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.

Key words

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

References and Notes

• 1a Lakshman MK. J. Organomet. Chem.  2002,  653:  234 
• 1b Agrofoglio LA. Gillaizeau I. Saito Y. Chem. Rev.  2003,  103:  1875 
• 1c Lakshman MK. Curr. Org. Synth.  2005,  2:  83 
• 2 De Clercq E. Med. Res. Rev.  2005,  25:  1 
• 3a Fujimoto K. Matsuda S. Takahashi N. Saito I. J. Am. Chem. Soc.  2000,  122:  5646 
• 3b Yoshimura Y. Noguchi Y. Sato H. Fujimoto K. ChemBioChem  2006,  7:  598 
• 4a Bråthe A. Gundersen L.-L. Rise F. Eriksen AB. Vollsnes AV. Wang L. Tetrahedron  1999,  55:  211 
• 4b Bråthe A. Gundersen L.-L. Nissen-Meyer J. Rise F. Spilsberg B. Bioorg. Med. Chem. Lett.  2003,  13:  877 
• 5 Langer PR. Waldrop AA. Ward DC. Proc. Natl. Acad. Sci. USA  1981,  78:  6633 
• 6 Ashwell M. Jones AS. Kumar A. Sayers JR. Walker RT. Sakuma T. De Clercq E. Tetrahedron  1987,  43:  4601 
• 7a Whale RF. Coe PL. Walker RT. Nucleosides Nucleotides  1991,  10:  1615 
• 7b Ding Y. Girardet J.-L. Hong Z. Shaw SZ. Yao N. Heterocycles  2006,  68:  521 
• 7c Bartholomä MD. Vortherms AR. Hillier S. Ploier B. Joyal J. Babich J. Doyle RP. Zubieta J. ChemMedChem  2010,  5:  1513 
• 8a Garg NK. Woodroofe CC. Lacenere CJ. Quake SR. Stoltz BM. Chem. Commun.  2005,  4551 
• 8b Ding H. Greenberg MM. J. Am. Chem. Soc.  2007,  129:  772 
• 8c Ogino M. Taya Y. Fujimoto K. Org. Biomol. Chem.  2009,  7:  3163 
• 8d Reddington MV. Cunninghan-Bryant D. Tetrahedron Lett.  2011,  52:  181 
• 9 Tobrman T. Dvořák D. Eur. J. Org. Chem.  2008,  2923 
• 10 Lagisetty P. Zhang L. Lakshman MK. Adv. Synth. Catal.  2008,  350:  602 
• 11 Štambaský J. Hocek M. Kočovský P. Chem. Rev.  2009,  109:  6729 
• 12 Shaughnessy KH. Chem. Rev.  2009,  109:  643 
• 13 Casalnuovo AL. Calabrese JC. J. Am. Chem. Soc.  1990,  112:  4324 
• 14a Western EC. Daft JR. Johnson EM. Gannett PM. Shaughnessy KH. J. Org. Chem.  2003,  68:  6767 
• 14b Čapek P. Pohl R. Hocek M. Org. Biomol. Chem.  2006,  4:  2278 
• 15a Thoresen LH. Jiao G.-S. Haaland WC. Metzker ML. Burgess K. Chem. Eur. J.  2003,  9:  4603 
• 15b Cho JH. Prickett CD. Shaughnessy KH. Eur. J. Org. Chem.  2010,  3678 
• 16 Alonso F. Beletskaya IP. Yus M. Tetrahedron  2005,  61:  11771 
• 18 Jones AS. Verhelst G. Walker RT. Tetrahedron Lett.  1979,  4415 
• 19a Louie J. Hartwig JF. Angew. Chem. Int. Ed.  1996,  35:  2359 
• 19b Strieter ER. Blackmond DG. Buchwald SL. J. Am. Chem. Soc.  2003,  125:  13978 
• 20 Amatore C. Blart E. Genêt JP. Jutand A. Lemaire-Audoire S. Savignac M. J. Org. Chem.  1995,  60:  6829 

17

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.