Copper-Catalyzed Cyanoisopropylalkenylation of N-Alkenyl-acrylamides to Give 1, 3-Dihydropyrrol-2-ones

Enrui Dai Qing Luo Chunlin Chen Fengyuan Ying Ying Dong Yingjie Liu Baoling Wang Yinhai Ma Deqiang Liang

Citation:  Dai Enrui, Luo Qing, Chen Chunlin, Ying Fengyuan, Dong Ying, Liu Yingjie, Wang Baoling, Ma Yinhai, Liang Deqiang. Copper-Catalyzed Cyanoisopropylalkenylation of N-Alkenyl-acrylamides to Give 1, 3-Dihydropyrrol-2-ones[J]. Chinese Journal of Organic Chemistry, 2019, 39(12): 3524-3531. doi: 10.6023/cjoc201905006 shu

铜催化N-烯基丙烯酰胺氰异丙基化/烯基化反应合成1, 3-二氢吡咯-2-酮

    通讯作者: 刘颖杰, liuyj691@nenu.edu.cn
    梁德强, liangdq695@nenu.edu.cn
  • 基金项目:

    国家自然科学基金 21702083

    云南省万人计划青年拔尖人才专项、云南省高校科技创新团队支持计划、云南省应用基础研究计划项目 2018FD028

    云南省万人计划青年拔尖人才专项、云南省高校科技创新团队支持计划、云南省应用基础研究计划项目 2018FH001-002

    黑龙江省自然科学基金优秀青年 YQ2019B004

    国家自然科学基金(No.21702083)、云南省万人计划青年拔尖人才专项、云南省高校科技创新团队支持计划、云南省应用基础研究计划项目(Nos.2018FD028,2018FH001-002)、黑龙江省自然科学基金优秀青年(No.YQ2019B004)、云南省教育厅资助性项目(No.2017ZDX048)和昆明学院人才引进(No.YJL19001)资助项目

    云南省教育厅资助性项目 2017ZDX048

    昆明学院人才引进 YJL19001

摘要: 报道了铜催化的化学选择性N-烯基丙烯酰胺氰异丙基化/环化级联反应,利用该反应可以实现1,3-二氢吡咯-2-酮的合成.丙烯酰胺的自由基环合反应中,用于捕获分子内自由基的基团主要局限于芳基、炔基和氰基,而本工作使用烯胺双键作为内置自由基捕获基团,以丙烯酰胺双键作为自由基受体.该反应的化学选择性可能是由自由基反应的极性匹配原则决定.

English

  • Radical-involved transformations have been witnessed to be burgeoning, [1] and acrylamide chemistry represents one of the most remarkable advances.[2-8] The methacryloyl group was proved to be an excellent radical acceptor, and upon addition by an external radical, it transforms into an alkyl radical stabilized by the carbonyl and methyl groups. This radical could be trapped by an inbuilt scavenger, leading to functionalized azacycles such as oxindoles, [2, 3] isoquinoline-1, 3-diones, [4] pyrrolidin-2-ones, [5, 6] and 3, 4-dihydroquinolin-2-ones (Scheme 1).[7, 8] However, the radical traps are restricted to the aryl, [2-5] alkynyl[6, 7] or cyano group, [8] and only a limited variety of products could be produced. Thus, it is highly desirable to develop new inbuilt radical-trapping groups to make an advancement in acrylamide chemistry and to give novel carbo- or heterocycles.

    Scheme 1

    Scheme 1.  Acrylamide-based radical cyclization

    The 1, 3-dihydropyrrol-2-one motif is frequently encountered in natural products, [9] pharmaceuticals[10] and dyes.[11] However, entries to this privileged structure are rather limited, and mainly restricted to the condensation reaction of amines with γ-keto esters.[11] Given our interest in radical chemistry, [12, 13] we hypothesized that the use of another alkenic bond as the inbuilt radical trap in cyclizations involving acrylamides might deliver novel heterocycles such as 1, 3-dihydropyrrol-2-ones (Scheme 1). However, such a reaction is challenging to effect, because both alkenyl groups might serve as radical acceptors, and the resulting radical intermediates upon addition would generally undergo further transformations to deteriorate desired reactions.[14] In light of our experience in C(sp2)—H functionalization, [15] electron-rich alkenes with high conjugation energies usually remain intact during reaction, and the cyanoalkylation/alkenylation cascade of N-(1-phenylvinyl) acrylamides were tested using 2, 2'-azo-bis(2-methylpro-pionitrile) (AIBN) as an external radical source.[13] Here the copper-catalyzed cyanoisopropylalkenylation reaction of N-alkenylacrylamides using the enaminic double bond as an inbuilt radical trap, which enables a direct and straightforward synthesis of 1, 3-dihydropyrrol-2-ones. Great chemo-selectivity was achieved, probably due to polarity matching, [16, 17] and the alkenic bonds of acrylamide and enamine moieties served as the radical acceptor and inbuilt radical trap, respectively.

