Annulation strategies for benzo[b]fluorene synthesis: efficient routes to the kinafluorenone and WS-5995 antibiotics.

Article abstract of DOI:10.1021/jo0056186

Intramolecular palladium-mediated arylation approaches to benzo[b]fluorenes have been investigated. The methodology has been applied in a short synthesis of tri-O-methylkinafluorenone, providing an effective alternative to Friedel-Crafts-based approaches. During the course of this work, an acid-promoted quinolactonization of naphthoquinones was also developed, providing direct access to either ortho or para isomers as desired. Application of this methodology in syntheses of the antibiotics WS-5995A, WS-5995C, and functional analogues was demonstrated, and antitumoral activity of this class was determined.

Full text of DOI:10.1021/jo0056186

J . Org. Chem. 2000, 65, 7187-7194
7187
An n u la tion Str a tegies for Ben zo[b]flu or en e Syn th esis: Efficien t
Rou tes to th e Kin a flu or en on e a n d WS-5995 An tibiotics
Ghassan Qabaja and Graham B. J ones*
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry, Northeastern University,
360 Huntington Avenue, Boston, Massachussetts 02115-5000
grjones@lynx.neu.edu
Received August 23, 2000
Intramolecular palladium-mediated arylation approaches to benzo[b]fluorenes have been investi-
gated. The methodology has been applied in a short synthesis of tri-O-methylkinafluorenone,
providing an effective alternative to Friedel-Crafts-based approaches. During the course of this
work, an acid-promoted quinolactonization of naphthoquinones was also developed, providing direct
access to either ortho or para isomers as desired. Application of this methodology in syntheses of
the antibiotics WS-5995A, WS-5995C, and functional analogues was demonstrated, and antitumoral
activity of this class was determined.
Sch em e 1
In tr od u ction
The search for new antibiotics continues at a steady
pace, and quinonoid-derived systems have been the
subject of a number of promising leads.1 Of the benzo-
[b]fluorenone family, the natural products stealthin C,
1,2 and prekinamycin, 3,3 have attracted considerable
interest, and both are accessible from the benzo[b]-
fluorenone 2.4 Additionally, tetracycle 3 is a known
intermediate in the biosynthesis of the kinamycin family
of antibiotics produced by Streptomyces murayamaensis,
and a number of these natural products show Gram
positive and negative antibacterial properties, and anti-
tumoral activity.5
biphenyls 5 (Scheme 1).6 Due to the versatility of transi-
tion metal mediated arylations, we were interested in
investigating the potential for a Pd-mediated closure from
6, which would offer a complimentary strategy for the
production of analogues of the natural products.
Resu lts a n d Discu ssion
To demonstrate the feasibility of the approach, ap-
propriate model substrates were assembled, either by
coupling arene 7 with 2-iodobenzoic acid, or in the case
of 10, acylation followed by Ti-catalyzed ortho-Fries
rearrangement (Scheme 2). Palladium-mediated closures
on substrates 8 and the methyl ether of 11 were con-
ducted using a variety of methods with limited success,
but optimal conditions were eventually found, involving
high-temperature closure with Pd(OAc)2 in dimethyl-
acetamide (DMA), as had been previously demonstrated
by Ames and Opalko in the cyclization of substituted
diphenyl ethers and benzophenones.7
With the model study complete, we sought application
in the synthesis of key structure 2.8 Accordingly, dim-
ethylanisole 13 was converted to iodoaldehyde 14 which
was subjected to 1,2 addition with the lithioarene derived
from aryl bromide 16, in turn prepared from methylju-
glone 15 (Scheme 3). The resulting benzylic alcohol was
oxidized (17) and the Pd-mediated closure attempted.
Using identical conditions to the model substrates, low
Though a number of different approaches to the basic
benzo[b]fluorenone skeleton 4 have been reported, most
involve variants of Friedel-Crafts type closures of acyl-
(1) CRC Handbook of Antibiotic Compounds; Berdy, J ., Ed.; CRC
Press: Boca Raton, 1980.
(2) Koyama, H.; Kamikawa, T. Tetrahedron Lett. 1997, 38, 3973-
3976. Gould, S. J .; Melville, C. R.; Cone, M. C.; Chen, J .; Carney, J . R.
J . Org. Chem. 1997, 62, 320-324.
(3) Gould, S. J .; Tamayo, N.; Melville, C. R.; Cone, M. C. J . Am.
Chem. Soc. 1994, 116, 2207-2208. Cone, M. C.; Hassan, A. M.; Gore,
M. P.; Gould, S. J .; Borders, D. B.; Alluri, M. R. J . Org. Chem. 1994,
59, 1923-1924. Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem.
1992, 57, 2774-2783.
(4) Gore, M. P.; Gould, S. J .; Weller, D. D. J . Org. Chem. 1991, 56,
2289-2291. Mohri, S.; Stefinovic, M.; Snieckus, V. J . Org. Chem. 1997,
62, 7072-7073.
(5) Gould, S. J .; Melville, C. R. Bioorg. Med. Chem. Lett. 1995, 5,
51-54.
(6) For the phthalide annulation route, see: Hauser, F. M.; Zhou,
M. J . Org. Chem. 1996, 61, 5722-5722.
(7) Ames, D. E.; Opalko, A. Tetrahedron 1984, 40, 1919-1925. For
related Pd-mediated closures, see: Bringmann, G.; J ansen, J . R.;
Reuscher, H.; Rubennacker, M.; Peters, K.; von Schnering, H. G.
Tetrahedron Lett. 1990, 31, 643-646; Deshpande, P. P.; Martin, O. R.
Tetrahedron Lett. 1990, 31, 6313-6316; Harayama, T.; Akiyama, T.;
Nakano, Y.; Shibaike, K. Heterocycles 1998, 48, 1989-1992.
(8) Preliminary communication: Qabaja, G.; J ones, G. B. Tetrahe-
dron Lett. 2000, 41, 5317-5320.
10.1021/jo0056186 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/26/2000

7188 J . Org. Chem., Vol. 65, No. 21, 2000
Qabaja and J ones
Sch em e 2
Sch em e 3
desired product 2, along with traces of unreacted 17.
Efforts to improve the product yields by extended ther-
molysis were unsuccessful, and after 2 min the solution
began to reflux, necessitating cessation of the reaction.
Similarly, microwave-accelerated closures to model sub-
strates 9 and 12 were successful, in both cases giving
comparable yields of product to the thermal process
(Scheme 2) within 1 min.
The speed and efficiency of the mW-accelerated cou-
pling suggests additional applications in transition metal
mediated processes may be worthy of investigation,
particularly in cases where product decomposition is an
issue. The described synthesis of 2 is competitive with
existing routes and may allow development of additional
natural product analogues. Gould has previously dem-
onstrated that the product of per-demethylation (BBr3)
of compound 2 (tri-O-methylkinafluorenone) is an inter-
mediate in the biosynthesis of both kinamycin C and D,
and it may be a realistic possibility to probe biosynthesis
of structural analogues using the requisite microorgan-
ism (S. murayamaensis).5
This synthesis notwithstanding, we were also inter-
ested in investigating additional acylation routes to core
structure 4, via appropriately substituted biaryls 5
(Scheme 1). Of particular interest was a route to differ-
entially methylated analogue 23, which might serve as
a useful starting material for QSAR analysis, and we
anticipated access via acylation of 22 (Scheme 4). Ac-
cordingly, aryl aldehyde 14 was converted to acyl chloride
19 and reacted with dihydroquinone 18, in turn prepared
from quinone 6 (Scheme 4).
