Synthesis and transformations of ethyl 3-(benzoylamino)-1H-indole-2- carboxylates

Article abstract of DOI:10.1055/s-2008-1067025

A number of ethyl 3-(benzoylamino)-lH-indole-2-car-boxylates were prepared by heating ethyl 2-(benzoylamino)-3-(phenylhydrazono)propanoates with polyphosphoric acid. The reaction of ethyl 3-(benzoylamino)-5-chloro-lH-indole- 2-carboxylate with hydrazine hydrate resulted in the formation of the debenzoylated hydrazide. Hydrolysis of the same ester with aqueous sodium hydroxide afforded 3-(benzoylamino)-5-chloro-lH-indole-2-carbox-ylic acid, which on heating underwent a decarboxylation reaction to givei N-(5-chloro-lH-indol- 3-yl)benzamide.

Full text of DOI:10.1055/s-2008-1067025

PAPER
1741
Synthesis and Transformations of Ethyl 3-(Benzoylamino)-1H-indole-
2-carboxylates
S
ynthesis and Tran
a
sformation
r
s
of Indo
m
les en Čuček, Bojan Verček*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: bojan.vercek@fkkt.uni-lj.si
Received 29 January 2008; revised 18 February 2008
H
N
H
Abstract: A number of ethyl 3-(benzoylamino)-1H-indole-2-car-
COOEt
N
PPA
N
COOEt
boxylates were prepared by heating ethyl 2-(benzoylamino)-3-(phe-
nylhydrazono)propanoates with polyphosphoric acid. The reaction
of ethyl 3-(benzoylamino)-5-chloro-1H-indole-2-carboxylate with
hydrazine hydrate resulted in the formation of the debenzoylated
hydrazide. Hydrolysis of the same ester with aqueous sodium hy-
droxide afforded 3-(benzoylamino)-5-chloro-1H-indole-2-carbox-
ylic acid, which on heating underwent a decarboxylation reaction to
give N-(5-chloro-1H-indol-3-yl)benzamide.
100–110 °C
1–2.5 h
NHCOPh
R
NHCOPh
R
1
2
R = H, 2-F, 2-Cl, 2-Br, 2-Me,
3-F, 3-Cl, 3-Br, 3-Me, 3-CF3,
15–61%
4-F, 4-Cl, 4-Br, 4-Me, 4-NO2, 4-CF3,
2,5-diF
Scheme 1
Key words: hydrazones, indoles, cyclization, Fischer indole syn-
thesis, rearrangement
Heating of ethyl 2-(benzoylamino)-3-(phenylhydra-
zono)propanoates 1a–q in polyphosphoric acid resulted in
the formation of ethyl 3-(benzoylamino)-1H-indole-2-
carboxylates 2 in 15–61% yields (Scheme 1, Table 1).
Indole is one of the most well-known bicyclic heterocy-
clic systems mainly due to its presence in numerous natu-
ral and synthetic biologically active compounds.1 As a
result, new approaches to this system and the synthesis of
new indole derivatives are still the subject of current in-
vestigations in organic chemistry.2 Indole-2-carboxylates
bearing a nitrogen substituent at the 3-position can be pre-
pared from indole-2-carboxylates by nitration,3 nitrosa-
tion,4 diazonium coupling,5 amination,6 and other
reactions. For example, 3-aminoindole-2-carboxylates
can be synthesized by the reduction of the corresponding
nitro,3 nitroso,4 and arylazo compounds.5 They can also be
prepared directly by the formation of the indole skeleton
by Thorpe cyclization of o-{[(ethoxycarbonyl)meth-
yl]amino}benzonitriles.7 The use of a-branched hydra-
zones in the Fischer indole synthesis resulted in the
formation of 3,3-disubstituted 3H-indoles (indolenines)
that are usually highly susceptible to migration of a group
from the 3- to the 2-position.8 Moreover, such migrations
are believed to take place in various electrophilic substitu-
tions on 3-substituted 1H-indoles.9
For the majority of reactions heating at 100 °C for one
hour was sufficient (TLC monitoring). There are two ex-
ceptions, the reaction with 4-nitrophenylhydrazone 1o,
which was carried out at 110 °C for 2.5 hours, and the re-
action with 4-(trifluoromethyl)phenylhydrazone 1p,
where the reaction time was 1.3 hours. The products 2a–
q precipitated from the reaction mixture after the addition
of ethanol. Dilution of the reaction mixtures with water re-
sulted in the precipitation of more impure products. An at-
tempt to isolate 2a via chloroform extraction after the
reaction mixture had been diluted with water, improved
the yield of the isolated product up to 60%. In another ex-
periment, when zinc chloride was used as a catalyst, 1a
underwent cyclization at 180 °C, giving 2a in 43% isolat-
ed yield. It is of interest to note, that no formation of the
corresponding pyrazole derivatives was noted in these re-
actions.
