HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 2, 2013, pp. 389-397
Received, 7th November, 2012, Accepted, 30th November, 2012, Published online, 6th December, 2012.
DOI: 10.3987/COM-12-12620

■ Synthesis of 3,4-Dihydroisoquinolines by Cyclization of 1-Bromo-2-(2-isocyanoalkyl)benzenes with Butyllithium

Kazuhiro Kobayashi,* Naoki Matsumoto, and Kota Matsumoto

Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

A new and convenient method for the preparation of 3,3-disubstituted 3,4-dihydroisoquinolines has been developed. Thus, the reaction of 1-bromo-2-(bromomethyl)benzenes with (1-isocyano-1-lithioalkyl)benzenes, generated by the treatment of (1-isocyanoalkyl)benzenes with butyllithium, in THF at –78 ˚C gave the corresponding 1-(2-aryl-2-isocyanoalkyl)-2-bromobenzenes, which in turn were transformed into the desired products on treatment with butyllithium in THF at –78 ˚C.

3,4-Dihydroisoquinoline derivatives are receiving considerable attention in relation to their biological activities1,2 and their uses in the preparation of more structurally complex and useful polycyclic compounds,3 such as 3,4-dihydro-7aH,15H-naphtho[1’,2’:5,6][1,3]oxazino[2,3-a]isoquinolines3m and 8,9-dihydro-6H-chromeno[4’,3’:4,5]pyrrolo[2,1-a]isoquinolines.3n Most of the methods for the preparation of 3,4-dihydroisoquinolines have been relied upon Bischler-Napieralski-type reactions of N-(2-arylethyl)carboxamides with various dehydrating agents, such as phosphoryl chloride and polyphosphoric acid,4 though several efficient methods based on other reactions have recently been reported.5 Therefore, there have been few reports on the synthesis of 3,3-disubstituted derivatives.6 Herein we describe a convenient synthetic route to 3,3-disubstituted 3,4-dihydroisoquinolines. We have found that this type of 3,4-dihydroisoquinolines (6) could be obtained by cyclization of 1-(2-aryl-2-isocyanoalkyl)-2-bromobenzenes (3), which could be easily prepared from 1-bromo-2-(bromomethyl)benzenes (1) and (1-isocyanoalkyl)benzenes (2), on treatment with butyllithium.
Our synthesis of 3,3-disubstituted 3,4-dihydroisoquinolines (6) from 1-bromo-2-(bromomethyl)benzenes (1) and (1-isocyanoalkayl)benzenes (2) was conducted according to the procedure illustrated in Scheme 1. Thus, the reaction of 1 with (1-isocyano-1-lithioalkyl)benzenes, generated by the treatment of 2 with butyllithium, in THF at –78 ˚C afforded 1-(2-aryl-2-isocyanoalkyl)-2-bromobenzenes (3) in good yields as listed in Table 1. These precursors (3) were then allowed to react with butyllithium in THF at –78 ˚C to generate 1-(2-aryl-2-isocyanoalkyl)-2-lithiobenzene intermediates (4), which cyclized by intramolecular attack of the carbanion on the isocyano carbon to give 1-lithio-3,4-dihydroisoquinoline intermediates (5). After aqueous workup followed by purification of the crude products by column chromatography on silica gel, the desired products (6) were obtained in moderate-to-fair yields as listed in Table 1 as well.

Unfortunately, however, it should be noted that attempted trapping reactions of 1-lithio-3,4-dihydroisoquinoline intermediates (5) with various electrophiles, such as iodomethane, benzaldehyde, benzoyl chloride, dimethyl disulfide and chlorotrimethylsilane, which enable us to introduce various substituents at the 1-position of 3,4-dihydroisoquinolines, all resulted in failure. In each case, the expected substitution product was not observed in the reaction mixture at all. Probably, the intermediates (5) abstract a proton quickly from 1-bromobutane, which was produced by the lithium-bromine exchange between butyllithium and 3, to lead to the formation of 6, as depicted in Scheme 1 as well.
