Synthesis of New 1,2,3,4-Tetrahydroisoquinoline Derivatives. 2-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)anilines

Article abstract of DOI:10.1134/S1070428018010086

A four-step procedure has been developed for the synthesis of new 2-(2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)anilines by acylation of 2-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)anilines at the amino group with isobutyryl chloride, reduction of the endocyclic C=N bond in N-[2-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)phenyl]isobutyramides, N-alkylation of N-[2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl]isobutyramides to N-[2-(2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl]isobutyramides, and acid hydrolysis of the latter.

Full text of DOI:10.1134/S1070428018010086

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 1, pp. 95–101. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © Yu.S. Rozhkova, T.S. Vshivkova, I.V. Plekhanova, Yu.V. Shklyaev, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54,
No. 1, pp. 97–102.
Dedicated to Corresponding Member of the Russian Academy of Sciences
V.F. Mironov on his 60th anniversary
Synthesis of New 1,2,3,4-Tetrahydroisoquinoline Derivatives.
2-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)anilines
Yu. S. Rozhkova,* T. S. Vshivkova, I. V. Plekhanova, and Yu. V. Shklyaev
Institute of Technical Chemistry, Ural Branch, Russian Academy of Sciences,
ul. Akad. Koroleva 3, Perm, 614013 Russia
*e-mail: rjs@mail.ru
Received July 5, 2017
Abstract—A four-step procedure has been developed for the synthesis of new 2-(2,3,3-trimethyl-1,2,3,4-
tetrahydroisoquinolin-1-yl)anilines by acylation of 2-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)anilines at the
amino group with isobutyryl chloride, reduction of the endocyclic C=N bond in N-[2-(3,3-dimethyl-3,4-di-
hydroisoquinolin-1-yl)phenyl]isobutyramides, N-alkylation of N-[2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquino-
lin-1-yl)phenyl]isobutyramides to N-[2-(2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl]isobutyr-
amides, and acid hydrolysis of the latter.
DOI: 10.1134/S1070428018010086
Isoquinoline derivatives of both natural and syn-
thetic origin attract interest primarily due to broad
spectrum of their biological activity. Among these
compounds, the highest activity has been revealed in
1,2,3,4-tetrahydroisoquinolines [1–10]. Therefore,
development of methods for the synthesis of new
functionalized 1,2,3,4-tetrahydroisoquinolines suitable
for further structural modifications with the goal of
creating libraries of biologically active compounds is
an important problem.
dimethyl-1,2,3,4-tetrahydroisoquinolines were found
to exhibit antiplatelet [9], anticoagulant [10], antiar-
rhythmic [8, 10], hypotensive [9], and β-adrenergic
blocking activities [8]. This makes it reasonable to
search for new compounds of that series, especially for
those containing groups capable of undergoing further
chemical transformations.
We selected 2-(3,3-dimethyl-3,4-dihydroisoquino-
lin-1-yl)anilines 1a and 1b as starting materials for the
synthesis of the target structure. 3,4-Dihydroiso-
quinoline 1a was synthesized for the first time by one-
pot three-component condensation of 1,2-dimethoxy-
benzene with isobutyraldehyde and 2-aminobenzo-
nitrile in concentrated sulfuric acid, which was
developed by us previously [11]. Compound 1b was
The present study was aimed at developing a proce-
dure for the synthesis of previously unknown 2,3,3-tri-
methyl-1,2,3,4-tetrahydroisoquinolines containing
a 2-aminophenyl substituent on C1. Interest in these
compounds arises from the fact that some N-alkyl-3,3-
Scheme 1.
Me
Me
R
Me
Me
OH
CN
CN
N
OMe
OMe
NH2
NH2
Me
94% H2SO4
R
+
+
+
[12]
NH2
Me
CHO
1a, 1b
R = MeO (a), H (b).
95

ROZHKOVA et al.
96
Scheme 2.
