2-Chloropyrazine methylation

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

With palladium catalysis, both 2,6-dichloropyrazine 3 and chloropyrazine N-oxide 5 were methylated using trimethylaluminum to give adducts 4 and 6, respectively [7,8]. 

Intriguingly, the Stille coupling of quaternary pyridylstannane 12 with 2-chloropyrazine (13) proceeded to afford adduct 14 [12]. A-Methylated 3-(tributylstannyl)pyridine 12 was easily prepared by refluxing 3-(tributylstannyl)pyridine (11) with methyl tosylate in EtOAc. By contrast, only 29% yield of the coupling adduct was isolated from the Stille reaction of 3-(tributylstannyl)pyridine A-oxide and 13. 

In the simplest example, 2-chloropyrazine can be treated with methylhydrazine to afford 244a Commencing with 244a, treatment with 3-methyl-2-butanone gives an enamine, which, after thermal Fischer-type cyclization, leads to 245 (Equation 88) <1994MI17>. 

The Stille coupling of pyridylstannanes was also extended to stannylpyridinium salts. 1-Methyl-3-tributylstannylpyridinium tosylate was coupled with 2-chloropyrazine in excellent yield (7.27.), Using the corresponding /V-oxidc the same coupling gave only 29% yield.38... 

Iodopyrazines are prepared from the corresponding chloropyrazines by treatment with a saturated solution of sodium iodide in methyl ethyl ketone containing a little hydriodic acid.295... 

Aminopyrazines are conveniently prepared from carboxamido-pyrazines by application of the Hofmann reaction (see Section V,B). Thus, Camerino and Palamidessi prepared aminopyrazine in 80% yield from carboxamidopyrazine.312 Aminopyrazine may also be prepared from the reaction of pyrazine with sodamide in liquid ammonia,313 and 3-amino-2,5-dimethylpyrazine is the product of amination of 2,5-dimethylpyrazine with sodamide in dimethyl-aniline.311 The ammonolysis of halopyrazines also represents a useful preparative procedure for aminopyrazines (see Section V,C). This reaction proceeds most easily in the case of fluoro compounds for example, fluoropyrazine is converted into aminopyrazine in 70% yield by treatment with concentrated aqueous ammonia at room temperature for 3 days,299 whereas the corresponding reaction with chloropyrazine has been carried out in a sealed tube at 150°.147 Alkaline hydrolysis of 2,4-dihydroxypteridines followed by decarboxylation yields aminopyrazines 315 thus, high-temperature alkaline hydrolysis of 7-methyl-2,4-dihydroxypteridine (7-methyIlumazine) gives, after decarboxylation of the intermediate pyrazinecarboxylic... 

Methyl 6-chloro-2-pyrazinecarboxylate 4-oxide gave methyl 6-thioxo-l,6-dihy-dro-2-pyrazinecarboxylate 4-oxide (138) (NaHS, EtOH, 20°C, 3 h 46%).89 2-Chloropyrazine gave 2( l//)-pyrazincthione [NaHS/MeOH (made in situ), reflux, 1 h 91%].1602... 

A Ally /V -methyl-3,5-bismethylamino-2,6-pyrazinedicarboxamide 2-Allyloxycarbonylamino-3,5,6-trichloropyrazine 2-Allyloxy-3-chloropyrazine 2-Allyloxy-6-chloropyrazine 2-Allyloxy-6-iodopyrazine 2-Allyloxy-3-isopropyl-5,6-dimethylpyrazine 2-Allyloxy-3-methylpyrazine... 

Many chloropyrazines have been prepared from hydroxypyrazines by reaction with mixed phosphorus pentachloride-phosphoryl chloride as follows 2-hydroxy-pyrazine to 2-chloropyrazine (818), 2-hydroxy-3-phenylpyrazine to 2-chloro-3-phenylpyrazine (535), 2-hydroxy-6-methyl- and 5-hydroxy-23-[Pg.102]

Fluoropyrazine has been prepared from 2-chloropyrazine and anhydrous potassium fluoride in refluxing dimethyl sulfoxide (882) or Af-methyl-2-pyrrolidone at 185° (883). Similarly 3-fluoro-2,5-dimethylpyrazine has been prepared from its chloro analogue and dry potassium fluoride in A -methyl-2-pyrrolidone and 2-chloro-6-fluoropyrazine and 2,6-difluoropyrazine from 2,6-dichloropyrazine (883). 

