Fast microwave promoted palladium-catalyzed synthesis of phthalides from bromobenzyl alcohols utilizing DMF and Mo(CO)6 as carbon monoxide sources

Article abstract of DOI:10.1016/j.tetlet.2004.04.110

A fast method utilizing in situ generated CO for the synthesis of phthalides has been developed. DMF and Mo(CO)₆ were applied as two alternative CO-sources in these microwave promoted carbonylation-lactone formation reactions. Mo(CO)₆ was found to be the more generally applicable CO-source and provided phthalides as well as dihydroisocoumarin, dihydroisoindone, and phthalimide from the corresponding aryl bromide via an efficient CO insertion within a 1h reaction time.

Full text of DOI:10.1016/j.tetlet.2004.04.110

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4635–4638
Fast microwave promoted palladium-catalyzed synthesis of
phthalides from bromobenzyl alcohols utilizing DMF and
Mo(CO)6 as carbon monoxide sources
Xiongyu Wu, A. K. Mahalingam, Yiqian Wan and Mathias Alterman*
Department of Organic Pharmaceutical Chemistry, BMC, Uppsala University, PO Box 574, SE-751 23 Uppsala, Sweden
Received 12 January 2004; revised 13 April 2004; accepted 21 April 2004
Abstract—A fast method utilizing in situ generated CO for the synthesis of phthalides has been developed. DMF and Mo(CO)6 were
applied as two alternative CO-sources in these microwave promoted carbonylation–lactone formation reactions. Mo(CO)6 was
found to be the more generally applicable CO-source and provided phthalides as well as dihydroisocoumarin, dihydroisoindone, and
phthalimide from the corresponding aryl bromide via an efficient CO insertion within a 1 h reaction time.
Ó 2004 Elsevier Ltd. All rights reserved.
Phthalides (3H-isobenzofuran-1-one) are commonly
found in many naturally occurring substances,1–6 as well
as some of their synthetically related compounds and
exhibit a broad spectrum of biological activities, for
example, noscapine, bicuculline.7 Furthermore, phtha-
lides are versatile starting materials for the synthesis of a
variety of structures, including key intermediates in the
synthesis of functionalized naphthalenes and anthrac-
enes, which in turn are used as synthons for tricyclic and
tetracyclic linear aromatic natural products.8–13
phthalides with CO gas as the carbonylation source.24–28
This synthetic approach has also been successfully
combined with supercritical CO2 as solvent.29
Today, the trend in industrial medicinal chemistry is to
move toward high-throughput chemistry, employing
small reaction scales and short reaction times.30–32 In
this context, microwave heating has emerged as an
attractive energy source for accelerated metal-catalyzed
transformations and has proven powerful in many dif-
ferent applications.33 Carbon monoxide is an important
building block but the somewhat troublesome gas hand-
ling procedure and the toxicity of carbon monoxide limit
the use of carbonylation reactions for the small-scale
synthesis of compound libraries.32;30;34
Due to their importance, several methods have been
developed for the synthesis of phthalides.14–17 Classical
methods for the preparation of phthalides rely on the
chloromethylation of benzoic acids, which unfortu-
nately often result in low yields and are not suitable for
the regioselective preparation of substituted phtha-
lides.18–20 Alternatively, the reduction of phthalic anhy-
drides or the oxidation of diols have been developed as
useful approaches to phthalides, although the regio-
selectivity of the product via these methods is frequently
a problem.21–23 More recently, palladium-catalyzed car-
bonylation reactions of ortho-halobenzyl alcohols have
been reported as a convenient route for the synthesis of
Recent reports from our laboratory describe a fast
microwave promoted palladium-catalyzed carbonyl-
ation protocol employing in situ generated carbon
monoxide from solid molybdenum hexacarbonyl
(Mo(CO)6)35–37 or liquid dimethylformamide38 (DMF)
and formamide.39 In light of the synthetic usefulness of
phthalides we wanted to explore the use of these sources
of carbon monoxide for the formation of this hetero-
cyclic scaffold.
We selected (2-bromophenyl)methanol as the model
substrate for a series of optimization experiments
(Scheme 1). Different palladium sources, ligands,
Keywords: Phthalides; Mo(CO)6; Carbon monoxide source.
* Corresponding author. Tel.: +46-18-471-4905; fax: +46-18-471-4474;
e-mail: mathias@orgfarm.uu.se
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.110

