Regiospecific synthesis of benzo[b]fluorenones via ring contraction by benzil-benzilic acid rearrangement of benz[a]anthracene-5,6-diones

Article abstract of DOI:10.1055/s-2006-942468

A regiospecific route to benzo[b]fluorenones is described. The synthesis is based upon a one-pot, regiospecific benzannulation of 1,4-dipolar synthons with naphthoquinone monoketal and ring contraction of the generated benz[a]anthracene-5,6-diones through benzil-benzilic acid rearrangement. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942468

2556
PAPER
Regiospecific Synthesis of Benzo[b]fluorenones via Ring Contraction by
Benzil–Benzilic Acid Rearrangement of Benz[a]anthracene-5,6-diones
R
egiospecific Synt
s
hesis of
B
i
enzo[
b
t
]fluorenones
P
via Benz[
a
]an
a
thracene-5,
t
6-dion
r
R
ing
C
a
ontraction , Sujit K. Ghorai, Saroj R. De, Dipakranjan Mal*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
E-mail: dmal@chem.iitkgp.ernet.in
Received 24 February 2006; revised 29 March 2006
Initially, we attempted to extend our previously reported
anionic [4+2] cyclocondensation methodology8a,10 to the
synthesis of 2,3,6,7-dibenzofluorenone 4. When
dimethoxybenzindenone (3)11 was subjected to the Hauser
annulation with phenylthiophthalide (2)10c in the presence
of lithium tert-butoxide, the expected condensed product
4 was obtained in 98% yield. This was duly characterized
by spectroscopic means. However, the analogous reaction
of 5 with benz[f]indenone (6)10b to form the parent diben-
zofluorenone 7 was only partially successful, giving a
maximum yield of 47% in the presence of sodium tert-bu-
toxide (Scheme 1). In view of the low yield and the prob-
lems cited earlier, we considered a ring contraction by the
benzil–benzilic acid rearrangement12 of the appropriate
a,b-diketo compounds as an alternative avenue to ben-
zo[b]fluorenones. Thus far, such rearrangements have
only been of mechanistic interest and have not found
many applications in multi-step synthesis;12 nevertheless,
we felt it important to investigate the retrosynthetic anal-
ysis shown in Scheme 2. This methodology should pro-
vide the five-membered benzo[b]fluorenone ring of 8a via
ring contraction of a precursor, six-membered, cyclic 1,2-
diketo structure 8c through the rearranged product 8b
(Scheme 2). Notably, compounds as 8b should also have
the potential to serve as Mosher’s acid analogues for the
determination of absolute configuration.13
Abstract: A regiospecific route to benzo[b]fluorenones is de-
scribed. The synthesis is based upon a one-pot, regiospecific ben-
zannulation of 1,4-dipolar synthons with naphthoquinone
monoketal and ring contraction of the generated benz[a]anthracene-
5,6-diones through benzil–benzilic acid rearrangement.
Key words: 1,4-dipolar synthons, benz[a]anthracene-5,6-diones,
benzo[b]fluorenones, benzannulation, benzil–benzilic acid rear-
rangement
Benzo[b]fluorene subunits have, in recent years, achieved
significant importance because of their occurrence in
many bioactive natural products. The secondary metabo-
lites prekinamycin (1a),1 kinafluorenone (1b),2 stealthins3
A (1c), B (1d), C (1e), kinobscurinone4, seongomycin5
and cysfluoretin6 (Figure 1) have all been found in ex-
tracts from Streptomyces murayamaensis. The wide range
of biological activities of these antibiotics as well as their
mode of action has made them important synthetic targets.
Since 1996, several routes to the synthesis of the naturally
occurring benzo[b]fluorenones have been developed.7,8
Typically, methods based on [4+2] cycloaddition, Suzuki
coupling, oxidative free radical cyclization or Heck cou-
pling have been employed. However, regioselective syn-
thesis of benzo[b]fluorenone natural products still
remains a challenge. Furthermore, the extended aromatic
structures, having both naphthyl and anthryl regions, are
important synthetic materials due to their interesting
physicochemical properties. As discussed by McLaughlin
et al.,9 their syntheses are also not trivial.
OMe
MeO
OH
tBuOLi, THF
–60 to 0 °C
SPh
O
98%
OMe
O
O
OMe
O
OH
HO
HO
O
3
2
4
O
Me
Me
SO2Ph
CHO
NaH
THF, tBuOH
N2
OH
O
O
OMe O
1a
1b
47%
O
HO
O
5
6
7
OH
R
1c: R = CH2OH
1d: R = CHO
1e: R = Me
Scheme 1
NH2
OH
O
X
X
X
Y
Figure 1 Structures of benzo[b]fluorene antibiotics
O
COOH
HO
O
Y
8a
Y
O
8b
8c
SYNTHESIS 2006, No. 15, pp 2556–2562
x
x.
x
x
.
2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942468; Art ID: Z04406SS
Scheme 2 Retrosynthesis of benzo[b]fluorenones
© Georg Thieme Verlag Stuttgart · New York

PAPER
Regiospecific Synthesis of Benzo[b]fluorenones via Benz[a]anthracene-5,6-dione Ring Contraction
2557
The synthesis of benzoanthracenediones 8c, for which
there has been no general synthetic method previously de-
scribed, was anticipated to be readily accomplished
through an extension of our previous work.14a Herein, we
describe a regiospecific synthesis of benz[a]anthracene-
5,6-diones 14a–c and their efficient conversion to ben-
zo[b]fluorenones 17a–c through core structures 15a–c.
Previously, we reported the annulation reaction14 of
isobenzofuranones 2 and 11 with substituted naphtho-
quinone monoketals to give angularly fused aromatic
polycyclic compounds, which ultimately led to the forma-
tion of 5-hydroxybenz[a]anthracene-7,12-diones.14a We
now show that similar annulation reactions of 1,4-dipolar
synthons 5, 9 and 1015 with naphthoquinone monoketal 12
provides a regiospecific synthetic route to the benz[a]an-
thracene-5,6-dione derivatives 14a–c (Scheme 3).
