Synthesis of 5-(7′-indolyl)oxazoles and 2,5-di-(7′-indolyl) oxazoles

Article abstract of DOI:10.1016/j.tet.2012.12.084

The synthesis of 7-aminoacetylindoles was achieved via the hydrogenation of 7-acylcyanides, which were produced through the oxidation of indole-7-cyanohydrin silylether intermediates. 7-Oxotryptamines were subsequently converted into 5-(7′-indolyl)oxazole

Full text of DOI:10.1016/j.tet.2012.12.084

Tetrahedron 69 (2013) 2193e2198
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Tetrahedron
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Synthesis of 5-(70-indolyl)oxazoles and 2,5-di-(70-indolyl)oxazoles
*
Hakan Kandemir, Kasey Wood, Naresh Kumar, David StC. Black
School of Chemistry, The University of New South Wales, 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 30 October 2012
Received in revised form 7 December 2012
Accepted 21 December 2012
Available online 11 January 2013
The synthesis of 7-aminoacetylindoles was achieved via the hydrogenation of 7-acylcyanides,
which were produced through the oxidation of indole-7-cyanohydrin silylether intermediates.
7-Oxotryptamines were subsequently converted into 5-(70-indolyl)oxazoles by reaction with acetic
anhydride followed by phosphoryl chloride, and to 2,5-di-(70-indolyl)oxazoles by reaction with
7-trichloroacetylindoles followed by phosphoryl chloride.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Bis-indoles
Oxazoles
7-Aminoacetylindoles
Indoles
1. Introduction
In view of the interesting biological activities exhibited by in-
dole linked oxazoles, we were interested in the development of
Indole-related natural products bearing the oxazole moiety are
an important class of heterocyclic scaffolds as they are naturally
occurring and known to display diverse biological activity. To date,
however, the structural variations offered in these systems are
confined to those with 5,30-linkages. For example, the naturally
occurring 5-(30-indolyl)oxazoles, such as the dipeptide derivative
almazole C,1 the extracellular alkaloid pimprinine 1,2,3 which pos-
sesses antiepileptic effects and its analogues WS-30581 A and B,
which show inhibitory effects of platelet aggregation.4 The labra-
dorins, such as labradorin 1 2 are other 2-substituted-5-(30-indolyl)
oxazoles, which display inhibitory activity against various human
cancer cells,5 while martefragin A 3 has been reported to be
a strong inhibitor of lipid peroxidation.6
novel 5-(7ʹ-indolyl)oxazoles and 2,5-di(70-indolyl)oxazoles.
Many synthetic approaches have been reported for the synthesis
of indole linked oxazoles. Some of these protocols involve
rhodium catalysed reactions of diazoacetylindoles with nitriles,7
aza-Wittig reactions of iminophosphoranes derived from 3-
azidoacetyl-1-methylindole with isocyanates8 and the conversion
of 3-acetylindole into 5-(30-indolyl)oxazoles using metal free
[hydroxyl(2,4-dinitrobenzenesulfonyloxy)iodo]benzene.9 Alterna-
tively, the indole ring can be derived from a 5-acylmethylene-
substituted-oxazole using the Fischer synthetic sequence.10
Recently, the synthetic preparation of indolyloxazoles has been
facilitated by the use of oxotryptamine via cyclodehydration of
acylaminoketo-
nes.5,6,11e13
3-Aminoacetylindole is most typically synthesised from the
corresponding 3-acylcyanide via hydrogenation using Pd/C in
acetic acid. In turn, the substrate indolyl-3-carbonyl nitrile can be
prepared via treatment of the readily available indole 3-acid chlo-
ride with copper (I) cyanide.14 Another efficient synthesis of the
acylcyanide can be achieved via the cyanohydrin silylether in-
termediate, which is prepared through the heating of indole-3-
carbaldehyde with trimethylsilylcyanide (TMSCN) under reflux in
acetonitrile. Oxidation of the silyl cyanohydrin intermediate with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane at
room temperature then affords the corresponding indole carbonyl
nitrile.15 It has been previously reported that 4,6-dimethoxyindoles
can react with oxalyl chloride to yield 7-glyoxyloyl chlorides and
some derived acids, esters or amides in 20e74% yields.16 In contrast,
indole-7-carbaldehydes can be prepared in 70e100% yields via
* Corresponding author. Tel.: þ61 2 9385 4657; fax: þ61 2 9385 6141; e-mail
address: d.black@unsw.edu.au (D.StC. Black).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.084

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H. Kandemir et al. / Tetrahedron 69 (2013) 2193e2198
Vilsmeier formylation.17 We therefore followed this latter approach
for the synthesis of 7-aminoacetylindoles followed by their use as
precursors for the preparation of 5-(70-indolyl)oxazoles and 2,5-
di(70-indolyl)oxazoles.
Interestingly, the 1H NMR spectrum of the anticipated com-
pound 7c demonstrated resonances for two H5 protons at 6.5 and
d
two indole NHs at 11.58 and 11.63. Two carbonyl resonances at
190.0 and 190.1 were observed in the 13C NMR spectrum, indicating
a mixture of halogenated and dehalogenated 7-aminoacetylindoles
7c and d, respectively. The formation of this mixture was further
confirmed by a high-resolution mass spectrum, which showed two
molecular ions at 345.0998 (MþH)þ and 311.1389 (MþH)þ corre-
sponding to oxotryptamines 7c and d, respectively. Attempts to
separate the mixture failed because of the high polarity of the
compounds, which remained on the baseline during attempted
thin layer chromatography.
