One-stage synthesis of adamantyl-containing α-aminonitriles

Article abstract of DOI:10.1134/S107042801308006X

Reactions of 2-adamantan-2-one, acetone cyanohydrin, and amine lead to the formation of substituted 2-amino-2-cyanoadamantanes. The reaction is of a general character as has been proved by examples on a series of ketones and amines and it proceeds through

Full text of DOI:10.1134/S107042801308006X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 8, pp. 1135−1138. © Pleiades Publishing, Ltd., 2013.
Original English Text © Yu.V. Popov, V.M. Mokhov, N.A. Tankabekyan, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 8, pp. 1153−1156.
One-Stage Synthesis of Adamantyl-Containing α-Aminonitriles
Yu. V. Popov, V. M. Mokhov, and N. A. Tankabekyan
Volgograd State Technical University, Volgograd, 400005 Russia
e-mail: xseoz@yandex.ru
Received January 11, 2013
Abstract—Reactions of 2-adamantan-2-one, acetone cyanohydrin, and amine lead to the formation of substituted
2
-amino-2-cyanoadamantanes. The reaction is of a general character as has been proved by examples on a series of
ketones and amines and it proceeds through the formation from the acetone cyanohydrin and amines of 2-amino-
-cyanopropane derivatives reacting further with the carbonyl compounds.
2
DOI: 10.1134/S107042801308006X
The research in the field of synthesis and studies of the
biological activity of adamantine derivatives substituted
in the position 2 are topical for these substances exhibt
various kinds of biological action and some among
them are used as drugs [1]. The search for the routes
to the synthesis of new adamantane amino derivatives
continues up till now. In particular, recently published
results of investigations on the biological activity of
hydroxyaminoalkyladamantanes substituted in the
position 2 of the adamantly group, structural analogs of
was presumed that the one-stage synthesis of 2-amino-
2-cyanoadamantane derivatives by the direct reaction of
an amine, adamantan-2-one (I), and acetone cyanohydrin
in suitable yields was impossible due to the side reaction
of amine with acetone cyanohydrin with the formation of
the respective 2-amino-2-cyanopropane derivatives [8].
A published information exists on the reactions of car-
bonyl compounds (benzaldehyde, valeraldehyde, cyclo-
hexanone) with amines (benzylamine, ethylenediamine,
piperidine, morpholine) and acetone cyanohydrin in water
or organic solvent with product yields from 13 to 99%
“
rimantadine” pharmaceutical, showed their significant
[9]. However the information on the possible synthesis
antiviralandothertypesofactivity[2, 3]. Initialcompounds
for the synthesis of aminomethyl derivatives are the
corresponding adamantyl-containing α-aminonitriles. The
traditional methods of α-aminonitriles synthesis consist
in the reaction of a carbonyl compound, amine, and
hydrogen cyanide. As a source of the latter alkali metal
cyanides [4] or silyl cyanide [5] are commonly used. The
obvious disadvantage of this method is the application of
highly toxic or fairly inaccessible reagents.
with the use of ketones of polycyclic structure is absent.
We found that adamantyl-containing aminonitriles
formed in yields 65–80% at mixing ketone I, the corre-
sponding amine, and acetone cyanohydrin at 100–120°C
without solvent in the presence of catalytic quantity of
potassium carbonate. In the course of the reaction the
calculated amount of acetone and water was distilled off.
We formerly have developed a procedure for the
preparation of adamantyl-containing aminonitriles un-
derlain by the reaction of 2-cyano-2-hydroxyadamantane
O
+
NRR'
CN
HO
RR'NH+
O
K CO
2
3
CN _
+
H O
2
(
adamantanone cyanohydrin) with ammonia, primary and
_
I
IIа IIe
R = H, R' = Cy (a), CH CH OH (b), Ph (c); R,R' = (CH )
2 5
secondary amines, and also with hydrazines [6]. For the
synthesis of adamantyl-containing α-aminonitriles from
low basic amines of aniline series another route was
developed consisting in the reaction of the correspond-
ing adamantylenimines with acetone cyanohydrin [7]. It
2
2
(
d), (CH ) O(CH ) (e).
2 2 2 2
This reaction is suitable for the preparation both of
1135

1136
POPOV et al.
alkyl- and arylaminonitriles with an adamantyl moiety.
