Synthesis of activated 3-substituted indoles: An optimised one-pot procedure

Article abstract of DOI:10.1016/j.tet.2004.10.060

3-Substituted-4,6-dimethoxyindoles can be synthesised in a one-pot procedure from 3,5-dimethoxyaniline and 2-haloketones in the presence of lithium bromide and sodium bicarbonate. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.060

Tetrahedron 61 (2005) 77–82
Synthesis of activated 3-substituted indoles: an
optimised one-pot procedure
*
Karin Pchalek, Ashley W. Jones, Monique M. T. Wekking and David StC. Black
School of Chemistry, University of New South Wales, UNSW, Sydney, NSW 2052, Australia
Received 13 July 2004; revised 7 October 2004; accepted 21 October 2004
Available online 5 November 2004
Abstract—3-Substituted-4,6-dimethoxyindoles can be synthesised in a one-pot procedure from 3,5-dimethoxyaniline and 2-haloketones in
the presence of lithium bromide and sodium bicarbonate.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
applied to 3,5-dimethoxyaniline and is an effective way for
the preparation of 4,6-dimethoxyindoles with overall yields
of 25–60% for aryl substituted indoles. Nevertheless, the
presence of substituents carrying sensitive functions such as
hydroxyl or ester groups contribute to a loss in yield, since
chromatographic workup is needed for some of the
intermediates prior to the next step in the reaction sequence.
This also involves lengthy work-up, which adds to the
accumulated reaction times needed for the four-step
synthesis. Furthermore, there has been no general synthetic
methodology for alkylindoles in this series.
The indole nucleus is present in a wide range of natural
products, and consequently a variety of methods for the
synthesis of indoles has been developed.1,2 Amongst these
numerous methods few practical and mild procedures are
available for the construction of activated 3-substituted-4,6-
dimethoxyindoles 6, and in particular for 3-alkyl-4,6-
dimethoxyindoles.3–5 Indoles carrying this substitution
pattern are of particular interest since they do not only
activate C7 and C2, but also enhance the general reactivity
of the indoles. An earlier study reported that 3-arylindoles
can be synthesised via a modified Bischler procedure in four
steps.6,7 This approach involved condensation of 3,5-
dimethoxyaniline 1 with phenacyl halides 2 (RZAr) to
afford arylamino ketones 3 which are consecutively
protected giving the N-protected amido ketones 4, prior to
their cyclisation in acid yielding the N-protected indoles 5.
These are deprotected by base to yield the desired
3-arylindoles 6. The N-protection is required to prevent
Bischler rearrangement to give 2-arylindoles 7 instead.6,8
This method has now been improved to provide a facile one-
pot procedure that could also be extended to the preparation
of 3-alkylindoles in good yields (Scheme 1).
After a close examination of the four-step synthesis the
crucial step was identified as the formation of the anilino
ketones 3, where both the quality and quantity of the
products were variable. Consequently, further investigations
were undertaken to gain control over this step.
2.2. From a four-step procedure to a one-pot reaction
In order to synthesise 4,6-dimethoxy-3-methylindole 6a via
the modified Bischler procedure the reaction conditions in
the first step had to be modified, eventually allowing the
preparation of 6a in 22% yield overall. Thus, in the crucial
first step of its synthesis 1-chloroacetone 2a was reacted
with 3,5-dimethoxyaniline 1 in refluxing ethanol containing
excess sodium bicarbonate and excess lithium bromide to
produce the methyl anilinoketone 3a, which ideally
precipitated out of solution upon cooling affording the
product in a variable yield of 30–67%. After a reaction
period of only 3 h, the anilinoketone 3a could be isolated in
70% yield, then cyclised using acetic anhydride to N-acetyl-
4,6-dimethoxy-3-methylindole in 70% yield, and this could
be hydrolysed with potassium hydroxide in ethanol to give
indole 6a in 90% yield. However, after longer reaction times
2. Results and discussion
2.1. Scope of the four-step procedure
The modified Bischler synthesis has been successfully
Keywords: Indoles; Haloketones; Lithium bromide; Electrophilic
substitution.
* Corresponding author. Tel.: C61 2 9385; fax: C61 2 9385 6141;
e-mail: d.black@unsw.edu.au
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.060

78
K. Pchalek et al. / Tetrahedron 61 (2005) 77–82
Scheme 1.
in the anilinoketone preparation and more appropriate
stoichiometry, a major by-product appeared in the reaction
mixture and was revealed by proton NMR spectroscopy to
be the 3-methylindole 6a. This was an interesting
observation, since the cyclisation of amino ketones to
indoles usually takes place under strongly acidic conditions.
The absence of the corresponding 2-methylindole 7a
indicated that under the reaction conditions chosen no
Bischler rearrangement could occur. With this information
at hand the conditions could be adjusted to yield the indole
6a in 74% yield, using molar equivalent amounts of all the
reagents and reactants resulting in an efficient, shortened
route to 6a.
