English

• 1.   Introduction

  3, 4-Dihydroisoquinolin-1(2H)-one is a key core structure commonly found in many natural products, pharmaceutical compounds, pesticides and functional organic materials, for example, pancratistatin and plicamine (Scheme 1).^[1] Among the various dihydroisoquinolin derivatives, the vinyl-substituted dihydroisoquinolone derivatives have attracted considerable interest because the existing double bonds could be converted into other functional groups to synthesize more complex products. Therefore, the development of efficient preparative methods for vinyl-substituted dihydroisoquinolone derivatives have always been the focus of synthetic chemists.

  Scheme 1

  

  Scheme 1.  Bioactive molecules containing the skeleton of dihydroisoquinolone derivatives

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  In past few decades, the directed group assisted transition metal catalyzed C-H activation technology has attracted more and more attention as a powerful platform to construct a variety of C-C, C-X bonds and even valuable heterocycles.^[2] In recent years, the strategy that involves ring opening of reactive rings has shown great synthetic application value due to their unique advantages of more atom-economical synthetic method with less amount of waste as well as diverse high reactivity, and significant progress have been made in the functionalization of C-H bonds to build structurally diversified and synthetically useful heterocycles.^[3] Among various reactive rings, 4-vinyl-1, 3-dioxolan-2-one has attracted considerable interest owing to the huge value of the corresponding synthetic products in both academic research and industry. Although excellent progress was achieved in transition metal-catalyzed directed allylation of C-H bonds with 4-vinyl-1, 3-dioxolan-2-one, ^[4] only a few examples have been reported for the synthesis of heterocycle compounds. In 2015, employing the Rh(Ⅲ)/Pd(Ⅱ) tandem catalysis strategy, Wang et al.^[5] first realized an elegant work for the annulation of C(sp²)-H bond of N-methoxybenzamide with vinyl-1, 3-dioxolan-2-one to the construction of 2- methoxy-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one derivatives (Scheme 2). Two years later, the Cp*Co(Ⅲ)-cata- lyzed domino C-H/N-H allylation of imidates^[6] with vinyl-1, 3-dioxolan-2-one was achieved by Ackermann^[7] (Scheme 2), giving rise to the corresponding 1-alkoxy- 3-vinyl-3, 4-dihydroisoquinoline derivatives. However, both of the above-mentioned reports require the use of strong acids or bases to convert the resulting product into the 3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one, thus resulting in operational complexity, poor functional group tolerance and narrow substrate scope. To address these problems, the development of new catalytic systems to the efficient one-pot synthesis of 3-vinyl-3, 4-dihydroisoquinolin- 1(2H)-one derivatives is highly desired. Herein, combined with our previous work, ^[8] we report a simple and efficient method to the formation of 3-vinyl-3, 4-dihydroisoquinolin- 1(2H)-one derivatives through Ru(Ⅱ)- catalyzed the annulation of C(sp²)-H bond of imidates with vinyl-1, 3-di- oxolan-2-one (Scheme 2). Notable features of our strategy include the use of Ru(Ⅱ) catalysis for the first time to the one-pot synthesis of a wide range of the 3-vinyl-3, 4-di- hydroisoquinolin-1(2H)-one derivatives and high functional group tolerance, and the incorporated vinyl group would then serve as a versatile transformable functional group for further decoration.

  Scheme 2

  

  Scheme 2.  Overview of the relevant work

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  2.   Results and discussion

  Ethyl benzimidate (1a) and vinyl-1, 3-dioxolan-2-one (2) were chosen as model substrates to our investigation (Table 1). The reaction was performed by the employment of [RuCl₂(p-cymene)₂]₂ as catalyst, AgSbF₆ and 1-adaman- tanecarboxylic acid as additive in 1, 1, 1, 3, 3, 3-hexafluoro- isopropanol (HFIP) at 80 ℃ under N₂ atmosphere. To our delight, the reaction proceeded smoo- thly to afford the desired product 3a in 41% yield (Table 1, Entry 1). Then, other common silver salts were screened, including AgNTf₂, AgOAc, Ag₂CO₃ and Ag₂SO₄. It was found that Ag₂SO₄ showed the best effect and gave the acyloxylated product 3a in the highest yield (Table 1, Entries 1~5). Among other acid additives, 1-AdCOOH turned out to be the most essential in the formation of desired product 3a (Table 1, Entries 5 and 7~12). An investigation of temperature revealed that the yield of product 3a would reduce when the temperature of the catalytic system was increased or decreased. The control experiments indicated that the reaction did not occur in the absence of Ru catalyst, silver salt or acid additives, respectively (Table 1, Entries 6, 13 and 16). Further optimization towards ruthenium catalysts (Table 1, Entries 17 and 18) and the solvents revealed that [RuCl₂(p-cymene)₂]₂ and HFIP were superior to other solvents and catalysts.