It is understandable, that reactions of the ortho-substituted
phenylhydrazones 1b–e provided the 7-substituted in-
doles 2b–e, and that cyclizations of the para-substituted
phenylhydrazones 1k–o resulted in the formation of the 5-
substituted indoles 2k–o. As expected, the reactions of the
meta-substituted starting compounds 1f–j took place only
at the sterically less hindered carbon atom C6 giving rise
to the formation of the 6-substituted indoles 2f–j. Evident-
ly, the reaction of (2,5-difluorophenyl)hydrazone 1q af-
forded 5,7-difluoro indole derivative 2q. When (2,4,6-
trichlorophenyl)hydrazone 1r was treated with polyphos-
phoric acid under standard reaction conditions, no indole
derivative was isolated, although such anomalous Fischer
indole syntheses with the migration of one ortho group are
sometimes observed.11
Recently, we have reported the synthesis of a series of eth-
yl 2-(benzoylamino)-3-(phenylhydrazono)propanoates,
and their transformation into pyrazole and indole deriva-
tives.10 This conversion into the indole derivatives is the
first example of the Fischer indole synthesis accompanied
by the migration of the ethoxycarbonyl group, and, as
such, also represents a novel approach to 3-amino-1H-
indole-2-carboxylate derivatives. In this paper, we report
on this transformation in more detail.
SYNTHESIS 2008, No. 11, pp 1741–1746
x
x.
x
x
.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1067025; Art ID: Z03408SS
© Georg Thieme Verlag Stuttgart · New York

1742
K. Čuček, B. Verček
PAPER
Table 1 Synthesis of 3-(Benzoylamino)-1H-indole-2-carboxylates 2 from Hydrazones 1
R4
H
N
R3
R1
R2
R3
R4
Yielda,b (%)
COOEt
Entry
Hydrazone
R
R2
NHCOPh
R1
1
2
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
17 (60,c 43d)
2-FC6H4
H
H
34
35
44
29
35
54
40
35
21
49
55
54
61
53e
47f
15
3
2-ClC6H4
2-BrC6H4
2-MeC6H4
3-FC6H4
H
H
Cl
Br
Me
H
H
H
H
H
H
H
H
H
H
H
F
4
H
H
5
H
H
6
H
F
7
1g
1h
1i
3-ClC6H4
3-BrC6H4
3-MeC6H4
3-F3CC6H4
4-FC6H4
2g
2h
2i
H
Cl
Br
Me
CF3
H
8
H
9
H
10
11
12
13
14
15
16
17
18
1j
2j
H
1k
1l
2k
2l
F
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-O2NC6H4
4-F3CC6H4
2,5-F2C6H3
2,4,6-Cl3C6H2
Cl
Br
Me
NO2
CF3
F
H
1m
1n
1o
1p
1q
1r
2m
2n
2o
2p
2q
–
H
H
H
H
H
a Isolation by filtration of solid which precipitated from the reaction mixture diluted with EtOH.
b Reaction conditions: PPA, 100 °C, 1 h, unless otherwise indicated.
c Isolation by extraction with CHCl3 from the reaction mixture diluted with H2O.
d Reaction catalyzed by ZnCl2; isolation by extraction with CHCl3 from the neutralized reaction mixture.
e Reaction conditions: PPA, 110 °C, 2.5 h.
f Reaction conditions: PPA, 100 °C, 1.3 h.
The most probable reaction pathway for the conversion 1 A few experiments with indole 2l were also carried out.
into 2 is outlined in Scheme 2. We believe that the reac- Our attention was focused on the transformation of the
tions proceed via indolenines A, which are converted into ethoxycarbonyl group and on the debenzoylation of the
1H-indoles 2 with migration of the ethoxycarbonyl group. benzoylamino group. Having submitted 2l to an excess of
Although several examples of the migration of this group hot hydrazine hydrate, we succeeded in preparing the hy-
were reported in various organic compounds, it was drazide 3. Hydrolysis of this ester with 20% sodium hy-
scarcely observed in indolenines.8,12 All attempts to iso- droxide yielded the indole-2-carboxylic acid 4, which
late indolenines A failed.
could be decarboxylated at 210–220 °C giving the benz-
amide 5 (Scheme 3).
The structures of the products 2 were established on the
basis of NMR, MS, and IR data and elemental analysis. In summary, we described a general synthetic route to
The chemical shifts of protons in the benzene part of di- ethyl 3-(benzoylamino)-1H-indole-2-carboxylates. The
versely substituted indole products are in agreement with transformation is a novel example of the use of hydra-
the reported data of the correspondingly substituted indole zones with an additional amino acid residue in heterocy-
derivatives prepared previously.13 Moreover, compound clic synthesis. The products can be used as the starting
2a was found to be identical to the product of the benzoy- compounds for further functionalization of the indole sys-
lation reaction of ethyl 3-amino-1H-indole-2-carboxy- tem.
late.14
Synthesis 2008, No. 11, 1741–1746 © Thieme Stuttgart · New York

PAPER
Synthesis and Transformations of Indoles
1743
(3 × 4 mL). The extracts were combined, dried (Na2SO4) and, after
evaporation of CHCl3, crude 2a (92 mg, 60%) was obtained.
