Tetrahydropyrazines reactions

In a series of detailed studies, Armand and coworkers have examined the electrochemical reduction of pyrazines (72CR(C)(275)279). The first step results in the formation of 1,4-dihydropyrazines (85), but the reaction is not electrochemically reproducible. The 1,4-dihydropyrazine is pH sensitive and isomerizes at a pH dependent rate to the 1,2-dihydro compound (83). The 1,2-dihydropyrazine then appears to undergo further reduction to 1,2,3,4-tetrahydropyrazine (88) which is again not electrochemically reproducible. Compound (88) then appears to undergo isomerization to another tetrahydro derivative, presumably (8, prior to complete reduction to piperazine (89). These results have been confirmed (72JA7295). 

The reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06T12084>. 

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. 

Electrochemical reduction of imines (25 Schiff bases) in acidic media proceeds via the iminium species, i.e. the protonated imine (26) (Scheme 5)29. Since 26 bears a positive charge, it is very easily reduced, so much so that the resulting neutral radical (27) is formed at a potential positive of its reduction potential. The products are therefore derived from 27 rather than the corresponding carbanion (28). This stands in contrast with the electrochemical behavior of imines in neutral media, where 27 is immediately reduced to 2830. Thus, cathodic reduction of /u. s-irnincs of 1,2-diamines (29) in DMF containing methanesulfonic acid affords tetrahydropyrazines (equation 13)31. A similar reaction can... 

Different cyclization reactions of ort o-ami no-substituted benzothiazepinones 54 lead to tricyclic derivatives 55, containing imidazole (X = CR), 1,2,3-triazole (X = N), or tetrahydropyrazine (X = CH2CH2) rings (Equation 3). These compounds are structural analogues of the anti-HIV product thiobenzimidazolone (TIBO) <1999EJM701>. 

Rossen et al. [71a] has reported a synthesis of piperazine 113, a key intermediate in the synthesis of the HIV protease inhibitor Crixivan . The reaction between a preformed imine 110, f-butyl isocyanide, and formic acid afforded the Ugi product 111, which was dehydrohalogenated with triethylamine and cyclized with KO Bu to the tetrahydropyrazine 112. Catalytic hydrogenation in the presence of Rh-BINAP (97% ee) and deformylation with aqueous hydrazine gave the target piperazine 113 (Scheme 2.40). 

The reactions of the isomeric dimethylpyrazines and trimethyl-pyrazine with methyllithium have been studied in order to gain insight into the factors involved in the competition between ring methylation and side-chain metalation.189 The major product from the reaction of 2,5-dimethylpyrazine and ethereal methyllithium was shown to be trimethylpyrazine, thus confirming Klein and Spoerri s earlier observation.190,191 Tetramethylpyrazine was also formed as a by-product. Proof of side-chain metalation was obtained by treatment of the reaction mixture with methyl benzoate and isolation of 2-methyl-5-phenacylpyrazine. Evidence for the presence of dihydro-and tetrahydropyrazine intermediates is derived from the infrared spectrum of the crude product obtained on hydrolysis of the reaction mixture which shows C=N and N-H absorptions (see Scheme 17). 

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... 

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). 

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

Dihydroxypyrazine with hexamethyldisilazane in the presence of ammonium sulfate produced 2,3-bis(trimethylsilyloxy)pyrazine (1111), and 2-amino-3-hydroxypyrazine behaved similarly (1111). 23-Bis(trimethylsilyloxy)pyrazine with 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide and silver perchlorate in benzene gave 1,4-bis(2, 3, 4, 6 -tetra-0-acetyl-/J-D-glucopyranosyl)-2,3-dioxo-l, 2,3,4-tetrahydropyrazine, and other similar reactions have also been described (1111). 

The reactions in the decomposition of 13,6-trimethyl-2-oxo-l, 2-dihydropyrazine methiodide with alkali metal hydroxide to give 1,4,6-trimethyl-3-methylene-2-oxo-1,2,3,4-tetrahydropyrazine (1105) and its reaction with benzenediazonium chloride or phenylhydrazine to give l,4,6-trimethyl-2-oxo-3-phenylazomethylene-l,2,3,4-tetrahydropyrazine (1105,1132) have been described. 

