Palladium-catalyzed amination in the synthesis and modification of acyclic oxadiamino cholane derivatives

Article abstract of DOI:10.1134/S1070428009120021

Palladium-catalyzed reactions of 24-(haloaryloxy)cholanes and 3,24-bis(haloaryloxy)cholanes with excess oxadiamines gave the corresponding mono- and bis(oxadiamino)-substituted cholanes which were subjected to palladium-catalyzed arylation with 1,3-dibrom

Full text of DOI:10.1134/S1070428009120021

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 12, pp. 1755–1768. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © E.R. Ranyuk, A.D. Averin, N.V. Lukashev, A.K. Buryak, I.P. Beletskaya, 2009, published in Zhurnal Organicheskoi Khimii, 2009,
Vol. 45, No. 12, pp. 1765–1776.
Palladium-Catalyzed Amination in the Synthesis
and Modification of Acyclic Oxadiamino Cholane Derivatives
E. R. Ranyuka, A. D. Averina, N. V. Lukasheva, A. K. Buryakb, 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
Received April 10, 2009
Abstract—Palladium-catalyzed reactions of 24-(haloaryloxy)cholanes and 3,24-bis(haloaryloxy)cholanes with
excess oxadiamines gave the corresponding mono- and bis(oxadiamino)-substituted cholanes which were
subjected to palladium-catalyzed arylation with 1,3-dibromobenzene, 2,6-dibromopyridine, 1,8-dichloroanthra-
cene, 9-bromoanthracene, 1-chloroanthracene, and 1-chloroanthraquinone. The results of these reactions were
found to strongly depend on the haloarene nature. The arylation with 1,3-dibromobenzene and 2,6-dibromo-
pyridine led to the formation of new macrocyclic compounds containing one cholane, one arene, and two
oxadiamine fragments.
DOI: 10.1134/S1070428009120021
We recently developed an efficient procedure for
the synthesis of macrocyclic compounds containing
steroid and polyamine fragments via palladium-cata-
lyzed amination of 3,24-bis(haloaryloxy)cholanes
[1–5]. This procedure can also be used to obtain de-
rivatives with linear polyamine chains appended to
steroid fragment. Steroidal compounds with polyamine
substituents on C3 and C17 were found to ensure ion
transport through lipid membranes. An analog of the
natural polyamine Squalamine was reported to effec-
tively transfer some anions [6], and amphiphilic poly-
amine dendrimers prepared from cholestamine were
shown to be promising as transmembrane ion-trans-
porting agents [7]. Squalamine exhibits biological
activity against Gram-negative and Gram-positive
bacteria [8], as well as antiangiogenic activity [9], and
replacement of the triamine spermidine fragment by
tetraamine spermine moiety considerably enhances the
activity toward various microorganisms [10]. Poly-
amine substituents are generally introduced by reduc-
tive amination of 3-oxo steroids [11, 12]. Therefore, in
the present work attempts were made to synthesize
mono- and bis(polyamino)-substituted steroid deriva-
tives via palladium-catalyzed amination and perform
their further modification with a view to obtain novel
macrocyclic compounds.
nobu reaction of cholane-3,24-diol (I) with 3-bromo-
phenol, following the procedure described previously
[1]. Reactions of II with 2.5–3 equiv of polyoxadi-
amines IIIa–IIIc gave the corresponding bis-amino
derivatives IVa–IVc (Scheme 1). These reactions were
carried out using the catalytic system Pd(dba)2/BINAP
(8/9 mol %) which turned out to be efficient in the
syntheses of macrocyclic compounds described previ-
ously, but the reactant concentration was higher (c ≈
0.1 M) to avoid possible cyclization. The reaction mix-
tures were heated for 7 h under reflux. In almost all
cases, compounds IVa–IVc were formed in nearly
1
quantitative yields (according to the H and 13C NMR
data) and were isolated from the reaction mixtures by
column chromatography on silica gel in 40, 72, and
82% yield, respectively.
We also tried to synthesize unsymmetrical macro-
cycles consisting of one steroid, one arene, and two
polyamine fragments. For this purpose, bis-amino-
substituted steroids IVa–IVc were treated with various
dihaloarenes (1,3-dibromobenzene, 2,6-dibromopyri-
dine, and 1,8-dichloroanthracene). However, no
desired cyclic compounds were formed from bis-
amines IV prepared in situ, but complex mixtures of
products with different structures were obtained.
Therefore, our further study was performed using as
model compound IVc which can be readily isolated by
chromatography. The reactions were carried out by
In the first step of our study we synthesized
3,24-bis(3-bromophenoxy)cholane (II) by the Mitsu-
1755

RANYUK et al.
1756
Scheme 1.
Me
Me
Me
Me
OH
DEAD, Ph3P
THF, 20–50°C
OH
O
Me
H
H
Me
H
H
+
4
H
H
H
H
Br
HO
O
Br
Br
I
II
Me
Me
O
H2NCH2XCH2NH2 (IIIa–IIIc, 2.5–3 equiv)
Pd(dba)2/BINAP (8/9 mol %), t-BuONa
dioxane, reflux
Me
H
H
H
X
H
O
N
H
X
NH2
N
NH2
H
IVa–IVc
O
NH2
O
NH2
H2N
O
H2N
O
IIIa
IIIb
O
H2N
O
O
NH2
IIIc
heating dilute solutions (c ≈ 0.02 M) of the reactants in
boiling dioxane over a period of 18 h. In the reaction
of IVc with an equimolar amount of 1,3-dibromoben-
zene, acyclic bis-arylamino derivative V was formed
instead of the expected cyclic product; it was isolated
in 17% yield. No cyclic compound was isolated when
the reaction was carried out wit insufficient m-di-
bromobenzene (0.7 equiv) to suppress bis-arylation
process. Surprisingly, in this case we isolated 18% of
linear bis-arylamino compound VI formed as a result
of hydrodebromination of the bromophenylamino frag-
ments in V (Scheme 2). Analogous bis-anthryl deriva-
tive VII was obtained in the reaction of IVc with
1,8-dichloroanthracene as potential ring-closing moi-
ety. It was isolated in 33% yield. We succeeded in
synthesizing the desired unsymmetrical macrocycle
only by the reaction of IVc with 2,6-dibromopyridine,
but the yield of VIII was as poor as 4%.
tive synthetic pathway using compound II and bis-
amino-substituted arenes as starting compounds. Ini-
tially, we prepared individual 1,3-disubstituted ben-
zene IX and 2,6-disubstituted pyridine X in 56 and
27% yield, respectively, by palladium-catalyzed
amination of 1,3-dibromobenzene and 2,6-dibromo-
pyridine with 2.5 equiv of trioxadiamine IIIc. The
reactions of IX and X with steroid II afforded the
desired macrocycles XI and VIII in 21 and 20% yield,
respectively (Scheme 3).
Acyclic polyamino derivatives of bis(pyridyloxy)-
cholane were synthesized using 24-(6-chloropyridin-2-
yloxy)cholane (XII) which was prepared from
cholane-3,24-diol according to the procedure described
in [3, 4]. Compound XII was treated with 2 equiv of
trioxadiamine IIIc in the presence of 8/9 mol % of
Pd(dba)2/BINAP at a reactant concentration of 0.1 M
in boiling dioxane (reaction time 4 h). We thus ob-
tained compound XIII, which was isolated in 66%
yield (Scheme 4). The reaction of XII with 2 equiv of
tetraamine IIId gave 14% of bis-steroid derivative
Taking into account difficulties encountered while
attempting to synthesize macrocyclic compounds from
bis-amino-substituted steroid, my examined an alterna-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

PALLADIUM-CATALYZED AMINATION
1757
Scheme 2.
Me
Me
Me
Me
O
O
Me
H
H
Me
H
Br
H
H
H
H
O
O
(0.7–1 equiv)
N
N
H
H
H
Br
Pd(dba)2/BINAP
(8/9 mol %)
O
O
N
H
N
H
O
O
O
O
O
O
O
O
O
O
R
H
H2N
N
H
N
H2N
R
IVc
V (17%), VI (18%)
V, R = Br; VI, R = H.
Me
Me
O
Me
H
H
H
Br
O
N
H
H
Pd(dba)2/BINAP (8/9 mol %)
N
IVc
+
O
Br
HN
O
(1 equiv)
O
O
O
O
H
HN
N
N
VIII (4%)
Me
Me
O
Me
H
H
H
H
O
Cl
Cl
N
H
Pd(dba)2/BINAP (8/9 mol %)
O
IVc
+
N
H
Cl
O
(0.7 equiv)
O
O
O
O
H
N
Cl
H
N
VII (33%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RANYUK et al.
1758
Scheme 3.
O
O
O
O
O
O
NH
Z
H2N
H2N
Br
Pd(dba)2/BINAP (8/9 mol %)
Z
+
IIIc (2.5 equiv)
Br
NH
IX (56%), X (27%)
Me
Me
O
Me
H
H
H
O
N
H
H
II, Pd(dba)2/BINAP (8/9 mol %)
O
HN
O
O
O
O
O
H
N
HN
Z
VIII (20%), XI (21%)
VIII, X, Z = N; IX, XI, Z = CH.
