Cesium carbonate-mediated reaction of dichloronaphthoquinone derivatives with O-nucleophiles

Article abstract of DOI:10.1007/s00706-007-0679-1

A cesium carbonate-mediated reaction of 2,3-dichloronaphthoquinone, 6,7-dichloro-5,8-quinolinedione, and -isoquinolinedione with oxygen nucleophiles has been described.

Full text of DOI:10.1007/s00706-007-0679-1

Monatshefte f u¨ r Chemie 138, 741–746 (2007)
DOI 10.1007/s00706-007-0679-1
Printed in The Netherlands
Cesium Carbonate-Mediated Reaction of Dichloronaphthoquinone
Derivatives with O-Nucleophiles
Do-Min Lee, Ju Hong Ko, and Kee-In Leeꢀ
Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Taejon, Korea
Received March 2, 2007; accepted (revised) March 8, 2007; published online May 23, 2007
#
Springer-Verlag 2007
Summary. A cesium carbonate-mediated reaction of
,3-dichloronaphthoquinone, 6,7-dichloro-5,8-quinolinedione,
and -isoquinolinedione with oxygen nucleophiles has been
described.
On the other hand, the reaction of naphthoquinones
with alcohol derivatives has not found much attention
in literature. Examples mainly include the synthesis
of 3-alkoxy-1,4-naphthoquinones by treatment of
2
Keywords. Dichloronaphthoquinone; Nucleophilic substitu-
tion; Oxygen nucleophile; Cesium carbonate; Alkoxynaphtho-
quinone.
2,3-dichloronaphthoquinone with various alkoxides
[
12–15]. However, this approach is hampered by the
poor yields and low chemoselectivity depending on
the reaction parameters, such as reagents and reac-
tion conditions. Notwithstanding the importance of
this system, existing methods for the synthesis of alk-
oxynaphthoquinones are limited in their scope and
generality. Thus, there is a need for the development
of more flexible strategies that will accommodate a
range of structural diversity. Here, we wish to report
a cesium carbonate-mediated reaction of 2,3-dichloro-
naphthoquinone (1), 6,7-dichloro-5,8-quinolinedione
Introduction
The naphthoquinone skeleton is found in many nat-
ural products and has been employed as a synthesis
intermediate for the preparation of numerous hetero-
cyclic compounds with interesting biological proper-
ties, such as antitumor, antibacterial, antifungal, and
anti-inflammatory agents [1, 2]. The quinoline alka-
loids, such as streptonigrin, streptonigron, and laven-
damycin, possess extraordinary cytotoxic activities,
and the quinolinedione moiety is responsible for the
antitumor activity because of its ability to degrade
DNA [3–5]. This structural pattern is also observed
in quinone antibiotics including mitomycin C, acti-
nomycin, and rifamycin, a class of inhibitors of DNA-
transcribing enzymes [6]. Thus, extensive studies on
the nucleophilic substitution of quinones including
naphthoquinone, quinolinequinone, and quinazoline-
quinone with aniline nucleophiles and their promis-
ing cytotoxic activities against human cancer cells
have been described [7–11].
(5), and -isoquinolinedione (8) with various oxygen
nucleophiles.
Results and Discussion
Initially, we undertook mono-substitution of 2,3-
dichloronaphthoquinone (1) with phenol under var-
ious conditions, as shown in Table 1. An attempted
reaction in refluxing EtOH showed no conversion.
Whereas K CO and pyridine gave mainly the
2
3
Zwitterion 4, at elevated temperature it accelerated
the displacement of both chlorines resulting in the
formation of 2,3-dialkoxynaphthoquinone 3 [1, 16].
Even though CeCl ꢁ 7H O was successfully employed
3
2
ꢀ Corresponding author. E-mail: kilee@krict.re.kr
in the amine displacement with various dihalo-

7
42
D.-M. Lee et al.
Table 1. Base-promoted substitution of 2,3-dichloronaphthoquinone (1) with phenol
Entry
Conditions
Yield of 2a (3, 4)=%
1
2
3
4
5
EtOH, reflux, 32 h
CeCl ꢁ 7H O, EtOH, rt, 48 h
NR
NR
24 (6, 48)
66
93
3
2
K CO , pyridine, rt, 2 h
2
3
Et N, THF, rt, 76 h
3
Cs CO , THF, rt, 76 h
2
3
naphthoquinones [10, 11], in this case, surprisingly,
it did not react at all. After examining a number of
bases, we found the mono-substitution was greatly
increased by adding Cs CO in THF at room tem-
derivatives 2b–2k in good to excellent yield. We
could extend this method to the readily available
benzyl (entry 12) and aliphatic alcohols (entries
13–16), without any problem. The reaction gener-
2
3
perature, and thus we obtained 2-chloro-3-phenoxy-
,4-naphthoquinone (2a) in 92% yield without any
1
side-product. With this promising result, we studied
mono-substitution reactions of 1 under mediation of
Cs CO with various alcoholic substrates to secure
2
3
synthesis of alkoxynaphthoquinone derivatives with
structural diversity.
