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Palladium-Catalyzed Regioselective Hydroaminocarbonylation of Alkynes to #, #-Unsaturated Primary Amides with Ammonium Chloride Xiaolei Ji, Bao Gao, Xibing Zhou, Zongjian Liu, and Hanmin Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01405 • Publication Date (Web): 28 Jun 2018 Downloaded from http://pubs.acs.org on June 28, 2018

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The Journal of Organic Chemistry

Palladium-Catalyzed Regioselective Hydroaminocarbonylation of Alkynes to α, β-Unsaturated Primary Amides with Ammonium Chloride Xiaolei Ji,† Bao Gao,‡ Xibing Zhou,‡ Zongjian Liu† and Hanmin Huang*,†, ‡ †

College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310024, China. Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, Center for Excellence in Molecular Synthesis, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, 230026, P. R. China. ‡

ABSTRACT: α,β-Unsaturated primary amides have found numerous applications in drug development, organic materials and polymer sciences. However, the catalytic synthesis of α,β-unsaturated primary amides via carbonylation of alkynes has long been an elusive endeavor. Here, we report a novel palladium-catalyzed hydroaminocarbonylation of alkynes with NH4Cl as the amine source, enabling highly chemo- and regioselective synthesis of α,β-unsaturated primary amides. A variety of alkynes including aromatic alkynes, aliphatic alkynes, terminal alkynes, internal alkynes as well as diynes with various functional groups react well. The method turns parasitic non-coordination ability of ammonium salts into a strategic advantage, enabling the gram-scale reaction to be performed in the presence of 0.05 mol% of catalyst with excellent selectivity tions have been reported for the synthesis of α,β-unsaturated primary amides.7

INTRODUCTION The amide has long been recognized as an important synthetic target because it participates in a variety of useful transformations.1 In addition, it also exists in myriad of natural products, pharmaceuticals, and agrochemicals with interesting biological activity.2 As such, the development of efficient methods for manipulation of amidic C-N bond has been a persistent research area of interest for decades. Compared to catalytic reactions employing carboxylic acid derivatives in which the carbonyl group is preinstalled, transition-metal catalyzed hydroaminocarbonylation reaction has attracted much interest due to its high atom- and step-economy as well as its use of cheap and abundant CO as a C1 feedstock. 3 In spite of the advantages of hydroaminocarbonylation reaction, early studies in this field with Fe, Co, Ni, and Ru as catalysts required harsh reaction conditions and resulted in poor chemoselectivity. 4 This situation has been greatly changed since the palladium catalysis system was established. In this context, the palladium-catalyzed hydroaminocarbonylation reaction initiated by palladium-hydride species has emerged as one of the most promising methods toward amides.5-6 However, in sharp contrast to the synthesis of tertiary and secondary amides, 7 the synthesis of primary amides via hydroaminocarbonylation reaction has received little attention, although the primary amides are more valuable building blocks in the synthesis of biologically active molecules and functional materials. α,βUnsaturated primary amides are attractive precursors, and have been utilized as very useful building blocks in a number of important reactions.8 However, to the best of our knowledge, no transition-metal-catalyzed hydroaminocarbonylation reac-

Recently, our group has disclosed a palladium-catalyzed regioselective hydroaminocarbonylation reaction between alkene and NH4Cl in NMP,5g which provides an efficient approach toward aliphatic primary amides. Mechanistic studies Scheme 1. Hydroaminocarbonylation of Alkynes to Primary Amides with NH4Cl

showed that the reaction was initiated by a palladium-hydride species generated in situ via oxidative addition of NH4Cl to Pd(0) (Scheme 1). The acylpalladium species produced via the hydrocarbonylative process was capable of capturing the NH2moiety directly from the ammonium salt in the presence of CO under the assistance of NMP (Scheme 1a). The NMP not only acts as solvent to dissolve NH4Cl, but also functions as a base to capture the released HCl.5g Moreover, the parasitic noncoordination ability of ammonium salts could enable the reac-

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tion to be performed with higher turnover number (TON). On the basis of this result, we surmised that alkynes could also react with palladium-hydride species and CO under appropriate reaction conditions to give the acylpalladium species, which should be capable of capturing the NH2-moiety from the ammonium salt to give the desired acrylamides (Scheme 1b). However, unlike the hydroaminocarbonylation of alkenes, the realization of such a process is more challenging, since the intramolecular hydroaminocarbonylation or hydroamination reaction of the produced α,β-unsaturated primary amide may take place to compete with the desired carbonylation reaction. We believe that the competition would be controlled by tuning the reaction condition and palladium catalyst. Herein, we describe the first palladium-catalyzed hydroaminocarbonylation of alkynes with NH4Cl as amine source, which provides an efficient access to various valuable α,β-unsaturated primary amides in excellent yields with high regioselectivities. Notably, the reaction could be performed smoothly with lower catalyst loading, which enhanced the practice of the present reaction.

