2.5- Diethoxy-3,6-dihydropyrazines

The earliest report on such lactim ether formation was from Sammes [72JCS(P1)2494], who converted piperazine-2,5-dione to 2,5-diethoxy-3,6-dihydropyrazine (173) with an excess of triethyloxonium fluoroborate. Subsequently, Rajappa and Advani (73T1299) converted proline-based piperazine-2,5-diones into the corresponding monolactim ethers. The starting material was a piperazinedione in which one of the amino acid units was the secondary amino acid proline, and the other a primary amino acid. This naturally led to the regiospecific formation of a monolactim ether (169) (on O-alkylation) from the secondary amide, whereas the tertiary amide remained intact. This was later extended to piperazine-2,5-diones in which the secondary amino acid was sarcosine [74JCS(P 1)2122], leading to the monolactim ethers (170). 

Diethoxy-3,6-dihydropyrazine (177) gave 2,5-bisdimethylamino-3,6-dihy-dropyrazine (178) (neat Me2NH, 60°C, sealed, 6 h 77%).70... 

Diethoxy-3,6-dihydropyrazine (188) and 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine (189) gave 2-ethoxy-5,8-bis(trifluoromethyl)-3,4-dihydropyrazino[2,3-dlpyridazine (190) by loss of N2 and EtOH from an intermediate Diels-Alder adduct (CCLj, reflux, 1 h 72%).708... 

Sammes and co-workers (314, 314a) have recently shown that piperazine-2,5-diones can be converted with excess triethyloxonium fluoroborate to 2,5-diethoxy-3,6-dihydropyrazines and then to 2,5-diethoxypyrazines. This reaction is discussed further in Section 6 below. 

Oxidation of 2,5-diethoxy-3,6-dihydropyrazine with dichlorodicyanobenzo-quinone (DDQ) formed 2,5-diethoxypyrazine (314), and the 3,6-dimethyl analogue reacted similarly (314). 2,5-Diisopropyl-3,6-dimethyl-2,5-dihydropyrazine was oxidized in alkaUne solution to 2,5-diisopropyl-3,6-dimethylpyrazine (225). Oxidation of 2,5-diethoxy-3,6-dimethyl-3,6-dihydropyrazine with lead tetraacetate in refluxing benzene gave both 2,5-diethoxy-3,6-dimethylpyrazine (minor product) and 2,5-diacetoxy-3,6-diethoxy-2,5-dimethyl-2,5-dihydropyrazine (1068). 

Pyrolysis of 2,5-diethoxy-3,6-dihydropyrazine in the range 250-270° in vacuo gave only unchanged starting material and no sign of 2,5-diethoxypyrazine (314), and the thermal instability of 2,5-dimethyl-3,6-dihydropyrazine has been reported to be due to its dimerization (190). Pyrolysis of r an -2,5-dibenzyl-3,6-diethoxy-... 

To 1050 mL THF solution containing 22.4 g 3(R)-isopropyl-2,5-diethoxy-3,6-dihydropyrazine (105.5 mmol) at —78°C, was added 42.2 mL 2.5 M n-BuLi in hexane, and the resulting solution was stirred for 1 h. Then 116 mL THF solution of 10.35 g propenylphosphonate (58.1 mmol) was added drop wise. After being stirred at —78°C until the completion of the reaction, the reaction mixture was quenched with AcOH and warmed to room temperature. Upon removal of the solvent in vacuo, the resulting material was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04 and evaporated, and the residue was purified by flash column chromatography (silica gel, EtOAc/hexane, 2 1-4 1) to yield 13.4 g (25, 5R,l R)-3,6-diethoxy-2-[2-(diethoxyphosphoryl)-l-(methyl)ethyl]-2,5-dihydro-5-isopropylpyrazine as a colorless oil, in a yield of 59%, Rf = 0.46 (EtOAc). 

