Well-defined ruthenium(II) carboxylate as catalyst for direct C-H/C-O bond arylations with phenols in water

Article abstract of DOI:10.1021/ol300671y

The ruthenium(II) carboxylate complex [Ru(O₂CMes) ₂(p-cymene)] enabled efficient direct arylations of unactivated C-H bonds with easily available, inexpensive phenols. Extraordinary chemoselectivity of the well-defined ruthenium cata

Full text of DOI:10.1021/ol300671y

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2146–2149
Well-Defined Ruthenium(II) Carboxylate
as Catalyst for Direct CÀH/CÀO Bond
Arylations with Phenols in Water
Lutz Ackermann,* Jola Pospech, and Harish Kumar Potukuchi
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received March 16, 2012
ABSTRACT
The ruthenium(II) carboxylate complex [Ru(O2CMes)2(p-cymene)] enabled efficient direct arylations of unactivated CÀH bonds with easily
available, inexpensive phenols. Extraordinary chemoselectivity of the well-defined ruthenium catalyst set the stage for challenging CÀH/CÀO
bond functionalizations to occur under solvent-free conditions as well as in water, and allowed first direct CÀH bond arylations with user-friendly
diaryl sulfates as electrophiles.
Transition-metal-catalyzed cross-coupling reactions be-
tween nucleophilic organometallic reagents and electro-
philic organic halides are arguably the most versatile tools
for the assembly of biaryls (Scheme 1a), key structural
motifs in medicinal chemistry or material sciences.1 While
these methods have matured to be highly reliable and
versatile, considerable recent efforts were directed toward
the development of more sustainable processes for biaryl
syntheses. Particularly, catalyzed arylations via CÀO bond
cleavages bear great potential,2,3 since the corresponding
electrophiles are readily accessible from inexpensive phe-
nols and can easily be implemented in site-selective arene
functionalizations.4 This approach gained a noteworthy
recent impetus through the use of fluorine-free phenol
derivatives, such as aryl carbamates, phosphates, or sulfa-
mates as arylating reagents (Scheme 1b).5 Despite this
remarkable progress in catalyzed CÀO bond activation
these protocols require stoichiometrically functionalized
organometallic nucleophiles, whereas significantly more
atom- and step-economical methods involved the direct
use of ubiquitous CÀH bonds6 as latent functional
groups (Scheme 1c).7 Unfortunately, all of these strategies
(5) For selected examples, see: (a) Leowanawat, P.; Zhang, N.;
Percec, V. J. Org. Chem. 2012, 77, 1018–1025. (b) Quasdorf, K. W.;
Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn,
T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am.
Chem. Soc. 2011, 133, 6352–6363. (c) Ackermann, L.; Sandmann, R.;
Song, W. Org. Lett. 2011, 13, 1784–1786. (d) Xi, L.; Li, B.-J.; Wu, Z.-H.;
Lu, X.-Y.; Guan, B.-T.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Org. Lett.
2010, 12, 884–887. (e) Shimasaki, T.; Tobisu, M.; Chatani, N. Angew.
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(p) Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428–2432 and
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(1) (a) Ackermann, L., Ed. Modern Arylation Methods; Wiley-VCH:
Weinheim, 2009. (b) de Meijere, A.; Diederich, F., Eds. Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
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Shi, Z.-J. Chem.;Eur. J. 2011, 17, 1728–1759. (c) Rosen, B. M.;
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r
10.1021/ol300671y
Published on Web 04/11/2012
2012 American Chemical Society

