HETEROCYCLES

Short Paper | Regular issue | Vol. 85, No. 10, 2012, pp. 2523-2529
Received, 11th July, 2012, Accepted, 31st July, 2012, Published online, 3rd August, 2012.
DOI: 10.3987/COM-12-12544

■ Synthesis of 3-Substituted 4-Alkoxyisoquinolin-1-amines by the Reaction of 2-[Alkoxy(lithio)methyl]benzonitriles with Nitriles

Kazuhiro Kobayashi,* Kota Matsumoto, and Kosuke Ezaki

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

Abstract

It has been found that the reaction of 2-[alkoxy(lithio)methyl]benzonitriles, generated in situ from 2-(alkoxymethyl)benzonitriles and two equivalents of lithium diisopropylamide in diglyme at –78 ˚C, with aliphatic and aromatic nitriles provides an efficient method for the one-pot preparation of 3-substituted 4-alkoxyisoquinolin-1-amines.

Considerable attention is paid to isoquinolin-1-amines because of their biological activities.1 This class of isoquinolines have been generally synthesized by the action of ammonia on isoquinoline-1(2H)-ones.1 A method based on the reaction of 2-(lithiomethyl)benzonitrile, generated by treating 2-methylbenzonitlrile with lithium dimethylamide in THF–hexamethylphosphoric triamide (HMPA) at –78 ˚C, with aromatic nitriles for the preparation of 3-arylisoquinolin-1-amines has also been reported.2 However, there have been few reports on the synthesis of 4-alkoxyisoquinolin-1-amines, though 4-ethoxyquinolin-1-amine has been prepared by the treatment of 1-bromo-4-ethoxyisoquinoline with potassium amide.3 On the other hand, we have recently reported that 2-[alkoxy(lithio)methyl]benzonitriles, generated in situ from 2-(alkoxymethyl)benzonitriles and two equivalents of lithium diisopropylamide (LDA) in diglyme at –78 ˚C, react with ethyl benzoates to give 2-[alkoxy(aroyl)methyl]benzonitriles, which in turn are treated with hydrogen peroxide in aqueous sodium hydroxide to afford, after subsequent acidification of the resulting solutions of 2-[alkoxy(aroyl)methyl]benzamides, 4-alkoxy-3-arylisoquinoline-1(2H)-ones.4 Therefore, we investigated the extensive use of these lithiated 2-(alkoxymethyl)benzonitriles for the direct and general preparation of 3-substituted 4-alkoxyisoquinolin-1-amines. We now report the results of their reactions with aliphatic and aromatic nitriles.
The synthesis of 3-substituted 4-alkoxyisoquinolin-1-amines (4) was accomplished according to the sequence illustrated in Scheme 1 in one pot from 2-(alkoxymethyl)benzonitriles (1). On treatment with two equivalents of LDA at –78 ˚C, the benzyl carbon of 1 was lithiated to generate 2-[alkoxy(lithio)methyl]benzonitriles (2) as reported previously.4 These benzyl anions (2) were then allowed to react with a range of nitriles. Addition of the anions to the nitrile carbon gave the imino anion intermediates (3), of which subsequent intramolecular cyclization by the attack of on the o-cyano carbon followed by tautomerization afforded, after workup with aqueous ammonium chloride solution and purification by column chromatography on silica gel, the desired products (4) in moderate to fair yields as summarized in Table 1.

As can be seen from Entries 6 and 7, even using aliphatic nitriles carrying α-hydrogen(s) the desired products (4f) and (4g) were formed cleanly and in the yields comparable to those using aromatic nitriles. Unfortunately, however, the reactions 2-(methoxymethyl)benzonitrile (1a) with 3-chlorobenzonitrile or 4-chlorobenzonitrile resulted in the formation of a considerably intractable mixture of products in each case, though the reason for this is not clear. When 2-ethoxymethyl-4,5-dimethoxybenzonitrile (1b) was used (Entries 8 and 9), the yields of the corresponding products (4h) and (4i) were somewhat lower than those using 1a. These results may be ascribed to lower acidity of the benzyl protons of 1b than those of 1a due to two electron-donating methoxy groups.
Subsequently, we examined the reaction of 2-[lithio(methoxy)methyl]benzonitrile (2a) with 4-chlorobutanenitrile. First, the benzyl anion was allowed to react with an equivalent of the chloro nitrile in expectation of the procurement of 3-(3-chloropropyl)-4-methoxyisoquinolin-1-amine, which may be of use synthetically. Unfortunately, however, it could not be obtained and 2-[4-(1-amino-4-methoxyisoquinolin-3-yl)-1-methoxybutyl]benzonitrile (5) was produced in 22% yield. When the reaction was conducted at the molar ratio of 2:1, compound (5) was obtained in moderate yield, as shown in Scheme 2.

