Intermolecular Nucleophilic Addition Reaction of a C-7 Anion from N-[Bis(dimethylamino)phosphoryl]indole to Electrophiles/Arynes: Synthesis of 7-Substituted Indoles

Abstract

A novel approach to the C-7 substitution of N-[bis(dimethylamino)phosphoryl]indole by nucleophilic addition of the corresponding C-7 carbanion to electrophiles or arynes is described. The directing group can be easily removed, providing a simple route to the synthesis of 7-functionalized indoles.

Key words

indoles - lithiation - arylation - substitution - directing groups

• References and Notes

• 1a Horton DA, Bourne GT, Smythe ML. Chem. Rev. 2003; 103: 893
• 1b Taylor RD, MacCoss M, Lawson DG. A. J. Med. Chem. 2014; 57: 5845 . Li G. Y., Yang T., Luo Y.-G., Chen X.-Z., Fang D.-M., Zhang G.-L.; Org. Lett.; 2009, 11: 3714
• 1c Cai S, Sun S, Peng J, Kong X, Zhou H, Zhu T, Gu Q, Li D. Tetrahedron 2014; 71: 3715
• 1d Tsukamoto S, Kato H, Samizo M, Nojiri Y, Onuki H, Hirota H, Ohta T. J. Nat. Prod. 2008; 71: 2064 ; corrigendum: J. Nat. Prod. 2013, 76, 1233
• 1e Fujimoto H, Sumino M, Okuyama E, Ishibashi M. J. Nat. Prod. 2004; 67: 98
• 1f Kuramochi K, Ohnishi K, Fujieda S, Nakajima M, Saitoh Y, Watanabe N, Takeuchi T, Nakazaki A, Sugawara F, Arai T, Kobayashi S. Chem. Pharm. Bull. 2008; 56: 1738
• 1g De Guzman FS, Gloer JB, Wicklow DT, Dowd PF. J. Nat. Prod. 1992; 55: 931
• 2a Garfunkle J, Kimball FS, Trzupek JD, Takizawa S, Shimamura H, Tomishima M, Boger DL. J. Am. Chem. Soc. 2009; 131: 16036
• 2b Takashima M, Sakai H. Bull. Agric. Chem. Soc. Jpn. 1960; 24: 647
• 2c Yeung K.-S, Qiu Z, Xue Q, Fang H, Yang Z, Zadjura L, D’Arienzo CJ, Eggers BJ, Riccardi K, Shi P.-Y, Gong Y.-F, Browning MR, Gao Q, Hansel S, Santone K, Lin P.-F, Meanwell NA, Kadow JF. Bioorg. Med. Chem. Lett. 2013; 23: 198
• 3a Humber L . G, Ferdinandi E, Demerson CA, Ahmed S, Shah U, Mobilio D, Sabatucci J, De Lange B, Labbadia F, Hughes P, DeVirgilio J, Neuman G, Chau TT, Weichman BM. J. Med. Chem. 1988; 31: 1712
• 3b Awakawa T, Zhang L, Wakimoto T, Hoshino S, Mori T, Ito T, Ishikawa J, Tanner ME, Abe I. J. Am. Chem. Soc. 2014; 136: 9910
• 3c Boonyarat C, Yenjai C, Vajragupta O, Waiwut P. Asian Pac. J. Cancer Prev. 2014; 15: 10483
• 4a Prabagar B, Yang Y, Shi Z. Chem. Soc. Rev. 2021; 50: 11249
• 4b Wen J, Shi Z. Acc. Chem. Res. 2021; 54: 1723
• 4c Yang Y, Qiu X, Zhao Y, Mu Y, Shi Z. J. Am. Chem. Soc. 2016; 138: 495
• 5 Joule JA, Mills K. Heterocyclic Chemistry, 5^th ed. Wiley; Chichester: 2010
• 6a Campbell AN, Meyer EB, Stahl SS. Chem. Commun. 2011; 47: 10257
• 6b Ikemoto H, Yoshino T, Sakata K, Matsunaga S, Kanai M. J. Am. Chem. Soc. 2014; 136: 5424
• 6c Islam S, Larrosa I. Chem. Eur. J. 2013; 19: 15093
• 6d Zhao D, Kim JH, Stegemann L, Strassert CA, Glorius F. Angew. Chem. Int. Ed. 2015; 54: 4508
• 6e Rewcastle GW, Katrizky AR. Adv. Heterocycl. Chem. 1993; 56: 155
• 7a Fukuda T, Maeda R, Iwao M. Tetrahedron 1999; 55: 9151
• 7b Hartung CG, Fecher A, Chapell B, Snieckus V. Org. Lett. 2003; 5: 1899
• 8 Leonoria D, Coldham I. Adv. Synth. Catal. 2009; 351: 2619
