A general large scale synthesis of 2-alkyl-7-methoxyindoles

Article abstract of DOI:10.3987/COM-01-9162

A general method has been developed for the large scale synthesis of 2-alkyl-7-methoxyindoles and analogs. This method involves an efficient preparation of the key intermediates, 1-(2-nitroaryl)-2-nitroalkanols and 1-(2-nitroaryl)-2-nitroalkenes, and affords 2-alkyl-7-methoxyindoles and analogs in 3 steps with good overall yields.

Full text of DOI:10.3987/COM-01-9162

HETEROCYCLES, Vol. 55, No. 5, 2001, pp. 951 – 960, Received, 19th January, 2001
A GENERAL LARGE SCALE SYNTHESIS OF
2-ALKYL-7-METHOXYINDOLES
Bang-Chi Chen,* John Hynes, Jr., Chennagiri R. Pandit, Rulin Zhao,
Amanda P. Skoumbourdis, Hong Wu, Joseph E. Sundeen, and Katerina Leftheris*
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute
Princeton, NJ 08543, USA
Abstract - A general method has been developed for the large scale synthesis of
2-alkyl-7-methoxyindoles and analogs. This method involves an efficient
preparation of the key intermediates, 1-(2-nitroaryl)-2-nitroalkanols and 1-(2-
nitroaryl)-2-nitroalkenes, and affords 2-alkyl-7-methoxyindoles and analogs in 3
steps with good overall yields.
2-Alkyl-7-methoxyindoles are common structural units found in a number of biologically important
molecules.1 They are also intermediates in the synthesis of medicinally useful agents,2 and in the
synthesis of natural products.3 Several methods have been previously reported for the preparation of 2-
alkyl-7-methoxyindoles.3-8 Many of these methods, however, were not effective primary due to the
unique substitution pattern in 2-alkyl-7-methoxyindole molecules.3-5 Perhaps the most direct approach to
2-alkyl-7-methoxyindoles is the reaction of 2-nitroanisoles with vinyl Grignard reagents. Unfortunately,
this approach has little synthetic value as shown in the reaction of 2-propenylmagnesium bromide with
4-methyl-2-nitroanisole.3 Only 5% of the desired 7-methoxyindole was obtained even with 3
equivalents of the vinyl Grignard reagent.3 The classical Fisher,4 and Bischler5 type approaches are also
ineffective. In both cases, 2-alkyl-7-methoxyindoles were obtained in <10% yields. While the yields of
the indole formation were improved to some degree (~40% vs. <10%) by using the Madelung,3 or
Gassman's6 method, the high reaction temperature,3 the use of chlorine gas6 and Raney nickel6 rendered
them impractical for large scale synthesis. The best methods reported so far for the synthesis of 2-alkyl-
7-methoxyindoles involved reductive cyclization of 3-methoxy-2-nitrobenzylketones,7 or deprotective
cyclization of 3-methoxy-2-N-(tert-butoxycarbonyl)aminobenzylketones.8 However, the number of
steps required for the preparation of the ketone precursors in addition to diazomethane and Raney nickel

