Synthesis of novel derivatives of 1,4,7-triazacyclononane

Article abstract of DOI:10.1021/ol016291d

(equation presented) The coordination environment of 1,4,7-triazacyclononane can be adapted, through sequential functionalization of two secondary amines, to generate ligands applicable in biomimetic studies. Two "amino acids" and an amino derivative have

Full text of DOI:10.1021/ol016291d

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2855-2858
Synthesis of Novel Derivatives of
1,4,7-Triazacyclononane
,†
Andrew Warden,† Bim Graham,† Milton T. W. Hearn,‡ and Leone Spiccia*
School of Chemistry, PO Box 23, and Department of Biochemistry and Molecular
Biology, PO Box 130, Monash UniVersity, 3800 Victoria, Australia
leone.spiccia@sci.monash.edu.au
Received June 17, 2001
ABSTRACT
The coordination environment of 1,4,7-triazacyclononane can be adapted, through sequential functionalization of two secondary amines, to
generate ligands applicable in biomimetic studies. Two “amino acids” and an amino derivative have been prepared from 1,4,7-triazatricyclo-
[5.2.1.04,10]decane. This synthon allows efficient attachment of one functional group to the macrocyclic ring, forming a monoamidinium salt.
Hydrolysis generates a formyl derivative, which was further functionalized at the secondary amine and hydrolyzed in strong acid to generate
ligands 1−3.
Interest in the development of novel acyclic and macrocyclic
ligand assemblies continues to be stimulated by the ability
of such ligands to form transition metal complexes with
tunable physicochemical and functional properties. The
resulting complexes find diverse applications as medicinal
inorganic compounds,1 photosensitizers in solar cells,2
catalysts for organic transformations,3 molecular devices
based on tunable properties,4 and mimics for enzymes
catalyzing redox5 and hydrolytic6 processes.
for example, mimic redox metalloenzymes (galactose oxi-
dase, hemocyanin, tyrosinase, and Mn catalases are ex-
amples),7 effectively cleave RNA or DNA,8,9 and catalyze
oxidative organic transformations.10 Photoelectrochemical
devices combining photoactive Ru centers with redox active
Mn centers are under development.11
Our own research focuses on the application of tacn and
derivatives of tacn, including multiple tacn assemblies, in
the development of models for multimetal biosites.12 The
recent attachment of tacn to an amino acid through amino
The small tridentate macrocycle 1,4,7-triazacyclononane
(tacn) has been at the forefront of developments in several
of these areas. Tacn and its derivatives form complexes that,
(7) (a) Chaudhuri, P.; Wieghardt, K. Prog. Inorg. Chem. 1987, 35, 329-
436. (b) Wieghardt, K. Angew. Chem., Int. Ed. Engl. 1989, 28, 1179-
1198. (c) Tolman, W. B. Acc. Chem. Res. 1997, 30, 227-237 and references
therein.
(8) (a) Hegg, E. L.; Burstyn, J. N. Inorg. Chem. 1996, 35, 7474-7481.
(b) Young, M. J.; Chin, J. J. Am. Chem. Soc. 1995, 117, 10577-10578.
(9) (a) Rossi, P.; Felluga, F.; Tecilla, P.; Formaggio, F.; Crisma, M.;
Toniolo, C.; Scrimin, P. J. Am. Chem. Soc. 1999, 121, 6948-6949. (b)
Sissi, C.; Rossi, P.; Felluga, F.; Formaggio, F.; Palumbo, M.; Tecilla, P.;
Toniolo, C.; Scrimin, P. J. Am. Chem. Soc. 2001, 123, 3169-3170. (c)
Rossi, P.; Felluga, F.; Tecilla, P.; Formaggio, F.; Crisma, M.; Scrimin, P.
Biopolymers (Peptide Science) 2001, 55, 496-501.
(10) (a) de Vos, D. E.; Meinershagen, J. L.; Bein, T. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2211-2213. (b) Zondervan, C.; Hage, R.; Feringa, B.
L. Chem. Commun. 1997, 419-420.
(11) Burdinski, D.; Bothe, E.; Wieghardt, K. Inorg. Chem. 2000, 39,
105-116.
(12) (a) Spiccia, L.; Graham, B.; Hearn, M. T. W.; Lazarev, G.;
Moubaraki, B.; Murray, K. S.; Tiekink, E. R. T. J. Chem. Soc., Dalton
Trans. 1997, 4089-4097. (b) Brudenell, S. J.; Spiccia, L.; Bond, A. M.;
Fallon, G. D.; Mahon, P. J.; Hockless, D. C. R.; Tiekink, E. R. T. Inorg.
Chem. 2000, 39, 881-892.
† Department of Chemistry.
‡ Department of Biochemistry and Molecular Biology.
(1) Medicinal Inorganic Chemistry. Chem. ReV. special ed. 1999, 99,
2201-2842 and references therein.
(2) Hagfeldt, A.; Gratzel, M. Chem. ReV. 1995, 95, 49-68.
(3) Hage, R.; Iburg, J. E.; Kerschner, J.; Koek, J. H.; Lempers, E. L.
M.; Martens, R. J.; Racherla, U. S.; Russell, S. W.; Swarthoff, T.; van Vliet,
M. R. P.; Warnaar, J. B.; van der Wolf, L.; Krljen, B. Science 1994, 369,
637-639.
(4) See for example: (a) Muller, A.; Peters F.; Pope, M. T.; Gatteschi,
D. Chem. ReV. 1998, 98, 239-271. (b) Beer, P. D.; Gale, P. A.; Chen, G.
Z. J. Chem. Soc., Dalton Trans. 1999, 1897-1910. (c) Fabrizzi, L.; Licchelli,
M.; Pallavicini, P. Acc. Chem. Res. 1999, 32, 846-853.
(5) See for example: Bioinorganic Enzymology. Chem. ReV. special ed.
1996, 96, 2237-3042 and references therein.
(6) (a) Stra¨ter, N.; Lipscomb, W. N.; Klabunde T.; Krebs, B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2024-2055. (b) Structure and Bonding;
Sadler, P. J., Ed.; Springer-Verlag: Berlin, New York, 1997; Vol. 89, pp
1-199.
10.1021/ol016291d CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/15/2001

