Convenient synthetic method for 3-(3-substituted indol-2-yl)quinoxalin-2- ones as VEGF inhibitor

Article abstract of DOI:10.1248/cpb.55.922

It has already been reported that 3-(indol-2-yl)quinoxalin-2-ones ¹⁾? have a potent inhibitory effect on the growth of tumor cells based on anti-angiogenesis activity. We have also carried out a structure-activity relationship (SAR) study of 3-(indol-2-yl)quinoxalin-2-ones, which showed a potent inhibitory activity toward the vascular endothelial growth factor (VEGF)-induced proliferation of human mesangial cells and the VEGF-induced auto-phosphorylation of human umbilical vein endothelial cells.²⁾ Moreover, one of these compounds has a potent medicinal effect based on anti-angiogenic action, by oral administration²⁾ (Chart 1, 9). However, since the existing synthetic methods¹⁾ for the preparation of 3-(indol-2-yl)quinoxalin-2-ones consist of multiple steps some of which require strict anhydrous conditions, a convenient and simple synthetic method in place of the existing method is desirable. As a result of the investigations into the synthetic procedures, 3-(3-substituted indol-2-yl)quinoxalin-2-ones can be easily prepared by the condensation of 3-substituted indoles with quinoxalin-2-ones in the presence of trifluoroacetic acid (TFA). Herein, we report the examination of these reaction conditions and the application of this new synthetic method to the synthesis of the derivatives as VEGF inhibitors.

Full text of DOI:10.1248/cpb.55.922

922
Notes
Chem. Pharm. Bull. 55(6) 922—925 (2007)
Vol. 55, No. 6
Convenient Synthetic Method for 3-(3-Substituted indol-2-yl)quinoxalin-2-
ones as VEGF Inhibitor
Katsuyuki AOKI, ,a,c Jyun-ichi KOSEKI,a Shuichi TAKEDA,a Masaki ABURADA,b and
*
c
Ken-ichi MIYAMOTO
a Research Division, Tsumura & Co.; 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300–1192, Japan: b Faculty of
Pharmacy, Musashino University; 1–1–20 Shinmachi, Nishitokyo, Tokyo 202–8585, Japan: and c Department of Clinical
Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University; 13–1 Takara-machi, Kanazawa,
Ishikawa 920–8641, Japan. Received December 26, 2006; accepted April 11, 2007; published online April 11, 2007
It has already been reported that 3-(indol-2-yl)quinoxalin-2-ones1) have a potent inhibitory effect on the
growth of tumor cells based on anti-angiogenesis activity. We have also carried out a structure–activity relation-
ship (SAR) study of 3-(indol-2-yl)quinoxalin-2-ones, which showed a potent inhibitory activity toward the vascu-
lar endothelial growth factor (VEGF)-induced proliferation of human mesangial cells and the VEGF-induced
auto-phosphorylation of human umbilical vein endothelial cells.2) Moreover, one of these compounds has a potent
medicinal effect based on anti-angiogenic action, by oral administration2) (Chart 1, 9). However, since the exist-
ing synthetic methods1) for the preparation of 3-(indol-2-yl)quinoxalin-2-ones consist of multiple steps some of
which require strict anhydrous conditions, a convenient and simple synthetic method in place of the existing
method is desirable. As a result of the investigations into the synthetic procedures, 3-(3-substituted indol-2-
yl)quinoxalin-2-ones can be easily prepared by the condensation of 3-substituted indoles with quinoxalin-2-ones
in the presence of trifluoroacetic acid (TFA). Herein, we report the examination of these reaction conditions and
the application of this new synthetic method to the synthesis of the derivatives as VEGF inhibitors.
