Synthesis of polyaza macrocycles by palladium-catalyzed amination of 1,2-dibromobenzene and 2-bromo-1,3-dichlorobenzene

Article abstract of DOI:10.1134/S1070428009090085

Palladium-catalyzed amination of 1,2-dibromobenzene with equimolar amounts of linear polyamines leads to the formation of polyaza macrocycles in low yields. The use of 2-bromo-1,3-dichlorobenzene as starting compound ensures considerably larger yields of

Full text of DOI:10.1134/S1070428009090085

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 9, pp. 1353–1364. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.D. Averin, A.V. Shukhaev, A.K. Buryak, I.P. Beletskaya, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 9,
pp. 1368–1378.
Synthesis of Polyaza Macrocycles
by Palladium-Catalyzed Amination of 1,2-Dibromobenzene
and 2-Bromo-1,3-dichlorobenzene
A. D. Averina, A. V. Shukhaeva, 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 January 11, 2009
Abstract—Palladium-catalyzed amination of 1,2-dibromobenzene with equimolar amounts of linear poly-
amines leads to the formation of polyaza macrocycles in low yields. The use of 2-bromo-1,3-dichlorobenzene
as starting compound ensures considerably larger yields of the target macrocycles, and the reaction is accom-
panied by side formation of N-aryl- and N,N′-diaryl-substituted polyamines, as well as of cyclic oligomers. The
yields strongly depend on the polyamine chain length. Reactions of excess 2-bromo-1,3-dichlorobenzene with
a series of polyamines gave the corresponding N,N′-diarylpolyamines in high yields, and the latter reacted with
the second polyamine molecule to form cyclic dimers. A relation between the yield of cyclic dimers and poly-
amine structure was revealed.
DOI: 10.1134/S1070428009090085
Polyaza macrocycles (aza crown ethers) attract per-
sistent interest due to their ability to effectively bind
various inorganic and organic ions, as well as some
polar molecules. During the past decades, hundreds of
such compounds containing nitrogen, oxygen, and sul-
fur atoms in the macroring have been synthesized [1].
However, the main problem is that such syntheses are
multistep and laborious; therefore, the yields of the
target products are often poor [2–5]. Many polyaza
macrocycles can be used as chemical sensors due to
photochemical or redox properties of aromatic frag-
ments therein. Aromatic groups capable of providing
a detectable response to coordination with metal ions
may be present as substituents on the nitrogen atoms
or incorporated into the macroring. In most cases,
aromatic substituents are linked to endocyclic nitrogen
atoms through methylene or methine bridges [6–11].
According to published data, the best response is ob-
tained when an aromatic group is directly attached to
nitrogen atom in the macroring; however, only a few
examples of such compounds have been reported up to
now [12–14].
cording to Buchwald–Hartwig [16]. This approach was
applied to the synthesis of polyaza and polyazapolyoxa
macrocycles containing 1,3-disubstituted benzene [17],
2,6- and 3,5-disubstituted pyridine [18, 19], and 1,8-
and 1,5-disubstituted anthracene and anthraquinone
fragments [20]. Macrocycles having anthracene and
anthraquinone fragments attract specific interest, for
their electronic absorption spectra lie in the visible
region, while anthracene derivatives show strong lumi-
nescence which makes them promising as molecular
sensors.
In the present work we tried to synthesize macro-
cyclic compounds on the basis of 1,2-disubstituted
benzene with a view to determine the scope of applica-
tion of the developed procedure since catalytic ortho-
diamination is known to be the most problematic
owing to ready reduction at the C–Hlg bond. It was
also important to elucidate how the yield of the target
macrocycles depends on the polyamine chain length
and to synthesize macrocyclic compounds each having
two benzene and two polyamine fragments (cyclic
dimers).
We recently developed an effective procedure for
arylation of linear polyamines with aryl halides [15]
via palladium-catalyzed amination of dihaloarenes ac-
As catalytic system we selected Pd(dba)2/BINAP,
taking into account that this system ensured good
results in both amination of various haloarenes [21]
1353

AVERIN et al.
1354
Scheme 1.
N
N
H
H
NH2
H2N
IIa
N
N
Pd(dba)2/BINAP (8–9 mol %)
t-BuONa, dioxane
H
H
NH HN
NH HN
Br
NH
HN
Br
+
IIIa, 12%
IVa, 12%
O
O
O
NH2
H2N
O
O
O
O
O
IIb
Br
Br
NH
HN
NH
Pd(dba)2/BINAP (8–9 mol %)
+
O
Br
Br
Br
NH2
I
IVb, 21%
Vb, 44%
P(C6H11-cyclo)2
Pd(dba)2/
O
O
O
Me2N
NH
NH
(16–18 mol %)
IIIb, 14%
Scheme 2.
Cl
Cl
H
N
HN
X
NH
Pd(dba)2/BINAP (8–9 mol %)
t-BuONa, dioxane
Br
Cl
ClCl
Cl
+
Cl
X
+
H2N
X
NH2
N
H
IIa–IIk
VI
VIIa, VIIb, VIId–VIIk
VIIIa, VIIIb, VIIId
VIIIg–VIIIi, VIIIk
HN
X
NH2
Cl
+
+
Cl
Cl
NH HN
X
n
IXc, IXd, IXk (n > 1)
Xa, Xc
X = CH2NH(CH2)2NHCH2 (a), CH2O(CH2)2O(CH2)2OCH2 (b), NH (c), CH2NHCH2 (d), NH(CH2)2NH (e), NH(CH2)3NH (f),
CH2NH(CH2)3NHCH2 (g), NH(CH2)2NH(CH2)2NH (h), NH(CH2)2NH(CH2)2NH(CH2)2NH (i), O(CH2)2O (j), CH2O(CH2)4OCH2 (k).
and catalytic synthesis of macrocycles. To synthesize
macrocycles containing an o-phenylenediamine frag-
ment we tried initially the simplest starting compound,
1,2-dibromobenzene (I), which was brought into reac-
tions with polyamines II. The reactions were carried
out by heating fairly dilute solutions (c = 0.02–0.04 M)
of the reactants in dioxane in the presence of sodium
tert-butoxide as a base. The reaction of equimolar
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

SYNTHESIS OF POLYAZA MACROCYCLES
1355
Table 1. Synthesis of macrocycles by amination of 2-bromo-1,3-dichlorobenzene (VI)
Run no.
Polyamine
Product
VIIa
Yield, %
01
02
NH2(CH2)3NH(CH2)2NH(CH2)3NH2 (IIa)
NH2(CH2)3NH(CH2)2NH(CH2)3NH2 (IIa)
47
VIIa
VIIIa
Xa
11
20
19
03
04
NH2(CH2)3O(CH2)2O(CH2)2O(CH2)3NH2 (IIb)
NH2(CH2)3O(CH2)2O(CH2)2O(CH2)3NH2 (IIb)
VIIb
VIIIb
IXb (n = 2)
24
12
17
VIIb
VIIIb
23
06
IXb (n = 2)
IXb (n = 3–5)
17
a27a
05
06
07
NH2(CH2)2NH(CH2)2NH2 (IIc)
NH2(CH2)3NH(CH2)3NH2 (IId)
NH2(CH2)3NH(CH2)3NH2 (IId)b
Xc
37
09
VIIId
VIId
IXd (n = 2–5)
08
50
08
09
10
NH2(CH2)2NH(CH2)2NH(CH2)2NH2 (IIe)
NH2(CH2)2NH(CH2)3NH(CH2)2NH2 (IIf)
NH2(CH2)3NH(CH2)3NH(CH2)3NH2 (IIg)
VIIe
VIIf
14
17
VIIg
VIIIg
27
07
11
12
NH2(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH2 (h)
VIIh
VIIIh
12
17
NH2(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH2 (IIi)
VIIi
VIIIi
10
21
13
14
NH2(CH2)2O(CH2)2O(CH2)2NH2 (IIj)
NH2(CH2)3O(CH2)4O(CH2)3NH2 (IIk)
VIIj
12
VIIk
VIIIk
IXk (n = 2)
IXk (n > 2)
17
10
10
11
a
In a mixture with acyclic oligomers.
In the presence of 16 mol % of the catalyst.
b
amounts of o-dibromobenzene with tetraamine IIa in
the presence of 8 mol % of the catalyst gave 12% of
macrocycle IIIa and N,N′-diaryl tetraamine derivative
IVa (Scheme 1).
may be rationalized taking into account that replace-
ment of the first bromine atom by amino group ham-
pers replacement of the second bromine atom owing to
positive mesomeric effect of the first amino group.
The reaction of o-dibromobenzene with trioxadi-
amine IIb did not lead to the desired macrocycle IIIb
in the presence of the same amount of the catalyst. We
isolated only linear N,N′-di- and N-monoaryl-substi-
tuted derivatives IVb and Vb in 21 and 44% yield,
respectively. No compound IIIb was formed when the
amount of the catalyst was increased to 16 mol %; in
this case, only the fraction of linear product IVb in the
reaction mixture was greater. We succeeded in obtain-
ing macrocycle IIIb in 14% yield using DavePHOS
(L) as donor ligand. The low yield of macrocyclic
compounds having a 1,2-diaminobenzene fragment
We made an attempt to enhance the reactivity of
aryl halide via introduction of an additional halogen
atom. The reaction of 2-bromo-1,3-dichlorobenzene
(VI) with tetraamine IIa in the presence of 8% of
Pd(dba)2/BINAP gave 47% of macrocyclic compound
VIIa (Scheme 2; Table 1, run no. 1). Analogous
reaction of VI with trioxa diamine IIb afforded 24% of
VIIb; in addition, N,N′-diaryl diamine VIIIb (12%)
and cyclic dimer IXb (17%) were formed (Table 1, run
no. 3). Increase in the reactant concentration different-
ly affected the reaction outcome, depending on the
polyamine nature. In the reaction with tetraamine IIa
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

