5-Chloro-2,3-dimethylpyrazine

The Heck reaction, first disclosed by the Mori and Heck groups in the early 1970s [65, 66], is the Pd-catalyzed coupling reaction of organohalides (or triflates) with olefins. Nowadays, it has become an indispensable tool for organic chemists. Inevitably, many applications to heterocyclic chemistry have been pursued and successfully executed. In one case, Ohta et al. reacted 2-chloro-3,6-dimethylpyrazine (49) with styrene to furnish ( )-2,5-dimethyl-3-styrylpyrazine (50) [67]. Here, only the E isomer was observed. The outcome will become apparent during the ensuing discussions on the mechanism. 

Ohta s group thoroughly studied the heteroaryl Heck reactions of chloropyrazines and jt-electron-rich heteroaryls [42-44], The substitution occurred at the electron-rich C(5) position of the imidazole ring for the heteroaryl Heck reaction of 2-chloro-3,6-dimethylpyrazine and N-methylimidazole. 

Akita and Ohta disclosed one of the earliest Sonogashira reactions of chloropyrazines and their A-oxides [24, 25]. The union of 2-chloro-3,6-dimethylpyrazine (23) and phenylacetylene led to 2,5-dimethyl-3-phenylethynylpyrazine (29). Subsequent Lindlar reduction of adduct 29 then delivered (Z)-2,5-dimethyl-3-styrylpyrazine (30), a natural product isolated from mandibular gland secretion of the Argentine ants, Iridomyrmex humilis. 

Akita and Ohta revealed one of the early Heck reactions of halopyrazines [23]. They reacted 2-chloro-3,6-dimethylpyrazine (23) with styrene in the presence of Pd(Ph3P)4 and KOAc using A(//-dimethylacetamide (DMA) as solvent to make ( )-2,5-dimethyl-3-styrylpyrazine (51). This methodology was later extended to 2-chloropyrazine IV-oxides although the yields were modest (28-38%) [37]. 

Along with some disubstituted furan 59, mono-arylation product 58 was isolated when 2-chloro-3,6-diethylpyrazine (57) and furan were refluxed in the presence of Pd(Ph3P)4 and KOAc. In the case of 2-chloro-3,6-dimethylpyrazine (23) and thiophene, monothienylpyrazine 60 was the sole product. When 2-chloro-3,6-diisobutylpyrazine was used as substrate, 9% of the disubstituted thiophene was detected. Analogous to the couplings with furan and thiophene, the heteroaryl... 

To synthesize pyrazinecarboxylic esters and pyrazinecarboxamides, chloropyrazines were subjected to Pd-catalyzed carbonylation reactions in either alcohols or dialkylamines [44, 45]. 2-Chloro-3,6-dimethylpyrazine (23) was smoothly carbonylated in methanol containing a catalytic amount of Pd(dba)2 and Ph3P to give 2-methoxycarbonyl-3,6-dimethylpyrazine (70). Somewhat lower yields were observed in the preparation of pyrazinecarboxylic diesters under the same conditions. 

The carbonylation was extended to 2-chloro-3,6-dimethylpyrazine too (7.61.). Under the same conditions as in 7.60. this compound led to the formation of the pyrazinecarboxylic ester in high yield.80... 

Chloro-3,6-dimethylpyrazine (124) gave 2-ethyl-3,6-dimethylpyrazine (125) [Et2Zn, NiCl2.(Ph2PCH2)2CH2, THF, A, 20°C, 3 h 71%] 55 2-ethyl-3,6-di-methylpyrazine 1-oxide (126) (46%) was made similarly 1594 and analogues likewise.551594... 

Chloro-3,6-dimethylpyrazine gave 2,5-dimethyl-3-(2,2,2-trifluoroethoxy)pyrazine [NaOCH2CF3 (prepared in situ), (Me2N)3PO, 150°C, 12 h 54%].787... 

Chloro-3,6-dimethylpyrazine (155, R = Cl) gave 2,5-dimethyl-3-phenylth-iopyrazine (155, R = SPh) [PhSNa (made in situ), Me2SO, reflux, 5 h ... 

Chloro-3,6-dimethylpyrazine (169) gave 2-azido-3,6-dimethylpyrazine (170) (NaN3, Me2NCHO, reflux, 10 h 83% 1314 or NaN3, Me2NCHO, 100°C, 24 h 80%) 231 also analogous products.232,242,1314... 

Chloro-3,6-dimethylpyrazine 4-oxide (224) and the 1,4-dioxide [NaB03, AcOH, 80°C, 24 h 56% and a trace, respectively note the difference in orientation of the product (224) from that (220) obtained from an homologous substrate using persulfate].208... 

Chloro-5,6-dimethyl-2-pyrazinamine 2-Chloro-3,5-dimethylpyrazine 2-Chloro-3,6-dimethylpyrazine 2-Chloro-5,6-dimethylpyrazine 5-Chloro-3,6-dimethyl-2-pyrazinecarbonitrile 5-Chloro-1,4-dimethyl-2,3 (17/, 47/)-... 

Chloro-3,6-dimethylpyrazine 1 -oxide 2-Chloro-3,6-dimethylpyrazine 4-oxide... 

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). 

Preparations of the corresponding hydrazino compounds from 2-chloro-3(or 6)-methylpyrazine and 2-chloro-3,6-dimethylpyrazine with 98% hydrazine in absolute ethanol at reflux (775) and from 2-chloro-3,5-dimethyl-, 2-chloro-3,5,6-trimethyl-, 2-chloro-5- and 6-methyl-3-propyl-, or 2-chloro-5,6-dimethyl-3-propylpyrazines with excess hydrazine hydrate in a sealed tube at 110-130° for 24 hours or for a similar period under reflux in butanol (826) have been described. 

The marked activation of the Ar-oxide function on the chlorine atom of 2-chloropyrazine 4-oxide and 2-chloro-3,6-dimethylpyrazine 4-oxide is also demonstrated by the milder conditions under which these compounds react with ammonia and amines compared with chloro-pyrazine and 2-chloro-3,6-dimethyI pyrazine, respectively. Although 2-chloropyrazine 4-oxide undergoes the expected displacement reaction with ammonia on heating at 115°-120° for 2.5 hours, reaction at 140° for 16 hours gives 2,3-diaminopyrazine, possibly as a result of an addition-elimination reaction on the initially formed 2-amino-pyrazine 4-oxide (Scheme 47).417... 

Akita and Ohta revealed one of the early Heck reactions of halopyrazines [75]. They reacted 2-chloro-3,6-dimethylpyrazine with styrene in the presence of and... 

Chloro-3,6-dimethylpyrazine was smoothly carbonylated in methanol containing a cat-... 

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