Nitrogen-directed ortho-selective homocoupling of aromatic compounds catalyzed by ruthenium complexes

Article abstract of DOI:10.1021/ol800439e

A nitrogen-directed regioselective homocoupling reaction of aromatic compounds has been found to be catalyzed by a ruthenium complex in the presence of methallyl acetate as a hydrogen scavenger.

Full text of DOI:10.1021/ol800439e

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1823-1826
Nitrogen-Directed Ortho-Selective
Homocoupling of Aromatic Compounds
Catalyzed by Ruthenium Complexes
Shuichi Oi,* Hitoshi Sato, Shoko Sugawara, and Yoshio Inoue*
Department of Biomolecular Engineering, Graduate School of Engineering,
Tohoku UniVersity, Sendai 980-8579, Japan
oishu@aporg.che.tohoku.ac.jp
Received February 27, 2008
ABSTRACT
A nitrogen-directed regioselective homocoupling reaction of aromatic compounds has been found to be catalyzed by a ruthenium complex in
the presence of methallyl acetate as a hydrogen scavenger.
Recently, C-H bond cleavage and C-C bond formation
between aromatic rings have gained significant attention.1
Among the several combinations of the aromatic compounds
for such direct coupling reactions, the coupling reaction
between two aromatic C-H bonds is the most desirable
transformation from the standpoint of simplicity, substrate
availability, and reduction of byproducts. However, inter-
molecular versions of such reactions are often limited due
to low conversions and/or lack of regioselectivity.2 A few
examples on the regioselective oxidative coupling reaction
have been reported, involving Cu-catalyzed coupling of
naphthols,3 Pd-catalyzed C-H homocoupling of thiophenes,4
and Pd-catalyzed C-H cross-coupling of naphthalene,5
benzofuranes,6 and indoles7 with simple arenes. The directing
group-assisted ortho-metalation of aromatic compounds is
one of the powerful solutions to the regioselectivity,8
resulting in ortho-selective C-C bond formation. Elegant
examples of such transformations were recently reported by
Sanford and co-workers, featuring a regioselective oxidative
homocoupling reaction of 2-arylpyridines9 and a cross-
coupling reaction of 2-arylpyridines with simple arenes10
using Pd catalysts. Our research, in contrast, focuses on Ru-
catalyzed ortho-selective direct coupling reactions of aromatic
compounds using substrates that possess coordinating func-
tional groups.11,12 In relation to our previous report on Ru-
catalyzed ortho-allylation of 2-arylpyridines with allyl ac-
(1) For recent reviews, see: (a) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. ReV. 2007, 36, 1173. (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichim. Acta 2007, 40, 35. (c) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. ReV. 2007, 107, 174. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (e) Godula, K.; Sames, D. Science 2006, 312, 67.
(4) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126,
5074. (b) Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori,
A.; Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128, 10930.
(5) Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25, 5973.
(6) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B.
Org. Lett. 2007, 9, 3137.
(2) (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879. (b)
Burton, H. A.; Kozhevnikov, I. V. J. Mol. Catal. A 2002, 185, 285. (c)
Yokota, T.; Sakaguchi, S.; Ishii, Y. AdV. Synth. Catal. 2002, 344, 849. (d)
Ackerman, L. J.; Sadighi, J. P.; Kurtz, D. M.; Labinger, J. A.; Bercaw,
J. E. Organometallics 2003, 22, 3884.
(7) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.
(8) Review: Omae, I. Coord. Chem. ReV. 2004, 248, 995.
(9) Hull, K. L.; Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 14047.
(3) (a) Li, X. L.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J. M.;
Kozlowski, M. C. J. Org. Chem. 2003, 68, 5500. A general review, see:
Whiting, D. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Pattenden, G., Eds.; Pergamon: Oxford, 1991; Vol. 3p 659.
(10) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
10.1021/ol800439e CCC: $40.75
Published on Web 04/01/2008
2008 American Chemical Society

