An improved synthesis of hydroxyindoles

Article abstract of DOI:10.1055/s-2004-834924

An improved synthetic procedure for the synthesis of 6- and 7-hydroxyindoles is described. In this method, the addition of two chlorine atoms in 1-benzyloxy-4,5-dichloro-2-nitrobenzene (3) and 1-benzyloxy-2,6- dichloro-3-nitrobenzene (9) facilitated the subsequent cyanomethylation step to give substituted cyanomethyl-dichloronitrobenzenes 4 and 10, leading to an overall increase in the yield of the hydroxyindoles 6 and 12.

Full text of DOI:10.1055/s-2004-834924

PAPER
3043
An Improved Synthesis of Hydroxyindoles
A
n
Improved
S
y
e
nthesis of
n
Hydroxyindo
a
les Lerman,a Marta Weinstock-Rosin,b Abraham Nudelman*a
a
Chemistry Department, Bar Ilan University, Ramat Gan, 52900, Israel
Fax +972(3)5351250; E-mail: nudelman@mail.biu.ac.il
Department of Pharmacology, Faculty of Medicine, Hebrew University, Ein Kerem, Jerusalem, 91120, Israel
b
Received 2 June 2004; revised 14 September 2004
tonitrile. To facilitate the reaction, the nitrobenzene ring
was activated by the addition of an electron-withdrawing
chloro substituent, to give the desired product in 68%
yield. In our investigations, the addition of a second chlo-
Abstract: An improved synthetic procedure for the synthesis of 6-
and 7-hydroxyindoles is described. In this method, the addition of
two chlorine atoms in 1-benzyloxy-4,5-dichloro-2-nitrobenzene (3)
and 1-benzyloxy-2,6-dichloro-3-nitrobenzene (9) facilitated the
subsequent cyanomethylation step to give substituted cyanomethyl- ro substituent further enhanced the reactivity of the substi-
dichloronitrobenzenes 4 and 10, leading to an overall increase in the
yield of the hydroxyindoles 6 and 12.
tuted nitrobenzene ring, whereby the yield of the
cyanoalkyl product increased to 82–85%. In addition, in
the course of the subsequent reductive cyclization, Mako-
sza, using 10% Pd/C in a mixture of EtOH–AcOH, report-
ed a 39% yield of 7-hydroxyindole. All our attempts to
repeat this procedure failed. However, when the reaction
was carried out in 95% EtOH in the presence of PtO2 but
in the absence of acid, the 7-benzyloxy-4,5-dichloroin-
dole was obtained in 35% yield. Reductive removal of the
benzyl and chloro groups was accomplished with ammo-
nium formate–MeOH–10% Pd/C, to give 7-hydroxyin-
dole in 85% yield.
Key words: indole synthesis, hydroxyindoles, cyanomethylation
Hydroxyindoles serve as useful starting materials and in-
termediates in various fields. Both 4- and 5-hydroxyin-
doles are readily available from commercial sources,
whereas 6- and 7-hydroxyindoles are supplied only in
minute amounts from combinatorial libraries.
Recently, 4-hydroxyindole was used as a starting material
in the synthesis of a new generation of dopaminergic
agents,1 and products of electrochemical oxidation of 4-
hydroxyindole were reported to produce substantial
changes in blood parameters of albino mice.2 5-Hydroxy-
indole has been used as an intermediate in the synthesis of
novel non-steroidal inhibitors of human prostatic a-
reductase3 and was reported to exhibit neuroprotective
properties without estrogenic side effects.4 Some 4-, 6-
and 7-hydroxyindoles have been used in the manufacture
of hair dyes.5
Our inability to carry out the reductive cyclization in the
presence of acetic acid is in agreement with Walker’s ob-
servation that in an attempted synthesis of indoles via an
analogous path to that described herein, the reduction
stopped at the amidinium stage when carried out in acetic
acid, due to a resonance stabilization or the inability of the
catalyst to adsorb the protonated amidinium intermedi-
ate.10 Under neutral conditions in EtOAc, the reaction pro-
ceeded satisfactorily, presumably via an intramolecular
cyclization followed by loss of ammonia. An alternative
mechanism involves hydrolysis of the imine (obtained by
reduction of the nitrile) to the corresponding aldehyde,
which cyclizes to an indoline intermediate that then
isomerizes to the indole.11 Our procedure calls for the use
of 95% EtOH as solvent in the absence of acid.
