Synthesis of tethered bis-macrocycles by cross-coupling of N-(3,5-dibromobenzyl)azacrowns with α,ω-diamino compounds

Article abstract of DOI:10.1016/j.mencom.2011.04.005

Palladium-catalyzed cross-coupling of N-(3,5-dibromobenzyl) derivatives of 1-aza-15-crown-5 and 1-aza-18-crown-6 with a,w-diamino compounds afforded macrocyclization products comprising two tethered different azacrowns.

Full text of DOI:10.1016/j.mencom.2011.04.005

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 132–133
Synthesis of tethered bis-macrocycles by cross-coupling
of N-(3,5-dibromobenzyl)azacrowns with a,w-diamino compounds
Maksim V. Anokhin,a Alexei D. Averin,*a Alexei K. Buryakb and Irina P. Beletskayaa,b
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 939 1139; e-mail: averin@org.chem.msu.ru
b A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences,
119991 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2011.04.005
Palladium-catalyzed cross-coupling of N-(3,5-dibromobenzyl) derivatives of 1-aza-15-crown-5 and 1-aza-18-crown-6 with a,w-diamino
compounds afforded macrocyclization products comprising two tethered different azacrowns.
Br
Br
Macrocyclic compounds containing two azacrown moieties are
known for about 20 years and they are of constant interest due
to unique coordination properties. General approaches to various
bicyclic cryptands and more sophisticated polycyclic supercryp-
tands and macropolycycles with isolated rings comprising aza-
crown ethers were developed by Krakowiak et al.1–3 using simple
nucleophilic substitution reactions. Many valuable compounds
contain two symmetrically arranged azacrown moieties attached
to various linkers, such as aromatic backbone,4,5 metallocenes,6
porphyrin,7 or simple functionalized alkane.8 Azacrown ethers can
be attached to calixarenes as substituents9 or form calixcrowns.10–12
To create fluorescent sensors on the basis of such macrobicyclic
compounds, fluorophores like coronene,10 perylene,11 anthracene,12
coumarin,13 or BODIPY14 were introduced as substituents via linkers
or were incorporated in the macrocycle. Bis(azacrown) ethers
were tested as photosensors for K+, Cs+,Ag+ and Ba2+ ions.11,12,14
According to literature data, in the majority of cases two identical
azacrown moieties are present in the polycyclic molecules.
As cyclen and cyclam can be regarded as tetraazacrown ethers,
it is worth noting that König15 synthesized bis(triBOCcyclen)-
substituted benzene and pyridine using Pd-catalyzed amination.
In the meantime, we proposed the Pd-catalyzed amination of
1,8-dichloroanthracene with 1-aza-15-crown-5 and trimethyl-
cyclam for the synthesis of face-to-face arranged bis-macro-
cycles.16 Recently, we have also accessed 1,3-bis(trimethylcyclen)-
and 1,3-bis(trimethylcyclam)-substituted benzenes.17 Here we
report a simple and enough general route to bis(azacrown) ethers
with two different isolated azacrown fragments.
Br
+
Br
O
O
n
n
O
HN
O
N
K2CO3
MeCN
reflux
O
O
O
O
Br
1 n = 1
2 n = 2
3 n = 1, 95%
4 n = 2, 90%
Pd(dba)2/L (8/9 mol%)
ButONa, dioxane, reflux
L = BINAP or DavePHOS
H2N
X
NH2
5a–d
X
O
a X =
b X =
c X =
O
O
HN
NH
O
O
O
n
N
H
O
N
H
N
d X =
O
O
N
H
6a–d n = 1
7a–d n = 2
Scheme 1
amination with equimolar amounts of trioxadiamine 5a, dioxa-
diamine 5b, triamine 5c and tetraamine 5d to afford the corre-
sponding bis-macrocyclic compounds 6a–d and 7a–d. The reac-
tions were run in refluxing dioxane (c 0.02 m) for 24 h using
8 mol% Pd(dba)2 and ButONa as base (Scheme 1, Table 1).‡
DavePHOS (2-dicyclohexylphosphino-2'-dimethylaminobiphenyl)
1-Aza-15-crown-5 1 and 1-aza-18-crown-6 2 were reacted
with 1 equiv. of 3,5-dibromobenzyl bromide in boiling acetonitrile
using K2CO3 as base to produce corresponding N-(3,5-dibromo-
benzyl) derivatives 3 and 4 in 95% and 90% yields, respectively
(Scheme 1).† These compounds were subjected to Pd-catalyzed
13C NMR (100.6 MHz, CDCl3) d: 54.4 (2C), 59.6 (1C), 69.8 (2C), 70.2
(2C), 70.5 (2C), 71.0 (2C), 122.7 (2C), 130.3 (2C), 132.4 (1C), 144.3 (1C).
