Ruthenium-catalyzed direct arylation of C-H bonds in aromatic amides containing a bidentate directing group: Significant electronic effects on arylation

Article abstract of DOI:10.1039/c2sc21506c

Arylation of ortho C-H bonds is achieved by a ruthenium-catalyzed reaction of aromatic amides having an 8-aminoquinoline moiety with aryl bromides. The reaction shows high functional group compatibility. The reaction proceeds in a highly selective manner at the less hindered C-H bonds of meta-substituted aromatic amides. Significant electronic effects are observed in Hammett plots. Electron-withdrawing groups on the aromatic amides facilitate the reaction. In contrast, both electron-donating groups and electron-withdrawing groups on aryl bromides accelerate the reaction. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2sc21506c

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Ruthenium-catalyzed direct arylation of C–H bonds in
aromatic amides containing a bidentate directing
group: significant electronic effects on arylation†
Cite this: DOI: 10.1039/c2sc21506c
*
Yoshinori Aihara and Naoto Chatani
Arylation of ortho C–H bonds is achieved by a ruthenium-catalyzed reaction of aromatic amides having an
8-aminoquinoline moiety with aryl bromides. The reaction shows high functional group compatibility. The
reaction proceeds in a highly selective manner at the less hindered C–H bonds of meta-substituted aromatic
amides. Significant electronic effects are observed in Hammett plots. Electron-withdrawing groups on the
aromatic amides facilitate the reaction. In contrast, both electron-donating groups and electron-
withdrawing groups on aryl bromides accelerate the reaction.
Received 12th September 2012
Accepted 18th October 2012
DOI: 10.1039/c2sc21506c
www.rsc.org/chemicalscience
efficiency of the reactions have not been examined in
detail.5e,g,6a,i
Introduction
The formation of aryl–aryl bonds is a useful synthetic reaction,
considering the fact that biaryl derivatives are important
synthetic targets, such as natural products, pharmaceuticals,
agrochemicals, and conjugated materials.1 The most commonly
used method for aryl–aryl bond formation involves the transi-
tion metal-catalyzed cross coupling of aryl halides with aryl
metal reagents, especially organoboron reagents, a reaction that
is referred to as Suzuki–Miyaura cross-coupling.2 The direct
introduction of aryl groups in conjunction with the cleavage of
C–H bonds has been extensively studied as an alternative
strategy for the construction of biaryl derivatives.3 While a
variety of transition metal complexes can be used in the aryla-
tion of C–H bonds, palladium or nickel catalysts are the most
reliable species. Oi et al. reported the rst example of the Ru(II)-
catalyzed arylation of C–H bonds, in which 2-phenylpyridine
derivatives reacted with aryl bromides to result in arylation at
the ortho position.4a Later, Ackermann, Dixneuf, Bruneau, and
others made some signicant contributions to this eld.5,6
Various nitrogen-containing directing groups such as N-
heterocycles and imines are applicable to the Ru(II)-catalyzed
arylation reactions.4–6 However, the Ru(II)-catalyzed arylation of
C–H bonds still remains at an early stage compared with the
extensively studied Pd-catalyzed C–H bond arylation reactions.7
Expanding the scope to include other types of substrates
continues to remain a critical challenge. Furthermore, the
reaction mechanism for Ru(II)-catalyzed arylation has not been
elucidated and even the electronic effects of substituents on the
Chelation-assisted transformation is now one of the viable
methods for transforming ortho C–H bonds. A wide variety of
directing groups has been evaluated to date, but in most cases,
structurally simple monodentate directing groups have been
used. If a bidentate directing group could be used in the
transformation of C–H bonds, it would open new avenues for
applications and for the development of new reactions, which
cannot currently be achieved using the conventional simple
directing groups. The use of 8-aminoquinoline or picolina-
mides as an N,N-bidentate directing group was reported in a
pioneering study by Daugulis et al. who discovered the Pd(II)-
catalyzed arylation of C–H bonds.8 Since this pioneering
example appeared in the literature, a number of reactions
utilizing an N,N-bidentate directing-assisted transformation of
C–H bonds have been developed, especially in the case of Pd(II)-
catalyzed reactions.9 In sharp contrast, bidentate directing
systems of other transition metal-catalyzed transformations of
C–H bonds are quite rare. We recently reported the Ru(0)-cata-
lyzed C–H bond carbonylation of aromatic and aliphatic amides
with a 2-pyridinylmethylamine moiety as the bidentate direct-
ing group10 and the Ni(0)-catalyzed oxidative annulation of
aromatic amides with alkynes leading to isoquinolones.11 We
wish to report on the Ru(II)-catalyzed ortho-arylation of aromatic
amides with a bidentate directing group and some interesting
electronic effects on the efficiency of the arylation (eqn (1)).
