English

• 1.   Introduction

  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

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  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.

  2.   Results and discussion

  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 conditions^a

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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-ones^a

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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

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  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.

  3.   Conclusions

  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.

  4.   Experimental

  4.1   General

  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 Ascend^TM 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]

  4.2   General procedure for the synthesis of enamide substrates 1

  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).

  4.3   General procedure for the synthesis of 1, 3-dihy- dropyrrol-2-ones (2)

  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, ¹J_C—F＝247.8 Hz), 142.82, 137.04, 130.40 (d, ³J_C—F＝8.3 Hz), 128.52, 127.55, 127.44, 125.66, 115.68 (d, ²J_C—F＝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, ¹J_C—F＝247.7 Hz), 159.72, 142.82, 138.62, 130.40 (d, ³J_C—F＝8.3 Hz), 129.58, 127.38 (d, ⁴J_C—F＝3.5 Hz), 125.68, 119.75, 115.70 (d, ²J_C—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, ¹J_C—F＝244.4 Hz), 143.52, 132.84 (d, ⁴J_C—F＝3.2 Hz), 131.23, 129.61 (d, ³J_C—F＝8.1 Hz), 129.26, 128.67, 128.42, 125.61, 115.27 (d, ²J_C—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, ¹J_C—F＝244.3 Hz), 143.74, 138.33, 133.05 (d, ⁴J_(C—F＝3.2 Hz), 131.12, 129.97, 129.67 (d, ³J_C—F＝8.0 Hz), 129.04, 128.55, 125.57, 125.53, 115.20 (d, ²J_C—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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      (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.
      

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  Scheme 1  Acrylamide-based radical cyclization

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  Scheme 2  Mechanistic investigations

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  Table 1.  Screening of reaction conditions^a

  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-ones^a

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