Arylation of adamantanamines: VII. Copper(I)-catalyzed N-heteroarylation of adamantane-containing amines with halopyridines

Article abstract of DOI:10.1134/S1070428015030021

Copper(I)-catalyzed N-heteroarylation of a wide series of adamantane-containing amines with 2-bromo- and 2- and 3-iodopyridines was studied. The corresponding N-pyridyl derivatives were formed in all cases, but iodopyridines were considerably more reactive. The best results were obtained with the catalytic system CuI-2-(2-methyl-1-oxopropyl)cyclohexanone-DMF which ensured up to 90% yield of the target products. The yield of N-pyridyl derivatives also depended on the steric environment of the amino group in the initial adamantane-containing amine. The yield of the heteroarylation products can be considerably increased using excess iodopyridine. The reaction of 2-(adamantan-1-yl)ethanamine with 2,6-dibromopyridine successfully afforded the corresponding diamine, and N,N′-dipyridyl derivatives were obtained in high yields from 2,2′-(adamantane-1,3-diyl)diethanamine.

Full text of DOI:10.1134/S1070428015030021

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 3, pp. 301–308. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © A.S. Abel, A.D. Averin, M.V. Anokhin, O.A. Maloshitskaya, G.M. Butov, E.N. Savelyev, B.S. Orlinson, I.A. Novakov, I.P. Beletskaya,
2015, published in Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 3, pp. 319–326.
Arylation of Adamantanamines: VII.* Copper(I)-Catalyzed
N-Heteroarylation of Adamantane-Containing Amines
with Halopyridines
A. S. Abela, A. D. Averina, M. V. Anokhina, O. A. Maloshitskayaa, G. M. Butovb,
E. N. Savelyevc, B. S. Orlinsonc, I. A. Novakovc, and I. P. Beletskayaa
a Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
e-mail: alexaveron@yandex.ru
b Volzhsky Polytechnical Institute, Volgograd State Technical University,
ul. Engel’sa 42a, Volzhskii, Volgograd oblast, 404130 Russia
c Volgograd State Technical University, pr. Lenina 28, Volgograd, 400005 Russia
Received October 18, 2014
Abstract—Copper(I)-catalyzed N-heteroarylation of a wide series of adamantane-containing amines with
2-bromo- and 2- and 3-iodopyridines was studied. The corresponding N-pyridyl derivatives were formed in all
cases, but iodopyridines were considerably more reactive. The best results were obtained with the catalytic
system CuI–2-(2-methyl-1-oxopropyl)cyclohexanone–DMF which ensured up to 90% yield of the target
products. The yield of N-pyridyl derivatives also depended on the steric environment of the amino group in the
initial adamantane-containing amine. The yield of the heteroarylation products can be considerably increased
using excess iodopyridine. The reaction of 2-(adamantan-1-yl)ethanamine with 2,6-dibromopyridine success-
fully afforded the corresponding diamine, and N,N′-dipyridyl derivatives were obtained in high yields from
2,2′-(adamantane-1,3-diyl)diethanamine.
DOI: 10.1134/S1070428015030021
[9–11], development of procedures for their synthesis
seems to be an important task. We previously studied
Pd(0)-catalyzed heteroarylation of adamantane-con-
taining amines with 2-bromopyridine [12], 3-bromo-
pyridine [1] and mono- and dichloroquinolines [13–15]
and showed that diaminoadamantane fragments can be
introduced into macroheterocycles [16]. It was also
noted that success of these reactions is largely deter-
mined by the structure of initial amines containing
a bulky adamantane moiety. Continuing these studies,
in the present work we examined copper(I)-catalyzed
N-heteroarylation of a wide series of adamantane-
containing amines with 2-bromo- and 2- and 3-iodo-
pyridines.
