A general palladium-catalyzed carbonylative synthesis of chromenones from salicylic aldehydes and benzyl chlorides

Article abstract of DOI:10.1002/chem.201301774

Cute CO! An interesting and straightforward procedure for the carbonylative synthesis of chromenones from readily available salicylic aldehydes and benzyl chlorides has been developed (see scheme; DPPP=1,3-bis(diphenylphosphino) propane). In the presence of a palladium catalyst, various coumarins were produced in good to excellent yields. Copyright

Full text of DOI:10.1002/chem.201301774

COMMUNICATION
DOI: 10.1002/chem.201301774
A General Palladium-Catalyzed Carbonylative Synthesis of Chromenones
from Salicylic Aldehydes and Benzyl Chlorides
Xiao-Feng Wu,*[a, b] Lipeng Wu,[b] Ralf Jackstell,[b] Helfried Neumann,[b] and
Matthias Beller*[b]
Chromenones (3-aryl-2H-chromen-2-one) is an important
scaffold found in many natural products and synthetic drugs
or drug candidates exhibiting a wide range of biological ac-
tivities, including anticancer, antioxidant, and anti-HIV
activities, as well as acting as enzymatic inhibitors
(Scheme 1).[1] In addition, applications in the perfume indus-
parent molecules can be readily lengthened, although the
carbonylated compounds also have important applications
in organic synthesis and advanced materials.
Heterocycle synthesis is one of the main branches in or-
ganic synthesis. Combining carbonylative transformations of
organohalides with subsequent intramolecular cyclization re-
actions allows efficient access to interesting heterocycles.[6]
Recently, we developed several methods for the carbonyla-
tive synthesis of heterocyclic compounds.[7] Furanones, ben-
zoxazinones, flavones, and some other heterocycles were
easily prepared from their parent molecules by installing
one or even two molecules of carbon monoxide. Our inter-
est in heterocycle synthesis prompted us to apply carbonyla-
tion to chromenone preparation. In the previous literature,
Larock and Kadnikov reported a procedure starting from in-
ternal alkynes and 2-iodophenols[8] and Alper and co-work-
ers developed the oxidative cyclocarbonylation of 2-vinyl-
phenols (Scheme 2).[9] As our experience is with the carbon-
ylation of benzyl chlorides and the study of coumarins,[10] we
Scheme 1. Selected examples of bioactive molecules.
try and advanced materials have been described.[2] As a
result, considerable synthetic effort has been aimed at their
synthesis over the past few decades.[3] The most frequent
routes to prepare chromenones include several named reac-
tions, such as the Wittig, Perkin, Pechmann, and Knoevena-
gel-condensation reactions.[4]
Palladium-catalyzed carbonylative transformation of orga-
nohalides has already become a powerful tool in modern or-
ganic synthesis.[5] The advantages of carbonylation reactions
are clear, and include 1) the fact that carbon monoxide
(CO) can be used as a cheap C1 source; and 2) carbonyl-
containing compounds can easily be prepared by introducing
one or more CO molecules. Thus, the carbon chain of
Scheme 2. Palladium-catalyzed carbonylative synthesis of coumarins
[a] Dr. X.-F. Wu
(TBAC=tetrabutylammonium chloride, BQ=1,4-benzoquinone).
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou, Zhejiang Province 310018 (P.R. China)
E-mail: xiao-feng.wu@catalysis.de
[b] Dr. X.-F. Wu, L. Wu, Dr. R. Jackstell, Dr. H. Neumann,
Prof. M. Beller
wish to report here a straightforward procedure for the car-
bonylation of salicylic aldehydes and benzyl chlorides to
form coumarins. Notably, the substrates and chemicals ap-
plied herein are stable and commercially available, which
highlights the synthetic importance of this method. Addi-
tionally, salicylic aldehydes are naturally occurring products
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301774.
Chem. Eur. J. 2013, 19, 12245 – 12248
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Table 2. Palladium-catalyzed carbonylative reaction of salicylic aldehyde
