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DOI: 10.1055/a-2538-1363
Regioselective Synthesis of Isonitrile-Containing Densely Functionalized Alkenes from Propynenitriles
Science and Engineering Research Board (SERB), New Delhi (CRG/2021/007938 and EMR/2017/000155) and Council of Scientific and Research (CSIR), New Delhi, [(02)0356/19/EMR-II, DST-FIST (SR/FST/CS-1/2020/154)].
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.
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Key words
chlorovinyl aldehydes - propynenitriles - isocyanocyanoalkenoates - Michael addition - pyrroles - silver catalysisPhenylpropynenitriles[1] belong to a versatile group of organic compounds that have attracted considerable interest from the research community due to their distinct chemical reactivity and wide-ranging applications.[2] Phenylpropynenitriles can serve as key components for crafting reactive intermediates[3] or heterocyclic scaffolds[4] known for their diverse chemical and biological properties.[5] Their notable characteristics, such as their Michael-acceptor ability, high electron density in the C≡C triple bond, and electron-withdrawing ability of the nitrile group, make phenylpropynenitriles unique building blocks in organic synthesis.[6] Similarly, isocyanoacetates are also versatile building blocks due to the presence of three reactive centers: the isocyanide, the ester, and the acidic CH fragment.[7] The presence of these potentially reactive sites imparts isocyanoacetates with exceptional reactivity and wide synthetic potential to generate peptides, active pharmaceutical ingredients, or heterocycles with potential biological activities.[8]
The versatile reactivity of these two building blocks motivated us to investigate their interaction for the generation of another densely functionalized building block containing five reactive sites in the form of isocyanide, nitrile, ester, aryl, and alkene functionalities.[9] These functional groups are vital in organic synthesis and play important roles in the pharmacological profiles of drugs.[10] As an example, the isocyanide group can easily undergo C–H insertion reactions.[11] Similarly, the nitrile group can be converted into an amine, amide, amidine, aldehyde, ketone, carboxylic acid, or ester group. These multiple functionalities underline the potential importance of these compounds in both synthetic and medicinal contexts.[12] A survey of the literature revealed two reports by the Yamamoto group of Cu2O/1,10-phenanthroline- and 1,3-bis(diphenylphosphinyl)propane-catalyzed regioselective syntheses of pyrrole derivatives (22–35%), although the study was limited to one propynenitrile derivative.[13] Therefore, we envisaged generating novel densely functionalized alkenes containing isocyanide, nitrile, and ester functionalities.
The present study commenced with gram-scale syntheses of the arylpropynenitriles 19–36 from the corresponding β-chlorovinyl aldehydes 1–18 (Scheme [1]);[14] these, in turn, were prepared from the corresponding aryl methyl ketones by using a Vilsmeier–Haack reagent.[15] The β-chlorovinyl aldehydes 1–18 were subjected to oxidative amination with aqueous NH3 and I2 to generate β-chlorovinyl nitriles, which were subsequently treated with aqueous NaOH to give the arylpropynenitriles 19–36, following the method of Sharma et al.[16]
To synthesize the designed prototype, 3-(4-chlorophenyl)prop-2-ynenitrile (21) and ethyl isocyanoacetate (A) were selected as model substrates for optimizing the reaction conditions. Initially, both the reactants were treated with 2.0 equivalents of K2CO3 in anhydrous DMSO at room temperature. Interestingly, the reaction was completed within 20 minutes and a polar product was observed on thin-layer chromatography. The product was isolated in 48% yield after a short silica gel column chromatographic purification (Table [1], entry 1), and a spectroscopic analysis revealed its structure to be that of a Z-alkene containing three functionalities (isocyanide, nitrile, and ester), identified as ethyl (3Z)-3-(4-chlorophenyl)-4-cyano-2-isocyanobut-3-enoate (21A). In a search for more-efficient reaction conditions, various solvents were screened in attempts to improve the yield of the desired product. When DMF was used as a solvent instead of DMSO, the product yield fell to 30% (entry 2). A longer reaction time (24 h) was required when the reaction was conducted in dry THF at room temperature in the presence of K2CO3 as a base (entry 3).
