Total synthesis of chlorocyclinone A, a PPAR-γ antagonist

Article abstract of DOI:10.1021/jo301712b

The first total synthesis of chlorocyclinone A (1) is regioselectively completed in 28 steps. The key steps are Pd-catalyzed methoxycarbonylation, unprecedented Hauser annulation, Krohn photo-oxidation, and regioselective gem-dichlorination.

Full text of DOI:10.1021/jo301712b

Article
pubs.acs.org/joc
Total Synthesis of Chlorocyclinone A, a PPAR‑γ Antagonist
Raju Karmakar and Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
S
* Supporting Information
ABSTRACT: The first total synthesis of chlorocyclinone A
(1) is regioselectively completed in 28 steps. The key steps are
Pd-catalyzed methoxycarbonylation, unprecedented Hauser
annulation, Krohn photo-oxidation, and regioselective gem-
dichlorination.
Yet, an annulation study on the model angular phthalide 10 was
initially conducted. Synthesis of the phthalide 10 was developed
in nine steps (Scheme 2), starting from commercially available
6-hydroxytetralin (11) via carboxylation and ortho-lithiation
followed by phenylsulfanylation. Following the literature
procedure,8 6-hydroxytetralin-7-carboxylic acid (12)8 was
INTRODUCTION
■
The angucycline family of antibiotics, characterized as benz-
[a]anthraquinone derivatives, has been the subject of growing
interest due to the wide range of their structures and biological
activities.1 In 2007, four new chlorinated members, namely
chlorocyclinones A−D (1−4, Figure 1), were isolated from a
broth culture of Streptomyces sp. (DSM 17045) by Potterat and
co-workers and their structures were elucidated by spectro-
scopic methods.2 Seven different substituents/functionalities
including chlorine at C2, similar to that of the antitumor
antibiotic BE-45985A1 (5),3 have featured this unique group of
angucyclines. Each of the chlorocyclinones (1−4), the first
PPAR-γ antagonists of natural origin, has been reported to
antagonize rosiglitazone-induced PPAR-γ activity with IC50
values between 0.60 and 7.0 μM, thus implying therapeutic
potential in antidiabetic therapies, especially for the treatment
of type II diabetes. The combination of the structural novelty
and the unique PPAR-γ activity of the molecules prompted us
to undertake their total synthesis. Although the synthesis of
angucyclines, in general, is an active area of research,4 that of
chlorocyclinones has not so far been reported.5
The primary challenge of the synthesis of such molecules is
regioselective assembly of the peripheral substituents/function-
alities with concomitant fabrication of the skeletal features. In
continuation of our work on the application of Hauser
annulation6 toward the total synthesis7a,b of angucycline natural
products, we undertook the project of the total synthesis of
chlorocyclinone A−D (1−4). The major impetus for choosing
the annulation was its regiochemical integrity and high
chemoselectivity. Since the structural attributes of A, B, and
C rings are identical for all the members 1−4, we proposed
Hauser donor 6 (Scheme 1) as the common intermediate for
the synthesis of chlorocyclinone A (1). It can be annulated with
cyclohexenone carboxylate 7 to furnish tetracyclic angular
quinol 8, which, in turn, can be aromatized to the advanced
intermediate 9 having all requisite functionalities.
1
prepared in two steps from 11. The H and 13C NMR data
of 12 are in good agreement with the reported values. The
resulting hydroxy acid 12 was then converted into correspond-
ing amide 139 in 72% yield (over three steps). The sequence
consisted of (i) Me2SO4, K2CO3 mediated esterification to
furnish 14,10 (ii) ester hydrolysis to give acid 15,8 and (iii)
amidation of the resulting acid 15 by treatment with oxalyl
chloride followed by diethylamine. Directed ortho-metalation11
of the amide 13 with t-BuLi, TMEDA, and DMF provided
aldehyde 16 (55%). This was then converted into angular
phthalaldehydic acid 17 in 85% yield by acid catalyzed
hydrolysis. Treatment of 17 with thiophenol and a catalytic
amount of p-TSA in refluxing benzene gave angular phthalide
18. Regioselective benzylic oxidation12 of 18 with K2S2O8−
CuSO4·5H2O in CH3CN−H2O produced the desired 3-
substituted angular phthalide 10 in 78% yield.
An attempted Hauser annulation of the phthalide 10 with 2-
cyclohexenone in the presence of t-BuOLi, t-BuOK, or LDA at
−78 °C resulted in recovery of the starting phthalide (Scheme
3). The desired Hauser product (cf. 8) was not formed.
However, angular phthalide 18 underwent reaction with 2-
cyclohexenone under the above conditions to yield conjugate
addition product 19a in good yield (67%). Unfortunately its
transformation to the desired annulation product 20a under
treatment with t-BuOLi−THF, NaOEt−EtOH, or t-BuOK/
Na2S2O4−THF at −78 °C (Scheme 3) could not be effected.
Similarly, annulation of methyl acrylate with phthalide 18 in the
presence of t-BuOLi−THF at −78 °C, as a test case, also
produced corresponding 1,4-addition product 21 (82%, Figure
2), while that of phthalide 18 with 22 (Figure 2) yielded an
intractable mixture of products.
RESULTS AND DISCUSSION
■
Although the Hauser chemistry of such angular phthalides (e.g.,
6) is unprecedented, the earlier studies with linear phthalides
suggested the sure success of the outlined scheme (Scheme 1).
Received: September 4, 2012
Published: October 18, 2012
© 2012 American Chemical Society
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Figure 1. Structures of A-ring chlorinated angucyclinones.
Scheme 1. First Approach: Hauser Reactivity of Angular Phthalides
a
Scheme 2. Synthesis of Angular Phthalides 10 and 18
a
Reagents and conditions: (a) Me2SO4, K2CO3, acetone, reflux, 3 h, 90%; (b) 5% aq KOH solution, reflux, 0.5 h, 82%; (c) (i) oxalyl chloride, DMF
(cat.), dry C6H6, 65 °C, 2 h and (ii) Et2NH, dry THF, 0 °C−rt, 15 min, 98%; (d) t-BuLi, TMEDA, DMF, dry THF, N2 atm, −78 °C−rt, overnight,
59%; (e) glacial AcOH, aq HCl, reflux, 10 h, 85%; (f) PhSH, p-TSA (cat.), dry C6H6, reflux, 10 h, 70%; (g) K2S2O8, CuSO4·5H2O, CH3CN−H2O
(1:1), reflux, 20 min, 78%.
a
Scheme 3. Results on the Hauser Chemistry of Angular Phthalides
a
Reagents and conditions: (a) t-BuOLi, t-BuOK or LDA or LiHMDS, 2-cyclohexenone, THF, −78−60 °C. (b) t-BuOLi, THF or NaOEt, EtOH, etc.
The unanticipated failed annulations prompted us to
examine the reactivity of a few modified angular phthalides,
e.g. 23−25 (Scheme 4), toward Hauser annulation. Oxidation
of 18 with m-CPBA in CH2Cl2 furnished corresponding sulfone
phthalide 23 in 91% yield. DDQ mediated dehydrogenation of
18 produced aromatized phthalide 24 in moderate yield (55%).
For the synthesis of cyanophthalide 25, compound 17 was
treated with KCN and conc. HCl followed by Vilsmeier’s salt or
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CO, dry MeOH, dppf, Et3N, and Pd(OAc)2 catalyst in DMF at
90−120 °C afforded compound 34 in 48% yield (Scheme 6).
Before undertaking the synthesis of required phthalide 27 from
diester 34, its bromination at C3 was attempted using Br2−
AcOH, with the idea that a late stage coupling reaction through
Stille, Suzuki, and Negishi cross-coupling would introduce vinyl
or ethyl side chains at C9 of the targets. But, unfortunately, the
undesired bromoterephthalate 35 was obtained. The site of the
bromine atom at C2 was established by NOESY experiment.21
The terephthalate 34 was converted into cyanoisobenzofur-
anone 27 in four steps: benzylic bromination followed by
thermal cyclization,22 selective lateral bromination, hydrolysis,
and hydrocyanation via lactone 36 and 3-bromoisobenzofur-
anone 37, with an overall yield of 34%. During hydrolysis of 37,
the temperature of H2O was maintained at 80−85 °C to obtain
38 solely or to obviate C5 ester hydrolyzed product 39, as
indicated in the 1H NMR spectrum. The AB ring synthon 287b
was obtained in five known steps. Annulation of phthalide 27
with acceptor 28 in the presence of LDA gave a very low yield
of 40 along with the starting materials. But, in the presence of t-
BuOLi at −78 °C, the benzanthraquinone 40 was obtained in
71% yield. Krohn photo-oxidation23 of 40 under sunlight
provided keto derivative 41 in quantitative yield. After several
experimentations, monochlorination24 of 41 at C2 could be
achieved using N-chlorosuccinimide and a catalytic amount of
thiourea in MeOH−CHCl3, yielding 42 as a mixture of
diastereomers in 65% yield. Aromatization of the 2-chlorote-
tracyclic compound 42 by the Saegusa method25 and DDQ25
mediated oxidation posed serious problems. Consequently, the
ortho-chloro phenolic A-ring motif was thought to be fabricated
by gem-α-dichlorination of 43, followed by aromatization via
dehydrochlorination. The inverse sequence, i.e., aromatization
of 43 followed by chlorination at C2, was avoided due to the
anticipated problems in selectivities.26 After brief experimenta-
tions, O-methyl ether 43 was gem-α-dichlorinated by the
application of the Prugh method27 using SO2Cl2 and dry HCl
gas to form 44 in 85% yield. Dehydrohalogenation28 of 44 with
NaOMe in refluxing methanol gave A-ring aromatized product
45 in 94% yield, the C1-OH and C10-CO2H protection of
which yielded compound 46 in 81% yield. Hydrolysis of the
ester group of 46 with LiOH (19 equiv) furnished 2-
chlorotetracyclic intermediate 29 in 89% yield with A−C ring
substituents in desired positions. Although the proposed
Hauser annulation, i.e. 27→40, was successful this time
(Scheme 6), the projected directed ortho-metalation and Yu
cyclization of 29 at the C9 position failed.29 In analogy with
Mortier’s work,14 several attempts were made to install an ethyl
Figure 2. Michael acceptors and 1,4-addition product.
NaCN−AcOH, but to no avail. After several experimentations,
the desired 3-cyanophthalide 25 was obtained in 95% yield by
treatment of formamide 16 with trimethylsilyl cyanide in the
presence of a catalytic amount of potassium cyanide and 18-
crown-6.13
Once again, to our dismay, angular phthalides 23 and 24
failed to produce annulation products, when subjected to a
reaction with 2-cyclohexenone under varied reaction conditions
(t-BuOLi, LDA or LiHMDS in THF at −78−60 °C). In both
cases, the corresponding 1,4-addition products, i.e. 19b (5%)
and 19d (80%), were respectively obtained (Scheme 3). When
3-cyanophthalide 25 was treated with 2-cyclohexenone in the
presence of t-BuOLi, KtOBu or LDA in dry THF at −78 °C or
t-BuOK-DMSO at rt, a complex mixture of products was
obtained. The presence of the corresponding 1,4-addition
product 19c was indicated from analysis of the H NMR
spectrum of the crude reaction mixture.
Anticipating that 2-cyclohexenone might undergo base-
catalyzed polymerization, we investigated a base-stable Michael
acceptor, i.e., 26 (Figure 2). Its reaction with cyanophthalide 25
in the presence of t-BuOLi in dry THF at −78 °C again
furnished an intractable mixture of products.
1
The exceptional failures of the Hauser annulation of angular
phthalides 10, 23, 24, and 25 compelled us to formulate the
sequence (Scheme 5) involving annulation of phthalide 27 with
napthalenone 287b and the directed ortho-metalation14 or Yu
lactonization15 of the tetracyclic carboxylic acid 29. The
structure 29 was envisaged as the common intermediate on
account of the fact that the structural diversity of the target
chlorocyclinones (1−4) emanates from C9.
The intermediate 29 was synthesized in 22 steps from
commercially available chemicals (Scheme 6). Base catalyzed
condensation of methyl acetoacetate with methyl crotonate
17
produced compound 30.16 Hg(OAc)2 mediated aromatiza-
tion and Tf2O-lutidine18 promoted selective triflation afforded
known compounds 3119 (73%) and 3220 (87%) respectively.
