C-Alkylation in the Schollkopf Synthesis

Note Treatment of the lithiated substrate with cuprous cyanide prior to addition of the alkyl halide has been found to improve yield and/or stereoselectivity in some cases. 

5-Diethoxy-3-isopropyl-3,6-dihydropyrazine (57) gave 2-[7-(tert-butyl-dimethylsiloxycarbonyl)heptyl]-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (58, R = Si liu Mco) (BuLi, THF, 78°C then CuCN J, 0°C, 2 min then I (CH2)7C02Si Bu Me2 J, -25°C, 18 h crude ester), and thence 2-(7-carboxy-heptyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (58, R = H) (Bu4 NF, THF, 20°C , 1 h 90%, overall).1532 

2-Allyl-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (59) gave 2-allyl-2-(2-hydroxyethyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (60) (BuLi, THF—C6H14, -78°C, A, 45 min then (CH2)20 [, BF3.Et20 j, -78°C, 1 h 60%).1615 

Also other examples using substituted ethylene oxides.211 

2-Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (53) gave 2-isopropyl-3, 6-dimethoxy-5-(2-methoxycarbonyl-l-methylethyl)-2,5-dihydropyrazine (61) (BuLi, THF—C6H14, N2, 78°C, 15 min then MeCH=CHC02Me J, 

As indicated in the intfoduction to Section 3.2.1.1, the crucial step in Schbl-Ikopf s synthesis of optically active a-amino acids is the C-alkylation of a chiral 

The same substrate (53) gave 2-(but-3-enyl)-5-isopropyl-3,6-dimethoxy-2, 

5-isopropyl-3,6-dimethoxy-2-(prop-2-ynyl)-2,5-dihydropyrazine (56) (BuLi, THF—( II -78°C, 1 h then BrCH2C=CH, 70 2()C. 15 h  

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