R2
5, 9 or 10
OMe
OMe
OMe
OMe
(see text for
conditions)
R1
O
O
12
13a–c
R2
R2
KOH
dioxane
O
COOH
OH
R1
R1
O
15a–c
14a (75%)
14b (73%)
14c (68%)
14d (0%)
CrO3
CH2N2
AcOH
H2O
R2
R1
R2
SPh
S
SOPh
CN
O
COOMe
OR3
R1
O
16a (74%)
16b (73%)
16c (68%)
in 2
steps
17a (57%)
17b (54%)
17c (42%)
17d
CO2Me
in 2
steps
O
O
10
11
9
Figure 2
a: R1 = H, R2 = H, R3 = Me
b: R1 = OMe, R2 = H, R3 = H
c: R1 = OMe, R2 = SMe, R3 = H
d: R1 = OMe, R2 = OMe
Annulation of 5 with naphthoquinone monoketal 12,14a
prepared from b-naphthol in one step, was carried out in
the presence of potassium tert-butoxide in a mixture of
tert-butanol and THF at room temperature under an inert
atmosphere to give a yellow solid. Treatment of this solid
with aqueous HCl in methanol provided compound 14a in
75% yield. For the proposed benzil–benzilic acid rear-
rangement of 14a, several classical reaction conditions
such as NaOH in water, KOH in a mixture of ethanol and
water, KOH in a mixture of dioxane and water and NaOEt
in ethanol were examined. Since none of these attempts
gave satisfactory results in terms of the desired product
15a, we turned our attention to the modified method of
Toda et al16 using powdered KOH in dioxane. Under these
conditions, compound 14a furnished the carboxylic acid
15a as a crude solid that was primarily characterized by
1H NMR data since purification proved problematic. Pu-
rification as the methyl ester derivative 16a, after treat-
ment of 15a with diazomethane in ether, gave an oil that
was however fully characterized. Oxidative decarboxyla-
tion of acid 15a with CrO3 in acetic acid provided ben-
zo[b]fluorenone 17a as a yellow solid whose spectral data
(1H NMR) compared well with reported values.17
Scheme 3
ketal 12 and treated with iodomethane to yield a yellow
residue that was hydrolyzed, without purification, to pro-
vide benz[a]anthracene-5,6-dione 14c in 68% yield. Its
structure was ascertained by analysis of NMR data, in par-
ticular, through the chemical shift of the C-1 proton. This
was then converted into benzo[b]fluorenone 17c through
15c, which was characterized as 16c after O-methylation
with diazomethane (Scheme 3).
In order to prepare dimethoxybenz[a]anthracenedione
14d and subsequently 17d, a target molecule harboring
the common structural features of the natural products
(Figure 1), isobenzofuranone 11 was reacted with naph-
thalenone 12 in the presence of lithium tert-butoxide in
tetrahydrofuran at –60 °C. The crude yellow solid ob-
tained was directly methylated with Me2SO4 and K2CO3
in refluxing acetone to give benz[a]anthracene-7,12-di-
one 19 as a yellow solid in 86% yield (Scheme 4). As pre-
viously reported,14b it is possible to trap anthracene
dioxide intermediates of type 18. However, in this case,
attempts to trap dioxide 18 in situ by treatment with meth-
yl iodide, following the annulation between 11 and 12,
gave 19 as the sole product and the desired 14d was not
obtained. The annulation of isobenzofuranone 2 with
quinone monoketal 12 showed a similar product profile to
that of 11. The formation of compound 19 is presumably
due to facile expulsion of one of the ketal methoxy groups
from 1,4-dioxy anion derivative 18 under the reaction
conditions.14a
When compound 9 was subjected to annulation with
quinone monoketal 12 under typical reaction conditions
(lithium tert-butoxide in THF at –60 °C) followed by
methylation with Me2SO4 and K2CO3 in refluxing acetone
and deketalization with aqueous HCl in methanol, com-
pound 14b was obtained as a red solid in 73% yield. This
was converted into 15b by treatment with powdered KOH
and was characterized as its methyl ester derivative 16b.
Compound 15b was converted into benzo[b]fluorenone
17b8i (Scheme 3) by refluxing with CrO3 in acetic acid.
Similarly, thiophthalide 10 was condensed with quinone
Synthesis 2006, No. 15, 2556–2562 © Thieme Stuttgart · New York

2558
A. Patra et al.
PAPER
Due to the very similar spectral data of the compounds, 19
was initially mistaken to be the expected annulated prod-
uct 14d and was, consequently, submitted to benzil–ben-
zilic acid rearrangement with powdered KOH in dioxane.
Interestingly, it underwent a Haller–Bauer18 reaction to
give the naphthalene derivative 20. Structure elucidation
of 20 was complicated by the possible formation of three
other regioisomeric compounds and by the overlap of a
proton signal with that of chloroform. Nevertheless, the
1
structure was determined by analysis of H NMR data
and, subsequently, confirmed by its conversion to, and
analysis of, the methyl ester derivative 21 upon treatment
with diazomethane. The 1H NMR spectrum of 21 showed
one aromatic singlet signal at d = 7.25 ppm and three
methoxy signals at d = 4.06, 3.78 and 3.43 ppm suporting
the structure shown in Scheme 4. Moreover, the positions
of these groups in the molecule were ascertained by de-
tailed analysis of heteronuclear multiple bond coherence
(HMBC) and heteronuclear multiple quantum coherence
(HMQC) spectra. In the HMBC spectrum, correlations
between the single aromatic proton (d = 7.25 ppm) with
one carbonyl carbon (d = 196.9 ppm, C-11) and two aro-
matic carbons (d = 147.4 and 128.0 ppm, for C-4 and C-
10 respectively), suggests that the singlet of aromatic pro-
ton is located at the C-2 position. In the HMQC spectrum,
the singlet aromatic proton (d = 7.25 ppm) was correlated
with an aromatic carbon at C-2 (d = 121.7 ppm). Finally,
the structure of compound 21 was firmly established by
X-ray crystallographic analysis (Figure 3).
Figure 3 ORTEP plot of X-ray crystal structure of 21
spectral data were in good agreement with those reported
for a sample recently prepared from o-tolunitrile.20 Sulf-
oxide 9 was also prepared from 22, as shown in Scheme 5.
Reaction of compound 22 with PhSH in the presence of
DBU followed by oxidation with NaIO4 in methanol af-
forded sulfoxide ester 9 in 72% overall yield.
