Rh(III)-catalyzed amide-directed cross-dehydrogenative heteroarylation of pyridines

Article abstract of DOI:10.1021/ol403311b

A new catalytic methodology has been developed for the synthesis of heteroaryled pyridines via a rhodium(III)-catalyzed dehydrogenative cross-coupling reaction. This protocol features a good substrate scope with a broad range of functional group tolerance and high regioselectivity of the pyridyl C-H activation.

Full text of DOI:10.1021/ol403311b

Letter
pubs.acs.org/OrgLett
Rh(III)-Catalyzed Amide-Directed Cross-Dehydrogenative
Heteroarylation of Pyridines
Yaping Shang, Xiaoming Jie, Huaiqing Zhao, Peng Hu, and Weiping Su*
A State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of
Sciences, Fuzhou, Fujian 350002, China
S
* Supporting Information
ABSTRACT: A new catalytic methodology has been
developed for the synthesis of heteroaryled pyridines via a
rhodium(III)-catalyzed dehydrogenative cross-coupling reac-
tion. This protocol features a good substrate scope with a
broad range of functional group tolerance and high
regioselectivity of the pyridyl C−H activation.
he structural motif of (hetero)arylated pyridine appears in
a large number of natural products and bioactive
the C-2 heteroarylation of pyridines in an atom-economic
fashion.8 Nevertheless, the use of a large quantity of pyridines
as solvent rendered this reaction less appealing. Therefore,
developing more efficient methods for the direct heteroar-
ylation of pyridines, especially with varied selectivity, would be
highly desirable.
T
compounds, as well as in pharmaceuticals and functional
materials.1 Consequently, synthetic organic chemists have made
great efforts to develop more efficient and versatile methods for
the direct (hetero)arylation of pyridines. However, unlike
various reliable means for the C−H arylation of other
(hetero)arenes,2 the methods for installing heteroarene groups
into pyridine rings through pyridyl C−H decoration raises
substantial challenges. The following difficulties were initially
envisaged to consider: (1) the relatively low reactivity of
pyridines due to their poor electron density; (2) strong
coordination of pyridines with transition metal centers; and (3)
levels of regioselectivity of pyridines.
Previously reported approaches for the heteroarylation of
pyridines mostly proceed by means of the transition-metal-
catalyzed cross-coupling of pyridyl halides or pseudohalides
with other heteroaryl organometallic reagents.3 These methods
suffer from tedious preparation procedures for organometallic
reagents and the generation of stoichiometric metal halide salts
as waste after the reaction finished. From the viewpoint of step
and atom economy, the development of oxidative C−H/C−H
cross-coupling of pyridines with heterocycles is highly desirable,
as this transformation would provide a more efficient and
straightforward access to the pyridine-containing biheteroaryls.4
In this context, Bergman, Ellman,4a−c Chatani,4d Hiyama,4e,f
Baran,4g and other groups4h−j reported C-2/C-4 arylation or
alkylation of unmodified pyridines by utilizing rhodium, nickel,
or silver catalysts. Very recently, the Yu group successfully
established palladium-catalyzed C-3 arylation and unprotected
pyridines or nicotinic/isonicotinic acid derivatives.5 At the same
time, the Sames group developed a novel protocol for selective
arylation of pyridines bearing various electron-withdrawing
groups.6
Additionally, although previous studies emphasized the
important role of palladium catalysts in biaryls formation
through oxidative C−H/C-H cross-couplings,9 the recently
developed rhodium(III)-catalyzed 2-fold C−H functionaliza-
tion reactions also proved to be an excellent means for
generating biaryl molecules.10,11 The Glorius group has
achieved a dehydrogenative cross-coupling reaction of
benzamide with simple arenes and heterocycles.12 Subse-
quently, the same group reported the synthesis of 2,2′-
bi(heteroaryl) compounds by dehydrogenative cross-coupling
of electron-rich heterocycles, such as furans, thiophenes,
indoles, and pyrroles.13 The You group also succeeded in the
oxidative cross-coupling of various nitrogen-containing hetero-
arenes with other heteroarenes by 2-fold C−H functionaliza-
tion.14 In spite of these achievements, the rhodium(III)-
catalyzed direct reactions of heterocycles with pyridines has
remained untouched. Herein, we report a rhodium(III)-
catalyzed amide-directed cross-dehydrogenative heteroarylation
of pyridines. Notably, this is the first example of Rh-catalyzed
C−H/C−H cross-coupling between directing-group-assisted
pyridines and heterocycles.
Initially, we began our investigation by evaluating the
reaction between N-phenyl isonicotiamide (1a) and 2-
methylthiophene (2a) in detail (Table 1).15 In light of the
previous contributions from Miura,11f Glorius,11a Fagnou,16a,b
and other groups, the traditional conditions of [RhCp*Cl2]2
(2.5 mol %), AgSbF6 (10%), Cu(OAc)2 (2.0 equiv), and
dioxane (2.0 mL) at 130 °C were used (Table1, entries 1−4).
We were pleased to obtain the desired product 3a in 6%
Furthermore, the Chang group achieved rhodium-catalyzed
C-8 arylation of quinolines.7 Later on, the palladium-catalyzed
direct C-2 heteroarylation of pyridines was achieved by
employing a large excess of pyridines as the substrate and
solvent, which represented considerable progress in achieving
Received: November 16, 2013
Published: December 26, 2013
© 2013 American Chemical Society
416
dx.doi.org/10.1021/ol403311b | Org. Lett. 2014, 16, 416−419

