Synthesis of a new family of adamantylpyridin-2-amines by palladium-catalyzed amination

Article abstract of DOI:10.1055/s-2007-983760

Palladium-catalyzed arylation of various adamantane-containing amines with 2-bromopyridine has been studied, and the influence of the phosphane ligand, concentration, and molar ratio of the reagents on the composition of the reaction mixture and on the yield of the target adamantylpyridin-2-amines has been analyzed. The dependence of the formation of N,N-diarylated products on the nature of the starting adamantylamines is shown. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983760

PAPER
2215
Synthesis of a New Family of Adamantylpyridin-2-amines by Palladium-
Catalyzed Amination
Synthesis of
A
dam
l
antylpy
e
ridin-2-am
x
ine
s
ei D. Averin,*a Elena R. Ranyuk,a Svetlana L. Golub,b Alexei K. Buryak,b Evgenii N. Savelyev,c
Boris S. Orlinson,c Ivan A. Novakov,c Irina P. Beletskaya*a
a
Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, Moscow 119992, Russian Federation
Fax +7(495)9393618; E-mail: averin@org.chem.msu.ru
A.N. Frumkin Institute of Physical Chemistry and Electrochemistry, 31 Leninskii prosp., Moscow 119991, Russian Federation
Volgograd State Technical University, 28 Lenina prosp., Volgograd 400131, Russian Federation
b
c
Received 8 December 2006; revised 14 May 2007
compounds 3a–f as well as byproducts were isolated by
column chromatography on silica gel. The reaction condi-
tions, yields, and other experimental data are summarized
in Table 1.
Abstract: Palladium-catalyzed arylation of various adamantane-
containing amines with 2-bromopyridine has been studied, and the
influence of the phosphane ligand, concentration, and molar ratio of
the reagents on the composition of the reaction mixture and on the
yield of the target adamantylpyridin-2-amines has been analyzed.
The dependence of the formation of N,N-diarylated products on the
nature of the starting adamantylamines is shown.
The result of the reaction (Scheme 1) proved to be strong-
ly dependent on the nature of the starting amines 1a–f and
mainly on the number of covalent bonds between the ami-
no group and the adamantane fragment. Thus, 1-amino-
adamantane (1a) showed low activity in the amination
process, and was converted into its pyridyl derivative 3a
in only 20% yield (Table 1, entries 1 and 2).9 Simulta-
neously, a notable amount of 2,2¢-bipyridyl (5) formed.
This may be due to the bulkiness of the 1-adamantyl sub-
stituent at the nitrogen atom in 1a.
Key words: amines, aminations, homogeneous catalysis, polycy-
cles, pyridines
Aminoadamantanes and their derivatives are important
compounds, which have found wide application as drugs,
and are extensively investigated for various applications
in pharmacology and biological studies. For example, 1-
aminoadamantane hydrochloride (amantadine), the sim-
plest compound of this type, has proved to be an efficient
medicine against Parkinson’s desease,1,2 and has also
found application in the treatment of hepatitis C infec-
tion.3 1-(1-Adamantyl)ethanamine (rimantadine)4 is
widely used as an antiviral agent, and memantine5 serves
as an N-methyl-D-aspartate (NMDA) antagonist; other
drugs have more complex structures, and often include ar-
omatic moieties, as in chlodantane6 (immunostimulant)
and ladasten7 (neurostimulating agent). From this per-
spective, we decided to elaborate a convenient procedure
to obtain a new family of N-arylated adamantane-contain-
ing amines for their further screening as potentially bioac-
tive molecules. In this communication we report the
synthesis of a series of adamantane-containing 2-ami-
nopyridines by palladium-catalyzed amination of 2-bro-
mopyridine with appropriate amines.
NH2
H
N
X
X
N
3a–f
1a–f
Pd(dba)2/L
+
+
t-BuONa,
dioxane
N
+
2,2'-bpy
N
Br
N
2
5
X
N
4b,c,e,f
Ad-X-NH2: 1-AdNH2 (1a)
1-AdCH2NH2 (1b)
1-AdCH(Et)NH2 (1c)
1-AdCH(Ph)NH2 (1d)
Amines 1a–f were employed in the reaction with 2-bro-
mopyridine (2) (Scheme 1). At first we used the catalytic
system Pd(dba)2/BINAP (2–4 mol%) [dba = dibenzylide-
neacetone; BINAP = 2,2¢-bis(diphenylphosphanyl)-1,1¢-
binaphthyl], proposed by Buchwald for the amination of
2- and 3-bromopyridines.8 The reactions were run in boil-
ing 1,4-dioxane (0.1–0.2 M), sodium tert-butoxide was
used as a base, and the composition of the reaction mix-
1-AdCH2CH(Et)NH2 (1e)
1-AdCH2CH(Me)NH2 (1f)
Scheme 1 The arylation of amines 1a–f with 2-bromopyridine (2)
The amination was more successful with amines 1b–d
where the amino and adamantyl groups are separated by
two bonds (Table 1, entries 6, 9–11). Bipyridyl 5 formed
in smaller amounts, whereas the formation of N,N-diaryl-
ated byproducts 4 depended strongly on the nature of the
amine: (aminomethyl)adamantane (1b) provided substan-
tial amounts of byproduct 4b (Table 1, entry 6), whereas
more sterically hindered 1c gave the corresponding 4c in
1
tures was analyzed by H NMR spectroscopy. Target
SYNTHESIS 2007, No. 14, pp 2215–2221
x
x.
x
x
.