    Cyanoisopropylalkenylation of N-benzyl-N-(1-phenyl-vinyl)metha-crylamide (1a) was investigated (Table 1). Exposure of 1, 5-diene (1a) to 10 mol% CuI[18] and 3 equiv. of AIBN at 80 ℃ in 1, 2-dichloroethane (DCE) furnished the desired 1, 3-dihydropyrrol-2-one (2a) in 34% yield (Entry 1). While toluene (Entry 2) and N, N-dimethylformamide (DMF, Entry 7) were proved to be ineffective for this transformation, the use of MeNO2 (Entry 3), MeCN (Entry 4), 1, 4-dioxane (Entry 6) or dimethylsulfoxide (DMSO, Entry 8) obtained 1, 3-dihydropyrrol-2-one 2a in diminished yields. Using tetrahydrofuran (THF) as the solvent, 2a was produced in 46% yield (Entry 5). CuI is the optimal catalyst, and slightly lower yields of 2a were obtained under the catalysis of CuBr (Entry 9), CuCl (Entry 10), Cu2O (Entry 11) or Cu(OAc)2 (Entry 12). FeCl3 (Entry 13) and AgOAc (Entry 14) are inferior to these copper salts in catalytic performance, whereas 1, 3-dihydropyrrol-2-one 2a was delivered in only 21% yield under catalyst-free conditions (Entry 15). The beneficial effect associated with CuI might reflect the abilities of transition metal salts to stabilize radicals and to facilitate the single-electron- transfer (SET) process.[1] Attempt to further improve the reaction efficiency by adding oxidative initiators met with no success, and the tested oxidants include anhydrous tert-butyl hydroperoxide (TBHP, Entry 16), di-tert-butyl peroxide (DTBP, Entry 17), benzoyl peroxide (BPO, Entry 18), K2S2O8 (Entry 19), dicumyl peroxide (DCP), oxone, PhI(OAc)2 and I2O5. Similar failures were experienced upon addition of 0.5 equiv. of additives such as HOAc, trifluoroacetic acid (TFA), TsOH, NaOAc, NaHCO3, K2CO3, K3PO4, KF, Et3N or 1, 4-diazabicyclo[2.2.2]octane (DABCO, Entries 20~29). Varying the catalyst loading (Entries 30 and 31) or increasing the dosage of AIBN (Entry 32) both led to a depreciation in yield. To our delight, the yield was improved to 57% when 4 equiv. of AIBN was used and added in two equal portions (Entry 33). No beneficial effect associated with the addition of AIBN in four equal portions (Entry 34) or with a higher reaction temperature (Entry 35) was observed. No reaction occurred at 50 ℃ (Entry 36).

    Table 1

    Table 1.  Screening of reaction conditionsa
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    Entry Catalyst(mol%) AIBN/equiv. Additive(equiv.) Solvent T/℃ Yield/%
    1 CuI (10) 3 DCE 80 34
    2 CuI (10) 3 Toluene 80 Trace
    3 CuI (10) 3 MeNO2 80 9
    4 CuI (10) 3 MeCN 80 16
    5 CuI (10) 3 THF 80 46
    6 CuI (10) 3 1, 4-Dioxane 80 15
    7 CuI (10) 3 DMF 80 Trace
    8 CuI (10) 3 DMSO 80 22
    9 CuBr (10) 3 THF 80 42
    10 CuCl (10) 3 THF 80 44
    11 Cu2O (10) 3 THF 80 42
    12 Cu(OAc)2 (10) 3 THF 80 38
    13 FeCl3 (10) 3 THF 80 31
    14 AgOAc (10) 3 THF 80 36
    15 3 THF 80 21
    16 CuI (10) 3 TBHPb (2) THF 80 26
    17 CuI (10) 3 DTBP (2) THF 80 31
    18 CuI (10) 3 BPO (2) THF 80 29
    19 CuI (10) 3 K2S2O8 (2) THF 80 38
    20 CuI (10) 3 HOAc (0.5) THF 80 38
    21 CuI (10) 3 TFA (0.5) THF 80 34
    22 CuI (10) 3 TsOH (0.5) THF 80 28
    23 CuI (10) 3 NaOAc (0.5) THF 80 18
    24 CuI (10) 3 NaHCO3 (0.5) THF 80 15
    25 CuI (10) 3 K2CO3 (0.5) THF 80 13
    26 CuI (10) 3 K3PO4 (0.5) THF 80 15
    27 CuI (10) 3 KF (0.5) THF 80 14
    28 CuI (10) 3 Et3N (0.5) THF 80 28
    29 CuI (10) 3 DABCO (0.5) THF 80 22
    30 CuI (20) 3 THF 80 41
    31 CuI (5) 3 THF 80 33
    32 CuI (10) 5 THF 80 43
    33 CuI (10) 4c THF 80 57
    34 CuI (10) 4d THF 80 49
    35 CuI (10) 4c THF 120 19
    36 CuI (10) 4c THF 50 nr
    a Reaction conditions: 1a (0.3 mmol), solvent (3 mL), Ar, 24 h. b 5.0~6.0 mol/L in decane. c AIBN was added in two equal portions at 12 h intervals. d AIBN was added in four equal portions at 6 h intervals.

