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Frontiers of Chemical Science and Engineering

ISSN 2095-0179

ISSN 2095-0187(Online)

CN 11-5981/TQ

Postal Subscription Code 80-969

2018 Impact Factor: 2.809

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Front. Chem. Sci. Eng.    2021, Vol. 15 Issue (3) : 679-686    https://doi.org/10.1007/s11705-020-1979-9
RESEARCH ARTICLE
A highly efficient methodology for the preparation of N-methoxycarbazoles and the total synthesis of 3,3'-[oxybis(methylene)]bis(9-methoxy-9H-carbazole)
Yongxin Zhang, Shucheng Wang, Yaodong Huang()
Key Laboratory of Systems Bioengineering (Ministry of Education), School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
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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.
Keywords N-methoxyl carbazole      dimeric N-methoxyl carbazole      alkaloid      total synthesis      double N-arylation of methoxyamine     
Corresponding Author(s): Yaodong Huang   
Just Accepted Date: 24 September 2020   Online First Date: 23 November 2020    Issue Date: 10 May 2021
 Cite this article:   
Yongxin Zhang,Shucheng Wang,Yaodong Huang. A highly efficient methodology for the preparation of N-methoxycarbazoles and the total synthesis of 3,3'-[oxybis(methylene)]bis(9-methoxy-9H-carbazole)[J]. Front. Chem. Sci. Eng., 2021, 15(3): 679-686.
 URL:  
https://academic.hep.com.cn/fcse/EN/10.1007/s11705-020-1979-9
https://academic.hep.com.cn/fcse/EN/Y2021/V15/I3/679
Fig.1  Scheme 1 Two synthetic routes for N-methoxycarbazole reported in the literature [15,16].
Fig.2  Scheme 2 Dimeric N-methoxycarbazole alkaloid OBMC.
Entry Xantphos /mol-% Pd/xantphos
/mol-%		 Temperature
/°C		 Reaction time
/h		 Yield
/%
1 5 0.5% 90 36 19
2 10 0.5% 90 36 28
3 15 0.5% 90 36 29
4 5 1% 90 36 24
5 10 1% 90 36 35
6 15 1% 90 36 37
7 5 1.5% 90 36 34
8 10 1.5% 90 36 45
9 15 1.5% 90 36 49
10 5 2% 90 36 35
11 10 2% 90 36 56
12 15 2% 90 36 60
13 5 2.5% 90 36 43
14 10 2.5% 90 36 78
15 15 2.5% 90 36 79
16 10 2.5% 50 60 0
17 10 2.5% 90 24 65
18 10 2.5% 120 36 78
19 10 2.5% 90 48 78
Tab.1  The yield of the reaction of 1a with methoxyamine under different conditions
Fig.3  Scheme 3 Synthetic routes for compounds 2a–2g. (a) Dibromobiaryl, CH3ONH2 (1.5 equiv), Pd2(dba)3CHCl3 (2.5 mol-%), xantphos (10 mol-%), K3PO4 (3 equiv), toluene, 90–120 °C, 24–60 h, 69%–92%; (b) 3,3′-dibromo-2,2′-binaphthalene, CH3ONH2 (1.5 equiv), Pd2(dba)3CHCl3 (2.5 mol-%), xantphos (10 mol-%), K3PO4 (3 equiv), toluene, 90 °C, 36 h, 80%.
Entry Starting material Product R1 R2 Reaction time/h Reaction temp/°C Yield/%
1 1a 2a H H 36 90 78
2 a) 1b 2b H t-Bu 60 120 69
3 1c 2c NO2 H 24 90 92
4 1d 2d NO2 t-Bu 48 90 75
5 1e 2e H COOMe 36 90 85
6a) 1f 2f OCH3 OCH3 60 120 72
Tab.2  Reaction details and yields in the syntheses of 2a–2f
Fig.4  Scheme 4 ?Route for the total synthesis of OBMC. (a) N,N-Dimethylformamide (DMF)/POCl3 (1:1), ClCH2CH2Cl, 85 °C, 24 h, 73%; (b) NaBH4 (1.2 equiv), EtOH, 25 °C, 2 h, 100%; (c) SOCl2 (1.2 equiv), THF, 25 °C, 4 h, 100%; (d) NaI (1.2 equiv), acetone, 25 °C, 2 h, 100%; (e) 4 (1 equiv), NaH (1.2 equiv), 6 (1.2 equiv), tetrabutylammonium bromide (TBAB), toluene, 90 °C, 36 h, 45%.
Fig.5  Scheme 5 Possible chemical structure of the unstable compound from the Pd-catalyzed reaction of 5-methyl-2,2′-biphenylylene ditriflate with methoxyamine.
Fig.6  Scheme 6 Total syntheses of 9-methoxy-9H-carbazole-3-carbaldehyde (3) by (a) Kawasaki and Somei and (b) Selvakumar et al.
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