Tetrahydropyrazines preparation

Praziquantel (9) was prepared by the cyclization of 4-cyclohexylcarbonyl-l-phenethyl-2-oxo-l,2,3,4-tetrahydropyrazine in cone. H2SO4 at room temperature in quantitative yield (98H(48)2279). 

Among the four isomers of dihydropyrazines, the 2,3-dihydro isomers are most explored because these reduced pyrazines have been easily prepared by condensation of 1,2-diamines and 1,2-dicarbonyl compounds. This class of compounds is unexpectedly unstable resulting in dimerization at room temperature. Thus, 2,3-dihydropyrazine 97 (R = = Me) gradually dimerizes to form tricyclic system 98, fused with two tetrahydropyrazine units... 

Acetyl-protected 1,2,3,4-tetrahydropyrazines 105, which are prepared by treatment of 2,3-dihydropyrazine with acetic anhydride and zinc (Scheme 27), undergo photooxidation to produce new dioxetanes 106 <1995JA9690>. Upon thermolysis, the dioxetanes 106 decompose quantitatively to tetraacyl ethylenediamines 107. Dimethyldioxirane oxidation of tetrahydropyrazine 105 affords novel epoxide 108, which is also generated by deoxygenation of dioxetane 106 with dimethyl sulfide. In 2,3,4,5-tetrahydropyrazine 1-oxide 109, which is prepared... 

Preparation of 2,3-dioxo-5,6-dicyano-l,2,3,4-tetrahydropyrazine (67) by condensation of DAMN with oxalyl cyanide or oxalyl chloride, and by reaction of DISN with oxalyl chloride, followed by the treatment of the intermediate with ethanethiol, was noted in Section V,B,1. 

Stevens and his co-workers report the preparation of 2-phenyl-3,3-dimethyl-3,4,5,6-tetrahydropyrazine (184) in 91% yield from the reaction of the epoxy ether (183) and ethylenediamine. The structural assignment is consistent with the observation of strong N-H and... 

Preparation of isopropyl (2/LS, 3.S )-3- (3/LS )-4-acetyl-3-isopropyl-2-oxo-6 -phenyl-1,2,3,4-tetrahydropyrazin-l-yl methylcarbonylamino-2-hydroxy-4-phenylbutyrate... 

In earlier investigations by the authors (1,2), 2-oxo-l,2,3,4-tetrahydropyrazines, (I), and thiazolidine derivatives, (II), respectively, were prepared, which were effective as chymase inhibitors. 

Aminoimidazo[l,2-a]pyrazine (456) has been prepared by the reaction of 2-aminopyrazine (455) with sodium cyanide and the bisulfite addition compound from formaldehyde (68TL3873). Another 3-aminoimidazo[l,2-a]pyrazine (458) was made by the reaction of the tetrahydropyrazine (457) with a-amino-a-cyanoacetamide (67MI41000, 67MIP41000). 

The following alkoxypyrazines have been prepared from the corresponding dichloropyrazines and alkoxide ions 2,3-dimethoxy-5,6-dimethyl(and diphenyl) (797) 2,3-dibenzyloxy (sodium benzyl oxide in benzyl alcohol at reflux for 24 hours (883)] [but 23-dichloropyrazine with sodium hydride and benzyl alcohol in xylene gave l,4-dibenzyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine)(988)] 2-chloro-5-methoxy (838) 2,5-diethoxy-3,6-dimethyl (872) 2methanolic sodium methoxide refluxed for 2 h) 2,5-dimethoxy-3-phenyl (817) 2-chloro-5-methoxy(and ethoxy)-3,6-diphenyl (817) 2,5-dimethoxy-3,6-dimethyl (and diisopropyl) (844) 2,5-dimethoxy-3-isopropyl-6-methyl (methanolic potassium methoxide at reflux for 6 days) (844) 2(5)-s-butyl-3-chloro-6-ethoxy-5(2)-isobutyl (93) 2-chloro-6-methoxy (838, 883) 2,6-dimethoxy (reflux for 8h) (832) 2,6-diethoxy (reflux for 14 h) (883) 2-benzyloxy-6-chloro (1 equiv. of sodium hydride and benzyl alcohol in benzene at reflux) (832) 2,6-dibenzyloxy (5 equiv. of sodium benzyloxide in benzene at reflux gave 70%) (832) and 3,5-dimethoxy-2-methyl (535). 

Diniethylpiperazine-2,5-dione (34) on treatment with triethyloxonium fluoroborate in dichloromethane gave 5-ethoxy-l,3-dimethyl-2-oxo-l, 2,3.6-tetrahydropyrazine which was oxidized by DDQ in dry benzene to 5-ethoxy-l 3 dimethyl-2-oxo-l,2-dihydropyrazine (35) (1067). l,3,6-Trimethylpiperazine-2,5-dione similarly treated gave three products, one of which was assigned the structure 5-methoxy-l 3,6-trimethyl-2-oxo-l, 2-dihydropyrazine 3-benzyl-5-methoxy-l, 6-dimethyl-2-0X0-1,2-dihydropyrazine was also prepared similarly (1078). When 3,6-diethoxy-2,5"dimethyl-2,5-dihydropyrazine was refluxed with lead tetraacetate in dry benzene it gave a mixture of 2,5-diacetoxy-3,6-diethoxy-2,5-dimethyl-2,5-dihydropyrazine (36) (4 parts) and 2,5-diethoxy-3,6-dimethylpyrazine (1 part) (1068). 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

