Synthesis of the indole core structures of conophylline

Article abstract of DOI:10.1002/jhet.5570450638

(Chemical Equation Presented) Conophylline is a bisindole alkaloid of unique structure that shows anti-cancer and anti-diabetic activities. Two indole core structures of conophylline, namely 6,7-dimethoxy-5-methoxymethoxy-1H- indole (1), and N-benzoyl-N-[2-(6-methoxymethoxy-2-vinyl-1H-indol-3-yl)ethyl] amine (2) has been synthesized starting with substituted benzene derivatives.

Full text of DOI:10.1002/jhet.5570450638

Nov-Dec 2008
1803
Synthesis of the Indole Core Structures of Conophylline
Shin Ando,a Yoshinari Okamoto,a Kazuo Umezawa,b and Masami Otsukaa*
aFaculty of Medical and Pharmaceutical Sciences, Kumamoto University
5-1 Oe-honmachi, Kumamoto 862-0973, Japan
bDepartment of Applied Chemistry, Faculty of Science and Technology, Keio University
Yokohama 223-0061, Japan
E-mail: motsuka@gpo.kumamoto-u.ac.jp
Received December 19, 2007
OH
MeO
MOMO
NHBz
MeO
N
O
HN
N
MeO
N
H
MOMO
N
H
H
H
OMe
MeO2C
O
N
H
1
2
OH
Conophylline
CO2Me
Conophylline is a bisindole alkaloid of unique structure that shows anti-cancer and anti-diabetic
activities. Two indole core structures of conophylline, namely 6,7-dimethoxy-5-methoxymethoxy-1H-
indole (1), and N-benzoyl-N-[2-(6-methoxymethoxy-2-vinyl-1H-indol-3-yl)ethyl]amine (2) has been
synthesized starting with substituted benzene derivatives.
J. Heterocyclic Chem., 45, 1803 (2008).
INTRODUCTION
sides [3]. Our synthetic plan is to synthesize the left and
the right indoles and assemble the two by constructing the
central dihydrofuran. Herein we report a facile synthesis
of trisubstituted indole 1 of the left wing and the right
indole 2 appropriately functionalized and protected for the
further elaboration.
Conophylline is a bisindole alkaloid isolated from the
leaves of the tropical plant Tabernaemontana divaricata
[1]. It shows anti-cancer activity against cells that express
K-ras [2] and, more recently, effect on diabetes was
disclosed [3]. We were interested in the anti-diabetic
effect of conophylline that was unprecedent as a bisindole
and considered that conophylline could be a new lead for
the drugs and therapies toward diabetes.
RESULTS AND DISCUSSION
Synthesis of 6,7-dimethoxy-5-methoxymethoxy-1H-
indole (1). As the left indole of conophylline has an array
of two methoxyl and a hydroxyl substituents on the
benzene ring, we started the synthesis of compound 1
with symmetrically substituted methyl 3,5-dihydroxy-4-
methoxybenzoate 3 [5]. Compound 3 was dissymmetrized
by the mono-nitration according to the method of
Anuradha et al. using nickel nitrate [6] to give nitro
derivative 4 in 70% yield. The differentiation of the two
OH
MeO
MeO
N
O
HN
N
H
H
MeO2C
O
N
H
OH
CO2Me
hydroxyl groups of compound
4 was successfully
Conophylline
achieved as follows. The higher acidity of the hydroxyl
group para to the nitro group of compound 4 facilitated
the regioselective protection to give mono-methoxy-
methyl ether 5 in 54% yield (with 31% recovery of 4).
The remaining hydroxyl group was methylated with
dimethyl sulfate to give dimethoxyphenol derivative 6
that is equipped with all necessary substituents on the left
wing phenyl moiety in 97% yield. After extensive
attempts including the conventional Fischer indole
synthesis, the left wing indole was found to be accessible
by the Magnus procedure [7], the cyclization of dinitro
compound 9. Thus, methyl ester 6 was treated with
NaBH4 to give (without reducing the nitro group) alcohol
MOMO
NHBz
MeO
N
H
MOMO
N
H
OMe
1
2
Figure 1
Conophylline has a unique structure comprising two
indoles segmented via a central dihydrofuran [4]. The
dihydrofuran seems crucial for the effect on diabetes,
determining the spatial relationships of the indoles of both

1804
S. Ando, Y. Okamoto, K. Umezawa, and M. Otsuka
Vol 45
7 (78% yield) that was further converted into the
corresponding aldehyde 8 by MnO2 oxidation (95%
yield). The aldehyde 8 was condensed with nitromethane
under the classical Henry reaction condition to give
dinitro compound 9 in 92% yield and the subsequent
reductive cyclization [7] proceeded smoothly to afford the
desired 6,7-dimethoxy-5-methoxymethoxy-1H-indole (1)
in 72% yield.
transformed to aldehyde 17 by LAH reduction (89%
yield) followed by MnO2 oxidation (quantitative). The
subsequent Wittig reaction of aldehyde 17 gave N-
benzoyl-N-[2-(6-methoxymethoxy-2-vinyl-1H-indol-3-
yl)ethyl]amine 2 in 81% yield.
