Concise synthesis of heterocycle-fused naphthoquinones by employing sonogashira coupling and tandem addition-elimination/intramolecular cyclization

Article abstract of DOI:10.1248/cpb.c13-00102

A concise method for the synthesis of heterocycle-fused naphthoquinones such as naphtho[2,3-b]-furan-4,9-dione, 1H-benz[f]indole-4,9-dione, and naphtho[2,3-b]thiophene-4,9-dione was developed. This method employed Sonogashira coupling and tandem addition-

Full text of DOI:10.1248/cpb.c13-00102

648
Regular Article
Chem. Pharm. Bull. 61(6) 648–654 (2013)
Vol. 61, No. 6
Concise Synthesis of Heterocycle-Fused Naphthoquinones by Employing
Sonogashira Coupling and Tandem Addition-Elimination/Intramolecular
Cyclization
,a
Kazunori Ueda,a Mitsuaki Yamashita,a Koichi Sakaguchi,a Harukuni Tokuda,b and Akira Iida*
a School of Agriculture, Kinki University; Nakamachi, Nara 631–8505, Japan: and b Department of
Complementary and Alternative Medicine R&D, Graduate School of Medical Science, Kanazawa University; Takara-
machi, Kanazawa 920–8640, Japan.
Received February 2, 2013; accepted March 19, 2013
A concise method for the synthesis of heterocycle-fused naphthoquinones such as naphtho[2,3-b]-
furan-4,9-dione, 1H-benz[f]indole-4,9-dione, and naphtho[2,3-b]thiophene-4,9-dione was developed. This
method employed Sonogashira coupling and tandem addition-elimination/intramolecular cyclization, and it
enabled the preparation of versatile heterocycle-fused naphthoquinones from one substrate.
Key words naphthoquinone; addition-elimination; intramolecular cyclization
Heterocycle-fused naphthoquinones such as naphtho[2,3- mo-2-(dimethylamino)-5-hydroxynaphthalene-1,4-dione
(2a)
b]furan-4,9-dione,1–7) 1H-benz[f]indole-4,9-dione,8–17) and with but-3-yn-2-ol (4a) because we29) and another research
naphtho[2,3-b]thiophene-4,9-dione,18–27) which display a va- group34) independently reported that the presence of the phe-
riety of biological activities, are found in various natural nolic hydroxy group at C-5 considerably increases the anti-
and artificial compounds. Despite the importance of these proliferative effect of naphthoquinones on human-tumor cell
compounds, a survey of the literature revealed that very few lines. We used our previously reported procedure with a few
efficient general methods have been developed to prepare modifications33,35) and examined the reaction of 2a (1eq) with
heterocycle-fused naphthoquinones although many proce- racemic 4a (2eq) in the presence of Cu2O (0.2eq), pyridine
dures have been established to prepare specific compounds. (100eq, i.e., pyridine–copper=50:1), and K2CO3 (0.4eq) in
We are interested in studying heterocycle-fused naphtho- N,N-dimethylformamide (DMF) at room temperature. The
quinones isolated from Tabebuia avellanedae Lorentz ex conversion of 2a to 3aa occurred using our reaction condi-
28)
Griseb (Bignoniaceae) (syn. T. impetiginosa). Among these tions, and 3aa was obtained in 84% yield (Table 1, entry 1).
constituents, we previously reported that (−)-5-hydroxy-2-(1′- Decreasing the amount of copper salt to 0.1eq gave a lower
hydoxyethyl)naphtho[2,3-b]furan-4,9-dione (1aa) has a strong yield of 3 (Table 1, entry 2). Next, using the reaction condi-
antiproliferative activity against various tumor cell lines29–31) tions shown in the entry 1 of Table 1, we tested the coupling
(Fig. 1). In addition, we reported the stereoselective synthesis reaction on a series of halogenated naphthoquinones 2 and ter-
of 1aa using Noyori reduction as a key step although tedious minal acetylenes 4. Alkynes bearing an aryl or alkyl substitu-
manipulations necessary in the synthesis and an inadequate ent reacted smoothly with the halogenated naphthoquinone 2a
enantiomeric excess from the final asymmetric hydrogenation to give the desired products 3ab and 3ac in good yields (Table
prevented its further application. Recently, indolequinones 1, entries 3, 4). In addition, a satisfactory result was obtained
were synthesized via Sonogashira coupling effectively, fol- using the halogenated naphthoquinone 2b which does not have
lowed by copper-catalyzed intramolecular cyclization.32,33) In a hydroxyl group on the aromatic ring as a substrate (Table 1,
this synthesis, halogenated quinones reacted smoothly with entry 5). The yield of 3ca decreased slightly when naphtho-
terminal acetylenes to give the coupling product. Therefore, quinone 2c, which has a hydroxyl group at C-8, was used as
we decided to use this methodology to synthesize 1aa and its the substrate (Table 1, entry 6).
