Assisted ruthenium-catalyzed C-H bond activation: Carboxylic acids as cocatalysts for generally applicable direct arylations in apolar solvents

Article abstract of DOI:10.1021/ol800773x

(Chemical Equation Presented) Catalytic amounts of aromatic carboxylic acid MesCO₂H enabled efficient ruthenium-catalyzed direct arylations in apolar solvents with unparalleled broad scope via a concerted deprotonation-metalation mechanism.

Full text of DOI:10.1021/ol800773x

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2299-2302
Assisted Ruthenium-Catalyzed C-H
Bond Activation: Carboxylic Acids as
Cocatalysts for Generally Applicable
Direct Arylations in Apolar Solvents
Lutz Ackermann,* Rube´n Vicente, and Andreas Althammer
Institut fu¨r Organische und Biomolekulare Chemie, Georg-August-UniVersitaet,
Tammannstrasse 2, 37077 Goettingen, Germany
lutz.ackermann@chemie.uni-goettingen.de
Received April 4, 2008
ABSTRACT
Catalytic amounts of aromatic carboxylic acid MesCO2H enabled efficient ruthenium-catalyzed direct arylations in apolar solvents with unparalleled
broad scope via a concerted deprotonation-metalation mechanism.
The arylation of (hetero)arenes through the functionalization
of C-H bonds is an attractive alternative to cross-couplings
with organometallic reagents because of its ecologically and
economically benign nature.1 While most of these direct
arylations are accomplished with palladium-based cata-
lysts,1–3 recent studies highlight the potential of ruthenium
complexes in these challenging transformations.1a Unfortu-
nately, experimental studies on the working mode of these
promising ruthenium complexes are thus far not available.1a,4
Recently, we found that efficient direct arylations of arenes
are achieved with ruthenium complexes derived from air-
stable (heteroatom-substituted) secondary phosphine oxide
(HA)SPO1b,5 preligands.6–9 Since ruthenacycles of substi-
tuted arenes were prepared stoichiometrically in the presence
of sodium acetate under mild reaction conditions,10 we
(2) Selected recent rhodium-catalyzed direct arylations: (a) Lewis, J. C.;
Wu, J. Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2006, 45,
1589–1591. (b) Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am.
Chem. Soc. 2006, 128, 11748–11749. (c) Proch, S.; Kempe, R. Angew.
Chem., Int. Ed. 2007, 46, 3135–3138. (d) Vogler, T.; Studer, A. Org. Lett.
2008, 10, 129–131, and references cited therein
(3) Copper-catalyzed direct arylations: (a) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 1128–1129. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem.
.
Soc. 2007, 1292, 1404–12405
.
(1) Recent reviews on C–H bond functionalizations: (a) Ackermann, L.
Top. Organomet. Chem. 2007, 24, 35–60. (b) Ackermann, L. Synlett 2007,
507–526. (c) Satoh, T.; Miura, M. Top. Organomet. Chem. 2007, 24, 61–
84. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205. (e) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–238. (f) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173–1193. (g) Bergman,
R. G. Nature 2007, 446, 391–393. (h) Campeau, L.-C.; Stuart, D. R.;
Fagnou, K. Aldrichim. Acta 2007, 40, 35–41. (i) Daugulis, O.; Zaitsev, V. G.;
Shabashov, D.; Pham, Q. N.; Lazareva, A. Synlett 2006, 3382–3388. (j)
(4) Ruthenium-catalyzed direct arylations were recently studied com-
¨
putationally: Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras,
F.; Bruneu, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156–1157
(5) Ackermann, L. Synthesis 2006, 1557–1571
(6) Ackermann, L. Org. Lett. 2005, 7, 3123–3125
(7) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed.
2006, 45, 2619–2622
(8) For the use of complexes derived from N-heterocyclic carbenes, see:
.
.
.
.
´
refs 4 and 6: Ackermann, L.; Born, R.; Alvarez-Bercedo, P. Angew. Chem.,
Int. Ed. 2007, 46, 6364–6367
Yu, J.-Q.; Giri, R.; Chen, S. Org. Biomol. Chem. 2006, 4041–4047
.
.
10.1021/ol800773x CCC: $40.75
Published on Web 04/26/2008
2008 American Chemical Society