Scheme 4.
Me
Me
O
Me
H
H
Me
Me
N
H
H
HO
O
N
IIIc (2 equiv)
Pd(dba)2/BINAP (8/9 mol %)
H
Me
H
H
N
O
H
H
HO
Cl
O
O
H2N
XII
XIII (66%)
Me
Me
O
Me
H
H
N
H
H
HO
N
H
Pd(dba)2/BINAP (8/9 mol %)
N
N
H
XII
+
Me
Me
H
HN
H2N
NH2
IIId (0.5–2 equiv)
O
N
HN
Me
H
H
H
H
HO
N
H
XIV: 14% from 2 equiv of IIId
27% from 0.5 equiv of IIId
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

PALLADIUM-CATALYZED AMINATION
1759
Scheme 5.
Me
Me
OH
DEAD, Ph3P
THF, 20°C
O
Me
H
H
I
+
N
N
H
H
Cl
2.5 equiv
O
Cl
N
Cl
XV
Me
Me
O
Me
H
H
N
H
H
O
N
H
N
IIIc (4 equiv), Pd(dba)2/BINAP (8/9 mol %)
O
N
H
O
O
O
O
O
H2N
H2N
XVIc (54%)
Me
Me
O
Me
H
H
Me
Me
N
H
H
O
O
Me
H
N
H
N
N
H
H
O
+
O
N
N
H
H
H
O
N
O
O
O
O
HN
O
O
O
H2N
H2N
XVII (head-to-tail, 20–32%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RANYUK et al.
1760
Scheme 6.
Me
Me
O
Me
H
H
IIIb, IIIc (4 equiv)
Pd(dba)2/BINAP (8/9 mol %)
N
H
X
H
XV
O
NH
N
X
N
H
NH2
H2N
XVIb, XVIc
Br
Me
Me
O
N
Me
H
H
NH
X
(6 equiv)
H
X
H
Pd(dba)2/BINAP (8/9 mol %)
+
O
NH
X
HN
HN
N
N
N
H
H
XVIIIb (13%), XVIIIc (10%)
XIXb (56%), XIXc (92%)
Compounds containing aminoanthracene and amino-
anthraquinone fragments attract interest as potential
optical sensors. Initially, we tried to synthesize such
compounds by reaction of quite reactive 9-bromo-
anthracene with cholane derivatives XVIb and XVIc
prepared in situ. We thus isolated the corresponding
bis(anthrylamino) derivatives XVIIIb and XVIIIc in
poor yields (13 and 10%, respectively; Scheme 6),
presumably because of difficulties in chromatographic
separation of the target products from N,N′-bisanthryl-
polyoxadiamines XIXb and XIXc. Therefore, it was
necessary to isolate cholane derivatives XVI as indivi-
dual substances in order to perform their subsequent
modifications.
XIV instead of expected analogous mono-aminopyr-
idyloxycholane. Compound XIV was synthesized in
a higher yield (27%) by reaction of the same com-
pounds at a XII:IIId ratio of 2:1 Compounds like
XIV can be used in regioselective (head-to-head) syn-
theses of cyclic dimers.
Bis(trioxaaminopyridyloxy)-substituted cholane
XVIc was synthesized in 54% yield by reaction of
3,24-bis(6-chloropyridin-2-yloxy)cholane (XV), which
was prepared from cholane-3,24-diol (I) [3, 4], with
4 equiv of trioxadiamine IIIc at a reactant concentra-
tion of 0.05 M. It was noted that increase of the re-
actant concentration to 0.1 or 0.2 M or the use of
a smaller amount of diamine IIIc (3 equiv) leads to
sharp reduction of the yield of XVIc and the formation
of three regioisomeric linear oligomer XVII (head-to-
head, head-to-tail, and tail-to-tail; only one of the pos-
sible regioisomers is shown in Scheme 5).
In fact, compounds XIII and XVIc reacted with
1-chloroanthraquinone to afford target products XX
and XXI (Scheme 7) in 19 and 53% yield, respec-
tively. However, we failed to isolate analogous prod-
ucts in the reactions of the same cholane derivatives
with 1-chloroanthracene. Alternative approach based
on the reaction of N-monoaryl-substituted diamines
XXII and XXIII with steroid XV was also inefficient:
the conversion of the initial compounds was as low as
5 and 30%, respectively, after heating for 15 h under
We tried to modify the primary amino groups in
disubstituted cholane derivatives XVI by introduction
of aryl fragments, such as anthracene and anthraqui-
none, taking into account that anthracene and anthra-
quinone derivatives are characterized by strong absorp-
tion and emission bands in the electronic spectra.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

PALLADIUM-CATALYZED AMINATION
1761
Scheme 7.
Me
Me
O
Me
H
N
H
H
Cl
O
HO
N
H
Pd(dba)2/BINAP (8/9 mol %)
H
t-BuONa or Cs2CO3
XIII
+
O
O
O
(2 equiv)
O
O
O
H
N
XX (19%)
Cl
Cl
O
IIIc (2 equiv)
Pd(dba)2/BINAP (8/9 mol %)
t-BuONa or Cs2CO3
or
or
O
NH
NH
O
O
O
O
O
H2N
H2N
O
O
O
XXII (84%)
XXIII (58%)
XV, Pd(dba)2/BINAP (8/9 mol %)
t-BuONa or Cs2CO3
Me
Me
Me
Me
Cl
O
O
O
Me
H
H
Me
H
H
N
N
H
H
H
H
O
O
N
N
O
H
H
(3 equiv)
N
N
O
O
Pd(dba)2/BINAP (8/9 mol %)
t-BuONa or Cs2CO3
N
N
H
H
O
O
O
O
O
O
O
O
O
O
H
N
H2N
O
O
O
H
N
H2N
O
XVIc
XXI (53%)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RANYUK et al.
1762
reflux. These findings indicated that introduction of
an aryl group into terminal amino group considerably
affects the reactivity of the remaining free amino
group.
4,7,10-trioxatridecyl)pyridine-2,6-diamine (X) [16]
were synthesized as described previously.
Bis(polyoxaaminoaryloxy)-substituted cholanes
IVa–IVc (general procedure). A 25-ml two-necked
flask was filled with argon and charged with the corre-
sponding reactants (see below). The mixture was
heated for 5–8 h under reflux and cooled, the precip-
itate of sodium bromide was filtered off, and the fil-
trate was evaporated. The solid or oily residue was
purified by chromatography on silica gel.
Thus we demonstrated the possibility for catalytic
synthesis of linear mono- and bis-polyoxaamino-sub-
stituted cholane derivatives, their transformation into
macrocyclic compounds, and arylation with halo
arenes. The results of the examined reactions were
shown to depend on the structure of the initial com-
pounds, so that the scope of their application was
determined.
N-{2-[2-(2-Aminoethoxy)ethoxy]ethyl}-3-
({(3β,5β,17α,20S)-3-[3-({2-[2-(2-aminoethoxy)-
ethoxy]ethyl}amino)phenoxy]cholan-24-yl}oxy)-
aniline (IVa) was synthesized from 470 mg
(0.7 mmol) of compound II and 259 mg (1.75 mmol)
of dioxadiamine IIIa in the presence of 32 mg of
Pd(dba)2, 39 mg of BINAP, and 270 mg (2.8 mmol) of
sodium tert-butoxide in 6 ml of anhydrous dioxane
(reaction time 7 h). Eluent CH2Cl2–MeOH, 5:1. Yield
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance-400 instrument at 400 and 100.6 MHz,
respectively. The mass spectra (MALDI TOF) were
obtained on a Bruker Daltonics Ultraflex spectrometer
using 1,8,9-trihydroxyanthracene as matrix. Commer-
cially available lithocholic acid (3α-hydroxy-5β-cho-
lan-24-oic acid), sodium tetrahydridoborate, boron
trifluoride–ether complex, diethyl azodicarboxylate,
3-bromophenol, 6-chloropyridin-2-ol, 1,3-dibromoben-
zene, 2,6-dibromopyridine, 1,8-dichloroanthraquinone,
1-chloroanthraquinone, 9-bromoanthracene, polyoxa-
(aza)diamines IIIa–IIId, BINAP, sodium tert-butox-
ide, and cesium carbonate were used without addi-
tional purification; triphenylphosphine was recrystal-
lized from ethanol; THF and dioxane were distilled
first over alkali and then over metallic sodium, diethyl
ether was distilled over alkali; methylene chloride and
methanol were purified by distillation. Silica gel with
a grain size of 40–60 μm (from Fluka) was used for
chromatography.
