Rh(NHC)-catalyzed direct and selective arylation of quinolines at the 8-position

Article abstract of DOI:10.1021/ja111670s

A new catalytic protocol for the regioselective direct arylation of quinoline derivatives at the 8-position has been developed. The reaction is catalyzed by a Rh(NHC) system, and the choice of the NHC ligand was most important for achieving high reactivit

Full text of DOI:10.1021/ja111670s

COMMUNICATION
pubs.acs.org/JACS
Rh(NHC)-Catalyzed Direct and Selective Arylation of Quinolines
at the 8-Position
Jaesung Kwak, Min Kim, and Sukbok Chang*
Department of Chemistry and Molecular Level Interface Research Center, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon 305-701, Republic of Korea
S Supporting Information
b
desire for the development of a direct catalytic functionalization
ABSTRACT: A new catalytic protocol for the regioselec-
tive direct arylation of quinoline derivatives at the 8-posi-
tion has been developed. The reaction is catalyzed by
a Rh(NHC) system, and the choice of the NHC ligand
was most important for achieving high reactivity and
selectivity.
of unmodified quinolines at the 8-postion. Described herein is
the Rh(NHC)-catalyzed direct 8-arylation of quinolines, represent-
ing the first example of complete regiocontrol to the best of our
knowledge.
Recently, we have demonstrated that N-heterocyclic carbene
(NHC) ligands can play a crucial role in Rh-catalyzed reactions,
thus dramatically improving both reactivity and selectivity.12
During the course of our research aimed at an efficient C-H
bond functionalization of heteroarenes,13 we were intrigued by
the feasible effects of NHC ligands on the resultant Rh-NHC
catalytic system ultimately to influence the catalytic activity and
regioselectivity in the direct arylation of quinoline (Table 1).
While Rh2(OAc)4 species (5 mol %) exhibited only negligible
activity in the absence of ligands (entry 1), the addition of the
IMes•HCl ligand (1 equiv) significantly improved the arylation
efficiency (entry 2). Importantly, a careful analysis of the obtained
products revealed that the arylation took place almost exclusively at
the 8-postion of quinoline to afford 8-(p-tolyl)quinoline (2b) albeit
in moderate yield under the employed conditions.14 Other NHC
ligands examined exhibited much lower effects on the catalytic
activity, but the selectivity still remained high in favor of 8-arylation
over the 2-position (entries 3-5). Interestingly, regioselectivity
was diminished upon the use of a bulky NHC ligand (e.g., IAd)
although the catalytic activity was improved moderately (entry 6).
In addition, no beneficial effect was observed when a phosphine
ligand was employed (entry 7).
The structure of an isolated Rh2(OAc)4(IMes) complex was
characterized,15 and it was confirmed that this pregenerated
catalyst performs the arylation with similar reactivity when
compared to that obtained under the in situ conditions
(compare entries 8 and 2). With the use of 2 equiv of quinoline
relative to bromoarene, the reaction proceeded more smoothly
to afford a synthetically acceptable yield even using a lesser
amount of catalyst (entry 9). A dramatic NHC effect was also
observed with other sources of Rh catalysts such as RhCl(PPh3)3,
[Rh(coe)2Cl]2, or Rh(acac)3 species (entries 10-13).16
Our result is highly significant in that the Bergman-Ellman
Rh-catalyst system for the arylation of quinolines gives only
2-arylated products via Rh-quinoline “carbene” intermediates.9c,d
Therefore, our Rh-NHC system is an extremely useful and
complementary route to obtain regioisomeric 8-arylquinolines.
For operational convenience, the protocol of generating a
Rh-NHC catalyst in situ was set up as the optimized conditions.
ecent progress on the catalytic C-H bond functionalization
R
methods has opened new possibilities for an ideal chemical
synthesis enabling straightforward formation of C-C or C-X
bonds from cheap and simple molecules.1 However, it is still
difficult to control the position of activated C-H bonds if the
substrates have more than one reacting site. Therefore, the
development of site-selective C-H bond activation is highly
desirable to achieve regioselective C-C or C-X bond formation
in subsequent steps.2
Quinoline, which is a prominent structural motif found in a
wide range of natural products of interesting biological activity,3
has been derivatized often via transition-metal-catalyzed ap-
proaches (Scheme 1).4-9 In such transformations, high regios-
electivity at the 2-position was readily obtained by converting
quinolines into their N-oxides.5b,c,6 More recently, catalytic C-2
arylation of unmodified quinolines was achieved by utilizing nickel
(Tobisu and Chatani),7 silver (Baran),8 or rhodium catalysts
(Bergman and Ellman).9 In addition, Yu developed a novel
method of arylation at the 3- or 4-position based on a chelation-
assisted strategy, thus requiring an amido group in the 4- or
3-position of quinolines to direct the regioselectivity.5d
In spite of the above important contributions, no direct
catalytic arylation method has been developed to functionalize
quinolines at the 8-position.10 In fact, the conventional method
requires the de novo synthesis of 8-halogenated quinolines
followed by cross-coupling.11 In this context, there is a strong
Scheme 1. Selectivity Controlled Direct Arylation of
Quinolines
Received: December 28, 2010
Published: February 28, 2011
r
2011 American Chemical Society
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|

