A concise route for the synthesis of pyranonaphthoquinone derivatives

Article abstract of DOI:10.1055/s-2005-916031

An efficient synthesis of pyranonaphthoquinones is achieved by ethylenediamine diacetate-catalyzed reactions of 4-hydroxy-2-quinolones with a variety of α,β-unsaturated aldehydes in moderate yields. This method provides a rapid entry into biologically interesting α-lapachone derivatives with a variety of substituents on the pyran ring. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-916031

3026
PAPER
A Concise Route for the Synthesis of Pyranonaphthoquinone Derivatives
S
ynthesis of Pyran
o
onaphthoqui
n
none
D
erivat
g
ives Rok Lee,*,a Jung Hyun Choi,a Dinh Thi Lan Trinh,a Nam Woo Kimb
a
School of Chemical Engineering and Technology, Yeungnam University, Gyeongsan 712-749, Korea
Fax +82(53)8104631; E-mail: yrlee@yu.ac.kr
Department of Herbal Biotechnology, Daegu Hanny University, Gyeongsan 712-751, Korea
b
Received 14 March 2005; revised 15 June 2005
verse transcriptase and DNA polymerase-a, and blocking
of activation of NF-kB and AP-1.6–12 They also have po-
tential clinical utility in the treatment of human leukemia
and prostate cancer.13,14 In particular, a combination of b-
Abstract: An efficient synthesis of pyranonaphthoquinones is
achieved by ethylenediamine diacetate-catalyzed reactions of 4-hy-
droxy-2-quinolones with a variety of a,b-unsaturated aldehydes in
moderate yields. This method provides a rapid entry into biological-
ly interesting a-lapachone derivatives with a variety of substituents lapachone (2) and taxol is combined synergistically to in-
on the pyran ring.
duce cell death in so many types of human carcinoma cells
such as ovarian, breast, prostate, lung, melanoma, colon
Key words: pyranonaphthoquinones, ethylenediamine diacetate,
tandem Knoevenagel–electrocyclic reaction, a-lapachone deriva-
tives
and pancreatic cells.15
Pyranokunthone A (10) and B (11) with pyranonaphtho-
quinone skeleton were isolated from the root bark extract
of Stereospermum kunthianum.16 They have been used as
a valuable remedy to treat fever in Uganda and they have
also shown a strong antimalarial activity.16
Pyranonaphthoquinones are widely distributed in nature
and play important physiological roles in animals and
plants.1 Among these, a-lapachone (1) and b-lapachone
(2) are primarily isolated from Tabebuia avellanedae in
Central and South America (Figure 1).2 a-Lapachone de-
rivatives 3–7 are isolated from Catalpa ovata, which is in
found in Japan and China.3 Dehydro-a-lapachone (8) and
a-caryopterone (9) were isolated from Zeyhera tubercu-
losa and Caryopteris clandonensis.4 They have antibacte-
rial, antifungal, antitrypanosomal, antimalarial, and
antitumor activities and are used in traditional medicines
for the treatment of pyrexia, jaundice, and edema by ne-
phritis in Japan and China.5 Biological properties include
reduction of HIV-1 replication, suppression of both acute
and chronic infections, inhibition of DNA topoisomerase
I, induction of chromosomal alterations, inhibition of re-
Several synthetic approaches of pyranonaphthoquinone
derivatives including a-lapachone (1) and b-lapachone (2)
have been reported.17 The common protocol was made by
the acid-catalyzed cyclization of lapachol which was syn-
thesized from 2-hydroxy-1,4-naphthoquinone (12). How-
ever, this synthetic exploitation has been limited due to
many reaction steps, strong reaction conditions, and side
reactions involving O-alkylation product. The necessity
for overcoming these problems has prompted research for
improved synthetic methods of pyranonaphthoquinone
derivatives. We have recently reported one-pot synthesis
of 2H-pyrans using a tandem Knoevenagel–electrocyclic
18
reaction in the presence of Yb(OTf)3 or InCl3. We ex-
O
O
O
O
R1
O
O
O
O
O
OMe O
R2
O
1
2
O
7
3 R1 = OH, R2 = H
4 R1 = H, R2 = OH
5 R1 = H, R2 = OMe
6 R1 = R2 = OH
O
α-lapachone
β-lapachone
O
O
O
O
O
O
R3
O
HO
O
HO
O
R4
8 R3 = R4 = H dehydro-α-lapachone
9 R3 = H, R4 = OH α-caryopterone
10 pyranokunthone A
11 pyranokunthone B
Figure 1
SYNTHESIS 2005, No. 18, pp 3026–3034
x
x.
x
x
.
2
0
0
5
Advanced online publication: 06.10.2005
DOI: 10.1055/s-2005-916031; Art ID: F05005SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyranonaphthoquinone Derivatives
3027
pand this work to the synthesis of pyranonaphthoquinone 18 was obtained in 64% yield (entry 6). This reaction pro-
derivatives by using other catalysts.
vides a rapid route to the synthesis of skeleton of biologi-
cally interesting pyranokunthone B (11).17a Similarly,
reaction with trans,trans-farnesal afforded product 19 in
60% yield (entry 7). With other a,b-unsaturated aldehydes
with cyclic ring, cycloaddition reaction was also success-
ful. For example, treatment of 12 with 1-cyclohexene-1-
carboxaldehyde afforded the product 20 with tetracyclic
ring in 92% yield (entry 8). Similarly, reactions with
chiral (–)-myrtenol and (–)-perillaldehyde afforded prod-
ucts 21 and 22 in 97% and 87% yields, respectively (en-
tries 9 and 10). These reactions provide a rapid route to the
synthesis of pyranonaphthoquinone derivatives, which
are known to have a number of biological activities.
