Synthesis of 3-nitro-1H-indole-2-carboxylic acid ethyl ester derivatives from Baylis-Hillman adducts

Article abstract of DOI:10.1055/s-2005-868499

A simple and direct synthesis of 3-nitro-1H-indole-2-carboxylic acid ethyl ester derivatives from acetylated Baylis-Hillman adducts of 2-nitrobenzaldehydes is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-868499

1480
LETTER
Synthesis of 3-Nitro-1H-indole-2-carboxylic Acid Ethyl Ester Derivatives from
Baylis–Hillman Adducts
S
ynthesis of 3-N
i
l
tro-1
H
e
-indole-2-ca
m
rboxylic
A
cid Ethy
e
l
Ester
D
er
n
ivatives s R. Horn, Michel Perez*
Pierre Fabre Research Center, 17 Avenue Jean Moulin, 81106 Castres, France
Fax +33(5)63714299; E-mail: michel.perez@pierre-fabre.com
Received 2 February 2005
Abstract: A simple and direct synthesis of 3-nitro-1H-indole-2-
carboxylic acid ethyl ester derivatives from acetylated Baylis–Hill-
man adducts of 2-nitrobenzaldehydes is described.
Key words: indoles, heterocycle, rearrangement, ring-closure,
Baylis–Hillman
During the past several years, the Baylis–Hillman reaction
has been extensively studied and is now one of the most
efficient carbon-carbon bond forming reaction.1 Many
heterocycles have been synthesized from Baylis–Hillman
adducts (BH adducts) including quinolines,2 dihydroquin-
olines,3 quinolones,4 pyrrolidines,5 and recently indoles
albeit in low yields and under harsh conditions.6
Despite some interesting properties as intermediates for
the preparation of pharmacologically active compounds,7
3-nitro-1H-indole-2-carboxylic acid ethyl ester deriva-
tives have been relatively poorly studied probably be-
cause of disappointing preparation procedures8 in terms of
regiochemistry and yields (nitration reaction).
In order to prepare the 8-nitronaphthalene derivative 7, we
decided to follow described conditions9 using the acetyl-
ated BH adduct 2a as starting material. Unexpectedly, un-
der these conditions compound 2a led to the formation of
3 compounds. Among them, we were able to identify the
8-chloronaphthalene derivative 4 and the quinoline N-ox-
ide 5 but we were unable, at that point, to determine the
structure of the major product (13/13/31% isolated yields,
respectively). Quinoline N-oxides have already been re-
ported from BH adducts albeit under acidic conditions.10
Isolation and full characterization including X-ray crys-
tallographic structure determination of the unknown com-
pound led to the identification of 4-chloro-3-nitro-1H-
indole-2-carboxylic acid ethyl ester (6a, Scheme 1).
Scheme 1
6a. We then examined the effect of the base. Using
Cs2CO3 instead of K2CO3 gave similar results but NaOMe
and KOH gave compound 6a in slightly lower yields (en-
tries 5, 6, 9). We also evaluated Hünig’s base (i-Pr2NEt),
which gave also a slightly lower yield of 6a but after a
much longer reaction time (24 h vs. 1 h, entry 7). Finally,
we decided to evaluate NaNO2 and KNO2 (entries 10, 11)
since these reagents behave as bases and as potential ‘NO2
donors’. These conditions clearly gave the best results
since, in both cases, we observed only the formation of
compound 6a in about 60% isolated yield (Table 1).
Due to the potential interest of this compound we decided
to optimize the reaction conditions in order to obtain ex-
clusively indole derivative 6a. We first tried to determine
the influence of the solvent on the selectivity of this reac-
tion. Replacing DMF by DMSO, acetonitrile or THF led
mainly to the formation of the naphthalene derivative 4
(51% isolated yield, entries 2–4). Thus, the use of DMF
seems essential to direct the reaction towards compound
The mechanism by which this 3-nitro-indole derivative is
formed from the BH adduct is not clear yet, but, in com-
parison with the mechanism proposed for the formation of
the naphthalene derivatives,9 we anticipated a common
intermediate of structure 3 (Scheme 2).
