A highly efficient methodology for the preparation of N-methoxycarbazoles and the total synthesis of 3,3'-[oxybis(methylene)]bis(9-methoxy-9H-carbazole)

Abstract

A convenient and highly efficient method is described for the synthesis of N-methoxycarbazole derivatives, including those with sterically demanding, benzannulated, or strongly electron-donating or -withdrawing substituents. Various N-methoxycarbazole derivatives were directly prepared in good-to-moderate yields by the Pd₂(dba)₃CHCl₃/9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene-catalyzed reactions of the corresponding dibromobiphenyl compounds and methoxya-mine. Based on this methodology, the first total synthesis of 3,3′-[oxybis(methylene)]bis(9-methoxy-9H-carbazole), an antimicrobial dimeric carbazole alkaloid previously isolated from the stem bark of Murraya koenigii, was achieved in 18% yield over seven steps from 1,2-dibromobenzene.

Graphical abstract

Keywords

N-methoxyl carbazole / dimeric N-methoxyl carbazole / alkaloid / total synthesis / double N-arylation of methoxyamine

References

[1] Chakraborty D P, Barman B K, Bose P K. On the constitution of Murrayanine, a carbazole derivative isolated from Murraya koengii Spreng. Tetrahedron, 1965, 21(1-2): 681–685

[2] Chakraborty D P. The Alkaloids. 1st ed. New York: Academic Press, 1993, 257–364

[3] Knölker H J, Reddy K R. Isolation and synthesis of biologically active carbazole alkaloids. Chemical Reviews, 2002, 102(11): 4303–4427

[4] Knölker H J. Topics in Current Chemistry: Natural Product Synthesis. 1st ed. Heidelberg: Springer, 2004, 244

[5] Schmidt A W, Reddy K R, Knölker H J. Occurrence, biogenesis, and synthesis of biologically active carbazole alkaloids. Chemical Reviews, 2012, 112(6): 3193–3328

[6] Greger H. Phytocarbazoles: alkaloids with great structural diversity and pronounced biological activities. Phytochemistry Reviews, 2017, 16(6): 1095–1153

[7] Liu Y P, Hu S, Liu Y Y, Zhang M M, Zhang W H, Qiang L, Fu Y H. Anti-inflammatory and antiproliferative prenylated carbazole alkaloids from Clausena vestita. Bioorganic Chemistry, 2019, 91: 103107

[8] Sun X Y, Ma J, Li C J, Zang Y D, Huang J W, Wang X Y, Chen N H, Chen X G, Zhang D M. Carbazole alkaloids with bioactivities from the stems of Clausena lansium. Phytochemistry Letters, 2020, 38: 28–32

[9] Peng W W, Fu X X, Xiong Z H, Wu H L, Chang J W, Huo G H, Li B T. Taxonomic significance and antitumor activity of alkaloids from Clausena lansium Lour. Skeels (Rutaceae). Biochemical Systematics and Ecology, 2020, 90: 104046

[10] Zhang S Y, Zhan Z J, Zhang H, Qi H, Zhang L Q, Chen S X, Gan L S, Wang J D, Ma L F. Morindolestatin, naturally occurring dehydromorpholinocarbazole alkaloid from soil-derived bacterium of the genus Streptomyces. Organic Letters, 2020, 22(3): 1113–1116

[11] Ito C, Wu T S, Furukawa H. New carbazole alkaloids from Murraya euchrestifolia. Chemical & Pharmaceutical Bulletin, 1988, 36(7): 2377–2380

[12] Rahman M M, Gray A I. A benzoisofuranone derivative and carbazole alkaloids from Murraya koenigii and their antimicrobial activity. Phytochemistry, 2005, 66(13): 1601–1606

[13] Wei R, Ma Q, Li T, Liu W, Sang Z, Li M, Liu S. Carbazole alkaloids with antiangiogenic activities from Clausena sanki. Bioorganic Chemistry, 2018, 77: 387–392

