Cu(II)-Mediated <i>β</i>-C—H Alkynylation of Acrylamides with Terminal Alkynes

Citation: Sun Shangzheng, Wang Xing, Cheng Taijin, Xu Hui, Dai Huixiong. Cu(II)-Mediated β-C—H Alkynylation of Acrylamides with Terminal Alkynes[J]. Chinese Journal of Organic Chemistry, 2020, 40(10): 3371-3379. doi: 10.6023/cjoc202005064 shu

铜参与的烯基酰胺β-碳氢键与端炔的炔基化反应

孙尚政 ^c, ,
王星 ^a,b, ,
程泰锦 ^a,b, ,
徐辉 ^a,b, ,
戴辉雄 ^{a,b,
,}

a.
中国科学院上海药物研究所上海 201203
b.
中国科学院大学北京 100049
c.
上海大学化学系上海大学创新药物研究中心上海 200444

通讯作者: 戴辉雄,

基金项目:
上海市科委 17JC1405000

国家自然科学基金 21772211

国家自然科学基金（No.21772211）、中国科学院青年创新促进会（Nos.2014229，2018293）、上海市科委（No.17JC1405000）资助项目

中国科学院青年创新促进会 2014229

中国科学院青年创新促进会 2018293

摘要: 基于噁唑啉酰胺导向基团实现了铜参与的烯基酰胺β-碳氢键与端炔的炔基化反应，构建了一系列1，3-共轭烯炔化合物.该反应条件温和，底物适用范围广，具有良好的区域及立体选择性.

关键词:

English

Cu(II)-Mediated β-C—H Alkynylation of Acrylamides with Terminal Alkynes

a.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
b.
University of Chinese Academy of Sciences, Beijing 100049
c.
Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444

Corresponding author: Dai Huixiong,

Received Date: 23 May 2020
Revised Date: 20 June 2020
Available Online: 25 October 2020
Fund Project:
the Science and Technology Commission of Shanghai Municipality 17JC1405000

the National Natural Science Foundation of China 21772211

Project supported by the National Natural Science Foundation of China (No. 21772211), the Youth Innovation Promotion Association CAS (Nos. 2014229, 2018293), and the Science and Technology Commission of Shanghai Municipality (No. 17JC1405000)

the Youth Innovation Promotion Association CAS 2014229

the Youth Innovation Promotion Association CAS 2018293

Abstract: Cu(Ⅱ)-mediated β-C-H alkynylation of acrylamides with terminal alkynes is described by employing amide-oxazoline bidentate auxiliary, forming the conjugated 1, 3-enynes. This protocol is characterized by its mild conditions, broad substarate scope and excellent regio- and stereo-selectivity.

Key words:

1. Introduction

1, 3-Enynes are important structural motifs and prevalent in nature product, pharmaceuticals and functional materials.^[1] For example, histrionicotoxin is toxins isolated from the poison-arrow frog Dendrobates histrionicus, ^[2] while terfinafine^[3] and oxamflatin^[4] are important pharmaceutically molecules (Scheme 1). 1, 3-Enynes are not only present in a range of compounds with functional significance, but also been employed as versatile building block in organic synthesis.^[5] Thus the development of an efficient and practical synthetic methodologies for the construction of 1, 3-enynes has been an important objective.

Scheme 1

Scheme 1. 1, 3-Enynes containing drug molecules

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In the past few decades, the transition-metal-catalyzed cross-coupling reactions were well documented for the preparation of 1, 3-enyne moieties.^[6] Particularly, the Pd and Cu co-catalyzed Sonogashira coupling of vinyl halides with terminal alkynes has been extensively studied and practiced in both academic and industrial settings (Scheme 2a).^[7] Recently, with the rapid development of transition-metal-catalyzed C—H functionalization, direct C—H alkynylation with alkyne reagents has received more and more attentions (Scheme 2b).^[8] Despite the elegant advances, noble metal catalysts (Pd, Rh, Ir), preactivated vinyl halides or alkynylating reagents such as hypervalent iodine reagents are often required in the reaction.^[9] Direct cross dehydrogenlative alkynylation of simple alkenes with alkynes could avoid prefunctionalization, thus enabling construction of 1, 3-enyne skeletons rapidly. To the best of our knowledge, this catalytic oxidative C—H/C—H coupling of alkenes with alkynes has been rarely reported in contrast with the alkynylation of arenes.^[10-11] In 2019, with the assistance of 8-aminoquinoline (AQ) directing group, You et al. ^[11a] reported Co(III)-catalyzed oxidative C—H/ C—H cross-coupling reaction of acrylamides with triisopropylsilylacetylene (Scheme 2c).

Scheme 2

Scheme 2. Construction of conjugated enynes via C—H alkynylation

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Based on our previous work on Cu-catalyzed C—H functionalization, ^[12-13] we questioned whether we could regio- and stereo-selectively construct 1, 3-enyne compounds via Cu-catalyzed or mediated olefinic C—H alkynylation with readily accessible terminal alkynes. Herein, we described a Cu(II)-mediated β-selective C—H alkynylation of acrylamides with terminal alkynes by employing amide-oxazoline bidentate auxiliary (Scheme 2d). Our protocol is characterized by its mild conditions, good functional group tolerance and regio- and stereo-selectivi- ty, thus enabling to access a variety of densely functionalized cis-enynes.

2. Results and discussion

Promoted by our previous work on Cu-mediated ortho C—H alkynylation of arenes, ^[14] our investigations were commenced by using acrylamide 1a with p-tolylacetylene (2a) as the starting material. By employing amide-oxazo- line as directing group, direct β-C—H alkynylation of acrylamide 1a with 2a (3 equiv.) could proceed in the presence of 1 equiv. of Cu(OAc)₂, providing cis-enyne 3a in 28% yield (Table 1, Entry 1). Homo-coupling product 1, 3-diynes were determined as the major byproduct. Next, the influence of bases was screened, and it was found that NaOAc provided the best result (Table 1, Entries 1~5). The yield could be improved to 39% when the reaction temperature was elevated to 80 ℃ (Table 1, Entries 6, 7). When the amount of NaOAc was increased to 3 equiv., 56% yield of desired product was obtained (Table 1, Entry 8). Increasing the reaction time did not improve the yields (Table 1, Entries 8~10). It is worth noting that no desired product was observed in the absence of copper, indicating that the copper is indispensable in the reaction (Table 1, Entry 11). Decreasing the loading of Cu(OAc)₂ to 20 mol% lead to the decreased yields (Table 1, Entry 12). For further investigation on the effect of the directing group, a variety of sterically diverse oxazoline groups were screened and it was found that oxazoline (Oxa) was the optimal choice (see the Supporting Information).