(Scheme 1b and c) strongly rely on a separate derivatiza-
tion step for the activation of the phenolic starting material.
This additional operation not only is time-consuming
but also generates additional undesired waste during the
formation and isolation of the electrophile. Indeed, a
considerable improvement of step economy would be
constituted by the direct use of phenols without a separate
functionalization step. To this end, we devised ruthenium-
catalyzed8,9 direct CÀH10 bond arylations with phenols via
CÀH/CÀOH bond functionalizations in a nonsequential
fashion.11 Unfortunately, these challenging arylations
could thus far solely be achieved with in situ generated
ruthenium complexes predominantly derived from a
secondary phosphine oxide12 as a preligand using aprotic
DMA as the solvent.11
Scheme 1. Recent Strategies for Sustainable Biaryl Syntheses
(6) Recent representative reviews on CÀH bond functionalizations:
(a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
DOI:10.1021/ar200185g. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011,
111, 1215–1292. (c) Ackermann, L.; Potukuchi, H. K. Org. Biomol.
Chem. 2010, 8, 4503–4513. (d) Daugulis, O. Top. Curr. Chem. 2010, 292,
57–84. (e) Fagnou, K. Top. Curr. Chem. 2010, 292, 35–56. (f) Boutadla,
Y.; Davies, D. L.; Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton
Trans. 2009, 5820–5831. (g) Thansandote, P.; Lautens, M. Chem.;Eur.
J. 2009, 15, 5874–5883. (h) Ackermann, L.; Vicente, R; Kapdi, A.
Angew. Chem., Int. Ed. 2009, 48, 9792–9826 and references cited therein.
(7) Direct CÀH bond arylations with fluorine-free phenol deriva-
tives: Heteroarenes: (a) Muto, K.; Yamaguchi, J.; Itami, K. J. Am.
Chem. Soc. 2012, 134, 169–172. (b) So, C. M.; Lau, C. P.; Kwong, F. Y.
Chem.;Eur. J. 2011, 17, 761–765. (c) Ackermann, L.; Fenner, S. Chem.
During studies on the working mode of ruthenium-
catalyzed CÀH bond functionalizations we recently un-
raveled carboxylate assistance13 as the key to success for
efficient direct arylations and identified ruthenium(II)
carboxylates as powerful catalysts for direct arylations
with aryl halides.14,15 Given our interest in employing
water as sustainable solvent for ruthenium-catalyzed16
CÀH bond transformations,17,18 we consequently became
attracted by probing well-defined ruthenium(II) com-
plexes in the challenging direct arylation with phenols in
water, on which we wish to report herein. Notable features
of the optimized catalyst include a significantly reduced
cocatalyst loading as compared to the in situ generated
catalyst as well as the use of widely available diaryl
sulfates19 for direct CÀH bond arylations.
€
Commun. 2011, 47, 430–432. (d) Ackermann, L.; Barfusser, S.; Pospech,
J. Org. Lett. 2010, 12, 724–726. (e) Ackermann, L.; Althammer, A.;
Fenner, S. Angew. Chem., Int. Ed. 2009, 48, 201–204. (f) Arenes:
Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed.
2006, 45, 2619–2622.
(8) A review: Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292,
211–229.
(9) For representative examples of ruthenium-catalyzed direct aryla-
tions with aryl halides, see: (a) Ackermann, L.; Diers, E.; Manvar, A.
Org. Lett. 2012, 14, 1154–1157. (b) Flegeau, E. F.; Bruneau, C.; Dixneuf,
P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133, 10161–10170.
(c) Lakshman, M. K.; Deb, A. C.; Chamala, R. R.; Pradhan, P.; Pratap,
R. Angew. Chem., Int. Ed. 2011, 50, 11400–11404. (d) Seki, M.;
Nagahama, M. J. Org. Chem. 2011, 76, 10198–10206. (e) Doherty, S.;
Knight, J. G.; Addyman, C. R.; Smyth, C. H.; Ward, N. A. B.;
Harrington, R. W. Organometallics 2011, 30, 6010–6016. (f) Ouellet,
S. G.; Roy, A.; Molinaro, C.; Angelaud, R.; Marcoux, J.-F.; O’Shea,
P. D.; Davies, I. W. J. Org. Chem. 2011, 76, 1436–1439. (g) Ackermann,
L.; Lygin, A. V. Org. Lett. 2011, 13, 3332–3335. (h) Yu, B.; Yan, X.;
Wang, S.; Tang, N.; Xi, C. Organometallics 2010, 29, 3222–3226.
(i) Miura, H.; Wada, K.; Hosokawa, S.; Inoue, M. Chem.;Eur. J. 2010,
16, 4186–4189. (j) Ackermann, L.; Born, R.; Vicente, R. ChemSusChem
We initiated our studies by testing well-defined complex
[Ru(O2CMes)2(p-cymene)] (1) in the direct arylation of
€
2009, 2, 546–549. (k) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen,
C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130,
