Palladium-catalyzed amination of isomeric dihalobenzenes with 1- and 2-aminoadamantanes

Article abstract of DOI:10.1134/S1070428010010069

Palladium-catalyzed amination of isomeric bromochloro- and dibromobenzenes with 1- and 2-aminoadamantanes was studied. The best yields of the corresponding monoamination products were obtained in the reactions of 2-aminoadamantane with bromochlorobenzenes

Full text of DOI:10.1134/S1070428010010069

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 1, pp. 64–72. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.D. Averin, M.A. Ulanovskaya, V.V.Kovalev, A.K. Buryak, B.S. Orlinson, I.A. Novakov, I.P. Beletskaya, 2010, published in
Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 1, pp. 64–72.
Palladium-Catalyzed Amination of Isomeric Dihalobenzenes
with 1- and 2-Aminoadamantanes
A. D. Averina, M. A. Ulanovskayaa, V. V. Kovaleva, A. K. Buryakb, B. S. Orlinsonc,
I. A. Novakovc, and I. P. Beletskayaa
a Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: averin@org.chem.msu.ru; beletska@org.chem.msu.ru
b Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Moscow, Russia
c Volgograd State Technical University, Volgograd, Russia
Received April 10, 2009
Abstract—Palladium-catalyzed amination of isomeric bromochloro- and dibromobenzenes with 1- and
2-aminoadamantanes was studied. The best yields of the corresponding monoamination products were obtained
in the reactions of 2-aminoadamantane with bromochlorobenzenes. The arylation of 1-aminoadamantane was
successful in the presence of donor phosphine ligand. The amination of o- and m-dibromobenzenes was
strongly complicated by formation of diamination products. Conditions ensuring predominant formation of the
latter were found. The arylation of 2-aminoadamantane was accompanied by oxidation of the initial amine and
reduction of aryl halide.
DOI: 10.1134/S1070428010010069
Adamantane is one of the simplest cage-like hydro-
carbons, which attracts researchers’ attention over
a period of more than 50 years. Up to now, thousands
compounds containing an adamantane fragment have
been synthesized and studied, and many of them have
found applications in various fields of practice, prima-
rily as physiologically active substances. Aminoada-
mantanes and their derivatives are especially interest-
ing as potential medicines; for example, adamantan-1-
amine hydrochloride (amantadine) turned out to be
effective in the treatment of Parkinson’s disease [1, 2]
and was also used in the treatment of hepatitis C [3].
1-(1-Adamantyl)ethanamine (rimantadine) [4] is
widely used as antiviral agent, memantine (derivative
with two amino groups) [5] is an N-methyl D-aspartate
receptor antagonist; many other drugs have more com-
plex structures and often contain aromatic fragments;
examples are chlodantane (immunostimulant) [6],
ladasten (neurostimulator) [7], etc. Most publications
deal with adamantan-1- and -2-amine derivatives pos-
sessing an amide group; many hundreds of such com-
pounds have already been reported. In the recent years,
successful biological tests have been performed with
various N-aryl- and N-hetarylaminoadamantanes, in-
cluding those containing halogen atoms (fluorine,
chlorine, bromine) in the aromatic substituent. There-
fore, we set ourselves the task of developing a conven-
ient procedure for the synthesis of a new family of
N-haloaryl-substituted adamantanamines with a view
to subsequently test them for biological activity.
There are hundreds publications on the synthesis
and applications of adamantan-1-amine; however, pub-
lished data on the synthesis of its N-aryl derivatives are
very scanty. Olifirov et al. [8] synthesized N-phenyl-
adamantan-1-amine in 51% yield from adamantan-1-ol
and aniline in the presence of aniline hydrochloride or
aluminum anilide hydrochloride. In the early publica-
tion by Kogay and Sokolenko [9], the use of 1,3-de-
hydroadamantane was described: this compound re-
acted with aniline in the presence of aniline hydro-
chloride to produce a mixture of aniline alkylation
products at the nitrogen atom and at the para-position
at a ratio of 4:1. N-(1-Adamantyl)aniline was isolated
in 55% yield. Stepanov and Stolyarov [10] synthesized
N-(1-adamantyl)aniline by alkylation of aniline with
1-bromoadamantane. The reaction occurred under
severe conditions and involved the nitrogen atom
(yield 20%) and benzene ring (yield 7%). When the
reaction was carried out in 10 equiv of aniline or in the
presence of an equivalent amount of K2CO3, the yield
64

PALLADIUM-CATALYZED AMINATION OF ISOMERIC DIHALOBENZENES
65
of N-(1-adamantyl)aniline increased to 40–53%, while
the yield of the corresponding C-adamantyl derivative
decreased to 1.5–2.3%. More recently [11], N-(1-ada-
mantyl)aniline was synthesized via oxidative coupling
catalyzed by copper(II). The yield was 57% in the
presence of potassium trifluoro(phenyl)borate and 67%
in the presence of phenylboronic acid. The synthesis of
N-(1-adamantyl)pyridin-2-amine in 44% yield from
pyridin-2-amine and hydroxylamine in the presence of
trifluoroacetic acid was described in [12]. As shown in
[13], N-(1-adamantylamino)pyridin-2-amine is a po-
tent TNF-α inducer in cancer cells in mice. The only
example of the use of palladium catalyst was described
in [14]: N-(1-adamantyl)pyridin-2-amine was synthe-
sized in 60% yield by cross coupling of adamantan-
1-amine with 2-bromopyridine in the presence of
Pd(dba)2/dppp as catalyst.
