Condensation of adamantanone with methylene-active compounds

Article abstract of DOI:10.1134/S1070427213030191

A convenient method was developed for the preparation of potentially bioactive substances with 2-adamantyl radical and of intermediates for their synthesis. Condensation of adamantanone with methylene-active compounds was performed, and the reaction features were determined.

Full text of DOI:10.1134/S1070427213030191

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2013, Vol. 86, No. 3, pp. 404−409. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © Yu.V. Popov, V.M. Mokhov, N.A. Tankabekyan, 2013, published in Zhurnal Prikladnoi Khimii, 2013, Vol. 86, No. 3, pp. 435−440.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Condensation of Adamantanone
with Methylene-Active Compounds
Yu. V. Popov, V. M. Mokhov, and N. A. Tankabekyan
Volgograd State Technical University, Volgograd, Russia
e-mail: xseoz@yandex.ru
Received July 12, 2012
Abstract—A convenient method was developed for the preparation of potentially bioactive substances with
2-adamantyl radical and of intermediates for their synthesis. Condensation of adamantanone with methylene-active
compounds was performed, and the reaction features were determined.
DOI: 10.1134/S1070427213030191
Chemistry of polyhedrane compounds, especially
of those containing adamantyl radical, attracts much
researchers’ attention. It is known that a wide series
of adamantane derivatives exhibit various kinds of
biological activity [1]; some of them are included in the
catalog of the Ministry of Public Health of the Russian
Federation and are produced under various trade names.
In particular, nitrogen-containing adamantane derivatives
exhibit biological activity and are used as antiviral
drugs (Remantadine, Midantane, Adapromine, etc.).
The adamantane derivatives bearing a substituent at
the methylene carbon atom (2-position) are often more
promising from the viewpoint of biological activity
than the derivatives substituted at the methine atom
(1-position) [2]. Thus, search for routes to 2-substituted
adamantane derivatives is a topical problem.
which exhibits the properties of dopamine release
stimulant and ligase inhibitor, was shown to be topical.
2-(Adamantylidenemethyl)quinoline can exhibit the
same properties, acting, in particular, as taurine inhibitor.
4-Adamantylidene-3-methyl-1-phenylpyrazolidin-5-one
may also be of considerable interest.
The anticipated practical significance of these
compounds was confirmed by Zoidis et al. [3], who
studied the synthesis and biological activity of 1- and
2-substituted amino derivatives of adamantane. They
showed, in particular, that adamantane-containing
derivatives of pyrrolidine, oxazolone, pyrazolone,
pyrazolinethione, and cyclopentylamine exhibit antiviral
activity toward influenza A viruses and kill parasitic
microorganisms trypanosomes. Adamantane-substituted
pyrrolidine exhibits 4 times higher antiviral activity than
Amantadine and Remantadine do, and toward African
blood trypanosomes the corresponding substituted
oxazolone is 3 times more active than Remantadine and
50 times more active than Amantadine [3].
The goal of this work was the development of
convenient methods for preparing these compounds,
based on condensation of adamantanone with various CH
acids, and study of further transformations of the products
obtained into amine.
Therefore, it is topical to search for procedures for
adamantane functionalization with the formation of a
new C–C bond in the 2-position of the adamantyl group.
To choose the structure of the target products
and plan the routes of their synthesis, the probable
biological activity of a series of 2-substituted adamantane
derivatives was predicted. The development of
procedures for preparing 2-(2-amino)ethyladamantane,
It is known that condensation of adamantanone
with CH acids is a convenient method for introducing
a side carbon into 2-position of the adamantyl group.
404

CONDENSATION OF ADAMANTANONE
405
Data on reactions of adamantanone with malonic acid
mononitrile derivatives CNCH2COX (Х = ОН, ОМе,
ОЕt, NH2) with the formation of the corresponding
adamantylidenemalonic acid derivatives are reported in
[4]. Reactions of adamantanone with potassium or sodium
cyanide and morpholine or ethyl 2-aminopropionate in
DMSO yield 2-morpholino-2-cyanoadamantane and
2-cyano-2-(1-ethoxycarbonylethylamino)adamantane,
respectively [5, 6]. 2-Benzylamino-2-cyanoadamantane
can be prepared in 67% yield by the reaction of
adamantanone with benzylamine and trimethylsilyl
cyanide [7]. However, published data on condensation
of adamantanone with ketones and carboxylic acid
derivatives are virtually lacking.
and relatively difficult availability of certain chemicals.
