English

• 1.   Introduction

  The construction of C—C bond is a key task for the synthesis of quaternary carbon centers, which are widespread structures in natural products and pharmaceutical drugs.^[1] Although numerous methods have been developed for the formation of quaternary carbon centers, an efficient and environmental synthesis of quaternary carbon center containing a nitrogen or other heteroatom atom, a prevalent structure in natural alkaloids, ^[2] is still a challenging task.^[3]

  As versatile and powerful starting materials, enamides have been widely used in constructing substantial bioactive N-heterocyclic motifs^[4-7] including nitrogen-containing quaternary carbon centers. Kobayashi's group^[8] firstly demonstrated a strong Brønsted or Lewis acid promoted self-coupling reaction of enecarbamates and enamides. Equilibrium between enamides and ketimines exists under acidic condition (Scheme 1a). Zhou's group^[9] reported a chiral Brønsted acid catalyzed asymmetric Friedel-Crafts reaction. α-Aryl enamides and indoles were applied as substrates to generate chiral amines with a quaternary carbon stereogenic center (Scheme 1b). Chiral 1, 1'-bi-2- naphthol (BINOL)-phosphate catalyzed and FeCl₃ catalyzed self-coupling of enamides were developed respectively by Tsogoeva's group^[10] and Guan's group.^[11] This self-coupling reaction featured high atom-economy (Schemes 1c, 1d). However, performing this self-coupling reaction efficiently and environmentally keeps a challenge. Iodide or hypervalent iodine-promoted C—C bond formation reactions have received considerable attention due to their environmental friendliness and high reactivity.^[12-13] Herein, we wish to report an iodide initiated self-coupling of enamides towards nitrogen-containing quaternary carbon centers.

  Scheme 1

  

  Scheme 1.  Reactions for the synthesis of nitrogen-containing quarternary carbon centers

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  2.   Results and discussion

  Our initial studies were commenced with readily available enamide 1a as model substrate to optimize the reaction conditions. To our delight, The desired C—C bond could be formed successfully in the presence of KI (10 mol%) and K₂S₂O₈ (20 mol%) in 1, 2-dichloroethane (DCE) at 70 ℃. (Z)-N, N'-(1, 3-Diphenylbut-1-ene-1, 3-diyl)diacetamide (2a) was isolated in 63% yield (Table 1, Entry 1), and the structure (Z configuration) of 2a was confirmed unambiguously by X-ray diffraction analysis (CCDC: 1439475, Figure 1). Then, various peroxides such as Na₂S₂O₈, tert-butyl hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), benzoyl peroxide (BPO), and tert-Butyl peroxybenzoate (TBPB) were screened. The results indicated that K₂S₂O₈ displayed the best ability for this transformation (Table 1, Entries 1~6). Subsequently, a range of iodides such as N-iodo-succininide (NIS), tetrabutylammonium iodide (TBAI), and I₂ were evaluated. Among these iodides, NIS exhibited an excellent ability and the reaction time could be reduced to 2 h (Table 1, Entries 7~9). A survey of solvents indicated that PhCl was the better medium for this conversion, 2a was given with 84% yield (Table 1, Entries 10~13). It was worth mentioning that, when the dosages of iodide and oxidant were reduced to a quarter, the yields could remained relatively stable (Table 1, Entries 14, 15). Finally, the optimized reaction conditions were obtained as follows: the self-coupling of enamides could be initiated by 2.5 mol% of NIS and 5 mol% of K₂S₂O₈ in PhCl at 70 ℃ (Table 1, Entry15).

  Figure 1

  

  Figure 1.  X-ray crystal structure of 2a (CCDC: 1439475)

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  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

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  Entry	Iodide (mol%)	Oxidant (mol%)	Solvent	Time/h	Yieldb/%
  1	KI (10)	K2S2O8 (20)	DCE	10	63
  2	KI (10)	Na2S2O8 (20)	DCE	10	60
  3	KI (10)	TBHP (20)	DCE	10	0
  4	KI (10)	DTBP (20)	DCE	10	0
  5	KI (10)	BPO (20)	DCE	10	0
  6	KI (10)	TBPB (20)	DCE	10	0
  7	NIS (10)	K2S2O8 (20)	DCE	2	73
  8	TBAI (10)	K2S2O8 (20)	DCE	10	14
  9	I2 (10)	K2S2O8 (20)	DCE	10	20
  10	NIS (10)	K2S2O8 (20)	CH3CN	2	0
  11	NIS (10)	K2S2O8 (20)	Dioxane	2	0
  12	NIS (10)	K2S2O8 (20)	Toluene	2	76
  13	NIS (10)	K2S2O8 (20)	PhCl	2	84
  14	NIS (5)	K2S2O8 (10)	PhCl	2	80
  15c	NIS (2.5)	K2S2O8 (5)	PhCl	2	81
  a Conditions: 1a (0.2 mmol), solvent (1 mL), under 70 ℃ and monitored by TLC. b Isolated yields. c For convenient operation, 0.4 mmol of 1a was used in Entry 15.

