Bromination of 4,6-dimethoxyindoles

Article abstract of DOI:10.1016/j.tet.2012.07.077

The bromination of activated 4,6-dimethoxyindoles can be carried out effectively provided that an electron-withdrawing group is also present. Thus the range of products includes 2-bromo-7-formyl or 2-bromo-7-acetylindoles 13a-c and 16, 7-bromo-2-acetylind

Full text of DOI:10.1016/j.tet.2012.07.077

Tetrahedron 68 (2012) 8163e8171
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Tetrahedron
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Bromination of 4,6-dimethoxyindoles
Peter S.R. Mitchell, Ibrahim F. Sengul, Hakan Kandemir, Stephen J. Nugent, Rui Chen,
*
Paul K. Bowyer, Naresh Kumar, David StC. Black
School of Chemistry, University of New South Wales, UNSW, Sydney NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2012
Received in revised form 23 June 2012
Accepted 23 July 2012
Available online 31 July 2012
The bromination of activated 4,6-dimethoxyindoles can be carried out effectively provided that an
electron-withdrawing group is also present. Thus the range of products includes 2-bromo-7-formyl or 2-
bromo-7-acetylindoles 13aec and 16, 7-bromo-2-acetylindole 21, 2,5-dibromo-7-acetylindole 17, 2,5-
dibromo-N-sulfonylindole 27, and 2,7-dibromo-N-acetylindole 24. Acetyl and sulfonyl protecting
groups on nitrogen can be removed to give 2-bromoindoles 28aeb, 2,5-dibromoindole 29, and 2,7-
dibromoindole 4.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
No bromination was observed at the equally activated but more
sterically hindered C5 position. However, all our attempts to bro-
Indole itself undergoes bromination under a variety of conditions to
yield 3-bromoindole.1e4 If C3 is substituted, as in the case of 3-
methylindole, then bromination affords 2-bromo-3-methylindole,
and if excess reagent is used some further bromination occurs at C6.1,5
The activated 4,6-dimethoxyindoles are more reactive to electrophilic
substitution and 4,6-dimethoxy-2,3-diphenylindole (1) can be bromi-
nated easily to give the 7-bromo-derivative 2, which is sufficiently
stable to be isolated and characterised fully.6 In this situation, the two
methoxy groups provide a smooth entry into 7-substituted derivatives.
minate 4,6-dimethoxy-3-phenylindole 3a have led to complex
mixtures of products and the only identified compound was a trace
of the 2,7-dibromo-derivative 4, observed when mild bromination
conditions of N-bromosuccinimide in the presence of silica7 were
used. 7-Bromoindole has been prepared in low yields by routes
commencing with the bromine atom already present in an arene. 3-
Bromo-2-nitrotoluene reacts with ethyl oxalate to give a glyoxylic
ester that can be reductively cyclised to give 7-bromoindole-2-
carboxylic acid, and decarboxylation gave 7-bromoindole in an
overall yield of 19%.8 Alternatively, 2-bromoaniline reacts with
chloracetonitrile and the resulting ketone can be reductively
cyclised to 7-bromoindole in a 32% yield for the sequence.9 We have
made some attempts to generate 7-bromo-4,6-dimethoxyindoles
by similar cyclisation routes. In an attempt to produce 2-bromo-
3,5-dimethoxyaniline as a starting material for a cyclisation route,
3,5-dimethoxyaniline 5 was first protected with an excess of formic
acid in order to avoid the formation of the hydrobromide salt
product. Bromination of the resulting formanilide 6 was then car-
ried out using a variety of different conditions, such as bromine in
dichloromethane at ꢀ78 ꢁC, trimethylphenylammonium tri-
bromide in tetrahydrofuran, and bromine in acetic acid at room
temperature. All these conditions generated the desired 2-
bromophenylformanilide 7 in up to only 20% yield and the un-
desired 4-bromoformanilide 8 in up to 17% yield after extensive
column chromatography (Scheme 1). The poor yield of 2-
bromoformanilide 7 was clearly not satisfactory to pursue this
route any further.
MeO
R
Ph
Ph
MeO
N
MeO
MeO
H
R
1
2
R = H
N
H
MeO
R = Br
3a R = H
MeO
Ph
3b R = Me
3c R = Et
Br
N
H
Br
Given the high reactivity of 4,6-dimethoxyindoles, it became
clear that successful bromination would require less reactive
structures, namely those activated indoles that also contained an
electronwithdrawing group. This general principle has already been
established for the successful nitration of activated indoles.10,11
4
* Corresponding author. E-mail address: d.black@unsw.edu.au (D.StC. Black).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.077

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P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
2. Results and discussion
Deactivation of the 4,6-dimethoxyindoles was achieved by the
attachment of formyl and acetyl groups at C7, an acetyl group at C2,
and acetyl and phenylsulfonyl groups at N1.
2.1. Preparation of 3-arylindoles 3aec
4,6-Dimethoxy-3-phenylindole (3a)12,13 and 4,6-dimethoxy-3-
(4-tolyl)indole (3b)14 have already beenreported. 4,6-Dimethoxy-3-
(4-ethylphenyl)indole (3c) was prepared by the standard route.13
The dimethoxyphenylaminoketone 9 was prepared from 3,5-
dimethoxyaniline (5) and 4-ethylphenacyl bromide, and sub-
sequently acetylated at nitrogen by treatment with acetic anhydride
to give compound 10. This product was cyclised by reaction with
trifluoroacetic acid to give the N-acetylindole 11, which on reaction
with potassium hydroxide yielded the indole 3c (Scheme 2).
Scheme 3. Bromination of 7-formylindoles 12aec. Reagents and conditions: (i) Br2/
HOAc, 13a (91%), 13b (89%), 13c (85%); (ii) NBS/silica/CH2Cl2, 13a (73%), 14a (14%).
2.3. Brominationof7-acetyl-4,6-dimethoxy-3-phenylindole(15)
Bromination of 7-acetyl-4,6-dimethoxy-3-phenylindole (15)
with N-bromosuccinimide in refluxing carbon tetrachloride, either
with or without the radical initiator 2,20-azobisisobutyronitrile,
gave the 2-bromoindole 16 in 61% yield, but also gave the 2,5-
dibromoindole 17 in 6% and 24% yield with and without the radi-
cal initiator, respectively.
The use of N-bromosuccinimide in combination with silica
resulted in a 68% yield of the 2-bromoindole 16. However, reaction
with bromine in acetic acid was the most effective process,
affording the 2-bromoindole 16 in 95% yield. The use of the acetyl
group as an electron withdrawing substituent introduces the pos-
sible problem of brominating the acetyl methyl group. This was not
observed with the reagents discussed so far. However, bromination
of the 7-acetylindole 15 with trimethylphenylammonium tri-
bromide gave the bromomethylindole 18 in 36% yield and the
dibromomethylindole 19 in 10% yield, in addition to the desired 2-
bromoindole 16 in 49% yield (Scheme 4).
Scheme 2. Preparation of indole 3c. Reagents and conditions: (i) 4-ethylphenacyl
bromide/NaHCO3/EtOH, 9 (80%); (ii) Ac2O, 10 (89%); (iii) TFA, 11 (90%); (iv) KOH/
MeOH, 3c (75%).
2.4. Bromination of 2-acetyl-4,6-dimethoxy-3-phenylindole (20)
2.2. Bromination of 3-aryl-7-formyl-4,6-dimethoxyindoles
12aec
The bromination of 2-acetyl-4,6-dimethoxy-3-phenylindole
(20) with a slight excess of bromine in acetic acid was complete
within 30 min and gave the 7-bromoindole 21 in 76% yield together
with the bromomethyl compound 22 in 9% yield (Scheme 5).
Interestingly, the second bromination occurred at the position
The bromination of 3-aryl-7-formyl-4,6-dimethoxyindoles
12aec with a slight excess of bromine in acetic acid afforded the
2-bromoindoles 13aec in 85e91% yield (Scheme 3). No secondary
bromination was observed for this reaction. When the aldehyde
12a was treated with a slight excess of N-bromosuccinimide in the
presence of silica, the bromo compound 13a was obtained in 73%
yield, but secondary bromination was also observed and resulted in
the formation of the 2,5-dibromoindole-7-carbaldehyde 14a in 14%.
This result is significant because reaction at C5 in 4,6-
dimethoxyindoles is particularly rare.
a
to the carbonyl of the acetyl group in preference to C5. The ob-
servance of some bromination at the 2-acetyl group in contrast to
no bromination at the 7-acetyl group under the same conditions is
a reflection on the weaker reactivity of 7-carbonyl substituents
compared with the corresponding 2-carbonyl substituents. Bro-
mination of indole 20 using a slight excess of N-bromosuccinimide
and silica gave only the 7-bromoindole 21 in slightly reduced yield
(70%). No secondary bromination was observed.

