Syntheses of Heterocycle-2,3-Fused Indoline and Azaindoline ­Derivatives

Abstract

We describe a practical method for synthesizing heterocycle-2,3-fused indoline or azaindoline derivatives through haloetherification and cyclization. We applied this method in syntheses of six- to eight-membered heterocycle-2,3-fused indoline and azaindoline derivatives. These derivatives, which contain sp³-hybridized carbons, might be useful as new scaffolds in medicinal chemistry.

Key words

haloetherification - indolines - azaindolines - morpholines - oxazepines - oxazocines

Publication History

Received: 12 March 2021

Accepted after revision: 27 March 2021

Article published online:
20 April 2021

• References and Notes

• 1a Taylor RD, MacCoss M, Lawson AD. G. J. Med. Chem. 2014; 57: 5845
• 1b Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 1c Blakemore DC, Castro L, Churcher I, Rees DC, Thomas AW, Wilson DM, Wood A. Nat. Chem. 2018; 10: 383
• 2a Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 2b Lovering F. Med. Chem. Commun. 2013; 4: 515
• 3 Silva TS, Rodrigues MT, Santos H, Zeoly LA, Almeida WP, Barcelos RC, Gomes RC, Fernandes FS, Coelho F. Tetrahedron 2019; 75: 2063
• 4a Jung ME, Slowinski F. Tetrahedron Lett. 2001; 42: 6835
• 4b Yang J, Wu H, Shen L, Qin Y. J. Am. Chem. Soc. 2007; 129: 13794
• 5a Padwa A, Price AT. J. Org. Chem. 1995; 60: 6258
• 5b Xiong H, Xu S, Liao S, Xie Z, Tang Y. J. Am. Chem. Soc. 2013; 135: 7851
• 6 Zhu M, Zheng C, Zhang X, You S.-L. J. Am. Chem. Soc. 2019; 141: 2636
• 7a Chataigner I, Hess E, Toupet L, Piettre SR. Org. Lett. 2001; 3: 515
• 7b Menozzi C, Dalko PI, Cossy J. Chem. Commun. 2006; 4638
• 7c Zheng C, Lu Y, Zhang J, Chen X, Chai Z, Ma W, Zhao G. Chem. Eur. J. 2010; 16: 5853
• 8a Cheng H.-G, Lu L.-Q, Wang T, Yang Q.-Q, Liu X.-P, Li Y, Deng Q.-H, Chen J.-R. Angew. Chem. Int. Ed. 2013; 52: 3250
• 8b Li T.-R, Lu L.-Q, Wang Y.-N, Wang B.-C, Xiao W.-J. Org. Lett. 2017; 19: 4098
• 8c Bai L, Liu J, Hu W, Li K, Wang Y, Luan X. Angew. Chem. Int. Ed. 2018; 57: 5151
• 8d Tu H.-F, Zhang X, Zheng C, Zhu M, You S.-L. Nat. Catal. 2018; 1: 601
• 9 Tong M.-C, Chen X, Li J, Huang R, Tao H, Wang C.-J. Angew. Chem. Int. Ed. 2014; 53: 4680
• 10 Cao W.-B, Xu X.-P, Ji S.-J. Org. Biomol. Chem. 2017; 15: 1651
• 11a De los Santos JM, Rubiales G, Es Sbai Z, Ochoa deRetana A. M, Palacios F. Org. Biomol. Chem. 2017; 15: 662
• 11b Boyko YD, Dorokhov VS, Sukhorukov AY, Loffe SL. Beilstein J. Org. Chem. 2017; 13: 2214
• 11c Lopes SM. M, Cardoso AL, Lemos A, Pinho e Melo TM. V. D. Chem. Rev. 2018; 118: 11324
• 12 Zhang Y, Stephens D, Hernandez G, Mendoza R, Larionov OV. Chem. Eur. J. 2012; 18: 16612
• 13 Ciccolini C, Mari G, Gatti FG, Gatti G, Mantellini F, Favi G. J. Org. Chem. 2020; 85: 11409
• 14 Huang H, Li Q.-Z, Liu Y.-Q, Leng H.-J, Xiang P, Dai Q.-S, He X.-H, Li J.-L. Org. Chem. Front. 2020; 7: 3862
• 15 Braun NA, Bray JD, Ciufolini MA. Tetrahedron Lett. 1999; 40: 4985
• 16a Song C, Liu K, Jiang X, Dong X, Weng Y, Chiang C.-W, Lei A. Angew. Chem. Int. Ed. 2020; 59: 7193
