Tandem annulation strategy for the convergent synthesis of benzonaphthopyranones: total synthesis of chartarin and O-methylhayumicinone

Article abstract of DOI:10.1016/j.tet.2008.01.039

A Hauser-initiated tandem annulation has been developed for the rapid regiospecific synthesis of benzonaphthopyranones via formation of two rings in one-pot operation. This strategy has been generalized with benzonaphthopyranones 26, 29, 32, and 35. It has also been employed in a short synthesis of chartarin (3) and O-methylhayumicinone (67).

Full text of DOI:10.1016/j.tet.2008.01.039

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3253e3267
www.elsevier.com/locate/tet
Tandem annulation strategy for the convergent synthesis
of benzonaphthopyranones: total synthesis of chartarin
and O-methylhayumicinone
*
Sutapa Ray, Asit Patra, Dipakranjan Mal
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 21 September 2007; received in revised form 17 December 2007; accepted 10 January 2008
Available online 16 January 2008
Abstract
A Hauser-initiated tandem annulation has been developed for the rapid regiospecific synthesis of benzonaphthopyranones via formation of
two rings in one-pot operation. This strategy has been generalized with benzonaphthopyranones 26, 29, 32, and 35. It has also been employed in
a short synthesis of chartarin (3) and O-methylhayumicinone (67).
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Hauser annulation; Benzonaphthopyranone; Chartreusin; Chrymutasin; Hayumicin
1. Introduction
Structurally allied chrymutasin6 A (2), on the contrary, has
not received any attention even though it showed stronger anti-
tumor activities than chartreusin (1). Neither, has it been the sub-
ject of any synthetic research activity. In view of the sustained
interest4a in chartreusin(1) and its striking similarities with chry-
mutasins, we decided to develop a diversity-oriented synthetic
approach7 for the titled molecules and analogs. Our interest in
this area was reinforced by the fact that the extended aromatic
structures have found important commercial applications in
electro-luminescence, field-effect transistors (FET), organic
light emitting diodes (OLED), and photovoltaic devices8 as
well as in the synthesis of axially chiral biaryl natural products.9
We focused our study on the aglycones, since the intercala-
tion of aglycones is known to be the main source of free en-
ergy of binding in any intercalated drugeDNA complex.10
In a recent communication,11 we reported a tandem annulation
route to benzonaphthopyranones. Herein, we present a detailed
account of the study leading to the first synthesis of
O-methylhayumicinone (67).
Aromatic polyketides featuring oxygenated benzonaphtho-
pyranone motifs are of considerable interest due to their
biological activity and structural intricacies. They exhibit
a wide range of biological activities (Fig. 1).1 Chartreusins
(e.g., 1), chrymutasins (e.g., 2), hayumicins (e.g., 5), gilvocar-
cins (e.g., 6), and arnottin l (e.g., 7) are few selective aromatic
polyketide antibiotics that share a benzonaphthopyranone moi-
ety. Chartreusin (1), the most studied member and first isolated
in 1953 from the culture broth and mycelial cake of Streptomy-
ces chartreuses was fully characterized in 1964. It shows sig-
nificant chemotherapeutic activity against cancer cell lines
(ascitic P388, L1210 leukemia, and B16 melanoma). Due to
poor solubility in water and rapid biliary excretion, none of
the chartreusins found any clinical application.2 Elsamicin
A3 and IST-622,4 a semi-synthetic derivative, which have
improved water solubility due to the amino sugar moiety are
currently undergoing phase II clinical trials in Japan for the
treatment of patients with breast cancer.5
2. Synthetic strategy
Chartreusin (1) and chrymutasin A (2), albeit structurally
very similar, differ markedly in the constitution of the B-rings.
* Corresponding author. Tel.: þ91 3222 283318; fax: þ91 3222 282252.
E-mail address: dmal@chem.iitkgp.ernet.in (D. Mal).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.039

3254
S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
O
CH3
O
CH3
12
O
1
O
OMe
11
2
3
OR
O
C
O
OR
E
A
E
A
OMe
10
O
9
8
C
B
B
D
7
D
O
O
O
4
O
6
5
OH
O
NH2
2. Chrymutasin A, R = 2-O- -
D-digitaloxy- -D-fucosyl
4. Chrymutin, R = H
1. Chartreusin, R = 2-O- -D-
digitaloxy- -D-fucosyl
3. Chartarin, R = H
7. Arnottin l
OH
H
Me
HO
Me
Me
O
O
HO
O
O
O
HO
O
HO
HO
O
O
OH
= S
H
RO
MeO
O
O
OMe
Me
MeO
OH OMe
6: Gilvocarcin V
5. Hayumicin A, R = S
5a. Hayumicinone, R = H
Figure 1. Structures of benzonaphthopyranone antibiotics.
O
Y
O
O
O
O
Y
+
X
Hauser
annulation
A
E
R
R
O
B
D
C
R
R'
R'
R'
O
O
O
O
OH
O
8
9
10
11
Scheme 1. Tandem annulation strategy for the synthesis of benzonaphthopyranones.
Yet, they possess a similar bioactivity profile, implying the
allowance of structural modification/diversity in the B-ring
part of the molecules. Consequently, we formulated a tandem
annulation strategy (Scheme 1) for the synthesis of B-ring
analogs by involving the Hauser annulation.12 The aryloxy an-
ion of the intermediate 10, generated by the initial annulation
of compound 8 with acceptor 9, was envisaged to undergo
intramolecular nucleophilic attack to the pendant ester in the
acceptor 9, providing in situ formation of the lactone ring of
the product 11. This synthetic approach proved to be success-
ful for the construction of both the C and E rings in one-pot in
a regiospecific manner.11 The A, B, and D rings were derivable
from the isobenzofuranones and the Michael acceptors with
a preset substitution pattern.
(entry 1, Table 1). When isobenzofuranone 13 was treated with
cinnamate 14 under similar conditions as above, it expectedly
gave benzonaphthopyran 15 (63%), which was duly character-
ized as its O-methyl derivative 16. For the preparation of the
thiopyran analog of 16, Michael acceptor 14 was annulated
with 3-phenylthio-3H-benzo[c]thiophen-1-one (17)14 under
the conditions described above to give 18 in 63% yield (entry
2). It was primarily characterized by 1H NMR data and for fur-
ther characterization compound 18 was subjected to acetyla-
tion with Ac2O/Et3N/DMAP (4-N,N-dimethylaminopyridine)
in CH2Cl2 to give 19 in 91% yields.
Next, we applied the annulation to a cinnamate derivative
with a poor nucleofuge at the ortho-position, i.e., 20. It reacted
with phthalide 1215 in the presence of lithium tert-butoxide in
dry THF at ꢀ60 ꢁC forming mono annulation product aryl-
naphthoquinol 21 in 85% yield (entry 3). The same compound
was obtained in 81% yield when sulfone phthalide 1316,12b,12c
was condensed with the cinnamate 20. The structure of aryl-
3. Results and discussion
3.1. Model study on the synthesis of benzo[d]naphtho-
[1,2-b]pyran-6-ones
1
naphthoquinol 21 was established by H NMR data. It was
also characterized as methyl ether 22, prepared by methylation
of 21 with Me2SO4/K2CO3 in 92% yield. Two 3H singlets at
The tandem strategy was first examined with the cinnamate
14,13 prepared in two steps from o-tolualdehyde by Wittig
reaction with Ph3P]CHCO2Et followed by benzylic bromina-
tion (NBS/Bz2O2, heat). Annulation of 14 with isobenzofura-
none 12 in the presence of lithium tert-butoxide at ꢀ60 ꢁC
afforded the desired doubly annulated product 15 in 65% yield
1
d 4.01 and 3.36 in the H NMR spectrum clearly indicated
the formation of dihydroxyarylnaphthoquinol 21. The com-
pound 21 was further transformed to 23 by oxidation with
ceric ammonium nitrate (CAN) in acetonitrile. The annulated
product 22 can be viewed as a potential intermediate for an

S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
Table 1 (continued)
3255
Table 1
Annulation between 3-substituted phthalides and Michael acceptors
Entry Isobenzofuranones Michael acceptors
Benzonaphthopyranes
Entry Isobenzofuranones Michael acceptors
Benzonaphthopyranes
O
O
O
MeO2C
CN
O
X
BrH2C
O
7
O
CO2Et
OAc
1
OR
OH
35 (76%)
O
EtO2C
O
O
24
34
15: R = H, 65%
16: R = Me
EtO2C
89%a
12: X = SPh
13: X = SO2Ph
14
O
MeO2C
S
O
CN
O
BrH2C
SPh
S
O
8
O
O
CO2Et
2
OR
OH O
35 (91%)
O
O
36
24
O
18: R = H, 63%
19: R = COCH3
91%b
EtO2C
17
14
O
S
MeO2C
SPh
S
OR
9
O
CH2SO2Ph
CO2Et
O
O
36
OH
O
17
OR
X
PhO2SH2C
37 (71%)
21: R = H, 85%
22: R = Me
92%a
83%c
a
b
c
O
Me2SO4/K2CO3, acetone.
Ac2O/Et3N/DMAP, dichloromethane.
CAN.
PhO2SH2C
3
O
O
CO2Et
12: X = SPh
13: X = SO2Ph
20
entry to angucyclines17 through anionic intramolecular
cyclization.
CO2Et
O
23
For the fabrication of a benzonaphthopyranone, structurally
akin to the target molecule, the ester appended cinnamate 2518
was prepared in two steps from commercially available phthal-
aldehydic acid by methylation (DBU/MeI, rt) followed by
Wittig reaction with Ph3P]CHCO2Et. LiOtBu promoted an-
nulation of cinnamate 25 with cyanophthalide 2419 under the
conditions described previously gave compound 26 (81%) re-
sembling the gilvocarcin nucleus (entry 4). This product was
characterized as its O-methyl derivative 27. Nitro substituted
isobenzofuranone 28 was similarly condensed with 25 to pro-
vide benzonaphthopyranone 29 as a yellow solid in 86% yield
(entry 5). The nitro group attached to the A-ring of benzo[d]-
naphtho[1,2-b]pyran-6-one 29 can, in principle, be trans-
formed to an array of substituents providing newer analogs
of benzonaphthopyranones. Methylation (Me2SO4/K2CO3) of
29 routinely provided 30 in 90% yield.
When Michael acceptor 31, prepared from the correspond-
ing cinnamic acid,20 was subjected to annulation reaction
with sulfone phthalide 13, benzo[d]naphtho[1,2-b]pyran-6-
one 32 was formed in 83% yield (entry 6). It was fully charac-
terized by analysis of IR, NMR, and mass spectral data, and its
conversion to O-methyl derivative 33. The formation of 32 can
be explained by the mechanism shown in Scheme 2. The
aryloxy anion intermediate 38 formed after initial annulation
underwent intramolecular cyclization through nucleophilic
attack of Oꢀ group to the cyano group to form 39 followed
by 40, which, probably during acidic work-up underwent hy-
drolysis to provide 32. It may be concluded that the tandem an-
nulation route to benzonaphthopyranone is applicable to
O
O
MeO2C
CO2Et
CN
O
CO2Et
4
OR
O
24
26: R = H, 81%
27: R = Me
92%a
25
O
O
MeO2C
CO2Et
SPh
O
CO2Et
5
O2N
O2N
OR
O
29: R = H, 86%
30: R = Me
28
90%a
25
O
O
SO2Ph
NC
O
O
6
CO2Me
OR
CO2Me
31
32: R = H, 83%
33: R = Me
92%a
13
(continued)