The reaction conditions were optimized using the
least sterically hindered 2-(adamantan-1-yloxy)ethan-
amine (1) and an equimolar amount of halopyridine at
a concentration of 0.5 M (Scheme 1). According to our
previous data, 2-bromopyridine is fairly reactive in
Cu(I)-catalyzed aminations [7]. Therefore, we initially
tried 2-bromopyridine as heteroarylating agent. When
Reactions of amines with aryl halides, catalyzed by
zero-valent palladium complexes, provide a convenient
general procedure for the synthesis of N-aryl and
N-heteroaryl amines and polyamines [2, 3]. An impor-
tant trend in the modern stage of development of
catalytic methods is replacement of expensive palla-
dium by considerably cheaper copper [4]; however,
Cu(I)-catalyzed amination requires more thorough
selection of the catalytic system for each particular
amine–aryl halide couple [5]. We have initiated a com-
prehensive study of the arylation [6] and heteroaryla-
tion [7, 8] of polyamines under catalysis by copper(I)
complexes and shown that the most efficient catalytic
systems are CuI–L-proline, CuI–N,N-dimethylglycine
and CuI–2-(2-methyl-1-oxopropyl)cyclohexanone. The
choice of the solvent (DMF, acetonitrile, propionitrile)
is also determined by the nature of particular reactants.
Taking into account high and diverse physiological
activity of heteroaryl derivatives of adamantanamines
* For communication VI, see [1].
301

ABEL et al.
302
Scheme 1.
H
N
N
CuI, L1–L6, Cs2CO3, EtCN or DMF
+
O
NH2
O
N
O
Hlg
Me
1
2
O
OH
OH
Me
N
COOH
Ph3P=O
Ph3P
COOH
N
Me
Me
H
L1
L2
L3
L4 (RS-BINOL)
L5
L6
Hlg = Br, I.
a mixture of amine 1 with 2-bromopyridine and cesium
carbonate was heated in DMF for 24 h at 140°C in the
absence of a catalyst, the yield of product 2 was as low
as 11% (Table 1, run no. 1). No reaction was observed
in boiling propionitrile in the presence of CuI–L1
(5/10 mol %, L1 = L-proline; run no. 2). Replacement
of the catalytic system by CuI–L2 [5/10 mol %, L2 =
2-(2-methyl-1-oxopropyl)cyclohexanone] and of the
solvent by DMF (110°C) increased the yield of 2 to
28% (run no. 3). Furthermore, the yield of 2 was
improved to 57% by raising the amount of the catalyst
and ligand to 10/20 mol % and the temperature to
140°C (run no. 4). The yield of 2 was considerably
lower (34%) in the presence of CuI–L1 (10/20 mol %;
DMF, 140°C; run no. 5).
L1 (5/10 mol %) the yield of 2 was 11% (run no. 6).
The system CuI–L2 (5/10 mol %) in DMF at 110°C
ensured 40% yield of 2 (run no. 8). The yield of 2 also
increased to an appreciable extent when the catalytic
system CuI–L1 was used in an amount of 10/20 mol %
(run no. 7). Compound 2 was formed in 72% yield in
the reaction carried out in DMF at 140°C under catal-
ysis by CuI–L2 (10/20 mol %; run no. 9).
Other potential catalytic systems were also tested to
optimize the yield. N,N-Dimethylglycine (L3) [17] was
less efficient than L-proline (L1): under comparable
conditions, the conversion was as low as 9% (run
no. 10). Racemic BINOL (L4) [18] afforded 50% of 2
(run no. 11). The use of some phosphine ligands has
been reported [19]. We tried triphenylphosphine (L6)
and triphenylphosphine oxide (L5) as components of
the catalytic system. The catalytic system CuI–L2–L5
In the reaction of 1 with more reactive 2-iodo-
pyridine in boiling propionitrile catalyzed by CuI–
Table 1. N-Heteroarylation of 2-(adamantan-1-yloxy)ethanamine (1) with 2-bromo- and 2-iodopyridines
Run no.
