Metal-mediated generation, stabilization, and controlled release of a biologically relevant, simple para quinone methide: BHT-QM [10]

Full text of DOI:10.1021/ja9809612

J. Am. Chem. Soc. 1998, 120, 7119-7120
7119
Scheme 1
Metal-Mediated Generation, Stabilization, and
Controlled Release of a Biologically Relevant, Simple
Para Quinone Methide: BHT-QM
Oded Rabin, Arkadi Vigalok, and David Milstein*
an isomeric form of an η1-methylene-p-phenoxy zwitterionic
metal complex (Scheme 1). The benzyl bromide 110 was
synthesized by silylation of 2,6-di-tert-butyl-4-methylphenol
(BHT) with (Me3Si)2NH11 and bromination of the resulting silyl
ether by N-bromosuccinimide (NBS). Serving as a BHT-QM
precursor, 1 contains a benzyl bromide moiety as an anchoring
point to metal centers, whereas the protecting silyl ether prevents
the base-catalyzed conversion of 1 into BHT-QM.12
Electron-rich chelating bisphosphine palladium and platinum
centers can form stable olefin complexes due to substantial back-
bonding to the olefin13 and are, therefore, good candidates for
QM stabilization. Unfortunately, oxidative addition of 1 to 3-
and 4-coordinated bisphosphine palladium(0) complexes pro-
ceeded with very low yields and resulted in mixtures. Therefore,
we have utilized (tmeda)PdMe2 (tmeda ) N,N,N′,N′-tetrameth-
ylethylenediamine) which can oxidatively add benzyl bromide
with elimination of C2H6.14 Upon mixing (tmeda)PdMe2 and 1
in cold acetone, the benzyl complex 2 was formed in 79% yield.
Addition of 1,2-bis(diphenylphosphino)ethane (dppe) led to the
displacement of tmeda and the bisphosphine benzyl complex 3
was quantitatively formed.
Department of Organic Chemistry
The Weizmann Institute of Science, RehoVot, Israel 76100
ReceiVed March 23, 1998
Quinone methides (QMs, I) are highly reactive transient
compounds involved in many chemical and biological processes.1
They were proposed as important intermediates in natural products
chemistry2,3 and implicated as the active forms of antitumor
drugs.4 They are highly reactive toward both nucleophiles and
electrophiles, and polymerize upon concentration of their dilute
solutions, hindering their isolation and characterization. It is also
difficult to study their behavior in biological systems due to
incompatibility with protic media. This is especially true for
simple quinone methides (I, R2dH), i.e. not bearing substituents
on the methylene group, which so far have not been isolated,
except in very special cases.5
Recently, we demonstrated that QMs can be stabilized and iso-
lated by complexation to a late transition metal center.6,7 The
crystal structure of two p-QM Rh(I) complexes have been re-
ported. However, in these complexes the QM moiety is part of
a specifically designed bis-chelating PCP-type ligand and is there-
fore very strongly coordinated to the metal and essentially inert.
We now report on (1) a novel synthetic route that leads to the
first stable simple p-QM complex, in which the QM is coordinated
to the metal center only via the exocyclic double bond; (2) the
crystal structure of this complex; and (3) the controlled release
of the coordinated QM into solution. We demonstrate our
approach by the stabilization of the biologically relevant 2,6-di-
Interestingly, when 3 was treated with 1 equiv of (n-Bu)4NF‚
3H2O in THF, (dppe)Pd(BHT-QM) 4 was obtained in 91% yield.
As shown in Scheme 2, the unobserved ammonium phenoxy
intermediate formed by the Si-O bond cleavage spontaneously
eliminated (n-Bu)4NBr to give 4.
