A tetrakis(tetrazolyl) Analogue of EDTA

Article abstract of DOI:10.1002/ejoc.200900016

The tetrazole moiety is usually established in situ with the corresponding inconveniences, such as reactant incompatibility, yield. In most of these cases, the tetrazole is formed in its nonprotected form. Subsequent protection is unattractive because of the promiscuous formation of two regioisomers. No particular protecting group has seen widespread use. The growing field of site-selective oxidation of unactivated hydrocarbons makes use of metal complexes based on multidentate ligands displaying nitrogen coordination sites. We have characterized an easily accessible, benzyl-protected synthon that allows the convergent introduction of the tetrazolylmethyl moiety and its smooth deprotection by catalytic hydrogenation. With the straightforward synthesis of the new hexadentate ligand EDTT, we have demonstrated the utility of this synthon for the fields of coordination, medicinal, and organocatalytic chemistry. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900016

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900016
A Tetrakis(tetrazolyl) Analogue of EDTA
Faycal Touti,[a] Philippe Maurin,[a] and Jens Hasserodt*[a]
Keywords: Nitrogen heterocycles / Protecting groups / Isosteres / N ligands
The tetrazole moiety is usually established in situ with the
corresponding inconveniences, such as reactant incompati-
bility, yield. In most of these cases, the tetrazole is formed in
its nonprotected form. Subsequent protection is unattractive
because of the promiscuous formation of two regioisomers.
No particular protecting group has seen widespread use. The
growing field of site-selective oxidation of unactivated hy-
drocarbons makes use of metal complexes based on multi-
dentate ligands displaying nitrogen coordination sites. We
have characterized an easily accessible, benzyl-protected
synthon that allows the convergent introduction of the tetra-
zolylmethyl moiety and its smooth deprotection by catalytic
hydrogenation. With the straightforward synthesis of the new
hexadentate ligand EDTT, we have demonstrated the utility
of this synthon for the fields of coordination, medicinal, and
organocatalytic chemistry.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
ligands, a vast number of new binary metal complexes are
within our reach, some of which have potentially unique
properties. Of course, the deprotonated carboxamide bond
has been known as an N ligand since the discovery of the
Biuret reaction. But the acidity of the carboxamide moiety
is negligible (pKa ≈ 26 in DMSO),[9] and only the thermo-
dynamic driving force of the formation of a particularly
strong binary complex with CuI in conjunction with the aid
of 1% KOH shifts the deprotonation equilibrium to the an-
ionic form. The intuitive presumption that incorporation of
the N–H “acidic” nitrogen atom into an extended π system
would appreciably lower the pKa does not hold. For
example, “monoacidic” dipyrrins[10] have received growing
attention as anionic N ligands, particularly for BODIPY-
derived dye development,[11,12] but they still show rather
high pKas (pKa = 18–21 in DMSO/H2O/Me4NOH).[13] Fur-
ther, their utility in the generation of a multidentate ligand
is severely limited by their complete rigidity. In fact, they
can be regarded as a coplanar fragment of the porphyrin
system. Even lower N–H acidity has been determined for
the porphyrins.[14] More recently, Limbach and Schwesinger
et al. estimated a pKa of approximately 37 in acetonitrile.[15]
In any case, this tetradentate system already dictates the
identity of four of the six coordinating units because of its
unique planar structure, and the grafting of a pendant arm
on it for occupation of a fifth coordination site leads to
thermodynamically very weak macrocyclic chelate rings.