SO2Ph
CH2Br
i) PhSO2Na
CO2Me
ii) NaOH
COOH
76%
22
23
i) PhSH, DBU
ii) NaIO4
i) NaBH4, I2
ii) PCC
SO2Ph
CH2OH
SOPh
O
11 or 2
tBuOLi, THF
MeI
14d
OMe
OMe
OMe
OMe
CO2Me
72%
H3O+
–60 °C
O
O
O
9
24
12
18
SO2Ph
MeI
H3O+
COOR
O
CHO
70%
10
1
O
O
5
KOH,
dioxane
11
2
OMe
4
OMe
Scheme 5
OMe
OMe
20: R = H
CH2N2
In conclusion, we have demonstrated that benzil–benzilic
acid rearrangement of benz[a]anthracene-5,6-diones
could be a viable route to oxygenated benz[b]fluorenones.
We have also shown that a variety of benz[a]anthracene-
5,6-diones could be regiospecifically synthesized by an-
ionic cyclocondensation reactions of a range of 1,4-dipo-
lar synthons with naphthoquinone monoketals. This
approach is regiospecific, efficient and experimentally
very simple. Further applications of this methodology for
the synthesis of highly functionalized benzo[b]fluorenone
targets are underway.
21: R = Me
19 (86%)
77% in 2 steps
Scheme 4
The 1,4-dipolar synthon 5 was prepared in five steps from
methyl o-toluate (Scheme 5). Bromination of methyl o-
toluate with NBS (1 equiv), in the presence of benzoyl
peroxide, gave the bromomethyl compound 22, which
was treated with sodium benzenesulfinate in dry DMF at
room temperature followed by hydrolysis of the resulting
ester with aqueous NaOH to give the carboxylic acid 23 in
76% overall yield. Reduction of the carboxylic acid of 23
Melting points were recorded on a Toshniwal hot-coil stage melting
point apparatus and are uncorrected. 1H NMR spectra were recorded
on a 200 MHz spectrometer (Brücker) as solutions in CDCl3 with
TMS as the internal standard. Chemical shifts are expressed in d
19
with NaBH4–I2 provided 24, which was oxidized with
PCC in dichloromethane, without further purification, to
provide sulfone aldehyde 5 in 70% yield. Its H NMR
1
Synthesis 2006, No. 15, 2556–2562 © Thieme Stuttgart · New York

PAPER
Regiospecific Synthesis of Benzo[b]fluorenones via Benz[a]anthracene-5,6-dione Ring Contraction
2559
units and coupling constants in Hz. 13C NMR spectra were recorded
on a 50 MHz spectrometer (Bruker) as solutions in CDCl3, unless
otherwise stated. IR spectra were recorded on a Thermo Nicolet
Nexus 870 FT-IR using KBr pellets. Only significant bands for the
IR spectra are quoted. EI-MS (70 eV) spectra were taken using a
VG Autospec M mass spectrometer. Elemental analyses were car-
ried out on a Vario EL instrument. THF was distilled from sodium–
benzophenone under an atmosphere of dry argon or nitrogen. All
solvents for column chromatography were distilled prior to use. In
most of the column chromatographic separations, EtOAc and petro-
leum ether (PE, 60–80 °C) were used as eluents, using silica gel
(60–120 mesh). The phrase 'usual workup' or 'worked up in usual
manner' refers to washing of the organic phase with H2O (2 × 1/4
the volume of the organic phase), then brine (1 × 1/4 the volume of
the organic phase), drying (Na2SO4), filtration, and concentration
under reduced pressure.
1H NMR (200 MHz, CDCl3): d = 9.81 (s, 1 H, CHO), 7.77–7.39 (m,
9 H, Ar), 5.02 (s, 2 H, CH2SO2Ph).
Dibenzo[b,h]fluoren-12-one (7)
Sulfone 5 (45 mg, 0.17 mmol) and benz[f]indenone (6) (30 mg, 0.17
mmol) were dissolved in a mixture of t-BuOH (2 mL) and THF (5
mL). NaH (75 mg, 3 equiv) was then added at r.t. and the resulting
mixture was stirred at r.t. overnight. Dilution with H2O (20 mL) fol-
lowed by the usual workup gave product 7.
Yield: 22 mg (0.078 mmol, 47%); yellow solid; mp 265–267 °C
(Lit.9 275–76 °C).
1H NMR (200 MHz, CDCl3): d = 8.28 (s, 2 H, Ar), 8.10 (s, 2 H, Ar),
7.91 (t, J = 8.5 Hz, 4 H, Ar), 7.62–7.42 (m, 4 H, Ar).
Methyl 2-(Phenylsufinylmethylbenzyl)benzoate (9)
A mixture of methyl o-toluate (0.92 g, 6.15 mmol), NBS (1.20 g,
6.74 mmol) and a catalytic amount of benzoyl peroxide (70 mg) in
CCl4 (40 mL) was heated at reflux under the exposure of a 100-watt
bulb for 1.5 h. Completion of the reaction was ascertained by disap-
pearance of NBS from the bottom of the flask. The mixture was
cooled, filtered and then concentrated under reduced pressure to
yield 22 as a yellow residue. This was dissolved in dry CHCl3 (25
mL) and treated with DBU (0.93 g, 6.1 mmol) and PhSH (660 mg,
6.0 mmol) at r.t. for 4 h. The mixture was diluted with Et2O (30
mL), washed with ice-cold aq NaOH (5%, 5 mL) and worked up in
the usual manner to yield a solid residue. The resulting residue was
dissolved in a mixture of MeOH (20 mL) and H2O (3 mL) and so-
dium periodate (1.30 g, 6.1 mmol) was added in portions. The re-
sulting mixture was stirred for 12 h at r.t., then the solvent was
removed under reduced pressure. After the usual workup, the crude
product was purified by silica gel column chromatography (EtOAc–
PE, 1:1) to afford 9.
5,13-Dihydroxy-6,11-dimethoxydibenzo[b,h]fluoren-12-one (4)
Prepared by annulation of phthalide 2 with indenone 3, following
the procedure adopted for the preparation of compound 14b, but the
reaction was stopped before methylation.
Yield: 98%; deep-red solid; mp 204–205 °C.
