Synthesis of 5(6H)-phenanthridones using Diels-Alder reaction of 3-nitro-2(1H)-quinolones acting as dienophiles

Article abstract of DOI:10.1248/cpb.54.204

Diels-Alder reactions of 3-nitro-2(1H)-quinolones with 1,3-butadiene derivatives were carried out to give the phenanthridone derivatives under both atmospheric and high pressure conditions. Furthermore, the reactivity of 3-substituted 2(1H)-quinolones acting as a dienophile with 2,3-dimethyl-1,3- butadiene was examined using molecular orbital (MO) calculation.

Full text of DOI:10.1248/cpb.54.204

2
04
Chem. Pharm. Bull. 54(2) 204—208 (2006)
Vol. 54, No. 2
Synthesis of 5(6H)-Phenanthridones Using Diels–Alder Reaction of
-Nitro-2(1H)-quinolones Acting as Dienophiles
3
Reiko FUJITA,* Toshiteru YOSHISUJI, Sota WAKAYANAGI, Hideaki WAKAMATSU, and Hisao MATSUZAKI
Tohoku Pharmaceutical University; 4–4–1 Komatsushima, Aoba-ku, Sendai 981–8558, Japan.
Received September 6, 2005; accepted November 2, 2005
Diels–Alder reactions of 3-nitro-2(1H)-quinolones with 1,3-butadiene derivatives were carried out to give the
phenanthridone derivatives under both atmospheric and high pressure conditions. Furthermore, the reactivity of
3-substituted 2(1H)-quinolones acting as a dienophile with 2,3-dimethyl-1,3-butadiene was examined using mole-
cular orbital (MO) calculation.
Key words 3-nitro-2(1H)-quinolone; Diels–Alder reaction; 6(5H)-phenanthridone; 1-methoxy-1,3-butadiene; 2,3-dimethoxy-
1
,3-butadiene; molecular orbital (MO) calculation
2(1H)-Quinolones are classified as aromatic heterocycles. 17%, 13%, entries 7, 8) in poor yields. But, DA reactions of
With regard to reactions of 2(1H)-quinolones, substitution re- 1a, b with 2b under HP condition (10 kbar) at 90 °C for 2 d
1—8)
actions
have been widely reported, but little attention has afforded DA adducts (5a, 57%; 5b, 55%, entries 9, 10) in
been focused on addition reactions. Diels–Alder (DA) reac- reasonable yields. Heating of 5a, b at 180 °C produced
tion of 2(1H)-quinolones with diene afforded the phenan- 6a (48%) and 6b (40%) aromatized by release of HNO2,
thridones in one pot. Recently, Weltin verified the ability followed by dehydrogenation, respectively. The stereo-
of the 6(5H)-phenanthridones to inhibit poly(ADP-ribose)- chemistries of the group at C-7 in 4a, b were determined by
9—12)
1
polymerase (PARP) activity in lymphoma cells.
Further- nuclear Overhauser effect (NOE) measurement of H-NMR
more, Cheng reported that 8,9-dimethoxyphenanthridinium spectra. The spectrum of 4a indicated a correlation between
13)
salts (A, Chart 1) possess activity against leukemias P388.
H-7 and H-10a, but no such correlation was seen in the 4b
We reported the synthesis of functionalized phenanthridones spectrum. Consequently, the stereochemistries between the
by novel DA reaction of 1-methyl-2(1H)-quinolones having methoxy group and H-10a were confirmed as trans in 4a and
an electron-withdrawing group (such as methoxycarbonyl, cis in 4b.
1
8,19)
acetyl, cyano) at the 4- or 3-position that acts as a
dienophlie.
Next, DA reactions of 3-nitro-2(1H)-quinolone (1c)
1
4—17)
It is well known that the nitro group func- with 2a, b, 1-methoxy-3-silyloxy-1,3-butadienes (2c, d) and
tion as a leaving group and a strong electron-withdrawing 2,3-disubstituted 1,3-butadienes (2b, e) were investigated
group. Herein, we report the synthesis of 6(5H)-phenanthri- under AP conditions, as shown in Table 2 and Chart 2.
dones by DA reaction of 3-nitro-2(1H)-quinolones under at- DA reactions of 1c with 2a were carried out in 1,2-
mospheric and high pressure (AP and HP) conditions, and dimethoxyethane (DME) and tetrahydrofurane (THF) since
we investigate of the reactivity of the 2(1H)-quinolones using 1c was insoluble in o-xylene. DA reaction of 1c with 2a at
molecular orbital (MO) calculation.