Table 1

Table 1. Screening of the reaction conditions^a

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Entry	Base	T/℃	Time/h	Yield/%
1	NaOAc	60	6	28
2	LiOAc	60	6	24
3	KOAc	60	6	25
4	Na₂CO₃	60	6	20
5	k₂co₃	60	6	17
6	NaOAc	80	6	39
7	NaOAc	100	6	30
8^c	NaOAc	80	6	56
9^c	NaOAc	80	4	51
10^c	NaOAc	80	9	56
11^{c, d}	NaOAc	80	6	0
12^{c, e}	NaOAc	80	6	16
^a Reaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.3 mmol, 3.0 equiv.), Cu(OAc)₂ (0.1 mmol, 1.0 equiv.), base (0.2 mmol, 1.0 equiv.), DMSO (5.0 mL), air. ^b Yield was determined by ¹H NMR analysis of crude reaction mixture using CH₂Br₂ as an internal standard. ^c NaOAc (0.3 mmol). ^d No Cu(OAc)₂. ^e20 mol% Cu(OAc)₂.

With the optimized reaction conditions in hand, we turned our attention to explore the generality of terminal alkynes. As shown in Table 3, a variety of functionalized aryl acetylenes with both electron-rich (3a~3d) and electron-deficient substituents (3e~3j) were tolerated. Notably, the halogen-containing substrates (3e~3i) were well tolerant, leaving a handle for further functionalization via metal-catalyzed cross-coupling reactions. Alkyne bearing heterocycle (2k) was also compatible, providing the product 3k in 40% yield. Aliphatic alkynes were well employed in the reaction, furnishing the desired cis-1, 3-enynes product in moderate yields (3l~3n). Next, we screened various substituents at both α- and β-position of acrylamides. To our delight, cis-1, 3-enyne products could be obtained in moderate to good yield, regardless of the aliphatic (3o, 3q, 3r) or aryl (3p, 3s~3v) groups. Noteworthy, cyclic acrylamides (3w, 3x) could proceed smoothly, giving the tetrasubstituted cis-1, 3-enyne products in moderate yields.

Table 2

Table 2. Substrate scope for the reaction^a

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^aReaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2 (0.3 mmol, 3.0 equiv.), Cu(OAc)₂ (0.1mmol, 1.0 equiv.), NaOAc (0.3 mmol, 3.0 equiv.), DMSO (5.0 mL), air, at 80 ℃ for 6 h.

To probe the reaction mechanism, 2 equiv. of radical scavengers 2, 2, 6, 6-tetramethylpiperidine-N-oxyl (TE-MPO) were added in the reaction. 52% yield of product 3a was obtaine, indicating that a radical pathway might not involve in the reaction (Scheme 3).

Scheme 3

Scheme 3. The effect of TEMPO

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Based on the control experiment and previous reports, ^[15] we proposed a possible mechanism on copper(II)-mediated C—H alkynylation of acrylamides (Scheme 4). Oxazo line-directed C—H activation of 1a with Cu(OAc)₂ formed the Cu(II) intermediate A, which then underwent disproportionation of copper(II) with Cu(OAc)₂ yielded Cu(III) complex B. Transmetallation of terminal alkyne with complex B formed the intermediate C, which subsequently underwent reductive elimination to release the cis-1, 3-enynesproduct 3a and Cu(I) species.

Scheme 4

Scheme 4. Plausible pathway

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3. Conclusions

In conclusion, we have documented a Cu(II)-mediated β-selective C—H alkynylation of acrylamides by employing amide-oxazoline as the directing group. Stereospecific cis-1, 3-enynes products were obtained in moderate to good yield. The reaction condition is mild, and a variety of (hetero)aryl and alkyl group at both α- and β-position of acrylamides could be well tolerated.

4. Experimental section

4.1 General procedure for the synthesis of 1

To a stirred solution of Et₃N (7.5 mmol) and 2-(4, 5-di- hydrooxazol-2-yl)aniline (5 mmol) in CH₂Cl₂ (15 mL) was added acyl chloride (5 mmol) dropwise at 0 ℃. Then the reaction mixture was stirred at room temperature for 6 h. Upon completion, EtOAc was added to dilute the mixture and washed with saturated NaHCO₃ (aq.). The organic fraction was dried over anhydrous Na₂SO₄. Then, the solvent was evaporated, and the crude product was purified by flash column chromatography with petroleum ether/ethyl acetate as the eluent.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)acrylamide (1a): White solid, m.p. 97~98 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.46 (s, 1H), 8.83 (d, J＝8.4 Hz, 1H), 7.86 (dd, J＝8.0, 1.6 Hz, 1H), 7.47 (t, J＝7.1 Hz, 1H), 7.08 (t, J＝7.6 Hz, 1H), 6.42 (dd, J＝17.1, 1.2 Hz, 1H), 6.31 (dd, J＝17.1, 10.2 Hz, 1H), 5.75 (dd, J＝10.2, 1.2 Hz, 1H), 4.38 (t, J＝9.5 Hz, 2H), 4.14 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.75, 164.38, 139.86, 132.80, 132.53, 129.17, 126.64, 122.40, 119.82, 113.26, 66.16, 54.65; HRMS (ESI-TOF) calcd for C₁₂H₁₃N₂O₂ [M+H]⁺ 217.0972, found 217.0974.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)methacrylamide (1b): White solid, m.p. 72~73 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.52 (s, 1H), 8.84 (dd, J＝8.5, 1.1 Hz, 1H), 7.86 (dd, J＝7.8, 1.6 Hz, 1H), 7.47 (ddd, J＝8.8, 7.4, 1.7 Hz, 1H), 7.07 (td, J＝7.6, 1.1 Hz, 1H), 6.01 (s, 1H), 5.50 (s, 1H), 4.37 (t, J＝9.5 Hz, 2H), 4.13 (t, J＝9.4 Hz, 2H), 2.10 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 168.16, 165.72, 142.07, 141.00, 133.49, 130.17, 123.20, 121.86, 120.73, 114.40, 67.15, 55.63, 19.75; HRMS (ESI-TOF) calcd for C₁₃H₁₅N₂O₂ [M+H]⁺ 231.1128, found 231.1131.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-2-phenylacrylamide (1c): White solid, m.p. 95~97 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.37 (s, 1H), 8.94 (d, J＝8.4 Hz, 1H), 7.81 (d, J＝7.2 Hz, 1H), 7.54~7.42 (m, 3H), 7.41~7.37 (m, 3H), 7.08 (t, J＝7.6 Hz, 1H), 6.29 (d, J＝1.1 Hz, 1H), 5.73 (d, J＝1.1 Hz, 1H), 4.22 (t, J＝9.5 Hz, 2H), 3.67 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 166.61, 164.04, 146.42, 139.83, 137.13, 132.36, 128.99, 128.82, 128.16, 128.13, 122.67, 122.44, 119.80, 113.55, 66.05, 54.26; HRMS (ESI-TOF) calcd for C₁₈H₁₇N₂O₂ [M+H]⁺ 293.1285, found 293.1284.

