New synthetic procedure for 2-aryl-1,4-naphthoquinone-1-oxime methyl ethers with potent antitumor activity

Article abstract of DOI:10.1055/s-0034-1378342

1,4-Naphthoquinone 1-oxime methyl ethers carrying an ester-substituted aryl pendant at 2-position were concisely prepared as seed compounds with structural flexibility for structure-activity relationship studies on antitumor activity. The key synthetic in

Full text of DOI:10.1055/s-0034-1378342

LETTER
▌2059
lNetteerw Synthetic Procedure for 2-Aryl-1,4-naphthoquinone-1-oxime Methyl
Ethers with Potent Antitumor Activity
Synthesis of 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers
Scebi Mkhize, Noriyuki Suzuki,* Ayako Kurosawa, Makiko Fujinami, Chanya Chaicharoenpong, Tsutomu Ishikawa*
Department of Medicinal Organic Chemistry, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo,
Chiba 260-8675, Japan
Fax +81(43)2262919; E-mail: n-suzuki@chiba-u.jp
Received: 09.05.2014; Accepted after revision: 26.05.2014
oxyphthalide), (4)],6 a unique neutral natural product with
Abstract: 1,4-Naphthoquinone 1-oxime methyl ethers carrying an
phthalide–tetralone spiro structure, via dihydroarnottin I
ester-substituted aryl pendant at 2-position were concisely prepared
{7,8-dimethoxy-2,3-methylenedioxy-6H-benzo[d]-3,4-
as seed compounds with structural flexibility for structure–activity
relationship studies on antitumor activity. The key synthetic inter-
dihydronaphtho[1,2-b]pyran-6-one, (7a)}7 directly pre-
mediate was a phthalide–tetralone spiro compound, which was pro- pared by palladium-catalyzed coupling reaction between
2-bromobenzoate and 1-tetralone.8 In this paper we pres-
ent the alternative concise preparation of ester-substituted
vided by palladium-coupling reaction between 2-bromobenzoate
and 1-tetralone followed by OsO4–NMO oxidation.
Key words: coupling reaction, oxidation, oxime, quinone, spiro
compound
naphthoquinone oximes like 1c through spiro compounds
like 4 as key synthetic intermediates.
At first we examined the synthesis of the known ester-
substituted naphthoquinone oxime 1c1b,3 and their conge-
ners 1d–f using dihydroarnottin II (8a)6,7 as a key interme-
diate (Scheme 1).9 According to the reported procedure,6
the spiro tetralone 8a was prepared by palladium-cata-
lyzed coupling reaction between 6-bromo-2,3-dimethoxy-
benzoate (5a) and 6,7-methylenedioxy-1-tetralone (6)
followed by dihydroxylation of dihydroarnottin I (7a)
formed with osmium tetroxide–N-methylmorpholine
(OsO4–NMO) system. Direct construction of the 1,4-
naphthoquinone 1-oxime unit by oxidation with hyperva-
lent iodine reagents such as IBX and PIFA, after conver-
sion of the tetralone 8a into oxime compound 9a, resulted
in ineffective production of the carboxyl-substituted
naphthoquinone oxime skeleton 1d (ca. 10%). Although
trials for the introduction of hydroxyl function to the spiro
oxime 9a by successive treatment of NBS and aqueous
THF failed, when the same treatment was applied to the
spiro tetralone 8a the oxidation reaction was successfully
proceeded to give the hydroxyl-inserted spiro tetralone
10a,10 which was composed of a ca 1:1 diastereoisomeric
mixture of cis (31%) and trans isomers (28%). The stereo-