Thus, the left and the right indoles of conophylline are
now available in good overall yields. We are engaging in
the side chain elaboration of the left indole 1 for the
construction of the dihydrofuran junction between the left
and the right indoles.
Scheme 1
HO
CO2Me
HO
CO2Me
NO2
MOMO
MeO
CO2Me
NO2
Scheme 2
a)
b)
MeO
MeO
CHO
CO2Me
b)
OH
OH
OH
a)
N3
3
4
5
MOMO
MOMO
10
11
MOMO
MeO
R
MOMO
MeO
NO2
c)
f)
CHO
c)
d)
NO2
NO2
MOMO
N
H
CO2Me
MOMO
N
H
CO2Me
OMe
OMe
6
7
8
R=CO2Me
R=CH2OH
R=CHO
9
d)
e)
12
13
NO2
CO2Me
NHBz
e)
MOMO
g)
MOMO
N
H
MOMO
N
R
H
MeO
N
H
15
R=CO2Me
16 R=CH2OH
17
14
OMe
f)
g)
1
R=CHO
NHBz
h)
Reagents and conditions; a) Ni(NO3)2•6H2O, PTSA, acetone; 70%, b)
MOMCl, 2,6-lutidine, CH2Cl2, 0°C to r.t.; 54% (31%; recovery), c)
(MeO)2SO2, K2CO3, acetone, reflux; 97%, d) NaBH4, THF, 0°C to r.t.;
MOMO
N
H
78%, e) MnO2, CH2Cl2, r.t.; 95%, f) MeNO , Et3N, MeOH, 0°C; then
NaOAc, Ac2O, 50°C; 92%, g) Pd/C (10%), HOAc, H2, MeOH, r.t.; 72%.
2
2
Reagents and conditions; a) N3CH2CO2Me, NaOMe, MeOH, 0°C to r.t.;
74%, b) toluene, reflux; quant., c) POCl3, DMF, CH2Cl2, 0°C; 56%
(40%; recovery), d) MeNO2, NH4Cl, MeOH, r.t.; then NaBH4, DMF,
0°C; 76%, e) Pd/C (10%), H2, NH4Cl, MeOH, r.t.; then BzCl, Et3N,
CH2Cl2, 0°C; 77%, f) LAH, THF, 0°C; 89%, g) MnO2, CH2Cl2, r.t.;
quant., h) CH3PPh3Br, KHMDS, THF, toluene, reflux; 81%.
Synthesis of N-benzoyl-N-[2-(6-methoxymethoxy-2-
vinyl-1H-indol-3-yl)ethyl]amine (2). The right indole 2
was synthesized by the Weidmann procedure [8], by
cyclization of the azide compound 11. Thus, 4-
(methoxymethoxy)benzaldehyde (10) [9] was coupled
with azidoacetate under strongly basic condition to give
azide 11 in 74% yield. It was gratifying that the
compound 11 gave indole 12 quantitatively simply by
heating at reflux in toluene. The Vilsmeier formylation
[10] was performed and aldehyde 13 was obtained in 56%
yield (with 40% recovery of 12) Condensation of
aldehyde 13 with nitromethane was carried out according
to the procedure of Young [11a] and Rodríguez [11b] and
the subsequent olefin reduction was feasible by using
NaBH4 [11b,11c,11d] to give nitro compound 14 with an
intact nitro group in 76% overall yield [12]. Reduction of
the nitro group of 14 was carried out by hydrogenation
with Pd/C and the resulting tryptamine was immediately
protected by a benzoyl group in order to avoid the
problematic lactam formation, affording the desired
benzamide 15 in 77% yield. The methyl ester 15 was
EXPERIMENTAL
Solvents and reagents were reagent-grade, purchased from
commercial suppliers, and used without further purification
unless otherwise stated. All products were dried under vacuum
before anal. characterization. Column chromatography (CC):
silica gel (60N, spherical, neutral; KANTO CHEMICAL CO,
INC), aluminium oxide (activated, neutral, Brockmann I,
standard grade, ~150 mesh, 58Å; ALDRICH). TLC: silica gel 60
F
(on glass; Merck), aluminium oxide 60 F
(on plastic
254
254
sheet; Merck), visualization by UV light at 254 nm or staining
with a soln. of H3(PMo12O40)·nH2O in EtOH. M.p.: Yanagimoto
Melting Point Apparatus; uncorrected. Optical rotations: JASCO
DIP-1000 digital polarimeter. IR spectra: JASCO IR A-100 FT-
IR spectrometer; in cmꢀ1. NMR spectra (1H and 13C): JEOL
JNM-AL300 (300/75 MHz, resp.) spectrometer; J in Hz, ꢀ in
ppm rel. to residual solvent signals, spectra were recorded at

Nov-Dec 2008
Synthesis of the Indole Core Structures of Conophylline
1805
25˚C. EI- and FAB-MS: JEOL JMS-BU20, JEOL JMS-700 mass
spectrometers; in m/z.
