Mechanistic insight into direct arylations with ruthenium(II) carboxylate catalysts

Article abstract of DOI:10.1021/ol102187e

Mechanistic studies revealed ruthenium-catalyzed direct arylations to proceed through reversible C-H bond activation and subsequent rate-limiting oxidative addition with aryl halides, which led to the development of widely applicable well-defined rutheniu

Full text of DOI:10.1021/ol102187e

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5032-5035
Mechanistic Insight into Direct
Arylations with Ruthenium(II)
Carboxylate Catalysts
Lutz Ackermann,* Rube´n Vicente, Harish K. Potukuchi, and Valentina Pirovano
Institut fuer Organische und Biomolekulare Chemie, Georg-August-UniVersita¨t,
Tammannstrasse 2, 37077 Go¨ttingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received September 13, 2010
ABSTRACT
Mechanistic studies revealed ruthenium-catalyzed direct arylations to proceed through reversible C-H bond activation and subsequent rate-
limiting oxidative addition with aryl halides, which led to the development of widely applicable well-defined ruthenium(II) carboxylate catalysts.
Transition metal-catalyzed direct arylations of (hetero)are-
nes are increasingly viable alternatives to traditional cross-
coupling reactions, which allow for an overall streamlining
of arene syntheses.1,2 In recent years, ruthenium complexes
have emerged as particularly attractive tools for C-H bond
functionalizations with inexpensive3,4 easily accessible aryl-
ating reagents.5,6 Despite this significant progress, detailed
experimental mechanistic studies on the working mode of
ruthenium catalysts in direct arylations with organic halides
are unfortunately not available. Thus, several distinct reaction
manifolds continue to be considered for these transforma-
tions. For instance, a rationale was put forward that involved
an initial oxidative addition of aryl halides7 to ruthenium(II)
complexes and a subsequent C-H bond functionalization.8
On the contrary, computational DFT calculations were
performed for direct arylations with in situ generated
ruthenium(II) catalyst in NMP as solvent.9 On the basis of
these studies and comparable isolated yields with differently
(1) Selected recent reviews: (a) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. ReV. 2010, 110, 624–655. (b) Ackermann, L.; Vicente, R.;
Kapdi, A. Angew. Chem., Int. Ed 2009, 48, 9792–9826. (c) Thansandote,
P.; Lautens, M. Chem.sEur. J. 2009, 15, 5874–5883. (d) Kakiuchi, F.;
Kochi, T. Synthesis 2008, 3013–3039. (e) Ackermann, L. Synlett 2007, 507–
(6) Representative examples: ArOTs: (a) Ackermann, L.; Althammer,
A.; Born, R. Angew. Chem., Int. Ed. 2006, 45, 2619–2622. ArCl: (b)
´
526. (f) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205
(2) Ackermann, L. Modern Arylation Methods; Wiley-VCH: Weinheim,
Germany, 2009
.
Ackermann, L.; Born, R.; Alvarez-Bercedo, P. Angew. Chem., Int. Ed. 2007,
46, 6364–6367. (c) Pozgan, F.; Dixneuf, P. H. AdV. Synth. Catal. 2009,
351, 1737–1743. (d) Ackermann, L.; Born, R.; Vicente, R. ChemSusChem
2009, 2, 546–549. (e) In the presence of H2O: Ackermann, L. Org. Lett.
2005, 7, 3123–3125.
.
(3) For selected recent examples of ruthenium-catalyzed direct arylations
with aryl bromides, see: (a) Oi, S.; Sasamoto, H.; Funayama, R.; Inoue, Y.
Chem. Lett. 2008, 37, 994–995. (b) Ackermann, L.; Althammer, A.; Born,
R. Tetrahedron 2008, 64, 6115–6124. (c) Oi, S.; Funayama, R.; Hattori,
T.; Inoue, Y. Tetrahedron 2008, 64, 6051–6059. (d) Ackermann, L.;
Althammer, A.; Born, R. Synlett 2007, 2833–2836, and references cited
(7) Grounds, H.; Anderson, J. C.; Hayter, B.; Blake, A. J. Organome-
tallics 2009, 28, 5289–5292.
(8) (a) Luo, N.; Yu, Z. Chem.sEur. J. 2010, 16, 787–791. (b) Oi, S.;
Sakai, K.; Inoue, Y. Org. Lett. 2005, 7, 4009–4011. (c) Oi, S.; Fukita, S.;
Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579–
2581.
therein
.
(4) For select recent examples of ruthenium-catalyzed direct arylations
with boron-based arylating reagents, see: (a) Kitazawa, K.; Kochi, T.; Sato,
M.; Kakiuchi, F. Org. Lett. 2009, 11, 1951–1954. (b) Park, Y. J.; Jo, E.-
A.; Jun, C.-H. Chem. Commun. 2005, 1185–1187, and references cited
¨
(9) (a) Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras,
F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157.
See also: (b) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am.
Chem. Soc. 2005, 127, 13754–13755. (c) Boutadla, Y.; Davies, D. L.;
Macgregor, S. A.; Poblador-Bahamonde, A. I. Dalton Trans. 2009, 5820–
5831.
therein
.
(5) A review: Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292,
211–229
.
10.1021/ol102187e  2010 American Chemical Society
Published on Web 10/07/2010