Me
Me
NH
MeI, MeCN
MeI, MeCN
1a
Mixture of N-methyl derivatives
Mixture of N-methyl derivatives
NH2
2a
prepared under the classical Ritter conditions from
2-methyl-1-phenylpropan-2-ol and 2-aminobenzoni-
trile [12] (Scheme 1).
isoquinolin-1-yl)anilines 1a and 1b (Scheme 3). In the
first step, the acylation of 1a and 1b with isobutyryl
chloride gave amides 3a and 3b in nearly quantitative
yield (97 and 98%, respectively). The endocyclic
C2=N bond in 3a and 3b was reduced with sodium
tetrahydridoborate in methanol to obtain 1,2,3,4-tetra-
hydroisoquinolines 4a and 4b which were alkylated
with methyl iodide in acetonitrile in the presence of
potassium carbonate. As a result, N-[2-(2,3,3-trimeth-
yl-1,2,3,4-dihydroisoquinolin-1-yl)phenyl]isobutyr-
amides 5a and 5b were isolated in good yields. Finally,
acid hydrolysis of 5a and 5b on heating in 20% aque-
ous HCl afforded the target 2,3,3-trimethyl-1,2,3,4-
tetrahydroisoquinolines 6a and 6b in 83 and 95%
yield, respectively. It should be noted that we failed to
accomplish alkaline hydrolysis [13] of 5a and 5b; in
this case, the initial compounds were recovered from
the reaction mixtures.
Traditional approaches to N-alkyl-1,2,3,4-tetrahy-
droisoquinolines, which are based on preparation of
N-alkyl-3,4-dihydroisoquinoline salts and their subse-
quent reduction or direct N-alkylation of 1,2,3,4-tetra-
hydroisoquinolines, cannot be applied to the synthesis
of 2,3,3-trimethyl-1,2,3,4-tetrahydroisoquinolines con-
taining a 2-aminophenyl group on C1. The alkylation
of 1a with methyl iodide in acetonitrile gave a mixture
of N-methyl derivatives at both endocyclic nitrogen
atom and exocyclic amino group (Scheme 2). Analo-
gous pattern was observed in the alkylation under the
same conditions of 1,2,3,4-tetrahydroisoquinoline 2a
which was prepared in turn by reduction of 3,4-di-
hydroisoquinoline 1a with sodium tetrahydridoborate
in methanol.
Therefore, we have developed an experimentally
simple four-step procedure for the synthesis of the
target compounds from 2-(3,3-dimethyl-3,4-dihydro-
The structure of all newly synthesized compounds
was determined on the basis of their elemental
analyses and IR, 1H and 13C NMR, and mass spectra.
Scheme 3.
Me
Me
Me
R
R
R
Me
N
NH
i
ii
Me
R
Me
1a, 1b
H
H
N
N
Me
Me
O
O
3a, 3b
4a, 4b
Me
Me
Me
Me
R
R
R
N
N
iii
iv
Me
H
Me
R
Me
NH2
N
Me
O
5a, 5b
6a, 6b
R = MeO (a), H (b); Reagents and conditions: i: Me2CHC(O)Cl, ClCH2CH2Cl, 25°C; ii: NaBH4, MeOH, 25°C;
iii: MeI, K2CO3, MeCN, 60°C; iv: 20% aq. HCl, reflux.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 1 2018

SYNTHESIS OF NEW 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES.
97
EXPERIMENTAL
130.92, 146.43, 147.61, 150.74, 162.59 (Carom). Mass
spectrum, m/z (Irel, %): 310 (25.3) [M]+, 309 [M – H]+
(100), 294 (10.6), 279 (28.2). Found, %: C 73.43;
H 7.11; N 9.05. C19H22N2O2. Calculated, %: C 73.52;
H 7.14; N 9.03. M 310.39.
The H and 13C (DEPT) NMR spectra were
recorded on a Bruker Avance III HD 400 spectrometer
at 400 and 100 MHz, respectively, using hexamethyl-
disiloxane as internal standard. The mass spectra were
obtained on an Agilent Technologies 6890N/5975B
GC/MS system (HP-5ms column, 30 m×0.25 mm,
film thickness 0.25 μm; carrier gas helium; electron
impact, 70 eV). The melting points were measured on
a Stuart SMP40 melting point apparatus and are
uncorrected. The IR spectra were recorded on a Bruker
IFS-66/S spectrometer with Fourier transform from
samples prepared as thin films. The elemental com-
positions were determined with a Leco CHNS-932
analyzer. Silica gel (0.063–0.200 mm, Alfa Aesar) was
used for column chromatography. The progress of
reactions was monitored, and the purity of the isolated
compounds was checked, by TLC on Sorbfil PTSKh-
AF-A-UF plates; spots were visualized under UV light
(λ 254 nm).