anhydrous MeOH (4 mL), NaBH4 (152 mg, 4.0 mmol) was
added little by little at 0°C under Ar atmosphere. After stirring
for 3 h at r.t., the reaction solution was cooled to 0°C and
neutralized with 1 N HCl. The resulting solution was extracted
with CH2Cl2 (3ꢀ), and the combined organic layer was washed
with brine, dried over (Na2SO4), and evaporated in vacuo. The
residue was purified by column chromatography on aluminium
oxide (CH2Cl2) to afford 85.2 mg (78%) of 7 as a yellow oil. Rf
0.09 (CH2Cl2). IR (neat): 2946, 1577, 1540, 1490, 1457, 1399,
1362, 1327, 1249, 1155, 1112, 964, 923, 881, 801. 1H-
NMR(CDCl3) ꢀ : 3.52 (3H, s, PhOCH2OCH3), 3.92 (3H, s,
PhOCH3), 3.99 (3H, s, PhOCH3), 4.61 (2H, s, PhCH2OH), 5.28
(2H, s, PhOCH2OCH3), 7.07 (1H, s, H-C(6)). 13C-NMR(CDCl3)
ꢀ : 56.5, 61.1, 62.3 (CH3), 61.1, 95.0 (CH2), 111.6 (CH), 129.6,
139.1, 142.7, 146.8, 153.0 (C). HR-MS(EI) for C11H15NO7 (M+),
calcd. 273.0840, found 273.0848.
3,4-Dimethoxy-5-methoxymethoxy-2-nitrobenzaldehyde
(8). A mixture of compound 13 (54.6 mg, 0.2 mmol) and MnO2
(174 mg 2.0 mmol) in CH2Cl2 (3 mL) was stirred at r.t. for 3 h
under Ar atmosphere. The resuting mixture was then filtered
through Celite, and the Celite was washed with CH2Cl2. The
filtrate was evaporated in vacuo, and the residue was purified by
column chromatography on silica gel (CH2Cl2) to afford 51.7 mg
(95%) of 8 as pale yellow oil. Rf 0.66 (CH2Cl2). IR (neat): 3336,
1703, 1577, 1543, 1490, 1460, 1390, 1367, 1328, 1254, 1156,
1111, 1060, 1013, 963, 924, 879. 1H-NMR(CDCl3) ꢀ : 3.54 (3H,
s, PhOCH2OCH3), 4.00 (3H, s, PhOCH3), 4.02 (3H, s, PhOCH3),
5.32 (2H, s, PhOCH2OCH3), 7.46 (1H, s, H-C(6)), 9.85 (1H, s,
PhCHO). 13C-NMR(CDCl3) ꢀ : 56.7, 61.4, 62.6 (CH3), 95.2
(CH2), 111.6, 185.7 (CH), 122.9, 141.0, 146.1, 148.5, 152.6 (C).
HR-MS(EI) for C11H13NO7 (M+), calcd. 271.0665, found
271.0692.
Methyl 3,5-dihydroxy-4-methoxy-2-nitro-benzoate (4).
PTSA (190 mg, 1.0 mmol) was added to a solution of methyl
3,5-dihydroxy-4-methoxybenzoate (3) [5] (1.98 g, 10 mmol) and
Ni(NO3)2·6H2O (3.19 g, 11 mmol) in anhydrous acetone (80 mL)
at 0°C under Ar atmosphere. After stirring for 2 h, about half
amount of acetone was removed in vacuo. The top clear layer of
the resulting mixture was immediately applied to column
chromatography on silica gel (CH2Cl2) to afford 1.70 g (70%) of
4 as a yellow amorphous solid. Rf 0.38 (AcOEt/n-hexane 2/1).
M.p. 139~140 °C. IR (nujor): 3182, 2856, 1711, 1594, 1550,
1447, 1365, 1307, 1253, 1105, 1020, 988, 922, 870, 675, 607.
1H-NMR(CD3OD) ꢀ: 3.92 (3H, s, PhOCH3), 4.04 (3H, s,
PhCO2CH3), 6.67 (1H, s, H-C(6)). 13C-NMR(CD3OD) ꢀ : 53.4,
61.3 (CH3), 108.5 (CH), 126.2, 127.8, 135.7, 149.7, 155.1, 166.6
(C). HR-MS(EI) for C9H9NO7 (M+), calcd. 243.0379, found
243.0383.ꢀ Anal. Calcd. for C9H9NO7: C, 44.45, H, 3.73, N,
5.76. Found: C, 44.18, H, 3.77, N, 5.97.
Methyl 3-hydroxy-4-methoxy-5-methoxymethoxy-2-nitro-
benzoiate (5). To a solution of compound 4 (486 mg, 2.0 mmol)
and 2,6-lutidine (304 μL, 2.6 mmol) in CH2Cl2 (20 mL), a
solution of MOMCl (167 μL, 2.2 mmol) in CH2Cl2 (20 mL) was
dropwised at 0°C. After stirring for 10 h at r.t., H2O (40 mL)
was added to the reaction solution. The organic layer was
separated and the aqueous layer was extracted with CH2Cl2 (2ꢀ).
