An easy route towards regioselectively difunctionalized cyclens and new cryptands

Article abstract of DOI:10.1039/b612293k

Reductive amination of various aldehydes with cyclen represents a very convenient method for the synthesis of a wide range of 1,7-difunctionalized cyclens, as well as new cryptands. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612293k

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An easy route towards regioselectively difunctionalized cyclens and new
cryptands
Fanny Chaux, Franck Denat,* Enrique Espinosa and Roger Guilard*
Received (in Cambridge, UK) 29th August 2006, Accepted 21st September 2006
First published as an Advance Article on the web 12th October 2006
DOI: 10.1039/b612293k
Reductive amination of various aldehydes with cyclen repre-
sents a very convenient method for the synthesis of a wide
range of 1,7-difunctionalized cyclens, as well as new cryptands.
Surprisingly, this method has rarely been applied to the
N-functionalization of cyclic polyamines. Bradshaw et al. have
12
used this tool for appending quinoline arms onto azacrowns.
A
mono-N-functionalized cyclen has been synthesized by reductive
amination, but poor selectivity in the formation of the mono- over
Functionalized tetraazacycloalkanes continue to see growing
interest, since they represent a class of chelating agents able to
form stable complexes with a large variety of metal ions, ranging
13
the di-N-functionalized derivative was observed. More recently,
the tetraalkylation of cyclen has been carried out by reductive
14
amination under high pressure conditions.
1
from transition metals to lanthanides and other heavy metals. The
affinity towards a given ion may be tuned by varying the size of the
macrocyclic ring, and by changing the number and the nature of
the pendant coordinating arms. Cyclen derivatives are probably
the most extensively studied macrocyclic polyamines, mainly
because of the wide use of some of their complexes in medical
applications. Indeed, Gd(III) chelates are well known as magnetic
In this paper, we report a new route for the synthesis of
selectively 1,7-difunctionalized cyclens by reacting two equivalents
of various aldehydes with cyclen under reductive amination
conditions, i.e. in the presence of 2.8 equimolar amounts of
NaBH(OAc) as reductant in 1,2-dichloroethane (0.02 M) at room
3
temperature (Scheme 1).{ Under such conditions, the trans-
difunctionalized compound is highly predominant, as shown by
2
resonance imaging (MRI) contrast agents, and radioactive metal
6
4
111
Cu, In, Y) complexes have been studied for both diagnostic
90
(
the NMR spectra of the crude products. This selectivity has been
13
attributed to steric effects. However, the reaction of cyclen with
3
and therapeutic purposes. Macrocycles incorporating Eu(III) and
4
Tb(III) have been used as fluorescent probes and labels, and some
two equivalents of benzyl bromide in the same solvent, at the same
concentration and in the presence of potassium carbonate gives a
mixture of mono-, di-, tri- and even tetra-N-benzylated macro-
cycles. Benzylcyclen, treated according to the conditions described
cyclen metal complexes have also been used in molecular
5
recognition and catalysis. All these applications require fine
tuning of the chelating properties of the ligand, the tuning of other
properties such as their hydrophilic/hydrophobic character, and
even the addition of an appropriate linker to attach the macrocycle
to the antibody. This can be achieved by mixing different pendant
arms, leading to so-called bifunctional chelating agents (BCAs).
The synthesis of such BCAs, and also the preparation of cryptands
or other macropolycycles, has attracted increasing interest, and
many different synthetic methods for the selective functionalization
above (2 equivalents of benzaldehyde, NaBH(OAc) , 1,2-dichloro-
3
ethane), yields the tribenzylated cyclen as the main product, while
it has been reported that full N-alkylation can be achieved by
1
4
running the reductive amination at high pressure. All these
experiments prove that further functionalization of disubstituted
6
of tetraazacycloalkanes have been devised. Indeed, cyclen
7
tetrafunctionalization is straightforward but partial functionaliza-
tion of the macrocycle is more tricky. Monofunctionalized cyclens
can be obtained by using a large excess of the starting macrocyclic
8
tetraamine or through the triBoc cyclen. More recently, the
bisaminal route proved to be a very convenient way to
9
functionalize cyclens directly from a linear precursor. However,
selective difunctionalization of cyclen is still difficult to achieve and
6,10
only a few methods have been reported.
