Synthesis of phthalides utilizing a one-pot intramolecular domino protocol

Article abstract of DOI:10.1039/c3ra45117h

A number of (E)-3-alkylidine-phthalide derivatives have been prepared at room temperature in excellent yields in a one-pot reaction by treating o-alkenylbenzoic acids with meta-chloroperbenzoic acid and para-toluenesulfonic acid. This reaction presumably occurs via domino epoxidation-intramolecular cyclization-acid catalyzed dehydration sequence of reactions. On the other hand, 3-(2-formyl-3,4-dihydro-naphthalen-1-yl)-acrylic acid esters and 3-(2-formyl-3,4-dihydro-naphthalen-1-yl)-acrylonitriles afforded phthalide derivatives under Pinnick reaction conditions involving oxidation-intramolecular Michael addition.

Full text of DOI:10.1039/c3ra45117h

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Synthesis of phthalides utilizing a one-pot
intramolecular domino protocol†
Cite this: RSC Adv., 2013, 3, 25631
a
b
*
Nasima Yasmin and Jayanta K. Ray
Received 14th September 2013
Accepted 22nd October 2013
DOI: 10.1039/c3ra45117h
www.rsc.org/advances
A number of (E)-3-alkylidine-phthalide derivatives have been rhodium for the synthesis of phthalides.6 In continuation of our
prepared at room temperature in excellent yields in a one-pot synthetic efforts for the development of newer methods for the
reaction by treating o-alkenylbenzoic acids with meta- preparation of heterocycles,7 we herein present an efficient, one-
chloroperbenzoic acid and para-toluenesulfonic acid. This reaction pot room temperature route to phthalide and 3-alkylidine-
presumably occurs via domino epoxidation – intramolecular cycli- phthalide derivatives via intramolecular domino protocol.
zation – acid catalyzed dehydration sequence of reactions. On the
Current assignment started with the conversion of o-alke-
other hand, 3-(2-formyl-3,4-dihydro-naphthalen-1-yl)-acrylic acid nylbenzaldehydes8 1 into o-alkenylbenzoic acids 2 exploiting
esters and 3-(2-formyl-3,4-dihydro-naphthalen-1-yl)-acrylonitriles Pinnick oxidation9 (Scheme 1). When the precursors 1 were
afforded phthalide derivatives under Pinnick reaction conditions treated with sodium chlorite (1.4 equiv.) in the presence of
involving oxidation-intramolecular Michael addition.
1(3H)-Isobenzofuranones or phthalides, fused-ring aromatic
g-lactones, have attracted the attention of various research
groups, regarding their isolation, structural elucidation,
biogenesis, biological activity as well as synthetic goals. In
particular, the importance of 3-substituted phthalide frame-
Scheme 1 Synthesis of o-alkenylbenzoic acids by Pinnick oxidation.
works is underscored by their wide distribution in a large
collection of natural products with broad and potentially path-
pointing biological activities.1
Phthalides are of special interests in polymer science in view
of their ring-chain isomerism. Phthalide-containing polymers
possess outstanding electrophysical and optical characteristics
and high heat resistance.2
Table 1 Optimization study of cyclization o-alkenylbenzoic acidsa
Since the classical work by Bistrzycki et al.,3 numerous
methods have been reported for the synthesis of phthalides.
Amongst them, the use of o-halobenzoic acid derivatives and
terminal alkynes as starting materials is one of the most attractive
routes.4 The rst one pot synthesis of phthalides was described by
Castro et al., but the methodology afforded mixture of phthalides
and isocoumarins.5 Of late, Phan et al. demonstrated an intra-
molecular hydroacylation reaction of ketones catalyzed by
Entry
mCPBA
p-TsOH
Yieldb (%)
1
2
3
—
1.0 mmol
—
1.0 mmol
NR
Dec
93
1.0 mmol
1.0 mmol
a
Reaction conditions: reaction was carried out with 2-(2-methoxy-
carbonyl-vinyl)-benzoic acid 2a (1.0 mmol), mCPBA(1.0 mmol)
and p-TsOH (1.0 mmol) in DCM (5 mL) at room temperature for 5–6 h.
aDepartment of Chemistry, Aliah University, Kolkata 700016, India
bDepartment of Chemistry, Indian Institute of Technology, Kharagpur 721302, India.
