Pyrido pteridines

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. 

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. 

The investigations on the pyrido[2,3-6]pyrazine ring were inspired by the related pteridine ring, of importance in natural products. Pteridines are very reactive systems with both liquid ammonia and KNH2 in liquid ammonia, but in neither medium have anionic (j-adducts ever been detected. Such adducts presumably form initially and rapidly evolve toward covalent amination and ring contraction products.119,121... 

Malononitrile (in THE at 20-25 °C overnight) and cyanoacetamide (in water at 20-25 °C for 5 days) react with pteridines, e.g. I, to give pyrido[2,3-6]pyrazines, e.g. 2, by addition across the 3,4-bond followed by scission of that bond and a nitrogen-eliminating recyclization. The intermediate of the reaction with cyanoacetamide can be isolated by addition of aqueous sodium hydroxide. Because the product from malononitrile can be generated under anhydrous conditions, it can be concluded that the reaction takes place by a concerted cyclization of the amidine intermediate with elimination of hydrogen cyanide, rather than via a pyridazinamine which could arise by hydrolysis of this amidine (cf. similar reactions in other fused pyrimidine series).56,64-66... 

Polarographic reduction of the parent gave a value for the half-wave potential (E1/2 = -0.85 v) which is intermediate between the values for quinoxaline ( 1/2 =-1.09 v) and pteridine ( 1/2 =-0.52 v). The electrochemical reduction of substituted pyrido[2,3-fc]pyrazines has been the subject of a recent study. Along with other fused pyrazine systems, the... 

Use of the aldehyde 75 avoids condensation directly onto the pyrazine ring. Reaction of this compound with the activated acetonitriles 76 at room temperature in the presence of JV-methylpiperidine gave the condensation products 77, which on treatment with alkali gave the 6-amino compound 78. It was also found that pteridine (79) gave pyrido[2,3-hjpyrazines directly on treatment with the acetonitriles. ... 

Cushman M, Wong WC, Bacher A (1986) Synthesis of bis(trifluoromethylated) pyrazine-containing nitrogen heterocycles from hexafluorobiacetyl turd ortho-diamines. Stabilization of the covalent dihydrates of pteridines and pyrido[3,4-b]pyiazines by trifluoromethyl groups. 

Reaction of 6,7-dialkynyl-l,3-dimethylpteridine-2,4-(lH,3H)-diones 3.832 with sodium azide in DMF at room temperature produced [l,2,3]triazolo[l, 5, l,2]-pyrido[4,3-g ]-pteridine-8,10(9fi,llH)-diones 3.833 together with the isomers 3.834 (Scheme 3.107) [337]. The mechanism involves 1,3-dipolar cycloaddition of azide ion to the triple bond followed by intramolecular nucleophilic addition of the intermediate 1,2,3-triazole N-anion to the second triple bond. 

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