P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
8165
2.5. Bromination of N-acetyl-4,6-dimethoxy-3-phenylindole
(23)
The success achieved in obtaining the reasonably controlled
bromination of activated indoles, provided that a moderately
deactivating group was also present, encouraged an investigation of
the bromination of N-substituted indoles. A potential advantage of
such starting materials was the possibility of subsequently re-
moving the nitrogen protecting group to afford simple bro-
moindoles. Reaction of N-acetyl-4,6-dimethoxy-3-phenylindole
(23) with N-bromosuccinimide and silica gave only the 2,7-
dibromo-N-acetylindole 24 in 60% yield and a monobromo com-
pound was never observed, regardless of the stoichiometry
(Scheme 6). Removal of the acetyl group was readily achieved using
methanolic potassium hydroxide to give the 2,7-dibromoindole 4
in 80% yield.
Scheme 4. Bromination of 7-acetylindole 15. Reagents and conditions: (i) NBS/AIBN/
CCl4, 16 (61%), 17 (24%); (ii) NBS/silica/CH2Cl2, 16 (68%); (iii) Br2/HOAc, 16 (95%); iv)
CuBr2/CHCl3/EtOAc, 16 (20%); (v) PhMe3NþBr3, 16 (49%), 18, (36%), 19 (10%).
Scheme 6. Formation of 2,7-dibromoindole 4. Reagents and conditions: (i) NBS/silica/
CH2Cl2, 24 (60%); (ii) KOH/MeOH, 4 (80%).
2.6. Bromination of 3-aryl-4,6-dimethoxy-N-phenylsulfonyl
indoles 25
It was hoped that a larger deactivating group, such as phenyl-
sulfonyl would provide some added regioselectivity to the bromi-
nation reaction. The phenylsulfonyl compounds 25aeb were
readily synthesised from indoles 3aeb, and treated with 1 equiv of
N-bromosuccinimide and silica to give the 2-bromo-N-sulfony-
lindoles 26aeb in 80 and 67% yields, respectively. Treatment of
indole 25a with 2 equiv gave the 2,5-dibromo-N-sulfonylindole 27
in 71% yield (Scheme 7).
Notably the phenylsulfonyl group protected C7 from bromina-
tion. The removal of the phenylsulfonyl group using methanolic
potassium hydroxide afforded the 2-bromoindoles 28aeb and the
2,5-dibromoindole 29 in 92, 66 and 98% yields, respectively. The
bromoindoles were perfectly stable to base and could be obtained
analytically pure. However they rapidly decomposed on treatment
with even traces of acid.
3. Conclusions
The bromination of 4,6-dimethoxyindoles has allowed the
isolation of a range of bromoindoles also containing electron-
withdrawing substituents, such as formyl, acetyl and phenyl-
sulfonyl. Significantly, simple 2-bromo-, 2,5-dibromo-, and
Scheme 5. Bromination of 2-acetylindole 20. Reagents and conditions: (i) Br2/HOAc, 21
(76%), 22 (9%); (ii) NBS/silica/CH2Cl2, 21 (70%).

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P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
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 spectrom-
eter using paraffin mulls or KBr discs. Ultravioletevisible spectra
were recorded using a Varian Cary 100 Scan spectrometer. Column
chromatography was carried out using Merck 230e400 mesh ASTM
silica gel, whilst preparative thin layer chromatography was per-
formed using Merck silica gel 7730 60GF254. Merck 60H silica gel
was employed for ’dry-column’ flash chromatography described by
Harwood.15 Compounds were detected by short and long wave-
length ultraviolet light and with iodine vapour.
4.1.1. 3,5-Dimethoxyphenylformamide (6). 3,5-Dimethoxyaniline 5
(35.0 g, 228 mmol) was heated at reflux in formic acid (>90%) for
4 h. The resulting red solution was allowed to cool to room tem-
perature, then cooled in an ice bath. The solvent was removed
under reduced pressure and the yellow residue chromatographed
through a short silica column (ethanol/chloroform) and the product
recrystallised from dichloromethane/n-hexane to give the title
compound 6 (33.8 g, 82%) as white crystals, mp 82e84 ꢁC (lit.16
84 ꢁC).
4.1.2. N-(2-Bromo-3,5-dimethoxyphenyl)formamide (7) and N-(4-
bromo-3,5-dimethoxyphenyl)formamide (8). To a solution of 3,5-
dimethoxyphenylformamide 6 (1 g, 5.52 mmol) in glacial acetic
acid (10 mL), bromine (0.311 mL, 6.07 mmol) in glacial acetic acid
(5 mL) was added dropwise and the resulting yellow solution was
stirred at room temperature for 1.5 h. The reaction mixture was
poured into ice water and treated with saturated sodium meta-
bisulfite (50 mL). The white precipitate obtained was filtered and
purified by column chromatography (dichloromethane/ethyl ace-
tate (70:30)) to give 2-bromo-3,5-dimethoxyphenylformamide 7
(0.286 g, 20%) and 4-bromo-3,5-dimethoxyphenylformamide
8
(0.25 g, 17%) as white powders.
(i)
107e108 ꢁC; nmax (KBr) 3256, 1637, 1592, 1529, 1342, 1152, 1071,
848 cmꢀ1 35,000 cmꢀ1 ꢀ1), 289 (2700).
lmax (MeOH) 218 nm (
1H NMR (300 MHz, DMSO-d6):
3.74 (3H, s, OMe), 3.81 (3H, s,
OMe), 6.47 (1H, d, J 2.7 Hz, H4), 7.41 (1H, d, J 2.74 Hz, H6), 8.33 (1H,
s, CHO), 9.58 (1H, bs, NH); 13C NMR (75 MHz, DMSO-d6):
55.8, 56.8
N-(2-Bromo-3,5-dimethoxyphenyl)formamide
(7),
mp
;
3
M
d
d
(OMe), 96.1, 100.8 (aryl CH), 94.4, 137.3, 156.8, 159.84 (aryl C), 161.0
(C]O); HRMS (þESI): [MþNa]þ, found 281.9738. C9H1079BrNO3
requires 281.9736.
(ii) N-(4-Bromo-3,5-dimethoxyphenyl)formamide (8), mp
183e184 ꢁC; nmax (KBr) 3119, 1682, 1589, 1484, 1273, 822 cmꢀ1
;
lmax
ꢀ1), 261 (15,800); 1H NMR
3.77 (3H, s, OMe), 3.79 (3H, s, OMe), 7.03
(2H, s, H2/6), 8.28 (1H, s, CHO), 10.29 (1H, bs, NH); 13C NMR
(MeOH) 215 nm (
3
32,900 cmꢀ1
M
(300 MHz, DMSO-d6):
d
Scheme 7. Formation of 2-bromoindoles 28aeb and 2,5-dibromoindole 29. Reagents
and conditions: (i) NBS/silica, 1 equiv, 26a (80%), 26b (67%); (ii) NBS/silica/CH2Cl2,
2 equiv, 27 (71%); (iii) KOH/MeOH, 28a (92%), 28b (66%), 29 (98%).
(75 MHz, DMSO-d6):
d 56.5, 56.7 (OMe), 95.0, 96.6 (aryl CH), 139.4,
156.8, 157.3 (aryl C), 160.3 (C]O); HRMS (þESI): [MþNa]þ, found
281.9732. C9H1079BrNO3 requires 281.9736.
2,7-dibromo-indoles could be obtained as pure compounds, and
provide considerable opportunities for further synthesis, especially
involving coupling reactions.
4.1.3. 1-(4-Ethylphenyl)-2-(3,5-dimethoxyphenylamino)ethanone
(9). A mixture of 3,5-dimethoxyaniline (5) (4.1 g, 26.8 mmol), 4-
ethylphenacyl bromide (6.0 g, 27.0 mmol), sodium bicarbonate
(2.5 g, 31.0 mmol) and absolute ethanol (50 mL) was heated under
reflux for 1.5 h. The reaction mixture was cooled to room temper-
ature and stirred for 1 h. The product was filtered, dried and
recrystallized from dichloromethane/n-hexane to afford the title
compound 9 (6.4 g, 80%) as a brown solid, mp 102 ꢁC; nmax (KBr)
3389, 2966, 2942, 2844, 1680, 1583, 1515, 1412, 1314, 1253, 1198,
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 Micro-
1158, 1072, 821, 797, 679 cmꢀ1
23,100 cmꢀ1 Mꢀ1), 253 (19,900); 1H NMR (300 MHz, CDCl3):
(3H, t, J 7.7 Hz, Me), 2.75 (2H, q, J 7.7 Hz, CH2), 3.81 (6H, s, OMe), 4.59
;
lmax (THF) 219 nm
(
3
d
1.28
analytical Laboratory, University of Otago, New Zealand. 1H and 13
C

P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
8167
(2H, s, CH2), 5.93 (3H, m, aryl H), 7.35 (2H, d, J 8.3 Hz, aryl H), 7.95
(2H, d, J 8.8 Hz, aryl H); 13C NMR (75 MHz, CDCl3):
15.2 (Me), 29.0,
30.1 (CH2), 50.2, 55.2 (OMe), 90.1, 92.0, 128.0, 128.4 (aryl CH), 132.6,
149.0, 151.0, 161.8 (aryl C), 194.4 (C]O); HRMS (þESI): [MþH]þ,
found 300.1587. C18H21NO3 requires 300.1521.
