HETEROCYCLES

Paper | Special issue | Vol. 86, No. 1, 2012, pp. 267-280
Received, 21st March, 2012, Accepted, 16th April, 2012, Published online, 19th April, 2012.
DOI: 10.3987/COM-12-S(N)7

■ Reissert-like Alkenylation of Azaaromatic Compounds with Alkenylzirconocene Chloride Complexes

Akio Saito,* Kohei Sudo, Koichi Iimura, Miki Hayashi, and Yuji Hanzawa*

Showa College of Pharmaceutical Sciences, 3-3165, Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan

Abstract

Reissert-like alkenylation of azaaromatic compounds by the use of alkenylzirconocene chloride as a nucleophile was carried out in the presence of a stoichiometric amount of ClCO2Et. The regioselectivity of the nucleophilic attack depends on reacting heterocycles, solvent, and the presence of copper catalyst. Thus, the reaction of quinoline derivatives with alkenylzirconocene chloride in MeNO2 proceeded in a preferential 1,2-addition manner to give N-ethoxycarbonyl-2-alkenyl-1,2-dihydroquinolines, and the reaction of pyridine in CH2Cl2 under Cu(I)-catalyzed conditions proceeded in a 1,4-addition manner to give N-ethoxycarbonyl-4-alkenyl-1,4-dihydropyridine. The alkenylation of 3,4 -dihydroisoquinoline with alkenylzirconocene chloride was also carried out in an enantioselective manner under Cu(I)/chiral Box-catalyzed conditions to give alkenylated tetrahydroisoquinoline compound (75%ee).

INTRODUCTION
Nucleophilic additions of carbon nucleophiles to N-acyliminium ions provide us with efficient procedures for the preparation of amine derivatives, and the procedure has been applied to the synthesis of alkaloids and medicinally significant molecules. 1 One of the typical reactions applied to azaaromatics, known as the Reissert reaction, employs a cyanide nucleophile in the presence of N-acylating agents affording N-acyl-2-cyano-1,2-dihydroheterocycles (Scheme 1).2 On the other hand, Reissert-like reactions of the azaaromatic compounds using organometallics (Mg,3 Cu,4 Sn,5 and their allyl6 or alkynyl species7) or metal enolates8 instead of the cyanide nucleophile have been extensively studied to enhance the chemical value of the Reissert reaction. Recently, it was shown that alkenyl boronic acid (Petasis-type reaction)9 or of the aluminum10 was another choice of organometallics for the Reissert-like alkenylation process.

In our continuous study about the carbon-carbon bond formation using organozirconocene chloride complexes as a synthetic reagent,11,12 we are tempted to examine the use of organozirconocene chloride complexes for the Reissert-like alkenylation. Although the alkenylzirconocene chlorides are readily accessible through the hydrozirconation of alkyne compounds with Schwartz reagent [Cp2Zr(H)Cl]13 or by the treatment of alkenyl halide with Negishi reagent [Cp2Zr-nBu2],14 the poor reactivity of the complexes toward the electrophiles, such as aldehydes, ketones and imines, often hampered their use for organic synthesis. Thus, the search for catalysts and/or activating agents is necessitated to achieve the objective carbon-carbon bond forming reactions. Our recent work revealed that the reaction of alkenylzirconocene chloride complexes and 3,4-dihydroisoquinoline in the presence of acylating agent brought about the enantioselective formation of 1-alkenyl-2-acyltetrahydroisoquinoline under the Cu(I)/chiral Box-catalyzed conditions.15 It was also found that Reissert-like alkenylation of quinoline with alkenylzirconocene chloride was promoted by the activation through acylating agent without the use of Cu(I)-catalyst, albeit the poor regioselectivity (1,2- vs 1,4-addition).15 In this paper, we describe the influence upon the regioselectivity of the Reissert-like alkenylation of azaaromatic compounds with alkenylzirconocene chlorides.

