Control of product selectivity by a styrene additive in ruthenium-catalyzed C-H arylation

Article abstract of DOI:10.1021/ol102325f

A unique effect of styrene additive on product selectivity was observed for RuH₂(CO)(PPh₃)₃-catalyzed C-H arylation of acetophenone derivatives bearing two ortho C-H bonds. Without styrene, the C-H arylation with arylboronates gives diarylation products as the major products throughout the reaction, but the use of styrene as an additive switches the product selectivity and leads to selective formation of monoarylation products.

Full text of DOI:10.1021/ol102325f

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5318-5321
Control of Product Selectivity by a
Styrene Additive in Ruthenium-Catalyzed
C-H Arylation
Shun Hiroshima, Daiki Matsumura, Takuya Kochi, and Fumitoshi Kakiuchi*
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity, 3-14-1
Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
kakiuchi@chem.keio.ac.jp
Received September 27, 2010
ABSTRACT
A unique effect of styrene additive on product selectivity was observed for RuH2(CO)(PPh3)3-catalyzed C-H arylation of acetophenone derivatives
bearing two ortho C-H bonds. Without styrene, the C-H arylation with arylboronates gives diarylation products as the major products
throughout the reaction, but the use of styrene as an additive switches the product selectivity and leads to selective formation of monoarylation
products.
Direct catalytic arylation of aromatic C-H bonds has been
one of the most intensively studied areas in organometallic
chemistry in recent years1 because it provides convenient
routes to biaryl frameworks, found in many biologically
active molecules2 and organic electronic and photonic
materials.3 Due to the ubiquitous nature of C-H bonds,
achievement of high regioselectivity in arylation is important
as a practical tool in synthesis. Chelation-assisted control of
regiochemistry in C-H bond cleavage has been employed
to achieve high ortho selectivity in many C-H functional-
izations,4 and a number of arylation methods have been
developed for arenes with various directing groups.1,4
One of the challenges in the chelation-assisted C-H
arylations is to prepare both mono- and diarylation products
selectively from substrates with two ortho hydrogens. When
the second arylation is not so fast, the product selectivity
can be controlled by changing the stoichiometry or the
reaction time.5 The monoarylation product should be obtained
by reducing the amount of the arylating agent or the reaction
time, while the diarylation product should become the major
product by applying more forcing reaction conditions.
However, in some C-H arylations, the second arylation is
so fast that the diarylation products start to form even at
low conversion of the substrate. To obtain the monoarylation
(1) Reviews: (a) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219,
211. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
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2009. (d) Chiusoli, G. P.; Catellani, M.; Costa, M.; Motti, E.; Della Ca′,
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Directed Metallation; Chatani, N., Ed.; Topics in Organometallic Chemistry;
Springer: Berlin, 2007; Vol. 24.
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1747. (b) Schmidt-Mende, L.; Fechtenko¨tter, A.; Mu¨llen, K.; Moons, E.;
Friend, R. H.; MacKenzie, J. D. Science 2001, 293, 1119. (c) Li, C.; Liu,
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Int. Ed. 1997, 36, 1740. (b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.;
Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (c) Oi, S.; Funayama, R.;
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C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837.
10.1021/ol102325f  2010 American Chemical Society
Published on Web 10/27/2010

