Palladium-catalyzed carbonylative cyclization of β-Bromo-α, β-unsaturated carboxylic acids leading to maleic anhydrides

Article abstract of DOI:10.1055/s-0033-1339309

β-Bromo-α,β-unsaturated carboxylic acids are carbonylatively cyclized under carbon monoxide pressure in acetic acid in the presence of a catalytic amount of a palladium catalyst along with a base to give the corresponding maleic anhydrides in high yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339309

1848▌
LETTER
letter
Palladium-Catalyzed Carbonylative Cyclization of β-Bromo-α,β-unsaturated
Carboxylic Acids Leading to Maleic Anhydrides
Synthesis of Maleic Anhydrides
Yeon Kyu Bae, Chan Sik Cho*
Department of Applied Chemistry, Kyungpook National University, Daegu 702-701, Republic of Korea
Fax +82(53)9506594; E-mail: cscho@knu.ac.kr
Received: 13.05.2013; Accepted after revision: 02.06.2013
O
O
Abstract: β-Bromo-α,β-unsaturated carboxylic acids are carbonyl-
atively cyclized under carbon monoxide pressure in acetic acid in
the presence of a catalytic amount of a palladium catalyst along with
a base to give the corresponding maleic anhydrides in high yields.
1. PBr3, DMF
[Pd], CO
OH
O
2. NaClO2, H2O2
O
Br
O
Key words: carbonylation, cyclization, heterocycles, homoge-
1
2
neous catalysis, palladium
Scheme 1 Synthetic route for maleic anhydrides
The starting β-bromo-α,β-unsaturated carboxylic acids 1
were prepared by initial conversion of ketones into β-bro-
mo-α,β-unsaturated aldehydes under bromination condi-
tions of the Vilsmeier–Haack reaction followed by
subsequent oxidation (Scheme 1).12
It is well-known that many maleic anhydride containing
compounds exhibit a wide spectrum of biological activi-
ties such as antibacterial, fungicidal, immunomodulating,
and plant-growth promoting.1 Thus, many synthetic meth-
ods have been developed for the construction of the struc-
tural core of maleic anhydrides.2 Among them, in
connection with this report, it is worth noting that carbo-
methoxyalkenyl triflates are carbonylatively cyclized to
maleic anhydrides in the presence of a palladium catalyst
under Ac2O and HCO2Na as the condensed source of car-
bon monoxide.2,3 During the course of our ongoing studies
directed towards palladium-catalyzed carbonylative cy-
clization reactions, we recently reported on the synthesis
of several carbonyl-group-containing heterocycles such
as furanones,4 alkyl 2,5-dihydro-5-oxofuran-2-carboxyl-
ates,5 hydroisoindol-1-ones,6 N-alkylmaleimides,7 and 1-
aryl-1H-pyrrol-2(5H)-ones8 from β-bromo-α,β-unsaturat-
ed aldehydes and their derivatives using such a carbonyl-
ative cyclization. The β-bromo-α,β-unsaturated aldehydes
and their derivatives can be readily prepared from the cor-
responding α-methylene containing ketones by the bromi-
nation conditions of the Vilsmeier–Haack reaction and
subsequent transformation and used as a building block
for the construction of various cyclic compounds.9–11 Un-
der these circumstances, such an intrinsic palladium-cata-
lyzed carbonylative cyclization protocol led us to seek for
a promising route for other carbonyl-group-containing
heterocyclic compounds using β-bromo-α,β-unsaturated
aldehydes and their derivatives. This report describes the
palladium-catalyzed carbonylative cyclization of β-bro-
mo-α,β-unsaturated carboxylic acids leading to maleic an-
hydrides (Scheme 1).