with benzyl chlorides.[a]
that can allow the avoidance of tedious pre-preparation in
some cases.
Based on our experience of palladium-catalyzed car
tion reactions, initial experiments were carried out with 2-
hydroxybenzaldehyde and benzyl chloride as the model
system. To our delight, by using Pd(OAc)2 (2 mol%), PPh3
(4 mol%), and NEt3 (as the base) in DMSO (2 mL), under
10 bar of CO at 1208C, 61% of 3-phenyl-2H-chromen-2-one
was produced after 16 h (Table 1, entry 1). The yield of the
ACHUTGTNRENNUGbonACHTUNGTERNyNUGN -
ACHTUNGTRENNUNGlaACHTUNGTRENNUNG
Entry
1
Benzyl chloride
Product
Yield
[%][b]
AHCTUNGTRENNUNG
87
Table 1. Palladium-catalyzed carbonylative reaction of salicylic aldehyde
and benzyl chloride.[a]
2
3
4
5
71
83
99
79
Entry
Ligand
([mol%])
Solvent
(2 mL)
T
[8C]
Conversion
[%][b]
Yield
[%][b]
G
N
1
2
3
4
5
6
7
PPh3 (4)
DMSO
DMSO
DMSO
dioxane
DMF
120
120
100
100
100
100
100
100
100
100
100
100
100
100
61
89
85
DPPP (2)
DPPP (2)
DPPP (2)
DPPP (2)
DPPP (2)
DPPP (2)
95 (86)[c]
79
toluene
dioxane
88
93[d]
[a] Reaction conditions: salicylic aldehyde (1.0 mmol), benzyl chloride
(1.1 mmol), Pd(OAc)2 (2 mol%), ligand, solvent (2 mL), temperature,
ACHTUNGTRENNUNG
CO (10 bar), NEt3 (2.0 mmol), 16 h. [b] Conversion and yield were deter-
mined by GC analysis based on salicylic aldehyde by using hexadecane
as the internal standard. [c] Yield of the isolated product. [d] CO (5 bar).
DPPP=1,3-bis(diphenylphosphino)propane; DMSO=dimethyl sulfox-
ide; DMF=N,N-dimethylformamide.
6
7
8
9
69
53
30
76
desired product can be further improved to 89% by using
DPPP as the ligand (89% yield; Table 1, entry 2). Attempts
to reduce the temperature were successful, and 85% yield
of the coumarin was formed at 1008C (Table 1, entry 3). Of
a variety of solvents, 1,4-dioxane was found to result in the
best yield of 3-phenyl-2H-chromen-2-one, allowing the isola-
tion of 86% yield of the product at 1008C (Table 1, entry 4).
Remarkably, a good yield can also be achieved under a
lower pressure (5 bar) of CO at 1008C.
10
71
With the best reaction conditions in hand (Table 1,
entry 4), the generality and limitations of this palladium-cat-
alyzed carbonylative synthesis of chromenones from salicylic
aldehydes and benzyl chlorides was proven by use of 20 dif-
ferent substrates (Tables 2 and 3).
[a] Reaction conditions: salicylic aldehyde (1.0 mmol), benzyl chloride
(1.1 mmol), Pd(OAc)2 (2 mol%), DPPP (2 mol%), 1,4-dioxane (2 mL),
1008C, CO (10 bar), NEt3 (2.0 mmol), 16 h. [b] Yields of the isolated
AHCTUNGTRENNUNG
product.
First, 2-hydroxybendaldehyde was used as the model sub-
strate to test different types of benzyl chloride in the reac-
tion. Good to excellent yields of the desired products were
isolated for the reaction of benzyl chlorides substituted with
electron-donating groups (69–99%; Table 2, entries 1–6). A
53% yield of 3-naphthyl-2H-chromen-2-one was produced
from the corresponding starting materials (Table 2, entry 7).
Interestingly, 4-vinyl substitution, which can cause problems
due to self-polymerization, was tolerated and gave the de-
sired product in a 30% yield under the same reaction condi-
tions (Table 2, entry 8). Additionally, 71–76% yields of the
corresponding chromenones were isolated when electron-
withdrawing substituents, such as 4-chloro, and 4-trifluoro-
methyl, were present in the benzyl chlorides (Table 2, en-
tries 9 and 10).
Various substituted salicylic aldehydes were also tested in
the reaction. In general, good to excellent yields of our
target products were isolated without further optimization
(44–95%; Table 3). Remarkably, 2-hydroxyacetophenone
can be applied as a substrate and gave the desired product
in a 44% yield without further optimization (Table 3,
entry 10). In the case of nitro-substituted substrates (4-nitro-
benzyl chloride and 5-nitrosalicylic aldehyde), none of the
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Chem. Eur. J. 2013, 19, 12245 – 12248

