Ligand designed with pending phenol group

Article abstract of DOI:10.1016/j.tetlet.2005.11.034

The synthesis of a salicylaldehyde derivative facing an encumbered phenol group on a naphthalene block as a molecular shaft is reported. This molecular unit has been designed to elaborate coordinating ligands holding non-coordinating phenol group for the generation of phenoxyl radical in the close proximity of a metal complex.

Full text of DOI:10.1016/j.tetlet.2005.11.034

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 569–571
Ligand designed with pending phenol group
Laurent Sabater,a Fabien Lachaud,a Christelle Hureaub,* and Ally Aukaulooa,*
a
ˆ
´
Laboratoire de Chimie Inorganique UMR 8613 Bat. 420 Universite Paris Sud, 91405 Orsay, France
bDe´partement de Biologie Joliot-Curie, Service de Bioe´nerge´tique, URA2096, CEA Saclay, F-91191 Gif-sur-Yvette Cedex, France
Received 12 October 2005; revised 3 November 2005; accepted 7 November 2005
Available online 29 November 2005
Abstract—The synthesis of a salicylaldehyde derivative facing an encumbered phenol group on a naphthalene block as a molecular
shaft is reported. This molecular unit has been designed to elaborate coordinating ligands holding non-coordinating phenol group
for the generation of phenoxyl radical in the close proximity of a metal complex.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Lippard et al. described the first example of a bio-
mimetic model of the R2 active site where they incorpo-
rated two main features, a (l-oxo)(l-carboxylato)-
diiron(III) core and a stable phenoxyl radical held close
but not coordinated to the metallic core.7 However, the
phenoxyl radical was not oriented towards the metallic
core contrary to what is observed in the ꢀreal thingꢁ. If
the topology of dinuclear metal complexes for biomim-
icry has been widely developed, there is still a paucity on
the design of ligands capable to hold at the same time
the metal ions and other features like potential centre
for generation of radicals in close proximity but not
directly coordinated to the metal ions. Recently, Nocera
et al. has devised a series of ꢀHangman ligandsꢁ contain-
ing porphyrin or salophen as redox molecular platforms
with a well positioned acid–base function acting as pro-
ton shuttle.8,9 These molecular systems have been used
to illustrate the proton coupled electron transfer events.
Tyrosyl radicals are known to play an essential role in
the functioning of different metalloenzymes. In photo-
system II (PSII), the tyrosyl radicals named Y z and
Å
Å
1,2
Y D are crucial for the photooxidation of water. Yz
stands between the manganese cluster of the oxygen
evolving complex and the pigment P680 and plays the
role as an electron relay in the photoaccumulation of
oxidising power at the OEC. In the Ribonucleotide
Reductase R2 protein, responsible for the transforma-
tion of ribonucleotides to deoxyribonucleotides, the
tyrosyl radical, Tyr122, is oriented towards the dimetallic
core where the closest distance between the phenolic
3–5
˚
oxygen atom and the iron atom is 5.3 A.
Other
selected examples can be found in a seminal review by
Stubbe et al.6 A stricking feature in the two above-men-
tioned examples is that the tyrosyl radical cofactor is not
directly coordinated to the metal core. Across the years,
bioinorganic chemists have designed well elaborated
ligands to generate as closely as possible the first coordi-
nation sphere of the metal ions as found in the natural
systems. However, although a high degree of sophistica-
tion has been introduced in the ligand design for the bio-
mimetic modelisation of enzymes, still a great synthetic
effort must be done to take into account other cofactors,
which are not in the first coordination sphere of the
metal catalytic centre.
Following the goal of bioinorganic chemists of under-
standing the basic principles of the structure–function
relationship of metalloprotein in our laboratory, we
have developed a series of ligands and studied the reac-
tivities of the metal complexes.10–12 In an effort to trans-
late the microenvironment of the metal ions at the active
sites of metalloproteins especially those where a tyrosine
residue plays a redox role, we describe hereby the syn-
thetic tactics to reach a novel family of ligands bearing
a salen-type coordinating cavity surmounted by a pend-
ing phenol group. Our idea is to elaborate a superstruc-
ture where a phenoxyl radical could be generated in the
right topology towards the metal ions in order to gain
insights into the physical properties of such metallorad-
ical species.
Keywords: Suzuki coupling; Duff reaction; Salen-type ligand; Pending
phenol.
*
Corresponding authors. Tel.: +33 1 69 15 47 56; fax: +33 1 69 15 47
54; e-mail addresses: chrishureau@yahoo.fr; aukauloo@icmo.u-psud.
fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.034