RESULTS AND DISCUSSION
At the outset, we focused on the improvement of the regioselectivity in the reaction of quinoline (1a) and (E)-styrylzirconocene chloride (2a, 2 equiv) in the presence of ethyl chloroformate (ClCO2Et, 1.2 equiv) (Table 1). In CH2Cl2 solvent, treatment of 1a with ClCO2Et at 0 °C for 30 min followed by the addition of 2a to the reaction mixture proceeded the Reissert-like alkenylation at ambient temperature within 2 h (by TLC) to afford a mixture of 1,2-adduct 3a (70%) and 1,4-adduct 4a (25%) (3a/4a = 2.8/1) (entry 1). The use of nitromethane (MeNO2) solvent, however, suppressed the formation of 1,4-adduct 4a (3-7%, entries 5-7), and the yield of 1,2-adduct 3a was improved up to 82% in the presence of 2.4 equiv of ClCO2Et (3a/4a = 27/1) (entry 7). Thus, the solvent choice is important for the regioselective formation of 1-acyl-2-alkenylation product 3a, albeit other examined solvents (toluene, THF and CH3CN) are unattractive (entries 2-4). Based on the results, the Reissert-like reactions of quinoline derivatives 1 with 2a and ClCO2Et were examined in either CH2Cl2 or MeNO2 solvent (Table 2). The reactions of quinoline derivatives 1a-d in CH2Cl2 completed at ambient temperature within 2 h (by TLC), except for the nitro-substituted 1e (24 h). In all cases examined, however, a considerable amount of 1,4-adducts 4a-e (10-36%) were formed along with 1,2-adducts 3a-e (63-83%) (left column, Table 2). The use of MeNO2 as a solvent brought about the improved 1,2-regioselectivities for the additions (3a-e: 52-93%, 4a-e: 3-9%) (right column).

In the reaction of pyridine (5) and 2a in the presence of ClCO2Et, however, the use of MeNO2 afforded a mixture of regioisomers 6 and 7 (53%) with a poor 1,2-regioselectivity (6/7 = 3.8/1) (Scheme 2). It should be noted that the alkenylation in CH2Cl2 brought about the nonselective formation of products (67%, 6/7 = 1/1.4). The 1,4-regioselectivity was remarkably enhanced by the addition of catalytic CuBr (10 mol%) to the reaction mixture at -78 °C to give a mixture of products in high yield (95%, 6/7 = 1/18). Contrary to the reaction of pyridine, CuBr-catalyzed reaction of quinoline (1a) did not give an improved selectivity of regioisomers (81%, 3a/4a = 1.3/1) (Table 1, entry 8) under otherwise identical conditions with pyridine. The presence of ClCO2Et is essential to bring about the reaction in every examined case. Thus, it is necessary to activate the azaaromatic compounds as shown in Scheme 1. Although details about the solvent effect and the role of the Cu(I)-catalyst for the regioselectivity remain uncertain at present,16 it has been reported that the addition of Cu(I)-catalysts to Grignard reagents3a or the use of organocoppers4 led to the preferred formation of the Reissert-like 1,4-addition product.

The alkenylation of isoquinoline derivative 8a or 8b with 2a in the presence of ClCO2Et proceeded smoothly in CH2Cl2 at ambient temperature giving rise to the corresponding product 9a or 9b as a sole product in high yield (Scheme 3). Extension of the alkenylation using 2a to 3,4-dihydroisoquinoline (10) reveals that Cu(I) catalyst in the coexisitence of N-acylating agent is required to bring about the efficient formation of alkenylated tetrahydroisoquinoline 11a (Table 3). Among the examined Cu(I) catalysts,17 Cu(OTf) (Entry 3) or [Cu(MeCN)4]PF6 (Entries 4-7) showed high efficiency for the formation of 11, and alkyl-substituted alkenylzirconocene chlorides (2b, 2c and 2d) were also efficient nucleophiles in the reaction.

An attempt to carried out the enantioselective addition of 2a to 10 using Cu(I)/chiral ligand catalytic systems indicated that chiral Box ligands to Cu(I) catalyst turned out to be fairly efficient in a sense of chiral induction (Table 4). Thus, by using a [Cu(MeCN)4]PF6 and (S,S)-Box ligand 12,18 the reaction of 10 with 2a and di-t-butyl dicarbonate [(Boc)2O] as an N-acylating agent at 0 °C for 24 h afforded (S)-13 (75%ee) in 65% yield (Entry 12). The absolute configuration of (S)-13 was determined by the conversion to compound 1419 whose absolute configuration has been established (Scheme 4).

