CC Cross‐Coupling Reactions of O⁶‐Alkyl‐2‐Haloinosine Derivatives and a One‐Pot Cross‐Coupling/O⁶‐Deprotection Procedure

Abstract

Reaction conditions for the C–C cross-coupling of O6-alkyl-2-bromo- and 2-chloroinosine derivatives with aryl-, hetaryl-, and alkylboronic acids were studied. Optimization experiments with silyl-protected 2-bromo-O6-methylinosine led to the identification of [PdCl2(dcpf)]/K3PO4 in 1,4-dioxane as the best condition for these reactions (dcpf = 1,1’-bis(dicyclohexylphosphino)ferrocene). Attempted O6-demethylation, as well as the replacement of the C-6 methoxy group by amines, was unsuccessful, which led to the consideration of Pd-cleavable groups such that C–C cross-coupling and O6-deprotection could be accomplished in a single step. Thus, inosine 2-chloro-O6-allylinosine was chosen as the substrate and, after re-evaluation of the cross-coupling conditions with 2-chloro-O6-methylinosine as a model substrate, one-step C–C cross-coupling/deprotection reactions were performed with the O6-allyl analogue. These reactions are the first such examples of a one-pot procedure for the modification and deprotection of purine nucleosides under C–C cross-coupling conditions.

A novel bis(pinacolato)diboron-mediated N–O bond deoxygenative route to C6 benzotriazolyl purine nucleoside derivatives

“…The C2 chlorination product formed in CH 2 Cl 2 would not be a problem as this would be reactive in the subsequent step. Via a minor modification of our previous results, 26 C–C cross coupling and deprotection of the O 6 -allyl group was performed in a single step to yield 2-phenylinosine derivative 18 . Finally, reaction of the amide group with BOP, using DBU as base, in MeCN gave the desired precursor 19 .…”

“…O 6 -Allyl-2′,3′,5′-tri- O -( t -butyldimethylsilyl)guanosine ( 15 ) was prepared from guanosine 15 and converted to the O 6 -allyl-2-bromo nucleoside ( 16 ) on the basis of our previously published route. 26 All other reagents were used as received from commercial suppliers. 1 H NMR spectra were obtained at 500 MHz in CDCl 3 and are referenced to the residual protonated solvent resonance.…”

Synthesis and Applications of Azolylpurine and Azolylpurine Nucleoside Derivatives

“…For example, the reaction between O 6 -methyl-2-bromoinosine derivative 148 and pyrazolylboronic acid derivative 149 gave product 150 (Scheme 39). [62] The best catalytic system for this transformation was [PdCl 2 (dcpf)]/K 3 PO 4 in 1,4-dioxane.…”

1,2,3-Triazoles as leaving groups: SNAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

“…Such intensive medicinal chemistry applications demand for constant development of novel synthetic methodologies. Frequently, the purine structure is modified in S N Ar reactions with N- [7][8][9][10][11] and S-nucleophiles [12][13][14] and in metal catalyzed reactions of halopurine derivatives [15][16][17][18][19][20]. Modifications of purines with O-nucleophiles are based on S N Ar reactions between 6-halopurine derivatives and alcohols [21][22][23][24][25][26][27][28] in the presence of a base.…”