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan. E-mail: chatani@chem.eng.osaka-u.ac.jp; Fax: +81-6-6879-
7396; Tel: +81-6-6879-7397
(1)
† Electronic supplementary information (ESI) available: Experimental details and
NMR spectra. See DOI: 10.1039/c2sc21506c
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NH is not included in the product formation at rst sight.
Amides having longer carbon chains, such as 6, did not give
the corresponding coupling product. However, it was found
that 2-methyl-N-(quinolin-8-yl)benzamide (7a) was also a good
Results and discussion
Initial studies
The reaction of amide 1a (0.3 mmol) with PhBr (0.4 mmol) in
the presence of [RuCl2(p-cymene)]2/PPh3 as the catalyst and
Na2CO3 as a base in toluene at 140 C for 18 h gave the ortho-
substrate and that 7a was more reactive than 1a.
A
ꢀ
phenylation product 2a in 46% NMR yield, along with 33% of
recovered 1a (eqn (2)). The use of 2 equivalents of PhBr
improved the product yield to 86% NMR yield (82% isolated
yield), with 1a being recovered in 3%. Product yield was
signicantly affected by the nature of base used: Li2CO3 0%,
K2CO3 75%, Cs2CO3 19%, NaOAc 38%, KOAc 16%, CsOAc 7%,
2,6-lutidine 0%. In most Ru-catalyzed arylation reactions of C–
H bonds reported to date,4–6 N-methylpyrrolidinone (NMP) was
the solvent of choice. Contrary to these previous examples,
when NMP was used in place of toluene, 2a was produced in
only 25% yield. Although carboxylic acids were well used as a
co-catalyst in the Ru(II)-catalyzed arylation reaction,2–6 the
addition of a carboxylic acid, such as 1-adamantancarboxylic
acid or MesCO2H did not result in the formation of 2a. The
addition of PPh3 was signicantly important. No reaction took
place when the reaction was carried out in the absence of PPh3.
The use of PCy3 gave 2a only in 38% yield. The efficiency of the
reaction was not affected by the nature of the catalyst. Among
the Ru(II) catalysts examined, RuCl2(PPh3)3 (81%) and
Ru(OAc)2(p-cymene) (85%) were found to be as equally effective
as [RuCl2(p-cymene)]2.
Table 1 Substrate scope with phenyl bromidea
Amide
Productb
(2)
We next examined the effect of a directing group. No
reaction occurred when the corresponding N-benzyl benza-
mide (3, Fig. 1) and 2-pyridynylmethyl ester 4 were used as the
substrate in place of 1a, indicating that coordination in an
N,N0-fashion by the 2-pyridinylmethylamine moiety is essen-
tial for the reaction to proceed. Furthermore, the use of
N-methyl amide 5 did not provide the phenylation product,
indicating that the presence of a proton on the amide
nitrogen is important for the reaction to proceed, although
a
Reaction conditions: amide (0.3 mmol), PhBr (0.36 mmol), [RuCl2(p-
cymene)]2 (0.015 mmol), PPh3 (0.12 mmol), Na2CO3 (0.6 mmol) in
b
c
toluene (2 mL) at 130 ꢀC for 15 h. Isolated yields. Ru(OAc)2(p-
d
e
cymene) (0.03 mmol) as the catalyst. Run at 140 ꢀC for 36 h. Run
f
g
at 140 ꢀC for 24 h. For 24 h. The bisphenylation product was
formed in 12% yield.
Fig. 1 Directing groups for phenylation of C–H bonds.
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considerably higher yield of the phenylation product 8a was
obtained when less PhBr (1.2 equivalents) was used at a lower
reaction temperature of 130 ꢀC for shorter reaction time
(15 h). Similar to the reaction of 1a, the choice of base was
important: Na2CO3 > K2CO3 [ Cs2CO3. The addition of PPh3
was again signicantly important. No reaction took place
when the reaction was carried out in the absence of PPh3. The
following conditions were nally selected as standard reac-
tion conditions: the reaction of amide 7a (0.3 mmol) with
PhBr (0.36 mmol) in the presence of [RuCl2(p-cymene)]2
(0.015 mmol), PPh3 (0.12 mmol), Na2CO3 (0.6 mmol) in
toluene (2 mL) at 130 ꢀC for 15 h gave 8a in 80% isolated yield
(eqn (3)).
Synthetic scope
With the optimized reaction conditions in hand, we exam-
ined the scope of the reaction. Table 1 shows the results for
the reaction of aromatic amides with an 8-quinolinyl group
under standard reaction conditions. A variety of functional
groups were tolerated in the reaction and the reaction pro-
ceeded in a highly regioselective manner. The reaction of
meta-substituted substrates resulted in the selective phenyl-
ation at the less hindered C–H bonds, irrespective of the
electronic nature of the substituent, indicating that
the regioselectivity was controlled by the steric nature of the
substituent groups.
