4-Chloro quinoxaline

Two closely related series are 2-chloroquinoline and 2-chloro-quinoxaline, and the 6- and 7-substituents in both series are of the... 

Reaction of quinoxaline with the fluorine-iodine-triethylamine system gives 2-fluoroquinoxaline 40 and 2,3-difluoroquinoxaline 41, whose yields depend on the fluorine usage (Equation 6) <1999J(P1)803>. Using 6-chloro-quinoxaline or 6,7-dichloroquinoxaline as the substrate, the monofluoro product is predominantly formed regardless of the amount of fluorine used. It is suggested that the reaction proceeds via attack of the fluoride ion on the a-carbon of an intermediate A -iodo quinoxalinium species followed by elimination of hydrogen iodide with triethylamine. 

Nucleophilic displacement of 2-chloro-3-phenylquinoxaline with methylamine at 100°-150° and with sodium phenoxide in excess of phenol of 100° gives the expected 2-methylamino- and 2-phenoxy-3-phenylquinoxalines.155 2-Chloroquinoxaline and its 3-phenyl derivative undergo ring closure with aminoacetaldehyde dimethylacetal to an imidazo[l,2-a]quinoxaline.136 Nucleophilic substitution of 2-chloro-quinoxaline with hydroxide ion in water is accelerated by cationic micelles and retarded by anionic micelles. These results were correlated with reactions of l-chloro-2,4-dinitrobenzene, and the characteristics of their transition states were discussed.137... 

Chloroquinoxalin-2(1 W)-one 4-oxide has been selectively hydrogenated to 6-chloro-quinoxalin-2(l/f)-one, using sulfided and non-sulfided catalysts, with the catalyst of choice being sulfided platinum. 

By using thiourea in 2N sulfuric acid, Cullen and Harrison (905) were able to convert 2-chloro-3-methylpyrazine at reflux for 30 minutes to 2-mercapto-3-methylpyrazine (55%), and 3-chloro-2,5-dimethylpyrazine similarly treated gave 3-mercapto-2,5-dimethylpyrazine together with another higher molecular weight compound, postulated as either (60) or (61). 2-Amino-3-chloropyrazine refluxed with thiourea in alcohol, and the thiouronium salt refluxed with aqueous sodium hydroxide, produced 2-amino-3-mercaptopyrazine (535). 2-Chloropyrazine failed to react with thiourea (821) under the mild conditions that converted 2-chloro-quinoxaline to 2-mercaptoquinoxaline (1014). 

Chloroquinoxaline undergoes facile nucleophilic displacement reactions with amines and aryloxides to give the corresponding 2-substituted quinoxalines. With diamines, besides the 2-amino derivatives, bis(quinoxalinyl)alkylenediamines are produced. When 2-chloro-quinoxaline is treated with a sodium aryloxide in an excess of the corresponding phenol, a mixture of the expected 2-aryloxyquinoxaline and the corresponding benzofuro[2,3-6]quinoxaline (144) is obtained. 2-Aryloxyquinoxalines are readily cyclized with polyphosphoric acid to benzofuro[2,3-6]quinoxalines. 2-Arylfuro[2,3-h]quinoxalines (146) result from cyclization of 2-phenacyl-3-quinoxalinones (145). ... 

A number of 3-chloro-, 3-methoxy-, and 3-methylthioquinoxaline-2-thiones have been reacted with acylating agents such as alkyl chlorofor-mates, alkyl chlorothioformates, and thiophosgene in the search for compounds for use as pesticides. For example, treatment of 3-chloro-quinoxaline-2-thione with ethyl chloroformate gives the ester 9. 

Analogous displacements have been carried out with thioalkoxide and thiophenoxide ions. Chloride ion has also been displaced from 2-chloro-quinoxalines with various carbon-containing nucleophiles derived from active methylene compounds. For example, with benzyl cyanide, the substituted acetonitrile 9 is obtained and with the carbanions derived from ketones, 2-quinoxalinylketones of type 10 are produced. ... 

A number of quinoxalines carrying substituents in the benzene ring base have been quaternized, including 5-ethoxy,6-methyl, 6-chloro, and some 2-phenyl derivatives, but in none of these cases has the position of quatemization been ascertained. 5-Hydroxy-quinoxaline gives a methiodide which can still form metal complexes, indicating that salt formation occurred on N-1. ... 

Kinetic studies have been carried out on the displacement reactions of various chloroazanaphthalenes with ethoxide ions and piperi-dine. - 2-Chloroquinoxaline is even more reactive than 2-chloro-quinazoline, thus demonstrating the powerfully electrophilic nature of the -carbon atoms in the quinoxaline nucleus. The ease of displacement of a-chlorine in the quinoxaline series is of preparative value thus, 2-alkoxy-, 2-amino-, - 2-raethylamino-, 2-dimethyl-amino-,2-benzylamino-, 2-mercapto-quinoxalines are all readily prepared from 2-chloroquinoxaline. The anions derived from substituted acetonitriles have also been used to displace chloride ion from 2-chloroquinoxaline, ... 

Aryl-5-oxo-1,2,3,5-tetrahydropyrido[ 1,2,3-i/e]quinoxaline-6-carboxy-mides were prepared from 7-chloro derivatives and arylboronic acids in the presence of Na2C03, diphenylphosphinated divinylbenzene-crosslinked polystyrene and Pd(PPh3)4 catalyst. 7-Chloro derivatives were obtained from 7-hydroxy derivatives by heating in POCI3 at 50°C for 3 h (01MIP12). 