Introduction
The selection of available organic multidentate ligands
for coordination chemistry is constantly growing. Metal
complexes with refined or novel properties are in great need
for fields as diverse as spin transition materials[1,2] or site-
selective oxidation of unactivated hydrocarbons.[3–7] Par-
ticularly, the latter often favors the use of redox-active iron
complexes with open coordination shells to accommodate
the substrate and in which the metal ion is in the oxidation
state +2. Such complexes are characterized by the preferred
or even exclusive presence of nitrogen donor sites, sites that
favor the ferrous state according to the HSAB theory. Pen-
dant arms offering imine-type nitrogen coordination sites
derived from pyridine, imidazole, or Schiff bases are par-
ticularly popular. These arms are frequently grafted onto
aliphatic nitrogen atoms because this atom offers the very
welcome possibility of creating branched multidentate li-
gands, which leads to five-membered chelate rings (for ex-
ample, see ref.[8]). Neither of these two types of N-coordi-
nating sites presents a negative charge as is often observed
for O-coordinating moieties (carboxylate, phenolate, cate-
cholate). The corresponding complexes are thus mostly cat-
ionic or strongly cationic, which limits (a) their thermo-
dynamic stability, (b) the range of catalytic properties at-
tainable, (c) the media where they can be employed, and (d)
the span of accessible redox potentials.
By expanding the armamentarium of pendant arms
available to the coordination chemist with new anionic N
[a] Laboratoire de Chimie, UMR CNRS 5182, Université de
Lyon – ENS,
Results and Discussion
46, Allée d’Italie, 69364 Lyon cedex 07, France
Fax: +33-4-72728860
In view of the above considerations, we have therefore
opted for the use of the tetrazole unit to provide the N-
anionic coordination site. Tetrazole exhibits a very attrac-
E-mail: jens.hasserodt@ens-lyon.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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F. Touti, P. Maurin, J. Hasserodt
SHORT COMMUNICATION
tive aqueous pKa of 4.90,[16] which is comparable to that of
acetic acid. Even 5-methyltetrazole still shows a pKa of
5.56, and further substitution on the 5-methyl group can
significantly lower this value.[17,18] The tetrazole moiety
thus offers a full negative charge at neutral pH for effective
coulombic compensation of metal-associated positive
charges, and thus contributes to maximum complex
strength at this pH, provided that all other requirements for
structural and orbital complementarity are satisfied. The
exploitation of tetrazole as a monodentate ligand dates far
back.[19,20] But its incorporation into multidentate ligands
that leads to five-membered chelate rings upon complex-
ation has not yet been attempted. In the domains of medici-
nal chemistry and drug design,[21,22] and lately also more
frequently in organocatalysis,[23–26] the tetrazole moiety is
of particular interest as a carboxylic acid “isoster”.[27] Here,
it is usually established in situ with the corresponding in-
conveniences (reactant incompatibility, yield). In most of
these cases, the tetrazole is formed in the nonprotected
form.[28] Subsequent introduction of a protecting group is
rarely attempted in view of the mixture of two regioisomers
obtained and the low yields encountered. A recent ap-
proach establishes the in situ formation of tetrazole as well,
but this time in the protected form.[29] However, this
method requires the prior establishment of an activated
(acylated) nitrile and its reaction with an activated azide,
measures that encourage consideration of alternative strate-
gies. Specifically, introduction of a preformed, preprotected
tetrazole in the form of a readily accessible synthon would
be attractive. Our thorough study of the literature also re-
vealed that no protecting group for tetrazoles has yet found
widespread acceptance and application. In fact, of the two
principal monographs on protecting group chemistry,[30,31]
only that by Wuts and Greene[30] offers any solution for
azoles, but it basically limits coverage to imidazoles and
pyrroles. Pyrazoles or tetrazoles, in particular, are not cov-
ered at all.
Unprotected 5-aminomethyltetrazoles (bidentate ligand
character) were synthesized by a direct synthesis.[32] How-
ever, no methyl groups bearing a suitable leaving group for
introduction into various systems by nucleophilic substitu-
tion were presented in that study. The only research on the
preparation of a suitably substituted tetrazole was per-
formed by Harvill et al. in 1952,[33] who applied the classic
tetrazole synthesis introduced by von Braun.[34] However,
while including the N-benzyl group in their study, they
did not consider it as a potential protecting group. We ap-
plied their protocol by fusing easily accessible hydrazoic
acid with the corresponding chloromethylchloroimine
(Scheme 1). The presence of a protecting group that can be
removed by catalytic hydrogenation was obviously at the
heart of the attractiveness of this synthetic target.