Halopyridine
Ligand
Cu–L, mol %
Solvent
Temperature, °C Yield of 2, %
01
02
03
04
05
06
07
08
09
10
11
12
13
2-Bromopyridine
2-Bromopyridine
2-Bromopyridine
2-Bromopyridine
2-Bromopyridine
2-Iodopyridine
2-Iodopyridine
2-Iodopyridine
2-Iodopyridine
2-Iodopyridine
2-Iodopyridine
2-Iodopyridine
2-Iodopyridine
–
00–
DMF
EtCN
DMF
DMF
DMF
EtCN
DMF
DMF
DMF
EtCN
DMF
DMF
DMF
140
097
110
140
140
097
140
110
140
097
140
140
140
11
00
28
57
34
11
50
40
72
09
50
62
72
L1
05/10
05/10
10/20
10/20
05/10
10/20
05/10
10/20
05/10
10/20
10/10/10
10/10/10
L2
L2
L1
L1
L1
L2
L2
L3
L4
L2/L5
L2/L6
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

ARYLATION OF ADAMANTANAMINES: VII.
303
Scheme 2.
Me
NH2
NH2
NH2
NH2
3
4
5
6
NH2
Me
N
NH
NH2
NH2
NH2
Ph
7
8
9
10
11
NH2
HN
X
N
N
CuI, L2, Cs2CO3, DMF, 140°C
X
N
N
+
N
I
3–11
12–20
21
an important advantage of Cu(I)-catalyzed amination
compared to analogous Pd(0)-catalyzed reactions is
almost complete absence of side N,N-diarylation of
monoamines, which could strongly complicate the syn-
thesis of some adamantanamine derivatives [12]. The
reactions with amines 3 and 4 were also carried out in
the presence of triphenylphosphine oxide as ligand;
however, as with amine 1, the yields of 12 and 13 were
lower, 78 and 53%, respectively (run nos. 2, 5). As
might be expected, more sterically loaded amines 5–7
reacted with 2-iodopyridine to give the corresponding
arylation products in lower yields (50–63%; run nos. 6,
7, 9). In the reaction of amine 6 with 3 equiv of
2-iodopyridine, the conversion of 6 increased from 55
to 90%, whereas the yield of 16 in the reaction with
amine 7 increased insignificantly, from 50 to 57% (run
nos. 8, 10). Further increase of steric hindrances in
going to amine 8 resulted in the reduction of the yield
of 17 to 15% (run no. 11). Adamantan-1-amine (9)
showed the lowest reactivity in Pd(0)-catalyzed amina-
tion, which was appreciably lower than the reactivity
of amine 8. However, Cu(I)-catalyzed heteroarylation
of 9 gave 36% of 18 (run no. 12). As expected, ada-
mantan-2-amine 10 was more reactive, and the yield of
(10/10/10 mol %) ensured 62% of 2 (run no. 12), and
the yield attained 72% in the presence of CuI–L2–L6
(10/10/10 mol %; run no. 13). Thus, the best catalytic
system for the arylation of amine 1 with 2-bromo- and
2-iodopyridines is CuI–L2 (10/20 mol %) in DMF at
140°C. In our further study, the reactions of 2-iodo-
pyridine with all other adamantane-containing amines
were carried out under these conditions.
Next, we examined the Cu(I)-catalyzed heteroaryla-
tion of a representative series of adamantane-contain-
ing amines 3–11 characterized by different steric
hindrances at the amino group. The reactions with
sterically unhindered amines 3 and 4 afforded even
higher yields (up to 90%) of heteroarylation products
12 and 13 (Scheme 2; Table 2, run nos. 1, 4); the reac-
tion with amine 3 was accompanied by side formation
of N,N-disubstituted product 21 (9%, run no. 1). It
should be noted that the formation of N,N-diheteroaryl
derivatives was observed by us previously in reactions
of some polyamines with 2-iodopyridine [7].
Interestingly, the same yields of 12 and 21 (90 and
9%, respectively) were obtained in special experiment
with 3 equiv of 2-iodopyridine (run no. 3). Thus,
Scheme 3.
NH2
HN
X
I
CuI, L2, Cs2CO3, DMF, 140°C
X
N
N
+
NH
N
1, 3–7, 10, 11, 22
23–31
22
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

ABEL et al.
304
Table 2. N-Heteroarylation of amines 3–11 with 2-iodo-
pyridine under optimized conditions (CuI–L2, 10/20 mol %;
DMF, 140°C)
19 was 55% (run no. 13). The reaction with cyclic
secondary amine, 4-(adamantan-2-yl)piperazine (11),
was also fairly efficient, and compound 20 was formed
in 55% yield (run no. 14).
