Adamantylation of carbonitriles with 1,3-dehydroadamantane and its homologs

Article abstract of DOI:10.1134/S1070428014090085

1,3-Dehydroadamantane and its methyl-substituted homologs react with carbonitriles at the α-carbon atom of the latter to give the corresponding α-adamantyl carbonitriles. This reaction provide a convenient one-step procedure for selective synthesis of branched nitriles which are difficult to obtain by traditional procedures.

Full text of DOI:10.1134/S1070428014090085

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 9, pp. 1279–1282. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © V.M. Mokhov, G.M. Butov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 9, pp. 1296–1299.
Adamantylation of Carbonitriles with 1,3-Dehydroadamantane
and Its Homologs
V. M. Mokhova and G. M. Butovb
a Volgograd State Technical University, pr. Lenina 28, Volgograd, 400005 Russia
b Volzhsky Polytechnical Institute (Branch), Volgograd State Technical University,
ul. Engel’sa 42a, Volzhskii, 404131 Russia
e-mail: butov@volpi.ru
Received April 15, 2014
Abstract—1,3-Dehydroadamantane and its methyl-substituted homologs react with carbonitriles at the
α-carbon atom of the latter to give the corresponding α-adamantyl carbonitriles. This reaction provide a con-
venient one-step procedure for selective synthesis of branched nitriles which are difficult to obtain by
traditional procedures.
DOI: 10.1134/S1070428014090085
Adamantyl-containing nitriles are important inter-
mediate products in the synthesis of some biologically
active compounds. Their reduction gives the corre-
sponding amines whose structural analogs exhibit
antiviral and anti-Parkinson activity [1]. In molecules
of most known adamantyl-containing nitriles, the ada-
mantyl radical and cyano group are separated by one
or more methylene groups. Published data on nitriles
of the general formula 1-AdCH(CN)R, where the
1-adamantyl radical is attached to the α-carbon atom
with respect to the cyano group, are few in number.
The first member of the series of such nitriles is
1-adamantylacetonitrile, which is obtained by reaction
of 1-adamantylmethyl p-toluenesulfonate with potas-
sium cyanide in DMF (24 h, 120°C [2]. The most
widely used procedure for the synthesis of adamantyl-
containing nitriles is based on dehydration of the
corresponding carboxylic acid amides [3, 4] which are
prepared in turn from acid chlorides. Phosphorus(III)
chloride and thionyl chloride were used as dehydrating
agents [5]. However, this procedure involves several
steps, and its scope is seriously limited by accessibility
of initial adamantyl-substituted carboxylic acids. The
synthesis of such acids is often laborious. Only three
adamantyl-containing carboxylic acids have been
reported: adamantane-1-carboxylic, 1-adamantylacetic,
and 3-(1-adamantyl)propionic [6, 7].
triles were obtained by reaction of 1-adamantylaceto-
nitrile with methyl iodide [8] or ethyl iodide [9] in the
presence of lithium diisopropylamide or butyllithium
in anhydrous tetrahydrofuran at –78°C [yield 39 (R =
Me) and 97% (R = Et)]. The reaction of 1-adaman-
tylacetonitrile with 11-bromoundec-1-ene in the pres-
ence of lithium diisopropylamide at 0°C afforded
2-(adamantan-1-yl)tridec-12-enenitrile [10]. An at-
tempt to accomplish electrochemical adamantylation
of cinnamonitrile with 1-bromoadamantane resulted in
the formation of an intractable mixture of different
nitriles (yield 15–25%), including 2-(adamantan-1-yl)-
3-phenylpropionitrile (15%) [11].
Thus, the existing methods for the synthesis of
branched α-(adamantan-1-yl) carbonitriles are multi-
step and hence laborious.