chemistry of the isomers was determined by NOE experi-
ments.11 Independent treatment of each isomer cis- and
trans-10a with NH2OMe smoothly afforded the intended
hydroxyl-inserted oxime derivative cis- and trans-11a, re-
spectively, with a major Z configuration of the oxime
function (E/Z = 1:3). In practical preparation, a diastereo-
isomeric mixture of hydroxyl-inserted spiro tetralones
10a was subjected to oximation without separation. The
hydroxyl oxime mixture 11a obtained was oxidized with
IBX followed by treatment with Et3N to provide the car-
boxyl-substituted naphthoquinone oxime skeleton 1d12 in
high yield. Conventional esterification of 1d smoothly af-
forded the target ester-substituted naphthoquinone oxime
1c,1b,3,13 and the corresponding phenolic derivatives 1e
and 1f14 were also prepared by selective demethylation of
2-Aryl-6,7-methylenedioxy-1,4-naphthoquinone-1-oxime
methyl ether derivatives 1, the synthetic intermediates for
12-methoxybenzo[c]phenanthridine alkaloids,1 showed
potent antitumor activity, and preliminary structure–
activity relationship (SAR) suggested that the 6,7-methy-
lenedioxy-1,4-naphthoquinone 1-oxime methyl ether
skeleton was responsible, while the 2-aryl pendant was
tolerant, for the strong cytotoxicity.2 Thus, at this stage,
although 2-methoxy-4,5-methylenedioxyphenyl- (1a),1a
7-methoxy-2-methylbenzofuran-4-yl- (1b),1b,3 and 3,4-di-
methoxy-2-methoxycarbonylphenyl-substituted naphtho-
quinone oximes (1c)1b,3 were nominated as seed
compounds for optimization, the last ester-substituted 1c
could be the most likely candidate as one of easily func-
tionalizable naphthoquinone derivatives for further in
vivo assay experiments. The 2-arylnaphthoquinone ox-
imes 1 (Figure 1) could be prepared by either basic nitro-
sation (i-AmONO, K2CO3 in DMF)4 of the corresponding
3-aryl-1-naphthols 2 followed by methylation or DDQ
oxidation5 of 2-aryl-1-tetralone oxime ethers 3 in hot
AcOH–benzene. However, these synthetic precursors 2
and 3 had been prepared from aryl benzyl ketones and
chalcones, respectively, through a linear step-by-step pro-
cedure. In addition, the latter DDQ oxidation was limited
to the preparation of naphthoquinone oximes carrying an
electron-rich aryl pendant such as the trialkoxyphenyl
function.5 These synthetic limitation forced us to develop
an alternative concise method for the synthesis of the
ester-substituted naphthoquinone oxime 1c and its ana-
logues with structural flexibility. We previously reported
the convergent asymmetric synthesis of (–)-arnottin II
[6,7-methylenedioxy-1-tetralone-2-spiro-3′-(6,7-dimeth-
SYNLETT 2014, 25, 2059–2063
Advanced online publication: 01.07.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378342; Art ID: st-2014-d0406-l
© Georg Thieme Verlag Stuttgart · New York

2060
S. Mkhize et al.
LETTER
OH
O
O
O
O
O
O
O
O
O
MeO
MeO
Ar
Ar
Ar
O
N
O
N
OMe
OMe
O
1
2
3
4
OMe
CO2Me
OMe
a Ar =
b Ar =
c Ar =
O
O
O
OMe
OMe
Figure 1 Structures of 2-aryl-1,4-naphthoquinone 1-oxime methyl ethers 1, 3-aryl-1-naphthols 2, 2-aryl-1-tetralone oxime ethers 3, and
(–)-arnottin II (4)
a methoxy function next to the carboxyl group of 1d and sition was carried out using the benzyl group as phenol
1c, respectively.
