Synthesis of macrobicyclic compounds containing aza-crown ether fragments and study of their complexation with zinc and cadmium nitrates

Article abstract of DOI:10.1007/s11172-011-0156-1

N-(3,5-Dibromobenzyl) derivatives of 1-aza-15-crown-5 and 1-aza-18-crown-6 were synthesized in high yields and their palladium-catalyzed amination reactions with various linear polyamines were studied. As a result, macrobicyclic compounds were obtained in

Full text of DOI:10.1007/s11172-011-0156-1

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 992—1003, May, 2011
992
Synthesis of macrobicyclic compounds containing azaꢀcrown ether fragments
and study of their complexation with zinc and cadmium nitrates*
M. V. Anokhin,a A. D. Averin,a A. K. Buryak,b and I. P. Beletskayaa,b
aM. V. Lomonosov Moscow State University, Department of Chemistry,
1 build. 3 Leninksie Gory, 119991 Moscow, Russian Federation.
Fax: +7 (495) 939 3618. Eꢀmail: beletska@org.chem.msu.ru
bA. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
34 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 955 4666
Nꢀ(3,5ꢀDibromobenzyl) derivatives of 1ꢀazaꢀ15ꢀcrownꢀ5 and 1ꢀazaꢀ18ꢀcrownꢀ6 were synꢀ
thesized in high yields and their palladiumꢀcatalyzed amination reactions with various linear
polyamines were studied. As a result, macrobicyclic compounds were obtained in yields up to
56%. The complexation of some macrocycles with zinc and cadmium nitrates was studied by
NMR titration.
Key words: macrocycles, amination, homogenous transition metal catalysis, azaꢀcrown
ethers, polyamines, complexation, NMR titration.
Palladiumꢀcatalyzed amination of dihalobenzenes with
polyamines and oxadiamines has been applied successfully
by us for the synthesis of the nitrogenꢀ and oxygenꢀconꢀ
taining macrocycles. As a result, the compounds containꢀ
ing one or two aromatic rings and polyamine fragments
have been prepared.1 Several examples of analogous comꢀ
pounds derived from oꢀ and pꢀphenylenediamines conꢀ
taining two oxadiamine chains are known, which have
been synthesized by nonꢀcatalytic methods.2,3 It has been
shown that these compounds exhibit complexation selecꢀ
tivity towards the PbII ions and, to some extent, the DyIII
ions; at the same time, they bind weakly the alkali metals.
The macrobicyclic compounds containing two azaꢀcrown
ether fragments are of considerable interest due to their
remarkable coordination properties. A convenient synthetic
approach to various biꢀ and polycyclic compounds of this
type, viz., cryptands and supercryptands based on azaꢀ
crown ethers, was first developed by Krakowiak at the
beginning of the 1990s using simple nucleophilic substituꢀ
tion reactions.4—6 The majority of the currently known
bis(azaꢀcrown) ethers contain two isolated macrocyclic
fragments positioned symmetrically relative to the aroꢀ
matic,7,8 metallocene,9 porphyrin,10 or calixarene11 spacers.
They can also serve as a basis for more complex macroꢀ
cycles, among which calixꢀcrown ethers are most comꢀ
mon.12—14 For the design of the metalꢀion sensors, such
fluorophores as coronene,12 perylene,13 anthracene,14 couꢀ
marin,15 and boron dipyrromethene complexes16 are inꢀ
corporated into the molecule, these substituents can be
bound to the azaꢀmacrocycles through linkers or constiꢀ
tute a part of the macrocycle. Bis(azaꢀcrown) ethers have
been studied as the sensors for the NaI, KI, CsI, BaII, AgI,
ZnII, and CdII ions.13,14,16 In the vast majority of studies,
the syntheses of almost all compounds were carried out
using nonꢀcatalytic methods. Palladiumꢀcatalyzed Nꢀarylaꢀ
tion of azaꢀcrown ether was first used by Witulski for the
preparation of the Nꢀanthryl derivative.17 In the present
work, we described the use of the catalytic amination of
the azaꢀcrown ether derivatives for the synthesis of a series
of macrobicyclic compounds with two different macroꢀ
cycles connected through a flexible benzylꢀtype linker,
which allows changing the distance between the ring cavities
for creation of the cooperative effect upon complexation.
Results and Discussion
Reactions of the starting 1ꢀazaꢀ15ꢀcrownꢀ5 (1) and
1ꢀazaꢀ18ꢀcrownꢀ6 (2) with 3,5ꢀdibromobenzylbromide
(1 equiv.) in refluxing acetonitrile in the presence of K2CO3
as a base afforded Nꢀ(3,5ꢀdibromobenzyl) derivatives 3
and 4 in yields of 95 and 90%, respectively (Scheme 1).
These compounds were subjected to the palladiumꢀ
catalyzed amination reaction with several diꢀ and polyꢀ
amines 5a—h, and the corresponding macrobicyclic comꢀ
pounds 6a—h and 7a—h with isolated macrocycles linked
through a short and relatively flexible linker were obtained
(Scheme 2). The reactions were carried out in refluxing
* Dedicated to the 60th anniversary of academician V. N.
Charushin.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 968—979, May, 2011.
1066ꢀ5285/11/6005ꢀ992 © 2011 Springer Science+Business Media, Inc.

Macrobicycles with azaꢀcrown fragments
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
993
Scheme 1
the use of BINAP is preferred due to its better ability to
coordinate zerovalent palladium compared to DavePhos.
On the whole, the reactions of 1ꢀazaꢀ18ꢀcrownꢀ6 deꢀ
rivative 4 with diꢀ and polyamines 5a—h furnished the
corresponding macrobicycles 7a—h in lower yields. For
example, the reaction of 4 with trioxadiamine 5a afforded
macrobicycle 7a in a yield of 30% with BINAP as a ligand
(see Table 1, Entry 13) and 32% with DavePhos (see Table 1,
Entry 14). Similar yield of the target macrobicycle 7d
(27%) was also obtained in the reaction of 4 with decaneꢀ
diamine 5d (see Table 1, Entry 19). The yields of the
macrobicycles with the dioxadiamine linkers were considꢀ
erably lower (see Table 1, Entries 15—18), the use of
BINAP being preferred. Finally, in the reactions of 4 with
triꢀ and tetramines 5c—h, only BINAP provided the forꢀ
mation of the desired products 7c—h and DavePhos was
totally ineffective. The lower yields of macrobicycles 7
compared to 6 can be explained by different abilities of
1ꢀazaꢀ15ꢀcrownꢀ5 and 1ꢀazaꢀ18ꢀcrownꢀ6 to coordinate
the sodium cation, which results in different efficacy of
sodium tertꢀbutoxide in the catalytic amination cycle.
Thus, we demonstrated for the first time the strong depenꢀ
n = 1 (1, 3), 2 (2, 4)
i. K2CO3, MeCN, reflux, 24 h.
dioxane at the equimolar ratio of the reactants (concenꢀ
tration 0.02 mol L–1) for 24 h using Pd(dba)2 as a catalyst
and ButONa as a base. The experimental results are given
in Table 1. It was found that the donor phosphine ligand
DavePhos (2ꢀdicyclohexylphosphinoꢀ2´ꢀdimethylaminoꢀ
biphenyl) is efficient in the reaction of the 1ꢀazaꢀ15ꢀ
crownꢀ5 derivative 3 with diꢀ and triamines 5a—e (see
Table 1, Entries 1—5). The highest yields of macrobicyꢀ
cles were obtained not only in the reaction with the "longꢀ
est" diamines 5a,b,d containing 12—15 atoms in the chain
(see Table 1, Entries 1, 2, and 4), but also with the shorter
dioxadiamine 5c (10 atoms in the chain), the yield being
41% (see Table 1, Entry 3). The yields attained are in
some cases higher than those of macrocyclization upon
catalytic amination of 1,3ꢀdibromobenzene.1 The yield
with triamine 5e decreased to 29% (see Table 1, Entry 5).
In the case of tetramine 5f, the ligand DavePhos was inefꢀ
ficient and we failed to obtain macrobicycle 6f (see Table 1,
Entry 6). However, with BINAP as the phosphine ligand
the corresponding macrobicycle was isolated in 18% yield
(see Table 1, Entry 7). The reaction with longer tetramine
5g proceeded better, both phoshpine ligands providing the
same yield (28%) of compound 6g (see Table 1, Entries 8
and 9). Tetramine 5h was less reactive: the yield of macroꢀ
bicycle 6h was only 8% with DavePhos and 15% with
BINAP (see Table 1, Entries 10 and 11). It is important to
note that BINAP was totally inefficient in the reactions
with diamines where DavePhos resulted in high yields of
macrobicycles (see Table 1, Entry 12). The increase in the
amount of the catalyst up to 16 mol.% did not lead to the
increase in the yield of macrobicycles 6. These facts sugꢀ
gest that in the case of the reactions with tetramines, which
can form more stable chelate complexes than oxadiamines
Table 1. Synthesis of macrobicycles 6a—h and 7a—h
Entry Azaꢀcrown Polyꢀ
Liganda
Product Yieldb
(%)
ether
amine
derivative
1
2
3
4
5
6
7
8
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5a
5b
5c
5d
5e
5f
DavePHOS
DavePHOS
DavePHOS
DavePHOS
DavePHOS
DavePHOS
BINAP
DavePHOS
BINAP
DavePHOS
BINAP
BINAP
BINAP
DavePHOS
BINAP
DavePHOS
BINAP
DavePHOS
BINAP
BINAP
BINAP
DavePHOS
BINAP
DavePHOS
BINAP
DavePHOS
6a
6b
6c
6d
6e
6f
53
56
41
51
29
0
18
28
28
8
5f
6f
5g
5g
5h
5h
5a
5a
5a
5b
5b
5с
5с
5d
5e
5f
6g
6g
6h
6h
6a
7a
7a
7b
7b
7c
7c
7d
7e
7f
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
15
5
30
32
15
12
14
8
27
27
28
0
5f
7f
5g
5g
5h
5h
7g
7g
7h
7h
20
0
16
0
a 8 mol.% Pd(dba)2 and 9 mol.% DavePhos or BINAP were used.
b The yields after chromatography on silica gel.