The developed synthetic procedure for preparation of
compounds IIa–IIe is convenient for it is a one-stage
process, requires the use of slight excess of acetone
cyanohydrin and amine, no solvent, and it provides a
possibility to carry out one-pot process and to distill the
product in the same reactor. We demonstrated that the
reaction under study can be applied to the preparation of a
wide range of α-aminonitriles by involving in the syntesis
various initial ketones. In particular, the general character
of the developed synthetic method was confirmed by the
examples of reactions with methyl isobutyl ketone, cyclo-
pentanone, and acetophenone, not described before [9].
Compounds IVa–IVd were purified by distillation,
their structure was confirmed by H NMR spectra, the
1
properties of known compounds were in agreement with
the published data [8]. The reaction of α-aminonitriles
IVa–IVd with adamantanone (I) was carried out at a small
excess of nitriles at heating in the presence of potassium
carbonate. In the course of the reaction an equivalent
amount of acetone was isolated.
R
O
N
R'
CN +
R'
N
O
K CO
2
3
+
CN
R
R4
IIа, IId, IIf
R4
N
2 5
2
R = H, R' = Cy (a), R,R' = (CH ) (d); R = H, R'= CH Ph (f).
O
O
HO
N
CN
K CO
2
3
R3
+
+
CN _
+
R1
R2
H O
2
It was found that this reaction led to the formation of
target nitriles IIa, IId, IIf in high yields.Asimilar reaction
was described in [10] by an example of cyclohexanone
and some aldehydes. At establishing its general charac-
ter it can be regarded as a new modification of Strecker
reaction.
R3
H
R1
R2
_
IIIа IIIe
1
2
3
4
1
R ,R = (CH ) , R ,R = (CH ) O(CH ) (a); R = Me,
2
4
2 2
2 2
1
2
3
4
2
R = i-Bu, R ,R = (CH ) O(CH ) (b); R = Me, R = Ph,
2
2
2 2
3
4
1
2
R ,R = (CH ) (c), (CH ) O(CH ) (d); R ,R = (CH ) ,
2
5
2 2
2 2
2 4
3
4
R = H, R = Ph (e).
The developed synthetic method can be used for the
preparation of a series of 2-alkyl(aryl)amino-2-cyanoO-
adamantanes whose hydrogenation can provide unsym-
metrical amines containing 2,2-disubstituted adamantyl
fragment, and the reaction with Grignard reagents can
afford amino-containing adamantylated ketones interest-
ing as potential biologically active substances.
The structure of compounds IIIa, IIIb, IIId, IIIe was
1
confirmed by H NMR spectra. In particular, the occur-
rence of this reaction is confirmed by the appearance
of the signals of the protons from the introduced alkyl
groups, and also of the protons of methine (methylene)
groups at the nitrogen atom in the region 2.5–3.5 ppm.
The properties of known compounds were in agreement
with the published data [8].
EXPERIMENTAL
In [9] in various conditions the other products were
detected: 2-amino-2-cyanopropane derivatives, imines,
cyanohydrins of initial ketones. However, the optimum
conditions of the formation of the target α-aminonitriles
were not established. Aiming at discovering the mecha-
nism of nitriles IIa–IIe formation we examined the pos-
sibility of proceeding of the presumed stage of the above
reaction, namely, the reaction of ketone I with 2-amino-
1H NMR spectra of compounds obtained were regis-
tered on a spectrometer Varian Mercury-300 (300 MHz) in
tetrachloromethane, internal references HMDS or TMS.
2
-Cyano-2-cyclohexylaminoadamantane (IIa). a.
Amixture of 5 g (0.033 mol) of 2-adamantanone (I), 4.7 g
0.055 mol) of acetone cyanohydrin, 5 g (0.05 mol) of
(
cyclohexylamine, and 0.1 g of potassium carbonate were
heated for 2 h in a round bottom flask equipped with a Li-
ebig condenser. During the reaction at 70–75°C equimolar
amount of water and acetone was distilled off. Then the
residue was distilled in a vacuum from the same flask col-
2
-cyanopropane derivatives. To this end we synthesized
α-aminonitriles IVa–IVd by the reaction between acetone
cyanohydrin and some amines.
