Synthesis of a macrobicycle incorporating the tris(pyrazolyl)methane ligand

Article abstract of DOI:10.1021/ol036408t

Steric crowding of the 3-position of tris(pyrazolyl)borate and -methane ligands has produced tetrahedral metal complexes with controlled reactivity. As an alternative, we propose to incorporate the tris(pyrazolyl)methane chelate in a macrobicyclic structu

Full text of DOI:10.1021/ol036408t

ORGANIC
LETTERS
2004
Vol. 6, No. 5
747-750
Synthesis of a Macrobicycle
Incorporating the Tris(pyrazolyl)methane
Ligand
Leyong Wang and Jean-Claude Chambron*
UniVersite´ de Bourgogne, Laboratoire d’Inge´nierie Mole´culaire pour la Se´paration et
les Applications des Gaz (CNRS, UMR 5633), 6, bouleVard Gabriel,
21100 Dijon, France
jean-claude.chambron@u-bourgogne.fr
Received December 11, 2003
ABSTRACT
Steric crowding of the 3-position of tris(pyrazolyl)borate and -methane ligands has produced tetrahedral metal complexes with controlled
reactivity. As an alternative, we propose to incorporate the tris(pyrazolyl)methane chelate in a macrobicyclic structure in order to create a
cavity with well-defined dimensions and shape. Acid-catalyzed equilibration of excess of the new pyrazole 3-(1H-pyrazol-3-yl)benzenemethanethiol
acetate with HC(3,5-Me2pz)3 followed by hydrolysis affords a functionalized tris(pyrazolyl)methane, which reacts with 1,3,5-tris(bromomethyl)-
benzene in K2CO /DMF to give the title compound.
3
Tris(pyrazolyl)borate (TpR,R′) or scorpionate ligands1,2 are
facially capping tridentate nitrogen donors that have been
used in particular as models of the metal binding sites of
several metalloenzymes including hemocyanin,3 blue copper
proteins,4 and carbonic anhydrase (CA).5 Substitution of the
pyrazole 3-position (R) by bulky groups in combination with
buttressing effects6 has been shown to enforce tetrahedral
coordination geometry at the metal7 and allow for the control
of the reactivity of the metal-bound species. In particular,
the use of large, hydrophobic substituents such as tert-butyl
in TptBu,Me or p-isopropylphenyl (p-cumenyl) in TpCum,Me has
led to the isolation of stable yet highly nucleophilic TpZn-
OH complexes. TptBu,MeZn-OH successfully mimics the
(1) The notation TpR,R′ is equivalent to HB(3-R-5-R′pz)3, where pz is
pyrazole. Analogous tris(pyrazolyl)methanes are noted TpmR,R′
.
(5) (a) Alsfasser, R.; Trofimenko, S.; Looney, A.; Parkin, G.; Vahren-
kamp, H. Inorg. Chem. 1991, 30, 4098-4100. (b) Alsfasser, R.; Ruf, M.;
Trofimenko, S.; Vahrenkamp, H. Chem. Ber. 1993, 126, 703-710. (c)
Looney, A.; Han, R.; McNeill, K.; Parkin, G. J. Am. Chem. Soc. 1993,
115, 4690-4697. (d) Vahrenkamp, H. Acc. Chem. Res. 1999, 32, 589-
596. (e) Parkin, G. Chem. Commun. 2000, 1971-1985.
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B. S.; Rheingold, A. L.; Walters, M. A. Inorg. Chem. 1995, 34, 4268-
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Ji, G.; Tipton, A. A. Inorg. Chem. 1999, 38, 906-913.
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Trofimenko, S. Chem. ReV. 1993, 93, 943-980. (c) Trofimenko, S.
Scorpionates, the Coordination Chemistry of Poly(pyrazolyl)borate Ligands;
Imperial College: London, 1999.
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10.1021/ol036408t CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/10/2004