4636
X. Wu et al. / Tetrahedron Letters 45 (2004) 4635–4638
Table 2. Examination of different palladium sources and ligands in the
carbonylation–lactone formation reaction with MoCO6 as CO-sourcea
O
Br
CO-source
[Pd]
O
OH
Entry Pd-source
Ligand
Temperature
(°C)
Isolated
yield (%)
Scheme 1.
1
2
3
4
5
6
7
Palladacycle
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
18077
18079
18062
180Trace
18088
19087
16070
b
c
P(o-Tol)3
––
temperatures, and reaction times were examined and
controlled microwave heating in sealed borosilicate
vessels was employed. Initially, DMF was explored as
the in situ CO generating source. The results are sum-
marized in Table 1. As a starting point, we utilized the
conditions used previously for formation of amides, that
is, Pd(OAc)2 (5 mol %), dppf (5 mol %), KOt-Bu
(1 equiv), and imidazole (1 equiv) in DMF (190 °C,
15 min).38 Unfortunately, these conditions were not
ideal with a benzyl hydroxyl group as nucleophile and
no phthalide product was detected in the reaction mix-
ture. The major side product was the debrominated
benzyl alcohol and not the expected dimethyl amide,
derived from the dimethylamine formed in the decom-
position of DMF. The temperature was therefore low-
ered to 170 °C and the sample was heated for 15 min. At
this temperature, the phthalide could be detected but the
starting bromide was not fully consumed. Prolonging
the time to one hour gave full conversion of the starting
material and the product was isolated although only in
8% yield (entry 1). Different ligands were evaluated to
optimize the reaction further. The best result was
obtained with P(o-Tol)3 at 170 °C, which gave an iso-
lated yield of 45%. Increasing or decreasing the reaction
temperature resulted in a reduced yield of the phthalide.
Although, an improved yield could be obtained with
P(o-Tol)3 as ligand, the major side product was still the
debrominated benzyl alcohol. In order to minimize
formation of this side product, the reaction was per-
formed under dry conditions. However, the competing
debromination reaction was not suppressed and the
yield of the phthalides could not be improved further
with this carbonylation method. We therefore decided to
investigate Mo(CO)6 as an alternative carbon monoxide
source.
dppf
dppf
dppf
b
a Reaction time 30min.
b Full conversion was not achieved during irradiation.
c Literature data of a similar reaction with 2-iodophenylmethanol as
the reagent gave the same product in 76% yield after 18 h at 5 atm
29
CO
.
ðgÞ
evaluated. The results are summarized in Table 2. Dif-
ferent catalytic systems were examined at a reaction
temperature of 180 °C with 1,4-dioxane as solvent. After
a reaction time of 30min most of the catalytic systems
used gave full conversion, except for P(o-Tol)3 (entry 3).
The best result was obtained with Pd(OAc)2 and dppf
resulting in 88% of the desired phthalide (entry 5).
Increasing the temperature to 190 °C did not improve
the isolated yield of the product and full conversion of
the starting material was not achieved when the tem-
perature was lowered to 160 °C (entries 6–7).
To determine the effect of substituents on the phenyl
ring a series of electron-rich and electron-poor bromo-
benzyl alcohols were evaluated in the reaction. The
preparative results are summarized in Table 3. The
electron-rich bromobenzyl alcohols (entries 2–4) all gave
good yields of the corresponding phthalides. However,
in the case of 2-bromo-4,5-dimethoxyphenylmethanol
the solubility of the starting material in 1,4-dioxane was
very low and consequently the isolated yield was only
27%. By changing the solvent to DMF the yield was
improved but unfortunately the competing dehydroxyl-
ation reaction was more pronounced and the product
could only be isolated in 52% yield (entry 5). The reac-
tion of the secondary alcohol gave a good yield of the
3-methyl substituted phthalide (entry 6) but slightly
lower than that of the primary alcohol. Both of the
halogen substituted compounds provided good yields,
although the chloride-encompassing compound had to
be treated at a lower temperature to suppress the con-
comitant dehalogenation of the product (entry 8). The
compound containing the nitro group was not a good
substrate for the phthalide formation reaction. Many
side products were produced due to simultaneous CO
reduction of the nitro group. Nevertheless, the aniline
phthalide compound could be isolated from the reaction
mixture in a 10% yield.
The solid CO-source, Mo(CO)6 has previously been
proved to give noncyclic esters in good yields.36 In these
series palladium on charcoal was used as the catalyst
with aryl iodides as the substrate, and the palladacycle
was used as the palladium source with the aryl bro-
mides. We wanted to explore aryl bromides and there-
fore the palladacycle and other palladium sources were
Table 1. Examination of different ligands in the carbonylation–lactone
formation reaction with DMF as CO-sourcea
Entry
Pd-source
Ligand
Temperature
(°C)
Isolated
yield (%)
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
dppf
Binap
1708
1708
This carbonylation–cyclization method can also be
applied in the synthesis of other important naturally
occurring scaffolds, that is dihydroisocoumarin, dihy-
droisoindone, and phthalimide (Table 4). 2-(2-Bromo-
phenyl)ethanol gave the dihydroisocoumarin in 74%
yield (entry 1) after 1 h of microwave irradiation at
P(c-Hex)3
P(o-Tol)3
P(o-Tol)3
P(o-Tol)3
17025
17045
150Trace
18018
a Reaction time 1 h.