  Table 1

  

  Table 1.  Optimization of reaction conditions^a

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  Entry	Ag salt	Additive	T/℃	Yieldb/%
  1	AgSbF6	1-AdCOOH	80	41
  2	AgNTf2	1-AdCOOH	80	57
  3	AgOAc	1-AdCOOH	80	65
  4	Ag2CO3	1-AdCOOH	80	50
  5	Ag2SO4	1-AdCOOH	80	74
  6	-	1-AdCOOH	80	0
  7	Ag2SO4	PivOH	80	53
  8	Ag2SO4	NaOAc	80	Trace
  9	Ag2SO4	HOAc	80	45
  10	Ag2SO4	Cyh-COOH	80	49
  11	Ag2SO4	Cyb-COOH	80	52
  12	Ag2SO4	PhCOOH	80	49
  13	Ag2SO4	-	80	0
  14	Ag2SO4	1-AdCOOH	100	66
  15	Ag2SO4	1-AdCOOH	70	59
  16c	Ag2SO4	1-AdCOOH	80	0
  17d	Ag2SO4	1-AdCOOH	80	0
  18e	Ag2SO4	1-AdCOOH	80	0
  a Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), [RuCl2(p-cymene)2]2 (0.01 mmol), [Ag] salt (0.06 mmol), additive (0.08 mmol) in HFIP (0.5 mL), under N2 at 80 ℃ for 12 h. b Yields of isolated products. HFIP=1, 1, 1, 3, 3, 3-hexa- fluoro-2-propanol, Cyh-COOH=cyclohexanecarboxylic acid, Cyb-COOH=cyclobutanecarboxylic acid. c Without [RuCl2(p-cymene)2]2. d Ru3(CO)12 instead of without [RuCl2(p-cymene)2]2. e RuCl3•(H2O)n instead of without [RuCl2(p-cymene)2]2.

  With the optimized reaction conditions in hand, we investigated the scope of imidates (Table 2). In general, the aryl ring of imidates possessing both electron-donating and electron-withdrawing substituent were reactive in the reaction, producing the 3-vinyl-3, 4-dihydroisoquinolin-1(2H)- one derivatives in moderate to good yields (3b~3k). Gratifyingly, the results showed that the meta-methyl substituted ethyl benzimidate (1b) delivered the corresponding product 3b in highest yield (80%). It was observed that halogenated substituents, such as trifluoromethyl (3d), fluoro (3e), chloro (3f), bromo (3g) and iodo (3h) were well tolerated in this transformation to give the corresponding annulated products in moderate yields, which provided the opportunity of further derivatization of the obtained products. More importantly, both the active formyl group and carboxylate group were also applicable under the current reaction conditions, affording the desired products containing formyl group and carboxylate group, which proved the great application prospect of this protocol (3i~3j). In addition, several fused-cyclic and heterocyclic moieties, such as naphthyl and thiophenyl, could serve as viable substrates in the reaction for the successful construction of the corresponding products in good yield (3l~3m). Unfortunately, no product was detected when the meta-CN and para-NO₂ substituted ethyl benzimidates was used as substrates. The ethyl cinnamimidate (1o) was also ineffective in this reaction condition.

  Table 2

  

  Table 2.  Substrate scope of imidate^{a, b}

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  This protocol is readily scalable, and when the reaction was scaled up to 5.0 mmol with a sub-gram scale, the 3- vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3a) was isolated in 70% yield (Scheme 3). Importantly, the vinyl group is a reliable handle for further transformation. For example, the oxygenation of the double bond in the presence of PdCl₂ and CuCl in N, N-dimethylformamide (DMF) under O₂ atmosphere afforded 3-acetyl-3, 4-dihydroisoquinolin- 1(2H)-one (4) in 88% yield (Scheme 3). The epoxidation of the vinyl group occurred without difficulty to give the 3-(oxiran-2-yl)-3, 4-dihydroisoquinolin-1(2H)-one (5) in 85% yield (Scheme 3). The aboved results demonstrated the huge synthetic application of vinyl-substituted 3, 4- dihydroisoquinolin-1(2H)-one.