AVERIN et al.
1356
Table 2. Synthesis of cyclic dimers IX
Run no.
Polyamine
Product
Yield, %
33
1
2
NH2(CH2)3NH(CH2)2NH(CH2)3NH2 (IIa)
NH2(CH2)3NH(CH2)3NH2 (IId)
XIa
IXd
XId
09
19
3
NH2(CH2)2O(CH2)2O(CH2)2NH2 (IIj)
IXj
XIIj
XIIIj
06
12
06
4
5
NH2(CH2)3O(CH2)4O(CH2)3NH2 (IIk)
IXk
IXb
23
27
NH2(CH2)3O(CH2)2O(CH2)2O(CH2)3NH2 (IIb)
small variation of the reactant concentration resulted in
significant decrease of the yield of VIIa, whereas ap-
preciable amounts of linear arylation products VIIIa
and Xa were obtained (Table 1; run nos. 1, 2). By con-
trast, even strong increase of the reactant concentration
in the reaction with diamine IIb almost did not change
the yield of compound VIIb (Table 1; run nos. 3, 4).
a longer chain gave rise to 8% of the corresponding
macrocyclic product (Table 1, run no. 7) in addition to
considerable amounts of cyclic oligomers IXd (n =
2–5; 50% in the reaction mixture). This result was
obtained only in the presence of a double amount of
the catalyst (16 mol %). In the reaction with 8 mol %
of the catalyst, N,N′-diaryl derivative VIIId was the
only product (Table 1, run no. 6). Tetraamines IIe–IIg
gave rise to the corresponding macrocycles VIIe–VIIg
in 14–27% yield (Table 1, run nos. 8–10), while in
going to pentaamine IIh and hexaamine IIi the yields
decreased to 12 and 10%, respectively. Simultaneous-
ly, the yields of linear compounds VIIh and VIIi
increased. Probable reasons are greater conformational
We also examined how the polyamine chain length
and the number of nitrogen and oxygen atoms therein
affect the yield of macrocyclic compounds and by-
products. Obviously, the chain length of triamine IIc
(seven atoms), is insufficient for ring closure, and the
reaction of IIc with haloarene VI gave only monoaryl
derivative Xc (Table 1, run no. 5). Triamine IId with
Scheme 3.
Cl
HN
X
NH
Pd(dba)2/BINAP (4–4.5 mol %)
t-BuONa, dioxane
Br
Cl
ClCl
Cl
Cl
+
H2N
X
NH2
IIa, IIb, IId, IIj, IIk
VI, 2,5 equiv
VIIIa, VIIIb, VIIId, VIIIj, VIIIk
H2N
X
NH2
Cl
Cl
Cl
HN
IIa, IIb, IId, IIj, IIk
Pd(dba)2/BINAP (16–18 mol %)
t-BuONa, dioxane
NH
X
X
HN
HN
NH
Cl
X
HN
X
NH2
+
NH
Cl
IXa, IXb, IXd, IXj, IXk
Xa, Xd
HN
O
O
NH
Cl
R
Cl
XIIj, XIIIj
XIIj, R = Cl; XIIIj, R = H.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

SYNTHESIS OF POLYAZA MACROCYCLES
1357
mobility of longer polyamine chains and increased
number of ethylenediamine units capable of chelating
palladium which is thus removed from the catalytic
series. In the reaction with dioxa diamine IIj the yield
of macrocycle VIIj was also poor (12%; Table 1, run
no. 13), presumably owing to insufficient chain length
in the initial diamine. In going to longer dioxa diamine
IIk the yield of the macrocyclic product increased to
17% (Table 1, run no. 14). In addition, 10% of cyclic
dimer IXk (n = 2) and 11% of a mixture of higher
cyclic oligomers (n > 2) were obtained. The above data
indicate that intramolecular diamination processes
leading to the target macrocycles do not go to com-
pletion even in the presence of a considerable amount
of the catalyst (8 mol %).
Cyclic dimers IX, as well as the corresponding
macrocycles VII, possess unsymmetrically substituted
polyamine chains. In addition, most signals in the
13C NMR spectrum of cyclic dimer IXb are doubled,
which may be due to existence of different stable
conformers fixed by intramolecular hydrogen bonding
with participation of six oxygen atoms and four amino
groups. Analogous pattern was observed previously for
cyclic dimers containing 1,3-disubstituted benzene
[17] and 2,6-disubstituted pyridine fragments [18].
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Bruker Avance-400 spectrometer at 400 and
100.6 MHz, respectively, using CDCl3 as solvent un-
less otherwise stated. The chemical shifts were deter-
mined relative to the residual proton and carbon
signals of the solvent (CHCl3, δ 7.25; CDCl3,
δC 77.0 ppm). The mass spectra (MALDI-TOF, posi-
tive ion detection) were obtained on a Bruker Dal-
tonics Ultrafex instrument using 1,8,9-trihydroxyan-
thracene as matrix. Preparative column chromatog-
raphy was performed on Merck silica gel (40–60 μm).
Commercial 1,2-dibromobenzene (I), 2-bromo-1,3-di-
chlorobenzene (VI), polyamines IIa–IIk, sodium tert-
butoxide, BINAP, and DavePHOS were used without
additional purification; Pd(dba)2 was synthesized ac-
cording to the procedure described in [22] and was not
additionally recrystallized. Dioxane was distilled first
over alkali and then over metallic sodium; methylene
chloride and methanol were purified by distillation.
Insofar as the polyamine chain in macrocycles VII
appears to be unsymmetrically substituted (a chlorine
atom is present in position 3 of the benzene ring), all
1
methylene groups showed nonequivalence in the H
and 13C NMR spectra. The difference in the chemical
shifts of protons in the methylene groups nearest to the
benzene ring reached 0.3 ppm.
We have developed a procedure for the synthesis of
cyclic dimers IX. It included formation of intermediate
N,N′-diaryl polyamines VIIIa, VIIIb, VIIId, VIIIj,
and VIIIk and their subsequent reaction with the
second polyamine molecule (Scheme 3). In the first
step the amount of the catalyst was smaller (4 mol %),
and the reactions were carried out in more concen-
trated solutions (dioxane, c = 0.1 M) using 2.5 equiv of
2-bromo-1,3-dichlorobenzene (VI). Intermediate com-
pounds VIII were formed in 85–90% yield and were
brought into reactions with polyamines IIa, IIb, IId,
IIj, and IIk without isolation from the reaction mix-
ture. The second step was carried out in more dilute
solutions (c = 0.04–0.05 M) using 16 mol % of the
catalyst. The yields of cyclic dimers IX very strongly
depended on the polyamine nature. No target macro-
cycle was obtained from tetraamine IIa; instead, linear
compound XIa was isolated (Table 2, run no. 1). In the
reaction with triamine IId, the yield of macrocycle
IXd was 9% (Table 2, run no. 2), and 19% of linear
compound XId was formed. The yield of cyclic dimer
IXj from diamine IIj was also poor (6%; Table 2, run
no. 3); in this case, partially reduced N,N′-diaryl dioxa
diamines XIIj and XIIIj were obtained as by-products
(yield 6 and 12%, respectively). Another dioxa di-
amine, compound IIk, gave rise to a higher yield of
cyclic dimer IXk (23%; Table 2, run no. 4). The best
yield of cyclic dimer (27%) was obtained in the reac-
tion with trioxa diamine IIb (Table 2, run no. 5).
Macrocycles IIIa, IIIb, VIIa, VIIb, and VIId–
VIIk (general procedure). Anhydrous dioxane, 25 ml,
amine IIa–IIk, 0.5 mmol, and sodium tert-butoxide,
1.5 mmol (144 mg), were added to a mixture of
0.5 mmol of 1,2-dibromobenzene (I) (118 mg) or
2-bromo-1,3-dichlorobenzene (VI) (113 mg),
0.04 mmol (23 mg) of Pd(dba)2, and 0.045 mol
(28 mg) of BINAP, and the mixture was heated for 24–
72 h under reflux in an argon atmosphere. The mixture
was cooled, the solution was separated by decanting,
the precipitate was washed with a small amount of
methylene chloride, the washings were combined with
the organic phase and evaporated under reduced pres-
sure, and the solid residue was subjected to chromato-
graphic separation on silica gel using the following
solvents as eluents (in succession): CH2Cl2, CH2Cl2–
MeOH (200:1 to 3:1), CH2Cl2–MeOH–aqueous NH3
(100:20:1 to 10:4:1). The yields of compounds VII–
XIII are given in Tables 1 and 2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