X. Wu et al. / Tetrahedron Letters 45 (2004) 4635–4638
4637
Table 3. Rapid palladium-catalyzed carbonylation–lactonization of
bromobenzyl alcohols using Mo(CO)6 as the CO sourcea
180 °C. With the more nucleophilic 2-bromobenzyl-
amine, the temperature had to be lowered to 160 °C to
permit isolation of the dihydroisoindone in a good yield
(entry 2). This was also the case for the phthalimide,
which required irradiation at 150 °C and was isolated in
70% yield.
Entry Bromide
Product
Isolated yield
(%)
O
Br
1
88
1
O
OH
Br
In summary, a fast method utilizing in situ generated
CO for the synthesis of phthalides has been developed.
Heat and base decomposed DMF has been used as a
liquid carbon monoxide source. This procedure was
found not to be optimal due to competing debromina-
tion of the starting material. Mo(CO)6 was, on the other
hand, an excellent and more generally applicable CO-
source in these carbonylation–lactonization reactions.
Under the present conditions, Mo(CO)6 gave phthalides
as well as dihydroisocoumarin, dihydroisoindone, and
phthalimide from aryl bromide precursors within a one
hour reaction time. We envisage that these reaction
conditions could be applied to parallel synthesis of these
synthetically important structures in the future.
O
2
3
92
90
84
52b
2
3
O
OH
O
Br
O
OH
Br
O
4
4
5
O
OH
O
O
O
O
O
O
Br
5
O
OH
O
O
Br
General procedure: A process vial was charged with
2-bromobenzyl
alcohol
(1.0mmol),
Mo(CO) 6
6
75
77
76c
10
6
O
OH
Br
(0.5 mmol), Pd(OAc)2 (0.05 mmol), 1,10-bis(diph-
enylphosphino)ferrocene (dppf) (0.05 mmol), DMAP
(2.0mmol), DIEA (2.0mmol), and dioxane (1 mL). The
reaction mixture was flushed with nitrogen and the cap
was tightened thoroughly. The vessel was exposed to
microwave heating for 30–60 min. The reaction tube was
thereafter cooled to room temperature and the mixture
was extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over potassium
carbonate, and the solvent was removed under reduced
pressure. The products were purified on silica gel.40–51
O
F
F
7
7
O
O
OH
Br
8
8
O
OH
Cl
Cl
NO2
NH2
O
Br
9
9
O
OH
a Reaction conditions: 2-bromo-aryl alcohol (1.0mmol), Mo(CO) 6
(0.5 mmol), Pd(OAc)2 (0.05 mmol), dppf (0.05 mmol), DMAP
(2.0mmol), DIEA (2.0mmol), and dioxane (1 mL); 30min, 180 °C.
b DMF as solvent, reaction time 1 h.
Acknowledgements
c Reaction temperature 150 °C.
We gratefully acknowledge financial support from the
Swedish foundation for Strategic Research (SSF). We
thank Personal Chemistry for providing the microwave
synthesizer.
Table 4. Rapid palladium-catalyzed carbonylation–cyclization reac-
tions of bromoaryls using Mo(CO)6 as the CO-sourcea
Entry
1
Bromide
Product
Isolated yield (%)
O
Br
74b
O
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10
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OH
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