CONCLUSIONS
The alkenylzirconocene chloride complex was found to be an efficient nucleophile for the Reissert-type alkenylation of azaaromatic compounds in the presence of a stoichiometric amount of ClCO2Et. In the reaction, solvent effect (MeNO2 or CH2Cl2) and/or the presence of Cu-catalyst are important for the regioselectivity of the alkenylation of quinolines and pyridines. The enantioselective addition of the alkenylzirconocene chloride to 3,4-dihydroisoquinoline was also achieved by the Cu(I)/chiral Box ligand catalytic system to give the biologically attractive tetrahydroisoquinoline compound in an optically active form.20 We believe that the reactivity of alkenylzirconocene chloride described in the present paper indicates a new possibility for the use of organozirconocene complexes in organic synthesis.

EXPERIMENTAL
All melting points were taken on a Yanaco SP-M1 melting point apparatus (Yanagimoto Co.) and were uncorrected. IR spectra were taken on a HORIBA FT-710 FT-IR spectrometer. 1H and 13C NMR spectra were measured in CDCl3 with a Bruker AV300M FT NMR spectrometer at 300 and 75 MHz, and the chemical shifts are given in ppm using CHCl3 (7.26 ppm) for 1H NMR and CDCl3 (77.0 ppm) for 13C NMR as an internal standard, respectively. Mass spectra and HRMS were recorded by FAB method on a JMS-HX110 Mass spectrometer. Elemental analysis were measured on a Perkin-Elmer 240B or Elemental Vavio EL. For the TLC analysis, Merck precoated TLC plates (silica gel 60 F254) were used. Column chromatography was performed on Silica gel 60N (63-200 µm, Kanto Kagaku Co., Ltd.). All of the organic solvents were dried over appropriate drying agents. Unless otherwise stated, all reactions were conducted under an argon atmosphere.
Starting Materials. 3,4-dihydroisoquinoline (10) was prepared by previously reported procedure.21 All other compounds were commercially available.
General procedure for the preparation of alkenylzirconocene chlorides 2 in CH2Cl2. To a suspension of Cp2Zr(H)Cl (258 mg, 1.0 mmol) in CH2Cl2 (2.0 mL) was added an alkyne compound (1.2 mmol) at an ambient temperature. After the reaction mixture was stirred for 30 min at the same temperature, the CH2Cl2 solutions were used in the following experiments without any changes.
Preparation of (E)-styrylzirconocene chloride (2a) in MeNO2. According to the above manner, the solution of 2a in CH2Cl2 (2.0 mL) was prepared from Cp2Zr(H)Cl (258 mg, 1.0 mmol) and phenylalkyne (132 µL, 1.2 mmol). After the CH2Cl2 was removed in vacuo, MeNO2 (2.0 mL) was added to the residue.
General procedure for the Reissert-like alkenylation of 2 with azaaromatic compounds. A premixed solution (30 min at 0 °C) of an azaaromatic compound (0.5 mmol) and ClCO2Et (0.6 or 1.2 mmol) in CH2Cl2 or MeNO2 (3.0 mL) was added to a solution of 2 (1.0 mmol) in CH2Cl2 or MeNO2 (2.0 mL) at an ambient temperature. After the consumption of the starting material (by TLC analysis), the reaction mixture was diluted with ether and filtered through a short alumina column. After concentration of the filtrate to dryness, the subsequent purification gave the corresponding acyl-alkenylated compound 3, 4, 6, 7, and/or 9.
