A Convenient Palladium-Catalyzed Carbonylative Synthesis of (E)-3-Benzylidenechroman-4-ones

Article abstract of DOI:10.1002/chem.201900015

A convenient palladium-catalyzed carbonylation reaction for the efficient synthesis of (E)-3-benzylidenechroman-4-ones has been developed. Using TFBen as a solid CO source, a range of substituted (E)-3-benzylidenechroman-4-ones were prepared in moderate to good yields with 2-iodophenols and allyl chlorides as the substrates. Additionally, substituted quinolin-4(1H)-ones can also be obtained with 2-iodoaniline as the starting material.

Full text of DOI:10.1002/chem.201900015

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Accepted Article
Title: A Convenient Palladium-Catalyzed Carbonylative Synthesis of
(E)-3-Benzylidenechroman-4-ones
Authors: Xiao-Feng Wu, Wei-Feng Wang, Jin-Bao Peng, Xinxin Qi, and
Jun Ying
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A Convenient Palladium-Catalyzed Carbonylative Synthesis of
(E)-3-Benzylidenechroman-4-ones
Wei-Feng Wang,[a] Jin-Bao Peng,*[a] Xinxin Qi,[a] Jun Ying,[a] Xiao-Feng Wu*[a,b]
Abstract: A convenient palladium-catalyzed carbonylation reaction
for the efficient synthesis of (E)-3-benzylidenechroman-4-ones has
been developed. Using TFBen as a solid CO source, a range of
substituted (E)-3-benzylidenechroman-4-one were prepared in
moderate to good yields with 2-iodophenols and allyl chlorides as
the substrates. Additionally, substituted quinolin-4(1H)-ones can also
be obtained with 2-iodoaniline as the starting material.
intramolecular carbonylative cyclizations of ortho-substituted
arenes.8 Even though the impressive progresses on
carbonylative synthesis of heterocycles, carbonylative procedure
for the synthesis of benzylidenechromanones which are also
widely existed in natural products, have not been reported to
date. Herein, we present our new results on palladium-catalyzed
carbonylative synthesis of benzylidenechromanones (Scheme 2,
eq. d). With 2-iodophenols and allyl chlorides as the substrates,
a range of desired products were prepared in moderate to good
yields. Additionally, substituted quinolin-4(1H)-one derivative can
also be obtained when 2-iodoaniline was used.
Chromanones represent a privileged class of oxygen-containing
heterocycles which is commonly present in large number of
natural
products
and
pharmaceutical
compounds.1
Benzylidenechromanone derivatives, in particular, have
attracted much attention owing to their significant biological
active properties (Scheme 1). In fact, this class of compound is
known to display a broad spectrum of biological activities
including antitumor, antibacterial, anti-HIV properties.1g
Benzylidenechromanones are also widely used as versatile
intermediates in organic synthesis.2 Owing to their important
biological properties and applications, a range of synthetic
methods have been developed for the preparation of this unique
heterocyclic
structure
(Scheme
2).
Traditionally,
benzylidenechromanones were produced by base promoted
condensation of 4-chromanone derivatives with benzaldehyde
derivatives (Scheme 2, eq. a).3 Acid promoted intramolecular
Friedel-Crafts acylation of (2E)-2-phenoxymethyl-3-phenylprop-
2-enoic
acid
derivatives
to
the
corresponding
benzylidenechromanones was achieved as well (Scheme 2, eq.
b).4 Recently, a methodology based on N-heterocyclic carbene-
catalyzed intramolecular hydroacylation of alkynes was
developed by Glorius and co-workers (Scheme 2, eq. c).5
Although we agree with the advantages of these interesting
Scheme 1. Selected examples of bio-active benzylidenechromanones.
synthetic
commercially available starting materials is always attractive.
On the other hand, transition metal-catalyzed
methodologies,
alternative
procedure
with
carbonylation reaction provides an direct and atom-economic
method to incorporating CO into organic compounds, and has
now emerged as a powerful platform for the synthesis of
carbonyl-containing compounds.6 Among them, the synthesis of
heterocyclic compounds via cascade carbonylation reactions
attracted particular attention during the past few dacades.7 From
four-membered rings to macrocycles; from single rings to fused
multi-cycles, many novel procedures have been established to
access target heterocycles, including several that involve
[a]
[b]
W.F. Wang, Dr. J.-B. Peng, Dr. X. Qi, Dr. J. Ying, Prof. Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou 310018, People’s Republic of China
E-mail: pengjb_05@zstu.edu.cn; xiao-feng.wu@catalysis.de
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-
Einstein-Straße 29a, 18059 Rostock (Germany)
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Methodologies for benzylidenechromanones synthesis.
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Initially, o-iodophenol 1a and cinnamyl chloride 2a were
selected as the model substrates for this carbonylation reaction.
