Arylation of adamantanamines: IV. Palladium-catalyzed arylation of amines of adamantane series with isomeric chloroquinolines

Article abstract of DOI:10.1134/S1070428012110012

Palladium-catalyzed arylation of diverse amines of the adamantane series with isomeric chloroquinolines was investigated. The 2-chloroquinoline is the most reactive, however the best yields of the N-arylation products are most frequently obtained in the r

Full text of DOI:10.1134/S1070428012110012

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 11, pp. 1391−1406. © Pleiades Publishing, Ltd., 2012.
Original English Text © O.K. Grigorova, A.D. Averin, A.S. Abel, O.A. Maloshitskaya, V.V. Kovalev, E.N. Savelev, B.S. Orlinson, I.A. Novakov, I.P. Beletskaya,
2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 11, pp. 1397−1411.
Arylation of Adamantanamines: IV.*
Palladium-Catalyzed Arylation of Amines of Adamantane
Series with Isomeric Chloroquinolines
O. K. Grigorovaa, A. D. Averina, A. S. Abela, O. A. Maloshitskayaa, V. V. Kovaleva,
E. N. Savelevb, B. S. Orlinsonb, I. A. Novakovb, and I. P. Beletskayaa
aLomonosov Moscow State University, Moscow,119991 Russia
e-mail: averin@org.chem.msu.ru
bVolgograd State Technical University, Volgograd, Russia
Received February 22, 2012
Abstract—Palladium-catalyzed arylation of diverse amines of the adamantane series with isomeric chloroquinolines
was investigated. The 2-chloroquinoline is the most reactive, however the best yields of the N-arylation products
are most frequently obtained in the reaction with the less reactive 6-chloroquinoline. The applicability of the
reaction is limited by the size of the substituent at the amino group. In some instances the noncatalytic amination
of chloroquinolines was possible.
DOI: 10.1134/S1070428012110012
The pharmacological activity of adamantane deriva- two patents, one of which describes the synthesis of vari-
tives is due to various factors, in particular, to the ability ous adamantane derivatives of 4-aminoquinolines [13],
to interact with biological membranes containing a lipid and the second mentions the preparation of N-(quinolin-
layer, and also with the hydrophobic fragments of proteins 2-yl) derivative of 1,3-adamantanediamine [14] that has
owing to the presence of a bulky lipophilic cage structure been obtained by noncatalytic procedure. The obtained
[2].Aspecial place in the series of adamantane derivatives quinolinyl derivatives of adamantanamines exhibited
belongs to amines, among them to 1-adamantanamine a high malaricidal activity like many among the other
hydrochloride (amantadine) [3, 4], 1-(1-adamantyl)
ethanamine hydrochloride (rimantadine) [5], 1,3-di-
4-aminoquinolines thus stimulating the synthesis and
the study of the pharmacological activity of the other
methyladamantan- 5-amine (memantine) [6]. Interesting N-quinoline-substituted amines having in their structure
results were obtained in the course of the examination of the adamantane framework.
the pharmacological activity of more complex adaman-
tanamine derivatives with heteroaromatic substituents.
Adamantylpyridine derivatives possess a high psychotro-
pic activity of the neurostimulating type and a sufficiently
low toxicity like also the halopyridinyl derivatives of
1- and 2-adamantanamines [7]. The psychotropic activ-
ity was also studied of adamantane derivatives with the
other nitrogen heterocycles: diphenylpyrazole [8], benz-
imidazole [9, 10], isoxazoles, isoxazolines, oxadiazoles,
imidazolines [11]. However the information is scanty on
the quinoline derivatives of adamantanamines: an article
has been published on the synthesis of N-(quinolin-4-yl)
Many examples of 2-chloroquinoline amination were
published, both noncatalytic and catalytic. The first type
constitute the reactions with piperidine [15, 16], linear
secondary amines [17], substituted benzotriazoles [18,
19], and the processes as a rule occur at high tempera-
ture (100–120°C) in the presence of a large excess of
the amine. As solvents toluene [15], 2-propanol [16],
and methanol (in the reactor at high pressure) [17] were
used. A sufficiently large number of 2-chloroquinoline
aminations was carried out in the presence of palladium
catalysts. The following catalytic systems were men-
tioned: Pd2(dba)3/BINAP [20], Pd(OAc)2 with donor li-
gands like 1-(dimethylamino)-2-(di-tert-butylphosphino)
benzene, 1-(dimethylamino)-2-(diadamantylphosphino)
derivatives of adamantan -1- and -2-amines [12], and also
––––––––––––––––
*For Communication III, see [1].
1391

GRIGOROVA et al.
1392
benzene [21], diadamantylbutylphosphine [22, 23],
2-(dicyclohexylphosphino)-N-phenylindole [24], 2-(di-
cyclohexylphosphino)biphenyl [23]. The amination of
2-chloroquinoline with cyclic secondary amines was also
performed in the presence of cobalt complexes [25, 26].
application of these catalytic systems in the adamantane
amination with amines of isomeric bromochloro- and
dibromobenzenes [1, 39, 40], of 2-bromopyridine [41],
chloro- and bromo-substituted naphthalene, anthracene,
and anthraquinone [42, 43].
In the majority of papers dealing with the amination
of the 4-chloroquinoline the process was carried out
without catalyst. The reagents used were primary and
secondary linear dialkylamines [17, 27, 28], aromatic
amines [28, 29], cyclic secondary amines [30], some
primary diamines [12, 31, 32], benzotriazole derivatives
[18], and also adamantan-1- and -2-amines [12]. A mul-
titude of solvents and bases was used in the amination
of the 4-chloroquinoline: The reaction was carried out in
N-methylpyrrolidinone at 135°C, in phenol at 180°C, in
the boiling glacial acetic acid, in DMF, in pyridine (used
simultaneously as a base), in methanol (in a steam reactor
at 100–120°C). N-Methylmorpholine, NaOH, K2CO3,
triethylamine, N,N-diisopropylethylamine, excess amine
reagent were applied as bases. The catalytic arylation of
amines with 4-chloroquinoline is far less investigated.
The palladium-catalyzed arylation of aniline and pyr-
rolidine with 4-chloroquinoline in DMF at 135°C was
described using potassium tert-butylate as a base and
PdCl2 complexes with di(tert-butyl)phosphinic acid as
catalyst [33].
The pharmacological activity of the amines of the
adamantane series strongly depends on the position of the
amino group with respect to the adamantane framework,
and also on the presence of the other atoms between these
two fragments of the molecule. We investigated in this re-
search amines I–VII differing by the spatial surrounding
of the amino group which was interesting for finding the
rules of the course of catalytic arylation of these amines
with isomeric chloroquinolines.
NH2
Ph
NH2
NH2
NH2
O
II
III
I
IV
H2N
NH2
NH2
The amination of 6-haloquinoline is less understood.
In all studies on this problem the palladium-catalyzed
arylation of amines was performed. In the most cases
secondary cyclic amines were used as reagents [34–36],
some infrequent information concerned the reactions with
aromatic amines. Often the amination of 6-bromoquino-
line was performed since the catalytic amination occurred
easier with bromo- than chloroderivatives. In a number of
studies the selectivity of amination of 6-bromo-2-chloro-
and 6-bromo-4-chloroquinolines was examined [36, 37].
In the amination of 6-chloroquinolines Pd2(dba)3–2-(di-
tert-butylphosphino)-2',4',6'-triisopropyl-1,1'-byphenyl
system was used as catalyst [38].
VI
VII
V
The synthesis of N-(quinolinyl)adamantanamines
VIII–XXVIII is presented in Scheme 1. The data on
the applied catalytic systems and the yields of the target
products in the reactions with adamantanamines I–V are
given in Table 1. The reactions were carried out under
standard conditions using catalytic systems Pd(dba)2–
BINAP and Pd(dba)2–DavePhos (4 mol%) at boiling in
dioxane (c 0.1 mol l−1) in the presence of a base (sodium
tert-butylate). If necessary the amount of the catalyst
was increased to 6–8 mol%. The reaction progress was
The analysis of these data led us to a conclusion that
it was necessary to perform a systematic investigation of
the amination of 2-, 4-, and 6-chloroquinolines with the
amines of the adamantane series using two principal cata-
lytic systems: Pd(dba)2–BINAPand Pd(dba)2–DavePhos
comparing them if possible with noncatalytic reactions
involving the more active 2- and 4-chloroquinolines.
In the laboratory of organoelemental compounds of the
Department of Chemistry of the Moscow State University
up till now a certain experience existed concerning the
1
monitored by the H NMR spectroscopy, the reaction
products were isolated by column chromatography on
silica gel. The reaction of amine I with 2-chloroquinoline
proceeded successfully, target amination product VIII
was isolated by the chromatography on silica gel in 67%
yield (Table 1, run no. 1). In this reaction we tested the
phosphine ligand DavePhos, and it turned out according
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1393
1
to the data of H NMR of the reaction mixture that the
To prevent the formation of side product XXIX we
decided to test a weaker base, cesium carbonate, inca-
pable to react with 2-chloroquinoline, but the yield of
the secondary amine VIII sharply decreased to 10–20%
yield of compound VIII was approximately the same as
at the use of the BINAP ligand, therefore in this case we
did not perform the chromatography (run no. 2).
Scheme 1.
H
N
N
VIII: X = OCHCH2
XI: X = CH2
X
XIV: X = CH(Ph)
XVII: X = CH2CH(CH3)
XX: X = CH(Et)
IX: X = OCHCH2
XII: X = CH2
XV: X = CH(Ph)
XVIII: X = CH2CH(CH3)
XXI: X = CH(Et)
H
NH2
X
N
X
Pd(dba)2_L
N
+
Cl
t-BuONa, dioxane
N
L = BINAP, DavePhos
2-chloroquinoline
4-chloroquinoline
6-chloroquinoline
I: X = OCHCH2
II: X = CH2
III: X = CH(Ph)
IV: X = CH2CH(CH3)
V: X = CH(Et)
H
X: X = OCHCH2
XIII: X = CH2
XVI: X = CH(Ph)
XIX: X = CH2CH(CH3)
XXII: X = CH(Et)
N
X
N
H
N
HN
N
N
XXIII: 1-NH
XXVI: 2-NH
NH2
H
N
Pd(dba)2_L
XXIV: 1-NH
XXVII: 2-NH
Cl
+
N
t-BuONa, dioxane
N
L = BINAP, DavePhos
2-chloroquinoline
4-chloroquinoline
6-chloroquinoline
VI: 1-NH2
VII: 2-NH2
H
N
XXV: 1-NH
XXVIII: 2-NH
N
Side products
Sideprodicts
PPh2
PPh2
BINAP :
DavePhos:
Me2N
PCy2
N
OBu-t
XXIX
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

GRIGOROVA et al.
Table 1. Arylation of amines of adamantane series I–V with chloroquinolines
1394
Pd(dba)2–L,
mol%
Secondary
amine
Run no.