IR (KBr): 3255, 2936, 2850, 1747, 1656, 1608, 1576, 1504, 1337,
1352, 1319, 1211, 1130, 1097, 1050, 998, 760 cm–1.
1H NMR (200 MHz): d = 9.69 (s, 1 H, OH), 8.35–8.23 (m, 3 H, Ar),
8.0 (d, J = 8.2 Hz, 1 H, Ar), 7.68–7.48 (m, 4 H, Ar), 4.35 (s, 3 H,
OCH3), 4.11 (s, 3 H, OCH3).
13C NMR (50 MHz): d = 192.1, 154.4, 151.2, 143.8, 141.8, 131.7,
131.0, 129.9, 129.8, 129.4, 128.4, 127.0, 127.0, 126.7, 125.6, 124.0,
123.9, 121.9, 121.7, 113.9, 111.8, 64.2, 63.5.
MS (EI, 70 eV): m/z (%) = 372 [M+], 357 (100), 342, 313, 164.
Yield: 1.02 g (3.86 mmol, 63%, from methyl o-toluate); white crys-
talline solid; mp 85–87 °C.
Anal. Calcd for C23H16O5: C, 74.19; H, 4.33. Found: C, 74.42; H,
4.12.
1H NMR (200 MHz, CDCl3): d = 8.00 (d, J = 7.1 Hz, 1 H, Ar),
7.60–7.3 (m, 7 H, Ar), 7.15 (d, J = 7.1 Hz, 1 H, Ar), 4.80 (d,
J = 12.0 Hz, 1 H, CHHSOPh), 4.31 (d, J = 12.0 Hz, 1 H, CHH-
SOPh), 3.87 (s, 3 H, OCH3).
13C NMR (50 MHz, CDCl3): d = 167.2, 143.8, 133.2, 132.3, 132.1,
131.1, 130.8, 129.4, 128.8, 128.4, 124.2, 62.9, 52.1.
2-(Phenylsulfonylmethyl)benzaldehyde (5)
A solution of 2-(phenylsulfonylmethyl)benzoic acid (23) (2.76 g,
10.45 mmol) in THF (10 mL) was slowly added to a suspension of
NaBH4 (460 mg, 12.1 mmol) in THF (10 mL) at r.t. over 10 min.
The mixture was stirred until evolution of gas ceased then iodine
(700 mg, 5.5 mmol) in THF (8 mL) was added at r.t. slowly over 10
min. The resulting mixture was stirred for 2 h then HCl (1 N, 15 mL)
was added carefully and the mixture was extracted with Et2O
(3 × 30 mL). The combined organic extracts were washed with
NaOH (1 N, 30 mL), brine (1 × 20 mL) and dried (Na2SO4). Con-
centration of the organic layer gave the corresponding alcohol 24 as
a solid residue.
Benz[a]anthracene-5,6-dione (14a)
Sulfone 5 (200 mg, 0.81 mmol) and quinone monoketal 12 (150 mg,
0.83 mmol) were dissolved in a mixture of t-BuOH (2 mL) and THF
(5 mL) and t-BuOK (275 mg, 3 equiv) was then added at 0 °C. The
resulting mixture was stirred at r.t. for 6 h then diluted with H2O (20
mL) and worked up as usual to give a yellow solid. HCl (10%, 10
mL) was added to a well-stirred solution of the solid in MeOH (10
mL) at r.t. and stirring was continued for 1 h. A red solid precipitate
appeared that was collected by filtration and thoroughly washed
with a mixture of MeOH and H2O (1:10) to give 14a.
1H NMR (200 MHz, CDCl3): d = 7.79–7.40 (m, 6 H, Ar), 7.35 (dt,
J = 1.4 Hz, 7.6 Hz, 1 H, Ar), 7.18 (dt, J = 1.4 Hz, 7.6 Hz, 1 H, Ar),
6.91 (d, J = 7.6 Hz, 1 H, Ar), 4.64 (d, J = 5.2 Hz, 2 H, CH2OH),
4.52 (s, 2 H, CH2SO2Ph), 2.69 (t, J = 5.2 Hz, 1 H, OH).
Yield: 155 mg (0.60 mmol, 75%); red solid; mp 264–267 °C (Lit.21
262–265 °C).
IR (KBr): 1671, 1618, 1590, 1485, 1442, 1283, 1227, 1175 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.71 (s, 1 H, Ar), 8.37 (s, 1 H, Ar),
8.22–8.10 (m, 2 H, Ar), 7.87 (t, J = 7.1 Hz, 2 H, Ar), 7.73 (dt,
J = 1.6 Hz, 7.7 Hz, 1 H, Ar), 7.64 (dt, J = 1.4 Hz, 7.5 Hz, 1 H, Ar),
7.54 (dt, J = 1.4 Hz, 7.6 Hz, 1 H, Ar), 7.45 (dt, J = 1.2 Hz, 7.6 Hz,
1 H, Ar).
13C NMR (50 MHz, CDCl3): d = 180.7, 180.6, 136.7, 136.6, 135.9,
133.6, 132.6, 131.4, 130.6, 130.4, 130.3, 130.3, 129.3, 128.7, 128.7,
128.1, 124.0, 124.0.
Without purification, 24 was dissolved in anhyd CH2Cl2 (50 mL)
and treated at r.t. with freshly prepared PCC (2.48 g, 11.54 mmol).
The reaction mixture was allowed to stir for 3 h then the organic lay-
er was decanted and the black gummy solid was thoroughly washed
with CH2Cl2 (2 × 30 mL). The combined organic phase was washed
with H2O (30 mL), brine (30 mL), dried (Na2SO4) and concentrated
under reduced pressure. The product was passed through a small
bed of silica gel and concentrated to give a solid that was subjected
to column chromatography (EtOAc–PE, 1:1) to provide sulfone al-
dehyde 5.
Yield: 1.81 g (7.29 mmol, 70% from 23); white solid; mp 141–
142 °C (Lit.20 143–145 °C).
MS (ESI, 70 eV): m/z = 259.0723 [M + H]+.
Synthesis 2006, No. 15, 2556–2562 © Thieme Stuttgart · New York

2560
A. Patra et al.
PAPER
7-Methoxybenz[a]anthracene-5,6-dione (14b)
lected by filtration and thoroughly washed with MeOH–H2O (1:10)
to give 14c.