In conclusion, we have demonstrated that the reaction of 2-[alkoxy(lithio)methyl]benzonitriles with nitriles offers a direct route to the general preparation of 3-substituted 4-alkoxyisoquinolin-1-amines. The present method may find some value in organic synthesis because of the readily availability of the starting materials and the easiness of operations.

EXPERIMENTAL
All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were recorded with a Shimadzu FTIR-8300 spectrophotometer. 1H NMR spectra were recorded in CDCl3 using TMS as an internal reference with a Bruker Biospin AVANCE II 600 spectrometer operating at 600 MHz or a JEOL ECP500 FT NMR spectrometer operating at 500 MHz. 13C NMR spectra were recorded in CDCl3 using TMS as an internal reference with a Bruker Biospin AVANCE II 600 spectrometer operating at 150 MHz or 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. 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. 2-(Methoxymethyl)benzonitrile (1a)4,5 and 2-bromomethyl-4,5- dimethoxybenzonitrile6 were prepared according to the appropriate reported methods. n-BuLi was supplied by Asia Lithium Corporation. All other chemicals used in this study were commercially available.
2-Ethoxymethyl-4,5-dimethoxybenzonitrile (1b). This compound was prepared from 2-bromomethyl- 4,5-dimethoxybenzonitrile6 and EtOH in 65% yield under conditions reported for the preparation of 1a;4,5 a white solid; mp 108–110 ˚C (hexane–Et2O); IR (neat) 2216, 1603 cm–1; 1H NMR (500 MHz,) δ 1.28 (t, J = 6.9 Hz, 3H), 3.62 (q, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.95 (s, 3H), 4.63 (s, 2H), 7.04 (s, 1H), 7.05 (s, 1H). Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.05; H, 6.91; N, 6.26.
Typical Procedure for the Preparation of 3-Substituted 4-Alkoxyisoquinolin-1-amines (4) and (5). 4-Methoxy-3-phenylisoquinolin-1-amine (4a). To a stirred solution of LDA (2.2 mmol), generated by the standard procedure from n-BuLi and i-Pr2NH, in diglyme (3 mL) at –78 ˚C was added a solution of 1a (0.16 g, 1.1 mmol) in diglyme (1 mL) dropwise; the solution immediately turned deep purple. After the solution was stirred for 15 min at the same temperature, PhCN (0.22 g, 2.2 mmol) was added dropwise and stirring was continued for an additional 1 h. Water (10 mL) was added and the mixture was extracted with AcOEt (3 × 10 mL). The combined extracts were washed with water (3 × 10 mL) and brine (10 mL), dried (Na2SO4), and concentrated by evaporation. The residue was purified by column chromatography on silica gel (AcOEt–hexane 1:4) to give 4a (0.15 g, 56%); a pale-yellow needles; mp 119–120 ˚C (hexane); IR (KBr) 3482, 3381, 1616 cm–1; 1H NMR (600 MHz) δ 3.60 (s, 3H), 5.04 (br s, 2H), 7.36 (tt, J = 7.5, 1.3 Hz, 1H), 7.46 (dd, J = 8.0, 7.5 Hz, 2H), 7.53 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.71 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 8.04 (dd, J = 8.0, 1.3 Hz, 2H), 8.12 (d, J = 8.3 Hz, 1H); 13C NMR (150 MHz) δ 61.07, 118.31, 122.23, 123.03, 126.28, 127.88, 128.23, 129.09, 130.31, 133.51, 137.83, 140.01, 142.50, 151.96; MS m/z 250 (M+, 100). Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.77; H, 5.74; N, 11.14.