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Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Anokhin et al.
Scheme 2
n = 1 (3, 6a—h), 2 (4, 7a—h)
i. P(dba)2, BINAP or DavePhos, ButONa, dioxane, reflux, 24 h.
dence of the result of catalytic amination on the nature of
a phosphine ligand in reactions of structurally close startꢀ
ing compounds.
ing salt 9 in 67% yield. This compound was refluxed with
ethanolic KOH for 72 h resulting in Nꢀ(3,5ꢀdibromoꢀ
benzyl)cyclene (10) in 65% yield (over two steps) (Scheme 3).
The cyclene derivative 10 reacted with oxadiamines
5a—c in the presence of the catalytic system Pd(dba)2/
DavePhos (8 or 16 mol.%); however, in this case, the yields
of the target products 11a—c were low (BINAP was totally
ineffective). For example, the reaction of 10 with triꢀ
oxadiamines 5a and 5b afforded macrobicycles 11a and
11b in yields of 13% and 10%, respectively, and comꢀ
pound 11c was isolated in only 2% yield (Scheme 4).
The attempts to perform reactions with tetramines failed;
however, total conversion of the starting cyclene derivaꢀ
tive 10 was observed in all cases.
In the NMR spectra of compounds 6a—e and 7a—e,
many signals are noticeably broadened (the halfꢀheight
1
line width Δν1/2 is up to 100 Hz in the Н NMR spectra
and up to 200 Hz in the 13C NMR spectra). This fact can
be explained by the hindered rotation of the benzyl group
due to the increase in the steric hindrance.
Having studied the possibilities of the synthesis of
macrobicyclic compounds with isolated rings based on
Nꢀ(3,5ꢀdibromobenzyl)azaꢀcrown ethers, we used this reꢀ
action to prepare macrobicycles containing the monosubꢀ
stituted cyclene. Thus, the reaction of cisꢀglyoxalꢀcyclene
8 (see Ref. 18) with 3,5ꢀdibromobenzylbromide (1 equiv.)
in toluene at room temperature afforded the correspondꢀ
Low reactivity of this compound in the amination reacꢀ
tions can be explained by remarkable coordination of zeꢀ

Macrobicycles with azaꢀcrown fragments
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
995
Scheme 3
on the course of complexation, we first titrated the startꢀ
ing azaꢀcrown ethers 1 and 2 with these metal salts. The
signals for the CH2N groups in both the starting azaꢀcrown
ethers 1 and 2 and their macrobicyclic derivatives 6а and
7а were most convenient for monitoring the complexation
process, since these signals do not overlap with the signals
for other groups and their chemical shifts depend strongly
on the amount of the metal salt added.
Titration of 1ꢀazaꢀ15ꢀcrownꢀ5 (1) showed that a reguꢀ
lar downfield shift of the signal for the CH2N groups from
δ 2.73 to δ 3.00 and 3.18, respectively, occured upon addiꢀ
tion of 0.25 and 0.5 equiv. of zinc nitrate, which was acꢀ
companied by broadening of the muliplet (Fig. 1, a, b),
and the signal was split into three broadened singlets of
unequal intensities at δ 2.81, 3.12, and 3.24 upon addition
of 0.75 equiv. of zinc nitrate (Fig. 1, c). Upon subsequent
addition of the metal salt, the chemical shifts of these
signals did not change (Fig. 1, d); however, the intensity
ratio changed slightly: the signal at δ 3.24 became less
intensive and the intensities of the signals at δ 2.82 and
3.12 increased, the latter having always equal intensities.
Upon heating the solution to 55 °C, these signals coaꢀ
lesced into a broadened singlet at δ 3.19 (Fig. 1, e). The
aboveꢀmentioned changes are represented graphically in
Fig. 2, a. The results obtained allow one to assume that
two different complexes are in equilibrium in a solution,
which is sufficiently slow on the NMR time scale at room
temperature, since both forms of the ligand in these comꢀ
plexes are observed simultaneously, but the signals are
noticeably broadened, and, with the increase in the temꢀ
perature, the exchange rate increases and only one avꢀ
eraged form is observed. The stoichiometry of these
two complexes must be different, since the average
ligand : metal ratio, at which the signals achieve plateau,
is about 1 : 0.75, which suggests the presence of the
ligand—metal complexes of the composition 1 : 1 and 2 : 1.
The chemical shifts for two CH2N protons in one of the
complexes, presumably of the composition 1 : 1, differ
strongly (by 0.3 ppm), which can be explained by the stagꢀ
gered conformation of the OCH2CH2N fragment due to
the coordination of the zinc ion to one azaꢀcrown ether.
In the second complex, presumably of the composiꢀ
tion 2 : 1, such an effect is not pronounced clearly, which
is apparently due to a less rigid fixation of the macrocycle
conformation in the sandwichꢀlike complex.
i. PhMe, 20 °C, 24 h; ii. KOH, EtOH, reflux, 72 h.
Scheme 4
i. Pd(dba)2, DavePhos, ButONa, dioxane, reflux, 24 h.
X = (CH2OCH2)3 (a), CH2O(CH2)4OCH2 (b), O(CH2)2O (c)
rovalent palladium to tetraazamacrocycle, whereby it is
removed from the catalytic amination cycle, other reacꢀ
tions, where the starting dibromoderivative 10 is conꢀ
sumed, beginning to play a leading role.
We performed preliminary studies of the coordination
properties of macrobicycles 6a and 7a by NMR titration
(1Н) with zinc and cadmium nitrates in CD3OD. In order
to compare the coordination properties of the starting azaꢀ
crown ether and macrobicyclic ligands prepared by us and
to reveal the influence of the second attached macrocycle
Another pattern was observed during titration of azaꢀ
crown ether 1 with cadmium nitrate: the signal for the
CH2N group was downfield shifted (from δ 2.73 to δ 2.98,
Fig. 3, a, b) upon slow addition of the metal salt up to
0.75 equiv. and split into two broadened singlets of equal
intensities at δ 2.90 and 3.11 upon addition of 1 equiv. of
cadmium nitrate (Fig. 3, с). The spectral pattern did not
change upon increase in the amount of cadmium nitrate
added and these signals coalesced into one broadened sinꢀ
glet at δ 3.03 upon heating to 55 °C (Fig. 3, d).

996
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
a
Anokhin et al.
δ
a
3.2
3.1
3.0
2.9
2.8
CH2N
(2.73)
*
4.0
4.0
3.5
3.5
3.0
δ
δ
b
c
CH2N
(3.18)
*
0
0.25 0.50 0.75 1.00 1.25 1.50 N/equiv.
δ
b
3.0
3.1
3.0
2.9
2.8
2.7
*
CH2N
(3.24) (3.12) (2.81)
4.0
3.5
3.0
δ
0
0.25 0.50 0.75 1.00 1.25 1.50 N/equiv.
*
d
Fig. 2. Changes in the chemical shifts of the CH2N protons in
the 1H NMR spectrum of 1ꢀazaꢀ15ꢀcrownꢀ5 (1) during titration
with zinc nitrate (a) and cadmium nitrate (b). Here and in
Figs 4, 5, and 7, N is the number of equivalents of the corresꢀ
ponding salt added during NMR titration.
CH2N
(3.24) (3.12) (2.82)
4.0
4.0
3.5
3.5
3.0
δ
δ
subsequent addition of zinc nitrate, there were no changes
in the spectrum, which suggests the formation of the
ligand—metal complex of the composition 2 : 1 (Fig. 4, a).
One can assume that not all the oxygen atoms of azaꢀ
crown ether are involved in coordiation of the zinc ion due
to unfavorable geometric factors; therefore, the remaining
coordination vacancies are occupied by the nitrogen and
oxygen atoms from the second macrocycle thereby creatꢀ
ing the sandwichꢀlike structure.
Upon addition of cadmium nitrate to a solution of
azaꢀcrown ether 2, the downfield shift of the signal for the
CH2N group was observed up to the addition of 1 equiv. of
the salt, whereafter no shift was observed, which suggests
the formation of the 1 : 1 complex (Fig. 4, b). The absence
of splitting of the signal for the methylene protons in this
case can indicate the conformation of the macrocycle in
the complex that is less rigidly fixed by the metal. Thus,
both azaꢀcrown ethers 1 and 2 afford the 1 : 1 complexes
with cadmium nitrate, while the formation of more comꢀ
plex structures is observed in both cases upon coordinaꢀ
tion of the zinc ion.
e
CH2N
(3.19)
*
3.0
Fig. 1. The 1H NMR spectra of 1ꢀazaꢀ15ꢀcrownꢀ5 (1) in CD3OD
before (a) and after addition of 0.5 (b), 0.75 (c) and 1 equiv. of
Zn(NO3)2 (d) at 20 °C, as well as after heating with Zn(NO3)2
(1 equiv.) to 55 °C (e). Here and in Figs 3 and 6, the signal for the
residual proton of the solvent is marked with an asterisk.
The aboveꢀmentioned changes are graphically presentꢀ
ed in Fig. 2, b. From the titrimetric data, one can conꢀ
clude that in this case the ligand—metal complex of the
composition 1 : 1 formed, wherein, as in the case of one of
the complexes of azaꢀcrown ether 1 with zinc nitrate, the
conformation mobility of the OCH2CH2N fragment is reꢀ
stricted due to roomꢀtemperature coordination of the zinc
ion and, for this reason, the chemical shifts of two CH2N
protons differ by 0.21 ppm.
Titration of macrobicycle 6а with zinc nitrate is also
characterized by the downfield shift of the signal for the
CH2N group of the azaꢀcrown ether ring (Fig. 5), altough
the dependence of the chemical shift on the amount of the
salt added is not so much pronounced in this case as in the
Titration of 1ꢀazaꢀ18ꢀcrownꢀ6 (2) with zinc nitrate
resulted in the downfield shift of the signals for the CH2N
group upon addition of 0.5 equiv. of the salt and, with

