Synthesis of chlorine-containing angucycline BE-23254 and its analogs

Article abstract of DOI:10.1016/j.tet.2006.07.090

The total synthesis of BE-23254, an unusual angucycline antibiotic is reported. This is achieved by adopting a Hauser annulation and a DDQ-promoted aromatization as the key steps. The strategy has been generalized for the synthesis of several analogs of the target molecule. A regioselective preparation of chlorine-containing phenols is also described.

Full text of DOI:10.1016/j.tet.2006.07.090

Tetrahedron 62 (2006) 9589–9602
Synthesis of chlorine-containing angucycline BE-23254
and its analogs
y
*
Dipakranjan Mal and Satyajit Dey
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, West Bengal, India
Received 4 April 2006; revised 10 July 2006; accepted 27 July 2006
Available online 17 August 2006
Abstract—The total synthesis of BE-23254, an unusual angucycline antibiotic is reported. This is achieved by adopting a Hauser annulation
and a DDQ-promoted aromatization as the key steps. The strategy has been generalized for the synthesis of several analogs of the target
molecule. A regioselective preparation of chlorine-containing phenols is also described.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
2. Synthetic strategy
Angucyclines and angucyclinones are a large group of qui-
nonoid natural products characterized by a benz[a]anthraqui-
none or a variant thereof as the core structure originating
from a decaketide chain precursor.1,2 This class of com-
pounds often displays a broad spectrum of biological activ-
ities, which include antiviral and antitumor activities,
cytotoxic activity against various cancer cell lines, inhibition
of angiogenesis and platelet aggregation, and inhibitory ac-
tivity against the pentagastrin-stimulated acid secretion. BE-
23254 (1), an unusual angucycline antibiotic with aromatic
A ring was isolated by Okabe et al.3 in 1992 from Strepto-
myces sp. A 23254. It was reported to possess activity against
the human colon cancer DLD-1 (IC50 0.75 mg mLꢀ1). It is
structurally unique in that it is the only member of angucy-
clines to contain a chlorine atom at the C-9 position of the
ring skeleton. The methyl group at C-3, which is present
in almost all other angucyclines numbering about 150, is
absent in BE-23254 (1). In addition, the presence of a carb-
oxylic acid at the C-2 position of BE-23254 is a rare struc-
tural feature of angucycline antibiotics. These unusual
structural features coupled with its bioactivity prompted
us to execute a short and efficient total synthesis of the
molecule that has been the subject of a recent communica-
tion4 from our laboratory. We now report a full account of
the investigation and the synthesis of analogs of the target
molecule.
During the past two decades, a good number of methodolo-
gies have been developed and employed for the total synthe-
sis of angucycline targets.5 While the Diels–Alder strategy
has been very successful for the total syntheses of complex
angucyclines, we introduced the notion of employing Hauser
annulation6a as a complementary means.6 We were particu-
larly attracted by the unambiguous regiochemical integrity
of the methodology in addition to the mildness of the reac-
tion conditions. The retrosynthetic disconnections for
BE-23254 (1) featuring a Hauser annulation are shown in
Scheme 1. It was planned to condense naphthalenone 4
(AB ring synthon) with the isobenzofuranones 3a and 3b
(D ring synthons) for the regiospecific fabrication of the
tetracyclic framework 2. DDQ-promoted aromatization of
COOMe
COOH
2
1
O
3
O
A
4
11
D
12
7
10
C
O
B
5
Cl
Cl
9
8
6
OMe O
OH
OH
OH
2
BE-23254 (1)
Hauser annulation
COOMe
X
MeO
Me
O
COOEt
Cl
Cl
Keywords: Angucyclines; Hauser annulation; Naphthalenone; Chlorinative
aromatization.
O
OMe
OH
5
O
4
* Corresponding author. Tel.: +91 3222 283318; fax: +91 3222 282252;
e-mail: dmal@chem.iitkgp.ernet.in
Present address: Department of Chemistry, Tamralipta Mahavidyalaya,
3a: X = CN
3b: X = SO2Ph
y
Tamluk 721636, West Bengal, India.
Scheme 1. Retrosynthetic plan for BE-23254 (1).
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.090

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D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
the nonaromatic A ring of the product 2 was expected to
furnish the complete chromophoric structure of the target
molecule.
to aromatization by DDQ in dry benzene under reflux for
3 days to furnish benz[a]anthraquinone 15 in 67% yield
1
(Scheme 3). Comparison of its H NMR and 13C NMR
spectroscopic data with the literature12 data confirmed the
structure.
3. Results and discussion
OH
3.1. Synthesis of naphthalenone 4 (AB ring synthon)
We began the synthesis of hitherto unreported naphthale-
none 4 (Scheme 2) starting from commercially available
6-methoxytetralone (6) through compound 7. Compound 7
was prepared from compound 6 in four steps in 43% overall
yield by the reported sequence7 of reactions. The IR and
NMR spectroscopic data of all the intermediate compounds
were in agreement with the reported7 values. It was then
demethylated by treatment with HBr–AcOH under reflux
conditions to give the hydroxyacid 88 in 81% yield. In order
to protect the acid functionality, the acid 8 was selectively
esterified with DBU–MeI9 in acetonitrile to afford com-
pound 9. Doubly methylated compound 10 was also isolated
as a co-product when a slight excess of MeI was used. Com-
pound 9 on treatment with 1.1 equiv of phenyliodonium
diacetate (PIDA) in MeOH at 0 ꢁC to rt furnished the naph-
thalenone 4 in 67% yield together with a small amount of
unknown byproducts. The structure of this compound was
O
ð1Þ
DDQ
or
OH
OH
OH
11
We then proceeded to execute the crucial annulation reaction
of cyanophthalide 12 with naphthalenone 4 to install the car-
boxylic acid group at C-2 (AB ring synthon). Annulation of
naphthalenone 4 with cyanophthalide 12 was carried out in
t
the presence of BuOLi, which has proved to be the best
base for such purposes, in THF at ꢀ60 ꢁC (CHCl3/liq. N2
bath) under an inert atmosphere. After usual work-up of
the reaction mixture and chromatographic purification of
the crude product, compound 16 was obtained in an unopti-
mized yield of 58%. It is noteworthy that the ester function-
ality in 4 did not interfere with the annulation process. For
aromatization, compound 16 was treated with DDQ
(6.0 equiv) in dry benzene at reflux for 10 days. Monitoring
the course of the reaction required recording 1H NMR spec-
tra of the reaction mixture at regular intervals because TLC
experiments were not useful. Formation of an inseparable
mixture of didehydro intermediate 17 and the desired prod-
uct 18 was revealed by analysis of the 1H NMR spectra. The
formation of didehydro intermediate 17 was ascertained by
appearance of two triplets at d 2.63 and 2.92 for two CH2
groups at C-4 and C-3, respectively, two singlets: one at
d 8.87 for ]CH at C-1 and other at d 13.48 for hydrogen
bonded –OH group at C-6. Although it was possible to re-
1
established by analysis of its IR, H NMR, and 13C NMR
1
spectra. The H NMR spectrum of 4 showed two doublets
at d 6.64 and 6.21 and one doublet of doublets at d 6.63
corresponding to olefinic protons at C-8, C-5, and C-7,
respectively, along with other characteristic signals.
COOR
COOH
1. NaBH4, MeOH
2. POCl3, DMF, heat
O
HBr, AcOH, 81%
3. Ag2O, aq. NaOH, rt
4. H2, Pd-C, EtOH
overall 43%
OMe
OMe
6
OH
8
7: R = H
10: R = Me
DBU, CH3I,
CH3CN, 93%
cord the H NMR spectrum of 18 in CDCl3, its 13C NMR
1
COOMe
COOMe
spectrum could not be recorded due to its poor solubility
in common deuterated solvents (e.g., CDCl3, CD3OD,
acetone-d6, DMSO-d6). This compound was further charac-
terized by analysis using IR spectroscopy and HRMS.
MeO
PhI(OAc)2 (1.1 equiv.),
MeOH, 0 °C-rt, 67%
O
4
OH
9
With the two successes (Schemes 3 and 4), we next exam-
ined annulation of the naphthalenone 4 with isobenzofura-
nones 19 and 20. This model study entails the differences
in the isobenzofuranone parts. Isobenzofuranones 19 and
20 were prepared from ethyl 2-hydroxy-5-methylbenzoate
(26), which, in turn, was obtained in two steps starting
from ethyl acetoacetate and crotonaldehyde according to
the published procedure.13 Transformation of compound
26 to 19 and 20 were achieved in four steps by literature
methods.11,14 Annulation reaction between 20 and 4 in the
presence of tBuOLi under the typical conditions used previ-
ously, afforded the angucycline analog 21 in 69% yield
(Scheme 5) after chromatographic purification. This was
aromatized by DDQ oxidation to give compound 22, which
was demethylated by treatment with anhydrous AlCl3 in
CH2Cl2 to furnish compound 23. Compounds 22 and 23
Scheme 2. Synthesis of naphthalenone 4.
3.2. Model synthetic study of benz[a]anthraquinones
At the outset, the synthesis of compound 15 representing the
chromophoric part of BE-23254 (1) was chosen for the
model study. We were apprehensive that compound 14 might
undergo benzylic oxidation or oxidative dimerization under
the influence of DDQ, which is known to cause such reac-
tions10 with structurally similar hydroxytetralin 11 (Eq. 1).
Yet, the easy accessibility of compound 14 led us to examine
Scheme 3. Isobenzofuranone 1211 was annulated with
t
naphthalenone 13 in the presence of BuOLi in dry THF
at ꢀ60 ꢁC and benz[a]anthraquinone 14 with a nonaromatic
1
A ring was obtained in 65% yield. This was then subjected
were primarily characterized by IR, H NMR, and mass