RESULTS AND DISCUSSION Table 1. Optimization of the Reaction Conditionsa

On the basis of our previous work, the palladium-catalyzed hydroaminocarbonylation of phenylacetylene 1a with NH4Cl as amine source was selected as a benchmark reaction. The reaction was conducted in the presence of 20 atm of CO with NMP as solvent. As shown in Table 1, the desired α,βunsaturated primary amides 2a and 3a were obtained in combined 23% yield with 70:30 regioselectivity, when the reaction

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was carried out at 120 oC for 3 hours with Pd(CH3CN)2Cl2/Xantphos as the catalytic system (Table 1, entry 1). These results indicated that the desired hydroaminocarbonylation of alkyne involving palladium-hydride species was indeed possible albeit in low reactivity and selectivity. Subsequently, further experiments were carried out to test various phosphine ligands with Pd(CH3CN)2Cl2 as the catalyst precursor and the results demonstrated that the branched amide 2a was favored to be obtained with good regioselectivity with DPEPhos as a ligand. Other ligands, including DPPF, DPPH (1,2-Bis(diphenylphosphino)hexane) and DPPPen (1,2Bis(diphenylphosphino)pentane) could also promote the reaction, but with lower yield and selectivity (Table 1, entries 1-5). We then turned our attention to investigate the palladium precursor with DPEPhos as the ligand and found that Pd(PPh 3)4 was better in terms of reactivity and selectivity. Encouraged by these results, we attempted to optimize the reaction conditions by screening of the reaction time and temperature. It was found that the yield could be increased to 75% when the reaction time was prolonged to 9 h (Table1, entry 14). To our delight, almost the same yield of product 2a with higher regioselectivity was achieved when the reaction temperature was decreased to 100 oC (Table1, entry 15). Moreover, further decreasing the reaction temperature to 80 oC resulted in higher regioselectivity and almost the same yield was obtained when the reaction time was prolonged to 24 h. However, further decreasing the temperature to 50 oC resulted in no reaction (Table 1, entry 18). Lowering CO pressure would lead to a decreasing yield, however, regioselectivity was not affected. (Table 1, entry 19). With the optimized reaction conditions established, we turned our attention to validating the generality of our hydroaminocarbonylation protocol. In general, the mild reaction conditions allow the use of a variety of alkynes containing different functional groups. Moreover, both aromatic alkynes and aliphatic alkynes are compatible with the reaction conditions. A variety of phenylacetylenes bearing different substituents on the aryl ring were initially surveyed. As shown in Table 2, the electronic properties of the substituents on the aromatic ring of the aromatic alkynes have a strong influence on the reactivity and selectivity. The aryl alkynes with electrondonating groups exhibited high reactivity and selectivity. For instance, the reactions of aryl alkynes (1b-1e), containing methyl, ethyl and methoxy groups on the aromatic ring, afforded the corresponding amides in good to excellent yields with excellent regioselectivities (2b-2e). In contrast, installing electron-withdrawing groups on the phenyl ring of the alkynes leading to lower reactivities and selectivities (2f -2l). The structures of 2e and 2f were confirmed by X-ray crystallographic analysis.9 A bromo group on the phenyl ring 2k also survives during the reaction and provides a potential synthetic handle for further coupling reactions. In addition, the corresponding amide 2m was successfully generated from hydroaminocarbonylation of 2-ethynyl-naphthalene in good yield with excellent regioselectivity. Moreover, under the slightly modified reaction conditions, we were pleased to find that the alkyne scope can be extended from aryl alkynes to aliphatic alkyne, although the corresponding amide (2n) was obtained in relative lower regioselectivity. To our surprise, linear amides 3o and 3p was obtained in 86% and 94% yields, respectively, when the steric hindrance 3,3-dimethyl-1-butyne 1o and trimethylsilyl acetylene 1p were subjected to the reaction conditions. The regioselectivities were completely changed, which