2. Results and discussion
2.1. Synthesis of 7-aminoacetylindoles
The synthesis of 7-acylcyanides 6aec was successfully accom-
plished over two consecutive steps as illustrated in Scheme 1. The
first step involved the treatment of 7-formylindoles 4aec with
TMSCN in acetonitrile at reflux to afford the 7-cyanohydrin sily-
lether intermediates 5aec in good yields. The stability of these 7-
indolyl silylethers at room temperature was found to be very
high in comparison to the 3-indolyl silylethers.
2.2. Synthesis of 5-(7ʹ-indolyl)oxazoles
It was of interest to use a monomeric model for the preparation
of 7-oxazole substituted indoles before extending the chemistry to
bis-indole systems. Therefore, the synthetic study began with the
acylation of readily available 7-oxotryptamines 7a, b with acetic
anhydride at 0e10 ꢁC for 4 h to produce the corresponding ketoa-
mides 8a, b in 72% and 71% yield, respectively.
The 1H NMR spectrum of compound 5c, for example, displayed
the trimethylsilyl protons at d 0.2, the CH proton at 6.19 and the H5
proton at 6.26. This assignment was confirmed by both HSQC and
HSBC analysis. The 13C NMR spectrum indicated the presence of the
trimethylsilyl groups and the nitrile groups with carbon resonances
at
d 0.58 and 119.2, respectively. Also, the nitrile absorption band
The next step involved the treatment of indoles 8a, b with excess
phosphoryl chloride at reflux in ethyl acetate for 2 h. This process
afforded the 7-methyloxazoles 9a, b in 79% and 51% yield, re-
spectively (Scheme 2).
was seen at 3428 cmꢀ1 in the infrared spectrum.
The compounds 5aec were subsequently oxidised with DDQ in
dioxane at room temperature to the corresponding 7-acylcyanides
6aec. Although a single product was isolated from the reaction
mixture, the residue was subjected to column chromatography in
order to eliminate baseline impurities. The orange products were
obtained in 80e90% yields. The ensuing step was hydrogenation of
the 7-acylcyanides to the 7-aminoacetylindoles as shown in Scheme
1. Accordingly, 7-acylcyanides 6aec were stirred under hydrogen in
the presence of 10% Pd/C in a mixture of ethyl acetate and acetic acid
(2:3) for 20 h to afford 7-aminoacetylindoles 7aec in 65e91% yields.
Scheme 2. Reagents and conditions: (a) (CH3CO)2, 0e10 ꢁC, 4 h (71e72%); (b) POCl3,
EtOAc, reflux, 2 h (51e79%).
2.3. Synthesis of 2,5-di(7-indolyl)oxazoles
With the successful execution of the monomeric model in hand,
preparation of related bis-indole systems was examined. The suc-
cessful preparation of 7,70-bis-oxazoles 12a, b was achieved with
a convenient two-step process as shown in Scheme 3. The first
step involved heating 7-aminoacetylindoles 7a, b with 7-trich-
loroacetylindoles 10a, b at reflux overnight in the presence of
triethylamine in acetonitrile to afford the unsymmetrical 7,70-am-
ide linked bis-indoles 11a, b in 61% and 55% yield, respectively.
The new amide functionality was clearly evident in the 1H NMR
and 13C NMR spectra of compound 11a, with the appearance of an
Scheme 1. Reagents and conditions: (a) TMSCN, CH3CN, reflux, overnight (64e78%);
(b) DDQ, dioxane, rt (80e90%); (c) H2, 10% Pd/C, EtOAc/AcOH, rt (only 7a,b 77e91% as
HCl and HOAc salts, respectively).
amide NH proton as a triplet at
d 9.33 (J 8.5 Hz) and the carbonyl

H. Kandemir et al. / Tetrahedron 69 (2013) 2193e2198
2195
4. Experimental
4.1. General
Melting points were measured using a Mel-Temp melting point
apparatus and are uncorrected. Infrared spectra were recorded on
a Mattson Genesis Series FTIR spectrophotometer as KBr disks.
Ultraviolet spectra were measured using a Varian Cary 100 spec-
trophotometer. 1H and 13C NMR spectra were obtained in the des-
ignated solvents on a Bruker DPX 300. High-resolution mass
spectrometry was performed by the Mass Spectrometry unit at the
Bioanalytical Mass Spectrometry unit in the School of Chemistry,
UNSW. Microanalysis was performed on a Carlo Erba Elemental
Analyzer EA 1108 at the Campbell Microanalytical Laboratory,
University of Otago, New Zealand. Anhydrous solvents were ob-
tained using a PureSolv MD Solvent Purification System. Ajax
Finechem Silica 200e325 mesh was used for column chromatog-
raphy and Merck silica gel 60H was used for flash chromatography.
4.2. 2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-(trime-
thylsilyloxy)acetonitrile (5a)
Indole-7-carbaldehyde 4a (1.70 g, 4.76 mmol) was heated under
reflux with TMSCN (3.00 mL, 22.5 mmol) in acetonitrile (30 mL)
overnight. The solution was cooled and the solvent removed under
reduced pressure. The residue was purified by flash chromatogra-
phy using dichloromethane as eluent to afford the title compound
5a (1.70 g, 78%) as a white solid, mp 171e173 ꢁC; nmax (KBr): 3474,
3054, 3003, 2957, 2842, 1599, 1518, 1448, 1354, 1254, 1076 cmꢀ1
lmax (THF): 245 nm (ε 37,900 cmꢀ1 ꢀ1), 324 (21,250); 1H NMR
(300 MHz, CDCl3): 0.26 (9H, s, Me), 3.73 (3H, s, OMe), 3.95 (3H, s,
OMe), 6.22 (1H, s, CH), 6.24 (1H, s, H5), 7.25e7.42 (10H, m, aryl H),
8.97 (1H, s, NH); 13C NMR (75 MHz, CDCl3):
0.51 (Me), 55.3, 56.7
;
M
d
Scheme 3. Reagents and conditions: (a) Et3N, CH3CN, reflux (55e61%); (b) POCl3, ethyl
acetate, reflux, 2 h (61e63%).