2-Benzyl-N-(2-(4, 5-dihydrooxazol-2-yl)phenyl)acrylamide (1d): White solid, m.p. 83~85 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.63 (s, 1H), 8.84 (d, J＝8.5 Hz, 1H), 7.86 (dd, J＝8.0, 1.6 Hz, 1H), 7.46 (t, J＝7.9 Hz, 1H), 7.35~7.25 (m, 4H), 7.22 (t, J＝7.0 Hz, 1H), 7.07 (t, J＝7.7 Hz, 1H), 6.10 (s, 1H), 5.39 (s, 1H), 4.36 (t, J＝9.5 Hz, 2H), 4.11 (t, J＝9.5 Hz, 2H), 3.81 (s, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 166.78, 164.68, 145.35, 139.92, 138.88, 132.46, 129.15, 129.10, 128.37, 126.21, 122.20, 121.02, 119.69, 113.33, 66.11, 54.60, 38.11; HRMS (ESI-TOF) calcd for C₁₉H₁₉N₂O₂ [M+H]⁺ 307.1441, found 307.1446.

(E)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)but-2-enamide (1e): White solid, m.p. 122~124 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.25 (s, 1H), 8.82 (dd, J＝8.5, 1.1 Hz, 1H), 7.84 (dd, J＝7.9, 1.7 Hz, 1H), 7.45 (ddd, J＝8.7, 7.3, 1.7 Hz, 1H), 7.05 (td, J＝7.6, 1.2 Hz, 1H), 7.01~6.94 (m, 1H), 6.02 (dd, J＝15.2, 1.7 Hz, 1H), 4.39 (t, J＝9.3 Hz, 2H), 4.14 (t, J＝9.3 Hz, 2H), 1.92 (dd, J＝6.9, 1.7 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.74, 164.69, 140.10, 132.44, 129.11, 126.90, 122.05, 119.74, 113.06, 66.08, 54.68, 17.81; HRMS (ESI-TOF) calcd for C₁₃H₁₅N₂O₂ [M+H]⁺ 231.1128, found 231.1128.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)cinnamamide (1f): White solid, m.p. 146~149 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.51 (s, 1H), 8.90 (dd, J＝8.4, 1.1 Hz, 1H), 7.87 (dd, J＝8.0, 1.5 Hz, 1H), 7.76 (d, J＝15.6 Hz, 1H), 7.58 (d, J＝6.1 Hz, 2H), 7.49 (t, J＝7.1 Hz, 1H), 7.38 (q, J＝8.4, 7.4 Hz, 3H), 7.08 (t, J＝7.6 Hz, 1H), 6.60 (d, J＝15.6 Hz, 1H), 4.38 (t, J＝9.5 Hz, 2H), 4.18 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.73, 164.67, 141.44, 140.06, 134.86, 132.47, 129.70, 129.17, 128.74, 127.91, 122.50, 122.25, 119.80, 113.12, 66.10, 54.70; HRMS (ESI-TOF) calcd for C₁₈H₁₇N₂O₂ [M+H]⁺ 293.1285, found 293.1286.

(E)-3-(4-Chlorophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)acrylamide (1g): White solid, m.p. 161~164 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.51 (s, 1H), 8.88 (dd, J＝8.4, 1.1 Hz, 1H), 7.87 (dd, J＝7.9, 1.6 Hz, 1H), 7.69 (d, J＝15.6 Hz, 1H), 7.49 (t, J＝9.3 Hz, 3H), 7.35 (d, J＝8.5 Hz, 2H), 7.09 (td, J＝7.6, 1.2 Hz, 1H), 6.56 (d, J＝15.6 Hz, 1H), 4.40 (t, J＝9.8 Hz, 2H), 4.19 (t, J＝9.2 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.80, 164.36, 140.12, 139.98, 135.54, 133.38, 132.57, 129.21, 129.13, 129.02, 123.00, 122.42, 119.87, 113.17, 66.16, 54.74; HRMS (ESI-TOF) calcd for C₁₈H₁₆ClN₂O₂ [M+H]⁺ 327.0895, found 327.0899.

(E)-3-(3-Bromophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)acrylamide (1h): White solid, m.p. 143~145 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.54 (s, 1H), 8.87 (dd, J＝8.5, 1.1 Hz, 1H), 7.88 (dd, J＝7.9, 1.7 Hz, 1H), 7.73 (t, J＝1.8 Hz, 1H), 7.66 (d, J＝15.6 Hz, 1H), 7.53~7.45 (m, 3H), 7.26 (t, J＝7.9 Hz, 1H), 7.10 (td, J＝7.6, 1.2 Hz, 1H), 6.58 (d, J＝15.6 Hz, 1H), 4.41 (t, J＝9.8 Hz, 2H), 4.22 (t, J＝9.8 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.79, 164.13, 139.92, 139.89, 137.04, 132.57, 132.50, 130.37, 130.30, 129.23, 126.84, 123.87, 122.90, 122.50, 119.91, 113.24, 66.19, 54.78; HRMS (ESI-TOF) calcd for C₁₈H₁₆BrN₂O₂ [M+H]⁺ 371.0390, found 371.0394.

(E)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-3-(thiophen-2-yl)acrylamide (1i): White solid, m.p. 114~116 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.44 (s, 1H), 8.87 (dd, J＝8.4, 1.2 Hz, 1H), 7.88 (dd, J＝7.9, 1.7 Hz, 1H), 7.87 (d, J＝15.3 Hz, 1H), 7.49 (ddd, J＝8.7, 7.3, 1.7 Hz, 1H), 7.35 (d, J＝5.0 Hz, 1H), 7.28 (d, J＝3.7 Hz, 1H), 7.09 (td, J＝7.7, 1.2 Hz, 1H), 7.06 (dd, J＝5.1, 3.6 Hz, 1H), 6.41 (d, J＝15.3 Hz, 1H), 4.40 (t, J＝9.2 Hz, 2H), 4.21 (t, J＝9.2 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.76, 164.47, 140.07, 140.04, 134.18, 132.54, 130.35, 129.19, 128.00, 127.54, 122.30, 121.32, 119.89, 113.14, 66.17, 54.76; HRMS (ESI-TOF) calcd for C₁₆H₁₅N₂O₂S [M+H]⁺ 299.0849, found 299.0853.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)cyclopent-1-ene-1-carboxamide (1j): White solid, m.p. 127~129 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.38 (s, 1H), 8.85 (dd, J＝8.4, 1.1 Hz, 1H), 7.85 (dt, J＝7.9, 1.8 Hz, 1H), 7.46 (td, J＝8.6, 7.9, 1.6 Hz, 1H), 7.05 (td, J＝7.6, 1.3 Hz, 1H), 6.77 (tt, J＝2.7, 1.6 Hz, 1H), 4.38 (td, J＝9.4, 2.1 Hz, 2H), 4.15 (td, J＝9.2, 2.2 Hz, 2H), 2.75~2.70 (m, 2H), 2.58~2.53 (m, 2H), 2.06~2.00 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.73, 164.45, 141.08, 140.15, 139.27, 132.50, 129.14, 121.97, 119.67, 113.09, 66.12, 54.66, 33.40, 31.44, 23.33; HRMS (ESI-TOF) calcd for C₁₅H₁₇N₂O₂ [M+H]⁺ 257.1285, found 257.1285.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)cyclohex-1-ene-1-carboxamide (1k): White solid, m.p. 126~128 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.28 (s, 1H), 8.85 (d, J＝8.5 Hz, 1H), 7.85 (dd, J＝7.9, 1.6 Hz, 1H), 7.45 (t, J＝7.9 Hz, 1H), 7.04 (t, J＝7.6 Hz, 1H), 6.90 (tt, J＝3.8, 1.7 Hz, 1H), 4.36 (t, J＝9.5 Hz, 2H), 4.13 (t, J＝9.5 Hz, 2H), 2.44~2.40 (m, 2H), 2.26~2.22 (m, 2H), 1.76~1.70 (m, 2H), 1.68~1.61 (m, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 167.54, 164.70, 140.29, 135.04, 134.47, 132.42, 129.12, 121.85, 119.85, 113.29, 66.09, 54.67, 25.76, 24.28, 22.30, 21.58; HRMS (ESI-TOF) calcd for C₁₆H₁₉N₂O₂ [M+H]⁺ 271.1441, found 271.1445.

