Arylation of adamantanamines: VI. Palladium-catalyzed arylation of amines and diamines of the adamantane series with 3-bromopyridine

Article abstract of DOI:10.1134/S1070428013010016

Palladium-catalyzed amination of 3-bromopyridine with amines of the adamantane series in the presence of Pd(dba)₂/L [L = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or 2-dimethylamino- 2′-dicyclohexylphosphinobiphenyl] gave the desired N-(pyridin-3-yl)- substituted amines in 74-97% yields. Diamines of the adamantane series reacted with 2 equiv of 3-bromopyridine in a complicated fashion to produce mono- and triaryl-substituted derivatives as by-products, while the yields of N,N′-diarylation products were 18-56%.

Full text of DOI:10.1134/S1070428013010016

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 1, pp. 1–7. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.D. Averin, T.Yu. Baranova, A.S. Abel, V.V. Kovalev, A.K. Buryak, G.M. Butov, E.N. Savelyev, B.S. Orlinson, I.A. Novakov,
I.P. Beletskaya, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 1, pp. 11–17.
Dedicated to Full Member of the Russian Academy of Sciences
G.A. Tolstikov on his 80th anniversary
Arylation of Adamantanamines: VI.* Palladium-Catalyzed
Arylation of Amines and Diamines of the Adamantane Series
with 3-Bromopyridine
A. D. Averina, b, T. Yu. Baranovaa, A. S. Abela, V. V. Kovaleva, A. K. Buryakb, G. M. Butovc,
E. N. Savelyevd, B. S. Orlinsond, I. A. Novakovd, and I. P. Beletskayaa, b
a Faculty of Chemistry, Moscow State University, Leninskie gory 1, Moscow, 119991 Russia
e-mail: averin@org.chem.msu.ru
b Frumkin Institute of Physical Chemistry and Electrochemistry,
Russian Academy of Sciences, Moscow, Russia
c Volzhsky Polytechnical Institute, Volzhskii, Russia
d Volgograd State Technical University, Volgograd, Russia
Received February 22, 2012
Abstract—Palladium-catalyzed amination of 3-bromopyridine with amines of the adamantane series in the
presence of Pd(dba)2/L [L = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or 2-dimethylamino-2′-dicyclohexyl-
phosphinobiphenyl] gave the desired N-(pyridin-3-yl)-substituted amines in 74–97% yields. Diamines of the
adamantane series reacted with 2 equiv of 3-bromopyridine in a complicated fashion to produce mono- and
triaryl-substituted derivatives as by-products, while the yields of N,N′-diarylation products were 18–56%.
DOI: 10.1134/S1070428013010016
Until present, numerous adamantane derivatives,
primarily adamantanamines, have been studied as
physiologically active substances, and extensive
studies in this field are now in progress. These com-
pounds exhibit mainly psychotropic or antibacterial
activity. An important place among adamantanamine
derivatives is occupied by those containing hetero-
cyclic substituents. Physiological action of N-pyri-
dinyl-substituted adamantanamines has not been
understood completely. It was found that some pyridin-
3-yl derivatives of adamantan-2-amine produced two-
or three-phase effect on spontaneous motor activity,
which is typical of many adamantane derivatives; all
these compounds were characterized by moderate to
low acute daily toxicity [2]. Compounds possessing
a high stimulating neuropsychotropic activity were
revealed among adamantyl derivatives of 3-amino-
pyridine [3, 4], and search for low-toxic long-acting
drugs enhancing working and mental capacities is pos-
sible in this series. Our studies are aimed at extending
the series of adamantane amines modified with aro-
matic and heteroaromatic substituents. By palladium-
catalyzed amination we synthesized a number of
N-(halophenyl)- [5–8] and N-(pyridin-2-yl)adamantan-
amines [8], and two of the latter showed some noo-
tropic activity. Taking the above stated into account, in
the present work we studied the formation of isomeric
N-(pyridin-3-yl)-substituted amines and diamines of
the adamantane series in palladium-catalyzed amina-
tion reactions.
