Synthesis of Optically Active 2,3-Disubstituted Indoline ­Derivatives through Cycloaddition Reactions between Benzynes and α,β-Unsaturated γ-Aminobutyronitriles

Abstract

We report a method for synthesizing optically active 2,3-disubstituted indolines by the cycloaddition reaction of benzynes with various 4-[(4-toluenesulfonyl)amino]-(E)-but-2-enenitriles, which are readily prepared from the corresponding l-amino acid derivatives.

Keywords

indolines - benzynes - cycloaddition - asymmetric synthesis - nucleophilic addition - amino acids

• References and Notes


For biologically active indoline papers, see:
• 1a Bechle BM. Didiuk MT. Fritzen EL. Garigipati RS. WO 2006032987, 2006
• 1b Goodman FR. Weiss GB. Hurley ME. Cardiovasc. Drug Rev. 1985; 3: 57
• 1c Poondra RR. Kumar NN. Bijian K. Prakesch M. Campagna-Slater V. Reayi A. Reddy PT. Choudhry A. Barnes ML. Leek DM. Daroszewska M. Lougheed C. Xu B. Schapira M. Alaoui-Jamali MA. Arya P. J. Comb. Chem. 2009; 11: 303
• 1d Gan Z. Reddy PT. Quevillon S. Couve-Bonnaire S. Arya P. Angew. Chem. Int. Ed. 2005; 44: 1366
• 1e Nicolaou KC. Roecker AJ. Pfefferkorn JA. Cao G.-Q. J. Am. Chem. Soc. 2000; 122: 2966
• 1f Rakhit A. Hurley ME. Tipnis V. Coleman J. Rommel A. Brunner HR. J. Clin. Pharmacol. 1986; 26: 156
• 1g Xiang L. Xing D. Wang W. Wang R. Ding Y. Du L. Phytochemistry 2005; 66: 2595
• 1h Yang Z. Liu C. Xiang L. Zheng Y. Phytother. Res. 2009; 23: 1032

For selected reviews on syntheses of indolines by dearomatization of indoles, see:
• 2a Zhang D. Song H. Qin Y. Acc. Chem. Res. 2011; 44: 447
• 2b Zi W. Zuo Z. Ma D. Acc. Chem. Res. 2015; 48: 702. For selected papers on indoline syntheses by dearomatization reactions, see
• 2c Kuwano R. Sato K. Kurokawa T. Karube D. Ito Y. J. Am. Chem. Soc. 2000; 122: 7614
• 2d Kubota K. Hayama K. Iwamoto H. Ito H. Angew. Chem. Int. Ed. 2015; 54: 8809
• 2e He F. Bo Y. Altom JD. Corey EJ. J. Am. Chem. Soc. 1999; 121: 6771
• 2f Kobayashi S. Ueda T. Fukuyama T. Synlett 2000; 883
• 2g Ishikawa H. Elliott GI. Velcicky J. Choi Y. Boger DL. J. Am. Chem. Soc. 2006; 128: 10596
• 2h Jones SB. Simmons B. Mastracchio A. MacMillan DW. C. Nature 2011; 475: 183
• 2i Mizoguchi H. Oikawa H. Oguri H. Nat. Chem. 2014; 6: 57
• 2j Awata A. Arai T. Angew. Chem. Int. Ed. 2014; 53: 10462

For selected reviews on indole synthesis, see:
• 3a Wu H. He Y.-P. Shi F. Synthesis 2015; 47: 1990
• 3b Zi W. Zuo Z. Ma D. Acc. Chem. Res. 2015; 48: 702
• 3c Taber DF. Tirunahari PK. Tetrahedron 2011; 67: 7195
• 3d Miller KA. Williams RM. Chem. Soc. Rev. 2009; 38: 3160

For reviews on syntheses of indolines through the formation of pyrrolidine rings, see:
• 4a Anas S. Kagan HB. Tetrahedron: Asymmetry 2009; 20: 2193
• 4b Liu D. Zhao G. Xiang L. Eur. J. Org. Chem. 2010; 3975

