Synthesis of Enantioenriched Azaborole Helicenes by Chirality Transfer from Axially Chiral Biaryls

Dedicated to Professor Holger Braunschweig on the occasion of his 60^th birthday

Abstract

We report the enantioselective synthesis of azaborole helicenes from enantioenriched axially chiral precursors. The borylation/metal-exchange reaction sequence affords the target compounds with full transfer of chirality from the corresponding biaryls. Experimental studies provided insights into the configurational stability of the heterobiaryls and their (chir)optical properties. The structure of the ­phenyl-substituted helicene was unambiguously confirmed by single-crystal X-ray analysis.

Key words

axial chirality - azaboroles - borylation - chirality transfer - helicenes - configurational stability

Publication History

Received: 30 June 2022

Accepted after revision: 01 August 2022

Accepted Manuscript online:
01 August 2022

Article published online:
30 August 2022

• References and Notes

• 1a Mori T. Chem. Rev. 2021; 121: 2373
• 1b Zhao W.-L, Li M, Lu H.-Y, Chen C.-F. Chem. Commun. 2019; 55: 13793
• 1c Yuan K, Volland D, Kirschner S, Uzelac M, Nichol GS, Nowak-Król A, Ingleson MJ. Chem. Sci. 2022; 13: 1136
• 1d Chen C.-F, Shen Y. Helicene Cemistry, Springer: Berlin, 2017.
• 2a Aillard P, Voituriez A, Dova D, Cauteruccio S, Licandro E, Marinetti A. Chem. Eur. J. 2014; 20: 12373
• 2b Gingras M. Chem. Soc. Rev. 2013; 42: 1051
• 3a Dhbaibi K, Favereau L, Crassous J. Chem. Rev. 2019; 119: 8846
• 3b Gingras M, Félix G, Peresutti R. Chem. Soc. Rev. 2013; 42: 1007
• 4a Brandt JR, Salerno F, Fuchter MJ. Nat. Rev. Chem. 2017; 1: 0045
• 4b Shen Y, Chen C.-F. Chem. Rev. 2012; 112: 1463
• 5a Klívar J, Šámal M, Jančařík A, Vacek J, Bednárová L, Buděšínský M, Fiedler P, Starý I, Stará IG. Eur. J. Org. Chem. 2018; 2018: 5164
• 5b Teplý F, Stará IG, Starý I, Kollárovič A, Šaman D, Vyskočil Š, Fiedler P. J. Org. Chem. 2003; 68: 5193
• 5c Hanada K, Nogami J, Miyamoto K, Hayase N, Nagashima Y, Tanaka Y, Muranaka A, Uchiyama M, Tanaka K. Chem. Eur. J. 2021; 27: 9313
• 5d Murayama K, Oike Y, Furumi S, Takeuchi M, Noguchi K, Tanaka K. Eur. J. Org. Chem. 2015; 1409
• 5e Heller B, Hapke M, Fischer C, Andronova A, Starý I, Stará IG. J. Organomet. Chem. 2013; 723: 98
• 5f Shibata T, Uchiyama T, Yoshinami Y, Takayasu S, Tsuchikama K, Endo K. Chem. Commun. 2012; 48: 1311
• 6a Nakamura K, Furumi S, Takeuchi M, Shibuya T, Tanaka K. J. Am. Chem. Soc. 2014; 136: 5555
• 6b Satoh M, Shibata Y, Tanaka K. Chem. Eur. J. 2018; 24: 5434
• 6c Hartung T, Machleid R, Simon M, Golz C, Alcarazo M. Angew. Chem. Int. Ed. 2020; 59: 5660
• 6d Pelliccioli V, Hartung T, Simon M, Golz C, Licandro E, Cauteruccio S, Alcarazo M. Angew. Chem. Int. Ed. 2022; 61: e202114577
• 7 Kötzner L, Webber MJ, Martínez A, De Fusco C, List B. Angew. Chem. Int. Ed. 2014; 53: 5202