Macrobicycles with azaꢀcrown fragments
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
997
δ
a
a
3.2
3.0
2.8
2.6
CH2N
(2.73)
*
4.0
3.5
3.0
δ
0
0.5
1.0
1.5 N/equiv.
b
δ
b
*
CH2N
(2.98)
3.0
2.9
2.8
4.0
3.5
3.0
δ
c
0
0.5
1.0
1.5
N/equiv.
*
CH2N
(3.11) (2.90)
Fig. 4. Changes in the chemical shifts of the CH2N protons in
the 1H NMR spectrum of 1ꢀazaꢀ18ꢀcrownꢀ6 (2) during titration
with zinc nitrate (a) and cadmium nitrate (b).
4.0
3.5
3.0
δ
δ
a
2
1
d
4.1
3.7
3.3
2.9
CH2N
(3.03)
*
4.0
3.5
3.0
δ
Fig. 3. The 1H NMR spectra of 1ꢀazaꢀ15ꢀcrownꢀ5 (1) in CD3OD
before (a) and after addition of 0.75 (b) and 1 equiv. of Cd(NO3)2 (c)
at 20 °C, as well as after heating with Cd(NO3)2 (1 equiv.)
to 55 °C (d).
0
0.25 0.50 0.75 1.00 1.25 1.50
N/equiv.
δ
b
case of the starting azaꢀcrown ether 1. We observed also
the downfield shift of the NH protons, which evidences in
favor of involvement of the second macrocycle in coordiꢀ
nation to the zinc ion. Most likely, the second macrocycle
coordinates the zinc ion through the oxygen atoms of the
trioxadiamine chain, and through these atoms the effect
of coordination is transferred to the NH protons. The data
obtained evidence the formation of the 1 : 1 complex, alꢀ
though the values of chemical shifts do not achieve the
plateau, which is evidently due to a lower stability of the
complex compared to that of azaꢀcrown ether 1. Thus,
with regard to the coordination properties towards the
zinc ions, macrobicycle 6а differs considerably from 1ꢀazaꢀ
15ꢀcrownꢀ5 (1) due to the involvement of the second macꢀ
3.1
3.0
2.9
0
0.25 0.50
0.75 1.00
1.25 N/equiv.
Fig. 5. Changes in the chemical shifts of the CH2N (1) and
NH (2) protons in the 1H NMR spectrum during titration of
macrobicycle 6a with zinc nitrate (a) and the CH2N protons
during titration with cadmium nitrate (b).

998
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Anokhin et al.
rocycle in coordination, which results in the formation of
only one complex in a solution.
In the case of macrobicycle 7а, titration with zinc
nitrate (Fig. 7, a) occured in a similar way as titration
of macrobicycle 6а and resulted in the formation of the
1 : 1 complex. In this case, owing to the fact that the sigꢀ
nals for the NH protons are considerably shifted downꢀ
field, one may also conclude that the second attached
macrocycle is involved in complexation through the
oxygen atoms. Since the chemical shifts of the CH2N
and NH protons do not achieve completely the plateau
at the ratio metal : ligand = 1 : 1, the complex that formed
is less stable than the complex of the starting 1ꢀazaꢀ18ꢀ
crownꢀ6 (2).
The result of titration of macrobicycle 7а with cadmiꢀ
um nitrate (Fig. 7, b) differed from that for macrobicycle
6а, since, in the case of 7a, there was a distinct inflexion
point corresponding to addition of 1 equiv. of Cd(NO3)2,
although the value of ΔδH (0.04) was much smaller than in
all other experiments, where it changed from 0.30 to 0.51.
There were also no changes in the chemical shifts of the
NH protons, which is evidence of the fact that in this case
the cadmium ion is coordinated only by the 1ꢀazaꢀ18ꢀ
crownꢀ6 fragment and the second attached macrocycle is
not involved in coordination to the metal. Finally, the
absence of splitting of the signals for the methylene proꢀ
tons in this case is very similar to the effect observed upon
Titration of macrobicycle 6а with cadmium nitrate (see
Fig. 5, b) suggests the formation of the ligand—metal comꢀ
plex of the composition 2 : 1. The downfield shift of the
CH2N protons from δ 2.87 to δ 2.94 was observed upon
addition of 0.25 equiv. of the salt (Fig. 6, a, b) and the
signal was split into two broadened singlets of equlal intenꢀ
sities at δ 3.16 and 2.82 upon addition of 0.5 equiv. of
cadmium nitrate (Fig. 6, c). Subsequent addition of the
salt (Fig. 6, d) caused no changes in the spectrum, which
allows conclusion on the formation of the ligand—metal
complex of the composition 2 : 1. In addition, the absence
of the shift of the signals for the NH protons evidences that
the second attached macrocycle is not involved in compꢀ
lexation with the cadmium ion. This is quite unexpected,
since the starting 1ꢀazaꢀ15ꢀcrownꢀ5 (1) formed the 1 : 1
complex with cadmium nitrate. In this case, probably due to
the changes in the conformation of azaꢀcrown ether induced
by the macrocyclic substituent at the nitrogen atom, the
cadmium ion is coordinated by not all the donor atoms of
azaꢀcrown ether, which results in the formation of the
sandwichꢀlike structure involving the second azaꢀcrown
ether fragment. However, splitting of the signal for the
methylene protons suggests the rigidly fixed conformation
of the macrocycle in the complex as it was upon coordinaꢀ
tion of the starting azaꢀcrown ether 1 to cadmium nitrate.
δ
a
2
1
a
4.1
3.7
3.3
2.9
CH2N
(2.87)
*
4.0
3.5
3.0
2.5
2.0
δ
b
0
0.25
0.50
0.75
1.00
N/equiv.
δ
CH2N
(2.94)
b
*
2.87
2.85
2.83
4.0
3.5
3.0
2.5
2.0
δ
c
*
CH2N
(3.16) (2.82)
0
0.25
0.50 0.75
1.00 1.25 N/equiv.
4.0
3.5
3.0
2.5
2.0
δ
Fig. 7. Changes in the chemical shifts of the CH2N (1) and
NH (2) protons in the 1H NMR spectrum of macrobicycle 7a
during titration with zinc nitrate (a) and the CH2N protons durꢀ
ing titration with cadmium nitrate (b).
Fig. 6. The 1H NMR spectra of macrobicycle 6a in CD3OD
before (a) and after addition of 0.25 (b) and 0.5 equiv. of
Cd(NO3)2 (c) at 20 °C.