Palladium-catalyzed amination of 3-bromopyridine
(I) with amines II–VIII of the adamantane series was
carried out with equimolar amounts of the reactants in
the presence of Pd(dba)2/BINAP [4–4.5 mol %,
BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]
and sodium tert-butoxide as base by heating in boiling
dioxane (c = 0.1 mol/l) for several hours (Scheme 1).
In most cases, the yields of target N-(pyridin-3-yl)-
substituted amines IX–XII and XV were 85–97% (see
table, run nos. 1–4, 9; hereinafter, the yields refer to
* For communication V, see [1].
1

AVERIN et al.
2
Scheme 1.
H
N
NH2
X
X
Pd(dba)2–BINAP (or DavePhos)
t-BuONa, dioxane
N
+
N
Br
II–VI
I
IX–XIII
Pd(dba)2–BINAP (or DavePhos)
t-BuONa, dioxane
+
+
I
N
NH2
NH2
N
H
VII
XIV
H
N
Pd(dba)2–BINAP (or DavePhos)
t-BuONa, dioxane
I
N
VIII
XV
II, IX, X = OCH2CH2; III, X, X = CH2; IV, XI, X = CHPh; V, XII, X = CH2CH(Me); VI, XIII, X = CH(Et).
the products isolated by column chromatography on
silica gel). Some difficulties were encountered in the
arylation of sterically hindered amines VI and VII.
The yields of XIII and XIV in the presence of BINAP
as ligand were as low as 37 and 20%, respectively (run
nos. 5, 7); however, replacement of BINAP by a more
efficient ligand, DavePhos [2-(dicyclohexylphos-
phino)-2′-dimethylaminobiphenyl] and increase of the
amount of the catalyst to 8 mol % improved the yields
to 70–74% (run nos. 6, 8).
the amount of 3-bromopyridine to 4 equiv and using
8 mol % of the catalyst were unsuccessful even with
least sterically hindered amine II; as a result, only
compound IX was obtained.
We also studied palladium-catalyzed N,N′-diaryla-
tion of diamines XVI–XIX under analogous condi-
tions (Scheme 2). The reaction of 3-bromopyridine
with adamantane-1,3-diyldimethanamine (XVI) was
difficult to occur, BINAP as ligand turned out to be
completely ineffective, and only the catalytic system
Pd(dba)2/DavePhos allowed us to obtain N,N′-diaryl
derivative XX in 18% yield; the major product was
monoarylation product XXI (yield 44%). The reaction
of 2,2′-(adamantane-1,3-diyl)diethanamine (XVII)
with 2 equiv of 3-bromopyridine gave 55% of N,N′-di-
In no case even traces of N,N-diarylation product
were detected, though the formation of tertiary amines
was a serious competing process in reactions of amines
II–VI with more reactive 2-bromopyridine [8]. Our
attempts to obtain N,N-diarylation products by raising
Synthesis of N-(pyridin-3-yl)-substituted adamantane amines IX–XV
Run no.
Initial amine
Ligand
Pd(dba)2/L, mol %
Product
Yield, %
1
2
3
4
5
6
7
8
9
II
BINAP
BINAP
BINAP
BINAP
BINAP
DavePhos
BINAP
DavePhos
BINAP
4:4.5
4:4.5
4:4.5
4:4.5
4:4.5
8:9.0
8:9.0
8:9.0
4:4.5
IX
85
95
97
88
37
74
20
70
95
III
IV
V
X
XI
XII
XIII
XIII
XIV
XIV
XV
VI
VI
VII
VII
VIII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

ARYLATION OF ADAMANTANAMINES: VI.
3
Scheme 2.