Mixtures of all four isomeric 4-, 5-, 6- and 7-hydroxyin-
doles have been isolated in poor yields by direct oxidation
of indole with H2O2–SbF5 or Fe+3–H2O2.6 6-Hydroxy-
indole has been obtained in an overall 62% yield via a
Baeyer–Villiger oxidation of 6-chloroacetyl-1-pivaloylin-
dole.7 7-Hydroxyindole was prepared via a multi-step ap-
proach in an overall 35% yield involving DDQ oxidation
of a 4,5,6,7-tetrahydroindole.8 Makosza et al. obtained it
in 39% overall yield via the 2-benzyloxy-4-chloro-6-cya-
nomethyl-nitrobenzene intermediate, that was prepared in
turn from 2-benzyloxy-4-chloronitrobenzene in 68%.9
7-Hydroxyindole (6) (Scheme 1) was prepared in five
steps starting from 3,4-dichlorophenol (1). Nitration of 1
led to a mixture of mono- and di-nitrophenols that was
separated. Isomer 2 was further benzylated to provide 3.
Cyanomethylation of 3 followed by catalytic hydrogena-
tion gave the substituted indole 5. In an attempted hydro-
genolytic cyclization of 4 in the presence of 5 or 10% Pd/
C catalyst, containing varying weight percentages of wa-
ter, only removal of the benzylic group was observed,
without concomitant cyclization. These results led us to
use platinum oxide as an alternative catalyst. Hydrogena-
tion in non-acidic media, as described above, using the
PtO2 was found to provide the best reaction conditions. Fi-
nally, the concomitant removal of the both chlorides to-
gether with the benzyl group gave the desired 7-
hydroxyindole (6) in an overall 8% yield.
In the course of our investigations we have developed an
improved synthesis for the 6- and 7-hydroxyindoles lead-
ing to better yields of the products.
Makosza’s procedure for 7-hydroxyindole is based on a
nucleophilic substitution of hydrogen on a nitrobenzene
ring by the carbanion obtained from 4-chlorophenoxyace-
SYNTHESIS 2004, No. 18, pp 3043–3046
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Advanced online publication: 17.11.2004
DOI: 10.1055/s-2004-834924; Art ID: T05804SS
© Georg Thieme Verlag Stuttgart · New York

3044
L. Lerman et al.
PAPER
Scheme 1
The presence of the chloride atoms increased the electro-
philicity of the nitro-aryl group towards the cyanomethyl-
ation, while preventing the unfavored para-substitution of
the ring. Thus, in the course of cyanomethylation of 9
(Scheme 2) the presence of two chlorides helped to direct
the substitution only to the desired, available ortho-posi-
tion, to give 10.
4,5-Dichloro-2-nitrophenol (2)
A solution of 3,4-dichlorophenol (1) (1.63 g, 10 mmol) and tetra-n-
butylammonium bromide (TBAB) (32 mg, 10% mol) in CH2Cl2 (30
mL) was added to a 6% aq solution of HNO3 (20 mmol). The reac-
tion mixture was stirred at r.t. for 24 h. The organic phase was sep-
arated, dried over MgSO4 and evaporated. The crude residue was
purified by silica gel flash chromatography (hexane–EtOAc, 15:1)
to give the 2 as a yellow solid (0.83 g, 40% yield); mp 60–65 °C.
m-Nitrophenol (7) underwent dichlorination at the ortho
positions to the phenolic OH to give 2,6-dichloro-3-nitro-
phenol (8),12 which was benzylated to provide the protect-
ed analog 9. Cyanomethylation of 9, followed by catalytic
hydrogenation, as in the case of 7-hydroxyindole, fol-
lowed by removal of the protective groups gave the 6-hy-
droxyindole (12).
