Dehydrative direct arylations of arenes with phenols via ruthenium-catalyzed C-H and C-OH bond functionalizations

Article abstract of DOI:10.1021/ol802252m

(Chemical Equation Presented) Phenols can be employed as proelectrophiles in operationally simple ruthenium-catalyzed dehydrative direct arylations, proceeding through chemo- and regioselective functionalizations of C-H and C-OH bonds.

Full text of DOI:10.1021/ol802252m

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5043-5045
Dehydrative Direct Arylations of Arenes
with Phenols via Ruthenium-Catalyzed
C-H and C-OH Bond Functionalizations
Lutz Ackermann* and Michael Mulzer
Institut fu¨r Organische and Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received September 27, 2008
ABSTRACT
Phenols can be employed as proelectrophiles in operationally simple ruthenium-catalyzed dehydrative direct arylations, proceeding through
chemo- and regioselective functionalizations of C-H and C-OH bonds.
Metal-catalyzed cross-coupling reactions have matured to
being indispensable tools for C-C bond formations, which
Scheme 1. Strategies for Catalytic Biphenyl Syntheses
have proved particularly useful for the synthesis of diversely
substituted biaryls. Traditionally, cross-coupling reactions
rely on the use of preactivated substrates, namely organic
(pseudo)halides and organometallic reagents as electrophiles
and nucleophiles, respectively (Scheme 1, (a)).1 Unfortu-
nately, these activated starting materials lead to undesired
waste from reagents, solvents, and additional purifications.
Therefore, focus has shifted in recent years to the develop-
ment of direct arylations employing unactivated arenes as
pronucleophiles (Scheme 1, (b)).2 While these C-H bond
functionalization protocols have been recognized as ecologi-
(1) (a) Beller, M., Bolm, C., Eds. Transition Metals for Organic
Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) de Meijere, A.;
Diederich, F., Eds. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
Wiley-VCH: Weinheim, 2004.
cally benign and economically attractive alternatives to
traditional cross-coupling strategies, the direct use of broadly
available, yet inexpensive phenols as proelectrophilic re-
agents has remained largely unexplored. As a result, a first
example of metal-catalyzed cross-couplings via C-OH bond
functionalizations (Scheme 1, (c)) was disclosed only very
recently. Thus, Fang and co-workers showed elegantly that
phosphonium salts enabled an in situ activation of tautomer-
izable heterocycles, as well as their subsequent palladium-
catalyzed cross-coupling using boronic acids as nucleo-
philes.3 However, this methodology required a separate
preformation of the corresponding heterocycle-phosphonium
salt electrophile in the absence of the palladium catalyst.
(2) Recent reviews: (a) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008,
949–957. (b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013–1025. (c) Satoh, T.; Miura, M. Top. Organomet. Chem.
2007, 24, 61–84. (d) Ackermann, L. Top. Organomet. Chem. 2007, 24, 35–
60. (e) Kalyani, D.; Sanford, M. S. Top. Organomet. Chem. 2007, 24, 85–
116. (f) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174–238. (g) Fairlamb, I. J. S. Chem. Soc. ReV. 2007, 36, 1036–1045. (h)
Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173–1193. (i)
Pascual, S.; de Mendoza, P.; Echavarren, A. M. Org. Biomol. Chem. 2007,
5, 2727–2734. (j) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim.
Acta 2007, 40, 35–41. (k) Ackermann, L Synlett 2007, 507–526. (l) Daugulis,
O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.; Lazareva, A. Synlett 2006,
3382–3388. (m) Yu, J.-Q.; Giri, R.; Chen, X. Org. Biomol. Chem. 2006,
4041–4047. (n) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253–
1264.
10.1021/ol802252m CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