2
0
0
7
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983760; Art ID: Z25506SS
© Georg Thieme Verlag Stuttgart · New York

2216
A. D. Averin et al.
PAPER
Table 1 Synthesis of Adamantylpyridin-2-amines 3a–fa
Entry
Amine
Ratio 1/2 Ligandb
Amounts
Pd(dba)2/L
(mol%)
Concn (M) Reaction
time (h)
Ratio 3/4/5
Conversion Product 3 Yieldc
of amine (%)
(%)
1
2
1a
1a
1a
1a
1a
1b
1b
1b
1c
1d
1d
1e
1e
1e
1e
1e
1f
1:1
BINAP
BINAP
L1
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
4/4.5
2/2.5
2/2.5
4/4.5
4/4.5
4/4.5
2/2.5
2/2.5
2/2.5
2/2.5
2/2.5
2/2.5
2/2.5
2/2.5
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.16
0.1
0.1
0.13
0.16
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
4
4.5
5
5
5
6
5
5
6
5
4
4
4
6
4
4
6
8
8
8
8
9
7
9
7
1:0:0.33
20
20
80
35
25
70
95
10d
45
70
75
62
50
50
75
95
55
82
84
84
70
33
22
17
13
3a
3a
12
12
1:1
1:0:0.35
3
1:1
1:0:0
4
1:1
L2
1:0:0.06
5
1:1
L3
1:0:0.33
6
1:1
BINAP
L1
1:0.65:0.01
1:0:0.01
3b
3b
41
92
7
1:1
8
1:1
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
L1
1:0:0
9
1:1.25
1:1.5
1:1.5
1:1
1:0.08:0.07
1:0:0.06
3c
3d
3d
41
37
64
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1:0:0.08
1:0.75:0.03
1:0.6:0.05
1:0.5:0.12
1:0.2:0.11
1:0.02:0.005
1:1.1:0.4
1:0.05:0.01
1:0.04:0.01
1:0.03:0.005
1:0.05:0
1:1
1:1.5
1:1.5
1:1
3e
3e
19
48
1:1.25
1:1
BINAP
L1
3f
3f
31
60
1f
1f
1:1
L2
1f
1:1
L3
1f
1:1
L4
1f
1:1
L5
1:0.03:0.06
1:0.02:0.06
1:0.02:0.04
1:0.02:0.04
1f
1:1
L6
1f
1:1
L7
1f
1:1
L8
a The reaction conditions are shown in Scheme 1.
b The ligands are defined in Figure 1.
c Isolated yield of 3.
d Cs2CO3 was used as the base instead of t-BuONa.
small quantities (entry 9). Amine 1d did not give the N,N- than in 1c and 1d. N,N-Diarylated derivatives 4e and 4f
diarylated derivative at all (Table 1, entries 10, 11), and formed in substantial amounts (Table 1, entries 12–15,
BINAP proved to be quite efficient for the synthesis of 3d. 17), like 4b (entry 6). Higher concentrations of the start-
As shown in Table 1, the application of an excess of 2- ing materials partially helped to solve the problem, with
bromopyridine (1.25–1.5 equiv) as well as a higher con- the yield of monoarylated species 3e increasing and the
centration (0.16 M instead of 0.1 M) can lead to a higher amount of diarylated product 4e decreasing, even when an
conversion and better yield of the product.
excess of bromopyridine was used (Table 1, entry 15). On
the other hand, a lower catalyst loading (2 mol% rather
than 4 mol%) led in all cases to lower conversions of the
The use of the BINAP ligand was moderately efficient for
amines 1e and 1f where the amino group is less hindered
Synthesis 2007, No. 14, 2215–2221 © Thieme Stuttgart · New York

PAPER
Synthesis of Adamantylpyridin-2-amines
2217
amine and to worse yields (Table 1, entries 13, 14). It (Scheme 2, Table 2). Two equivalents of 2-bromopyri-
should be noted that BINAP normally does not provide dine were used because products 7a,b of monoarylation of
diarylation products, unlike 1,1¢-bis(diphenylphosphan- both amino groups were the target compounds. It was
yl)ferrocene (dppf).10 Our own experiments on the poly- found that BINAP was useless for this purpose: in the case
arylation of diamines showed that N,N-diarylation of of 6a it provided a 2:1 mixture of tri- and diarylated prod-
linear polyamines occurred only when a great excess of ucts 8a and 7a (Scheme 2, Table 2, entry 1), whereas with
the arylating agent and generous amounts of the catalyst 6b only tri- and tetraarylated derivatives 8b and 9b were
were used.11
detected and isolated (Table 2, entry 3). It is possible that
the use of a greater amount of catalyst and a more concen-
trated solution additionally aggravated the situation. The
ligand L1 gave much better results: in the reaction with 6a
no triarylated byproduct 8a was detected at all, and the
isolated yield of the target compound reached 81%
(Table 2, entry 2); the reaction with 6b provided 77% of
the desired product 7b owing to a substantial decrease of
N,N-diarylation (Table 2, entry 4). It was possible to re-
duce the amount of catalyst from 4% to 2%, and this led
to a further decrease in 8b formation (Table 2, entry 5).
Ligands L2 and L3 proved to be equally effective in the
reaction (Table 1, entries 6–8).