Key words indole; quinoxalin-2-one; trifluoroacetic acid; Friedel–Crafts reaction; vascular endothelial growth factor inhibitor
3-(Indol-2-yl)quinoxalin-2-ones has already been reported VI had been also reported. One of them is the A-route con-
as an anti-angiogenesis agent by Ladouceur et al.1) These sisting of the crossing coupling of (indol-2-yl)boric acids
compounds have a potent inhibitory effect on the growth of with 2,3-dichloroquinoxalines. Another is the B-route in
tumor cells with angiogenesis activity. We have also carried which (indol-2-yl)oxoacetate is condensed with phenylenedi-
out a structure–activity relationship (SAR) study of 3-(indol- amine. In the case of the former, II was prepared by the reac-
2-yl)quinoxalin-2-ones, which showed a potent inhibitory ac- tion of I, which was protected at the 1-position of indole with
tivity toward the VEGF-induced proliferation of human a suitable protecting group, with a boric acid ester using an
mesangial cells and the VEGF-induced auto-phosphorylation alkyl lithium reagent. Then III was prepared by the crossing
of human umbilical vein endothelial cells.2) Moreover, these coupling of II with 2,3-dichloroquinoxalines, which had pre-
compounds have a potent medicinal effect based on anti-an- viously been prepared separately. This route requires strict
giogenic action, by oral administration2) (Chart 1, 9).
anhydrous conditions and low temperature. Moreover, two
On the other hand, as shown in Chart 2, the two conven- kinds of regioisomers of III might be generated by the cou-
tional synthetic method1) of 3-(indol-2-yl)quinoxalin-2-ones pling reaction of II with the substituted 2,3-dichloroquinoxa-
lines. On the other hand, in the case of the latter route, the
preparation of IV also needs strict anhydrous conditions and
low temperature like A-route. In addition, V may be obtained
as two different regioisomers by the reaction of IV with the
substituted phenylenediamines. When more complicated de-
rivatives are prepared for more extensive SAR studies, it
could be expected that the number of steps would increase
Chart 1. Structure of the VEGF Inhibitor 9
A: synthesis of framework via (indol-2-yl)boric acid. B: synthesis of framework via (indol-2-yl)oxoacetate. PG: protecting group.
Chart 2. Conventional Synthetic Method for 3-(Indol-2-yl)quinoxalin-2-ones1)
∗ To whom correspondence should be addressed. e-mail: aoki_katsuyuki@mail.tsumura.co.jp
© 2007 Pharmaceutical Society of Japan

June 2007
923
Chart 3. Reported Synthetic Method4) for 3-(Indol-3-yl)quinoxalin-2-ones (C) and Our Strategy of Synthetic Method for 3-(Indol-2-yl)quinoxalin-2-ones
(D)
Table 1. TFA-Catalyzed Coupling Reaction of 3-Substituted Indoles or Indole with Quinoxalin-2-one
Temp and
time
Yield
(%)a)
Entry
Indoles
R
Solvent
Product
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1e
1f
CH3
CH3
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
DCE
r.t., 2 h
refl., 1 h
r.t., 4 h
r.t., 24 h
refl., 2 h
refl., 18 h
refl., 24 h
refl., 2 h
refl., 2 h
2a
2a
2b
2c
2d
2e
2h
—
2h
60
75
66
62
61
43
20
—
40
CH2CH2OH
CH2CH2NH2
CH2CONH2
CH2CH2COOCH3
COOCH3
1g
1h
OCOCH3
H
—: decomposition of indoxyl acetate. DCM: dichloromethane. DCE: 1,2-dichloroethane. These reaction conditions were not optimized. a) Isolated yield.
Chart 4. Alternative Synthesis1) of 2a
because the protection and/or de-protection of intermediates Chemistry
are necessary in both routes. Therefore, a new and simple
Thus, the TFA-catalyzed condensation of 1a with quinox-
synthetic method, using highly regiospecific reactions and alin-2-ones in dichloromethane (DCM) was actually carried
minimizing protection/de-protection steps as much as possi- out. As Table 1 shows, the reaction proceeded quite fast even
ble, was desired for the SAR study of these derivatives.