Using Pd2dba3 and BuPAd2 catalyst system, when a solution of
o-iodophenol 1a and cinnamyl chloride 2a was stirred in the
presence of Na2CO3 at 100 ℃ under a CO (HCO2H/Ac2O)
atmosphere for 20 h, only trace amount of the desired product
3a was detected (Table 1, entry 1). Non-carbonylated product
benzofuran 4a was obtained as the main byproduct. To our
delight, the yield of 3a could be improved to 28% when K3PO4
was used as the base (Table 1, entry 2). With a continuous
interest in developing green and CO-gas-free carbonylation
reactions, we tested some other CO surrogates in this reaction.
The desired product 3a was obtained in 22% yield when
HCO2H/DCC was used as the CO source (Table 1, entry 3). The
yield was improved to 35% when TFBen (benzene-1,3,5-triyl
triformate), a solid CO surrogate developed in our group, was
used as the CO source (Table 1, entry 4). Subsequently, we
examined different palladium catalysts in this reaction.
Pd(PPh3)4 and Pd(OAc)2 were found to be effective catalysts for
this transformation, and produced the desired product 3a in 32%
and 31% yields, respectively (Table 1, entries 5 and 6). Although
a slightly decreased yield of 3a was obtained when Pd(OAc)2
was used, the ratio of byproduct 4a was much smaller than that
of Pd2dba3. And the yield of 3a could be improved to 40% when
2 equivalent of TFBen was used (Table 1, entry 7). So, we
selected Pd(OAc)2 as the catalyst for further optimization. The
screening of ligands revealed that BuPAd2 was the optimal
ligand, other tested ligands including monodentate and bidentate
phosphine ligands were all less effective (Table 1, entries 8 and
9, see details in SI). The reaction temperature played an
important role in this reaction. A higher yield of 56% was
obtained when the reaction was performed at 90 ℃ (Table 1,
4
Pd2dba3
BuPAd2
BuPAd2
BuPAd2
BuPAd2
PPh3
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
35
32
31
40
28
38
56
31
71
5
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
6
7c
8c
9c
PCy3
10c,d
11c,e
12c,d,f
BuPAd2
BuPAd2
BuPAd2
13c,d,f,
75
(68)
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
BuPAd2
BuPAd2
BuPAd2
TFBen/Et3N
TFBen/Et3N
TFBen/Et3N
g
14c,d,f,
K3PO4
K3PO4
38
27
g,h
15c,d,f,
g,i
aReaction conditions: o-iodophenol (0.50 mmol), cinnamyl chloride (0.60
mmol), [Pd] (4 mol%), ligand (8 mol%), [CO] (2 mmol), base (2 eq.), solvent (2
mL), 100 ºC, 20 h. bYields were determined by GC analysis using dodecane
as an internal standard. c[CO] (3 mmol). d90 ºC. e110 ºC. fCinnamyl chloride (1
mmol). g 25 h. h.THF (2 mL). i.toluene (2 mL).
With the optimized reaction conditions in hand (Table 1,
entry 13), we investigated the generality of this carbonylation
reaction. As summarized in Table 2, a series of cinnamyl
chloride derivatives with various substitutions at different
position of benzene ring were applied under the optimized
conditions and the corresponding benzylidenechromanone
products were obtained in moderate to good yields (Table 2, 3a-
3l). It should be noted that more steric bulky cinnamyl chlorides
generate higher yields of the carbonylated products. For
example, a high yield (85%) of desired product 3b was obtained
when ortho-methyl substituted cinnamyl chloride was used as
the substrate, while meta- and para-methyl substituted cinnamyl
chlorides provided the corresponding products 3c and 3d in 72%
and 67% yield, respectively. Both electron-donating and
electron-withdrawing substituents on the benzene ring were well
tolerated. Generally, electron-donating groups substituted
cinnamyl chlorides gave slightly higher yields than that of
electron-withdrawing groups (Table 2, 3b-3f vs 3g-3l). Halides,
such as fluoro- chloro- and bromo-substitution, were compatible
in this reaction (Table 2, 3g-3l). In addition to substituted
cinnamyl chlorides, heteroaryl substituted allyl chlorides were
also tolerated. For example, when naphthyl-, furyl- and thienyl-
substituted allyl chlorides were subjected to the reaction
conditions, the corresponding products were successfully
obtained in moderate yields (Table 2, 3m-3p). Besides, alkyl
substituted allyl chloride was tolerated as well (Table 2, 3q).
However, in the case of terminal allyl chloride 2w, two isomers
3w and 3w’ were obtained (Scheme 3).
entry 10). Increasing reaction temperature resulted in
a
decreased yield (Table 1, entry 11). However, no carbonylation
reaction took place when the reaction was carried out at 70 ℃.
