Active methylene compounds in a very effective approach to 3-substituted isobenzofuranones through tandem aldol/lactonization reactions

Article abstract of DOI:10.1016/j.tet.2012.05.079

In this article we describe a new accessible methodology for the synthesis of isobenzofuran-1(3H)-ones. In this process we exploited an effective, economic, useful and environmentally benign K₂CO₃ catalyzed, solvent-free one-pot tandem aldol-lactonization reaction between active methylene compounds and methyl 2-carboxy benzaldehyde. A particularly simple work-up and purification procedure are additional advantages addressed to a general green chemistry approach to this important class of heterocyclic compounds.

Full text of DOI:10.1016/j.tet.2012.05.079

Tetrahedron 68 (2012) 6146e6151
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Active methylene compounds in a very effective approach to 3-substituted
isobenzofuranones through tandem aldol/lactonization reactions
,
c
a
b
b
Antonia Di Mola b , Gianluca Croce , Vijaykumar More , Paolo De Caprariis , Rosanna Filosa ,
*
,
Antonio Massa a
*
a
ꢀ
Dipartimento di Chimica e Biologia, Universita di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
b Dipartimento di Scienze Farmaceutiche e Biomediche, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy
c DISIT-Universita’ del Piemonte Orientale, Viale T. Michel 11, 15121 Alessandria, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 March 2012
Received in revised form 27 April 2012
Accepted 21 May 2012
Available online 27 May 2012
In this article we describe a new accessible methodology for the synthesis of isobenzofuran-1(3H)-ones. In
this process we exploited an effective, economic, useful and environmentally benign K2CO3 catalyzed,
solvent-free one-pot tandem aldol-lactonization reaction between active methylene compounds and methyl
2-carboxy benzaldehyde. A particularly simple work-up and purification procedure are additional advan-
tages addressed to a general green chemistry approach to this important class of heterocyclic compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Phthalides
Tandem reactions
Aldol addition
Active methylene compounds
1. Introduction
substituted phenylphthalides. Transition metal complexes yield 3-
aryl and 3-alkenyl phthalides through catalyzed ketone hydro-
Phthalides [isobenzofuran-1(3H)-ones] are integral parts of many
naturally occurring substances and they have a wide range of medi-
cinal properties.1 In particular, 3-substituted phthalides are vital
heterocyclic motifs in many bioactive compounds, such as iso-
coumarins, anthraquinones, anthracyclines and several alkaloids.2a
Typical examples are typhaphthalide,2b catalpalactone,2c vermista-
tin,2d isopestacin2e isoochracin and herbaric acid.2f They possess
a wide range of biological activities, which include antibacterial, an-
ticonvulsant and anti-HIV.3a,b Phthalides also serve as valuable syn-
thetic intermediates into the synthesis of several alkaloids4a (e.g., the
convulsant alkaloid biculline),4b and isoindolinones.4c In view of their
importance, various methods have been developed for the synthesis
of phthalides [isobenzofuran-1(3H)-ones]. These methods include
cyclization reactions catalyzed by strong acids, such as trifluoroacetic
acid5a and trifluoromethanesulfonic acid5b or strong bases, such as
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),5c,d sodium hydroxide and
potassium hydroxide.5e-g Nucleophilic addition of alkyl or aryl or-
ganometallic compounds on appropriately substituted phthalalde-
hydic acids and its derivatives,6a photochemical rearrangements,6b
intramolecular cyclization,6c Tischenko reaction6d and condensation
acylation and cascade addition/intramolecular cyclization processes.8
Chiral rhodium catalysts provided an asymmetric version of this
reaction,8e while one organo-catalytic approach has been described.9
Conversely, due to the biological importance of chiral 3-substituted
phthalides, chiral auxiliaries and resolutions of racemates have
been intensively explored to develop asymmetric synthesis.10
Nevertheless relatively few methods focus on the synthesis of
isobenzofuran-1(3H)-ones, substituted in the 3-position with 1,3-
dicarbonyl groups. Although these derivatives are particularly
useful in the synthesis of important bioactive compounds, such as
isopestacin or herbaric acid,5d all these methods involve high
temperature,7b,c the use of transition metals or harmful acids or
bases, and show rather limited scope and selectivity.
