Synthesis of Sterically Hindered α-Aminonitriles through 1, 6-Aza-conjugate Addition of Anilines to δ-Cyano Substituted para-Quinone Methides

Lin Wang Nan Wang Yue Qi Shutao Sun Xigong Liu Wei Li Lei Liu

Citation:  Wang Lin, Wang Nan, Qi Yue, Sun Shutao, Liu Xigong, Li Wei, Liu Lei. Synthesis of Sterically Hindered α-Aminonitriles through 1, 6-Aza-conjugate Addition of Anilines to δ-Cyano Substituted para-Quinone Methides[J]. Chinese Journal of Organic Chemistry, 2020, 40(11): 3934-3943. doi: 10.6023/cjoc202004027 shu

基于δ-腈基取代对亚甲基苯醌1, 6-氮杂共轭加成的大位阻α-氰胺合成研究

    通讯作者: 刘希功, 201990000024@sdu.edu.cn
    李伟, liwei6911@163.com
    刘磊, leiliu@sdu.edu.cn
  • 基金项目:

    国家自然科学基金(Nos.21722204, 21971148)资助项目

    国家自然科学基金 21971148

    国家自然科学基金 21722204

摘要: 目前对亚甲基苯醌参与的1,6-共轭加成反应的研究主要集中在对预先合成的δ-单取代底物进行三级碳中心的构建.报道了一级芳胺对预先制备的δ-氰基-δ-芳基二取代对亚甲基苯醌的1,6-氮杂共轭加成反应,高效地合成了一系列含有四级碳手性中心的大位阻胺类化合物.该方法条件温和、反应迅速,同时芳胺和对亚甲基苯醌的适用范围广泛.此外,环状二级胺例如吗啉和咪唑也是合适的亲核试剂.

English

  • para-Quinone methides (p-QMs), structurally characterized by the assembly of carbonyl and olefinic moieties, have been widely employed as prominent acceptors for 1, 6-conjugate addition reactions.[1-3] However, existing methods suffered from notable structural restriction on p-QMs, probably due to the stability issue.[4] Current studies predominantly concentrate on p-QMs having two bulky α-substituents (e.g. tBu). Additionally, p-QM substrates typically contain a mono-aryl substitution at the δ-position for tertiary stereocenter construction. Sun and co-workers developed a delicate protocol to address the structural limitations by in situ generating p-QM intermediates bearing two electron-donating groups (EDGs) at the δ-position via Brønsted acid catalyzed dehydration of p-hydroxybenzyl alcohols.[5] Despite great innovation, p-QM intermediates bearing a δ-electron-withdrawing group (EWG) might not be accessible through the protocol. In addition, the electrophilicity of p-QMs bearing two EDGs at δ-position towards 1, 6-conjugate addition might be impaired. Recently, our group employed an oxidative C—H cleavage strategy to in situ generate δ-EWG substituted p-QMs.[6] However, diverse nucleophiles might not be compatible with the strongly oxidative conditions, and therefore the utilities of the protocol would be restricted. Therefore, further expanding the scope of p-QMs and applying them to address existing synthetic challenges would be highly desired. Using pre-prepared, isolable, and storable p-QMs as substrates would be an attractive solution. Placing an electron-withdrawing cyano group at the exocyclic methylene δ-position would tune the molecular electron-density distribution, and the stability of resulting p-QMs might be improved by lowering their polymerizability.[7]

    Sterically hindered amines with a fully substituted α carbon center are important structural motifs in various natural products and pharmaceuticals.[8] C—N bond forming reactions represent practical and robust approaches for their synthesis. In this context, 1, 6-aza-conjugate addition of amines to p-QMs has received considerable attentions.[9] However, existing methods typically involved intra- or inter-molecular addition of cyclic secondary amines to p- QMs providing corresponding adducts with a tertiary α carbon center. To our knowledge, 1, 6-aza-conjugate addition for the synthesis of sterically hindered amines with an acyclic, fully substituted α carbon center has never been reported. In addition, the use of primary amines as nucleophiles for 1, 6-conjugate addition proved to be challenging due to the instability of the resulting adducts.[2e] Given the significance of α-amino-nitriles in organic synthesis and pharmaceutical science, [10] we herein reported a 1, 6-aza- conjugate addition of a range of primary anilines to δ-CN-δ-aryl substituted p-QMs for efficient synthesis of sterically hindered amines with a fully substituted α carbon center. The generality of the method was further demonstrated by 1, 6-aza-conjugate addition with valuable secondary amines.

    Initially, 1, 6-aza-conjugate addition of aniline 2a to δ-CN-δ-phenyl substituted p-QM 1a in CH2Cl2 was selected as the model reaction for optimization (Table 1). When diphenyl phosphate was used as a Brønsted acid catalyst, the reaction proceeded smoothly, affording the expected sterically hindered amine 3a in 52% yield together with undesired triarylmethane 3a' in 16% yield (Entry 1, Table 1). The solvent effect was then carefully investigated, and MeOH was identified to be optimal with respect to the chemoselectivity and efficiency (Entries 1~7, Table 1). Notably, no undesired 3a' was detected (Entry 7, Table 1). An extensive screen of Brønsted and Lewis acid additives revealed that the 1, 6-aza-conjugate addition proceeded most efficiently when p-toluenesulfonic acid (PTSA) was used as the catalyst, furnishing desired 3a in 91% yield within 0.5 h (Entries 7~11, Table 1).

    Table 1

    Table 1.  Reaction condition optimizationa
    下载: 导出CSV
    Entry Catalyst Solvent Time/h Yieldb/%
    3a 3a'
    1 DPP CH2Cl2 6 52 16
    2 DPP Toluene 6 57 8
    3 DPP EtOAc 6 60 10
    4 DPP THF 2 66 18
    5 DPP Acetone-d6 0.5 69 15
    6 DPP CH3CN 0.5 71 13
    7 DPP MeOH 0.5 75 < 5
    8 AcOH MeOH 0.5 82 < 5
    9 PTSA MeOH 0.5 91 < 5
    10 BF3•OEt2 MeOH 1 77 < 5
    11 AgOTf MeOH 1 68 < 5
    a Reaction conditions, unless otherwise specified: a solution of 1a (0.1 mmol), 2a (0.105 mmol), catalyst (0.01 mmol) in solvent (1.0 mL) at room temperature for indicated time period. b Isolated yield. DPP=diphenyl phosphate. PTSA=p-toluenesulfonic acid, Tf=trifluoromethanesulfonyl.

    With the optimized conditions in hand, the scope of δ-CN substituted p-QMs was examined (Scheme 1). A wide variety of p-QMs 1 bearing electronically varied aryl groups with diverse substituent patterns at the δ-position joined in the 1, 6-aza-conjugate addition reactions smoothly, furnishing corresponding sterically hindered amines 3a~3o in 85%~94% yields (Scheme 1A). δ-Polyarene naphthalene substituted p-QMs were also suitable substrates, as demonstrated by the formation of respective 3p and 3q in 94% and 90% yields. The substituent pattern on quinone moiety was then explored (Scheme 1B). p-QMs 1r~1u bearing diverse electron-donating and electron- withdrawing small substituents at α-position were well tolerated, giving respective 3r~3u in 90%~94% yields.

    Scheme 1

    Scheme 1.  Scope of p-QM components

    The scope of aniline components was next evaluated (Scheme 2). A broad range of anilines bearing diverse electron-donating and electron-withdrawing substituents at para-position were competent nucleophilic partners, as illustrated by the generation of respective sterically hindered amines 4a~4d in high efficiency. Anilines 2e~2g bearing substituents at meta- or ortho-position were also well tolerated, and respective 4e~4g were isolated in 88%~90% yields. 2-Naphthalene substituted 2h was suitable component for the 1, 6-aza-conjugate addition process.

