The Ullmann coupling between 2-chlorobenzoic acids and amino acids; a valuable reaction for preparing 2-substituted 1-acetyl-1H-indol-3-yl acetates

Article abstract of DOI:10.1055/s-0029-1216851

2-Substituted 3-acetoxy-1-acetyl-1H-indoles were prepared by condensing 2-chlorobenzoic acids with amino acids under Ullmann conditions in good yields, and further cyclodecarboxylation using the Roessing method in moderate to good yields. Georg Thieme Ver

Full text of DOI:10.1055/s-0029-1216851

PAPER
2345
The Ullmann Coupling between 2-Chlorobenzoic Acids and Amino Acids;
A Valuable Reaction for Preparing 2-Substituted 1-Acetyl-1H-indol-3-yl
Acetates
P
reparatio
u
n of 2-Substi
a
tute
d
1-Ace
n
tyl-1
H
-
indol-3-yl
Ccetates arlos Rodriguez Dominguez, Xiao Gang, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique (LIMBP), Université Paul Verlaine-Metz, Institut Jean Barriol,
1 Boulevard Arago, 57078 Metz, France
Fax +33(3)87315801; E-mail: kirsch@univ-metz.fr
Received 25 February 2009; revised 23 March 2009
Dedicated to Dr. Michel Wierzbicki on the occasion of his 60th birthday
yields. Subsequent Rossing cyclodecarboxylation of 4a–g
allowed us to obtain 2-substituted 3-acetoxy-1-acetyl-1H-
indoles 6a–g in moderate to good yields (Table 2).
Abstract: 2-Substituted 3-acetoxy-1-acetyl-1H-indoles were pre-
pared by condensing 2-chlorobenzoic acids with amino acids under
Ullmann conditions in good yields, and further cyclodecarboxyla-
tion using the Rössing method in moderate to good yields.
Key words: Ullmann coupling, chlorobenzoic acids, amino acids,
cyclodecarboxylation, 2-substituted indoles
Reagents were purchased from Acros Organics. TLC was carried
out using silica gel plates Alugram Sil G/UV 254 (CHCl3–EtOAc–
AcOH, 8:6:1). Melting points were determined on a Stuart SMP3
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
corded on a AC Bruker 250 MHz spectrometer in DMSO-d6. MS
spectra were performed on an Agilent Technologies GC-MS instru-
ment equipped with a 7683 injector, 6890N gas chromatograph and
a 5973 mass selective detector. The mass spectrometer was operat-
ed in EI mode at 70 eV and MS spectra were recorded from m/z 50
to 650.
N,O-Diacetylindoxyls (1-acetyl-1H-indol-3-yl acetates,
3-acetoxy-1-acetyl-1H-indoles) are present as precursors
of some aglicons in chromogenic compounds that are very
useful in the identification of various microorganisms.1–3
However, 2-substituted 3-acetoxy-1-acetyl-1H-indoles
are rarely found in literature and there are no procedures
available that describe the synthesis of these compounds
from the corresponding unactivated amino acid and 2-
chlorobenzoic acids by the Ullman procedure. Neverthe-
less, 2-substituted 3-acetoxy-1-acetyl-1H-indoles have
been used as the starting point for the preparation of 2-
substituted 1-acetyl-1,2-dihydro-3H-indol-3-ones.4
2-[(Carboxymethyl)amino]benzoic Acids 4 and 5
These compounds were prepared according to a previously reported
procedure.5,6 Mass spectra were not possible to obtain due to rapid
thermal decomposition once they were injected into the equipment.
2-{[Carboxy(phenyl)methyl]amino}benzoic Acid (4a)
Mp 210–212 °C (Lit.7 226 °C).
1H NMR: d = 12.94 (s, 2 H), 8.88 (s, 1 H), 7.79 (d, J = 7.70 Hz, 1
H), 7.51–7.18 (m, 8 H), 6.57–6.47 (m, 2 H), 5.29 (s, 1 H).
On the other hand, only one compound, 3-acetoxy-1-
acetyl-2-methyl-1H-indole, has been prepared from the
corresponding N-acetylated 2-[(carboxymethyl)ami-
no]benzoic acid, but it was not prepared using the Ullman
conditions.4
13C NMR: d = 171.95, 169.58, 148.58, 138.29, 134.13, 131.67,
128.51, 127.02, 126.82, 115.09, 112.43, 111.17, 58.99.
2-(1-Carboxyethylamino)benzoic Acid (4b)
Mp 258 °C (Lit.8 209–211 °C).
In previous work we reported a simple two-step procedure
for the preparation of 3-acetoxy-1-acetyl-6-chloro-1H-in-
1H NMR: d = 7.75 (d, J = 8.47 Hz, 1 H), 6.67–6.66 (m, 2 H), 6.62
dole from 2,4-dichlorobenzoic acid and an unactivated (d, J = 1.95 Hz, 1 H), 6.59 (d, J = 1.95 Hz, 1 H), 4.28–4.22 (m, 1 H),
amino acid in good yield.5 Encouraged by this result, we
1.39 (d, J = 6.8 Hz, 3 H).
13C NMR: d = 174.51, 169.28, 150.42, 139.25, 134.1, 114.82,
110.54, 109.37, 50.01, 17.83.
decided to carry out the preparation of other substituted 3-
acetoxy-1-acetyl-1H-indoles starting from the corre-
sponding 2-chlorobenzoic acids.6 These papers made us
think about the possibility of using the same procedure to
prepare 2-substituted 3-acetoxy-1-acetyl-1H-indoles 6
from 2-chlorobenzoic acids 1 and 2-substituted amino
acids 2 or 5-aminopentanoic acid (3). We started by using
the same reaction conditions given in previous papers and
using 2-chlorobenzoic acids 1a–d and amino acids 2a–c
or 3 to give Ullman compounds, 2-[(carboxymethyl)ami-
no]benzoic acids 4a–g and 5a–c (Table 1) in very good
2-(1-Carboxyethylamino)-4-chlorobenzoic Acid (4c)
Mp 245 °C (Lit.9 mp 251–252 °C).
1H NMR: d = 8.28 (d, J = 7.32 Hz, 1 H), 7.79 (d, J = 4.25 Hz, 1 H),
6.66 (d, J = 1.93 Hz, 1 H), 6.61 (dd, 1 H), 4.31–4.2 (m, 1 H), 1.38
(d, J = 6.65 Hz, 3 H).
13C NMR: d = 177.36, 169.10, 150.28, 139.21, 133.48, 114.80,
110.93, 109.44, 50.04, 18.13.
SYNTHESIS 2009, No. 14, pp 2345–2348
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Advanced online publication: 29.05.2009
DOI: 10.1055/s-0029-1216851; Art ID: Z03009SS
© Georg Thieme Verlag Stuttgart · New York