  Scheme 3

  

  Scheme 3.  Sub-gram-scale synthesis and further application of 3a

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  To gain insight into the mechanism, a series of mechanistic experiments were performed (Scheme 4). The addition of radical scavenging reagents such as 2, 2, 6, 6- tetramethyl-1-piperidinyloxy (TEMPO) into the reaction had no influence on the reaction efficiency, indicating that a radical pathway may not be involved in the reaction process. The reaction of substrate 1a with the D₂O in the absence of vinyl-1, 3-dioxolan-2-one (2) under the standard reaction conditions was performed and the deuterium- proton exchange of the recovered substrate 1a was observed. The result illustrated that the C-H cleavage step may be reversible. In addition, when benzonitrile was used as a substrate to react with vinyl-1, 3-dioxolan-2-one (2), the desired product 3a was not isolated. However, the 1-ethoxy-3-vinyl-3, 4-dihydroisoquinoline could obtain the target product in excellent yield under standard reaction conditions, thus implying that the 1-ethoxy-3-vinyl- 3, 4-dihydroisoquinoline was the key intermediate in the reaction. The intermolecular competition experiments between electronically differentiated aryl imidates revealed that electron-rich arenes reacted slightly preferentially, which can be rationalized by a base-assisted intramolecular electrophilic-type (BIES) C-H metalation.

  Scheme 4

  

  Scheme 4.  Control experiments

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  Based on the above experimental results and previous reports, ^[5-9] a plausible reaction pathway is proposed as depicted in Scheme 5. First, in the presence of Ag₂SO₄ and 1-AdCOOH, cationic Ru(Ⅱ) is generated in situ as the active catalyst, which coordinates to imidate and further undergoes C-H cleavage to afford rutheacyclic inter- mideate A. Then, the Ru(Ⅱ) coordinates with vinyl-1, 3- dioxolan-2-one (2) followed by migratory insertion and along with CO₂ extrusion to generate the cyclometalated intermediate C, which undergoes the β-O elimination to enable the formation of the 1-ethoxy-3-vinyl-3, 4-dihy- droisoquinoline (7) and liberate the Ru(Ⅱ) species. The active catalyst Ru(Ⅱ) complex was regenerated through ligand exchange by HX. Finally, The isomerization of 1-ethoxy-3-vinyl-3, 4-dihydroisoquinoline under standard reaction condition delivered the target product 3a.

  Scheme 5

  

  Scheme 5.  Plausible catalytic cycle

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  3.   Conclusions

  In conclusion, a one-pot approach to the synthesis of 2, 4-dialkenylindoles by vinyl-substituted dihydroisoquinolone derivatives through ruthenium-catalyzed tandem C-H functionalization/annulation of imidates with vinyl- 1, 3-dioxolan-2-one was developed. Notable features of this protocol include broad substrate scopes, excellent regioselectivity and good functional group compatibility. More significantly, the vinyl group in the final products could be readily converted to other functional group by using different reaction conditions.

  4.   Experimental section

  4.1   General Information

  ¹H NMR and ¹³C NMR spectra were recorded at 400 MHz and 100 MHz using TMS as internal standard, respectively. Mass spectroscopy data of the products were collected on an HRMS-TOF instrument. All reactions were performed under N₂ atmosphere in a 25 mL sealed tube. Toluene was dried and distilled according to the standard procedures before the use. Other materials and solvents were purchased from common commercial sources and used without additional purification. Starting materials were synthesized according to literature procedures.^[10]

  4.2   Typical procedure for the synthesis of products 3

  A 25 mL sealed tube was charged with imine ester 1 (0.3 mmol), 4-vinyl-1, 3-dioxolan-2-one (2, 0.2 mmol), [RuCl₂-(p-cymene)₂]₂ (6.2 mg, 0.01 mmol), Ag₂SO₄ (20.7 mg, 0.06 mmol), 1-AdCOOH (17.1 mg, 0.08 mmol) and HFIP (0.5 mL). The vial was evacuated and filled with N₂ atmosphere for three times, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petro- leum ether (V:V, 1:3~1:1), to afford the desired products 3.