d
(OMe), 57.2 (CH), 88.0 (C5), 98.9 (C), 114.1 (C), 114.5 (C), 119.3 (CN),
126.0 (CH), 127.1 (CH), 127.3 (CH), 127.8 (CH), 128.5 (CH), 131.4 (CH),
132.6 (C), 132.9 (C), 135.4 (C), 135.6 (C), 152.7 (C), 156.1 (C); HRMS
(ESIþ): [MþH]þ, found 457.1941. C27H29N2O3Si requires 457.1947.
groups at 167.5 and 194.1. The 1H NMR spectrum also showed the
indole NH protons as downfield singlets at
d 11.10 and 11.29, in-
dicating strong hydrogen bonding between the carbonyl groups
and the indole NHs. The methylene protons appeared as a broad
4.3. 2-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-((trime-
singlet at
d 4.93. In addition, the infrared spectrum also showed two
thylsilyl)oxy)-acetonitrile (5b)
carbonyl resonances at 1588 and 1615 cmꢀ1
.
In the next step, cyclodehydration was carried out by the
treatment of bis-indoles 11a, b with excess phosphoryl chloride at
reflux in ethyl acetate for 2 h. The process afforded the desired di-
indolyloxazoles 12a, b in 63% and 61% yield, respectively (Scheme
3). Purification by column chromatography removed baseline
impurities.
The high-resolution mass spectrometry of indole 12b showed
a molecular ion at 640.2414, which was consistent with the struc-
ture 12b (MþNa)þ. The 1H NMR spectrum of the compound 12b
indicated the disappearance of the amide nitrogen protons of the
Indole-7-carbaldehyde 4b (3.69 g, 12.5 mmol) was heated under
reflux with TMSCN (7 mL, 52.5 mmol) in acetonitrile (60 mL)
overnight. The solution was cooled and the solvent removed under
reduced pressure. The residue was purified by flash chromatogra-
phy using dichloromethane as eluent to afford the title compound
5b (3.16 g, 64%) as a white solid, mp 119e121 ꢁC; (found: C, 67.08; H,
6.92; N, 7.14; C22H26N2O3Si requires C, 66.97; H, 6.64; N, 7.10%); nmax
(KBr): 3348, 1620, 1589, 1466, 1343, 1254, 1215, 1072, 849 cmꢀ1
lmax (MeOH): 295 nm (ε 13,550 cmꢀ1 ꢀ1); 1H NMR (300 MHz,
CDCl3): 0.01 (9H, s, Me), 2.19 (3H, s, Me), 3.62 (3H, s, OMe), 3.72
;
M
d
starting material 11b at
7.64. The indole nitrogens remained as downfield singlets at
and 11.31. The compound 12b was not soluble enough to obtain
13C NMR spectrum.
d
9.37 and the appearance of a CH proton at
(3H, s, OMe), 6.0 (1H, s, CH), 6.05 (1H, s, H5), 6.87 (1H, d, J 2.4 Hz,
H2), 7.00, 7.29 (4H, 2d, J 8.3 Hz, aryl H), 8.68 (1H, s, NH); 13C NMR
d
10.56
(75 MHz, CDCl3): d 0.47 (Me), 21.2 (Me), 55.3, 56.8 (OMe), 57.0 (CH),
a
87.9 (C5), 99.4 (C), 111.6 (C), 118.6 (C), 119.4 (CN), 121.5 (C2), 128.4
(CH), 129.5 (CH), 132.8 (C), 135.4 (C), 136.5 (C), 152.8 (C), 156.0 (C);
HRMS (ESIþ): [MþH]þ, found 395.1785. C22H27N2O3Si requires
395.1791.
3. Conclusions
In conclusion, the synthesis of 7-aminoacetylindoles was suc-
cessfully achieved via hydrogenation of the corresponding indole-
7-acylcyanides. Amide linked bis-indoles were obtained upon re-
action of 7-aminoacetylindoles with indole-7-trichloroacetyl
chlorides and underwent cyclisation with phosphoryl chloride to
form oxazole linked bis-indoles. The preparation of monomeric 7-
oxadiazoles from 7-ketoamides was also achieved in the same
manner.