In conclusion, we have synthesized 3,3-disubstituted 3,4-dihydroisoquinolines via a two-step sequence from 1-bromo-2-(bromomethyl)benzenes and (1-isocyanoalkayl)benzenes. The present method may be of value in organic synthesis, because starting materials are readily available and manipulations are very simple. Further investigations toward syntheses of related heterocycles utilizing methodologies similar to that described here are now in progress in our laboratory.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Perkin–Elmer Spectrum65 FTIR spectrophotometer. 1H NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz or a JEOL LA400FT NMR spectrometer operating at 400 MHz. 13C NMR spectra were recorded in CDCl3 using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. Low-resolution MS spectra (EI, 70 eV) were measured by a JEOL JMS AX505 HA spectrometer. High-resolution MS spectra (DART, positive) were measured by a Thermo Scientific Exactive spectrometer. TLC was carried out on Merck Kieselgel 60 PF254. Column chromatography was performed using WAKO GEL C-200E. All of the organic solvents used in this study were dried over appropriate drying agents and distilled prior to use.
Starting Materials. 1-Bromo-2-(bromomethyl)-4-chlorobenzene (1b) and 1-bromo-2-(bromomethyl)-4-methoxybenzene (1c) were prepared by the procedure reported by Hirashima et al.7 n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially available.
N-(1-Arylalkyl)formamides. N-(1-Phenylethyl)formamide was prepared by N-formylation of 1-phenylethanamine by the procedure reported by Chantrapromma et al.8 N-(1-Phenylpropyl)formamide was prepared by the method reported by Musatov et al.9 The others were prepared from the respective 1-arylalkan-1-ones under the conditions reported for the preparation of 1-arylethanamines by Ho et al.10 by omitting the last acidic hydrolysis procedure.
N-[1-(3-Methoxyphenyl)ethyl]formamide: yield: 71%; a beige oil; Rf 0.12 (AcOEt–hexane 1:2); IR (neat) 3272, 1661, 1601 cm–1; 1H NMR (400 MHz) δ 1.50 and 1.55 (2d, J = 6.8 Hz each, combined 3H), 3.80 and 3.81 (2s, combined 3H), 5.15–5.22 (m, 1H), 5.96 (br s, 1H), 6.80–6.92 (m, 3H), 7.24–7.28 (m, 1H), 8.12 and 8.16 (2s, combined 1H). Anal. Calcd for C10H13NO2: C, 67.02; H, 7.31; N, 7.82. Found: C, 66.92; H, 7.40; N, 7.80.
N-[1-(4-Chlorophenyl)ethyl]formamide: yield: 66%; a white solid; mp 81–83 ˚C (hexane–CH2Cl2); IR (KBr) 3277, 1662 cm–1; 1H NMR (400 MHz) δ 1.50 and 1.55 (2d, J = 6.9 Hz each, combined 3H), 5.16–5.22 (m, 1H), 5.80 (br 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 8.18 (s, 1H). Anal. Calcd for C9H10ClNO: C, 58.86; H, 5.49; N, 7.63. Found: C, 58.88; H, 5.52; N, 7.69.
N-(Diphenylmethyl)formamide: yield: 85%; colorless needles; mp 131–132 ˚C (hexane–CH2Cl2) (lit.,11 mp 132–133 ˚C); IR (KBr) 3229, 3193, 1682, 1652 cm–1; 1H NMR (400 MHz) δ 5.74–6.36 (m, 2H), 7.21–8.25 (m, 11H). Anal. Calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.58; H, 6.40; N, 6.50.