  With the optimized reaction conditions in hands (Table 1, Entry 15), the substrate scope of this self-coupling was investigated and the results were summarized in Table 2. Generally, the position of the substituents significantly influenced this transformation. Enamides with electron-donating or electron-withdrawing substrates such as methyl, methoxy, phenyl, fluoro, chloro, bromo, and trifluoromethyl at the para- or meta-position of the aromatic ring were transformed efficiently and the corresponding products were generated in good to high yields (2b, 2c, 2e, 2f, 2h~2j, 2l~2o). Whereas o-methyl-substituted enamide 1d, α-naphthyl-substituted enamide 1g and o-chlorosubsti- tuted enamide 1k couldn't work under standard conditions. And enamide with a nitro group at the para-position of the aromatic ring 1p also couldn't transform smoothly to the corresponding product 2p under standard conditions. Additionally, N-propionyl and N-isobutyryl enamides were also examined, and the reaction proceeded well to obtain the corresponding products with moderate yields (2q, 2r).

  Table 2

  

  Table 2.  Substrate scope of enamides

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  To gain mechanistic insight into this transformation, a radical-trapping experiment was carried out (Scheme 2). By the addition of a free radical scavenger 2, 2, 6, 6-tetra- methylpiperidin-1-oxyl (TEMPO), this self-coupling can be inhibited absolutely, and a little amount of TEMPO-trapped N-(1-phenylethylidene)acetamide 3a was obtained. This result suggested that the reaction might be involved a radical process.

  Scheme 2

  

  Scheme 2.  Controlled experiment

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  Based on the previous literature reports^{[7-8, 10-11, 13]} and the above results, the possible mechanism for this transformation is proposed, as illustrated in Scheme 3. First, the isomerization of enamide 1a afforded ketimine 1b. Then the primary radical genetated from NIS and K₂S₂O₈ activated 1a to obtain radical A and tautomeric radical B. And radical B could be inhibited by TEMPO to afford amide 3a. Subsequently, the radical addition of B with 1b led to radical C. Finally, hydrogen atom abstraction of enamide 1a by intermediate C produced intermediate D. The isomerization of D could afford the desired product 2a.

  Scheme 3

  

  Scheme 3.  Proposed mechanism

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  3.   Conclusions

  In summary, we have demonstrated a novel transition metal free self-coupling reaction of enamides. This NIS/ K₂S₂O₈ initiated C—C bond formation reaction is a convenient access to enamido-substituted nitrogen-contai- ning quaternary carbon centers. Additionally, the protocol not only offers several notable advantages including the environmental friendliness and atom-economy feature of this transformation, but also provides a useful and attractive strategy to form this kind of quaternary carbon centers.

  4.   Experimental section

  4.1   General

  ¹H NMR spectra were recorded at 400 MHz. Chemical shifts were referenced to tetramethylsilane (δ 0) in CDCl₃ or DMSO (δ 2.50) in DMSO-d₆ as an internal standard. ¹³C NMR spectra were obtained at 100 MHz and were calibrated with CDCl₃ (δ 77.00) or DMSO-d₆ (δ 39.50). The high-resolution mass spectra (HRMS) were recorded on an FT-ICR mass spectrometer using electrospray ionization (ESI). Products were purified by flash chromatography on 200~300 mesh silica gels. Unless otherwise noted, commercially available reagents and solvents were used without further purification. The enamides 1a~1r were prepared from the corresponding ketoximes according to the reported literature.^[4]

  4.2   Synthesis

  A test tube equipped with a magnetic stir bar was charged with enamides 1 (0.4 mmol), NIS (0.01 mmol, 2.2 mg), K₂S₂O₈ (0.02 mmol, 5.4 mg) in 1 mL of PhCl. Then the reaction mixture was stirred at 70 ℃ (oil bath temperature). After completion of the reaction (monitored by TLC, about 2~4 h), the reaction mixture was concentrated in vacuo. The residues were purified by column chromatography, eluting with petroleum ether/EtOAc to afford the desired products.