4.4. 2-(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-
(trimethylsilyloxy)acetonitrile (5c)
Indole-7-carbaldehyde 4c (1.70 g, 5.39 mmol) was heated under
reflux with TMSCN (3 mL, 22.5 mmol) in acetonitrile (40 mL)
overnight. The solution was cooled and the solvent was removed
under reduced pressure. The residue was purified by flash

2196
H. Kandemir et al. / Tetrahedron 69 (2013) 2193e2198
chromatography using dichloromethane as eluent to afford the title
solid obtained was filtered and washed with water until a colour-
less filtrate was observed. The red solid was dissolved in
dichloromethane and the solution passed through a plug of silica to
yield the title compound 6c (1.05 g, 85%) as an orange solid, mp
230e232 ꢁC; nmax (KBr): 3411, 1590, 1471, 1352, 1248, 1219, 1094,
compound 5c (1.60 g, 71%) as a white solid, mp 155e157 ꢁC; nmax
(KBr): 3428, 2962, 1594, 1518, 1462, 1343, 1255, 1212, 1052 cmꢀ1
;
lmax (THF): 234 nm (ε 34,550 cmꢀ1
M
ꢀ1), 285 (17,500); 1H NMR
(300 MHz, CDCl3): 0.20 (9H, s, Me), 3.83 (3H, s, OMe), 3.93 (3H, s,
d
OMe), 6.19 (1H, s, CH), 6.26 (1H, s, H5), 7.08 (1H, d, J 2.4 Hz, H2),
796 cmꢀ1
;
lmax (THF): 218 nm (ε 27,700 cmꢀ1
M
ꢀ1), 266 (21,850),
3.96 (3H, s, OMe),
7.33, 7.51 (4H, 2d, J 8.6 Hz, aryl H), 8.93 (1H, s, NH); 13C NMR
364 (12,100); 1H NMR (300 MHz, DMSO-d6):
d
(75 MHz, CDCl3):
d
0.58 (Me), 55.2, 56.7 (OMe), 56.9 (CH), 87.8 (C5),
4.04 (3H, s, OMe), 6.46 (1H, s, H5), 7.18 (1H, d, J 2.4 Hz, H2), 7.36,
99.3 (C), 111.2 (C), 117.4 (C), 119.2 (CN), 121.7 (C2), 127.6 (CH), 130.7
(CH), 131.6 (C), 134.2 (C), 136.4 (C), 152.8 (C),155.7 (C); HRMS (ESIþ):
[MþH]þ, found 415.1237. C21H24ClN2O3Si requires 415.1245.
7.48 (4H, 2d, J 8.8 Hz, aryl H), 11.63 (1H, d, J 2.4 Hz, NH); 13C NMR
(75 MHz, DMSO-d6):
d 56.7, 57.4 (OMe), 88.9 (C5), 103.3 (C), 110.2
(C), 116.1 (C), 117.6 (CN), 124.3 (C2), 128.0 (CH), 131.1 (CH), 131.1,
134.0 (C), 136.8 (C), 160.3 (C), 163.5 (C), 164.1 (C]O); HRMS (ESIþ):
[MþNa]þ, found 363.0502. C18H13ClN2NaO3 requires 363.0512.
4.5. 4,6-Dimethoxy-2,3-diphenyl-1H-indole-7-carbonyl cya-
nide (6a)
4.8. 2-Amino-1-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-
A solution of DDQ (0.760 g, 3.35 mmol) in dioxane (15 mL) was
added dropwise to the indole 5a (1.02 g, 2.23 mmol) dissolved in
dioxane (30 mL) at room temperature. The mixture was stirred for
3 h and the solid formed was thereafter filtered off. The filtrate was
concentrated, the resulting residue was treated with water, the
solid obtained was filtered and washed with water until a colour-
less filtrate was observed. The red solid was dissolved in
dichloromethane and the solution passed through a plug of silica to
yield the title compound 6a (0.77 g, 90%) as an orange solid, mp
208e210 ꢁC; nmax (KBr): 3403, 1675, 1574, 1501, 1467, 1352,
ethanone hydrochloride (7a)
A mixture of 7-carbonyl cyanide 6a (1.08 g, 2.82 mmol) and 10%
Pd/C (0.4 g) in a mixture of ethyl acetate/acetic acid solution (20:40,
60 mL) was stirred under a balloon of hydrogen gas. After 20 h, the
reaction mixture was filtered over Celite and the filtrate was con-
centrated under reduced pressure. The resulting residue was dis-
solved in ethanol containing concentrated hydrochloric acid (5% by
volume). Concentration under reduced pressure yielded the title
compound 7a (1.09 g, 91%) as a yellow solid, mp 262 ꢁC (dec); nmax
(KBr): 3423, 2848, 2578, 1624, 1590, 1544, 1462, 1393, 1360, 1252,
987 cmꢀ1
363 (16,250); 1H NMR (300 MHz, CDCl3):
(3H, s, OMe), 6.13 (1H, s, H5), 7.24e7.34 (10H, m, aryl H), 10.53 (1H,
s, NH); 13C NMR (75 MHz, CDCl3):
55.8, 56.4 (OMe), 87.3 (C5),
;
lmax (THF): 231 nm (ε 33,250 cmꢀ1 Mꢀ1), 293 (23,900),
d
3.86 (3H, s, OMe), 4.09
1168, 1146, 989 cmꢀ1
;
lmax (MeOH): 328 nm (ε 22,150 cmꢀ1 Mꢀ1);
3.80 (3H, s, OMe), 4.06 (3H, s,
1H NMR (300 MHz, DMSO-d6):
d
d
OMe), 4.30 (2H, d, J 4.0 Hz, CH2), 6.48 (1H, s, H5), 7.23e7.32 (10H, m,
103.3 (C), 113.0 (C),115.4 (C),115.6 (CN),126.6 (CH),127.5 (CH), 127.6
(CH), 127.8 (CH), 128.5 (CH), 131.1 (CH), 131.4 (C), 133.6 (C), 134.5 (C),
137.2 (C), 161.3 (C), 163.2 (C), 164.2 (C]O); HRMS (ESIþ): [M]þ,
found 382.1306. C24H18N2O3 requires 382.1317.
aryl H), 8.45 (3H, br s, NH3), 11.08 (1H, br s, NH); 13C NMR (75 MHz,
DMSO-d6): d 48.6 (CH2), 56.3, 57.4 (OMe), 89.0 (C5), 101.7 (C), 112.8
(C), 114.8 (C), 126.9 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH), 129.1
(CH), 131.5 (CH), 132.1 (C), 132.9 (C), 135.5 (C), 137.4 (C), 161.3 (C),
162.2 (C), 190.8 (C]O); HRMS (ESIþ): [MþH]þ, found 387.1702.