Nucleophilic halogen exchange, using cesium fluoride and 18-crown-6 in tetrahydrofuran, gave high yields of 2-, 3-, and 2,3,-di-fluoroquinoxalines from the chloro analogues [87H)26)1215]. The Balz-Schiemann process has been used successfully to make 2-fluoro-quinoxaline (84MI8). 

Both 2-chloro- and 2,6-dichloro-quinoxalines can be made by ring expansion of 1-methylimidazole using trichloromethyl radicals (91MI5). 

Benzenediamine (148) and frani-l-chloro-l,2-bis(hydroxyimino)ethane (149) gave 2(177)-quinoxalinone oxime (150), perhaps better formulated as 2-hydroxyaminoquinoxaline (151) (EtOH, 20°C, 3 h 71%) 6,7-dibromo-l,2-benzenediamine likewise gave 6,7-dibromo-2-hydroxyamino-quinoxaline. ... 

The same substrate (242) and methyl 4-[2-chloro-2-(p-chlorophenylhydrazono) acetyljbutyrate (245) gave 2-(p-chlorophenylhydrazino)-3-(3-methoxycarbo-nylpropyl)quinoxaline (246) (EtaN, EtOH, reflux, 15 min 42%). ... 

Only one procedure has been reported recently within this category. Thus 7-chloro-l-methyl-5-phenyl-2,3-dihydro-lH-benzodiazepin-2-one 4-oxide (437) with dimethyl acetylenedicarboxylate in methylene chloride at 20° C for 3 days gave a separable mixmre of the primary tricyclic adduct, dimethyl lO-chloro-6-oxo-llb-phenyl-5,6,7, 1 lb-tetrahydroisoxazolo[2,3-t/] [ l,4]benzodiazepine-1,2-dicarboxylate (438), and its rearrangement product, 6-chloro-4-(2-methoxalyl-2-methoxycarbonyl-l-phenylvinyl)-l-methyl-3,4-dihydro-2(lT0-quinoxalinone (439) each product afforded 6-chloro-l-methyl-2(l//)-quinoxalinone (440) on refluxing in ethanol (see also Section 1.7.13). However, the final quinoxaline (440) was best obtained in 75% yield) by simply heating the initial substrate (437) and dimethyl... 

Although derivatives of 2,1,3-benzoxadiazole have been used extensively to make quinoxalines (see Section 1.6.7), the corresponding selena and thia systems have been paid scant attention for that purpose. However, 5-chloro-4-nitro-2,l,3-benzoselenadiazole (456) has been used as a convenient source of 4-chloro-3-nitro-1,2-benzenediamine (457) (HCl + HI, 20°C, 2 h 88%), which was then converted into 6-chloro-5-nitro-2,3(l//,4//)-quinoxalinedione (458) (oxalic acid, 2M HCl, reflux, 2.5 h 23%). ° In addition, irradiation of 2,1,3-benzoselenadiazole (460, X = Se) or 2,1,3-benzothiadiazole (460, X = S) with dimethyl acetylenedicarboxy-late afforded, among other products, dimethyl 2,3-quinoxalinedicarboxylate (459)... 

Dimethyl 4-(A -p-bromobenzylidene-A-methylhydrazino)-8-chloro-3aH-isoxa-zolo[2,3-fl]quinoxaline-2,3-dicarboxylate (568) in refluxing dimethylformamide for 10 h afforded 2-(A -p-bromobenzylidene-A-methylhydrazino)-6-chloroquinoxa-line (569) in 17% yield." ... 

Chloro-1 -methyl-3-trifluoromethyl- //-[ 1,3,4]oxadiazmo[5,6-fc]quinoxaline (570) suffered thiolytic ring fission in refluxing pyridine (containing phosphorus penta-sulfide) during 1 h to provide 7-chloro-3-[7/-methyl-A( -(triiluoroacetyl)hydrazino]-2(17/)-quinoxalinethione (571) in 87% yield. ... 

Acetonyl-3-chloroquinoxaline (111) gave, as the main product, 2-chloro-3-(2-chloroprop-l-enyl)quinoxaline (112) (POCI3, 30 min 42%) also homologs... 

Note A surprising aminolytic displacement of a phenylethynyl group has been observed when it occupies a position adjacent to a chloro substituent on the quinoxaline ring. 

Chloro-3-phenylethynylquinoxaline gave 2,3-dipiperidinoquinoxaline (piperidine, reflux, 5h 90%), 2,3-dimorpholinoquinoxaline (morpholine, similarly 95%), or 2,3-bis(2-hydroxyethylamino)quinoxaline (ethanolamine, PhH-EtOH, reflux, 15 h 74%). For an example of amine addition to the triple bond, see Section 4.2.1. 

Chloro-3-methylquinoxaline 4-oxide gave 3-chloro-2-quinoxalinecarbalde-hyde 1-oxide (172) (SeOi, PhH, reflux, h 72%) dioxane may be used as solvent for such oxidations yielding, for example, 3-amino-2-quinoxaline-carbaldehyde ethyl acetate may also be so used. 

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