Synthesis of 3-substituted 4-alkoxyisoquinolin-1-amines by the reaction of 2-[alkoxy(lithio)methyl]-benzonitriles with nitriles

Article abstract of DOI:10.3987/COM-12-12544

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 effi

Full text of DOI:10.3987/COM-12-12544

HETEROCYCLES, Vol. 85, No. 10, 2012
2523
HETEROCYCLES, Vol. 85, No. 10, 2012, pp. 2523 - 2529. © 2012 The Japan Institute of Heterocyclic Chemistry
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; E-mail: kkoba@chem.tottori-u.ac.jp
Abstract
–
It
has
been
found
that
the
in
reaction
of
2-[alkoxy(lithio)methyl]benzonitriles,
generated
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

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HETEROCYCLES, Vol. 85, No. 10, 2012
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.
OR2
Li+
OR2
OR2
CN
R1
R1
R1
R1
R3
Li+
R1
R1
LDA (2 equiv.), diglyme, –78 ˚C
R3CN, –78 ˚C
N
CN
CN
1
2
3
OR2
R1
R1
R3
H3O+
addition
tautomerization
N
NH2
4
Scheme 1
Table 1. Preparation of 3-substituted 4-alkoxyisoquinolin-1-amines (4)
Entry
1
R3
Ph
4
Yield/%a
56
54
1
2
3
4
5
6
7
8
9
1a (R1 = H, R2 = Me)
1a
1a
1a
1a
1a
4a
4b
4c
4d
4e
4f
4g
4h
4i
3-MeC6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
Et
i-Pr
Ph
3-MeC6H4
56
48
48
52
48
43
41
1a
1b (R1 = OMe, R2 = Et)
1b
a Isolated yields.
As can be seen from Entries 6 and 7, even using aliphatic nitriles carrying !-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

HETEROCYCLES, Vol. 85, No. 10, 2012
2525
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.
NC
OMe
OMe
(CH2)3
1. LDA (4 equiv.)
2
N
2. Cl(CH2)3CN
3. H3O+
OMe
CN
NH2
1a
5 42%
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
1
uncorrected. IR spectra were recorded with a Shimadzu FTIR-8300 spectrophotometer. H 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.

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HETEROCYCLES, Vol. 85, No. 10, 2012
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,) " 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) " 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) " 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
1
(hexane); IR (KBr) 3484, 3376, 1616 cm–1; H NMR (600 MHz) " 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 =
13
7.4, 1.1 Hz, 1H), 7.80–7.84 (m, 3H), 8.11 (d, J = 8.6 Hz, 1H); C NMR (150 MHz) " 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) " 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

HETEROCYCLES, Vol. 85, No. 10, 2012
2527
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)
" 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) " 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) " 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
1
(hexane–Et2O); IR (KBr) 3480, 3372, 1607 cm–1; H NMR (500 MHz) " 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) "
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) " 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),
13
7.75 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H); C NMR (125 MHz) " 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) " 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) "
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
1
(AcOEt–hexane 2:3); IR (neat) 3468, 3370, 1624 cm–1; H NMR (500 MHz) " 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,

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HETEROCYCLES, Vol. 85, No. 10, 2012
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) "
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
1
0.26 (AcOEt–hexane 1:1); IR (neat) 3452, 3376, 1626 cm–1; H NMR (500 MHz) " 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,
13
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); C
NMR (125 MHz) " 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) " 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) "
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.
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