Convenient synthesis of mono- and ditosylated 1,4,7-triazacyclononane

Article abstract of DOI:10.1081/SCC-100105889

Mono- and ditosylated 1,4,7-triazacyclononane (2, 3) were synthesized by rapid partial deprotection of 1,4,7-tritosyl-1,4,7-triazacyclononane (1) in vigorously stirred refluxing acetic acid-hydrobromic acid mixture.

Full text of DOI:10.1081/SCC-100105889

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CONVENIENT SYNTHESIS OF MONO- AND
DITOSYLATED 1,4,7-TRIAZACYCLONONANE
István Lázár a & Zsuzsanna Takács a
a Faculty of Natural Sciences, Department of Inorganic and Analytical Chemistry ,
Debrecen University , Debrecen-10, Pf. 21, 4010, Hungary
Published online: 16 Aug 2006.
To cite this article: István Lázár & Zsuzsanna Takács (2001) CONVENIENT SYNTHESIS OF MONO- AND DITOSYLATED 1,4,7-
TRIAZACYCLONONANE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:20, 3141-3144, DOI: 10.1081/SCC-100105889
To link to this article: http://dx.doi.org/10.1081/SCC-100105889
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SYNTHETIC COMMUNICATIONS, 31(20), 3141–3144 (2001)
CONVENIENT SYNTHESIS OF
MONO- AND DITOSYLATED
1,4,7-TRIAZACYCLONONANE
Istvan Lazar* and Zsuzsanna Takacs
Debrecen University, Faculty of Natural Sciences,
Department of Inorganic and Analytical Chemistry,
Debrecen-10, Pf. 21, 4010 Hungary
ABSTRACT
Mono- and ditosylated 1,4,7-triazacyclononane (2, 3) were
synthesized by rapid partial deprotection of 1,4,7-tritosyl-
1,4,7-triazacyclononane (1) in vigorously stirred refluxing
acetic acid–hydrobromic acid mixture.
Recently it has been discovered that a partially tosylated polyaza-
macrocycle, 1-benzyl-4,7,10-tritosyl-1,4,7,10-tetraazacyclododecane, showed
cytotoxic activity against human leukemic cells.1 Our interest in detosylation
of macrocyclic p-toluenesulfonamides2 led us to the development of a simple
method for the synthesis of partially tosylated triaza macrocycles, which can
serve as starting materials for future developments and as new candidates
for anticancer research. Regioselectively tosylated polyaza-macrocycles were
prepared so far from free macrocyclic polyamines,3 which, in turn,
*Corresponding author. E-mail: lazar@tigris.klte.hu
3141
Copyright & 2001by Marcel Dekker, Inc.
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LAZAR AND TAKACS
were synthesized from their pertosylated derivatives. Several methods have
been developed3–5 for detosylations, one of them is a simple but time-con-
suming hydrolysis with HBr/HOAc6 mixture.
Our study of this process (see Scheme) revealed that the low solubility
of 1 in HBr/HOAc mixture, its strong tendency to form a foam when boiling
and poor efficiency of the magnetic stirbars all together resulted in too short
contact time of 1 with the acid mixture, consequently it led to prolonged
reaction times. We have found it possible to virtually stop the reaction
sequence mostly at the monoprotected stage based upon the somewhat
increased hydrolytic stability of 3 in the reaction mixture. Technically
the crucial point for rapid partial detosylation was to provide high intensity
stirring at the top of the reaction mixture for which an apparatus shown
on Figure 1was used. This process was found to be fairly advantageous
not only for its rapidity and simplicity but also because it provided the
target compounds 2 and 3 directly from 1 in one step, significantly cut the
necessary amount of fine chemicals and reduced the volume of toxic waste.
Scheme. Partial detosylation of 1 to a mixture of 2 and 3. (Isolated yields are given).
The amount of 4 has been found negligible.
19.1 g (32.3 mmol) of 17 was placed into a heart shaped three necked
flask of 1–1.5 dm3 volume and 256 cm3 hydrobromic acid (48%) and 144 cm3
glacial acetic acid was added. The mixture was brought to and kept in
boiling under vigorous stirring untill dissolvation of 1. This usually required
2–3 hours of time. Since longer reflux time favoured formation of 4 it was
avoided.
The reaction mixture was cooled down, filtered if necessary and then
evaporated on a rotary evaporator to dryness. The residue was taken up
with 250 ml of water and let to stand overnight in ice. The precipitate was
filtered off, washed twice with water and dried. This white solid proved to
be pure 2ÁHBr (4.98 g, 9.60 mmol, 30%). The filtrate was evaporated to
dryness, the residue was taken up with absolute ethanol, filtered off,
washed with ethanol and ether and dried to constant weight yielding

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MONO- AND DITOSYLATED 1,4,7-TRIAZACYCLONONANE
3143
Figure 1. Apparatus for partial detosylation of 1. (a) variable speed stirring motor,
(b) flexible electric heating tape (optional), (c) variable temperature electric heating
mantle.
3Á2HBr (9.63 g, 21.6 mmol, 68%) as a beige solid. Free bases 2 and 3 were
liberated from 2ÁHBr and 3Á2HBr, respectively, by a strong base and
extracted into chloroform from which the products were received after
evaporation of the solvent as waxy white solids. Both 2 and 3 gave satis-
1
factory elemental analysis and H and 13C NMR spectra.
ACKNOWLEDGMENT
Financial support from the Hungarian National Research Foundation
(OTKA T-023810) and Bolyai Scholarship (BO/00452/99) is gratefully
acknowledged.
REFERENCES
1. Hall, I.H.; Elkins, A.L.; Karthikeyan, S.; Spielvogel, B.F. Anticancer
Research 1997, 17, 1195, Chem. Abstr. Vol. 127, 377u.
2. Lazar, I. Synth. Commun. 1995, 25, 3181.

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LAZAR AND TAKACS
3. Helps, I.M.; Parker, D.; Chapman, J.; Ferguson, G. J. Chem. Soc.
Chem. Commun. 1988, 1094.
4. Searles, S.; Nukina, S. Chem. Rev. 1960, 1077.
5. Hosseini, M.W.; Lehn, J.M. J. Amer. Chem. Soc. 1982, 104, 3525.
6. Martin, L.Y.; Sperati, C.R.; Busch, D.H. J. Amer. Chem. Soc. 1977,
99, 2968.
7. Richman, J.E.; Atkins, T.J. J. Amer. Chem. Soc. 1974, 96, 2268.
Received in the Netherlands December 20, 2000

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