Regioselective Synthesis of Isonitrile-Containing Densely Functionalized Alkenes from Propynenitriles

Dedicated to Professor Vinod Kumar Tiwari for his seminal contributions to alkyne–azide cycloaddition chemistry.

Abstract

A transition-metal-free base-mediated approach has been devised for the synthesis of novel densely functionalized alkenes containing isocyanide, nitrile, and ester functionalities. The strategy was found to be applicable to gram-scale synthesis, and a library of functionalized alkenes with significant diversity was developed. The strategy could also be used for the synthesis of trisubstituted pyrrole derivatives by modifying the reaction conditions. The advantages of this approach are its operationally simple procedure, short reaction time (10–30 min), broad substrate scope, high atom economy, metal-free conditions, and high regioselectivity with good to excellent product yields.

Key words

chlorovinyl aldehydes - propynenitriles - isocyanocyanoalkenoates - Michael addition - pyrroles - silver catalysis

Publikationsverlauf

Eingereicht: 01. Januar 2025

Angenommen nach Revision: 12. Februar 2025

Accepted Manuscript online:
12. Februar 2025

Artikel online veröffentlicht:
26. März 2025

• References and Notes

• 1a Liu P, Clark RJ, Zhu L. J. Org. Chem. 2018; 83: 5092
• 1b Du Y, Li Z. Tetrahedron Lett. 2018; 59: 4622
• 2a Ishii A, Aoki Y, Nakata N. J. Org. Chem. 2014; 79: 7951
• 2b Fang W.-Y, Wang S.-M, Zhang Z.-W, Qin H.-L. Org. Lett. 2020; 22: 8904
• 3a Guan Z, Liu Z, Shi W, Chen H. Tetrahedron Lett. 2017; 58: 3602
• 3b Trofimov BA, Andriyankova LV, Nikitina LP, Belyaeva KV, Mal’kina AG, Afonin AV, Ushakov IA. Synlett 2012; 23: 2069
• 3c Kumar R, Kumar A, Ram S, Angeli A, Bonardi A, Nocentini A, Gratteri P, Supuran CT, Sharma PK. Arch. Pharm. 2022; 355: e2100241
• 3d Sharma PK, Kumar R, Ram S, Chandak N. Synth. Commun. 2021; 51: 1847
• 3e Xie C, Wu S, Zhang R. ACS Omega 2023; 8: 6854
• 3f Qu C, Huang R, Li Y, Liu T, Chen Y, Song G. Beilstein J. Org. Chem. 2021; 17: 2822
• 4a Liu E.-C, Topczewski JJ. J. Am. Chem. Soc 2021; 143: 5308
• 4b Singh PR, Gopal B, Kumar M, Goswami A. Org. Biomol. Chem. 2022; 20: 4933
• 4c Xue M.-X, Guo C, Gong L.-Z. Synlett 2009; 2191
• 4d Zhao M.-X, Zhou H, Tang W.-H, Qu W.-S, Shi M. Adv. Synth. Catal. 2013; 355: 1277
• 4e Zhang H, Li M, Wang K, Chen Y, Liao B, Wang Q, Yi W. J. Org. Chem. 2024; 89: 1692
• 4f Tao L.-F, Qian L, Liao J.-Y. Synlett 2022; 33: 1873
• 4g Fragkiadakis M, Neochoritis CG. Synlett 2022; 33: 1913
• 5a Chen M.-E, Gan Z.-Y, Hu Y.-H, Zhang F.-M. J. Org. Chem. 2023; 88: 3954
• 5b Kumari C, Goswami A. J. Org. Chem. 2022; 87: 8396
• 6 Kumari C, Goswami A. Eur. J. Org. Chem. 2021; 2021: 429
• 7 Gulevich AV, Zhdanko AG, Orru RV. A, Nenajdenko VG. Chem. Rev. 2010; 110: 5235
• 8a Sadjadi S, Heravi MM, Nazari N. RSC Adv. 2016; 6: 53203
• 8b Wang Y, Kumar RK, Bi X. Tetrahedron Lett. 2016; 57: 5730
• 8c Uno H, Tanaka M, Inoue T, Ono N. Synthesis 1999; 1999: 471
• 8d Váradi A, Palmer TC, Dardashti RN, Majumdar S. Molecules 2016; 21: 19
• 9a Huang H, Chen J, Jiang Y, Xiao T. Org. Chem. Front. 2021; 8: 5955
• 9b He D, Zhong W, Zhou M, Wang B, Li M, Jiang H, Wu W. Org. Lett. 2022; 24: 5802
• 9c Meng L.-G, Li C.-T, Zhang J.-F, Xiao G.-Y, Wang L. RSC Adv. 2014; 4: 7109
• 9d Belyaeva KV, Andriyankova LV, Nikitina LP, Mal’kina AG, Afonina AV, Ushakova IA, Bagryanskaya IY, Trofimov BA. Tetrahedron 2014; 70: 1091