Given the ever increasing necessity of new environmentally
friendly methodologies for the synthesis of valuable compounds,
herein we report a direct and efficient one-pot tandem aldol-
lactonization reaction for the preparation of 3-substituted iso-
benzofuran-1(3H)-ones, reacting malonates, diketones, b-ketoesters
and nitroalkanes as model nucleophiles under solvent free conditions
and in the presence of catalytic amount of the inexpensive K2CO3.
7a
reactions catalysed by ZrOCl2 are also used in the synthesis of 3-
2. Results and discussion
The aldol addition of readilyenolizable 1,3-dicarbonyl compounds
to aldehydes is very difficult to achieve, and very few applications are
* Corresponding authors. Tel.: þ39 089 969565; fax: þ39 089 969603; e-mail
address: amassa@unisa.it (A. Massa).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.079

A. Di Mola et al. / Tetrahedron 68 (2012) 6146e6151
6147
available for these reactions: we recently demonstrated that the
success of this challenging aldol addition is mainly related to the in
situ trapping of the unstable aldol adducts by chlorosilane re-
agents11,12 or by intramolecular trapping at the cyano group of 2-
cyanobenzaldehyde.13 In analogy to the reactivity of 2-
cyanobenzaldehyde, that efficiently led to a series of 3-substituted
isoindolinones,13 we explored the reaction of methyl 2-carboxy
benzaldehyde with several active methylene compounds in the
synthesis of 3-substituted isobenzofuran-1(3H)-ones (Scheme 1).
we finally obtained 3a in almost quantitative yield at rt also in the
presence of catalytic amount of base (Table 1, entries 1 and 2);
however only traces of the final product were detected in acetone
(Table 1, entry 6) and THF (Table 1, entry 7), while in 1,4-dioxane,
dichloromethane and 1,2-dimethoxyethane the starting materials
were recovered unreacted, even in the presence of 2 equiv of K2CO3
in a slurry mixture (Table 1, entries 3e5). Conversely a sufficient
reactivity was also observed in DCM using a combination of K2CO3
and Et3N probably due to the formation of a phase transfer system
(Table 1, entry 8). Starting from these preliminary experiments we
also explored the possibility to perform the reaction without the
use of any solvent. Under these new conditions we were pleased to
observe that in the presence of catalytic amount of K2CO3 at rt, 3a
was obtained in quantitative yield (Table 1, entry 9). Furthermore
the observed high selectivity and the absence of byproducts gave us
the possibility to obtain the final product without additional work-
up, after only a quick filtration on a short pad of silica gel. This
particular combination of conditions is an important goal for the
atom economy philosophy and for a green approach to these iso-
benzofuranones, since the current methodologies require harsh
conditions and more harmful reagents.5e7
Interestingly, 0.3 equiv of Et3N were also effective, giving the
final product in 96% yield in 18 h, a result that can be particularly
useful for future developments of asymmetric versions.
Conversely, under these new conditions, control experiments,
without the use of any base, were unsuccessful and we recovered
the starting materials unreacted.
Considering the convenience to perform reactions under K2CO3
catalyzed, solvent-free conditions, we analyzed the scope of this
protocol in the presence of different classes of active methylene
compounds. Thus we were pleased to observe that this method-
ology is very general and gave the opportunity to synthesize an
unprecedented variety of 3-substituted isobenzofuran-1(3H)-ones
in quantitative yields and in reasonable reaction times with all the
tested nucleophiles (Table 2).
lactonization
aldol
base
O
O
O
O
H
O
O
O
base
EWG'
EWG
H
O
+
EWG-CHR-EWG'
R
EWG'
1
EWG
2
4
R
3
R=H, CH3
Scheme 1. Synthesis of substituted isobenzofuran-1(3H)-ones from methyl 2-carboxy
benzaldehyde and active methylene compounds.