Organic Letters
Letter
a
a
Table 1. Selected Screening Results for Reacion Conditions
Scheme 1. Influence of the Directing Groups
b
entry
base
oxidant
solvent
yield (%)
<5
c
1
PivOCs
PivOCs
PivOCs
PivOCs
K2CO3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Ag2CO3
toulene
t-AmOH
DMF
c
d
2
n.d.
c
3
n.d.
6
c
4
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
5
<5
<5
<5
35
52
61
23
<5
n.d.
<5
6
Na2CO3
PivONa
KOAc
7
8
9
K3PO4
10
11
12
13
14
15
16
K2HPO4
Na3PO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
PhCl
a
dioxane
dioxane
dioxane
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [RhCp*Cl2]2
(2.5 mol %), Cu(OAc)2 (2.0 equiv), K2HPO4 (1.5 equiv), dioxane (1.0
mL), 130 °C, 24 h, N2, isolated yield.
e
Cu(OAc)2
Cu(OAc)2
65
f
70
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), [RhCp*Cl2]2
(2.5 mol %), oxidant (2.0 equiv), base (1.5 equiv), AgSbF6 (10 mol
thiophene (2a) for the one-step synthesis of the desired
product (3a) in 49% isolated yield (Scheme 4).
b
c
%), solvent (2.0 mL), 130 °C, 24 h, N2. Isolated yield. PivOCs (1.0
equive). The formation of product was not detected. Dioxane (1.0
mL). [Cp*RhCl2]2 (1.5 mol %), AgSbF6 (6.0 mol %), dioxane (1.0
mL).
d
e
With the optimized conditions in hand, the substrate scope
of the reaction was initially expanded with respect to
heterocycles. As shown in Scheme 2, this reaction was
applicable to a variety of substituted thiophenes and furans,
affording the corresponding products with excellent selectivity.
A range of diverse functional substituents were compatible
under our conditions, including both electron-rich (3b, 3f, 3g)
and electron-withdrawing groups (3d, 3e). Moreover, 3-
substituted thiophenes (3c, 3j) also provided corresponding
products. Additionally, electron-rich benzothiophene (3l) and
benzofuran (3n) furnished the product in moderate yields.
Notably, the bromo-containing substrates (3k, 3m) also
participated in this cross-coupling reaction smoothly. For
other heterocycles, 2-methythiazole (3p) was suitable for this
reaction system to afford a low yield.
The generality of the N-phenyl isonicotinamide substrate was
subsequently evaluated (Scheme 3). Both electron-deficient
(4a, 4c) and electron-rich (4b) group substituted N-phenyl
isonicotinamides provided monosubstituted heteroarylation
products. Substitution at the ortho position (4i, 4j, 4k) was
also well tolerated. Furthermore, N-phenyl quinoline-4-
carboxamide (4d) and N-phenyl quinoline-3-carboxamide
(4e) both provided the expected products, respectively, in
moderate to excellent yields. In addition, unsubstituted
thiophene (4h) not only was compatible but also gave a
monoheteroarylated product.
f
isolated yield. After screening various bases, the results revealed
K2HPO4 (1.5 equiv) was the most effective base, affording the
desired product 3a in 61% isolated yield (Table 1, entry 10).
Then, the effect of solvent was investigated, yet there was no
significant improvement in the product yield (Table 1, entries
12−13). When Ag2CO3 was used in place of Cu(OAc)2,
unfortunately, only a trace of the desired product was obtained
(Table 1, entry 14). In addition, using [RhCp*(MeCN)3]-
(SbF6)2 as the catalyst, the desired product was just obtained in
26% yield.15 An attempt to increase the concentration of
substrates led to a slight increase in yield to 65% (Table 1, entry
15). Encouraged by these results, we further examined the
influence of the directing groups (Scheme 1). However, the
results showed us that electron-withdrawing N-polyfluorophen-
yl amides (1ab, 1ac), steric N-2,6-diisopropylphenyl amide
(1ad), N-alkyl amides (1aj, 1ak), N-dialkyl amide (1ap),
isonicotinamide (1aq), N-benzyl amide (1am), N-piv amide
(1aa), N-disubstituted amide (1al), N-methoxyl amide (1ao),
and N-4-methoxyphenyl amide (1af) gave only a trace of the
corresponding cross-coupling product. Although N-4-methyl-
phenyl amide (1ag), N-4-fluorophenyl amide (1ai), N-4-
methoxycarbony amide (1an), N-3,5-dimethylphenyl amide
(1ae), and N-2,3-dimethylphenyl amide (1ah) afforded the
target products in moderate yields, there was no obvious
improvement in the reaction outcomes. To our delight,
decreasing the catalyst loading to 1.5 mol % improved the
yield to 70% (Table 1, entry 16). Remarkably, this procedure
exhibited high selectivity for the monosubstituted product. In
order to demonstrate the utility of the present method, the
reaction was conducted in 5.0 mmol scale, under the optimized
conditions of N-phenyl isonicotiamide (1a) and 2-methyl-
Based on the above results and previous research,16 the
following mechanism was proposed. Initially the coordination
of the rhodium(III) species with N-phenyl amide (1a) activated
the ortho C−H bond via a five-membered ring transition17 to
form an aryl-rhodium(III) intermediate, followed by a reaction
with 2-methythiophene (2a) to form a complex. Subsequently,
reductive elimination from the rhodium(III) center generated
the final product (3a) and a rhodium(I) species. Finally, the
catalytic cycle was completed when rhodium(III) was
regenerated by oxidation of the copper salt.
417
dx.doi.org/10.1021/ol403311b | Org. Lett. 2014, 16, 416−419