E-mail: jkray@chem.iitkgp.ernet.in
b
Isolated yields aer purication by column chromatography. NR: no
other reaction and complete recovery of the starting material. Dec:
decomposition of the starting material.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra45117h
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Table 2 Synthesis of 3-alkylidene-phthalidesa
sodium dihydrogen phosphate buffer (1.0 equiv.) and hydrogen
peroxide (1 mol%) in aqueous acetonitrile solvent at 0 ꢀC for 1–2
h, o-alkenylbenzoic acids 2 were obtained almost quantitatively.
Our next study was focused on cyclizing model substrate 2-
(2-methoxycarbonyl-vinyl)-benzoic acid 2a into lactone 3a. A
preliminary experiment with 2a using 1.0 equiv. of mCPBA and
1.0 equiv. of p-TsOH in dichloromethane at room temperature
afforded (E)-alkylidine-phthalide 3a exclusively in 93% yield.
Comparing literature report,10 the E-stereochemistry of 3a was
established. The reaction proceeded smoothly, and no trace
amount of either isocoumarin or (Z)-alkylidine-phthalide was
obtained as byproduct. In the absence of mCPBA, 2a was
recovered (Table 1, entry 1), while decomposed reaction mixture
was obtained in the absence of p-TsOH (Table 1, entry 2).
With the optimal conditions in hand, we next probed the
generality and scope of the present cyclization reaction with a
series of other o-alkenylbenzoic acids 2 by varying substituent
on benzene ring and ester carbonyl group (Table 2).11 The
strategy not only offered excellent yields of the corresponding
(E)-alkylidine-phthalides, but also showed tolerance towards
sterically demanding tertiary butyl ester (Table 2, entry 3).
The intramolecular domino cyclization reaction was
presumably triggered by the generation of an epoxide (Scheme
2). Our assumption is based on the literature reports12 where
electron-decient alkene produced epoxides employing mCPBA.
Then intramolecular anti-attack of the carboxylic acid at the
epoxide, followed by acid catalyzed dehydration leads to
the alkylidine-phthalide. Absence of the Z-product rules out the
possibility of E1-mechanism for the dehydration stage. Here
elimination of water molecule cannot follow the normal car-
bocationic pathway, because the electron withdrawing ester
group opposes formation of carbocation. This phenomenon
resembles acid-catalyzed dehydration of some primary alcohols
which does not follow E1-pathway, instead involves E2-elimi-
nation as the primary carbocation is highly unfavorable.13
Similarly, in this case acid-catalyzed E2-elimination of H2O
proceeds. Stereospecicity of the reaction in favor of the
E-isomer supports E2-mechanism. Even if the initial epoxida-
tion step may be sluggish, subsequent rapid intramolecular
attack and dehydration, both of which are entropically favored,
accounts for the overall fast reaction rate thereby decreasing
reaction time. Also thermodynamic stability of the conjugated
alkylidine-phthalides adds to the driving force.
Time Yield
Alkylidine-phthalide 3 (h) (%)
Entry Acid 2
1
5
93
2
3
5.5 90
6
5
85
89
4
5
6
6
85
90
6
a
Reaction condition: substrate (1.0 mmol), mCPBA (1.0 mmol), p-TsOH
(1.0 mmol), DCM (5 mL), room temperature, 5–6 h.
Scheme 2 Plausible mechanism of (E)-3-alkylidine phthalide synthesis.
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Table 3 Synthesis of lactones
Table 3 (Contd. )
Time (h) Yielda (%)
Entry Formyl-alkene 4
Lactone 5
Time (h) Yielda (%)
Entry Formyl-alkene 4
Lactone 5
1
2
99
95
9
2
95
92
90
2
3
2.5
10
2.5
11
3
3
92
a
Reaction conditions: substrate 4 (1.0 mmol), NaClO2 (1.4 mmol),
NaH2PO4 (1.0 mmol), H2O2 (1 mol%), CH3CN (2 mL), H2O (1 mL).
Reaction time: 2–3 h. Reaction temp.: RT.
4
5
2
2
98
95
We did not screen alkaline hydrogen peroxide, which is the
general reagent for epoxidation of electron decient-alkene, to
avoid additional step to carry out dehydration of the interme-
diate separately to afford our desired alkylidine-phthalide.
Current methodology being one-pot and effective was obviously
our primary choice.