DA Reaction Firstly, DA reactions of 3-nitro- (1a) and (7,
180 °C for 1 d in DME (entry 1) gave 6(5H)-phenanthridone
52%) possing bioactivity and exo-DA adduct (8,
with 1,3-bu- 33%) an excellent yield. The same reaction for 5 d in DME
2
1,22)
1
8,19)
3,6-dinitro-1-methyl-2(1H)-quinolones (1b)
tadienes (2a, b) were investigated under AP and HP condi- (entry 2) afforded 7 (50%) and 8 (30%), and in THF for 3 d
tions, as shown in Table 1 and Chart 1. DA reactions of 1a, b (entry 3), afforded 7 (44%) and 8 (28%). Heating of 8 at
with 1-methoxy-1,3-butadiene (2a) were carried out at 180 °C in sealed tube produced 7 (8% only) aromatized by
1
80 °C for 5 d in o-xylene (entries 1, 4), and gave 6(5H)- elimination of HNO and MeOH. Based on the above facts, it
2
20)
phenanthridones (3a, 83%; 3b, 68%), respectively. The can be presumed that 7 mostly result by aromatization from
same reaction of 3a at 160 °C for 3 d (entry 2), also afforded corresponding endo-DA adduct. DA reaction of 1c with 1-
3
a (63%). On the other hand, DA reaction of 1a with 2a was methoxy-3-trimethylsilyloxy-1,3-butadiene (2c) at 160 °C for
performed under HP conditions (10 kbar) at 90 °C for 2 d 3 d in DME (entry 4) gave 9-hydroxy-6(5H)-phenanthridone
23)
(
entry 3), and gave endo-DA adduct (4a, 57%) and exo-DA (9, 43%) and 9-methoxy-6(5H)-phenanthridone (11, 7%),
adduct (4b, 20%), respectively. Heating of 4a, b at 180 °C in and the same reaction at 180 °C (entry 5) gave 9 (57%) and
sealed tube produced 3a (67%, 64%, respetively) aromatized 11 (9%) in good yield. Similerly, DA reaction of 1c with
by elimination of hydrogen and nitrogen dioxide (HNO2), 1-methoxy-3-t-butyldimethylsilyloxy-1,3-butadiene (2d) at
followed by release of MeOH. These facts indicated that 180 °C for 3 d in DME (entry 6) afforded 9 (56%), 11 (1%)
3
a, b resulted from release of HNO and MeOH of corre- and 9-t-butyldimethylsilyloxy-6(5H)-phenanthridone (10,
2
sponding DA adducts (such as 4a) under AP conditions. Fur- 38%) in quantitative yield. Treatment of 10 with tetra-n-
thermore, DA reactions of 1a with 2,3-dimethoxy-1,3-butadi- butylammonium fluoride (TBAF) in THF at 30 °C for 6 h
ene (2b) at 180 °C under AP condition gave 1-methyl-8,9- produced 9 in 80% yield. Moreover, DA reaction of 1c with
3)
dimethoxy-6(5H)-phenanthridone (6a ; 31%, 45%, entries 5, 2b at 160 °C for 5 d (entry 7) afforded 8,9-dimethoxy-6(5H)-
2
4)
6
) which was the synthetic intermediate for A possessing a phenanthridone (13a, 20%) and 8-methoxy-6(5H)-phenan-
23)
bioactivity. DA reactions of 1b with 2b at 180 °C afforded thridone (14, 30%). The same reactions at 180 °C for 3 or
1-methyl-8,9-dimethoxy-2-nitro-6(5H)-phenanthridone (6b; 5 d (entries 8, 9) also gave 13a (22%, 33%) and 14 (16%,
∗
To whom correspondence should be addressed. e-mail: refujita@tohoku-pharm.ac.jp
© 2006 Pharmaceutical Society of Japan

February 2006
205
Chart 1
Table 1. Diels–Alder Reactions of 1a, b with 2a, b
Entry
Quinolone
Diene
Temp. (°C)
Time (d)
Solvent
Pressure (kbar)
Product
Yield (%)
1
2
3
1a
1a
1a
2a
2a