used in the former method,7 and the strong base as s-BuLi used for aromatic lithiation in the latter,8 made
them unattractive for large scale synthesis. In one of our drug discovery programs, we required a facile
preparation of 2-alky-7-methoxyindoles in large quantity. Herein, we describe a general large scale
synthesis of the titled compounds.
Our synthesis of 2-alkyl-7-methoxyindoles (5) entails the reductive cyclization of β-alkyl-3-methoxy-
2,β-dinitrostyrenes (4) (Scheme 1). The reduction of the parent 2,β-dinitrostyrene to indole was
reported in 1925 and this chemistry has been successfully extended to the preparation of other 2-
unsubstituted indoles including 2-unsubstituted 7-methoxyindoles.10 However, report on the application
of this approach to the synthesis of 2-alkylindoles is rare.11 To the best of our knowledge, no report has
appeared on the synthesis of the titled compounds using this approach.
Scheme 1
OH
CHO
NO2
R
KF/18-C-6
R
NO2
+
NO2
X
X
i-PrOH
NO2
OMe
OMe
2a, R=H
b, R=Me
c, R=Et
3a, X=CH, R=H
b, X=CH, R=Me
c, X=CH, R=Et
d, X=CH, R=Pr-n
e, X=C(OMe), R=Me
f, X=N, R=Me
1a, X=CH
b, X=C(OMe)
c, X=N
d, R=Pr-n
R
H2/10%Pd-C
Ac2O/NaOAc
KF/18-C-6
R
X
NO2
X
N
NO2
EtOH/HOAc/EtOAc
H
OMe
OMe
5a, X=CH, R=H
b, X=CH, R=Me
c, X=CH, R=Et
d, X=CH, R=Pr-n
e, X=C(OMe), R=Me
f, X=N, R=Me
4a, X=CH, R=H
b, X=CH, R=Me
c, X=CH, R=Et
d, X=CH, R=Pr-n
e, X=C(OMe), R=Me
f, X=N, R=Me
Initially, we tried to prepare the key intermediates, β-alkyl-3-methoxy-2,β-dinitrostyrenes (4), by direct
condensation of 3-methoxy-2-nitrobenzaldehydes with nitroalkanes. Thus, treatment of 1a with excess
nitroethane (2b) using ammonium acetate in refluxing acetic acid, a common condition for this type of
condensation,12 did afford the desired product (4b) directly. However, the conversion was disappointing.
Only about 33% of 4b was observed by HPLC, along with ~13% of the starting aldehyde (1a) and
numerous other unidentified products. Use of methylamine hydrochloride13 instead of ammonium

acetate improved the conversion only slightly to ~45% by HPLC. These results, coupled with polymeric
materials obtained from the reaction, indicate that the resulting 3-methoxy-2,β-dinitrostyrenes,
compared to their des-3-methoxy counterparts, are more prone to oligomerization and or polymerization
under these reaction conditions through Michael additions.14 Considering the success of fluoride anion
mediated coupling of nitroalkanes with aldehydes to give β-hydroxy nitroalkanes and nitroalkenes,15 we
turned our attention to the step-wise protocol for the preparation of our β-alkyl-3-methoxy-2,β-
dinitrostyrenes (4). By isolating the hydroxy dinitro intermediates (3) formed in the first step to remove
any excess nitroalkane, the potential oligomerization and or polymerization of the resulting 4 in the next
step is expected to be minimized, if not eliminated. Thus, treatment of the commercially available 3-
methoxy-2-nitrobenzaldehyde (1a) with nitroethane (2b) in isopropanol in the presence of potassium
fluoride and 18-crown-6 (18-C-6) at room temperature overnight cleanly afforded the hydroxy dinitro
product (3b) in 96% isolated yield as a mixture of diastereomers. Treatment of 3b with acetic anhydride
and sodium acetate in the presence of potassium fluoride and 18-crown-6 (18-C-6) gave 3-methoxy-β-
methyl-2,β-dinitrostyrene (4b) in 96% isolated yield. Reductive cyclization of 4b was carried out using
H2 and 10% Pd/C in a mixture of solvents, giving 7-methoxy-2-methylindole (5b) in 62% isolated yield.
Other 2-alkyl-7-methoxyindoles were prepared in a similar manner as summarized in Table 1.
Table 1: Preparation of 2-Alkyl-7-methoxyindoles
Entry
X
R
3
4
5
Time (h)a Yield
(%)b
Time (h)a Yield (%)b
Time (h)a Yield
(%)b
2.5
1
2
3
4
5
6
CH
CH
CH
CH
C(OM
e)
H
20
16
20
20
16
16
98
64
64
64
64
72
72
91
96
88
87
61
89d
58c
Me
Et
96
3
62
93
2.5
2.5
12
12
45c
32c
81c
66c
Pr-n
Me
Me
97
96d
97d
N
b
c
aReaction time. Isolated yield by crystallization unless otherwise indicated. Isolated yield after flash
d
chromatography. Isolated yield after extractive work-up.
As can be seen from Table 1, the step-wise procedure worked very well for the preparation of β-alkyl-
3-methoxy-2,β-dinitrostyrenes (4). The length of the alkyl chain of nitroalkanes (2) had little effect on
the overall yields (Table 1, Entries 1-4), although the substituent group on the phenyl ring showed some