D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
9591
MeO
O
O
O
CN
O
13
O
DDQ, dry C6H6
reflux, 3 d, 67%
t
BuOLi, THF,
-60 °C-rt, 6 h,
65%
O
OH
O
15
OH
12
14
Scheme 3. Synthesis of model compound 15.
examined a sequence of NBS bromination and HBr elimina-
tion. This sequence was applied to compound 21 (Scheme 6).
COOMe
COOMe
O
12,
MeO
t
BuOLi, THF
CO2Me
CO2Me
-60 °C-rt, 6 h,
58%
O
O
O
OH
O
4
16
Ac2O, pyridine
rt, 95%
DDQ (6 equiv.),
C6H6, reflux,
10 d, 56%
OMe O
OH
OMe O
OAc
24
21
COOMe
O
COOMe
2
NBS (2 equiv.),
benzoyl peroxide,
CCl4, reflux, 3 h
3
1
O
O
4
5
6
OH
CO2Me
Br
CO2Me
O
OH
O
O
18
17
DBU (2 equiv.),
C6H6, rt, 2 h
Br
Scheme 4. Synthesis of model compound 18.
5%
OMe O
25
OAc
spectral data. The poor solubility of the compounds in com-
mon deuterated solvents precluded recording of 13C NMR
spectra. The H NMR spectrum of compound 23 showed
OMe O
22
OH
1
Scheme 6. Bromination and HBr elimination approach for aromatization
study.
two sharp singlets at d 12.10 and 11.80 characteristics of
two H-bonded OH groups present at C-6 and C-8 positions.
In the aromatic region it showed two sharp singlets, one at
d 10.15, characteristic of the proton at C-1 and the other at
d 7.67 for the aromatic proton at C-5. It may be noted that
the use of sulfone phthalide 19 in the above reaction with
naphthalenone 4 provided no annulation product, i.e., 21.
Naphthalenone 4 could be recovered in a substantial amount
from the reaction, whereas sulfone phthalide 19 was de-
stroyed during the reaction. The failure of the reaction is
presumably due to a steric interaction between the sulfone
group of phthalide and the OMe group at C-4a position of
the naphthalenone.
Compound 24, prepared by acetylation of 21, was bromi-
nated with NBS (2 equiv) in the presence of benzoyl perox-
ide and the resulting crude brominated product 25 was
treated with DBU (2 equiv). However, the yield of the
expected aromatized product 22 was very low (5%).
3.3. Synthesis of isobenzofuranones 3a and 3b
(D ring synthons)
For the synthesis of key isobenzofuranones 3a and 3b
(D ring synthons), the phenolic ester 26 was chosen as the
starting material, since it had all the necessary substituents
except the chlorine, and it was easily accessible.13 We
studied its direct chlorination with different chlorinating
agents, while we were aware that methods for selective ortho
In order to find a suitable substitute for the DDQ-promoted
aromatization, which typically gave nearly 50% yields of
the aromatized products for compounds 14, 16, and 21, we
CO2Me
CO2Me
CO2Me
X
O
O
tBuOLi, THF,
MeO
DDQ, benzene,
reflux, 5 d
51%
O
-60 °C-rt, 6 h
69%
O
OMe
OMe O
OH
O
Y
O
--
OH
19: X = SO2Ph
20: X = CN
4
--
21
22: Y = OMe
AlCl3, CH2Cl2, rt
69%
23: Y = OH
Scheme 5. Synthesis of dechloro analog of BE-23254 (1).

9592
D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
Table 1. Product distribution of chlorination of phenol 26
Entry Reagents and conditions Yield of Yield of Yield of
Cl
Cl
Cl
MeI, K2CO3,
Acetone, rt
Me
Me
NBS, AIBN
CCl4, reflux
CHBr2
5 (%)
27 (%)
28 (%)
76%
COOEt
COOEt
COOEt
1
2
3
Cl2 (excess), AcOH, rt
SO2Cl2, 100 ꢁC, 3 h
NCS (1.1 equiv), CCl4,
reflux, 4–5 h
NCS (1.1 equiv), AcOH,
reflux, 4–5 h
NaOCl (1.1 equiv), AcOH, Trace
reflux, 4–5 h
Cl2 (1.2 equiv), AcOH, rt
Cl2 (1.2 equiv), AcOH, rt
(inverse addition)
—
—
11
—
—
53
79
65
—
OH
27
OMe
29
OMe
32
NBS, AIBN
CCl4, reflux
69%
4
5
Trace
35
15
—
49
Cl
Cl
(CH2)6N4,
AcOH (aq.) rt
CH2Br
CHO
6
7
—
—
47
74
21
—
COOEt
COOEt
OMe 30
OMe
33
AgNO3 (aq.),
acetone, rt
chlorination of substituted phenols are rare in the litera-
ture.15 Initially, the phenolic ester was subjected to chlorina-
tion by passing chlorine gas through a stirred solution of the
phenol 26 dissolved in AcOH (entry 1, Table 1; Scheme 7). It
was difficult to control the absorption of the required amount
of chlorine gas. As a result, an excess of chlorine gas was
absorbed and only the dichlorophenol 28 was obtained in
79% yield as a white solid after column chromatographic
purification. The same dichloro compound 28 was also
obtained in 65% yield by heating the phenolic ester 26
with sulfuryl chloride (1.5 equiv). Alternatively, the chlori-
nation at C-3 position of compound 26 was tried with NCS
(1.1 equiv) in CCl4, NCS (1.1 equiv) in AcOH, and aq
NaOCl in AcOH. However, in each of these cases, an insep-
arable mixture of monochloro compounds 5, 27, and di-
chloro compound 28 was obtained in different ratios. In
another mode, the phenol 26 was added to a solution of chlo-
rine gas (1.2 equiv) dissolved in acetic acid (entry 6) and
a 2:1 mixture of monochlorophenol 27 and dichlorophenol
28 was obtained in 68% yield. The monochloro compound
27 was obtained as the sole chlorinated product in 74% yield
on addition of chlorine (1.2 equiv) in acetic acid to a stirred
solution of the phenolic ester 26 taken in acetic acid (entry
7). The structure of product 27 was confirmed by analysis
of 1H NMR, 13C NMR, and NOE spectra and also by a num-
ber of chemical transformations (Scheme 8). In the NOE
spectrum of 27, irradiation of the Me-signal at d 2.62 pro-
duced no NOE enhancement of the Ar-H signal at d 6.79.
NBS, AIBN,
CCl4, reflux,
3-4 h, 76%
Cl
Cl
Cl
X
O
O
CH2ONO2
CO2Et
O
+
O
OMe
OMe
31 (19%)
OMe
34 (18%)
35 X = Br
PhSH, Et3N,
rt, 4-5 h, 50%
36 X = SPh
Scheme 8. Chemical transformations of monochlorophenol 27.
were separated by column chromatography. The chloroph-
thalide 31 was then transformed into phenylthiophthalide
36 by reaction with NBS (1.1 equiv) followed by the treat-
ment of the resulting bromophthalide 35 with a 1:1 mixture
of thiophenol and triethylamine in chloroform at room
temperature.
The above unwanted results on chlorination of phenolic ester
26 led us to select cyclohexenone 37 as the alternative start-
ing material, the immediate precursor of the phenolic ester
26. In the first attempt on the way to compound 5, excess
of chlorine gas was passed through a solution of cyclohexe-
none ester 37 taken in AcOH during 2 h at room temperature
and the resulting crude product was treated with DBU
(2 equiv) to afford the dichloro compound 38 in 43% yield
(Scheme 9). The structure of this product was confirmed
by analysis of its NMR and NOE spectra. In the NOE spec-
trum, irradiation of the Me-signal at d 2.52 produced NOE
enhancement of the Ar-H signal at d 6.87. This indicated
that the Ar-H and the Me group are present on vicinal carbon
atoms of compound 38. Finally, the problem of preparing
monochloro compound 5 was solved by sulfuryl chloride
promoted chlorination of cyclohexenone 37. Its reaction
with sulfuryl chloride (2 equiv) followed by treatment with
DBU (3 equiv) at room temperature afforded, after usual
work-up, the desired chloro compound 5 in 41% yield
(Scheme 9). The structure of this product was confirmed
by analysis of its NMR and NOE spectra. In the NOE spec-
trum, irradiation of the Me-signal at d 2.52 produced NOE
The chlorophenol 27 was methylated with methyl iodide in
the presence of K2CO3 and the methoxy compound 29, when
reacted with NBS (2.2 equiv) and AIBN in CCl4, gave
monobromo derivative 30, instead of dibromo compound
32 (Scheme 8). The monobromo compound 30 was then sub-
jected to Sommelet reaction with urotropine in acetic acid,
but aldehyde 33 was not formed. Alternatively, compound
30 was treated with aqueous silver nitrate solution. After
stirring at room temperature for 2 h, a mixture of chloroph-
thalide 3116 and nitrite 34 was obtained. The two products
Cl
Cl
See table 1
Me
Me
Me
Me
for reagents &
conditions
+
+
CO2Et
Cl
CO2Et
CO2Et
Cl
CO2Et
OH
26
OH
5
OH
OH
28
27
Scheme 7. Product distribution of chlorination of phenol 26.

D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
9593
δ 6.67
δ 6.87
nOe
nOe
δ 2.52
δ 2.52
H
H
1. SO2Cl2 (2 equiv.),
CCl4, rt - reflux
Me
Me
CO2Et
Cl
Cl
Me
CO2Et
1. Cl2, AcOH, rt
2. DBU, rt
43%
2. DBU, rt,
41%
CO2Et
Cl
O
37
OH
5
OH
38
Scheme 9. Chlorination study on cyclohexenone 37.
enhancement of the Ar-H signal at d 6.67. This observation
indicated that the Ar-H and the benzylic CH3 group are pres-
ent on vicinal carbon atoms of compound 5.
synthons 3a and 3b were then prepared according to the
general procedures reported for the preparation of cyanoph-
thalides11 and phenylsulfone phthalides.18 Reaction of
phthalaldehydic acid 41 with KCN in the presence of concd
HCl afforded cyanophthalide 3a in 83% yield. Its structure
was established by analysis of IR, NMR (1H and 13C), and
mass spectral data. Similarly, the corresponding sulfone
phthalide 3b was prepared in 70% yield from phthalalde-
hydic acid 41 by its reaction with phenylsulfinic acid in
the presence of BF3$etherate.
Chlorophenol 5 was then transformed into isobenzofura-
nones 3a and 3b in four steps (Scheme 10). The phenolic
OH group of compound 5 was methylated (Me2SO4,
K2CO3) to give ester 39, which was subjected to benzylic
bromination with NBS (2.2 equiv) to furnish compound 40.
Dibromo compound 40 was hydrolyzed with a refluxing
mixture of AcOH, HCl, and H2O to produce corresponding
phthalaldehydic acid 41. This five-step synthesis of 41 ap-
pears to be competitive to its earlier synthesis.17 Two key
3.4. Total synthesis of BE-23254 (1)
3-Phenylsulfonylphthalides are generally preferred to the 3-
cyanophthalides as the Hauser-donors due to difficulties in
the preparation of the latter. Consequently, we first attemp-
ted to condense sulfone phthalide 3b with naphthalenone 4
(Scheme 11). Their reaction in the presence of lithium
tert-butoxide from ꢀ60 to 0 ꢁC, followed by stirring over-
night at room temperature and routine work-up did not yield
the expected annulation product 2. Naphthalenone 4 could
be recovered from the reaction in a substantial amount,
whereas sulfone phthalide 3b was destroyed during the reac-
tion. This failure with the sulfone phthalide was appre-
hended on the basis of the experiment described for 19
(Scheme 5). However, this experiment was performed to re-
inforce our explanation that this failure was due to the steric
effect. The polar effect of the chlorine atom has little influ-
ence on the failure.
CHBr2
CO2Et
Me
NBS (2.2 equiv.),
benzoyl peroxide,
Me2SO4,
K2CO3, acetone
Cl
Cl
CO2Et
CCl4,
5
reflux, 7 h,
67%
OMe
40
rt, 76%
OMe
39
AcOH, HCl,
H2O, reflux
CN
O
72%
OH
KCN,
conc. HCl, rt
Cl
O
OMe
3a
83%
O
O
Cl
PhSO2H,
OMe
41
BF3.ether
SO2Ph
70%
O
O
Cl
OMe
3b
Alternatively, reaction of cyanophthalide 3a with naphthale-
t
none 4 in the presence of BuOLi at ꢀ60 ꢁC followed
Scheme 10. Synthesis of isobenzofuranones 3a and 3b.
by stirring at room temperature for 6 h provided the
CO2Me
CO2Me
CO2Me
2
tBuOLi, THF
-60 °C-rt
O
X
1
3
4
O
MeO
DDQ, C6H6,
reflux
O
+
71%
Cl
49%
Cl
Cl
O
OMe
O
OMe O
--
OH
OMe O
OH
4
4
42
3b: X = SO2Ph
3a: X = CN
2
CO2H
CO2Me
CO2Me
O
O
O
AlCl3, CH2Cl2,
rt
aq. NaOH, rt
92%
Cl
78%
Cl
Cl
OH
O
OH
OH
O
OH
OMe O
OH
BE-23254 (1)
44
43
Scheme 11. Total synthesis of BE-23254 (1).