at room temperature and afforded the desired product 2a in
We have already reported the direct condensation3) of in- 60% of yield (Entry 1). In this TFA-catalyzed condensation,
dole or 7-azaindole with various substituted quinoxalin-2- only the desired product was obtained by stirring a mixture
ones in the presence of TFA, which proceeds under mild con- of 3-methylindole and quinoxalin-2-one in DCM in the pres-
ditions (Chart 3, C). In this reaction, the desired products are ence of 10% (v/v) TFA, followed by a certain oxidation6) in
obtained by heating a mixture of indoles and quinoxalin-2- situ, without generating any saturated side products,3) unlike
ones in DMF in the presence of 10% (v/v) TFA, followed by that observed in C (Chart 3). The structure of 2a has been
treating with suitable oxidizers such as MnO2. Therefore, it determined by alternative synthesis employing the similar
was thought that the similar reaction4) via the indolenine process,1) as depicted in Chart 4. The various 3-substituted
and/or direct pathway5) of 3-substituted indoles with quinox- indoles react with quinoxalin-2-ones in DCM or 1,2-
alin-2-ones might proceed and, as expected, the desired 3-(in- dichloroethane (DCE), and the reaction is compatible with
dolyl-2-yl)quinoxalin-2-ones can be prepared under these functional groups which are sensitive to strong base (see
mild conditions (Chart 3, D).
Table 1, Entry 3—6). Generally, the coupling reaction of in-

924
Vol. 55, No. 6
(a) acetic anhydride, imidazole, 130 °C, (b) 10% Pd–C, NaBH4, 2-PrOH, refl., (c) t-Boc2O, Et3N, DMAP, CH3CN, r.t., (d) H2, 10% Pd–C, AcOEt, r.t., (e) 1-(2-chloroethyl)piperi-
dine, Cs2CO3, DMF, 60 °C, (f) 6-fluoroquinoxalin-2-ones, TFA, DCE, refl.
Chart 5. Preparation of 9
(400 MHz, DMSO-d6) d: 2.77 (3H, s), 7.05 (1H, t, Jꢀ7.5 Hz), 7.20 (1H, t,
Jꢀ7.5 Hz), 7.29—7.46 (2H, m), 7.51 (1H, dt, Jꢀ1.2, 8.6 Hz), 7.63 (1H, t,
Jꢀ7.5 Hz), 7.65 (1H, d, Jꢀ7.5 Hz), 7.83 (1H, d, Jꢀ8.5 Hz), 11.63 (1H, s),
12.75 (1H, br s). 13C-NMR (100 MHz, DMSO-d6) d: 11.56 (s), 112.52 (s),
115.21 (s), 115.97 (s), 119.06 (s), 123.65 (s), 127.90 (s), 128.14 (s), 129.17
(s), 129.48 (s), 130.59 (s), 132.51 (s), 135.75 (s), 148.34 (s), 155.14 (s). ESI-
MS m/z: ꢁESI 276 (Mꢁ1), ꢂESI 274 (Mꢂ1). HR-ESI-MS m/z: 298.0963
(Calcd for C17H13N3ONa: 298.0956).
doles bearing a substituent which raises the electron density
on the ring tends to proceed promptly. However, in the case
of 1f, in which the electron density on the ring is lowered, an
unexpected reaction accompanying decarobxylation pro-
ceeded to give 2h3,7) in about 20% yield (Entry 7). The reac-
tion of derivatives of 1a, in which the indole was protected at
1-position with an electron withdrawing substituents such as
a benzenesulfonyl group,8) also failed. The TFA-catalyzed
condensation of (3-indoxyl)acetate 1g with quinoxalin-2-
ones lead to decomposition of 1g (Entry 8). The reaction
using the indole 1h, which does not have a substituent at the
3-position, afforded only 2h,3,7) in which substitution had
taken place at the 3-position on the indole, in about 40%
yield (Entry 9).
