Reduction of unsaturated adamantane-containing nitriles

Article abstract of DOI:10.1134/S107036321507004X

The regularities of reduction of adamantane-containing unsaturated nitriles with Raney nickel were studied. It was shown that in the reaction conditions simultaneous reduction of both the double bond and the nitrile group occurs. The reduction of 2-(5-hydroxyadamant-2-ylidene)alkyl nitriles requires a longer time.

Full text of DOI:10.1134/S107036321507004X

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 7, pp. 1602–1605. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © I.A. Novakov, B.S. Orlinson, N.N. Mamutova, E.N. Saveliev, E.A. Potaenkova, 2015, published in Zhurnal Obshchei Khimii, 2015,
Vol. 85, No. 7, pp. 1076–1079.
Reduction of Unsaturated Adamantane-Containing Nitriles
I. A. Novakov, B. S. Orlinson, N. N. Mamutova, E. N. Saveliev, and E. A. Potaenkova
Volgograd State Technical University, ul. Lenina 28, Volgograd, 400005 Russia
e-mail: phanchem@vstu.ru
Received March 5, 2015
Abstract—The regularities of reduction of adamantane-containing unsaturated nitriles with Raney nickel were
studied. It was shown that in the reaction conditions simultaneous reduction of both the double bond and the
nitrile group occurs. The reduction of 2-(5-hydroxyadamant-2-ylidene)alkyl nitriles requires a longer time.
Keywords: adamantane, adamantanone, unsaturated nitriles, reduction, Raney nickel
DOI: 10.1134/S107036321507004X
Adamantane amine derivatives exhibit various
kinds of pharmacological activity [1], and may also be
used as intermediates in the synthesis of polymers with
high performance characteristics [2]. In [3–8] it was
found that 2-substituted adamantanes exhibit a wider
spectrum of biological activity compared to the 1-
substituted derivatives. Thus, spiro[cyclopropane-1,2'-
adamantane]-2-amines are active at micromolar
concentrations against influenza A H2N2 strain in
concentrations 125 times smaller than in the case of
amantadine [3, 4].
diabetes, cardiovascular disease, apoplexy, and certain
types of cancer [5, 6]. Thus, 2-adamantyl derivatives
exhibit high inhibitory activity against 11β-hydroxyl-
steroid dehydrogenase 11β-HSD1 [7]. It should also be
noted that 4-({[2-(adamant-2-yl)ethyl]amino}methyl)-
benzoic acid obtained on the basis of 2-(adamant-2-yl)-
ethylamine exhibits high anticancer activity [8]. In this
regard, developing effective methods for the prepara-
tion of 2-substituted amino derivatives of adamantane
seems an urgent task.
In this work, reduction of adamantane-containing
unsaturated nitriles with nickel-aluminum alloy was
performed to obtain a number of adamant-2-yl
substituted amines IIa–IIf in high yields The synthesis
was carried out as follows.
Recent studies on the therapeutic drugs design
showed that compounds containing bulky lipophilic
groups like adamantyl-containing amides behave as
substances that reduce the risk of developing type 2
R
R
NH2
NiAl2, KOH, H2O
THF
CN
Х
Х
Ia_If
IIa_IIf
R = H, X = H (а); R = CH3, X = H (b); R = C2H5, X = H (c); R = H, X = OH (d); R = CH3, X = OH (e); R = C2H5, X = OH (f).
The reduction of unsaturated adamantane nitriles
was carried out using active hydrogen obtained by
reacting aluminum from Raney nickel-aluminum alloy
(Al : Ni = 50 : 50) with potassium hydroxide. In this
case potassium aluminate formed along with hydrogen
that reduced both the conjugated double bond and the
nitrile group.
The structure of the compounds obtained was con-
firmed by gas chromatography-mass spectrometry, IR
and 1H NMR spectroscopy.
Several methods for the preparation of 2-(adamant-
2-yl)ethylamine have been known. The starting com-
pound was 2-adamantyleneacetonitrile. The reduction
1602

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REDUCTION OF UNSATURATED ADAMANTANE-CONTAINING NITRILES
has been performed with either hydrogen over
palladium under pressure (50 at) to give adamantan-2-
ylacetonitrile and reducing the latter with lithium
aluminum hydride in tetrahydrofuran [9], or by lithium
aluminum hydride in anhydrous tetrahydrofuran to
give a mixture of 2-(adamant-2-yl)ethylamine and (2-
adamantylidene)ethylamine in a weight ratio of 7 : 3,
respectively [10].
