Chemical Transformations of Tetracyclo[3.3.1.13,7.01,3]decane (1,3-Dehydroadamantane): VII. Reaction of 1,3-Dehydroadamantane with Alkanediols and Amino Alcohols

Article abstract of DOI:10.1134/S1070428018120035

The reaction of 1,3-dehydroadamantane with C₂–C₆ α,ω-alkanediols selectively afforded ω-(adamantan- 1-yloxy)alkan-1-ols in 87–94% yield. The reaction of 1,3-dehydroadamantane with ω-aminoalkan-1- ols (2-aminoethanol and 3-aminopropan-1-ol) gave mixtures of addition products through the oxygen and nitrogen atoms, which can be readily separated by fractional vacuum distillation or crystallization.

Full text of DOI:10.1134/S1070428018120035

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 12, pp. 1760–1763. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © G.M. Butov, V.M. Mokhov, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 12, pp. 1746–1749.
Chemical Transformations of Tetracyclo[3.3.1.13,7.01,3]decane
(1,3-Dehydroadamantane): VII.1 Reaction of 1,3-Dehydro-
adamantane with Alkanediols and Amino Alcohols
G. M. Butova, b* and V. M. Mokhovb
a Volzhsky Polytechnic Institute (Branch), Volgograd State Technical University,
ul. Engel’sa 42a, Volzhsky, Volgograd oblast, 404121 Russia
*e-mail: butov@volpi.ru
b Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
Received May 16, 2018; revised September 12, 2018; accepted September 19, 2018
Abstract—The reaction of 1,3-dehydroadamantane with C2–C6 α,ω-alkanediols selectively afforded ω-(ada-
mantan-1-yloxy)alkan-1-ols in 87–94% yield. The reaction of 1,3-dehydroadamantane with ω-aminoalkan-1-
ols (2-aminoethanol and 3-aminopropan-1-ol) gave mixtures of addition products through the oxygen and
nitrogen atoms, which can be readily separated by fractional vacuum distillation or crystallization.
DOI: 10.1134/S1070428018120035
ω-(Adamantan-1-yloxy)- and ω-(adamantan-1-yl-
amino)alkan-1-ols are convenient intermediate prod-
ucts for the introduction of an adamantyl fragment and
an oxygen-containing spacer into pharmacophoric
molecules. In particular, 2-(adamantan-1-yloxy)ethanol
was used as precursor to 2-(adamantan-1-yloxy)-5-
[hydroxy(tetrahydrofuran-2-yl)amino]isoxazole-3-car-
boxylate tested as a lipoxygenase inhibitor [2], as well
as to synthesize carnitine acyltransferase-1 (CAT-1)
inhibitors [3]. The synthesis of tosyloxymethylphos-
phonic acid esters, key intermediate products for the
preparation of nucleoside phosphonate antiviral agents,
on the basis of 2-, 3-, and 4-(adamantan-1-yloxy)-
alkan-1-ols has been described in [4–6].
ethylene glycol dimethyl ether [10]. 3-(Adamantan-1-
yloxy)propan-1-ol was also synthesized by reaction of
1-(allyloxy)adamantane with the BH3–Me2S complex
in THF, followed by treatment with sodium hydroxide
and hydrogen peroxide [10]. Thus, the known methods
of synthesis of ω-(adamantan-1-yloxy)alkan-1-ols
require elevated temperature (>110°C), long reaction
times (5–24 h), and the use of specific reagents.
We have developed a selective procedure for the
synthesis of C2–C6 ω-(adamantan-1-yloxy)alkan-1-ols
from 1,3-dehydroadamantane (1,3-DHA, tetracyclo-
[3.3.1.13,7.01,3]decane) and the corresponding α,ω-al-
kanediols. As shown previously, 1,3-DHA (1) is
a highly reactive propellane capable of reacting with
activated C–H bonds of various organic compounds
[11], as well as with various NH acids [12].
n-(Adamantan-1-yloxy)alkan-1-ols were used to
synthesize supramolecular compounds, e.g., complexes
with β-cyclodextrin (n = 2) [7], or novel water soluble
rhenium-containing dendrimers as potential radio-
therapeutic agents (n = 3) [8].
There are a few data on reactions of 1,3-DHA with
hydroxy compounds. In particular, reactions of 1 at
fairly acidic O–H bonds of carboxy (acetic acid [13]
and unsaturated acids [14]) and peroxycarboxy groups
[15] have been reported. Propellane 1 readily and
selectively reacted with mono- and dihydric phenols
[16, 17] to give the corresponding adamantyl phenyl
ethers.
n-(Adamantan-1-yloxy)alkan-1-ols (n = 2–4) were
previously obtained by reaction of 1-bromoadaman-
tane with the corresponding glycols on heating in
an argon atmosphere for 24 h in the presence of
an equimolar amount of triethylamine [6, 8, 9], for 5 h
at 100°C in the presence of 1,8-diazabicyclo[5.4.0]un-
dec-7-ene and triethylamine [6], or for 24 h in di-
1,3-Dehydroadamantane (1) reacted with methanol
in the presence of a catalyst [18], as well as with
peroxy alcohols in which the hydroxy group is activat-
* For communication VI, see [1].
1760