2346
J. C. Rodriguez Dominguez et al.
PAPER
Table 1 Ullman Compounds 4 and 5 from the Coupling of 2-Chlorobenzoic Acids 1 and Amino Acids 2 and 3
R3
R2
R1
COOH
NH
2
H2N
CO2H
R2
R1
CO2H
Cl
K2CO3, Cu (s)
DMF, reflux
R3
CO2H
4
3
R2
CO2H
NH
H2N
4 CO2H
1
R1
4 CO2H
5
Entry
Chlorobenzoic acid
R1
Amino acid
Product
Yield (%)
R2
R3
1
2
1a
1a
1b
1b
1b
1c
1c
1d
1d
1d
H
H
2a
2b
2b
2a
3
Ph
4a
4b
4c
4d
5a
4e
5b
4f
79
86
89
85
79
78
75
91
82
90
H
H
Me
3
Cl
Cl
Cl
NO2
NO2
H
H
Me
4
H
Ph
5
H
–
6
H
2b
3
Me
7
H
–
8
NO2
NO2
NO2
2b
3
Me
9
H
–
5c
4g
10
H
2c
(CH2)2SMe
Table 2 2-Substituted 3-Acetoxy-1-acetyl-1H-indoles 6 from the Rossing Cyclodecarboxylation Reaction of 4a–g
OAc
R2
R1
CO2H
NH
R2
R1
Ac2O, NaOAc, reflux
R3
N
Ac
R3
CO2H
4
6
Entry
Substrate
R1
H
R2
R3
Product
6a
Yield (%)
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
H
Ph
40
43
25
53
33
32
44
H
H
Me
6b
Cl
Cl
NO2
H
H
Me
6c
H
Ph
6d
H
Me
6e
NO2
NO2
Me
6f
4g
H
(CH2)2SMe
6g
2-{[Carboxy(phenyl)methyl]amino}-4-chlorobenzoic Acid (4d)
Mp 236–237 °C.
2-(4-Carboxybutylamino)-4-chlorobenzoic Acid (5a)
Mp 177–179 °C.
1H NMR: d = 8.79 (d, J = 5.97 Hz, 1 H), 7.53 (d, J = 8.42 Hz, 1 H),
7.22–7.04 (m, 5 H), 6.35–6.38 (m, 2 H), 5.12 (d, J = 5.85 Hz, 1 H).
1H NMR: d = 8.37 (d, J = 8.32 Hz, 1 H), 7.78 (d, J = 8.5 Hz, 1 H),
6.68 (d, J = 1.92 Hz, 1 H), 6.60 (dd, 1 H), 4.08–4.03 (m, 1 H), 2.20–
2.12 (m, 1 H), 0.99–0.94 (m, 6 H).
13C NMR: d = 171.81, 168.99, 149.38, 138.86, 137.80, 133.38,
131.09, 128.77, 128.68, 127.59, 115.06, 111.83, 110.02, 58.65.
13C NMR: d = 173.23, 169.32, 151.23, 139.24, 133.47, 114.74,
110.86, 109.44, 60.10, 30.34, 18.87, 17.84.
Synthesis 2009, No. 14, 2345–2348 © Thieme Stuttgart · New York