9594
D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
tetrahydrobenz[a]anthraquinone 2 in 71% yield, which was
characterized by analysis of IR, NMR (1H and 13C), and
mass spectral data. The 1H NMR spectrum of the compound
2 showed three sharp singlets: at d 13.00 (H-bonded OH
group at C-6), 4.01 (OCH3), and 3.74 (COOCH3). In the
aromatic region, it revealed two one-hydrogen doublets at
d 7.99 and 7.82, and one singlet at d 7.06 for hydrogen at
C-5. The nonequivalent protons of the CH2 group at C-1 ap-
peared as doublet of doublets at d 3.61 and 3.30. Each proton
was equally splitted by the other (Jgem¼18.6 Hz) and un-
equally by the neighboring proton (i.e., a to ester function-
ality) at C-2 (Jvic¼10.0 and 5.6 Hz). IR, 13C NMR, and
mass spectral data of this compound were also in accordance
with the structure. Aromatization of the A-ring in 2 was ef-
fected by DDQ in refluxing benzene to provide 43 in 49%
yield. This reaction required careful monitoring by 1H
NMR spectra of the interrupted reaction mixtures because
the reaction progressed through the formation of inseparable
mixtures of didehydro intermediate 42 and the desired prod-
uct 43. Prolonged refluxing seemed to destroy the aroma-
tized product 43 into an unidentified product. Formation of
the didehydro intermediate 42 was ascertained by the
appearance of two triplets at d 2.89 and 2.60 for two CH2
groups at C-4 and C-3, respectively, and two singlets: one
at d 8.70 for C-1 hydrogen and other at d 13.43 for hydrogen
bonded –OH group. Demethylation of compound 43 was
done by treatment with anhydrous AlCl3 in CH2Cl2 at
room temperature to afford 44 in 78% yield. Base (NaOH)
catalyzed hydrolysis of 44 yielded the natural product BE-
23254 (1) in 92% yield. All the A-ring aromatic compounds
of this series (1, 43, and 44) were characterized by analysis
accordance with the literature procedure.23 The amine 48
was obtained in 45% yield along with hydroxy amine com-
pound 49 in 19% yield.
NO2
Me
Me
Me
AcONO2, Ac2O
-5 to -10 °C
+
O2N
CO2Et
CO2Et
OMe
47 (43%)
CO2Et
OMe
OMe
45
46 (57%)
SnCl2.2H2O,
EtOH-H2O
70 °C, 2 h
Me
Me
+
H2N
CO2Et
H2N
CO2Et
OMe
48 (45%)
OH
49 (19%)
Scheme 12. Synthesis of amine 48.
In order to avoid the formation of 49 and thereby increase the
yield of 48, we submitted compound 46 to hydrogenation
over 10% Pd–C24 in absolute ethanol at room temperature.
In this case (Scheme 13), the amine 48 was obtained in
77% yield with the side product 50 in 18% yield.
H2, 10% Pd-C,
EtOH, rt
Me
Me
Me
C2H5O
+
O2N
CO2Et
H2N
CO2Et
N
H
CO2Et
OMe
OMe
OMe
48 (77%)
46
50 (18%)
1
of IR, H NMR, and HRMS spectra. 13C NMR spectra of
compounds 1, 43, and 44 could not be recorded due to their
poor solubility in common deuterated solvents including
pyridine-d5.
Scheme 13. Reduction of nitro compound 46 to amine 48.
The required fluorophthalide 55 was synthesized from amine
48 in five steps (Scheme 14). Amine 48 was treated with
NaNO2 and HCl followed by cold HPF6 solution to obtain
the corresponding phosphorus hexafluoride salt 51, which
was filtered, dried, and without purification decomposed at
120–125 ꢁC.25 After the decomposition was complete, the
residue was processed in usual manner to yield fluoro com-
pound 52, after purification, in overall 19% yield. Compound
52 was then subjected to benzylic bromination with NBS
(2.2 equiv) to furnish dibromo compound 53, which was then
hydrolyzed with a refluxing mixture of AcOH, HCl, and H2O
to yield corresponding phthalaldehydic acid 54 in 75% yield.
Finally, the cyanophthalide 55 was prepared according to the
general procedure.11 Reaction of phthalaldehydic acid 54
with KCN in the presence of concd HCl afforded, after
column chromatographic purification, the cyanophthalide
55 in 79% yield. Structures of the compounds 52–55 were es-
tablished by the analysis of IR, NMR (1H and 13C), and mass
spectral data. The 1H NMR spectra of compounds 54 and 55
had a pair of double doublets corresponding to C-4 and C-5
hydrogens due to coupling with each other and with fluorine
at C-6. In addition, these also showed a doublet for the me-
thoxy group at C-7 due to its coupling with the fluorine.
3.5. Synthesis of fluoro analog of BE-23254
As a matter of course, our next effort was directed at synthe-
sizing a fluorine-containing analog of BE-23254 (1). It is
well established that the selective introduction of a fluorine
atom or a fluorinated residue into a biologically active mol-
ecule is an effective means for modifying its physicochemi-
cal properties and consequently its physiological behavior.19
For the synthesis of the required fluoro cyanophthalide 55,
we commenced with anisic ester 45, obtained from phenolic
ester 25. Considering the fact that acetyl nitrate is orthose-
lective,20 anisic ester 45 was treated with acetyl nitrate21 at
ꢀ5 to ꢀ10 ꢁC in acetic anhydride (Scheme 12). It yielded
a mixture of ortho- and para-nitro anisic esters 46 and 47
in 57 and 43% yield, respectively. These were separated
by column chromatography and characterized by analysis
of their IR and NMR (1H and 13C) spectra. Both the com-
pounds 46 and 47 showed the same coupling pattern in their
1H NMR spectrum but they were distinguished by compar-
ing the chemical shift of the methyl groups at C-6. In com-
pound 46, the methyl group appeared at d 2.36, while that
in compound 47 appeared at d 2.48 as it is closer to the elec-
tron withdrawing nitro group. These data are comparable to
that of the corresponding methyl esters.22 Ester 46 was then
transformed to the corresponding amine 48 by treatment
with stannous chloride dihydrate in ethanol at 70 ꢁC in
Treatment of naphthalenone 4 with the anion of fluorophtha-
lide 55 (Scheme 15) generated with lithium tert-butoxide in
THF at ꢀ60 ꢁC (CHCl3/liq. N2 bath) under N2 atmosphere
provided tetracyclic compound 56. The structure of the
annulated product 56 was characterized by examination of

D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
9595
Me
Me
Me
1. NaNO2, aq. HCl
Decomposition
0-5 °C
at 120-125 °C
H2N
CO2Et
-
PF6 +N2
CO2Et
2. 65% HPF6,
F
CO2Et
19%
-5 to -10 °C
OMe
OMe
52
OMe
48
51
NBS (2.2 equiv.),
benzoyl peroxide,
CCl4, 57%
CN
OH
O
4
CHBr2
CO2Et
AcOH, HCl,
5
KCN,
H2O, reflux
75%
O
conc. HCl
F
F
F
79%
O
O
OMe
55
OMe
53
OMe
54
Scheme 14. Synthesis of fluoro cyanophthalide 55.
1
IR, NMR, and mass spectral data. Its H NMR spectrum
showed a sharp singlet at d 13.02 for the H-bonded hydroxyl
group at C-6. In the aromatic region, it revealed two double
doublets at d 8.02 (JH–F(o)¼10.1 Hz and JH–H(o)¼8.7 Hz)
and 7.45 (JH–F(m)¼5.0 Hz and JH–H(o)¼8.7 Hz) correspond-
ing to C-10 and C-11 hydrogens. The singlet at d 7.06 corre-
sponds to hydrogen at C-5. In addition, it also exhibited
a doublet at d 4.08 (JOMe–F¼3.3 Hz) for the methoxy group
at C-8 due to its coupling with fluorine and another singlet at
d 3.74 for carbomethoxy group. Due to the inefficiency in the
conversion of 48/52, further investigations with 56 on the
way to obtain fluoro analog of BE-23254 (1) were stalled.
mixture of 2H-chloroform and CCl4, or in mixture of
2H-chloroform and DMSO-d6 with TMS as an internal stan-
dard. Chemical shifts are expressed in d unit and 1H–1H cou-
pling constants in hertz. 13C NMR spectra were recorded on
€
a 50, 75, or a 125 MHz spectrometer (Brucker) instrument
2
with solution of compounds in H-chloroform, mixture of
2H-chloroform and CCl4, and mixture of 2H-chloroform
and DMSO-d6. IR spectra were recorded on a Thermo Nico-
let Nexus 870 FTIR spectrometer using KBr pellets. EIMS
(70 eV) spectra were taken using a VG Autospec M mass
spectrometer. Elemental analyses were carried out by using
an elemental analyzer VARIO EL instrument. All solvents
for chromatography (column and preparative layer chroma-
tography) were distilled prior to use. In most of the column
chromatographic separations, ethyl acetate, chloroform, and
petroleum ether (60–80 ꢁC) were used as eluants. Columns
were prepared with silica gel (60–120 mesh). For preparative
thin layer chromatographic (PLC) separations, the layer was
prepared over a glass plate using water gel. The mixture of
silica gel-GF254 and silica gel-G was used for the PLC plate
preparation. The phrase ‘usual work-up’ or ‘worked up in
usual manner’ refers to washing of the organic phase with
water and brine, drying (Na2SO4), filtration, and concentra-
tion under reduced pressure. Solid compounds were recrys-
tallized from ethyl acetate–petroleum ether or otherwise
mentioned.
CO2Me
CO2Me
O
CN
O
MeO
tBuOLi, THF
+
-60 °C-rt, 6 h,
F
F
74%
O
OMe
55
O
OMe O
56
OH
4
Scheme 15. Annulation of cyanophthalide 55 with naphthalenone 4.
4. Conclusions
In conclusion, we have presented a regiospecific total syn-
thesis of BE-23254 (1) starting from commercially available
6-methoxytetralone, and showcased the applicability and
brevity of Hauser annulation–DDQ-promoted aromatization
strategy in the synthesis of angucyclines. Use of the strategy
has culminated in the synthesis of several angucycline ana-
logs, namely 15, 18, 22, and fluoro analog 56. We have
also executed a new regiospecific preparation of ortho-chlo-
rinated phenols based on chlorinative aromatization of a cy-
clohexenone derivative (Scheme 9). It would be interesting
to examine the biological activities of the newly prepared
A-ring nonaromatic benz[a]anthraquinone derivatives like
2, 14, 16, 21, and 56.
5.2. General procedure for annulation reaction
To a stirred solution of lithium tert-butoxide (9.84 mmol) in
THF (40 mL) at ꢀ60 ꢁC (chloroform/liq. N2 bath) under an
inert atmosphere was added a solution of a phthalide
(3.28 mmol) in THF (5 mL). The resulting yellowish solu-
tion was stirred at ꢀ60 ꢁC for 30 min, after which a solution
of a Michael acceptor (1.0–1.5 equiv unless otherwise
stated) in THF (5 mL) was added to it. Cooling bath was
removed after about 1 h at ꢀ60 ꢁC and the reaction mixture
was brought to room temperature over a period of 1 h and
further stirred for 2–6 h. The reaction was then quenched
with 10% NH4Cl (15 mL) and the resulting solution was
concentrated in vacuo. Generally, a bright yellow solid ap-
peared, which was filtered and washed with 1:1 mixture
(20 mL) of diethyl ether and petroleum ether. Otherwise,
the residue was diluted with ethyl acetate (50 mL) and the
layers were separated. The aqueous layer was extracted
with ethyl acetate (3ꢂ25 mL). The combined extracts
were washed with brine, H2O, dried (Na2SO4), and
5. Experimental
5.1. General
1H NMR spectra were recorded on a 200, 300, or a 500 MHz
spectrometer (Brucker) as solution in 2H-chloroform or
€