The above data indicate exceptional practical im-
portance of N-aryl-substituted aminoadamantanes. We
have accumulated much experience related to the syn-
thesis of various arylamines via palladium-catalyzed
amination of aryl halides [28–31]. We have also
studied catalytic arylation of various adamantane
derivatives with 2-bromopyridine [32] and tried to syn-
thesize polyaza macrocycles with the use of 1,3-bis(2-
aminoethyladamantane) [33]. In the present work we
examined palladium-catalyzed arylation of adamantan-
1- and -2-amines with isomeric dihalobenzenes with
a view to find out how the reactant structure affects the
reaction course and outcome.
Adamantan-1-amine (I) was subjected to arylation
with p-, m-, and o-bromochlorobenzenes and p-, m-,
and o-dibromobenzenes. The reactions were carried
out using 4–8 mol% of Pd(dba)2 as catalyst and
BINAP [34] or DavePHOS [35] as phosphine ligand;
the initial reactants were taken in equimolar amounts,
and their concentration was 0.1 M in anhydrous di-
oxane as solvent (Scheme 1). The reaction of adaman-
tan-1-amine (I) with p-bromochlorobenzene in the
presence of Pd(dba)2/BINAP gave only 50% of the
corresponding substituted p-chloroamine II (Table 1,
run no. 1), while in the presence of a donor phosphine
ligand, 2′-(dicyclohexylphosphanyl)-N,N-dimethylbi-
phenyl-2-amine (DavePHOS), the yield of II increased
to 78% (Table 1, run no. 2). Using the same ligand,
m- and o-derivatives III and IV were obtained in 75
and 62% yield, respectively, and in both cases the
reaction was accompanied by formation of diamination
products. The yield of diamine IX in the reaction with
m-bromochlorobenzene was 7%, and the yield of anal-
ogous diamination product X in the reaction with
o-bromochlorobenzene was 25% (Table 1; run nos. 1,
Adamantan-2-amine and its derivatives also attract
much interest. Among them, the most studied is
N-(2-adamantyl)-4-bromoaniline which is more widely
known as ladasten (bromantane, a very potent psycho-
stimulant [7, 15]). Ladasten was synthesized in 96%
yield by the Leuckart reaction [16], and its stimulant-
like psychotropic activity was noted. The effect of dif-
ferent doses of ladasten on the behavior and fertility of
rats was studied in [17–22]. Ladasten was also found
to stimulate expression of genes responsible for bio-
synthesis of dopamine in different brain areas in rats
[23]. The action of ladasten on blood pressure and
vasoconstrictive effect of adrenaline and noradrenaline
[24] was studied, and its specific effect on blood tissue
was described [25]. Ladasten is also used as immuno-
stimulant [26]; it partially prevents development of
immune disorders in immune-deficient mice and coor-
dinates cellular immune reactions [27].
Scheme 1.
NH2
HN
HN
Br
HN
Hlg
Pd(dba)2/L, t-BuONa
dioxane
+
+
Hlg
I
II–VII
VIII–X
NMe2
L = BINAP,
(DavePHOS);
PCy2
II, Hlg = p-Cl; III, Hlg = m-Cl; IV, Hlg = o-Cl; V, Hlg = p-Br; VI, Hlg = m-Br; VII, Hlg = o-Br;
VIII, para isomer; IX, meta isomer; X, ortho isomer.
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AVERIN et al.
66
Table 1. Synthesis of N-aryl-substituted adamantan-1-amines II–Xa
Amine–dihalobenzene
Run no.
Dihalobenzene
Pd–L, mol %
Product (yield, %)
II (50)
ratio
01
02
1-Br-4-ClC6H4
1-Br-4-ClC6H4
1-Br-3-ClC6H4
1-Br-2-ClC6H4
1,4-Br2C6H4
1,3-Br2C6H4
1,3-Br2C6H4
1,2-Br2C6H4
1,2-Br2C6H4
1,4-Br2C6H4
1,3-Br2C6H4
1,3-Br2C6H4
1,2-Br2C6H4
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
2:1
6:1
2:1
Pd(dba)2–BINAP, 5:6
Pd(dba)2–DavePHOS, 5:6
Pd(dba)2–DavePHOS, 5:6
Pd(dba)2–DavePHOS, 5:6
Pd(dba)2–BINAP, 10.5:11
Pd(dba)2–BINAP, 10.5:11
Pd(dba)2–DavePHOS, 5:6
Pd(dba)2–BINAP, 5:6
II (78)
03
III (75), IX (7)
IV (62, 57a), X (25, 24a)
V (72)
VI (56, 23a), IX (11)
VI (15), IX (60)
VII (48)
VII (50, 16a)
VIII (45, –a)
IX (69)
04
05
b06b
c07c
d08d
e09e
10
Pd(dba)2–BINAP, 10.5:11
Pd(dba)2–DavePHOS, 10.5:11
Pd(dba)2–DavePHOS, 10:11.5
Pd(dba)2–DavePHOS, 10.5:11
Pd(dba)2–DavePHOS, 10.5:11
f11f
f12f
13
IX (54)
X (60, 58a) VII (20)
a
b
c
d
e
f
After chromatographic separation.
Conversion of m-dibromobenzene 80%.
Conversion of m-dibromobenzene 95%.
Conversion of o-dibromobenzene 48%.
Conversion of o-dibromobenzene 67%.
Joint chromatographic separation: yield of IX 27%.