2a
180
180
90
5
3
2
o-Xylene
o-Xylene
CH Cl
Atmospheric
Atmospheric
10
3a
3a
4a
83
63
57
20
68
31
45
17
13
57
55
2
2
4b
4
5
6
7
8
9
1b
1a
1a
1b
1b
1a
1b
2a
2b
2b
2b
2b
2b
2b
180
180
180
180
180
90
5
5
3
5
3
2
2
o-Xylene
o-Xylene
o-Xylene
o-Xylene
o-Xylene
CH Cl
Atmospheric
Atmospheric
Atmospheric
Atmospheric
Atmospheric
10
3b
6a
6a
6b
6b
5a
6b
2
2
2
1
0
90
CH Cl
10
2
8%), respectively. DA reaction of 1c with 2,3-dimethyl-1,3- occupied the 9-position, and that in 14 occupied at the 8-po-
butadiene (2e) at 180 °C for 3 d (entry 10) afforded only 8,9- sition. It was considered that 14 was drived from 13a by
25)
dimethyl-6(5H)-phenanthridone (13b, 48%).
elimination of HNO and demethanolation. Desilylation of
2
The stereochemistry of between the methoxy group at C-7 10 gave 9, so that the silyloxy group in 10 occupied the 9-po-
and H-10a in 8 was confirmed that since the methylation of 8 sition. It was assumed that methylation of 9 for production of
27)
gave 4b, that in 8 was also cis. The structures of 9, 10, 11 11 would be a source of DME.
and 14 were determined as follows. Methylation of 9 and 11 Yields of Adducts and Activation Energy We theoreti-
26)
produced a known compound (12) bearing a methoxy cally studied the reactivity of the DA reactions of 3-substi-
group at the 9-position. Similarly, methylation of 14 also pro- tuted and non-substituted quinolones (1a, c, 16a, b, 18a, b)
26)
duced a known compound (15) bearing a methoxy group at with dimethylbutadiene (2e; Chart 3). We calculated activa-
the 8-position. Consequently, the methoxy group in 9 and 11 tion energies (Ea) of the DA reactions listed in Table 3 using

2
06
Vol. 54, No. 2
Chart 2
Table 2. Diels–Alder Reactions of 1c with 2a—e under the Atmospheric
28)
Gaussian 98 at B3LYP/6-31G(d) level. We searched and
obtained the endo- and exo-type transition states (TS). Since
the exo-type TS have lower energy than the endo-type in
these DA reactions and the both TS’s lead to the same prod-
uct, we calculated Ea as a difference in energy between the
exo-type TS and the initial state. The calculated values of Ea,
the yields of adducts, and the SM recoveries are shown in
Table 3. Since the fraction of side reactions is thought to be
small from these data, we can regard the yield of adduct as
an index of the reactivity. The yields of DA reactions of 3-
substituted N-methylquinolones (1a, 16a) are well correlated
with the calculated values of Ea. The yields of DA reactions
of non-substituted quinolones (18a, b) with 2e were zero.
They are consistent with the fact that the calculated values of
Ea of these reactions are considerably larger than the others.
The yields of the DA reactions of NH-quinolones (1c, 16b)
are smaller than those of N-methylquinolones (1a, 16a), re-
spectively. Whereas, the calculated values of Ea expect the
reverse results. Nevertheless, NH-quinolones (1c, 16b) cause
a keto–enol tautomerization. We calculated the energies of
the keto- and enol-type quinolones (1c, 16b) at B3LYP/6-
Conditions
Temp.
°C)
Time
(d)
Product
No.
