Palladium-catalyzed hydroxycarbonylation of aryl and vinyl triflates by in situ generated carbon monoxide under microwave irradiation

Article abstract of DOI:10.1055/s-2006-926288

An operationally simple hydroxycarbonylation of aryl and vinyl inflates to the corresponding carboxylic acids with a palladium-mediated microwave system was carried out in water. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926288

594
SHORT PAPER
Palladium-Catalyzed Hydroxycarbonylation of Aryl and Vinyl Triflates by in
situ Generated Carbon Monoxide under Microwave Irradiation
M
icrowave-Assist
i
e
d
H
yd
o
roxycarbony
r
lation of
d
T
riflates ano Lesma, Alessandro Sacchetti, Alessandra Silvani*
Dipartimento di Chimica Organica e Industriale e Centro Interdisciplinare Studi biomolecolari e applicazioni Industriali (CISI), Università
degli Studi di Milano, via G. Venezian 21, 20133 Milan, Italy
Fax +39(02)50314078; E-mail: alessandra.silvani@unimi.it
Received 27 June 2005; revised 12 September 2005
Despite the usefulness of aryl carboxylic acids as key in-
Abstract: An operationally simple hydroxycarbonylation of aryl
termediates in many synthetic protocols, only one exam-
and vinyl triflates to the corresponding carboxylic acids with a pal-
ladium-mediated microwave system was carried out in water.
ple is reported8 related to microwave-assisted generation
of p-methylbenzoic acid from tolyl iodide utilizing in situ
Key words: carbonylations, carboxylic acids, microwaves, molyb-
generated carbon monoxide from Mo(CO)6.
denum hexacarbonyl, triflates
Both the lack of asserted procedures regarding the synthe-
sis of carboxylic acids and the fact that only aryl halides
are described as precursors in this kind of procedures, en-
couraged us to investigate the scope and limitations of hy-
droxycarbonylation reactions, particularly of vinyl and
aryl triflates, by mean of fast and safe conditions. Trif-
lates, which are often more accessible than the corre-
sponding halide derivatives, represent a suitable class of
starting materials and their use in palladium-catalyzed
coupling reactions is well established.9 Aryl triflates are
readily available from the corresponding phenols on reac-
tion with triflic anhydride in the presence of pyridine and
are reasonably stable. The possibility of utilizing phenols
for carboxylic acid generation would greatly expand the
choice of possible starting materials and accordingly en-
hance the synthetic utility of these key intermediates.
The development of environmentally friendly and ultra-
fast organic transformations is becoming an area of grow-
ing importance, in order to support high-speed chemistry
and automated organic synthesis.1
For our research purposes, we recently became interested
in hydroxycarbonylation of aryl triflates on a preparative
scale, in a safe, fast and convenient way. Palladium-cata-
lyzed preparation of aryl carboxylic acids from aryl elec-
trophiles is known as a useful synthetic method2 to yield
benzoic acid derivatives, which are valuable intermedi-
ates in the manufacture of pharmaceuticals and chemicals.
The procedure is quite general, widely applicable to di-
versely substituted aryl fragments, but suffers from some
disadvantages involved in the use of carbon monoxide at-
mosphere, often under pressure. This gas is readily avail-
able and cheap, but the extreme toxicity and the
troublesome handling procedures discourage its use in
high-throughput chemistry and in automated, small-scale
synthesis. For these reasons, the development of tech-
niques where carbon monoxide is generated in situ is a tar-
get of great current interest.3 Quite recently, Larhed and
co-workers4,5 developed efficient carbonylation processes
based on commercially available, stable sources of carbon
monoxide such as Mo(CO)6,6 N,N-dimethylformamide or
formamide and microwave flash heating. Non-gaseous
CO precursors were successfully employed in
aminocarbonylations4 and in ester syntheses5 from aryl io-
dides and aryl bromides, affording good isolated yields
for a wide range of aryl substrates. Generally, the use of
microwave ovens dramatically accelerates the rate of re-
actions. Because of the fast and homogeneous heating,
microwave-irradiated reactions not only are faster but of-
ten proceed with higher purity and, consequently, higher
yields.7
Herein, we report an operationally simple and environ-
mentally safe hydroxycarbonylation of diversely substi-
tuted aryl and vinyl triflates, using palladium diacetate as
metal catalyst and Mo(CO)6 as a commercially available,
stable and solid carbon monoxide source (Equation 1).
Pd(OAc)2/dppf, Mo(CO)6,
ROTf
RCO2H
H2O, pyridine, 150 °C,
MW, 20 min
2a–u
1a–u
R = aryl, vinyl
Equation 1
The reaction of trifluoromethanesulfonic acid p-tolyl ester
with Mo(CO)6 (0.5 equiv) in the presence of Pd(OAc)2
(0.1 equiv) and dppf (0.1 equiv) was initially examined as
the model system, fitting the best conditions employed in
literature for tolyl iodide.8 In a typical experiment, the sol-
id components Pd(OAc)2 and dppf were mixed in a reac-
tion vessel with aqueous K2CO3 as base and diglyme as
solvent. Then, the triflate was added, followed by
Mo(CO)6. The vial was immediately capped under air and
irradiated with microwaves under stirring for 20 minutes
at 150 °C. The corresponding p-toluic acid could be iso-
lated in 41% yield, together with a large amount (37%) of