3, 4). The amination of p-dibromobenzene in the pres-
ence of 10.5 mol % of Pd(dba)2/BINAP resulted in the
formation of target compound V) in a high yield (72%;
Table 1; run no. 5). Compound I reacted with m-di-
bromobenzene under analogous conditions to give
56% of monoamination product VI, while the yield of
diamine IX was 11%, the overall conversion of initial
m-dibromobenzene being 80% (Table 1; run no. 6).
The use of donor DavePHOS in the synthesis of com-
pound VI was poorly effective: the yield of diamina-
tion product IX sharply increased (60%), while the
yield of VI decreased almost 4-fold; the overall con-
version of m-dibromobenzene was almost quantitative
(Table 1; run no. 7).
formation of C–N bond but consume the initial aryl
halide.
Taking into account that the reactions of equimolar
amounts of adamantan-1-amine (I) with o- and m-di-
bromobenzenes were accompanied by formation of
considerable amounts of diamination products, we
tried to obtain the latter as major products by using
2 equiv of amine I. In the reaction with o-dibromo-
benzene we succeeded in increasing the yield of di-
amino derivative X to 60% (Table 1, run no. 13), while
the yield of IX in the reaction with m-dibromobenzene
increased from 56 to only 69% (Table 1, run no. 11).
The use of a larger excess (6 equiv) of the amine led to
even lower yield of IX (Table 1, run. no. 12). How-
ever, the most difficult was to obtain diamination prod-
uct from p-dibromobenzene. Although compound VIII
was formed in 45% yield (in the reaction mixture), all
attempts to isolate it by chromatography were un-
successful (Table 1, run no. 10).
Isomeric adamantan-2-amine (XI) is characterized
by lesser steric hindrances at the nitrogen atom, and it
turned out to be much more reactive than adamantan-
1-amine (I) (Scheme 2). The yields of compounds
XII–XIV in the reactions with isomeric bromochloro-
benzenes were 80–83% (Table 2, run nos. 1–3), and
the reaction with o-bromochlorobenzene was accom-
We did not use DavePHOS as ligand in the reaction
with o-dibromobenzene, for in this case the yield of
the corresponding diamination product would be even
larger. The yield of target product VII in the reaction
with standard amount of Pd(dba)2–BINAP (5/6 mol %)
was 48%, the conversion of o-dibromobenzene being
appropriate (Table 1, run no. 8). Raising the amount of
the catalyst to 10.5 mol % increased the conversion
of o-dibromobenzene to 67%, but the yield of VII
remained almost unchanged (Table 1, run no. 9). These
data indicated that palladium-catalyzed amination in-
volves concurrent processes which do not result in the
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PALLADIUM-CATALYZED AMINATION OF ISOMERIC DIHALOBENZENES
67
Scheme 2.
Br
H
N
H
N
NH2
Pd(dba)2/L, t-BuONa
dioxane
+
+
Hlg
HN
Hlg
XI
XII–XVII
XIX–XXI
H
N
O
+
+
XVIII
Me
Me
NMe2
L = BINAP,
(DavePHOS);
(Xanthphos);
O
PCy2
PPh2
PPh2
XII, Hlg = p-Cl; XIII, Hlg = m-Cl; XIV, Hlg = o-Cl; XV, Hlg = p-Br; XVI, Hlg = m-Br; XVII, Hlg = o-Br;
XIX, para isomer; XX, meta isomer; XXI, ortho isomer.
panied by formation of an appreciable amount of the
diamination product (Table 2, run no. 3). The yield of
o-diamino derivative XXI in the reaction with o-di-
bromobenzene was comparable with that of mono-
amination product XVII (Table 2, run no. 7); an at-
tempt to raise the yield of the latter using less active
catalytic system Pd(dba)2/Xanthphos was unsuccess-
ful: the yield of XVII fell down to 25%, but the
formation of o-phenylenediamine derivative XXI was
not suppressed completely (7%), and the major product
Table 2. Synthesis of N-aryl-substituted adamantan-2-amines XII–XXIa
Amine–dihalobenzene
Run no.
Dihalobenzene
Pd–L, mol %
Product (yield, %)
XII (83)
ratio
01
02
1-Br-4-ClC6H4
1-Br-3-ClC6H4
1-Br-2-ClC6H4
1,4-Br2C6H4
1,4-Br2C6H4
1,3-Br2C6H4
1,2-Br2C6H4
1,2-Br2C6H4
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
Pd(dba)2–BINAP, 5:5.5
Pd(dba)2–BINAP, 4:5
Pd(dba)2–BINAP, 5:5.5
Pd(dba)2–BINAP, 4:5
Pd(dba)2–Xanthphos, 4:4.5
Pd(dba)2–BINAP, 4:5
Pd(dba)2–BINAP, 4:5
Pd(dba)2–Xanthphos, 4:4.5
XIII (80)
03
XIV (82), XXI (18)
04
b05b
XV (57)
XV (28, 7a)
06
XVI (63), XVIII (7), XX (5)
c07c
d08d
XVII (53), XXI (42)
XVII (25, 25a), XVIII (10, 7a),
XXI (7)
09
10
1,4-Br2C6H4
1,4-Br2C6H4
1,3-Br2C6H4
1,2-Br2C6H4
1,2-Br2C6H4
2:1
3:1
2:1
2:1
3:1
Pd(dba)2–BINAP, 10.5:11
Pd(dba)2–DavePHOS, 8:9
Pd(dba)2–BINAP, 8:9
Pd(dba)2–BINAP, 4:4.5
Pd(dba)2–BINAP, 8:9
XVIII (31, 31a)
XV (17), XVIII (22), XIX (5)
XVI (54), XVIII (16), XX (6)
XXI (70), XVIII (18)
XXI (59), XVIII (13)
11
12
c13c
a
b
c
d
After chromatographic separation.