O-Methylation of 32 with MeI−K2CO3 furnished toluate 33 in
excellent yield. Methoxycarbonylation20 of the triflate 33 with
Scheme 4. Synthesis of Angular Phthalide Derivatives
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Scheme 5. Second Approach: Annulation of Linear Phthalide Combined with Directed ortho-Metalation or Yu Lactonization
a
Scheme 6. Synthesis of Tetracyclic Chlorocyclinone 29
a
Reagents and conditions: (a) Hg(OAc)2, NaOAc, AcOH, reflux, 2 h, 82%; (b) Tf2O, 2,6-lutidine, CH2Cl2, 0 °C−rt, N2 atm, 18 h, 70%; (c) MeI,
K2CO3, acetone, 0 °C−rt, 96%; (d) CO, MeOH, Et3N, dppf, Pd(OAc)2, DMF, 90−120 °C, 48%; (e) Br2−AcOH, rt, 70%; (f) (i) NBS, AIBN, CCl4,
hν, reflux and (ii) 150−160 °C, 30 min, 69% (2 steps); (g) NBS, AIBN, CCl4−C6H6, hν, reflux, 70%; (h) H2O, 80 °C, 90%; (i) KCN, conc. HCl, 0
°C−rt, 71%; (j) 28, t-BuOLi, THF, N2 atm, −78 °C−rt; 71%; (k) CHCl3, sunlight, 5−6 h, quantitative yield; (l) MeI, K2CO3, acetone, 0 °C−rt,
87%; (m) NCS, thiourea (cat.), MeOH−CHCl3, rt, 65%; (n) SO2Cl2, dry HCl, CHCl3, rt, 85%; (o) NaOMe, MeOH, reflux, 94%; (p) MeI, K2CO3,
acetone, 0 °C−rt, 81%; (q) LiOH, THF−H2O (5:1), rt, 4 h, 89%. dppf: 1,1-diphenylphosphinoferrocene; LTMP: Lithium tetramethylpiperidide;
TMP: 2,2,6,6-tetramethylpiperidine; TMEDA: tetramethylethylenediamine; NCS: N-chlorosuccinimide.
group at C9 of tetracyclic acid 29. Lithiation with LTMP (n-
BuLi + TMP) followed by treatment with EtI in THF at −30 to
60 °C failed to give the desired product. The model reaction of
4-methoxy-9,10-anthraquinone-2-carboxylic acid amide with t-
BuLi, TMEDA, and EtI at −78 °C in THF returned only the
starting material. Nevertheless, Scheme 6 paved the way for the
standardization of A-ring chemistry, especially the introduction
of C1 methoxy and C2 chlorine.
acylation30 of 4831 in the presence of TiCl4 to provide heavily
substituted benzene derivative 49 in 75% yield (Scheme 7). To
achieve selectivity in bromination, compound 49 was converted
into its acetate 50. NBS bromination of 50 followed by
thermolysis22 followed by deacetylation of 51 provided
compound 52 (52% over two steps). The sequence involving
(i) reduction32 of the acyl carbonyl in 52 with trifluoroacetic
acid and triethylsilane, (ii) BBr3-mediated demethylation of
53,33 and (iii) selective protection20 leading to activation of
phenolic OH group of 54 using N-phenyltriflimide and Cs2CO3
at 10−15 °C, followed by O-methylation of ensuing triflate 55,
In the revised approach, annulation of isobenzofuranone 47
was investigated, which differs from 27 with respect to an ethyl
substituent at C6. Its synthesis began with Friedel−Crafts
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a
Scheme 7. Synthesis of Isobenzofuranone 47
a
Reagents and conditions: (a) TiCl4, CH3COCl, CH2Cl2, 0 °C−rt, 75%; (b) CH3COCl, Et3N, CH2Cl2, 0 °C−rt, 96%; (c) (i) NBS, (PhCO)2O2,
CCl4, hν, reflux and (ii) 150−160 °C, 63% (2 steps); (d) MeOH, K2CO3, 0 °C−rt, 83%; (e) TFA, Et3SiH, rt, 87%; (f) BBr3, CH2Cl2, 0 °C−rt, 86%;
(g) PhNTf2, Cs2CO3, acetone, 0−15 °C, 66%; (h) MeI, K2CO3, acetone, 0 °C−rt, 100%; (i) CO, Pd(OAc)2, dppf, MeOH, Et3N, DMF, 90−120 °C,
50%; (j) NBS, AIBN, CCl4, hν, reflux, 58%; (k) H2O, 80 °C, 95%; (l) PhSH, Et3N, CH2Cl2, rt, 6 h, 74%; (m) (i) KCN, conc. HCl, 0 °C−rt and (ii)
p-TSA (cat.), CHCl3, rt, 71%. TFA: trifluoroacetic acid; AIBN: azobisisobutylonitrile.
a
Scheme 8. Successful Synthesis of Chlorocyclinone A (1)
a
Reagents and conditions: (a) CHCl3, sunlight, quantitative; (b) MeI, K2CO3, acetone, 0 °C−rt, 88%; (c) SO2Cl2, dry HCl gas, CHCl3, rt, 94%; (d)
MeI, K2CO3, acetone, 0 °C−rt, 65%.
produced compound 56 (49% over four steps). During
selective O-triflation, the low temperature was crucial to
avoiding ditriflation34 of 54 and thus low overall yield. Pd-
catalyzed methoxycarbonylation20 of the triflate 56 with carbon
monoxide afforded ester 57 (50%) along with 6-ethyl-7-
methoxy-3H-isobenzofuran-1-one (58) as a side product
(10%). The structure of 57 was confirmed by an X-ray
crystallographic analysis.21 NBS mediated bromination of
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a
Table 1. Key NOESY Interaction of 67 and HMBC Correlations of 69
a
1
s: strong H−13C HMBC interaction.
phthalide 57 in refluxing CCl4 under light (100 W) selectively
produced 59 in 58% yield as the sole product. The resulting 3-
bromophthalide 59 was carefully heated in water at 80 °C (to
avoid C5 ester hydrolysis) to obtain acid 60 in 95% yield.
Compound 59, when treated with thiophenol and Et3N,
furnished corresponding 3-SPh phthalide 61 in 74% yield.
Treatment of the compound 60 with KCN in an acidic medium
at 0 °C resulted in the corresponding cyanohydrin 62, which
underwent lactonization to the desired cyanophthalide 47 in
71% yield, upon standing overnight at rt in chloroform solvent
containing a catalytic amount of p-TSA.
Next, we explored the competition between the Hauser
annulation and Staunton−Weinreb annulation35 of isobenzo-
furanone 47 under the influence of a base weaker than LDA,
which is known to effect both of the annulations. When
cyanophthalide 47 and napthalenone 28 were submitted to
annulation (Scheme 8) in the presence of t-BuOLi at −78 °C,
tetracycle 63 was formed as the sole product (85%). There was
no sign of a Staunton−Weinreb product, i.e., a Michael−
Claisen product arising from lithiation of the ethyl chain of 47.
It should be noted that sulfanylphthalide 61 failed to provide
annulation product 63, when treated with napthalenone 28
under similar conditons. Then intermediate 64 was regiose-
lectively prepared in five steps from 63 (Scheme 8). As earlier,
compound 63 was selectively oxidized to keto compound 65 in
quantitative yield under Krohn conditions.23 In a similar
manner as described for 41→46, compound 65 was converted
to 64 via 66−68, the chlorocyclinone A methyl diether, having
all the groups in desired positions, with an overall yield of 51%
(four steps).
furnish the trihydroxy compound 70 in 64% yield, which was
strikingly unstable, apparently due to its susceptibility toward
oxidation. The resulting crude compound 70 was immediately
subjected to methylation using MeI−K2CO3 in acetone and the
chlorocyclinone A (1) was obtained in 39% yield. The spectral
data of the synthetic 1 are in good agreement with the reported
values.2
CONCLUSIONS
■
In conclusion, the first total synthesis of chlorocyclinone A (1)
has been achieved in 28 steps from commercially available
starting materials. This study also has resulted in two methyl
ethers, namely, 64 and 69. Although selective demethylation of
64 remains a factual challenge, selective methylation of the
phenolic OH group is found to be more convenient than
selective O-demethylation.
EXPERIMENTAL SECTION
■
General. All reactions utilizing moisture-sensitive reagents were
performed under an inert atmosphere. Solvents DMF, CH2Cl2, THF,
MeOH, etc. were dried prior to use, according to the standard
protocols. Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm silica gel plates (60-F254). All solvents
for chromatography were distilled prior to use. The products were
purified by column chromatography on silica gel. Columns were
prepared with silica gel (60−120 or 230−400 mesh). NMR spectra
were recorded with a 400 MHz (1H: 400 MHz, 13C: 100 MHz) and
200 MHz (1H: 200 MHz, 13C: 50 MHz) spectrometer and referenced
to the signal of CHCl3 at 7.26 ppm (1H) and 77.16 ppm (13C) for
CDCl3. Another solvent used for recording NMR data was d6-DMSO.
Splitting patterns are indicated as follows: br, broad; s, singlet; d,
doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet. Infrared
spectra were recorded with FT-IR spectrophotometers and reported as
wavenumbers (cm−1). Melting points are uncorrected. High-resolution
mass spectra were recorded with a mass spectrometer in positive ion
mode. The phrase “usual workup” refers to washing of the organic
phase with water (2 × 1/4 the volume of organic phase) and brine (1
× 1/4 the volume of organic phase) and drying (Na2SO4), filtration,
and concentration under reduced pressure. Solvents used for the
column chromatography are ethyl acetate and petroleum ether. Due to
partial decomposition under thermal conditions, HRMS data of
compounds 37, 59, 62, and 70 could not satisfactorily be recorded. All
The site of the chlorine atoms in 67 was ascertained by NOE
studies.21 The cross peaks due to NOE interaction between H4
and H5 confirm the location of two chlorine atoms at the C2
21
1
position and not at C4 (Table 1). The H−13C HMBC
studies of 68 again support its structural arrangement. Finally,
we attempted the selective demethylation of the C6 and C8
OMe group of 64 to complete the total synthesis. AlCl3, a well-
known reagent for selective demethylations,36 was employed to
meet this purpose. But, to our dismay, the reaction resulted in a
complex mixture of products. BBr3-mediated demethylation at
−78 °C was unsuccessful. Treatment of 64 or 68 with BCl3 in
CH2Cl2 at −78 °C produced a compound with two H-bonded
phenolic OH groups (δ 12.72 and 10.80 respectively) in
excellent yield (90%), which is confirmed as 69 by analysis of
HMBC21 and HSQC spectral data (Table 1). With selective
demethylation being abortive at the final step, selective
methylation was perceived to be applied. For the preparation
of the required trihydroxy compound 70, compound 69 was
treated with a large excess of AlCl3 (40 equiv) in CH2Cl2 to
1
the known compounds were characterized by matching with the H
NMR data reported in the literature.
N,N-Diethyl-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-
carboxamide (13).9 To a stirred solution of 15 (2.4 g, 0.011 mol) in
dry benzene (80 mL) were added oxalyl chloride (5.08 mL, 0.058
mol) and a catalytic amount of DMF (0.24 mL), and the reaction
mixture was heated at 65 °C under a N2 atmosphere for 2 h. Benzene
was removed under reduced pressure and dried, and then the crude
residue was dissolved in dry THF (80 mL). To the resultant mixture
Et2NH (3.65 mL, 0.035 mol) was added dropwise at 0 °C in a N2
atmosphere and stirred for 15 min at the same temperature. Solvent
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was evaporated under reduced pressure, and the residue was diluted
with water (30 mL) and dichlomethane (100 mL). The layers were
separated, and the aqueous part was extracted with CH2Cl2 (3 × 100
mL). The combined layers were worked up in the usual manner. The
crude residue was purified by column chromatography (50% ethyl
acetate−petroleum ether) on silica gel to afford compound 13 (2.97 g,
98%) as a yellowish solid. Rf = 0.3 (30% ethyl acetate−petroleum
(CH2); HRMS (EI+) m/z calcd for C19H18O3S [M+]: 326.0977, found
326.0973.
4-Methoxy-1-phenylsulfanyl-7,8-dihydro-1H,6H-naphtho-
[1,2-c]furan-3,9-dione (10). To a stirred solution of 18 (100 mg,
0.307 mmol) in 1:1 CH3CN−H2O (15 mL) was added K2S2O8 (248
mg, 0.92 mmol) and CuSO4·5H2O (77 mg, 0.307 mmol) at rt, and the
mixture was allowed to reflux for 20 min. Solvents were then
evaporated under reduced pressure, and the crude residue was diluted
with water (10 mL) and extracted with ethyl acetate (3 × 40 mL). The
combined ethyl acetate part was then subjected to the usual workup.
The crude solid on chromatographic purification (80% ethyl acetate−
petroleum ether) yielded 10 as a white solid (78%). Rf = 0.2 (50%
ethyl acetate−petroleum ether); mp 129−130 °C; 1H NMR (200
MHz, CDCl3): δ 7.46 (dd, 2H, J = 1.8 Hz, 7.6 Hz), 7.27 − 7.22 (m,
3H), 7.04 (s, 1H), 6.72 (s, 1H), 3.95 (s, 3H), 3.07−2.98 (m, 2H),
2.84−2.52 (m, 2H), 2.24−2.10 (m, 2H); 13C NMR (50 MHz,
CDCl3): δ 195.4, 166.1, 160.5, 154.9, 151.7, 135.0 (CH), 133.6, 130.3,
129.1 (CH), 128.9 (CH), 120.8, 111.6 (CH), 86.9 (CH), 56.5
(OCH3), 39.3 (CH2), 31.0 (CH2), 22.7 (CH2); HRMS (EI+) m/z
calcd for C19H16O4S [M+]: 340.0769, found 340.0772.