A variety of aryl bromides or iodides were applicable to
the arylation reaction, as shown in Table 2, however when
phenyl chloride was used, 8e was produced in only a low
yield. Various functional groups, such as dimethylamino,
methoxy, chloro, ester, triuoromethyl, and ketone
groups, were tolerated in the reaction. Electron-rich aryl
bromides gave higher yields than electron-poor aryl
bromides. Various heteroaromatic bromides also partici-
pated in the present arylation reaction of C–H bonds as
coupling partners.
(3)
Mechanistic aspects
Table 2 Scope of aryl halidesa,b
To investigate the mechanism for the reaction, the deuter-
ated amide 7a-d7 was reacted for 1 h under otherwise
standard reaction conditions (eqn (4)). We observed a
signicant amount of H/D exchange between at the
ortho position (the d-content dropped from >98% to 34%)
and on the nitrogen in the recovered amide. Even for a
shorter reaction time of 0.5 h in the absence of PhBr, a
signicant amount of H/D exchange again occurred at
the ortho position (the d-content dropped from >98% to
30%) and on the nitrogen (eqn (5)), indicating that the
cleavage of C–H bonds is reversible and very rapid.
This result indicates that the cleavage of C–H bonds is
likely not the rate determining step. It was also found that
PPh3 accelerates the cleavage of C–H bonds. When the
reaction was run in the absence of PPh3 (eqn (5)), H/D
exchange occurred at only 11% (89% d-content) at the ortho
position.
(4)
a
Reaction conditions: amide 7e (0.3 mmol), ArBr (0.36 mmol), [RuCl2(p-
cymene)]2 (0.015 mmol), PPh3 (0.12 mmol), Na2CO3 (0.6 mmol) in
b
toluene (2 mL) at 130 ꢀC for 15 h. Yields are isolated yields based on
c
d
7e. NMR yield. Ru(OAc)2(p-cymene) (0.03 mmol) as the catalyst at
140 ꢀC for 24 h.
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We next carried out the reaction of 7d with an electronically
different set of para-substituted aryl bromides (see Table S2 in
ESI†). We observed a V-shaped Hammett plot,12 as shown in
Fig. 3. The Hammett plot shows two segments and the two r
values for the two segments are ꢁ0.5 and +2.1, respectively. This
result suggests that the mechanism or rate-determining step for
the reaction changes, depending on the nature of the substit-
uents on the aryl bromides.
To collect additional information on the reaction mecha-
nism, competition experiments using 4-dimethylaminophenyl
bromide and methyl 4-bromobenzoate, both of which are highly
active substrates, as shown in Fig. 3, were carried out. It was
observed that 23 gave higher yields than 24, irrespective of the
electronic nature of the substituent at the meta position of the
aromatic amide (eqn (6), Fig. 4). However, the ratio of 23 and 24
decreased to close to 1 : 1 when the electron-donating nature of
the substituents became stronger. These results suggest that the
electronic nature of a substituent in the aromatic amide is a
dominant factor.
Fig. 2 Hammett plot of m-R-C6H4CONHQ (Q ¼ 8-quinolinyl) 7a–f with PhBr.
(5)
(6)
To probe the electronic effects on the arylation, the reaction
of an electronically different set of meta-substituted aromatic
amides 7a–f with PhBr was carried out (see Table S1 in ESI†). A
Hammett plot was constructed from the correlation for the
conversion of 7a–f with sp for meta-substituted aromatic amides
(Fig. 2). The plot resulted in a linear t with a positive slope of
r ¼ 0.38, indicating that electron-withdrawing groups clearly
facilitate the reaction.
We next performed competition experiments of a mixture of
7f and 7c with three different aryl bromides (eqn (7)). As shown
in Fig. 3, Me2N- and MeO2C-substituted aryl bromides are
highly reactive, but CF3-substituted aryl bromide is less reac-
tive.13 However, only 7f reacted to give 25, 27, or 29 in the
competition experiments, irrespective of electronic nature of
Fig. 3 Hammett plot of 7d with p-X-C6H4Br.
Fig. 4 Hammett plot for eqn (6).