1
225 mg (40%), light yellow oily substance. H NMR
3
spectrum, δ, ppm: 0.64 s (3H), 0.93 d (3H, J =
6.6 Hz), 0.96 s (3H), 0.99–2.00 m (28H), 2.85 br.s
3
(4H), 3.25 t (4H, J = 4.8 Hz), 3.49 br.s (4H), 3.59 s
3
(8H), 3.66 t (4H, J = 5.0 Hz), 3.81–3.89 m (2H),
3
4.52 br.s (1H), 6.15–6.28 m (6H), 7.00 t (1H, J =
3
7.8 Hz), 7.02 t (1H, J 7.9 = Hz); signals from NH
protons were not assigned unambiguously. 13C NMR
spectrum, δC, ppm: 12.0 (1C), 18.6 (1C), 21.0 (1C),
23.8 (1C), 24.2 (1C), 24.6 (1C), 25.9 (1C), 26.2 (1C),
26.6 (1C), 28.2 (1C), 30.4 (1C), 32.0 (1C), 34.8 (1C),
35.5 (1C), 35.6 (1C), 36.9 (1C), 39.9 (1C), 40.2 (1C),
41.1 (1C), 42.7 (1C), 43.4 (2C), 56.1 (1C), 56.6 (1C),
68.2 (1C), 69.6 (2C), 69.6 (2C), 70.1 (4C), 71.9 (2C),
72.3 (1C), 99.5 (1C), 101.2 (1C), 103.2 (1C), 104.8
(1C), 105.8 (1C), 106.0 (1C), 129.7 (1C), 129.8 (1C),
149.5 (1C), 149.6 (1C), 158.9 (1C), 160.3 (1C). Mass
spectrum: m/z 807.48 [M + H]+.
(3α,5β)-Cholane-3,24-diol (I) was synthesized by
reduction of lithocholic acid with diborane in THF, and
(3β,5β)-3,24-bis(3-bromophenoxy)cholane (II) was
prepared from (3α,5β)-cholane-3,24-diol (I), according
to the procedures described in [1]; (3α,5β)-24-(6-
chloropyridin-2-yloxy)cholane (XII) and (3β,5β)-3,24-
bis(6-chloropyridin-2-yloxy)cholane (XV) were ob-
tained from (3α,5β)-cholane-3,24-diol (I) as reported
in [3, 4]; 1,8-dichloroanthracene and 1-chloroanthra-
cene were synthesized by reduction of 1,8-dichloro-
anhtraquinone and 1-chloroanthraquinone, respec-
tively, with zinc in ammonia [13]; bis(dibenzylidene-
acetonato)palladium(II) was prepared as described in
[14]. N,N′-Bis(13-amino-4,7,10-trioxatridecyl)ben-
zene-1,3-diamine (IX) [15] and N,N′-bis(13-amino-
N-{3-[4-(3-Aminopropoxy)butoxy]propyl}-3-
({24-[3-({3-[4-(3-aminopropoxy)butoxy]propyl}-
amino)phenoxy]cholan-3-yl}oxy)aniline (IVb) was
synthesized from 140 mg (0.21 mmol) of compound II
and 129 mg (0.63 mmol) of dioxadiamine IIIb in the
presence of 10 mg of Pd(dba)2, 12 mg of BINAP, and
70 mg (0.73 mmol) of sodium tert-butoxide in 2 ml of
anhydrous dioxane (reaction time 8 h). Eluent CH2Cl2–
MeOH (5:1), CH2Cl2–MeOH–aq. NH3 (10:3:1). Yield
1
138 mg (72%), light yellow oily substance. H NMR
3
spectrum, δ, ppm: 0.65 s (3H), 0.93 d (3H, J =
6.2 Hz), 0.96 s (3H), 1.02–2.03 m (44H), 3.18 br.s
(8H), 3.43 br.s (4H), 3.45 br.s (4H), 3.50–3.58 m (8H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

PALLADIUM-CATALYZED AMINATION
1763
3.86 br.s (2H), 4.53 s (1H), 6.12–6.25 m (6H), 7.01 t
benzene in the presence of 11 mg of Pd(dba)2, 13 mg
of BINAP, and 90 mg (0.92 mmol) of sodium tert-
butoxide in 11 ml of anhydrous dioxane (reaction time
18 h). Eluent CH2Cl2–MeOH, 100:1. Yield 24 mg
(17%), transparent light yellow oily substance which
3
3
(1H, J = 7.7 Hz), 7.02 t (1H, J = 7.8 Hz); signals
from NH protons were not assigned unambiguously.
13C NMR spectrum, δC, ppm: 12.1 (1C), 18.6 (1C),
21.1 (1C), 23.8 (1C), 24.2 (1C), 24.7 (1C), 25.9 (1C),
26.3 (1C), 26.4 (4C), 26.6 (1C), 28.3 (1C), 29.3 (2C),
29.4 (2C), 30.5 (2C), 32.1 (1C), 34.8 (1C), 35.5
(1C), 35.7 (1C), 37.0 (1C), 39.2 (2C), 40.0 (1C), 40.3
(1C), 41.9 (2C), 42.7 (1C), 56.2 (1C), 56.6 (1C), 68.2
(1C), 68.9 (2C), 69.3 (2C), 70.7 (2C), 70.9 (2C), 72.3
(1C), 99.2 (1C), 100.7 (1C), 102.8 (1C), 104.6
(1C), 105.5 (1C), 105.8 (1C), 129.8 (2C), 149.8 (1C),
149.9 (1C), 159.0 (1C), 160.4 (1C). Mass spectrum:
m/z 919.48 [M]+.
1
slowly crystallized on storage. H NMR spectrum, δ,
3
ppm: 0.66 s (3H), 0.95 d (3H, J = 6.3 Hz), 0.97 s
(3H), 0.98–2.02 m (28H), 1.86 quint (8H, 3J = 6.3 Hz),
3.16–3.24 m (8H), 3.55–3.70 m (24H), 3.84–3.91 m
(2H), 4.17 br.s (4H), 4.54 br.s (1H), 6.13–6.25 m (6H),
3
4
6.47 d.d (2H, J = 8.1, J = 2.1 Hz), 6.71 br.s (2H),
6.75 d (2H, 3J = 8.1 Hz), 6.97 t (2H, 3J = 8.0 Hz), 7.02 t
3
(1H, 3J = 7.9 Hz), 7.03 t (1H, J = 8.1 Hz). 13C NMR
spectrum, δC, ppm: 12.1 (1C), 18.6 (1C), 21.1 (1C),
23.9 (1C), 24.2 (1C), 24.7 (1C), 26.0 (1C), 26.3 (1C),
26.6 (1C), 28.3 (1C), 28.9 (2C), 29.2 (2C), 29.2 (2C),
32.2 (1C), 34.9 (1C), 35.5 (1C), 35.7 (1C), 37.0 (1C),
40.1 (1C), 40.3 (1C), 41.8 (4C), 42.8 (1C), 56.3 (1C),
56.7 (1C), 68.3 (1C), 69.8 (2C), 69.8 (2C), 70.3 (4C),
70.7 (4C), 72.3 (1C), 99.3 (1C), 101.0 (1C), 102.8
(1C), 104.4 (1C), 105.6 (1C), 105.8 (1C), 111.4 (2C),
115.1 (2C), 119.5 (2C), 123.2 (2C), 129.7 (1C), 129.8
(1C), 130.4 (2C), 149.9 (3C), 150.0 (1C), 159.0 (1C),
160.4 (1C).
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}-
propyl)-3-([(3β,5β,17α,20S)-24-{3-[(3-{2-[2-(3-
aminopropoxy)ethoxy]ethoxy}propyl)amino]-
phenoxy}cholan-3-yl]oxy)aniline (IVc) was synthe-
sized from 908 mg (1.35 mmol) of compound II and
1.189 g (5.4 mmol) of trioxadiamine IIIc in the pres-
ence of 62 mg of Pd(dba)2, 76 mg of BINAP, and
520 mg (5.4 mmol) of sodium tert-butoxide in 13 ml
of anhydrous dioxane (reaction time 8 h). Eluent
CH2Cl2–MeOH, 5:1. Yield 1.05 g (82%), light yellow
oily substance. 1H NMR spectrum, δ, ppm: 0.63 s (3H),
N-(3-{2-[2-(3-Phenylaminopropoxy)ethoxy]-
ethoxy}propyl)-3-([(3β,5β)-24-{3-[(3-{2-[2-(3-phen-
ylaminopropoxy)ethoxy]ethoxy}propyl)amino]-
phenoxy}cholan-3-yl]oxy)aniline (VI) was synthe-
sized from 334 mg (0.35 mmol) of compound IVc and
55 mg (0.23 mmol) of 1,3-dibromobenzene in the pres-
ence of 11 mg of Pd(dba)2, 13 mg of BINAP, and
90 mg (0.92 mmol) of sodium tert-butoxide in 11 ml
of anhydrous dioxane (reaction time 18 h). Eluent
CH2Cl2–MeOH, 100:1. Yield 23 mg (18%), transparent
3
0.92 d (3H, J = 6.6 Hz), 0.95 s (3H), 0.98–2.02 m
3
(28H), 1.84 br.s (4H), 1.89 quint (4H, J = 6.3 Hz),
2.99 t (4H, 3J = 5.5 Hz), 3.18 t (4H, 3J = 5.7 Hz), 3.55–
3.66 m (24H), 3.82–3.88 m (2H), 4.52 br.s (1H), 6.10–
6.26 m (6H), 6.99 t (1H, 3J = 7.8 Hz), 7.00 t (1H, 3J =
8.0 Hz); signals from NH protons were not assigned
unambiguously. 13C NMR spectrum, δC, ppm: 12.0
(1C), 18.6 (1C), 21.0 (1C), 23.8 (1C), 24.1 (1C), 24.6
(1C), 25.9 (1C), 26.2 (1C), 26.5 (1C), 28.1 (1C), 28.2
(2C), 29.0 (2C), 30.4 (2C), 32.1 (1C), 34.8 (1C), 35.5
(1C), 35.6 (1C), 36.9 (1C), 39.7 (2C), 40.0 (1C), 40.2
(1C), 41.6 (2C), 42.7 (1C), 56.1 (1C), 56.6 (1C), 68.2
(1C), 69.6 (2C), 69.8 (2C), 69.9 (2C), 70.0 (4C), 70.4
(2C), 72.2 (1C), 99.5 (1C), 101.1 (1C), 103.0 (1C),
104.7 (1C), 105.8 (1C), 106.1 (1C), 129.7 (1C), 129.7
(1C), 149.8 (1C), 149.9 (1C), 158.9 (1C), 160.3 (1C).