protection (Scheme 2).9 The spiro tetralone 8b was pre-
pared from 4-benzyloxy-2-bromo-5-methoxybenzoate
(5b), which was derived from the corresponding benzal-
dehyde by Pinnick oxidation and esterification, by palla-
dium-coupling reaction followed by OsO4–NMO
Next, the synthesis of a structurally isomeric ester-substi-
tuted naphthoquinone oxime 1g with 5-hydroxy-4-
methoxy-2-methoxycarbonylphenyl pendant at the 2-po-
O
R2
Br
(a)
O
O
R2
O
+
O
MeO
CO2t-Bu
MeO
R1
O
R1
O
(b)
5a R1 = OMe, R2 = H
5c R1 = H, R2 = Oi-Pr
6
7a R1 = OMe, R2 = H
7c R1 = H, R2 = Oi-Pr
OH
N
OH
O
R2
R2
R2
O
O
O
O
O
(e)
(d)
MeO
MeO
MeO
O
O
O
O
R1
O
R1
R1
OMe
O
O
O
11a R1 = OMe, R2 = H
10a R1 = OMe, R2 = H
8a R1 = OMe, R2 = H
8c R1 = H, R2 = Oi-Pr
(β-OH for cis-11a; α-OH for trans-11a)
11c R1 = H, R2 = Oi-Pr
(β-OH for cis-10a; α-OH for trans-10a)
10c R1 = H, R2 = Oi-Pr
on 8a
(c)
(f)
O
MeO
MeO
1d R1 = R3 = H, R2 = OMe
1e R1 = R3 = H, R2 = OH
1c R1 = Me, R2 = OMe, R3 = H
1f R1 = Me, R2 = OH, R3 = H
1h R1 = R2 = H, R3 = Oi-Pr
1i R1 = Me, R2 = H, R3 = Oi-Pr
1g R1 = Me, R2 = H, R3 = OH
O
O
(h)
(g)
(j)
O
O
O
N
R1O2C
R2
OMe
O
(i)
9a
N
(g)
OMe
MeO
low yield
IBX or PIFA
R3
1d
Scheme 1 Preparation of carboxylate-substituted naphthoquinone oximes 1c–i. Reagents and conditions: (a) Pd(dba)3, Cs2CO3, Xantphos,
Na2S2O5, toluene, 100 °C, 48 h, argon (7a: 72%; 7c: 73%); (b) OsO4, NMO, CH2Cl2–acetone–H2O, 40 °C, 10 d on 7a (30 °C, 5 d on 7c; 8a:
96%; 8c: 79%); (c) NH2OMe·HCl, pyridine, 80 °C, 41 h (95%); (d) (1) NBS, AIBN, benzene, 85 °C, 1.5 h on 8a (2 h on 8c), argon; (2) THF,
H2O, r.t., 16 h on 8a [17 h on 8c; 10a: 59% (trans-10a: 28%; cis-10a: 31%); 10c: 66%]; (e) NH2OMe·HCl, pyridine, 65 °C, 2 d on trans-10a
(1 d on cis-10a and 10c; trans-11a: 92%; cis-11a: 94%; 11c: 86%); (f) (1) IBX, DMSO, 60 °C, 2 h; (2) Et3N, CH2Cl2, r.t., 17 h (1d: 90%; 1h:
69%); (g) MeI, K2CO3, DMF, r.t., 2 h (1e: 92%; 1i: 68%); (h) BCl3, CH2Cl2, –40 °C, 16 h (63%); (i) BCl3, CH2Cl2, –78 °C, 2 h (92%); (j) (1)
MeI, K2CO3, DMF, r.t., 1 h (68%); (2) BBr3, CH2Cl2, –78 °C, 40 min (73%).
Synlett 2014, 25, 2059–2063
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers
2061
oxidation as described in Scheme 1. Unfortunately, the tional exchange of the protecting group in this synthetic
NBS-mediated hydroxyl-insertion giving hydroxyl- procedure. The problem was caused by the selection of the
inserted spiro tetralone 10b was unsuccessful. Although benzyl group as a phenol protection.
the failure may be caused by the presence of benzyloxy
group, no products were formed even after removal of the
benzyl protection. Therefore, our attention was turned to
Therefore, we further examined the alternative synthesis
of 1g by use of isopropyl group as a protecting group
(Scheme 1).9 In the improved method the ester-substituted
spiro oxime 13 with easily deprotectable acetyl function
naphthoquinone oxime 1g was provided in shorter eight
albeit in much lower yield in comparison with tetralone
steps from the 2-bromobenzoate 5c, albeit in the almost
same overall yield (12%).