4-Methoxy-1-(3-oxo-cyclohexyl)-1-phenylsulfanyl-6,7,8,9-
tetrahydro-1H-naphtho[1,2-c]furan-3-one (19a). To a stirred
suspension of t-BuOLi (52 mg, 0.644 mmol) in dry THF (5 mL) was
added a solution of phthalide 18 (70 mg, 0.214 mmol) in THF (3 mL)
at −78 °C under an inert atmosphere. The resulting light yellow
colored solution was stirred at −78 °C for 30 min. Then a solution of
acceptor 2-cycloxhexenone (0.03 mL, 0.322 mmol) in THF (2 mL)
was added dropwise into it. The same temperature was maintained for
another 1 h. The cooling bath was removed, and the reaction mixture
was allowed to stir at rt overnight. It was then quenched with a
saturated aq. NH4Cl solution (2 mL). The resulting solution was
concentrated under reduced pressure, and the residue was diluted with
water (4 mL) and extracted with ethyl acetate (3 × 15 mL). The
combined extracts were then subjected to the usual workup. Column
chromatography of the crude product using 50% ethyl acetate−
petroleum ether as the eluant gave 19a as a yellowish solid (60 mg,
67%). mp 124−126 °C; 1H NMR (200 MHz, CDCl3): δ (7:3 mixture
of diastereomers) 7.23−7.00 (m), 6.44 (s), 6.42 (s), 3.74 (s), 3.72 (s),
3.65−3.43 (m), 3.13−3.01 (m), 2.95−2.72 (m), 2.65−2.17 (m), 2.16−
1.90 (m), 1.89−1.67 (m); 13C NMR (100 MHz, CDCl3): δ 210.2,
210.0, 166.7, 166.5, 155.4, 148.6, 148.0, 147.4, 147.3, 136.7 (Ar−CH),
136.6 (Ar−CH), 129.7 (Ar−CH), 128.5 (Ar−CH), 128.4 (Ar−CH),
128.0, 127.8, 123.7, 123.6, 112.4 (Ar−CH), 112.3 (Ar−CH), 112.0,
111.8, 98.0, 97.9, 55.8 (OCH3), 44.1, 44.0, 43.2 (CH2), 42.6 (CH2),
41.1 (CH2), 41.0 (CH2), 30.9 (CH2), 30.8 (CH2), 26.5 (CH2), 25.9
(CH2), 24.8 (CH2), 24.7 (CH2), 24.5 (CH2), 22.7 (CH2), 22.6 (CH2),
22.4 (CH2), 22.3 (CH2); IR (KBr, cm−1) νmax 1773, 1705, 1654, 1617,
1492, 1300, 1042, 752, 693; HRMS (EI+) m/z calcd for C25H26O4S
[M+]: 422.1552, found 422.1554.
1
ether); mp 58−60 °C; H NMR (200 MHz, CDCl3): δ 6.84 (s, 1H),
6.54 (s, 1H), 3.73 (s, 3H), 3.52 (q, 2H, J = 7.2 Hz), 3.15 (q, 2H, J =
7.2 Hz), 2.73−2.63 (m, 4H), 1.76−1.70 (m, 4H), 1.20 (t, 3H, J = 7.1
Hz), 1.01 (t, 3H, J = 7.1 Hz); 13C NMR (50 MHz, CDCl3): δ 169.3,
152.9, 138.8, 129.3, 127.9 (CH), 124.4, 111.3 (CH), 55.6 (OCH3),
42.9 (CH2), 38.8 (CH2), 29.8 (CH2), 28.4 (CH2), 23.3 (CH2), 23.0
(CH2), 13.9, 12.9.
N,N-Diethyl-1-formyl-3-methoxy-5,6,7,8-tetrahydronaph-
thalene-2-carboxamide (16). To a stirred solution of 13 (2 g, 0.007
mol) in dry THF (80 mL) was added TMEDA (6.9 mL, 0.046 mol) at
rt, and then the reaction mixture was cooled to −78 °C. To the
reaction mixture, t-BuLi (1.7 M) (27 mL, 0.046 mol) was added
dropwise in an inert atmosphere with the same temperature
maintained for 45 min. To the cooled solution DMF (4.7 mL, 0.061
mol) was added dropwise and allowed to stir at rt for 12 h. The
reaction mixture was quenched with a few drops of water, THF was
evaporated, and the crude residue was diluted with water (60 mL) and
diethyl ether (150 mL). The layers were separated, and the aqueous
part was extracted with diethyl ether (3 × 150 mL). The combined
extracts were subjected to the usual workup. The crude residue was
purified by column chromatography (30% ethyl acetate−petroleum
ether) on silica gel to afford compound 16 (1.3 g, 59%) as a yellowish
solid. Rf = 0.2 (50% ethyl acetate−petroleum ether); mp 105−107 °C;
1H NMR (200 MHz, CDCl3): δ 10.23 (s, 1H), 6.83 (s, 1H), 3.80 (s,
3H), 3.71−3.45 (m, 2H), 3.18−3.05 (m, 4H), 2.89−2.71 (m, 2H),
1.83−1.75 (m, 4H), 1.27 (t, 3H, J = 7.1 Hz), 1.02 (t, 3H, J = 7.1 Hz);
13C NMR (50 MHz, CDCl3): δ 192.3, 167.5, 153.1, 140.3, 131.9,
131.3, 128.1, 117.2, 56.1, 43.0, 39.1, 30.7, 26.4, 23.1, 22.3, 13.7, 12.6;
HRMS (ES+) m/z calcd for C17H23NO3 [M + H]+: 290.1756, found
290.1741.
1-Hydroxy-4-methoxy-6,7,8,9-tetrahydro-1H-naphtho[1,2-
c]furan-3-one (17). To a stirred suspension of compound 16 (1.32 g,
0.004 mol) in glacial AcOH (20 mL) was added 10% aq HCl (22 mL),
and the resulting mixture was allowed to reflux for 10 h. Afterward, the
reaction mixture was diluted with water (30 mL) and extracted with
ethyl acetate (3 × 80 mL). The combined extracts were then subjected
to the usual workup. On evaporation of organic solvent followed by a
hexane wash, 17 was obtained as a white solid (860 mg, 85%). Rf = 0.2
1
(80% ethyl acetate−petroleum ether); mp 192−194 °C; H NMR
(400 MHz, CDCl3): δ δ 6.70 (s, 1H), 6.45 (s, 1H), 3.93 (s, 3H),
2.96−2.85 (m, 3H), 2.70−2.63 (m, 1H), 1.90−1.76 (m, 4H); 13C
NMR (50 MHz, CDCl3): δ 167.5, 155.5, 147.6, 146.8, 125.5, 113.4
(Ar−CH), 111.6, 96.0 (CH−OH), 55.9 (OCH3), 30.5 (CH2), 24.1
(CH2), 22.5 (CH2), 22.4 (CH2); IR (KBr, cm−1) νmax 1768, 1749,
1698, 1621, 1498, 1302, 1072, 1053, 949, 775. HRMS (ES+) m/z
calcd for C13H14O4 [M + H]+: 235.0970, found 235.0956.
Methyl-3-(4-methoxy-3-oxo-1-phenylsulfanyl-1,3,6,7,8,9-
hexahydronaphtho[1,2-c]furan-1-yl)-propionate (21). Com-
pound 21 was synthesized from 18 (40 mg, 0.123 mmol) and
methacrylate (0.014 mL, 0.147 mmol), following the protocol
described for the transformation 18→19a. Purification was done by
PLC using 50% ethyl acetate−petroleum ether to afford 21 as a
semisolid. Rf = 0.3 (50% ethyl acetate−petroleum ether); Yield = 41
4-Methoxy-1-phenylsulfanyl-6,7,8,9-tetrahydro-1H-
naphtho[1,2-c]furan-3-one (18). To a stirred solution of 17 (600
mg, 2.56 mmol) in dry benzene (50 mL), taken in a round-bottom
flask fitted with a Dean−Stark apparatus, was added p-TSA (cat.)
followed by PhSH (0.21 mL, 2.1 mmol), and the mixture was allowed
to reflux for 10 h. Benzene was removed under reduced pressure. The
crude residue was then diluted with water (30 mL) and extracted with
ethyl acetate (3 × 70 mL). The combined extract was then subjected
to the usual workup. Purification by column chromatography (30%
ethyl acetate−petroleum ether) yielded a white solid 18 (560 mg,
70%). Rf = 0.3 (50% ethyl acetate−petroleum ether); mp 161−163
1
mg (82%); H NMR (200 MHz, CDCl3): δ 7.26−7.05 (m, 5H), 6.48
(s, 1H), 3.75 (s, 3H), 3.56 (s, 3H), 3.56−3.36 (m, 1H), 2.85−2.75 (m,
2H), 2.70−2.52 (m, 2H), 2.44−2.28 (m, 1H), 2.17−1.15 (m, 6H); 13C
NMR (50 MHz, CDCl3): δ 172.6, 166.3, 155.4, 148.2, 147.4, 136.5
(CH), 129.7 (CH), 128.6 (CH), 128.2, 124.1, 112.7 (CH), 112.2, 94.7,
55.8 (OCH3), 51.8 (OCH3), 31.8 (CH2), 30.9 (CH2), 28.9 (CH2),
24.6 (CH2), 22.7 (CH2), 22.4 (CH2); HRMS (EI+) m/z calcd for
C23H24O5S [M + H]+: 413.1431, found 413.1420.
1
°C; H NMR (200 MHz, CDCl3): δ 7.54−7.48 (m, 2H), 7.31−7.26
1-Benzenesulfonyl-4-methoxy-6,7,8,9-tetrahydro-1H-
naphtho[1,2-c]furan-3-one (23). To a stirred solution of 18 (420
mg, 1.29 mmol) in dry CH2Cl2 (30 mL) was added m-CPBA (1.00 g,
5.79 mmol) at rt, and the reaction mixture was allowed to stir at the
same temperature for 4 h. CH2Cl2 was evaporated, and the crude
residue was diluted with water (30 mL) and extracted with ethyl
(m, 3H), 6.62 (s, 1H), 6.47 (s, 1H), 3.88 (s, 3H), 3.29−3.15 (m, 1H),
2.90−2.79 (m, 2H), 2.67−2.55 (m, 1H), 1.99−1.77 (m, 4H); 13C
NMR (100 MHz, CDCl3): δ 167.5, 155.8, 147.2, 146.5, 133.6 (Ar−
CH), 130.9, 129.0 (CH), 128.8 (CH), 124.4, 112.7 (CH), 111.5, 85.0
(CH−SPh), 55.9 (OCH3), 30.6 (CH2), 25.1 (CH2), 22.5 (CH2), 22.4
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acetate (3 × 60 mL). The combined ethyl acetate part was then
washed with an aqueous saturated NaHCO3 solution (2 × 10 mL),
followed by the usual workup which gave a solid compound, which
upon chromatographic purification (50% ethyl acetate−petroleum
ether) yielded compound 23 (420 mg, 91%) as a white solid. Rf = 0.2
Experimental procedure is similar to that described for the
transformation 55→56. Rf = 0.5 (15% ethyl acetate−petroleum
1
ether); mp 49−50 °C; H NMR (400 MHz, CDCl3): δ 6.73 (s, 1H),
6.66 (d, 1H, J = 1.6 Hz), 3.92 (s, 3H), 3.84 (s, 3H), 2.32 (s, 3H); 13C
NMR (CDCl3, 100 MHz): δ 167.3, 157.7, 150.3, 138.8, 123.8, 118.67
(q, J = 319 Hz), 114.7(CH), 102.4(CH), 56.2, 52.4, 19.3; HRMS (EI
+) m/z calcd for C11H11F3O6S [M]+: 328.0228, found 328.0225.
Dimethyl 2-Methoxy-6-methyl-terephthalate (34). It was
obtained from 33 as a yellowish solid. The experimental procedure
is similar to that described for the transformation 56→57. Rf = 0.2
1
(30% ethyl acetate−petroleum ether); mp 199−202 °C; H NMR
(400 MHz, CDCl3): δ 7.90 (d, 2H, J = 7.2 Hz), 7.68 (t, 1H, J = 7.6
Hz), 7.60−7.52 (m, 2H), 6.76 (s, 1H), 6.08 (s, 1H), 3.91 (s, 3H),
3.38−3.28 (m, 1H), 3.00−2.80 (m, 2H), 2.80−2.72 (m, 1H), 2.05−
1.74 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 165.8, 156.1, 148.4,
139.8, 134.7 (Ar-CH), 133.7, 129.7 (Ar−CH), 129.1 (Ar−CH), 128.2,
114.3 (Ar−CH), 111.5, 90.2 (CH2−SO2Ph), 56.0 (OCH3), 30.6
(CH2), 26.2 (CH2), 22.4 (CH2), 22.2 (CH2); IR (KBr, cm−1) νmax
1763, 1617, 1493, 1322, 1304, 1232, 1153, 1008, 726, 592, 541;
HRMS (ES+) m/z calcd for C19H18O5S [M+H]+: 359.0953, found
359.0931.