    Scheme 2

    Scheme 2.  Scope of aniline components

    The success in amination with primary anilines prompted us to further explore 1, 6-aza-conjugate addition with secondary amines (Scheme 3). Triarylmethane 7 bearing a morpholine moiety has been identified as a potent inhibitor of apolipoprotein E production (Scheme 3A).[11] Under the standard conditions, morpholine (5) reacted with 1a giving diarylmethane 6 bearing a fully substituted stereocenter in 85% yield. Clotrimazole (10) is a broad-spectrum antifungal drug that is used for the treatment of dermal infections caused by various species of pathogenic dermatophytes, yeasts, and Malassezia furfur (Scheme 3B).[12] Imidazole (8) participated in 1, 6-aza-conjugate addition of 1a smoothly, affording diarylmethane 9 bearing a fully substituted stereocenter in 90% yield. These results suggested that the method would provide a robust handle to facilely prepare structurally diverse and sterically hindered amines for further medicinal study.

    Scheme 3

    Scheme 3.  Secondary amine components

    In summary, an efficient 1, 6-aza-conjugate addition of primary anilines to δ-CN-δ-aryl disubstituted p-QMs for facile access to sterically hindered amines with a fully substituted α carbon center has been described. The mild and expeditious method exhibited broad scopes of both aniline and p-QM components. The generality of the method in modular preparation of medicinally valuable, sterically hindered amines was further demonstrated by using cyclic secondary amines like morpholine and imidazole as nucleophilic components. Ongoing studies focus on applying the method in mecicinal chemistry study.

    Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 500 MHz respectively. Carbon nuclear magnetic resonance (13C NMR) spectra were recorded at 126 MHz respectively. The solvent peak was used as a reference value for 1H NMR (CDCl3 δ 7.26, (CD3)2CO δ 2.05) and for 13C NMR (CDCl3 δ 77.23, (CD3)2CO δ 206.23/29.82). Analytical thin-layer chromatography (TLC) was performed on precoated silica gel GF254 plates. Column chromatography was carried out on silica gel (200~300 mesh). HRMS were carried out on an Orbitrap analyzer.

    To a solution of S-1 (10 mmol, 1.0 equiv.) in anhydrous tetrahydrofuran (THF) at 0 ℃ was added PhMgBr (1.0 mol•L-1, 10 mL) in THF dropwise under N2 (Scheme 4). After stirred at the same temperature for 0.5 h, the reaction was warmed up to room temperature slowly and stirred for 2 h. Upon completion, the mixture was quenched by a saturated aqueous NH4Cl solution (15 mL). The organic layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine, and dried over anhydrous MgSO4. The solvent was removed under vacuum to afford crude alcohol for next step.

    Scheme 4

    Scheme 4.  Preparation of substrate 1

    Regent and conditions: (a) PhMgBr (1.0 equiv.), THF, 0 ℃; (b) InCl3 (0.1 equiv.), TMSCN (1.3 equiv.), CH2Cl2, 0 ℃; (c) Pd/C (10%), MeOH, hydrogen balloon, r.t.; (d) DDQ (1.0 equiv.), CH2Cl2, r.t.

    To a mixture of InCl3 (1.0 mmol, 0.1 equiv.) and TMSCN (13 mmol, 1.3 equiv.) in anhydrous CH2Cl2 (20 mL) was added a solution of crude alcohol in anhydrous CH2Cl2 (10 mL) at 0 ℃. The reaction was stirred at the same temperature and monitored by TLC until the complete conversion. Then it was quenched by saturated aqueous NaHCO3 solution (20 mL) and extracted with CH2Cl2. The combined organic layers were washed with saturated brine, and dried over anhydrous MgSO4. The solvent was removed under vacuum to provide the crude product, which was used as such for next step.

    The crude product was dissolved in 20 mL of MeOH solution, and 10% Pd/C was added. The mixture was stirred overnight under a hydrogen balloon at room temperature before it was filtered through a Celite pad. The solvent was removed under vacuum and the residue was purified by a column chromatography on silica gel using ethyl acetate/petroleum ether as eluent to give S-2.

    To a solution of S-4 in CH2Cl2 (20.0 mL) was added DDQ (1.0 equiv.) and it was stirred at room temperature for 1 h. Then the solvent was removed under vacuum and the residue was purified by silica gel chromatography using ethyl acetate/petroleum ether as eluent to afford expected 1a.

    (4-Oxocyclohexa-2, 5-dien-1-ylidene)-2-phenylacetoni- trile (1a): 1H NMR (500 MHz, CDCl3) δ: 7.84 (dd, J=10.0, 2.7 Hz, 1H), 7.56~7.50 (m, 5H), 7.48 (dd, J=10.1, 2.7 Hz, 1H), 6.61 (dd, J=10.0, 1.9 Hz, 1H), 6.48 (dd, J=10.1, 1.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.6, 139.8, 137.1, 134.6, 132.1, 131.6, 131.5, 131.5, 130.6, 129.5, 124.2, 117.3; HRMS (ESI) calcd for C14H10NO [M+H]+ 208.0757, found 208.0760.

    ([1, 1'-Biphenyl]-4-yl)-2-(4-oxocyclohexa-2, 5-dien-1- ylidene)acetonitrile (1b): 1H NMR (500 MHz, CDCl3) δ: 7.87 (dd, J=10.0, 2.7 Hz, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.66~7.60 (m, 4H), 7.58 (dd, J=10.1, 2.7 Hz, 1H), 7.53~7.48 (m, 2H), 7.46~7.41 (m, 1H), 6.63 (dd, J=10.0, 1.8 Hz, 1H), 6.52 (dd, J=10.1, 1.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.7, 144.5, 139.6, 139.5, 137.2, 134.7, 131.5, 131.3, 131.0, 129.3, 128.7, 128.1, 127.4, 124.0, 117.3; HRMS (ESI) calcd for C20H14NO [M+H]+ 284.1070, found 284.1065.

    (4-Oxocyclohexa-2, 5-dien-1-ylidene)-2-(p-tolyl)acetoni- trile (1c): 1H NMR (500 MHz, CDCl3) δ: 7.83 (dd, J=10.0, 2.7 Hz, 1H), 7.51 (dd, J=10.1, 2.7 Hz, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 6.60 (dd, J=10.0, 1.9 Hz, 1H), 6.48 (dd, J=10.1, 1.9 Hz, 1H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 186.8, 142.5, 139.2, 137.2, 134.9, 131.4, 131.4, 130.7, 130.3, 129.4, 124.5, 117.4, 21.8; HRMS (ESI) calcd for C15H12NO [M+H]+ 222.0913, found 222.0915.

    (4-Isopropylphenyl)-2-(4-oxocyclohexa-2, 5-dien-1-yli- dene)acetonitrile (1d): 1H NMR (500 MHz, CDCl3) δ: 7.83 (dd, J=10.0, 2.7 Hz, 1H), 7.53 (dd, J=10.1, 2.7 Hz, 1H), 7.48~7.43 (m, 2H), 7.40~7.36 (m, 2H), 6.60 (dd, J=10.0, 1.9 Hz, 1H), 6.48 (dd, J=10.1, 1.9 Hz, 1H), 3.04~2.94 (m, 1H), 1.30 (s, 3H), 1.29 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 186.7, 153.2, 139.2, 137.2, 134.9, 131.4, 131.3, 130.9, 129.7, 127.7, 124.5, 117.4, 34.4, 23.9; HRMS (ESI) calcd for C17H16NO [M+H]+ 250.1226, found 250.1229.

    (4-(tert-Butyl)phenyl)-2-(4-oxocyclohexa-2, 5-dien-1- ylidene)acetonitrile (1e): 1H NMR (500 MHz, CDCl3) δ: 7.84 (dd, J=10.0, 2.7 Hz, 1H), 7.56~7.51 (m, 3H), 7.50~7.44 (m, 2H), 6.60 (dd, J=10.0, 1.9 Hz, 1H), 6.49 (dd, J=10.1, 1.9 Hz, 1H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3) δ: 186.8, 155.5, 139.3, 137.3, 135.0, 131.4, 131.4, 130.7, 129.4, 126.6, 124.5, 117.4, 35.4, 31.3; HRMS (ESI) calcd for C18H18NO [M+H]+ 264.1383, found 264.1386.

