The synthesis of 1,2-bis(1,5,9-triazacyclododecyl)ethane: A showcase for the importance of the linker length within bis(alkylating) reagents

Article abstract of DOI:10.1021/ol7021627

(Chemical Equation Presented) 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.

Full text of DOI:10.1021/ol7021627

ORGANIC
LETTERS
2
007
Vol. 9, No. 23
829-4831
The Synthesis of
,2-Bis(1,5,9-triazacyclododecyl)ethane:
4
1
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
spingler@aci.uzh.ch
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
7
ethylendiamine units with two equivalents of ditosylates or
8
9
(1) Schaber, P. M.; Fettinger, J. C.; Churchill, M. R.; Nalewajek, D.;
simply reacting 1,2-dibromo /ditosylate -ethane with pre-
Fries, K. Inorg. Chem. 1988, 27, 1641-1646; Iranzo, O.; Kovalevsky, A.
Y.; Morrow, J. R.; Richard, J. P. J. Am. Chem. Soc. 2003, 125, 1988-
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C.; Wong, W.-T. Tetrahedron 2004, 60, 5595-5601.
(5) Da Pieve, C.; Medina-Molner, A.; Spingler, B. Synthesis 2007, 679-
682.
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2381-2383.
1
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.
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(
(
Nakashima, H.; Balzarini, J.; Debyser, Z.; Murrer, B. A.; Schwartz, D.;
Thornton, D.; Bridger, G.; Fricker, S.; Henson, G.; Abrams, M.; Picker, D.
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Kimura, E. J. Am. Chem. Soc. 2001, 123, 7911-7912; Gao, J.; Reibenspies,
J. H.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 4242-4247.
1
0.1021/ol7021627 CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/17/2007

formed azamacrocycles. In this letter, we present the
synthesis of 1,2-bis(1,5,9-triazacyclododecyl)ethane (1) in
a straightforward synthetic route and discuss the reactivity
of various bis(alkylating) reagents.
Scheme 3
When we followed the Snodin method10 in order to
synthesize the novel 1,2-bis(1,5,9-triazacyclododecyl)ethane
as a product, the unexpected tetracyclic compound 2 was
obtained in 80% yield (see Scheme 1). Ethylene bistriflate
integrals were used to determine the ratio between the two
isomers, which was found to be 10:1. DFT calculations, at
1
1
the mPW1PW91/6-31G(d) level of theory, showed that 2a
was 4.6 kcal/mol lower in energy than 2b (Scheme 3). The
energetically more favored isomer 2a has the propylene
bridge across the two quaternary nitrogen atoms in an
equatorial position and the ethylene bridge in the axial
position. For 2b, the substitution patterns are exactly op-
posite. The DFT calculations were further used to predict
Scheme 1
1
3
12
the C NMR spectra for both isomers 2a and 2b. The
calculated C NMR shifts were agreeing well with the
experimental values (Table 1). The differences between the
had reacted as an intramolecular bisalkylating reagent. This
is in remarkable contrast to the analogous reaction with
propylene bistriflate. In that case, exclusively monoalkylation
at one nitrogen atom of the two 1,5,9-triazatricyclo[7.3.1.0]-
13
10
tridecane units was observed. Scheme 2 shows the possible
Table 1. Experimental and Calculated 13C NMR Shifts of
Isomers 2a and 2b (See Supporting Information for Further
Details)
Scheme 2
exptl
calcd
∆ exptl ∆ calcd
C atom
2a
2b
2a
2b
2a,2b
2a,2b
a
b
c
d
e
f
102.76 96.82 107.70 100.72
5.94
-1.61
-0.26
1.64
-2.86
6.25
6.98
-1.21
-0.34
-2.66
-3.45
11.34
0.26
50.42 52.03
20.13 20.39
54.07 52.43
60.61 63.47
64.17 57.92
18.48 18.11
54.20
24.43
65.85
57.37
67.05
22.93
55.41
24.77
68.51
60.82
55.71
22.67
reaction pathway following the first alkylation of 1,5,9-
g
0.37
triazatricyclo[7.3.1.0]-tridecane. When R ) CH
intramolecular ring closure is faster than the C-N breakage
case A in Scheme 2). However in the case of R ) CH
CH CH OTf, the C-N bond breaks before the intramolecular
alkylation can occur (case B in Scheme 2). As a consequence,
the positive charge on the N-C-N acts as a protecting
group, leading to a highly selective intermolecular dialky-
lation. Having an ethylene instead of a propylene linker
changes the reaction from an inter- to an intramolecular
pathway. The linker length within a dialkylating reagent
seems to be crucial for the different reactivity observed.
The dication of 2 can exist as two isomers that are not
interconvertible without breaking a bond (Scheme 3). NMR
2 2
CH OTf, the
(
2
-
two isomers for the experimental and calculated shifts
respectively were coinciding even better. The main isomer
of compound 2 crystallized by vapor diffusion of cyclohex-
ane into a solution of 2 in ethanol (see Figure 1 and
Supporting Information for further details).
As a consequence, a new synthetic pathway had to be
found to obtain 1,2-bis(1,5,9-triazacyclododecyl)ethane. In
2 2
a first attempt, BrCH CH Br was used. However no reaction
was observed, even when adding two equivalents of potas-
sium iodide. Thus, a more reactive alkylating agent was
chosen. Oxalyl chloride seemed the most appropriate due to
the formation of two amides, which would reduce the
possibility of an intramolecular bisalkylation. If R is an acyl
2
2
(8) Haidar, R.; Ipek, M.; DasGupta, B.; Yousaf, M.; Zompa, L. J. Inorg.
Chem. 1997, 36, 3125-3132; Sch a¨ fer, K.-O.; Bittl, R.; Zweygart, W.;
Lendzian, F.; Haselhorst, G.; Weyherm u¨ ller, T.; Wieghardt, K.; Lubitz, W.
J. Am. Chem. Soc. 1998, 120, 13104-13120.
(11) Frisch, A.; Frisch, M. J.; Trucks, G. W. Gaussian 03 User’s
Reference; Gaussian, Inc.: Pittsburgh PA, 2003.
(9) Wieghardt, K.; Tolksdorf, I.; Herrmann, W. Inorg. Chem. 1985, 24,
1
230-1235.
10) Snodin, M. D.; Beer, P. D.; Drew, M. G. B. J. Chem. Soc., Dalton
Trans. 1997, 3407-3408.
(12) London, F. J. Phys. Radium 1937, 8, 397-409; McWeeny, R. Phys.
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Chem. Soc. 1990, 112, 8251-8260.
(
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Org. Lett., Vol. 9, No. 23, 2007

