Quinoxalines hydrogenation

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

This method is widely applicable to the unambiguous synthesis of quinoxalin-2-ones." It involves the intermediate preparation of a l,2,3,4-tetrahydro-2-oxoquinoxaline by the reductive ring closure of the o-nitrophenyl derivative of an a-aminoacid. These derivatives are formed readily from the aminoacid and an o-nitrohalogenobenzene. The final step of oxidation of the tetrahydro- to the dihydro-quinoxa-line is carried out with potassium permanganate or hydrogen peroxide. The preparation of 7-nitroquinoxalin-2-one illustrates the application of this synthesis ... 

Catalytic reduction of 2-acetyl-3-methylquinoxaline (29) in ethanol with 1 mole of hydrogen, gives a deep crimson solution, from which red-brown needles of 2-acetyl-l,4-dihydro-3-methylquinoxaline (30) are obtained. Ethanolic solutions of (30) reoxidize on exposure to air to 2-acetyl-3-methylquinoxaline, but the solid dye is stable in air for several days. Similar results are obtained with 2-acetyl-3-phenyl-quinoxaline (31), from the reduction of which a purple-red dye (32) is obtained. ... 

Tetrahydro derivatives are formed when either quinoxaline or 6-chloroquinoxaline is reduced with lithium aluminum hydride in ethereal solution. Similar reduction of 2,3-dimethylquinoxaline gives the meso-(cts)-1,2,3,4-tetrahydro derivative. This is shown to be a stereospecific reduction since lithium aluminum hydride does not isomerize the dl-(trans)-compound. Low temperature, platinum catalyzed, hydrogenation of 2,3-dimethylquinoxaline in benzene also gives meso (cis) -l,2,3,4-tetrahydro-2,3-dimethylquinoxaline. ... 

Hydrogenation of quinoxaline, or 1,2,3,4-tetrahydroquinoxaline, over a 5% rhodium-on-alumina catalyst at 100°C and 136 atm, or over... 

In the preparation of quinoxaline N-oxides, it is advantageous to use peracetic acid rather than aqueous hydrogen peroxide as the... 

Oxidation of 4-methylquinoxalin-3-one 2-carboxy-fV -methylamlide (45) with hydrogen peroxide and acetic acid furnishes the 1-oxide but, on removal of either or both of the fV-raethyl groups (giving 46, 47, or 48), oxidation with hydrogen peroxide or with peracetic or perbenzoic acid results in the removal of the carboxyamide groups and the formation of a quinoxaline-2,3-dione. ... 

Methylthioquinoxaline is oxidized by hydrogen peroxide in acetic acid at room temperature mainly to 2-methylsulfonylquinoxa-line (88) at 55°C, 2-methylsulfonylquinoxaline 4-oxide (89) and quinoxaline-2,3-dione are formed. 

Catalytic hydrogenation of 5-oxy-7,8,9,10-tetrahydro-6a//-pyrido[l,2-a]quinoxalin-6-ylamines 352 over Pearlman s catalyst under 5 atm of H2 in MeOH for 5-7 days at room temperature gave 6,6u,7,8,9,10-hexahydro-5//-pyrido[ 1,2-u]quinoxalines (01EJOC987). 

Aryl-5-oxo-l,2,3,5-tetrahydropyrido[l,2,3-ife]quinoxaline-6-carboxa-mides were prepared from 1-benzyl derivatives by catalytic hydrogenation over 10% Pd/C (01MIP12). 

Benzocyclobutene-l,2-dione (11) can be condensed with benzene-1.2-diamine to provide an annulated quinoxaline (cf. Houben-Weyl, Vol. E9b/Part 2, p203), which on oxidation with hydrogen peroxide in acetic acid leads to the 1,4-diazocine derivative 12.34... 

Catalytic hydrogenation or chemical reduction with concomitant cyclization has been used to convert several types of such nitro substrates into a variety of quinoxalines. The following examples, classified according to type of substrate, illustrate the possibilities available. 

