Triphenylphosphine/1,2-Diiodoethane-Promoted Formylation of Indoles with N,N-Dimethylformamide

Yu-Rong Zhu; Jin-Hong Lin; Ji-Chang Xiao

doi:10.1055/a-1675-1043

Synlett, Table of Contents

Synlett 2022; 33(03): 259-263
DOI: 10.1055/a-1675-1043

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Triphenylphosphine/1,2-Diiodoethane-Promoted Formylation of Indoles with N,N-Dimethylformamide

Yu-Rong Zhu

^aCollege of Chemistry and Materials Science, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, P. R. of China

^bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), 345 Lingling Road, Shanghai, 200032, P. R. of China

,

Jin-Hong Lin∗

^bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), 345 Lingling Road, Shanghai, 200032, P. R. of China

^cDepartment of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai, 200444, P. R. of China

,

Ji-Chang Xiao∗

^aCollege of Chemistry and Materials Science, Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, P. R. of China

^bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences (CAS), 345 Lingling Road, Shanghai, 200032, P. R. of China

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Abstract

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Abstract

Despite intensive studies on the synthesis of 3-formylindoles, it is still highly desirable to develop efficient methods for the formylation of indoles, due to the shortcomings of the reported methods, such as inconvenient operations and/or harsh reaction conditions. Here, we describe a Ph₃P/ICH₂CH₂I-promoted formylation of indoles with DMF under mild conditions. A Vilsmeier-type intermediate is readily formed from DMF promoted by the Ph₃P/ICH₂CH₂I system. A one-step formylation process can be applied to various electron-rich indoles, but a hydrolysis needs to be carried out as a second step in the case of electron-deficient indoles. Convenient operations make this protocol attractive.

Key words

formylation - indoles - aldehydes - Vilsmeier-type intermediate - dimethylformamide

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References

References and Notes

1a Vilsmeier A, Haack A. Ber. Dtsch. Chem. Ges. 1927; 60: 119
1b Meth-Cohn O, Stanforth SP. In Comprehensive Organic Synthesis, Vol. 2, Chap. 3.6. Trost BM, Fleming I. Pergamon; Oxford: 1991: 777

2 Wynberg H. Chem. Rev. 1960; 60: 169
3 Lindoy LF, Meehan GV, Svenstrup N. Synthesis 1998; 1029
4 Rieche A, Gross H, Höft E. Chem. Ber. 1960; 93: 88
5 Thanikachalam PV, Maurya RK, Garg V, Monga V. Eur. J. Med. Chem. 2019; 180: 562

6a Wu W, Su W. J. Am. Chem. Soc. 2011; 133: 11924
6b Chen J, Liu B, Liu D, Liu S, Cheng J. Adv. Synth. Catal. 2012; 354: 2438
6c Li L.-T, Huang J, Li H.-Y, Wen L.-J, Wang P, Wang B. Chem. Commun. 2012; 48: 5187
6d Li L.-T, Li H.-Y, Xing L.-J, Wen L.-J, Wang P, Wang B. Org. Biomol. Chem. 2012; 10: 9519
6e Zhang L, Peng C, Zhao D, Wang Y, Fu H.-J, Shen Q, Li J.-X. Chem. Commun. 2012; 48: 5928
6f Li X, Gu X, Li Y, Li P. ACS Catal. 2014; 4: 1897
6g Zhang B, Liu B, Chen J, Wang J, Liu M. Tetrahedron Lett. 2014; 55: 5618
6h Lu L, Xiong Q, Guo S, He T, Xu F, Gong J, Zhu Z, Cai H. Tetrahedron 2015; 71: 3637
6i Zhang W, Tang J, Yu W, Huang Q, Fu Y, Kuang G, Pan C, Yu G. ACS Catal. 2018; 8: 8084
6j Ling F, Cheng D, Liu T, Liu L, Li Y, Li J, Zhong W. Green Chem. 2021; 23: 4107
6k Wang Q.-D, Zhou B, Yang J.-M, Fang D, Ren J, Zeng B.-B. Synlett 2017; 28: 2670
6l Lin D.-Z, Huang J.-M. Org. Lett. 2019; 21: 5862
6m Yang L, Liu Z, Li Y, Lei N, Shen Y, Zheng K. Org. Lett. 2019; 21: 7702
6n Tongkhan S, Radchatawedchakoon W, Kruanetr S, Sakee U. Tetrahedron Lett. 2014; 55: 3909