Rates of methylation (from n.m.r. studies) of 2-fluoro- and 2-chloropyrazines with methyl iodide in dimethyl sulfoxide at room temperature relative to pyrazine have been determined as 0.16 and 0.15, respectively (666). Methylation of 2-chloropyrazine with methyl iodide in benzene at reflux gave one methiodide (912). 2-Chloropyrazine also formed a p-fluorophenacyl bromide salt (913). 

Chloro-l-methylpyrazinium ion with liquid ammonia reacted by addition at the 2-position to give 2-amino-3-chloro-l-methyl-1,2-dihydropyrazine (24) (609). The hexafluoroantimonate salt of perfluoropyrazine has been prepared and F n.m.r. measurements used to determine the relative order of its base strength with other perfluoroheterocycles (914). Hydrogen-deuterium exchange rates of Hj and Hg in 3-chloro(and other substituted)pyrazine l-oxide(s) have been correlated with a-constants, and the logs of the H2 exchange rates have been shown to be linearly related to the pK values (745). The pK value of 3-chloropyrazine 1-oxide is - 1.05 (745). 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

Chloropyrazine with trimethylamine in benzene at 100° did not give the trimethylammonio compound but gave 2-dimethylaminopyrazine with loss of methyl halide (936). 2-Chloro-5-phenylpyrazine heated with hexamethylphosphoric triamide at 200° for 1 hour gave 2-dimethylamino-5-phenylpyrazine, and similar reactions were observed with 3-chloro-2,5-diethyl-, 3-chloro-2,5-diisobutyl-,... 

Normal nucleophilic substitution occurred on treatment of 2-carbamoyl-3-chloropyrazine with alcoholic methylamine at 130° (423, 836) 2-chloro-3-(4 -morpholinocarbonyOpyrazine with morpholine at reflux in benzene (867) 2dimethyl sulfoxide at 65° (857) and cyclohexylamine in benzene at reflux (946) 3-chloro-2-methoxycarbonyl-5-phenylpyrazine with alcoholic methylamine at 140° (375) 2-carboxy-3-chloropyrazine with anhydrous ammonia at 100° for 5 hours (947) 2-carbamoyl-6-chloropyrazine with aqueous methylamine at reflux (940) 2-chloro-6-(4 -morpholinocarbonyl)pyrazine (and other amides) and 2-chloro-6-methoxycarbonylpyrazine with morpholine (and other amines) (870, 948, 949) and 2-chloro-6-methoxycarbonylpyrazine with liquid ammonia at 80° (870). 2-Chloro-3-methoxycarbonylpyrazine fused with guanidine carbonate gave 2-amino4-hydroxypteridine and its 7-methyl-, 7-phenyl, and 6,7-diphenyl analogues were prepared similarly (371,375). 

Replacement reactions of chloropyrazines with a large number of alkoxides have been observed. Some examples are 2-chloropyrazine with methoxide (974), perdeuteromethoxide (975), ethoxide and isopropoxide ions (668a), and as follows. Methoxide ion 2-chloro-3-methyl (49, 686, 687, 735, 736, 976) 2-chloro-5-deutero-3-methyl (687) 2-chloro-5-methyl (686, 735, 736) 2-chloro-6-methyl (686, 735, 736) 2-chloro-3,5-dimethyl (687, 844) 3-chloro-2,5-dimethyl (844, 977-979) 2-chloro-3-s-butyl (80, 649, 693) 2-chloro-3-isobutyl (80, 693) ... 