To a stirred solution of t-BuOLi (620 mg, 7.75 mmol) in THF (20
mL) at –60 °C (CHCl3–liquid N2 bath) under an inert atmosphere
was added a solution of sulfoxide 9 (700 mg, 2.55 mmol) in THF (5
mL). The resulting yellowish solution was stirred at –60 °C for 25
min, after which a solution of 12 (500 mg, 2.70 mmol) in THF (5
mL) was added. The cooling bath was removed after 1 h at –60 °C
and the reaction mixture was brought to r.t. over a period of 1 h and
further stirred for 6 h. The reaction was quenched with NH4Cl (5%,
15 mL) and the resulting solution was concentrated to give a residue
that was diluted with EtOAc (20 mL). The aqueous layer was ex-
tracted with EtOAc (3 × 25 mL) and the combined organic extracts
were worked up in the usual manner to give a semi-solid residue.
This residue was dissolved in dry acetone (10 mL) under N2-atmo-
sphere and dry K2CO3 (15 mmol) and Me2SO4 (4 mmol; freshly pu-
rified) were added. After 2 h of reflux, on completion of the
reaction, inorganic salts were filtered and the filtrate was concen-
trated to afford a residue that was diluted with Et2O (30 mL), treated
with Et3N (400 mg, 4 mmol) at r.t. and stirred for 30 min. The reac-
tion mixture was then diluted with EtOAc (50 mL), washed with
H2O (2 × 20 mL) and subjected to the usual workup to give 13b.
Yield: 265 mg (0.79 mmol, 68%); orange solid; mp 142–144 °C.
IR (KBr): 3435, 1673, 1595, 1534, 1483, 1436, 1376, 1305, 1221,
1135, 1063, 990, 938, 796, 763, 683 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.76 (dd, J = 8.3 Hz, 1.0 Hz, 1 H,
Ar), 8.43 (t, J = 8.8 Hz, 2 H, Ar), 8.04 (dd, J = 7.8 Hz, 1.4 Hz, 1 H,
Ar), 7.85–7.57 (m, 3 H, Ar), 7.50 (dt, J = 1.0 Hz, 7.4 Hz, 1 H, Ar),
4.21 (s, 3 H, OCH3), 2.21 (s, 3 H, SCH3).
13C NMR (50 MHz, CDCl3): d = 184.1, 180.3, 162.4, 139.3, 138.6,
136.6, 134.1, 132.1, 131.3, 131.0, 130.0, 129.3, 128.9, 128.4, 128.1,
127.9, 125.5, 119.2, 64.7, 21.0.
MS (ESI, 70 eV): m/z = 334.0888 [M + H]+.
Anal. Calcd for C20H14O3S: C, 71.84; H, 4.22. Found: C, 71.68; H,
4.12.
Benzil–Benzilic Acid Rearrangement; Typical Procedure
A mixture of a benz[a]anthracene-5,6-dione derivative 14c (500
mg, 1.50 mmol), powdered KOH (1.2 g, 21.4 mmol) and 10 drops
of dioxane was stirred for 30 min at r.t. and the resulting mixture
was diluted with H2O (50 mL). The aqueous phase was extracted
with Et2O (2 × 25 mL) and then acidified with dilute HCl and ex-
tracted with Et2O (3 × 30 mL). The latter Et2O extracts were evap-
orated to dryness to furnish the corresponding hydroxycarboxylic
1H NMR (200 MHz, CDCl3): d = 8.24 (d, J = 8.0 Hz, 1 H, Ar), 7.94
(s, 1 H, Ar), 7.84 (t, J = 8.0 Hz, 2 H, Ar), 7.60–7.30 (m, 5 H, Ar),
4.10 (s, 3 H, OCH3), 3.37 (s, 6 H, 2 × OCH3).
Compound 13b was dissolved in MeOH (10 mL) at r.t. and HCl
(10%, 10 mL) was added with stirring. After 1 h stirring a solid pre-
cipitate appeared that was collected by filtration and thoroughly
washed with MeOH–H2O (1:1) to give dione 14b.
1
acid 15c as a white residue that was primarily characterized by H
NMR data and then directly used for the next step.
Yield: 535 mg (1.86 mmol, 73%); red solid; mp 216–218 °C.
11-Hydroxy-11H-benzo[b]fluorene-11-carboxylic Acid (15a)
1H NMR (200 MHz, CDCl3): d = 8.65 (s, 1 H, Ar), 8.11 (d, J = 7.6
Hz, 1 H, Ar), 7.97 (d, J = 7.2 Hz, 1 H, Ar), 7.84 (d, J = 7.4 Hz, 1 H,
Ar), 7.64 (s, 1 H, Ar), 7.64–7.40 (m, 4 H, Ar), 7.32 (d, J = 7.4 Hz,
1 H, Ar).
IR (KBr): 3435, 1667, 1603, 1560, 1487, 1421, 1371, 1318, 1264,
1179, 1132, 1062, 987, 951, 882, 759, 688, 636 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.33 (d, J = 8.2 Hz, 1 H, Ar), 8.20
(s, 1 H, Ar), 8.17 (d, J = 8.1 Hz, 1 H Ar), 7.88 (d, J = 8.1 Hz, 1 H,
Ar), 7.74 (t, J = 7.2 Hz, 1 H, Ar), 7.69–7.51 (m, 3 H, Ar), 7.46 (t,
J = 7.5 Hz, 1 H, Ar), 4.13 (s, 3 H, OCH3).
13C NMR (50 MHz, CDCl3): d = 181.6, 180.3, 163.7, 137.4, 137.3,
135.7, 131.5, 130.9, 129.7, 129.3, 129.1, 128.7, 128.0, 124.9, 124.4,
120.2, 63.4 (signals of two aromatic carbons were not observed).
11-Hydroxy-10-methoxy-11H-benzo[b]fluorene-11-carboxylic
Acid (15b)
1H NMR (200 MHz, CDCl3): d = 8.24–8.14 (m, 1 H, Ar), 8.00 (dd,
J = 1.3 Hz, 7.5 Hz, 1 H, Ar), 7.84–7.78 (m, 1 H, Ar), 7.75–7.51 (m,
3 H, Ar), 7.49 (dd, J = 1.4 Hz, 7.5 Hz, 1 H, Ar), 7.43 (s, 1 H, Ar),
7.35 (dd, J = 1.4 Hz, 7.5 Hz, 1 H, Ar), 4.09 (s, 3 H, CH3).
