Room-temperature B(OAc)3-promoted diels-alder reaction of juglone with styrenes: Total syntheses of tetrangulol and anhydrolandomycinone

Article abstract of DOI:10.1021/jo202448e

The Diels-Alder reaction of juglone with various styrenes in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) was promoted by B(OAc)₃ at room temperature. The reaction proceeded smoothly and gave the products in a good yield and with

Full text of DOI:10.1021/jo202448e

Article
pubs.acs.org/joc
Room-Temperature B(OAc)3-Promoted Diels−Alder Reaction of
Juglone with Styrenes: Total Syntheses of Tetrangulol and
Anhydrolandomycinone
Day-Shin Hsu* and Jiun-Yi Huang
Department of Chemistry and Biochemistry, National Chung Cheng University, Minhsiung, Taiwan 621
S
* Supporting Information
ABSTRACT: The Diels−Alder reaction of juglone with various
styrenes in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ ) was promoted by B(OAc)3 at room temperature. The
reaction proceeded smoothly and gave the products in a good yield
and with excellent regioselectivity. This strategy was applied to the
total syntheses of tetrangulol and anhydrolandomycinone.
derivatives,4,5 and this motivated us to use a boron Lewis acid in
INTRODUCTION
Angucyclinones are a large group of naturally occurring quinones
that have a benz[a]anthracenequinone framework (Figure 1) and
■
the Diels−Alder reaction of juglone with styrenes. Herein, we
report the reaction conditions that aid the rapid construction of
the angucyclinone skeleton at low temperatures with high yield
and regioselectivity.
RESULTS AND DISCUSSION
■
(a). Cycloaddition of Juglone and Styrene. At the
outset, styrene (2a) was used to examine the reaction conditions
(Table 1). First, juglone (1 equiv) and B(OAc)36 (1.1 equiv) were
mixed in dichloromethane at room temperature for 10 min and
then, styrene (4 equiv) and DDQ (3 equiv) were added. DDQ
was chosen as the oxidant because we expected the reaction to
proceed at room temperature in the presence of such a strong
oxidant.7 To our delight, the desired product 3a was formed under
these conditions; however, the reaction was not completed even
after 24 h probably because of the polymerization of styrene under
Lewis acid conditions.8 Therefore, additional amounts of B(OAc)3
(1.1 equiv), styrene (4 equiv), and DDQ (3 equiv) were added to
the reaction mixture after 24 h, and this addition was repeated
every 24 h until juglone was completely consumed. Finally, the
reaction was completed after 72 h, and a single product 3a was
obtained in 81% yield (entry 1). The structure of 3a was con-
firmed by comparing its spectral data with those reported in the
literature.3b The reaction with other Lewis acids was also examined
under the same conditions. A strong Lewis acid only resulted in
the polymerization of styrene (entries 2−6), whereas a weak Lewis
acid resulted in the recovery of juglone and styrene (entry 7).
When chloranil was used as the oxidant, a trace amount of 3a was
Figure 1. Structure of angucyclinones.
exhibit a broad range of biological activities.1 Owing to the bio-
logical importance of angucyclinones, considerable attention has
been focused on the development of methods that facilitate
the efficient and rapid syntheses of these compounds. Thus far,
many synthetic methods have been developed for the synthesis of
this class of compounds.2 Among them, the most straightforward
strategy is the Diels−Alder reaction of naphthoquinones with sty-
renes and an oxidant such as chloranil.3 However, these reactions
require harsh conditions and a long time for completion because
styrenes typically act as dienophiles rather than dienes, especially in
the Diels−Alder reaction. Further, the product yield and regios-
electivity of these reactions are poor. Therefore, although these
reactions have been studied for over three decades, their applica-
tions in organic synthesis are limited.
The Lewis-acid-promoted Diels−Alder reaction of juglone
(5-hydroxy-1,4-naphthoquinone)4 and its derivatives5 with dienes
is well-known; however, similar reactions with styrenes are rare.3a,c
Lewis acids increase not only the reactivity but also the regios-
electivity of the substrate.4a,b Boron reagents are the most com-
monly used Lewis acids for reactions involving juglone and its
Received: December 4, 2011
Published: February 22, 2012
© 2012 American Chemical Society
2659
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
Table 1. Various Lewis-acid-promoted Diels−Alder Reactions of Juglone with Styrene in the Presence of an Oxidant
a
entry
Lewis acid
oxidant
solvent
CH2Cl2
temp
time (h)
yield
1
2
3
4
5
6
7
8
9
B(OAc)3
BF3·OEt2
TiCl4
DDQ
rt
72
2
81%
b
DDQ
CH2Cl2
rt
_
b
DDQ
CH2Cl2
rt
2
_
b
FeCl3
DDQ
CH2Cl2
rt
2
_
b
AlCl3
DDQ
CH2Cl2
rt
2
_
c
MgBr2
DDQ
CH2Cl2
rt
72
72
3.5
18
_
c
B(OAc)3
B(OAc)3
B(OAc)3
chloranil
DDQ
CH2Cl2
rt
trace
46%
38%
ClCH2CH2Cl
ClCH2CH2Cl
reflux
reflux
chloranil
a
b
c
Isolated yield. Polymerization of styrene. Recovery of starting materials.
obtained along with the starting materials. Attempts to reduce the
reaction time by increasing the reaction temperature resulted in
lower yields (entries 8−9). Thus, the best yield was observed when
the reaction was carried out at room temperature with B(OAc)3
and DDQ.
cycloadducts from DDQ and styrenes under these conditions.
This was probably because the reactivity of juglone was activated
by B(OAc)3, which could react with styrenes more rapidly than
DDQ.
Under the same conditions, the styrenes 5−911 bearing an
electron-withdrawing group or electron-donating group at the β
position did not yield any cycloadducts and only the starting
materials were recovered (Figure 2).
(b). Cycloaddition of Juglone and Styrene Derivatives.
Under the same reaction conditions mentioned earlier, we
examined the substrate scope of the substituted styrenes.
The results are listed in Table 2. We found that a variety of
styrenes could afford the cycloaddition products 3b−l in moderate
to good yields with complete regiocontrol. Most of these reactions
were completed in 24 h and yielded a single regioisomer 11-
hydroxybenz[a]anthracene-7,12-dione 3. When styrenes with an
electron-donating group were used, the reactions were completed
within 24 h (entries 1−8), whereas when styrenes with an
electron-withdrawing substituent were used, the reactions were
slow and the desired products were obtained in moderate yields
(entries 9−11). Attempts to improve the yields by changing the
reaction temperatures or by using other Lewis acids were un-
successful. It should be mentioned that juglone was completely
consumed in all cases. However, in several cases, the cycloadducts
were obtained in moderate yields, probably because the reaction
also generated intractable materials that were insoluble or did not
elute on silica gel. In the case of entry 2, two regioisomers 3c and
3c′ were obtained in a 2:1 ratio and they could not be separated
by column chromatography. The 3c:3c′ ratio was determined by
1H NMR analysis. However, the pure major isomer 3c could be
obtained by recrystallization. 3c′ was obtained as the minor pro-
duct probably because of the steric clash between the methyl and
carbonyl groups. A similar result was also observed for styrene 2f
(entry 5). In the case of entry 4, the yield of 3e decreased owing
to the formation of an additional byproduct 4e. Attempts to
suppress the formation of this byproduct by using other Lewis
acids or by changing the reaction temperatures were unsuccessful.