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The Journal of Organic Chemistry might be attributed to the steric hindrance of the tertiary-butyl group and trimethylsilyl group located adjacent to the alkyne moiety.5 The solid structure of 3p was unambiguously determined by single-crystal X-ray diffraction analysis which provided solid evidence to confirm the regioselectivity.9 The remote ester functional group attached in the aliphatic alkyne 1q was tolerated to give the corresponding amide 2q in 64% isolated yield with relatively lower regioselectivity. The estrone derivative bearing a steroid scaffold 1r was also compatible with the reaction condition to afford the corresponding amide 2r in 63% yield with high regioselectivity. As expected, the substrate scope can be extended from terminal alkynes to internal alkynes. For example, the reaction of diphenylethyne underwent smoothly to provide product 2s in good yield. Other internal alkynes substituted with diphenylethyne, such as 1t and 1u, were also successfully transferred to the desired α,βunsaturated primary amides with this protocol to produce amide 2t and 2u in 74% and 62% isolated yields, respectively. However, under these reaction conditions, no amide products formed from heteroaromatic alkynes, and further investigations of these substrates are currently in progress.

firmed that the hydroaminocarbonylation reaction took place at only one position among the several active sites of diynes.9 To demonstrate the synthetic utility of the present new reaction, the gram-scale reaction of trimethylsilyl acetylene 1p was conducted under 0.05 mol% of palladium catalyst (Scheme 2). Under the slightly modified reaction conditions, the reaction underwent smoothly to give the desired product 3p in 95% yield with excellent regioselectivity. Notably, this result represents a Table 3. Substrate Scope of Diyne a

Table 2. Substrate Scope of Alkynea

turnover number (TON) of 1900, which is among the highest reported for palladium-catalyzed hydroaminocarbonylation reactions.3 The trimethylsilyl group of 3p can be easily removed to produce the acrylamide which is widely used in industry to synthesize polyacrylamide (PAM).10 To the best of our knowledge, this is the first example for the synthesis of acrylamide by using of hydroaminocarbonylation reaction. Moreover, the versatile trimethylsilyl group contained in this product provided an additional handle for further derivatization.11 Scheme 2. Synthetic Application

Figure1. Plausible Reaction Mechanism

On the other hand, diynes 4 containing various electron-rich or –deficient phenyl rings reacted smoothly with CO and NH4Cl to give the desired amides in high yields (Table 3). The reaction was amenable to a range of substituted 1,4diphenylbuta-1,3-diynes, giving the corresponding primary amides 5a-5f in 74-92% yields and obtained products did not further reacted with NH4Cl, which may be attributed to steric hindrance effect. The obtained versatile carbon-carbon triple bond and double bond provides a potential handle for later elaboration. The X-ray crystallographic analysis of 5f con-



On the basis of these results and our previous work on hydroaminocarbonylation of alkenes under palladium catalysis,5g we propose the following catalytic mechanism (Figure 1). Initially, the in situ formed Pd(0) undergoes oxidative addition with NH4Cl to furnish the active palladium hydride species. Subsequent regioselective hydropalladation of alkyne substrate affords alkenylpalladium intermediate A or B, which may depend on the electronics of the substituent on the aromatic ring. CO insertion leads to the corresponding acyl palladium species C or D, and the resultant acylpalladium species C or D directly reacted with NH4Cl in the presence of CO to generate the desired amides. The key palladium-hydride species was simultaneously generated to enter the next catalytic cycle and the released HCl was trapped by NMP solvent to finish the catalytic cycle. In summary, we have successfully developed a practical protocol for the synthesis of α,β-unsaturated primary amides via palladium-catalyzed hydroaminocarbonylation of alkynes with NH4Cl as amine source in the presence of CO. A variety of α,β-unsaturated primary amides have been obtained in high yields with good to excellent regioselectivities, which represents the first example of the direct conversion of NH 4Cl to α,β-unsaturated primary amides. The scaled-up reaction demonstrated that the reaction could be conducted in 0.05 mol% of palladium catalyst, which enhanced the synthetic value of this transformation. The success of this reaction could also provide more evidence for the mechanism we have proposed before that the acylpalladium species generated in the catalytic system could directly incorporate the amine-moiety from the ammonium salts. In addition, the use of ammonium salts as practical alternatives to gaseous ammonia in a variety of C-N bond-forming manifolds is proved more and more promising.

