Diaryl ethers using fischer chromium carbene mediated benzannulation

Article abstract of DOI:10.1021/ol990949u

(formula presented) The biological relevance and irresistible synthetic challenge of compounds containing the diaryl ether linkage encourages the development of new methodologies targeted toward this structural subunit. The syntheses of diaryl ethers 2 us

Full text of DOI:10.1021/ol990949u

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1721-1723
Diaryl Ethers Using Fischer Chromium
Carbene Mediated Benzannulation
Shon R. Pulley,* Subhabrata Sen, Andrei Vorogushin, and Erika Swanson
Department of Chemistry, UniVersity of MissourisColumbia,
Columbia, Missouri 65211-7600
pulleys@missouri.edu
Received August 15, 1999
ABSTRACT
The biological relevance and irresistible synthetic challenge of compounds containing the diaryl ether linkage encourages the development
of new methodologies targeted toward this structural subunit. The syntheses of diaryl ethers 2 using a benzannulation strategy that formally
involves a [3 + 2 + 1] cycloaddition between aryloxy-substituted Fischer carbenes 1 and alkynes are described. This methodology provides
a neutral near ambient temperature formation of diaryl ethers.
The diaryl ether moiety is crucial to a number of molecules
with pronounced biological activity.1 These range from K-13
a noncompetitive inhibitor of angiotensin I converting
enzyme (ACE)2 to the structurally more complex glycopep-
tide antibiotics such as vancomycin. Vancomycin is clinically
used in the fight against methicillin-resistant Staphylococcus
aureus and other gram-positive bacteria.3 Oligomeric ella-
gitannins, important constituents in plant chemical defense
systems, herbal medicines, leather tanning, and the food and
beverage industry, result from an oxidative carbon-oxygen
coupling to form a dehydrodigalloyl diaryl ether between
monomeric ellagitannins. The dimeric ellagitannin sanguiin
H-6 demonstrates an in vitro potency 100-250 times the
clinically useful DNA topoisomerase II inhibitor etoposide
(VP-16).4 On another front, the diaryl ether thyroxine is an
effective small molecule inhibitor of amyloid fibril formation
in the amyloidogenic transthyretin (TTR) protein. Amyloid
fibril formation of TTR and other normally soluble amy-
loidogenic proteins is thought to be the causative agent in
human amyloid diseases.5
When considering syntheses of these compounds or
structural variants for structure-activity relationship studies
(SAR), the formation of the diaryl ether moiety plays a key
role in the synthetic design. Current procedures for the
formation of the diaryl ether subunit involve the following:6
(1) Ullmann coupling strategies;7 (2) thallium(III) trinitrate
(TTN) oxidative phenolic coupling; (3) aromatic nucleophilic
substitution (SNAr); and (4) displacement of bromine from
bromobenzoquinones with phenols to yield O-aryl benzo-
quinones. Given the interest in the synthesis of diaryl ethers
and various disadvantages of the above-mentioned technolo-
gies, there is a great deal of activity in the development of
new methods or improving existing technology. Several
alternative approaches include complexation of haloaromatics
(1) For general reviews see: (a) Itokawa, H.; Takeya, K. Heterocycles
1993, 35, 1467-1501. (b) In Glycopeptide Antibiotics; Nagarajan, R., Ed.;
Marcel Decker, Inc.: New York; 1994.
(2) Kase, H.; Kaneka, M.; Yamada, K. J. Antibiot. 1987, 40, 450-454.
(3) Williams, D. H.; Bardsley, B. Angew. Chem., Int. Ed. Engl. 1999,
38, 1172-1193.
(4) For reviews on the chemistry of ellagitannins, see: (a) Quideau, S.;
Feldman, K. S. Chem. ReV. 1996, 96, 475-503. (b) Plant Polyphenols
Synthesis, Properties, Significnace; Hemingway, R. W., Lacs, P. E., Eds.;
Plenum: New York, 1992. (c) Okuda, T.; Yoshida, T.; Hatano, T.
Phytochemistry 1993, 32, 507-521.
(5) Miroy, G. J.; Lai, Z.; Lashuel, H. A.; Peterson, S. A.; Strang, C.;
Kelly, J. W. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 15051-15056.
(6) For reviews, see: (a) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.;
Rao, A. S. Chem. ReV. 1995, 95, 2135-2167. (b) Evans, D. A.; DeVries,
K. D. In Glycopeptide Antibiotics; Nagarajan, R., Ed.; Marcel Dekker: New
York; 1994; pp 63-103.
(7) For recent work with the Ullmann reaction, see: (a) Kalinin, A. V.;
Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999, 64, 2986-
2987. (b) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976-
2977.
10.1021/ol990949u CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/28/1999