The combined organic layer was washed with brine, dried over
(Na2SO4), and evaporated in vacuo. The residue was purified by
column chromatography on silica gel (CH2Cl2, starting solution
of crude was added 0.5 % HOAc) to afford 310 mg (54%) of 5
as a yellow solid along with 151 mgꢀ of compound 4 (31%:
recovery), (recovery yieldꢀ of 5, 78%). Rf 0.1 (CH2Cl2). M.p.
90~91 ˚C. IR (KBr): 3372, 2959, 1722, 1590, 1545, 1339, 1269,
1242, 1066, 1003, 867, 775, 763, 735, 613. 1H-NMR(CDCl3) ꢀ :
3.52 (3H, s, PhOCH2OCH3), 3.91 (3H, s, PhOCH3), 3.97 (3H, s,
PhCO2CH3), 5.31 (2H, s, PhOCH2OCH3), 6.97 (1H, s, H-C(6))
9.91 (br, PhOH). 13C-NMR(CDCl3) ꢀ : 53.3, 56.8, 61.3 (CH3),
95.0 (CH2), 108.2 (CH), 125.6, 128.6, 139.4, 149.1, 154.8, 166.0
(C). HR-MS(EI) for C11H13NO8 (M+), calcd. 287.0641, found
287.0629. Anal. Calcd. for C11H13NO8: C, 46.00, H, 4.56, N,
4.88. Found: C, 46.00, H, 4.55, N, 4.96.
Methyl 3,4-dimethoxy-5-methoxymethoxy-2-nitro-
benzoate (6). A mixture of compound 5 (144 mg, 0.5 mmol),
(MeO)2SO2 (56.8 μL, 0.6 mmol), K2CO3 (138 mg, 1.0 mmol) in
acetone (10 mL) was stirred at reflux for 12 h under Ar
atmosphere. The resulting mixture was then filtered, and the
filtrate was evaporated in vacuo. The residue was dissolved in
CH2Cl2 (20 mL) and washed with H2O and brine, and the
organic layer was dried over (Na2SO4) and evaporated in vacuo.
The residue was purified by column chromatography on silica
gel (CH2Cl2) to afford 147 mg (97%) of 6 as a pale yellow
amorphous. Rf 0.66 (CH2Cl2). (M.p. 63~64 °C. IR (neat): 3133,
2870, 1735, 1543, 1339, 1233, 1156, 1111, 1068, 1012, 978,
923, 870, 807, 739. 1H-NMR(CDCl3) ꢀ : 3.53 (3H, s,
PhOCH2OCH3), 3.87 (3H, s, PhOCH3), 3.96 (3H, s, PhOCH3),
3.99 (3H, s, PhCO2CH3), 5.29 (2H, s, PhOCH2OCH3), 7.52 (1H,
s, H-C(6)). 13C-NMR(CDCl3) ꢀ : 52.9, 56.6, 61.3, 62.6 (CH3),
95.2 (CH2), 112.7 (CH), 117.8, 141.0, 145.9, 147.2, 151.6, 163.0
(C). HR-MS(EI) for C12H15NO8 (M+), calcd. 301.0798, found
301.0775.
2,3-Dimethoxy-1-methoxymethoxy-4-nitro-5-(2-nitroethen-
yl)benzene (9). Compound 8 (27.1 mg, 0.1 mmol) was dissolved
in 55% solution of MeNO2 in MeOH (1 mL), and Et3N (10 μL)
was added to this solution at 0°C under Ar atmosphere. After
stirring for 2 h at the temperature, H2O (5 mL) was added to the
reaction solution. This mixture was extracted with CH2Cl2 (2ꢀ),
and this combined organic layer was washed with brine, dried
over (Na2SO4), and evaporated in vacuo. The residue was
dissolved in Ac2O (1 mL), and NaOAc (0.8 mg, 0.01 mmol) was
added to this solution. This mixture was stirred for 3 h at 50°C
under Ar atmosphere, and H2O was then added to the resulting
mixture. This mixture was extracted with CH2Cl2 (2ꢀ), and this
combined organic layer was washed with brine, dried over
(Na2SO4), and evaporated in vacuo. The residue was purified by
column chromatography on silica gel (CH2Cl2) to afford 29.0 mg
(92%) of 9 as a yellow amorphous. Rf 0.63 (CH2Cl2). M.p.
56~57 °C. IR (neat): 3109, 2957, 1638, 1576, 1533, 1490, 1343,
1
1273, 1223, 1171, 1092, 1014, 967, 922, 840. H-NMR(CDCl3)
ꢀ : 3.55 (3H, s, PhOCH2OCH3), 3.99 (3H, s, PhOCH3), 4.00 (3H,
s, PhOCH3), 5.30 (2H, s, PhOCH2OCH3), 7.13 (1H, s, H-C(6)),
7.46 (1H, d, J = 13.55 Hz, PhꢁCH=CHNO2), 7.85 (1H, d, J =
13.55 Hz, PhꢁCH=CHNO2). 13C-NMR(CDCl3) ꢀ : 56.7, 61.4,
62.5 (CH3), 95.4 (CH2), 109.2, 118.2, 139.6 (CH), 131.7, 141.2,
146.3, 146.8, 153.0 (C). HR-MS(EI) for C12H14N2O8 (M+), calcd.