Taking all these facts into consideration, we tried another
ligand,
2-(dicyclohexylphosphanyl)-2¢-(dimethylami-
no)biphenyl (L1) (Figure 1), in the reaction of 1e with 2.12
The result was excellent: 95% conversion of the starting
amine was achieved and only traces of diarylated com-
pound 4e were observed after the reaction ran to comple-
tion (Table 1, entry 16). The same ligand, even in smaller
amount, allowed the isolation of 3b in 92% yield (Table 1,
entry 7). Using amine 1f, we compared the efficiency of
different donor ligands (Figure 1) in the arylation of ada-
mantane-containing amines. As is clear from Table 1, bi-
phenyl-based phosphane ligands L1–L3 provided high
yields of the target derivative 3f owing to high conversion
of the starting amine and insignificant formation of the di-
arylated byproduct 4f (Table 1, entries 18–20). Ligand L4
afforded a somewhat poorer result (Table 1, entry 21),
whereas ligands L5–L813 based on xanthene and diphenyl
ether were inefficient (Table 1, entries 22–25). As for the
most sterically hindered amine, 1-aminoadamantane (1a),
use of ligand L1 led to its highest conversion into the cor-
responding product 2a, with no bipyridyl formation
(Table 1, entry 3), while ligands L2 and L3 were less ac-
tive (Table 1, entries 4, 5). We also tried cesium carbonate
as a base instead of sodium tert-butoxide, but this led to
insignificant conversion of the amine (Table 1, entry 8).
NH2
n
Pd(dba)2/L
+
NH2
t-BuONa,
N
Br
dioxane
2
n
6a: n = 0
6b: n = 1
N
N
n
H
HN
N
n
7a: n = 0
7b: n = 1
We also investigated the reactions of adamantane-based
diamines 6a,b with two equivalents of 2-bromopyridine
+
N
N
N
N
n
N
H
n
P(Cy)2
P(Cy)2
P(t-Bu)2
N
N
N
N
Me2N
N
n
N
n
L1
L2
L3
9a: n = 0
9b: n = 1
8a: n = 0
8b: n = 1
Scheme 2 Arylation of adamantane-based diamines 6a,b
P(t-Bu)2
O
Me2N
P(Cy)2
L5
P(Cy)2
Some of synthesized adamantane-containing pyridyl-
amines, namely 3b–f, were tested on mice for their phys-
iological activity, and phenyl-containing amine 3d was
found to act as a depressant.
L4
P(i-Pr)2
P(i-Pr)(t-Bu)
P(t-Bu)2
To summarize, we have investigated the reactions of var-
ious adamantane-containing amines with 2-bromopyri-
dine and optimized the conditions to obtain preparatory
yields of N-monoarylated derivatives 3 and 7. The appli-
cation of biphenyl-based donor phosphane ligands was
shown to be advantageous over BINAP in many cases.
O
O
O
(t-Bu)(i-Pr)P
(t-Bu)2P
(i-Pr)2P
L6
L7
L8
Figure 1 Donor phosphane ligands L1–L8
Synthesis 2007, No. 14, 2215–2221 © Thieme Stuttgart · New York

2218
A. D. Averin et al.
PAPER
Table 2 Synthesis of Bis(2-pyridyl)-Substituted Diamines 7a,ba
Entry
Amine
Ratio 6/2
Ligandb
Amounts
Pd(dba)2/L
(mol%)
Concn (M) Time (h)
Ratio
pyNH/py2N
Product 7
Yieldc (%)
1
2
3
4
5
6
7
8
6a
6a
6b
6b
6b
6b
6b
6b
1:2
1:2
1:2.5
1:2
1:2
1:2
1:2
1:2
BINAP
L1
4/4.5
4/4.5
8/9
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
6
5
5
5
5
7
7
7
2:1
7a
7a
–
32d
81
1:0:
e
BINAP
L1
1:3.2
1:0.15
1:0.11
1:0.11
1:0.1
1:0.2
–
4/4.5
2/2.5
4/4.5
2/2.5
2/2.5
7b
77
L1
L2
L2
L3
a The reaction conditions are shown in Scheme 2.
b The ligands are defined in Figure 1.
c Isolated yield of 7.
d Yield of mixture of 7a and 8a.
e Isolated yields: 23% (9b), 17% (8b).
NMR spectra were recorded on a Bruker Avance-400 spectrometer
at r.t.; the chemical shifts d were measured in ppm relative to TMS.
MALDI-TOF mass spectra were recorded on a Bruker Daltonics
Ultraflex spectrometer with dithranol or trihydroxyacetophenone as
matrix. Column chromatography was performed on 40–60-mesh
silica gel purchased from Fluka. 2-Bromopyridine (pyBr) was pur-
chased from Acros, 1,4-dioxane was distilled successively over
NaOH and Na, and CH2Cl2 and MeOH were used freshly distilled.
Pd(dba)2 was obtained by a described method.14 The starting amines
1-aminoadamantane (1a),15 1-(aminomethyl)adamantane (1b),16
1,3-bis(aminomethyl)adamantane (6a), and 1,3-bis(2-aminoeth-
yl)adamantane (6b)17 were synthesized according to known proce-
dures.
1-(1-Adamantyl)butan-2-amine (1e)
The procedure is analogous to the synthesis of 1d described above,
but EtI (11.3 g, 0.14 mol) was used instead of PhBr, 1-(cyanometh-
yl)adamantane (17.5 g, 0.1 mol) was used instead of 1-cyanoada-
mantane, and the amount of LAH was decreased (5.63 g, 0.15 mol).
The reaction time was reduced to 3 h (first stage) and 20 h (second
stage).
Yield: 16.6 g (80%); colorless liquid; bp 98–102 °C/4 Torr.