First, synthesis of dehydro-a-lapachone (8) was attempted
starting from 2-hydroxy-1,4-naphthoquinone (12) and 3-
methyl-2-butenal under several catalysts (Table 1). Both
indium(III) chloride (10 mol%) and ytterbium(III) triflate
(10 mol%) catalysts in MeCN afforded a small fraction of
product 8 in 5% and 10% yields, respectively. The higher
yield (55%) was obtained in DMF at 100 °C for five hours
in the presence of Yb(OTf)3. In order to obtain optimal re-
action conditions, we surveyed other catalysts. With pyri-
dine, cycloadduct 8 was produced in 54% yield. With
ethylenediamine diacetate (10 mol%), cycloadduct was
obtained in increased yield. There was a solvent depen-
dence. The best yield was obtained in benzene (80%). The synthesized dehydro-a-lapachone (8) can be readily
Other solvents included THF (47%) and MeOH (75%). converted to a-lapachone derivatives with a variety of
Our finding was very surprising in comparison with the substituents on the pyran ring as shown in Scheme 1. For
reported results that ethylenediamine diacetate-catalyzed example, dehydro-a-lapachone (8) can be selectively hy-
reactions of 1,3-dicarbonyl compounds with enals have drogenated in the presence of 10% Pd/C (10 psi, 20 min)
usually been carried out in polar solvent such as MeCN or to produce a-lapachone (1) in 99% yield.20 Spectroscopic
MeOH.19 The spectral data of synthetic material 8 are in data of our synthetic material 1 are same as the values re-
good agreement with those of natural product reported in ported in the literature for the natural product.4a Oxidation
the literature.2a
of 8 with dimethyl dioxirane in acetone at room tempera-
ture leads to product 23 with epoxide ring in 87% yield.
When 8 was treated with NBS in aqueous THF at 0 °C for
seven hours, bromohydrin 24 was produced in 50% yield.
Compound 24 can be used in the synthesis of naturally oc-
curring compound 3 by reduction of bromide. Treatment
with osmium tetroxide–NMO at room temperature for
three hours afforded cis-diol 25 in 52% yield.
Table 1 Effect of Catalysts and Solvents on the Reaction of 12 and
3-Methyl-2-butenal
O
O
O
H
OH
O
8
12
O
O
Further conversion to a-lapachone derivatives was carried
out by ring opening reaction of epoxide 23 with several
nucleophiles in basic and acidic conditions. The epoxide
23 was then reacted with oxygen, nitrogen and sulfur-con-
taining nucleophiles at room temperature in neat or in a
suitable solvent as shown in Table 3. Reaction of 23 with
water in the presence of catalytic amount of InCl3 at room
temperature for five hours afforded both cis-diol 25 and
trans-diol 26 in 30% and 42% yields, respectively, where-
as treatment with NaOH in water at room temperature for
two hours afforded trans-diol 26 as the sole product in
62% yield. The cis- and trans-isomers were easily sepa-
rated by silica gel column chromatography and are as-
signed by spectral data. The 1H NMR spectrum of cis-diol
25 showed two characteristic methine signals at d = 4.95
(d, J = 4.8 Hz, 1 H) and 4.04 (d, J = 4.8 Hz, 1 H), which
are in agreement with product obtained from osmylation
reaction of 8. The trans-diol 26 showed two methine pro-
tons of pyran ring at d = 4.74 (d, J = 7.5 Hz, 1 H) and 3.76
(d, J = 7.5 Hz, 1 H). Similarly, indium(III)-catalyzed ring
opening with MeOH afforded cis-product 27 and trans-
product 28 in 41% and 45% yields, respectively, whereas
opening with NaOMe in MeOH gave 28 in 68% yield.
Treatment with NaOEt in EtOH also afforded 29 in 60%
yield. To further expand the utility of this conversion, oth-
er nucleophiles were investigated in the presence of InCl3.
When 23 was treated with phenol in CH2Cl2, two products
30 and 31 were also obtained in 34% and 40% yields, re-
Catalyst
Conditions
Yield
(%)
InCl3 (10 mol%)
MeCN, reflux, 5 h
MeCN, reflux, 5 h
DMF, 100 °C, 5 h
MgSO4, reflux, 5 h
5
10
55
54
47
75
Yb(OTf)3 (10 mol%)
Yb(OTf)3 (10 mol%)
pyridine (excess)
ethylenediamine diacetate (10 mol%) InCl3 (10 mol%)