  3-Vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3a): 74%, 25.1 mg, yellow solid. R_f=0.13 (petroleum ether/EtOAc, V:V=3:1). m.p. 116.2~117.3 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.06 (d, J=7.6 Hz, 1H), 7.46 (t, J=7.2 Hz, 1H), 7.34~7.37 (m, 1H), 7.19~7.21 (m, 1H), 7.01 (s, 1H), 5.86~5.94 (m, 1H), 5.31~5.35 (m, 1H), 5.21~5.23 (m, 1H), 4.29 (s, 1H), 3.07~3.12 (m, 1H), 2.91~2.97 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 166.1, 136.8, 136.5, 131.9, 127.6, 127.4, 126.9, 126.6, 116.7, 53.2, 35.9; HRMS (EI-TOF) calcd for C₁₁H₁₁NO 173.0841, found 173.0844.

  7-Methyl-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3b): 80%, 29.9 mg, yellow solid. R_f=0.38 (petroleum ether/EtOAc, V:V=1:1). m.p. 139.8~141.6 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 7.87 (s, 1H), 7.27 (s, 1H), 7.08~7.10 (m, 1H), 7.03 (s, 1H), 5.85~5.93 (m, 1H), 5.29~5.34 (m, 1H), 5.20~5.22 (m, 1H), 4.26 (s, 1H), 2.03~3.08 (m, 1H), 2.85~2.91 (m, 1H), 2.37 (m, 3H); ¹³C NMR (CDCl₃, 100 MHz) δ: 167.2, 137.4, 137.1, 134.5, 133.4, 128.4, 127.5, 125.5, 117.3, 53.9, 34.0, 21.2; HRMS (EI-TOF) calcd for C₁₂H₁₃NO 187.0997, found 187.1000.

  6-Methoxy-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3c): 58%, 23.4 mg, yellow solid. R_f=0.28 (petroleum ether/EtOAc, V:V=1:1). m.p. 161.3~162.5 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.02 (d, J=8.8 Hz, 1H), 7.27 (s, 1H), 6.85~6.87 (m, 1H), 6.69 (s, 1H), 5.85~5.98 (m, 1H), 5.29~5.34 (m, 1H), 5.20~5.23 (m, 1H), 4.26 (s, 1H), 3.85 (s, 3H), 3.02~3.06 (m, 1H), 2.88~2.94 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 166.2, 139.7, 137.6, 130.3, 124.1, 12.3, 119.2, 117.3, 112.7, 55.5, 54.2, 35.0; HRMS (EI-TOF) calcd for C₁₂H₁₃NO₂ 203.0946, found 203.0946.

  6-(Trifluoromethyl)-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3d): 41%, 19.8 mg, yellow solid. R_f=0.39 (petroleum ether/EtOAc, V:V=1:1). m.p. 134.2~134.3 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.18 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.00 (s, 1H), 5.85~5.94 (m, 1H), 5.32~5.36 (m, 1H), 5.24~5.27 (m, 1H), 4.32 (s, 1H), 3.15~3.20 (m, 1H), 2.97~3.03 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 165.3, 138.1, 136.7, 134.1 (J_C-F=32.0 Hz), 131.5, 128.7, 128.0 (J_C-F=27.4 Hz), 124.7, 124.2, 124.0 (J_C-F=5.2 Hz), 122.4, 121.4 (J_C-F=4.4 Hz), 117.9, 53.6, 34.3; HRMS (EI-TOF) calcd for C₁₂H₁₀F₃NO 241.0714, found 241.0715.

  6-Fluoro-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3e): 40%, 15.3 mg, yellow solid. R_f=0.33 (petroleum ether/ EtOAc, V:V=1:1). m.p. 129.3~130.7 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.06 (s, 1H), 7.45~7.78 (m, 1H), 7.00~7.05 (m, 2H), 5.68~5.76 (m, 1H), 4.02~5.06 (m, 1H), 4.95~4.97 (m, 1H), 4.07 (s, 1H), 3.00~3.05 (m, 1H), 2.74~2.79 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 165.8, 164.1, 163.3, 141.2, 141.1, 138.9, 130.3, 130.2, 126.0, 116.2, 115.2, 114.8, 114.4, 114.2, 52.3, 33.4; HRMS (EI-TOF) calcd for C₁₁H₁₀FNO 191.0746, found 191.0748.

