Selective syntheses of partially etherified derivatives of tetrakis(2-hydroxyphenyl)ethene. An alternative to the calix[4]arene ligand system

Article abstract of DOI:10.1021/ol0491639

Stereoselective syntheses of (E)- and (Z)-1,2-bis(2′-hydroxyphenyl)- bis(2′-methoxyphenyl)ethene have been developed, the former by convergent coupling of an orthogonally protected 2,2′-benzophenone derivative and the latter by selective partial dealkylat

Full text of DOI:10.1021/ol0491639

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2653-2656
Selective Syntheses of Partially
Etherified Derivatives of
Tetrakis(2-hydroxyphenyl)ethene. An
Alternative to the Calix[4]arene Ligand
System
Megumi Fujita, Guizhong Qi, Udo H. Verkerk, Trevor L. Dzwiniel,
Robert McDonald,† and Jeffrey M. Stryker*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
jeff.stryker@ualberta.ca
Received May 7, 2004
ABSTRACT
Stereoselective syntheses of (E)- and (Z)-1,2-bis(2′-hydroxyphenyl)-bis(2′-methoxyphenyl)ethene have been developed, the former by convergent
coupling of an orthogonally protected 2,2′-benzophenone derivative and the latter by selective partial dealkylation of tetrakis(2-methoxyphenyl)-
ethene. Selective single demethylation has also been demonstrated in the 5-tert-butyl series. Thus, divalent and monovalent derivatives of the
preorganized tetrakis(2-hydroxyphenyl)ethene ligand system are now available for use in coordination chemistry, analogous to corresponding
calix[4]arene systems.
We recently introduced a new structurally constrained multi-
dentate ligand system based on tetrakis(2-hydroxyphenyl)-
ethene 1,1 a topologically distinct alternative to the ubiquitous
calix[4]arene structural class.2
been targeted. Among the most useful modifications ac-
complished in the calix[4]arene series is the selective partial
etherification of the phenoxy residues, providing a malleable
ligand system accommodating a range of metallic binding
and valencies.3
In an effort to enhance the potential utility of this new
ligand template in coordination chemistry and catalysis, the
development of functionally differentiated derivatives has
In this communication, we report stereoselective syntheses
of the (E)- and (Z)-1,2-disubstituted bis(ether) derivatives I
t
(R ) H, Bu), as well as selective generation of the tris-
† Department of Chemistry X-ray Crystallography Laboratory.
(1) Verkerk, U.; Fujita, M.; Dzwiniel, T. L.; McDonald, R.; Stryker, J.
M. J. Am. Chem. Soc. 2002, 124, 9988-9989.
(2) (a) Calixarenes 2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens,
J., Eds.; Kluwer Academic: Dordrecht, 2001. (b) Gutsche, C. D. Calix-
arenes; Royal Society of Chemistry: Cambridge, 1989.
t
(ether) derivative II (R ) Bu). The (E)-bis(ether) isomer
(3) Review: Thondorf, I.; Shivanyuk, A.; Bo¨hmer, V. In Calixarenes
2001; Asfari, Z., Bo¨hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer
Academic: Dordrecht, 2001; Chapter 2, pp 26-53.
10.1021/ol0491639 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004