  (Z)-N, N'-(1, 3-Diphenylbut-1-ene-1, 3-diyl)diacetamide (2a):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.28 (s, 1H), 8.49 (s, 1H), 7.36~7.34 (m, 2H), 7.31~7.25 (m, 5H), 7.23~7.17 (m, 3H), 5.59 (s, 1H), 1.99 (s, 3H), 1.59 (s, 3H), 1.23 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.21, 167.26, 143.54, 138.35, 136.74, 127.89, 127.82, 127.60, 125.96, 125.34, 123.84, 57.80, 33.96, 22.93, 22.23; EI-MS m/z: 322.

  (Z)-N, N'-(1, 3-Di-p-tolylbut-1-ene-1, 3-diyl)diacetamide (2b):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.25 (s, 1H), 8.46 (s, 1H), 7.24~7.2 (m, 2H), 7.10~7.04 (m, 6H), 5.53 (s, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 1.98 (s, 3H), 1.56 (s, 3H), 1.23 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.15, 167.31, 140.65, 136.85, 136.62, 135.55, 134.88, 128.51, 128.36, 125.91, 125.33, 123.08, 57.65, 34.02, 22.99, 22.26, 20.76, 20.51; EI-MS m/z: 350.

  (Z)-N, N'-(1, 3-Di-m-tolylbut-1-ene-1, 3-diyl)diacetamide (2c): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.24 (s, 1H), 8.48 (s, 1H), 7.19~7.12 (m, 4H), 7.07~7.05 (m, 1H), 7.01~6.98 (m, 3H), 5.55 (s, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.99 (s, 3H), 1.57 (s, 3H), 1.23 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.17, 167.37, 143.36, 138.45, 136.91, 136.88, 128.30, 127.83, 127.77, 126.63, 126.46, 126.37, 123.51, 123.23, 122.14, 57.72, 34.20, 22.94, 22.28, 21.10, 21.09. ESI-HRMS calcd for C₂₂H₂₆N₂O₂Na [M+Na⁺] 373.1892, found 373.1895.

  (Z)-N, N'-(1, 3-Bis(3-methoxyphenyl)but-1-ene-1, 3-diyl)-diacetamide (2e):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.28 (s, 1H), 8.48 (s, 1H), 7.23~7.17 (m, 2H), 6.96~6.94 (m, 1H), 6.88~6.83 (m, 2H), 6.80~6.73 (m, 3H), 5.63 (s, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 1.99 (s, 3H), 1.60 (s, 3H), 1.29 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.18, 167.49, 145.31, 140.03, 136.61, 128.98, 128.85, 123.96, 118.49, 117.49, 112.89, 111.74, 111.64, 111.10, 57.72, 55.05, 54.76, 33.78, 22.97, 22.31; EI-MS m/z: 382.

  (Z)-N, N'-(1, 3-Di([1, 1'-biphenyl]-4-yl)but-1-ene-1, 3-diyl)-diacetamide (2f):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.38 (s, 1H), 8.60 (s, 1H), 7.68~7.57 (m, 8H), 7.49~7.44 (m, 6H), 7.38~7.33 (m, 4H), 5.74 (s, 1H), 2.05 (s, 3H), 1.69 (s, 3H), 1.29 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.34, 167.42, 142.91, 140.05, 139.79, 139.40, 138.02, 137.51, 136.44, 128.99, 127.46, 127.28, 126.61, 126.54, 126.26, 126.19, 126.12, 124.09, 57.74, 33.66, 23.01, 22.25; EI-MS m/z: 474.

  (Z)-N, N'-(1, 3-Di(naphthalen-2-yl)but-1-ene-1, 3-diyl)dia-cetamide (2h):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.39 (s, 1H), 8.71 (s, 1H), 7.93~7.75 (m, 8H), 7.57~7.42 (m, 6H), 5.85 (s, 1H), 2.09 (s, 3H), 1.75 (s, 3H), 0.97 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.46, 167.39, 141.22, 136.93, 135.98, 132.86, 132.76, 132.69, 131.73, 128.09, 127.94, 127.41, 127.32, 127.17, 126.20, 125.94, 125.63, 124.89, 124.69, 124.64, 124.40, 123.14, 58.11, 33.59, 23.12, 22.14; EI-MS m/z: 422.

  (Z)-N, N'-(1, 3-Bis(4-chlorophenyl)but-1-ene-1, 3-diyl)dia-cetamide (2i):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.32 (s, 1H), 8.57 (s, 1H), 7.35~7.31 (m, 6H), 7.22~7.19 (m, 2H), 5.64 (s, 1H), 1.98 (s, 3H), 1.59 (s, 3H), 1.30 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.41, 167.32, 142.63, 137.15, 135.73, 132.20, 130.63, 127.95, 127.80, 127.72, 127.48, 124.52, 57.49, 33.28, 22.94, 22.15; EI-MS m/z: 390.

