Construction of the flavones and aurones through regioselective carbonylative annulation of 2-bromophenols and terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2013.01.043

The easily available and efficient catalyst containing a benzimidazolium ligand and PdCl₂(PPh₃)₂ demonstrated excellent catalytic activity to construct the flavones and aurones, respectively. This reaction can be operated under mild conditions, affording the desired products in moderate to good yields. This protocol was used to prepare the flavones and aurones by a slight modification of amines.

Full text of DOI:10.1016/j.tetlet.2013.01.043

Tetrahedron Letters 54 (2013) 1802–1807
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of the flavones and aurones through regioselective
carbonylative annulation of 2-bromophenols and terminal alkynes
⇑
Jianming Liu, Muwen Liu, Yuanyuan Yue, Ningfei Zhang, Yuanli Zhang, Kelei Zhuo
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Environmental Science, Henan Normal University,
Xinxiang, Henan 453007, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The easily available and efficient catalyst containing a benzimidazolium ligand and PdCl2(PPh3)2 demon-
strated excellent catalytic activity to construct the flavones and aurones, respectively. This reaction can
be operated under mild conditions, affording the desired products in moderate to good yields. This pro-
tocol was used to prepare the flavones and aurones by a slight modification of amines.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 8 October 2012
Revised 7 January 2013
Accepted 11 January 2013
Available online 30 January 2013
Keywords:
2-Bromophenols
Carbonylative annulation
Flavones
Aurones
Palladium-catalyzed carbonylative reactions of organic halides
in the presence of various nucleophiles have undergone a great
deal of development since the pioneering work of Heck and co-
workers in 1974.1 A wide range of aromatic acyl derivatives, such
as aldehydes, acids, esters, amides, and ketones could be selec-
tively synthesized by carbonylation reaction.2 Among these com-
pounds, both flavones and aurones are indispensable
intermediate moieties in many biologically active molecules.3–5
Therefore, developing highly efficient and selectivity methods for
constructing these two classes of chromones from readily accessi-
ble substrates continues to be a hot research topic. In general, tra-
ditional synthetic methods for those compounds rely on the
following strategies: (i) cyclization of l-(2-X-phenyl)-3-phenyl-
1,3-propanediones (X = OH, OR, Br, Cl),6 (ii) 20-hydroxychalcones
initiated by acid or base,7 (iii) Pd-catalyzed oxidative arylation of
chromones with phenylboronic acids,8 (iv) Pd-catalyzed carbony-
lative cyclization using CO gas as carbonyl resource,9 (v) the
Wheeler aurone synthesis from chalcone dihalides,10 (vi) oxidative
cyclization of 20-hydroxychalcones,11 and (vii) ring closure of o-
hydroxyaryl phenylethynyl ketones.12 Despite the existence of
many methods for the preparation of flavones and aurones, more
general and easily available routes would be still highly required.
Direct transformation of the simple 2-iodophenols and terminal al-
kynes into the corresponding chromones via the Pd-catalyzed car-
bonylative annulation reaction is arguably a highly efficient and
easy method.13 Until now, the difficult activation and easy avail-
ability of 2-bromophenols could not be applied successfully to con-
struct the chromone derivatives. Therefore we present a facile
route to prepare the flavones and aurones through Pd-catalyzed
carbonylative annulation reaction of 2-bromophenols and terminal
alkynes in secondary amines (Scheme 1). The key of the route just
presents one-pot synthesis of chromones from easily available sub-
strates. As our extending work in developing carbonylative reac-
tions, herein we report a Pd-catalyzed cascade carbonylative
cyclization approach to the flavones and aurones that proceeds in
good to excellent yields. To the best of our knowledge, this is the
first catalytic process to obtain the chromones from 2-bromophe-
nols and terminal alkynes controllably by different amines.
Based on previous research on palladium-catalyzed carbonyla-
tive coupling reactions,14 the reaction of 2-bromophenol with
phenylacetylene was chosen as a model reaction to explore and
optimize the cascade carbonylative reaction in the presence of
2.0 MPa CO. In our initial screens, the effects of different reaction
parameters (i.e., catalytic precursor, ligand, temperature, and sol-
vent) were investigated, respectively, and the results are summa-
rized in Table 1. The yield decreased when the pressure of CO
was below 2.0 MPa and the reaction temperature below 130 °C
(Table 1, entries 1–3). To our delight, the reaction obtained a 78%
yield of the desired flavones under the optimized reaction (Table 1,
entry 6). Then the effect of solvent on the reaction was also inves-
tigated. A survey of solvents revealed that n-Pr2NH is a better sol-
vent than the others (Table 1, entries 5–10). Subsequently, the
⇑
Corresponding author.
E-mail address: klzhuo@263.net (K. Zhuo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.043