4-Methoxy-3-(3-methylphenyl)isoquinolin-1-amine (4b): a pale-yellow needles; mp 113–115 ˚C (hexane); IR (KBr) 3484, 3376, 1616 cm–1; 1H NMR (600 MHz) δ 2.44 (s, 3H), 3.60 (s, 3H), 5.06 (br s, 2H), 7.19 (d, J = 7.4 Hz, 1H), 7.35 (dd, J = 8.6, 7.4 Hz, 1H), 7.53 (td, J = 7.4, 1.1 Hz, 1H), 7.70 (td, J = 7.4, 1.1 Hz, 1H), 7.80–7.84 (m, 3H), 8.11 (d, J = 8.6 Hz, 1H); 13C NMR (150 MHz) δ 21.57, 61.07, 118.25, 122.18, 122.94, 126.13, 126.22, 128.07, 128.57, 129.67, 130.11, 133.46, 137.69, 138.05, 140.58, 142.49, 151.85; MS m/z 264 (M+, 100). Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.20; H, 6.37; N, 10.67.
4-Methoxy-3-(4-methylphenyl)isoquinolin-1-amine (4c): a pale-yellow solid; mp 144–146 ˚C (hexane–Et2O); IR (KBr) 3491, 3454, 1629, 1617 cm–1; 1H NMR (500 MHz) δ 2.41 (s, 3H), 3.61 (s, 3H), 5.01 (br s, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.51 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.69 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz) δ 21.32, 60.93, 118.20, 122.14, 122.93, 125.97, 128.92, 128.95, 130.04, 133.48, 135.31, 137.56, 140.42, 142.37, 151.82; MS m/z 264 (M+, 100). Anal. Calcd for C17H16N2O: C, 77.25; H, 6.10; N, 10.60. Found: C, 77.20; H, 6.18; N, 10.57.
4-Methoxy-3-(3-methoxyphenyl)isoquinolin-1-amine (4d): a pale-yellow solid; mp 135–137 ˚C (hexane–CH2Cl2); IR (KBr) 3460, 3364, 1620 cm–1; 1H NMR (600 MHz) δ 3.62 (s, 3H), 3.89 (s, 3H), 5.12 (br s, 2H), 6.93 (ddd, J = 8.0, 1.6, 0.9 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.53 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.60 (dd, J = 2.4, 1.6 Hz, 1H), 7.63 (ddd, J = 8.0, 2.4, 0.9 Hz, 1H), 7.71 (ddd, J = 8.3, 7.0 1.3 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H); 13C NMR (150 MHz) δ 55.34, 61.11, 114.04, 114.23, 116.40, 121.71, 122.26, 122.97, 126.24, 129.18, 130.17, 133.50, 139.51, 140.08, 142.62, 151.86, 159.57; MS m/z 280 (M+, 100). Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.54; H, 5.53; N, 10.02.
4-Methoxy-3-(4-methoxyphenyl)isoquinolin-1-amine (4e): colorless needles; mp 147–148 ˚C (hexane–Et2O); IR (KBr) 3480, 3372, 1607 cm–1; 1H NMR (500 MHz) δ 3.61 (s, 3H), 3.87 (s, 3H), 5.01 (br s, 2H), 6.99 (d, J = 8.6 Hz, 2H), 7.50 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.69 (ddd, J = 8.6, 6.9, 1.1 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.6 Hz, 1H); 13C NMR (150 MHz) δ 55.26, 60.77, 113.60, 118.04, 122.02, 122.94, 125.82, 130.03, 130.35, 130.70, 133.50, 140.00, 142.00, 151.83, 159.32; MS m/z 280 (M+, 100). Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.72; H, 5.85; N, 9.70.
3-Ethyl-4-methoxyisoquinolin-1-amine (4f): a white solid; mp 125–126 ˚C (hexane–Et2O); IR (KBr) 3480, 3387, 3326, 1656, 1623 cm–1; 1H NMR (500 MHz) δ 1.31 (t, J = 7.4 Hz, 3H), 2.82 (q, J = 7.4 Hz, 2H), 3.85 (s, 3H), 4.94 (br s, 2H), 7.45 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.65 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz) δ 13.87, 24.75, 62.09, 117.59, 121.52, 123.01, 125.25, 129.88, 132.67, 141.35, 145.93, 152.05; MS m/z 202 (M+, 100). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85. Found: C, 71.04; H, 7.04; N, 13.74.
