Synthesis of selectively 18O-labeled phthalides using water-assisted cyclization

Article abstract of DOI:10.1016/j.tetlet.2013.04.112

Two selectively ¹⁸O-labeled phthalides containing ¹⁸O either in the carbonyl (i.e., C¹⁸O) or in the alkoxy group (i.e., OC-¹⁸O) of the lactone ring were prepared in good yields (ca. 70%) from the corresponding m

Full text of DOI:10.1016/j.tetlet.2013.04.112

Tetrahedron Letters 54 (2013) 3533–3537
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Synthesis of selectively 18O-labeled phthalides using water-assisted cyclization
a
a
b
a
a,
⇑
ˇ
ˇ
ˇ
Jirí Vána , Illia Panov , Milan Erben , Miloš Sedlák , Jirí Hanusek
a Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
b Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Two selectively 18O-labeled phthalides containing 18O either in the carbonyl (i.e., C@18O) or in the alkoxy
group (i.e., O@C–18O) of the lactone ring were prepared in good yields (ca. 70%) from the corresponding
methyl 2-(bromomethyl)benzoate and its selectively C@18O labeled derivative, respectively, using water-
assisted cyclization. The reaction mechanism involving formation of a cyclic carboxonium bromide and
its water-assisted decomposition to the lactone is proposed.
Article history:
Received 2 February 2013
Revised 11 April 2013
Accepted 26 April 2013
Available online 3 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Phthalide
Labeling
Cyclization
Mechanism
Methyl 2-(bromomethyl)benzoate
The phthalide [1(3H)-isobenzofuranone] skeleton is present in
many natural products and in a number of commercially signifi-
cant compounds. More than 180 naturally occurring phthalides
can be found in plants, fungi, and liverworts and most of them
show biological activity.1–3 For this reason several phthalide-con-
taining plants are commonly used in traditional Chinese medicine
for the treatment of cerebro- and cardiovascular diseases.1 The
most promising single derivative is 3-butylphthalide which, since
2002, has been intensively tested for the treatment of hyperten-
sion4 and for its neuroprotective effects.5,6 Several phthalides also
show herbicidal7 and antifungal8–10 properties. For instance,
4,5,6,7-tetrachlorophthalide9 can be applied to paddy fields to pre-
vent rice blast. Another example of the application of phthalides
comes from analytical chemistry: many phthalide-containing dyes
(e.g., phenolphthalein, thymolphthalein, rhodamine B, fluorescein,
crystal violet lactone, etc.) are used as pH/fluorescence indica-
tors.11 Phthalide derivatives have also been prepared as novel flu-
oroionophores,12 or as an activating group for nucleophilic
aromatic substitution in the synthesis13 of poly(aryl ether phthal-
ide)s. Phthalides containing an isothiuronium side chain are easily
transformed into 2H-isoindole-2-carbothioamides.14
bration of unlabeled phthalide with slightly enriched H218O
(1.6 at % 18O). Although the authors claimed that the 18O isotope
is present only in C@18O, they did not provide any evidence for
its exact position in the lactone ring; they analyzed only carbon
dioxide formed after total oxidation.
The most efficient synthesis of the phthalide skeleton involves
cyclization of alkyl 2-(bromoalkyl)benzoates on heating16–20 under
solvent-free conditions. Although the detailed mechanism for this
18O
O
O
18O
1a
1b
Figure 1. Synthesized 18O-labeled phthalides.
OR
Br
R
a)
OR
Here we report the synthesis of regioselectively 18O-labeled
phthalides 1a–b (Fig. 1).
O
O
O
There exists only one report15 in the literature concerning the
preparation of 1a. This preparation involves acid-catalyzed equili-
O
+ RBr
O
b)
Br
O
Br
⇑
Corresponding author. Tel.: +420 466 037 015.
E-mail address: Jiri.Hanusek@upce.cz (J. Hanusek).
Scheme 1. Possible mechanisms for lactonization under heating.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.112

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J. Vána et al. / Tetrahedron Letters 54 (2013) 3533–3537
3534
ring closure was not studied, it can be suggested that the
mechanism involves internal nucleophilic attack at the benzylic
carbon by the carbonyl or alkoxy oxygen (SN1i or SN2i), which is fol-
lowed by another nucleophilic displacement where the leaving
bromide acts as an external nucleophile attacking the carbon of
the alkyl group (Scheme 1).
The suggested reaction mechanism (a) in Scheme 1 is more
probable because a similar reaction pathway involving formation
of cyclic carboxonium salts from 2-haloethyl esters and their cleav-
age by the action of an external halide anion has previously
been reported.21 Also, the lactonization of 4-chlorobutyrate and
5-chlorovalerate in the gas phase involves similar carboxonium
salts.22 However, the second possibility (b) cannot be completely
excluded because many processes involving anchimeric assistance
by alkoxyl groups have also been published.23–25
In order to verify the reaction mechanism and to prepare selec-
tively 18O-labeled phthalides, we have modified the original Davies
procedure16 which used water as the solvent. Water itself can have
a dual role during the lactonization process. First, it can act as a sol-
vent with significant ionizing power,26–28 in terms of the Grun-
wald–Winstein Y-scale, in the first step of the mechanism.
Second, the water molecule can act as a nucleophile which com-
petes with bromide in the second step, or it can attack directly
the carbonyl of the intermediate in route (a), with subsequent
cleavage of an alkoxide. Uncatalyzed hydrolyses of ester or benzyl
bromide groups to give free carboxylic acid and benzyl alcohol,
Figure 2. Selected signals in the 13C NMR spectra (400 MHz, CDCl3) of 18O-enriched phthalides.