MALDI-TOF, m/z: 465.0146 (M+); calcd for C17H25Br2NO4: 465.0150.
7-(3,5-Dibromobenzyl)-1,4,10,13,16-pentaoxa-7-azacyclooctadecane 4
was synthesized analogously to compound 3, starting from 1-aza-18-crown-6
2 (3.8 mmol, 1 g), 3,5-dibromobenzyl bromide (3.8 mmol, 1.25 g) in dry
acetonitrile (12 ml) and potassium carbonate (10.4 mmol, 1.44 g). A yel-
†
7-(3,5-Dibromobenzyl)-1,4,10,13-tetraoxa-7-azacyclopentadecane 3.
A flask equipped with a condenser and a magnetic stirrer was charged
with 1-aza-15-crown-5 1 (3 mmol, 657 mg) and 3,5-dibromobenzyl bromide
(3.04 mmol, 1 g) dissolved in dry acetonitrile (10 ml). Potassium carbonate
(7.68 mmol, 1.06 g) was added and the reaction mixture was refluxed for
24 h. After cooling to ambient temperature the precipitate was filtered off,
acetonitrile evaporated in vacuo, the residue was taken with dichloro-
methane (10 ml), filtered, washed with water (10 ml), organic phase was
dried over MgSO4, solvent was evaporated in vacuo to give product 3 as
a yellowish oil. Yield 1.33 g (95%). 1H NMR (400 MHz, CDCl3) d: 2.75
(t, 4H, J 5.9 Hz), 3.61 (t, 4H, J 6.5 Hz), 3.61–3.64 (m, 6H), 3.67 (s, 4H),
3.66–3.69 (m, 4H), 7.44 (d, 2H, J 1.4 Hz), 7.50 (t, 1H, J 1.4 Hz).
1
lowish oil. Yield 1.75 g (90%). H NMR (400 MHz, CDCl3) d: 2.73 (t,
4H, J 5.2 Hz), 3.50–3.60 (m, 16H), 3.61 (s, 4H), 3.63 (s, 2H), 7.30 (br.s,
2H), 7.46 (t, 1H, J 1.5 Hz). 13C NMR (100.6 MHz, CDCl3) d: 54.4 (2C),
56.5 (1C, line width 15 Hz), 68.3 (2C, line width 10 Hz), 69.9 (2C), 70.0
(2C), 70.1 (2C), 70.2 (2C), 122.6 (2C), 130.4 (2C), 132.3 (1C), 143.1 (1C);
MALDI-TOF, m/z: 509.0429 (M+); calc. for C19H29Br2NO5: 509.0412.
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 132–133
Table 1 Synthesis of bis-macrocycles 6 and 7.
formed better (entries 9, 10). The reaction with triamine 5c
catalyzed by Pd0/BINAP system provided 27% yield of the target
macrobicycle 7c (entry 11). As for tetraamine 5d, only BINAP
catalyzed the reaction (entries 12, 13). We may explain poorer
yields of the macrocycles 7a–d by the difference in the ability of
1-aza-15-crown-5 and 1-aza-18-crown-6 to coordinate Na+ what
changes substantially the efficacy of ButONa as base which is
crucial for the intramolecular diamination process.
