us to addressing the challenge of developing a versatile, mild,
and general method for the formation of such structural
motifs in an enantio- and diastereoselective fashion. Herein,
we report a new lanthanide-catalyzed domino aryl-Claisen
reaction as an effective and general means to stereoselectively
access bisphenols with contiguous aryl-C(sp3) bonds.
It was envisaged that the synthesis of bisarylated targets
such as 4 could be accessed via a domino aryl-Claisen
rearrangement approach from an appropriately functionalized
1,2-dioxygenated precursor such as diol 1 (Scheme 1). These
defining feature of a domino reaction. The stereochemistry
of the newly formed aryl-C(sp3) bonds would be controlled
by the diol and alkene stereochemistry in 1. Thus, as a result
of suprafacial migration, the stereochemistry of 2 should
define the stereoconfiguration of the product. The overall
transformation of 2 into 4 would achieve the one-pot
synthesis of two contiguous aryl-C(sp3) bonds.
The rearrangement of 2a into 4a was chosen for proof of
concept studies. The effective O-arylation of secondary
alcohols is still a difficult process. The only synthetic method
that encompasses both a wide substrate scope and arene
variability are copper(II)-catalyzed routes.12 Hence, a mod-
ifed mild Cu(II)-catalyzed aryl ether synthesis13 using
potassium aryltrifluoroborate salts was employed on trans-
cyclohex-3-ene-1,2-diol14 for the formation of 2a.15 For
substrates incorporating electron deficient arenes a one-pot
double SNAr was performed using conditions based upon
an existing monoarylative SNAr procedure.16 Both routes
achieve an unprecedented double arylation of sterically
hindered secondary vicinal hydroxyls to give bisaryl ethers
in modest yields ranging from 14% to 68%.
Scheme 1. General Synthetic Route to Bisphenol 4
Various methods to effect the domino aryl-Claisen rear-
rangement on 2a to form 4a were attempted. Use of classical
thermal conditions on 2a using H2O at 160 °C for 3 d did
not produce 4a. However, microwave-assisted aryl-Claisen
rearrangement17 of 2a in DMF at 250 °C for 1 h afforded
56% of 4a, although several byproducts were formed under
these harsh conditions. The use of europium(III)-tris-
(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedionate) (Eu-
(fod)3) to effect a high-yielding aryl-Claisen rearrangement
with very good chirality transfer has been previously
reported,9a,18,19 whereas stronger Lewis acidic lanthanide
triflates led to racemization.18 Application of the domino
rearrangement on 2a using 5 mol % Eu(fod)3 in tetrachlo-
roethane at 120 °C for 6 h20 afforded 4a in 60% yield (Table
1). Further screening indicated the mildest conditions that
resulted in the highest yield of 4a, and using the most
environmentally benign solvent was Eu(fod)3 in PhMe at 120
1,2-diols (either acyclic or cyclic) that are adjacent to alkenyl
π-bonds would in turn be accessible through standard
stereoselective methods such as alkene dihydroxylation. A
stepwise or unprecedented concomitant dual arylation of 1
would then be required to form bisaryl ether domino aryl-
Claisen precursor 2. The key domino aryl-Claisen rearrange-
ment would proceed via the intermediacy of 3 to give product
4. The rearrangement of the second aryl ring can only occur
following the allylic transposition that happens as a result
of the initial aryl-Claisen rearrangement of 2 into 3, a
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(9) Recent examples include: stepwise C-glycoside formation, followed
by phenol addition and [3,3]-sigmatropic rearrangement, see: (a) Yeager,
A. R.; Min, G. K.; Porco, J. A., Jr.; Schaus, S. E. Org. Lett. 2006, 8,
5065-5068. (b) The formation of two contiguous trans aryl-C(sp3) bonds
infused 2,3-dihydrofurans (non-enantioselective), see: Wang, Q.-F.; Hou,
H.; Hui, L.; Yan, C.-G. J. Org. Chem. 2009, 74, 7403–7406. (c) An
enantioselective Pd-catalyzed cyclization of propargylic carbonates with
2-(2-hydroxyphenyl)acetates, see: Yoshida, M.; Higuchi, M.; Shishido, K.
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(15) See the Supporting Information for details.
(16) Mono-SNAr procedure: Adams, S. R.; Kao, J. P. Y.; Grynkiewicz,
G.; Minta, A.; Tsien, R. Y. J. Am. Chem. Soc. 1988, 110, 3212–3220.
(17) (a) Stadler, A.; Kappe, C. O. MicrowaVe Assisted Organic Synthesis;
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2005; p 206. (b) Gignere, R. J.; Bray, T.; Duncan, S. M.; Majetich, G.
Tetrahedron Lett. 1986, 27, 4945–4948.
(10) For examples on the use of the Ireland-Claisen rearrangement to
afford these moieties through the formation of a σ-bond between two non-
aryl carbon atoms, see: Corey, E. J.; Lee, D.-Y. J. Am. Chem. Soc. 1991,
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(18) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815–816
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(19) For other examples of other Eu(fod)3-catalyzed aryl-Claisen rear-
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(20) Reaction conditions were modified from ref 19c.
Org. Lett., Vol. 12, No. 20, 2010
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