The resulting product was first methylated and then
subjected to Pd-catalyzed closure using established con-
ditions.7 Our original plan was to effect hydrolysis of the
lactone moiety and attempt some form of acyl capture
on 22 to yield benzo[b]fluorene 23. To our initial surprise,
the sole product isolated was quinone 24, presumably
formed by in situ oxidation. This serendipitous observa-
tion prompted us to search for applications in the
synthesis of quinonoid antibiotics. Indeed, one could
predict that close geometric isomers of the kinamycin
family would retain some vestiges of biological activity.
On the basis of the structure of 24 itself, our attention
was directed to the naphthoquinone lactone WS-5995,
first isolated from Streptomyces auranticolor and struc-
turally determined in 1983.12 Though several pyranon-
a
CCl4, NBS, and then K2CO3, dioxane, 40%. b nBuLi, hexanes,
I2 -78 °C 80%. c COCl2, DMSO, 95%. Na2S2O4, ether, and then
d
Me2SO4, K2CO3 85%. e CCl4, Br2 99%, and then K2CO3, Me2SO4
60%. f tBuLi, ether, -78 °C (quant). PCC, CH2Cl2, 80%.
g
Ta ble 1. Attem p ted P d -Ca ta lyzed Ar yla tion of 17
temp,
entry
catalyst
solvent
DMA
DMA
DMA
CH3CN
THF/CH3CN
NMI
°C
time % 2
1
2
3
4
5
6
7
8
9
Pd(OAc)2/NaOAc7
PdCl2(PPh3)2/NaOAc
Pd(OAc)2(PPh3)2/NaOAc
Pd(OAc)2/Et3N
130 12 h
130 18 h
130 6 h
80 24 h
80 36 h
170 24 h
130 24 h
130 24 h
0
29
31
0
<5
0
Pd(PPh3)4/Et3N
PdCl2(PPh3)2/NMI
Pd(OAc)2/Bu4NCl/NaOAc27 DMA
0
0
Pd(OAc)2/LiCl/NaOAc28
PdCl2(PPh3)2/NaOAc
Pd(OAc)2(PPh3)2/NaOAc
DMA
DMA-mW
DMA-mW
140 1 min 53
160 1 min 49
10
yields of 2 were isolated, presumably reflecting a com-
bination of the electronic influence of the o-methoxy
group in the oxidative addition step and developing
(repulsive) interactions between the aryloxy groups.
Complicating the process was product decomposition
which ensued at the high temperatures and extended
reaction times necessary to effect closure (Table 1). Since
metal-catalyzed processes are often ideal candidates for
acceleration using microwaves,9,10 a reaction was con-
ducted using microwave irradiation (mW). Additionally,
DMA, which has a dielectric constant of 37.8D, would be
expected to heat rapidly during the irradiation process.
Accordingly, a sample of 17, PdCl2(PPh3)2, and sodium
acetate dissolved in DMA, in a round-bottomed flask was
placed in the center of a conventional microwave oven
and irradiated for 60 s.11 During this period, the solution
temperature reached 140 °C and gave a 53% yield of
(11) For previous reports from this laboratory, see: Huber, R. S.;
J ones, G. B. J . Org. Chem. 1992, 57, 5778-5780. J ones, G. B.; Huber,
R. S.; Chau, S. Tetrahedron. 1993, 49, 369-380; J ones, G. B.;
Chapman, B. J . J . Org. Chem. 1993, 58, 5558-5559.
(12) Ikushima, H.; Takase, S.; Kawai, Y.; Itoh, Y.; Okamoto, M.;
Tanaka, H.; Imanaka, H. Agric. Biol. Chem. 1983, 47, 2231-2235.
(9) Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991, 20,
1-47.
(10) For pioneering examples in organic synthesis, see: Giguere,
R. J .; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron Lett. 1986,
27, 4945-4948.

Annulation Strategies for Benzo[b]fluorene Synthesis
J . Org. Chem., Vol. 65, No. 21, 2000 7189
Sch em e 4
aphthoquinone antibiotics have been identified, including
nanaomycin A, kalafungin, and eleutherin, relatively few
members of the corresponding naphthoquinone lactones
have been found, making WS-5995A an interesting
target. Structural analogues including its open form WS-
5995C are known,13 and these agents have demonstrated
chemoprotective activity against Eimeria tenella infec-
tion.14 Though the origin of their biological activity
remains to be clarified, it has been shown that the
bacterium Streptomyces acidizcabies (present in acidic
soils) produces the WS-5995 compounds, and that they
likely contribute to the observed pathogenicity of this
organism.15 Furthermore, on the basis of structural
similarities between WS5995A and the gilvocarcin anti-
biotics, it is conceivable that these agents may function
as topoisomerase inhibitors, rendering them potential
antitumor agents.16 We opted to develop an expeditious
route to the core structure of the WS-5995 family,
focusing on novel annulation chemistry.
Sch em e 5
p-quinone 25 in good yield (Scheme 5). Subsequent
demethylation gave WS-5995A directly, identical in all
respects with natural material. Intriguingly, in an at-
tempt to optimize the lactonization step, when 24 was
exposed to TFAA, the alternate o-quinone 26 was pro-
duced exclusively. Interconversion of this, presumably
less thermodynamically stable, quinone isomer to 25 was
possible either using MSA or TMSOTf, but using TFAA
even after refluxing with 26 for 18 h, a 2.5:1 ratio of ortho:
para isomers still existed. o-Quinone 26 underwent
regioselective demethylation using lithium iodide to give
phenol 27, hydrolysis of which resulted in concomitant
formation of the natural product WS-5995C. Further-
more, interconversion of WS-5995C into WS-5995A was
effected using a published procedure,13 thus establishing
two independent routes to the target compound.
Accordingly, lactonization of hydroxy acid 24 was
investigated using methanesulfonic acid, which gave the
(13) Syntheses of WS-5995A-C antibiotics: (a) Watanabe, M.; Date,
M.; Furukawa, S. Chem. Pharm. Bull. 1989, 37, 292-297. de Frutos,
O.; Echavarren, A. M. Tetrahedron Lett. 1996, 37, 8953-8956. (b)
Tamayo, N.; Echavarren, A. M.; Paredes, M. C. J . Org. Chem. 1991,
56, 6488-6491. (c) Echavarren, A. M.; Tamayo, N.; Cardenas, D. J . J .
Org. Chem. 1994, 59, 6075-6083. (d) McKenzie, T. C.; Choi, W.-B.
Synth. Commun. 1989, 19, 1523-1532.
(14) Ikushima, H.; Okamoto, M.; Tanaka, H.; Ohe, O.; Kohsaka, M.;
Aoki, H.; Imanaka, H. J . Antibiot. 1980, 33, 1107-1113 and references
cited therein.
(15) King, R. R.; Lawrence, C. H. J . Agric. Food Chem. 1996, 44,
2849-2851.
(16) Matson, J . A.; Rose, W. C.; Bush, J . A.; Myllymaki, R.; Bradner,
W. T.; Doyle, T. W. J . Antibiot. 1989, 42, 1446-1448.
Prompted by the unexpected quinolactonization to give
26, a model compound was prepared to investigate the
generality of the annulation process. Commercially avail-
able 28 was esterified and then subjected to Pd-mediated
closure to give 30 (Scheme 6). Following hydrolysis, the
substrate 31 was subjected to a variety of acid-catalyzed

7190 J . Org. Chem., Vol. 65, No. 21, 2000
Qabaja and J ones
Ta ble 3. Electr och em istr y a n d Cytotoxicity of Or th o/
P a r a Qu in on es
Sch em e 6
growth inhibitionc
compound E° (mV)a IC50 (µM)b H-460 MCF-7 SF-268
WS-5995A
WS-5995C
-370
-1415
-550
1
100
15
27
26
24
32
33
31
-
+
-
-
+
-
-
+
-
+
+
-
+
-
-
+
-
-
-585
2
-1025
-360
>15d
10
-370
5
125
-1015
a
b
Values relative to Ag/AgCl reference electrode. Determined
using MTS:PMS assay on L1210 mouse lymphoma cells. c Denotes
ability (+) of candidate to reduce growth of H-460 lung, MCF-7
breast, or SF-S68 CNS cancer cells to 32% or less using sulfor-
d
hodamine assay. Insolubility precluded studies at higher con-
centration.
