Three-component synthesis of 1-substituted 6′,7′-dimethoxy- 4′H-spiro[adamantane-2,3′-isoquinolines]

Full text of DOI:10.1134/S1070428010050295

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 762−764. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © Yu.S. Rozhkova, A.A. Gorbunov, Yu.V. Shklyaev, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 5,
pp. 766−768.
SHORT
COMMUNICATIONS
Three-Component Synthesis of 1-Substituted
6',7'-Dimethoxy-4'H-spiro[adamantane-2,3'-isoquinolines]
Yu. S. Rozhkova,A.A. Gorbunov, andYu. V. Shklyaev
Institute of Technical Chemistry, Ural Division, Russian Academy of Sciences
Perm’, 614013 Russia; e-mail: rjs@mail.ru
Received October 27, 2009
DOI: 10.1134/S1070428010050295
Adamantane derivatives like amantadine and
rimantadine exhibit antiviral activity. They also proved to
be efficient in the treatment of Alzheimer’s and
Parkinson’s disease, the disorders of the central nervous
system [1, 2]. In search for new analogs of the amanta-
dine and rimantadine synthetic procedures were develop-
ed for quite a number of spiroadamantane derivatives
including both carbocycles [3] and versatile heterocycles
[4–6]. Interestingly some of these compounds proved to
be more effective than rimantadine and amantadine. We
report on the development of the preparation method of
spiro[adamantane-2,3'-isoquinolines].
styrenes [8]. In [9] a simple method was developed for
the synthesis of 1-substituted 3,4-dihydroisoquinolines
by a three-component condensation of an activated
arene (1,2- or 1,4-dimethoxybenzene), isobutylene oxide,
and a nitrile in a concentrated sulfuric acid. Here the
necessary carbocation formed in situ by the acid-
catalyzed alkylation of the arene with the isobutylene
oxide.
In this study we explored the possibility to apply
2-epoxymethyleneadamantane to the synthesis of 4'H-
spiro[adamantane-2,3'-isoquinoline] derivatives by the
three-component condensation. We established that the
reaction of 2-epoxymethyleneadamantane with 1,2-di-
methoxybenzene and nitriles Ia–Ie in the concentrated
sulfuric acid afforded 6',7'-dimethoxy-4'H(or 2'H,4'H)-
spiro-[adamantane-2,3'-isoquinolines] IIa–IIe in 38–70%
yields.
Ritter reaction as one among traditional synthetic
procedures for 3,4-dihydroisoquinoline derivatives
involves the use as the source of carbocations of alcohols
from the series of 2-methyl-1-phenylpropan-2-ol [7], 2-
methyl-1-phenylpropan-1-ol, or the corresponding
MeO
N
MeO
O
MeO
R
H2SO4
IIа_IIc
+
+
RCN
MeO
Ia_Ie
MeO
MeO
NH
COR'
IId, IIe
I, R = SMe (a), Me (b), Ph (c), CH2COOEt (d), CH2CONH2 (e); II, R = SMe (a), Me (b), Ph (c), R'= OEt (d), NH2 (e).
762