AVERIN et al.
1358
1,2,3,4,5,6,7,8,9,10,11,12-Dodecahydro-1,5,8,12-
spectrum, δ, ppm: 1.93 quint (4H, 3J = 6.2 Hz), 3.27 q
3
benzotetraazacyclotetradecine (IIIa) was synthe-
sized from 0.5 mmol (118 mg) of 1,2-dibromobenzene
(I) and 0.5 mmol (87 mg) of tetraamine IIa. Eluent
CH2Cl2–MeOH–aq. NH3, 100:20:3. Yield 15 mg
(12%), light yellow oily substance. 1H NMR spectrum,
(4H, J = 5.5 Hz), 3.57–3.64 m (8H), 3.65–3.70 m
3
(4H), 4.63 br.s (2H), 6.53 t (2H, J = 7.6 Hz), 6.62 d
3
3
(2H, J = 8.0 Hz), 7.15 t (2H, J = 7.7 Hz), 7.39 d.d
3
4
(2H, J = 7.9, J = 1.1 Hz). 13C NMR spectrum, δC,
ppm: 29.0 (2C), 41.6 (2C), 69.6 (2C), 70.4 (2C), 70.6
(2C), 109.6 (2C), 111.1 (2C), 117.3 (2C), 128.4 (2C),
132.3 (2C), 145.2 (2C). Mass spectrum: m/z 528.0649
[M]+. C22H30Br2N2O3. Calculated: M 528.0623.
3
3
δ, ppm: 1.82 quint (4H, J = 6.5 Hz), 2.69 t (4H, J =
3
6.5 Hz), 2.75 s (4H), 3.28 t (4H, J = 6.5 Hz), 6.58–
6.61 m (2H), 6.61–6.64 m (2H) (four NH proton sig-
nals could not be assigned unambiguously). 13C NMR
spectrum, δC, ppm: 27.7 (2C), 43.0 (2C), 48.2 (2C),
49.5 (2C), 111.1 (2C), 118.0 (2C), 138.2 (2C). Mass
spectrum: m/z 248.91 [M + H]+.
N-(3-{2-[2-(3-Aminopropoxy)ethoxy]ethoxy}-
propyl)-2-bromoaniline (Vb) was isolated as the sec-
ond product in the synthesis of IVb. Elyuent CH2Cl2–
MeOH–aq. NH3, 100:20:1 to 10:4:1. Yield 83 mg
(44%), light yellow oily substance. 1H NMR spectrum,
N1,N1′-Ethane-1,2-diylbis[N3-(2-bromophenyl)-
propane-1,3-diamine] (IVa) was isolated as the
second product in the synthesis of compound IIIa.
Eluent CH2Cl2–MeOH–aq. NH3, 100:20:1. Yield
3
δ, ppm: 1.71 quint (2H, J = 6.7 Hz), 1.93 quint (2H,
3J = 6.0 Hz), 2.77 t (2H, 3J = 6.7 Hz), 3.27 q (2H, 3J =
3
5.9 Hz), 3.53 t (2H, J = 6.1 Hz), 3.55–3.68 m (10H),
1
3
20 mg (16%), light yellow oily substance. H NMR
4.64 br.s (1H), 6.53 t (1H, J = 7.6 Hz), 6.62 d (1H,
3
3J = 8.1 Hz), 7.15 t (1H, 3J = 7.7 Hz), 7.39 d (1H, 3J =
7.8 Hz) (two NH proton signals cannot be assigned un-
ambiguously). 13C NMR spectrum, δC, ppm: 28.9,
33.0, 39.4, 41.4, 69.5, 70.0, 70.3, 70.4 (2C), 70.5,
109.4, 110.9, 117.2, 128.3, 132.2, 145.1. Mass spec-
trum: m/z 374.1270 [M]+. C16H27BrN2O3. Calculated:
M 374.1205.
spectrum, δ, ppm: 1.82 quint (4H, J = 6.7 Hz), 2.76 t
(4H, 3J = 6.7 Hz), 2.86 s (4H), 3.23 t (4H, 3J = 6.6 Hz),
3
4
3
6.52 t.d (2H, J = 7.9, J = 1.4 Hz), 6.63 d (2H, J =
8.0 Hz), 7.15 (2H, 3J = 7.8 Hz), 7.39 d.d (2H, 3J = 7.9,
4J = 1.4 Hz) (four NH proton signals could not be as-
signed unambiguously). 13C NMR spectrum, δC, ppm:
29.2 (2C), 42.7 (2C), 52.7 (4C), 109.5 (2C), 111.3
(2C), 117.4 (2C), 128.4 (2C), 132.3 (2C), 145.2 (2C).
13-Chloro-1,2,3,4,5,6,7,8,9,10,11,12-dodecahy-
dro-1,5,8,12-benzotetraazacyclotetradecine (VIIa)
was synthesized from 0.5 mmol (113 mg) of 2-bromo-
1,3-dichlorobenzene (VI) and 0.5 mmol (87 mg) of
tetraamine IIa in the presence of 0.04 mmol (24 mg)
of Pd(dba)2 and 0.045 mmol (28 mg) of BINAP in
25 ml of dioxane. Eluent CH2Cl2–MeOH–aq. NH3,
1,2,3,4,6,7,9,10,12,13,14,15-Dodecahydro-
5,8,11,1,15-benzotrioxadiazacycloheptadecine (IIIb)
was synthesized from 0.5 mmol (118 mg) of 1,2-di-
bromobenzene (I) and 0.5 mmol (110 mg) of trioxa-
diamine IIb in the presence of 0.08 mmol (48 mg) of
Pd(dba)2 and 0.08 mmol (31 mg) of 2′-(dicyclohexyl-
λ3-phosphanyl)-N,N-biphenyl-2-amine (DavePHOS) in
12 ml of dioxane. Eluent CH2Cl2–MeOH, 100:1.
Yield 20 mg (14%), light yellow oily substance.
1
100:20:2. Light yellow oily substance. H NMR spec-
3
trum, δ, ppm: 1.81 quint (2H, J = 5.3 Hz), 1.84 quint
3
(2H, J = 5.5 Hz), 2.75–2.79 m (2H), 2.80–2.84 m
3
1H NMR spectrum, δ, ppm: 1.93 quint (4H, J =
3
(2H), 2.85–2.92 m (4H), 2.94 t (2H, J = 5.5 Hz),
3
3
3
5.5 Hz), 3.28 q (4H, J = 5.5 Hz), 3.62–3.66 m (4H),
3.19 t (2H, J = 5.3 Hz), 6.43 d (1H, J = 8.0 Hz),
3
4
3
3.67–3.72 m (8H), 3.94 br.s (2H), 6.59–6.63 m (2H),
6.71–6.75 m (2H). 13C NMR spectrum, δC, ppm: 28.7
(2C), 42.7 (2C), 70.8 (4C), 71.1 (2C), 110.2 (2C),
118.2 (2C), 137.1 (2C). Mass spectrum: m/z 294.1990
[M]+. C16H26N2O3. Calculated: M 294.1943.
6.64 d.d (1H, J = 8.0, J = 1.1 Hz), 6.86 t (1H, J =
8.0 Hz) (four NH proton signals cannot be assigned
unambiguously). 13C NMR spectrum, δC, ppm: 27.1,
28.9, 45.7, 46.6, 47.0, 47.8, 48.5, 50.2, 108.5, 116.5,
125.3, 129.3, 134.4, 145.6. Mass spectrum: m/z
282.1622 [M]+. C14H23ClN4. Calculated: M 282.1611.
N,N′-{3,3′-[2,2′-Oxybis(ethane-2,1-diyl)bisoxy]-
bis(propane-3,1-diyl)}bis(2-bromoaniline) (IVb)
was synthesized from 0.5 mmol (118 mg) of 1,2-di-
bromobenzene (I) and 0.5 mmol (110 mg) of trioxa-
diamine IIb in the presence of 0.04 mmol (24 mg) of
Pd(dba)2 and 0.045 mmol (28 mg) of BINAP in 25 ml
of dioxane. Eluent CH2Cl2–MeOH, 200:1. Yield
N1,N1′-(Ethane-1,2-diyl)bis[N3-(2,6-dichloro-
phenyl)propane-1,3-diamine] (VIIIa) was isolated as
by-product in the synthesis of VIIa from 2 mmol
(452 mg) of 2-bromo-1,3-dichlorobenzene (VI) and
2 mmol (348 mg) of tetraamine IIa in the presence of
0.04 mmol (96 mg) of Pd(dba)2 and 0.045 mmol
(112 mg) of BINAP in 75 ml of dioxane. Eluent
1
28 mg (21%), light yellow oily substance. H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