Reductive amination of carbonyl derivatives is a convenient
method for the N-alkylation of amines. In such reactions, the
reducing agent must be selective enough to reduce the imine or
iminium species formed in situ, without reacting with the starting
aldehyde. Among the different reducing agents, sodium tetra-
11
3
acetoxyborohydride (NaBH(OAc) ) has been widely used.
Laboratoire d’Ing e´ nierie Mol e´ culaire pour la S e´ paration et les
Applications des Gaz, LIMSAG UMR 5633, Universit e´ de Bourgogne, 9
Av. Alain Savary BP47870, 21078 Dijon, France. E-mail: limsag@
u-bourgogne.fr; Fax: +33 380 396 117; Tel: +33 380 396 120
Scheme 1
5
054 | Chem. Commun., 2006, 5054–5056
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cyclen is possible, and that the excellent selectivity is certainly due
to reasons other than a steric one. One may suggest the formation
of a bisaminal species, which is then reduced to give the
difunctionalized macrocycle, according to our observations in
cyclam series. Attempts to isolate the bisaminal adducts, expected
from the reaction of cyclen with two equivalents of various
aldehydes, failed in the absence of reducing agent. Under such
conditions, only the monoaminal compound was formed. In our
opinion, the reaction proceeds through the in situ-reduction of a
bisiminium species formed at an earlier stage. In order to minimize
the electrostatic repulsion between the two positive charges of the
iminium groups, the reaction takes place on the two nitrogens in
trans positions. The exceptional selectivity observed could result
from these interactions.
17
Fig. 2 ORTEP view of the Cu(II) complex of 6 showing thermal
ellipsoids at a 50% probability level. Hydrogen atoms are omitted for
clarity.
The few examples shown in Scheme 1 illustrate the scope of the
method. Any kind of aldehyde can be used a priori. All these
macrocycles are new compounds except 1, which is prepared
straightforwardly according to this procedure. Among these
compounds, 1,7-bis(ferrocenylmethyl)cyclen (4) is of particular
interest. Indeed, ferrocene has been widely used as a redox active
moiety attached to various host molecules for the electrochemical
detection of guest binding. Ferrocene units have been appended to
1
contrast, the H NMR spectrum of the cryptand incorporating the
rigid dibenzofuran unit, recorded at room temperature, shows only
one singlet for the protons of the methylene groups linking the
dibenzofuran to the cyclen. This singlet splits into two doublets
upon lowering the temperature (Fig. 3). This feature can be
attributed to a swinging motion of the handle that occurs rapidly
at room temperature on the NMR time scale and considerably
more slowly at 200 K. This structural study suggests that these two
cryptands should possess very different ligating properties.
1
5
the periphery of crown ethers or cyclam in various ways. To our
knowledge, there is only one report in the literature describing a
cyclen that has been N-functionalized by one ferrocenylmethyl
1
6
unit. No cyclen derivative containing two organometallic
The method described herein is a powerful tool for the synthesis
of 1,7-difunctionalized cyclens and cryptands incorporating a
cyclen unit. The reaction is highly regioselective and represents a
very convenient alternative to previously described methods for the
preparation of known compounds. Moreover, the use of
aldehydes, instead of the halogenated compounds commonly used
for the alkylation of cyclic polyamines by nucleophilic substitution,
allows access to new ligands. Ansa-cyclens, cryptands which are
usually obtained through tedious multi-step syntheses, implying
moieties has been prepared until now. The crystal structure of
1
7
compound 4 has been solved, and an ORTEP view is shown in
Fig. 1.{ This compound has a crystallographically imposed two-
fold symmetry.