Scheme 1. Introduction of the flexible N substituent in a previously
reported[33] access to a tetrazolyl-bearing synthon.
extraction. We were cautious because of the known diffi-
culty of removing the benzyl group from nitrogen sites. We
thus included the diphenylmethyl group in our study for its
demonstrated superiority in its removal from regular ali-
phatic amines.[35] Subsequent transformation into the chlo-
roimines 2a,b by use of phosphorus pentachloride is
straightforward, but care has to be taken in driving out all
traces of hydrogen chloride before proceeding to the next
step (see Supporting Information).
A concentrated solution of hydrazoic acid in toluene is
easily prepared by extraction of a sodium azide solution
treated with sulfuric acid, whilst working under a properly
operating fume hood. This solution is then merged with the
toluene solution of the crude chloroimine and stirred at
room temperature overnight to give tetrazoles 3a,b in 75%
yield over two steps (Harvill et al. reported a yield of 52%).
Only 2 equiv. NaN3 should be used in order to prevent
losses in yield as a result of secondary attack on the chlo-
rine-bearing methylene group. The 1,5-substitution pattern
of the thus obtained tetrazoles, intrinsically tied to the con-
stitution of the starting material, was demonstrated through
X-ray structure analysis of a crystalline sample of 3b (Fig-
ure 1). We first explored hydrogenation of these compounds
in order to learn the precise conditions for efficient removal
of the protecting group. During the experiments, we eventu-
ally realized that the chlorine atom is reliably replaced by a
hydrogen atom, no matter how smooth the conditions ap-
Chloroacetyl chloride was thus reacted with exactly
2 equiv. of the benzylamine or diphenylmethylamine to fur-
nish the corresponding amides 1a and 1b, respectively, in
almost quantitative yield (Harvill et al. reported a yield of
39% for a different protocol[20]). The second equivalent of
amine can of course be recycled from the mixture by simple Figure 1. 1,5-substitution pattern in 3b (X-ray structure analysis).
1496 Eur. J. Org. Chem. 2009, 1495–1498
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A Tetrakis(tetrazolyl) Analogue of EDTA
plied. We also learned that the benzyl group leaves so easily drogen hardly advanced at all. We then embarked on a
that use of the more labile diphenylmethyl group would not thorough optimization of the conditions monitored by
be necessary. We thus decided to continue to demonstrate LCMS analysis. Eventually, it was established that complete
the introduction of the tetrazolylmethyl moiety into nucleo- removal of all four protecting groups was possible in 48 h
phile-displaying entities using only the benzylated version with 600 wt.-% of catalyst powder, at 20 °C and 1 atm hy-
3a.
drogen. Importantly, any additional amount of catalyst
In our desire to generate bidentate N-coordinating moie- added at a later time to jumpstart a potentially slowing hy-
ties offering a negative charge at physiological pH and that drogenation was ineffective even when applying great care
lead to five-membered chelate rings, we identified the classic in purging the flask with hydrogen; it is thus imperative that
EDTA ligand as the appropriate target to transform into a the necessary amount of catalyst for complete conversion is
tetrakis(tetrazolyl) analogue, N,N,NЈ,NЈ-tetrakis(tetrazolyl- added at the beginning. On the positive side, no side prod-
methyl)-1,2-ethanediamine EDTT (5, Scheme 2). EDTT ucts were formed at this “catalyst” loading as demonstrated
should a priori display the same zwitterionic character as by monitoring with mass spectrometry. However, we ob-
EDTA. The use of acetonitrile as solvent and K2CO3 as served that a picolyl group, if linked to an aliphatic nitrogen
base (commonly used conditions for alkylation) did not ad- atom present in a compound bearing multiple benzyltet-
vance the reaction of ethylenediamine with a quantity of razolylmethyl groups, is effectively removed under these
3a that slightly exceeds four equivalents. After one week, conditions. Purification of the resulting zwitterionic target
virtually all possible species were detected in the reaction compound 5 was accomplished by chromatography on a
mixture by LCMS analysis. However, four decades ago, the reversed-phase column (C18) by using a mobile-phase gra-
formation of the all-picolyl analogue of EDTA (TPEN: an dient composed of acetonitrile and water. Of course, ion
altogether basic hexadentate ligand that has found wide- exchange chromatography would be an alternative means.