C24H23N2O3 requires 387.1709.
4.6. 2-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-carbonyl cya-
nide) (6b)
4.9. 2-Amino-1-(4,6-dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-
A solution of DDQ (2.40 g, 10.6 mmol) in dioxane (50 mL) was
added dropwise to the indole 5b (2.61 g, 6.62 mmol) dissolved in
dioxane (30 mL) at room temperature. The mixture was stirred for
3 h and the solid formed was thereafter filtered off. The filtrate was
concentrated, the resulting residue was treated with water, the
solid obtained was filtered and washed with water until a colour-
less filtrate was observed. The red solid was dissolved in
dichloromethane and the solution passed through a plug of silica to
yield the title compound 6b (1.69 g, 80%) as an orange solid, mp
220e222 ꢁC; (found: C, 71.18; H, 4.99; N, 8.75; C19H16N2O3 requires
C, 71.24; H, 5.03; N, 8.74%); nmax (KBr): 3381, 1583, 1502, 1466,
ethanone hydroacetate (7b)
A mixture of 7-carbonyl cyanide 6b (1.00 g, 3.12 mmol) and 10%
Pd/C (0.40 g) in a mixture of ethyl acetate/acetic acid (30:60, 90 mL)
was stirred under a balloon of hydrogen. After 20 h, the reaction
mixture was filtered over Celite and the filtrate concentrated under
reduced pressure to yield the title compound 7b (0.886 g, 77%) as
a white solid, mp 181e183 ꢁC; nmax (KBr): 3289, 2941, 1563, 1465,
1397, 1344, 1248, 1217, 1184, 1104, 791 cmꢀ1
(ε 28,050 cmꢀ1 ꢀ1); 1H NMR (300 MHz, DMSO-d6):
;
lmax (MeOH): 330 nm
1.84 (3H, s,
M
d
Me), 2.32 (3H, s, Me), 3.90 (3H, s, OMe), 4.02 (3H, s, OMe), 4.93 (2H,
1350, 1313, 1284, 1213, 1091, 976 cmꢀ1
(ε 14,250 cmꢀ1 Mꢀ1), 364 (10,450); 1H NMR (300 MHz, DMSO-d6):
2.32 (3H, s, Me), 3.96 (3H, s, OMe), 4.06 (3H, s, OMe), 6.47 (1H, s,
H5), 7.12 (1H, s, H2), 7.15, 7.37 (4H, 2d, J 8.1 Hz, aryl H), 11.57 (1H, s,
NH); 13C NMR (75 MHz, DMSO-d6):
21.2 (Me), 56.7, 57.4 (OMe),
;
lmax (MeOH): 305 nm
br s, CH2), 6.48 (1H, s, H5), 7.23e7.32 (5H, m, aryl HþH2), 8.45 (3H,
br s, NH3), 11.08 (1H, br s, NH). 13C NMR (75 MHz, DMSO-d6):
d 21.2,
d
22.5 (Me), 52.2 (CH2), 56.0, 57.1 (OMe), 88.5 (C5),102.9 (C),110.5 (C),
117.5 (C), 123.3 (C2),128.7 (CH), 129.4 (CH), 133.1 (C), 134.9 (C), 137.9
(C), 159.9 (C), 161.2 (C), 173.1 (C]O), 197.2 (C]O); HRMS (ESIþ):
[MþH]þ, found 325.1546. C19H21N2O3 requires 325.1552.
d
88.9 (C5), 103.4 (C), 110.5 (C), 116.3 (C), 119.0 (CN), 123.8 (C2), 128.8
(CH), 129.5 (CH), 132.3 (C), 135.5 (C), 136.9 (C), 160.3 (C), 163.6 (C),
164.4 (C]O); HRMS (ESIþ): [MþH]þ, found 321.1239. C19H16N2O3
requires 321.1239.
4.10. N-(2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-
oxoethyl)-acetamide (8a)
4.7. 3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indole-7-carbonyl
cyanide (6c)
7-Aminoacetylindole 7a (0.340 g, 0.880 mmol) was dissolved in
acetic anhydride (15 mL) and the mixture was stirred for 4 h in an
ice-water bath. Ice-water was added and the resulting solid was
filtered, washed with water and dried. The crude product was
recrystallised from dichloromethane/n-hexane to give the title
compound 8a (0.25 g, 72%) as a yellow solid, mp 220e222 ꢁC;
(found: C, 72.76; H, 5.60; N, 6.56; C26H24N2O4 requires C, 72.88; H,
5.65; N, 6.54%); nmax (KBr): 3405, 1614, 1587, 1390, 1223, 1165,
A solution of DDQ (1.64 g, 7.22 mmol) in dioxane (35 mL) was
added dropwise to the indole 5c (1.50 g, 3.62 mmol) dissolved in
dioxane (30 mL) at room temperature. The mixture was stirred for
3 h and the solid formed was thereafter filtered off. The filtrate was
concentrated, the resulting residue was treated with water, the

H. Kandemir et al. / Tetrahedron 69 (2013) 2193e2198
2197
990 cmꢀ1
;
lmax (THF): 324 nm (ε 33,750 cmꢀ1
M
ꢀ1); 1H NMR
(0.051 g, 51%) as a white solid, mp 202e204 ꢁC; nmax (KBr): 3253,
(300 MHz, CDCl3):
d
2.13 (3H, s, Me), 3.80 (3H, s, OMe), 4.04 (3H, s,
2956, 2923, 1596, 1541, 1459, 1339, 1299, 1208, 1121, 1098,
OMe), 4.74 (2H, d, J 4.2 Hz, CH2), 6.16 (1H, s, H5), 6.89 (1H, br s, NH),
814 cmꢀ1 lmax (THF): 322 nm (ε 24,000 cmꢀ1 ꢀ1); 1H NMR
; M
7.23e7.40 (10H, m, aryl H), 11.06 (1H, br s, NH); 13C NMR (75 MHz,
(300 MHz, CDCl3):
d 2.31 (3H, s, Me), 2.51 (3H, s, Me), 3.76 (3H, s,
CDCl3):
d
23.3 (Me), 50.9 (CH2), 55.4, 56.2 (OMe), 87.0 (C5), 102.2
OMe), 3.91 (3H, s, OMe), 6.28 (1H, s, H5), 7.01 (1H, d, J 2.4 Hz, H2),
7.10e7.42 (4H, 2d, J 8.1 Hz, aryl H), 7.33 (1H, s, CH), 9.23 (1H, br s,
(C), 113.1 (C), 114.5 (C), 126.3 (CH), 127.3 (CH), 127.5 (CH), 127.8 (CH),
128.5 (CH), 131.4 (CH), 132.3 (C), 132.9 (C), 135.5 (C), 138.1 (C), 160.8
(C), 161.6 (C), 170.1 (C]O), 193.5 (C]O); HRMS (ESIþ): [MþNa]þ,
found 451.1623. C26H24N2NaO4 requires 451.1634.
