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

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

Publication History

Received: 09 September 2021

Accepted after revision: 20 October 2021

Accepted Manuscript online:
20 October 2021

Article published online:
10 November 2021

• 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. DOI: 10.1002/047084289X.rt376.pub2
• 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