precipitate filtered, dried and recrystallised (dichloromethane/pe-
troleum ether) to afford the 2-bromo compound 13a as an off-white
powder (0.42 g, 91%); mp 246 ꢁC (dec); [Found: C, 56.7; H, 3.9; N,
3.9. C17H14BrNO3 requires C, 56.7; H, 3.9; N, 3.7%]; nmax (Nujol)
d
3240, 1640, 1590, 1340, 1240, 1220, 1150, 1110, 980, 750 cmꢀ1
;
lmax
ꢀ1), 251 (24,700), 320 (12,700),
347 (9300); 1H NMR (300 MHz, CDCl3):
3.83 (3H, s, OMe), 3.99
(3H, s, OMe), 6.15 (1H, s, H5), 7.30e7.50 (5H, m, aryl H), 10.36 (1H, s,
CHO), 10.48 (1H, bs, NH). 13C NMR (75 MHz, CDCl3):
55.4, 56.3
(MeOH) 228 nm ( M
16,800 cmꢀ1
3
4.1.4. N-Acetyl-1-(4-ethylphenyl)-2-(3,5-dimethoxyphenylamino)
d
ethanone (10). A mixture of phenylaminoketone
9 (8.5 g,
28.6 mmol) and acetic anhydride (20 mL, 211.5 mmol) was heated
at 50 ꢁC for 1 h. Water (100 mL) was added and the mixture was
stirred overnight at room temperature. The precipitated product
was filtered, washed with water and dried to afford the title com-
pound 10 (8.7 g, 89%) as a brown solid, mp 81 ꢁC; nmax (KBr) 2964,
2934, 2837, 1691, 1664, 1588, 1422, 1333, 1225, 1194, 1158, 1060, 976,
d
(OMe), 87.0 (C5), 126.7, 127.3, 130.8 (aryl CH), 103.9, 105.2, 111.3,
126.0, 133.5, 136.5 (aryl C), 160.3 and 162.7 (C-OMe), 188.1 (C]O).
Mass spectrum: m/z 362 (Mþ1, 81Br, 17%), 361 (M, 81Br, 100), 360
(Mþ1, 79Br, 17), 359 (M, 79Br, 100), 346 (17), 344 (17), 275 (13) 273
(13), 265 (57), 194 (24), 180 (56), 178 (28), 139 (65).
839, 830, 822, 700, 665 cmꢀ1
17,500 cmꢀ1 ꢀ1), 248 (17,300), 282 (2450); 1H NMR (300 MHz,
CDCl3): 1.24 (3H, t, J 7.6 Hz, Me), 2.06 (3H, s, CH3), 2.68 (2H, q, J
;
lmax (THF) 229 nm
(
3
M
4.1.8. Reaction of 4,6-dimethoxy-3-phenylindole-7-carbaldehyde
(12a) with N-bromosuccinimide and silica in dichloromethane. 7-
Formylindole 12a17,18 (0.35 g, 1.25 mmol) was dissolved in dichloro-
methane (20 mL) containing silica (0.05 g). N-Bromosuccinimide
(1.1 equiv 0.24 g, 1.37 mmol) was added to this solution and the re-
action mixture was stirred at room temperature for 30 min. After this
time the solution was filtered to remove the silica and the filtrate was
concentrated under reduced pressure. The residuewasthendissolved
in carbon tetrachloride (20 mL) and filtered once more to remove
residual succinimide. The filtrate was again concentrated under re-
duced pressure and the residue purified via column chromatography
(eluent dichloromethane) to give two products.
d
7.6 Hz, CH2), 3.81 (6H, s, OMe), 5.08 (2H, s, CH2), 6.44 (1H, t, aryl H),
6.57 (2H, d, J 2.2 Hz, aryl H), 7.28 (2H, d, J 8.6 Hz, aryl H), 7.87 (2H, d, J
8.6 Hz, aryl H); 13C NMR (75 MHz, CDCl3):
d 15.2, 22.0 (Me), 29.0,
31.0 (CH2), 55.5, 56.0 (OMe), 100.2, 106.3, 128.2 (aryl CH), 133.0,
145.3, 150.5, 161.3 (aryl C), 170.7, 193.2 (C]O); HRMS (ESI):
[MþH]þ, found 342.1698. C20H23NO4 requires 342.1627.
4.1.5. 1-Acetyl-3-(4-ethylphenyl)-4,6-dimethoxyindole (11). A mix-
ture of the acetyl compound 10 (8.7 g, 25.5 mmol) and trifluoro-
acetic acid (10 mL) was refluxed under an argon atmosphere for 2 h.
The reaction mixture was cooled to room temperature and poured
into ice-cold water (200 mL). The precipitated product was filtered,
washed with cold water and dried to afford the title compound 11
(7.4 g, 90%) as a white solid, mp 172 ꢁC; nmax (KBr) 2959, 1701, 1574,
(i) 2-Bromo-4,6-dimethoxy-3-phenylindole-7-carbaldehyde 13a
(0.33 g, 73%).
(ii) 2,5-Dibromo-4,6-dimethoxy-3-phenylindole-7-carbaldehyde
14a as an off-white powder (0.08 g, 14%); mp 184e186 ꢁC; nmax
1422, 1389, 1304, 1268, 1207, 1109, 1035, 968, 826, 684 cmꢀ1
(THF) 215 nm (
21,900 cmꢀ1 Mꢀ1), 237 (24,650), 253 (26,350), 316
(4650); 1H NMR (300 MHz, CDCl3):
1.30 (3H, t, J 7.7 Hz, Me), 2.66
;
lmax
(Nujol) 3320, 1610, 1600, 1570, 1290, 1230, 1150, 1090 cmꢀ1 1H
;
3
NMR (300 MHz, CDCl3):
7.38e7.55 (5H, m, aryl H), 10.40 (1H, s, CHO), 10.50 (1H, bs, NH); 13C
NMR (75 MHz, CDCl3): 61.7, 64.6 (OMe), 127.5, 127.9, 138.7 (aryl
d 3.27 (3H, s, OMe), 4.05 (3H, s, OMe),
d
(3H, s, Me), 2.73 (2H, q, J 7.5 Hz, CH2), 3.80 (3H, s, OMe), 3.93 (3H, s,
OMe), 6.44 (1H, d, J 2.0 Hz, H5), 7.18 (1H, s, H7), 7.24 (2H, d, J 8.7 Hz,
aryl H), 7.52 (2H, d, J 8.4 Hz, aryl H), 7.82 (1H, d, J 2.20 Hz, H2); 13C
d
CH), 104.9, 109.9, 111.2, 116.4, 118.8, 132.5, 135.2 (aryl C), 158.9 and
158.9 (CeOMe), 189.8 (C]O); Mass spectrum: m/z 442 (Mþ1,
81Br81Br, 7%), 441 (M, 81Br81Br, 43), 440 (Mþ1, 81Br79Br, 11), 439 (M,
81Br79Br, 82), 438 (Mþ1, 79Br79Br, 9), 437 (M, 79Br79Br, 42), 424 (17),
345 (17), 343 (19), 274 (12), 272 (13),193 (19),165 (23),164 (34),149
(57). The compound was not obtained analytically pure.
NMR (75 MHz, CDCl3):
d 15.6, 24.2 (Me), 28.6 (CH2), 55.2, 55.8
(OMe), 92.9 (C5), 95.8 (C7), 120.6 (C2), 127.2, 129.4 (aryl CH), 112.5,
124.4, 131.6, 138.2, 143.1, 154.3, 159.7 (aryl C), 169.0 (C]O); HRMS
(ESI): [MþH]þ, found 324.1588. C20H21NO3 requires 324.1521.
4.1.6. 3-(4-Ethylphenyl)-4,6-dimethoxyindole (3c). To a suspension
of the acetylindole 11 (6.5 g, 20 mmol) in methanol was added
potassium hydroxide (2.5 g, 44.6 mmol) and the mixture was stir-
red at room temperature for 1 h and then poured into iceewater.
The precipitated product was filtered, washed with water and dried
to afford the title compound 3c (4.2 g, 75%) as a white solid, mp
100 ꢁC; nmax (KBr) 3360, 2955, 1542, 1513, 1451, 1323, 1198, 1135,
4.1.9. 2-Bromo-4,6-dimethoxy-3-(4-tolyl)indole-7-carbaldehyde
(13b). Bromine (0.23 g,1.41 mmol) was weighed into a small amount
of glacial acetic acid (5 mL) and this solution was added to 7-
formylindole 12b19 (0.37 g, 1.28 mmol) in glacial acetic acid (25 mL).
After 40 min stirring at room temperature the reaction mixture was
poured into ice water (100 mL) and the resultant precipitate filtered,
dried and recrystallised (dichloromethane/n-hexane) to afford the
title compound 13b as a yellow solid (0.41 g, 89%), mp 236e238 ꢁC
(from diethyl ether); [Found: C, 58.4; H, 5.0; N, 3.3.