spread application as a membrane-permeable Zn chelator In our hands, the final yield of pure 5 was thus 70%.
to induce apoptosis by Zn deprivation)[36] was ac-
complished in a heterogeneous reaction by treating an
aqueous solution of ethylenediamine and NaOH with the
Conclusions
insoluble liquid picolyl chloride (48% yield).[37] When we
applied similar conditions, we were forced to heat the mix-
ture to 70 °C in order to melt solid 3a and achieve some
degree of homogeneity by vigorous stirring. To our delight,
we thus obtained the crude target compound 4 in an over-
night reaction in quantitative yield. Column chromatog-
raphy on silica gel preconditioned with TEA somewhat lim-
ited the yield of pure basic 4 to 82%. A supplementary
attempt at reacting the diphenylmethyl analogue 3b in this
fashion was not successful because 3b did not melt even at
100 °C.
We have demonstrated that introduction of a tetrazolyl-
methyl group into a nucleophile-bearing compound is
straightforward when a preformed tetrazolyl synthon is
used rather than when this heterocycle is established in situ
as reported widely in the literature. The synthon already
contains the benzyl moiety, a protecting group particularly
popular for its smooth removal conditions, which are com-
patible with most chemistries found in the target com-
pounds. No complications stemming from a lack of 1,2-
regioselectivity have to be feared. The presented protocol of
synthon preparation as originally developed by Harvill et
al.[33] is likely transferable to tetrazoles bearing other 5-sub-
stituents, provided that they are compatible with PCl5 treat-
ment of the corresponding amide. Benzyl removal is cata-
lytic and requires only a hydrogen-filled balloon. However,
in the case of multiple units grafted onto one molecule and
particularly in the presence of tertiary amine sites, the
quantity of Pd/C has to be significantly increased. We wish
to stress here that compounds 4 and 5 appear to be much
more stable thermodynamically relative to picolyl-bearing
species such as TPEN[37] or TPTACN.[38] The latter tend to
lead to rapid darkening in the course of the reactions
whether they are starting material or the product.[37,38] It is
thus often difficult to obtain light-colored samples by puri-
fication, and the yields are accordingly limited. By contrast,
the chemistry of compounds/ligands decorated with the tet-
razolylmethyl group, whether benzyl-protected or not, is
characterized by high yields and colorless material.
Scheme 2. Grafting of four tetrazolyl units onto ethylenediamine.
Supporting Information (see footnote on the first page of this arti-
In contrast to our observations with 3a, we were sur- cle): Experimental procedures and full spectroscopic data for all
new compounds are presented.
prised to discover that hydrogenation of pure 4 with cata-
lytic amounts of 5% Pd/C in a mixture of dichloromethane
CCDC-696050 contains the supplementary crystallographic data
and ethanol (4 is scarcely soluble in ethanol) at 1 atm hy- for this paper. These data can be obtained free of charge from The
Eur. J. Org. Chem. 2009, 1495–1498
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Touti, P. Maurin, J. Hasserodt
SHORT COMMUNICATION
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Acknowledgments
We thank C. Aronica and the Centre de Diffractométrie H.
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Received: January 8, 2009
Published Online: February 23, 2009
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