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COMMUNICATION
Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Aryl Bromides and Quinoline Derivatives
in the Rh(NHC)-Catalyzed Direct Arylationa
yield
(%)b
ratio of
2b/3bc
entry
catalyst system (mol %)
Rh2(OAc)4 (5)
1
3
58
8
-
2
Rh2(OAc)4 (5)/IMes HCl (5)
>99:1
29:1
10:1
16:1
2:1
3
3
Rh2(OAc)4 (5)/SIMes HCl (5)
3
4
Rh2(OAc)4 (5)/IPr HCl (5)
4
3
5
Rh2(OAc)4 (5)/IiPr HBF4 (5)
7
3
6
Rh2(OAc)4 (5)/IAd HBF4 (5)
20
5
3
7
Rh2(OAc)4 (5)/PCy3 (5)
5:1
8
Rh2(OAc)4(IMes) (5)
57
84
8
>99:1
>99:1
>1:99
79:1
>99:1
>99:1
9
Rh2(OAc)4 (3)/IMes HCl (6)d
3
10
11
12
13
RhCl(PPh3)3 (10)e
RhCl(PPh3)3 (6)/IMes HCl (6)d
[RhCl(coe)2]2 (3)/IMes HCl (6)d
80
84
59
3
3
Rh(acac)3 (6)/IMes HCl (6)d
3
a Quinoline (1a, 0.3 mmol), 4-bromotoluene (0.3 mmol), and t-BuONa (2.5
equiv) in toluene (0.3 mL) at 95 °C for 24 h. b Yield of 2b þ 3b determined
1
c
by H NMR using an internal standard. Determined by GC integration.
d 2 equiv of quinoline were used. e Performed at 130 °C without base.
In general, a broad range of quinolines and aryl bromides was
successfully employed for the selective arylation (Table 2).
Electronic variation on bromoarenes little affected the reaction
efficiency (2a-2e). An acetal group was well tolerated (2f), and
bromonaphthalene could also be used as a facile reactant (2g).
On the other hand, reaction of ortho-substituted aryl bromides
(e.g., 2-bromotoluene) was quite sluggish under the present
conditions presumably due to steric reasons. Interestingly, when
chlorobenzene was employed as a reacting partner instead of
bromobenzene, almost the same product yield was obtained
under otherwise identical conditions (2a, 90% vs 89%).
a Reaction conditions: quinolines (1, 0.6 mmol), aryl bromides (0.3
mmol), t-BuONa (0.75 mmol), Rh2(OAc)4 (3 mol %), IMes•HCl (6
mol %) in toluene (0.3 mL) at 95 °C for 24 h. b Chlorobenzene was used
instead of bromobenzene.
Quinolines substituted with a methyl group at various positions
were all efficiently arylated at the 8-position (2h-2j). Arylation of
quinolinyl ethers such as methyl, benzyl, phenyl, or MOM derivatives
took place also selectively in high yields (2k-2n). It was noted that a
silyl-protected quinolinol underwent the arylation without a problem
(2o). Significantly, quinolines bearing amino groups were arylated at
the 8-position in excellent yields (2p-2r). It was observed that
polycondensed hetereoarenes such as phenanthridine, benzo-
[f]quinoline, acridine, and phenazine were all arylated with excellent
regioselectivity in high yields (2u, 2v, 2w, and 2x, respectively).
Ellman et al. elegantly demonstrated that a base inhibits the
formation of Rh-carbene species in their Rh(I)-catalyzed direct
arylation of heteroarenes.9c,d As a result, it is postulated that the
generation of such Rh-carbene intermediates is excluded under our
present reaction conditions. Instead, it is tentatively proposed that
base-assisted concerted proton abstraction and metalation are
operative in the present 8-arylation reaction.17 Intermolecular
kinetic isotope effects (KIE) were measured from a competition
experiment between quinoline (1a) and its deuterated derivative
(1a-d7), revealing a high value of KIE (2.76).14
Although more comprehensive studies are required to de-
scribe the mechanistic details of the present reaction, especially
with regard to the origin of regioselectivity and structure of active
catalytic species, we propose that the formation of a bimetallic Rh
species bound to an NHC ligand could be responsible for the
outcomes (Scheme 2, I). In fact, Rh2(OAc)4-mediated activation
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dx.doi.org/10.1021/ja111670s |J. Am. Chem. Soc. 2011, 133, 3780–3783