3256
S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
N
C
N
NC
O
O
O
13, t-BuOLi
THF
CO2Me
CO2Me
38
CO2Me
OH
39
31
NH2
NH3
HO
O
HO
O
O
O
H3O
CO2Me
CO2Me
CO2Me
OH
40
OH
41
OH
32
Scheme 2. Mechanism for the formation of benzonaphthopyranone 32.
a Michael acceptor with a cyano appendage. The monoannu-
lated product corresponding to the dianion 38, i.e., the proton-
ated form of 38 was not isolated.
CH2Cl2 (Scheme 3). Sulfone aldehyde 42, available from
our recently reported22 six-step synthesis from methyl o-
toluate was reacted with the Wittig reagent in CH2Cl2 to
give unsaturated ester 20 in 94% yield.
For the synthesis of the pentacyclic model compound 35, rep-
resenting the core structure of chartarin (3), annulation reaction
between 24 and 34 was conducted under the conditions used for
the preceding examples. In one-pot operation, three new rings
were formed in one-pot to afford triply annulated product 35
in 76% yield (entry 7). It is important to note that the phenolic
acetate group in 34 did not impede the annulation. The desired
core structure of chartarin (3) was obtained instead of B-ring
seco derivative. The expected doubly annulated product with
an intact phenolic acetate group was not isolated. In a similar
vein, we examined the annulation of coumarin 36, prepared ac-
cording to the literature procedure21 from 3-hydroxybenzoic
acid through a regioselective Duff reaction as a key step. Its re-
action with 3-cyano-1(3H)-isobenzofuranone (24) in the pres-
ence of lithium tert-butoxide provided, as expected, the
doubly annulated pentacyclic product 35 (entry 8). In order to
examine whether the reaction can be applied to the preparation
of E-ring thio analog of chartreusin, we considered the annula-
tion between phthalide 17 and coumarin 36 (entry 9). Under the
conditions as described above, it provided pentacyclic 37 as
a yellow solid. Both the pentacyclic compounds 35 and 37
have diminished solubility in organic solvents compared to
the tetracyclic compound 26.
Similarly, methyl 2-formyl-3-hydroxybenzoate21 43 was re-
acted with Ph3P]CHCO2Et in CH2Cl2 at room temperature to
give cinnamate 44 in 94% yield, which on acetylation with
Ac2O/Et3N/DMAP provided 34 in 96% yield (Scheme 3).
3.3. Total synthesis of chartarin (3)
For the total synthesis of chartarin (3), the required couma-
rin 49 was prepared as depicted in Scheme 4. Although the
synthesis looked straightforward at the outset, it required lot
of experimentation and optimization due to the non-availabil-
ity of detailed procedures. The synthesis was begun with nitra-
tion of methyl o-toluate (45). Treatment of 45 with a mixture
of concentrated H2SO4 and concentrated HNO3 provided
a mixture of methyl 2-methyl-5-nitrobenzoate and the corre-
sponding ortho-isomer, which were separated by fractional
crystallization from a MeOH/H2O system. The yields of the
products were 50% and 30%, respectively. Reduction of nitro
group in the para-isomer to amine group was performed by
hydrogenation in the presence of 10% PdeC in MeOH to
give methyl 5-amino-2-methylbenzoate (46)23 in 94% yield.
Diazotization of the amino group in 46 with NaNO2/H2SO4,
followed by reflux in H2O furnished the phenol 4724 in
66% yield. Duff reaction of 47 with (CH2)6N4/PPA (polyphos-
3.2. Preparation of synthons 20 and 44
1
phoric acid) at 100 ꢁC afforded ester 48 in 30% yield. The H
Both the Michael acceptors 20 and 34 were prepared by
a Wittig reaction with freshly prepared Ph3P]CHCO2Et in
NMR data of 48 was in conformity with its structure. Two 1H
doublets at d 7.36 and 6.98 with coupling constants J¼8.7 Hz
MeO2C
MeO2C
OHC
SO2Ph
SO2Ph
OH
CHO
43
42
OR
Ph3P=CHCO2Et
CH2Cl2
rt
EtO2C
CH2Cl2
rt
34 R= Ac
44 R=H
CO2Et
20
Scheme 3. Synthesis of compounds 20 and 44.

S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
3257
CH3
i) HNO3, H2SO4
0 to - 5 °C
CH3
CO2Me
CH3
CO2Me
5.4 vol% H2SO4,
CO2Me
NaNO2, 0 °C
then reflux
66%
ii) 10% Pd/C,
H2 (1 atm), EtOH,
OH
NH2
47% for 2 steps
47
46
45
OMe
CN
O
CH3
CH3
CO2Me
O
CO2Me
(CH2)6N4, PPA
100 °C, 30%
Ph3P=CHCO2Et
Et2NPh, reflux
95%
50
t-BuOLi, THF
CHO
O
86%
OH
48
O
49
O
Me
O
O
Me
O
OH
O
OMe O
HBr, AcOH
reflux, 81%
OH
O
OH
O
3
51
Scheme 4. Total synthesis of chartarin 3.
corresponding to the aromatic hydrogens were in support
of the desired formylation. Treatment of 48 with
Ph3P]CHCO2Et in Et2NPh at reflux for 20 min, followed
by usual work-up gave coumarin ester 49 in 95% yield. The
structure of 49 was elucidated on the basis of IR, NMR, and
Hauser and Combs in the total synthesis of chartarin,16 the
present strategy provided a significantly shorter route. The
pentacyclic framework as in 51 was fabricated in one-pot
operation. The key to our success in this area was the choice
of cyanophthalide 24 instead of phthalide sulfone 13 for the
crucial condensation reaction with coumarin 49.
3
MS (mass spectral) data. The J coupling constants of two H
atoms of the lactone ring in 49 were in accordance with the
structure.
3.4. Model studies of chrymutasin and hayumicin aglycones
Annulation of 4-methoxycyanophthalide 5019 with couma-
t
rin 49 in the presence of BuOLi under typical conditions
Following the total synthesis of chartarin (3), we deployed
the tandem annulation strategy to the synthesis of chrymuta-
sins and hayumicins, which could be considered as B-ring
carbon analogs of chartreusins. As the initial target, we chose
model compound 55, embodying the entire chromophoric part
of hayumicin aglycone (5a). We were apprehensive that the re-
action between 24 and the required naphthoquinone monoketal
5225a might lead to the formation of hydroxymethoxyanthra-
quinone in accordance with our reported results.25 Neverthe-
less, cyanophthalide 24 was reacted with Michael acceptor
52 in the presence of tBuOLi in THF to give pentacyclic com-
pound 53 as a yellow solid in 87% yield. It may be noted that
phthalide sulfone 13 was not compatible to react with the
followed by usual work-up gave 51 as a yellow solid in
86% yield (Scheme 4). Unlike the pentacyclic compounds
35 and 37, this compound is fairly soluble in common organic
solvents. It could be purified by column chromatography
(silica gel) followed by recrystallization from ethyl acetate/
petroleum ether. 1H NMR spectrum of this compound showed
a broad singlet at d 11.57 for the peri-hydroxy group (6-OH).
In the aromatic region, it revealed four 1H doublets at d 8.06,
7.54, 7.46, and 7.19, and a 1H triplet at d 7.59. These data
were indicative of two aromatic rings, one of which is
1,2,3-trisubstituted and the other is a 1,2,3,4-tetrasubstituted
ring system. 13C NMR, IR, and MS data of this sample also
matched the structure. HBr-promoted demethylation of 51
1
naphthoquinone monoketal 52. The H NMR spectrum of 53
1
provided chartarin (3) in 81% yield. The H NMR spectrum
exhibited a 6H singlet at d 3.41, characteristic of two chemi-
cally equivalent OCH3 groups supporting the monoketal struc-
ture of 53. It also showed a sharp singlet at d 13.48
corresponding to the hydrogen-bonded OH group. Acid cata-
lyzed deketalization of ketal 53 furnished the model com-
pound 55 in 98% yield.
(200 MHz) of 3 recorded in DMSO-d6 was not well resolved.
However, it compared well with the reported3b one. For fur-
ther verification, its 1H NMR spectrum was recorded in
CDCl3 on a 500 MHz spectrometer. The spectrum was well
resolved and the data were in conformity with reported
values.
Although the concept of condensation of a coumarin with
a 3-substituted isobenzofuranone to give the corresponding
benzo[b]naphtho[d]pyran-6-one was originally introduced by
Similarly, methoxycyanophthalide 50 was reacted with qui-
t
none monoketal 52 in the presence of BuOLi in THF at
ꢀ60 ꢁC to give pentacyclic monoketal 54 in 92% yield as
a yellow solid. The signals at d 13.54 (OH), 4.12 (3H,