H
N
N
NH2
NH2
I, Pd(dba)2/DavePhos (8 mol %)
t-BuONa, dioxane
+
H
N
H
NH2
N
N
N
XVI
XX, 18%
XXI, 44%
N
N
NH2
N
N
H
H
I, Pd(dba)2/BINAP (4 mol %)
t-BuONa, dioxane
+
N
N
NH2
N
N
H
N
XVII
XXII, 55%
XXIII, 25%
N
NH2
N
H
I, Pd(dba)2/BINAP (8 mol %)
t-BuONa, dioxane
H
NH2
N
Me
Me
Me
Me
N
XVIII
XXIV, 47%
N
NH2
N
NH2
H
I, Pd(dba)2/BINAP (4 mol %)
t-BuONa, dioxane
or
+ XXVI
N
N
NH2
N
H
N
H
XIX
XXVI, 56%
XXV, 56%
16%
arylation product XXII and 25% of N,N,N′-triaryl
derivative XXIII. This reaction is the only example of
diarylation of a primary amino group with 3-bromo-
pyridine. Arylation of both amino groups in unsym-
metrical diamine XVIII containing aminomethyl and
2-aminoethyl fragments was fairly successful in the
presence of BINAP as ligand, and the yield of N,N′-di-
arylation product XXIV was 47%. As might be
expected, unsymmetrical diamine XIX reacted with
1 equiv of 3-bromopyridine mainly at the aromatic
amino group to produce 31% of compound XXV and
16% of diaryl derivative XXVI. The latter was isolated
in 56% yield in the reaction of XIX with 2 equiv of
3-bromopyridine.
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 (δ 7.25, δC 77.00 ppm). The mass spectra
(MALDI-TOF, positive ion detection) were obtained
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

AVERIN et al.
4
13
on a Bruker Daltonics Ultraflex instrument using
1,8,9-trihydroxyanthracene as matrix and poly(ethyl-
ene glycols) as internal references. Preparative column
chromatography was performed on silica gel (40–
60 μm; Merck). Commercially available 3-bromopyri-
dine, sodium tert-butoxide, BINAP, and DavePhos
were used without additional purification. Amines II
[9] and III–VIII [8, 10–12] and diamines XVI–XIX
[8, 10] were synthesized according to known methods;
Pd(dba)2 was prepared as described in [13] and was
used without recrystallization. Dioxane was distilled
first over alkali and then over metallic sodium; meth-
ylene chloride and methanol were distilled.
2.8 Hz). C NMR spectrum, δC, ppm: 28.2 (3C), 33.9
(1C), 36.9 (3C), 40.5 (3C), 55.6 (1C), 117.9 (1C),
123.5 (1C), 135.9 (1C), 137.9 (1C), 145.1 (1C). Mass
spectrum: m/z 243.190 [M + H]+. C16H23N2. Calculated
(M + H) 243.186.
N-[Adamantan-1-yl(phenyl)methyl]pyridin-3-
amine (XI) was synthesized from 0.25 mmol (60 mg)
of amine IV; eluent CH2Cl2–MeOH (50:1 to 35:1).
Yield 77 mg (97%). 1H NMR spectrum, δ, ppm: 1.46–
1.52 m (3H), 1.55–1.61 m (3H), 1.65–1.74 m (6H),
3
1.99 br.s (3H), 3.85 d (1H, J = 6.3 Hz), 4.42 d (1H,
3J = 6.3 Hz), 6.65 d.d.d (1H, 3J = 8.3, 4J = 2.7, 1.1 Hz),
3
6.89 d.d (1H, J = 8.2, 4.7 Hz), 7.19–7.29 m (5H),
3
4
7.81 d (1H, J = 4.7 Hz), 7.98 d (1H, J = 2.7 Hz).
13C NMR spectrum, δC, ppm: 28.4 (3C), 36.5 (1C),
36.9 (3C), 39.3 (3C), 67.7 (1C), 118.7 (1C), 123.5
(1C), 127.1 (1C), 127.8 (2C), 128.7 (2C), 136.7 (1C),
138.2 (1C), 139.3 (1C), 143.8 (1C). Mass spectrum:
m/z 319.214 [M + H]+. C22H27N2. Calculated: (M + H)
319.217.