    Although a satisfactory yield was not achieved, we consider the results acceptable, considering that the cyanoisopropyl radical derived from AIBN possesses tremendous steric hindrance upon coupling.[13]

    Under the optimized conditions, the scope of the cyanoalkylation/alkenylation cascade was explored (Table 2). N-Alkenylacrylamides bearing a phenyl- (2a), 4-methyl-phenyl- (2b) or 3-methylphenyl-substituted enamine moiety (2c) underwent the cyclization with comparable ease, affording corresponding 1, 3-dihydropyrrol-2-ones 2a~2c in 58%~62% yields. Steric effects adjacent to the enaminic double bond play a negligible role in the reaction, and the ortho-methyl styryl substrate reacted with AIBN to afford related product 2d in 68% yield. When 1-(4-fluoro-phenyl) enamide was used as the substrate, 1, 3-dihydro- pyrrol-2-one (2e) was afforded in a lower yield of 48%. The electronic nature of the substituents on the N-benzyl ring exerts weak effects on the reaction kinetics, and electron-donating substituents such as methyl (2f) and methoxy group (2g~2j), and electron-withdrawing motifs like chloro (2k~2m) and fluoro atoms (2n, 2o), at para, meta, or ortho-positions were both tolerated, affording 1, 3-dihydro-pyrrol-2-one products 2f~2o in 46%~65% yields. Interestingly, steric effects were observed in the cases concern N-(2-chlorobenzyl) enamides, and the yields of related 1, 3-dihydropyrrol-2-ones (2l, 2m) were slightly compromised. The cyanoisopropylalkenylation of the 2-methyl enamide also proceeded well, affording 1, 3-dihydropyrrol-2-one product 2p albeit in a lower yield. To our delight, the N-methyl protecting group is compatible with this transformation as well, and the enamide substrates derived from methanamine reacted with AIBN to afford 1, 3-dihydro-pyrrol-2-ones (2q, 2r) in 63%~72% yields.

    Table 2

    Table 2.  Synthesis of 1, 3-dihydropyrrol-2-onesa
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    To probe the reaction mechanism, radical trapping experiments were performed (Scheme 2). Upon addition of 2 equiv. of either 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEM-PO) or butylated hydroxytoluene (BHT) as the radical scavenger, the model reactions under otherwise standard conditions were completely suppressed. Furthermore, cyanoisopropyl-BHT adduct 3 was formed in 57% yield in the BHT experiment. The radical clock reaction of N-(2-methylallyl)-N-phenylacetamide (4) with AIBN proceeded smoothly to furnish the cyanoalkyl indoline 5 in 32% yield, [13b] while N, N-diallylaniline 6 reacted with AIBN under standard conditions to give a complex mixture. These results suggest that the cyanoisopropyl radical might be involved in the title reaction. No reaction occurred upon exposure of N-alkenylacrylamide (1a) to 1 equiv. of Cu(OAc)2 at 80 ℃ in THF in the presence of either 2 equiv. of a radical scavenger such as TEMPO, BHT, or 1, 1-diphenylethylene (DPE), or 5 equiv. of a nucleophile like MeOH, HOAc, N-hydroxyphthalimide (NHPI), TsNH2, phthalimide, or pyrrolidin-2-one (Scheme 2), suggesting that an enaminic radical cation is not likely to be involved in this transformation.

    Scheme 2

    Scheme 2.  Mechanistic investigations

    On the basis of the above observations and previous works, [2-8, 12, 13] a plausible mechanism is proposed (Scheme 2). At the beginning, thermal decomposition of AIBN occurs to release the cyanoisopropyl radical A, the addition of which to the alkenic bond of the acrylamidyl moiety leads to the alkyl radical intermediate B with a newly formed C—C bond. Intramolecular radical tapping by the enaminic double bond ensues, furnishing ring closure intermediate C. Subsequent SET from C to Cu(II) leads to cationic intermediate D as well as Cu(I). While Cu(I) is oxidized to Cu(II) by the cyanoisopropyl radical A to finish the catalytic cycle, the dehydrogenation of cation D proceeds to afford 1, 3-dihydropyrrol-2-one product 2a.

    In conclusion, a copper-catalyzed cyanoisopropylation/alkenylation cascade of N-alkenylacrylamides is reported, providing a straightforward and chemoselective access to 1, 3-dihydropyrrol-2-ones. The enaminic double bond was used as an inbuilt radical trap, while the olefinic bond acrylamide moiety acted as the radical acceptor.