Furthermore, the use of stoichiometric amounts of organo-
metallic reagents in this cross-coupling reaction resulted,
unfortunately, again in the generation of undesired byproduct
(vide supra).3
Scheme 2. Dehydrative Direct Arylations of Oxazoline 2a
On the contrary, a significantly more sustainable approach
would be represented by unprecedented direct arylations of
arenes as pronucleophiles with phenols as proelectrophilic
arylating reagents Via functionalizations of C-H and C-OH
bonds (Scheme 1, (d)). Herein, we present a first example
of such a dehydrative coupling between simple arenes and
inexpensive phenols,4 which was accomplished with a highly
chemo- and regioselective ruthenium5 catalyst.
As part of our program directed toward the development
of sustainable metal-catalyzed direct arylations,6 we probed
different transition metals, (pre)ligands, bases, and additives
for the envisioned dehydrative direct arylation with phenols.
Among a variety of reaction conditions, a system comprising
ruthenium precursor [{RuCl2(p-cymene)}2] and HASPO7
preligand 1, along with K2CO3, p-toluenesulfonyl chloride
(p-TsCl), and N,N-dimethylacetamide (DMA), was found to
be superior (Tables S-1, and S-2 in the Supporting Informa-
tion).
Thereby, an efficient and selective in situ activation of
the phenolic starting material was accomplished. The meth-
odology turned out to be operationally simple, since a
successive addition of reagents for a preformation of the
electrophile was not necessary. In addition to its chemical
stability, the in situ generated catalyst displayed a remarkable
chemo- and regioselectivity. Hence, undesired byproducts
originating from nucleophilic reactivities of the phenols8,9
or from desulfinylative coupling reactions10 were not ob-
served.11
With an optimized catalytic system in hand, we tested its
scope in dehydrative direct arylations of oxazoline 2a using
differently substituted phenols (Scheme 2). These studies
highlighted a broad functional group tolerance, which set
the stage for the efficient conversion of electron-deficient
(4a-f), as well as electron-rich (4g-i) phenols, bearing inter
alia an ester, ketones, alkyl, and aryl fluorides, or an ether.
Importantly, the high efficacy of the ruthenium catalyst
allowed further for catalytic reactions to be performed at a
reduced reaction temperature of 100 °C, as illustrated for
the preparation of oxazoline 4b.
Notably, dehydrative direct arylations were not restricted
to oxazolines as pronucleophiles but could be employed for
the direct functionalization of pyrazolyl-substituted arenes
as well (Scheme 3). Hence, functionalized, electron-deficient,
as well as electron-rich phenols 3 provided the desired
biphenyls 6a-i in high yields. Additionally, pyridyl-
substituted pronucleophiles could be directly arylated, giving
selectively the desired biphenyls 7a-c.
(3) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130,
11300–11302.
(4) For elegant ruthenium-catalyzed arylations of aryl ethers through
C-OMe or C-NMe2 bond functionalizations, see: (a) Kakiuchi, F.; Usui,
M.; Ueno, S.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2004, 126, 2706–
2707. (b) Ueno, S.; Mizushima, E.; Chatani, N.; Kakiuchi, F. J. Am. Chem.
Soc. 2006, 128, 16516–16517. (c) Ueno, S.; Chatani, N.; Kakiuchi, F. J. Am.
Chem. Soc. 2007, 129, 6098–6099. (d) For alkenylations with alkenyl
acetates, see: Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.;
Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858–9859.
(8) Review on copper-catalyzed O-arylations of phenols: (a) Ley, S. V.;
Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449. (b) Recent
reviews on palladium-catalyzed arylations: Surry, D. S.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 6338–6361. (c) Hartwig, J. F. Acc. Chem.
Res. 2008, 41, DOI: 10.1021/ar800098p.
(9) For rhodium-catalyzed ortho-arylations of phenols, see: (a) Bedford,
R. B.; Betham, M.; Caffyn, A. J. M.; Charmant, J. P. H.; Lewis-Alleyne,
L. C.; Long, P. D.; Polo-Ceron, D.; Prashar, S. Chem. Commun. 2008, 990–
992. (b) Oi, S.; Watanabe, S.-I.; Fukita, S.; Inoue, Y. Tetrahedron Lett.
2003, 44, 8665–8668. (c) Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.;
Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42, 112–114.
(5) Representative ruthenium-catalyzed direct arylations: (a) Kakiuchi,
F.; Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936–
5945. (b) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70,
3113–3119. (c) Oi, S.; Sato, H.; Sugawara, S.; Inoue, Y. Org. Lett. 2008,
10, 1823–1826. (d) Selected examples from our laboratories: Ackermann,
L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115–6124. (e)
Ackermann, L.; Althammer, A.; Born, R. Synlett 2007, 2833–2836. (f)
(10) Dubbaka, S. R.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674–
7684.
(11) Representative procedure, synthesis of product 4h: A suspension
of [{RuCl2(p-cymene)}2] (7.7 mg, 0.012 mmol, 2.50 mol %), oxazoline 2a
(80.9 mg, 0.502 mmol), preligand 1 (21.4 mg, 0.050 mmol, 10.0 mol %),
K2CO3 (173 mg, 1.25 mmol), naphthalen-2-ol (3h) (86.5 mg, 0.600 mmol),
and p-TsCl (114 mg, 0.600 mmol) in dry DMA (1.5 mL) was stirred for 5
min at ambient temperature and then for 18 h at 120 °C under N2. At ambient
temperature, EtOAc (70 mL) and H2O (50 mL) were added to the reaction
mixture, and the separated aqueous phase was extracted with EtOAc (2 ×
70 mL). The combined organic layers were washed with brine (30 mL),
dried over Na2SO4, and concentrated in vacuo. The remaining residue was
purified by column chromatography on silica gel (n-hexane/EtOAc, 15/1
f 2/1) to yield 4h (111 mg, 77%) as an off-white solid.
´
Ackermann, L.; Born, R.; Alvarez Bercedo, P. Angew. Chem., Int. Ed 2007,
46, 6364–6367. (g) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem.,
Int. Ed. 2006, 45, 2619–2622. (h) Ackermann, L. Org. Lett. 2005, 7, 3123–
3125, and references cited therein.
(6) Recent examples: (a) Ackermann, L.; Potukuchi, H. K.; Landsberg,
D.; Vicente, R. Org. Lett. 2008, 10, 3081–3084. (b) Ackermann, L.; Vicente,
R.; Born, R. AdV. Synth. Catal. 2008, 350, 741–748. (c) Kozhushkov, S. I.;
Yufit, D. S.; Ackermann, L. Org. Lett. 2008, 10, 3409–3412. (d) Ackermann,
L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627–1629.
(7) Ackermann, L. Synthesis 2006, 1557–1571.
5044
Org. Lett., Vol. 10, No. 21, 2008