Taking into account that the hydrogen atom in the
α-position with respect to the cyano group possesses
acidic properties, it was presumed that this position
can be involved in reactions with bridged [3.3.1]-
propellanes, including 1,3-dehydroadamantane (Ia)
and its homologs, 3-methyl-1,3-dehydroadamantane
(Ib) and 5,7-dimethyl-1,3-dehydroadamantane (Ic).
We previously showed that propellane Ia reacts with
a number of CH acids [12, 13], in particular with
relatively weak ones [14, 15]. There are no published
data on reactions of propellanes with aliphatic nitriles
and structurally related compounds, except for the
reaction of [1.1.1]propellane with cyanogen bromide,
which involved cleavage of the C–Br bond [16].
1-Adamantylacetonitrile was used to synthesize
α-substituted nitriles of the general formula
1-AdCH(CN)R. Branched adamantyl-containing ni-
1279

MOKHOV, BUTOV
In continuation of our studies on the chemical prop-
likely to be determined by steric effect of bulkier
1280
α-naphthyl group which appreciably hinders attack on
molecule Ia. No products of addition to the aromatic
fragments of nitriles IIf and IIg were detected. Intro-
duction of methyl groups into 1,3-dehydroadamantane
molecule did not affect the reactivity of [3.3.1]pro-
pellanes Ib and Ic toward nitriles to an appreciable
extent. Their reactions with nitriles IIh and IIe
afforded 77–79% of α-adamantyl-substituted nitriles
IIIi and IIIj.
erties of bridged [3.3.1]propellanes, we have devel-
oped a new procedure for the synthesis of branched
nitriles containing an adamantyl substituent on the
α-carbon atom (Scheme 1).
Scheme 1.
CN
R3
CN
+
R1
R1
R3
R4
R2
R2
R4
The structure of compounds IIIa–IIIj was con-
1
Ia–Ic
IIa–IIh
IIIa–IIIj
firmed by their IR, H NMR, and mass spectra. In the
I, R1 = H, R2 = H (a), Me (b); R1 = R2 = Me (c); II, R3 =
H, R4 = H (a), Me (b), Et (c), Pr (d), i-Pr (e), Ph (f),
1-naphthyl (g); R3 = R4 = Me (h); III, R1 = R2 = R3 = H,
R4 = H (a), Me (b), Et (c), Pr (d), i-Pr (e), Ph (f),
1-naphthyl (g); R1 = R2 = H, R3 = R4 = Me (h); R1 = H, R2 =
R3 = R4 = Me (i), R1 = R2 = Me, R3 = H, R4 = i-Pr (j).
IR spectra of IIIa–IIIj the C≡N stretching vibration
band was observed in the region 2232–2268 cm–1.
Protons in the adamantane fragment resonated in the
1H NMR spectra as several signals at about δ 1.64 and
2.03 ppm, the α-CH signal appeared at δ 2.5 ppm, and
the α-CH signal of IIIf was a singlet at δ 3.90 ppm.
Initial nitriles IIa–IIi contained both donor (alkyl)
and acceptor substituents (phenyl, 1-naphthyl), so that
their CH acidity varied over a wide range. The reac-
tions of 1,3-dehydroadamantane Ia with nitriles IIa–
IIi were carried out using 3–10 equiv of the latter by
heating the reactants for 8 h at 60–140°C. Reactions of
nitriles with cycloalkanes were not reported. Addition
to the α-carbon atom is typical only for reactive
alkenes in the presence of strongly basic catalysts.
High steric strain of the three-membered ring in
propellanes Ia–Ic allows them to add to nitriles that
are weak CH acids (pKa 25–26 in water) in the absence
of a catalyst under fairly mild conditions.
The yield of (adamantan-1-yl)acetonitrile (IIIa)
was 30%, while the yield of 2-(adamantan-1-yl)-3-
methylbutanenitrile (IIIe) was 92%. Relatively low
yield of IIIa as compared to the addition products of
some β-dicarbonyl compounds [13] or ketones [14] to
compound Ia under analogous temperature conditions
is likely to be determined by the lower CH acidity of
acetonitrile. The direct dependence of the reactivity of
nitriles on their CH acidity may be rationalized as-
suming ionic mechanism of the reaction, where the
rate of addition is directly related to the rate of
deprotonation of CH acid. The addition of Ia to high-
boiling nitriles at 100–110°C was complete in 4–5 h
with high yields (80–92%).