products in these cases, approaches other than the adjustment
of the stoichiometry or the reaction time need to be applied.
Two strategies have been reported to form monoarylation
products selectively using the catalyst systems where fast
generation of the diarylation products occurs (Figure 1).6,7
For example, when the reaction of acetophenone (1a) with
an equimolar amount of phenylboronate 2a was performed
with 2.5 mol % of RuH2(CO)(PPh3)3 (3) in refluxing pina-
colone8b for 2 h, mono- and diarylation products, 4aa and
5aa, were obtained in 12% and 58% yields, respectively,
based on 2a10 (Table 1, entry 1). Increasing the amount of
Table 1. Effect of Styrene (6) as an Additive on the Product
Selectivitya
yields (based on 2a)b
entry
1a
6
4aa
5aa
1
2
3
4
5
6
7
8
1 mmol 0 mmol
3 mmol 0 mmol
1 mmol 1 mmol
3 mmol 1 mmol
5 mmol 1 mmol
3 mmol 0.1 mmol 34%
3 mmol 3 mmol
3 mmol 5 mmol
12%
15%
28%
58%
64%
16%
56% (0.56 mmol) 17% (0.09 mmol)
58%
Figure 1. Strategies to control mono-/diarylation selectivity other
16%
58%
8%
than changing the stoichiometry or the reaction time.
55%
55%
9%
One is the use of a different directing group to slow the
second arylation (Figure 1a),6 while the other is to employ
a different leaving group to control the reactivity of the
arylating agent (Figure 1b).7 In these reactions, the monoary-
lation products were obtained essentially by changing the
substrates. We envisioned that, if simple additives can control
the mono-/diarylation product selectivity, monoarylation
products would be selectively obtained without altering the
structures of the substrates (Figure 1c).
In this paper, we describe that the use of styrene as an
additive in ruthenium-catalyzed arylation of aromatic
ketones8b effectively switches the product selectivity. Monoary-
lation products are obtained as major products7a,9 in the
presence of styrene, while diarylation occurs rapidly without
the additive.
a Reaction conditions: 1a (1-5 mmol), 2a (1 mmol), 6 (0.1-5 mmol),
pinacolone (1 mL), reflux, 2 h. b GC yields based on 2a.
1a to 3 equiv had little effect on the mono-/diarylation
product ratio (entry 2).
Styrene was then examined as an additive for the C-H
arylation. We speculated that styrene would slow the second
C-H functionalization based on the result that the C-H
alkylation of 1a with styrene catalyzed by 3 afforded only
the monoalkylation product, while the reaction with many
other olefins such as vinylsilanes also provides dialkylation
products.11 In fact, when the C-H arylation under the
conditions for entry 1 of Table 1 was carried out in the
presence of 1 equiv of styrene (6), reversal of the mono-/
diarylation selectivity was observed and 4aa became the
major product (Table 1, entry 3). In this case, the use of 3
equiv of 1a improved the mono-/diarylation product ratio,
and 4aa was obtained in 56% yield (entry 4). Further increase
of 1a to 5 equiv had little impact on the product yields (entry
5). Reduction of the amount of 6 to 10 mol % resulted in
significant lowering of the mono- to diarylation selectivity
(entry 6). On the other hand, an increase of the amount of 6
to 3 or 5 equiv did not improve the yield of 4aa (entries 7
and 8). GC analyses of the reaction mixtures obtained using
6 showed that the coupling of 1a with 6 proceeded as a side
reaction. This observation suggests that an excess amount
of 6 is necessary to maintain the presence of 6 during the
Previously, our group reported a ruthenium-catalyzed C-H
arylation of aromatic ketones with organoboronates.8 In this
reaction, aryl groups are introduced selectively at the ortho
positions to the acyl group, but when acetophenone was used
as a substrate, diarylation products are formed as major
products throughout the reaction, even at low conversion.
(6) (a) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y. Org. Lett. 2002, 4, 1783.
(b) Oi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113.
(c) Oi, S.; Sasamoto, H.; Funayama, R.; Inoue, Y. Chem. Lett. 2008, 37,
994. (d) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010,
49, 1275
.
¨
(7) (a) Gu¨rbu¨z, N.; Ozdemir, I.; C¸ etinkaya, B. Tetrahedron Lett. 2005,
46, 2273. (b) Ackermann, L. Org. Lett. 2005, 7, 3123. (c) Ackermann, L.;
Althammer, A.; Born, R. Angew. Chem., Int. Ed. 2006, 45, 2619. (d)
Ackermann, L.; Born, R.; Vicente, R. ChemSusChem 2009, 3, 546
.
(8) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem.
Soc. 2003, 125, 1698. (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N.
J. Am. Chem. Soc. 2005, 127, 5936.
(10) Yields of 4 and 5 described in this paper are calculated based on
the amounts of arylboronates 2, which were used as limiting reagents.
(11) (a) Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn. 1995, 68, 62. (b) Kakiuchi,
F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(9) For synthesis of monoarylated aromatic ketones by ortho C-H
arylation, see: Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am. Chem.
Soc. 2010, 132, 8569. See also ref 7a.
Org. Lett., Vol. 12, No. 22, 2010
5319