3258
S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
O
O
MeO2C
R
O
O
R
O
24 or 50
aq. HCl
MeOH
OMe
OMe
OMe t-BuOLi, THF
O
OMe
- 60 °C
OH
OH
O
O
55: R = H
56: R = OMe
53: R = H
54: R = OMe
52
Scheme 5. Synthesis of hayumicinone analogs.
OCH3), and 3.40 (6H, 2ꢂOCH3) in 1H NMR spectrum were in
agreement with the structure of the compound. Acid catalyzed
deketalization of 54 provided hayumicinone analog 56 in 98%
yield (Scheme 5). Like compound 55, it was poorly soluble in
methoxyhomophthalate, (iii) reduction of N,N-diethyl 2-for-
myl-6-methoxynaphthalene-1-carboxamide, and (iv) elabora-
tion of 6-methoxytetralone through cyanohydrin formation,
Shapiro reaction, and nitromethane addition. Eventually,
a eight-step synthesis of the naphthoate 65 from 57, depicted
in Scheme 6, was executed.
6-Benzyloxytetralone (57), prepared by O-benzylation26 of
6-hydroxy-a-tetralone was methylenated with paraformalde-
hyde and N-methylanilinium trifluoroacetate to give 58. Zn/
AcOH reduction of 58 followed by reaction with PBr3 fur-
nished alkenyl bromide 60, which was homologated via lithia-
tion and reaction with carbon dioxide to give acid 61 in
moderate overall yield. This was then methylated with DBU/
CH3I27 to give ester 62. DDQ-promoted aromatization of 62,
followed by reductive debenzylation with H2/PdeC provided
naphthoate 64. As expected, oxidation of 64 with PhI(OAc)2
in methanol at 0 ꢁC resulted in the formation of naphthoqui-
none monoketal 65 in 70% yield.
1
common organic solvents. In H NMR spectrum, it exhibited
a sharp singlet at d 14.52 for the hydroxy group (5-OH). In
the aromatic region, it revealed four 1H doublets at d 8.71,
8.64, 8.20, and 7.34 and two 1H triplets at d 7.77 and 7.69 cor-
responding to two aromatic rings, which are 1,2,3-trisubsti-
tuted ring systems.
4. Extension to the synthesis of O-methylhayumicinone
(67)
For the synthesis of hayumicinone 5a by extension of the
above methodology, naphthoquinone monoketal 65 was re-
quired. With the synthesis of 52 reported in the literature
that of structurally analogous ketal 65 appeared to be straight-
forward. However, it necessitated rigorous studies. It was
partly because of our keenness to utilize readily available 6-
methoxytetralone. At the initial stages, we examined, without
success, several approaches, which included (i) FriedeleCrafts
reaction of anisole with 3-methylfuran-2-carboxylic acid,
(ii) Michael-initiated ring closure reaction of dimethyl
With both 65 and 50 in hand, we explored their condensa-
tion chemistry for the synthesis of hayumicinone (5a). Treat-
ment of the quinone monoketal 65 with cyanophthalide 50
in the presence of LiOtBu afforded the desired pentacyclic an-
nulation product (66) in 78% yield, which characteristically
1
gave a H NMR signal at d 13.71 for the hydrogen-bonded
CH3
CH3
O
O
O
R
PhNMeH+ TFA-,
(CH2O)n
PBr3,
benzene
Zn, AcOH
reflux
47%
reflux
53%
THF, reflux
58%
OCH2Ph
OCH2Ph
57
OCH2Ph
OCH2Ph
60 R= Br
n-BuLi, CO2
THF, -78 °C
58%
58
59
61 R= CO2H
DBU, MeI,
72%
62 R= CO2Me
CH3
CH3
MeO2C
MeO2C
DDQ,
benzene
PhI(OAc)2
62
OMe
OMe
MeOH
70%
reflux
78%
O
OR
63 R= CH2Ph
64 R= H
H2, Pd-C
50%
65
Scheme 6. Synthesis of o-naphthoquinone monoketal 65.

S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
3259
O
CH3
O
CH3
10% HCl
OR
O
O
OMe
CN
O
OMe O
MeOH-H2O
65
70%
t-BuOLi
OMe
OMe
THF
- 60 °C
O
O
OH
OH
66
O
78%
67 R= Me
5a R= H
50
Scheme 7. Synthesis of O-methylhayumicinone.
proton and IR signal at 1737 cmꢀ1 for lactone carbonyl. Deke-
talization of 66 with aq HCl solution in methanol furnished
hayumicinone 67 in yield via ketoeenol transposition. The
possibility of 67 existing in the isomeric ortho-quinone struc-
ture was ruled out on the basis of calculated minimized energy
(MM2). However, the final O-demethylation of 67 remained to
be accomplished (Scheme 7). The preliminary attempts with
HBr/AcOH were unsuccessful.
was stirred at ꢀ60 ꢁC for 25 min, after which a solution of
a Michael acceptor (1.0e1.5 equiv unless otherwise stated)
in THF (5 mL) was added to it. The cooling bath was removed
after about 1 h at ꢀ60 ꢁC and the reaction mixture was
brought to room temperature over a period of 1 h and further
stirred for 2e6 h. The reaction was then quenched with 10%
NH4Cl (15 mL) and the resulting solution was concentrated.
Generally, a bright yellow solid appeared, which was filtered
and washed with 1:1 mixture (20 mL) of diethyl ether and pe-
troleum ether. Otherwise, the residue was diluted with ethyl
acetate (50 mL) and the layers were separated. The aqueous
layer was extracted with ethyl acetate (3ꢂ25 mL). The com-
bined extracts were washed with H2O (15 mL), brine
(15 mL), dried (anhydrous Na2SO4), and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel or by recrystallization to get
a pure product.
5. Conclusion
In conclusion, a tandem annulation (formation of more than
one ring in one-pot) has been introduced for the one-pot regio-
specific fabrication of a variety of benzonaphthopyranones
from readily accessible starting materials. This strategy has
been utilized in the total synthesis of chartarin (3) and O-meth-
ylhayumicinone (67) from 57. Work is in progress for incorpo-
ration of the peripheral amino group toward completion of the
synthesis of chrymutin (4).
6.3. General procedure of O-methylation of phenolic
compounds
6. Experimental
A hydroxy compound (3.0 mmol) was dissolved in dry ac-
etone (20 mL) under N2-atmosphere. To this solution were
added dry K2CO3 (15 mmol) and Me2SO4 [6 mmol; freshly
washed with cold water (10 mL), saturated NaHCO3 solution
(15 mL), brine (15 mL), and dried over anhydrous K2CO3].
After 2 h of reflux, on completion of the reaction, the inor-
ganic salts were filtered and the filtrate was concentrated.
The residue was diluted with ethyl acetate (15 mL), treated
with Et3N (6 mmol) at room temperature and stirred for
30 min. The reaction mixture was then diluted with ethyl ace-
tate (50 mL), washed with 5% aq HCl solution (15 mL) and
water (15 mL) and subjected to usual work-up (drying over an-
hydrous Na2SO4 and concentrating under reduced pressure) to
get a crude residue, which was further purified by recrystalli-
zation or by column chromatography on silica gel to give
a pure methoxy compound.
6.1. General experimental
Melting points are uncorrected. IR spectra were recorded
on a Thermo Nicolet Nexus 870 FT-IR spectrophotometers us-
ing KBr pellet. 1H and 13C NMR spectra of the samples in the
indicated solvents were recorded on 200 MHz, 300 MHz or
400 MHz spectrometer (Brucker) as solution in CDCl or
3
¨
DMSO-d6 or mixture of CDCl3 and DMSO-d6 with residual
CHCl3 as the internal standard. Chemical shifts are expressed
in d unit and coupling constant in hertz. Mass spectra were
taken using a VG Autospec M mass spectrometer. Elemental
analyses were carried out by using an elemental analyzer
VARIO EL instrument. Dry solvents used for reactions were
purified, before use, according to the standard protocols. All
solvents for chromatography were distilled prior to use.
Columns were prepared with silica gel (60e120 or 230e400
mesh).
6.4. Chartarin (3)3b
6.2. General procedure for annulation reaction
Compound 53 (100 mg, 0.29 mmol) was dissolved in a solu-
tion of acetic acid (5.0 mL) and 42% aq HBr (5.0 mL). The
mixture was heated at reflux for 8 h. After cooling the reaction
mixture, the brown resulting solid was separated by filtration
and further purified by repeated washing with petroleum ether
to furnish 3 as an amorphous solid (78 mg, 81%). Mp: 280 ꢁC
To a stirred solution of lithium tert-butoxide (9.84 mmol) in
THF (40 mL) at ꢀ60 ꢁC (chloroform/liquid N2 bath) under an
inert atmosphere was added a solution of a phthalide
(3.28 mmol) in THF (5 mL). The resulting yellowish solution

