Arylation of Pyridines via Suzuki–Miyaura Cross-Coupling and Pyridine-­Directed C–H Activation Using a Continuous-Flow Approach

Dedicated to Professor Manfred Schlosser who is missing in the Swiss alps he loved so much

Abstract

Suzuki–Miyaura cross-coupling reactions between heteroaryl bromides and arylboronic acids were performed employing a continuous-flow approach using a simple flow reactor designed in-house. Pd(PPh₃)₄ was used as catalyst, and arylboronic acids containing both electron-withdrawing and electron-donating groups were applied. The coupling process required 23 minutes of residence time to be completed and generally good yields were obtained. Subsequent arylation of 2-phenyl pyridine was carried out via a C–H activation strategy using substituted bromobenzene compounds and a ruthenium(II) catalyst. To the best of our knowledge in this work we present for the first time the possibility of performing intermolecular C–H activation in a continuous-flow system.

Key words

heterocycles - cross coupling - flow chemistry - C–H activation - catalysis

• References and Notes

• 1a Baumann M, Baxendale IR, Ley SV, Nikbin N. Beilstein J. Org. Chem. 2011; 7: 442
• 1b Heterocycles in Life and Society: An Introduction to Heterocyclic Chemistry and Biochemistry and the Role of Heterocycles in Science, Technology, Medicine, and Agriculture. Pozharsky AF, Soldatenkov AT, Katritzky AR. John Wiley and Sons; Chichester: 1997
• 1c Bellus D. Lect. Heterocycl. Chem. 1987; 9: 65
• 1d Muller T, Bräse S. Angew. Chem. Int. Ed. 2011; 50: 11844
• 1e Rasmussen SC, Schwiderski RL, Mulholland ME. Chem. Commun. 2011; 47: 11394
• 1f Maly KE. J. Mat. Chem. 2009; 19: 1781
• 1g Elbing M, Bazan GC. Angew. Chem. Int. Ed. 2008; 47: 834

For reviews on cross-coupling on heterocyclic substrates, see:
• 2a Schnürch M, Flasik R, Khan AF, Spina M, Mihovilovic MD, Stanetty P. Eur. J. Org. Chem. 2006; 3283
• 2b Schroeter S, Stock C, Bach T. Tetrahedron 2005; 61: 2245
• 2c Wang J.-R, Manabe K. Synthesis 2009; 1405
• 2d Djakovitch L, Batail N, Genelot M. Molecules 2011; 16: 5241
• 2e Slagt VF, de Vries AH. M, de Vries JG, Kellog RM. Org. Process Res. Dev. 2010; 14: 30
• 2f Fairlamb IJ. S. Chem. Soc. Rev. 2007; 36: 1036
• 2g Banwell MG, Goodwin TE, Ng S, Smith JA, Wong DJ. Eur. J. Org. Chem. 2006; 3043
• 2h Nicolaou KC, Bulger PG, Sarlah D. Angew. Chem. Int. Ed. 2005; 44: 4442
• 2i Magano J, Dunetz JR. Chem. Rev. 2011; 111: 2177
• 3 Noël T, Buchwald SL. Chem. Soc. Rev. 2011; 40: 5010
• 4 Glasnov TN, Kappe CO. Adv. Synth. Catal. 2010; 352: 3089
• 5a Baxendale IR, Hayward JJ, Lanners S, Ley SV, Smith CD In Microreactors in Organic Synthesis and Catalysis. Wirth T. Wiley-VCH; Weinheim: 2008: 84-122
• 5b Irfan M, Glasnov TN, Kappe CO. ChemSusChem 2011; 4: 300

