1408
R. J. Cregge et al. / Tetrahedron Letters 42 (2001) 1407–1409
CO2H
NH
N
N
O
Cl
CN
Cl
Cl
N
b,c
a
NH
d
CO2Et
2
CO2H
77-95%
52-83%
72-91%
NH
NH
8a-c
O
Cl
Cl
Cl
(Z) 7a-c
(E) 9a-c
a) pyrid-2-yl, b) pyrid-3-yl, c) pyrid-4-yl
Scheme 2. (a) Pyridylacetonitrile, cat. piperidine, EtOH, D. (b) H2SO4/HOAc, D. (c) LiOH, THF/H2O. (d) 6N NaOH, THF, D.
that the reaction of arylacetonitriles with indole alde-
hyde 2 afforded the corresponding arylpropenenitriles
(Scheme 1). In a typical experiment, indole aldehyde 2
(1.43 g, 5.0 mmol), the arylacetonitrile (1.0 equiv., 5.0
mmol) and piperidine (four drops) were refluxed for 16
h in EtOH (95%, 30 mL). After cooling to rt, the
reaction was diluted with Et2O and the resulting solid
was filtered, washed with Et2O, and dried under vac-
uum. Chromatography afforded ethyl 4,6-dichloro-3-(2-
cyano-2-aryl-vinyl)-1H-indole-2-carboxylates (3a–c) in
moderate yield, as E/Z mixtures (Scheme 1).5 Acid
hydrolysis of propenenitrile esters 3a–c under the indi-
cated conditions afforded propenamide esters 4a–c,
which upon subsequent alkaline hydrolysis gave the
propenamide acids 5a–c (Scheme 1). The propenamide
acids 5a–c are very stable, and attempts to further
hydrolyze them to the desired dicarboxylic acid analogs
6a–c were either unsuccessful or required harsh condi-
tions.6 Under analogous conditions, a different course
of events was observed in the case of the pyridyl
analogs 7a–c, which are obtained exclusively as Z iso-
mers from the Knoevenagel reaction (Scheme 2).7
Unique to the pyridyl series is the formation of
azepinoindole8 intermediates 8a–c. As a representative
example, azepinoindole 8a is characterized by two
sharp singlets at l 13.43 (indole NH) and l 12.10
(azepinedione NH) in the 1H NMR spectrum (400
MHz, DMSO-d6), and two carbonyl resonances at l
163.5 and l 157.8 (proximal to indole) in the 13C NMR
spectrum.9 Treatment of azepinoindoles 8a–c with 6N
NaOH and heating for 16 h provided the desired
E-pyridyl indole dicarboxylic acids, 9a–c, in good to
moderate yields.
in exclusive formation of the Z isomer of propeneni-
triles 3a–c, and subsequent formation of the respective
azepinoindole intermediate necessary for complete con-
version to the desired dicarboxylic acids 6a–c. It is
envisaged that the intramolecular presence of a pyridine
ring facilitates not only the exclusive formation of the Z
indole propenenitrile intermediates 7a–c, but also their
subsequent cyclization to provide the azepinoindole
intermediates 8a–c observed in only the pyridyl series.
In conclusion, the one-step preparation of arylprope-
nenitriles 3a–c and 7a–c provided a convenient entry
into a class of compounds related to MDL 105,519, 1.
Conditions were developed for the synthesis of the
propenamide carboxylic acids 5a–c via this route, in
three short steps (Scheme 1). In addition, the 2-, 3- and
4-substituted pyridine analogs of MDL 105,519, 9a–c,
were synthesized in three steps in good to moderate
yields (Scheme 2). Analog 9b was found to have an
affinity for the glycine-site of the NMDA receptor of
126 nM (IC50 versus [3H]glycine).
References
1. Choi, D. W.; Rothman, S. M. Annu. Rev. Neurosci. 1990,
13, 171–182.
2. (a) Baron, B. M.; Harrison, B. L.; Kehne, J. H.; et al.
Eur. J. Pharmacol. 1997, 323, 181–192; (b) [3H]MDL
105,519 is commercially available (Amersham Pharmacia
Biotech) as a high-affinity radioligand for the NMDA
receptor-associated glycine recognition site, see: Baron, B.
M.; et al. J. Pharmacol. Exp. Ther. 1996, 279, 62–68.
3. For a review of the Knoevenagel reaction, see: Jones, G.
Org. React. 1967, 15, 204–599.
4. Aldehyde 2 was readily obtained in high yield by the
reaction of 2-ethoxycarbonyl-4,6-dichloroindole11 with
POCl3 and DMF in dichloroethane at 90°C.
5. Depending on the aryl substituent, the Knoevenagel con-
densation can be sluggish and may proceed in low yield
with starting material being recovered. While substituted
phenyl and pyridylacetonitriles reacted to give acceptable
yields of the condensation product, thiophene and furan
acetonitriles did not react.
It appears that formation of an azepinoindole interme-
diate is a prerequisite for successful hydrolysis to the
desired indole dicarboxylic acids under reasonably mild
conditions. While indole propenenitriles 3a–c contain a
proportion of the Z isomer required for cyclization to
the corresponding azepinoindole intermediate,8 and
while E/Z equilibration of 3a–c under the hydrolysis
conditions appears conceivable, azepinoindole forma-
tion from 3a–c was not observed under similar reaction
conditions. Attempts were made to increase the propor-
tion of the Z isomer of 3a–c, based on the observation
that the E/Z distribution is dependent on the number
of equivalents of base used and the reaction tempera-
ture.10 Unfortunately, increased temperature and addi-
tion of pyridine to the reaction mixture failed to result
6. 3-(2-Carbamoyl-2-phenylvinyl)-4,6-dichloro-1H-indole-2-
carboxylic acid ethyl ester 4a can be hydrolyzed to MDL
105,519, 1, using 9 M H2SO4 in refluxing dioxane for 16
h, as described in: Myers, A. G.; Yang, B. H.; Chen, H.;
Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361–9362.
Cregge, Robert J.
