Tetrazine C-Nucleosides

During the preparation of 3-pyrazolyl C-nucleosides from aldose hydra-zonoyl halides (282) and acetylenic esters (Section VII,B,I Scheme 61), Tronchet et al. isolated the 3,6-diglycosyl-l,2,4,5-tetrazine C-nucleoside 1084 in 30% yield together with the pyrazol-3-yl C-nucleosides 248 and 285 (72HCA2121 76MI8) (Scheme 316). 

A simple approach to pyridazine-substituted pyrimidine nucleosides (52) in the reaction of alkyne derivatives (51) with tetrazine diester (48) was reported by Maggiora and Mertes (Equation (2)) <86JOC950> use of the 1,2,4-triazine triester as diene yields the corresponding pyridine derivatives. A new route to the novel C-nucleosides (55) with substituted pyridazines as aglycones by the reaction of tetrazines (48) and (53) with the sugar alkyne (54) has been described (Equation (3)) <94AP(327)365>. 

The reactivity of pyridazines in Pd-catalyzed reactions was of interest. For example, the Heck alkenylation at C5 of 6-phenyl-3(2//)-pyridazinones was investigated, with the aim of suppressing production of 4-phenyl-6-substituted-2-phthalazinone byproducts <04TL3459>. In another study, the reactivity of 5-iodopyridazin-3(2f/)-ones in Pd-catalyzed reactions was investigated to develop an efficient route to 2,5-disubstituted pyridazin-3(2/f)-ones <04T12177>. Other pyridazine syntheses relied on condensation approaches. Benzo[g]pyridazino[l,2-i>]-phthalazine-6,13-diones 16 and 17 related to certain anthracyclinones were obtained by cycloaddition of 1,3-dienes to benzo[g]phthalazine-l,4-dione <04H(63)1299>, and pyridazine C-nucleosides synthesized by 14-i-2 cyclocondensation of alkynyl C-nucleosides with substituted tetrazines afforded, upon extrusion of a nitrogen atom, pyrrole C-nucleosides in good yields... 

Compounds 875 belonging to this class of C-nucleosides were synthesized by Diels-Alder cycloaddition with inverse electron demand of 3,6-disubstituted 1,2,4,5-tetrazines containing a highly reactive diazadiene system and /if-D-ribofuranosylacetylenes (305) (94AP365) (Scheme 248). 

Inverse Diels-Alder cycloaddition of the /3-D-ribofuranosyl formimidate (1054) and 3,6-bis(trifluoromethyl)tetrazine formed the adduct 1055, which then lost a nitrogen molecule to afford the 5-(y3-D-ribofuranosyl)l,2,4-triazine C-nucleoside 801 (95API 75) (Scheme 306). 

Novel pyrrole C-nucleosides 233 were synthesized in two steps by cycloaddition of alkynyl C-nucleosides 231 to dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 150 <1994AP365>, followed by extrusion of nitrogen from the resultant pyridazine C-nucleosides 232 using electrochemical and/or chemical reduction (Scheme 59) <2004TL1031>. 

Seitz et al. prepared various l,2,4-triazine-C -nucleosides 340 via cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 to monosaccharide-derived imido esters 339 as intermediates in their quest for new pyridine C-nucleosides <1999ZNB549, 1997ZNB851, 1995AP175>. Similarly, the same group reported the preparation of novel 2-(2 -pyrrolidinyl)pyridines from (3 )- and (R)-proline via cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 147 to heterodienophilic imidates or hydrazones derived from (3)- and (R)-proline <1999TA573>. Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate 150 with either 0-methylisourea or cyanamide gave... 

Examples of synthesis of trifluoromethyl-substituted 1,2,4-triazines by transformation of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 49 ring are presented at Scheme 20. The anomeric C-glycosyl precursors 50, functionalized by an imidate group and appropriate for C-nucleoside synthesis were utilized as heterodienophiles in a Diels-Alder reaction with inverse electron demand to yield the 0-benzyl protected 5-( 3-D-ribofuranozyl)- and 5-(a-D-ribofuranosyl)-1,2,4-triazines 51 (Scheme 20) [30]. 

Pyridazine C-nucleosides have been made by cyclizations of tetrazines and ribofuranosyl alkynes, as in the case of 109 and 110, which gave 111 after deprotection. 1,2,4-Triazines have been similarly prepared by cycloadditions to ribofuranosyl imidates use of 109 gave 112. Pyrazolo[l,5-a]pyrimidine C-nucleosides such as 113 have been prepared by interaction of 3-aminopyrazole with a previously-described intermediate. ... 

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