effect (compare Table 1, Entries 2 and 5). For the reductive ring closure of 4 to give indoles (5), as the
length of the 2-alkyl chain increased, the overall yield tended to decrease (Table 1, Entries 2-4).
Importantly, the new method not only worked for the preparation of 2-alkyl-7-methoxyindoles (Table 1,
Entries 2-5), but also worked for 7-methoxy-6-azaindole (Table 1, Entry 6) and 2-unsubstituted 7-
methoxyindole (Table 1, Entry 1).
To extend the scope of this new process, two aldehydes (6a) and (6b), without a methoxy group on the
aromatic ring, were examined (Scheme 2). In both cases, the corresponding β-methyl-2,β-styrenes (8a)
and (8b) were obtained in 89 and 83% yields, respectively. Hydrogenation of 8a on 10% Pd-C as
described above gave 2-methylindole (9a) in 81% yield. Interestingly, hydrogenation of 8b under the
same reaction conditions afforded after isolation a mixture of 2-methylazaindole (9b) and the
1
corresponding N-hydroxyindole (10b) in a ratio of 3:1 as determined by H NMR.16 Subjecting this
mixture to zinc powder in acetic acid at reflux cleanly afforded 9b in 94% yield.
Scheme 2
OH
CHO
KF/18-C-6
NO2
2b
+
X
NO2
X
i-PrOH
NO2
NO2
6a, X=CH
b, X=N
7
Ac2O/NaOAc
KF/18-C-6
H2/10%Pd-C
NO2
X
EtOH/HOAc/EtOAc
NO2
8
+
X
X
N
N
H
OH
9
10
Zn/HOAc (X=N)
In summary, a general method has been developed for the large scale synthesis of 2-alkyl-7-
methoxyindoles. This new method was also found to work well for the preparation of other indole
molecules such as 2-unsubstituted 7-methoxyindoles, 2-alkylindoles, 2-alkyl-6-azaindoles and 2-alkyl-6-
aza-7-methoxyindoles. In addition, the new efficient procedures developed for the synthesis of

intermediates (3, 4, 7 and 8) are of synthetic value since these compounds are useful intermediates in the
synthesis of important molecules other than indoles.17,18
EXPERIMENTAL
Proton and carbon-13 NMR spectra were recorded in CDCl3 using TMS as internal standard. Melting
points are uncorrected. 3-Methoxy-2-nitrobenzaldehyde (1a) and 3,4-dimethoxy-2-nitrobenzaldehyde
(1b) were obtained from Aldrich Company and used as received. 2-Methoxy-3-nitropyridine-4-
carboxaldehyde (1c)19a and 3-nitropyridine-4-carboxaldehyde (6b)19b were prepared according to
literature procedures.
Preparation of 1-(3-Methoxy-2-nitrophenyl)-2-nitropropanol (3b): To a 2L round bottomed flask
equipped with a magnetic stirrer and a nitrogen bubbler were added 2-nitro-3-methoxybenzaldehyde (1a,
125.7 g, 0.69 mol), nitroethane (2b, 72.94 g, 0.97 mol), 18-C-6 (18.34 g, 0.069 mol), isopropanol (420
mL) and KF (20.17 g, 0.35 mol). The mixture was stirred at rt for 16 h. The solvent was removed on a
rotary evaporator to give an oil. Isopropanol (100 mL) and de-ionized water (250 mL) were added. The
mixture was put on a rotary evaporator to remove isopropanol to give a slurry. The slurry was stirred
for 1 h and filtered. The cake was washed with de-ionized water (4x100 mL) and dried to give 1-(3-
methoxy-2-nitrophenyl)-2-nitropropanol (3b) as a diastereomeric mixture in a ratio of 3:2 (170.3g, 96%)
which was used in the next reaction without further purification. 1H NMR for the major isomer:
(CDCl3) δ 7.05-7.52 (m, 3H), 5.08 (d, J=8.6 Hz, 1H), 4.90 (m, 1H), 3.92 (s, 3H), 2.94 (s, 1H), 1.38 (d,
J=6.9 Hz, 3H).
1-(3-Methoxy-2-nitrophenyl)-2-nitroethanol (3a): prepared similarly in 98% yield from 1a and 2a
1
and used in the next reaction without further purification. H NMR (CDCl3) δ 7.08-7.52 (m, 3H), 5.47
(m, 1H), 4.63 (m, 2H), 3.92 (s, 3H), 3.63 (br, 1H).
1-(3-Methoxy-2-nitrophenyl)-2-nitrobutanol (3c): prepared similarly in 93% yield as a mixture of
diastereomers in a ratio of 4:1 from 1a and 2c and used in the next reaction without further purification:
1H NMR for the major isomer: (CDCl3) δ 7.04-7.50 (m, 3H), 5.06 (d, J=8.4 Hz, 1H) 4.70-4.75 (m, 1H),
3.93 (s, 3H), 2.97 (br, 1H), 1.86-1.94 (m, 1H), 1.45-1.51 (m, 1H), 0.90 (t, J=7.4 Hz, 3H).
1-(3-Methoxy-2-nitrophenyl)-2-nitropentanol (3d): prepared similarly in 97% yield as a mixture of
diastereomers in a ratio of 3:1 from 1a and 2d and used in the next reaction without further purification.
1H NMR for the major isomer: (CDCl3) δ 7.04-7.51 (m, 3H), 5.05 (d, J=8.3 Hz, 1H) 4.80-4.85 (m, 1H),
3.92 (s, 3H), 1.86-1.94 (m, 2H), 1.27-1.36 (m, 2H), 0.88 (m, J=7.3 Hz, 3H).