• 10a Fleming FF, Yao L, Ravikumar PC, Funk L, Shook BC. J. Med. Chem. 2010; 53: 7902
• 10b Bonatto V, Lameiro RF, Rocho FR, Lameira J, Leitão A, Montanari CA. RSC Med. Chem. 2023; 14: 201
• 10c Neto SS. J, Zeni G. ChemCatChem 2020; 12: 3335
• 11 Vlaar T, Ruijter E, Maes BU. W, Orru RV. A. Angew. Chem. Int. Ed. 2013; 52: 7084
• 12 Bode ML, Gravestock D, Rousseau AL. Org. Prep. Proced. Int. 2016; 48: 89
• 13a Kamijo S, Kanazawa C, Yamamoto Y. J. Am. Chem. Soc. 2005; 127: 9260
• 13b Kamijo S, Kanazawa C, Yamamoto Y. Tetrahedron Lett. 2005; 46: 2563
• 14 Saini P, Jyoti Jyoti, Sharma PK, Singh V. Eur. J. Org. Chem. 2024; e202401058
• 15a Brahma S, Ray JK. Tetrahedron 2008; 64: 2883
• 15b Ghosh M, Ray JK. Tetrahedron 2017; 73: 3731
• 16 Sharma PK, Ram S, Chandak N. Adv. Synth. Catal. 2016; 358: 894
• 17a Tiwari DK, Phanindrudu M, Aravilli VK, Sridhar B, Likhar PR, Tiwari DK. Chem. Commun. 2016; 52: 4675
• 17b Tiwari DK, Pogula J, Sridhar B, Tiwari DK, Likhar PR. Chem. Commun. 2015; 51: 13646
• 17c Li Petri G, Spanò V, Spatola R, Holl R, Raimondi MV, Barraja P, Montalbano A. Eur. J. Med. Chem. 2020; 208: 112783
• 17d McGeary RP, Tan DT. C, Selleck C, Pedroso MM, Sidjabat HE, Schenk G. Eur. J. Med. Chem. 2017; 137: 351
• 17e Wallace MB, Adams ME, Kanouni T, Mol CD, Dougan DR, Feher VA, O’Connell SM, Shi L, Halkowycz P, Dong Q. Bioorg. Med. Chem. Lett. 2010; 20: 4156
• 17f Goel A, Agarwal N, Singh FV, Sharon A, Tiwari P, Dixit M, Pratap R, Srivastava AK, Maulik PR, Ram VJ. Bioorg. Med. Chem. Lett. 2004; 14: 1089
• 18a Singh M, Paul AK, Singh V. New J. Chem. 2020; 44: 12370
• 18b Das B, Chakraborty N, Dhara HN, Bhattacharyya P, Patel BK. J. Org. Chem. 2024; 89: 1331
• 18c Singh V, Hutait S, Biswas S, Batra S. Eur. J. Org. Chem. 2010; 2010: 531
• 18d Sharma M, Pandey V, Poli G, Tuccinardi T, Lolli ML, Vyas VK. Bioorg. Chem. 2024; 146: 107249
• 18e Khuntia R, Maity D, Pan SC. Chem. Eur. J. 2025; 31: e202404511
• 18f Wei H, Cao Y, Zhao C, Shao Z, Huo X, Pan J, Zhuang R. Chem. Biol. Drug Des. 2024; 103: e14484
• 18g Kumar S, Malakar CC, Singh V. ChemistrySelect 2021; 6: 4005
• 18h Kumar A, Mishra PK, Verma AK. Chem. Commun. 2023; 59: 7263
• 18i Qi X, Xiang H, Yang C. Org. Lett. 2015; 17: 5590
• 19 Ethyl (3Z)-3-(4-Chlorophenyl)-4-cyano-2-isocyanobut-3-enoate (21A); Typical Procedure An oven-dried, 10 mL, round-bottomed flask was charged with Cs₂CO₃ (0.404 g, 1.24 mmol) and a solution of ethyl isocyanoacetate (A; 0.075 mL, 0.683 mmol) in anhyd DMSO (1.5 mL) at rt, and the mixture was stirred for 2–3 min. 3-(4-Chlorophenyl)prop-2-ynenitrile (21; 0.10 g, 0.62 mmol) was added, and the mixture was stirred at rt for 10 min until the reaction was complete (TLC). The mixture was then poured onto crushed ice, and the organic layer was separated with EtOAc, washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel (60–120 mesh), EtOAc–hexane (20:80)] to give an off-white solid; yield: 0.144 g (85%); mp 68–70 °C; R_f = 0.48 (EtOAc–hexane, 20:80). IR (neat): 2227 (CN), 1611, 1669 (C=C), 1735 (COOEt) cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 1.21 (t, J = 7.1 Hz, 3 H, CO₂CH₂CH ₃), 4.20 (q, J = 7.1 Hz, 2 H, CO₂CH ₂CH₃), 6.03 (s, 1 H, –C=CH), 7.37 (d, J = 8.2 Hz, 2 H, ArH), 7.41 (s, 1 H, ArH), 7.43 (d, J = 1.9 Hz, 2 H, ArH). ¹³C NMR (150 MHz, CDCl₃): δ = 14.8, 29.8, 69.8, 93.3, 112.5, 118.1, 128.7, 130.3, 133.2, 135.8, 142.0, 151.3, 157.1. HRMS (ESI): m/z [M + H]⁺ Calcd for C₁₄H₁₂ClN₂O₂: 275.0582; found: 275.0590.