C−H Arylation of Thiophenes with Aryl Bromides by a Parts-per-Million Loading of a Palladium NNC-Pincer Complex

Abstract

A palladium NNC-pincer complex efficiently catalyzed the direct arylation of thiophene derivatives with extremely low palladium loadings of the order of parts per million. Thus, the reaction of various thiophenes with aryl bromides in the presence of 25–100 mol ppm of chlorido[(2-phenyl-κ-C ²)-9-phenyl-1,10-phenanthroline-κ²-N,N′]palladium(II) NNC-pincer complex, K₂CO₃, and pivalic acid in N,N-dimethyl­acetamide afforded the corresponding 2- or 5-arylated thiophenes in good to excellent yields. A combination of the present C–H arylation and Hiyama coupling with the same NNC-pincer complex provides an efficient synthesis of unsymmetrical 2,5-thiophenes with catalyst loadings at mol ppm levels.

Key words

C–H functionalization - arylation - palladium catalysis - pincer complexes - thiophenes - Hiyama coupling

• References and Notes

• 1a Torborg C, Beller M. Adv. Synth. Catal. 2009; 351: 3027
• 1b Magano J, Dunetz JR. Chem. Rev. 2011; 111: 2177
• 1c Busacca CA, Fandrick DR, Song JJ, Senanayake CH. Adv. Synth. Catal. 2011; 353: 1825
• 1d Xu S, Kim EH, Wei A, Negishi E.-i. Sci. Technol. Adv. Mater. 2014; 15: 04420
• 2 ICH; Quality Guidelines; International Council for Harmonisation: Geneva; https://www.ich.org/page/quality-guidelines (accessed Jul 16, 2020)
• 3a Usluer Ö, Abbas M, Wantz G, Vignau L, Hirsch L, Grana E, Brochon C, Cloutet E, Hadziioannou G. ACS Macro Lett. 2014; 3: 1134
• 3b Egorova KS, Ananikov VP. Angew. Chem. Int. Ed. 2016; 55: 12150
• 3c Egorova KS, Ananikov VP. Organometallics 2017; 36: 4071
• 3d Hayler JD, Leahy DK, Simmons EM. Organometallics 2019; 38: 36
• 4 Farina V. Adv. Synth. Catal. 2004; 346: 1553
• 5 Thomé I, Nijs A, Bolm C. Chem. Soc. Rev. 2012; 41: 979
• 6 Deraedt C, Astruc D. Acc. Chem. Res. 2014; 47: 494
• 7 Roy D, Uozumi Y. Adv. Synth. Catal. 2018; 360: 602
• 8a Allard S, Forster M, Souharce B, Thiem V, Scherf U. Angew. Chem. Int. Ed. 2008; 47: 4070
• 8b Mishra A, Fischer MK. R, Bäuerle P. Angew. Chem. Int. Ed. 2009; 48: 2474
• 8c Mei J, Diao Y, Appleton AL, Fang L, Bao Z. J. Am. Chem. Soc. 2013; 135: 6724
• 8d Okamoto K, Zhang J, Housekeeper JB, Marder SR, Luscombe CK. Macromolecules 2013; 46: 8059 ; corrigendum: Macromolecules 2013, 46, 7565
• 8e Cinar ME, Ozturk T. Chem. Rev. 2015; 115: 3036
• 9a Dadiboyena S. Eur. J. Med. Chem. 2012; 51: 17
• 9b Mabkhot YN, Alatibi F, El-Sayed NN. E, Al-Showiman S, Kheder NA, Wadood A, Rauf A, Bawazeer S, Ben Hadda T. Molecules 2016; 21: 222
• 9c Metil DS, Sonawane SP, Pachore SS, Mohammad A, Dahanukar VH, McCormack PJ, Reddy CV, Bandichhor R. Org. Process Res. Dev. 2018; 22: 27 ; corrigendum: Org. Process. Res. Dev. 2018, 22, 420
• 10 Ohta A, Akita Y, Ohkuwa T, Chiba M, Fukunaga R, Miyafuji A, Nakata T, Tani N. Heterocycles 1990; 31: 1951