The Cs-mediated substitution was successfully
applicable to the synthesis of 3-phenoxynaphthoqui-
none derivatives from 1 with an array of phenolic
nucleophiles (Table 2, entries 2–11) in the presence
of Cs CO at ambient temperature. The substitu-
2
3
tion uniformly provided 3-phenoxynaphthoquinone
Table 2. Synthesis of 3-alkoxynaphthoquinone derivatives
Entry
ROH
Time=h 2 (yield=%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
PhOH
76
20
20
76
96
76
96
72
72
48
96
180
180
180
180
2a (93)
2b (95)
2c (98)
2d (92)
2e (73)
2f (95)
2g (88)
2h (84)
2i (95)
2j (86)
2k (67)
2l (65)
2m (34)
2n (43)
2o (62)
2p (52)
2-OMe-PhOH
3-OMe-PhOH
4-OMe-PhOH
4-OEt-PhOH
4-Me-PhOH
4-Et-PhOH
4-NO -PhOH
2
2,3-(OMe) -PhOH
2
1
1
1
1
1
1
1
3,5-(OMe) -PhOH
2
2-NO -4-OMe-PhOH
2
PhCH OH
2
Me(CH ) OH
2
3
Et N(CH ) OH
2 2
1-(2-Hydroxyethyl)piperidine
4-(2-Hydroxyethyl)morpholine 180
2
Fig. 1. Crystal structures of a) 6-(4-methoxyphenyloxy)-7-
chloroquinolinedione (6b) and b) 6-chloro-7-(4-methoxyphe-
nyloxy)isoquinolinedione (10c)

Cs CO -Mediated Reaction of Dichloronaphthoquinone Derivatives
2
743
3
ally allowed the introduction of a wide range of
hydroxyl group-containing nucleophiles, and the
results are summarized in Table 2. However, car-
boxyl group-containing nucleophiles, such as acetic
and benzoic acid did not react at all.
The substitution works very effectively for the
mono-alkoxylation of naphthoquinone. So far, we
examined its applicability to similarly related struc-
tures, quinolinedione and isoquinolinedione, with
oxygen nucleophiles. Reaction of 6,7-dichloro-5,8-
quinolinedione (5) with 4-methoxyphenol gave two
regioisomeric products at the 1:1 molar ratio, which,
in turn, were very difficult to isolate by convention-
al separation. To confirm the regiochemistry of the
products, we tried to prepare a single crystal for
X-ray crystallography. Fortunately, we were able to
obtain a crystal of one isomer, and the X-ray crystal
diffraction analysis proved its constitution as 6-(4-
methoxyphenyloxy)-7-chloroquinolinedione (6b), as
depicted in Fig. 1a.
Based on the crystal data, these two isomers could
be distinguished by means of chemical shifts of the
1
H NMR spectra in CDCl . Although C2-H and C3-H
3
protons rather centers at ꢀ ¼ 9.09–9.04 and 7.73–
7.71 ppm regardless of the regioisomers, the differ-
ences between the chemical shifts of C4-H protons
showed distinctive values as shown in Table 3. The
spectrum of the isomeric mixtures displayed two sets
of peaks around ꢀ ¼ 8.53–8.52 and 8.39–8.37 ppm,
attributed to the C4-H for each isomer. The spectral
data of these isomers showed that the C4-H chemical
shifts of the C7-quinolinediones 7 were considerably
Table 3. Reaction of 6,7-dichloro-5,8-quinolinedione (5) with phenols
a
b,c
Yield=%
Entry
PhOH
ꢀC4-H=ppm
6
7
1
2
3
4-Et-PhOH (a)
4-OMe-PhOH (b)
4-OEt-PhOH (c)
8.39
8.37
8.38
8.53
8.53
8.52
87
86
87
a
1
b
c
H NMR recorded in CDCl3; combined yield of the regioisomers 6 and 7 at 1:1 molar ratio; trace of disubstituted
quinolinedione was observed
Table 4. Reaction of 6,7-dichloro-5,8-isoquinolinedione (8) with phenols
a
a
b,c
Yield=%
Entry
PhOH
ꢀC1-H=ppm
ꢀC4-H=ppm
9
10
9
10
1
2
3
4
3-Me-PhOH (a)
4-Et-PhOH (b)
4-OMe-PhOH (c)
4-OEt-PhOH (d)
9.46
9.46
9.47
9.45
9.29
9.26
9.29
9.28
7.84
7.83
7.83
7.82
8.00
7.99
8.00
9.99
80
86
85
81
a
1
b
c
H NMR recorded in CDCl3; combined yield of the regioisomers 9 and 10 at ꢂ1:5 molar ratio; in each case ꢃ10% of
disubstituted isoquinolinedione 11 was isolated

7
44
D.-M. Lee et al.
