Aqueous-Phase Heck Coupling of 5-Iodouridine and Alkenes under Phosphine-Free Conditions

Abstract

Palladium-catalyzed Heck couplings between 5-iodouridine and alkenes were carried out in aqueous media in the presence of triethylamine under phosphine-free conditions to give the desired products in high yields. In the absence of phosphine ligand, triethyl­amine appears to play a critical role in both generating the active catalyst species and serving as the base in the reaction.

aqueous phase - cross-coupling - Heck reaction - nucleosides - palladium

References and Notes

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General Procedure for Heck Coupling of 5-IdU: All reagents were purchased from commercial sources and used as received. 5-IdU (0.3 mmol), Pd(OAc)₂ (3.4 mg, 0.015 mmol), and TPPTS (17.1 mg, 0.03 mmol, if used) were placed in a round-bottomed flask under nitrogen. Deoxy-genated H₂O-MeCN (1:1, 3 mL) was added to the reaction vessel, followed by the addition of the alkene (1.2 mmol) and Et₃N (61.0 mg, 0.600 mmol). The reaction was heated in an oil bath at 80 ˚C until RP-HPLC (C-18 column, eluted with a gradient ranging from 10% MeOH in H₂O to 100% MeOH in H₂O) or RP-TLC [C-18, H₂O-MeOH (1:2) eluent] showed complete conversion. The reaction mixture was diluted to 10 mL with H₂O-MeOH (1:1) and the pH was adjusted to 6-7 using 10% aq HCl. After removal of solvent, the crude product was purified by chromatography [RP-SiO₂, H₂O → MeOH-H₂O (60:40)].
Butyl ( E )-3-(2′-Deoxyurid-5-yl)propenoate (3): With no phosphine. Yield: 75.0 mg (64%). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 11.69 (s, 1 H), 8.45 (s, 1 H), 7.39 (d, J = 15.5 Hz, 1 H), 6.88 (d, J = 15.5 Hz, 1 H), 6.17 (dd, J = 6.5, 6.5 Hz, 1 H), 5.29 (d, J = 4.5 Hz, 1 H), 5.20 (t, J = 5.0 Hz, 1 H), 4.28-4.31 (m, 1 H), 4.14 (t, J = 6.8 Hz, 2 H), 3.84 (dd, J = 7.0, 3.5 Hz, 1 H), 3.60-3.72 (m, 2 H), 2.17-2.26 (m, 2 H), 1.60-1.66 (m, 2 H), 1.35-1.43 (m, 2 H), 0.94 (t, J = 7.5 Hz, 3 H). ^¹³C NMR (126 MHz, DMSO-d ₆): δ = 166.7, 161.6, 149.1, 143.8, 137.8, 116.4, 108.1, 87.5, 84.7, 69.6, 63.4, 60.7, 39.9, 30.2, 18.6, 13.5.

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