In order to evaluate the effectiveness of our hypothesis, the re-
action of methyl 2-carboxy benzaldehyde and di-tert-butyl malo-
nate was performed under different conditions. First of all the
mixture of these reagents was stirred for 24 h in the absence of base
in DCM and no conversion was detected. Then we performed an
experiment under similar conditions that led to 3-substituted iso-
indolinones, in the presence of Et3N in DCM,13 but unfortunately we
recovered unreacted starting materials. However, since we believe
that the lactonization is the limiting step of the tandem process, we
thought that bases, such as K2CO3 could be more effective for both
aldol and cyclization reactions. Thus, as shown in Table 1, in DMF,
Table 1
Reaction of methyl 2-carboxy benzaldehyde with di-tert-butyl malonate in the
presence of 2 and 0.3 equiv of potassium carbonate in different solventsa
Entry
Solvent
Amount of K2CO3
Time (h)
Yieldb (%)
In particular from the data reported in the Table 2, it is possible
to note that whatever is the nature and the hindrance of the ester
groups of malonates and b-ketoesters, this does not affect the re-
activity of the tandem process (Table 2, entries 3e10).
The method was particularly simple and effective also on
2 mmol scale (Table 2, entry 2), opening the opportunity of further
1
2
3
4
5
6
7
8c
9
DMF
DMF
CH2Cl2
1,4-Dioxane
1,2-Dimetoxy ethane
Acetone
THF
CH2Cl2
Solvent free
2 equiv
0.3 equiv
2 equiv
2 equiv
24
24
24
24
24
24
24
24
5 h
93%
94%
0%
0%
0%
Traces
Traces
50%
99%
2
equiv
2 equiv
2 equiv
2 equiv
0.3 equiv
scale-up. Also nitro-compounds (Table 2, entries 11 and 12) and b-
diketones (Table 2, entries 13 and 14) were particularly effective,
giving 3 in quantitative yields, although 1,3-cyclohexanedione re-
quired a longer reaction time (Table 2, entry 14).
Very interestingly, products with contiguous tertiary and qua-
ternary stereocenters (Table 2, entries 5, 9 and 10) were obtained in
a
Reaction conditions: methyl 2-carboxy benzaldehyde (0.31 mmol), di-tert-butyl
malonate (0.34 mmol), K2CO3 rt, 1 mL solvent.
b
Yields refer to chromatographically pure compounds.
An additional 1 equiv of Pr2NEt was used.
c
i
Table 2
Synthesis of substituted isobenzofuran-1(3H)-ones by reacting methyl 2-carboxy benzaldehyde with active methylene compoundsa
Entry
2
3 Product
Time
5 h
Yieldb (%)
O
O
1
2a
CH2(CO2-tBu)2
3a
99
O
O
OtBu
OtBu
O
O
2c
2b
CH2(CO2Me)2
3b
12 h
99
O
(continued on next page)
O
OMe
OMe

6148
A. Di Mola et al. / Tetrahedron 68 (2012) 6146e6151
Table 2 (continued )
Entry
2
3 Product
Time
8 h
Yieldb (%)
O
O
3
4
5
6
7
2c
CH2(CO2Et)2
3c
98
O
O
OEt
OEt
O
O
2d
2e
2f
CH2(CO2Bn)2
3d
12 h
18 h
12 h
7 h
99
O
O
OBn
OBn
O
O
CH3CH(CO2Me)2
Methyl acetoacetate
Ethyl acetoacetate
tert-Butyl acetoacetate
3e
98
O
O
OMe
OMe
O
O
3f
99 (dr 1.5/1)d
O
O
OMe
O
O
2g
3g
99 (dr 1.3/1)d
O
O
OEt
O
O
8
9
2h
3h
4 h
98 (dr 1.5/1)d
O
O
OtBu
O
O
2i
2-Methyl ethyl acetoacetate
3i
3j
5 h
98 (dr 2/1)d
O
O
OEt
O
O
10
2j
Ethyl 2-oxocyclopentane carboxylate
15 h
98 (dr 2/1)d,e
O
O
OEt
O
O
11
2k
Nitroethane
3k
2 h
99 (dr 1.3/1)d
NO2

A. Di Mola et al. / Tetrahedron 68 (2012) 6146e6151
6149
Table 2 (continued )
Entry
2
3 Product
Time
8 h
Yieldb (%)
O
O
12
2l
Nitropropane
3l
99 (dr 1/1)d
NO2
O
O
13
2m
Acetylacetone
3m
12 h
96
98
O
O
O
O
14
2n
1,3-Cyclohexanedionef
3n
48 h
OH
O
a
Reaction conditions: 1 (0.31 mmol), 2 (0.34 mmol), K2CO3 (30% mol), rt, solvent free.