1-propanol or ethylene glycol showed a significant decrease
in the reaction times and increase in the yields, in examples
incorporating less reactive, electron withdrawing aryl
groups. A change of the ratio of the reactants and reagents
would not only result in a shift of the equilibrium but also a
change of pH, which plays an important role in the reaction.
By use of excess amine 1 and/or sodium bicarbonate a basic
pH is maintained throughout the reaction and this inhibits
cyclisation and produces mostly the uncyclised intermediates
3. If, on the other hand insufficient base is added to the
reaction mixture to neutralise the released HBr completely,
a moderate amount of the 2-arylindole 7 is produced.
Therefore, it is important to maintain a neutral pH. An
excess of the haloketone 2 had a positive effect on the rate
and the yield of the reaction, but it also led to a new by-
product, the N-substituted indole 8. Because of this the
excess of 2 was reduced to a minimum of 1.05 mequiv,
giving good yields of 6.
A similar observation was made for the reaction of 3,5-
dimethoxyaniline 1 with ethyl 4-chloroacetoacetate 2b. A
reaction period of 3 h led to crude anilinoketone 3b, which
was converted with acetic anhydride to the N-acetyl
compound 4b, which was cyclised in trifluoroacetic acid
to the N-acetylindole 5b in an overall yield of 30%:
hydrolysis with ethanolic potassium hydroxide gave indole
6b in 70% yield. In contrast, a reflux period of 8 h in the
initial step directly led to isolation of indole 6b in 30%
yield.
2.3. Comparison of the four-step procedure and the
one-pot reaction
The lithium bromide templated one-pot synthesis can be
alternatively used to synthesise a variety of different
3-substituted 4,6-dimethoxyindoles 6. Depending on the
reactivity of the substituent different alcohols had to be
chosen as the solvent and also adjustments of the ratios of
the reagents had to be made. Overall it was found to be a
quicker, less labour-intensive and better yielding procedure
than the four-step-procedure, especially for alkyl-substi-
tuted indoles as can be seen from Table 1.
The one-pot method was also applied to the preparation of
the 2-benzylindole 6c, and the 3-arylindoles 6d–f. Indole 6f
was also prepared by the stepwise process and intermediate
compounds isolated and characterised.
Lithium bromide, being a crucial reagent, is assumed not
only to exchange with the chloro group to facilitate the
formation of the anilinoketone but also to act as a Lewis acid
to allow cyclisation without rearrangement at neutral
conditions and moderate temperatures.
3. Conclusions
Next, the scope and limitations of the lithium-mediated one-
pot reaction were investigated. Depending on the reactivity
of the desired substituent at C3 of the indole the conditions
(temperature and ratio of the reactants and reagents) had to
be slightly modified. Higher boiling solvents such as
The synthesis of activated indoles based on electron-rich
arenes, e.g. dimethoxyanilines, can be achieved in a one-pot
process by a direct cyclisation of an arylaminoketone, in the
presence of lithium bromide and under essentially neutral
conditions.

K. Pchalek et al. / Tetrahedron 61 (2005) 77–82
79
Table 1. Comparison of four-step and one-pot reaction
Reaction time (h) Overall yield (%)
Four-step One-pot
was removed under reduced pressure to yield an oil, which
was dissolved in trifluoroacetic acid (20 mL). The solution
was refluxed for 1 h after which ice/water was added and the
resulting solid was filtered off. The precipitate was washed
with water until neutral, dried and recrystallised from
ethanol resulting in N-acetyl-4,6-dimethoxy-3-methylindole
5a as a white solid (3.9 g, 70%), mp 144–145 8C (ethanol)
(Found: C, 65.7; H, 6.3; N, 5.9. C13H15NO3$0.25 H2O
requires C, 65.7; H, 6.6; N, 5.9%). nmax: 1750, 1710, 1660,
1560, 1500, 1270, 1200 cmK1. 1H NMR spectrum (CDCl3):
d 2.35 (d, JZ1.5 Hz, 3H, Me), 2.52 (s, 3H, COMe), 3.84 and
3.86 (2s, 6H, OMe), 6.33 (d, JZ2.0 Hz, 1H, H5), 6.85 (d,
JZ1.0 Hz, 1H, H2), 7.65 (d, JZ2.0 Hz, 1H, H7). 13C NMR
spectrum (CDCl3): d 12.28 (Me), 23.95 (COMe), 55.20 and
55.66 (OMe), 92.92 (C5), 95.12 (C7), 119.39 (C2), 114.60,
118.76, 137.82, 154.46, 159.46 (C Ar), 168.57 (C]O).
Mass spectrum (EI): m/z 234 (MC1, 15%), 233 (M, 80),
191 (100), 190 (25), 176 (90).