EXPERIMENTALSECTION General Information. All non-aqueous reactions and manipulations were using standard Schlenk techniques. All solvents before use were dried and degassed by standard methods and stored under nitrogen atmosphere. All reactions were monitored by TLC with silica gel-coated plates. NMR spectra were recorded on BRUKER Avence III 400 MHz spectrometers. Chemical shifts were reported in parts per million (ppm) down field from TMS with the solvent resonance as the internal standard. Coupling constants (J) were reported in Hz and refered to apparent peak multiplications. High resolution mass spectra (HRMS) were recorded on Bruker MicroTOF-QII mass (ESI). GC analysis were performed on Agilent 7890B with Hp-5 column. GS-MS analysis were performed with Agilent 7890B/5975B GC-MS system. Aromatic alkynes (1a-1l, 1n-1p, 1s) purchased from Alfa Aesar or Sigma Aldrich. Alkynes (1m, 1q, 1r, 1t-1u, 5a5f) were known compounds and synthesized according to the reported methods.12 General Procedure A. In a glove box, a mixture of NH4Cl (80.3 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol), DPEPhos (32.3 mg, 0.06 mmol) and NMP (3.0 mL) was added into a dry glass vessel. The resulting mixture was stirred for 10 minutes at room temperature and then alkynes 1 (1.0 mmol) was added into the reaction mixture. The glass vessel was put into an autoclave and then taken out from the glove box. The autoclave was purged for three times and charged with CO (20 atm). The reaction mixture was stirred at 80 oC for 24 hours. After the reaction finished, the autoclave was cooled to room temperature and the pressure was carefully released in the

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fume hood. The regioselectivity was measured by GC and GCMS, respectively. Then the corresponding reaction mixture was purified by flash column chromatography on silica gel and eluted with petroleum ether/ethyl acetate (50/1 - 1/1) to give the desired products 2. General Procedure B. In a glove box, a mixture of NH4Cl (80.3 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol), DPEPhos (32.3 mg, 0.06 mmol) and NMP (3.0 mL) was added into a dry glass vessel. The resulting mixture was stirred for 10 minutes at room temperature and then alkynes (1.0 mmol) was added into the reaction mixture. The glass vessel was put into an autoclave and then taken out from the glove box. The autoclave was purged for three times and charged with CO (20 atm). The reaction mixture was stirred at 120 oC for 12 hours. After the reaction finished, the autoclave was cooled to room temperature and the pressure was carefully released in the fume hood. The regioselectivity was measured by GC and GCMS, respectively. Then the corresponding reaction mixture was purified by flash column chromatography on silica gel and eluted with petroleum ether/ethyl acetate (50/1 - 1/1) to give the desired products 2. General Procedure C. In a glove box, a mixture of NH4Cl (80.3 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol), DPEPhos (32.3 mg, 0.06 mmol) and NMP (3.0 mL) was added into a dry glass vessel. The resulting mixture was stirred for 10 minutes at room temperature and then alkynes (1.0 mmol) was added into the reaction mixture. The glass vessel was put into an autoclave and then taken out from the glove box. The autoclave was purged for three times and charged with CO (20 atm). The reaction mixture was stirred at 140 oC for 12 hours. After the reaction finished, the autoclave was cooled to room temperature and the pressure was carefully released in the fume hood. Then the corresponding reaction mixture was purified by flash column chromatography on silica gel and eluted with petroleum ether/ethyl acetate (50/1 - 1/1) to give the desired products 5. Spectroscopic Data of the Products: 2-phenylacrylamide (2a): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 105.8 mg, 72% yield. 1 H NMR (400 MHz, CDCl3) δ 5.68 (d, J = 0.8 Hz, 2H), 5.97 (br, 1H), 6.21 (d, J = 0.8 Hz, 1H), 7.38-7.41 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 123.2, 128.2, 128.7, 128.8, 137.1, 144.3, 169.7; HRMS (ESI) calcd. for C9H9NONa [M+Na]: 170.0576, found: 170.0584. cinnamamide (3a): The title compound was purified as byproduct from several reactions together by column chromatography to give a white solid. 1H NMR (400 MHz, CDCl3) δ 5.72 (br, 1H), 5.88 (br, 1H), 6.46 (d, J = 15.6 Hz, 1H), 7.37-7.38 (m, 3H), 7.51-7.53 (m, 2H), 7.63 (d, J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 119.6, 128.1, 129.0, 130.1, 134.6, 142.7, 168.0; HRMS (ESI) calcd. for C9H10NO [M+H]: 148.0757, found: 148.0749. 2-(p-tolyl)acrylamide (2b): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 144.2 mg, 90% yield. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 5.63 (d, J = 1.2 Hz, 1H), 5.72 (br, 1H), 6.14 (s, 1H), 6.25 (br, 1H), 7.18 (d, J = 8.0 Hz, 2H); 7.28 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.3, 122.7, 128.2, 129.5, 134.3, 138.6, 144.1, 169.7; HRMS (ESI) calcd. for C10H11NONa [M+Na]: 184.0733, found: 184.0731. 2-(m-tolyl)acrylamide (2c): The title compound was