oxime 9a. The spiro oxime 13 was smoothly prepared by
three-step reactions of debenzylation, oximation, and
acetylation. However, an additionally bromine-incorpo-
rating hydroxyl oxime 14, not a hydroxyl oxime like 11,
In conclusion we established the concise preparation
method for potentially antitumor active naphthoquinone
oximes with structural flexibility for structure–activity
relationship study. Strong cytotoxic activity has been
was unexpectedly formed in 29% yield when 13 was sub-
jected to NBS-mediated hydroxylation. Extra insertion of
observed in 2-(3-hydroxy-4-methoxy-2-methoxycarbon-
the bromine atom during the reaction could be deduced by
ylphenyl)-1,4-naphthoquinone 1-oxime methyl ether (1f)
three successive reactions of benzylic bromination, dehy-
drobromination, and bromohydrin formation. Conversion
of the spiro bromohydrin 14 into the naphthoquinone ox-
ime structure 15 was similarly achieved by combination
among the ester-substituted naphthoquinone oximes and
their analogues synthesized here.17 Further chemical mod-
ifications based on the ester-substituted naphthoquinone
oxime 1f applicable to in vivo assay experiments are in
progress in our laboratory.
of IBX oxidation and base treatment as shown in Scheme
1 (11a → 1d). Finally, palladium-catalyzed reductive
debromination15 of 15 smoothly afforded the target naph-
thoquinone oxime 1g16 after methylation. Thus, 1g was
Acknowledgment
provided in overall 11% yield in 13 steps from the 2-bro-
The project was financially supported by JSPS Grants-in-Aid for
mobenzoate 5b; however, there was a drawback of addi-
Scientific Research (C) (Grant No. 23590041).
O
BnO
O
BnO
MeO
Br
(a)
(b)
BnO
MeO
O
MeO
+
6
O
O
CO2t-Bu
O
O
O
5b
7b
8b
O
(c)
1. NBS, AIBN
2. H2O
OH
RO
AcO
MeO
Br
O
O
O
O
(e)
MeO
OH
BnO
MeO
O
O
N
O
O
N
OMe
OMe
O
O
14
12 R = H
13 R = Ac
O
(d)
O
(f)
O
10b
O
N
O
O
O
Br
MeO2C
O
RO2C
(h)
O
OMe
N
MeO
OMe
MeO
OH
OH
1g
15 R = H
16 R = Me
(g)
Scheme 2 Preparation of 5-hydroxy-4-methoxy-2-methoxycarbonylphenyl-naphthoquinone oxime 1g. Reagents and conditions: (a) Pd(dba)3,
Cs2CO3, Xantphos, Na2S2O5, toluene, 100 °C, 36 h (81%); (b) OsO4, NMO, CH2Cl2–acetone, r.t., 5 d (86%); (c) (1) TfOH, IPy2BF4, CH2Cl2,
0 °C, 20 min; (2) NH2OMe·HCl, pyridine, 90 °C, 12 h (98%); (d) Ac2O, Et3N, I2, THF, 40 °C, 7 h (90%); (e) (1) NBS, AIBN, benzene, 70 °C,
3 h; (2) acetone, H2O, 40 °C, 20 h (29%); (f) (1) IBX, DMSO, 50 °C, 2 h; (2) Et3N, CH2Cl2, r.t., 2 h (99%); (g) MeI, K2CO3, DMF, r.t., 2 h
(65%); (h) Pd(OAc)2, K2CO3, Ph3P, BuOH, 100 °C, 2 h (93%).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2059–2063

2062
S. Mkhize et al.
LETTER
385 [M + H]+. Anal. calcd for C20H18O8·1/3H2O: C, 61.54;
H, 4.30. Found: C, 61.79; H, 4.11.
Supporting Information for this article is available online
at http://www.thieme-connect.com/products/ejournals/journal/
(11) The same orientation of oxygen functions at the 2- and
4-positions of the tetralone unit is assigned to be cis
configuration.
10.1055/s-00000083.SunpfgIpi
o
o
nr
i
References and Notes
(12) 2,3-Dimethoxy-6-[2-(1-methoxyimino-6,7-methylene-
dioxy-4-oxo-1,4-dihydronaphthyl)]benzoic Acid (1d)
A mixture of 11a (230 mg, 0.556 mmol) and IBX (260 mg,
0.929 mmol) in DMSO (4 mL) was stirred at 60 °C for 2 h.
