2- -6-chloropyrazine

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Nucleophilic substitution of the chlorine atom in 2-chloropyrazine and 2-chloroquinoxa-lines has been effected with a variety of nucleophiles, including ammonia and amines, oxygen nucleophiles such as alkoxides, sodium azide, hydrazine, sulfur containing nucleophiles, cyanide, etc., and reactions of this type are typical of the group (see Chapter 2.02). 

Piperidine in weakly polar solvents at 75.2°. The solvent was piperidine for 2-chloropyridine and toluene for 2-chloropyrazine the comparison is not correct but is justified by evidence given in Section III. 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

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. 

Indolylboronic acid (21), easily obtained from commercially available 5-bromoindole, was coupled with 2-chloropyrazine (13) to efficiently furnish 5-(2-pyrazinyl)indole (22) [18]. 

In a similar fashion, ethylation reactions of the corresponding 1-oxide and 4-oxide of 23 have been described using triethylaluminum, diethylzinc and triethylborane. Pentylation and octylation of 2-chloropyrazines and its 4-oxides were also feasible using pentylstannane and octylstannane, but pentylation and octylation of 2-chloropyrazine 1-oxide failed [9],... 

Initially, 31 was obtained as the Sonogashira adduct of 2-chloro-3,6-diisobutylpyrazine and trimethylsilylacetylene. Interestingly, 31 underwent an additional Sonogashira coupling with 2-chloropyrazine (13) to afford unsymmetrical 1,2-bispyrazinylacetylene 32 in excellent yield [26], Here, desilylation occurred in situ, and the resulting terminal alkyne was then coupled with 13. 

The Sonogashira reaction of 2-chloropyrazine 1-oxide gave only recovered starting material. Pentylation and octylation of 2-chloropyrazine 1-oxide also failed [9]. Possible explanations for these results were either catalyst agglomeration or metal formation from pyrazinylpalladium... 

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]. 

Pd-catalyzed carbonylation of 2-chloropyrazine 1-oxide failed, whereas that of 3-chloropyrazine 1-oxide (40) proceeded without deoxygenation of the IV-oxide function to give 3-methoxycarbonylpyrazine 1-oxide (73). This observation was in accord with the failure of Stille reactions of 2-chloropyrazine 1-oxide [9,18]. 

To summarize, both chloropyrazines and chloroquinoxalines are sufficiently activated to serve as viable substrates for palladium chemistry under standard conditions. In contrast to chlorobenzene, the inductive effect of the two nitrogen atoms polarizes the C—N bonds. Therefore, oxidative additions of both chloropyrazines and chloroquinoxalines to Pd(0) occur readily. One exception is 2-chloropyrazine A-oxide, which does not behave as a simple chloropyrazine. All Pd-catalyzed reactions with 2-chloropyrazine A-oxide failed, presumably because the nitrogen atom no longer possesses the electronegativity required for activation. 

In a similar way, 2-arylpyrimidines and 2-arylpyrazines have been prepared from 2-chloropyrimidine and 2-chloropyrazine and various functionalized aryl halides. An iron anode is used in order to generate iron salts that allow the desired couphng reaction (Scheme 150) [267]. 

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... 

Like halopyridines, diazines participate in Sonogashira coupling too. 3,6-dimethyl-2-chloropyrazin, for example on coupling with phenylacetylene under standard conditions, gave the desired compound in good yield, which was further reduced to give a natural product (7.36.)51 (NB. the Heck reaction, which could be considered as an alternate approach would be expected to furnish predominantly the c/.v-olcfin as product). 

The use of the same, highly active catalyst system and microwave heating also allowed for the drastic reduction of the reaction time. The coupling of 3-chloropyridine and 4-toluidine in the presence of 1 % catalyst and sodium /ert-butoxidc gave on 10 minute irradiation the coupled product in 89% yield (7.74.). 2-Chloropyridine, 2-chloroquinoline and 2-chloropyrazine coupled equally well under the same conditions.95... 

In the sole case studied, LiTMP deprotonation of 2-chloropyrazine (112) followed by electrophile quench gave the 3-substituted derivatives 113 in good yields (Scheme 34) (88S881). 

Analogue routes from 4-fluoropyridine (88JHC81), 2-chloroquinoline (89JHC1589), 2-chloropyrazine (88S881), and 3,6-dichloropyridazine (90JHC1377) lead, respectively, to condensed aza-xanthones 155-158 (Scheme 44). 

Displacement of cr-fluorine atoms by nucleophiles is extremely fast the rate of hydrolysis of 2-fluoropyrazine in 0.01 /V NaOH at 26° is 240 times greater than that of 2-chloropyrazine.160 Hexafluoroquinoxaline with 1 mole of sodium methoxide in methanol at —15° yields 2-methoxy-3,5,6,7,8-pentafluoroquinoxaline (149) with 2 moles, the 2,3-dimethoxy analog (150) is formed. 59... 

Reactivity increases in the diazines as compared with pyridines. 3-Chloropyridazine (910) and 2-chloropyrazine, for example, undergo the usual nucleophilic replacements (cf. Section 3.2.3.10.6.ii) rather more readily than does 2-chloropyridine. 2-, 4- and 6-Halogen atoms in pyrimidines are easily displaced. The reactivity of halogens in pyridazine 1-oxides toward nucleophilic substitution is in the sequence 5 > 3 > 6 > 4. 

Amides aminate 2-fluoropyrazine smoothly at 40-50°C in excellent yield (84H(22)i 105). The animation of 2-chloropyrazines 1-oxide needs higher temperatures (100-110°C). 

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