acid side chain modification13 led us to examine synthetic
pathways to a wider array of tacn “amino acid” derivatives.
We report the synthesis of two “amino acid” derivatives of
tacn, 1-aminopropyl-4-acetato-1,4,7-triazacyclononane (1)
and 1-acetato-4-benzyl-1,4,7-triazacyclononane (2), and a
new amine derivative, 1-benzyl-4-formyl-7-aminopropyl-
1,4,7-triazacyclononane (3). The syntheses apply 1,4,7-
formyl derivative (6) in 97% yield, identified by characteristic
1H NMR signals at 8.22 and 8.41 ppm and the expected Cd
O stretch at 1667 cm-1 in the IR spectrum. As is typical for
many products containing this group, two conformational
isomers are seen in the NMR spectra as a result of slow
rotation about the C-N amide bond.15 Reaction of 6 with
ethyl bromoacetate gave 7 as a honey-colored oil in 94%
yield, which was hydrolyzed by refluxing in 5 M HCl to
remove the phthalimide, formyl, and ester protecting groups
from the primary amino, secondary amino, and acetate
groups, respectively. Workup of the solution, after filtration
to remove the phthalic acid that precipitated on cooling,
yielded an oil. As can be the case for molecules exhibiting
zwitterionic character or complex acid-base equilibria,
because of the presence functional groups with distinctly
different acid-base properties, the purification of 1 presented
some difficulty. Of the various purification attempts, treat-
ment of the oil with a hydrobromic acid/acetic acid mixture
and precipitation with ether was most successful, producing
1 as a white, hygroscopic trihydrobromide salt in 62% yield.
The microanalytical data fitted for the dihydrate, the ESI
mass spectrum showed a signal due to the parent molecular
ion {1 + H}+ at m/z ) 245, and the spectroscopic data (IR
triazatricyclo[5.2.1.04,10]decane (tacn orthoamide, 4),14
a
synthon that has been previously used to prepare function-
alized tacn derivatives.15
The synthetic route to the trihydrobromide salt of 1 is
described in Scheme 1 below. The key synthon, 1,4,7-
Scheme 1a
1
and H and 13C NMR) were as expected for 1.
The synthesis of the trihydrobromide salt of 2 is outlined
in Scheme 2.
Scheme 2a
a (a) N-(3-Bromopropyl)phthalimide/CH3CN; (b) H2O; (c)
BrCH2CO2Et/Na2CO3/CH3/CN; (d) (i) 5 M HCl, (ii) HBr/
CH3COOH.
triazatricyclo[5.2.1.04,10]decane (tacn orthoamide, 4), was
prepared by refluxing 1,4,7-triazacyclononane with 1 equiv
of dimethylformamide dimethylacetal in toluene.14 Reaction
of 4 with N-(3-bromopropyl)phthalimide in acetonitrile gave
the insoluble monoamidinium bromide salt (5) in 71% yield.
The 1H NMR spectrum and CdO stretches at 1770 and 1713
cm-1 in the IR spectrum confirmed the attachment of the
N-(3-propyl)phthalimide. Hydrolysis of 5 in water gave the
a (a) BrCH2Ph/THF; (b) H2O; (c) BrCH2CO2Et/Na2CO3/CH3CN;
(d) (i) 5 M HCl, (ii) CH3COOH/HBr(g).
(13) Rossi, P.; Felluga, F.; Scrimin, P. Tetrahedron Lett. 1998, 39, 7159-
7162.
The monobenzyl, formyl derivative, 8, was produced in
92% yield by the reaction of 4 with 1 molar equiv of benzyl
(14) (a) Atkins, T. J. J. Am. Chem. Soc. 1980, 102, 6364-6365. (b)
Weisman, G. R.; Johnson, V.; Fiala, R. E. Tetrahedron Lett. 1980, 21,
3635-3638.
(15) Blake, A. J.; Fallis, I. A.; Parsons, S.; Ross, S. A.; Schroder, M. J.
Chem. Soc., Dalton Trans. 1996, 525-532.
1
bromide in THF and hydrolysis in water. The H and 13C
NMR spectra of 8 exhibited characteristic signals due to the
benzyl group and the tacn ring, confirming the formation of
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Org. Lett., Vol. 3, No. 18, 2001