Chloroquinoline
Amine
Ligand L
BINAP
Yield, % a
1
2
3b
4b
5c
6d
7
8c
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
4-chloroquinoline
4-chloroquinoline
6-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
4-chloroquinoline
6-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
4-chloroquinoline
6-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
4-chloroquinoline
6-chloroquinoline
2-chloroquinoline
4-chloroquinoline
6-chloroquinoline
I
I
4/4.5
4/4.5
4/4.5
4/4.5
–
VIII
VIII
VIII
VIII
VIII
VIII
IX
67
(65)
(10)
(20)
(65) 42
(15) 9
78
DavePhos
DavePhos
BINAP
–
I
I
I
I
I
–
–
BINAP
–
4/4.5
–
I
IX
(20)
68
9
I
BINAP
BINAP
DavePhos
–
BINAP
BINAP
BINAP
DavePhos
–
4/4.5
4/4.5
8/9
X
10
11
12c
13
14
15
16
17c
18
19
20
21
22c
23
24
25
26
27
II
II
II
II
II
III
III
III
III
III
IV
IV
IV
IV
IV
V
V
V
XI
(48) 41
(50)
(48) 34
52
XI
XI
XII
–
4/4.5
4/4.5
4/4.5
8/9
XIII
XIV
XIV
XIV
XV
64
(41) 32
(50)
(11)
63
–
BINAP
BINAP
BINAP
DavePhos
–
4/4.5
4/4.5
4/4.5
8/9
XVI
XVII
XVII
XVII
XVIII
XIX
XX
83
(24)
38
22
–
BINAP
BINAP
DavePhos
DavePhos
DavePhos
4/4.5
4/4.5
8/9
8/9
8/9
91
88
0e
56
67
XXI
XXII
a Yields of individual compounds after chromatography on silica gel; the yields of compounds in the reaction mixtures according to 1H NMR
data are given in parentheses.
b Base Cs2CO3.
c Solvent DMF, base K2CO3.
d Solvent DMSO, base K2CO3.
e 50% of compound XXIX has formed.
(runs nos. 3, 4). We also tested the noncatalytic proce-
dures of the reaction. At boiling in DMF for 14 h using
K2CO3 as a base we succeeded to obtain the secondary
amine VIII whose yield in the reaction mixture was about
65% and 42% after chromatographing (run no. 5) Yet
this yield was considerably lower than that obtained in
the catalytic reaction (run no. 1). The attempt to raise the
reaction temperature for the activation of the nucleophilic
substitution by the replacement of DMF by DMSO was
unsuccessful (run no. 6).
tion of amine I with the isomeric 4-chloroquinoline re-
sulted in a high preparative yield of secondary amine IX
(78%, run no. 7), whereas the attempt at the noncatalytic
reaction in DMF (run no. 8) was unsuccessful, and the
yield of compound IX in the reaction mixture was only
20%. The reaction of amine I with 6-chloroquinoline
proceeded cleanly at the use of 4 mol% of the catalyst,
the preparative yield of compound X reached 68% (run
no. 9). The reactions with the isomeric haloquinolines
proceed with considerably different rates. The analysis of
The use of the standard catalytic system in the reac-
the 1
H NMR spectra of the reaction mixtures after equal
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1395
time intervals showed that the reaction of amine I with
2-chloroquinoline was completed within 15 min after
the start of boiling, the reaction with 4-chloroquinoline
required 1 h for the completion, and in the reaction with
less active 6-chloroquinoline after 2 h the reaction mixture
contained still 20% of the initial halide.All reactions were
carried out in the presence of 4 mol% of the standard cata-
lytic system. Thus it is possible to optimize the reaction
time; however, the long boiling of the reaction mixtures
after the completion of the reaction did not result in the
decomposition of the products.
lower yield of the secondary amine XIV in the reaction
mixture compared to analogous compounds VIII and
XI, secondly, XI, a large amount of the side product of
alkoxylation XXIX was formed, and a half of the start-
ing amine III was recovered by the chromatography (run
no. 15) at the complete conversion of the 2-chloroquino-
line. The application of the ligand DavePhos did not result
in a significant increase in the yield of reaction product
XIV (run no. 16). The attempt at the noncatalytic process
was unsuccessful, and the yield of compound XIV in the
reaction mixture was only 11% (run no. 17). In the pres-
ence of the standard catalytic system the total conversion
of 2-chloroquinoline is attained in 30 min. The attempt
to decrease the quantity of the base to 1 equiv to prevent
the alkoxylation resulted in the smaller yield of seconadry
amine XIV in the reaction mixture.
1
All compounds obtained were characterized by H,
13C NMR spectra and MALDI mass spectra of positive
ions. In the 1H NMR spectra a characteristic upfield shift
is observed of the proton signals in the ortho-position with
respect to the amino group, and this shift is considerably
more pronounced in monoaryl derivatives VIII–X than in
the N,N-diaryl derivatives, therefore the composition of
the reaction mixtures is easily analyzed. In the 13C NMR
spectra also the analogous upfield shift of carbon atoms of
the ring in the ortho-position with respect to amino group
is observed. In the mass spectra alongside the signals of
the pseudomolecular ions [M + H]+ strong signals [M –
H]+ are present characteristic of arylalkylamines contain-
ing a fragment ArNHCHR indicating the formation of
imines in the course of the sample irradiation with the
laser and its reaction with the unsaturated matrix.
In the reaction of amine III with 4-chloroquinoline
the preparative yield of compound XV reached 63% (run
no. 18), and the unreacted amine III was also partially
recovered. Note that in the amination reaction the regen-
eration of pure initial amine is observed relatively seldom.
The most successful reaction was with 6-chloroquinoline
and compound XVI was obtained in a high yield (83%,
run no. 19).
Amine IV at the first sight seems less spatially
hindered than amine III since in this compound the
adamantane moiety is farther from the amino group,
and in the α-position to the NH2 group a methyl
substituent is located. Yet the reaction of amine IV with
2-chloroquinoline using the standard catalytic system led
to the formation of the tert-butoxyderivative XXIX that
even prevailed over secondary amine XVII in the reaction
mixture (run no. 20). The application of the catalytic
system Pd(dba)2–DavePhos (8 mol%) proved to be more
efficient apparently due to the acceleration of the catalytic
amination compared to the noncatalytic alkoxylation, and
compound XVII was isolated in 38% yield (run no. 21).
The reaction with amine IV can occur also in noncatalytic
conditions (run no. 22), but the yield of compound XVII is
considerably lower (22%). Bringing into the reaction the
4- and 6-chloroquinolines possessing less labile chlorine
atom resulted in very high yields of the amination products
XVIII and XIX, ~90% (run no. 23, 24).
The reaction of more sterically hindered amine II
with 2-chloroquinoline in the presence of 4 mol% of
the standard catalytic system led to the formation of
compound XI in 48% yield in the reaction system (41%
after chromatography, run no. 10). The use of DavePhos
as the ligand did not increase the yield of compound XI
in the reaction mixture (50%, run no. 11). The formation
of compound XI under noncatalytic conditions using
DMF and potassium carbonate is of the similar efficiency
(run no. 12), but like the case of compound VIII, the
chromatographic separation is of low efficiency. A good
yield of secondary amine XII was found in the reaction
with the isomeric 4-chloroquinoline (52%, run no. 13),
the 6-chloroquinoline reacted even better, and the yield
of amine XIII after the chromatography reached 64%
(run no. 14).
Amine III possesses even larger spatial hindrances
at the amino group with the phenyl substituent in the
α-position with respect to the amino group. In the reaction
with the 2-chloroquinoline in the presence of the catalytic
system Pd(dba)2–BINAP (4 mol%) was found, firstly, a
Isomeric amine V, the most sterically hindered among
all studied since it contained an ethyl and an adaman-
tyl substituents in the α-position to the amino group,
proved to be the most problematic in the amination of
the 2-chloroquinoline (run no. 25). Though the more ac-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

GRIGOROVA et al.
1396
tive catalytic system Pd(dba)2–DavePhos (8 mol%) was
used, in the reaction mixture about 50% of alkoxylation
product XXIX was detected, and secondary amine XX
was obtained in the trace amount. The amination of two
other chloroquinolines proceeded more successfully:
in the reaction with 4-chloroquinoline amine XXI was
isolated in 56% yield, and in the reaction with 6-chloro-
quinoline, compound XXII was obtained in 67% yield
(runs nos. 25, 26).
the noncatalytic conditions resulted in an insignificant
amount of amine XXIII (run no.3). In the reactions with
4-chloroquinoline the yields were also low both at the use
as ligands of BINAP and DavePhos (runs nos. 4, 5) that
may be ascribed to the steric influence of the hydrogen
atom in the peri-position of the 4-chloroquinoline on the
substitution with the bulky aminoadamantyl structure.
The experiments with 6-chloroquinoline were far more
satisfactory. In the reaction catalyzed with the complex
with BINAP the yield of compound XXV in the reaction
mixture attained 25% because of incomplete conversion
of the initial 6-chloroquinoline (run no. 6), but at the use
of 8 mol% of the catalyst and DavePhos as the ligand
the yield of compound XXV grew to 82% (run no. 7).
Thus again the 6-chloroquinoline was the most reactive
substrate in the arylation.
The research carried out formerly in the laboratory
of organoelemental compounds showed that the use of
4 mol% of the standard catalytic system Pd(dba)2–BINAP
was insufficient for the amination of bromochloro- and
dibromobenzenes with adamantan-1-amine. Therefore
in the reaction of amine VI with chloroquinolines we
increased the content of the catalyst to 6 mol% (Table 2).
In these conditions the yield of the amination product of
2-chloroquinoline in the reaction mixture was small (run
no. 1), whereas the main reaction product was compound
XXIX. On increasing the catalyst amount to 8 mol% and
replacing BINAPby DavePhos we succeeded to increase
the yield of compound XXIII to 50% in the reaction
mixture (isolated 24%), but compound XXIX was still
formed in a large amount (run no. 2). The reaction in
The reaction with the isomeric adamantan-2-amine
(VII) proceeded easier, apparently due to the weaker
spatial hindrances at the nitrogen atom, therefore we used
in all cases the catalytic system Pd(dba)2–BINAP. Even at
4 mol% of the standard catalytic system we succeeded to
obtain the product of 2-chloroquinoline amination XXVI
in 49% yield (run no. 8); the application of the double
amount of the same catalyst did not virtually increase
Table 2. Arylation of adamantanamines VI, VII with chloroquinolines
Pd(dba)2–L,
mol%
Run no.