• 8a Liu P, Bao X, Naubron J.-V, Chentouf S, Humbel S, Vanthuyne N, Jean M, Giordano L, Rodriguez J, Bonne D. J. Am. Chem. Soc. 2020; 142: 16199
• 8b Jia S, Li S, Liu Y, Qin W, Yan H. Angew. Chem. Int. Ed. 2019; 58: 18496
• 9a Šámal M, Chercheja S, Rybáček J, Vacek Chocholoušová J, Vacek J, Bednárová L, Šaman D, Stará IG, Starý I. J. Am. Chem. Soc. 2015; 137: 8469
• 9b Crittall MR, Fairhurst NW. G, Carbery DR. Chem. Commun. 2012; 48: 11181
• 10 Dhawa U, Tian C, Wdowik T, Oliveira JC. A, Hao J, Ackermann L. Angew. Chem. Int. Ed. 2020; 59: 13451
• 11a Weimar M, Correa da Costa R, Lee F.-H, Fuchter MJ. Org. Lett. 2013; 15: 1706
• 11b Kaneko E, Matsumoto Y, Kamikawa K. Chem. Eur. J. 2013; 19: 11837
• 12 Nakano K, Hidehira Y, Takahashi K, Hiyama T, Nozaki K. Angew. Chem. Int. Ed. 2005; 44: 7136
• 13a Murai T, Xing Y, Kuribayashi T, Lu W, Guo J.-D, Yella R, Hamada S, Sasamori T, Tokitoh N, Kawabata T, Furuta T. Chem. Pharm. Bull. 2018; 66: 1203
• 13b Murai T, Xing Y, Kurokawa M, Kuribayashi T, Nikaido M, Elboray EE, Hamada S, Kobayashi Y, Sasamori T, Kawabata T, Furuta T. J. Org. Chem. 2022; 87: 5510
• 14 Terrasson V, Roy M, Moutard S, Lafontaine M.-P, Pèpe G, Félix G, Gingras M. RSC Adv. 2014; 4: 32412
• 15 Full F, Wölflick Q, Radacki K, Braunschweig H, Nowak-Król A. Chem. Eur. J. 2022; in press; DOI
• 16 Full J, Panchal SP, Götz J, Krause A.-M, Nowak-Król A. Angew. Chem. Int. Ed. 2021; 60: 4350
• 17a Zheng J, You S.-L. Angew. Chem. Int. Ed. 2014; 53: 13244ee
• 17b Wang Q, Zhang W.-W, Zheng C, Gu Q, You S.-L. J. Am. Chem. Soc. 2021; 143: 114
• 18a Carmona JA, Rodríguez-Franco C, Fernández R, Hornillos V, Lassaletta JM. Chem. Soc. Rev. 2021; 50: 2968
• 18b Wencel-Delord J, Panossian A, Leroux FR, Colobert F. Chem. Soc. Rev. 2015; 44: 3418
• 18c Bringmann G, Price Mortimer AJ, Keller PA, Gresser MJ, Garner J, Breuning M. Angew. Chem. Int. Ed. 2005; 44: 5384
• 19 Trapp O. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2008; 875: 42
• 20 Watson AA, Willis AC, Wild SB. J. Organomet. Chem. 1993; 445: 71
• 21 Tan JS. J, Paton RS. Chem. Sci. 2019; 10: 2285
• 22 (M)-EH3-Me₂: Enantioselective SynthesisEnantioenriched (R _a)-BA3 (96% ee) (16.0 mg, 31.6 μmol, 1.0 equiv) was dissolved in CH₂Cl₂ (1.5 mL) under argon. DIPEA (5.90 μL, 4.50 mg, 34.8 μmol, 1.1 equiv) was added and the mixture was cooled to –78 °C. A 1.0 M solution of BBr₃ in CH₂Cl₂ (95.0 µL, 95.0 μmol, 3.0 equiv) was added dropwise, and the mixture was warmed to rt and stirred at rt for 22 h. The solvent was removed in vacuo and the resulting orange solid was washed with dry hexane (3 × 1 mL) under argon. The resulting residue was dissolved in CH₂Cl₂ (2 mL), and a 2.0 M solution of AlMe₃ in toluene (46.7 μL, 93.3 µmol, 3.0 equiv) was added dropwise to the mixture under argon. The resulting mixture was stirred at rt for 1 h, then cooled to 0 °C. H₂O (2 mL) was added and the mixture was extracted with CH₂Cl₂ (4 × 5 mL). The combined organic phases were then dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica hexane/EtOAc (4:1)] to give a yellow solid; yield: 6.00 mg (11.0 μmol, 35%, 96% ee).HPLC: Reprosil Chiral-MIF, 250 × 4.6 mm, hexane–CH₂Cl₂ (87:13), 2 mL/min. ¹H NMR (400 MHz, CD₂Cl₂): δ = 8.88 (d, J = 7.9 Hz, 1 H, Ar-H), 8.83–8.74 (m, 3 H, Ar-H), 8.59 (d, J = 7.7 Hz, 1 H, Ar-H), 8.55 (d, J = 5.8 Hz, 1 H, Ar-H), 8.17 (d, J = 8.2, 1 H, Ar-H), 8.10 (d, J = 7.8 Hz, 1 H, Ar-H), 7.98 (d, J = 8.7 Hz, 1 H, Ar-H), 7.83 (d, J = 5.8 Hz, 1 H, Ar-H), 7.82–7.74 (m, 3 H, Ar-H), 7.34–7.70 (m, 2 H, Ar-H), 7.67 (d, J = 7.9 Hz, 1 H, Ar-H), 7.52 (d, J = 8.3, 1 H, Ar-H), 7.37 (t, J = 8.2, 1 H, Ar-H), 7.26 (d, J = 8.2 Hz, 1 H, Ar-H), 6.99 (t, J = 7.2 Hz, 1 H, Ar-H), 6.59 (t, J = 7.2 Hz, 1 H, Ar-H), 6.38 (t, J = 7.2 Hz, 1 H, Ar-H), 0.37 (s, 3 H, CH₃), 0.20 (s, 3 H, CH₃).The synthesis of (P)-EH3-Me₂ from (S _a)-BA3 is described in the SI.
• 23 CCDC 2182824 contains the supplementary crystallographic data for compound EH3-Ph₂ . The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 24 (M)-EH3-Ph₂: Enantioselective SynthesisEnantioenriched (R _a)-BA3 (98% ee) (6.00 mg, 11.9 μmol, 1.0 equiv) was dissolved in CH₂Cl₂ (0.75 mL) under argon. DIPEA (2.20 μL, 1.69 mg, 13.1 μmol, 1.1 equiv) was added and the mixture was cooled to –78 °C. A 1.0 M solution of BBr₃ in CH₂Cl₂ (35.6 μL, 35.6 μmol, 3.0 equiv) was added dropwise, and the mixture was warmed to rt and stirred at rt for 22 h. The solvent was then removed in vacuo and the resulting orange solid was washed with dry hexane (3 × 0.5 mL) under argon. The residue was dissolved in toluene (0.75 mL) and a 1.0 M solution of AlPh₃ in Et₂O (35.5 μL, 35.5 µmol, 3.0 equiv) was added dropwise under argon. The resulting mixture was stirred at 90 °C for 4 h, then cooled to 0 °C. H₂O (1.5 mL) was added and the mixture was extracted with EtOAc (4 × 3 mL). The combined organic phases were dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by column chromatography [silica , cyclohexane/CH₂Cl₂ (3:1)] to give a yellow solid; yield: 4.50 mg (6.72 μmol, 57%, 98% ee). HPLC: Reprosil Chiral-MIF, 250 × 4.6 mm, hexane–CH₂Cl₂ (87:13), 2 mL/min (For details, see SI). ¹H NMR (400 MHz, CD₂Cl₂) δ = 8.89 (d, J = 8.0 Hz, 1 H, Ar-H), 8.81–8.69 (m, 3 H, Ar-H), 8.61–8.57 (m, 1 H, Ar-H), 8.56 (d, J = 5.9 Hz, 1 H, Ar-H), 8.18 (d, J = 8.5 Hz, 1 H, Ar-H), 8.14 (d, J = 8.0 Hz, 1 H, Ar-H), 8.03 (d, J = 8.6 Hz, 1 H, Ar-H), 7.82 (d, J = 5.9 Hz, 1 H, Ar-H), 7.81–7.63 (m, 6 H, Ar-H), 7.60 (d, J = 8.5 Hz, 1 H, Ar-H), 7.56–7.52 (m, 2 H, Ar-H), 7.41 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H, Ar-H), 7.38–7.27 (m, 5 H, Ar-H), 7.26–7.20 (m, 1 H, Ar-H), 7.16–7.07 (m, 3 H, Ar-H), 7.02 (ddd, J = 8.3, 7.1, 1.4 Hz, 1 H, Ar-H), 6.64 (ddd, J = 8.4, 6.9, 1.2 Hz, 1 H, Ar-H), 6.43 (ddd, J = 8.3, 7.1, 1.2 Hz, 1 H, Ar-H).The syntheses of (P)-EH3-Ph₂ from (S _a)-BA3 and of rac-EH3-Ph₂ from rac-BA3 are described in the SI.