1
2-(3,3-Dimethyl-3,4-dihydroisoquinolin-1-yl)-
aniline (1b) was synthesized according to the proce-
dure described in [12] from 3.75 g (25 mmol) of
2-methyl-1-phenylpropan-2-ol and 2.95 g (25 mmol)
of 2-aminobenzonitrile. The product was purified by
column chromatography using petroleum ether–ethyl
acetate (3:1) as eluent. Yield 3.94 g (63%), light
yellow crystals, mp 83.1–84.3°C (from i-PrOH) [12]),
Rf 0.74 (petroleum ether–EtOAc, 3:1). IR spectrum, ν,
cm–1: 3451, 3328, 3065, 3024, 2965, 2883, 2825, 1614,
1555, 1493, 1450, 1316, 1304, 1262, 1304, 1262,
1
1245, 1158, 959, 785, 753, 740. H NMR spectrum
(DMSO-d6), δ, ppm: 1.17 s (6H, 3-CH3), 2.74 s (2H,
4-H), 5.68 br.s (2H, NH2), 6.57 d.d.d (1H, Harom, J =
7.7, 7.2, 1.2 Hz), 6.77 d.d (1H, Harom, J = 8.1, 1.0 Hz),
7.00 d.d (1H, Harom, J = 7.7, 1.5 Hz), 7.06–7.12 m (2H,
Harom), 7.23 d.d (1H, Harom, J = 7.5, 1.3 Hz), 7.25–
7.29 m (1H, Harom), 7.39 t.d (1H, Harom, J = 7.4,
1.3 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
25.71 (2C, CH3), 37.84 (CH2), 54.01; 114.86, 115.82
(CHarom); 120.24, 126.39 (CHarom), 127.07 (Carom);
127.52, 128.25, 129.21, 130.05, 130.47 (CHarom);
137.19, 147.50 (Carom); 163.10 (C=N). Mass spectrum,
m/z (Irel, %): 250 (26.0) [M]+, 249 (100) [M – H]+, 233
(10.2). Found, %: C 81.64; H 7.21; N 11.23. C17H18N2.
Calculated, %: C 81.56; H 7.25; N 11.19. M 250.34.
2-(6,7-Dimethoxy-3,3-dimethyl-3,4-dihydroiso-
quinolin-1-yl)aniline (1a). A mixture of 2.36 g
(20.0 mmol) of powdered 2-aminobenzonitrile and
40 mL of 94% sulfuric acid was stirred for 5 min.
A mixture of 2.0 mL (22.0 mmol) of isobutyraldehyde
and 2.55 mL (20.0 mmol) of 1,2-dimethoxybenzene
was slowly added dropwise on cooling, and the
mixture was stirred for 1 h at room temperature. It was
then poured into a mixture of 100 g of ice and 120 mL
of aqueous ammonia (to pH 7) and extracted with ethyl
acetate (4×100 mL). The combined extracts were
washed with water and dried over sodium sulfate, the
solvent was distilled off under reduced pressure, and
the residue was purified by column chromatography
using petroleum ether–ethyl acetate–triethylamine
(5:1:0.3) as eluent. Yield 3.72 g (60%), light yellow
crystals, Rf 0.29 (petroleum ether–EtOAc–Et3N,
5:1:0.3), mp 120.8–121.8°C (from acetone–hexane).
IR spectrum, ν, cm–1: 3445, 3334, 3021, 2964, 2934,
2866, 2832, 1614, 1574, 1556, 1513, 1493, 1463,
1451, 1348, 1272, 1213, 1170, 1159, 1107, 753, 629.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.17 s (6H,
3-CH3), 2.65 s (2H, 4-H), 3.58 s (3H, OCH3), 3.82 s
2-(6,7-Dimethoxy-3,3-dimethyl-1,2,3,4-tetrahy-
droisoquinolin-1-yl)aniline (2a). Compound 1a,
0.31 g (1 mmol), was dissolved in 5 mL of methanol,
and 0.19 g (5 mmol) of NaBH4 was added in small
portions over a period 30 min with stirring. The mix-
ture was left for 24 h at room temperature, the solvent
was distilled off, and the residue was treated with
a saturated solution of sodium hydrogen carbonate and
extracted with ethyl acetate. The extract was washed
with water, dried over Na2SO4, and evaporated, and the
residue (containing more than 97% of 2a, according
1
to the H NMR data), was used in further syntheses
without additional purification. Yield 0.292 g (94%),
light yellow crystals, mp 106.5–120.7°C (from
EtOAc–hexane), Rf 0.21 (petroleum ether–EtOAc–
Et3N, 3:1:0.3). IR spectrum, ν, cm–1: 3424, 3307,
3018, 3004, 2961, 2934, 2909, 2831, 1612, 1513,
1496, 1463, 1302, 1255, 1222, 1116, 1039, 1000, 837,
(3H, OCH3), 5.82 br.s (2H, NH2), 6.57 t.d (1H, Harom
J = 7.6, 1.2 Hz), 6.66 s (1H, Harom), 6.76 d (1H, Harom
,
,
J = 8.0 Hz), 6.91 s (1H, Harom), 7.03–7.12 m (2H,
H
arom). 13C NMR spectrum (DMSO-d6), δC, ppm: 27.62
(2C, CH3), 37.44 (CH2), 53.82, 55.54 (OCH3), 55.60
(OCH3); 111.70, 111.78, 114.77, 115.89 (CHarom);
120.04, 120.21 (Carom); 129.17, 130.08 (CHarom);
1
796, 752. H NMR spectrum (DMSO-d6), δ, ppm:
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ROZHKOVA et al.