Ethyl 2-[(E)-styryl]quinoline-1(2H)-carboxylate (3a) IR (neat) ν 1716 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.33 (t, 3H, J = 7.1 Hz), 4.21-4.35 (m, 2H), 5.66-5.70 (m, 1H), 6.00-6.08 (m, 2H), 6.47-6.56 (m, 1H), 7.00-7.09 (m, 2H), 7.14-7.28 (m, 6H), 7.61 (br.d, 1H, J = 7.9 Hz); 13C NMR (75 MHz, CDCl3) δ 14.5, 54.3, 62.2, 124.1, 124.3, 125.6, 126.4, 126.7, 126.9, 127.1, 127.6, 127.7, 128.5, 131.5, 134.7, 136.5, 154.3; FAB-LM m/z 305.3 (M+H+); FAB-HM Calcd for C20H20NO2 306.1494, Found 306.1481. Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.59; H, 6.36; N, 4.57.
Ethyl 4-[(E)-styryl]quinoline-1(4H)-carboxylate (4a). IR (neat) ν 1716 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.1 Hz), 4.16 (dd, 1H, J = 8.0, 5.0 Hz), 4.32 (q, 2H, J = 7.1 Hz), 5,28 (dd, 1H, J = 7.8, 5.0 Hz), 6.16 (dd, 1H, J = 15.7, 8.0 Hz), 6.41 (d, 1H, J = 15.7 Hz), 7.06-7.34 (m, 9H), 8.04 (d, 1H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 14.5, 41.5, 62.5, 111.1, 121.4, 125.0, 126.2, 126.3, 127.4, 128.5, 128.7, 129.4, 131.6, 135.8, 137.0, 152.6; FAB-LM m/z 304.2 (M+H+); FAB-HM Calcd for C20H20NO2 306.1494, Found 306.1483.
Ethyl 3-methyl-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3b). IR (neat) ν 1712 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J = 7.1 Hz), 1.97 (s, 3H), 4.19-4.39 (m, 2H), 5.44 (d, 1H, J = 7.3 Hz), 6.00 (dd, 1H, J = 15.7, 7.3 Hz), 6.30 (s, 1H), 6.35 (d, 1H, J = 15.7 Hz), 7.00-7.06 (m, 2H), 7.11-7.31 (m, 6H), 7.59 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.6, 20.7, 58.9, 62.2, 121.4, 124.0, 124.1, 124.4, 125.7, 126.6, 126.7, 127.7, 128.4, 131.8, 133.4, 136.5, 136.7, 154.2; FAB-LM m/z 319.2 (M+H+); FAB-HM Calcd for C21H22NO2 320.1651. Found 320.1658.
Ethyl 3-methyl-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4b). IR (neat) ν 1719 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.1 Hz), 1.83 (s, 3H), 3.91 (d, 1H, J = 8.3 Hz), 4.32 (q, 2H, J = 7.1 Hz), 6.08 (dd, 1H, J = 15.5, 8.3 Hz), 6.41 (d, 1H, J = 15.5 Hz), 6.83-6.84 (m, 1H), 7.09-7.37 (m, 8H), 8.01 (d, 1H, J = 8.3 Hz); 13C NMR (75 MHz, CDCl3) δ 14.5, 18.5, 47.6, 62.4, 119.7, 121.3, 121.5, 124.8, 126.4, 126.6, 127.3, 128.5, 128.6, 129.3, 130.3, 131.6, 135.8, 137.0, 152.6; FAB-LM m/z 319.2 (M+H+); FAB-HM Calcd for C21H22NO2 320.1651. Found 320.1642.
Ethyl 6-methyl-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3c). IR (neat) ν 1722 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.33 (t, 3H, J = 7.1 Hz), 2.29 (s, 3H), 4.20-4.38 (m, 2H), 5.65-5.70 (mt, 1H), 5.99-6.09 (m, 2H), 6.47-6.53 (m, 2H), 6.90 (d, 1H, J = 1.7 Hz), 7.00 (dd, 1H, J = 8.3, 1.7 Hz), 7.15-7.29 (m, 5H), 7.48-7.50 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.5, 20.8, 54.3, 62.1, 124.1, 125.7, 126.6, 126.7, 126.9, 127.7, 128.3, 128.4, 131.4, 132.2, 133.6, 136.6, 154.4; FAB-LM m/z 319.3 (M+H+); FAB-HM Calcd for C21H22NO2 320.1651. Found 320.1659. Anal. Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.81; H, 6.72; N, 4.29.