For reviews, see:
• 11a Roger J, Gottumukkala AL, Doucet H. ChemCatChem 2010; 2: 20
• 11b Ackermann L. Chem. Rev. 2011; 111: 1315
• 11c Mercier LG, Leclerc M. Acc. Chem. Res. 2013; 46: 1597
• 11d Bellina F. Top. Organomet. Chem. 2015; 55: 77
• 11e Bheeter CB, Chen L, Soulé J.-F, Doucet H. Catal. Sci. Technol. 2016; 6: 2005

For selected examples, see:
• 12a Join B, Yamamoto T, Itami K. Angew. Chem. Int. Ed. 2009; 48: 3644
• 12b Liégault B, Lapointe D, Caron L, Vlassova A, Fagnou K. J. Org. Chem. 2009; 74: 1826
• 12c Liégault B, Petrov I, Gorelsky SI, Fagnou K. J. Org. Chem. 2010; 75: 1047
• 12d Tamba S, Okubo Y, Tanaka S, Monguchi D, Mori A. J. Org. Chem. 2010; 75: 6998
• 12e Kamiya H, Yanagisawa S, Hiroto S, Itami K, Shinokubo H. Org. Lett. 2011; 13: 6394
• 12f Baghbanzadeh M, Pilger C, Kappe CO. J. Org. Chem. 2011; 76: 8138
• 12g Schipper DJ, Fagnou K. Chem. Mater. 2011; 23: 1594
• 12h Ghosh D, Lee HM. Org. Lett. 2012; 14: 5534
• 12i Gorelsky SI, Lapointe D, Fagnou K. J. Org. Chem. 2012; 77: 658
• 12j Jia N.-N, Tian X.-C, Qu X.-X, Chen X.-X, Cao Y.-N, Yao Y.-X, Gao F, Zhou X.-L. Sci. Rep. 2017; 7: 43758
• 12k Li H.-H, Maitra R, Kuo Y.-T, Chen J.-H, Hu C.-H, Lee HM. Appl. Organomet. Chem. 2018; 32: e3956
• 12l Mao S, Shi X, Soulé J.-F, Doucet H. Adv. Synth. Catal. 2018; 360: 3306
• 13a Roy D, Mom S, Beaupérin M, Doucet H, Hierso J.-C. Angew. Chem. Int. Ed. 2010; 49: 6650
• 13b Martin AR, Chartoire A, Slawin AM. Z, Nolan SP. Beilstein J. Org. Chem. 2012; 8: 1637
• 13c Yamada YM. A, Yuyama Y, Sato T, Fujikawa S, Uozumi Y. Angew. Chem. Int. Ed. 2014; 53: 127
• 13d Li Y, Wang J, Huang M, Wang Z, Wu Y, Wu Y. J. Org. Chem. 2014; 79: 2890
• 13e Luo B.-T, Liu H, Lin Z.-J, Jiang J, Shen DS, Liu R.-Z, Ke Z, Liu F.-S. Organometallics 2015; 34: 4881
• 13f Ouyang J.-S, Li Y.-F, Shen D.-S, Ke Z, Liu F.-S. Dalton Trans. 2016; 45: 14919
• 13g Colletto C, Panigrahi A, Fernández-Casado J, Larrosa I. J. Am. Chem. Soc. 2018; 140: 9638
• 14a Roger J, Požgan F, Doucet H. Green Chem. 2009; 11: 425
• 14b Roger J, Požgan F, Doucet H. Adv. Synth. Catal. 2010; 352: 696
• 14c Bheeter CB, Bera JK, Doucet H. J. Org. Chem. 2011; 76: 6407
• 14d Zhao L, Bruneau C, Douchet H. Tetrahedron 2013; 69: 7082
• 15a Takenaka K, Uozumi Y. Adv. Synth. Catal. 2004; 346: 1693
• 15b Takenaka K, Minakawa M, Uozumi Y. J. Am. Chem. Soc. 2005; 127: 12273
• 15c Sarkar SM, Uozumi Y, Yamada YM. A. Angew. Chem. Int. Ed. 2011; 50: 9437
• 15d Yamada YM. A, Sarkar SM, Uozumi Y. J. Am. Chem. Soc. 2012; 134: 3190
• 15e Yamada YM. A, Sarkar SM, Uozumi Y. J. Am. Chem. Soc. 2012; 134: 9285