Complexes. The structure of an n a charge-transfer complex between quinoxaline and two iodine atoms has been obtained by X-ray analysis and its thermal stability compared with those of related complexes. The hydrogen bond complex between quinoxaline and phenol has been studied by infrared spectroscopy and compared with many similar complexes. Adducts of quinoxaline with uranium salts and with a variety of copper(II) alkano-ates have been prepared, characterized, and studied with respect to IR spectra or magnetic properties, respectively. 

Whether activated or not, halogeno substituents may be removed in favor of hydrogen by chemical reduction or by catalytic hydrogenation (usually in the presence of a base and often accompanied by nuclear reduction). Such dechlorination may also be achieved by loss of hydrogen halide from a nucleus-reduced quinoxaline. The following examples illustrate these procedures. 

Dimethyl-6-methylamino-5-quinoxalinamine (175) (prepared freshly as an ethanolic solution by catalytic hydrogenation of the corresponding nitro compound) and cyanogen bromide gave 3,4,8-trimethyl-3//-imidazo-[4,5-/]quinoxalin-2-amine (176) (20°C, 3.5 h 75%) the analogous... 

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

The iV-( -nitrophcnyl)pipcrazinc-2-carbonitrilc 251 (Y = NBOC) was reductively cyclized to the tricyclic /V-oxides 252 (Y = NBOC) either by catalytic hydrogenation, or by electrochemical reduction. Electrochemical reduction gave lower yield. Compounds 251 were prepared by electrochemical cyanation of the iV-(o-nitrophenyl)piperazine 250. The jV-oxides 252 were further hydrogenated to the 2,3,4,4 ,5,6-hexahydro-l//-pyrazino[l,2- ]quinoxaline 253 (Y = NBOC) (Scheme 46) <2001EJ0987>. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Figure 10. Crystal structure of quinoxaline showing the unit cell and the C-H—N hydrogen bonded catemer. Top Experimental structure with Z = 5. The symmetry independent molecules are numbered. Bottom Structure determined with the Polymorph Predictor (Cerius2) software and having Z =1. The two structures are nearly equivalent. Would one find other related structures with different values of Z ...

Thus, the substituted tetrazoles 113 upon oxidation with lead tetraacetate gave rise to the fused tetrazoles 114, in most cases in high yields. Tetrazole derivatives 115, bearing an anisidine side chain, also underwent oxidative cyclization and afforded 10-methoxycarbonylmethyltetrazolo[l,5- ]quinoxaline 116 in good yield. This compound was obtained as a mixture of tautomers (with participation of the methylene hydrogen atoms) and the depicted tautomeric form 116 proved to be dominant. 

Chan and coworkers developed a new diphosphine 9, related to MeO-BiPhep 5 (Fig. 10) [21]. [lr(p-Cl)(COD)]2/9/l2 catalytic system provided similar enantios-electivities than [lr(p-Cl)(COD)]2/5/l2 in the Ir-catalyzed hydrogenation of quinolines but higher enantioselectivitites in the reduction of 2-methyl-quinoxaline and 2,3,3-trimethylindolenine (Fig. 10). 

Binol-derived phosphoroamidite PipPhos (19) has been successfully used as a ligand for the Ir-catalyzed asymmetric hydrogenation of 2- and 2,6-substituted quinolines [39], 2- and 2,6-substituted quinoxalines [40], and IV-aryl imines [41] (Fig. 16). 

In the hydrogenation of 2- and 2,6-substituted quinoxalines, the presence of piperidine hydrochloride as additive full conversions and enantioselectivities of up to 96% were obtained [40]. These results represent the highest selectivity reached for this class of heterocyclic compounds reported as yet [22, 42, 43]. 

Fig. 16 Summary of the best results obtained in the Ir-catalyzed hydrogenation of quinolines, quinoxalines, and Af-aryl imines using binol-derived phosphoroamidite PipPhos 19 ligand...

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