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the substituent on the aryl bromide. These results again suggest addition of PhBr followed by reductive elimination gives 34,
that the electronic nature of the substituent in the aromatic which undergoes protonation to afford the phenylation product
amide is a dominant factor.
with the regeneration of ruthenium(II). As shown in eqn (2), the
cleavage of C–H bonds is a reversible and rapid step, and is not
the rate determining step. The Hammett plots shown in Fig. 2
and the region on the le in Fig. 3 suggest that the reductive
elimination is the rate-determining step and it proceeds
through the transition state 35, in which a developing negative
charge is stabilized by the carbonyl group and the substitu-
ents.15 If the oxidative addition of PhBr to 32 is the rate deter-
mining step, the Hammett r shown should be a straight line
with a positive slope in Fig. 3 because electron-decient aryl
bromides accelerate the oxidative addition. However, a V-sha-
ped Hammett plot was observed in Fig. 3, suggesting that the
rate determining step changes depending on the substituent on
the aryl bromide. These collective results suggest that the
reaction is dominantly affected by the electronic nature of the
substituent R in the aromatic amides. However, the reaction is
also accelerated by the electron-withdrawing nature of the
substituent X in the aryl bromides. This suggests that the
oxidative addition proceeds through a nucleophilic substitution
mechanism as in 36. The equilibrium position can be shied to
33 from 32 by the electron-withdrawing groups, such as an ester
and a ketone functional group on the ArBr.
(7)
The directing group could be easily removed and recovered
by hydrolysis under acidic conditions (eqn (8)).
(8)
A proposed mechanism is shown in Scheme 1. Coordination
of the amide 30 to the ruthenium center followed by ligand
exchange with the concomitant generation of HX gives the
ruthenium complex 31, which undergoes reversible cyclo-
metalation to give the complex 32 probably via a concerted
metalation–deprotonation (CMD) mechanism.14 The oxidative
Conclusions
We report on the Ru(II)-catalyzed arylation of ortho C(sp2)–H
bonds in aromatic amides, in which the presence of a bidentate
directing group, such as 2-pyridynylmethylamino or 8-amino-
quiloline is essential for the arylation to proceed. The reaction
proceeds in a highly selective manner at the less hindered C–H
bonds of meta-substituted aromatic amides. Contrary to most
Ru-catalyzed ortho-arylations, in which NMP is a solvent of
choice, a common solvent, such as toluene gave the best results
in the present system. Although the mechanism is not currently
completely understood, dramatically different slopes were
obtained in Hammett plots. The elucidation of the mechanism
for the reaction is the subject of current investigations.16,17
Acknowledgements
This work was supported, in part, by a Grant-in-Aid for Scientic
Research on Innovative Areas "Molecular Activation Directed
toward Straightforward Synthesis" from The Ministry of
Education, Culture, Sports, Science and Technology.
Notes and references
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Scheme 1 A proposed mechanism.
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S. Inoue, Y. Fukumoto and N. Chatani, J. Am. Chem. Soc.,
2011, 133, 8070.
C–H bonds in aromatic imines or 2-phenylpyridine. See
ref. 5e, 6a, and i
11 H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto and N. Chatani, J. 15 To the best of our knowledge, there are no reports in which
Am. Chem. Soc., 2011, 133, 14952.
electronic effects on the reductive elimination from Ru(IV) to
form C–C bonds have been examined. See: T. Matsubara,
N. Koga, D. Musaev and K. Morokuma, Organometallics,
2000, 19, 2318. For a recent paper on reductive elimination
from Pd(II), see: J. L. Klinkenberg and J. F. Hartwig, J. Am.
Chem. Soc., 2012, 134, 5758 and references cited therein.
12 For recent papers on catalytic reactions in which V-shaped
Hammett plots are observed, see: (a) M. J. Zdilla,
J. L. Dexheimer and M. M. Abu-Omar, J. Am. Chem. Soc.,
2007, 129, 11505; (b) D. R. Edwards, Y. B. Hleba, C. J. Lata,
L. A. Calhoun and C. M. Crudden, Angew. Chem., Int. Ed.,
2007, 46, 7799; (c) B. J. Stokes, K. J. Richert and 16 Ackermann reported that the Ru(II)-catalyzed arylation of
T. G. Driver, J. Org. Chem., 2009, 74, 6442; (d)
M. M. Konnick, N. Decharin, B. V. Popp and S. S. Stahl,
Chem. Sci., 2011, 2, 326.
C–H bonds proceeds through reversible C–H bond
cleavage and rate limiting oxidative addition with aryl
halides. See ref. 5e. In contrast to ref. 5e, different
electronic effects of substituents were observed. See ref. 5h.
17 Dixneuf and Jutand reported that the cleavage of C–H bonds
is irreversible and the oxidative addition of PhBr to the Ru(II)
center is the rate determining step. See ref. 6i.
13 In the case of individual reactions, 7f reacted with PhBr 2.5
times faster than 7c.
14 A CMD mechanism or SE3 mechanism was proposed in the
cleavage of C–H bonds in the Ru(II)-catalyzed arylation of
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Chem. Sci.