Four-step
One-pot
6a
6b
6c
6d
6e
6f
9a
6
9
12
18
5
22
14
N/A
74
30
9a
N/A
61
65b
75b
29
23a
57
26
9.5a
12
a Plus four work-ups.
b Plus 5–10% of 2-substituted isomers 7 and 10–15% of N-substituted
indoles 8.
4. Experimental
4.1. General
Melting points were measured using a Mel-Temp melting
point apparatus, and are uncorrected. Microanalyses were
performed on a Carlo Erba Elemental Analyser EA 1108 at
the Campbell Microanalytical Laboratory, University of
Otago, New Zealand. 1H and 13C NMR spectra were
obtained on a Bruker DPX300 (300 MHz) spectrometer.
Mass spectra were recorded on either a Bruker FT-ICR MS
(EI) or a Micromass ZQ2000 (ESI) at UNSW, or a
Shimadzu LCMS QP 8000 (ESI) at the University of
Otago, New Zealand. Infrared spectra were recorded with a
Thermo Nicolet 370 FTIR Spectrometer using KBr discs.
Ultraviolet–visible spectra were recorded using a Varian
Cary 100 Scan Spectrometer. Column chromatography was
carried out using Merck 230–400 mesh ASTM silica gel.
The N-acetylindole 5a (2.0 g, 8.6 mmol) was partially
dissolved in ethanol (50 mL). An excess of crushed
potassium hydroxide was added to the above mixture and
allowed to stir for 2 h. The resulting precipitate was filtered
off and the solvent was removed from the filtrate, both solids
were combined to yield 4,6-dimethoxy-3-methylindole 6a
as a light tan solid (1.5 g, 90%), mp 72–73 8C (lit.5 mp 73–
1
74 8C). H NMR spectrum (CDCl3): d 2.46 (d, JZ1.0 Hz,
3H, Me), 3.83 and 3.89 (2s, 6H, OMe), 6.21 (d, JZ2.0 Hz,
1H, H5), 6.37 (d, JZ1.0 Hz, 1H, H7), 6.67–6.68 (m, 1H,
H2), 7.69 (bs, 1H, NH). 13C NMR spectrum (CDCl3): d
11.98 (Me), 55.12, 55.51 (OMe), 86.81 (C5), 91.22 (C7),
118.84 (C2), 112.02, 112.69, 138.00, 155.43, 157.36 (C Ar).
4.1.1. 4,6-Dimethoxy-3-methylindole (6a). Method A
(stepwise). A mixture of 3,5-dimethoxyaniline 1 (10.0 g,
65.3 mmol), chloroacetone 2a (6.11 g, 66.0 mmol), sodium
hydrogen carbonate (11.0 g, 130.6 mol) and lithium bro-
mide (8.5 g, 98.0 mmol) in absolute ethanol (100 mL) was
heated under reflux for 3 h with stirring. After cooling, the
resulting precipitate was filtered off and washed with water
to give 1-(3,5-dimethoxyphenylamino)-propan-2-one 3a
(9.6 g, 70%) as a white solid, mp 92–94 8C (ethanol)
(Found: C, 63.2; H, 7.1; N, 6.7. C11H15NO3 requires C, 63.1;
H, 7.2; N, 6.7%). nmax: 3400, 1720, 1620, 1590, 1510, 1510,
1480, 1266, 1210, 1170, 1160 cmK1. lmax (MeOH): 222 nm
Method B (one-pot). 3,5-Dimethoxyaniline 1 (2.00 g,
13.1 mmol), chloroacetone 2a (1.03 mL, 13.1 mmol),
NaHCO3 (1.09 g, 13.1 mmol) and LiBr (1.10 g,
13.1 mmol) were partially dissolved in EtOH (36 mL) and
refluxed for 6 h. The solvent was evaporated and the crude
residue extracted with CH2Cl2 (40 mL). The extract was
washed with water (3!20 mL), dried (MgSO4) and
evaporated to give a yellow-green solid (2.62 g), which
was purified by column chromatography (CH2Cl2/light
petroleum, 9:1), yielding indole 6a as a yellow solid
(1.84 g, 74%), mp 72–74 8C (lit.5 73–74 8C).
1
(3 16,200 cmK1 MK1), 236 (7500), 246 (8300). H NMR
spectrum (CDCl3): d 2.20 (s, 3H, Me), 3.32 (s, 6H, OMe),
3.93 (s, 2H, CH2), 4.57 (bs, 1H, NH), 5.75 (d, JZ2.0 Hz,
2H, H2, H6), 5.88 (t, JZ2.0 Hz, 1H, H4). 13C NMR
spectrum (CDCl3): d 27.20 (Me), 54.06 (CH2), 55.03
(OMe), 90.09 (C4), 91.64 (C2, C6), 148.70, 161.73 (C
Ar), 203.80 (C]O). Mass spectrum (EI): m/z 210 (MC1,
15%), 209 (M, 60), 167 (20), 166 (100), 138 (20).