I-E is accessible in reasonable selectivity by convergent
synthesis; both (Z)-diether I-Z and tris(ether) II can be
prepared from symmetrically tetrasubstituted precursors
directly by selective dealkylation reactions4 starting with the
readily accessible tetrakis(2-methoxyphenyl)ethene and tet-
rakis(5-tert-butyl-2-methoxyphenyl)ethene.1
amount of p-toluenesulfonic acid, providing an isomeric
mixture of (E)- and (Z)-1,2-bis(2′-benzyloxyphenyl)-bis(2′-
methoxyphenyl)ethenes 5E and 5Z in high yield. At this
stage, the isomers are inseparable by column chromatography
on silica gel and indistinguishable both by thin-layer chro-
matography and NMR spectroscopy.
The synthesis of isomer 2E begins with 2-methoxy-2′-
hydroxybenzophenone 3,5 prepared by the highly selective
partial deprotection of 2,2′-dimethoxybenzophenone follow-
ing a known procedure. Benzylation under standard condi-
tions affords the differentially protected benzophenone 4 in
near quantitative yield (Scheme 1).6 Conversion to the tetra-
The oxidation of the hydrazone requires monitoring by
thin-layer chromatography to minimize over-oxidation. Pro-
longed exposure to nickel peroxide leads to increasing
formation of a byproduct, tentatively identified as the known
diarylbenzofuran 69 on the basis of NMR spectroscopy and
high-resolution mass spectrometry.6 This compound is
presumed to arise from oxidation at the benzylic position,
generating a transient benzyloxy carbocation, which ulti-
mately undergoes intramolecular trapping by the diazoalkane
prior to extrusion of dinitrogen (eq 1).10
Scheme 1
Catalytic hydrogenolysis of 5E/Z proceeds in polar
medium at moderate pressure, producing a mixture of (E)-
and (Z)-1,2-diols 2E and 2Z, respectively, in good yield
(Scheme 1). The ratio of stereoisomers varies from 3 to 7:1,
depending on the precise reaction conditions, but always
favors the formation of the (E)-isomer, presumably due to
steric considerations. At this stage, separation of the olefin
isomers can be accomplished either by selective crystalliza-
tion or careful chromatography, the former abetted by the
distinctly different crystal morphologies of the two isomers.
This reproducibly delivers the pure (E)-isomer in isolated
yields of about 40%, along with lesser amounts of the pure
(Z)-isomer and mixed fractions.
Stereochemical assignment of the (E)- and (Z)-isomers of
compound 2 was unambiguously established by X-ray
crystallography of the more polar (Z)-isomer, which selec-
tively crystallizes upon slow diffusion of hexanes into ethyl
acetate (Figure 1).6,11
In an attempt to generate exclusively the (E)-isomer of 2,
tetrakis(2-hydroxyphenyl)ethene 1 was subjected to DDQ
oxidation, with the expectation of “protecting” two trans-
disposed arene rings as extended quinone 7 (Scheme 2). In
the event, however, the oxidation proceeds exclusively to
kis(2-alkoxyphenyl)ethene 5 then proceeds by acid-catalyzed
coupling of the corresponding diazo derivative under condi-
tions analogous to those developed by Verkerk for the
synthesis of tetrakis(2-methoxyphenyl)ethene.1,7 Thus, hy-
drazone formation, quantitative under standard conditions,
was followed by oxidation with nickel peroxide8 and in situ
decomposition of the diazo intermediate using a catalytic
(4) In the calix[4]arene series, 1,2-bis(ether) derivatives (corresponding
roughly to (Z)-isomer I-Z) and tris(ether) derivatives can be prepared by
selective dealkylation of symmetrical tetrakis(ether) substrates. 1,2-Diether
derivatives: (a) Arduini, A.; Casnati, A.; Dodi, L.; Pochini, A.; Ungaro, R.
J. Chem. Soc., Chem. Commun. 1990, 968-970. (b) Casnati, A.; Arduini,
A.; Ghidini, E.; Pochini, A.; Ungaro, R. Tetrahedron 1991, 47, 2221-
2228. Tris(ether) derivatives: (c) Iwamoto, K.; Shinkai, I. J. Org. Chem.
1992, 57, 7066-7073. (d) Ho, Z.-C.; Ku, M.-C.; Shu, C.-M.; Lin, L.-G.
Tetrahedron 1996, 52, 13189-13200. The 1,3-dialkylated calix[4]arenes
(corresponding to (E)-isomer I-E), as well as 1,2-diethers, are accessible
by selective alkylation of the symmetrical parent. 1,3-Substitution: (e) van
Loon, J. D.; Arduini, A.; Coppi, L.; Verboom, W.; Pochini, A.; Ungaro,
R.; Harkema, S.; Reinhoudt, D. N. J. Org. Chem. 1990, 55, 5639-5646.
1,2-Substitution: (f) Bottino, F.; Giunta, L.; Pappalardo, S. J. Org. Chem.
1989, 54, 5407-5409. (g) Groenen, L. C.; Ruel, B. H. M.; Casnati, A.;
Timmerman, P.; Verboom, W.; Harkema, S.; Pochini, A.; Ungaro, R.;
Reinhoudt, D. N. Tetrahedron Lett. 1991, 32, 2675-2678. (h) Ferguson,
G.; Gallagher, J. F.; Giunta, L.; Neri, P.; Pappalardo, S.; Parisi, M. J. Org.
Chem. 1994, 59, 42-53.
(5) Dean, F. M.; Goodchild, J.; Houghton, L. E.; Martin, J. A.; Morton,
R. B.; Parton, B.; Price, A. W.; Somvichien, N. Tetrahedron Lett. 1966, 7,
4153-4159.
(6) Experimental procedures and complete characterization data are
provided as Supporting Information.
(7) This olefination procedure is adapted from the literature: Roberts,
J. D.; Watanabe, W. J. Am. Chem. Soc. 1950, 72, 4869-4879. Bethell, D.;
Callister, J. D. J. Chem. Soc. 1963, 3801-3808.
(8) Nakagawa, K.; Onoue, H.; Minami, K. J. Chem. Soc., Chem.
Commun. 1966, 730-731.
(9) Sonoda, T.; Kobayashi, S.; Taniguchi, H. Bull. Chem. Soc. Jpn. 1976,
49, 2560-2566.
(10) Nickel peroxide reagent contains residual alkali; the observed over-
oxidation product may arise by a less direct mechanism than suggested by
eq 1.
(11) Crystal data for 2Z: C28H24O4, crystal size 0.25 × 0.12 × 0.04
mm3, monoclinic, space group P21/c (No. 14), Mo KR (λ ) 0.71073 Å), a
) 10.9757(13) Å, b ) 15.4466(18) Å, c ) 13.6421(13) Å, â )
99.547(2)°, V ) 2280.8(4) Å3, Z ) 4, µ ) 0.082 mm-1, Fcalcd ) 1.236 g
cm-3, F000 ) 896, T ) -80 °C, 2θmax ) 51.60°, 12 189 total reflections,
4356 unique reflections (Rint ) 0.1625), least-squares refinement on F2,
2
R1(F) ) 0.0659 (for 1167 reflections with Fo2 g 2σ(Fo )), wR2(F2) ) 0.1837,
GOF(F2) ) 0.771 (for all unique data).
Org. Lett., Vol. 6, No. 16, 2004
2654

