Pyrazino quinoxalines

Amino-3-phenyl-3,4-dihydro-2(l//)-quinoxalinone (194) gave 5-phenyl-2,3-dihydro-17/, 5//-pyrazino[l,2,3-tie]quinoxaline-2,3,6(77/)-trione (195) [(COCl)2,... 

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

Enantiomers of the 8,9-dichloro-2,3,4,4 ,5,6-hexahydro-177-pyrazino[l,2-tf]quinoxalin-5-one (structure 249 Rz = R3 = Cl R1 = R4 = H) could be separated by normal-phase, chiral high-performance liquid chromatography (HPLC) with increased retention and separation factors if ethoxynonafluorobutane was used as solvent, instead of -hexane <2001JCH(918)293>. 

The only publication on the angularly condensed benzologues, pyrimido[2,l-tf]quinoxalines, describes the synthesis of 161 by formation of both the pyrimido and the pyrazino ring from [6+0] atom fragments. Compound 160, the targeted cyclocondensation product of the propanediamine derivative 159, spontaneously cyclized to the pyri-mido[2,l- ]quinoxaline A-oxide 161 (Equation 17) <2002S2687>. 

The iV-( -nitrophcnyl)pipcrazinc-2-carbonitrilc 251 (Y = NBOC) was reductively cyclized to the tricyclic /V-oxides 252 (Y = NBOC) either by catalytic hydrogenation, or by electrochemical reduction. Electrochemical reduction gave lower yield. Compounds 251 were prepared by electrochemical cyanation of the iV-(o-nitrophenyl)piperazine 250. The jV-oxides 252 were further hydrogenated to the 2,3,4,4 ,5,6-hexahydro-l//-pyrazino[l,2- ]quinoxaline 253 (Y = NBOC) (Scheme 46) <2001EJ0987>. 

Formation of ring C of the 2,3,4,4 ,5,6-hexahydro-l-oxo-l//-pyrazino[l,2-tf]quinoxalines 255 from [6+0] atom fragments, by bond formation 7 to the ring junction nitrogen starting from the appropriately substituted quinoxalines 254 is described in a Japanese patent (Scheme 47) <1999WO99/33804>. 

The l,2,3,4,4 ,5-hcxahydro-pyrazino[2,l-t ][l,4]benzoxazinc 350 was prepared from the appropriately substituted benzoxazine 349, as shown in Scheme 56 <1997BML763, 2003JME2877>. Diethyl oxalate <2001USP6169086> and dibromoethane <2002W02002/020533> were also utilized to build the pyrazino ring of [l,4]oxazino[4,3-tf]quinoxalines. 

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