ethylenediamine diacetate (10 mol%) MeOH, r.t., 5 h
ethylenediamine diacetate (10 mol%) benzene, reflux, 5 h 80
In order to extend the utility of this cycloaddition, further
reactions with other types of a,b-unsaturated aldehydes
were next investigated (Table 2). Reaction with crotonal-
dehyde in the presence of ethylenediamine diacetate (10
mol%) in refluxing benzene afforded 13 in 49% yield (en-
try 1). With trans-2-pentenal and trans-2-hexenal, cy-
cloadducts 14 and 15 were produced in 74% and 60%
yields, respectively (entries 2 and 3). With trans-cinnam-
aldehyde and trans-2-methyl-2-butenal, expected addi-
tion products 16 and 17 were obtained in 40% and 49%
yields, respectively (entries 4 and 5). In the cases of citral
and trans,trans-farnesal with a long chain, the reaction
was successful. When 12 was treated with citral, adduct
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3028
Y. R. Lee et al.
PAPER
Table 2 Reaction of 2-Hydroxy-1,4-naphthoquinone (12) with a,b-Unsaturated Aldehydes
Entry
1
Starting material a,b-Unsaturated aldehyde
Product
Yield (%)
49
74
60
40
O
H
O
O
13
O
O
2
3
4
O
H
O
14
O
O
O
H
O
15
O
O
O
O
O
H
OH
O
16
12
O
O
5
6
49
64
60
92
97
87
O
H
O
O
O
O
O
O
17
O
O
O
H
18
O
O
7
O
H
19
O
O
8
O
O
H
H
20
O
O
9
21
O
O
10
O
H
22
O
spectively. Treatment with ethanethiol afforded products 52% yields, respectively. Similarly, reaction with aniline
32 and 33 in 16% and 65% yields, respectively. In this afforded the corresponding products 37 and 38 in 28%
case, trans-product was obtained as the major component. and 59% yields, respectively. In view of our results, trans-
More interestingly, reaction with thiophenol afforded adducts were obtained as the major component in basic
trans-product 34 as the single compound in 75% yield. conditions. As contrasted with base-catalyzed cleavage,
Last, a series of aliphatic and aromatic amines were inves- reactions with the indium(III) catalyst mainly afforded
tigated. Treatment with pyrrolidine at room temperature both cis and trans products. These transformations pro-
for two hours resulted in products 35 and 36 in 30% and
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PAPER
Synthesis of Pyranonaphthoquinone Derivatives
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Table 3 Ring-Opening Reaction of Epoxide 23 with Several Nucleophiles
O
Nu
O
O
Nu
O
OH
OH
NuH
+
catalyst
O
O
O
23
O
NuH/catalyst
H2O–InCl3
O
O
Entry
1
Solvent
CH2Cl2
Product (yield)
O
O
OH
O
O
OH
OH
OH
OH
O
25
42% 26
30%
O
O
2
3
4
5
6
NaOH
H2O
OH
26
62%
O
O
O
MeOH–InCl3
MeONa
MeOH
MeOH
EtOH
CH2Cl2
OMe
O
OMe
OH
OH
OH
O
O
45%
28
41%
27
O
O
O
OMe
28
O
68%
O
O
EtONa
OEt
OH
29
60%
O
O
O
PhOH–InCl3
O
O
OPh
OPh
OH
OH
O
O
40% 31
30
34%
O
O
7
EtSH
CH2Cl2
O
SEt
SEt
OH
OH
O
O
33
32
O
O
O
16%
65%
8
9
PhSH
CH2Cl2
CH2Cl2
SPh
OH
34
O
76%
O
O
pyrrolidine
O
N
N
O
OH
OH
O
36
52%
O
30%
35
O
O
10
aniline
CH2Cl2
NHPh
OH
O
NHPh
OH
O
O
37
38
59%
28%
O
O
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Y. R. Lee et al.
PAPER
O
O
O
23
87%
O
O
O
O
acetone
O
O
O
O
OH
Br
H2
NBS, H2O
THF
Pd/C
O
O
O
8
1
99%
O
24
50%
OsO4
NMO
O
OH
OH
O
O
25
52%
Scheme 1
2-Methyl-2H-benzo[g]chromene-5,10-dione (13)
vided a rapid entry to the synthesis of biologically inter-
Reaction of 12 (174 mg, 1 mmol) with crotonaldehyde (140 mg, 2
mmol) in benzene (10 mL) afforded 13 (111 mg, 49%) as a solid;
mp 96 °C.
esting a-lapachone derivatives.
In conclusion, the synthesis of pyranonaphthoquinones is
achieved by reactions of 4-hydroxy-1,4-naphthoquinone
and a variety of a,b-unsaturated aldehydes in the presence
of ethylenediamine diacetate in moderate yields. The ad-
duct obtained by this methodology is readily converted to
biologically interesting pyranonaphthoquinone deriva-
tives with a variety of substituents on the pyran ring.
IR (KBr): 3067, 2924, 2855, 2361, 2342, 1674, 1647, 1634, 1593,
1572, 1408, 1366, 1337, 1304, 1260, 1130, 966 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.06 (m, 2 H), 7.71–7.67 (m,
2 H), 6.69 (dd, J = 10.0, 1.6 Hz, 1 H), 5.78 (dd, J = 10.0, 3.4 Hz, 1
H), 5.30–5.25 (m, 1 H), 1.53 (d, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 181.6, 179.6, 152.6, 134.0, 133.2,
131.3, 131.2, 127.1, 126.2, 126.1, 118.3, 116.5, 74.2, 21.5.
HRMS: m/z [M+] calcd for C14H10O3: 226.0630; found: 226.0632.
All experiments were carried out under a N2 atmosphere. Merck
precoated silica gel plates (Art. 5554) with fluorescent indicator
were used for analytical TLC. Flash column chromatography was
performed using silica gel 9385 (Merck). Melting points were deter-
mined in capillary tubes on a Fisher-Johns apparatus and are uncor-
rected. 1H NMR (300 MHz) and 13C NMR spectra (75 MHz) were
recorded on a Bruker Model ARX (300 MHz) spectrometer. IR
spectra were recorded on a Jasco FTIR 5300 spectrophotometer.
HRMS spectra measurements were carried out at Korea Basic Sci-
ence Institute.
2-Ethyl-2H-benzo[g]chromene-5,10-dione (14)
Reaction of 12 (174 mg, 1 mmol) with trans-2-pentenal (168 mg, 2
mmol) in benzene (10 mL) afforded 14 (178 mg, 74%) as a solid;
mp 65 °C.
IR (KBr): 2971, 2926, 2876, 1674, 1649, 1593, 1572, 1335, 1300,
1258, 1202, 1119, 997, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.06 (m, 2 H), 7.72–7.66 (m,
2 H), 6.71 (dd, J = 10.0, 1.6 Hz, 1 H), 5.79 (dd, J = 10.0, 3.4 Hz, 1
H), 5.14–5.09 (m, 1 H), 1.90–1.81 (m, 2 H), 1.04 (t, J = 7.4 Hz, 3 H).
