Azolidene Carbenes Derived from Biologically Relevant Molecules. Synthesis and Characterization of Iridium Complexes of Imidazolidene Ligands Based upon the Antifungal Drugs Econazole and Miconazole

Full text of DOI:10.1021/ic9806277

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Inorg. Chem. 1998, 37, 5412-5413
Azolidene Carbenes Derived from Biologically Relevant Molecules.1 Synthesis and Characterization of
Iridium Complexes of Imidazolidene Ligands Based upon the Antifungal Drugs Econazole and Miconazole
James H. Davis, Jr.,*,† Charles M. Lake,*,‡ and Melissa A. Bernard†
Departments of Chemistry, University of South Alabama, Mobile, Alabama 36688, and The University of Alabama at Birmingham,
Birmingham, Alabama 35294
ReceiVed June 5, 1998
Imidazole and other -azole ring systems are structural features
of many drugs and natural products.2 Azoles are typically
susceptible to N-alkylation, forming azolium cations.3 Many of
the latter undergo deprotonation of a ring C-H R to the nitrogen,
generating an azolidene carbene.4 In at least one case, that of
thiamine (vitamin B1), such a carbene is thought to be involved
in the biological function of the molecule.5 In turn, the capacity
of azolidene carbenes to function as ligands in transition-metal
complexes is well-established.6 Consequently, biologically rel-
evant molecules containing azoles are candidates as carbene
sources for metal complexation. We consider the utilization of
drugs or natural products in this role to be a potentially useful
approach for the development of compounds of interest for
medicinal and biochemical applications. Further, since N-
methylation is a common metabolic event,7 studies of such
molecules may ultimately provide new insights into possible
modes of metal-azole interactions in biological systems.8
We report here the results of our initial work in this area, the
utilization of the antifungal drugs econazole and miconazole as
carbene ligand precursors for complex formation with iridium
(Scheme 1). The new complexes are the first to link a drug-
based ligand to a metal via a metal-carbon σ bond, and they
complement a small family of antifungal drug-metal conjugates
possessing metal-nitrogen linkages.9
Scheme 1
of the ether solutions yielded the free bases in essentially
quantitative yield. Alkylation of the free bases was accomplished
by refluxing each in neat methyl iodide, followed by evaporation
to dryness.11 The off-white powders (1, econazole derivative; 2,
miconazole derivative) obtained in this fashion are used without
purification.
Both econazole and miconazole were prepared as the respective
free bases from the commercially available nitrate salts.10 The
salts were dissolved in water and the solutions brought to pH )
8 with aqueous base and then extracted with Et2O. Evaporation
In THF at 0 °C, the econazolium salt 1 reacted with the
phosphazene base P4-t-Bu,12 as ascertained by a change in color
of the solutions from near colorless to yellow upon mixing.
Subsequent addition at 0 °C of the putative free-carbene solution
to a light orange, THF suspension of [η4-(1,5-COD)IrCl]2 resulted
in a color change of the latter to dark yellow-orange, accompanied
by the complete dissolution of the iridium complex. After an
additional 15 min of stirring, no further color change was observed
and the THF was removed in vacuo. The residue was extracted
into CH2Cl2 and filtered through silica to remove the putative
P4-t-Bu:HX byproduct. Removal of the solvent in vacuo produced
† University of South Alabama.
‡ The University of Alabama at Birmingham.
(1) Presented in part at the 214th National Meeting of the American Chemical
Society, Las Vegas, NV, September 1997; Abstract INOR 378.
(2) Roth, H. J.; Kleeman, A. Pharmaceutical Chemistry; John Wiley: New
York, 1988; p 218.
(3) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic Chemistry, 3rd ed.;
Chapman & Hall: New York, 1995.
(4) (a) Reference 3. (b) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J.
Am. Chem. Soc. 1991, 113, 361. (c) Arduengo, A. J., III; Dias, H. V.
R.; Harlow, R. L.; Klooster, W. T.; Koetzle, T. F. J. Am. Chem. Soc.
1994, 116, 6812. (d) Alder, R. W.; Allen, P. R.; Williams, S. J. J. Chem.
Soc., Chem. Commun. 1995, 1267.
(5) (a) Breslow, R. J. Am. Chem. Soc. 1957, 79, 1762. (b) Breslow, R. J.
Am. Chem. Soc. 1958, 80, 3719.
a yellow-orange microcrystalline product, the H and 13C NMR
1
spectra of which support its being an iridacarbene.13 A key
spectroscopic element in this assignment is the appearance of a
(6) (a) Wanzlick, H.-W.; Scho¨nherr, H.-J. Angew. Chem., Int. Ed. Engl. 1968,
7, 141. (b) O¨ fele, K. J. Organomet. Chem. 1968, 12, P42. (c) Herrmann,
W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2163.
(7) (a) Transmethylation: Proceedings of the Conference on Transmethyla-
tion, Bethesda, Maryland, U.S.A., on October 16-19, 1978; Usdin, E.,
Borchardt, T., Creveling, C. R., Eds.; Developments in Neuroscience;
Elsevier/North Holland: New York, 1979; Vol. 5. (b) DNA Methyla-
tion: Biochemistry and Biological Significance; Razin, A., Cedar, H.,
Riggs, A. D., Eds.; Springer Series in Molecular Biology; Springer
Verlag: New York, 1984.