MS (ESI, 70 eV): m/z = 289.0786 [M + H]+.
Anal. Calcd for C19H12O3: C, 79.16; H, 4.20. Found: C, 78.92; H,
4.32.
11-Hydroxy-10-methoxy-5-methylsulfanyl-11H-benzo[b]fluo-
rene-11-carboxylic Acid (15c)
1H NMR (200 MHz, CDCl3): d = 9.09 (d, J = 8.5 Hz, 1 H, Ar), 8.86
(d, J = 7.5 Hz, 1 H, Ar), 8.11 (d, J = 8.0 Hz, 1 H, Ar), 7.70–7.35 (m,
5 H, Ar), 4.10 (s, 3 H, OCH3), 2.41 (s, 3 H, SCH3).
7-Methoxy-12-methylsulfanylbenz[a]anthracene-5,6-dione
(14c)
To a stirred solution of t-BuOLi (300 mg, 3.75 mmol) in THF (15
mL) at –60 °C (CHCl3–liquid N2 bath) under an inert atmosphere
was added a solution of 10 (300 mg, 1.16 mmol) in THF (4 mL).
The resulting yellowish solution was stirred at –60 °C for 20 min,
after which a solution of Michael acceptor 12 (230 mg, 1.28 mmol)
in THF (4 mL) was added. After 1 h, the resulting mixture was
warmed to 0 °C and then treated with MeI (1.5 g, 10.5 mmol). Stir-
ring was continued at that temperature for 1 h and then the mixture
was brought to r.t. and quenched with NH4Cl (5%, 15 mL). The re-
sulting solution was concentrated under vacuum and the residue
was diluted with EtOAc (30 mL) and the layers were separated. The
aqueous layer was extracted with EtOAc (3 × 20 mL) and the com-
bined organic layers were worked up as usual to give 13c (>90% pu-
rity).
O-Methylation of Carboxylic Acids; General Procedure
To a stirred solution of carboxylic acid (0.32 mmol) in Et2O (10
mL) at 0 °C was added diazomethane (excess) in Et2O. The result-
ing solution was stirred for 30 min. at 0 °C and then diluted with
H2O (30 mL). The organic layer was washed with a sat. aq soln of
NaHCO3 (20 mL), brine (10 mL) and concentrated to give a crude
residue that was purified by chromatography on silica gel (EtOAc–
PE, 2:1) to give the corresponding methyl ester.
Methyl 11-Methoxy-11H-benzo[b]fluorene-11-carboxylate
(16a)
Yield: 76% (two steps from 14a); oil.
IR (KBr): 1726, 1439, 1279, 1213, 1132, 1079 cm–1.
1H NMR (200 MHz, CDCl3): d = 8.58 (s, 1 H, Ar), 8.04 (d, J = 7.7
Hz, 1 H, Ar), 7.97 (d, J = 7.1 Hz, 1 H, Ar), 7.83 (d, J = 8.4 Hz, 1 H,
Ar), 7.64 (s, 1 H, Ar), 7.62–7.54 (m, 3 H, Ar), 7.50 (t, J = 8.7 Hz,
1 H, Ar), 7.32 (d, J = 7.4 Hz, 1 H, Ar), 3.69 (s, 3 H, CH3), 3.56 (s,
3 H, CH3).
1H NMR (200 MHz, CDCl3): d = 8.78 (dd, J = 8.0 Hz, 1 H, Ar),
8.30 (dd, J = 8.0 Hz, 8.0 Hz, 2 H, Ar), 7.90–7.32 (m, 5 H, Ar), 4.09
(s, 3 H, OCH3), 3.37 (s, 6 H, 2 × OCH3), 2.21 (s, 3 H, SCH3).
Compound 13c was dissolved in MeOH (10 mL) and stirred with
HCl (10%, 10 mL) at r.t. for 1 h. The resulting precipitate was col-
Synthesis 2006, No. 15, 2556–2562 © Thieme Stuttgart · New York

PAPER
Regiospecific Synthesis of Benzo[b]fluorenones via Benz[a]anthracene-5,6-dione Ring Contraction
2561
13C NMR (50 MHz, CDCl3): d = 167.5, 167.4, 143.4, 139.3, 134.5,
131.6, 131.6, 131.0, 130.8, 129.8, 129.6, 129.0, 128.9, 128.3, 128.1,
127.7, 127.2, 126.6, 51.9, 51.8.
Ar), 7.59–7.38 (m, 3 H, Ar), 7.32 (t, J = 7.3 Hz, 1 H, Ar), 4.36 (s,
3 H, CH3).
13C NMR (50 MHz, CDCl3): d = 190.5, 157.1, 143.9, 139.3, 138.0,
136.2, 134.3, 129.6, 129.0, 128.3, 126.5, 125.2, 124.0, 120.5, 118.4,
114.2, 63.2 (corresponding to 129.6 was not resolved).
MS (ESI, 70 eV): m/z = 289.0811 [M – CH3]+, 245.0931 [M –
CO2CH3]+.
Methyl 11-Hydroxy-10-methoxy-11H-benzo[b]fluorene-11-car-
boxylate (16b)
10-Methoxy-5-methylsulfanyl-benzo[b]fluoren-11-one (17c)
Yield: 42% (two steps from 14c); yellow solid; mp 154–157 °C.
Yield: 73% (two steps from 14b); white solid; mp 170–172 °C.
1H NMR (200 MHz, CDCl3): d = 9.03 (d, J = 7.8 Hz, 1 H, Ar), 8.70
(d, J = 8.3 Hz, 1 H, Ar), 8.35 (d, J = 8.1 Hz, 1 H, Ar), 7.82–7.45 (m,
4 H, Ar), 7.39 (t, J = 7.4 Hz, 1 H, Ar), 4.30 (s, 3 H, OCH3), 2.38 (s,
3 H, SCH3).
13C NMR (50 MHz, CDCl3): d = 190.2, 157.6, 144.3, 139.6, 136.8,
134.6, 130.3, 129.3, 126.9, 126.8, 126.0, 125.4, 123.7, 63.5, 19.5
(signals of four aromatic carbons were not observed).