An attempt was made to optimize the synthesis with the
aim to simplify it and make preparation of the target
product cheaper. In particular, dimethyl sulfoxide was
used instead of 18-crown-6 as cosolvent for KОН. Despite
the absence of the crown ether, almost quantitative yield
of adamantylideneacetonitrile IIIa was attained in 4 h.
An attempt to perform the reaction under heterogeneous
conditions without DMSO was also successful, but the
yield of IIIa in 6 h was lower, about 70% (the remainder
was unchanged adamantanone).
Replacement of KОН by more readily available NaOH
in the presence of DMSO showed that NaOH was also
suitable, but quantitative yield of the desired nitrile was
not attained. Finally, the worst result (no more than 30–
40% yield of IIIa) was obtained when the condensation
was performed in the presence of NaOH without dimethyl
sulfoxide. It should be noted, however, that the low yield
in this synthesis is not of crucial importance, because
the unchanged adamantanone can be fully regenerated
and the cost of the other chemicals is relatively low.
The improved procedure appeared to be also suitable
for preparing other adamantyl-containing unsaturated
nitriles of similar structure. In particular, the products of
the condensation of adamantanone I with propionitrile
IIb and butyronitrile IIc (compounds IIIb and IIIc) were
obtained in 65–70% yields:
This study deals with crotonic condensation of
adamantanone with ketones and aliphatic carbonitriles
in the presence of strong bases and acid catalysts, and
also with condensation of adamantanone with some
heterocyclic CH acids.
As shown previously [8], the reaction of adamantanone
with acetonitrile in the presence of finely divided KOH
and 18-crown-6 as catalyst yields the unsaturated nitrile,
and the same reaction performed in the presence of
NaH in dimethyl sulfoxide yields 2-hydroxyadamant-2-
ylacetonitrile.
However, implementation of this route to unsaturated
nitriles of the adamantane series is restricted by high cost
Products IIIb and IIIc were purified by vacuum
distillation. Despite the fact that these substances are
structural analogs of readily polymerizing acrylonitrile,
owing to the steric effect of the adamantyl group they are
thermally stable and are distilled without polymerization
or decomposition.
adamantylideneacetonitrile) at 4.89 ppm.
Amines of the adamantane series are potential antiviral
agents and antiparkinson drugs [1]. 2-(2-Aminoethyl)
adamantane and its substituted homologs are used for
treatment of neurodegenerative diseases; such compounds
exhibit neuroprotective and positive symptomatic effect
[9]. However, synthesis of aminoalkyladamantanes in
which the alkyl group is bonded to the bridge carbon
atom of adamantane has been developed relatively poorly.
As a route of converting the product of condensation
of I with IIa (compound IIIa) into 2-(2-aminoethyl)
The compositions and structures of IIIa–IIIc were
1
confirmed by Н NMR spectroscopy. In the spectra,
there are characteristic singlets from two kinds of
adamantane CH protons at 1.75 and 2.00 ppm and
a singlet from the =СН–СN proton (in the case of
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POPOV et al.
adamantane IV, we chose reduction of IIIa with lithium
aluminum hydride. It is known [8] that the reduction of
adamantylideneacetonitrile IIIa in diethyl ether involves
only the nitrile group, with the double bond remaining
intact. Therefore, we used as solvent tetrahydrofuran
and performed the reduction at its boiling point for 8 h.
The reduction of adamantylidenebutyronitrile IIIc was
performed similarly:
The reaction products were purified by vacuum
distillation. They were colorless transparent liquids.
A study by gas chromatography–mass spectrometry
showed that the reactions yielded mixtures of saturated
(IVa, IVc) and unsaturated (Va, Vc) amines, with the
prevalence of saturated amines. The IVa : Va ratio was
7 : 3 (total yield 68%), and the IVс : Vc ratio was 1 : 1
(total yield 65%).