CHEMICAL TRANSFORMATIONS OF TETRACYCLO[3.3.1.13,7.01,3]DECANE ... VII.
1761
Scheme 1.
OH
+
( )n
OH
HO
( )n
O
1
2a–2e
3a–3e
n = 1 (a), 2 (b), 3 (c), 4 (d), 5 (e).
ed due to the effect of alkylperoxy group [19].
However, the use of an acid catalyst is not always
appropriate because of the possibility of dehydration of
alcohols and reduction of the reaction selectivity.
Therefore, in this work the reactions of 1 with diols
2a–2e were carried out in the absence of a catalyst in
diethyl ether at 35–40°C (2–3 h), the 1-to-2 molar ratio
being 1:(2.7–3.7) (Scheme 1).
ω-aminoalkan-1-ols in the presence of triethylamine
(10 h at 120°C), but the yield was low ~13% [22, 23],
whereas the major products were ω-(adamantan-1-
ylamino)alkan-1-ols (87%) [23]. Another method of
synthesis of ω-(adamantan-1-ylamino)alkan-1-ols is
based on the reaction of adamantan-1-amine hydro-
chloride with ω-bromoalkan-1-ols in the presence of
sodium hydrogen carbonate on heating [24]. These
reactions require elevated temperature and long time.
When the reaction was complete, compound 3a–3e
was separated from excess diol 2a–2e by vacuum
distillation. The structure of 3a–3e was confirmed by
1H NMR and mass spectra. Analysis of the reaction
mixtures by gas chromatography–mass spectrometry
showed high chemoselectivity of the reaction. The
properties and spectral characteristics of known com-
pounds were consistent with published data [6, 9, 10].
Thus, the reactions occurred under mild conditions in
a shorter time with high selectivity.
In order to eliminate the above noted disadvantages
and compare the reactivity of O–H and N–H bonds in
ω-aminoalkan-1-ols, we studied the reactions of pro-
pellane 1 with 2-aminoethan-1-ol (4a) and 3-amino-
propan-1-ol (4b). The reactions were carried out using
10 equiv of the amino alcohol. According to the
GC/MS data, the products were mixtures of approxi-
mately equal amounts of O- and N-alkylation products
5a, 5b and 6a, 6b. The product mixtures were readily
separated by fractional distillation under reduced pres-
sure. Crystalline amino alcohols 6a and 6b were
additionally purified by recrystallization.
Apart from ω-(adamantan-1-yloxy)alkan-1-ols,
important precursors to biologically active adamantane
derivatives are ω-(adamantan-1-ylamino)alkan-1-ols
and ω-(adamantan-1-yloxy)alkan-1-amines which
provide a nitrogen-containing spacer between the
adamantane fragment and pharmacophore such as urea
or thiourea residue. These compounds were used to
obtain soluble epoxide hydrolase (sEH) inhibitors
[20, 21], and an influence of the spacer structure on the
activity (IC50), solubility in water, and melting point of
the inhibitors was revealed.
The formation of mixtures of O- and N-alkylation
products in the reaction of 1,3-DHA with ɷ-amino-
alkan-1-ols attracts interest since the OH proton is
much more mobile than protons of the amino group, so
that predominant or even exclusive addition of pro-
pellane to the O–H bond could be expected. Presum-
ably, the reason is strong hydrogen bonding in
ɷ-aminoalkan-1-ol molecules, which equalizes to
some extent the reactivities of the O–H and N–H
groups. Probably, the attack of 1,3-DHA is directed not
at a particular O–H or N–H bond but at associated
OH···NH groups. The formation of mixture of O- and
N-alkylation products was also observed in the reac-
tions of amino alcohols with 1-bromoadamantane [22].
Like ω-(adamantan-1-yloxy)alkan-1-ols, reactions
of 1-haloadamantanes with amino alcohols are widely
used to obtain ω-(adamantan-1-ylamino)alkan-1-ols.
However, in most cases these reactions are not selec-
tive. ω-(Adamantan-1-yloxy)alkan-1-amines can be
obtained by reaction of 1-bromoadamantane with
Scheme 2.
NH2
+
+
( )n
NH2
OH
HO
( )n
( )n
O
N
H
1
4a, 4b
5a, 5b
6a, 6b
n = 1 (a), 2 (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 12 2018