Synthesis of 8 and 13–22; General Procedure
2-Hydroxy-1,4-naphthoquinone (12; 174 mg, 1 mmol) and a,b-un-
saturated aldehydes (2 mmol) were dissolved in benzene (10 mL),
and ethylenediamine diacetate (18 mg, 0.1 mmol) was added at r.t.
The mixture was refluxed for 4–7 h and then cooled to r.t. Removal
of the solvent at reduced pressure left an oily residue, which was
then purified by column chromatography on silica gel to give the
products.
13C NMR (75 MHz, CDCl3): d = 181.7, 179.6, 153.0, 134.0, 133.2,
131.4, 131.3, 126.2, 126.1, 125.8, 118.5, 117.1, 78.9, 28.7, 8.4.
HRMS: m/z [M+] calcd for C15H12O3: 240.0786; found: 240.0787.
2-Propyl-2H-benzo[g]chromene-5,10-dione (15)
Reaction of 12 (174 mg, 1 mmol) with trans-2-hexenal (196 mg, 2
mmol) in benzene (10 mL) afforded 15 (153 mg, 60%) as a solid;
mp 56 °C.
Dehydro-a-lapachone (8)
Reaction of 12 (174 mg, 1 mmol) with 3-methyl-2-butenal (168 mg,
2 mmol) in benzene (10 mL) afforded 8 (192 mg, 80%) as a solid;
mp 145–146 °C (Lit.2d 148 °C).
IR (KBr): 2959, 2924, 2870, 1672, 1643, 1589, 1566, 1412, 1337,
1294, 1254, 1200, 968, 718 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.06 (m, 2 H), 7.72–7.59 (m,
2 H), 6.69 (dd, J = 10.0, 1.5 Hz, 1 H), 5.79 (dd, J = 10.0, 3.5 Hz, 1
H), 5.20–5.10 (m, 1 H), 1.89–1.69 (m, 2 H), 1.60–1.40 (m, 2 H),
0.95 (t, J = 7.3 Hz, 3 H).
IR (KBr): 3079, 3017, 2976, 2922, 1676, 1647, 1593, 1570, 1416,
1331, 1275, 1211, 1190, 1134, 968, 947 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.11–8.05 (m, 2 H), 7.70–7.64 (m,
2 H), 6.64 (d, J = 10.0 Hz, 1 H), 5.71 (d, J = 10.0 Hz, 1 H), 1.54 (s,
6 H).
HRMS: m/z [M+] calcd for C16H14O3: 254.0943; found: 254.0939.
Synthesis 2005, No. 18, 3026–3034 © Thieme Stuttgart · New York

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Synthesis of Pyranonaphthoquinone Derivatives
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2-Phenyl-2H-benzo[g]chromene-5,10-dione (16)
Reaction of 12 (174 mg, 1 mmol) with trans-cinnamaldehyde (264
mg, 2 mmol) in benzene (10 mL) afforded 16 (115 mg, 40%) as a
solid; mp 98 °C.
1H NMR (300 MHz, CDCl3): d = 8.06–8.02 (m, 2 H), 7.70–7.62 (m,
2 H), 6.32 (s, 1 H), 5.18 (dd, J = 11.6, 5.7 Hz, 1 H), 2.57–2.49 (m,
1 H), 2.37–2.31 (m, 1 H), 2.11–1.76 (m, 4 H), 1.50–1.32 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 181.9, 179.3, 151.3, 140.6, 133.7,
133.0, 131.2, 131.1, 125.9, 125.8, 117.6, 108.5, 79.9, 35.1, 33.5,
26.9, 24.3.
IR (KBr): 3069, 2924, 1654, 1647, 1585, 1331, 1292, 1258, 1188,
1107, 958, 717 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10–8.03 (m, 2 H), 7.73–7.63 (m,
2 H), 7.47–7.44 (m, 2 H), 7.40–7.34 (m, 3 H), 6.91 (dd, J = 10.0, 1.5
Hz, 1 H), 6.15 (dd, J = 3.8, 1.5 Hz, 1 H), 5.96 (dd, J = 10.0, 3.8 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 181.7, 179.3, 152.2, 138.5, 134.0,
133.3, 131.4, 131.3, 129.3, 129.3, 128.9, 128.9, 127.5, 126.3, 126.2,
124.9, 118.0, 117.0, 78.8.
HRMS: m/z [M+] calcd for C17H14O3: 266.0943; found: 266.0946.
Compound (21)
Reaction of 12 (174 mg, 1 mmol) with (1R)-(–)-myrtenal (300 mg,
2 mmol) in benzene (10 mL) afforded 21 (297 mg, 97%) as a solid;
mp 125 °C; [a]22D –372.0 (c = 1, CHCl3).
IR (KBr): 2948, 2912, 2867, 1650, 1566, 1335, 1287, 1252, 1196,
1049, 984, 806, 718 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10–8.05 (m, 2 H), 7.71–7.64 (m,
2 H), 6.35 (d, J = 2.6 Hz, 1 H), 5.21–5.15 (m, 1 H), 2.77–2.67 (m, 2
H), 2.45–2.37 (m, 1 H), 2.28–2.21 (m, 1 H), 2.18–2.13 (m, 1 H),
1.60–1.52 (m, 1 H), 1.32 (s, 3 H), 0.89 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 182.9, 179.8, 153.5, 144.0, 134.2,
133.7, 131.9, 131.8, 126.6, 126.5, 123.0, 111.2, 72.4, 49.7, 42.9,
40.4, 32.2, 25.9, 25.2, 22.2.
HRMS: m/z [M+] calcd for C19H12O3: 288.0786; found: 288.0786.
2,3-Dimethyl-2H-benzo[g]chromene-5,10-dione (17)
Reaction of 12 (174 mg, 1 mmol) with trans-2-methyl-2-butenal
(168 mg, 2 mmol) in benzene (10 mL) afforded 17 (118 mg, 49%)
as a solid; mp 107 °C.