The BHT-QM complex 4 was fully characterized by IR and
multinuclear NMR spectroscopy, elemental analysis and X-ray
crystallography. The 31P NMR spectrum of 4 in C6D6 consists
of two sharp doublets at 29.07 and 37.49 ppm (JPP ) 14.2 Hz),
indicative of two inequivalent phosphorus nuclei in a mutual cis
configuration. The upfield 13C chemical shift of the two exocyclic
double-bond carbons and their J-coupling to the two inequivalent
phosphorus atoms, δ(CH2) ) 51.34 ppm (d, JPC ) 30.7 Hz) and
δ(CR2) ) 82.28 ppm (dd, JPC ) 12.5 and 4.8 Hz), as well as the
doublet of doublets originating from the benzylic protons in the
1H NMR spectrum at δH ) 3.40 ppm (JPH ) 7.1 and 3.8 Hz),
strongly suggest that coordination takes place through the
exocyclic R2CdCH2 group. The carbonyl carbon gives rise to a
signal in the 13C NMR spectrum at 183.96 ppm (br d, JPC ) 3.7
Hz), in the region observed for other 2,5-cyclohexadienones and
quinones.15 The carbonyl moiety exhibits a characteristic, strong
tert-butyl-4-methylene-2,5-cyclohexadienone (BHT-QM),1c,8
a
metabolite of the antioxidant 2,6-di-tert-butyl-4-methylphenol
(BHT), and the toxicology of which has been extensively studied.9
The synthetic strategy presented here is based on the fact that
an η2-methylene-coordinated p-QM complex can be viewed as
(1) For reviews, see: (a) Turner, A. B. Quart. ReV. 1964, 18, 347. (b)
Wagner, H.-U.; Gompper, R. In The Chemistry of Quinonoid Compounds;
Patai, S., Ed.; Wiley & Sons: New York, 1974; Vol. 1, p 1145. (c) Volod’kin,
A. A.; Ershov, V. V. Russ. Chem. ReV. 1988, 57, 336. (d) Peter, M. G. Angew.
Chem., Int. Ed. Engl. 1989, 28, 555. (e) Wan, P.; Barker, B.; Diao, L.; Fischer,
M.; Shi, Y.; Yang, C. Can. J. Chem. 1996, 74, 465. See also: (f) Diao, L.;
Yang, C.; Wan, P. J. Am. Chem. Soc. 1995, 117, 5369 and references therein.
(2) See, for example: (a) Angle, S. R.; Louie, M. S. Tetrahedron Lett.
1993, 34, 4751. (b) Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J.
C. J. Am. Chem. Soc. 1971, 93, 6696. (c) Marino, J. P.; Dax, S. L. J. Org.
Chem. 1984, 49, 3671.
(3) (a) Shevchenko, S. M.; Apushkinskii, A. G. Russ. Chem. ReV. 1992,
61, 105. (b) Prota, G. Progress in the Chemistry of Organic Natural Products;
Springler-Verlag: Wien, New York, 1995; Vol. 64, p 93.
(4) (a) Moore, H. W.; Czerniak, R. Med. Res. ReV. 1981, 1, 249. (b) Moore,
H. W.; Czerniak, R.; Hadman A. Drugs Exp. Clin. Res. 1986, 12, 475. (c)
Gunatilaka, A. A. L. Progress in the Chemistry of Organic Natural Products;
Springler-Verlag: Wein, New York, 1996; Vol. 67, p 1.
IR absorption band at 1598 cm-1 1c
.
(9) For a review, see: (a) Thompson, D. C.; Thompson, J. A.; Sugumaran,
M.; Moldeus, P. Chem.-Biol. Interact. 1993, 86, 129. See also: (b) Gram, T.
E. Pharm. ReV. 1997, 49, 297. (c) Bolton, J. L.; Turnipseed, S. B.; Thompson,
J. A. Chem.-Biol. Interact. 1997, 107, 185. (d) Reed, M.; Thompson, D. C.
Chem. Res. Toxicol. 1997, 10, 1109. (e) Guyton, K. Z.; Bhan, P.; Kuppusamy,
P.; Zweier, J. L.; Trush, M. A.; Kensler, T. W. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 946. (f) Thompson, D. C.; Cha, Y.-N.; Trush, M. A. J. Biol. Chem.
1989, 264, 3957. (g) Yamamoto, K.; Kato, S.; Tajima, K.; Mizutani, T. Biol.
Pharm. Bull. 1997, 20, 571.
(10) For the synthesis and characterization of this and other reported
compounds, see the Supporting Information.
(11) Friedman, S.; Kaufman, M. L.; Wender, I. J. Org. Chem. 1962, 27,
664.
(5) Two examples of isolable simple QMs, both containing fused aromatic
rings (with neglible quinonoid character) have been reported: (a) Starnes,
W. H., Jr. J. Org. Chem. 1970, 35, 1974. (b) Boger, D. L.; Nishi, T.; Teegarden,
B. R. J. Org. Chem. 1994, 59, 4943.
(6) (a) Vigalok, A.; Milstein, D. J. Am. Chem. Soc. 1997, 119, 7873. (b)
Vigalok, A.; Shimon, L. J. W.; Milstein, D. J. Am. Chem. Soc. 1998, 120,
477.