Yields refer to chromatographically pure compounds.
b
c
d
e
f
Reaction performed on 2 mmol scale.
Diastereomeric ratios were calculated on the basis of 1H NMR spectrum of the crude product.
The configuration of the major diastereomer is RS,RS.
Reaction performed by adding a few drops of CH3CN.
high yields by reacting 1 with a series of 2-substituted 1,3-
On the basis of the obtained results we can confidently propose
a catalytic tandem mechanism as described in Scheme 1, in which,
after the reversible deprotonation of 2 and its subsequent nucleo-
philic addition to the aldehyde 1, the unstable aldol intermediate 4
is entrapped by a regioselective intramolecular lactonization to give
the title isobenzofuran-1(3H)-one. The possibility of using catalytic
amounts of base is likely due to an autocatalysis pathway given that
methoxide is generated during the lactonization step.
In conclusion a new method of isobenzofuran-1(3H)-ones syn-
thesis has been developed. In this process we exploited an effective,
economic, useful and environmentally benign K2CO3 catalyzed,
solvent-free one-pot tandem aldol addition/lactonization reactions
of active methylene compounds with methyl 2-carboxy benzalde-
hyde. Furthermore a particularly simple work-up and purification
procedure are additional advantages addressed to a general green
chemistry approach to this important class of heterocyclic
compounds.
dicarbonyl compounds. This is a further important goal that all
the current methods for isobenzofuran-1(3H)-ones synthesis do
not allow.5e7 Usually low levels of diastereoselectivity were ob-
served, although the diastereomers of 3j and 3l were easily sepa-
rated by chromatography. 3j was subsequently crystallized, with
a hexane/ethyl acetate mixture, by slow evaporation in order to
obtain suitable single crystals for X-ray diffraction measurement.
This gave the possibility to further characterise the major di-
astereomer of 3j confirming its structure with a relative configu-
ration 3RS, 1RS (Fig. 1). It is worthy to note that the configuration of
the already reported diastereomeric mixtures (3g, 3k and 3l) has
never been described. For this reason we would be tempted to
extend this assignation to the other mixtures for analogy. However,
considering the possibility of interconversion of those compounds
with the relatively acidic methine proton, the characterization of
molecules like 3j with contiguous tertiary and quaternary stereo-
centers is more relevant.
3. Experimental section
3.1. General remarks
Column chromatographic purification of products was carried
out using silica gel 60 (70e230 mesh, Merck). The reagents
(Aldrich and Across) were used without further purification. The
NMR spectra were recorded on Bruker DRX 400, 300, 250 spec-
trometers (400 MHz, 300 MHz, 250 MHz, 1H; 100 MHz, 75 MHz,
62.5 MHz, 13C). Spectra were referenced to residual CHCl3
(7.26 ppm, 1H, 77.23 ppm, 13C). Coupling constants J are reported
in hertz. FT-IR spectra were recorded as thin films on KBr plates
using Bruker Vertex 70 spectrometer and absorption maxima are
reported in wavenumber (cmꢀ1). Yields are given for isolated
products showing one spot on a TLC plate and no impurities de-
tectable in the NMR spectrum. Mass spectral analyses were car-
ried out using an electrospray spectrometer, Waters 4 micro
Fig. 1. Drawing of the asymmetric unit of 3j compound with atomic displacement
ellipsoids drawn at the 30% probability level.