J. Liu et al. / Tetrahedron Letters 54 (2013) 1802–1807
1803
O
O
Br
PdCl2(PPh3)2/L
R1
+
R1
O
+
R2 CO
n-Pr2NH
OH
R2
O
O
Br
PdCl2(PPh3)2/L
R2
R1
+
+
R2 CO
+
R1
R1
n-Pr2NH/i-Pr2NH
OH
O
R2
Major product
Minor product
N
N
N
N
N
L
Scheme 1. Synthesis of flavones and aurones.
Table 1
Screening the conditions for the Pd-catalyzed carbonylative annulation of 2-bromo-
on the reaction conditions are necessary to afford good yields of
flavones, and no formation of aurones was observed in this
transformation.
phenol and phenylacetylenea
O
According to the results obtained by the synthesis of flavones
between 2-iodophenols and terminal alkynes previously,13 a plau-
sible mechanism for the present process can be proposed as shown
in Figure 1. Benzimidazole–triazole ligand maybe stabilized the
generated Pd(0), this can make for the oxidative insertion of the
aryl halide to generate the arylpalladium complex. The Pd(0) cata-
lyst first underwent oxidative addition of the aryl halide to gener-
ate the arylpalladium complex. Insertion of carbon monoxide into
the aryl carbon–palladium bond could afford the aroylpalladium
Br
Pd catalyst
+
+
CO
OH
O
Ph
1a
2a
3aa
Entry
Catalyst
N-Ligand
T (°C)
Solvent
Yieldb (%)
1c
2
3
4
5
6
7
8
9
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
L
L
L
L
L
L
L
L
130
110
90
n-Pr2NH
n-Pr2NH
n-Pr2NH
n-Pr2NH
Et2NH
n-Pr2NH
i-Pr2NH
n-Bu2NH
Morpholine
Et3N
46
21
10
Trace
68
78
NR
72
19
5.0
36
bromide complex (I), and then the a,b-alkynyl ketone intermediate
II could be obtained by alkynes’ attack of the enolate carbon on the
palladium atom and reductive elimination. In this catalytic cycle, II
would be a critical intermediate in the formation of VII and VIII.
The intermediate II then underwent Michael addition of the n-
Pr2NH to proceed through IV and V stages or a direct 6-endo-dig
cyclization to generate flavones (VII). On the other hand,13f the
compound II may subsequently form a complex III with palladium
(0), followed by undergoing rearrangement and reductive elimina-
tion to afford aurones (VIII).
130
130
130
130
130
130
130
130
130
L
L
10
11
12
Phen
—
n-Pr2NH
n-Pr2NH
37
Encouraged by the good results mentioned above, we then
tested the catalytic activity of benzimidazole–triazole ligand and
PdCl2(PPh3)2 for the formation of aurones. We observed that
decreasing the amount of n-Pr2NH proceeded uneventfully to ob-
tain the product of aurone. While i-Pr2NH was used as solvent,
no flavone and aurone were obtained. A probable reason why the
compound II was not formed was that the cabonylative reaction
of acetylene with 2-bromophenol was not carried out. Such results
suggest that the intermediate II did not undergo Michael addition
of i-Pr2NH to obtain IV. Then it may form a complex III with Pd(0),
followed by the rearrangement and reductive elimination to afford
aurones. On the basis of the above studies, the reaction conditions
using benzimidazole–triazole ligand and PdCl2(PPh3)2 in n-Pr2NH
a
Reactions were carried out in 4.0 mL of solvent under 2.0 MPa pressure of CO at
130 °C for 24 h with 2-bromophenol (1.0 mmol), phenylacetylene (2.0 mmol), Pd
catalyst (0.05 mmol), and benzimidazolium ligands (0.05 mmol).
b
Isolated yield.
1.0 MPa CO.
c
desired product was observed in a 36% yield in the presence of
1,10-phenanthroline (Table 1, entry 11).
Having established the effective catalytic system for the one-
pot synthesis of flavones, then we focus our attention on exploring
the generality of this methodology with respect to various acety-
lenes and substitute of 2-bromophenols. Under the optimal reac-
tion,15 it was found that alkyne reagents with an alkyl group in
the para positions of phenyl group with 2-bromophenol were able
to undergo the cascade reaction to afford the desired products in
72–86% yields (Table 2, entries 2–4). Furthermore, the reaction of
1-hexyyne with 2-bromophenols occurs in a highly regioselective
fashion to give the corresponding flavones in 65% and 43% yields,
respectively (Table 2, entries 5 and 6). To probe the scope and lim-
itation of this process, we also examined other 2-bromophenols
under the standard reaction conditions. All of the substrates bear-
ing either an electron-rich group or an electron-poor group at the
para-positions of the phenyl groups were well tolerated in this
transformation (Table 2, entries 7–13). From the results, it is evi-
dent that 2-bromophenols bearing an electron-withdrawing group
lead to an increase obviously in the yields. Overall, no adjustments
(8.0 lL) and i-Pr2NH (4.0 mL) were employed as the standard reac-
tion conditions for other substrates. The results are presented in
Scheme 2. It indicated that benzimidazole–triazole ligand and
PdCl2(PPh3)2 catalyst system could be successfully employed for
the one-pot synthesis of a range of aurones. All processes were
highly regioselective, and gave the E-isomer as the main product.
When different alkynes were employed, the 2-bromophenol effi-
ciently provided the aurones in 62–75% yields (4aa–4ad) and the
flavones in 3–8% yields (3aa–3ad). Gratifyingly, the reaction of al-
kynes with 2-bromophenols with electron-rich and electron-poor
phenyl moieties gave the desired products in good to high yields
(4ba–4cd).
In summary, we have developed a simple and efficient Pd-cata-
lyzed cascade carbonylative cyclization of various 2-bromophenols