1-(3,4-Dimethoxy-2-nitrophenyl)-2-nitropropanol (3e): prepared similarly in 96% yield as a mixture
of diastereomers in a ratio of 3:2 from 1b and 2b and used in the next reaction without further
1
purification. H NMR for the major isomer (CDCl3) δ 7.70-7.06 (m, 2H), 5.01 (m, 1H), 4.90 (m, 1H),
3.94 (s, 3H), 3.94 (s, 3H), 1.36 (d, J=6.9 Hz, 3H).
1-(3-Methoxy-2-nitro-4-pyridinyl)-2-nitropropanol (3f): prepared similarly in 97% yield as a mixture
of diastereomers in a ratio of 3:2 from 1c and 2b and used in the next reaction without further
1
purification. H NMR for the major isomer (CDCl3) δ 8.33 (d, J=5.2 Hz, 1H), 7.07 (d, J=5.3 Hz, 1H),
5.16 (d, J=8.1 Hz, 1H), 4.89 (m, 1H), 4.07 (s, 3H), 1.46 (d, J=6.9 Hz, 3H).
1-(2-Nitrophenyl)-2-nitropropanol (7a): prepared similarly in 93% yield as a mixture of diastereomers
1
in a ratio of 5:4 from 6a and 2b and used in the next reaction without further purification. H NMR for
the major isomer (CDCl3) δ 7.54-8.15 (m, 4H), 6.12 (br s, 1H), 5.20 (m, 1H), 3.21 (br s, 1H), 1.58 (d,
J=6.9 Hz, 3H).
1-(2-Nitro-4-pyridinyl)-2-nitropropanol (7b): prepared similarly in 86% yield as a mixture of
diastereomers in a ratio of 2:1 from 6b and 2b and used in the next reaction without further purification.
1H NMR for the major isomer (CDCl3) δ 9.22 (s, 1H), 8.87 (d, J=5.1 Hz, 1H), 7.62 (d, J=5.1 Hz, 1H),
6.18 (br s, 1H), 4.88 (m, 1H), 3.25 (br s, 1H), 1.45 (d, J=7.0 Hz, 3H).
Preparation of 1-(3-Methoxy-2-nitrophenyl)-2-nitropropene (4b): To a 5L three-necked round
bottomed flask equipped with a mechanical stirrer and a nitrogen bubbler were added 3b (169.0 g, 0.659
mol), acetic anhydride (450 mL), 18-C-6 (17.41 g, 0.067 mol) and KF (38.25 g, 0.658 mol). The
reaction mixture was stirred at rt for 64 h. The reaction mixture was cooled in an ice-water bath. De-
ionized water (2250 mL) was added slowly. The resulted slurry was stirred at 0oC for 2 h and then
filtered. The cake was washed with de-ionized water (3x250 mL) and suction dried for 20 h to give 1-
(3-methoxy-2-nitrophenyl)-2-nitropropene (4b) (150.7 g, 96%) and used in the next reaction without
1
further purification. H NMR (CDCl3) δ 7.89 (s, 1H), 7.53 (pseudo t, J=8.1 Hz, 1H), 7.13 (d, J=8.5 Hz,
1H), 6.94 (d, J=7.8 Hz, 1H), 3.95 (s, 3H), 2.30 (s, 3H).
1-(2-Nitro-3-methoxyphenyl)-2-nitroethene (4a): prepared similarly in 91% yield from 3a and used
in the next reaction without further purification. The spectroscopic data were consistent with those
reported for this compound.20
1-(3-Methoxy-2-nitrophenyl)-2-nitrobutene (4c): prepared similarly in 88% yield from 3c as a
mixture of E/Z isomers and used in the next reaction without further purification.
1-(3-Methoxy-2-nitrophenyl)-2-nitropentene (4d): prepared similarly in 87% yield from 3d as a
mixture of E/Z isomers and used in the next reaction without further purification.