    (4-Bromophenyl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1f): 1H NMR (500 MHz, CDCl3) δ: 7.82 (dd, J=10.0, 2.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.45~7.37 (m, 3H), 6.62 (dd, J=10.0, 1.5 Hz, 1H), 6.50 (dd, J=10.1, 1.6 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.5, 140.2, 136.9, 134.1, 132.9, 132.0, 131.8, 130.9, 126.5, 122.7, 116.9; HRMS (ESI) calcd for C14H9BrNO [M+H]+ 285.9862, found 285.9858.

    (4-Chlorophenyl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1g): 1H NMR (500 MHz, CDCl3) δ: 7.82 (dd, J=10.0, 2.7 Hz, 1H), 7.55~7.50 (m, 2H), 7.49~7.45 (m, 2H), 7.43 (dd, J=10.1, 2.7 Hz, 1H), 6.62 (dd, J=10.0, 1.9 Hz, 1H), 6.50 (dd, J=10.1, 1.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.5, 140.2, 138.1, 136.9, 134.1, 131.9, 131.8, 130.5, 129.9, 122.6, 117.0; HRMS (ESI) calcd for C14H9ClNO [M+H]+ 242.0367, found 242.0364.

    (4-Fluorophenyl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1h): 1H NMR (500 MHz, CDCl3) δ: 7.84 (dd, J=10.0, 2.7 Hz, 1H), 7.58~7.52 (m, 2H), 7.46 (dd, J=10.1, 2.7 Hz, 1H), 7.29~7.23 (m, 2H), 6.63 (dd, J=10.0, 1.8 Hz, 1H), 6.51 (dd, J=10.1, 1.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.6, 165.5, 163.4, 139.9, 137.0, 134.3, 132.9, 132.8, 131.7, 131.7, 128.2, 128.2, 122.8, 117.1, 117.0, 116.9; HRMS (ESI) calcd for C14H9- FNO [M+H]+ 226.0663, found 226.0659.

    (4-Oxocyclohexa-2, 5-dien-1-ylidene)-2-(4-(trifluorome-thyl)phenyl)acetonitrile (1i): 1H NMR (500 MHz, CDCl3) δ: 7.85~7.77 (m, 3H), 7.65 (d, J=8.2 Hz, 2H), 7.38 (dd, J=10.1, 2.7 Hz, 1H), 6.62 (dd, J=10.0, 1.8 Hz, 1H), 6.48 (dd, J=10.1, 1.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.3, 141.1, 136.7, 135.4, 133.8, 133.1, 132.9, 132.1, 132.0, 130.9, 126.5, 126.5, 126.5, 126.4, 124.6, 122.5, 121.9, 116.8; HRMS (ESI) calcd for C15H9F3NO [M+H]+ 276.0631, found 276.0635.

    (4-Oxocyclohexa-2, 5-dien-1-ylidene)-2-(m-tolyl)aceto- nitrile (1j): 1H NMR (500 MHz, CDCl3) δ: 7.82 (dd, J=10.0, 2.7 Hz, 1H), 7.48 (dd, J=10.1, 2.7 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.36~7.27 (m, 3H), 6.59 (dd, J=10.0, 1.8 Hz, 1H), 6.47 (dd, J=10.1, 1.9 Hz, 1H), 2.43 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 186.6, 139.6, 139.5, 137.1, 134.8, 132.3, 132.0, 131.5, 131.4, 131.0, 129.3, 127.8, 124.4, 117.3, 21.5; HRMS (ESI) calcd for C15H12NO [M+H]+ 222.0913, found 222.0915.

    (3-Bromophenyl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1k): 1H NMR (500 MHz, CDCl3) δ: 7.81 (dd, J=10.0, 2.7 Hz, 1H), 7.71~7.64 (m, 2H), 7.46~7.39 (m, 3H), 6.62 (dd, J=10.0, 1.8 Hz, 1H), 6.50 (dd, J=10.1, 1.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.4, 140.7, 136.7, 134.4, 134.0, 133.8, 133.1, 132.0, 131.9, 131.0, 129.1, 123.6, 122.0, 116.9; HRMS (ESI) calcd for C14H9- BrNO [M+H]+ 285.9862, found 285.9859.

    (3-Chlorophenyl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1l): 1H NMR (500 MHz, CDCl3) δ: 7.82 (dd, J=10.0, 2.7 Hz, 1H), 7.55~7.46 (m, 3H), 7.45~7.38 (m, 2H), 6.63 (dd, J=10.0, 1.9 Hz, 1H), 6.51 (dd, J=10.1, 1.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.5, 140.7, 136.8, 135.7, 134.0, 133.6, 132.0, 132.0, 131.5, 130.8, 130.3, 128.7, 122.1, 116.9; HRMS (ESI) calcd for C14H9- ClNO [M+H]+ 242.0367, found 242.0363.

    (3-Fluorophenyl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1m): 1H NMR (500 MHz, CDCl3) δ: 7.85 (dd, J=10.0, 2.7 Hz, 1H), 7.81 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.1 Hz, 2H), 7.38 (dd, J=10.1, 2.7 Hz, 1H), 6.64 (dd, J=10.0, 1.9 Hz, 1H), 6.50 (dd, J=10.1, 1.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.6, 163.9, 161.9, 140.6, 136.9, 134.2, 133.8, 133.7, 133.1, 131.9, 131.9, 131.3, 131.3, 126.4, 126.4, 122.4, 118.6, 118.5, 117.6, 117.4, 116.9, 115.6; HRMS (ESI) calcd for C14H9FNO [M+H]+ 226.0663, found 226.0661.

    (4-Oxocyclohexa-2, 5-dien-1-ylidene)-2-(o-tolyl)aceto- nitrile (1n): 1H NMR (500 MHz, CDCl3) δ: 7.85 (dd, J=10.0, 2.6 Hz, 1H), 7.45~7.39 (m, 1H), 7.36~7.29 (m, 2H), 7.18 (dd, J=7.6, 0.9 Hz, 1H), 7.08 (dd, J=10.1, 2.6 Hz, 1H), 6.61 (dd, J=10.0, 1.9 Hz, 1H), 6.39 (dd, J=10.1, 1.9 Hz, 1H), 2.37 (s, 3H); 13C NMR (126 MHz, CDCl3) δ: 186.7, 141.6, 137.4, 136.4, 134.5, 131.9, 131.5, 131.4, 131.0, 130.9, 130.7, 126.7, 123.4, 116.4, 20.2; HRMS (ESI) calcd for C15H12NO [M+H]+ 222.0913, found 222.0917.

    (3, 5-Dimethylphenyl)-2-(4-oxocyclohexa-2, 5-dien-1- ylidene)acetonitrile (1o): 1H NMR (500 MHz, CDCl3) δ: 7.82 (dd, J=10.0, 2.7 Hz, 1H), 7.50 (dd, J=10.1, 2.7 Hz, 1H), 7.17 (s, 1H), 7.12 (s, 2H), 6.60 (dd, J=10.0, 1.9 Hz, 1H), 6.48 (dd, J=10.1, 1.9 Hz, 1H), 2.39 (s, 6H); 13C NMR (126 MHz, CDCl3) δ: 186.8, 139.6, 139.4, 137.2, 135.0, 133.3, 132.1, 131.5, 131.2, 128.4, 124.8, 118.5, 117.4, 21.5; HRMS (ESI) calcd for C16H14NO [M+H]+ 236.1070, found 236.1073.