C18H16BrNO3.0.5(C2H5)2O requires C, 58.5; H, 4.9; N, 3.4%]; nmax (KBr)
3450, 3257, 2871, 1641, 1584,1544,1464,1378, 1346,1240, 1216,1158,
1090, 1047, 946, 786, 747, 702 cmꢀ1
41,250 cmꢀ1 ꢀ1), 271 (17,100), 297 (11,100); 1H NMR (300 MHz,
CDCl3): 1.30 (3H, t, J 7.5 Hz, Me), 2.69 (2H, q, J 7.6 Hz, CH2), 3.84
;
lmax (THF) 231 nm (
3
M
d
(3H, s, OMe), 3.88 (3H, s, OMe), 6.29 (1H, s, H5), 6.52 (1H, s, H7), 7.02
(1H, d, J 2.2, H2), 7.23 (2H, d, J 8.4 Hz, aryl H), 7.56 (2H, d, J 8.4 Hz,
1112,982,790,726cmꢀ1 1950 cmꢀ1 Mꢀ1), 274
;
lmax (MeOH)321nm(
3
aryl H), 8.10 (1H, s, NH); 13C NMR (75 MHz, CDCl3):
d
15.6 (Me), 28.6
(1250), 231 (4750); 1H NMR (300 MHz, CDCl3):
d 2.44 (3H, s, Me), 3.87
(CH2), 55.1, 55.6 (OMe), 86.8 (C5), 92.2 (C7), 120.2 (C2), 127.2, 129.4
(aryl CH), 110.4, 118.9, 133.3, 138.3, 141.6, 155.0, 157.6 (aryl C); HRMS
(ESI): [MþH]þ, found 282.1481. C18H19NO2 requires 282.1416.
(3H, s, OMe), 4.02(3H, s,OMe), 6.18 (1H, s, H5), 7.25 (2H, d,J 7.8 Hz, aryl
H), 7.40 (2H, d, J 8.1 Hz, aryl 2H),10.39 (1H, s, CHO),10.49 (1H, s, indole
NH); 13C NMR (75 MHz, CDCl3):
d 21.3 (Me), 55.4, 56.3 (OMe), 87.0,
128.1,130.6(aryl CH) 103.9,105.8,111.3,116.7,136.3,136.7,142.3,160.3,
4.1.7. Reaction of 4,6-dimethoxy-3-phenylindole-7-carbaldehyde
(12a) with bromine in glacial acetic acid. Bromine (1.1 equiv
0.23 g, 1.41 mmol) was weighed into a small amount of glacial
acetic acid (5 mL) and this solution was added slowly to a solution
of 7-formylindole 12a17,18 (0.36 g, 1.28 mmol) in glacial acetic acid
(25 mL). After 40 min stirring at room temperature the reaction
mixture was poured into ice water (100 mL) and the resultant
162.7 (aryl C), 188.1 (CHO); HRMS (ESI): [M]þ, found 374.0381.
79
C18
H BrNO3 requires 374.0392.
16
4.1.10. 3-(4-Ethylphenyl)-4,6-dimethoxyindole-7-carbaldehyde
(12c). Indole 3c (1.23 g, 4.37 mmol) was dissolved in N,N-dime-
thylformamide (10 mL) and the solution cooled in ice. Phosphoryl
chloride (0.40 mL, 4.37 mmol) was added to an ice cooled solution

8168
P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
of N,N-dimethylformamide (5 mL) and the resulting solution stirred
at room temperature for 3 h. Ice cold water (5 mL) was added and
the mixture was basified to pH 14 with 5 M sodium hydroxide. The
mixture was then stirred at room temperature for 30 min. The
resulting precipitate was filtered, dried and purified via flash
chromatography (dichloromethane) to afford the title compound
12c as a yellow solid (1.47, 87%), mp 164e168 ꢁC; [Found: C, 73.5; H,
6.1; N, 4.6. C19H19NO3 requires C, 73.8; H, 6.2; N, 4.5%]; nmax (KBr)
3335, 2999, 2964, 1644, 1608, 1589, 1578, 1467, 1344, 1320, 1256,
(0.31 g,1.06 mmol) in glacial acetic acid (25 mL). After stirring at room
temperature for 1 h the reaction mixture was poured into ice water
(100 mL) and the resulting precipitate filtered, dried and recrystal-
lised (dichloromethane/petroleum ether) to afford 1-(2-bromo-4,6-
dimethoxy-3-phenylindol-7-yl)ethanone 16 (3.7 g, 95%).
4.1.14. Reaction of 1-(4,6-dimethoxy-3-phenylindol-7-yl)ethanone
(15) with N-bromosuccinimide in carbon tetrachloride. N-Bromo-
succinimide (0.38 g, 0.212 mmol) was added to a solution of 7-
acetylindole 15 (0.57 g, 0.19 mmol) dissolved in carbon tetrachlo-
ride (40 mL). The reaction mixture was stirred for 30 min under
gentle reflux. Upon cooling, the solution was filtered and the sol-
vent was removed under reduced pressure. The residue was flash
chromatographed (dichloromethane) to give two products.
(i) 1-(2-Bromo-40,-dimethoxy-3-phenylindol-7-yl)ethanone 16
(0.44 g, 61%).
1214, 1175, 1089, 982, 759 cmꢀ1
8000 cmꢀ1 ꢀ1), 275 (10,000), 232(6600); 1H NMR (300 MHz,
CDCl3): 1.33 (3H, t, J 7.2 Hz, Me), 2.75 (2H, q, J 7.5 Hz, CH2), 3.96
;
lmax (MeOH) 333 nm
(
3
M
d
(3H, s, OMe), 4.02 (3H, s, OMe), 6.22 (1H, s, H5), 7.11 (1H, d, J 2.2 Hz,
H2), 7.24 (2H, d, J 7.9 Hz, aryl H), 7.55 (2H, d, J 6.3 Hz, aryl H), 10.43
(1H, s, CHO), 10.05 (1H, s, NH); 13C NMR (75 MHz, DMSO-d6):
d 15.5
(Me), 28.5 (CH2), 55.4, 56.4 (OMe), 86.7, 121.6, 127.8, 129.3 (aryl CH),
104.4, 110.2, 118.8, 132.6, 137.7, 141.9, 161.5, 163.0 (aryl C), 188.3
(CHO); HRMS (ESI): [M]þ, found 310.1434. C19H19NO3 requires
310.1443.
(ii) 1-(2,5-Dibromo-4,6-dimethoxy-3-phenylindol-7-yl)ethanone
17 as an off-white powder (0.05 g, 6%) mp 173e175 ꢁC (dichloro-
methane/light petroleum); [Found: C, 47.8; H, 3.6; N, 2.9.
C18H15Br2NO3 requires C, 47.8; H, 3.3; N, 3.1%]; nmax (Nujol) 3280,
4.1.11. 2-Bromo-3-(4-ethylphenyl)-4,6-dimethoxyindole-7-
carbaldehyde (13c). Bromine (0.12 g, 0.70 mmol) was weighed into
a small amount of glacial acetic acid (5 mL) and this solution was
added to 7-formylindole 12c (0.18 g, 0.63 mmol) in glacial acetic
acid (25 mL). After 40 min stirring at room temperature the re-
action mixture was poured into ice water (100 mL) and the re-
1660, 1590, 1560, 1540, 1290, 1250, 1150, 1080, 980, 970, 760 cmꢀ1
;
lmax (MeOH) 250 nm (
(300 MHz, CDCl3): 2.83 (3H, s, Me), 3.26 (3H, s, OMe), 3.99 (3H, s,
OMe), 7.34e7.54 (5H, m, aryl H), 10.84 (1H, bs, NH; 13C NMR
75 MHz, CDCl3): 31.6 (Me), 61.4 and 62.7 (OMe), 127.3, 127.8,
3
22,000 cmꢀ1 ꢀ1), 334 (11,500); 1H NMR
M
d
d
130.78 (aryl CH), 105.7, 109.7, 112.1, 116.0, 118.7, 132.8, 136.4 (aryl C),
155.3, 156.3 (CeOMe), 199.3 (C]O); Mass spectrum: m/z 456 (Mþ1,
81Br81Br, 8%), 455 (M, 81Br81Br, 51), 454 (Mþ1, 81Br79Br, 17), 453 (M,
81Br79Br, 100), 452 (Mþ1, 79Br79Br, 8), 451 (M, 79Br79Br, 51), 438
(16), 410 (29), 359 (18), 357 (18), 220 (11), 192 (13), 43 (87).
sultant
precipitate
filtered,
dried
and
recrystallised
(dichloromethane/n-hexane) to afford the title compound 13c as
a yellow solid (0.20 g, 85%), mp 228e230 ꢁC; [Found: C, 59.2; H, 4.8;
N, 3.6. C19H18BrNO3 requires C, 58.8; H, 4.7; N, 3.6%]. nmax (KBr)
3255, 3007, 2942, 2871, 1643, 1583, 1540, 1521, 1380, 1345, 1312,
1238, 1217, 1156, 1111, 982, 842, 799 cmꢀ1
9050 cmꢀ1
CDCl3): 1.34 (3H, t, J 7.6 Hz, Me), 2.76 (2H, q, J 7.5 Hz, CH2), 3.87
;
lmax (MeOH) 231 nm (
3
4.1.15. Reaction of 1-(4,6-dimethoxy-3-phenylindol-7-yl)ethanone
(15) with N-bromosuccinimide in carbon tetrachloride. N-Bromo-
succinimide (0.24 g, 1.4 mmol) and a catalytic amount of AIBN
(20 mg) was added to a solution of 7-acetylindole 15 (0.27 g,
0.9 mmol) dissolved in carbon tetrachloride (20 mL). The reaction
mixture was stirred for 15 min under gentle reflux. Upon cooling,
the solution was filtered and the solvent removed under reduced
pressure. The residue was flash chromatographed (dichloro-
methane) to give two products.
