Synthesis of 1-adamantyloxyalkanols

Full text of DOI:10.1134/S1070428010110217

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 11, pp. 1741−1742. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.N. Reznikov, M.Yu. Skomorokhov, Yu.N. Klimochkin, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 11,
pp. 1730−1731.
SHORT
COMMUNICATIONS
Synthesis of 1-Adamantyloxyalkanols
A. N. Reznikov, M. Yu. Skomorokhov, and Yu. N. Klimochkin
Samara State Technical University, Samara, 443100 Russia
e-mail: orgchem@samgtu.ru
Received December 22, 2009
DOI: 10.1134/S1070428010110217
The synthesis of biologically active adamantane de-
rivatives that further may be used as drugs against viral
diseases is an urgent problem [1]; mechanism of their
action is related to the blocking of M2 protein serving
as an ion channel of the virus [2]. The high lipophilicity
and bulky structure of the adamantyl group at its intro-
duction into the molecules of various biologically active
compounds significantly modifies their pharmacological
action. In this way the structure was modified of a seies of
antimicrobial, antitumor, immunodepressant, hormonal,
analgesic, antiphlogistic, and neurotropic drugs [1, 3].
It is presumed that the modification of the biological
action is due to the changes in the spatial arrangement,
hydrophobicity and lipophilicity of compounds and to
the facilitation of their transport through the biologic
membranes [4].
scanty. A method was described of adamantyloxypropa-
nol preparation from 1-bromoadamantane and propane-
1,3-diole in the presence of triethylamine [5] and of
adamantyloxyethanol by photochemical reaction of
1-bromoadamantane with ethylene glycol [6], but in the
latter reaction the yield of the target product was very low.
We carried out the synthesis of a series of 1-adaman-
tyloxyalkanols IIIa–IIIg from 1-bromoadamantane (Ia)
and 1-bromo-3-ethyladamantane (Ib) and diols II in the
presence of triethylamine.
1-Adamantyloxyalkanols IIIa–IIIg. A mixture of
70 mmol of bromoderivative Ia or Ib, 0.1 mol of trieth-
ylamine, and 1.5 mol of diol II was boiled at stirring in
an argon atmosphere, then it was cooled and poured into
0.5 l of water. The reaction products were extracted into
chloroform (3 × 50 ml). The organic layer was separated,
washed with a little water, and dried with sodium sulfate.
The solvent was distilled off.
Aiming at the search for new adamantane derivatives
of high antiviral activity and also of lipophilic modifiers
for designing prodrugs of high biologic accessibility we
synthesized a series of adamantyloxyalkanols with vari-
able length of the aliphatic chain permitting changes in
the lipophilicity of compounds obtained in a wide range.
2-(Adamant-1-yloxy)ethanol (IIIa). Yield 82%, mp
38–39°C. Found, %: C 73.26; H 10.25. C12H20O2. Cal-
culated, %: C 73.43; H 10.27. 1H and 13C NMR spectra
are consistent with the published data [6].
The information on preparation methods of adaman-
tyloxyalkanols and on their biological activity is very
4-(Adamant-1-yloxy)butan-1-ol (IIIb). Yield 85%,
nD20 1.5021. 1H NMR spectrum (CDCl3), δ, ppm: 1.58 m
R
R
n
k
HO
O
II
OH
m
Et3N
n
k
O
OH
Br
O
m
IIIa_IIIg
Ia, Ib
I, R = H (a), Et (b); III, R = H: k = 0, m = 0, n = 2 (a), 4 (b); k = 2, m = 1, n = 2 (c); R = Et: k = 0, m = 0, n = 2 (d), 3 (e),
4 (f); k = 2, m = 1, n = 2 (g).
1741