The presence of unsaturated amines can be attributed
to the steric effect of the adamantyl group, preventing
1,4-addition of metal hydrides to α,β-unsaturated nitriles,
despite the fact that exhaustive reduction of acrylonitrile
homologs with lithium aluminum hydride has been
reported [9]. Nevertheless, all the amines synthesized
are of interest for further evaluation of their probable
pharmacological activity.
Along with derivatives of carboxylic acids and
carbonyl compounds, there are a number of other
compounds with labile CH protons. As one of such
substances we took 3-methyl-N-phenylpyrazolidin-5-
one VI. First, it was brought into condensation with
adamantanone I in the presence of toluenesulfonic acid in
toluene with azeotropic distillation of the released water.
By this procedure, we obtained condensation product
VII in 60% yield. However, we showed later that these
compounds can react without solvent and catalyst at
temperatures higher than 120°С, with the yield of VII
increasing to 90%:
1
We also used 2-methylquinoline VIII as the starting
methylene-active compound. The condensation of
VIII occurred under relatively severe conditions in the
presence of toluenesulfonic acid; the yield of product IX
did not exceed 50%:
The structure of VII was proved by Н NMR
spectroscopy. In particular, the signal from the СН2
protons of the starting heterocycle VI was absent,
and signals of the adamantyl and phenyl groups were
observed.
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CONDENSATION OF ADAMANTANONE
407
2-Adamantylidenemethylquinoline IX was purified
by vacuum distillation.
toluene under acid catalysis at I : X molar ratio of 1 : 1
and temperature of approximately 110°С for 16–18 h.
Along with the desired adamantylideneacetophenone XI,
acetophenone self-condensation product was obtained (1 :
1 ratio under reaction conditions):
To evaluate the reactivity of adamantanone I in
condensation with ketones, we studied its reaction
with acetophenone X. The reaction was performed in
The mixture was refluxed with stirring for 10 h. After
the reaction completion, 50 ml of water was added, the
mixture was cooled, the solid phase was filtered off, and
product IIIa was dried and recrystallized from hexane.
Yield of adamantylideneacetonitrile IIIa 5.14 g (0.03 mol,
100%), white crystalline substance with characteristic
odor, mp 74–75°С.
1Н NMR spectrum, δ, ppm: 1.75–2.00 m (12H, 2,2-
Ad); 2.52 s (1H, CH, Ad); 3.07 s (1H, CH, Ad); 4.89 s
(1H, CHCN). Mass spectrum, m/e (Irel, %): 174 [M+]
(100), 173 (56), 158 (12), 117 (10).
We found that the reaction was slow and was accompanied
by the release of an equimolar amount of water.
Adamantanone was considerably inferior in reactivity
to both aromatic aldehydes and aliphatic ketones.
Similar results were obtained when the condensation
was performed in ethanol with KOH as catalyst. The
yield of the target product did not exceed 45–50%. The
synthesized compound XI can be used for preparing
amino and heterocyclic derivatives of adamantane.
As starting reagent for preparing 2-hydroxy-2-
aminomethyladamantane XIII we used 2-hydroxy-
2-cyanoadamantane XII synthesized as described in
[10]. 2-Hydroxy-2-cyanoadamantane was reduced to
2-hydroxy-2-aminomethyladamantane with lithium
aluminum hydride in absolute tetrahydrofuran; the
reaction was performed for 6 h:
Example 2. Similarly to example 1, from 5 g
(0.03 mol) of I, 16 ml (0.45 mol) of IIa, and 5.04 g
(0.09 mol) of granulated KOH without DMSO, in the
reaction performed for 10 h, we obtained 3.6 g (0.02 mol,
70%) of IIIa.
Example 3. Similarly to example 1, from 5 g
(0.03 mol) of I, 16 ml (0.45 mol) of IIa, and 3.6 g
(0.09 mol) of granulated NaOH in the presence of 10 ml
of DMSO, we obtained 4.5 g (0.026 mol, 90%) of IIIa.
Example 4. Similarly to example 1, from 5 g
(0.03 mol) of I, 16 ml (0.45 mol) of IIa, and 3.6 g
(0.09 mol) of NaOH without DMSO, we obtained 1.54 g
(0.0089 mol, 30%) of IIIa.