1H NMR (200 MHz, CDCl3): d = 10.45 (br s, 1 H, OH), 8.23 (s, 1
H, H-C3), 7.35 (s, 1 H, H-C6).
13C NMR (200 MHz, CDCl3): d = 153.5 (C1), 142.3 (C5), 125.8
(C3), 124.4 (C2), 124.1 (C4), 121.5 (C6).
MS (DCI, CH4): m/z (%) = 206.95 (100) [M].
HRMS (DCI, CH4): m/z [MH+] calcd for C6H3Cl2NO3: 206.948999;
found: 206.947236.
Anal. Calcd for C6H3Cl2NO3 (207.8): C, 34.65; H, 1.45; N, 6.73.
Found: C, 34.63; H, 1.49; N, 6.53.
1H and 13C NMR spectra were obtained on Bruker AC-200 and AM-
300 spectrometers at 200 MHz and 300 MHz, respectively. Chemi-
cal shifts are expressed in ppm downfield from TMS, which was
used as internal standard. The values are given in d scale. Mass
spectra were obtained on a Varian Mat 731 spectrometer (CI =
chemical ionization). HRMS were obtained on a VG AutoSpec E
spectrometer. Progress of the reactions was monitored by TLC on
silica gel (Merck, Art. 5554) or alumina (Riedel-de Haen, Art.
37349). Flash chromatography was carried out on silica gel (Merck,
Art. 9385). Commercially available 3,4-dichlorophenol (1) and m-
nitrophenol (7) were used without further purification.
2,6-Dichloro-3-nitrophenol (8)12
To a solution of m-nitrophenol (7) (2 g, 14.3 mmol) in toluene (100
mL) was added sulfuryl chloride (2.18 mL, 28.6 mmol) and distilled
diethylamine (0.11 mL, 1.12 mmol). The reaction mixture was
stirred at 70 °C overnight. The mixture was concentrated under re-
duced pressure and the crude residue was purified by flash chroma-
tography (hexane–EtOAc, 10:1) to provide 8 as a white solid (1.04
g, 35% yield); mp 105–110 °C [lit.12 107–108 °C].
1H NMR (200 MHz, CDCl3): d = 7.52–7.39 (ABq, J = 8.8 Hz, 2 H,
H-C5, H-C4), 6.31 (br s, 1 H, OH).
Scheme 2
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PAPER
An Improved Synthesis of Hydroxyindoles
3045
13C NMR (200 MHz, CDCl3): d = 149.5 (C1), 146.9 (C3), 127.8
(3-Benzyloxy-5,6-dichloro-2-nitrophenyl)acetonitrile (4)
(C5), 125.7 (C6), 117.2 (C4), 115.1 (C2).
Compound 4, prepared from 3 by general procedure B, precipitated
as a white solid, when the 5% HCl was added to a reaction mixture.
The precipitate was filtered and dried under vacuum over P2O5. Re-
crystallization from EtOH provided 4 as a white solid in 82% yield;
mp 135–140 °C.
MS (EI): m/z (%) = 207 (70) [M].
HRMS (DCI, CH4): m/z [MH+] calcd for C6H3Cl2NO3: 206.948999;
found: 206.941014.
1H NMR (200 MHz, CDCl3): d = 7.42–7.38 (m, 5 H, Ph), 7.22 (s, 1
H, H-C4), 5.20 (s, 2 H, CH2Ph), 3.80 (s, 2 H, CH2CN).
Anal. Calcd for C6H3Cl2NO3 (207.8): C, 34.65; H, 1.45; N, 6.73.