3-[3-(2-Hydroxyethyl)-1H-indol-2-yl]quinoxalin-2(1H)-one, 2b 1H-
NMR (400 MHz, DMSO-d6) d: 3.47 (2H, t, Jꢀ7.3 Hz), 3.73 (2H, t,
Jꢀ7.3 Hz), 4.68 (1H, br s), 7.05 (1H, dd, Jꢀ7.1, 7.8 Hz), 7.20 (1H, dd,
Jꢀ7.8, 9.0 Hz), 7.33—7.40 (2H, m), 7.53 (1H, t, Jꢀ8.0 Hz), 7.63 (1H, d,
Jꢀ7.1 Hz), 7.68 (1H, d, Jꢀ9.0 Hz), 7.86 (1H, d, Jꢀ8.0 Hz), 11.66 (1H, s),
12.78 (1H, br s). 13C-NMR (100MHz, DMSO-d6) d: 29.43 (s), 61.41 (s),
112.55 (s), 115.19 (s), 117.62 (s), 119.19 (s), 119.38 (s), 123.59 (s), 123.71
(s), 127.89 (s), 128.31 (s), 129.52 (s), 129.61 (s), 130.68 (s), 132.50 (s),
135.77 (s), 147.84 (s), 155.06 (s). ESI-MS m/z: ꢁESI 306 (Mꢁ1), ꢂESI
We then applied the new synthetic method to the prepara- 304 (Mꢂ1). HR-ESI-MS m/z: 328.1061 (Calcd for C18H15N3O2Na:
328.1062).
tion of a series of our VEGF inhibitors and give an example
3-[3-(2-Aminoethyl)-1H-indol-2-yl]quinoxalin-2(1H)-one,
2c 1H-
of their preparation here (Chart 5). The formylation of 5
using the method of Bergman9) afforded 6 in 91% yield.
Then, the reduction10) of 6 with 10% Pd–C and sodium
tetrahydroborate in 2-propanol gave 7 in 84% yield. The pro-
tection of the 1-position on the indole ring of 7 by tert-
Boc2O, followed by de-benzylation with 10% Pd–C in
AcOEt under hydrogen atmosphere, provided 8 in 95%
yield after 2 steps. The coupling reaction of 8 with 1-(2-
chloroethyl)piperidine in the presence of cesium carbonate
(Cs2CO3) in DMF, followed by the TFA-catalyzed condensa-
tion with 6-fluoroquinoxalin-2-ones,4) easily provided 9 in
reasonable yield without further purification. In this method,
9 could be prepared easily owing to the facile de-protection
of tert-Boc under the TFA-catalyzed reaction condition.
In summary, we investigated a convenient and simple syn-
thetic method for 3-(3-substituted indol-2-yl)quinoxalin-2-
ones and demonstrated a concise synthesis of 9, which may
NMR (400 MHz, DMSO-d6) d: 3.17 (2H, t, Jꢀ7.6 Hz), 3.58 (2H, t,
Jꢀ7.6 Hz), 7.11 (1H, t, Jꢀ8.1 Hz), 7.24 (1H, t, Jꢀ8.1 Hz), 7.29—7.40 (2H,
m), 7.53 (1H, t, Jꢀ7.3 Hz), 7.69 (1H, d, Jꢀ8.1 Hz), 7.73 (1H, d, Jꢀ8.1 Hz),
8.03 (1H, d, Jꢀ7.3 Hz), 11.86 (1H, br s). 13C-NMR (100 MHz, DMSO-d6) d:
24.26 (s), 112.90 (s), 115.03 (s), 118.83 (s), 119.60 (s), 123.55 (s), 123.84
(s), 127.35 (s), 128.67 (s), 129.85 (s), 130.04 (s), 131.08 (s), 132.55 (s),
135.78 (s), 147.45 (s), 155.27 (s). ESI-MS m/z: ꢁESI 305 (Mꢁ1), ꢂESI
303 (Mꢂ1). HR-ESI-MS m/z: 305.1423 (Calcd for C18H17N4O: 305.1402).
2-[2-(3-Oxo-3,4-dihydroquinoxalin-2-yl)-1H-indol-3-yl]acetamide, 2d
1H-NMR (400 MHz, DMSO-d6) d: 4.14 (2H, s), 6.80 (1H, br s), 7.07 (1H, t,
Jꢀ7.6 Hz), 7.22 (1H, t, Jꢀ7.6 Hz), 7.27 (1H, br s), 7.34—7.38 (2H, m), 7.52
(1H, dt, Jꢀ1.5, 8.0 Hz), 7.66 (1H, d, Jꢀ7.6 Hz), 7.68 (1H, d, Jꢀ7.6 Hz),
7.87 (1H, d, Jꢀ8.0 Hz), 11.74 (1H, s). 13C-NMR (100 MHz, DMSO-d6) d:
33.23 (s), 112.63 (s), 114.53 (s), 115.31 (s), 119.36 (s), 119.51 (s), 123.67
(s), 127.97 (s), 128.17 (s), 129.71 (s), 130.00 (s), 130.87 (s), 132.39
(s), 135.79 (s), 147.83 (s), 155.15 (s), 172.90 (s). ESI-MS m/z: ꢁESI
319 (Mꢁ1), ꢂESI 317 (Mꢂ1). HR-ESI-MS m/z: 341.1022 (Calcd for
C18H14N4O2Na: 341.1014).