1
(15% ethyl acetate−petroleum ether); mp 84−86 °C; H NMR (200
MHz, CDCl3): δ 7.50 (d, 1H, J = 0.6 Hz), 7.41 (s, 1H), 3.93 (s, 3H),
3.92 (s, 3H), 3.87 (s, 3H), 2.31 (s, 3H); 13C NMR (CDCl3, 50 MHz):
δ 168.1, 166.5, 156.3, 136.6, 131.7, 127.8, 123.7 (Ar−CH), 109.2 (Ar−
CH), 56.0, 52.3, 52.4, 19.1; HRMS (EI+) m/z calcd for C12H14O5
[M]+: 238.0841, found 238.0840.
4-Methoxy-1-phenylsulfanyl-1H-naphtho[1,2-c]furan-3-one
(24). To a stirred solution of 18 (200 mg, 0.613 mmol) in dry benzene
(10 mL) was added DDQ (840 mg, 3.68 mmol) and refluxed for 7 d
(168 h). Benzene was removed under reduced pressure. The resulting
residue was charged into a silica gel column. Compound 24 (100 mg,
55%) was eluted with 30% ethyl acetate−petroleum ether as a white
solid. Rf = 0.4 (30% ethyl acetate−petroleum ether); mp 146−148 °C;
1H NMR (200 MHz, CDCl3): δ 8.35 (d, 1H, J = 8 Hz), 7.85 (d, 1H, J
Dimethyl 2-Bromo-5-methoxy-3-methyl-terephthalate (35).
To a stirred solution of 34 (200 mg, 0.84 mmol) in AcOH (4 mL) was
added Br2 (0.04 mL, 0.84 mmol) dropwise at 0 °C, and the mixture
was allowed to stir at rt overnight. Then it was diluted with water (15
mL) and extracted with ethyl acetate (3 × 30 mL). The combined
extract was then submitted to the usual workup. Column purification
of the crude material resulted in compound 35 as a yellowish solid
1
(185 mg, 70%). mp 71−74 °C; H NMR (200 MHz, CDCl3): δ 7.02
= 8.2 Hz), 7.71−7.52 (m, 2H), 7.43 (dd, 2H, J = 1.6 Hz, J = 8 Hz),
7.32−7.15 (m, 3H), 7.14 (s, 1H), 6.91 (s, 1H), 4.01 (s, 3H); 13C NMR
(50 MHz, CDCl3): δ 167.2, 153.8, 147.8, 138.3, 134.1 (CH), 129.8
(CH), 129.7, 129.2 (CH), 129.0 (CH), 127.8 (CH), 125.1 (CH),
124.9 (CH), 122.1, 115.5, 108.1 (CH), 84.5 (CH), 56.0 (OCH3); IR
(KBr, cm−1) νmax 1751, 1634, 1470, 1310, 1051, 961, 750; HRMS (EI
+) m/z calcd for C19H14O3S [M+]: 322.0664, found 322.0666.
4-Methoxy-3-oxo-1,3,6,7,8,9-hexahydronaphtho[1,2-c]-
furan-1-carbonitrile (25). To a stirred solution of 16 (600 mg, 2.07
mmol) in dry CH2Cl2 (mL) was added TMSCN (0.28 mL, 2.28
mmol) at 0 °C, followed by KCN (27 mg, 0.415 mmol) and 18-crown-
6 (110 mg, 0.415 mmol) at the same temperature in a N2 atmosphere.
The resulting reaction mixture was allowed to stir at 0 °C for 1.5 h and
at rt for 3 h. Thereafter, the reaction mixture was concentrated under
reduced pressure, and the residue was dissolved in AcOH (20 mL) and
stirred at rt for 15 h. Then an aqueous NaOH solution (40 mL, 1 M)
was added dropwise until turbidity appeared and then extracted with
ethyl acetate (3 × 120 mL). The combined ethyl acetate part was then
subjected to the usual workup to give a solid compound, which on
chromatographic purification (50% ethyl acetate−petroleum ether)
yielded compound 25 (480 mg, 95%) as a white solid. Rf = 0.3 (60%
ethyl acetate−petroleum ether); 1H NMR (200 MHz, CDCl3): δ 6.77
(s, 1H), 5.83 (s, 1H), 3.95 (s, 3H), 2.95−2.78 (m, 3H), 2.62−2.47 (m,
1H), 1.95−1.75 (m, 4H); 13C NMR (50 MHz, CDCl3): δ 165.9,
156.5, 148.7, 142.1, 124.0, 113.8 (Ar−CH), 113.1, 109.4, 64.1 (CH−
CN), 56.1 (OCH3), 30.5 (CH2), 24.2 (CH2), 22.2 (CH2), 22.1 (CH2);
HRMS (ES+) m/z calcd for C14H13NO3 [M+H]+: 244.0974, found
244.0970.
(s, 1H), 3.91 (s, 6H), 3.81 (s, 3H), 2.34 (s, 3H); 13C NMR (CDCl3,
50 MHz): δ 167.4, 167.3, 155.0, 137.5, 135.6, 127.7, 114.6, 110.6, 56.4,
52.8, 52.7, 21.0; HRMS (ES+) m/z calcd for C12H13O5Br [M + H]+:
317.0025, found 317.0039.
Methyl 7-Methoxy-1-oxo-1,3-dihydroisobenzofuran-5-car-
boxylate (36). It was obtained from 34 as a fluffy white solid. The
experimental procedure is similar to that described for the trans-
formation 50→51. Rf = 0.1 (30% ethyl acetate−petroleum ether); mp
1
186−188 °C; H NMR (200 MHz, CDCl3): δ 7.73 (d, 1H, J = 0.8
Hz), 7.64 (s, 1H), 5.32 (s, 2H), 4.10 (s, 3H), 4.02 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ 168.1, 165.7, 158.4, 149.3, 137.4, 123.4, 116.7,
114.8 (Ar−CH), 111.7 (Ar−CH), 68.7 (CH2), 56.3, 52.8; IR (KBr,
cm−1) νmax 1758, 1718, 1612, 1440, 1336, 1244, 1106, 1051, 769;
HRMS (EI+) m/z calcd for C11H10O5 [M]+: 222.0528, found
222.0529.
Methyl 3-Bromo-7-methoxy-1-oxo-1,3-dihydroisobenzofur-
an-5-carboxylate (37). It was obtained from 36 as a white solid. The
experimental procedure is similar to that described for the trans-
formation 57→59. Rf = 0.5 (30% ethyl acetate−petroleum ether); mp
1
185−190 °C; H NMR (200 MHz, CDCl3): δ 7.79 (s, 1H), 7.66 (s,
1H), 7.34 (s, 1H), 4.07 (s, 3H), 3.98 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 165.1, 164.3, 158.4, 151.4, 138.7, 116.2 (Ar−CH), 114.7
(tert-C), 113.7 (Ar−CH), 73.6 (CH−Br), 56.7, 53.0
Methyl 3-Hydroxy-7-methoxy-1-oxo-1,3-dihydroisobenzo-
furan-5-carboxylate (38). It was obtained from 37 as a white
solid. The experimental procedure is similar to that described for the
transformation 59→60. Rf = 0.2 (80% ethyl acetate−petroleum ether);
1
mp 199−200 °C; H NMR (400 MHz, d6-DMSO): δ 8.17 (s, 1H,
4-Methoxy-1-(3-oxo-cyclohexyl)-1-phenylsulfanyl-1H-
naphtho[1,2-c]furan-3-one (19d). Compound 19d was synthesized
from 24 (40 mg, 0.124 mmol) and 2-cyclohexenone, following the
protocol described for the transformation 18→19a. Purification was
done by PLC using 30% ethyl acetate−petroleum ether. Rf = 0.2 (30%
ethyl acetate−petroleum ether); Yield = 42 mg (80%, white solid); mp
168−170 °C; 1H NMR (200 MHz, CDCl3): δ (6:4 mixture of
diastereomers) 8.43−8.32 (m), 7.80−7.69 (m), 7.67−7.47 (m), 7.09−
6.98 (m), 6.96 (s), 6.93 (s), 6.90−6.82 (m), 3.85 (s), 3.83 (s), 3.25−
2.65 (m), 2.40−2.10 (m), 1.93−1.29 (m); 13C NMR (50 MHz,
CDCl3): δ 209.9, 209.4, 166.3, 153.3, 150.0, 149.4, 138.4, 136.3, 136.2,
129.8, 128.5, 128.2, 127.4, 127.2, 125.3, 124.8, 124.7, 121.5, 115.7,
108.0, 107.8, 97.5, 55.9, 45.9, 43.3, 42.2, 41.0, 26.6, 25.7, 24.6, 24.2; IR
(KBr, cm−1) νmax 1774, 1705, 1630, 1465, 1401, 1302, 1262, 1170,
1102, 1037, 752, 693; HRMS (ES+) m/z calcd for C25H22O4S [M +
H]+: 419.1317, found 419.1298.
broad), 7.63 (s, 1H), 7.61 (s, 1H), 6.58 (s, 1H, broad), 3.97 (s, 3H),
3.90 (s, 3H); 13C NMR (d6-DMSO, 100 MHz): δ 171.0, 165.6, 157.7,
150.8, 137.5, 117.5, 116.0 (Ar−CH), 113.5 (Ar−CH), 97.0 (CH−
OH), 56.6, 53.3; HRMS (TOF-ES+) m/z calcd for C11H10O6 [M +
Na]+: 261.0375, found 261.0381.
Methyl 3-Cyano-7-methoxy-1-oxo-1,3-dihydroisobenzofur-
an-5-carboxylate (27). It was obtained from 38 as a white solid. The
experimental procedure is similar to that described for the trans-
formation 60→47. But, addition of CHCl3 and p-TSA (cat.) was not
required here. Compound 27 was obtained directly from 38 without
isolation of the cyanohydrin intermediate, when treated with KCN in
an acidic medium; Rf = 0.3 (30% ethyl acetate−petroleum ether); mp
1
194−196 °C; H NMR (200 MHz, CDCl3): δ 7.86 (s, 1H), 7.75 (s,
1H), 6.04 (s, 1H), 4.09 (s, 3H), 4.00 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ 164.8, 164.4, 158.8, 144.2, 139.0, 115.1 (Ar−CH), 114.9,
114.3 (Ar−CH), 113.4, 64.8 (CH−CN), 56.7, 53.1; IR (KBr, cm−1)
νmax 1758, 1718, 1612, 1440, 1336, 1244, 1106, 1051, 7691803, 1718,
Methyl 2-Methoxy-6-methyl-4-trifluoromethanesulfonylox-
ybenzoate (33). It was obtained from 32 as a low melting solid.
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1610, 1488, 1344, 1259, 1020, 765; HRMS (ES+) m/z calcd for
C12H9NO5 [M + H]+: 248.0559, found 248.0564.
(Ar−CH), 114.0 (Ar−CH), 92.1, 56.8, 56.7, 52.8, 45.2, 36.3 (CH2),
16.1; HRMS (TOF-ES+) m/z calcd for C23H18Cl2O7 [M + H]+:
477.0508, found 477.0515 or, [M + Na]+: 499.0328, found 499.0326.
2-Chloro-1-hydroxy-6,8-dimethoxy-3-methyl-7,12-dioxo-
7,12-dihydrobenz[a]anthracene-10-carboxylic acid (45). It was
obtained from 44 as a black solid. The experimental procedure is
similar to that described for the transformation 67→68; Rf = 0.2 (90%
Methyl 6-Hydroxy-8-methoxy-3-methyl-7,12-dioxo-
1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(40). This was obtained from 27 as a red solid. The experimental
procedure is similar to that described for the transformation 47→63.
1
mp 216−218 °C; H NMR (400 MHz, CDCl3): δ 13.1 (s, 1H, OH),
1
8.48 (d, 1H, J = 1.2 Hz), 7.92 (d, 1H, J = 0.8 Hz), 7.03 (s, 1H), 4.12
(s, 3H), 4.00 (s, 3H), 3.45−3.37 (m, 1H), 3.17−3.06 (m, 1H), 2.90
(dd, 1H, J = 3.2 Hz, 17.2 Hz), 2.48 (dd, 1H, J = 10.8, 17.2 Hz), 2.02−
1.95 (m, 1H), 1.89−1.84 (m, 1H), 1.39−1.24 (m, 1H), 1.07 (d, 3H, J
= 6.8 Hz); 13C NMR (CDCl3, 100 MHz): δ 188.4, 184.1, 165.4, 160.6,
160.1, 149.1, 137.5, 135.9, 134.0, 129.5, 124.7, 122.9, 120.7, 117.2,
116.4, 56.9, 52.8, 39.8, 31.4, 28.8, 27.8, 21.5; HRMS (TOF-ES+) m/z
calcd for C22H20O6 [M+]: 380.1260, found 380.1267.
ethyl acetate−petroleum ether); mp >242 °C; H NMR (400 MHz,
CDCl3): δ 11.69 (s, 1H), 8.45 (s, 1H), 7.97 (s, 1H), 7.49 (s, 1H), 7.22
(s, 1H), 4.10 (s, 3H), 4.05 (s, 3H), 2.54 (s, 3H); HRMS (ES+) m/z
calcd for C22H15O7Cl [M + H]+: 427.0585, found 427.0578. 13C NMR
could not be recorded due to decomposition under ambient
conditions.