98
1.10 s and 1.20 s (3H each, 3-CH3), 2.21 br.s (1H,
NH), 2.48 d and 2.72 d (1H each, 4-H, J = 15.6 Hz),
3.46 s (3H, OCH3), 3.71 s (3H, OCH3), 4.98 s (1H,
1-H), 5.12 br.s (2H, NH2), 6.24 s (1H, Harom), 6.53 d.d
(1H, Harom, J = 7.3, 1.2 Hz), 6.57 d.d (1H, Harom, J =
147.11, 151.39 (Carom); 164.26 (C=N), 175.42 (C=O).
Mass spectrum, m/z (Irel, %): 380 (3.3) [M]+, 337 (100)
[M – CH(CH3)2]+. Found, %: C 72.68; H 7.36; N 7.39.
C23H28N2O3. Calculated, %: C 72.60; H 7.42; N 7.36.
M 380.48.
8.1, 1.0 Hz), 6.64 s (1H, Harom), 6.98 d.d.d (1H, Harom
,
N-[2-(3,3-Dimethyl-3,4-dihydroisoquinolin-1-yl)-
phenyl]-2-methylpropanamide (3b). Yield 0.314 g
(98%), oily material, Rf 0.44 (petroleum ether–EtOAc,
10:1). IR spectrum, ν, cm–1: 3203, 3101, 3067, 3025,
2967, 2930, 2873, 1693, 1604, 1582, 1561, 1521,
1445, 1315, 1293, 1270, 1160, 962, 786, 762, 743.
1H NMR spectrum (DMSO-d6), δ, ppm: 0.96 d [6H,
CH(CH3)2, J = 6.9 Hz], 1.23 s (6H, 3-CH3), 2.36 sept
[1H, CH(CH3)2, J = 6.9 Hz], 2.80 s (2H, 4-H), 7.00 d.d
(1H, Harom, J = 7.7, 0.8 Hz), 7.17 t.d (1H, Harom, J =
7.6, 1.1 Hz), 7.22 t.d (1H, Harom, J = 7.6, 1.3 Hz),
7.29 d.d (1H, Harom, J = 7.5, 1.3 Hz), 7.33 d.d (1H,
J = 7.9, 7.3, 1.6 Hz), 7.06 d.d (1H, Harom, J = 7.4,
1.5 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
23.41 (CH3), 31.15 (CH3), 41.46 (CH2), 48.83, 55.39
(OCH3), 55.44 (OCH3), 57.02 (CH); 110.33, 112.22,
115.44, 115.67 (CHarom); 126.86 (Carom), 127.58
(CHarom), 128.38 (Carom), 130.19 (CHarom); 146.63,
147.15, 147.32 (Carom). Mass spectrum, m/z (Irel, %):
312 (100) [M]+, 297 (56.5) [M – CH3]+, 281 (19.8),
254 (38.7), 239 (25.0), 224 (25.9), 204 (12.7), 180
(9.8), 119 (9.2). Found, %: C 72.93; H 7.81; N 8.90.
C19H24N2O2. Calculated, %: C 73.05; H 7.74; N 8.97.
M 312.41.
Harom, J = 7.8, 1.5 Hz), 7.36–7.48 m (2H, Harom), 8.03 d
(1H, Harom, J = 8.1 Hz), 10.40 br.s (1H, NH). 13C NMR
spectrum (DMSO-d6), δC, ppm: 18.99 (2C, CH3), 27.23
(2C, CH3), 35.29 (CH), 37.67 (CH2), 54.31; 122.64,
122.99, 126.46, 126.97 (CHarom); 127.24, 127.37
(Carom); 128.19, 129.25, 130.23, 130.82 (CHarom);
137.00, 137.05 (Carom); 163.08 (C=N), 174.25 (C=O).