4.1.2. Ethyl (4,6-dimethoxyindol-3-yl)acetate (6b).
Method A (stepwise). A mixture of 3,5-dimethoxyaniline 1
(5.00 g, 32.6 mmol), ethyl 4-chloroacetoacetate 2b (5.4 g,
32.6 mmol), sodium hydrogen carbonate (5.5 g, 65.3 mmol)
and LiBr (4.25 g, 44.0 mmol) in absolute ethanol (50 mL)
was heated under reflux for 3 h with stirring. After cooling,
water was added to the reaction mixture, which was
extracted with dichloromethane, dried and concentrated to
yield the crude amino ketone 3b as a dark golden oil, which
was then dissolved in acetic anhydride (10 mL) and stirred
at room temperature for 3 h. Water (1 mL) was added and
the solution was warmed to 50–60 8C. Water was then added
slowly so that the temperature did not drop below 50 8C
until the volume was tripled. Stirring was continued until the
solution returned to room temperature. The solution was
then extracted with ethyl acetate. The organic phase was
washed with water until neutral, saturated sodium hydrogen
carbonate solution, saturated brine solution and dried
The anilino ketone 3a (5.0 g, 23.9 mmol) was partially
dissolved in acetic anhydride (10 mL) and stirred at room
temperature for 3 h. Water (1 mL) was added and the
solution was warmed to 50–60 8C. Water was then added
slowly so that the temperature did not drop below 50 8C
until the volume was tripled. Stirring was continued until the
solution returned to room temperature. The solution was
then extracted with ethyl acetate, the extract washed with
water until neutral, saturated sodium hydrogen carbonate
solution, saturated brine and dried (Na2SO4). The solvent

80
K. Pchalek et al. / Tetrahedron 61 (2005) 77–82
(Na2SO4). The solvent was removed under reduced pressure
to yield the crude protected anilinoketone, which was then
dissolved in trifluoroacetic acid (10 mL). The solution was
refluxed for 1 h after which ice/water was added and the
resulting solid was filtered off and purified by chromato-
graphy (silica plug) and recrystallisation from ethanol to
yield ethyl N-acetyl-4,6-dimethoxyindole-3-acetate 5b as a
light tan solid (3.00 g, 30%), mp 106–107 8C (ethanol).
nmax: 1730, 1695, 1600, 1590, 1570, 1410, 1280, 1200,
228 nm (3 13,500), 271 (3800), 475 (600). 1H NMR
spectrum (300 MHz, CDCl3): d 3.82 (s, 6H, OMe), 4.24
(s, 2H, CH2), 6.19 (d, JZ1.5 Hz, 1H, H5), 6.40 (d, JZ
1.9 Hz, 1H, H7), 6.53 (d, JZ1.1 Hz, 1H, H2), 7.15–7.30 (m,
5H, Ph), 7.72 (s, 1H, NH). 13C NMR spectrum (75 MHz,
CDCl3): d 32.9 (CH2), 55.0 (OMe), 55.5 (OMe), 86.7 (C5),
91.5 (C7), 112.1, 116.6, 119.5 (C2), 125.4 (CH Ph), 128.0
(CH Ph), 128.8 (CH Ph), 138.0, 142.4, 155.2, 157.5. Mass
spectrum (ES): m/z (%) 267.1 (100, MC), 252.1 (39), 190.1
(49), 132.1 (20).
1
1160 cmK1. H NMR spectrum (CDCl3): d 1.25 (t, JZ
7.1 Hz, 3H, CH2Me), 2.55 (s, 3H, COMe), 3.79 (d, JZ
3.3 Hz, 2H, CH2), 3.80 and 3.84 (2s, 6H, OMe), 4.17 (q,
JZ7.1 Hz, 2H, CH2Me), 6.31 (d, JZ1.9 Hz, 1H, H5), 6.71
(s, 1H, H2), 7.63 (d, JZ1.9 Hz, 1H, H7). Mass spectrum
(EI): m/z 306 (MC1, 5%), 305 (M, 50), 263 (45), 190 (100).
4.1.4. 2-4,6-Dimethoxy-3-phenylindole (6d) and 2-(4,6-
di-methoxy-3-phenylindol-1-yl)-1-phenylethanone (8d).