IR (KBr): 2967, 1671, 1647, 1591, 1572, 1385, 1337, 1304, 1256,
1202, 966, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.03 (m, 2 H), 7.75–7.63 (m,
2 H), 6.43 (s, 1 H), 5.08 (q, J = 6.6 Hz, 1 H), 1.88 (s, 3 H), 1.45 (d,
J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 181.9, 179.6, 150.2, 137.3, 133.7,
133.1, 131.4, 131.3, 126.1, 125.9, 119.2, 111.7, 76.6, 19.6, 19.1.
HRMS: m/z [M+] calcd for C20H18O3: 306.1256; found: 306.1255.
3-Isopropenyl-2,3,4,4a-tetrahydro-1H-benzo[b]xanthene-6,11-
dione (22)
Reaction of 12 (174 mg, 1 mmol) with (S)-(–)-perillaldehyde (300
mg, 2 mmol) in benzene (10 mL) afforded 22 (267 mg, 87%) as a
solid; mp 120 °C; [a]22D +210.3 (c = 1, CHCl3).
HRMS: m/z [M+] calcd for C15H12O3: 240.0786; found: 240.0786.
IR (KBr): 3073, 2924, 2856, 1649, 1593, 1444, 1389, 1339, 1296,
1250, 1200, 995, 890, 714 cm–1.
2-Methyl-2-(4-methylpent-3-enyl)-2H-benzo[g]chromene-5,10-
dione (18)
Reaction of 12 (174 mg, 1 mmol) with citral (304 mg, 2 mmol) in
1H NMR (300 MHz, CDCl3): d = 8.07–8.03 (m, 2 H), 7.68–7.64 (m,
2 H), 6.35 (s, 1 H), 5.27 (dd, J = 11.5, 6.2 Hz, 1 H), 4.74 (s, 1 H),
4.72 (s, 1 H), 2.64–2.57 (m, 1 H), 2.46–2.39 (m, 1 H), 2.25–2.07 (m,
2 H), 1.93–1.85 (m, 1 H), 1.83–1.75 (m, 1 H), 1.72 (s, 3 H), 1.42–
1.28 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 182.3, 179.7, 151.8, 147.8, 140.2,
134.2, 133.5, 131.7, 131.6, 126.4, 126.4, 118.1, 110.2, 109.2, 78.0,
43.5, 40.2, 33.1, 32.1, 21.2.
benzene (10 mL) afforded 18 (197 mg, 64%) as a liquid.
IR (neat): 2978, 2926, 1676, 1651, 1595, 1572, 1449, 1412, 1339,
1273, 1211, 1115, 966, 901, 797, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10–8.05 (m, 2 H), 7.71–7.63 (m,
2 H), 6.68 (d, J = 10.0 Hz, 1 H), 5.65 (d, J = 10.0 Hz, 1 H), 5.09–
5.03 (m, 1 H), 2.15–2.05 (m, 2 H), 1.99–1.89 (m, 1 H), 1.71–1.64
(m, 1 H), 1.60 (s, 3 H), 1.53 (s, 3 H), 1.50 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 181.6, 179.5, 152.6, 133.8, 133.0,
132.1, 131.3, 131.2, 129.6, 126.0, 126.0, 123.3, 117.3, 115.8, 82.9,
41.4, 27.4, 25.5, 22.5, 17.5.
HRMS: m/z [M+] calcd for C20H18O3: 306.1256; found: 306.1258.
a-Lapachone (1)
To the synthetic material 8 (300 mg, 1.25 mmol) in a Parr bottle in
EtOAc (10 mL) was added 10% Pd/C (20 mg). The bottle was shak-
en for 20 min at 10 psi of H2. Removal of the solvent at reduced
pressure left an oily residue, which was then purified by column
chromatography on silica gel to give 1 (299 mg, 99%) as a solid; mp
113–114 °C (Lit.2d 116 °C, Lit.17e 112–115 °C).
HRMS: m/z [M+] calcd for C20H20O3: 308.1412; found: 308.1414.
2-(4,8-Dimethylnona-3,7-dienyl)-2-methyl-2H-ben-
zo[g]chromene-5,10-dione (19)
Reaction of 12 (174 mg, 1 mmol) with trans,trans-farnesal (441 mg,
2 mmol) in benzene (10 mL) afforded 19 (226 mg, 60%) as a liquid.
IR (KBr): 2974, 2948, 1682, 1638, 1613, 1578, 1391, 1341, 1310,
1273, 1208, 1119, 961 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08–8.02 (m, 2 H), 7.70–7.62 (m,
2 H), 2.60 (t, J = 6.6 Hz, 2 H), 1.80 (t, J = 6.6 Hz, 2 H), 1.42 (s, 6 H).
IR (neat): 2969, 2926, 1676, 1653, 1597, 1572, 1449, 1410, 1337,
1273, 1211, 966, 720 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08–8.05 (m, 2 H), 7.72–7.63 (m,
2 H), 6.68 (d, J = 10.0 Hz, 1 H), 5.66 (d, J = 10.0 Hz, 1 H), 5.10–
5.01 (m, 2 H), 2.15–1.85 (m, 8 H), 1.64 (s, 3 H), 1.62 (s, 3 H), 1.53
(s, 3 H), 1.50 (s, 3 H).
2,2-Dimethyl-3,4-epoxy-2H-naphtho[2,3-b]pyran-5,10-dione
(23)
A stirred mixture of 8 (0.5 g, 2.08 mmol) in acetone (10 mL) was
treated with dimethyldioxirane (25 mL, 0.09 M in acetone) at r.t. for
4 h. Evaporation of the solvent and purification of the residue by
column chromatography on silica gel afforded 23 (464 mg, 87%) as
a solid; mp 139–140 °C.