IR (KBr): 3439, 1733, 1638, 1586, 1349, 1260, 1108, 1079, 758
cm–1.
1H NMR (200 MHz, CDCl3): d = 8.14–8.04 (m, 1 H, Ar), 7.95–7.87
(m, 1 H, Ar), 7.88 (s, 1 H, Ar), 7.79 (d, J = 8.3 Hz, 1 H, Ar), 7.56–
7.30 (m, 5 H, Ar), 4.09 (s, 3 H, CH3), 3.64 (s, 3 H, CH3).
13C NMR (50 MHz, CDCl3): d = 174.8, 153.0, 145.3, 140.2, 139.5,
136.6, 132.7, 129.9, 128.9, 128.7, 128.3, 126.9, 125.8, 123.5, 122.4,
120.9, 115.0, 81.1, 63.0, 53.4.
MS (ESI, 70 eV): m/z = 307.0880 [M + H]+.
5,6-Dimethoxybenz[a]anthracene-7,12-dione (19)
This compound was prepared by annulation of phthalides (2 or 11)
with 12, following the procedure adopted for the preparation of
compound 14c.
MS (ESI, 70 eV): m/z = 343.0793 [M + Na]+.
Anal. Calcd for C20H16O4: C, 74.99; H, 5.03. Found: C, 75.12; H,
4.82.
Yield: (86% from 11 and 83% from 2); yellow solid; mp 148–
150 °C.
Methyl 11-Hydroxy-10-methoxy-5-methylsulfanyl-11H-ben-
zo[b]fluorene-11-carboxylate (16c)
Yield: 68% (two steps from 14c); Oil.
IR (KBr): 1666, 1596, 1562, 1487, 1450, 1372, 1331, 1290, 1230,
1099, 995, 957, 861, 794, 758, 693, 606 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.57–9.50 (m, 1 H, Ar), 8.26–8.05
(m, 3 H, Ar), 7.77–7.52 (m, 4 H, Ar), 4.17 (s, 3 H, OCH3), 4.04 (s,
3 H, OCH3).
13C NMR (50 MHz, CDCl3): d = 185.4, 184.1, 154.8, 146.7, 134.3,
133.6, 133.4, 133.1, 131.9, 130.4, 129.0, 128.9, 128.5, 126.9, 126.4,
125.9, 121.8, 61.6, 61.5 (signal of one aromatic carbon was not ob-
served).
IR (KBr): 3431, 1733, 1616, 1442, 1326, 1256, 1187, 1114, 1081,
1033, 759 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.07 (d, J = 7.8 Hz, 1 H, Ar), 8.85
(d, J = 8.6 Hz, 1 H, Ar), 8.11 (d, J = 7.8 Hz, 1 H, Ar), 7.68–7.35 (m,
5 H, Ar), 4.08 (s, 3 H, CH3), 3.63 (s, 3 H, CH3), 2.40 (s, 3 H, SCH3).
13C NMR (50 MHz, CDCl3): d = 174.7, 153.5, 145.8, 142.7, 140.7,
138.3, 133.6, 130.0, 129.2, 129.0, 128.5, 127.6, 126.9, 126.1, 124.3,
123.1, 122.7, 80.4, 63.1, 53.4, 19.2.
MS (ESI, 70 eV): m/z = 319.0869 [M + H]+.
MS (ESI, 70 eV): m/z = 389.0583 [M + Na]+, 349.0678 [M – OH]+.
Anal. Calcd for C20H14O4: C, 75.46; H, 4.43. Found: C, 75.58; H,
4.72.
Anal. Calcd for C21H18O4S: C, 68.83; H, 4.95. Found: C, 68.58; H,
4.72.
2-(3,4-Dimethoxynaphthalene-1-carbonyl)benzoic Acid (20)
This compound was obtained when compound 19 was submitted to
the general procedure for benzil–benzilic acid rearrangement.
1H NMR (200 MHz, CDCl3): d = 8.92–8.84 (m, 1 H, Ar), 8.25–8.14
(m, 1 H, Ar), 8.05–7.96 (m, 1 H, Ar), 7.70–7.50 (m, 5 H, Ar), 7.26
(s, 1 H, Ar), 4.04 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3).
Oxidative Decarboxylation of Hydroxyl Acids 15; General Pro-
cedure
To a stirred solution of a carboxylic acid (1.13 mmol) in a mixture
of AcOH (9 mL) and H2O (5 mL) was added CrO3 (650 mg. 6.5
mmol) and the resulting mixture was heated at reflux for 45 min.
After completion of the reaction, the mixture was diluted with H2O
(30 mL) and the yellow precipitate was extracted with Et2O (3 × 25
mL). The combined organic extracts were successively washed with
aq NaOH (1 M, 15 mL), brine (15 mL), H2O (15 mL), dried
(Na2SO4) and concentrated. Purification of the crude product by
column chromatography on silica gel (EtOAc–PE, 1:1) furnished
the corresponding benzo[b]fluorenone.
Methyl 2-(3,4-Dimethoxynaphthalene-1-carbonyl)benzoate
(21)
This compound was obtained from 20, by treatment with diazo-
methane according to general procedure for esterification.
Yield: 82% (two steps from 19); white solid; mp 99–102 °C.
1H NMR (200 MHz, CDCl3): d = 8.95–8.85 (m, 1 H, Ar), 8.28–8.14
(m, 1 H, Ar), 8.05–7.90 (m, 1 H, Ar), 7.71–7.51 (m, 5 H, Ar), 7.25
(s, 1 H, Ar), 4.06 (s, 3 H, CH3), 3.78 (m, 3 H, CH3), 3.43 (s, 3 H,
CH3).
13C NMR (50 MHz, CDCl3): d = 196.9, 167.0, 147.4, 145.8, 142.3,
131.8, 130.3, 130.1, 129.9, 129.4, 128.7, 128.0, 126.6, 126.1, 121.9,
121.6, 61.1, 57.1, 52.2 (signals of two aromatic carbons were not
observed).