A mixture of 3,5-dimethoxyaniline 1 (1.0 g, 6.53 mmol),
2-bromoacetophenone 2d (1.62 g, 8.16 mmol), LiBr
(0.57 g, 6.53 mmol) and NaHCO3 (0.55 g, 6.53 mmol) in
1-propanol (25 mL) was refluxed overnight. The solvent
was removed in vacuo, the residue extracted into CH2Cl2
(25 mL) and washed with water (3!15 mL). The combined
organic layers were dried over MgSO4 and the solvent
removed under reduced pressure. The resulting product
mixture was separated by column chromatography on silica
gel (CH2Cl2) yielding compound 8d as yellow crystals
(0.36 g, 15%) in the first band, mp 54–56 8C. (Found: C,
77.8; H, 5.8; N, 3.6. C24H21NO3 requires C, 77.6; H, 5.7; N,
3.8%). nmax (KBr): 3427, 1699, 1600, 1501, 1450, 1340,
1219, 1201, 1144, 1060, 757, 690 cmK1. lmax (CH2Cl2):
237 nm (3 38,000), 248 (10,000). 1H NMR (300 MHz,
CDCl3): d 3.80 (s, 6H, OMe), 5.36 (s, 2H, CH2), 6.25 (s, 1H,
H5), 6.29 (s, 1H, H7), 6.88 (s, 1H, H2), 7.23–7.28 (m, 1H,
Ph), 7.34–7.39 (m, 2H, Ph), 7.47–7.53 (m, 2H, Ph), 7.62–
7.64 (m, 3H, Ph), 7.98–8.00 (m, 2H, Ph). 13C NMR
(75 MHz, CDCl3): d 52.4 (CH2), 55.1 (OMe), 55.6 (OMe),
85.3 (C7), 92.2 (C5), 110.9, 118.7, 125.0 (C2), 125.6 (CH
Ph), 127.4 (CH Ph), 128.0 (CH Ph), 128.9 (CH Ph), 129.5
(CH Ph), 133.9 (CH Ph), 134.7, 135.8, 139.1, 155.1, 157.7,
192.9 (CO). Mass spectrum (ES): m/z (%) 371.1 (47, MC),
266.1 (100), 250.1 (36).
The N-acetylindole 5b (2.00 g, 6.6 mmol) was partially
dissolved in ethanol (20 mL). Crushed KOH (0.26 g,
6.6 mmol) was added to the above mixture which was
allowed to stir for 2 h. The resulting precipitate was filtered
off to yield ethyl (4,6-dimethoxyindol-3-yl)acetate 6b as a
light tan solid (1.21 g, 70%), mp 105–106 8C (ethanol)
(Found: C, 60.8; H, 6.1; N, 5.1. C14H17O4N.0.65 H2O
requires C, 61.1; H, 6.7; N, 5.1%). nmax: 3360, 1725, 1362,
1585, 1550, 1510, 1390, 1335, 1260, 1200 cmK1. lmax
:
225 nm (3 21,900 cmK1 MK1), 269 (4900). 1H NMR
spectrum (CDCl3): d 1.27 (t, JZ7.1 Hz, 3H, CH2Me),
3.79 and 3.82 (2s, 6H, OMe), 3.87 (s, 2H, CH2), 4.18 (q, JZ
7.1 Hz, 2H, CH2Me), 6.15 (d, JZ1.5 Hz, 1H, H5), 6.36 (d,
JZ1.5 Hz, 1H, H7), 6.82 (d, JZ1.5 Hz, 1H, H2), 7.97 (bs,
1H, NH). 13C NMR spectrum (CDCl3): d 14.25 (CH2Me),
32.50 (CH2Me), 54.96, 55.50 (OMe), 60.37 (CH2), 86.75
(C5), 91.43 (C7), 120.29 (C2), 108.65, 111.91, 137.67,
154.72, 157.49 (C Ar), 172.92 (C]O). Mass spectrum (EI):
m/z 264 (MC1, 5%), 263 (M, 40), 190 (100), 160 (35), 145
(30).
Method B (one-pot): A mixture of 3,5-dimethoxyaniline 1
(2.00 g, 13.1 mmol), ethyl-4-chloroacetoacetate 2b
(1.85 mL, 13.7 mmol), NaHCO3 (1.10 g, 13.1 mmol) and
LiBr (1.14 g, 13.1 mmol) was refluxed in EtOH (60 mL) for
8 h, the solvent evaporated and the crude residue extracted
with CH2Cl2 (40 mL). The extract was washed with water
(3!20 mL), dried (MgSO4) and evaporated to give a
brown-green solid, which was purified by column chroma-
tography (CH2Cl2/MeOH, 98:2), yielding indole 6b as a
yellow solid (1.03 g, 30%), mp 102–104 8C.
The second band eluted from the column yielded 6d as a
brown powder (1.08 g, 65%), mp 57–59 8C (lit.7 58 8C). 1H
NMR (300 MHz, CDCl3): d 3.86 (s, 6H, OMe), 6.34 (d, JZ
2.0 Hz, 1H, H5), 6.45 (d, JZ2.0 Hz, 1H, H7), 6.97 (d, JZ
2.1 Hz, 1H, H2), 7.32–7.72 (m, 5H, Ph), 8.07 (br s, 1H, NH).
4.1.5. 3-(4-Chlorophenyl)-4,6-dimethoxyindole (6e) and
1-(4-chlorophenyl)-2-[3-(4-chlorophenyl)-4,6-di-methoxy-
indol-1-yl]ethanone (8e). A mixture of 3,5-dimethoxyani-
line 1 (1.0 g, 6.53 mmol), 2-bromoacetophenone 2e (1.9 g,
8.14 mmol), LiBr (0.57 g, 6.53 mmol) and NaHCO3
(0.55 g, 6.53 mmol) in 1-propanol (25 mL) was refluxed
overnight. The solvent was evaporated in vacuo, the residue
extracted into CH2Cl2 (25 mL) and washed with water (3!