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S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
(sublimed) (lit.3b mp: 308e309 ꢁC); 1H NMR (500 MHz,
CDCl3): d 11.59 (s, 1H), 8.63 (s, 1H), 8.10 (d, 1H,
J¼8.2 Hz), 7.64 (t, 1H, J¼8.0 Hz), 7.59 (d, 1H, J¼8.3 Hz),
7.52 (d, 1H, J¼8.4 Hz), 7.34 (d, 1H, J¼7.7 Hz), 2.91 (s, 3H).
6.8. Ethyl 12-acetoxy-6H-dibenzo[c,h]thiochromene-11-
carboxylate (19)
To a stirred solution of hydroxy compound 18 (200 mg,
0.60 mmol) in CH2Cl2 (10 mL) were added acetic anhydride
(120 mg, 1.20 mmol), Et3N (120 mg, 1.20 mmol), and DMAP
(10 mg). The reaction mixture was stirred at 25 ꢁC for 4 h.
The resulting reaction mixture was partitioned between
CH2Cl2 (100 mL) and H2O (50 mL) and the organic layer
was washed with dilute HCl (20 mL), brine (20 mL), dried (an-
hydrous Na2SO4), and concentrated. The residue was purified
by column chromatography on silica gel (Rf 0.60, 1:1 ethyl ace-
tate/petroleum ether) to furnish 19 in 91% yield (200 mg) as
a white solid. Mp: 134e137 ꢁC; nmax (KBr, cmꢀ1): 1773 (s),
1724 (s), 1626, 1582, 1460, 1365, 1298, 1239, 1199 (s), 1153,
1068, 1019, 945, 860, 753, 715; 1H NMR (200 MHz, CDCl3):
d 8.02 (d, 1H, J¼8.2 Hz), 7.84 (d, 1H, J¼8.2 Hz), 7.68e7.50
(m, 4H), 7.38e7.30 (m, 2H), 4.58 (q, 2H, J¼7.1 Hz), 4.18 (s,
2H), 2.48 (s, 3H), 1.46 (t, 3H, J¼7.1 Hz); 13C NMR
(50 MHz, CDCl3): d 168.9, 166.6, 144.5, 143.3, 140.3, 139.0,
134.9, 131.3, 127.9 (CH), 126.7 (CH), 126.6 (CH), 126.5
(CH), 125.3, 124.6 (CH), 124.3 (CH), 122.8 (CH), 121.6
(CH), 118.8, 61.7 (CH2), 35.3 (CH2), 20.5 (CH3), 14.1 (CH3);
MS EI (70 eV): 378 (Mþ), 346, 336, 318, 304 (100%), 290,
272, 262, 258, 230, 202. Anal. Calcd for C22H18O4S: C,
69.82; H, 4.79. Found: C, 70.05; H, 4.63.
6.5. Ethyl 12-hydroxy-6H-dibenzo[c,h]chromene-11-
carboxylate (15)
This compound was prepared as a greenish yellow liquid in
65% yield by the reaction between 12 and 14, according to the
general procedure described in Section 6.2. It was also pre-
pared in 61% yield by the reaction between 13 and 14. The
crude product was purified by column chromatography on sil-
ica gel (Rf 0.70, 1:5 ethyl acetate/petroleum ether) to furnish
pure 15. nmax (CHCl3, cmꢀ1): 3437, 1724, 1655 (s), 1438,
1
1391 (s), 1320, 1229, 1154, 1084, 1030, 938, 758, 617; H
NMR (200 MHz, CDCl3): d 11.33 (s, 1H), 8.39 (dd, 1H,
J¼7.8, 1.7 Hz), 8.21 (dd, 1H, J¼7.3, 1.5 Hz), 7.69e7.53 (m,
2H), 7.34e7.14 (m, 4H), 5.18 (s, 2H), 4.34 (q, 2H,
J¼7.1 Hz), 1.20 (t, 3H, J¼7.1 Hz); 13C NMR (50 MHz,
CDCl3): d 171.3, 156.0, 145.5, 130.8, 130.2, 129.4 (CH),
128.2, 127.2 (CH), 127.1 (CH), 126.9 (CH), 126.4 (CH),
125.6, 124.3 (CH), 124.1 (CH), 122.0 (CH), 114.8, 69.3
(CH2), 61.2 (CH2), 13.7 (CH3) (signal of one aromatic carbon
was not observed). Anal. Calcd for C20H16O4: C, 74.99; H,
5.03. Found: C, 75.20; H, 4.89.
6.9. Ethyl 3-(2-phenylsulfonylmethylphenyl)acrylate (20)
6.6. Ethyl 12-methoxy-6H-dibenzo[c,h]chromene-11-
carboxylate (16)
To a solution of 2-(phenylsulfonylmethyl)benzaldehyde
(42) (900 mg, 3.46 mmol) in dry CH2Cl2 (30 mL) was added
freshly prepared Ph3P]CHCO2Et (1.45 g, 4.16 mmol). The
resulting mixture was stirred for 2 h at room temperature.
The reaction mixture was then diluted with CH2Cl2
(100 mL) and successively washed with H2O (30 mL), brine
(30 mL), dried (anhydrous Na2SO4), and concentrated. Purifi-
cation of the crude residue by chromatography on silica gel (Rf
0.70, 3:7 ethyl acetate/petroleum ether) gave 20 (1.07 g, 94%)
as a white solid. Mp: 110e112 ꢁC; nmax (KBr, cmꢀ1): 2981,
2934, 1706, 1629, 1483, 1443, 1374, 1311, 1181, 1130,
This compound was prepared as a white solid in 89% yield
from 15, following the general procedure of methylation de-
scribed in Section 6.3. The crude product was purified by col-
umn chromatography on silica gel (Rf 0.40, 1:10 ethyl acetate/
petroleum ether) to furnish pure 16 as a white solid. Mp: 98e
100 ꢁC; nmax (KBr, cmꢀ1): 1727 (s), 1634, 1452, 1387, 1346,
1304, 1267, 1228 (s), 1185, 1082 (s), 1011, 936, 857, 759,
654; 1H NMR (200 MHz, CDCl3): d 8.30e8.25 (m, 1H),
8.11e8.05 (m, 1H), 7.60e7.42 (m, 3H), 7.38e7.20 (m, 3H),
5.20 (s, 2H), 4.44 (q, 2H, J¼7.1 Hz), 4.06 (s, 3H), 1.35 (t,
3H, J¼7.1 Hz); 13C NMR (50 MHz, CDCl3): d 168.3, 149.1,
148.3, 131.6, 129.7, 128.3, 127.9, 127.3, 127.2, 127.1,
126.8, 124.7, 124.0, 122.8, 122.6, 121.2, 115.1, 69.2, 63.7,
61.5, 14.0; MS EI (70 eV): 334 (Mþ), 319, 305, 291, 275,
261, 247, 231, 217, 202, 189 (100%). Anal. Calcd for
C21H18O4: C, 75.43; H, 5.43. Found: C, 75.73; H, 5.29.
1
1080, 1024, 987, 873, 761, 686, 615; H NMR (200 MHz,
CDCl3): d 7.60e7.34 (m, 9H), 7.4 (d, 1H, J¼15.6 Hz), 5.96
(d, 1H, J¼15.6 Hz), 4.46 (s, 2H), 4.22 (q, 2H, J¼7.1 Hz),
1.35 (t, 3H, J¼7.1 Hz); 13C NMR (50 MHz, CDCl3):
d 165.7, 139.8, 137.6, 135.0, 133.7, 132.8, 129.8, 129.3,
128.9, 128.7, 127.5, 126.7, 120.8, 60.3, 59.4, 14.3. Anal. Calcd
for C18H18O4S: C, 65.43; H, 5.49. Found: C, 65.49; H, 5.45.
6.7. Ethyl 12-hydroxy-6H-dibenzo[c,h]thiochromene-11-
carboxylate (18)
6.10. Ethyl 3-(2-phenylsulfonylmethylphenyl)-
1,4-dihydroxynaphthalene-2-carboxylate (21)
This compound was prepared as a solid in 63% yield by the
reaction between 14 and 17, according to the general proce-
This compound was prepared as a white solid in 85% yield
by the reaction between 12 and 20 according to the general
procedure described in Section 6.2. It was also obtained
from the reaction between 13 and 20 in 81% yield. The crude
product was purified by column chromatography on silica gel
(Rf 0.60, 1:3 ethyl acetate/petroleum ether) to furnish 21 as
1
dure described in Section 6.2. H NMR (200 MHz, CDCl3):
d 11.72 (s, 1H), 8.44 (d, 1H, J¼8.2 Hz), 8.06 (d, 1H,
J¼9.0 Hz), 7.92 (d, 1H, J¼7.9 Hz), 7.70e7.10 (m, 5H), 4.63
(q, 2H, J¼7.2 Hz), 4.11 (s, 2H), 1.50 (t, 3H, J¼7.2 Hz).

S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
3261
1
a white solid. Mp: 116e119 ꢁC; 1H NMR (200 MHz, CDCl3):
d 12.34 (s, 1H), 8.46 (d, 1H, J¼8.4 Hz), 8.26 (d, 1H,
J¼8.4 Hz), 7.70e7.20 (m, 11H), 4.22 (s, 2H), 3.91 (q, 2H,
J¼7.2 Hz), 0.69 (t, 3H, J¼7.2 Hz, 3H).
853, 791, 756, 696; H NMR (200 MHz, CDCl3): d 10.92 (s,
1H), 8.52 (d, 1H, J¼8.3 Hz), 8.42 (d, 2H, J¼7.8 Hz), 7.83e
7.53 (m, 5H), 4.39 (q, 2H, J¼7.1 Hz), 1.21 (t, 3H,
J¼7.1 Hz); 13C NMR (50 MHz, CDCl3): d 170.6, 161.0,
156.7, 142.0, 134.9, 132.8 (CH), 130.5 (CH), 129.7 (CH),
128.2 (CH), 127.6 (CH), 126.7, 125.6, 124.1 (CH), 122.4
(CH), 121.8, 110.9, 101.8, 62.0 (CH2), 13.7 (CH3) (one aro-
matic carbon signal was not observed); MS EI (70 eV): 334
(Mþ), 288 (100%), 260, 232, 204, 176. Anal. Calcd for
C20H14O5: C, 71.85; H, 4.22. Found: C, 71.90; H, 4.17.
6.11. Ethyl 3-(2-phenylsulfonylmethylphenyl)-1,4-
dimethoxynaphthalene-2-carboxylate (22)
This compound was prepared as a white solid in 92% yield
from 21, following the general procedure of methylation de-
scribed in Section 6.3. It was purified by column chromatogra-
phy on silica gel (Rf 0.55, 1:3 ethyl acetate/petroleum ether) to
furnish 22 as a white solid. Mp: 96e98 ꢁC; nmax (KBr, cmꢀ1):
1726 (s), 1630, 1590, 1448, 1402, 1357, 1307 (s), 1229, 1147,
1083, 1011, 966, 860, 755, 693; 1H NMR (200 MHz, CDCl3):
d 8.20e8.13 (m, 1H), 8.10e8.02 (m, 1H), 7.85e7.78 (m,
1H), 7.74e7.46 (m, 5H.), 7.42e7.28 (m, 5H), 4.38 (d, 2H,
J¼4.2 Hz), 4.01 (s, 3H), 3.94 (q, 2H, J¼7.1 Hz), 3.36 (s, 3H),
0.88 (t, 3H, J¼7.1 Hz); 13C NMR (50 MHz, CDCl3): d 166.6,
149.9, 149.2, 139.7, 136.6, 133.1, 130.9, 130.0, 129.3, 128.7,
128.4, 128.2, 128.1, 127.8, 127.5, 127.0, 125.7, 122.9, 63.6,
61.5, 61.1, 59.4, 13.5 (signals of 3 aromatic carbons were not
observed). Anal. Calcd for C26H26O6S: C, 68.55; H, 5.34.
Found: C, 68.59; H, 5.25.
6.14. Ethyl 12-methoxy-6-oxo-6H-dibenzo[c,h]chromene-11-
carboxylate (27)
This compound was prepared as a white solid in 92% yield
from 26, following the general procedure of methylation de-
scribed in Section 6.3. The residue was purified by column
chromatography on silica gel (Rf 0.40, 1:10 ethyl acetate/
petroleum ether) to furnish 27. Mp: 159e161 ꢁC; nmax (KBr,
cmꢀ1): 1719 (s), 1607, 1480, 1455, 1361, 1311, 1281, 1233,
1192, 1083 (s), 1017, 998, 939, 847, 795, 757, 696; 1H
NMR (200 MHz, CDCl3): d 8.65e8.58 (m, 1H), 8.49 (dd,
1H, J¼7.8, 1.4 Hz), 8.14e8.06 (m, 1H), 7.91 (d, 1H,
J¼8.2 Hz), 7.78 (dt, 1H, J¼7.6, 1.4 Hz), 7.74e7.55 (m, 3H),
4.57 (q, 2H, J¼7.1 Hz), 4.06 (s, 3H), 1.43 (t, 3H,
J¼7.1 Hz); 13C NMR (75 MHz, CDCl3): d 168.3, 160.5,
150.7, 144.3, 134.6, 133.9, 130.8, 128.8, 128.6, 128.3,
127.8, 125.2, 123.8, 123.0, 122.3, 121.5, 120.3, 110.1, 64.0,
62.3, 13.9; MS EI (70 eV): 348 (Mþ), 303, 291 (100%),
275, 261, 231, 201, 176. Anal. Calcd for C21H16O5: C,
72.41; H, 4.63. Found: C, 72.46; H, 4.60.
6.12. Ethyl 3-(2-benzenesulfonylmethylphenyl)-1,4-
naphthoquinone-2-carboxylate (23)
To a solution of arylnaphthoquinol 21 (600 mg, 1.30 mmol)
in CH3CN (10 mL) was added aqueous solution of ceric ammo-
nium nitrate (1.78 mg, 3.25 mmol in 10 mL H2O) and stirring
was continued at room temperature for 1.5 h. The resulting
mixture was concentrated and after the usual work-up, the res-
idue was purified by column chromatography (Rf 0.60, 3:7 ethyl
acetate/petroleum ether) to give 23 (495 mg, 83%) as a yellow
solid. Mp: 133e134 ꢁC; nmax (KBr, cmꢀ1): 1734 (s), 1663 (s),
1597, 1450, 1379, 1287 (s), 1229, 1143, 1080, 1012, 935,
6.15. Ethyl 12-hydroxy-2-nitro-6-oxo-6H-
dibenzo[c,h]chromen-11-carboxylate (29)
This compound was prepared as a yellow solid in 86%
yield by the reaction between 28 and 25 according to the gen-
eral procedure described in Section 6.2. The crude product
was purified by column chromatography on silica gel (Rf
0.60, 1:5 ethyl acetate/petroleum ether) to furnish 29. Mp:
225e227 ꢁC; nmax (KBr, cmꢀ1): 3380, 1754 (s), 1679 (s),
1625, 1598, 1529, 1483, 1423, 1378, 1344 (s), 1319, 1263,
1
891, 856, 756, 605; H NMR (200 MHz, CDCl3): d 8.20e
8.12 (m, 2H), 7.86e7.72 (m, 2H), 7.60e7.10 (m, 8H), 6.80
(d, 1H, J¼7.0 Hz), 4.90 (d, 1H, J¼14.5 Hz), 4.12 (d, 1H,
J¼14.5 Hz), 4.10 (q, 2H, J¼7.1 Hz), 0.94 (t, 3H, J¼7.1 Hz);
13C NMR (50 MHz, CDCl3): d 183.2, 181.8, 163.9, 144.5,
139.0, 137.5, 134.6, 134.1, 133.7, 132.6, 132.4, 132.2, 131.5,
130.8, 129.3, 128.9, 128.7, 128.2, 127.2, 126.9, 126.6, 62.0,
60.9, 13.7; HRMS ESI (70 eV) for C26H21O6S [MþH]þ calcd:
461.1059, found: 461.1070.
1
1238, 1199, 1120, 1068, 1024, 968, 844, 765, 740, 703; H
NMR (300 MHz, CDCl3): d 10.88 (s, 1H), 9.25 (d, 1H,
J¼2.1 Hz), 8.58 (d, 1H, J¼9.0 Hz), 8.46e8.35 (m, 2H), 7.71
(dt, 1H, J¼7.5, 1.5 Hz), 7.63e7.40 (m, 2H), 4.36 (q, 2H,
J¼7.1 Hz), 1.15 (t, 3H, J¼7.1 Hz); 13C NMR (200 MHz,
CDCl3): d 170.0, 160.1, 156.6, 146.8, 141.1, 133.9, 133.1,
130.0, 129.5, 129.2, 127.9, 124.9, 124.2, 123.7, 122.3,
120.8, 114.8, 104.1, 62.6, 13.6. HRMS ESI (70 eV) for
C20H14NO7 [MþH]þ calcd: 380.0770, found: 380.0751.
6.13. Ethyl 12-hydroxy-6-oxo-6H-dibenzo[c,h]chromene-11-
carboxylate (26)
This compound was prepared as a white crystalline solid in
81% yield by the reaction between 24 and 25, according to the
general procedure described in Section 6.2. The crude product
was purified by column chromatography on silica gel (Rf 0.70,
1:5 ethyl acetate/petroleum ether) to furnish 26. Mp: 111e
114 ꢁC; nmax (KBr, cmꢀ1): 3437, 1743 (s), 1654, 1595,
1481, 1446, 1374, 1322, 1277, 1238, 1160, 1090, 1023, 958,
6.16. Ethyl 12-methoxy-2-nitro-6-oxo-6H-
dibenzo[c,h]chromen-11-carboxylate (30)
This compound was prepared as a pale yellow solid in 90%
yield from 29, following the general procedure of methylation