Chloroquinoline
Amine
Ligand L
BINAP
Secondary amine
Yield, % a
1
2
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
4-chloroquinoline
4-chloroquinoline
6-chloroquinoline
6-chloroquinoline
2-chloroquinoline
2-chloroquinoline
2-chloroquinoline
4-chloroquinoline
4-chloroquinoline
6-chloroquinoline
VI
VI
6/7
8/9
–
XXIII
XXIII
XXIII
XXIV
XXIV
XXV
(25)b
(50) 24
(22)
30
DavePhos
–
3c
4
VI
VI
BINAP
DavePhos
BINAP
DavePhos
BINAP
BINAP
–
6/7
8/9
6/7
8/9
4/4.5
8/9
–
5
VI
20
6
VI
(25)
82
7
VI
XXV
8
VII
VII
VII
VII
VII
VII
XXVI
XXVI
XXVI
XXVII
XXVII
XXVIII
49
9
52
10c
11
12
13
(15)
89
BINAP
BINAP
BINAP
4/4.5
4/4.5
8/9
(55)
(80) 56
a Yields of individual compounds after chromatography on silica gel; the yields of compounds in the reaction mixtures according to 1H NMR
data are given in parentheses.
b 70% of compound XXIX has formed.
c Solvent DMF, base K2CO3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1397
the yield of compound XXVI (run no. 9). The reaction
in the noncatalytic conditions gave a low yield of the
secondary amine XXVI (run no. 10). 4-Chloroquino-
line fairly well reacted with adamantan-2-amine giving
compound XXVII in 89% yield (run no. 11) using only
4 mol% of the catalyst. The same amount of the catalyst
proved to be insufficient for the complete conversion of
6-chloroquinoline (run no. 12); at the double quantity of
the catalyst we succeeded to isolate 56% of the amina-
tion product XXVIII (run no. 13). The comparison of the
obtained data shows that the chlorine atom in the posi-
tion 4 of the quinoline structure is far more reactive than
in the position 6 therefore in the absence of the sterical
hindrances the successful amination of 4-chloroquinoline
requires less catalyst.
tion of amine I in the presence of 4 mol% of the catalyst
the N,N-diarylation product XXX was isolated in 30%
yield, and at the use of the double amount of the catalyst
and 4 equiv of 2-chloroquinoline the yield of compound
XXX increased to 78%. At the attempt to synthesize the
N,N-diaryl derivative with the isomeric 4-chloroquino-
line we obtained exclusively the monoarylation product
IX apparently due to the steric factor. With the spatially
unhindered 6-chloroquinoline at the use of 4 equiv of this
compound and 8 mol% of the catalyst the N,N-diarylation
product XXXI was obtained in 91% yield. In the reac-
tion of more sterically hindered amine II with 1 equiv of
2-chloro-quinoline the yield of the diarylation product
XXXII was substantial (36%), and using the double
quantity of the catalyst and 4 equiv of 2-chloroquinoline
its yield grew to 62%. However in contrast to adamantan-
1-amine (I) amine II did not form the diarylation product
in the reaction with 6-chloroquinoline.
In some reactions involving 2-chloroquinoline N,N-
diarylation products were detected, therefore we specially
investigated the conditions of the formation of these
compounds (Scheme 2). The reactions were carried out
in the presence of the catalytic system Pd(dba)2–BINAP
(8 mol%) with 4 equiv of chloroquinoline at boiling for
a longer time.
Thus in the course of experiments diverse N-quinolinyl
derivatives of various amines of the adamantane series
were synthesized. In the most cases the best yields were
obtained using of the less reactive 6-chloroquinoline. The
ligand DavePhos in more favorable than the ligand BINAP
Even using 1 equiv of 2-chloroquinoline in the reac-
Scheme 2.
N
N
N
O
N
NH2
X
N
XXX
_
Pd(dba)2 BINAP
Cl
N
t-BuONa, dioxane
N
N
N
2-chloroquinoline
4-chloroquinoline
I: X = OCHCH2
6-chloroquinoline
II, X = CH2
XXXII
4 equiv.
O
N
XXXI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

GRIGOROVA et al.
1398
in the reactions with the spatially hindered amines. In the
case of amines with insignificant sterical hindrances the
N,N-diarylation of the amino group is possible. In the ami-
nation of the more reactive 2-chloroquinoline the arising
difficulty consists in the competing alkoxylation reaction.
The obtained compounds will be tested for various kinds
of the physiological, first of all psychotropic, activity.
(eluent CH2Cl2–MeOH, 100 : 1) 54 mg (67%). With the
same eluent 17 mg (30%) of diarylation product XXX
was isolated.
b. With the same quantities of amine I and 2-chlo-
roquinoline was used 6 mg (4 mol%) of Pd(dba)2, 5 mg
(4.5 mol%) of DavePhos, and 36 mg (1.5 equiv) of sodium
tert-butylate, the mixture was boiled for 7 h.According to
1H NMR spectrum of the reaction mixture the ratio of the
products of monoarylation (65%) and diarylation (35%)
was similar to the data of the preceding experiment; the
products were not subjected to chromatography.
EXPERIMENTAL
1H and 13C NMR spectra were registered on a spec-
trometer Bruker Avance-400 (operating frequencies 400
and 100.6 MHz respectively) in CDCl3. Chloroform
signals (δH 7.25, δC 77.00 ppm) served as internal refer-
ences. Mass spectra MALDI-TOF of positive ions were
obtained on an instrument Bruker Daltonics Autoflex II
using 1,8,9-trihydroxyanthracene as a matrix and polyeth-
ylene glycols as internal references. UV spectra were re-
corded on a spectrophotometer Perkin Elmer Lambda 40.
The preparative column chromatography was performed
using silica gel Merck (40/60). Commercially available
2-, 4-, 6-chloroquinolines, 2,2’-bis(diphenylphosphino)-
1,1’-binaphthyl (BINAP), 2-dicyclohexylphosphino-2’-
dimethylaminobiphenyl (DavePhos), sodium tert-butyl-
ate, and cesium carbonate were used without additional
purification.Amines I–V were synthesized by procedures
[41, 44, 45], adamantan-1-amine (VI) was prepared by the
method [46], adamantan-2-amine (VII), by the method
[47]. Dioxane was distilled in succession over alkali and
then over sodium metal; dichloromethane, petroleum
ether, and methanol were distilled. The synthesis of
Pd(dba)2 is described in [48].
c. With the same quantities of amine I and 2-chloro-
quinoline was used 6 mg (4 mol%) of Pd(dba)2, 5 mg
(4.5 mol%) of DavePhos, and 163 mg (2 equiv) of cesium
carbonate. According to 1H NMR spectrum the reaction
mixture contained 10% of compound VIII; the products
were not subjected to chromatography.
d. With the same quantities of amine I and 2-chlo-
roquinoline was used 6 mg (4 mol%) of Pd(dba)2, 7 mg
(4.5 mol%) of BINAP, 163 mg (2 equiv) of cesium
carbonate. According to 1H NMR spectrum the reaction
mixture contained 20% of secondary amine VIII; the
products were not subjected to chromatography.
e. The reaction was carried out without catalyst:
0.2 mmol (39 mg) of amine I and 0.2 mmol (33 mg) of
2-chloroquinoline in the presence of 110 mg (4 equiv) of
potassium carbonate was boiled for 14 h in 1 ml of DMF.
Yield after chromatography (eluent CH2Cl2–MeOH,
100:1) 27 mg (42%).
f. The reaction was carried out without catalyst:
0.2 mmol (39 mg) of amine I and 0.2 mmol (33 mg) of
2-chloroquinoline in the presence of 110 mg (4 equiv)
of potassium carbonate was boiled for 14 h in 1 ml of
DMSO. The reaction mixture was treated with water, the
reaction products were extracted into dichloromethane,
the extract was dried, evaporated, the residue was sub-
jected to chromatography (eluent CH2Cl2–MeOH, 100:1).
Yield 6 mg (9%), light-yellow crystalline powder, mp
N-Quinolinylamines of the amantane series. In
a flask filled with argon was placed 0.25 mmol (1 mmol at
the synthesis of N,N-diaryl derivatives) 2-, 4-, or 6-chlo-
roquinoline, 6–12 mg (4–8 mol%) of Pd(dba)2, 7–14 mg
(4.5–9 mol%) of BINAP or 5–9 mg (4.5–9 mol%) of
DavePhos, 2.5 ml of anhydrous dioxane, 0.25 mmol of
an appropriate amine I–VII, 37–96 mg (1.5–3 equiv) of
sodium tert-butylate, and the mixture was boiled for 7 h.
The reaction mixture was filtered, dioxane was evapo-
rated in a vacuum, the residue was chromatographed on
silica gel.
1
110–112°C. H NMR spectrum, δ, ppm: 1.55–1.68 m
(6H, CH2Ad), 1.75 br.s (6H, CH2Ad), 2.14 br.s (3H,
CHAd), 3.65 br.s (4H, OCH2CH2N), 5.13 br.s (1H NH),
6.64 d (1H, H3 , 3J 8.8 Hz), 7.18 t (1H, H6 , 3J 7.4 Hz),
Q
Q
7.50 t (1H, H7 , 3J 7.6 Hz), 7.56 d (1H, H5 , 3J 7.8 Hz),
N-[2-(Adamantan-1-yloxy)ethyl]quinolin-2-
amine (VIII). a. A mixture of 0.25 mmol (49 mg) of
amine I, 0.25 mmol (41 mg) of 2-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate was boiled for 7 h in
2.5 ml of anhydrous dioxane. Yield after chromatography
Q
Q
7.66 d (1H, H8 , 3J 8.5 Hz), 7.78 d (1H, H4 , 3J 8.9 Hz).
Q
Q
13C NMR spectrum, δ, ppm: 30.5 (3C, CHAd), 39.4 (3C,
CH2Ad), 41.6 (3C, CH2Ad), 42.0 (1C, CH2N), 58.8 (1C,
CH2O), 72.4 (1C, CAd), 111.9 (1C, C3 ), 121.9 (1C, CQ),
Q
123.4 (1C, CQ4a), 126.1 (1C, CQ), 127.4 (1C, CQ), 129.4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1399
(1C, CQ), 137.1 (1C, C4 ), 148.0 (1C, CQ8a), 156.9 (1C,
According to 1H NMR spectrum of the reaction mixture
the yield was 14%, the product was not chromatographed.
1H NMR spectrum, δ, ppm: 1.56–1.68 m (6H, CH2Ad),
1.77 br.s (6H, CH2Ad), 2.16 br.s (3H, CHAd), 3.42 q (2H,
CH2N, 3J 4.9 Hz), 3.74 t (2H, CH2O, 3J 5.1 Hz), 5.61 br.s
(1H, NH), 6.42 d (1H, H3 , 3J 5.3 Hz), 7.42 t (1H, H6 ,
Q
C2 ). Mass spectrum: m/z 323.210 [M + H]+. C21H27N2O.
Q
Calculated (M + H) 323.212.
N-[2-(Adamantan-1-yloxy)ethyl]-N-(quinolin-2-
yl)quinolin-2-amine (XXX). A mixture of 0.25 mmol
(49 mg) of amine I, 1 mmol (146 mg) of 2-chloroquino-
line, 12 mg (8 mol%) of Pd(dba)2, 14 mg (9 mol%) of
BINAP, 144 mg (6 equiv) of sodium tert-butylate, 2.5
ml of anhydrous dioxane was boiled for 7 h. Yield after
chromatography (eluent – CH2Cl2–MeOH, 200:1) 87 mg
(78%), light-brown crystalline powder, mp 118–120°C.