[14] Lv H N, Wen R, Zhou Y, Zeng K W, Li J, Guo X Y, Tu P F, Jiang Y. Nitrogen oxide inhibitory trimeric and dimeric carbazole alkaloids from Murraya tetramera. Journal of Natural Products, 2016, 78(10): 2432–2439

[15] Somei M, Kawasaki T. A new and simple synthesis of 1-hydroxyindole derivatives. Heterocycles, 1989, 29(7): 1251–1254

[16] Selvakumar N, Khera M K, Reddy B Y, Srinivas D, Azhagan A M, Iqbal J. An efficient total synthesis of 9-methoxycarbazole-3-carbaldehyde based on a novel methodology for the preparation of methoxyindoles. Tetrahedron Letters, 2003, 44(37): 7071–7074

[17] Nozaki K, Takahashi K, Nakano K, Hiyama T, Tang H Z, Fujiki M, Yamaguchi S, Tamao K. The double N-arylation of primary amines: toward multisubstituted carbazoles with unique optical properties. Angewandte Chemie International Edition, 2003, 42(18): 2051–2053

[18] Xiao H B, Leng B, Tian H. Hole transport triphenylamine-spirosilabifluorene alternating copolymer: synthesis and optical, electrochemical and electroluminescent properties. Polymer, 2005, 46(15): 5707–5713

[19] Tashiro M, Yamato T. Studies on selective preparation of aromatic compounds. 20. Selective preparation of 2-mono- and 2,2′-disubstituted biphenyl using the tert-butyl group as a positional protective group. Journal of Organic Chemistry, 1979, 44(17): 3037–3041

[20] Mo Y Q, Tian R Y, Shi W, Cao Y. Ultraviolet-emitting conjugated polymer poly(9,9′-alkyl-3,6-silafluorene) with a wide band gap of 4.0 eV. Chemical Communications, 2005, 39: 4925–4926

[21] Tashiro M, Fukuda Y. Preparation of 4,4′-di-tert-butylbiphenyl derivatives. Organic Preparations and Procedures International, 1983, 15(4): 271–275

[22] Ronde N J, Totev D, Müller C, Lutz M, Spek A L, Vogt D. Molecular-weight-enlarged multiple-pincer ligands: synthesis and application in palladium-catalyzed allylic substitution reactions. ChemSusChem, 2009, 2(6): 558–574

[23] McKillop A, Turrell A G, Young D W, Taylor E C. Thallium in organic synthesis. 58. Regiospecific intermolecular oxidative dehydrodimerization of aromatic compounds to biaryls using thallium(III) trifluoroacetate. Journal of the American Chemical Society, 1980, 102(21): 6504–6512

[24] Motomura T, Nakamura H, Suginome M, Murakami M, Ito Y. Synthesis and structural analysis of oligo(naphthalene-2,3-diyl)s. Bulletin of the Chemical Society of Japan, 2005, 78(1): 142–146

[25] Kuwahara A, Nakano K, Nozaki K. Double N-arylation of primary amines: carbazole synthesis from 2,2′-biphenyldiols. Journal of Organic Chemistry, 2005, 70: 413–419

[26] Meadows R E, Woodward S. Steric effects in palladium-catalysed amination of aryl triflates and nonaflates with the primary amines PhCH(R)NH₂ (R= H, Me). Tetrahedron, 2008, 64(7): 1218–1224

[27] Ito C, Okahana N, Wu T S, Wang M L, Lai J S, Kuoh C S, Furukawa H. New carbazole alkaloids from Murraya euchrestifolia. Chemical & Pharmaceutical Bulletin, 1992, 40: 230–232

[28] Kawasaki T, Somei M. The first total syntheses of 9-methoxycarbazole-3-carboxaldehyde and methoxybrassinin. Heterocycles, 1990, 31: 1605–1608

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