Ligand-promoted C-3 selective C-H olefination of pyridines with Pd catalysts

Article abstract of DOI:10.1021/ja2021075

Pd-catalyzed C-3 selective olefination of pyridines is developed for the first time using 1,10-phenanthroline as the ligand. This finding provides a novel disconnection for the synthesis of pyridine-containing alkaloids and drug molecules as well as a new approach for developing Pd-catalyzed C-H functionalizations of pyridines.

Full text of DOI:10.1021/ja2021075

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pubs.acs.org/JACS
Ligand-Promoted C-3 Selective CÀH Olefination of Pyridines with Pd
Catalysts
Mengchun Ye, Guo-Lin Gao, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
to date. Herein, we report the first Pd-catalyzed C-3 selective
ABSTRACT: Pd-catalyzed C-3 selective olefination of
CÀH olefination enabled by a bisdentate ligand that weakens the
pyridines is developed for the first time using 1,10-phenan-
throline as the ligand. This finding provides a novel dis-
connection for the synthesis of pyridine-containing alkaloids
and drug molecules as well as a new approach for developing
Pd-catalyzed CÀH functionalizations of pyridines.
coordination of the Pd catalyst with the pyridyl N atom through
the trans-effect (eq 3). This novel method provides access to
3-alkenyl pyridine derivatives that are closely related to a variety
of biologically active natural products, such as sulcatin and
acuminatopyrone, and drug molecules, including zimelidine
(Figure 1).
At the onset of our studies, two major factors had to be
considered. The reactivity of pyridyl CÀH bonds is generally low
due to the poor electron density of the pyridyl ring. In addition,
strong coordination of the pyridine N atom with the Pd(II)
center can prevent the catalyst from interacting with pyridine
C(3)ÀH and C(4)ÀH bonds. Because this strong coordination
is a major obstacle, we sought an operationally simple strategy to
overcome this problem. Since pyridine could potentially coordi-
nate with Pd(II) through either the N atom to form I or the
electron-deficient pyridine ring to form II, we envisioned that a
bisdentate pyridyl ligand could enhance the ligand exchange due
to a strong trans-effect17 of the pyridyl ligand (Scheme 1).
Although pyridine prefers to coordinate with Pd(II) via the
N atom, the presence of only a small amount of II could be
sufficient to trigger the catalytic reaction. It was anticipated that
solvent, ligands, and counteranions would significantly influence
this equilibrium.
Guided by this rationale, we used pyridine as the representa-
tive substrate to screen solvents, anions, and ligands. We found
that the Pd(OAc)2-catalyzed C-3 selective olefination of pyridine
using ethyl acrylate as the limiting reagent occurred in DMF in
the presence of air and a catalytic amount of Ag2CO3 to give the
desired product in 21% yield (Table 1, entry 1). We reasoned
that two molecules of pyridine acted as ligands as shown in
Scheme 1. The excess pyridine relative to olefin in DMF is
presumably required for the formation of II because the binding
of Pd(II) with the π-ring is relatively weak. We, therefore,
focused on the extensive screening of a variety of bisdentate
pyridyl ligands to seek improved reactivity (entries 2À14).18 A
number of bisdentate pyridyl ligands were found to increase the
yields of the olefination products, with 1,10-phenanthroline
(Phen) and bathophenanthroline giving the highest yields
(entries 9, 10, 12). Under these conditions, other solvents such
as dioxane, acetonitrile, DMA, and DMSO gave less than 10%
yields (see Supporting Information). Other palladium sources
were also tested. The use of Pd(TFA)2 afforded the olefinated
product in 75% yield, while other catalysts such as Pd(OTf)2 and
yridine rings are among the most important heterocyclic
P
structural motifs and are found in a large number of natural
products, pharmaceuticals, materials, and ligands.1 Consequen-
tly, the development of short routes for the preparation of pyridine-
containing compounds through pyridyl CÀH functionalizations
has received intensive attention.2À11 The use of zirconium,2 ruthe-
nium,3,4 rhodium,5,6 and iridium7 catalysts has yielded promising
results with pyridine. Pioneering efforts by Hiyama and Nakao have
recently led to important discoveries of novel Ni-catalyzed alkenyla-
tion of pyridyl CÀH bonds.8 Remarkably, two laboratories inde-
pendently found that the coordination of a strong and bulky
aluminum-based Lewis acid with the pyridyl N atom not only
activated the pyridyl rings but also favored C(4)ÀHcleavagefor the
first time through steric hindrance.9
Among CÀH functionalizations catalyzed by various metals,
Pd-catalyzed CÀH functionalizations directed by synthetically
useful functional groups offer great versatility in terms of achiev-
ing a broad range of transformations.12 Unfortunately, this ap-