Analysis of their reduction potentials highlighted mea-
surable differences between the ortho/para isomers, a
phenomenon which could be expected to have an impact
under biological conditions (Table 3). Initial cytotoxicity
assays against a murine cell line revealed that in addition
to WS-5995, o-quinone 26 and model quinone 32 were
appreciably cytotoxic, and they were subjected to a
broader screen (Table 3).18 Comparison of the cytotoxici-
ties of 26 and 27 suggests that the hydrogen bonding
phenolic group may attenuate the function of the o-
quinone moiety to some degree, and it also has a
noticeable impact on the reduction potential. On the basis
of these results, compounds 26, 32, and 33 are now the
focus of additional studies at NCI.19 It is well-known that
the differing reduction potentials of ortho and para
quinones can play a dramatic role in electron transfer
chemistry, and we are currently investigating the anti-
proliferative capacity of the entire family of analogues
under a variety of hypoxic and aerobic screens.
Ta ble 2. Acid -P r om oted Qu in ola cton iza tion s
(Sch em e 6)a
temp
entry substrate reagent solvent (°C) time % 32 % 33
1
2
3
4
5
6
7
8
9
31
31
31
31
31
31
31
32
32
33
MSA
TFAA
(COCl)2 CH2Cl2
TFAA THF
TMSOTf CH2Cl2
-
25 12 h
25 6 h
40 24 h
25 36 h
25 4 h
19
25
75
16
74
75
0
55
-
-
81
75
25
84
26
25
100
45
100
100
CH2Cl2
TMSOTf CH2Cl2 -78 4 h
TFAA
TFAA
MSA
Et2O
25 4 h
CH2Cl2 -78 12 h
-
25 4 h
25 4 h
10
TFAA
CH2Cl2
a
All reactions run to quantitative conversion (HPLC), and then
isomer ratios were determined by 1H NMR.
Con clu sion s
quinolactonization procedures, which would normally be
expected to yield para quinone 33 via the corresponding
mixed anhydride. Though acetic anhydride was ineffec-
tive, TFAA gave product 33 cleanly and in high yield
(Table 2). However, under the influence of specific Lewis
acids, the alternate o-quinone product 32 could again be
produced. As in the case of 26, this is presumably the
result of enolization of the p-quinone carbonyl, encour-
aged by chelation of the phenol with the Lewis acid.
Attempts were made to optimize the yield of isomer 32,
and TMS triflate was found to be most effective, giving
good isolated yields of the desired product, easily sepa-
rable from the para isomer 33 by precipitation. As
expected, extended exposure of 32 to various acids
resulted in isomerization to the more thermodynamically
stable 33, methanesulfonic acid proving most efficient.
On the basis of these findings, regioselective quinolac-
tonizations may in fact be general in the naphthoquinone
family. Such methods could perhaps best be applied in
the synthesis of “unnatural isomers” of natural products,
a developing theme in chemical genetics.17
In summary, efficient routes to both the kinafluorenone
and WS-5995 family of antibiotics have been developed.
Key outcomes include the synthesis of an unprecedented
and biologically active o-quinone analogue of WS-5995A,
and the finding that a Pd-catalyzed intramolecular
arylation can be accelerated by nonconventional means.
The annulation strategies demonstrated in each offer
opportunity for application in related natural product
syntheses and the design of antiproliferatives.
Exp er im en ta l Section
General experimental procedures have been published.20
Unless otherwise stated, all reagents were purchased from the
1
Aldrich Chemical Co. and used as supplied. H and 13C NMR
spectra were obtained either on a 300 MHz Varian Mercury,
300 MHz Bruker AC 300, or 500 MHz Varian Unity machine.
HRMS determinations were conducted at the University of
Illinois mass spectrometry laboratories. Chromatographic
separations were made using E. Merck 230-400 mesh 60H
silica gel or using a Harrison Research Inc. chromatotron unit.
(18) Preliminary communication: Qabaja, G.; Perchellet, E.; Perch-
ellet, J .; J ones, G. B. Tetrahedron Lett. 2000, 41, 3007-3010.
(19) Compounds 26, 32, and 33 were selected for evaluation against
the NCI panel of 60 human tumor cell lines. Full details of this and
cell cycle assays will be reported elsewhere.
(20) General experimental procedures have been reported: J ones,
G. B.; Wright, J . M.; Plourde, G. W., II; Hynd, G.; Huber, R. S.;
Mathews, J . E. J . Am. Chem. Soc. 2000, 122, 1937-1944.
Since quinones as a class are generally biologically
active, we decided to investigate and compare both the
reduction potential and antiproliferative ability of the
synthetic analogues and also the natural products.
(17) Schreiber, S. L. Bioorg. Med. Chem. 1998, 6, 1127-1152.

Annulation Strategies for Benzo[b]fluorene Synthesis
J . Org. Chem., Vol. 65, No. 21, 2000 7191
Solvents were condensed in vacuo using a Buchler rotary
evaporator, with recirculating refrigerant maintained at -15°
C by means of an Isotemp 1013S unit.
63.87. Without further purification, the methyl ether (0.63 g,
1.63 mmol), Pd(OAc)2 (36.60 mg, 0.16 mmol), and Na2CO3 (0.26
g, 2.45 mmol) were dissolved in dry dimethylacetamide (30
mL), and the mixture was heated at 130 °C for 10 h. On
cooling, the solution was diluted with ether (50 mL), the
mixture washed with HCl, and the organic extracts were
condensed in vacuo to give a residual oil. Purification by SGC
(hexane:ethyl acetate 9:1) gave the title compound (0.36 g,
85%) as a yellow solid: mp ) 127-129 °C; 1H NMR (CDCl3) δ
8.26 (d, 1H J 8.1 Hz), 7.68 (d, 2H, J 7.8 Hz), 7.61 (d, 1H, J 7.2
Hz), 7.36-7.55 (m, 4H), 7.28 (t, 1H, J 7.2 Hz), 4.35 (s, 3H);
13C NMR (CDCl3) δ 190.74, 157.33, 144.21, 139.51, 138.24,
136.49, 134.54, 129.84, 129.79, 129.28, 128.60, 126.8, 125.45,
124.21, 120.78, 118.63, 114.52, 63.51. Anal. Calcd for
(2,5-Dim eth oxyp h en yl)(2-iod op h en yl)m eth a n on e (8).
A mixture of 2-iodobenzoic acid (1.59 g, 6.41 mmol) and 1,4-
dimethoxybenzene (0.88 g, 6.41 mmol) were refluxed in trif-
luoroacetic acid (10 mL) and trifluoroacetic anhydride (5 mL)
for 12 h. On cooling to room temperature, crushed ice (20 g)
was added followed by ether (100 mL) and the organic layer
washed with NaHCO3. The solution was dried over Na2SO4
and condensed in vacuo to give the title compound (2.38 g,
100%) as white solid: mp ) 74-75 °C; 1H NMR (CDCl3) δ 7.88
(dd, 1H, J 8.1 and 1.32 Hz), 7.36 (dt, 1H, J 7.44 and 1.08 Hz),
7.23-7.3 (m, 2H), 7.05-7.13 (m, 2H), 6.87 (d, 1H, J 9.0 Hz),
3.79 (s, 3H), 3.55 (s, 3H); 13C NMR (CDCl3) δ 196.16, 153.8,
153.5, 145.9, 139.67, 130.85, 128.64, 127.59, 126.92, 120.88,
115.24, 113.88, 91.71, 56.43, 55.8. Anal. Calcd for C15H13IO3:
C, 48.93; H, 3.56. Found: C, 49.25; H, 3.57.