3-[2-(3-Oxo-3,4-dihydroquinoxalin-2-yl)-1H-indol-3-yl]propanoate, 2e
1H-NMR (400 MHz, DMSO-d6) d: 2.75 (2H, t, Jꢀ7.8 Hz), 3.54 (2H, t,
be a promising VEGF inhibitor. Moreover, since it is not nec- Jꢀ7.8 Hz), 3.59 (3H, s), 7.07 (1H, t, Jꢀ7.8 Hz), 7.21 (1H, t, Jꢀ7.8 Hz),
essary for our synthetic method to be carried out under strict
anhydrous conditions and does not require special purifica-
tion in the work-up process, it is likely that this reaction will
7.36—7.39 (2H, m), 7.53 (1H, t, Jꢀ6.8 Hz), 7.66 (1H, d, Jꢀ7.8 Hz), 7.68
(1H, d, Jꢀ7.8 Hz), 7.76 (1H, d, Jꢀ6.8 Hz), 11.74 (1H, s), 12.83 (1H, br s).
13C-NMR (100 MHz, DMSO-d6) d: 34.16 (s), 51.13 (s), 112.71 (s), 115.31
(s), 119.02 (s), 119.09 (s), 119.37 (s), 123.70 (s), 123.79 (s), 127.09 (s),
be a very useful method in order to synthesize the concerned
basic framework.
128.09 (s), 129.33 (s), 129.65 (s), 130.69 (s), 132.58 (s), 135.71 (s), 147.61
(s), 155.13 (s), 173.27 (s). ESI-MS m/z: ꢁESI 348 (Mꢁ1), ꢂESI 346
(Mꢂ1). HR-ESI-MS m/z: 370.1162 (Calcd for C20H17N3O3Na: 370.1168).
3-(Indol-3-yl)quinoxalin-2(1H)-one, 2h7) 1H-NMR (400 MHz, DMSO-
d6) d: 7.21—7.40 (4H, m), 7.42 (1H, t, Jꢀ7.0 Hz), 7.50 (1H, m), 7.87 (1H,
d, Jꢀ8.0 Hz), 8.86 (1H, m), 8.93 (1H, d, Jꢀ2.9 Hz), 11.77 (1H, s), 12.38
(1H, s). 13C-NMR (100 MHz, DMSO-d6) d: 111.26 (s), 111.82 (s), 114.88
(s), 120.93 (s), 122.49 (s), 122.91 (s), 123.18 (s), 126.15 (s), 127.54 (s),
1127.93 (s), 130.13 (s), 132.60 (s), 133.01 (s), 136.23 (s), 151.93 (s), 154.35
(s). ESI-MS m/z: ꢁESI 262 (Mꢁ1), ꢂESI 260 (Mꢂ1).
Alternative synthesis of 2a. Methyl 1-(tert-Butoxycarbonyl)-3-methyl-
1H-indole-2-glyoxylate, 4 To a solution of 3 (3.00 g, 12.9 mmol) in DCM
(50 ml) was added dropwise tert-butyl lithium (1.57 mol/l in pentane, 9.0 ml,
14.2 mmol) during 20 min period at ꢂ78 °C, and then the reaction mixture
was allowed to stir for 1 h at ꢂ78 °C. A solution of dimethyl oxalate (3.92 g,
33.2 mmol) in DCM (25 ml) was added to the stirring reaction mixture at
ꢂ78 °C, and then the reaction mixture was stirred at ꢂ78 °C for 1 h. The re-
sulting reaction mixture was quenched with saturated NH4Cl aq., and the
Experimental
The 1H- and 13C-NMR spectra were measured with JEOL JNM-AL
(400 MHz) or JEOL EX-200 (200 MHz) spectrometer with TMS as the in-
ternal reference, and chemical shifts are expressed in d (ppm). The HR-ESI-
MS was taken on a MICROMASS Q-Tof micro.
