Pd(II)-catalyzed sequential C-C/C-O bond formations: A new strategy to construct trisubstituted furans

Article abstract of DOI:10.1021/ol400451t

Palladium-catalyzed oxidative difunctionalization of enol ethers with 1,3-dicarbonyl compounds to construct trisubstituted furans in one step under mild conditions is described. The reaction is thought to proceed through a C-C bond formation along with a C-O bond closing the ring structure. Oxygen is the sole oxidant regenerating the Pd(II) catalyst.

Full text of DOI:10.1021/ol400451t

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd(II)-Catalyzed Sequential CꢀC/CꢀO
Bond Formations: A New Strategy to
Construct Trisubstituted Furans
Meifang Zheng, Liangbin Huang, Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P.R. China
jianghf@scut.edu.cn
Received February 18, 2013
ABSTRACT
Palladium-catalyzed oxidative difunctionalization of enol ethers with 1,3-dicarbonyl compounds to construct trisubstituted furans in one step
under mild conditions is described. The reaction is thought to proceed through a CꢀC bond formation along with a CꢀO bond closing the ring
structure. Oxygen is the sole oxidant regenerating the Pd(II) catalyst.
Bond formation through transition-metal-catalyzed
functionalization of unsaturated hydrocarbons continues
to be a fantastic research arena due to its great potential for
applications in natural product and bioactive compound
synthesis.1 Because of this potential, increasing effort has
been devoted to the Pd-catalyzed difunctionalization of
alkenes, such as carboamination,2 carboetherification,3
carbohalogenation,4 and carboesterification5 of alkenes.
Most of these reactions employed terminal alkenes as the
substrates, and strong oxidants are needed. However,
literature reports on oxidative difunctionalization of the
internal alkenes have not been prevalent.6 As a subclass
method of alkene difunctionalization, carboetherificated
decoration of an alkene enables the formation of a CꢀO
bond during ring closure along with a CꢀC bond adjacent
to the ring,7 which adds considerable utility in the con-
struction of related heterocycles. Aryl-substituted enol
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r
10.1021/ol400451t
XXXX American Chemical Society

ethers, as readily available and versatile substrates, have
seldom been employed because of their self-intramolecular
FriedelꢀCrafts cyclizations.8 In addition, the utilization of
molecular oxygenasa green and inexpensiveoxidant is one
of the most important goals in oxidation chemistry.9 Here-
in, we report a palladium-catalyzed highly selective oxida-
tive carboetherification of alkyl enol ethers with 1,3-
dicarbonyl compounds, which illustrates an efficient ex-
ample of achieving trisubstituted furans in one step under
mild conditions.
The furan moiety represents a key structural unit that
occurs ubiquitously in biologically active natural and
pharmaceutical compounds.10 Thus, the development of
a practical and efficient synthetic method for furans is of
significant importance. Although diverse approaches to-
ward the synthesis of furans have been exploited, improve-
ment is still needed for a mild and efficient synthetic
method of high regioselectivity.11 In recent years, our
