Hydroxypyrazines oxidation

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. 

Condensation of 1,2-diaminopropane and 2,3-dioxobutane similarly gives 5,6-dihydro-2,3,5-trimethylpyrazine which is oxidized to the corresponding pyrazine in 58% yield by treatment with potassium hydroxide pellets.111 Hydroxypyrazines are very conveniently prepared from a,j8-dicarbonyl compounds and a-amino acid amides [Eq. (1)],30,112 and pyrazinecarboxylic acids have been prepared by condensation of an a,)5-diketone with an a,/ -diaminocarboxylic acid, followed by oxidation (Scheme 2). Thus, condensation of benzil and... 

Direct ring syntheses are also available for the preparation of hydroxypyrazines. Thus, haloacylation of an a-aminoketone, followed by reaction with ammonia and oxidation represents a general synthesis of 5,6-disubstituted and 3,5,6-trisubstituted 2-hydroxypyrazines.339 This is illustrated by the preparation of 5,6-dimethyl-2-hydroxy-pyrazine (Scheme 39). Hydroxypyrazines are very conveniently... 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

A. oryzae A21 grown in media containing 0.05 Af valine and 0.01 Af isoleucine gave 3-s-butyl-2-hydroxy-6-isopropylpyrazine 1-oxide (104a). Tetramethylpyrazine has been obtained from a strain of Bacillus subtilis (105) and fromfi. natto (106), and emimycin, 3-hydroxypyrazine I-oxide (19), has been isolated from the broth of Streptomyces No 2020-1 (107,108). 

HYDROXYPYRAZINE 1-OXIDES FROM a-AMINOHYDROXAMIC ACIDS AND 1,2-DICARBONYL COMPOUNDS OR a,P-UNSATURATED a-BROMOALDEHYDES... 

Dunn and co-workers (545, 546) first reported the reaction of a-amino-hydroxamic acids (8) with 1,2-dicarbonyl compounds (9) to give 2-hydroxypyrazine 1-oxides (10). For example, DL-alanine hydroxamic acid (8, R = Me) and diacetyl (9, = Me) gave 2-hydroxy-3,5,6-trimethylpyrazine 1-oxide (10, R = R =... 

In an attempt to force the condensation of an a-aminohydroxamic acid and a potential a-keto aldehyde to give 3,6-disubstituted 2-hydroxypyrazine 1-oxides, Dunn and co-workers (545, 546) studied the condensation of a-aminohydroxamic... 

The preparation of 3,6-disubstituted 2-hydroxypyrazine 1-oxides from (11), which were derived from a-aminohydroxamic acids and a,fl-unsaturated a-bromo-... 

Klein et al. (978) first attempted the alkaline hydrolysis of 3-chloropyrazine 1 -oxide to 3-hydroxypyrazine 1 -oxide, and although spectroscopic evidence indicated the formation of the hydroxy compound, good quality homogeneous material could not be isolated. Later work by Berkowitz and Bardos (1034) has shown that 3-chloropyrazine 1-oxide was hydrolyzed by refluxing with two equivalents of aqueous sodium hydroxide, and treatment of the product with trimethylsilyl chloride and triethylamine gave 3-(trimethylsilyl)oxypyrazine 1-oxide. 3,6-Di-s-butyl-2-hydroxypyrazine 1-oxide has been prepared from the chloro analogue (no details given) (982). Hydrolysis of 2-amino-6-chloro-3-cyano-5-methylpyrazine... 

Amino-2prepared from 2-amino-3-cyanopyrazine 1-oxide by reflux with acetic acid-acetic anhydride followed by ready deacetylation by refluxing in methanol (538), and in a similar manner 3-amino-2-ethoxycarbonyl-5-hydroxypyrazine has been prepared from 2-amino-3-ethoxycarbonylpyrazine 1 -oxide through 3-acetamido-2-ethoxycarbonyl-5 ydroxy-pyrazine (538), and 2-amino-3-carbamoyl-6-hydroxy-5-methylpyrazine from 2-amino-3-cyano-5-methylpyrazine 1-oxide (538). The preparation of 24 ydroxy-6-methoxycarbonylpyrazine (10) has been claimed from 3-methoxycarbonylpyrazine 1-oxide with acetic anhydride followed by hydrolysis (1057) [cf. Nov Cek et al. (839), who claim it to be the 5-isomer, and Foks (744)]. 

Ethoxypyrazine 1-oxide refluxed with 40% alcoholic hydrogen chloride yielded 2-ethoxy-5-hydroxypyrazine (1069). Ultraviolet irradiation of 2,5-dimethyl-pyrazine 1-oxide in water afforded 3-hydroxy-2,5-dimethylpyrazine (10%) and 2,5-diphenylpyrazine 1-oxide in benzene gave 3-hydroxy-2,5-diphenylpyrazine (3%) (742). A small yield of 2-ethyI-5-hydroxy-3,6-dimethylpyrazine has been isolated as by-product from the reaction of 2,5-dimethylpyrazine with ethyllithium in ether (615). 