Found: C, 34.64; H, 1.47; N, 6.6.
13C NMR (300 MHz, CDCl3): d = 149.0 (C3), 136.9 (C5), 134.0
(Ph), 129.0 (Ph), 128.9 (Ph), 128.6 (C2), 127.2 (Ph), 127.1 (Ph),
126.9 (C6), 123.7 (C1), 116.6 (C4), 113.9 (CN), 72.0 (CH2Ph), 19.2
(CH2CN).
General Procedure A
To a solution of a phenol (0.13 mol) in DMF (200 mL), CsCO3 (0.13
mol) was added portion-wise. To this vigorously stirred suspension
was rapidly added benzyl bromide (0.13 mol) and the obtained mix-
ture was stirred at r.t. for 16 h, giving a mustard colored suspension.
To the mixture was added toluene (100 mL) and 1 N aq NaOH (100
mL), and the layers were separated. The organic phase was washed
with 1 N aq HCl (100 mL). Both the acidic and alkaline aqueous
layers were further extracted with toluene (1 × 20 mL and 3 × 20
mL, respectively) and the combined organic phase was washed with
water (40 mL), brine (40 mL), dried with MgSO4, and concentrated
to provide the O-benzylated phenol.
+
MS (DCI, CH4): m/z (%) = 91 (50) [C7H7 ], 336 (20) [M], 427 (100)
+
[M + C7H7 ].
HRMS (DCI, CH4): m/z [M] calcd for C15H10Cl2N2O3: 336.006848;
found: 336.015868.
Anal. Calcd for C15H10Cl2N2O3 (336.8): C, 53.44; H, 2.99; N, 8.31.
Found: C, 53.37; H, 2.98; N, 7.73.
(4-Benzyloxy-3,5-dichloro-2-nitrophenyl)acetonitrile (10)
Compound 10 was prepared from 9 by general procedure B. The
crude residue was purified by flash chromatography (hexane–
EtOAc, 20:1) and was isolated as a white solid in 57% yield; mp 75–
80 °C.
1-Benzyloxy-4,5-dichloro-2-nitrobenzene (3)
Compound 3, prepared from 2 by general procedure A, was isolated
as a yellow solid (90% yield); mp 103–107 °C and used without fur-
ther purification.
1H NMR (200 MHz, CDCl3): d = 7.63 (s, 1 H, H-C6), 7.58–7.50 (m,
2 H, Ph), 7.46–7.40 (m, 3 H, Ph), 5.10 (s, 2 H, CH2Ph), 3.73 (s, 2 H,
CH2CN).
13C NMR (300 MHz, CDCl3): d = 152.3 (C4), 134.9 (C2), 132.8
(Ph), 131.0 (C5), 129.2 (Ph), 128.9 (Ph), 128.6 (Ph), 128.6 (C6),
123.2 (C1), 121.9 (C3), 114.7 (CN), 75.8 (CH2Ph), 19.8 (CH2CN).
MS (ES+): m/z (%) = 337 (30) [MH+], 359 (30) [MNa+].
HRMS (DCI, CH4): m/z [MH+] calcd for C15H10Cl2N2O3:
1H NMR (200 MHz, CDCl3): d = 8.03 (s, 1 H, H-C3), 7.47–7.35 (m,
5 H, Ph), 7.22 (s, 1 H, H-C6), 5.22 (s, 2 H, CH2Ph).
13C NMR (300 MHz, CDCl3): d = 150.9 (C1), 141.2 (C5), 138.5
(C2), 134.5 (Ph), 128.6 (Ph), 128.6 (Ph), 127.1 (C3), 124.4 (C4),
117.1 (C6), 71.5 (CH2Ph).
+
MS (DCI/CH4): m/z (%) = 91 (100) [C7H7 ], 181 (20) [M –
C3HClNO2].
