1,4-Bis-(4-toluenesulphonyl)-1,4,7,10-tetraazacyclododecane from the direct tosylation of 1,4,7,10-tetraazacyclododecane

Article abstract of DOI:10.1016/S0040-4039(02)01766-5

The reaction between 1,4,7,10-tetraazacyclododecane and 4-toluenesulphonyl chloride in triethylamine/chloroform yields both the disubstituted isomers of bis-(4-toluenesulphonyl)-1,4,7,10-tetraazacyclododecane. This has been confirmed by ¹H NMR

Full text of DOI:10.1016/S0040-4039(02)01766-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7301–7302
1,4-Bis-(4-toluenesulphonyl)-1,4,7,10-tetraazacyclododecane from
the direct tosylation of 1,4,7,10-tetraazacyclododecane
Jonathan P. Hill,* Christopher E. Anson and Annie K. Powell
Institut fu¨r Anorganische Chemie, Universita¨t Karlsruhe, Engesserstr. 15, Geb. 30.45, D-76128 Karlsruhe, Germany
Received 5 August 2002; accepted 22 August 2002
Abstract—The reaction between 1,4,7,10-tetraazacyclododecane and 4-toluenesulphonyl chloride in triethylamine/chloroform
1
yields both the disubstituted isomers of bis-(4-toluenesulphonyl)-1,4,7,10-tetraazacyclododecane. This has been confirmed by H
NMR and X-ray crystallographic analyses. © 2002 Elsevier Science Ltd. All rights reserved.
Derivatives of 1,4,7,10-tetraazacyclododecane (cyclen)
have attracted interest because of the stability of their
lanthanide complexes and the potential use of these as
MRI contrast agents.1 1-(4-Toluenesulphonyl)cyclen
provides a convenient starting point in the synthesis of
unsymmetrically substituted compounds bearing one
non-identical group that can then be subject to further
functionalization. Additionally, cyclen is unique in that
the 1,7-ditosylamide is available in high yield from the
direct tosylation of the macrocycle in pyridine.2 Appar-
ently, the 1,4-ditosylamide has not been observed as a
byproduct from this reaction or from the alternative
route using chloroform/triethylamine as the reaction
medium.2,3 Previously, 1,4-bis-(4-toluenesulphonyl)-
cyclen has only been accessible via the macrocyclization
of open chain ditosylates.4
A sample (100 mg) of the cube-like crystals was sepa-
1
rated from the mixture and subjected to H NMR and
X-ray crystallographic analysis. The 1H NMR spectrum
could be unequivocally assigned to the 1,4-regioiso-
mer.5 The crystal structure provided final proof of
identity and this is shown in Figs. 1 and 2.6 The small
needle crystals were identified as the 1,7-regioisomer
1
from their H NMR spectrum.
A sample of the crystalline mixture was also subject to
1H NMR in order to obtain the composition and hence
the yield of the 1,4-regioisomer although this was
expected to be low since the initial experiment was
aimed at the synthesis of the 1-monosubstituted macro-
cycle. The mixture contained approximately 30% of the
1,4-ditosylamide with the remainder being mostly the
1,7-derivative and a small amount (<1%) of what is
probably the 1,4,7-tritosylamide. This composition
equates to overall yields of 4% and 8% of the 1,4- and
1,7-ditosylamides, respectively. The monotosylamide
was obtained in 68% yield leaving 19% macrocycle
unreacted.
In this note, we would like to report that the 1,4-bis-(4-
tosylamide) is, in fact, accessible via the direct reaction
of 1,4,7,10-tetraazacyclododecane (Strem Chemical Co.
Ltd.) with 4-toluenesulphonyl chloride in chloroform/
triethylamine. In the synthesis of the 1-(4-toluene-
sulphonyl)cyclen there are inevitably some disubstituted
and trisubstituted byproducts. These were isolated from
the mono-substituted and unreacted macrocycle as pre-
viously reported,2 the more highly substituted reaction
products being insoluble in water. The more highly
substituted reaction products were then recrystallized
from methanol yielding a mixture of very small needle-
like crystals along with larger pale yellow cubes. The
structures of the two possible ditosylamides of cyclen
are shown in Scheme 1.
That no-one has detected the 1,4-ditosylamide from the
reaction between cyclen and 4-toluenesulphonylchloride
is rather unusual given that its presence is obvious from
1
the H NMR spectra of the mixture of ditosylamides.
Scheme 1. Ditosylamides derived from 1,4,7,10-tetra-
azacyclododecane; R=(4-toluenesulphonyl).
* Corresponding author. Fax: +00 49 721 608 8142; e-mail: thanhill@
hotmail.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01766-5

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J. P. Hill et al. / Tetrahedron Letters 43 (2002) 7301–7302
sulphonyl oxygens into chains parallel to the crystal
c-axis.
Currently, we are trying to ascertain whether the syn-
thesis of the 1,4-ditosylamide can be optimized in a
similar manner to that of the 1,7-ditosylamide. It
appears that the isomers can be separated by virtue of
their differing crystal habits rather than by chromato-
graphy so that exclusive synthesis of the 1,4-ditosyl-
amide is not necessarily required.
Acknowledgements
This work was supported by a grant from The Royal
Society (J.P.H.).
Figure 1. Molecular structure of 1,4-bis-(4-toluenesulphonyl)-
1,4,7,10-tetraazacyclododecane. Probability ellipsoids at 30%
level.
References
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5. 1H NMR (CDCl3) of 1,4-bis-[(4-methylphenyl)sulphonyl)]-
1,4,7,10-tetraazacyclo dodecane: 7.73 (4H, d), 7.35 (4H, d),
3.53 (4H, s), 3.14 (4H, t), 1.99 (4H, t), 2.73 (4H, s), 2.45
(6H, s). 1H NMR (CDCl3) of 1,7-bis-[(4-methylphenyl)-
sulphonyl)]-1,4,7,10-tetraazacyclododecane: 7.75 (4H, d),
7.37 (4H, d), 3.19 (8H, t), 2.87 (8H, t), 2.44 (6H, s).
6. Crystal data: C22H32N4O4S2, FW=480.64; T=200 K;
Figure 2. View of 1,4-bis-(4-toluenesulphonyl)-1,4,7,10-tetra-
azacyclododecane down the a-axis. Hydrogen bonding
between adjacent molecules leading to chains.
orthorhombic, Pbcn, Z=4, a=23.0510(13), b=10.2219(8),
3
,
,
c=10.2806(5) A, V=2422.4(3) A ; 8278 data, 2076 unique,
R
int=0.0339, 209 parameters (all non-H anisotropic, all H
fully refined), wR2=0.0829 (all data), R1=0.0341 (1374
−3
However, the 1,7-derivative is predominant despite
being the statistically less favoured isomer and the
reason for this probably lies in a combination of steric
and electrostatic effects.7,8
,
with I>2|(I)), largest diff. peak/hole +0.22/−0.20 e A
.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication nos. CCDC 191103. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
In the crystal, the molecule lies on a twofold rotational
axis. The dimethylene unit between the substituted
nitrogens has an anti configuration (torsion angle about
C(1)ꢀC(1%) 169.4°); the remaining three are gauche (tor-
sion angles about C(2)ꢀC(3) and C(4)ꢀC(4%) are −57.7°
and −74.9°, respectively). The molecules are linked by
pairs of hydrogen bonds between NꢀH groups and
7. Van Westrenem, J.; Sherry, A. D. Bioconjugate Chem.
1992, 3, 524.
8. Desreux, J. F.; Merciny, E.; Loncin, M. F. Inorg. Chem.
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