Macrobicycles with azaꢀcrown fragments
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
999
were placed in a flask equipped with a reflux condenser and the
reaction mixture was magnetically stirred under reflux for 24 h.
After cooling to room temperature, the precipitate that formed
was filtered off, the solvent was evaporated in vacuo, and the oily
residue was dissolved in dichloromethane (10 mL), washed with
water (10 mL), the organic phase was dried with magnesium
sulfate, and the solvent was evaporated in vacuo to yield product
3 as an oily pale yellow substance. The yield was 1.33 g (95%).
1Н NMR (CDCl3), δ: 2.75 (t, 4 H, CH2CH2N, J = 5.9 Hz); 3.61
(t, 4 H, CH2О, J = 6.5 Hz); 3.61—3.64 (m, 6 H, CH2О,
ArCH2N); 3.67 (s, 4 H, CH2О); 3.66—3.69 (m, 4 H, CH2О);
7.44 (d, 2 H, Н(2), Н(6), J = 1.4 Hz); 7.50 (t, 1 H, Н(4),
J = 1.4). 13C NMR (CDCl3), δ: 54.4 (2 C, CH2CH2N); 59.6
(1 C, ArCH2N); 69.8 (2 C, CH2О); 70.2 (2 C, CH2О); 70.5 (2 C,
CH2О); 71.0 (2 C, CH2О); 122.7 (2 C, C(3), C(5)); 130.3 (2 C,
C(2), C(6)); 132.4 (1 C, C(4)); 144.3 (1 C, C(1)). MS (MALDI),
m/z: [M]+, found 465.0146, calculated 465.0150. C17H25Br2NO4.
16ꢀ(3,5ꢀDibromobenzyl)ꢀ1,4,7,10,13ꢀpentaoxaꢀ16ꢀazacycloꢀ
octadecane (4). Anhydrous acetonitrile (10 mL), 1ꢀazaꢀ18ꢀ
crownꢀ6 (2) (1 g, 3.8 mmol), 3,5ꢀdibromobenzyl bromide (1.44 g,
3.8 mmol), and potassium carbonate (1.44 g, 10.4 mmol) were
placed in a flask equipped with a reflux condenser and the reacꢀ
tion mixture was magnetically stirred under reflux for 24 h. After
cooling to room temperature, the precipitate that formed was
filtered off, the solvent was evaporated in vacuo, and the oily
residue was dissolved in dichloromethane (10 mL), washed with
water (10 mL), the organic phase was dried with magnesium
sulfate, and the solvent was evaporated in vacuo to yield product
4 as an oily pale yellow substance. The yield was 1.75 g (90%).
1Н NMR (CDCl3), δ: 2.73 (t, 4 H, CH2CH2N, J = 5.2 Hz);
3.50—3.60 (m, 16 H, CH2О); 3.61 (s, 4 H, CH2O); 3.63 (s, 2 H,
ArCH2N); 7.30 (br.s, 2 H, Н(2), Н(6)); 7.46 (t, 1 H, Н(4),
J = 1.5 Hz). 13C NMR (CDCl3), δ: 54.4 (2 C, CH2CH2N); 56.5
(1 C, ArCH2N, Δν1/2 = 15 Hz); 68.3 (2 C, CH2O, Δν1/2 = 10 Hz);
69.9 (2 C, CH2O); 70.0 (2 C, CH2O); 70.1 (2 C, CH2O); 70.2
(2 C, CH2O); 122.6 (2 C, C(3), C(5)); 130.4 (2 C, C(2), C(6));
132.3 (1 C, C(4)); 143.1 (1 C, C(1)). MS (MALDI), m/z: [M]+,
found 509.0429, calculated 509.0412. C19H29Br2NO5.
complexation of the starting azaꢀcrown ether 2 with cadꢀ
mium nitrate.
Thus, in the present study, we developed an efficient
method for the synthesis of macrobicyclic compounds conꢀ
taining two structurally different fragments of azaꢀcrown
ethers using palladiumꢀcatalyzed amination. We also
showed the possibility of variation in the size of the second
attached macrocycle and the amount of the nitrogen and
oxygen atoms therein and established the dependence of
the yields of the target macrobicycles on the nature of the
starting compounds. It was shown that this approach has
restrictions with regard to the use of analogous derivatives
of tetraazamacrocycles. The coordination properties of the
starting azaꢀcrown ethers and two representatives of novel
macrobicycles were studied by NMR titration, which
showed that 1ꢀazaꢀ15ꢀcrownꢀ5 (1) forms the ligand—metal
complexes of the composition 1 : 1 and 2 : 1 with zinc
nitrate and the 1 : 1 complex with cadmium nitrate and
1ꢀazaꢀ18ꢀcrownꢀ6 (2) affords the 2 : 1 complex with the
zinc ion and the 1 : 1 complex with the cadmium ion.
Macrobicycles 6a and 7a form the 1 : 1 ligand—metal comꢀ
plexes with the zinc ions, macrobicycle 6a forms the 2 : 1
ligandꢀmetal complex with the cadmium ion, and comꢀ
pound 7a forms the 1 : 1 complex with the cadmium ion,
two macrocycles being involved in complexation upon
coordination to the zinc ions and only the fragments of
the starting azaꢀcrown ethers being involved in complexꢀ
ation upon coordination to the cadmium ions.
Experimental
1
Н and 13C NMR spectra were recorded at 298 K on a Bruker
Avanceꢀ400 (400 and 100 МHz, respectively) spectrometer. The
1
chemical shifts in the Н and 13C NMR spectra are given in the
δ scale relative to Me4Si (internal standard). MALDI—TOF mass
spectra were obtained on a Bruker Ultraflex instrument in the
positive ion mode using 1,8,9ꢀtrihydroxyanthracene as a matrix
and poly(ethylene glycols) as the internal standards. The starting
azaꢀcrown ethers 1 and 2, 3,5ꢀdibromobenzyl bromide, diꢀ and
polyamines 5a—h, the phosphine ligands BINAP and DavePhos
(Aldrich or Acros) were used without additional purification.
cisꢀGlyoxalꢀcyclene 8 was synthesized from cyclene according
to the known procedure;18 Pd(dba)2 was synthesized accoding to
the published procedure.19 Dioxane was distilled over alkali and
metallic sodium, acetonitrile was distilled over calcium hydride,
dichloromethane and methanol were distilled.
NMR titration was performed as follows: a solution of azaꢀ
crown ether 1, 2 or macrobicycles 6a, 7a (50 μmol) in CD3OD
(0.5 mL, c = 0.1 mol L–1) was placed in an NMR tube, a solution
of hexaqua zinc nitrate or tetraaqua cadmium nitrate in CD3OD
(c = 0.2 mol L–1) was added at the interval of 12.5 μmol (63 μL
of a solution), the mixture was thoroughly stirred, and then
1Н NMR spectra were recorded.
Synthesis of macrobicycles 6 and 7 (general procedure). Azaꢀ
crown ether derivative 3 or 4 (0.25 mmol, 116 mg or 128 mg,
respectively), dry dioxane (12 mL), Pd(dba)2 (12 mg, 8 mol.%),
and BINAP or DavePhos (14 mg or 9 mg, respectively, 9 mol.%)
were placed in a twoꢀnecked flask flushed with dry argon and
equipped with a reflux condenser. The reaction mixture was
magnetically stirred for 2 min, the corresponding polyamine
5a—h (0.25 mmol) and sodium tertꢀbutoxide (72 mg, 0.75 mmol)
were added, and the mixture was refluxed for 24 h. The reaction
mixture was cooled to room temperature, the precipitate that
formed was filtered off, and dioxane was evaporated in vacuo.
The residue was chromatographed on silica gel using the following
elution with CH2Cl2, CH2Cl2—MeOH (from 50 : 1 to 3 : 1),
CH2Cl2—MeOH—NH3 (from 100 : 20 : 1 to 10 : 4 : 1). The
target macrobicycles were obtained as viscous oily pale yellow or
pale beige compounds vitrifying on standing. Numbering of the
atoms of the benzene ring in the 1Н and 13C NMR spectra of
compounds 6 and 7 is shown in Scheme 2.
19ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
6,9,12ꢀtrioxaꢀ2,16ꢀdiazabicyclo[15.3.1]enicosaꢀ1(21),17,19ꢀ
triene (6a) was synthesized from trioxadiamine 5а (55 mg) in the
presence of DavePhos (9 mg, 9 mol.% or 18 mg, 18 mol.%).
Since the spectra of both reaction mixtures were identical, the
13ꢀ(3,5ꢀDibromobenzyl)ꢀ1,4,7,10ꢀtetraoxaꢀ13ꢀazacycloꢀ
pentadecane (3). Anhydrous acetonitrile (10 mL), 1ꢀazaꢀ15ꢀ
crownꢀ5 (1) (657 mg, 3 mmol), 3,5ꢀdibromobenzyl bromide
(1 g, 3.04 mmol), and potassium carbonate (1.06 г, 7.68 mmol)