In summary, we report on the development of a first direct
arylation between simple arenes as pronucleophiles and
Scheme 3. Scope of Dehydrative Direct Arylations
Scheme 4. Dehydrative Direct Arylations in an Apolar Solvent
inexpensive, broadly available phenols as proelectrophiles.
Notably, this operationally simple dehydrative arylation was
achieved with a highly chemo- and regioselective ruthenium
catalyst and proceeded through the functionalizations of both
C-H as well as C-OH bonds.
Acknowledgment. Support by the DFG and the Fonds
der Chemischen Industrie is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL802252M
When apolar toluene was used as solvent, a catalyst
derived from carboxylic acid MesCO2H12 enabled most
efficient direct arylations of oxazoline 2a(Table S-2 in the
(13) For recent examples of C-H bond functionalizations based on
concerted metalation-deprotonation mechanisms:(a) Davies, D. L.; Donald,
S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754–13755.
(b) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880–6886. (c) Gorelsky,
S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
Supporting
Information)
through
a
concerted
metalation-deprotonation12,13 mechanism (Scheme 4).
¨
(d) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras, F.;
(12) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299–2305.
Bruneau, C.; Dixneuf, P. H J. Am. Chem. Soc. 2008, 130, 1156–1157, and
references cited therein.
Org. Lett., Vol. 10, No. 21, 2008
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