(7) (a) Complexation of a metal center to the endocyclic double bond of
nonsimple o-QM has recently been reported: Kopach, M. E.; Harman, W. D.
J. Am. Chem. Soc. 1994, 116, 6581. (b) An unobserved o-QM rhodium
complex has been proposed as intermediate in a carbonylation reaction:
Heldeweg, R. F.; Hogeveen, H. J. Am. Chem. Soc. 1976, 98, 6040.
(8) (a) Filar, L. J.; Winstein, S. Tetrahedron Lett. 1960, 25, 9. (b) Dyall,
L. K.; Winstein, S. J. Am. Chem. Soc. 1972, 94, 2196. (c) Omura, K. J. Org.
Chem. 1984, 49, 3046.
(12) A similar quinone methide precursor has been used by: (a) Li, T.;
Zeng, Q.; Rokita, S. E. Bioconjugate Chem. 1994, 5, 497. (b) Rokita, S. E.;
Yang, J.; Pande, P.; Greenberg, W. A. J. Am. Chem. Soc. 1997, 62, 33010.
(13) (a) Ittel, S. D.; Ibers, J. A. AdV. Organomet. Chem. 1976, 14, 33. (b)
Nelson, J. H.; Jonassen, H. B. Coord. Chem. ReV. 1971, 6, 27.
(14) (a) de Graaf, W.; Boersma, J.; Smeets, W. J. J.; Spek, A. L.; van
Koten, G. Organometallics 1989, 8, 2907. (b) de Graaf, W.; Boersma, J.; van
Koten, G. Organometallics 1990, 9, 1479.
S0002-7863(98)00961-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/03/1998

7120 J. Am. Chem. Soc., Vol. 120, No. 28, 1998
Communications to the Editor
Scheme 2
as a result of back-donation from the metal. This is also
manifested in the loss of planarity around C(2): the exocyclic
methylene is bent out of the ring plane by 10.78° away from the
palladium atom. Similar structural features were also observed
in other P2Pd conjugated-olefin complexes.18
Complex 4 is a thermally stable compound both in solution
and in the solid state. No traces of decomposition were observed
upon storage of a dry sample of 4 for a month under a dinitrogen
atmosphere. Remarkably, 4 is stable even toward nucleophilic
attack by water or MeOH and is recovered unchanged after
heating in aqueous methanol at 55 °C for 10 h. As free BHT-
QM is known to react immediately under these conditions,8a no
spontaneous dissociation of the QM moiety from the P2Pd
fragment takes place.
The reactivity of 4 was tested with respect to ligand exchange
reactions. Addition of the hard ligands acetonitrile or pyridine
did not result in the release of the BHT-QM. However, when 4
was reacted with 1 equiv of DBA (dibenzylideneacetone) in a
C6D6 solution at room temperature instantaneous dissociation of
free BHT-QM took place, as was detected by 1H NMR spectros-
copy,19 with concomitant formation of the known complex (dppe)-
Pd(DBA).18c Similarly, substitution of BHT-QM was achieved
by the use of diphenylacetylene, although at a slower rate. When
the substitution reactions were performed in methanol, immediate
trapping of the free quinone methide by a solvent molecule took
place at room temperature to give the 1,6-Michael-type addition
product, 2,6-di-tert-butyl-4-methoxymethylphenol (5), as was
Scheme 3
1
detected by H NMR spectroscopy and by GC-MS.20 When
CD3OD was used as solvent, incorporation of the CD3O group
into the organic product took place. Thus, complex 4 allows
controlled release of free BHT-QM into a solution where it can
be effectively trapped by nucleophiles. This together with the
high thermal stability of 4 and its compatibility with protic media
can make it relevant to selective drug delivery.
In summary, for the first time a simple quinone methide was
generated, stabilized, and released with the aid of a metal center.
The complex formed was fully characterized (including X-ray
structure analysis). It was stable even in protic solvents. A simple
chemical stimulus promoted the controlled release of the quinone
methide which could be trapped by reaction with nucleophiles.
Studies involving other biologically relevant QMs using this
approach are currently underway.