For selected examples, see:
• 6a Kirschning A, Solodenko W, Mennecke K. Chem. Eur. J. 2006; 12: 5972
• 6b Wegner J, Ceylan S, Kirschning A. Adv. Synth. Catal. 2012; 354: 17
• 6c Solodenko W, Wen H, Leue S, Stuhlmann F, Sourkouni-Argirusi G, Jas G, Schönfeld H, Kunz U, Kirschning A. Eur. J. Org. Chem. 2004; 3601
• 6d He P, Haswell SJ, Fletcher PD. I. Appl. Catal., A 2004; 274: 111
• 6e Wilson NS, Sarko CR, Roth GP. Org. Process Res. Dev. 2004; 8: 535
• 6f Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK. Chem. Eur. J. 2006; 12: 4407
• 6g Nagaki A, Kenmoku A, Moriwaki Y, Hayashi A, Yoshida J.-i. Angew. Chem. Int. Ed. 2010; 49: 7543
• 6h Noel T, Musacchio AJ. Org. Lett. 2011; 13: 5180
• 6i Noel T, Kuhn S, Musacchio AJ, Jensen KF, Buchwald SL. Angew. Chem. Int. Ed. 2011; 50: 5943
• 7a Lyons TW, Sanford MS. Chem. Rev. 2010; 110: 1147
• 7b Chen X, Engle KM, Wang D.-H, Yu J.-Q. Angew. Chem. Int. Ed. 2009; 48: 5094
• 8 Zhang L, Geng M, Teng P, Zhao D, Lu X, Li J.-X. Ultrason. Sonochem. 2012; 19: 250

For reviews on C–H activation, see:
• 9a Engle KM, Mei T.-S, Wasa M, Yu J.-Q. Acc. Chem. Res. 2012; 45: 788
• 9b Du Bois J. Chemtracts 2005; 18: 1
• 9c Davies HM. L, Loe O. Synthesis 2004; 16: 2595
• 9d Davies HM. L, Beckwith RE. J. Chem. Rev. 2003; 103: 2861
• 9e Godula K, Sames D. Science 2006; 312: 67
• 9f Yeung CS, Dong VM. Chem. Rev. 2011; 111: 1215
• 9g Zhang C, Tang T, Jiao N. Chem. Soc. Rev. 2012; 41: 3464
• 9h Ackermann L. Chem. Rev. 2011; 111: 1315
• 9i Jazzar R, Hitce J, Renaudat A, Sofack-Kreitzer J, Baudoin O. Chem. Eur. J. 2010; 16: 2654
• 9j Schnürch M, Dastbaravardeh N, Ghobrial M, Mrozek B, Mihovilovic MD. Curr. Org. Chem. 2011; 15: 2694
• 10a Sersen S, Kljun J, Pozgan F, Stefane B, Turel I. Organometallics 2013; 32: 609
• 10b Pozgan F, Dixneuf PH. Adv. Synth. Catal. 2009; 351: 1737
• 10c Oezdemir I, Demir S, Cetinkaya B, Gourlaouen C, Maseras F, Bruneau C, Dixneuf PH. J. Am. Chem. Soc. 2008; 130: 1156
• 10d Oi S, Fukita S, Inoue Y. Chem. Commun. 1998; 2439
• 10e Yu B, Yan X, Wang S, Tang N, Xi C. Organometallics 2010; 29: 3222
• 10f Yoshikai N, Matsumoto A, Norinder J, Nakamura E. Synlett 2010; 313
• 10g Prades A, Poyatos M, Peris E. Adv. Synth. Catal. 2010; 352: 1155
• 11a Hartman RL, Naber JR, Zaborenko N, Buchwald SL, Jensen KV. Org. Process Res. Dev. 2010; 14: 1347
• 11b Noel T, Naber JR, Hartman RL, McMullen JP, Jensen KF, Buchwald SL. Chem. Sci. 2011; 2: 287
• 11c Kuhn S, Noel T, Gu L, Heider PL, Jensen KV. Lab-on-a-Chip 2011; 11: 2488
• 12a Koley M, Dastbaravardeh N, Schnürch M, Mihovilovic MD. ChemCatChem 2012; 4: 1696
• 12b Chu J.-H, Tsai S.-L, Wu M.-J. ChemInform 2010; 41: 3757