  (Z)-N, N'-(1, 3-Bis(3-chlorophenyl)but-1-ene-1, 3-diyl)dia-cetamide (2j):^{[10] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.30 (s, 1H), 8.59 (s, 1H), 7.41 (m, 1H), 7.32~7.25 (m, 5H), 7.21~7.17 (m, 2H), 5.69 (s, 1H), 2.00 (s, 3H), 1.62 (s, 3H), 1.33 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.41, 167.40, 146.10, 140.67, 135.53, 132.89, 132.78, 129.81, 129.74, 127.52, 126.15, 125.74, 125.46, 125.08, 124.73, 124.20, 57.59, 33.06, 22.93, 22.17; EI-MS m/z: 390.

  (Z)-N, N'-(1, 3-Bis(4-bromophenyl)but-1-ene-1, 3-diyl)dia-cetamide (2l):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.33 (s, 1H), 8.58 (s, 1H), 7.49~7.44 (m, 4H), 7.31~7.29 (m, 2H), 7.16~7.14 (m, 2H), 5.65 (s, 1H), 1.99 (s, 3H), 1.59 (s, 3H), 1.31 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.42, 167.33, 143.02, 137.51, 135.87, 130.86, 130.64, 128.13, 127.86, 124.42, 120.81, 119.09, 57.53, 33.26, 22.94, 22.13; EI-MS m/z: 478.

  (Z)-N, N'-(1, 3-Bis(3-bromophenyl)but-1-ene-1, 3-diyl)dia-cetamide (2m): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.27 (s, 1H), 8.59 (s, 1H), 7.55~7.54 (m, 1H), 7.47~7.33 (m, 4H), 7.27~7.21 (m, 3H), 5.67 (s, 1H), 1.99 (s, 3H), 1.62 (s, 3H), 1.33 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.38, 167.35, 146.28, 140.91, 135.42, 130.41, 130.09, 130.05, 129.07, 128.54, 128.28 125.11, 124.57, 121.50, 121.39, 57.53, 33.05, 22.92, 22.19. ESI-HRMS calcd for C₂₀H₂₀Br₂N₂O₂Na [M+Na⁺] 500.9789, found 500.9791.

  (Z)-N, N'-(1, 3-Bis(4-fluorophenyl)but-1-ene-1, 3-diyl)dia-cetamide (2n):^{[11] 1}H NMR (400 MHz, DMSO-d₆) δ: 9.36 (s, 1H), 8.55 (s, 1H), 7.40~7.36 (m, 2H), 7.24~7.21 (m, 2H), 7.14~7.06 (m, 4H), 5.58 (s, 1H), 1.99 (s, 3H), 1.59 (s, 3H), 1.32 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.39, 167.31, 161.89 (d, J_C-F＝243 Hz), 160.64 (d, J_C-F＝240 Hz), 139.66 (d, J_C-F＝3 Hz), 135.80, 134.73 (d, J_C-F＝3 Hz), 127.98 (d, J_C-F＝8 Hz), 127.45 (d, J_C-F＝8 Hz), 123.94, 114.75 (d, J_C-F＝20 Hz), 114.44 (d, J_C-F＝21 Hz), 57.47, 33.74, 22.96, 22.28; EI-MS m/z: 358.

  (Z)-N, N'-(1, 3-Bis(4-(trifluoromethyl)phenyl)but-1-ene- 1, 3-diyl)diacetamide (2o): ¹H NMR (400 MHz, DMSO-d₆) δ: 9.34 (s, 1H), 8.71 (s, 1H), 7.66~7.63 (m, 4H), 7.59~7.57 (m, 2H), 7.45~7.43 (m, 2H), 5.79 (s, 1H), 2.01 (s, 3H), 1.66 (s, 3H), 1.24 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 170.61, 167.31, 148.22, 142.36, 135.83, 124.39 (q, J_C-F＝270 Hz), 124.36 (q, J_C-F＝270 Hz), 128.03 (d, J_C-F＝31 Hz), 127.49 (d, J_C-F＝12 Hz), 127.11, 126.61 (d, J_C-F＝34 Hz), 125.89, 124.90 (d, J_C-F＝3 Hz), 124.75 (d, J_C-F＝3 Hz), 57.76, 33.03, 22.88, 21.90. ESI- HRMS calcd for C₂₂H₂₀F₆N₂O₂Na [M+Na⁺] 481.1327, found 481.1329.