HRMS: m/z [M+] calcd for C25H28O3: 376.2038; found: 376.2038.
2,3,4,4a-Tetrahydro-1H-benzo[b]xanthene-6,11-dione (20)
Reaction of 12 (174 mg, 1 mmol) with 1-cyclohexene-1-carboxal-
dehyde (220 mg, 2 mmol) in benzene (10 mL) afforded 20 (245 mg,
92%) as a solid; mp 156 °C.
IR (KBr): 2987, 2936, 1682, 1651, 1618, 1595, 1578, 1435, 1399,
1341, 1314, 1277, 1211, 1154, 1086, 965, 851, 725 cm–1.
IR (KBr): 2940, 1672, 1649, 1597, 1574, 1395, 1345, 1204, 1007,
721 cm–1.
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Y. R. Lee et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 8.14–8.07 (m, 2 H), 7.76–7.65 (m,
2 H), 4.33 (d, J = 4.4 Hz, 1 H), 3.52 (d, J = 4.4 Hz, 1 H), 1.68 (s, 3
H), 1.43 (s, 3 H).
IR (KBr): 3495, 2984, 2922, 1684, 1645, 1595, 1580, 1372, 1341,
1308, 1273, 1211, 1132, 1096, 1042, 957, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10–8.04 (m, 2 H), 7.73–7.69 (m,
2 H), 4.74 (d, J = 7.5 Hz, 1 H), 3.76 (d, J = 7.5 Hz, 1 H), 1.77 (s, 3
H), 1.27 (s, 3 H).
HRMS: m/z [M+] calcd for C15H12O4: 256.0736; found: 256.0738.
3-Bromo-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (24)
HRMS: m/z [M+] calcd for C15H14O5: 274.0841; found: 274.0843.
To a solution of 8 (240 mg, 1 mmol) in THF (5 mL) and H2O (5 mL)
was added NBS (214 mg, 1.2 mmol). The reaction mixture was
stirred for 7 h at 0 °C, the reaction mixture was extracted with Et2O,
and the organic layer was dried over MgSO4. Removal of solvent at
reduced pressure left an oily residue, which was then purified by
column chromatography on silica gel to give 24 (169 mg, 50%) as
a solid; mp 176 °C.
trans-3,4-Dihydroxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (26)
Reaction of 23 (128 mg, 0.5 mmol) with 2 N NaOH (1 mL) using
InCl3 in H2O (5 mL) afforded 26 (85 mg, 62%).
cis-3-Hydroxy-4-methoxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (27) and trans-3-Hydroxy-4-meth-
oxy-2,2-dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-
dione (28)
IR (KBr): 3453, 2926, 1686, 1638, 1618, 1595, 1576, 1460, 1308,
1271, 1208, 1175, 1119, 1034, 953, 727 cm–1.
Reaction of 23 (128 mg, 0.5 mmol) with MeOH (5 mL) using InCl3
afforded 27 (59 mg, 41%) and 28 (65 mg, 45%).
1H NMR (300 MHz, CDCl3): d = 8.10–8.05 (m, 2 H), 7.76–7.69 (m,
2 H), 5.06 (d, J = 6.9 Hz, 1 H), 4.13 (d, J = 6.9 Hz, 1 H), 4.08 (s, 1
H), 1.70 (s, 3 H), 1.55 (s, 3 H).
HRMS: m/z [M+] calcd for C15H13BrO4: 335.9997; found:
335.9998.
27
Mp 145–147 °C.
IR (KBr): 3497, 2938, 1682, 1651, 1616, 1580, 1385, 1337, 1306,
1271, 1213, 1128, 1049, 976, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.06 (m, 2 H), 7.73–7.66 (m,
2 H), 5.28 (s, 1 H), 4.49 (d, J = 4.9 Hz, 1 H), 3.76 (d, J = 4.9 Hz, 1
H), 3.69 (s, 3 H), 1.51 (s, 3 H), 1.44 (s, 3 H).
3,4-Dihydroxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (25)
To a solution of osmium tetroxide (10 mg, 0.04 mmol) and NMO
(0.165 g, 1.1 mmol) in t-BuOH–THF–H2O (10:3:1, 10 mL) was
added 8 (240 mg, 1 mmol) and the reaction mixture was stirred at
r.t. for 12 h. Saturated NaHSO3 solution (50 mL) was added, the
mixture was stirred for 1 h, and extracted with CH2Cl2. Removal of
the solvent at reduced pressure left an oily residue, which was then
purified by column chromatography on silica gel to give 25 (143
mg, 52%) as a solid; mp 63 °C.
HRMS: m/z [M+] calcd for C16H16O5: 288.0998; found: 288.0999.
28
Mp 197–199 °C.
IR (KBr): 3486, 3011, 2984, 2934, 2907, 2830, 1672, 1651, 1618,
1595, 1579, 1383, 1337, 1312, 1271, 1209, 1128, 972, 870 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.07 (m, 2 H), 7.74–7.63 (m,
2 H), 4.33 (d, J = 3.0 Hz, 1 H), 3.89 (d, J = 3.0 Hz, 1 H), 3.63 (s, 3
H), 1.56 (s, 3 H), 1.47 (s, 3 H).
IR (KBr): 3495, 2926, 1684, 1657, 1615, 1462, 1373, 1337, 1308,
1271, 1213, 1130, 1051, 961, 775 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.13–8.08 (m, 2 H), 7.70–7.69 (m,
2 H), 4.95 (d, J = 4.8 Hz, 1 H), 4.04 (d, J = 4.8 Hz, 1 H), 1.64 (s, 3
H), 1.46 (s, 3 H).
HRMS: m/z [M+] calcd for C16H16O5: 288.0998; found: 288.0996.