This observation reveals that a relative high temperature was
essential for the carbonylation to take place, while too high of
temperature would facilitate the dissociation of CO from the
catalyst and result decarbonylation. The ratio of o-iodophenol 1a
and cinnamyl chloride 2a also played an important role in this
reaction. The product 3a was obtained in 75% yield (68%
isolated yield) when 2 equivalent of cinnamyl chloride 2a was
used with a prolonged reaction time (Table 1, entries 12 and 13).
Other solvents, such as THF and toluene, were found to be less
effective and lower yields of 3a were obtained (Table 1, entries
14 and 15).
Table 1. Optimization of the reaction conditions.a
Entry
[Pd]
Ligand
[CO]
Base
Yieldb
trace
28
1
2
3
Pd2dba3
Pd2dba3
Pd2dba3
BuPAd2
BuPAd2
BuPAd2
HCO2H/Ac2O
HCO2H/Ac2O
HCO2H/DCC
Na2CO3
K3PO4
K3PO4
Then, we tested the generality of this reaction with respect
to the o-iodophenol coupling partner. Different substituted o-
iodophenols were well tolerated and produced the desired
22
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aReaction conditions: o-iodophenol (0.50 mmol), cinnamyl chloride (1.0 mmol),
Pd(OAc)2 (4 mol%), BuPAd2 (8 mol%), TFBen (1 mmol), K3PO4 (1 mmol),
dioxane (2 mL), 90 ºC, 25 h, isolated yield.
products in 51%-69% yields (Table 2, 3r-3t). Moreover, when
substituted 2-iodoanilines were used instead of 2-iodophenol,
substituted quinolin-4(1H)-one derivatives were isolated in
moderate yields (Table 2, 3u and 3v).
Since the allylic ether 5a might serve as an intermediate in
this cascade reaction, we subjected 5a to the standard reaction
conditions. Indeed, benzylidenechromanone 3a was produced in
71% yield (Scheme 3). On the basis of the experimental results
and literature,8 a plausible mechanism is illustrated in Scheme 4.
Initially, in the presence of base, cinnamyl chloride 1a reacts
with 2-iodophenol 2a to give an ether 5. Pd(OAc)2 was reduced
into Pd(0) by phosphine and subsequently stabilized. Then,
oxidative addition of the in-situ generated Pd(0) to the carbon-
iodide bond of 5 gives the aryl-palladium complex 6. Then,
coordination and insertion of carbon monoxide to 6 forms an
acyl-palladium intermediate 7, which undergoes a 6-exo-trig
cyclization to give the intermediate 8. Finally, β-H elimination of
8 releases the desired product 3a. Catalytic active Pd(0) is
regenerated by reductive elimination in the presence of base.
On the other hand, in the absence of CO, aryl-palladium
complex 6 undergoes a 5-exo-trig cyclization followed by β-H
elimination to generate the benzofuran derivative 4a.
Scheme 3. Control experiment.
Table 2. Carbonylative synthesis of benzylidenechromanone.a
Scheme 4. Proposed reaction mechanism.
In summary, we have developed a palladium-catalyzed
carbonylation
benzylidenechromanone. Using 2-iodophenols and allyl
chlorides as the substrates, range of substituted
reaction
for
the
synthesis
of
a
benzylidenechromanones were prepared in moderate to good
yields. Additionally, substituted quinolin-4(1H)-one derivatives
can also be obtained when 2-iodoanilines were used.
Experimental Section
General procedure: Under nitrogen atmosphere, Pd(OAc)2 (4 mol%),
BuPAd2 (8 mol%), K3PO3 (1 mmol.), 2-iodophenol (0.5 mmol), cinnamyl
chloride (1 mmol), 1,4-dioxane (2 mL) were added to an oven-dried 15
mL In-Ex tube. TFBen (1 mmol) and Et3N (1 mmol) were added to the
small inner tube. Then the tube was sealed and the mixture was stirred at
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90 °C for 25 h. After the reaction was completed, the reaction mixture
was filtered and concentrated under vacuum. The crude product was
purified by column chromatography on silica gel to afford the
corresponding product.
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The authors thank the financial supports from NSFC (21801225,
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Keywords: palladium catalyst • carbonylation •
benzylidenechromanone • heterocycle synthesis • cascade
reaction
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Wei-Feng Wang, Jin-Bao Peng,* Xinxin
Qi, Jun Ying, Xiao-Feng Wu*
Page No. – Page No.
A Convenient Palladium-Catalyzed
Carbonylative Synthesis of (E)-3-
Benzylidenechroman-4-ones
A palladium-catalyzed carbonylation reaction for the synthesis of
benzylidenechromanone has been developed. Using 2-iodophenols and allyl
chlorides as the substrates, a range of substituted benzylidenechromanones were
prepared in moderate to good yields. Additionally, substituted quinolin-4(1H)-one
derivatives can also be obtained when 2-iodoanilines were used.
This article is protected by copyright. All rights reserved.