Adamantan-2-one (55%), p-bromoaniline (13%).
Joint chromatographic separation: XVII (35%), XXI (35%).
Adamantan-2-one (60%), o-bromoaniline (25%).
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AVERIN et al.
68
was adamantan-2-one resulting from oxidation of
amine XI (60%; Table 2, run no. 8). The reaction of
adamantan-2-amine with m-dibromobenzene gave
much better results: target product XVI was formed in
63% yield, and insignificant amounts of reduction
product XVIII and m-phenylenediamine derivative
XX were obtained (Table 2, run no. 6). In the reaction
of XI with p-dibromobenzene, BINAP also turned out
to be much more effective than Xanthphos. In the latter
case, a large amount of adamantan-2-one was isolated
(Table 2, run nos. 4, 5). Presumably, Xanthphos favors
oxidation of adamantan-2-amine to adamantanone
through the corresponding imine and reduction of the
initial dibromobenzenes to bromobenzene (the latter
was almost undetectable in the NMR spectra of the
product mixtures, for it was removed together with
dioxane by distillation under reduced pressure). The
other reduction product, compound XVIII, was not
formed at all (Table 2, run no. 5) or its yield was
several times lower than the yield of adamantan-2-one
(Table 2, run no. 8). The results of our attempts to
obtain o-diamine XXI as the major product showed
that (as in the reaction with adamantan-1-amine)
increase of the amount of the initial amine did not
improve the yield of XXI; by contrast, its yield slightly
decreased (Table 2, run nos. 12, 13). Unfortunately, we
failed to obtain m-diamino derivative XX; instead,
54% of monoamination product XVI was formed
(Table 2, run no. 11). The reason for such behavior
remains unclear. Likewise, the yield of p-diamino
derivative XIX did not exceed a few percent (Table 2,
run no. 10); therefore, we succeeded in isolating by
chromatography only reduction product XVIII. p- and
m-Diamino-substituted adamantanes XIX and XX
were identified only by spectral methods in the reac-
tion mixtures. Compound XIX displayed in the
1H NMR spectrum a signal at δ 6.53 ppm (s, 4H) from
aromatic protons, and in the mass spectrum (MALDI)
of the reaction mixture we observed a peak with
m/z 376.35 [M]+. Compound XX was identified by
1H NMR signals at δ 5.85 (t, 1H) and 5.96 ppm
(d.d, 2H).
EXPERIMENTAL
The H and 13C NMR spectra were recorded from
solutions in CDCl3 on a Bruker Avance-400 spectrom-
eter at 400 and 100.6 MHz, respectively, using the sol-
vent signals (δ 7.25, δC 77.00 ppm) as reference. The
mass spectra (MALDI-TOF, positive ion detection)
were obtained on a Bruker Daltonics Ultrafex instru-
ment using 1,8,9-trihydroxyanthracene as matrix.
Silica gel (Merck, 40–60 μm) was used for preparative
column chromatography. Commercially available iso-
meric bromochloro- and dibromobenzenes, sodium
tert-butoxide, BINAP, DavePHOS, and Xanthphos
were used without additional purification. Adamantan-
1-amine (I) [36], adamantan-2-amine (XI) [37], and
Pd(dba)2 [38] were synthesized according to known
methods (the latter was not recrystallized). Dioxane
was distilled first over alkali and then over metallic
sodium; CH2Cl2 and MeOH were distilled.
1
N-Aryladamantanamines II–VII and XII–XVIII
(general procedure). A two-necked flask was filled
with argon and charged with required reactants, sol-
vent, and catalyst. The mixture was heated under
reflux, cooled, and filtered, the filtrate was evaporated
under reduced pressure, the solid residue was dissolved
in methylene chloride, the solution was washed with
water, and the organic phase was dried over sodium
sulfate and evaporated under reduced pressure. The
product mixtures were separated by chromatography
on silica gel using (in succession) petroleum ether–
methylene chloride (4 : 1 to 1 : 4) and methylene
chloride as eluent.
N,N′-Diadamantylbenzenediamines VIII–X and
XIX–XXI (general procedure). A two-necked flask
was filled with argon and charged with required reac-
tants, solvent, and catalyst. The mixture was heated
under reflux, cooled, and filtered, the filtrate was
evaporated under reduced pressure, the solid residue
was dissolved in methylene chloride, the solution was
washed with water, and the organic phase was dried
over sodium sulfate and evaporated under reduced
pressure. The product mixtures were separated by
chromatography on silica gel using (in succession)
petroleum ether–methylene chloride (4 :1 to 1:4),
methylene chloride, and methylene chloride–methanol
(100:1) as eluent.
To conclude, we have studied palladium-catalyzed
amination of 1- and 2-aminoadamantanes with iso-
meric bromochloro- and dibromobenzenes, optimized
conditions for the synthesis of N-(halophenyl)adaman-
tanamines and N,N′-diadamantylbenzenediamines, and
revealed unusually facile formation of N,N′-diadaman-
tylbenzene-1,2-diamines and catalytic reduction of
bromine in the initial haloarene.
N-(4-Chlorophenyl)adamantan-1-amine (II) was
synthesized from 0.2 mmol (30 mg) of adamantan-1-
amine and 0.2 mmol (38 mg) of p-bromochloroben-
zene in the presence of 6 mg (5 mol %) of Pd(dba)2,
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PALLADIUM-CATALYZED AMINATION OF ISOMERIC DIHALOBENZENES
69
4.5 mg (6 mol %) of DavePHOS, and 37 mg
(0.39 mmol) of sodium tert-butoxide in 2 ml of anhy-
drous dioxane. The reaction mixture was heated for
7 h. Yield 41 mg (78%), colorless oily substance.