catalyzed formation of diaryl ethers is also gaining increasing
attention due to the efforts of Buchwald and Hartwig.12
Common to each of the above-mentioned strategies is the
formation of the carbon-oxygen bond between two aromatic
rings or their equivalents. Strategies that build the aromatic
ring via a cycloaddition reaction benzannulation are much
less common.13 Olsen’s Diels-Alder reaction between
acetylenes and O-arylbutadienes leads to a model for
isodityrosine14 and Feldman’s dimerization of orthoquinones
provides an efficient route to the dehydrodigalloyl diaryl
ether of the oligomeric ellagitannins.15 This method is
significant in that the steric crowding around the ether linkage
and the electron-rich nature of the two-galloyl rings severely
limits all the existing technologies for diaryl ether synthesis.
Our interest in benzannulation strategies to diaryl ethers
led us to propose an approach to diaryl ethers 8-15 (Table
1) that involves the Do¨tz benzannulation16 between aryloxy
Fischer chromium carbene complexes 5-7 (Scheme 1) and
Table 1. Diaryl Ethers from Benzannulation with Alkynes
Scheme 1. Synthesis of Aryloxy Fischer Chromium Carbene
Complexes 5-7
a Isolated purified yields and yields in parentheses are from ultrasonic
irradiation
alkynes.17 While this work was in progress Wulff described
the formation of aryloxy carbenes and their reaction with
alkynes in a study probing electronic effects in the Do¨tz
reaction.18
This approach to diaryl ethers involves a formal [3 + 2 + 1]
cycloaddition between an aryloxy -substituted Fischer chro-
mium carbene complex and an alkyne. In general, Fischer
carbene complexes are either alkoxy- or alkylamino-
substituted and until recently only two aryloxy-substituted
carbene complexes were known.19 For our work the synthesis
with ruthenium followed by displacement,8 substitution of
aryl iodonium salts by sodium phenolates,9 ring opening of
cyclohexenone oxides with phenols,10 and substitution of 2,6-
dihalo-substituted triazenes with phenols.11 The palladium-
(8) Pearson, A. J.; Bignan, G.; Zhang, P.; Chelliah, M. J. Org. Chem.
1996, 61, 3940-3941.
(9) Crimmin, M. J.; Brown, A. G. Tetrahedron Lett. 1990, 31, 2017-
2020.
(10) For this and related methods, see: Jung, M. E.; Starkey, L. S.
Tetrahedron 1997, 53, 8815-8824.
(11) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li,
H.; Bra¨se, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421-3422.
(12) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378 and
references therein. (b) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig,
J. F. J. Am. Chem. Soc. 1999, 121, 3224-3225 and references therein. (c)
Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2046-2067.
(13) For a Robinson annulation, see: Feng, X.; Edstrom, E. D.
Tetrahedron: Asymmetry 1999, 10, 99-105.
(14) Olsen, R. K.; Feng, X.; Campbell, M.; Shao, R.-L.; Math, S. K. J.
Org. Chem. 1995, 60, 6025-6031.
(15) (a) Feldman, K. S.; Sahasrabudhe, K. J. Org. Chem. 1999, 64, 209-
216. (b) Feldman, K. S.; Quideau, S.; Appel, J. M. J. Org. Chem. 1996,
61, 6656-6665.
1722
Org. Lett., Vol. 1, No. 11, 1999