Moreover, an exceptional selectivity was also observed when
reacting cyclen with dialdehydes, thus providing a very straightfor-
ward route towards three-dimensional macropolycycles. For
instance, new cryptands 5 and 6, bearing a dibenzofuran and a
diphenylether handle, respectively, can be prepared by a very
convenient one-pot procedure in 75–78% yield. The [1 + 1]
condensation of cyclen and dialdehyde has been evidenced by mass
spectrometry and X-ray diffraction. The only discrepancy between
cryptands 5 and 6 is the presence of a C–C bond between the two
phenyl groups, which makes the handle planar in 5. Consequently,
these two compounds adopt different geometries both in the solid
state and in solution, as shown by their NMR spectra. Indeed, the
two protons of each methylene group of the handle in compound 6
1
are diastereotopic and appear as an AB system in the H NMR
spectrum, either at room temperature or at 200 K, proving that the
2
cryptand exhibits C symmetry, similar to that observed in the
solid state for the corresponding Cu(II) complex (Fig. 2).{ In
1
7
1
Fig. 3 0–6 ppm region of the H NMR spectrum (500 MHz, CDCl
Fig. 1 ORTEP view of 4 showing thermal ellipsoids at a 50%
3
) of
probability level. Hydrogen atoms are omitted for clarity.
5, recorded between 300 and 190 K (S = solvent).
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1
See, for example: M. Meyer, V. Dahaoui-Gindrey, C. Lecomte and
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protection/deprotection sequences, can be prepared in high yields
by an one-pot reaction using dialdehydes as starting materials. The
coordination properties of these new ligands are currently being
investigated and will be discussed in forthcoming papers.
2 V. Jacques and J.-F. Desreux, in The Chemistry of Contrast Agents in
Medical Magnetic Resonance Imaging, ed. A. E. Merbach and E. Toth,
John Wiley & Sons, New York, 2001.
Notes and references
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4
5
T. Gunnlaugsson and J. P. Leonard, Chem. Commun., 2005, 3114.
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{ Typical experimental procedure. Synthesis of 1,7-bis(ferrocenyl-
methyl)-1,4,7,10-tetraazacyclododecane (4).
2002, 121.
A solution of ferrocenecarboxaldehyde (1.39 g, 6.51 mmol) in 1,2-
dichloroethane (50 cm ) was added dropwise to a stirred solution of
3
6 F. Denat, S. Brand e` s and R. Guilard, Synlett, 2000, 561 and references
therein.
1,4,7,10-tetraazacyclododecane (cyclen) (0.56 g, 3.3 mmol) and fresh
sodium triacetoxyborohydride (1.93 g, 9.12 mmol) in 1,2-dichloroethane
7
T. Fricke, S. Chrapava and B. K o¨ nig, Synth. Commun., 2002, 32, 3595.
3
100 cm ). The solution was stirred at room temperature under an
8 S. Brand e` s, C. Gros, F. Denat, P. Pullumbi and R. Guilard, Bull. Soc.
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9 F. Boschetti, F. Denat, E. Espinosa, J.-M. Lagrange and R. Guilard,
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(
atmosphere of nitrogen for 24 h. The reaction mixture was quenched by the
3
addition of a 1M NaOH solution (150 cm ), and the product extracted with
3
chloroform (3 6 100 cm ). The organic layer was dried over MgSO
4
and
evaporated under reduced pressure to give the compound as a brown oil.
1
0 J. Yoo, D. E. Reichert and M. J. Welch, Chem. Commun., 2003, 766;
J. Yoo, D. E. Reichert and M. J. Welch, J. Med. Chem., 2004, 47, 6625;
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The oil was washed with cyclohexane and the product obtained as a brown
solid, m.p. 206–208 uC (1.46 g, 79%). d
10 H, m), 2.55–2.56 (8 H, m), 3.52 (4 H, s), 4.09–4.10 (14 H, m) and 4.12–
.13 (4 H, m); d (125 MHz, CDCl ): 46.3, 51.8, 55.4, 68.8, 69.2, 70.7 and
H 3
(500 MHz, CDCl ): 2.50–2.52
(
4
C
3
11 A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C. A. Maryanoff and
R. D. Shah, J. Org. Chem., 1996, 61, 3849.
83.9; m/z (MALDI-TOF) 568.61.