4-Methoxy-3-(1-methylethyl)isoquinolin-1-amine (4g): a pale-yellow solid; mp 86–88 ˚C (hexane–Et2O); IR (KBr) 3535, 3436, 3342, 1639, 1623 cm–1; 1H NMR (500 MHz) δ 1.28 (d, J = 6.9 Hz, 6H), 3.52 (sept, J = 6.9 Hz, 1H), 3.85 (s, 3H), 4.95 (br s, 2H), 7.43 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.62 (ddd, J = 8.6, 6.9, 1.1 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H); 13C NMR (125 MHz) δ 22.07, 27.85, 62.31, 117.52, 121.66, 122.97, 125.17, 129.71, 132.57, 140.37, 149.42, 152.16; MS m/z 216 (M+, 100). Anal. Calcd for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.23; H, 7.64; N, 12.87.
4-Ethoxy-6,7-dimethoxy-3-phenylisoquinolin-1-amine (4h): a colorless viscous oil; Rf 0.26 (AcOEt–hexane 2:3); IR (neat) 3468, 3370, 1624 cm–1; 1H NMR (500 MHz) δ 1.26 (s, J = 7.4 Hz, 3H), 3.71 (q, J = 7.4 Hz, 2H), 4.02 (s, 3H), 4.06 (s, 3H), 4.81 (br s, 2H), 7.02 (s, 1H), 7.34 (tt, J = 7.4, 1.1 Hz, 1H), 7.42 (s, 1H), 7.44 (dd, J = 8.0, 7.4 Hz, 2H), 8.01 (dd, J = 8.0, 1.1 Hz, 2H); 13C NMR (125 MHz) δ 15.81, 55.95, 55.97, 69.30, 101.27, 102.23, 113.30, 127.54, 128.11, 128.99, 130.14, 138.49, 139.42, 141.36, 149.45, 150.47, 152.67; MS m/z 324 (M+, 100). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.21; H, 6.50; N, 8.59.
4-Ethoxy-6,7-dimethoxy-3-(3-methylphenyl)isoquinolin-1-amine (4i): a pale-yellow viscous oil; Rf 0.26 (AcOEt–hexane 1:1); IR (neat) 3452, 3376, 1626 cm–1; 1H NMR (500 MHz) δ 1.27 (t, J = 7.4 Hz, 3H), 2.43 (s, 3H), 3.71 (q, J = 7.4 Hz, 2H), 4.03 (s, 3H), 4.05 (s, 3H), 4.82 (br s, 2H), 7.02 (s, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.33 (dd, J = 8.0, 7.4 Hz, 1H), 7.42 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.82 (s, 1H); 13C NMR (125 MHz) δ 15.82, 21.53, 55.94, 56.05, 69.25, 101.22, 102.20, 113.24, 126.08, 127.96, 128.28, 129.59, 130.13, 137.55, 138.43, 139.64, 141.30, 149.38, 150.42, 152.61; MS m/z 338 (M+, 100). Anal. Calcd for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28. Found: C, 70.81; H, 6.74; N, 8.27.
2-[4-(1-Amino-4-methoxyisoquinolin-3-yl)-1-methoxybutyl]benzonitrile (5): a pale-yellow viscous oil; Rf 0.29 (THF–C6H6 1:6); IR (neat) 3459, 3381, 2181, 1624 cm–1; 1H NMR (500 MHz) δ 1.60–1.67 (m, 1H), 1.72–1.82 (m, 2H), 1.97–2.05 (m, 1H), 2.14–2.27 (m, 2H), 3.14 (s, 3H), 3.52 (s, 3H), 4.26 (dd, J = 8.0, 3.4 Hz, 1H), 5.08 (br s, 2H), 7.38 (dd, J = 8.0, 7.4 Hz, 1H), 7.44–7.46 (m, 2H), 7.55–7.59 (m, 2H), 7.74 (dd, J = 8.6, 6.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz) δ 16.88, 22.35, 36.78, 56.53, 61.30, 79.13, 118.22, 120.13, 122.11, 123.08, 125.66, 126.45, 127.24, 128.47, 129.94, 130.33, 132.83, 137.53, 140.47, 141.22, 141.93, 151.79; MS m/z 361 (M+, 100). Anal. Calcd for C22H23N3O2: C, 73.11; H, 6.41; N, 11.63. Found: C, 73.04; H, 6.41; N, 11.54.

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

References

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