Regioselective palladium-catalyzed olefination of coumarins via aerobic oxidative Heck reactions

Article abstract of DOI:10.1039/c2cc37676h

Pd-catalyzed oxidative Heck reactions of coumarins were developed via simultaneous C-H functionalization at the C3 position of coumarins under aerobic conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2cc37676h

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Regioselective palladium-catalyzed olefination of
coumarins via aerobic oxidative Heck reactions†
Cite this: Chem. Commun.,
2013, 49, 196
Minsik Min, Yechan Kim and Sungwoo Hong*
Received 22nd October 2012,
Accepted 12th November 2012
DOI: 10.1039/c2cc37676h
www.rsc.org/chemcomm
Pd-catalyzed oxidative Heck reactions of coumarins were developed efficient coumarin synthetic methods, our group recently
via simultaneous C–H functionalization at the C3 position of coumarins described a Pd(II)-catalyzed direct arylation of coumarins using
under aerobic conditions.
simple arenes, thereby permitting the construction of a variety
of 4-arylcoumarins (Scheme 1a).7 This finding prompted us to
In recent years, notable progress has been made toward enhancing explore the feasibility of the expeditious synthetic approach for
the efficiency of direct C–H bond activation in (hetero)arenes.1 The the installation of an olefin at the C3 position of coumarins to
current approach is advantageous in that it enables the direct extend the p-electron system, yielding enhanced optical properties.
formation of target molecules without requiring prefunctionaliza- Herein, we describe a regioselective Pd(II)-catalyzed C–H olefina-
tion of the starting materials, thereby minimizing undesired waste tion of coumarins with the use of 1 atm O2 as the stoichiometric
in fewer reaction steps. Since the discovery of direct olefination of oxidant in the absence of a co-oxidant.
benzene by Fujiwara,2 substantial progress has been made with
We explored the prospects of the proposed Pd-catalyzed
oxidative Heck reactions toward improving the reaction efficiency coupling reaction by investigating the reactivity of 7-methoxy-
as promising alternatives to conventional procedures.3 The scope of coumarin (1a) and tert-butyl acrylate (2a) as model substrates.
these reactions has remained limited, however, due to difficulties We were pleased to observe that the coupling product 3a was
associated with controlling a single C–H bond in the presence of obtained using a catalytic system comprising both Pd(OPiv)2 and
electronically or sterically similar C–H bonds.4
Cu(OAc), albeit in a 20% yield (entry 1). The functionalization
Coumarin derivatives exhibit a broad range of biological
activities5 and have been extensively investigated for their out-
standing optical properties.6 Over the course of developing
Table 1 Optimization of alkenylation conditionsa
Entry Oxidant (equiv.) Additive (equiv.)
Base
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (3)
Ag2CO3 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
TEMPO (1.2)
Air (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
—
—
—
—
—
—
—
—
—
—
20
35
Ag2CO3 30
K2CO3
K2CO3
K2CO3
K2CO3
40
75
76
81
CsOPiv 65
9
Cu(OAc)2 (0.1)
HPMoV (0.1)
PPh3 (0.2)
Xantphos (0.2)
K2CO3
K2CO3
K2CO3
K2CO3
59
63
44
40
45
10
11
12
13
Scheme 1 Regioselective oxidative coupling of coumarins.
Ethyl nicotinate (0.2) K2CO3
a
Reactions were conducted with coumarin, tert-butyl acrylate
Department of Chemistry, Korea Advanced Institute of Science and Technology
(KAIST), Daejeon, 305-701, Korea. E-mail: hongorg@kaist.ac.kr;
Fax: +82 42-350-2810; Tel: +82 42-350-2811
(2.0 equiv.), Pd(OPiv)2 (0.2 equiv.), and base (3 equiv.) in PivOH at
100 1C for 9 h. Yields are reported after isolation and purification by
flash silica gel chromatography. Piv = pivaloyl, TEMPO = 2,2,6,6-tetra-
methylpiperidin-1-yl)oxyl, HPMoV = molybdovanadophosphoric acid,
Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
b
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2cc37676h
c
196 Chem. Commun., 2013, 49, 196--198
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Table 2 Direct C3-olefination of the coumarins with various alkenesa
Fig. 1 Pd-catalyzed H/D exchange experiments analysed by 1H NMR: (a) without
D2O (0% exchange); (b) after 3 h (16% exchange); (c) after 12 h (41% exchange).
occurred selectively at the C3 position of the coumarin core. Among
the Pd species screened, Pd(OPiv)2 was most effective in promoting
the reaction. Both the base and the solvent were found to funda-
mentally influence the efficiency of the reaction, with K2CO3 and
pivalic acid8 being the optimal base and solvent, respectively. The
oxidant’s properties were also critical to the reaction efficiency, and
the use of TEMPO dramatically improved the catalytic efficiency
(entry 5). Recent advances in palladium-catalyzed aerobic oxidation
reactions suggested that the resulting Pd–H or Pd(0) species in this
coupling reaction could be oxidized by employing an environmen-
tally benign terminal oxidant, such as air or O2.9 To our delight, the
