Regiospecific synthesis of 3-(2,6-dihydroxyphenyl)phthalides: application to the synthesis of isopestacin and cryphonectric acid

Article abstract of DOI:10.1016/j.tet.2007.08.048

DBU catalyzed condensation of phthalaldehydic acids and 1,3-diketones has been developed to be a general method for the synthesis of 3-substituted phthalides. This method, in combination with mercuric acetate mediated oxidative aromatization has been util

Full text of DOI:10.1016/j.tet.2007.08.048

Tetrahedron 63 (2007) 11781–11792
Regiospecific synthesis of 3-(2,6-dihydroxyphenyl)phthalides:
application to the synthesis of isopestacin and
cryphonectric acid
*
Dipakranjan Mal, Pallab Pahari and Saroj Ranjan De
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, West Bengal, India
Received 25 April 2007; revised 31 July 2007; accepted 16 August 2007
Available online 22 August 2007
Abstract—DBU catalyzed condensation of phthalaldehydic acids and 1,3-diketones has been developed to be a general method for the syn-
thesis of 3-substituted phthalides. This method, in combination with mercuric acetate mediated oxidative aromatization has been utilized for
the regiospecific synthesis of isopestacin (9) and cryphonectric acid (10).
Ó 2007 Published by Elsevier Ltd.
1. Introduction
unit. In addition, the resorcinolyl carboxylic acid moiety of
10 strongly resembles the aromatic subunit of balanol,
well-known PKC inhibitor.5 The potential biological activity
alongwith unusual structural features promptedusto develop
a synthesis of 9,6 which was published in a communication.
We now report a full account of the investigation as well as
its extension to the first synthesis of cryphonectric acid (10).
1(3H)-Isobenzofuranones (phthalides) are a prominent class
of natural products by virtue of their significantly varied bio-
logical properties.1 In particular, 3-substituted phthalide
moieties are embodied in numerous natural products. Typi-
cal examples are fuscinarin (1),2a typhaphthalide (2),2b cata-
lpalactone (3),2c alcyopterosin E (4),2d (+)-spirolaxine (5),2e
vermistatin (6),2f rubiginone-H (7),2g (ꢀ)-hydrastine (8),2h
isopestacin (9),2i and cryphonectric acid (10).2j They possess
a wide range of biological activities, which include antibac-
terial,3a anticonvulsant,3b and anti-HIV.2a Phthalides also
serve as valuable synthetic intermediates.4
O
OH
O
O
O
O
O
O
O
O
O
HO
O
ONO2
Me
OH
The newer members, isopestacin (9) and cryphonectric acid
(10), are distinguished in having a resorcinol moiety at-
tached at the C-3 position of phthalides (Fig. 1). Isopestacin
(9) was isolated in 2002 by Strobel et al.2i from culture
broths of the endophytic fungus Pestalopsis microspore. It
shows antifungal activity and acts as an antioxidant toward
both superoxide radical and hydroxyl free radicals, the activ-
ity being comparable to that of vitamin C. Cryphonectric
acid (10) was isolated by Arnone et al.2j from cultures of
a hypovirulent strain of Cryphonectrica parasitica. It has
been shown to inhibit the formation of tomato seedlings.
typhaphthalide (2)
fuscinarin (1)
catalpalactone (3) alcyopterosin E (4)
O
O
MeO
O
O
OMe
O
O
OH
OMe
OMe
O
O
O
HO
O
OH
O
(CH2)5
AcO
rubiginone H (7)
(+)-spirolaxine (5)
vermistatin (6)
OH
O
OH
O
OMe
O
Both the phthalides 9 and 10 have a resorcinol moiety at-
tached through C-2 to the C-3 of the isobenzofuranone
MeO
O
O
HO
O
OH
HO
O
Me
OH
HO
O
N
CO2H
Keywords: Isopestacin; Cryphonectric acid; Isobenzofuranone; Oxidative
aromatization.
* Corresponding author. Tel.: +91 3222 283318; fax: +91 3222 282252;
e-mail: dmal@chem.iitkgp.ernet.in
isopestacin (9) cryphonectric acid (10)
(-)-hydrastine (8)
Figure 1. Examples of 3-substituted isobenzofuranone natural products.
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.08.048

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D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
O
2. Synthetic strategy
O
O
O
O
Since the classical work by Bistrzycki et al.,7a many methods
have been reported for the synthesis of phthalides. These in-
clude preparation of phthalides by acid catalyzed condensa-
tion of phthalaldehydic acids with arenes,7b base catalyzed
reaction of appropriate nucleophiles with substituted phtha-
lides,7c oxidation of ortho-alkyl substituted benzoic acids,7d
electrophilic addition of aldehydes with ortho-metallated es-
ters, amides, or protected benzaldehydes,7e nucleophilic ad-
dition of alkyl or aryl metals on properly substituted
phthalaldehydic acids and its derivatives,7f metallic or mi-
crobial hydrogenation of 4-oxo carboxylic esters,7g,h,j photo-
chemical rearrangements,7i intramolecular cyclization,7j
Tischenko reaction, etc.7k
piperidine
O
OH
+
ethanol
reflux
65%
O
OH
11
13
12
Scheme 1.
Base catalyzed aldol reaction of 1,3-cyclohexanedione with
phthalaldehydic acid followed by aromatization of the con-
densation product was expected to furnish the resorcinol unit
present in the target molecules. The chemistry of lithiated
resorcinol derivatives was considered but not pursued in
view of the presence of a –COOH group in 10.10b
For the present target molecules 9 and 10, the development
of a newer method was warranted for ensuring regiospecifi-
city in the synthesis of their 3-(2,6-dihydroxyphenyl)phtha-
lide backbone. Acid catalyzed condensation of resorcinol
with phthalaldehydic acid is not suitable, as it produces
3-(2,4-dihydroxyphenyl)isobenzofuran-1-one arising from
substitution at undesired position.8 Similarly, formylation
or bromination of 3,5-dihydroxybenzoic acid leads to
formation of 2- and 6-substituted products.9 Mindful of
this problem, we envisaged an application of condensation
of phthalaldehydic acid 11 with dimedone 12 in the
presence of piperidine giving 1:1 condensation product 13
(Scheme 1).10a
3. Results and discussion
3.1. Reaction of phthalaldehydic acid with b-keto car-
bonyl compounds
First we studied the reported10 aldol reaction of phthalalde-
hydic acid (11) with dimedone (12) and noted that the same
reaction could be effected more efficiently in shorter time if
DBU was used as a base. It took place at room temperature in
excellent yield (95%). The product 13 was characterized by
comparison of its spectroscopic data with the reported values
as well as by conversion to its acetate derivative 14. The
Table 1. Reaction of phthalaldehydic acid (11) with few 1,3-dicarbonyl compounds in the presence of DBU
Entry
1,3-Diketone
Product(s)
Yield (%)
Derivative
O
O
O
O
O
O
OAc
OH
1
95
O
O
12
13
14
O
O
CO2Et
O
O
+
2
O
81
O
O
15
OH
O
O
O
17
O
18
16
O
O
O
O
EtO
O
O
+
3
55
O
O
EtO
EtO
19
OH
21
O
O
O
O
22
20
O
O
O
O
O
4
86
O
23
24

D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
11783
OR
HO
increased efficiency of the reaction with DBU led to the gen-
OR
O
O
O
OR
eralization of the process with some cyclic and open chain
1,3-diones. The results are summarized in Table 1. Unlike
cyclic 1,3-diketones, product of the open chain diones (en-
tries 2 and 3) existed as inseparable mixture of both keto
and enol forms. The yield of the reaction appeared to depend
upon the acidity of the methylene proton of 1,3-diketones.
For acetylacetone (15), the yield of the products 16 and 17
was 81% requiring lesser reaction time (10–12 h), whereas
for ethyl acetoacetate (19), the yield of the products 20
and 21 was 55% and the reaction required 20–24 h for com-
pletion. When we tried to prepare the ethoxy derivative of 16
by treatment with EtOH, p-toluenesulfonic acid (PTSA), and
benzene, a ring opened product 18 was formed, contrary to
the enol ether6 earlier reported by us. Attempted conversion
of 20 to its acetate derivative (pyridine, Ac2O, reflux) led to
decarboxylation to compound 22. Indane-1,3-dione (23)
gave product 24 at room temperature. Attempted preparation
of ethoxy derivative of 24 using EtOH, C6H6, and PTSA
failed to give any product.
O
O
O
25
ii
O
OH
OH
i
OH
32a; R = Me
32b; R = H
34; R = Me
33a; R = Me, 68%
33b; R = H, 74%
Scheme 3. Model synthetic study of 34. (i) CH3CN, DBU, reflux. (ii)
Hg(OAc)2, NaOAc, AcOH, reflux; 86%.
the corresponding phenol 29 by AlCl3 or BBr3 proved to
be a serious problem. Alternatively, we examined CuCl2/
LiCl12 system. Its reaction with the compound 26 in
DMF produced our desired phenol 29 in 45% yield along
with a nuclear chlorinated product 30. Remarkable im-
provement of the yield (up to 95%) of our desired phenol
29 was observed when compound 26 was heated at reflux
in acetic acid in the presence of Hg(OAc)2 and NaOAc.13
To prove the presence of two hydroxyl groups, we con-
verted 29 to its diacetate derivative 31. The structures of
all new products 26, 27, 28, 29, 30, and 31 were confirmed
3.2. Synthesis of model compounds 29 and 34
by analysis of their IR, H NMR, 13C NMR, MS spectra,
and CHN analysis data. The structure of compound 31
was re-confirmed by an X-ray crystallographic analysis
(Fig. 2).
1
Having worked out the condensation, we focused our atten-
tion to assemble the phthalides and resorcinol units of
isopestacin (9). Initially, we targeted the synthesis of
unsubstituted model compound 29 (Scheme 2) and
7-methoxy substituted model compound 34 (Scheme 3).
The reaction of phthalaldehydic acid (11) with cyclohex-
ane-1,3-dione (25) in the presence of DBU furnished the
expected product 26 in 70% yield. The compound 26 ex-
isted in the enol form and there was no trace of the keto
Next we targeted compound 34, which resembled pestacin
(9) with respect to the position of methoxy group.
Accordingly, 3-hydroxy-7-methoxy-1(3H)-isobenzofura-
none (32a)14 was condensed with 25 in the presence of
DBU to produce 33a (68%), which was then aromatized
with Hg(OAc)2/NaOAc to compound 34 (Scheme 3). Simi-
larly, 3,7-dihydroxy-1(3H)-isobenzofuranone (32b) pro-
duced condensation product 33b (74%) containing both
keto and enol forms, aromatization of which proved to be
difficult. The structures of 33a, 33b, and 34 were confirmed
1
form as evident from its H NMR spectrum. The ethoxy
derivative 27 was prepared by EtOH/PTSA (Scheme 2).
Next most important task was to aromatize the adduct
26. Although initial attempt with Pd/C mediated oxidative
aromatization in refluxing p-cymene or diphenylether
failed, we could aromatize the compound by the treatment
with I2 in refluxing MeOH11 and obtained the dimethoxy
compound 28. However, subsequent didemethylation to
by analysis of their IR, H NMR, 13C NMR spectrum, and
CHN analysis data. The presence of characteristic 2H dou-
blet at d 6.19 corresponded to resorcinol moiety of the
product (34).
1
O
O
O
O
O
O
iii
11
OMe
OR
i
MeO
O
26; R = H
27; R = Et
28
25
ii
v
iv
O
O
O
O
O
O
+
OR
OH
Cl
OH
RO
HO
HO
29; 45%
29; R = H
31; R = C(O)CH3
30; 10%
vi
Scheme 2. (i) DBU, CH3CN, reflux; 70%. (ii) EtOH, PTSA, C6H6, reflux;
73%. (iii) I2, MeOH, reflux; 77%. (iv) CuCl2, LiCl, DMF, reflux. (v)
Hg(OAc)2, NaOAc, AcOH, reflux; 95%. (vi) Ac2O, concd H2SO4 (cat.),
reflux; 75%.
Figure 2. X-ray crystal structure of compound 31.