For reviews, see:
• 13a Wencel-Delord J, Droge T, Liu F, Glorius F. Chem. Soc. Rev. 2011; 40: 4740
• 13b Arockiam PB, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879
• 13c Ritleng V, Sirlin C, Pfeffer M. Chem. Rev. 2002; 102: 1731
• 13d Kakiuchi F, Chatani N. Ruthenium-Catalyzed Reactions via sp C–H, sp² C–H, sp³ C–H, and C–Halogen Bond Activations. In Ruthenium in Organic Synthesis. Murahashi S.-I. Wiley-VCH; Weinheim: 2004: 219-255
• 14 Oi S, Funayama R, Hattori T, Inoue Y. Tetrahedron 2008; 64: 6051
• 15 Oi S, Fukita S, Hirata N, Watanuki N, Miyano S, Inoue Y. Org. Lett. 2001; 3: 2579
• 16a Dastbaravardeh N, Kirchner K, Schnürch M, Mihovilovic MD. J. Org. Chem. 2012; 78: 658
• 16b Dastbaravardeh N, Schnürch M, Mihovilovic MD. Eur. J. Org. Chem. 2013; 2878
• 16c Dastbaravardeh N, Schnürch M, Mihovilovic MD. Org. Lett. 2012; 14: 1930
• 16d Dastbaravardeh N, Schnürch M, Mihovilovic MD. Org. Lett. 2012; 14: 3792
• 17 Preparation of 2-Aryl- and 3-Aryl Derivatives 3a–f and 5a–f To a round-bottomed flask was added the appropriate amount of 2-bromo- or 3-bromopyridine (1 or 4, 1 equiv, 1 mmol), boronic acid 2a–f (1.2 equiv, 1.2 mmol), K₂CO₃ (2 equiv, 276 mg, 2 mmol), Pd(PPh₃)₄ (2.1 mol%, 24 mg, 0.021 mmol), and a dioxane–H₂O mixture as solvent (1:1, 20 mL). The mixture was stirred for 5 min at r.t. and was then filtered through filter paper, before being transferred to the syringe pump. The residence time was 23 min, and the temperature of the heating plate was set to 90 °C. The inner diameter of the capillary was 1 mm. The flow rate was 0.695 mL/min, and the volume of the reactor was 16 mL. Reference NMR Spectra for 2-(4-methoxyphenyl)-pyridine (3d) ¹H (200 MHz CDCl₃): δ = 3.86 (s, 3 H), 6.95–7.05 (m, 2 H), 7.13–7.23 (m, 1 H), 7.62–7.79 (m, 2 H), 7.90–8.01 (m, 2 H), 8.60–8.71 (m, 1 H). ¹³C (50 MHz, CDCl₃): δ = 55.5 (q), 114.3 (d), 120.0 (d), 121.6 (d), 128.3 (d), 132.1 (s), 136.9 (d), 149.6 (d), 157.2 (s), 160.6 (s). Preparation of ortho-Arylated 2-Phenylpyridine Derivatives 7a–e, 8a–f To a round-bottomed flask was added the appropriate amount of 2-arylpyridine derivative 7a or 7b (1 equiv, 0.25 mmol), the appropriate bromobenzene derivative 6a–e (3 equiv, 0.75 mmol), DBU (4 equiv, 152 mg, 1 mmol), Ph₃P (10 mol%, 6.5 mg, 0.025 mmol), dichloro(p-cymene)ruthenium(II) dimer [5 mol%, 7.6 mg, 0.0125 mmol; with the exception of the synthesis of 8f, in which 7.5 mol% of dichloro(p-cymene)ruthenium(II) dimer were used (7.5 mol%, 11.5 mg, 0.01875 mmol) and NMP as solvent (1 mL)]. The mixture was stirred at r.t. until complete dissolution of all reagents. Then this solution was transferred to the syringe pump system. The flow rate was set to 0.533 mL/min which corresponded to a residence time of 30 min, and the temperature of the heating plate was set to 160 °C. After pumping through the reaction mixture, 20 mL pure solvent was pumped through as well. The inner diameter of the capillary was 1 mm. The volume of the reactor was 16 mL. Reference NMR spectra for 2-[4′-methoxy-(1,1′-biphenyl)-2-yl]pyridine (7b) ¹H (200MHz, CDCl₃): δ = 3.78 (s, 3 H), 6.72–6.82 (m, 2 H), 6.90 (dt, J = 7.8, 1.0 Hz, 1 H), 7.01–7.15 (m, 3 H), 7.33–7.50 (m, 4 H), 7.61–7.73 (m, 1 H). ¹³C (50 MHz, CDCl₃): δ = 55.3 (q), 113.7 (d), 121.4 (d), 125.6 (d), 127.4 (d), 128.6 (d), 130.6 (d), 130.6 (d), 130.9 (d), 133.8 (s), 135.4 (d), 139.5 (s), 140.3 (s), 149.6 (d), 158.6 (s), 159.6 (s).