  6-Chloro-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3f): 52%, 21.3 mg, yellow solid. R_f=0.43 (petroleum ether/ EtOAc, V:V=1:1). m.p. 157.8~158.9 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 7.99 (d, J=8.0, 1H), 7.33 (d, J=8.0, 1H), 7.20 (s, 1H), 6.80 (s, 1H), 5.84~5.91 (m, 1H), 5.30~5.35 (m, 1H), 5.23 (d, J=10.0, 1H), 4.27 (s, 1H), 3.05~3.10 (m, 1H), 2.89~2.95 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 165.1, 138.5, 138.0, 136.2, 129.0, 127.0, 126.9, 126.1, 117.0, 53.0, 35.9; HRMS (EI-TOF) calcd for C₁₁H₁₀ClNO 207.0451, found 207.0451.

  6-Bromo-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3g): 46%, 23.1 mg, yellow solid. R_f=0.43 (petroleum ether/ EtOAc, V:V=1:1). m.p. 187.6~189.3 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 7.92 (d, J=8.0 Hz, 1H), 7.48~7.50 (m, 1H), 7.38 (s, 1H), 6.85 (s, 1H), 5.84~5.92 (m, 1H), 5.30~5.35 (m, 1H), 5.22~5.25 (m, 1H), 4.28 (s, 1H), 3.05~3.10 (m, 1H), 2, 89~2.95 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 166.0, 139.3, 136.9, 137, 130.6, 129.8, 127.4, 127.3, 117.7, 53.8, 34.2; HRMS (EI-TOF) calcd for C₁₁H₁₀- BrNO 250.9946, found 250.9943.

  6-Iodo-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3h): 50%, 29.8 mg, yellow solid. R_f=0.32 (petroleum ether/ EtOAc, V:V=1:1). m.p. 185.9~187.3 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 7.74~7.76 (m, 1H), 7.70~7.72 (m, 1H), 7.59 (s, 1H), 6.88 (s, 1H), 5.83~5.91 (m, 1H), 5.30~5.34 (m, 1H), 5.21~5.24 (m, 1H), 4.27 (s, 1H), 2.03~3.08 (m, 1H), 2.86~2.92 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 166.1, 139.2, 136.9, 136.7, 136.6, 129.7, 127.9, 117.7, 100.0, 53.7, 34.0; HRMS (EI-TOF) calcd for C₁₁H₁₀INO 298.9807, found 298.9803.

  Methyl-1-oxo-3-vinyl-1, 2, 3, 4-tetrahydroisoquinoline-6-carbo-xylate (3i): 63%, 29.0 mg, yellow solid. R_f=0.27 (petroleum ether/EtOAc, V:V=1:1). m.p. 192.7~194.5 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.12~8.14 (m, 1H), 7.99~8.01 (m, 1H), 7.89 (s, 1H), 6.86 (s, 1H), 5.86~5.94 (m, 1H), 5.31~5.36 (m, 1H), 5.22~5.25 (m, 1H), 4.32 (s, 1H), 3.94 (s, 3H), 3.14~3.19 (m, 1H), 2.96~3.02 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 166.5, 165.5, 137.6, 137.0, 133.5, 132.2, 128.9, 128.3, 128.2, 117.7, 53.8, 52.5, 34.3; HRMS (EI-TOF) calcd for C₁₃H₁₃NO₃ 231.0895, found 231.0896.

  1-Oxo-3-vinyl-1, 2, 3, 4-tetrahydroisoquinoline-6-carbaldehyde (3j): 43%, 17.2 mg, yellow solid; R_f=0.22 (petroleum ether/EtOAc, V:V=1:1). m.p. 182.0~183.7 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 10.07 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 7.84~7.87 (m, 1H), 7.75 (s, 1H), 6.86 (s, 1H), 5.87~5.94 (m, 1H), 5.33~5.37 (m, 1H), 5.24~5.26 (m, 1H), 4.35 (s, 1H), 3.19~3.24 (m, 1H), 3.00~3.06 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 191.8, 165.2, 138.9, 138.3, 136.9, 133.5, 128.9, 128.3, 124.1, 117.9, 53.7, 34.3; HRMS (EI-TOF) calcd for C₁₂H₁₁NO₂ 201.0790, found 201.0793.