3262
S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
described in Section 6.3. The crude product was purified by
column chromatography on silica gel (Rf 0.50, 1:5 ethyl ace-
tate/petroleum ether) to furnish 30. Mp: 246e248 ꢁC; nmax
(KBr, cmꢀ1): 1753 (m), 1722 (s), 1601, 1529, 1477, 1444,
1342 (s), 1272, 1248 (m), 1225, 1117, 1091, 1064, 1012,
978, 667; 1H NMR (200 MHz, CDCl3): d 9.03 (d, 1H,
J¼2.1 Hz), 8.79 (d, 1H, J¼9.2 Hz), 8.54 (dd, 1H, J¼7.6,
1.4 Hz), 8.44 (dd, 1H, J¼9.2, 2.1 Hz), 7.98 (d, 1H,
J¼8.1 Hz), 7.85 (dt, 1H, J¼7.8, 1.4 Hz), 7.71 (dt, 1H,
J¼7.6, 1.4 Hz), 4.60 (q, 2H, J¼7.2 Hz), 4.13 (s, 3H), 1.44
(t, 3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3): d 167.5,
159.8, 151.7, 147.3, 143.9, 135.0, 133.1, 131.1, 130.1,
127.6, 127.3, 125.3, 124.3, 122.8, 122.0, 121.8, 119.2,
113.9, 65.0, 62.7, 14.0; HRMS ESI (70 eV) for C21H16NO7
[MþH]þ calcd: 394.0927, found: 394.0920.
chromatography on silica gel (Rf 0.60, 1:3 ethyl acetate/petro-
leum ether) to furnish 34. Mp: 58e60 ꢁC; nmax (KBr, cmꢀ1):
1759, 1722 (s), 1645, 1458, 1369, 1311, 1277, 1227, 1195,
1
1172, 1025, 912, 758; H NMR (300 MHz, CDCl3): d 7.93
(d, 1H, J¼16.3 Hz), 7.84 (d, 1H, J¼7.6 Hz), 7.42 (t, 1H,
J¼7.6 Hz), 7.26 (d, 1H, J¼7.6 Hz), 6.15 (d, 1H, J¼16.3 Hz),
4.26 (q, 2H, J¼7.1 Hz), 3.89 (s, 3H), 2.27 (s, 3H), 1.33 (t,
3H, J¼7.1 Hz); MS EI (70 eV): 292 (Mþ), 250, 233, 219,
204, 187, 177 (100%), 145. Anal. Calcd for C15H16O6: C,
61.64; H, 5.52. Found: C, 61.74; H, 5.49.
6.20. 6-Hydroxy-benzo[h]chromeno[5,4,3-cde]chromene-
5,12-dione (35)
This compound was prepared as a yellow solid in 91%
yield by the condensation between 24 and 34, according to
the general procedure described in Section 6.2. The crude
product was purified by column chromatography on silica
gel (Rf 0.40, 1:1 ethyl acetate/petroleum ether) to furnish 35.
Mp: >400 ꢁC; nmax (KBr, cmꢀ1): 3496, 1754 (s), 1683 (s),
1612 (s), 1502, 1378 (m), 1330, 1259, 1205, 1143, 1085,
1070 (m), 914, 752 (s); 1H NMR (200 MHz, CDCl3):
d 11.42 (s, 1H), 8.57 (t, 2H, J¼8.4 Hz), 8.27 (dd, 1H,
J¼6.5, 2.5 Hz), 7.91 (dt, 1H, J¼7.7, 1.3 Hz), 7.81e7.60 (m,
3H); MS ESI (70 eV): [MþH]þ, 305.07. Anal. Calcd for
C18H8O5: C, 71.06; H, 2.65. Found: C, 71.26; H, 2.59. The
poor solubility of this compound in deuterated solvent pre-
vented us from recording 13C NMR data.
6.17. Methyl 12-hydroxy-6-oxo-6H-dibenzo[c,h]chromene-
11-carboxylate (32)
This compound was prepared as a white solid in 83% yield
by the reaction between 13 and 31 according to the general
procedure described in Section 6.2. The residue was purified
by column chromatography on silica gel (Rf 0.50, 1:1 ethyl ace-
tate/petroleum ether) to furnish 32. Mp: 229e233 ꢁC; nmax
(KBr, cmꢀ1): 3422, 1735 (s), 1657, 1615, 1478, 1441, 1366,
1336, 1274, 1237, 1168, 1086, 1030, 993, 880, 842, 792,
753, 696; 1H NMR (200 MHz, CDCl3): d 10.78 (s, 1H),
8.50 (d, 1H, J¼8.2 Hz), 8.41 (d, 2H, J¼8.0 Hz), 7.82e7.48
(m, 5H), 3.86 (s, 3H); 13C NMR (50 MHz, CDCl3): d 170.9,
160.9, 156.6, 142.0, 134.9, 133.0, 130.5, 129.8, 128.3,
128.2, 127.1, 126.8, 125.6, 124.2, 122.4, 121.8, 110.8,
101.5, 52.2; HRMS ESI (70 eV) for C19H13O5 [MþH]þ calcd:
321.0763, found: 321.0758.
6.21. 6-Hydroxy-4-oxa-11-thia-benzo[def]chrysene-
5,12-dione (37)
This compound was prepared as a yellow solid in 71%
yield by the reaction between 17 and 36 according to the gen-
eral procedure of annulation described in Section 6.2. The
crude product was purified by column chromatography on sil-
ica gel (Rf 0.50, 1:1 ethyl acetate/petroleum ether) to furnish
37. nmax (KBr, cmꢀ1): 3433, 1678 (s), 1647 (m), 1626, 1597,
1502, 1371, 1344, 1317, 1246 (m), 1157, 1101, 1047, 890,
808, 765, 669; 1H NMR (200 MHz, CDCl3): d 12.77 (s,
1H), 8.66 (dd, 1H, J¼8.3, 1.6 Hz), 8.37e8.32 (m, 1H), 8.22
(d, 1H, J¼8.3 Hz), 7.87 (dt, 1H, J¼1.3, 8.3 Hz), 7.84e7.73
(m, 3H); MS EI (70 eV): 320 (Mþ, 100%), 292, 273, 256,
236, 208, 172. Anal. Calcd for C18H8O4S: C, 67.49; H, 2.52.
Found: C, 67.72; H, 2.47. The poor solubility of this com-
pound in deuterated solvent prevented us from recording 13C
NMR data.
6.18. Methyl 12-methoxy-6-oxo-6H-dibenzo[c,h]chromene-
11-carboxylate (33)
This compound was prepared as a white solid in 92% yield
from 32, following the general procedure described in Section
6.3. The crude product was purified by column chromatogra-
phy on silica gel (Rf 0.55, 1:1 ethyl acetate/petroleum ether)
to furnish 33. Mp: 195e197 ꢁC; nmax (KBr, cmꢀ1): 1724 (s),
1602, 1485, 1441, 1360, 1311, 1281, 1234, 1086, 1031, 995,
760; 1H NMR (200 MHz, CDCl3): d 8.70e8.62 (m, 1H),
8.51 (d, 1H, J¼7.7 Hz), 8.18e8.10 (m, 1H), 7.84e7.58 (m,
5H), 4.08 (s, 3H), 4.07 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 168.8, 160.5, 150.9, 144.4, 134.8, 133.9, 130.9, 128.9,
128.7, 128.4, 127.9, 125.4, 123.6, 123.1, 122.4, 121.7,
120.0, 110.2, 64.1, 53.0; HRMS ESI (70 eV) for C20H15O5
[MþH]þ calcd: 335.0920, found: 335.0915.
6.22. Methyl 2-(2-ethoxycarbonylvinyl)-3-hydroxybenzoate
(44)
6.19. Methyl 3-acetoxy 2-(2-ethoxycarbonyl-vinyl)-benzoate
(34)
This compound was prepared as a white solid in 94% yield
from 43, following the procedure for the preparation of com-
pound 14. The crude product was purified by column chroma-
tography on silica gel (Rf 0.55, 1:3 ethyl acetate/petroleum
ether) to furnish pure compound 44. Mp: 120e123 ꢁC; nmax
(KBr, cmꢀ1): 3354, 1718 (s), 1680 (s), 1624, 1595, 1460,
This compound was prepared as a white solid in 96% yield
from 44, following the procedure for the preparation of com-
pound 22. The crude product was purified by column