related compounds. Here, we describe the development of a
Next, we tested a range of reaction conditions for the
general and concise method for constructing heterocycle-fused cyclization step, whose results are summarized in Table 2.
naphthoquinone motifs involving Sonogashira coupling and Unfortunately, the hydrolysis and cyclization of 3aa under
tandem addition-elimination/intramolecular cyclization.
acidic or basic conditions failed, and only the degradation
of the starting material 3aa was observed.36) We assumed
that degradation occurred under these reaction conditions
Results and Discussion
Chart 1 shows our strategies. The product 3 that is synthe- because of the lability of the compound 3 as hydrolysis oc-
sized from the halogenated naphthoquinone 2 with the termi- curred smoothly under acidic conditions in the absence of an
nal acetylene 4 using Sonogashira coupling was a key inter- alkynyl group at C-3.37) However, we found that the desired
mediate in the synthesis of heterocycle-fused naphthoquinones product could be obtained when the reaction mixture was
1 because the replacement of the dimethylamino group of 3 by
another functional group (a hydroxyl, thiol, or amino group)
followed by intramolecular cyclization would allow the con-
struction of diverse heterocycle-fused naphthoquinone motifs.
First, we investigated the Sonogashira coupling of 3-bro-
The authors declare no conflict of interest.
Fig. 1. Structure of 1aa
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: iida@nara.kindai.ac.jp

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649
Chart 1. Synthesis of 1 from 2
Table 1. Reaction of 3-Bromo-2-(dimethylamino)-naphthalene-1,4-dione (2) with Acetylene (4)a)
Entry
1
Substrate 2 X, Y
OH, H (2a)
Acetylene 4 R
Time (h)
17
Product
Yield (%)b)
CH(OH)CH3 (4a)
84
3aa
2c)
OH, H (2a)
OH, H (2a)
CH(OH)CH3 (4a)
Ph (4b)
22
17
3aa
59 (24)d)
93
3
3ab
3ac
4e)
OH, H (2a)
H, H (2b)
CH2CH2Ph (4c)
5
92
91
5
CH(OH)CH3 (4a)
17
3ba
3ca
6
H, OH (2c)
CH(OH)CH3 (4a)
21
62
a) Substrate 1 (0.5mmol), Pd(OAc)2 (3mol%), Cu2O (0.1mmol), acetylene (1.0mmol), pyridine (8.0mL), and K2CO3 (0.2mmol) were stirred in DMF at rt. b) Isolated yield.
c) Cu2O (0.05mmol) was used. d) The numbers in parentheses are the yields of 2a recovered. e) At 50°C.
refluxed in wet methanol (Table 2, entry 1). We screened a pleted within approximately 4h, and cyclized products were
range of solvents and solvent-volume ratios to identify the obtained in similar yields (Table 2, entries 10, 11). Using one
most-effective reaction system and found that polar aprotic equivalent or 0.5eq of H2O to 1eq of MeOH did not increase
solvents such as MeCN, tetrahydrofuran (THF), acetone, and the yield (the total volume was 30mL in each case) (Table 2,
dioxane were ineffective in promoting the reaction (Table 2, entries 12, 13), suggesting that the optimum solvent mixture
entries 4–8). In contrast, polar protic solvents such as alcohols contains 2eq of H2O to 1eq of MeOH (with a total volume of
afforded the cyclized product 1aa in 55–61% yields (Table 2, 30mL). Finally, we found that using DMF as a co-solvent in-
entries 2, 3). The reaction of 3aa in MeOH (without H2O) was creased the yield (Table 2, entry 14), and we speculate that the
examined, but only a trace of the desired product was found increased solubility of the substrate 3aa contributed to better
indicating that a certain amount of H2O is essential for this yields. Moreover, we tested large-scale reactions at higher and
reaction (Table 2, entry 9). Therefore, we tested the effect of lower concentrations (Table 2, entries 15, 16, respectively) and
reaction concentration and the volume ratio of H2O to MeOH. found results comparable to those shown in the entry 14 of the
Irrespective of reaction concentration, the reactions were com- Table 2.

650
Vol. 61, No. 6
We tested a range of reaction conditions to evaluate the po- hydrogen bond between carbonyl oxygen at C-4 and hydroxyl
tential of the general synthetic methods for heterocycle-fused group at C-5 plays a crucial role in the addition-elimination
naphthoquinones. The reaction of the substrate 3aa with Na2S step.