XII
2-Hydroxy-2-aminomethyladamantane can be used
as reagent in synthesis of spiro heterocycles of the
adamantane series. It is also of interest from the viewpoint
of testing for antiviral and antiparkinson activity.
2-Adamantylidenepropionitrile IIIb. Similarly to
example 1, from 3 g (0.02 mol) of I, 10 g (0.18 mol)
of IIb, and 3 g (0.05 mol) of NaOH, we obtained 2.6 g
1
(0.014 mol, 70%) of IIIb. Н NMR spectrum, δ, ppm:
EXPERIMENTAL
1.54–1.72 m (12Н, Ad); 1.83 s (3H, CH3); 2.90 s (1H,
Ad); 3.02 s (1H, Ad). Mass spectrum, m/e (Irel, %): 187
[M+] (100), 172 (28), 133 (14).
Adamantylideneacetonitrile IIIа. Example 1. A
round-bottomed flask equipped with a magnetic stirrer
was charged with 5 g (0.03 mol) of adamantanone I, 16
ml (0.45 mol) of acetonitrile IIa, and 5.04 g (0.09 mol)
of granulated KOH in the presence of 10 ml of DMSO.
2-Adamantylidenebutyronitrile IIIc. Similarly to
example 1, from 3 g (0.02 mol) of I, 10 g (0.15 mol) of
IIc, and 3 g (0.05 mol) of NaOH, after vacuum distillation
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POPOV et al.
1
we obtained 2.6 g (0.013 mol, 65%) of IIIc. Н NMR
spectrum, δ, ppm: 1.05 t (3H, CH3); 1.64–1.74 m (12Н,
Ad); 2.03 q (2H, CH2); 2.87 s (1H, Ad); 3.03 s (1H, Ad).
Example 2. A flask was charged with 3 g (0.02 mol)
of I, 3.3 g (0.02 mol) of VI, and 0.1 g of toluenesulfonic
acid. The mixture was refluxed in toluene with azeotropic
distillation of the released water. After the catalyst
neutralization, solvent removal by distillation, and
recrystallization from hexane, we obtained 3.9 g
(0.015 mol, 60%) of VII.
2-(2-Aminoethyl)adamantane IVa and 2-(2-amino-
ethylidene)adamantane Va. A round-bottomed flask
equipped with a magnetic stirrer was charged with
4 g (0.105 mol) of lithium aluminum hydride, 30 ml
of absolute tetrahydrofuran, and 5 g (0.03 mol) of
adamantylideneacetonitrile IIIa. The mixture was refluxed
with stirring for 8 h. After the reaction completion, 6 ml
of water was added, the precipitate was filtered off,
tetrahydrofuran was distilled off from the filtrate, and the
residue was vacuum-distilled. The mixture of IVa and Va
is a colorless transparent liquid with characteristic amine
odor, bp140–150°С (20 mm Hg).
2-(Adamantylidenemethyl)quinoline IX. A flask
was charged with 2 g (0.013 mol) of I, 3 g (0.02 mol)
of 2-methylquinoline VIII, and catalytic amount of
toluenesulfonic acid. The mixture was heated at 150°С
for 7–10 h. The reaction is accompanied by the release of
0.24 g (0.013 mol) of water.After the reaction completion,
excess 2-methylquinoline VIII was distilled off under
reduced pressure. The product was vacuum-distilled, and
1.8 g (0.0065 mol, 50%) of 2-(adamantylidenemethyl)
quinoline IX was obtained, bp 265°С (20 mm Hg), mp
67–70°С.
Mass spectrum of 2-(2-aminoethyl)adamantane
IVa, m/e (Irel, %): 179 [M+] (1), 175 (76), 148 (13),
135 [С10Н15+] (100), 80 (29); 2-(2-aminoethylidene)
adamantane Va: 177 [M+] (27), 162 (100), 133 (17).
1Н NMR spectrum, δ, ppm: 0.81–2.37 m (12H, Ad);
2.44 s (1H, CH); 4.09 s (1H, CH); 6.2 s (1H, –CH=);
6.13–7.97 m (6H, C7H6N).