H
N
N
COOEt
N
COOEt
NHCOPh
In the case of 2a, an alternative procedure using ZnCl2 as a catalyst
was also carried out: A suspension of 1a (325 mg, 1 mmol) in sat.
aq ZnCl2 soln (1.5 mL) was heated at 180 °C for 10 min. The mix-
ture was cooled to r.t., then aq HCl (1:1, 1.5 mL) was added and the
mixture was heated under reflux for another 10 min. After cooling
to r.t., the mixture was diluted with H2O (3 mL), neutralized with
NaHCO3, and extracted with CHCl3 (4 × 50 mL). The extracts were
combined and dried (Na2SO4). After CHCl3 evaporated, the solid
residue was purified with radial chromatography with CH2Cl2 giv-
ing 2a (133 mg, 43%).
NHCOPh
R
R
A
1
+ H+
H
H
H
N
N+
COOEt
+
COOEt
NHCOPh
R
R
NHCOPh
– H+
Ethyl 3-(Benzoylamino)-1H-indole-2-carboxylate (2a)
Mp 171–171.5 °C (EtOH) (Lit.14 mp 160–163 °C).
H
N
IR (KBr): 3205, 1675, 1650, 1265, 750 cm–1.
COOEt
R
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.31 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.08 (ddd, J = 8.2,
7.0, 1.0 Hz, 1 H, H5), 7.30 (ddd, J = 8.3, 7.0, 1.2 Hz, 1 H, H6), 7.46
(ddd, J = 8.3, 1.0, 1.0 Hz, 1 H, H7), 7.52–7.65 (m, 3 H, Ph), 7.71 (d,
J = 8.2 Hz, 1 H, H4), 8.02–8.09 (m, 2 H, Ph), 10.09 (s, 1 H, NHCO),
11.77 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.14, 60.34, 112.52, 118.84,
119.58, 120.33, 121.88, 122.83, 125.15, 127.50, 128.45, 131.55,
134.31, 135.19, 161.28, 164.93.
NHCOPh
2
Scheme 2
H
N
H
N
NH2NH2⋅H2O
COOEt
CONHNH2
Cl
Cl
NHCOPh
2l
NH2
3
MS (EI, 70 eV): m/z (%) = 308 (20) [M+].
NaOH
Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
69.73; H, 5.03; N, 9.05.
H
N
H
Ethyl 3-(Benzoylamino)-7-fluoro-1H-indole-2-carboxylate (2b)
Mp 224–225.5 °C (EtOAc).
N
∆
COOH
IR (KBr): 3310, 1700, 1655, 1565, 1485, 1330, 1240 cm–1.
Cl
Cl
NHCOPh
NHCOPh
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.30 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.05 (ddd, J = 8.0,
4.8, 7.8 Hz, 1 H, H5), 7.14 (ddd, J = 11.4, 7.8, 1.0 Hz, 1 H, H6),
7.48–7.65 (m, 4 H, 3 H of Ph, H4), 8.01–8.09 (m, 2 H, Ph), 10.14
(s, 1 H, NHCO), 12.29 (s, 1 H, NH).
4
5
Scheme 3
Melting points were determined on a Kofler micro hot stage. IR
spectra were recorded on a Perkin-Elmer 1310 or 727 B spectropho-
tometer. NMR spectra were recorded on a Bruker Avance DPX-300
spectrometer (300 MHz for 1H and 75.5 MHz for 13C) in DMSO-d6
with TMS as an internal standard. MS spectra were obtained on a
VG-Analytical AutoSpec Q instrument. Elemental analyses were
performed on a Perkin-Elmer CHN Analyzer 2400. TLC was car-
ried out on Fluka silica gel TLC cards. Radial chromatography was
performed on Merck Kieselgel PF254 silica gel. Compounds 1a–q
were prepared as described in the literature.10 All other compounds
were used without purification as obtained from commercial sour-
ces.
13C NMR (75.5 MHz, DMSO-d6): d = 14.05, 60.53, 109.43, 117.81,
119.80, 120.78, 123.69, 126.73, 127.55, 128.06, 128.46, 131.65,
134.16, 149.24, 160.89, 165.10.
MS (EI, 70 eV): m/z (%) = 326 (34) [M+].
Anal. Calcd for C18H15FN2O3: C, 66.25; H, 4.63; N, 8.58. Found: C,
66.03; H, 4.72; N, 8.46.
Ethyl 3-(Benzoylamino)-7-chloro-1H-indole-2-carboxylate (2c)
Mp 214.5–215.5 °C (EtOH).