Reduction of l,4-diacetyl-5,6-diphenyl-l,2,3,4-tetrahydropyrazine with lithium aluminum hydride formed l,4-diethyl-5,6-diphenyl-l,2,3,4-tetrahydropyrazine (1562). Both l,4-dibenzenesulfonyl-2-hydroxy-l,2,3,4-tetrahydropyrazine and l,4-dibenzenesulfonyl-2,5-dihydroxypiperazine reacted with hot acidic methanol to produce l,4-dibenzenesulfonyl-2-methoxy-l,2,3,4-tetrahydropyrazine (1602). The tosyl analogue behaved similarly. Reaction of 2-hydroxy-l,4-ditosyl-l,2,3,4-tetrahydropyrazine (73, X = OH) with benzenethiol in acidified acetone gave 2-phenylthio-l,4-ditosyl-l,2,3,4-tetrahydropyrazine (73, X = SPh) (1602). 

Reactions of piperazine-2,5-diones with phosphorus pentachloride and phosphorus pentabromide have been described in Sections V.ID and V.IF, respectively. Aromatic aldehydes condense with 3-methylpiperazine-2,5-dione in the presence of acetic anhydride to form mainly mono-A -acetyl derivatives of trans-3-arylidene-6-methylpiperazine-2,5-diones (e.g., 96, R = Ac) (1066). In these products the acetyl group was shown to be attached to position 1 and the 4,5-amide group was found to be sterically hindered. Photolysis formed the cis isomers. Both isomers were deacetylated with methanolic potassium hydroxide (1066). Condensation of 1,4-diacetylpiperazine-2,5-diones with aldehydes has been applied to the synthesis of unsymmetrical 3,6-diarylidenepiperazine-2,5-diones and the reaction has been extended to l,4-diacetyl-3,6-dimethylpiperazine-2,5-diones (1624). Treatment of (96, R = H) with triethyloxonium tetrafluoroborate in dichloromethane gave the monoimino ether, 5-benzylidene-6-ethoxy-3-hydroxy-2-methyl-2,5-dihydropyrazine (97) (1066). l-Methylpiperazine-2,5-dione similarly treated gave 5-ethoxy-l-methyl-2-oxo-l,2,3,6-tetrahydropyrazine (which was condensed with anthranilic acid at 150° to 2-methyl-l,2-dihydropyrazino[2,l-fi]quinazoline-3(4/0.6-dione (98) (1625), and l,4-dimethylpiperazine-2,5-dione gave 5-ethoxy-l,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrazine and 5,5-diethoxy-l,4-dimethylpiperazin-2-one (1626). 

The reaction of dichlorocarbene with ketones and diamines results in near quantitative formation of a mixture piperazinones 584 and 585 (80JOC754). As shown in Section III,C,2, piperazine 78 [R = H, R + R = (CH2)s], the minor product of the Rh2(OAc)4-catalyzed decomposition of diazo ester 73, is the result of the dimerization of the intermediate ylide 76 (84JOC113). Tetrahydropyrazines were synthesized through ring expansion of imidazolidines. Thermolysis or photolysis of diazo compounds... 

Nitrogen heterocycles.1 4 DISN (1) is extremely useful for synthesis of nitrogen heterocycles. For example, DISN undergoes [2 + 4] cycloaddition reactions with electron-rich olefins. Thus reaction of (1) with os-1,2-dimethoxyethylene (2) in acetonitrile results in formation of 2,3-dimethoxy-5,6-dicyano-l,2,3,4-tetrahydropyrazine (3) with retention of configuration in 76% yield. 

N-l acetyl derivative. A much more powerful synthesis of the tert-butylamides was the Ritter reaction of the corresponding nitrile, which allowed direct production of N-l-acylated tetrahydropyrazines [18]. These in turn could be selectively further functionalized at N-4 so that selective protective group removal was possible, giving access to the final N-4 Boc substitution pattern [2], Some examples of the results obtained in the original screening are given in Tab. 7. 

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. 

In cyclic dipeptides cyclo(Gly)2 and cyclo(Ala)2 a single type of radical is formed, in each case by abstracting a carbon-bound H atom at the ring (49). In N2O-O2 atmosphere, peroxyl radicals eliminate superoxide ions in a base-catalyzed reaction. The main products are 3-hydroxy-2,5-dioxopiperazine, 2,3,5-trioxopiperazine and 2,5-dioxo-2,3,4,5-tetrahydropyrazine. 

General Procedure for the Synthesis of Triazole-Fused Tetrahydropyr-azin-6-ones To a solution of chloroacetylated alkyne (1 mmol) in DMF (5 mL) was added NaN3 (5 mmol). The mixture was heated to 100 °C for appropriate time. After the reaction was complete (monitored by TLC) DMF was evaporated under vacuum, and the compound was extracted from the reaction mixture with CH2CI2 (25 mL). The combined organic layer was then dried with anhydrous Na2S04, filtered, and concentrated to obtain the corresponding triazole-fused tetrahydropyrazin-6-ones. 

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). ... 

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