Amine 2-Iodopyridine,
Run no.
01
Product
Yield, %
no.
equiv
Having studied the amination of 2-halopyridines,
we examined Cu(I)-catalyzed amination of less active
3-iodopyridine with adamantane-containing amines 1,
3–7, 10, 11, and 22 (Scheme 3). 3-Bromopyridine was
not tested in these reactions, taking into account its
inactivity in analogous copper-catalyzed reactions with
polyamines. The reaction of 3-iodopyridine with amine
1 in the presence of CuI–L1 and CuI–L2 in DMF gave
compound 23 in 43 and 74% yield, respectively
(Table 3; run nos. 1, 2); therefore, the reactions with
the other amines were carried out using only CuI–L2 as
catalytic system.
03
1
12
21
90a
9a
0b2b
03
03
03
1
3
12
78
12
21
90
9
04
0b5b
06
07
08
09
10
11
04
04
05
06
06
07
07
08
09
10
11
1
1
1
1
3
1
3
1
1
1
1
13
13
14
15
15
16
16
17
18
19
20
90a
53
63
55 (46)a
90
Sterically unhindered amines 3 and 4 reacted with
3-iodopyridine to afford the corresponding hetero-
arylation products 24 and 25 in high yields (run
nos. 3, 4). In the reactions with more sterically hin-
dered amines 5–7, the yields of the heteroarylation
products were lower, 40 to 59% (run nos. 5, 7, 8). The
use of 3-equiv of 3-iodopyridine in the reactions with
amines 5, 7 allowed us to increase the yields to 75%
(run nos. 6, 9). Reactions of 3-iodopyridine with
strongly hindered amines 8 and 9 were not studied.
A good yield (67%) was obtained in the reaction with
adamantan-2-amine 10 (run no. 10); the reaction of
secondary amine 11 with 1 equiv of 3-iodopyridine
gave 51% (in the reaction mixture) of heteroarylation
product 30, and the yield of 30 was 65% in the reaction
with 3 equiv of 3-iodopyridine (run nos. 11, 12).
However, the yield of 31 in the reaction with isomeric
amines 22 did not exceed 35% (run no. 13), indicating
specific dependence of the reaction outcome on the
initial amine nature.
50
57
15
12
13
14
36
55 (42)a
55 (34)a
a
Isolated by chromatography.
Catalytic system CuI–L2–L5 (10/10/10 mol %).
b
Table 3. N-Heteroarylation of amines 1, 3–7, 10, 11, and 22
with 3-iodopyridine under optimized conditions (CuI–L2,
10/20 mol %; DMF, 140°C)
Amine 3-Iodopyridine,
Run no.
Product
Yield, %
no.
equiv
a01a
02
03
04
05
06
07
08
09
10
11
12
13
01
01
03
04
05
05
06
07
07
10
11
11
22
1
1
1
1
1
3
1
1
3
1
1
3
1
23
23
24
25
26
26
27
28
28
29
30
30
31
47
74
83 (50)b
85 (43)b
49
Successful N,N′-diheteroarylation of adamantane-
containing diamine 32 was accomplished using 2 equiv
of 2- and 3-iodopyridine (Scheme 4). The reaction
with 2-iodopyridine gave 70% of 33, and compound
34 was obtained in 75% yield from 3-iodopyridine. In
these cases, the amount of the catalytic system was
also doubled (CuI–L2 (20/40 mol %).
75
73 (41)b
59
75
The possibility of Cu(I)-catalyzed diamination in
the pyridine series was demonstrated by the reaction of
2,6-dibromopyridine with 4 equiv of amine 3
(Scheme 5) in the presence of two catalytic systems
CuI–L1 and CuI–L2 (20/40 mol %; DMF, 140°C). In
the first case, the yield of diamination product 35 was
70%, and in the second case, it was nearly quantitative.
67
51 (27)b
65
35 (20)b
a
Catalytic system CuI–L1.
Isolated by chromatography.
b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

ARYLATION OF ADAMANTANAMINES: VII.