After addition of H2O (10 mL) insoluble precipitate was
removed by filtration, and the filtrate was extracted with
EtOAc (3 × 20 mL). The combined organic solutions were
washed with H2O (3 × 1 mL) and brine (10 mL), dried over
Na2SO4, and evaporated. The residue was dissolved in
CH2Cl2 (20 mL), stirred with Et3N (0.2 mL, 1.42 mmol) at
r.t. for 1 h, and extracted with H2O (3 × 20 mL). The
combined aqueous solutions were acidified with 10% HCl
aqueous solution (pH ca. 3) and extracted with CHCl3 (3 ×
20 mL). The combined organic solutions were washed with
brine (10 mL), dried over Na2SO4, and evaporated. Column
chromatography of the residue (SiO2, acetone–toluene =
1:20) afforded 1d (211 mg, 92%) as pale yellow solid, mp
207–209 °C. IR (ATR): 1725, 1624 cm–1. 1H NMR (400
MHz, CDCl3): δ (Z-isomer) = 3.98 (s, 3 H), 3.99 (s, 3 H),
4.03 (s, 3 H), 6.10 (s, 2 H), 6.54 (s, 1 H), 7.11 (d, J = 8.4 Hz,
1 H), 7.15 (d, J = 8.4 Hz, 1 H), 7.68 (s, 1 H), 8.33 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ (Z-isomer) = 55.9, 61.0,
64.4, 102.8, 105.0, 109.2, 113.1, 123.7, 125.8, 127.5, 127.8
(2 C), 130.2, 144.8, 145.2, 149.4, 151.3, 151.4, 153.0, 167.8,
182.1. MS–FAB: m/z = 434 [M + Na]+, 412 [M + H]+. Anal.
calcd for C21H17NO8: C, 61.31; H, 4.17; N, 3.40. Found: C,
61.14; H, 3.98; N, 3.28.
(1) (a) Ishikawa, T.; Saito, T.; Ishii, H. Tetrahedron 1995, 51,
8447. (b) Watanabe, T.; Ohashi, Y.; Yoshino, R.; Komano,
N.; Eguchi, M.; Maruyama, S.; Ishikawa, T. Org. Biomol.
Chem. 2003, 1, 3024.
(2) (a) Ishikawa, T.; Saito, T.; Kurosawa, A.; Watanabe, T.;
Maruyama, S.; Ichikawa, Y.-I.; Yamada, R.; Okuzawa, H.;
Sato, H.; Ueno, K. Chem. Pharm. Bull. 2011, 59, 472.
(b) Sato, H.; Yamada, R.; Yanagihara, M.; Okuzawa, H.;
Iwata, H.; Kurosawa, A.; Ichinomiya, S.; Suzuki, R.; Okabe,
H.; Yano, T.; Kumamoto, T.; Suzuki, N.; Ishikawa, T.;
Ueno, K. J. Pharmacol. Sci. 2012, 118, 467.
(3) Ishikawa, T.; Hino, K.; Yoneda, T.; Murota, M.; Yamaguchi,
K.; Watanabe, T. J. Org. Chem. 1999, 64, 5691.
(4) Ishikawa, T.; Watanabe, T.; Tanigawa, H.; Saito, T.; Kotake,
K.-I.; Ohashi, Y.; Ishii, H. J. Org. Chem. 1996, 61, 2774.
(5) Watanabe, T.; Oku, Y.; Ishii, H.; Ishikawa, T. Synlett 1997,
161.
(6) Ishikawa, T.; Murota, M.; Watanabe, T.; Harayama, T.;
Ishii, H. Tetrahedron Lett. 1995, 36, 4269.
(7) Ishii, H.; Ishikawa, T.; Murota, M.; Aoki, Y.; Harayama, T.
J. Chem. Soc., Perkin Trans. 1 1993, 1019.
(8) Konno, F.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K.
J. Org. Chem. 2005, 71, 9818.
(9) Synthetic procedures for compounds shown in Schemes 1
and 2, except those described in Note, are given in
Supporting Information.