314.0750, found 314.0729. Anal. Calcd for C12H14N2O8: C,
45.86, H, 4.49, N, 8.91. Found: C, 45.93, H, 4.45, N, 8.74.
6,7-Dimethoxy-5-methoxymethoxy-1H-indole
(1).
A
mixture of compound 9 (31.4 mg, 0.1 mmol) and Pd/C (10%,
3.1 mg) in HOAc/MeOH (17%, 1 mL) was stirred at r.t. for 5 h
under H2 atmosphere. The mixture was then filtered through
(3,4-Dimethoxy-5-methoxymethoxy-2-nitrophenyl)meth-
anol (7). To a solution of compound 6 (120 mg, 0.4 mmol) in

1806
S. Ando, Y. Okamoto, K. Umezawa, and M. Otsuka
Vol 45
Celite, and the Celite was washed with CH2Cl2. The filtrate was
diluted with CH2Cl2 and washed with saturated NaHCO3 and
brine. The organic layer was dried over (Na2SO4) and
evaporated in vacuo, and the residue was purified by column
chromatography on silica gel (CH2Cl2) to afford 17.0 mg (72%)
of 1 as a white solid. Rf 0.27 (CH2Cl2). M.p. 74~75 °C. IR
(KBr): 3341, 3109, 2932, 1581, 1464, 1311, 1221, 1141, 1109,
1060, 1031, 990, 906, 873, 852, 749, 591, 560. 1H-NMR(CDCl3)
ꢀ : 3.56 (3H, s, ArOCH2OCH3), 3.92 (3H, s, ArOCH3), 4.07 (3H,
s, ArOCH3), 5.23 (2H, s, ArOCH2OCH3), 6.43 (1H, dd, J = 2.56,
2.56 Hz, H-C(3)), 7.11 (1H, s, H-C(4)), 7.13 (1H, dd, J = 2.56,
2.56 Hz, H-C(2)), 8.19 (br, H-N(1)). 13C-NMR(CDCl3) ꢀ : 56.1,
61.0, 61.5 (CH3), 96.4 (CH2), 102.8, 102.9, 124.1 (CH), 123.8,
125.5, 138.6, 138.8, 146.3 (C). HR-MS(EI) for C12H15NO4 (M+),
calcd. 237.1004, found 237.1001.
mL), followed by stirring for 1 h at r.t. CH2Cl2 was removed in
vacuo and the pale yellow crystalline precipitated was filtered
and the filtrate was extracted with AcOEt (3ꢁ). The combined
organic layer was dried over (Na2SO4), and evaporated in vacuo.
The residue and filtered crystalline was mixed and washed with
CH2Cl2/n-hexane (50%) solution to afford 0.73 g (56%) of 13 as
a pale yellow crystalline. The filtrate was evaporated, and the
residue was purified by column chromatography on silica gel
(3.3% MeOH/CH2Cl2) to recover 0.47 g of 12ꢀ(40% recovery)
(recovery yield of 13, 92%). Rf 0.45 (CH2Cl2/MeOH 50/1). M.p.
194~196 °C. IR (KBr): 3174, 1714, 1637, 1577, 1526, 1378,
1
1360, 1248, 1213, 1147, 1078, 986, 838. H-NMR (DMSO-D6)
ꢀ: 3.41 (3H, s, OCH2OCH3), 3.98 (3H, s, CO2CH3), 5.24 (2H, s,
OCH2OCH3), 7.02 (1H, dd, J = 8.79, 2.20 Hz, H-C(5)), 7.15
(1H, d, J = 2.20 Hz, H-C(7)), 8.12 (1H, d, J = 8.79 Hz, H-C(4)),
10.57 (s, CHO). 13C-NMR (DMSO-D6) ꢀ:52.6, 55.6 (CH3), 94.2
(CH2), 98.1, 115.7, 123.2, 187.6 (CH), 118.7, 119.7, 131.7,
136.8, 155.8, 160.5 (C). MS (EI) m/z 263 (M+). Anal. Calcd. for
C13H13NO5: C, 59.31, H, 4.98, N, 5.32. Found: C, 59.01, H, 4.98,
N, 5.31.
Methylꢀ (Z)-2-azido-3-(4-methoxymethoxyphenyl)propen-
oate (11). To anhydrous MeOH (150 mL), Na metal (4 g) was
added at 0˚C, and stirred at the temperature to finish the
resolution. To this solution,
a solution of 4-(methoxy-
methoxy)benzaldehyde (10) [9] (9.96 g, 60 mmol) and methyl
azidoacetate (20.7 g, 180 mmol) in anhydrous MeOH (50 mL)
was dropwised at ꢀ10˚C under Ar atmosphere, and warmed to
r.t. gradually. After sitirring for 12 h at r.t., the reaction mixture
was cooled to 0˚C and added ice cold H2O (200mL). MeOH was
removed in vacuo, and the aqueous layer was extracted with
CH2Cl2 (3ꢁ). The combined organic layer was washed with
brine, dried over (Na2SO4), and evaporated in vacuo. The
residue was purified by column chromatography on silica gel
(CH2Cl2) to afford 11.2 g (74%) of 11 as a yellow amorphous. Rf
0.74 (CH2Cl2). IR (neat): 2953, 2359, 2119, 1713, 1602, 1508,
Methyl 3-(2-nitroethyl)-6-methoxymethoxy-1H-indole-2-
carboxylate (14). Compound 13 (1.32 g, 5 mmol) and NH4OAc
(385 mg, 5.0 mmol) was added to 55% solution of MeNO2 in
MeOH (30 mL) and stirred for 48 h at r.t. under Ar atmosphere.