    Chemicals were purchased from commercial sources and used without treatment unless stated otherwise. Reactions were monitored by thin layer chromatography (TLC) using silica gel F254 plates. Products were purified by column chromatography over 300~400 mesh silica gel under a positive pressure of air. 1H NMR, 19F NMR, 13C NMR and DEPT spectra were recorded at 25 ℃ on a Bruker AscendTM 400 spectrometer using tetramethyl silane (TMS) as an internal standard. High-resolution mass spectra (HRMS) were obtained using a Bruker microTOF II Focus spectrometer (ESI). Substrates 1 were synthesized according to the literature procedure.[19]

    Take the synthesis of 1a as an example, [19] a mixture of benzylamine (1.49 g, 13.9 mmol), acetophenone (1.67 g, 13.9 mmol), and 4 Å molecular sieves (MSs) in toluene (50 mL) was stirred at 120 ℃ for 12 h, which furnished the corresponding crude imine. After removal of the MSs by filtration, triethylamine (2.90 mL, 28.5 mmol) and methacryloyl chloride (0.971 g, 9.29 mmol) were added to the crude imine solvent at 0 ℃, and the mixture was stirred at 0 ℃ for 12 h. After warming to room temperature, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3 and brine, and concentrated. The crude product was purified by a silica gel column chromatography [V(petroleum ether):V(ethyl acetate)=80:1] to give N-benzyl-N-(1-phenylvinyl)methacrylamide (1a) as a pale yellow oil (2.24 g, 58% yield).

    Take the synthesis of 2a as an example, a 10-mL Schlenk tube, equipped with a magnetic stirring bar, was charged under argon with N-benzyl-N-(1-phenylvinyl)methacryl-amide (1a, 83 mg, 0.3 mmol), AIBN (99 mg, 0.6 mmol) and CuI (6 mg, 0.03 mmol), followed by addition of THF (3.0 mL). The mixture was stirred at 80 ℃ for 12 h. Another portion of AIBN (99 mg, 0.6 mmol) was added under argon. The resulting mixture was stirred at 80 ℃ for another 12 h. It was quenched with saturated aqueous Na2S2O3 (1.0 mL) and water (10.0 mL), and extracted with CH2Cl2 (10.0 mL) three times. The residue obtained after evaporation of the solvent was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, V:V=15:1) to afford 3-(1-benzyl-3-methyl-2-oxo-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2a) as a colorless oil (64 mg, 62% yield).

    3-(1-Benzyl-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2a): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.01 (s, 3H), 1.33 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.5 Hz, 1H), 2.16 (d, J=14.4 Hz, 1H), 4.53 (d, J=15.4 Hz, 1H), 4.82 (d, J=15.4 Hz, 1H), 5.63 (s, 1H), 6.96~6.99 (m, 2H), 7.18~7.22 (m, 3H), 7.28~7.31 (m, 2H), 7.33~7.39 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 182.91, 143.82, 137.13, 131.31, 129.15, 128.59, 128.42, 127.69, 127.33, 125.68, 112.43, 48.72, 47.04, 44.54, 31.40, 29.72, 26.35, 24.77; HRMS (ESI-TOF) calcd for C23H25N2O [M+H]+ 345.1961, found 345.1963.

    3-(1-Benzyl-3-methyl-2-oxo-5-(p-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2b): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.99 (s, 3H), 1.32 (s, 3H), 1.36 (s, 3H), 2.02 (d, J=14.4 Hz, 1H), 2.14 (d, J=14.4 Hz, 1H), 2.37 (s, 3H), 4.52 (d, J=15.4 Hz, 1H), 4.81 (d, J=15.4 Hz, 1H), 5.59 (s, 1H), 6.99~7.01 (m, 2H), 7.15~7.24 (m, 7H); 13C NMR (100 MHz, CDCl3) δ: 182.99, 143.87, 139.15, 137.25, 129.27, 128.42, 128.38, 128.30, 127.67, 127.29, 125.70, 112.01, 48.66, 47.04, 44.51, 31.39, 29.72, 26.36, 24.72, 21.35; HRMS (ESI-TOF) calcd for C24H27N2O [M+H]+ 359.2118, found 359.2119.

    3-(1-Benzyl-3-methyl-2-oxo-5-(m-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2c): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.02 (s, 3H), 1.33 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 2.30 (s, 3H), 4.50 (d, J=15.4 Hz, 1H), 4.81 (d, J=15.4 Hz, 1H), 5.61 (s, 1H), 6.99~7.00 (m, 2H), 7.04 (s, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.18~7.26 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 183.00, 144.03, 138.23, 137.34, 131.17, 129.88, 129.08, 128.49, 128.39, 127.77, 127.31, 125.70, 125.54, 112.14, 48.69, 47.01, 44.64, 31.40, 29.72, 26.38, 24.73, 21.33; HRMS (ESI-TOF) calcd for C24H27N2O [M+H]+ 359.2118, found 359.2116.