(8) Bray, M. R.; Deeth, R. J. J. Chem. Soc., Dalton Trans. 1997, 4005.
(9) (a) Sanchez-Delgado, R. A.; Lazardi, K.; Rincon, L.; Urbina, J. A. J.
Med. Chem. 1993, 36, 2041. (b) Sanchez-Delgado, R. A.; Perez, H.;
Urbina, J. A. J. Med. Chem. 1996, 39, 1095. (c) Sanchez-Delgado, R.
A.; Perez, H.; Navarro, M. J. Med. Chem. 1997, 40, 1937.
(10) Sigma Chemical Company, St. Louis, MO.
(11) Caution! Methyl iodide is highly toxic. Handle with care in an efficient
fume hood.
(12) Pietzonka, T.; Seebach, D. Chem. Ber. 1991, 124, 1837.
(13) 13C NMR(75.57 MHz, δ, CDCl3): 29.18, 29.99, 33.09, 34.11 (all COD);
37.62 (N-CH3); 50.81, 51.90, 54.48 (all COD); 68.64 (N-CH2-); 77.52
(PhCH2O-); 84.64 (COD); 85.19(O-CH2-PhCH2); 120.90, 122.64
(imidazole C4 and C5); 122.64, 127.65, 128.49, 129.05, 129.32, 129.52,
129.81, 129.95, 133.53, 134.68, 135.55, 136.26 (all aryl); 181.26 (carbene
1
C). H NMR (300.53 MHz, δ, CDCl3): 1.27-1.67 (m, br, 4H, COD);
2.14-2.16 (m, br, 4H, COD); 2.75 (m, 1H, COD); 2.97 (m, 1H, COD);
3.99 (s, 3H, N-CH3); 4.04 (dd, 1H, PhOCHPhCH2); 4.30 (s, br, 2H,
NCH2CH-); 4.60 (m, br, 2H, PhCH2O); 4.85 (m, 1H, COD); 5.41 (m,
1H, COD); 6.76 (d, 1H, imidazole H); 6.99 (d, 1H, imidazole H); 7.10-
7.18 (m, 2H, aryl); 7.23-7.34 (m, 3H, aryl); 7.44 (m, 1H, aryl); 7.54
(m, 1H, aryl). All reported data for major (chloro) derivative.
10.1021/ic9806277 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/24/1998

Communications
Inorganic Chemistry, Vol. 37, No. 21, 1998 5413
brown-orange suspension was filtered through 1 cm of silica,
yielding a bright orange solution. Subsequent vapor diffusion
of hexane into the solution produced yellow microcrystals of 4.
The 13C NMR spectrum21 of 4 exhibits a singlet at δ 181.26,
confirming the incorporation of a carbene ligand. The spectrum
also exhibits the expected resonances for the remaining compo-
nents of the miconazolidene ligand. Between 127 and 135 ppm
are peaks for the dichlorophenyl carbons, while singlets for the
imidazolidene C4 and C5 atoms appear at 120.98 and 122.51 ppm.
A total of eight COD-carbon resonances between 29.21 and 84.70
ppm are observed, consistent with the asymmetric nature of the
complex imposed by the racemic carbene ligand. Peaks at 85.16,
78.37 and 68.64 ppm arise from the miconazolidene benzyl ether
and N-CH2 units. The resonance for the terminal N-CH3 carbon
is observed at 37.61 ppm. The FAB-MS and elemental analysis
data of 4 are consistent with the proposed formulation.22
The preparation of compounds 3 and 4 demonstrates the
feasibility of assembling stable drug-metal complex conjugates
by means of linking the two species via M-Ccarbene interactions.
Other studies currently underway in our laboratory have given
encouraging results for the utilization of a variety of natural
products as carbene precursors. We expect to report on the results
of these experiments in due course.
Acknowledgment. J.H.D. thanks the University of South
Alabama Research Council for support of this work. We also
thank Dr. N. Dale Ledford for the acquisition of the NMR data.
Figure 1.
Supporting Information Available: Tables of crystal data, thermal
parameters, bond distances and angles, and atomic coordinates for
complex 3 (7 pages). Ordering information is given on any current
masthead page.
resonance in the 13C spectrum at 181.26 ppm, characteristic of
an iridium-bound carbene carbon.14
X-ray quality crystals of 3 were grown by the slow diffusion
of hexane vapor into a CH2Cl2 solution of the product. The crystal
structure and the labeling of the atoms of 3 are shown (Figure
1). The 16e- iridium center adopts a distorted square planar
geometry which includes a hybrid iodo/chloro halogen site and
the econazolidene carbene. The carbene-carbon to iridium
distance of 2.017(7) Å is similar to that of other published
iridium-carbene complexes.14 The crystal structure exists as
discrete molecules of 3 with no anomalous intermolecular
contacts.15
IC9806277
(16) Siemens SHELXTL-PC Manual, release 4.1; Siemens Analytical Instru-
ments: Madison, WI, 1990.