SYNTHESIS OF POLYAZA MACROCYCLES
1359
CH2Cl2–MeOH–aq. NH3, 100:20:1, light yellow oily
δC, ppm: 30.6 (2C), 45.0 (2C), 69.2 (2C), 70.4 (2C),
70.6 (2C), 121.2 (2C), 125.8 (4C), 128.8 (4C), 142.8
(2C). Mass spectrum: m/z 507.87 [M]+.
1
substance. H NMR spectrum, δ, ppm: 1.71 quint (4H,
3
3J = 6.7 Hz), 2.67 s (4H), 2.68 t (4H, J = 6.8 Hz),
3
3.36 q (4H, J = 6.1 Hz), 4.24 br.s (2H), 6.70 t (2H,
1,23-Dichloro-5,6,7,8,10,11,13,14,16,17,18,19,24,-
25,26,27,29,30,32,33,35,36,37,38-tetracosahydrodi-
benzo[l,c1][1,4,7,18,21,24,11,14,28,31]hexaoxatetra-
azacyclotetratriacontine (IXb). Eluent CH2Cl2–
3J = 8.0 Hz), 7.16 d (4H, 3J = 8.0 Hz) (two NH proton
signals cannot be assigned unambiguously). 13C NMR
spectrum, δC, ppm: 30.9 (2C), 46.0 (2C), 47.7 (2C),
49.5 (2C), 121.3 (2C), 125.9 (4C), 128.7 (4C), 142.9
(2C). Mass spectrum: m/z 462.0877 [M]+. C20H26Cl4N4.
Calculated: M 462.0912.
1
MeOH, 50:1. Light yellow oily substance. H NMR
spectrum, δ, ppm: 1.80–1.86 m (4H), 1.89 quint (4H,
3
3
3J = 6.6 Hz), 2.95 t (4H, J = 7.0 Hz), 3.19 t (4H, J =
N1-[2-(3-Aminopropylamino)ethyl]-N3-(2,6-di-
chlorophenyl)propane-1,3-diamine (Xa) was isolated
as as the second by-product in the synthesis of VIIa.
Eluent CH2Cl2–MeOH–aq. NH3, 10:4:1. Light yellow
5.6 Hz), 3.54–3.70 m (24H), 4.71 br.s (1H), 4.89 br.s
3
4
(1H), 6.43–6.47 m (2H), 6.64 d.d (2H, J = 7.9, J =
3
1.1 Hz), 6.84 t (2H, J = 8.0 Hz) (two NH proton sig-
nals could not be assigned unambiguously). 13C NMR
spectrum, δC, ppm: 29.1 and 29.5 (2C), 30.4 and 30.5
(2C), 41.2 and 41.4 (2C), 44.2 and 44.5 (2C), 69.3 and
69.4 (2C), 69.6 (2C), 70.2 (2C), 70.3 and 70.4 (2C),
70.6 (4C), 108.3 and 108.5 (2C), 116.4 and 116.5 (2C),
124.6 and 124.7 (2C), 128.4 and 128.5 (2C), 131.3
(2C), 144.7 (2C). Mass spectrum: m/z 656.3075 [M]+.
C32H50Cl2N4O6. Calculated: m/z 656.3107.
1
oily substance. H NMR spectrum, δ, ppm: 1.57 quint
3
3
(2H, J = 6.7 Hz), 1.67 quint (2H, J = 6.6 Hz), 2.59 t
3
3
(2H, J = 6.9 Hz), 2.63 br.s (6H), 2.70 t (2H, J =
3
6.6 Hz), 3.08 br.s (4H), 3.30 t (2H, J = 6.6 Hz),
3
4.18 br.s (1H), 6.66 t (1H, J = 8.0 Hz), 7.11 d (2H,
3J = 8.0 Hz). Mass spectrum: m/z 318.1400 [M]+.
C14H24Cl2N4. Calculated: M 318.1378.
Mixture of cyclic oligomers IXb (n = 3–5). Eluent
CH2Cl2–MeOH, 10:1–3:1. Light yellow oily substance.
1H NMR spectrum, δ, ppm: 1.78–1.85 m (2 n H),
16-Chloro-1,2,3,4,6,7,9,10,12,13,14,15-dodecahy-
dro-5,8,11,1,15-benzotrioxadiazacycloheptadecine
(VIIb) was synthesized from 0.5 mmol (113 mg) of
2-bromo-1,3-dichlorobenzene (VI) and 0.5 mmol
(110 mg) of trioxadiamine IIb in the presence of
0.04 mmol (24 mg) of Pd(dba)2 and 0.045 mmol
(28 mg) of BINAP in 25 ml of dioxane. Eluent
CH2Cl2–MeOH, 200:1 to 100:1, light yellow oily sub-
3
3
1.88 quint (2n H, J = 6.5 Hz), 2.93 t (2 n H, J =
3
5.6 Hz), 3.18 t (2 n H, J = 5.7 Hz), 3.52–3.66 m
3
(12nH), 4.69 br.s (nH), 6.46 d (nH, J = 7.8 Hz),
3
3
6.63 d (n H, J = 7.9 Hz), 6.84 t (n H, J = 8.0 Hz)
(signals from n NH protons could not be assigned un-
ambiguously). 13C NMR spectrum, δC, ppm: 29.5 (nC),
30.5 (nC), 41.2 (nC), 44.4 (nC), 69.3 (nC), 69.7 (nC),
70.2 (nC), 70.3 (nC), 70.6 (2nC), 108.5 (nC), 116.5
(nC), 124.7 (nC), 128.8 (nC), 131.3 (nC), 144.7 (nC).
Mass spectrum: m/z 984.35 [M]+ (n = 3), 1312.73 [M]+
(n = 4), 1641.09 [M]+ (n = 5).
1
stance. H NMR spectrum, δ, ppm: 1.86 quint (2H,
3
3J = 5.7 Hz), 1.89 quint (2H, J = 5.9 Hz), 3.04 t (2H,
3
3J = 6.5 Hz), 3.30 q (2H, J = 5.1 Hz), 3.60–3.66 m
(4H), 3.67 s (4H), 3.70–3.74 m (4H), 4.86 br.s (1H),
3
3
6.46 d (1H, J = 8.1 Hz), 6.64 d (1H, J = 7.9 Hz),
3
6.84 t (1H, J = 8.0 Hz) (the NH proton signal could
N1-(2-Aminoethyl)-N2-(2,6-dichlorophenyl)-
ethane-1,2-diamine (Xc) was synthesized from
0.5 mmol (113 mg) of 2-bromo-1,3-dichlorobenzene
(VI) and 0.5 mmol (52 mg) of triamine IIc in the
presence of 0.04 mmol (24 mg) of Pd(dba)2 and
0.045 mmol (28 mg) of BINAP in 25 ml of dioxane.
Eluent CH2Cl2–MeOH–aq. NH3, 100:20:2 to 100:20:3.
not be assigned unambiguously). 13C NMR spectrum,
δC, ppm: 28.9, 30.6, 40.4, 43.3, 68.3, 69.1, 70.6, 70.9,
71.0 (2C), 108.1, 116.3, 124.5, 128.4, 131.4, 144.1.
Mass spectrum: m/z 328.1594 [M]+. C16H25ClN2O3.
Calculated: M 328.1554.
Compounds VIIIb and IXb were isolated as by-
products.
1
Light yellow oily substance. H NMR spectrum
3
N,N'-{3,3′-[2,2′-Oxybis(ethane-2,1-diyl)bis(oxy)]-
bis(propane-3,1-diyl)}bis(2,6-dichloroaniline)
(VIIIb). Eluent CH2Cl21–MeOH, 100:1–50:1. Light
yellow oily substance. H NMR spectrum, δ, ppm:
1.84 quint (4H, 3J = 6.4 Hz), 3.44 q (4H, 3J = 6.7 Hz),
(DMSO-d6), δ, ppm: 3.16 t (2H, J = 6.2 Hz), 3.22 t
(4H, 3J = 6.0 Hz), 3.44 br.s (2H), 4.90 br.s (1H), 6.91 t
3
3
(1H, J = 8.0 Hz), 7.33 d (2H, J = 8.0 Hz) (three NH
proton signals could not be assigned unambiguously).
13C NMR spectrum (DMSO-d6), δC, ppm: 35.5 (1C),
43.1 (1C), 44.5 (1C), 47.6 (1C), 122.7 (1C), 126.0
(2C), 129.1 (2C), 141.9 (1C). Mass spectrum:
m/z 247.11 [M]+.
3
3.57 t (4H, J = 6.2 Hz), 3.57–3.60 m (4H), 3.62–
3.66 m (4H), 4.21 t (2H, 3J = 6.4 Hz), 6.73 t (2H, 3J =
8.0 Hz), 7.19 d (4H, 3J = 8.0 Hz). 13C NMR spectrum,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