M
ꢀ1), 274 (2700), 321 (3250); 1H NMR (300 MHz,
d
(3H, s, OMe), 4.01 (3H, s, OMe), 6.18 (1H, s, H5), 7.25 (2H, d, J 8.0 Hz,
aryl H), 7.45 (2H, d, J 8.2 Hz, aryl H), 10.38 (1H, s, CHO), 10.49 (1H, s,
NH); 13C NMR (75 MHz, CDCl3):
d 15.3 (Me), 28.6 (CH2), 55.5, 56.3
(OMe), 87.0, 126.8, 130.6 (aryl CH) 103.8, 105.8, 111.2, 116.8, 136.7,
142.5, 160.3, 162.7 (aryl C), 188.1 (CHO); HRMS (ESI): [M]þ, found
388.0541. C19H1879BrNO3 requires 388.0548.
(i) 1-(2-Bromo-4,6-dimethoxy-3-phenylindol-7-yl)ethanone 16
(0.21 g, 61%).
(ii) 1-(2,5-Dibromo-4,6-dimethoxy-3-phenylindol-7-yl)ethanone
17 (0.098 g, 24%).
4.1.12. Reaction of 1-(4,6-dimethoxy-3-phenylindol-7-yl)ethanone
(15) with copper (II) bromide. A solution of 7-acetylindole 15
(0.13 g, 0.44 mmol) in dry chloroform (15 mL) was added to
a refluxing solution of copper (II) bromide (1.96 g, 0.88 mmol) in
dry ethyl acetate (20 mL) and heated at reflux for 3 h. Upon cooling
the reaction mixture was filtered and the solvent removed from the
filtrate under reduced pressure. The residue was flash chromato-
graphed (eluent dichloromethane) to give starting material and 1-
(20-bromo-40,60-dimethoxy-3-phenylindol-7-yl)ethanone 16 as an
off-white powder (0.03 g, 20%), mp 167e169 ꢁC; [Found: C, 58.0; H,
4.5; N, 3.7. C18H16BrNO3 requires C, 57.8; H, 4.3; N, 3.7%]. nmax
4.1.16. Reaction of 1-(4,6-dimethoxy-3-phenylindol-7-yl)ethanone
(15) with N-bromosuccinimide and silica in dichloromethane. 7-
Acetylindole 15 (0.27 g, 0.92 mmol) was dissolved in dichloro-
methane (20 mL) containing silica (0.1 g). N-Bromosuccinimide
(0.18 g, 1.0 mmol) was added to this solution and the reaction
mixture was stirred at room temperature for 30 min. After this time
the solution was filtered to remove the silica and the filtrate con-
centrated under reduced pressure. The residue was then dissolved
in carbon tetrachloride (15 mL) and filtered once more to remove
residual succinimide. The filtrate was again concentrated under
reduced pressure and the residue purified via column chromatog-
raphy (dichloromethane) to give two products.
(Nujol) 3280, 1590, 1560, 1350, 1260, 1150 cmꢀ1
248 nm (
25,600 cmꢀ1 ꢀ1), 319 (14,000), 334 (12,000). 1H NMR
(300 MHz, CDCl3): 2.67 (3H, s, Me), 3.80 (3H, s, OMe), 3.99 (3H, s,
OMe), 6.18 (1H, s, H5), 7.28e7.50 (5H, m, aryl H), 11.02 (1H, bs, NH);
13C NMR (75 MHz, CDCl3):
33.1 (Me), 55.2, 56.0 (OMe), 87.5, 126.5,
; lmax (MeOH)
3
M
d
d
127.2, 130.8 (aryl CH), 104.2, 105.6, 111.4, 116.4, 133.8, 138.0 (aryl C),
158.3, 160.6 (CeOMe), 198.4 (C]O); Mass spectrum: m/z 376 (Mþ1,
81Br, 18%), 375 (M, 81Br, 100), 374 (Mþ1, 79Br, 17), 373 (M, 79Br, 98)
360 (26), 358 (28) 332 (22), 330 (26), 279 (35), 264 (20), 178 (31).
(i) 1-(2-Bromo-4,6-dimethoxy-3-phenylindol-7-yl)ethanone 16
(0.23 g, 68%).
(ii) 1-(20,5-Dibromo-40,60-dimethoxy-30-phenylindol-7-yl)etha-
none 17 (0.02 g, 5%).
4.1.13. Reaction of 1-(4,6-dimethoxy-3-phenylindol-7-yl)ethanone
(15) with bromine in glacial acetic acid. Bromine (0.18 g, 1.16 mmol)
was weighed into a small amount of glacial acetic acid (5 mL) and the
resulting solution added dropwise to a solution of 7-acetylindole 15
4.1.17. Reaction of 1-(4,6-dimethoxy-3-phenylindol-7-yl)ethanone (15)
with phenyltrimethylammomium tribromide in tetrahydrofuran. 7-
Acetylindole 15 (0.47 g, 1.58 mmol) was dissolved in dry tetrahy-
drofuran (20 mL) and phenyltrimethylammonium tribromide

P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
8169
(1.24 g, 3.32 mmol) was added to the solution. After stirring for 24 h
the reaction mixture was filtered and the solvent removed from the
filtrate under reduced pressure. The residue was flash chromato-
graphed (dichloromethane/light petroleum (30:70)) to give three
products.
(11), 373 (15), 360 (32), 358 (35), 250 (25), 178 (43), 150 (35). The
compound could not be obtained analytically pure.
4.1.19. Reaction of 1-(4,6-dimethoxy-3-phenylindol-2-yl)ethanone
(20) with N-bromosuccinimide and silica in dichloromethane. 2-
Acetylindole 20 (0.28 g, 0.95 mmol) was dissolved in dichloro-
methane (20 mL) containing silica (0.05 g). N-Bromosuccinimide
(0.19 g, 1.04 mmol) was added to this solution and the reaction
mixture stirred at room temperature for 10 min. After this time the
solution was filtered to remove the silica and the filtrate was con-
centrated under reduced pressure. The residue was then dissolved
in carbon tetrachloride (20 mL) and filtered once more to remove
residual succinimide. The filtrate was again concentrated under
reduced pressure and the residue purified via column chromatog-
raphy (eluent dichloromethane) to give 1-(7-bromo-4,6-dimethoxy-
3-phenylindol-2-yl)ethanone 21 (0.25 g, 70%) as white crystals.
(i) 1-(2-Bromo-4,6-dimethoxy-3-phenylindol-7-yl)ethanone 16 as
an off-white powder (0.29 g, 49%).
(ii) 2-Bromo-1-(2-bromo-4,6-dimethoxy-3-phenylindol-7-yl)etha-
none18 asanoff-white powder(0.26 g, 36%), mp177e180 ꢁC;[Found:
C, 47.6; H, 3.5; N, 2.9. C18H15Br2NO3 requires C, 47.8; H, 3.3; N, 3.1%];
nmax (Nujol) 3400, 1630, 1580, 1350 cmꢀ1
;
lmax (CH2Cl2) 325 nm (
ꢀ1), 342 (6800), 352 (15,600); 1H NMR (300 MHz,
3.78 (3H, s, OMe), 4.01 (3H, s, OMe), 4.66 (2H, s, CH2), 6.15
(1H, s, H5), 7.27e7.49 (5H, m, aryl H), 10.87 (1H, bs, NH); 13C NMR
(75 MHz, CDCl3): 39.3 (CH2), 55.4, 56.3 (OMe), 87.3 (C5),126.7,127.3,
3
7900 cmꢀ1
CDCl3):
M
d
d
130.8 (aryl CH), 101.5, 105.8, 111.6, 116.9, 133.5, 138.1 (aryl C), 159.4,
160.6 (CeOMe), 189.9 (C]O); Mass spectrum: m/z 456 (Mþ1,
81Br81Br, 9%), 455 (M, 81Br81Br, 51), 454 (Mþ1, 81Br79Br, 10), 453 (M,
81Br79Br, 100), 452 (Mþ1, 79Br79Br, 9), 451 (M, 79Br79Br, 51), 438 (9),
375 (51), 373 (6), 360 (53), 358 (53), 346 (24), 344 (27), 199 (100).