Mass spectrum: m/z 951.60 [M + H]+.
1
light yellow oily substance. H NMR spectrum, δ,
3
ppm: 0.66 s (3H), 0.94 d (3H, J = 6.6 Hz), 0.97 s
(3H), 0.99–2.03 m (28H), 1.86 quint (4H, 3J = 5.7 Hz),
3
3
1.88 quint (4H, J = 5.7 Hz), 3.22 t (8H, J = 6.6 Hz),
3.54–3.69 m (24H), 3.83–3.93 m (2H), 4.54 br.s (1H),
6.08–6.26 m (6H), 6.59 d (4H, 3J = 8.6 Hz), 6.66 t (2H,
3
3
3J = 7.4 Hz), 7.02 t (1H, J = 8.3 Hz), 7.03 t (1H, J =
3
8.1 Hz), 7.15 t (4H, J = 7.8 Hz); signals from NH
protons were not assigned unambiguously. 13C NMR
spectrum, δC, ppm: 12.1 (1C), 18.6 (1C), 21.1 (1C),
23.8 (1C), 24.2 (1C), 24.9 (1C), 26.0 (1C), 26.3 (1C),
26.6 (1C), 28.3 (1C), 29.1 (2C), 30.4 (2C), 30.5 (2C),
32.1 (1C), 34.9 (1C), 35.5 (1C), 35.7 (1C), 37.0 (1C),
40.0 (1C), 40.3 (1C), 41.7 (4C), 42.7 (1C), 56.2 (1C),
56.6 (1C), 68.3 (1C), 69.7 (4C), 70.3 (4C), 70.6 (4C),
72.3 (1C), 99.2 (1C), 100.9 (1C), 102.7 (1C), 104.3
(1C), 105.6 (1C), 105.8 (1C), 112.7 (4C), 117.0 (2C),
The other compounds were synthesized and isolat-
ed in a similar way.
N-[3-(2-{2-[3-(3-Bromophenylamino)propoxy]-
ethoxy}ethoxy)propyl]-3-{[(3β,5β)-24-(3-{[3-(2-{2-
[3-(3-bromophenylamino)propoxy]ethoxy}ethoxy)-
propyl]amino}phenoxy)cholan-3-yl]oxy}aniline (V)
was synthesized from 214 mg (0.225 mmol) of com-
pound IVc and 53 mg (0.225 mmol) of 1,3-dibromo-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RANYUK et al.
1764
3
129.2 (4C), 129.7 (1C), 129.8 (1C), 148.5 (2C), 149.9
(1C), 150.0 (1C), 158.9 (1C), 160.4 (1C).
(2H), 7.22 t (1H, J = 7.8 Hz); signals from NH
protons were not assigned unambiguously.
N-(8-Chloroanthracen-1-yl)-3-[2-(2-{3-[3-
({(3β,5β)-24-[3-({3-[2-(2-{3-[(8-chloroanthracen-1-
yl)amino]propoxy}ethoxy)ethoxy]propyl}amino)-
phenoxy]cholan-3-yl}oxy)phenylamino]propoxy}-
ethoxy)ethoxy]propane-1-amine (VII) was synthe-
sized from 334 mg (0.35 mmol) of compound IVc and
57 mg (0.23 mmol) of 1,8-dichloroanthracene in the
presence of 11 mg of Pd(dba)2, 13 mg of BINAP, and
90 mg (0.92 mmol) of sodium tert-butoxide in 11 ml of
anhydrous dioxane (reaction time 18 h). Eluent
CH2Cl2–MeOH, 100:1. Yield 52 mg (33%), yellow–
b. Compound VIII was synthesized from 68 mg
(0.1 mmol) of cholane derivative II and 52 mg
(0.1 mmol) of 2,6-disubstituted pyridine X in the pres-
ence of 4.5 mg of Pd(dba)2, 5.5 mg of BINAP, and
30 mg (0.3 mmol) of sodium tert-butoxide in 5 ml of
anhydrous dioxane (reaction time 20 h). Eluent
CH2Cl2–MeOH, 25:1. Yield 21 mg (20%).
Macrocyclic compound (XI) was synthesized
from 200 mg (0.3 mmol) of compound II and 154 mg
(0.3 mmol) of 1,3-disubstituted benzene IX in the pres-
ence of 14 mg of Pd(dba)2, 17 mg of BINAP, and
86 mg (0.9 mmol) of sodium tert-butoxide in 15 ml of
anhydrous dioxane (reaction time 29 h). Eluent
CH2Cl2–MeOH, 25:1. Yield 63 mg (21%), yellow oily
1
brown oily substance. H NMR spectrum, δ, ppm:
3
0.66 s (3H), 0.94 d (3H, J = 5.8 Hz), 0.97 s (3H),
3
1.78 quint (4H, J = 6.1 Hz), 1.00–2.07 (28H),
3
3
1
2.12 quint (4H, J = 6.1 Hz), 3.14 t (4H, J = 6.4 Hz),
substance. H NMR spectrum, δ, ppm: 0.66 s (3H),
3
3
3.46 t (4H, J = 5.4 Hz), 3.55–3.77 m (24H), 3.83–
0.94 d (3H, J = 6.4 Hz), 0.97 s (3H), 1.01–2.01 m
3
3.90 m (2H), 4.52 br.s (1H), 6.08–6.28 m (6H), 6.49 d
(28H), 1.86 br.s (8H), 3.18 t (4H, J = 5.9 Hz), 3.19 t
(2H, 3J = 6.6 Hz), 7.02 t (1H, 3J = 8.2 Hz), 7.03 t (1H,
3
(4H, J = 5.8 Hz), 3.55–3.61 m (16H), 3.63–3.68 m
3
3J = 8.0 Hz), 7.28–7.58 m (6H), 7.95 d (2H, J =
(8H), 3.87 br.s (2H), 4.54 s (1H), 5.85 s (1H), 5.97 d
9.1 Hz), 8.00 d (2H, 3J = 8.6 Hz), 8.33 s (2H), 8.39 s
(2H); signals from NH protons were not assigned un-
ambiguously. 13C NMR spectrum, δC, ppm: 12.1 (1C),
18.6 (1C), 21.08 (1C), 23.8 (1C), 24.2 (1C), 24.7 (1C),
26.0 (1C), 26.2 (1C), 26.6 (1C), 28.3 (1C), 28.9 (2C),
29.1 (1C), 29.1 (1C), 30.5 (2C), 32.1 (1C), 34.8 (1C),
35.5 (1C), 35.6 (1C), 37.0 (1C), 40.0 (1C), 40.2 (1C),
41.7 (2C), 42.7 (1C), 42.8 (2C), 56.2 (1C), 56.6 (1C),
68.3 (1C), 69.6 (2C), 70.1 (2C), 70.2 (2C), 70.5 (2C),
70.6 (2C), 70.6 (2C), 72.3 (1C), 99.2 (1C), 100.9 (1C),
101.4 (2C), 102.7 (1C), 104.3 (1C), 105.6 (1C), 105.8
(1C), 116.9 (2C), 118.9 (2C), 123.8 (2C), 124.8 (2C),
125.4 (2C), 126.3 (2C), 127.7 (2C), 128.4 (2C), 129.7
(1C), 129.8 (1C), 130.8 (2C), 131.5 (2C), 132.0 (2C),
132.6 (2C), 143.6 (2C), 149.9 (1C), 149.9 (1C), 159.0
(1C), 160.4 (1C).
