Synthesis of 6-Alkynyl-6-hydroxyindoloquinazolinone Scaffolds via Copper-Catalyzed Alkynylation of Tryptanthrins

Abstract

We report a copper-catalyzed direct alkynylation reaction of tryptanthrins with terminal alkynes under mild reaction conditions. The developed method provides an array of synthetic building blocks of 6-alkynyl-6-hydroxyindoloquinazolinone compounds in moderate to good yields with varied functional group compatibility. Furthermore, the obtained adducts can be smoothly converted into versatile building blocks via hydrogenation, hydration, and further Sonogashira coupling transformations.

Key words

alkynylation - tryptanthrin - indoloquinazolinone - copper catalysis

Publication History

Received: 03 April 2021

Accepted after revision: 21 June 2021

Accepted Manuscript online:
21 June 2021

Article published online:
06 July 2021

• References and Notes


For selected examples on chemistry of propargylic alcohols, see:
• 1a Cadierno V, Crochet P, Garcia-Garrido SE, Gimeno J. Dalton Trans. 2010; 39: 4015
• 1b Bauer EB. Synthesis 2012; 44: 1131
• 1c Wang Q, Pu L. Synlett 2013; 24: 1340
• 1d Zhu Y, Sun L, Lu P, Wang Y. ACS Catal. 2014; 4: 1911
• 1e Zhang L, Fang G, Kumar RK, Bi X. Synthesis 2015; 47: 2317
• 1f Kumar RK, Bi X. Chem. Commun. 2016; 52: 853

For selected reviews, see:
• 2a Trost BM, Weiss AH. Adv. Synth. Catal. 2009; 351: 963
• 2b Liu Y.-L, Lin X.-T. Adv. Synth. Catal. 2019; 361: 876
• 2c Shibasaki M, Kanai M. Chem. Rev. 2008; 108: 2853