S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
3263
1436, 1373, 1338, 1294 (s), 1196, 1170, 1136, 1010, 987, 765.
1H NMR (300 MHz, CDCl3): d 8.11 (d, 1H, J¼16.3 Hz), 7.44
(d, 1H, J¼8.1 Hz), 7.25 (t, 1H, J¼8.1 Hz), 7.11 (d, 1H,
J¼8.1 Hz), 6.66 (d, 1H, J¼16.3 Hz), 4.29 (q, 2H, J¼7.2 Hz),
3.90 (s, 3H), 1.35 (t, 3H, J¼7.2 Hz); 13C NMR (50 MHz,
CDCl3): d 168.6, 168.3, 156.0, 139.8, 132.4, 129.7, 123.1,
122.0, 121.3, 120.0, 61.0, 52.5, 14.1. Anal. Calcd for
C13H14O5: C, 62.39; H, 5.64. Found: C, 62.50; H, 5.56.
extracts were washed with brine, dried (anhydrous Na2SO4),
and concentrated. Purification of the crude product by column
chromatography on silica gel (Rf 0.50, 1:10 ethyl acetate/
petroleum ether) provided 48 (290 mg, 30%) as a white solid.
Mp: 71e73 ꢁC; nmax (KBr, cmꢀ1): 3414, 1720, 1658, 1472,
1
1437, 1298, 1225, 1185, 1045, 998, 945, 882, 833, 731; H
NMR (200 MHz, CDCl3): d 11.55 (s, 1H), 9.91 (s, 1H), 7.36
(d, 1H, J¼8.7 Hz), 6.98 (d, 1H, J¼8.7 Hz), 3.97 (s, 3H),
2.29 (s, 3H); 13C NMR (50 MHz, CDCl3): d 194.9 (CH),
167.8, 160.4, 139.0 (CH), 136.0, 126.7, 119.5 (CH), 116.7,
52.6 (OCH3), 18.6 (CH3). Anal. Calcd for C10H10O4: C,
61.85; H, 5.19. Found: C, 61.98; H, 5.09.
6.23. Methyl 5-amino-2-methylbenzoate (46)23
To a well-stirred solution of methyl o-toluate (45) (6.0 g.
40.0 mmol) at 0e5 ꢁC was added dropwise a solution of ni-
trating agent (a mixture of 4.0 mL concentrated H2SO4 and
4.0 mL concentrated HNO3, cooled to 0e5 ꢁC). The resulting
reaction mixture was further stirred for 2 h at this temperature.
The mixture was then poured into 100 g of crushed ice and
stirred for few minutes. A white solid appeared, which was fil-
tered and washed with H2O and dried under vacuum. 1H NMR
of the crude solid indicated the presence of methyl 2-methyl-
5-nitrobenzoate and its corresponding ortho-isomer in 5:3
ratio. Methyl 2-methyl-5-nitrobenzoate was separated by frac-
tional crystallization from MeOH and H2O system to give it as
a white solid. This solid was dissolved in dry ethanol (50 mL)
was hydrogenated in the presence of 10% PdeC (250 mg) at
atmospheric pressure during 16 h. The catalyst was removed
by filtration and the filtrate was concentrated. After chromato-
graphic purification on silica gel (Rf 0.50, 1:1 ethyl acetate/
petroleum ether), compound 46 (3.10 g, 47%) was obtained
6.26. Methyl 6-methylcoumarin-5-carboxylate (49)
(Carboethoxymethylene)triphenylphosphorane
(765 mg,
2.2 mmol) was added to a solution of methyl 2-formyl-3-
hydroxy-6-methylbenzoate (48) (388 mg, 2 mmol) in Et2NPh
(10 mL), and the resulting reaction mixture was heated at re-
flux for 20 min. After cooling, the mixture was diluted with
water (30 mL) and extracted with ethyl acetate (3ꢂ40 mL).
The combined organic extracts were washed with 5% HCl
(20 mL), brine (20 mL), dried (anhydrous Na2SO4), and con-
centrated. The residue was column chromatographed on silica
gel (Rf 0.50, 1:4 ethyl acetate/petroleum ether) to provide 49
(415 mg, 95%) as a white solid. Mp: 90e93 ꢁC; nmax (KBr,
cmꢀ1): 1752 (s), 1722 (s), 1628, 1583, 1438, 1380, 1292
1
(m), 1252 (m), 1182, 1115, 1047, 1006, 928, 889, 822; H
NMR (200 MHz, CDCl3): d 7.83 (d, 1H, J¼10.0 Hz), 7.39
(d, 1H, J¼8.6 Hz), 7.31 (d, 1H, J¼8.6 Hz), 6.45 (d, 1H,
J¼10.0 Hz), 3.99 (s, 3H), 2.41 (s, 3H); 13C NMR (50 MHz,
CDCl3): d 167.4, 159.8, 152.1, 140.6 (CH), 133.8 (CH),
132.4, 130.5, 118.4 (CH), 117.3 (CH), 116.2, 52.5 (CH3),
19.6 (CH3); MS EI (70 eV): 218 (Mþ, 100%), 187, 159,
131. Anal. Calcd for C12H10O4: C, 66.05; H, 4.62. Found:
C, 66.21; H, 4.47.
1
as a colorless oil. H NMR (200 MHz, CDCl3): d 7.25 (d,
1H, J¼2.6 Hz), 7.00 (d, 1H, J¼8.0 Hz), 6.74 (dd, 1H,
J¼8.0, 2.6 Hz), 3.86 (s, 3H), 2.45 (s, 3H).
6.24. Methyl 5-hydroxy-2-methylbenzoate (47)
To a stirred solution of methyl 5-amino-2-methylbenzoate
(46) (4.5 g, 27.27 mmol) in a mixture of H2O (75 mL) and
concentrated H2SO4 (4.4 mL) was added dropwise NaNO2 so-
lution (1.88 g, 27.27 mmol in H2O (10 mL)) at 0e5 ꢁC. At the
end of the addition, the cooling bath was removed and the re-
action mixture was allowed to warm to room temperature and
then heated at reflux for 0.5 h. On cooling, crystals deposited
were collected by filtration and recrystallized from ethyl ace-
tate/petroleum ether system to give 47 (2.95 g, 66%) as a white
solid (Rf 0.40, 3:7 ethyl acetate/petroleum ether). Mp: 75e
6.27. 6-Hydroxy-10-methoxy-1-methylbenzo[h]chromeno-
[5,4,3-cde]chromene-5,12-dione (51)
This compound was prepared as a yellow crystalline solid
in 86% yield by the reaction between 49 and 50 according
to the general procedure described in Section 6.2. The crude
product was purified by column chromatography on silica
gel (Rf 0.50, 1:1 ethyl acetate/petroleum ether) to furnish 51.
Mp: 237e239 ꢁC; nmax (KBr, cmꢀ1): 3440, 1739 (s), 1697
(s), 1585, 1500, 1450, 1376 (m), 1319, 1255 (m), 1155 (m),
1043, 773; 1H NMR (200 MHz, CDCl3): d 11.57 (s, 1H),
8.06 (d, 1H, J¼8.4 Hz), 7.59 (t, 1H, J¼8.1 Hz), 7.54 (d, 1H,
J¼8.4 Hz), 7.46 (d, 1H, J¼8.4 Hz), 7.19 (d, 1H, J¼7.8 Hz),
4.09 (s, 3H), 2.88 (s, 3H); 13C NMR (125 MHz, CDCl3):
d 165.1, 159.5, 157.6, 157.2, 146.7, 140.3, 139.3, 132.9
(CH), 128.5 (CH), 127.1, 121.1 (CH), 120.3, 119.0, 117.9,
116.5 (CH), 111.7 (CH), 108.6, 96.7, 56.7 (CH3), 22.6
(CH3); MS EI (70 eV): 348 (Mþ), 333, 320, 305, 284, 273,
256, 236, 214, 198, 172, 69, 54 (100%). Anal. Calcd for
C20H12O6: C, 68.97; H, 3.47. Found: C, 69.21; H, 3.32.
1
76 ꢁC (lit.24 mp: 74e76 ꢁC); H NMR (200 MHz, CDCl3):
d 7.40 (d, 1H, J¼2.7 Hz), 7.09 (d, 1H, J¼8.3 Hz), 6.91 (dd,
1H, J¼8.3, 2.7 Hz), 3.87 (s, 3H), 2.49 (s, 3H).
6.25. Methyl 2-formyl-3-hydroxy-6-methylbenzoate (48)
Hexamethylenetetramine (700 mg, 5 mmol) was added to
a stirred solution of methyl 5-hydroxy-2-methylbenzoate
(47) (830 mg, 5 mmol) in 80% polyphosphoric acid (4 mL)
at 100 ꢁC and the reaction mixture was stirred for 45 min. Af-
ter cooling, the mixture was diluted with cold water (100 mL)
and extracted with ethyl acetate (3ꢂ50 mL). The combined