1000
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Anokhin et al.
latter were combined and chromatographed (CH2Cl2—MeOH,
10 : 1). The total yield was 140 mg (53%). 1Н NMR (CDCl3), δ:
1.77 (qu, 4 Н, CH2CH2CH2, J = 5.6 Hz); 2.93 (br.s, 4 H,
CH2CH2N, Δν1/2 = 30 Hz); 3.24 (t, 4 Н, CН2NAr, J = 6.3 Hz);
3.53 (t, 4 Н, CH2O, J = 5.2 Hz); 3.55—3.67 (m, 26 H, CH2O,
ArCH2N); 5.97 (br.s, 2 H, Н(2), Н(6)); 6.05 (br.s, 1 H, H(4))
(no signals for the NH protons were observed). 13C NMR
(CDCl3), δ: 29.5 (2 C, CH2CH2CH2); 41.7 (2 C, CH2NAr);
54.1 (2 C, CH2CH2N); 60.1 (1 C, ArCH2N); 67.2 (2 C, CH2O,
Δν = 10 Hz); 69.3 (2 C, CH2O, Δν = 10 Hz); 69.4 (2 C,
CH2NHAr); 54.3 (2 C, CH2CH2N); 60.5 (1 C, ArCH2N); 69.0
(2 C, CH2O, Δν
= 25 Hz); 70.1 (2 C, CH2O); 70.2 (2 C,
1/2
CH2O); 70.6 (2 C, CH2O); 93.5 (1 C, C(4)); 105.3 (2 C, C(2),
C(6)); 145.1 (1 C, C(1)); 150.0 (2 C, C(3), C(5)). MS (MALDI),
m/z: [M + Н]+, found 478.25, calculated 478.36. C27H48N3O4.
13ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
2,6,10ꢀtriazabicyclo[9.3.1]pentadecaꢀ1(15),11,13ꢀtriene (6e)
was synthesized from triamine 5e (33 mg). The eluent was
CH2Cl2—MeOH—NH3 (100 : 20 : 3). The yield was 32 mg
(29%). 1Н NMR (CDCl3), δ: 1.62 (br.s, 4 H, CH2CH2CH2,
Δν = 15 Hz); 2.67 (br.s, 4 H, CH2CH2CH2, Δν = 15 Hz);
1/2
1/2
CH2O); 69.5 (2 C, CH2O, Δν = 10 Hz); 69.6 (2 C, CH2O,
1/2
1/2
1/2
Δν1/2 = 10 Hz); 69.9 (2 C, CH2O); 70.7 (2 C, CH2O); 95.9 (1 C,
C(4)); 103.6 (2 C, C(2), C(6)); 128.1 (1 C, C(1), Δν1/2 = 20 Hz);
150.4 (2 C, C(3), C(5)). MS (MALDI), m/z: [M]+, found
525.3334, calculated 525.3414. C27H47N3O7.
2.79 (br.s, 4 H, CH2CH2N Δν
= 50 Hz); 3.42 (br.s, 4 H,
1/2
CH2NAr, Δν1/2 = 50 Hz); 3.50—3.70 (m, 18 H, CH2O, ArCH2N);
5.98 (br.s, 2 H, Н(2), Н(6)); 7.05 (br.s, 1 H, Н(4), Δν1/2 = 30 Hz)
(no signals for the NH protons were observed). 13C NMR
(CDCl3), δ: 30.1 (2 C, CH2CH2CH2, Δν1/2 = 10 Hz); 39.6 (2 C,
18ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
6,11ꢀdioxaꢀ2,15ꢀdiazabicyclo[14.3.1]icosaꢀ1(20),16,18ꢀtriene
(6b) was synthesized from dioxadiamine 5b (51 mg). The eluent
was CH2Cl2—MeOH (10 : 1). The yield was 71 mg (56%).
1Н NMR (CDCl3), δ: 1.73—1.77 (m, 4 H, CH2CH2CH2CH2);
1.80 (qu, 4 H, CH2CH2CH2, J = 5.3 Hz); 2.74 (br.s, 4 H,
CH2CH2N, Δν1/2 = 50 Hz); 3.23 (t, 4 H, CH2NAr, J = 6.1 Hz);
3.38—3.43 (m, 4 H, CН2О); 3.50 (t, 4 H, CН2О, J = 5.0 Hz);
3.56—3.62 (m, 6 H, CН2О, ArCH2N); 3.64—3.74 (m, 12 H,
CН2О); 6.01 (br.s, 2 H, Н(2), Н(6)); 6.05 (br.s, 1 H, Н(4))
(no signals for the NH protons were observed). 13C NMR (CDCl3),
δ: 26.5 (2 C, CH2CH2CH2CH2); 30.0 (2 C, CH2CH2CH2); 42.3
CH2NAr, Δν = 10 Hz); 45.9 (2 C, CH2CH2CH2); 54.0 (2 C,
1/2
CH2CH2N, Δν = 15 Hz); 60.7 (1 C, ArCH2N); 69.2 (2 C,
1/2
CН2О); 70.1 (6 C, CН2О Δν
= 90 Hz); 94.8 (1 C, C(4),
1/2
Δν1/2 = 20 Hz); 103.6 (2 C, C(2), C(6)); 149.9 (2 C, C(3), C(5))
(the signal for one quarternary aromatic carbon atom was not
observed). MS (MALDI), m/z: [M + Н]+, found 437.30, calcuꢀ
lated 437.31. C23H40N4O4.
15ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
2,5,9,12ꢀtetraazabicyclo[11.3.1]heptadecaꢀ1(17),13,15ꢀtriene
(6f) was synthesized from tetramine 5f (40 mg). The eluent was
CH2Cl2—MeOH—NH3 (100 : 25 : 3). The yield was 21 mg
(18%). 1Н NMR (CDCl3), δ: 1.70 (br.s, 2 Н, CH2CH2CH2);
2.72 (t, 4 Н, CH2CH2N, J = 5.2 Hz); 2.78—2.87 (m, 8 Н,
CH2CH2N); 3.46 (t, 4 Н, CH2NAr, J = 4.6 Hz); 3.55—3.67
(m, 18 Н, CH2O, ArCH2N); 6.02 (br.s, 2 Н, Н(2), Н(6)); 6.15
(br.s, 1 Н, Н(4)) (no signals for the NH protons were observed).
13C NMR (CDCl3), δ: 24.9 (1 C, CH2CH2CH2); 42.2 (2 C,
CH2NAr); 48.8 (2 C, CH2CH2NН); 49.9 (2 C, CH2CH2NН);
54.7 (2 C, CH2CH2N); 60.6 (1 C, ArCH2N); 69.4 (2 C, CН2О);
69.8 (2 C, CН2О); 70.1 (2 C, CН2О); 70.6 (2 C, CН2О); 94.3
(1 C, C(4)); 105.0 (2 C, C(2), C(6)); 148.8 (2 C, C(3), C(5)) (the
signal for one quarternary aromatic carbon atom was not obꢀ
served). MS (MALDI), m/z: [M + Н]+, found 466.3445, calcuꢀ
lated 466.3393. C24H44N5O4.
17ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
2,6,10,14ꢀtetraazabicyclo[13.3.1]nonadecaꢀ1(19),15,17ꢀtriene
(6g) was synthesized from tetramine 5g (44 mg). The eluent was
CH2Cl2—MeOH—NH3 (100 : 25 : 5). The yield was 33 mg
(28%). 1Н NMR (CDCl3), δ: 1.68 (qu, 4 Н, CH2CH2CH2,
J = 5.4 Hz); 2.67 (t, 4 Н, CH2CH2CH2NH, J = 5.6 Hz); 2.68
(s, 4 H, NHCH2CH2NH); 2.74 (t, 4 Н, CH2CH2N, J = 5.5 Hz);
3.32 (t, 4 Н, CH2NAr, J = 6.2 Hz); 3.58—3.67 (m, 14 H, CH2O,
ArCH2N); 3.65 (s, 4 H, CH2O); 4.88 (br.s, 2 H, NHAr); 5.93
(br.s, 2 H, Н(2), Н(6)); 6.13 (br.s, 1 H, Н(4)) (the signals for two
NH protons were not observed). 13C NMR (CDCl3), δ: 31.5
(2 C, CH2CH2CH2); 41.3 (2 C, CH2NAr); 46.0 (2 C, CН2NH);
49.1 (2 C, CН2NH); 54.5 (2 C, CH2CH2N); 60.8 (1 C, ArCH2N);
69.7 (2 C, CH2O); 70.0 (2 C, CH2O); 70.2 (2 C, CH2O); 70.7
(2 C, CH2O); 93.0 (1 C, C(4)); 104.5 (2 C, C(2), C(6)); 141.1 (1 C,
C(1)); 150.4 (2 C, C(3), C(5)). MS (MALDI), m/z: [M + Н]+,
found 479.3407, calculated 479.3472. C23H40N4O4.
(2 C, CH2NAr); 54.5 (2 C, CH2CH2N, Δν = 30 Hz); 60.2
1/2
(1 C, ArCH2N, Δν1/2 = 40 Hz); 67.2 (2 C, CН2О, Δν1/2 = 20 Hz);
69.1 (6 C, CН2О, Δν1/2 = 60 Hz); 69.9 (4 C, CН2О); 95.4 (1 C,
C(4), Δν1/2 = 30 Hz); 103.4 (2 C, C(2), C(6)); 130.3 (1 C, C(1),
Δν
= 20 Hz); 150.6 (2 C, C(3), C(5)). MS (MALDI), m/z:
1/2
[M]+, found 509.3440, calculated 509.3465. C27H47N3O6.
14ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
5,8ꢀdioxaꢀ2,11ꢀdiazabicyclo[10.3.1]hexadecaꢀ1(16),12,14ꢀtriꢀ
ene (6c) was synthesized from dioxadiamine 5c (37 mg). The
eluent was CH2Cl2—MeOH (3 : 1). The yield was 47 mg (41%).
1Н NMR (CDCl3), δ: 2.73 (br.s, 4 H, CH2CH2N, Δν1/2 = 60 Hz);
3.37 (t, 4 Н, CH2NAr, J = 4.9 Hz); 3.56—3.63 (m, 14 Н, CH2O,
ArCH2N); 3.65—3.75 (m, 12 H, CH2O); 6.15 (br.s, 2 H, Н(2),
Н(6)); 6.86 (br.s, 1 H, Н(4)) (no signals for the NH protons were
observed). 13C NMR (CDCl3), δ: 45.1 (2 C, CH2NAr); 54.7
(2 C, CH2CH2N, Δν = 30 Hz); 60.5 (1 C, ArCH2N, Δν
=
1/2
1/2
= 200 Hz); 67.1 (2 C, CH2O, Δν1/2 = 30 Hz); 68.8—69.6 (m, 6 C,
CH2O); 70.2 (2 C, CH2O); 72.0 (2 C, CH2O); 98.8 (1 C, C(4));
106.2 (2 C, C(2), C(6)); 149.7 (2 C, C(3), C(5)) (the signal for
one quarternary aromatic carbon atom was not observed). MS
(MALDI), m/z: [M]+, found 453.2827, calculated 453.2839.
C23H39N3O6.
16ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
2,13ꢀdiazabicyclo[12.3.1]octadecaꢀ1(18),14,16ꢀtriene (6d) was
synthesized from diamine 5d (43 mg). Elution was carried out
with CH2Cl2—MeOH (3 : 1) and CH2Cl2—MeOH—NH3 (100 :
1
20 : 1). The yield was 61 mg (51%). Н NMR (CDCl3), δ: 1.33
(br.s, 4 Н, CH2CH2CH2CH2); 1.38 (br.s, 4 Н, CH2CH2CH2CH2);
1.60 (qu, 4 Н, CH2CH2NHAr, J = 7.0 Hz); 2.88 (br.s, 4 Н,
CH2CH2N), 3.14 (t, 4 Н, CH2NHAr, J = 7.6 Hz); 3.61—3.67
(m, 18 Н, CH2O, ArCH2N); 4.54 (br.s, 2 Н, NH); 5.91 (br.s, 1 Н,
Н(4)); 5.97 (br.s, 2 Н, Н(2), Н(6)). 13C NMR (CDCl3), δ: 24.5
(2 C, CH2CH2CH2CH2); 26.5 (2 C, CH2CH2CH2CH2); 26.6
(2 C, CH2CH2CH2CH2); 28.0 (2 C, CH2CH2NHAr); 44.1 (2 C,
17ꢀ(1,4,7,10ꢀTetraoxaꢀ13ꢀazacyclopentadecꢀ13ꢀylmethyl)ꢀ
2,6,10,14ꢀtetraazabicyclo[13.3.1]nonadecaꢀ1(19),15,17ꢀtriene
(6h) was synthesized from tetramine 5h (47 mg). The eluent was
CH2Cl2—MeOH—NH3 (10 : 4 : 1). The yield was 19 mg (15%).