C3-alkenylation process worked well when the reaction was carried
out in the open air (entry 6, 76%). A slightly higher product yield
was obtained under an O2 atmosphere (entry 7, 81%). Ligands,
such as PPh3, Xantphos, pyridine or ethyl nicotinate, which have
been used in other Pd-catalyzed aerobic reactions10 led to lower
yields under the reaction conditions (entries 11–13 and the ESI†). In
addition, no beneficial effects were observed in the presence of
electron-transfer mediators, such as Cu(OAc)2 (entry 9) or HPMoV
a
Reactions were conducted with coumarin, alkene (2.0 equiv.),
Pd(OPiv)2 (0.2 equiv.), and K2CO3 (3 equiv.) in PivOH at 100 1C under an
b
O2 atmosphere for 3–9 h. A 1 : 1 mixture of isomers was produced.
c
Reactions were conducted at 120 1C. Yields are reported after isolation
Fig. 2 Proposed mechanistic pathways underlying the present reactions.
and purification by flash silica gel chromatography.
c
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(entry 10).11 The optimized catalytic conditions allowed for the Heck reaction. The choice of palladium catalyst source and base
direct installation of olefins at the C-3 position with the use of were important factors for achieving a high reaction efficiency, and
1 atm O2 as the sole oxidant, presenting an efficient and O2 was successfully utilized as the sole oxidant. This approach led
sustainable approach to the synthesis of a variety of fluorescent to the construction of a variety of 3-vinyl and 3-styryl coumarin
3-vinylcoumarin derivatives (Table 1).
scaffolds, which are privileged structures and prevalent motifs in
To elucidate the present alkenylation process, a mechanistic many biologically active compounds and fluorophores.
analysis of the initial interaction of Pd(II) with coumarin 1a was
carried out by means of a H/D exchange experiment.12
This research was supported by National Research Founda-
tion of Korea (NRF) through general research grants (NRF-2010-
A
significant level of deuterium incorporation (after 12 h, 41% D) 0022179, 2011-0016436, 2011-0020322). M. Min is the recipient
was observed at the C3 position of coumarin (1a) when the of a Global PhD Fellowship (NRF-2011-0007511).
reaction mixture was treated with D2O (20 equiv.) as a deuterium
source under the optimized conditions and in the absence of
alkene, as shown in Fig. 1 (see the ESI† for the full spectra).
Notes and references
¨
1 For selected recent reviews, see: (a) J. Wencel-Delord, T. Droge,
Based on the above observations, we proposed a mechanism
for the present reaction pathway (Fig. 2). Electrophilic pallada-
tion of coumarin at the C3 position with the Pd(II) species was
favorable due to the more nucleophilic 3-position, thereby
affording the intermediate II. In the presence of an alkene
substrate, the C3-palladated species II inserted into the olefin,
and the subsequent reductive elimination of a Pd/alkyl inter-
mediate III provided the desired coupled product 3. Finally, the
reoxidation by molecular oxygen regenerated the Pd(II) catalyst
to complete the catalytic cycle.
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With the optimized conditions in hand, we next investigated
the substrate scope of both the coumarin and the arene
substrate (Table 2). The present C3-alkenylation process was
amenable to the presence of a variety of functional groups. For
example, alkene substrates conjugated with the ester (3b and
3c), amide (3d), or phosphonate (3e) groups all smoothly
coupled with 7-methoxycoumarin at the C3 position. When
2-methyl substituted methyl arylate was employed as a sub-
strate, a mixture of regioisomers 3g (1 : 1) formed. Methyl
cinnamate also readily reacted with the coumarin to afford
the corresponding desired product (3f). The addition of the
styryl group to the 3 position of the coumarin core was expected
to induce a red-shift in the emission wavelength by extending
the p-electron system.13 To our delight, a variety of styrene
substrates were compatible with the coupling reaction condi-
tions, and modest to good yields of the desired products were
obtained (3h, 3i, 3j, 3k, and 3l). The scope of the coumarin
substrates was subsequently examined, and a relatively broad
range of functional groups (e.g., alkyl, chloro, methoxy, ethoxy,
benzoxy, triflate, and diethylamino) on the coumarin core were
compatible with the coupling conditions. Substitution with an
electron-donating OMe group at the 7-position enhanced the
reaction efficiency (3a vs. 3m). Notably, a coumarin bearing a
triflate substituent yielded the synthetically versatile 3r with an
intact triflate moiety under the reaction conditions. We further
investigated additional substrates and were pleased to observe
that quinolinones also worked well in the optimized system,
leading to the formation of 3u, 3v and 3w.
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´
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c
198 Chem. Commun., 2013, 49, 196--198
This journal is The Royal Society of Chemistry 2013