R'
RR'NH
HO
N
CN
lecting the fraction of bp 224–227°C (20 mm Hg). Yield
CN
_
H O
2
R
1
6
.9 g (81%), mp 93–94°C (mp 93–94°C [6]). H NMR
_
IVа IVd
spectrum, δ, ppm: 0.68 s (1H, NH), 1.05–2.25 m (14H,
2
,2-Ad; 10H, Cy), 2.62 m (1H, CHN).
R,R' = piperidino (a), moppholino (b); R = H, R' = Cy (c),
Bn (d).
b. A mixture of 3 g (0.02 mol) of compound I, 3.7 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

ONE-STAGE SYNTHESIS OF ADAMANTYL-CONTAINING α-AMINONITRILES
1137
(0.022 mol) of 2-cyano-2-cyclohexylaminopropane, and
H 8.92; N 11.42. C H N O. Calculated, %: C 73.17;
1
5
22
2
0
.1 g of potassium carbonate were heated in a round bot-
H 8.94; N 11.38.
-Benzylamino-2-cyanoadamantane (IIf). b.
From 2 g (0.0133 mol) of adamantan-2-one and 2.4 g
0.0138 mol) of 2-benzylamino-2-cyanopropane was
tom flask equipped with a Liebig condenser at 80–100°C
within 30–40 min; therewith equimolar quantity of
acetone was distilled off. The residue was distilled in a
vacuum. Yield 3.5 g (67%), bp 225–28°C (20 mm Hg),
mp 93–94°C (mp 93–94°C [6]).
2
(
obtained 2.9 g (81%) of compound IIf, bp 215–217°C (20
1
mm Hg), mp 103–104°C (mp104– 105°C [6]). H NMR
Compounds IIb–IIf, IIIa–IIIe were obtained simi-
spectrum, δ, ppm: 1.60–1.85 m (12H, Ad), 2.52 s (1H,
larly.
Ad), 3.01 s (1H, Ad), 4.38 s (2H, CH ), 7.03–7.24 m
2
(
5H, Ph).
2
-(β-Hydroxyethylamino)-2-cyanoadamantane
IIb) was obtained along method a from 5 g (0.033 mol)
of compound I, 4 g (0.047 mol) of acetone cyanohydrin,
.6 g (0.043 mol) of 2-aminoethanol, and 0.1 g of potas-
(
2-Morpholino-2-cyanocyclopentane (IIIa). a. From
4.2 g (0.05 mol) of cyclopentanone, 5 g (0.058 mol) of
morpholine, and 5 g (0.059 mol) of acetone cyanohy-
drin was obtained 4.86 g (54%) of compound IIIa, bp
2
sium carbonate. Yield 5.7 g (79%), oily substance, bp
90–193°C (20 mm Hg). H NMR spectrum, δ, ppm:
1
1
1
145–147°C (20 mm Hg). H NMR spectrum, δ, ppm:
1
.20 s (1H, NH), 1.43–2.24 m (14H, 2,2-Ad), 2.68 s (1H,
1.64–1.69 m (2H, CH ), 1.81 m (4H, 2CH ), 2.11 m (2H,
2
2
OH), 3.01 t (2H, CH N), 3.59 t (2H, CH O). Found, %:
CH ), 2.48 t [4H, (CH ) N], 3.56 t [4H, (CH ) O]. Found,
2
2
2 2 2 2 2
C 70.88; H 9.07; N 12.69. C H N O. Calculated, %:
%: C 66.68; H 8.99; N 15.52. C H N O. Calculated,
10 16 2
1
3
20
2
C 70.91; H 9.09; N 12.73.
%: C 66.63; H 8.95; N 15.54.
2
-Phenylamino-2-cyanoadamantane (IIc) was
b. From 4.2 g (0.05 mol) of cyclopentanone and
8.5 g (0.055 mol) of 2-morpholino-2-cyanopropane was
obtained 5.3 g (69%) of compound IIIa, bp 152–154°C
(20 mm Hg).
obtained along method a from 5 g (0.033 mol) of com-
pound I, 3.5 g (0.038 mol) of aniline, 4.3 g (0.05 mol) of
acetone cyanohydrin, and 0.1 g of potassium carbonate.
Yield 6.3 g (75%), mp 171–173°C (172–173°C [6]). H
NMR spectrum, δ, ppm: 1.53–2.30 m (14H, Ad), 3.48 s
1
4
-Methyl-2-morpholino-2-cyanopentane (IIIb).
a. From 5.0 g (0.05 mol) of methyl isobutyl ketone,
g (0.058 mol) of morpholine, and 5 g (0.059 mol)
(
1H, NH), 6.74–6.77 m (3H, Ph), 7.05–7.12 m (2H, Ph).