substituted aryl bromides, ruthenium-catalyzed direct aryla-
tions were proposed to proceed through an irreversible
carbonate-assisted C-H bond metalation, along with a
reversible oxidative addition of aryl bromides.
Scheme 2. Direct Arylations with Well-Defined Complex 3
Recently, we disclosed the beneficial effect of carboxylic
acids or carboxylates as additives in ruthenium-catalyzed
C-H bond functionalizations with organic halides.10,11
Given the novel working mode of these in situ generated
catalytic systems, we became interested in identifying
structurally well-defined ruthenium complexes, and in un-
ravelling the mechanism of ruthenium-catalyzed C-H bond
functionalizations. As a result, we disclose herein our
findings, which provide strong evidence for a mechanism
involving a reversible C-H bond metalation and an irrevers-
ible oxidative addition with aryl halides. Importantly, these
studies also led to the isolation of structurally well-character-
ized ruthenium(II) carboxylate catalysts with ample
scope.
At the outset, we performed stoichiometric experiments
to elucidate the nature of the in situ generated catalyst. Hence,
reaction of [RuCl2(p-cymene)]2 (1) with carboxylic acid 2
selectively delivered ruthenium(II) biscarboxylate complex
3 (Scheme 1).12
Scheme 1. Synthesis of Complex 3
Importantly, well-defined ruthenium(II) carboxylate 3 was
found to be catalytically competent even in toluene as
solvent,13 and displayed a remarkable broad scope in the
direct arylations of arenes 4 (Scheme 2).14 Thus, various
arenes 4 were directly functionalized with differently sub-
stituted (hetero)aryl chlorides 5 in a highly regioselective
fashion. Generally, transformations with electron-deficient
aryl halides proceeded more efficiently (vide infra), and
reactions with meta-substituted arenes 4 occurred with
excellent site-selectivities, providing biphenyls 6ba-be
through steric interactions as the sole products.
(10) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10,
2299–2302
.
(11) For examples of applications to direct arylations, see: (a)
Ackermann, L.; Nova´k, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K.
Synthesis 2010, 2245–2253. (b) Ackermann, L.; Vicente, R. Org. Lett. 2009,
11, 4922–4925. (c) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043–
5045. (d) Ackermann, L. Pure Appl. Chem. 2010, 82, 1403–1413. (e) For
direct alkylations, see: Ackermann, L.; Novak, P.; Vicente, R.; Hofmann,
N. Angew. Chem., Int. Ed. 2009, 48, 6045-6048. (f) Ackermann, L.; Nova´k,
P. Org. Lett. 2009, 11, 4966–4969. (g) Ackermann, L. Chem. Commun.
Notably, direct arylations of alkenes 4 enabled the dias-
tereoselective formation of desired products 6 as well
(Scheme 3).
Interestingly, intramolecular competition experiments with
m-fluoro-substituted arenes 4b and 4c delivered predomi-
nantly biphenyls 6bo and 6bq, respectively (Scheme 4).15
Given the remarkable reactivity profile of complex 3,
we subsequently probed its mode of action through
2010, 46, 4866–4877
.
(12) The crystal structure of complex 3 has been deposited at the
Cambridge Crystallographic Data Centre (CCDC-757573).
(13) Mechanistic studies in NMP as solvent are hampered among others
by its potential competitive coordination to ruthenium complexes, which
in our hands results in catalytic reactions with lower robustness.
(14) Under otherwise identical reaction conditions, complex 1 provided
product 6aa in the absence of MesCO2H in only unsatisfactory low yields
of 8% (GC) or 47% when using K2CO3 or KOAc as base, respectively (see
also Table S-1 in the Supporting Information).
(15) (a) Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron
2007, 63, 1568–1576. (b) Clot, E.; Me´gret, C.; Eisenstein, O.; Perutz, R. N.
J. Am. Chem. Soc. 2009, 131, 7817–7827.
Org. Lett., Vol. 12, No. 21, 2010
5033