reaction, but a too large excess of 6 may promote the C-H/
olefin coupling to give the alkylation product.12 From these
results, we decided to conduct further examination under the
reaction conditions for entry 4.
to the reaction with no additive (entries 13 and 14).
Therefore, simple styrene (6) was found to be the best
additive among the olefins screened and used for the
following investigation.
Then the reaction of 1a was performed with several
arylboronates, and in all cases, the product selectivity was
switched by the addition of 6 to give monoarylation product
4a as major products (Table 3, entries 1-8). Whether 6 was
Investigation of the olefin additive was next performed
(Table 2). First, styrenes with several electron-donating and
Table 2. Screening of Olefin Additivesa
Table 3. Screenings of Acetophenones and Arylboronatesa
a Reaction conditions: 1a (3 mmol), 2a (1 mmol), additive (1 mmol),
pinacolone (1 mL), reflux, 2 h. b GC yields based on 2a. c (Yield of 4aa)/
(yield of 4aa + 5aa) × 100%.
-withdrawing groups at the 2- or 4-position of the benzene
ring were used as additives for the reaction of 1a with 2a
(entries 1-8). In general, comparable results to that with 6
were obtained, but in most cases, slight lowering of the
selectivity or the yield was observed. Only with CF3-
substituted styrenes, the arylation proceeded with similar
selectivity, but the yield of 4aa was somewhat decreased
(entries 4 and 8). The use of a more sterically hindered olefin,
2,4,6-trimethylstyrene, gave a similar result to that obtained
without any additive (entry 9). Introduction of substituents
on the vinyl group of styrene also considerably reduced the
selectivity to 4aa (entries 10-12). Aliphatic olefins such as
vinylcyclohexane and cyclohexene showed selectivity similar
a Reaction conditions: 1 (3 mmol), 2 (1 mmol), 6 (0 or 1 mmol),
pinacolone (1 mL), reflux, 2 h. b GC yields based on 2. Values in parentheses
are isolated yields. c Not determined.
added or not, the use of arylboronates bearing electron-
donating groups such as -NMe2 and -OMe groups offered
high combined yields of 4a and 5a (entries 1-4). In the
presence of 6, monoarylation occurred mainly, and 4ab and
(12) On the basis of GC analyses, more than 10% of 6 was used for the
C-H alkylation for entries 3-8 of Table 1.
5320
Org. Lett., Vol. 12, No. 22, 2010

4ac were isolated in 71% and 62% yields, respectively
(entries 1 and 3). Arylboronates with electron-withdrawing
groups gave relatively lower yields, probably due to the
inherent instability toward deboronation (entries 5-8).
The selective monoarylation was also conducted for
substituted acetophenones (entries 9 and 10). The coupling
reactions of p-methoxy- (1b) and p-tert-butylacetophenones
(1c) with arylboronate 2b afforded monoarylation products
in 65% and 83% yields.
To investigate the role of 6, a deuterium-labeling study
was carried out using acetophenone-d5 (1a-d5) (Scheme 1).
Figure 2. Proposed role of styrene (6) in determining the mono-/
diarylation selectivity.
Scheme 1. Deuterium-Labeling Experiment Using 1a-d5
of 6, the following oxidative addition is considered to be
faster than the ketone dissociation, based on the fact that
diarylation products are formed more than monoarylation
products throughout the reaction.13 However, the presence
of 6 on the metal would retard the C-H oxidative addition
due to the reduced electron density of the ruthenium center.
As a result, the immediate oxidative addition may become
slower than the dissociation of the ketone to provide the
monoarylation product mainly.
In summary, the mono-/diarylation selectivitity in a
ruthenium-catalyzed arylation of aromatic ketone was con-
trolled by the use of styrene as an additive. In the presence
of styrene, monoarylation products are formed as major
products, while without the additive, diarylation occurs
mainly throughout the reaction. Particularly, the reaction of
relatively electron-rich arylboronates provided the monoary-
lation products in high yields.
When the coupling of 1a-d5 with arylboronate 2a using 6 in
refluxing pinacolone was carried out for 5 min, mono- and
diarylation products were obtained in 40% and 11% yields,
and partial H/D exchange between 1a-d5 and 6 was observed.
The 2H NMR spectrum of the mixture showed partial
deuteration of three vinylic protons of 6. Incorporation of
protons at the ortho positions of acetophenone was also
Acknowledgment. This work was supported, in part, by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology (MEXT),
Japan, and by The Science Research Promotion Fund.
1
indicated by H NMR analysis. This result suggests the
presence of an intermediate in which both 1a and 6 are
present on a ruthenium center and an equilibrium where C-H
oxidative addition, hydroruthenation of 6, and ꢀ-hydride
elimination occur rapidly.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
Although the role of 6 is still unclear, a possible explana-
tion is shown in Figure 2. Reductive elimination to form a
biaryl framework (step a) may be facilitated by coordination
of π-acid such as 6. If the reductive elimination occurs when
6 is on the metal, the intermediate formed after the reductive
elimination still bears 6 on the metal center. In the absence
OL102325F
(13) The C-H arylation of the monoarylation product is much slower
than the diarylation of acetophenone in the absence of styrene. Therefore,
it is likely that most of the diarylation product is formed directly from
acetophenone without dissociating from the ruthenium center as the
monoarylation product.
Org. Lett., Vol. 12, No. 22, 2010
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