(iii) 2,2-Dibromo-1-(2-bromo-4,6-dimethoxy-3-phenylindol-7-yl)
ethanone 19 as an off-white powder (0.09 g, 10%), mp 148e150 ꢁC;
[Found: C, 39.2; H, 2.9; N, 2.2. C18H14Br3NO3.H2O requires C, 39.3; H,
2.9; N, 2.5%]; nmax (Nujol) 3400, 1620, 1580, 1570, 1350, 1310, 1290,
4.1.20. 1-Acetyl-2,7-dibromo-4,6-dimethoxy-3-phenylindole (24). N-
Acetylindole 23 (0.22 g, 0.75 mmol) was dissolved in dichloro-
methane (15 mL) containing silica (0.2 g). N-Bromosuccinimide
(0.28 g, 1.57 mmol) was added in two portions to this solution and
the reaction mixture stirred at room temperature for 30 min, then
brought to reflux for 1 h. The solution was filtered to remove the
silica and the filtrate concentrated under reduced pressure. The
residue was then dissolved in carbon tetrachloride (20 mL) and fil-
tered once more to remove residual succinimide. The filtrate was
again concentrated under reduced pressure and the residue purified
via column chromatography (dichloromethane) and recrystallised
(dichloromethane/petroleum ether) to give the 2,7-dibromoindole 24
as an off-white powder (0.203 g, 60%), mp 143e145 ꢁC; [Found: C,
47.8; H, 3.6; N, 2.9. C18H15Br2NO3 requires C, 47.8; H, 3.3; N, 3.1%];
nmax (Nujol) 3280,1660,1590,1560,1540,1290,1250,1150,1080, 980,
1220, 1150, 880 cmꢀ1 lmax (MeOH) 249 nm (
(20,000), 326 (10,000); 1H NMR (300 MHz, CDCl3):
OMe), 4.08 (3H, s, OMe), 6.19 (1H, s, H5), 7.32 (1H, s, CH), 7.30e7.52
(5H, m, aryl H), 10.88 (1H, bs, NH); 13C NMR (75 MHz, CDCl3):
44.7
3
8100 cmꢀ1 Mꢀ1), 252
d
3.81 (3H, s,
d
(C2), 54.8, 56.1 (OMe), 87.1, 126.1, 126.7, 130.1 (aryl CH), 63.1, 98.2,
106.2, 117.3, 133.4, 138.6 (aryl C), 160.3, 160.6 (CeOMe), 185.4 (C]
O); Mass spectrum: m/z 535 (M, 81Br81Br81Br, 4%), 533 (M,
81Br81Br79Br, 23), 531 (M, 81Br79Br79Br, 45), 529 (M, 79Br79Br79Br,
15), 455 (15), 453 (37), 369 (86), 190 (40), 178 (86). The compound
was not obtained analytically pure.
970, 760 cmꢀ1
(11,500); H NMR (300 MHz, CDCl3):
;
lmax (MeOH) 250 nm (
3
22,000 cmꢀ1 ꢀ1), 334
M
1
d
2.83 (3H, s, Me), 3.26 (3H, s,
OMe), 3.99 (3H, s, OMe), 7.34e7.54 (5H, m, aryl H),10.84 (1H, bs, NH);
4.1.18. Reaction of 1-(4,6-dimethoxy-3-phenylindol-2-yl)ethanone
(20) with bromine in glacial acetic acid. Bromine (1.1 equiv 0.17 g,
1.04 mmol) was weighed into a small amount of glacial acetic acid
(5 mL) and this solution was added slowly to a solution of 2-
acetylindole 20 (0.28 g, 0.95 mmol) in glacial acetic acid (30 mL).
After 30 min stirring at room temperature the reaction mixture was
poured into ice water (100 mL) and the resultant precipitate filtered
and dried. The crude reaction product was purified via column
chromatography (dichloromethane). Two products were eluted,
and were each obtained as off-white crystals when recrystallised
(dichloromethane/petroleum ether).
13C NMR (75 MHz, CDCl3):
d
31.6 (Me), 61.4, 62.7 (OMe), 127.3, 127.8,
130.8 (aryl CH), 105.7, 109.7, 112.1, 116.0, 118.7, 132.8, 136.4 (aryl C),
155.3, 156.3 (CeOMe), 199.3 (C]O); Mass spectrum: m/z 456 (Mþ1,
81Br81Br, 1%), 455 (M, 81Br81Br, 3), 454 (Mþ1, 81Br79Br, 1), 453 (M,
81Br79Br, 8), 452 (Mþ1, 79Br79Br, 1), 451 (M, 79Br79Br, 3), 413 (49), 412
(19), 411(100), 410 (13), 409 (50), 398 (14), 396 (29), 394 (16), 317
(11), 315 (12), 193 (11), 177 (17), 164 (31).
4.1.21. 2,7-Dibromo-4,6-dimethoxy-3-phenylindole
(4). 2,7-
Dibromo-N-acetylindole 24 (0.097 g, 0.21 mmol) and potassium
hydroxide (0.1 g) were suspended in dry methanol (10 mL) and
heated under reflux for 45 min. The cooled reaction mixture was
poured into ice water and filtered, and the dried solid was recrys-
tallised from dichloromethane/light petroleum affording the
dibromoindole 4 as white crystals (0.088 g, 80%), mp 220 ꢁC (dec);
[Found: C, 46.5; H, 3.5; N, 3.1. C16H13Br2NO2 requires C, 46.8; H, 3.2;
(i) 1-(70-Bromo-40,60-dimethoxy-30-phenylindol-20-yl)ethanone
21 (0.27 g, 76%), mp 173e174 ꢁC; [Found: C, 58.0; H, 4.6; N, 3.6.
C18H16BrNO3 requires C, 57.8; H, 4.3; N, 3.7%]; nmax (Nujol) 3300,
1640, 1620, 1560, 1520, 1270, 1220, 1210, 1140, 980 cmꢀ1
;
lmax
9400 cmꢀ1 Mꢀ1), 259 (12,600), 321 (12,400), 344
(1100); 1H NMR (300 MHz, CDCl3):
1.97 (3H, s, Me), 3.62 (3H, s,
OMe), 3.96 (3H, s, OMe), 6.22 (1H, s, H5), 7.38e7.41 (5H, m, aryl H),
9.08 (1H, bs, NH); 13C NMR (75 MHz, CDCl3):
28.1 (Me), 55.5, 57.2
(MeOH) 216 nm (
3
d
N, 3.4%]; nmax (Nujol) 3420, 1630, 1330, 1210, 1150, 1130, 770 cmꢀ1
lmax (MeOH) 235 nm (
23,500 cmꢀ1 ꢀ1), 383 (10,600); 1H NMR
(300 MHz, CDCl3): 3.72 and 3.96 (6H, each s, OMe), 6.32 (1H, s,
H5), 7.33e7.51 (5H, m, aryl H), 8.25 (1H, bs, NH); 13C NMR (75 MHz,
CDCl3): 55.6, 57.4 (OMe), 84.2 (C7), 90.6 (C5), 105.7 (C2), 112.5
;
3
M
d
d
(OMe), 90.0 (C5), 127.6, 130.4 (aryl CH), 83.9 (C7), 114.3, 125.7, 131.6,
135.3, 136.5 (aryl C), 155.8, 156.5 (CeOMe), 190.3 (C]O); Mass
spectrum: m/z 377 (Mþ2, 81Br,1%), 376 (Mþ1, 81Br,19), 375 (M, 81Br,
98), 374 (Mþ1, 79Br, 30), 373 (M, 79Br, 100), 372 (11), 360 (17), 358
(18), 236 (13), 194 (11), 180 (23), 172 (22), 164 (20), 150 (23).
(ii) 2-Bromo-1-(70-bromo-40,60-dimethoxy-30-phenylindol-20-yl)
ethanone 22 (0.04 g, 9%), mp 154e156 ꢁC; nmax (Nujol) 3300, 1600,
d
(C3a), 118.1 (C3), 126.5, 127.3, 130.8 (aryl CH), 133.7, 136.4 (C7a and
C10), 152.9,153.2 (CeOMe); Mass spectrum: m/z 414 (Mþ1, 81Br81Br,
8%), 413 (M, 81Br81Br, 50), 412 (Mþ1, 81Br79Br, 19), 411 (M, 81Br79Br,
100), 410 (Mþ1, 79Br79Br, 12), 409 (M, 79Br79Br, 50), 398 (16), 396
(34), 394 (18), 315 (25), 302 (14), 300 (15), 274 (21), 272 (22), 193
(26), 165 (25), 164 (34), 152 (28), 150 (35) 138 (29).