wondered whether the high catalytic efficacy of (HA)SPO
preligands originated from an assisted intramolecular proton
abstraction mechanism,11 illustrated as transition-state model
3 in Scheme 1. By analogy, a concerted cyclometalation-
All ruthenium-catalyzed direct arylations with organic
electrophiles were limited to the use of the highly polar
solvent N-methylpyrrolidinone (NMP).1a Consequently, we
focused on the use of significantly less polar toluene as
solvent (Table 1). As expected, no reaction occurred in
Scheme 1. Cooperative Metalation-Deprotonation
Table 1. Ruthenium-Catalyzed Direct Arylation of Triazole 5a
in PhMea
entry
cocatalyst
HIPrClb
isolated yield (%)
deprotonation process should be also accessible through the
use of substoichiometric amounts of carboxylates12 via
transition state 4. Consequently, we probed the use of acids
as cocatalysts in ruthenium-catalyzed direct arylations with
aryl (pseudo)halides13 as electrophiles.
1
2
3
4
5
6
7
8
9
9
20
85
85
66
69
50
93
89
b
PPh3
(1-Ad)2P(O)Hb
(1-Ad)CO2Hc
t-BuCO2Hc
Methodologies for copper-catalyzed regioselective syn-
theses of 1,2,3-triazoles 514 recently enabled their widespread
applications in various research areas, ranging from bioor-
ganic chemistry to material sciences.15 Therefore, we set out
to probe this valuable heterocyclic scaffold in novel ruthenium-
catalyzed direct arylations.
i-PrCO2Hc
(PhO)2P(O)OHc
MesCO2Hc
10
MesCO2Hb
a Reaction conditions: [RuCl2(p-cymene)]2 (2.5 mol %), cocatalyst
(10.0-30.0 mol %), K2CO3 (1.0 mmol), 5a (0.50 mmol), 6a (0.75 mmol),
PhMe (2 mL), 120 °C, 22 h. b 10.0 mol %. c 30 mol %. HIPrCl ) N,N′-
bis-(2,6-diisopropyl phenyl)imidazolium chloride.
(9) For the use of PPh3 as ligand in ruthenium-catalyzed direct arylations
with aryl bromides in NMP, see: (a) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue,
Y. J. Org. Chem. 2005, 70, 3113–3119. (b) Oi, S; Sakai, K.; Inoue, Y.
Org. Lett. 2005, 7, 4009–4011, and references cited therein. See also: (c)
Ackermann, L.; Althammer, A.; Born, R. Synlett 2007, 2833–2836.
(10) (a) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.; Hilton,
S. T.; Russell, R. D. Dalton Trans. 2003, 4132–4138. (b) For previous work
on ortho-metalations of functionalized arenes, see: Fernandez, S.; Pfeffer,
M.; Ritleng, V.; Sirlin, C. Organometallics 1999, 18, 2390–2394, and
references cited therein.
toluene16 in the absence of an additive (entry 1). Various
N-heterocyclic carbene precursors4,8 or phosphines9 failed
to provide satisfactory results as well (entries 2, and 3).
On the contrary, an efficient ruthenium-catalyzed direct
arylation of triazole 5a was achieved with air-stable SPO
(1-Ad)2P(O)H6 as preligand (entry 4). Thus, triazole 7a was
exclusively formed with a regioselectivity that is comple-
mentary to the one observed in palladium-catalyzed17 direct
arylations of the heterocyclic moiety in 1,2,3-triazoles.
Remarkably, carboxylic (entries 5-7) or phosphoric acids
(entry 8) enabled efficient C-H bond functionalizations of
triazole 5a in toluene as well. Among a variety of cocatalysts,
aromatic sterically hindered carboxylic acid MesCO2H
proved superior (entry 9), thus allowing for a reduction of
cocatalyst loading (entry 10).
With a highly active catalytic system in hand, we probed
its scope in direct arylations of 1,2,3-triazoles 5 employing
apolar toluene as solvent (Table 2).18 A variety of function-
alized electron-poor (entries 1-5) as well as electron-rich
(entries 6, and 7) aryl bromides was converted with high
efficacy. Additionally, a heteroaryl bromide enabled the
chemo- and regioselective preparation of triazole 7i with
excellent isolated yield (entry 8).
(11) Cooperative mechanisms were previously proposed for transition
metal-catalyzed C-H bond functionalizations: (a) Ryabov, A. D Chem.
ReV. 1990, 90, 403–424. (b) Davies, D. L.; Donald, S. M. A. Macgregor,
S. A. J. Am. Chem. Soc. 2005, 127, 13754–13755. (c) Tenn, W. J., III;
Young, K. J. H.; Bhalla, G.; Oxgaard, J.; Goddard, W. A., III; Periana, R.
A J. Am. Chem. Soc. 2005, 127, 14172–14173. (d) Feng, Y.; Lail, M.;
Barakat, K. A.; Cundari, T. R.; Gunnoe, T. B.; Petersen, J. L. J. Am. Chem.
Soc. 2005, 127, 14174–14175. (e) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066–1067.
(f) Feng, Y.; Lail, M.; Foley, N. A.; Gunnoe, T. B.; Barakat, K. A.; Cundari,
T. R.; Petersen, J. L. J. Am. Chem. Soc. 2006, 128, 7982–7994. (g) Tenn,
W. J., III; Young, K. J. H.; Oxgaard, J.; Nielsen, R. J.; Goddard, W. A.,
III; Periana, R. A. Organometallics 2006, 25, 5173–5175. (h) Oxgaard, J.;
Tenn, W. J., III; Nielsen, R. J.; Periana, R. A.; Goddard, W. A., III
Organometallics 2007, 26, 1565–1567. (i) Garcia-Cuadrado, D.; de Men-
doza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. J. Am. Chem.
Soc. 2007, 129, 6880–6886. (j) Pascual, S.; de Mendoza, P.; Echavarren,
A. M. Org. Biomol. Chem. 2007, 2727–2734.
(12) Pivalic acid was used in highly efficient palladium-catalyzed direct
arylations: (a) Lafrance, M.; Fagnou, K J. Am. Chem. Soc. 2006, 128,
16496–16497. (b) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem.
Soc. 2007, 129, 14570–14571.
(13) For ruthenium-catalyzed direct arylations and alkenylations with
organometallic reagents, see: Ueno, S.; Chatani, N.; Kakiuchi, F. J. Org.
Chem. 2007, 72, 3600–3602, and references cited therein.
(14) (a) Huisgen, R. Angew. Chem. 1963, 75, 604–637. (b) Rostovtsev,
V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596–2599. (c) Tornoe, C. W.; Christensen, C.; Meldal, M. J.
Org. Chem. 2002, 67, 3057–3064.
(16) Under otherwise identical reaction conditions, triazole 7a was only
isolated in 22% yield when NMP was used as solvent.
(15) Selected recent reviews (a) Nandivada, H.; Jiang, X.; Lahann, J.
AdV. Mater. 2007, 19, 2197–2208. (b) Angell, Y. L.; Burgess, K. Chem.
Soc. ReV. 2007, 36, 1674–1689. (c) Lutz, J.-F. Angew. Chem., Int. Ed. 2007,
46, 1018–1025.
(17) (a) Ackermann, L.; Vicente, R.; Born, R. AdV. Synth. Catal. 2008,
350, 741–748. (b) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.; Gevorgyan,
V. Org. Lett. 2007, 9, 2333–2336. (c) Iwasaki, M.; Yorimitsu, H.; Oshima,
K. Chem. Asian J. 2007, 2, 1430–1435.
2300
Org. Lett., Vol. 10, No. 11, 2008

