| 95% |
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In N,N-dimethyl-formamide; at 110℃; for 18h;Product distribution / selectivity; |
General Experimental Procedure; A solution of <strong>[4016-63-1]8-bromoguanosine</strong> (520 mg, 1.5 mmol, 1 eqv.) in dry DMF (12 mL) was added to the substituted phenylacetylene (1.8 mmol, 1.2 eqv.) and dry triethylamine (0.63 mL, 4.5 mmol, 3 eqv.) in a vacuum dried Schlenk tube. PdCl2 (PPh3)2 (11 mg, 0.015 mmol, 1 mol percent) and CuI (6 mg, 0.030 mmol, 2 mol percent) were added and the reaction mixture was left to stir at 110° C. for 18 h, after which time it was allowed to cool to 40° C. and the DMF removed in vacuo to leave a brown solid. The solid was transferred to a sintered glass filter and was washed with boiling water (5.x.200 mL), EtOAc (5.x.25 mL) and diethylether (2.x.25 mL) yielding the product as a light cream solid (0.53 g, 91percent).Representative data for 8-(2'-phenylethynyl)guanosine: Mp 234-236° C. (decomp.); numax (DMSO solution)/cm-1 1695 (CO), 3126 and 3328 (NH), 3421 (OH); deltaH (400 MHz; DMSO-d6) 3.65 (1H, m), 3.88 (1H, m), 3.84 (1H, s), 4.19 (1H, s), 4.99 (2H, m), 5.15 (1H, br s), 5.50 (1H, d, J 6.4), 5.89 (1H, d, J 6.4), 6.62 (2H, s), 7.51 (3H, m), 7.64 (2H, m), 10.90 (1H, s); deltaC (128 MHz; DMSO-d6) 61.9, 70.4, 70.8, 79.4, 85.6, 88.2, 92.6, 117.5, 120.4, 128.9, 129.3, 129.9, 131.5, 151.1, 153.9, 156.0; m/z (FAB) MH+ 384 (2.5percent), 369, 354, 277, 185 (100percent); HRMS (MH+): 384.1299 (Calcd. for C18H18N5O5 384.1307).; Example 1Determining Optimum Synthesis Conditions Sonogashira alkynylation protocol for the cross-coupling of 1 with phenylacetylene 9a to give 5a (Equation 1, Scheme 1). Initially, standard conditions for Sonogashira alkynylation of 1 were selected from the literature (10 mol percent (Ph3P)2PdCl2, 10 mol percent CuI, 1.2 equiv. 9a and 3 equiv. Et3 N in DMF at 110° C. for 18 hours). This proved to be a generally ineffective protocol, affording the product in yields of ca. 20percent with poor purity (believed to be due to the uptake of Pd and/or Cu; the uptake was confirmed by X-ray photoelectron spectroscopy (XPS)), which led to optimisation of the conditions. Rapid Pd agglomeration and precipitation were thought to contribute to the low yields, which relates the optimal palladium concentration (vide supra).Lowering the amount of (Ph3P)2 PdCl2 to 5 mol percent and CuI to 10percent resulted in an improved yield (52percent). It was established that 1 mol percent (Ph3P)2 PdCl2 and 2 mol percent CuI proved the most effective catalyst/co-catalyst combination, affording the cross-coupled product in 95percent yield (after only 2 hours). Such a successful reaction means that this reaction is suitable for scale up.Under similar conditions, the acetate protected guanosine derivative 2 reacted with 9a to produce 6a in 88percent yield, which was more cumbersome to purify than 5a, as column chromatography on silica-gel was required (eluting with methanol/chloroform solvent mixtures (1:99, v/v).; Example 2Assessment of the Effect of Cu(I) on YieldsThe purity of 5a was also questionable at the higher Cu(I) loading; the solid is a light green colour, rather than an off-white, due to the presence of trace quantities guanosine derived copper complexes (bidentate coordination through N-1 and O-6). This has been confirmed by infra-red spectroscopic experiments, which show the expected carbonyl shifts (in frequency) from uncoordinated ligand to coordinated ligand. The increased catalytic activity can be explained to a certain extent by the production of higher concentrations of alkynylcuprate, although an alternative role could also be responsible for the rate enhancement vide infra.A further experiment was carried out, where it was determined that 1 mol percent PdCl2 and 2 mol percent CuI was an ineffective catalyst/co-catalyst combination, highlighting the importance of the activating phosphine ligand in the intimate steps of the catalytic cycle-it was noted that palladium nanoparticles were rapidly formed in this reaction. |
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