1H NMR (400 MHz, CDCl3): d (1e·HCl) = 1.04 (t, J = 7.4 Hz, 3 H),
1.43 (dd, J = 14.9, 5.1 Hz, 1 H), 1.48–1.56 (m, 7 H), 1.59–1.70 (m,
6 H), 1.71–1.82 (m, 2 H), 1.95 (s, 3 H), 3.22 (q, J = 5.5 Hz, 1 H),
8.24 (br s, 3 H).
13C NMR (100.6 MHz, CDCl3): d (1e·HCl) = 9.97 (1 C), 28.30 (1
C), 28.38 (3 C), 32.11 (1 C), 36.69 (3 C), 42.36 (3 C), 46.92 (1 C),
49.33 (1 C).
1-(1-Adamantyl)-1-phenylmethanamine (1d)
A three-necked flask equipped with a stirrer, dropping funnel, and
condenser was charged with Mg (3.6 g, 0.15 mol) and absolute Et2O
(100 mL). PhBr (15.75 mL, 0.15 mol) dissolved in absolute Et2O
(300 mL) was added in 30 min, followed by the addition of 1-cy-
anoadamantane (16.1 g, 0.1 mol) dissolved in THF (300 mL). The
reaction mixture was stirred for an additional 8 h and was then add-
ed to a suspension of LAH (7.8 g, 0.21 mol) in THF (300 mL). The
mixture was refluxed for 40 h, cooled to r.t., and then H2O (11 mL),
12% aq NaOH (30 mL), and again H2O (30 mL) were added se-
quentially. The residue was collected by filtration and washed with
Et2O (3 × 150 mL). The organic phases were combined and the sol-
vents were evaporated. The residue was distilled under vacuum.
Anal. Calcd for C14H26ClN: C, 68.97; H, 10.75; N, 5.74. Found: C,
68.59; H, 10.61; N, 5.37.
1-(1-Adamantyl)propan-1-amine (1c)
The procedure is analogous to the synthesis of 1e described above,
but 1-cyanoadamantane (16.1 g, 0.1 mol) was used instead of 1-(cy-
anomethyl)adamantane. The reaction time was 3 h (first stage) and
25 h (second stage).
Yield: 13.5 g (70%); colorless liquid; bp 98–102 °C/4 Torr.
1H NMR (400 MHz, CDCl3): d = 0.88–0.90 (m, 3 H), 0.99 (br s, 2
H), 1.45 (s, 6 H), 1.54–1.65 (m, 8 H), 1.90 (s, 3 H), 1.96 (d, J = 8.9
Hz, 1 H).
Yield: 15.7 g (65%); colorless crystals; bp 159–163 °C/4 Torr; mp
67–68 °C.
13C NMR (100.6 MHz, CDCl3): d = 12.23 (1 C), 23.00 (1 C), 28.42
(3 C), 36.00 (1 C), 37.21 (3 C), 38.27 (3 C), 62.50 (1 C).
1H NMR (400 MHz, CDCl3): d = 1.47 (d, J = 11.6 Hz, 3 H), 1.54–
1.66 (m, 11 H), 1.95 (s, 3 H), 3.49 (s, 1 H), 7.22–7.30 (m, 5 H).
13C NMR (100.6 MHz, CDCl3): d = 28.41 (3 C), 37.00 (3 C), 38.63
(3 C), 39.00 (1 C), 65.94 (1 C), 126.62 (1 C), 127.35 (2 C), 128.37
(2 C), 142.69 (1 C).
Anal. Calcd for C13H23N: C, 80.76; H, 11.99; N, 7.25. Found: C,
80.50; H, 12.27; N, 6.94.
1-(1-Adamantyl)propan-2-amine (1f)
Anal. Calcd for C17H23N: C, 84.59; H, 9.60; N, 5.80. Found: C,
84.32; H, 9.94; N, 5.48.
A two-necked flask equipped with a condenser and thermometer
was charged with 1-adamantylpropan-2-one (38.4 g, 0.2 mol),
99.7% formic acid (45 g, 1 mol), and formamide (135 g, 3 mol). The
reaction mixture was refluxed at 165–175 °C for 20 h, cooled down
Synthesis 2007, No. 14, 2215–2221 © Thieme Stuttgart · New York

PAPER
Synthesis of Adamantylpyridin-2-amines
2219
to r.t., poured into H2O (200 mL), and extracted with benzene
(3 × 150 mL). The organic layers were combined and evaporated.
The residue was worked up with H2O (100 mL) and concd HCl (100
mL) to fully dissolve the residue. Then it was neutralized with 40%
aq NaOH and extracted with benzene (3 × 150 mL). After the sol-
vent had been evaporated, the residue was distilled under vacuum.
Yield: 221 mg (41%); pale yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 500:1 to 250:1).
1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 7.4 Hz, 3 H), 1.10–
1.22 (m, 1 H), 1.50–1.72 (m, 12 H), 1.73–1.82 (m, 1 H), 1.95 (s, 3
H), 3.17 (t, J = 10.2 Hz, 1 H), 4.26 (d, J = 9.3 Hz, 1 H), 6.37 (d,
J = 8.6 Hz, 1 H), 6.42–6.47 (m, 1 H), 7.31–7.36 (m, 1 H), 8.00 (d,
J = 5.0 Hz, 1 H).
Yield: 32.8 g (85%); colorless liquid; bp 135–138 °C/20 Torr.