15 mL). The combined organic layers were dried (MgSO4)
and the solvent removed under reduced pressure. The
resulting product mixture was separated by column
chromatography on silica gel (CH2Cl2/light petroleum,
7:3) yielding indole 8e as yellow crystals (0.35 g,
0.80 mmol, 12%) in the first band, mp 74–76 8C. (Found:
C, 65.5; H, 4.4; N, 3.2. C24H19Cl2NO3 requires C, 65.5; H,
4.4; N, 3.2%). nmax (KBr): 3406 (br), 2933, 2838 (w), 1700,
4.1.3. 3-Benzyl-4,6-dimethoxyindole (6c). A suspension of
3,5-dimethoxyaniline 1 (1.73 g, 11.3 mmol), 1-chloro-3-
phenylpropan-2-one 2c (2.00 g, 11.9 mmol), NaHCO3
(0.95 g, 11.3 mmol) and LiBr (0.98 g, 11.3 mmol) in
1-propanol (25 mL) was refluxed for 16 h. The mixture
was cooled to room temperature and the precipitated salts
filtered off. The remaining solution was concentrated to
about one quarter of its volume and kept at room
temperature for some time before filtration of the crude
product. It was purified by column chromatography
(CH2Cl2), yielding indole 6c as a pale brown solid
(1.85 g, 61%), mp 114–116 8C (Found: C, 76.5; H, 6.5; N,
5.2. C17H17Cl2NO2 requires C, 76.4; H, 6.4; N, 5.2%). nmax
(KBr): 3369, 1619, 1590, 1510, 1459, 1221, 1201, 1155,
1138, 1081, 938, 813, 740, 715 cmK1. lmax (CH2Cl2):
1588, 1545, 1335, 1217 (s), 1146, 1092, 1060, 834 cmK1
lmax (CH2Cl2): 248 nm (3 34,000). 1H NMR spectrum
.

K. Pchalek et al. / Tetrahedron 61 (2005) 77–82
81
(300 MHz, DMSO-d6): d 3.71 (s, 3H, OMe), 3.75 (s, 3H,
OMe), 5.83 (s, 2H, CH2), 6.24 (d, JZ1.5 Hz, 1H, H5), 6.62
(d, JZ1.5 Hz, 1H, H7), 7.19 (s, 1H, H2), 7.36 (d, JZ8.7 Hz,
2H, Ar), 7.51 (d, JZ8.7 Hz, 2H, Ar), 7.67 (d, JZ8.7 Hz,
2H, Ar), 8.09 (d, JZ8.7 Hz, 2H, Ar). 13C NMR spectrum
(75 MHz, DMSO-d6): d 52.5 (CH2), 55.1 (OMe), 55.6
(OMe), 85.0 (C5), 92.3 (C7), 117.8, 124.7 (C2), 127.5 (CH
Ar), 129.3 (CH Ar), 129.4 (CH Ar), 130.1, 130.6 (CH Ar),
131.5, 132.8, 134.1, 139.0, 140.6, 155.0, 157.9, 191.7 (CO).
Mass spectrum (ES): m/z (%) 440.95 (36), 438.96 (50, MC),
302.05 (35), 300.06 (100).
2H, ArOH), 7.83 (d, JZ8.7 Hz, 2H, ArOH), 10.43 (br s, 1H,
OH). 13C NMR spectrum (75 MHz, DMSO-d6): d 22.3
(Me), 55.7 (CH2), 55.8 (OMe), 99.8 (CH), 106.4 (CH),
115.7 (CH), 126.8, 130.8 (CH), 145.6, 161.1, 162.8, 169.5,
192.5. Mass spectrum (EI): m/z (%) 329 (7, MC), 208 (17),
166 (100), 121 (93).
A solution of N-acetylanilino ketone 4f (5.0 g, 15.2 mmol)
in TFA (25 mL) was stirred at room temperature for 1.5 h. A
green ppt formed after quenching with ice/water (100 mL),
which was filtered off and washed with water until rinsings
were neutral. Recrystallisation from EtOH yielded N-acetyl-
4,6-dimethoxy-3-(4-hydroxyphenyl)indole 5f as a pale grey
solid (3.89 g, 12.5 mmol, 83%), mp 210–212 8C. nmax
(KBr): 3252, 1681, 1574, 1508, 1426, 1310, 1208, 1167,
1042, 966, 825, 688 cmK1. lmax (MeOH): 209 nm (3
41,500), 252 (31,600), 319 (7100). (Found: C, 69.2; H,
5.6; N, 4.5. C18H17NO4 requires C, 69.4; H, 5.5; N, 4.5%).