For selected papers, see:
• 4c Dounay AB. Overman LE. Wrobleski AD. J. Am. Chem. Soc. 2005; 127: 10186
• 4d Nakanishi M. Katayev D. Besnard C. Kündig EP. Angew. Chem. Int. Ed. 2011; 50: 7438
• 4e Miyaji R. Asano K. Matsubara S. Org. Lett. 2013; 15: 3658
• 4f Minatti A. Buchwald SL. Org. Lett. 2008; 10: 2721
• 4g Ruano JL. G. Alemán J. Catalán S. Marcos V. Monteagudo S. Parra A. del Pozo C. Fustero S. Angew. Chem. Int. Ed. 2008; 47: 7941
• 4h Hyde AM. Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 177
• 4i Pian J.-X. He L. Du G.-F. Guo H. Dai B. J. Org. Chem. 2014; 79: 5820

For selected recent reviews on benzynes, see:
• 5a Sanz R. Org. Prep. Proced. Int. 2008; 40: 215
• 5b Kitamura T. Aust. J. Chem. 2010; 63: 987
• 5c Bhunia A. Yetra SR. Biju AT. Chem. Soc. Rev. 2012; 41: 3140
• 5d Tadross PM. Stoltz BM. Chem. Rev. 2012; 112: 3550
• 5e Wu C. Shi F. Asian J. Org. Chem. 2013; 2: 116
• 5f Dubrovskiy AV. Markina NA. Larock RC. Org. Biomol. Chem. 2013; 11: 191
• 5g Yoshida H. In Comprehensive Organic Synthesis II . Vol. 4, Chap. 4.09. Knochel P. Molander GA. Elsevier; Amsterdam: 2014: 517
• 5h Yoshida S. Hosoya T. Chem. Lett. 2015; 44: 1450
• 5i Karmakar R. Lee D. Chem. Soc. Rev. 2016; 45: 4459
• 5j Zeng Y. Hu J. Synthesis 2016; 48: 2137

For stereoselective benzyne reactions, see:
• 6a Webster R. Lautens M. Org. Lett. 2009; 11: 4688
• 6b Peña D. Pérez D. Guitián E. Chem. Rec. 2007; 7: 326
• 6c Caeiro J. Peña D. Cobas A. Párez D. Guitián E. Adv. Synth. Catal. 2006; 348: 2466
• 6d Dockendorff C. Sahli S. Olsen M. Milhau L. Lautens M. J. Am. Chem. Soc. 2005; 127: 15028

For indoline syntheses through reactions with benzynes, see:
• 7a Guo J. Kiran CI. N. Gao J. Reddy RS. He Y. Tetrahedron Lett. 2016; 57: 3481
• 7b Gilmore CD. Allan KM. Stoltz BM. J. Am. Chem. Soc. 2008; 130: 1558

During the preparation of this manuscript (see Ref. 9), closely related work was published by the groups of Sudalai and She:
• 8a Aher RD. Suryavanshi GM. Sudalai A. J. Org. Chem. 2017; 82: 5940
• 8b Xu D. Zhao Y. Song D. Zhong Z. Feng S. Xie X. Wang X. She X. Org. Lett. 2017; 19: 3600
• 9 For preliminary work carried out in relation to this study, see: Ikawa T. Sumii Y. Takagi A. Akai S. The 135th Annual Meeting of the Pharmaceutical Society of Japan (Kobe, March, 2015), Abstract Book No. 2 . Pharmaceutical Society of Japan: Tokyo: 83

For studies discussing the addition of nitrogen nucleophiles to benzynes, see:
• 10a Liu Z. Larock RC. J. Am. Chem. Soc. 2005; 127: 13112
• 10b Liu Z. Larock RC. J. Org. Chem. 2006; 71: 3198
• 10c Liu Z. Larock RC. Org. Lett. 2003; 5: 4673
• 10d Li L. Qiu D. Shi J. Li Y. Org. Lett. 2016; 18: 3726
• 11 The use of our newly developed precursor, 2-(trimethyl­silyl)phenyl trimethylsilyl ether (see Ref. 12) instead of 5a also gave trans-1f (46%, dr = 14:1) and 6f (39%), which was very similar to Table 1, entry 6. The reaction was performed with the silyl ether (1.5 equiv), nonaflourobutane-1-sulfonyl fluoride (2.3 equiv), 3f (1.0 equiv), and CsF (4.5 equiv) in MeCN (0.10 M) at 60 °C for 26 h.
• 12 Ikawa T. Masuda S. Nakajima H. Akai S. J. Org. Chem. 2017; 82: 4242