Synthesis of Chromenones
COMMUNICATION
Table 3. Palladium-catalyzed carbonylative reaction of salicylic aldehydes
with benzyl chlorides.[a]
Entry
1
Salicylic aldehyde
Product
Yield
[%][b]
86
75
2
3
Scheme 3. Proposed reaction mechanism.
80
75
salicylic aldehyde on the acylpalladium complex, which gave
the terminal product after intramolecular condensation.[11]
Pd0 can be regenerated under the assistance of base and is
then ready for the next catalytic cycle.
4
In conclusion, an interesting and straightforward proce-
dure for the carbonylative synthesis of chromenones from
readily available salicylic aldehydes and benzyl chlorides has
been developed. Various coumarins were produced in good
to excellent yields.
5
6
66
70
69
95
54
44
Experimental Section
7
Typical reaction procedure for the synthesis of 3-phenyl-2H-chromen-2-
one: A vial (12 mL) was charged with PdACTHNUTRGNEUNG(OAc)2 (2 mol%) and DPPP
(2 mol%), and a stirring bar was added. Then, dioxane (2 mL), the sali-
cylic aldehyde (1 mmol) and the benzyl chloride (1.1 mmol) were injected
by syringe. The vial was placed in an alloy plate, which was transferred
into an autoclave (300 mL) of the 4560 series from Parr Instruments
under an argon atmosphere. After flushing the autoclave three times
with CO, the pressure of CO was increased to 10 bar CO at ambient tem-
perature. The reaction was performed for 16 h at 1008C. After the reac-
tion finished, the autoclave was cooled to room temperature and the
pressure was carefully released. The solution was extracted 3–5 times
from an aqueous solution with ethyl acetate (2–3 mL). After evaporation
of the organic solvent the residue was adsorbed on silica gel and the
crude product was purified by column chromatography using n-heptane/
AcOEt as the eluent.
8
9
10
[a] Reaction conditions: salicylic aldehyde (1.0 mmol), benzyl chloride
(1.1 mmol), Pd(OAc)2 (2 mol%), DPPP (2 mol%), 1,4-dioxane (2 mL),
ACHTUNGTRENNUNG
1008C, CO (10 bar), NEt3 (2.0 mmol), 16 h. [b] Yields of the isolated
product.
Acknowledgements
desired products were produced; the reduction of the nitro
functionality to the amine, followed by a self-polymerization
reaction occurred instead.
Concerning the reaction pathway, we propose a probable
reaction mechanism (Scheme 3). The reaction starts from
Pd0, which was reduced from PdII by the phosphine ligand.
This was followed by the oxidative addition of benzyl chlor-
ide to Pd0 to give the organopalladium species. After the co-
ordination and insertion of CO, the key intermediate acyl-
palladium complex was formed. 2-Formylphenyl 2-phenyl-
The authors thank the state of Mecklenburg–Vorpommern, the Bundes-
ministerium fꢀr Bildung und Forschung (BMBF) and the Chinese Schol-
arship Council (grants for L.W.) for financial support. We also thank Mr.
K. Mevius, Dr. W. Baumann, Dr. C. Fischer, and Mr. S. Buchholz
(LIKAT) for analytical support.
Keywords: benzyl chlorides · carbonylation · chromenones ·
palladium · salicylic aldehydes
ACHTUNGTRENNUNGacetate was then eliminated after nucleophilic attack of the
Chem. Eur. J. 2013, 19, 12245 – 12248
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Received: May 8, 2013
Published online: August 12, 2013
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Chem. Eur. J. 2013, 19, 12245 – 12248