Macrobicycles with azaꢀcrown fragments
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
1001
1Н NMR (CDCl3), δ: 1.75 (br.s, 6 Н, CH2CH2CH2); 2.73 (t, 4 Н,
CH2CH2N, J = 5.5 Hz); 2.75 (t, 4 Н, CH2CH2N, J = 6.0 Hz);
2.78 (t, 4 Н, CH2CH2N, J = 5.6 Hz); 3.28 (t, 4 Н, CH2NAr,
J = 7.2 Hz); 3.57—3.66 (m, 18 Н, CH2O, ArCH2N); 5.94 (br.s, 3 Н,
Н(2), Н(4), Н(6)) (no signals for the NH protons were observed).
13C NMR (CDCl3), δ: 27.7 (1 C, CH2CH2CH2); 29.0 (2 C,
CH2CH2CH2); 42.2 (2 C, CH2NAr); 47.2 (2 C, CH2CH2NН);
49.5 (2 C, CH2CH2NН); 54.5 (2 C, CH2CH2N); 60.9 (1 C,
ArCH2N); 69.7 (2 C, CH2O); 70.0 (2 C, CH2O); 70.3 (2 C,
CH2O); 70.8 (2 C, CH2O); 93.9 (1 C, C(4)); 104.2 (2 C, C(2),
C(6)); 141.2 (1 C, C(1)); 149.2 (2 C, C(3), C(5)). MS (MALDI),
m/z: [M + Н]+, found 494.3681, calculated 494.3706. C26H48N5O4.
19ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethyl)ꢀ
6,9,12ꢀtrioxaꢀ2,16ꢀdiazabicyclo[15.3.1]enicosaꢀ1(21),17,19ꢀ
triene (7a) was synthesized from trioxadiamine 5а (55 mg) in the
presence of DavePhos (9 mg, 9 mol.% or 18 mg, 18 mol.%).
Since the spectra of the reaction mixtures were identical, the
latter were combined and chromatographed. The eluent was
CH2Cl2—MeOH (10 : 1). The total yield was 90 mg (32%).
1Н NMR (CDCl3), δ: 1.77 (qu, 4 Н, CH2CH2CH2, J = 5.2 Hz);
= 80 Hz); 69.4—69.8 (m, 8 C, CH2О); 70.2 (2 C, CH2О); 72.0
(2 C, CH2О); 98.5 (1 C, C(4)); 106.2 (2 C, C(2), C(6)); 149.7
(2 C, C(3), C(5)) (the signal for one quarternary aromatic carbon
atom was not observed). MS (MALDI), m/z: [M + Na]+, found
520.3077, calculated 520.2999. C25H43N3NaO7.
16ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethꢀ
yl)ꢀ2,13ꢀdiazabicyclo[12.3.1]octadecaꢀ1(18),14,16ꢀtriene (7d)
was synthesized from diamine 5d (44 mg). The eluent was
1
CH2Cl2—MeOH (5 : 1). The yield was 35 mg (27%). Н NMR
(CDCl3), δ: 1.28 (br.s, 4 Н, CН2CН2CН2CН2); 1.33 (br.s, 8 Н,
CН2CН2CН2CН2); 1.54 (br.s, 4 Н, CН2CН2NHAr); 2.73 (br.s,
CH2CH2N); 3.09 (t, 4 Н, CH2NAr, J = 7.6 Hz); 3.50—3.65
(m, 22 Н, CH2О, ArCH2N); 5.86 (br.s, 1 Н, Н(4)); 5.91 (br.s,
2 Н, Н(2), Н(6)) (no signals for the NH protons were observed).
13C NMR (CDCl3), δ: 24.3 (2 C, CН2CН2CН2CН2); 26.3 (2 C,
CН2CН2CН2CН2); 26.4 (2 C, CН2CН2CН2CН2); 27.7 (2 C,
CН2CН2CН2CН2); 43.7 (2 C, CH2NAr); 54.3 (2 C, CH2CH2N,
Δν = 50 Hz); 57.2 (1 C, ArCH2N, Δν1/2 = 50 Hz); 67.2 (2 C,
1/2
CH2О, Δν = 100 Hz); 69.4 (2 C, CH2О); 69.5 (2 C, CH2О);
1/2
69.6 (2 C, CH2О); 69.7 (2 C, CH2О); 93.3 (1 C, C(4)); 105.3
(2 C, C(2), C(6)); 138.9 (1 C, C(1)); 150.3 (2 C, C(3), C(5)). MS
(MALDI), m/z: [M + H]+, found 522.3997, calculated 522.3907.
C29H52N3O5.
2.70 (br.s, 4 H, CH2CH2N, Δν
= 60 Hz); 3.24 (t, 4 Н,
1/2
CH2NAr, J = 6.2 Hz); 3.53 (t, 4 Н, CH2O, J = 5.1 Hz); 3.55—3.70
(m, 30 H, CH2O, ArCH2N); 5.90 (br.s, 2 H, Н(2), Н(6)); 6.04
(br.s, 1 H, Н(4)) (no signals for the NH protons were observed).
13C NMR (CDCl3), δ: 29.6 (2 C, CH2CH2CH2); 41.7 (2 C,
13ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethꢀ
yl)ꢀ2,6,10ꢀtriazabicyclo[9.3.1]pentadecaꢀ1(15),11,13ꢀtriene (7e)
was synthesized from triamine 5e (33 mg). The eluent was
CH2Cl2—MeOH—NH3 (100 : 20 : 3). The yield was 32 mg
(27%). 1Н NMR (CDCl3), δ: 1.65 (br.s, 4 H, CH2CH2CH2,
Δν = 15 Hz); 2.69 (br.s, 4 H, CH2NHCH2, Δν = 15 Hz);
CH2NAr); 53.6 (2 C, CH2CH2N); 59.1 (1 C, ArCH2N, Δν
=
1/2
= 30 Hz); 67.3 (2 C, CH2O, Δν1/2 = 50 Hz); 69.2 (2 C, CH2O);
69.3 (4 C, CH2O); 69.4 (4 C, CH2O); 70.0 (2 C, CH2O); 70.8
(2 C, CH2O); 95.6 (1 C, C(4), Δν1/2 = 15 Hz); 103.4 (2 C, C(2),
C(6)); 150.5 (2 C, C(3), C(5)) (the signal for one quarternary
aromatic carbon atom was not observed). MS (MALDI), m/z:
[M + K]+, found 608.3331, calculated 608.3313. C29H51KN3O8.
18ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethꢀ
yl)ꢀ6,11ꢀdioxaꢀ2,15ꢀdiazabicyclo[14.3.1]icosaꢀ1(20),16,18ꢀtriꢀ
ene (7b) was synthesized from dioxadiamine 5b (51 mg). The
eluent was CH2Cl2—MeOH (5 : 1). The yield was 21 mg (15%).
1Н NMR (CDCl3), δ: 1.73—1.77 (m, 4 H, CH2CH2CH2CH2);
1.79 (qu, 4 H, CH2CH2CH2, J = 4.7 Hz); 2.70 (br.s, 4 H
CH2CH2N, Δν1/2 = 100 Hz); 3.22 (t, 4 H, CH2NAr, J = 5.7 Hz);
3.37—3.42 (m, 4 H, CH2CH2CH2CH2); 3.50 (t, 4 H, CН2О,
J = 4.4 Hz); 3.55—3.68 (m, 26 H, CН2О, ArCH2N); 5.99 (br.s, 2 H,
Н(2), Н(6)); 6.06 (br.s, 1 H, Н(4)) (no signals for the
NH protons were observed). 13C NMR (CDCl3), δ: 26.4 (2 C,
CH2CH2CH2CH2); 30.0 (2 C, CH2CH2CH2); 42.3 (2 C,
1/2
1/2
3.25 (br.s, 4 H, CH2CH2N, Δν
= 35 Hz); 3.44 (br.s, 4 H,
1/2
CH2NAr, Δν1/2 = 30 Hz); 3.55—3.62 (m, 14 H, CH2О, ArCH2N);
3.64 (s, 4 H, CH2О); 3.71 (br.s, 4 H, CH2О, Δν1/2 = 15 Hz); 6.03
(br.s, 2 H, Н(2), Н(6)); 6.95 (br.s, 1 H, Н(4), Δν = 15 Hz)
1/2
(no signals for the NH protons were observed). 13C NMR (CDCl3),
δ: 29.6 (2 C, CH2CH2CH2, Δν1/2 = 10 Hz); 39.3 (2 C, CH2NAr);
45.7 (2 C, CH2NHCH2); 54.1 (2 C, CH2CH2N, Δν1/2 = 15 Hz);
60.0 (1 C, ArCH2N); 69.6 (2 C, CH2О); 69.7 (2 C, CH2О); 70.1
(2 C, CH2О); 70.4 (2 C, CH2О); 70.5 (2 C, CH2О); 95.5 (1 C,
C(4), Δν1/2 = 25 Hz); 104.3 (2 C, C(2), C(6)); 150.3 (2 C, C(3),
C(5)) (the signal for one quarternary aromatic carbon atom was
not observed). MS (MALDI), m/z: [M + H]+, found 481.28,
calculated 481.34. C25H44N4O5.
15ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctꢀ16ꢀylmethyl)ꢀ
2,5,9,12ꢀtetraazabicyclo[11.3.1]heptadecaꢀ1(17),13,15ꢀtriene
(7f) was synthesized from tetramine 5f (40 mg). The eluent was
CH2Cl2—MeOH—NH3 (10 : 4 : 1). The yield was 36 mg (28%).
1Н NMR (CDCl3), δ: 1.57 (br.s, 2 Н, CH2CH2CH2); 2.67—2.77
(m, 12 Н, CH2NHCH2, CH2CH2N); 3.33 (t, 4 Н, CH2NAr,
J = 4.7 Hz); 3.55—3.69 (m, 22 Н, CH2О, ArCH2N); 5.98 (br.s,
2 Н, Н(2), Н(6)); 6.19 (br.s, 1 Н, Н(4)) (no signals for the NH
protons were observed). 13C NMR (CDCl3), δ: 26.6 (1 C,
CH2CH2CH2); 43.7 (2 C, CH2NAr); 49.2 (2 C, CH2NHCH2);
49.6 (2 C, CH2NHCH2); 54.3 (2 C, CH2CH2N); 60.0 (1 C,
ArCH2N); 69.7 (2 C, CH2О); 70.2 (2 C, CH2О); 70.5 (4 C,
CH2О); 70.7 (2 C, CH2О); 94.5 (1 C, C(4)); 104.6 (2 C, C(2),
C(6)); 141.4 (1 C, C(1)); 149.1 (2 C, C(3), C(5)). MS (MALDI),
m/z: [M + H]+, found 510.3626, calculated 510.3655. C26H48N5O5.
17ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethꢀ
yl)ꢀ2,6,10,14ꢀtetraazabicyclo[13.3.1]nonadecaꢀ1(19),15,17ꢀ
triene (7g) was synthesized from tetramine 5g (33 mg). The eluent
was CH2Cl2—MeOH—NH3 (10 : 4 : 1). The yield was 26 mg
CH2NAr); 53.9 (2 C, CH2CH2N, Δν = 15 Hz); 58.3 (1 C,
1/2
ArCH2N, Δν1/2 = 90 Hz); 69.5 (4 C, CН2О, Δν1/2 = 25 Hz); 69.8
(10 C, CН2О); 95.5 (1 C, C(4), Δν1/2 = 90 Hz); 103.5 (2 C, C(2),
C(6), Δν = 20 Hz); 150.6 (2 C, C(3), C(5)) (the signal for
1/2
one quarternary aromatic carbon atom was not observed). MS
(MALDI), m/z: [M + Na]+, found 553.3691, calculated 553.3727.
C29H51N3NaO7.
14ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethꢀ
yl)ꢀ5,8ꢀdioxaꢀ2,11ꢀdiazabicyclo[10.3.1]hexadecaꢀ1(16),12,14ꢀ
triene (7c) was synthesized from dioxadiamine 5c (37 mg). The
eluent was CH2Cl2—MeOH (from 5 : 1 to 2.5 : 1). The yield was
13 mg (14%). 1Н NMR (CDCl3), δ: 2.75 (br.s, 4 H, CH2CH2N,
Δν = 90 Hz); 3.38 (t, 4 Н, CH2NAr, J = 4.6 Hz); 3.55—3.71
1/2
(m, 30 H, CH2О, ArCH2N); 6.08 (br.s, 2 H, Н(2), Н(6)); 6.87
(br.s, 1 H, Н(4)) (no signals for the NH protons were observed).
13C NMR (CDCl3), δ: 45.0 (2 C, CH2NAr); 53.6 (2 C, CH2CH2N,
Δν1/2 = 12 Hz); 61.2 (1 C, ArCH2N); 67.4 (2 C, CH2О, Δν
=
1/2