    3-(1-Benzyl-3-methyl-2-oxo-5-(o-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2d): white solid, m.p. 104~105 ℃. 1H NMR (400 MHz, CDCl3) δ: 1.04 (s, 3H), 1.33 (s, 3H), 1.37 (s, 3H), 2.01 (d, J=14.4 Hz, 1H), 2.03 (s, 3H), 2.17 (d, J=14.4 Hz, 1H), 4.40 (d, J=14.6 Hz, 1H), 4.49 (d, J=14.6 Hz, 1H), 5.49 (s, 1H), 6.79 (d, J=6.6 Hz, 2H), 7.09~7.21 (m, 6H), 7.32 (ddd, J=1.2, 7.5, 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 182.09, 142.40, 137.58, 136.82, 130.75, 130.27, 130.18, 129.37, 128.62, 128.13, 127.42, 125.69, 125.51, 112.47, 48.98, 46.75, 44.34, 31.38, 29.67, 26.76, 24.96, 19.58; HRMS (ESI-TOF) calcd for C24H27N2O [M+H]+ 359.2118. Found 359.2121.

    3-(1-Benzyl-5-(4-fluorophenyl)-3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2e): pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.03 (s, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.4 Hz, 1H), 2.16 (d, J=14.4 Hz, 1H), 4.48 (d, J=15.5 Hz, 1H), 4.82 (d, J=15.5 Hz, 1H), 5.61 (s, 1H), 6.97~6.99 (m, 2H), 7.04 (dddd, J=2.8, 1.9, 8.7, 8.7 Hz, 2H), 7.21~7.28 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 182.77, 163.17 (d, 1JCF=247.8 Hz), 142.82, 137.04, 130.40 (d, 3JCF=8.3 Hz), 128.52, 127.55, 127.44, 125.66, 115.68 (d, 2JCF=21.6 Hz), 112.64, 48.76, 47.02, 44.51, 31.37, 29.72, 26.31, 24.89; 19F NMR (376 MHz, CDCl3) δ: -111.52 (m, 1F); HRMS (ESI-TOF) calcd for C23H24- FN2O [M+H]+ 363.1867, found 363.1862.

    2, 2-Dimethyl-3-(3-methyl-1-(4-methylbenzyl)-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)propanenitrile (2f): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.01 (s, 3H), 1.32 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 2.28 (s, 3H), 4.51 (d, J=15.3 Hz, 1H), 4.76 (d, J=15.3 Hz, 1H), 5.62 (s, 1H), 6.86 (d, J=8.0 Hz, 2H), 7.00 (d, J=8.0 Hz, 2H), 7.30~7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 182.88, 143.89, 136.93, 134.12, 131.38, 129.11, 129.07, 128.56, 128.44, 127.67, 125.73, 112.36, 48.70, 47.03, 44.26, 31.41, 29.73, 26.35, 24.75, 21.08; HRMS (ESI-TOF) calcd for C24H27N2O [M+H]+ 359.2118, found 359.2129.

    3-(1-(3-Methoxybenzyl)-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2g): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.03 (s, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.4 Hz, 1H), 2.16 (d, J=14.4 Hz, 1H), 3.69 (s, 3H), 4.52 (d, J=15.4 Hz, 1H), 4.80 (d, J=15.4 Hz, 1H), 5.63 (s, 1H), 6.50 (s, 1H), 6.60 (d, J=7.6 Hz, 1H), 6.74 (dd, J=2.2, 8.2 Hz, 1H), 7.12 (dd, J=7.9, 7.9 Hz, 1H), 7.28~7.41 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 182.85, 159.64, 143.80, 138.68, 131.34, 129.47, 129.15, 128.61, 128.43, 125.68, 119.98, 113.26, 112.79, 112.42, 55.10, 48.71, 47.03, 44.46, 31.40, 29.73, 26.38, 24.78; HRMS (ESI-TOF) calcd for C24H27N2O2 [M+H]+ 375.2067, found 375.2068.

    3-(1-(3-Methoxybenzyl)-3-methyl-2-oxo-5-(p-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2h): pale yellow solid, m.p. 90~91 ℃. 1H NMR (400 MHz, CDCl3) δ: 1.02 (s, 3H), 1.32 (s, 3H), 1.37 (s, 3H), 2.02 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 2.37 (s, 3H), 3.69 (s, 3H), 4.50 (d, J=15.4 Hz, 1H), 4.79 (d, J=15.4 Hz, 1H), 5.60 (s, 1H), 6.53 (s, 1H), 6.62 (d, J=7.4 Hz, 1H), 6.74 (dd, J=1.6, 8.0 Hz, 1H), 7.11~7.26 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 182.93, 159.64, 143.84, 139.15, 138.80, 129.46, 129.28, 128.40, 128.31, 125.69, 119.94, 113.21, 112.77, 111.99, 55.08, 48.65, 47.02, 44.42, 31.39, 29.73, 26.39, 24.74, 21.33; HRMS (ESI-TOF) calcd for C25H29N2O2 [M+H]+ 389.2224, found 389.2230.