It is noteworthy that the cycloadduct 3i (entry 8) was formed in
24 h at room temperature in 44% yield. In an earlier study, this
compound was prepared using the same starting materials
juglone and styrene 2iin refluxing toluene, but the reaction
required 6 days and provided 37% yield.9 Although the yields from
both the strategies were similar, our strategy was easy to handle
and required mild reaction conditions and a shorter reaction time.
It should be mentioned that DDQ can also be used as a dieno-
phile10 in the cycloaddition; however, we did not observe any
The structure of 3 was elucidated by carrying out IR, 1H and
13C NMR, and low- and high-resolution mass spectral analyses.
The position of the hydroxyl group in 3 was determined by
performing an HMBC experiment. The HMBC spectra of 3
revealed two cross-peaks between one carbonyl group and
hydrogen atom but no cross-peak between the other carbonyl
group and hydrogen atom (Figure 3).
(c). Mechanism and Structural Effects of Diels−Alder
Reaction. The mechanism of the Diels−Alder reaction of
juglone and styrenes is proposed on the basis of the above
results and is depicted in Schemes 2 and 3. First, juglone and
B(OAc)3 formed a boroacetate complex 10,4a which activated
the C-2 position of juglone. Then, the β carbon of the styrenes
facilitated addition at this position, and a benzylic carbocation
intermediate 11 was formed (Scheme 1). Subsequent cyclization
formed 12, which was further transformed into 13 via tauto-
merization and double bond isomerization. Finally, oxidation with
DDQ yielded the cycloadducts 3. Thus, the cycloaddition reaction
proceeded fast with an electron-rich styrene, whereas it proceeded
slowly or did not proceed at all with an electron-deficient styrene.
The lone pair on the oxygen atom at the para-position in
styrene could stabilize the benzylic carbocation intermediate 14
through resonance (Scheme 2). Consequently, the tautomeri-
zation of 15 and the subsequent oxidation of the tautomeric
form 16 by DDQ may proceed more easily than cyclization and
result in the formation of naphthoquinone 17. Finally, acetate may
attack the benzylic position in 17 to form naphthoquinone 4e.
(d). Total Syntheses of Tetrangulol and Anhydrolan-
domycinone. After the efficient regiocontrolled synthesis of
angucyclinones, we decided to apply our strategy to the total
syntheses of tetrangulol and anhydrolandomycinone. Tetrangu-
lol, which was isolated from Streptomyces rimosus,12 is the first
member of the family of naturally occurring angucyclinones.
Anhydrolandomycinone was isolated from Streptomyces cyano-
genus S-136 in 2011;13 however, in 1990, it was identified as the
2660
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
Table 2. Yields for B(OAc)3-promoted Diels−Alder Reaction
of Juglone with Various Styrenes in the Presence of DDQ at
Room Temperature
Figure 2. Styrenes not yielding any cycloadducts.
Figure 3. Key HMBC correlations to establish structure of 3.
Scheme 1. Plausible Mechanism to Form 3
Scheme 2. Plausible Mechanism to Form 4e
from the same intermediate 20. This common intermediate 20
was synthesized using our proposed strategy, that is, the Diels−
Alder reaction of O-methylnaphthazarin 21 and bromostyrene 2k.
The bromostyrene 2k was prepared from 2215 via a benzylic
oxidation followed by the Wittig reaction (Scheme 4). The role
of bromine in 2k was set to control the orientation of the
Diels−Alder reaction with 21. Two regioisomers might be
obtained in the Diels−Alder reaction without bromine in 2k.
With bromostyrene 2k in hand, the tetracyclic compound 20
was obtained as a single isomer in 63% yield from the
regiocontrolled intermolecular Diels−Alder reaction of 2116
with 2k in the presence of B(OAc)3 and DDQ (Scheme 5).
The next step in the synthesis of tetrangulol was the removal of
a
Isolated yield.
dehydration product of landomycinone.14 Anhydrolandomyci-
none shows cytotoxicity against both the human breast cancer
cell lines MCF-7 and MAD-231.13
Our retrosynthetic analysis is summarized in Scheme 3.
Tetrangulol and anhydrolandomycinone could be obtained
2661
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
palladium-catalyzed formate reduction; however, the reaction
was not successful. The reaction was not completed even after
the addition of an excess amount of reagents or a considerable
extension of the reaction time. However, this issue was resolved by
converting the phenolic hydroxyl group to methyl ether before the
reduction, and then, the desired debromination product 27 was
obtained in good yield (Scheme 6). Global deprotection of the
Scheme 3. Retrosynthetic Analysis
Scheme 6. Total Synthesis of Anhydrolandomycinone
Scheme 4. Preparation of Bromostyrene 2k
methyl ether with BBr3 gave the target molecule anhydrolando-
mycinone (19). The spectral data were in good agreement with
those reported in the literature.14
CONCLUSION
■
In summary, we developed a simple strategy for the synthesis of
angucyclinones; B(OAc)3 was used as a Lewis acid to promote
the Diels−Alder reaction of juglone with various styrenes in
the presence of DDQ at room temperature. We successfully
applied this strategy to the total syntheses of tetrangulol and
anhydrolandomycinone from O-methylnaphthazarin 21 and
styrene 2k.
Scheme 5. Total Synthesis of Tetrangulol
EXPERIMENTAL SECTION
■
General Information. Unless stated otherwise, reagents were
obtained from commercial sources and used without further purification.
All reactions were performed under a nitrogen atmosphere in anhydrous
solvents, which were dried prior to use following standard procedures.
Reactions were monitored by thin-layer chromatography on 0.25 mm E.
Merck silica gel plates (60F-254) using 7% ethanolic phosphomolybdic
acid as developing agent. Merck silica gel 60 (particle size 0.04−0.063 mm)
was employed for flash chromatography. Melting points are uncorrected. IR
1
spectra were recorded as films on KBr plates. H NMR spectra were
obtained in CDCl3 unless otherwise noted at 400 or 500 MHz. 13C NMR
spectra were obtained at 100 or 125 MHz. Chemical shifts were reported in
δ (ppm) using solvent resonance as the internal reference.