General Procedure for the Synthesis of 2a, 2b, 2c, 2d, 2e and 2h. 3-(3-
Methylindol-2-yl)quinoxalin-2-ones, 2a To a mixture of 3-methylindole
(65.5 mg, 0.5 mmol) and quinoxalin-2-ones (73.1 mg, 0.5 mmol) in DCM
(2.5 ml) was added TFA (0.2 ml) at room temperature, and then the reaction
mixture was allowed to stir for 2 h at room temperature. The resulting reac-
tion mixture was diluted with AcOEt, washed with saturated Na2CO3 aq.,
and the organic phase then dried over Na2SO4. After removing the organic
solvent in vacuo, the residue was triturated in a small amount of MeOH. The
precipitated product was collected by filtration and washed with Et2O to
give 2a (83.0 mg, 0.30 mmol) as a yellow solid. Yield: 60.3%, 1H-NMR

June 2007
925
water phase was extracted with Et2O. The combined organic phase was quinoxalin-2(1H)-one, 9 To a solution of 8 (2.30 g, 9.30 mmol) in DMF
washed with brine, and then dried over Na2SO4. After removing the organic (46 ml) and Cs2CO3 (9.10 g, 27.9 mmol) was added 1-(2-chloroethyl)-
solvent in vacuo, the residue was purified by flash column chromatography piperidine hydrochloride (2.60 g, 14.1 mmol) at room temperature, and
on silica gel (hexane/AcOEt, 20/1→4/1), and then re-crystallized from
then the reaction mixture was stirred at 60 °C for 5 h. Water was added
Et2O/hexane to give 4 (0.86 g, 2.71 mmol) as a yellow solid. Yield: 21%. 1H- to the resulting reaction mixture, and the water phase was extracted with
NMR (400 MHz, CDCl3) d: 1.64 (9H, s), 2.43 (3H, s), 3.88 (3H, s), 7.32 AcOEt. The combined organic phase was washed with brine and dried over
(1H, t, Jꢀ8.0 Hz), 7.48 (1H, dd, Jꢀ8.0, 8.5 Hz), 7.64 (1H, d, Jꢀ8.0 Hz), Na2SO4. After removing the organic solvent in vacuo, the residue was dis-
8.00 (1H, d, Jꢀ8.5 Hz). ESI-MS m/z: ꢁESI 340 (M+Na), ꢂESI 318 (Mꢁ1).
2a: A mixture of 4 (502 mg, 1.57 mmol) and 1,2-phenylenediamine line-2-one (1.85 g, 11.4 mmol) and TFA (8 ml) at room temperature, and the
(188 mg, 1.74 mmol) in MeOH (5.0 ml) was refluxed for 13 h, and then TFA reaction mixture was refluxed for 0.5 h. Saturated NaHCO3 aq was added to
solved in DCE (100 ml). To the above solution were added 6-fluoroquinoxa-
(0.5 ml) was added to the reaction mixture, and the reaction mixture was re- the resulting reaction mixture, and the water phase was extracted with
fluxed for 1 h. After cooling, the precipitated product was collected by filtra- AcOEt. The combined organic phase was washed with brine and dried over
tion and washed with Et2O to give 2a (124 mg, 0.45 mmol) as a yellow solid. Na2SO4. After removing of organic solvent in vacuo, the residue was puri-
Yield: 28.6%, Comparison of 1H-, 13C-NMR and MS spectrum data with
fied by flash column chromatography on silica gel (CHCl3/MeOH, 30/1),
those of 2a, described previously, showed them to be identical.
