Synthesis of unsymmetrical o-biphenols and o-binaphthols via silicon-tethered Pd-catalyzed C-H arylation

Article abstract of DOI:10.1021/ol100924n

A mild, practical, and efficient method for the synthesis of unsymmetrical o-biphenols (including o-phenol-naphthols and o-binaphthols) has been developed. Unsymmetrical bis-aryloxy silanes, which were readily prepared in a semi-one-pot fashion, underwent the Pd-catalyzed intramolecular arylation followed by a routine TBAF desilylation step to furnish valuable unsymmetrical biphenols without necessity of isolation of seven-membered intermediates. The excellent functional group tolerance allows for synthesis of a variety of functionalized o-biphenols and o-binaphthols from easily available staring materials.

Full text of DOI:10.1021/ol100924n

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2442-2445
Synthesis of Unsymmetrical o-Biphenols
and o-Binaphthols via Silicon-Tethered
Pd-Catalyzed C-H Arylation
Chunhui Huang and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
Vlad@uic.edu
Received April 21, 2010
ABSTRACT
A mild, practical, and efficient method for the synthesis of unsymmetrical o-biphenols (including o-phenol-naphthols and o-binaphthols) has
been developed. Unsymmetrical bis-aryloxy silanes, which were readily prepared in a semi-one-pot fashion, underwent the Pd-catalyzed
intramolecular arylation followed by a routine TBAF desilylation step to furnish valuable unsymmetrical biphenols without necessity of isolation
of seven-membered intermediates. The excellent functional group tolerance allows for synthesis of a variety of functionalized o-biphenols and
o-binaphthols from easily available staring materials.
The o-biphenol framework is a key unit found in natural
and synthetic bioactive molecules1 and in various ligand
families.2 Due to the favorable single-electron phenolic
oxidation,3 the strategies toward assembly of biphenols
largely concentrate on the oxidative phenol coupling reac-
tions. Nonetheless, the synthesis of biphenols via these
approaches is limited to symmetrical and electron-rich
systems, often employing toxic heavy metal oxidants.4 The
synthesis of unsymmetrical biphenols via oxidative cross-
coupling of phenols suffers from significant amounts of self-
coupling byproducts and undesired oligomers.3c,5 There are
a few reports on the synthesis of unsymmetrical biphenols
employing a silicon tether,6 yet these reactions are limited
to electron-rich substrates. Recently, we7 reported the Pd-
catalyzed arylation of phenols8 via an easy-on and -off
silicon-tethered strategy,9 which allowed assembly of unsym-
metrical biphenol C via further oxidation of a six-membered
(1) (a) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. ReV.
2009, 38, 3193. (b) Quideau, S.; Feldman, K. S. Chem. ReV. 1996, 96,
475. (c) Tweardy, D. J.; Huang, X.; Kasembeli, M. M. Patent WO 149192
A1, 2009.
(4) (a) Armstrong, D. R.; Cameron, C.; Nonhebel, D. C.; Perkins, P. G.
J. Chem. Soc., Perkin Trans. 2 1983, 581. (b) Hwang, D.-R.; Chen, C.-P.;
Uang, B.-J. Chem. Commun. 1999, 1207. (c) Yadav, J. S.; Reddy, B. V. S.;
Gayathri, K. U.; Prasad, A. R. New J. Chem. 2003, 27, 1684. (d) Malkowsky,
I. M.; Rommel, C. E.; Fro¨hlich, R.; Griesbach, U.; Pu¨tter, H.; Waldvogel,
S. R. Chem.sEur. J. 2006, 12, 7482.
(2) (a) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 9, 1375. (b) Alexakis, A.; Benhaim, C.; Rosset,
S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262. (c) Hua, Z.; Vassar,
V. C.; Choi, H.; Ojima, I. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5411.
(d) Wang, J.; Hu, X.; Jiang, J.; Gou, S.; Huang, X.; Liu, X.; Feng, X. Angew.
Chem., Int. Ed. 2007, 46, 8468. (e) Wang, J.; Wang, W.; Li, W.; Hu, X.;
Shen, K.; Tan, C.; Liu, X.; Feng, X. Chem.sEur. J. 2009, 15, 11642.
(3) (a) Taylor, W. I.; Battersby, A. R. OxidatiVe Coupling of Phenols;
Marcel Dekker: New York, 1967. (b) Pal, T.; Pal, A. Curr. Sci. 1996, 71,
106. (c) Lessene, G.; Feldman, K. S. In Modern Arene Chemistry; Astruc,
D., Eds.; Wiley-VCH: Weinheim, 2002; Chapter 14.
(5) Nishino, H.; Itou, N.; Nagashima, M.; Kurasawa, K. Bull. Chem.
Soc. Jpn. 1992, 65, 620
.
(6) (a) Takada, T.; Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma, H.;
Kita, Y. J. Org. Chem. 1998, 63, 7698. (b) Schmittel, M.; Haeuseler, A. Z.
Naturforsch. B. 2003, 58, 211.
(7) Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844.
10.1021/ol100924n  2010 American Chemical Society
Published on Web 04/27/2010