3264
S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
6.28. 6-Hydroxy-4,4-dimethoxy-4H-11-oxa-
benzo[def]chrysene-5,12-dione (53)
MS ESI (70 eV): 316 (Mþ), 288, 273, 256, 236, 232, 208.
Anal. Calcd for C19H8O5: C, 72.16; H, 2.55. Found: C, 71.96;
H, 2.41. The poor solubility of this compound in deuterated
solvent prevented us from recording 13C NMR data.
This compound was prepared as a yellow solid in 87%
yield by the condensation between 24 and 52 according to
the general procedure described in Section 6.2. The crude
product was purified by column chromatography on silica
gel (Rf 0.60, 1:1 ethyl acetate/petroleum ether) to furnish 53.
Mp: 175e177 ꢁC; nmax (KBr, cmꢀ1): 3434, 1733 (s), 1624
(m), 1578 (m), 1496 (m), 1454 (m), 1380 (m), 1319, 1275
(m), 1220, 1159, 1070 (s), 981 (m), 768; 1H NMR
(200 MHz, CDCl3): d 13.48 (s, 1H), 8.51e8.44 (m, 3H),
8.16 (dd, 1H, J¼7.6, 1.1 Hz), 7.83 (dt, 1H, J¼7.7, 1.2 Hz),
7.73 (t, 1H, J¼7.8 Hz), 7.68 (dt, 1H, J¼7.6, 1.1 Hz), 3.41 (s,
6H); 13C NMR (50 MHz, CDCl3): d 195.6, 160.7, 160.0,
139.0, 134.3, 132.9, 131.7, 131.3, 130.5, 129.1, 128.2,
127.9, 125.5, 124.7, 122.0, 120.7, 108.4, 104.2, 95.1, 52.2;
MS EI (70 eV): 362 (Mþ), 331 (100%), 315, 302, 288, 273,
257, 232, 204, 176, 150, 144. Anal. Calcd for C21H14O6: C,
69.61; H, 3.89. Found: C, 69.72; H, 3.82.
6.31. 5-Hydroxy-10-methoxy-4H-benzo[2,3]phenanthro-
[4,5-bcd]pyran-4,6,12-trione (56)
This compound was prepared as a brown solid in 98% yield
from 54, following the procedure for the preparation of com-
pound 55. The solid precipitate obtained after reaction was
collected by filtration and thoroughly washed with MeOH/
H2O to give pure 56. Mp: 375e377 ꢁC; nmax (KBr, cmꢀ1):
3436, 1741 (s), 1687, 1633, 1591, 1490, 1456, 1384, 1348,
1
1324, 1265 (s), 1105, 1070, 1039, 1002, 808, 746, 671; H
NMR (500 MHz, CDCl3): d 14.52 (s, 1H), 8.71 (d, 1H,
J¼7.4 Hz), 8.64 (d, 1H, J¼7.5 Hz), 8.20 (d, 1H, J¼7.8 Hz),
7.77 (t, 1H, J¼8.3 Hz), 7.69 (t, 1H, J¼8.4 Hz), 7.34 (d, 1H,
J¼7.7 Hz), 4.14 (s, 3H); MS ESI (70 eV): [MþH]þ
347.0500, [MꢀCO2] 302.1913. Anal. Calcd for C20H10O6:
C, 69.37; H, 2.91. Found: C, 69.45; H, 2.84. The poor solubil-
ity of this compound in deuterated solvents prevented us from
recording 13C NMR data.
6.29. 6-Hydroxy-10-methoxy-4,4-dimethoxy-4H-11-oxa-
benzo[def]chrysene-5,12-dione (54)
This compound was prepared as a yellow solid in 87% yield
by the condensation between 52 and 50, according to the general
procedure of annulation described in Section 6.2. The crude
product was purified by column chromatography on silica gel
(Rf 0.60, 1:3 ethyl acetate/petroleum ether) to furnish 54. Mp:
176e178 ꢁC; nmax (KBr, cmꢀ1): 3438, 1735 (s), 1639, 1602,
1582, 1511, 1488, 1457, 1427, 1382, 1344, 1313, 1268, 1214,
6.32. 6-Benzyloxy-2-methylene-3,4-dihydro-2H-naphthalen-
1-one (58)
To a stirred solution of N-methylanilinium trifluroacetate
(210 mg, 0.95 mmol) in THF (10 mL) at room temperature,
was added paraformaldehyde (110 mg, 1.2 mmol), followed
by a solution of 57 (200 mg, 0.79 mmol) in THF (2 mL)
over a period of 0.5 h. The resulting solution was heated at re-
flux for about 6 h. After completion of the reaction, the reac-
tion mixture was cooled and diluted with ether (50 mL). The
ether layer was washed with saturated aqueous sodium bicar-
bonate solution (2ꢂ10 mL) and water (2ꢂ10 mL). The or-
ganic layer was dried (anhydrous Na2SO4), filtered, and
concentrated under reduced pressure. Column chromatography
of the residue afforded naphthalen-1-one 58 as a low melting
solid (120 mg, 58%). Rf 0.65 (1:3 ethyl acetate/petroleum
ether); nmax (KBr, cmꢀ1): 3029, 2935, 1945, 1594, 1301,
1232, 1103, 991, 802, 694; 1H NMR (200 MHz, CDCl3):
d 8.07 (d, 1H, J¼8.7 Hz), 7.34e7.40 (m, 5H), 6.91 (dd, 1H,
J1¼2.5 Hz, J2¼8.7 Hz), 6.77 (d, 1H, J¼2.3 Hz), 6.16 (s,
1H), 5.39 (d, 1H, J¼1.5 Hz), 5.10 (s, 2H), 2.94 (t, 2H,
J¼5.7 Hz), 2.82 (t, 2H, J¼5.5 Hz); 13C NMR (50 MHz,
CDCl3): d 186.3, 162.8, 146.6, 143.4, 136.2, 130.4, 128.6,
128.2, 127.4, 126.9, 121.0, 114.0, 113.5, 70.0, 31.7, 30.0;
HRMS ESI (70 eV) for C18H17O2 [MþH]þ calcd: 265.1229,
found: 265.1225.
1
1201, 1103, 1085, 1070, 1037, 1006, 827, 808, 757, 748; H
NMR (300 MHz, CDCl3): d 13.54 (s, 1H), 8.48 (dd, 1H,
J¼7.8, 1.1 Hz), 8.15 (dd, 1H, J¼8.7, 1.1 Hz), 8.12 (d, 1H,
J¼8.1 Hz), 7.72 (t, 1H, J¼7.8 Hz), 7.58 (t, 1H, J¼8.1 Hz),
7.24 (d, 1H, J¼8.1 Hz), 4.12 (s, 3H), 3.40 (s, 6H); 13C NMR
(50 MHz, CDCl3): d 195.8, 160.4, 160.3, 157.4, 140.6, 134.1,
132.6, 131.2, 131.0, 129.0, 128.8, 128.2, 120.3, 119.6, 116.8,
113.0, 108.5, 104.9, 95.2, 56.6, 52.3; HRMS ESI (70 eV) for
C22H17O7 [MþH]þ calcd: 393.0974, found: 393.0970.
6.30. 5-Hydroxy-4H-benzo[2,3]phenanthro[4,5-bcd]pyran-
4,6,12-trione (55)
To a well-stirred solution of a ketal 53 (725 mg, 2 mmol) in
methanol (10 mL) at room temperature was added 10% HCl so-
lution (10 mL) and stirring was continued for 1 h. A solid pre-
cipitate appeared. The resulting precipitate was collected by
filtration and thoroughly washed with MeOH/H2O to give 55
(620 mg, 98%) as an amorphous brown-red solid. Mp: 370e
372 ꢁC; nmax (KBr, cmꢀ1): 3452, 3085, 1747 (s), 1689, 1637,
1606, 1589, 1569, 1512, 1494, 1463, 1440, 1390, 1348, 1299,
6.33. 6-Benzyloxy-2-methyl-3,4-dihydro-2H-naphthalen-1-
one (59)
1
1280, 1205, 1137, 1074, 998, 889, 846, 802, 759, 682; H
NMR (200 MHz, CDCl3): d 14.32 (s, 1H), 8.71 (dd, 1H,
J¼7.8, 1.2 Hz), 8.65 (dd, 1H, J¼7.8, 1.1 Hz), 8.56 (dd, 1H, J¼
7.8, 1.1 Hz), 8.52 (dd, 1H, J¼7.8, 1.1 Hz), 7.92 (dt, 1H, J¼7.8,
1.1 Hz), 7.79 (t, 1H, J¼7.8 Hz), 7.77 (dt, 1H, J¼7.8, 1.1 Hz);
To a stirred solution of 58 (100 mg, 0.38 mmol) in acetic
acid (4 mL) was added Zn dust (74.3 mg, 1.04 mmol) in por-
tions over a period of 5 min. The resulting mixture was heated