-Piperidino-2-cyanoadamantane (IId). a. From
g (0.033 mol) of compound I, 4.3 g (0.05 mol) of
5
2
of acetone cyanohydrin was obtained 6.56 g (68%) of
1
5
compound IIIb, bp 153–154°C (20 mm Hg). H NMR
piperidine, 5.1 g (0.06 mol) of acetone cyanohydrin,
and 0.1 g of potassium carbonate was obtained 6.4 g
spectrum, δ, ppm: 0.67 t (3H, CH ), 1.07 t (6H, 2CH ),
3
3
1.30 d (2H, CH ), 1.55 m (1H, CH), 2.18 t (4H, CH N),
2
2
(
80%) of compound IId, bp 210–212°C (18 mm Hg),
3.27 t (4H, CH2O). Found, %: C 67.25; H 10.24; N 11.32.
C H N O. Calculated, %: C 67.31; H 10.27; N 14.27.
1
mp 77–78°C (mp 77–78°C [6]). H NMR spectrum, δ,
ppm: 1.35–2.32 m (20H, 2,2-Ad + 3 CH ), 2.60 br.s (4H,
2
11 20
2
2
b. From 5.0 g (0.05 mol) of methyl isobutyl ketone and
8.5 g (0.055 mol) of 2-morpholino-2-cyanopropane was
obtained 6.4 g (65%) of compound IIIb, bp 152–154°C
CH N).
2
b. From 4 g (0.027 mol) of compound I, 5 g (0.032 mol)
(
20 mm Hg).
of 2-piperidino-2-cyanopropane, and 0.2 g of potassium
carbonate was obtained 5.1 g (78%) of compound IId,
mp 78–79°C, bp 211–213°C (18 mm Hg). 1H NMR
spectrum, δ, ppm: 1.35–2.34 m (20H, 2,2-Ad + 3 CH2),
2-Piperidino-2-phenylpropionitrile (IIIc). a. From
4.8 g (0.04 mol) of acetophenone, 5.2 g (0.06 mol) of
piperidine, 6 g (0.07 mol) of acetone cyanohydrin was
2
.60 br.s (4H, 2CH N).
obtained 5.2 g (0.024 mol, 60%) of compound IIIc, bp
2
1
1
59–161°C (20 mm Hg). H NMR spectrum, δ, ppm:
2
-Morpholino-2-cyanoadamantane (IIe). a. From
1
.39 s (3H, CH ), 1.40–1.48 m (6H, 3CH ), 2.43 t (4H,
5
g (0.033 mol) of compound I, 3.5 g (0.04 mol) of mor-
3
2
CH N), 7.35 t (2H, Ph), 7.42 t (1H, Ph), 7.82 d (2H, Ph).
pholine, 4.3 g (0.05 mol) of acetone cyanohydrin, and
.1 g of potassium carbonate was obtained 6.4 g (79%)
2
Found, %: C 78.50; H 8.51; N 12.99. C H N . Calcu-
0
14 18
2
1
lated, %: C 78.46; H 8.47; N 13.07.
of compound IIe, bp 170–180°C (15 mm Hg). H NMR
spectrum, δ, ppm: 1.38–2.13 m (14H, 2,2-Ad), 2.56 t
1-Morpholino-1-cyanocyclohexane (IIId). b. From
[
4H, (CH ) N], 3.72 t [4H, (CH ) O]. Found, %: C 73.20;
4.9 g (0.05 mol) of cyclohexanone and 9.1 g (0.06 mol)
2
2
2 2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

1138
POPOV et al.
of 2-morpholino-2-cyanopropane was obtained 6.0 g
trum, δ, ppm: 1.03–1.15 m (4H, 2 CH ), 1.21–1.32 m (2H,
2
(
{
88%) of compound IIId, bp 149–150°C (20 mm Hg)
bp 160–162°C (18 mm Hg) [11]}. H NMR spectrum,
CH ), 1.35 C (6H, 2 CH ), 1.52 d (1H, NH), 1.64–1.71 m
(2H, CH ), 1.82–1.84 m (2H, CH ), 2.58 m (1H, CHN).