1H NMR (400 MHz, CDCl3): d = 0.89 (d, J = 6.3 Hz, 3 H), 0.96 (dd,
J = 14.0, 6.3 Hz, 1 H), 1.02 (dd, J = 14.0, 4.0 Hz, 1 H), 1.23 (br s, 2
H), 1.37 (s, 6 H), 1.45–1.55 (m, 6 H), 1.78 (s, 3 H), 2.88–2.96 (m, 1
H).
13C NMR (100.6 MHz, CDCl3): d = 26.55 (1 C), 28.34 (3 C), 32.17
(1 C), 36.74 (3 C), 42.01 (1 C), 42.72 (3 C), 54.98 (1 C).
13C NMR (100.6 MHz, CDCl3): d = 11.58 (1 C), 22.33 (1 C), 28.28
(3 C), 36.97 (3 C), 37.30 (1 C), 38.68 (3 C), 62.15 (1 C), 105.83 (1
C), 111.47 (1 C), 137.05 (1 C), 147.77 (1 C), 160.24 (1 C).
MS (MALDI-TOF): m/z [M+] calcd for C18H26N2: 270.21; found:
270.17.
N-[(1-Adamantyl)(phenyl)methyl]pyridin-2-amine (3d)
Compound 3d was obtained from 1d (964 mg, 4 mmol) and 2 (948
mg, 6 mmol) in the presence of Pd(dba)2 (92 mg, 4 mol%) and
BINAP (110 mg, 4.5 mol%).
Anal. Calcd for C13H23N: C, 80.76; H, 11.99; N, 7.25. Found: C,
80.58; H, 11.67; N, 6.98.
Amines 3a–f; General Procedure
A flask flushed with anhyd argon and equipped with a magnetic stir-
rer and condenser was charged with pyBr (2; 0.5 mmol), Pd(dba)2
(2–4 mol%), the phosphane ligand (2.5–4.5 mol%), the appropriate
amine 1a–f (0.5 mmol), and absolute 1,4-dioxane (5 mL). t-BuONa
(0.55 mmol) was added, and the mixture was stirred under reflux for
4–9 h, and then cooled down to r.t.; the 1,4-dioxane was evaporated
under vacuum, and the residue was chromatographed (silica gel,
CH2Cl2, then CH2Cl2–MeOH, 500:1 to 3:1).
Yield: 810 mg (64%); pale yellow oil; chromatography (silica gel,
CH2Cl2).
1H NMR (400 MHz, CDCl3): d = 1.45–1.60 (m, 6 H), 1.63–1.75 (m,
6 H), 1.97 (s, 3 H), 4.05 (d, J = 7.6 Hz, 1 H), 5.35 (d, J = 7.6 Hz, 1
H), 6.11 (d, J = 8.3 Hz, 1 H), 6.44–6.48 (m, 1 H), 7.19–7.29 (m, 6
H), 8.00–8.02 (m, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 28.30 (3 C), 36.38 (1 C), 36.78
(3 C), 39.02 (3 C), 66.39 (1 C), 105.91 (1 C), 112.66 (1 C), 126.83
(1 C), 127.55 (2 C), 128.54 (2 C), 137.41 (1 C), 139.59 (1 C), 148.05
(1 C), 158.49 (1 C).
N-(1-Adamantylmethyl)pyridin-2-amine (3b)
Compound 3b was obtained from 1b (330 mg, 2 mmol) and 2 (316
mg, 2 mmol) in the presence of Pd(dba)2 (23 mg, 2 mol%) and
ligand L1 (20 mg, 2.5 mol%).
MS (MALDI-TOF): m/z [M+] calcd for C22H26N2: 318.21; found:
318.22.
Yield: 444 mg (92%); pale yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 500:1 to 200:1).
1H NMR (400 MHz, CDCl3): d = 1.56 (s, 6 H), 1.62–1.72 (m, 6 H),
1.98 (s, 3 H), 2.94 (d, J = 6.1 Hz, 2 H), 4.55 (br s, 1 H), 6.37 (d,
J = 8.3 Hz, 1 H), 6.48–6.53 (m, 1 H), 7.33–7.40 (m, 1 H), 8.03 (d,
J = 4.1 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 28.29 (3 C), 33.89 (1 C), 37.00
(3 C), 40.48 (3 C), 54.15 (1 C), 106.18 (1 C), 112.29 (1 C), 137.30
(1 C), 148.06 (1 C), 159.48 (1 C).
N-[1-(1-Adamantylmethyl)propyl]pyridin-2-amine (3e)
Compound 3e was obtained from 1e (828 mg, 4 mmol) and 2 (948
mg, 6 mmol) in the presence of Pd(dba)2 (92 mg, 4 mol%) and
BINAP (110 mg, 4.5 mol%).
Yield: 541 mg (48%); pale yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 1:0, then 250:1).
1H NMR (400 MHz, CDCl3): d = 0.88 (t, J = 7.5 Hz, 3 H), 1.17 (dd,
J = 14.4, 8.6 Hz, 1 H), 1.32 (dd, J = 14.4, 2.6 Hz, 1 H), 1.44–1.58
(m, 8 H), 1.56–1.69 (m, 6 H), 1.90 (s, 3 H), 3.64–3.70 (m, 1 H), 4.24
(d, J = 8.3 Hz, 1 H), 6.30 (d, J = 8.3 Hz, 1 H), 6.48 (ddd, J = 7.1,
5.1, 0.8 Hz, 1 H), 7.37 (ddd, J = 8.7, 7.7, 2.0 Hz, 1 H), 8.04 (ddd,
J = 5.1, 2.1, 0.8 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 9.73 (1 C), 28.62 (3 C), 29.53
(1 C), 32.38 (1 C), 36.96 (3 C), 42.95 (3 C), 48.00 (1 C), 50.02 (1
C), 106.04 (1 C), 111.91 (1 C), 137.31 (1 C), 148.29 (1 C), 158.03
(1 C).