group has developed efficient methods for the construction
of functionalized furan derivatives via Cu-, Ag-, Fe-cata-
lyzed intramolecular procedures.12 Evidently, an oxidative
cross-coupling reaction between enol ethers and 1,3-carbonyl
compounds to construct trisubstituted furans, using oxygen
as the sole oxidant, would be a fascinating approach.
DCE. As we expected, carboetherification of 1a indeed
preceded readily under 1 atm air at 75 °C to give the furan
product3aa inmoderateyield (Table1, entry 1). Tofurther
improve the yield, we examined a range of acids, and
In(OTf)3 was found to be the most effective, while other
Lewis acids were either poorly effective [FeCl2, SnCl2,
Sc(OTf)3, MgClO4, Sc(OTf)3 (entries 2ꢀ3 and entries
5ꢀ6)] or entirely ineffective [ZnCl2, Yb(OTf)3 (entries
7ꢀ8)]. The reaction did not proceed at all in the absence
of acid additives or palladium catalyst (entries 9ꢀ10).
When a Brønsted acid, such as HOTf, was added for this
transformation, phenylacetaldehyde was the main product
through hydrolysis (entry 11). It must be noted that with
the same amounts of PdCl2 and PdI2 as the catalyst the
reaction took place in 12% and 20% yield, respectively
(entries 12ꢀ13). The examination of the solvent effect
revealed that DCE was the best choice for this system
(entry 4), while other solvents were less efficient (entries
15ꢀ16) or even totally ineffective (entry 14). At a lower
temperature (50 °C), the conversion of 1a decreased and
gave only 78% of 3aa (entry 17). Moreover, the reaction
could not occur without oxygen atmosphere (entry 18).
Table 2. Scope of 1,3-Diketonesa
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
additive
solvent
yieldc (%)
1b
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
ꢀ
Zn(OTf)2
FeCl2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
DMA
dioxane
DCE
DCE
51
22
3
SnCl4
19
4
In(OTf)3
Sc(OTf)3
MgClO4
ZnCl2
91 (85)d
66
5
6
47
7
trace
trace
N.P.
trace
trace
12
8
Yb(OTf)3
ꢀ
9
10
11
12
13
14
15
16
17e
18f
In(OTf)3
HOTf
Pd(OAc)2
PdCl2
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
PdI2
20
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
N.P.
trace
61
a The reaction was carried out with 0.3 mmol of 2-methoxyvinylben-
zene and 1.2 equiv of acetyl acetone in DCE (0.5 mL) at 75 °C in 1 atm O2
balloon for 18 h b Determined by GCꢀMS.
78
N.P.
a Reaction conditions: unless otherwise noted, the reaction was
carried out with 0.05 mmol of methoxystyrene and 1.2 equiv of acetyl
acetone in solvent (0.5 mL) at 75 °C in 1 atm O2 balloon for 18 h. b The
reaction was performed in the open air. c Determined by GCꢀMS. d Iso-
lated yield. e The reaction was performed at 50 °C for 18 h. f Under N2.
With optimized reaction conditions established, we
started to investigate other 1,3-carbonyl compounds in
this Pd-catalyzed, oxidative cyclization reaction (Table 2).
(10) (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo,
T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955–2020. (b)
Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076–2080. (c) Lipshutz, B. H.
Chem. Rev. 1986, 86, 795–819.
The reaction of 2-methoxyvinylbenzene (1a) and acetyl
acetone (2a) was initially employed in the presence of
5 mol % Pd(OAc)2 and 10 mol % Zn(OTf)2 in 1 mL of
B
Org. Lett., Vol. XX, No. XX, XXXX