of aryloxy carbenes 5-7 follows a modification of Fischer’s
original procedure.20 The optimum procedure involves ad-
dition of acetyl bromide to the ammonium ate complex 3,
resulting in the metal acyl complex 4, followed immediately
by the addition of lithium or sodium phenoxide (Scheme 1).
Complexes 5-7 are isolated as deep red oils by standard
chromatographic techniques and are stable to storage (-20
°C) under an inert atmosphere for several weeks.
alanine or lactam products depending on reaction conditions
or substituent effects. The results of these studies will appear
in due course.
In addition to the phenylalanine diaryl ethers, complex 7a
yields the protected diaryl ether glycinol derivative 20 upon
reaction with the ethynylglycine equivalent 19 derived from
Garner’s aldehyde.24
With aryloxy carbenes 5-7 in hand, subsequent thermoly-
sis with both internal and terminal acetylenes generally led
to the desired diaryl ethers 8-15 in fair to excellent yields
(Table 1). The reactions were complete in 16-36 h, at 50-
55 °C, 0.05 M with 1.2 equiv of alkyne.
The regiochemistry of 8-15 is consistent with the accepted
mechanism of the Do¨tz benzannulation that involves rate-
limiting loss of CO from the carbene complex followed by
alkyne coordination and insertion leading to a vinyl carbene
complex. Subsequent insertion of CO forms a vinyl ketene
which then undergoes electrocyclization and aromatization
to yield the diaryl ethers.21 Although these reactions are
unoptimized, high intensity ultrasound significantly improves
the yield and reduces the reaction time for the formation of
14 and 15. For example, reaction of 7b with O-benzyl
propargyl alcohol gives the diaryl ether 14 in 25% after 33
h at 55 °C while ultrasonic irradiation gives a 55% yield
after 5 h. The use of ultrasound is suggested to promote the
rate-limiting loss of CO from the initial carbene complex.22
A general and very mild method of forming diaryl ethers
is a valuable addition to the synthetic methods available for
the construction of this important subunit. The neutral near
ambient temperature formation of diaryl ethers with the Do¨tz
benzannulation offers a potentially attractive method for the
construction of diaryl ethers in synthetic endeavors toward
complex natural products with sensitive functionality. To
demonstrate this potential, treating complexes 7b-e with
propargylglycinate23 16 results in the diaryl ether phenyl-
alanine analogues 17a-d. The moderate yield of these
Again, ultrasound significantly reduces the reaction time
and results in an improved yield (59% after 2 h with
sonication versus 53% after 21 h at 55 °C).
Each of the above examples lend further support to our
hypothesis that aryloxy-substituted Fischer chromium car-
bene complexes can lead too highly functionalized diaryl
ethers. These preliminary results provide a foundation to
expand this methodology and demonstrate its usefulness in
the synthesis of diaryl ethers with biological significance.
Acknowledgment. Financial support of this work by the
National Institutes of Health, NIGMS Grant GM59350-01,
the University of Missouri, and Monsanto is gratefully
acknowledged. A.V. and E.S. thank the Stevens Summer
Undergraduate Research program at the University of Mis-
souri for financial support. We thank Mr. Greg Brown for
contributing to the formation of 20.
Supporting Information Available: Experimental pro-
cedures for the preparation of 5-7, 8-15, 17, and 20 and
1
their characterization data. H NMR and 13C NMR spectra
for 5b-d, 6, 7a-e 8a-c, 9-12, 15, 17b, and 18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL990949U
(16) (a) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644-645.
(b) Wulff, W. D. In ComprehensiVe Organometallic Chemistry II; Abel,
A. W., Stone, F. G. A., Wilkinson, G., Eds.; Perganom: Oxford, 1995;
Vol. 12, pp 469-547.
(17) Pulley, S. R.; Vorogushin, A.; Sen, S. Abstracts of Papers; 215th
National Meeting of the American Chemical Society, Dallas, TX; American
Chemical Society: Washington, DC, 1998; ORGN 0374.
(18) Waters, M. L.; Brandvold, T. A.; Isaacs, L.; Wulff, W. D.
Organometallics 1998, 17, 4298-4308.
(19) See ref 18 and (a) Fischer, E. O.: Kalbfus, W. J. Organomet. Chem.
1972, 46, C15-C18. (b) Connor, J. A.; Jones, E. M. J. Chem. Soc. Part A
1971, 3368-3372.
(20) Fischer, E. O.; Maasbo¨l, A. Angew. Chem., Int. Ed. Engl. 1964, 3,
580.
(21) Torrent, M.; Duran, M.; Sola` M. J. Am. Chem. Soc. 1999, 121,
1309-1316 and references therein.
(22) Harrity, J. P. A.; Kerr, W. J.; Middlemiss, D. Tetrahedron 1993,
49, 5565-5576.
(23) Leukart, O.; Caviezel, M.; Eberle, A.; Escher, E.; Tun-Kyi, A.;
Schwyzer, R. HelV. Chim. Acta. 1976, 6, 2181-2183.
(24) (a) Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18-28. (b) Meffre,
P.; Gauzy, L.; Peridgues, C.; Desanges-Levecque, F.; Branquet, E.; Durand,
P.; Le Goffic, F. Tetrahedron Lett. 1995, 36, 877-880.
compounds is the result of the formation of lactams such as
18, as a side product in these reactions. The lactams result
from the attack of nitrogen on the intermediate ketene
involved in the mechanism of the Do¨tz reaction.21 Currently
we are investigating the potential to form either the phenyl-
Org. Lett., Vol. 1, No. 11, 1999
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