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D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
3.3. Synthesis of isopestacin (9)
from commercially available gallic acid in two steps by
methylation followed by ester hydrolysis.17b Condensation
of 43 with phthalaldehydic acid (11) produced adduct 44
in 73% yield. Hg(OAc)2/NaOAc mediated aromatization
of 44 followed by conversion of the carboxylic acid group
to the corresponding ester by SOCl2/MeOH produced 46
(Scheme 5). The new compounds of the sequence were
duly characterized by spectroscopic means.
With the synthesis of the model compounds 29 and 34 stan-
dardized, we focused our attention to the synthesis of isopes-
tacin (9). The required phthalaldehydic acid 36 was prepared
from N,N-diethyl-2-methoxy-4-methylbenzamide (35) by
ortho-metallation (s-BuLi, tetramethylethylenediamine) fol-
lowed by formylation with dimethylformamide, which, in
turn, was prepared from 2,5-dimethylanisole by the three-
step reported procedure.15 Condensation of phthalaldehydic
acid 36 with 1,3-cyclohexanedione (25) gave desired prod-
uct 37 in moderate yield (60%), aromatization (Hg(OAc)2/
NaOAc) of which gave phenol 38 in 93% yield. Room tem-
perature demethylation of 38 with anhydrous AlCl3 in di-
chloromethane solvent provided isopestacin (9) in 65%
yield (Scheme 4). The spectroscopic data of the synthetic
material were identical with that of the reported values for
natural product. There was, however, some discrepancy in
melting point (mp: 269–270 ꢁC; lit.2g 218–220 ꢁC), al-
though the TLC behavior of the synthetic compound
matched well with that of an authentic natural sample pro-
vided by Professor G. Strobel. Briefly, we also examined
the preparation of enantiopure analogs using L-proline as
chiral base. However, the study was not encouraging as the
compound 26 prepared by this route did not show any optical
rotation.
O
O
O
O
O
O
11
OH ii
OH
O
HO
i
R
R
R
41; R = Me, 89%
45; R = CO2H, 93%
46; R = CO2Me, 77%
39; R = Me
43; R = CO2H
40; R = Me, 73%
44; R = CO2H, 73%
iii
iv
O
O
OMe
MeO
R
42; R = Me, 65%
OMe
OMe
O
CONEt2
Scheme 5. Model synthetic study of cryphonectric acid (10). (i) DBU,
CH3CN, reflux. (ii) Hg(OAc)2, NaOAc, AcOH, reflux. (iii) SOCl2,
MeOH, rt. (iv) I2, MeOH, reflux.
i
O
Me
Me
OH
36
25
35
3.5. Synthesis of cryphonectric acid (10)
ii
Application of the preceding strategy to the synthesis of cry-
phonectric acid (10) called for 5,7-dimethoxyphthalaldehy-
dic acid 53, the preparation of which is known in the
literature.18 However, due to inconvenience in the adaptation
of Diels–Alder process described by Freskos et al.18a or the
difficulty in reproducing the ortho-lithiation process de-
scribed by Trost et al.,18b we sought to develop a new
method. 4-Carbomethoxy-3-hydroxy-5-methyl-cyclohexe-
none (47)19 prepared by base catalyzed condensation of
methyl acetoacetate with methyl crotonate was aromatized
with I2/MeOH to give 48. Instead of commonly conceivable
O-methyl derivative, we prepared the acetate 49, since 2,4-
dimethoxy-6-methylbenzoate is known to produce nuclear
OR
HO
OMe
O
O
O
iii
O
Me
Me
OH
OH
O
38; R = Me
9; R = H (Isopestacin)
37
iv
Scheme 4. Synthesis of isopestacin (9). (i) (a) s-BuLi, TMEDA, DMF; 59%;
(b) AcOH/HCl, reflux; 64%. (ii) CH3CN, DBU, reflux; 60%. (iii) Hg(OAc)2,
NaOAc, AcOH, reflux; 93%. (iv) AlCl3, CH2Cl2, rt; 65%.
3.4. Model study for cryphonectric acid (10)
OAc
OR
OH
In extending the above strategy to the synthesis of crypho-
nectric acid (10) that has a nuclear carboxylic acid in the
resorcinol moiety, we considered oxidation of methyl group
of 41 or 42 for incorporation of a carboxylic acid (Scheme
5). To this end, we prepared compound 40 from commer-
cially available 5-methyl-1,3-cyclohexanedione (39) and
phthalaldehydic acid (11). Aromatization of 40 with
Hg(OAc)2/NaOAc and I2/MeOH produced 41 (89%) and
42 (65%), respectively (Scheme 5). Attempted oxidation
of the methyl group of 41 or 42 by various literature prece-
dents like ZnO/DMF,16a PCC,16b Ce(NH4)2(NO2)6,16c NBS/
O2,16d and KMnO4/pyridine16e did not work. Consequently,
we avoided the oxidation step and prepared carboxylic acid
43, albeit low yield, by the Birch reduction of 3,4,5-
trimethoxybenzoic acid.17a This, in turn, was synthesized
CO2Me
CHBr2
CO2Me
CO2Me
Me
iii
i
MeO
MeO
48; R = H
Me
ii
O
50
47
49; R = Ac
OH
O
OMe
OMe
O
CO2Me
CHO
v
iv
vi
O
O
MeO
MeO
MeO
OH
OH
51
52
53
Scheme 6. (i) I2, MeOH, reflux; 56%. (ii) CH3COCl, Et3N, CH2Cl2; 68%.
(iii) NBS (2 equiv), AIBN, CCl4, reflux. (iv) AcOH, HCl, reflux; overall
38% for two steps from 49. (v) K2CO3, MeI, acetone; 73%. (vi) aq NaOH
(10%), MeOH; 83%.

D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
11785
OMe
OMe
O
O
O
O
OMe
O
OR1
MeO
MeO
OH
43
ii
R1O
O
O
i
MeO
OH
CO2R2
CO2H
55; R1 = H, R2 = H
56; R1 = H, R2 = Me
57; R1 = Me, R2 = Me
53
54
iii
iv
Scheme 7. (i) DBU, CH3CN, reflux; 30%. (ii) Hg(OAc)2, NaOAc, AcOH, reflux; 60%. (iii) SOCl2, MeOH, rt; 73%. (iv) K2CO3, MeI, acetone; 77%.
brominated products on reaction with NBS.20 Benzylic bro-
mination of 49 with NBS (2 equiv) followed by hydrolysis of
the resultant dibromo compound in refluxing AcOH/HCl/
H2O produced 7-dihydroxy-4-methoxyphthalaldehydic
acid 51. Methylation of 51 with MeI and K2CO3 followed
by ester hydrolysis with NaOH gave the desired phthalalde-
hydic acid 53 (Scheme 6). All the new compounds gave
satisfactory spectral data, and those of 52 and 53 agreed
well with the reported21 values.
well with the literature values.2j Alkaline hydrolysis (dil
NaOH) of 58 gave cryphonectric acid (10) in 79% yield
(Scheme 8). The analysis of its spectral data (IR, 1H NMR,
13C NMR, and MS) left no doubt about the structural iden-
tity.
4. Conclusion
In conclusion, we have developed a generalized regiospe-
cific synthetic route to the 3-(2,6-dihydroxyphenyl)isoben-
zofuranones. It has been applied to the synthesis of
isopestacin (9) and cryphonectric acid (10) in completely re-
giospecific manners. Furthermore, its simplicity and brevity
appear to be suitable for generating a wide variety of analogs
of the natural products.
Attempted condensation of phthalaldehydic acid 51 with
3,5-diketohexahydrobenzoic acid (43) in the presence of
DBU provided an intractable mixture of products. Possibly
due to the presence of free hydroxyl group in 51 and the
resulting diminished electrophilicity of the latent formyl
group, the condensation was disfavored. On the other
hand, corresponding permethylated phthalaldehydic acid
53 when condensed with 43 in the presence of DBU
(2 equiv) produced 54, but the yield of the reaction was
low (30%). Base catalyzed destruction of 43 could be a major
side reaction, since the starting phthalaldehydic acid 53 was
recovered after the reaction. Hg(OAc)2/NaOAc promoted
aromatization of 54 to 55, followed by esterification by
MeOH/SOCl2 produced 56. Both the compounds 55 and
56 were duly characterized. The presence of four singlets
in the aromatic region of their 1H NMR spectrum was indic-
ative of their fully aromatized structures. Methylation
(K2CO3/MeI) of 56 produced permethylated cryphonectric
acid methyl ester 57 (Scheme 7). Spectral data of compound
57 were identical to the reported values.2j
5. Experimental
5.1. General
Melting points are uncorrected. IR spectra were recorded on
a Thermo Nicolet Nexus 870 FTIR spectrophotometer using
1
KBr pellet. H and 13C NMR spectra of the samples in the
indicated solvents were recorded on 200 MHz, 300 MHz,
€
or 400 MHz spectrometer (Brucker) as solution in CDCl3
or DMSO-d6 or mixture of CDCl3 and DMSO-d6 or
MeOH-d4 or in acetone-d6 with TMS as the internal stan-
dard. Chemical shifts are expressed in d unit and coupling
constant in hertz. Mass spectra were taken using a VG Auto-
spec M mass spectrometer. Elemental analyses were carried
out by using an elemental analyzer VARIO EL instrument.
Dry solvents used for reactions were purified, before use, ac-
cording to the standard protocols. All solvents for chromato-
graphy were distilled prior to use. Columns were prepared
with silica gel (60–120 or 230–400 mesh).
Attempted demethylation of compound 55 by refluxing in
HBr/AcOH provided a solid compound, which defied puri-
fication. Consequently, the crude mixture was submitted
to esterification with SOCl2/MeOH. The resulting solid
compound was identified as the methyl ester of cryphonec-
tric acid, i.e., 58, spectroscopic data of which matched
5.1.1. Isopestacin (9).2i To a stirred solution of compound
38 (90 mg, 0.31 mmol) in dichloromethane (5 mL), AlCl3
(84 mg, 0.62 mmol) was added. The mixture was stirred
for 5–6 h, and after completion of the reaction as judged
by TLC, it was quenched by dropwise addition of H2O
(5 mL). The mixture was extracted with ethyl acetate
(2ꢂ50 mL) and the combined organic layer was washed
with 10% HCl (5 mL), H2O (2ꢂ20 mL), and brine (5 mL)
and dried (Na2SO4). Concentration of the organic layer
and chromatographic separation (1:1 ethyl acetate/petro-
leum ether) of the resulting residue produced compound
9 (55 mg) as a light brown crystalline solid. Yield: 65%;
OMe
OH
O
O
O
O
i, ii
MeO
HO
OH
OH
HO
HO
CO2H
CO2R
55
58; R = Me
10; R = H
iii
Scheme 8. Synthesis of cryphonectric acid (10). (i) HBr, AcOH, reflux,
12 h. (ii) SOCl2, MeOH, rt; overall 42% for two steps. (iii) aq NaOH
(10%), MeOH; 79%.