3
3
(2H, J = 7.8 Hz), 6.13–6.25 m (6H), 6.94 t (1H, J =
3
3
7.9 Hz), 7.02 t (1H, J = 7.7 Hz), 7.03 t (1H, J =
7.7 Hz); signals from NH protons were not assigned
unambiguously. 13C NMR spectrum, δC, ppm: 12.0
(1C), 18.6 (1C), 21.1 (1C), 23.8 (1C), 24.2 (1C), 24.6
(1C), 25.9 (1C), 26.2 (1C), 26.6 (1C), 28.2 (1C), 29.0
(2C), 29.3 (2C), 30.4 (2C), 32.1 (1C), 34.8 (1C), 35.5
(1C), 35.6 (1C), 36.9 (1C), 40.0 (1C), 40.2 (1C), 41.5
(2C), 41.6 (2C), 42.7 (1C), 56.2 (1C), 56.6 (1C), 68.2
(1C), 69.6 (2C), 69.7 (2C), 70.2 (4C), 70.6 (4C), 72.2
(1C), 97.0 (1C), 99.1 (1C), 100.8 (1C), 102.5 (2C),
102.6 (1C), 104.2 (1C), 105.6 (1C), 105.8 (1C), 129.7
(1C), 129.8 (2C), 149.6 (2C), 149.8 (1C), 149.9 (1C),
158.9 (1C), 160.3 (1C).
(3α,5β)-24-{3-[(3-{2-[2-(3-Aminopropoxy)-
ethoxy]ethoxy}propyl)amino]phenoxy}cholan-3-ol
(XIII) was synthesized from 280 mg (0.59 mmol) of
compound XII and 260 mg (1.18 mmol) of trioxadi-
amine IIIc in the presence of 27 mg of Pd(dba)2,
33 mg of BINAP, and 115 mg (1.18 mmol) of sodium
tert-butoxide in 6 ml of anhydrous dioxane (reaction
time 4 h). Eluent CH2Cl2–MeOH (5:1, 2.5 : 1),
CH2Cl2–MeOH–aq. NH3 (100:20:1, 100:20:2). Yield
257 mg (66%), light yellow oily substance. 1H NMR
spectrum, δ, ppm: 0.54 s (3H), 0.80 s (3H), 0.83 d (3H,
Macrocyclic compound (VIII). a. The reaction
was carried out with 214 mg (0.23 mmol) of com-
pound IVc and 53 mg (0.23 mmol) of 2,6-dibromo-
pyridine in the presence of 11 mg of Pd(dba)2, 13 mg
of BINAP, and 90 mg (0.92 mmol) of sodium tert-
butoxide in 11 ml of anhydrous dioxane (reaction time
18 h). Eluent CH2Cl2–MeOH, 25:1. Yield 9 mg (4%),
1
yellow oily substance. H NMR spectrum, δ, ppm:
3
0.65 s (3H), 0.94 d (3H, J = 6.4 Hz), 0.96 s (3H),
3
3J = 7.0 Hz), 0.90–1.90 m (32H), 2.66 t (2H, J =
3
0.99–2.01 m (28H), 1.86 q (8H, J = 5.8 Hz), 3.20 q
3
3
3
3
(4H, J = 6.3 Hz), 3.27 t (4H, J = 6.3 Hz), 3.51–
6.1 Hz), 3.24 t (2H, J = 5.6 Hz), 3.44 t (2H, J =
3.69 m (24H), 3.83–3.91 m (2H), 4.53 br.s (1H), 5.67 d
(2H, J = 7.8 Hz), 6.11–6.27 m (6H), 6.98–7.06 m
6.3 Hz), 3.46–3.50 m (6H), 3.52–3.56 m (4H), 3.56–
3.60 m (1H), 4.03 br.s (2H), 5.81 d (1H, J = 7.6 Hz),
3
3
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PALLADIUM-CATALYZED AMINATION
1765
3
3
3
3
5.84 d (1H, J = 8.0 Hz), 7.18 t (1H, J = 7.8 Hz);
signals from NH and OH protons were not assigned
unambiguously. 13C NMR spectrum, δC, ppm: 11.8
(1C), 18.4 (1C), 20.6 (1C), 23.2 (1C), 24.0 (1C), 25.5
(1C), 26.2 (1C), 27.0 (1C), 28.0 (1C), 29.1 (1C), 29.4
(1C), 30.3 (1C), 31.9 (1C), 33.0 (1C), 34.3 (1C), 35.2
(1C), 35.3 (1C), 35.6 (1C), 36.2 (1C), 39.3 (1C), 40.0
(1C), 40.2 (1C), 41.9 (1C), 42.4 (1C), 55.9 (1C), 56.3
(1C), 65.8 (1C), 69.2 (2C), 69.9 (2C), 70.3 (2C), 70.7
(1C), 96.7 (1C), 97.3 (1C), 139.5 (1C), 157.7 (1C),
163.2 (1C). Mass spectrum: m/z 657.74 [M]+.
5.82 d (1H, J = 7.9 Hz), 5.85 d (1H, J = 7.8 Hz),
5.91 d (2H, 3J = 7.8 Hz), 7.24 t (1H, 3J = 7.8 Hz), 7.25 t
(1H, J = 7.8 Hz); signals from protons in the primary
3
amino groups were not assigned unambiguously.
13C NMR spectrum, δC, ppm: 12.0 (1C), 18.5 (1C),
21.0 (1C), 23.7 (1C), 24.1 (1C), 24.9 (1C), 25.7 (1C),
26.2 (1C), 26.4 (4C), 26.5 (1C), 28.2 (1C), 29.4 (2C),
30.6 (2C), 32.1 (1C), 33.4 (2C), 34.8 (1C), 35.4 (1C),
35.6 (1C), 37.1 (1C), 39.6 (2C), 39.9 (1C), 40.0 (2C),
40.2 (1C), 42.6 (1C), 56.2 (1C), 56.6 (1C), 66.0 (1C),
68.8 (2C), 69.0 (2C), 70.1 (1C), 70.6 (2C), 70.7 (2C),
96.8 (1C), 97.0 (1C), 97.2 (1C), 98.0 (1C), 139.6 (1C),
139.7 (1C), 157.8 (2C), 162.8 (1C), 163.4 (1C). Mass
spectrum: m/z 920.87 [M]+.
(3α,5β,3′α,5′β)-24,24′-[Ethane-1,2-diyldi(imino-
propane-3,1-diyliminopyridine-6,2-diyloxy)]bis-
(cholan-3-ol) (XIV) was synthesized from 460 mg
(0.97 mmol) of compound XII and 85 mg (0.5 mmol)
of tetraamine IIId in the presence of 22 mg of Pd(dba)2,
27 mg of BINAP, and 140 mg (1.45 mmol) of sodium
tert-butoxide in 5 ml of anhydrous dioxane (reaction
time 6 h). Eluent CH2Cl2–MeOH–aq. NH3 (100:20:1,
100:20:2, 100:20:3). Yield 140 mg (27%), light yel-
low crystalline powder, mp 110–112°C. 1H NMR spec-
trum, δ, ppm: 0.59 s (6H), 0.86 s (6H), 0.88 d (6H, 3J =
6,6′-[(3β,5β)-Cholane-3,24-diyldi(oxy)]bis[N-(3-
{2-[2-(3-aminopropoxy)ethoxy]ethoxy}propyl)pyri-
din-2-amine] (XVIc). a. The reaction was carried out
with 693 mg (1.18 mmol) of compound XV and 1.04 g
(4.72 mmol) of trioxadiamine IIIc in the presence of
54 mg of Pd(dba)2, 66 mg of BINAP, and 340 mg
(3.5 mmol) of sodium tert-butoxide in 24 ml of anhy-
drous dioxane (reaction time 4 h). Eluent CH2Cl2–
MeOH (5:1, 2.5:1),. Yield 605 mg (54%), light yellow
oily substance. 1H NMR spectrum, δ, ppm: 0.56 s (3H),
3
6.8 Hz), 0.95–1.95 m (60H), 2.82 t (4H, J = 5.7 Hz),
2.96 s (4H), 3.31 br.s (4H), 3.52–3.60 m (2H), 3.98–
3
3
4.08 m (4H), 4.70 br.s (2H), 5.89 d (2H, J = 7.7 Hz),
0.85 d (3H, J = 6.4 Hz), 0.88 s (3H), 0.92–1.91 m
3
3
3
5.93 d (2H, J = 7.8 Hz), 7.23 t (2H, J = 7.8 Hz);
signals from two NH protons (CH2NHCH2) were not
assigned unambiguously. 13C NMR spectrum, δC, ppm:
11.9 (2C), 18.5 (2C), 20.7 (2C), 23.3 (2C), 24.1 (2C),
25.7 (2C), 26.3 (2C), 27.1 (2C), 27.7 (2C), 28.2 (2C),
30.4 (2C), 32.0 (2C), 34.4 (2C), 35.3 (2C), 35.5
(2C), 35.7 (2C), 36.3 (2C), 39.3 (2C), 40.1 (2C), 40.3
(2C), 42.0 (2C), 42.6 (2C), 46.4 (4C), 56.0 (2C),
56.4 (2C), 66.4 (2C), 71.5 (2C), 96.1 (2C), 98.6 (2C),
139.8 (2C), 157.8 (2C), 163.3 (2C). Mass spectrum:
m/z 1049.09 [M]+.