7a Fei H, Yu J, Jiang Y, Guo H, Cheng J. Org. Biomol. Chem. 2013; 11: 7092
7b Betterley NM, Kerdphon S, Chaturonrutsamee S, Kongsriprapan S, Surawatanawong P, Soorukram D, Pohmakotr M, Andersson PG, Reutrakul V, Kuhakarn C. Asian J. Org. Chem. 2018; 7: 1642

8a Chen J, Lin J.-H, Xiao J.-C. Org. Lett. 2018; 20: 3061
8b Chen J, Lin J.-H, Xiao J.-C. Chem. Commun. 2018; 54: 7034
8c Zhang W, Chen J, Lin J.-H, Xiao J.-C, Gu Y.-C. iScience 2018; 5: 110
8d Zhang W, Gu Y.-C, Lin J.-H, Xiao J.-C. Org. Lett. 2020; 22: 6642

9a Johnson RA, Herr ME. J. Org. Chem. 1972; 37: 310
9b Castro BR. Org. React. Hoboken, NJ, U. S. A.: 1983. 29, 1
9c Dormoy J.-R, Castro B, Crawley ML. In Encyclopedia of Reagents for Organic Synthesis . Wiley; Hoboken: 2009.

10a Formylation of Electron-Rich Indoles; General Procedure A 25 mL tube was charged with Ph₃P (0.75 mmol, 1.5 equiv), ICH₂CH₂I (0.75 mmol, 1.5 equiv), the appropriate indole 1 (0.5 mmol, 1 equiv), DMF (2 mL), and H₂O (5 mL) under air, and the mixture was stirred at 80 °C for 2 h. The mixture was then cooled to rt and sat. aq brine was added. The crude organic product was extracted with CH₂Cl₂, and the combined organic phase was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, pentane–EtOAc). Formylation of Electron-Deficient Indoles; General Procedure A 25 mL tube was charged with Ph₃P (0.75 mmol, 1.5 equiv), ICH₂CH₂I (0.75 mmol, 1.5 equiv), the appropriate indole 1 (0.5 mmol, 1 equiv), DMAP (0.5 mmol, 1 equiv), and DMF (2 mL) under air, and the mixture was stirred at 80 °C for 2 h. H₂O (5 mL) was added and the mixture was stirred at 80 °C for a further 2 h. Similar workup to the above gave the pure product. 5-Vinyl-1H-indole-3-carbaldehyde (4t) White solid; yield: 49.4 mg (58%); mp 164.9–166.7 °C. IR (neat): 3148, 1635, 1615, 1522, 1473, 1440, 1392, 1245, 1129, 911, 819, 790 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.18 (s, 1 H), 9.94 (s, 1 H), 8.28 (s, 1 H), 8.14 (s, 1 H), 7.52–7.41 (m, 2 H), 6.85 (dd, J = 17.5, 10.9 Hz, 1 H), 5.76 (d, J = 17.6 Hz, 1 H), 5.18 (d, J = 10.9 Hz, 1 H). ¹³C NMR (400 MHz, DMSO-d ₆): δ = 185.50 (s), 139.36 (s), 137.94 (s), 137.35 (s), 132.08 (s), 124.88 (s), 122.02 (s), 119.57 (s), 118.80 (s), 113.06 (s), 112.75 (s). HRMS (EI): m/z [M]⁺ calcd for C₁₁H₉NO: 171.0684; found: 171.0682.
10b Myers AG, Hammond M, Wu Y, Xiang J.-N, Harrington PM, Kuo EY. J. Am. Chem. Soc. 1996; 118: 10006
10c Dorta RL, Rodríguez MS, Salazar JA, Suárez E. Tetrahedron Lett. 1997; 38: 4675

11a Myers AG, Hammond M, Wu Y, Xiang J.-N, Harrington PM, Kuo EY. J. Am. Chem. Soc. 1996; 118: 10006
11b Dorta RL, Rodríguez MS, Salazar J, Suárez E. Tetrahedron Lett. 1997; 38: 4675

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