IR (KBr): 3340, 1705, 1655, 1590, 1485, 1325, 1250, 1235 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.31 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.10 (dd, J = 8.1, 7.5
Hz, 1 H, H5), 7.40 (dd, J = 7.5, 0.9 Hz, 1 H, H6), 7.53–7.64 (m, 3
H, Ph), 7.66 (dd, J = 8.1, 0.9 Hz, 1 H, H4), 8.03–8.08 (m, 2 H, Ph),
10.16 (s, 1 H, NHCO), 11.94 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.06, 60.55, 116.87, 120.57,
120.64, 120.91, 121.08, 124.76, 125.11, 127.55, 128.46, 131.66,
132.12, 134.10, 160.83, 165.14.
Ethyl 3-(Benzoylamino)-1H-indole-2-carboxylates 2; General
Procedure
These reactions were conducted according to the procedure for the
preparation of 2l reported previously:10a A mixture of 1 (1 mmol)
and PPA (600–700 mg) was heated at 100 °C for 1 h with occasional
stirring. The mixture was then cooled to r.t., and EtOH (2–3 mL)
was added. Upon cooling, the separated solid was filtered off to give
crude 2. In the case of 1o, the reaction was carried out at 110 °C for
2.5 h. In the case of 1p, the reaction time was 1.3 h. In the case of
1q, a mixture of EtOH (2 mL) and H2O (1 mL) was added.
MS (EI, 70 eV): m/z (%) = 342 (32) [M+].
Anal. Calcd for C18H15ClN2O3: C, 63.07; H, 4.41; N, 8.17. Found:
C, 62.73; H, 4.34; N, 8.00.
In the case of 2a, another attempt with an alternative isolation pro-
cedure was carried out: After heating of 1a (163 mg, 0.5 mmol) in
PPA (325 mg) at 100 °C for 1 h, the mixture was cooled to r.t., then
H2O (4 mL) was added and the mixture was extracted with CHCl3
Ethyl 3-(Benzoylamino)-7-bromo-1H-indole-2-carboxylate (2d)
Mp 187–188 °C (EtOAc).
Synthesis 2008, No. 11, 1741–1746 © Thieme Stuttgart · New York

1744
K. Čuček, B. Verček
PAPER
IR (KBr): 3340, 1700, 1650, 1580, 1480, 1320, 1240, 1225 cm–1.
Ethyl 3-(Benzoylamino)-6-bromo-1H-indole-2-carboxylate (2h)
Mp 241–243 °C (EtOAc).
IR (KBr): 3320, 1685, 1660, 1580, 1485, 1355, 1320, 1240 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.24 (t, J = 7.2 Hz, 3 H,
CH2CH3), 4.30 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.05 (dd, J = 8.1, 7.5
Hz, 1 H, H5), 7.53–7.65 (m, 4 H, 3 H of Ph, H6), 7.69 (dd, J = 8.1,
0.9 Hz, 1 H, H4), 8.01–8.07 (m, 2 H, Ph), 10.15 (s, 1 H, NHCO),
11.69 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.07, 60.56, 104.98, 120.96,
121.06, 121.10, 121.21, 125.00, 127.57, 128.06, 128.46, 131.67,
133.58, 134.10, 160.79, 165.17.
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.32 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.22 (dd, J = 8.7, 1.8
Hz, 1 H, H5), 7.53–7.65 (m, 4 H, 3 H of Ph, H7), 7.70 (dd, J = 8.7,
0.6 Hz, 1 H, H4), 8.02–8.07 (m, 2 H, Ph), 10.14 (s, 1 H, NHCO),
11.93 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.11, 60.59, 114.87, 118.12,
119.40, 120.48, 121.67, 122.72, 124.00, 127.51, 128.49, 131.69,
134.08, 135.73, 161.03, 164.92.
MS (EI, 70 eV): m/z (%) = 386 (20) [M+].
Anal. Calcd for C18H15BrN2O3: C, 55.83; H, 3.90; N, 7.23. Found:
C, 55.66; H, 3.90; N, 7.17.
MS (EI, 70 eV): m/z (%) = 386 (19) [M+].
Anal. Calcd for C18H15BrN2O3: C, 55.83; H, 3.90; N, 7.23. Found:
C, 55.66; H, 3.89; N, 7.35.
Ethyl 3-(Benzoylamino)-7-methyl-1H-indole-2-carboxylate (2e)
Mp 182.5–185.5 °C (EtOH).
IR (KBr): 3355, 1690, 1655, 1565, 1480, 1325, 1240, 1225 cm–1.
Ethyl 3-(Benzoylamino)-6-methyl-1H-indole-2-carboxylate (2i)
Mp 193–195 °C (EtOAc).