The resulting mixture was then added H2O (30 mL), and MeOH
was removed in vacuo. The aqueous layer was extracted with
AcOEt (2ꢁ), and the organic layer was washed with brine, dried
over (Na2SO4), and evaporated in vacuo. This crude compound
was dissolved in DMF (10 mL) and cooled to 0˚C. To this
solution was added NaBH4 (200 mg) little by little and stirred
for 1 h. The reaction solution was then neutralized with 1 M HCl
and extracted with AcOEt (2ꢁ). The organic layer was washed
with brine (2ꢁ), dried over (Na2SO4), and evaporated in vacuo.
The residue was purified by column chromatography on silica
gel (2% MeOH/CH2Cl2) to afford 1.17 g (76%) of 14 as a white
solid. Rf 0.49 (CH2Cl2/MeOH 50/1). M.p. 122~123 °C. IR
(KBr): 3324, 1690, 1629, 1549, 1459, 1380, 1336, 1254, 1214,
1150, 1101, 1074, 999. 1H-NMR (CDCl3) ꢀ: 3.50 (3H, s,
OCH2OCH3), 3.76 (2H, t, J = 7.33 Hz, CH2CH2NO2), 3.95 (3H,
s, CO2CH3), 4.67 (2H, t, J = 7.33 Hz, CH2CH2NO2), 5.22 (2H, s,
OCH2OCH3), 6.93 (1H, dd, J = 8.79, 2.20 Hz, H-C(5)), 7.04
(1H, d, J = 2.20 Hz, H-C(7)), 7.57 (1H, d, J = 8.79 Hz, H-C(4)),
10.98 (br, H-N(1)). 13C-NMR (CDCl3) ꢀ: 51.9, 56.0 (CH3), 23.2,
75.2, 94.8 (CH2), 97.4, 113.3 121.0 (CH), 118.1, 122.7, 123.1,
136.6, 156.8, 161.8 (C). MS (EI) m/z 308 (M+). Anal. Calcd. for
C14H16N2O6: C, 54.54, H, 5.23, N, 9.09. Found: C, 54.62, H,
5.14, N, 9.07.
Methyl 3-[2-(benzoylamino)ethyl]-6-methoxymethoxy-1H-
indole-2-carboxylate (15). Compound 14 (124 mg, 0.4 mmol)
and NH4Cl (107 mg, 2.0 mmol) was dissolved in MeOH (12
mL). Pd/C (10%, 12.4 mg) was added to this solution and stirred
at r.t. for 18 h under H2 atmosphere. The resulting mixture was
then filtered through Celite, and the Celite was washed with
CH2Cl2. The filtrate was dried over (Na2SO4) and evaporated in
vacuo. The residue was dissolved in CH2Cl2 (10 mL) and added
Et3N (390 μL 2.8 mmol) at 0°C. BzCl (70 μL, 0.6 mmol) was
added to this solution immediately and stirred for 30 min. To the
reaction solution, H2O was added at 0°C, and the organic layer
was separated. The aqueous layer was extracted with CH2Cl2
(2ꢁ), and the combined organic layer was washed with brine,
dried over (Na2SO4), and evaporated in vacuo. The residue was
purified by column chromatography on silica gel (50%
1
1437, 1376, 1322, 1240, 1175, 1152, 1079, 992, 833. H-NMR
(CDCl3) ꢀ: 3.48 (3H, s, OCH2OCH3), 3.90 (3H, s, CO2CH3),
5.21 (2H, s, OCH2OCH3), 6.88 (1H, s, PhꢀCH=C), 7.04 (2H, d,
J = 8.81 Hz, H-C(3)), 7.78 (2H, d, J = 8.81 Hz, H-C(2)). 13C-
NMR (CDCl3) ꢀ: 52.8, 56.1 (CH3), 94.1 (CH2), 116.0, 125.5,
132.3 (CH), 123.5, 127.0, 158.0, 164.2 (C). HR-MS (EI) for
C12H13N3O4 (M+), calcd. 263.0906, found 263.0910.
Methyl 6-methoxymethoxy-1H-indole-2-carboxylate (12).
