Copper-catalyzed ortho-acylation of phenols with aryl aldehydes and its application in one-step preparation of xanthones

Article abstract of DOI:10.1039/c2cc36176k

In the presence of triphenylphosphine, copper(ii) chloride can catalyze an intermolecular ortho-acylation reaction of phenols with aryl aldehydes. The reaction proceeds smoothly with a wide range of starting materials, and furthermore, it can be used to s

Full text of DOI:10.1039/c2cc36176k

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COMMUNICATION
Copper-catalyzed ortho-acylation of phenols with aryl aldehydes and its
application in one-step preparation of xanthonesw
Jun Hu,a Enoch A. Adogla,a Yong Ju,b Daping Fanc and Qian Wang*a
Received 24th August 2012, Accepted 26th September 2012
DOI: 10.1039/c2cc36176k
In the presence of triphenylphosphine, copper(II) chloride can
catalyze an intermolecular ortho-acylation reaction of phenols
with aryl aldehydes. The reaction proceeds smoothly with a wide
range of starting materials, and furthermore, it can be used to
synthesize xanthone derivatives in a single step in high yields.
pharmacological properties, such as antitumoral, antibacterial
and antiinflammatory.14
To investigate the optimized reaction protocol, 3-methoxy-
benzaldehyde (1a) and 4-methoxyphenol (2a) were refluxed in
toluene for 24 h in the presence of 5 mol% Pd(OAc)2,
7.5 mol% triphenylphosphine and 2.2 equiv. K2CO3, and
the product (3aa) was obtained in 77% yield. With this
promising result, a systematic screening of catalysts, ligands,
and bases was carried out and the results are summarized in
Table S1 (ESIw). Based on the results of Table S1 (ESIw), we
chose 1 mmol aldehyde, 1.3 mmol phenol in toluene at 110 1C
in the presence of 5 mol% of CuCl2, 7.5 mol% of PPh3 and
K3PO4 (2.2 equiv.) as the standard reaction conditions.
We next explored the reaction scope with various phenols
and aryl aldehydes, and sixteen ortho-acylation products were
synthesized (Table 1). The results showed that regardless of
the substitution of aryl aldehydes, electron withdrawing or
donating, all compounds furnished the desired ortho-acylation
Direct acylation of the aromatic rings of phenols is an
important transformation in organic synthesis since phenols
are one of the most abundant aromatic compounds in nature
and industry.1 Two major synthetic pathways can be followed
in this transformation, namely, the well-known Friedel–Crafts
reaction,2 and the transition-metal-catalyzed C–H activation
pathway.3 However, classical Friedel–Crafts reactions often
suffer from harsh reaction conditions and usage of air/water
sensitive Lewis acids.4 While transition-metal-catalyzed C–H
activation can convert a carbon–hydrogen bond into carbon–
oxygen,5 carbon–nitrogen,6 carbon–halide,7 carbon–sulfur8 or
carbon–carbon bonds,9 till now, there is only one report about
the acylation reaction of unprotected phenols.10 In that work,
Miura and co-workers prepared 2-benzoyl-1-naphthol as a
control experiment when they synthesized benzofuran-2(3H)-
ones; however, no in-depth investigation was reported.
Table 1 ortho-Acylation of phenols with aryl aldehydesa
In the process of synthesizing a natural product, SsnB
(Sparstolonin B, a xanthone derivative isolated from a Chinese
herb showing effective anti-inflammatory activity),11 an
effective ortho-acylation of substituted phenol and a facile
protocol to form the xanthone ring are needed. Herein, we
established a versatile synthetic method in-depth to achieve
ortho-acylation of phenols firstly, and its application in syn-
thesizing different xanthone derivatives. Xanthones constitute
the core of the natural and biologically active family of
compounds present in higher plants and microorganisms,12
as well as the secondary metabolites found in higher plant
families and lichens.13 They exhibit diverse physicochemical and
Entry
R1
R2
Product
Yieldb,c (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1a
1b
1c
1d
1g
1a
1b
1d
1g
1g
1a
3-OCH3
4-CH3
H
3-Cl
4-F
2,6-OCH3
3-OCH3
4-CH3
H
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
2d
2e
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
H
H
H
H
I
NO2
3aa
3ba
3ca
3da
3ea
3fa
3ab
3bb
3cb
3db
3gb
3ac
3bc
3dc
3gc
3gd
—
91 (79)
70 (60)
79 (64)
83 (70)
84 (73)
77 (65)
94 (82)
73 (60)
63 (48)
92 (79)
70 (58)
56 (47)
64 (50)
78 (67)
42 (31)
62 (51)
—
9
10
11
12
13
14
15
16d
17
3-Cl
4-NO2
3-OCH3
4-CH3
3-Cl
4-NO2
4-NO2
3-OCH3
a Department of Chemistry and Biochemistry,
University of South Carolina, Columbia, SC 29208, USA.
E-mail: WANG263@maibox.sc.edu
b Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical
Biology, Ministry of Education, Department of Chemistry,
Tsinghua University, Beijing 100084, China
c School of Medicine, University of South Carolina, Columbia,
SC 29209, USA
a
c
1 mmol aldehyde and 1.3 mmol phenol. b 1H NMR yield. Isolated
d
yield (in parentheses). Cross-coupling reaction between iodine and
w Electronic supplementary information (ESI) available: Tables S1
and S2, experimental details, data and spectra of MS, 1H NMR,
13C NMR. See DOI: 10.1039/c2cc36176k
hydroxyl was observed besides the ortho-acylation reaction.
c
11256 Chem. Commun., 2012, 48, 11256–11258
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Table 2 One-step ortho-acylation of phenols with 2-substituted alde-