the product. As for 6, two signals due to the formyl proton
were observed in the H NMR spectrum (at 7.97 and 8.12
it was extracted into an organic solvent and isolated as the
oil. The analytical data confirmed the formation of the ligand.
Molecular mechanics calculations16 were carried out on
the neutral forms of 1 and 2 in order to establish the preferred
conformations of these ligands. Both ligands were anticipated
to exist as zwitterions with one protonated amine group and
deprotonated carboxylate group. Because several zwitterionic
forms are possible for 1 and 2 (as a result of the presence of
primary (1), secondary (1 and 2), and tertiary (1 and 2) amine
groups), it was important to establish the preferred site of
protonation and conformation of these ligands. It was also
of interest to examine whether interactions such as hydrogen-
bond stabilization could be important in determining the
structures of 1 and 2.
1
ppm). In the IR spectrum, a CdO stretch associated with
formyl groups was observed at 1662 cm-1, and bands at 700
and 731 cm-1 confirmed the presence of the aromatic ring.
Attachment of the carboxylate ester was achieved in 77%
yield by refluxing 8 in CH3CN with 1 equiv of ethyl
bromoacetate in the presence of a base. The NMR spectra
of 9 also exhibited the duplicity imparted by the resonance
forms of the amide group. The presence of the ester group
was confirmed by characteristic NMR signals and a νCO
stretch at 1739 cm-1. Hydrolysis of 10 by refluxing in 5 M
HCl, followed by a workup similar to that used for 1, gave
an oil, which was dissolved in glacial acetic acid and treated
with HBr(g) to yield the trihydrobomide dihydrate salt of 2.
The microanalytical data fitted for this composition, and the
ESI mass spectrum showed a signal due to the parent
molecular ion {2 + H}+ at m/z ) 278. The 1H and 13C NMR
spectra provided further confirmation of the constitution of
the product.
For 1, the compound with one pendant carboxylate and
one pendant propylamino group, four zwitterionic forms are
possible because four different amino groups are present.
The most stable conformation is the zwitterion in which the
pendant primary propylamine is protonated (see Figure 1)
Scheme 3 outlines the synthesis of 3. Treatment of 8 with
N-(3-bromopropyl)phthalimide (1 equiv) in CH3CN attached
Scheme 3a
Figure 1. Energy-minimized structure of 1.
rather than the secondary or tertiary amines of the tacn ring.
This zwitterion is stabilized by a moderately strong hydrogen-
bonding interaction between the protonated pendant propyl-
amino group and the carboxylate group, N‚‚‚O distance 2.72
Å. The formation of such a H-bond is facilitated by the
flexibility of the pendant propylamino group. Zwitterionic
forms with the site of protonation at either the secondary or
tertiary ring nitrogens give rise to minimized structures with
much higher strain energies (typically 70-100 kcal mol-1
higher), as does the nonzwitterionic neutral form in which
the carboxylate group is protonated. Thus, for 1 energetically
favorable intramolecular H-bonding interactions between the
positively charged primary amine and the negatively charged
carboxylate force the two pendant groups on the same side
on the macrocyclic ring, thereby significantly influencing
the preferred conformation of the ligand.
a (a) N-(3-Bromoprophyl)phthalimide/Na2CO3/CH3CN; (d) (i) 5
M HCl, (ii) CHCl3.
the N-(3-propyl)phthalimide pendant arm to the tacn ring.
The product, 10, was isolated as an orange oil and showed
CdO stretches due to the phthalimide (1770 and 1711 cm-1)
and the formyl (1667 cm-1) groups in the IR spectrum. It
was anticipated that base hydrolysis of 10 would remove
the formyl group, thereby generating a secondary amine,
which could be derivatized through the attachment of a
carboxylate ester group and, finally, hydrolyzed to produce
a tacn “amino acid” derivative. However, a time-dependent
IR study of the hydrolysis of 10 in a KOH/ethanol solution
established that the CdO stretches at 1713 and 1770 cm-1
gradually diminished, indicating the loss of the phthalimide
group. Over the same period of time, there was little change
in the intensity of the formyl CdO stretch located at 1668
cm-1. Full hydrolysis of 10 to generate 3 was achieved at
elevated temperatures under both acidic (as used for 1 and
2) and basic conditions. Since 3 is neutral in basic conditions,
For 2, the compound with one pendant carboxylate and
one pendant benzyl group, three zwitterions are possible, and
our calculations indicate that these are energetically favored
over the nonzwitterionic form with the protonated carbox-
(16) Molecular mechanics calculations applied the cvff force field in the
Biosym/MSI Discover II molecular simulation package.
Org. Lett., Vol. 3, No. 18, 2001
2857