AVERIN et al.
1360
1
Light yellow oily substance. H NMR spectrum, δ,
10-Chloro-2,3,4,5,6,7,8,9-octahydro-1H-1,4,8-
ppm: 2.68 t (2H, 3J = 6.1 Hz), 2.78 t (2H, 3J = 6.1 Hz),
benzotriazacycloundecine (VIId) was synthesized
from 0.5 mmol (113 mg) of 2-bromo-1,3-dichloroben-
zene (VI) and 0.5 mmol (66 mg) of triamine IIb in the
presence of 0.08 mmol (48 mg) of Pd(dba)2 and
0.09 mmol (56 mg) of BINAP in 25 ml of dioxane.
Eluent CH2Cl2–MeOH–aq. NH3, 100:20:1. Light yel-
3
2.80–2.87 m (6H), 3.36 t (2H, J = 6.7 Hz), 4.24 br.s
3
3
(1H), 6.49 d (1H, J = 8.0 Hz), 6.53 t (1H, J =
7.9 Hz), 6.62 d (1H, 3J = 7.9 Hz) (three NH proton sig-
nals could not be assigned unambiguously). 13C NMR
spectrum, δC, ppm: 40.8, 42.1, 46.8, 48.6, 52.5, 52.9,
110.1, 118.1, 118.5, 130.5, 130.8, 136.3. Mass spec-
trum: m/z 254.76 [M + H]+.
1
low oily substance. H NMR spectrum, δ, ppm:
3
3
1.71 quint (2H, J = 5.0 Hz), 1.86 quint (2H, J =
3
3
5.4 Hz), 3.03 t (2H, J = 5.6 Hz), 3.07 t (2H, J =
5.3 Hz), 3.16 t (2H, J = 4.7 Hz), 3.26 t (2H, J =
12-Chloro-2,3,4,5,6,7,8,9,10,11-decahydro-1H-
1,4,8,11-benzotetraazacyclotridecine (VIIf) was syn-
thesized from 0.5 mmol (113 mg) of 2-bromo-1,3-di-
chlorobenzene (VI) and 0.5 mmol (80 mg) of tetra-
amine IIf in the presence of 0.04 mmol (24 mg) of
Pd(dba)2 and 0.045 mmol (28 mg) of BINAP in 25 ml
of dioxane. Eluent CH2Cl2–MeOH–aq. NH3, 100:20:2.
3
3
3
5.5 Hz), 4.70 br.s (1H), 6.61 d (1H, J = 7.6 Hz),
6.79 d (1H, 3J = 8.0 Hz), 6.87 t (1H, 3J = 7.9 Hz) (two
NH proton signals could not be assigned unambigu-
ously). 13C NMR spectrum, δC, ppm: 26.0, 28.1, 40.4,
44.7, 47.6, 49.1, 108.3, 116.9, 122.9 (three quaternary
carbon signals could not be assigned unambiguously).
Mass spectrum: m/z 239.18 [M]+.
1
Light yellow oily substance. H NMR spectrum, δ,
3
3
ppm: 1.76 quint (2H, J = 6.6 Hz), 2.67 t (4H, J =
A mixture of cyclic oligomers IXd (n = 2–5) was
isolated as by-product. Eluent CH2Cl2–MeOH–aq.
NH3, 100:20:2 to 100:20:3. Light yellow oily sub-
6.6 Hz), 2.80 br.s (4H), 3.31 br.s (4H), 6.42 d (1H, 3J =
3
3
7.9 Hz), 6.51 t (1H, J = 7.9 Hz), 6.58 d (1H, J =
7.9 Hz) (four NH proton signals could not be assigned
unambiguously). 13C NMR spectrum, δC, ppm: 26.4,
40.3, 43.7, 47.3, 47.5, 49.4, 51.8, 109.2, 117.2, 118.0,
128.7, 130.2, 135.6. Mass spectrum: m/z 268.80
[M + H]+.
1
stance. H NMR spectrum, δ, ppm: 2.06 br.s (4nH),
2.82–3.22 m (8nH), 6.33 d (3J = 8.2 Hz) and 6.34 d
(3J = 8.0 Hz) (nH), 6.62 t (3J = 7.6 Hz) and 6.64 t (3J =
7.4 Hz) (nH), 6.82 t (3J = 8.1, nH) (NH proton signals
could not be assigned unambiguously). Mass spec-
trum: m/z 478.20 [M]+ (n = 2), 717.26 [M]+ (n = 3),
956.18 [M]+ (n = 4), 1196.01 [M]+ (n = 5).
14-Chloro-2,3,4,5,6,7,8,9,10,11,12,13-dodecahy-
dro-1H-1,5,9,13-benzotetraazacyclopentadecine
(VIIg) was synthesized from 0.5 mmol (113 mg) of
2-bromo-1,3-dichlorobenzene (VI) and 0.5 mmol
(94 mg) of tetraamine IIg in the presence of
0.04 mmol (24 mg) of Pd(dba)2 and 0.045 mmol
(28 mg) of BINAP in 25 ml of dioxane. Eluent
CH2Cl2–MeOH–aq. NH3, 100:20:1 to 100:20:2. Light
N-(2,6-Dichlorophenyl)-N′-[3-(2,6-dichlorophen-
ylamino)propyl]propane-1,3-diamine (VIIId) was
synthesized from 0.5 mmol (113 mg) of 2-bromo-1,3-
dichlorobenzene (VI) and 0.5 mmol (66 mg) of
triamine IIb in the presence of 0.04 mmol (24 mg) of
Pd(dba)2 and 0.045 mmol (28 mg) of BINAP in 25 ml
of dioxane. Eluent CH2Cl2–MeOH, 10:1. Light yellow
1
yellow oily substance. H NMR spectrum, δ, ppm:
1.80 quint (2H, J = 6.5 Hz), 1.87 quint (2H, J =
3
3
1
3
oily substance. H NMR spectrum, δ, ppm: 1.73 quint
5.3 Hz), 1.96 quint (2H, J = 5.9 Hz), 2.82–2.86 m
(4H, 3J = 6.8 Hz), 2.70 t (4H, 3J = 6.8 Hz), 3.37 t (4H,
(4H), 2.89 t (2H, 3J = 5.2 Hz), 2.95 t (2H, 3J = 5.5 Hz),
3J = 6.7 Hz), 4.21 br.s (2H), 6.71 t (2H, 3J = 8.0 Hz),
3
3
2.99 t (2H, J = 5.8 Hz), 3.33 t (2H, J = 5.0 Hz),
3
3
7.17 d (4H, J = 8.0 Hz) (NH proton signals could not
5.07 br.s (1H), 6.47 d (1H, J = 8.0 Hz), 6.70 d (1H,
be assigned unambiguously). 13C NMR spectrum, δC,
ppm: 30.9 (2C), 46.0 (2C), 47.9 (2C), 121.3 (2C),
126.0 (4C), 128.7 (4C), 142.8 (2C). Mass spectrum:
m/z 419.10 [M]+.
3J = 8.1 Hz), 6.86 t (1H, 3J = 8.0 Hz) (three NH proton
signals could not be assigned unambiguously).
13C NMR spectrum, δC, ppm: 25.9, 26.2, 27.7, 42.6,
43.0, 46.0, 48.4, 49.0, 50.6, 108.7, 117.5, 124.9, 130.1,
131.7, 144.3. Mass spectrum: m/z 296.07 [M]+.
11-Chloro-1,2,3,4,5,6,7,8,9,10-decahydro-
1,4,7,10-benzotetraazacyclododecine (VIIe) was syn-
thesized from 0.5 mmol (113 mg) of 2-bromo-1,3-di-
chlorobenzene (VI) and 0.5 mmol (73 mg) of tetra-
amine IIe in the presence of 0.04 mmol (24 mg) of
Pd(dba)2 and 0.045 mmol (28 mg) of BINAP in 25 ml
of dioxane. Eluent CH2Cl2–MeOH–aq. NH3, 100:20:2.
N1,N1′-(Propane-1,3-diyl)bis[N3-(2,6-dichloro-
phenyl)propane-1,3-diamine] (VIIIg) was isolated as
by-product. Eluent CH2Cl2–MeOH–aq. NH3, 100:20:2.
1
Light yellow oily substance. H NMR spectrum, δ,
ppm: 1.91–2.00 m (6H), 2.74–2.81 m (8H), 3.19 t (4H,
3J = 6.5 Hz), 6.75 t (2H, J = 8.0 Hz), 7.19 t (4H, J =
3
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