Yield
(%)
Entry
Diene
Solvent
(
1
2
3
4
5
6
2a
2a
2a
2c
2c
2d
180
180
180
160
180
180
1
5
3
3
3
3
DME
DME
THF
7
8
7
8
7
8
9
52
33
50
30
44
28
43
7
57
9
56
38
1
20
30
22
16
33
8
DME
DME
DME
1
1
9
1
9
0
1
1
1
1
7
8
9
2b
2b
2b
2e
160
180
180
180
5
3
5
3
DME
DME
DME
DME
14a
1
5
14a
1
5
14a
1
5
1
0
14b
48
3
1ꢀꢀG (d, p) level. The obtained energies of keto-type

February 2006
207
Chart 3
Table 3. Yields of Adducts and Activation Energies (Ea) Calculated Using Gaussian 98 at B3LYP/6-31G(d) Level
a)
Group on
the 3-position
Ea
(kcal/mol)
Population
(%)
Yield
(%)
SM recov.
(%)
Quinolone
R
Adduct
1
5)
1
1
7a
7b
9a
9b
a
c
NO2
NO2
COOMe
COOMe
H
Me
H
Me
H
Me
H
20.41
19.65
23.82
23.33
27.01
26.30
—
36
—
41
—
99
14c
14b
18a
18b
20a
20b
95
48
40
0
0
0
—
32
51
97
96
97
15)
1
1
1
1
H
a) Population of the keto-type quinolones calculated at B3LYP/6-31ꢀꢀG(d, p) level.
quinolones are 0.51 and 0.32 kcal/mol larger than those of with acetone–hexane (1 : 2) was evaporated to give 5,6,6a,7,8,10a-hexahy-
dro-7b-methoxy-5-methyl-cis-6a-nitro-6(5H)-phenanthridone (4b). The sec-
enol-type of 1c and 16b, respectively. These differences in
energy respectively correspond to the populations of keto-
ound fraction was evaporated to give 5,6,6a,7,8,10a-hexahydro-7a-methoxy-
5-methyl-cis-6a-nitro-6(5H)-phenanthridone (4a). The yields of the above
type of 36% and 41%, as shown in Table 3. We can presume
that the lowered populations of keto-type quinolones caused
the drop of reactivity of these DA reactions and leaded to
small yields of adducts.
In conclusion, we prepared the desired phenanthridones
using DA reactions of 3-nitro-2(1H)-quinolones with 1-
compounds are summarized in Table 1.
Heating of 4a, b a) The solution of 4a (43.2 mg, 0.15 mmol) in 3 ml o-
xylene was heated at 180 °C for 1 d and then concentrated in vacuo. The
residue was purified by chromatography on a silicagel. The fraction eluted
with hexane–ethyl acetate (1 : 1) was evaporated to give 3a (21 mg, 67%). b)
Heating of 4b (15 mg, 0.052 mmol) was carried out under the same condi-
tion and the product was purified by preparative TLC over silicagel with
methoxy-, 3-silyloxy- and 2,3-disubstituted 1,3-butadienes. hexane–ethyl acetate (1 : 1) to give 3a (6 mg, 64%).
Typical Procedure for DA Reaction of 1a, b with 2b a) A o-xylene so-
lution (3 ml) of 1a (204 mg, 1 mmol) and 2b (575 mg, 5 mmol) was heated at
80 °C for 3 d in a sealed tube. The reaction mixture was concentrated in
vacuo, and the residue was subjected to chromatography on a silica gel col-
umn. The first fraction eluted with acetone–hexane (1 : 1) was evaporated to
gave 6a. b) Reactions of 1a, b (1 mmol) with 2b (5 mmol) were carried out
under the conditions listed in Table 1 and products were purified as de-
We have also developed a methodology for phenanthridone
synthesis. We can understand qualitatively the reactivity of
DA reactions listed in Table 3 in terms of the activation ener-
gies and the population of keto-type quinolones.
