Palladium-Catalysed Direct Heteroarylations of Heteroaromatics Using Esters as Blocking Groups at C2 of Bromofuran and Bromothiophene Derivatives: A One-Step Access to Biheteroaryls

Abstract

Methyl 5-bromo-2-furoate and ethyl 5-bromothiophene-2-carboxylate have been found to be useful alternative reagents to 2-halofurans and 2-halothiophenes for the palladium-catalysed direct arylation of heteroaromatics. As their C5 is blocked by ester groups, the use of these substrates prevents the formation of dimers or oligomers, and therefore allows the formation of biheteroaryls in high yields. A very wide variety of heteroaromatics can be coupled with these two reagents. Moreover, with methyl 5-bromo-2-furoate, sequential catalytic C5 arylation, decarboxylation, catalytic C2-arylation reactions allowed the synthesis of 2,5-diarylated furan derivatives.

Key words

methyl 5-bromo-2-furoate - ethyl 5-bromothiophene-2-carboxylate - palladium - direct arylation - heteroaromatics - biheteroaryls

• References and Notes


For examples of palladium cross-couplings with heteroaromatic compounds, see:
• 1a Li JJ, Gribble GW. Palladium in Heterocyclic Chemistry . Pergamon; Amsterdam: 2000
• 1b Ackermann L. Modern Arylation Methods . Wiley-VCH; Weinheim: 2009
• 2a Alberico D, Scott ME, Lautens M. Chem. Rev. 2007; 107: 174
• 2b Satoh T, Miura M. Chem. Lett. 2007; 36: 200
• 2c Campeau L.-C, Stuart DR, Fagnou K. Aldrichimica Acta 2007; 40: 35
• 2d Seregin IV, Gevorgyan V. Chem. Soc. Rev. 2007; 36: 1173
• 2e Li B.-J, Yang S.-D, Shi Z.-J. Synlett 2008; 949
• 2f Bellina F, Rossi R. Tetrahedron 2009; 65: 10269
• 2g Ackermann L, Vincente R, Kapdi AR. Angew. Chem. Int. Ed. 2009; 48: 9792
• 2h Roger J, Gottumukkala AL, Doucet H. ChemCatChem 2010; 2: 20
• 2i Fischmeister C, Doucet H. Green Chem. 2011; 13: 741
• 2j Mori A. J. Synth. Org. Chem. Jpn. 2011; 69: 1202

For selected examples of palladium-catalysed direct arylations of hereroaromatics, see:
• 3a Ohta A, Akita Y, Ohkuwa T, Chiba M, Fukunaga R, Miyafuji A, Nakata T, Tani N, Aoyagi Y. Heterocycles 1990; 31: 1951
• 3b Bellina F, Cauteruccio S, Rossi R. Eur. J. Org. Chem. 2006; 1379
• 3c Cerna I, Pohl R, Klepetarova B, Hocek M. Org. Lett. 2006; 8: 5389
• 3d Turner GL, Morris JA, Greaney MF. Angew. Chem. Int. Ed. 2007; 46: 7996
• 3e Wang X, Gribkov DV, Sames D. J. Org. Chem. 2007; 72: 1476
• 3f Campeau L.-C, Bertrand-Laperle M, Leclerc J.-P, Villemure E, Gorelsky S, Fagnou K. J. Am. Chem. Soc. 2008; 130: 3276
• 3g Nakano M, Tsurugi H, Satoh T, Miura M. Org. Lett. 2008; 10: 1851
• 3h Besselievre F, Mahuteau-Betzer F, Grierson DS, Piguel S. J. Org. Chem. 2008; 73: 3278
• 3i Yanagisawa S, Ueda K, Sekizawa H, Itami K. J. Am. Chem. Soc. 2009; 131: 14622
• 3j Lapointe D, Markiewicz T, Whipp CJ, Toderian A, Fagnou K. J. Org. Chem. 2011; 76: 749
• 3k Nadres ET, Lazareva A, Daugulis O. J. Org. Chem. 2011; 76: 471

For selected examples from our laboratory, see:
• 4a Dong JJ, Roger J, Požgan F, Doucet H. Green Chem. 2009; 11: 1832
• 4b Dong JJ, Roger J, Doucet H. Tetrahedron Lett. 2009; 50: 2778
• 4c Fall Y, Doucet H, Santelli M. ChemSusChem 2009; 2: 153
• 4d Roger J, Doucet H. Tetrahedron 2009; 65: 9772
• 4e Roger J, Verrier C, Le Goff R, Hoarau C, Doucet H. ChemSusChem 2009; 2: 951
• 4f Roger J, Doucet H. Adv. Synth. Catal. 2009; 351: 1977
• 4g Ionita M, Roger J, Doucet H. ChemSusChem 2010; 3: 367
• 4h Chen L, Roger J, Bruneau C, Dixneuf PH, Doucet H. Chem. Commun. 2011; 47: 1872
• 4i Beydoun K, Zaarour M, Williams JA. G, Doucet H, Guerchais V. Chem. Commun. 2012; 48: 1260

For examples of palladium-catalysed direct heteroarylation at C2 of oxazole, imidazole or thiazole derivatives, see:
• 5a Martin T, Verrier C, Hoarau C, Marsais F. Org. Lett. 2008; 10: 2909
• 5b Shibahara F, Yamaguchi E, Murai T. Chem. Commun. 2010; 46: 2471
• 5c Chen W, Wang M, Li P, Wang L. Tetrahedron 2011; 67: 5913
• 5d Huang C, Giokaris A, Gevorgyan V. Chem. Lett. 2011; 40: 1053
• 6a Sánchez RS, Zhuravlev FA. J. Am. Chem. Soc. 2007; 129: 5824
• 6b Strotman NA, Chobanian HR, Guo Y, He J, Wilson J. Org. Lett. 2010; 12: 3578
• 6c Théveau L, Verrier C, Lassalas P, Martin T, Dupas G, Querolle O, Van Hijfte L, Marsais F, Hoarau C. Chem.–Eur. J. 2011; 17: 14450