8 h with the use of (4–5)-fold molar excess of hyd-
rogen. The reduction of Ia–Ic under the same con-
ditions afforded the target compounds in 97–99%
yield. An increase in the temperature to 65°C resulted
in a significant increase in the reaction rate. In
addition, the yield of the target compounds increased
sharply and amounted to 80–90%. At the same time, it
should be noted that a temperature increase for all the
hydroxy-containing nitriles led to a decrease in selec-
tivity. For example, when reducing nitrile Id 2-(ada-
mant-2-yl)ethylamine, 2-ethyladamantane, and 1,4-di-
oxyadamantane were detected in the reaction mixture
as by-products. The formation of 2-(adamant-2-yl)ethyl-
amine and 2-ethyladamante is due to successive hyd-
rogenolysis of C–O and C–N bonds in the target com-
pound; 1,4-dihydroxyadamantane is formed by hyd-
rolysis of the starting Id at elevated temperature in the
presence of alkali.
Raney nickel is used to reduce various compounds
containing both unsaturated bonds (e.g., adamant-2-
ylideneacetic acid [11]), and various functional groups
(e.g. aliphatic-aromatic unsaturated nitriles) (yield of
17–36%). We investigated the simultaneous reduction
of adamantane unsaturated nitriles with Raney nickel [12].
The reduction process was carried out in the
temperature range of 25–65°C; the reaction time was
4–8 h. It was shown that by using Ia–Ic as a starting
material the reaction proceeds with a satisfactory rate
at room temperature: after 4 hours, the content of
target compounds IIa–IIc was 48–62%. At the same
time, in the case of IId–IIf the synthesis should be
carried out at 65°C for 8 h.
It should also be noted that a strong influence on
the process selectivity and the reaction rate has an
excess of a reducing reagent. Thus, a significant
increase in the yield of the target amine IIa–IIf was
observed when (4–5)-fold molar excess of hydrogen
was used. It was also found that reducing compound Ic
with 10-fold molar excess (compared with the
theoretical) of hydrogen resulted in the formation of
multicomponent mixture containing 11% of 2-methyl-
adamantane. The formation of the latter is due to a
subsequent fragmentation reaction by the action of the
reducing agent.
We found that the reduction of unsaturated
adamantane-containing nitriles with nickel-aluminum
alloy occurred via initial hydrogenation of the double
bond and subsequent reduction of the nitrile group.
The reduction of compound Ia was studied as a model.
According to gas chromatography-mass spectrometry
data, an intermediate B was formed by the
hydrogenation of the double bond, and the product of
reducing the nitrile group with preserved unsaturation
was not detected in the reaction mixture.
In the mass spectra of compounds IId–IIf obtained
peaks of molecular ions of isomeric compounds were
observed. According to [13], it is presumable that 1,4-
disubstituted adamantane derivatives are a mixture of
syn- and anti-isomers in a ratio of 1 : 3 (IId), 1 : 1.2
(IIe), 1 : 1.15 (IIf). Mass spectra of the isomeric
compounds were qualitatively the same, but have
differences in intensity of certain peaks, such as m/e
[M – 18]+.
R
N
Х
B
Depending on the structure of the starting nitrile,
product B content in the reaction mixture ranges from
17 to 34%.
In summary, the introduction of a substituent into
the α-position to the nitrile group led to an increase in
the duration of the reduction of unsaturated ada-
mantane nitriles. The reduction of 2-(5-hydroxyada-
mant-2-ylidene)alkyl nitrile is necessary to carry out at
elevated temperatures.
It should be noted that the introduction of the
substituent into the α-position to the nitrile group (Ib,
Ic) led to a prolongation of the synthesis. Thus, the
reduction of 2-(5-hydroxyadamant-2-ylidene)alkyl nitriles
Id–If proceeded longer. It has been found that the
content of the target compounds IId–IIf did not exceed
3–5% when the reaction was carried out at 25°C for
EXPERIMENTAL
Н1 NMR spectra (ССl4) were recorded on a Varian
Mercury-300 BB spectrometer (300.73 MHz), internal
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NOVAKOV et al.
reference HMDS. Gas chromatography-mass spectro-
metry was performed on a Varian Saturn 2100 T/G
C3900 instrumant. IR spectra were registered on a
FTIR spectrometer Nicolet-6700 (Termo Electron Co.).