The results of several attempted carbonylative cycliza-
tions of 2-bromocyclohex-1-enecarboxylic acid (1a) for
the optimization of the reaction conditions are listed in
Table 1. Treatment of 1a under CO (10 atm) in AcOH in
the presence of a catalytic amount of PdCl2 and Ph3P
along with Et3N afforded 4,5,6,7-tetrahydroisobenzofu-
Table 1 Optimization of Conditions for the Reaction with 1aa
O
O
cat. [Pd], CO
OH
O
120 °C
Br
O
1a
2a
Entry
Pd catalyst
Base
Solvent
Yield (%)
1
PdCl2/Ph3P
PdCl2/Ph3P
PdCl2/dppp
PdCl2/dppf
Et3N
–
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
DMF
92
trace
96
95
83
88
0
2
3
Et3N
Et3N
Et3N
Et3N
NaOAc
K2CO3
K3PO4
Et3N
Et3N
4
5
Pd(OAc)2/dppp
PdCl2(PPh3)2
PdCl2/dppp
6
7
8
PdCl2/dppp
10
5
9
PdCl2/dppp
10b
11b
PdCl2(PPh3)2
PdCl2(PPh3)2
3
MeCN
7
a Reaction conditions: 1a (0.5 mmol), Pd catalyst (0.025 mmol), Ph3P
(0.05 mmol, 0.03 mmol in the case of bidentate ligand), base (2
mmol), solvent (8 mL), at 120 °C, 3 h, under CO (10 atm).
b CO (15 atm) for 15 h.
SYNLETT 2013, 24, 1848–1850
Advanced online publication: 01.08.2013
DOI: 10.1055/s-0033-1339309; Art ID: ST-2013-U0446-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of Maleic Anhydrides
1849
Table 2 Palladium-Catalyzed Carbonylative Cyclization of 1 Lead-
ing to 2a (continued)
ran-1,3-dione (2a) in 92% isolated yield with complete
conversion of 1a, which was monitored until 1a had dis-
appeared on TLC (Table 1, entry 1). However, the reac-
tion did not proceed at all in the absence of a base, and 1a
was recovered almost completely (Table 1, entry 2). From
the activity of several palladium precursors examined un-
der the employed conditions, all exhibited nearly similar
catalytic activity as PdCl2/Ph3P (Table 1, entries 3–6).
When the reaction was carried out with other bases except
for Et3N, 2a was scarcely formed (Table 1, entries 7–9).
Among the solvents examined, acetic acid was crucial for
the formation of 2a. Performing the reaction in DMF or
MeCN resulted in lower yield of 2a with incomplete con-
version of 1a under higher CO pressure for a longer reac-
tion time (Table 1, entries 10 and 11).
Entry
1
2
Yield (%)
O
O
Br
O
O
OH
4
84
O
1d
1e
1f
2d
2e
2f
O
OH
O
5
6
89
99
Br
O
After the reaction conditions had been established, vari-
ous β-bromo-α,β-unsaturated carboxylic acids were sub-
jected to the reaction under CO pressure in order to
investigate the reaction scope, and several representative
results are summarized in Table 2.13,14 From the reaction
of six-membered β-bromo-α,β-unsaturated carboxylic ac-
ids 1b and 1c, the corresponding hydroisobenzofuran-1,3-
diones 2b and 2c were produced in good yields irrespec-
tive of methyl and phenyl substituents on 1b and 1c. With
cyclic β-bromo-α,β-unsaturated carboxylic acids 1d–f
having various ring sizes, the carbonylative cyclized prod-
ucts 2d–f were also formed in the range of 84–99% yields,
and the product yield was gradually increased with the in-
crease in ring size. To test for the effect of the position of
bromide and carboxy group on β-bromo-α,β-unsaturated
carboxylic acids 1g and 1h were employed. Even though
the carbonylative cyclization took place irrespective of
the position, higher product yield was observed with 1g.
O
O
OH
O
Br
O
O
O
OH
O
7
8
81
42
Br
O
2g
2g
1g
1h
Br
O
OH
Table 2 Palladium-Catalyzed Carbonylative Cyclization of 1 Lead-
ing to 2a
a Reaction conditions: 1 (0.5 mmol), PdCl2 (0.025 mmol), dppp (0.03
mmol), Et3N (2 mmol), AcOH (8 mL), 120 °C, 3 h, under CO (10
atm).
Entry
1
1
2
Yield (%)
96
O
O
In summary, it has been shown that β-bromo-α,β-unsatu-
rated carboxylic acids undergo carbonylative cyclization
in acetic acid under CO pressure in the presence of a pal-
ladium catalyst to give maleic anhydrides. The present re-
action provides a straightforward method for the synthesis
of valuable heterocycles from readily available ketones.