    (Naphthalen-2-yl)-2-(4-oxocyclohexa-2, 5-dien-1-yli- dene) acetonitrile (1p): 1H NMR (500 MHz, CDCl3) δ: 8.02 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.96~7.87 (m, 3H), 7.68~7.54 (m, 4H), 6.64 (dd, J=10.0, 1.8 Hz, 1H), 6.52 (dd, J=10.1, 1.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.7, 139.8, 137.2, 134.9, 134.2, 132.9, 131.7, 131.7, 131.6, 129.5, 129.0, 128.8, 128.1, 127.8, 126.5, 124.3, 117.4; HRMS (ESI) calcd for C18H12NO [M+H]+ 258.0913, found 258.0918.

    (Naphthalen-1-yl)-2-(4-oxocyclohexa-2, 5-dien-1-ylide- ne)acetonitrile (1q): 1H NMR (500 MHz, CDCl3) δ: 8.03 (d, J=8.3 Hz, 1H), 8.00~7.93 (m, 2H), 7.88~7.82 (m, 1H), 7.66~7.55 (m, 3H), 7.47 (dd, J=7.1, 0.9 Hz, 1H), 7.08 (dd, J=10.1, 2.6 Hz, 1H), 6.67 (dd, J=10.0, 1.9 Hz, 1H), 6.34 (dd, J=10.1, 1.9 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 186.8, 142.5, 136.4, 134.8, 133.9, 132.0, 131.8, 131.3, 131.1, 129.6, 129.1, 128.8, 128.2, 127.4, 125.4, 124.7, 122.2, 117.0; HRMS (ESI) calcd for C18H12NO [M+H]+ 258.0913, found 258.0916.

    2-(3-Methyl-4-oxocyclohexa-2, 5-dien-1-ylidene)-2-phe-nylacetonitrile (1r): 1r was obtained as a 1:1 mixture of the Z:E isomers. 1H NMR (500 MHz, CDCl3) δ: 7.78 (dd, J=9.9, 2.7 Hz, 1H), 7.68~7.65 (m, 1H), 7.56~7.48 (m, 10H), 7.40 (dd, J=10.0, 2.7 Hz, 1H), 7.31~7.27 (m, 1H), 6.60 (d, J=9.9 Hz, 1H), 6.47 (d, J=10.0 Hz, 1H), 2.14 (d, J=1.4 Hz, 3H), 2.03 (d, J=1.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ: 187.0, 140.5, 140.3, 140.3, 136.8, 134.3, 133.7, 132.3, 131.4, 131.3, 131.1, 130.7, 130.6, 129.4, 129.4, 122.2, 122.1, 117.7, 16.8, 16.5; HRMS (ESI) calcd for C15H12NO [M+H]+ 222.0913, found 222.0916.

    (3-Bromo-4-oxocyclohexa-2, 5-dien-1-ylidene)-2-phen- ylacetonitrile (1s): 1s was obtained as a 1:1 mixture of the Z:E isomers. 1H NMR (500 MHz, CDCl3) δ: 8.30 (d, J=2.5 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.85 (dd, J=9.8, 2.5 Hz, 1H), 7.61~7.51 (m, 10H), 7.51~7.48 (m, 1H), 6.75 (d, J=9.8 Hz, 1H), 6.63 (d, J=10.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 179.2, 179.1, 139.6, 139.4, 138.4, 137.1, 136.6, 136.2, 134.8, 133.3, 132.0, 131.9, 131.9, 130.8, 130.8, 130.7, 130.7, 130.6, 130.2, 129.8, 129.7, 124.7, 124.7, 117.1, 117.1; HRMS (ESI) calcd for C14H9BrNO [M+H]+ 285.9862, found 285.9866.

    2-(3-Chloro-4-oxocyclohexa-2, 5-dien-1-ylidene)-2-phe-nylacetonitrile (1t): 1t was obtained as a 1:1 mixture of the Z:E isomers. 1H NMR (500 MHz, CDCl3) δ: 8.02 (d, J=2.5 Hz, 1H), 7.83 (dd, J=9.9, 2.5 Hz, 1H), 7.65 (d, J=2.5 Hz, 1H), 7.59~7.50 (m, 10H), 7.50~7.45 (m, 1H), 6.71 (d, J=9.9 Hz, 1H), 6.59 (d, J=10.0 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ: 179.1, 179.0, 139.2, 139.1, 137.5, 137.3, 136.9, 134.7, 134.3, 132.1, 131.9, 131.8, 131.1, 131.1, 130.7, 130.6, 129.7, 129.6, 124.9, 124.8, 117.0; HRMS (ESI) calcd for C14H9ClNO [M+H]+ 242.0367, found 242.0369.

    2-(3-Fluoro-4-oxocyclohexa-2, 5-dien-1-ylidene)-2-phe-nylacetonitrile (1u): 1u was obtained as a 2:1 mixture of the Z:E isomers. 1H NMR (500 MHz, CDCl3) δ: 7.78 (dd, J=9.9, 2.5 Hz, 1H), 7.56~7.37 (m, 8H), 7.09 (dd, J=11.1, 2.5 Hz, 1H), 6.63 (dd, J=9.9, 7.4 Hz, 1H), 6.50 (dd, J=9.9, 7.3 Hz, 0.5 H); 13C NMR (126 MHz, CDCl3) δ: 178.4, 178.2, 157.2, 157.1, 155.0, 154.9, 139.8, 139.7, 136.7, 134.5, 132.0, 132.0, 131.8, 131.7, 131.2, 131.2, 131.2, 131.2, 130.8, 130.5, 129.7, 129.6, 125.2, 125.1, 117.1, 117.1, 117.0, 116.7, 116.6, 114.6, 114.5; HRMS (ESI) calcd for C14H9FNO [M+H]+ 226.0663, found 226.0659.

    To a solution of 1 (0.1 mmol, 1.0 equiv.) in MeOH (1.0 mL) was successively added 2 (0.105 mmol, 1.05 equiv.), PTSA (0.01 mmol, 10 mol%) at room temperature. The mixture was stirred at the same temperature for 30 min~6 h. The solvent was removed and the residue was purified by flash column chromatography to give the desired product.

    2-(4-Hydroxyphenyl)-2-phenyl-2-(phenylamino)acetoni-trile (3a): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3a 27.2 mg, 91% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.65 (s, 1H), 7.67~7.56 (m, 2H), 7.49~7.29 (m, 5H), 7.18~7.04 (m, 2H), 6.94~6.83 (m, 2H), 6.75 (t, J=7.9 Hz, 3H), 6.02 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.1, 145.2, 140.8, 131.4, 129.4, 128.9, 128.1, 126.6, 120.6, 116.4, 65.0; HRMS (ESI) calcd for C20H15N2O [M-H]- 299.1190, found 299.1195.

    2-([1, 1'-Biphenyl]-4-yl)-2-(4-hydroxyphenyl)-2-(phen- ylamino)acetonitrile (3b): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3b 31.9 mg, 85% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.67 (s, 1H), 7.76~7.65 (m, 6H), 7.49~7.44 (m, 4H), 7.39 (d, J=7.5 Hz, 1H), 7.13 (dd, J=8.5, 7.4 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.83~6.73 (m, 3H), 6.07 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.4, 145.4, 141.7, 140.4, 140.1, 131.5, 129.5, 129.1, 128.3, 128.2, 128, 0, 127.4, 127.4, 120.7, 119.6, 116.6, 116.3, 65.0; HRMS (ESI) calcd for C26H19- N2O [M-H]- 375.1503, found 375.1506.

    2-(4-Hydroxyphenyl)-2-(phenylamino)-2-(p-tolyl)aceto-nitrile (3c): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3c 27.2 mg, 87% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.62 (d, J=12.2 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.41~7.37 (m, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.10 (dd, J=8.6, 7.3 Hz, 2H), 6.89~6.85 (m, 2H), 6.78~6.71 (m, 3H), 5.95 (s, 1H), 2.33 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 158.3, 145.5, 138.9, 138.2, 131.8, 130.1, 129.0, 128.3, 126.8, 120.9, 119.5, 116.5, 116.2, 64.9, 20.6; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1342.