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D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
Rf: 0.8 (1:1 ethyl acetate/petroleum ether); mp: 269–270 ꢁC
(lit.2i 218–220 ꢁC); nmax (KBr, cmꢀ1): 3415 (br), 2936, 1723,
1615, 1319, 1041, 772; H NMR (300 MHz, MeOH-d4):
d 6.97 (t, 1H, J¼8.1 Hz), 6.93 (s, 1H), 6.66 (s, 1H), 6.53
(s, 1H), 6.29 (d, 2H, J¼8.1 Hz), 2.32 (s, 3H); 13C NMR
(75 MHz, MeOH-d4): d 173.7, 158.8, 157.2, 154.8, 148.8,
131.4, 116.4, 114.4, 111.6, 110.1, 107.8, 77.0, 22.0; MS
ESI (70 eV): 272 (40), 254 (55), 239 (60), 227 (100).
Anal. Calcd for C15H12O5: C, 66.17; H, 4.44. Found: C,
66.34; H, 4.50.
cmꢀ1): 2962, 1768, 1722, 1677, 1467, 1369, 1286, 1232;
1H NMR (200 MHz, CDCl3): d 7.86 (d, 1H, J¼7.4 Hz),
7.60 (t, 1H, J¼7.4 Hz), 7.51 (t, 1H, J¼7.4 Hz), 7.25 (d,
1H, J¼7.4 Hz), 6.54 (s, 1H), 2.48 (s, 2H), 2.37 (s, 2H),
1.82 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 196.8, 170.9, 168.3, 166.7, 148.9,
133.7, 128.2, 125.8, 125.1, 122.0, 121.9, 73.4, 50.7, 43.0,
31.9, 27.9, 27.4, 20.2; HRMS ESI (70 eV) for C18H19O5
[M+H]+ calcd: 315.1232, found: 315.1289. Anal. Calcd for
C18H18O5: C, 68.78; H, 5.77. Found: C, 68.92; H, 5.71.
1
5.1.2. Cryphonectric acid (10).2j An aqueous solution of
NaOH (2 mL, 10%) was added to a solution of compound
58 (20 mg, 0.06 mmol) in methanol (1 mL) and stirred at
room temperature for 4 h. The reaction was acidified by
addition of 6 N HCl (5 mL) and extracted with ethyl acetate
(2ꢂ30 mL). The combined organic layer was washed with
H2O (2ꢂ10 mL) and brine (5 mL), dried (Na2SO4), concen-
trated, and purified by flash column chromatography (ethyl
acetate) to produce compound 10 (15 mg) as a light brown
crystalline solid. Yield: 79%; Rf: 0.2 (ethyl acetate); mp:
>350 ꢁC; nmax (KBr, cmꢀ1): 3350 (br), 1733, 1718, 1617,
5.1.5. 3-(1,3-Dihydro-3-oxo-1-isobenzofuranyl)-2,4-pen-
tanedione (16).22 This compound was obtained as an insep-
arable mixture with tautomer 17. To a stirred solution of
acetylacetone (15) (675 mg, 6.75 mmol) in CHCl3 (5 mL),
DBU (1.01 mL, 6.75 mmol) was added dropwise at room
temperature. After 5 min, phthalaldehydic acid (11)
(1.01 g, 6.75 mmol) was added to it and the mixture was al-
lowed to stir for 5 h at room temperature. The reaction was
quenched with 10% HCl (3 mL) and diluted with ethyl ace-
tate (100 mL). The organic layer was separated and washed
with H2O (2ꢂ20 mL) and brine (10 mL), dried (Na2SO4),
and concentrated. The residue was purified by recrystalliza-
tion from ethyl acetate to give 16 (1.27 g) as a white solid.
Yield: 81%; Rf: 0.5 (1:1 ethyl acetate/petroleum ether);
1
1436, 1051, 804; H NMR (400 MHz, acetone-d6): d 9.32
(s, 1H, OH), 9.09 (s, 2H, OH), 8.41 (s, 1H, OH), 7.11 (s,
2H), 6.91 (s, 1H), 6.34 (s, 1H), 6.24 (s, 1H); 13C NMR
(100 MHz, acetone-d6): d 171.8, 167.2, 165.8, 158.3,
154.6, 133.4, 132.1, 115.0, 109.1, 106.1, 102.7, 101.4, 75.5.
1
mp: 104–105 ꢁC; H NMR (200 MHz, CDCl3) for the keto
isomer: d 7.83 (d, 1H, J¼7.4 Hz), 7.70–7.40 (m, 2H), 7.33
(d, 1H, J¼7.4 Hz), 6.11 (d, 1H, J¼9.1 Hz), 4.00 (d, 1H,
J¼9.1 Hz), 2.34 (s, 3H), 2.20 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 200.7, 199.6, 169.3, 147.3, 134.6, 130.0, 126.0,
125.7, 123.2, 78.6, 72.0, 31.0, 29.9.
5.1.3. 3-(2-Hydroxy-4,4-dimethyl-6-oxo-cyclohexen-1-
yl)-3H-isobenzofuran-1-one (13). To a stirred solution of
dimedone (12) (500 mg, 3.57 mmol) in CHCl3 (5 mL),
DBU (0.53 mL, 3.57 mmol) was added dropwise at room
temperature. After 5 min, phthalaldehydic acid (11)
(535 mg, 3.57 mmol) was added to it and the mixture was al-
lowed to stir for 5 h at room temperature. The reaction was
quenched with 10% HCl (5 mL) and diluted with ethyl ace-
tate (100 mL). The organic layer was separated and washed
with H2O (2ꢂ20 mL) and brine (10 mL), dried (Na2SO4),
and concentrated. The residue was purified by recrystalliza-
tion from ethyl acetate to give 13 (922 mg) as a white solid.
Yield: 95%; Rf: 0.1 (ethyl acetate); mp: 207–208 ꢁC (lit.10
mp: 208–210 ꢁC); nmax (KBr, cmꢀ1): 3506 (br), 2962,
1770, 1575, 1381, 1318, 1294; 1H NMR (200 MHz,
DMSO-d6+CDCl3): d 7.71 (d, 1H, J¼7.3 Hz), 7.53 (t, 1H,
J¼7.3 Hz), 7.38 (t, 1H, J¼7.3 Hz), 7.19 (d, 1H,
J¼7.3 Hz), 6.60 (s, 1H), 2.22 (s, 4H), 0.98 (s, 6H); 13C
NMR (50 MHz, DMSO-d6+CDCl3): d 185.9, 171.5, 150.6,
133.5, 127.9, 126.7, 124.3, 121.2, 108.4, 74.5, 46.7, 31.7,
28.0. HRMS ESI (70 eV) for C16H17O4 [M+H]+ calcd:
273.1127, found: 273.1141.
5.1.6. Methyl 2-(2-acetyl-3-oxo-but-1-enyl)benzoate (18).
A stirred solution of 16 and 17 (200 mg, 0.86 mmol), PTSA
(5 mg) in EtOH (5 mL), and C6H6 (10 mL) was heated at re-
flux with constant removal of water by means of Dean–Stark
apparatus for 48 h. It was then diluted with ethyl acetate
(70 mL). The organic layer was separated and washed with
saturated NaHCO3 (10 mL), H2O (2ꢂ15 mL), and brine
(10 mL), dried (Na2SO4), and concentrated. The crude prod-
uct was purified by column chromatography (1:3 ethyl ace-
tate/petroleum ether) to give 18 (120 mg) as a semi solid.
Yield: 53%; Rf: 0.5 (1:3 ethyl acetate/petroleum ether);
mp: 93–94 ꢁC; nmax (KBr, cmꢀ1): 1714, 1666, 1619, 1596,
1
1479, 1367, 1268, 1079, 763, 715; H NMR (200 MHz,
CDCl3): d 8.21 (s, 1H), 8.15–8.02 (m, 1H), 7.58–7.40 (m,
2H), 7.28 (d, 1H, J¼8.4 Hz), 4.38 (q, 2H, J¼7.2 Hz), 2.46
(s, 3H), 2.04 (s, 3H), 1.40 (t, 3H, J¼7.2 Hz); 13C NMR
(50 MHz, CDCl3): d 203.7, 196.4, 165.8, 142.6, 141.6,
135.4, 132.4, 130.8, 129.7, 129.3, 128.7, 61.2, 31.5, 26.5,
14.0; HRMS ESI (70 eV) for C15H17O4 [M+H]+ calcd:
261.1127, found: 261.1120.
5.1.4. 3-(2-Acetoxy-4,4-dimethyl-6-oxo-cyclohexen-1-yl)-
3H-isobenzofuran-1-one (14). Ac2O (1 mL) was added to
a solution of 13 (100 mg, 0.37 mmol) in pyridine (1 mL).
The mixture was stirred for 18–20 h at room temperature.
After completion of the reaction as checked by TLC, it
was quenched by addition of saturated CuSO4 solution
(5 mL) and extracted with ethyl acetate (2ꢂ30 mL). The
combined organic layer was washed with H2O (2ꢂ10 mL)
and brine (5 mL), dried (Na2SO4), concentrated, and purified
by column chromatography (1:1 ethyl acetate/petroleum
ether) to produce 14 (86 mg) as a waxy solid. Yield: 67%;
Rf: 0.5 (1:1 ethyl acetate/petroleum ether); nmax (KBr,
5.1.7. Ethyl 1-acetyl-1-(1,3-dihydro-3-oxoisobenzofura-
nyl)acetate (20).23 This compound was obtained as an in-
separable mixture, other component being its tautomer 21.
To a stirred solution of ethyl acetoacetate (19) (600 mg,
4.61 mmol) in CHCl3 (5 mL), DBU (0.69 mL, 4.61 mmol)
was added dropwise at room temperature. After 5 min,
phthalaldehydic acid (11) (692 mg, 4.61 mmol) was added
to it and the mixture was allowed to stir for 5 h at room tem-
perature. The reaction was quenched with 10% HCl (3 mL)
and diluted with ethyl acetate (60 mL). The organic layer