Avance 300 ultrashield at 300.12 and 75.03 MHz. The data
for X-ray structure determination was collected on graphite-
moved downfield with respect to those of the C6-
isomers 6. This phenomenon agreed nicely with the
previous results observed in amine cases [8].
˚
monochromated Mo-Kꢁ radiation (l ¼ 0.71073 A) equipped
with a Bruker SMART Apex II X-ray diffractometer.
Analogously, reaction of 6,7-dichloro-5,8-iso-
quinolinedione (8) with 4-methoxyphenol (entry 3,
Table 4) gave two regioisomers at a ratio of 1:5
Typical Procedure as Exemplified for the Synthesis of 2-Chloro-
3
To a solution of 227 mg 1 (1mmol) and 149 mg 4-methoxy-
-(4-methoxyphenoxy)-1,4-naphthoquinone (2d, C H ClO )
17 11 4
1
(
H NMR). The X-ray crystal diffraction analysis
3
phenol (1.2mmol) in 10cm THF was added 325 mg Cs CO
of the major isomer proved the 6-chloro-7-(4-me-
thoxyphenyloxy)isoquinolinedione (10c) as depicted
in Fig. 1b. One possible explanation for the prefer-
ence of the C7-substitution (such as 10) is that the
C5-carbonyl group, which is para to the nitrogen, is
more electronegative than the C8-carbonyl in reso-
nance structures, in terms of charge separation. Thus,
2
3
(1mmol). The reaction mixture was stirred for 76h at room
temperature. The mixture was partitioned with H O and
ethyl acetate. The organic phase was washed with brine, dried
2
(MgSO ), and evaporated under reduced pressure to give a
residue. This residue was purified by column chromatography
4
on silica gel (n-hexane=EtOAc¼ 9=1) to afford 289 mg (92%)
ꢄ
1
2
d. Mp 113 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.20 (dd, 1H,
3
J ¼ 9.0, 2.2 Hz), 8.03 (dd, 1H, J ¼ 9.0, 2.3 Hz), 7.79–7.75 (m,
1
,4-addition might be expected to be dominated
2
3
1
H), 6.97 (d, 2H, J ¼ 6.0 Hz), 6.85 (d, 2H, J ¼ 6.0 Hz), 3.79 (s,
by the C5-carbonyl group [7]. The chemical shifts
of C1-H and C4-H protons are greatly affected by
the regioselectivity between C6- and C7-substitu-
tion patterns. Although C2-H proton rather centers
at ꢀ ¼ 9.12–9.10 ppm regardless of the regioisomers,
the differences between the chemical shifts of C2-H
and C4-H protons showed distinctive values as
shown in Table 4. The spectral data of these isomers
showed that the C4-H chemical shifts of the C7-qui-
nolinediones 10 were considerably moved downfield
with respect to those of the C6-isomers 9, whereas
the C1-H chemical shifts of the C7-quinolinediones
moved upfield. Such phenomena are very consistent,
and could be useful criteria for assigning regioselec-
tivity of similarly related structures.
13
H) ppm; C NMR (CDCl ): ꢀ ¼ 178.9, 178.6, 156.5, 154.3,
3
50.8, 134.9, 134.7, 133.4, 131.6, 131.1, 127.7, 127.5, 118.3,
þ
115.1, 56.0ppm; EIMS (70 eV): m=z (%) ¼ 316 (M , 10), 314
þ
(
(
M , 28), 251 (13), 191 (13), 163 (24), 135 (26), 123 (12), 99
31), 76 (58), 63 (100), 50 (100).