2329.5, 2840.8 (CHAd), 2898.9, 2962.1, 3348.2 (NH2).
1Н NMR spectrum, δ, ppm (J, Hz): 0.80 d.t (3Н, СН3,
J 7.1, 0.2), 1.24–1.32 m [1H, CH(C2H5)CH2NH2],
1.44–1.84 m [17Н, NH2, СН(СH2CН3)СН2NH2], 2.75
d.d [2Н, СН(С2Н5)СН2NH2, J 12.4]. Mass spectrum
(EI, 70 eV), m/e (Irel, %): 208 (100), 207 (10) [M], 192
(2), 178 (17), 177 (14), 176.5 (1), 162 (8), 161.1 (12),
135 (8).
Nitriles Ia–If were prepared by the procedure
described in [10].
2-(Adamant-2-yl)ethylamine (IIa). To a solution
of 8.9 g (0.052 mol) of 2-adamantylideneacetonitrile
Ia in 110 mL of THF were added with stirring 7.48 g
(0.13 mol) of KOH and 110 mL of water. Then 33.7 g
(0.624 g-atom Al) of Raney Ni/Al-alloy (Ni : Al = 50 : 50)
was added in portions within 4 h while maintaining
moderate gas evolution. The reaction mixture was
refluxed for 3 h. The precipitate was filtered off and
washed with THF. The aqueous layer was extracted
with toluene (3 × 100 mL), the organic phase was
evaporated, and the residue was distilled in a vacuum.
Yield 8.7 g (0.048 mol, 93%), bp 98–102°C (4 mmHg).
IR spectrum, ν, cm–1: 1013.6, 1042.4, 1065.1, 1099.3,
1214.8, 1309.5, 1353.5, 1452.2, 1469.4, 1605.4, 1652.9,
2745.7, 2805.4, 2848.4 (CHAd), 2893.7, 3348.2 (NH2).
1H NMR spectrum, δ, ppm: 0.77 s (2Н, NH2), 1.22 m
(1H, CHAd), 1.42–1.80 m (17H, CH2CH2NH2, Ad),
2.57–2.64 m (2Н, СН2СН2NH2). Mass spectrum (EI,
70 eV), m/e (Irel, %): 180 (100) [M]+, 179.3 (10) [M],
178.3 (5), 176.5 (1), 175.7 (1), 105.2 (1).
4-(2-Amino)ethyladamant-1-ol (IId) was prepared
similarly from 10.7 g (0.052 mol) of (5-hydroxyada-
mant-2-ylidene)acetonitrile Id, 33.7 g (0.624 g-atom Al)
of Raney alloy and 7.48 g (0.13 mol) of KOH. Yield
9.1 g (0.047 mol, 90%). IR spectrum, ν, cm–1: 922.3,
1013.8, 1042.1, 1068.3, 1218.1, 1309.5, 1353.5, 1452.2,
1469.4, 1607.4, 1652.1, 2329.5, 2648.7, 2701.5, 2745.7,
1
2805.4 (CHAd), 2912.0, 3348.2 (NH2). Н NMR spec-
trum, δ, ppm (J, Hz): 0.89–0.94 m (3Н, NH2, CHAd),
1.15–1.16 m (2H, CH2CH2NH2), 1.33–1.53 m (16H,
Ad), 2.02 s (1Н, OH), 2.25–2.31 d.t (2Н, СН2СН2NH2,
J 7.1, 0.9). Mass spectrum (EI, 70 eV), m/e (Irel, %):
196.3 (6) [M]+, 195.3 (41) [M], 177 (14), 176 (100)
[M – 17]+, 162 (8), 161.1 (12), 133.2 (9).
4-(1-Aminopropan-2-yl)adamantan-1-ol (IIe) was
prepared similarly from 10.7 g (0.052 mol) of 2-(5-
hydroxyadamant-2-ylidene)propanenitrile Ie, 33.7 g
(0.624 g-atom Al) of Raney alloy and 7.48 g
(0.13 mol) of KOH. Yield 9.9 g (0.047 mol, 91%). IR
spectrum, ν, cm–1: 810.0, 922.3, 965.3, 1054.6, 1091.7,
1151.7, 1303.3, 1339.8, 1451.1, 1596.7, 1665.7, 2912.0
2-(Adamant-2-yl)propan-1-amine (IIb) was pre-
pared similarly from 9.7 g (0.052 mol) of 2- (adamant-
2-ylidene)propionitrile Ib, 33.7 g (0.624 g-atom Al) of
Raney alloy and 7.48 g (0.13 mol) of KOH. Yield 9.6 g
(0.050 mol, 96%), bp 115–118°C (4 mmHg). IR spec-
trum, ν, cm–1: 932.8, 977.0, 94.8, 1043.3, 1061.4,
1099.0, 1314.6, 1354.3, 1452.2, 1469.4, 1605.4, 1653.0,
2329.5, 2840.8 (CHAd), 2898.7, 2960.1, 3346.2 (NH2).