    3-(1-(3-Methoxybenzyl)-3-methyl-2-oxo-5-(o-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2i): pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.06 (s, 3H), 1.33 (s, 3H), 1.37 (s, 3H), 2.02 (d, J=14.4 Hz, 1H), 2.06 (s, 3H), 2.17 (d, J=14.4 Hz, 1H), 3.65 (s, 3H), 4.38 (d, J=14.6 Hz, 1H), 4.46 (d, J=14.6 Hz, 1H), 5.50 (s, 1H), 6.30 (dd, J=1.8, 1.8 Hz, 1H), 6.42 (d, J=7.6 Hz, 1H), 6.70 (dd, J=2.0, 8.2 Hz, 1H), 7.03 (dd, J=7.9, 7.9 Hz, 1H), 7.12 (d, J=7.4 Hz, 1H), 7.18~7.21 (m, 2H), 7.32 (ddd, J=1.3, 7.6, 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 182.04, 159.31, 142.35, 138.26, 137.59, 130.75, 130.29, 130.16, 129.36, 129.17, 125.68, 125.51, 120.92, 113.60, 113.42, 112.46, 55.05, 48.97, 46.69, 44.31, 31.36, 29.66, 26.78, 24.94, 19.63; HRMS (ESI-TOF) calcd for C25H29N2O2 [M+H]+ 389.2224, found 389.2221.

    3-(5-(4-Fluorophenyl)-1-(3-methoxybenzyl)-3-methyl-2-oxo-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2j): white solid, m.p. 68~69 ℃. 1H NMR (400 MHz, CDCl3) δ: 1.04 (s, 3H), 1.34 (s, 3H), 1.38 (s, 3H), 2.04 (d, J=14.4 Hz, 1H), 2.16 (d, J=14.4 Hz, 1H), 3.71 (s, 3H), 4.45 (d, J=15.6 Hz, 1H), 4.80 (d, J=15.6 Hz, 1H), 5.61 (s, 1H), 6.53 (s, 1H), 6.58 (d, J=7.6 Hz, 1H), 6.75 (dd, J=2.2, 8.2 Hz, 1H), 7.05 (dd, J=8.6, 8.6 Hz, 2H), 7.14 (dd, J=7.9 Hz, 1H), 7.28~7.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 182.75, 163.18 (d, 1JC—F=247.7 Hz), 159.72, 142.82, 138.62, 130.40 (d, 3JC—F=8.3 Hz), 129.58, 127.38 (d, 4JC—F=3.5 Hz), 125.68, 119.75, 115.70 (d, 2JC—F=21.6 Hz), 113.16, 112.77, 112.62, 55.12, 48.75, 47.01, 44.44, 31.39, 29.74, 26.35, 24.89; 19F NMR (376 MHz, CDCl3) δ: -111.52 (m, 1F); HRMS (ESI-TOF) calcd for C24H26FN2O2 [M+H]+ 393.1973, found 393.1973.

    3-(1-(4-Chlorobenzyl)-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2k): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.01 (s, 3H), 1.32 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 4.50 (d, J=15.4 Hz, 1H), 4.77 (d, J=15.4 Hz, 1H), 5.63 (s, 1H), 6.90 (ddd, J=2.4, 1.8, 8.5 Hz, 2H), 7.18 (ddd, J=2.5, 2.0, 8.5 Hz, 2H), 7.27~7.30 (m, 2H), 7.35~7.43 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 182.91, 143.51, 135.63, 133.22, 131.13, 129.30, 129.20, 128.70, 128.60, 128.39, 125.57, 112.56, 48.75, 46.98, 43.89, 31.36, 29.67, 26.35, 24.92; HRMS (ESI-TOF) calcd for C23H24ClN2O [M+H]+ 379.1572, found 379.1573.

    3-(1-(2-Chlorobenzyl)-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2l): pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.19 (s, 3H), 1.41 (s, 3H), 1.42 (s, 3H), 2.07 (d, J=14.4 Hz, 1H), 2.19 (d, J=14.4 Hz, 1H), 4.58 (d, J=16.8 Hz, 1H), 4.92 (d, J=16.8 Hz, 1H), 5.72 (s, 1H), 7.12~7.14 (m, 1H), 7.17~7.26 (m, 4H), 7.28~7.37 (m, 4H); 13C NMR (100 MHz, CDCl3) δ: 183.16, 144.04, 134.80, 132.43, 130.82, 129.53, 129.21, 128.73, 128.43, 127.83, 127.56, 127.01, 125.64, 112.39, 48.74, 47.13, 42.57, 31.43, 29.77, 26.38, 24.99; HRMS (ESI-TOF) calcd for C23H24ClN2O [M+H]+ 379.1572, found 379.1573.

    3-(1-(2-Chlorobenzyl)-3-methyl-2-oxo-5-(p-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2m): white solid: m.p. 123~124 ℃. 1H NMR (400 MHz, CDCl3) δ: 1.18 (s, 3H), 1.40 (s, 3H), 1.42 (s, 3H), 2.07 (d, J=14.4 Hz, 1H), 2.18 (d, J=14.4 Hz, 1H), 2.33 (s, 3H), 4.58 (d, J=16.9 Hz, 1H), 4.90 (d, J=16.9 Hz, 1H), 5.69 (s, 1H), 7.09~7.15 (m, 5H), 7.18~7.25 (m, 2H), 7.31~7.34 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 183.23, 144.05, 139.25, 134.88, 132.36, 129.49, 129.41, 128.37, 127.85, 127.67, 127.39, 127.00, 125.67, 111.87, 48.65, 47.10, 42.55, 31.42, 29.76, 26.38, 24.88, 21.30; HRMS (ESI-TOF) calcd for C24H26ClN2O [M+H]+ 393.1728, found 393.1729.