1H NMR spectrum, δ, ppm: 1.60–1.71 m (6H), 1.83 br.s
N-(3-Bromophenyl)adamantan-1-amine (VI).
Yield 14 mg (23%); eluent petroleum ether–methylene
chloride (2:1); colorless oily substance. 1H NMR spec-
trum, δ, ppm: 1.67 br.s (6H), 1.87 br.s (6H), 2.11 br.s
(3H), 3.40 br.s (1H), 6.65 d.d.d (1H, 3J = 8.1, 4J = 2.3,
3
3
4
(6H), 2.09 br.s (3H), 3.28 br.s (1H), 6.70 d (2H, J =
0.9 Hz), 6.83 d.d.d (1H, J = 7.8, J = 1.8, 0.9 Hz),
8.6 Hz), 7.08 d (2H, 3J = 8.6 Hz). 13C NMR spectrum,
δC, ppm: 29.6 (3C), 36.3 (3C), 43.3 (3C), 52.3 (1C),
120.0 (2C), 123.8 (1C), 128.6 (2C), 144.6 (1C).
6.89 t (1H, J = 2.0 Hz), 6.97 t (1H, J = 8.0 Hz).
13C NMR spectrum, δC, ppm: 29.6 (3C), 36.3 (3C),
43.1 (3C), 52.1 (1C), 116.4 (1C), 120.3 (1C), 121.0
(1C), 122.5 (1C), 129.9 (1C), 147.6 (1C). Mass spec-
trum (MALDI-TOF): m/z 305.0800 [M]+. C16H20BrN.
Calculated: M 305.0779.
4
3
Compounds III and IV were synthesized in a simi-
lar way.
N-(3-Chlorophenyl)adamantan-1-amine (III).
Yield 39 mg (75%), colorless oily substance. 1H NMR
spectrum, δ, ppm: 1.66 br.s (6H), 1.87 br.s (6H),
2.10 br.s (3H), 3.43 br.s (1H), 6.60 d.d (1H, 3J = 8.2,
4J = 1.2 Hz), 6.68 d (1H, 3J = 7.9 Hz), 6.73 t (1H, 4J =
N-(2-Bromophenyl)adamantan-1-amine (VII).
Yield 10 mg (16%); eluent petroleum ether–methylene
chloride (5:1); colorless crystals, mp 110–112°C.
1H NMR spectrum, δ, ppm: 1.69 br.s (6H), 1.96 br.s
3
3
2.0 Hz), 7.01 t (1H, J = 8.0 Hz). 13C NMR spectrum,
(6H), 2.12 br.s (3H), 4.16 br.s (1H), 6.55 t.d (1H, J =
4
3
4
7.5, J = 1.6 Hz), 7.03 d.d (1H, J = 8.2, J = 1.5 Hz),
δC, ppm: 29.6 (3C), 36.3 (3C), 43.1(3C), 52.1 (1C),
115.9 (1C), 117.3 (1C), 118.0 (1C), 129.7 (1C), 134.3
(1C), 147.5 (1C). Mass spectrum (MALDI-TOF):
m/z 260.96 [M]+.
3
4
3
7.10 t.d (1H, J = 7.6, J = 1.5 Hz), 7.41 d.d (1H, J =
4
8.0, J = 1.4 Hz). 13C NMR spectrum, δC, ppm: 29.7
(3C), 36.5 (3C), 43.1 (3C), 52.6 (1C), 113.0 (1C),
116.8 (1C), 118.4 (1C), 127.7 (1C), 132.7 (1C), 143.6
(1C). Mass spectrum (MALDI-TOF): m/z 305.0773
[M]+. C16H20BrN. Calculated: M 305.0779.
N-(2-Chlorophenyl)adamantan-1-amine (IV).
Yield 30 mg (57%); eluent petroleum ether–methylene
chloride (4:1); colorless oily substance. Elution with
petroleum ether–methylene chloride (1:1) and then
with methylene chloride gave 9 mg (24%) of com-
N,N′-Bis(1-adamantyl)benzene-1,4-diamine
(VIII). a. The reaction of 0.2 mmol (30 mg) of ada-
mantan-1-amine with 0.1 mmol (24 mg) of p-dibromo-
benzene in the presence of 6 mg (10 mol%) of
Pd(dba)2, 4.5 mg (11.5 mol %) of DavePHOS, and
37 mg (0.39 mmol) of sodium tert-butoxide in 2 ml of
anhydrous dioxane (reaction time 7 h) gave 45% of
compound VIII (identified in the reaction mixture by
NMR spectra). We failed to isolate the product by
1
pound X. H NMR spectrum, δ, ppm: 1.70 br.s (6H),
1.96 br.s (6H), 2.13 br.s (3H), 4.15 br.s (1H), 6.60–
6.65 m (1H), 7.02–7.08 m (2H), 7.22–7.26 m (1H).
13C NMR spectrum, δC, ppm: 29.7 (3C), 36.4 (3C),
43.1 (3C), 52.4 (1C), 116.9 (1C), 117.9 (1C), 121.7
(1C), 127.0 (1C), 129.3 (1C), 142.5 (1C). Mass spec-
trum (MALDI-TOF): m/z 261.1350 [M]+. C16H20ClN.
Calculated: M 261.1284.