Further study of synthetic applications to heterocycles
starting from ketones and a reaction pathway including
the role of acetic acid is in progress.
OH
O
Br
O
1a
2a
O
O
OH
O
2
3
73
82
Br
O
1b
Acknowledgment
2b
O
O
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2010-0007563).
Ph
Ph
OH
O
Br
O
1c
2c
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1848–1850

1850
Y. K. Bae, C. S. Cho
LETTER
(13) Yields of Several β-Bromo-α,β-unsaturated Carboxylic
Acids from the Corresponding β-Bromo-α,β-
References and Notes
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Weinheim, 2008. (f) Brennführer, A.; Neumann, H.; Beller,
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unsaturated Aldehydes and Spectroscopic Data
Compound 1c: 250 mg (89%); solid; mp 136–137 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.89–2.02 (m, 2 H), 2.45–2.54
(m, 1 H), 2.76–2.83 (m, 3 H), 2.87–2.95 (m, 1 H), 7.20–7.25
(m, 3 H), 7.30–7.34 (m, 2 H). 13C NMR (100 MHz, CDCl3):
δ = 30.98, 36.37, 38.71, 39.04, 126.88, 126.95, 128.85,
129.22, 129.75, 144.59, 171.93.
Compound 1f: 246 mg (85%); solid; mp 116–117 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.33–1.38 (m, 12 H), 1.55–
1.61 (m, 2 H), 1.72–1.78 (m, 2 H), 2.44–2.48 (m, 2 H), 2.58–
2.62 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 22.47,
22.82, 24.34, 24.39, 24.44, 24.58, 25.72, 25.98, 28.66,
33.91, 128.44, 134.84, 173.57.
Compound 1g: 127 mg (50%); solid; mp 123–124 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.72–2.76 (m, 2 H), 2.86–2.90
(m, 2 H), 7.15–7.17 (m, 1 H), 7.27–7.34 (m, 2 H), 7.85–7.89
(m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 27.51, 27.79,
127.27, 127.39, 128.68, 129.52, 129.58, 130.34, 133.53,
137.56, 172.32.
Compound 1h: 159 mg (63%); solid; mp 133–134 °C. 1H
NMR (400 MHz, CDCl3): δ = 2.87–2.91 (m, 2 H), 2.96–3.00
(m, 2 H), 7.14–7.17 (m, 1 H), 7.22–7.25 (m, 3 H). 13C NMR
(100 MHz, CDCl3): δ = 28.99, 34.70, 124.43, 124.63,
127.29, 128.09, 128.59, 130.76, 133.01, 133.39, 172.51.
(14) General Procedure for the Palladium-Catalyzed
Carbonylative Cyclization of β-Bromo-α,β-unsaturated
Carboxylic Acids Leading to Maleic Anhydrides
To a 50 mL stainless steel autoclave were added β-bromo-
α,β-unsaturated carboxylic acid 1 (0.5 mmol), PdCl2 (0.025
mmol), dppp (0.03 mmol), Et3N (2 mmol), and AcOH (8
mL). After the system was flushed and then pressurized with
CO to 10 atm, the reaction mixture was allowed to react at
120 °C for 3 h. The reaction mixture was poured into H2O
and extracted with EtOAc twice. The combined organic
layer was dried over Na2SO4 and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography (silica gel, hexane–EtOAc mixture) to
afford maleic anhydrides 2. Except for 2f, all products are
known.
(8) Cho, C. S.; Son, J. I.; Yoon, N. S. Appl. Organomet. Chem.
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Compound 2f: 117 mg (99%); white solid; mp 87–88 °C. 1H
NMR (400 MHz, CDCl3): δ = 1.27–1.34 (m, 4 H), 1.38–1.44
(m, 8 H), 1.75–1.81 (m, 4 H), 2.50 (t, J = 7.1 Hz, 4 H). 13
C
NMR (100 MHz, CDCl3): δ = 22.09, 22.23, 24.34, 25.14,
25.48, 145.10, 166.05. Anal. Calcd (%) for C14H20O3: C,
71.16; H, 8.53. Found: C, 71.11; H, 8.67.
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Synlett 2013, 24, 1848–1850
© Georg Thieme Verlag Stuttgart · New York