in H2O and MeOH (H2O–MeOH=1:10) proceeded smoothly
Finally, the ability of (S)-1bb, which was synthesized from
to give thiophene-fused naphthoquinone 1bb in 88% yield 3aa and commercially available (S)-4a using the developed
(Table 3, entry 1). However, the replacement of the dimeth- method, to suppress the growth of human tumor cell lines, in-
ylamino group of 3aa by an amino group, without a second cluding A549 (lung) and MCF-7 (breast), was tested. The com-
cyclization, occurred when aqueous NH3 solution was used. pound (S)-1bb exhibited comparable antiproliferative effects
Adding an excess of K2CO3 to the reaction mixture resulted to that of β-lapachone against both cell lines, with the IC50 of
in conversion to the cyclized product 1cc in 57% yield (Table (S)-1bb and β-lapachone against A549 being 5.57 and 4.21µm,
3, entry 2). Moreover, these reaction conditions were suitable respectively, and the IC50 of (S)-1bb and β-lapachone against
for the reaction with methylamine although sodium hydrox- MCF-7 being 5.57 and 9.96µm, respectively. β-Lapachone
ide was used as the base, giving N-methylated pyrrole-fused is known as a potent anticancer compound contained in Ta-
naphthoquinones 1dd in 72% yield. We conducted further in- bebuia avellanedae similarly to 1aa and β-lapachone-based
vestigations using various substrates and reacted the coupling anticancer drug is recently developing in U.S.A.38) Therefore,
products 3ba, 3ab, 3ac, and 3ca under conditions A–D (de- heterocycle-fused naphthoquinone analogues are promising
tailed in Table 3). The reaction of 3ba, which contains a more anticancer compounds.
general naphthoquinone motif, using reaction conditions A–C
gave the cyclized products 1ee, 1ff, and 1gg, respectively, with
rather lower chemical yields than those obtained for 1bb or
Conclusion
In conclusion, we developed a general method to construct
1dd. (Table 3, entries 4–6). The substrate 3ab, which has a heterocycle-fused naphthoquinones utilizing Sonogashira cou-
phenyl substituent, gave the desired product 1hh in moderate pling and tandem addition-elimination/intramolecular cycliza-
yield, whereas a lower yield was surprisingly found when the tion. The future applications of this strategy and the biological
substrate 3ac, which has a 2-phenylethyl substituent, was used activities of the various naphthoquinones synthesized are cur-
(Table 3, entries 7, 8). Unsatisfactory yields were obtained rently being investigated and will be reported in due course.
when the naphthoquinone 3ca, which has a hydroxyl group at
C-8, was used as the substrate (Table 3, entry 9). TLC analysis
during the reaction shown in the entry 9 of the Table 3 re-
Experimental
General All melting points are uncorrected. 1H- and
vealed that the consumption of the substrate was slower in this 13C-NMR spectra (500MHz for 1H and 125MHz for 13C)
reaction than that while using the substrate shown in the entry were obtained in CDC13, unless otherwise noted. The chemi-
14 of the Table 2, under the same reaction conditions. Thus, cal shift values are expressed in ppm relative to internal
we speculated that the lower reactivity of the substrate 3ca in tetramethylsilane. Abbreviations are as follows: s, singlet;
the first addition-elimination step causes degradation to un- d, doublet; t, triplet; m, multiplet; br, broad. IR is expressed
known compounds during the reaction, and the intramolecular in cm−1. Purification was performed using silica gel column
Table 2. Conversion of the Coupling Product 3aa to the Cyclized Product 1aaa)
Entry
Solvent
Volume ratio H2O : Solvent
Time (h)
(
)-1aa Yield (%)b)
1
2
MeOH
EtOH
2:1
2:1
1.5
5
56
55
3
4
5
6
7
8
9
BuOH
MeCN
THF
Acetone
Dioxane
DMF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2:1
2:1
2:1
2:1
2:1
2:1
12
12
12
12
12
4
36
2
4
4
20
5
5
5
61
41
No reaction
37
0
39
Trace
52
52
39
44
74
66
77
MeOH only
2:1
10c)
11d)
12
13
14e)
15ꢀꢀf–h)
16ꢀf,h,i)
2:1
1:1
1:2
2:1
2:1
2:1
a) A solution of the substrate 3 (0.11mmol) in H2O and solvent (total volume: 30mL) were refluxed. b) Isolated yield. c) Total volume was 9mL. d) Total volume was
90mL. e) DMF (500µL) was used. f) Substrate 3 (0.50mmol) was used. g) Total volume was 45mL. h) DMF (2.5mL) was used. i) Total volume was 144mL.