1002
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Anokhin et al.
(20%). 1Н NMR (CDCl3), δ: 1.67 (qu, 4 Н, CH2CH2CH2,
J = 5.2 Hz); 2.68 (t, 4 Н, CH2CH2CH2NH, J = 5.4 Hz); 2.69
(s, 4 H, NHCH2CH2NH); 2.73 (t, 4 Н, CH2CH2N, J = 5.5 Hz);
3.32 (t, 4 Н, CH2NAr, J = 6.2 Hz); 3.55—3.59 (m, 8 H, CH2О);
3.61—3.66 (m, 14 H, CH2О, ArCH2N); 5.90 (br.s, 2 H, Н(2),
Н(6)); 6.13 (br.s, 1 H, Н(4)) (no signals for the NH protons were
observed). 13C NMR (CDCl3), δ: 31.4 (2 C, CH2CH2CH2); 41.3
(2 C, CH2NAr); 46.0 (2 C, CН2NHCH2); 48.9 (2 C, CН2NHCH2);
54.2 (2 C, CH2CH2N); 59.8 (1 C, ArCH2N); 69.6 (2 C, CH2О);
70.1 (2 C, CH2О); 70.5 (4 C, CH2О); 70.7 (2 C, CH2О); 92.9
(1 C, C(4)); 104.3 (2 C, C(2), C(6)); 141.2 (1 C, C(1)); 150.4 (2 C,
C(3), C(5)). MS (MALDI), m/z: [M + H]+, found 524.3797,
calculated 524.3812. C27H50N5O7.
NCH2Ar); 7.42 (br.s, 2 Н, Н(2), Н(6)); 7.51 (br.s, 1 Н, Н(4))
(no signals for the NH protons were observed). 13C NMR
(CDCl3), δ: 45.6 (2 C, CH2N); 46.6 (2 C, CH2N); 47.6 (2 C,
CH2N); 51.7 (2 C, CH2N); 58.5 (1 C, NCH2Ar); 122.8 (2 C,
C(3), C(5)); 130.6 (2 C, C(2), C(6)); 132.7 (1 C, C(4)); 143.4
(1 C, C(1)). MS (MALDI), m/z: [M + H]+, found 419.0470,
calculated 419.0446. C15H25Br2N4.
The general procedure for the synthesis of macrobicycles
11a—c is identical with that for macrobicycles 6 and 7. Numberꢀ
ing of the atoms of the benzene ring in the 1Н and 13C NMR
spectra of compounds 11 is shown in Scheme 4.
19ꢀ(1,4,7,10ꢀTetraazacyclododecꢀ1ꢀylmethyl)ꢀ6,9,12ꢀtriꢀ
oxaꢀ2,16ꢀdiazabicyclo[15.3.1]enicosaꢀ1(21),17,19ꢀtriene (11a).
According to the first method, compound 11a was synthesized
from compound 10 (104 mg, 0.25 mmol) and trioxadiamine 2а
(55 mg, 0.25 mmol) in the presence of Pd(dba)2 (12 mg, 8 mol.%),
DavePhos (9 mg, 9 mol.%), and sodium tertꢀbutoxide (72 mg,
0.375 mmol) in dioxane (12 mL). According to the second methꢀ
od, compound 11a was synthesized from compound 10 (104 mg,
0.25 mmol) and trioxadiamine 2а (55 mg, 0.25 mmol) in the
presence of Pd(dba)2 (24 mg, 16 mol.%), DavePhos (18 mg,
18 mol.%), and sodium tertꢀbutoxide (72 mg, 0.375 mmol) in
dioxane (12 mL). The combined reaction mixtures were chroꢀ
matographed on silica gel. The eluent was CH2Cl2—MeOH—NH3
(100 : 25 : 5). The total yield was 32 mg (13%). 1Н NMR (CDCl3),
δ: 1.78 (qu, 4 Н, CH2CH2CH2, J = 5.7 Hz); 2.52—2.92 (m, 16 Н,
CН2N); 3.23 (t, 4 Н, CН2NAr, J = 5.9 Hz); 3.44—3.63 (m, 14 Н,
CH2О, ArCH2N); 5.86 (s, 2 Н, Н(2), Н(6)); 6.02 (s, 1 Н, Н(4))
(no signals for the NH protons were observed). 13C NMR
(CDCl3), δ: 29.5 (2 C, CH2CH2CH2); 41.8 (2 C, CН2NHAr);
45.5 (2 C, CН2N); 45.8 (2 C, CН2N); 47.6 (2 C, CН2N); 51.2
(2 C, CН2N); 60.3 (1 C, ArCH2N); 69.4 (2 C, CH2О); 69.9 (2 C,
CH2О); 70.7 (2 C, CH2О); 95.7 (1 C, C(4)); 102.9 (2 C, C(2),
C(6)); 140.3 (1 C, C(1)); 150.2 (2 C, C(3), C(5)). MS (MALDI),
m/z: [M + H]+, found 479.3675, calculated 479.3709. C25H47N6O3.
18ꢀ(1,4,7,10ꢀТeтрazacyclododecꢀ1ꢀylmethyl)ꢀ6,11ꢀdioxaꢀ
2,15ꢀdiazabicyclo[14.3.1]icosaꢀ1(20),16,18ꢀtriene (11b) was
synthesized from compound 10 (104 mg, 0.25 mmol) and dioxaꢀ
diamine 2b (51 mg, 0.25 mmol) in the presence of Pd(dba)2
(12 mg, 8 mol.%), DavePhos (9 mg, 9 mol.%), and sodium tertꢀ
butoxide (72 mg, 0.375 mmol) in dioxane (12 mL). The eluent
was CH2Cl2—MeOH—NH3 (100 : 20 : 3). The yield was 11 mg
(10%). 1Н NMR (CDCl3), δ: 1.76 (br.s, 4 Н, CH2CH2CH2CH2);
1.81 (qu, 4 Н, CH2CH2CH2, J = 4.7 Hz); 2.72—2.82 (m, 12 Н,
CН2NНCН2); 2.93—2.97 (m, 4 Н, CН2N); 3.24 (t, 4 Н,
CН2NAr, J = 5.6 Hz); 3.38—3.45 (m, 6 Н, CH2CH2CH2CH2,
ArCH2N); 3.52 (t, 4 Н, CН2О, J = 4.6 Hz); 5.89 (s, 2 Н, Н(2),
Н(6)); 6.05 (s, 1 Н, Н(4)) (no signals for the NH protons were
observed). 13C NMR (CDCl3), δ: 26.5 (2 C, CH2CH2CH2CH2);
30.0 (2 C, CH2CH2CH2); 42.5 (2 C, CН2NAr); 45.8 (2 C,
CН2N); 46.9 (2 C, CН2N); 48.4 (2 C, CН2N); 51.5 (2 C, CН2N);
61.1 (1 C, ArCH2N); 69.9 (4 C, CH2О); 95.3 (1 C, C(4)); 102.4
(2 C, C(2), C(6)); 150.4 (2 C, C(3), C(5)) (the signal for one
quarternary aromatic carbon atom was not observed). MS
(MALDI), m/z: [M + H]+, found 463.39, calculated 463.38.
C25H47N6O2.
17ꢀ(1,4,7,10,13ꢀPentaoxaꢀ16ꢀazacyclooctadecꢀ16ꢀylmethꢀ
yl)ꢀ2,6,10,14ꢀtetraazabicyclo[13.3.1]nonadecaꢀ1(19),15,17ꢀ
triene (7h) was synthesized from tetramine 5h (47 mg). The eluent
was CH2Cl2—MeOH—NH3 (10 : 4 : 1). The yield was 21 mg
(16%). 1Н NMR (CDCl3), δ: 1.74 (br.s, 6 Н, CH2CH2CH2);
2.70 (t, 4 Н, CH2CH2N, J = 4.9 Hz); 2.72—2.80 (m, 8 Н,
CH2CH2N); 3.28 (t, 4 Н, CH2NAr, J = 7.1 Hz); 3.55—3.69
(m, 22 Н, CH2О, ArCH2N); 5.92 (br.s, 2 Н, Н(2), Н(6)); 5.95 (br.s,
1 Н, Н(4)) (no signals for the NH protons were observed).
13C NMR (CDCl3), δ: 28.3 (1 C, CH2CH2CH2); 29.3 (2 C,
CH2CH2CH2); 42.2 (2 C, CH2NAr); 47.3 (2 C, CН2NHCH2);
49.5 (2 C, CН2NHCH2); 54.1 (2 C, CH2CH2N); 60.0 (1 C,
ArCH2N); 69.7 (2 C, CH2О); 70.2 (2 C, CH2О); 70.6 (4 C,
CH2О); 70.7 (2 C, CH2О); 93.7 (1 C, C(4)); 103.9 (2 C, C(2),
C(6)); 149.4 (2 C, C(3), C(5)) (the signal for one quarternary
aromatic carbon atom was not observed). MS (MALDI), m/z:
[M + H]+, found 538.4001, calculated 538.3968. C28H52N5O5.
1ꢀ(3,5ꢀDibromobenzyl)ꢀ1,4,7,10ꢀtetraazacyclododecane (10).
3,5ꢀDibromobenzyl bromide (5.32 g, 16.2 mmol) was added to
a solution of cisꢀglyoxalꢀcyclene (8) (3.14 g, 16.2 mmol) in anꢀ
hydrous toluene (30 mL) and the mixture was stirred for 24 h at
room temperature. The white crystalline precipitate that formed
was filtered off, washed with toluene (25 mL), then with acetone
(25 mL), and dried in vacuo to yield 2aꢀ(3,5ꢀdibromobenzyl)ꢀ
decahydroꢀ4a,6a,8aꢀtriazaꢀ2aꢀazoniacyclopenta[fg]acenaphthylꢀ
1
ene bromide (9) (5.71 g, 67%). Н NMR (D2O), δ: 2.45—2.55
(m, 4 Н, CH2N); 2.73—2.85 (m, 3 Н, CH2N); 2.87—2.91 (m, 1 Н,
CH2N); 3.02—3.10 (m, 1 Н, CH2N); 3.15 (d, 1 Н, CH2N,
J = 12.3 Hz); 3.20—3.34 (m, 3 Н, CH2N); 3.47 (td, 1 Н, CH2N,
J = 8.5 Hz, J = 2.9 Hz); 3.52—3.62 (m, 3 Н, CH2N); 3.71 (d, 1 Н,
CHN2, J = 2.3 Hz); 4.01 (d, 1 Н, CHN2, J = 2.3 Hz); 4.15 (td, 1 Н,
CH2N, J = 11.1 Hz, J = 3.4 Hz); 4.64 (d, 1 Н, ArCH2N,
J = 13.6 Hz); 4.83 (d, 1 Н, ArCH2N, J = 13.6 Hz); 7.73 (br.s, 2 Н,
Н(2), Н(6)); 7.98 (br.s, 1 Н, Н(4)). 13C NMR (D2O), δ: 43.7
(1 C, CH2N); 47.4 (1 C, CH2N); 47.6 (1 C, CH2N); 48.1 (1 C,
CH2N); 48.2 (1 C, CH2N); 51.2 (1 C, CH2N); 57.2 (1 C, CH2N);
59.9 (1 C, CH2N); 61.4 (1 C, CH2N); 71.6 (1 C, CHN2); 83.0
(1 C, CHN2); 123.4 (2 C, C(3), C(5)); 130.4 (1 C, C(1)); 133.9
(2 C, C(2), C(6)); 136.6 (1 C, C(4)). Compound 9 was dissolved
in ethanol (60 mL), КОН (8.9 g, 0.159 mol) was added, and the
mixture was refluxed for 72 h. Upon completion of the reaction,
the solvent was evaporated in vacuo, the solid residue was exꢀ
tracted with dichloromethane (3×25 mL), dried with magneꢀ
sium sulfate, and the solvent was evaporated in vacuo to yield
compound 10 as a pale yellow crystalline powder. The yield was
15ꢀ(1,4,7,10ꢀТeтрazacyclododecꢀ1ꢀylmethyl)ꢀ5,9ꢀdioxaꢀ
2,12ꢀdiazabicyclo[11.3.1]heptadecaꢀ1(17),13,15ꢀtriene (11c)
was synthesized from compound 10 (104 mg, 0.25 mmol) and
dioxadiamine 2c (37 mg, 0.25 mmol) in the presence of Pd(dba)2
(12 mg, 8 mol.%), DavePhos (9 mg, 9 mol.%), and sodium
1
4.45 g (98%, 65% over two steps), m.p. 119—121 °C. Н NMR
(CDCl3), δ: 2.55—2.60 (m, 8 Н, CH2N); 2.67 (t, 4 Н, CH2N,
J = 4.9 Hz); 2.83 (t, 4 Н, CH2N, J = 4.9 Hz); 3.56 (s, 2 Н,