proach has been largely unsuccessful with pyridyl CÀH
bonds.13À16 Pd-catalyzed arylation of C(3)ÀH and C(4)ÀH
bonds directed by an acidic amide has recently been reported, but
with a limited substrate scope (eq 1).14b The use of pyridyl
N-oxide and N-iminopyridinium ylide substrates has allowed for
the development of a number of CÀH functionalization reac-
tions but is limited to the C-2 positions (eq 2).15
Despite such progress, palladium-catalyzed C-3 or C-4 selec-
tive CÀH functionalizations of pyridine have not been achieved
Received: March 8, 2011
Published: April 14, 2011
r
2011 American Chemical Society
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Table 2. Pd-Catalyzed Olefination of Pyridine Derivatives a,b,c
Figure 1. Bioactive 3-alkenyl or 3-alkyl pyridine derivatives.
Scheme 1. Assembly of Reactive Precursor via a trans-Effect
Table 1. Ligand Effectsa
a Reaction conditions: 1a (8.0 mmol), 2a (0.5 mmol), Pd(OAc)2
(10 mol %), Ligand (13 mol %), and Ag2CO3 (0.25 mmol) in DMF
(1 mL). b Isolated yield of C-3 product. c Ratio of C-3/C-2/C-4 was
determined by 1H NMR. d Bathophenanthroline (13 mol %), 24 h. e 3.0
and 1.5 mmol of pyridine substurate were used respectively.
In general, broadening the scope of substrates and reaction
partners in C-3 or C-4 pyridyl CÀH functionalizations has
proven extremely challenging in previous studies.2À9,13À16 We
first examined the compatibility of the olefin coupling partners
(Table 2). Terminal olefin coupling partners containing ester,
amide, ketal, and aryl moieties were found to be suitable reactants
(3aÀ3f) while internal olefins gave low yields (∼15%). The
scope of the pyridine substrates was also extensively surveyed.
Pyridines containing both electron-donating and -withdrawing
groups were olefinated selectively in synthetically useful yields
(3gÀ3i). Substitution at the C-2 position by either methoxy,
chloride, or fluoride was also tolerated (3jÀ3r). The relatively
high reactivity of 2-methoxy-5-trifluoromethylpyridine allowed
for the use of 6.0 or 3.0 equiv of the pyridine substrate to give
product (3j) in 68% and 48% yields respectively. It is worth
noting that methoxy, chloride, and fluoride on C-2 are versatile
handles for further transformations.19 The presence of a 2-CF3
a Reaction conditions: 1a (8.0 mmol), 2a (0.5 mmol), Pd(OAc)2
(10 mol %), Ligand (13 mol %), and Ag2CO3 (0.25 mmol) in DMF
(1 mL). b Yield and isomer ratio (C-3/C-2/C-4) were determined by 1H
c
NMR of crude reaction mixture. Ag2CO3 was reduced to 0.1 mmol
under 1 atm of O2. d 1a was reduced to 2.0 mmol.
PdCl2 gave poor yields (∼40%). Using the Phen ligand, the
amount of Ag2CO3 could be reduced to 0.2 equiv without
decreasing the yield significantly (entry 10). However, the yield
was found to decrease from 87% to 37% when the amount of
pyridine was reduced from 16 to 4 equiv (entry 11).
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Scheme 2. Kinetic Isotope Effect
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group resulted in a low yield (3s). Para-substitution also reduced
the yield significantly due to steric hindrance (3t). Olefination of
quinoline and pyrimidine also gave relatively low yields (3u and
3v, respectively).
To gain insights into the origin of the reactivity and selectivity
of this novel Pd-catalyzed CÀH functionalization of pyridines,
we performed a kinetic isotope effect study (Scheme 2).
A significant isotope effect was observed (kH/kD = 4.0), which is
consistent with a mechanism that involves a Pd-mediated CÀH
cleavage step rather than a Lewis acid mediated FriedelÀCrafts
reaction. Further kinetic studies are necessary to determine whether
CÀH cleavage is the rate-limiting step.
In summary, a novel protocol to effect Pd-catalyzed C(3)ÀH
olefination of pyridines has been developed using air and catalytic
Ag2CO3 as the oxidants. The assembly of the reactive complex is
enabled by a strong trans-effect from the bispyridine ligands. The
resulting C-3-olefinated pyridines are highly useful building
blocks for the synthesis of bioactive alkaloid natural products
and drug molecules. This initial success in achieving selective
palladation of pyridyl CÀH bonds should now permit exploita-
tion of previously established catalytic systems for Pd-catalyzed
CÀH functionalization, providing a new avenue for developing
CÀC and CÀheteroatom bond-forming reactions of pyridines.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
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’ AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge the Scripps Research Institute for
financial support. G.-L.G. is a visiting student from the State Key
Laboratory of Applied Organic Chemistry, School of Chemistry
and Chemical Engineering, Lanzhou University and is sponsored
by the China Scholarship Council.
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