1
chromatography. H NMR spectrum, δ, ppm: 1.58–
1.68 m (12H), 1.75 br.s (12H), 2.06 br.s (6H), 2.89 br.s
(2H), 6.68 s (4H). 13C NMR spectrum, δC, ppm:
29.7 (6C), 36.5 (6C), 43.7 (6C), 52.3 (2C), 122.5
(4C), 139.0 (2C). Mass spectrum (MALDI-TOF):
m/z 376.25 [M]+.
N-(4-Bromophenyl)adamantan-1-amine (V) was
synthesized from 0.2 mmol (30 mg) of adamantan-1-
amine and 0.2 mmol (47 mg) of p-dibromobenzene
using 12 mg (10.5 mol %) of Pd(dba)2, 14 mg
(11 mol%) of BINAP, and 37 mg (0.39 mmol) of
sodium tert-butoxide in 2 ml of anhydrous dioxane
(reaction time 7 h). Yield 44 mg (72%), colorless oily
Compounds IX and X were obtained in a similar
way.
1
substance. H NMR spectrum, δ, ppm: 1.63–1.71 m
b. Compound VIII was obtained from 0.6 mmol
(91 mg) of adamantan-1-amine and 0.1 mmol (24 mg)
of m-dibromobenzene in the presence of 6 mg
(10 mol %) of Pd(dba)2, 4.5 mg (11.5 mol%) of
DavePHOS, and 70 mg (0.73 mmol) of sodium tert-
butoxide in 2 ml of anhydrous dioxane (reaction time
7 h). Yield 20 mg (27%; a, b); eluent methylene
chloride–methanol (100:1); colorless oily substance.
1H NMR spectrum, δ, ppm: 1.65 br.s (12H), 1.86 br.s
(6H), 1.83–1.85 m (6H), 2.10 br.s (3H), 3.32 br.s (1H),
3
3
6.65 d (2H, J = 8.6 Hz), 7.22 d (2H, J = 8.6 Hz).
13C NMR spectrum, δC, ppm: 29.6 (3C), 36.4 (3C),
43.3 (3C), 52.2 (1C), 110.8 (1C), 120.2 (2C), 131.5
(2C), 145.1 (1C). Mass spectrum (MALDI-TOF):
m/z 305.04 [M]+.
Compounds VI and VII were synthesized in a simi-
lar way.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

AVERIN et al.
(12H), 2.09 br.s (6H), 3.18 br.s (2H), 6.25 d.d (2H, 3J =
70
benzene in the presence of 6 mg (5 mol %) of
Pd(dba)2, 7 mg (5.5 mol %) of BINAP, and 37 mg
(0.39 mmol) of sodium tert-butoxide in 2 ml of anhy-
drous dioxane (reaction time 7 h). Yield 42 mg (82%),
4
4
8.0, J = 2.1 Hz), 6.30 t (1H, J = 2.1 Hz), 6.90 t (1H,
3J = 7.9 Hz). 13C NMR spectrum, δC, ppm: 29.8 (6C),
36.5 (6C), 43.6 (6C), 52.2 (2C), 110.1 (1C), 110.8
(2C), 128.8 (1C), 146.5 (2C). Mass spectrum
(MALDI-TOF): m/z 376.21 [M]+.
1
colorless oily substance. H NMR spectrum, δ, ppm:
1.64 d (2H, 3J = 12.8 Hz), 1.78 br.s (2H), 1.81–2.01 m
3
(8H), 2.05 br.s (2H), 3.62 d (1H, J = 7.3 Hz), 4.72 d
N,N′-Bis(1-adamantyl)benzene-1,2-diamine (X).
Yield 22 mg (58%); eluent petroleum ether–methylene
chloride (1:1), methylene chloride; colorless oily sub-
3
3
4
(1H, J = 6.7 Hz), 6.58 t.d (1H, J = 7.6, J = 1.3 Hz),
3
3
4
6.64 d (1H, J = 8.4 Hz), 7.11 t.d (1H, J = 7.8, J =
1.2 Hz), 7.26 d.d (1H, 3J = 7.8, 4J = 1.5 Hz). 13C NMR
spectrum, δC, ppm: 27.2 (1C), 27.4 (1C), 31.5 (2C),
31.6 (2C), 37.3 (2C), 37.6 (1C), 56.5 (1C), 111.6 (1C),
116.4 (1C), 118.8 (1C), 127.7 (1C), 129.2 (1C), 143.0
(1C). Mass spectrum (MALDI-TOF): m/z 261.11 [M]+.
1
stance. H NMR spectrum, δ, ppm: 1.64 br.s (12H),
1.84 br.s (12H), 2.07 br.s (6H), 3.06 br.s (2H), 6.70–
6.75 m (2H), 6.88–6.93 m (2H). 13C NMR spectrum,
δC, ppm: 29.8 (6C), 38.6 (6C), 43.4 (6C), 52.6 (2C),
120.2 (2C), 121.9 (2C), 138.1 (2C). Mass spectrum
(MALDI-TOF): m/z 376.2800 [M]+. C26H36N2. Cal-
culated: M 376.2878.
N-(4-Bromophenyl)adamantan-2-amine (XV).
a. Compound XV was synthesized from 0.15 mmol
(23 mg) of adamantan-2-amine and 0.15 mmol
(35 mg) of p-dibromobenzene in the presence of 4 mg
(4 mol %) of Pd(dba)2, 4.5 mg (5 mol%) of BINAP,
and 23 mg (0.24 mmol) of sodium tert-butoxide in
1.5 ml of anhydrous dioxane (reaction time 7 h). Yield
26 mg (57%).