and then re-crystallized from CHCl3/hexane/MeOH to give 9 (1.92 g,
5-(Benzyloxy)-1H-indole-3-carbaldehyde, 6 To a mixture of imidazole 4.58 mmol) as a yellow solid. 2 steps yield: 49%. 1H-NMR (400 MHz,
(1.52 g, 22.4 mmol) and acetic anhydride (9.0 ml) was added dropwise a so-
lution of 5 (5.00 g, 22.4 mmol) in acetic anhydride (14.5 ml) during a 30 min
DMSO-d6) d: 1.38—1.55 (6H, m), 2.49—2.51 (4H, m), 2.73 (2H, t,
Jꢀ6.0 Hz), 2.74 (3H, s), 4.11 (2H, t, Jꢀ6.0 Hz), 6.87 (1H, dd, Jꢀ2.2,
period at 130 °C. The reaction mixture was allowed to stir for 1 h at 130 °C. 8.8 Hz), 7.10 (1H, s), 7.36—7.40 (2H, m), 7.53 (1H, d, Jꢀ8.8 Hz), 7.63 (1H,
A solution of NaOH (4.20 g, 105 mmol) in EtOH (80 ml) and H2O (20 ml)
dd, Jꢀ2.7, 9.5 Hz), 11.58 (1H, s), 12.79 (1H, br s), 13C-NMR (100 MHz,
was added carefully to the reaction mixture, and then the solution was re- DMSO-d6) d: 11.84 (s), 23.85 (s), 25.49 (s), 54.39 (s), 57.55 (s), 65.84 (s),
fluxed for 1 h. After cooling the resulting reaction mixture to room tempera- 100.64 (s), 112.86 (d, JFꢀ22.3 Hz), 113.60 (s), 115.97 (s), 116.25 (d,
ture, the solution was acidified with 1 mol/l HCl aq. The deposited precipi-
tate was collected by filtration to give 6 (4.98 g, 19.8 mmol) as a yellow 129.46 (s), 131.48 (s), 132.99 (d, JFꢀ12.4Hz), 149.14 (s), 152.67 (s), 154.90
solid. Then, after removing the organic solvent of the filtrate in vacuo, the (s), 158.23 (d, JFꢀ240 Hz). ESI-MS m/z: ꢁESI 421 (Mꢁ1), ꢂESI 419
JFꢀ9.1 Hz), 116.48 (s), 117.10 (d, JFꢀ12.4 Hz), 127.33 (s), 128.12 (s),
residue was purified by flash column chromatography on silica gel (Mꢂ1). HR-ESI-MS m/z: 421.2049 (Calcd for C24H26N4O2F: 421.2040).
(hexane/AcOEt, 1/1) to give 6 (114 mg, 0.45 mmol) as a yellow solid. Total
yield: 91%. 1H-NMR (200 MHz, CDCl3) d: 5.14 (2H, s), 7.00 (1H, dd, References and Notes
Jꢀ2.5, 8.9 Hz), 7.31—7.51 (6H, m), 7.79 (1H, d, Jꢀ3.2 Hz), 7.88 (1H, d,
Jꢀ2.5 Hz), 9.98 (1H, s), 11.04 (1H, br s).
1) Ladouceur G. H., Bear B., Bi C., Brittelli D. R., Burke M. J., Chen G.,
Cook J., Dumas J., Sibley R., Turner M. R., WO 2004043950 (2004).
2) Inhibitory effect of 9 toward the VEGF-induced proliferation of
human glomerular endothelium cells in vitro [IC50 (mmol/l)ꢀ0.04]. In-
hibitory effect of 9 toward the VEGF-induced auto-phosphorylation
with human umbilical vein endothelial cells in vitro [IC50
(mmol/l)ꢀ0.02]. Inhibitory effect of the derivative 9 on VEGF-induced
dye leakage in rat skin (7 week-old male Wistar rats were used in this
study) [70% against control at 25 mg/kg p.o.].
3) Aoki K., Obata T., Yamazaki Y., Mori Y., Hirokawa H., Koseki J.,
Hattori T., Niitsu K., Takeda S., Aburada M., Miyamoto K., Chem.
Pharm. Bull., 55, 255—267 (2007).