2
-Chloro-3-phenoxy-1,4-naphthoquinone (2a, C H ClO )
16 9 3
ꢄ
1
Mp 138–139 C; H NMR (300MHz, CDCl ): ꢀ ¼ 8.22 (dd,
3
1
H, J ¼ 9.0, 2.1 Hz), 8.06 (dd, 1H, J ¼ 9.0, 2.1 Hz), 7.80–7.76
(m, 2H), 7.34 (t, 2H, J ¼ 7.8 Hz), 7.16 (d, 1H, J ¼ 7.5 Hz),
þ
7.02 (d, 2H, J ¼ 8.1 Hz) ppm; EIMS: m=z (%) ¼ 286 (M ,
þ
2
7
2), 284 (M , 65), 249 (52), 221 (40), 165 (44), 123 (29),
7 (97), 51 (100).
2-Chloro-3-(2-methoxyphenoxy)-1,4-naphthoquinone
(
2b, C H ClO )
17 11 4
ꢄ
1
Mp 145–146 C; H NMR (300MHz, CDCl ): ꢀ ¼ 8.20 (dd,
3
In conclusion we developed a method that pro-
vides an efficient synthesis of alkoxynaphthoquinone
derivatives with structural diversity. Central to this
strategy is the application of Cs CO -mediated sub-
1H, J ¼ 9.0, 1.8 Hz), 8.02 (dd, 1H, J ¼ 8.7, 1.8 Hz), 7.77–7.73
(m, 2H), 7.11 (t, 2H, J ¼ 6.9 Hz), 6.95 (t, 2H, J ¼ 7.2 Hz), 3.75
þ
þ
(
2
s, 3H) ppm; EIMS: m=z (%) ¼ 316 (M , 24), 314 (M , 100),
79 (39), 261 (31), 206 (40), 163 (54), 135 (100), 121 (96),
9 (89), 77 (81).
2
3
9
stitution of 2,3-dichloronaphthoquinone, 6,7-dichloro-
quinolinedione, and 6,7-dichloroisoquinolinedione
with oxygen nucleophiles. The reaction is shown to
be quite general for a wide array of aryl and aliphatic
alcohols. It is noteworthy that the chemical shifts of
phenyl protons are greatly affected by the substitution
patterns in quinolinedione and isoquinolinedione.
2
-Chloro-3-(3-methoxyphenoxy)-1,4-naphthoquinone
(2c, C H ClO )
1
7
11
ꢄ
4
1
Mp 91–92 C; H NMR (300MHz, CDCl ): ꢀ ¼ 8.22 (dd, 1H,
3
J ¼ 9.0, 2.4 Hz), 8.06 (dd, 1H, J ¼ 9.0, 2.4 Hz), 7.80–7.76 (m,
2
H), 7.21 (t, 1H, J ¼ 8.4 Hz), 6.70–6.41 (m, 3H), 3.80 (s, 3H)
þ þ
ppm; EIMS: m=z (%) ¼ 316 (M , 34), 314 (M , 65), 279
(
6
87), 251 (68), 223 (43), 152 (26), 123 (36), 92 (66), 77 (92),
3 (100), 50 (53).
Experimental
2-Chloro-3-(4-ethoxyphenoxy)-1,4-naphthoquinone
6
(
,7-Dichloro-5,8-quinolinedione (5) and -isoquinolinedione
8) were prepared according to Refs. [7, 17]. Other chemicals
(2e, C18
H
13ClO
4
)
ꢄ
1
Mp 145–146 C; H NMR (300MHz, CDCl ): ꢀ ¼ 8.20 (dd,
3
were purchased from Aldrich and used without further purifi-
cation. Melting points were measured on a Barnstead Electro-
thermal IA9100 apparatus. Mass spectra were recorded on a
Varian 1200 GC=MS operating at an ionization potential of
1H, J ¼ 9.0, 2.1 Hz), 8.04 (dd, 1H, J ¼ 9.0, 2.4 Hz), 7.79–7.75
(m, 2H), 6.96 (d, 2H, J ¼ 6.6 Hz), 6.84 (d, 2H, J ¼ 6.9 Hz),
4.00 (q, 2H, J ¼ 6.9 Hz), 1.40 (t, 3H, J ¼ 6.9 Hz) ppm; EIMS:
þ
m=z (%) ¼ 328 (M , 66), 299 (31), 264 (30), 236 (28), 190
1
13
7
0eV. H and C NMR spectra were measured with a Bruker
(29), 162 (46), 135 (51), 99 (100), 75 (92), 64 (88).

