Synthesis of 4′H-spiro[adamantane-2,3′-isoquinoline] derivatives

Full text of DOI:10.1134/S1070428009120264

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 12, pp. 1874–1876. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © Yu.S. Rozhkova, O.A. Maiorova, Yu.V. Shklyaev, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 12,
pp. 1875–1877.
SHORT
COMMUNICATIONS
Synthesis of 4′H-Spiro[adamantane-2,3′-isoquinoline] Derivatives
Yu. S. Rozhkova, O. A. Maiorova, and Yu. V. Shklyaev
Institute of Ttechnical Chemistry, Ural Division, Russian Academy of Sciences,
ul. Akademika Koroleva 3, Perm, 614013 Russia
e-mail: rjs@mail.ru
Received December 26, 2008
DOI: 10.1134/S1070428009120264
Syntheses of adamantane derivatives with various
nitrogen-containing heterocyclic fragments, such as
pyrrolidine [1, 2], diaziridine [3], piperidine, morpho-
line [4, 5], and perhydroazepine [5], have been re-
ported. Introduction of an adamantane fragment into
molecules of analogous biologically active hetero-
cycles is known to affect their pharmacological prop-
erties, giving rise to antiviral, antitumor, neurotropic,
and other kinds of biological activity.
stituted carboxylic acid amides [10]. Analogous reac-
tions were also reported for 2-alkyladamantan-2-ols.
For example, the corresponding N-(2-methyladaman-
tan-2-yl)alkanamides were obtained from 2-methyl-
adamantan-2-ol and nitriles [11].
We found that tertiary adamantyl alcohol I reacts
with nitriles to give 1-substituted spiro[adamantane-
2,3′-isoquinolines] IIa, IIb, IIIa, and IIIb (Scheme 1).
Compound IIb was isolated as hydrochloride IV.
Presumably, intermediate cation A is stabilized via
intramolecular cyclization with formation of isoquino-
line structure possessing a spiro-fused adamantane
fragment at C3 (Scheme 2). The structure of isoquino-
line derivatives IIa, IIIa, and IIIb and hydrochloride
The goal of the present work was to develop a pro-
cedure for the synthesis of hitherto unknown 4′H-spiro-
[adamantane-2,3′-isoquinolines] as potential biologi-
cally active substances. Isoquinoline derivatives can be
synthesized according to Ritter, by reaction of dialkyl-
benzylcarbinols, 2-methyl-1-phenylpropan-1-ol, or the
corresponding styrenes with nitriles in concentrated
sulfuric acid [6, 7]. We examined Ritter reactions of
2-benzyladamantan-2-ol (I) with different cyano com-
pounds. Adamantane derivatives in concentrated sul-
furic acid are known to undergo various rearrange-
ments, as well as oxidation, disproportionation, and
decomposition processes [8, 9]. Nevertheless, it was
shown previously that adamantan-1-ol reacts with
nitriles in concentrated sulfuric acid to produce con-
ventional Ritter reaction products, N-adamantyl-sub-
1
IV was proved by the H and 13C NMR, IR, and mass
spectra.
2-Benzyladamantan-2-ol (I) was synthesized ac-
cording to the procedure described in [12] from 15.1 g
(0.1 mol) of benzylmagnesium chloride [prepared from
16.1 g (0.1 mol) of benzyl chloride and 3.12 g
(0.13 mol) of metallic magnesium] and 15 g (0.1 mol)
of adamantan-2-one. The product was isolated by flash
chromatography on neutral silica gel using hexane–
ethyl acetate (50:1) as eluent. Yield 7.74 g (32%),
mp 47–51°C. 1H NMR spectrum, δ, ppm: 1.22–2.20 m
Scheme 1.
OH
CH2Ph
H2SO4
+
RCN
or
N
NH
R
COR
I
IIa, IIb
IIIa, IIIb
II, R = MeS (a), PhCH2S (b); III, R = EtO (a), H2N (b).