N-Pyridinyl-substituted amines IX–XV (general
procedure). A two-necked flask was charged under
argon with 0.25 mmol (40 mg) of 3-bromopyridine,
4 mol % (6 mg) of Pd(dba)2, and 4.5 mol % (7 mg) of
BINAP, and 2.5 ml of anhydrous dioxane, 0.25 mmol
of amine II–VIII, and 0.38 mmol (35 mg) of sodium
tert-butoxide were added. The mixture was stirred for
7 h under reflux and cooled, the precipitate was filtered
off, the filtrate was evaporated, the solid residue was
dissolved in methylene chloride, the solution was
washed with water, the organic phase was dried over
sodium sulfate and evaporated under reduced pressure,
and the residue was subjected to chromatographic
separation on silica gel using a sequence of eluents:
CH2Cl2, CH2Cl2–MeOH (200:1 to 3:1), CH2Cl2–
MeOH–aq. NH3. The products were isolated with
CH2Cl2–MeOH (50:1) (unless otherwise stated) as
colorless or light yellow oily substances.
N-[1-(Adamantan-1-yl)propan-2-yl]pyridin-3-
amine (XII) was synthesized from 0.25 mmol (48 mg)
of amine V. Yield 59 mg (88%). 1H NMR spectrum, δ,
ppm: 1.14 d (3H, 3J = 6.2 Hz), 1.24 d.d (1H, 2J = 14.5,
2
3
3J = 4.3 Hz), 1.29 d.d (1H, J = 14.5, J = 7.0 Hz),
1.50–1.52 m (6H), 1.55–1.69 m (6H), 1.91 br.s (3H),
3.44 br.s (1H), 3.57 br.s (1H), 6.80 d.d.d (1H, 3J = 8.3,
3
4J = 2.9, 1.3 Hz), 7.03 d.d (1H, J = 8.3, 4.7 Hz),
3
4
4
7.87 d.d (1H, J = 4.7, J = 1.3 Hz), 7.94 d (1H, J =
13
2.9 Hz). C NMR spectrum, δC, ppm: 23.0 (1C), 28.5
(3C), 32.4 (1C), 36.9 (3C), 43.0 (3C), 43.9 (1C), 52.7
(1C), 118.3 (1C), 123.7 (1C), 136.1 (1C), 137.8 (1C),
143.2 (1C). Mass spectrum: m/z 271.224 [M + H]+.
C18H27N2. Calculated: (M + H) 271.217.
N-[2-(Adamantan-1-yloxy)ethyl]pyridin-3-amine
(IX) was synthesized from 0.25 mmol (49 mg) of
1
amine II. Yield 58 mg (85%). H NMR spectrum, δ,
N-[1-(Adamantan-1-yl)propyl]pyridin-3-amine
(XIII). a. Compound XIII was synthesized from
0.25 mmol (48 mg) of amine VI using Pd(dba)2/
BINAP (4/4.5 mol %, 6/7 mg) as catalytic system.
Yield 25 mg (37%).
ppm: 1.55–1.64 m (6H), 1.70–1.72 m (6H), 2.13 br.s
3
3
(3H), 3.22 q (2H, J = 5.2 Hz), 3.60 t (2H, J =
3
4
5.2 Hz), 4.12 br.s (1H), 6.87 d.d.d (1H, J = 8.2, J =
3
2.8, 1.3 Hz), 7.04 d.d (1H, J = 8.2, 4.7 Hz), 7.92 d.d
3
4
4
(1H, J = 4.7, J = 1.3 Hz), 8.03 d (1H, J = 2.8 Hz).
13C NMR spectrum, δC, ppm: 30.4 (3C), 36.3 (3C),
41.5 (3C), 43.9 (1C), 58.0 (1C), 72.4 (1C), 118.9 (1C),
123.6 (1C), 136.4 (1C), 138.8 (1C), 144.3 (1C). Mass
spectrum: m/z 273.193 [M + H]+. C17H25N2O. Calculat-
ed: (M + H) 273.197.
b. The reaction was carried out with the same
amounts of the reactants using Pd(dba)2/DavePhos
(8/9 mol %, 12/9 mg) as catalytic system. Eluent
CH2Cl2–MeOH (100:1). Yield 50 mg (74%). 1H NMR
3
spectrum, δ, ppm: 0.87 t (3H, J = 7.3 Hz), 1.16 d.d.q
2
(1H, J = 14.6, 3J = 10.8, 7.3 Hz), 1.47–1.72 m (12H),
N-(Adamantan-1-ylmethyl)pyridin-3-amine (X)
was synthesized from 0.25 mmol (41 mg) of amine III.