Mass spectrum, m/z (Irel, %): 320 (2.5) [M]+, 277 (100)
[M – (CH3)2CH]+, 249 (5.7) [M – (CH3)2CHC(O)]+,
234 (11.4) [M – (CH3)2CHC(O)NH]+. Found, %:
C 78.84; H 7.53; N 8.70. C21H24N2O. Calculated, %:
C 78.71; H 7.55; N 8.74. M 320.43.
Compounds 3a and 3b (general procedure).
A solution of 0.11 mL (1.1 mmol) of isobutyryl
chloride in 0.6 mL of 1,2-dichloroethane was added
with stirring and cooling (10°C) to a solution of
1 mmol of compound 1a or 1b in 3 mL of 1,2-di-
chloroethane. The mixture was stirred for 7 h at room
temperature and treated with a saturated aqueous
solution of sodium hydrogen carbonate. The organic
phase was separated, washed with water, dried over
Na2SO4, and evaporated. The residue contained more
1
than 99% of 3a or 3b (according to the H NMR and
GC/MS data) and was used without additional
purification.
Compounds 4a and 4b (general procedure).
Sodium tetrahydridoborate, 0.265 g (7 mmol), was
added in small portions over a period of 30 min with
stirring to a solution of 1 mmol of compound 3a or 3b
in 5 mL of methanol. The mixture was stirred for 14 h
at room temperature, the solvent was distilled off, and
the residue was treated with a saturated aqueous
solution of NaHCO3 and extracted with ethyl acetate.
The extract was washed with water, dried over
Na2SO4, and evaporated, and the residue was recrys-
tallized from ethyl acetate (4a) or ethyl acetate–hexane
(4b). In the synthesis of 4b, the mother liquor obtained
after recrystallization was evaporated, and the residue
was purified by chromatography (petroleum ether–
acetone, 10:1).
N-[2-(6,7-Dimethoxy-3,3-dimethyl-3,4-dihydro-
isoquinolin-1-yl)phenyl]-2-methylpropanamide
(3a). Yield 0.37 g (97%), light yellow crystals, Rf 0.23
(hexane–EtOAc, 4:1), mp 117.8–119°C. IR spectrum,
ν, cm–1: 3203, 3063, 2966, 2933, 1689, 1604, 1581,
1557, 1515, 1464, 1444, 1348, 1292, 1273, 1212,
1
1168, 1129, 1092, 953, 756. H NMR spectrum
(CDCl3), δ, ppm: 1.24 d [6H, CH(CH3)2, J = 6.8 Hz],
1.30 s (6H, 3-CH3), 2.47 sept [1H, CH(CH3)2, J =
6.8 Hz], 2.69 s (2H, 4-H), 3.71 s (3H, OCH3), 3.93 s
(3H, OCH3), 6.71 s (1H, Harom), 6.76 s (1H, Harom),
7.05 t.d (1H, Harom, J = 7.6, 1.2 Hz), 7.33 d.d (1H,
Harom, J = 7.6, 1.2 Hz), 7.37 d.d.d (1H, Harom, J = 8.4,
7.2, 1.6 Hz), 8.46 d.d (1H, Harom, J = 8.2, 0.8 Hz),
11.14 br.s (1H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 19.55 (CH3), 27.81 (CH3), 37.15 (CH), 38.41
(CH2), 54.64, 56.01 (OCH3), 56.12 (OCH3); 111.20,
112.18 (CHarom); 120.63; 122.04, 122.12 (CHarom);
125.13; 129.92, 130.49 (CHarom); 131.39, 138.11,
N-[2-(6,7-Dimethoxy-3,3-dimethyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)phenyl]-2-methylpropan-
amide (4a). Yield 0.306 g (80%), white crystals,
Rf 0.17 (hexan–EtOAc, 4:1), mp 138.5–140.5°C (from
EtOAc). IR spectrum, ν, cm–1: 3289, 2965, 2934, 2833,
1682, 1610, 1590, 1518, 1466, 1448, 1301, 1256,
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SYNTHESIS OF NEW 1,2,3,4-TETRAHYDROISOQUINOLINE DERIVATIVES.