1874

SYNTHESIS OF 4′H-SPIRO[ADAMANTANE-2,3′-ISOQUINOLINE] DERIVATIVES
1875
Scheme 2.
OH
CH2Ph
H+
N
–H2O
R
R
C
N
IIa, IIb, IIIa, IIIb
N
CH
R
A
(15H, CH, CH2, OH), 2.98 s (2H, CH2Ph), 7.19–
7.33 m (5H, Harom). Mass spectrum, m/z (Irel, %): 242
(1) [M]+, 224 (30), 181 (3), 167 (6), 151 (100), 133 (3),
107 (6), 91 (25), 77 (7), 55 (3).
mp 114–118°C (from propan-2-ol). IR spectrum, ν,
1
cm–1: 3264, 1648, 1616, 1605, 1572. H NMR spec-
trum, δ, ppm: 1.29 t (3H, OCH2CH3, J = 6.9 Hz);
1.66 m (8H), 1.92 m (4H), and 2.15 m (2H) (Ad);
3.07 s (2H, 4-H), 4.17 q (2H, OCH2CH3, J = 6.9 Hz),
5.15 s (1H, =CH), 7.21 m (3H, Harom), 7.63 d (1H,
Harom, J = 7.5 Hz), 9.69 s (1H, NH). 13C NMR spec-
trum, δC, ppm: 14.68 (OCH2CH3); 27.02, 27.09, 35.28
(CH, Ad); 32.70, 33.55, 37.77, 38.34 (CH2, Ad, C4);
55.55 (C3); 58.49 (OCH2CH3); 77.64 (CH=); 124.79,
126.71, 128.99, 130.45 (C5, C6, C7, C8); 129.09, 134.77
(C4a, C8a); 155.14 (C1); 171.37 (C=O). Mass spectrum,
m/z (Irel, %): 265 (100) [M – COOEt + H]+, 250 (8),
222 (18), 196 (6), 184 (13), 170 (24), 157 (18), 144 (25),
114 (11), 91 (5). Found, %: C 78.24; H 8.01; N 4.20.
C22H27NO2. Calculated, %: C 78.30; H 8.06; N 4.15.
1′-Methylsulfanyl-4′H-spiro[adamantane-2,3′-
isoquinoline] (IIa). A mixture of 0.94 g (4 mmol) of
2-benzyladamantan-2-ol (I) and 0.29 g (4 mmol) of
methyl thiocyanate in 2 ml of methylene chloride was
added dropwise under vigorous stirring to 10 ml of
concentrated sulfuric acid, maintaining the temperature
at 10–15°C by cooling with tap water. The mixture was
stirred for 20 min at 20–25°C, poured into water,
treated with sodium carbonate until pH 8–9, and ex-
tracted with methylene chloride (3×20 ml). The com-
bined extracts were dried over MgSO4, the solvent was
distilled off, and the residue was recrystallized from
isopropyl alcohol. Yield 0.5 g (42%), mp 109–112°C.
IR spectrum, ν, cm–1: 1612, 1600, 1568. 1H NMR spec-
trum, δ, ppm: 1.42 m (2H), 1.62 m (6H), and 1.85 m
(4H) (CH2, CH in Ad); 2.46 s (3H, SCH3), 2.49 m (2H,
Ad), 2.91 s (2H, CH2), 7.13 d (1H, Harom, J = 7.4 Hz),
7.26 m (2H, Harom), 7.59 d (1H, Harom, J = 7.4 Hz).
13C NMR spectrum, δC, ppm: 12.21 (SCH3); 27.48,
27.99, 35.00 (CH, Ad); 32.87, 33.85, 36.25, 38.70 (CH2,
Ad, C4); 61.56 (C3); 124.26, 126.68, 128.14, 130.53
(C5, C6, C7, C8); 129.05 135.53 (C4a, C8a); 158.75 (C1).
Mass spectrum, m/z (Irel, %): 297 (43) [M]+, 282 (100)
[M – Me]+, 264 (6), 250 (4) [M – SMe]+, 202 (4), 189
(3), 176 (4), 162 (4), 154 (3), 134 (3), 116 (6), 91 (8),
79 (6), 67 (3). Found, %: C 76.69; H 7.73; N 4.75.