HRMS (DCI, CH4): m/z [M+] calcd for C13H9Cl2NO3: 296.995949;
found: 296.988127.
337.014673; found: 337.007332.
Anal. Calcd for C15H10Cl2N2O3 (336.8): C, 53.44; H, 2.99; N, 8.31.
Found: C, 53.74; H, 3.16; N, 8.18.
1-Benzyloxy-2,6-dichloro-3-nitrobenzene (9)
Compound 9, prepared from 8by general procedure A, was isolated
as a white solid (91% yield); mp 65–68 °C.
1H NMR (200 MHz, CDCl3): d = 7.67–7.60 (d, J = 9.5 Hz, 1 H, H-
C4), 7.58–7.35 (m, 6 H, H-C5, Ph), 5.10 (s, 2 H, CH2Ph).
13C NMR (300 MHz, CDCl3): d = 152.8 (C1), 135.4 (C3), 134.5
(Ph), 128.9 (Ph), 128.7 (C5), 128.6 (Ph), 128.6 (Ph), 124.1 (C6),
121.0 (C4), 116.6 (C2), 75.5 (CH2Ph).
General Procedure C
A suspension of a substituted (2-nitrophenyl)acetonitrile (10 mmol)
and PtO2 (0.25 g) in EtOH 95% (50 mL) was hydrogenated (30–35
psi) for 2 h at r.t. The catalyst was filtered through celite, and the fil-
trate was concentrated under vacuum to a yellow-brown oil, which
was purified by flash chromatography (hexane–EtOAc, 15:1) to
give the desired indole.
MS (EI): m/z (%) = 181 (100) [C10H8OCl], 220 (67) [C7H4NO3Cl2],
299 (50) [M].
7-Benzyloxy-4,5-dichloro-1H-indole (5)
Compound 4 was hydrogenated as described in general procedure
C. The isolated 5 was recrystallized from hexane as a white solid in
30% yield; mp 90–95 °C.
1H NMR (200 MHz, CDCl3): d = 8.50 (br s, 1 H, NH), 7.46–7.38
(m, 5 H, Ph), 7.2–7.18 (m, 1 H, H-C2), 6.80 (s, 1 H, H-C6), 6.60–
6.57 (m, 1 H, H-C3), 5.12 (s, 2 H, CH2Ph).
13C NMR (200 MHz, CDCl3): d = 148.1 (C7), 136.2 (Ph), 128.8
(Ph), 128.5 (Ph), 127.9 (Ph), 125.0 (C5), 124.9 (C6), 123.7 (C9),
105.6 (C2), 102.5 (C3), 71.0 (CH2Ph).
HRMS (DCI, CH4): m/z [M – H] calcd for C13H9Cl2NO3:
295.988124; found: 295.988501.
Anal. Calcd for C13H9Cl2NO3 (298.12): C, 52.37; H, 3.04; N, 4.70.
Found: C, 52.35; H, 3.08; N, 4.74.
General Procedure B
A solution of an O-benzyl protected nitrophenol (50 mmol) and (4-
chlorophenoxy)acetonitrile (55 mmol) in DMF (40 mL) was added
dropwise to a solution of t-BuOK (0.11 mol) in DMF (100 ml) at
–20 °C to –10 °C. The purple mixture obtained was stirred at this
temperature for 30 min and then poured into ice-cold 5% HCl giv-
ing a yellow colored suspension. In some cases the product solidi-
fied at this stage, and was isolated, otherwise the mixture was
extracted several times with toluene. The combined organic phase
was washed with water, brine, dried over MgSO4 and evaporated to
give a yellow-brown oil, which was further purified.
MS (ES+): m/z (%) = 158 (60) [C6H3NCl2], 294 (100) [MH+].
HRMS (DCI, CH4): m/z [M] calcd for C15H11Cl2NO: 291.02177;
found: 291.026236.