For an introduction to telescoping syntheses, see:
• 13a Nishimura K. Saitoh T. Chem. Pharm. Bull. 2016; 64: 1043
• 13b Anderson NG. Practical Process Research & Development . Academic Press; San Diego: 2000
• 13c Ikemoto T. In Process Chemistry of Pharmaceuticals . Kagaku-Dojin Publishing; Kyoto: 2013. (in Japanese)
• 14 Sudalai and co-workers reported that γ-amino α,β-unsaturated nitriles could not be obtained (see Ref. 8a).

For selected examples related to 3-methoxybenzyne, see:
• 15a Shi J. Qiu D. Wang J. Xu H. Li Y. J. Am. Chem. Soc. 2015; 137: 5670
• 15b Umezu S. dos Passos Gomes G. Yoshinaga T. Sakae M. Matsumoto K. Iwata T. Alabugin I. Shindo M. Angew. Chem. Int. Ed. 2017; 56: 1298
• 15c Matsumoto T. Hosoya T. Katsuki M. Suzuki K. Tetrahedron Lett. 1991; 32: 6735
• 15d Yoshida H. Shirakawa E. Honda Y. Hiyama T. Angew. Chem. Int. Ed. 2002; 41: 3247
• 15e Tadross PM. Gilmore CD. Bugga P. Virgil SC. Stoltz BM. Org. Lett. 2010; 12: 1224