Cs CO -Mediated Reaction of Dichloronaphthoquinone Derivatives
2
745
3
2
-Chloro-3-(p-tolyloxy)-1,4-naphthoquinone (2f, C H ClO )
17 11 3
2-Butoxy-3-chloro-1,4-naphthoquinone (2m, C H ClO )
14 13
3
ꢄ
1
1
Mp 146–147 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.21 (dd,
A semi-solid; H NMR (300MHz, CDCl ): ꢀ ¼ 8.14 (dd,
3
3
1
H, J ¼ 9.0, 2.1 Hz), 8.04 (dd, 1H, J ¼ 9.0, 2.4Hz), 7.79–7.75
1H, J ¼ 9.0, 2.7 Hz), 8.08 (dd, 1H, J ¼ 9.0, 2.4 Hz), 4.57 (t,
2H, J ¼ 6.3Hz), 1.79 (quintet, 2H, J ¼ 6.6 Hz), 1.52 (sextet,
2H, J ¼ 7.5 Hz), 0.98 (t, 3H, J ¼ 7.5 Hz) ppm; EIMS: m=z
(
2
1
(
m, 2H), 7.13 (d, 2H, J ¼ 8.4 Hz), 6.91 (d, 2H, J ¼ 8.4 Hz),
þ
þ
.33 (s, 3H) ppm; EIMS: m=z (%) ¼ 300 (M , 37), 298 (M ,
þ
þ
00), 263 (85), 235 (22), 207 (64), 179 (54), 163 (29), 135
58), 123 (58), 99 (67), 91 (73), 65 (92).
(%) ¼ 266 (M , 16), 264 (M , 40), 221 (10), 208 (100),
180 (98), 173 (24), 123 (44).
2
-Chloro-3-(4-ethylphenoxy)-1,4-naphthoquinone
2-Chloro-3-(2-diethylaminoethoxy)-1,4-naphthoquinone
(
2g, C H ClO )
13
(2n, C16
A semi-solid; H NMR (300 MHz, CDCl
H18ClNO )
3
1
8
3
ꢄ
1
1
Mp 121–122 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.22 (dd,
3
): ꢀ ¼ 8.14 (dd, 1H,
3
1
(
2
H, J ¼ 9.0, 2.1 Hz), 8.05 (dd, 1H, J ¼ 9.0, 2.4Hz), 7.80–7.76
m, 2H), 7.15 (d, 2H, J ¼ 8.4 Hz), 6.93 (d, 2H, J ¼ 6.9 Hz),
.63 (q, 2H, J ¼ 7.5 Hz), 1.23 (t, 3H, J ¼ 7.5Hz) ppm; EIMS:
J ¼ 9.0, 2.7Hz), 8.09–8.03 (m, 1H), 7.73–7.70 (m, 2H), 4.80
(t, 2H, J ¼ 4.8Hz), 2.90 (t, 2H, J ¼ 4.8Hz), 2.58 (q, 4H,
J ¼ 6.9Hz), 0.87 (t, 6H, J ¼ 6.9 Hz) ppm; EIMS: m=z (%) ¼
þ
þ
þ
þ
m=z (%) ¼ 314 (M , 29), 312 (M , 77), 297 (100), 277 (29),
310 (M , 1), 308 (M , 3), 250 (3), 149 (22), 111 (26), 97 (39),
83 (43), 71 (53), 57 (100).
1
91 (34), 163 (61), 135 (38), 99 (74), 77 (99), 51 (35).
2-Chloro-3-(2-piperidin-1-ylethoxy)-1,4-naphthoquinone
2
-Chloro-3-(4-nitrophenoxy)-1,4-naphthoquinone
(
2o, C H ClNO )
3
(
2h, C H ClNO )
1
17 18
6
8
5
1
ꢄ
1
A semi-solid; H NMR (300MHz, CDCl ): ꢀ ¼ 8.09 (dd,
Mp 181–182 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.28–
3
3
1
2
H, J ¼ 9.0, 2.1 Hz), 8.02 (dd, 1H, J ¼ 9.0, 2.1 Hz), 4.71 (t,
H, J ¼ 4.8 Hz), 2.61 (t, 2H, J ¼ 4.8 Hz), 2.30 (br s, 4H),
8
2
.25 (m, 3H), 8.02 (dd, 1H, J ¼ 9.0, 2.7 Hz), 7.87–7.79 (m,
H), 7.11 (d, 2H, J ¼ 9.0 Hz) ppm; EIMS: m=z (%) ¼ 331
þ
þ
2.01 (s, 4H), 0.88–0.76 (m, 2H) ppm; EIMS: m=z (%) ¼ 321
(
(
M , 25), 329 (M , 51), 301 (20), 220 (26), 191 (18), 163
53), 135 (30), 99 (51), 76 (100), 63 (41), 50 (65).