A solution of compound 11 (5.26 g, 20 mmol) in toluene (300
mL) was stirred at reflux for 12 h. The reaction solution was
then evaporated in vacuo. Recrystallization from toluene
afforded 4.69 g (quant.) of 11 as a white crystalline. Rf 0.56
(CH2Cl2/MeOH 50/1). M.p. 106~107 °C. IR (KBr): 3311, 2952,
2897, 1699, 1629, 1524, 1445, 1253, 1209, 1148, 1121, 1076,
1
1004, 824. H-NMR (CDCl3) ꢀ: 3.51 (3H, s, CH2OCH3), 3.93
(3H, s, CO2CH3), 5.23 (2H, s, OCH2OCH3), 6.90 (1H, dd, J =
8.81, 2.20 Hz, H-C(5)), 7.10 (1H, d, J = 2.20 Hz, H-C(7)), 7.16
(1H, d, J = 0.92 Hz, H-C(3)), 7.56 (1H, d, J = 8.81 Hz, H-C(4)),
8.98 (br, H-N(1)). 13C-NMR (CDCl3) ꢀ: 51.9, 56.0 (CH3), 94.9
(CH2), 97.5, 109.0, 113.1, 123.4 (CH), 122.7, 126.5, 137.8,
156.3, 162.4 (C). MS (EI) m/z 235 (M+). Anal. Calcd. for
C12H13NO4: C, 61.27, H, 5.57, N, 5.95. Found: C, 61.19, H, 5.50,
N, 5.89.
Methyl 3-formyl-6-methoxymethoxy-1H-indole-2-carbox-
ylate (13). To a solution of DMF (3 mL) in anhydrous CH2Cl2
(20 mL), POCl3 (1 mL) was dropwised at 0˚C under Ar
atmosphere and stirred for 30 min at the temperature and for
further 30 min at r.t. The solution was then cooled to 0˚C and
compound 12 (1.18 g, 5.0 mmol) was added little by little. After
stirring for 30 min at the temperature and for further 30 min at
r.t, the reaction solution was cooled to 0˚C again, and the
reaction was quenched be the addition of saturated NaHCO3 (30

Nov-Dec 2008
Synthesis of the Indole Core Structures of Conophylline
1807
AcOEt/n-hexane) to afford 118 mg (77%) of 15 as a white solid.
Rf 0.41 (AcOEt/n-hexane 1/1). M.p. 156~157 °C.ꢀ IR (KBr):
3313, 2971, 2924, 2853, 1691, 1640, 1542, 1459, 1377, 1257,
stirring for 15 min, this solution was dropwised to a solution of
compound 17 (35.3 mg, 0.1 mmol) in anhydrous THF (1 mL)
under Ar atmosphere, and this reaction mixture was stirred at
reflux for 18 h. The resulting solution was then quenched by
addition of H2O (2 mL), and extracted with CH2Cl2 (3ꢀ). The
combined organic layer was washed with brine, dried over
(Na2SO4), and evaporated in vacuo. The residue was purified by
column chromatography on aluminium oxide (50% AcOEt/n-
hexane) to afford 28.5 mg (81%) of 2 as a colorless oil (unstable
to light). Rf 0.54 (AcOEt/n-hexane 1/1). IR (neat): 3479, 3115,
3041, 2841, 1729, 1574, 1539, 1345, 1309, 1248, 1149, 1072,
1
1146, 1068, 1016, 461. H-NMR (CDCl3) ꢀ: 3.41 (2H, t, J =
6.97 Hz, CH2CH2NHBz), 3.48 (3H, s, OCH2OCH3), 3.77 (2H,
dt, J = 6.97, 6.97 Hz, CH2CH2NHBz), 3.86 (3H, s, CO2CH3),
5.19 (2H, s, OCH2OCH3), 6.83 (br, CH2CH2NHBz), 6.86 (1H,
dd, J = 8.80, 2.20 Hz, H-C(5)), 7.03 (1H, d, J = 2.20 Hz, H-
C(7)), 7.32-7.46 (3H, m, H-Ph), 7.59 (1H, d, J = 8.80 Hz, H-
C(4)), 7.67-7.69 (2H, m, H-Ph), 8.94 (br, H-N(1)) 13C-NMR
(CDCl3) ꢀ: 51.7, 55.9 (CH3), 24.1, 41.2, 94.8 (CH2), 97.4, 112.9,
121.4, 126.8, 128.3, 131.1 (CH), 122.4, 122.7, 123.1, 134.5,
136.9, 156.7, 162.8, 167.5 (C). HR-MS (FAB) for C21H23N2O5
(MH+), calcd. 383.1607, found 383.1615.
1
1004, 898, 845, 805, 694. H-NMR (CDCl3) ꢀ: 3.09 (2H, t, J =
6.60 Hz, CH2CH2NHBz), 3.51 (3H, s, OCH2OCH3), 3.71 (2H,
dt, J = 6.60, 6.60 Hz, CH2CH2NHBz), 5.18 (1H, d, J = 11.36 Hz,
ꢁCH=CHaHb), 5.21 (2H, s, OCH2OCH3), 5.41 (1H, d, J = 17.60
Hz, ꢁCH=CHaHb), 6.13 (br, CH2CH2NHBz), 6.80 (1H, dd, J =
11.36, 17.60 Hz, ꢁCH=CH2), 6.84 (1H, dd, J=8.80, 2.20 Hz, H-
C(5)), 7.05 (1H, d, J =2.20 Hz, H-C(7)), 7.34-7.49 (3H, m, H-
Ph), 7.68 (1H, d, J = 8.80 Hz, H-C(4)), 7.62-7.65 (2H, m, H-Ph),
8.04 (br, H-N(1)). 13C-NMR (CDCl3) ꢀ: 55.9 (CH3), 23.8, 40.5,
95.2, 110.9 (CH2), 97.9, 111.1, 119.5, 125.1, 126.8, 128.4, 131.3
(CH), 112.5, 123.9, 132.8, 134.5, 137.0, 154.8, 167.5 (C). HR-
MS (EI) for C21H22N2O3 (M+), calcd. 350.1630, found 350.1620.