C19H23NS. Calculated, %: C 76.72; H 7.79; N 4.71.
[4′H-Spiro[adamantane-2,3′-isoquinolin]-
1′(2′H)-ylidene]acetamide (IIIb) was synthesized
from 0.94 g (4 mmol) of 2-benzyladamantan-2-ol and
0.34 g (4 mmol) of cyanoacetamide. Yield 0.36 g
(58%), mp 158°C (decomp.; from ethyl acetate). IR
spectrum, ν, cm–1: 3476, 3292, 3212, 3164, 1748,
1
1624, 1604, 1568. H NMR spectrum, δ, ppm: 1.65 m
(8H), 1.91 m (4H), and 2.18 m (Ad); 3.05 s (2H, CH2),
4.91 br.s (2H, NH2), 5.06 s (1H, =CH), 7.13–7.35 m
(3H, Harom), 7.58 d (1H, Harom, J = 7.5 Hz), 10.41 s
(1H, NH). 13C NMR spectrum, δC, ppm: 27.10, 27.1,
35.38 (CH, Ad); 32.68, 33.60, 37.81, 38.42 (CH2, Ad,
C4); 55.34 (C3); 78.52 (CH=); 124.41, 126.52, 129.12,
130.14 (C5, C6, C7, C8); 129.33, 135.01 (C4a, C8a);
153.93 (C1); 173.33 (C=O). Mass spectrum, m/z
(Irel, %): 265 (100) [M – CONH2 + H]+, 250 (8), 236
(3), 222 (19), 208 (9), 196 (7), 184 (16), 170 (30), 157
(22), 144 (32), 115 (16), 91 (9), 77 (7), 65 (2), 41 (5).
Found, %: C 79.92; H 7.89; N 9.05. C20H24N2O. Cal-
culated, %: C 79.89; H 7.84; N 9.08.
Compounds IIIa, IIIb, and IV were synthesized in
a similar way.
Ethyl [4′H-spiro[adamantane-2,3′-isoquinolin]-
1′(2′H)-ylidene]acetate (IIIa) was synthesized from
0.94 g (4 mmol) of 2-benzyladamantan-2-ol and 0.45 g
(4 mmol) of ethyl cyanoacetate. Yield 0.68 g (50%),
1′-Benzylsulfanyl-4′H-spiro[adamantane-2,3′-
isoquinoline] hydrochloride (IV) was synthesized
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

ROZHKOVA et al.
1876
from 0.94 g (4 mmol) of 2-benzyladamantan-2-ol and
0.60 g (4 mmol) of benzyl thiocyanate. After removal
of solvent from the extract, the residue was dissolved
in ethyl acetate, and gaseous hydrogen chloride was
passed through the solution. The precipitate was fil-
tered off and recrystallized from ethanol–ethyl acetate.
Yield 0.56 g (34%), mp 125–130°C. IR spectrum, ν,
This study was performed under financial support
by the President of the Russian Federation (project
no. MK-2198.2008.3), by the Collaboration Program
of the Ural and Siberian Divisions of the Russian
Academy of Sciences, and by the Presidium of the
Russian Academy of Sciences (program no. 18).
1
cm–1: 1646, 1604, 1586, 1544. H NMR spectrum, δ,
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ppm: 1.79 m (10H, Ad), 2.16 br.s (2H, Ad), 3.36 s (2H,
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(3H) (Harom), 8.04 d (1H, Harom, J = 7.8 Hz), 11.90 br.s
(1H, HCl). 13C NMR spectrum, δC, ppm: 26.35, 32.57
(CH, Ad); 32.21, 33.14, 35.91, 37.40, 37.81 (CH2, Ad,
C4, SCH2Ph); 64.99 (C3); 128.11, 128.49, 128.81,
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C25H27NS·HCl. Calculated, %: C 73.23; H 6.88;
N 3.42.
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