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The Journal of Organic Chemistry prepared according to the general procedure and purified by column chromatography to give a white solid, 119.1 mg, 74% yield. 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 5.64 (s, 1H), 5.73 (br, 1H), 6.17 (s, 1H), 6.42 (br, 1H), 7.16-7.20 (m, 3H); 7.25-7.29 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 123.1, 125.3, 128.7, 128.9, 129.4, 137.1, 138.5, 144.3, 169.7; HRMS (ESI) calcd. for C10H11NONa [M+Na]: 184.0733, found: 184.0734. 2-(4-ethylphenyl)acrylamide (2d): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 143.3 mg, 82% yield. 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J = 7.6 Hz, 3H), 2.63 (q, J = 7.6 Hz, 2H), 5.63 (s, 1H), 5.76 (br, 1H), 6.13 (s, 1H), 6.55 (br, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 15.5, 28.6, 122.3, 128.1, 128.2, 134.4, 144.2, 144.8, 170.2; HRMS (ESI) calcd. for C11H13NONa [M+Na]: 198.0889, found: 198.0890. 2-(4-methoxyphenyl)acrylamide (2e): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 164.6 mg, 92% yield. 1H NMR (400 MHz, CDCl3) δ 3.83 (s, 3H), 5.61 (d, J = 0.8 Hz, 1H), 5.71 (br, 1H), 5.89 (br, 1H), 6.10 (d, J = 1.2 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 55.5, 114.2, 121.8, 129.5, 143.8, 160.0, 169.9, HRMS (ESI) calcd. for C10H11NO2Na [M+Na]: 200.0682, found: 200.0674. 2-(4-fluorophenyl)acrylamide (2f): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 84 mg, 51% yield. 1H NMR (400 MHz, CDCl3) δ 5.66 (s, 1H), 5.72 (br, 1H), 6.14 (s, 1H), 6.32 (br, 1H), 7.06-7.10 (m, 2H), 7.37-7.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 115.7, 115.9, 123.0, 130.0, 130.1, 133.0, 133.0, 143.3, 161.8, 164.3, 169.7; 19F NMR (376 MHz, CDCl3) δ -112.8; HRMS (ESI) calcd. for C9H9FNO [M+H]: 166.0663, found: 166.0662. 2-(3-fluorophenyl)acrylamide (2g): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 103.3 mg, 62% yield. 1H NMR (400 MHz, CDCl3) δ 5.71 (s, 1H), 5.78 (br, 1H), 6.16 (s, 1H), 6.57 (br, 1H), 7.04-7.21 (m, 3H), 7.33-7.38 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 115.2, 115.4, 115.6, 115.8, 123.7, 123.9, 123.9, 130.4, 130.4, 139.0, 139.1, 143.3, 161.6, 164.0, 169.3; 19F NMR (376 MHz, CDCl3) δ -112.3; HRMS (ESI) calcd. for C9H9FNO [M+H]: 166.0663, found: 166.0669. 2-(4-chlorophenyl)acrylamide (2h): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 97.7 mg, 54% yield. 1H NMR (400 MHz, CDCl3) δ 5.69 (s, 2H), 6.14 (s, 2H), 7.36 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 123.2, 129.0, 129.6, 134.8, 135.4, 143.3, 169.2; HRMS (ESI) calcd. for C9H9ClNO [M+H]: 182.0367, found: 182.0367. 2-(3-chlorophenyl)acrylamide (2j): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 115.2 mg, 63% yield. 1H NMR (400 MHz, CDCl3) δ 5.70-5.78 (m, 2H), 6.15 (s, 1H), 6.55 (br, 1H), 7.27-7.36 (m, 3H), 7.41 (d, J = 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 123.8, 126.4, 128.3, 128.8, 130.1, 134.7, 138.8, 143.2, 169.0; HRMS (ESI) calcd. for C9H9ClNO [M+H]: 182.0367, found: 182.0363. 2-(2-chlorophenyl)acrylamide (2j): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 106.8 mg, 59%

