S. M. Landge et al. / Tetrahedron Letters 49 (2008) 4505–4508
4507
O
4. General procedure
O
Phthalaldehydic acid, ketones, and K-10 montmorillonite were
purchased from Aldrich and used without further purification.
The reactions were carried out at constant temperatures (usually
170 °C) in a Discover Benchmate microwave reactor, with continu-
ous stirring. The temperature was measured and controlled by a
built-in infrared detector. The 1H, 13C, and 19F NMR spectra were
obtained on a 300 MHz Varian NMR spectrometer in CDCl3. Tetra-
methylsilane, CFCl3 (for 19F NMR), or the residual solvent signal
were used as reference. The MS identification of the products
was carried out with an Agilent 6850 GC–5973 MS system (70 eV
electron-impact ionization) using a 30 m long DB-5 column (J&W
Scientific). The melting points are uncorrected and were recorded
on a MEL-TEMP apparatus.
OH
1
O
O
O
H
OH
OH
O
tautomerism
O
H
O+
H
HO
HO
H
O
δ+
OH
O
δ+
K-10
K-10
OH
OH
HO
O
O
O
OH
OH
O
O
4.1. One-pot microwave-assisted synthesis of isobenzofuran-
1(3H)-ones—general procedure
In a typical reaction, phthalaldehydic acid (0.8 mmol) and a
ketone (1 mmol) were dissolved in 9 ml of methylene chloride
and 1 ml of methanol. Five hundred milligrams of K-10 montmo-
rillonite were added to the mixture, which was stirred for 2 min.
Then the solvent was evaporated in vacuo. The dry mixture was
transferred into a reaction tube and irradiated in a microwave
reactor under continuous stirring (CEM Discover Benchmate) in
an open system under atmospheric pressure. During optimization,
the progress of the reaction was monitored by GC–MS. When the
reaction was completed the product was dissolved in CH2Cl2,
separated from the catalyst by filtration and the solvent was
removed in vacuo. The crude product was purified by flash
chromatography.
aldol intermediate
Scheme 2. Proposed mechanism for the synthesis of 3-phenacylphthalides via
microwave-assisted montmorillonite K-10 catalyzed cyclizations.
necessary during the preparation of the reaction mixtures that
makes the process even greener.
Based on the above studies, we found that the reaction took
place in high yields with excellent selectivities under optimized
conditions, although time may vary in reactions of different reac-
tants (ketones). To explore the scope of our methodology, a wide
variety of ketones were selected to synthesize substituted iso-
benzofuran-1(3H)-ones. The results are summarized in Table 3.
As the data indicated, all ketones gave excellent yields (>90%).
The yields were not affected by the substituents, as neither elec-
tronic nor steric effects were predominant. The cyclization ap-
peared to be a generally applicable process for the synthesis of a
wide range of the target compounds.
Excluding two compounds (entries i and j), all products synthe-
sized in this study are known and their spectral characterization
showed satisfactory agreement with literature data. Here, the
spectral data are listed only for the new compounds.
4.1.1. 3-(2-(4-Cyanophenyl)-2-oxoethyl)isobenzofuran-1(3H)-
one (Table 3; entry j)
Yield: 98%; mp 165–167 °C (hexane/ethylacetate 80:20) 1H
NMR (300 MHz, CDCl3); 8.03 (d, 2H, J = 8.7 Hz, Ar-H), 7.91 (d,
1H, J = 7.8 Hz, Ar-H), 7.78 (d, 2H, J = 8.7 Hz, Ar-H), 7.66 (qd,
1H, J = 7.5, 1.2 Hz, Ar-H), 7.50–7.61 (m, 2H, Ar-H), 6.13 (t, 1H,
J = 6.3 Hz, CH), 3.73 (dd, 1H, J = 18.0, 6.3 Hz, CH), 3.40 (dd, 1H,
J = 17.7, 6.6 Hz, CH); 13C NMR (75.5 MHz, CDCl3); 194.7, 174.2,
149.2, 147.6, 139.8, 134.4, 132.7, 129.6, 128.5, 125.9, 122.5,
116.6, 116.2, 76.7, 43.9; MS-C17H11NO3 (277), m/z (%): 277
(M+, 10), 232 (12), 207 (10), 147 (100), 130 (82), 102 (68), 77
(44).
Phthalaldehydic acid is often represented in two forms,
2-formylbenzoic acid and 3-hydroxyphthalide (1), which are in
equilibrium with each other. The reaction proceeds in two steps;
an aldol condensation and the subsequent cyclization. The first
reaction follows the regular mechanism of acid-catalyzed
condensation reactions and results in an aldol intermediate that
immediately undergoes lactonization. It is known that K-10 mont-
morillonite possesses both Lewis and Brønsted acid centers on its
surface and depending on the conditions, one or the other takes
a leading role in catalysis.8a,b,e,11 We suggest that in the present
case, the reaction is driven by the Brønsted acid centers via the
open form of the formyl benzoic acid. The existence of the cyclic
hydroxyphthalide form is not favored by the strongly acidic and
extremely polar conditions. The proposed mechanism is illustrated
in Scheme 2.
4.1.2. 3-(2-Oxocyclohexyl)isobenzofuran-1(3H)-one and 3-(2-
hydroxycyclohex-1-enyl)isobenzofuran-1(3H)-one (Table 3;
entry i)
Yield: 98%; oil; 1:1 mixture of tautomers 1H (300 MHz, CDCl3);
8.07 (d, 1H, J = 7.5 Hz, Ar-H, keto), 7.89 (d, 1H, J = 7.5 Hz, Ar-H,
enol), 7.61–7.68 (m, 2H, Ar-H, keto/enol), 7.49–7.53 (m, 2H, Ar-H,
keto/enol), 7.36 (t, 1H, Ar-H, keto/enol), 7.23 (t, 1H, Ar-H, keto/
enol), 6.11 (d, 1H, J = 3.0 Hz, CH, enol), 5.98 (d, 1H, J = 6.0 Hz, CH,
keto), 3.20 (m, 1H, keto), 1.51–2.76 (m, 17H, 8CH2, keto/enol);
13C (75.5 MHz, CDCl3); 199.6, 174.1, 172.4, 166.0, 150.8, 134.0,
133.9, 129.1, 125.53, 125.51, 124.1, 122.7, 116.6, 79.7, 79.0, 53.2,
42.1, 34.2, 28.5, 27.6, 26.9, 26.5, 24.2, 20.9; MS-C14H14O3 (230),
enol: m/z (%): 230 (M+, 40), 212 (93), 201 (58), 133 (100), 105
(25), 77 (28); keto: m/z (%): 230 (M+, 47), 212 (98), 201 (55), 133
(100), 105 (27), 77 (22).
3. Conclusion
A new, solid acid-catalyzed, effective, economic, and environ-
mentally benign one-pot synthesis of 3-substituted phthalides
has been developed. The products were obtained in excellent
yields and exclusive selectivities in short reaction times. This sim-
ple, sustainable synthesis is a novel method for the preparation of
the target compounds. Due to the importance of the products, our
approach may contribute to widening pharmaceutical and
biomedical applications of phthalide derivatives.