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L. Sabater et al. / Tetrahedron Letters 47 (2006) 569–571
Scheme 1. Reagents and conditions: (i) Na2CO3, Pd(PPh3)4 (5 mol %) in toluene/EtOH/H2O (2/2/1) reflux 12 h; (ii) Br2 in CHCl3 0 °C; (iii) n-BuLi/
ClSiMe3 in THF À78 °C; (iv) n-BuLi/B(OMe)3 in THF; (v) Na2CO3, Pd(PPh3)4 (5 mol %) in toluene/EtOH/H2O (2/2/1) reflux 12 h; (vi) HCl 1 M;
(vii) BBr3 in CH2Cl2 0 °C.
The synthetic scheme leading to our target ligand is
shown in Scheme 1. The 1,8-diiodonaphthalene deriva-
tive 1 was chosen as the molecular shaft13 and the first
deck was fixed following a Suzuki cross coupling reac-
tion14 using 1 equiv of 3-formyl-4-methoxyphenyl-
boronic acid 2 and 1 equiv of 1 in typical literature
procedure in a mixture of toluene/ethanol/water (2/2/
1) using Na2CO3 as base and Pd(PPh3)4 (5 mol %) as
catalyst. After conventional workup, compound 3 was
purified from a silica gel column chromatography using
CH2Cl2 as eluent with a yield of 35%. The other com-
pounds were characterised as the dicoupled compound
and the unreacted material. The upper module for
our synthesis, 3,5-di-tert-butyl-4-trimethylsilyloxyphen-
yl boronic acid 7 was prepared following literature
procedures starting from the commercially available
compound 2,6-di-tert-butylphenol 4. Bromination in
the para position of the OH group was carried out at
low temperature and under inert atmosphere with bro-
mine to give compound 5.15 The OH group was pro-
tected upon treatment with n-BuLi followed by
addition of chlorotrimethylsilane 6.16 The boronic acid
derivative 7 was synthesised by treatment of 6 with n-
BuLi at low temperature followed by the addition of
trimethylborate.17 The presence of the tert-butyl groups
on the phenol ring is to enhance the solubility on one
side and to protect the ortho positions of the oxygen
atom from perfoming radical chemistry as it is known
that the spin density on a phenoxyl radical is strongly
delocalised in the ortho and para positions. Moreover,
the bulky tert-butyl groups should also prevent any
direct coordination with the metal centre in the coordi-
nating cavity on the lower deck. The coupling reaction
was realised under the same conditions as mentioned
above and after heating at 100 °C for 12 h. Compound
8 was isolated after purification on column chromato-
graphy (silica gel and CH2Cl2 as eluent) in a 75% yield.
The trimethylsilyloxy group was cleaved by treatment
with a one molar solution of HCl to give compound 9,
and both phenol groups could be freed upon treatment
with BBr3 to give compound 10, which was recovered
1
as a yellow solid (70% yield).18,19 The H NMR spec-
trum of 10 translates the dissymmetry of the protons
on the naphthalene skeleton.
The condensation of 1 equiv of the primary amine deriv-
ative 11 on the aldehyde derivative 10 leads to the ligand
LH2, which was isolated as an off yellow solid (Scheme
2).
As an introductory chapter of the coordination chemis-
try of this family of ligand LH2, we have realised the
metallation of the pentadentate coordinating cavity with
zinc(II) ion. The choice of zinc(II) was guided for its
electrochemical inactivity and diamagnetic nature. The
metallation was performed upon treatment of 1 equiv
of the ligand with 1 equiv of Zn(ClO4)2Æ4H2O and
1 equiv of 2,6-dimethyl-pyridine as a base, in absolute
ethanol. A white solid was isolated. Up to now we have
not been able to obtain crystals of sufficient quality for
an X-ray diffraction analysis. However, the electrospray
mass spectrum of the isolated solid indicates a molecular
peak at 739.3 corresponding to [LHZn]+ motif and the
isotopic pattern is well reproduced by the simulation
(Fig. S1). Preliminary electrochemical studies have been
performed on compound 9 (where only the pending phe-
nol is subjected to oxidation) and the zinc complex for
comparison of the redox potential of the pending

L. Sabater et al. / Tetrahedron Letters 47 (2006) 569–571
571
´ `
The authors wish to thank Dr. Elodie Anxolabehere-
Mallart for fruitful discussions. C.H. acknowledges
Dr. S. Un and Dr. W. Rutherford, for allowing her to
complete the present work.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.11.034.
References and notes
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encumbered di-tert-butyl phenol group. Both cyclic vol-
tammetry traces recorded in acetonitrile show an irre-
versible anodic process associated with the oxidation
of the di-tert-butyl phenol function at 1.11 V versus
SCE and 0.85 V versus SCE, respectively. This shift
can be tentatively assigned to a more pronounce polar-
isation of the O–H group in the presence of the Zn(II)
ion.20 Note that a test cyclic voltammogram on the
Zn(II) complex within the N4O only cavity indicates
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mental conditions. More electrochemical studies are cur-
rently undertaken to elucidate this issue.
´ `
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This type of ligand opens up a new coordination chem-
istry where bioinorganic chemists will be able to analyse
the properties and reactivities of metalloradical species
where the radical stands close to the metal centre but
not directly coordinated to the metal ion. Along this
line, manganese, iron and copper complexes with LH2
are currently underway in our laboratory.
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Acknowledgements
This work was supported by the CEA for the LRC pro-
ject (LRC-CEA No. 33V) and the European Commis-
sion for financial support (STRP SOLAR-H 516510).