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651
Table 3. Conversion of the Coupling Product 3 to the Cyclized Product 1
Entry
1
Substrate
Time (h)
15
Conditions
Product
Yield (%)a)
Na2S, H2O–MeOH (1:10),
rt (condition B)
88
1bb
3aa
28% NH3 aq, K2CO3, DMF,
at 80°C (condition C)
2
3
3aa
3aa
3
3
57
72
1cc
CH3NH2·HCl, Et3N, NaOH,
NMP–H2O (10:1),
at 80°C (Condition D)
1dd
H2O–MeOH (2:1),
reflux (condition A)
4
20
47
1ee
3ba
5
6
3ba
3ba
24
3
Condition B
Condition C
56
38
1ff
1gg
7
8
24
24
Condition A
Condition A
70
40
3ab
3ac
1hh
1ii
9
24
Condition A
30
1jj
3ca
a) Isolated yield. Condition A: Substrate 3 (0.5mmol) were refluxed in H2O–MeOH (2:1) (total volume: 144mL). Condition B: Substrate 3 (0.5mmol) and Na2S (1.0mmol)
were stirred in H2O–MeOH (1:10) (total volume: 11mL) at rt. Condition C: Substrate 3 (0.5mmol), 28% NH3 aq. (5.0mmol) and K2CO3 (2.5mmol) were stirred in the solvent
(30mL) at 80–100°C. Condition D: Substrate 3 (0.5mmol), CH3NH2·HCl (1.5mmol), Et3N (1.5mmol) and NaOH (5.0mmol) were stirred in the solvent (33mL) at 80°C.
chromatography. All reagents were purchased from chemical added a solution of N-bromosuccinimide (NBS) (491mg,
companies and used as received. All reactions were conducted 2.76mmol) in DMF (6mL), and the mixture was stirred for
under an argon atmosphere, unless otherwise stated.
0.5h at rt. The mixture was quenched with H2O at 0°C and
3-Bromo-2-(dimethylamino)-5-hydroxynaphthalene-1,4-di- extracted with EtOAc. The organic extracts were washed with
one (2a)39): To a solution of 2-(dimethylamino)-5-hydroxynaph- H2O and brine, dried over Na2SO4, and then concentrated.
thalene-1,4-dione (500mg, 2.30mmol) in DMF (15mL) was The column chromatography (hexane–EtOAc=12:1) gave 2a

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Vol. 61, No. 6
1
(656mg, 96% yield) as red solid with mp 90–91°C. H-NMR The column chromatography (hexane–EtOAc=12:1) gave
δ: 3.29 (6H, s), 7.18–7.20 (1H, m), 7.46–7.50 (2H, m), 12.45 3ab (147mg, 93% yield) as purple solid with mp 128–129°C.
(1H, s). 13C-NMR δ: 45.0, 109.7, 113.7, 119.5, 124.4, 131.3, 1H-NMR δ: 3.47 (6H, s), 7.17–7.19 (1H, m), 7.31–7.35 (3H, m),
134.6, 154.3, 160.5, 181.2, 183.1.
7.43–7.48 (2H, m), 7.50–7.53 (2H, m), 12.78 (1H, s). 13C-NMR
δ: 45.1, 84.2, 102.4, 104.1, 114.5, 118.8, 123.4, 124.4, 128.3,
2-Bromo-3-(dimethylamino)naphthalene-1,4-dione (2b)35)
:
To the solution of 2-bromonaphthalene-1,4-dione (2.00g, 128.4, 130.9, 132.2, 134.4, 154.9, 160.4, 182.4, 187.4. IR (KBr):
8.44mmol) in toluene (100mL) was added dimethylamine 1680, 1618, 1338, 1161, 1067, 922, 880, 754. HR-MS (ESI)
(12.6mL, 2.0m solution in THF, 25.3mmol) at 0°C. After the m/z: [M+Na]+ Calcd for [C20H15NO3Na]+, 340.0950; Found,
mixture was stirred for 12h, the solvent was removed under 340.0939.
reduced pressure. The residue was purified by column chro-
2-(Dimethylamino)-5-hydroxy-3-(4-phenylbut-1-yn-1-yl)-
matography (hexane–EtOAc=4:1) to give 2-(dimethylamino)- naphthalene-1,4-dione (3ac): Starting from 2a and 4c, this
naphthalene-1,4-dione (2.13g, 90% yield) as red solid. To a compound was prepared according to the general procedure
solution of 2-(dimethylamino)naphthalene-1,4-dione (1.50g, at 50°C. The column chromatography (hexane–EtOAc=
7.50mmol) in DMF (30mL) was added a solution of NBS 12:1) gave 3ac (159mg, 92% yield) as purple solid with mp
1
(1.60g, 9.00mmol) in DMF (15mL), and the mixture was 88–90°C. H-NMR δ: 2.85–2.89 (2H, dd), 2.93–2.97 (2H, dd),
stirred for 0.5h at rt. The mixture was quenched with H2O 3.17 (6H, s), 7.15–7.32 (6H, m), 7.43–7.44 (2H, m), 12.80 (1H,
at 0°C and extracted with EtOAc. The organic extracts s). 13C-NMR δ: 22.1, 34.7, 44.7, 75.5, 103.0, 104.7, 114.4, 118.7,
were washed with H2O and brine, dried over Na2SO4, and 124.3, 126.3, 128.4, 128.5, 132.1, 134.3, 140.5, 155.2, 160.3,
then concentrated. The column chromatography (hexane– 182.6, 187.9. IR (KBr): 2920, 1666, 1616, 1475, 1383, 1066,
EtOAc=12:1) gave 2b (1.60g, 76% yield) as red solid with 947, 845, 783, 762. HR-MS (ESI) m/z: [M+Na]+ Calcd for
1
mp 110–112°C. H-NMR δ: 3.25 (6H, s), 7.61–7.69 (2H, m), [C22H19NO3Na]+, 368.1263; Found, 368.1255.