1,4-Dim eth oxy-9H-flu or en on e (9). A mixture of 8 (0.111
g, 0.300 mmol), PdCl2(PPh3)2 (0.048 g, 0.070 mmol), and
sodium acetate (0.1 g, 1.2 mmol) was dissolved in dry dim-
ethylacetamide (10 mL), and the solution was degassed and
then heated to 130 °C for 15 h. On cooling to room tempera-
ture, the solution was diluted with ether (50 mL) and washed
with HCl, and the ethereal extracts were dried over Na2SO4.
The solution was filtered, the filtrate condensed in vacuo, and
the resulting oil purified by SGC (hexane:ethyl acetate 7:3) to
give the title compound (0.1 g, 92%) as a yellow solid: mp )
148-150 °C;1H NMR (CDCl3) δ 7.83 (d, 1H, J 8.4 Hz), 7.6 (d,
1H, J 7.2 Hz), 7.43 (t, 1H, J 7.7 Hz), 7.23 (t, 1H, J 7 Hz), 7.03
(d, 1H, J 9.3 Hz), 6.78 9 (d, 1H, J 9.0 Hz), 3.93 (s, 6H); 13C
NMR (CDCl3) δ 192.29, 152.73, 149.85, 142.71, 134.3 134.2,
132.61, 128.47, 124.51, 123.90, 121.36, 120.49, 114.36, 56.46,
56.27. Anal. Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C,
75.25; H, 5.18.
C
18H12O2: C, 83.06; H, 4.64. Found: C, 83.36; H, 4.85.
2-Iod o-3-m et h oxy-5-m et h ylb en zyl Alcoh ol. Prepared
from 3-methoxy-5-methylbenzyl alcohol according to the pro-
cedure of J ung and J ung,21 giving the title compound (43%)
1
as a white solid: mp ) 110 °C (lit.21 112-113 °C); H NMR
(CDCl3) δ 6.92 (s,1H), 6.61 (s, 1H), 4.7 (s, 2H), 3.9 (s, 3H), 2.35
(s, 3H), 2.12 (s, 1H). 13C NMR (CDCl3) δ 157.8, 143.9, 139.75,
121.9, 111.2, 85.4, 69.6, 56.5, 21.3.
2-Iod o-3-m et h oxy-5-m et h ylb en za ld eh yd e (14). Dry
DMSO (1.05 mL, 14.74 mmol) in CH2Cl2 (5 mL) was added to
oxalyl chloride (0.70 mL, 8.04 mmol) in CH2Cl2 (20 mL) at -78
°C after 5 min as solution of the alcohol (1.86 g, 6.70 mmol) in
CH2Cl2 (20 mL) added dropwise, after 15 min triethylamine
(4.7 mL, 33.5 mmol) added dropwise, the mix was allowed to
warm to RT, diluted with ether (100 mL), and washed with
water and HCl, and organic extracts were dried over Na2SO4
and concentrated in vacuo to give the title compound (1.78 g,
96%) as a pale yellow solid: mp ) 70-72 °C; 1H NMR (CDCl3)
δ 10.16 (s, 1H), 7.33 (s, 1H), 6.88 (s, 1H), 3.93 (s, 3H), 2.39 (s,
3H). 13C NMR (CDCl3) δ 196.74, 158.33, 140.19, 136.40, 123.07,
117.44, 90.34, 56.99, 21.37. Anal. Calcd for C9H9IO2: C, 39.16;
H, 3.29. Found: C, 39.22; H, 3.5.
(1-Hyd r oxy-2-n a p h th yl)(2-iod op h en yl)m eth a n on e (11).
A solution of 2-iodobenzoyl chloride (2.76 g, 11.40 mmol) in
dry THF (10 mL) was added over a 5 min period to a precooled
(0 °C) solution of 1-naphthol (1.49 g, 10.36 mmol), DMAP
(0.127 g, 1.040 mmol), and ethyldiisopropylamine (3.6 mL, 20.6
mmol) in dry THF (10 mL). The reaction mix was stirred for
2 h and then diluted with ether (150 mL), washed with
NaHCO3 and HCl, dried (Na2SO4). Condensation in vacuo gave
the 1-naphthyl 2-iodobenzoate (3.77 g, 97.5%) as an oil. The
crude 1-naphthyl 2-iodobenzoate (0.73 g, 1.95 mmol) and TiCl4
(0.34 mL, 3.12 mmol) were heated at 120 °C for 2 h. The
resulting brown solid was cooled to 80 °C and hydrolyzed with
4 N HCl and ether, and the organic layer was washed
successively with 4 N HCl, water, and NaHCO3 and dried over
Na2SO4. The product was isolated and purified by flash
chromatography using hexane:ethyl acetate (9:1) to give the
title compound (0.45 g, 51%) as a yellow solid: mp ) 104-
105 °C;1H NMR (CDCl3) δ 14.0 (s, 1H), 8.58 (d,1H, J 8.4 Hz),
8.12 (d, 1H, J 8.8 Hz), 7.95 (d, 1H, J 8.1 Hz), 7.82 (dt, 1H, J
6.9 and 1.0 Hz), 7.66-7.78 (m, 2H), 7.58 (dd,1H, J 7.7 and 1.6
Hz), 7.36-7.48 (m, 2H), 7.2 (d, 1H, J 8.8 Hz); 13C NMR (CDCl3)
δ 206.94, 165.33, 145.32, 141.14, 139.52, 133.11, 132.6, 130.06,
129.63, 129.5, 128.56, 128.07, 126.64, 125.67, 120.47, 114.2,
93.15. Anal. Calcd for C17H11IO2: C, 54.57; H, 2.96. Found:
C, 54.79; H, 3.14.
10-Met h oxy-11H -b en zo[b]flu or en -11-on e (12). Com-
pound 11 (1.30 g, 3.48 mmol), K2CO3 (2.0 g, 14.5 mmol), and
dimethyl sulfate (2.00 mL, 21.13 mmol) were dissolved in
acetone (50 mL) and refluxed for 24 h. On cooling to room
temperature, the solution was filtered through Celite and
condensed in vacuo, and the residue was dissolved in ether
(100 mL). Triethylamine (4 mL, 29 mmol) was added, the
mixture was stirred for 1 h and then washed with water and
10% HCl, and the ethereal extracts were dried over Na2SO4.