SYNTHESIS OF POLYAZA MACROCYCLES
1361
8.0 Hz) (four NH proton signals could not be assigned
unambiguously). 13C NMR spectrum, δC, ppm: 29.6
(2C), 29.9 (1C), 45.8 (2C), 47.8 (2C), 48.6 (2C), 121.9
(2C), 127.7 (4C), 128.8 (4C), 142.1 (2C). Mass spec-
trum: m/z 475.95 [M]+.
amino]ethyl}ethane-1,2-diamine (VIIIi) was isolated
as by-product. Eluent CH2Cl2–MeOH–aq. NH3, 100:
1
20:3. Light yellow oily substance. H NMR spectrum,
δ, ppm: 2.75–2.85 m (16H), 3.32–3.43 m (4H), 6.73 t
3
3
(2H, J = 7.9 Hz), 7.18 t (4H, J = 7.9 Hz) (signals
from six NH protons could not be assigned unambigu-
ously). 13C NMR spectrum, δC, ppm: 46.7 (2C), 48.5
(2C), 48.8 (2C), 49.0 (2C), 49.4 (2C), 121.3 (2C),
125.9 (4C), 128.7 (4C), 142.9 (2C).
14-Chloro-2,3,4,5,6,7,8,9,10,11,12,13-dodecahy-
dro-1H-1,4,7,10,13-benzopentaazacyclopentadecine
(VIIh) was synthesized from 0.5 mmol (113 mg) of
2-bromo-1,3-dichlorobenzene (VI) and 0.5 mmol
(95 mg) of pentaamine IIh in the presence of
0.04 mmol (24 mg) of Pd(dba)2 and 0.045 mmol
(28 mg) of BINAP in 25 ml of dioxane. Eluent
CH2Cl2–MeOH–aq. NH3, 100:20:3. Light yellow oily
11-Chloro-1,2,3,5,6,8,9,10-octahydro-4,7,1,10-
benzodioxadiazacyclododecine (VIIj) was synthe-
sized from 0.5 mmol (113 mg) of 2-bromo-1,3-di-
chlorobenzene (VI) and 0.5 mmol (74 mg) of dioxa
diamine IIj in the presence of 0.04 mmol (24 mg) of
Pd(dba)2 and 0.045 mmol (28 mg) of BINAP in 25 ml
of dioxane. Eluent CH2Cl2–MeOH, 100:1. Light brown
1
substance. H NMR spectrum, δ, ppm: 2.61–2.85 m
(12H), 3.35 br.s (2H), 3.43 br.s (2H), 6.47 d.d (1H, 3J =
4
3
7.9, J = 1.4 Hz), 6.52 t (1H, J = 7.9 Hz), 6.62 d.d
3
4
1
(1H, J = 7.9, J = 1.4 Hz) (signals from five NH pro-
tons could not be assigned unambiguously). 13C NMR
spectrum, δC, ppm: 40.4, 46.2, 48.2, 48.9 (2C), 49.4,
51.8, 51.9, 109.5, 117.7, 118.0, 128.7, 130.4, 135.7.
Mass spectrum: m/z 296.86 [M]+.
crystals, mp 85–87°C. H NMR spectrum, δ, ppm:
3
3.17–3.22 m (4H), 3.59 t (2H, J = 4.3 Hz), 3.67–
3
3.70 m (2H), 3.75–3.78 m (2H), 3.87 t (2H, J =
3
4.9 Hz), 6.04 br.s (1H), 6.44 d (1H, J = 8.0 Hz),
3
3
6.65 d (1H, J = 7.9 Hz), 6.86 t (1H, J = 8.0 Hz) (the
NH proton signal could be assigned unambiguously).
13C NMR spectrum, δC, ppm: 43.4, 46.4, 69.4, 69.5,
70.3, 70.8, 108.4, 116.5, 124.8, 129.0, 130.9, 145.0.
Mass spectrum: m/z 256.06 [M]+.
N1-(2,6-Dichlorophenyl)-N2-{2-[2-(2-[2,6-di-
chlorophenylamino]ethylamino)ethylamino]ethyl}-
ethane-1,2-diamine (VIIIh) was isolated as by-prod-
uct. Eluent CH2Cl2–MeOH–aq. NH3, 100:20:3. Light
1
yellow oily substance. H NMR spectrum, δ, ppm:
15-Chloro-1,2,3,4,6,7,8,9,11,12,13,14-dodecahy-
dro-5,10,1,14-benzodioxadiazacyclohexadecine
(VIIk) was synthesized from 0.5 mmol (113 mg) of
2-bromo-1,3-dichlorobenzene (VI) and 0.5 mmol
(102 mg) of dioxa diamine IIk in the presence of
0.04 mmol (24 mg) of Pd(dba)2 and 0.045 mmol
(28 mg) of BINAP in 25 ml of dioxane. Eluent
CH2Cl2–MeOH, 200:1. Light yellow oily substance.
1H NMR spectrum, δ, ppm: 1.71–1.76 m (4H),
3
2.73 s (8H), 2.82 t (4H, J = 5.7 Hz), 3.32–3.44 m
(4H), 6.73 t (2H, 3J = 8.1 Hz), 7.19 d (4H, 3J = 8.1 Hz)
(signals from five NH protons could not be assigned
unambiguously). 13C NMR spectrum, δC, ppm: 46.9
(2C), 49.0 (2C), 49.4 (2C), 49.5 (2C), 121.3 (2C),
125.3 (4C), 128.8 (4C), 143.0 (2C).
17-Chloro-1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16-
hexadecahydro-1,4,7,10,13,16-benzohexaazacyclo-
octadecine (VIIi) was synthesized from 0.5 mmol
(113 mg) of 2-bromo-1,3-dichlorobenzene (VI) and
0.5 mmol (116 mg) of hexaamine IIi in the presence of
0.04 mmol (24 mg) of Pd(dba)2 and 0.045 mmol
(28 mg) of BINAP in 25 ml of dioxane. Eluent
CH2Cl2–MeOH–aq. NH3, 100:20:3. Light yellow oily
3
3
1.83 quint (2H, J = 5.6 Hz), 1.84 quint (2H, J =
3
3
5.9 Hz), 3.05 t (2H, J = 6.2 Hz), 3.35 q (2H, J =
5.0 Hz), 3.51–3.55 m (4H), 3.58 t (2H, J = 5.4 Hz),
3
3
3.66 t (2H, J = 5.5 Hz), 5.02 br.s (1H), 6.47 d (1H,
3J = 8.1 Hz), 6.64 d (1H, 3J = 8.0 Hz), 6.85 t (1H, 3J =
8.0 Hz) (the NH proton signal could not be assigned
unambiguously. 13C NMR spectrum, δC, ppm: 26.0
(2C), 28.6, 30.3, 39.7, 43.2, 66.3, 67.5, 70.0, 70.9,
107.9, 116.1, 124.6, 129.0, 131.2, 144.1. Mass spec-
trum: m/z 312.06 [M]+.
1
substance. H NMR spectrum, δ, ppm: 2.75–2.85 m
3
4
(16H), 3.32–3.43 m (4H), 6.47 d.d (1H, J = 7.5, J =
3
3
1.8 Hz), 6.52 t (1H, J = 7.5 Hz), 6.61 d.d (1H, J =
7.5, 4J = 1.8 Hz) (signals from six NH protons could be
assigned unambiguously). 13C NMR spectrum, δC,
ppm: 40.3, 46.2, 46.5, 46.8, 48.1 (2C), 48.7 (2C), 51.8
(2C), 109.5, 117.5, 118.0, 129.5, 131.4, 135.0. Mass
spectrum: m/z 340.01 [M]+.
N,N′-{3,3′-[Butane-1,4-diylbis(oxy)]bis(propane-
3,1-diyl)}bis(2,6-dichloroaniline) (VIIIk). Eluent
CH2Cl2–MeOH, 200:1 to 100:1. Light yellow oily sub-
1
stance. H NMR spectrum, δ, ppm: 1.63 br.s (4H),
N1-(2-Chlorophenyl)-N2-{2-[2-(2-[2-(2,6-di-
chlorophenylamino)ethylamino]ethylamino)ethyl-
1.83 quint (4H, 3J = 6.3 Hz), 3.42 br.s (4H), 3.43 t (4H,
3
3
3J = 6.9 Hz), 3.51 t (4H, J = 6.0 Hz), 4.25 t (2H, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