isomeric 2E and 2Z, along with other, as yet unidentified
products.15
Selective synthesis of (Z)-1,2-bis(2′-hydroxyphenyl)-bis-
(2′-methoxyphenyl)ethene 2Z was more straightforward,
proceeding directly by partial dealkylation of a symmetric
precursor. Thus, treatment of tetrakis(2-methoxyphenyl)-
ethene1 with 1 equiv of boron tribromide at low temperature
proceeds cleanly to the doubly deprotected (Z)-isomer, a
reaction that proceeds equally selectively starting from
tetrakis(5-tert-butyl-2-methoxyphenyl)ethene1 (Scheme 3).
Scheme 3
Figure 1. ORTEP diagram of compound 2Z showing the atom
labeling scheme. Non-hydrogen atoms are represented by Gaussian
ellipsoids at the 20% probability level. Hydroxyl and methyl
hydrogen atoms are shown with arbitrarily small thermal param-
eters; all other hydrogen atoms are not shown.
Scheme 2
No more than minor quantities of other isomers are observed
in the crude reaction mixture, and purified products 2Z
and 9Z are readily obtained by flash chromatography.6 For
the tert-butyl derivative 9Z, the stereochemistry was con-
firmed by X-ray crystallography on the corresponding mono-
sodium salt, prepared by treatment of 9Z with 1 equiv of
NaH (Figure 2).16
give the interesting cis-fused dihydrobenzofuro[2,3]-benzo-
furan 8;12 confirmation of the structure and stereochemistry
was obtained by X-ray crystallography.6,13
The formation of this product is readily rationalized by
assuming that conversion to the expected quinone 7 is fol-
lowed by intramolecular conjugate addition of each phenolic
oxygen onto the opposite ortho-quinomethide “enone” frag-
ment.14
Methylation of the phenolic residues of 8 proceeds cleanly
under standard conditions, but unfortunately, alkali metal-
induced reductive fragmentation12a was nonselective under
all conditions investigated, producing complex mixtures of
(12) A few structurally related diaryl-substituted dihydrobenzofuro[2,3]-
benzofurans have been reported, invariably formed as one product in a
complex reaction mixture: (a) Rigaudy, J.; Scribe, P.; Breliere, C.
Tetrahedron 1981, 37, 2593-2597. (b) Wong, R. Y.; Jurd, L. Aust. J. Chem.
1984, 37, 2585-2593.
(13) See Supporting Information for ORTEP diagrams and complete
crystal data.
(14) Similar quinone-derived cyclizations are observed upon oxidation
of various calix[4]arene compounds: Litwak, A. M.; Biali, S. E. J. Org.
Chem. 1992, 57, 1943-1945. Litwak, A. M.; Grynszpan, F.; Aleksiuk, O.;
Cohen, S.; Biali, S. E. J. Org. Chem. 1993, 58, 393-402. Grynszpan, F.;
Biali, S. E. J. Chem. Soc., Chem. Commun. 1994, 2545-2546.
Figure 2. View of compound Na-9Z approximately along the C1-
C2 bond. Non-hydrogen atoms are represented by Gaussian
ellipsoids at the 20% probability level.
Org. Lett., Vol. 6, No. 16, 2004
2655