N-Benzoyl-N-[2-(2-hydroxymethyl-6-methoxymethoxy-
1H-indol-3-yl)ethyl]amine (16). To a solution of compound 15
(76.6 mg, 0.2 mmol) in anhydrous THF (2 mL), LAH (75.9 mg,
2.0 mmol) was added little by little at 0°C under Ar atmosphere.
After stirring for 2 h at the temperature, H2O/THF (50%)
solution was added carefully to quench the reaction, and the
resulting mixture was filtered to remove the inorganic salt. The
filtrate was extracted with AcOEt (3ꢀ), and the organic layer
was washed with brine, dried over (Na2SO4), and evaporated in
vacuo. The residue was purified by column chromatography on
silica gel (AcOEt) to afford 63.0 mg (89%) of 16 as a white
solid. Rf 0.42 (AcOEt). M.p. 89~92 °C.ꢀIR (nujor): 3033, 1644,
Acknowledgement.
The present study was financially
supported in part by a Grant-in- Aid for Scientific Research
(NO.17390030 to MO), Kumamoto Technology and Industry
Foundation (to YO), and Shorai Foundation for Science and
Technology (to MO).
1
1575, 1530, 1147, 1074, 1005, 917, 709. H-NMR (CD3OD) ꢀ:
3.05 (2H, t, J = 6.97 Hz, CH2CH2NHBz), 3.45 (3H, s,
OCH2OCH3), 3.59 (2H, t, J = 6.97 Hz, CH2CH2NHBz), 4.69
(2H, s, CH2OH), 5.14 (2H, s, OCH2OCH3), 6.73 (1H, dd, J =
8.80, 2.20 Hz, H-C(5)), 7.01 (1H, d, J = 2.20 Hz, H-C(7)), 7.36-
7.48 (3H, m, H-Ph), 7.46 (1H, d, J = 8.80 Hz, H-C(4)), 7.70-
7.73 (2H, m, H-Ph) 13C-NMR (CD3OD) ꢀ: 56.1 (CH3), 24.9,
42.3, 56.4, 94.8 (CH2), 99.4, 111.4, 120.0, 128.2, 129.5, 132.5
(CH), 110.3, 125.1, 135.4, 135.8, 137.9, 155.1, 170.4 (C). HR-
MS (FAB) for C20H22N2O4 (M+), calcd. 354.1580, found
354.1611.
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N-Benzoyl-N-[2-(2-formyl-6-methoxymethoxy-1H-indol-
3-yl)ethyl]amine (17). Compound 16 (70.8 mg, 0.2 mmol) was
dissolved in anhydrous CH2Cl2 (2 mL), and MnO2 (17.4 mg, 2.0
mmol) was added to this solution under Ar atmosphere. After
stirring for 2 h at r.t., the reaction mixture was then filtered
through Celite, and the Celite was washed with CH2Cl2. The
filtrate was dried over (Na2SO4) and evaporated in vacuo, and
the residue was purified by column chromatography on silica gel
(50% AcOEt/n-hexane) to afford 70.2 mg (quant.) of 17 as a
white solid. Rf 0.57 (AcOEt/n-hexane 2/1). M.p. 152~153 °C.ꢀ
IR (KBr): 3419, 3296, 1646, 1546, 1439, 1310, 1232, 1198,
1
1148, 1073, 1013, 698. H-NMR (CD3OD) ꢀ: 3.36 (2H, t, J =
6.97 Hz, CH2CH2NHBz), 3.45 (3H, s, OCH2OCH3), 3.66 (2H, t,
J = 6.97 Hz, CH2CH2NHBz), 5.20 (2H, s, OCH2OCH3), 6.80
(1H, dd, J = 8.80, 2.20 Hz, H-C(5)), 7.03 (1H, d, J = 2.20 Hz, H-
C(7)), 7.36-7.50 (3H, m, H-Ph), 7.68 (1H, d, J = 8.80 Hz, H-
C(4)), 7.64-7.77 (2H, m, H-Ph), 9.85 (1H, s, CHO) 13C-NMR
(CD3OD) ꢀ: 56.3 (CH3), 24.6, 42.7, 95.8 (CH2), 98.5, 114.1,
123.3, 128.2, 129.5, 132.6, 181.6 (CH), 124.2, 127.9, 134.0,
135.6, 140.8, 159.1, 170.4 (C). HR-MS (FAB) for C20H21N2O4
(MH+), calcd. 353.1501, found 353.1504.
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