MS (MALDI-TOF): m/z [M+] calcd for C16H22N2: 242.18; found:
242.20.
N-(1-Adamantylmethyl)-N-(2-pyridyl)pyridin-2-amine (4b)
Compound 4b was obtained as a byproduct in the synthesis of 3b
from 1b (83 mg, 0.5 mmol) and 2 (79 mg, 0.5 mmol) in the presence
of Pd(dba)2 (12 mg, 4 mol%) and BINAP (14 mg, 4.5 mol%).
Yield: 38 mg (24%); yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 200:1).
1H NMR (400 MHz, CDCl3): d = 1.48 (s, 6 H), 1.56–1.74 (m, 6 H),
1.84 (s, 3 H), 4.03 (s, 2 H), 6.77–6.81 (m, 2 H), 7.03 (d, J = 8.3 Hz,
2 H), 7.42–7.47 (m, 2 H), 8.27 (d, J = 3.8 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 28.38 (3 C), 36.26 (1 C), 36.86
(3 C), 41.10 (3 C), 58.75 (1 C), 115.25 (2 C), 116.74 (2 C), 136.77
(2 C), 147.87 (2 C), 158.86 (2 C).
MS (MALDI-TOF): m/z [M + H+] calcd for C19H29N2: 285.23;
found: 285.19.
N-[1-(1-Adamantylmethyl)propyl]-N-(2-pyridyl)pyridin-2-
amine (4e)
Compound 4e was obtained as a byproduct in the synthesis of 3e
(isolated as a mixture with 3e; molar ratio 4e/3e ca. 1:1); chroma-
tography (silica gel, CH2Cl2–MeOH, 100:1).
MS (MALDI-TOF): m/z [M+] calcd for C21H25N3: 319.20; found:
319.25.
1H NMR (400 MHz, CDCl3): d = 0.85 (t, J = 7.3 Hz, 3 H), 1.32 (dd,
J = 14.7, 4.3 Hz, 1 H), 1.43–1.67 (m, 13 H), 1.81 (dd, J = 14.9, 6.8
Hz, 1 H), 1.85 (s, 3 H), 1.98 (ddd, J = 16.6, 9.1, 7.3 Hz, 1 H), 5.08–
5.10 (m, 1 H), 6.78 (ddd, J = 7.1, 4.8, 0.8 Hz, 2 H), 6.85 (d, J = 8.4
Hz, 2 H), 7.41 (ddd, J = 9.1, 7.0, 1.0 Hz, 2 H), 8.33 (ddd, J = 5.0,
2.0, 0.8 Hz, 2 H).
N-[1-(1-Adamantyl)propyl]pyridin-2-amine (3c)
Compound 3c was obtained from 1c (386 mg, 2 mmol) and 2 (395
mg, 2.5 mmol) in the presence of Pd(dba)2 (46 mg, 4 mol%) and
BINAP (55 mg, 4.5 mol%).
13C NMR (100.6 MHz, CDCl3): d = 11.69 (1 C), 28.55 (3 C), 29.33
(1 C), 32.59 (1 C), 36.90 (3 C), 42.43 (3 C), 48.66 (1 C), 54.95 (1
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2220
A. D. Averin et al.
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C), 116.54 (2 C), 116.64 (2 C), 136.59 (2 C), 148.16 (2 C), 158.15
(2 C).
MS (MALDI-TOF): m/z [M+] calcd for C22H28N4: 348.23; found:
348.24.
MS (MALDI-TOF): m/z [M + H+] calcd for C24H32N3: 362.25;
found: 362.23.
1-[(Di-2-pyridylamino)methyl]-3-[(2-pyridylamino)methyl]ad-
amantane (8a)
Compound 8a was obtained as a byproduct in the synthesis of 7a
from 6a (97 mg, 0.5 mmol) and 2 (158 mg, 1 mmol) in the presence
of Pd(dba)2 (12 mg, 4 mol%) and BINAP (14 mg, 4.5 mol%).
N-[2-(1-Adamantyl)-1-methylethyl]pyridin-2-amine (3f)
Compound 3f was obtained from 1f (97 mg, 0.5 mmol) and 2 (79
mg, 0.5 mmol) in the presence of Pd(dba)2 (6 mg, 2 mol%) and
ligand L1 (5 mg, 2.5 mol%).
Yield: 44 mg (21%); yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 50:1).
Yield: 81 mg (60%); yellowish oil; chromatography (silica gel,
CH2Cl2, then CH2Cl2–MeOH, 500:1).
1H NMR (400 MHz, CDCl3): d = 1.15 (d, J = 6.3 Hz, 3 H), 1.22–
1.32 (m, 2 H), 1.53 (s, 6 H), 1.55–1.67 (m, 6 H), 1.90 (s, 3 H), 3.80–
3.91 (m, 1 H), 4.30 (d, J = 8.0 Hz, 1 H), 6.31 (d, J = 8.3 Hz, 1 H),
6.46–6.50 (m, 1 H), 7.33–7.39 (m, 1 H), 8.04 (d, J = 5.0 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 23.42 (1 C), 28.56 (3 C), 32.45
(1 C), 36.91 (3 C), 42.82 (1 C), 42.88 (3 C), 52.68 (1 C), 106.34 (1
C), 112.02 (1 C), 137.22 (1 C), 148.31 (1 C), 157.75 (1 C).