Yield 58 mg (95%). 1H NMR spectrum, δ, ppm: 1.53–
1.55 m (6H), 1.60–1.73 m (6H), 1.97 br.s (3H), 2.76 d
2
3
1.79 d.q.d (1H, J = 14.6, J = 7.3, 2.9 Hz), 1.95 br.s
(3H), 2.78 t.d (1H, 3J = 10.5, 2.9 Hz), 3.42 d (1H, 3J =
3
4
10.0 Hz), 6.83 d.d.d (1H, J = 8.4, J = 2.6, 0.9 Hz),
3
3
3
3
6.98 d.d (1H, J = 8.4, 4.6 Hz), 7.81 d (1H, J =
(2H, J = 6.1 Hz), 3.79 br.s (1H), 6.84 d.d.d (1H, J =
4
3
13
8.2, J = 2.8, 1.3 Hz), 7.00 d.d (1H, J = 8.2, 4.5 Hz),
4.6 Hz), 8.01 br.s (1H). C NMR spectrum, δC, ppm:
3
4
4
7.87 d.d (1H, J = 4.5, J = 1.3 Hz), 8.01 d (1H, J =
11.9 (1C), 22.9 (1C), 28.4 (3C), 37.1 (3C), 37.8 (1C),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

ARYLATION OF ADAMANTANAMINES: VI.
5
39.0 (3C), 64.3 (1C), 117.6 (1C), 123.6 (1C), 135.8
(1C), 137.2 (1C), 146.3 (1C). Mass spectrum:
m/z 271.211 [M + H]+. C18H27N2. Calculated: (M + H)
271.217.
N-{[3-(Aminomethyl)adamantan-1-yl]methyl}-
pyridin-3-amine (XXI) was the major product of the
reaction of diamine XVI with 3-bromopyridine. It was
isolated by chromatography using CH2Cl2–MeOH–aq.
NH3 (100:20:1) as eluent. Yield 30 mg (44%).
1H NMR spectrum, δ, ppm: 1.33 br.s (2H), 1.38–
1.55 m (8H), 1.60 br.s (2H), 2.07 br.s (2H), 2.41 s
(2H), 2.80 s (2H), 2.83 br.s (2H), 3.93 s (1H), 6.85 d.d
N-(Adamantan-1-yl)pyridine-3-amine (XIV).
a. Compound XIV was synthesized from 0.25 mmol
(38 mg) of amine VII using Pd(dba)2/BINAP
(8/9 mol %, 12/14 mg) as catalytic system. Yield
12 mg (20%).
3
4
3
(1H, J = 8.1, J = 2.5 Hz), 7.02 d.d (1H, J = 8.1,
3
4
4.6 Hz), 7.85 d (1H, J = 4.6 Hz), 8.03 d (1H, J =
b. The reaction was carried out with the same
amounts of the reactants in the presence of Pd(dba)2/
DavePhos (8/9 mol %, 12/9 mg). Yield 40 mg (70%).
1H NMR spectrum, δ, ppm: 1.61–1.70 m (6H), 1.84–
1.86 m (6H), 2.10 br.s (3H), 3.35 br.s (1H), 7.02 d.d
13
2.5 Hz). C NMR spectrum, δC, ppm: 28.3 (2C), 34.2
(1C), 34.6 (1C), 36.4 (1C), 39.4 (2C), 40.1 (2C), 42.7
(1C), 53.7 (1C), 55.4 (1C), 118.1 (1C), 123.7 (1C),
135.8 (1C), 137.8 (1C), 145.2 (1C). Mass spectrum:
m/z 272.210 [M + H]+. C17H26N3. Calculated: (M + H)
272.213.