IR (KBr): 3340, 1680, 1655, 1580, 1480, 1330, 1255 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.24 (t, J = 7.1 Hz, 3 H,
CH2CH3), 2.54 (dd, J = 1.0, 0.7 Hz, 3 H, Me), 4.30 (q, J = 7.1 Hz, 2
H, CH2CH3), 6.99 (dd, J = 8.1, 6.9 Hz, 1 H, H5), 7.09 (qdd, J = 6.9,
1.0, 0.9 Hz, 1 H, H6), 7.50 (qdd, J = 8.1, 0.9, 0.7 Hz, 1 H, H4), 7.52–
7.65 (m, 3 H, Ph), 8.02–8.08 (m, 2 H, Ph), 10.07 (s, 1 H, NHCO),
11.52 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.14, 16.90, 60.27, 119.10,
119.49, 119.85, 120.68, 122.07, 123.05, 125.49, 127.51, 128.41,
131.50, 134.36, 134.88, 161.37, 165.01.
1H NMR (300 MHz, DMSO-d6): d = 1.26 (t, J = 7.1 Hz, 3 H,
CH2CH3), 2.42 (s, 3 H, Me), 4.30 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.91
(dd, J = 8.3, 1.0 Hz, 1 H, H5), 7.23 (s, 1 H, H7), 7.52–7.67 (m, 4 H,
3 H of Ph, H4), 8.01–8.08 (m, 2 H, Ph), 10.08 (s, 1 H, NHCO),
11.61 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.17, 21.52, 60.25, 111.85,
117.82, 120.62, 120.72, 121.72, 121.89, 127.47, 128.48, 131.57,
134.31, 134.81, 135.75, 161.42, 164.74.
MS (EI, 70 eV): m/z (%) = 322 (57) [M+].
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.68; H, 5.82; N, 8.66.
MS (EI, 70 eV): m/z (%) = 322 (62) [M+].
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.77; H, 5.83; N, 8.66.
Ethyl 3-(Benzoylamino)-6-fluoro-1H-indole-2-carboxylate (2f)
Mp 227.5–229 °C (EtOAc).
Ethyl 3-(Benzoylamino)-6-(trifluoromethyl)-1H-indole-2-car-
boxylate (2j)
IR (KBr): 3320, 1685, 1655, 1590, 1560, 1480, 1330, 1260, 1240
cm–1.
Mp 245–246.5 °C (MeOH) (Lit.15 237–239 °C).
1H NMR (300 MHz, DMSO-d6): d = 1.27 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.31 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.97 (ddd, J = 9.4,
9.1, 2.2 Hz, 1 H, H5), 7.16 (dd, J = 9.8, 2.2 Hz, 1 H, H7), 7.53–7.66
(m, 3 H, Ph), 7.78 (dd, J = 9.1, 5.6 Hz, 1 H, H4), 8.01–8.08 (m, 2 H,
Ph), 10.14 (s, 1 H, NHCO), 11.86 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.14, 60.44, 97.77, 109.07,
119.15, 119.58, 120.82, 124.03, 127.51, 128.51, 131.69, 134.14,
135.20, 160.92, 161.03, 164.89.
IR (KBr): 3330, 1680, 1655, 1580, 1480, 1340, 1235, 1115 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.27 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.35 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.37 (dd, J = 8.6, 1.7
Hz, 1 H, H5), 7.54–7.66 (m, 3 H, Ph), 7.78 (s, 1 H, H7), 7.92 (d,
J = 8.6 Hz, 1 H, H4), 8.03–8.10 (m, 2 H, Ph), 10.20 (s, 1 H, NHCO),
12.27 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.06, 60.82, 110.04, 15.52,
119.86, 121.86, 123.22, 124.84, 125.15, 125.23, 127.56, 128.49,
131.72, 133.63, 134.04, 160.86, 165.12.
MS (EI, 70 eV): m/z (%) = 326 (42) [M+].
Anal. Calcd for C18H15FN2O3: C, 66.25; H, 4.63; N, 8.58. Found: C,
66.34; H, 4.79; N, 8.65.
MS (EI, 70 eV): m/z (%) = 376 (4) [M+].
Anal. Calcd for C19H15F3N2O3: C, 60.64; H, 4.02; N, 7.44. Found:
C, 60.44; H, 3.99; N, 7.37.
Ethyl 3-(Benzoylamino)-6-chloro-1H-indole-2-carboxylate (2g)
Mp 248–249 °C (DMF–MeOH).
IR (KBr): 3310, 1680, 1660, 1580, 1480, 1355, 1320, 1235 cm–1.
Ethyl 3-(Benzoylamino)-5-fluoro-1H-indole-2-carboxylate (2k)
Mp 230.5–231.5 °C (EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 1.27 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.32 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.11 (dd, J = 8.7, 1.6
Hz, 1 H, H5), 7.47 (d, J = 1.6 Hz, 1 H, H7), 7.52–7.67 (m, 3 H, Ph),
7.77 (d, J = 8.7 Hz, 1 H, H4), 8.02–8.10 (m, 2 H, Ph), 10.15 (s, 1 H,
NHCO), 11.90 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.12, 60.58, 111.84, 119.48,
120.22, 120.53, 121.41, 123.80, 127.51, 128.49, 129.88, 131.69,
134.09, 135.34, 161.05, 164.91.