ylate. The lowest energy conformation is one in which the
proton is located on the secondary amine rather than the two
tertiary amines bearing either the benzyl or the carboxylate
pendant groups. In contrast to 1, the lowest energy confor-
mation has the carboxylate and the protonated amine
hydrogens on the opposite side of the tacn ring (Figure 2)
and not involved in H-bonding to each other. Weak H-
bonding interactions between the protonated secondary amine
and the two tertiary amines (N‚‚‚N ) 2.92 and 3.00 Å)
stabilize this conformation. The most notable feature that
distinguishes the predicted structure of 2 from that of 1 is
that the two pendant groups (i.e., the aromatic ring and the
carboxylate group) lie on the opposite sides of the plane
formed by the nitrogens of the macrocyclic ring, an orienta-
tion likely to be preferred on steric grounds.
In summary, convenient synthetic procedures are reported
for three derivatives of tacn. Notably, molecular mechanics
calculations carried out on 1 and 2 indicate that, as a result
of difference in the strength of intramolecular H-bonding
interactions, these derivatives are likely to adopt quite
different conformations. The application of these ligands in
biomimetic studies focusing on various metalloproteins is
currently under examination.
Acknowledgment. This work was supported by the
Australian Research Council. B.G. was the recipient of an
Australian Postgraduate Award.
Supporting Information Available: Detailed descrip-
tions of experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 2. Energy-minimized structure of 2.
OL016291D
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Org. Lett., Vol. 3, No. 18, 2001