HRMS: m/z [M+] calcd for C15H14O5: 274.0841; found: 274.0842.
trans-3-Hydroxy-4-methoxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (28)
Reaction of 23 (128 mg, 0.5 mmol) with NaOMe (108 mg, 2 mmol)
Ring Opening of Epoxide 23 with Nucleophiles; General Proce-
dure
in MeOH (5 mL) afforded 28 (98 mg, 68%).
In(III)-Catalyzed Reaction: To a solution of epoxide 23 (128 mg,
0.5 mmol) and nucleophile in neat or in CH2Cl2 (5 mL) was added
InCl3 (11 mg, 0.05 mmol). The reaction mixture was stirred at r.t.
for 5 h and the solvent was removed under reduced pressure. The
residue was purified by column chromatography to give the prod-
uct.
trans-4-Ethoxy-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (29)
Reaction of 23 (128 mg, 0.5 mmol) with NaOMe (136 mg, 2 mmol)
in EtOH (5 mL) afforded 29 (91 mg, 60%) as a solid; mp 187–189
°C.
Base-Catalyzed Reaction: Nucleophile was added to a solution of
epoxide 23 (128 mg, 0.5 mmol) in a solvent (5 mL). The reaction
mixture was stirred at r.t. for 2 h, the mixture was acidified by 2 N
HCl solution, and extracted with EtOAc. Removal of the solvent at
reduced pressure left an oily residue, which was then purified by
column chromatography on silica gel to give the product.
IR (KBr): 3468, 2980, 1682, 1651, 1618, 1385, 1337, 1273, 1209,
1134, 1090, 964, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.10–8.07 (m, 2 H), 7.74–7.66 (m,
2 H), 4.43 (d, J = 3.0 Hz, 1 H), 3.95–3.80 (m, 3 H), 1.56 (s, 3 H),
1.50 (s, 3 H), 1.21 (t, J = 7.0 Hz, 3 H).
HRMS: m/z [M+] calcd for C17H18O5: 316.1311; found: 316.1314.
cis-3,4-Dihydroxy-2,2-dimethyl-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (25) and trans-3,4-Dihydroxy-2,2-
dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione (26)
Reaction of 23 (128 mg, 0.5 mmol) with H2O (36 mg, 2 mmol) us-
ing InCl3 in CH2Cl2 (5 mL) afforded 25 (41 mg, 30%) and 26 (58
mg, 42%).
cis-3-Hydroxy-2,2-dimethyl-4-phenoxy-3,4-dihydro-2H-ben-
zo[g]chromene-5,10-dione (30) and trans-3-Hydroxy-2,2-di-
methyl-4-phenoxy-3,4-dihydro-2H-benzo[g]chromene-5,10-
dione (31)
Reaction of 23 (128 mg, 0.5 mmol) with PhOH (188 mg, 2 mmol)
using InCl3 in CH2Cl2 (5 mL) afforded 30 (60 mg, 34%) and 31 (70
mg, 40%).
26
Mp 39–40 °C.
Synthesis 2005, No. 18, 3026–3034 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyranonaphthoquinone Derivatives
3033
30
cis-3-Hydroxy-2,2-dimethyl-4-pyrrolidin-1-yl-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione (35) and trans-3-Hydroxy-2,2-
dimethyl-4-pyrrolidin-1-yl-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione (36)
Reaction of 23 (128 mg, 0.5 mmol) with pyrrolidine (142 mg, 2
mmol) using InCl3 in CH2Cl2 (5 mL) afforded 35 (49 mg, 30%) and
36 (85 mg, 52%).
Mp 183–185 °C.
1H NMR (300 MHz, CDCl3): d = 8.15–8.07 (m, 2 H), 7.71–7.67 (m,
2 H), 7.37–7.32 (m, 2 H), 7.22–7.19 (m, 2 H), 7.09–7.04 (m, 1 H),
5.54 (d, J = 4.7 Hz, 1 H), 3.96 (d, J = 4.7 Hz, 1 H), 1.54 (s, 3 H),
1.21 (s, 3 H).
IR (KBr): 3497, 2926, 2857, 1723, 1682, 1651, 1618, 1595, 1493,
1466, 1385, 1337, 1271, 1217, 1130, 1055, 976 cm–1.
HRMS: m/z [M+] calcd for C21H18O5: 350.1154; found: 350.1155.
35
Mp 133–135 °C.
IR (KBr): 3447, 2973, 1682, 1649, 1611, 1578, 1337, 1306, 1271,
1211, 1130, 1044, 982, 729 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.11–8.04 (m, 2 H), 7.73–7.66 (m,
2 H), 4.25 (d, J = 5.7 Hz, 1 H), 3.86 (d, J = 5.7 Hz, 1 H), 3.37–3.28
(m, 2 H), 3.01–2.97 (m, 2 H), 1.89–1.77 (m, 4 H), 1.46 (s, 3 H), 1.43
(s, 3 H).
31
Mp 200–202 °C.
IR (KBr): 3488, 3069, 3011, 2982, 2934, 1676, 1649, 1628, 1591,
1489, 1385, 1341, 1275, 1221, 1128, 1073, 1026, 966 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.14–8.08 (m, 2 H), 7.75–7.62 (m,
2 H), 7.36–7.31 (m, 2 H), 7.15–7.13 (m, 2 H), 7.05–7.01 (m, 1 H),
5.41 (d, J = 2.4 Hz, 1 H), 3.98 (d, J = 2.4 Hz, 1 H), 1.59 (s, 3 H),
1.55 (s, 3 H).
HRMS: m/z [M+] calcd for C19H21NO4: 327.1471; found: 327.1472.
36
HRMS: m/z [M+] calcd for C21H18O5: 350.1154; found: 350.1157.
Mp 140–141 °C.