4.2 General procedure for the synthesis of 3

To a 15 mL sealed tube was added acrylamides 1 (0.1 mmol, 1.0 equiv.), Cu(OAc)₂ (0.1 mmol, 18.1 mg, 1.0 equiv.), NaOAc (0.3 mmol, 24.6 mg, 3.0 equiv.), DMSO (5 mL), and alkynes 2 (0.3 mmol, 3.0 equiv.). The reaction vessel was placed into a pre-heated oil bath at 80 ℃ for 6 h. Upon completion, EtOAc was added to dilute the mixture, then washed with NH₃•H₂O and saturated aq. NaCl. The organic fraction was dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure. The residue was purified through silica gel packed flash chromatography column using ethyl acetate/hexane as the eluent.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(p-tolyl)-pent-2-en-4-ynamide (3a): 17.4 mg, 53% yield. White solid, m.p. 68~70 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.56 (s, 1H), 8.90 (dd, J＝8.5, 1.1 Hz, 1H), 7.86 (dd, J＝7.9, 1.7 Hz, 1H), 7.48 (ddd, J＝8.8, 7.4, 1.7 Hz, 1H), 7.36 (d, J＝8.1 Hz, 2H), 7.14~7.06 (m, 3H), 6.28 (s, 2H), 4.23 (t, J＝9.5 Hz, 2H), 4.00 (t, J＝9.5 Hz, 2H), 2.34 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.36, 163.33, 139.70, 139.23, 132.76, 132.43, 131.89, 129.10, 129.03, 122.43, 120.07, 119.75, 118.83, 113.35, 100.41, 86.09, 66.09, 54.61, 21.52; HRMS (ESI-TOF) calcd for C₂₁H₁₉N₂O₂ [M+H]⁺ 331.1441, found 331.1441.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-phenylpent-2-en-4-ynamide (3b): 12.9 mg, 41% yield. White solid, m.p. 116~118 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.57 (s, 1H), 8.90 (dd, J＝8.5, 1.1 Hz, 1H), 7.86 (dd, J＝7.9, 1.6 Hz, 1H), 7.52~7.44 (m, 3H), 7.35~7.26 (m, 3H), 7.10 (td, J＝7.6, 1.2 Hz, 1H), 6.32 (d, J＝11.5 Hz, 1H), 6.28 (d, J＝11.5 Hz, 1H), 4.24 (t, J＝9.5 Hz, 2H), 4.02 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.44, 163.26, 139.70, 133.29, 132.49, 131.96, 129.14, 128.92, 128.27, 122.85, 122.51, 120.12, 118.68, 113.38, 99.99, 86.55, 66.12, 54.63; HRMS (ESI-TOF) calcd for C₂₀H₁₇N₂O₂ [M+H]⁺ 317.1285, found 317.1286.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(4-methoxy-phenyl)pent-2-en-4-ynamide (3c): 17.0 mg, 49% yield. White solid, m.p. 95~97 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.54 (s, 1H), 8.90 (d, J＝8.7 Hz, 1H), 7.85 (dd, J＝8.0, 1.6 Hz, 1H), 7.48 (t, J＝7.2 Hz, 1H), 7.41 (d, J＝8.7 Hz, 2H), 7.08 (t, J＝7.4 Hz, 1H), 6.82 (d, J＝8.6 Hz, 2H), 6.28 (d, J＝11.5 Hz, 1H), 6.24 (d, J＝11.5 Hz, 1H), 4.23 (t, J＝9.5 Hz, 2H), 4.00 (t, J＝9.5 Hz, 2H), 3.79 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.34, 163.39, 160.19, 139.73, 133.59, 132.40, 132.14, 129.10, 122.38, 120.04, 119.03, 114.90, 113.92, 113.31, 100.54, 85.81, 66.09, 55.23, 54.60; HRMS (ESI-TOF) calcd for C₂₁H₁₉N₂O₃ [M+H]⁺ 347.1390, found 347.1391.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(4-(dimeth-ylamino)phenyl)pent-2-en-4-ynamide (3d): 23.4 mg, 65% yield. Yellow solid, m.p. 132~135 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.51 (s, 1H), 8.90 (d, J＝8.5 Hz, 1H), 7.86 (dd, J＝7.9, 1.6 Hz, 1H), 7.48 (t, J＝7.7 Hz, 1H), 7.33 (d, J＝8.7 Hz, 2H), 7.08 (t, J＝7.6 Hz, 1H), 6.59 (d, J＝8.8 Hz, 2H), 6.29 (d, J＝11.5 Hz, 1H), 6.17 (d, J＝11.5 Hz, 1H), 4.22 (t, J＝9.5 Hz, 2H), 3.99 (t, J＝9.5 Hz, 2H), 2.97 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.26, 163.80, 150.55, 139.88, 133.43, 132.36, 130.70, 129.09, 122.24, 120.16, 119.26, 113.38, 111.54, 109.36, 102.58, 85.76, 66.13, 54.66, 40.03; HRMS (ESI-TOF) calcd for C₂₂H₂₂- N₃O₂ [M+H]⁺ 360.1707, found 360.1701.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(2-fluoroph-enyl)pent-2-en-4-ynamide (3e): 13.0 mg, 39% yield. White solid, m.p. 114~116 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.57 (s, 1H), 8.89 (dd, J＝8.4, 1.1 Hz, 1H), 7.86 (dd, J＝7.9, 1.6 Hz, 1H), 7.52~7.44 (m, 2H), 7.33~7.29 (m, 1H), 7.13~7.02 (m, 3H), 6.35 (d, J＝11.5 Hz, 1H), 6.32 (d, J＝11.5 Hz, 1H), 4.28 (t, J＝9.5 Hz, 2H), 4.05 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.51, 163.01, 162.68 (d, J＝252.8 Hz), 139.68, 133.95, 133.80, 132.48, 130.74, 130.68, 129.11, 123.95 (d, J＝3.8 Hz), 122.54, 120.12, 115.47 (d, J＝20.9 Hz), 113.39, 111.59 (d, J＝15.5 Hz), 93.09, 91.25 (d, J＝3.4 Hz), 66.14, 54.63; ¹⁹F NMR (471 MHz, CDCl₃) δ: －108.99 (m); HRMS (ESI-TOF) calcd for C₂₀H₁₆FN₂O₂ [M+H]⁺ 335.1190, found 335.1192.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(4-fluoroph-enyl)pent-2-en-4-ynamide (3f): 20.0 mg, 60% yield. White solid, m.p. 142~145 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.54 (s, 1H), 8.89 (d, J＝8.4 Hz, 1H), 7.86 (dd, J＝8.0, 1.7 Hz, 1H), 7.48 (dt, J＝8.7, 6.3 Hz, 3H), 7.10 (td, J＝7.7, 1.1 Hz, 1H), 7.01 (t, J＝8.7 Hz, 2H), 6.31 (d, J＝11.5 Hz, 1H), 6.26 (d, J＝11.5 Hz, 1H), 4.29 (t, J＝9.5 Hz, 2H), 4.04 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.52, 163.12, 162.90 (d, J＝250.2 Hz), 139.70, 133.99 (d, J＝8.6 Hz), 133.18, 132.52, 129.16, 122.55, 120.07, 119.02 (d, J＝3.0 Hz), 118.83, 115.63 (d, J＝22.0 Hz), 113.32, 98.97, 86.45 (d, J＝1.3 Hz), 66.14, 54.63; ¹⁹F NMR (471 MHz, CDCl₃) δ: －109.63 (t, J＝7.1 Hz); HRMS (ESI-TOF) calcd for C₂₀H₁₆FN₂O₂ [M+H]⁺ 335.1190, found 335.1192.