7.96–7.98 (1H, m), 8.07–8.09 (1H, m). 13C-NMR δ: 44.7, 112.9,
2-(Dimethylamino)-3-(3-hyd roxybut-1-y n-1-yl)-
126.6, 126.7, 131.2, 131.3, 132.7, 133.9, 153.5, 177.8, 181.8.
naphthalene-1,4-dione (3ba): Starting from 2b and 4a, this
2-Bromo-3-(dimethylamino)-5-hydroxynaphthalene-1,4-di- compound was prepared according to the general procedure.
one (2c)39): To a solution of 2-(dimethylamino)-8-hydroxynaph- The column chromatography (hexane–EtOAc=2:1) gave
thalene-1,4-dione (1.0g, 4.61mmol) in DMF (30mL) was 3ba (122mg, 91% yield) as purple solid with mp 117–118°C.
added a solution of NBS (980mg, 5.53mmol) in DMF (12mL), 1H-NMR δ: 1.55 (3H, d, J=6.6Hz), 3.35 (6H, s), 4.86 (1H, q,
and the mixture was stirred for 0.5h at rt. The mixture was J=6.6Hz), 7.56 (1H, ddd, J=1.4, 7.5, 7.5Hz), 7.63 (1H, ddd,
quenched with H2O at 0°C and extracted with EtOAc. The J=1.4, 7.5, 7.5Hz), 7.88 (1H, dd, J=1.4, 7.5Hz), 8.00 (1H, dd,
organic extracts were washed with H2O and brine, dried over J=1.4, 7.5Hz). 13C-NMR δ: 23.8, 44.9, 58.8, 78.9, 104.5, 104.6,
Na2SO4, and then concentrated. The column chromatography 125.8, 126.3, 132.0, 132.3, 132.4, 133.9, 154.6, 182.2, 183.0. IR
(hexane–EtOAc=12:1) gave 2c (980mg, 72% yield) as red (KBr): 3423, 1670, 1547, 1340, 1279, 1016, 978, 723. HR-MS
1
solid with mp 109–111°C. H-NMR δ: 3.25 (6H, s), 7.17 (1H, (ESI) m/z: [M+H]+ Calcd for [C16H16NO3]+, 270.1130; Found,
dd, J= 1.1, 8.3Hz), 7.54–7.58 (1H, m), 7.65 (1H, dd, J=1.1, 270.1136.
7.5Hz), 11.81 (1H, s). 13C-NMR δ: 44.9, 114.3, 114.8, 119.5,
3-(Dimethylamino)-5-hydroxy-2-(3-hydroxybut-1-yn-1-yl)-
123.3, 131.5, 136.6, 153.0, 161.8, 177.4, 186.9.
naphthalene-1,4-dione (3ca): Starting from 2c and 4a, this
General Procedure for Sonogashira Reaction of Naph- compound was prepared according to the general procedure.
thoqionone 2 with Acetylene 4 Under Ar atmosphere, a The column chromatography (hexane–EtOAc=3:1) gave 3ca
mixture of Cu2O (14mg, 0.10mmol), acetylene 4 (1.00mmol), (88mg, 62% yield) as purple solid with mp >135°C (dec).
K2CO3 (28mg, 0.20mmol), and pyridine (8.0mL, 100mmol) 1H-NMR δ: 1.57 (3H, d, J=6.6Hz), 3.42 (6H, s), 4.87 (1H, q,
was stirred for 2h at rt. A solution of compound 2 (0.50mmol) J=6.6Hz), 7.13 (1H, dd, J=1.5, 7.9Hz), 7.55 (1H, dd, J=7.5,
and Pd(OAc)2 (3.4mg, 0.015mmol) in DMF (5.0mL) was 7.9Hz), 7.59 (1H, dd, J=1.5, 7.5Hz), 11.87 (1H, s). 13C-NMR
added to this suspension, and the reaction mixture was stirred δ: 23.9, 45.3, 59.0, 78.8, 105.5, 106.5, 114.9, 118.6, 123.0, 132.4,
at rt. The mixture was quenched with H2O at 0°C and extract- 136.9, 153.9, 161.7, 181.6, 187.8. IR (KBr): 1680, 1618, 1550,
ed with CHCl3. The organic extracts were washed with H2O 1477, 1386, 1296, 1066, 922, 754. HR-MS (ESI) m/z: [M+H]+
and brine, dried over Na2SO4, and then concentrated.