9596
D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
concentrated. The crude product was purified by column
chromatography or by recrystallization to get a pure product.
129, 111, 97, 83, 69; HRMS m/z (ESI) calcd for
C19H935ClO6 (M+ꢀH): 367.0009; found: 367.0026.
5.3. General procedure for DDQ oxidation
5.5.2. Methyl 9-chloro-6-hydroxy-8-methoxy-1,2,3,4-tet-
rahydrobenz[a]anthracene-7,12-dione-2-carboxylate
(2). This compound was prepared as a yellow solid by annu-
lation of 6-chloro-7-methoxy cyanophthalide (3a) with
Michael acceptor 4 following the general procedure in Sec-
tion 5.2. Yield: 71%; mp: 135–136 ꢁC; nmax (KBr, cmꢀ1):
3408, 1733, 1634, 1273, 1025, 763, 697; 1H NMR
(200 MHz, CDCl3+CCl4): 13.00 (s, 1H), 7.99 (d, 1H,
J¼8.0 Hz), 7.82 (d, 1H, J¼8.0 Hz), 7.06 (s, 1H), 4.01 (s,
3H), 3.74 (s, 3H), 3.61 (dd, 1H, J¼5.6 and 18.6 Hz), 3.30
(dd, 1H, J¼10.0 and 18.6 Hz), 2.94–2.89 (m, 2H), 2.80–
2.68 (m, 1H), 2.21–2.12 (m, 1H), 2.03–1.90 (m, 1H); 13C
NMR (50 MHz, CDCl3): 187.8, 183.7, 175.4, 160.7, 156.1,
147.8, 136.5, 135.8, 135.2, 131.8, 129.9, 126.2, 124.5,
124.2, 116.4, 61.6, 51.9, 39.8, 30.9, 29.9, 24.1; MS m/z
(EI): 400 (M+), 369, 340, 326, 322, 297, 284, 256, 236,
197; HRMS m/z (ESI) calcd for C21H1335ClO6 (M++H):
401.0792; found: 401.0755.
To a stirred solution of 1,2,3,4-tetrahydrobenz[a]anthraqui-
none compound (280 mmol) in dry benzene (10 mL) under
an inert atmosphere was added DDQ (6 equiv). The resulting
mixture was refluxed with stirring for 3–12 days under inert
atmosphere. The progress of the reaction was monitored by
1H NMR spectroscopy and disappearance of the signals in
the aliphatic region was followed. TLC was not useful for
the purpose because of the formation of the inseparable mix-
tures of didehydro compound and final aromatized product
at the intermediate stage of the reaction. After completion
of the reaction, benzene was removed under reduced pres-
sure. The aromatized product was purified by column chro-
matography using mixtures of CHCl3 and petroleum ether
(5:1) as eluant.
5.4. General procedure for O-demethylation
of phenolic ether
5.5.3. 6-Chloro-3-cyano-7-methoxyphthalide (3a). To a
solution of KCN (1.25 g, 19.2 mmol) in water (5 mL) was
added phthalaldehydic acid 41 (0.5 g, 2.78 mmol). The clear
reddish solution was stirred for 10 min at room temperature
and cooled to 0 ꢁC. After addition of ice (w5 g), concentrated
HCl (4 mL) was added and the resulting clear colorless
solution was removed from the ice bath and stored at room
temperature for 5 h. A white precipitate deposited. This
was filtered, dried, and recrystallized from ethyl acetate to
give a white crystalline solid (430 mg, 1.92 mmol). Yield:
83%; mp: 90–91 ꢁC; nmax (KBr, cmꢀ1): 1788, 1601, 1390,
To a stirred solution of a methoxy compound (0.105 mmol)
in dry CH2Cl2 (2 mL) at 0 ꢁC under Ar-atmosphere was
added anhydrous AlCl3 (5 equiv). After 1 h of stirring at
0 ꢁC, the reaction mixture was allowed to come to room tem-
perature and stirring was continued for additional 6 h. The
reaction mixture was quenched with 2 M HCl (4 mL). Usual
work-up of the organic extract afforded a solid that was
further purified by column chromatography (3:1 mixture
of CHCl3/petroleum ether).
1
5.5. General procedure of O-methylation
of phenolic compounds
1024, 768; H NMR (200 MHz, CDCl3+CCl4): 7.84–7.80
(d, 1H, J¼8.0 Hz), 7.33–7.28 (d, 1H, J¼8.0 Hz), 6.97 (s,
1H), 4.21 (s, 3H); 13C NMR (50 MHz, CDCl3): 163.8,
155.5, 141.6, 137.5, 130.3, 117.4, 116.6, 113.2, 64.6, 62.9;
MS m/z (EI): 223 (M+), 205, 194, 177, 167, 149, 137, 100,
75; HRMS m/z (ESI) calcd for C10H6N35ClO3 (M++H):
224.0114; found: 224.0106.
A phenolic compound (3.0 mmol) was dissolved in dry
acetone (15 mL) under N2-atmosphere. To this solution
were added dry K2CO3 (15 mmol) and Me2SO4 (6 mmol)
(freshly washed with cold water, saturated NaHCO3 solu-
tion, brine, and then dried over anhydrous K2CO3). After
2 h of reflux, on completion of the reaction, inorganic salts
were filtered and the filtrate was concentrated. The residue
was diluted with ether, treated with Et3N (6 mmol) at room
temperature, and stirred for 30 min. The reaction mixture
was then diluted with ethyl acetate (50 mL), washed with
water and 5% HCl, and subjected to usual work-up to get
a crude residue, which was further purified by recrystalliza-
tion or by column chromatography to give a pure methoxy
compound.
5.5.4. 3-Benzenesulfonyl-6-chloro-7-methoxy-3H-iso-
benzofuran-1-one (3b). This compound was prepared
from compound 41 following the procedure of Mal et al.18
To a stirred mixture of phthalaldehydic acid 41 (200 mg,
0.93 mmol) and a freshly prepared benzenesulfinic acid
(400 mg, 2.82 mmol) in dry dichloromethane (5 mL) at
room temperature under Ar-atmospherewas added 4–5 drops
of boron trifluoride diethyl etherate. The mixture was stirred
for about 12 h. A pale yellow solid separated on addition of
ice-cold water (15 mL) into the reaction mixture. It was fil-
tered and recrystallized from ethyl acetate–hexane to give
sulfone phthalide 3b as white crystalline solid (220 mg,
0.65 mmol). Yield: 70%, mp: 138–139 ꢁC; nmax (KBr,
cmꢀ1): 1781, 1596, 1469, 1348, 1155, 1004, 835, 719, 682,
593; 1H NMR (200 MHz, CDCl3): 7.84–7.48 (m, 7H), 6.07
(s, 1H), 4.01 (s, 3H); 13C NMR (50 MHz, CDCl3): 164.2,
155.2, 139.5, 137.1, 135.0, 140, 130.5, 129.7, 129.3, 120.1,
118.3, 89.5, 62.0; HRMS m/z (ESI) calcd for C15H1135ClO5S
(M++H): 339.0094; found: 339.0107.
5.5.1. BE-23254 (1). To a stirred solution of ester compound
44 (20 mg, 0.05 mmol) in methanol (5 mL), 20% aq solution
of NaOH (2 mL) was added. The resulting pink colored
solution was allowed to stir overnight. Then the reaction
mixture was acidified with dilute HCl and extracted with
ethyl acetate (3ꢂ30 mL). Usual work-up of the organic ex-
tract afforded a red solid that was further purified by column
chromatography (3:1 CHCl3/petroleum ether). Yield: 92%;
mp: 324–326 ꢁC; nmax (KBr, cmꢀ1): 3409, 1705, 1618,
1
1425, 1233, 1050, 759; H NMR (200 MHz, pyridine-d5):
d 10.9 (s, 1H), 8.55 (d, 1H, J¼8.3 Hz), 7.90–7.81 (m, 4H);
5.5.5. Methyl 1,2,3,4-tetrahydro-4a-methoxy-6-oxo-
naphthalene-2-carboxylate (4). To a stirred solution of
MS m/z (EI): 368 (M+), 354, 323, 256, 236, 194, 152, 137,