Hydrolysis of 2-amino-3-hydroxy-l-methylpyrazinium toluenesulfonate (87) with aqueous sodium hydroxide at 95° afforded 3-hydroxy-l-methyl-2-oxo-l, 2-dihydropyrazine which was also prepared in poor yield from the action of nitrous acid on 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (832) and hydrolysis of 6-chloro-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine with boiling methanolic sodium methoxide (followed by acidification) gave 6-hydroxy-l-methyl-2-oxo-3,5-diphenyl-1,2-dihydropyrazine (873). 1,3,6-Trimethyl-2-oxo-1,2-dihydropyrazine methiodide has been converted through l,4,6-trimethyl-3-methylene-2-oxo-l,2,3,4-tetrahy dropy razine and 3-benzoylmethylene-1,4,6-trimethyl-2-oxo-1,2,3,4-tetra-hydropyrazine (in water) to 1,4,6-trimethyl-2,3-dioxo-l, 2,3,4-tetrahydropyrazine (1129). 

Reduction of 2-carbamoylpyrazine in ethanol over palladium-charcoal at atmospheric pressure gave 2-carbamoylpiperazine (870, 1269, 1352), and the 2-carbamoyl-3-carboxy (1269) and 2,3-dicarbamoyl (1269, 1352) analogues were prepared similarly, but 2,3-dicarboxypyrazine imide gave 50% 2,3-dicarboxy-1,4,5,6-tetrahydropyrazine imide (1269). 2-Hydroxy-3-V-phenylcarbamoylpyrazine oxidized with hydrogen peroxide in acetic acid at 50° for 96 hours did not give an 7V-oxide but only a tar and 2,3-dihydroxypyrazine (1055). 

It has been claimed (25) that 2,3-diphenyl-5,6-dihydropyrazine when heated with acetic or benzoic anhydride gives a derivative of the 1,4-dihydropyrazine ring system, but this has been shown by Chen and Fowler (1562) to be in error [the products have been shown to be 1,4-diacetyl(or dibenzoyl)-5,6-diphenyl-l,2,3,4-tetrahydropyrazine (26, R = Me or Ph), respectively, together with 23-diphenyl-pyrazine]. Hexamethyl-2,3-dihydropyrazine cannot undergo oxidation to a pyrazine, but it rapidly dimerized in air in the presence of hydrochloric acid to give compound (27, X = Cl) (also prepared as the iodide with iodine in ether) (1550). 

Methylpyrazinium ion in liquid ammonia at — 28° forms a 2,3-diadduct, 2,3-diamino-l-methyl-l,2,3,4-tetrahydropyrazine (59) (609), and 1,4-diacetyl-2,3-di(indo -3 -yl)-l,2,3,4-tetrahydropyrazine has been prepared by refluxing pyrazine with indole in acetic anhydride (1592). 

The second approach, hydrogenation of tetrahydropyrazine derivatives was much more fruitful, as the substrate reactivity could be tuned by modification of the substituents on N-l and N-4 [17]. Initially the esters were synthesized by partial hydrogenation of the corresponding pyrazine derivatives followed by mono-functionalization at N-l (see Fig. 14). The corresponding amides could only be prepared through trapping the intermediate tetrahydropyrazine as the less reactive... 

According to Sheldon et al. (1986), two molecules of the 2,3-dihydropyrazines can form a mixture of the corresponding pyrazine and 1,2,3,4-tetrahydropyrazine by disproportionation. It was also observed by Masuda et al. (1980) that dehydrogenation of 2,3-dimethyl-5,6-dihydropyrazine generated the disproportionation compounds 2,3-dimethyl-1,2,5,6-tetrahydropyrazine and 5-ethyl-2,3-dimethylpyrazine in addition to the desired 2,3-dimethylpyrazine in a sodium ethoxide/ethanol solution. It was then deduced that the carbanion of 2,3-dimethyl-5,6-dihydropyrazine was formed with the base and then reacted with acetaldehyde, present in ethanol in small quantities, to yield the 5-substituted pyrazine. On the basis of this result the authors prepared in high yield a series of nine, 5-substituted, 2,3-dimethylpyr-azines by reaction of 2,3-dimethyl-5,6-dihydropyrazines with six aldehydes and three ketones under the same basic conditions. 

Treatment of 2-(2-hydroxyethylamino)pyrazine (40) with thionyl chloride, followed by cyclization of the resultant chloro compound in boiling ethanol, gave a considerable amount of tar together with 6.5% of the 2,3-dihydroimidazo compound (41). The 5,6-diphenyl analogue of 41 has been similarly prepared in undisclosed yield. The tetrahydro derivative 44 was obtained when the tetrahydropyrazine 42 was heated in ethanolic hydrochloric acid with a-amino-a-cyanoacetamide (43). " ... 

The previously unknown l,2,3,6-tetrahydropyrazin-2-ones (270) are easily prepared by mixing 2,2-dimethyl-3-phenylazirine (271) with the methyl esters of a-amino-acids. " Another example of the use of this azirine is seen in its reaction with ammonia to give the amino-pyrazine (272) in 72% yield (Scheme 107). ... 

Di-iminosuccinonitrile (506) is prepared by the base-catalysed addition of hydrogen cyanide to cyanogen and undergoes two types of addition with nucleophilic olefins. Thus styrene gives the aziridine (507) whereas /Nmeth-> oxystyrene yields the tetrahydropyrazine (508). Aziridine formation occurs with >98% retention of olefin stereochemistry, as shown using cis- and... 

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