General Procedure for the Diels−Alder Reaction of Juglone
and Styrenes. A mixture of juglone (1) (187 mg, 1 mmol) and
B(OAc)3 (206 mg, 1.1 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature for 10 min and then styrene derivative (4 mmol) and
DDQ (680 mg, 3 mmol) were added to the reaction mixture. After
stirred at room temperature for 24 h, additional B(OAc)3 (206 mg, 1.1
mmol), styrene derivatives (4 mmol), and DDQ (680 mg, 3 mmol)
were added to the reaction mixture, and this addition was repeated
every 24 h until juglone was completely consumed. The reaction was
quenched with saturated aqueous NaHCO3, and extracted with
CH2Cl2. The combined organic extracts were washed successively with
water, brine, dried over MgSO4, filtered and concentrated. The crude
product was recrystallizd from CH3CN to give 3. The filtrate was
further purified by flash silica-gel chromatography (hexanes/CH2Cl2)
to give additional 3. Analytically pure 3 was obtained by crystallization
from CH2Cl2−hexane.
the hydroxyl group and bromine. For this purpose, the deoxy-
genation and debromination of 20 were carried out by the
conversion of 20 to triflate 24 and by palladium-catalyzed
formate reduction.17 Finally, deprotection of the methyl ethers
in 25 by BBr3 gave tetrangulol (18).18
Next, we focused on the synthesis of anhydrolandomy-
cinone through the removal of the bromine moiety in 20 by
2662
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
11-Hydroxybenz[a]anthracene-7,12-dione (3a). Red solid; mp
202−204 °C; IR (neat) ν 1664, 1631, 1459, 1381, 1297, 1226, 1209,
145−147 °C; IR (neat) ν 1728, 1645, 1610, 1513, 1456, 1366, 1236,
1175, 1027, 760 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.89 (s, 1H),
7.65−7.60 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 1H),
6.88 (d, J = 8.5 Hz, 2H), 6.70 (s, 1H), 5.99 (dd, J = 9.0, 5.0 Hz, 1H),
3.78 (s, 3H), 3.14 (dd, J = 14.0, 5.0 Hz, 1H), 2.98 (dd, J = 14.0, 9.0
Hz, 1H), 2.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.9, 183.9,
170.1, 161.2, 159.6, 148.3, 136.5, 136.3, 131.9, 131.4, 127.8, 124.3,
119.5, 115.0, 114.0, 73.4, 55.2, 37.0, 21.1; MS (EI) m/z (% base peak)
366 (M+, 3), 324 (29), 306 (21), 291 (5), 247 (4), 218 (4), 188 (14),
137 (100), 109 (15) 92 (20); HRMS (EI) calcd for C21H18O6
366.1103, Found 366.1105.
11-Hydroxy-3-methoxybenz[a]anthracene-7,12-dione (3f)
and 11-Hydroxy-1-methoxybenz[a]anthracene-7,12-dione
(3f′). Red solid; 1H NMR (500 MHz, CDCl3) δ 12.83 (s, 1H),
11.64 (s, 1H), 9.71 (d, J = 9.5 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.26
(d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H),
7.80 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.66−7.59 (m, 4H),
7.51 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 9.5, 3.0 Hz, 1H), 7.33−7.30
(m, 2H), 7.20 (d, J = 3.0 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 4.01
(s, 3H), 3.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.2, 188.8,
183.0, 182.8, 162.2, 160.0, 159.5, 157.5, 139.0, 138.1, 136.1, 135.2,
134.6, 134.2, 134.1, 132.5, 132.4, 132.0, 130.1, 130.0, 128.6, 127.5,
127.2, 125.6, 124.6, 123.8, 123.5, 123.3, 122.6, 122.3, 120.7, 118.8,
117.0, 109.6, 106.9, 106.4, 56.0, 55.4.
1
1075, 852, 751 cm−1; H NMR (500 MHz, CDCl3) δ 12.83 (s, 1H),
9.76 (d, J = 9.0 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.5 Hz,
1H), 7.92 (d, J = 8.5 Hz, 1H), 7.80−7.75 (m, 2H), 7.68−7.63 (m,
2H), 7.32 (dd, J = 8.5, 1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
δ 192.1, 182.3, 162.2, 136.7, 136.2, 136.1, 134.4, 132.3, 130.5, 130.2,
129.0, 128.8, 128.5, 128.4, 124.9, 122.6, 119.0, 117.1; MS (EI) m/z
(% base peak) 274 (M+, 100), 246 (27), 218 (34), 189 (81), 163 (16),
137 (5), 126 (7), 109 (9), 94 (17); HRMS (EI) calcd for C18H10O3
274.0630, Found 274.0626. Anal. Calcd for C18H10O3: C, 78.82; H,
3.67. Found: C, 79.02; H, 4.03.
11-Hydroxy-2-methylbenz[a]anthracene-7,12-dione (3b).
Red solid; mp 180−182 °C; IR (neat) ν 1663, 1631, 1586, 1461,
1
1367, 1295, 1230, 1205, 859, 792, 740 cm−1; H NMR (500 MHz,
CDCl3) δ 12.81 (s, 1H), 9.48 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.09
(d, J = 8.5 Hz, 1H), 7.75−7.73 (m, 2H), 7.61 (dd, J = 8.5, 8.5 Hz, 1H),
7.44 (dd, J = 8.5, 1.0 Hz, 1H), 7.28 (dd, J = 8.5, 1.0 Hz, 1H), 2.59
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.1, 183.4, 162.2, 140.7,
136.0, 135.9, 135.1, 134.5, 132.4, 131.0, 130.8, 128.8, 127.8, 127.4,
124.8, 121.7, 118.9, 117.1, 22.6; MS (EI) m/z (% base peak) 288 (M+,
100), 273 (31), 260 (7), 231 (9), 202 (17), 189 (13), 144 (6), 101
(4); HRMS (EI) calcd for C19H12O3 288.0786, Found 288.0783.
11-Hydroxy-3-methylbenz[a]anthracene-7,12-dione (3c)
and 11-Hydroxy-1-methylbenz[a]anthracene-7,12-dione (3c′).
Red solid; 1H NMR (400 MHz, CDCl3) δ 12.82 (s, 1H), 11.84
(s, 1H), 9.62 (d, J = 9.2 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.24 (d, J = 8.4
Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.79−7.55
(m, 9H), 7.33−7.29 (m, 2H), 2.59 (s, 3H), 2.54 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 192.2, 189.8, 183.3, 183.2, 162.3, 160.6, 141.2,
139.2, 137.6, 137.4, 137.2, 136.1, 136.0, 135.7, 135.5, 133.9, 133.8, 132.8,
132.6, 132.4, 128.8, 128.7, 128.5, 128.2, 128.1, 127.7, 126.7, 126.6, 124.7,
124.3, 122.7, 121.5, 119.0, 118.9, 117.3, 117.2, 21.9, 21.5.