Finally, preliminary investigation has provided a direct
synthesis of the tris(ether) derivative, (5-tert-butyl-2-hydroxy-
phenyl)-tris(5-tert-butyl-2-methoxyphenyl)ethene 10, also by
selective desymmetrization of tetrakis(5-tert-butyl-2-meth-
oxyphenyl)ethene (Scheme 3). In this case, the reagent of
choice is iodotrimethylsilane,4b,17,18 but only the first de-
methylation proceeds with sufficient selectivity to be synthetic-
ally useful. Thus, the reaction of tetrakis(5-tert-butyl-2-
methoxyphenyl)ethene with 1 equiv of TMSI proceeds to
approximately 50% conversion and yields tris(ether) deriva-
tive 10 almost exclusively. Higher absolute yields of 10 can
be obtained from the reaction with excess TMSI, but the
progress of the reaction must be monitored by TLC analysis
and terminated immediately upon complete disappearance
of starting material. Under these conditions, however, the
formation of tris(ether) 10 is accompanied by a complex
mixture of bis(ether) and mono(ether) byproducts, each
formed in relatively minor amounts. Both procedures require
chromatographic purification, but the partial conversion is
preferred at scale for operational simplicity and recovery of
the valuable starting material.19
The tetrakis(2-hydroxyphenyl)ethene template offers a
geometrically constrained multidentate binding platform
complementary to the more familiar calix[4]arene structural
class. The preparation of partially etherified tetrakis(2-hy-
droxyphenyl)ethene ligands significantly expands the poten-
tial contexts in which the coordination chemistry of this
system may be developed. Further synthetic manipulation
of the tetrakis(2-hydroxyphenyl)ethene framework remains
under investigation, including the potential for selective
partial alkylation of the phenolic residues.
Acknowledgment. Financial support from NOVA Chemi-
cals Corporation and Natural Sciences and Engineering
Research Council of Canada (CRD and CRO grant programs)
is gratefully acknowledged.
(15) Under some conditions, the major product of the reduction appears
to be the one remaining isomer, 1,1-bis(2′-hydroxyphenyl)-2,2-bis(2′-
methoxyphenyl)ethene, on the basis of spectroscopic analysis of impure
material. A byproduct missing two methoxy residues (by mass spectrometry)
was also obtained under some conditions.
(16) Colorless single crystals of the sodium salt of 9Z were obtained in
27% yield as a nonstoichiometric THF solvate.6 Crystal data for Na-9Z‚1/4
n-C6H14: C49.5H66.5NaO5, crystal size 0.33 × 0.31 × 0.29 mm3, triclinic,
space group P1h (No. 2), Mo KR (λ ) 0.71073 Å), a ) 11.2460(7) Å, b )
14.8004(9) Å, c ) 16.0461(10) Å, R ) 109.1463(12)° â ) 90.7286(12)°,
Supporting Information Available: Experimental pro-
cedures and complete characterization data for all new
compounds; details of the X-ray crystallography for com-
pounds 2Z, 8, and the monosodium salt of 9Z. This material
is available free of charge via the Internet at http://pubs.acs.org.
γ ) 109.0012(11)°, V ) 2364.1(3) Å3, Z ) 2, µ ) 0.075 mm-1, Fcalcd
)
1.074 g cm-3, F000 ) 829, T ) -80 °C, 2θmax ) 50.00°, 11 433 total
reflections, 8257 unique reflections (Rint ) 0.0235), least-squares refinement
on F2, R1(F) ) 0.0938 (for 5500 reflections with Fo2 g 2σ(Fo )), wR2(F2)
2
OL0491639
) 0.2980, GOF(F2) ) 1.029 (for all unique data).
(17) Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42, 3761-3762.
(18) Use of in situ-derived TMSI reagent was not successful.
(19) Qualitatively similar results have been obtained from reactions of
TMSI and the parent tetrakis(2-methoxyphenyl)ethene.
2656
Org. Lett., Vol. 6, No. 16, 2004