Ethyl 6-methyl-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4c). Mp 50 °C; IR (KBr) ν 1729 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J = 7.1 Hz), 2.29 (s, 3H), 4.12 (dd, 1H, J = 8.0, 5.0 Hz), 4.32 (q, 2H, J = 7.1 Hz), 5.26 (dd, 1H, J = 8.0, 5.0 Hz), 6.16 (dd, 1H, J = 15.7, 8.0 Hz), 6.42 (d, 1H, J = 15.7 Hz), 6.95-7.08 (m, 3H), 7.19-7.38 (m, 5H), 7.94 (d, 1H, J = 8.5 Hz); 13C NMR (75 MHz, CDCl3) δ 14.5, 20.7, 41.6, 62.4, 110.9, 121.2, 126.2, 126.4, 127.4, 127.5, 128.5, 129.1, 129.2, 131.8, 133.3, 134.5, 137.1, 152.6; FAB-LM m/z 319.2 (M+H+); FAB-HM Calcd for C21H22NO2 320.1651, Found 320.1641.
Ethyl 6-methoxy-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3d). IR (neat) ν 1716 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.28 (t, 3H, J = 7.1 Hz), 3.79 (s, 3H), 4.16-4.33 (m, 2H), 5.65-5.69 (m, 1H), 5.99-6.07 (m, 2H), 6.45-6.52 (m, 2H), 6.62 (d, 1H, J = 2.9 Hz), 6.74 (dd, 1H, J = 8.9, 2.9 Hz), 7.13-7.28 (m, 5H), 7.50-7.52 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.6, 54.2, 55.5, 62.1, 111.2, 113.1, 125.5, 125.6, 126.6, 127.7, 128.0, 128.4, 131.5, 136.5, 154.4, 156.1; FAB-LM m/z 335.2 (M+H+); FAB-HM Calcd for C21H22NO3 336.1600. Found 336.1602.
Ethyl 6-methoxy-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4d). IR (neat) ν 1716 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.35 (t, 3H, J = 7.1 Hz), 3.96 (s, 3H), 4.12 (dd, 1H, J = 8.0, 4.9 Hz), 4.31 (q, 2H, J = 7.1 Hz), 5,24 (dd, 1H, J = 7.8, 4.9 Hz), 6.14 (dd, 1H, J = 15.7, 8.0 Hz), 6.32 (d, 1H, J = 15.7 Hz), 6.68 (d, 1H, J = 3.0 Hz), 6.78 (dd, 1H, J = 9.2, 3.0 Hz), 7.04-7.07 (m, 1H), 7.16-7.43 (m, 4H), 7.99 (d, 1H, J = 9.2 Hz); 13C NMR (75 MHz, CDCl3) δ 14.5, 41.8, 55.5, 62.4, 110.5, 112.2, 113.4, 122.5, 126.1, 126.4, 127.4, 128.5, 129.5, 130.1, 130.8, 131.5, 152.6, 156.6; FAB-LM m/z 335.2 (M+H+); FAB-HM Calcd for C21H22NO3 336.1600. Found 336.1598.
Ethyl 6-nitro-2-[(E)-styryl]qunoline-1(2H)-carboxylate (3e). Mp 125 °C; IR (KBr) ν 1720 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.38 (t, 3H, J = 7.1 Hz), 4.31-4.38 (m, 2H), 5.71-5.75 (m, 1H), 6.03 (dd, 1H, J = 15.8, 6.6 Hz), 6.10-6.24 (m, 1H), 6.47-6.52 (m, 1H), 6.61-6.65 (m, 1H), 7.19-7.30 (m, 5H), 7.81-7.90 (m, 1H), 7.97-8.12 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 14.4, 45.1, 54.8, 63.1, 121.8, 122.9, 124.1, 124.5, 126.6, 127.2, 128.2, 131.8, 132.5, 135.9, 140.2, 143.5, 153.7; FAB-LM m/z 351.3 (M+H+); FAB-HM Calcd for C20H19N2O4 351.1345. Found 351.1344. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.85; H, 5.26; N, 7.74.
Ethyl 6-nitro-4-[(E)-styryl]qunoline-1(4H)-carboxylate (4e). Mp 71 °C; IR (KBr) ν 1735 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.40 (t, 3H, J = 7.1 Hz), 4.26 (dd, 1H, J = 8.1, 5.0 Hz), 4.37 (q, 2H, J = 7.1 Hz), 5,34 (dd, 1H, J = 7.8, 5.0 Hz), 6.15 (dd, 1H, J = 15.7, 8.1 Hz), 6.47 (d, 1H, J = 15.7 Hz), 7.10 (d, 1H, J = 7.8 Hz), 7.22-7.41 (m, 5H), 8.06-8.29 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 14.4, 41.3, 63.4, 110.7, 115.6, 121.8, 121.9, 122.3, 124.4, 125.7, 126.5, 127.8, 128.6, 130.1, 130.3, 130.7, 136.4, 144.3; FAB-LM m/z 351.3 (M+H+); FAB-HM Calcd for C20H19N2O4 351.1345. Found 351.1351.