Calcd for [C16H16NO4]+, 286.1079; Found, 286.1077.
2-(Dimethylamino)-5-hydroxy-3-(3-hydroxybut-1-yn-1-yl)-
General Procedure for Tandem Addition-Elimination/
naphthalene-1,4-dione (3aa): Starting from 2a and 4a, this Intramolecular Cyclization Reaction Condition A:
A
compound was prepared according to the general procedure. solution of compound 3 (0.50mmol) in DMF (2.5mL) was
The column chromatography (hexane–EtOAc=3:1) gave added to the solution of H2O (96mL) and MeOH (48mL) and
3aa (120mg, 84% yield) as purple solid with mp 126–128°C. was stirred at reflux. The mixture was extracted with EtOAc
1H-NMR δ: 1.57 (3H, d, J=6.6Hz), 3.42 (6H, s), 4.86 (1H, q, and the organic extracts were washed with brine, dried over
J=6.6Hz), 7.18–7.20 (1H, m), 7.45–7.47 (2H, m), 12.68 (1H, s). Na2SO4, and then concentrated.
13C-NMR δ: 24.0, 45.3, 59.1, 78.3, 103.0, 104.2, 114.5, 119.0,
Condition B: To a suspension of Na2S (78mg, 1.00mmol)
124.6, 132.2, 134.5, 155.5, 160.4, 182.6, 187.7. IR (KBr): 3464, in MeOH (10mL) and H2O (1mL) was added compound 3
1624, 1547, 1473, 1068, 935, 895, 779. High resolution (HR)- (0.50mmol), then stirred at rt. The mixture was quenched
MS (electrospray ionization (ESI)) m/z: [M+H]+ Calcd for with H2O at 0°C and extracted with EtOAc. The organic ex-
[C16H16NO4]+, 286.1079; Found, 286.1077.
tracts were washed with H2O and brine, dried over Na2SO4,
2-(Dimethylamino)-5-hydroxy-3-(phenylethynyl)- and then concentrated.
naphthalene-1,4-dione (3ab): Starting from 2a and 4b, this
Condition C: To a solution of compound (0.50mmol)
compound was prepared according to the general procedure. in DMF (30mL) was added 28% aqueous NH3 (0.40mL,

June 2013
653
5.00mmol), and then, the mixture was stirred at 80°C. TLC of dd, J=7.3, 8.4Hz), 7.65 (1H, dd, J=1.1, 7.3Hz), 12.58 (1H, s).
the mixture (hexane–EtOAc=1:1) showed absence of starting 13C-NMR δ: 22.2, 33.4, 62.1, 105.1, 115.5, 119.2, 124.1, 126.8,
material. After adding K2CO3 (345mg, 2.50mmol), the reac- 131.8, 134.4, 135.4, 145.4, 162.0, 175.7, 186.8.
tion mixture was stirred at 80°C. The mixture was extracted
with CHCl3. The organic extracts were washed with H2O and Starting from 3ba, this compound was prepared according
brine and dried over Na2SO4 and then concentrated. to the general procedure (Condition A). The column chroma-
2-(1-Hydroxyethyl)naphtho[2,3-b]furan-4,9-dione
(1ee):
Condition D: A mixture of compound 3 (0.50mmol), tography (hexane–EtOAc=2:1) gave 1ee (57mg, 47% yield)
1
MeNH2· HCl (101mg, 1.50mmol) and Et3N (0.21mL, as yellow solid with mp 153–155°C. H-NMR δ: 1.59 (d, 3H,
1.50mmol) in NMP (30mL) was stirred for 0.5h at 80°C. A J=6.7Hz), 4.98 (1H, q, J=6.7Hz), 6.79 (1H, s), 7.66–7.71
solution of NaOH (200mg, 5.00mmol) in H2O (3mL) was (2H, m), 8.10–8.16 (2H, m). 13C-NMR δ: 21.5, 63.9, 103.8,
added to this mixture and was stirred at 80°C. The mixture 126.9, 127.0, 131.3, 132.4, 133.1, 133.8, 134.0, 152.0, 165.1,
was extracted with CHCl3. The organic extracts were washed 173.5, 180.7. IR (KBr): 3350, 1680, 1591, 1537, 1365, 1219,
with H2O and brine and dried over Na2SO4 and then concen- 1196, 1103, 955, 713. HR-MS (ESI) m/z: [M+H]+ Calcd for
trated.
5-Hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione
[C14H11O4]+, 243.0657; Found, 243.0670.