To try to understand the mechanism of this reaction, we
decided to modify the established conditions by removing
EtNO2 in order to determine what products will be formed
if KNO2 was used alone. To our surprise, in these condi-
tions in which intermediate 3 cannot be formed, we ob-
tained selectively compound 6a in a 50% yield. This result
SYNLETT 2005, No. 9, pp 1480–1482
0
1.
0
6.
2
0
0
5
Advanced online publication: 27.04.2005
DOI: 10.1055/s-2005-868499; Art ID: D03005ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Nitro-1H-indole-2-carboxylic Acid Ethyl Ester Derivatives
Table 2 Optimization of the Reaction Conditions with KNO2
1481
Table 1 Optimization of the Reaction Conditions Using EtNO2
(2 equiv)
Product R1
R2
R3
KNO2 Temp
(equiv) (°C)
Time Yield
Entry Base
(2 equiv)
Solventa Time Yield of Yield of Yield of
(h)
(%)
(h)
4 (%)
13
51
56
16
11
6
5 (%)
13
16
0
6a (%)
31
7
6a
6a
6a
6a
6b
6c
6d
Cl
Cl
Cl
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
H
3
1
6
3
3
3
3
r.t.
1
50
1
2
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOH
DMF
DMSO
THF
1
r.t.
1
NDa
45
1
r.t.
1
3
48
72
1
0
0 °C
0 °C
0 °C
1
77
4
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
7
4
1
55
5
11
3
28
21
24
3
H
1
65
6
24
24
1
H
–20 °C
to r.t.
3
23
7
i-Pr2NEt
DABCO
MeONa
NaNO2
KNO2
3
7
6e
H
H
NO2
3
–20 °C
to r.t.
3
48
8
5
1
9
1
7
7
26
60
59
a Incomplete reaction.
10
11
1
0
0
To extend the scope of this reaction these conditions were
applied to other BH adducts (Table 2). Chloro-substituted
BH adducts 2b and 2c gave comparable yields of the cor-
responding chloro-3-nitroindoles 6b and 6c. To determine
if this cyclization was specific to chloro-substituted BH
adducts, we also evaluated these conditions with BH
adducts 2d and 2e. The 3-nitroindoles 6d and 6e were ef-
fectively obtained, however, with low to moderate yields
and at lower temperature.
1
0
0
a All reactions were performed at r.t. except the one in THF, which
was under reflux.
In conclusion, we have developed a convenient and easy
procedure for the synthesis of 3-nitro-1H-indole-2-car-
boxylic acid ethyl ester derivatives starting from Baylis–
Hillman acetates that may be useful intermediates for the
synthesis of biologically active compounds.
General Methods
The BH acetates were prepared according to literature procedures12
1
and gave satisfactory data. H NMR spectra were obtained at 400
Scheme 2 Anticipated structure of the intermediates
MHz and 13C NMR spectra at 100 MHz.
Preparation of 3-Nitro-1H-indole-2-carboxylic Acid Ethyl
Ester
clearly indicates that, since the intermediate of this specif-
ic reaction cannot be 3, we may have either two distinct
mechanisms for the formation of 6a depending on the
reaction conditions or different intermediates (3¢ and 3)
for the formation of 6a versus 4 and 5 in the conditions
including EtNO2. Under conditions using only KNO2 the
intermediate is probably 3¢ as very recently described for
the synthesis of coumarin derivatives.11
Method A: a suspension of K2CO3 (2 equiv) and nitroethane (2
equiv) in DMF was stirred at r.t. After 10 min the BH acetate (1
equiv) dissolved in DMF was added. At the end of the reaction, con-
trolled by TLC, H2O was added and the suspension was extracted
twice with EtOAc. The organic phase was dried over Na2SO4, and
concentrated to give the indoles, generally as yellow solids, which
were obtained in pure form after silica gel chromatography.