Ethyl 2-[(E)-styryl]pyridine-1(2H)-carboxylate (6). Mp 52 °C; IR (KBr) ν 1716 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J = 7.1 Hz), 4.20-4.30 (m, 2H), 5.26-5.59 (m, 3H), 5.99-6.04 (m, 1H), 6.18-6.25 (m, 1H), 6.44-6.58 (m, 1H), 6.70-6.84 (m, 1H), 7.21-7.41 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.5, 53.3, 62.3, 105.3, 120.5, 122.0, 124.9, 125.6, 127.7, 128.5, 131.2, 136.7, 155.7; FAB-LM m/z 255.2 (M+H+); FAB-HM Calcd for C16H18NO2 256.1338. Found 256.1336.
Ethyl 4-[(E)-styryl]pyridine-1(4H)-carboxylate (7). IR (neat) ν 1718 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.32 (t, 3H, J = 7.1 Hz), 3.74-3.77 (m, 1H), 4.26 (q, 2H, J = 7.1 Hz), 4.86-4.93 (m, 2H), 6.15 (dd, 1H, J = 15.8, 7.4 Hz), 6.36 (d, 1H, J = 15.8 Hz), 6.77-6.92 (m, 2H), 7.20-7.42 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.5, 36.2, 62.5, 108.5, 120.8, 122.8, 126.3, 127.0, 128.5, 132.9, 137.2, 150.2; FAB-LM m/z 254.2 (M+H+); FAB-HM Calcd for C16H18NO2 256.1338. Found 256.1332.
Ethyl 1-[(E)-styryl]isoqunoline-2(1H)-carboxylate (9a). IR (neat) ν 1712 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.36 (t, 3H, J = 7.1 Hz), 4.26-4.39 (m, 2H), 5.87 (d, 1H, J = 7.8 Hz), 6.01 (br.s, 1H), 6.29 (dd, 1H, J = 15.8, 6.0 Hz), 6.38 (d, 1H, J = 15.8 Hz), 6.96 (br.s, 1H), 7.07-7.34 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 14.4, 57.3, 62.2, 108.0, 124.7, 124.9, 126.6, 126.7, 127.0, 127.6, 127.8, 128.3, 130.9, 136.5, 153.1; FAB-LM m/z 305.2 (M+H+); FAB-HM Calcd for C20H20NO2 306.1494. Found 306.1489.
Ethyl 4-bromo-1-[(E)-styryl]isoqunoline-2(1H)-carboxylate (9b). IR (neat) ν 1733 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.34 (t, 3H, J = 7.1 Hz), 4.25-4.32 (m, 2H), 5.80-6.03 (m, 1H), 6.20-6.27 (m, 1H), 6.35 (d, 1H, J = 15.7 Hz), 6.89-7.35 (m, 9H), 7.48-7.51 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 14.5, 57.2, 62.9, 103.3, 124.9, 125.6, 128.3, 128.5, 131.0, 136.1,153.5; FAB-LM m/z 383.1 (M+H+); FAB-HM Calcd for C20H19NO2Br 384.0599. Found 383.0526. Anal. Calcd for C20H18NO2Br: C, 62.51; H, 4.72; N, 3.65. Found: C, 62.65; H, 5.11; N, 3.57.
Cu(I)-catalyzed acyl-alkenylation of 2a with pyridine (5). A premixed solution (30 min at 0 °C) of pyridine (40 mL, 0.5 mmol) and ClCO2Et (114 mL, 1.2 mmol) in CH2Cl2 (3.0 mL) was added to solution of 2a (1.0 mmol) with CuBr (7.2 mg, 50 mmol) in CH2Cl2 (2.0 mL) at -78 °C. After being stirred at -78 °C for 3 h, the yields of 6 and 7 was determined by 1H-NMR analysis using toluene as a internal standard.