6150
A. Di Mola et al. / Tetrahedron 68 (2012) 6146e6151
quadrupole. Elemental analyses were performed with FLASHEA
1112 series-Thermo Scientific for CHNSeO apparatus. Single
crystal diffraction data were collected on a Oxford Xcalibur CCD
3.2.5. Dimethyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-
methylmalonate 3e. Filtration with hexane/ethyl acetate 7/3. Pale
yellow oil (82 mg). Yield: 98%. IR (neat): 1761, 1747, 1026,
786 cmꢀ1.1H NMR (400 MHz, CDCl3): 7.86 (d, J¼7.4 Hz, 1H, Ar),
7.63e7.51 (m, 3H, Ar), 6.19 (s, 1H, CH), 3.80 (s, 3H, CO2CH3), 3.76 (s,
3H, CO2CH3), 1.13 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): 170.8,
170.7, 170.0, 147.1, 135.5, 131.0, 128.1, 126.9, 125.1, 82.7, 58.6, 54.5,
54.3, 15.6. ESI-MS: m/z¼279 (Mþ1). Anal. Calcd for C14H14O6: C,
60.43; H, 5.07. Found: C, 60.56; H, 5.30.
area detector diffractometer, using graphite monochromatic Mo
ꢁ
Ka
(
l
¼0.71069A) radiation. Data reduction and absorption cor-
rection were performed using CrysAlisPRO 171.34.44 (Oxford
Diffraction). The structure was solved by direct methods using
SIR200814 and refined by full-matrix least squares using SHELX-
97.15 Hydrogen atoms were generated in calculated position using
SHELX-97. 3j crystallized in the centrosymmetric [P21/c] space
group and the crystal packing is driven at first by
p
e
p
contribu-
3.2.6. Methyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-
oxobutanoate 3f (mixture of diastereoisomers). Filtration with hex-
ane/ethyl acetate 7/3. White solid (75 mg). Yield: 99%. 1H NMR
(300 MHz, CDCl3): 7.87 (d, J¼7.4 Hz, 1Hþ1H, Ar), 7.67e7.61 (m,
2Hþ1H, Ar), 7.57e7.42 (m, 1Hþ3H, Ar), 6.07 (d, J¼8.4 Hz, 1Hþ1H),
3.89 (d, J¼8.1 Hz, 1H, CHCH), 3.87 (d, J¼8.3 Hz, 1H, CHCH), 3.78 (s,
CO2CH3, 3H, minor), 3.72 (s, CO2CH3, 3H, major), 2.37 (s, COCH3, 3H,
major), 2.27 (s, COCH3, 3H, minor). 13C NMR (75 MHz, CDCl3):
199.67,199.04,169.33,169.23,166.30,166.03,146.99,146.78,134.35,
129.82, 126.0, 125.87, 125.77, 123.24, 77.95, 63.47, 62.64, 53.05,
52.81, 30.55, 30.33. ESI-MS: m/z¼249 (Mþ1). Anal. Calcd for
C13H12O5: C, 62.90; H, 4.88. Found: C, 62.75; H, 4.79.
tion and the fine tuning of molecular unit docking is defined by
short contacts (less than the sum of van der Waals radii) between
the molecular units.
3.2. General procedure for the synthesis of
isobenzofuranones
To a solution of aldehyde (50 mg, 0.31 mmol, 1 equiv) and po-
tassium carbonate (12.6 mg, 0.093 mmol, 0.3 equiv) methylene
active compounds (0.34 mmol,1.1 equiv) were added dropwise. The
mixture was stirred until starting material disappeared. Purifica-
tion consists of a filtration on a short pad of silica gel with hexane/
ethyl acetate mixtures to give the products 3.