2-(1-Hydroxyethyl)naphtho[2,3-b]thiophene-4,9-dione (1ff):
(1aa)2): Starting from 3aa, this compound was prepared ac- Starting from 3ba, this compound was prepared according
cording to the general procedure (Condition A). The column to the general procedure (Condition B). The column chroma-
chromatography (hexane–EtOAc=4:1) gave 1aa (100mg, tography (hexane–EtOAc=2:1) gave 1ff (72mg, 56% yield)
1
1
77% yield) as yellow solid with mp 164–165°C. H-NMR δ as yellow solid with mp 175–176°C. H-NMR δ: 1.67 (3H, d,
(CDCl3): 1.66 (d, 3H, J=6.6Hz), 2.23 (d, 1H, J=5.3Hz), 5.05 J=6.3Hz), 5.21 (1H, q, J=6.3Hz), 7.74–7.76 (2H, m), 8.15–8.31
(m, 1H), 6.85 (d, 1H, J=0.7Hz), 7.28 (dd, 1H, J=1.2, 8.5Hz), (2H, m). 13C-NMR δ: 25.3, 66.5, 121.9, 126.9, 127.2, 133.3,
7.62 (dd, 1H, J=7.6, 8.5Hz), 7.76 (dd, 1H, J=1.2, 7.6Hz), 12.18 133.6, 133.7, 133.8, 142.9, 144.0, 160.4, 178.1, 179.6. IR (KBr):
(s, 1H). 13C-NMR (CDCl3) δ: 21.5, 63.8, 103.4, 115.2, 120.0, 3280, 1668, 1593, 1460, 1325, 1301, 1265, 1096, 710. HR-MS
125.3, 131.0, 132.7, 136.3, 152.1, 162.3, 165.4, 172.7, 186.5.
5-Hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]thiophene-4,9- Found, 281.0242.
dione (1bb): Starting from 3aa, this compound was prepared 2-(1-Hydroxyethyl)-1H-benzo[f]indole-4,9-dione
(ESI) m/z: [M+Na]+ Calcd for [C14H10SO3Na]+, 281.0248;
(1gg):
according to the general procedure (Condition B). The column Starting from 3ba (0.19mmol), this compound was prepared
chromatography (hexane–EtOAc=4:1) gave 1bb (121mg, according to the general procedure (Condition C). The col-
88% yield) as yellow solid with mp 179–181°C. 1H-NMR umn chromatography (hexane–EtOAc=4:1) gave 1gg (17mg,
1
(CDCl3–MeOD) δ: 1.62 (3H, d, J=6.5Hz), 5.14 (1H, q, 38% yield) as yellow solid with mp >188°C (dec). H-NMR
J=6.5Hz), 7.26 (1H, dd, J=1.0, 8.3Hz), 7.47 (1H, s), 7.62 (1H, (CDCl3–MeOD) δ: 1.58 (3H, d, J=6.6Hz), 4.94 (1H, q,
dd, J=7.5, 8.3Hz), 7.74 (1H, dd, J=1.0, 7.5Hz), 12.33 (1H, s). J=6.6Hz), 6.60 (1H, s), 7.67–7.70 (2H, m), 8.10–8.15 (2H, m).
13C-NMR (CDCl3–MeOD) δ: 25.1, 65.9, 115.7, 120.0, 121.1, 13C-NMR (CDCl3–MeOD) δ: 22.9, 63.3, 104.7, 126.4, 126.9,
124.8, 133.9, 136.3, 142.6, 144.0, 162.4, 162.6, 177.7, 185.3. IR 128.2, 132.2, 133.3, 133.4, 133.7, 134.2, 146.2, 175.8, 181.9.
(KBr): 3290, 1634, 1454, 1296, 1223, 1093, 752, 702. HR-MS IR (KBr): 3340, 1630, 1513, 1371, 1200, 920, 723. HR-MS
(ESI) m/z: [M+Na]+ Calcd for [C14H10SO4Na]+, 297.0198; (ESI) m/z: [M+H]+ Calcd for [C14H12NO3]+, 242.0817; Found,
Found, 297.0207.
242.0805.
5-Hydroxy-2-phenylnaphtho[2,3-b]furan-4,9-dione
(S)-1bb: Pale yellow needles with mp 209–211°C. [α]D25
(1hh):
−10.8 (c=0.12, CHCl3) for >99% ee (HPLC, Daicel Chiral- Starting from 3ab, this compound was prepared according
pak AD-H, hexane–i-PrOH=9:1, 1.0mL/min, 254nm, minor: to the general procedure (Condition A). The column chroma-
24.9min and major: 30.4min).