3
3
4
(1H, J = 8.1, 4.4 Hz), 7.07 d.d.d (1H, J = 8.1, J =
2.7, 1.5 Hz), 7.98 d (1H, 3J = 4.4 Hz), 8.10 d (1H, 4J =
2.7 Hz). C NMR spectrum, δC, ppm: 29.6 (3C), 36.3
13
N,N′-[Adamantane-1,3-diylbis(ethane-2,1-diyl)]-
dipyridin-3-amine (XXII). a. Compound XXII was
synthesized from 0.25 mmol (56 mg) of diamine XVII
and 0.55 mmol (87 mg) of 3-bromopyridine in the
presence of 8 mol % (12 mg) of Pd(dba)2, 9 mol %
(14 mg) of BINAP, and 0.73 mmol (70 mg) of sodium
tert-butoxide in 2.5 ml of dioxane. The product was
isolated by chromatography using CH2Cl2–MeOH
(20:1 to 10:1) as eluent. Yield 51 mg (54%).
(3C), 43.2 (3C), 52.3 (1C), 123.2 (1C), 124.3 (1C),
139.9 (1C), 140.7 (1C), 142.3 (1C). Mass spectrum:
m/z 229.173 [M + H]+. C15H21N2. Calculated: (M + H)
229.171.
N-(Adamantan-2-yl)pyridin-3-amine (XV) was
synthesized from 0.25 mmol (38 mg) of amine VIII;
eluent CH2Cl2–MeOH (100:1 to 50:1). Yield 54 mg
1
(95%). H NMR spectrum, δ, ppm: 1.60 d (2H, J =
12.6 Hz), 1.74 br.s (2H), 1.76–1.92 m (8H), 1.99 br.s
(3H), 3.51 br.s (1H), 3.99 br.s (1H), 6.82 d.d.d (1H,
b. The reaction was carried out with the same
amounts of the reactants using 4 mol % (6 mg) of
Pd(dba)2 and 4.5 mol % (7 mg) of BINAP; eluent
CH2Cl2–MeOH (35:1 to 10:1). Yield 53 mg (55%).
1H NMR spectrum, δ, ppm: 1.31 br.s (2H), 1.39–
1.48 m (8H), 1.51–1.57 m (4H), 1.61 br.s (2H),
2.05 br.s (2H), 3.07–3.13 m (4H), 3.58 br.s (2H),
6.83 d.d (2H, 3J = 8.2, 4J = 2.4 Hz), 7.05 d.d (2H, 3J =
8.2, 4.7 Hz), 7.92 d (2H, 3J = 4.7 Hz), 7.98 d (2H, 4J =
4
3
3J = 8.3, J = 2.8, 1.3 Hz), 7.03 d.d (1H, J = 8.3,
3
4
4.7 Hz), 7.88 d.d (1H, J = 4.7, J = 1.3 Hz), 8.00 d
4
13
(1H, J = 2.8 Hz). C NMR spectrum, δC, ppm: 27.2
(1C), 27.3 (1C), 31.3 (2C), 31.4 (2C), 37.2 (2C), 37.5
(1C), 56.5 (1C), 118.5 (1C), 123.6 (1C), 136.4 (1C),
138.0 (1C), 143.3 (1C). Mass spectrum: m/z 229.163
[M + H]+. C15H21N2. Calculated: (M + H) 229.171.
N,N′-[Adamantane-1,3-diylbismethylene]dipyri-
din-3-amine (XX) was synthesized from 0.25 mmol
(49 mg) of diamine XVI and 0.55 mmol (87 mg) of
3-bromopyridine in the presence of 8 mol % (12 mg)
of Pd(dba)2, 9 mol % (9 mg) of DavePhos, and
0.73 mmol (70 mg) of sodium tert-butoxide in 2.5 ml
of dioxane. The product was isolated by chromatog-
raphy using CH2Cl2–MeOH (10:1) as eluent. Yield
13
2.3 Hz). C NMR spectrum, δC, ppm: 28.8 (2C), 32.7
(2C), 36.3 (1C), 38.2 (2C), 41.9 (4C), 43.4 (2C), 47.7
(1C), 118.3 (2C), 123.7 (2C), 135.9 (2C), 138.4 (2C),
144.3 (2C). Mass spectrum: m/z 377.268 [M + H]+.
