 10 min gave 1 R-(la,8p,9a9aa)-7,8,9-trihydroxyperhydropyrido[l, 2-u]pyrimidine (112, R = H) in 27% yield (99T6759). Reaction of 5-bromo-5-deoxy-D-xylofuranose and A -methyl-1,3-propanediamine in H2O at room temperature afforded a 5 1 mixture of 1-methyl 117 and 5-methyl 118 derivatives of 7,8,9-trihydroxyperhydropyr-ido[l, 2-u]pyrimidine 112 (R = H). When this reaction was carried out in the presence of 3 moles of NEts the product ratio of 117 to 118 was 1 2. The influence of NEt3 on the product ratio may be a consequence of it scavenging HBr and freeing the more basic and more nucleophilic methylamino group for participation in the displacement reaction. 

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