305
Scheme 4.
N
H
NH2
N
CuI, L2, Cs2CO3, DMF, 140°C
+
I
NH2
N
N
N
H
32
33, 34
33, pyridin-2-yl; 34, pyridin-3-yl.
Scheme 5.
CuI–L1 or CuI–L2
Cs2CO3, DMF
+
NH2
N
N
N
H
Br
N
Br
H
3
35
In summary, copper(I)-catalyzed heteroarylation of
adamantane-containing amines with 2- and 3-iodopyri-
dines has been successfully accomplished. The most
efficient catalytic system is CuI–L2 in DMF at 140°C,
and N,N′-diheteroarylation of adamantane-containing
diamine, as well as diamination of 2,6-dibromopyri-
dine, is also possible. Strong steric hindrances at the
amino group, e.g., as in amines 8 and 9, considerably
reduce the yield of the target products, which is also
typical of Pd(0)-catalyzed arylation of the same amines
studied previously.
N-Pyridyl-substituted adamantane-containing
amines 2, 12–20, and 23–31 (general procedure).
A two-necked flask equipped with a reflux condenser
and a magnetic stirrer was charged under argon with
0.5 mmol (103 mg) of 2- or 3-iodopyridine, 0.5 mmol
of the corresponding adamantane-containing amine,
0.05 mmol (9.5 mg) of copper(I) iodide, 0.1 mmol
(17 mg) of 2-(2-methyl-1-oxopropyl)cyclohexanone,
1 mmol (326 mg) of cesium carbonate, and 1 mL of
DMF. The mixture was heated for 24 h at 140°C under
stirring, cooled, and diluted with 5 mL of methylene
chloride, and the precipitate was filtered off and
washed with methylene chloride (5 mL). The filtrate
was combined with the washings and evaporated under
reduced pressure, the residue was dissolved in meth-
ylene chloride (5 mL), the solution was treated with
water (5 mL), and the organic layer was separated,
dried over anhydrous sodium sulfate, and evaporated
under reduced pressure. If necessary, the residue was
subjected to silica gel chromatography using methy-
lene chloride–petroleum ether (1:4 to 4:1), methylene
chloride, or methylene chloride–methanol (100:1 to
3:1) as eluent. The products were isolated as slightly
colored solids or oily substances. The spectral param-
eters of compounds 14, 16–18, and 33 were given in
[12], and of 23, 26, 28, 29, and 34, in [1].
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance-400 spectrometer at 400 and
100.6 MHz, respectively, using CDCl3 as solvent and
reference (CHCl3, δ 7.25 ppm; CDCl3, δC 77.00 ppm).
The mass spectra (MALDI TOF, positive ion detec-
tion) were taken on a Bruker Daltonics Autoflex II
instrument using 1,8,9-trihydroxyanthracene as matrix
and poly(ethylene glycols) as standards. Silica gel
(40–60 μm; Merck) was used for preparative column
chromatography. Commercial 2-bromopyridine, 2- and
3-iodopyridines, copper(I) iodide, cesium carbonate,
L-proline, N,N-dimethylglycine, 2-(2-methyl-1-oxo-
propyl)cyclohexanone, (RS)-BINOL, triphenylphos-
phine, and triphenylphosphine oxide were used with-
out additional purification. Amines 1 [20], 5, 7, 8, 32
[12, 21], 9, 10 [22, 23], 3, 4, 6 [24–26], and 11, 22 [27]
were synthesized according to known methods. Di-
methylformamide was purified by vacuum distillation
over calcium hydride; propionitrile, methanol, petro-
leum ether, and methylene chloride were distilled
prior to use.
N-[2-(Adamantan-1-yloxy)ethyl]pyridin-2-amine
(2) was synthesized from 98 mg of amine 1. The prod-
uct was isolated by chromatography (CH2Cl2–MeOH,
1
200:1); yield 68 mg (50%). H NMR spectrum, δ,
ppm: 1.51–1.61 m (6H), 1.68–1.70 m (6H), 2.09 br.s
3
3
(3H), 3.37 q (2H, J = 5.3 Hz), 3.56 t (2H, J =
5.1 Hz), 4.90 br.s (1H), 6.35 d (1H, 3J = 8.3 Hz), 6.46–
6.52 m (1H), 7.31–7.36 m (1H), 8.03 d (1H, J =
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

ABEL et al.