1-Amino-2-(2-adamantyl)butane IVc and 1-amino-
2-adamantylidenebutane Vc. A flat-bottomed flask
equipped with a magnetic stirrer was charged with
2 g (0.53 mol) of lithium aluminum hydride, 30 ml
of absolute tetrahydrofuran, and 4 g (0.02 mol) of
2-adamantylidenebutyronitrile IIIc. The mixture
was refluxed with stirring for 8 h. After the reaction
completion, 4 ml of water was added, the precipitate was
filtered off, tetrahydrofuran was distilled off from the
filtrate, and the residue was vacuum-distilled. The mixture
of IVc and Vc is a colorless transparent liquid with
characteristic amine odor, bp 150–155°С (20 mm Hg).
2-Adamantylideneacetophenone XI. To 11.3 g
(0.075 mol) of I, 9.1 g (0.076 mol) of acetophenone
X, 70 ml of toluene, and 0.5 g of toluenesulfonic acid
were added. The mixture was refluxed for 7–8 h until
the equivalent amount of water was released. Then the
mixture was neutralized with a 10% sodium carbonate
solution. The aqueous layer was separated, and
toluene was distilled off from the organic layer. After
fractional distillation of the residue, we obtained 9.05
g of 2-adamantylideneacetophenone XI, bp 253–256°С
Mass spectrum of 1-amino-2-(2-adamantyl)butane
IVc, m/e (Irel, %): 208 [M+] (100), 191 (9), 161 (8);
1-amino-2-adamantylidenebutane Vc: 205 [M+] (21),
189 (32), 176 (100).
1
(25 mm Hg), yield 45%. Н NMR spectrum, δ, ppm:
1.50–2.42 m (14 Н,Ad); 6.47 s (1Н, СО–СН=); 7.30–7.82
m (5Н, С6Н5). Mass spectrum, m/e (Irel, %): 252 [M+]
(48), 251 [М – 1] (100), 105 [C6H5С(О)] (6).
4-Adamantylidene-3-methyl-1-phenylpyrazolidin-
5-one VII. Example 1. A flask was charged with 3 g
(0.02 mol) of I and 3.3 g (0.02 mol) of 3-methyl-N-
phenylpyrazolidin-5-one VI. The mixture was refluxed
for 4 h at 120–130°С. After recrystallization from
n-hexane, 5.3 g (0.02 mol, 90%) of VII was obtained;
yellow crystals, mp 121–123°С.
1Н NMR spectrum, δ, ppm: 1.19–2.07 m (14H, Ad);
2.26 s (3H, CH3); 7.01–7.88 m (5H, Ph).
Mass spectrum, m/e (Irel, %): 306 [M+] (90.6), 265
[М – МеСN] (25.8), 229 [M – C6H5] (6.6), 77 [С6Н5]
(100).
2-Hydroxy-2-aminomethyladamantane XIII.
A solution of 5 g (0.033 mol) of adamantanone
cyanohydrin XII in 30 ml of diethyl ether was added
to a suspension of 2 g (0.053 mol) of lithium aluminum
hydride in 20 ml of absolute tetrahydrofuran. The
mixture was refluxed with stirring for 6 h, after which it
was cooled, and the reduced complex was decomposed
with water (5 ml) and 3 ml of 20% alkali to coagulate
the precipitate. Then the mixture was separated from the
inorganic precipitate on a Schott filter, the solvent mixture
was distilled off, and the residue was recrystallized from
ether–hexane. Yield of XIII 2.5 g (0.014 mol, 49%),
mp 178–180°С.
IR spectrum, ν, cm–1: 1820 (С=О), 3358 (NH).
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CONDENSATION OF ADAMANTANONE
409
1Н NMR spectrum, δ, ppm: 1.35–2.12 m (16Н, Ad,
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CONCLUSION
Condensation of adamantanone with methylene-
active compounds was studied. Convenient procedures
were developed for the preparation of potentially
bioactive substances with the 2-adamantyl radical and
of intermediates for their synthesis. The influence of the
reaction conditions on the product yields was determined.
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kunst, Leipzig: Barth, 1964, 3rd ed.
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Volgogradsk. Gos. Tekh. Univ., Sb Nauchn. Tr., 2005,
issue 2, no. 1, pp. 42–45.
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