To further explore the substrate scope, we then considered
replacement of the benzene ring of substrates 2 by dihy-
dronapthalene ring and in order to prepare the correspond-
ing acids when we carried out Pinnick oxidation of 3-(2-
formyl-3,4-dihydro-naphthalen-1-yl)-acrylic acid esters8 4.1
and 3-(2-formyl-3,4-dihydro-naphthalen-1-yl)-acrylonitriles8b
4.2, to our surprise, lactones 5 were obtained almost quan-
titatively (Table 3).14 Here also the lactonization reaction
followed domino process. The intermediate acids underwent
intramolecular Michael addition reaction in the reaction
medium (Scheme 3). Somewhat similar observations were
published by Li et al. recently, where o-alkynylbenzaldehydes
afforded phthalides via an intramolecular 5-exo-dig cycliza-
tion under NaClO2 oxidation conditions.15
6
7
8
2
94
92
90
2.5
3
In conclusion, we have accomplished novel one-pot domino
synthetic routes for the construction of phthalides and E-alkyli-
dine-phthalides via intramolecular lactonization protocol without
using any metal catalyst or ligand. While o-alkenylbenzoic acids
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Scheme 3 Mechanism of lactone synthesis.
provided (E)-3-alkylidine-phthalide derivatives under domino
epoxidation–heteroannulation–dehydration strategy, formyl-
dihydronapthyl substrate offered phthalides simply under
NaClO2 oxidation condition. Since the reagent system in either
case is cheap and easy to handle, these one-pot methodologies
should nd practical usage in the synthesis of phthalides, an
important class of molecules.
6 D. H. T. Phan, B. Kim and V. M. Dong, J. Am. Chem. Soc.,
2009, 131, 15608.
7 (a) R. Jana, S. Samanta and J. K. Ray, Tetrahedron Lett., 2008,
49, 851; (b) S. Samanta, H. Mohapatro, R. Jana and J. K. Ray,
Tetrahedron Lett., 2008, 49, 7153; (c) N. Yasmin and J. K. Ray,
Synlett, 2009, 2825.
8 (a) S. Samanta, R. Jana and J. K. Ray, Tetrahedron Lett., 2009,
50, 6751; (b) N. Yasmin and J. K. Ray, Synlett, 2010, 924.
9 B. S. Bal, W. E. Childers Jr and H. W. Pinnick, Tetrahedron,
1981, 37, 2091.
Acknowledgements
10 M. M. Kayser, K. L. Hatt and D. L. Hooper, Can. J. Chem.,
1992, 70, 1985.
We thank DST, New Delhi for nancial support. N.Y. thanks
CSIR for the fellowship.
11 General Procedure for the synthesis of 3-alkylidine
phthalides (3a–f): to a solution of o-alkenylbenzoic acid
(1 mmol) in dry DCM (5 mL), mCPBA (1 mmol) and
p-TsOH (1 mmol) was added and the mixture was stirred at
rt for 5–6 h. Then the reaction mixture was quenched with
saturated aq. NaHCO3 solution and extracted with DCM.
The organic solvent was washed with aq NaHCO3 and
brine solution, and then dried over Na2SO4. The solvent
was evaporated and then the product was puried by
column chromatography using ethyl acetate/petroleum
ether as eluent. Spectral data of representative compounds:
Notes and References
1 (a) G. Lin, S. S.-K. Chan, H.-S. Chung, S.-L. Li, Chemistry and
Biological Action of Naturally Occurring Phthalides, in Studies
in Natural Products Chemistry, ed. Atta-ur-Rahman, Elsevier,
Amsterdam, 2005, vol. 32, p. 611; (b) K. Yoganathan,
C. Rossant, S. Ng, Y. Huang, M. S. Butler and A. D. Buss, J.
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and C. B. Rogers, Phytochemistry, 2002, 61, 955; (d)
J. A. Palermo, M. V. R. Brasco, C. Spagnuolo and
A. M. Seldes, J. Org. Chem., 2000, 65, 4482; (e) C. Puder,
A. Zeeck and W. Beil, J. Antibiot., 2000, 53, 329; (f) G. Strobel,
E. Ford, J. Worapong, J. K. Harper, A. M. Arif, D. M. Grant,
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179; (g) D. Mal and P. Pahari, Chem. Rev., 2007, 107, 1892;
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Cluj-Napoca, 2009, 37, 129.