Methyl 2-Chloro-1,6,8-trimethoxy-3-methyl-7,12-dioxo-
7,12-dihydrobenz[a]anthracene-10-carboxylate (46). Rf = 0.3
(60% ethyl acetate−petroleum ether); state: red solid; mp 245−248
Methyl 6-Hydroxy-8-methoxy-3-methyl-1,7,12-trioxo-
1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(41). This was obtained from 40 as a red solid. The experimental
procedure is similar to that described for the transformation 63→65.
1
°C; H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 7.88 (s, 1H), 7.41
(s, 1H), 7.31 (s, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 4.00 (s, 3H), 3.86 (s,
3H), 2.54 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 186.4, 181.2,
165.5, 158.5, 155.5, 153.5, 140.0, 137.9, 137.0, 136.5, 135.2, 126.5,
126.3, 126.0, 123.2, 118.0, 117.9, 117.0, 111.7, 61.4, 56.7, 56.5, 52.8,
21.2; HRMS (ES+) m/z calcd for C24H19ClO7 [M + H]+: 455.0897,
found 455.0899.
1
Rf = 0.2 (40% ethyl acetate−petroleum ether); mp 218−220 °C; H
NMR (400 MHz, CDCl3): δ 12.86 (s, 1H, OH), 8.37 (s, 1H), 7.95 (s,
1H), 6.99 (s, 1H), 4.11 (s, 3H), 3.99 (s, 3H), 2.95−2.85 (m, 2H),
2.65−2.57 (m, 1H), 2.51−2.30 (m, 2H), 1.17 (d, 3H, J = 5.6 Hz); 13C
NMR (CDCl3, 100 MHz): δ 197.6, 187.9, 183.9, 165.1, 163.6, 160.3,
152.7, 138.0, 137.2, 136.8, 128.3, 122.4, 121.2 (Ar−CH), 120.6 (Ar−
CH), 117.8 (Ar−CH), 117.7, 57.0, 53.0, 47.5(CH2), 38.7(CH2), 30.3,
21.3; HRMS (TOF-ES+) m/z calcd for C22H18O7 [M + H]+:
395.1131, found 395.1128.
2-Chloro-1,6,8-trimethoxy-3-methyl-7,12-dioxo-7,12-
dihydrobenz[a]anthracene-10-carboxylic Acid (29). To a stirred
solution of 46 (40 mg, 0.088 mmol) in THF (4 mL) was added a
solution of LiOH (40 mg, 1.67 mmol, 19 equiv) in a 5:1 mixture of
THF−H2O (2.4 mL) dropwise, and the mixture was allowed to stir at
rt for 4 h. Solvent was evaporated under reduced pressure, and the
residue was acidified with 6 N HCl and diluted with ethyl acetate (15
mL). The usual workup of the mixture using ethyl acetate and H2O,
followed by evaporation of organic solvent, gave compound 29 (34
mg, 89%) as a red solid. Rf = 0.2 (ethyl acetate); mp 239 °C
(charring); 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.92 (s, 1H),
7.42 (s, 1H), 7.32 (s, 1H), 4.08 (s, 3H), 4.06 (s, 3H), 3.88 (s, 3H),
2.55 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 186.3, 181.1, 168.5,
158.5, 155.4, 153.3, 140.0, 137.9, 136.8, 136.6, 134.1, 126.8, 126.5,
126.0, 123.2, 118.6, 117.9, 117.2, 111.7, 61.3, 56.7, 56.5, 21.2; HRMS
(TOF-ES+) m/z calcd for C23H17ClO7 [M + Na]+: 463.0561, found
463.0558.
Methyl 2-Chloro-6-hydroxy-8-methoxy-3-methyl-1,7,12-tri-
oxo-1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(42, 1:1 Mixture of Diastereomers). To a stirred solution of N-
chlorosuccinimide (122 mg, 0.913 mmol) in a mixture of dry methanol
and chloroform (3:2, 10 mL) was added a catalytic amount of thiourea
at rt. After 5 min, compound 41 (100 mg, 0.254 mmol) was added to
the resulting solution and the mixture was allowed to stir at rt
overnight under a nitrogen atmosphere. After completion of the
reaction the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography to provide
the chlorotetracycle 42 as a yellow solid (70 mg, 65%). 1H NMR (200
MHz, CDCl3): δ 12.89 (s, 1H), 12.87 (s, 1H), 8.39 (s, 2H), 7.96 (s,
2H), 6.99 (s, 2H), 4.54 (d, 1H, J = 2.4 Hz), 4.48 (d, 1H, J = 8.4 Hz),
4.12 (s, 6H), 3.99 (s, 6H), 3.29 (dd, 2H, J = 17.1 Hz, 4.5 Hz), 3.04−
2.55 (m, 4H), 1.26 (t, 6H, J = 7 Hz); 13C NMR (CDCl3, 100 MHz): δ
190.6, 187.8, 183.0, 165.1, 164.0, 163.9, 160.4, 151.0, 150.5, 138.1,
137.6, 137.0, 125.8, 122.3, 121.2 (Ar−CH), 120.7 (Ar−CH), 118.0,
117.9 (Ar−CH), 66.3 (CH−Cl), 66.2 (CH−Cl), 57.0 (OCH3), 53.0
(OCH3), 38.6, 35.8, 35.7 (CH2), 33.7 (CH2), 19.3, 17.3; HRMS
(TOF-ES+) m/z calcd for C22H17ClO7 [M + H]+: 429.0742, found
429.0734.
Methyl 6,8-Dimethoxy-3-methyl-1,7,12-trioxo-1,2,3,4,7,12-
hexahydrobenz[a]anthracene-10-carboxylate (43). It was ob-
tained from 41 as an orange solid. The experimental procedure is
similar to that described for the transformation 65→66. Rf = 0.2 (50%
ethyl acetate−petroleum ether); mp 234−236 °C (charring); 1H
NMR (400 MHz, CDCl3): δ 8.27 (d, 1H, J = 1.2 Hz), 7.88 (s, 1H),
6.93 (s, 1H), 4.04 (s, 3H), 4.02 (s, 3H), 3.98 (s, 3H), 2.93 (m, 2H),
2.66 (m, 1H), 2.48 (m, 2H), 1.18 (d, 3H, J = 6 Hz); 13C NMR
(CDCl3, 100 MHz): δ 197.3, 185.6, 181.2, 165.5, 160.9, 158.7, 151.0,
139.3, 137.1, 135.1, 127.2, 126.2, 123.9, 119.3, 117.3, 114.6, 56.7, 52.7,
47.4, 38.9, 30.5, 21.3 (one C missing). HRMS (TOF-ES+) m/z calcd
for C23H20O7 [M + Na]+: 431.1107, found 431.1106.
Methyl 3-Acetyl-2-hydroxy-4-methoxy-6-methylbenzoate
(49). To a stirred solution of 48 (28 g, 0.142 mol) in dry CH2Cl2
(1 lit) was added TiCl4 (62.6 mL, 0.57 mol) dropwise at 0 °C in a N2
atmosphere. Afterward, CH3COCl (24.5 mL, 0.36 mol) was added
dropwise at the same temperature. The solution was stirred for 12 h at
rt. After addition of water (300 mL) and 10% aq HCl (200 mL) the
mixture was extracted with CH2Cl2 (3 × 800 mL) and worked up in
the usual manner. The crude product was purified by column
chromatography to obtain acetyl compound 49 (31 g, 91%) as a
yellow solid. mp 47−49 °C; Rf = 0.4 (15% ethyl acetate−petroleum
1
ether); H NMR (200 MHz, CDCl3): δ 13.66 (s, 1H, OH), 6.24 (s,
1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.62 (s, 3H), 2.36 (s, 3H); 13C NMR
(CDCl3, 50 MHz): δ 204.2, 168.4, 162.5, 161.8, 145.9, 115.0, 110.1,
103.7, 55.9, 52.3, 33.4, 21.5; IR (KBr, cm−1) νmax 3450, 1727, 1610,
1452, 1292, 1189. HRMS (ES+): calcd for C12H14O5 [M + Na]+
261.0739, found 261.0741.
Methyl 2-Acetoxy-3-acetyl-4-methoxy-6-methylbenzoate
(50). To an oven-dried round-bottomed flask fitted with a magnetic
stirring bar were added compound 49 (54 g, 0.227 mol) and CH2Cl2
(300 mL) followed by Et3N (62 mL, 0.45 mol) dropwise at 0 °C. The
resulting reaction mixture was then allowed to stir for 10 min at the
same temperature. Afterward, CH3COCl (24.3 mL, 0.34 mol) was
added dropwise at 0 °C and allowed to stir for 5 h at rt. The reaction
mixture was then diluted with CH2Cl2 (400 mL), and water (100 mL)
was added. The layers were separated, and the aqueous part was
extracted with CH2Cl2 (3 × 200 mL). The combined extracts were
washed with brine, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude residue was purified by column
chromatography on silica gel to afford compound 50 (61 g, 96%) as a
white crystalline solid. mp 116−120 °C; 1H NMR (CDCl3, 200
Methyl 2,2-Dichloro-6,8-dimethoxy-3-methyl-1,7,12-trioxo-
1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(44). It was obtained from 43 as a deep red solid. The experimental
procedure is similar to that described for the transformation 66→67;
1
Rf = 0.2 (50% ethyl acetate−petroleum ether); mp 150−152 °C; H
NMR (400 MHz, CDCl3): δ 8.31 (d, 1H, J = 0.8 Hz), 7.90 (s, 1H),
6.89 (s, 1H), 4.05 (s, 3H), 4.03 (s, 3H), 3.98 (s, 3H), 3.09 (dd, 2H, J =
5.6 Hz, J = 8.4 Hz), 2.86−2.75 (m, 1H), 1.46 (d, 3H, J = 6.4 Hz); 13C
NMR (CDCl3, 100 MHz): δ 184.3, 183.9, 180.6, 165.4, 161.6, 158.8,
148.0, 140.9, 136.7, 135.3, 125.9, 124.7, 122.9, 119.4 (Ar−CH), 117.5
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MHz): δ 6.67 (s, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.47 (s, 3H), 2.43 (s,
3H), 2.21 (s, 3H); 13C NMR (CDCl3, 50 MHz): δ 199.6, 168.9, 166.1,
158.2, 146.3, 141.9, 122.4, 119.3, 111.0, 56.0, 52.1, 31.6, 21.1, 20.6; IR
(KBr, cm−1) νmax 1781, 1724, 1700, 1655, 1610, 1563, 1527, 1461,
1438, 1408, 1371, 1319, 1275, 1238, 1206, 1106, 1041, 1017, 968, 857;
HRMS (ES+) m/z calcd for C14H16O6 [M(CH2CO +
OMe)]+: 207.0657, found 207.0649.
diluted with ethyl acetate (200 mL) and water (50 mL). The resultant
mixture was then subjected to the usual workup. The crude residue
was purified by column chromatography on silica gel to afford
compound 54 (8.4 g, 86%) as a white solid. Rf = 0.2 (40% ethyl
1
acetate−petroleum ether); Mp 197−198 °C; H NMR (CDCl3, 200
MHz): δ 7.82 (s, 1H, OH), 6.43 (s, 1H), 5.21 (s, 2H), 2.69 (q, 2H, J =
7.5 Hz), 1.16 (t, 3H, J = 7.5); 13C NMR (d6-DMSO, 100 MHz): δ
170.3, 162.5, 154.5, 147.0, 117.2, 102.8, 100.4, 68.8, 15.6, 13.5; IR
(KBr, cm−1) νmax 1691, 1630, 1449, 1347, 1320, 1260, 1143, 1100,
1052, 1018, 993, 829, 750; HRMS (ES+): calcd for C10H10O4 [M +
Na]+ 217.0477, found 217.0480.