IR (KBr): 3515, 2967, 2866, 1678, 1649, 1607, 1578, 1335, 1273,
1211, 1046, 974, 725 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.08–8.03 (m, 2 H), 7.72–7.24 (m,
2 H), 3.82 (d, J = 7.6 Hz, 1 H), 3.66 (d, J = 7.6 Hz, 1 H), 3.10–3.00
(m, 2 H), 2.77–2.65 (m, 2 H), 1.79–1.72 (m, 4 H), 1.63 (s, 3 H), 1.34
(s, 3 H).
cis-4-Ethylsulfanyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione (32) and trans-4-Ethylsulfanyl-3-
hydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-
dione (33)
Reaction of 23 (128 mg, 0.5 mmol) with EtSH (124 mg, 2 mmol)
using InCl3 in CH2Cl2 (5 mL) afforded 32 (25 mg, 16%) and 33 (103
mg, 65%).
HRMS: m/z [M+] calcd for C19H21NO4: 327.1471; found: 327.1470.
32
cis-3-Hydroxy-2,2-dimethyl-4-phenylamino-3,4-dihydro-2H-
benzo[g]chromene-5,10-dione (37) and trans-3-Hydroxy-2,2-
dimethyl-4-phenylamino-3,4-dihydro-2H-benzo[g]chromene-
5,10-dione (38)
Reaction of 23 (128 mg, 0.5 mmol) with aniline (186 mg, 2 mmol)
using InCl3 in CH2Cl2 (5 mL) afforded 37 (49 mg, 28%) and 38 (103
mg, 59%).
Mp 139–141 °C.
IR (KBr): 3432, 2982, 1682, 1645, 1611, 1578, 1366, 1337, 1271,
1219, 1127, 1092, 1042, 974, 723 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.06 (m, 2 H), 7.74–7.64 (m,
2 H), 4.06 (d, J = 6.2 Hz, 1 H), 3.92 (d, J = 6.2 Hz, 1 H), 3.06–2.97
(m, 2 H), 1.58 (s, 3 H), 1.36 (t, J = 7.4 Hz, 3 H), 1.28 (s, 3 H).
HRMS: m/z [M+] calcd for C17H18O4S: 318.0926; found: 318.0927.
37
Mp 178–180 °C.
33
IR (KBr): 3437, 3353, 1711, 1682, 1603, 1578, 1499, 1368, 1335,
1304, 1271, 1211, 1130, 1049, 976, 748 cm–1.
Mp 167–169 °C.
1H NMR (300 MHz, CDCl3): d = 8.12–8.03 (m, 2 H), 7.74–7.64 (m,
2 H), 7.31–7.26 (m, 2 H), 6.96–6.90 (m, 3 H), 4.58 (d, J = 4.8 Hz, 1
H), 3.91 (d, J = 4.8 Hz, 1 H), 1.61 (s, 3 H), 1.44 (s, 3 H).
IR (KBr): 3513, 2975, 2919, 1667, 1651, 1607, 1576, 1364, 1339,
1277, 1208, 1123, 1051, 961, 725 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.09–8.06 (m, 2 H), 7.74–7.63 (m,
2 H), 3.80 (d, J = 6.2 Hz, 1 H), 3.64 (d, J = 6.2 Hz, 1 H), 3.09–2.88
(m, 2 H), 1.57 (s, 3 H), 1.39 (s, 3 H), 1.34 (t, J = 7.4 Hz, 3 H).
HRMS: m/z [M+] calcd for C21H19NO4: 349.1314; found: 349.1316.
HRMS: m/z [M+] calcd for C17H18O4S: 318.0926; found: 318.0925.
38
Mp 165–167 °C.
trans-3-Hydroxy-2,2-dimethyl-4-phenylsulfanyl-3,4-dihydro-
2H-benzo[g]chromene-5,10-dione (34)
Reaction of 23 (128 mg, 0.5 mmol) with PhSH (220 mg, 2 mmol)
using InCl3 in CH2Cl2 (5 mL) afforded 34 (143 mg, 78%) as a solid;
mp 180–182 °C.
IR (KBr): 3484, 3401, 1684, 1605, 1574, 1501, 1370, 1335, 1275,
1211, 1138, 965, 750 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.11–8.03 (m, 2 H), 7.77–7.65 (m,
2 H), 7.27–7.22 (m, 2 H), 6.92–6.79 (m, 3 H), 4.58 (d, J = 6.1 Hz, 1
H), 3.95 (d, J = 6.1 Hz, 1 H), 1.58 (s, 3 H), 1.46 (s, 3 H).
IR (KBr): 3505, 3065, 2984, 2922, 1669, 1655, 1610, 1578, 1480,
1366, 1335, 1308, 1277, 1211, 1123, 1057, 961, 727 cm–1.
HRMS: m/z [M+] calcd for C21H19NO4: 349.1314; found: 349.1315.
1H NMR (300 MHz, CDCl3): d = 8.13–8.06 (m, 2 H), 7.75–7.65 (m,
2 H), 7.60–7.57 (m, 2 H), 7.33–7.29 (m, 3 H), 4.10 (d, J = 5.7 Hz, 1
H), 3.86 (d, J = 5.7 Hz, 1 H), 2.40 (s, 1 H), 1.60 (s, 3 H), 1.41 (s, 3
H).
Acknowledgment
This work was supported by grant number R12-2003-002-05001-0
from the basic research program of the Korea Science and Engi-
neering Foundation. Dr. Ronald Tepper is greatly thanked for useful
discussion of this work.
HRMS: m/z [M+] calcd for C21H18O4S: 366.0926; found: 366.0929.
Synthesis 2005, No. 18, 3026–3034 © Thieme Stuttgart · New York

3034
Y. R. Lee et al.
PAPER
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