D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
11787
was washed with H2O (2ꢂ20 mL) and brine (10 mL), dried
(Na2SO4), and concentrated. The residue was purified by re-
crystallization from ethyl acetate to give 20 (665 mg) as
a white solid. Yield: 55%; Rf: 0.5 (1:3 ethyl acetate/petro-
7.48 (dd, 1H, J¼7.4, 7.2 Hz), 7.37 (dd, 1H, J¼7.7,
7.2 Hz), 7.20 (d, 1H, J¼7.4 Hz), 6.67 (s, 1H), 2.42–2.30
(m, 4H), 1.93–1.83 (m, 2H); 13C NMR (50 MHz, DMSO-
d6): d 186.6, 170.9, 150.8, 133.8, 128.2, 126.6, 124.3,
121.5, 109.3, 74.4, 32.8, 20.2; HRMS ESI (70 eV) for
C14H12O4Na [M+Na]+ calcd: 267.0633, found: 267.0626.
1
leum ether); mp: 78–79 ꢁC; H NMR (200 MHz, CDCl3)
for the keto isomer: d 7.87 (d, 1H, J¼7.3 Hz), 7.80–7.35
(m, 3H), 6.08 (d, 1H, J¼7.9 Hz), 4.30–4.05 (m, 2H),
3.90–3.81 (m, 1H), 2.36 (s, 3H), 1.27–1.11 (m, 3H);
13C NMR (50 MHz, CDCl3): d 199.5, 178.5, 165.9,
147.1, 134.4, 129.8, 125.5, 123.1, 121.5, 77.9, 62.5, 62.1,
30.4, 13.8.
5.1.11. 3-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-3H-iso-
benzofuran-1-one (27). A stirred solution of 26 (100 mg,
0.41 mmol), PTSA (5 mg) in EtOH (5 mL), and C6H6
(10 mL) was heated at reflux with constant removal of water
by means of Dean–Stark apparatus for 48 h. It was then di-
luted with ethyl acetate (30 mL). The organic layer was sep-
arated and washed with saturated NaHCO3 (5 mL), H2O
(2ꢂ5 mL), and brine (5 mL), dried (Na2SO4), and concen-
trated. The crude product was purified by column chromato-
graphy (1:3 ethyl acetate/petroleum ether) to give 27
(80 mg) as a white solid. Yield: 73%; Rf: 0.5 (1:1 ethyl ace-
tate/petroleum ether); mp: 143–144 ꢁC; nmax (KBr, cmꢀ1):
2989, 1758, 1633, 1590, 1386, 1058, 734; 1H NMR
(200 MHz, CDCl3): d 7.84 (d, 1H, J¼7.3 Hz), 7.57 (dd,
1H, J¼7.5, 6.4 Hz), 7.44 (dd, 1H, J¼7.5, 7.3 Hz), 7.24 (d,
1H, J¼6.4 Hz), 6.79 (s, 1H), 3.99–3.65 (m, 2H), 2.62–2.40
(m, 4H), 2.10–1.94 (m, 2H), 0.86 (t, 3H, J¼7.0 Hz); 13C
NMR (50 MHz, CDCl3): d 195.9, 177.3, 171.2, 150.4,
133.2, 127.7, 126.6, 124.2, 121.0, 112.8, 73.8, 64.2, 35.6,
25.4, 20.0, 13.7; HRMS ESI (70 eV) for C16H17O4
[M+H]+ calcd: 273.1127, found: 273.1140.
5.1.8. 3-(2-Oxopropyl)-3H-isobenzofuran-1-one (22).23
Ac2O (2 mL) was added to a solution of 20 and 21
(200 mg, 0.76 mmol) in pyridine (2 mL). The mixture was
stirred for 18–20 h at room temperature and then heated at
reflux for 3–4 h. The reaction mixture was quenched by ad-
dition of saturated CuSO4 solution (5 mL) and diluted with
ethyl acetate (50 mL). The organic layer was separated
and washed with H2O (2ꢂ10 mL) and brine (5 mL), dried
(Na2SO4), and concentrated. The crude product was purified
by column chromatography (1:1 ethyl acetate/petroleum
ether) to give 22 (86 mg, 0.58 mmol) as a white solid. Yield:
74%; Rf: 0.3 (1:1 ethyl acetate/petroleum ether); mp: 191–
192 ꢁC; 1H NMR (200 MHz, CDCl3): d 7.87 (d, 1H,
J¼7.3 Hz), 7.65 (t, 1H, J¼7.3 Hz), 7.52 (t, 1H, J¼7.3 Hz),
7.46 (d, 1H, J¼7.3 Hz), 5.91 (t, 1H, J¼6.7 Hz), 3.12 (dd,
1H, J¼17.5, 6.7 Hz), 2.91 (dd, 1H, J¼17.5, 6.7 Hz), 2.25
(s, 3H); 13C NMR (50 MHz, CDCl3): d 204.3, 169.9,
149.2, 134.2, 129.3, 125.5, 122.2, 76.6, 47.9, 30.5 (one qua-
ternary carbon was absent).
5.1.12. 3-(2,6-Dimethoxyphenyl)-3H-isobenzofuran-1-
one (28). I2 (125 mg, 0.50 mmol) was added to a stirred so-
lution of 26 (60 mg, 0.24 mmol) in MeOH (10 mL). The
mixture was heated at reflux for 0.5 h and then quenched
by addition of saturated sodium thiosulfate solution
(10 mL) after removal of methanol in vacuum. Then it was
diluted with ethyl acetate (50 mL). The organic layer was
separated and washed with H2O (2ꢂ10 mL) and brine
(5 mL), dried (Na2SO4), and concentrated. The crude prod-
uct was purified by column chromatography (1:1 ethyl ace-
tate/petroleum ether) to give 28 (50 mg) as a white solid
compound. Yield: 77%; Rf: 0.4 (1:1 ethyl acetate/petroleum
ether); mp: 151–152 ꢁC; nmax (KBr, cmꢀ1): 2213, 1762,
1596, 1473, 1253, 1106, 744; 1H NMR (200 MHz,
CDCl3): d 7.91(d, 1H, J¼7.0 Hz), 7.55 (dd, 1H, J¼7.4,
7.2 Hz), 7.46 (dd, 1H, J¼7.2, 7.0 Hz), 7.32–7.19 (m, 2H),
6.54 (s, 1H), 6.52 (d, 2H, J¼8.4 Hz), 3.64 (br s, 6H); 13C
NMR (50 MHz, CDCl3): d 171.7, 159.3, 150.8, 133.3,
130.9, 128.1, 127.1, 124.7, 121.5, 111.8, 104.4, 75.0, 55.8;
MS ESI (70 eV): 271.2050. Anal. Calcd for C16H14O4: C,
71.10; H, 5.22. Found: C, 69.83; H, 5.12.
5.1.9. 2-(1,3-Dihydro-3-oxo-1-isobenzofuranyl)-1H-in-
dene-1,3(2H)-dione (24).6 To a stirred solution of indane-
1,3-dione (23) (220 mg, 1.51 mmol) in CHCl3 (5 mL),
DBU (0.22 mL, 1.51 mmol) was added dropwise at room
temperature. After 5 min, phthalaldehydic acid (11)
(226 mg, 1.51 mmol) was added to it and the mixture was al-
lowed to stir for 5 h at room temperature. The reaction was
quenched with 10% HCl (3 mL) and diluted with ethyl ace-
tate (40 mL). The organic phase was separated and washed
with H2O (2ꢂ10 mL) and brine (5 mL), dried (Na2SO4),
and concentrated. The residue was purified by recrystalliza-
tion from ethyl acetate to give 24 (360 mg) as a light brown
solid. Yield: 86%; Rf: 0.7 (1:1 ethyl acetate/petroleum
ether); mp: 216–217 ꢁC; IR and NMR data are provided in
Ref. 6.
5.1.10. 3-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-3H-iso-
benzofuran-1-one (26). To a stirred solution of cyclo-
hexane-1,3-dione (25) (800 mg, 7.1 mmol) in CH3CN
(10 mL), DBU (1.06 mL, 7.1 mmol) was added dropwise
at room temperature. After 5 min, phthalaldehydic acid
(11) (1.07 g, 7.1 mmol) was added and the mixture heated
at reflux for 6–7 h. Then the reaction was quenched with
10% HCl (10 mL) and diluted with ethyl acetate (100 mL).
The organic layer was separated and washed with H2O
(2ꢂ20 mL) and brine (10 mL), dried (Na2SO4), and concen-
trated. The crude product was purified by recrystallization
from ethyl acetate to give 26 (1.22 g) as a white solid. Yield:
70%; Rf: 0.2 (ethyl acetate); mp: 219–220 ꢁC; nmax (KBr,
5.1.13. 3-(2,6-Dihydroxyphenyl)-3H-isobenzofuran-1-
one (29). To a stirred solution of 26 (240 mg, 0.98 mmol)
in AcOH (5 mL), Hg(OAc)2 (940 mg, 2.95 mmol) and anhy-
drous NaOAc (242 mg, 2.95 mmol) were added. The mix-
ture was heated at reflux for 3 h when initially formed
precipitates were dissolved. After cooling, 6 N HCl (5 mL)
was added to it and stirred for another 15 min. The mixture
was filtered through a pad of Celite and the filtrate was di-
luted by addition of ethyl acetate (60 mL). The organic layer
was washed with H2O (2ꢂ10 mL) and brine (5 mL), dried
(Na2SO4), and concentrated. The crude product was purified
by column chromatography (1:1 ethyl acetate/petroleum
1
cmꢀ1): 3433 (br), 2947, 1753, 1568, 1385, 1065, 761; H
NMR (200 MHz, DMSO-d6): d 7.74 (d, 1H, J¼7.7 Hz),