þ þ
(M , 38), 319 (M , 100), 279 (43), 167 (9), 149 (11), 98 (32).
2
-Chloro-3-(2-morpholin-4-ylethoxy)-1,4-naphthoquinone
2
-Chloro-3-(2,3-dimethoxyphenoxy)-1,4-naphthoquinone
(
2p, C H ClNO )
1
6
16
4
1
(
2i, C H ClO )
1
8
13
5
ꢄ
ꢄ
1
Mp 104–105 C; H NMR (300MHz, CDCl ): ꢀ ¼ 8.17 (dd,
3
Mp 123–125 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.19 (dd,
3
1
H, J ¼ 8.9, 2.4 Hz), 8.09 (dd, 1H, J ¼ 8.9, 2.3 Hz), 7.77–7.73
1
(
6
H, J ¼ 8.4, 1.5 Hz), 8.02 (dd, 1H, J ¼ 8.4, 1.5Hz), 7.79–7.72
m, 2H), 7.06 (t, 1H, J ¼ 8.4 Hz), 6.81 (d, 1H, J ¼ 8.4 Hz),
.74 (d, 1H, J ¼ 8.4 Hz), 3.87 (s, 3H), 3.72 (s, 3H) ppm;
(
(
(
m, 2H), 4.77 (t, 2H, J ¼ 4.6 Hz), 3.26 (t, 4H, J ¼ 4.1 Hz), 2.69
t, 2H, J ¼ 4.6 Hz), 2.39 (t, 4H, J ¼ 4.5 Hz) ppm; EIMS: m=z
þ
þ
%) ¼ 323 (M , 9), 321 (M , 37), 208 (3), 163 (3), 113 (6),
þ
þ
EIMS: m=z (%) ¼ 346 (M , 18), 344 (M , 83), 329 (19),
13 (21), 251 (10), 206 (12), 163 (33), 135 (48), 99 (53), 95
75), 76 (40), 51 (100).
100 (100), 56 (12).
3
(
Typical Procedure as Exemplified for the Synthesis of 7-Chloro-
-(4-methoxyphenoxy)-5,8-quinolinedione (6b, C H ClNO )
6
1
6
10
4
2
-Chloro-3-(3,5-dimethoxyphenoxy)-1,4-naphthoquinone
and 6-Chloro-7-(4-methoxyphenoxy)-5,8-quinolinedione
7b, C H ClNO )
To a solution of 100 mg 5 (0.44 mmol) and 60mg 4-meth-
(
2j, C H ClO )
1
8
13
5
ꢄ
1
(
16 10
4
Mp 118–119 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.21 (dd,
3
1
H, J ¼ 9.0, 2.4 Hz), 8.07 (dd, 1H, J ¼ 9.0, 2.4Hz), 7.83–7.74
3
oxyphenol (0.48 mmol) in 5 cm THF was added 143 mg
Cs CO (0.44 mmol) at room temperature. The reaction mix-
2 3
ture was stirred for 24h. The mixture was partitioned with
H O and ethyl acetate. The organic extracts were washed with
(m, 2H), 6.24–6.01 (m, 3H), 3.76 (s, 3H), 3.75 (s, 3H) ppm;
þ
þ
EIMS: m=z (%) ¼ 346 (M , 14), 344 (M , 43), 309 (100), 294
85), 265 (16), 172 (25), 133 (51), 99 (51), 63 (62).
(
2
brine, dried (MgSO ), and evaporated under reduced pressure
4
2
-Chloro-3-(4-methoxy-2-nitrophenoxy)-1,4-naphthoquinone
to give the residue. This residue was purified by column chro-
matography on silica gel (n-hexane=EtOAc¼ 3=1) to afford
119 mg (86%) of two regioisomeric products (6b and 7b).
Each analytical sample was obtained by repeated column chro-
matography and then recrystallization (n-hexane-CH Cl ) of
(
2k, C H ClNO )
1
7
10
6
1
ꢄ
Mp 123–124 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.20 (dd,
3
1
H, J ¼ 8.7, 1.5 Hz), 7.98 (dd, 1H, J ¼ 8.9, 1.7Hz), 7.80–7.74
(
3
1
m, 2H), 7.60 (d, 1H, J ¼ 2.9 Hz), 7.13–7.07 (m, 2H), 3.89 (s,
2
2
þ
H) ppm; EIMS: m=z (%) ¼ 359 (M , 2), 313 (40), 235 (3),
the enriched isomer, respectively.