1-(3,4-Dimethoxy-2-nitrophenyl)-2-nitropropene (4e): prepared similarly in 61 % yield from 3e and
1
used in the next reaction without further purification. H NMR (CDCl3) δ 7.75 (s, 1H), 7.01 (dd, J=11.9,
3.2 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.27 (s, 3H).
1-(3-Methoxy-2-nitro-4-pyridinyl)-2-nitropropene (4f): prepared similarly in 89% yield from 3f and
1
used in the next reaction without further purification. H NMR (CDCl3) δ 8.39 (d, J=5.2 Hz, 1H), 7.88
(s, 1H), 6.89 (d, J=5.1 Hz, 1H), 4.11 (s, 1H), 2.3 (s, 3H).
1-(2-Nitrophenyl)-2-nitropropene (8a): prepared similarly in 89% yield from 7a and used in the next
reaction without further purification. The spectroscopic data were consistent with those reported for this
compound.12
1-(2-Nitro-4-pyridinyl)-2-nitropropene (8b): prepared similarly in 83% yield from 7b and used in the
1
next reaction without further purification. H NMR (CDCl3) δ 9.46 (s, 1H), 8.97 (d, J=4.9 Hz, 1H), 8.28
(s, 1H), 7.36 (d, J=4.9 Hz, 1H), 2.27 (s, 3H).
Preparation of 2-Methyl-7-methoxyindole (5b): To a 2L hydrogenation flask were added 4b (43.72 g,
0.1854 mol), 10% Pd/C (4.37 g, ~50% water wet), ethyl acetate (595 mL), acetic acid (90.5 mL) and
absolute ethanol (75 mL). The reaction mixture was hydrogenated at <60 psi for 3 h and then filtered.
The cake was washed with EtOAc (3x100 mL). The filtrate was concentrated to remove ethyl acetate
and ethanol. De-ionized water (200 mL) was then added slowly. The resulted slurry was stirred for 0.5
h at rt and filtered. The cake was washed with 1:2 HOAc/H2O (2x30 mL) 1:4 HOAc/H2O (50 mL),
water (2x80 mL) and suction dried for 18 h to give 7-methoxy-2-methylindole (5b) (18.3 g, 62%). mp
1
78-80oC, lit.,6 mp 79-81oC. H NMR (CDCl3) δ 8.10 (s, 1H), 7.12 (d, J=7.7 Hz, 1H), 6.97 (pseudo t,
J=7.7 Hz, 1H), 6.57 (d, J=7.7 Hz, 1H), 6.18 (pseudo t, J=1.1 Hz, 1H), 3.94 (s, 3H), 2.42 (s, 3H).
7-Methoxyindole (5a): prepared similarly from 4a, 58% yield as an oil. The spectroscopic data were
consistent with those reported for this compound.21
1
2-Ethyl-7-methoxyindole (5c): prepared similarly from 4c, 45% yield as an oil: H NMR (CDCl3) δ
8.10 (br s, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.98 (pseudo t, J=7.7 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.21 (s,
13
1H) 3.94 (s, 3H), 2.74-2.79 (m, 2H), 1.32 (t, J=7.5 Hz, 3H); C NMR δ 145.9, 141.4, 130.5, 126.5,
120.3, 113.1, 101.6, 99.5, 55.7, 21.8, 13.8; HRMS 175.0999 [ESI, (M+H)+] calcd for C11H14NO2
175.0997.
2-(n-Propyl)-7-methoxyindole (5d): prepared similarly from 4d, 32% yield as an oil: 1H NMR
(CDCl3) δ 8.09 (br s, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.00 (pseudo t, 1H), 6.62 (d, J=7.7 Hz, 1H), 6.23 (s,
13
1H) 3.97 (s, 3H), 1.81-1.74 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); C NMR δ 145.9, 139.8, 130.5, 126.4,