11788
D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
ether) to give 29 (225 mg) as a white solid. Yield: 95%; Rf:
0.8 (2:1 ethyl acetate/petroleum ether); mp: 239–240 ꢁC;
nmax (KBr, cmꢀ1): 3469 (br), 2612, 1722, 1612, 1470,
1017, 720; 1H NMR (200 MHz, DMSO-d6+CDCl3): d 8.78
(br s, 2H, OH), 7.65 (d, 1H, J¼7.4 Hz), 7.34 (dd, 1H,
J¼8.1, 7.3 Hz), 7.29 (dd, 1H, J¼8.1, 7.4 Hz), 7.13 (d, 1H,
J¼7.3 Hz), 6.88 (s, 1H), 6.75 (t, 1H, J¼8.1 Hz), 6.13 (d,
2H, J¼8.1 Hz); 13C NMR (50 MHz, DMSO-d6+CDCl3):
d 172.0, 157.3, 151.2, 133.3, 130.2, 127.8, 127.2, 124.3,
121.9, 108.6, 107.1, 75.9; MS ESI (70 eV): 242 (M+), 225,
197, 168. Anal. Calcd for C14H10O4: C, 69.42; H, 4.16.
Found: C, 69.74; H, 4.30.
CDCl3+DMSO-d6): d 7.37 (dd, 1H, J¼7.9, 7.2 Hz), 6.91
(d, 1H, J¼7.2 Hz), 6.84 (d, 1H, J¼7.2 Hz), 6.41 (s, 1H);
13C NMR (50 MHz, CDCl3+DMSO-d6): d 168.9, 156.6,
148.0, 136.2, 117.7, 114.5, 112.3. Anal. Calcd for C8H6O4:
C, 57.84; H, 3.64. Found: C, 57.98; H, 3.58.
5.1.17. 3-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-7-meth-
oxy-3H-isobenzofuran-1-one (33a). To a stirred solution
of cyclohexane-1,3-dione (25) (68 mg, 0.61 mmol) in
CH3CN (5 mL), DBU (0.09 mL, 0.61 mmol) was added
dropwise at room temperature. After 5 min, phthalaldehydic
acid 32a (110 mg, 0.61 mmol) was added and the mixture
heated at reflux for 6–7 h. Then the reaction was quenched
with 10% HCl (3 mL) and diluted with ethyl acetate
(30 mL). The organic layer was separated and washed with
H2O (2ꢂ5 mL) and brine (5 mL), dried (Na2SO4), and con-
centrated. The crude product was purified by recrystalliza-
tion from ethyl acetate to give 33a (115 mg) as a white
solid. Yield: 68%; Rf: 0.1 (ethyl acetate); mp: 245–246 ꢁC;
nmax (KBr, cmꢀ1): 3480 (br), 2927, 1751, 1662, 1639,
1373, 1182; 1H NMR (400 MHz, MeOH-d4): d 7.49 (t, 1H,
J¼8.0 Hz), 6.91 (d, 1H, J¼8.2 Hz), 6.72 (d, 1H,
J¼7.6 Hz), 6.50 (s, 1H), 3.85 (s, 3H), 2.40–2.30 (m, 3H),
1.95–1.82 (m, 3H); 13C NMR (100 MHz, MeOH-d4):
d 170.9, 158.1, 153.6, 136.0, 113.7, 112.7, 109.8, 109.7,
74.0, 54.7, 32.6, 20.1, due to very poor solubility in common
deuteriated solvents including deuteriated MeOH, the car-
bonyl peak is absent; HRMS ESI (70 eV) for C15H15O5
[M+H]+ calcd: 275.0920, found: 275.0909.
5.1.14. 3-(3-Chloro-2,6-dihydroxyphenyl)-3H-isobenzo-
furan-1-one (30). This compound was obtained as a side
product along with the expected phenol 29. A mixture of
compound 26 (410 mg, 1.68 mmol), CuCl2$2H2O (571 mg,
3.36 mmol), and LiCl (142.8, 3.36 mmol) in 8 mL DMF
was heated at reflux for 1 h. After dilution with ethyl acetate
(50 mL), the organic layer was washed with H2O (2ꢂ10 mL)
and brine (5 mL), dried (Na2SO4), and concentrated. The re-
sulting crude product was purified through column chroma-
tography (1:1 ethyl acetate/petroleum ether) to give 30
(140 mg, 0.51 mmol) as a white solid along with 29
(205 mg). Yield: 30%; Rf: 0.5 (2:1 ethyl acetate/petroleum
ether); mp: 196–197 ꢁC; nmax (KBr, cmꢀ1): 3480 (br),
1
2364, 1729, 1600, 1463, 1311, 973; H NMR (400 MHz,
MeOH-d4): d 7.77 (d, 1H, J¼7.6 Hz), 7.58 (dd, 1H, J¼7.6,
7.2 Hz), 7.45 (dd, 1H, J¼7.6, 7.2 Hz), 7.23 (d, 1H,
J¼7.6 Hz), 7.03 (d, 1H, J¼8.8 Hz), 7.01 (s, 1H), 6.26 (d,
1H, J¼8.8 Hz); 13C NMR (100 MHz, MeOH-d4): d 174.2,
157.8, 154.0, 152.1, 135.1, 131.3, 129.6, 128.3, 125.6,
122.9, 112.6, 112.1, 108.9, 77.6; HRMS ESI (70 eV) for
C14H1035ClO4 [M+H]+ calcd: 277.0268, found: 277.0260.
5.1.18. 3-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-7-hy-
droxy-3H-isobenzofuran-1-one (33b).6 This compound
was prepared as a mixture of tautomeric keto and enol forms.
To a stirred solution of cyclohexane-1,3-dione (25) (20 mg,
0.18 mmol) in CHCl3 (5 mL), DBU (0.05 mL, 0.18 mmol)
was added dropwise at room temperature. After 5 min,
phthalaldehydic acid 32b (30 mg, 0.18 mmol) was added
to it and the mixture was allowed to stir for 5 h at room tem-
perature. The reaction was quenched with 10% HCl (3 mL)
and diluted with ethyl acetate (30 mL). The organic layer
was separated and washed with H2O (2ꢂ5 mL) and brine
(5 mL), dried (Na2SO4), and concentrated. The residue
was purified by recrystallization from ethyl acetate to give
33b (35 mg) as a white solid. Yield: 74%; Rf: 0.1 (ethyl ace-
tate); mp: 250–251 ꢁC; IR and NMR data are given in Ref. 6.
5.1.15. 3-(2,6-Diacetoxyphenyl)-3H-isobenzofuran-1-one
(31). To a stirred solution of phenol 29 (100 mg,
0.70 mmol) in Ac2O (3 mL), one drop of concd H2SO4
was added and the resulting solution was heated at reflux
for 30 min. The reaction was quenched by the addition of
saturated NaHCO3 solution (5 mL) and diluted with ethyl
acetate (40 mL). The organic layer was washed with H2O
(2ꢂ10 mL) and brine (5 mL), dried (Na2SO4), concentrated,
and the resulting crude product was purified by column chro-
matography (1:5 ethyl acetate/petroleum ether) to furnish 31
(100 mg, 0.30 mmol) as solid crystals. Yield: 76%; Rf: 0.3
(1:3 ethyl acetate/petroleum ether); mp: 172–173 ꢁC; nmax
(KBr, cmꢀ1): 1768, 1612, 1467, 1293, 1181, 750; 1H
NMR (200 MHz, CDCl3): d 7.96 (d, 1H, J¼7.4 Hz), 7.64
(dd, 1H, J¼7.5, 7.3 Hz), 7.55 (dd, 1H, J¼7.4, 7.3 Hz),
7.43 (t, 1H, J¼8.3 Hz), 7.35 (d, 1H, J¼7.5 Hz), 7.02 (d,
2H, J¼8.3 Hz), 6.55 (s, 1H), 2.05 (br s, 6H); 13C NMR
(50 MHz, CDCl3): d 170.5, 168.5, 150.0, 148.6, 134.4,
130.4, 129.2, 126.1, 125.0, 122.9, 120.9, 120.1, 74.5, 20.4.
Anal. Calcd for C18H14O6: C, 66.26; H, 4.32. Found: C,
66.10; H, 4.25.
5.1.19. 3-(2,6-Dihydroxyphenyl)-7-methoxy-3H-isoben-
zofuran-1-one (34). To a stirred solution of 33a (70 mg,
0.25 mmol) in AcOH (3 mL), Hg(OAc)2 (244 mg,
0.75 mmol) and anhydrous NaOAc (63 mg, 0.75 mmol)
were added. The mixture was heated at reflux for 3 h,
when initially formed precipitates were dissolved. After
cooling, 6 N HCl (2 mL) was added to it and stirred for
another 15 min. The mixture was filtered through a pad of
Celite and the filtrate was diluted by addition of ethyl acetate
(30 mL). The organic layer was washed with H2O (2ꢂ5 mL)
and brine (5 mL), dried (Na2SO4), and concentrated. The
crude product was purified by column chromatography
(1:1 ethyl acetate/petroleum ether) to give 34 (60 mg) as
a white solid. Yield: 86%; Rf: 0.4 (1:1 ethyl acetate/petro-
leum ether); mp: 269–270 ꢁC; nmax (KBr, cmꢀ1): 3470
(br), 1714, 1610, 1469, 1303, 1068, 790; 1H NMR
(400 MHz, MeOH-d4): d 7.49 (t, 1H, J¼8.0 Hz), 6.93 (d,
5.1.16. 3,7-Dihydroxy-1(3H)isobenzofuranone (32b).
This compound was prepared by AlCl3 mediated demethyl-
ation of 32a following the procedure described for the prep-
aration of 9 from 37. Yield: 67%; Rf: 0.5 (2:1 ethyl acetate/
petroleum ether); mp: 120–121 ꢁC; nmax (KBr, cmꢀ1): 3473
1
(br), 1722, 1608, 1475, 1303, 1141; H NMR (200 MHz,