(Z)-5-(2-Chlorophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)pent-2-en-4-ynamide (3g): 16.1 mg, 46% yield. White solid, m.p. 92~94 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.57 (s, 1H), 8.88 (dd, J＝8.5, 1.1 Hz, 1H), 7.85 (dd, J＝7.9, 1.6 Hz, 1H), 7.52 (dd, J＝7.6, 1.8 Hz, 1H), 7.48 (ddd, J＝8.7, 7.4, 1.7 Hz, 1H), 7.38 (dd, J＝7.9, 1.3 Hz, 1H), 7.25 (td, J＝7.7, 1.8 Hz, 1H), 7.20 (td, J＝7.5, 1.3 Hz, 1H), 7.10 (td, J＝7.6, 1.2 Hz, 1H), 6.37 (d, J＝11.5 Hz, 1H), 6.34 (d, J＝11.5 Hz, 1H), 4.26 (t, J＝9.4 Hz, 2H), 4.04 (t, J＝9.4 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.48, 163.07, 139.68, 136.04, 134.02, 133.98, 132.47, 129.88, 129.23, 129.11, 126.40, 122.90, 122.56, 120.11, 118.27, 113.45, 96.23, 91.14, 66.14, 54.64; HRMS (ESI-TOF) calcd for C₂₀H₁₆ClN₂O₂ [M+H]⁺ 351.0895, found 351.0896.

(Z)-5-(4-Chlorophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)pent-2-en-4-ynamide (3h): 12.6 mg, 36% yield. White solid, m.p. 129~132 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.56 (s, 1H), 8.88 (dd, J＝8.5, 1.1 Hz, 1H), 7.86 (dd, J＝7.9, 1.7 Hz, 1H), 7.48 (ddd, J＝8.7, 7.4, 1.7 Hz, 1H), 7.43~7.40 (m, 2H), 7.31~7.27 (m, 2H), 7.10 (td, J＝7.6, 1.1 Hz, 1H), 6.33 (d, J＝11.5 Hz, 1H), 6.27 (d, J＝11.5 Hz, 1H), 4.29 (t, J＝9.5 Hz, 2H), 4.04 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.50, 163.02, 139.63, 135.00, 133.49, 133.17, 132.52, 129.16, 128.64, 122.58, 121.35, 120.03, 118.70, 113.29, 98.74, 87.53, 66.14, 54.61; HRMS (ESI-TOF) calcd for C₂₀H₁₆ClN₂O₂ [M+H]⁺ 351.0895, found 351.0894.