C17H26N3. Calculated: (M + H) 377.271.
N-[2-(3-{2-[Di(pyridin-3-yl)amino]ethyl}ada-
mantan-1-yl)ethyl]pyridin-3-amine (XXIII) was iso-
lated as the second product in the reaction of diamine
XVII with 3-bromopyridine. Yield 32 mg (37%)
(a; eluent CH2Cl2–MeOH, 10 : 1); 21 mg (25%)
1
16 mg (18%). H NMR spectrum, δ, ppm: 1.38 br.s
(2H), 1.46–1.59 m (8H), 1.64 br.s (2H), 2.12 br.s (2H),
3
2.83 s (4H), 3.78 br.s (2H), 6.85 d (2H, J = 8.1 Hz),
1
3
3
(b; CH2Cl2–MeOH, 20:10 to 10:1). H NMR spec-
7.03 d.d (2H, J = 8.1, 4.5 Hz), 7.89 d (2H, J =
13
trum, δ, ppm: 1.28 br.s (2H), 1.38–1.48 (8H), 1.49–
1.56 m (4H), 1.60 br.s (2H), 2.04 br.s (2H), 3.06–
3.12 m (2H), 3.61 br.s (1H), 3.71–3.77 m (2H), 6.82 d
4.5 Hz), 8.02 br.s (2H). C NMR spectrum, δC, ppm:
28.3 (2C), 34.8 (2C), 36.3 (1C), 40.0 (4C), 43.5 (1C),
55.4 (2C), 118.1 (2C), 123.6 (2C), 136.0 (2C), 138.2
(2C), 145.0 (2C). Mass spectrum: m/z 349.245
[M + H]+. C22H29N4. Calculated: (M + H) 349.239.
3
3
(1H, J = 8.2 Hz), 7.04 d.d (1H, J = 8.2, 4.8 Hz),
3
3
7.17 d.d (2H, J = 8.1, 4.5 Hz), 7.25 d (2H, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

AVERIN et al.
8.1 Hz), 7.90 d (1H, J = 4.8 Hz), 7.97 br.s (1H),
6
3
141.2 (1C), 144.9 (1C). Mass spectrum: m/z 348.235
[M + H]+. C23H30N3. Calculated: (M + H) 348.244.
3
4
8.21 d (2H, J = 4.5 Hz), 8.31 d (2H, J = 2.3 Hz).
13C NMR spectrum, δC, ppm: 28.8 (2C), 32.6 (2C),
36.3 (1C), 38.2 (1C), 40.1 (1C), 41.5 (2C), 41.8 (2C),
43.4 (1C), 46.9 (1C), 47.4 (1C), 118.3 (1C), 123.6
(1C), 123.8 (2C), 127.4 (2C), 135.8 (1C), 138.4 (1C),
142.7 (2C), 142.9 (2C), 143.2 (2C), 144.3 (1C). Mass
spectrum: m/z 454.302 [M + H]+. C29H36N5. Calculat-
ed: (M + H) 454.297.