1H NMR spectrum (300 MHz, DMSO-d6): d 2.61 (s, 1H,
COMe), 3.71 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.46 (d, JZ
1.9 Hz, 1H, H5), 6.75 (d, JZ8.3 Hz, 2H, ArOH), 7.35 (d,
JZ8.3 Hz, 2H, ArOH), 7.47 (s, 1H, H2), 7.63 (d, JZ1.9 Hz,
1H, H7), 9.34 (s, 1H, OH). 13C NMR spectrum (75 MHz,
DMSO-d6): d 24.4 (COMe), 55.6 (OMe), 55.8 (OCH3), 93.2
(C5), 95.5 (C7), 112.3, 114.8 (CH Ar), 122.0 (C2), 123.0,
125.1, 130.8 (CH Ar), 137.8, 154.2, 156.8, 159.2, 170.0
(CO). Mass spectrum (EI): m/z (%) 311 (18, MC), 269 (20),
254 (40), 69 (50), 43 (100).
The second band eluted from the column yielded indole 6e a
pale yellow solid (1.40 g, 75%), mp 188–190 8C (lit.7 185–
187 8C). H NMR spectrum (300 MHz, CDCl3): d 3.80 (s,
1
3H, OMe), 3.85 (s, 3H, OMe), 6.27 (d, JZ1.9 Hz, 1H, H5),
6.49 (d, JZ1.9 Hz, 1H, H7), 6.99 (d, JZ2.6 Hz, 1H, H2),
7.32 (d, JZ8.6 Hz, 2H, Ar), 7.53 (d, JZ8.6 Hz, 2H, Ar),
8.08 (br s, 1H, NH).
4.1.6. 4,6-Dimethoxy-3-(4-hydroxyphenyl)indole (6f).
Method A (stepwise). A mixture of 3,5-dimethoxyaniline 1
(10.0 g, 66.6 mmol), 4-hydroxyacetophenone9 2f (15.0 g,
69.0 mmol) and NaHCO3 (5.6 g, 66.6 mmol) in MeOH
(160 mL) was refluxed for 3 h. A yellow precipitate was
obtained after cooling to room temperature and was filtered
off and washed with water (30 mL). Recrystallisation from
EtOH yielded 2-(3,5-dimethoxyphenylamino)-1-(4-hydroxy-
phenyl)ethanone 3f as a white powder (10.4 g, 36.2 mmol,
56%), mp 166–168 8C. (Found: C, 66.6; H, 6.1; N, 4.9.
C16H17NO4 requires C, 66.9; H, 6.0; N, 4.9%). nmax (KBr):
3456, 3405, 1667, 1626, 1579, 1518, 1315, 1254, 1209,
1195, 1168, 1158, 1072, 961, 809, 799, 676, 591 cmK1. lmax
(MeOH): 219 nm (3 32,500), 278 (18,600). 1H NMR
spectrum (300 MHz, DMSO-d6): d 3.63 (s, 6H, OMe),
4.49 (d, JZ5.3 Hz, 2H, CH2), 5.69–5.74 (m, 2H, NH and
H40), 5.87 (d, JZ1.5 Hz, 2H, H20 and H60), 6.86 (d, JZ
9.3 Hz, 2H, ArOH), 7.94 (d, JZ9.3 Hz, 2H, ArOH), 10.37
(br s, 1H, OH). 13C NMR spectrum (75 MHz, DMSO-d6):
49.8 (CH2), 55.2 (OMe), 89.3, 91.8 (CH), 115.7 (CH),
127.0, 130.8 (CH), 150.3, 161.5 (CH), 162.7, 194.8 (CO).
Mass spectrum (EI): m/z (%) 287 (25, MC), 166 (100), 122
(42).
A suspension of N-acetylindole 5f (3.40 g, 10.9 mmol) and
KOH (2.5 g, 44.6 mmol) in MeOH (55 mL) was stirred for
3 h, followed by the addition of aqueous HCl solution (5 M,
8–10 mL) until no further precipitation was observed. The
salts were filtered off, the solvent removed under reduced
pressure, the remaining mixture diluted with CH2Cl2
(50 mL), and washed with water (3!20 mL). The organic
layer was dried with MgSO4 and the solvent removed in
vacuo. The crude product was flash chromatographed
(CH2Cl2/MeOH, 96:4) and recrystallised in EtOH to yield
indole 6f as a pale yellow solid (2.01 g, 7.47 mmol, 69%),
mp 212–214 8C.