11-Hydroxy-3-methoxybenz[a]anthracene-7,12-dione (3f).
Red solid; mp 216−218 °C; IR (neat) ν 1662, 1632, 1469, 1296,
1
1214, 852, 780, 741 cm−1; H NMR (500 MHz, CDCl3) δ 12.82
(s, 1H), 9.67 (d, J = 9.5 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 8.08 (d, J =
8.8 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 8.0, 7.5 Hz, 1H),
7.39 (d, J = 9.5 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 3.98
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.3, 183.1, 162.2, 159.5,
139.0, 136.1, 134.6, 132.5, 132.4, 130.2, 128.7, 125.7, 124.6, 123.4,
122.7, 118.9, 117.1, 106.9, 55.4; MS (EI) m/z (% base peak) 304 (M+,
0.1), 288 (100), 273 (23), 260 (16), 245 (4), 232 (12), 202 (17), 189
(13), 176 (4), 139 (4), 101 (8); HRMS (EI) calcd for C19H12O4
304.0736, Found 304.0734.
11-Hydroxy-3-methylbenz[a]anthracene-7,12-dione (3c).
Red solid; mp 219−221 °C; IR (neat) ν 1663, 1624, 1587, 1469,
1
1296, 1216, 1036, 851, 781, 740 cm−1; H NMR (500 MHz, CDCl3)
δ 12.84 (s, 1H), 9.63 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.10
(d, J = 8.5 Hz, 1H), 7.79 (dd, J = 7.8, 1.3 Hz, 1H), 7.67 (br s, 1H),
7.64 (dd, J = 8.3, 7.8 Hz, 1H), 7.58 (dd, J = 9.0, 1.5 Hz, 1H), 7.31
(dd, J = 8.3, 1.3 Hz, 1H), 2.55 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 192.2, 183.3, 162.2, 139.1, 137.1, 136.1, 135.5, 133.7, 132.6, 132.4,
128.6, 128.5, 128.2, 128.0, 124.7, 122.7, 118.9, 117.1, 21.6; MS (EI)
m/z (% base peak) 288 (M+, 100), 273 (27), 260 (20), 232 (16), 202
(28), 189 (20), 163 (4), 139 (6), 101 (9); HRMS (EI) calcd for
C19H12O3 288.0786, Found 288.0779. Anal. Calcd for C19H12O3: C,
79.16; H, 4.20. Found: C, 79.12; H, 4.62.
11-Hydroxy-2,3-dimethoxybenz[a]anthracene-7,12-dione
(3g). Red solid; mp 268−270 °C; IR (neat) ν 1659, 1627, 1585, 1485,
1
1430, 1368, 1303, 1262, 1215, 1075, 1040, 870, 741 cm−1; H NMR
(500 MHz, CDCl3) δ 12.97 (s, 1H), 9.31 (s, 1H), 8.26 (d, J = 8.5 Hz,
1H), 8.05 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.64 (dd, J =
8.5, 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.16 (s, 1H), 4.15 (s, 3H),
4.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 192.5, 183.3, 162.3,
153.1, 151.3, 136.0, 134.2, 134.1, 132.9, 132.7, 127.1, 126.6, 124.6,
121.7, 118.8, 117.3, 107.0, 106.9, 56.2, 56.0; MS (EI) m/z (% base
peak) 334 (M+,100), 291 (23), 263 (9), 248 (4), 220 (14), 205 (2),
192 (6), 163 (11), 138 (3), 88 (3); HRMS (EI) calcd for C20H14O5
334.0841, Found 334.0847. Anal. Calcd for C20H14O5: C, 71.85; H,
4.22. Found: C, 71.60; H, 4.30.
11-Hydroxy-5-methylbenz[a]anthracene-7,12-dione (3d).
Red solid; mp 243−245 °C; IR (neat) ν 1667, 1628, 1586, 1460,
1
1371, 1294, 1214, 1078, 754 cm−1; H NMR (500 MHz, CDCl3)
δ 12.88 (s, 1H), 9.80 (d, J = 9.0 Hz, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.5
Hz, 1H), 7.78−7.68 (m, 3H), 7.63 (dd, J = 8.5, 8.0 Hz, 1H), 7.31
(dd, J = 8.5, 0.5 Hz, 1H), 2.83 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 191.9, 183.5, 162.2, 143.9, 135.9, 135.8, 133.9, 132.3, 130.7, 129.7,
129.0, 128.7, 127.1, 124.9, 124.7, 123.4, 118.8, 117.1, 20.7; MS (EI)
m/z (% base peak) 288 (M+, 100), 273 (10), 260 (13), 231 (14), 202
(20), 189 (8), 139 (4), 101 (7); HRMS (EI) calcd for C19H12O3
288.0786, Found 288.0793.
11-Hydroxy-2-methoxybenz[a]anthracene-7,12-dione (3e).
Red solid; mp 208−210 °C; IR (neat) ν 1665, 1633, 1580, 1466,
1352, 1296, 1224, 1201, 1073, 1042, 854, 737 cm−1; 1H NMR (500 MHz,
CDCl3) δ 12.95 (s, 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.5 Hz,
1H), 8.12 (d, J = 8.5 Hz, 1H), 7.80−7.77 (m, 2H), 7.63 (dd, J = 8.0, 8.0
Hz, 1H), 7.32−7.29 (m, 2H), 4.05 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 192.2, 183.4, 162.3, 161.5, 136.0, 135.9, 134.9, 132.6, 132.5,
132.4, 130.4, 126.7, 124.8, 121.7, 120.7, 118.9, 117.2, 106.4, 55.6; MS (EI)
m/z (% base peak) 304 (M+, 100), 275 (15), 261 (11), 233 (16), 205 (6),
176 (11), 152 (6), 111 (4), 97 (6); HRMS (EI) calcd for C19H12O4
304.0736, Found 304.0734.
11-Hydroxy-1,3-dimethoxybenz[a]anthracene-7,12-dione
(3h). Red solid; mp 183−185 °C; IR (neat) ν 1662, 1639, 1608, 1451,
1
1276, 1212, 1164, 1078, 741 cm−1; H NMR (500 MHz, CDCl3) δ
11.60 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.74
(d, J = 7.5 Hz, 1H), 7.60 (dd, J = 8.0, 7.5 Hz, 1H), 7.28 (d, J = 8.0 Hz,
1H), 6.81 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 3.96 (s, 3H),
3.95 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 189.1, 182.7, 161.3,
160.0, 158.6, 139.5, 135.3, 134.4, 133.1, 132.5, 132.3, 123.6, 123.2,
118.8, 118.0, 117.0, 102.2, 99.3, 56.0, 55.7; MS (EI) m/z (% base
peak) 334 (M+, 100), 316 (71), 287 (19), 273 (12), 245 (11), 220
(13), 192 (9), 176 (11), 163 (14), 150 (4), 88 (8); HRMS (EI) calcd
for C20H14O5 334.0841, Found 334.0838. Anal. Calcd for C20H14O5:
C, 71.85; H, 4.22. Found: C, 71.43; H, 4.35.