{ High quality yellow single crystals of 4 and violet single crystals of 6 were
grown from THF and acetonitrile, respectively. Both crystal structures were
solved using direct methods, and the refinement was carried out by full-
1
2 G. Xue, P. B. Savage, K. E. Krakowiak, R. M. Izatt and J. S. Bradshaw,
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N. Zaccheroni, Tetrahedron, 2002, 58, 4809.
18
2
19
matrix least-squares on F . Anisotropic thermal parameters were used for
non-hydrogen atoms. Hydrogens were located by Fourier synthesis and
placed at calculated positions using a riding model, except for that bonded
to the nitrogen atom N2 in 4, for which the positional parameters were
refined, and those bonded to the nitrogen atoms in 6, which were refined
then placed at the mean N–H distances observed from neutron diffraction
1
1
3 D. Maffeo and J. A. G. Williams, Inorg. Chim. Acta, 2003, 355, 127.
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1
1
2
0
F. Sancenon, A. Benito, F. J. Hernandez, J. M. Lloris, R. Martinez-
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Inorg. Chem., 2004, 43, 3777.
experiments (1.01 s). In both crystal structures, all hydrogens were
refined with a global isotropic thermal factor.
2 4
Crystal data for C30H40Fe N (4): M 5 568.36, monoclinic, space group
C2/c, a 5 19.8821(4), b 5 12.4231(3), c 5 10.8980(3) s, b 5 102.466(1)u,
3
23
U 5 2628.3(1) s , Z 5 4, T 5 115(2) K, D
c
5 1.436 g cm , l(Mo-Ka) 5
.71069 s, m(Mo-Ka) 5 1.131 mm , 5717 reflections collected, 3025
unique (Rint 5 0.0312). The maximum and minimum residual electron
2
1
0
16 V. Boldrini, G. B. Giovenzana, R. Pagliarin, G. Palmisano and M. Sisti,
Tetrahedron Lett., 2000, 41, 6527.
23
densities were 0.336 and 20.320 e s2 . The final agreement factors were
R(F) 5 0.0324 and 0.0560, and wR(F ) 5 0.0714 and 0.0783 for I . 2s(I)
and all data, respectively. A half of the molecular unit belongs to the
asymmetric unit. CCDC 619209.
17 M. N. Burnett and C. K. Johnson, ORTEP-III: Oak Ridge Thermal
Ellipsoid Plot Program for Crystal Structure Illustrations, Report
ORNL-6895, Oak Ridge National Laboratory, Oak Ridge, TN,
USA, 1996; ORTEP-3 for Windows: L. J. Farrugia, J. Appl.
Crystallogr., 1997, 30, 565.
18 SIR97 program: A. Altomare, M. C. Burla, M. Camalli, G. L.
Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G. Moliterni,
G. Polidori and R. Spagna, J. Appl. Crystallogr., 1999, 32, 115.
19 G. M. Sheldrick, SHELXL-97, Program for the refinement of crystal
structures, University of G o¨ ttingen, Germany, 1997.
Crystal data for C22
group P2 /n, a 5 12.1266(2), b 5 13.4493(3), c 5 15.1931(3) s, b 5
4.260(1)u, U 5 2471.06(8) s , Z 5 4, T 5 115(2) K, D
2 4 9
H30Cl CuN O (6): M 5 628.94, monoclinic, space
1
3
23
,
9
c
5 1.691 g cm
21
l(Mo-Ka) 5 0.71069 s, m(Mo-Ka) 5 1.162 mm , 10890 reflections
collected, 5676 unique (Rint 5 0.0442). The maximum and minimum
electron densities were 0.599 and 20.724 e s2 . The final agreement factors
were R(F) 5 0.0447 and 0.0776, and wR(F ) 5 0.1004 and 0.1117 for I .
23
2
s(I) and all data, respectively. CCDC 619210.
For crystallographic data in CIF or other electronic format see DOI:
0.1039/b612293k
20 International Tables for Crystallography, ed. A. J. C. Wilson and
E. Prince, Kluwer Academic Publishers, Dordrecht, 2nd edn, 1999,
vol. C, pp. 800.
1
5
056 | Chem. Commun., 2006, 5054–5056
This journal is ß The Royal Society of Chemistry 2006