1340, 1270 cmꢀ1 1H NMR (300 MHz, CDCl3):
; d 3.62 (3H, s, OMe),
3.97 (3H, s, OMe), 3.76 (2H, s, CH2Br); 6.21 (1H, s, H5), 7.40e7.50
(5H, m, aryl H), 9.09 (1H, bs, NH); Mass spectrum: m/z 456 (Mþ1,
81Br81Br, 9%), 455 (M, 81Br81Br, 50), 454 (Mþ1, 79Br81Br, 19), 453 (M,
81Br79Br, 100), 452 (Mþ1, 79Br79Br, 13), 451 (M, 79Br79Br, 100), 357
4.1.22. 2-Bromo-4,6-dimethoxy-3-phenyl-1-phenylsulfonylindole
(26a). N-Phenylsulfonylindole 25a10 (1.54 g, 3.92 mmol) was sus-
pended in carbon tetrachloride (30 mL) and dissolved with

8170
P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
warming. N-Bromosuccinimide (0.77 g, 4.31 mmol) was added to
the warmed solution and the mixture brought to a gentle reflux for
5 h. After cooling, the reaction mixture was filtered and the filtrate
concentrated under reduced pressure. The resulting residue was
passed though a plug of silica, using dichloromethane as the eluent,
and recrystallised from dichloromethane/light petroleum to give
the 2-bromoindole 26a as white crystals (1.48 g, 80%), mp
136e138 ꢁC; [Found: C, 55.7; H, 4.1; N, 2.9. C22H18BrSNO4 requires
C, 55.9; H, 3.8; N, 3.0%]; nmax (Nujol) 1610, 1600, 1190, 1120,
suspended in carbon tetrachloride (30 mL) and dissolved with
warming. N-Bromosuccinimide (0.10 g, 0.61 mmol) was added to
the warmed solution and the mixture brought to a gentle reflux for
5 h. After cooling, the reaction mixture was filtered and the filtrate
concentrated under reduced pressure. The resulting residue was
passed through a plug of silica, using dichloromethane as the elu-
ent, and was recrystallised from dichloromethane and n-hexane to
give the 2-bromoindole 26b (0.18 g, 67%) as a yellow powder, mp
235e237 ꢁC (from acetonitrile/n-hexane); nmax (KBr) 3396, 3420,
2921, 2849, 1631, 1554, 1539, 1451, 1361, 1281, 1258, 1200,
780 cmꢀ1
;
lmax (MeOH) 229 nm (
3
19,500 cmꢀ1 Mꢀ1), 246 (17,000),
3.57 (3H, s,
308 (3200), 334 (1300); 1H NMR (300 MHz, CDCl3):
d
10,941,026, 822, 738 cmꢀ1
;
lmax (MeOH) 203 nm
(
3
OMe), 3.92 (3H, s, OMe), 6.31 (1H, d, J 2.0 Hz, H5), 7.27e7.56 (4H, m,
9400 cmꢀ1 Mꢀ1), 248 (12,000); 1H NMR (300 MHz, DMSO-d6) 2.32
(3H, s, Me), 3.67 (3H, s, OMe), 3.85 (3H, s, OMe), 6.35 (1H, d, J 1.8 Hz,
H5), 7.11e7.21 (6H, m, aryl and H7), 7.47 (2H, d, J 7.5 Hz, aryl H), 7.95
(2H, m, aryl H); 13C NMR (DMSO-d6) 21.2 (Me), 55.7, 56.1 (OMe),
91.9, 95.8, 127.0, 127.7, 128.6, 129.1, 130.6, 134.0 (aryl CH), 113.4,
aryl H and H7), 7.89e7.95 (2H, m, aryl H); 13C NMR (75 MHz, CDCl3):
d
55.3, 55.9 (OMe), 91.9 (C5), 95.8 (C7), 127.1, 127.2, 127.5, 129.1,
130.6, 134.1 (aryl CH), 113.4, 126.5, 133.4, 138.3, 139.4 (aryl C), 105.6
(C2), 153.5, 159.2 (CeOMe); Mass spectrum: m/z 474 (Mþ1, 81Br,
2%), 473 (M, 81Br, 12), 472 (Mþ1, 79Br, 2), 471 (M, 79Br, 10), 333 (28),
332 (98), 331 (34), 330 (100), 316 (10), 193 (20), 164 (18), 139 (36).
126.4, 133.3, 138.2, 139.3 (aryl C); HRMS (ESI): [M]þ, found
79
486.0358. C23
H BrNO4S requires 486.0375.
20
4 . 1. 2 3 . 2 , 5 - D i b r o m o - 4 , 6 - d i m e t h o x y - 3 - p h e n y l - 1 -
phenylsulphonylindole (27). This was prepared as described for 2-
bromo-N-phenylsulfonylindole 26a from N-phenylsulfonylindole
25a (0.4 g, 1.02 mmol) in carbon tetrachloride (30 mL) using N-
bromosuccinimide (0.4 g, 2.24 mmol) with gentle heating under
reflux for 5 h. The crude dibromoindole was purified by passing
through a plug of silica and recrystallised (dichloromethane/light
petroleum) to give 2,5-dibromo-N-phenylsulfonylindole 27 as white
crystals (0.40 g, 71%), mp 168e170 ꢁC; [Found: C, 47.8; H, 3.3; N, 2.3.
C22H17NO4Br2S requires C, 47.9; H, 3.1; N, 2.5%]; nmax (Nujol) 1600,
4.1.26. 2-Bromo-4,6-dimethoxy-3-phenylindole (28a). 2-Bromo-N-
phenylsulfonylindole 25a (0.32 g, 6.8 mmol) and potassium hy-
droxide (1.2 g) were suspended in dry methanol (20 mL) and
heated under reflux for 1 h. After cooling, the reaction mixture
was poured into ice water (100 mL) and the resulting precipitate
filtered and washed with cold methanol (1 mL) to give the 2-
bromoindole 28a as a white powder (0.21 g, 92%), mp 166e168 ꢁC
(dec); [Found: C, 57.6; H, 4.5; N, 4.0. C16H14BrNO2 requires C, 57.9;
H, 4.3; N, 4.2%]; nmax (Nujol) 3360, 1590, 1570, 1540, 1510, 1330,
1310, 1230, 1200s, 1150, 1120, 1040, 810, 700, 660 cmꢀ1
(MeOH) 234 nm (
19,500 cmꢀ1 ꢀ1), 266 (6900), 291 (3500); 1H
NMR (300 MHz, CDCl3): 3.69 (3H, s, OMe), 3.84 (3H, s, OMe), 6.22
(1H, d, J 2.0 Hz, H5), 6.44 (1H, d, J 2.0 Hz, H7), 7.28e7.53 (5H, m,
aryl H), 8.06 (1H, bs, NH); 13C NMR (75 MHz, CDCl3):
55.2, 55.6
; lmax
1330, 1190, 1150, 1110, 1080, 760, 740 cmꢀ1
20,000 cmꢀ1 Mꢀ1); 1H NMR (300 MHz, CDCl3):
4.03 (3H, s, OMe), 7.35e7.90 (10H, m, aryl H), 7.84 (1H, s, H7); 13C
NMR (75 MHz, CDCl3): 57.0, 61.1 (OMe), 95.5 (C7), 127.2, 127.7,
;
lmax (MeOH) 238 nm (
3
3
M
d
3.09 (3H, s, OMe),
d
d
d
128.0, 129.3, 130.6, 134.4 (aryl CH), 104.4, 107.7 (C2 and C5), 117.8,
125.1, 132.2, 138.0, 138.1 (aryl C), 150.6, 154.9 (CeOMe); Mass
spectrum: m/z 553 (M, 81Br81Br, 1%), 551 (M, 81Br79Br, 2), 549 (M,
79Br79Br, 1), 412 (27), 411 (10), 410 (54), 408 (28), 164 (19), 141 (16),
77 (100).
(OMe), 86.4 (C5), 92.6 (C7), 104.2 (C2), 111.5 (C3a), 117.2 (C3), 126.5,
127.2, 130.9 (aryl CH), 134.1, 137.6 (C7a and C10), 154.0, 157.7
(CeOMe); Mass spectrum: m/z 334 (Mþ1, 81Br, 16), 333 (M, 81Br,
96), 332 (Mþ1, 79Br, 20), 331 (M, 79Br, 100), 318 (23), 316 (24), 245
(15), 273 (16), 238 (12), 237 (62), 222 (17), 194 (20), 178 (16), 166
(25), 139 (64), 126 (22).
4.1.24. 4,6-Dimethoxy-1-(phenylsulfonyl)-3-(p-tolyl)indole
(25b). Potassium hydroxide was added to dimethylsulfoxide
(20 mL) and the mixture was stirred at room temperature for 5 min.
4,6-Dimethoxy-3-(p-tolyl)indole 3b (0.42 g, 1.53 mmol) was added
and stirring was continued for 1 h at room temperature. n-Butyl-
lithium (0.16 mL, 1.6 M, 1.73 mmol) was added slowly over 5 min
and the solution stirred for 1 h at room temperature. The reaction
mixture was then poured into ice water and extracted with diethyl
ether (3ꢂ50 mL). The combined organic layers were dried (Na2SO4)
and the solvent was removed under reduced pressure. The residue
was purified via column chromatography (dichloromethane/n-
hexane) to give the N-phenylsulfonylindole 25b as a white powder
(0.48 g, 75%), mp 154e156 ꢁC; [Found: C, 68.08; H, 4.95; N, 3.48.