Method B: the BH acetate was dissolved in DMF. The solution was
cooled to 0 °C and 3 equiv KNO2 were added. At the end of the re-
action, controlled by TLC, the same work up described in method
A was used to afford the pure compounds.
Since these conditions were simpler, we decided to opti-
mize this new methodology. Decreasing the number of
equivalents of KNO2 from three to one gave an incom-
plete reaction and increasing to 6 equivalents lowered the
yield. Due to the previous results, DMF was retained as
solvent but we decided to work at 0 °C instead of room
temperature. Thus, working with BH adduct 2a in DMF
and using three equivalents of KNO2 at 0 °C gave, in one
hour, compound 6a in 77% isolated yield (Table 2).
5-Chloro-1-oxyquinoline-3-carboxylic acid ethyl ester (5): 13%
yield, mp 214 °C. IR (KBr): 3274, 1706, 1379, 1254 cm–1. 1H NMR
(d6-DMSO): d = 8.88 (s, 1 H), 8.52 (d, J = 8.8 Hz, 1 H), 8.48 (s, 1
H), 8.04 (d, J = 7.5 Hz, 1 H), 7.94 (t, J = 7.6 Hz, 1 H), 4.42 (q,
J = 7.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H). 13C NMR (d6-DMSO):
d = 162.5, 143.4, 134.3 (CH), 132.42 (CH), 132.36, 130.0 (CH),
Synlett 2005, No. 9, 1480–1482 © Thieme Stuttgart · New York

1482
C. R. Horn, M. Perez
LETTER
126.7, 121.5 (CH), 118.5 (CH), 62.0 (CH2), 13.9 (CH3). MS (ESI):
m/z (%) = 252 (100) [MH]+. Anal. Calcd for C11H9N2O4Cl: C,
57.27; H, 4.01; N, 5.57; Cl, 14.09. Found C, 57.32; H, 4.14; N, 5.55;
Cl, 13.87.13
(CH), 118.8 (CH), 110.3 (CH), 62.9 (CH2), 13.7 (CH3). MS (ESI):
m/z (%) = 247 (100), 280 (40) [MH]+. Anal. Calcd for
C11H9N3O6·0.3EtOAc: C, 47.32; H, 3.80; N, 13.91. Found: C,
47.19; H, 3.83; N, 13.97.
4-Chloro-3-nitro-1H-indole-2-carboxylic acid ethyl ester (6a):
77% yield; mp 177 °C. IR (KBr): 3275, 1706, 1537, 1339, 1254
cm–1. 1H NMR (d6-DMSO): d = 13.24 (s, NH, 1 H), 7.57 (d, J = 8.4
Hz, 1 H), 7.42 (m, 2 H), 4.40 (q, J = 7.2 Hz, 2 H), 1.32 (t, J = 7.2
Hz, 3 H). 13C NMR (d6-DMSO): d = 158.1, 134.6 (2 s), 129.6, 126.9
(CH), 123.3 (CH), 121.3, 115.7, 112.7 (CH), 62.0 (CH2), 13.7
(CH3). MS (ESI): m/z (%) = 269 (100) [MH]+. Anal. Calcd for
C11H9N2O4Cl: C, 49.18; H, 3.38; N, 10.43; Cl, 13.20. Found: C,
49.36; H, 3.77; N, 10.06; Cl, 13.28.
Acknowledgment
The authors whish to thank the European Commission for financial
support (Marie Curie grant for CRH). We also warmly thank Dr.
Marie Lamothe for fruitful discussions and the Pierre Fabre Depart-
ment of Chemistry for analytical evaluations.
References
Crystal preparation for X-ray diffraction: an EtOAc solution of 6
was layered with hexanes at r.t. After 4 d, yellow needles were col-
lected by filtration and air-dried.