D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
9597
compound 9 (300 mg, 1.46 mmol) in methanol (10 mL) at
0 ꢁC under N2 atmosphere was portionwise added PIDA
(560 mg, 1.74 mmol). The temperature was held at 0 ꢁC
for about 30 min. Then the mixture was allowed to come
to ambient temperature during a period of 1 h. Bulk of meth-
anol was removed under reduced pressure and the residue
upon quick silica gel filtration afforded compound 4 as
waxy solid. Yield: 65%; nmax (KBr, cmꢀ1): 1735, 1667,
1636, 1441, 1305, 1207, 1085, 987, 891; 1H NMR
(200 MHz, CDCl3): 6.64 (d, 1H, J¼10.0 Hz), 6.63 (dd,
1H, J¼1.9 and 10.0 Hz), 6.21 (d, 1H, J¼1.4 Hz), 3.65 (s,
3H), 3.02 (s, 3H), 2.53–2.20 (m, 5H), 1.60–1.41 (m, 2H);
13C NMR (50 MHz, CDCl3): 185.8, 174.6, 160.5, 149.8,
131.3, 127.1, 72.7, 51.82, 51.7, 40.5, 37.5, 31.0, 29.9. No
attempt was made for preparing an analytical sample due
to its propensity to decomposition on silica gel chromato-
graphy or standing.
acid was removed. Usual work-up of the residue furnished
the desired product 8 as a white solid. This was recrystallized
from ethyl acetate and petroleum ether. Yield: 81%; mp:
137–138 ꢁC; nmax (KBr, cmꢀ1): 3257, 1691, 1608, 1456,
1239, 942; 1H NMR (200 MHz, DMSO-d6+CDCl3): d 7.72
(d, 1H, J¼8.0 Hz), 6.46–6.38 (m, 2H), 3.91 (br s, 1H),
2.75–2.39 (m, 5H), 2.04–1.94 (m, 1H), 1.72–1.59 (m, 1H);
13C NMR (50 MHz, CDCl3): d 176.9, 154.2, 136, 129.0,
124.9, 114.3, 112.7, 39.3, 30.1, 27.8, 25.0.
5.5.9. Methyl 6-hydroxy-1,2,3,4-tetrahydronaphthalene-
2-carboxylate (9). This was prepared in accordance with
the procedure9 of Mal. To a solution of 1,2,3,4-tetrahydro-6-
hydroxynaphthalene-2-carboxylic acid (1.00 g, 7.81 mmol)
and DBU (1.20 g, 7.88 mmol) in acetonitrile (15 mL) cooled
to 0 ꢁC was slowly added methyl iodide (0.5 mL, 8.1 mmol)
over 5 min. The resulting solution was stirred for 30 min at
0 ꢁC and then for 2 h at room temperature. Solvent was re-
moved under reduced pressure and the residue was diluted
with water (30 mL). The aqueous solution was extracted
with ether (3ꢂ25 mL). The combined organic layer was
washed with NaHCO3 solution (20 mL), brine, and concen-
trated. Purification of the crude residue by column chromato-
graphy (3:7 mixture of ethyl acetate–petroleum ether) gave
compound 9 as a white solid. Yield: 96%; mp: 90–91 ꢁC;
nmax (KBr, cmꢀ1): 3439, 1701, 1619, 1587, 1499, 1266,
5.5.6. Ethyl 3-chloro-2-hydroxy-6-methylbenzoate (5). To
the stirred solution of cyclohexenone 37 (4.22 g, 23.2 mmol)
in CCl4 at 0 ꢁC was added SO2Cl2 (3.8 mL, 46.9 mmol)
dropwise. The reaction mixture was allowed to stir for addi-
tional half an hour at room temperature. Thereafter, it was
heated at reflux for 4 h. After completion of the reaction,
the product was extracted with dichloromethane, dried
over sodium sulfate, and solvent was then removed. The
crude residue was then dissolved in benzene (10 mL) and
treated with 3 equiv of DBU with occasional stirring at
room temperature for about 4–5 h. Benzene was removed
under reduced pressure. Finally, the mixture was extracted
with ethyl acetate (3ꢂ25 mL) and washed with cold 10%
aq HCl (15 mL). The extract was worked up in usual manner
to give the desired product, which was further purified by
column chromatography using petroleum ether and ethyl
acetate (15:1) to afford a pure product 5 as white solid
(2.04 g). Yield: 41%; mp: 55–56 ꢁC; nmax (KBr, cmꢀ1):
1
1221, 1145, 1009, 808, 584; H NMR (200 MHz, CDCl3):
d 6.93 (d, 1H, J¼8.2 Hz), 6.65 (dd, 1H, J¼2.0 and 8.2 Hz),
6.59 (d, 1H, J¼2.0 Hz), 3.74 (s, 3H), 2.95–2.89 (m, 2H),
2.82–2.63 (m, 3H), 2.22–2.10 (m, 1H), 1.89–1.75 (m, 1H);
13C NMR (50 MHz, CDCl3): d 176.6, 153.9, 136.9, 129.0,
126.6, 115.1, 113.4, 51.9, 40.2, 30.9, 28.5, 25.7; HRMS m/z
(ESI) calcd for C12H14O3 (M+ꢀH): 205.0779; found:
205.0788.
5.5.10. Methyl 1,2,3,4-tetrahydro-6-methoxynaphtha-
lene-2-carboxylate (10). This product was obtained as a
side product during the esterification of compound 8 with
DBU–MeI in acetonitrile. Colorless liquid. Yield: 5%;
nmax (KBr, cmꢀ1): 1734, 1613, 1502, 1443, 1265, 1227,
1166, 1035, 821; 1H NMR (200 MHz, CDCl3+CCl4):
d 6.98 (d, 1H, J¼8.3 Hz), 6.64 (dd, 1H, J¼2.1 and
8.3 Hz), 6.57 (d, 1H, J¼2.1 Hz), 3.76 (s, 3H), 3.72 (s, 3H),
2.84 (m, 4H), 2.68 (m, 1H), 2.18 (m, 1H), 1.85 (m, 1H);
13C NMR (50 MHz, CDCl3+CCl4): d 175.3, 157.6, 136.3,
129.6, 126.6, 113.1, 112.0, 54.8, 51.3, 39.9, 30.7, 28.6, 25.6.
1
3442, 1663, 1424, 1256, 1205, 802; H NMR (200 MHz,
CDCl3+CCl4): 11.97 (s, 1H), 7.37 (d, 1H, J¼8.0 Hz), 6.67
(d, 1H, J¼8.0 Hz), 4.50 (q, 2H, J¼7.0 Hz), 2.52 (s, 3H),
1.44 (t, 3H, J¼7.0 Hz); 13C NMR (50 MHz, CDCl3):
172.4, 158.1, 140, 134, 122.8, 120, 113.6, 62.1, 23.8, 14.1;
HRMS m/z (ESI) calcd for C10H1135ClO3 (M++H):
215.0475; found: 215.0461.
5.5.7. 1,2,3,4-Tetrahydro-6-methoxynaphthalene-2-car-
boxylic acid (7). This compound was prepared following
the procedure reported by Reddy and Rao7 in four steps start-
ing from 6-methoxytetralone (6) . White solid. Yield: 91%,
mp: 146–147 ꢁC (lit.7 mp: 152 ꢁC). nmax (KBr, cmꢀ1):
5.5.11. 6-Hydroxybenz[a]anthracene-7,12-dione (15).
This compound was prepared from 14 according to the gen-
eral procedure in Section 5.3. Red solid. Yield: 67%; mp:
203 ꢁC (lit.12 mp: 201–204 ꢁC); nmax (KBr, cmꢀ1): 3429,
1641, 1589, 1442, 1379, 1307; 1H NMR (300 MHz,
CDCl3): d 12.46 (s, 1H), 9.49–9.46 (m, 1H), 8.30–8.28 (m,
2H), 7.82 (m, 2H), 7.88–7.77 (m, 1H), 7.74–7.69 (s, 1H),
7.58–7.52 (m, 2H); 13C NMR (50 MHz, CDCl3): d 190.1,
185.4, 156.8, 139.2, 135.0, 133.6, 132.0, 129.9, 129.5,
128.9, 128.5, 127.9, 127.3, 127.2, 126.4, 126.2, 121.1, 119.5.
1
2947, 1694, 1431, 1302, 1264, 959; H NMR (200 MHz,
CDCl3+DMSO-d6): d 6.86 (1H, d, J¼8.0 Hz), 6.57–6.46
(m, 2H), 5.15 (br s, 1H), 2.80–2.66 (m, 4H), 2.60–2.43 (m,
1H), 2.12–1.99 (m, 1H), 1.74–1.60 (m, 1H); 13C NMR
(50 MHz, CDCl3+DMSO-d6): d 176.6, 156.7, 136.1,
129.0, 126.4, 112.5, 111.3, 54.3, 39.1, 30.0, 27.9, 24.9;
HRMS m/z (ESI) calcd for C12H14O3 (M++H): 207.1021;
found: 207.1014.
5.5.8. 6-Hydroxy-1,2,3,4-tetrahydronaphthalene-2-car-
boxylic acid (8). A mixture of naphthalene-2-carboxylic
acid 7 (2.5 g, 12.13 mmol), 20 mL of hydrobromic acid
(48% aq solution), and 20 mL of acetic acid was heated at
reflux for 3–4 h. After completion of the reaction, acetic
5.5.12. Methyl 6-hydroxy-1,2,3,4-tetrahydrobenz[a]-
anthracene-7,12-dione-2-carboxylate (16). This compound
was prepared as a yellow solid by annulation of cyano-
phthalide 12 with Michael acceptor 4 following the gen-
eral procedure of annulation in Section 5.2. Yield: 58%;