NH); 13C NMR (75 MHz, CDCl3):
d 14.2, 21.2 (Me), 55.3, 56.5 (OMe),
88.6 (C5), 94.6 (C), 111.2 (C), 118.6 (C), 121.1 (CH), 124.0 (C2),
128.4 (CH), 129.5 (CH), 132.9 (C), 134.5 (C), 135.4 (C), 148.0 (C), 153.6
(C), 154.8 (C), 158.0 (C); HRMS (ESIþ): [M]þ, found 348.1472.
C21H20N2O3 requires 348.1474.
4.11. N-(2-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-
oxoethyl)-acetamide (8b)
4.14. (N-(2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-
oxoethyl)-4,6-dimethoxy-2,3-diphenyl-1H-indole-7-
carboxamide) (11a)
7-Aminoacetylindole 7b (0.330 g, 1.02 mmol) was dissolved in
acetic anhydride (15 mL) and the mixture was stirred for 4 h in an
ice-water bath. Ice-water was added and the resulting solid was
filtered, washed with water and dried. The crude product was
recrystallised from dichloromethane/n-hexane to give the title
compound 8b (0.23 g, 71%) as a yellow solid, mp 208e210 ꢁC;
(found: C, 68.78; H, 6.27; N, 7.53; C21H22N2O4 requires C, 68.84; H,
To a suspension of 7-aminoacetylindole 7a (0.215 g, 0.557 mmol)
and 7-trichloroacetylindole 10a (0.240 g, 0.510 mmol) in acetoni-
trile (40 mL), triethylamine (10 drops, w0.5 mL) was added and the
mixture was heated under reflux overnight. The solvent was re-
moved under reduced pressure and the resulting solid was treated
with water, filtered, dried and washed with methanol to give the
title compound 11a (0.23 g, 61%) as a white solid, mp 291e293 ꢁC;
nmax (KBr): 1615, 1588, 1493, 1461, 1388, 1340, 1221, 1165, 994,
6.05; N, 7.65%); (nmax KBr): 3408, 1615, 1583, 1345, 1222, 1085 cmꢀ1
lmax (THF): 328 nm (ε 13,300 cmꢀ1 ꢀ1); 1H NMR (300 MHz,
CDCl3): 2.13 (3H, s, Me), 2.41 (3H, s, Me), 3.93 (3H, s, OMe), 4.06
;
M
d
(3H, s, OMe), 4.72 (2H, d, J 3.7 Hz, CH2), 6.22 (1H, s, H5), 6.88 (1H, br
s, NH), 7.10 (1H, d, J 2.4 Hz, H2), 7.21, 7.48 (4H, 2d, J 8.1, aryl H), 10.93
697 cmꢀ1
;
lmax (THF): 325 nm (ε 52,800 cmꢀ1
M
ꢀ1); 1H NMR
(1H, br s, NH); 13C NMR (75 MHz, CDCl3):
d
21.2, 23.3 (Me), 50.9
(300 MHz, CDCl3): d
3.67 (3H, s, OMe), 3.71 (3H, s, OMe), 3.98 (3H, s,
(CH2), 55.4, 56.2 (OMe), 86.8 (C5),102.4 (C),110.5 (C),118.7 (C),121.4
(C2), 128.5 (CH), 129.4 (CH), 132.5 (C), 135.6 (C), 139.0 (C), 160.7 (C),
161.7 (C), 170.1 (C]O), 193.4 (C]O); HRMS (ESIþ): [MþH]þ, found
367.1653. C21H23N2O4 requires 367.1658.
OMe), 4.09 (3H, s, OMe), 4.93 (2H, d, J 4.4 Hz, CH2), 6.09 (1H, s, H5),
6.16 (1H, s, H5), 7.09e7.35 (20H, m, aryl H), 9.33 (1H, t, J 8.5 Hz, NH),
11.10 (1H, br s, NH), 11.29 (1H, br s, NH); 13C NMR (75 MHz, CDCl3):
d
51.4 (CH2), 55.3, 55.3, 56.3, 57.2 (OMe), 87.0 (C5), 87.8 (C5), 97.7 (C),
102.5 (C), 113.0 (C), 113.6 (C), 113.7 (C), 114.4 (C), 125.9 (CH), 126.2
(CH), 126.9 (CH), 127.2 (CH), 127.4 (CH), 127.5 (CH), 128.0 (CH), 128.1
(CH), 128.3 (CH), 128.5 (CH), 131.4 (CH), 131.6 (CH), 132.6 (C), 132.7
(C), 133.0 (C), 133.1 (C), 135.6 (C), 136.1 (C), 138.2 (C), 138.7 (C), 157.1
(C), 157.5 (C), 160.5 (C), 161.4 (C), 167.5 (C]O), 194.1 (C]O); HRMS
(ESIþ): [MþH]þ, found 742.2916. C47H40N3O6 requires 742.2917.