IR (KBr): 3310, 1685, 1655, 1560, 1480, 1330, 1260, 1185 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.32 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.18 (ddd, J = 9.1,
9.1, 2.4 Hz, 1 H, H6), 7.43 (dd, J = 10.0, 2.4 Hz, 1 H, H4), 7.47 (dd,
J = 9.1, 4.7 Hz, 1 H, H7), 7.52–7.66 (m, 3 H, Ph), 8.02–8.08 (m, 2
H, Ph), 10.09 (s, 1 H, NHCO), 11.91 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.10, 60.52, 105.97, 114.07,
114.26, 120.22, 120.45, 122.70, 127.52, 128.46, 131.62, 131.89,
134.16, 156.58, 161.04, 164.91.
MS (EI, 70 eV): m/z (%) = 342 (29) [M+].
Anal. Calcd for C18H15ClN2O3: C, 63.07; H, 4.41; N, 8.17. Found:
C, 62.81; H, 4.17; N, 8.10.
MS (EI, 70 eV): m/z (%) = 326 (100) [M+].
Anal. Calcd for C18H15FN2O3: C, 66.25; H, 4.63; N, 8.58. Found: C,
65.96; H, 4.75; N, 8.59.
Synthesis 2008, No. 11, 1741–1746 © Thieme Stuttgart · New York

PAPER
Synthesis and Transformations of Indoles
1745
Ethyl 3-(Benzoylamino)-5-bromo-1H-indole-2-carboxylate
(2m)
Ethyl 3-(Benzoylamino)-5,7-difluoro-1H-indole-2-carboxylate
(2q)
Mp 255–256 °C (DMF–MeOH).
Mp 233–235 °C (EtOH–H2O).
IR (KBr): 3320, 1690, 1660, 1580, 1480, 1325, 1260 cm–1.
IR (KBr): 3280, 1695, 1660, 1565, 1355, 1265, 1235 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.27 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.32 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.39–7.45 (m, 2 H,
H6, H7), 7.53–7.66 (m, 3 H, Ph), 7.92 (dd, J = 1.3, 1.3 Hz, 1 H, H4),
8.03–8.08 (m, 2 H, Ph), 10.13 (s, 1 H, NHCO), 12.01 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.09, 60.62, 112.02, 114.71,
119.48, 119.89, 124.11, 127.54, 127.76, 128.48, 131.69, 133.69,
134.05, 161.00, 164.92.
1H NMR (300 MHz, DMSO-d6): d = 1.21 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.28 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.78 (ddd, J = 10.3,
8.5, 3.0 Hz, 1 H, H5), 7.10 (ddd, J = 10.6, 8.5, 3.6 Hz, 1 H, H6),
7.50–7.64 (m, 3 H, Ph), 7.98–8.05 (m, 2 H, Ph), 10.08 (s, 1 H, NH-
CO), 12.63 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 13.97, 60.63, 104.46, 109.19,
116.60, 117.94, 122.99, 125.07, 127.53, 128.37, 131.54, 134.18,
145.59, 152.09, 160.14, 166.06.
MS (EI, 70 eV): m/z (%) = 386 (23) [M+].
MS (EI, 70 eV): m/z (%) = 344 (42) [M+].
Anal. Calcd for C18H15BrN2O3: C, 55.83; H, 3.90; N, 7.23. Found:
C, 55.96; H, 3.61; N, 7.11.
Anal. Calcd for C18H14F2N2O3: C, 62.79; H, 4.10; N, 8.14. Found:
C, 62.65; H, 4.07; N, 8.11.
Ethyl 3-(Benzoylamino)-5-methyl-1H-indole-2-carboxylate
(2n)
Mp 205.5–207.5 °C (DMF–MeOH).
IR (KBr): 3320, 1690, 1655, 1585, 1480, 1330, 1255, 1190 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, J = 7.1 Hz, 3 H,
CH2CH3), 2.37 (s, 3 H, Me), 4.29 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.13
(dd, J = 8.5, 1.5 Hz, 1 H, H6), 7.35 (d, J = 8.5 Hz, 1 H, H7), 7.47 (s,
1 H, H4), 7.52–7.65 (m, 3 H, Ph), 8.02–8.09 (m, 2 H, Ph), 10.04 (s,
1 H, NHCO), 11.64 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.14, 21.14, 60.23, 112.30,
118.99, 119.75, 120.80, 123.11, 127.13, 127.50, 128.27, 128.43,
131.52, 133.71, 134.34, 161.28, 164.91.
3-Amino-5-chloro-1H-indole-2-carboxylic Acid Hydrazide (3)
A mixture of 2l (171 mg, 0.5 mmol) and 99% hydrazine hydrate (1.6
mL) was heated at 110 °C for 3 h. The mixture was cooled and the
separated solid was filtered off and washed (MeOH) to give crude
3 (105 mg, 94%); mp 241.5–244 °C (DMF–MeOH).