For selected examples on catalytic addition of terminal alkynes to ketones, see:
• 2d Ahn JH, Joung MJ, Yoon NM. J. Org Chem. 1995; 60: 6173
• 2e Han Y, Huang Y.-Z. Tetrahedron Lett. 1995; 36: 7277
• 2f Jiang B, Si Y.-G. Tetrahedron Lett. 2002; 43: 8323
• 2g Ishikawa T, Mizuta T, Hagiwara K, Aikawa T, Kudo T, Saito S. J. Org. Chem. 2003; 68: 3702
• 2h Weil T, Schreiner PR. Eur. J. Org. Chem. 2005; 2213
• 2i Dhondi PK, Carberry P, Choi LB, Chisholm JD. J. Org. Chem. 2007; 72: 9590
• 2j Correia CA, McQuade DT, Seeberger PH. Adv Synth Catal. 2013; 355: 3517
• 2k Chintareddy VR, Wadhwa K, Verkade JG. J. Org Chem. 2011; 76: 4482
• 2l Yamashita Y, Saito Y, Imaizumi T, Kobayashi S. Chem. Sci. 2014; 5: 3958
• 2m Czerwiński P, Molga E, Cavallo PL, Poater A, Michalak M. J. Chem. Eur. 2016; 22: 8089
• 2n Chen Q, Tang Y, Huang T, Liu X, Lin L, Feng X.-M. Angew. Chem. Int. Ed. 2016; 55: 5286
• 2o Liu X.-D, Ma H.-Y, Xing C.-H, Lu L. Tetrahedron Lett. 2017; 58: 1564
• 2p Tang Y, Xu J, Yang J, Lin L, Feng X.-M, Liu X.-H. Chem 2018; 4: 1658
• 3a Jao C.-W, Lin W.-C, Wu Y.-T, Wu P.-L. J. Nat. Prod. 2008; 71: 1275
• 3b Pergola C, Jazzar B, Rossi A, Northoff H, Hamburger M, Sautebin L, Werz O. Br. J. Pharmacol. 2012; 165: 765
• 3c Krivogorsky B, Nelson AC, Douglas KA, Grundt P. Bioorg. Med. Chem. 2013; 23: 1032
• 3d Han N.-R, Moon P.-D, Kim H.-M, Jeong H.-J. Arch. Biochem. Biophys. 2014; 542: 14
• 3e Jun K.-Y, Park S.-E, Liang JL, Jahng PY, Kwon PY. ChemMedChem 2015; 10: 827
• 3f Hao Y, Guo J, Wang Z, Liu Y, Li Y, Ma D, Wang Q. J. Agric. Food Chem. 2020; 68: 5586
• 4a Kang G, Luo Z, Liu C, Gao H, Wu Q, Wu H, Jiang J. Org. Lett. 2013; 15: 4738
• 4b Gao H, Luo Z, Ge P, He J, Zhou F, Zheng P, Jiang J. Org. Lett. 2015; 17: 5962
• 4c Wang N, Liu H.-X, Gao H, Zhou J.-F, Zheng L.-Z, Li J, Xiao H.-P, Li X-H, Jiang J. Org. Lett. 2019; 21: 6684
• 4d Chen W.-L, Liu C.-X, Xiao H.-P, Jiang J. Synlett 2016; 27: 1989
• 5 Liao F.-M, Liu Y.-L, Yu J.-S, Zhou F, Zhou J. Org. Biomol. Chem. 2015; 13: 8906
• 6a Xu N, Gu D.-W, Zi J, Wu X.-Y, Guo X.-X. Org. Lett. 2016; 18: 2439
• 6b Paria S, Lee H.-J, Maruoka K. ACS Catal. 2019; 9: 2395
• 6c Chen J.-F, Li C.-K. Org. Lett. 2020; 22: 4686
• 7 Chen G, Wang Y, Gao S, He H.-P, Li S.-L, Zhang J.-X, Ding J, Hao X.-J. J. Heterocycl. Chem. 2009; 46: 217
• 8 Copper-Catalyzed Addition Reaction of Tryptanthrins and Alkynes – General Procedure In air, a clean and dried Schlenk tube was charged with CuCl₂·2H₂O (0.02 mmol,10 mol%), K₂CO₃ (0.4 mmol, 2.0 equiv.), tryptanthrin 1a (0.2 mmol, 1.0 equiv.), alkyne 2 (1.0 mmol, 5.0 equiv.), and 1,4-dioxane or THF (2 mL). The resulting mixture was stirred at the 60 °C or 80 °C for 36 h until the reaction completed. The crude mixture was purified through flash column chromatography on a silica gel using DCM/EtOAc (100:1, v/v) as eluent to give the desired products. 6-Hydroxy-6-(phenylethynyl)indolo[2,1-b]quinazolin-12(6H)-one (3a) This compound was prepared according to the typical procedure, which was purified using DCM/EtOAc (100:1, v/v) as eluent and was obtained (55.3 mg, 79% yield) as a white solid; mp 246.7–247.2 °C. ¹H NMR (500 MHz, DMSO): δ = 8.44 (d, J = 8.0 Hz, 1 H), 8.32 (d, J = 7.4 Hz, 1 H), 7.97–7.81 (m, 3 H), 7.69–7.56 (m, 3 H), 7.53–7.33 (m, 6 H). ¹³C NMR (126 MHz, DMSO): δ = 158.68, 158.19, 146.87, 137.97, 134.96, 132.84, 131.55, 130.66, 129.30, 128.73, 127.93, 127.79, 127.31, 126.54, 124.84, 121.52, 121.05, 116.40, 87.35, 85.20, 70.85. HRMS (ESI): m/z calcd for C₂₃H₁₅N₂O₂ ⁺ [M + H]⁺: 351.1128; found: 351.1124. 6-[(2-Bromophenyl)ethynyl]-6-hydroxyindolo[2,1-b]quinazolin-12(6H)-one (3b) This compound was prepared according to the typical procedure, which was purified using DCM/EtOAc (100:1, v/ v) as eluent and was obtained (57.5 mg, 67% yield) as a yellow solid; mp 239.5–240.9 °C. ¹H NMR (500 MHz, DMSO): δ = 8.47 (d, J = 8.0 Hz, 1 H), 8.33 (d, J = 7.2 Hz, 1 H), 7.98–7.87 (m, 3 H), 7.74–7.56 (m, 5 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.44–7.32 (m, 2 H). ¹³C NMR (126 MHz, DMSO): δ = 158.67, 157.91, 146.86, 137.96, 135.00, 133.73, 132.60, 132.53, 131.03, 130.73, 127.99, 127.83, 127.82, 127.29, 126.56, 125.00, 124.91, 122.99, 121.50, 116.39, 91.55, 83.69, 70.97. HRMS (ESI): m/z calcd for C₂₃H₁₄BrN₂O₂ ⁺ [M + H]⁺: 429.0233; found: 429.0239.