306
3
4
4.7 Hz). 13C NMR spectrum, δC, ppm: 30.3 (3C), 36.3
(3C), 41.1 (3C), 42.3 (1C), 58.4 (1C), 72.2 (1C), 107.1
(1C), 112.5 (1C), 137.1 (1C), 147.8 (1C), 158.7 (1C).
Mass spectrum: m/z 273.188 [M + H]+. C17H25N2O.
Calculated: M + H 273.197.
8.04 d.d (1H, J = 5.1, J = 1.9 Hz). 13C NMR spec-
trum, δC, ppm: 16.0, 27.7, 27.9, 29.0, 29.2, 31.6, 32.1,
32.2, 38.1, 39.1, 39.3, 46.1, 47.2, 106.1, 112.4, 137.4,
148.1, 159.2. Mass spectrum: m/z 271.213 [M + H]+.
C18H27N2. Calculated: M + H 271.217.
N-[2-(Adamantan-1-yl)ethyl]pyridin-2-amine
(12) was synthesized from 90 mg of amine 3. The
product was isolated by chromatography (CH2Cl2);
yield 115 mg (90%). 1H NMR spectrum, δ, ppm: 1.36–
1.42 m (2H), 1.55 br.s (6H), 1.60–1.72 m (6H),
1.95 br.s (3H), 3.20–3.26 m (2H), 4.41 br.s (1H),
N-(Adamantan-2-yl)pyridin-2-amine (19) was
synthesized from 103 mg of amine 10. The product
was isolated by chromatography (CH2Cl2); yield
1
52 mg (42%). H NMR spectrum, δ, ppm: 1.61 d (2H,
3J = 12.6 Hz), 1.74 br.s (4H), 1.81–1.98 m (6H),
2.01 br.s (2H), 3.73 br.s (1H), 4.96 br.s (1H), 6.35 d
3
3
3
6.35 d (1H, J = 8.5 Hz), 6.51–6.55 m (1H), 7.37–
(1H, J = 8.1 Hz), 6.49–6.53 m (1H), 7.39 t (1H, J =
7.8 Hz), 8.05 br.s (1H). 13C NMR spectrum, δC, ppm:
27.2 (1C), 27.3 (1C), 31.5 (2C), 31.7 (2C), 37.2
(2C), 37.6 (1C), 55.4 (1C), 106.2 (1C), 112.3 (1C),
137.5 (1C), 147.9 (1C), 158.0 (1C). Mass spectrum:
m/z 229.175 [M + H]+. C15H21N2. Calculated:
M + H 229.171.
7.43 m (1H), 8.05 d (1H, 3J = 4.3 Hz). 13C NMR spec-
trum, δC, ppm: 28.6 (3C), 32.0 (1C), 37.1 (4C), 42.3
(3C), 43.9 (1C), 106.3 (1C), 112.5 (1C), 137.5 (1C),
148.0 (1C), 158.8 (1C). Mass spectrum: m/z 257.209
[M + H]+. C17H25N2. Calculated: M + H 257.202.
N-[2-(Adamantan-1yl)ethyl]-N-(pyridin-2-yl)-
pyridin-2-amine (21) was isolated by chromatography
(CH2Cl2–MeOH, 100:1) as by-product in the synthesis
1-(Adamantan-2-yl)-4-(pyridin-2-yl)piperazine
(20) was synthesized from 110 mg of amine 11. The
product was isolated by chromatography (CH2Cl2–
1
of 12. Yield 14 mg (9%). H NMR spectrum, δ, ppm:
1
1.20–1.26 m (2H), 1.46 br.s (6H), 1.52–1.68 m (6H),
1.92 br.s (3H), 3.60–3.65 m (2H), 7.01–7.08 m (4H),
7.69–7.75 m (2H), 8.23–8.26 m (2H). Mass spectrum:
m/z 334.24 [M + H]+. C22H28N3. Calculated: M + H
334.23.