4.12. 5-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-
methyloxazole (9a)
To a solution of the indole 8a (0.120 g, 0.280 mmol) in ethyl
acetate (20 mL), phosphoryl chloride (5 mL) was added and the
solution was heated under reflux for 2 h. The solvent was evapo-
rated under reduced pressure and the residue was treated with
water (20 mL) and made strongly alkaline by the addition of 5 N
NaOH (20 mL). The resulting precipitate was collected by filtration,
washed with water, dried and purified by flash chromatography
using dichloromethane as eluent to afford the title compound 9a
(0.092 g, 79%) as a brown solid, mp 229e231 ꢁC; (found: C, 74.75; H,
5.31; N, 6.61; C26H22N2O3 0.1 CH2Cl2 requires C, 74.82; H, 5.34; N,
6.69%); nmax (KBr): 3364, 2931, 2838, 1603, 1451, 1433, 1347,
4.15. N-(2-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-
oxoethyl)-4,6-dimethoxy-3-(p-tolyl)-1H-indole-7-
carboxamide (11b)
To a suspension of 7-aminoacetylindole 7b (0.241 g, 0.744 mmol)
and 7-trichloroacetylindole 10b (0.270 g, 0.650 mmol) in acetoni-
trile (40 mL), triethylamine (10 drops, w0.5 mL) was added and the
mixture was heated under reflux overnight. The solvent was re-
moved under reduced pressure and the resulting solid was treated
with water, filtered, dried and washed with methanol to give the
title compound 11b (0.22 g, 55%) as a brown solid, mp 284e286 ꢁC;
1298, 1266, 1209, 1071, 990, 699 cmꢀ1
(ε 32,050 cmꢀ1 Mꢀ1); 1H NMR (300 MHz, CDCl3):
;
lmax (THF): 334 nm
2.64 (3H, s, Me),
d
3.77 (3H, s, OMe), 4.03 (3H, s, OMe), 6.37 (1H, s, H5), 7.28e7.45
(11H, m, CH, aryl H), 9.33 (1H, br s, NH); 13C NMR (75 MHz, CDCl3):
nmax (KBr): 1618, 1585, 1492, 1462, 1332, 1212, 1150, 1105, 794 cmꢀ1
lmax (THF): 323 nm (ε 45,950 cmꢀ1 Mꢀ1); 1H NMR (300 MHz, CDCl3):
d 2.32 (3H, s, Me), 2.33 (3H, s, Me), 3.84 (3H, s, OMe), 3.87 (3H, s,
;
d
14.3 (Me), 55.4, 56.5 (OMe), 88.9 (C5), 94.3 (C), 113.7 (C), 114.7 (C),
124.0 (CH), 126.1 (CH), 127.2 (CH), 127.4 (CH), 127.9 (CH), 128.6 (CH),
131.5 (CH), 132.6 (C), 132.9 (C), 133.6 (C), 135.7 (C), 148.0 (C), 153.7
(C), 155.0 (C), 158.0 (C); HRMS (ESIþ): [MþH]þ, found 411.1706.
C26H23N2O3 requires 411.1709.
OMe), 4.05 (3H, s, OMe), 4.13 (3H, s, OMe), 4.92 (2H, d, J 4.3 Hz, CH2),
6.19, 6.26 (2H, 2s, H5), 7.04, 7.05 (2H, 2d, J 2.5 Hz, H2), 7.10, 7.13 (4H,
2d, J 7.8 Hz, aryl H), 7.41, 7.43 (4H, 2d, J 8.0 Hz, aryl H), 9.37 (1H, t, J
4.3 Hz, NH), 11.0 (1H, br s, NH), 11.12 (1H, br s, NH); HRMS (ESIþ):
[MþNa]þ, found 640.2414. C37H35N3NaO6 requires 640.2424. The
sample was not soluble enough for 13C NMR measurement.
4.13. 5-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-
methyloxazole (9b)
To a solution of the indole 8b (0.105 g, 0.287 mmol) in ethyl
acetate (30 mL), phosphoryl chloride (5 mL) was added and the
solution was heated under reflux for 2 h. The solvent was evapo-
rated under reduced pressure and the residue was treated with
water (20 mL) and made strongly alkaline by the addition of 5 N
NaOH (20 mL). The resulting precipitate was collected by filtration,
washed with water, dried and purified by flash chromatography
using dichloromethane as eluent to afford the title compound 9b
4.16. 2,5-Bis-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-ox-
azole (12a)
To a solution of the bis-indole 11a (0.130 g, 0.175 mmol) in ethyl
acetate (30 mL), phosphoryl chloride (10 mL) was added and the
solution was heated under reflux for 2 h. The solvent was evapo-
rated under reduced pressure and the residue was treated with
water (30 mL) and made strongly alkaline by the addition of 5 N

2198
H. Kandemir et al. / Tetrahedron 69 (2013) 2193e2198
NaOH (30 mL). The resulting precipitate was collected by filtration,
washed with water, dried and recrystallised from methanol to af-
ford the title compound 12a (0.081 g, 63%) as a yellow solid, mp
278e280 ꢁC; nmax (KBr): 3384, 1599, 1449, 1427, 1299, 1165, 1143,
3.94 (3H, s, OMe), 4.09 (3H, s, OMe), 4.25 (3H, s, OMe), 6.63 (1H,
s, H5), 6.69 (1H, s, H5), 7.18, 7.20 (4H, 2d, J 7.1 Hz, aryl H), 7.31
(1H, br s, H2), 7.46, 7.50 (4H, 2d, J 7.8 Hz, aryl H), 7.57 (1H, br s,
H2), 7.64 (1H, s, CH), 10.56 (1H, br s, NH), 11.31 (1H, br s, NH).