(28H), 1.62 quint (4H, J = 6.6 Hz), 1.77 quint (4H,
3J = 5.7 Hz), 2.68 t (4H, 3J = 6.8 Hz), 3.25 br.s (4H),
3
3.45 t (4H, J = 6.2 Hz), 3.47–3.51 m (12H), 3.53–
3
3.57 m (8H), 3.99–4.09 m (2H), 4.72 t (1H, J =
4.6 Hz), 4.76 t (1H, 3J = 5.7 Hz), 5.09 s (1H), 5.79 d
(1H, 3J = 7.8 Hz), 5.82 d (1H, 3J = 7.9 Hz), 5.86 d (2H,
3J = 7.8 Hz), 7.19 t (1H, J = 7.8 Hz), 7.20 t (1H, J =
7.8 Hz); signals from protons in the primary amino
groups were not assigned unambiguously. 13C NMR
spectrum, δC, ppm: 11.8 (1C), 18.4 (1C), 20.8 (1C),
23.6 (1C), 24.0 (1C), 24.7 (1C), 25.5 (1C), 26.0 (1C),
26.4 (1C), 28.0 (1C), 29.1 (2C), 30.5 (2C), 31.9 (1C),
33.1 (2C), 34.6 (1C), 35.3 (1C), 35.4 (1C), 36.9 (1C),
39.3 (2C), 39.4 (2C), 39.7 (1C), 40.0 (1C), 42.5 (1C),
56.0 (1C), 56.4 (1C), 65.8 (1C), 69.2 (4C), 69.9 (4C),
70.3 (5C), 96.6 (1C), 96.9 (1C), 97.3 (1C), 97.6 (1C),
139.4 (1C), 139.5 (1C), 157.7 (2C), 162.6 (1C), 163.2
(1C). Mass spectrum: m/z 952.89 [M]+.
3
3
6,6′-[(3β,5β)-Cholane-3,24-diyldi(oxy)]bis-
(N-{3-[4-(3-aminopropoxy)butoxy]propyl}pyridin-
2-amine) (XVIb) was synthesized from 290 mg
(0.49 mmol) of compound XV and 400 mg (1.96 mmol)
of dioxadiamine IIIb in the presence of 23 mg of
Pd(dba)2, 27 mg of BINAP, and 140 mg (1.5 mmol) of
sodium tert-butoxide in 5 ml of anhydrous dioxane.
Yield 90% (in the reaction mixture). The product was
brought into reaction with 9-bromoanthracene without
b. The reaction of 290 mg (0.47 mmol) of com-
pound XV with 310 mg (1.41 mmol) trioxadiamine
IIIc in the presence of 22 mg of Pd(dba)2, 26 mg of
BINAP, and 135 mg (1.4 mmol) of sodium tert-butox-
ide in 5 ml of anhydrous dioxane (7 h under reflux)
gave 125 mg (32%) of acyclic oligomer XVII as by-
product. Eluent CH2Cl2–MeOH (2.5:1), light yellow
1
isolation. H NMR spectrum, δ, ppm: 0.60 s (3H),
3
0.89 d (3H, J = 6.6 Hz), 0.92 s (3H), 0.96–1.95 m
3
(36H), 1.65 quint (4H, J = 6.5 Hz), 1.81 quint (4H,
3J = 5.5 Hz), 2.73 t (4H, J = 6.8 Hz), 3.24–3.31 m
3
(4H), 3.35–3.49 m (16H), 4.04–4.12 m (2H), 4.63 t
(1H, 3J = 5.0 Hz), 4.66 t (1H, 3J = 5.1 Hz), 5.13 s (1H),
oily substance. H NMR spectrum, δ, ppm: 0.63 s
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RANYUK et al.
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3
(6H), 0.91 d (6H, J = 6.3 Hz), 0.94 s (6H), 0.96–
2.00 m (68H), 3.14 br.s (4H), 3.30 br.s (8H), 3.58 br.s
(36H), 4.01–4.13 m (4H), 4.66 br.s (2H), 4.71 br.s
(2H), 5.10 s and 5.13 s (1H each), 5.85–5.99 m (8H),
XVIIIb. Eluent CH2Cl2–MeOH, 100:1. Yield 304 mg
(56%), yellow–brown oily substance. 1H NMR spec-
3
trum, δ, ppm: 1.80 br.s (4H), 2.00 quint (4H, J =
3
6.0 Hz), 3.49 t (4H, J = 6.2 Hz), 3.54–3.57 m (4H),
3
3
7.27 t (4H, J = 7.7 Hz); signals from protons in the
3.66 t (4H, J = 5.8 Hz), 7.40–7.46 m (8H), 7.93–
primary amino groups were not assigned unambigu-
ously. 13C NMR spectrum, δC, ppm: 12.0 (2C), 18.6
(2C), 21.0 (2C), 23.8 (2C), 24.2 (2C), 24.9 (2C), 25.7
(2C), 26.2 (2C), 26.6 (2C), 28.2 (2C); 29.0, 29.1, and
29.2 (6C); 30.7 (4C), 32.1 (2C), 34.8 (2C), 35.5 (2C),
35.6 (2C), 37.1 (2C); 39.3, 39.4, and 39.7 (6C); 39.9
(2C), 40.2 (2C), 42.7 (2C), 56.2 (2C), 56.6 (2C), 66.1
(2C), 69.3 (2C), 69.4 (2C), 69.8 (8C), 70.1 (2C), 70.2
(2C), 70.3 (2C), 70.5 (2C), 96.1 (1C), 96.9 (1C), 97.1
(1C), 97.4 (1C), 97.5 (1C), 97.7 (1C), 97.9 (1C), 98.2
(1C), 139.8 and 139.9 (4C), 158.0 (2C), 162.8 (2C),
163.4 (2C). Mass spectrum: m/z 1685.38 [M]+.
7.98 m (4H), 8.10 s (2H), 8.26–8.32 m (4H); signals
from NH protons were not assigned unambiguously.
13C NMR spectrum, δC, ppm: 26.7 (2C), 30.8 (2C), 50.4
(2C), 70.1 (2C), 71.1 (2C), 121.0 (2C), 123.2 (4C),
124.4 (4C), 125.1 (4C), 125.2 (4C), 128.8 (4C), 132.3
(4C), 142.2 (2C). Mass spectrum: m/z 556.47 [M]+.
N-[3-(2-{2-[3-(9-Anthrylamino)propoxy]ethoxy}-
ethoxy)propyl]-6-({(3β,5β)-24-[(6-{[3-(2-{2-[3-(9-an-
thrylamino)propoxy]ethoxy}ethoxy)propyl]amino}-
pyridin-2-yl)oxy]cholan-3-yl}oxy)pyridin-2-amine
(XVIIIc) was synthesized from compound XVIc (pre-
pared in situ) and 830 mg (3.2 mmol) of 9-bromo-
anthracene in the presence of 34 mg of Pd(dba)2,
41 mg of BINAP, and 420 mg (4.3 mmol) of sodium
tert-butoxide in 5 ml of anhydrous dioxane (reaction
time 4 h). Eluent CH2Cl2–MeOH, 50:1. Yield 62 mg
(10%, calculated on the initial compound XV taken for
the synthesis of 0.49 mol of diamine XVIc), yellow–
N-(3-{4-[3-(9-Anthrylamino)propoxy]butoxy}-
propyl)-6-{[(3β,5β)-24-({6-[(3-{4-[3-(9-anthryl-
amino)propoxy]butoxy}propyl)amino]pyridin-2-yl}-
oxy)cholan-3-yl]oxy}pyridin-2-amine (XVIIIb) was
synthesized from compound XVIb (prepared in situ)
and 830 mg (3.2 mmol) of 9-bromoanthracene in the
presence of 34 mg of Pd(dba)2, 41 mg of BINAP, and
420 mg (4.3 mmol) of sodium tert-butoxide in 5 ml of
anhydrous dioxane (reaction time 4 h). Eluent CH2Cl2–
MeOH (25:1). Yield 82 mg (13%, calculated on the
initial compound XV taken for the preparation of
0.49 mol of XVIb), yellow–brown oily substance.
1H NMR spectrum, δ, ppm: 0.64 s (3H), 0.92 d (3H,
3J = 4.9 Hz), 0.96 s (3H), 0.98–1.95 m (36H),
1
brown oily substance. H NMR spectrum, δ, ppm:
3
0.64 s (3H), 0.93 d (3H, J = 6.3 Hz), 0.96 s (3H),
3
0.99–2.00 m (32H), 2.01 quint (4H, J = 6.1 Hz),
3
3
3.25 q (4H, J = 6.7 Hz), 3.33 q (4H, J = 6.7 Hz),
3.44–3.75 m (24H), 4.08–4.16 m (2H), 4.63 br.s (2H),
3
4.69 br.s (2H), 5.17 s (1H), 5.83 d (1H, J = 7.8 Hz),
3
3
5.87 d (1H, J = 7.8 Hz), 5.97 d (2H, J = 7.7 Hz),
3
3
7.26 d (1H, J = 7.8 Hz), 7.27 d (1H, J = 7.8 Hz),
7.40–7.45 m (8H), 7.93–7.97 m (4H), 8.09 s (2H),
8.27–8.31 m (4H). 13C NMR spectrum, δC, ppm: 12.0
(1C), 18.6 (1C), 21.0 (1C), 23.8 (1C), 24.2 (1C), 24.9
(1C), 25.7 (1C), 26.2 (1C), 26.6 (1C), 28.2 (1C), 29.3
(2C), 30.7 (4C), 32.1 (1C), 34.8 (1C), 35.5 (1C), 35.6
(1C), 37.1 (1C), 39.7 (1C), 39.9 (2C), 40.2 (1C), 42.7
(1C), 50.3 (2C), 56.2 (1C), 56.6 (1C), 66.1 (1C), 69.4
(2C), 70.1 (2C), 70.2 (2C), 70.4 (1C), 70.5 (2C), 70.6
(4C), 97.0 (1C), 97.1 (1C), 97.5 (1C), 97.9 (1C), 120.9
(2C), 123.3 (4C), 124.4 (4C), 125.1 (4C), 125.2 (4C),
128.8 (4C), 132.3 (4C), 139.8 (2C), 142.2 (2C), 157.9
(2C), 162.8 (1C), 163.4 (1C). Mass spectrum: m/z
1305.01 [M]+.