1H NMR (400 MHz, CDCl3): d = 1.32 (s, 2 H), 1.37–1.60 (m, 10 H),
1.94 (s, 2 H), 2.88 (d, J = 5.8 Hz, 2 H), 4.06 (s, 2 H), 4.59 (t, J = 5.8
Hz, 1 H), 6.30 (d, J = 8.4 Hz, 1 H), 6.44–6.49 (m, 1 H), 6.76–6.80
(m, 2 H), 6.99 (d, J = 8.4 Hz, 2 H), 7.30–7.36 (m, 1 H), 7.40–7.46
(m, 2 H), 7.98 (d, J = 5.0 Hz, 1 H), 8.25 (d, J = 4.6 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 28.45 (2 C), 34.64 (1 C), 36.23
(1 C), 36.94 (1 C), 39.80 (2 C), 40.62 (2 C), 43.98 (1 C), 53.79 (1
C), 58.40 (1 C), 106.30 (1 C), 112.17 (1 C), 115.25 (2 C), 116.94 (2
C), 136.98 (2 C), 137.41 (1 C), 147.69 (1 C), 148.03 (2 C), 158.86
(2 C), 159.27 (1 C).
MS (MALDI-TOF): m/z [M + H+] calcd for C18H27N2: 271.21;
found: 271.17.
MS (MALDI-TOF): m/z [M+] calcd for C27H31N5: 425.26; found:
425.39.
N-[2-(1-Adamantyl)-1-methylethyl]-N-(2-pyridyl)pyridin-2-
amine (4f)
Compound 4f was obtained as a byproduct in the synthesis of 3f
from 1f (386 mg, 2 mmol) and 2 (395 mg, 2.5 mmol) in the presence
of Pd(dba)2 (46 mg, 4 mol%) and BINAP (55 mg, 4.5 mol%).
1,3-Bis[(di-2-pyridylamino)methyl]adamantane (9a)
Compound 9a was obtained as a byproduct in the synthesis of 7a
from 6a (97 mg, 0.5 mmol) and 2 (158 mg, 1 mmol) in the presence
of Pd(dba)2 (12 mg, 4 mol%) and BINAP (14 mg, 4.5 mol%).
Yield: 28 mg (4%); yellow oil; chromatography (silica gel, CH2Cl2–
MeOH, 200:1).
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 6.7 Hz, 3 H), 1.44–
1.70 (m, 7 H), 1.49 (s, 6 H), 1.80 (dd, J = 14.6, 5.5 Hz, 1 H), 1.87
(s, 3 H), 5.25 (td, J = 12.8, 6.5 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 2 H),
6.81–6.86 (m, 2 H), 7.42–7.48 (m, 2 H), 8.36 (d, J = 4.1 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 22.19 (1 C), 28.69 (3 C), 32.73
(1 C), 37.07 (3 C), 42.59 (3 C), 48.81 (1 C), 50.68 (1 C), 116.93 (2
C), 116.99 (2 C), 136.93 (2 C), 148.40 (2 C), 157.73 (2 C).
Yield: 10 mg (4%); yellow oil; chromatography (silica gel, CH2Cl2–
MeOH, 50:1).
1H NMR (400 MHz, CDCl3): d = 1.30–1.55 (m, 12 H), 1.85 (s, 2 H),
4.00 (s, 4 H), 6.74–6.80 (m, 4 H), 6.98 (d, J = 8.3 Hz, 4 H), 7.40–
7.47 (m, 4 H), 8.24 (d, J = 5.2 Hz, 4 H).
13C NMR (100.6 MHz, CDCl3): d = 28.72 (2 C), 36.17 (2 C), 36.97
(1 C), 40.61 (4 C), 44.65 (1 C), 58.65 (2 C), 115.40 (4 C), 116.82 (4
C), 136.85 (4 C), 147.95 (4 C), 158.89 (4 C).
MS (MALDI-TOF): m/z [M+] calcd for C32H34N6: 502.28; found:
502.35.
MS (MALDI-TOF): m/z [M + H+] calcd for C23H30N3: 348.24;
found: 348.21.
1,3-Bis[2-(2-pyridylamino)ethyl]adamantane (7b)
Compound 7b was obtained from 6b (444 mg, 2 mmol) and 2 (632
mg, 4 mmol) in the presence of Pd(dba)2 (46 mg, 4 mol%) and
ligand L1 (35 mg, 4.5 mol%).
Diamines 7a,b; General Procedure
A flask flushed with anhyd argon and equipped with a magnetic stir-
rer and condenser was charged with pyBr (2; 1 mmol), Pd(dba)2 (2–
4 mol%), the phosphane ligand (2.5–4.5 mol%), the appropriate
amine 6a,b (0.5 mmol), and absolute 1,4-dioxane (5 mL). t-BuONa
(1.1 mmol) was added, and the mixture was stirred under reflux for
5–7 h, and cooled down to r.t. The 1,4-dioxane was evaporated un-
der vacuum, and the residue was chromatographed (silica gel,
CH2Cl2–MeOH, 1:0, then 200:1 to 3:1).
Yield: 580 mg (77%); yellowish oil; chromatography (silica gel,
CH2Cl2–MeOH, 100:1 to 25:1).
1H NMR (400 MHz, CDCl3): d = 1.33 (s, 2 H), 1.36–1.55 (m, 12 H),
1.59 (s, 2 H), 2.03 (s, 2 H), 3.19–3.26 (m, 4 H), 4.37 (s, 2 H), 6.34
(d, J = 8.3 Hz, 2 H), 6.50–6.54 (m, 2 H), 7.35–7.41 (m, 2 H), 8.05
(d, J = 4.3 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 28.75 (2 C), 32.51 (1 C), 36.27
(2 C), 36.91 (2 C), 41.75 (4 C), 43.42 (2 C), 47.35 (1 C), 106.31 (2
C), 112.37 (2 C), 137.17 (2 C), 148.02 (2 C), 158.80 (2 C).
1,3-Bis[(2-pyridylamino)methyl]adamantane (7a)
Compound 7a was obtained from 6a (388 mg, 2 mmol) and 2 (632
mg, 4 mmol) in the presence of Pd(dba)2 (46 mg, 4 mol%) and
ligand L1 (35 mg, 4.5 mol%).
MS (MALDI-TOF): m/z [M+] calcd for C24H32N4: 376.26; found:
376.37.
Yield: 562 mg (81%); yellowish oil, slowly solidifying into color-
less crystals; mp 185–187 °C; chromatography (silica gel, CH2Cl2–
MeOH, 50:1 to 25:1).
1H NMR (400 MHz, CDCl3): d = 1.34 (s, 2 H), 1.41–1.55 (m, 8 H),
1.59 (s, 2 H), 2.06 (s, 2 H), 2.98 (d, J = 5.9 Hz, 4 H), 4.61 (t, J = 5.9
Hz, 2 H), 6.35 (d, J = 8.5 Hz, 2 H), 6.46–6.50 (m, 2 H), 7.31–7.37
(m, 2 H), 8.01 (ddd, J = 4.1, 1.8, 0.8 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 28.28 (2 C), 34.55 (1 C), 36.28
(2 C), 39.84 (4 C), 43.15 (1 C), 53.56 (2 C), 106.29 (2 C), 112.32
(2 C), 137.24 (2 C), 147.94 (2 C), 159.32 (2 C).
1-[2-(Di-2-pyridylamino)ethyl]-3-[2-(2-pyridylamino)ethyl]ad-
amantane (8b)
Compound 8b was obtained as a byproduct in the synthesis of 7b
from 6b (444 mg, 2 mmol) and 2 (790 mg, 5 mmol) in the presence
of Pd(dba)2 (92 mg, 8 mol%) and BINAP (110 mg, 9 mol%).
Yield: 158 mg (17%); yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 100:1 to 25:1).
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Synthesis of Adamantylpyridin-2-amines
2221
1H NMR (400 MHz, CDCl3): d = 1.31–1.60 (m, 16 H), 2.02 (s, 2 H),
3.19–3.26 (m, 2 H), 4.17–4.24 (m, 2 H), 4.39 (s, 1 H), 6.33 (d,
J = 8.3 Hz, 1 H), 6.49–6.54 (m, 1 H), 6.78–6.82 (m, 2 H), 7.05 (d,
J = 8.6 Hz, 2 H), 7.35–7.40 (m, 1 H), 7.45–7.50 (m, 2 H), 8.05 (dd,
J = 5.1, 1.0 Hz, 1 H), 8.31 (ddd, J = 4.8, 2.0, 0.8 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 28.72 (2 C), 32.40 (1 C), 32.53
(1 C), 36.32 (1 C), 36.84 (1 C), 41.04 (1 C), 41.42 (2 C), 41.78 (2
C), 43.16 (1 C), 43.38 (1 C), 46.99 (1 C), 106.33 (1 C), 112.24 (1
C), 114.36 (2 C), 116.50 (2 C), 136.79 (2 C), 137.08 (1 C), 147.88
(1 C), 148.07 (2 C), 157.06 (2 C), 158.71 (1 C).
References
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MS (MALDI-TOF): m/z [M+] calcd for C29H35N5: 453.29; found:
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453.43.
1,3-Bis[2-(di-2-pyridylamino)ethyl]adamantane (9b)
Compound 9b was obtained as a byproduct in the synthesis of 7b
from 6b (444 mg, 2 mmol) and 2 (790 mg, 5 mmol) in the presence
of Pd(dba)2 (92 mg, 8 mol%) and BINAP (110 mg, 9 mol%).
Yield: 241 mg (23%); yellow oil; chromatography (silica gel,
CH2Cl2–MeOH, 100:1 to 50:1).
1H NMR (400 MHz, CDCl3): d = 1.38 (s, 2 H), 1.43–1.58 (m, 14 H),
2.00 (s, 2 H), 4.17–4.23 (m, 4 H), 6.75–6.79 (m, 4 H), 7.05 (d,
J = 8.3 Hz, 4 H), 7.42–7.47 (m, 4 H), 8.29 (ddd, J = 4.8, 2.0, 0.8 Hz,
4 H).
13C NMR (100.6 MHz, CDCl3): d = 28.80 (2 C), 32.53 (2 C), 36.47
(1 C), 41.12 (2 C), 41.54 (4 C), 43.23 (2 C), 46.86 (1 C), 114.37 (4
C), 116.48 (4 C), 136.76 (4 C), 148.07 (4 C), 157.10 (4 C).
MS (MALDI-TOF): m/z [M+] calcd for C34H38N6: 530.32; found:
530.46.
(14) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J.
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Acknowledgment
This work was supported by RFBR grants N 06-03-32376, 05-03-
32905, and 03-03-22001 and by the Russian Academy of Sciences
program P-8 ‘Development of methods of organic synthesis and
construction of compounds with valuable properties’.
Synthesis 2007, No. 14, 2215–2221 © Thieme Stuttgart · New York