    2-(4-Hydroxyphenyl)-2-(4-isopropylphenyl)-2-(phenyl- amino)acetonitrile (3d): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3d 30.7 mg, 90% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.64 (s, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.10 (dd, J=8.4, 7.5 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 6.79~6.71 (m, 3H), 2.95~2.90 (m, 1H), 1.23 (s, 3H), 1.22 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 158.2, 149.7, 145.4, 138.6, 131.6, 129, 0, 128.2, 127.4, 126.8, 120.8, 119.4, 116.5, 116.2, 64.9, 34.0, 23.8; HRMS (ESI) calcd for C23H21N2O [M-H]- 341.1659, found 341.1655.

    2-(4-(tert-Butyl)phenyl)-2-(4-hydroxyphenyl)-2-(phen- ylamino)acetonitrile (3e): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V: V=1:9~1:4) as eluent to afford 3e (31.3 mg, 88% yield). 1H NMR (500 MHz, Acetone-d6) δ: 8.64 (s, 1H), 7.53~7.50 (m, 2H), 7.49~7.45 (m, 2H), 7.44~7.41 (m, 2H), 7.17~7.05 (m, 2H), 6.91~6.85 (m, 2H), 6.82~6.68 (m, 3H), 5.98 (s, 1H), 1.30 (s, 9H); 13C NMR (126 MHz, Acetone-d6) δ: 158.2, 152.0, 145.5, 138.3, 131.5, 129.0, 128.2, 126.5, 126.4, 120.8, 119.4, 116.5, 116.2, 64.9, 34.8, 31.2; HRMS (ESI) calcd for C24H23N2O [M-H]- 355.1816, found 355.1814.

    2-(4-Bromophenyl)-2-(4-hydroxyphenyl)-2-(phenylami-no)acetonitrile (3f): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3f 33.9 mg, 90% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.72 (s, 1H), 7.63 (d, J=8.5 Hz, 2H), 7.59~7.54 (m, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.16~7.09 (m, 2H), 6.93~6.87 (m, 2H), 6.80~6.72 (m, 3H), 6.07 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.2, 144.9, 140.2, 132.4, 130.9, 128.9, 128.7, 128.1, 122.4, 120.2, 119.6, 116.4, 116.1, 64.6; HRMS (ESI) calcd for C20H14BrN2O [M-H]- 377.0295, found 377.0291.

    2-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-2-(phenylami-no)acetonitrile (3g): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3g 29.6 mg, 89% yeild. 1H NMR (500 MHz, Acetone-d6) δ: 8.70 (s, 1H), 7.66~7.59 (m, 2H), 7.51~7.45 (m, 2H), 7.43~7.38 (m, 2H), 7.12 (dd, J=8.5, 7.5 Hz, 2H), 6.91~6.85 (m, 2H), 6.79~6.72 (m, 3H), 6.07 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.5, 145.1, 139.9, 134.5, 131.2, 129.6, 129.1, 128.7, 128.3, 120.4, 119.7, 116.6, 116.3; HRMS (ESI) calcd for C20H14ClN2O [M-H]- 333.0800, found 333.0803.

    2-(4-Forophenyl)-2-(4-hydroxyphenyl)-2-(phenylami- no)acetonitrile (3h): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3h 29.2 mg, 92% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.69 (s, 1H), 7.70~7.59 (m, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.24~7.17 (m, 2H), 7.15~7.07 (m, 2H), 6.89 (d, J=8.6 Hz, 2H), 6.79~6.71 (m, 3H), 6.06 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 163.5, 161.6, 157.9, 144.7, 136.6, 136.6, 130.9, 128.5, 127.8, 120.1, 119.1, 116.0, 115.8, 115.8, 115.6, 64.1; HRMS (ESI) calcd for C20H14FN2O [M-H]- 317.1096, found 317.1099.

    2-(4-Hydroxyphenyl)-2-(phenylamino)-2-(4-(trifluoro- methyl)phenyl)acetonitrile (3i): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3i 34.5 mg, 94% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.75 (s, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.45 (d, J=7.4 Hz, 2H), 7.14 (t, J=7.9 Hz, 2H), 6.95~6.85 (m, 2H), 6.84~6.72 (m, 3H), 6.18 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.1, 158.0, 144.8, 144.5, 144.5, 130.4, 130.2, 130.0, 128.6, 127.8, 127.1, 126.1, 126.1, 125.2, 123.1, 119.7, 119.4, 116.1, 115.9, 115.8, 64.5; HRMS (ESI) calcd for C21H14F3N2O [M-H]- 367.1064, found 367.1069.

    2-(4-Hydroxyphenyl)-2-(phenylamino)-2-(m-tolyl)ace- tonitrile (3j): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3j 27.6 mg, 88% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.65 (s, 1H), 7.46 (s, 1H), 7.41 (dd, J=11.9, 5.1 Hz, 3H), 7.31 (t, J=7.7 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.14~7.06 (m, 2H), 6.90~6.85 (m, 2H), 6.76 (d, J=8.6 Hz, 3H), 5.97 (s, 1H), 2.34 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 158.2, 145.4, 141.0, 139.2, 131.6, 129.7, 129.3, 129.0, 128.3, 127.2, 123.8, 120.8, 119.4, 116.5, 116.1, 65.1, 21.1; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1343.

    2-(3-Bromophenyl)-2-(4-hydroxyphenyl)-2-(phenylami-no)acetonitrile (3k): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3k 34.7 mg, 92% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.73 (s, 1H), 7.78 (s, 1H), 7.65 (dd, J=8.0, 0.7 Hz, 1H), 7.59~7.55 (m, 1H), 7.47~7.40 (m, 3H), 7.14 (dd, J=8.4, 7.5 Hz, 2H), 6.91 (d, J=8.6 Hz, 2H), 6.79~6.74 (m, 3H), 6.13 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.4, 144.9, 143.4, 132.0, 131.5, 130.8, 129.4, 129.0, 128.1, 125.7, 122.9, 120.1, 119.7, 116.5, 116.2, 64.6; HRMS (ESI) calcd for C20H14BrN2O [M-H]- 377.0295, found 377.0293.

    2-(3-Chlorophenyl)-2-(4-hydroxyphenyl)-2-(phenylami-no)acetonitrile (3l): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3l 30.3 mg, 91% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.75 (d, J=1.8 Hz, 1H), 7.66~7.56 (m, 2H), 7.53~7.38 (m, 4H), 7.13 (dd, J=8.5, 7.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 6.82~6.71 (m, 3H), 6.14 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.4, 144.9, 143.2, 134.8, 131.2, 130.9, 129.1, 129.0, 128.1, 126.5, 125.3, 120.1, 119.7, 116.5, 116.2, 64.7; HRMS (ESI) calcd for C20H14ClN2O [M-H]- 333.0800, found 333.0797.

    2-(3-Fluorophenyl)-2-(4-hydroxyphenyl)-2-(phenylami-no)acetonitrile (3m): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3m 29.8 mg, 94% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.71 (s, 1H), 7.53~7.48 (m, 2H), 7.45 (dd, J=6.9, 1.9 Hz, 2H), 7.36 (dd, J=10.3, 1.0 Hz, 1H), 7.19~7.08 (m, 3H), 6.90 (dd, J=7.0, 1.7 Hz, 2H), 6.80~6.72 (m, 3H), 6.11 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 164.4, 162.5, 158.5, 145.04, 143.8, 143.7, 131.6, 131.6, 131.1, 129.1, 128.2, 122.7, 122.7, 120.3, 119.8, 116.6, 116.3, 116.0, 115.8, 113.8, 113.6, 64.8; HRMS (ESI) calcd for C20H14FN2O [M-H]- 317.1096, found 317.1091.