etates,13 we have found that, when 2-aryloxazolines were
employed as the substrates, substantial amounts of homo-
coupling products were formed along with the expected
allylated products. Herein, we report that the homocoupling
reaction of 2-aryloxazilines predominantly proceeded by
choosing an appropriate allyl acetate, in the presence of Ru
catalyst. In addition to 2-aryloxazolines, our reaction was
applicable to substrates that possess nitrogen-containing
functional groups, such as 2-arylimidazoles, -oxazoles, and
-thiazoles and 1-arylpyrazoles and -indazoles. Furthermore,
insights into the reaction mechanism involving a ruthe-
nium(IV) intermediate are also presented.
As shown in Scheme 1, 2-tolyl-2-oxazoline (1a) was
treated with allyl acetates 2a-d in the presence of a base
(K2CO3) and a catalytic amount of [RuCl2(cod)]n (5 mol %
based on Ru) with PPh3 (10 mol %) in xylene at 120 °C for
20 h. In the case of 2a, homocoupling (ortho position)
product 3a was obtained in 39% yield together with a mixture
of isomers of allylated products. Consequently, the conditions
that promote the formation of the homocoupling products
were explored. Our results show that the structure of the allyl
acetates greatly affected the yield of 3a; methallyl acetate
(2b) resulted in the predominant formation of 3a in 79%
yield, whereas crotyl acetate (2c) and 3-buten-2-yl acetate
(2d) resulted in moderate formation of 3a.
substituent (1h and i) selectively underwent the coupling
reaction at the 6-position to avoid the steric hindrance of
the meta substituent (entries 8 and 9). 2-(1-Naphthyl)-2-
oxazoline (1j) also underwent the coupling reaction to afford
the product 3j in a good yield of 82% (entry 10). On the
other hand, the reaction of 2-phenyl-2-oxazoline (1k), despite
the complete consumption of the substrate, did not form
the expected coupling product (entry 11). In this case, the
absence of the desired product can be attributed to the
formation of oligomers due to the extended coupling reac-
tions at both ortho positions. A series of reactions were then
carried out to examine the effect of the directing group. In
contrast to the unsuccessful reaction of 2-phenyl-2-oxazoline
(1k), the reaction of N-methyl-2-phenylimidazole (1l) se-
lectively gave homocoupling product 3l in 74% yield (entry
12). In this case, the methyl group of the imidazole ring
prevented the second coupling reaction at the alternate ortho
position. Similarly, N-methyl-(3-methylphenyl)imidazole
(1m), which corresponds to 1 h (entry 8), selectively afforded
coupling (6-position) product 3m in 76% yield (entry 13).
Other directing groups such as 2-thiazolyl (1n, entry 14),
2-oxazolyl (1o, entry 15), 1-pirazolyl (1p, entry 16), and
1-indazolyl groups (1q, entry 17) were also effective in the
present homocoupling reaction.
Several experiments were carried out to gain insight into
the reaction mechanism. As shown in Scheme 2, to confirm
the role of allyl acetate, the reaction was carried out using
ortho-deuterated 1b-d1 and 2-phenylallyl acetate (2e), result-
ing in a nearly quantitative yield of coupling product 3e and
deuterated R-methylstyrene (4-d1). Deuteration of the methyl
group of 4-d1 indicates that the C-O bond of 2e was cleaved
through the reaction, and two deuterium atoms of 1b-d1 were
introduced to the cleaved C-O bond.
Scheme 1
Scheme 2
The homocoupling of various substrates, in the presence
of 2b, was examined (Table 1). The yield of 3a increased to
83% by adding powdered molecular sieves 4 Å (entry 1).
Reactions of 2-aryl-2-oxazolines having an ortho substituent
(1a-g) proceeded smoothly to afford the corresponding
homocoupling products (3a-g) in good to excellent yields
(entries 1–7). Reactions of 2-aryl-2-oxazolines having a meta
(11) (a) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue,
Y. Org. Lett. 2001, 3, 2579. (b) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y.
Org. Lett. 2002, 4, 1783. (c) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J.
Org. Chem. 2005, 70, 3113. (d) Oi, S.; Sakai, K.; Inoue, Y. Org. Lett. 2005,
7, 4009.
Next, as shown in Scheme 3, ruthenacycle complex 5,
which was prepared by the reaction between 1b and [(η6-
C6H6)RuCl2]2,14 was utilized as an intermediate in the
stoichiometric coupling reaction with 1a. Although the re-
(12) Related Ru-catalyzed ortho-arylation: (a) Ackermann, L Org. Lett.
2005, 7, 3123. (b) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem.,
Int. Ed. 2006, 45, 2619. (c) Ackermann, L.; Althammer, A. Born, R. Synlett
2007, 2833. (d) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani,
N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858. (e) Ozdemir, I.; Demir,
S.; Cetinkaya, B.; Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H.
J. Am. Chem. Soc. 2008, 130, 1156.
(14) (a) Fernandez, S.; Pfeffer, M.; Ritleng, V.; Sirlin, C. Organome-
tallics 1999, 18, 2390. (b) Ryabov, A. D.; Le Lagadec, R.; Estevez, H.;
Toscano, R. A.; Hernandez, S.; Alexandrova, L.; Kurova, V. S.; Fischer,
A.; Sirlin, C.; Pfeffer, M. Inorg. Chem. 2005, 44, 1626.
(13) Oi, S.; Tanaka, Y.; Inoue, Y. Organometallics 2006, 25, 4773.
1824
Org. Lett., Vol. 10, No. 9, 2008