Cu(I)-catalyzed acyl-alkenylation of 2 with 3,4-dihydroisoquinoline (10). A premixed solution (30 min at 0 °C) of pyridine (40 mL, 0.5 mmol) and ClCO2Et (114 mL, 1.2 mmol) in CH2Cl2 (3.0 mL) was added to solution of 2a (1.0 mmol) with [Cu(MeCN)4]PF6 (18.6 mg, 50 µmol) in CH2Cl2 (2.0 mL) at an ambient temperature. After the consumption of the starting material (by TLC analysis), workup and purification as above described yielded 11.
Ethyl 3,4-dihydro-1-[(E)-styryl]isoquinoline-2(1H)-carboxylate (11a). IR (neat) ν 1704 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.29 (t, 3H, J = 7.1 Hz), 2.73-2.81 (m, 1H), 2.90-3.01 (m, 1H), 3.29-3.33 (m, 1H), 4.12-4.25 (m, 2H), 5.78-5.81 (m, 1H), 6.32 (dd, 1H, J = 15.8, 5.6 Hz), 6.41 (d, 1H, J = 15.8 Hz), 7.13-7.37 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 14.8, 28.7, 38.5, 56.3, 61.5, 126.2, 126.5, 126.8, 127.7, 128.1, 129.0, 129.1, 131.4, 134.7, 136.6, 155.6; FAB-LM m/z 307.4 (M+H+); FAB-HM Calcd for C20H22NO2 308.1651. Found 308.1644. Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C, 77.98; H, 7.09; N, 4.52.
Ethyl 1-[(E)-hex-1-enyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (11b). IR (neat) ν 1714 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J = 7.1 Hz), 1.24-1.38 (m, 4H), 1.29 (t, 3H, J = 7.1 Hz), 2.02 (dt, 2H, J = 6.8, 6.8 Hz), 2.73 (dt, 1H, J = 16.0, 3.7 Hz), 2.86-2.99 (m, 1H), 3.19-3.33 (m, 1H), 4.03-4.32 (m, 3H), 5.49 (dt, 1H, J = 14.9, 6.8 Hz), 5.50-5.66 (m, 2H), 7.08-7.23 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 13.8, 14.7, 22.1, 28.6, 31.2, 31.8, 38.1, 56.1, 61.2, 125.9, 126.5, 127.9, 128.7, 129.3, 132.9, 134.4, 135.6, 155.4; FAB-LM m/z 288.3 (M+H+); FAB-HM Calcd for C18H26NO2 288.1964. Found 288.1956. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.01; H, 8.76; N, 4.74.
Ethyl 3,4-dihydro-1-[(E)-3,3-dimethylbut-1-enyl]isoquinoline-2(1H)-carboxylate (11c). IR (neat) ν 1716 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.99 (s, 9H), 1.28 (t, 3H, J = 7.1 Hz), 2.73 (dt, 1H, J = 16.0, 3.7 Hz), 2.86-3.00 (m, 1H), 3.18-3.30 (m, 1H), 4.12-4.31 (m, 3H), 5.46 (dd, 1H, J = 15.4, 5.5 Hz), 5.51-5.67 (m, 2H), 7.07-7.25 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.7, 28.7, 29.4, 32.9, 38.1, 56.3, 61.2, 123.9, 126.0, 126.5, 127.9, 128.8, 134.5, 135.8, 143.7, 155.5; FAB-LM m/z 288.3 (M+H+); FAB-HM Calcd for C18H26NO2 288.1964. Found 288.1971.