PAPER
Preparation of 2-Substituted 1-Acetyl-1H-indol-3-yl Acetates
2347
2-(1-Carboxyethylamino)-4-nitrobenzoic Acid (4e)
Mp 226–227 °C.
3-Acetoxy-1-acetyl-6-chloro-2-methyl-1H-indole (6c)
Mp 133 °C.
1H NMR: d = 8.41 (s, 1 H), 7.90 (d, J = 16.6 Hz, 1 H), 7.60 (s, 2 H),
4.36 (t, 1 H), 1.45 (d, J = 9.65 Hz, 3 H).
1H NMR: d = 8.26 (d, J = 1.67 Hz, 1 H), 7.39 (d, J = 8.35 Hz, 1 H),
7.29 (dd, 1 H), 2.69 (s, 3 H), 2.45 (s, 3 H), 2.39 (s, 3 H).
13C NMR: d = 174.10, 168.65, 151.2, 149.66, 133.47, 123.68,
108.66, 105.82, 50.24, 8.64.
13C NMR: d = 169.81, 168.58, 134.05, 132.64, 130.74, 126.35,
123.98, 122.12, 117.57, 116.22, 27.17, 20.46, 13.08.
MS: m/z = 265, 223, 181.
2-(4-Carboxybutylamino)-4-nitrobenzoic Acid (5b)
Mp 183–185 °C.
3-Acetoxy-1-acetyl-6-chloro-2-phenyl-1H-indole (6d)
Mp 136–137 °C.
1H NMR: d = 8.49 (d, J = 8.02 Hz, 1 H), 8.02 (d, J = 8.62 Hz, 1 H),
7.40–7.32 (m, 2 H), 4.20–4.14 (m, 1 H), 2.25–2.18 (m, 1 H), 1.01–
0.97 (m, 6 H).
1H NMR: d = 8.34 (d, J = 1.62 Hz, 1 H), 7.56–7.43 (m, 6 H), 7.38
(dd, 1 H), 2.21 (s, 3 H), 1.97 (s, 3 H).
13C NMR: d = 172.98, 168.82, 151.23, 150.57, 133.46, 115.41,
108.60, 105.72, 60.27, 30.30, 18.86, 17.81.
13C NMR: d = 170.69, 168.79, 134.19, 132.06, 130.23, 129.59,
129.48, 129.29, 129.27, 128.80, 123.85, 121.64, 119.21, 115.74,
27.16, 20.07.
2-(1-Carboxyethylamino])-5-nitrobenzoic Acid (4f)
Mp 253 °C.
MS: m/z = 327, 285, 243, 207.
1H NMR: d = 9.10 (d, J = 6.75 Hz, 1 H), 8.62 (d, J = 2.45 Hz, 1 H),
8.16 (dd, 1 H), 6.82 (d, J = 9.45 Hz, 1 H), 4.44 (t, 1 H), 1.44 (d, J =
6.85 Hz, 3 H).
3-Acetoxy-1-acetyl-2-methyl-6-nitro-1H-indole (6e)
Mp 137 °C.
1H NMR: d = 9.10 (d, J = 1.77 Hz, 1 H), 8.11 (dd, 1 H), 7.58 (d, J =
8.7 Hz, 1 H), 2.74 (s, 3 H), 2.55 (s, 3 H), 2.41 (s, 3 H).
13C NMR: d = 173.79, 168.91, 153.35, 135.19, 129.34, 128.51,
112.08, 110.12, 50.31, 17.96.
13C NMR: d = 171.01, 168.67, 144.14, 132.64, 131.70, 131.17,
127.77, 118.38, 117.26, 112.05, 26.8, 20.24, 12.6.
2-(4-Carboxybutylamino)-5-nitrobenzoic Acid (5c)
Mp 199–200 °C.
MS: m/z = 276, 234, 192, 162, 146.
1H NMR: d = 9.18 (s, 1 H), 8.63 (s, 1 H), 8.14 (d, J = 9.17 Hz, 1 H),