yield. 1H NMR (400 MHz, CDCl3) δ 5.48 (br, 1H), 5.63 (d, J = 1.2 Hz, 1H), 5.95 (br, 1H), 6.47 (d, J = 1.2 Hz, 1H), 7.31-7.36 (m, 3H), 7.43-7.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 126.8, 127.2, 129.9, 130.1, 131.3, 133.5, 136.5, 141.9, 167.7; HRMS (ESI) calcd. for C9H8ClNONa [M+Na]: 204.0192, found: 204.0188. 2-(4-bromophenyl)acrylamide (2k): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 140.8 mg, 62% yield. 1H NMR (400 MHz, CDCl3) δ 5.68 (s, 1H), 5.79 (br, 1H), 6.11 (s, 1H), 6.62 (br, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 122.9, 129.8, 131.9, 135.8, 143.4, 169.5; HRMS (ESI) calcd. for C9H9BrNO [M+H]: 225.9862, found: 225.986. 2-(4-(trifluoromethyl)phenyl)acrylamide (2l): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 98.9 mg, 46% yield. 1H NMR (400 MHz, CDCl3) δ 5.71-5.77 (m, 2H), 6.21 (s, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 122.7, 124.1, 125.4, 125.7, 125.8, 125.8, 125.8, 128.6, 128.7, 130.6, 131.0, 132.2, 132.3, 140.5, 143.4, 168.9; 19F NMR (376 MHz, CDCl3) δ 62.7; HRMS (ESI) calcd. for C10H9F3NO [M+H]: 216.0631, found: 216.0629. 2-(naphthalen-2-yl)acrylamide (2m): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 103.7 mg, 52% yield. 1H NMR (400 MHz, CDCl3) δ 5.72-5.80 (m, 3H), 6.28 (d, J = 0.8 Hz, 1H), 7.50-7.53 (m, 3H), 7.84-7.89 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 123.7, 125.8, 126.8, 126.8, 127.6, 127.8, 128.3, 128.6, 133.2, 133.3, 134.5, 144.2, 169.3; HRMS (ESI) calcd. for C13H11NONa [M+Na]: 220.0733, found: 220.0733. 2-methylenehexanamide (2n): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 91.2 mg, 72% yield. 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J = 7.2 Hz, 3H), 1.33-1.50 (m, 4H), 2.29-2.33 (t, J = 7.2 Hz, 2H), 5.35 (s, 1H), 5.70 (s, 1H), 5.89 (br, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.4, 30.3, 32.0, 118.8, 144.7, 171.1; HRMS (ESI) calcd. for C7H13NONa [M+Na]: 150.0889, found: 150.0889. (E)-4,4-dimethylpent-2-enamide (3o): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 109.3 mg, 83% yield. 1H NMR (400 MHz, CDCl3) δ 1.07 (s, 9H), 5.72 (d, J = 15.6 Hz, 2H), 6.15 (br, 1H), 6.84 (d, J = 15.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 28.8, 33.6, 118.1, 156.2, 169.0; HRMS (ESI) calcd. for C7H14NO [M+H]: 128.107, found: 128.1068. (E)-3-(trimethylsilyl)acrylamide (3p): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 128.0 mg, 90% yield. 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 9H), 5.87 (br, 1H), 6.17 (d, J = 18.8 Hz, 1H), 6.40 (br, 1H), 6.99 (d, J = 18.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -1.7, 135.9, 145.7, 167.9; HRMS (ESI) calcd. for C6H14NOSi [M+H]: 144.0839, found: 144.0838. 4-carbamoylpent-4-en-1-yl benzoate (2q): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 149.3 mg, 64% yield. 1H NMR (400 MHz, CDCl3) δ 1.94-2.01 (m, 2H), 2.48 (t, J = 7.6 Hz, 2H), 4.34 (t, J = 6.4 Hz, 2H), 5.42 (s, 1H), 5.73 (s, 1H), 6.03 (br, 2H), 7.42-7.46 (m, 2H), 7.54-