Ethyl 1-[(E)-hex-3-en-3-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (11d). IR (neat) ν 1704 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J = 7.5 Hz), 1.05 (t, 3H, J = 7.5 Hz), 1.27 (t, 3H, J = 7.1 Hz), 1.94-2.09 (m, 3H), 2.13-2.28 (m, 1H), 2.71 (dt, 1H, J = 16.0, 3.8 Hz), 2.84-3.01 (m, 1H), 3.19-3.37 (m, 1H), 3.92-4.35 (m, 3H), 4.80 (t, 1H, J = 7.2 Hz), 5.59-5.85 (m, 1H), 6.98-7.05 (m, 1H), 7.08-7.20 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 13.6, 14.3, 14.7, 20.8, 21.6, 28.1, 37.5, 58.3, 61.2, 125.4, 126.5, 128.6, 131.8, 135.2, 135.4, 141.0, 155.7; FAB-LM m/z 288.3 (M+H+); FAB-HM Calcd for C18H26NO2 288.1964. Found 288.1965. Anal. Calcd for C18H25NO2: C, 75.22; H, 8.77; N, 4.87. Found: C, 74.95; H, 8.84; N, 4.66.
Enantioselective acyl-alkenylation of 2a with 3,4-dihydroisoquinoline (10). A premixed solution (30 min at 0 °C) of 10 (65.6 mg, 0.5 mmol) and (Boc)2O (131 mg, 1.2 mmol) in CH2Cl2 (3.0 mL) was added at 0 °C to solution of 2a (1.0 mmol) in CH2Cl2 (2.0 mL), which was pretreated with a premixed solution (5 min at a ambient temperature) of [Cu(MeCN)4]PF6 (18.6 mg, 50 µmol) and Box ligand 12 (11.8 mg, 50 µmol) in CH2Cl2 (1.0 mL). After being stirred at 0 °C for 24 h, the workup and purification as above described yielded 13 (115.7 mg, 69%, 75% ee, [α]D = 122.7).
tert-Butyl 3,4-dihydro-1-[(E)-styryl]isoquinoline-2(1H)-carboxylate (13). IR (neat) ν 1698 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.52 (s, 9H), 2.71-2.79 (m, 1H), 2.88-2.99 (m, 1H), 3.23-3.29 (m, 1H), 4.07-4.13 (m, 1H), 5.69-5.71 (m, 1H), 6.29 (dd, 1H, J = 15.8, 5.8 Hz), 6.40 (d, 1H, J = 15.8 Hz), 7.12-7.34 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 28.5, 28.8, 79.9, 126.2, 126.3, 126.5, 126.8, 127.6, 128.1, 128.5, 128.9, 129.3, 131.1, 134.9, 134.9, 136.7, 154.7; FAB-LM m/z 336.4 (M+H+); FAB-HM Calcd for C22H26NO2 336.1964. Found 336.1962. Anal. Calcd for C22H25NO2: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.84; H, 7.63; N, 4.18.
Conversion of 13 to (R)-1,2,3,4-tetrahydro-1-phenethylisoquinoline (14). Under hydrogen atmosphere, a solution of 13 (124.4 mg, 0.37 mmol, 75% ee) and 10% Pd-C (150 mg) was stirred at an ambient temperature for 12 h. After concentration of the obtained filtrate by the removal of Pd-C, a solution of the residue in CH2Cl2 (5.0 mL) was treated with TMSOTf (130 µL, 0.72 mmol) at an ambient temperature for 10 min. The reaction mixture was quenched with sat. NaHCO3 and extrated with AcOEt. The combined organic extracts was dried over anhydrous MgSO4 and concentrated on vacuo. The residue was purified on silica gel column chromatography to give 14 (73.5 mg, 84%, [α]D = -18.9). 14 was identified by 1H-NMR spectrum reported in the literature.19

ACKNOWLEDGEMENTS
This work was supported by Grant-in-Aid for Scientific Research (C), Japan Society for the Promotion of Science (No 22590016).

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