• 9a Song Z, Samanta R, Antonchick AP. Org. Lett. 2013; 15: 5662
• 9b Xu L, Zhang C, He Y, Tan L, Ma D. Angew. Chem. Int. Ed. 2016; 55: 321
• 9c Iagafarova IE, Vorobyeva DV, Loginov DA, Peregudov AS, Osipov SN. Eur. J. Org. Chem. 2017; 840
• 10a Leitch JA, Bhonoah Y, Christopher GF. ACS Catal. 2017; 7: 5618
• 10b Yang Y, Shi Z. Chem. Commun. 2018; 54: 1676
• 11 Quan Y, Lan G, Shi W, Xu Z, Fan Z, Fan Y, You E, Jiang X, Wang C, Lin W. Angew. Chem. Int. Ed. 2021; 60: 3115
• 12 C-7 Substitution of N-[Bis(dimethylamino)phosphoryl] indole (1); General Procedure A flame-dried, two-necked, round-bottomed flask equipped with a magnetic stirrer bar, a septum cap, and a bubbler was charged with a solution of protected indole 1 (0.5 g, 1 equiv) in anhyd THF (10 mL) under an inert atmosphere. The solution was cooled to –78 °C and BuLi (2.2 equiv) was added dropwise. An orange-red color appeared immediately, and the solution was stirred at –78 °C for 15 minutes. The appropriate electrophile (2.2 equiv) was then added, and the reaction mixture was stirred at –78 °C for another 30 min. The reaction was then quenched with sat. aq NH₄Cl (20 mL), and the mixture was added to Et₂O (20 mL). The organic layer was separated, and the aqueous layer was further extracted with Et₂O (2 × 10 mL). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to obtain a crude product that was purified by flash chromatography [silica gel (230–400 mesh), hexane–EtOAc]. N-[Bis(dimethylamino)phosphoryl)-7-methylindole (3a) Clear viscous oil; yield: 0.52 g (99%). ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.61 (m, 1 H,), 7.46–7.44 (m, 1 H), 7.17–7.10 (m, 2 H), 6.36–6.35 (m, 1 H), 2.69 (s, 6 H), 2.66 (s, 6 H), 2.55 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 140.3, 140.2, 139.4, 139.3, 130.6, 130.5, 122.9, 121.3, 119.5, 113.7, 107.5, 107.4, 36.6, 36.5, 16.0. HRMS (ES⁺): m/z [M + H]⁺calcd for C₁₃H₂₁N₃OP: 266.1422; found: 266.1316. Deprotection of C-7-Functionalized N-[Bis(dimethylamino)phosphoryl)indoles; General Procedure A single-necked round-bottomed flask equipped with a magnetic stirrer bar and drying tube was charged with a solution of the appropriate C-7-substituted protected indole 3 (1 equiv) in anhyd THF (10 mL), and LAH (1.1 equiv) was added at 0 °C. After completion of the addition of LAH, the ice bath was removed and the mixture was stirred at rt for 2 h. The mixture was then cooled to 0 °C and the reaction was quenched with 15% aq NaOH (5 mL). The mixture was extracted with CHCl₃ (3 × 10 mL). The organic layer was washed with brine, dried, and concentrated under reduced pressure to afford a crude product that was purified by column chromatography [silica gel (60–120 mesh) hexane–EtOAc (4:1)]. 7-Methyl-1H-indole (4a) Light-brown solid; yield: 0.12 g (99%); mp 84–86 °C (Lit.¹¹ 85 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (br s, 1 H), 7.51 (d, J = 7.56 Hz, 1 H), 7.25–7.22 (m, 1 H), 7.19–7.03 (m, 2 H), 6.20 (s, 1 H), 2.41 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 138.0, 129.0, 124.1, 122.0, 120.9, 119.8, 119.6, 102.6, 13.7.