(Z)-5-(4-Chlorophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)pent-2-en-4-ynamide (3i): 11.9 mg, 30% yield. White solid, m.p. 103~105 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.55 (s, 1H), 8.88 (d, J＝8.4 Hz, 1H), 7.87 (dd, J＝7.9, 1.5 Hz, 1H), 7.49 (t, J＝8.0 Hz, 1H), 7.45 (d, J＝8.4 Hz, 2H), 7.34 (d, J＝8.4 Hz, 2H), 7.10 (t, J＝7.6 Hz, 1H), 6.34 (d, J＝11.5 Hz, 1H), 6.26 (d, J＝11.5 Hz, 1H), 4.30 (t, J＝9.5 Hz, 2H), 4.05 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.55, 163.05, 139.67, 133.59, 133.37, 132.55, 131.59, 129.18, 123.33, 122.61, 121.86, 120.09, 118.66, 113.34, 98.78, 87.69, 66.16, 54.64; HRMS (ESI-TOF) calcd for C₂₀H₁₆BrN₂O₂ [M+H]⁺ 395.0390, found 395.0386.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(4-(trifluo-romethyl)phenyl)pent-2-en-4-ynamide (3j): 14.6 mg, 38% yield. White solid, m.p. 113~115 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.58 (s, 1H), 8.88 (d, J＝8.4 Hz, 1H), 7.87 (d, J＝7.8 Hz, 1H), 7.60 (d, J＝8.4 Hz, 2H), 7.57 (d, J＝8.4 Hz, 2H), 7.49 (t, J＝7.9 Hz, 1H), 7.11 (t, J＝7.6 Hz, 1H), 6.38 (d, J＝11.4 Hz, 1H), 6.29 (d, J＝11.4 Hz, 1H), 4.31 (t, J＝9.5 Hz, 2H), 4.06 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.61, 162.85, 139.63, 134.34, 132.58, 132.16, 130.45 (q, J＝32.6 Hz), 129.21, 126.70, 125.19 (q, J＝3.8 Hz), 123.84 (q, J＝272.5 Hz), 122.69, 120.07, 118.44, 113.34, 98.08, 88.66, 66.17, 54.64; ¹⁹F NMR (471 MHz, CDCl₃) δ: －82.86; HRMS (ESI-TOF) calcd for C₂₁H₁₆F₃N₂O₂ [M+H]⁺ 385.1158, found 385.1152.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-5-(thiophen- 3-yl)pent-2-en-4-ynamide (3k): 12.9 mg, 40% yield. White solid, m.p. 101~103 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.55 (s, 1H), 8.88 (dd, J＝8.4, 1.2 Hz, 1H), 7.86 (dd, J＝7.8, 1.7 Hz, 1H), 7.52 (dd, J＝3.0, 1.1 Hz, 1H), 7.48 (ddd, J＝8.7, 7.4, 1.7 Hz, 1H), 7.27~7.24 (m, 1H), 7.13 (dd, J＝5.0, 1.1 Hz, 1H), 7.10 (td, J＝7.6, 1.1 Hz, 1H), 6.30 (d, J＝11.5 Hz, 1H), 6.26 (d, J＝11.5 Hz, 1H), 4.28 (t, J＝9.5 Hz, 2H), 4.03 (t, J＝9.5 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.43, 163.25, 139.70, 132.92, 132.49, 130.08, 129.90, 129.14, 125.34, 122.52, 122.04, 120.10, 118.79, 113.34, 95.30, 86.33, 66.16, 54.65; HRMS (ESI-TOF) calcd for C₁₈H₁₅N₂O₂S [M+H]⁺ 323.0849, found 323.0851.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)dec-2-en-4-ynamide (3l): 13.0 mg, 42% yield. White solid, m.p. 45~46 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.36 (s, 1H), 8.84 (dd, J＝8.4, 1.1 Hz, 1H), 7.85 (dd, J＝7.9, 1.6 Hz, 1H), 7.45 (ddd, J＝8.6, 7.3, 1.6 Hz, 1H), 7.07 (td, J＝7.6, 1.2 Hz, 1H), 6.19 (d, J＝11.4 Hz, 1H), 6.08 (dt, J＝11.4, 2.5 Hz, 1H), 4.37 (t, J＝9.5 Hz, 2H), 4.13 (t, J＝9.5 Hz, 2H), 2.42 (td, J＝7.2, 2.4 Hz, 2H), 1.58~1.53 (m, 2H), 1.39~1.35 (m, 3H), 1.32~1.24 (m, 3H), 0.86 (t, J＝7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.55, 163.31, 139.79, 132.43, 132.01, 129.09, 122.36, 120.35, 120.15, 113.30, 102.98, 77.78, 66.13, 54.73, 31.12, 28.16, 22.18, 20.14, 13.87; HRMS (ESI-TOF) calcd for C₁₉H₂₃N₂O₂ [M+H]⁺ 311.1754, found 311.1755.

(Z)-5-Cyclohexyl-N-(2-(4, 5-dihydrooxazol-2-yl)phenyl)- pent-2-en-4-ynamide (3m): 17.0 mg, 53% yield. White solid, m.p. 85~87 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.32 (s, 1H), 8.83 (dd, J＝8.5, 1.1 Hz, 1H), 7.84 (dd, J＝7.9, 1.6 Hz, 1H), 7.45 (ddd, J＝8.7, 7.4, 1.7 Hz, 1H), 7.07 (td, J＝7.7, 1.2 Hz, 1H), 6.18 (d, J＝11.5 Hz, 1H), 6.09 (dd, J＝11.5, 2.3 Hz, 1H), 4.36 (t, J＝9.5 Hz, 2H), 4.12 (t, J＝9.5 Hz, 2H), 2.60 (tq, J＝9.1, 3.2 Hz, 1H), 1.87~1.79 (m, 2H), 1.74~1.67 (m, 2H), 1.54~1.43 (m, 3H), 1.33~1.25 (m, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.52, 163.37, 139.78, 132.41, 132.02, 129.07, 122.31, 120.23, 120.14, 113.27, 106.50, 77.70, 66.12, 54.73, 32.25, 30.26, 25.82, 24.82; HRMS (ESI-TOF) calcd for C₂₀H₂₃FN₂O₂ [M+H]⁺ 323.1754, found 323.1755.

(Z)-5-Cyclopropyl-N-(2-(4, 5-dihydrooxazol-2-yl)phenyl)pent-2-en-4-ynamide (3n): 14.0 mg, 50% yield. White solid, m.p. 85~87 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.34 (s, 1H), 8.85 (dd, J＝8.5, 1.1 Hz, 1H), 7.85 (dd, J＝8.0, 1.6 Hz, 1H), 7.46 (ddd, J＝8.7, 7.4, 1.7 Hz, 1H), 7.07 (td, J＝7.6, 1.1 Hz, 1H), 6.16 (d, J＝11.4 Hz, 1H), 6.03 (dd, J＝11.4, 2.5 Hz, 1H), 4.37 (t, J＝9.5 Hz, 2H), 4.13 (t, J＝9.5 Hz, 2H), 1.49 (ttd, J＝7.8, 5.0, 2.4 Hz, 1H), 0.87 (ddt, J＝8.2, 5.8, 3.0 Hz, 2H), 0.81 (tt, J＝5.1, 2.8 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.53, 163.29, 139.80, 132.44, 131.78, 129.09, 122.33, 120.37, 120.11, 113.25, 106.48, 73.58, 66.15, 54.71, 9.25, 0.99; HRMS (ESI-TOF) calcd for C₁₇H₁₇N₂O₂ [M+H]⁺ 281.1285, found 281.1286.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-2-methyl-5-(p-tolyl)pent-2-en-4-ynamide (3o): 19.9 mg, 58% yield. White solid, m.p. 102~104 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.71 (s, 1H), 8.90 (dd, J＝8.4, 1.1 Hz, 1H), 7.85 (dd, J＝7.9, 1.6 Hz, 1H), 7.49 (ddd, J＝8.7, 7.4, 1.7 Hz, 1H), 7.11 (t, J＝7.5 Hz, 3H), 7.03 (d, J＝7.9 Hz, 2H), 6.03 (d, J＝1.7 Hz, 1H), 4.06 (t, J＝9.8 Hz, 2H), 3.90 (t, J＝9.8 Hz, 2H), 2.30 (s, 3H), 2.17 (d, J＝1.6 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 166.57, 163.95, 144.01, 139.47, 138.59, 132.42, 131.31, 129.11, 128.97, 122.50, 120.17, 120.05, 113.76, 111.74, 95.98, 85.80, 66.04, 54.60, 21.43, 20.63; HRMS (ESI-TOF) calcd for C₂₂H₂₁N₂O₂ [M+H]⁺ 345.1598, found 345.1598.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-2-phenyl-5-(p-tolyl)pent-2-en-4-ynamide (3p): 20.6 mg, 51% yield. White solid, m.p. 165~168 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.78 (s, 1H), 8.98 (d, J＝8.4 Hz, 1H), 7.85 (dd, J＝7.9, 1.7 Hz, 1H), 7.59~7.50 (m, 3H), 7.41~7.33 (m, 3H), 7.16~7.11 (m, 3H), 7.04 (d, J＝7.8 Hz, 2H), 6.41 (s, 1H), 4.10 (t, J＝9.5 Hz, 2H), 3.82 (t, J＝9.5 Hz, 2H), 2.31 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 166.39, 163.88, 147.70, 139.47, 138.78, 136.32, 132.46, 131.50, 129.02, 129.00, 128.75, 128.58, 127.13, 122.71, 120.19, 119.94, 113.80, 110.42, 98.18, 86.27, 66.05, 54.48, 21.48; HRMS (ESI-TOF) calcd for C₂₇H₂₃N₂O₂ [M+H]⁺ 407.1754, found 407.1759.