Acetic Acid 5-Acetyl-6-methoxy-3-oxo-1,3-dihydroisoben-
zofuran-4-yl ester (51). To a stirred solution of 50 (5 g, 0.017
mol) in dry CCl4 (70 mL) in an oven-dried round-bottomed flask
fitted with a reflux condenser was added N-bromosuccinimide (3.87 g,
0.023 mol) and benzoyl peroxide (30 mg). Under the exposure of a
100 W lamp, the reaction mixture was then allowed to reflux at 80 °C
for 2.5 h, cooled to rt, and filtered. The residue was washed with CCl4,
and the resulting filtrate was evaporated under reduced pressure. The
resulting gummy material, without further purification, was heated at
150−160 °C in a round-bottomed flask for 40 min. The resulting black
solid was purified by column chromatography on silica gel to afford
compound 51 (2.5 g, 63%, brsm) as a white crystalline solid along with
deacetylated compound 52 (800 mg, 24%, brsm). Rf = 0.4 (50% ethyl
6-Ethyl-7-hydroxy-1-oxo-1,3-dihydroisobenzofuran-5-yl Tri-
fluoromethanesulfonate (55). To a stirred solution of 54 (2.5 g,
0.013 mol) in dry acetone (140 mL) was added Cs2CO3 (4.2 g, 0.013
mol) and PhNTf2 (4.12 g, 0.011 mol) at 0 °C under a N2 atmosphere
and allowed to stir for 3.5 h at temperatures not higher than 15 °C.
After completion of reaction (evaluated by TLC), acetone was
removed under reduced pressure and diluted with ethyl acetate (80
mL) and a 5% aq solution of NH4Cl (50 mL) was also added. The
layers were separated, and the aqueous part was extracted with ethyl
acetate (3 × 80 mL). The combined extracts were worked up in the
usual manner. The crude residue was purified by column
chromatography on silica gel to afford compound 55 (2.7 g, 66%)
as a white crystalline solid along with a small amount of a ditriflate
compound. Rf = 0.7 (10% ethyl acetate−petroleum ether); mp 75−76
1
acetate−petroleum ether); mp 138−140 °C; H NMR (400 MHz,
CDCl3): δ 6.84 (s, 1H), 5.23 (s, 2H), 3.95 (s, 3H), 2.45 (s, 3H), 2.36
(s, 3H); 13C NMR (CDCl3, 100 MHz): 198.8, 168.7, 167.6, 162.8,
151.2, 146.1, 126.3, 111.3, 102.1, 69.0, 56.9, 32.0, 20.6; IR (KBr, cm−1)
νmax 1779, 1754, 1705, 1620, 1468, 1444, 1362, 1338, 1304, 1255,
1186, 1165, 1091, 1008, 876, 747; HRMS (ES+) m/z calcd for
C13H12O6 [M + H]+: 265.0712, found 265.0706.
1
°C; H NMR (CDCl3, 200 MHz): δ 8.15 (s, 1H), 6.69 (s, 1H), 5.34
(s, 2H), 2.79 (q, 2H, J = 7.5 Hz), 1.21 (t, 3H, J = 7.5 Hz); 13C NMR
(CDCl3, 50 MHz): δ 173.1, 157.2, 154.2, 146.0, 126.5, 119.7 (q, J =
300 Hz), 111.6, 108.2, 71.8, 18.45, 14.2; IR (KBr, cm−1) νmax 1737,
1629, 1610, 1424, 1407, 1244, 1220, 1137, 1088, 1008, 959, 868, 729;
HRMS (ES+) m/z calcd for C11H9O6SF3 [M+H]+: 327.0150, found
6-Acetyl-7-hydroxy-5-methoxy-3H-isobenzofuran-1-one
(52). To a stirred solution of 51 (13 g, 0.049 mol) in dry methanol
(200 mL) was added oven-dried K2CO3 (14.2 g, 0.098 mol), and the
resulting suspension was allowed to stir at rt for 1 h. Then the mixture
was decanted off and evaporated under reduced pressure. The
resulting residue was diluted with CH2Cl2 (200 mL), and water (70
mL) was added, acidified with 2 N HCl. The layers were separated,
and the aqueous part extracted with CH2Cl2 (3 × 100 mL). The
combined extracts were then subjected to the usual workup. The crude
residue was purified by column chromatography on silica gel to afford
compound 52 (9 g, 83%) as white solid. Rf = 0.3 (50% ethyl acetate−
1
327.0143. Bistriflate of 54: H NMR (200 MHz, CDCl3): δ 7.52 (s,
1H), 5.36 (s, 2H), 2.91 (q, 2H, J = 7.6 Hz), 1.27 (t, 3H, J = 7.6 Hz);
13C NMR (100 MHz, CDCl3): δ 165.3, 152.3, 147.4, 144.4, 132.8,
118.9, 118.5 (OTf, q, J = 319 Hz), 118.3 (OTf, q, J = 318 Hz), 115.8
(Ar-CH), 68.6, 18.5 (CH2), 13.2 (CH3).
6-Ethyl-7-methoxy-1-oxo-1,3-dihydroisobenzofuran-5-yl
Trifluoromethanesulfonate (56). To a stirred solution of 55 (4 g,
0.012 mol) in dry acetone (140 mL) was added K2CO3 (6.8 g, 0.049
mol). The mixture was stirred for 5 min, and then MeI (4 mL, 0.06
mol) was added dropwise at 0 °C. The reaction flask was stoppered.
The resulting reaction mixture was allowed to come to rt, with stirring
continued for 12 h. After completion of the reaction, the suspended
acetone solution was filtered and the filtrate evaporated under reduced
pressure. The residue was treated with ethyl acetate (90 mL) and
water (30 mL). The layers were separated, and the aqueous part was
extracted with ethyl acetate (3 × 90 mL). The combined extracts were
worked up in the usual manner. The crude residue was purified by
column chromatography on silica gel to afford compound 56 (4.17 g,
100%) as a colorless liquid. Rf = 0.3 (10% ethyl acetate−petroleum
1
petroleum ether); mp 187−191 °C; H NMR (CDCl3, 200 MHz): δ
14.43 (s, 1H, OH), 6.47 (s, 1H), 5.16 (s, 2H), 4.01 (s, 3H), 2.67 (s,
3H); 13C NMR (CDCl3, 50 MHz): δ 205.2, 168.0, 166.8, 164.1, 156.6,
110.9, 106.1, 95.0, 68.6, 56.6, 33.6; IR (KBr, cm−1) νmax 1760, 1633,
1601, 1463, 1423, 1387, 1358, 1266, 1196, 1162, 1101, 1057, 1015,
906, 793, 702, 602; HRMS (EI+) m/z calcd for C11H10O5 [M + H]+:
223.0615, found 223.0620.
6-Ethyl-7-hydroxy-5-methoxy-3H-isobenzofuran-1-one
(53).33 To a stirred solution of 52 (27.9 g, 0.125 mol) in
trifluoroacetic acid (100 mL) was added triethylsilane (62 mL, 0.388
mol) at rt and under a N2 atmosphere. The resulting reaction mixture
was stirred at rt for 12 h. After completion (TLC monitoring) of the
reaction, trifluoroacetic acid was removed by bubbling nitrogen gas
into the round-bottomed flask. The residue was diluted with ethyl
acetate (300 mL) and water (100 mL). The layers were separated, and
the aqueous part extracted with ethyl acetate (3 × 150 mL). The
combined extracts were then worked up in the usual manner. The
crude residue was purified by column chromatography on silica gel to
afford compound 53 (22.6 g, 87%) as a white crystalline solid. Rf = 0.6
1
ether); H NMR (CDCl3, 200 MHz): δ 7.13 (s, 1H), 5.27 (s, 2H),
4.20 (s, 3H), 2.78 (q, 2H, J = 7.5 Hz), 1.18 (t, 3H, J = 7.5 Hz); 13C
NMR (CDCl3, 50 MHz): δ 167.3, 159.0, 152.1, 147.4, 131.1, 118.4 (q,
CF3, J = 318 Hz), 116.3, 109.7, 68.6, 63.4, 17.8, 13.8; IR (KBr, cm−1)
νmax 1765, 1613, 1545, 1527, 1460, 1419, 1362, 1318, 1292, 1215,
1138, 1109, 1082, 1011, 967, 943, 867, 810, 764, 732, 697; HRMS (ES
+) m/z calcd for C12H11F3O6S [M + H]+: 341.0306, found 341.0298.
Methyl 6-Ethyl-7-methoxy-1-oxo-1,3-dihydroisobenzofur-
an-5-carboxylate (57). To compound 56 (1.02 g, 0.003 mol)
taken in an oven-dried pressure tube were added dppf (24 × 10−3 mol,
0.083 g), Pd(OAc)2 (15 × 10 −3 mol, 0.033 g), MeOH (12 mL), Et3N
(93 × 10−2 mol, 1.29 mL), and finally DMF (15 mL) sequentially in a
N2 atmosphere. Freshly generated CO gas was then allowed to purge
through the reaction mixture for 10 min. The pressure tube was then
sealed with a teflon cap and heated at 90−120 °C for 17 h. After
completion of the reaction (checked by TLC), the reaction mixture
was cooled to rt, and water (90 mL) and diethyl ether (100 mL) were
added. The layers were separated. The aqueous part was then extracted
with diethyl ether (3 × 50 mL). The combined organic layer was
subjected to the usual workup. Column chromatography of the
1
(25% ethyl acetate−petroleum ether); mp 168−169 °C; H NMR
(CDCl3, 200 MHz): δ 7.70 (s, 1H), 6.48 (s, 1H), 5.24 (s, 2H), 3.89 (s,
3H), 2.67 (q, 2H, J = 7.4 Hz), 1.10 (t, 3H, J = 7.5 Hz); 13C NMR
(CDCl3, 50 MHz): δ 172.9, 164.9, 154.3, 146.0, 119.1, 104.0, 96.2,
70.5, 56.5, 56.2, 15.8, 13.3; IR (KBr, cm−1) νmax 1729, 1609, 1625,
1495, 1463, 1348, 1290, 1256, 1143, 1095, 1054, 999, 983, 835, 744,
659.
6-Ethyl-5,7-dihydroxy-3H-isobenzofuran-1-one (54). To a
stirred solution of 53 (10.5 g, 0.05 mol) in dry CH2Cl2 (120 mL)
was added neat BBr3 (34 mL, 0.353 mol) at 0 °C under a N2
atmosphere. The resulting red color suspension was then allowed to
come to rt and stirred overnight. After completion of the reaction,
CH2Cl2 was removed under reduced pressure and the residue was
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resulting crude gummy material gave compound 57 (340 mg, 50%) as
a colorless crystal. This reaction also provides a white solid compound
in 10% yield, which was characterized as 58. Rf = 0.3 (10% ethyl
acetate−petroleum ether); mp 57−59 °C; 1H NMR (CDCl3, 200
MHz): δ 7.49 (s, 1H), 5.25 (s, 2H), 4.13 (s, 3H), 3.94 (s, 3H), 2.94 (q,
2H, J = 7.4 Hz), 1.19 (t, 3H, J = 7.4 Hz); 13C NMR (CDCl3, 50
MHz): δ 168.3, 167.7, 158.3, 145.9, 139.0, 138.1, 119.1, 117.9, 69.0,
63.0, 63.4, 52.8, 20.6, 15.5; IR (KBr, cm−1) νmax 1752, 1723, 1686,
1654, 1615, 1585, 1561, 1544, 1525, 1509, 1457, 1413, 1365, 1299,
1254, 1223, 1113, 1083, 1019, 996, 908, 782; HRMS (ES+) m/z calcd
for C13H15O5 [M + H]+: 251.0919, found 251.0901; X-ray structure
provided.
5-(Cyano-hydroxymethyl)-2-ethyl-3-methoxyterephthalic
Acid 1-Methyl Ester (62). Semisolid; 1H NMR (CDCl3, 200 MHz):
7.88 (s, 1H), 5.73 (s, 1H), 3.95 (s, 1H), 3.93 (s, 1H), 3.02 (q, 2H, J =
7.6 Hz), 1.21 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 50 MHz): δ
169.5, 167.2, 157.2, 141.7, 133.8, 132.6, 128.9, 125.0, 118.5, 63.5, 61.2,
52.7, 21.0, 15.2.
Methyl 3-Cyano-6-ethyl-7-methoxy-1-oxo-1,3-dihydroiso-
benzofuran-5-carboxylate (47). To a stirred suspension of 60
(200 mg, 0.75 mmol) in water (10 mL) was added KCN (727 mg,
11.3 mmol) in portions, and the mixture was allowed to stir at rt for 10
min. The reaction mixture was then cooled to 0 °C and treated with
conc. HCl (1.2 mL, 52 equiv) and again stirred at rt for another 5 h.