N-(4-Chlorophenyl)adamantan-2-amine (XII)
was synthesized from 0.2 mmol (30 mg) of adaman-
tan-2-amine and 0.2 mmol (38 mg) of p-bromochloro-
benzene in the presence of 6 mg (5 mol %) of
Pd(dba)2, 7 mg (5.5 mol %) of BINAP, and 37 mg
(0.39 mmol) of sodium tert-butoxide in 2 ml of anhy-
drous dioxane (reaction time 7 h). Yield 43 mg (83%),
b. The reaction of 0.18 mmol (27 mg) of adaman-
tan-2-amine with 0.18 mmol (43 mg) of p-dibromo-
benzene in the presence of 4 mg (4 mol %) of
Pd(dba)2, 5 mg (4.5 mol %) of Xanthphos, and 30 mg
(0.31 mmol) of sodium tert-butoxide in 2 ml of anhy-
drous dioxane (reaction time 7 h) gave 4 mg (7%) of
XV as a colorless oily substance (eluent petroleum
ether–methylene chloride, 4:1). Elution with petro-
leum ether–methylene chloride (1:1) gave 4 mg (13%)
of p-bromoaniline, and elution with methylene chlo-
1
colorless oily substance. H NMR spectrum, δ, ppm:
1.60 d (2H, 3J = 12.6 Hz), 1.76 br.s (2H), 1.78–1.94 m
3
(8H), 2.00 br.s (2H), 3.48 br.s (1H), 3.98 d (1H, J =
3
3
6.8 Hz), 6.51 d (2H, J = 8.2 Hz), 7.09 d (2H, J =
8.2 Hz). 13C NMR spectrum, δC, ppm: 27.2 (1C), 27.3
(1C), 31.4 (2C), 31.5 (2C), 37.3 (2C), 37.6 (1C), 56.8
(1C), 114.0 (2C), 121.0 (1C), 129.0 (2C), 145.8 (1C).
Mass spectrum (MALDI-TOF): m/z 261.08 [M]+.
N-(3-Chlorophenyl)adamantan-2-amine (XIII)
was synthesized from 0.15 mmol (23 mg) of adaman-
tan-2-amine and 0.15 mmol (29 mg) of m-bromo-
chlorobenzene in the presence of 4 mg (4 mol %) of
Pd(dba)2, 4.5 mg (5 mol %) of BINAP, and 23 mg
(0.24 mmol) of sodium tert-butoxide in 1.5 ml of
anhydrous dioxane (reaction time 7 h). Yield 31 mg
1
ride gave 15 mg (55%) of adamantan-2-one. H NMR
3
spectrum of XV, δ, ppm: 1.60 d (2H, J = 12.0 Hz),
1.74 br.s (2H), 1.79–1.92 m (8H), 1.99 br.s (2H),
3
3.47 br.s (1H), 3.98 d (1H, J = 7.0 Hz), 6.46 d (2H,
3J = 8.8 Hz), 7.21 d (2H, 3J = 8.8 Hz). 13C NMR spec-
trum, δC, ppm: 27.2 (1C), 27.3 (1C), 31.4 (2C), 31.5
(2C), 37.3 (2C), 37.6 (1C), 56.7 (1C), 108.0 (1C),
114.5 (2C), 131.9 (2C), 146.3 (1C).
1
(80%), colorless oily substance. H NMR spectrum, δ,
ppm: 1.61 d (2H, J = 12.6 Hz), 1.75 br.s (2H), 1.79–
3
1.94 m (8H), 2.00 br.s (2H), 3.50 br.s (1H), 4.05 d (1H,
N-(3-Bromophenyl)adamantan-2-amine (XVI)
was synthesized from 0.15 mmol (23 mg) of adaman-
tan-2-amine and 0.15 mmol (35 mg) of m-dibromoben-
zene in the presence of 4 mg (4 mol%) of Pd(dba)2,
4.5 mg (5 mol %) of BINAP, and 23 mg (0.24 mmol)
of sodium tert-butoxide in 1.5 ml of anhydrous diox-
ane (reaction time 7 h). yield 29 mg (63%), colorless
oily substance. 1H NMR spectrum, δ, ppm: 1.60 d (2H,
3J = 12.0 Hz), 1.75 br.s (2H), 1.80–1.94 m (8H),
3J = 7.0 Hz), 6.45 d.d.d (1H, 3J = 8.2, 4J = 2.2, 0.8 Hz),
4
3
4
6.55 t (1H, J = 2.1 Hz), 6.60 d.d.d (1H, J = 7.8, J =
1.9, 0.7 Hz), 7.04 t (1H, J = 8.0 Hz). 13C NMR spec-
3
trum, δC, ppm: 27.2 (1C), 27.3 (1C), 31.4 (2C), 31.5
(2C), 37.3 (2C), 37.6 (1C), 56.6 (1C), 111.3 (1C), 112.4
(1C), 116.4 (1C), 130.1 (1C), 135.0 (1C), 148.5 (1C).