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Scheme 2. A Possible Mechanistic Pathway
elucidate the origin of such high regioselectivity and structure of
active catalytic species.
’ ASSOCIATED CONTENT
1
S
Supporting Information. Experimental details and H
b
and 13C NMR spectra of new compounds, and CIF file of
Rh2(OAc)4(IMes). This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
sbchang@kaist.ac.kr
of an ortho C-H bond of PPh3 was known,18 and a similar type of
C-H bond activation has been well documented in a number of
different types of metal clusters (e.g., Ru3(CO)12 or Os3(CO)10-
(CH3CN)2).19 In addition, Rh2(NHC)Ln species are reported to
catalyze a range of reactions while maintaining their dimeric
integrity during the course of the catalytic cycle.12a,15 However,
the observation that certain precursors of monomeric rhodium
species also showed significant catalytic activity and regioselec-
tivity led us to consider the possibility that the formation of a
four-membered rhodacycle involving a monomeric Rh-NHC
species (II) is also a plausible intermediate.20
’ ACKNOWLEDGMENT
Dedicated with respect to Professor Eun Lee for his honorable
retirement. This work was supported by the National Research
Foundation (Star Faculty Program, KRF-2008-C00024), MIRC
(NRF-2010-0001957), and Carbon Dioxide Reduction & Se-
questration Research Center (AC3-101). The authors also thank
Dr. Seung Hwan Cho for experimental assistance and helpful
discussions.
Although a clear-cut relationship between the reactivity and
structure of the NHC ligands cannot be formulated at present, it
is postulated that the presence of a bound NHC ligand is
essential influencing the subsequent oxidative addition of a
rhodium metal center, in the form of either intermediate I or
II, onto a coupling partner, arylbromides. Indeed, it was pro-
posed that Ellman’s rhodium-carbene species, such as III gener-
ated in situ from the reaction of N-methylbenzimidazole with
[RhCl(coe)2]2 in the presence of PCy3, has high electron density
at the rhodium center allowing subsequent oxidative addition
to aryl halides to proceed more readily.9 For the same reason,
we envision that an oxidative addition of intermediate I or II in
our case is also enhanced by the preinstalled Rh-carbene
species.21
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Journal of the American Chemical Society
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