Condensation in vacuo gave (1.21 g, 90%) as an essentially
pure yellow oil: 1H NMR (CDCl3) δ 8.2 (d, 1H, J 8.0 Hz), 7.98
(d, 1H, J 7.6 Hz), 7.88 (d, 1H, J 7.8 Hz), 7.5-7.72 (m, 4H), 7.4
(m, 2H), 7.18 (m, 1H), 3.8 (s, 3H); 13C NMR (CDCl3) δ 196.6,
154.94, 144.78, 140.15, 137.07, 131.54, 129.69, 128.58, 128.03,
127.99, 127.71, 126.77, 126.6, 125.76, 123.96, 123.56, 92.38,
2-Br om o-1,4,8-tr im eth oxyn a p h th a len e (16). A mixture
of 2-bromo-4,8-dimethoxynaphthol22 (0.427 g, 1.510 mmol),
dimethyl sulfate (1.0 mL, 10.6 mmol), and K2CO3 (1.00 g, 7.25
mmol) in acetone (30 mL) was refluxed for 24 h. On cooling,
the mixture was filtered through Celite, the filtrate condensed
in vacuo, and the resulting residue dissolved in a mixture of
ether (100 mL) and triethylamine (3.00 mL, 21.75 mmol). The
resulting solution was stirred for 0.5 h and then washed with
water and HCl. The organic extracts were dried (Na2SO4) and
condensed in vacuo, and the residual solid was purified by SGC
(hexane:ethyl acetate 97:3) to give the title compound (0.350
g, 78%) as a pale yellow solid, mp ) 72-73 °C; 1H NMR
(CDCl3) δ 7.83 (dd, 1H, J 8.4 and 0.9 Hz), 7.39 (t, 1H, J 8.1
Hz), 6.947 (d, 1H, J 7.8 Hz), 6.942 (s, 1H), 4.01 (s, 3H), 3.96
(s, 3H), 3.86 (s, 3H); 13C NMR (CDCl3) δ 155.41, 151.76, 146.99,
128.12, 126.02, 121.2, 115.01, 114.19, 108.95, 107.92, 61.67,
56.37, 55.92. Anal. Calcd for C13H13BrO3: C, 52.55; H, 4.41.
Found: C, 52.74; H, 4.51.
(2-Iod o-3-m eth oxy-5-m eth ylp h en yl)(1,4,8-tr im eth oxy-
2-n a p h th yl)m eth a n on e (17). tert-Butyllithium (1.68 M in
hexane, 1.32 mL, 2.25 mmol) was added dropwise over 5 min
to a solution of 2-bromo-1,4,8-trimethoxynaphthalene (0.45 g,
1.50 mmol) in ether (20 mL) at -78 °C. After stirring for 15
min, a solution of aldehyde 14 (0.33 g, 1.20 mmol) in ether
(10 mL) was added, the mixture allowed to warm to 25 °C,
and then water (10 mL) added cautiously. The solution was
extracted with ether, and the ethereal extracts were dried
(MgSO4) and then condensed in vacuo, the residual oil was
dissolved in CH2Cl2 (10 mL) and added quickly to a suspension
of PCC (522 mg, 2.42 mmol) in CH2Cl2 (10 mL), and the
resulting mixture was stirred at 25 °C for 12 h. The mixture
was diluted with ether (100 mL), filtered through a pad of silica
gel, and then condensed in vacuo. The resulting solid was
purified by SGC (hexane:ethyl acetate 4:1) to give the title
(21) J ung, M. E.; J ung, Y. H. Tetrahedron Lett. 1988, 29, 2517-
2520.
(22) Hannan, R. L.; Barber, R. B.; Rapoport, H. J . Org. Chem. 1979,
44, 2153-2158.

7192 J . Org. Chem., Vol. 65, No. 21, 2000
Qabaja and J ones
compound (0.470 g, 80%) as a white solid: mp ) 160-162 °C;
1H NMR (CDCl3) δ 7.9 (dd, 1H, J 8.3 and 0.96 Hz), 7.5 (t, 1H,
J 8.0 Hz), 7.1 (s, 1H), 6.97 (d, 1H, J 7.8 Hz), 6.82 (s, 1H), 6.7
(s, 1H), 4.03 (s, 3H), 4.0 (s, 3H), 3.95 (s, 3H), 3.6 (s, 3H), 2.36
(s, 3H); 13C NMR (CDCl3) δ 198.14, 157.82, 157.08, 152.01,
151.39, 147.97, 139.37, 131.36, 128.18, 127.86, 122.13, 120.24,
114.83, 113.02, 107.42, 104.4, 80.64, 64.0, 56.57, 56.17, 55.88,
21.3. Anal. Calcd for C22H21IO5: C, 53.67; H, 4.3. Found: C,
54.08; H, 4.16.
P r ep a r a tion of 2 [con ven tion a l m eth od ]. A suspension
of ketone17 (0.1 g, 0.2 mmol), sodium acetate (32 mg, 0.4
mmol), and PdCl2(PPh3)2 (28.5 mg, 0.04 mmol) in dimethylac-
etamide (5 mL) was degassed (triple freeze-thaw cycle) and
then heated at 130 °C for 24 h. On cooling to 25 °C, the mixture
was diluted with ether (5 ml) and then washed with HCl (10%,
3 × 30 mL), and the organic extracts were dried (Na2SO4).
Condensation of the extracts in vacuo followed by SGC of the
residual solid (CH2Cl2:ethyl acetate 95:5) gave the title com-
pound (0.023 g, 30%) as an orange solid: mp 108-110 °C (Lit.3
104-112 °C).
Micr ow a ve Acceler a ted Rou te to 2. A heavy-walled (5
mm) boiling tube (100 mL) equipped with a virgin septum and
magnetic stir bar was flame-dried under a stream of nitrogen
gas. Ketone 17 (92 mg, 0.18 mmol), sodium acetate (46 mg,
0.54 mmol), and dichlorobis(triphenylphosphine)palladium(II)
(20 mg, 0.027 mmol) in dimethylacetamide (50 mL) were
introduced, and the mixture was degassed (N2) for 2 h. The
tube was placed in a 100 mL beaker within the cavity of a
domestic microwave oven (450 W) and irradiated at full power
for 60 s. On cooling, the mixture was poured into ether (100
mL) and washed with HCl (1 M, 3 × 30 mL). The combined
organic extracts were dried (MgSO4) and condensed in vacuo,
and the resulting residue was purified by flash chromatogra-
phy (5% EtOAc: 95% CH2Cl2) to give 2 (36 mg, 53%) isolated
as an orange solid spectroscopically identical with authentic
material.3
solid was dissolved in THF (5 mL), then DMAP (5 mg) and
ethyldiisopropylamine (1.05 mL, 6.00 mmol) were added, and
the mixture was cooled to 0 °C for 10 min. Freshly prepared
19 (1.81 g, 5.86 mmol) in dry THF (10 mL) was added to the
mixture via cannula, and the resulting mixture was stirred
at 25 °C for 2 h, diluted with ether (150 mL), and quenched
by the addition of water (15 mL). The organic layer was
washed with HCl and NaHCO3 and then dried (Na2SO4) and
concentrated in vacuo: 1H NMR (acetone-d6) δ 9.4 (s, 1H), 7.65
(dd, 1H, J 8.4 and 0.96 Hz), 7.54 (t, 1H, J 7.74 Hz), 7.51 (s,
1H), 7.47 (d, 1H, J 8.4 Hz), 7.19 (s,1H), 7.145 (d, 1H, J 7.5
Hz), 6.93 (d, 1H, J 8.4 Hz), 4.10 (s, 3H), 4.03 (s, 3H), 2.4 (s,
3H); 13C NMR (acetone-d6) δ 168.08, 160.643, 158.33, 154.8,
142.3, 140.41, 140.32, 131.21, 128.78, 124.49, 121.84, 117.11,
116.49, 116.43, 110.49, 106.79, 83.43, 58.07, 57.81, 22.04. Due
to decomposition on standing, the crude material was used
directly in the next step without further purification.
4,5-Dim eth yl-1-n a p h th yl 2-Iod o-3-m eth oxy-5-m eth yl-
ben zoa te. The resulting residue (20) was dissolved in acetone
(50 mL), then dimethyl sulfate (3.0 mL, 31.7 mmol) and K2-
CO3 (3.0 g, 21.7 mmol) were added, and the mixture was
refluxed for 24 h. On cooling, the solution was condensed in
vacuo, and the residue was resuspended in ether (100 mL) and
triethylamine (5 mL, 36.25 mmol). The resulting mixture was
stirred at 25 °C for 1 h, washed with water and then HCl,
and the organic extracts were dried (Na2SO4) and condensed
in vacuo. The crude residue was purified by SGC (hexane:
EtOAc 6:4) to give the title compound (1.88 g, 67%) as a white
solid: mp 130-132 °C; 1H NMR (acetone-d6) δ 7.63 (dd, 1H, J
7.32 and 1.05 Hz), 7.46-7.55 (m, 3H), 7.2 (s, 1H), 7.0-7.1 (m,
2H), 4.05 (s, 6H), 3.95 (s, 3H), 2.25 (s, 3H); 13C NMR (acetone-
d6) δ 168.01, 160.67, 159.54, 157.56, 142.32, 141.74, 140.3,
131.99, 129.18, 124.51, 120.54, 120.4, 116.47, 115.17, 108.65,
107.0, 83.48, 58.09, 57.71, 57.45, 22.05. Anal. Calcd for C21H19
IO5: C, 52.74; H, 4.00. Found: C, 52.71; H, 3.89.
-
1,10,12-Tr im eth oxy-8-m eth yl-6H-diben zo[c,h ]ch r om en -
6-on e (21). A solution of 4,5-dimethyl-1-naphthyl 2-iodo-3-
methoxy-5-methylbenzoate (1.60 g, 3.35 mmol), PdCl2(PPh3)2
(0.60 g, 0.77 mmol), and sodium acetate (0.9 g, 11 mmol) in
dimethylacetamide (300 mL) was degassed (triple freeze-thaw
cycles) and heated at 130 °C for 24 h. On cooling, water (200
mL) and CH2Cl2 (300 mL) were added, the aqueous layer was
removed, and the organic layer was washed with HCl (2 N, 3
× 30 mL) and then dried (Na2SO4). Following condensation
in vacuo, the resulting residue was purified by SGC (hexane:
ethyl acetate:CH2Cl2 4:5:1) to give the title compound (0.88 g,
75%) as a pale yellow solid: mp 240-242 °C; 1H NMR (CDCl3)
δ 8.39 (s, 1H), 8.21 (d, 1H, J 8.6), 7.93 (s, 1H), 7.5 (t, J 8.1
Hz), 7.12 (s, 1H), 6.98 (d, 1H J 7.8 Hz), 4.05 (s, 3H), 4.03 (s,
3H), 4.0 (s, 3H), 2.25 (s, 3H); 13C NMR (CDCl3) δ 161.47,
157.16, 156.63, 152.7, 140.48, 139.75, 127.14, 126.66, 123.15,
122.76, 12.93, 118.08, 117.43, 114.82, 113.7, 107.91, 104.31,
56.7, 56.51, 56.2, 21.62. Anal. Calcd for C21H18O5: C, 71.99;
H, 5.18. Found: C, 72.35; H, 5.16.
5-Meth oxy-1,4-n aph th alen ediol (18). A solution of Na2S2O4
(1.0 g, 5.2 mmol) in water (5 mL) was added to a solution of
5-methoxy-1,4-naphthoquinone (0.20 g, 1.06 mmol) in ether
(15 mL) and CH2Cl2 (3.0 mL). The mixture was shaken
vigorously in a 50 mL separatory funnel for 15 min, the
aqueous layer separated, and the organic layer then washed
with brine, dried (Na2SO4), and condensed in vacuo to give
the title compound (0.2 g, 99%) as a gray solid: mp 184-188
1
°C (lit.23 183-185 °C); H NMR (acetone-d6) δ 8.9 (s, 1H), 8.8
(s, 1H), 7.88 (dd, 1H, J 8.8 and 0.96 Hz), 7.41 (t, 1H, J 7.8
Hz), 7.05 (d, 1H, J 7.71 Hz), 6.89 (d, 1H, J 8.2 Hz), 6.68 (d,
1H, J 8.2 Hz), 4.4 (s, 3H).
2-Iod o-3-m et h oxy-5-m et h ylb en zoic Acid . Prepared by
oxidation of 2-iodo-3-methoxy-5-methylbenzyl alcohol accord-
ing to the method of Suzuki,24 giving the title compound (94%)
1
as a pale yellow solid: mp ) 207 °C (lit.24 209 °C); H NMR
(acetone-d6) δ 7.16 (d, 1H, J 1.0 Hz), 7.05 (d, 1H, J 1.0 Hz),
4.0 (s, 3H), 2.4 (s, 3H); 13C NMR (acetone-d6) δ 169.78, 160.4,
141.7, 141.36, 124.16, 115.67, 83.15, 57.92, 21.9.
2-(3-H yd r oxym et h oxy-1,4-d ioxo-1,4-d ih yd r o-2-n a p h -
th yl)-3-m eth yl-5-m eth oxyben zoic Acid (24). A mixture of
pyran 21 (0.13 g, 0.37 mmol) and KOH (10%, 10 mL) in THF
(20 mL) was stirred at 25 °C for 5 h, resulting in formation of
a deep red solution. Ether (25 mL) was added, and the organic
layer was separated and acidified with HCl (concentrated, 2.0
mL), resulting in formation of a yellow solution, which was
diluted with CH2Cl2 (30 mL) and then dried (Na2SO4). Con-
densation in vacuo gave the title compound (130 mg, 95%) as
2-Iod o-3-m eth oxy-5-m eth ylben zoyl Ch lor id e (19). Thio-
nyl chloride (0.51 mL, 6.99 mmol) was added to 2-iodo-3-
methoxy-5-methylbenzoic acid (1.71 g, 5.85 mmol) in CH2Cl2
(3 mL) and DMF (0.1 mL), and the mix was refluxed under
nitrogen atmosphere for 1 h. After cooling to RT, it was
concentrated in vacuo to give the title compound (1.81 g, 100%)
as a pale yellow solid which was used directly in the next step.
4-Hyd r oxy-5-m eth oxy-1-n a p h th yl 2-Iod o-3-m eth oxy-5-
m eth ylben zoa te (20). A solution of Na2S2O4 (5.0 g, 28.7
mmol) in water (10 mL) was added to a solution of 5-methoxy-
1,4-naphthoquinone (1.10 g, 5.85 mmol) in ether (20 mL) and
CH2Cl2 (5 mL). The mixture was shaken vigorously in a 250
mL separatory funnel for 15 min, the aqueous layer separated,
and the organic layer then washed with brine (30 mL) and
dried (Na2SO4). Following condensation in vacuo, the residual
1
a residual yellow solid: mp ) 228-230 °C; H NMR (CDCl3)
δ 7.8 (dd, 1H, J 7.8 and 1.0 Hz), 7.74 (s, 1H), 7.69 (t, 1H, J
7.74 Hz), 7.16 (d, 1H, J 8.0 Hz), 7.15 (s, 1H), 4.05 (s, 3H), 3.95
(s, 3H), 2.4 (s, 3H); 13C NMR (CDCl3) δ 183.26, 179.85, 171.04,
160.1, 157.17, 152.35, 139.96, 136.30, 135.4, 130.14, 123.88,
120.00, 118.46, 118.12, 117.2, 116.6, 116.41, 56.43, 56.11,
21.56. Anal. Calcd for C20H16O7: C, 65.22; H, 4.38 Found: C,
65.57; H, 4.38.
1,8-Dim eth oxy-3-m eth yl-7,12-d ih yd r o-5H-d iben zo[c,g]-
ch r om en e-5,7,12-tr ion e (25). Methanesulfonic acid (0.2 mL)
was added to precooled (-20 °C) solution of 24 (30 mg, 0.081
mmol) in CH2Cl2 (50 mL), and the resulting yellow solution
(23) Pearson, M. S.; J ensky, B. J .; Greer, F. X.; Hagstrom, J . P.;
Wells, N. M. J . Org. Chem. 1978, 43, 4617-4621.
(24) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J . Am.
Chem. Soc. 1994, 116, 1004-1015.

Annulation Strategies for Benzo[b]fluorene Synthesis
J . Org. Chem., Vol. 65, No. 21, 2000 7193
was stirred at -20 °C for 1 h and then warmed through 25 °C
for 12 h. Crushed ice (15 g) was added, the mixture was
extracted with CHCl3 (2 × 10 mL), and the organic layer
washed with water and then NaHCO3 and then dried (Na2-
SO4). Condensation in vacuo gave the title compound (26 mg,
165.55, 153.99, 142.14, 140.28, 134.30, 133.69, 131.89, 128.53,
127.77, 127.47, 126.61, 126.17, 122.87, 121.39, 118.26, 103.26,
95.26, 56.09. Anal. Calcd for C18H13IO3: C, 53.49; H, 3.24.
Found: C, 53.01; H, 3.16
12-Met h oxy-6H -d ib en zo[c,h ]ch r om en e-6-on e
(30).
1
92%) as an orange solid: mp 236-239 °C (lit.13a 237 °C); H
Ester 29 (3.82 g, 9.46 mmol), PdCl2(PPh3)2 (1.33 g, 1.90 mmol),
and sodium acetate (2.36 g, 28.40 mmol) were dissolved in
dimethylacetamide (200 mL), and the solution was degassed
and then heated at 130 °C for 24 h. The mixture was diluted
with ether (300 mL) and washed with HCl (2 N, 3 × 40 mL).
The organic layer was dried (Na2SO4) and concentrated in
vacuo, and the residue was purified by SGC (hexane:ethyl
acetate 3:1), to give the title compound (1.51 g, 58%) as a white
NMR (CDCl3) δ 7.8 (s, 1H), 7.64-7.74 (m, 2H), 7.28 (dd, 1H,
J 8.0 and 1.19 Hz), 7.10 (s, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 2.5
(s, 3H); 13C NMR (CDCl3) δ 181.62, 174.52, 159.93, 159.36,
156.95, 148.8, 143.76, 136.61, 135.58, 124.41, 122.28, 120.76,
119.36, 119.29, 118.98, 118.26, 117.16, 56.56 (2C), 29.7.
1,10-Dimethoxy-8-methyl-11,12-dihydro-6H-dibenzo[c,h]-
chromene-6,11,12-trione (26)
1
Trifluoroacetic anhydride (0.20 mL, 1.41 mmol) was added
dropwise at -78 °C to a solution of 24 (0.13 g, 0.35 mmol) in
CH2Cl2 (30 mL), and the resulting deep red solution was
warmed through room temperature and stirred for 4 h. The
solution was diluted with CHCl3 (30 mL) and then washed
with NaHCO3 and the organic layer dried (Na2SO4). Conden-
sation in vacuo gave the title compound (112 mg, 91%) as a
solid: mp ) 230-231 °C; H NMR (CDCl3) δ 8.55 (dd, 1H, J
7.2 and 0.9 Hz), 8.48 (dd, 1H, J 7.5 and 1.5 Hz), 8.28 (dd, 1H,
J 7.5 and 1.5 Hz), 8.15 (d, 1H, J 8.1 H), 7,88 (dt, 1H, J 7.5 and
1.2 Hz), 7.65 (m, 3H), 7.19 (s, 1H), 4.05 (s, 3H); 13C NMR
(CDCl3) δ 165.4, 153.92, 142.11, 140.18, 134.26, 133.56, 131.84,
128.4, 127.66, 127.34, 126.54, 126.06, 122.72, 121.26, 118.07,
103.12, 95.18, 56.06. Anal. Calcd for C18H12O3: C, 78.25; H,
4.38. Found: C, 78.52; H, 4.17.
1
residual deep red solid: mp ) 240-243 °C; H NMR (CDCl3)
δ 7.8 (dd, 1H J 7.8 and 1.0 Hz), 7.74 (s, 1H), 7.69 (t, 1H, J
7.74 Hz), 7.16 (d, 1H, J 8 Hz), 7.15 (s, 1H), 4.05 (s, 1H), 3.95
(s, 3H), 2.4 (s, 3H); 13C NMR (CDCl3) δ 181.57, 181.19, 161.67,
159.48, 156.12, 155.64, 141.87, 136.86, 132.58, 122.35, 121.77,
119.68, 119.35, 117.7, 117.49, 115.81, 114.92, 56.52, 56.34,
21.8. Anal. Calcd for C20H14O6: C, 68.57; H, 4.03. Found: C,
68.93; H, 4.28.
2-(3-H yd r oxy-1,4-d ioxo-1,4-d ih yd r o-2-n a p h t h a len yl)-
ben zoic Acid (31). KOH (10%, 10 mL) was added to a solution
of compound 30 (0.70 g, 2.53 mmol) in THF (30 mL), and the
mixture was stirred at 25 °C for 15 h, producing a deep red
solution. Ether (25 mL) was added, the mixture was acidified
with HCl (concentrated, 2.0 mL), and the resulting yellow
solution was diluted with CH2Cl2 (30 mL). The organic layer
was dried (Na2SO4) and then concentrated in vacuo to give
the title compound (0.43 g, 65%) isolated as a residual yellow
solid: mp ) 235 °C; 1H NMR (acetone-d6) δ 9.5 (br s, 1H),
8.05-8.2 (m, 3H), 7.8-7.95 (m, 2H), 7.65 (dt, 1H, J 7.8 and
1.5 Hz), 7.48-7.58 (m, 2H); 13C NMR (acetone-d6) δ 183.56,
181.82, 167.23, 152.67, 134.94, 133.38, 133.12, 131.94, 131.87
(2C), 131.34, 130.45, 130.4, 128.38, 126.55, 125.93, 124.95.
Anal. Calcd for C17H10O5: C, 70.13; H, 3.92. Found: C, 70.47;
H, 3.45.
1-H yd r oxy-10-m e t h oxy-8-m e t h yl-11,12-d ih yd r o-6H -
d iben zo[c,h ]ch r om en e-6,11,12-tr ion e (27). Lithium iodide
(0.011 g, 0.082 mmol) was added to a solution of compound 26
(0.024 g, 0.069 mmol) in 2,6-lutidine (3.0 mL), and the mixture
was heated at 170 °C for 7 h. On cooling, ethyl acetate (10
mL) was added followed by HCl (10%, 20 mL), and then the
organic layer was separated and washed with HCl (10%, 2 ×
10 mL). The organic extracts were dried (Na2SO4) and con-
densed in vacuo, and the resulting residue was purified by SGC
(hexane:ethyl acetate 1:1 with 1% v/v HOAc added) to give
the title compound (17 mg, 72%) as an orange solid: mp )
140 °C; 1H NMR (acetone-d6) δ 11.4 (bs, 1H), 7.79 (t, 1H, J 8.4
Hz), 7.61 (dd, 1H, J 7.32 and 1.0 Hz), 7.54 (s, 1H), 7.31 (dd,
11,12-Dih yd r o-6H -d ib en zo[c,h ]ch r om en e-6,11,12-t r i-
on e (32). Trimethylsilyl triflate (1.0 M, CH2Cl2, 1.5 mL, 1.5
mmol) was added dropwise to a precooled (-78 °C) solution of
31 (0.039 g, 0.133 mmol) in CH2Cl2 (20 mL), and the mixture
stirred at -78 °C for 3 h. The solution was diluted with CH2-
Cl2 (30 mL) and washed with NaHCO3, and the organic
extracts were dried (Na2SO4). Careful condensation in vacuo
precipitated the title compound (26 mg, 74%) as an orange
1H, J 8.4 and 1.0 Hz), 7.19 (s, 1H), 3.9 (s, 3H), 2.4 (s, 3H); 13
C
NMR (acetone-d6) δ 188.0, 183.81, 169.73, 162.44, 158.74,
154.03, 140.91, 138.48, 134.58, 132.58, 124.48, 124.00, 123.92,
120.57, 120.22, 117.28, 115.11, 57.10, 22.36. Anal. Calcd for
1
C
19H12O6: C, 67.86; H, 3.6. Found 68.24; H, 3.79.