99
1224, 1117, 1075, 758. 1H NMR spectrum (DMSO-d6),
δ, ppm: 0.81 d and 1.02 d [3H each, CH(CH3)2, J =
6.8 Hz], 1.14 s and 1.27 s (3H each, 3-CH3), 2.21 sept
[1H, CH(CH3)2, J = 6.8 Hz], 2.59 d and 2.80 d (1H
each, 4-H, J = 16.0 Hz), 3.10 br.s (1H, NH), 3.41 s
(3H, OCH3), 3.69 s (3H, OCH3), 5.06 s (1H, 1-H),
6.09 s (1H, Harom), 6.68 s (1H, Harom), 7.08 t.d (1H,
Harom, J = 7.4, 1.3 Hz), 7.27 t.d (1H, Harom, J = 7.8,
1.6 Hz), 7.39 d.d (1H, Harom, J = 7.5, 1.4 Hz), 8.04 d
(1H, Harom, J = 8.0 Hz), 10.78 br.s (1H, NH). 13C NMR
spectrum (DMSO-d6), δC, ppm: 18.90, 19.21, 23.15,
31.11 (CH3); 35.99 (CH), 41.37 (CH2), 48.84, 55.38
(OCH3), 55.50 (OCH3), 57.34 (CH); 110.14, 112.26,
121.29, 122.57 (CHarom); 126.14 (Carom), 127.59
(CHarom), 127.77 (Carom), 130.61 (CHarom); 131.98,
138.03, 146.79, 147.70 (Carom); 173.61 (C=O). Mass
spectrum, m/z (Irel, %): 382 (46.2) [M]+, 381 (24.2)
[M – H]+, 367 (29.9) [M – CH3]+, 311 (100) [M –
(CH3)2CHC(O)]+, 296 (59.2) [M – (CH3)2CHC(O)NH]+,
255 (14.7), 254 (69.5), 239 (12.2), 238 (16.4), 220
(12.8), 219 (10.6), 204 (10.3), 58 (10.8), 43 (20.6).
Found, %: C 72.23; H 7.81; N 7.35. C23H30N2O3.
Calculated, %: C 72.22; H 7.91; N 7.32. M 382.50.
Compounds 5a and 5b (general procedure).
Potassium carbonate, 0.55 g (4 mmol), was added to
a solution of 1 mmol of compound 4a or 4b in 4 mL of
acetonitrile, and 0.19 mL (3 mmol) of methyl iodide
was then added dropwise with stirring. The mixture
was stirred for 8 h at 60°C, left overnight at room
temperature, and heated again for 4 h at 60°C (TLC).
The solvent was evaporated, and the residue was
treated with water and ethyl acetate. The organic phase
was separated, and the aqueous phase was extracted
with ethyl acetate. The extract was combined with the
organic phase, washed with water, dried over Na2SO4,
and evaporated, and the residue was recrystallized
from ethyl acetate (5a) or purified by chromatography
using petroleum ether–acetone (10:1) as eluent (5b).
N-[2-(6,7-Dimethoxy-2,3,3-trimethyl-1,2,3,4-
tetrahydroisoquinolin-1-yl)phenyl]-2-methylpro-
panamide (5a). Yield 0.35 g (88%), white crystals,
Rf 0.29 (hexane–EtOAc, 4:1), mp 144–146.5°C (from
EtOAc). IR spectrum, ν, cm–1: 3179, 3104, 2968, 2934,
2833, 1687, 1611, 1590, 1519, 1466, 1447, 1301,
1
1260, 1225, 1116, 1012, 757. H NMR spectrum
(DMSO-d6), δ, ppm: 0.85 d [3H, CH(CH3)2, J =
6.8 Hz], 0.96 s (3H, 3-CH3), 1.06 d [3H, CH(CH3)2,
J = 6.8 Hz], 1.34 s (3H, 3-CH3), 2.14 s (3H, NCH3),
2.27 sept [1H, CH(CH3)2, J = 6.8 Hz], 2.66 d and
2.94 d (1H each, 4-H, J = 16.0 Hz), 3.40 s (3H, OCH3),
3.69 s (3H, OCH3), 4.51 s (1H, 1-H), 6.07 s (1H,
Harom), 6.67 s (1H, Harom), 7.10 t.d (1H, Harom, J = 7.2,
1.2 Hz), 7.26 t.d (1H, Harom, J = 8.0, 1.2 Hz), 7.43 d.d
(1H, Harom, J = 7.2, 1.2 Hz), 8.12 d (1H, Harom, J =
7.8 Hz), 10.67 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 13.92, 18.87, 19.37, 29.62,
33.88 (CH3); 36.01 (CH), 43.33 (CH2), 52.72, 55.22
(OCH3), 55.42 (OCH3), 66.31 (CH); 110.72, 111.41,
120.61, 122.58 (CHarom); 125.41, 127.31 (Carom);
127.61, 130.92 (CHarom); 137.46, 146.71, 147.63
(Carom); 173.72 (C=O). Mass spectrum, m/z (Irel, %):
396 (9.3) [M]+, 381 (100) [M – CH3]+, 353 (16.9) [M –
CH(CH3)2]+, 311 (17.2), 254 (14.8), 72 (9.2), 43 (9.8).