tography (hexane–EtOAc=6:1) gave 1hh (101mg, 70% yield)
1
5-Hydroxy-2-(1-hydroxyethyl)-1H-benzo[f]indole-4,9-dione as red solid with mp >237°C (dec). H-NMR (pyridine) δ:
(1cc): Starting from 3aa, this compound was prepared ac- 7.36 (1H, dd, J=1.2, 8.5Hz), 7.42–7.48 (3H, m), 7.57 (1H, s),
cording to the general procedure (Condition C). The column 7.60–7.62 (1H, m), 7.88 (1H, dd, J=1.2, 7.5Hz), 7.91–7.94 (2H,
chromatography (hexane–EtOAc=4:1) gave 1cc (73mg, m), 12.55 (1H, s). 13C-NMR (pyridine) δ: 103.3, 115.6, 119.5,
1
57% yield) as yellow solid with mp >215°C (dec). H-NMR 122.7, 124.8, 125.6, 128.4, 129.3, 130.3, 133.4, 136.5, 150.0,
(dimethyl sulfoxide (DMSO)) δ: 1.49 (3H, d, J=6.5Hz), 4.83 160.2, 162.2, 172.1, 193.0. IR (KBr): 3120, 1635, 1535, 1483,
(1H, dq, J=5.3, 6.5Hz), 5.50 (1H, d, J=5.3Hz), 6.63 (1H, s), 1452, 1221, 823, 762. HR-MS (ESI) m/z: [M+Na]+ Calcd for
7.29 (1H, dd, J=1.2, 8.3Hz), 7.63 (1H, dd, J=1.2, 7.4Hz), 7.71 [C18H10O4Na]+, 313.0477; Found, 313.0485.
(1H, dd, J=7.4, 8.3Hz), 12.69 (1H, s), 12.93 (1H, s). 13C-NMR
5-Hydroxy-2-phenethylnaphtho[2,3-b]furan-4,9-dione (1ii):
(DMSO) δ: 23.9, 62.6, 104.5, 115.7, 119.1, 124.4, 126.8, 132.4, Starting from 3ac, this compound was prepared according
134.1, 136.4, 148.8, 161.8, 174.1, 187.5. IR (KBr): 3290, 1628, to the general procedure (Condition A). The column chroma-
1253, 1207, 1097, 827, 764, 704. HR-MS (ESI) m/z: [M+Na]+ tography (hexane–EtOAc=6:1) gave 1ii (64mg, 40% yield)
Calcd for [C14H11NO4Na]+, 280.0586; Found, 280.0575.
as yellow solid with mp 167–168°C. 1H-NMR δ: 3.06–3.16
5-Hydroxy-2-(1-hydroxyethyl)-1-methyl-1H-benzo[ f ]- (4H, m), 6.54 (1H, s), 7.19–7.32 (6H, m), 7.60 (1H, dd, J=7.4,
indole-4,9-dione (1dd)33): Starting from 3aa, this compound 8.3Hz), 7.74 (1H, dd, J=1.1, 7.4Hz), 12.17 (1H, s). 13C-NMR δ:
was prepared according to the general procedure (Condi- 30.1, 33.5, 104.4, 115.2, 119.8, 125.0, 126.6, 128.2, 128.6, 131.4,
tion D). The column chromatography (hexane–EtOAc=3:1) 132.8, 136.1, 139.7, 151.8, 162.2, 163.7, 172.4, 186.7. IR (KBr):
gave 1ee (98mg, 72% yield) as yellow solid with mp 219°C. 1678, 1635, 1472, 1379, 1043, 845, 762. HR-MS (ESI) m/z:
1H-NMR δ: 1.69 (3H, d, J=6.5Hz), 4.13 (3H, s), 4.95 (1H, q, [M+Na]+ Calcd for [C20H14O4Na]+, 341.0790; Found, 341.0789.
J=6.5Hz), 6.68 (1H, s), 7.18 (1H, dd, J=1.1, 8.4Hz), 7.54 (1H,
8-Hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione

654
Vol. 61, No. 6
(1jj)2): Starting from 3ca, this compound was prepared accord-
ing to the general procedure (Condition A). The column chro-
matography (hexane–EtOAc=4:1) gave 1jj (39mg, 30% yield)
Tetrahedron Lett., 50, 6769–6771 (2009).
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1
as yellow solid with mp 173–175°C. H-NMR δ: 1.66 (3H, d,
J=6.6Hz), 5.05 (1H, q, J=6.6Hz), 6.86 (1H, s), 7.26 (1H, dd,
J=1.0, 8.4Hz), 7.60 (1H, m), 7.71 (1H, dd, J=1.0, 7.4Hz), 12.02
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cells were maintained in usual 10% fetal serum Dulbecco’s
minimum essential medium (DMEM) through experiments
and exposed to four dose concentrations of (S)-1bb in a hu-
midified atmosphere (37°C, 5% CO2) for 72h. After the reac-
tion, cells were further incubated with 0.25% trypan blue dye
for 20min and counted for viable cells under light microscopic
1205–1214 (2005).
apparatus. IC50 values were calculated from separate experi-
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Acknowledgments This study was supported in part
by Grants-in-Aid for Young Scientists (B) (KAKENHI:
24790116) to MY. The authors are grateful to Taheebo Japan
Co., Ltd. and SANSHIN METAL WORKING Co., Ltd. for
their generous financial support to this project.
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