Table 2. Ruthenium-Catalyzed Direct Arylations of Triazoles 5a
Table 3. Scope of Ruthenium-Catalyzed Direct Arylationsa
a Reaction conditions: 5 (0.50 mmol), 6 (0.75 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), MesCO2H (30.0 mol %), K2CO3 (2.0 equiv), PhMe
(2 mL), 120 °C, 16-20 h; yields of isolated product.
Importantly, direct arylations with MesCO2H as cocatalyst
were not restricted to triazoles as pronucleophiles but proved
broadly applicable (Table 3). Hence, oxazolines (entries
1-10), pyridines (entries 11-13, and 16), and pyrazoles
(entries 14, and 15) were directly arylated in toluene as
solvent. C-H bond functionalizations with aryl bromides
as electrophiles could be conveniently performed at reaction
a Reaction conditions: 8 (0.50 mmol), 6 (0.75 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), MesCO2H (30.0 mol %), K2CO3 (1.00 mmol), PhMe
(2 mL), 120 °C, 16-20 h; yields of isolated product. [b] 100 °C. [c] 80 °C.
temperatures as low as 80-100 °C (entries 3, 4, and 7).
Readily available, but less reactive aryl chlorides (entries 5,
Org. Lett., Vol. 10, No. 11, 2008
2301

8, and 12) or tosylates (entries 6, 9, and 13) provided the
desired products with comparably high yields. Finally, the
use of an alkene allowed for the diastereoselective formation
of trisubstituted alkene 9i (entry 16).
In conclusion, mechanistic considerations on the working
mode of ruthenium-catalyzed direct arylations resulted in the
development of a highly active catalyst with ample scope.
Thus, substoichiometric amounts of carboxylic acid
MesCO2H enabled ruthenium-catalyzed direct arylations with
organic halides to be performed efficiently in an apolar
solvent. With respect to both electrophiles and pronucleo-
philes, the catalytic system displayed an unparalleled broad
scope, which allowed inter alia for the use of triazoles in
ruthenium-catalyzed direct arylations.
Acknowledgment. Support by the Spanish Ministerio de
Educacio´n y Ciencia, the Alexander-von-Humboldt founda-
tion (fellowships to R.V.), the DFG, the Fonds der Chemis-
chen Industrie, and Sanofi-Aventis (Frankfurt) is gratefully
acknowledged.
(18) Representative Procedure (Table 1, Entry 9). A suspension of
[RuCl2(p-cymene)]2 (7.7 mg, 0.012 mmol, 2.5 mol %), MesCO2H (25 mg,
0.15 mmol, 30 mol %), K2CO3 (138 mg, 1.00 mmol), 5a (108 mg, 0.50
mmol), and 6a (140 mg, 0.75 mmol) in PhMe (2 mL) was stirred under N2
for 18 h at 120 °C. Thereafter, Et2O (75 mL) and H2O (75 mL) were added
to the reaction mixture at ambient temperature. The separated aqueous phase
was extracted with Et2O (2 × 75 mL). The combined organic layers were
washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and
concentrated in vacuum. The remaining residue was purified by column
chromatography on silica gel (n-hexane/EtOAc 3:1) to yield 7a as a colorless
oil (149 mg, 93%).
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.
OL800773X
2302
Org. Lett., Vol. 10, No. 11, 2008