1H NMR spectrum, δ, ppm: 1.50–1.62 m (6H, CH2Ad),
1.71 br.s (6H, CH2Ad), 2.08 br.s (3H, CHAd), 3.89 t
Q
Q
3J 7.6 Hz), 7.61 t (1H, H7 , 3J 7.6 Hz), 7.74 d (1H, H5 ,
Q
Q
3J 8.3 Hz), 7.97 d (1H, H8 , 3J 8.3 Hz), 8.52 d (1H, H2 ,
Q
Q
3J 5.3 Hz). 13C NMR spectrum, δ, ppm: 30.4 (3C, CHAd),
36.3 (3C, CH2Ad), 41.6 (3C, CH2Ad), 43.4 (1C, CH2N),
57.8 (1C, CH2O), 72.8 (1C, CAd), 98.8 (1C, C3 Q), 118.7
(1C, CQ4a), 119.7 (1C, CQ), 124.9 (1C, CQ), 128.9 (1C,
CQ), 129.4 (1C, CQ), 147.2 (1C, CQ8a), 149.9 (1C, C2 ),
Q
150.5 (1C, CQ ). Mass spectrum: m/z 323.207 [M + H]+.
4
3
3
(2H, CH2O, J 6.5 Hz), 4.60 t (2H, CH2N, J 6.5 Hz),
7.38 t (2H, H6 , 3J 7.2 Hz), 7.46 d (2H, H3 , 3J 9.0 Hz),
C21H27N2O. Calculated (M + H) 323.212.
Q
Q
7.61 t (2H, H7 , 3J 7.5 Hz), 7.70 d (2H, H5 , 3J 8.0 Hz),
Q
Q
4
N-[2-(Adamantan-1-yloxy)ethyl]quinolin-6-
amine (X). A mixture of 0.25 mmol (49 mg) of amine
I, 0.25 mmol (41 mg) of 6-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP,
36 mg (1.5 equiv) of sodium tert-butylate was boiled for
7 h in 2.5 ml of anhydrous dioxane. Yield after chroma-
tography (eluent CH2Cl2–MeOH, 100:1) 55 mg (68%),
yellow oily substance, exhibits luminescence on dis-
solving in organic solvents. 1H NMR spectrum, δ, ppm:
1.54–1.70 m (6H, CH2Ad), 1.76 br.s (6H, CH2Ad), 2.15 br.s
(3H, CHAd), 3.33 q (2H, CH2N, 3J 5.2 Hz), 3.68 t (2H,
7.84 d (2H, H8 , 3J 8.3 Hz), 7.96 d (2H, HQ , 3J 9.0 Hz).
Q
13C NMR spectrum, δ, ppm: 30.4 (3C, CHAd), 36.4 (3C,
CH2Ad), 41.5 (3C, CH2Ad), 49.7 (1C, CH2N), 58.2 (1C,
CH2O), 72.4 (1C, CAd), 116.4 (2C, C3 ), 124.2 (2C, CQ),
Q
125.1 (2C, CQ4a), 127.2 (2C, CQ), 127.8 (2C, CQ), 129.3
4
(2C, CQ), 136.7 (2C, CQ ), 147.4 (2C, CQ8a), 156.0 (2C,
C2 ). Mass spectrum: m/z 450.259 [M + H]+. C30H32N3O.
Q
Calculated (M+H) 450.255.
After chromatography (eluent CH2Cl2) the yield of
side product 2-tert-butoxyquinoline (XXIX) 63 mg
1
CH2O, 3J 5.1 Hz), 4.39 br.s (1H, NH), 6.70 d (1H, H5 ,
(31%). H NMR spectrum, δ, ppm: 1.70 s (9H, CH3),
Q
6.79 d (1H, H3 , 3J 8.8 Hz), 7.33 t (1H, H6 , 3J 7.5 Hz),
4J 2.3 Hz), 7.11 d.d (1H, H7 , 3J 8.8, 4J 2.5 Hz), 7.24 d.d
Q
Q
Q
7.57 t (1H, H7 , 3J 7.6 Hz), 7.66 d (1H, H5 , 3J 8.0 Hz),
(1H, H3 , J 8.3, 4.3 Hz), 7.85 d (1H, H8 , J 9.1 Hz),
3
3
Q
Q
4
Q
Q
7.79 d (1H, H8 , 3J 8.3 Hz), 7.91 d (1H, HQ , 3J 8.8 Hz).
7.89 d (1H, HQ , 3J 8.3 Hz), 8.59 d (1H, H2 , 3J 4.0 Hz).
4
Q
Q
13C NMR spectrum, δ, ppm: 28.6 (3C, CH3), 80.1 (1C,
13C NMR spectrum, δ, ppm: 30.5 (3C, CHAd), 36.4 (3C,
CCH3), 115.0 (1C, C3 ), 123.6 (1C, CQ), 124.5 (1C,
CH2Ad), 41.6 (3C, CH2Ad), 44.3 (1C, CH2N), 58.1 (1C,
Q
CQ4a), 127.2 (1C, CQ), 127.5 (1C, CQ), 129.0 (1C, CQ),
CH2O), 72.5 (1C, CAd), 103.3 (1C, C7 ), 121.3 (1C, CQ),
Q
137.9 (1C, CQ ), 146.5 (1C, C8 ), 161.9 (1C, C2 ). Mass
4
121.8 (1C, CQ), 130.1 (2C, CQ, CQ4a), 133.8 (1C, CQ),
143.2 (1C, CQ8a), 146.0 (1C, C2 ), 146.4 (1C, C6 ). Mass
Q
Q
spectrum: m/z 202.120 [M + H]+. C13H16NO. Calculated
Q
Q
spectrum: m/z 323.208 [M + H]+. C21H27N2O. Calculated
(M + H) 202.123.
(M + H) 323.212.
N-[2-(Adamantan-1-yloxy)ethyl]quinoline-4-
amine (IX). a. A mixture of 0.25 mmol (49 mg) of
amine I, 0.25 mmol (41 mg) of 4-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate was boiled for 7 h in
2.5 ml of anhydrous dioxane. Yield after chromatography
(eluent CH2Cl2–MeOH, 10:1) 63 mg (78%), light-yellow
crystalline powder, mp 144–146°C.
N-[2-(Adamantan-1-yloxy)ethyl]-N-(quinolin-6-
yl)quinolin-6-amine (XXXI) A mixture of 0.25 mmol
(49 mg) of amine I, 1 mmol (146 mg) of 6-chloroquino-
line, 12 mg (8 mol%) of Pd(dba)2, 14 mg (9 mol%) of
BINAP, 96 mg (4 equiv) of sodium tert-butylate was
boiled for 7 h in 25 ml of anhydrous dioxane. Yield after
chromatography (eluent CH2Cl2–MeOH, 50 : 1) 102 mg
(91%), yellow thick oily substance, exhibits luminescence
on dissolving in organic solvents. 1H NMR spectrum, δ,
ppm: 1.47–1.60 m (6H, CH2Ad), 1.67 br.s (6H, CH2Ad),
2.06 br.s (3H, CHAd), 3.71 t (2H, CH2O, 3J 5.7 Hz), 4.13 t
b. The reaction was carried out without catalyst.
A mixture of 0.25 mmol (49 mg) of amine I, 0.25 mmol
(41 mg) of 4-chloroquinoline, 138 mg (4 equiv) of po-
tassium carbonate, 1 ml of DMF was boiled for 5.5 h.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

GRIGOROVA et al.
1400
(2H, CH2N, 3J 5.7 Hz), 7.31 d.d (2H, H3 , 3J 8.2, 4.2 Hz),
quinolin-2-amine (XXXII). A mixture of 0.25 mmol
(41 mg) of amine II, 1 mmol (146 mg) of 2-chloroquino-
line, 12 mg (8 mol%) of Pd(dba)2, 14 mg (9 mol%) of
BINAP, 96 mg (4 equiv) of sodium tert-butylate, 2.5 ml of
anhydrous dioxane was boiled for 7 h. Yield after chroma-
tography (eluent CH2Cl2) 70 mg (62%), light-brown oily
substance. 1H NMR spectrum, δ, ppm: 1.60–1.69 m (12H,
CH2Ad), 1.90 br.s (3H, CHAd), 4.45 s (2H, CH2N), 7.31 d
Q
7.47 d (2H, H5 , J 1.9 Hz), 7.54 d.d (2H, H7 , J 9.0,
4
3
Q
Q
4J 1.9 Hz), 7.95 d (2H, H8 , 3J 9.0 Hz), 7.96 d (2H, HQ ,
3J 7.6 Hz), 8.74 d (2H, H2 , 3J 4.0 Hz). 13C NMR spec-
4
Q
Q
trum, δ, ppm: 30.3 (3C, CHAd), 36.3 (3C, CH2Ad), 41.5
(3C, CH2Ad), 53.2 (1C, CH2N), 56.8 (1C, CH2O), 72.6
(1C, CAd), 116.9 (2C, C7 ), 121.4 (2C, CQ), 126.0 (2C,
Q
CQ), 129.4 (2C, CQ4a), 130.2 (2C, CQ), 134.8 (2C, CQ),
144.8 (2C, CQ8a), 145.5 (2C, C6 ), 148.3 (2C, C2 ). Mass
3
3
(2H, H3 , J 8.9 Hz), 7.38 d.d.d (2H, H6 , J 8.0, 7.0,
Q
Q
Q
Q
4J 1.0 Hz), 7.63 d.d.d (2H, 3J 8.4, H7 , 3J 7.0, 4J 1.4 Hz),
spectrum: m/z 450.262 [M + H]+. C30H32N3O. Calculated
Q
7.70 d.d (2H, H5 , J 8.0, J 1.0 Hz), 7.91 d (2H, H8 ,
3
4
(M + H) 450.255.
Q
Q
3J 8.5 Hz), 7.93 d (2H, HQ , 3J 8.9 Hz). 13C NMR spec-
trum, δ, ppm: 28.5 (3C, CHAd), 35.2 (1C, CAd), 36.9 (3C,
CH2Ad), 41.5 (3C, CH2Ad), 59.2 (1C, CH2N), 116.5 (2C,
4
N-[(Adamantan-1-yl)methyl]quinolin-2-amine
(XI). a. A mixture of 0.25 mmol (41 mg) of amine
II, 0.25 mmol (41 mg) of 2-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h, after chromatography (elu-
ents CH2Cl2, CH2Cl2–MeOH, 200:1) we isolated 30 mg
(41%) of compound XI and 19 mg (36%) of diarylation
product XXXII.
C3 ), 124.2 (2C, CQ), 125.0 (2C, CQ4a), 127.1 (2C, CQ),
Q
4
127.8 (2C, CQ), 129.3 (2C, CQ), 136.5 (2C, CQ ), 147.4
(2C, CQ8a), 157.2 (2C, C2 ). Mass spectrum: m/z 420.241
Q
[M + H]+. C29H30N3. Calculated (M + H) 420.244.
With a mixture of CH2Cl2–MeOH, 200:1 28 mg (35%)
of monoarylation product XI was eluted.
N-[(Adamantane-1-yl)methyl]quinoline-4-amine
(XII). A mixture of 0.25 mmol (41 mg) of amine II,
0.25 mmol (41 mg) of 4-chloroquinoline, 6 mg (4 mol%)
of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg (1.5
equiv) of sodium tert-butylate was boiled for 7 h in 2.5
ml of anhydrous dioxane. Yield after chromatography
(eluent CH2Cl2–MeOH, 50:1) 38 mg (52%), light-brown
oily substance. UV spectrum (CH2Cl2): λmax 321 nm
b. A mixture of the same quantities of amine and
2-chloroquinoline, 12 mg (8 mol%) of Pd(dba)2, 9 mg
(9 mol%) of DavePhos, and 36 mg (1.5 equiv) of sodium
tert-butylate was boiled for 7 h. According to 1H NMR
spectrum the reaction mixture contained 50% of sec-
ondary amine XI; the products were not subjected to
chromatography.
c. The reaction was carried out without catalyst.