Organic Letters
Letter
a
Scheme 2. Scope of Heterocycles
Scheme 4. Application for the Synthesis of 3-Heteroarylation
of Pyridine 3a
In summary, a novel method for the heteroarylation of
pyridines has been developed based on a rhodium(III)-
catalyzed dehydrogenative cross-coupling reaction of aromatic
heterocycles with amide-directed pyridines for the first time.
This protocol features a good substrate scope with respect to a
broad range of functional group tolerance. Additionally, the
research offers high regioselectivity of the pyridyl C−H bond
cleavage. This catalytic system can provide a new methodology
for the direct synthesis of heteroarylated pyridines through dual
C−H bond cleavage. Further studies to uncover the
comprehensive reaction mechanism and to expand the scope
of simple arenes as coupling partners are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wpsu@fjirsm.ac.cn.
Notes
The authors declare no competing financial interest.
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), [RhCp*Cl2]2
(1.5 mol %), Cu(OAc)2 (2.0 equiv), K2HPO4 (1.5 equiv), dioxane (1.0
mL), 130 °C, 24 h, N2, isolated yield. K3PO4 (1.0 equiv) was used
instead of K2HPO4. Carried out at 150 °C.
ACKNOWLEDGMENTS
b
■
c
Financial support from the 973 Program (2011CB932404,
2001CBA00501), NSFC (20925102, 21202164), and National
Key Technology R & D Program (2012BAE06B08) is greatly
appreciated.
a
Scheme 3. Scope of the N-Phenyl Isonicotinamide
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