An improved synthesis of 1-acetyl-1H-indol-3-yl acetates

Article abstract of DOI:10.1002/jhet.5570440146

(Chemical Equation Presented) An efficient two steps procedure for the synthesis of 1-acetyl-1H-indol-3-yl acetates, starting from 2-chlorobenzoic acids, was developed and in general, moderate to good yields were obtained.

Full text of DOI:10.1002/jhet.5570440146

Jan-Feb 2007
273
An Improved Synthesis of 1-Acetyl-1H-indol-3-yl Acetates
Juan C. Rodríguez-Domínguez 1,2*, Alexander Balbuzano-Deus1,
Miguel A. López-López1, Gilbert Kirsch 2
1. Department of Chemistry, Center of Pharmaceutical Chemistry, 200 y 21, Atabey, Playa, 11600, Ciudad de
la Habana, Cuba. Email: jcrdchem@yahoo.com
2. Laboratory of Molecular Engineering and Pharmacological Biochemistry, Université Paul Verlaine-Metz, 1,
Boulevard Arago, 57078, Metz, France. Email: kirsch@univ-metz.fr
Received May 23, 2006
O
O
COOH
Cl
COOH
Glycine
NaOAc
Ac2O
R
R
R
K2CO3/Cu
DMF
N
NHCH2COOH
O
An efficient two steps procedure for the synthesis of 1-acetyl-1H-indol-3-yl acetates, starting from
2-chlorobenzoic acids, was developed and in general, moderate to good yields were obtained.
J. Heterocyclic Chem., 44, 273 (2007).
total consumption of the bromine and almost all the
starting 2-chlorobenzoic acid within 24 hours giving
1a in 95 % yield (Scheme I).
The condensation step between 2-chlorobenzoic acids
(1a-f) and glycine took place from two to six hours with
good yields and purity of the obtained 2-[(carboxymethyl)
amino]benzoic acids (2a-f) (Scheme II).
INTRODUCTION
Different indoxyl moieties are present as aglicons in
different chromogenic compounds which are very
useful to identify certain microorganisms [1,2,3]. In the
literature [4] the preparation of most of them consists
of five to six steps of synthesis starting from the
commercially available toluidines or anthranilic acids.
For this procedure long reaction time is required for the
aminoalkylation step and poor yields are obtained [5],
even in the case of 1-acetyl-1H-indol-3-yl acetate [6].
In a previous work we described an improved two steps
procedure for obtaining 3b starting from 2,4-dichloro-
benzoic acid [7]. Encouraged by this result, we decided
to carry out the preparation of other substituted 1-
acetyl-1H-indol-3-yl acetate derivatives starting from
the corresponding 2-chloro benzoic acids.
Scheme II
R2
R1
COOH
Cl
R2
R1
COOH
Glycine
K2CO3
Cu
NHCH2COOH
DMF
1 (a-f)
2 (a-f)
NaOAc
Ac2O
O
RESULTS AND DISCUSSION
O
R2
R1
Most of the 2-chlorobenzoic acids employed in this
work are commercially available. 5-Bromo-2,4-
dichlorobenzoic acid (1a) had to be prepared. The only
procedure described in literature to synthesize 1a does
not give full experimental details, used a large
quantity of chlorosulfonic acid and 1a was only
characterized by its melting point [8]. In order to carry
out the synthesis of 1a we followed the described
procedure using less than the half of chlorosulfonic
acid from the literature. The reaction took place with
N
O
3 (a-f)
a
R1 = Cl
R2 = Br
b
e
R1 = Cl
R2 = H
c R1 = H
R2 = Cl
d
R1, R2 = H
R1 = H
R2 = NO2
f
R1 = NO2
R2 = H
Subsequent Rössing cyclodecarboxylation [9] with
sodium acetate in acetic anhydride at reflux gave the
corresponding 1-acetyl-1H-indol-3-yl acetates (3a-f) with
moderated to good yields. Only for compound 3d lower
yields were obtained. In general no further purification
was necessary.
Scheme I
COOH
Cl
Br
Cl
COOH
Cl
Br2
HSO3Cl, S8
60-70°C, 24 h
Cl
1a