  6-(tert-Butyl)-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (3k): 49%, 22.5 mg. Yellow solid; R_f=0.36 (petroleum ether/EtOAc, V:V=1:1). m.p. 175.2~176.3 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 7.98 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.97 (s, 1H), 5.87~5.95 (m, 1H), 5.31~5.35 (m, 1H), 5.20~5.23 (m, 1H), 4.28 (s, 1H), 3.04~3.09 (m, 1H), 2.89~2.95 (m, 1H), 1.33 (s, 9H); ¹³C NMR (CDCl₃, 100 MHz) δ: 167.0, 156.3, 137.5, 137.3, 127.9, 125.7, 124.5, 119.2, 117.2, 54.1, 35.1, 34.8, 31.6, 31.3, 30.3; HRMS (EI-TOF) calcd for C₁₅H₁₉NO 229.1467, found 229.1467.

  3-Vinyl-3, 4-dihydrobenzo[g]isoquinolin-1(2H)-one (3l): 70%, 30.9 mg, yellow solid. R_f=0.36 (petroleum ether/ EtOAc, V:V=1:1). m.p. 205.6~206.8 ℃; ¹H NMR (CDCl₃, 400 MHz) δ: 8.64 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.51~7.55 (m, 1H), 7.45~7.49 (m, 1H), 7.07 (s, 1H), 5.87~5.95 (m, 1H), 5.31~5.35 (m, 1H), 5.18~5.21 (m, 1H), 4.32 (s, 1H), 3.23~3.28 (m, 1H), 3.03~3.09 (m, 1H); ¹³C NMR (CDCl₃, 100 MHz) δ: 166.6, 137.5, 135.4, 133.4, 132.3, 129.5, 129.3, 128.3, 127.3, 126.6, 126.2, 126.0, 117.3, 54.0, 34.9; HRMS (EI-TOF) calcd for C₁₅H₁₃NO 223.0997, found 223.0998.

  5-Vinyl-5, 6-dihydrothieno[2, 3-c]pyridin-7(4H)-one (3m): 43%, 15.4 mg, yellow solid. R_f=0.40 (petroleum ether/ EtOAc, V:V=1:1). m.p. 179.9~180.9 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 7.79 (s, 1H), 7.64 (d, J=5.2 Hz, 1H), 6.92~6.94 (m, 1H), 5.72~5.80 (m, 1H), 5.06~5.11 (m, 1H), 4.97~5.00 (m, 1H), 4.13 (s, 1H), 2.89~2.95 (m, 1H), 2.65~2.71 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 162.2, 143.7, 139.0, 131.6, 131.1, 128.1, 116.0, 54.1, 30.1; HRMS (EI-TOF) calcd for C₉H₉NOS 179.0405, found 179.0400.

  4.3   Gram-scale synthesis of 3a

  A Schlenk tube with a magnetic stir bar was charged with ethyl benzimidate 1a (1.5 mmol), 4-vinyl-1, 3-dioxolan- 2-one (2, 1.0 mmol), [RuCl₂(p-cymene)₂]₂ (31 mg, 0.05 mmol), Ag₂SO₄ (103.5 mg, 0.3 mmol), 1-AdCOOH (85.5 mg, 0.4 mmol) and HFIP (2.5 mL). The vial was evacuated and filled with N₂ atmosphere, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (V:V, 1:2~1:1) to afford the desired cyclized product 3a (70% yield).