Compounds 3b, 3g, 3ken are known and have been character-
ized by comparing their spectroscopic data with those reported in
Ref. 5d and 5i.
3.2.7. Ethyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-
oxobutanoate 3g. Filtration with hexane/ethyl acetate 7/3. White
solid (75 mg). Yield: 99%. Spectroscopic data are in agreement with
those reported in literature.5d ESI-MS: m/z¼263 (Mþ1). Anal. Calcd
for C14H12O4: C, 64.12; H, 5.38. Found: C, 64.34; H, 5.23.
3.2.1. Di-tert-butyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-malo-
nate 3a. Filtration with hexane/ethyl acetate 8/2. Pale yellow oil
(105 mg). Yield: 99%. IR (neat): 1762, 1747, 1056, 745 cmꢀ1.1H NMR
(300 MHz, CDCl3): 7.89 (d, J¼7.5 Hz, 1H, Ar), 7.65e7.53 (m, 3H, Ar),
5.96 (d, J¼6.1 Hz, 1H, CHCH), 3.73 (d, J¼6.1 Hz, 1H, CHCH), 1.43 (s,
9H, C(CH3)3), 1.32 (s, 9H, C(CH3)3). 13C NMR (75 MHz, CDCl3): 169.6,
165.1, 164.9, 147.1, 133.9, 129.5, 126.6, 125.4, 123.4, 82.9, 82.8, 77.9,
57.5, 21.7, 21.6. ESI-MS: m/z¼349 (Mþ1). Anal. Calcd for C19H24O6:
C, 65.50; H, 6.94. Found: C, 65.36; H, 6.70.
3.2.8. tert-Butyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-3-
oxobutanoate 3h (mixture of diastereoisomers). Filtration with
hexane/ethyl acetate 7/3. White solid (72 mg). Yield: 98%. 1H NMR
(300 MHz, CDCl3): 7.86 (d, J¼7.2 Hz, Ar), 7.63e7.26 (m, Ar), 6.22 (s,
1H, enol), 6.03 (d, J¼7.2 Hz, 1Hþ1H), 3.90 (d, J¼7.2 Hz, 1H, minor),
3.77 (d, J¼7.2 Hz, 1H, major), 2.34 (s, 3H, COCH3, minor), 2.28 (s, 3H,
COCH3, major), 2.23 (s, 3H, COCH3, enol), 1.37 (s, 9H, C(CH3)3, ma-
jor), 1.29 (s, 9H, C(CH3)3, minor), 1.03 (s, 9H, C(CH3)3, enol). 13C NMR
(75 MHz, CDCl3): 201.51, 201.40, 170.87, 170.83, 166.29, 166.0,
148.62, 148.53, 135.49, 134.97, 130.96, 130.92, 129.80, 127.57, 126.95,
126.82, 126.49, 125.03, 124.29, 122.48, 84.79, 84.73, 79.35, 79.31,
65.82, 64.68, 31.57, 31.20, 28.93, 28.87, 20.57. ESI-MS: m/z¼291
(Mþ1). Anal. Calcd for C16H18O5: C, 66.19; H, 6.25. Found: C, 66.34;
H, 6.10.
3.2.2. Dimethyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-malonate
3b. Filtration with hexane/ethyl acetate 7/3. Pale yellow oil
(79 mg). Yield: 99%. Spectroscopic data are in agreement with those
reported in literature.5h ESI-MS: m/z¼265 (Mþ1). Anal. Calcd for
C13H12O6: C, 59.09; H, 4.58. Found: C, 59.24; H, 4.40.
3.2.3. Diethyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-malonate
3c. Filtration with hexane/ethyl acetate 7/3. Pale yellow oil (88 mg).