C23H21NO4S requires C, 67.79; H, 5.19; N, 3.44%]; nmax (KBr) 3439,
2989, 2929, 2832, 1602, 1589, 1568, 1490, 1467, 1417, 1367, 1333,
4.1.27. 2-Bromo-4,6-dimethoxy-3-(p-tolyl)indole (28b). 2-Bromo-
N-phenylsulfonylindole 26b (0.15 g, 0.30 mmol) and excess potas-
sium hydroxide were suspended in dry methanol (20 mL) and
heated under reflux for 1 h. After cooling, the reaction mixture was
poured into ice water (100 mL) and the resulting precipitate was
filtered and washed with cold methanol to give 2-bromoindole 28b
(0.07 g, 66%) as a white powder, mp>300 ꢁC; [Found: C, 57.46; H,
4.52; N, 3.84. C17H16NO2.0.5H2O requires C, 57.48; H, 4.82; N,
3.94%]; nmax (KBr) 3340, 3004, 2957, 2936, 2837, 1623, 1583, 1545,
1508, 1465, 1448, 1428, 1394, 1333, 205, 1196, 1147, 1123, 1046, 932,
808 cmꢀ1
;
lmax (MeOH) 225 nm (
3
61,000 cmꢀ1 Mꢀ1), 265 (22,150);
1H NMR (300 MHz, DMSO-d6):
d
2.31 (3H, s, Me), 3.69 (3H, s, OMe),
3.81 (3H, s, OMe), 6.21 (1H, d, J 1.9 Hz, H5), 6.40 (1H, d, J 1.9 Hz, H7),
7.19 (2H, d, J 7.8 Hz, aryl H), 7.43 (2H, dd, J 1.6, 1.5 Hz, aryl 2H), 8.05
1206, 1114, 1100, 819, 754 cmꢀ1
30,300 cmꢀ1 ꢀ1); 1H NMR (300 MHz, DMSO-d6):
;
lmax (MeOH) 204 nm
(
3
(1H, s, indole NH); 13C NMR (DMSO-d6):
d 21.3 (Me), 55.4, 55.7
M
d
2.32 (3H, s,
(OMe), 87.2, 92.4, 128.1, 131.0 (aryl CH), 105.3, 115.3, 129.2, 129.9,
Me), 3.67 (3H, s, OMe), 3.58 (3H, s, OMe), 6.35 (1H, d, J 1.8 Hz, H5),
7.11 (1H, d, J 2.1 Hz, H7), 7.15 (2H, d, J 7.8 Hz, aryl H), 7.42 (2H, d, J
8.1 Hz, aryl H), 7.53 (1H, s, H2), 7.60e7.63 (3H, m, aryl H), 8.06 (2H,
131.8,132.0,132.1,138.3 (aryl C); HRMS (ESI): [M]þ, found 346.0434.
79
C17
H BrNO2 requires 346.0443.
16
d, J 7.2 Hz, aryl H); 13C NMR (DMSO-d6):
d
21.2 (Me), 55.7, 56.1
4.1.28. 2,5-Dibromo-4,6-dimethoxy-3-phenylindole (29). This was
prepared as described for 2-bromoindoles 26 using 2,5-dibromo-N-
phenylsulfonyl-indole 27 (0.32 g, 5.7 mmol) and potassium hy-
droxide (1.1 g) suspended in dry methanol (20 mL) and heated
under reflux for 45 min. The cooled reaction mixture was poured
into ice water and filtered and the dried solid was recrystallised
from dichloromethane/light petroleum to give the dibromoindole
(OMe), 90.1, 95.6, 121.7, 127.3, 128.6, 129.7, 130.3, 135.1 (aryl CH),
112.5, 124.4, 134.0, 136.2, 137.1, 154.8, 159.4 (aryl C); HRMS (ESI):
[M]þ, found 408.1255. C23H21NO4S requires 408.1270.
4.1.25. 2-Bromo-4,6-dimethoxy-1-(phenylsulfonyl)-3-(p-tolyl)indole
(26b). N-Phenylsulfonyindole 25b (0.23 g, 0.56 mmol) was

P.S.R. Mitchell et al. / Tetrahedron 68 (2012) 8163e8171
8171
29 as white crystals (0.23 g, 98%), mp 220 ꢁC (dec); [Found: C, 46.6;
H, 3.4; N, 3.2. C16H13Br2NO2 requires C, 46.8; H, 3.2; N, 3.4%]; nmax
(Nujol) 3300, 1380, 1300, 1080 cmꢀ1
lmax (MeOH) 241 nm (
15,500 cmꢀ1 ꢀ1), 271 (9500), 294 (7800); 1H NMR (300 MHz,
CDCl3): 3.21 (3H, s, OMe), 3.93 (3H, s, OMe), 6.70 (1H, s, H7),
7.35e7.58 (5H, m, aryl H), 8.21 (1H, bs, NH); 13C NMR (75 MHz,
CDCl3): 56.8, 61.0 (OMe), 90.3 (C7), 127.0, 127.6, 130.8 (aryl CH),
References and notes
1. Powers, J. C. In The Chemistry of Heterocyclic Compounds, Indoles, Part 2;
Houlihan, W. J., Ed.; John Wiley: New York, NY, 1972.
2. Joule, J. A.; Smith, G. F. Heterocyclic Chemistry, 2nd ed.; Chapman and Hall:
London, 1978.
3. Piers, K.; Meimaroglou, C.; Jardine, R. V.; Brown, R. K. Can. J. Chem. 1963, 41,
2339e2401.
4. Bocchi, V.; Palla, G. Synthesis 1982, 1096e1097.
;
3
M
d
d
100.7, 106.2 (C2 and C5), 115.5 (C3a), 116.6 (C3), 133.1, 136.6 (C7a
and C10), 150.6, 153.3 (CeOMe); Mass spectrum: m/z 414 (Mþ1,
81Br81Br, 9%), 413 (M, 81Br81Br, 50), 412 (Mþ1, 81Br79Br, 18), 411 (M,
81Br79Br, 100), 410 (Mþ1, 79Br79Br, 13), 409 (M, 79Br79Br, 53), 398
(10), 396 (20), 394 (13), 353 (20), 317 (45), 315 (47), 302 (20), 300
(22), 274 (22), 272 (23), 206 (36), 193 (36), 178 (34), 177 (36), 165
(50), 164 (60).
5. Hinman, R. L.; Baumann, C. P. J. Org. Chem. 1964, 29, 1206e1215.
6. Black, D. StC.; Keller, P. A.; Kumar, N. Tetrahedron 1992, 36, 7601e7608.
7. Mistry, A. G.; Smith, G.; Bye, M. R. Tetrahedron Lett. 1986, 27, 1051e1054.
8. Legetter, B. E.; Brown, R. K. Can. J. Chem. 1960, 38, 1467e1471.
9. Glennon, R. A.; Schubert, E.; Jacyno, J. M. J. Med. Chem. 1980, 23, 1222e1226.
10. Jones, A. W.; Purwono, B.; Bowyer, P. K.; Mitchell, P. S. R.; Kumar, N.; Nugent, S.
J.; Jolliffe, K. A.; Black, D. StC. Tetrahedron 2004, 60, 10779e10786.
11. Keawin, T.; Rajviroongit, S.; Black, D. StC. Tetrahedron 2005, 61, 853e861.
12. Black, D. StC.; Kumar, N.; Wong, L. C. H. Aust. J. Chem. 1986, 39, 15e20.
13. Black, D. StC.; Bowyer, M. C.; Bowyer, P. K.; Ivory, A. J.; Kim, M.; Kumar, N.;
McConnell, D. B.; Popiolek, M. Aust. J. Chem. 1994, 47, 1741e1750.
14. Clayton, K. A.; Black, D. StC.; Harper, J. B. Tetrahedron 2007, 63, 10615e10621.
15. Harwood, L. M. Aldrichimica Acta 1985, 18, 25.
Acknowledgements
16. Kobayashi, G.; Saito, T.; Kitano, Y. Synthesis 2011, 3225e3234.
17. Black, D. StC.; Craig, D. C.; Kumar, N.; Wong, L. C. H. J. Chem. Soc., Chem. Commun.
1985, 1172e1173.
18. Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R. J. Chem. Soc., Chem.
Commun. 1993, 819e821.
Financial support from the Australian Research Council is
gratefully acknowledged. P.S.R.M. and S.J.N. acknowledge receipt of
postgraduate scholarships from the Australian Government. I.F.S.
and H.K. acknowledge receipt of postgraduate scholarships from
the Turkish Government.
19. Wood, K.; Black, D. StC.; Namboothiri, I. N. N.; Kumar, N. Tetrahedron Lett. 2010,
51, 1606e1608.