    2-(4-Hydroxyphenyl)-2-(phenylamino)-2-(o-tolyl)aceto-nitrile (3n): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3n 28.2 mg, 90% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.73 (s, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.37~7.22 (m, 5H), 7.12 (dd, J=8.4, 7.5 Hz, 2H), 6.89 (d, J=8.7 Hz, 2H), 6.80~6.69 (m, 3H), 5.86 (s, 1H), 2.36 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 158.0, 144.8, 136.5, 136.3, 132.8, 129.8, 128.8, 128.4, 128.0, 126.0, 120.3, 119.4, 118.7, 115.8, 115.6, 63.1, 20.3; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1343.

    2-(3, 5-Dimethylphenyl)-2-(4-hydroxyphenyl)-2-(phen- ylamino)acetonitrile (3o): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3o 28.1 mg, 86% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.64 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.24 (s, 2H), 7.10 (dd, J=8.6, 7.4 Hz, 2H), 7.00 (s, 1H), 6.87 (dd, J=6.9, 4.9 Hz, 2H), 6.75 (t, J=8.2 Hz, 3H), 5.93 (s, 1H), 2.29 (s, 6H); 13C NMR (126 MHz, Acetone-d6) δ: 157.7, 145.0, 140.6, 138.5, 131.2, 130.0, 128.4, 127.7, 123.9, 120.3, 118.9, 116.0, 115.6, 64.6, 20.5; HRMS (ESI) calcd for C22H19N2O [M-H]- 327.1503, found 327.1507.

    2-(4-Hydroxyphenyl)-2-(naphthalen-2-yl)-2-(phenyla- mino)acetonitrile (3p): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3p 32.8 mg, 94% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.67 (s, 1H), 8.18 (s, 1H), 8.00~7.91 (m, 3H), 7.70 (d, J=8.7 Hz, 1H), 7.58~7.53 (m, 2H), 7.52~7.43 (m, 2H), 7.11 (t, J=7.9 Hz, 2H), 6.88 (d, J=7.2 Hz, 2H), 6.81 (d, J=7.9 Hz, 2H), 6.75 (t, J=7.4 Hz, 1H), 6.13 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.3, 145.4, 138.3, 133.7, 131.5, 129.5, 129.0, 128.9, 128.4, 128.1, 127.4, 127.3, 125.8, 124.4, 120.7, 119.6, 65.3; HRMS (ESI) calcd for C24H17N2O [M-H]- 349.1346, found 349.1343.

    2-(4-Hydroxyphenyl)-2-(naphthalen-1-yl)-2-(phenyl- amino)acetonitrile (3q): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3q 31.4 mg, 90% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.76 (d, J=16.6 Hz, 1H), 8.42~8.30 (m, 1H), 8.04~7.97 (m, 2H), 7.62~7.46 (m, 4H), 7.45~7.39 (m, 2H), 7.19~7.06 (m, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.85~6.79 (m, 2H), 6.79~6.69 (m, 1H), 6.07 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.5, 145.2, 135.5, 134.2, 130.9, 130.6, 130.3, 129.7, 129.4, 129.0, 127.5, 126.7, 126.4, 125.9, 125.3, 120.4, 120.3, 119.3, 116.4, 116.3, 63.8; HRMS (ESI) calcd for C24H17N2O [M-H]- 349.1346, found 349.1348.

    2-(4-Hydroxy-3-methylphenyl)-2-phenyl-2-(phenylami- no)acetonitrile (3r): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3r 28.2 mg, yield 90%. 1H NMR (500 MHz, Acetone-d6) δ: 8.54 (s, 1H), 7.62 (d, J=7.4 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.39~7.32 (m, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.14~7.06 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 6.79~6.72 (m, 3H), 5.98 (s, 1H), 2.19 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 156.2, 145.4, 141.1, 131.6, 129. 5, 129.3, 129.0, 126.8, 125.5, 125.5, 120.8, 119.4, 116.5, 115.3, 65.1, 16.0; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1342.

    2-(3-Bromo-4-hydroxyphenyl)-2-phenyl-2-(phenylami- no)acetonitrile (3s): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3s 34.7 mg, 92% yield. 1H NMR (500 MHz, CDCl3) δ: 7.72 (d, J=2.3 Hz, 1H), 7.61~7.57 (m, 2H), 7.47~7.37 (m, 4H), 7.17 (t, J=7.9 Hz, 2H), 7.02 (d, J=8.6 Hz, 1H), 6.87 (t, J=7.4 Hz, 1H), 6.63 (d, J=7.9 Hz, 2H), 4.41 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 153.1, 143.6, 139.6, 133.3, 130.3, 129.6, 129.4, 129.3, 127.5, 126.4, 120.6, 119.8, 116.9, 116.4, 111.0, 64.7; HRMS (ESI) calcd for C20H14BrN2O [M-H]- 377.0295, found 377.0299.

    2-(3-Chloro-4-hydroxyphenyl)-2-phenyl-2-(phenylami- no)acetonitrile (3t): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3t 30.3 mg, 91% yield. 1H NMR (500 MHz, CDCl3) δ: 7.65~7.56 (m, 3H), 7.46~7.37 (m, 4H), 7.20~7.14 (m, 2H), 7.06~7.01 (m, 1H), 6.87 (t, J=7.4 Hz, 1H), 6.63 (d, J=7.7 Hz, 2H), 5.72 (s, 1H), 4.37 (s, 1H); 13C NMR (126 MHz, CDCl3) δ: 152.1, 143.5, 139.6, 133.0, 129.6, 129.4, 129.3, 127.3, 126.8, 126.4, 120.8, 120.6, 119.7, 117.1, 116.4, 64.8; HRMS (ESI) calcd for C20H14ClN2O [M-H]- 333.0800, found 333.0803.

    2-(3-Fluoro-4-hydroxyphenyl)-2-phenyl-2-(phenylami- no)acetonitrile (3u): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 3u 29.8 mg, 94% yield. 1H NMR (500 MHz, Acetone-d6) δ: 9.00 (s, 1H), 7.66~7.61 (m, 2H), 7.48~7.43 (m, 2H), 7.42~7.36 (m, 1H), 7.35~7.26 (m, 2H), 7.15~7.09 (m, 2H), 7.06 (t, J=8.8 Hz, 1H), 6.77 (t, J=8.1 Hz, 3H), 6.12 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 152.8, 150.8, 145.8, 145.7, 145.1, 140.6, 132.6, 132.6, 129.6, 129.3, 129.0, 126.7, 123.2, 123.2, 120.3, 119.7, 118. 7, 118.7, 116.6, 114.9, 114.7, 64.8; HRMS (ESI) calcd for C20H14FN2O [M-H]- 317.1096, found 317.1091.

    2-(4-Hydroxyphenyl)-2-phenyl-2-(p-tolylamino)acetoni- trile (4a): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 4a 28.8 mg, 92% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.67 (s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.42 (t, J=7.9 Hz, 4H), 7.36 (t, J=7.3 Hz, 1H), 6.90 (dd, J=19.7, 8.3 Hz, 4H), 6.68 (d, J=8.2 Hz, 2H), 5.84 (s, 1H), 2.18 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 157.9, 142.7, 140.9, 131.5, 129.2, 129.2, 128.7, 128.2, 128.0, 126.5, 120.6, 116.5, 115.9, 65.1, 19.9; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1350.

    2-((4-Bromophenyl)amino)-2-(4-hydroxyphenyl)-2- phenylacetonitrile (4b): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V: V=1:9~1:4) as eluent to afford 4b 34.3 mg, 91% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.71 (s, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.47~7.37 (m, 5H), 7.27 (d, J=8.8 Hz, 2H), 6.91~6.86 (m, 2H), 6.75~6.68 (m, 2H), 6.26 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.4, 144.6, 140.4, 131.8, 131.0, 129.6, 129.2, 128.3, 126.7, 120.4, 118.3, 116.2, 111.1, 65.0; HRMS (ESI) calcd for C20H14BrN2O [M-H]- 377.0295, found 377.0298.