oxasilacylce B (eq 1). However, oxidation of the C-Si bond
required harsh conditions and is limited to the particular
substitution pattern. Herein, we wish to report a mild, general,
and efficient method for the synthesis of unsymmetrical
biphenols 3 via intramolecular Pd-catalyzed C-H aryla-
tion7,10 of 1 to form 2, followed by a routine desilylation
step (eq 2).
Table 1. Optimization of Reaction Conditionsa
additive
(equiv)
no.
R
base (equiv)
yield, %b 2:4c
1
2
3
4
5
6
H (1a)
1a
1a
1a
1a
K2CO3d (2)
K3PO4 (2)
Ag2CO3 (2)
K3PO4 (2)
K3PO4 (2)
K3PO4 (2)
Ag2CO3 (0.5)
K3PO4 (2)
Ag2CO3 (1.5)
K3PO4 (1)
Ag2CO3 (1)
K3PO4 (2)
Ag2CO3 (1)
none
none
none
PivOH (0.3)
25
31
49
42
5:1
14:1
15:1
15:1
17:1
26:1
3-NO2-Py (0.3) 43
1a
none
none
none
none
none
none
none
66
7
8
9
1a
1a
1a
73
41:1
32:1
78
We hypothesized that if intramolecular C-H arylation10f-k
of easily available bis-aryloxy silane 1 would be efficient to
form seven-membered11 silacycles 2, it would provide an
easy route to biphenols 3 via a simple deprotection. To test
this hypothesis, we subjected 1a to the previously reported
arylation conditions.7 However, under these conditions only
reductive debromination occurred, with trace amounts of 2a
produced. Fagnou showed the possibility of seven-membered
ring formation employing bulky electron-deficient bidentate
ligands combined with palladium acetate.10i,j Still, employ-
ment of these conditions did not give any arylation product
in the silicon-tethered case, as only reductive product 4 was
obtained. After extensive screening of reaction parameters,
including palladium sources, ligands, bases, and solvents,12
we found that bulky electron-deficient monodentate ligand
P(C6F5)3 in nonpolar solvents is capable of suppressing the
C-Br reduction process. Employment of bases K3PO4 and
Ag2CO3 resulted in higher efficiency of arylation (Table 1,
entries 2, 3). Application of additives did not cause improve-
ment (entries 4, 5). Gratifyingly, the combination of K3PO4
85 (73)
(70)
(90)
(80)
34:1
10 p-OMe (1b) K3PO4 (2)
Ag2CO3 (1)
11 p-CF3 (1c) K3PO4 (2)
Ag2CO3 (1)
>99:1
>99:1
100:0
12 o-Me (1d)
K3PO4(2)
Ag2CO3 (1)
a See Supporting Information for details. b GC yields of 2, isolated yields
are in parentheses. c GC ratio. d p-Xylene was used as a solvent.
and Ag2CO3 dramatically improved the yield and the
arylation/reduction ratio, resulting in 73% isolated yield of
2a and high arylation/reduction ratio (entry 9). Next, these
conditions were tested on substrates 1b-d (entries 10-12).
In all cases, the yields were high with negligible amounts
of debromination byproducts 4 obtained. Naturally, the
standard TBAF deprotection protocol afforded 3a quanti-
tively.12 Semi-one-pot procedure from 1a to 3a demonstrated
the same efficiency (Table 2, entry 1). For easier separation,
all other biphenols were isolated as acetates without loss of
the yields.
Next, the scope of this protocol toward synthesis of
unsymmetrical biphenols, phenol-naphthols, and binaphthols
was examined (Table 2). Gratifyingly, it was found that this
method is general and efficient, regardless on the electronic
properties of substituents on either phenol ring. Thus, a
variety of functional groups, such as MeO, F, Cl, CF3, CHO,
NO2, and even Br, can be perfectly tolerated under these
reaction conditions producing the unsymmetrical biphenol
acetates in 3-step semi-one-pot in high to excellent overall
yields. As expected, meta-substituted phenols gave mixtures
of regioisomers. The regioselectivity was affected by both
electronics and sterics. For example, although CF3 and Me
groups are comparable in size, the substrate 1k, possessing
an electron-withdrawing group (R ) CF3), reacted more
regioselectively compared to Me-substituted 1j. Expectedly,
the steric effect on the regioselectivity of arylation has also
been observed. Thus, differently O-protected resorcinol
(8) (a) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E.
Angew. Chem., Int. Ed. 2003, 42, 112. (b) Oi, S.; Watanabe, S.-i.; Fukita,
S.; Inoue, Y. Tetrahedron Lett. 2003, 44, 8665. (c) Hennings, D. D.; Iwasa,
S.; Rawal, V. H. J. Org. Chem. 1997, 62, 2. (d) Bajracharya, G. B.; Daugulis,
O. Org. Lett. 2008, 10, 4625. (e) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai,
J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468.
(9) (a) Stork, G.; Suh, H. S.; Kim, G. J. Am. Chem. Soc. 1991, 113,
7054. For a review, see, for example: (b) Fensterbank, L.; Malacria, M.;
Sieburth, S. M. Synthesis 1997, 813.
(10) For reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV.
2007, 36, 1173. (c) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica
Acta 2007, 40, 35. (d) Ashenhurst, J. A. Chem. Soc. ReV. 2010, 39, 540.
See also: (e) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am.
Chem. Soc. 2010, 132, 4978. For intramolecular arylations, see examples:
(f) Garc´ıa-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880. (g) Garc´ıa-Cuadrado,
D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc.
2006, 128, 1066. (h) Pascual, S.; de Mendoza, P.; Braga, A. A. C.; Maseras,
F.; Echavarren, A. M. Tetrahedron 2008, 64, 6021. (i) Campeau, L.-C.;
Parisien, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186. (j) Leblanc,
M.; Fagnou, K. Org. Lett. 2005, 7, 2849. (k) Shimizu, M.; Mochida, K.;
Hiyama, T. Angew. Chem., Int. Ed. 2008, 47, 9760.
(11) For challenges in formation of a seven-membered ring via C-H
arylation, see refs 10i, j.
(12) See the Supporting Information for details.
Org. Lett., Vol. 12, No. 10, 2010
2443