120.2, 113.1, 101.4, 100.3, 55.7, 30.7, 23.0, 14.3; HRMS 189.1153 [ESI, (M+H)+] calcd for C11H14NO2
189.1154.
2-Methyl-6,7-dimethoxyindole (5e): prepared similarly from 4e, 81% yield: mp 76-77 °C (hexane); 1H
NMR (CDCl3) δ 7.89 (br s, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.62 (d, J=8.5 Hz, 1H), 5.96 (s, 1H) 3.84 (s,
3H), 3.75 (s, 3H), 2.23 (s, 3H); 13C NMR δ 146.8, 135.2, 134.3, 130.8, 126.0, 114.8, 108.4, 100.7, 61.2,
55.7, 14.3; HRMS 192.1028 [ESI, (M+H)+] calcd for C11H14NO2 192.1025. Anal. Calcd for C11H13NO2:
C, 69.09; H, 6.85; N, 7.32. Found: C, 68.51; H, 6.54; N, 6.89.
2-Methyl-6-aza-7-methoxyindole (5f): prepared similarly from 4f, 66% yield: mp 146 oC (hexane); 1H
NMR (CDCl3) δ 8.43 (br s, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.07 (d, J=5.6 Hz, 1H), 6.21 (d, J=0.8 Hz, 1H),
13
4.10 (s, 3H), 2.47 (s, 3H);. C NMR (CDCl3) δ 150.9, 137.8, 135.8, 135.6, 121.0, 109.9, 101.1, 53.3,
14.1; HRMS 163.0878 [ESI, (M+H)+] calcd for C9H10N2O 162.0793. Anal. Calcd for C9H10N2O: C,
66.64; H, 6.21; N, 17.27; Found: C, 66.41; H, 6.07; N, 17.08.
o
o
2-Methylindole (9a): prepared similarly from 8a, 81% yield: mp 59-60 C, lit.,22 mp 59-61 C. 1H
NMR (CDCl3) δ 7.90 (br s, 1H), 7.55-7.10 (m, 4H), 6.23 (s, 1H), 2.45 (s, 3H).
2-Methyl-6-azaindole (9b): prepared similarly from 8b. After hydrogenation, the reaction mixture was
filtered and concentrated on a rotary evaporator. Acetic acid (20 mg/mL) and powdered zinc (3 equiv)
were added and the reaction heated at reflux for 3 h. The reaction mixture was concentrated to an oil
and purified via flash chromatography (10% MeOH/CH2Cl2). The product (9b) was isolated in 94%
1
yield: mp 182 oC, lit.,23 mp 185 oC; H NMR (CDCl3) δ 10.72 (br s, 1H), 8.67 (s, 1H), 8.12 (d, J=5.5 Hz,
1H), 7.37 (d, J=5.8 Hz, 1H), 6.18 (s, 1H), 2.45 (s, 3H).
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