D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
11789
1H, J¼8.4 Hz), 6.88 (s, 1H), 6.87 (dd, 1H, J¼8.4, 7.2 Hz),
6.72 (d, 1H, J¼7.2 Hz), 6.19 (d, 2H, J¼8.0 Hz), 3.89 (s,
3H); 13C NMR (100 MHz, MeOH-d4): d 172.8, 159.4,
159.0, 155.6, 137.4, 131.6, 115.4, 114.7, 111.2, 109.8,
107.7, 76.8, 56.2. Anal. Calcd for C15H12O5: C, 66.17; H,
4.44. Found: C, 66.37; H, 4.35.
2.05 (s, 3H); 13C NMR (100 MHz, MeOH-d4): d 174.6,
158.7, 153.0, 142.2, 134.9, 129.2, 128.3, 125.4, 122.9,
108.5, 106.8, 78.0, 21.6; HRMS ESI (70 eV) for C15H13O4
[M+H]+ calcd: 257.0814, found: 257.0825.
5.1.24. 3-(2,6-Dimethoxy-4-methylphenyl)-3H-isobenzo-
furan-1-one (42). This compound was prepared as a white
solid by the I2/MeOH mediated aromatization of 40, follow-
ing the procedure described for the preparation of 28 from
26. Yield: 65%; Rf: 0.4 (1:3 ethyl acetate/petroleum ether);
mp: 189–190 ꢁC; nmax (KBr, cmꢀ1): 1754, 1610, 1463,
5.1.20. 3-(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)-7-meth-
oxy-5-methyl-3H-isobenzofuran-1-one (37). This com-
pound was prepared as a white solid from phthalaldehydic
acid 36 and cyclohexane-1,3-dione (25), following the
same procedure adopted for the preparation of 26. Yield:
60%; Rf: 0.1 (ethyl acetate); mp: 267–268 ꢁC; nmax (KBr,
cmꢀ1): 3430 (br), 2592, 1757, 1577, 1480, 1375, 1294,
1057, 995; 1H NMR (200 MHz, DMSO-d6): d 6.82 (s,
1H), 6.58 (s, 1H), 6.37 (s, 1H), 3.85 (s, 3H), 2.50–2.30 (m,
4H), 2.34 (s, 3H), 1.89–1.80 (m, 2H); 13C NMR (50 MHz,
DMSO-d6): d 186.4, 168.3, 157.2, 153.8, 146.9, 113.4,
111.4, 111.2, 109.7, 72.6, 55.5, 32.8, 21.8, 20.2; MS ESI
(70 eV): 288 (M+), 259, 243, 232, 149. Anal. Calcd for
C16H16O5: C, 66.66; H, 5.59. Found: C, 66.40; H, 5.50.
1
1122, 744; H NMR (400 MHz, CDCl3): d 7.90 (d, 1H,
J¼7.6 Hz), 7.54 (dd, 1H, J¼8.0, 7.6 Hz), 7.45 (dd, 1H,
J¼7.6, 7.2 Hz), 7.22 (d, 1H, J¼7.6 Hz), 7.02 (s, 1H), 6.33
(br s, 2H), 3.63 (br s, 6H), 2.32 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 171.7, 159.0, 151.0, 141.4, 133.2,
127.9, 127.0, 124.6, 121.5, 108.6, 105.1, 75.1, 55.7, 22.1.
Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found: C,
72.01; H, 5.62.
5.1.25. 3-(4-Carboxy-2-hydroxy-6-oxo-1-cyclohexen-1-
yl)-3H-isobenzofuran-1-one (44). To a stirred solution of
43 (170 mg, 1.09 mmol) in CH3CN (5 mL), DBU
(0.32 mL, 2.18 mmol) was added dropwise at room temper-
ature. After 5 min, phthalaldehydic acid (11) (164 mg,
1.09 mmol) was added and the mixture was heated at reflux
for 10–12 h. The reaction was quenched by the addition of
10% HCl (5 mL) and diluted with ethyl acetate (70 mL).
The organic layer was separated and washed with H2O
(2ꢂ10 mL) and brine (5 mL), dried (Na2SO4), and concen-
trated. The crude product was purified by column chromato-
graphy (1:1 ethyl acetate/methanol) to get 44 (230 mg,
0.80 mmol) as a white solid. Yield: 73%; Rf: 0.4 (1:1 ethyl
acetate/methanol); mp: 252–254 ꢁC; nmax (KBr, cmꢀ1):
5.1.21. 3-(2,6-Dihydroxyphenyl)-7-methoxy-5-methyl-
3H-isobenzofuran-1-one (38).6 To a stirred solution of 37
(90 mg, 0.31 mmol) in AcOH (3 mL), Hg(OAc)2 (298 mg,
0.93 mmol) and anhydrous NaOAc (77 mg, 0.93 mmol)
were added. The mixture was heated at reflux for 3 h when
initially formed precipitates were dissolved. After cooling,
6 N HCl (2 mL) was added to it and stirred for another
15 min. The mixture was filtered through a pad of Celite
and the filtrate was diluted by addition of ethyl acetate
(30 mL). The organic layer was washed with H2O
(2ꢂ5 mL) and brine (5 mL), dried (Na2SO4), and concen-
trated. The crude product was purified by column chromato-
graphy (1:1 ethyl acetate/petroleum ether) to give 38
(85 mg) as a white solid. Yield: 93%; Rf: 0.3 (1:1 ethyl ace-
tate/petroleum ether); mp: 305–306 ꢁC; IR and NMR data
are provided in Ref. 6.
1
3310 (br), 1718, 1675, 1639, 1396, 1110, 939, 730; H
NMR (400 MHz, MeOH-d4): d 7.74 (d, 1H, J¼7.6 Hz),
7.57 (t, 1H, J¼7.2 Hz), 7.43 (dd, 1H, J¼7.6, 7.2 Hz), 7.22
(d, 1H, J¼7.2), 6.61 (s, 1H), 3.20–3.01 (m, 1H), 2.99–2.90
(m, 1H), 2.74–2.50 (m, 3H); 13C NMR (100 MHz, MeOH-
d4): d 195.3, 174.5, 172.6, 150.7, 133.8, 128.2, 126.6,
124.2, 121.2, 109.6, 74.8, 37.3, 34.7; HRMS ESI (70 eV)
for C15H13O6 [M+H]+ calcd: 289.0712, found: 289.0695.
5.1.22. 3-(2-Hydroxy-4-methyl-6-oxo-1-cyclohexen-1-yl)-
3H-isobenzofuran-1-one (40). This compound was
prepared as a white solid from phthalaldehydic acid 11
and cyclohexane-1,3-dione 39, following the same proce-
dure adopted for the preparation of 26. Yield: 73%; Rf: 0.5
(ethyl acetate); mp: 119–120 ꢁC; nmax (KBr, cmꢀ1): 3490
(br), 1762, 1571, 1386, 1317, 1027, 757; 1H NMR
(400 MHz, MeOH-d4): d 7.71 (d, 1H, J¼7.6 Hz), 7.55 (dd,
1H, J¼7.6, 7.2 Hz), 7.40 (dd, 1H, J¼7.6, 7.2 Hz), 7.21 (d,
1H, J¼7.6 Hz), 6.59 (s, 1H), 2.45–2.30 (m, 2H), 2.20–2.00
(m, 3H), 0.98 (d, 3H, J¼5.2 Hz); 13C NMR (100 MHz,
MeOH-d4): d 189.6, 174.1, 152.3, 135.1, 129.4, 128.1,
125.9, 122.9, 110.6, 76.4, 42.1, 29.4, 21.0. Anal. Calcd for
C15H14O4: C, 69.76; H, 5.46. Found: C, 69.91; H, 5.53.
5.1.26. 4-(1,3-Dihydro-3-oxo-1-isobenzofuranyl)-3,5-di-
hydroxybenzoic acid (45). To a stirred solution of 44
(130 mg, 0.45 mmol) in AcOH (3 mL), Hg(OAc)2
(431 mg, 1.35 mmol) and anhydrous NaOAc (111 mg,
1.35 mmol) were added. The mixture was heated at reflux
for 3 h when initially formed precipitates were dissolved.
After cooling, 6 N HCl (3 mL) was added to it and stirred
for another 15 min. The mixture was filtered through a pad
of Celite and the filtrate was diluted by addition of ethyl ace-
tate (30 mL). The organic layer was washed with H2O
(2ꢂ5 mL), brine (5 mL), dried (Na2SO4), and concentrated.
The crude product was purified by column chromatography
(2:1 ethyl acetate/petroleum ether) to give 45 (120 mg) as
a white solid. Yield: 93%; Rf: 0.9 (ethyl acetate); mp: par-
tially melted at 158–160 ꢁC, charred at 290–291 ꢁC; nmax
(KBr, cmꢀ1): 3615 (br), 1710, 1604, 1436, 1251, 1052,
738; 1H NMR (400 MHz, MeOH-d4): d 7.77 (d, 1H,
J¼7.6 Hz), 7.58 (t, 1H, J¼7.6 Hz), 7.45 (dd, 1H, J¼7.6,
7.2 Hz), 7.24 (d, 1H, J¼7.6 Hz), 7.01 (s, 1H), 6.89 (s, 2H);
13C NMR (100 MHz, MeOH-d4): d 172.9, 168.0, 157.3,
5.1.23. 3-(2,6-Dihydroxy-4-methylphenyl)-3H-isobenzo-
furan-1-one (41). This compound was prepared as a white
solid by aromatization of 40, following the same procedure
described for the preparation of 29 from 26. Yield: 89%; Rf:
0.6 (1:1 ethyl acetate/petroleum ether); mp: 238–239 ꢁC;
nmax (KBr, cmꢀ1): 3212 (br), 1725, 1621, 1598, 1465,
1
1049, 738; H NMR (400 MHz, MeOH-d4): d 7.72 (d, 1H,
J¼7.6 Hz), 7.53 (t, 1H, J¼7.2 Hz), 7.40 (dd, 1H, J¼7.6,
7.2 Hz), 7.19 (d, 1H, J¼7.2 Hz), 6.92 (s, 1H), 6.01 (s, 2H),

11790
D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
150.5, 133.7, 132.5, 128.1, 126.7, 124.1, 121.4, 112.8, 107.4,
75.7; HRMS ESI (70 eV) for C15H11O6 [M+H]+ calcd:
287.0556, found: 287.0562.
71 ꢁC; nmax (KBr, cmꢀ1): 1648, 1617, 1328, 1268, 1155,
815; 1H NMR (400 MHz, CDCl3): d 11.80 (s, 1H), 6.33 (s,
1H), 6.28 (s, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 2.50 (s, 3H);
13C NMR (100 MHz, CDCl3): d 172.1, 165.5, 163.8,
143.0, 111.1, 105.1, 98.6, 55.2, 51.8, 24.3. Anal. Calcd for
C10H12O4: C, 61.22; H, 6.16. Found: C, 61.52; H, 6.03.
5.1.27. Methyl 4-(1,3-dihydro-3-oxo-1-isobenzofuranyl)-
3,5-dihydroxybenzoate (46). To a stirred solution of 45
(50 mg, 0.17 mmol) in methanol (4 mL), SOCl2 (0.01 mL,
0.17 mmol) was added dropwise at 0 ꢁC. The mixture was
stirred at room temperature for 3–4 h. After completion of
the reaction as checked by TLC, it was concentrated in vac-
uum and saturated NaHCO3 solution (5 mL) was added to it.
The mixture was extracted with ethyl acetate (2ꢂ20 mL)
and the combined organic layer was washed with H2O
(2ꢂ10 mL) and brine (5 mL), dried (Na2SO4), and concen-
trated. The crude product was purified by column chromato-
graphy (1:1 ethyl acetate/petroleum ether) to give 46
(40 mg) as a white solid. Yield: 77%; Rf: 0.7 (1:1 ethyl ace-
tate/petroleum ether); mp: 286–287 ꢁC; nmax (KBr, cmꢀ1):
5.1.30. Methyl 2-acetoxy-4-methoxy-6-methylbenzoate
(49). Et3N (9.0 mL, 65 mmol) was added to a solution of
methyl 2-hydroxy-4-methoxy-6-methylbenzoate (48) (6.3 g,
32.1 mmol) in 30 mL dichloromethane and stirred for
10 min. Acetyl chloride (3.4 mL, 48.1 mmol) was then added
to this mixture dropwise at 0 ꢁC and allowed to stir for 4–5 h at
room temperature. Reaction was quenched by the addition of
water and extracted with dichloromethane (2ꢂ50 mL). The
combined organic layer was washed with H2O (2ꢂ30 mL)
and brine (20 mL), dried (Na2SO4), and concentrated. The
crude product was purified by column chromatography (1:5
ethyl acetate/petroleum ether) to give 49 (5.2 g) as a colorless
liquid. Yield: 68%; Rf: 0.2 (1:5 ethyl acetate/petroleum ether);
1
3410 (br), 1727, 1600, 1432, 1261, 1052, 771; H NMR
(400 MHz, MeOH-d4): d 7.75 (d, 1H, J¼7.6 Hz), 7.55 (dd,
1H, J¼7.6, 7.2 Hz), 7.43 (dd, 1H, J¼7.6, 7.2 Hz), 7.21 (d,
1H, J¼7.6 Hz), 6.98 (s, 1H), 6.84 (s, 2H), 3.74 (s, 3H);
13C NMR (100 MHz, MeOH-d4): d 172.8, 166.7, 157.5,
150.5, 133.7, 131.8, 128.2, 126.8, 124.2, 121.5, 113.2,
107.2, 75.7, 51.3. Anal. Calcd for C16H12O6: C, 64.00; H,
4.03. Found: C, 64.22; H, 4.11.
1
nmax (KBr, cmꢀ1): 1772, 1722, 1614, 1272, 1153, 773; H
NMR (400 MHz, CDCl3): d 6.64 (s, 1H), 6.47 (s, 1H), 3.85
(s, 3H), 3.80 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 169.3, 166.5, 161.2, 150.6, 140.7,
117.9, 114.3, 106.2, 55.4, 51.9, 21.1, 20.8. Anal. Calcd for
C12H14O5: C, 60.50; H, 5.92. Found: C, 60.28; H, 5.85.
5.1.28. 3-Hydroxy-4-carbomethoxy-5-methylcyclohexe-
none (47). Methyl acetoacetate (14 g, 120.6 mmol) was
added to a solution of NaOMe, prepared by the addition of
Na (4 g, 17.04 mmol) in MeOH (50 mL) at 0 ꢁC and the
mixture was heated at reflux for 30 min. Methyl crotonate
(12.06 g, 120.6 mmol) was then added to it dropwise and
the mixture heated at reflux for another 22 h. Excess metha-
nol was removed and the solid mass was dissolved in water
(20 mL). It was extracted with ethyl acetate (50 mL). The or-
ganic layer was discarded and the water layer acidified with
concd HCl (5 mL). The aqueous layer was extracted with
ethyl acetate (2ꢂ100 mL) and the combined organic layer
was washed with H2O (2ꢂ30 mL) and brine (20 mL), dried
(Na2SO4), and concentrated. The crude product was purified
by recrystallization from ethyl acetate to provide compound
47 (15.5 g) as a colorless solid. Yield: 70%; Rf: 0.3 (ethyl
acetate); mp: 127–128 ꢁC; nmax (KBr, cmꢀ1): 3450 (br),
1739, 1614, 1240, 1157, 759; 1H NMR (400 MHz,
CDCl3): d 12.17 (s, 1H), 5.65 (s, 1H), 3.85 (s, 3H), 3.84–
2.10 (m, 4H), 1.20–0.80 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 191.7, 185.4, 171.1, 103.7, 58.2, 52.4, 37.2,
31.7, 19.7. Anal. Calcd for C9H12O4: C, 58.69; H, 6.57.
Found: C, 58.40; H, 6.67.
5.1.31. 3,7-Dihydroxy-5-methoxy-1(3H)-isobenzofura-
none (51). A mixture of methyl 2-acetoxy-4-methoxy-6-
methylbenzoate (49) (3.6 g, 15.1 mmol) and NBS (5.87 g,
33.2 mmol) in CCl4 (40 mL) containing AIBN (5 mg) was
heated at reflux for 10 h while irradiated by a 100 W electric
bulb. At the end of the reaction, the reaction mixture was
chilled (ice bath) and filtered. Removal of solvent from the
filtrate furnished the crude dibromo compound 50 (4.5 g,
11.3 mmol). It was, without further purification, mixed
with concd HCl (3 mL), AcOH (3 mL), and H2O (10 mL)
and heated at reflux for 5 h. The solution was diluted with
ethyl acetate (30 mL) and extracted with saturated sodium
bicarbonate solution (2ꢂ30 mL). The organic part was dis-
carded and the water layer was acidified with concd HCl
(10 mL). It was again extracted with ethyl acetate
(2ꢂ100 mL) and the combined organic layer was washed
with H2O (2ꢂ30 mL) and brine (20 mL), dried (Na2SO4),
and concentrated. The crude product was purified by recrys-
tallization from ethyl acetate to furnish 51 (1.12 g) as a white
solid. Yield: 38%; Rf: 0.4 (2:1 ethyl acetate/petroleum
ether); mp: 159–160 ꢁC; nmax (KBr, cmꢀ1): 3399 (br),
1747, 1617, 1224, 1166, 1031; 1H NMR (400 MHz,
MeOH-d4): d 6.61 (s, 1H), 6.43 (s, 2H), 3.83 (s, 3H); 13C
NMR (100 MHz, MeOH-d4): d 169.7, 168.8, 159.4, 150.4,
106.6, 104.2, 103.9, 101.8, 56.6. Anal. Calcd for C9H8O5:
C, 55.11; H, 4.11. Found: C, 55.40; H, 4.20.
5.1.29. Methyl 2-hydroxy-4-methoxy-6-methylbenzoate
(48). To a solution of 47 (10.5 g, 57.06 mmol) in methanol
(30 mL) was added iodine (29 g, 114.1 mmol) and the mix-
ture was heated at reflux for 3 h. Excess methanol was re-
moved and saturated Na2S2O3 solution (40 mL) was added
to the residue. The resulting mixture was extracted with
ethyl acetate (2ꢂ70 mL) and the combined organic layer
was washed with H2O (2ꢂ30 mL) and brine (20 mL), dried
(Na2SO4), and concentrated. The crude product was purified
by column chromatography (1:10 ethyl acetate/petroleum
ether) to give 48 (6.3 g) as a low melting solid. Yield:
56%; Rf: 0.8 (1:10 ethyl acetate/petroleum ether); mp: 70–
5.1.32. Methyl 2-formyl-4,6-dimethoxybenzoate (52).21
To a stirred solution of 51 (300 mg, 1.53 mmol) in acetone
(5 mL) was added K2CO3 (633 mg, 4.59 mmol). After
stirring for 10 min, MeI (0.38 mL, 6.0 mmol) was added
to it and the mixture was allowed to stir for 12–15 h.
After completion of the reaction as checked by TLC,
acetone was removed and the mixture was diluted with ethyl
acetate (50 mL). The organic layer was washed with H2O
(2ꢂ10 mL) and brine (10 mL), dried (Na2SO4), and