1
Experimental
The following instruments were used to obtain physical data: Melting scribed above to give 6a, b. The respective yields of the above compounds
points, Yanaco micromelting point apparatus (values are uncorrected); IR
are summarized in Table 1.
spectra, Perkin Elmer ET-IR 1725X spectrometer; MS, JEOL JMN-DX
DA Reaction of 1a with 2b under HP Condition A mixture of 1a
03/JMA-DA5000 spectrometer; NMR spectra, JNM-GSX 400 ( H-NMR, (57 mg, 0.28 mmol) and 2b (141 mg, 1 mmol) in dichloromethane (3 ml) was
00 MHz; C-NMR, 100 Hz), JNM-EX270 ( H-NMR, 270 MHz; C-NMR, placed in a Teflon tube. The tube was placed in a high pressure reactor and
7.5 MHz), JEOL JNM-PMX 60SI spectrometer with tetra-methylsilane pressurized to 10 kbar, followed by heating at 90 °C for 2 d. Pressure was re-
1
3
4
6
13
1
13
(TMS) as an internal standard; and elemental analysis, PERKINELMER
leased and the reaction mixture was concentrated in vavuo. The residue was
2400 CHN Elemental Analyzer. Chromatography was carried out under the
subjected to chromatography on a silica gel column to give 5,6,6a,7,8,10a-
following experimental conditions: column chromatography, Merk Kieselgel hexahydro-8,9-dimethoxy-5-methyl-cis-6a-nitro-6(5H)-phenanthridone (5a).
silica gel 60 (230—400 mesh); TLC, pre-coated TLC plates with 60F254
2 mm, Merck).
Heating of 5a, b a) The solution of 5a (5 mg, 0.015 mmol) in 1 ml o-xy-
lene was heated at 180 °C for 1 d and then concentrated in vacuo. The
(
Typical Procedure for DA Reactions of 1a, b with 2a a) A o-xylene residue was purified by preparative TLC over silicagel with hexane–ethyl ac-
solution (3 ml) of 1a (204 mg, 1 mmol) and 2a (420 mg, 5 mmol) was heated
at 180 °C for 5 d in a sealed tube. The reaction mixture was concentrated in
vacuo. The residue was subjected to chromatography on a silica gel column.
The first fraction eluted with acetone–hexane (1 : 2) was evaporated to gave
etate (1 : 1) to give 6a (2 mg, 48%). b) Heating of 5b (15 mg, 0.041 mmol)
was carried out under the same condition and product was purified as de-
scribed above to give 6b (6 mg, 40%).
Typical Procedure for DA Reaction of 1c with 2a a) A DME solution
(1.5 ml) of 1c (50 ml, 0.26 mmol) and 2a (0.13 ml, 1.315 mmol) was heated
at 180 °C for 3 d in a sealed tube. The reaction mixture was concentrated in
vacuo, and the residue was subjected to chromatography on a silica gel col-
umn. The fraction eluted with ethyl acetate was evaporated and the residue
6)
3
a. b) Reactions of 1a, b (1 mmol) with 2a (5 mmol) were carried out under
the conditions listed in Table 1 and products were purified as described
above to gave 3a, b. The respective yields of the above compounds are sum-
marized in Table 1.
DA Reaction of 1a with 2a under HP Condition A mixture of 1a was added CHCl3 (20 ml). The CHCl3 layer was washed with saturated
(
53 mg, 0.26 mmol) and 2a (141 mg, 1 mmol) in dichloromethane (3 ml) was
aqueous NaCl and concentrated in vacuo. The residue was subjected to
chromatography on a silica gel column. The first fraction eluted with ace-
tone–hexane (1 : 2) was evaporated to give 5,6,6a,7,8,10a-hexahydro-7-
methoxy-cis-6a-nitro-6(5H)-phenanthridone (8). The second fraction was
evaporated to give 7. The yields of 8 are summarized in Table 2.
placed in a Teflon tube. The tube was placed in a high pressure reactor and
pressurized to 10 kbar, followed by heating at 90 °C for 2 d. Pressure was re-
leased and the reaction mixture was concentrated in vavuo. The residue was
subjected to chromatography on a silica gel column. The first fraction eluted

2
08
Vol. 54, No. 2
Heating of 8 a) The solution of 8 (50 mg, 0.183 mmol) in 1.5 ml DME
was heated at 180 °C for 3 d and then concentrated in vacuo. The residue
washed with saturated aqueous NaCl and dried over MgSO . The ethyl ac-
etate was evapolated in vacuo and the residue was chromatographed on a
4
was purified by preparative TLC over silicagel with hexane–ethyl acetate column of silica gel. The solvent of first fraction eluted with ethyl
(
1 : 1) to give 7 (3 mg, 8%, Rfꢁ0.35) and the recovery of 8 (38 mg, 76%,
acetate–hexane (1 : 1) was evaporated to give 15 (11 mg, 54%). The solvent
of second fraction was evaporated to recover 14 (9 mg, 40%).