    3-(1-(4-Fluorobenzyl)-3-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2n): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.98 (s, 3H), 1.32 (s, 3H), 1.37 (s, 3H), 2.03 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 4.53 (d, J=15.3 Hz, 1H), 4.76 (d, J=15.3 Hz, 1H), 5.62 (s, 1H), 6.85~6.94 (m, 4H), 7.28~7.31 (m, 2H), 7.36~7.44 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 182.89, 162.04 (d, 1JC—F=244.4 Hz), 143.52, 132.84 (d, 4JC—F=3.2 Hz), 131.23, 129.61 (d, 3JC—F=8.1 Hz), 129.26, 128.67, 128.42, 125.61, 115.27 (d, 2JC—F=21.3 Hz), 112.58, 48.75, 46.98, 43.78, 31.36, 29.67, 26.34, 24.83; HRMS (ESI-TOF) calcd for C23H24FN2O [M+H]+ 363.1867, found 363.1868.

    3-(1-(4-Fluorobenzyl)-3-methyl-2-oxo-5-(m-tolyl)-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2): pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.00 (s, 3H), 1.31 (s, 3H), 1.37 (s, 3H), 2.02 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 2.33 (s, 3H), 4.49 (d, J=15.2 Hz, 1H), 4.75 (d, J=15.2 Hz, 1H), 5.59 (s, 1H), 6.87~6.96 (m, 4H), 7.04 (s, 1H), 7.10 (d, J=7.4 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.27 (dd, J=7.4, 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 182.93, 162.04 (d, 1JC—F=244.3 Hz), 143.74, 138.33, 133.05 (d, 4J(C—F=3.2 Hz), 131.12, 129.97, 129.67 (d, 3JC—F=8.0 Hz), 129.04, 128.55, 125.57, 125.53, 115.20 (d, 2JC—F=21.3 Hz), 112.29, 48.71, 46.98, 43.88, 31.35, 29.67, 26.34, 24.84, 21.34; 19F NMR (376 MHz, CDCl3) δ: -115.04 (m, 1F); HRMS (ESI-TOF) calcd for C24H26FN2O [M+H]+ 377.2024, found 377.2035.

    3-(1-Benzyl-3, 4-dimethyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2p): pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.10 (s, 3H), 1.28 (s, 3H), 1.37 (s, 3H), 1.77 (s, 3H), 2.03 (d, J=14.6 Hz, 1H), 2.07 (d, J=14.6 Hz, 1H), 4.37 (d, J=15.2 Hz, 1H), 4.76 (d, J=15.2 Hz, 1H), 6.90~6.93 (m, 2H), 7.16~7.20 (m, 5H), 7.31~7.37 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 181.71, 137.96, 137.14, 130.27, 129.89, 128.78, 128.47, 128.27, 127.90, 127.19, 124.94, 118.10, 50.09, 45.32, 44.41, 30.98, 30.47, 25.69, 25.22, 10.29; HRMS (ESI-TOF) calcd for C24H27N2O [M+H]+ 359.2118, found 359.2119.

    3-(1, 3-Dimethyl-2-oxo-5-phenyl-2, 3-dihydro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2q): pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.13 (s, 3H), 1.28 (s, 3H), 1.39 (s, 3H), 2.01 (d, J=14.4 Hz, 1H), 2.15 (d, J=14.4 Hz, 1H), 3.05 (s, 3H), 5.61 (s, 1H), 7.36~7.48 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 183.01, 143.84, 131.15, 129.13, 128.71, 127.99, 125.58, 112.05, 48.78, 47.31, 31.34, 29.77, 28.48, 25.87, 24.83; HRMS (ESI-TOF) calcd for C17H21N2O [M+H]+ 269.1648, found 269.1652.

    3-(5-(4-Methoxyphenyl)-1, 3-dimethyl-2-oxo-2, 3-dihy-dro-1H-pyrrol-3-yl)-2, 2-dimethylpropanenitrile (2r): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.12 (s, 3H), 1.27 (s, 3H), 1.39 (s, 3H), 2.00 (d, J=14.4 Hz, 1H), 2.13 (d, J=14.4 Hz, 1H), 3.04 (s, 3H), 3.85 (s, 3H), 5.54 (s, 1H), 6.96 (ddd, J=2.9, 2.1, 8.8 Hz, 2H), 7.39 (ddd, J=2.8, 2.1, 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 183.05, 160.26, 143.51, 129.38, 125.64, 123.54, 114.13, 111.13, 55.38, 48.70, 47.31, 31.34, 29.79, 28.39, 25.89, 24.77; HRMS (ESI-TOF) calcd for C18H23N2O2 [M+H]+ 299.1754, found 299.1750.

