Palladium-catalyzed tandem reactions of β-(2-bromophenyl)-α, β-unsaturated carbonyl compounds with 2-hydroxyphenylboronic acid: A new route to benzo[c]chromenes

Article abstract of DOI:10.1002/ejoc.201101670

Palladium-catalyzed tandem reactions of β-(2-bromophenyl)-α, β-unsaturated carbonyl compounds with 2-hydroxyphenylboronic acid for the synthesis of benzo[c]chromenes are presented. This mild reaction allows formation of onecarbon-carbon bond and one carbo

Full text of DOI:10.1002/ejoc.201101670

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101670
Palladium-Catalyzed Tandem Reactions of β-(2-Bromophenyl)-α,β-Unsaturated
Carbonyl Compounds with 2-Hydroxyphenylboronic Acid: A New Route to
Benzo[c]chromenes
Qihua Zhu,[a] Xuyan Wang,[a] and Yungen Xu*[a]
Keywords: Palladium / Boron / Fused-ring systems / Cross-coupling
Palladium-catalyzed tandem reactions of β-(2-bromophenyl)-
α,β-unsaturated carbonyl compounds with 2-hydroxyphen-
ylboronic acid for the synthesis of benzo[c]chromenes are
presented. This mild reaction allows formation of one
carbon–carbon bond and one carbon–oxygen bond in one
pot.
We herein describe a new strategy involving a palladium-
catalyzed Suzuki–Miyaura aryl–aryl bond formation reac-
tion for the synthesis of benzo[c]chromenes in high yield.
Compared with existing procedures, this methodology has
several advantages, including operational simplicity, high
yields, short reaction times, and simple materials.
Introduction
Benzo[c]chromenes are important structural units which
are widespread in many naturally and biologically active
compounds. For example, 5H-dibenzo[c,g]chromen-3-ol has
been reported to be an estrogen receptor agonist.[1,2] They
are also the basic structure of cannabinols.[3] Although di-
verse synthetic approaches toward benzo[c]chromenes have
been developed,[4,5] convenient and efficient methodologies
to synthesize these compounds are still in need.
Results and Discussion
In this reaction, β-(2-bromophenyl)-α,β-unsaturated
carbonyl compounds were coupled with 2-hydroxyphen-
ylboronic acid to form an aryl–aryl bond by a Suzuki–Mi-
yaura reaction. Attack of the hydroxy group of the resulting
intermediate at the olefinic carbon atom then afforded the
benzo[c]chromenes. Reaction between 1a and 2 was chosen
as a model reaction to optimize the reaction conditions.
Several Pd sources were investigated (Table 1, Entries 1–5),
and Pd(PPh3)4 exhibited the highest efficiency (Table 1, En-
try 2). Subsequently, a series of solvents, including acetoni-
trile, toluene, 1,4-dioxane, DMF, DMA, and DME, were
screened, and it was found that DME was the best solvent.
With the optimal reaction conditions in hand, the scope of
this transformation was investigated by studying the reac-
tion of β-(2-bromophenyl)-α,β-unsaturated carbonyl com-
pounds with 2-hydroxyphenylboronic acid, Pd(PPh3)4, and
2 m Na2CO3 in DME.
Reactions of β-(2-bromophenyl)-α,β-unsaturated carb-
onyl compounds 1b–l with 2 under the optimal conditions
were then examined (Table 2, Entries 2–12). We were ple-
ased to find that the reaction between 1 containing either
electron-withdrawing or -donating functional groups on the
aromatic ring and 2 proceeded smoothly under the optimal
conditions (Table 2, Entries 2–12) and provided the desired
products in excellent yields. For example, substrate 1h and
1l, both bearing a nitro group at the 5-position of the aro-
matic ring, were treated with 2 to efficiently provide the
products in good yield (Table 2, Entries 8 and 12). Substrate
Recently, Motti[6] reported the preparation of benzo[c]-
chromenes through palladium- and norbornene-catalyzed
reactions of ortho-substituted aryl iodides, o-bromophenols,
and activated olefins. Li et al.[7] reported that benzo[c]-
chromenes could be obtained by palladium-catalyzed annu-
lations of 2-(2-iodophenoxy)-1-arylethanones and 1-(2-
iodophenoxy)propan-2-one with arynes. They had ex-
ploited palladium-catalyzed aryl–aryl cross-coupling reac-
tions to form palladium-bonded biphenylyl structures con-
taining an ortho-phenolic moiety.
The synthesis of biaryls through C–C bond-formation re-
actions is of great interest because of their presence in many
natural products and functional materials.[8] The transition-
metal-catalyzed formation of C–C bonds by cross-coupling
reactions has thus been developed in the past decades.[9]
Among the various biaryl coupling methods, the Suzuki–
Miyaura coupling has attracted attention due to its high
substrate tolerance and the lower toxicity of boronic acids
compared to that of other organometallic reagents.[10]
Therefore, the homocoupling of arylboronic acids is a valu-
able method to obtain asymmetrical biaryls.
[a] Department of Medicinal Chemistry,
China Pharmaceutical University,
Nanjing 210009, China
Fax: +86-25-83271487
E-mail: xu_yungen@hotmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101670.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 1112–1114

