Exploring the Use of the Suzuki Coupling Reaction in the Synthesis of 4′-Alkyl-2′-hydroxyacetophenones

Abstract

A series of 4′-alkyl-2′-hydroxyacetophenones were prepared by Suzuki cross-coupling reactions of 4′-bromo-2′-hydroxyacetophenone. In these reactions, alkyl(trifluoro)borates were found to be better reactants than alkylboronic acids. 4′-Alkyl-2′-hydroxyacetophenones are key intermediates for the further synthesis of ­lipoflavonoids that are more readily incorporated into lipid bilayer membranes than flavonoids and should, therefore, have superior ­biological effects through increased bioavailability.

Key words

alkylation - cross-coupling - catalysis - palladium - ketones

• References

• 1 Suzuki A. J. Organomet. Chem. 1999; 576: 147
• 2 Zou G, Krishna Reddy Y, Falck JR. Tetrahedron Lett. 2001; 42: 7213
• 3 Wawrzyniak P, Heinicke J. Tetrahedron Lett. 2006; 47: 8921
• 4 Baltus CB, Press NJ, Spencer J. Synlett 2012; 23: 2477
• 5 Ehlers P, Petrosyan A, Ghochikyan TV, Saghyan AS, Neubauer A, Lochbrunner S, Langer P. Synlett 2013; 24: 359
• 6 Littke AF, Dai C, Fu GC. J. Am. Chem. Soc. 2000; 122: 4020
• 7 So FV, Guthrie N, Chambers AF, Carroll KK. Cancer Lett. 1997; 112: 127
• 8 Pouget C, Fagnere C, Basly J.-P, Besson A.-E, Champavier Y, Habrioux G, Chulia A.-J. Pharm. Res. 2002; 19: 286
• 9 Rice-Evans CA, Miller NJ, Paganga G. Free Radical Biol. Med. 1996; 20: 933
• 10 Erlund I. Nutr. Res. (N. Y., NY U. S.) 2004; 24: 851
• 11 Dangles O. Curr. Org. Chem. 2012; 16: 692
• 12 Movileanu L, Neagoe I, Flonta ML. Int. J. Pharm. (Amsterdam, Neth.) 2000; 205: 135
• 13 Pawlikowska-Pawlęga B, Gruszecki W, Misiak L, Paduch R, Piersiak T, Zarzyka B, Pawelec J, Gawron A. Biochim. Biophys. Acta, Biomembr. 2007; 1768: 2195
• 14 Košinová P, Berka K, Wykes M, Otyepka M, Trouillas P. J. Phys. Chem. B 2012; 116: 1309
• 15 Bennett CJ, Caldwell ST, McPhail DB, Morrice PC, Duthie GG, Hartley RC. Bioorg. Med. Chem. 2004; 12: 2079
• 16 Britton RG, Horner-Glister E, Pomenya OA, Smith EE, Denton R, Jenkins PR, Steward WP, Brown K, Gescher A, Sale S. Eur. J. Med. Chem. 2012; 54: 952
• 17 Moriarty RM, Grubjesic S, Surve BC, Chandersekera SN, Prakash O, Naithani R. Eur. J. Med. Chem. 2006; 41: 263
• 18 Rao YK, Fang S-H, Tzenga Y.-M. Bioorg. Med. Chem. 2005; 13: 6850
• 19 Zhuravel MA, Nguyen ST. Tetrahedron Lett. 2001; 42: 7925
• 20 Kabalka GW, Pagni RM, Hair CM. Org. Lett. 1999; 1: 1423
• 21 Molander GA, Yun CS. Tetrahedron 2002; 58: 1465
• 22 Bumagin NA, Bykov VV. Tetrahedron 1997; 53: 14437
• 23 Tikad A, Dehbi O, Akssira M, Aadil M, Massip S, Leger JM, Jarry C, Guillaumet G, Routier S. Synthesis 2013; 45: 491
• 24 Koini EN, Avlonitis N, Martins-Duarte ES, de Souza W, Vommaro RC, Calogeropoulou T. Tetrahedron 2012; 68: 10302
• 25 El Akkaoui A, Bassoude I, Koubachi J, Berteina-Raboin S, Mouaddib A, Guillaumet G. Tetrahedron 2011; 67: 7128
• 26 Molander GA, Ito T. Org. Lett. 2001; 3: 393
• 27 Molander GA, Yun CS, Ribagorda M, Biolatto B. J. Org. Chem. 2003; 68: 5534
• 28 van den Hoogenband A, Lange JH. M, Terpstra JW, Koch M, Visser GM, Visser M, Korstanje TJ, Jastrzebski JT. B. H. Tetrahedron Lett. 2008; 49: 4122
• 29 Dreher SD, Lim SE, Sandrock DL, Molander GA. J. Org. Chem. 2009; 74: 3626
• 30 Dreher SD, Dormer PG, Sandrock DL, Molander GA. J. Am. Chem. Soc. 2008; 130: 9257
• 31 4′-Alkyl-2′-hydroxyacetophenones; General Procedure with Alkylboronic Acids Alkylboronic acid RB(OH)₂ (1.1 equiv), PdCl₂·dppf (0.1 equiv), and 3 M aq NaOH (3 equiv) were added to a solution of 4′-bromo-2′-hydroxyacetophenone in THF (10 mL), and the mixture was refluxed for the appropriate time. After cooling, the mixture was diluted with water (10 mL), acidified with 3 M aq HCl, and extracted with CH₂Cl₂ (3 × 20 mL). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude product was purified by TLC [silica gel, hexane–EtOAc (9:1)]. All the compounds were obtained as colorless oils.
• 32 4′-Alkyl-2′-hydroxyacetophenones; General Procedure for Microwave-Assisted Synthesis with Potassium Alkyl(trifluoro)borates 4′-Bromo-2′-hydroxyacetophenone, K⁺ (RBF₃)^– (1.5 equiv), Pd(OAc)₂ (0.1 equiv), RuPhos (0.2 equiv), 3 M aq NaOH (0.5 mL, 3 equiv), and toluene (5 mL) were placed in a 10 mL microwave vessel that was sealed with a pressure lock. The mixture was then subjected to microwave irradiation in an Anton Paar Monowave 300 microwave reactor at 120 °C (150 W) for 5 h.
• 33 4′-Butyl-2′-hydroxyacetophenone ¹H NMR (400 MHz, CDCl₃): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.35 (m, 2 H), 1.60 (m, 2 H), 2.60 (t, J = 7.5 Hz, 2 H), 2.60 (s, 3 H, COCH₃), 6.72 (dd, J = 1.6, 8.2 Hz, 1 H, H-5′), 6.79 (d, J = 1.2 Hz, 1 H, H-3′), 7.63 (d, J = 8.2 Hz, 1 H, H-6′), 12.28 (s, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 13.9 (CH₃), 22.3 (CH₂), 26.5 (CH₃–CO), 32.8 (CH₂), 35.9 (CH₂), 117.8 (Cq, C-1′), 117.8 (CH, C-3′), 119.6 (CH, C-5′), 130.6 (CH, C-6′), 153.0 (Cq, C-4′), 162.6 (Cq, C-2′), 203.9 (C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₇O₂: 193.1223; found: 193.1225.
• 34 4′-Decyl-2′-hydroxyacetophenone ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.27 (m, 14 H), 1.61 (m, 2 H), 2.59 (t, J = 7.5 Hz, 2 H), 2.60 (s, 3 H, COCH₃), 6.72 (dd, J = 1.3, 8.2 Hz, 1 H, H-5′), 6.79 (br s, 1 H, H-3′), 7.63 (d, J = 8.2 Hz, 1 H, H-6′), 12.28 (s, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (CH₃), 22.7 (CH₂), 26.5 (CH₃–CO), 29.2 (CH₂), 29.3 (CH₂), 29.4 (CH₂), 29.5 (CH₂), 29.6 (CH₂), 30.7 (CH₂), 31.9 (CH₂), 36.2 (CH₂), 117.8 (Cq, C-1′), 117.8 (CH, C-3′), 119.6 (CH, C-5′), 130.6 (CH, C-6′), 153.1 (Cq, C-4′), 162.6 (Cq, C-2′), 203.9 (C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₉O₂: 277.2162; found: 277.2162.
• 35 4′-Hexyl-2′-hydroxyacetophenone ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.30 (m, 6 H), 1.61 (m, 2 H), 2.59 (t, J = 7.4 Hz, 2 H), 2.60 (s, 3 H, COCH₃), 6.72 (dd, J = 1.6, 8.2 Hz, 1 H, H-5′), 6.79 (d, J = 1.3 Hz, 1 H, H-3′), 7.63 (d, J = 8.2 Hz, 1 H, H-6′), 12.28 (s, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (CH₃), 22.6 (CH₂), 26.5 (CH₃–CO), 28.9 (CH₂), 30.6 (CH₂), 31.7 (CH₂), 36.2 (CH₂), 117.8 (Cq, C-1′), 117.8 (CH, C-3′), 119.6 (CH, C-5′), 130.6 (CH, C-6′), 153.0 (Cq, C-4′), 162.6 (Cq, C-2′), 203.9 (C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₂₁O₂: 221.1536; found: 221.1538.
• 36 2′-Hydroxy-4′-octylacetophenone ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.28 (m, 10 H), 1.61 (m, 2 H), 2.59 (t, J = 6.7 Hz, 2 H), 2.60 (s, 3 H, COCH₃), 6.72 (dd, J = 1.1, 8.2 Hz, 1 H, H-5′), 6.79 (br s, 1 H, H-3′), 7.63 (d, J = 8.2 Hz, 1 H, H-6′), 12.28 (s, 1 H, OH). ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (CH₃), 22.7 (CH₂), 26.5 (CH₃–CO), 29.2 (2 × CH₂), 29.4 (CH₂), 30.7 (CH₂), 31.9 (CH₂), 36.2 (CH₂), 117.8 (Cq, C-1′), 117.8 (CH, C-3′), 119.6 (CH, C-5′), 130.6 (CH, C-6′), 153.1 (Cq, C-4′), 162.6 (Cq, C-2′), 203.9 (C=O). HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₅O₂: 249.1849; found: 249.1850.