7.58 (m, 1H), 8.03-8.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 27.1, 28.8, 64.1, 119.3, 128.4, 129.5, 130.2, 132.9, 143.4, 166.6, 170.7; HRMS (ESI) calcd. for C13H16NO3 [M+H]: 234.1130, found: 234.1125. 22-((8R,9S,13S,14S)-13-methyl-17-oxo7,8,9,11,12,13,14,15,16,17-decahydro-6Hcyclopenta[a]phenanthren-3-yl)acrylamide (2r): The title compound was prepared according to the general procedure and purified by column chromatography to give a yellow solid, 203.4 mg, 63% yield. 1H NMR (400 MHz, CDCl3) δ 0.92 (s, 3H), 1.43-1.67 (m, 6H), 1.96-2.18 (m, 4H), 2.31-2.32 (m, 1H), 2.42-2.55 (m, 2H), 2.92-2.95 (m, 2H), 5.65 (s, 1H), 5.72 (br, 1H), 6.15 (s, 2H), 7.14 (s, 1H), 7.18 (d, J = 8 Hz, 1H), 7.277.32 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 13.9, 21.7, 25.8, 26.5, 29.5, 31.7, 35.9, 38.2, 44.5, 48.1, 50.6, 122.7, 125.6, 125.8, 128.8, 134.7, 137.1, 140.5, 169.7, 220.9; HRMS (ESI) calcd. for C21H26NO2 [M+H]: 324.1964, found: 324.1956. (E)-2,3-diphenylacrylamide (2s): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 142.1 mg, 64% yield. 1H NMR (400 MHz, CDCl3) δ 5.49 (br, 1H), 6.42 (br, 1H), 7.0 (d, J = 7.2 Hz, 2H), 7.12-7.20 (m, 3H), 7.27-7.30 (m, 2H), 7.40-7.45 (m, 3H), 7.86 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 128.3, 128.6, 128.9, 129.7, 129.8, 130.6, 133.8, 134.8, 136.5, 138.1, 169.4; HRMS (ESI) calcd. for C15H14NO [M+H]: 224.1070, found: 224.1066. (E)-2,3-bis(4-methoxyphenyl)acrylamide (2t): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 209.0 mg, 74% yield. 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.87 (s, 3H), 5.48 (br, 1H), 5.99 (br, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.97-7.00 (m, 4H), 7.19 (d, J = 8.4 Hz, 2H), 7.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.2, 55.3, 113.7, 115.1, 127.5, 128.7, 130.9, 131.0, 132.1, 137.7, 159.6, 160.0, 169.9; HRMS (ESI) calcd. for C17H17NO3Na [M+Na]: 306.1101, found: 306.1089. (E)-2,3-bis(4-fluorophenyl)acrylamide (2u): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 160.6 mg, 62% yield. 1H NMR (400 MHz, CDCl3) δ 5.44 (br, 1H), 6.30 (br, 1H), 6.84-6.88 (m, 2H), 6.96-6.70 (m, 2H), 7.14-7.19 (m, 2H), 7.25-7.28 (m, 2H), 7.82 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 115.4, 115.6, 116.9, 117.1, 130.8, 130.8, 131.7, 131.7, 132.0, 132.1, 132.3, 132.4, 132.6, 137.4, 161.6, 161.6, 164.1, 169.3; 19F NMR (376 MHz, CDCl3) δ -112.1, 110.9; HRMS (ESI) calcd. for C15H11F2NONa [M+Na]: 282.0701, found: 282.0691. (E)-2-benzylidene-4-phenylbut-3-ynamide (5a): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 222.5 mg, 90% yield. 1H NMR (400 MHz, CDCl3) δ 6.18 (br, 1H), 6.77 (br, 1H), 7.39-7.46 (m, 6H), 7.53-7.55 (m, 2H), 8.03-8.06 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 85.5, 99.4, 113.6, 122.3, 128.7, 128.8, 129.4, 130.5, 130.6, 131.6, 134.7, 144.1, 166.2; HRMS (ESI) calcd. for C17H13NONa [M+Na]: 270.0889, found: 270.0888. (E)-2-(4-methylbenzylidene)-4-(p-tolyl)but-3-ynamide (5b): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 242.1 mg, 88% yield. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 6H), 6.26 (br, 1H), 6.77 (br, 1H), 7.19-7.25 (m, 4H), 7.41 (d, J = 8.4 Hz, 2H), 7.94-7.99 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 21.7, 21.7, 85.2, 99.6, 112.7, 119.4, 129.4,

