Synthesis of adamantyl-containing isothiocyanates

Full text of DOI:10.1134/S1070428015120246

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 12, pp. 1795–1796. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © V.V. Burmistrov, G.M. Butov, D.A. Pitushkin, 2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 12,
pp. 1828–1829.
SHORT
COMMUNICATIONS
Synthesis of Adamantyl-Containing Isothiocyanates
V. V. Burmistrov, G. M. Butov, and D. A. Pitushkin
Volzhsky Polytechnic Institute (Branch), Volgograd State Technical University,
ul. Engel’sa 42a, Volzhskii, Volgograd oblast, 404130 Russia
e-mail: butov@volpi.ru
Received September 14, 2015
DOI: 10.1134/S1070428015120246
1
Adamantyl-containing isothiocyanates are promis-
ing precursors to thioureas that are efficient inhibitors
of mammalian and human soluble epoxide hydrolase
(sEH, EC 3.3.2.10) targeted by therapy of hypertonic,
inflammatory, and pain disorders [1–4]. Thioureas are
also promising as non-peptide inhibitors of plasmino-
gen/urokinase activator (uPA) responsible for the
development of cancer [5].
structure was confirmed by H NMR, IR, and mass
spectra and elemental analyses.
The possibility for variation of the structure of the
adamantane component, as well as easy isolation
procedure, makes the proposed method quite general
and applicable for the preparation of difficultly acces-
sible isothiocyanates of the adamantane series.
1-Isothiocyanatoadamantane (1). Phenyl isothio-
cyanate, 7.84 g (0.058 mol), was added to a solution of
10.57 g (0.07 mol) of adamantan-1-amine in 150 mL
of toluene, and the mixture was heated for 3 h at
110°C. When the reaction was complete, the solvent
was distilled off, and the residue was recrystallized
from ethanol. Yield 11.0 g (80%), mp 167–169°C [9].
1H NMR spectrum, δ, ppm: 1.41–2.18 m (15H).
13C NMR spectrum, δC, ppm: 29.3 (C3, C5, C7),
35.6 (C4, C6, C10), 43.8 (C2, C8, C9), 58.5 (C1), 129.4
(NCS). Mass spectrum, m/z (Irel, %): 193 (10) [M]+,
135 (100) [Ad]+.
Traditional methods of synthesis of 1-adamantyl
isothiocyanate are based on reactions of adamantan-1-
amine with carbon disulfide in the presence of potas-
sium hydroxide (20°C, 12 h) [6], of adamantan-1-
amine with thiophosgene in the presence of potassium
carbonate (25°C, 2 h) [7], of trimethylsilyl isothio-
cyanate with 1-chloroadamantane in the presence of
titanium chloride in methylene chloride (0°C, 3 h) [8],
and of 1-bromoadamantane with potassium thiocya-
nate in dimethylformamide (153°C, 5 h) [9]. However,
these procedures require the use of corrosive and
highly toxic reagents, and the syntheses are multistep.
1-Isothiocyanato-3,5-dimethyladamantane (2).
Phenyl isothiocyanate, 7.84 g (0.058 mol), was added
to a solution of 12.53 g (0.07 mol) of 3,5-dimethyl-
adamantan-1-amine in 150 mL of toluene, and the
mixture was heated for 3 h at 110°C. When the reac-
tion was complete, the solvent was distilled off, and
the product was isolated by vacuum distillation. Yield
10.05 g (65%), bp 141°C (400 Pa) [10]. IR spectrum,
Herein we report on the synthesis of adamantyl-
containing isothiocyanates 1–3 (instead of expected
thioureas) by heating a solution of adamantan-1-amine,
1,3-dimethyladamantan-1-amine, or 1-(1-adamantyl)-
ethan-1-amine with phenyl isothiocyanate in boiling
toluene for 3 h. The products were isolated in 65–80%
yield after recrystallization from ethanol, and their
R
R
NCS
NH2
+
+
NH2
NCS
R
X
R
X
1–3
1, X = bond, R = H; 2, X = bond, R = Me; 3, X = MeCH, R = H.
1795