Scheme 3
.
Direct Arylations of Alkenes 4
Scheme 5
.
Synthesis of and Catalysis with Cyclometalated
Complex 7
Scheme 4. Intramolecular Competition Experiments with
m-Fluoro-Substituted Arenes
Scheme 6
.
Catalytic Direct Arylation with Isotopically Labeled
Starting Materials
stoichiometric experiments (Scheme 5). Hence, ruthe-
nium(II) carboxylate 3 turned out to be inert in the
presence of aryl chloride 5a, even at elevated reaction
temperatures. Contrarily, cyclometalation of arene 4b
occurred readily, thereby yielding catalytically competent
cyclometalated complex 7.16
Importantly, experiments with isotopically labeled starting
materials clearly revealed a D/H-exchange17 reaction (Scheme
6). Contrary to previous proposals, these results suggest the
C-H bond metalation step to be reversible in nature.
Moreover, competition experiments with an excess of
differently substituted electrophiles showed that electron-
deficient aryl halides reacted preferentially (Scheme 7). This
chemoselectivity was independent of the nature of the leaving
group or solvent, and optimal isolated yields were obtained
in toluene.
On the basis of our experimental studies we propose
complex 3 to undergo an initial reversible cyclometalation
through a carboxylate-assisted deprotonation (Scheme 8).18
Thereafter, complex 7 reacts in the rate-limiting step with
aryl halide 5 to yield intermediate 9.19 Finally, reductive
(16) Generally, the following order in reactivity is observed in ruthenium-
catalyzed direct arylations: ArBr > ArCl > ArOTs. For the synthesis of a
cyclometalated complex, see: Fernandez, S.; Pfeffer, M.; Ritleng, V.; Sirlin,
C. Organometallics 1999, 18, 2390–2394. See also ref 5.
5034
Org. Lett., Vol. 12, No. 21, 2010

Scheme 7
.
Intermolecular Competition Experiments
Scheme 8. Proposed Mechanism of Ruthenium-Catalyzed Direct
Arylations
through a reversible C-H bond metalation, along with a
subsequent rate-determining activation of the aryl halide. In
addition, we prepared novel well-defined ruthenium(II)
carboxylate complexes with ample scope and high activity
in C-H bond arylations.
elimination regioselectively gives rise to functionalized
arenes 6, and thereby regenerates catalyst 3.
In summary, we have provided strong experimental
evidence for ruthenium-catalyzed direct arylations to proceed
(17) For previous studies on the reversibility of ruthenium-catalyzed
C-H bond cleavage/C-C bond formation reactions, see: (a) Kozhushkov,
S. I.; Yufit, D. S.; Ackermann, L. Org. Lett. 2008, 10, 3409–3412, and
references cited therein. (b) During the preparation of this manuscript a
study on ruthenium-catalyzed C-H bond functionalizations in NMP as
solvent was reported: Prades, A.; Poyatos, M.; Peris, E. AdV. Synth. Catal.
2010, 352, 1155–1162.
Acknowledgment. Support by the DFG, as well as the
DAAD and the Alexander-von-Humboldt foundation (fel-
lowships to H.K.P. and R.V., respectively), is gratefully
acknowledged. Further, we thank Dr. Carola Schulzke
(Trinity College Dublin, Ireland) for an X-ray crystal
structure analysis of complex 3.
(18) Addition of 1 equiv of 2,6-di-tert-butyl-p-cresol or catalytic amounts
of galvinoxyl did not affect the outcome of representative ruthenium-
catalyzed direct arylations with aryl chlorides 5. However, lower yields
were obtained when employing 1 equiv of galvinoxyl or of TEMPO. For
reactions of radical traps with transition metal hydrides, see for example:
Albe´niz, A. C.; Espinet, P.; Lo´pez-Ferna´ndez, R.; Den, A. J. Am. Chem.
Soc. 2002, 124, 11278–11279.
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.
(19) Intermolecular competition experiments between differently sub-
stituted arenes 4 indicate the oxidative addition, rather than the reductive
elimination to be rate determining (see Scheme 7, and Scheme S-1 in the
Supporting Information).
OL102187E
Org. Lett., Vol. 12, No. 21, 2010
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