1
in a total yield of 43% based on the starting material 1,5,9-
triaza- tricyclo[7.3.1.0]tridecane (Scheme 4). An interesting
behavior was observed in this final reaction step. When
compound 4 was refluxed for less than 18 h in triflic acid,
an intermediate could be isolated (5). Only one of the two
rings was fully hydrolyzed in this intermediate, whereas the
other ring presented new features. The middle carbon had
reorganized and now was linked to the former amide nitrogen
to give a quaternary ammonium cation and leave a secondary
amine in that ring (Scheme 4). It seems that even under these
acidic conditions a preferential rearrangement of the central
carbon atom to the most basic tertiary amine can take place.
Suitable crystals for X-ray analysis could be grown by vapor
diffusion of cyclohexane into ethanol for compound 5 (see
Figure 2 and Supporting Information) and by vapor diffusion
Figure 1. ORTEP presentation of the dication of 2 (ellipsoids
drawn at 50% probability; most H atoms and the two triflate anions
were omitted for clarity).
group (Scheme 2), the amide nitrogen would strongly prefer
2
3
an sp hybridization (B) rather than the sp one (A). This
13
synthetic strategy turned out to be successful:
4
1
,5,9-Triaza-tricyclo[7.3.1.0]tridecane1 was first reacted
with oxalyl chloride; thus, both rings were now linked by a
diamide (see Scheme 4) which had to be reduced in order
Scheme 4
Figure 2. ORTEP presentation of compound 5. (Ellipsoids drawn
at 50% probability; hydrogen atoms, one methanol molecule, and
four triflate groups were omitted for clarity).
of diethylether into ethanol for ligand 1 (see Supporting
Information).
A highly efficient and selective synthetic route to the bis-
(azamacrocycle) 1 has been reported. All reaction steps were
very high yielding without the need for chromatographic
purifications or any kind of protecting group. In addition,
the interesting double ammonium salt 2 has been fully
analyzed. This compound can exist in two noninterconvert-
ible isomers, which could be identified by NMR. Its
characterization allowed studying the influence of the linker
length within bis(alkylating) reagents upon the second
alkylation. Finally an unusual rearrangement during acidic
hydrolysis could be observed. In both cases, crystal structures
were essential in revealing reaction intermediates.
Acknowledgment. This work was supported by the Swiss
National Science Foundation. We thank the whole Alberto
group for valuable discussions. Thanks to L. Kromer and
Dr. L. Bigler from the University of Z u¨ rich for measuring
the MS spectra.
to further proceed with the normal synthetic path. The amides
were reduced with LiAlH
Scheme 4). Without further purification, compound 4 was
then refluxed in triflic acid to form the hexaprotonated ligand
4
to yield the corresponding amines
(
Supporting Information Available: All experimental
details and analyses, an ORTEP presentation of 1, crystal-
lographic data and CIF files for the crystal structures of 1,
(13) Ciampolini, M.; Micheloni, M.; Nardi, N.; Vizza, F.; Buttafava, A.;
Fabbrizzi, L.; Perotti, A. J. Chem. Soc., Chem. Commun. 1984, 998-999;
Urfer, A.; Kaden, T. A. HelV. Chim. Acta 1994, 77, 23-35; Chartres, J.
D.; Groth, A. M.; Lindoy, L. F.; Lowe, M. P.; Meehan, G. V. J. Chem.
Soc., Perkin Trans. 1 2000, 3444-3450.
2
, and 5. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Alder, R. W.; Mowlam, R. W.; Vachon, D. J.; Weisman, G. R. J.
Chem. Soc., Chem. Commun. 1992, 507-508.
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