Rfꢁ0.45).
Methylation of 8 To a suspention of cesium carbonate (470 mg,
1.45 mmol) and 8 (80 mg, 0.29 mmol) in THF (5.4 ml) was added MeI
References and Notes
(
0.05 ml, 0.87 mmol)] at room temperature under N . The mixture was re-
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2
fluxed for 5 h. The reaction mixture was concentrated in vacuo, quenched
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2
washed with saturated aqueous NaCl and dried over MgSO . The ethyl ac-
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4
etate was evapolated in vacuo and the residue was chromatographed on
a column of silica gel. The solvent of first fraction eluted with ethyl ac-
etate–hexane (1 : 2) was evaporated to give 4b (84 mg, quant).
Typical Procedure for DA Reaction of 1c with 2c, d a) A solution of
c (150 mg, 0.789 mmol) and 2c (0.75 ml, 3.945 mmol) in DME (4.5 ml) was
5) Tomisawa H., Fujita R., Hongo H., Kato H., Chem. Pharm. Bull., 22,
2091—2096 (1974).
1
heated at 180 °C for 3 d in a sealed tube. The reaction mixture was concen-
trated in vacuo and diluted with chloroform (20 ml). To the reaction mixture,
TFA (0.75 ml) was added with stirring at room temperature for 20 min and
concentrated in vacuo. The residue was chromatographed on a column of
silica gel. The solvent of first fraction eluted with ethyl acetate–hexane
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(
2 : 1) was evaporated to give 11. The solvent of second fraction was evapo-
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.95 mmol) in DME (4.5 ml) was heated at 180 °C for 3 d in a sealed tube.
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3
(
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chromatographed on a column of silica gel. The solvent of first fraction
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vent of second fraction was evaporated to give 11. The solvent of third frac-
tion was evaporated to give 9.
Treatment of 10 with TBAF To a solution of 10 (15 mg, 0.047 mmol)
in THF (1 ml) was added 1 mol/THF TBAF (0.14 ml, 0.14 mmol) and the re-
action solution was stirred at 30 °C for 6 h. The reaction mixture was evapo-
rated in in vacuo. The residue was chromatographed on a column of sil-
icagel. The soluvent of first fraction with eluted acetone–hexane (1 : 1) was
evaporated in in vacuo to give 9 (8 mg, 80%).
12) Mondon A., Krohn K., Chem. Ber., 108, 445—463 (1975).
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Methylation of 9 To a suspention of cesium carbonate (115 mg,
0
.335 mmol) and 9 (15 mg, 0.071 mmol) in THF (6 ml) was added MeI
18) Kaneko C., Naito T., Hashiba M., Fujii H., Somei M., Chem. Pharm.
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(0.017 ml, 0.284 mmol)] at room temperature under N . The mixture was re-
2
fluxed for 5 h. The reaction mixture was concentrated in vacuo, quenched
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with H O (6 ml) and extacted with ethyl acetate. The organic layer was 20) Ninomiya I., Naito T., Kiuchi T., J. Chem. Soc., Perkin Trans. 1, 1973,
2
washed with saturated aqueous NaCl and dried over MgSO . The ethyl ac-
2257—2261 (1973).
4
etate was evapolated in vacuo and the residue was chromatographed on
a column of silica gel. The solvent of first fraction eluted with ethyl ac-
etate–hexane (1 : 2) was evaporated to give 12 (17 mg, quant).
21) Harayama T., Akamatsu H., Okumura K., Miyagie T., Akiyama T.,
Abe H., Takeuchi Y., J. Chem. Soc., Perkin Trans. 1, 2001, 523—528
(2001).
Methylation of 11 To a suspention of cesium carbonate (114 mg,
22) Harayama T., Akiyama T., Kawano K., J. Chem. Bull., 44, 1634—1636
0.335 mmol) and 11 (16 mg, 0.07 mmol) in THF (6 ml) was added MeI
(1996).