Table 1. Nitrogen-Directed Homocoupling of Aromatic Compounds 1 Catalyzed by a Ruthenium Complexa
a Reactions were carried out using 0.5 mmol of 1, 1.5 mmol of 2b, 1.0 mmol of K2CO3, 50 mg of powdered molecular sieves 4 Å, 0.025 mmol (based
on Ru) of [RuCl2(cod)]n, and 0.05 mmol of PPh3 in 1 mL of xylene at 120 °C for 20 h.
action between 5 (0.1 mmol) and 1a (0.1 mmol) in the
presence of PPh3 and K2CO3 in xylene at 120 °C for 20 h
did not afford any coupling products, addition of methallyl
acetate (2b, 0.2 mmol) to the reaction mixture afforded the
Org. Lett., Vol. 10, No. 9, 2008
1825

Scheme 3
Scheme 4
cross-coupling product 3ab in 54% yield, clearly indicating
that 5 first reacted with 2b and then with 1a to give the
coupling product. We also examined the stoichiometric
reaction of complex 5 with 2b in the absence of 1a, which
resulted in the formation of an allylated product of 1b. It
can be assumed that a η1- or η3-allyl complex would be
formed by oxidative addition of methallyl acetate to complex
5 and then reductive elimination would give the allylated
product.
Based on these results, a reaction mechanism as shown
in Scheme 4 can be proposed. The nitrogen-directed ruth-
enation of 1 with a ruthenium(II) complex gives a ruthena-
cycle complex 6. For this step, a proton abstraction mech-
anism was proposed by Dixneuf and Maseras from DFT
calculations.12e The ruthenacycle complex 6 would then
undergo oxidative addition with 2 to give an η1- or
η3-allylruthenium(IV) intermediate 7. A second ruthenation
of 1 with 7, while releasing isobutene, would give a
diarylruthenium intermediate 8. Although details are not clear
at present, the ortho hydrogen atom of 1 would be transferred
to methallyl group on the ruthenium center in this step. The
formation of 4-d1 in the deuterium label experiment (Scheme
2) also supports such transformations. The homocoupling
product 3 is then formed through reductive elimination from
8, with the simultaneous regeneration of the initial ruthe-
nium(II) complex.
groups, the present reaction provides a useful and powerful
method for the synthesis of 2,2′-disubstituted-1,1′-biaryls.
Further investigations to expand the scope of the reaction
are currently underway.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT), Japan.
In conclusion, we have successfully demonstrated the
nitrogen-directed oxidative coupling reaction of aromatic
compounds catalyzed by ruthenium complexes, which shows
complete regioselectivity and wide applicability. As the
oxazolinyl group can be derived to a variety of functional
Supporting Information Available: Experimental details
and analytical and spectral data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL800439E
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Org. Lett., Vol. 10, No. 9, 2008