274
J. C. Rodríguez-Domínguez, A. Balbuzano-Deus, M. A. López-López, G. Kirsch
Vol 44
Table 1
Analytical data of prepared 2-[(carboxymethyl) amino] benzoic acids
Compound
Time (h)
4
Yield
(%)
Mplit (°C)
Mpobt (°C)
NMR data.
2a
71
84
87
53
1H nmr: ꢀ 13.06 (s, 2H, 2COOH), 8.22 (s, 1H, N-H), 8.00 (s, 1H, 6-H), 6.90 (s, 1H,
3-H), 4.05 (s, 2H, CH2)
13C nmr: ꢀ 171.00, 167.69, 149.59, 138.63, 135.55, 113.21, 111.30, 104.56, 44.10
1H nmr: ꢀ 7.88 (d, 1H, 6-H, J= 8.5), 6.62 (dd, 1H, 4-H, J4,6 = 8.5, J4,3 = 1.9), 6.53 (d,
1H, 3-H, J1,3 = 1.9), 3.97 (s, 2H, CH2)
13C nmr: ꢀ 171.6, 169.6, 150.3, 140.3, 133.3, 115.3, 110.5, 109.2, 44.67.
1H nmr: ꢀ 8.15 (s, 1H, N-H), 7.62 (d, 1H, 6-H, J=2.53), 7,24 (dd, 1H, 4-H, J=2.53
and J=8.95), 6.82 (d, 1H, 3-H, J=8.95), 4.16 (s, 2H, CH2)
13C nmr: ꢀ 171.62, 168.10, 149.57, 133.26, 129.71, 122.40, 120.92, 118.45, 47.46.
230 [4]
238
2b
2c
2d
6
3
2
228 [10]
225
210 [5]
210-215
1H nmr: ꢀ 7.91 (d, 1H, Ph-H, J= 7.95), 7.33 (m, 1H, Ph-H), 6.57 (m, 2H, Ph-H),
220 [11]
220
3.95 (s, 2H, CH2).
13C nmr: ꢀ 172.28, 150.49, 134.94, 132.15, 129.77, 129.08, 115.26, 112.03, 44.67.
2e
2f
2
2
97
75
226-227 [12]
222-223
1H nmr: ꢀ 8.05 (m, 2H, Ph-H), 7.37 (m, 2H, Ph-H), 4.10 (s, 2H, CH2)
13C nmr: ꢀ 171.04, 168.65, 154.31, 135.47, 129.59, 128.68, 112.64, 109.92, 44.54.
1H nmr: ꢀ 8.35 (s, 1H, N-H), 8.00 (d, 1H, Ph-H, J=8.5), 7.34-7.30 (m, 2H, Ph-H),
240-242 [13]a
243-244b
4.10 (s, 2H, CH2)
13C nmr: ꢀ: 171.77, 168.99, 151.67, 150.72, 133.82, 115.92, 109.02, 106.38, 44.66.
a From water b From absolute ethanol.
Table 2
Analytical Data of prepared 1-acetyl-1H-indol-3-yl acetates
Compound
Yield
(%)
Mplit (°C)
NMR data
Mpobt (°C).
3a
64
45
45
10
70
57
176 [4]
1H nmr: ꢀ 8.51 (s, 1H, Ph-H), 7.99 (s, 2H, Ph-H and pyrrole-H), 2.62 (s, 3H, NCOCH3), 2.39
171-172
(s, 3H, OCOCH3)
13C nmr: ꢀ 172.24, 169.86, 132.29, 131.89, 129.92, 124.33, 122.84, 118.37, 117.52, 116.28,
23.76, 20.71.
3b
3c
3d
3e
3f
112-113 [4]
111-113
1H nmr: ꢀ 8.34 (d, 1H, 7-H, J= 1.9), 7.90 (s, 1H, 2-H), 7.52 (d, 1H, 4-H, J= 8.5), 7.34 (dd,
1H, 5-H, J= 1.9, J= 8.5), 2.61 (s, 3H, CH3, NCOCH3), 2.28 (s, 3H, OCOCH3)
13C nmr: ꢀ 169.36, 167.95, 133.02, 132.57, 130.08, 123.56, 122.27, 119.06, 116.33, 115.59,
23.36, 20.25.
130 [4]
1H nmr: ꢀ 8.3 (d, 1H, Ph-H, J= 8.95), 7.91 (s, 1H, pyrrole-H), 7.57 (d, 1H, Ph-H, J= 2.07),
7.36 (dd, 1H, J= 8.95 and J= 2.07), 2.62 (s, 3H, NCOCH3), 2.39 (s, 3H, OCOCH3)
13C nmr: ꢀ 169.96, 168.91, 133.14, 131.56, 131.57, 128.53, 126.03, 125.58, 118.05, 117.95,
24.06, 20.98.
134-135
83 [4], 88 [14]
84-86
1H nmr: ꢀ 8.36 (d, 1H, Ph-H, J= 7.9), 7.90 (s, 1H, Pyrrole-H), 7.41 (m, 3H, Ph-H), 2.62 (s,
3H, NCOCH3), 2.39 (s, 3H, OCOCH3)
13C nmr: ꢀ 169.29, 168.18, 133.43, 132.44, 125.53, 123.46, 123.34, 117.64, 115.90, 115.50,
23.57, 20.37.
219-220 [12]
221-222
1H nmr: ꢀ 8.55 (m, 2H, Ph-H), 8.27 (d, 1H, Ph-H, J= 9.15), 8.15 (s, 1H, Pyrrole-H), 2.68 (s,
3H, NCOCH3), 2.44 (s, 3H, OCOCH3)
13C nmr: ꢀ 170.14, 168.66, 143.72, 135.50, 133.64, 124.04, 120.89, 119.58, 116.94, 114.62,
24.04, 20.79.
195 [15]
195-198
1H nmr: ꢀ 9.18 (d, 1H, Ph-H, J= 1.83), 8.29 (s, 1H, Pyrrole-H), 8.21-8.17 (m, 1H, Ph-H),
7.77 (d, 1H, Ph-H, J= 9.15), 2.70 (s, 3H, NCOCH3), 2.48 (s, 3H, OCOCH3)
13C nmr: ꢀ: 169.73, 168.14, 144.92, 132.62, 130.95, 128.09, 121.60, 118.57, 118.40, 111.82,
23.46, 20.31.