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129.5 130.5, 131.4, 132.0, 139.6, 141.0, 143.6, 166.6; HRMS (ESI) calcd. for C19H18NO [M+H]: 276.1383, found: 276.1371. (E)-2-(3-methylbenzylidene)-4-(m-tolyl)but-3-ynamide (5c): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 253.2 mg, 92% yield. 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 2.38 (s, 3H), 6.79-6.81 (m, 2H), 7.19-7.35 (m, 6H), 7.81 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 8.00 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3, 21.5, 85.4, 99.6, 113.5, 122.2, 127.7, 128.5, 128.6, 130.1, 131.0, 131.3, 132.0, 134.6, 138.1, 138.5, 143.9, 166.6; HRMS (ESI) calcd. for C19H18NO [M+H]: 276.1383, found: 276.1371. (E)-2-(4-fluorobenzylidene)-4-(4-fluorophenyl)but-3ynamide (5d): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 240.3 mg, 85% yield. 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.42 (m, 4H), 7.60 (br, 1H), 7.69 (br, 1H), 7.79-7.82 (m, 2H), 7.88 (s, 1H), 8.15-8.18 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 85.2, 97.9, 115.0, 115.7, 115.9, 115.9, 116.1, 118.4, 118.4, 131.1, 131.1, 132.1, 132.1, 134.0, 134.1, 140.6, 161.1, 161.5, 163.6, 164.0, 164.7; 19F NMR (376 MHz, DMSO-d6) δ -109.7, -109.4; HRMS (ESI) calcd. for C17H12F2NO [M+H]: 284.0881, found: 284.0884. (E)-2-(3-fluorobenzylidene)-4-(3-fluorophenyl)but-3ynamide (5e): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 251.0 mg, 89% yield. 1H NMR (400 MHz, CDCl3) δ 6.24 (br, 1H), 6.70 (br, 1H), 7.10-7.16 (m, 2H), 7.22-7.23 (m, 1H), 7.24-7.43 (m, 3H), 7.64 (d, J = 7.6 Hz, 1H), 7.87-7.90 (m, 1H), 8.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 85.8, 98.7, 98.8, 114.6, 116.1, 116.3, 116.9, 117.1, 117.5, 117.7, 118.2, 118.5, 123.6, 123.7, 126.8, 126.8, 127.5, 127.5, 130.2, 130.3, 130.5, 130.6, 136.5, 136.6, 143.2, 143.3, 161.3, 161.5, 163.8, 164.0, 165.5; 19F NMR (376 MHz, CDCl3) δ 112.3, -111.8; HRMS (ESI) calcd. for C17H11F2NONa [M+Na]: 306.0701, found: 306.0691. (E)-2-(2-fluorobenzylidene)-4-(2-fluorophenyl)but-3ynamide (5f): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 209.2 mg, 74% yield. 1H NMR (400 MHz, CDCl3) δ 5.88 (br, 1H), 6.83 (br, 1H), 7.11-7.23 (m, 4H), 7.37-7.44 (m, 2H), 7.46-7.50 (m, 1H), 8.34 (s, 1H), 8.56-8.60 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 90.4, 93.3, 110.9, 114.8, 115.6, 115.7, 115.8, 115.9, 122.6, 122.7, 123.9, 124.0, 124.4, 124.4, 129.2, 131.1, 131.2, 132.2, 132.3, 132.8, 135.6, 135.6, 160.2, 161.7, 162.7, 164.2, 165.0; 19F NMR (376 MHz, CDCl3) δ -113.3, -109.6; HRMS (ESI) calcd. for C17H11F2NONa [M+Na]: 306.0701, found: 306.0689. Gram-scale reaction: In the glove box, a mixture of trimethylsilyl acetylene 1p (2.5 g, 25 mmol), NH4Cl (2 g, 37.5 mmol), Pd(PPh3)4 (14.5 mg, 0.0125 mmol, 0.05 mol%) with DPEPhos (8.0 mg, 0.015 mmol, 0.06 mol%), NMP (20 mL) were added to a 100 mL round bottom flask. The round bottom flask was put into an autoclave and then the autoclave was taken out from glove box. The autoclave was purged for three times and charged with CO (20 atm). The reaction mixture was stirred at 120 oC for 72 hours. After the reaction finished, the autoclave was cooled to room temperature and the pressure was carefully released in the fume hood. The regioselectivity were measured by GC and GC-MS, respectively. Then the corresponding reaction mixture was purified by flash column chromatography on silica gel and eluted with petroleum ether/ethyl acetate (20/1 -


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The Journal of Organic Chemistry 1/1) to give the desired products 3p (3.4 g, 95% yield, L:B = 99:1).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.xxxxxx. Experimental procedures, crystallographic details and copies of NMR and mass spectra (PDF) Crystallographic data for 2e (CCDC 1843492) (CIF) Crystallographic data for 2f (CCDC 1843493) (CIF) Crystallographic data for 3p (CCDC 1843495) (CIF) Crystallographic data for 5f (CCDC 1843497) (CIF)

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes X. Ji and B. Gao contribute equally to this work. The authors declare no competing financial interest.

ACKNOWLEDGMENT This research was supported by the National Natural Science Foundation of China (21790333, 21702197 and 21672199), CAS Interdisciplinary Innovation Team, the Fundamental Research Funds for the Central Universities and the Anhui Provincial Natural Science Foundation (1708085MB28).

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