ORGANIC
LETTERS
2
007
Vol. 9, No. 23
829-4831
The Synthesis of
,2-Bis(1,5,9-triazacyclododecyl)ethane:
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A Showcase for the Importance of the
Linker Length within Bis(alkylating)
Reagents
Alfredo Medina-Molner, Olivier Blacque, and Bernhard Spingler*
UniVersity of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Received September 3, 2007
ABSTRACT
The synthesis of 1,2-bis(1,5,9-triazacyclododecyl)ethane (1) showcases how different bis(alkylating) reagents change the reaction from an
intra- to an intermolecular pathway. The isolation of the intermediate hexahydro-3a,6a-ethano-1H,4H,7H,9bH-9a-aza-3a,6a-diazoniaphenalene-
3a,6a-diium (2) explained why initially the synthesis of 1 was not possible. Both isomers of 2 were found in solution. DFT calculations revealed
that isomer 2a is 4.6 kcal/mol lower in energy than 2b. Synthesis of 1 was finally achieved by using oxalyl chloride.
Synthetic azamacrocycles are widely used not only in
Since selective alkylations in polyazamacrocycles are
1
2
3
4
chemistry but also in biochemistry and medicine. Azamac-
rocycles have a strong tendency to form stable transition-
metal complexes. The properties of these ligands can be
tuned by varying the number and size of donor atoms, the
size of the macrocycle, or the metal-to-metal distance in the
case of dinuclear complexes.
rarely possible, several protection and deprotection steps
5
in a long synthetic pathway are normally needed, and as a
consequence, often low overall yields are obtained. Bis-
azamacrocycles, also called “earmuff ligands”, have been
6
described in the literature. In particular, ethylene-bridged
azamacrocycles have been synthesized by either reaction of
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ethylendiamine units with two equivalents of ditosylates or
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9
(1) Schaber, P. M.; Fettinger, J. C.; Churchill, M. R.; Nalewajek, D.;
simply reacting 1,2-dibromo /ditosylate -ethane with pre-
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682.
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(7) Murase, I.; Ueno, S.; Kida, S. Inorg. Chim. Acta 1986, 111, 57-60;
Pulacchini, S.; Shastri, K.; Dixon, N. C.; Watkinson, M. Synthesis 2001,
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993; Spingler, B.; Da Pieve, C. Dalton Trans. 2005, 1637-1643; Notni,
J.; Gorls, H.; Anders, E. Eur. J. Inorg. Chem. 2006, 1444-1455.
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Am. Chem. Soc. 1992, 114, 10134-10137.
3) De Clercq, E.; Yamamoto, N.; Pauwels, R.; Baba, M.; Schols, D.;
(
(
Nakashima, H.; Balzarini, J.; Debyser, Z.; Murrer, B. A.; Schwartz, D.;
Thornton, D.; Bridger, G.; Fricker, S.; Henson, G.; Abrams, M.; Picker, D.
Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 5286-5290; Kikuta, E.; Aoki, S.;
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J. H.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 4242-4247.
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0.1021/ol7021627 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/17/2007