    2-((4-Chlorophenyl)amino)-2-(4-hydroxyphenyl)-2-ph- enylacetonitrile (4c): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 4c 30.6 mg, 92% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.72 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.50~7.33 (m, 5H), 7.14 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 6.77 (d, J=8.8 Hz, 2H), 6.23 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.1, 143.9, 140.2, 130.8, 129.3, 128.9, 128.6, 128.0, 126.5, 123.6, 120.2, 117.6, 116.0, 64.9; HRMS (ESI) calcd for C20H14ClN2O [M-H]- 333.0800, found 333.0797.

    2-(4-Hydroxyphenyl)-2-phenyl-2-((4-(trifluorometho- xy)phenyl)amino)acetonitrile (4d): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 4d 36.4 mg, 95% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.73 (s, 1H), 7.66~7.58 (m, 2H), 7.48~7.35 (m, 5H), 7.12 (d, J=8.5 Hz, 2H), 6.94~6.87 (m, 2H), 6.87~6.80 (m, 2H), 6.34 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.2, 144.3, 141.7, 140.2, 130.8, 129.4, 129.0, 128.1, 126.5, 122.0, 120.2, 120.0, 116.9, 116.1, 64.9; HRMS (ESI) calcd for C21H14F3N2O2 [M-H]- 383.1013, found 383.1009.

    2-(4-Hydroxyphenyl)-2-phenyl-2-(m-tolylamino)aceto- nitrile (4e): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 4e 27.8 mg, 89% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.68 (s, 1H), 7.64~7.58 (m, 2H), 7.46~7.39 (m, 4H), 7.36 (t, J=4.6 Hz, 1H), 6.97 (t, J= 7.8 Hz, 1H), 6.90~6.84 (m, 2H), 6.65 (s, 1H), 6.58 (d, J=7.5 Hz, 1H), 6.51~6.45 (m, 1H), 5.92 (s, 1H), 2.16 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 158.1, 145.2, 141.0, 138.3, 131.6, 129.4, 128.9, 128.7, 128.2, 126.7, 120.7, 120.3, 117.3, 116.1, 113.4, 65.0, 21.2; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1343.

    2-((3-Chlorophenyl)amino)-2-(4-hydroxyphenyl)-2- phenylacetonitrile (4f): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V: V=1:9~1:4) as eluent to afford 4f 30.0 mg, 90% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.71 (s, 1H), 7.61 (d, J=7.6 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.43~7.37 (m, 3H), 7.11 (t, J=8.1 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.82 (d, J=1.7 Hz, 1H), 6.77 (d, J=7.9 Hz, 1H), 6.68 (dd, J=8.2, 1.6 Hz, 1H), 6.34 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.4, 146.7, 140.3, 134.2, 130.9, 130.4, 129.6, 129.2, 128.2, 126.7, 120.3, 119.1, 116.2, 116.1, 114.7, 64.9; HRMS (ESI) calcd for C20H14ClN2O [M-H]- 333.0800, found 333.0805.

    2-(4-Hydroxyphenyl)-2-phenyl-2-(o-tolylamino)aceto- nitrile (4g): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 4g 27.6 mg, 88% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.69 (s, 1H), 7.69~7.62 (m, 2H), 7.48~7.41 (m, 4H), 7.38~7.34 (m, 1H), 7.13 (d, J=7.2 Hz, 1H), 6.93~6.86 (m, 3H), 6.74~6.69 (m, 1H), 6.49 (d, J=8.1 Hz, 1H), 5.03 (s, 1H), 2.32 (s, 3H); 13C NMR (126 MHz, Acetone-d6) δ: 158.3, 142.6, 141.1, 131.8, 130.7, 129.6, 129.0, 128.0, 126.5, 126.3, 125.5, 120.8, 119.7, 116.3, 115.4, 64.7, 17.6; HRMS (ESI) calcd for C21H17N2O [M-H]- 313.1346, found 313.1348.

    2-(4-Hydroxyphenyl)-2-(naphthalen-2-ylamino)-2-ph- enylacetonitrile (4h): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 4h 32.2 mg, 92% yield. 1H NMR (500 MHz, Acetone-d6) δ: 8.77 (s, 1H), 7.69 (dd, J=21.8, 8.1 Hz, 4H), 7.49~7.36 (m, 6H), 7.33~7.25 (m, 2H), 7.22 (t, J=7.3 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 6.82 (s, 1H), 6.31 (s, 1H); 13C NMR (126 MHz, Acetone-d6) δ: 158.3, 142.8, 140.6, 134.7, 131.2, 129.5, 129.3, 129.0, 128.9, 128.6, 128.3, 127.9, 126.8, 126.6, 123.2, 120.5, 119.8, 116.2, 110.0, 65.1; HRMS (ESI) calcd for C24H17- N2O [M-H]- 349.1346, found 349.1343.

    2-(4-Hydroxyphenyl)-2-morpholino-2-phenylacetonitri- le (6): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 6 25.0 mg, 85% yield. 1H NMR (500 MHz, CDCl3) δ: 7.67 (d, J=7.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.39~7.33 (m, 2H), 7.29~7.27 (m, 1H), 6.81 (d, J=8.7 Hz, 2H), 5.69 (s, 1H), 3.85~3.77 (m, 4H), 2.60 (d, J=4.1 Hz, 4H); 13C NMR (126 MHz, CDCl3) δ: 156.1, 139.3, 130.9, 129.3, 128.6, 128.0, 126.4, 117.0, 116.1, 75.5, 67.2, 49.6; HRMS (ESI) calcd for C18H17N2O2 [M-H]- 293.1296, found 293.1291.

    2-(4-Hydroxyphenyl)-2-(1H-imidazol-1-yl)-2-phenyl- acetonitrile (9): It was purified by flash chromatography on silica gel using acetone/petroleum ether (V:V=1:9~1:4) as eluent to afford 9 24.7 mg, 90% yield. 1H NMR (400 MHz, CD3OD) δ: 7.52~7.46 (m, 3H), 7.43 (s, 1H), 7.22~7.09 (m, 4H), 7.06 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H); 13C NMR (101 MHz, CD3OD) δ: 160.6, 138.4, 131.4, 131.1, 130.6, 130.5, 130.4, 128.3, 128.1, 127.6, 120.3, 117.1, 67.9; HRMS (ESI) calcd for C17H12N3O [M-H]- 274.0986, found 274.0990.

    Supporting Information  Copies of 1H NMR and 13C NMR spectra. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.


    Dedicated to the 40th anniversary of Chinese Journal of Organic Chemistry.
    1. [1]

      (a) Turner, A. B. Q. Rev., Chem. Soc. 1964, 18, 347.
      (b) Peter, M. G. Angew. Chem. Int. Ed. 1989, 28, 555.
      (c) Itoh, T. Prog. Polym. Sci. 2001, 26, 1019.
      (d) Parra, A.; Tortosa, M. ChemCatChem 2015, 7, 1524.
      (e) Li, W.; Xu, X.; Zhang, P.; Li, P. Chem. Asian J. 2018, 13, 2350.