Anal. Calcd for C15H11Cl2NO·1/4H2O (296.5): C, 60.70; H, 3.88; N,
4.71. Found: C, 60.50; H, 3.86; N, 4.93.
Synthesis 2004, No. 18, 3043–3046 © Thieme Stuttgart · New York

3046
L. Lerman et al.
PAPER
6-Benzyloxy-5,7-dichloro-1H-indole (11)
Compound 11 was obtained from 10 by general procedure C as a
white solid that was recrystallized from hexane as a white solid in
33% yield.
6-Hydroxyindole (12)7
Compound 12 was obtained from 11 in 85% yield using general
procedure D. The 1H NMR data correspond to that described in the
literature; mp 125–130 °C [lit.7 128–129 °C].
1H NMR (300 MHz, CDCl3): d = 8.38 (br s, 1 H, NH), 7.67–7.62
(m, 3 H, H-C4, Ph), 7.45–7.42 (m, 3 H, Ph), 7.26–7.24 (m, 1 H, H-
C2), 6.54–6.53 (m, 1 H, H-C3), 5.10 (s, 2 H, CH2Ph).
13C NMR [200 MHz, (CD3)2CO]: d = 149.8 (C6), 137.1 (C8), 124.7
(C2), 120.4 (C4), 120.2 (C9), 115.1 (C5), 102.2 (C3), 97.2 (C7).
13C NMR (200 MHz, CDCl3): d = 146.0 (C7), 136.8 (Ph), 135.0
(C8), 128.5 (Ph), 128.4 (Ph), 128.3 (Ph), 125.8 (C4), 125.2 (C9),
121.7 (C6), 119.8 (C2), 111.5 (C5), 103.2 (C3), 75.7 (CH2Ph).
Acknowledgment
Generous support for this work by the ‘Marcus Center for Pharma-
ceutical and Medicinal Chemistry’ and the ‘Bronia and Samuel
Hacker Fund for Scientific Instrumentation’ at Bar Ilan University
is gratefully acknowledged.
MS (ES+): m/z (%) = 200 (100) [C8H4NOCl2], 291 (93) [M+].
Anal. Calcd for C15H11Cl2NO·1/4H2O (296.5): C, 60.70; H, 3.88; N,
4.71. Found: C, 60.68; H, 4.09; N, 4.86.
General Procedure D
References
A stirred solution of a substituted benzyloxy dichloroindole (0.4
mmol) and ammonium formate (2 mmol) in a anhyd MeOH was de-
gassed and then 10% Pd/C (50% wt) was added under nitrogen. The
mixture was stirred at r.t. over night, the catalyst was filtered
through celite and the filtrate was concentrated under vacuum. The
crude residue was dissolved in acetone and filtered again through
celite to remove salts. The filtrate was evaporated to give the hy-
droxyindole in 83–85% yield.
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1H NMR [200 MHz, (CD3)2CO]: d = 7.28–7.23 (d, J = 3.2 Hz, 1 H,
H-C2), 7.11–7.05 (dd, J = 7.9, 1.1 Hz, 1 H, H-C4), 6.88–6.80 (t, J =
7.9 Hz, 1 H, H-C5), 6.65–6.61 (dd, J = 7.9, 1.1 Hz, 1 H, H-C6),
6.62–6.60 (d, J = 3.2 Hz, 1 H, H-C3).
13C NMR [200 MHz, (CD3)2CO]: d = 148.0 (C7), 124.6 (C2), 120.4
(C4), 116.0 (C8), 115.3 (C9), 112.6 (C5), 106.3 (C6), 102.5 (C3).
1018.
(8) van der Berg, E. M. M.; Jansen, F. J. H. M.; de Goede, A. T.
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Bas 1990, 109, 287.
(9) Makosza, M.; Danikiewicz, W.; Wojciechowski, K. Liebigs
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MS (ES+): m/z (%) = 134 (40) [MH+].
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Synthesis 2004, No. 18, 3043–3046 © Thieme Stuttgart · New York