HRMS (ESIþ): [MþH]þ, found 600.2490. C37H34N3O5 requires
600.2498. The sample was not soluble enough for 13C NMR
measurement.
991, 697 cmꢀ1 lmax (THF): 326 nm (ε 39,300 cmꢀ1 ꢀ1), 358
; M
(38,600), 377 (48,450), 398 (38,650); 1H NMR (300 MHz, CDCl3):
3.44 (3H, s, OMe), 3.77 (3H, s, OMe), 3.78 (3H, s, OMe), 4.08 (3H, s,
d
OMe), 6.28 (1H, s, H5), 6.41 (1H, s, H5), 7.27e7.45 (20H, m, aryl H),
7.74 (1H, s, CH), 10.35 (1H, br s, NH), 11.32 (1H, br s, NH); 13C NMR
(75 MHz, CDCl3): d 55.4, 55.5, 56.6, 57.8 (OMe), 88.9 (C5), 89.3 (C5),
Acknowledgements
93.3 (C), 95.0 (C), 113.4 (C), 113.7 (C), 114.5 (C), 114.6 (C), 123.5 (CH),
125.8 (CH), 126.0 (CH), 127.1 (CH), 127.2 (CH), 127.3 (CH), 127.4 (CH),
128.1 (CH), 128.4 (CH), 128.5 (CH), 129.0 (CH), 131.5 (CH), 131.6 (CH),
132.9 (C), 133.2 (C), 133.5 (C), 133.8 (C), 135.6 (C), 135.8 (C), 135.9 (C),
136.0 (C),146.0 (C), 153.5 (C),155.0 (C), 155.8 (C),156.7 (C),157.0 (C);
HRMS (ESIþ): [MþH]þ, found 724.2811. C47H38N3O5 requires
724.2804.
We thank the University of New South Wales and the Turkish
Government for their financial support.
References and notes
1. Guella, G.; Mancini, I.; Pietra, F. Helv. Chim. Acta 1994, 77, 1999e2006.
2. Naik, S. R.; Harindran, J.; Varde, A. B. J. Biotechnol. 2001, 88, 1e10.
3. Koyama, Y.; Yokose, K.; Dolby, L. J. Agric. Biol. Chem. 1981, 45, 1285e1287.
4. Kelly, T. R.; Fu, Y.; Xie, R. L. Tetrahedron Lett. 1999, 40, 1857e1860.
5. Pettit, G. R.; Knight, J. C.; Delbert, L.; Davenport, R.; Pettit, R. K.; Tucker, B. E.;
Schmidt, J. M. J. Nat. Prod. 2002, 65, 1793e1797.
4.17. 2,5-Bis-(4,6-dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-ox-
azole (12b)
6. Nishida, A.; Fuwa, M.; Fujikawa, Y.; Nakahata, E.; Furuno, A.; Nakagawa, M.
Tetrahedron Lett. 1998, 39, 5983e5986.
To a solution of the bis-indole 11b (0.112 g, 0.182 mmol) in
ethyl acetate (25 mL), phosphoryl chloride (10 mL) was added
and the solution was heated under reflux for 2 h. The solvent was
evaporated under reduced pressure and the residue was treated
with water (30 mL) and made strongly alkaline by the addition of
5 N NaOH (30 mL). The resulting precipitate was collected by
filtration, washed with water, dried and recrystallised from
methanol to afford the title compound 12b (0.067 g, 61%) as
a white solid; mp 294 ꢁC (dec); nmax (KBr): 3406, 3377, 2934,
7. Doyle, K. J.; Moody, C. J. Synthesis 1994, 1994, 1021e1022.
8. Molina, P.; Fresneda, P. M.; Almendros, P. Synthesis 1993, 1993, 54e56.
9. Kumar, D.; Sundaree, S.; Patel, G.; Kumar, A. J. Heterocycl. Chem. 2010, 47,
1425e1428.
€
10. Grotkopp, O.; Ahmad, A.; Frank, W.; Muller, T. J. J. Org. Biomol. Chem. 2011, 9,
8130e8140.
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13. Miyake, F.; Hashimoto, M.; Tonsiengsom, S.; Yakushijin, K.; Horne, D. A. Tetra-
hedron 2010, 66, 4888e4893.
14. Hogan, I. T.; Sainsbury, M. Tetrahedron 1984, 40, 681e682.
15. Janosik, T.; Johnson, A. L.; Bergman, J. Tetrahedron 2002, 58, 2813e2819.
16. Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron 1996, 52, 8925e8936.
17. Black, D. StC.; Bowyer, M. C.; Kumar, N.; Mitchell, P. S. R. J. Chem. Soc., Chem.
Commun. 1993, 819e821.
2838, 1596, 1463, 1340, 1305, 1208, 1153, 791 cmꢀ1
375 nm (ε 49,050 cmꢀ1 ꢀ1), 396 (39,900); 1H NMR (600 MHz,
DMSO-d6): 2.35 (3H, s, Me), 2.36 (3H, s, Me), 3.89 (3H, s, OMe),
; lmax (THF):
M
d