6.87 (d, J = 7.92 Hz, 1 H), 4.31 (s, 1 H), 2.24 (s, 1 H), 1.01–0.94 (m,
6 H).
3-Acetoxy-1-acetyl-2-methyl-5-nitro-1H-indole (6f)
Mp 156–157 °C.
1H NMR: d = 8.38–8.31 (m, 2 H), 8.13 (dd, 1 H), 2.74 (s, 3 H), 2.49
(s, 3 H), 2.44 (s, 3 H).
13C NMR: d = 173.1, 168.87, 151.75, 150.9, 130.35, 116.34, 108.52,
106.1, 60.1, 30.04, 18.71, 17.5.
13C NMR: d = 170.98, 168.79, 143.17, 135.91, 131.54, 129.85,
123.24, 119.23, 116.38, 112.96, 26.94, 20.36, 12.35.
2-{[1-Carboxy-3-(methylsulfanyl)propyl]amino}-5-nitro-
benzoic Acid (4g)
Mp 142–144 °C.
MS: m/z = 276, 234, 192, 162, 146.
1H NMR: d = 9.11 (d, J = 7.75 Hz, 1 H), 8.64 (d, J = 2.8 Hz, 1 H),
8.18 (dd, 1 H), 6.89 (d, J = 9.57 Hz, 1 H), 4.58–4.50 (m, 1 H), 2.54–
2.49 (m, 2 H), 2.22–2.06 (m, 2 H), 2.03 (s, 3 H).
3-Acetoxy-1-acetyl-2-[2-(methylsulfanyl)ethyl]-1H-indole (6g)
Mp 129–130 °C.
1H NMR: d = 8.37 (d, J = 1.2 Hz, 1 H), 8.14 (d, J = 2.25 Hz, 2 H),
3.16 (t, 2 H), 2.84 (s, 3 H), 2.69 (t, 2 H), 2.43 (s, 3 H), 2.06 (s, 3 H).
13C NMR: d = 172.5, 168.53, 153.64, 135.37, 129.41, 128.44,
112.02, 109.92, 53.83, 31.15, 29.04, 14.59.
13C NMR: d = 170.54, 168.84, 143.03, 135.62, 132.65, 131.08,
123.14, 119.15, 116.30, 113.76, 31.98, 27.36, 24.5, 20.39, 14.53.
1-Acetyl-2-phenyl-1H-indol-3-yl Acetates 6
These compounds were prepared according to the Rossing cyclode-
carboxylation reaction.10
MS: m/z = 336, 294, 252, 220, 178.
Acknowledgment
3-Acetoxy-1-acetyl-2-phenyl-1H-indole (6a)
Mp 130–131 °C.
We want to thank to Prof. Pierre Seck for his valuable help with per-
forming mass spectra, and Mrs. Veronique Poddig for recording the
NMR spectra.
1H NMR: d = 8.30 (d, J = 8.25 Hz, 1 H), 7.52–7.29 (m, 8 H), 2.21
(s, 3 H), 2.02 (s, 3 H).
13C NMR: d = 170.52, 168.86, 134.03, 132.59, 129.94, 129.52,
128.99, 128.73, 128.36, 125.79, 123.56, 122.78, 117.68, 115.87,
27.26, 20.08.
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Synthesis 2009, No. 14, 2345–2348 © Thieme Stuttgart · New York

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J. C. Rodriguez Dominguez et al.
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Synthesis 2009, No. 14, 2345–2348 © Thieme Stuttgart · New York