Thus, the proposed procedure for the synthesis of
adamantyl-containing nitriles from propellanes Ia–Ic
is promising, for it ensures preparation of difficultly
accessible branched nitriles with complex structure in
one step and with high yields.
EXPERIMENTAL
1
The H NMR spectra were recorded on Varian
Mercury-300 (300 MHz) and Bruker DRX-500
(500 MHz) spectrometers using hexamethyldisiloxane
as internal reference. The mass spectra (electron
impact, 70 eV) were obtained on a Kratos MS-30
instrument.
(Adamantan-1-yl)acetonitrile (IIIa). A solution of
2 g (0.015 mol) of 1,3-dehydroadamantane (Ia) in
20 mL of anhydrous diethyl ether was added to 6 g
(0.14 mol) of anhydrous acetonitrile (IIa), the solvent
was distilled off, and the mixture was heated for 8 h at
80–82°C. Excess acetonitrile was distilled off, and the
residue was distilled under reduced pressure. Yield
0.8 g (0.0046 mol, 31%), mp 76–78°C; published data
[5]: mp 78°C.
Compounds IIIb–IIIj were synthesized in a similar
way.
2-(Adamantan-1-yl)propanenitrile (IIIb) was
synthesized from 6 g (0.11 mol) of anhydrous propio-
nitrile (IIb) and 2 g (0.015 mol) of propellane Ia; the
mixture was heated at 95–97°C. Yield 2.3 g
The low yield of (adamantan-1-yl)acetonitrile
(IIIa) (pKa of acetonitrile 25) compared to (adaman-
tan-1-yl)phenylacetonitrile IIIf (pKa of IIf 21.9 [17]),
other conditions being similar, is also explained by the
lower CH acidity of acetonitrile. Reduction of the yield
in going from R4 = Ph (IIf) to R4 = 1-naphthyl (IIg) is
1
(0.014 mol, 82%), bp 120–122°C (2 mm). H NMR
spectrum (CCl4), δ, ppm: 1.20 t (3H, CH3, J = 7.6 Hz),
1.52–2.10 m (15H, Ad), 2.31 s (1H, CH). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 9 2014

ADAMANTYLATION OF CARBONITRILES WITH 1,3-DEHYDROADAMANTANE
1281
C 82.44; H 9.98; N 7.21. C13H19N. Calculated, %:
C 82.48; H 10.12; N 7.40.
spectrum (CCl4), δ, ppm: 1.64–2.36 m (15H, Ad),
4.15 s (1H, CH), 7.90–8.60 m (7H, C10H7). Found, %:
C 87.44; H 7.95; N 4.61. C22H23N. Calculated, %:
C 87.66; H 7.69; N 4.65.
2-(Adamantan-1-yl)butanenitrile (IIIc) was syn-
thesized from 30 g (0.15 mol) of butyronitrile (IIc and
2 g (0.015 mol) of compound Ia; the mixture was
heated at 118–120°C. Yield 2.66 g (0.013 mol, 89%),
mp 51–53°C; published data [9]: mp 53–54°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 1.05 t (3H,
CH3, J = 8.7 Hz), 1.46–2.05 m (17H, Ad, CH2), 2.40 s
(1H, CH). Found, %: C 82.73; H 10.43; N 6.84.
C14H21N. Calculated, %: C 82.70; H 10.41; N 6.89.