(
0.013 ml, 0.21 mmol)] at room temperature under N . The mixture was re- 23) Swenton J. S., Ikeler T. J., Smyser G. I., J. Org. Chem., 38, 1157—
2
fluxed for 3 h. The reaction mixture was concentrated in vacuo, quenched
1166 (1973).
with H O (6 ml) and extacted with ethyl acetate. The organic layer was 24) Narasimhan N. S., Chandrachood P. S., Tetrahedron, 37, 825—827
2
washed with saturated aqueous NaCl and dried over MgSO . The ethyl ac-
(1981).
4
etate was evapolated in vacuo and the residue was chromatographed on
a column of silica gel. The solvent of first fraction eluted with ethyl ac-
etate–hexane (1 : 2) was evaporated to give 12 (11 mg, 65%).
25) Beccalli E. M., Clerici F., Gelmi M. L., Tetrahedron, 55, 8579—8586
(1999).
26) Naito T., Ninomiya I., Heterocycles, 22, 1705—1708 (1984).
Typical Procedure for DA Reaction of 1c with 2b, e a) A DME solu- 27) Fujita R., Wakayanagi S., Wakamatsu H., Matsuzaki H., Chem.
tion (1.5 ml) of 1c (50 mg, 0.26 mmol) and 2b (0.16 ml, 1.315 mmol) was
heated at 180 °C for 3 d in a sealed tube. The reaction mixture was concen-
trated in vacuo, and the residue was subjected to chromatography on a silica
gel column. The fraction eluted with ethyl acetate was evaporated and the
Pharm. Bull., 54, 209—212 (2006); DA reaction of 1-methyl-nitroiso-
quinolone with 2e in DME afforded DA adduct having hydroxy group.
Heating of DA adduct in DME gave DA adduct having methoxy
group.
residue was added CHCl (20 ml). The CHCl layer was washed with satu- 28) Gaussian 98, Revision A.9, Frisch M. J., Trucks G. W., Schlegel H. B.,
3
3
rated aqueous NaCl and concentrated in vacuo. The residue was subjected to
chromatography on a silica gel column. The first fraction eluted with ace-
tone–hexane (1 : 2) was evaporated to gave 14. The second fraction was
evaporated to give 1c (10 mg, 10%). The third fraction was evaporated to
gave 13a. The respective yields of the above compounds are summarized in
Table 2. b) Reactions of 1c (0.26 mmol) with 2e (5 mmol) was carried out
under the conditions listed in Table 2 and products were purified as de-
scribed above to gave 13b and the recover of 1c.
Scuseria G. E., Robb M. A., Cheeseman J. R., Zakrzewski V. G.,
Montgomery J. A., Jr., Stratmann R. E., Burant J. C., Dapprich S., Mil-
lam J. M., Daniels A. D., Kudin K. N., Strain M. C., Farkas O., Tomasi
J., Barone V., Cossi M., Cammi R., Mennucci B., Pomelli C., Adamo
C., Clifford S., Ochterski J., Petersson G. A., Ayala P. Y., Cui Q., Mo-
rokuma K., Malick D. K., Rabuck A. D., Raghavachari K., Foresman J.
B., Cioslowski J., Ortiz J. V., Baboul A. G., Stefanov B. B., Liu G.,
Liashenko A., Piskorz P., Komaromi I., Gomperts R., Martin R. L.,
Fox D. J., Keith T., Al-Laham M. A., Peng C. Y., Nanayakkara A.,
Challacombe M., Gill P. M. W., Johnson B., Chen W., Wong M. W.,
Andres J. L., Gonzalez C., Head-Gordon M., Replogle E. S., and Pople
J. A., Gaussian, Inc., Pittsburgh PA, 1998.
Methylation of 14 To a suspention of cesium carbonate (144 mg,
0.445 mmol) and 9 (20 mg, 0.089 mmol) in THF (6 ml) was added MeI
(
0.016 ml, 0.269 mmol) at room temperature under N . The mixture was re-
2
fluxed for 7 h. The reaction mixture was concentrated in vacuo, quenched
with H O (8 ml) and extacted with ethyl acetate. The organic layer was
2