Crystal structures of 3,5,6-tri-t-butyl-2-hydroxypyrazine (1093) 2,5-dichloro-3-methoxypyrazine (915) and 2,3-dichloro-5-ethylamino-6-methoxypyrazine (916) have been determined. The dipole moment of 2-amino-5-bromo-3-methoxypyrazine (2.94D in benzene) is consistent with the S-cis configuration (52) (749) and the polarographic behavior of 3-hydroxy(and methoxy)-2,5-dimethylpyrazine (and their A(-oxides) at various pH values has been investigated (588). 

Ribosidation of the trimethylsilyl derivative of 2-hydroxypyrazine (69) (prepared with trimethylsilyl chloride and bistrimethylsilylamine) with 1,2,3,5-tetra-O-acetyl-/J-D-ribofuranose and titanium tetrachloride in 1,2-dichloroethane, followed by deacetylation with sodium methoxide, gave 2-oxo-l-( -D-ribofuranosyl)-l, 2-dihydropyrazine and its 4-oxide was prepared similarly (1035). A similar reaction occurred with the trimethylsilyl derivative of 3-hydroxypyrazine 1-oxide and 1,2,3-tri-<3-acetyl-D-erythrose (1110). 

Oxidations of hydroxypyrazines to their A -oxides are described in Section lOB. 

PREPARATION OF HYDROXYPYRAZINE A-OXIDES AND EXTRANUCLEAR HYDROXYPYRAZINE A-OXIDES... 

Preparations of hydroxypyrazine A-oxides by primary syntheses have been included in Chapter III and are summarized briefly as follows Section 1II.3, 2-hydroxypyrazine 1-oxides from a-aminohydroxamic acids and 1,2-dicarbonyl compounds or a,/l-unsaturated a-bromo aldehydes (545-548) Section III.4, 2-hydroxy-3,6-dimethylpyrazine 1-oxide from the bisulfite derivatives of pyruvo-hydroxamic acid and aminoacetone (548) and Section III.5, ring closure of the C-C-N-C-C-N-0 system (545, 546, 548-553). In addition to these preparations... 

Oxidation of nuclear and extranuclear hydroxypyrazines (and derivatives) to their Af-oxides has been achieved with hydrogen peroxide in acetic acid, and with m-chloroperoxybenzoic acid in 1,2-dichIoroethane. 3-Hydroxy-2,5-diisobutyl-pyrazine was oxidized with 30% hydrogen peroxide in acetic acid at 70 to 3-hydroxy-2,5-diisobutylpyrazine 1-oxide (101), 3-hydroxy-2-(Af-methyl-A -phenyl-carbamoyl)pyrazine 1-oxide (90) was also prepared from the conesponding pyrazine [its A -4-methyl derivative was prepared similarly and also by methylation of (90) (1055)], and 3-hydroxy-2-(A -methyl-AAp-tolylcarbamoyl)pyrazine 1-oxide (1055) was synthesized analogously. 

Benzoyloxypyrazine was oxidized with m-chloroperoxybenzoic acid in 1,2-dichloroethane to 3-benzoyloxypyrazine 1-oxide (1035), which with methanolic sodium methoxide gave 3-hydroxypyrazine 1-oxide (1035) the 5- and 6-methyl-and 5-methoxycarbonyl analogues were prepared similarly (1035). 

Alkaline hydrolysis of halogenopyrazine A -oxides to hydroxypyrazine 7V-oxides has been described in Section V.7A(2). 

Aminopyrazine 1-oxide with nitrous acid in sulfuric acid on wanning and dilution with water (108, 547a), and also by treatment with potassium cuprous cyanide (838), has been shown to give 3-hydroxypyrazine 1-oxide. 2-Amino-3,5-dimethylpyrazine 1 -oxide with about 40% sodium hydroxide at reflux in a bath at 140° produced 2-hydroxy-3,5-dimethylpyrazine 1-oxide (524). 

Alkoxypyrazine A -oxides may be hydrolyzed with acid to hydroxypyrazine A -oxides. Some examples are the hydrolysis of 3-ethoxy-2,5-dimethylpyrazine 1-oxide at reflux with 3 A hydrochloric acid to give 3-hydroxy-2,5-dimethylpyrazine 1-oxide (872) 2,5-diethoxy-3,6-dimethylpyrazine 1,4-dioxide with 2N hydrochloric acid at 70° gave 2-ethoxy-5-hydroxy-3,6-dimethylpyrazine 1,4-dioxide and 2,5-dibenzyloxy-3,6-dimethylpyrazine 1,4-dioxide similarly treated but at room temperature gave the 2-benzyloxy analogue (842), but with lOAf hydrochloric acid at room temperature it gave 2,5-dihydroxy-3,6-dimethylpyrazine 1,4-dioxide (842). 