2 2
2
3
1
δ, ppm: 1.20–1.61 m (6H, 3CH ), 1.70 m (2H, CH ),
2
2
2-Benzylamino-2-cyanopropane (IVd) was obtained
1
.99 m (2H, CH ), 2.48 t (4H, CH N), 3.58 t (4H, CH O).
from 5 g (0.047 mol) benzylamine and 5 g (0.059 mol) of
2
2
2
acetone cyanohydrin. Yield 7.5 g (91%), bp 145–146°C
1
-Phenylamino-1-cyanocyclohexane (IIIe). b. From
1
(20 mm Hg). H NMR spectrum, δ, ppm: 1.33 s (6H,
2
2
g (0.02 mol) of cyclohexanone, 3.2 g (0.02 mol) of
-phenylamino-2-cyanopropane and 0.05 g of potassium
carbonate was obtained 2.76 g (69%) of compound IIIe,
bp 166–168°C (15 mm Hg), mp 66–68°C (mp 71–75°C
12]). H NMR spectrum, δ, ppm: 1.55 br.s (4H, 2CH ),
2
CH ), 3.72 s (2H, CH ), 7.04–7.22 m (5H, Ph). Found,
3 2
%
: C 75.78; H 8.12; N 16.10. C H N . Calculated, %:
11 14 2
C 75.82; H 8.10; N 16.08.
1
[
1
2
REFERENCES
.74 m (2H, CH ), 2.05–2.15 m (2H, CH ), 2.30–2.32 m
2 2
(
(
2H, CH ), 3.78 br.s (1H, NH), 6.52 d (2H, Ph), 6.85 t
1H, Ph), 7.08 t (2H, Ph).
2
1
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2
-Piperidino-2-cyanopropane (IVa). A mixture
of 8.5 g (0.1 mol) of piperidine and 8.5 g (0.1 mol) of
acetone cyanohydrin was heated for 1 h at 100°C; after
that the reaction mixture separated in two phases. The
upper organic layer was distilled in a vacuum collecting
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the fraction of bp 114–115°C (20 mm Hg), {bp 93.5°C
1
(
6 mm Hg) [11]}. Yield 9.9 g (65%). H NMR spectrum,
4
. Orere, D.M. and Reese, C.B., J. Chem. Soc., 1977, p. 280.
δ, ppm: 1.33–1.47 m (2H, CH ), 1.40 s (6H, 2CH ),
2
3
5. Evans, D.A., Truesdale, L.K., and Carroll, G.L., J. Chem.
Soc., 1973, p. 55.
1
.52 m (4H, 2CH ), 2.49 t [4H, (CH ) N].
2 2 2
6
7
8
. Popov, Yu.V., Mokhov, V.M., Tankabekyan, N.A., and
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p. 151.
Compounds IVb–IVd were similarly obtained.
-Morpholino-2-cyanopropane (IVb) was obtained
from 8.6 g (0.1 mol) of morpholine and 8.5 g (0.1 mol) of
2
acetone cyanohydrin. Yield 9.6 g (76%), bp 116–117°C
1
(
15 mm Hg) {bp 129–130°C (5 mm Hg) [11]}. H NMR
spectrum, δ, ppm: 1.38 s (6H, 2CH ), 2.49 t [4H,
9. Galletti, P., Pori, M., and Giacomini, D., Eur. J. Org. Chem.,
011, vols. 20–21, p. 3896.
0. Yanovskaya, L.A., Shachidayatov, Ch., Prokofiev, E.P.,
Andrianova, G.M., and Kucherov, V.F., Tetrahedron, 1968,
vol. 24, p. 4477.
3
2
(
CH ) N], 3.57 t [4H, (CH ) O].
2 2 2 2
1
2
-Cyano-2-cyclohexylaminopropane (IVc) was ob-
tained from 15 g (0.15 mol) of cyclohexylamine and 12 g
0.14 mol) of acetone cyanohydrin. Yield 17.0 g (73%),
(
1
1. Shakhidayatov, Kh., Zh. Org. Khim., 1973, vol. 9, p. 1373.
white crystals, mp 47–50°C, bp 119–120°C (20 mm Hg)
12. Walter, V. and Hubner, U.. J. Prakt. Chem., 1916, vol. 93,
1
{
mp 56°C, bp 68°C (2 mm Hg) [11]}. H NMR spec-
p. 119.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013