A mixture of 0.2 mmol (33 mg) of amine II, 0.2 mmol
(33 mg) of 2-chloroquinoline, 111 mg (4 equiv) of potas-
sium carbonate, 1 ml of DMF was boiled for 14 h. Yield
of compound XI after chromatography (eluent CH2Cl2–
MeOH, 200:1) 20 mg (34%), light-yellow oily substance.
UV spectrum (CH2Cl2): λmax 343 nm (ε 6400). 1H NMR
spectrum, δ, ppm: 1.61–1.75 m (12H, CH2Ad), 1.99 br.s
1
(ε 11800). H NMR spectrum, δ, ppm: 1.64 br.s (6H,
CH2Ad), 1.65–1.78 m (6H, CH2Ad), 2.02 br.s (3H, CHAd),
2.99 d (2H, CH2N, 3J 5.8 Hz), 5.12 br.s (1H, NH), 6.44 d
3
3
(1H, H3 , J 5.4 Hz), 7.40 d.d.d (1H, H6 , J 8.4, 6.9,
Q
Q
4J 1.2 Hz), 7.60 t.d (1H, H7 , 3J 8.4, 4J 1.2 Hz), 7.73 d
Q
(1H, H5 , 3J 8.4 Hz), 7.96 d (1H, H8 , 3J 8.4 Hz), 8.51 d
Q
Q
(1H, H2 , 3J 5.4 Hz). 13C NMR spectrum, δ, ppm: 28.2
Q
3
(3C, CHAd), 34.1 (1C, CAd), 36.8 (3C, CH2Ad), 40.7
(3H, CHAd), 3.19 d (2H, CH2N, J 6.1 Hz), 4.82 br.s
(3C, CH2Ad), 54.9 (1C, CH2N), 98.6 (1C, C3 ), 118.6
(1H, NH), 6.66 d (1H, H3 , 3J 8.8 Hz), 7.17 d.d.d (1H,
Q
Q
(1C, CQ4a), 119.1 (1C, CQ), 124.5 (1C, CQ), 129.0 (1C,
H6 , 3J 8.0, 7.0, 4J 1.1 Hz), 7.50 d.d.d (1H, H7 , 3J 8.5,
Q
Q
4
CQ), 129.7 (1C, CQ), 148.1 (1C, CQ8a), 150.4 (1C, CQ ),
7.0, J 1.5 Hz), 7.55 d.d (1H, H5 , J 8.0, J 1.1 Hz),
4
3
4
Q
150.7 (1C, C2 ). Mass spectrum: m/z 293.197 [M + H]+.
7.64 d (1H, H8 , 3J 8.5 Hz), 7.79 d (1H, HQ , 3J 8.8 Hz).
4
Q
Q
13C NMR spectrum, δ, ppm: 28.3 (3C, CHAd), 34.0 (1C,
C20H25N2. Calculated (M + H) 293.202.
CAd), 37.0 (3C, CH2Ad), 40.5 (3C, CH2Ad), 53.6 (1C,
N-[(Adamantan-1-yl)methyl]quinolin-6-amine
(XIII). A mixture of 0.25 mmol (41 mg) of amine
II, 0.25 mmol (41 mg) of 6-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate was boiled for 7 h in
2.5 ml of anhydrous dioxane. Yield after chromatography
(eluent CH2Cl2–MeOH, 100:1) 47 mg (63%), light-green
CH2N), 110.8 (1C, C3 ), 121.7 (1C, CQ), 123.3 (1C,
Q
CQ4a), 125.9 (1C, CQ), 127.4 (1C, CQ), 129.5 (1C, CQ),
137.3 (1C, CQ ), 148.1 (1C, CQ8a), 157.7 (1C, C2 ). Mass
4
Q
spectrum: m/z 293.207 [M + H]+. C20H25N2. Calculated
(M + H) 293.202.
N-[(Adamantan-1-yl)methyl]-N-(quinolin-2-yl)-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1401
viscous oily substance, exhibits luminescence on dissolv-
ing in organic solvents. UV spectrum (CH2Cl2): λmax 361
nm (ε 7500). 1H NMR spectrum, δ, ppm: 1.60 br.s (6H,
CH2Ad), 1.63–1.76 m (6H, CH2Ad), 2.00 br.s (3H, CHAd),
2.88 d (2H, CH2N, 3J 4.3 Hz), 4.01 br.s (1H, NH), 6.67 d
(1H, H5 , 4J 2.7 Hz), 7.08 d.d (1H, H7 , 3J 9.0, 4J 2.7 Hz),
4J 1.1 Hz), 7.18–7.23 m (1H, H4Ph), 7.25–7.31 m (4H,
H2Ph, H3Ph), 7.47–7.51 m (2H, H7 , H5 ), 7.62 d (1H,
Q
Q
H8 , 3J 8.0 Hz), 7.70 d (1H, HQ , 3J 9.0 Hz). 13C NMR
4
Q
spectrum, δ, ppm: 28.4 (3C, CHAd), 36.5 (1C, CAd), 36.8
(3C, CH2Ad), 39.1 (3C, CH2Ad), 66.0 (1C, CHN), 109.8
(1C, C3 ), 121.8 (1C, CQ), 123.4 (1C, CQ4a), 125.8 (1C,
Q
Q
Q
7.21 d.d (1H, H3 , J 8.3, 4.2 Hz), 7.83 d (1H, H8 ,
CQ), 126.9 (1C, CHPh), 127.4 (1C, CQ), 127.6 (2C, CHPh),
3
Q
Q
3J 9.0 Hz), 7.87 d.d (1H, HQ , J 8.5, 4J 1.0 Hz), 8.56 d.d
(1H, H2 , 3J 4.2, 4J 1.6 Hz). 13C NMR spectrum, δ, ppm:
128.2 (2C, CHPh), 129.5 (1C, CQ), 137.5 (1C, CQ ), 139.8
4 3
4
(1C, C1Ph), 148.0 (1C, CQ8a), 157.1 (1C, C2 ). Mass
Q
Q
28.2 (3C, CHAd), 33.8 (1C, CAd), 36.9 (3C, CH2Ad), 40.7
spectrum: m/z 369.225 [M + H]+. C26H29N2. Calculated
(3C, CH2Ad), 56.0 (1C, CH2N), 102.4 (1C, C7 ), 121.2
(M + H) 369.233.
Q
(1C, CQ), 121.3 (1C, CQ), 130.0 (1C, CQ), 130.2 (1C,
N-[(Adamantan-1-yl)(phenyl)methyl]quinolin-4-
amine (XV). A mixture of 0.25 mmol (60 mg) of amine
III, 0.25 mmol (41 mg) of 4-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h. Yield after chromatography
(eluent CH2Cl2–MeOH, 25:1) 58 mg (63%), light-brown
oily substance. Initial amine III (28%) was recovered by
chromatography. 1H NMR spectrum, δ, ppm: 1.55–1.65 m
(6H, CH2Ad), 1.68–1.80 m (6H, CH2Ad), 2.03 br.s (3H,
CQ4a), 133.5 (1C, CQ), 142.9 (1C, CQ8a), 145.7 (1C, C2 ),
Q
147.0 (1C, C6 ). Mass spectrum: m/z 293.206 [M + H]+.
Q
C20H25N2. Calculated (M + H) 293.202.
N-[(Adamantan-1-yl)(phenyl)methyl]quinolin-2-
amine (XIV). a. A mixture of 0.25 mmol (60 mg) of
amine III, 0.25 mmol (41 mg) of 2-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h.
3
CHAd), 4.09 d (1H, CHN, J 6.3 Hz), 5.73 d (1H, NH,
b. The same reaction mixture was boiled for 0.5 h to
reduce the amount of the side product, 2-tert-butoxy-
quinoline (XXIX).
3
3J 6.3 Hz), 6.13 d (1H, H3 , J 5.3 Hz), 7.21–7.30 m
Q
(5H, Ph), 7.48 d.d.d (1H, H6 , J 8.2, 7.0, J 1.0 Hz),
3
4
Q
7.62 d.d.d (1H, H7 , 3J 8.2, 7.0, 4J 1.1Hz), 7.86 d (1H,
Q
The reaction products were chromatographed (eluent
petroleum ether–CH2Cl2, 1:2) to obtain 58 mg (32%)
of compound as light-yellow crystalline powder, mp
131–133°C; elution with dichloromethane provided 36%
of 2-tert-butoxyquinoline (XXIX) and also 50% of initial
amine III.
H5 , 3J 8.3 Hz), 7.95 d (1H, H8 , 3J 8.5 Hz), 8.33 d (1H,
Q
Q
H2 , 3J 5.3 Hz). 13C NMR spectrum, δ, ppm: 28.3 (3C,
Q
CHAd), 36.5 (1C, CAd), 36.8 (3C, CH2Ad), 39.3 (3C,
CH2Ad), 67.0 (1C, CHN), 100.1 (1C, C3 ), 118.7 (1C, CQ),
Q
119.0 (1C, CQ4a), 124.6 (1C, CQ), 127.3 (1C, C4Ph), 127.9
(2C, CHPh), 128.3 (2C, CHPh), 128.8 (1C, CQ), 130.1 (1C,
c. A mixture of the same amounts of amine III and
2-chloroquinoline, 12 mg (8 mol%) of Pd(dba)2, 9 mg
(9 mol%) of DavePhos, and 36 mg (1.5 equiv) of sodium
tert-butylate was boiled for 7 h. According to 1H NMR
spectrum of the reaction mixture the yield of compound
XIV was 50%; the products were not subjected to chro-
matography.
CQ), 138.3 (1C, C1Ph), 148.2 (1C, CQ8a), 148.7 (1C, CQ ),
4
150.9 (1C, C2 ). Mass spectrum: m/z 369.230 [M + H]+.
Q
C26H29N2. Calculated (M + H) 369.233.
N-[(Adamantan-1-yl)(phenyl)methyl]quinoline-
6-amine (XVI). A mixture of 0.25 mmol (60 mg) of
amine III, 0.25 mmol (41 mg) of 6-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h. Yield after chromatography
(eluent CH2Cl2–MeOH, 200:1) 77 mg (83%), yellow-
d. The reaction was carried out in noncatalytic con-
ditions. A mixture of 0.2 mmol (48 mg) of amine III,
0.2 mmol (33 mg) of 2-chloroquinoline, 111 mg (4 equiv)
of potassium carbonate, 1 ml of DMF was boiled for 14 h.