  4.4   Synthesis of 4 by Wacker-type oxidation

  To a stirred solution of PdCl₂ (4.4 mg, 0.025 mmol) and CuCl (24.8 mg, 0.025 mmol) in DMF and H₂O (V:V=7:1, 2 mL) was added 3a (43.3 mg, 0.25 mmol) under ambient O₂ atmosphere. The mixture was stirred at ambient temperature for 16 h and extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄ and evaporated in vacuo. The crude product was separated by column chromatography (EtOAc/petroleum ether, V:V=1:1) to afford product 3-acetyl-3, 4- dihydroisoquinolin-1(2H)-one (4) (42.3 mg, 90%) as a white solid. R_f=0.16 (petroleum ether/EtOAc, V:V=1:1). m.p. 167.2~169.1 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.12 (s, 1H), 789~7.90 (m, 1H), 7.51~7.54 (m, 1H), 7.35~7.42 (m, 5H), 4.41 (s, 1H), 3.37~3.41 (m, 1H), 3.26~3.30 (m, 1H), 2.21 (s, 3H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 164.2, 136.3, 131.9, 128.7, 127.6, 126.9, 126.8, 126.7, 58.7, 29.2, 26.4; HRMS (EI-TOF) calcd for C₁₁H₁₁NO₂ 189.0790, found 189.0790.

  4.5   Epoxidation procedure

  The 3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (0.25 mmol) was dissolved in CH₂Cl₂ (3.3 mL/mmol). Commercial m-CPBA (w=85%) (1 mmol) was added and the mixture was stirred at room temperature. After thin layer chromatography (TLC) showed full conversion of the alkene (56 h) the suspension was cooled on an ice bath. The mixture was treated with Na₂SO₃ aqueous (w=10%) (1.5 equiv.) followed by Na₂CO₃ aqueous (w=10%, 1.3 equiv.) and stirred for 5 min. The reaction mixture was diluted with CH₂Cl₂, and washed with saturated NaHCO₃ (10 mL× 2) and brine (10 mL×1). The organic extract was dried over Na₂SO₄, concentrated in vacuo and purified by flash chromatography. The crude product was separated by column chromatography (EtOAc/petroleum ether, V:V=1:1) to afford product 3-(oxiran-2-yl)-3, 4-dihydroisoquinolin- 1(2H)-one (5) (44.7 mg, 95%). Yellow solid. R_f=0.11 (petroleum ether/EtOAc, V:V=1:1). m.p. 161.1~163.8 ℃; ¹H NMR (DMSO-d₆, 400 MHz) δ: 8.19~8.21 (m, 1H), 7.86~7.90 (m, 1H), 7.48~7.54 (m, 1H), 7.32~7.41 (m, 2H), 3.52~3.54 (m, 1H), 3.14~3.22 (m, 1H), 2.95~3.02 (m, 2H), 2.67~2.77 (m, 1H), 2.58~2.62 (m, 1H); ¹³C NMR (DMSO-d₆, 100 MHz) δ: 165.4, 138.4, 133.2, 133.0, 129.1, 128.8, 128.0, 54.7, 53.6, 44.4, 30.9; HRMS (EI-TOF) calcd for C₁₁H₁₁NO₂ 189.0790, found 189.0791.

  4.6   Radical trapping experiment

  A Schlenk tube with a magnetic stir bar was charged with ethyl benzimidate (1a, 0.3 mmol), 4-vinyl-1, 3-dioxolan- 2-one (2, 0.2 mmol), [RuCl₂(p-cymene)₂]₂ (6.2 mg, 0.01 mmol), Ag₂SO₄ (20.7 mg, 0.06 mmol), 1-AdCOOH(17.1 mg, 0.08 mmol), TEMPO (62.5 mg, 0. 4 mmol) and HFIP (0.5 mL). The vial was evacuated and filled with N₂ atmosphere, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (V:V=1:2~1:1), to afford the desired cyclized product 3a (69% yield).

  4.7   H/D exchange experiments

  A Schlenk tube with a magnetic stir bar was charged with ethyl benzimidate 1a (0.3 mmol), 4-vinyl-1, 3-dioxolan- 2-one (2, 0.2 mmol), [RuCl₂(p-cymene)₂]₂ (6.2 mg, 0.01 mmol), Ag₂SO₄ (20.7 mg, 0.06 mmol), 1-AdCOOH(17.1 mg, 0.08 mmol), D₂O (18 μL, 1.0 mmol) and HFIP (0.5 mL). The vial was evacuated and filled with N₂ atmosphere, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (V:V=1:1), to afford the desired product D-1a.