(13) Methyl 2,3-Dimethoxy-6-[2-(1-methoxyimino-6,7-
methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benzoate
(1c)
(10) 4-Hydroxy-6,7-methylenedioxy-1-tetralone-2-spiro-3′-
(6,7-dimethoxyphthalide) (10a)
A mixture of 8a (82 mg, 0.223 mmol), NBS (43 mg, 0.243
mmol), and AIBN (5 mg, 0.029 mmol) in dry benzene (8
mL) was stirred at 85 °C for 1.5 h under argon. After
addition of EtOAc (30 mL) the solution was washed with
H2O (20 mL) and brine (10 mL), dried over Na2SO4, and
evaporated. The residual oil was dissolved in THF (10 mL)
and H2O (8 mL). The mixture was stirred at r.t. for 16 h and
extracted with CHCl3 (3 × 20 mL). The combined organic
solutions were washed with brine (10 mL), dried over
Na2SO4, and evaporated. Column chromatography of the
residue (SiO2, toluene–EtOAc = 10:1 → 1:1) afforded trans-
10a (24 mg, 28%) as colorless solid, mp 212–213 °C, and
cis-10a (27 mg, 31%) as colorless solid, mp 209–211 °C.
trans-10a: IR (ATR): 1767, 1682 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 2.35 (d, J = 7.1 Hz, 1 H, exchangeable), 2.63
(dd, J = 13.7, 9.4 Hz, 1 H), 2.71 (dd, J = 13.7, 4.9 Hz, 1 H),
3.93 (s, 3 H), 4.14 (s, 3 H), 5.36 (ddd, J = 9.4, 7.1, 4.9 Hz, 1
H), 6.09 (s, 2 H), 7.03 (d, J = 8.3 Hz, 1 H), 7.21 (s, 1 H), 7.24
(d, J = 8.3 Hz, 1 H), 7.41 (s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 43.6, 56.8, 62.4, 64.4, 85.3, 102.2, 106.2, 106.6,
117.1, 117.9, 119.7, 124.2, 141.8, 144.5, 147.9, 148.3,
153.2, 153.7, 167.3, 187.9. MS–FAB: m/z = 407 [M + Na]+,
385 [M + H]+. Anal. calcd for C20H18O8: C, 62.50; H, 4.20.
Found: C, 62.21; H, 3.96.
A mixture of 1d (211 mg, 0.512 mmol), MeI (0.07 mL, 1.10
mmol), and K2CO3 (140 mg, 1.01 mmol) in DMF (5 mL)
was stirred at r.t. for 2 h, diluted with H2O (10 mL), and
extracted with EtOAc (3 × 20 mL). The combined organic
solutions were washed with H2O (2 × 10 mL), sat. NaHCO3
aqueous solution (5 mL), and brine (10 mL), dried over
Na2SO4, and evaporated. Column chromatography of the
residue (SiO2, EtOAc–hexane = 1:6 → 1:3) afforded 1c (201
mg, 92%) as pale yellow solid, mp 172–173 °C (lit.1b mp
171–173 °C). IR (ATR): 1715, 1638 cm–1. 1H NMR (400
MHz, CDCl3): δ (Z-isomer) = 3.66 (s, 3 H), 3.93 (s, 2 × 3 H),
4.08 (s, 3 H), 6.12 (s, 2 H), 6.57 (s, 1 H), 7.01 (d, J = 8.3 Hz,
1 H), 7.11 (d, J = 8.3 Hz, 1 H), 7.69 (s, 1 H), 8.33 (s, 1 H).
ESI–HRMS: m/z calcd for C22H19NNaO8: 448.10084; found:
448.10020.
(14) Methyl 2-Hydroxy-3-methoxy-6-[2-(1-methoxyimino-
6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benz-
oate (1f)
To a stirred solution of 1c (29 mg, 6.8·10–2 mmol) in CH2Cl2
(7 mL) was added a 1 mol solution of BCl3 in CH2Cl2 (0.14
mL, 7.0·10–2 mmol) at –78 °C under argon, and the mixture
was stirred at the same temperature for 2 h. After addition of
H2O (5 mL) the mixture was extracted with CHCl3 (3 × 10
mL). The combined organic solutions were washed with
brine (5 mL), dried over Na2SO4, and evaporated.