AVERIN et al.
1362
3
3
6.5 Hz), 6.72 t (2H, J = 8.0 Hz), 7.18 t (4H, J =
8.0 Hz). 13C NMR spectrum, δC, ppm: 26.4 (2C), 30.6
(2C), 45.0 (2C), 68.7 (2C), 70.8 (2C), 121.1 (2C),
125.7 (4C), 128.7 (4C), 142.8 (2C). Mass spectrum:
m/z 492.0943 [M]+. C22H28Cl4N2O2. Calculated:
m/z 492.0905.
decanting, the precipitate was washed with a small
amount of methylene chloride, the washings were
combined with the organic phase and evaporated, and
the solid residue was subjected to chromatography on
silica gel using the following solvent systems as
eluents (in succession): CH2Cl2; CH2Cl2–MeOH,
200:1 to 3:1; CH2Cl2–MeOH–aq. NH3, 100:20:1 to
10:4:1. The yields are given in Table 2.
1,22-Dichloro-5,6,7,8,10,11,12,13,15,16,17,18,23,-
24,25,26,28,29,30,31,33,34,35,36-tetracosahydrodi-
benzo[f,v][1,12,17,28,5,8,21,24]tetraoxatetraaza-
cyclodotriacontine (IXk). Eluent CH2Cl2–MeOH,
100:1. Light yellow oily substance. H NMR spec-
trum, δ, ppm: 1.64–1.70 m (8H), 1.82 quint (4H, J =
6.3 Hz), 1.90 quint (4H, J = 6.1 Hz), 2.99 t (4H, J =
6.7 Hz), 3.22 t (4H, J = 6.2 Hz), 3.42–3.47 m (8H),
3.54 t (4H, J = 6.0 Hz), 3.58 t (4H, J = 6.0 Hz),
4.95 br.s (2H), 6.46 d (2H, J = 8.0 Hz), 6.65 d (2H,
N1-{3-[2-(3-Aminopropylamino)ethylamino]-
propyl}-3-chloro-N2-(3-{2-[3-(2,6-dichlorophenyl-
amino)propylamino]ethylamino}propyl)benzene-
1,2-diamine (XIa) was obtained from compound
VIIIa. Eluent CH2Cl2–MeOH–aq. NH3, 100:20:3.
1
3
3
3
1
3
Light yellow oily substance. H NMR spectrum, δ,
3
3
ppm: 1.67–1.85 m (8H), 2.63–2.78 m (14H), 2.89 br.s
3
3
(4H), 3.05–3.16 m (4H), 3.34 t (2H, J = 6.0 Hz),
3
3J = 8.1 Hz), 6.85 t (2H, 3J = 8.0 Hz) (signals from two
NH protons could not be assigned unambiguously).
13C NMR spectrum, δC, ppm: 26.5 (2C), 26.6 (2C),
29.1 (2C), 30.6 (2C), 41.6 (2C), 44.2 (2C), 68.7 (2C),
69.3 (2C), 70.8 (2C), 71.0 (2C), 108.3 (2C), 116.4
(2C), 124.6 (2C), 128.8 (2C), 131.4 (2C), 144.7 (2C).
Mass spectrum: m/z 624.3209 [M]+. C32H50Cl2N4O4.
Calculated: M 624.3165.
3.60 br.s (3H), 6.38 d (1H, J = 8.1 Hz), 6.60 d (1H,
3
3
3J = 6.6 Hz), 6.69 t (1H, J = 8.0 Hz), 6.80 t (1H, J =
3
7.8 Hz), 7.15 d (2H, J = 8.0 Hz) (signals from six
NH protons could not be assigned unambiguously).
13C NMR spectrum, δC, ppm: 28.4 (1C), 29.5 (1C),
30.5 (2C), 42.0 (1C), 42.2 (2C), 45.0 (1C), 47.6 (4C),
48.2 (1C), 48.3 (1C), 49.0 (2C), 108.4 (1C), 116.3
(1C), 121.3 (1C), 124.5 (1C), 125.9 (2C), 128.6 (3C),
131.2 (1C), 142.5 (1C), 144.4 (1C). Mass spectrum:
m/z 600.18 [M]+.
Cyclic oligomers IXk (n > 2) were isolated as
a mixture of by-products in the synthesis of compound
VIId. Eluent CH2Cl2–MeOH, 50:1. Light yellow oily
Cyclic dimer (IXb) was obtained from 0.5 mmol
(110 mg) of triamine IIb. Eluent CH2Cl2–MeOH, 50:1
to 20:1. Light yellow oily substance. The NMR and
mass spectra of IXb are given above.
1
substance. H NMR spectrum, δ, ppm: 1.60–1.69 m
3
(2nH), 1.83 quint (nH, J = 5.8 Hz), 1.89 quint (nH,
3J = 6.3 Hz), 2.95 q (nH, J = 5.3 Hz), 3.19 br.s (nH),
3
3.43 br.s (2nH), 3.47–3.57 m (2nH), 4.75 br.s (nH),
1,17-Dichloro-5,6,7,8,9,10,11,12,13,18,19,20,-
21,22,23,24,25,26-octadecahydrodibenzo[b,m]-
[1,4,8,12,15,19]hexaazacyclodocosine (IXd) was syn-
thesized from 0.5 mmol (66 mg) of triamine IId.
Eluent CH2Cl2–MeOH–aq. NH3, 100:20:2. Light yel-
3
6.44–6.50 m (nH), 6.64 d (nH, J = 8.0 Hz), 6.84 t
(nH, 3J = 8.0) (signals from n NH protons could not be
assigned unambiguously).
Cyclic dimers IXa, IXb, IXd, IXj, and IXk
(general procedure). A mixture of 1.25 mmol (283 mg)
of 2-bromo-1,3-dichlorobenzene (VI), 0.02 mmol
(12 mg) of Pd(dba)2, 0.023 mol (14 mg) of BINAP,
5 ml of anhydrous dioxane, 0.5 mmol of diamine IIa,
IIb, IId, IIj, or IIk, and 1.5 mmol (144 mg) of sodium
tert-butoxide was heated for 6 h under reflux in an
argon atmosphere. The mixture was cooled, a sample
containing N,N′-diaryl derivative VIIIa, VIIIb, VIIId,
VIIIj, or VIIIk was withdrawn to record NMR and
MALDI-TOF mass spectra, 7 ml of anhydrous diox-
ane, 0.08 mmol (46 mg) of Pd(dba)2, 0.09 mol (56 mg)
of BINAP, 0.5 mmol of the corresponding amine II,
and 1.5 mmol (144 mg) of sodium tert-butoxide were
added, and the mixture was heated for 24–30 h under
reflux. After cooling, the solution was separated by
1
low oily substance. H NMR spectrum, δ, ppm:
3
3
1.87 quint (4H, J = 6.9 Hz), 1.91 quint (4H, J =
3
3
6.1 Hz), 2.84 t (4H, J = 6.7 Hz), 2.87 t (4H, J =
6.8 Hz), 2.97 t (4H, J = 6.7 Hz), 3.20 t (4H, J =
6.2 Hz), 5.28 br.s (2H), 6.43 d (2H, J = 7.8 Hz),
3
3
3
6.65 d.d (2H, 3J = 8.1 Hz, 4J = 1.0 Hz), 6.85 t (2H, 3J =
8.0 Hz) (signals from four NH protons could not be
assigned unambiguously). 13C NMR spectrum, δC,
ppm: 30.3 (2C), 30.6 (2C), 42.5 (2C), 44.7 (2C), 47.6
(2C), 48.3 (2C), 108.4 (2C), 116.6 (2C), 124.8 (2C),
128.8 (2C), 131.2 (2C), 144.8 (2C). Mass spectrum:
m/z 478.2477 [M]+. C24H36Cl2N6. Calculated:
M 478.2379.
N1-[3-(3-Aminopropylamino)propyl]-3-chloro-
N2-{3-[3-(2,6-dichlorophenylamino)propylamino]-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