(17) International Tables for Crystallography; Kluwer Academic Publish-
ers: Dordrecht, The Netherlands, 1995; Vol. C, pp 713-791.
(18) The crystal was discovered to be a mixture of both the iodo and chloro
derivatives. The static disorder problem was initially identified by the
anomalous iridium-halogen bond length. The distance Ir-X was
determined to be 2.512(2) Å, which is intermediate between the distances
expected for Ir-Cl and Ir-I bonds (2.390 and 2.729 Å, respectively).19
This anomaly led to further examination of the difference Fourier map.
The peak height associated with the halogen site had a height equivalent
of 34.42% of that associated with the Ir center. This corresponds to
approximately 26.5 e-, which again is clearly between chloride and
iodide. This clearly demonstrates that the overall crystal structure must
be the result of a statistical averaging of both chloro and iodo derivatives
(bromide being excluded by other experimental data). The percent
composition of the crystal was estimated to be 26.4% iodo and 73.6%
chloro.20 The disordered chlorine and iodine atoms are in too close a
proximity to be effectively resolved by the X-ray study. The resulting
Ir-X bond distance is a statistical average of these two different Ir-
halogen distances. During refinement, a hybrid iodo/chloro atom was
inserted into the halogen site with occupancy k ) 0.264 for I and 0.736
for Cl.
The related miconazolidene-Ir complex 4 was prepared
utilizing finely divided sodium acetate as a base. The base,
N-methylmiconazolium iodide (2), and [η4-(1,5-COD)IrCl]2 were
combined in THF and refluxed for 3 h. After cooling, the dark
(14) Kocher, C.; Herrmann, W. A. J. Organomet. Chem. 1997, 532, 261 and
references therein.
(15) X-ray data collection, structure determination, and refinement for 3: A
single crystal of 3 (dimensions 0.25 × 0.20 × 0.20 mm) was sealed
into a thin-walled glass capillary under aerobic conditions. It was then
mounted and aligned upon an Enraf-Nonius CAD4 single-crystal X-ray
diffractometer (Mo KR radiation, λ ) 0.710 73 Å). Details of the data
collection are collected in the Supporting Information. Unit cell
parameters demonstrate that the crystal belongs to the triclinic system.
Intensity statistics clearly favored the centrosymmetric space group P1h
(No. 2) over the noncentrosymmetric space group P1 (No. 1). This was
later verified by successful solution and refinement of the crystal
structure. All crystallographic calculations were carried out with the use
of the Siemens SHELXTL-PC program package.16 The potential and
anisotropic thermal parameters of all non-hydrogen atoms were refined
(except for the disordered halogen, which was refined isotropically).
Hydrogen atoms were included in their idealized staggered geometries
with d(C-H) set at 0.96 Å.17 The treated model was refined until
(19) Churchill, M. R. Inorg. Chem. 1973, 12, 1213.
(20) Determined by the algebraic expression 53X + 17(1 - X) ) 26.5 (iodine
) 53 e-; chlorine ) 17 e-; unknown peak ) 26.5 e-).
(21) 13C NMR (75.57 MHz, δ, CDCl3): 29.21, 29.96, 33.14, 34.06 (all COD);
37.61 (N-CH3); 50.87, 51.89, 54.46 (all COD); 71.22 (N-CH2-); 84.69
(COD); 85.16 (O-CH2-PhCH2); 120.30, 122.51 (imidazole C4/C5);
127.06, 127.64, 129.00, 129.11, 129.77, 130.70, 134.03, 134.12, 134.74,
135.29 (all aryl); 181.26 (carbene C). 1H NMR (300.53 MHz, δ,
CDCl3): 1.50-1.80 (m, br, 4H, COD); 2.04-2.23 (m, br, 4H, COD);
2.75 (m, 1H, COD); 2.96 (m, 1H, COD); 3.97 (s, 3H, N-CH3); 4.11
(dd, 1H, PhOCHPhCH2); 4.43 (dd, 2H, NCH2CH-); 4.60 (m, br, 2H,
PhCH2O); 4.86 (dd, 1H, COD); 5.44 (dd, 1H, COD); 6.75 (d, 1H,
imidazole H); 6.99 (d, 1H, imidazole H); 7.13-7.28 (m, 4H, aryl); 7.44
(m, 1H, aryl); 7.52 (d, 1H, aryl).
convergence, with the final residual indices being R ) 3.87% and Rw
)
5.23% for all 3519 independent reflections and R ) 3.25% for those
3089 data with |F| > 6σ(|Fo|). After refinement, the anomalous features
present on the difference Fourier map were a peak of 2.11 e Å-3 and a
hole of -1.32 e Å-3, both of which were associated with the substitutional
disorder at the halogen site.18
(22) C, H, N analytical data calcd for 4, C27H28N2Cl4IIrO: C, 37.82; H, 3.29;
N, 3.27. Found: C, 37.75; H, 3.23; N, 3.10.