11-Hydroxy-1-methoxy-4-methylbenz[a]anthracene-7,12-
dione (3i). Red solid; mp 180−182 °C; IR (neat) ν 1666, 1631, 1579,
1
1456, 1349, 1291, 1219, 1202, 1076, 1031, 858, 739 cm−1; H NMR
(500 MHz, CDCl3) δ 11.61 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.22
(d, J = 8.5 Hz, 1H), 7.75 (dd, J = 7.5, 1.0 Hz, 1H), 7.60 (dd, J = 8.5,
7.5 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.5, 1.0 Hz, 1H),
7.00 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 2.65 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 189.0, 182.9, 160.0, 155.9, 136.9, 135.2, 134.4, 133.6,
Acetic acid 2-(5-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-
2-yl)-1-(4-methoxyphenyl)ethyl ester (4e). Orange solid; mp
2663
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
132.4, 130.6, 130.5, 126.7, 123.8, 122.1, 121.4, 118.8, 118.0, 109.3,
55.9, 18.9; MS (EI) m/z (% base peak) 318 (M+, 95), 300 (100), 287
(22), 275 (14), 247 (5), 218 (5), 202 (10), 189 (13), 159 (8), 127 (6),
101 (6); HRMS (EI) calcd for C20H14O4 318.0892, Found 318.0885.
Anal. Calcd for C20H14O4: C, 75.46; H, 4.43. Found: C, 75.48; H, 5.18.
4-Bromo-11-hydroxy-1-methoxybenz[a]anthracene-7,12-
dione (3j). Red solid; mp 243−245 °C; IR (neat) ν 1666, 1638, 1600,
116.1, 109.6, 55.4, 24.0; MS (EI) m/z (% base peak) 228 (100), 226
(M+, 99), 213 (6), 211 (5), 185 (18), 183 (19), 147 (39), 132 (19),
115 (22), 104 (25), 77 (20); HRMS (EI) calcd for C10H1179BrO
225.9993, Found 225.9996.
4-Bromo-11-hydroxy-1,8-dimethoxy-3-methylbenz[a]-
anthracene-7,12-dione (20). A mixture of 21 (204 mg, 1 mmol)
and B(OAc)3 (206 mg, 1.1 mmol) in CH2Cl2 (10 mL) was stirred at
room temperature for 10 min and then 2k (907 mg, 4 mmol) and
DDQ (680 mg, 3 mmol) were added to the reaction mixture. After
stirred at room temperature for 24 h, additional B(OAc)3 (206 mg,
1.1 mmol), 2k (907 mg, 4 mmol), and DDQ (680 mg, 3 mmol) were
added to the reaction mixture, and this addition was repeated every
24 h until 21 was completely consumed. The reaction was quenched
with saturated aqueous NaHCO3, and extracted with CH2Cl2. The
combined organic extracts were washed successively with water, brine,
dried over MgSO4, filtered and concentrated. The crude product was
purified by flash silica-gel chromatography (hexanes/CH2Cl2 = 1:3) to
give 20 (270 mg, 63%) as a red solid. Analytically pure 20 was obtained
by crystallization from CH2Cl2−hexane: mp 244−246 °C; IR (neat) ν
1661, 1637, 1580, 1458, 1435, 1360, 1251, 1175, 1021, 832, 733 cm−1; 1H
NMR (500 MHz, CDCl3) δ 11.51 (s, 1H), 8.57 (d, J = 9.0 Hz, 1H), 8.32
(d, J = 9.0 Hz, 1H), 7.31 (m, 2H), 6.99 (s, 1H), 4.02 (s, 3H), 3.97 (s,
3H), 2.65 (s, 3H); 1 3 C NMR (125 MHz, CDCl3 )
δ 188.5, 181.4, 156.2, 154.2, 153.7, 140.4, 135.9, 134.5, 133.3, 133.0,
125.6, 123.8, 121.5, 120.6, 118.8, 117.9, 115.4, 112.2, 56.9, 56.0, 24.7; MS
(EI) m/z (% base peak) 428 (100), 426 (M+, 99), 409(15), 393 (44), 391
(42), 379 (16), 364 (13), 347 (12), 302 (14), 300 (16), 261 (8), 233 (4),
176 (11), 151 (13), 88 (9); HRMS (EI) calcd for C21H1579BrO5
426.0103, Found 426.0101.
1
1579, 1448, 1347, 1291, 980, 848, 744 cm−1; H NMR (500 MHz,
CDCl3) δ 11.53 (s, 1H), 8.50 (d, J = 9.0 Hz, 1H), 8.33 (d, J = 9.0 Hz,
1H), 7.88 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.64 (dd, J =
8.0, 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H),
3.98 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 188.4, 182.5, 160.2,
157.2, 135.9, 135.5, 134.3, 133.6, 133.4, 132.3, 124.1, 123.7, 122.7,
119.0, 117.8, 114.8, 113.7, 110.0, 56.1; MS (EI) m/z (% base peak)
384 (90), 382 (M+, 90), 366 (100), 364 (99), 353 (20), 351 (19), 313
(11), 280 (13), 260 (8), 204 (35), 176 (36), 151(14), 88 (19); HRMS
(EI) calcd for C19H1179BrO4 381.9841, Found 381.9847.
4-Bromo-11-hydroxy-1-methoxy-3-methylbenz[a]-
anthracene-7,12-dione (3k). Red solid; mp 268−270 °C; IR (neat)
ν 1665, 1643, 1602, 1578, 1443, 1360, 1292, 1206, 1078, 846, 740
1
cm−1; H NMR (500 MHz, CDCl3) δ 11.55 (s, 1H), 8.58 (d, J = 8.5
Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.0 Hz, 1H), 7.63 (dd,
J = 8.5, 7.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 3.98
(s, 3H), 2.66 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 188.6, 182.6,
160.1, 156.4, 140.8, 136.4, 135.4, 134.2, 133.6, 133.3, 132.4, 124.0,
123.7, 121.2, 118.9, 117.9, 115.4, 112.3, 56.1, 24.7; MS (EI) m/z
(% base peak) 398 (77), 396 (M+, 78), 380 (100), 378 (98), 367 (15),
274 (16), 218 (27), 189 (63), 163 (16), 101 (13), 94 (16); HRMS
(EI) calcd for C20H1379BrO4 395.9997, Found 396.0006.