IR (KBr): 3340, 1620, 1600, 1580, 1545, 1520, 1395, 1330, 1220,
785 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 4.38 (s, 2 H, NH2), 5.54 (s, 2
H, NH2), 7.15 (dd, J = 8.7, 2.3 Hz, 1 H, H6), 7.26 (d, J = 8.6 Hz, 1
H, H7), 7.78 (d, J = 2.3 Hz, 1 H, H4), 8.77 (s, 1 H, NH), 10.26 (s, 1
H, NH).
MS (EI, 70 eV): m/z (%) = 224 (69) [M+].
MS (EI, 70 eV): m/z (%) = 322 (81) [M+].
Anal. Calcd for C9H9ClN4O: C, 48.12; H, 4.04; N, 24.94. Found: C,
48.04; H, 4.07; N, 24.80.
Anal. Calcd for C19H18N2O3: C, 70.79; H, 5.63; N, 8.69. Found: C,
70.64; H, 5.67; N, 8.79.
3-(Benzoylamino)-5-chloro-1H-indole-2-carboxylic Acid (4)
A mixture of 2l (384 mg, 1.12 mmol), dioxane (18 mL), and 20%
NaOH (8 mL) was heated at 100 °C for 2.5 h. The mixture was
cooled to r.t. and the lower layer was discarded. The residue was
acidified with 7% HCl until pH 1 and evaporated. After addition of
H2O (5 mL) the separated solid was filtered off to give crude 4 (327
mg, 93%); mp 218–221 °C (EtOH).
Ethyl 3-(Benzoylamino)-5-nitro-1H-indole-2-carboxylate (2o)
Mp 315–319 °C (DMF–EtOH).
IR (KBr): 3270, 1680, 1655, 1590, 1475, 1325, 1265 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 1.29 (t, J = 7.1 Hz, 3 H,
CH2CH3), 4.36 (q, J = 7.1 Hz, 2 H, CH2CH3), 7.57–7.69 (m, 4 H, 3
H of Ph, H7), 8.05–8.10 (m, 2 H, Ph), 8.16 (dd, J = 9.2, 2.3 Hz, 1 H,
H6), 8.85 (d, J = 2.3 Hz, 1 H, H4), 10.35 (s, 1 H, NHCO), 12.52 (s,
1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.05, 60.98, 113.39, 119.80,
120.04, 121.23, 122.49, 127.59, 128.59, 131.94, 133.75, 137.51,
140.81, 160.80, 164.87.
IR (KBr): 3300, 1670, 1600, 1475, 1325, 1250 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.29 (dd, J = 8.8, 2.1 Hz, 1 H,
H6), 7.45 (dd, J = 8.8, 0.6 Hz, 1 H, H7), 7.53–7.67 (m, 3 H, Ph),
7.83 (ddd, J = 2.1, 0.6, 0.6 Hz, 1 H, H4), 8.02–8.08 (m, 2 H, Ph),
10.19 (s, 1 H, NHCO), 11.91 (s, 1 H, NH), 13.43 (br s, 1 H, COOH).
13C NMR (75.5 MHz, DMSO-d6): d = 114.25, 119.96, 120.15,
121.49, 122.98, 123.82, 125.07, 127.51, 128.57, 131.73, 133.35,
134.11, 162.72, 164.64.
MS (EI, 70 eV): m/z (%) = 353 (9) [M+].
Anal. Calcd for C18H15N3O5: C, 61.19; H, 4.28; N, 11.89. Found: C,
60.98; H, 3.89; N, 12.14.
MS (EI, 70 eV): m/z (%) = 314 (38) [M+].
Ethyl 3-(Benzoylamino)-5-(trifluoromethyl)-1H-indole-2-car-
boxylate (2p)
Mp 258–261 °C (EtOAc).
Anal. Calcd for C16H11ClN2O3: C, 61.06; H, 3.52; N, 8.90. Found:
C, 60.94; H, 3.50; N, 8.70.
IR (KBr): 3320, 1685, 1655, 1585, 1335, 1260, 1100 cm–1.
N-[5-Chloro-1H-indol-3-yl]benzamide (5)
1H NMR (300 MHz, DMSO-d6): d = 1.28 (t, J = 7.2 Hz, 3 H,
CH2CH3), 4.34 (q, J = 7.2 Hz, 2 H, CH2CH3), 7.55–7.68 (m, 5 H, 3
H of Ph, H6, H7), 8.04–8.09 (m, 2 H, Ph), 8.15–8.18 (m, 1 H, H4),
10.24 (s, 1 H, NHCO), 12.26 (s, 1 H, NH).
13C NMR (75.5 MHz, DMSO-d6): d = 14.04, 60.73, 113.67, 120.15,
120.41, 120.42, 121.11, 121.15, 121.53, 125.08, 127.54, 128.50,
131.77, 133.92, 136.24, 160.97, 164.96.
The acid 4 (95 mg, 0.3 mmol) was heated at 210–220 °C for 10 min
on a Kofler micro hot stage. Upon cooling the residue was purified
by radial chromatography with EtOAc to give crude 5 (57 mg,
70%); mp 224–225.5 °C (EtOAc).