Macrobicycles with azaꢀcrown fragments
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
1003
tertꢀbutoxide (72 mg, 0.375 mmol) in dioxane (12 mL). The
eluent was CH2Cl2—MeOH—NH3 (100 : 25 : 5). The yield
was 2 mg (2%). 1Н NMR (CDCl3), δ: 2.64—2.76 (m, 12 Н,
CН2NНCН2); 2.86 (t, 4 Н, CН2N, J = 4.9 Hz); 3.25 (t, 4 Н,
CН2NAr, J = 5.2 Hz); 3.61—3.65 (m, 10 Н, CH2О, ArCH2N);
5.82 (s, 1 Н, Н(4)); 6.02 (s, 2 Н, Н(2), Н(6)) (no signals for the
NH protons were observed). 13C NMR (CDCl3), δ: 43.5 (2 C,
CН2NAr); 45.9 (2 C, CН2N); 46.3 (2 C, CН2N); 48.1 (2 C,
CН2N); 51.6 (2 C, CН2N); 60.5 (1 C, ArCH2N); 69.8 (2 C,
CH2О); 70.1 (2 C, CH2О); 96.3 (1 C, C(4)); 103.7 (2 C, C(2),
C(6)); 141.3 (1 C, C(1)); 149.6 (2 C, C(3), C(5)). MS (MALDI),
m/z: [M + H]+, found 407.3179, calculated 407.3134. C21H39N6O2.
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This work was financially supported by the Russian
Academy of Sciences (Program "Development of the
methodology of organic synthesis and design of comꢀ
pounds with valuable applied properties") and the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ00735).
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Received March 1, 2011;
in revised form April 13, 2011