THREE-COMPONENT SYNTHESIS
763
The composition and structure of compounds IIa–IIe
were confirmed by the elemental analyses, mass and
1H NMR spectra.
1'-Phenyl-6',7'-dimethoxy-4'H-spiro[adaman-
tane-2,3'-isoquinoline] (IIc). Yield 0.19 g (49%), mp
190–192°C (ethyl acetate). IR spectrum, ν, cm–1: 1601
1
(C=N), 1559, 1512. H NMR spectrum, δ, ppm: 1.48–
The developed method is a simple and efficient
procedure of the preparation of spiro[adamantane-2,3'-
isoquinolines]. These structures undoubtedly are interest-
ing from the viewpoint of biological action for they
combine the fragments of adamantane and 3,4-di-
hydroisoquinoline.
2.22 m (12H, HAd), 2.59–2.66 m (2H, HAd), 2.91 s (2H,
CH2), 3.70 s (3H, OCH3), 3.90 s (3H, OCH3), 6.75 s
(1H, H5), 6.81 s (1H, H8), 7.32–7.40 m (3H, Ph), 7.62–
7.69 m (2H, Ph). Mass spectrum, m/z (Irel, %): 387 (100)
[M]+, 370 (3.8), 344 (14.8), 318 (3.3), 306 (10.8), 292
(16.3), 279 (14.2), 266 (12.6), 250 (2.8), 239 (5.2), 208
(1.6), 165 (2.3), 115 (1.1), 79 (2.1), 41 (1.1). Found, %: C
80.51; H 7.46; N 3.60. C26H29NO2. Calculated, %: C
80.59; H 7.54; N 3.61. M 387.22.
4'H-Spiro[adamantane-2,3'-isoquinolines IIa–IIe.
General procedure. A mixture of 1 mmol of 2-epoxy-
methyleneadamantane, 1 mmol of nitrile Ia–Id, and 1 mmol
of 1,2-dimethoxybenzene in 1 ml of CH2Cl2 was added
dropwise to 4 ml of 96% H2SO4 at vigorous stirring and
cooling with ice water. The mixture was stirred for 20 min
at room temperature, then it was poured in water and
neutralized with aqueous ammonia till pH 8–9. The
products were extracted into CH2Cl2 (3×15 ml). The
combined extracts were dried with MgSO4, the solvent
was distilled off, the residue was recrystallized.
Ethyl 2-(6',7'-dimethoxy-2’H,4'H-spiro[adaman-
tane-2,3'-isoquinolin]-1'-ylidene)acetate (IId). Yield
0.19 g (48%), mp 196–198°C (2-propanol–ethyl acetate).
IR spectrum, ν, cm–1: 3273 (NH), 1738 (C=O), 1634
1
(C=N), 1601, 1573, 1515. H NMR spectrum, δ, ppm:
1.30 t (3H, OCH2CH3), 1.60–1.77 m (8H, HAd), 1.83–
2.02 m (4H, HAd), 2.12–2.22 m (2H, HAd), 3.01 s (2H,
CH2), 3.88 s (3H, OCH3), 3.90 s (3H, OCH3), 4.18 q
(2H, OCH2CH3), 5.04 s (1H, =CH–), 6.34 s (1H, H5),
7.11 s (1H, H8), 9.66 br.s (1H, NH). Mass spectrum,
m/z (Irel, %): 325 (100) [M – COOEt + H]+, 310 (10.1),
296 (4.1), 282 (21.4), 268 (5.8), 256 (5.5), 244 (16.1),
230 (25.9), 217 (22.2), 204 (22.2), 188 (3.3), 160 (2.3),
115 (3.0), 91 (5.0), 79 (5.2). Found, %: C 72.56; H 7.93;
N 3.49. C24H31NO4. Calculated, %: C 72.52; H 7.86;
N 3.52. M 397.23.
1'-Methylthio-6',7'-dimethoxy-4'H-spiro-
[adamantane-2,3'-isoquinoline] (IIa). Yield 0.25 g
(70%), mp 173.5–175.5°C (2-propanol). IR spectrum, ν,
1
cm–1: 1636 (C=N), 1600, 1570, 1514. H NMR spectrum,
δ, ppm: 1.40–1.51 m (2H, HAd), 1.60–1.75 m (6H, HAd),
1.81–2.00 m (4H, HAd), 2.47 s (3H, SCH3), 2.53 br.s
(2H, HAd), 2.86 s (2H, CH2), 3.89 s (3H, OCH3), 3.90 s
(3H, OCH3), 6.66 s (1H, H5), 7.14 s (1H, H8). Mass
spectrum, m/z (Irel, %): 357 (46.1) [M]+, 342 (100) [M –
Me]+, 324 (7.1), 310 (3.0) [M – SMe]+, 262 (3.8), 222
(4.2), 176 (7.1), 150 (1.4), 115 (1.1), 91 (4.1), 79 (3.8), 67
(1.8). Found, %: C 70.49; H 7.62; N 3.86; S 8.89.
C21H27NO2S. Calculated, %: C 70.55; H 7.61; N 3.92; S
8.97. M 357.18.
2-(6',7'-Dimethoxy-2’H,4'H-spiro[adamantanε-
2,3'-isoquinolin]-1'-ylidene)acetamide (IIe). 0.084 g
(1 mmol) of cyanoacetamide was dissolved in 4 ml of
96% H2SO4. Then a mixture was added of 0.16 g
(1 mmol) of 2-epoxymethyleneadamantane and 0.11 g
(1 mmol) of 1,2-dimethoxybenzene in 1 ml of CH2Cl2.
Further the reaction mixture was worked up as described
in the general procedure. Yield 0.14 g (38%), mp 227–
230°C (2-propanol–dichloromethane). IR spectrum, ν,
cm–1: 3473 (NHfree), 3278 (NHbound), 3143 (NHbound),
1631 (C=O), 1619 (C=N), 1604, 1571, 1513. 1H NMR
spectrum, δ, ppm: 1.55–2.04 m (12H, HAd), 2.15–2.25 m
(2H, HAd), 3.00 s (2H, CH2), 3.89 s (3H, OCH3), 3.91 s
(3H, OCH3), 4.84 br.s (1H, CONH2), 4.95 s (1H,
=CH–), 6.64 s (1H, H5), 7.06 s (1H, H8), 10.39 s (1H,
NH). Mass spectrum, m/z (Irel, %): 325 (100) [M –
CONH2 + H]+, 310 (9.7), 296 (3.8), 282 (19.3), 268 (5.6),
256 (5.3), 244 (15.5), 230 (24.5), 217 (20.8), 204 (21.8),
188 (3.2), 160 (2.1), 115 (2.8), 91 (4.0), 79 (4.3). Found,
1'-Methyl-6',7'-dimethoxy-4'H-spiro[adaman-
tane-2,3'-isoquinoline] (IIb). Yield 0.14 g (43%), mp
144–148°C (2-propanol). IR spectrum, ν, cm–1: 1624
1
(C=N), 1601, 1573, 1510. H NMR spectrum, δ, ppm:
1.41–1.48 m (2H, HAd), 1.59–1.76 m (6H, HAd), 1.81–
2.00 m (4H, HAd), 2.36 s (3H, CH3), 2.41–2.51 m (2H,
HAd), 2.82 s (2H, CH2), 3.89 s (3H, OCH3), 3.91 s (3H,
OCH3), 6.67 s (1H, H5), 6.97 s (1H, H8). Mass spectrum,
m/z (Irel, %): 325 (100) [M]+, 310 (10.0) [M – Me]+, 296
(4.1), 282 (20.7), 268 (5.5), 256 (5.3), 244 (15.2), 230
(23.3), 217 (19.9), 204 (19.9), 176 (1.4), 160 (2.1), 141
(2.2), 115 (2.3), 79 (3.5), 41 (1.8). Found, %: C 77.61;
H 8.36; N 4.23. C21H27NO2. Calculated, %: C 77.50;
H 8.36; N 4.30. M 325.20.
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ROZHKOVA et al.
764
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