• 16b Liu K, Song W, Deng Y, Yang H, Song C, Abdelilah T, Wang S, Cong H, Tang S, Lei A. Nat. Commun. 2020; 11: 3
• 17 Takemoto T, Iio Y, Nishi T. Tetrahedron Lett. 2000; 41: 1785
• 18 Abe T, Kosaka Y, Asano M, Harasaka N, Mishina A, Nagasue M, Sugimoto Y, Katakawa K, Sueki S, Anada M, Yamada K. Org. Lett. 2019; 21: 3367
• 19a Das BC, Gero SD, Lederer E. Biochem. Biophys. Res. Commun. 1967; 29: 211
• 19b Olsen RK. J. Org. Chem. 1970; 35: 1912
• 19c Aurelio L, Brownlee RT. C, Hughes AB. Chem. Rev. 2004; 104: 5823
• 20 Yamashiro T, Yamada K, Yoshida H, Tomisaka Y, Nishi T, Abe T. Synlett 2019; 30: 2247
• 21 Kan T, Fukuyama T. Chem. Commun. 2004; 353
• 22 Mérour J.-Y, Buron F, Plé K, Bonnet P, Routier S. Molecules 2014; 19: 19935
• 23 tert-Butyl [2-({3-Bromo-1-tosyl-2,3-dihydro-1H-indol-2-yl}oxy)ethyl]carbamate (6a): Typical ProcedureNBS (4.92 g, 27.6 mmol) was added to a solution of 1-tosylindole (5a; 5.00 g, 18.4 mmol) and N-Boc-2-aminoethanol (1; 8.91 g, 55.3 mmol) in C₆H₅CF₃ (100 mL), and the mixture was stirred at r.t. for 4 h. The mixture was then diluted with brine and extracted with EtOAc. The organic layer was dried (MgSO₄) and concentrated in vacuo, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (8:1 to 3:1)] to give a white solid; yield: 7.34 g (78%); mp 118–120 °C.¹H NMR (500 MHz, CDCl₃): δ = 7.66 (t, J = 8.6 Hz, 2 H), 7.33 (m, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.11 (m, 1 H), 5.66 (s, 1 H), 4.95 (s, 1 H), 4.76 (br s, 1 H), 3.99 (m, 1 H), 3.82 (m, 1 H), 3.39 (m, 1 H), 3.31 (m, 1 H), 2.33 (s, 3 H), 1.44 (s, 9 H). ¹³C NMR (125 MHz, CDCl₃): δ = 155.9, 144.7, 140.6, 135.1, 131.3, 130.7, 129.6, 127.7, 126.3, 125.5, 117.0, 98.8, 79.5, 67.9, 47.3, 40.2, 28.5, 21.6. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₇BrN₂NaO₅S: 533.0722 and 535.0701; found: 533.0703 and 535.0686.tert -Butyl (4a R* ,9b R* )-5-Tosyl-2,3,5,9b-tetrahydro[1,4]oxazino[2,3- b ]indole-1(4a H )-carboxylate (1a): Typical ProcedureCompound 6a (5.00 g, 9.78 mmol) was treated with Ag₂O (11.32 g, 48.8 mmol) in EtOAc (150 mL) at 80 °C for 4 h. The mixture was then cooled to r.t. and filtered through a Celite pad. The solvent was removed in vacuo, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (8:1 to 3:1)] to give a white solid; yield: 3.37 g (80%); mp 197–199 °C. Byproduct 8a was also obtained as a white solid; yield: 406 mg (10%).¹H NMR (500 MHz, DMSO-d ₆): δ = 7.83 (m, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.24 (br s, 2 H), 6.93–7.06 (m, 2 H), 5.89 + 5.80 (both d, J = 5.2 Hz, total 1 H), 5.36 + 5.21 (both d, J = 5.2 Hz, total 1 H), 3.37–3.65 (m, 2 H), 3.48 + 3.38 (both m, total 1 H), 2.80 + 2.63 (both m, total 1 H), 2.47 + 2.32 (both s, total 3 H), 1.44 + 1.38 (both s, total 9 H). ¹³C NMR (125 MHz, DMSO-d ₆, 100 °C): δ = 155.0, 144.8, 140.8, 136.8, 130.3, 130.1, 129.5, 127.8, 124.6, 124.6, 114.2, 87.1, 80.8, 60.9, 54.2, 41.0, 28.6, 21.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₆N₂NaO₅S: 453.1460; found: 453.1451.