Yield: 98%. IR (neat): 1768, 1741, 1045, 765, 734 cmꢀ1.1H NMR
(400 MHz, CDCl3): 7.86 (d, J¼7.5 Hz, 1H, Ar), 7.66e7.51 (m, 3H, Ar),
6.02 (d, J¼6.8 Hz, 1H, CHCH), 4.21 (q, J¼7.05 Hz, 2H, CO2CH2CH3),
4.13 (q, J¼7.1 Hz, 2H, CO2CH2CH3), 3.83 (d, J¼6.8 Hz, 1H, CHCH), 1.22
3.2.9. Ethyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-methyl-3-
oxobutanoate 3i (mixture of diastereoisomers). Filtration with hex-
ane/ethyl acetate 7/3. Pale yellow oil (82 mg). Yield: 98%. 1H NMR
(400 MHz, CDCl3): 7.87 (d, J¼7.6 Hz, Ar), 7.66e7.65 (m, Ar),
7.55e7.47 (m, Ar), 6.26 (s,1H, CH), 4.27 (q, J¼7.2 Hz, 2H, CO2CH2CH3,
minor), 4.18 (q, J¼7.2 Hz, 2H, CO2CH2CH3, major), 2.35 (s, 3H,
COCH3, major), 2.20 (s, 3H, COCH3, minor), 1.28 (t, J¼7.2 Hz,
CO2CH2CH3, minor), 1.18 (t, J¼7.2 Hz, CO2CH2CH3, major), 1.16 (, 3H,
CH3, major), 1.07 (s, 3H, CH3, minor), 13C NMR (100 MHz, CDCl3):
204.79, 203.19, 171.02, 170.81, 170.57, 169.78, 147.71, 147.50, 135.58,
135.51, 130.97, 130.92, 128.30, 127.87, 126.99, 126.92, 125.62, 125.13,
83.11, 82.79, 65.01, 64.50, 63.79, 63.42, 28.04, 27.69, 15.44, 15.20,
15.09, 14.95. ESI-MS: m/z¼277 (Mþ1). Anal. Calcd for C15H16O5: C,
65.21; H, 5.84. Found: C, 65.14; H, 5.80.
(t, J¼7.1 Hz, 3H, CO2CH2CH3), 1.15 (t, J¼7.1 Hz, 3H, CO2CH2CH3). 13
C
NMR (100 MHz, CDCl3): 170.6, 166.9 (ꢁ2), 147.9, 135.5, 131.1, 127.6,
126.9,124.4, 78.9, 63.4, 63.4, 57.1,15.1,15.0 ESI-MS: m/z¼293 (Mþ1).
Anal. Calcd for C15H16O6: C, 61.64; H, 5.52. Found: C, 61.46; H, 5.40.
3.2.4. Dibenzyl-2-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-malonate
3d. Filtration with hexane/ethyl acetate 7/3. Pale yellow oil
(127 mg). Yield: 99%. IR (neat): 1759, 1743, 1034, 743 cmꢀ1.1H NMR
(300 MHz, CDCl3): 7.81 (d, J¼6.8 Hz, 1H, Ar), 7.56e7.48 (m, 3H, Ar),
7.33e7.21 (m, 10H, Ar), 6.07 (d, J¼6.8 Hz, 1H, CHCH), 5.19 (d,
J¼12 Hz, 2H, CHHPh), 5.16 (d, J¼12 Hz, 2H, CHHPh), 5.11 (s, 2H,
CH2Ph), 3.96 (d, J¼6.8 Hz, 1H, CHCH). 13C NMR (75 MHz, CDCl3):
169.21, 165.4, 165.3, 146.29, 134.66, 134.48, 134.14, 129.75, 128.55,
128.43, 128.30, 126.17, 125.69, 122.98, 67.85, 67.80, 55.86. ESI-MS:
m/z¼417 (Mþ1). Anal. Calcd for C25H20O6: C, 72.11; H, 4.84.
Found: C, 72.25; H, 4.70.