(Z)-2-Benzyl-N-(2-(4, 5-dihydrooxazol-2-yl)phenyl)-5-(p-tolyl)pent-2-en-4-ynamide (3q): 23.2 mg, 55% yield. White solid, m.p. 106~108 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.79 (s, 1H), 8.88 (d, J＝8.5 Hz, 1H), 7.84 (dd, J＝7.9, 1.6 Hz, 1H), 7.51~7.46 (m, 1H), 7.34~7.27 (m, 4H), 7.25~7.21 (m, 1H), 7.11 (t, J＝7.7 Hz, 1H), 7.07 (d, J＝8.0 Hz, 2H), 7.01 (d, J＝7.9 Hz, 2H), 5.85 (s, 1H), 4.03 (t, J＝9.4 Hz, 2H), 3.87 (t, J＝9.4 Hz, 2H), 3.86 (s, 2H), 2.30 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 166.24, 163.81, 147.84, 139.40, 138.69, 138.00, 132.37, 131.30, 129.31, 129.06, 128.98, 128.55, 126.55, 122.54, 120.22, 119.96, 113.80, 112.16, 97.05, 85.57, 66.01, 54.62, 39.84, 21.42; HRMS (ESI-TOF) calcd for C₂₈H₂₅N₂O₂ [M+H]⁺ 421.1911, found 421.1917.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-3-methyl-5-(p-tolyl)pent-2-en-4-ynamide (3r): 11.0 mg, 32% yield. White solid, m.p. 110~113 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.36 (s, 1H), 8.89 (d, J＝8.5 Hz, 1H), 7.85 (dd, J＝7.9, 1.6 Hz, 1H), 7.47 (ddd, J＝8.7, 7.4, 1.6 Hz, 1H), 7.37 (d, J＝7.9 Hz, 2H), 7.11 (d, J＝7.9 Hz, 2H), 7.07 (t, J＝7.6 Hz, 1H), 6.15 (d, J＝1.5 Hz, 1H), 4.24 (t, J＝9.5 Hz, 2H), 4.04 (t, J＝9.5 Hz, 2H), 2.34 (s, 3H), 2.17 (d, J＝1.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.46, 163.79, 140.04, 139.05, 132.45, 131.92, 130.24, 129.10, 129.01, 128.98, 122.16, 120.12, 119.92, 113.24, 99.68, 88.16, 66.08, 54.73, 25.24, 21.54; HRMS (ESI-TOF) calcd for C₂₂H₂₁N₂O₂ [M+H]⁺ 345.1598, found 345.1595.

(Z)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-3-phenyl-5-(p-tolyl)pent-2-en-4-ynamide (3s): 17.0 mg, 42% yield. Yellow solid, m.p. 172~175 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.63 (s, 1H), 8.96 (d, J＝8.4 Hz, 1H), 7.87 (dd, J＝7.9, 1.7 Hz, 1H), 7.83 (d, J＝6.4 Hz, 2H), 7.51 (t, J＝7.5 Hz, 1H), 7.44 (dt, J＝9.0, 4.5 Hz, 5H), 7.14 (d, J＝7.9 Hz, 2H), 7.10 (t, J＝7.8 Hz, 1H), 6.70 (s, 1H), 4.24 (t, J＝9.5 Hz, 2H), 4.03 (t, J＝9.4 Hz, 2H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.45, 163.91, 139.98, 139.31, 137.85, 132.49, 131.94, 129.39, 129.14, 129.08, 128.80, 128.58, 127.78, 127.15, 122.35, 120.19, 119.82, 113.34, 101.53, 86.66, 66.11, 54.73, 21.57; HRMS (ESI-TOF) calcd for C₂₇H₂₃N₂O₂ [M+H]⁺ 407.1754, found 407.1754.

(Z)-3-(4-Chlorophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)-5-(p-tolyl)pent-2-en-4-ynamide (3t): 17.1 mg, 39% yield. Yellow solid, m.p. 142~145 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.64 (s, 1H), 8.95 (dd, J＝8.5, 1.1 Hz, 1H), 7.87 (dd, J＝7.9, 1.6 Hz, 1H), 7.75 (d, J＝8.6 Hz, 2H), 7.50 (ddd, J＝8.7, 7.3, 1.7 Hz, 1H), 7.42 (dd, J＝12.8, 8.3 Hz, 4H), 7.14 (d, J＝7.9 Hz, 2H), 7.10 (td, J＝7.7, 1.1 Hz, 1H), 6.66 (s, 1H), 4.24 (t, J＝9.5 Hz, 2H), 4.03 (t, J＝9.5 Hz, 2H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.44, 163.57, 139.86, 139.49, 136.22, 135.38, 132.48, 131.91, 131.28, 129.14, 129.10, 128.73, 128.39, 127.80, 122.42, 120.11, 119.54, 113.29, 101.82, 86.25, 66.09, 54.68, 21.57; HRMS (ESI-TOF) calcd for C₂₇H₂₂ClN₂O₂ [M+H]⁺ 441.1364, found 441.1362.

(Z)-3-(3-Bromophenyl)-N-(2-(4, 5-dihydrooxazol-2-yl)-phenyl)-5-(p-tolyl)pent-2-en-4-ynamide (3u): 20.4 mg, 42% yield. Yellow solid, m.p. 147~150 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.66 (s, 1H), 8.95 (dd, J＝8.6, 1.2 Hz, 1H), 7.95 (t, J＝1.9 Hz, 1H), 7.87 (dd, J＝7.9, 1.7 Hz, 1H), 7.74 (dd, J＝7.9, 0.8 Hz, 1H), 7.54 (ddd, J＝8.0, 1.9, 0.9 Hz, 1H), 7.51 (ddd, J＝8.7, 7.4, 1.6 Hz, 1H), 7.44 (d, J＝8.1 Hz, 2H), 7.31 (t, J＝7.9 Hz, 1H), 7.14 (d, J＝7.9 Hz, 2H), 7.11 (td, J＝7.6, 1.2 Hz, 1H), 6.66 (s, 1H), 4.25 (t, J＝9.5 Hz, 2H), 4.04 (t, J＝9.5 Hz, 2H), 2.36 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.41, 163.44, 139.88, 139.80, 139.53, 132.47, 132.23, 131.94, 130.99, 130.15, 130.04, 129.14, 129.10, 128.47, 125.69, 122.69, 122.47, 120.13, 119.48, 113.33, 101.92, 86.12, 66.10, 54.69, 21.57; HRMS (ESI-TOF) calcd for C₂₇H₂₂BrN₂O₂ [M+H]⁺ 485.0859, found 485.0863.