Entry
Dibromide
Diamine
Liganda
Yields of 6 and 7b
1
2
3
4
5
6
7
8
9
10
11
12
13
3
3
3
3
3
3
4
4
4
4
4
4
4
5a
5b
5c
5d
5a
5d
5a
5a
5b
5b
5c
5d
5d
DavePHOS
DavePHOS
DavePHOS
DavePHOS
BINAP
BINAP
BINAP
DavePHOS
BINAP
DavePHOS
BINAP
6a, 53%
6b, 41%
6c, 29%
6d, 28%
6a, 5%
6d, 28%
7a, 32%c
In the NMR spectra of bis-macrocycles 6a–c and 7a–c some
signals are broad (line widths up to 100 Hz in 1H NMR and 200 Hz
in 13C NMR). This fact can be explained by a hindered rotation
ofthebenzylgroupduetoitsfusionwiththesecondazamacrocycle
and possibly by through-the-space interactions of closely arranged
macrorings. In previous investigations we often obtained cyclic
dimers and oligomers as by-products in the macrocycles synthesis
by the Pd-catalyzed amination of dihaloarenes. However, in the
described reactions with compounds 3 and 4 we did not observe
formation of such cyclooligomers. As no unreacted stating com-
pounds were found in the reaction mixtures after the completion
of reactions, it is likely that linear oligomers were formed as side
products.
In conclusion, we worked out a simple and efficient access to
bis-macrocycles consisting of two different azacrown moieties
using Pd-catalyzed amination, demonstrated the possibility to
vary the size of the second macrocycle and the number of N and
O atoms in it, and revealed the substrate dependence of the yields
of the target products. Synthesized bis-macrocycles may provide
cooperative effect of two azacrown moieties in coordinating
metal cations and these investigations are underway now.
7b, 14%
7c, 8%
7c, 27%
7d, 20%
7b, 0%
BINAP
DavePHOS
aPd(dba)2/L 8/9 mol%. bYields after column chromatography on silica gel.
c Chromatography of combined reaction mixtures (entries 7 and 8).
was suitable for the reactions with the 1-aza-15-crown-5 deriva-
tive 3 (entries 1–4). The highest yield was achieved by the longest
trioxadiamine 5a (53%, entry 1). Dioxadiamine 5b with a shorter
chain also gave macrocycle 6b in a good yield (41%, entry 2).
These yields are among the highest ever observed for the syn-
thesis of nitrogen- and oxygen-containing macrocycles via Pd-
catalyzed amination. The application of 16 mol% catalyst did
not improve the yields. The use of triamine 5c and tetraamine 5d
resulted in somewhat lower yields (29%, entry 3; 28%, entry 4).
We also tried more common BINAP as ligand in these processes,
however, in the case of oxadiamines it turned to be inefficient
(5% yield with trioxadiamine 5a, entry 5). In the meantime, with
tetraamine 5d, BINAP was of the same efficiency as DavePHOS
providing 28% yield of bis-macrocycle 6d (entries 4, 6).
This work was supported by the Russian Foundation for Basic
Research (grant nos. 09-03-00735 and 08-03-00628) and the
Russian Academy of Sciences program P-8 ‘Development of the
methods for the synthesis of new chemicals and creation of new
materials’.
The reactions of another substituted azacrown ether 4 with
the same a,w-diamines 5a–d gave lower yields of the target bis-
macrocycles 7a–d, the use of BINAP being preferable. Only
with trioxadiamine 5a, BINAP and DavePHOS were of the similar
efficiency (entries 7, 8), while with dioxadiamine 5b BINAP per-
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.04.005.
‡
Typical procedure for the synthesis of bis-macrocycles 6 and 7. A two-
neck flask equipped with a magnetic stirrer and a condenser was flushed
with dry argon, charged with dibromobenzyl derivative of azacrown ethers
3 or 4 (0.25 mmol, 116 or 128 mg, respectively), absolute dioxane (12 ml),
Pd(dba)2 (12 mg, 8 mol%) and BINAP or DavePHOS (14 or 9 mg re-
spectively, 9 mol%). The mixture was stirred for 2 min, then appropriate
a,w-diamine 5a–d (0.25 mmol) and ButONa (0.75 mmol, 72 mg) were
added, and the reaction mixture was refluxed for 24 h. After cooling to
ambient temperature and filtration of the precipitate, dioxane was evaporated
in vacuo and the residue was chromatographed on silica gel using a sequence
of eluents CH2Cl2, CH2Cl2–MeOH (50:1–3:1), CH2Cl2–MeOH–NH3(aq)
(100:20:1–10:4:1) to obtain the target bis-macrocycles as pale-yellow glassy
compounds.
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Received: 18th January 2011; Com. 11/3663
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