Found, %: C 72.59; H 8.08; N 7.11. C24H32N2O3.
Calculated, %: C 72.70; H 8.13; N 7.06. M 396.52.
N-[2-(3,3-Dimethyl-1,2,3,4-dihydroisoquinolin-1-
yl)phenyl]-2-methylpropanamide (4b). Yield 0.297 g
(92%), white crystals, mp 125.6–126.8°C (from
EtOAc–hexane), Rf 0.23 (petroleum ether–acetone,
10:1). IR spectrum, ν, cm–1: 3285, 3188, 3106, 3018,
2966, 2930, 2873, 1682, 1609, 1590, 1525, 1448,
1382, 1367, 1300, 1197, 1160, 944, 757, 744. 1H NMR
spectrum (DMSO-d6), δ, ppm: 0.73 d and 0.98 d [3H
each, CH(CH3)2, J = 6.8 Hz], 1.15 s and 1.29 s (3H
each, 3-CH3), 2.17 sept [1H, CH(CH3)2, J = 6.9 Hz],
2.69 d and 2.88 d (1H each, 4-H, J = 16.3 Hz),
3.19 br.s (1H, NH), 5.14 s (1H, 1-H), 6.56 d (1H,
Harom, J = 7.7 Hz), 6.93–7.00 m (1H, Harom), 7.05–
7.12 m (3H, Harom), 7.26 t.d (1H, Harom, J = 7.6,
1.6 Hz), 7.40 d.d (1H, Harom, J = 7.5, 1.5 Hz), 8.03 d
(1H, Harom, J = 8.0 Hz), 10.74 br.s (1H, NH). 13C NMR
spectrum (DMSO-d6), δC, ppm: 18.86 (CH3), 19.12
(CH3), 23.14 (CH3), 31.13 (CH3), 36.00 (CH), 41.81
(CH2), 48.78, 57.65 (CH); 121.33, 122.58, 125.58,
125.92, 126.16, 127.62, 128.80, 130.96 (CHarom);
131.87, 133.67, 135.97, 137.96 (Carom); 173.52 (C=O).
Mass spectrum, m/z (Irel, %): 322 (20.3) [M]+, 307
(24.9) [M – CH3]+, 277 (11.5), 251 (100) [M –
(CH3)2CHC(O)]+, 236 (42.3) [M – (CH3)2CHC(O)NH]+,
194 (44.6), 178 (14.9), 144 (17.7), 58 (13), 43 (20.2).
Found, %: C 78.15; H 8.17; N 8.62. C21H26N2O.
Calculated, %: C 78.22; H 8.13; N 8.69. M 322.44.
N-[2-(2,3,3-Trimethyl-1,2,3,4-dihydroisoquino-
lin-1-yl)phenyl]-2-methylpropanamide (5b). Yield
0.286 g (85%), white crystals, mp 136.6–138.1°C
(from EtOAc), Rf 0.38 (petroleum ether–acetone,
10:1). IR spectrum, ν, cm–1: 3234, 3184, 3106, 3061,
2968, 2930, 2873, 2808, 2792, 1691, 1608, 1590,
1527, 1494, 1469, 1445, 1382, 1367, 1302, 1197,
1
1161, 1147, 990, 941, 757, 743. H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 1 2018

ROZHKOVA et al.
100
(CHarom); 130.81, 146.48, 147.23 (Carom). Mass spec-
trum, m/z (Irel, %): 326(20.9) [M]+, 325 (9.9) [M – H]+,
311 (100) [M – CH3]+, 283 (11.7), 234 (14.1). Found,
%: C 73.68; H 8.07; N 8.52. C20H26N2O2. Calculated,
%: C 73.59; H 8.03; N 8.58. M 326.43.