(1-Isocyanoalkyl)benzenes 2. These compounds were prepared by the dehydration of the respective N-(1-arylalkyl)formamides with POCl3/Et3N under the conditions reported previously by us.12
(1-Isocyanoethyl)benzene (2a): yield: 77%; a pale-yellow liquid; Rf 0.68 (AcOEt–hexane 1:5). The spectral data (IR and 1H NMR) were identical to those reported previously.13
1-(1-Isocyanoethyl)-3-methoxybenzene (2b): yield: 77%; a pale-yellow liquid; Rf 0.60 (AcOEt–hexane 1:2); IR (neat) 2140, 1604 cm–1; 1H NMR (400 MHz) δ 1.66–1.69 (m, 3H), 3.83 (s, 3H), 4.79 (q, J = 6.8 Hz, 1H), 6.87 (dd, J = 7.8, 2.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H). HR MS. Calcd for C10H12NO (M+H): 162.0920. Found: m/z 162.0909.
1-Chloro-3-(1-Isocyanoethyl)benzene (2c): yield: 76%; a yellow liquid; Rf 0.36 (Et2O–hexane 1:5); IR (neat) 2140 cm–1; 1H NMR (400 MHz) δ 1.66–1.69 (m, 3H), 4.80 (q, J = 6.9 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H). HR MS. Calcd for C9H9ClN (M+H): 166.0424. Found: m/z 166.0423.
(1-Isocyanopropyl)benzene (2d):14 yield: 87%; a yellow liquid; Rf 0.34 (Et2O–hexane 1:5); IR (neat) 2140 cm–1; 1H NMR (500 MHz) δ 1.05 (t, J = 7.4 Hz, 3H), 1.91–1.94 (m, 2H), 4.64 (t, J = 5.7 Hz, 1H), 7.33–7.41 (m, 5H).
[Isocyano(phenyl)methyl]benzene (2e): yield; 90%: a white solid; mp 33–35 ˚C (hexane–Et2O) (lit.,15 35–36 ˚C); IR (KBr) 2144 cm–1; 1H NMR (500 MHz) δ 5.91 (s, 1H), 7.31–7.40 (m, 10H).
Typical Procedure for the Preparation of 1-(2-Aryl-2-isocyanoalkyl)-2-bromobenzenes (3). 1-Bromo-2-(2-isocyano-2-phenylpropyl)benzene (3a). To a stirred solution of 2a (0.47 g, 3.5 mmol) in THF (10 mL) at –78 ˚C was added n-BuLi (1.6 M in hexane; 3.5 mmol) dropwise. After 5 min, a solution of 1a (0.88 g, 3.5 mmol) in THF (2 mL) was added and stirring was continued for an additional 10 min before saturated aqueous NH4Cl (20 mL) was added. The mixture was warmed to room temperature and extracted with Et2O (3 × 15 mL). The combined extracts were washed with brine (15 mL), dried (anhydrous Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on silica gel to give 3a (0.92 g, 88%); a colorless oil; Rf 0.32 (Et2O–hexane 1:10); IR (neat) 2130, 1602 cm–1; 1H NMR (500 MHz) δ 1.86 (s, 3H), 3.26 (d, J = 14.3 Hz, 1H), 3.54 (d, J = 14.3 Hz, 1H), 7.12–7.16 (m, 1H), 7.23 –7.25 (m, 2H), 7.35 (t, J = 6.8 Hz, 1H), 7.40 (dd, J = 8.0, 6.8 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H). HR MS. Calcd for C16H15BrN (M+H): 300.0389. Found: m/z 300.0375.
1-Bromo-2-[2-isocyano-2-(3-methoxyphenyl)propyl]benzene (3b): a colorless oil; Rf 0.37 (Et2O–hexane 1:10); IR (neat) 2132, 1603 cm–1; 1H NMR (400 MHz) δ 1.79 (s, 3H), 3.25 (d, J = 14.2 Hz, 1H), 3.53 (d, J = 14.2 Hz, 1H), 3.82 (s, 3H), 6.88 (dd, J = 7.8, 2.4 Hz, 1H), 7.01 (t, J = 2.4 Hz, 1H), 7.05 (dd, J = 7.8, 2.4 Hz, 1H), 7.14 (ddd, J = 7.8, 6.9, 1.4 Hz, 1H), 7.23–7.34 (m, 3H), 7.57 (d, J = 7.8 Hz, 1H). HR MS. Calcd for C17H17BrNO (M+H): 330.0494. Found: m/z 330.0491.