3
3
2.00 quint (4H, J = 5.9 Hz), 2.12 quint (4H, J =
6.2 Hz), 3.25–3.34 m (8H), 3.36–3.70 m (16H), 4.08–
4.18 m (2H), 4.68 br.s (4H), 5.16 s (1H), 5.86 d (1H,
3J = 8.1 Hz), 5.89 d (1H, 3J = 8.1 Hz), 5.97 d (2H, 3J =
7.6 Hz), 7.25–7.31 m (2H), 7.38–7.45 m (8H), 7.91–
7.97 m (4H), 8.10 s (2H), 8.25–8.30 m (4H). 13C NMR
spectrum, δC, ppm: 12.0 (1C), 18.6 (1C), 21.1 (1C),
23.8 (1C), 24.2 (1C), 25.0 (1C), 25.8 (1C), 26.3 (1C),
26.5 (1C), 26.6 (4C), 28.2 (1C), 29.5 (3C), 30.7 (2C),
32.1 (1C), 34.9 (1C), 35.5 (1C), 35.7 (1C), 37.1 (1C),
40.0 (1C), 40.1 (2C), 40.3 (1C), 42.7 (1C), 50.5 (2C),
56.2 (1C), 56.6 (1C), 66.1 (1C), 69.1 (2C), 70.1 (2C),
70.3 (1C), 70.7 (2C), 71.1 (2C), 96.9 (1C), 97.1 (1C),
97.3 (1C), 98.1 (1C), 121.0 (2C), 123.2 (4C), 124.5
(4C), 125.1 (4C), 125.3 (4C), 128.8 (4C), 132.3 (4C),
139.8 (2C), 142.2 (2C), 157.9 (2C), 162.9 (1C), 163.5
(1C). Mass spectrum: m/z 1272.18 [M]+.
N,N′-{3,3′-[2,2′-Oxydi(ethane-2,1-diyl)di(oxy)]-
di(propane-3,1-diyl)}bis(anthracen-9-amine) (XIXc)
was isolated as the major product in the synthesis of
compound XVIIIc. Eluent CH2Cl2–MeOH, 500:1.
Yield 515 mg (92%), yellow–brown oily substance.
N,N′-{3,3′-[Butane-1,4-diyldi(oxy)]bis(propane-
3,1-diyl)}di(anthracen-9-amine) (XIXb) was isolated
as the major product in the synthesis of compound
3
1H NMR spectrum, δ, ppm: 1.95 quint (4H, J =
3
6.1 Hz), 3.47 t (4H, J = 6.3 Hz), 3.61–3.65 m (8H),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

PALLADIUM-CATALYZED AMINATION
1767
MeOH, 100:1. Yield 166 mg (53%), dark red oily sub-
3.70–3.75 m (4H), 7.41–7.49 m (8H), 7.94–7.99 m
(4H), 8.11 s (2H), 8.28–8.34 m (4H); signals from NH
protons were not assigned unambiguously. 13C NMR
spectrum, δC, ppm: 30.6 (2C), 50.2 (2C), 70.2 (2C),
70.3 (2C), 70.5 (2C), 120.8 (2C), 123.2 (4C), 124.3
(4C), 125.0 (4C), 125.1 (4C), 128.7 (4C), 132.2 (4C),
142.2 (2C). Mass spectrum: m/z 572.47 [M]+.
stance. 1H NMR spectrum, δ, ppm: 0.60 s (3H), 0.89 d
3
(3H, J = 6.4 Hz), 0.92 s (3H), 0.95–1.94 m (28H),
3
3
1.83 quint (2H, J = 6.3 Hz), 1.84 quint (2H, J =
6.1 Hz), 1.98 quint (4H, 3J = 6.3 Hz), 3.31 q (4H, 3J =
5.9 Hz), 3.40 q (4H, J = 6.3 Hz), 3.54 t (4H, J =
3
3
3
5.9 Hz), 3.55 t (4H, J = 6.1 Hz), 3.57–3.70 m (16H),
4.04–4.14 m (2H), 4.65 t (2H, 3J = 5.0 Hz), 4.68 t (2H,
1-({3-[2-(2-{3-[(6-{[(3α,5β)-3-Hydroxyсholan-24-
yl]oxy}pyridin-2-yl)amino]propoxy}ethoxy)ethoxy]-
propyl}amino)-9,10-dihydroanthracene-9,10-dione
(XX) was synthesized from 180 mg of compound XIII
and 133 mg (0.55 mmol) of 1-chloroanthraquinone in
the presence of 12 mg of Pd(dba)2, 15 mg of BINAP,
and 176 mg (0.54 mmol) of cesium carbonate in
6.75 ml of anhydrous dioxane (reaction time 24 h).
Eluent CH2Cl2–MeOH, 100:1. Yield 33 mg (19%),
3J = 4.9 Hz), 5.14 s (1H), 5.85 d (1H, J = 7.9 Hz),
3
3
3
5.88 d (1H, J = 7.9 Hz), 5.92 d (1H, J = 7.8 Hz),
5.93 d (1H, 3J = 7.8 Hz), 7.02 d (2H, 3J = 8.4 Hz), 7.25 t
(1H, 3J = 7.9 Hz), 7.26 t (1H, 3J = 7.8 Hz), 7.45 t (2H,
3J = 7.9 Hz), 7.52 d.d (2H, 3J = 7.2, 4J = 1.2 Hz), 7.64 t
(2H, J = 7.4 Hz), 7.70 t.d (2H, J = 7.2, J = 0.7 Hz),
8.17 d.d (2H, 3J = 7.6, 4J = 0.9 Hz), 8.20 d.d (2H, 3J =
3
3
4
4
3
7.8, J = 0.9 Hz), 9.72 t (2H, J = 4.7 Hz). 13C NMR
spectrum, δC, ppm: 11.9 (1C), 18.5 (1C), 21.0 (1C),
23.7 (1C), 24.1 (1C), 24.8 (1C), 25.7 (1C), 26.1 (1C),
26.5 (1C), 28.2 (1C), 29.2 (4C), 30.6 (2C), 32.0 (1C),
34.8 (1C), 35.4 (1C), 35.5 (1C), 37.0 (1C), 39.7 (2C),
39.9 (3C), 40.1 (1C), 42.6 (1C), 56.1 (1C), 56.5 (1C),
66.0 (1C), 68.5 (2C), 69.3 (2C), 70.1 (3C), 70.3 (2C),
70.5 (4C), 96.9 (1C), 97.0 (1C), 97.4 (1C), 97.9 (1C),
112.7 (2C), 115.4 (2C), 117.8 (2C), 126.5 (4C), 132.7
(2C), 132.8 (2C), 133.7 (2C), 134.4 (2C), 134.8 (2C),
135.1 (2C), 139.7 (2C), 151.6 (2C), 157.8 (2C), 162.8
(1C), 163.3 (1C), 183.6 (2C), 184.6 (2C). Mass spec-
trum: m/z 1365.11 [M]+.
1
dark red oily substance. H NMR spectrum, δ, ppm:
3
0.60 s (3H), 0.88 s (3H), 0.90 d (3H, J = 6.4 Hz),
3
0.93–1.95 m (29H), 1.85 quint (2H, J = 6.2 Hz),
2.00 quint (2H, 3J = 6.5 Hz), 3.32 q (2H, 3J = 6.1 Hz),
3
3.44 q (2H, J = 6.3 Hz), 3.54–3.70 m (13H), 4.05–
4.15 m (2H), 4.66 t (1H, 3J = 5.3 Hz), 5.88 d (1H, 3J =
3
3
7.9 Hz), 5.93 d (1H, J = 7.8 Hz), 7.07 d (1H, J =
3
3
8.3 Hz), 7.27 t (1H, J = 7.9 Hz), 7.50 t (1H, J =
7.9 Hz), 7.56 d.d (1H, 3J = 7.2, J = 0.9 Hz), 7.67 t.d
4
(1H, 3J = 7.6, 4J = 1.3 Hz), 7.73 t.d (1H, 3J = 7.5, 4J =
3
4
1.2 Hz), 8.21 d.d (1H, J = 7.6, J = 0.9 Hz), 8.25 d.d
3
4
3
(1H, J = 7.6, J = 0.9 Hz), 9.77 t (1H, J = 5.0 Hz).