3.2.10. Ethyl-1-(1,3-dihydro-1-oxoisobenzofuran-3-yl)-2-ox-
ocyclopentane carboxylate 3j (single diastereoisomer). Filtration
with hexane/ethyl acetate 75/25. (85 mg). Yield: 98%. White solid,
recrystallised from hexane/ethyl acetate 8/2 for slow evaporation.
IR (KBr): 1772, 1737, 1690, 1028, 756 cmꢀ1.1H NMR (400 MHz,
CDCl3): 7.90 (d, J¼7.6 Hz, 1H, Ar), 7.65 (t, J¼7.6 Hz, 1H, Ar), 7.57e7.52
(m, 2H, Ar), 6.25 (s, 1H, CH), 4.29 (q, J¼7.2 Hz, 2H, CO2CH2CH3),

A. Di Mola et al. / Tetrahedron 68 (2012) 6146e6151
6151
2.52e2.43 (m, 2H, CH2), 2.27e2.05 (m, 2H, CH2), 1.98e1.92 (m, 1H,
References and notes
CHH), 1.44e1.38 (m, 1H, CHH), 1.31 (t, J¼7.2 Hz, 2H, CO2CH2CH3). 13
C
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21.08, 15.29. ESI-MS: m/z¼289 (Mþ1). Anal. Calcd for C16H16O5: C,
66.66; H, 5.59. Found: C, 66.44; H, 5.60.
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3.2.11. 3-(1-Nitroethyl)isobenzofuran-1(3H)-one 3k. Filtration with
hexane/ethyl acetate 7/3. Pale yellow oil (63 mg). Yield: 99%.
Spectroscopic data are in agreement with those reported in liter-
ature.5i ESI-MS: m/z¼208 (Mþ1). Anal. Calcd for C10H9NO4: C,
57.97; H, 4.38. Found: C, 57.84; H, 4.50.
3.2.12. 3-(1-Nitropropyl)isobenzofuran-1(3H)-one 3l. Filtration with
hexane/ethyl acetate 8/2. White solid (66 mg). Yield: 99%. Spec-
troscopic data are in agreement with those reported in literature.5i
The main diastereomer was easily recrystallised according to ref 5i.
ESI-MS: m/z¼222 (Mþ1). Anal. Calcd for C11H11NO4: C, 59.73; H,
5.01. Found: C, 59.84; H, 4.90.
3.2.13. 3-(2,4-Dioxopentan-3-yl)isobenzofuran-1(3H)-one
3m. Filtration with hexane/ethyl acetate 8/2. Yield: 96%. Melting
point and spectroscopic data are in agreement with those reported
in literature.5d ESI-MS: m/z¼233 (Mþ1). Anal. Calcd for C13H12O4: C,
67.23; H, 5.21. Found: C, 67.12; H, 5.37.
3.2.14. 3-(2-Hydroxy-6-oxocyclohex-1-enyl)isobenzofuran-1(3H)-
one 3n. Filtrationwith ethyl acetate/MeOH 98/2. White solid (72 mg).
Yield: 98%. Melting point and spectroscopic data are in agreement
with those reported in literature.5d ESI-MS: m/z¼245 (Mþ1). Anal.
Calcd for C14H12O4: C, 68.85; H, 4.95. Found: C, 68.74; H, 4.70.
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Acknowledgements
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Financial support from the MIUR (FARB 2011) is gratefully
acknowledged.
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Supplementary data
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All the 1H NMR and 13C NMR spectra of the new compounds
have been provided as additional material. Crystallographic table of
compound 3j is provided as additional material. CCDC 869877
contains the supplementary crystallographic data for compound 3j.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif. Supplementary data related to this article can be found
online at doi:10.1016/j.tet.2012.05.079.
13. More, V.; Di Mola, A.; Perillo, M.; De Caprariis, P.; Filosa, R.; Peduto, A.; Massa, A.
Synthesis 2011, 3027e3031.
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