9598
D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
mp: 196–197 ꢁC; nmax (KBr, cmꢀ1): 3435, 1739, 1660, 1634,
1587, 1456, 1360, 1283, 1250, 1176, 1017, 795, 722; H
6 h at ambient temperature and then poured into crushed ice
(25 g) and extracted with ether (3ꢂ15 mL). The extract was
washed several times with CuSO4 solution followed by usual
work-up gave a crude product. This was purified by column
chromatography (ethyl acetate–petroleum ether) to furnish
24 as a yellow solid. Mp: 168–169 ꢁC; nmax (KBr, cmꢀ1):
1768, 1727, 1668, 1587, 1469, 1369, 1257, 1031, 944,
1
NMR (200 MHz, CDCl3+CCl4): 13.03 (s, 1H), 8.40–8.09
(m, 2H), 7.92–7.60 (m, 2H), 7.04 (s, 1H), 3.75 (s, 3H),
3.64–3.61 (m, 1H), 3.40–3.25 (m, 1H), 2.96–2.89 (m, 2H),
2.79–2.65 (m, 1H), 2.15–2.10 (m, 1H), 2.05–1.92 (m, 1H);
13C NMR (50 MHz, CDCl3): 188.7, 175.4, 160.9, 148.1,
135.5, 134.5, 133.4, 132.3, 130.5, 130.1, 127.3, 126.2,
124.1, 121.3, 115.7, 51.9, 39.9, 31.0, 30.0, 24.1; HRMS
m/z (ESI) calcd for C20H16O5 (M++H): 337.1017; found:
337.1021.
1
790, 759, 678, 584; H NMR (200 MHz, CDCl3): d 7.74–
7.58 (m, 3H), 7.09 (s, 1H), 4.07 (s, 3H), 3.73 (s, 3H),
3.68–3.58 (m, 1H), 3.43–3.29 (m, 1H), 2.97–2.89 (m, 2H),
2.78–2.68 (m, 1H), 2.47 (s, 3H), 2.17–2.03 (m, 1H), 1.98–
1.86 (m, 1H); 13C NMR (50 MHz, CDCl3): 185.7, 181.9,
175.3, 170.1, 159, 147.3, 144.1, 136.8, 136.1, 134.5,
132.6, 129.8, 126.5, 122.1, 119.1, 117.1, 56.6, 51.9, 39.7,
31, 29.4, 24.1, 21.2; HRMS m/z (ESI) calcd for C23H20O7
(M++H): 409.1229; found: 409.1239.
5.5.13. Methyl 6-hydroxybenz[a]anthracene-7,12-dione-
2-carboxylate (18). This compound was prepared from 16
according to the general procedure in Section 5.3. Red solid.
Yield: 56%; mp: 262–263 ꢁC; nmax (KBr, cmꢀ1): 3444,
1
1720, 1639, 1587, 1533, 1662, 1319, 1275, 1216, 748; H
NMR (200 MHz, CDCl3): 12.56 (s, 1H), 10.19 (s, 1H),
8.36–8.25 (m, 2H), 8.14 (dd, 1H, J¼2.0 and 8.0 Hz), 7.91–
7.69 (m, 4H), 4.02 (s, 3H); HRMS m/z (ESI) calcd for
C20H12O5 (M++H): 333.0763; found: 333.0761.
5.5.18. Ethyl 3-chloro-6-hydroxy-2-methylbenzoate (27).
To a stirred solution of ethyl 2-hydroxy-6-methylbenzoate
(26) (1 g, 5.55 mmol) in acetic acid (5 mL) was added drop-
wise a solution of chlorine (0.470 g, 6.62 mmol) in acetic
acid (3 mL) and stirring was continued for additional 2 h.
The solution was evaporated to dryness and the residue
was extracted with ethyl acetate (2ꢂ25 mL) and usual
work-up of the extract furnished the product 27, which
was further purified by column chromatographic separation
using petroleum ether–ethyl acetate (10:1). White solid.
Yield: 75%; mp: 54–55 ꢁC; nmax (KBr, cmꢀ1): 3439, 1664,
5.5.14. Methyl 6-hydroxy-8-methoxy-1,2,3,4-tetrahydro-
benz[a]anthracene-7,12-dione-2-carboxylate (21). This
compound was prepared by annulation of cyanophthalide
20 with Michael acceptor 4 following the general procedure
in Section 5.2. Orange solid. Yield: 69%; mp: 174–175 ꢁC;
nmax (KBr, cmꢀ1): 3432, 1730, 1632, 1582, 1466, 1361,
1290, 1229, 1174, 1031, 1065, 948, 919, 838, 785; 1H
NMR (200 MHz, CDCl3): d 13.23 (s, 1H), 7.86 (d, 1H,
J¼7.8 Hz), 7.72 (dd, 1H, J¼7.8 and 8.2 Hz), 7.30 (d, 1H,
J¼8.2 Hz), 7.03 (s, 1H), 4.01 (s, 3H), 3.70 (s, 3H), 3.68–
3.56 (m, 1H), 3.38–3.24 (m, 1H), 2.97–2.85 (m, 2H),
2.80–2.65 (m, 1H), 2.20–1.80 (m, 2H).
1
1597, 1452, 1382, 1320, 1293, 1213, 1023, 914; H NMR
(200 MHz, CDCl3): 10.95 (s, 1H), 7.38 (d, 1H,
J¼10.0 Hz), 6.79 (d, 1H, J¼10.0 Hz), 4.44 (q, 2H,
J¼7.0 Hz), 2.62 (s, 3H), 1.43 (t, 3H, J¼7.0 Hz); 13C NMR
(50 MHz, CDCl3): 170.7, 160.6, 137.6, 134.7, 125.8,
122.6, 116.4, 62.0, 19.4, 14.0; HRMS m/z (ESI) calcd for
C10H1135ClO3 (M++H): 215.0475; found: 215.0466.
5.5.15. Methyl 6-hydroxy-8-methoxybenz[a]anthracene-
7,12-dione-2-carboxylate (22). This compound was pre-
pared from 21 according to the general procedure in Section
5.3. Red solid. Yield: 51%; mp: 266–267 ꢁC; nmax (KBr,
cmꢀ1): 3414, 1710, 1643, 1452, 1286, 1255, 1221, 1033,
5.5.19. Ethyl 3,5-dichloro-2-hydroxy-6-methylbenzoate
(28). To a stirred solution of phenolic ester 26 (1.5 g,
8.3 mmol) in acetic acid, excess of chlorine gas (generated
by dropwise addition of concd HCl to solid KMnO4) was ab-
sorbed at room temperature for 2 h. After completion of the
reaction, acetic acid was removed under reduced pressure
and the residue was extracted with ethyl acetate (3ꢂ20 mL)
and usual work-up of the combined extract furnished crude
product 28, which was purified by column chromatography.
Yield: 79%; nmax (KBr, cmꢀ1): 3408, 1577, 1453, 1387,
1319, 1287, 1278, 1031, 957, 808, 670; 1H NMR (200 MHz,
CDCl3+CCl4): 11.31 (s, 1H), 7.53 (s, 1H), 4.53–4.40 (q, 2H,
J¼7.2 Hz), 2.56 (s, 3H), 1.48–1.40 (t, 3H, J¼7.2 Hz); 13C
NMR (50 MHz, CDCl3): 170.4, 156.1, 136.6, 134.3, 125.7,
120.4, 115.6, 62.7, 19.3, 14.1; HRMS m/z (ESI) calcd for
C10H1035Cl2O3 (M++H): 249.0035; found: 249.0039.
1
939, 763. H NMR (200 MHz, CDCl3): d 12.67 (s, 1H),
9.98 (s, 1H), 8.06 (d, 1H, J¼9.0 Hz), 7.90 (d, 1H,
J¼7.7 Hz), 7.72 (m, 2H), 7.60 (s, 1H), 7.31 (d, 1H,
J¼8.1 Hz), 4.04 (s, 3H), 3.95 (s, 3H); HRMS m/z (ESI) calcd
for C21H14O6 (M++H): 363.0869; found: 363.0872.
5.5.16. Methyl 6,8-dihydroxybenz[a]anthracene-7,12-di-
one-2-carboxylate (23). This compound was prepared as
a brick red solid by AlCl3 catalyzed demethylation of com-
pound 22 following the procedure adopted for compound 43.
Yield: 69%; mp: 278–279 ꢁC; nmax (KBr, cmꢀ1): 3410,
1716, 1633, 1590, 1457, 1409, 1309, 1223, 1106, 1081,
1
758; H NMR (200 MHz, CDCl3): d 12.10 (1H, s), 11.80
(s, 1H), 10.15 (s, 1H), 8.13 (d, 1H, J¼8.6 Hz), 7.85 (d, 1H,
J¼7.6 Hz), 7.79–7.68 (m, 2H), 7.67 (s, 1H), 7.31 (d, 1H,
J¼8.3 Hz), 4.02 (s, 3H); HRMS m/z (ESI) calcd for
C20H12O6 (M++H): 349.0712; found: 349.0721.
5.5.20. Ethyl 3-chloro-6-methoxy-2-methylbenzoate (29).
This compound was prepared from ethyl 3-chloro-6-hy-
droxy-2-methylbenzoate (27) following the general proce-
dure in Section 5.5. Colorless liquid. Yield: 76%; nmax
(KBr, cmꢀ1): 2988, 1733, 1566, 1468, 1261, 1024, 808;
1H NMR (200 MHz, CDCl3+CCl4): 7.30 (d, 1H, J¼8 Hz),
6.70 (d, 1H, J¼8 Hz), 4.40 (q, 2H, J¼7 Hz), 3.79 (s, 3H),
2.81 (s, 3H), 1.37 (t, 3H, J¼7 Hz); 13C NMR (50 MHz,
CDCl3): 167.4, 154.7, 133.8, 130.3, 126.3, 125.7, 109.8,
61.4, 56.0, 17.0, 14.1.
5.5.17. Methyl 6-acetoxy-8-methoxy-1,2,3,4-tetrahydro-
benz[a]anthracene-7,12-dione-2-carboxylate (24). Phe-
nolic compound 20 (100 mg, 0.27 mmol) was dissolved in
a mixture of distilled acetic anhydride (0.5 mL) and pyridine
(1.5 mL). The resulting solution was allowed to stir for about