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J. Liu et al. / Tetrahedron Letters 54 (2013) 1802–1807
Table 2
Carbonylative annulation of various 2-bromophenol and acetylenesa
O
O
Br
PdCl2(PPh3)2/L
R1
+
R1
+
R2 CO
n-Pr2NH
OH
R2
1
2
3
Entry
1
2-Bromophenol
RC„CH
Product
Yieldb (%)
Br
O
OH
78
O
O
Br
OH
2
3
82
72
O
O
Br
MeO
OH
O
O
OMe
Br
OH
4
86
O
O
O
Br
5
6
65
43
OH
Br
O
OH
Br
O
O
OH
7
8
83
73
O
O
Br
OH
O
O
Br
OH
9
84
90
O
F
Br
O
F
OH
10
O

J. Liu et al. / Tetrahedron Letters 54 (2013) 1802–1807
1805
Table 2 (continued)
Entry
2-Bromophenol
RC„CH
Product
Yieldb (%)
F
Br
O
F
OH
11
12
88
81
O
O
F
Br
MeO
F
OH
O
O
OMe
F
Br
F
OH
13
89
O
a
Reactions were carried out in 4.0 mL of n-Pr2NH under 2.0 MPa pressure of CO at 130 °C for 24 h with 2-bromophenols (1.0 mmol), phenylacetylene (2.0 mmol),
PdCl2(PPh3)2 (0.05 mmol), and benzimidazolium ligands (0.05 mmol).
b
Isolated yield.
Ln
Pd Br
Br
R1
R1
CO
OH
OH
1
O
PdLnBr
LnP
d(0)
R1
O
OH
I
R2
+
Base
R2
O
Pd
R2
or
R1
PdBr
H
OH
OH
O
O
O
R2
O
LnPd(0)
R'R'NH
R1
R1
R2
Pd
H
R1
Michael
addition
OH
R2
NR'R'
III
O-
II
IV
6-endo-trig
cyclization
O-
O
R2
6-endo-dig
cyclization
R1
R1
NR'R'
R2
Pd
O
VI
O
O
O
V
R1
R1
O
VIII
R2
O
VII
R2
Figure 1. Proposed mechanistic interpretation for the formation of flavone and aurone.
and phenylacetylenes for the synthesis of flavone and aurone
derivatives. A range of 2-bromophenols and various phenylacetyl-
enes could undergo the cascade reaction smoothly to give the
responding chromones in satisfactory yields. The reaction tolerates
various functionalities, such as methyl, methoxy, tert-buty, and
fluoro groups.

1806
J. Liu et al. / Tetrahedron Letters 54 (2013) 1802–1807
O
O
O
Br
R2
PdCl2(PPh3)2/L
+
R1
R1
R1
+
+
R2
CO
O
n-Pr2NH/i-Pr2NH
R2
OH
1
2
3
4
O
O
O
O
O
O
O
O
E/Z= 45:1 75% 4aa
OMe
3% 3aa
O
E/Z= 29:1 68% 4ab
5% 3ab
O
Bu-t
O
O
O
O
O
O
OMe
Bu-t
6% 3ac
O
E/Z= 11:1 61% 4ac
E/Z= 11:1 74% 4ad
8% 3ad
O
O
O
O
O
O
O
E/Z= 28:1 71% 4bb
E/Z= 22:1 62% 4ba
5% 3bb
4% 3ba
Bu-t
O
O
F
O
O
O
F
O
O
O
Bu-t
7% 3ca
E/Z= 15:1 80% 4bd
7% 3bd
O
E/Z= 44:1 78% 4ca
OMe
F
O
F
O
O
F
F
O
O
O
OMe
O
8% 3cb
E/Z= 24:1 78% 4cb
7% 3cc
E/Z= 11:1 76% 4cc
O
Bu-t
F
O
O
F
O
Bu-t
E/Z= 21:1 79% 4cd
8% 3cd
Scheme 2. Carbonylative annulation of various 2-bromophenols and phenylacetylenes.
2. For a recent review, see: Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2009, 48, 4114.
Acknowledgments
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We are grateful for the financial support from the National Nat-
ural Science Foundation of China (No. 21103044, 21173070,
21205029), Ph.D. Programs Foundation of Ministry of Education
of China (No. 20114104120003, 20124104120004), and Founda-
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