The synthesis of 2 involves 3-(1H-pyrazol-3-yl)benzene-
methanol 4, a known compound15 prepared in this study by
NaBH4 reduction (MeOH, 0 °C) of the corresponding
aldehyde 3,16 in 82% yield (Scheme 1). Subsequent reaction
Scheme 1
Figure 1. TpCum,MeZn-OH (1)8 and macrobicycle 2 incorporating
the tris(pyrazolyl)methane chelate system.
active site of CA,5 and TpCum,MeZn-OH (1 of Figure 1)
performs the hydrolysis of a range of small molecule
substrates.8 The combination of TpiPr2 and bulky thiols has
produced rare tetrahedral copper(II) complexes that closely
mimic the spectroscopic characteristics of the blue copper
proteins.4b,c As a further example of the use of hindered
homoscorpionates to control reactivity, copper(I) complexes
of TpMs (Ms is mesityl) have been shown to catalyze the
cyclopropanation of olefins by ethyldiazoacetate with re-
markable cis diastereoselectivity.9 Good enantiocontrol (85%
ee) of the same reaction has been achieved with optically
active C3-symmetric Tps that have been tailored from
asymmetric pyrazoles.10
By contrast, tris(pyrazolyl)methane (Tpm) ligands,1,11 the
neutral analogues of scorpionates, have received less atten-
tion. In a few instances, they have led to metal complexes
with decreased stability,12 as clearly demonstrated for Zn2+,
in particular.13
In this letter, we present the synthesis of a macrobicycle
incorporating the tris(pyrazolyl)methane ligand system (2 of
Figure 1) by closing a functionalized tris(pyrazolyl)methane
derivative with a mesitylene cap. This approach is reminis-
cent of cyclophane chemistry.14 Macrobicycle 2 is the first
example of a new, general strategy for the control of the
metal environment in complexes of Tpm ligands, and
hopefully for improving their robustness.
with thiolacetic acid in Mitsunobu reaction conditions (PPh3,
DIAD, THF, 0 °C)17 afforded the benzenemethanethiol
acetate derivative 5 in 83% yield after chromatography (25%
EtOAc in heptane). The acetyl protecting group was removed
by reaction of 5 with potassium carbonate in methanol at
room temperature, followed by acidic workup, affording
3-(1H-pyrazol-3-yl)benzenemethanethiol 6 quantitatively.
Tris(pyrazolyl)methanes are classically prepared from
chloroform by reaction with the appropriate pyrazolate that
is either preformed11,18 or generated in situ (phase-transfer
catalysis),19 i.e., basic reaction conditions that are not adapted
to the use of either 5 or 6 as substrates. However, it was
shown recently that acid-catalyzed equilibration of tris-
(pyrazolyl)methane itself or TpmMe2 with pyrazoles allowed
the preparation of various Tpm ligands.20 Of particular
interest for our study was the preparation of TpmPh (10) in
67% yield by reaction of TpmMe2 (7) with 10 equiv of
3-phenyl-1H-pyrazole (8) in the presence of 1 equiv of TsOH
in refluxing toluene (Scheme 2). The disubstituted product
(9) was obtained in 33% yield.
(8) Ruf, M.; Vahrenkamp, H. Chem. Ber. 1996, 129, 1025-1028.
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J. J. Am. Chem. Soc. 2001, 123, 3167-3168.
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1992, 11, 2737-2739. (b) Keyes, M. C.; Chamberlain, B. M.; Caltagirone,
S. A.; Halfen, J. A.; Tolman, W. B. Organometallics 1998, 17, 1984-
1992.
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5126.
Benzylthiol-substituted pyrazole 6 did not appreciably react
under these conditions. By contrast the acetyl-protected deriv-
ative 5 afforded a complex mixture of hetero-tris(pyrazolyl)-
methanes, due to the fact that the acetyl group had been
cleaved in part. Column chromatography (silicagel, dichloro-
methane/heptane) allowed separation of the simple pyrazoles,
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J. H. Inorg. Chem. 1995, 34, 3801-3808. (b) Reger, D. L.; Collins, J. E.;
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B.; Fro¨hlich, R.; Meyer, O.; Hoppe, D. Chem.sEur. J. 2001, 7, 423-435.
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748
Org. Lett., Vol. 6, No. 5, 2004