2-(Adamantan-1-yl)-2-methylpropanenitrile
(IIIh) was synthesized from 10 g (0.145 mol) of iso-
butyronitrile (IIh) and 2 g (0.015 mol) of compound
Ia; the mixture was heated at 105–110°C. Yield 2.55 g
(0.013 mol, 85%), bp 116–118°C (3 mm), mp 84–
1
85°C. H NMR spectrum (DMSO-d6), δ, ppm: 1.02 t
(6H, CH3, J = 12.6 Hz), 1.89–2.35 m (15H, Ad).
Found, %: C 82.65; H 10.26; N 6.94. C14H21N. Cal-
culated, %: C 82.70; H 10.41; N 6.89.
2-(Adamantan-1-yl)pentanenitrile (IIId) was
synthesized from 12 g (0.15 mol) of valeronitrile (IId)
and 2 g (0.015 mol) of compound Ia; the mixture was
heated at 110–115°C. Yield 2.66 g (0.012 mol, 80%),
2-(3-Methyladamantan-1-yl)-2-methylpropane-
nitrile (IIIi) was synthesized from 10 g (0.145 mol) of
nitrile IIh and 2.7 g (0.018 mol) of compound Ib;
the mixture was heated at 100–105°C. Yield 3.4 g
(0.014 mol, 79%), bp 154–156°C (5 mm), mp 75–
1
bp 154–156°C (5 mm), mp 41–42°C. H NMR spec-
trum (DMSO-d6), δ, ppm: 0.92 t (3H, CH3, J =
14.5 Hz), 1.37–1.70 m (16H, Ad, CH2), 12.03 s (3H,
Ad), 2.39 s (1H, CH). Found, %: C 82.83; H 10.73;
N 6.44. C15H23N. Calculated, %: C 82.89; H 10.67;
N 6.44.
1
77°C. H NMR spectrum (CCl4), δ, ppm: 0.80 s (3H,
CH3), 1.19 s (6H, CH3), 1.28–1.62 m (12H, Ad), 2.05 s
(2H, Ad). Found, %: C 82.92; H 10.62; N 6.46.
C15H23N. Calculated, %: C 82.89; H 10.67; N 6.44.
2-(Adamantan-1-yl)-3-methylbutanenitrile (IIIe)
was synthesized from 5 g (0.06 mol) of isovaleronitrile
(IIe) and 2 g (0.015 mol) of compound Ia; the mixture
was heated at 130–140°C. Yield 2.27 g (0.014 mol,
2-(3,5-Dimethyladamantan-1-yl)-3-methyl-
butanenitrile (IIIj) was synthesized from 10 g
(0.121 mol) of nitrile IIe) and 3 g (0.018 mol) of
compound Ic; the mixture was heated at 105–110°C.
Yield 3.4 g (0.014 mol, 77%), bp 160–161°C (5 mm),
mp 44–46°C. 1H NMR spectrum (CCl4), δ, ppm: 0.80 s
(6H, CH3), 1.05–1.12 m (6H, CH3), 1.25–2.39 m (12H,
Ad), 1.45 s (1H, Ad), 1.73 m (1H, CH), 2.13 s (1H,
CHCN). Found, %: C 83.13; H 11.11; N 5.76.
C17H27N. Calculated, %: C 83.20; H 11.09; N 5.71.
1
92%), bp 151–153°C (5 mm), mp 38–39°C. H NMR
spectrum (DMSO-d6), δ, ppm: 0.80 t (6H, CH3, J =
14.9 Hz), 1.50–2.40 m (16H, Ad, CH), 2.33 d (1H,
CHCN, J = 15.8 Hz). Found, %: C 82.82; H 10.51;
N 6.67. C15H23N. Calculated, %: C 82.89; H 10.67;
N 6.44.
2-(Adamantan-1-yl)-2-phenylacetonitrile (IIIf)
was synthesized from 10 g (0.085 mol) of phenylaceto-
nitrile (IIf) and 4 g (0.03 mol) of compound Ia; the
mixture was heated for 4 h at 70–80°C. Yield 6.77 g
(0.027 mol, 90%), bp 173–175°C (3 mm), mp 118–
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