Similarly, a longer reaction time (24 h) was required when Na2CO3 was used as a base in DMSO and, more surprisingly, a mixture of products was obtained (Table [1], entry 4). A reaction in the presence of t-BuOK in DMSO was completed within one hour, but a mixture of products was obtained (entry 5). To our delight, an excellent yield of 85% was obtained within ten minutes when the reaction was performed with Cs2CO3 (2.0 equiv) as a base in DMSO at room temperature (entry 6). With DBU as the base, the reaction was also completed within 10 minutes under similar reaction conditions, but the desired product was obtained in only 41% yield (entry 7). From these results, we concluded that Cs2CO3 is the most suitable base for this approach. However, no encouraging results were obtained when the reaction was performed with Cs2CO3 in MeCN (43%), 1,4-dioxane (48%), or THF (entries 8–10). When a reaction was performed without a base, the desired product was not obtained, even after 24 h, showing that use of a base is necessary for this transformation (entries 11 and 12). Next, we investigated the effect of the loading of the base on the efficiency of the reaction and we found that no increment in the yield of the desired product was observed upon lowering the amount of Cs2CO3 (entries 13–15). When the same reaction was executed at a higher temperature (60 °C), the reaction was completed almost immediately (≤5 minutes) and the desired product 21A was isolated in 71% yield. When the reaction was continued for longer periods (30 min to 6 h) under heating, traces of pyrrole derivatives were formed, but continuing the reaction for 20 hours resulted in a complete decomposition of both products. Also, when the reaction was performed at 0 °C the reaction was extremely slow due to frozen reaction content and it took more than three hours for completion to furnish the desired product 21A in 73% yield. These optimization studies revealed that 2.0 equivalents of Cs2CO3 in anhydrous DMSO at room temperature provide the optimal conditions for the synthesis of the densely functionalized alkene.
a Reaction conditions: 21 (0.124 mmol, 1.0 equiv), A (0.136 mmol, 1.1 equiv), solvent (1 mL), base (2.0 equiv).
b Anhyd solvents were used.
c Isolated yield after column chromatography.
d MP = mixture of products.
e Cs2CO3 (1.0 equiv).
f Cs2CO3 (1.1 equiv).
e Cs2CO3 (1.5 equiv).
With the established reaction conditions in hand, we investigated the scope of the strategy by employing diverse para-substituted aryl propynenitriles 19–29 for reaction with ethyl isocyanoacetate (A; Scheme [2]). To our delight, all the substrates responded positively and furnished the desired substituted alkenes in yields of 46–88% within 10–20 minutes in the presence of 2.0 equivalents of Cs2CO3 in anhydrous DMSO at room temperature. The halogen-substituted phenylpropynenitriles 20–22 delivered the desired products 20A–22A in yields of 70–85% within ten minutes. Strongly electron-withdrawing substituents such as NO2, CF3, and OCF3 groups were also well tolerated, and furnished the desired products 23A–25A in yields of 48–88% within 10–15 minutes. Arylpropynenitriles with electron-donating substituents (Me, OMe, OEt, Ph) delivered the desired products 26A–29A in slightly lower yields of 46–61%, although the reaction was completed within 10 to 20 minutes. Overall, the diversely functionalized alkenes 19–29A were readily obtained in all cases with a minor impact of the substituents on the product yields. Continuation of the reaction after completion for a total of 24 hours led to decomposition of the product, and no pyrrole derivative was obtained.
Next, the scope of the reaction was investigated with the ortho- and meta-substituted and disubstituted arylpropynenitriles 30–36 with the isocyanoacetates A (R = Et) and B (R = Me) (Scheme [3]). Surprisingly, no significant steric effect was observed in the case of the arylpropynenitriles 30–34, and, in all cases, the reaction was complete within 10–30 min. The reaction of α- and β-naphthyl-substituted propynenitriles 35 and 36 with ethyl isocyanoacetate (A) also proceeded smoothly and furnished the corresponding products 35A and 36A in yields of 67 and 79% within 20 and 10 min, respectively. Next, we carried out the reaction of methyl isocyanoacetate (B) with propynenitrile 33 under similar reaction conditions to give the desired product 33B in 56% yield within 10 minutes.