IR (KBr): 3395, 1640, 1510, 1480, 1310, 1095, 800, 700 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 7.11 (dd, J = 8.6, 1.9 Hz, 1 H,
H6), 7.40 (d, J = 8.6 Hz, 1 H, H7), 7.49–7.63 (m, 3 H, Ph), 7.91 (d,
J = 2.3 Hz, 1 H, H2), 7.98–8.08 (m, 3 H, 2 H of Ph, H4), 10.20 (s, 1
H, NHCO), 11.14 (s, 1 H, NH).
MS (EI, 70 eV): m/z (%) = 376 (48) [M+].
Anal. Calcd for C19H15F3N2O3: C, 60.64; H, 4.02; N, 7.44. Found:
C, 60.80; H, 3.95; N, 7.57.
Synthesis 2008, No. 11, 1741–1746 © Thieme Stuttgart · New York

1746
K. Čuček, B. Verček
PAPER
(5) Kurilo, G. N.; Boyarintseva, O. N.; Grinev, A. N. Khim.
13C NMR (75.5 MHz, DMSO-d6): d = 112.93, 114.74, 118.03,
118.37, 121.30, 121.99, 122.83, 127.70, 128.22, 131.16, 132.16,
134.69, 164.73.
Geterotsikl. Soedin. 1975, 664; Chem. Abstr. 1975, 83,
114137u.
(6) Lenaršič, R.; Kočevar, M.; Polanc, S. J. Org. Chem. 1999,
MS (EI, 70 eV): m/z (%) = 270 (41) [M+].
64, 2558.
Anal. Calcd for C15H11ClN2O: C, 66.55; H, 4.10; N, 10.35. Found:
C, 66.25; H, 4.43; N, 9.95.
(7) (a) Unangst, P. C. J. Heterocycl. Chem. 1983, 20, 495.
(b) Viti, G.; Giannotti, D.; Nannicini, R.; Ricci, R.;
Pestellini, V. J. Heterocycl. Chem. 1991, 28, 379.
(8) See, for example: Liu, K. G.; Robichaud, A. J.; Lo, J. R.;
Mattes, J. F.; Cai, Y. Org. Lett. 2006, 8, 5769.
(9) Joule, J. A. In Science of Synthesis, Vol. 10; Thomas, E. J.,
Ed.; Georg Thieme Verlag: Stuttgart, 2006, 361.
(10) (a) Čuček, K.; Verček, B. Synlett 1999, 120. (b) Čuček, K.;
Golobič, A.; Verček, B. Heterocycles 2007, 73, 555.
(11) Sundberg, R. J. Indoles, In Best Synthetic Methods;
Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W., Eds.;
Academic Press: London, 1996, 1.
Acknowledgment
We thank The Slovenian Research Agency and The Ministry of
Higher Education, Science and Technology of Slovenia (P1-0230-
0103) for financial support.
References
(1) (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry, Vol. 4; Katritzky, A. R.; Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984, 313. (b) Sundberg, R. J. In
Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 119. (c) Gribble, G. W. In
Comprehensive Heterocyclic Chemistry II, Vol. 2;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 207.
(12) See, for example: Acheson, R. M.; Booth, S. R. G. J. Chem.
Soc. C 1968, 30; and references cited therein.
(13) (a) Morales-Ríos, M. S.; Espiñeira, J.; Joseph-Nathan, P.
Magn. Reson. Chem. 1987, 25, 377. (b) Lee, M.; Phillips, R.
S. Magn. Reson. Chem. 1992, 30, 1035. (c) Burton, G.;
Ghini, A. A.; Gros, E. G. Magn. Reson. Chem. 1986, 24,
829. (d) Morales-Ríos, M. S.; del Río, R. E.; Joseph-Nathan,
P. Magn. Reson. Chem. 1988, 26, 552. (e) Joseph-Nathan,
P.; del Río, R. E.; Morales-Ríos, M. S. Heterocycles 1988,
27, 377.
(2) See, for example: Kranjc, K.; Kočevar, M. Tetrahedron
2008, 64, 45; and references cited therein.
(14) Monge, A.; Palop, J. A.; Parrado, P.; Perez-Ilzarbe, C.
J. Heterocycl. Chem. 1987, 24, 437.
(15) Salituro, F. G.; Baron, B. M. EP 483,881 1992, Chem. Abstr.
(3) Salituro, F. G.; Tomlinson, R. C.; Baron, B. M.; Demeter, D.
A.; Weintraub, H. J. R.; McDonald, I. A. Bioorg. Med.
Chem. Lett. 1991, 1, 455.
(4) Monge, A.; Palop, J. A.; Recalde, I.; Martinez-Crespo, F.;
Fernández-Alvarez, E. An. Quim., Ser. C 1985, 81, 267.
1992, 117, 90153p.
Synthesis 2008, No. 11, 1741–1746 © Thieme Stuttgart · New York