The reaction mixture was then extracted with ethyl acetate (3 × 40
mL), and the combined extracts were subjected to the usual workup to
obtain a semisolid compound (cyanohydrin 62), which without further
purification was dissolved in CHCl3 (10 mL) containing p-TSA (cat.)
followed by 1 h of heating. The resulting solution was allowed to stand
at rt overnight. CHCl3 was evaporated, and the residue was charged to
column chromatography to obtain compound 47 as a pure yellow
semisolid (146 mg, 71%). Rf = 0.9 (90% ethyl acetate−petroleum
6-Ethyl-7-methoxy-3H-isobenzofuran-1-one (58). Rf = 0.8
(20% ethyl acetate−petroleum ether); white needle-shaped solid; mp
1
144−145 °C; H NMR (CDCl3, 200 MHz): δ 7.49 (d, 1H, J = 7.6
Hz), 7.08 (d, 1H, J = 7.6 Hz), 5.22 (s, 2H), 4.10 (s, 3H), 2.72 (q, 2H, J
= 7.5 Hz), 1.21 (t, 3H, J = 7.5 Hz); 13C NMR (CDCl3, 50 MHz): δ
169.0, 157.4, 146.9, 137.8, 136.3, 117.0, 116.9, 68.9, 62.8, 22.9, 15.3;
HRMS (EI+) m/z calcd for C11H12O3 [M]+: 192.0786, found
192.0776.
1
ether); H NMR (CDCl3, 200 MHz): δ 7.69 (s, 1H), 6.00 (s, 1H),
Methyl 3-Bromo-6-ethyl-7-methoxy-1-oxo-1,3-dihydroiso-
benzofuran-5-carboxylate (59). To a stirred solution of 57 (1.2
g, 0.0048 mol) in dry CCl4, in a round bottomed flask, fitted with a
condenser and a CaCl2 guard tube were added N-bromosuccinimide
(0.85 g, 0.0048 mol) and catalytic amount of AIBN. The reaction
mixture was then heated at reflux for 1.5 h under the exposure of a 100
W lamp. After 1.5 h, when the reaction was completed, the reaction
mixture was filtered and washed with CCl4. The filtrate was evaporated
under reduced pressure. The resulting gummy brown residue was
chromatographed to afford pure compound 59 (600 mg, 58%, brsm)
as a light yellow gum. Rf = 0.5 (10% ethyl acetate−petroleum ether);
1H NMR (CDCl3, 200 MHz): δ 7.62 (s, 1H), 7.33 (s, 1H), 4.18 (s,
4.18 (s, 1H), 3.97 (s, 1H), 2.97 (q, 2H, J = 7.4 Hz), 1.20 (t, 3H, J = 7.3
Hz); 13C NMR (CDCl3, 50 MHz): δ 166.7, 164.9, 158.9, 141.8, 140.7,
139.3, 118.3, 116.9, 113.9, 65.2, 63.7, 53.0, 20.8, 15.2; IR (KBr, cm−1)
νmax 1790, 1729, 1611, 1589, 1451, 1410, 1296, 1254, 1220, 1086,
1017, 910, 767; HRMS (EI+) m/z calcd for C14H13NO5 [M+]:
275.0794, found 275.0798.
Methyl 9-Ethyl-6-hydroxy-8-methoxy-3-methyl-7,12-dioxo-
1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(63). To a stirred solution of t-BuOLi (117 mg, 1.46 mmol) in THF
(7 mL) was added a solution of phthalide 47 (125 mg, 0.454 mmol) in
THF (3.5 mL) at −78 °C under an inert atmosphere. The resulting
red color solution was stirred at −78 °C for 30 min, after which a
solution of acceptor 28 (87 mg, 0.453 mmol) in THF (3.5 mL) was
added dropwise. After 1 h at −78 °C, the cooling bath was removed
and reaction mixture was allowed to stir at rt overnight. The resulting
deep red colored reaction mixture turned yellow when quenched with
a saturated aq. NH4Cl solution (5 mL). The resulting solution was
concentrated, and the residue was diluted with ethyl acetate (15 mL).
The ethyl acetate layer was separated from an aqueous layer. The aq
part was extracted with ethyl acetate (3 × 10 mL). The combined
extracts were dried over Na2SO4 and concentrated. The crude product
was washed with 15% ethyl acetate−petroleum ether to get 63 (158
mg, 85%) as a pure red solid. mp 162−164 °C; 1H NMR (CDCl3, 400
MHz): δ 13.16 (s, 1H), 8.40 (s, 1H), 7.05 (s, 1H), 3.97 (s, 3H), 3.95
(s, 3H), 3.43 (m, 1H), 3.17−3.10 (m, 1H), 3.05 (q, 2H, J = 7.50 Hz),
2.91 (dd, 1H, J = 3 Hz, J = 17 Hz), 2.53−2.46 (m, 1H), 2.02−1.98 (m,
1H), 1.89−1.85 (m, 1H), 1.39−1.32 (m, 1H), 1.24 (t, 3H, J = 7.4 Hz),
1.05 (d, 3H, J = 6.4 Hz); 13C NMR (CDCl3, 50 MHz): δ 188.4, 184.0,
167.0, 160.9, 159.5, 149.6, 146.8, 137.0, 134.7, 134.2, 129.7, 126.2,
125.0, 124.8, 116.7, 62.9, 52.8, 40.0, 31.7, 28.9, 28.0, 21.7, 20.9, 15.4;
IR (KBr, cm−1) νmax 1724, 1636, 1582, 1450, 1337, 1293, 1267, 1228,
1082, 1042, 800; HRMS (EI+) m/z calcd for C24H24O6 [M+]:
408.1573, found 408.1575.
3H), 3.96 (s, 3H), 2.95 (q, 2H, J = 7.4 Hz), 1.20 (t, 3H, J = 7.4 Hz);
13C NMR (CDCl3, 50 MHz): δ 166.9, 164.5, 158.3, 147.7, 141.1,
138.9, 119.0, 116.3, 74.0, 63.4, 52.8, 20.8, 15.1; IR (KBr, cm−1) νmax
1752, 1718, 1636,1543, 1458, 1298, 1220, 1104, 1035, 939, 772.
Methyl 6-Ethyl-3-hydroxy-7-methoxy-1-oxo-1,3-dihydroiso-
benzofuran-5-carboxylate (60). A water (5 mL) suspension of
bromo compound 59 (200 mg, 0.61 mmol) was heated at 80 °C for
0.5 h and then diluted with ethyl acetate (30 mL). The layers were
separated. The aqueous part was then washed with ethyl acetate (3 ×
20 mL), and the combined organic part was subjected to the usual
workup. Column chromatography of the crude product yielded pure
compound 60 in 95% yield (150 mg) as a white solid. Rf = 0.2 (ethyl
acetate); mp 55−57 °C; 1H NMR (CDCl3, 200 MHz): δ 7.64 (s, 1H),
6.52 (d, 1H, J = 4.8 Hz), 4.14 (s, 3H), 3.94 (s, 3H), 2.93 (q, 2H, J =
7.3 Hz), 1.17 (t, 3H, J = 7.4 Hz); 13C NMR (CDCl3, 50 MHz): δ
167.7, 166.7, 157.5, 146.0, 140.9, 138.2, 119.6, 119.3, 97.0, 63.4, 52.8,
20.6, 15.3; IR (KBr, cm−1) νmax 1732, 1618, 1591, 1459, 1443, 1407,
1292, 1220, 1116, 1082, 1038, 928, 769. HRMS (ES+) m/z calcd for
C13H14O6 [M + Na]+: 289.0688, found 289.0687.
Methyl 6-Ethyl-7-methoxy-1-oxo-3-phenylsulfanyl-1,3-dihy-
droisobenzofuran-5-carboxylate (61). To a stirred solution of 59
(200 mg, 0.608 mmol) in dry CH2Cl2 (10 mL) was added Et3N (0.1
mL, 0.668 mmol) and thiophenol (0.07 mL, 0.668 mmol) at rt. The
reaction mixture was then allowed to stir at rt for 6 h. After completion
of the reaction, monitored by TLC, the reaction mixture was diluted
with CH2Cl2 (40 mL) and washed with 10 mL of a 5% aq NaOH
solution followed by 10 mL of water. Then the resulting CH2Cl2 part
was worked up in the usual manner. The crude residue was purified by
column chromatography on silica gel to afford compound 61 (160 mg,
74%) as a semisolid. Rf = 0.2 (10% ethyl acetate−petroleum ether); 1H
NMR (CDCl3, 200 MHz): δ 7.66 (s, 1H), 7.51−7.45 (m, 2H), 7.30−
7.25 (m, 3H), 6.64 (s, 1H), 3.97 (s, 3H), 2.89 (q, 2H, J = 7.3 Hz), 1.50
(t, 3H, J = 7.3 Hz); 13C NMR (CDCl3, 50 MHz): δ 167.3, 166.2,
157.8, 145.5, 140.0, 138.0, 134.4 (Ar−CH), 129.9, 129.2 (Ar−CH),
119.1 (Ar−CH), 119.0, 85.6 (CH−SPh), 63.2, 52.8, 20.6 (CH2), 15.4
(one C missing); HRMS (ES+) m/z calcd for C19H18O5S [M + H]+:
359.0953, found 359.0959.
Methyl 9-Ethyl-6-hydroxy-8-methoxy-3-methyl-1,7,12-tri-
oxo-1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(65). A CHCl3 (distilled) solution (8 mL) of compound 63 (20 mg,
0.049 mmol) was taken in a dry test tube and allowed to stand for 6 h
in open air, in sunlight. Removal of CHCl3 solvent under reduced
pressure gave 65 (20 mg, 100%) as a red solid which did not require
any purification. Rf = 0.2 (30% ethyl acetate−petroleum ether); mp
1
86−90 °C ; H NMR (CDCl3, 400 MHz): δ 12.87 (s, 1H), 8.32(s,
1H), 7.00 (s, 1H), 3.96 (s, 1H), 3.94 (s, 1H), 3.06 (q, 2H, J = 7.3 Hz),
2.95−2.91 (m, 2H), 2.65−2.58 (m, 1H), 2.51−2.41 (m, 2H), 1.24 (t,
3H, J = 7.4 Hz), 1.18 (d, 3H, J = 6 Hz); 13C NMR (CDCl3, 50 MHz):
δ 197.7, 187.9, 183.2, 166.5, 163.5, 163.6, 159.7, 152.8, 147.4, 137.5,
137.3, 134.6, 128.5, 125.7, 124.8, 121.1, 117.7, 62.9, 52.7, 47.5, 38.7,
30.3, 21.3, 20.8, 15.2; IR (KBr, cm−1) νmax 1731, 1700, 1674, 1638,
1587, 1446, 1405, 1367, 1342, 1294, 1229, 1167, 1082, 1040, 798;
10245
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Article
HRMS (TOF-ES+) m/z calcd for C24H22O7 [M + Na]+: 445.1263,
found 445.1275.
To a stirred solution of 68 (36 mg, 0.077 mmol) in dry acetone (5
mL) was added K2CO3 (104 mg, 0.753 mmol). After 5 min, MeI
(0.072 mL, 1.15 mmol) was added dropwise at 0 °C and the flask was
stoppered. The resulting reaction mixture was then allowed to come to
rt. After 12 h of stirring, on completion of reaction, the suspended
acetone solution was filtered and the filtrate was evaporated under
reduced pressure. The resulting residue was diluted with water (5 mL)
and ethyl acetate (15 mL). The layers were separated, and the aqueous
part was extracted with ethyl acetate (3 × 15 mL). The combined
organic part was then washed with an aq. saturated Na2S2O3 solution
(5 mL), dried over Na2SO4, filtered, and evaporated under reduced
pressure. Purification by PLC (25% ethyl acetate−petroleum ether)
gave 64 (24 mg, 65%) as a red solid. Rf = 0.3 (20% ethyl acetate−
petroleum ether); mp 206−208 °C; 1H (CDCl3, 200 MHz): δ 8.15 (s,
1H), 7.41 (s, 1H), 7.31 (s, 1H), 4.05 (s, 3H), 3.40 (s, 3H), 3.97 (s,
3H), 3.86 (s, 3H), 3.06 (q, 2H, J = 7 Hz), 2.55 (s, 3H), 1.23 (t, 3H, J =
7 Hz); 13C NMR (CDCl3, 100 MHz): δ 185.5, 182.0, 167.1, 158.3,
155.5, 153.8, 145.8, 140.3, 137.4, 136.9, 135.8, 134.8, 129.0, 126.8,
126.5, 123.4, 122.0, 118.2, 111.8, 63.5 61.7, 56.8, 52.8, 21.4, 21.0, 15.4;
IR (KBr, cm−1) νmax 1732, 1680, 1608, 1588, 1543, 1446, 1408, 1363,
1275, 1226, 1119, 1081, 1053, 869; HRMS (EI+) m/z calcd for
C26H23ClO7 [M+]: 482.1132, found 482.1130.
Methyl 2-Chloro-9-ethyl-1,8-dihydroxy-6-methoxy-3-meth-
yl-7,12-dioxo-7,12-dihydrobenz[a]anthracene-10-carboxylate
(69). To a stirred solution of 64 (16 mg, 0.033 mmol) in dry CH2Cl2
(10 mL) was added BCl3 (1 M CH2Cl2, 0.208 mL, 0.208 mmol)
dropwise under a N2 atmosphere at −78 °C. The resulting solution
immediately turned black after addition of BCl3, and it was then
allowed to stir at the same temperature for 1 h. The reaction was
quenched with water (1 mL) at −78 °C. The usual workup of the
resulting mixture using CH2Cl2 and H2O, followed by evaporation of
the organic solvent, gave compound 69 (13 mg, 90%) as a black solid.