BURMISTROV et al.
1796
1
ν, cm–1: 2065, 1190, 895, 675. H NMR spectrum, δ,
ppm: 0.82 s (6H), 1.35–2.15 m (13H). Mass spectrum,
m/z (Irel, %): 221 (10) [M]+, 163 (100) [(CH3)2Ad]+,
133 (13) [Ad]+.
This study was performed under financial support
by the Council for Grants at the President of the
Russian Federation (program for state support of young
candidates of science, project no. MK-5809.2015.3).
1-(1-Isothiocyanatoethyl)adamantane (3). Phenyl
isothiocyanate, 7.84 g (0.058 mol), was added to
a solution of 12.53 g (0.07 mol) of 1-(1-adamantyl)-
ethan-1-amine in 150 mL of toluene, and the mixture
was heated for 3 h at 110°C. When the reaction was
complete, the solvent was distilled off, and the residue
was recrystallized from ethanol. Yield 10.8 g (70%),
REFERENCES
1. Hwang, S.H., Wecksler, A.T., Zhang, G., Morisseau, C.,
Nguyen, L.V., Fu, S.H., and Hammock, B.D., Bioorg.
Med. Chem. Lett., 2013, vol. 23, p. 3732.
2. Kodani, S.D. and Hammock, B.D., Drug Metab.
Dispos., 2015, vol. 43, p. 788.
3. Burmistrov, V., Morisseau, C., Lee, K.S.S., Shiha-
dih, D.S., Harris, T.R., Butov, G.M., and Ham-
mock, B.D., Bioorg. Med. Chem. Lett., 2014, vol. 24,
p. 2193.
4. Butov, G.M., Burmistrov, V.V., Danilov, D.V., Pitush-
kin, D.A., Morisseau, C., and Hammock, B.D., Izv.
Akad. Nauk, Ser. Khim., 2015, no. 7, p. 1569.
5. Venkatraj, M., Messagie, J., Joossens, J., Lambeir, A.M.,
Haemers, A., Van der Veken, P., and Augustyns, K.,
Bioorg. Med. Chem., 2012, vol. 20, p. 1557.
6. Takeda, K., Tsuboyama, K., and Takeura, M., Chem.
Pharm. Bull., 1989, vol. 37, p. 2334.
7. Nam, K.D., Han, M., Yoon, J., Kim, E., Cho, S., and
Hahn, H., Bull. Korean Chem. Soc., 2013, vol. 34,
p. 271.
1
mp 141°C. H NMR spectrum, δ, ppm: 1.57 d (3H,
CH3, J = 7.2 Hz), 1.70–1.87 m (15H), 3.44 q (1H, CH,
J = 7.2 Hz). Mass spectrum, m/z (Irel, %): 221 (74) [M]+,
163 (28) [Ad – CH(CH3)]+, 135 (100) [Ad]+. Found,
%: C 70.51; H 8.63; N 6.40; S 14.46. C13H19NS. Cal-
culated, %: C 70.54; H 8.65; N 6.33; S 14.48.
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on a Bruker DRX 500 spectrometer
(500 MHz); tetramethylsilane was used as internal
standard. The mass spectra were obtained on
an Agilent 5975 mass-selective detector coupled with
an Agilent 7820 gas chromatograph (HP-5MS quartz
capillary column, 30 m; carrier gas helium; oven tem-
perature programming from 80 to 280°C; injector
temperature 250°C). The elemental compositions were
determined on a Perkin Elmer 2400 Series II analyzer.
8. Sasaki, T., Nakanishi, A., and Ohno, M., J. Org. Chem.,
1981, vol. 46, p. 5445.
Commercial adamantan-1-amine, 3,5-dimethylada-
mantan-1-amine, 1-(1-adamantyl)ethan-1-amine, and
phenyl isothiocyanate (Aldrich) were used without
additional purification. Toluene and ethanol were dis-
tilled before use.
9. Stetter, J. and Wulff, D., Chem. Ber., 1962, vol. 95,
p. 2302.
10. Klimochkin, Yu.N., Moiseev, I.K., Abramov, O.V.,
Vladyko, G.V., Korobchenko, L.V., and Boreko, E.I.,
Pharm. Chem. J., 1991, vol. 25, no. 7, p. 489.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 12 2015