Pd-Catalyzed Tandem Reactions: A Route to Benzo[c]chromenes
Table 1. Optimization of reaction conditions for the formation of
3.[a]
Entry
Catalyst
Solvent
Tempera-
ture
[°C]
Yield
[%][b]
1
2
3
4
5
7
8
9
Pd(dppf)2Cl2
Pd(PPh3)4
Pd(dba)2
DME
DME
DME
DME
DME
reflux
reflux
reflux
reflux
reflux
102
reflux
reflux
102
80
95
23
34
83
33
60
30
56
Scheme 1. The possible reaction mechanism.
Pd(PPh3)2Cl2
Pd(dppf)2Cl2·CH2Cl2
Pd(PPh3)4
Conclusions
DMF
In summary, we have developed a mild method for the
synthesis of 6H-benzo[c]chromenes by palladium-catalyzed
tandem reactions of β-(2-bromophenyl)-α,β-unsaturated
carbonyl compounds with 2-hydroxyphenylboronic acid.
This new route allows formation of one carbon–carbon
bond and one carbon–oxygen bond in one pot. Import-
antly, we provide a convenient approach for the preparation
of 6H-benzo[c]chromenes. Efforts to extend the applications
of this transformation in organic synthesis and screening of
these types of compounds for biological activity are cur-
rently underway.
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
1,4-dioxane
acetonitrile
DMA
10
[a] Reaction conditions: 1 (0.78 mmol), 2 (1.0 equiv.), [Pd] (10 mol-
%), 2 m Na2CO3 (2 mL). [b] Isolated yield.
1 with a methoxy group also exhibited high reactivity.
Moreover, it was found that 1d and 1i, both containing a
fluorine atom on the benzene ring, were also suitable sub-
strates for this tandem reaction, and they afforded the cor-
responding products in excellent yields (Table 2, Entries 4
and 9).
Experimental Section
Table 2. Palladium-catalyzed tandem reactions of β-(2-bromo-
phenyl)-α,β-unsaturated carbonyl compounds with 2-hydroxyphen-
ylboronic acid to form benzo[c]chromenes.[a]
General Procedure for the Synthesis of 6H-Benzo[c]chromenes: To a
Schlenk-type flask containing a DME solution of a β-(2-bromo-
phenyl)-α,β-unsaturated carbonyl compound (0.78 mmol) and (2-
hydroxyphenyl)boronic acid (0.78 mmol) was added 2 m Na2CO3
(2 mL) and Pd(PPh3)4 (0.1 g, 10%mmol) under an atmosphere of
N2. The resulting mixture was heated at reflux for 4 h. After cool-
ing to room temperature, the solid was filtered. The filtrate was
concentrated under reduced pressure. The crude was purified im-
mediately by flash chromatography (silica gel 60, particle size 200–
300 mesh, petroleum ether/EtOAc, 15:1).
Entry
1
R1
R2
R3
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
OMe
OMe
H
H
H
OMe
F
H
H
OMe
H
F
H
OMe
H
CO2Et
CO2Et
CO2Et
CO2Et
COMe
COMe
COMe
COMe
COMe
COPh
COPh
COPh
95
90
92
91
90
91
95
92
93
95
90
92
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for compounds 1a–l; copies of the 1H
NMR, 13C NMR, and HRMS spectra for all new compounds.
H
OMe
OMe
NO2
H
H
OMe
NO2
Acknowledgments
9
This work was financially supported by the Fundamental Research
Funds for the Central Universities (Program No. JKY2011031). We
also appreciate the support from Center for Instrumental Analysis,
China Pharmaceutical University, for their contribution in the
structural confirmation.
10
11
12
1j
1k
1l
[a] Reaction conditions: 1 (0.78 mmol), 2 (1.0 equiv.), [Pd] (10 mol-
%), and 2 m Na2CO3 (2 mL) in DME at reflux for 4 h. [b] Isolated
yield.
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Q. Zhu, X. Wang, Y. Xu
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Received: November 22, 2011
Published Online: January 16, 2012
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Eur. J. Org. Chem. 2012, 1112–1114