According to 1H NMR spectrum of the reaction mixture
the yield of compound XIV was 11%; the products were
1
green crystalline powder, mp 113–115°C. H NMR
spectrum, δ, ppm: 1.49–1.62 m (6H, CH2Ad), 1.65–1.76 m
1
(6H, CH2Ad), 2.00 br.s (3H, CHAd), 4.00 d (1H, CHN,
not subjected to chromatography. H NMR spectrum,
3J 6.6 Hz), 4.70 d (1H, NH, 3J 6.6 Hz), 6.46 d (1H, H5 ,
δ, ppm: 1.53–1.62 m (6H, CH2Ad), 1.65–1.70 m (3H,
CH2Ad), 1.73–1.79 m (3H, CH2Ad), 2.00 br.s (3H, CHAd),
4.36 d (1H, CHN, 3J 6.9 Hz), 5.63 d (1H, NH, 3J 6.9 Hz),
Q
4J 2.4 Hz), 7.11–7.15 m (2H, H3 , H7 ), 7.18–7.23 m
Q
Q
(1H, H4Ph), 7.26–7.33 m (4H, H2Ph, H3Ph), 7.71 d (1H,
4 3
HQ , J 7.8 Hz), 7.81 d (1H, H8 , 3J 9.1 Hz), 8.53 d.d (1H,
6.52 d (1H, H3 , 3J 9.0 Hz), 7.14 d.d.d (1H, H, 3J 8.0, 7.0,
Q
Q
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

GRIGOROVA et al.
1402
H2 , 3J 4.2, 4J 1.5 Hz). 13C NMR spectrum, δ, ppm: 28.3
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h. Yield after chromatography
(eluent CH2Cl2–MeOH, 50:1) 73 mg (91%), light-brown
oily substance. 1H NMR spectrum, δ, ppm: 1.27 d (3H,
CH3, 3J 6.4 Hz), 1.39 d.d (1H, CH2, 2J 14.7, 3J 3.6 Hz),
1.51–1.60 m (7H, CH2Ad, CH2), 1.63–1.68 m (6H,
CH2Ad), 1.90 br.s (3H, CHAd), 3.82–3.91 m (1H, CHN),
Q
(3C, CHAd), 36.4 (1C, CAd), 36.8 (3C, CH2Ad), 39.1 (3C,
CH2Ad), 67.9 (1C, CHN), 103.8 (1C, C7 ), 121.0 (1C,
Q
CQ), 121.5 (1C, CQ), 126.9 (1C, C4Ph), 127.6 (2C, CHPh),
128.5 (2C, CHPh), 129.9 (1C, CQ), 133.7 (1C, CQ), 139.5
(1C, C1Ph), 142.9 (1C, CQ8a), 145.5 (1C, C2 ), 145.8 (1C,
Q
C6 ), (quaternary atom CQ was not detected). Mass
spectrum: m/z 369.238 [M + H]+. C26H29N2. Calculated
4a
Q
5.23 d (1H, NH, 3J 7.1 Hz), 6.44 d (1H, H3 , 3J 5.6 Hz),
Q
7.40 d.d.d (1H, H6 , 3J 8.2, 3J 6.9, 4J 1.2 Hz), 7.59 d.d.d
(M + H) 369.233.
Q
(1H, H7 , J 8.2, 6.9, J 1.3 Hz), 7.79 d (1H, H5 ,
3J 8.5 Hz), 7.98 d (1H, H8 , 3J 8.4 Hz), 8.49 d (1H, H2 ,
3
4
N-[1-(Adamantan-1-yl)propan-2-yl]quinolin-2-
amine (XVII). a. A mixture of 0.25 mmol (48 mg) of
amine IV, 0.25 mmol (41 mg) of 2-chloroquinoline,
6 mg (4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP,
36 mg (1.5 equiv) of sodium tert-butylate, 2.5 ml of anhy-
drous dioxane was boiled for 7 h. According to 1H NMR
spectrum of the reaction mixture the yield of reaction
product XVII was 24%, of side compound XXIX, 27%;
the products were not chromatographed.
Q
Q
Q
Q
3J 5.6 Hz). 13C NMR spectrum, δ, ppm: 22.4 (1C, CH3),
28.4 (3C, CHAd), 32.5 (1C, CAd), 36.8 (3C, CH2Ad), 42.9
(3C, CH2Ad), 44.2 (1C, CH2), 52.3 (1C, CHN), 98.2 (1C,
C3 ), 118.5 (1C, CQ4a), 119.8 (1C, CQ), 124.7 (1C, CQ),
Q
128.5 (1C, CQ), 129.4 (1C, CQ), 147.0 (1C, CQ8a), 149.1
(1C, CQ ), 149.5 (1C, C2 ). Mass spectrum: m/z 321.228
4
Q
[M + H]+. C22H29N2. Calculated (M + H) 321.233.
N-[1-(Adamantan-1-yl)propan-2-yl]quinolin-6-
amine (XIX). A mixture of 0.25 mmol (48 mg) of amine
IV, 0.25 mmol (41 mg) of 6-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h. Yield after chromatography
(eluent CH2Cl2–MeOH, 200:1) 71 mg (88%), yellow-
green viscous oily substance, exhibits luminescence on
b. A mixture of the same amounts of the amine and
2-chloroquinoline, 12 mg (8 mol%) of Pd(dba)2, 9 mg
(9 mol%) of DavePhos, and 36 mg (1.5 equiv) of sodium
tert-butylate was boiled for 7 h. Yield after chromatogra-
phy (eluent CH2Cl2–MeOH, 200:1) 30 mg (38%).
c. The reaction was carried out without catalyst with
0.2 mmol (39 mg) of amine IV, 0.2 mmol (33 mg) of
2-chloroquinoline, 111 mg (4 equiv) of potassium car-
bonate, 1 ml of DMF; the mixture was boiled for 14
h. Yield after chromatography (eluent CH2Cl2–MeOH,
100:1) 24 mg (22%), light-brown oily substance. 1H NMR
spectrum, δ, ppm: 1.24 d (3H, CH3, 3J 6.5 Hz), 1.29 d.d
(1H, CH2, 2J 14.5, 3J 4.2 Hz), 1.37 d.d (1H, CH2, 2J 14.5,
3J 7.5 Hz), 1.58 br.s (6H, CH2Ad), 1.58–1.68 m (6H,
CH2Ad), 1.92 br.s (3H, CHAd), 4.15–4.28 m (1H, CHN),
1
dissolving in organic solvents. H NMR spectrum, δ,
3
ppm: 1.21 d (3H, CH3, J 5.9 Hz), 1.28 d.d (1H, CH2,
2J 14.8,3J 3.7 Hz), 1.35 d.d (1H, CH2, 2J 14.8,3J 6.8 Hz),
1.54–1.57 m (6H, CH2Ad), 1.57–1.68 m (6H, CH2Ad),
1.92 br.s (3H, CHAd), 3.67–3.76 m (2H, CHN, NH),
4
3
6.65 d (1H, H5 , J 2.6 Hz), 7.00 d.d (1H, H7 , J 9.0,
Q
Q
4J 2.6 Hz), 7.22 d.d (1H, H3 , 3J 8.3, 4.2 Hz), 7.48 d (1H,
Q
H8 , J 9.0 Hz), 7.88 d.d (1H, HQ , J 8.3, J 1.5 Hz),
3
4
3
4
4.49 d (1H, NH, 3J 7.0 Hz), 6.59 d (1H, H3 , 3J 8.9 Hz),
Q
Q
8.57 d.d (1H, H8 , 3J 4.2, 4J 1.6 Hz). 13C NMR spectrum,
7.17 d.d.d (1H, H6 , J 8.0, 6.9, J 1.1 Hz), 7.50 d.d.d
3
4
Q
Q
(1H, H7 , 3J 8.3, 6.9, 4J 1.4 Hz), 7.55 d.d (1H, H5 , 3J 8.0,
δ, ppm: 22.8 (1C, CH3), 28.6 (3C, CHAd), 32.5 (1C, CAd),
Q
Q
4J 1.3 Hz), 7.65 d (1H, H8 , 3J 8.3 Hz), 7.79 d (1H, HQ ,
4
36.9 (3C, CH2Ad), 43.0 (3C, CH2Ad), 44.2 (1C, CH2), 52.7
Q
(1C, CHN), 102.5 (1C, C7 ), 121.2 (1C, CQ), 121.6 (1C,
3J 8.9 Hz). 13C NMR spectrum, δ, ppm: 23.9 (1C, CH3),
28.7 (3C, CHAd), 32.7 (1C, CAd), 37.0 (3C, CH2Ad), 42.8
(1C, CH2), 43.0 (3C, CH2Ad), 52.9 (1C, CHN), 111.0 (1C,
Q
CQ), 130.2 (1C, CQ), 130.3 (1C, CQ4a), 133.5 (1C, CQ),
142.9 (1C, CQ8a), 145.0 (1C, C6 ), 145.6 (1C, C2 ). Mass
Q
Q
spectrum: m/z 321.231 [M + H]+. C22H29N2. Calculated
C3 ), 121.6 (1C, CQ), 123.3 (1C, CQ4a), 126.1 (1C, CQ),
Q
4
(M + H) 321.233.
127.4 (1C, CQ), 129.4 (1C, CQ), 137.2 (1C, CQ ), 147.3
(1C, CQ8a), 156.0 (1C, C2 ). Mass spectrum: m/z 321.235
N-[1-( Adamantan-1-yl)propyl]quinolin-4-amine
(XXI). A mixture of 0.25 mmol (48 mg) of amine V,
0.25 mmol (41 mg) of 4-chloroquinoline, 12 mg (8 mol%)
of Pd(dba)2, 9 mg (9 mol%) of DavePhos, 36 mg
(1.5 equiv) of sodium tert-butylate, 2.5 ml of anhydrous
dioxane was boiled for 7 h. Yield after chromatography
Q
[M + H]+. C22H29N2. Calculated (M + H) 321.233.
N-[1-(Adamantan-1-yl)propan-2-yl]quinolin-4-
amine (XVIII). A mixture of 0.25 mmol (48 mg) of
amine IV, 0.25 mmol (41 mg) of 4-chloroquinoline, 6 mg
(4 mol%) of Pd(dba)2, 7 mg (4.5 mol%) of BINAP, 36 mg
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1403
(eluents CH2Cl2–MeOH, 50:1–20:1) 45 mg (56%),
light-brown oily substance. 1H NMR spectrum, δ, ppm:
0.89 t (3H, CH3, 3J 7.3 Hz), 1.33 d.d.q (1H, CH2, 2J 14.5,
3J 11.0, 7.3 Hz), 1.57–1.72 m (12H, CH2Ad), 1.90 d.q.d
(1H, CH2, 2J 14.5, 3J 7.3, 2.7 Hz), 1.96 br.s (3H, CHAd),
was detected and 50% of 2-tert-butoxyquinoline XXIX.
N-(Adamantan-1-yl)quinolin-2-amine (XXIII). a. A
mixture of 0.25 mmol (38 mg) of amine VI, 0.25 mmol
(41 mg) of 2-chloroquinoline, 8.5 mg (6 mol%) of
Pd(dba)2, 10 mg (7 mol%) of BINAP, 36 mg (1.5 equiv)
of sodium tert-butylate, 2.5 ml of anhydrous dioxane
3
3.18 t.d (1H, CHN, J 10.7, 2.4 Hz), 4.76 d (1H, NH,
3J 10.0 Hz), 6.48 d (1H, H3 , 3J 5.6 Hz), 7.41 d.d.d (1H,
1
Q
was boiled for 7 h. According to H NMR spectrum of
H6 , 3J 8.2, 6.9, 4J 1.3 Hz), 7.61 d.d.d (1H, H7 , 3J 8.2,
Q
Q
the reaction mixture the yield of reaction product XXIII
was 25%, of side compound XXIX, 70%; the products
were not chromatographed.