hydes to afford xanthonesa
Table 3 Scope of reaction of 2-nitrobenzaldehydes with phenols to
prepare xanthonesa
Yieldb,c
(%)
Yieldb,c
(%)
Yieldb,c (%)
Product
Product
Entry
R1
R2
Product
1
1h
1i
1j
1i
1j
1i
1j
1i
OCH3
NO2
Br
NO2
Br
NO2
Br
NO2
2a
2a
2a
2b
2b
2c
2c
2d
OCH3
OCH3
OCH3
i-Pr
i-Pr
H
4a
4a
4a
4b
4b
4c
4c
4d
85 (71)
87 (74)
68 (52)
92 (81)
64 (56)
81 (70)
55 (43)
73 (62)
2
3d
4
4a
4b
87 (74)
92 (81)
4k
4l
69 (55)
43 (30)
5d
6
7d
8
H
I
a
1 mmol 2-substituted aldehydes and 1.3 mmol phenol. b 1H NMR
c
d
yield. Isolated yield (in parentheses). Cross-coupling reaction
between bromo and hydroxyl groups was observed for entries 3
(17%), 5 (14%) and 7 (13%) besides the ortho-acylation reaction.
4c
4d
4e
81 (70)
77 (62)
73 (62)
4m
4n
4o
75 (64)
84 (72)
90 (80)
products in almost similar yields when reacted with the same
phenol (70–91%, entries 1–6; 63–94%, entries 7–11; 42–78%,
entries 12–15); even for 4-nitrobenzaldehyde, the corresponding
product 3gb was obtained in 70% yield (entry 11). However, the
substituted group of phenols played a more important role
compared with that of aryl aldehydes. The stronger electron-
donating group phenols possessed, the more effective the acyl-
ation reactions were. For example, the methoxy and isopropyl
substituted phenols (2a and 2b) offered higher yields than
unsubstituted phenols (2c); conversely with electron-deficient
4-nitrophenol (2e), no reaction was detected (entry 17). When
4-iodophenol was used, cross-coupling reaction between iodine
and hydroxyl was observed besides the acylation reaction
(entry 16).15 Additionally, aliphatic aldehydes were ineffective
to react with phenols (data not shown).
4f
72 (59)
82 (73)
4p
4q
73 (61)
83 (70)
4g
4h
4i
76 (60)
4r
82 (70)
Interestingly, we found that when 2-substituted aryl aldehydes
(1h–j) reacted with phenols, xanthones were obtained in high
yield in one step (Table 2). Albeit many methods are available for
the synthesis of xanthones, most of them either require advanced
starting materials, exotic reaction conditions, or involve multi-
step transformations.16 There are only a few one-step syntheses
of xanthones existing in the literature.17 Hence our method offers
a concise and straightforward strategy to construct xanthones
directly without the preactivation of aldehydes (Scheme 1).
As shown in Table 2, 2-methoxybenzaldehyde (1h) and
2-nitrobenzaldehyde (1i) produced the corresponding xanthones
in good yields (62–81%) (entries 1, 2, 4, 6 and 8), while with
70 (58)
71 (55)
4s
4t
80 (69)
68 (57)
4j
a
1 mmol 2-nitrobenzaldehydes, 1.3 mmol phenols. b 1H NMR yield.
Isolated yield (in parentheses).
c
2-bromobenzaldehyde (1j) as the starting material, lower
yields were observed, likely due to the cross-coupling reaction
between bromo and hydroxyl groups (entries 3, 5 and 7, yields
are listed in the footnote). It is believed that the ring-closed
xanthone products are achieved via the ortho-acylation of
phenols with 2-substituted aryl aldehydes first, and then under
basic conditions, the ortho-substituents of aldehydes serving as
leaving groups lead to the final ring-closed xanthones.
Since the nitro group gave better results than other leaving
groups, the reaction substrates of 2-nitrobenzaldehydes and
phenols were investigated (Table 3). It showed that alkoxy,
alkyl, aryl and halide substituents were tolerated on the phenols
Scheme 1 One-step synthesis of xanthones.
c
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to furnish the desired xanthones affording moderate to good
yields. While an electron-donating group on phenols can promote
the reaction, an electron-withdrawing group (NO2 or CN) will
block the reaction completely (data not shown). If the substituted
group was at the para position of the phenol, the yield was higher
than when it was at the ortho position, possibly due to the steric
effect (4d vs. 4e, 4g vs. 4h). The steric effect can also explain the
excellent regioselectivity of this reaction (e.g. 4i was the sole
product) as well as the sluggish reactivity of ortho-t-butylphenol
(no product was observed). Disubstituted and trisubstituted
xanthones could also be prepared via this copper-catalyzed
ortho-acylation reaction affording moderate yields (4m–p and 4t).
Although the detailed mechanism is not very definitive, it is
conceivable that this reaction is a Friedel–Crafts type reaction,
which involves the nucleophilic addition of phenols to aldehydes
under basic conditions, and then followed by a dehydrogenative
oxidation in air to give ortho-acylation products.11,18 If ortho-
substituents of aldehydes are good leaving groups, ring-closed
xanthones will form automatically. During this process, copper
(serving as a Lewis acid) may interact with the phenol oxygen and
stabilize the intermediates which lead to a smooth transformation.
In summary, we first demonstrated an intermolecular cata-
lytic ortho-acylation of phenols with various aryl aldehydes
in-depth using copper(II) as the catalyst in the presence of
triphenylphosphine. Furthermore, this method can be used
to synthesize xanthones in one step in high yield. We are
currently investigating the expansion of this ortho-acylation
strategy to a broader scope of substrates.
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