REZNIKOV et al.
1742
(8H, 3CH2, Ad, 2CH2), 1.70 m (6H, 3CH2, Ad), 2.11 m
(3H, 3CH, Ad), 3.05 s (1H, OH), 3.37 t (2H, CH2O,
3JHH 7.0 Hz), 3.55 t (2H, CH2O, 3JHH 7.0 Hz). 13C NMR
spectrum (CDCl3), δ, ppm: 27.86 s (CH2), 30.42 s (CH2),
30.56 s (3CH, Ad), 36.37 s (3CH2, Ad), 41.38 s (3CH2,
Ad), 59.66 s (CH2O), 62.52 s (CH2O), 74.43 s (C, Ad).
Found, %: C 74.60; H 10.74. C14H24O2. Calculated, %:
C 74.95; H 10.78.
2-[2-(Adamant-1-yloxy)ethoxy]ethanol (IIIc). Yield
94%, nD20 1.5015. 1H NMR spectrum (CDCl3), δ, ppm:
1.55–1.65 m (6H, 3CH2, Ad), 1.71–1.81 m (6H, 3CH2,
Ad), 2.22 s (3H, 3CH,Ad), 2.95 s (1H, OH), 3.55–3.75 m
(8H, 4CH2O). 13C NMR spectrum (CDCl3), δ, ppm:
30.50 s (3CH, Ad), 36.40 s (3CH2, Ad), 41.41 s (3CH2,
Ad), 59.60 s (CH2O), 61.91 s (CH2O), 71.19 s (2CH2O),
72.69 s (C, Ad). Found, %: C 69.90; H 10.01. C14H24O3.
Calculated, %: C 69.96; H 10.07.
(2CH2, Ad), 45.78 s (CH2, Ad), 59.91 s (CH2O), 63.73 s
(CH2O), 73.59 s (C, Ad). Found, %: C 76.10; H 11.15.
C16H28O2. Calculated, %: C 76.14; H 11.18.
2-[2-(3-Ethyladamant-1-yloxy)ethoxy]ethanol
1
(IIIg). Yield 93%, nD20 1.5018. H NMR spectrum
(CDCl3), δ, ppm: 0.76 t (3H, CH3, Et, 3JHH 7.0 Hz), 1.15 q
(2H, CH2, Et, 3JHH 7.0 Hz), 1.30–2.26 m (14H,Ad), 3.29 s
(1H, OH), 3.52–3.72 m (8H, 4CH2O). 13C NMR spectrum
(CDCl3), δ, ppm: 7.10 s (CH3, Et), 30.52 s (2CH, Ad),
35.82 s (CH2, Et), 36.02 s (CH2,Ad), 40.84 s (2CH2,Ad),
40.94 s (2CH2, Ad), 45.68 s (CH2, Ad), 59.71 s (CH2O),
61.86 s (CH2O), 71.17 s (CH2O), 72.66 s (CH2O), 73.63 s
(C, Ad). Found, %: C 71.56; H 10.50. C16H28O3. Calcu-
lated, %: C 71.60; H 10.52.
NMR spectra were registered on a spectrometer
BrukerAM-300 at operating frequencies 300.13 (1H) and
75.47 (13C) MHz. The measurements were carried out
without additional references with the stabilization on the
signal of the deuterated solvent. Elemental analysis was
performed on a CHNSO-analyzer EuroVektor EA3000.
2-(3-Ethyladamant-1-yloxy)ethanol (IIId). Yield
90%, nD20 1.5015. 1H NMR spectrum (CDCl3), δ, ppm:
0.78 t (3H, CH3, Et, 3JHH 7.0 Hz), 1.19 q (2H, CH2, Et,
3JHH 7.0 Hz), 1.30–2.25 m (14H, Ad), 2.45 C (1H, OH),
3
3.51 t (2H, CH2O, JHH 5.0 Hz), 3.76 t (2H, CH2O,
ACKNOWLEDGMENTS
3JHH 5.0 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 7.14 s
(CH3, Et), 32.43 s (2CH, Ad), 35.71 s (CH2, Et), 35.97 s
(C, Ad), 36.17 s (CH2, Ad), 40.82 s (2CH2, Ad), 41.02 s
(2CH2, Ad), 45.31 s (CH2, Ad), 60.45 s (CH2O), 63.21 s
(CH2O), 73.51 s (C, Ad). Found, %: C 74.90; H 10.72.
C14H24O2. Calculated, %: C 74.95; H 10.78.
The study was carried out in the framework of the
Federal Central Scientific and Technical Program “Re-
search and development on priority directions of the sci-
entific and technical complex of Russia for 2007–2012”
(State contract no. 02.552.11.7077) and ”Scientific and
pedagogical personnel of the innovational Russia for
2009–2013” (State contract no. P706 of 12.08.2009 and
02.740.11.0394).
3-(3-Ethyladamant-1-yloxy)propan-1-ol (IIIe).
Yield 89%, nD20 1.5020. 1H NMR spectrum (CDCl3), δ,
ppm: 0.75 t (3H, CH3, Et, 3JHH 7.0 Hz), 1.18 q (2H, CH2,
Et, 3JHH 7.0 Hz), 1.30–2.25 m (16H, Ad + CH2), 3.05 s
(1H, OH), 3.65 t (2H, CH2O, 3JHH 6.0 Hz), 3.76 t (2H,
REFERENCES
3
CH2O, JHH 6.0 Hz). 13C NMR spectrum (CDCl3), δ,
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Antiviral Res., 1998, vol. 37, no. 2, p. 83.
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ra, I.N., Aminy s karkasnymi fragmentami i ikh proizvodnye
(Amines with Frame Fragments and Their Derivatives),
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4. Litvinov, V.P., Khim. Geterotsikl. Soedin., 2002, p. 12.
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ton, D.C., J. Am. Chem. Soc., 1976, vol. 98, p. 8135.
ppm: 7.16 s (CH3, Et), 30.58 s (2CH, Ad), 32.35 s (CH2),
35.85 s (CH2, Et), 35.88 s (C, Ad), 36.10 s (CH2, Ad),
40.93 s (2CH2, Ad), 41.06 s (2CH2, Ad), 45.85 s (CH2,
Ad), 60.13 s (CH2O), 63.02 s (CH2O), 73.57 s (C, Ad).
Found, %: C 75.50; H 10.92. C15H26O2. Calculated, %:
C 75.58; H 10.99.
4-(3-Ethyladamant-1-yloxy)butan-1-ol (IIIf). Yield
92%, nD20 1.5019. 1H NMR spectrum (CDCl3), δ, ppm:
0.77 t (3H, CH3, Et, 3JHH 7.0 Hz), 1.15 q (2H, CH2, Et,
3JHH 7.0 Hz), 1.30–2.15 m (16H,Ad + 2CH2), 3.11 s (1H,
OH), 3.45 m (2H, CH2O), 3.61 m (2H, CH2O). 13C NMR
spectrum (CDCl3), δ, ppm: 7.13 s (CH3, Et), 28.06 s
(CH2), 30.55 s (2CH, Ad), 35.85 s (CH2, Et), 35.93 s
(C, Ad), 40.64 s (CH2, Ad), 40.90 s (2CH2, Ad), 40.98 s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 11 2010