    2-(3, 5-di-tert-Butyl-1-methyl-4-oxocyclohexa-2, 5-dien-1-yl)-2-methylpropanenitrile (3): yellow solid, m.p. 69~70 ℃. 1H NMR (400 MHz, CDCl3) δ: 1.17 (s, 18H), 1.22 (s, 6H), 1.34 (s, 3H), 6.47 (s, 2H); 13C NMR (100 MHz, CDCl3) δ: 185.50, 149.24, 140.69, 123.41, 42.68, 39.75, 35.10, 29.41, 22.86, 22.55; HRMS (ESI-TOF) Calcd for C19H30NO [M+H]+ 288.2322, found 288.2327.

    3-(1-Acetyl-3-methylindolin-3-yl)-2, 2-dimethylpropan-enitrile (5): colorless oil. 1H NMR (400 MHz, CDCl3) δ: 1.13 (s, 3H), 1.43 (s, 3H), 1.52 (s, 3H), 1.88 (d, J=14.9 Hz, 1H), 2.08 (d, J=14.9 Hz, 1H), 2.27 (s, 3H), 3.85 (d, J=10.8 Hz, 1H), 4.40 (d, J=10.8 Hz, 1H), 7.05 (dd, J=7.4, 7.3 Hz, 1H), 7.13 (d, J=7.0 Hz, 1H), 7.22~7.26 (m, 1H), 8.22 (d, J=8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 168.91, 141.80, 138.51, 128.50, 125.18, 123.81, 122.30, 117.19, 60.60, 50.92, 43.58, 30.44, 30.35, 28.35, 27.66, 24.29; HRMS (ESI-TOF) calcd for C16H21N2O [M+H]+ 257.1648, found 257.1651.

    Supporting Information Copies of 1H NMR, 13C NMR, 19F NMR and 2D NMR spectra of compounds 2a~2r, 3, 5. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.


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    19. [19]

      (a) Pankajakshan, S.; Xu, Y.; Cheng, J. K.; Low, M. T.; Loh, T. Angew. Chem., Int. Ed. 2012, 51, 5701.
      (b) Kobayashi, M.; Suda, T.; Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2011, 50, 1664.

  • Scheme 1  Acrylamide-based radical cyclization

    Scheme 2  Mechanistic investigations

    Table 1.  Screening of reaction conditionsa

    Entry Catalyst(mol%) AIBN/equiv. Additive(equiv.) Solvent T/℃ Yield/%
    1 CuI (10) 3 DCE 80 34
    2 CuI (10) 3 Toluene 80 Trace
    3 CuI (10) 3 MeNO2 80 9
    4 CuI (10) 3 MeCN 80 16
    5 CuI (10) 3 THF 80 46
    6 CuI (10) 3 1, 4-Dioxane 80 15
    7 CuI (10) 3 DMF 80 Trace
    8 CuI (10) 3 DMSO 80 22
    9 CuBr (10) 3 THF 80 42
    10 CuCl (10) 3 THF 80 44
    11 Cu2O (10) 3 THF 80 42
    12 Cu(OAc)2 (10) 3 THF 80 38
    13 FeCl3 (10) 3 THF 80 31
    14 AgOAc (10) 3 THF 80 36
    15 3 THF 80 21
    16 CuI (10) 3 TBHPb (2) THF 80 26
    17 CuI (10) 3 DTBP (2) THF 80 31
    18 CuI (10) 3 BPO (2) THF 80 29
    19 CuI (10) 3 K2S2O8 (2) THF 80 38
    20 CuI (10) 3 HOAc (0.5) THF 80 38
    21 CuI (10) 3 TFA (0.5) THF 80 34
    22 CuI (10) 3 TsOH (0.5) THF 80 28
    23 CuI (10) 3 NaOAc (0.5) THF 80 18
    24 CuI (10) 3 NaHCO3 (0.5) THF 80 15
    25 CuI (10) 3 K2CO3 (0.5) THF 80 13
    26 CuI (10) 3 K3PO4 (0.5) THF 80 15
    27 CuI (10) 3 KF (0.5) THF 80 14
    28 CuI (10) 3 Et3N (0.5) THF 80 28
    29 CuI (10) 3 DABCO (0.5) THF 80 22
    30 CuI (20) 3 THF 80 41
    31 CuI (5) 3 THF 80 33
    32 CuI (10) 5 THF 80 43
    33 CuI (10) 4c THF 80 57
    34 CuI (10) 4d THF 80 49
    35 CuI (10) 4c THF 120 19
    36 CuI (10) 4c THF 50 nr
    a Reaction conditions: 1a (0.3 mmol), solvent (3 mL), Ar, 24 h. b 5.0~6.0 mol/L in decane. c AIBN was added in two equal portions at 12 h intervals. d AIBN was added in four equal portions at 6 h intervals.
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    Table 2.  Synthesis of 1, 3-dihydropyrrol-2-onesa

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  • 收稿日期:  2019-05-05
  • 修回日期:  2019-07-02
  • 网络出版日期:  2019-12-25
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