(E)-N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-3-(thiophen-2-yl)-5-(p-tolyl)pent-2-en-4-ynamide (3v): 19.0 mg, 46% yield. Yellow solid, m.p. 161~164 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.57 (s, 1H), 8.93 (dd, J＝8.5, 1.1 Hz, 1H), 7.87 (dd, J＝7.8, 1.6 Hz, 1H), 7.60 (dd, J＝3.7, 1.2 Hz, 1H), 7.53~7.45 (m, 3H), 7.37 (dd, J＝5.1, 1.2 Hz, 1H), 7.15 (d, J＝7.9 Hz, 2H), 7.13~7.06 (m, 2H), 6.65 (s, 1H), 4.27 (t, J＝9.5 Hz, 2H), 4.06 (t, J＝9.5 Hz, 2H), 2.37 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.44, 163.50, 142.56, 139.97, 139.49, 132.45, 131.95, 129.12, 129.09, 127.88, 127.79, 127.38, 126.18, 124.40, 122.30, 120.13, 119.50, 113.24, 100.24, 85.70, 66.11, 54.69, 21.59; HRMS (ESI-TOF) calcd for C₂₅H₂₁N₂O₂S [M+H]⁺ 413.1318, found 413.1328.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-2-((4-methoxyph- enyl)ethynyl)cyclopent-1-ene-1-carboxamide (3w): 20.5 mg, 53% yield. White solid, m.p. 154~157 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 12.42 (s, 1H), 8.89 (dd, J＝8.5, 1.2 Hz, 1H), 7.85 (dd, J＝7.9, 1.7 Hz, 1H), 7.48 (ddd, J＝8.7, 7.3, 1.7 Hz, 1H), 7.34 (d, J＝2.1 Hz, 1H), 7.33 (d, J＝2.1 Hz, 1H), 7.09 (td, J＝7.6, 1.2 Hz, 1H), 6.82 (d, J＝2.1 Hz, 1H), 6.80 (d, J＝2.1 Hz, 1H), 4.16 (t, J＝9.4 Hz, 2H), 3.92 (t, J＝9.4 Hz, 2H), 2.90 (tt, J＝7.6, 2.4 Hz, 2H), 2.78 (tt, J＝7.9, 2.4 Hz, 2H), 2.02 (quint, J＝7.7 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ: 164.14, 163.96, 159.92, 142.19, 139.88, 133.30, 132.39, 129.76, 129.14, 122.23, 120.41, 115.25, 113.90, 113.55, 98.97, 84.90, 66.11, 55.29, 54.66, 39.26, 33.81, 22.29; HRMS (ESI-TOF) calcd for C₂₄H₂₃N₂O₃ [M+H]⁺ 387.1703, found 387.1704.

N-(2-(4, 5-Dihydrooxazol-2-yl)phenyl)-2-((4-methoxyph-enyl)ethynyl)cyclohex-1-ene-1-carboxamide (3x): 19.2 mg, 48% yield. White sticky foam; ¹H NMR (500 MHz, CDCl₃) δ: 12.50 (s, 1H), 8.91 (dd, J＝8.5, 1.1 Hz, 1H), 7.83 (dd, J＝7.9, 1.7 Hz, 1H), 7.48 (ddd, J＝8.7, 7.3, 1.7 Hz, 1H), 7.12 (d, J＝2.1 Hz, 1H), 7.11 (d, J＝3.4 Hz, 1H), 7.10~7.07 (m, 1H), 6.73 (d, J＝2.1 Hz, 1H), 6.72 (d, J＝2.1 Hz, 1H), 4.06 (td, J＝9.3, 1.3 Hz, 2H), 3.96~3.90 (td, J＝9.3, 1.3 Hz, 2H), 3.77 (s, 3H), 2.53 (dq, J＝6.1, 2.9 Hz, 2H), 2.42 (dq, J＝5.9, 3.2 Hz, 2H), 1.73 (hept, J＝6.1 Hz, 4H); ¹³C NMR (125 MHz, CDCl₃) δ: 168.28, 163.95, 159.53, 139.79, 139.75, 132.85, 132.40, 129.08, 122.21, 122.02, 120.16, 115.54, 113.80, 113.72, 94.78, 87.89, 66.01, 55.25, 54.71, 31.24, 26.70, 21.93, 21.80; HRMS (ESI-TOF) calcd for C₂₅H₂₅N₂O₃ [M+H]⁺ 401.1860, found 401.1865.

Supporting Information Optimization Studies, typical Procedure for mmol-Scale reaction and ¹H NMR and ¹³C NMR spectra for compounds 1 and 3. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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Scheme 1 1, 3-Enynes containing drug molecules

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Scheme 2 Construction of conjugated enynes via C—H alkynylation

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Scheme 3 The effect of TEMPO

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Scheme 4 Plausible pathway

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Table 1. Screening of the reaction conditions^a


Entry	Base	T/℃	Time/h	Yield/%
1	NaOAc	60	6	28
2	LiOAc	60	6	24
3	KOAc	60	6	25
4	Na₂CO₃	60	6	20
5	k₂co₃	60	6	17
6	NaOAc	80	6	39
7	NaOAc	100	6	30
8^c	NaOAc	80	6	56
9^c	NaOAc	80	4	51
10^c	NaOAc	80	9	56
11^{c, d}	NaOAc	80	6	0
12^{c, e}	NaOAc	80	6	16
^a Reaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.3 mmol, 3.0 equiv.), Cu(OAc)₂ (0.1 mmol, 1.0 equiv.), base (0.2 mmol, 1.0 equiv.), DMSO (5.0 mL), air. ^b Yield was determined by ¹H NMR analysis of crude reaction mixture using CH₂Br₂ as an internal standard. ^c NaOAc (0.3 mmol). ^d No Cu(OAc)₂. ^e20 mol% Cu(OAc)₂.

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Table 2. Substrate scope for the reaction^a






^aReaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2 (0.3 mmol, 3.0 equiv.), Cu(OAc)₂ (0.1mmol, 1.0 equiv.), NaOAc (0.3 mmol, 3.0 equiv.), DMSO (5.0 mL), air, at 80 ℃ for 6 h.

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