Table 2. Synthesis of Unsymmetrical o-Biphenols, o-Phenol-naphthols, and o-Binaphthols via Silicon-Tethered C-H Arylation
(3-Steps, Semi-one-pot)a b
,
a Isolated yields. b To simplify isolation, the biphenols were further converted to their corresponding acetates. c Two-step semi-one-pot procedure gave
d
unprotected 2,2′-biphenol in 72% yield; yield in the parentheses is desilylation from 2a to 3a. 1H NMR yield (against CH2Br2 as an internal standard).
e Major regioisomer shown. f 4 equiv of TBAF, 15 equiv of Ac2O, and 15 equiv of pyridine were used; 3m ) 3n.
2444
Org. Lett., Vol. 12, No. 10, 2010

provided varied regioselectivity increasing with bulkier
protecting groups (1l < 1m < 1n). 1-Naphthols and 2-naph-
thols could efficiently be employed in this arylation reaction,
as well (entries 15-25). Thus, differently substituted 2-bro-
mophenols underwent smooth arylation with 1-naphthol
producing unsymmetrical phenol-naphthols in 61-96%
yields. The unsymmetrical mixed 1- and 2-naphthol products
(3v, 3w) were also obtained highly efficiently. It deserves
mentioning that 3w represents the core structure of a series
of small molecule inhibitors of Stat3 oncogene.1c Arylation
of 1y afforded a 1.7:1 mixture of unsymmetrical 2,2′-
BINOL13 derivative (3y) and 1,2′-binaphthyl-2,3′-diol de-
rivative (3y′) in excellent overall yield (entry 25).
In summary, a mild, practical, and efficient method for
the synthesis of symmetrical and unsymmetrical o-biphenols,
o-phenol-naphthols, and o-binaphthols has been developed.
The method involves a Pd-catalyzed intramolecular C-H
arylation of unsymmetrical bis-aryloxy silanes to give the
seven-membered oxasilacycles, which via a consecutive
routine TBAF deprotection furnishes valuable unsymmetrical
o-biphenols and o-binaphthols. The method allows for easy
synthesis of a wide variety of functionalized symmetrical
and unsymmetrical o-biphenols and o-binaphthols from easily
available staring materials.
Acknowledgment. This work was supported by the
National Institutes of Health (Grant GM-64444).
Supporting Information Available: General experimental
procedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For a review, see 1a For examples, see: (a) Li, X.; Yang, J.;
Kozlowski, M. C. Org. Lett. 2001, 3, 1137. (b) Mulrooney, C. A.; Li, X.;
DiVirgilio, E. S.; Kozlowski, M. C. J. Am. Chem. Soc. 2003, 125, 6856.
(c) Guo, Q.-X.; Wu, Z.-J.; Luo, Z.-B.; Liu, Q.-Z.; Ye, J.-L.; Luo, S.-W.;
Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129, 13927. (d) Egami,
ˇ
H.; Katsuki, T. J. Am. Chem. Soc. 2009, 131, 6082. (e) Hovorka, M.; Scˇigel,
R.; Guterova´, J.; Tichy´, M.; Za´vada, J. Tetrahedron 1992, 48, 9503.
OL100924N
Org. Lett., Vol. 12, No. 10, 2010
2445