We also examined the gram-scale applicability of this procedure and found that 3-(4-chlorophenyl)prop-2-ynenitrile (21) reacted smoothly with ethyl isocyanoacetate (A) to give 1.7 g (83% yield) of the desired product 21A, although a reaction time of 25 minutes was required (Scheme [4]).
Next, we inspected the scope of the strategy for a [3+2] cycloaddition reaction of the diversely substituted propynenitriles 20, 26, 32–33, and 35 with ethyl isocyanoacetate (A), and we found that the annulation proceeded smoothly in the presence of Ag2CO3 (10 mol%) in DMSO to afford the corresponding trisubstituted pyrrole derivatives 37–41 in yields of 67–85% after one to two hours (Scheme [5]).[17] It is pertinent to mention that the [3+2] cycloaddition was completely regioselective in nature. Moreover, the reaction was clean in both DMSO and DMF, but it was much faster and more efficient in DMSO than in DMF. Also, Ag2CO3 was found to be a more efficient catalyst than AgNO3 for this [3+2] cycloaddition reaction.
To obtain insight into the reaction mechanism, control experiments were conducted in which the isolated alkene 21A was treated with Ag2CO3 at 80 °C for 24 hours [Scheme [6](i)] or with Cs2CO3 at room temperature for 24 hours [Scheme [6](ii)], but no pyrrole framework was obtained in either case. These results showed that the Ag2CO3-promoted [3+2] cycloaddition reaction of propynenitrile 21 with A proceeds in a concerted manner, and not through the alkene intermediate 21A.
Based on these observations and previous findings,[13] [18] a mechanism is proposed, as depicted as Figure [1]. A CO3 2– ion (Cs2CO3/Ag2CO3) abstracts the active methylene proton from A to give an anion 42, which undergoes Michael addition with propynenitrile 20 to give the intermediate 43, which tautomerizes to form 44 and takes up a proton to give the stable alkene 20A in the case of Cs2CO3. However, when Ag2CO3 is used as the catalyst, the Ag-chelated intermediate 45 undergoes [3+2] cycloaddition in a concerted manner to give 46, which, upon undergoing a 1,3-hydrogen shift, gives the pyrrole derivative 37.
In conclusion, we have developed an efficient strategy for the synthesis of novel densely functionalized alkenes containing isocyanide, nitrile, and ester functionalities, which could serve as useful intermediates for the synthesis of diverse heterocycles.[19] Furthermore, a Ag-catalyzed [3+2] cycloaddition strategy was developed for the synthesis of trisubstituted pyrrole derivatives. The strategy offers such advantages as operational simplicity, short reaction times, a broad substrate scope, 100% atom economy, gram-scale applicability, and high regioselectivity.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
Jyoti is grateful to the University Grant Commission, New Delhi, India for Junior and Senior Research fellowships. R.J. and V.S. gratefully acknowledge SERB-DST and CSIR New Delhi, whereas Deepika thanks the Dr B R Ambedkar National Institute of Technology (NIT), Jalandhar, and the Ministry of Human Resource and Development, New Delhi, India, for Junior and Senior Research Fellowships. DST-FIST, New Delhi, and the Central Instrumentation Laboratory of the Central University of Punjab, Bathinda, is acknowledged for providing HRMS, NMR, FTIR, and other characterization facilities.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2538-1363.
- Supporting Information
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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
- 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; Rf = 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.
Corresponding Author
Publication History
Received: 01 January 2025
Accepted after revision: 12 February 2025
Accepted Manuscript online:
12 February 2025
Article published online:
26 March 2025
© 2025. Thieme. All rights reserved
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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
- 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; Rf = 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.
