Phosphine oxides as preligands in ruthenium-catalyzed arylations via C-H bond functionalization using aryl chlorides

Article abstract of DOI:10.1021/ol051216e

(Chemical Equation Presented) The use of air-stable, electron-rich phosphine oxides as preligands allows for unprecedented general ruthenium-catalyzed arylation reactions of pyridines and imines through C-H-bond activation using aryl chlorides. The catalytic system derived from a sterically hindered adamantyl-substituted phosphine oxide proves highly efficient and tolerates a number of important functional groups.

Full text of DOI:10.1021/ol051216e

ORGANIC
LETTERS
2
005
Vol. 7, No. 14
123-3125
Phosphine Oxides as Preligands in
Ruthenium-Catalyzed Arylations via C
Bond Functionalization Using Aryl
Chlorides
3
−H
Lutz Ackermann*
Department of Chemistry and Biochemistry, Ludwig-Maximilians-UniVersit a¨ t M u¨ nchen,
Butenandtstrasse 5-13, D-81377 M u¨ nchen, Germany
Lutz.Ackermann@cup.uni-muenchen.de
Received May 24, 2005
ABSTRACT
The use of air-stable, electron-rich phosphine oxides as preligands allows for unprecedented general ruthenium-catalyzed arylation reactions
of pyridines and imines through C H-bond activation using aryl chlorides. The catalytic system derived from a sterically hindered adamantyl-
substituted phosphine oxide proves highly efficient and tolerates a number of important functional groups.
−
Transition-metal-catalyzed cross-coupling reactions of or-
ganometallic reagents such as organoboron or -tin compounds
with aryl halides constitute reliable tools for the syntheses
contrary, have only rarely been used. Particularly, a general
5
,7
protocol for ruthenium-catalyzed arylations employing
inexpensive, but less reactive, aryl chlorides has proven
1
8
of biaryls. However, the organometallic starting materials
elusive.
are frequently not commercially available, are expensive, and
give rise to undesired byproducts. These problems can
potentially be circumvented by developing protocols for the
direct cross-coupling of organic compounds via C-H-bond
functionalization. Comparably few examples of such inter-
Recently, Sames et al. showed elegantly that an anionic
phosphido ligand, formed in-situ from PPh through C-P-
3
(3) Palladium-catalysis: (a) Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1740-1742. (b) Terao,
Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001,
123, 10407-10408. (c) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura,
M.; Nomura, M. J. Org. Chem. 2003, 68, 5236-5243. (d) Zaitsev, V. G.;
Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156-4157; and references
therein.
2
molecular transformations have been described. Methodolo-
gies for both the directed ortho-arylation of benzene
3-5
derivatives and the regioselective arylation of heterocyclic
6
(4) Rhodium-catalysis: (a) Bedford, R. B.; Limmert, M. E. J. Org. Chem.
compounds using aryl iodides and bromides have been
2
003, 68, 8669-8682. (b) Oi, S.; Watanabe, S.-I.; Fukita, S.; Inoue, Y.
Tetrahedron Lett. 2003, 44, 8665-8668; and references therein.
5) Ruthenium-catalysis: (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki,
developed. More readily available aryl chlorides, on the
(
(
1) de Meijere, A., Diederich, F., Eds. Metal-catalyzed Cross-Coupling
N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579-2581. (b) Oi, S.; Ogino,
Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783-1785. (c) Kakiuchi, F.;
Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698-
1699. (d) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70,
3113-3119.
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(
2) (a) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077-
1
2
101. (b) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 212-
37.
1
0.1021/ol051216e CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/03/2005