1-Bromo-2-[2-(4-chlorophenyl)-2-isocyanopropyl]benzene (3c): a colorless oil; Rf 0.43 (Et2O–hexane 1:20); IR (neat) 2130 cm–1; 1H NMR (400 MHz) δ 1.80 (s, 3H), 3.25 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 7.13–7.17 (m, 1H), 7.25–7.26 (m, 2H), 7.37 (s, 4H), 7.56 (d, J = 7.8 Hz, 1H). HR MS. Calcd for C16H14BrClN (M+H): 333.9999. Found: m/z 333.9987.
1-Bromo-2-(2-isocyano-2-phenylbutyl)benzene (3d): a pale-yellow oil; Rf 0.33 (Et2O–hexane 1:30); IR (neat) 2131 cm–1; 1H NMR (400 MHz) δ 0.81 (t, J = 7.4 Hz, 3H), 1.95–2.03 (m, 1H), 2.21–2.28 (m, 1H), 3.23 (d, J = 14.6 Hz, 1H), 3.62 (d, J = 14.6 Hz, 1H), 7.09–7.22 (m, 3H), 7.31–7.44 (m, 5H), 7.55 (d, J = 7.8 Hz, 1H). HR MS. Calcd for C17H17BrN (M+H): 314.0545. Found: m/z 314.0528.
1-Bromo-2-(2-isocyano-2,2-diphenylethyl)benzene (3e): colorless crystals; mp 101–104 ˚C (hexane–Et2O); IR (KBr) 2129 cm–1; 1H NMR (500 MHz) δ 3.93 (s, 2H), 6.90 (dd, J = 6.8, 2.0 Hz, 1H), 7.06–7.12 (m, 2H), 7.34–7.36 (m, 10H), 7.50 (dd, J = 7.8, 2.0 Hz, 1H). Anal. Calcd for C21H16BrN: C, 69.62; H, 4.45; N, 3.87. Found: C, 69.42; H, 4.61; N, 3.79.
1-Bromo-4-chloro-2-(2-isocyano-2-phenylpropyl)benzene (3f): a colorless oil; Rf 0.40 (hexane); IR (neat) 2130 cm–1; 1H NMR (500 MHz) δ 1.83 (s, 3H), 3.23 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 7.01–7.13 (m, 2H), 7.34–7.46 (m, 5H), 7.49 (d, J = 8.6 Hz, 1H). HR MS. Calcd for C16H14BrClN (M+H): 333.9999. Found: m/z 333.9994.
1-Bromo-4-chloro-2-[2-isocyano-2-(3-methoxyphenyl)propyl]benzene (3g): a colorless oil; Rf 0.41 (Et2O–hexane 1:10); IR (neat) 2131, 1606 cm–1; 1H NMR (400 MHz) δ 1.81 (s, 3H), 3.22 (d, J = 13.7 Hz, 1H), 3.48 (d, J = 13.7 Hz, 1H), 3.83 (s, 3H), 6.90 (dd, J = 8.8, 2.9 Hz, 1H), 6.98 (dd, J = 2.9, 2.0 Hz, 1H), 7.02 (d, J = 9.8 Hz, 1H), 7.11–7.14 (m, 2H), 7.33 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 9.8 Hz, 1H). HR MS. Calcd for C17H16BrClNO (M+H): 364.0105. Found: m/z 364.0092.
1-Bromo-4-chloro-2-(2-isocyano-2-phenylbutyl)benzene (3h): a pale-yellow oil; Rf 0.33 (Et2O–hexane 1:50); IR (neat) 2131 cm–1; 1H NMR (400 MHz) δ 0.86 (t, J = 7.3 Hz, 3H), 1.98–2.07 (m, 1H), 2.20–2.27 (m, 1H), 3.19 (d, J = 13.7 Hz, 1H), 3.58 (d, J = 13.7 Hz, 1H), 7.00 (d, J = 2.9 Hz, 1H), 7.09 (dd, J = 8.8, 2.9 Hz, 1H), 7.33–7.43 (m, 5H), 7.47 (d, J = 8.8 Hz, 1H). HR MS. Calcd for C17H16BrClN (M+H): 348.0155. Found: m/z 348.0147.