A series of furans could be obtained in good to excellent
yields from different 1,3-diketones. Compared with un-
symmetrical 1,3-carbonyls, the symmetrical ones provided
higher furan yields. When the cyclohexane-1,3-dione was
used under standard conditions, 2-phenyl-6,7-dihydroben-
zofuran-4(5H)-one (3ab) was obtained in excellent yield.
Moreover, the 5-methyl- or 5-dimethyl-substituted cyclo-
hexane-1,3-diones were also incorporated, delivering the
corresponding furans regioselectively (3ac and 3ad). In an
expansion of the substrates, β-keto esters 2e and 2f were
used in the reaction with 2-methoxyvinylbenzene (1a), and
the corresponding products 3ae and 3af could be obtained
successfully in high yields and consistent chemoselectivity.
Notably, when both R1 and FG were aryl groups, the
target furans were provided as isomers in lower yields
(3ag). The 1,3-dicarbonyl compound bearing an amide
group was also reacted with 1a and afforded the furan
product 3ah in 10% yield. Unfortunately, 2-bromo-1-
phenylethanone was not a suitable substrate for the reac-
tion under the current conditions (3ai).
Table 3. Scope of β-Methoxystyrenesa
Next, a variety of methoxystyrene compounds were
evaluated in this Pd-catalyzed, oxidative cyclization reac-
tion (Table 3). Both electron-donating and -withdrawing
groups could be tolerated on the aromatic moieties to access
the 2,3,5-trisubstituted furans, including alkyl (3baꢀ3da,
3ha, and 3la), alkoxyl (3ea, 3fa), halogen (3iaꢀ3ka), amine
(3ga), and aromatic (3ma) groups. 1-Methyl-, 1-ethyl-, and
1-tert-butyl-substituted (2-methoxyvinyl)benzenes under-
went cyclization preferentially at the less hindered position
to afford the corresponding furans with a single regioisomer
in excellent yields (87%, 82%, and 82% respectively). Sub-
stituents at the meta positions of 2-methoxyvinyl-derived
moieties (1gꢀ1i) were tolerated, delivering good yields of the
corresponding furans (3gaꢀ3ia). Impressively, in the case
of 3-(2-methoxyvinyl)aniline (1g), 78% of the carboether-
ification product, 1-(5-(3-aminophenyl)-2-methylfuran-3-yl)-
ethanone (3ga), was isolated, which clearly demonstrated that
a meta substitution effect caused by the NH2ꢀ group also
existed in the present transformation. A similar reactivity
trend for 5-(biphenyl-4-yl)-2-methyl-3-acetate-furan (3ma)
a The reaction was carried out with 0.3 mmol of 2-methoxyvinylben-
zene and 1.2 equiv of acetyl acetone in DCE (0.5 mL) at 75 °C in 1 atm O2
balloon for 18 h. b The reaction was performed at 60 °C.
was observed during our investigations on the usage of
4-phenylmethoxystyrene. When 4-fluoro-methoxylstyrene
was employed, 5-(4-fluorophenyl)-2-methyl-3-acetate-fur-
an (3ja) was obtained with excellent yield and exclusive
regioselectivity. For example, substrates bearing an elec-
tron-rich substituent all gave good conversions and che-
moselectivity (3ea and 3fa). Generally, compared with
halogen substituents, the electron-rich groups on the aro-
matic ring improved this procedure (3baꢀ3fa, 3gaꢀ3ha,
and 3la), favoring the chemoselectivity of the products
(3iaꢀ3ka). This might reveal that the electronic nature of
the substituents on the phenyl ring has a pronounced effect
on the overall efficiency of the process.
Notably, polysubstituted furans could also be acquired
via oxidative CꢀC/CꢀO formations under this catalytic
system. To further investigate the property of the methoxyl
group of methoxystyrene, several experiments were con-
ducted under the standard conditions with alternative
substrates instead of 2-methoxyvinylbenzene (Scheme 1).
Interestingly, 1-chloro-2-(2-methoxyvinyl)benzene which
possessed the ortho site gave the other regioselective
carboetherification product 3na in lower yields, which
might be due to the steric hindrance. Note that when ethyl
acetoacetate was used instead of acetylacetone, the same
positionedsubstitutedfuran3nf wasobtainedingoodyield
(eq 1 in Scheme 1). Neither buta-1,3-dienylbenzene13 nor
styrene could carry out the carboetherification effectively
(eq 2 in Scheme 1). Furthermore, although the styrenyl
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Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Control Experiments
Scheme 2. Possible Reaction Mechanism
acetate could be successfully converted to the desired furan
in 62% yield, conversion was lower than that of the
β-methoxystyrene (eq 3 in Scheme 1).
multisubstituted furans. This catalytic cyclization process
with the use of oxygen as the sole oxidant, has a broad
substrate scope and affords furan derivatives in good to
excellent yields. Ongoing researchinvolves the extension of
substrate scope, and further investigations of the synthetic
application as well as detailed mechanistic studies are
underway in our labortary.
On the basis of the above results, a tentative mechanism
for the Pd(II)-catalyzed oxidative coupling between
2-methoxyvinylbenzenes and 1,3-diketones is proposed
(Scheme 2). First, In(OTf)3 reacts with the enolized form
of a β-diketone to generate the In(III) intermediate and
release triflic acid which then effects transmetalation with
Pd(OAc)2, furnishing an alkylpalladium complex A.14
A
theninserts into the styrenyl methyl ether toform B instead
of B0 because of the electronic property of the ꢀOMe
group governing the more stable intermediate. The sub-
sequent oxypalladation gives palladacycle C.15 Reductive
elimination of C leads to precursor D, followed by the
extrusion of methanol to deliver the target product 3aa.
Finally, Pd(0) is oxidized by O2 to regenerate the Pd(II)
catalyst.
In conclusion, we have developed a new Pd-catalyzed
method for the formation of C(sp2)ꢀC(sp3) and CꢀO
bonds through carboetherification of enol ethers
with 1,3-carbonyls, which allows the facile synthesis of
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20932002,
21172076, and 21202046), the National Basic Research
Program of China (973 Program) (2011CB808600), Guang-
dong Natural Science Foundation (10351064101000000
and S2012040007088), China Postdoctoral Science Foun-
dation (2012T50673), and the Fundamental Research
Funds for the Central Universities (2012ZP0003 and
2012ZB0011). We also thank the Yangtze River scholars
and innovative team of Ministry of Education for support.
Supporting Information Available. Typical experimen-
tal procedure and characterization for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX