From phenylacetylphenylacetic acids and 1-benzylisoquinolines to 6,11-dihydrobenzo[b]naphtho[2,3-d]furan-6,11-diones, 6H-dibenzo[c,h]chroman-6-ones and 7,12-dihydro-5H-dibenzo[c,g]chroman-5,7,12-triones via 2-phenyl-3-hydroxy-1,4-dihydro-1,4-naphthalenediones or 2-phenyl-1-naphthols

Article abstract of DOI:10.1016/S0040-4020(00)00551-2

We describe the synthesis of 6,11-dihydrobenzo[b]naphtho[2,3-d]furane-6,11-diones, 6H-Dibenzo[c,h]chroman-6-ones and 7,12-dihydro-5H-dibenzo[c,g]chroman-5,7,12-triones from 2-(2'-phenyl)-3-hydroxy-1,4-dihydro-1,4-naphthalenediones or 2-phenyl-1-naphthols obtained from 2-(2'-bromophenylacetyl)-phenylacetic acids or 1-benzylisoquinolines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00551-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 6023±6030
From Phenylacetylphenylacetic Acids and 1-Benzylisoquinolines
to 6,11-Dihydrobenzo[b]naphtho[2,3-d]furan-6,11-diones,
6H-Dibenzo[c,h]chroman-6-ones
and 7,12-Dihydro-5H-dibenzo[c,g]chroman-5,7,12-triones
via 2-Phenyl-3-hydroxy-1,4-dihydro-1,4-naphthalenediones
or 2-Phenyl-1-naphthols
*
    Â
Elena Martõnez, Luis Martõnez, Monica Treus, Juan C. Estevez, Ramon J. Estevez
and Luis Castedo
Â
 Â
Departamento de Quõmica Organica e Unidade Asociada (C.S.I.C.), Universidade de Santiago de Compostela,
15706 Santiago de Compostela, Spain
Received 21 January 2000; accepted 20 May 2000
AbstractÐWe describe the synthesis of 6,11-dihydrobenzo[b]naphtho[2,3-d]furane-6,11-diones, 6H-Dibenzo[c,h]chroman-6-ones and
7,12-dihydro-5H-dibenzo[c,g]chroman-5,7,12-triones from 2-(20-phenyl)-3-hydroxy-1,4-dihydro-1,4-naphthalenediones or 2-phenyl-1-
naphthols obtained from 2-(20-bromophenylacetyl)-phenylacetic acids or 1-benzylisoquinolines. q 2000 Elsevier Science Ltd. All rights
reserved.
The pharmacological activities of the anticoccidial anti-
biotic WS-5995A (1a) (Fig. 1),1 a natural dibenzochroma-
none isolated from S. auranticolor, and ravidomycin (2a),2 a
natural dibenzochromanone from S. ravidus which exhibits
signi®cant antibiotic and antitumor activity, have been
attributed to their embedded planar 2-phenyl-1,4-naphtho-
quinone subunit,3 the planarity of which is ensured by the
lactone bridge. This structure is also present in related biolo-
gically and pharmacologically active compounds, including
benzofuronaphthoquinones 3,4,5 which also have industrial
applications.
In most syntheses of 1,6 27 and 3,8 the key step is the linkage
of appropriately functionalized naphthalenes and benzenes,
which is followed by completion of the heterocyclic ring.
However, in one approach to 1a, the intermediate phenyl-
naphthoquinone 6a is obtained from ketoacid 4a (Scheme
1).9 Our interest in synthetic applications of phenylacetyl-
phenylacetic acids 410 has led us to study the extension of
this latter method to the preparation of other naphtho-
quinone-based compounds.11,12 We describe here the syn-
thesis of benzofuronaphthoquinones 3 by intramolecular
Ullmann coupling reaction of bromophenylnaphthoquinones
Figure 1.
Keywords: antitumour compounds; chromones; furans; quinones; Ullmann reactions.
* Corresponding author. Tel.: 134-981-563100, ext. 14242; fax: 134-981-591014; e-mail: qorjec@usc.es
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00551-2

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6024
Scheme 1.
6 obtained from either bromophenylacetylphenylacetic acids
410 or 1-benzylisoquinolines 8, and related synthesis of 1b
and 2b.
N-methyl-1-benzylisoquinolinium iodide (9a), which was
then heated in a re¯uxing solution of NaOH in water/
methanol to afford 2-phenyl-1-naphthol 13a in 85% yield.
The formation of 13a may be explained as follows: in the
basic media the salt 9a is in equilibrium with carbinolamine
10a, which is in turn in equilibrium with ketoenamine 11a;
hydrolysis of 11a gives ketoaldehyde 12a (similar to keto-
acids 4), and in the basic reaction conditions 12a undergoes
intramolecular aldol condensation followed by dehydration
to 13a.14 Subsequent oxidation15 of 13a with Fremy's salt
furnished phenylnaphthoquinone 6d in 80% yield, and
heating16 of 6d in a solution of NaOH in water/methanol
solution gave hydroxyphenylnaphthoquinone 6e in almost
quantitative yield.
Bromoketoester 4b (R0ˆMe) was prepared by esteri®cation
of the corresponding bromoketoacid10a (R0ˆH) and was
re¯uxed for 30 min in a solution of KOH in water/ethanol
affording the red bromophenylnaphthoquinone 6b by intra-
molecular Dieckmann condensation followed by oxidation
of the cyclization product 5b in the reaction medium.
Re¯uxing a solution of 6b, cuprous oxide, potassium car-
bonate and pyridine under argon for 2 h, gave a 92% yield of
benzofuronaphthoquinone 3b,12 which was identi®ed from
its analytical and spectroscopic data. Its 1H NMR spectrum
shows four singlets at 3.99, 4.02, 4.06 and 4.07 ppm due to
the four methoxyl groups, and four singlets at 7.11, 7.58,
7.62 and 7.64 corresponding to the four aromatic protons.
The same strategy transformed bromoketoester 4c10b
(R0ˆMe) almost quantitatively into dimethoxy-benzofuro-
naphthoquinone 3c via naphthoquinone 6c. Compound 3c is
a red solid of mp 260±2618C; its 1H NMR spectrum shows
two singlets at 4.05 and 4.06 ppm due to the two methoxyl
groups, a multiplet at 7.45±7.69 ppm due to three aromatic
protons, two singlets at 7.63 and 7.64 ppm due to two
aromatic protons, and a multiplet at 8.25 ppm due to the
remaining aromatic proton.
Note that as papaverine (8a) is obtained from N-phenyl-
acetylphenylethylamine 7,13 the above synthesis involves
regiospeci®c transfer of a phenylacetyl group from the nitro-
gen atom of phenylethylamide 7 to the desired position of
11a by a four step sequence that includes a Bischler±
Napieralski cyclization. This method of acylation of
aromatic rings is less dependent than Friedel±Crafts acyl-
ations on the electronic properties of substituents.10
We next applied this new route to naphthoquinones 6 to the
synthesis of benzofuronaphthoquinones 3. Bromination of
papaverine (8a) followed by treatment with methyl iodide
and ®nal heating of the resulting bromobenzylisoquino-
linium salt 9b in a re¯uxing solution of NaOH in water/
methanol, led us to the expected 2-phenyl-1-naphthol 13b,
in albeit only 45% yield, the competitive formation of
isoquinoline by cleavage of C1±Ca bond under the basic
reaction conditions being favoured by the electron-with-
drawing bromine atom.17 Subsequent oxidation of 13b
with Fremy's salt furnished an 80% yield of bromophenyl-
naphthoquinone 6f, which was heated in a solution of NaOH
in water/methanol to give hydroxyphenylnaphthoquinone
Unfortunately, this short, ef®cient new route to benzofuro-
naphthoquinones 3 is of limited scope because the range of
ketoacids 4 is restricted by the limitations of the Friedel±
Crafts acylation reactions by which they are obtained.10 In
order to avoid this problem we developed an alternative
closely related route to phenylnaphthoquinones 6 starting
from readily available 1-benzylisoquinolines 8 (Scheme 2).
Commercially available papaverine (8a)13 was treated with
methyl iodide at room temperature, to give a 92% yield of

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6025
Scheme 2. 6: b XˆBr, YˆOH; d XˆYˆH; e XˆH, YˆOH; f XˆBr, YˆH; 8, 9, 10, 11, 12, 13: a XˆH, b XˆBr.
6b. Ullmann reaction of 6b as above afforded tetramethoxy-
benzofuronaphthoquione 3b; additionally, Ullmann
reaction of 13b under the same conditions afforded benzo-
naphthofuran 14.
1H NMR spectrum showed three singlets at 3.91, 3.98 and
4.01 ppm for the four methoxyl groups (the 4.01 ppm signal
corresponding to deshielded methoxyl group contiguous to
the carbonyl group), signals at 6.99±7.72 ppm for the six
aromatic protons, and a broad singlet at 8.65 due to the
hydroxyl group. The formation of 13d may be attributed
to metalation of position C-20 (a process facilitated by the
contiguous methoxyl group) followed by transfer of the
amide group to the phenyl substituent. Re¯uxing a solution
of 13d in acetic acid for 6 h gave the chromanone 2b, iden-
ti®ed from its analytical and spectroscopic data; the mass
spectrum showed the expected peak for the molecular ion at
m/zˆ366 and the IR exhibited a carbonyl band at
1732 cm21, while the 1H NMR spectrum included two
singlets for aromatic protons at 7.12 and 7.76 ppm, and
two AB systems at 7.42 and 7.87 ppm and at 7.55 and
The above route from papaverine (8a) to 2-phenyl-1-
naphthol 13a was next combined with directed ortho meta-
lation and subsequent remote acyl transfer18 to achieve a
new regiocontrolled synthesis of dibenzochromanones 1
and 2. Heating a solution of naphthol 13a and N,N-diethyl-
carbamoyl chloride in dry pyridine at 1008C under argon for
4.5 days gave the expected carbamate 13c as a white solid of
mp 118±1208C (Et2O) (Scheme 3). Reaction of 13c with
LDA gave a solid identi®ed as compound 13d on the
basis of its analytical and spectroscopic data; the mass spec-
trum con®rmed the molecular formula C27H29NO6 and its
Scheme 3.

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6026
Scheme 4.
7.82 ppm; the possibility of 16 having been obtained via 15
was ruled out by an HMBC study that showed correlation
between d 7.77 (H4) and d 106.4 (C1) and between d 7.12
(H1) and d 100.9 (C4), (Additionally, correlation between d
157.8 (C6) and d 7.87 (H10) indicated that the carbonyl is
attached to C(6a).)
2.1 mmol), EtOH (30 mL) and 20% aqueous NaOH solution
(30 mL) was re¯uxed for 30 min. The EtOH was then
evaporated in vacuo, the residue was suspended in water
(250 mL), and this mixture was acidi®ed with 10% aqueous
HCl and extracted with Cl2H2 (3£50 mL). The organic
layers were dried, ®ltered and concentrated in vacuo to
give quinone 6b (0.92 g, 96%) as a red solid, mp 222±
2248C (MeOH). IR (n, cm21, KBr): 3335 (±OH), 1617
Finally, dibenzochromanone 1b was obtained as follows.
Naphthol 13d (Scheme 4) was easily and ef®ciently
oxidized to naphthoquinone 6g by stirring for 9 h at room
temperature in a solution of Fremy's salt and potassium
bisulfate in acetone. Addition of an excess of NaOH to a
solution of 6g in 80:20 methanol/water, and heating at 508C
for 7 h then gave hydroxynaphthoquinone 6h as a red solid
of mp 233±2358C. Re¯uxing a solution of 6h in acetic acid
for 6 h gave the cyclized dibenzochromanone 1b, identi®ed
from its spectroscopic data.
1
(CvO). H NMR (d, ppm): 3.83 (s, 3H, ±OCH3), 3.88 (s,
3H, ±OCH3), 4.01 (s, 6H, 2£±OCH3), 6.75 (s, 1H, Ar±H),
7.12 (s, 1H, Ar±H), 7.52 (s, 1H, Ar±H), 7.55 (s, 1H, ±OH),
7.58 (s, 1H, Ar±H). 13C NMR (d, ppm): 56.0 (±OCH3), 56.1
(±OCH3), 56.5 (±OCH3), 56.6 (±OCH3), 107.8 (CH), 109.0
(CH), 114.1 (CH), 114.5 (C), 115.5 (CH), 121.6 (C), 123.6
(C), 123.9 (C), 128.1 (C), 148.3 (C), 149.8 (C), 152.9 (C),
153.1 (C), 154.8 (C), 180.8 (CvO), 182.8 (CvO). Ms (m/z,
%): 450 (M1, 0.05), 448 (M1, 0.05), 369 (100). Anal. Calcd
for C20H17BrO7: C, 53.47; H, 3.81. Found: C, 53.63; H, 3.56.
To sum up, we have con®rmed the utility of ketoacids 4 as
starting materials for the preparation of condensed naphtho-
quinones by using them as the basis of a new total synthesis
of benzofuronaphthoquinones 3. Additionally, we have
developed an alternative route to 2-phenyl-3-hydroxy-1,4-
naphthoquinones 6 starting from 1-benzylisoquinolines, and
have used its end-products or intermediates to synthesize
Procedure B: A solution of compound 6f (316 mg,
0.73 mmol) and NaOH (146 mg, 3.65 mmol) in deoxy-
genated 4:1 MeOH/water (20 mL) was heated at 508C for
4.5 h under argon. Water (50 mL) was added, the resulting
suspension was acidi®ed with 10% aqueous HCl solution,
the precipitate was ®ltered out and the ®ltrate was extracted
with Cl2CH2 (3£30 mL). The pooled organic layers were
dried, ®ltered and concentrated in vacuo to give a solid
identical to the ®ltration residue. The pooled solids were
crystallized from MeOH to give compound 6b (320 mg,
98% yield).
benzofuronaphthoquinones and dibenzochromanones
1
and 2. This new route to 6 avoids having to start from
ketoacids 4 prepared by Friedel±Crafts acylations, a process
of well-known limitations.
2,3,8,9-Tetramethoxy-6,11-dihydrobenzo[b]naphtho[2,3-d]-
furan-6,11-dione (3b). A mixture of compound 6b
(100 mg, 0.2 mmol), CuO (56 mg, 0.7 mmol) and K2CO3
(159 mg, 1.15 mmol) in dry deoxygenated pyridine (3 mL)
was re¯uxed under argon for 2 h. The mixture was then
added to 20% aqueous HCl solution (40 mL) and the result-
ing suspension was extracted with Cl2CH2 (3£25 mL). The
pooled organic layers were then washed with 10% aqueous
NaOH solution, dried, ®ltered and concentrated in vacuo to
give compound 3b (75 mg, 92% yield), mp 282±2848C
Experimental
Melting points were determined on a Ko¯er Thermogerate
apparatus and are uncorrected. Infrared spectra were
recorded on a MIDAC FTIR spectrophotometer. Nuclear
magnetic resonance spectra were recorded on a Bruker
WM-250 apparatus, using deuteriochloroform solutions
containing tetramethylsilane as an internal standard. Mass
spectra were obtained on a Kratos MS 50 TC mass spectro-
meter. Thin layer chromatography (TLC) was performed
using Merck GF-254 type 60 silica gel and Cl2CH2/MeOH
mixtures as eluant; the TLC spots were visualized with
ultraviolet light or iodine vapor. Column chromatography
was carried out using Merck type 9385 silica gel. Solvents
were puri®ed as per Ref. 19. Solutions of extracts in organic
solvents were dried with anhydrous sodium sulfate.
1
(MeOH). IR (n, cm21, KBr): 1665 (CvO). H NMR (d,
ppm): 3.99 (s, 3H, ±OCH3), 4.02 (s, 3H, ±OCH3), 4.06 (s,
3H, ±OCH3), 4.07 (s, 3H, ±OCH3), 7.11 (s, 1H, Ar±H), 7.58
(s, 1H, Ar±H), 7.62 (s, 1H, Ar±H), 7.64 (s, 1H, Ar±H). 13C
NMR (d, ppm): 56.8 (±OCH3), 56.9 (3£±OCH3), 95.7
(CH), 103.1 (CH), 108.8 (CH), 108.9 (CH), 115.6 (C),
124.7 (C), 127.5 (C), 128.2 (C), 149.8 (2£C), 152.6 (C),
153.1 (C), 153.5 (2£C), 174.5 (CvO), 181.9 (CvO). Ms
(m/z, %): 368 (M1, 100), 325 (13), 69 (18). Anal. Calcd for
C20H16O7: C, 65.22; H, 4.38. Found: C, 65.01; H, 4.39.
2-(20-Bromo-40,50-dimethoxyphenyl)-6,7-dimethoxy-1,4-
dihydro-3-hydroxy-1,4-naphthalenedione (6b). Procedure
A: A mixture of bromoketoester 4b (R0ˆMe) (1 g,

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6027
2-(20-Bromophenyl)-6,7-dimethoxy-1,4-dihydro-3-hydroxy-
1,4-naphthalenedione (6c). Compound 6c was obtained in
99% yield from compound 4c (R0ˆMe) (1 g, 2.46 mmol)
following the same procedure as for compound 6b (Pro-
cedure A), mp 224±2258 C (MeOH). IR (n, cm21, KBr):
3350 (±OH), 1649 (CvO). 1H NMR (d, ppm): 4.05 (s, 6H,
2£OCH3), 7.30 (m, 2H, 2£Ar±H), 7.42 (m, 1H, Ar±H),
7.51 (s, 1H, ±OH), 7.57 (s, 1H, Ar±H), 7.62 (s, 1H, Ar±
H), 7.69 (m, 1H, Ar±H). 13C NMR (d, ppm): 56.9 (±OCH3),
57.0 (±OCH3), 108.2 (CH), 109.5 (CH), 122.0 (C), 123.8
(C), 124.5 (C), 127.6 (CH), 128.5 (C), 130.5 (CH), 132.0
(CH), 132.5 (C), 133.1 (CH), 153.0 (C), 153.2 (C), 155.3
(C), 181.1 (CvO), 182.9 (CvO). Ms (m/z, %): 310 (21),
309 (100). Anal. Calcd for C18H13BrO5: C, 55.55; H, 3.37.
Found: C, 55.81; H, 3.18.
with 10% aqueous HCl solution, and extracted with Cl2CH2
(3£15 mL). The pooled organic layers were dried, ®ltered
and concentrated in vacuo to give a residue that was puri®ed
by ¯ash column chromatography (1:1 EtOAc/hexane) to
afford compound 13a (93 mg, 85% yield) as a white solid,
mp 165±1678C (MeOH/Et2O). IR (n, cm21, NaCl): 3443
(±OH).1H NMR (d, ppm): 3.91 (s, 3H, ±OCH3), 3.93 (s,
3H, ±OCH3), 4.01 (s, 3H, ±OCH3), 4.03 (s, 3H, ±OCH3),
5.87 (s, 1H, ±OH), 6.98±7.09 (m, 3H, 3£Ar±H), 7.11 (s,
1H, Ar±H), 7.21 (d, Jˆ8.3 Hz, 1H, Ar±H), 7.32 (d,
Jˆ8.3 Hz, 1H, Ar±H), 7.55 (s, 1H, Ar±H). 13C NMR (d,
ppm): 56.2 (±OCH3), 56.3 (±OCH3), 56.4 (2£±OCH3),
101.6 (CH), 106.6 (CH), 112.4 (CH), 112.9 (CH), 119.0
(CH), 119.7 (C), 120.4 (C), 121.7 (CH), 126.3 (CH),
130.4 (C), 130.5 (C), 147.3 (C), 149.1 (C), 149.7 (C),
150.2 (C), 150.3 (C). Ms (m/z, %): 340 (M1, 100), 325
(14). Anal. Calcd for C20H20O5: C, 70.57; H, 5.92. Found:
C, 70.62; H, 6.11.
8,9-Dimethoxy-6,11-dihydrobenzo[b]naphtho[2,3-d]furan-
6,11-dione (3c). Compound 3c was prepared in 99% yield
from compound 6c (123 mg, 0.3 mmol) by the procedure
described above for compound 3b, mp 260±2618C
2-(30,40-Dimethoxyphenyl)-6,7-dimethoxy-1,4-dihydro-
1,4-naphthalenedione (6d). A solution of Fremy's salt
(456 mg, 1.7 mmol) and KH2PO4 (44 mg, 0.32 mmol) in
water (4 mL) was added to a solution of compound 13a
(340 mg, 1 mmol) in acetone (4 mL) and the resulting
mixture was stirred at rt for 2 h. The acetone was evaporated
in vacuo, the resulting precipitate was ®ltered out and the
®ltrate was extracted with Cl2CH2 (3£50 mL). The pooled
organic layers were dried, ®ltered and concentrated in vacuo
to give a solid identical to the ®ltration residue. The pooled
solids were crystallized from MeOH to give compound 6d
(283 mg, 80% yield) as an orange solid, mp 192±1948C. IR
1
(MeOH). IR (n, cm21, KBr): 1665 (CvO). H NMR (d,
ppm): 4.05 (s, 3H, ±OCH3), 4.06 (s, 3H, ±OCH3), 7.45±
7.69 (m, 3H, 3£Ar±H), 7.63 (s, 1H, Ar±H), 7.64 (s, 1H, Ar±
H), 8.25 (m, 1H, Ar±H). 13C NMR (d, ppm): 57.0 (±OCH3),
57.1 (±OCH3), 109.0 (2£CH), 113.2 (CH), 123.3 (C), 124.2
(CH), 126.3 (CH), 127.1 (C), 128.4 (C), 129.6 (CH), 153.5
(2£C), 153.9 (C), 154.0 (C), 156.6 (C), 175.6 (CvO), 181.5
(CvO). Ms (m/z, %): 308 (M1, 100), 237 (13), 194 (13).
Anal. Calcd for C18H12O5: C, 70.13; H, 3.92. Found: C,
70.01; H, 3.76.
1
1-(30,40-Dimethoxybenzyl)-6,7-dimethoxy-2-methyliso-
quinolinium iodide (9a). A mixture of papaverine hydro-
chloride (4.7 g, 12.5 mmol) and 20% aqueous NaOH
solution (100 ml) was stirred at rt for 30 min and then
extracted with Cl2CH2 (3£50 mL). The pooled organic
layers were dried, ®ltered and concentrated in vacuo to
give 4.1 g (12.1 mmol) of pure paraverine, which was
dissolved with MeI (4.14 mL, 66.4 mmol) in dry acetone
(20 mL). This solution was stirred at rt, more MeI
(0.83 mL, 13.30 mmol) being added every 12 h until, after
3 days, TLC showed no starting material. The white solid
formed was ®ltered out and washed with dry acetone to give
compound 9a (5.36 g, 92% yield), mp 152±1548C
(n, cm21, NaCl): 1651 (CvO). H NMR (d, ppm): 3.92 (s,
6H, 2£±OCH3), 3.99 (s, 6H, 2£±OCH3), 6.90 (s, 1H, Ar±
H), 6.93 (s, 1H, Ar±H), 7.12±7.19 (m, 2H, 2£Ar±H), 7.45
(s, 1H, Ar±H), 7.52 (s, 1H, Ar±H). 13C NMR (d, ppm): 55.9
(2£±OCH3), 56.4 (2£±OCH3), 107.3 (CH), 108.5 (CH),
111.0 (CH), 112.6 (CH), 122.8 (CH), 126.2 (C), 126.9
(C), 127.3 (C), 133.6 (CH), 147.1 (C), 148.8 (C), 150.9
(C), 153.5 (C), 153.6 (C), 184.3 (CvO), 184.8 (CvO).
Ms (m/z, %): 354 (M1, 74), 338 (28), 323 (100). Anal.
Calcd for C20H18O6: C, 67.79; H, 5.12. Found: C, 67.64;
H, 5.02.
2-(30,40-Dimethoxyphenyl)-6,7-dimethoxy-3-hydroxy-1,4-
dihydro-1,4-naphthalenedione (6e). Starting from
compound 6d (40 mg, 0.11 mmol), compound 6e was
obtained in 90% yield following the same procedure as
for compound 6b (Procedure B), mp 234±2368C (MeOH).
1
(acetone). IR (n, cm21, NaCl): 1645 (CvN). H NMR (d,
ppm): 3.76 (s, 3H, ±OCH3), 3.82 (s, 3H, ±OCH3), 3.98 (s,
3H, ±OCH3), 4.12 (s, 3H, ±OCH3), 4.51 (s, 3H, ±NCH3),
5.08 (s, 2H, ±CH2±), 6.20 (dd, Jˆ8.3 Hz, Jˆ1.8 Hz, 1H,
Ar±H), 6.65 (d, Jˆ8.3 Hz, 1H, Ar±H), 6.99 (d, Jˆ1.8 Hz,
1H, Ar±H), 7.48 (s, 1H, Ar±H), 7.66 (s, 1H, Ar±H), 8.27 (d,
Jˆ6.8 Hz, 1H, Ar±H), 8.71 (d, Jˆ6.8 Hz, 1H, Ar±H). 13C
NMR (d, ppm): 35.2 (CH2), 47.2 (CH3), 55.9 (±OCH3), 56.5
(±OCH3), 57.0 (±OCH3), 57.7 (±OCH3), 105.1 (CH), 106.7
(CH), 111.8 (CH), 112.2 (CH), 119.5 (CH), 123.1 (CH),
124.6 (C), 126.1 (C), 136.1 (CH), 136.3 (C), 148.7 (C),
149.8 (C), 153.5 (C), 155.0 (C), 157.5 (C). Ms (m/z, %):
454 (M1, 8), 142 (100).
1
IR (n, cm21, NaCl): 3327 (±OH), 1645 (CvO). H NMR
(d, ppm): 3.98 (s, 3H, ±OCH3), 3.99 (s, 3H, ±OCH3), 4.01
(s, 3H, ±OCH3), 4.02 (s, 3H, ±OCH3), 7.00 (d, Jˆ8.0 Hz,
1H, Ar±H), 7.08 (s, 1H, ±OH), 7.18 (d, Jˆ8.0 Hz, 1H, Ar±
H), 7.51 (s, 1H, Ar±H), 7.60 (s, 2H, 2£Ar±H). 13C NMR (d,
ppm): 55.8 (±OCH3), 55.9 (±OCH3), 56.5 (±OCH3), 56.6
(±OCH3), 107.5 (CH), 109.0 (CH), 110.6 (CH), 114.1 (CH),
120.8 (C), 122.6 (C), 123.4 (C), 123.9 (CH), 128.1 (C),
148.3 (C), 149.3 (C), 151.8 (C), 152.8 (C), 154.6 (C),
180.9 (CvO), 183.7 (CvO). Ms (m/z, %): 370 (M1,
100), 355 (14), 339 (42). Anal. Calcd for C20H18O7: C,
64.86; H, 4.90. Found: C, 64.59; H, 4.93.
2-(30,40-Dimethoxyphenyl)-6,7-dimethoxy-1-naphthol (13a).
A solution of compound 9a (0.15 g, 0.31 mmol) and NaOH
(0.7 g, 17.5 mmol) in deoxygenated MeOH (15 mL) was
re¯uxed under argon for 20 h. Water (50 mL) was then
added, and the reaction mixture was then acidi®ed to pH 3
1-(20-Bromo-40,50-dimethoxybenzyl)-6,7-dimethoxyiso-
quinoline (8b). A solution of bromine (1.8 mL, 31 mmol) in

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6028
AcOH (17 mL) was added dropwise, over 30 min, to a solu-
tion of papaverine (4.55 g, 13.42 mmol) in 1:1 AcOH/water
(100 mL) maintained at 108C with an ice/water bath. The
mixture was then stirred at rt for 3.5 h and added to water
(100 mL). After extraction with Cl2CH2 (3£50 mL), the
pooled organic layers were washed with saturated aqueous
Na2S2O3 solution, 10% aqueous NaHCO3 solution and
water, dried, ®ltered and concentrated in vacuo to give
bromopapaverine (8b; 4.57 g, 88% yield), mp 168±1708C
prepared from 13b (90 mg, 0.21 mmol) in 80% yield
using the same procedure as for compound 6d, mp 166±
1688C (MeOH). IR (n, cm21, NaCl): 1656 (CvO). 1H NMR
(d, ppm, CDCl3/DMSO): 3.85 (s, 3H, ±OCH3), 3.90 (s, 3H,
±OCH3), 4.01 (s, 3H, ±OCH3), 4.02 (s, 3H, ±OCH3), 6.76
(s, 1H, Ar±H), 6.84 (s, 1H, Ar±H), 7.10 (s, 1H, Ar±H), 7.49
(s, 1H, Ar±H), 7.52 (s, 1H, Ar±H). 13C NMR (d, ppm,
CDCl3/DMSO): 57.8 (±OCH3), 57.9 (±OCH3), 58.0
(2£±OCH3), 109.2 (CH), 110.2 (CH), 115.0 (C), 115.4
(CH), 117.5 (CH), 128.5 (C), 128.6 (C), 128.9 (C), 138.7
(CH), 150.0 (C), 150.9 (C), 152.0 (C), 155.4 (C), 155.5 (C),
184.5 (CvO), 186.5 (CvO). Ms (m/z, %): 434 (M1, 0.6),
432 (M1, 0.6), 353 (100). Anal. Calcd for C20H17BrO6: C,
55.44; H, 3.95. Found: C, 55.38; H, 3.97.
1
(MeOH). IR (n, cm21, NaCl): 1618 (CvN). H NMR (d,
ppm): 3.59 (s, 3H, ±OCH3), 3.83 (s, 3H, ±OCH3), 3.97 (s,
3H, ±OCH3), 3.99 (s, 3H, ±OCH3), 4.64 (s, 2H, ±CH2±),
6.66 (s, 1H, Ar±H), 7.03 (s, 1H, Ar±H), 7.04 (s, 1H, Ar±H),
7.33 (s, 1H, Ar±H), 7.44 (d, Jˆ5.7 Hz, 1H, Ar±H), 8.37 (d,
Jˆ5.7 Hz, 1H, Ar±H). 13C NMR (d, ppm): 41.3 (CH2), 55.8
(±OCH3), 55.9 (±OCH3), 56.0 (±OCH3), 56.3 (±OCH3),
104.3 (CH), 105.2 (CH), 113.0 (CH), 113.7 (C), 115.1
(CH), 118.9 (CH), 123.0 (C), 131.0 (C), 133.4 (C), 140.8
(CH), 148.3 (C), 148.7 (C), 150.2 (C), 152.7 (C), 157.5 (C).
Anal. Calcd for C20H20BrNO4: C, 57.43; H, 4.82; N, 3.35.
Found: C, 57.61; H, 4.90; N, 3.10.
2,3,8,9-Tetramethoxybenzo[b]naphtho[2,1-d]furan (14).
A mixture of compound 13b (68 mg, 0.16 mmol), CuO
(41 mg, 0.51 mmol) and K2CO3 (116 mg, 0.84 mmol) in
dry deoxygenated pyridine (5 mL) was re¯uxed under
argon for 2 h and then added over 20% aqueous HCl solu-
tion (40 mL). The resulting suspension was extracted with
Cl2CH2 (325 mL), and the pooled organic layers were
washed with 10% aqueous NaOH solution, dried, ®ltered
and concentrated in vacuo to give compound 14 (35 mg,
1-(20-Bromo-40,50-dimethoxybenzyl)-6,7-dimethoxy-2-
methylisoquinolinium iodide (9b). Compound 9b was
prepared in 92% yield from compound 8b (2 g,
4.78 mmol) by the same procedure as for compound 9a,
mp 234±2368C (acetone). IR (n, cm21, NaCl): 1700
1
64% yield), mp 208±2108C (MeOH). H NMR (d, ppm):
4.00 (s, 3H, ±OCH3), 4.02 (s, 3H, ±OCH3), 4.04 (s, 3H,
±OCH3), 4.11 (s, 3H, ±OCH3), 7.24 (s, 1H, Ar±H), 7.27
(s, 1H, Ar±H), 7.39 (s, 1H, Ar±H), 7.59 (d, Jˆ8.4 Hz, 1H,
Ar±H), 7.63 (s, 1H, Ar±H), 7.76 (d, Jˆ8.4 Hz, 1H, Ar±H).
13C NMR (d, ppm): 55.9 (±OCH3), 56.0 (±OCH3), 56.3
(±OCH3), 56.6 (±OCH3), 95.9 (CH), 99.6 (CH), 102.0
(CH), 107.5 (CH), 116.1 (CH), 116.6 (C), 117.0 (C),
118.7 (C), 121.6 (CH), 127.9 (C), 146.5 (C), 149.0 (C),
149.3 (C), 150.0 (C), 150.7 (C), 151.6 (C). Ms (m/z, %):
338 (M1, 100), 323 (34). Anal. Calcd for C20H18O5: C,
70.99; H, 5.36. Found: C, 70.73; H, 5.21.
1
(CvN). H NMR (d, ppm, CDCl3/DMSO): 3.60 (s, 3H,
±OCH3), 3.83 (s, 3H, ±OCH3), 3.94 (s, 3H, ±OCH3), 4.12
(s, 3H, ±OCH3), 4.58 (s, 3H, ±NCH3), 5.02 (s, 2H, ±CH2±),
6.39 (s, 1H, Ar±H), 7.03 (s, 1H, Ar±H), 7.37 (s, 1H, Ar±H),
7.72 (s, 1H, Ar±H), 8.38 (d, Jˆ6.8 Hz, 1H, Ar±H), 8.85 (d,
Jˆ6.8 Hz, 1H, Ar±H). 13C NMR (d, ppm, CDCl3/DMSO):
35.4 (CH2), 46.7 (CH3), 56.0 (±OCH3), 56.4 (±OCH3), 56.5
(±OCH3), 57.1 (±OCH3), 104.6 (CH), 106.3 (CH), 112.0
(CH), 114.1 (C), 116.2 (CH), 123.3 (CH), 124.5 (C),
125.4 (C), 136.1 (CH), 136.4 (C), 149.3 (C), 149.5 (C),
153.5 (C), 154.0 (C), 157.7 (C). Ms (m/z, %): 434
((M11)1, 5), 432 ((M11)1, 5), 433 (M1, 20), 431 (M1,
20), 418 (20), 416 (20), 91 (100). Anal. Calcd for
C21H23BrINO4: C, 45.02; H, 4.14; N, 2.50. Found: C,
45.15; H, 4.02; N, 2.77.
N,N-Diethylamino-2-(30,40-dimethoxyphenyl)-6,7-dimeth-
oxy-1-naphthyloxymethanone (13c).
A
solution of
naphthol 13a (0.7 g, 2.02 mmol) and N,N-diethylcarbamoyl
chloride (1.53 mL, 12 mmol) in dry pyridine (3 mL) was
heated at 1108C in a sealed tube for 4.5 days. The reaction
mixture was then added to ice/water, and after extraction
with Et2O (3£75 mL), the pooled organic layers were
washed (®rst with 10% aqueous HCl solution (3£75 mL)
and then with saturated aqueous NaHCO3 solution
(75 mL), dried, ®ltered and concentrated in vacuo to give
a residue which was puri®ed by ¯ash column chromato-
graphy (1:1 EtOAc/hexene) to afford compound 13c
2-(20-Bromo-40,50-dimethoxyphenyl)-6,7-dimethoxy-1-
naphthol (13b). Following the procedure described for
compound 13a, compound 13b was obtained from
compound 9b (1 g, 1.78 mmol) in 45% yield, mp 142±
1448C (MeOH). IR (n, cm21, NaCl): 3377 (±OH). 1H
NMR (d, ppm): 3.84 (s, 3H, ±OCH3), 3.92 (s, 3H, ±OCH3),
4.01 (s, 3H, ±OCH3), 4.03 (s, 3H, ±OCH3), 5.44 (s, 1H,
±OH), 6.88 (s, 1H, Ar±H), 7.12 (d, Jˆ8.5 Hz, 1H, Ar±H),
7.13 (s, 1H, Ar±H), 7.17 (s, 1H, Ar±H), 7.33 (d, Jˆ8.5 Hz,
1H, Ar±H), 7.57 (s, 1H, Ar±H). 13C NMR (d, ppm): 55.8
(±OCH3), 55.9 (±OCH3), 56.1 (±OCH3), 56.3 (±OCH3),
101.4 (CH), 106.3 (CH), 114.5 (CH), 114.9 (C), 115.9
(CH), 118.4 (CH), 119.3 (C), 119.8 (C), 126.2 (CH),
129.6 (C), 130.5 (C), 147.1 (C), 149.0 (C), 149.4 (C),
149.7 (C), 150.2 (C). Ms (m/z, %): 420 (M1, 27), 418
(M1, 27), 308 (100). Anal. Calcd for C20H19BrO5: C,
57.29; H, 4.57. Found: C, 57.03; H, 4.60.
(0.66 g, 75% yield), mp 118±1208C (Et2O). IR (n, cm21
,
1
NaCl): 1714 (CvO). H NMR (d, ppm): 1.04±1.08 (m,
3H, ±CH3), 1.17±1.22 (m, 3H, ±CH3), 3.27±3.34 (m, 2H,
±CH2±), 3.40±3.45 (m, 2H, ±CH2±), 3.89 (s, 3H, ±OCH3),
3.91 (s, 3H, ±OCH3), 3.97 (s, 3H, ±OCH3), 4.00 (s, 3H,
±OCH3), 6.92 (d, Jˆ7.8 Hz, 1H, Ar±H), 7.04±7.07 (m,
2H, 2£Ar±H), 7.12 (s, 1H, Ar±H), 7.15 (s, 1H, Ar±H),
7.35 (d, Jˆ8.4 Hz, 1H, Ar±H), 7.59 (d, Jˆ8.4 Hz, 1H,
Ar±H). 13C NMR (d, ppm): 13.7 (CH3), 14.7 (CH3), 42.3
(CH2), 42.5 (CH2), 56.0 (±OCH3), 56.2 (±OCH3), 56.3
(±OCH3), 56.4 (±OCH3), 100.9 (CH), 106.8 (CH), 111.4
(CH), 112.9 (CH), 121.9 (CH), 124.1 (C), 124.3 (CH),
126.9 (CH), 130.2 (C), 130.3 (C), 131.9 (C), 143.4 (C),
148.5 (C), 148.9 (C), 150.1 (C), 150.5 (C), 154.2 (CvO).
2-(20-Bromo-40,50-dimethoxyphenyl)-6,7-dimethoxy-1,4-
dihydro-1,4-naphthalenedione (6f). Compound 6f was

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6029
1
Ms (m/z, %): 439 (M1, 15), 100 (100). Anal. Calcd for
C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C, 68.09;
H, 6.53; N, 3.36.
(CvO). H NMR (d, ppm): 0.96±1.07 (m, 6H, 2£±CH3),
3.07±3.21 (m, 4 H, 2£±CH2±), 3.82 (s, 3H, ±OCH3), 3.90
(s, 3H, ±OCH3), 3.97 (s, 3H, ±OCH3), 3.98 (s, 3H, ±OCH3),
6.94 (s, 1H, Ar±H), 7.05 (d, Jˆ8.4 Hz, 1H, Ar±H), 7.06 (d,
Jˆ8.4 Hz, 1H, Ar±H), 7.44 (s, 2H, 2£Ar±H). 13C NMR (d,
ppm): 12.3 (±CH3), 13.5 (±CH3), 38.3 (±CH2±), 43.1
(±CH2±), 55.9 (±OCH3), 56.4 (±OCH3), 56.5 (±OCH3),
61.6 (±OCH3), 107.5 (CH), 108.3 (CH), 111.9 (CH),
124.2 (C), 126.8 (CH), 127.1 (C), 132.2 (C), 135.9 (CH),
145.2 (C), 146.8 (C), 153.4 (2£C), 153.6 (2£C), 166.5
(CvO), 183.8 (CvO), 184.4 (CvO). Ms (m/z, %): 453
(M1, 5), 382 (100). Anal. Calcd for C25H27NO7: C, 66.21;
H, 6.00; N, 3.09. Found: C, 66.38; H, 6.15, N, 3.31.
N,N-Diethyl-6-(10-hydroxy-60,70-dimethoxy-20-naphthyl)-
2,3-dimethoxybenzamide (13d). A solution of LDA in
THF (1.14 mmol) was added dropwise to a solution of
urethane 13c (0.2 g, 0.45 mmol) in dry THF (1.5 mL) kept
at 2788C with an acetone/dry ice bath. The resulting
mixture was ®rst stirred at 2788C for 30 min, then at rt
for 1 h and ®nally at 808C for 15 h. The THF was evaporated
off and the residue suspended in water. After extraction with
Et2O (3£75 mL), the pooled organic layers were dried,
®ltered and concentrated in vacuo, and the resulting residue
was puri®ed by ¯ash column chromatography (6:4 EtOAc/
cyclohexane) to give compound 13d (82 mg, 41% yield) as
a yellow solid, mp 186±1948C (Et2O, decomposition). IR
N,N-Diethyl-6-(30-hydroxy-60,70-dimethoxy-10,40-dioxo-
10,40-dihydro-20-naphthalenyl)-2,3-dimethoxybenzamide
(6h). A solution of compound 6d (67 mg, 1.48 mmol) and
NaOH (325 mg, 8.13 mmol) was transformed into
compound 6h (79%) following the same procedure as for
1
(n, cm21, NaCl): 3417 (±OH), 1708 (CvO). H NMR (d,
ppm): 0.79±0.92 (m, 6H, 2£±CH3), 2.98±3.08 (m, 2H,
±CH2±), 3.11±3.45 (m, 2H, ±CH2±), 3.91 (s, 6H,
2£±OCH3), 3.98 (s, 3H, ±OCH3), 4.01 (s, 3H, ±OCH3),
6.99 (s, 2H, 2£Ar±H), 7.03 (d, Jˆ8.5 Hz, 1H, Ar±H),
7.06 (s, 1H, Ar±H), 7.25 (d, Jˆ8.5 Hz, 1H, Ar±H), 7.72
(s, 1H, Ar±H), 8.65 (bs, 1H, ±OH). 13C NMR (d, ppm):
11.7 (CH3), 13.5 (CH3), 39.1 (CH2), 43.1 (CH2), 55.8
(±OCH3), 55.9 (2£±OCH3), 61.6 (±OCH3), 102.7 (CH),
105.8 (CH), 113.1 (CH), 118.7 (CH), 121.5 (C), 122.5
(C), 126.7 (CH), 127.7 (CH), 129.5 (C), 130.4 (C), 131.6
(C), 144.0 (C), 148.9 (C), 149.2 (C), 149.9 (C), 151.8 (C),
169.9 (CvO). Ms (m/z, %): 439 (M1, 2.5), 366 (100).
6b, mp 227±2358C (MeOH, decomposition). IR (n, cm21
,
1
NaCl): 3391 (±OH), 1660 (CvO). H NMR (d, ppm):
0.83±1.09 (m, 6H, 2£±CH3), 3.11±3.35 (m, 4H, 2£
±CH2±), 3.84±3.85 (bs, 3H, ±OCH3), 3.90±3.92 (bs, 3H,
±OCH3), 3.99 (s, 3H, ±OCH3), 4.00 (bs, 3H, ±OCH3), 6.98
(s, 1H, Ar±H), 6.99 (s, 1H, Ar±H), 7.49 (s, 2H, 2£Ar±H).
13C NMR (d, ppm, CD3OD): 12.6 (CH3), 13.6 (CH3), 39.3
(CH2), 44.3 (CH2), 56.4 (±OCH3), 56.7 (±OCH3), 56.8
(±OCH3), 61.7 (±OCH3), 109.4 (CH), 114.3 (CH), 125.8
(C), 126.8 (C), 127.1 (C), 129.6 (CH), 129.9 (CH), 131.2
(C), 132.9 (C), 146.0 (C), 152.8 (2£C), 153.0 (C), 156.3 (C),
171.0 (CvO), 185.0 (CvO), 190.0 (CvO). Ms (m/z, %):
469 (M1, 12), 368 (100).
2,3,7,8-Tetramethoxy-6H-dibenzo[c,h]chroman-6-one
(2b). A solution of compound 13d (115 mg, 0.26 mmol) in
AcOH (5 mL) was re¯uxed under a calcium chloride tube
for 6 h. The reaction mixture was then concentrated in
vacuo and the resulting residue was crystallized from
Et2O to give compound 15 (74 mg, 77% yield) as a solid,
mp 218±2208C. IR (n, cm21, NaCl): 1732 (CvO). 1H NMR
(d, ppm): 3.98 (s, 3H, ±OCH3), 4.03 (s, 6H, 2£±OCH3),
4.10 (s, 3H, ±OCH3) 7.12 (s, 1H, Ar±H), 7.42 (d,
Jˆ9 Hz, 1H, Ar±H), 7.55 (d, Jˆ8.8 Hz, 1H, Ar±H), 7.76
(s, 1H, Ar±H), 7.82 (d, Jˆ8.8 Hz, 1H, Ar±H), 7.87 (d,
Jˆ9 Hz, 1H, Ar±H). 13C NMR (d, ppm): 55.8 (±OCH3),
56.3 (±OCH3), 56.4 (±OCH3), 61.4 (±OCH3), 100.9 (CH),
106.4 (CH), 111.5 (C), 115.1 (C), 117.4 (CH), 117.6 (CH),
118.8 (C), 119.5 (CH), 122.5 (CH), 129.8 (2£C), 145.4 (C),
150.1 (C), 150.5 (C), 151.5 (C), 152.9 (C), 157.8 (CvO).
Ms (m/z, %): 366 (M1, 100). Anal. Calcd for C21H18O6: C,
68.85; H, 4.95. Found: C, 69.03; H, 4.79.
3,4,9,10-Tetramethoxy-7,12-dihydro-5H-dibenzo[c,g]-
chroman-5,7,12-trione (1b). A solution of compound 6h
(48 mg, 0.1 mmol) in AcOH (4 mL) was re¯uxed under a
calcium chloride tube for 6 h. The reaction mixture was then
concentrated in vacuo and the residue was precipitated from
Cl2CH2 as amorphous solid 1b (33 mg, 82% yield). IR (n,
cm21, KBr): 1753 (CvO), 1667 (CvO).13C NMR (d, ppm,
CF3CO2D): 54.7 (±OCH3), 54.9 (±OCH3), 55.0 (±OCH3),
60.8 (±OCH3), 107.5 (CH), 108.5 (CH), 116.0 (C), 120.2
(CH), 122.0 (C), 123.0 (C), 126.2 (CH), 127.1 (C), 147.0
(C), 148.0 (C), 152.7 (C), 154.0 (C), 154.9 (C), 161.5 (C),
177.0 (CvO), 184.0 (2£CvO). Ms (m/z, %): 396 (M1,
100). HRMS Calcd for C21H16O8: 396.0845. Found:
396.0839.
Acknowledgements
N,N-Diethyl-6-(60,70-dimethoxy-10,40-dioxo-10,40-dihydro-
20-naphthalenyl)-2,3-dimethoxy-benzamide (6g). A solu-
tion of Fremy's salt (229 mg, 0.85 mmol) and KH2PO4
(23.5 mg, 0.13 mmol) in water (5 mL) was added to a solu-
tion of compound 13d (75 mg, 0.17 mmol) in acetone
(3.5 mL) and the resulting mixture was stirred at rt for
9 h. The acetone was then evaporated in vacuo, the precipi-
tate was ®ltered out and the ®ltrate was extracted with
Cl2CH2 (3£25 mL). The pooled organic layers were dried,
®ltered and concentrated in vacuo to give a solid identical to
the ®ltration residue. Crystallization of the pooled solids
from MeOH gave compound 6g (68 mg, 88% yield) as an
orange solid, mp 231±2328C. IR (n, cm21, NaCl): 1660
We thank the Spanish Ministry of Education and Culture
(DGES) and the Xunta de Galicia for ®nancial support.
References
1. (a) Ikushima, H.; Iguchi, E.; Okamoto, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1980, 33, 1103. (b) Ikushima, H.; Okamoto, M.;
Tanaka, H.; Obe, O.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Anti-
biot. 1980, 33, 1107. (c) Tanaka, H.; Itoh, Y.; Ikushima, H.;
Okamoto, M.; Kawai, Y.; Imanaka, H. Tetrahedron Lett. 1980,
21, 4539.

Â
E. Martõnez et al. / Tetrahedron 56 (2000) 6023±6030
6030
Scheme 5.
2. (a) Seghal, S. N.; Czerkawski, H.; Kudelski, A.; Pandev, K.;
Â
Saucier, R.; Vezima, C. J. Antibiot. 1983, 36, 355. (b) Findlay,
8. For syntheses of benzofuronaphthoquinones see: (a) Ishikawa,
S.; Takagi, M. Nippon Kagaku Kaisi 1988, 752. (b) Yoshida, K;
Adachi, T.; Oga, N.; Kubo, Y. Chem. Lett. 1990, 2049. (c)
Yoshida, K.; Yamanaka, Y.; Ueno, Y. Chem. Lett. 1994, 2051.
(d) Echavarren, A. M.; Tamayo, N.; de Frutos, O.; Garcia, A.
Tetrahedron 1997, 49, 16835.
J. A.; Liu, J. S.; Radics, L.; Rakhit, S. Can. J. Chem. 1981, 59,
3018. (c) Findlay, J. A.; Liu, J. S.; Radics, L. Can. J. Chem. 1983,
61, 323. (d) Singh, K. J. Antibiot. 1984, 37, 71.
3. Cheng, C. C. Structural aspects of antineoplastic agents Ð a
new approach. In Progress in Medicinal Chemistry, Ellis, G. P.,
West, G. B., Eds.; Elsevier (Biomedical Division): Amsterdam,
1988; Vol. 25, pp 35±83.
9. Watanabe, M.; Date, M.; Furukawa, S. Chem. Pharm. Bull.
1989, 37, 292.
 Â
10. (a) Castedo, L.; Estevez, R. J.; Saa, J. M.; Suau, R. J. Hetero-
4. Sartori, M. F. Chem. Rev. 1963, 63, 279. (b) Chatterjea, N. J.;
Mehrotra, V. N. J. Indian Chem. Soc. 1963, 40, 203. (c) Chatterjea,
N. J.; Jha, O. P. J. Indian Chem. Soc. 1970, 47, 56. (d) Jha, O. P.
J. Indian Chem. Soc. 1973, 50, 740. (e) Ishikawa, S.; Takagi, M.
Nippon Kagaku Kaishi 1988, 752. (f) Yoshida, K.; Adachi, T.;
Oga, N.; Kubo, Y. Chem. Lett. 1990 2049. (g) Yoshida, K.;
Yamanaka, Y.; Ueno, Y. Chem. Lett. 1994, 2051.
Â
cycl. Chem. 1982, 19, 1319. (b) Estevez, J. C.; Villaverde, M. C.;
Â
Estevez, R. J.; Seijas, J. A.; Castedo, L. Can. J. Chem. 1990, 68,
 Â
964. (c) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo,
Â
L. Heterocycles 1994, 38, 1. (d) Estevez, J. C.; Villaverde, M. C.;
Â
Estevez, R. J.; Castedo, L. Tetrahedron 1994, 50, 2107 and
 Â
references therein. (e) Estevez, J. C.; Villaverde, M. C.; Estevez,
R. J.; Castedo, L. Tetrahedron 1993, 49, 2783 and references
5. Cheng, C. C.; Dong, Q.; Liu, D.-F.; Luo, Y.-L.; Liu, L.-F.;
Chen, A.-Y.; Yu, C.; Savaraj, N.; Chou, T.-C. J. Med. Chem.
1993, 36, 4108.
 Â
therein. (f) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.;
Castedo, L. Tetrahedron 1995, 51, 4075 and references therein.
 Â
11. Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron Lett.
6. For the synthesis of antibiotic WS-5995A see: (a) Tanaka, H.;
Itoh, Y.; Ikushima, H.; Okamoto, M.; Kawai, Y.; Imanaka, H.
Tetrahedron Lett. 1980, 21, 4359. (b) McKenzie, T. C.; Hassen,
W. Tetrahedron Lett. 1987, 19, 1523. (c) McKenzie, T. C.; Choi,
W.-B. Synth. Commun. 1989, 19, 1523. (d) Echavarren, A. M.;
1993, 34, 6479.
12. For a preliminary communication see: Martõnez, E.; Martõnez,
 Â
L.; Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron Lett.
Â
Â
1998, 39, 2175.
13. Le Quang, N. T.; Gardent J. Bull. Soc. Chim. Fr. 1966, 2401.
14. Decker, H. Ann. 1908, 362, 305.
Â
Tamayo, N.; Cardenas, D. J. J. Org. Chem. 1994, 59, 6075.
7. For syntheses of ravidomycin and related compounds see: (a)
Findlay, J. A.; Daljeet, A.; Murray, P. J.; Rej, R. N. Can. J. Chem.
1987, 65, 427. (b) Patten, A. D.; Nguyen, N. H.; Danishefsky, S. J.
J. Org. Chem. 1988, 53, 1003. (c) McKenzie, T. C.; Hassen, W.;
Macdonald, S. J. F. Tetrahedron Lett. 1987, 28, 5435. (d) Jung,
M. E.; Jung, Y. H. Tetrahedron Lett. 1988, 29, 2517. (e) Parker,
K. A.; Coburn, C. A. J. Org. Chem. 1991, 56, 1666. (f) Hart, D. J.;
Merriman, G. H.; Young, D. G. J. Tetrahedron 1996, 52, 14437. (g)
Echavarren, A. M.; de Frutos, O. Tetrahedron Lett. 1996, 37, 8953.
(h) James, C. A.; Snieckus, V. Tetrahedron Lett. 1997, 38, 8149
and references cited therein.
15. Matsuo, K.; Ishida, S. Chem. Pharm. Bull. 1994, 42, 1325.
16. Buckle, D. R.; Cantello, B. C. C.; Smith, H.; Smith, R. J.;
Spicer, B. A. J. Med. Chem. 1977, 20, 1059.
17. Compound 9b easily undergoes cleavage to an isoquinolone
and an o-bromotoluene, a process favoured by the electron-with-
drawing bromine (Scheme 5). See: Neumeyer, M.; McCarthy, K.
K.; Levins, P. L. J. Org. Chem. 1968, 33, 2890.
18. Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424.
19. Perring, D. D.; Armarego, W. L. F. Puri®cation of Laboratory
Chemicals, Pergamon: Oxford, 1988.