1-Bromo-2-(2-isocyano-2-phenylpropyl)-4-methoxybenzene (3i): a colorless oil; Rf 0.41 (Et2O–hexane 1:10); IR (neat) 2131 cm–1; 1H NMR (400 MHz) δ 2.04 (s, 3H), 3.22 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 3.69 (s, 3H), 6.70–6.73 (m, 2H), 7.33–7.44 (m, 4H), 7.47 (d, J = 7.8 Hz, 2H). HR MS. Calcd for C17H17BrNO (M+H): 330.0494. Found: m/z 330.0479.
1-Bromo-2-(2-isocyano-2-phenylbutyl)-4-methoxybenzene (3j): a pale-yellow oil; Rf 0.25 (Et2O–hexane 1:20); IR (neat) 2131 cm–1; 1H NMR (400 MHz) δ 0.83 (t, J = 7.4 Hz, 3H), 1.97–2.02 (m, 1H), 2.20–2.26 (m, 1H), 3.18 (d, J = 14.3 Hz, 1H), 3.60 (d, J = 14.3 Hz, 1H), 3.66 (s, 3H), 6.66 (d, J = 2.9 Hz, 1H), 6.68 (dd, J = 8.6, 2.8 Hz, 1H), 7.32–7.35 (m, 1H), 7.38–7.42 (m, 5H). HR MS. Calcd for C18H19BrNO (M+H): 344.0651. Found: m/z 344.0638.
Typical Procedure for the Preparation of Dihydroisoquinolines (6). 3-Methyl-3-phenyl-3,4-dihydroisoquinoline (6a). To a stirred solution of 3a (0.12 g, 0.41 mmol) in Et2O (5 mL) at –78 ˚C was added n-BuLi (1.6M in hexane; 0.41 mmol) dropwise. After 5 min, saturated aqueous NH4Cl (10 mL) was added, and the mixture was warmed to room temperature and extracted with AcOEt (3 × 10 mL). The combined extracts were washed with brine (10 mL), dried (anhydrous Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on silica gel to give 6a (53 mg, 58%); a white solid; mp 62–63 ˚C (hexane–CH2Cl2); IR (neat) 1628 cm–1; 1H NMR (500 MHz) δ 1.50 (s, 3H), 3.04 (d, J = 16.0 Hz, 1H), 3.15 (d, J = 16.0 Hz, 1H), 7.15 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.28–7.37 (m, 5H), 7.55 (dd, J = 8.0, 1.1 Hz, 2H), 8.46 (s, 1H); 13C NMR (125 MHz) δ 27.51, 38.70, 60.17, 125.66, 126.35, 127.15, 127.26, 127.69, 127.97, 128.16, 131.36, 135.10, 147.94, 158.42; MS m/z 221 (100, M+). Anal. Calcd for C16H15N: C, 86.84; H, 6.83; N, 6.33. Found: C, 86.76; H, 6.96; N, 6.24.
3-(3-Methoxyphenyl)-3-methyl-3,4-dihydroisoquinoline (6b): a pale-yellow oil; Rf 0.42 (AcOEt–hexane 1:3); IR (neat) 1626, 1601 cm–1; 1H NMR (500 MHz) δ 1.49 (s, 3H), 3.03 (d, J = 16.0 Hz, 1H), 3.13 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H), 6.76 (ddd, J = 8.0, 1.7, 1.1 Hz, 1H), 7.11–7.16 (m, 3H), 7.25 (dd, J = 8.0, 7.4 Hz, 1H), 7.27–7.32 (m, 2H), 7.35 (td, J = 7.4, 1.7 Hz, 1H), 8.46 (s, 1H); 13C NMR (125 MHz) δ 27.52, 38.66, 55.15, 60.19, 111.56, 111.97, 127.14, 127.23, 127.70, 127.95, 129.06, 131.33, 135.09, 142.84, 149.76, 158.33, 159.48; MS m/z 251 (100, M+). Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.07; H, 6.92; N, 5.37.