1156–1157. (l) Ackermann, L.; Althammer, A.; Born, R. Tetrahedron 2008,
64, 6115–6124. (m) Oi, S.; Sasamoto, H.; Funayama, R.; Inoue, Y. Chem.
Lett. 2008, 37, 994–995. (n) Ackermann, L.; Althammer, A.; Born, R.
Synlett 2007, 2833–2836 and references cited therein.
(10) For recent KumadaÀCorriu and SuzukiÀMiyaura cross-cou-
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(16) For selected recent examples of palladium-catalyzed direct
arylations in water, see: (a) Nishikata, T.; Abela, A. R.; Lipshutz,
B. H. Angew. Chem., Int. Ed. 2010, 49, 781–784. (b) Turner, G. L.;
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(17) For ruthenium-catalyzed CÀH bond arylations in water as green
solvent, see: (a) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548–
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Org. Lett., Vol. 14, No. 8, 2012
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unactivated CÀH bonds on pyrazolyl- and oxazolinyl-
substituted arenes 2, directly employing inexpensive phe-
nols 3 in toluene as the solvent (Scheme 2). Gratifyingly,
both electron-rich and -deficient proelectrophiles 3 could
be employed, bearing important functional groups, such as
ester, keto, or fluoro substituents. Furthermore, a hetero-
aromatic hydroxyquinoline chemoselectively furnished the
corresponding biaryl 4l as well.
To our delight, the extraordinary chemoselectivity of well-
defined ruthenium complex 1 further allowed first direct
CÀH/CÀOH bond arylations to be performed in water as
a green solvent (Scheme 4). Notably, the protocol proved
tolerant of a wide diversity of functional groups, and
chemoselectively delivered the monoarylated products 4
not only when employing ortho-substituted arenes but also
with para-substituted substrates 2.
Scheme 2. Scope of Direct CÀH/CÀOH Bond Arylation with
Complex 1a
Scheme 4. Formal Dehydrative Direct Arylations with Water as
Sustainable Solvent
An intramolecular competition experiment with meta-
substituted arene 2b in water as the solvent led to the direct
arylation predominantly occurring at the less sterically
congested CÀH bond (Scheme 5).
a Yields of isolated products. bIn parentheses: Isolated yields for
reactions with preformed aryl tosylates.
Diaryl sulfates 5 are easily accessible, inexpensive elec-
trophiles, which have thus far not been utilized for transi-
tion-metal-catalyzed CÀH bond functionalizations.6 Yet,
catalyst 1 allowed for the unprecedented direct arylation of
arene 2a with di(p-tolyl) sulfate 5, thereby providing the
desired product 4b in a high yield (Scheme 3).
Scheme 5. Intramolecular Competition Experiment with Cata-
lyst 1 in Water (Ar = 4-C6H4C(O)Ph)
Scheme 3. Direct Arylation Using Diaryl Sulfate 5
Finally, we probed the direct arylation of arene 2a in
the absence of solvent,20 which fortunately also gave rise
(20) Recent examples of palladium-catalyzed direct arylations in the
absence of solvent: (a) Bedford, R. B.; Mitchell, C. J.; Webster, R. L.
Chem. Commun. 2010, 46, 3095–3097. (b) Bedford, R. B.; Engelhart,
J. U.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L. Dalton Trans. 2010,
39, 10464–10472. For direct alkylations, see ref 17c.
2148
Org. Lett., Vol. 14, No. 8, 2012

to the chemoselective formation of desired product 4e
(Scheme 6).
inexpensive phenols. The highly step-economical CÀH/
CÀOH bond functionalization process was characterized
by a wide substrate scope and an outstanding chemoselec-
tivity, which allowed for direct arylations to be performed
in water as a sustainable solvent as well as under solvent-
free reaction conditions. The high catalytic efficacy of
[Ru(O2CMes)2(p-cymene)] (1) was further reflected by
the unprecedented direct CÀH bond arylation with user-
friendly diaryl sulfates as arylating reagents.
Scheme 6. Direct Arylation under Solvent-Free Reaction Con-
ditions
Acknowledgment. Support by the DFG, and the
DAAD (fellowship to H.K.P.) is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, we have reported on the first use of a well-
defined ruthenium(II) biscarboxylate complex for highly
efficient direct arylations of unactivated CÀH bonds using
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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