solid: mp ) 270-272 °C; H NMR (CDCl3) δ 9.15 (d, 1H, J
P r ep a r a tion of WS-5995C (fr om 27). A solution of KOH
8.1 Hz), 8.4 (dd, 1H, J 8.1 and 0.9 Hz), 8.27 (d, 1H, J 8.4 Hz),
8.19 (dd, 1H, J 7.8 and 1.5 Hz), 7.8 (dt, 1H, J 8.7 and 1.5 Hz),
7.83 (dt, 1H, J 7.5 and 1.2 Hz), 7.7-7.6 (m, 2H); 13C NMR
(DMF-d6) δ 185.65, 179.28, 164.5, 137.85, 137.85, 137.57,
136.89, 136.23, 134.32, 131.5, 130.71, 130.2, 128.60, 128.15,
127.87, 127.12, 122.25. Anal. Calcd for C17H8O4: C, 73.91; H,
2.92. Found: C, 74.32; H, 3.22.
(10%, 2 mL) was added to compound 27 (0.02 g, 0.06 mmol)
dissolved in THF (10 mL), and the mixture was stirred at 25
°C for 3 h. The resulting deep red solution was acidified with
HCl (concd, 1.0 mL), the resulting yellow solution was ex-
tracted with CH2Cl2 (2 × 15 mL) and the organic extracts were
dried (Na2SO4). Condensation in vacuo gave the title compound
(20 mg, 95%) as a residual orange solid: mp 210-213 °C (lit.13d
mp 212-213 °C); 1H NMR (DMSO-d6) δ 11.4 (s, 1H), 10.5 (s,-
1H), 7.73 (t, 1H, J 8.6 Hz), 7.47 (dd, 1 H, J 7.35 and 1.02 Hz),
7.35 (dd, 1H, J 8.34 and 1.02 Hz), 7.12 (s, 1H), 3.7 (s, 3H), 2.4
(s, 3H). 13C NMR (DMSO-d6) δ 185.98, 183.71, 168.64, 161.35,
158.14, 154.69, 140.28, 138.48, 133.71, 133.11, 126.00, 124.25,
123.59, 120.00, 119.70, 116.83, 114.88, 57.20, 22.30.
4-Meth oxy-1-n a p h th yl-2-iod oben zoa te (29). A solution
of 2-iodobenzoyl chloride (15.78 mmol, 1.1 equiv) in THF (20
mL) was cannulated dropwise into a mixture of 4-methoxy-1-
naphthol (2.50 g, 14.35 mmol), DMAP (0.175 g, 1.430 mmol,
0.1 equiv), and ethyldiisopropylamine (7.5 mL, 28.7 mmol, 2.0
equiv) in THF (150 mL). The solution was stirred at 0 °C for
15 min, warmed to 25 °C, and stirred for a further 3 h. Ether
(150 mL) was added, and the mixture was washed with water
(100 mL), NaHCO3 (sat. 100 mL), and then HCl (1 N, 30 mL).
The combined organic extracts were dried (MgSO4) and then
condensed in vacuo to give the title compound (5.1 g, 88%) as
a white solid: mp ) 95-97 °C; 1H NMR (CDCl3) δ 7.3 (m, 1H),
8.24 (dd, 1H, J 7.5 and 1.8 Hz), 8.13 (dd, 1H J 8.1 and 1.5
Hz), 7.88 (m, 1H), 7.55 (m, 3H), 7.33 (d, 1H, J 8.4 Hz), 7.27
(m, 1H), 6.8 (d, 1H, J 8.4 Hz), 4.0 (s, 3H); 13C NMR (CDCl3) δ
7,12-Dih yd r o-5H -d ib en zo[c,g]ch r om en e-5,7,12-t r ion e
(33). A solution of 31 (0.030 g, 0.102 mmol) in methanesulfonic
acid (5 mL) was stirred at 25 °C for 5 h. Crushed ice (15 g)
was added, the mixture was extracted with CHCl3, and the
organic extracts were washed with water and NaHCO3 and
then dried (Na2SO4). Condensation in vacuo gave the title
compound (27.5 mg, 99%) as a residual yellow solid: mp )
1
248 °C; H NMR (CDCl3) δ 9.32 (d, 1H, J 8.4 Hz), 8.44 (dd, 1
H, J 7.8 and 0.9 Hz), 8.22 (m, 2H), 7.92 (t, 1H, J 7.2 Hz), 7.7-
7.9 (m 3 H); 13C NMR (CDCl3) δ 183.78, 176.89, 159.04, 151.15,
136.22, 135.19, 134.47, 132.68, 132.31, 131.6, 130.6, 130.49,
128.99, 127.39, 126.92, 123.08, 116.99. Anal. Calcd for
C
17H8O4: C, 73.91; H, 2.92. Found: C, 74.10; H, 3.08.
Con ver sion of 32 in to 33. Compound 32 (10.0 mg) was
dissolved in methanesulfonic acid (5 mL), and the mixture was
stirred at RT for 5 h. The reaction mixture was poured onto
ice (10 g) and water (10 mL) and extracted with CH2Cl2 (3 ×
10 mL), and the organic extracts were washed with NaHCO3
(sat. 4 × 10 mL), dried (Na2SO4), and condensed in vacuo to
give compound 33 (9.0 mg, 90%).
Gen er a l P r oced u r e for Deter m in a tion of Qu in on e
Red u ction P oten tia ls. Published laboratory procedures were

7194 J . Org. Chem., Vol. 65, No. 21, 2000
Qabaja and J ones
followed.25 Solutions of quinone (2.0-4.0 mg) in DMF (2 mL,
HPLC grade) containing tetraethylammonium fluoroborate
(33 mg) were swept between +0.4 and -1.5 V at a rate of 100
mV/s. E° values were determined against Ag/Ag+, with a
system precalibrated against ferrocene, swept under identical
conditions.
Sciences (RO1GM57123), The Petroleum Research Fund
(33920-AC1), and The American Cancer Society. We
thank Professors E. M. Perchellet and J .-P. Perchellet
(Anti-Cancer Drug Laboratory, Kansas State Univer-
sity) for performing initial bioassays.
Bioa ssa y Meth od s. Preliminary growth inhibition assays
against murine L1210 cells were determined using the MTS
method,26 and H-460, MCF-7, and SF-268 cells using the
standard NCI screening protocol.19
J O0056186
(26) Cory, A. H.; Owen, T. C.; Barltrop, J . A.; Cory, J . G. Cancer
Commun. 1991, 3, 207-212; Perchellet, E. M.. Ladesich, J . B.; Magill,
M. J .; Chen, Y.; Hua, D. H.; Perchellet, J . P. Anti-Cancer Drugs 1999,
10, 489-504.
(27) J effery, T. Tetrahedron 1996, 52, 10113-10130.
(28) J effery, T.; David, M. Tetrahedron Lett. 1998, 39, 5751-5754.
Ack n ow led gm en t. This work was supported by
grants from the National Institute of General Medical
(25) Sivakolundu, S. G.; Mabrouk, P. A. J . Am. Chem. Soc. 2000,
122, 1513-1521.