Purification of the residue by PTLC (CHCl3) afforded 1f (26
mg, 92%) as yellow solid, mp 154–156 °C. IR (ATR): 2919,
1667, 1634 cm–1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer)
= 3.60 (s, 3 H), 3.96 (s, 3 H), 3.97 (s, 3 H), 6.13 (s, 2 H), 6.54
(s, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 7.02 (d, J = 8.3 Hz, 1 H),
7.72 (s, 1 H), 8.34 (s, 1 H), 10.8 (s, 1 H). 13C NMR (100
MHz, CDCl3): δ (Z-isomer) = 52.4, 56.1, 64.5, 102.2, 106.2,
cis-10a: IR (ATR): 1769, 1684 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 2.59 (d, J = 9.7 Hz, 1 H, exchangeable), 2.71
(dd, J = 13.6, 7.1 Hz, 1 H), 2.83 (dd, J = 13.6, 5.1 Hz, 1 H),
3.90 (s, 3 H), 4.14 (s, 3 H), 5.16 (ddd, J = 9.7, 7.1, 5.1 Hz, 1
H), 6.11 (s, 2 H), 6.82 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 8.2
Hz, 1 H), 7.18 (s, 1 H), 7.43 (s, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 42.2, 56.8, 62.4, 65.5, 84.7, 102.4, 106.7, 107.5,
116.5, 117.9, 119.1, 124.2, 140.2, 142.3, 148.8, 148.9,
153.4, 153.9, 166.5, 188.1. MS–FAB: m/z = 407 [M + Na]+,
Synlett 2014, 25, 2059–2063
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers
2063
109.8, 113.6, 114.2, 120.7, 124.1, 126.8, 128.7, 130.3,
dried over Na2SO4, and evaporated. Column chromatography
of the residue (SiO2, EtOAc–hexane = 1:1) afforded 1g (5
mg, 93%) as pale yellow solid, mp 89–91 °C. IR (ATR):
3437, 1771 cm–1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer)
= 3.64 (s, 3 H), 3.97 (s, 3 H), 4.00 (s, 3 H), 6.12 (s, 2 H), 6.49
(s, 1 H), 6.91 (s, 1 H), 7.49 (s, 1 H), 7.70 (s, 1 H), 8.35 (s, 1
H). 13C NMR (100 MHz, CDCl3): δ (Z-isomer) = 52.2, 56.4,
64.5, 102.3, 106.4, 110.2, 112.4, 116.6, 123.1, 124.6, 127.3,
129.0, 133.2, 146.1, 146.5, 148.7, 149.5, 151.5, 153.4,
167.1, 183.6. ESI-HRMS: m/z calcd for C21H17NNaO8:
434.08519; found: 434.08329.
146.3, 148.9, 149.4, 150.0, 151.4, 153.7, 170.7, 183.6. ESI-
HRMS: m/z calcd for C21H17NNaO8: 434.08519; found:
434.08440.
(15) Chen, J.; Zhang, Y.; Yang, L.; Zhang, X.; Liu, J.; Li, L.;
Zhang, H. Tetrahedron 2007, 63, 4266.
(16) Methyl 4-Hydroxy-5-methoxy-2-[2-(1-methoxyimino-
6,7-methylenedioxy-4-oxo-1,4-dihydronaphthyl)]benz-
oate (1g)
A mixture of 16 (7 mg, 1.3·10–3 mmol), Pd(OAc)2 (0.15 mg,
7·10–5 mmol), and Ph3P (0.7 mg, 2.6·10–4 mmol) in n-BuOH
(3 mL) was stirred at 100 °C for 2 h under nitrogen, diluted
with EtOAc (6 mL), and filtered through Celite pad. The
filtrate was washed with H2O (2 × 3 mL) and brine (3 mL),
(17) Results on the cytotoxic activity of these naphthoquinone
oximes will be reported elsewhere.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2059–2063

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