N-(4-{3-[2-(Pyridin-3-ylamino)ethyl]adamantan-
1-yl}phenyl)pyridin-3-amine (XXVI) was synthe-
sized from 0.25 mmol (68 mg) of diamine XIX and
0.5 mmol (79 mg) of 3-bromopyridine in the presence
of 4 mol % (6 mg) of Pd(dba)2, 4.5 mol % (7 mg) of
BINAP, and 0.75 mmol (73 mg) of sodium tert-butox-
ide in 2.5 ml of dioxane. The product was isolated by
chromatography using CH2Cl2–MeOH (20:1) as
eluent. Yield 60 mg (56%). 1H NMR spectrum, δ, ppm:
1.45–1.49 m (2H), 1.51–1.71 m (8H), 1.84 br.s (4H),
2.17 br.s (2H), 3.11–3.15 m (2H), 3.62 br.s (1H),
N-({3,5-Dimethyl-7-[2-(pyridin-3-ylamino)ethyl]-
adamantan-1-yl}methyl)pyridin-3-amine (XXIV)
was synthesized from 0.25 mmol (59 mg) of diamine
XVIII and 0.55 mmol (87 mg) of 3-bromopyridine in
the presence of 4 mol % (6 mg) of Pd(dba)2, 4.5 mol %
(7 mg) of DavePhos, and 0.73 mmol (70 mg) of
sodium tert-butoxide in 2.5 ml of dioxane. The product
was isolated by chromatography using CH2Cl2–MeOH
(20:1 to 10:1) as eluent. Yield 46 mg (47%). H NMR
spectrum, δ, ppm: 0.86 s (6H), 1.12–1.22 m (12H),
1.45–1.49 m (2H), 2.86 d (2H, J = 5.8 Hz), 3.09–
3.12 m (2H), 3.54 br.s (1H), 3.72 br.s (1H), 6.82 d.d.d
3
4
6.07 br.s (1H), 6.82 d.d.d (1H, J = 8.2, J = 2.8,
3
1.4 Hz), 7.02–7.07 m (3H), 7.11 d.d (1H, J = 8.2,
4.7 Hz), 7.26 d (2H, 3J = 8.5 Hz), 7.34 d.d.d (1H, J =
3
3
8.3, 4J = 2.7, 1.5 Hz), 7.92 d (1H, J = 4.7 Hz), 7.99 d
(1H, 4J = 2.8 Hz), 8.10 d (1H, 3J = 4.7 Hz), 8.33 d (1H,
1
4J = 2.7 Hz). C NMR spectrum, δC, ppm: 29.2 (2C),
13
3
33.0 (1C), 36.0 (1C), 36.4 (1C), 38.2 (1C), 41.6 (2C),
42.5 (2C), 43.5 (1C), 48.5 (1C), 118.3 (1C), 118.5
(2C), 122.7 (1C), 123.6 (1C), 123.7 (1C), 125.8 (2C),
135.9 (1C), 138.4 (1C), 139.5 (1C), 139.6 (1C), 140.3
(1C), 141.3 (1C), 144.4 (1C), 144.6 (1C). Mass spec-
trum: m/z 425.266 [M + H]+. C28H33N4. Calculated:
(M + H) 425.271.
3
4
3
(1H, J = 8.3, J = 2.9, 1.3 Hz), 6.85 d.d.d (1H, J =
8.3, 4J = 2.9, 1.3 Hz), 7.02–7.07 m (2H), 7.90 d.d (1H,
3J = 4.6, J = 2.9 Hz), 7.93 d.d (1H, J = 4.7, J =
4
3
4
4
4
2.9 Hz), 7.98 d (1H, J = 1.3 Hz), 8.02 d (1H, J =
13
1.3 Hz). C NMR spectrum, δC, ppm: 30.1 (2C), 31.7
(2C), 34.2 (1C), 36.5 (1C), 38.4 (1C), 42.7 (1C), 44.4
(1C), 46.4 (2C), 48.3 (2C), 50.6 (1C), 54.9 (1C), 118.1
(1C), 118.3 (1C), 123.6 (2C), 135.9 (1C), 136.0 (1C),
138.3 (1C), 138.5 (1C), 144.3 (1C), 145.0 (1C). Mass
spectrum: m/z 391.288 [M + H]+. C25H35N4. Calculat-
ed: (M + H) 391.286.
This study was performed under financial support
by the Russian Academy of Sciences (program no. P-8,
“Development of the Methodology of Organic Synthe-
sis and Design of Compounds with Valuable Practical
Properties”) and by the Russian Foundation for Basic
Research (project no 10-03-01108).
N-{4-[3-(2-Aminomethyl)adamantan-1-yl]-
phenyl}pyridin-3-amine (XXV) was synthesized
from 0.37 mmol (102 mg) of diamine XIX and
0.37 mmol (60 mg) of 3-bromopyridine in the presence
of 4 mol % (9 mg) of Pd(dba)2, 4.5 mol % (10 mg) of
BINAP, and 0.56 mmol (54 mg) of sodium tert-butox-
ide in 3.5 ml of dioxane. The product was isolated by
chromatography using CH2Cl2–MeOH–aq. NH3
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