Scheme 2. Synthesis of TpmPh (Ref 20)
Scheme 5
including those resulting from transacetylation, i.e., 11 (7.1%)
and 12 (traces), from the Tpm mixture, from which pure
tris(pyrazolyl)methane 13 could be isolated in 7.4% yield
after crystallization (Scheme 3). In other experiments, the
particular case of the tripode-tripode coupling strategy.22
Accordingly (Scheme 5), Tpm 15 was reacted with 1,3,5-
tris(bromomethyl)benzene 1623 under high dilution conditions
in DMF at 55 °C, using K2CO3 as the base. After chroma-
tography (silicagel, CH2Cl2) and crystallization from CH2Cl2/
heptane, macrobicycle 2 was obtained in 28% yield as
colorless crystals.
Scheme 3
Spectroscopic data fully support the closed structure of
this C3-symmetric compound. The MALDI-TOF spectrum
shows the expected molecular peak at m/z 694.9. Methine
resonances at 8.15 (1H) and 81.9 ppm (13C) ppm are
diagnostic NMR signals for the tris(pyrazolyl)methane che-
late fragment. Successful and complete capping is confirmed
by the presence of two close singlets at 3.63 and 3.60 ppm
(1H) and at 36.4 and 36.3 ppm (13C) for the benzylic
methylene groups.24
Following earlier work,25 preliminary metal complexation
studies with copper(I) have been undertaken. Handling of
Corey-Pauling-Koltun (CPK) molecular models suggests
that once the metal is chelated by the tris(pyrazolyl)methane
fragment of the cage, only a limited space is left for a
possible ancillary ligand. In particular, triaatomic, end-on
bound molecules such as CH3CN are very likely to be
excluded from the cavity.
difficult separation of 13 was not attempted and the crude
mixture of Tpms was directly reacted with potassium
carbonate (DMF, MeOH) as described for 5, affording a
simple mixture of hetero-tris(pyrazolyl)methane 14 and
homo-tris(pyrazolyl)methane 15 (Scheme 4). Column chro-
Scheme 4
We are currently exploring the complexation proper-
ties of macrobicycle 2 and preparing other members of this
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Chim. Acta 1985, 68, 289-299.
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matography (silicagel, 0.5-3% AcOEt in toluene) allowed
separation of the target 15 (42% yield) from the disubstituted
derivative 14 (15%), both obtained as colorless oils.
One-step capping of C3-symmetric nucleophiles with 1,3,5-
trisubstituted benzene electrophiles or vice-versa is a well-
established method for making cage molecules,21 as a
(24) Data collected in CDCl3 solution. In (CD3)2CO, the proton methine
and methylene resonances are shifted, respectively, to 9.06 and 3.86 and
3.78 ppm (see Supporting Information).
(25) (a) Reger, D. L.; Collins, J. E.; Rheingold, A. L.; Liable-Sands, L.
M. Organometallics 1996, 15, 2029-2032. (b) Cvetkovic, M.; Batten, S.
R.; Moubaraki, B.; Murray, K. S.; Spiccia, L. Inorg. Chim. Acta 2001, 324,
131-140.
Org. Lett., Vol. 6, No. 5, 2004
749

1
new class of Tpm ligands. The results will be reported in
due course.
Supporting Information Available: Copies of the H
NMR, 13C NMR, FT-IR, and MALDI-TOF spectra of 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This letter is dedicated to the memory
of Jean-Marc Kern. We thank the Conseil Re´gional de
Bourgogne for a fellowship to L.W.
OL036408T
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Org. Lett., Vol. 6, No. 5, 2004