3-(4-Chlorophenyl)-3-methyl-3,4-dihydroisoquinoline (6c): a colorless needles; mp 98–99 ˚C (hexane–CH2Cl2); IR (KBr) 1625 cm–1; 1H NMR (500 MHz) δ 1.47 (s, 3H), 3.00 (d, J = 16.6 Hz, 1H), 3.09 (d, J = 16.6 Hz, 1H), 7.15 (d, J = 6.9 Hz, 1H), 7.28–7.38 (m, 5H), 7.49 (d, J = 8.6 Hz, 2H), 8.44 (s, 1H); 13C NMR (125 MHz) δ 27.52, 38.60, 59.89, 127.19 (2C), 127.31, 127.60, 127.97, 128.24, 131.49, 132.12, 134.79, 146.55, 158.63; MS m/z 255 (100, M+). Anal. Calcd for C16H14ClN: C, 75.14; H, 5.52; N, 5.48. Found: C, 75.09; H, 5.58; N, 5.21.
3-Ethyl-3-phenyl-3,4-dihydroisoquinoline (6d): a pale-yellow oil; Rf 0.31 (AcOEt–hexane 1:5); IR (neat) 1629 cm–1; 1H NMR (400 MHz) δ 0.77 (t, J = 7.3 Hz, 3H), 1.84–2.04 (m, 2H), 3.08 (d, J = 16.1 Hz, 1H), 3.15 (d, J = 16.1 Hz, 1H), 7.13–7.33 (m, 7H), 7.48 (d, J = 7.8 Hz, 2H), 8.51 (s, 1H); 13C NMR (125 MHz3) δ 8.70, 34.63, 36.19, 63.04, 126.17, 126.34, 126.99, 127.10, 127.86, 127.95, 128.19, 131.24, 135.26, 145.52, 158.67; MS m/z 235 (100, M+). Anal. Calcd For C17H17N: C, 86.77; H, 7.28; N, 5.95. Found: C, 86.59; H, 7.30; N, 5.91.
3,3-Diphenyl-3,4-dihydroisoquinoline (6e): a white solid; mp 116–118 ˚C (hexane–CH2Cl2); IR (KBr) 1629 cm–1; 1H NMR (400 MHz) δ 3.48 (s, 2H), 7.15 (t, J = 7.4 Hz, 2H), 7.21–7.25 (m, 7H), 7.35–7.38 (m, 5H), 8.54 (s, 1H); 13C NMR (125 MHz) δ 37.89, 65.73, 126.39, 127.09, 127.19, 127.36, 127.52, 127.91, 128.13, 131.66, 135.37, 147.09, 159.18; MS m/z 283 (100, M+). Anal. Calcd for C21H17N: C, 89.01; H, 6.05; N, 4.94. Found: C, 88.73; H, 6.02; N, 4.94.
6-Chloro-3-methyl-3-phenyl-3,4-dihydroisoquinoline (6f): a pale-yellow oil; Rf 0.39 (THF–hexane 1:6); IR (neat) 1627 cm–1; 1H NMR (500 MHz) δ 1.50 (s, 3H), 3.01 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H), 7.15 (d, J = 1.1 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.26–7.29 (m, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 8.43 (s, 1H); 13C NMR (125 MHz) δ 27.66, 38.48, 60.02, 125.60, 126.09, 126.53, 127.40, 128.18, 128.21, 128.25, 128.42, 137.03, 147.35, 157.27; MS m/z 255 (100, M+). Anal. Calcd for C16H14ClN: C, 75.14; H, 5.52; N, 5.48. Found: C, 75.08; H, 5.79; N, 5.21.
