Adamantylation of saturated nitrogen-containing heterocycles

Full text of DOI:10.1134/S1070428014030270

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 447–448. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © G.M. Butov, V.M. Mokhov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 3, pp. 455–456.
SHORT
COMMUNICATIONS
Adamantylation of Saturated Nitrogen-Containing Heterocycles
G. M. Butov and V. M. Mokhovb
a
a
Volzhsky Polytechnical Institute (branch), Volgograd State Technical University,
ul. Engel’sa 42a, Volzhskii, Volgograd oblast, 404121 Russia
e-mail: butov@volpi.ru
b
Volgograd State Technical University, pr. Lenina 28, Volgograd, 400005 Russia
Received October 4, 2013
DOI: 10.1134/S1070428014030270
Among biologically active adamantane derivatives,
a particular place is occupied by those containing
nitrogen heterocycles, including saturated rings with
one or two nitrogen atoms and morpholine ring, where
the adamantyl radical is attached to the nitrogen atom.
Derivatives of 1- and 2-aminoadamantane in which the
amino nitrogen atom is a part of heterocyclic fragment
attract interest as antiviral and anti-Parkinson drugs
imidazoles, benzimidazoles [8], pyrazoles [9], and di-
carboxylic acid imides [10]. These reactions involved
cleavage of the propellane bond to afford a new bond
between the bridgehead carbon atom of adamantane
and nitrogen atom.
1
,3-Dehydroadamantane (I) was brought into reac-
tions with piperidine (IIa), morpholine (IIb), and
piperazine (IIc). The reactions of I with saturated
heterocycles IIa–IIc were expected to occur in a com-
plicated nonselective fashion, taking into account the
nature of the N–H bond in compounds IIa–IIc that are
secondary amines with a higher basicity as compared
to heterocycles used previously [8–10]. The NH proton
in IIa–IIc is weakly acidic, and these heterocycles
cannot be alkylated with unactivated alkenes or cyclo-
propane derivatives under mild noncatalytic condi-
tions. There are also published data according to which
some other propellanes failed to react with piperidine
at the N–H bond [11, 12].
[1, 2]. The known methods of synthesis of such com-
pounds are based on adamantylation of piperidine,
piperazine, or morpholine [3] with haloadamantanes or
cyclization of difunctional amines, N,N-bis(2-hydroxy-
or 2-chloroethyl)adamantan-1-amines. In the first case,
the reactions require high temperature, long reaction
time, and the use of excess heterocyclic amine to bind
liberated hydrogen halide and are accompanied by side
Grob fragmentation, tarring, and other undesirable pro-
cesses. The synthesis from 1-aminoadamantane [4] is
multistep, and the yield of the target products is low.
With a view to develop a convenient procedure for
the synthesis of saturated nitrogen heterocycles with
an adamantyl group on the nitrogen atom, we tried as
adamantylating agent 1,3-dehydroadamantane (I, tetra-
In our case, the reactions of I with excess hetero-
cycles IIa–IIc were carried out at 80–100°C for 6–8 h.
The products were purified by vacuum distillation.
Compounds IIIa–IIIc were isolated as white crystal-
line substances, and their structure was confirmed by
3
,7
1,3
cyclo[3.3.1.1. .0. ]decane) which is classed with
small-ring propellanes. We previously found that com-
pound I readily reacts with various OH, SH, and CH
acids [5–7], as well as with some nitrogen-containing
compounds possessing NH acidity, specifically with
1
IR and H NMR spectra and elemental analyses. The
IR spectra of IIIa and IIIb lacked NH absorption at
–
1
3
200–3400 cm , typical of initial heterocycles IIa and
IIb. The properties of IIIa–IIIc were consistent with
the data reported in [3, 13].
X
+
N
The fact of alkylation of NH-heterocycles IIa–IIc
with 1,3-dehydroadamantane (I) indicates high reac-
tivity of the propellane bond in the latter, which makes
strongly basic nitrogen heterocycles capable of react-
ing as proton donors.
X
N
H
I
IIa–IIc
IIIa–IIIc
X = CH (a), O (b), NH (c).
2
4
47

4
48
BUTOV, MOKHOV
Radical addition of some propellanes across the
CH , J = 17.5 Hz). Found, %: C 76.35; H 10.92;
2
C–H bond of tertiary amines has been reported in [14].
In particular, [1.1.1]propellane reacted in such a way
with triethylamine at the α-carbon atom. Analogous
addition path was not observed in the reaction of
N 12.73. C H N . Calculated, %: C 76.31; H 10.98;
1
4
24
2
N 12.71.
1
The H NMR spectra were recorded on a Varian
Mercury-300 spectrometer (300 MHz) from solutions
in carbon tetrachloride. The chemical shifts were deter-
mined relative to hexamethyldisiloxane or tetramethyl-
silane.
1
,3-dehydroadamantane (I) with heterocycles IIa–IIc.
Thus, the results of our study allowed us to develop
a convenient preparative procedure for the adamantyla-
tion of saturated nitrogen-containing heterocycles,
which ensures mild one-step synthesis of heterocyclic
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (basic part of government assign-
ment no. 2014/16, project no. 28-79).
1
-aminoadamantane derivatives with high yields and
easy isolation of the products. The proposed procedure
may be successfully used for the preparation of ada-
mantyl derivatives containing other saturated rings
with one or more nitrogen atoms and different numbers
of carbon atoms in the ring.
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(
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8
N 6.36. C H N. Calculated, %: C 82.13; H 11.49;
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25
N 6.39.
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4
(
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(
(
[
2
3
0.011 mol, 75%) of compound IIIb, bp 145°C
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1
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2
.52 t (4H, CH , J = 15.8 Hz). Found, %: C 76.02;
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1
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14
23
2
013, vol. 49, p. 1403.
H 10.47; N 6.33.
-(1-Adamantyl)piperazine (IIIc). From 8.5 g
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1
1
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(
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1
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1
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2
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