(DMSO-d6), δ, ppm: 0.78 d [3H, CH(CH3)2, J =
6.8 Hz], 0.97 s (3H, 3-CH3), 1.03 d [3H, CH(CH3)2,
J = 6.8 Hz], 1.35 s (3H, 3-CH3), 2.14 s (3H, NCH3),
2.23 sept [1H, CH(CH3)2, J = 6.8 Hz], 2.77 d and
3.02 d (1H each, 4-H, J = 16.4 Hz), 4.60 s (1H, 1-H),
6.56 d (1H, Harom, J = 8.0 Hz), 6.89–7.01 m (1H,
2-(2,3,3-Trimethyl-1,2,3,4-tetrahydroisoquinolin-
1-yl)aniline (6b). Yield 0.253 g (95%), white crystals
turning yellowish on exposure to air, mp 145.6–
147.0°C (from EtOAc), Rf 0.44 (petroleum ether–
acetone, 15:1). IR spectrum, ν, cm–1: 3424, 3308,
3018, 3003, 2961, 2934, 2854, 1612, 1512, 1496,
1462, 1302, 1255, 1222, 1116, 1076, 837, 752.
1H NMR spectrum (DMSO-d6), δ, ppm: 0.89 s and
1.27 s (3H each, 3-CH3), 2.10 s (3H, NCH3), 2.60 d
and 2.96 d (1H each, 4-H, J = 15.9 Hz), 4.39 s (1H,
1-H), 5.19 br.s (2H, NH2), 6.50 d.d (1H, Harom, J = 7.9,
1.1 Hz), 6.55 t.d (1H, Harom, J = 7.3, 1.2 Hz), 6.66 d
(1H, Harom, J = 7.5 Hz), 6.90–6.98 m (2H, Harom), 7.00–
7.05 m (2H, Harom), 7.13 d.d (1H, Harom, J = 7.4,
1.5 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
13.66 (CH3), 29.69 (CH3), 33.88 (CH3), 43.98 (CH2),
52.35, 66.71 (CH); 115.34, 115.46, 125.15, 125.50
(CHarom); 126.11 (Carom); 126.48, 127.48, 127.76,
131.10 (CHarom); 133.71, 136.59, 146.50 (Carom). Mass
spectrum, m/z (Irel, %): 266 (23.1) [M]+, 251 (100)
[M – CH3]+, 220 (16.9), 194 (16.2), 158 (16.1) Found,
%: C 81.21; H 8.28; N 10.51. C18H22N2. Calculated, %:
C 81.16; H 8.32; N 10.52. M 266.38.
H
arom), 7.05–7.14 m (3H, Harom), 7.26 t.d (1H, Harom,
J = 7.6, 1.6 Hz), 7.44 d.d (1H, Harom, J = 7.5, 1.6 Hz),
8.08 d (1H, Harom, J = 7.9 Hz), 10.58 br.s (1H, NH).
13C NMR spectrum (DMSO-d6), δC, ppm: 13.95 (CH3),
18.87 (CH3), 19.30 (CH3), 29.66 (CH3), 33.91 (CH3),
36.04 (CH), 43.76 (CH2), 52.70, 66.50 (CH); 120.73,
122.66, 125.66, 126.22, 126.73, 127.66, 128.17
(CHarom); 130.90 (Carom), 131.30 (CHarom); 133.00,
135.58, 137.39 (Carom); 173.66 (C=O). Mass spectrum,
m/z (Irel, %): 336 (8.5) [M]+, 321 (100) [M – CH3]+,
293 (15.4) [M – (CH3)2CH]+, 265 (16.4) [M –
(CH3)2CHC(O)]+, 251 (12.0), 194 (9.8), 158 (15.3), 72
(12.9), 43 (12.9). Found, %: C 78.44; H 8.35; N 8.38.
C22H28N2O. Calculated, %: C 78.53; H 8.39; N 8.33.
M 336.47.
Compounds 6a and 6b (general procedure).
A solution of 1 mmol of compound 5a or 5b in 15 mL
of 20% aqueous HCl was refluxed for 2 h. The mix-
ture was cooled and neutralized to pH 7–8 by adding
aqueous ammonia with stirring and cooling. The
precipitate was extracted with ethyl acetate, the extract
was washed with water, dried over Na2SO4, and
evaporated, and the residue was purified by chroma-
tography using hexane–acetone (6:1) or petroleum
ether–acetone (15:1) as eluent for compounds 6a and
6b, respectively.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-03-00561).
2-(6,7-Dimethoxy-2,3,3-trimethyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)aniline (6a). Yield 0.271 g
(83%), colorless crystals, Rf 0.31 (hexane–EtOAc,
4:1), mp 152.5–153.7°C (from EtOAc). IR spectrum,
ν, cm–1: 3423, 3288, 2999, 2965, 2912, 2833, 2782,
1611, 1518, 1496, 1463, 1303, 1260, 1223, 1115, 1013,
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