D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
9599
5.5.21. Ethyl 2-bromomethyl-3-chloro-6-methoxybenzoate
(30). Benzylic bromination was performed using 1.1 equiv
of NBS following the procedure adopted for the preparation
of compound 40 from 39. 1H NMR (200 MHz, CDCl3+CCl4):
7.37 (d, 1H, J¼8.8 Hz), 6.83 (d, 1H, J¼8.8 Hz), 4.53 (s, 2H),
4.48 (q, 2H, J¼7.2 Hz), 3.83 (s, 3H), 1.42 (t, 3H, J¼7.2 Hz).
removed in vacuo. The product was extracted with ethyl
acetate (3ꢂ15 mL). The extract was dried over Na2SO4
and solvent was removed. The residue was then dissolved
in CCl4 (10 mL) and treated with 2 equiv of DBU with
stirring at room temperature. Stirring was continued for
5–6 h. The reaction mixture was extracted with ethyl acetate
(3ꢂ10 mL) and washed with cold 10% aq HCl. The extract
was worked up in usual manner to give a crude product,
which was purified by column chromatography to get
pure 38. White solid. Yield: 43%; mp: 98–99 ꢁC; nmax
5.5.22. 4-Chloro-7-methoxyphthalide (31). An aqueous
solution of silver nitrate (0.270 g, 1.6 mmol) was added to
50% ethanolic solution of ethyl 2-bromomethyl-3-chloro-
6-methoxybenzoate (30) (0.410 g, 1.33 mmol). The result-
ing mixture was then stirred at room temperature for about
4–5 h. Solid materials were filtered off and the filtrate was
evaporated. The residue on usual work-up furnished a crude
mixture of products 31 and 34. Phthalide 31 was separated
by column chromatographic separation using petroleum
ether and ethyl acetate (3:1). White solid. Yield: 19%; mp:
163–164 ꢁC (lit.16 mp: 167–168 ꢁC); nmax (KBr, cmꢀ1):
1759, 1485, 1288, 1028, 819; 1H NMR (200 MHz,
CDCl3+CCl4): 7.54 (d, 1H, J¼8.6 Hz), 6.92 (d, 1H,
J¼8.6 Hz), 5.20 (s, 2H), 3.99 (s, 3H); 13C NMR (50 MHz,
CDCl3+CCl4): 167.3, 157.4, 146.6, 135.2, 118.9, 115.2,
112.4, 67.4. 56.1; HRMS m/z (ESI) calcd for C9H735ClO3
(M+ꢀH): 197.0005; found: 197.0004.
1
(KBr, cmꢀ1): 3445, 1657, 1387, 1259, 1193, 860, 800. H
NMR (200 MHz, CDCl3+CCl4): 12.33 (s, 1H), 6.87 (s,
1H), 4.46 (q, 2H, J¼7.2 Hz), 2.52 (s, 3H), 1.44 (t, 3H,
J¼7.2 Hz); 13C NMR (50 MHz, CDCl3): 171.2, 159.7,
140.0, 138.2, 134.0, 123.6, 111.7, 62.4, 23.8, 14.1; HRMS
m/z (ESI) calcd for C10H1035Cl2O3 (M++H): 249.0035;
found: 249.0037.
5.5.27. Ethyl 3-chloro-2-methoxy-6-methylbenzoate (39).
This compound was prepared as a colorless liquid from phe-
nolic ester 5 (2.11 g, 9.84 mmol) following the general pro-
cedure in Section 5.5. Yield: 68%; nmax (KBr, cmꢀ1): 1731,
1461, 1272, 1107, 807; 1H NMR (200 MHz, CDCl3+CCl4):
7.27 (d, 1H, J¼8.0 Hz), 6.88 (d, 1H, J¼8.0 Hz), 4.41 (q, 2H,
J¼7.0 Hz), 3.90 (s, 3H), 2.28 (s, 3H), 1.39 (t, 3H, J¼7.0 Hz);
13C NMR (50 MHz, CDCl3+CCl4): 166.8, 152.9, 134.9,
130.9, 130.6, 126.3, 125.1, 61.7, 61.1, 18.8, 14.2.
5.5.23. Ethyl 3-chloro-6-methoxy-2-nitrooxymethylben-
zoate (34). This was obtained as a co-product in the reaction
of ethyl 2-bromomethyl-3-chloro-6-methoxybenzoate (30)
with aq silver nitrate as described above. Colorless liquid.
5.5.28. Ethyl 3-chloro-2-methoxy-6-dibromomethyl-
benzoate (40). A mixture of compound 39 (1.17 g,
5.12 mmol) and NBS (2.00 g, 11.2 mmol) in CCl4 (15 mL)
containing a catalytic amount of benzoyl peroxide was
heated at reflux for 1 h while irradiated by a 100 W electric
bulb. At the end of the reaction, the mixture was chilled (ice
bath) and filtered. Removal of solvent from the filtrate fur-
nished the crude dibromo compound 40. This was further
purified by column chromatography separation. Light yel-
low colored liquid. Yield: 67%; nmax (KBr, cmꢀ1): 1720,
1
Yield: 18%; nmax (KBr, cmꢀ1): 1730, 1639, 1275, 851; H
NMR (200 MHz, CDCl3+CCl4): 7.40 (d, 1H, J¼8.8 Hz),
6.91 (d, 1H, J¼8.8 Hz), 5.59 (s, 2H), 4.39 (q, 2H,
J¼7.2 Hz), 3.84 (s, 3H), 1.37 (t, 3H, J¼7.2 Hz); 13C NMR
(50 MHz, CDCl3+CCl4): 165.6, 155.4, 131.4, 128.0, 126.6,
113.7, 68.8, 61.7, 56.1, 29.6, 14.0.
5.5.24. 3-Bromo-4-chloro-7-methoxyphthalide (35). Ben-
zylic bromination of compound 31 was performed using
1.2 equiv of N-bromosuccinimide according to the proce-
dure adopted for compound 39. Light brown colored liquid.
Crude yield: 75% (as judged by NMR); 1H NMR (200 MHz,
CDCl3+CCl4): 7.63 (d, 1H, J¼8.8 Hz), 7.23 (s, 1H), 7.02 (d,
1H, J¼8.8 Hz), 4.02, (s, 3H).
1
1461, 1268, 938, 692; H NMR (200 MHz, CDCl3+CCl4):
7.72 (d, 1H, J¼8.0 Hz), 7.51 (d, 1H, J¼8.0 Hz), 6.75 (s,
1H), 4.46 (q, 2H, J¼7.0 Hz), 3.91 (s, 3H), 1.44 (t, 3H,
J¼7.0 Hz); 13C NMR (50 MHz, CDCl3): 165.0, 152.2,
138.5, 132.4, 131.7, 129.2, 126.2, 62.2, 62.0, 35.4, 14.1.
5.5.25. 4-Chloro-3-phenylthio-7-methoxyphthalide (36).
To a stirred solution of 3-bromo-4-chloro-7-methoxyphtha-
lide (35) (20 mg, 0.072 mmol) in dry chloroform, triethyl-
amine (0.072 mmol) and thiophenol (0.072 mmol) were
added and the resulting mixture was stirred for 4–5 h. After
completion of the reaction, it was diluted with diethyl ether
(15 mL), washed with 5% NaOH (15 mL) solution, and
worked up in usual manner. Crude product 36 was purified
by column chromatography. Yield: 50%; mp: 117–118 ꢁC;
nmax (KBr, cmꢀ1): 1754, 1590, 1473, 1442, 1281, 1199,
1160, 1046, 946; 1H NMR (200 MHz, CDCl3+CCl4):
7.52–7.43 (m, 3H), 7.26–7.19 (m, 3H), 6.82 (d, 1H,
J¼8.6 Hz), 6.50 (s, 1H), 3.90 (s, 3H).
5.5.29. 6-Chloro-3-hydroxy-7-methoxyphthalide (41). A
mixture of dibromo compound 40 (2.20 g, 5.7 mmol), concd
hydrochloric acid (3 mL), acetic acid (3 mL), and water
(10 mL) was heated at reflux for 4 h. The solution was con-
centrated to dryness under reduced pressure and the concen-
trate was extracted with saturated sodium bicarbonate
solutions, which on acidification (10% aq HCl), extraction
into ethyl acetate layer, and usual work-up of the organic
phase furnished compound 41 as a crystalline solid. The
undissolved part of the residue was further hydrolyzed by
repeating the procedure described above to furnish 41 as
a crystalline solid. Yield: 72%; mp: 147–148 ꢁC (lit.17 mp:
159–163 ꢁC); nmax (KBr, cmꢀ1): 1741, 1633, 1383; 1H
NMR (200 MHz, DMSO-d6+CDCl3): 7.60 (d, 1H,
J¼8.0 Hz), 7.16 (d, 1H, J¼8.0 Hz), 6.42 (s, 1H), 5.16 (br
s, 1H), 4.05 (s, 3H); 13C NMR (50 MHz, DMSO-
d6+CDCl3): 165.2, 153.9, 147.8, 136.1, 128.7, 119.2,
118.5, 96.5, 62.2; MS m/z (EI): 214 (80) M+, 203, 196,
184, 178, 169, 156, 139, 126, 110, 99, 77.
5.5.26. Ethyl 3,4-dichloro-2-hydroxy-6-methylbenzoate
(38). Excess chlorine gas was passed through a stirred solu-
tion of ethyl 6-methyl-2-oxo-3-cyclohexenecarboxylate (37)
(1.00 g, 5.46 mmol) in acetic acid during half an hour and
stirring was continued for additional 2 h. Acetic acid was