SYNTHESIS OF POLYAZA MACROCYCLES
1363
propyl}benzene-1,2-diamine (XId) was isolated as
δC, ppm: 43.2 (1C), 46.9 (1C), 69.5 (1C), 70.4 (1C),
70.5 (2C), 111.4 (1C), 117.3 (1C), 119.5 (1C), 121.6
(1C), 126.2 (2C), 127.7 (1C), 128.8 (2C), 129.1 (1C),
142.7 (1C), 144.0 (1C). Mass spectrum: m/z 402.0694
[M]+. C18H21Cl3N2O2. Calculated: M 402.0669.
the second product. Eluent CH2Cl2–MeOH–aq. NH3,
1
100:20:3. Light yellow oily substance. H NMR spec-
3
trum, δ, ppm: 1.69 quint (2H, J = 6.8 Hz), 1.73–
3
1.87 m (6H), 2.69–2.78 m (8H), 2.81 t (2H, J =
3
3
6.1 Hz), 2.92 t (2H, J = 6.2 Hz), 3.14 t (2H, J =
5.8 Hz), 3.37 t (2H, 3J = 6.7 Hz), 4.02 br.s (3H), 6.43 d
(1H, 3J = 7.6 Hz), 6.63 d (1H, 3J = 8.0 Hz), 6.73 t (1H,
3J = 8.0 Hz), 6.83 t (1H, 3J = 8.0 Hz), 7.18 d (2H, 3J =
8.0 Hz) (signals from four NH protons could not be as-
signed unambiguously). 13C NMR spectrum, δC, ppm:
28.9 (1C), 30.3 (2C), 31.0 (1C), 40.2 (1C), 42.0 (2C),
45.2 (1C), 47.5 (1C), 47.6 (1C), 47.7 (1C), 47.8 (1C),
108.6 (1C), 116.7 (1C), 121.5 (1C), 124.7 (1C), 126.1
(2C), 128.7 (3C), 131.3 (1C), 142.7 (1C), 144.5 (1C).
Mass spectrum: m/z 514.24 [M]+.
N,N′-{2,2′-[Ethane-1,2-diylbis(oxy)]bis(ethane-
2,1-diyl)}bis(2-chloroaniline) (XIIIj). Eluent
CH2Cl2–MeOH, 500:1. Light yellow oily substance.
3
1H NMR spectrum, δ, ppm: 3.35 t (4H, J = 5.2 Hz),
3
3.68 s (4H), 3.74 t (4H, J = 5.4 Hz), 4.66 br.s (2H),
3
3
6.63 t (2H, J = 7.7 Hz), 6.66 d (2H, J = 7.8 Hz),
3
4
3
7.12 t.d (2H, J = 7.7, J = 0.9 Hz), 7.24 d.d (2H, J =
7.7, J = 0.8 Hz). 13C NMR spectrum, δC, ppm: 43.2
4
(2C), 69.5 (2C), 70.5 (2C), 111.3 (2C), 117.3 (2C),
119.5 (2C), 127.7 (2C), 129.1 (2C), 144.0 (2C). Mass
spectrum: m/z 368.1083 [M]+. C18H22Cl2N2O2. Calcu-
lated: M 368.1058.
N,N′-[2,2′-(Ethane-1,2-diylbisoxy)bis(ethane-2,1-
diyl)]bis(2,6-dichloroaniline) (VIIIj) was synthesized
from 1.25 mmol (283 mg) of 2-bromo-1,3-dichloro-
benzene (VI) and 0.5 mmol (74 mg) of diamine IIj.
Yield 85% (in the reaction mixture). Light yellow oily
substance. 1H NMR spectrum, δ, ppm: 3.51 q (4H, 3J =
Cyclic dimer (IXk) was synthesized from 0.5 mmol
(102 mg) of diamine IIk. Eluent CH2Cl2–MeOH,
100:1 to 50:1. Light yellow oily substance. The NMR
and mass spectra are given above.
This study was performed under financial support
by the Russian Academy of Sciences (program P-8
“Development of Methodologies of Organic Synthesis
and Design of Compounds with Practically Important
Properties”) and by the Russian Foundation for Basic
Research (project nos. 06-03-32376, 08-03-00628).
3
5.5 Hz), 3.60 t (4H, J = 5.0 Hz), 3.63 s (4H), 4.51 t
(2H, 3J = 6.0 Hz), 6.74 t (2H, 3J = 8.0 Hz), 7.19 d (4H,
3J = 8.0 Hz). 13C NMR spectrum, δC, ppm: 46.9 (2C),
70.4 (2C), 70.5 (2C), 121.6 (2C), 126.2 (2C), 128.8
(2C), 142.7 (2C).
1,18-Dichloro-5,6,7,9,10,12,13,14,19,20,21,-
23,24,-26,27,28-hexadecahydrodibenzo[h,t]-
[1,4,13,16,7,10,19,22]tetraoxatetraazacyclotetra-
cosine (IXj) was synthesized from 0.5 mmol (74 mg)
of diamine IIj. Eluent CH2Cl2–MeOH, 100:1. Light
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3
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3
3J = 5.0 Hz), 3.62 t (2H, J = 5.1 Hz), 3.66 s (4H),
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3
3
7.7 Hz), 6.66 d (1H, J = 7.8 Hz), 6.76 t (1H, J =
3
3
7.8 Hz), 7.12 t (1H, J = 7.7 Hz), 7.21 d (2H, J =
7.8 Hz), 7.24 d (1H, 3J = 7.7 Hz). 13C NMR spectrum,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009

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1364
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 9 2009