LETTER
2253
Efficient Carbonylation of Aryl and Heteroaryl Bromides under Atmospheric
Pressure of CO
a
c
c
b
C
W
arbonylation of
A
ryl
a
e
nd
H
eteroar
i
yl Bro
z
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
b
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P. R. of China
E-mail: jssun@sioc.ac.cn
c
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. of China
Received 30 April 2011
alkoxycarbonylation methods, we decided to investigate
these conversions in detail.
Abstract: In the presence of Et N and n-BuOH, efficient alkoxy-
carbonylation of (hetero)aromatic bromides was achieved under at-
3
mospheric pressure of carbon monoxide with in situ generated In 2004, Albaneze-Walker et al. published their
palladium/rac-BINAP as catalyst.
(
BINAP)PdCl catalyst system, which showed improved
2
6,9
Key words: palladium catalyst, cross-coupling, atmospheric pres- catalyst potential over those reported in the literature for
sure, carbonylation, alkoxycarbonylation
10
the carbonylation of heterocyclic chlorides. In addition,
this work also demonstrated that the bite angle of the
ligand had a profound effect on the reactivity of the cata-
Aromatic and heteroaromatic carboxylate derivatives are lyst system. Ligands with bite angles of around 90°
versatile intermediates in the manufacture of agrochemi- proved to be optimal to catalyze alkoxycarbonylation re-
cals, dyes, pharmaceuticals, as well as other industrially actions efficiently. Although improvements are obvious,
1
important building blocks. Palladium-catalyzed carbony- some drawbacks, including the need for preprepared cata-
lations of aryl and heteroaryl halides, which was estab- lyst and high CO pressure (3.4 atm), still complicates the
lished in the mid-1970s by the pioneering work of Heck experimental manipulations of these carbonylation reac-
2
and co-workers, represent one of the most attractive tions. Inspired by Albaneze-Walker’s work, we speculat-
methods due to its high atom-economy, easy availability ed that if the reactivity of the substrates is improved by
of starting materials, and broad functional-group toler- selecting heterocyclic bromides as starting materials, with
3
ance. Ever since the establishment, significant progress the in situ generated palladium/rac-BINAP as catalyst
with respect to the development of more convenient (low system, alkoxycarbonylation transformations could be
CO pressure), general (broad substrate scope), and effec- conducted under mild conditions (1 atm CO). We report
tive (high yield) palladium catalyst systems for various herein our recent exploration in this important field.
4
carbonylation has been reported. However, in some
Indeed, under the effect of PdCl (2 mol% relative to the
bromide) and rac-BINAP (4 mol%), 7-bromoisoquinoline
could be converted into butyl isoquinoline-7-carboxylate
2
transformations, especially for alkoxycarbonylations, in
order to secure satisfactory yields, harsh reaction condi-
tions including high pressure of CO (> 1 atm) and high
in high yield under atmospheric pressure of CO (Table 1,
temperature (>150 °C) are demanded, which comprise the
15
11
entry 1), while n-BuOH and Et N (1.5 equiv to bro-
3
5
advantages of Heck’s carbonylation reactions. Extensive
investigations have led to the realization of alkoxycarbo-
mide) were proved to be the optimal solvent and base, re-
spectively. With the mild conditions in hand, we then
turned our attention to investigating the scope and limita-
tions of the substrates. When 4-bromoisoquinoline was
subjected to the above-mentioned conditions, gratifying-
6
7
nylation of aryl chlorides and iodides under mild condi-
tions (1 atm CO and lower temperature). On the contrary,
similar transformations of aryl bromides under mild con-
ditions were less investigated. To the best of our knowl-
edge, only Buchwald and co-workers reported their mild
alkoxycarbonylation results with aryl bromides as starting
materials in which only 1 atmosphere of CO was required.
Nevertheless, in order to obtain satisfactory yields, expen-
ly, a high yield of butyl carboxylate was obtained
15
(
Table 1, entry 2). Besides bromoisoquinoline ana-
logues, bromopyridine derivatives were also suitable sub-
strates for our alkoxycarbonylation conditions, and good
to excellent yields of butyl carboxylates were registered
8
sive phosphine ligands were used. During the course of
9b,12
(
Table 1, entries 3 and 4).
The protocol also worked
our synthetic investigation towards naturally occurring
bioactive alkaloids, we needed to convert a bromo func-
tionality into a carboxyl group in a heteroaryl scaffold.
Considering the shortage of efficient and mild heteroaryl
well with bromothiophene compounds, such as 2- and 3-
bromothiophene, giving better yields than those obtained
5a
in the existing method (Table 1, entries 5 and 6).
Encouraged by the success made in heterocyclic bro-
mides, subsequently, we checked the applicability of our
protocol in alkoxycarbonylation of aryl bromides. Em-
ploying identical conditions applied for heterocyclic bro-
SYNLETT 2011, No. 15, pp 2253–2255
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Advanced online publication: 24.08.2011
DOI: 10.1055/s-0030-1261193; Art ID: W10411ST
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Georg Thieme Verlag Stuttgart · New York