  4.8   Control experiments

  A Schlenk tube with a magnetic stir bar was charged with benzonitrile 6 (0.3 mmol), 4-vinyl-1, 3-dioxolan-2-one (2, 0.2 mmol), [RuCl₂(p-cymene)₂]₂ (6.2 mg, 0.01 mmol), Ag₂SO₄ (20.7 mg, 0.06 mmol), 1-AdCOOH (17.1 mg, 0.08 mmol) and HFIP (0.5 mL). The vial was evacuated and filled with N₂ atmosphere, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The desired product 3a was not detected.

  A Schlenk tube with a magnetic stir bar was charged with 1-ethoxy-3-vinyl-3, 4-dihydroisoquinoline 7 (0.3 mmol), [RuCl₂(p-cymene)₂]₂ (6.2 mg, 0.01 mmol), Ag₂SO₄ (20.7 mg, 0.06 mmol), 1-AdCOOH(17.1 mg, 0.08 mmol) and HFIP (0.5 mL). The vial was evacuated and filled with N₂ atmosphere, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (V:V=1:2~1:1), to afford the desired cyclized product 3a (90% yield).

  4.9   Competing reaction

  A Schlenk tube with a magnetic stir bar was charged with 6-methoxy-3-vinyl-3, 4-dihydroisoquinolin-1(2H)-one (1c, 0.3 mmol), 6-(trifluoromethyl)-3-vinyl-3, 4-dihydroiso- quinolin-1(2H)-one (1d, 0.3 mmol), 4-vinyl-1, 3-dioxolan- 2-one (2, 0.4 mmol), [RuCl₂(p-cymene)₂]₂ (12.4 mg, 0.02 mmol), Ag₂SO₄ (41.4 mg, 0.12 mmol), 1-AdCOOH (34.2 mg, 0.16 mmol) and HFIP (0.5 mL). The vial was evacuated and filled with N₂ atmosphere, and stirred at 80 ℃ for 12 h. The mixture was then cooled to room temperature, diluted with EtOAc, filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/petroleum ether (V:V=1:2~1:1), to afford the desired cyclized products 3c (37% yield) and 3d (34% yield).

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

  
  
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• 

  Scheme 1  Bioactive molecules containing the skeleton of dihydroisoquinolone derivatives

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  Scheme 2  Overview of the relevant work

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  Scheme 3  Sub-gram-scale synthesis and further application of 3a

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  Scheme 4  Control experiments

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  Scheme 5  Plausible catalytic cycle

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  Table 1.  Optimization of reaction conditions^a

  Entry	Ag salt	Additive	T/℃	Yieldb/%
  1	AgSbF6	1-AdCOOH	80	41
  2	AgNTf2	1-AdCOOH	80	57
  3	AgOAc	1-AdCOOH	80	65
  4	Ag2CO3	1-AdCOOH	80	50
  5	Ag2SO4	1-AdCOOH	80	74
  6	-	1-AdCOOH	80	0
  7	Ag2SO4	PivOH	80	53
  8	Ag2SO4	NaOAc	80	Trace
  9	Ag2SO4	HOAc	80	45
  10	Ag2SO4	Cyh-COOH	80	49
  11	Ag2SO4	Cyb-COOH	80	52
  12	Ag2SO4	PhCOOH	80	49
  13	Ag2SO4	-	80	0
  14	Ag2SO4	1-AdCOOH	100	66
  15	Ag2SO4	1-AdCOOH	70	59
  16c	Ag2SO4	1-AdCOOH	80	0
  17d	Ag2SO4	1-AdCOOH	80	0
  18e	Ag2SO4	1-AdCOOH	80	0
  a Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), [RuCl2(p-cymene)2]2 (0.01 mmol), [Ag] salt (0.06 mmol), additive (0.08 mmol) in HFIP (0.5 mL), under N2 at 80 ℃ for 12 h. b Yields of isolated products. HFIP=1, 1, 1, 3, 3, 3-hexa- fluoro-2-propanol, Cyh-COOH=cyclohexanecarboxylic acid, Cyb-COOH=cyclobutanecarboxylic acid. c Without [RuCl2(p-cymene)2]2. d Ru3(CO)12 instead of without [RuCl2(p-cymene)2]2. e RuCl3•(H2O)n instead of without [RuCl2(p-cymene)2]2.

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  Table 2.  Substrate scope of imidate^{a, b}

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•