An unusual palladium-catalyzed carbonylative cyclization of β-bromovinyl aldehydes leading to lactones

Article abstract of DOI:10.1016/j.tetlet.2006.03.184

β-Bromovinyl aldehydes are carbonylatively cyclized under carbon monoxide pressure in MeCN at 100 °C in the presence of a catalytic amount of a palladium catalyst along with a base to give the corresponding lactones in high yields.

Full text of DOI:10.1016/j.tetlet.2006.03.184

Tetrahedron Letters 47 (2006) 3835–3837
An unusual palladium-catalyzed carbonylative cyclization
of b-bromovinyl aldehydes leading to lactones
Chan Sik Choa,* and Hyung Sup Shimb
aResearch Institute of Industrial Technology, Kyungpook National University, Daegu 702-701, South Korea
bDepartment of Applied Chemistry, Kyungpook National University, Daegu 702-701, South Korea
Received 7 March 2006; revised 27 March 2006; accepted 29 March 2006
Available online 27 April 2006
Abstract—b-Bromovinyl aldehydes are carbonylatively cyclized under carbon monoxide pressure in MeCN at 100 °C in the presence
of a catalytic amount of a palladium catalyst along with a base to give the corresponding lactones in high yields.
Ó 2006 Elsevier Ltd. All rights reserved.
Palladium-catalyzed carbonylative cyclization process
has been recognized as a useful synthetic tool for hetero-
cyles, which play an important role as a basic unit for
the design of many pharmacologically and biologically
active compounds.1 Many methods for such a palla-
dium-catalyzed version have also been attempted for
the construction of lactones because of the facility and
efficiency of reaction and the wide availability of sub-
strate.2 During the course of our ongoing studies on pal-
ladium-catalyzed cyclization reactions, we also recently
reported on the synthesis of various heterocycles such
as isoindolinones,3 b-lactams4 and phthalides5 via a car-
bonylative cyclization. Among them, in connection with
this report, 2-bromobenzaldehyde was found to be cyc-
lized with carboxylic acids in the presence of a palladium
catalyst and a base under carbon monoxide pressure to
afford 3-oxo-1,3-dihydro-1-isobenzofuranyl alkano-
ates.6 The present work was disclosed during the course
of the extension of this protocol to the reaction with b-
bromovinyl aldehydes, which are readily prepared from
ketones via the bromo analogue of Vilsmeier reaction
(Scheme 1).7 Herein, we describe an unusual palla-
dium-catalyzed lactonization of b-bromovinyl aldehydes
via intrinsic carbonylative cyclization.8
CHO
Br
[Pd], CO
PBr3/DMF/CHCl3
O
O
O
Scheme 1.
various conditions are listed in Table 1. In contrast to
our recent report on palladium-catalyzed synthesis of
3-oxo-1,3-dihydro-1-isobenzofuranyl alkanoates from
2-bromobenzaldehyde and carboxylic acids,6 treatment
of 1a with 4 equiv of acetic acid in MeCN in the pres-
ence of PdCl2/4PPh3 along with Et3N under carbon
monoxide pressure (20 atm) afforded 4,5,6,7-tetra-
hydro-3H-isobenzofuran-1-one (2a) in 53% yield, no
cyclized product 3 incorporated with acetic acid being
produced (entry 1).9 This result indicates that the pres-
ent cyclization proceeds irrespective of acetic acid. Thus,
when the reaction was carried out in the absence of ace-
tic acid, 2a was also obtained as a sole cyclized product
with complete conversion of 1a on TLC (entry 2).10
However, the present reaction did not proceed at all
under atmospheric pressure of CO. The reaction was
monitored until 1a had disappeared on TLC, which
occurred within 3 h. From the activity of several palla-
dium precursors examined under the employment of
Et3N as base, PdCl2(PPh3)2 is revealed to be the catalyst
of choice (entries 2–7). Other palladium catalytic
systems such as PdCl2/4PPh3, Pd(OAc)2/4PPh3 and
Pd(PPh3)4 were moderately effective for the formation
of 2a. With other bases such as K2CO3 and NaOAc
combined with PdCl2(PPh3)2, the yield of 2a was lower
than that when Et3N was employed (entries 8 and 9).
The results of several attempted carbonylative cycliza-
tions of 2-bromocyclohex-1-enecarbaldehyde (1a) under
Keywords: b-Bromovinyl aldehydes; Carbon monoxide; Carbonylative
cyclization; Lactones; Palladium catalyst.
*
Corresponding author. Tel.: +82 53 950 7318; fax: +82 53 950
6594; e-mail: cscho@knu.ac.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.184