Benzo[b]fluoren-11-one (17a)
Yield: 57% (two steps from 14a); yellow solid; mp 142–145 °C.
(Lit.17 143–145 °C).
1H NMR (200 MHz, CDCl3): d = 8.17 (s, 1 H, Ar), 7.89 (d, J = 8.1
Hz, 1 H, Ar), 7.87 (s, 1 H, Ar), 7.83 (d, J = 8.1 Hz, 1 H, Ar), 7.74 (t,
J = 7.0 Hz, 2 H, Ar), 7.60–7.40 (m, 3 H, Ar), 7.34 (t, J = 7.4 Hz,
1 H, Ar).
10-Methoxy-11H-benzo[b]fluoren-11-one (17b)
Yield: 54% (two steps from 14b); yellow solid; mp 126–128 °C;
(Lit.8i 127–129 °C).
Anal. Calcd for C21H18O5: C, 71.99; H, 5.18. Found: C, 71.78; H,
4.92.
1H NMR (200 MHz, CDCl3): d = 8.29 (d, J = 7.9 Hz, 1 H, Ar),
7.78–7.67 (m, 2 H, Ar), 7.67 (d, J = 8.1 Hz, 1 H, Ar), 7.56 (s, 1 H,
2-(Phenylsulfonylmethyl)benzoic Acid (23)
To a well stirred solution of 22 (1.18 g, 5.15 mmol) in dry DMF (12
mL) was added sodium benzenesulfinate (1.30 g, 7.93 mmol) in
Synthesis 2006, No. 15, 2556–2562 © Thieme Stuttgart · New York

2562
A. Patra et al.
PAPER
portions. The mixture was stirred overnight at r.t. and the resulting
mass was poured into cold H2O (35 mL). The white crystalline ma-
terial precipitated was filtered and recrystallized from a EtOAc-pe-
troleum ether system to give a shiny crystalline product (mp 85–
87 °C). The solid product was dissolved in a mixture of aq NaOH
(20%, 15 mL) and MeOH (15 mL) and stirred at r.t. overnight. At
the end of the reaction, excess MeOH was removed under reduced
pressure and the residue was diluted with H2O (30 mL) and extract-
ed with EtOAc (2 × 20 mL). The aqueous fraction was acidified
with dilute HCl and to give a white precipitate that was filtered and
washed repeatedly with H2O to remove inorganic acid. The result-
ing solid was recrystallized from EtOAc–PE to provide acid 23.
(7) M-Contelles, J.; Molina, T. M. Curr. Org. Chem. 2003, 7,
1433.
(8) (a) Mal, D.; Hazra, N. K. Tetrahedron Lett. 1996, 37, 2641.
(b) Hauser, F. M.; Zhou, M. J. Org. Chem. 1996, 61, 5722.
(c) Chuang, C. P.; Wang, S. F. Synlett 1996, 829.
(d) Kumamoto, T.; Tabe, N.; Yamaguchi, K.; Ishikawa, T.
Tetrahedron Lett. 2000, 41, 5693. (e) Mohri, S.; Stefinovic,
M.; Snieckus, V. J. Org. Chem. 1997, 62, 7072.
(f) Koyama, H.; Kamikawa, T. Tetrahedron Lett. 1997, 38,
3973. (g) Williams, W.; Sun, X.; Jebaratnam, D. J. Org.
Chem. 1997, 62, 4364. (h) Gore, M. P.; Gould, S. J.; Weller,
D. D. J. Org. Chem. 1992, 57, 2774. (i) Qabaja, G.; Jones,
G. B. J. Org. Chem. 2000, 65, 7187. (j) Gonzalez-
Cantalapiedra, E.; de Frutos, O.; Atienza, C.; Mateo, C.;
Echavarren, A. M. Eur. J. Org. Chem. 2006, 1430.
(9) Morris, J. L.; Becker, C. L.; Fronczek, F. R.; Daly, W. H.;
McLaughlin, M. L. J. Org. Chem. 1994, 59, 6484.
(10) (a) Mal, D.; Ghorai, S.; Hazra, N. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2001, 40, 994. (b) Ghorai, S.
K.; Hazra, N. K.; Mal, D. Tetrahedron Lett. 1998, 39, 689.
(c) Ghorai, S. K.; Roy, H. N.; Bandopadhyay, M.; Mal, D. J.
Chem. Res., Synop. 1999, 30.
Yield: 1.022 g (3.87 mmol, 72%); white solid; mp 156–157 °C.
1H NMR (200 MHz, CDCl3): d = 8.02 (dd J = 1.7 Hz, 7.4 Hz, 1 H,
Ar), 7.70–7.41 (m, 7 H, Ar), 7.34 (dd, J = 1.6 Hz, 7.4 Hz, 1 H, Ar),
5.07 (s, 2 H, CH2SO2Ph).
13C NMR (50 MHz, CDCl3): d = 171.0, 138.0, 133.8, 133.7, 133.0,
131.8, 129.9, 129.4, 129.0, 128.9, 128.6, 59.4.
Acknowledgements
(11) Mal, D.; Hazra, K. N.; Murty, K. V. S. N.; Majumdar, G.
Financial assistance from DST and CSIR, New Delhi for this work
is gratefully acknowledged. A.P. and S.R.D. thank CSIR, New De-
lhi for their research fellowships.
Synlett 1995, 1239.
(12) (a) Gill, G. B. Comprehensive Organic Synthesis, Vol. 3;
Pattenden, G., Ed.; Pergamon: New York, 1991, 821, 38.
(b) Ott, G. D.; Smith, G. G. J. Am. Chem. Soc. 1955, 77,
2325.
(13) Iwamoto, H.; Kobayashi, Y.; Kawatani, T.; Suzuki, M.;
Fukazawa, Y. Tetrahedron Lett. 2006, 47, 1519.
(14) (a) Mal, D.; Roy, H. N.; Hazra, N. K.; Adhikari, S.
Tetrahedron 1997, 53, 2177. (b) Hauser, F. M.; Dorsch, W.
A.; Mal, D. Org. Lett. 2002, 4, 2237. (c) Mal, D.; Patra, A.;
Roy, H. Tetrahedron Lett. 2004, 45, 7895.
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Synthesis 2006, No. 15, 2556–2562 © Thieme Stuttgart · New York