Rf = 0.4 (30% ethyl acetate−petroleum ether); mp >255 °C; 1H NMR
(CDCl3, 400 MHz): δ 12.72 (s, 1H, OH), 10.80 (s, 1H, OH), 8.12 (s,
1H), 7.54 (s, 1H), 7.25 (s, 1H), 4.10 (s, 3H), 4.00 (s, 3H), 3.06 (q,
2H, J = 7.3 Hz), 2.55 (s, 3H), 1.27 (t, 3H, J = 7.2 Hz); 13C NMR
(CDCl3, 100 MHz): δ 189.3, 188.7, 166.8, 160.4, 156.0, 150.5, 143.4,
141.1, 137.5, 137.2, 135.2, 131.0, 127.2, 123.3, 121.3 (Ar−CH), 120.6
(Ar−CH), 117.5 (Ar−CH), 117.3, 115.8, 56.9 (OCH3), 52.9 (OCH3),
21.4, 21.0 (CH2), 14.1; HRMS (EI+) m/z calcd for C24H19ClO7 [M+]:
454.0819, found 454.0816.
Methyl 9-Ethyl-6,8-dimethoxy-3-methyl-1,7,12-trioxo-
1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-carboxylate
(66). To a stirred solution of 65 (42 mg, 0.099 mmol) in dry acetone
(5 mL) was added K2CO3 (90 mg, 0.652 mmol). After 5 min, MeI
(0.15 mL, 2.39 mmol) was added dropwise into it at 0 °C. The
reaction vessel was stoppered. The resulting reaction mixture was then
allowed to come to rt and stirred for 12 h. After completion of the
reaction, the suspended acetone solution was filtered and the filtrate
was evaporated under reduced pressure. The resulting residue was
diluted with water (5 mL) and ethyl acetate (15 mL). The layers were
separated, and the aqueous part was extracted with ethyl acetate (3 ×
10 mL). The combined organic layer was then washed with an aq.
saturated Na2S2O3 solution (5 mL), dried over Na2SO4, filtered, and
evaporated under reduced pressure. Purification by PLC (40% ethyl
acetate−petroleum ether) gave 66 (38 mg, 88%) as a pure yellowish
solid. Rf = 0.2 (40% ethyl acetate−petroleum ether); mp 228−230 °C;
1H NMR (CDCl3, 200 MHz): δ 8.22 (s, 1H), 6.93 (s, 1H), 4.03 (s,
1H), 3.95 (s, 1H), 3.94 (s, 1H), 3.05 (q, 2H, J = 7.3 H3), 3.04−2.90
(m, 2H), 2.73−2.43 (m, 3H), 1.25−1.17 (m, 6H); 13C NMR (CDCl3,
50 MHz): δ 197.5, 185.1, 181.9, 166.8, 160.9, 158.3, 151.3, 146.6,
139.6, 135.7, 133.9, 129.1, 127.5, 124.0, 123.4, 114.7, 63.4, 56.9, 52.6,
47.6, 39.1, 30.7, 21.4, 20.9, 15.3; IR (KBr, cm−1) νmax 1728, 1679,
1586, 1451, 1294, 1232, 1089, 1043; HRMS (ES+) m/z calcd for
C25H24O7 [M + H]+: 437.1600, found 437.1605.
Methyl 2,2-Dichloro-9-ethyl-6,8-dimethoxy-3-methyl-
1,7,12-trioxo-1,2,3,4,7,12-hexahydrobenz[a]anthracene-10-
carboxylate (67). Freshly prepared dry HCl gas was purged through
a solution of 66 (32 mg, 0.073 mmol) in dry CH2Cl2 (6 mL) for 10
min. Afterward, SO2Cl2 (0.06 mL, 0.74 mmol) was added dropwise.
The flask was stoppered, and the mixture was stirred at rt for 2.5 h.
Thereafter, solvent was evaporated under reduced pressure, and
CHCl3 (6 mL) was added to the resulting yellow solid. Again, dry HCl
gas was purged through the solution for 10 min, SO2Cl2 (0.06 mL,
0.74 mmol) was added, and the mixture was allowed to stir at rt for 60
h. Removal of CHCl3 under reduced pressure followed by column
chromatography gave 67 (30 mg, 94%) as a pure yellow solid. Rf = 0.2
1
(40% ethyl acetate−petroleum ether); mp 182−186 °C; H NMR
(CDCl3, 400 MHz): δ 8.26 (s, 1H), 6.90 (s, 1H), 4.04 (s, 1H), 3.96 (s,
1H), 3.94 (s, 1H), 3.16−3.02 (m, 4H), 2.86−2.82 (m, 1H), 1.46 (d,
3H, J = 8 Hz), 1.22 (t, 3H, J = 8 Hz); 13C NMR (CDCl3, 50 MHz): δ
184.1, 183.7, 181.3, 166.7, 161.7, 158.5, 148.3, 147.0, 141.2, 135.9,
133.5, 128.9, 124.9, 123.6, 123.2, 114.2, 92.3, 63.4, 57.1, 52.7, 45.4,
36.5, 20.9, 16.3, 15.3; IR (KBr, cm−1) νmax 1727, 1684, 1636, 1588,
1458, 1296, 1233, 1100, 1065, 866, 802. HRMS (EI+) m/z calcd for
C25H22Cl2O7 [M+]: 504.0743, found 504.0739.
Methyl 2-Chloro-9-ethyl-1,6,8-trihydroxy-3-methyl-7,12-
dioxo-7,12-dihydrobenz[a]anthracene-10-carboxylate (70).
To a stirred solution of 69 (8 mg, 0.017 mmol) in dry CH2Cl2 (5
mL) was added anhydrous AlCl3 (95 mg, 0.704 mmol, 40 equiv)
portionwise under a N2 atmosphere at 0 °C. The resulting solution
gradually turned deep blue, and it was then allowed to stir at rt for 18
h. The reaction was quenched with water (2 mL), and 2 N HCl (1
mL) was added. An usual workup of the mixture using CH2Cl2 and
H2O, followed by evaporation of organic solvent, gave compound 70
(5 mg, 64%) as a yellowish solid. Rf = 0.4 (15% ethyl acetate−
petroleum ether); 1H NMR (CDCl3, 200 MHz): δ 12.20 (s, 1H, OH),
12.06 (s, 1H, OH), 11.30 (s, 1H), 8.14 (s, 1H), 7.59 (s, 1H), 7.13 (s,
3H), 4.00 (s, 3H), 3.05 (q, 2H, J = 7.3 Hz), 2.51 (s, 3H), 1.28 (t, 3H, J
= 7.4 Hz).
Methyl 2-Chloro-9-ethyl-1-hydroxy-6,8-dimethoxy-3-meth-
yl-7,12-dioxo-7,12-dihydrobenz[a]anthracene-10-carboxylate
(68). To a methanolic solution (5 mL) of 67 (45 mg, 0.089 mmol) in
an oven-dried round bottomed flask, fitted with a condenser, was
added NaOMe (15 mg, 0.277 mmol). The red colored solution
immediately turned black. It was then heated at reflux for 1 h. After
completion of the reaction, methanol was evaporated under reduced
pressure, diluted with ethyl acetate (15 mL), and 2 N HCl was also
added. After the usual workup, followed by evaporation of ethyl
acetate, a black solid was obtained. This, on purification by silica gel
column chromatography, gave 68 as a black solid (39 mg, 94%). Rf =
0.7 (40% ethyl acetate−petroleum ether); mp 188−190 °C; 1H NMR
(CDCl3, 200 MHz): δ 12.09 (s, 1H), 8.30 (s, 1H), 7.44 (s, 1H), 7.16
(s, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.97 (s, 3H), 3.05 (q, 2H, J = 6.7
Hz), 2.51 (s, 3H), 1.23 (t, 3H, J = 7 Hz); 13C NMR (CDCl3, 50
MHz): δ 189.8, 184.1, 166.8, 157.7, 154.1, 150.7, 147.6, 140.0, 136.7,
135.9, 133.4, 132.0, 131.9, 127.9, 125.1, 122.1, 120.2, 117.1, 116.0,
63.7, 56.8, 52.9, 21.3, 15.2; IR (KBr, cm−1) νmax 1732, 1682, 1653,
1582, 1455, 1400, 1364, 1287, 1260, 1221, 1109, 1056, 866. HRMS
(EI+) m/z calcd for C25H21ClO7 [M+]: 468.0976, found 468.0972.
[M+2] peak also found.
Chlorocyclinone A (1).2 To a stirred solution of 70 (5 mg, 0.011
mmol) in dry acetone (3 mL) was added K2CO3 (6 mg, 0.04 mmol)
followed by MeI (1 μL, 0.018 mmol) which was added dropwise at 0
°C, and the flask was stoppered. The resulting reaction mixture was
then allowed to come to rt, while stirring was continued for 12 h. The
newly formed spot found on the TLC plate showed blue coloration
when exposed to NH3 vapor. After completion of the reaction, the
suspension was filtered and the filtrate was evaporated under reduced
pressure. The resulting residue was diluted with water (2 mL) and
ethyl acetate (6 mL), and the layers were separated. The aqueous part
was extracted with ethyl acetate (3 × 6 mL). The combined organic
part was then washed with aq saturated Na2S2O3 solution (2 mL),
dried over Na2SO4, filtered, and evaporated under reduced pressure.
Purification by PLC (10% ethyl acetate−petroleum ether) gave 1 (2
mg, 39%) as a red solid. Rf = 0.5 (10% ethyl acetate−petroleum ether);
Methyl 2-Chloro-9-ethyl-1,6,8-trimethoxy-3-methyl-7,12-
dioxo-7,12-dihydrobenz[a]anthracene-10-carboxylate (64).
10246
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The Journal of Organic Chemistry
Article
1H NMR (CDCl3, 400 MHz): δ 12.10 (s, 1H, OH), 11.50 (s, 1H,
OH), 7.98 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 3.99 (s, 3H), 3.83 (s,
3H), 3.04 (q, 2H, J = 7.2 Hz), 2.54 (s, 3H), 1.27 (t, 3H, J = 7.4 Hz);
13C NMR (CDCl3, 100 MHz): δ 193.3, 183.6, 166.8, 160.7, 156.6,
154.0, 141.6, 140.8, 139.0, 138.1, 137.3, 133.3, 127.1, 123.0, 119.7,
119.6, 119.2, 117.8, 115.7, 61.4, 52.5, 21.3, 20.7, 14.1; HRMS (EI+)
m/z calcd for C24H19ClO7 [M + H+]: 455.0897, found 455.0891.
(10) Boger, D. L.; Mullican, M. D. J. Org. Chem. 1984, 49, 4033−
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, 2D spectra for all new compounds and X-ray structure
of 57. This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 6097−6100.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dmal@chem.iitkgp.ernet.in.
■
(16) (a) Marmor, R. S. J. Org. Chem. 1972, 37, 2901−2904.
(b) Nouguier, R.; Bertrand, M. P.; Picon, P.; Perfetti, P. Tetrahedron
Lett. 1994, 35, 8171−8172.
Notes
(17) Oliver, J. E.; Wilzer, K. R.; Waters, R. M. Synthesis 1990, 1117−
1119.
The authors declare no competing financial interest.
(18) Bender, C. F.; Yoshimoto, F. K.; Paradise, C. L.; Brabander, J. K.
ACKNOWLEDGMENTS
D. J. Am. Chem. Soc. 2009, 131, 11350−11352.
(19) Wilson, Z. E.; Brimble, M. A. Org. Biomol. Chem. 2010, 8, 1284−
1286.
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Oorui, M.; Suzuki, K. Chem.Eur. J. 2007, 13, 9791−9823.
(21) Supporting Information.
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R. F.; Wakselman, M. J. Org. Chem. 1999, 64, 713−720. (b) The
benzylic bromo compound obtained from 34 (or 50) was inseparable
from the unreacted starting compound 34 (or 50). Therefore, its
thermolysis was carried out with the crude product.
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911−913.
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(b) Parker, K. A.; Ding, Q. Tetrahedron 2000, 56, 10249−10254.
(26) Yu, M.; Snider, B. B. Org. Lett. 2011, 13, 4224−4227.
(27) Prugh, J. D.; Deana, A. A.; Wiggins, J. M. Synthesis 1989, 554−
556.
■
The authors are grateful to the Science and Engineering
Research Board, New Delhi; the Council of Scientific and
Industrial Research (CSIR), New Delhi; and IIT Kharagpur for
financial support. R.K. is thankful to CSIR for his research
fellowship. The authors are also grateful to Prof. Manas Ghorai,
IIT Kanpur for interest in the work.
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