1Н NMR spectrum, δ, ppm (J, Hz): 0.70 s (2Н, NH2),
0.81–0.83 d (3Н, СН3, J 6.4), 1.27 d (1Н, CHAd, J
10.7) 1.44 d (2H, СHAd, J 12.0), 1.617–1.815 m (14H,
Ad), 2.35 d.d [1Н, СН(СН3)СН2NH2, J 12.6, 7.1], 2.64
d.d [1Н, СН(СН3)СН2NH2, J 12.4, 3.0]. Mass spec-
trum (EI, 70 eV), m/e (Irel, %): 194.9 (6) [M]+, 194 (41)
[M], 177 (14), 177 (14) [M – 17]+, 176 (100) [M – 17],
162 (8), 161.1 (12), 133.2 (9).
1
(CHAd), 3507.8 (NH2). Н NMR spectrum, δ, ppm
(J, Hz): 0.83–0.84 d (3Н, СН3, J 6.6), 0.85–2.08 m
[19Н, NH2, CHAd, OH, СН(СН3)СН2NH2], 2.36–2.44
d.d [1Н, СН(СН3)СН2NH2, J 12.6, 7.1] 2.69–2.77 d.d
[1Н, СН(СН3)СН2NH2, J 12.4, 3.0]. Mass spectrum
(EI, 70 eV), m/e (Irel, %): 210.2 (100) [M]+, 209.3 (9)
[M], 192.3 (11), 191.3 (7), 190.4 (5).
4-(1-Aminobut-2-yl)adamantan-1-ol (IIf) was
prepared similarly from 11.3 g (0.052 mol) of 2-(5-
hydroxyadamant-2-ylidene)butanenitrile Ie, 33.7 g of
(0.624 g-atom Al) of Raney alloy and 7.48 g
(0.13 mol) of KOH. Yield 10.7 g (0.048 mol, 93%). IR
spectrum, ν, cm–1: 961.3, 1054.6, 1091.7, 1154.7, 1303.3,
1339.8, 1451.1, 1596.7, 1665.7, 2912.0 (CHAd), 3515.8
2-(Adamant-2-yl)butan-1-amine (IIc) was pre-
pared similarly from 10.5 g (0.052 mol) of 2-(adamant-
2-ylidene)butyronitrile Ic, 33.7 g (0.624 g-atom Al) of
Raney alloy and 7.48 g (0.13 mol) of KOH. Yield 9.7 g
(0.047 mol, 90%), bp 126–128°C (4 mmHg). IR spec-
trum, ν, cm–1: 934.8, 1013.6, 1042.4, 1065.1, 1099.3,
1214.8, 1309.5, 1353.5, 1452.2, 1469.4, 1605.4, 1652.9,
1
(NH2). Н NMR spectrum, δ, ppm (J, Hz): 0.81–0.84
d.t (3Н, СН3, J 7.1), 1.24–1.32 m [1H, CH(C2H5)·
CH2NH2], 1.44–1.84 m [17Н, NH2, СН(СH2CН3)·
СН2NH2], 2.1 s (1H, OH), 2.60–2.80 d.d [2Н, СН(С2Н5)·
СН2NH2, J 12.4, 3.0]. Mass spectrum (EI, 70 eV), m/e
(Irel, %): 224.1 (15) [M]+, 223.2 (100), 206.8 (3), 206.2
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7. Su, X., Vicker, N., Trusselle, M., Halem, H., Culler, M.D.,
and Potter, B.V.L., Mol. Cell. Endocrinol., 2009, vol. 301,
nos. 1–2, p. 169. DOI: 10.1016/j.mce.2008.08.006.
(1), 194.2 (6), 193.2 (4), 192.3 (12), 188.5 (2), 187.1
(2), 178 (3), 177 (18), 134 (6), 133.2 (11).
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