MeOH, 100:1); yield 50 mg (34%). H NMR spec-
3
trum, δ, ppm: 1.39 d (1H, J = 11.0 Hz), 1.60–1.71 m
(4H), 1.74–1.87 m (4H), 1.98–2.14 m (5H), 2.47–
2.55 m (4H), 3.45–3.53 m (4H), 6.56 d.d (1H, 3J = 7.2,
3
5.1 Hz), 6.61 d (1H, 3J = 8.6 Hz), 7.43 d.d.d (1H, J =
4
3
4
8.6, 7.2, J = 2.0 Hz), 8.16 d.d (1H, J = 5.1, J =
2.0 Hz). 13C NMR spectrum, δC, ppm: 27.3 (1C), 27.5
(1C), 28.9 (2C), 31.2 (1C), 31.3 (2C), 37.2 (2C), 37.7
(1C), 45.6 (2C), 49.3 (2C), 106.9 (1C), 112.9 (1C),
137.2 (1C), 147.9 (1C), 160.4 (1C). Mass spectrum:
m/z 298.231 [M + H]+. C19H28N3. Calculated:
M + H 298.228.
N-[2-(Adamantan-2-yl)ethyl]pyridin-2-amine
(13) was synthesized from 90 mg of amine 4. The
product was isolated by chromatography (petroleum
1
ether–CH2Cl2, 2:1); yield 115 mg (90%). H NMR
3
spectrum, δ, ppm: 1.51 d (2H, J = 12.3 Hz), 1.68–
1.89 m (15H), 3.19–3.24 m (2H), 4.55 br.s (1H), 6.35 d
3
3
4
(1H, J = 8.5 Hz), 6.52 d.d.d (1H, J = 7.0, 5.1, J =
3
4
0.8 Hz), 7.39 d.d.d (1H, J = 8.5, 7.0, J = 1.9 Hz),
N-[2-(Adamantan-1-yl)ethyl]pyridin-3-amine
(24) was synthesized from 90 mg of amine 3. The
product was isolated by chromatography (CH2Cl2–
8.05 d.d.d (1H, J = 5.1, J = 1.9, 0.8 Hz). 13C NMR
spectrum, δC, ppm: 28.0 (1C), 28.2 (1C), 31.6 (2C),
31.9 (2C), 32.4 (1C), 38.3 (1C), 39.1 (2C), 40.7 (1C),
41.9 (1C), 106.2 (1C), 112.5 (1C), 137.4 (1C), 148.1
(1C), 158.9 (1C). Mass spectrum: m/z 257.198
[M + H]+. C17H25N2. Calculated: M + H 257.202.
3
4
1
MeOH, 100:1); yield 64 mg (50%). H NMR spec-
trum, δ, ppm: 1.33–1.38 m (2H), 1.51–1.53 m (6H),
1.58–1.71 m (6H), 1.94 br.s (3H), 3.05–3.11 m (2H),
3.68 br.s (1H), 6.82 d (1H, 3J = 8.1 Hz), 7.06 br.s (1H),
7.91 br.s (2H). 13C NMR spectrum, δC, ppm: 28.5 (3C),
31.9 (1C), 36.9 (3C), 38.1 (1C), 42.4 (3C), 43.7 (1C),
118.1 (1C), 123.9 (1C), 135.7 (1C), 138.0 (1C), 144.8
(1C). Mass spectrum: m/z 257.206 [M + H]+.
C17H25N2. Calculated: M + H 257.202.