2-Bromo-11-hydroxybenz[a]anthracene-7,12-dione (3l). Red
Trifluoromethanesulfonic Acid 4-Bromo-1,8-dimethoxy-3-
methyl-7,12-dioxo-7,12-dihydrobenz[a]-anthracen-11-yl Ester
(24). To a stirred solution of 20 (120 mg, 0.28 mmol) in CH2Cl2
(15 mL) at 0 °C were added Tf2O (172 mg, 0.56 mmol) and pyridine
(0.5 mL). After stirred at 0 °C for 1 h, the reaction mixture was
quenched with water and extracted with CH2Cl2. The combined organic
extracts were washed with brine, dried over MgSO4, filtered and con-
centrated. The crude product was purified by flash silica-gel chromato-
graphy (hexanes/CH2Cl2 = 1:3) to give 24 (150 mg, 95%) as an orange
red solid. Analytically pure 24 was obtained by crystallization from
EtOAc: mp 283−285 °C; IR (neat) ν 1666, 1604, 1472, 1432, 1227,
solid; mp 218−220 °C; IR (neat) ν 1666, 1631, 1580, 1455, 1292,
1
1201, 859, 737 cm−1; H NMR (500 MHz, CDCl3) δ 12.68 (s, 1H),
9.95 (d, J = 0.5 Hz, 1H), 8.33 (d, J = 8.3 Hz, 1H), 8.13 (d, J = 8.3 Hz,
1H), 7.77−7.70 (m, 3H), 7.64 (dd, J = 8.5, 8.0 Hz, 1H), 7.31 (dd, J =
8.5, 1.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 191.4, 182.8, 162.4,
136.3, 136.0, 135.0, 134.9, 132.2, 132.1, 131.2, 130.7, 130.2, 127.3,
125.4, 125.1, 123.0, 119.1, 116.9; MS (EI) m/z (% base peak) 354
(88), 352 (M+, 89), 324 (10), 296 (8), 274 (16), 245 (12), 217 (36),
189 (32), 163 (18), 136 (11), 94 (25); HRMS (EI) calcd for
C18H979BrO3 351.9735, Found 351.9742. Anal. Calcd for C18H9BrO3:
C, 61.22; H, 2.57. Found: C, 60.95; H, 3.06.
1
1204, 1138, 1011, 970, 818, 745 cm−1; H NMR (500 MHz, CDCl3) δ
8.57 (d, J = 9.0 Hz, 1H), 8.25 (d, J = 9.0 Hz, 1H), 7.56 (d, J = 9.0 Hz,
1H), 7.26 (d, J = 9.0 Hz, 1H), 6.98 (s, 1H), 4.06 (s, 3H), 4.01 (s, 3H),
2.65 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 183.3, 180.6, 158.7, 155.9,
141.0, 138.7, 135.8, 135.4, 133.2, 132.4, 132.2, 128.5, 123.5, 121.8, 120.4,
118.9 (q, J = 319 Hz), 116.8, 115.2, 111.9, 56.9, 56.0, 24.9; MS (EI) m/z
(% base peak) 560 (94), 558 (M+, 89), 427 (12), 425 (12), 368 (26), 366
(26), 318 (100), 303 (33), 213 (12), 176 (7), 150 (3); HRMS (EI) calcd
for C22H1479BrF3O7S 557.9596, Found 557.9600.
2-Bromo-5-methoxy-3-methylbenzaldehyde (23). A mixture
of (2-Bromo-5-methoxy-3-methylphenyl)methanol (22) (2 g, 8.7
mmol) and MnO2 (15 g, 173 mmol) in CH2Cl2 was stirred at room
temperature for 3 h. Filtration and concentration in vacuo gave 23
(1.84 g, 92%) as a white solid. Mp 84−85 °C; IR (neat) ν 3016, 2978,
2938, 2841, 1679, 1589, 1464, 1388, 1315, 1160, 1076, 939, 869, 757,
614 cm−1; 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.25 (d, J =
2.8 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 192.5, 158.6, 140.6, 134.4, 123.7, 120.8,
110.3, 55.6, 22.8; MS (EI) m/z (% base peak) 230 (99), 228 (M+,
100), 200 (30), 199 (20), 169 (5), 148 (8), 120 (19), 105 (14), 91
(36); HRMS (EI) calcd for C9H979BrO2 227.9786, Found 227.9780.
Anal. Calcd for C9H9BrO2: C, 47.19; H, 3.96. Found: C, 47.13; H,
4.19.
1,8-Dimethoxy-3-methylbenz[a]anthracene-7,12-dione (25).
A mixture of 24 (30 mg, 0.05 mmol), i-PrNEt2 (58 mg, 0.5 mmol),
HCO2H (14 mg, 0.3 mmol), and Pd(PPh3)2Cl2 (4 mg, 0.005 mmol)
in dry DMF (6 mL) under Ar atmosphere was heated to 80 °C for
24 h. After cooled to room temperature, the mixture was diluted with
CH2Cl2 and washed successively with NH4Cl, brine, and dried over
MgSO4, filtered and concentrated. The crude product was purified by
flash silica-gel chromatography (hexanes/CH2Cl2 = 1:2) to give 25
(15.3 mg, 86%) as an orange-yellow solid. Mp 191−193 °C; IR (neat)
2-Bromo-5-methoxy-1-methyl-3-vinylbenzene (2k). To a
suspension of methyltriphenylphosphonium bromide (5.6 g, 15.7
mmol) in THF (20 mL) at 0 °C was added t-BuOK (1.76 g, 15.7
mmol). After stirred for 1 h, aldehyde 23 (3 g, 13.1 mmol) in THF (15
mL) was added, and stirred at room temperature for another 3 h. The
reaction mixture was quenched with water and the solvent was eva-
porated. The residue was dissolved in CH2Cl2 and washed successively
with water, brine and dried over MgSO4, filtered and concentrated.
The crude product was purified by flash silica-gel chromatography
(hexanes/EtOAc = 3:1) to give 2k (2.64 g, 88%) as a yellowish oil. IR
1
ν 1664, 1619, 1588, 1470, 1444, 1137, 1009, 947, 839, 754 cm−1; H
NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.5
Hz, 1H), 7.69−7.67 (m, 2H), 7.25−7.24 (m, 2H), 6.89 (s, 1H), 4.04
(s, 3H), 3.98 (s, 3H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
186.5, 182.2, 159.4, 157.0, 140.3, 139.4, 137.7, 135.2, 134.9, 133.9,
132.5, 122.6, 120.7, 120.1, 119.1, 118.5, 116.3, 111.2, 56.4, 56.0, 22.1;
MS (EI) m/z (% base peak) 332 (M+, 100), 315 (56), 285 (17), 273
(9), 257 (5), 231 (6), 215 (11), 202 (17), 189 (13), 163 (3), 139 (3),
107 (5), 101 (10); HRMS (EI) calcd for C21H16O4 332.1049, Found
332.1053.