S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
3265
1
at reflux for 1.5 h. After completion of the reaction, the reac-
tion mixture was cooled and diluted with ether (50 mL). The
ether layer was washed with aqueous sodium bicarbonate so-
lution (2ꢂ10 mL) and water (2ꢂ10 mL). The organic layer
was dried (anhydrous Na2SO4), filtered, and concentrated un-
der reduced pressure. Column chromatography of the residue
afforded naphthalen-1-one 59 as a yellow oil (50 mg, 47%).
Rf 0.65 (1:4 ethyl acetate/petroleum ether); nmax (KBr, cmꢀ1):
1010, 811, 698; H NMR (200 MHz, CDCl3): d 7.22e7.42
(m, 6H), 6.75e6.84 (m, 2H), 5.05 (s, 2H), 2.76 (t, 2H,
J¼7.4 Hz), 2.32 (t, 2H, J¼7.9 Hz), 2.14 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 174.5, 157.7, 141.4, 137.1, 136.5, 128.6,
127.9, 127.4, 126.2, 125.8, 125.0, 114.5, 112.2, 70.0, 30.9,
28.1, 21.8; HRMS ESI (70 eV) for C19H17O3 [MꢀH]þ calcd:
293.1178, found: 293.1165.
1
3064, 2931, 1600, 1454, 1375, 1249, 1159, 1025, 696; H
6.36. 6-Benzyloxy-2-methyl-3,4-dihydro-naphthalene-1-
NMR (200 MHz, CDCl3): d 8.01 (d, 1H, J¼8.7 Hz), 7.31e
7.44 (m, 5H), 6.89 (dd, 1H, J1¼2.4 Hz, J2¼8.7 Hz), 6.76 (d,
1H, J¼2.3 Hz), 5.11 (s, 2H), 2.92e3.00 (m, 2H), 2.49e2.58
(m, 1H), 2.10e2.22 (m, 1H), 1.82e1.89 (m, 1H), 1.23 (d,
3H, J¼6.81 Hz); 13C NMR (50 MHz, CDCl3): d 199.5,
162.5, 146.6, 136.3, 129.8, 128.6, 128.2, 127.4, 126.2, 113.7,
113.4, 70.0, 42.2, 31.4, 29.1, 15.5; HRMS ESI (70 eV) for
C18H19O2 [MþH]þ calcd: 267.1385, found: 267.1383.
carboxylic acid methyl ester (62)
To a stirred solution of 61 (100 mg, 0.34 mmol) in acetoni-
trile (3 mL) was added DBU (0.05 mL, 51.7 mg, 0.34 mmol)
and the reaction stirred for 10 min. Then iodomethane
(0.1 mL, 241.5 mg, 1.7 mmol) was added to this mixture and
stirring continued for 4 h at room temperature. The reaction
mixture was then diluted with water and extracted with ether
(2ꢂ50 mL). The organic layer was washed successively with
hydrochloric acid (5 mL), water (10 mL), saturated aqueous
solution of sodium thiosulfate (5 mL), and brine. The organic
layer was dried (anhydrous Na2SO4), filtered, and concen-
trated under reduced pressure. Column chromatography of
the residue afforded ester 62 as a yellow oil (100 mg, 96%).
Rf 0.70 (1:4 ethyl acetate/petroleum ether); nmax (KBr,
cmꢀ1): 3490, 2948, 1724, 606, 1500, 1257, 1018, 804, 698;
1H NMR (200 MHz, CDCl3): d 7.30e7.45 (m, 5H), 6.95e
7.03 (m, 1H), 6.71e6.79 (m, 2H), 5.04 (s, 2H), 3.86 (s, 3H),
2.77 (t, 2H, J¼7.5 Hz), 2.28 (t, 2H, J¼8.1 Hz), 2.0 (s, 3H),
13C NMR (50 MHz, CDCl3): d 169.7, 157.7, 137.9, 137.0,
136.2, 128.5, 127.9, 127.4, 127.3, 125.2, 125.1, 114.5,
112.1, 69.9, 51.6, 30.0, 28.0, 21.3; HRMS ESI (70 eV) for
C20H21O3 [MþH]þ calcd: 309.1491, found: 309.1478.
6.34. 7-Benzyloxy-4-bromo-3-methyl-1,2-dihydro-
naphthalene (60)
To a stirred solution of 59 (100 mg, 0.38 mmol) in dry
benzene (4 mL), phosphorus tribromide (0.05 mL, 153 mg,
0.56 mmol) was added dropwise over a period of 5 min. The re-
sulting mixture was heated at reflux for 2 h. After completion of
the reaction, the reaction mixture was cooled and diluted with
ether (50 mL). The ether layer was washed with water
(2ꢂ10 mL), dried (anhydrous Na2SO4), filtered, and concen-
trated under reduced pressure. Column chromatography of the
residue afforded 1,2-dihydro-naphthalene 60 as a yellow oil
(65 mg, 53%). Rf 0.70 (1:4 ethyl acetate/petroleum ether);
nmax (KBr, cmꢀ1): 3421, 2925, 1598, 1494, 1259, 1024, 798,
696; 1H NMR (200 MHz, CDCl3): d 7.32e7.53 (m, 6H),
6.73e6.83 (m, 2H), 5.06 (s, 2H), 2.76 (t, 2H, J¼7.4 Hz), 2.37
(t, 2H, J¼7.6 Hz), 2.08 (s, 3H); 13C NMR (50 MHz, CDCl3):
d 157.9, 137.0, 136.9, 134.2, 128.5, 127.9, 127.7, 127.6,
127.4, 117.6, 113.9, 111.9, 70.0, 31.4, 28.2, 24.2; HRMS ESI
(70 eV) for C18H18BrO [MþH]þ calcd: 329.0541, found:
329.0526.
6.37. 6-Benzyloxy-2-methyl-naphthalene-1-carboxylic acid
methyl ester (63)
To a stirred solution of 62 (80 mg, 0.26 mmol) in dry benz-
ene (5 mL), DDQ (120 mg, 0.52 mmol) was added and the
reaction heated at reflux for 12 h. After completion of the re-
action the mixture was cooled and filtered. Then the filtrate
was concentrated and column chromatography of the crude
gave methyl ester (63) as oil (62 mg, 78%). Rf 0.70 (1:3 ethyl
acetate/petroleum ether); nmax (KBr, cmꢀ1): 2962, 1724, 1600,
6.35. 6-Benzyloxy-2-methyl-3,4-dihydro-naphthalene-1-
carboxylic acid (61)
1
A stirred solution of 60 (100 mg, 0.30 mmol) in dry THF
(5 mL) was cooled to ꢀ78 ꢁC. To it n-butyllithium
(0.24 mL, 1.6 M, 0.39 mmol) was added dropwise and stirred
for 1 h. Then dry CO2 was passed through this solution for 1 h
at ꢀ78 ꢁC. Afterward, the reaction mixture was stirred at room
temperature for 3 h under a CO2 atmosphere. After completion
of the reaction, the reaction mixture was diluted with ethyl ace-
tate (50 mL). The organic layer was washed with hydro-
chloric acid (15 mL) and water (2ꢂ10 mL). This was dried
(anhydrous Na2SO4), filtered, and concentrated under reduced
pressure. Column chromatography of the residue afforded
carboxylic acid 61 as a white solid (52 mg, 58%). Rf 0.20
(2:1 ethyl acetate/petroleum ether); mp: 98e99 ꢁC; nmax
(KBr, cmꢀ1): 2861, 1689, 1500, 1427, 1326, 1251, 1122,
1411, 1261, 1020, 800, 698; H NMR (200 MHz, CDCl3):
d 7.23e7.48 (m, 10H), 5.17 (s, 2H), 4.03 (s, 3H), 2.47 (s,
3H); 13C NMR (50 MHz, CDCl3): d 170.2, 156.3, 136.7,
132.8, 131.1, 129.9, 129.9, 128.6, 128.0, 127.5, 126.1,
125.6, 120.0, 107.5, 70.0, 52.1, 19.9; HRMS ESI (70 eV) for
C20H19O3 [MþH]þ calcd: 307.1334, found: 307.1348.
6.38. 6-Hydroxy-2-methyl-naphthalene-1-carboxylic acid
methyl ester (64)
To a stirred solution of 63 (100 mg, 0.33 mmol) in dry
methanol (5 mL), were added formic acid (2 drops) and
PdeC (50 mg). The resulting mixture was stirred under H2 at-
mosphere for 6 h. After completion of the reaction the mixture

3266
S. Ray et al. / Tetrahedron 64 (2008) 3253e3267
was filtered through Celite. The filtrate was concentrated and
column chromatography of the crude gave methyl ester 64
as an oil (35 mg, 70%). Rf 0.50 (1:3 ethyl acetate/petroleum
ether); nmax (KBr, cmꢀ1): 2962, 1704, 1513, 1263, 1097,
802, 663; 1H NMR (200 MHz, CDCl3): d 7.58e7.73 (m,
2H), 7.26 (d, 1H, J¼3.2 Hz), 7.06e7.14 (m, 2H), 4.03 (s,
3H), 2.45 (s, 3H); 13C NMR (50 MHz, CDCl3): d 171.0,
153.4, 132.9, 130.8, 129.5, 128.8, 128.3, 126.1, 125.1,
119.0, 109.8, 52.3, 19.8; HRMS ESI (70 eV) for C13H13O3
[MþH]þ calcd: 217.0865, found: 217.0865.
solution (5 mL) and stirring was continued for 1 h. A solid
precipitate appeared. The precipitate was collected by filtra-
tion and thoroughly washed with MeOH/H2O to give 67
(62 mg, 98%) as an amorphous deep violet solid: mp:
>300 ꢁC; nmax (KBr, cmꢀ1): 3438, 2362, 1731, 1596, 1459,
1
1272, 1072, 798, 470; H NMR (200 MHz, CDCl3): d 14.8
(s, 1H), 8.51 (d, 1H, J¼7.98 Hz), 8.16 (dd, 1H, J1¼8.28 Hz,
J2¼0.92 Hz), 7.32e7.72 (m, 3H), 4.12 (s, 3H), 2.99 (s, 3H);
HRMS ESI (70 eV) for C21H13O6 [MþH]þ calcd: 361.0712,
found: 361.0730. The poor solubility of this compound in deu-
terated solvent prevented us from recording 13C NMR data.
6.39. 5,5-Dimethoxy-2-methyl-6-oxo-5,6-dihydro-
naphthalene-1-carboxylic acid methyl ester (65)
Acknowledgements
A stirred solution of 64 (100 mg, 0.46 mmol) in dry meth-
anol (3 mL) under nitrogen atmosphere was cooled to 0 ꢁC. To
it iodobenzenediacetate (327.9 mg, 1.02 mmol) was added and
the mixture stirred for 2 h at 0 ꢁC. Then the mixture was
slowly warmed to room temperature. The reaction mixture
was then extracted with ether (2ꢂ50 mL). The organic layer
was then washed successively with sodium bicarbonate satu-
rated solution (5 mL) and brine. Then the organic layer was
dried (anhydrous Na2SO4), filtered, and concentrated under
reduced pressure. Column chromatography of the residue
afforded ester 65 as yellow oil (90 mg, 70%), which tends to
decompose on standing. Rf 0.55 (1:3 ethyl acetate/petroleum
ether): nmax (KBr, cmꢀ1): 1718, 1680, 1452, 1387, 1276,
1250, 1190, 1146, 1076; 1H NMR (200 MHz, CDCl3):
d 7.66 (d, 1H, J¼7.9 Hz), 7.24e7.36 (m, 2H), 6.14 (d, 1H,
J¼10.6 Hz), 3.97 (s, 3H), 3.26 (s, 6H), 2.31 (s, 3H); 13C
NMR (50 MHz, CDCl3): d 194.9, 168.7, 140.1, 137.1, 135.9,
133.6, 131.6, 129.2, 128.6, 126.1, 95.3, 52.4, 51.9, 51.9, 19.7.
This research was supported by the Department of Science
and Technology, New Delhi. A.P. and S.R. are thankful to
CSIR, New Delhi for their research fellowships.
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6.40. 6-Hydroxy-4,4,10-trimethoxy-1-methyl-4H-11-oxa-
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This compound was prepared as a yellow solid in 78%
yield by condensation between 65 and 50 according to the
general procedure of annulation described in Section 6.2.
The crude product was purified by column chromatography
on silica gel (Rf 0.60, 1:1 ethyl acetate/petroleum ether) to fur-
nish 66. Mp: 115e116 ꢁC; nmax (KBr, cmꢀ1): 2964, 2362,
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3267
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