Pteridines from pyrazines

Theoretically there are seven ways of constructing the pyrimidine ring upon a suitably substituted pyrazine precursor to complete the pteridine system. However, in practice only three methods have been widely used. In general, syntheses of pteridines from pyrazines give products of unambiguous structure which makes such syntheses particularly useful. The main limitation is the availability of the suitably substituted pyrazine (see Section 6.2.2.). 

Other syntheses of pteridines from pyrazines are those in which all of the atoms are present but a cyclization is required to complete the structure. This cyclization can involve formation of the 2,3-, the 1,2- or the 3,4-bonds. 

Table 9 Alkyloxymethyl pteridine synthesis from pyrazines (Scheme 31) <1996EJM273>...

Pyrazine 168 underwent cross-coupling with propyne in the tri-o-tolylphosphine, and copper(l) iodide to provide 170. The isocyanate or methyl chloroformate and sodium hydride to give An isolated example of the synthesis of chiral pteridines from a (Scheme 33). 2-Isothiocyanatopyrazine-3-carboxylates have been isothiocyanatopyrazine-2-carboxylate 172 reacted with R)- —) provided the pteridine derivative 173 and uncyclized pyrazine with pyridine precursors afforded pyrido[2,3 Pytitnidines. 

Pteridine synthesis from pyrazine precursors are usually applied in such cases where the formation of special derivatives cannot be achieved easily by the pyrimidine approach. Methyl 3-amino-2-pyrazinecarboxylate (362) reacts with thiophosgene to give the corresponding 3-isothiocyanato derivative (363) which cyclizes with primary amines, arylalkylamines, aminoalcohols, amino acids,... 

Although pteridines can be made from pyrazines, it is usually much easier to prepare them from 4,5-pyrimidinediamines or the like.1689 Since many pteridines can be easily degraded to pyrazines, this process offers a practical primary synthetic route to a variety of pyrazine derivatives. However, in comparison with more than 150 examples cited by Barlin from pre-1978 literature,1686 recent use of the method has been modest. Typical examples follow ... 

Pteridine Studies. Part XXXIX. Pteridines unsubstituted in the 4-position. A New Synthesis from Pyrazines, via 3,4-dihydropteridines. 

Most pteridines are degraded to pyrazines and when they do yield pyrimidines, these may well be the ones from which they were made. However, some useful preparations of pyrimidines from pteridines are known. Thus, reduction of pteridin-7(8//)-one (732) and subsequent hydrolysis yields N-(4-aminopyrimidin-5-yl)glycine (733) (52JCS1620) and hydrolysis of 5,8-dimethylpteridine-6,7(5Ff,8Ff)-dione (734) gives dimethyl-... 

Apart from the nuclear bromination observed (Section 2.15.13.1) in the attempted radical bromination of a side-chain methyl group leading to (396), which may or may not have involved radical intermediates, the only other reaction of interest in this section is a light-induced reduction of certain hydroxypyrido[3,4-f)]pyrazines or their 0x0 tautomers analogous to that well-known in the pteridine field (63JCS5156). Related one-electron reduction products of laser photolysis experiments with 1 -deazaflavins have been described (79MI21502). 

CN/CC replacement has also been observed on treatment of pteridine with malonitrile or cyanoacetamide 6-amino-7-R-pyrido[2,3,-h]pyrazine (R = CN, CONH2) beingformed (73JCSP(1)1615) (Scheme 15). The reaction involves initial addition of the reagent to the N-3-C-4 bond, scission of the dihydro bond between N-3 and C-4 in the covalent adduct, and recycli-zation. This mechanism is fundamentally different from the mechanism mentioned in Scheme 14, where two molecules of the reagent were used for addition and where the bond breaking takes place between N-1 and C-2. 

Pteridines, Quinazolines Supplement I, and The Pyrazines, Supplement I), are also from the pen of Dr. D. J. Brown. 

Nobuhiro Sato was born in Niigata, Japan, in 1945. He received his B.Sc. degree from Yokohama City University in 1968 and his Ph.D. degree from Tokyo Metropolitan University in 1981. After a postdoctoral position with E. C. Taylor at Princeton University, he returned to japan, where he is now professor of chemistry at Yokohama City University. His research interests include synthesis and reactivity of heterocyclic compounds, particularly pyrazines and pteridines, as optically functional materials or bioactive products. 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

---