  (Z)-N, N'-(1, 3-Diphenylbut-1-ene-1, 3-diyl)dipropionami-de (2q):^{[11] 1}H NMR (400 MHz, CDCl₃) δ: 9.16 (s, 1H), 7.43~7.41 (m, 2H), 7.31~7.18 (m, 8H), 6.28 (s, 1H), 5.35 (s, 1H), 2.34~2.22 (m, 2H), 1.82~1.72 (m, 1H), 1.58 (s, 3H), 1.46~1.37 (m, 1H), 1.20 (t, J＝7.6 Hz, 3H), 0.73 (t, J＝7.6 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 174.00, 172.07, 142.10, 138.87, 138.40, 128.26, 128.07, 127.92, 126.41, 126.24, 125.32, 121.89, 57.17, 35.79, 29.93, 28.96, 9.98, 8.71; EI-MS m/z: 350.

  (Z)-N, N'-(1, 3-Diphenylbut-1-ene-1, 3-diyl)bis(2-methyl-propanamide) (2r): ¹H NMR (400 MHz, CDCl₃) δ: 9.30 (s, 1H), 7.40~7.39 (m, 2H), 7.30~7.17 (m, 8H), 6.20 (s, 1H), 5.31 (s, 1H), 2.50~2.40 (m, 1H), 1.82~1.72 (m, 1H), 1.57 (s, 3H), 1.25 (t, J＝6.8 Hz, 3H), 1.16 (t, J＝6.8 Hz, 3H), 0.86 (t, J＝6.8 Hz, 3H), 0.68 (t, J＝6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 176.84, 174.89, 142.35, 138.85, 138.74, 128.29, 128.01, 127.80, 126.39, 126.17, 125.24, 122.09, 57.82, 36.04, 35.83, 35.00, 19.88, 19.59, 19.26, 18.24; ESI-HRMS calcd for C₂₄H₃₀N₂O₂Na [M+ Na⁺] 401.2205, found 401.2208.

  N-(1-Phenyl-2-((2, 2, 6, 6-tetramethylpiperidin-1-yl)oxy)-ethylidene)acetamide (3a):^{[6] 1}H NMR (400 MHz, CDCl₃) δ: 7.77~7.74 (m, 2H), 7.50~7.39 (m, 3H), 5.05 (s, 2H), 2.35 (s, 3H), 1.60~1.32 (m, 6H), 1.20 (s, 6H), 1.14 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ: 183.46, 158.86, 135.08, 131.49, 128.54, 127.33, 75.97, 60.33, 39.85, 32.63, 25.84, 20.56, 16.93; EI-MS m/z (M+H⁺) 317.

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

  
  
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  Scheme 1  Reactions for the synthesis of nitrogen-containing quarternary carbon centers

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  Figure 1  X-ray crystal structure of 2a (CCDC: 1439475)

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  Scheme 2  Controlled experiment

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  Scheme 3  Proposed mechanism

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  Table 1.  Optimization of the reaction conditions^a

  Entry	Iodide (mol%)	Oxidant (mol%)	Solvent	Time/h	Yieldb/%
  1	KI (10)	K2S2O8 (20)	DCE	10	63
  2	KI (10)	Na2S2O8 (20)	DCE	10	60
  3	KI (10)	TBHP (20)	DCE	10	0
  4	KI (10)	DTBP (20)	DCE	10	0
  5	KI (10)	BPO (20)	DCE	10	0
  6	KI (10)	TBPB (20)	DCE	10	0
  7	NIS (10)	K2S2O8 (20)	DCE	2	73
  8	TBAI (10)	K2S2O8 (20)	DCE	10	14
  9	I2 (10)	K2S2O8 (20)	DCE	10	20
  10	NIS (10)	K2S2O8 (20)	CH3CN	2	0
  11	NIS (10)	K2S2O8 (20)	Dioxane	2	0
  12	NIS (10)	K2S2O8 (20)	Toluene	2	76
  13	NIS (10)	K2S2O8 (20)	PhCl	2	84
  14	NIS (5)	K2S2O8 (10)	PhCl	2	80
  15c	NIS (2.5)	K2S2O8 (5)	PhCl	2	81
  a Conditions: 1a (0.2 mmol), solvent (1 mL), under 70 ℃ and monitored by TLC. b Isolated yields. c For convenient operation, 0.4 mmol of 1a was used in Entry 15.

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  Table 2.  Substrate scope of enamides

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