9600
D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
5.5.30. Methyl 9-chloro-6-hydroxy-8-methoxybenz[a]-
anthracene-7,12-dione-2-carboxylate (43). This com-
pound was prepared from compound 2 according to the
general procedure in Section 5.3. Red solid. Yield: 49%;
mp: 234–235 ꢁC; nmax (KBr, cmꢀ1): 3426, 1725, 1644,
1570, 1459, 1314, 1265, 1222, 1019, 760; 1H NMR
(200 MHz, CDCl3): d 12.42 (s, 1H), 10.04 (s, 1H), 8.12 (d,
1H, J¼8.4 Hz), 8.08 (d, 1H, J¼8.6 Hz), 7.86 (d, 1H,
J¼8.4 Hz), 7.75 (d, 1H, J¼8.6 Hz). 7.68 (s, 1H), 4.06 (s,
3H), 4.01 (s, 3H); HRMS m/z (ESI) calcd for
C21H1335ClO6 (M++H): 397.0479; found: 397.0468.
5.5.34. Ethyl 3-amino-6-methoxy-2-methylbenzoate (48).
To a solution of nitro compound 46 (1.5 g, 6.24 mmol) in
ethanol (25 mL), 20 mg of 10% Pd–C was added. The solu-
tion was then deoxygenated under vacuum and was allowed
to absorb hydrogen gas from a balloon. The mixture was
stirred at rt for 5–6 h under hydrogen atmosphere. After
completion of the reaction, the catalyst was removed by fil-
tration and solvent was removed under vacuum. The crude
product was purified by column chromatographic separation
using a 1:5 mixture of ethyl acetate and petroleum ether as
eluant. Colorless liquid. Yield: 77%; nmax (KBr, cmꢀ1):
3447, 3369, 1718, 1652, 1550, 1506, 1495, 1264, 1058,
817; 1H NMR (200 MHz, CDCl3): d 6.80–6.76 (d, 1H,
J¼8.4 Hz), 6.74–6.70 (d, 1H, J¼8.4 Hz), 4.46–4.35 (q,
2H, J¼7.0 Hz), 3.80 (s, 3H), 2.20 (s, 3H), 1.42–1.35 (t,
3H, J¼7.0 Hz); 13C NMR (50 MHz, CDCl3): 167.9, 143.4,
137.4, 128.1, 125.6, 124.2, 116.7, 60.6, 60.0, 17.8, 13.7.
5.5.31. Methyl 9-chloro-6,8-dihydroxy-benz[a]anthra-
cene-7,12-dione-2-carboxylate (44). To a stirred solution
of compound 43 (40 mg, 0.105 mmol) in dry CH2Cl2
(2 mL) at 0 ꢁC under Ar-atmosphere was added anhydrous
AlCl3 (5 equiv). After 1 h of stirring at 0 ꢁC, the reaction
mixture was allowed to come to room temperature and stir-
ring was continued for additional 6 h. The reaction mixture
was quenched with 2 M HCl (4 mL). Usual work-up of the
organic extract afforded a solid, which was purified by
column chromatography (CHCl3–petroleum ether, 3:1) to
give 44 as a red solid. Yield: 78%; mp: 273–274 ꢁC; nmax
(KBr, cmꢀ1): 3407 (br s), 1713, 1627, 1419, 1282, 1224,
1128, 1080, 994, 761; 1H NMR (200 MHz, CDCl3):
d 12.34 (s, 1H), 11.90 (s, 1H), 10.15 (s, 1H), 8.14 (dd, 1H,
J¼1.5 and 8.7 Hz), 7.83 (s, 2H), 7.76 (d, 1H, J¼8.7 Hz),
7.71 (s, 1H), 4.02 (s, 3H); MS m/z (EI): 382 (100) M+, 351
(64), 323 (39), 256, 236, 175, 137, 123, 103, 91, 80, 69,
54; HRMS m/z (ESI) calcd for C20H1135ClO6 (M+ꢀH):
381.0166; found: 381.0150.
5.5.35. Ethyl 3-amino-2-hydroxy-6-methylbenzoate (49).
A mixture of nitro compound 46 (250 mg, 1.04 mmol),
SnCl2$2H2O (1.17 g, 5.18 mmol), and ethanol (8 mL) was
heated at 70 ꢁC for 1 h. After the reaction was cooled to
room temperature, 10% aq NaOH was added until the mix-
ture became strongly alkaline. Extraction of the mixture with
ethyl acetate (15 mL) followed by usual work-up yielded,
after column chromatographic separation, amino phenol 49
as a colorless liquid in 19% yield along with amine 48 in
45% yield. nmax (KBr, cmꢀ1): 3457, 3376, 1723, 1655,
1
1598, 1451, 1291, 1261, 1189, 1026, 799, 758; H NMR
(200 MHz, CDCl3): d 11.61 (br s, 1H), 6.78 (d, 1H, J¼
8.1 Hz), 6.56 (d, 1H, J¼8.1 Hz), 4.43 (q, 2H, J¼7.2 Hz),
3.80 (s, 3H), 2.83 (br s, 2H), 1.42 (t, 3H, J¼7.2 Hz).
5.5.32. Ethyl 2-methoxy-6-methyl-3-nitrobenzoate (46).
Acetyl nitrate was prepared by dropwise addition of fuming
HNO3 (0.270 mg, 3 mmol) with rapid stirring to 1.5 mL of
acetic anhydride taken in a flask at 0–10 ꢁC. After 15 min,
the resulting solution was added to a stirred solution of ethyl
2-methoxy-6-methylbenzoate (460 mg, 2.8 mmol) in acetic
anhydride (4 mL) at temperature between 0 and ꢀ10 ꢁC.
Stirring was continued at this temperature for about 1 h
and then allowed to come to room temperature. The mixture
was then poured into 10 mL of cold water and triturated with
saturated solution of NaHCO3 solution and then extracted
with ether (3ꢂ20 mL). Usual work-up of the combined
extracts furnished a light yellow liquid. The crude product
was purified by column chromatography to give compound
46 as a yellow liquid. Yield: 57%; nmax (KBr, cmꢀ1): 1730,
5.5.36. Ethyl 3-ethoxyamino-2-methoxy-6-methylben-
zoate (50). This was obtained as a co-product during the re-
duction of nitro compound 46 by hydrogenation over 10%
Pd–C in ethanol. Reddish liquid. Yield: 18%; nmax (KBr,
cmꢀ1): 3401 (br s), 1728, 1608, 1504, 1456, 1329, 1265,
1
1118, 1062, 802; H NMR (200 MHz, CDCl3): d 6.83 (d,
1H, J¼8.2 Hz), 6.31 (d, 1H, J¼8.2 Hz), 4.40 (q, 2H,
J¼7.1 Hz), 3.80 (s, 3H), 3.14 (q, 2H, J¼7.1 Hz), 2.20 (s,
3H), 1.38 (t, 3H, J¼7.1 Hz), 1.25 (t, 3H, J¼7.1 Hz); 13C
NMR (50 MHz, CDCl3,): 168.3, 149.4, 143.6, 139.5,
127.9, 126.1, 122.7, 112.2, 60.9, 60.7, 38.2, 18.2, 14.7, 14.1.
5.5.37. Ethyl 3-fluoro-2-methoxy-6-methylbenzoate (52).
Amine 48 (210 mg, 1.0 mmol) was dissolved in a mixture
of concd HCl (2 mL) and water (5 mL). The solution was
cooled and held at the range of 0 to ꢀ10 ꢁC. Diazotization
was done by dropwise addition of an aq solution of
NaNO2 (80 mg, 1.16 mmol) dissolved in water. While this
solution was still cold, 65% aq HPF6 (0.2 mL) was added
rapidly in one portion with the help of plastic disposal
syringe. The mixture was cooled again to 0–5 ꢁC before fil-
tration. The phosphorous hexafluoride salt 51 was collected
by filtration, washed with cold water followed by a 4:1 mix-
ture of diethyl ether, and MeOH to facilitate drying. The
solid was powdered and dried in vacuum overnight. Decom-
position of phosphorous hexafluoride salt 51 was carried out
by portionwise addition through the condenser fitted with
a flask held at decomposition temperature at 120–125 ꢁC.
After the decomposition was complete, the residue was
extracted with ethyl acetate (20 mL) and worked up in the
1
1592, 1526, 1351, 1273, 1120, 1066; H NMR (200 MHz,
CDCl3): 7.85 (d, 1H, J¼8.4 Hz), 7.06 (d, 1H, J¼8.4 Hz),
4.42 (q, 2H, J¼7.1 Hz), 3.87 (s, 3H), 2.36 (s, 3H), 1.39 (t,
3H, J¼7.1 Hz); 13C NMR (50 MHz, CDCl3): 165.7, 150.7,
142.6, 140.8, 131.4, 125.8, 125.5, 63.3, 61.5, 19.0, 13.8.
5.5.33. Ethyl 6-methoxy-2-methyl-3-nitrobenzoate (47).
This was obtained as a co-product during the nitration
(described above) of ethyl 2-methoxy-6-methylbenzoate by
acetyl nitrate. Light yellow solid. Yield: 43%; mp: 70 ꢁC;
nmax (KBr, cmꢀ1): 1730, 1603, 1583, 1513, 1471, 1347,
1
1261, 1110, 1070, 1027, 824, 650; H NMR (200 MHz,
CDCl3): d 8.07 (d, 1H, J¼9.2 Hz), 6.83 (d, 1H, J¼9.2 Hz),
4.41 (q, 2H, J¼6.9 Hz), 3.90 (s, 3H), 2.48 (s, 3H), 1.37 (t,
3H, J¼6.9 Hz); 13C NMR (CDCl3, 50 MHz): 166.2, 159.3,
142.6, 132.5, 127.7, 126.3, 108.5, 61.7, 56.2, 16.9, 13.9.

D. Mal, S. Dey / Tetrahedron 62 (2006) 9589–9602
9601
usual manner to furnish the crude product. The crude prod-
uct was purified by column chromatography (ethyl acetate–
petroleum ether, 1:15) to give 52 as a colorless liquid. Yield:
19%; nmax (KBr, cmꢀ1): 1731, 1608, 1490, 1417, 1276,
2.97–2.89 (m, 2H), 2.76–2.68 (m, 1H), 2.21–2.12 (m, 1H),
1.98–1.90 (m, 1H); HRMS m/z (ESI) calcd for C21H17FO6
(M++H): 385.1087; found: 385.1057.
1
1133, 1066, 1020, 958, 813; H NMR (200 MHz, CDCl3):
d 7.00 (dd, 1H, J¼8.5 and 11.2 Hz), 6.83 (dd, 1H, J¼5.1
and 8.5 Hz), 4.39 (q, 2H, J¼7.1 Hz), 3.93 (d, 3H,
J¼1.8 Hz), 2.25 (s, 3H), 1.38 (t, 3H, J¼7.1 Hz); 13C NMR
(50 MHz, CDCl3): 167.0 (d, J¼3.5 Hz), 153.3 (d,
J¼244 Hz), 144.5 (d, J¼12.3 Hz), 131.4 (d, J¼3.6 Hz),
129.6, 125.2 (d, J¼6.7 Hz), 117.5 (d, J¼18.9 Hz), 61.8 (d,
J¼5.6 Hz), 61.3, 18.6, 14.2.
Acknowledgements
Financial assistance from DST, New Delhi and CSIR, New
Delhi for this work is gratefully acknowledged.
References and notes
5.5.38. Ethyl 6-dibromomethyl-3-fluoro-2-methoxyben-
zoate (53). This compound was prepared from 52 using
2 equiv of NBS following the procedure described for the
preparation of compound 40 from 39. Colorless liquid.
Yield: 57%; nmax (KBr, cmꢀ1): 1723, 1458, 1266, 935,
1. For reviews, see: (a) Rohr, J.; Thiericke, R. Nat. Prod. Rep.
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18–21; (b) Uesato, S.; Tokunaga, T.; Takeuchi, K. Bioorg.
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1
703; H NMR (200 MHz, CDCl3): d 7.71 (dd, 1H, J¼4.5
and 9.0 Hz), 7.31 (dd, 1H, J¼9.0 and 15.3 Hz), 6.79 (s,
1H), 4.45 (q, 2H, J¼6.9 Hz), 3.96 (d, 3H, J¼1.9 Hz), 1.42
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5.5.39. 6-Fluoro-3-hydroxy-7-methoxy-3H-isobenzo-
furan-1-one (54). This compound was prepared from the di-
bromo compound 53 following the procedure described for
the synthesis of compound 41 from 40. White crystalline
solid. Yield: 75%; mp: 131 ꢁC; nmax (KBr, cmꢀ1): 3352,
1731, 1503, 1426, 1294, 1261, 1139, 1108, 1057, 1031,
1
908, 839, 772, 732; H NMR (200 MHz, CDCl3): d 7.42
(dd, 1H, J¼8.2 and 11.6 Hz), 7.20 (dd, 1H, J¼3.5 and
8.2 Hz), 6.50 (s, 1H), 4.20 (d, 3H, J¼2.8 Hz); 13C NMR
(50 MHz, CDCl3): 165.4, 154.7 (d, J¼247 Hz), 145.8 (d,
J¼11.5 Hz), 142.4, 123.3 (d, J¼21.6 Hz), 119.2, 117.3 (d,
J¼8.1 Hz), 96.4, 62.0 (d, J¼4.9 Hz); HRMS m/z (ESI) calcd
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5.5.40. 3-Cyano-6-fluoro-7-methoxy-3H-isobenzofuran-
1-one (55). This compound was prepared from the phthal-
aldehydic acid 54 according to the procedure adopted for
the preparation of chlorocyanophthalide 3a from 41. White
crystalline solid. Yield: 83%; mp: 104–105 ꢁC; nmax (KBr,
cmꢀ1): 1789, 1603, 1501, 1291, 1255, 1087, 1022, 971,
1
925; H NMR (200 MHz, CDCl3): d 7.53 (dd, 1H, J¼8.3
and 11.7 Hz), 7.24 (dd, 1H, J¼8.3 and 8.5 Hz), 5.98 (d,
1H, J¼0.7 Hz), 4.24 (d, 3H, J¼3.3 Hz); 13C NMR
(50 MHz, CDCl3): 159.1, 151.5 (d, J¼250 Hz), 146.3 (d,
J¼11.8 Hz), 137.3, 124.1 (d, J¼22.6 Hz), 111.5, 111.3 (d,
J¼8.1 Hz), 108.6, 59.5, 57.4 (d, J¼6.0 Hz); HRMS m/z
(ESI) calcd for C10H6FNO3 (M++H): 208.0410; found:
208.0405.
5.5.41. Methyl 9-fluoro-6-hydroxy-8-methoxy-1,2,3,4-tet-
rahydrobenz[a]anthracene-7,12-dione-2-carboxylate
(56). This compound was prepared by annulation of 6-fluo-
ro-7-methoxycyanophthalide (55) with Michael acceptor 4
following the general procedure in Section 5.2. Orange solid.
Yield: 74%; mp: 153–54 ꢁC; nmax (KBr, cmꢀ1): 3432, 1731,
1
1631, 1572, 1449, 1411, 1327, 1262, 1102, 1017, 796; H
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(s, 1H), 4.08 (d, 3H, J¼1.3 Hz), 3.74 (s, 3H), 3.60 (dd, 1H,
J¼5.3 and 18.2 Hz), 3.30 (dd, 1H, J¼9.5 and 18.2 Hz),

9602
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