For selected recent papers on silylbenzynes, see:
• 16a Akai S. Ikawa T. Takayanagi S.-i. Morikawa Y. Mohri S. Tsubakiyama M. Egi M. Wada Y. Kita Y. Angew. Chem. Int. Ed. 2008; 47: 7673
• 16b Dai M. Wang Z. Danishefsky SJ. Tetrahedron Lett. 2008; 49: 6613
• 16c Diemer V. Begaud M. Leroux FR. Colobert F. Eur. J. Org. Chem. 2011; 341
• 16d Ikawa T. Nishiyama T. Shigeta T. Mohri S. Morita S. Takayanagi S.-i. Terauchi Y. Morikawa Y. Takagi A. Ishikawa Y. Fujii S. Kita Y. Akai S. Angew. Chem. Int. Ed. 2011; 50: 5674
• 16e Ikawa T. Tokiwa H. Akai S. J. Synth. Org. Chem., Jpn. 2012; 70: 1123
• 16f Bronner SM. Mackey JL. Houk KN. Garg NK. J. Am. Chem. Soc. 2012; 134: 13966
• 16g Ikawa T. Takagi A. Goto M. Aoyama Y. Ishikawa Y. Itoh Y. Fujii S. Tokiwa H. Akai S. J. Org. Chem. 2013; 78: 2965
• 16h Yoshida H. Yoshida R. Takaki K. Angew. Chem. Int. Ed. 2013; 52: 8629
• 16i Ikawa T. Urata H. Fukumoto Y. Sumii Y. Nishiyama T. Akai S. Chem. Eur. J. 2014; 20: 16228
• 16j Ikawa T. Masuda S. Takagi A. Akai S. Chem. Sci. 2016; 7: 5206
• 17 The corresponding diastereomer of (±)-1s was below the detection limit of ¹H NMR (>50:1).
• 18 Indolines 1a–r; General ProcedureA test tube was charged with the appropriate benzyne precursor 5 (1.5 equiv) and a magnetic stir bar. THF (1.0 mL, 50 mM), which did not have to be anhydrous, was added to the tube and the mixture was stirred for a few minutes to dissolve 5. The γ-tosylamino α,β-unsaturated nitrile 3 (1.0 equiv) and 18-crown-6 (3.0 equiv) were added to the solution, and the flask was equipped with a screw cap. (This solution was stirred for 10 min at the indicated temperature when the reaction was conducted at 0 °C or below.) CsF (3.0 equiv) was quickly added to the test tube, which was then resealed with the screw cap, and the mixture was stirred at the appropriate temperature until either the α,β-unsaturated nitrile 3 or the benzyne precursor 5 was consumed (TLC). The mixture was then passed through a short pad of silica gel with elution by EtOAc, and solvents were removed under reduced pressure. The residue was subjected to ¹H NMR analysis to determine the ratio of the two diastereomers (trans-1 and cis-1). The crude product was purified by flash column chromatography (silica gel) or by preparative TLC (hexane–EtOAc, hexane–CH₂Cl₂, or EtOAc) to afford the required substituted indoline 1 and the single-addition product 6.
• 19 {(2S,3R)-2-Isopropyl-1-tosyl-2,3-dihydro-1H-indol-3-yl}acetonitrile (trans-1f)According to the general procedure, a mixture of CsF (91 mg, 0.60 mmol), 18-crown-6 (0.16 g, 0.60 mmol), triflate 5a (90 mg, 0.30 mmol), and sulfonamide 3f (56 mg, 0.20 mmol) was stirred in THF (2.0 mL, 0.10 M) for 1 h at r.t. The crude product (trans-1f/cis-1f = 16:1, determined by 400 MHz ¹H NMR analysis) was purified by column chromatography [silica gel, hexane–EtOAc (20:1 to 4:1)] to give a colorless solid; yield: 51 mg (72%, >99% ee); mp 139–141 °C; [α]_D ²⁵ –137.4 (c 0.12, CHCl₃).The relative stereochemistry was determined by NOESY spectro­scopy, and the optical purity was determined by HPLC. HPLC: CHIRALCEL AD-3 [hexane–i-PrOH (80:20), 1.0 mL/min, 20 °C]; t_r = 12.7 min (2S,3R), 9.1 min (2R,3S). IR (neat): 3446, 2964, 2251, 1597 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.81 (d, J = 7.0 Hz, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 1.11 (dd, J = 17.0, 9.5 Hz, 1 H), 1.68 (dd, J = 17.0, 7.0 Hz, 1 H), 2.15 (sept d, J = 7.0, 5.0 Hz, 1 H), 2.36 (s, 3 H), 3.05–3.09 (m, 1 H), 3.77 (dd, J = 5.0, 2.0 Hz, 1 H), 7.08 (dd, J = 7.5, 7.5 Hz, 1 H), 7.14 (d, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.32 (ddd, J = 7.5, 7.5, 1.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 7.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 16.4, 18.1, 21.5, 24.0, 33.3, 39.2, 72.1, 117.3, 117.5, 124.5, 125.1, 127.0, 129.5, 129.8, 132.9, 134.6, 141.6, 144.5. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₀H₂₂N₂NaO₂S: 377.1294; found: 377.1291. All spectroscopic data for product (2S,3R)-1f were in good agreement with those for (±)-trans-1f, synthesized from (±)-3f.
• 20 {(2S,3S)-2-Isopropyl-1-tosyl-2,3-dihydro-1H-indol-3-yl}acetonitrile (cis-1f)Obtained from above-mentioned crude reaction mixture as a colorless solid; yield: 2.4 mg (3%); mp 131–133 °C; [α]_D ²⁰ –2.4 (c 0.12, CHCl₃). The relative stereochemistry was determined by NOESY spectroscopy. IR (neat): 2967, 2371, 1597 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.51 (d, J = 7.0 Hz, 3 H), 1.22 (d, J = 7.0 Hz, 3 H), 1.96 (sept d, J = 7.0, 2.5 Hz, 1 H), 2.37 (s, 3 H), 2.54 (dd, J = 17.0, 9.0 Hz, 1 H), 2.68 (dd, J = 17.0, 7.0 Hz, 1 H), 2.97–3.02 (m, 1 H), 4.33 (dd, J = 8.5, 2.5 Hz, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 7.10–7.15 (m, 1 H), 7.14 (d, J = 8.0 Hz, 2 H), 7.30 (dd, J = 8.0, 8.0 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.66 (d, J = 8.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.8, 17.4, 21.0, 21.6, 29.0, 40.7, 69.3, 118.2, 119.5, 121.8, 126.1, 126.9, 128.9, 129.7, 134.9, 135.2, 142.8, 144.2. HRMS (MALDI): m/z [M + Na]⁺ calcd for C₂₀H₂₂N₂NaO₂S: 377.1294; found: 377.1294.