Figure 1. An ORTEP representation of the crystal structure of 4 with
the thermal ellipsoids at 50% probability. Selected bond distances (Å)
and angles (deg): Pd(1)-C(1), 2.088(2); Pd(1)-C(2), 2.208(2); C(1)-
C(2), 1.437(2); C(5)-O(5), 1.251(2); C(2)-C(3), 1.443(3); C(3)-C(4)
1.362(2); C(4)-C(5) 1.474(3); C(5)-C(6) 1.474(3); C(6)-C(7)
1.364(3); C(2)-C(7) 1.441(2); P(2)-Pd(1)-P(3) 86.73(2); Pd(1)-C(1)-
C(2) 75.06(10); Pd(1)-C(2)-C(1) 65.97(10).
Acknowledgment. We thank Dr. L. J. W. Shimon for performing
the X-ray structural analysis. This work was supported by the US-Israel
Binational Science Foundation, Jerusalem, Israel, and by the MINERVA
Foundation, Mu¨nich, Germany. D.M. is the holder of the Israel Matz
professorial chair of organic chemistry.
Supporting Information Available: Text describing the synthesis
and characterization of compounds 1-4 and tables of crystal data and
structure refinement, atomic coordinates, bond lengths and angles,
anisotropic displacement parameters, and hydrogen atom coordinates for
4 (11 pages, print/PDF). See any current masthead page for ordering
information and Web access instructions.
Orange crystals of 4 suitable for a single-crystal X-ray
diffraction study were obtained by slow diffusion of pentane into
a solution of 4 in Et2O.16 The palladium atom lies in a trigonal
planar environment, coordinated to the two phosphorus atoms and
the exocyclic double bond (Figure 1).13a A practically negligible
torsion angle of 2.78° is observed between the P(2)-Pd(1)-P(3)
plane and the Pd(1)-C(1)-C(2) plane. There is no interaction
between the metal and the QM ring, with the Pd(1)-C(7) distance
being 2.923(3) Å. The quinonoid character of the ligand is
strongly reflected in the ring bond distances with the C(3)-C(4)
and C(6)-C(7) bond lengths being shorter than the rest of the
C-C bonds of the ring by at least 0.077 Å. The carbonyl C(5)-
O(5) distance of 1.251(2) Å is in the range reported for other
quinonoid compounds.17 The coordinated C(1)-C(2) bond is
notably elongated (1.437(2) Å) compared to that of free olefins,
JA9809612
(17) For example, the crystal structure of 2,6-dimethylbenzoquinone as
reported by: Rabinovich, D.; Schmidt, M. J. J. Chem. Soc. B 1967, 127.
(18) (a) For example, in the structurally related (PMe3)2Pd(η2-CH2d
C5Me4), the exocyclic double bond distance of the coordinated fulvene
molecule is 1.424(2) Å and makes a 10.81° angle with the fulvene ring:
Werner, H.; Crisp, G. T.; Jolly, P. W.; Kraus, H.-J.; Kruger, C. Organometallics
1983, 2, 1369. (b) Benn, R.; Betz, P.; Goddard, R.; Jolly, P. W.; Kokel, N.;
Kruger, C.; Topalovic, I. Z. Naturforsch. 1991, 46B, 1395. (c) Herrmann, W.
A.; Thiel, W. R.; Brossmer, C.; O¨ fele, K.; Priermeier, T. J. Organomet. Chem.
1993, 461, 51. (d) Kranenburg, M.; Delis, J. G. P.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Vrieze, K.; Veldman, N.; Spek, A. L.; Goubitz, K.;
Fraanje, J. J. Chem. Soc., Dalton Trans. 1997, 1839.
(15) Pouchert, C. J.; Behnke, J. The Aldrich Library of 13C and 1H FT
NMR Spectra; Aldrich Chemical Co., Inc.: Milwaukee, WI, 1993; Vol. 1.
(16) Crystal structure data for 4: C41H46OP2Pd, orange prisms, monoclinic,
P2(1)/n, a ) 9.553(2) Å, b ) 28.122(6) Å, c ) 13.774(3) Å, â ) 107.52(3)°,
Z ) 4, R1(I > 2σI) ) 0.0290.
(19) BHT-QM, 1H NMR (C6D6, ppm): δ ) 1.37 (18H, t-Bu), 5.20 (2H,
exo-CH2), 6.77 (2H, CH). See also ref 8b.
(20) (a) Macomber, R. S. J. Org. Chem. 1982, 47, 2481. (b) Satish, S.;
Ganeshpure, P. A. Proc. Ind. Acad. Sci., Chem. Sci. 1986, 96, 59.