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C. S. Cho, H. S. Shim / Tetrahedron Letters 47 (2006) 3835–3837
Table 1. Palladium-catalyzed carbonylative cyclization of 1a under
various conditionsa
Table 2. Palladium-catalyzed synthesis of lactones 2a
b-Bromovinyl aldehydes 1
Lactones 2
Yield (%)
85
OAc
CHO
O
CHO
cat. [Pd], CO
O
O
Br
MeCN, 100 oC, 3 h
O
Br
1a
2a
O
O
1a
2a
3
CHO
O
Entry
Palladium catalysts
Bases
Isolated yield (%)
79
86
Br
O
1b
2
3
4
5
6
7
8
9
PdCl2/4PPh3
PdCl2/4PPh3
Pd(OAc)2/4PPh3
PdCl2(PhCN)2
Pd(dba)2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
53
62
65
52
47
66
85
34
59
1b
2b
CHO
O
Br
O
Pd(PPh3)4
1c
2c
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
CHO
K2CO3
NaOAc
O
80
89
78
61
73
23
Br
a Reaction conditions: 1a (0.5 mmol), palladium catalyst (0.025 mmol),
base (2 mmol), CO (20 atm), MeCN (5 mL), 100 °C, for 3 h.
b Acetic acid (2 mmol) was added.
O
1d
2d
CHO
O
Having the established reaction conditions, various b-
bromovinyl aldehydes were subjected to cyclize with car-
bon monoxide in order to investigate the reaction scope
and several representative results are summarized in
Table 2. With cyclic b-bromovinyl aldehydes (1a–e),
the carbonylative cyclized a,b-butenolides (2a–e) were
formed in the range of 79–89% yields without any iden-
tifiable side product. Here again, the starting substrates
completely disappeared within 3 h. The product yield
was not significantly affected by the ring size of 1a–e.
Bromo-5-methylcyclohex-1-enecarbaldehyde (1f) was
also cyclized under the employed conditions to give 5-
methyl-4,5,6,7-tetrahydro-3H-isobenzofuran-1-one (2f)
in 78% yield. To test for the effect of the position of for-
myl group and bromide on cyclic b-bromovinyl alde-
hydes, 1g and 1h were employed. However, the
carbonylative cyclization took place similarly irrespec-
tive of the position. Lower reaction rate and yield were
observed with acyclic b-bromovinyl aldehyde 1i,11 the
carbonylative cyclized product 3-phenyl-5H-furan-2-
one (2i) being obtained in only 23% yield (24% yield
for 20 h).
Br
O
1e
2e
2f
CHO
O
Br
O
1f
O
O
CHO
Br
O
1g
2g
O
Br
CHO
1h
2h
O
Ph
Br
Ph
O
CHO
1i
2i
a Reaction conditions: 1 (0.5 mmol), PdCl2(PPh3)2 (0.025 mmol), Et3N
(2 mmol), CO (20 atm), MeCN (5 mL), 100 °C, for 3 h.
As to the reaction pathway, it seems to proceed via the
initial carbonyl reduction of b-bromovinyl aldehyde
to bromoallyl alcohol, which in turn triggers carbonyla-
tive cyclization to give a,b-butenolide. However,
unfortunately, we confirmed in a separate experiment
that 2-bromocyclohex-1-enylmethanol did not undergo
carbonylative cyclization under the employed condi-
tions. Thus, this result indicates that the present reaction
excludes the initial carbonyl reduction pathway.
the solvent left a crude mixture, which was separated by
thin layer chromatography (silica gel, ethyl acetate–hex-
ane mixture) to give a,b-butenolides 2.
In summary, we have demonstrated that b-bromovinyl
aldehydes undergo an unusual carbonylative cyclization
under carbon monoxide pressure in the presence of a
palladium catalyst and a base to afford a,b-butenolides.
The mechanistic rationale and synthetic applications are
currently under investigation.
General experimental procedure: To a 50 mL stainless
steel autoclave were added b-bromovinyl aldehyde 1
(0.5 mmol), PdCl2(PPh3)2 (0.025 mmol), Et3N (2 mmol)
and MeCN (5 mL). After the system was flushed and
then pressurized with carbon monoxide to 20 atm, the
mixture was stirred at 100 °C for 3 h. The reaction mix-
ture was passed through a short silica gel column (ethyl
acetate–hexane) to eliminate inorganic salts. Removal of
Acknowledgement
This present work was supported by a Research Professor
Grant of Kyungpook National University (2005).

C. S. Cho, H. S. Shim / Tetrahedron Letters 47 (2006) 3835–3837
3837
6. Cho, C. S.; Baek, D. Y.; Kim, H. Y.; Shim, S. C.; Oh, D.
H. Synth. Commun. 2000, 30, 1139.
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