D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
11791
concentrated. The crude product was purified by column
chromatography (1:1 ethyl acetate/petroleum ether) to fur-
nish compound 52 (250 mg) as a white solid. Yield: 73%;
Rf: 0.6 (1:1 ethyl acetate/petroleum ether); mp: 85–86 ꢁC
(lit.21 85–87 ꢁC); nmax (KBr, cmꢀ1): 1724, 1698, 1606,
3H); 13C NMR (100 MHz, MeOH-d4): d 172.4, 168.7,
168.1, 160.6, 158.9, 157.1, 133.2, 114.8, 108.6, 99.4, 98.6,
75.9, 56.5, 56.3, 52.7. Anal. Calcd for C18H16O8: C, 60.00;
H, 4.48. Found: C, 60.11; H, 4.57.
1
1265, 960; H NMR (400 MHz, CDCl3): d 9.93 (s, 1H),
5.1.37. Methyl 4-(1,3-dihydro-4,6-dimethoxy-3-oxo-1-
(57).2j
6.91 (s, 1H), 6.65 (s, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.80
(s, 3H); 13C NMR (100 MHz, CDCl3): d 190.1, 166.9,
161.9, 158.3, 135.7, 117.4, 104.9, 104.2, 56.2, 55.7, 52.6.
isobenzofuranyl)-3,5-dimethoxybenzoate
To
a stirred solution of 56 (30 mg, 0.083 mmol) in acetone
(5 mL) was added K2CO3 (35 mg, 0.25 mmol) and stirred
for 10 min. MeI (0.03 mL, 0.41 mmol) was added to it drop-
wise and stirred at room temperature for 15–20 h. After com-
pletion of the reaction as judged by TLC, inorganic salts were
filtered,acetonewasremoved, andtheresiduewasdilutedwith
ethylacetate(40 mL)andH2O(10 mL).Theorganiclayerwas
separated, washed with H2O (2ꢂ10 mL) and brine (5 mL),
dried (Na2SO4), and concentrated. The crude product was pu-
rified bycolumnchromatography(1:1 ethyl acetate/petroleum
ether) to furnish 57 (25 mg) as a white solid. Yield: 77%; Rf:
0.5 (1:1 ethyl acetate/petroleum ether); mp: 175–176 ꢁC
(lit.2j 170–175 ꢁC); nmax (KBr, cmꢀ1): 3350 (br), 1752,
5.1.33. 3-Hydroxy-5,7-dimethoxy-1(3H)-isobenzofura-
none (53).18 To
a stirred solution of 52 (90 mg,
0.40 mmol) in methanol (4 mL) was added a solution of
NaOH (320 mg, 8.0 mmol) in 3 mL H2O. The reaction mix-
ture was stirred for 2–3 h and quenched by addition of concd
HCl (2 mL). The mixture was extracted with ethyl acetate
(2ꢂ30 mL) and the combined organic layer was washed
with H2O (2ꢂ10 mL) and brine (5 mL), dried (Na2SO4),
and concentrated. The crude product was purified by recrys-
tallization from ethyl acetate to furnish 53 (70 mg) as a white
solid. Yield: 83%; Rf: 0.6 (ethyl acetate); mp: 185–186 ꢁC
(lit.21 186–189 ꢁC); nmax (KBr, cmꢀ1): 3280 (br), 1735,
1616, 1465, 1216, 1060; 1H NMR (400 MHz, CDCl3):
d 6.64 (d, 1H, J¼1.6 Hz), 6.56 (d, 1H, J¼1.6 Hz), 6.34 (s,
1H), 3.84 (s, 3H), 3.83 (s, 3H).
1
1720, 1612, 1459, 1328, 1218, 773; H NMR (400 MHz,
CDCl3): d 7.20 (br s, 2H), 6.88 (s, 1H), 6.39 (s, 1H), 6.18 (s,
1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.79 (s, 3H), 3.59 (br s, 6H);
13C NMR (100 MHz, CDCl3): d 169.2, 166.4, 166.3, 159.2
(br), 159.0, 155.1, 132.2, 116.7, 107.7, 105.9 (br), 98.4,
97.1, 73.2, 56.2, 55.9, 55.8, 52.4.
5.1.34. 3-(4-Carboxy-2-hydroxy-6-oxo-1-cyclohexen-1-
yl)-5,7-dimethoxy-3H-isobenzofuran-1-one (54). It was
prepared as a white solid from phthalaldehydic acid 53
and cyclohexane-1,3-dione 43, following the procedure
adopted for the preparation of 44. Yield: 30% (50% based
on recovered phthalaldehydic acid 53). Rf: 0.3 (methanol);
mp: 299–300 ꢁC; nmax (KBr, cmꢀ1): 3230 (br), 1729, 1702,
5.1.38. Methyl 4-(1,3-dihydro-4,6-dihydroxy-3-oxo-1-iso-
benzofuranyl)-3,5-dihydroxybenzoate (58).2j Compound
55 (50 mg, 0.14 mmol) was added to a mixture of HBr
(1 mL) and AcOH (1 mL) and the mixture was heated at re-
flux for 15–16 h. The solution was concentrated and diluted
with ethyl acetate (50 mL). The layers were separated and
the organic phase was washed with water (2ꢂ10 mL) and
brine (5 mL). After drying (Na2SO4) and concentration,
the crude product was dissolved in methanol (2 mL) and
SOCl2 (0.1 mL) was added to it dropwise at 0 ꢁC. The mix-
ture was again stirred at room temperature for 5 h and
quenched by addition of H2O (5 mL). It was diluted with eth-
yl acetate (50 mL) and the layers were separated. The or-
ganic layer was washed with water (2ꢂ10 mL) and brine
(5 mL). Drying (Na2SO4) and solvent removal produced
a residue, which was purified by column chromatography
(1:1 ethyl acetate/petroleum ether) to get 58 (20 mg) as
a white solid. Yield: 42%; Rf: 0.5 (1:1 ethyl acetate/petro-
leum ether); mp: 165–166 ꢁC; nmax (KBr, cmꢀ1): 3585
(br), 1727, 1712, 1614, 1434, 1051, 773; 1H
NMR (400 MHz, acetone-d6): d 9.34 (s, 1H, –OH), 9.11
(s, 2H, –OH), 8.44 (s, 1H, –OH), 7.08 (s, 2H), 6.91 (s,
1H), 6.34 (s, 1H), 6.24 (s, 1H), 3.83 (s, 3H); 13C NMR
(100 MHz, MeOH-d4): d 173.6, 168.3, 166.7, 159.3, 159.0,
156.2, 133.1, 115.4, 108.7, 106.2, 103.1, 101.2, 76.2, 52.8.
1
1614, 1394, 1078, 838; H NMR (400 MHz, MeOH-d4):
d 7.83 (s, 1H, –OH), 6.51 (s, 1H), 6.35 (s, 1H), 6.26 (s,
1H), 3.78 (s, 3H), 3.74 (s, 3H), 2.90–2.75 (m, 1H), 2.60–
2.45 (m, 4H); 13C NMR (100 MHz, MeOH-d4): d 193.7,
173.3, 168.3, 160.4, 159.9, 108.8, 108.2, 108.0, 101.7,
101.3, 78.3, 56.1, 55.9, 41.6, 39.9; HRMS ESI (70 eV) for
C17H17O8 [M+H]+ calcd: 349.0923, found: 349.0915.
5.1.35. 4-(1,3-Dihydro-4,6-dimethoxy-3-oxo-1-isobenzo-
furanyl)-3,5-dihydroxybenzoic acid (55). This compound
was obtained as a white solid along with an unidentified com-
pound by the Hg(OAc)2/NaOAc mediated aromatization of 54
as described for the preparation of 29 from 26. Yield: 60%; Rf:
0.2 (ethyl acetate); mp: 311–312 ꢁC; nmax (KBr, cmꢀ1): 1725,
1
1709, 1602, 1436, 1047; H NMR (400 MHz, MeOH-d4):
d 6.87 (s, 2H), 6.80 (s, 1H), 6.43 (s, 1H), 6.23 (s, 1H), 3.83
(s, 3H), 3.71 (s, 3H); 13C NMR (100 MHz, MeOH-d4):
d 172.5, 169.5, 168.6, 160.6, 158.8, 157.2, 133.9, 114.6,
108.9, 108.5, 99.4, 98.7, 75.9, 56.5, 56.3. Anal. Calcd for
C17H14O8: C, 58.96; H, 4.07. Found: C, 59.19; H, 4.15.
5.1.36. Methyl 4-(1,3-dihydro-4,6-dimethoxy-3-oxo-1-
isobenzofuranyl)-3,5-dihydroxybenzoate (56). This com-
pound was prepared as a white solid from 55 by the
SOCl2/MeOH mediated esterification as described for the
preparation of 46 from 45. Yield: 73%; Rf: 0.2 (1:1 ethyl ace-
tate/petroleum ether); mp: 284–285 ꢁC; nmax (KBr, cmꢀ1):
3392 (br), 1741, 1725, 1610, 1438, 1078; 1H NMR
(400 MHz, MeOH-d4): d 6.86 (s, 2H), 6.80 (s, 1H), 6.44
(s, 1H), 6.23 (s, 1H), 3.84 (s, 3H), 3.75 (s, 3H), 3.71 (s,
Acknowledgements
Financial support was provided by DST, New Delhi. P.P. and
S.R.D. gratefully acknowledge the receipt of their Senior
Research Fellowships of the CSIR, New Delhi. Authors
are thankful to Mr. Snehadri Narayan Khatua for X-ray crys-
tallographic analysis. We are also thankful to Dr. Samik
Nanda and Dr. Arup Maity for providing us with relevant
articles.