1
63 (27), 151 (38), 135 (59), 123 (97), 99 (48), 75 (82), 63
ꢄ
6
b: Mp 181 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 9.07
3
(100), 51 (82).
(
7
dd, 1H, J ¼ 4.8, 1.5 Hz), 8.37 (dd, 1H, J ¼ 7.8, 1.5 Hz),
.72 (dd, 1H, J ¼ 7.8, 4.8 Hz), 6.98 (d, 2H, J ¼ 10.2 Hz),
2
-Benzyloxy-3-chloro-1,4-naphthoquinone (2l, C H ClO )
1
6.85 (d, 2H, J ¼ 10.2 Hz), 3.79 (s, 3H) ppm; EIMS: m=z
7
11
3
ꢄ
1
þ þ
Mp 78–80 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 8.14–8.07 (m,
(%) ¼ 317 (M , 18), 315 (M , 46), 192 (12), 164 (18),
3
2
7
H), 7.74 (dd, 2H, J ¼ 9.0, 3.0 Hz), 7.43 (d, 2H, J ¼ 7.5 Hz),
.38–7.35 (m, 3H), 5.65 (s, 2H) ppm; EIMS: m=z (%) ¼ 300
136 (66), 100 (61), 92 (47), 77 (79), 63 (100), 50 (74).
ꢄ
1
7b: Mp 170 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 9.04
3
þ
þ
(M , 15), 298 (M , 58), 263 (13), 181 (10), 123 (15), 91 (88).
(dd, 1H, J ¼ 4.8, 1.5Hz), 8.53 (dd, 1H, J ¼ 7.8, 1.5Hz),

7
46
D.-M. Lee et al.: Cs CO -Mediated Reaction of Dichloronaphthoquinone Derivatives
2 3
˚
˚
ꢄ
ꢄ
ꢄ
7
.73 (dd, 1H, J ¼ 7.8, 4.8 Hz), 6.98 (d, 2H, J ¼ 10.5Hz), 6.84
13.6253(4) A, ꢁ ¼ 90 , ꢂ ¼ 99.946(2) , ꢃ ¼ 90 ; volume,
3
3
(
(
d, 2H, J ¼ 10.5 Hz), 3.78 (s, 3H) ppm; EIMS: m=z (%) ¼ 317
1393.52(8)A ; density (calculated), 1.505 Mg=m ; reflections
collected, 13993; final R indices [I>2ꢄ(I)], R1 ¼ 0.0505,
wR2 ¼ 0.1027; R indices (all data), R1 ¼ 0.1382, wR2 ¼
þ
þ
M , 14), 315 (M , 60), 280 (16), 136 (63), 100 (73), 77 (66),
4 (100), 50 (65).
6
0
.1351. Atomic coordinates and crystallographic parameters
have been deposited at the Cambridge Crystallographic Data
Centre (CCDC 639462). These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk=data_request=cif.
Crystallographic Data for 6b
Empirical formula, C H ClNO ; formula weight, 315.70;
1
6
10
4
crystal system, orthorhombic; space group, P2(1)2(1)2(1);
˚
˚
unit cell dimensions, a ¼ 5.1790(4) A, b ¼ 8.1796(7) A,
˚
3
ꢄ
ꢄ
ꢄ
c ¼ 32.047(3) A, ꢁ ¼ 90 , ꢂ ¼ 90 , ꢃ ¼ 90 ; volume,
3
˚
357.56(19) A ; density (calculated), 1.545 Mg=m ; reflections
1
Acknowledgements
collected, 8026; final R indices [I>2ꢄ(I)], R1 ¼ 0.0653,
wR2 ¼ 0.1394; R indices (all data), R1 ¼ 0.1667, wR2 ¼
We are grateful to the Korea Research Council for Industrial
Science and Technology for financial support on this work
0
.1809. Atomic coordinates and crystallographic parameters
have been deposited at the Cambridge Crystallographic Data
Centre (CCDC 639461). These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk=data_request=cif.
(
KK-0701-D0).