    2. [2]

      (a) Angle, S. R.; Turnbull, K. D. J. Am. Chem. Soc. 1989, 111, 1136.
      (b) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1990, 55, 3708.
      (c) Baik, W.; Lee, H. J.; Jang, J. M.; Koo, S.; Kim, B. H. J. Org. Chem. 2000, 65, 108.
      (d) Reddy, V.; Anand, R. V. Org. Lett. 2015, 17, 3390.
      (e) Ramanjaneyulu, B. T.; Mahesh, S.; Anand, R. V. Org. Lett. 2015, 17, 3952.
      (f) Shen, Y.; Qi, J.; Mao, Z.; Cui, S. Org. Lett. 2016, 18, 2722.
      (g) Huang, X. Y.; Ding, R.; Mo, Z. Y.; Xu, Y. L.; Tang, H. T.; Wang, H. S.; Chen, Y. Y.; Pan, Y. M. Org. Lett. 2018, 20, 4819.
      (h) Wu, Q. Y.; Ao, G. Z.; Liu, F. Org. Chem. Front. 2018, 5, 2061.
      (i) Ke, M.; Song, Q. Adv. Synth. Catal. 2017, 359, 384.

    3. [3]

      (a) Chu, W. D.; Zhang, L. F.; Bao, X.; Zhao, X. H.; Zeng, C.; Du, J. Y.; Zhang, G. B.; Wang, F. X.; Ma, X. Y.; Fan, C. A. Angew. Chem. Int. Ed. 2013, 52, 9229.
      (b) Caruana, L.; Kniep, F.; Johansen, T. K.; Poulsen, P. H.; Jørgensen, K. A. J. Am. Chem. Soc. 2014, 136, 15929.
      (c) Lou, Y.; Cao, P.; Jia, T.; Zhang, Y.; Wang, M.; Liao, J. Angew. Chem. Int. Ed. 2015, 54, 12134.
      (d) Dong, N.; Zhang, Z. P.; Xue, X. S.; Li, X.; Cheng, J. P. Angew. Chem. Int. Ed. 2016, 55, 1460.
      (e) Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Org. Lett. 2016, 18, 428.
      (f) Ge, L.; Lu, X.; Cheng, C.; Chen, J.; Cao, W.; Wu, X.; Zhao, G. J. Org. Chem. 2016, 81, 9315.
      (g) Ma, C.; Huang, Y.; Zhao, Y. ACS Catal. 2016, 6, 6408.
      (h) He, F. S.; Jin, J. H.; Yang, Z. T.; Yu, X.; Fossey, J. S.; Deng, W. P. ACS Catal. 2016, 6, 652.
      (i) Jarava-Barrera, C.; Parra, A.; López, A.; Cruz-Acosta, F.; Collado-Sanz, D.; Cárdenas, D. J.; Tortosa, M. ACS Catal. 2016, 6, 442.
      (j) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. ACS Catal. 2017, 7, 2805.
      (k) Huang, G. B.; Huang, W. H.; Guo, J.; Xu, D. L.; Qu, X. C.; Zhai, P. H.; Zheng, X. H.; Weng, J.; Lu, G. Adv. Synth. Catal. 2019, 361, 1241.

    4. [4]

      Errede, L. A.; Szwarc, M. Q. Rev., Chem. Soc. 1958, 12, 301.

    5. [5]

      (a) Wang, Z.; Wong, Y. F.; Sun, J. Angew. Chem. Int. Ed. 2015, 54, 13711.
      (b) Chen, M.; Sun, J. Angew. Chem. Int. Ed. 2017, 56, 11966.

    6. [6]

      (a) Wang, Z.; Zhu, Y.; Pan, X.; Wang, G.; Liu, L. Angew. Chem. Int. Ed. 2020, 59, 3053.
      (b) Pan, X.; Wang, Z.; Kan, L.; Mao, Y.; Zhu, Y.; Liu, L. Chem. Sci. 2020, 11, 2414.

    7. [7]

      Qi, Y.; Zhang, F.; Wang, L.; Feng, A.; Zhu, R.; Sun, S.; Li, W.; Liu, L. Org. Biomol. Chem. 2020, 18, 3522.

    8. [8]

      (a) Beatty, J. W.; Stephenson, C. R. J. Acc. Chem. Res. 2015, 48, 1474.
      (b) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
      (c) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47, 258.
      (d) Legnani, L.; Bhawal, B. N.; Morandi, B. Synthesis 2017, 49, 776.
      (e) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39.

    9. [9]

      (a) Jadhav, A. S.; Pankhade, Y. A.; Anand, R. V. J. Org. Chem. 2018, 83, 8596.
      (b) Jiang, F.; Yuan, F. R.; Jin, L. W.; Mei, G. J.; Shi, F. ACS Catal. 2018, 8, 10234.
      (c) Feng, Z.; Yuan, Z.; Zhao, X.; Huang, Y.; Yao, H. Org. Chem. Front. 2019, 6, 3535.
      (d) Roy, D.; Panda, G. Synthesis 2019, 51, 4434.
      (e) Torán, R.; Vila, C.; Sanz-Marco, A.; Muñoz, M.; Pedro, J.; Blay, G. Eur. J. Org. Chem. 2020, 5, 627.
      (f) Zhang, J.-R.; Jin, H.-S.; Wang, R.-B.; Zhao, L.-M. Adv. Synth. Catal. 2019, 361, 4811.

    10. [10]

      (a) Otto, N.; Opatz, T. Chem. Eur. J. 2014, 20, 13064.
      (b) Huang, P. Q. Acta Chim. Sinica 2018, 76, 357(in Chinese).
      (黄培强, 化学学报, 2018, 76, 357.)
      (c) Gao, Y. J.; Xiao, Z. H.; Liu, L. X.; Huang, P. Q. Chin. J. Org. Chem. 2017, 37, 1189.

    11. [11]

      Singh, M.; Schott, J. T.; Leon, M. A.; Granata, R. T.; Dhaha, H. K.; Welles, J. A.; Boyce, M. A.; Oseni-Olalemi, H. S.; Mordaunt, C. E.; Vargas, A. J.; Patel, N. V.; Maitra, S. Bioorg. Med. Chem. Lett. 2012, 22, 6252.

    12. [12]

      (a) Tiffert, T.; Ginsburg, H.; Krugliak, M.; Elford, B. C.; Lew, V. L. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 331.
      (b) Saliba, K. J.; Kirk, K. Trans. R. Soc. Trop. Med. Hyg. 1998, 92, 666.

  • Scheme 1  Scope of p-QM components

    Scheme 2  Scope of aniline components

    Scheme 3  Secondary amine components

    Scheme 4  Preparation of substrate 1

    Regent and conditions: (a) PhMgBr (1.0 equiv.), THF, 0 ℃; (b) InCl3 (0.1 equiv.), TMSCN (1.3 equiv.), CH2Cl2, 0 ℃; (c) Pd/C (10%), MeOH, hydrogen balloon, r.t.; (d) DDQ (1.0 equiv.), CH2Cl2, r.t.

    Table 1.  Reaction condition optimizationa

    Entry Catalyst Solvent Time/h Yieldb/%
    3a 3a'
    1 DPP CH2Cl2 6 52 16
    2 DPP Toluene 6 57 8
    3 DPP EtOAc 6 60 10
    4 DPP THF 2 66 18
    5 DPP Acetone-d6 0.5 69 15
    6 DPP CH3CN 0.5 71 13
    7 DPP MeOH 0.5 75 < 5
    8 AcOH MeOH 0.5 82 < 5
    9 PTSA MeOH 0.5 91 < 5
    10 BF3•OEt2 MeOH 1 77 < 5
    11 AgOTf MeOH 1 68 < 5
    a Reaction conditions, unless otherwise specified: a solution of 1a (0.1 mmol), 2a (0.105 mmol), catalyst (0.01 mmol) in solvent (1.0 mL) at room temperature for indicated time period. b Isolated yield. DPP=diphenyl phosphate. PTSA=p-toluenesulfonic acid, Tf=trifluoromethanesulfonyl.
    下载: 导出CSV
  • 加载中
计量
  • PDF下载量:  0
  • 文章访问数:  60
  • HTML全文浏览量:  2
文章相关
  • 发布日期:  2020-11-25
  • 收稿日期:  2020-04-17
  • 修回日期:  2020-05-14
  • 网络出版日期:  2020-05-19
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

/

返回文章