Method B (one-pot). A mixture of 3,5-dimethoxyaniline 1
(1.02 g, 6.66 mmol), 4-hydroxyphenacylbromide 2f (1.50 g,
6.98 mmol), NaHCO3 (0.56 g, 6.66 mmol) and LiBr
(0.58 g, 6.66 mmol) in 1-propanol (20 mL) was refluxed
for 12 h. The mixture was cooled to room temperature and
the precipitated salts filtered off. The remaining solution
was concentrated to about one quarter of its volume and
kept at room temperature for 3 h, after which the crude
product was filtered off. It was purified by column
chromatography (CH2Cl2/MeOH, 96:4), yielding indole 6f
as pale brown needles (0.52 g, 29%), mp 210–212 8C. nmax
(KBr): 3443, 3334, 1541, 1501, 1320, 1199, 1161, 1149,
1041, 838, 811, 550 cmK1. lmax (MeOH): 231 nm (3
27,000), 261 (13,500). (Found: C, 70.4; H, 5.7; N, 5.1.
C16H15NO3$(1/4)H2O requires C, 70.2; H, 5.7; N, 5.1%). 1H
NMR spectrum (300 MHz, DMSO-d6): d 3.70 (s, 3H, OMe),
3.74 (s, 3H, OMe), 6.14 (d, JZ1.9 Hz, 1H, H5), 6.47 (d, JZ
1.9 Hz, 1H, H7), 6.69 (dd, JZ6.4, 1.9 Hz, 2H, Ar), 7.00 (d,
JZ2.3 Hz, 1H, H2), 7.29 (dd, JZ6.4, 1.9 Hz, 2H, Ar), 9.09
(br s, 1H, OH), 10.89 (br s, 1H, NH); 13C-NMR spectrum
(75 MHz, DMSO-d6): d 55.2 (OMe), 55.5 (OMe), 87.6 (C5),
A solution of anilinoketone 3f (10.0 g, 34.8 mmol) in acetic
anhydride (50 mL) was stirred at room temperature for 3 h,
after which water (10 mL) was added, the solution heated to
50–60 8C and kept at this temperature, while more water
(150 mL) was added. The mixture was cooled to room
temperature, extracted with EtOAc (40 mL), and washed
with water (2!25 mL), saturated aqueous NaHCO3 (2!
25 mL) and brine (2!25 mL). The organic layer was dried
(MgSO4) and the solvent evaporated under reduced
pressure. Recrystallisation from EtOH yielded 2-(N-
acetyl-3,5-dimethoxyphenylamino)-1-(4-hydroxyphenyl)
ethanone 4f as a white solid (9.5 g, 28.8 mmol, 82%), mp
186–188 8C. (Found: C, 65.5; H, 6.0; N, 4.1. C18H19NO5
requires C, 65.6; H, 5.8; N, 4.3%). nmax (KBr): 3178, 1696,
1608, 1578, 1425, 1341, 1242, 1192, 1156, 1154, 1078, 981,
849, 702, 561 cmK1. lmax (MeOH): 218 nm (3 22,000), 278
(18,000). 1H NMR spectrum (300 MHz, DMSO-d6): d 1.89
(s, 1H, COMe), 3.72 (s, 6H, OMe), 4.98 (s, 2H, CH2), 6.46
(s, 1H, H40), 6.53 (s, 2H, H20 and H60), 6.84 (d, JZ8.7 Hz,

82
K. Pchalek et al. / Tetrahedron 61 (2005) 77–82
2. Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970.
91.8 (C7), 110.2, 114.7 (CH Ar), 117.3, 120.8 (C2), 127.6,
130.3 (CH Ar), 138.8, 154.6, 155.5, 156.8. Mass spectrum
(EI): m/z (%) 269 (100, MC), 254 (48), 211 (20).
3. Magnus, P.; Mitchell, I. S. Tetrahedron Lett. 1998, 39,
4595–4598.
4. Hall, R. J.; Shannon, P. V. R.; Oliveira-Campos, A. M. F.;
Queiroz, M. J. R. P. J. Chem. Res., Synop. 1992, 2–3.
5. Black, D. S. C.; Rothnie, N. E.; Wong, L. C. H. Aust. J. Chem.
1983, 36, 2407–2412.
Acknowledgements
Financial support from the Australian Research Council is
gratefully acknowledged. K.P. also acknowledges receipt of
an International Postgraduate Research Scholarship.
6. Black, D. S. C.; Kumar, N.; Wong, L. C. H. Aust. J. Chem. 1986,
39, 15–20.
7. Black, D. S. C.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.;
Kim, M.; Kumar, N.; McConnell, D. B.; Popiolek, M. Aust.
J. Chem. 1994, 47, 1741–1750.
8. Brown, R. K. Indoles Part One; Wiley-Interscience: New York,
1972.
References and notes
9. Malik, M. L.; Grover, S. K. Indian J. Chem., Sect. B: Org.
Chem. Include. Med. Chem. 1976, 14B, 513–515.
1. Sundberg, R. J. Indoles; Academic Press: New York, 1996.