For examples of palladium-catalysed direct heteroarylation using C5-substituted 2-halofurans, see:
• 7a McClure MS, Glover B, McSorley E, Millar A, Osterhout MH, Roschangar F. Org. Lett. 2001; 3: 1677
• 7b Derridj F, Gottumukkala AL, Djebbar S, Doucet H. Eur. J. Inorg. Chem. 2008; 2550

For examples of palladium-catalysed direct heteroarylation using C5-substituted halothiophenes, see:
• 8a Ellinger S, Kreyes A, Ziener U, Hoffmann-Richter C, Landfester K, Möller M. Eur. J. Org. Chem. 2007; 5686
• 8b Bellina F, Cauteruccio S, Di Flore A, Rossi R. Eur. J. Org. Chem. 2008; 5436
• 8c Liégaut B, Lapointe D, Caron L, Vlassova A, Fagnou K. J. Org. Chem. 2009; 74: 1826
• 9 For examples of palladium-catalysed intramolecular direct heteroarylation using halothiophenes, see: Choi YL, Lee H, Kim BT, Choi K, Heo J.-N. Adv. Synth. Catal. 2010; 352: 2041

For examples of palladium-catalysed direct heteroarylation using unsubstituted halothiophenes, see:
• 10a Pivsa-Art S, Satoh T, Kawamura Y, Miura M. Bull. Chem. Soc. Jpn. 1998; 71: 467
• 10b Park C.-H, Ryabova V, Seregin IV, Sromek AW, Gevorgyan V. Org. Lett. 2004; 6: 1159
• 10c Borghese A, Geldhof G, Antoine L. Tetrahedron Lett. 2006; 47: 9249
• 10d Verrier C, Martin T, Hoarau C, Marsais F. J. Org. Chem. 2008; 73: 7383
• 10e Ruiz-Rodríguez J, Albericio F, Lavilla R. Chem.–Eur. J. 2010; 16: 1124
• 10f Baghbanzadeh M, Pilger C, Kappe CO. J. Org. Chem. 2011; 76: 8138
• 10g Ioannidou HA, Koutentis PA. Org. Lett. 2011; 13: 1510

For ‘concerted metallation deprotonation’ mechanism, see:
• 11a Davies DL, Donald SM. A, Macgregor SA. J. Am. Chem. Soc. 2005; 127: 13754
• 11b Lapointe D, Fagnou K. Chem. Lett. 2010; 39: 1118
• 12a Goossen LJ, Rodriguez N, Goossen K. Angew. Chem. Int. Ed. 2008; 47: 3100
• 12b Rodriguez N, Goossen LJ. Chem. Soc. Rev. 2011; 40: 530
• 12c Lange PP, Goossen LJ, Podmore P, Underwood T, Sciammetta N. Chem. Commun. 2011; 47: 3628
• 13 Typical Experiment for the Synthesis of Products 1–19 and 22–28 The reaction of the heteroaryl bromide (1 mmol), heteroarene (2 mmol), and KOAc (0.196 g, 2 mmol) at 120 °C during 16 h in DMAc (4 mL) with Pd(OAc)₂ (2.24 mg, 0.01 mmol), under argon affords the coupling product after evaporation of the solvent and purification on silica gel. Methyl 5-(2-Isobutylthiazol-5-yl)-furan-2-carboxylate (1) ¹H NMR (400 MHz, CDCl₃): δ = 7.90 (s, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 6.50 (d, J = 2.3 Hz, 1 H), 3.84 (s, 3 H), 2.81 (d, J = 7.7 Hz, 2 H), 2.10–2.00 (m, 1 H), 0.94 (d, J = 7.7 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.0, 158.8, 150.3, 143.7, 139.8, 126.7, 119.9, 108.3, 52.0, 42.4, 29.8, 22.2. Anal. Calcd (%) for C₁₃H₁₅NO₃S (265.33): C, 58.85; H, 5.70. Found: C, 58.99; H, 5.57
• 14a Fu HY, Doucet H. Eur. J. Org. Chem. 2011; 7163
• 14b Chen L, Bruneau C, Dixneuf PH, Doucet H. Green Chem. 2012; 14: 1111
• 15 Typical Experiment for the Synthesis of Products 29–31 The reaction of the heteroaryl bromide (1 mmol), heteroarene (1.5 mmol), KOAc (0.196 g, 2 mmol), and K₂CO₃ (0.276 g, 2 mmol) at 150 °C during 16 h in DMAc (4 mL) with Pd(OAc)₂ (4.48 mg, 0.02 mmol), under argon affords the coupling product after evaporation of the solvent and purification on silica gel. 4-[5-(3,5-Dimethylisoxazol-4-yl)-furan-2-yl]benzonitrile (29) ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (d, J = 8.2 Hz, 2 H), 7.61 (d, J = 8.2 Hz, 2 H), 6.84 (d, J = 2.7 Hz, 1 H), 6.43 (d, J = 2.7 Hz, 1 H), 2.60 (s, 3 H), 2.41 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.0, 157.5, 151.1, 146.9, 134.2, 132.7, 123.7, 118.9, 110.4, 109.7, 109.0, 108.0, 12.7, 11.8. Anal. Calcd (%) for C₁₆H₁₂N₂O₂ (264.28): C, 72.72; H, 4.58. Found: C, 72.57; H, 4.40