Amino-3-cyano-5-methylpyrazine 1,4-dioxide (91) refluxed for several minutes with acetic anhydride formed 3-acetamido-2-cyano-5-hydroxy-6-methylpyrazine 1-oxide (92) (24%) (532) and 2-acetoxymethyl-5-methylpyrazine 1,4-dioxide refluxed with acetic anhydride afforded a mixture of2,5-di(acetoxymethyl)pyrazine 1-oxide, with some 2,5-diacetoxymethylpyrazine and a monoxide of 2-acetoxy-methyl-5-methylpyrazine (625). 2-Formylpyrazine hydrate 1,4-dioxide with aqueous sodium hydroxide or bicarbonate at < 37° in an unusual reaction gave 3-carboxy-pyrazine 1-oxide mixed with 5 [Pg.188]

The antibiotic emimycin was first isolated (107) from Streptomyces No. 2021-1 and subsequent work (108) showed it to be 3-hydroxypyrazine 1-oxide which from infrared evidence (Nujol) was assigned the pyrazine structure (99, R = H) [alkyl derivatives have been assigned similar structures (978)]. It had an acidic pAi, 6.2 (108) and was a stronger acid than 2-hydroxypyrazine [acidic pA 8.23 (1082)]. Emimycin did not form acetyl derivatives under a variety of conditions acetic anhydride and pyridine, acetyl chloride and pyridine, or acetic anhydride and sulfuric acid (108). 

The reactions of phosphoryl chloride and some hydroxypyrazine A-oxides with an unsubstituted position adjacent to the A-oxide function to give chlorohydroxy-pyrazines have been described in Section V.IG. In this way 3-hydroxy-2,5-diisobutylpyrazine 1-oxide was converted to 2-chloro-5-hydroxy-3,6-diisobutyl-pyrazine (101) and 2-hydroxy-3,5-diphenylpyrazine 1-oxide gave 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873). 

When 2-hydroxy-3,5-diphenylpyrazine 1-oxide was heated under reflux with an excess of acetic anhydride, a crystalline triacetoxy compound was obtained which was thought to have an open chain structure [AcO-CH=CPh-N=CPh-C(OAc)=N-OAc], but when the 2-hydroxypyrazine-l-oxide was boiled with a mixture of acetic anhydride and acetic acid, 2,6-diacetoxy-3,5-diphenylpyrazine was obtained (873) which was hydrolyzed by potassium hydrogen carbonate in methanol to 2,6-dihydroxy-3,5-diphenylpyrazine (873). 2-Hydroxy-5-methyl-3-phenylpyrazine 1-oxide behaved differently and when refluxed with acetic anhydride gave 5-acetoxymethyl-2-hydroxy-3-phenylpyrazine (100) and 2-hydroxy-3-methyl-5-phenylpyrazine 1-oxide similarly gave 3-acetoxymethyl-2-hydroxy-5-phenylpyrazine (873). When 2- l-hydroxy-2 -methylpropyl)-5-isobutylpyrazine 1-oxide was heated with a mixture of acetic anhydride and sodium acetate on a water bath 2-(l -acetoxy-2 -methylpropyl)-5-isobutylpyrazine 1 oxide was obtained (760a). 

Many hydroxypyrazine A oxides have been A(-deoxygenated to pyrazines with a variety of reducing agents which include heating with hydrazine hydrate in alcohols hydriodic acid and red phosphorus in acetic or phosphoric acid iodine and red phosphorus in refluxing acetic acid phosphorus tribromide in ethyl acetate sodium dithionite catalytic reduction with hydrogen over Raney nickel dry distillation with copper-chromite catalyst and titanium trichloride in tetrahydrofuran at room temperature. 

Hydroxypyrazine 1 oxide was reduced with hydrogen at atmospheric pressure over Raney nickel to 2-hydroxypyrazine (108) [but failed to react with phosphorus trichloride in chloroform (108)], and 3-hydroxy-2-isobutyl-5-isopropylpyrazine 1,4-dioxide was reduced with hydrogen over nickel to 3-hydroxy-2-isobutyl-5-isopropylpyrazine (740a). 2-(A -Anilino-yV-methylcarbamoyl)-4-methyl-3oxo-3,4-dihydropyrazine 1 oxide with sodium dithionite produced 3-(A -anilino-A -methyl-carbamoyl)- -methyl-2oxo-l, 2-dihydropyrazine (1137). 

The alkylation of hydroxypyrazine A oxides to C- and A-alkoxypyrazine N-oxides has been described in Section 11C. 

Hydroxypyrazine 1-oxide with trimethylsilyl chloride and bistrimethylsilyl-atnine heated at 90-95° for 1 hour and the 3-(trimethylsilyl)oxypyrazine 1-oxide in 1,2-dichloro ethane treated with l,23,5-tetra-0-acetyl-(3-D-ribofuranose and titanium tetrachloride at reflux for 4 hours followed by deacetylation produced 3-oxo4-(/J-D-ribofuranosyl)-3,4-dihydropyrazine 1-oxide (1035). Treatment of 3-(trimethylsilyl)oxypyrazine 1-oxide with 2-deoxy-3,5-di-0-(p-chlorobenzoyl)-a-D-eo rtro-pentofuranosyl chloride in benzene in the presence of 4A molecular sieves gave an anomeric mixture (a/0 = 1.2 1.0) of 4-[2 -deoxy-3, 5 -di-0-(p-chlorobenzoyl)-a(and 0)-D-e/y rhro-pentofuranosyl]-3-oxo-3,4-dihydropyrazine 1 -... 

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