1
(neat) ν 2958, 1578, 1460, 1398, 1314, 1161, 1018, 916 cm−1; H
NMR (400 MHz, CDCl3) δ 7.11 (dd, J = 17.4, 10.9 Hz, 1H), 6.92 (d,
J = 3.0 Hz, 1H), 6.75 (d, J = 3.0 Hz, 1H), 5.64 (dd, J = 17.4, 1.2 Hz,
1H), 5.33 (dd, J = 10.9, 1.2 Hz, 1H), 3.80 (s, 3H). 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.4, 139.5, 138.8, 136.9, 117.1, 116.5,
Tetrangulol (18). To a stirred solution of 25 (8 mg, 0.024 mmol)
in CH2Cl2 (2 mL) was added BBr3 (0.06 mL, 0.06 mmol) at −78 °C.
2664
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
After stirred at −78 °C for 3 h, the reaction mixture was diluted with
CH2Cl2 and quenched with water. The organic layer was washed
successively with water, brine and dried over MgSO4, filtered and
concentrated. The crude product was purified by flash silica-gel
chromatography (hexanes/CH2Cl2 = 1:1) to give 18 (7 mg, 97%) as a
brown solid. Mp 199−201 °C; IR (neat) ν 1637, 1616, 1577, 1543,
1499, 1477, 1453, 1412, 1374, 1292, 1254, 1157, 1080, 793, 698 cm−1;
1H NMR (400 MHz, CDCl3) δ 12.24 (s, 1H), 11.27 (s, 1H), 8.30 (d,
J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 1H),
7.68 (dd, J = 8.0, 7.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 1.6
Hz, 1H), 7.13 (d, J = 1.6 Hz, 1H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 189.6, 187.8, 161.6, 155.2, 142.0, 139.1, 137.7, 136.9,
134.78, 134.77, 132.3, 124.7, 121.8, 121.3, 121.2, 120.1, 120.0, 114.6,
21.2; MS (EI) m/z (% base peak) 304 (M+, 100), 287 (5), 275 (7),
247 (7), 231 (3), 202 (5), 189 (6), 176 (2), 152 (4), 101 (4); HRMS
(EI) calcd for C19H12O4 304.0736, Found 304.0730.
7.08 (s, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, CD2Cl2) δ 190.2,
185.5, 158.1, 157.3, 154.2, 141.3, 138.4, 137.5, 135.0, 130.8, 129.7,
129.5, 121.0, 120.8, 119.7, 119.1, 113.0, 110.5, 20.2; MS (EI) m/z
(% base peak) 320 (M+, 100), 302 (22), 291 (9), 261 (7), 217 (6),
189 (18), 163 (13), 152 (13), 128 (10), 109 (5); HRMS (EI) calcd for
C19H12O5 320.0685, Found 320.0692.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR for compounds 2k, 3, 4e, 18−20,
and 23−27. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*chedsh@ccu.edu.tw
■
4-Bromo-1,8,11-trimethoxy-3-methylbenz[a]anthracene-
7,12-dione (26). A mixture of 20 (42 mg, 0.098 mmol), MeI (30 mg,
0.2 mmol), and K2CO3 (20 mg, 0.15 mmol) in acetone (3 mL) was
heated to reflux for 24 h. After cooled to room temperature, the
mixture was quenched with water and extracted with CH2Cl2. The
combined organic extracts were washed with brine and dried over
MgSO4, filtered and concentrated. The crude product was purified by
flash silica-gel chromatography (hexanes/CH2Cl2 = 1:5) to give 26
(43 mg, 98%) as a yellow solid. Analytically pure 26 was obtained by
crystallization from CH2Cl2−hexane: mp 221−223 °C; IR (neat) ν
1675, 1658, 1577, 1409, 1362, 1271, 1230, 1138, 1057, 1010, 800
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Professor Peter Wipf for providing experimental
procedures for the preparation of O-methylnaphthazarin from
1,5-dimethoxynaphthalene. We are also grateful to the National
Science Council (NSC) of the Republic of China for their
financial support (NSC 99-2119-M-194-004-MY2).
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.8 Hz, 1H), 8.21
(d, J = 8.8 Hz, 1H), 7.26 (d, J = 9.3 Hz, 1H), 7.18 (d, J = 9.3 Hz, 1H),
6.92 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.98 (s, 3H), 2.63 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 186.9, 182.2, 155.8, 153.3, 150.8, 140.3,
137.5, 135.7, 132.9, 130.9, 127.8, 123.6, 122.2, 120.5, 119.6, 117.3,
115.3, 111.5, 57.3, 56.8, 56.2, 24.8; MS (EI) m/z (% base peak) 442
(100), 440 (M+, 100), 425 (33), 423 (30), 393 (14), 381 (8), 343
(10), 315 (5), 288 (3), 221(5), 176 (5), 158(4), 101 (3); HRMS (EI)
calcd for C22H1779BrO5 440.0259, Found 440.0253.
REFERENCES
(1) Rohr, J; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103.
■
(2) (a) Carreno, M. C.; Urbano, A.; Fischer, J. Angew. Chem., Int. Ed.
̃
Engl. 1997, 36, 1621. (b) Kim, K.; Boyd, V. A.; Sobti, A.; Sulikowski,
G. A. Isr. J. Chem. 1997, 37, 3. (c) Carreno, M. C.; Urbano, A.; Di
̃
Vitta, C. Chem.Eur. J. 2000, 6, 906. (d) Krohn, K.; Micheel, J.;
Zukowski, M. Tetrahedron 2000, 56, 4753. (e) Carreno, M. C.;
̃
1,8,11-Trimethoxy-3-methylbenz[a]anthracene-7,12-dione
(27). A mixture of 26 (21 mg, 0.05 mmol), i-PrNEt2 (58 mg, 0.5
mmol), HCO2H (14 mg, 0.3 mmol), and Pd(PPh3)2Cl2 (4 mg, 0.005
mmol) in dry DMF (3 mL) under Ar atmosphere was heated to 80 °C
for 16 h. After cooled to room temperature, the mixture was diluted
with CH2Cl2 and washed successively with NH4Cl, brine, and dried
over MgSO4, filtered and concentrated. The crude product was
purified by flash silica-gel chromatography (hexanes/CH2Cl2 = 1:3) to
give 27 (12.2 mg, 71%) as an orange red solid. Mp >250 °C (dec.); IR
(neat) ν 1660, 1622, 1574, 1486, 1417, 1275, 1233, 1137, 1056, 1011,
Urbano, A. Angew. Chem., Int. Ed. 2002, 41, 2755. (f) Motoyoshiya, J.;
Masue, Y.; Iwayama, G.; Yoshioka, S.; Nishii, Y.; Aoyama, H. Synthesis
2004, 2099. (g) Carreno, M. C.; Urbano, A. Synlett 2005, 1.