2 Y. I. Puzin, T. V. Chebaeva, E. I. Galinurova, R. R Muslukhov,
Y. B. Monakov and A. M. Syrkin, Russ. J. Org. Chem., 2004, 40,
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3 A. Bistrzycki and G. J. Oehlert, Ber. Dtsch. Chem. Ges., 1894,
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(6-Methyl-3-oxo-3H-isobenzofuran-1-ylidene)-acetic
acid
ꢀ
methyl ester (3d): white solid. M. P. 122–124 C. FTIR (KBr,
cmꢁ1): 2960, 2362, 1805, 1719, 1650, 1478, 1437, 1210,
1
1149, 1030, 972, 851, 773, 691. H NMR (CDCl3, 200 MHz):
d ¼ 2.54 (s, 3H), 3.80 (s, 3H), 6.08 (s, 1H), 7.47 (d, J ¼ 7.8
Hz, 1H), 7.80 (d, J ¼ 7.8 Hz, 1H), 8.81 (s, 1H). 13C NMR
(CDCl3, 50 MHz): d ¼ 22.41, 51.90, 101.56, 124.05, 125.17,
128.35, 133.63, 136.44, 146.81, 158.23, 165.63, 166.11.
HRMS calcd for C12H11O4 (MH+) m/z ¼ 219.0657, found m/
z ¼ 219.0661. Elemental anal. calcd for C12H10O4: C, 66.05;
H, 4.62. Found C, 66.13; H, 4.87%.
12 (a) V. R. Valente and J. L. Wolagen, J. Org. Chem., 1966, 31,
2509; (b) S. N. Ege, A. D. Adams, E. J. Gess, K. S. Ragone,
B. J. Kober, M. B. Lampert, P. Umrigar, D. C. Lankin and
G. W. Griffin, J. Chem. Soc., Perkin Trans. 1, 1983, 325; (c)
A. W. Murray and R. G. Reid, Synthesis, 1985, 35.
13 X. Xu, C. P. D. Almeida and M. J. Antal Jr, Ind. Eng. Chem.
Res., 1991, 30, 1478.
14 General procedure for the synthesis of lactones (5): to a
solution of 3-(2-formyl-cycloalkenyl)-acrylic esters 4.1 or
3-(2-formyl cycloalkenyl)-acrylonitriles 4.2 (1 mmol) in
acetonitrile at 0 ꢀC, NaH2PO4 (1 mmol) dissolved in 1 mL
5 C. E. Castro, E. J. Gaughan and D. C. Owsley, J. Org. Chem.,
1966, 31, 4071.
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water was added. To it H2O2 (1 mol%) was added. Then
NaClO2 (1.4 mmol) dissolved in minimum amount of
water, was added drop wise and stirred for 1–2 h. Upon
completion of the reaction the mixture was diluted with
EtOAc, washed with saturated aq. NaHCO3 and then brine,
dried over Na2SO4 and then evaporated to give pure
lactone. Spectral data of representative lactone: (3-oxo-
1368, 1318, 1167, 1063, 1011, 766, 613. 1H NMR (CDCl3,
200 MHz): d ¼ 2.25–2.66 (m, 3H), 2.86–3.05 (m, 3H), 3.65
(s, 3H), 5.67–5.73 (m, 1H), 7.07–7.31 (m, 4H). 13C NMR
(CDCl3, 50 MHz): d ¼ 18.16, 27.85, 38.71, 52.23, 76.37,
123.90, 125.96, 127.15, 127.32, 128.92, 131.05, 137.81, 157.73,
169.79, 171.89. HRMS calcd for C15H15O4 (MH+) m/z ¼
259.0970, found m/z ¼ 259.0967. Elemental anal. calcd for
C15H14O4: C, 69.76; H, 5.46. Found C, 69.62; H, 5.33%.
1,3,4,5-tetrahydronaphtho[1,2-c]furan-1-yl)-acetic
acid
methyl ester (5a): colourless crystalline solid. M. P. 130– 15 J. Li, E. Chin, A. S. Lui and L. Chen, Tetrahedron Lett., 2010,
132ꢀC. FTIR (KBr, cmꢁ1): 2942, 1749, 1733, 1650, 1439,
51, 5937.
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