BUTOV, MOKHOV
1762
Thus, on the basis of the reaction of 1,3-dehydro-
(42), 69.1 (63), 41.1 (30). Found, %: C 75.46; H 10.93.
adamantane with α,ω-alkanediols and ω-aminoalkanols
we have developed a one-step procedure for chemo-
selective introduction of an adamantan-1-yl substituent
into molecules of difunctional compounds in 87–94%
(α,ω-alkanediols) and 39–44% yield (ω-amino-
alkanols).
C15H26O2. Calculated, %: C 75.58; H 10.98. M 238.36.
6-(Adamantan-1-yloxy)hexan-1-ol (3e) was
synthesized from 2 g (0.015 mol) of 1 and 5.3 g
(0.045 mol) of 2e. Yield 3.4 g (0.0135 mol, 90%),
viscous liquid. Mass spectrum, m/z (Irel, %): 252.3 (2)
[M]+, 196.1 (4), 177.2 (5), 165.2 (4), 151.1 (7) [AdO]+,
135.2 (100) [Ad]+, 117.0 (40), 95.1 (99), 83.1 (61),
55.1 (55), 41.1 (25). Found, %: C 76.40; H 11.23.
C16H28O2. Calculated, %: C 76.14; H 11.18. M 252.38.
EXPERIMENTAL
The mass spectra were recorded on an Agilent GC
7820/MSD 5975 instrument (HP-5MS quartz capillary
column, 30 m; carrier gas helium; oven temperature
programming from 80 to 280°C; injector temperature
2-(Adamantan-1-yloxy)ethan-1-amine (5a) and
2-(adamantan-1-ylamino)ethan-1-ol (6a). A mixture
of 2 g (0.015 mol) of 1,3-DHA and 9.2 g (0.15 mol) of
2-aminoethanol (4a) was heated for 1 h at 60–70°C.
Excess 2-aminoethanol (4a) was distilled off under
reduced pressure, and the residue was subjected to
vacuum distillation to collect fractions with bp 120–
122°C (2 mm) (5a) and 139–142°C (2 mm) (6a). Yield
of 5a 1.4 g (0.007 mol, 49%), nD20 = 1.4567. Mass
spectrum, m/z (Irel, %): 195.3 (5) [M]+, 164 (75) [M –
CH2OH]+, 135.1 (100) [Ad]+, 107.1 (10), 93.2 (18),
79.0 (20), 44.0 (11). Compound 6a was purified by
recrystallization from benzene. Yield 1.3 g (0.006 mol,
44%), mp 98–99°C; published data [23]: mp 97–99°C.
1
250°C). The H NMR spectra were measured on
Bruker DRX 500 (500.13 MHz) and Varian Mercury-
300 (300 MHz) spectrometers using DMSO-d6 as
1
solvent; the H chemical shifts are given relative to
tetramethylsilane. The elemental analyses were ob-
tained with a Perkin Elmer 2400 Series II analyzer.
2-(Adamantan-1-yloxy)ethanol (3a). A mixture of
2 g (0.015 mol) of 1,3-dehydroadamantane (1) and 3 g
(0.05 mol) of ethane-1,2-diol (2a) in 10 mL of diethyl
ether was heated for 1 h at 35°C. The solvent was dis-
tilled off, excess diol 2a was removed under reduced
pressure, and the residue was purified by vacuum
distillation. Yield 2.7 g (0.014 mol, 93%), viscous
liquid which crystallized on storage, mp 38–39°C [9].
3-(Adamantan-1-yloxy)propan-1-amine (5b) and
3-(adamantan-1-ylamino)propan-1-ol (6b) were syn-
thesized in a similar way from 2 g (0.015 mol) of 1 and
11.3 g (0.15 mol) of 3-aminopropan-1-ol (4b). Yield
of 5b 1.3 g (0.006 mol, 42%). Yield of 6b 1.2 g
(0.0058 mol, 39%), mp 94–95°C; published data [23]:
mp 93–95°C.
Compounds 3b–3e were synthesized in a similar
way.
3-(Adamantan-1-yloxy)propan-1-ol (3b) was
synthesized from 2 g (0.015 mol) of 1 and 3.8 g
(0.05 mol) of 2b. Yield 2.7 g (0.013 mol, 87%),
viscous liquid. Mass spectrum, m/z (Irel, %): 210.3 (3)
[M]+, 179.2 (11), 151.1 (15) [AdO+], 135.2 (100)
[Ad+], 117.1 (41), 104.0 (36), 95.1 (99), 79.0 (42), 41.1
(30). The 1H NMR spectrum of 3b was consistent with
that given in [9].
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation in the framework of the base part
of state assignment for 2017–2019 (project
no. 4.7491.2017/BCh, publication no. 4.7491.2017/8.9)
using the equipment purchased according to the
Program for Strategic Development of Volgograd State
Technical University in 2012–2016.
4-(Adamantan-1-yloxy)butan-1-ol (3c) was
synthesized from 2 g (0.015 mol) of 1 and 4.5 g
(0.05 mol) of 2c. Yield 3.2 g (0.014 mol, 94%), nD20
=
1.5024; published data [6]: nD20 = 1.5021. Mass spec-
trum, m/z (Irel, %): 224 (12) [M + 2]+, 207 (1)
[M – OH]+, 135 (100) [Ad]+.
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