6.9, 4J 1.1 Hz), 7.73 d (1H, H5 , 3J 8.4 Hz), 7.96 d (1H,
Q
HQ , J 8.4, J 1.3 Hz), 8.47 d (1H, H2 , J 5.6 Hz).
13C NMR spectrum, δ, ppm: 11.6 (1C, CH3), 22.6 (1C,
8
3
4
3
Q
b. The same amounts of amine and 2-chloroquinoline,
12 mg (8 mol%) of Pd(dba)2, 9 mg (9 mol%) of DavePhos,
and 36 mg (1.5 equiv) of sodium tert-butylate were boiled
for 7 h. Yield of compound XXIII after chromatography
(eluent CH2Cl2–MeOH, 200:1) 17 mg (24%), light-yel-
low crystalline substance, mp 131–133°C. By elution with
CH2Cl2 50 mg (33%) of compound XXIX was isolated.
CH2), 28.3 (3C, CHAd), 37.0 (3C, CH2Ad), 37.9 (1C, CAd),
39.0 (3C, CH2Ad), 63.7 (1C, CHN), 98.8 (1C, C3 ), 118.3
Q
(1C, CQ4a), 118.8 (1C, CQ), 124.3 (1C, CQ), 128.9 (1C,
CQ), 130.0 (1C, CQ), 148.6 (1C, CQ8a), 150.9 (1C, C2 ),
Q
151.1 (1C, CQ ). Mass spectrum: m/z 321.239 [M + H]+.
4
C22H29N2. Calculated (M + H) 321.233.
N-[1-(Adamantan-1-yl)propyl]quinolin-6-amine
(XXII). A mixture of 0.25 mmol (48 mg) of amine V,
0.25 mmol (41 mg) of 6-chloroquinoline, 12 mg (8 mol%)
of Pd(dba)2, 9 mg (9 mol%) of DavePhos, 36 mg
(1.5 equiv) of sodium tert-butylate was boiled for 7 h in
2.5 ml of anhydrous dioxane. Yield after chromatography
(eluent CH2Cl2–MeOH, 100:1) 54 mg (67%), yellow-
green viscous oily substance, exhibits luminescence on
dissolving in organic solvents. 1H NMR spectrum, δ, ppm:
0.91 t (3H, CH3, 3J 7.3 Hz), 1.20 d.d.q (1H, CH2, 2J 14.6,
3J 11.0, 7.3 Hz), 1.54–1.70 m (12H, CH2Ad), 1.83 d.q.d
(1H, CH2, 2J 14.6, 3J 7.3, 2.6 Hz), 1.95 br.s (3H, CHAd),
c. The reaction was carried out without catalyst.
Amixture of 0.2 mmol (30 mg) of amine VI and 0.2 mmol
(33 mg) of 2-chloroquinoline, 111 mg (4 equiv) of potas-
sium carbonate, 1 ml DMF was boiled for 14 h.According
to 1H NMR spectrum of the reaction mixture the yield of
reaction product XXIII was 22%, the products were not
chromatographed. 1H NMR spectrum, δ, ppm: 1.74 br.s
(6H, CH2Ad), 2.14 br.s (3H, CHAd), 2.18 br.s (6H, CH2Ad),
4.57 br.s (1H, NH), 6.62 d (1H, H3 , 3J 9.0 Hz), 7.16 t
Q
(1H, H6 , 3J 7.4 Hz), 7.48 t (1H, H7 , 3J 7.6 Hz), 7.53 d
Q
Q
(1H, H5 , 3J 8.0 Hz), 7.63 d (1H, H8 , 3J 8.3 Hz), 7.73 d
Q
Q
(1H, HQ , 3J 8.8 Hz). 13C NMR spectrum, δ, ppm: 29.7
4
3
2.96 t.d (1H, CHN, J 10.5, 2.6 Hz), 3.68 d (1H, NH,
(3C, CHAd), 36.6 (3C, CH2Ad), 42.4 (3C, CH2Ad), 52.0
3J 10.0 Hz), 6.67 d (1H, H5 , 4J 2.6 Hz), 7.08 d.d (1H,
Q
(1C, CAd), 113.0 (1C, C3 ), 121.7 (1C, CQ), 122.9 (1C,
H7 , 3J 9.0, 4J 2.6 Hz), 7.19 d.d (1H, H3 , 3J 8.3, 4.2 Hz),
Q
Q
Q
CQ4a), 126.3 (1C, CQ), 127.2 (1C, CQ), 129.2 (1C, CQ),
7.81 d (1H, H8 , 3J 8.9 Hz), 7.83 d (1H, HQ , 3J 8.1 Hz),
8.52 d.d (1H, H2 , 3J 4.2, 4J 1.5 Hz). 13C NMR spectrum,
4
Q
136.5 (1C, CQ), 148.0 (1C, CQ8a), 156.4 (1C, C2 ). Mass
Q
Q
spectrum: m/z 279.180 [M + H]+. C19H23N2. Calculated
δ, ppm: 11.9 (1C, CH3), 22.9 (1C, CH2), 28.4 (3C, CHAd),
(M + H) 279.186.
37.1 (3C, CH2Ad), 37.9 (1C, CAd), 39.1 (3C, CH2Ad),
64.4 (CHN), 102.2 (1C, C7 ), 121.1 (1C, CQ), 121.2 (1C,
N-(Adamantan-1-yl)quinolin-4-amine (XXIV). a.
Amixture of 0.25 mmol (38 mg) of amine VI, 0.25 mmol
(41 mg) of 4-chloroquinoline, 8.5 mg (6 mol%) of
Pd(dba)2, 10 mg (7 mol%) of BINAP, 36 mg (1.5 equiv)
of sodium tert-butylate, 2.5 ml of anhydrous dioxane
was boiled for 7 h. Yield after chromatography (eluent
CH2Cl2–MeOH, 25:1) 21 mg (30%).
Q
CQ), 130.1 (1C, CQ), 130.3 (1C, CQ4a), 133.3 (1C, CQ),
142.6 (1C, CQ8a), 145.4 (1C, C2 ), 148.2 (1C, C6 ). Mass
Q
Q
spectrum: m/z 321.232 [M + H]+. C22H22N2. Calculated
(M+H) 321.233.
Reaction of amine V with 2-chloroquinoline. The
reaction product of amine V and 2-chloroquinoline ob-
tained in the presence of 12 mg (8 mol%) of Pd(dba)2,
9 mg (9 mol%) of DavePhos, 36 mg (1.5 equiv) of sodium
tert-butylate after boiling for 7 h in 2.5 ml of dioxane was
not isolated in the pure state. In the 1H NMR spectrum
of the reaction mixture a small amount of compound XX
b. A mixture of the same quantities of the amine and
4-chloroquinoline, 12 mg (8 mol%) of Pd(dba)2, 9 mg
(9 mol%) of DavePhos, and 36 mg (1.5 equiv) of sodium
tert-butylate was boiled for 7 h. Yield after chromatogra-
phy (eluent CH2Cl–MeOH, 25:1) 14 mg (20%), yellow-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

GRIGOROVA et al.
1404
1
2-chloroquinoline, 12 mg (8 mol%) of Pd(dba)2, 14 mg
(9 mol%) of BINAP, and 36 mg (1.5 equiv) of sodium tert-
butylate was boiled for 7 h. Yield after chromatography
(eluent CH2Cl2–MeOH, 100:1) 36 mg (52%).
brown crystalline powder, mp 134–136°C. H NMR
spectrum, δ, ppm: 1.75 br.s (6H, CH2Ad), 2.12 br.s
(6H, CH2Ad), 2.20 br.s (3H, CHAd), 5.02 br.s (1H, NH),
6.75 d (1H, H3 , 3J 5.6 Hz), 7.40 t (1H, H6 , 3J 7.6 Hz),
Q
Q
7.59 t (1H, H7 , 3J 7.6 Hz), 7.70 d (1H, H5 , 3J 8.5 Hz),
c. The reaction was carried out without catalyst. A
mixture of 0.2 mmol (30 mg) of amine VII and 0.2 mmol
(33 mg) of 2-chloroquinoline, 111 mg (4 equiv) of po-
tassium carbonate, 1 ml of DMF was boiled for 14 h.
According to 1H NMR spectrum of the reaction mixture
the yield of reaction product was 15%; the product was
not subjected to chromatography. 1H NMR spectrum, δ,
ppm: 1.60–1.66 m (2H, CH2Ad), 1.77 br.s (2H, CHAd),
1.84–2.00 m (8H, CH2Ad), 2.09 br.s (2H, CHAd), 4.05 d
Q
Q
7.96 d (1H, H8 , 3J 8.2 Hz), 8.45 d (1H, H2 , 3J 5.5 Hz).
Q
Q
13C NMR spectrum, δ, ppm: 29.5 (3C, CHAd), 36.3 (3C,
CH2Ad), 41.9 (3C, CH2Ad), 52.6 (1C, CAd), 101.6 (1C,
C3 ), 119.2 (1C, CQ), 124.7 (1C, CQ), 129.2 (1C, CQ),
Q
129.3 (1C, CQ), 147.6 (1C, CQ8a), 148.2 (1C, CQ ), 149.2
4
(1C, C2 ), the quaternary atom C4a was not detected. Mass
Q
spectrum: m/z 279.184 [M + H]+. C19H23N2. Calculated
(M + H) 279.186.
3
3
(1H, CHN, J 7.4 Hz), 5.19 d (1H, NH, J 6.6 Hz),
6.65 d (1H, H3 , 3J 9.0 Hz), 7.17 t (1H, H6 , 3J 7.4 Hz),
N-(Adamantan-1-yl)quinolin-6-amine (XXV). a. A
mixture of 0.25 mmol (38 mg) of amine VI, 0.25 mmol
(41 mg) of 6-chloroquinoline, 8.5 mg (6 mol%) of
Pd(dba)2, 10 mg (7 mol%) of BINAP, 36 mg (1.5 equiv)
of sodium tert-butylate, 2.5 ml of anhydrous dioxane was
boiled for 7 h. According to H NMR spectrum of the
reaction mixture the yield of reaction product was 25%,
the conversion of 6-chloroquinoline was incomplerte.
Q
Q
7.50 d.d.d (1H, H7 , 3J 8.3, 7.1, 4J 1.3 Hz), 7.56 d (1H,
H5 , 3J 8.1 Hz), 7.63 d (1H, H8 , 3J 8.3 Hz), 7.81 d (1H,
HQ , 3J 9.0 Hz). 13C NMR spectrum, δ, ppm: 27.2 (1C,
CAd), 27.3 (1C, CAd), 31.7 (2C, CAd), 32.0 (2C, CAd), 37.3
(2C, CAd), 37.7 (1C, CAd), 56.2 (1C, CHN), 110.6 (1C,
CQ), 121.7 (1C, CQ), 123.3 (1C, CQ4a), 125.9 (1C, CQ),
Q
Q
Q
4
1
4
127.4 (1C, CQ), 129.5 (1C, CQ), 137.4 (1C, CQ ), 148.3
b. The same quantities of the amine and 2-chloro-
quinoline, 12 mg (8 mol%) of Pd(dba)2, 9 mg (9 mol%)
of DavePhos, and 36 mg (1.5 equiv) of sodium tert-
butylate were boiled for 7 h. Yield after chromatography
(eluent CH2Cl2–MeOH, 100:1) 57 mg (82%), yellow
oily substance, exhibits luminescence on dissolving in
(1C, CQ8a), 156.4 (1C, C2 ). Mass spectrum: m/z 279.184
Q
[M + H]+. C19H23N2. Calculated (M + H) 279.186.
N-(Adamantane -2-yl)quinoline-4-amine (XXVII).
Amixture of 0.25 mmol (38 mg) of amine VII, 0.25 mmol
(41 mg) of 4-chloroquinoline, 6 mg (4 mol%) of Pd(dba)2,
7 mg (4.5 mol%) of BINAP, 36 mg (1.5 equiv) of sodium
tert-butylate, 2.5 ml of anhydrous dioxane was boiled for
7 h. Yield after chromatography (eluent CH2Cl2–MeOH,
10:1) 62 mg (89%), light-brown crystalline powder, mp
1
organic solvents. H NMR spectrum, δ, ppm: 1.69 br.s
(6H, CH2Ad), 1.97 br.s (6H, CH2Ad), 2.12 br.s (3H, CHAd),
3.72 br.s (1H, NH), 6.95 d (1H, H5 , 4J 2.5 Hz), 7.10 d.d
Q
(1H, H7 , J 9.1, J 2.5 Hz), 7.22 d.d (1H, H3 , J 8.2,
3
4
3
Q
Q
1
4.2 Hz), 7.82 d (1H, H8 , J 9.1 Hz), 7.88 d (1H, HQ ,
3
4
143–145°C. H NMR spectrum, δ, ppm: 1.66–1.73 m
Q
3J 7.8 Hz), 8.59 d.d (1H, H2 , 3J 4.2,4J 1.5 Hz). 13C NMR
(2H, CH2Ad), 1.79 br.s (2H, CHAd), 1.85–1.97 m (8H,
CH2Ad), 2.08 br.s (2H, CHAd), 3.75–3.79 m (1H, CHN),
Q
spectrum, δ, ppm: 29.6 (3C, CHAd), 36.4 (3C, CH2Ad),
5.32 d (1H, NH, 3J 6.6 Hz), 6.39 d (1H, H3 , 3J 5.5 Hz),
42.9 (3C, CH2Ad), 52.2 (1C, CAd), 108.4 (1C, C7 ), 121.1
Q
Q
7.41 d.d.d (1H, H6 , J 8.3, 6.9, J 1.3 Hz), 7.60 d.d.d
3
4
(1C, CQ), 124.5 (1C, CQ), 129.6 (1C, CQ4a), 129.8 (1C,
Q
(1H, H7 , 3J 8.3, 6.9, 4J 1.3 Hz), 7.75 d.d (1H, H5 , 3J 8.3,
CQ), 133.8 (1C, CQ), 143.2 (1C, CQ8a), 144.2 (1C, C6 ),
Q
Q
Q
4J 1.1 Hz), 7.96 d.d (1H, HQ , 3J 8.4, 4J 1.2 Hz), 8.51 d
8
146.4 (C2 ). Mass spectrum: m/z 279.191 [M + H]+.
Q
(1H, H2 , 3J 5.5 Hz). 13C NMR spectrum, δ, ppm: 27.0
C19H23N2. Calculated (M + H) 279.186.
Q
(1C, CAd), 27.1 (1C, CAd), 31.1 (2C, CAd), 31.8 (2C, CAd),
37.0 (2C, CAd), 37.3 (1C, CAd), 56.3 (1C, CHN), 98.9 (1C,
N-(Adamantan-2-yl)quinolin-2-amine (XXVI). a. A
mixture of 0.25 mmol (38 mg) of amine VII, 0.25 mmol
(41 mg) of 2-chloroquinoline, 6 mg (4 mol%) of Pd(dba)2,
7 mg (4.5 mol%) of BINAP, 36 mg (1.5 equiv) of sodium
tert-butylate, 2.5 ml of anhydrous dioxane was boiled for
7 h. Yield after chromatography (eluent CH2Cl–MeOH,
200:1) 34 mg (49%), light-yellow crystalline substance,
mp 115–117°C.
C3 ), 118.6 (1C, CQ4a), 119.1 (1C, CQ), 124.7 (1C, CQ),
Q
129.1 (1C, CQ), 129.3 (1C, CQ), 147.5 (1C, CQ8a), 148.9
(1C, CQ ), 150.0 (1C, C2 ). Mass spectrum: m/z 279.182
4
Q
[M + H]+. C19H23N2. Calculated (M + H) 279.186.
N-(Adamantan-2-yl)quinolin-6-amine (XXVIII). a.
Amixture of 0.25 mmol (38 mg) of amine VII, 0.25 mmol
(41 mg) of 6-chloroquinoline, 6 mg (4 mol%) of Pd(dba)2,
b. A mixture of the same amounts of the amine and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

ARYLATION OF ADAMANTANAMINES: IV.
1973.
1405
7 mg (4.5 mol%) of BINAP, 36 mg (1.5 equiv) of sodium
tert-butylate, 2.5 ml of anhydrous dioxane was boiled for
7 h.According to 1H NMR spectrum of the reaction mix-
ture the yield of reaction product was 55%, the conversion
of the initial 6-chloroquinoline was 60%; the product was
not subjected to chromatography.
4. Gilligan, B.S., Veale, J., and Wodak, J., Med. J. Austral.,
1970, vol. 2, p. 634.
5. Dolin, R. and Bentley, D.W., Options Contr. Influenza.
Proc. Viratek–Ucla, Symp., Keystone. Apr., 20–25, 1985,
New York: 1986.
6. Svenson, T.N., Eur. J. Pharm., 1973, vol. 34, p. 232.
7. Klimova, N.V., Zaitseva, N.M., Avdyunina, N.I., Pya-
tin, B.M., Morozov, I.S., Bykov, N.P., and Kuz’min, V.I.,
Khim.-Farm. Zh., 1990, p. 26.
8. Morozov, I.S., Petrov, V.I., and Sergeeva, S.A., Farmak-
ologiya adamantanov (Pharmacology of Adamantanes),
Volgograd: Izd. Volgograd. Med. Akad., 2001.
9. Avdyunina, N.I., Morozov, I.S., Bol’shakova, R.F., Milita-
reva, N.A., Klimova, N.A., Pyatin, B.M., Khranilov, A.A.,
and Dvalishvili, E.G., Khim.-Farm. Zh., 1988, 819.
10. Da Settimo, A., Marini, A.M., Primofiore, G., and da Set-
timo, F., Farmacology, 1995, vol. 50, p. 321.
b. A mixture of the same quantities of the amine and
6-chloroquinoline, 12 mg (8 mol%) of Pd(dba)2, 14 mg
(9 mol%) of BINAP, and 36 mg (1.5 equiv) of sodium
tert-butylate was boiled for 7 h. Yield after chromatogra-
phy (eluent CH2Cl2–MeOH, 200:1) 39 mg (56%), light-
green crystalline powder, mp 128–130°C, the substance
exhibits luminescence on dissolving in organic solvents.
1H NMR spectrum, δ, ppm: 1.57–1.64 m (2H, CH2Ad),
1.75 br.s (2H, CHAd), 1.83–1.96 m (8H, CH2Ad), 2.09 br.s
(2H, CHAd), 3.64 br.s (1H, CHN), 4.30 br.s (1H, NH),
4
6.63 d (1H, H5 , J 2.6 Hz), 7.08 d.d (1H, H7 , 3J 9.1,
Q
Q
4J 2.6 Hz), 7.20 d.d (1H, H3 , 3J 8.3, 4.2 Hz), 7.84 d (1H,
HQ , J 9.0 Hz), 7.85 d (1H, HQ , J 8.2 Hz), 8.56 d.d (1H,
H2 , 3J 4.2, 4J 1.5 Hz). 13C NMR spectrum, δ, ppm: 27.2
11. Ficarra, R., Ficarra, P., Tommasini, A., Fenech, G., Pizze-
menti, F.C., and Bisignano, G., Bull. Chim. Farm., 1984,
vol. 123, p. 317.
Q
8 3
4 3
Q
(1C, CAd), 27.3 (1C, CAd), 31.3 (2C, CAd), 31.6 (2C, CAd),
37.2 (2C, CAd), 37.5 (1C, CAd), 56.8 (1C, CHN), 102.9
12. Ismail, F.M.D., Dascombe, M.I., Carrand, P., and
North, S.E., J. Pharm. Pharmacol., 1996, vol. 48, p. 841.
13. Gerzon, K., US Patent 3730956, 1971; Chem. Abstr., 1973,
vol. 79, P18597r.
14. Aranyi, P., Bata, I., Batory, S., Boronkay, E., Bovy, P.,
Kapui, Z., Edit, S., Szabo, T., Urban-Szabo, K., and Var-
ga, M., WO Patent WO2005021536, 2003; Chem. Abstr.,
2005, vol. 142, 298122.
(1C, C7 ), 121.2 (1C, CQ), 121.5 (1C, CQ), 130.2 (2C,
Q
CQ, CQ4a), 133.4 (1C, CQ), 142.8 (1C, CQ8a), 145.1 (1C,
C6 ), 145.7 (1C, C2 ). Mass spectrum: m/z 279.193 [M +
Q
Q
H]+. C19H23N2. Calculated (M + H) 279.186.
ACKNOWLEDGMENTS
15. Abdulqader, A., Alhaider, M., Abdelkader, A., and
Lien, E.J., J. Med. Chem., 1985, vol. 28, p. 1394.
16. Asagarasu, A., Matsui, T., Hayashi, H., Tamaoki, S., Yam-
auchi, Y., Minato, K., and Sato, M., J. Med. Chem., 2010,
vol. 53, p. 7549.
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haltert, J.H., J. Med. Chem., 1988, vol. 31, p. 1347.
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Lansiaux, A., Cheґrouvrier, J., Domona, L., Picot, L.,
Bailly, C., Besson, T., and Thierry, V., Eur. J. Med. Chem.,
2009, vol. 44, p. 3858.
19. Sayed, I., van der Veken, P., Steert, K., Dhooghe, L.,
Hostyn, S., V. Baelen, G., Lemiere, G., Bert, U., Maes, W.,
Cos, P., Maes, L., Joossens, J., Haemers,A., Pieters, L., and
Augustyns, K., J. Med. Chem., 2009, vol. 52, p. 2979.
20. Deraeve, C., Maraval, A., Vendier, L., Faugeroux, V.,
Pitié, M., and Meunier, B., Eur. J. Inorg. Chem., 2008,
p. 5622.
The study was carried out under the financial sup-
port of the Russian Academy of Sciences (program P-8
“Development of the methods of organic synthesis and
creation of compounds with valuable applied properties”)
and the Rusian Foundation for Basic Research (grant no.
10-03-01108).
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