N-[2-(Adamantan-2-ylpropy]pyridin-2-amine
(15) was synthesized from 6 mg of amine 6. The
product was isolated by chromatography (CH2Cl2);
yield 62 mg (46%). 1H NMR spectrum, δ, ppm: 0.96 d
3
3
(3H, J = 6.7 Hz), 1.39 d (1H, J = 10.7 Hz), 1.48–
1.57 m (2H), 1.65–1.98 m (12H), 1.99–2.07 m (1H),
N-[2-(Adamantan-2-yl)ethyl]pyridin-3-amine
(25) was synthesized from 90 mg of amine 4. The
product was isolated by chromatography (CH2Cl2–
2
3
2.95 d.d.d (1H, J = 12.5, J = 7.8, 5.7 Hz), 3.37 d.d.d
(1H, 2J = 12.5, 3J = 5.7, 3.3 Hz), 4.59 br.s (1H), 6.35 d
3
3
4
1
(1H, J = 8.5 Hz), 6.52 d.d.d (1H, J = 7.2, 5.1, J =
MeOH, 100:1); yield 55 mg (43%). H NMR spec-
3
4
3
0.9 Hz), 7.39 d.d.d (1H, J = 8.5, 7.2, J = 1.9 Hz),
trum, δ, ppm: 1.52 (2H, J = 12.3 Hz), 1.66–1.75 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 51 No. 3 2015

ARYLATION OF ADAMANTANAMINES: VII.
307
1
(9H), 1.76–1.89 m (6H), 3.05–3.10 m (2H), 3.80 br.s
(1H), 6.84 d (1H, 3J = 8.2 Hz), 7.06 br.s (1H), 7.94 br.s
(2H). 13C NMR spectrum, δC, ppm: 27.9 (1C), 28.1
(1C), 31.6 (3C), 31.9 (1C), 32.3 (1C), 38.2 (1C), 39.0
(2C), 42.0 (2C), 118.1 (1C), 123.8 (1C), 135.7 (1C),
138.0 (1C), 144.3 (1C). Mass spectrum: m/z 257.199
[M + H]+. C17H25N2. Calculated: M + H 257.202.
the reaction mixture). H NMR spectrum (DMSO-d6),
δ, ppm: 1.25–1.30 m (4H), 1.42–1.46 m (6H), 1.51 br.s
(6H), 1.55–1.69 m (12H), 1.89 br.s (6H), 3.14–3.20 m
3
3
(4H), 5.50 d (2H, J = 7.8 Hz), 5.71 t (2H, J =
4.9 Hz), 6.92 t (1H, J = 7.8 Hz). 13C NMR spectrum,
3
δC, ppm: 28.0 (6C), 32.0 (2C), 36.5 (6C), 41.7
(6C), 42.2 (2C), 43.4 (2C), 93.9 (2C), 137.1 (1C),
158.1 (2C). Mass spectrum: m/z 434.350 [M + H]+.
C29H44N3. Calculated: M + H 434.354.
N-[2-(Adamantan-2-yl)propyl]pyridin-3-amine
(27) was synthesized from 97 mg of amine 6. The
product was isolated by chromatography (CH2Cl2–
This study was performed under financial support
by the Russian Academy of Sciences (program P-8,
“Development of Methodology of Organic Synthesis
and Design of Compounds with Valuable Applied
Properties”) and by the Russian Foundation for Basic
Research (project no. 13-03-00572).
1
MeOH, 200:1); yield 55 mg (41%). H NMR spec-
3
trum, δ, ppm: 0.94 d (3H, J = 6.6 Hz), 1.36 d (1H,
3J = 10.6 Hz), 1.46–1.57 m (2H), 1.65–1.94 m (12H),
2
3
1.97–2.08 m (1H), 2.77 d.d (1H, J = 12.1, J =
8.2 Hz), 3.23 d.d (1H, 2J = 12.1, 3J = 2.5 Hz), 3.92 br.s
(1H), 6.85 d (1H, 3J = 7.8 Hz), 7.11 br.s (1H), 7.97 br.s
(2H). 13C NMR spectrum, δC, ppm: 16.0, 27.6, 27.8,
29.0, 29.3, 31.6, 31.9, 32.1, 38.1, 39.0, 39.2, 47.4,
47.5, 118.0, 123.8, 135.5, 137.5, 144.7. Mass spec-
trum: m/z 271.221 [M + H]+. C18H27N2. Calculated:
M + H 271.217.
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MeOH, 100:1); yield 40 mg (27%). H NMR spec-
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(4H), 3.25–3.30 m (4H), 7.15 br.s (2H), 8.08 br.s (1H),
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