Table 1. C-H Bond Activation of Pyridine 1 Employing Aryl
Chloride 2aa
Table 2. Scope of Directed C-H Bond Activation of Pyridine
1
a
a
Reaction conditions: 1 (1.0 mmol), 2a (2.2 mmol), K2CO3 (3.0 mmol),
[
2
2
RuCl2(p-cymene)]2 (2.5 mol %), ligand (10 mol %), NMP (2 mL); Ar )
b
c
,6-(i-Pr)2C6H3. Determined by GC-analysis. NMP (2 mL), H2O (1 mL),
d
0 h. 24 h.
bond cleavage, gives rise to the catalytically active species
in a ruthenium-catalyzed arylation of pyridine with iodo-
9
benzene. Anionic P-bonded ligands are also obtained by
10
reaction of air-stable phosphine oxides with transition-metal
complexes.11 Consequently, such preligands were probed
in ruthenium-catalyzed arylation reactions through C-H-
bond activation using aryl chlorides.
12
(6) Selected examples: (a) Okazawa, T.; Satoh, T.; Miura, M.; Nomura,
M. J. Am. Chem. Soc. 2002, 124, 5286-5287. (b) Mori, A.; Sekiguchi, A.;
Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T.
J. Am. Chem. Soc. 2003, 125, 1700-1701. (c) Gallagher, W.; Maleczka,
R. E. J. Org. Chem. 2003, 68, 6775-6779. (d) Sezen, B.; Sames, D. J.
Am. Chem. Soc. 2003, 125, 5274-5275. (e) Sezen, B.; Sames, D. Org.
Lett. 2003, 5, 3607-3610. (f) Lewis, J. C.; Wiedemann, S. H.; Bergman,
R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35-38. (g) Park, C.-H.; Ryabova,
V.; Seregin, I. V.; Sromek, A. W.; Gevorgyn, V. Org. Lett. 2004, 6, 1159-
a
Reaction conditions: 1 (1.0 mmol), 2 (2.2 mmol), K2CO3 (3.0 mmol),
[
RuCl2(p-cymene)]2 (2.5 mol %), 9 (10 mol %), NMP (2 mL), 120 °C.
On the outset of the studies a range of different ligands
were tested in the ruthenium-catalyzed directed arylation of
-phenylpyridine (1) using chlorobenzene (2a) (Table 1).
While N-heterocyclic carbene precursor 4
well as phosphine oxides 5, 6, 7, and 8 (entries 2-5)
enabled diarylation, the adamantyl-derivative 9 gave more
1
162. (h) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127, 5284-5285;
and references therein.
7) Kakiuchi, F.; Chatani, N. In Ruthenium in Organic Synthesis;
(
5a
2
Murahashi; S.-I., Ed.; Wiley-VCH: Weinheim 2004; pp 219-255.
1
3,14
(entry 1) as
(
(
8) For a single low-yielding example, see ref 5b.
9) Godula, K.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127,
1
5
12
16
3
648-3649.
10) Dubrovina, N. V.; B o¨ rner, A. Angew. Chem., Int. Ed. 2004, 43,
883-5886.
11) (a) Beaulieu, W. B.; Rauchfuss, T. B.; Roundhill, D. M. Inorg.
Chem. 1975, 14, 1732-1734. (b) Li, G. Y. J. Org. Chem. 2002, 67, 3643-
650. (c) For the synthesis of a related ruthenium complex, see: Chan, E.
(
5
(
(13) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(14) For studies on the use of in-situ generated carbene complexes from
this laboratory, see: (a) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem.
Commun. 2004, 2824-2825. (b) Ackermann, L. Org. Lett. 2005, 7, 439-
442.
(15) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem., Int. Ed. 2000,
39, 4605-4607.
3
Y. Y.; Zhang, Q.-F.; Sau, Y.-K.; Lo, S. M. F.; Sung, H. H. Y.; Williams,
I. D.; Haynes, R. K.; Leung, W.-H. Inorg. Chem. 2004, 43, 4921-4926.
(12) For the use of diaminophosphine oxides in Suzuki-reactions, see:
Ackermann, L.; Born, R. Angew. Chem., Int. Ed. 2005, 44, 2444-2447.
3124
Org. Lett., Vol. 7, No. 14, 2005

efficient catalysis (entries 6-8). Note that 9 is directly
accessible from inexpensive adamantane on a multigram
scale in two reaction steps. Reagent grade K CO was
2 3
Table 3. C-H Bond Functionalization with Aryl Chlorides 2a
1
7
employed as stoichiometric base without the need for prior
drying, proving the tolerance of the catalytic system to the
presence of water (entry 7).
The optimized catalyst allowed for quantitative conversion
of both electron-poor (Table 2, entries 2-4) and electron-
rich aryl chlorides (entry 5) with good to excellent isolated
yields. Importantly, a wide variety of important functional
groups, such as an ester (entry 2), a cyano group (entry 3),
and an enolizable ketone (entry 4), were tolerated by the
catalytic system. However, nitro-substituted aryl chloride 2f
was not converted.
Given the practical importance of imines for organic
synthesis, phosphine oxide 9 was probed as preligand in the
ruthenium-catalyzed functionalization of differently substi-
5
b
tuted ketimines with aryl chlorides (Table 3). Subjection
of ketimines 10 and aryl chlorides 2 to the reaction conditions
yielded selectively the monoarylated products. The corre-
sponding ketones were isolated after hydrolysis in high
yields. Again, electron-poor (entries 1-6) as well as electron-
rich aryl chlorides (entries 7-10) could be employed. Not
only meta- but also ortho-substituted aryl chlorides were
efficiently converted (entries 6 and 10). The functional group
tolerance of the catalytic system constitutes a valuable asset
of the present protocol.
In summary, the use of air-stable adamantyl-substituted
secondary phosphine oxide 9 as preligand enables unprec-
edented ruthenium-catalyzed diarylation of pyridines and
mono-arylation of imines via C-H-bond functionalization
using diversely substituted aryl chlorides. The catalytic
system shows good tolerance of functional groups, such as
enolizable ketones, nitriles, and esters. Mechanistic studies
as well as further applications of the present catalytic system
are ongoing and will be reported in due course.
Acknowledgment. Support by Professor Paul Knochel,
the DFG (Emmy Noether-Programm), the Fonds der Che-
mischen Industrie, and the Ludwig-Maximilians-Universit a¨ t
is gratefully acknowledged.
Supporting Information Available: Experimental pro-
1
13
cedures, characterization data, and H and C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051216E
(
16) Examples for the use in cross-coupling reactions: (a) Li, G. Y.
a
Reaction conditions: 10 (1.0 mmol), 2 (1.2-2.2 mmol), K2CO3 (2.0-
Angew. Chem., Int. Ed. 2001, 40, 1513-1516. (b) Wolf, C.; Lerebours, R.
Org. Lett. 2004, 6, 1147-1150; and references therein.
(17) Goerlich, J. R.; Fischer, A.; Jonas, P. G.; Schmutzler, R. Z.
Naturforsch. 1994, 49b, 801-811.
3
1
%
.0 mmol), [RuCl2(p-cymene)]2 (2.5 mol %), 9 (10 mol %), NMP (2 mL),
20 °C, 3 Å mol-sieves, Ar′ ) 4-MeOC6H4. [RuCl2(p-cymene)]2 (5.0 mol
), 9 (20 mol %).
b
Org. Lett., Vol. 7, No. 14, 2005
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