6-Chloro-3-(3-methoxyphenyl)-3-methyl-3,4-dihydroisoquinoline (6g): a pale-yellow oil; Rf 0.46 (AcOEt–hexane 1:3); IR (neat) 1623 cm–1; 1H NMR (500 MHz) δ 1.49 (s, 3H), 3.00 (d, J = 16.0 Hz, 1H), 3.11 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H), 6.77 (dd, J = 8.4, 2.3 Hz, 1H), 7.08–7.11 (m, 2H), 7.15 (s, 1H), 7.24–7.28 (m, 3H), 8.42 (s, 1H); 13C NMR (125 MHz) δ 27.67, 38.47, 55.22, 60.31, 111.63, 112.01, 117.98, 126.07, 127.40, 128.21, 128.42, 129.19, 129.21, 137.03, 149.17, 157.25, 159.54; MS m/z 285 (100, M+). Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90. Found: C, 71.45; H, 5.65; N, 4.60.
6-Chloro-3-ethyl-3-phenyl-3,4-dihydroisoquinoline (6h): a pale-yellow oil; Rf 0.38 (AcOEt–hexane 1:3); IR (neat) 1628 cm–1; 1H NMR (500 MHz) δ 0.77 (t, J = 7.4 Hz, 3H), 1.85–2.04 (m, 2H), 3.05 (d, J = 16.0 Hz, 1H), 3.12 (d, J = 16.0 Hz, 1H), 7.13 (br s, 1H), 7.17–7.23 (m, 3H), 7.29 (dd, J = 8.0, 7.4 Hz, 2H), 7.44 (dd, J = 8.0, 1.1 Hz, 2H), 8.48 (s, 1H); 13C NMR (125 MHz) δ 8.66, 34.77, 36.00, 62.87, 126.25, 126.35, 126.54, 127.23, 128.05, 128.26, 136.85, 137.21, 144.95, 157.52, 157.54; MS m/z 269 (100, M+). Anal. Calcd for C17H16ClN: C, 75.69; H, 5.98; N, 5.19. Found: C, 75.59; H, 6.03; N, 5.04.
6-Methoxy-3-methyl-3-phenyl-3,4-dihydroisoquinoline (6i): a white solid; mp 72–74 ˚C (hexane–CH2Cl2); IR (KBr) 1626, 1606 cm–1; 1H NMR (400 MHz) δ 1.62 (s, 3H), 2.98 (d, J = 15.6 Hz, 1H), 3.12 (d, J = 15.6 Hz, 1H), 3.83 (s, 3H), 6.68 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 7.8, 2.0 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.4 Hz, 2H), 7.53 (dd, J = 7.4, 2.0 Hz, 2H), 8.37 (s, 1H); 13C NMR (125 MHz) δ 27.61, 39.21, 55.27, 59.79, 111.79, 113.74, 121.52, 125.65, 126.27, 128.10, 138.98, 137.28, 147.99, 157.71, 161.89; MS m/z 251 (100, M+). Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 80.96; H, 6.89; N, 5.62.
3-Ethyl-6-methoxy-3-phenyl-3,4-dihydroisoquinoline (6j): a pale-yellow oil; Rf 0.30 (AcOEt–hexane 1:3); IR (neat) 1626, 1606 cm–1; 1H NMR (400 MHz) δ 0.77 (t, J = 7.4 Hz, 3H), 1.85–2.04 (m, 2H), 3.04
(d, J = 16.6 Hz, 1H), 3.11 (d, J = 16.6 Hz, 1H), 3.80 (s, 3H), 6.67 (d, J = 1.7 Hz, 1H), 6.73 (dd, J = 8.0, 1.7 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.0, 7.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 8.42 (s, 1H); 13C NMR (125 MHz) δ 8.70, 34.69, 36.71, 55.28, 62.67, 111.60, 113.71, 122.06, 126.12, 126.34, 127.93, 128.85, 137,47, 145.65, 158.02, 161.80; MS m/z 265 (100, M+). Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.49; H, 7.17; N, 5.09.

ACKNOWLEDGEMENTS
We thank Mrs. Miyuki Tanmatsu of our university for recording mass spectra and performing combustion analyses.

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