N-(2-Chlorophenyl)adamantan-2-amine (XIV)
was synthesized from 0.2 mmol (30 mg) of adaman-
tan-2-amine and 0.2 mmol (38 mg) of o-bromochloro-
3
2.00 br.s (2H), 3.49 br.s (1H), 4.04 br.s (1H, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 1 2010

PALLADIUM-CATALYZED AMINATION OF ISOMERIC DIHALOBENZENES
71
3
4
3
7.2 Hz), 6.49 d.d (1H, J = 8.1, J = 1.5 Hz), 6.71 br.s
(2H), 3.54 br.s (1H), 3.96 br.s (1H), 6.59 d (2H, J =
3
3
3
3
(1H), 6.74 d (1H, J = 7.8 Hz), 6.98 t (1H, J =
8.0 Hz). 13C NMR spectrum, δC, ppm: 27.2 (1C), 27.3
(1C), 31.4 (2C), 31.5 (2C), 37.3 (2C), 37.6 (1C), 56.6
(1C), 111.7 (1C), 115.3 (1C), 119.3 (1C), 123.3 (1C),
130.5 (1C), 148.7 (1C). Mass spectrum (MALDI-
TOF): m/z 305.12 [M]+.
7.8 Hz), 6.64 t (1H, J = 7.4 Hz), 7.15 t (2H, J =
7.8 Hz). 13C NMR spectrum, δC, ppm: 27.3 (1C), 27.5
(1C), 31.6 (4C), 37.4 (2C), 37.7 (1C), 56.8 (1C), 113.0
(2C), 116.7 (1C), 129.3 (2C), 147.4 (1C). Mass spec-
trum (MALDI-TOF): m/z 227.1620 [M]+. C16H21N.
Calculated: M 227.1674.
N,N′-Bis(2-adamantyl)benzene-1,2-diamine
(XXI) was obtained from 0.45 mmol (68 mg) of ada-
mantan-2-amine and 0.15 mmol (35 mg) of o-dibromo-
benzene in the presence of 7 mg (8 mol %) of
Pd(dba)2, 8.5 mg (9 mol %) of BINAP, and 45 mg
(0.47 mmol) of sodium tert-butoxide in 1.5 ml of an-
hydrous dioxane (reaction time 7 h). The product was
isolated by chromatography together with those ob-
tained in the synthesis of compound XVII according to
method a. Yield 39 mg (35%); eluent petroleum ether–
methylene chloride (4:1, 2:1). Elution with petroleum
ether–methylene chloride (4:1) gave 4.5 mg (13%) of
N-(2-Bromophenyl)adamantan-2-amine (XVII).
a. Compound XVII was synthesized from 0.15 mmol
(23 mg) of adamantan-2-amine and 0.15 mmol
(35 mg) of o-dibromobenzene in the presence of 4 mg
(4 mol %) of Pd(dba)2, 4.5 mg (5 mol %) of BINAP,
and 23 mg (0.24 mmol) of sodium tert-butoxide in
5 ml of anhydrous dioxane (reaction time 7 h). The
product was isolated by chromatography together with
those obtained in the synthesis of compound XXI;
eluent petroleum ether–methylene chloride (10:1).
Yield 16 mg (35%), colorless oily substance.
b. The reaction of 0.18 mmol (27 mg) of adaman-
tan-2-amine with 0.18 mmol (43 mg) of o-dibromo-
benzene in the presence of 4 mg (4 mol %) of
Pd(dba)2, 5 mg (4.5 mol %) of Xanthphos, and 30 mg
(0.31 mmol) of sodium tert-butoxide in 2 ml of anhy-
drous dioxane (reaction time 7 h) gave 14 mg (25%) of
compound XVII (eluent petroleum ether–methylene
chloride, 4:1). Elution with petroleum ether–methyl-
ene chloride (2:1) gave 2.5 mg (7%) of compound
XXI and 3 mg (7%) of XVIII, and subsequent elution
with methylene chloride gave 8 mg (25%) of o-bromo-
aniline and 16 mg (60%) of adamantan-2-one. 1H NMR
1
compound XVIII. H NMR spectrum of XXI, δ, ppm:
1.61 d (4H, 3J = 12.4 Hz), 1.76 br.s (4H), 1.78–1.92 m
(16H), 2.03 br.s (4H), 3.50 br.s (2H), 3.66 br.s (2H),
6.64–6.68 m (2H), 6.70–6.74 m (2H). 13C NMR spec-
trum, δC, ppm: 27.5 (2C), 27.6 (2C), 31.9 (4C), 32.0
(4C), 37.4 (4C), 37.8 (2C), 56.9 (2C), 113.6 (2C),
118.8 (2C), 136.8 (2C). Mass spectrum (MALDI-
TOF): m/z 376.2880 [M]+. C26H36N2. Calculated:
M 376.2878.
This study was performed under financial support
by the Russian Academy of Sciences (program no. P-8,
“Development of Methodology of Organic Synthesis
and Design of Compounds with Practically Important
Properties”) and by the Russian Foundation for Basic
Research (project no. 06-03-32376).
3
spectrum, δ, ppm: 1.62 d (2H, J = 12.7 Hz), 1.76 br.s
(2H), 1.79–1.99 m (8H), 2.03 br.s (2H), 3.60 d (1H,
3J = 7.3 Hz), 4.71 d (1H, 3J = 6.4 Hz), 6.50 t (1H, 3J =
3
3
7.6 Hz), 6.60 d (1H, J = 8.1 Hz), 7.13 t (1H, J =
7.7 Hz), 7.40 d (1H, 3J = 7.9 Hz). 13C NMR spectrum,
δC, ppm: 27.3 (1C), 27.4 (1C), 31.4 (2C), 31.7 (2C),
37.3 (2C), 37.7 (1C), 56.7 (1C), 111.7 (1C), 117.0
(1C), 124.5 (1C), 128.4 (1C), 132.5 (1C), 144.0 (1C).
Mass spectrum (MALDI-TOF): m/z 305.0800 [M]+.
C16H20BrN. Calculated: M 305.0779.
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