̃
(h) Carreno, M. C.; Somoza, A.; Ribagorda, M.; Urbano, A. Chem.
̃
Eur. J. 2007, 13, 879. (i) Kaliappan, K. P.; Ravikumar, V. J. Org. Chem.
2007, 72, 6116.
(3) (a) Manning, W. B. Tetrahedron Lett. 1979, 20, 1661.
(b) Manning, W. B.; Muschik, G. M.; Tomaszewski, J. E. J. Org.
Chem. 1979, 44, 699. (c) Manning, W. B. Tetrahedron Lett. 1981, 22,
1571.
1
960, 852, 810 cm−1; H NMR (500 MHz, CDCl3) δ 8.10 (d, J =
(4) (a) Kelly, T. R.; Montury, M. Tetrahedron Lett. 1978, 19, 4311.
(b) Boeckman, R. K. Jr.; Dolak, T. M.; Culos, K. O. J. Am. Chem. Soc.
1978, 100, 7098. (c) Rozek, T.; Janowski, W.; Hevko, J. M.; Tiekink,
E. R. T.; Dua, S.; Stone, D. J. M.; Bowie, J. H. Aust. J. Chem. 1998, 51,
515. (d) Landells, J. S.; Larsen, D. S.; Simpson, J. Tetrahedron Lett.
2003, 44, 5193. (e) Hsu, D.-S.; Matsumoto, T.; Suzuki, K. Chem. Lett.
2006, 1016.
(5) (a) Caygill, G. B.; Larsen, D. S.; McFarlane, B. S. Aust. J. Chem.
1997, 50, 301. (b) Matsuo, G.; Miki, Y.; Nakata, M.; Matsumura, S.;
Toshima, K. J. Org. Chem. 1999, 64, 7101. (c) Andrews, F. L.; Larsen,
D. S.; Larsen, L. Aust. J. Chem. 2000, 53, 15.
(6) Lalancette, J. M.; Bessette, F.; Cliche, J. M. Can. J. Chem. 1966,
44, 1577.
(7) Braude, E. A.; Brook, A. G.; Linstead, R. P. J. Chem. Soc. 1954,
3569.
(8) Satoh, K.; Kamigaito, M.; Sawamoto, M. Macromolecules 2000,
33, 5830.
8.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 9.5 Hz, 1H), 7.23
(s, 1H), 7.16 (d, J = 9.5 Hz, 1H), 6.85 (s, 1H), 4.00 (s, 3H), 3.99
(s, 3H), 3.97 (s, 3H), 2.51 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
187.2, 182.6, 156.6, 153.2, 150.8, 140.3, 137.6, 137.4, 132.7, 131.3,
128.0 122.3, 122.2, 120.0, 119.6, 118.7, 117.1, 110.7, 57.4, 56.8, 56.0,
22.1; MS (EI) m/z (% base peak) 362 (M+, 68), 345 (53), 315 (34),
289 (26), 273 (29), 261 (32), 215 (54), 202 (90), 189 (87), 163 (60),
139 (68), 127 (27), 101 (15), 57 (100); HRMS (EI) calcd for
C22H18O5 362.1154, Found 362.1150.
Anhydrolandomycinone (19). To a stirred solution of 27 (20
mg, 0.055 mmol) in CH2Cl2 (3 mL) was added BBr3 (1.5 mL, 1.5
mmol) at −78 °C. After stirred at −78 °C for 1 h, the reaction mixture
was warmed to −30 °C and stirred at this temperature for another 3 h.
The mixture was diluted with CH2Cl2 and quenched with water. The
organic layer was washed successively with water, brine and dried over
MgSO4, filtered and concentrated. The crude product was purified by
flash silica-gel chromatography (hexanes/CH2Cl2 = 1:1) to give 19
(17 mg, 96%) as a brown-black solid. Analytically pure 19 was
obtained by crystallization from CH2Cl2−pentane: mp 214−216 °C;
IR (neat) ν 1609, 1584, 1554, 1505, 1453, 1262, 1185, 835, 816, 793,
709 cm−1; 1H NMR (500 MHz, CD2Cl2) δ 12.89 (s, 1H), 12.39
(s, 1H), 10.98 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz,
1H), 7.29 (d, J = 9.5 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.25 (s, 1H),
(9) Ross Kelly, T.; Magee, J. A.; Weibel, F. R. J. Am. Chem. Soc. 1980,
102, 798.
(10) (a) Wallace, D. J.; Gibb, A. D.; Cottrell, I. F.; Kennedy, D. J.;
Brands, K. M. J.; Dolling, U. H. Synthesis 2001, 1784. (b) Ronan, B.;
́ ̀ ́
Bacque, E.; Barriere, J.-C.; Sable, S. Tetrahedron 2003, 59, 2929.
(c) Zhou, X.; Kitamura, M.; Shen, B.; Nakajima, K.; Takahashi, T.
2665
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666

The Journal of Organic Chemistry
Article
Chem. Lett. 2004, 410. (d) Stone, M. T.; Anderson, H. L. J. Org. Chem.
2007, 72, 9776. (e) Conchon, E.; Anizon, F.; Aboab, B.; Prudhomme,
M. Synthesis 2008, 2569. (f) Feltenberger, J. B.; Hsung, R. P. Org. Lett.
2011, 13, 3114.
(11) (a) Julia, M.; Righini, A.; Uguen, D. J. Chem. Soc., Perkin Trans. 1
1978, 1646. (b) Gharpure, S. J.; Sathiyanarayanan, A. M.;
Jonnalagadda, P. Tetrahedron Lett. 2008, 49, 2974.
(12) Kuntsmann, M. P.; Mitscher, L. A. J. Org. Chem. 1966, 31, 2920.
(13) Shaaban, K. A.; Srinivasan, S.; Kumar, R.; Damodaran, C.; Rohr,
J. J. Nat. Prod. 2011, 74, 2.
(14) Henkel, T.; Rohr, J.; Beale, J. M.; Schwenen, L. J. Antibiot. 1990,
43, 492.
(15) Holzwarth, R.; Bartsch, R.; Cherkaoui, Z.; Solladie, G. Chem.
́
Eur. J. 2004, 10, 3931.
(16) (a) Laatsch, H. Liebigs Ann. Chem. 1990, 1151. (b) Wipf, P.;
Jung, J.-K. Angew. Chem., Int. Ed. Engl. 1997, 36, 764.
(17) (a) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821. (b) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.; Liao, C.-C.
J. Org. Chem. 2002, 67, 6493.
(18) Matsumoto, T.; Sohma, T.; Yamaguchi, H.; Kurata, S.; Suzuki,
K. Tetrahedron 1995, 51, 7347.
2666
dx.doi.org/10.1021/jo202448e | J. Org. Chem. 2012, 77, 2659−2666