p-methylphenol. In order to improve the yield of the de-
SYNTHESIS 2006, No. 4, pp 0594–0596
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926288; Art ID: T09205SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Microwave-Assisted Hydroxycarbonylation of Triflates
595
sire product and to minimise the hydrolysis of triflate, the By avoiding use of gaseous carbon monoxide, high boil-
influence of the base was briefly investigated. Aqueous ing solvents and exploiting the advantages of microwaves
tertiary aliphatic amines instead of inorganic carbonate irradiation, the procedure would be fully suitable for fast
were found to be ineffective. Also DBU, which is and environmentally safe applications.
reported5 to be highly productive in similar reactions, was
Table 1 Preparation of Triflates 2
found to dramatically lower the reaction yields. At last,
we were pleased to find that pyridine led to a significant
Entry
Triflate 1
Product 2
Isolated
increase in the yield (up to 60%) of p-toluic acid, totally
preserving the starting triflate from competitive hydroly-
sis to phenol. With the aim of carrying out a convenient
protocol, which would overcome the trouble of using the
high boiling diglyme, the employment of other polar sol-
vents was investigated. We observed that diglyme could
be efficiently substituted by dioxane, which is more toxic
but easier to remove. More surprisingly, we succeeded in
developing the best conditions when we replaced the or-
ganic solvent with water. Carrying out the reaction in a
heterogeneous system, under vigorous stirring, a 73%
yield could be obtained for the reference substrate (Table
1, entry 1). Finally, attempts to reduce the amount of
Pd(OAc)2 and dppf to 5 mol% led to a significant lower-
ing of the yield. With the aim of shortening the reaction
time, we tried to heat the reaction cocktail above 150 °C,
but yields were reproducible only if irradiation was kept
to 20 minutes.
yield (%)
CO2H
OTf
1
2
3
4
73
80
35
55
Me
2a10
Me
CO2H
CO2H
OTf
O2N
O2N
MeO
2b11
OTf
MeO
2c10
CO2H
OTf
Ph
2d12
O
Ph
O
CO2H
OTf
5
94
O
2e13
O
Cl
Under the optimised conditions so far developed for tri-
fluoromethanesulfonic acid p-tolyl ester, we extended this
procedure to a variety of triflates as shown in Table 1.
Moderate to almost quantitative yields were obtained with
a variety of electron-poor, neutral and electron-rich aryl
and vinyl triflates. A clear influence of substitution should
be noted, with p-substituted electron-poor substrates
working best, probably due to favoured oxidative addition
to Pd(0) in the first step of the catalytic cycle (entries 2, 5–
8). Also o-substitution is well tolerated (entries 12–15),
even if yields decrease in case of steric compression at the
reaction site (entry 18). Acceptable yields could also be
obtained for electron-rich substrates (entries 3, 4, 11, 14,
16) except for the particularly unfavourable case of tri-
fluoromethanesulfonic acid 2,6-dimethoxyphenyl ester
(entry 17). Interestingly, complete chemoselectivity was
observed with halogenated compounds, such as trifluo-
romethanesulfonic acid p-chloro- and p-bromophenyl es-
ters, which afforded in high yield the desired p-chloro and
p-bromo benzoic acids, without side products derived
from competitive addition of Pd(0) into Ar–halogen bond
(entries 6 and 7).
CO2H
CO2H
OTf
OTf
6
7
8
95
80
91
Cl
2f14
Br
2g15
Br
CO2H
OTf
EtO2C
EtO2C
2h16
CO2H
OTf
9
10
11
79
54
95
Me
2i14
Me
CO2H
OTf
NO2
NO2
2j17
CO2H
OTf
OMe
2k18
OMe
OTf
CO2H
In order to compare the obtained results with those ob-
tained by performing the same hydroxycarbonylation
with classic high-temperature heating, reactions on tri-
fluoromethanesulfonic acid p-tolyl ester and on trifluo-
romethanesulfonic acid p-nitrophenyl ester (entries 1 and
2) were also conducted in a closed steel tube with an oil
bath. After heating at 180 °C for 12 hours, with diglyme
instead of water as solvent, much lower yields were ob-
tained for both carboxylic acids.
12
13
14
34
45
26
Me
Me
2l19
CO2H
NO2
OTf
NO2
2m20
2n21
CO2H
OMe
OTf
OMe
In conclusion, we have demonstrated an efficient palladi-
um-catalyzed conversion of triflates into carboxylic acids.
Synthesis 2006, No. 4, 594–596 © Thieme Stuttgart · New York

596
G. Lesma et al.
SHORT PAPER
Table 1 Preparation of Triflates 2 (continued)
ter workup, the yields of carboxylic acids were found to be lower
than the reported microwave results (51% for 2a and 55% for 2b).
Entry
15
Triflate 1
Product 2
Isolated
yield (%)
All compounds were characterised by comparison of the physical
and/or spectroscopic data with the reported ones.10–25
CO2H
O
OTf
O
93
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2u25
All chemicals were purchased from commercial sources and were
used directly, unless otherwise indicated. The H and 13C NMR
1
spectra were recorded on Bruker 300 MHz and 400 MHz Avance
NMR spectrometers. Microwave heating was carried out using a
Milestone instrument, supplied by FKV (Bergamo, Italy). Reaction
vessels in Pyrex (12 mL) with ceramic septum were supplied by the
same company.
Microwave Procedure
Pd(OAc)2 (92 mg, 0.4 mmol), dppf (224 mg, 0.4 mmol), water (12
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microwave vessel. Finally, Mo(CO)6 (528 mg, 2 mmol) was added
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Synthesis 2006, No. 4, 594–596 © Thieme Stuttgart · New York