The reactivity of 2-fluoropyrazine with aqueous sodium hydroxide to give 2-hydroxypyrazine has been investigated (882, 884). In 1.07N sodium hydroxide at 26° the reaction followed pseudo-first-order kinetics with a half-life of 43 minutes, whereas under the same conditions 2-chloropyrazine had a half-life of 18 days, and 2-iodopyrazine and 2-fluoropyridine remained unchanged (882, 884). Thus, under the above conditions, 2-fluoropyrazine was 640 times more reactive than 2-chloropyrazine (882). Hydrolysis of 2-fluoropyrazine in 61V hydrochloric acid proceeded at a much slower rate with a half-life of 4 days at room temperature (884). Some literature preparations of hydroxypyrazines by hydrolysis of halogenopyrazines (chloropyrazines with aqueous sodium or potassium hydroxide unless otherwise specified) are as follows 2-hydroxy (150°) (818) 2-hydroxy-3-methyl (reflux) (680) 2-hydroxy-3,5-dimethyl (reflux) (978) 3-hydroxy-2,5-dimethyl (reflux) (98, 312, 680, 740) [at 120° (978)] 3-hydroxy-2,5-di- -butyl (powdered potassium... 

Halogenopyrazines react with alkylthiolate ions to give alkylthiopyrazines, by replacement of one or, in some cases, two halogeno substituents the reaction is usually carried out at reflux or at elevated temperatures in sealed tubes. The following pyrazines have been prepared by these methods from the chloropyrazines unless otherwise specified 2-ethylthio and 2-isopropylthio (668a) 2-methyl-3-methylthio (735, 844,977) 2-methyl-5(and 6)-methylthio (735) 2,5-dimethyl-3-methyl(ethyl,... 

Fluoropyrazine refluxed with aqueous sodium sulfite for 2 hours gave the sodium salt of 2-sulfopyrazine (ca. 70%) (882,884), whereas 2-chloropyrazine with aqueous sodium sulfite at 150° for 12 hours gave only 44% of the desired product (819, 884). 2-Chloro-3-methylpyrazine (71) with magnesium (and a little methyl iodide) in tetrahydrofuran with phenyldimethylchlorosilane (72) gave 2-methyl-3-dimethylphenylsilylpyrazine (73) (929). 

Chloropyrazine 1-oxide and 3-chloropyrazine 1-oxide both react with sulfanilamide to give the corresponding sulfanilamidopyrazine 7V-oxides (1032, 1033) 3-chloro-2-methylpyrazine 1-oxide with piperidine at reflux gave 2-methyl-3-piperidinopyrazine I -oxide, and with dimethylamine gave 3-dimethylamino-2-methylpyrazine 1-oxide (793) 2-amino-3-chloropyrazine 1-oxide with aqueous ammonia and copper powder at 140-150 for 18 hours gave 2,3-diaminopyrazine... 

Methyl-2-oxo-l, 2-dihydropyrazine with phosphorus pentasulfide in pyridine at reflux was converted into l-methyl-2-thio-l,2-dihydropyrazine (18) (821,1100), and 3-chloropyrazine 1-oxide with sodium hydrogen sulflde in ethanol at room temperature gave 3-mercaptopyrazine 1-oxide (19) (1035). Whereas 3-chloro-2,5-dimethyipyrazine 1-oxide reacted slowly with thiourea in ethanol, and the use of water in place of ethanol caused some increase in reaction rate, the reaction in 2A sulfuric acid at reflux for 30 minutes gave 3-mercapto-2,5-dimethylpyrazine 1-oxide (85%), and 3-mercapto-2-methylpyrazine 1-oxide was prepared similarly (905). 

Alkylpyrazines with other substituents have been oxidized to carboxylic acids as follows 2-acetamido-6-methylpyrazine was oxidized in aqueous magnesium sulfate with potassium permanganate to 2-acetamido-6aqueous potassium permanganate at room temperature to 2-carboxy-3-chloropyrazine, which was also obtained by oxidation of 2-chloro-3-methylpyrazine with selenium dioxide in boiling aqueous pyridine (947). Oxidations of 2-methoxy-3-methyl-... 

High-speed Pd-catalyzed amination of 2-chloropyrazine with 2V-methylaniline under temperature-controlled microwave heating produced 2-(7V-methyl-7V-phenyl)pyrazine in high yield (151) [73]. 

KOAc using MA-cli methyl acetamide (DMA) as solvent to make ( )-2,5-dimethyl-3-styrylpyrazine (153). This methodology was later extended to 2-chloropyrazine-A-oxides although the yields were modest (28-38%) [76]. 

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