References
[
[
[
1] Sartori MF (1963) Chem Rev 63: 279
Typical Procedure as Exemplified for the Synthesis of 6-
Chloro-7-(4-methoxyphenoxy)-5,8-isoquinolinedione (10c,
C H ClNO ) and 6,7-Bis(4-methoxyphenoxy)-5,8-
2] Behforouz M, Haddad J, Gu Z (1998) J Org Chem 63: 343
3] Boger DL, Yasuda M, Mitscher LA, Drake SD, Kitos
PA, Thompson SC (1987) J Med Chem 30: 1918
1
6
10
4
isoquinolinedione (11c, C H NO )
2
3
17
6
[4] Hargreaves R, David CL, Whitesell L, Skibo EB (2003)
Bioorg Med Chem Lett 13: 3075
[5] Saito N, Koizumi Y-I, Tanaka C, Suwanborirux K,
Amnuoypol S, Kubo A (2003) Heterocycles 61: 79
[6] Boger DL, Hong J (1998) J Am Chem Soc 120: 1218
To a solution of 23 mg 8 (0.1mmol) and 14mg 4-methoxy-
3
phenol (0.11 mmol) in 1 cm THF was added 33mg Cs CO
2
3
(0.1mmol) at room temperature. The reaction mixture was
stirred for 36 h. The mixture was partitioned with H O and
2
ethyl acetate. The organic extracts were washed with brine,
dried (MgSO ), and evaporated under reduced pressure to give
[
[
[
7] Ryu C-K, Lee I-K, Jung S-H, Lee C-O (1999) Bioorg
Med Chem Lett 9: 1075
8] Yoon EY, Choi HY, Shin KJ, Yoo KH, Chi DY, Kim DJ
4
the residue. The residue was purified by column chromatogra-
phy on silica gel (n-hexane=EtOAc¼ 9=1) to afford 27mg
(2000) Tetrahedron Lett 41: 7475
(
(
85%) of two regioisomeric products (9c and 10c) and 4 mg
10%) 11c. An analytical sample of the major isomer 10c was
9] Lazo JS, Aslan DC, Southwick EC, Cooley KA, Ducruet
AP, Joo B, Vogt A, Wipf P (2001) J Med Chem 44: 4042
obtained by repeated column chromatography followed by
recrystallization (n-hexane-CH Cl ).
[
10] Kim Y-S, Park S-Y, Lee H-J, Suh M-E, Schollmeyer D,
Lee C-O (2003) Biorog Med Chem 11: 1709
2
2
ꢄ
1
1
0c: Mp 132 C; H NMR (300MHz, CDCl ): ꢀ ¼ 9.29 (s,
3
[11] Park HJ, Kim Y-S, Kim JS, Lee E-J, Yi Y-J, Hwang HJ,
Suh M-E, Ryu C-K, Lee SK (2004) Bioorg Med Chem
Lett 14: 3385
1
2
H), 9.11 (d, 1H, J ¼ 5.1 Hz), 8.00 (d, 1H, J ¼ 5.1 Hz), 6.98 (d,
H, J ¼ 9.0 Hz), 6.87 (d, 2H, J ¼ 9.0 Hz), 3.80 (s, 3H) ppm;
þ
þ
EIMS: m=z (%) ¼ 317 (M , 40), 315 (M , 61), 44 (37), 43
[12] Lien J-C, Huang L-J, Teng C-M, Wang J-P, Kuo S-C
(
37), 40 (100).
1
(2002) Chem Pharm Bull 50: 672
ꢄ
1
1c: Mp 114 C; H NMR (300 MHz, CDCl ): ꢀ ¼ 9.34
3
[13] Sarhan AAO, El-Dean AMK, Abdel-Monem MI (1998)
Monatsh Chem 129: 205
(
6
(
s, 1H), 9.08 (d, 1H, J ¼ 5.0 Hz), 7.89 (d, 1H, J ¼ 5.0 Hz),
.86–6.74 (m, 8H), 3.75 (s, 6H) ppm; EIMS: m=z (%) ¼ 403
[
[
14] Lien J-C, Huang L-J, Wang J-P, Teng C-M, Lee K-H,
Kuo S-C (1996) Chem Pharm Bull 44: 1181
15] Hodnett EM, Wongwiechintana C, Dunn WJ III, Marrs P
þ
M , 100), 375 (5), 252 (8), 240 (8), 196 (5), 169 (6), 135
38), 123 (24), 92 (30), 40 (41).
(
(1983) J Med Chem 26: 570
Crystallographic Data for 10c
Empirical formula, C H ClNO ; formula weight, 315.70;
[16] Chang H-X, Chou T-C, Savaraj N, Liu LF, Yu C, Cheng
CC (1999) J Med Chem 42: 405
1
6
10
4
crystal system, monoclinic; space group, P2(1)=c; unit
˚
[17] Shaikh IA, Johnson F, Grollman AP (1986) J Med Chem
29: 1329
˚
cell dimensions, a ¼ 5.3200(2) A, b ¼ 19.5179(7) A, c ¼