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

Shangzheng Sun Xing Wang Taijin Cheng Hui Xu Huixiong Dai

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

    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.

English

  • 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

    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

    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.

    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 conditionsa
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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
    8c NaOAc 80 6 56
    9c NaOAc 80 4 51
    10c NaOAc 80 9 56
    11c, d NaOAc 80 6 0
    12c, 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 reactiona
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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

    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

    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.

    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.

    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

    Scheme 2  Construction of conjugated enynes via C—H alkynylation

    Scheme 3  The effect of TEMPO

    Scheme 4  Plausible pathway

    Table 1.  Screening of the reaction conditionsa

    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
    8c NaOAc 80 6 56
    9c NaOAc 80 4 51
    10c NaOAc 80 9 56
    11c, d NaOAc 80 6 0
    12c, 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 reactiona

    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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  • 发布日期:  2020-10-25
  • 收稿日期:  2020-05-23
  • 修回日期:  2020-06-20
  • 网络出版日期:  2020-07-08
通讯作者: 陈斌, bchen63@163.com
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