4) For review on typical example of TFA-promoted Friedel–Crafts type
reaction, see: Fei L., Yong-Jun C., Yong S., Li L., Dong W., Synlett, 8,
1160—1164 (2003).
5) Similar indolenine and/or direct pathway as in the mechanism of
Pictet–Spengler reaction may be engaged in this TFA-promoted cou-
pling process of 3-substituted indoles with quinoxalin-2-ones. For re-
view on discussion about this mechanism, see: Enrique L. L., Marcela
A., Andrea B. J. B., Teodoro S. K., ARKIVOC. Issue in Honor of Prof.
Rosa Lederkremer, (xii), 98—153 (2005).
6) Although it is not yet ascertained about the details of the oxidization
mechanism, it seems that it is probably based on auto-oxidation. For
review on example of similar reaction, see: ref. 7.
7) Chupakhin O. N., Sidorov E. O., Postovskii I. Y., Khimiya Geterotsik-
licheskikh Soedinenii, 10, 1433—1434 (1975).
8) The TFA-catalyzed coupling of 3-methyl-1-(phenylsulfonyl)-1H-in-
dole with quinoxaline-2-one was failed in our result.
5-(Benzyloxy)-3-methyl-1H-indole, 7 To a mixture of 6 (5.0 g, 19.9
mmol) and 10% Pd–C (wet type, 2.5 g) in 2-propanol (250 ml) was care-
fully added portionwise sodium borohydride (12 g, 317 mmol). The reac-
tion mixture was then refluxed for 3 h. After removal of the precipitates by
filtration, the filtrate was concentrated in vacuo. Water was added to the
residue, and the water phase was then extracted with Et2O. The combined
organic phase was washed with brine and dried over Na2SO4. After remov-
ing the organic solvent in vacuo, the residue was purified by flash column
chromatography on silica gel (hexane/AcOEt, 3/1) to give 7 (3.95 g,
1
16.7 mmol) as a yellow solid. Yield: 84%. H-NMR (200 MHz, CDCl3) d:
2.29 (3H, s), 5.12 (2H, s), 6.90—7.52 (9H, m).
tert-Butyl 5-Hydroxy-3-methyl-1H-indole-1-carboxylate, 8 To a mix-
ture of 7 (10.9 g, 46.1 mmol), 4-dimethylaminopyridine (2.70 g, 22.1 mmol)
and triethylamine (7.2 ml, 51.6 mmol) in CH3CN (200 ml) was added di-tert-
butyl dicarbonate (12.0 g, 55.5 mmol) at room temperature, and the reaction
mixture was allowed to stir for 5 h at room temperature. After removing
the organic solvent of the resulting reaction mixture, the residue was puri-
fied by flash column chromatography on silica gel (hexane/AcOEt, 10/1)
to give tert-butyl 5-(benzyloxy)-3-methyl-1H-indole-1-carboxylate (15.2 g,
45.1 mmol) as a viscous oil. A solution of tert-butyl 5-(benzyloxy)-3-
methyl-1H-indole-1-carboxylate (ca. 13.0 g, 38.5 mmol) and 5% Pd–C (dry
type, 2.8 g) in AcOEt (400 ml) was then stirred for 5 h at room temperature
under hydrogen. After removing the precipitates by filtration, the filtrate was
concentrated in vacuo. The residue was purified by flash column chromatog-
raphy on silica gel (hexane/AcOEt, 9/1) to give 8 (9.27 g, 37.5 mmol) as a
1
yellow solid. 2 steps yield: 95%. H-NMR (200 MHz, CDCl3) d: 1.64 (9H,
s), 2.20 (3H, s), 4.67 (1H, s), 6.82 (1H, dd, Jꢀ2.5, 8.7 Hz), 6.90 (1H, d,
Jꢀ2.5 Hz), 7.32 (1H, s), 7.95 (1H, d, Jꢀ8.7 Hz).
9) Jan B., Lars R., Birger S., Tetrahedron, 36, 2505—2511 (1980).
10) Heacock R. A., Hutzinger O., Can. J. Chem., 42, 514—521 (1964).
6-Fluoro-3-[3-methyl-5-(2-piperidin-1-ylethoxy)-1H-indol-2-yl]-