Jan-Feb 2007
An Improved Synthesis of 1-Acetyl-1H-indol-3-yl Acetates
275
General procedure for the synthesis of 1-acetyl-1H-indol-
3-yl acetates from 2-[(carboxymethyl) amino] benzoic acids.
A mixture 8.36 mmol of the corresponding 2-[(carboxymethyl)-
amino]benzoic acid (2a, 2b, 2c, 2d, 2e, 2f) 12.8 mL of acetic
anhydride and 32.06 mmol of dry sodium acetate were heated at
reflux. When the gas evolution had finished, the mixture while
still hot was poured into a beaker and left to cool overnight at
0°C. The precipitate was collected and poured into 35 mL of ice
water and stirred for 1 h, collected again and dried in vacuum to
yield the corresponding 1-acetyl-1H-indol-3-yl acetates (3a, 3b,
3c, 3d, 3e, 3f) (see Table 2).
The 1-acetyl-1H-indol-3-yl acetates (3a, 3b, 3c, 3e and
3f) were synthesized with an overall yield ranging from
38% to 68%.
EXPERIMENTAL
Thin layer chromatography (TLC) were performed on
Silicagel plates ALUGRAM Sil G/UV 254 and
CHCl3:AcOEt:AcOH (8:6:1) as the solvent system. The
TLC plates were visualized by means of a Bioblock lamp
1
with a wavelength of 254 nm. The H and 13C NMR spectra
Acknowledgements. Authors want to thank the University
Paul Verlaine-Metz, France, and the Conseil Régional de
Lorraine for supporting this work and Mrs. Véronique Poddig
for recording the NMR spectra.
were recorded on a Bruker AC 250F spectrometer in
deuterated dimethylsulfoxide as solvent. The coupling
constants are in Hz. Melting points were determined on a
Stuart Scientific SMP 3 capillary melting point apparatus
and were uncorrected
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