11792
D. Mal et al. / Tetrahedron 63 (2007) 11781–11792
Scheffler, J.-L.; Mortreux, A.; Carpentier, J.-F. Tetrahedron
Supplementary data
Lett. 2001, 42, 1899–1901; (h) Kitayama, T. Tetrahedron:
Asymmetry 1997, 8, 3765–3774; (i) Kobayashi, K.; Itoh, M.;
Sasaki, A.; Suginome, H. Tetrahedron 1991, 47, 5437–5452;
(j) Kawasaki, T.; Saito, S.; Yamamoto, Y. J. Org. Chem.
2002, 67, 2653–2658; (k) Crimmin, M. R.; Barrett, A. G. M.;
Hill, M. S.; Procopiou, P. A. Org. Lett. 2007, 9, 331–333.
8. Singh, E.; Gupta, P. C. J. Indian Chem. Soc. 1973, 50, 676–679.
9. Carey, F. A.; Giuliano, R. M. J. Org. Chem. 1981, 46, 1366–1371.
10. (a) Nagarajan, K.; Shenoy, S. J. Indian J. Chem. 1992, 31B, 73–
87; (b) Simas, A. B. C.; Coelho, A.; Costa, P. R. R. Synthesis
1999, 1017–1021.
11. Kotnis, A. S. Tetrahedron Lett. 1990, 31, 481–484.
12. Kosower, E. M.; Wu, G. S. J. Org. Chem. 1963, 28, 633–638.
13. Oliver, J. E.; Wilzer, K. R.; Waters, R. M. Synthesis 1990,
1117–1119.
14. (a) Soriano, D. S.; Lombardi, A. M.; Persichini, P. J.;
Nalewajek, D. J. Chem. Educ. 1988, 65, 637; (b) Hauser,
F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180.
15. (a) Chenard, B. L.; Dolson, M. G.; Sercel, A. D.; Swenton, J. S.
J. Org. Chem. 1984, 49, 318–325; (b) Hauser, F. M.;
Ellenberger, S. R. Synthesis 1987, 723–724.
16. (a) Gupta, M.; Paul, S.; Gupta, R.; Loupy, A. Tetrahedron Lett.
2005, 46, 4957–4960; (b) Rahaman, H.; Mahmood, T.;
Hossein, V. Synlett 2005, 2769–2770; (c) Syper, L.
Tetrahedron Lett. 1966, 37, 4493–4498; (d) Laundon, B.;
Morrison, G. A.; Brooks, J. S. J. Chem. Soc. D 1971, 36–40;
(e) Adams, C. P.; Fairway, S. M.; Hardy, C. J.; Hibbs, D. E.;
Hursthouse, M. B.; Morley, A. D.; Sharp, B. W.; Vicker, N.;
Warner, I. J. Chem. Soc., Perkin Trans. 1 1995, 2355–2362.
17. (a) Smith, A. B.; Richmond, R. E. J. Am. Chem. Soc. 1983, 105,
575–585; (b) Srivastava, V.; Darokar, M. P.; Fatima, A.; Kumar,
J. K.; Chowdhury, C.; Saxena, H. O.; Dwivedi, G. R.;
Shrivastava, K.; Gupta, V.; Chattopadhyay, S. K.; Luqman,
S.; Gupta, M. M.; Negi, A. S.; Khanuja, S. P. S. Bioorg. Med.
Chem. 2007, 15, 518–525.
18. (a) Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem.
1985, 50, 805–810; (b) Trost, B. M.; Rivers, G. T.; Gold, J. M.
J. Org. Chem. 1980, 45, 1835–1838.
19. (a) Marmor, R. S. J. Org. Chem. 1972, 37, 2901–2904; (b)
Nouguier, R.; Bertrand, M. P.; Picon, P.; Perfetti, P.
Tetrahedron Lett. 1995, 35, 8171–8172.
Crystallographic data of compound 31. Supplementary data
associated with this article can be found in the online ver-
sion, at doi:10.1016/j.tet.2007.08.048.
References and notes
1. Lin, G.; Chan, S. S.-K.; Chung, H.-S.; Li, S.-L. Chemistry and
Biological Action of Natural Occurring Phthalides; Atta-ur-
Rahman, Ed.; Studies in Natural Products Chemistry;
Elsevier: Amsterdam, 2005; Vol. 32, pp 611–669.
2. (a) Yoganathan, K.; Rossant, C.; Ng, S.; Huang, Y.; Butler,
M. S.; Buss, A. D. J. Nat. Prod. 2003, 66, 1116–1117; (b)
Shode, F. O.; Mahomed, A. S.; Rogers, C. B. Phytochemistry
2002, 61, 955–957; (c) Inouye, H.; Okuda, T.; Hirata, Y.;
Nagakura, N.; Yoshizaki, M. Chem. Pharm. Bull. Jpn. 1967,
15, 786–792; (d) Palermo, J. A.; Brasco, M. V. R.;
Spagnuolo, C.; Seldes, A. M. J. Org. Chem. 2000, 65, 4482–
4486; (e) Arnone, A.; Assante, G.; Nasini, G.; De Pava, O. V.
Phytochemistry 1990, 29, 613–616; (f) Fuska, J.; Uhrin, D.;
Proksa, B.; Voticky, Z.; Ruppeldt, J. J. Antibiot. 1986, 39,
1605–1608; (g) Puder, C.; Zeeck, A.; Beil, W. J. Antibiot.
2000, 53, 329–336; (h) Blasko, G.; Gula, D. J.; Shamma, M.
J. Nat. Prod. 1982, 45, 105–122; (i) Strobel, G.; Ford, E.;
Worapong, J.; Harper, J. K.; Arif, A. M.; Grant, D. M.; Fung,
P. C. W.; Chau, R. M. W. Phytochemistry 2002, 60, 179–183;
(j) Arnone, A.; Assante, G.; Nasini, G.; Strada, S.; Vercesi,
A. J. Nat. Prod. 2002, 65, 48–50.
3. (a) Brady, S. F.; Wagenaar, M. M.; Sing, M. P.; Janso, J. E.;
Clardy, J. Org. Lett. 2000, 2, 4043–4046; (b) Yang, Y.; Chen, Y.
Yaoxue Tongbao 1984, 19, 670–671.
4. (a) Mal, D.; Pahari, P. Chem. Rev. 2007, 107, 1892–1918; (b)
Len, C.; Renoux, B. Targets in Heterocyclic Systems:
Chemistry and Properties; Attanasi, O. A., Spinalli, D., Eds.;
Italian Society of Chemistry: Rome, 2005; Vol. 9, pp 311–326.
5. Kulanthaivel, P.; Hallock, Y. F.; Boros, C.; Hamilton, S. F.;
Janzen, W. P.; Ballas, L. M.; Loomis, C. R.; Jiang, J. B.
J. Am. Chem. Soc. 1993, 115, 6452–6453.
6. Pahari, P.; Senapati, B.; Mal, D. Tetrahedron Lett. 2004, 45,
5109–5112.
20. Jongen, R.; Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin
Trans. 1 1979, 2588–2592.
21. Taub, D.; Girotra, N. N.; Hoffsommer, R. D.; Kuo, C. H.;
Slates, H. L.; Weber, S.; Wendler, W. L. Tetrahedron 1968,
24, 2443–2461.
22. Lee, D. Y.; Cho, C. S.; Jiang, L. H.; Wu, X.; Shim, S. C.; Oh,
D. H. Synth. Commun. 1997, 27, 3449–3455.
23. Donati, C.; Prager, R. H.; Weber, B. Aust. J. Chem. 1989, 42,
787–795.
7. (a) Bistrzycki, A.; Oehlert, G. J. Ber. 1894, 27, 2632–2640; (b)
Al-Hamdany, R.; Al-Rawi, J. M.; Ibrahim, S. J. Prakt. Chem.
1987, 329, 126–130; (c) Hung, T. V.; Mooney, B. A.; Prager,
R. H.; Ward, A. D. Aust. J. Chem. 1981, 34, 151–162; (d)
Hayat, S.; Rahaman, A.-U.; Choudhary, M. I.; Khan, K. M.;
Bayer, E. Tetrahedron Lett. 2001, 42, 1647–1649; (e)
Pedrosa, R.; Sayalero, S.; Vicente, M. Tetrahedron 2006, 62,
10400–10407; (f) Knepper, K.; Ziegert, R. E.; Brase, S.
Tetrahedron 2004, 60, 8591–8603; (g) Everaere, K.;