Piperazine Derivatives. Treatment of piperazine-2,5-diones with an excess of triethyloxonium fluoroborate gives 2,5-diethoxy-3,6-dihydropyrazines (390), which can be oxidized to the parent pyrazines (391) by dichloro-cyanobenzoquinone. c/s-Diben lpiperazin ione gives a mixture of cis- and /ra j-dihydropyrazines (390). Pyrolysis of the /ro s-isomer gives 3-benzyl-2,5-diethoxypyrazine (392) in high yield with the elimination of... 

Diethoxy-3-isopropyl-3,6-dihydropyrazine gave 2,5-diethoxy-3-isopropyl-6-(2,3,4,5-tetraacetoxy-l-hydroxypentyl)-3,6-dihydropyrazine (78) [BuLi, THF, 50°C then Et2AlCl J, -78°C then AcOCH2(CHOAc)3CHO, 78°C, 3... 

Diethoxypyrazine (87) gave the unisolated dihydro adduct (88), and thence racmic-2-butyl-3,6-diethoxy-2,5-dihydropyrazine (89) (BuLi, Et2NCH2CH2NEt2, THF, -70°C, 3 h then pH 7 buffer 75%) this underwent normal Schollkopf lithiation/alkylation at the 5-position but the product and derived amino acid were naturally both racemic.539... 

Bromobutyl)-(257, R = Br) gave 2-(4-azidobutyl)-3,6-diethoxy-5-iso-propyl-2-methyl-2,5-dihydropyrazine (257, R = N3) (NaN3, Me2NCHO, 90°C, 13 h 78%) 1609 homologues likewise.1609 Also other examples.152 228 1106 1348... 

Bromoethyl)-3,6-diethoxy-2,5-dihydropyrazine (281) gave 3,6-diethoxy-2,5-diazabicyclo[2.2.2]octa-2,5-diene (282) (BuLI, THF—C6H14, -78°C, 3 h 91%).792 Also other examples.993... 

Acetyl-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine (20) gave potassium 3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydro-2-pyrazinecarboxylate (21, R = K) (KOC1, dioxane—H20,4 — 20°C, 1 h cmde) that was characterized as the corresponding ester, methyl 3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydro-2-pyrazinecarboxylate (21, R = Me) (Mel, THF, 0°C, 48 h 46% overall).170,371... 

Diethoxy-3-isopropyl-6-methyl-3,6-dihydropyrazine (289) gave 2-acetyl-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine (290) (BuLi, THF, -80°C, 20 min then AcCl, 80°C, 2 h 87%).371... 

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). 

Methylation of 2-hydroxy-3-7V-phenylcarbamoylpyrazine with dimethyl sulfate and potassium carbonate in boiling acetone gave l-methyl-2-oxo-3-A -phenylcarbamoyl-1,2-dihydropyrazine and the 3-(A -methyl-Af-phenylcarbamoyl) analogue was prepared likewise (1055). Similar methylation of 2-hydroxy-3-(o-methylaminophenyl)pyrazine produced 1 -methyl-3-(o-methylaminophenyl)-2-oxo-1,2-dihydropyrazine (1055). A series of 24iydroxy-3-(a-hydroxybenzyl)pyrazines has been methylated with dimethyl sulfate in aqueous sodium hydroxide to the 2-methoxy analogues (1045) and 2-benzyl-3,6-dihydroxy-5-methylpyrazine with diethyl sulfate and sodium ethoxide formed 2-benzyl-3,6-diethoxy-6-methylpyrazine (1066). 

Diethoxy-3,6-dimethylpyrazine similarly gave 3,6-diethoxy-2,5-dimethyl-2,5-epidioxy-2,5-dihydropyrazine, which was reduced by sodium borohydride to 3,6-diethoxy-2,5-dihydroxy-2,5-dimethyl-2,5-dihydropyrazine (1127). 

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). 

Diethoxy-3-isopropyl-3,6-dihydropyrazine gave 2,5-diethoxy-3-isopropyl-... 

Diethoxy-3-isopropyl-6-methyl-3,6-dihydropyrazine (289) gave 2-acetyl-... 

---