13C NMR spectrum, δC, ppm: 12.0 (1C), 18.6 (1C),
20.7 (1C), 23.4 (1C), 23.5 (1C), 24.2 (1C), 25.8 (1C),
26.3 (1C), 27.1 (1C), 28.2 (1C), 28.7 (1C), 29.3 (2C),
32.1 (1C), 32.6 (1C), 34.7 (1C), 35.3 (1C), 35.6 (1C),
35.8 (1C), 39.8 (1C), 40.0 (1C), 40.1 (1C), 40.2 (1C),
42.6 (1C), 56.2 (1C), 56.4 (1C), 66.1 (1C), 66.5 (1C),
68.6 (1C), 69.4 (1C), 70.2 (1C), 70.4 (1C), 70.6 (2C),
97.0 (1C), 97.4 (1C), 112.9 (1C), 115.5 (1C), 117.9
(1C), 126.5 (1C), 126.6 (1C), 132.8 (1C), 133.0 (1C),
133.9 (1C), 134.6 (1C), 135.0 (1C), 135.2 (1C), 139.8
(1C), 151.8 (1C), 157.9 (1C), 163.5 (1C), 183.8 (1C),
184.8 (1C). Mass spectrum: m/z 863.55 [M]+.
1-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}pro-
pylamino)-9,10-dihydroanthracene-9,10-dione
(XXII) was synthesized from 1 mmol (243 mg) of
1-chloroanthraquinone and 3 mmol (660 mg) of
trioxadiamine IIIc in the presence of 23 mg of
Pd(dba)2, 28 mg of BINAP, and 1 g (3 mmol) of cesi-
um carbonate in 5 ml of anhydrous dioxane (reaction
time 8 h). Eluent CH2Cl2–MeOH (5:1, 2.5:1). Yield
350 mg (84%), dark red oily substance. 1H NMR spec-
3
trum, δ, ppm: 1.68 quint (2H, J = 6.4 Hz), 1.96 quint
3
3
(2H, J = 6.3 Hz), 2.26 br.s (2H), 2.75 t (2H, J =
3
6.7 Hz), 3.35–3.42 m (4H), 3.49 t (2H, J = 6.2 Hz),
3.51–3.65 m (8H), 7.02 d.d (1H, 3J = 8.3, 4J = 1.3 Hz),
3
3
4
1-{[3-(2-{2-[3-({6-([(3β,5β)-24-{[6-({3-[2-(2-{3-
[(9,10-Dioxo-9,10-dihydroanthracen-1-yl)amino]-
propoxy}ethoxy)ethoxy]propyl}amino)pyridin-2-yl]-
oxy}cholan-3-yl]oxy)pyridin-2-yl}amino)propoxy]-
ethoxy}ethoxy)propyl]amino}-9,10-dihydroanthra-
cene-9,10-dione (XXI) was synthesized from 220 mg
(0.23 mmol) of compound XVIc and 168 mg
(0.7 mmol) of 1-chloroanthraquinone in the presence
of 11 mg of Pd(dba)2, 13 mg of BINAP, and 300 mg
(0.9 mmol) of cesium carbonate in 5.75 ml of anhy-
drous dioxane (reaction time 24 h). Eluent CH2Cl2–
7.45 t (1H, J = 7.7 Hz), 7.49 d.d (1H, J = 7.3, J =
3
4
1.5 Hz), 7.62 t.d (1H, J = 7.5, J = 1.6 Hz), 7.68 t.d
(1H, 3J = 7.5, 4J = 1.5 Hz), 8.15 d.d (1H, 3J = 7.6, 4J =
3
4
1.1 Hz), 8.18 d.d (1H, J = 7.7, J = 1.1 Hz), 9.69 t
3
(1H, J = 4.9 Hz). 13C NMR spectrum, δC, ppm: 29.2
(1C), 32.7 (1C), 39.4 (1C), 39.9 (1C), 68.5 (1C), 69.3
(1C), 70.0 (1C), 70.3 (1C), 70.4 (2C), 112.7 (1C),
115.4 (1C), 117.8 (1C), 126.5 (2C), 132.7 (1C), 132.8
(1C), 133.8 (1C), 134.4 (1C), 134.8 (1C), 135.1 (1C),
151.6 (1C), 183.6 (1C), 184.7 (1C). Mass spectrum:
m/z 426.22 [M]+.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009

RANYUK et al.
1768
3. Averin, A.D., Ranyuk, E.R., Lukashev, N.V., Go-
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}-
lub, S.L., Buryak, A.K., and Beletskaya, I.P., Tetra-
hedron Lett., 2008, vol. 49, p. 1188.
4. Averin, A.D., Ranyuk, E.R., Lukashev, N.V., Bu-
ryak, A.K., and Beletskaya, I.P., Russ. J. Org. Chem.,
2009, vol. 45, p. 78.
5. Averin, A.D., Uglov, A.N., Ranyuk, E.R., Luka-
shev, N.V., and Beletskaya, I.P., Russ. J. Org. Chem.,
2009, vol. 45, p. 273.
propyl)anthracen-1-amine (XXIII) was synthesized
from 1 mmol (213 mg) of 1-chloroanthracene and
3 mmol (660 mg) of trioxadiamine IIIc in the presence
of 23 mg of Pd(dba)2, 28 mg of BINAP, and 290 mg
(3 mmol) of potassium tert-butoxide in 5 ml of anhy-
drous dioxane (reaction time 8 h). Eluent CH2Cl2–
MeOH (2.5:1), CH2Cl2–MeOH–aq. NH3 (100:20:1).
1
Yield 230 mg (58%), yellow oily substance. H NMR
6. Deng, G., Dewa, T., and Regen, S.L., J. Am. Chem. Soc.,
1996, vol. 118, p. 8975.
7. Sakai, N. and Matile, S., Tetrahedron Lett., 1997,
3
spectrum, δ, ppm: 1.68 quint (2H, J = 6.0 Hz),
3
3
2.08 quint (2H, J = 6.0 Hz), 2.82 t (2H, J = 6.3 Hz),
3
3.33–3.36 m (4H), 3.39 t (4H, J = 5.9 Hz), 3.47–
3.51 m (2H), 3.61 br.s (4H), 3.69 t (2H, J = 5.6 Hz),
5.58 br.s (1H), 6.44 d (1H, J = 6.3 Hz), 7.26–7.41 m
vol. 38, p. 2613.
3
8. Moore, K.S., Wehrli, S., Roder, H., Rodgers, M.,
Forrest, J.M., McCrimmon, D., and Zasloff, M., Proc.
Natl. Acad. Sci. USA, 1993, vol. 90, p. 1354.
9. Sills, A.K., Jr., Williams, J.I., Tyler, B.M., Epstein, D.S.,
Sipos, E.P., Davis, J.D., McLane, M.P., Pitchford, S.,
Cheshire, K., Gannon, F.H., Kinney, W.A., Chao, T.L.,
Donowitz, M., Laterra, J., Zasloff, M., and Brem, H.,
Cancer Res., 1998, vol. 58, p. 2784.
10. Rao, M., Shinnar, A.E., Noecker, L.A., Chao, T.L.,
Feibush, B., Snyder, B., Sharkansky, I., Sarkahian, A.,
Zhang, X., Jones, S.R., Kinney, W.A., and Zasloff, M.,
J. Nat. Prod., 2000, vol. 63, p. 631.
3
3
3
(4H), 7.90 d (1H, J = 7.1 Hz), 8.00 d (1H, J =
8.8 Hz), 8.28 s (1H), 8.49 s (1H). 13C NMR spectrum,
δC, ppm: 28.5 (1C), 33.0 (1C), 39.1 (1C), 42.3 (1C),
69.1 (1C), 69.7 (1C), 69.9 (1C), 70.2 (1C), 70.3 (1C),
70.4 (1C), 101.1 (1C), 116.5 (1C), 118.8 (1C), 123.5
(1C), 124.5 (1C), 125.1 (1C), 126.0 (1C), 126.1 (1C),
127.4 (1C), 128.1 (1C), 130.5 (1C), 131.2 (1C), 132.3
(1C), 143.4 (1C). Mass spectrum: m/z 396.07 [M]+.
This study was performed under financial support
by the Russian Academy of Sciences (program P-8,
“Development of Methodology of Organic Synthesis
and Design of Compounds with Practically Important
Properties”), and by the Russian Foundation for Basic
Research (project nos. 06-03-32376, 07-03-00619, 08-
03-91308-Ind).
11. Shu, Y., Jones, S.R., Kinney, W.A., and Selinsky, B.S.,
Steroids, 2002, vol. 67, p. 291.
12. Khan, S.N., Bae, S.-Y., and Kim, H.-S., Tetrahedron
Lett., 2005, vol. 46, p. 7675.
13. Golden, R. and Stock, L.M., J. Am. Chem. Soc., 1972,
vol. 94, p. 3080.
14. Ukai, T., Kawazura, H., Ishii, Y., Bonnet, J.J., and
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 12 2009