• 15f Sato T, Ohno A, Sarkar SM, Uozumi Y, Yamada YM. A. ChemCatChem 2015; 7: 2141
• 15g Hamasaka G, Roy D, Tazawa A, Uozumi Y. ACS Catal. 2019; 9: 11640
• 16a Hamasaka G, Sakurai F, Uozumi Y. Chem. Commun. 2015; 51: 3886
• 16b Hamasaka G, Ichii S, Uozumi Y. Adv. Synth. Catal. 2018; 360: 1833
• 16c Ichii S, Hamasaka G, Uozumi Y. Chem. Asian J. 2019; 14: 3850
• 17 C–H Arylation of 1-Benzothiophene (1); General Procedure A Schlenk tube containing a magnetic stirrer bar was charged with 1-benzothiophene (1; 2 mmol), the appropriate aryl bromide 2 (1 mmol), K₂CO₃ (0.5 mmol), pivalic acid (0.3 mmol), a 0.5 mM solution of DPP-NNC in anhyd DMA (100 μL; 5 ×10^–5 mmol Pd), and anhyd DMA (1.9 mL). The resulting mixture was degassed and stirred vigorously at 150 °C under N₂ for 20 h. The mixture was then cooled to r.t., diluted with EtOAc, transferred to a separatory funnel, and washed with water (×3). The organic layer was dried (Na₂SO₄) and concentrated in vacuo, and the resulting residue was purified by chromatography (silica gel, hexane/AcOEt).
• 18 2-(2,6-Dimethylphenyl)benzo[b]thiophene (3j) White solid; yield: 218 mg (92%). ¹H NMR (396 MHz, CDCl₃): δ = 7.81 (d, J = 8.3 Hz, 1 H), 7.75 (d, J = 7.1 Hz, 1 H), 7.52 (s, 1 H), 7.36–7.24 (m, 4 H), 6.98 (s, 1 H), 2.37 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 144.6, 140.7, 139.4, 138.5, 134.1, 130.1, 124.4, 124.3, 124.1, 123.5, 122.2, 119.2, 21.26. HRMS (FAB): m/z [M⁺] calcd for C₁₆H₁₄S: 238.0816; found: 238.0823. 2-(2-Isopropylphenyl)benzo[b]thiophene (3n) Colorless oil; yield: 152 mg (60%). ¹H NMR (396 MHz, CDCl₃): δ = 7.84 (d, J = 7.9 Hz, 1 H), 7.79 (d, J = 7.1 Hz, 1 H), 7.42–7.31 (m, 5 H), 7.22–7.20 (m, 1 H), 7.18 (s, 1 H), 3.38–3.31 (m, 1 H), 1.22 (d, J = 6.7 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 147.8, 143.3, 140.3, 140.0, 133.0, 131.0, 129.0, 125.7, 125.4, 124.3, 124.0, 123.4, 123.1, 122.0, 29.7, 24.4. EI-MS: m/z = 252 [M⁺]. HRMS (FAB): m/z [M⁺] calcd for C₁₇H₁₆S: 252.0973; found: 252.0961. 2-(2,6-Difluorophenyl)benzo[b]thiophene (3o) White solid; yield: 152 mg (62%). ¹H NMR (396 MHz, CDCl₃): δ = 7.88–7.83 (m, 2 H), 7.74 (s, 1 H), 7.38–7.35 (m, 2 H), 7.31–7.25 (m, 1 H), 7.10–7.00 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.1 (dd, J = 252.9, 6.8 Hz), 140.3 (t, J = 2.9 Hz), 139.2, 129.7 (t, J = 2.8 Hz), 129.2 (t, J = 10.5 Hz), 126.2 (t, J = 5.7 Hz), 124.8, 124.3, 123.9, 121.8, 112.1 (q, J = 17.2 Hz), 111.9 (dd, J = 24.9, 1.9 Hz). EI-MS: m/z = 246 [M⁺]. HRMS (FAB): m/z [M⁺] calcd for C₁₄H₈F₂S: 246.0315; found: 246.0323.
• 19 King WJ, Nord FF. J. Org. Chem. 1949; 14: 638