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J. Vána et al. / Tetrahedron Letters 54 (2013) 3533–3537
3535
Figure 3. IR spectra of sample of 18O-enriched phthalides.
18O
OCH3
O
H3CO 18OH2
O
respectively, are improbable because both reactions are very
slow,28,29 similar to the lactonization of 2-(bromomethyl)benzoic
acid30 or 2-(hydroxymethyl)benzoic acid.31
OCH3
H218O
O
O
CH OH
–
3
– HBr
We performed two independent experiments. In the first
experiment we started from methyl 2-(bromomethyl)benzoate
selectively 18O-labeled in the carbonyl group (25% enrichment)
which was prepared using adapted and known procedures.32,33
Heating of this compound (0.5 g) with standard water (0.2 ml) at
100 °C for 12 h produced, after crystallization from water, 0.2 g
yield (68%) of 1b as the only product.34 The identity and purity
of the product were proved by EI-MS, NMR, and IR. The unambig-
uous position of the 18O labeled oxygen in product 1b was deter-
mined from inspection of the 13C NMR spectrum where two
signals for the carbonyl, benzylic, and aromatic carbon atom (3a)
appeared (Fig. 2).
Br
1a
Br
Scheme 2. Water-assisted lactonization of methyl 2-(bromomethyl)benzoate.
EI-MS has been used for the determination of the 18O enrich-
ment of the prepared compounds (Fig. 4). The intensity of the
molecular peaks at m/z 134 and 136 shows phthalide 1a to
be enriched by 25% and 1b by 20%, respectively. This method
can also be used for determination of the position of 18O in
the molecule. In the EI-MS spectrum of the unlabeled phthalide
and the labeled phthalide 1b, a typical fragment corresponding
to the benzoyl ion (m/z 105) appears.37 In the spectrum ob-
tained from a mixture containing phthalide 1a, a new signal
at m/z 107 appears, which confirms the presence of 18O in
the carbonyl group.
The 18O-isotope upfield shift for the carbonyl carbon (171.074
and 171.061 ppm) is 0.013 ppm, for the benzylic carbon (69.608
and 69.584) is 0.024 ppm and for the aromatic carbon next to the
benzyl carbon (146.455 and 146.450) is only 0.005 ppm. These val-
ues of the isotope shifts35 confirm 1b as the only labeled product.
The same conclusion can be reached from inspection of the IR spec-
tra (Fig. 3) which each contain only one band for the C@O vibration
at 1743 cmÀ1 which is identical with the unlabeled compound. On
the other hand, the bands near 1000 cmÀ1 corresponding to the C–
O vibrations are duplicated. These results prove the internal nucle-
ophilic attack at the benzylic carbon by the carbonyl oxygen. On
the other hand, when unlabeled 2-(bromomethyl)benzoate was
treated with isotopically enriched water (51% 18O) under the same
conditions, the only labeled product isolated from the reaction
mixture was the lactone 1a in 73% yield (after crystallization).36
In this case the 13C NMR spectrum shows two signals only for
the carbonyl carbon atom (171.155 and 171.119 ppm) with an
18O-isotope upfield shift of 0.036 ppm (Fig. 2) and the IR spectrum
contains two bands at 1743 and 1729 cmÀ1 corresponding to the
C@16O and C@18O vibrations. The bands near 1000 cmÀ1 show no
duplication (Fig. 3). This observation confirms 1a as the only isoto-
pically labeled product.
On the basis of the results presented above the following reac-
tion mechanism involving water-assisted lactonization can be con-
sidered (Scheme 2).
Further evidence for the mechanism presented in Scheme 2
comes from pH measurements taken during the reaction. It was
found that the mixture was acidic after the reaction due to the
presence of hydrogen bromide. This hydrogen bromide cannot
come from hydrolysis of the alternative product–methyl
bromide–because such hydrolysis is very slow. Moreover, the
evolved methyl bromide would escape quickly from the boiling
reaction mixture as it has a very low boiling point.
In conclusion, we developed a new procedure for the synthesis
of selectively 18O-labeled phthalides from the corresponding
methyl 2-(bromomethyl)benzoate in good yields (ca. 70%) and pro-
posed the reaction mechanism involving formation of a cyclic car-
boxonium bromide and its water-assisted decomposition to the
lactone.

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J. Vána et al. / Tetrahedron Letters 54 (2013) 3533–3537
Figure 4. EI-MS spectra of 18O-enriched phthalides.
Acknowledgment
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m
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.
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O
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