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5-Chloro-3-nitro-1H-indole-2-carboxylic acid ethyl ester (6b):
55% yield; mp 148 °C. IR (KBr): 3293, 1677, 1509, 1362, 1250
cm–1. 1H NMR (d6-DMSO): d = 13.61 (s, 1 H), 8.03 (s, 1 H), 7.65
(d, J = 8.8 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 4.46 (q, J = 6.8 Hz, 2
H), 1.29 (t, J = 6.8 Hz, 3 H). 13C NMR (d6-DMSO): d = 159.2,
131.6, 129.7, 129.2, 128.5, 126.1 (CH), 120.7, 119.0 (CH), 115.6
(CH), 65.2 (CH2), 13.7 (CH3). MS (ESI): m/z (%) = 269 (100)
[MH]+. A correct microanalysis could not be obtained.
(3) Kim, J. N.; Kim, H. S.; Gong, H. G.; Chung, Y. M.
Tetrahedron Lett. 2001, 42, 8341.
6-Chloro-3-nitro-1H-indole-2-carboxylic acid ethyl ester (6c):
65% yield; mp 194 °C. IR (KBr): 3265, 1694, 1507, 1353, 1260
cm–1. 1H NMR (d6-DMSO): d = 13.49 (s, 1 H), 8.03 (d, J = 8.6 Hz,
1 H), 7.65 (s, 1 H), 7.44 (d, J = 8.6 Hz, 1 H), 4.46 (q, J = 7.2 Hz, 2
H), 1.29 (t, J = 7.2 Hz, 3 H). 13C NMR (d6-DMSO): d = 159.2,
133.5, 130.4, 129.2, 126.9, 125.0 (CH), 121.5 (CH), 118.6, 113.2
(CH), 62.6 (CH2), 13.7 (CH3). MS (ESI): m/z (%) = 269 (100)
[MH]+. Anal. Calcd for C11H9N2O4Cl: C, 49.18; H, 3.38; N, 10.43;
Cl, 13.20. Found: C, 49.37; H, 3.50; N, 10.14; Cl, 13.05.
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3-Nitro-1H-indole-2-carboxylic acid ethyl ester (6d): 23% yield;
mp 137 °C. IR (KBr): 3283, 1683, 1513, 1367, 1260 cm–1. 1H NMR
(d6-DMSO): d = 13.39 (s, 1 H), 8.06(d, J = 7.0 Hz, 1 H), 7.62 (d,
J = 8.2 Hz, 1 H), 7.46 (m, 2 H), 4.47 (q, J = 6.8 Hz, 2 H), 1.36 (t,
J = 6.8 Hz, 3 H). 13C NMR (d6-DMSO): d = 159.6, 133.2, 128.5,
127.0, 126.3 (CH), 125.0 (CH), 120.3 (CH), 119.8, 113.6 (CH),
62.4 (CH2), 13.7 (CH3). MS (ESI): m/z (%) = 235 (100) [MH]+.
Anal. Calcd for C11H10N2O4·0.15H2O: C, 55.77; H, 4.38; N, 11.82.
Found: C, 55.94; H, 4.45; N, 11.66.
3,6-Dinitro-1H-indole-2-carboxylic acid ethyl ester (6e): 48%
yield; mp 176 °C. IR (KBr): 3326, 1735, 1519, 1380, 1248 cm–1. 1H
NMR (d6-DMSO): d = 14.11 (s, 1 H), 8.46 (s, 1 H), 8.24 (s, 1 H),
4.50 (q, J = 6.8 Hz, 2 H), 1.36 (t, J = 6.8 Hz, 3 H). 13C NMR
(d6-DMSO): d = 158.9, 144.9, 132.9, 131.8, 126.7, 123.8, 120.8
(13) This compound was also synthesized by an alternative route
via the corresponding quinoline using the method of: Ono, I.;
Fujiki, Y.; Fujinami, N.; Hoshi, T. Chem. Lett. 1989, 371;
the NMR spectra were the same as for 5.
Synlett 2005, No. 9, 1480–1482 © Thieme Stuttgart · New York