Introduction of the 1H-indol-3-yl(phenyl)methyl residue into some CH acids

Article abstract of DOI:10.1023/A:1011394114927

A new method of inlroducing the 1H-indol-3-yl(phenyl)methyl residue into some CH acids was developed.

Full text of DOI:10.1023/A:1011394114927

Russian Chemical Bulletin, International Edition, Vol. 50, No. 3, pp. 543—545, March, 2001
543
Brief Communications
Introduction of the 1H-indol-3-yl(phenyl)methyl residue into some CH acids
«
B. B. Semenov and Yu. I. Smushkevich
Department of Organic Chemistry, D. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation.
Fax: +7 (095) 200 4204. E-mail: SMU@muctr.edu.ru, semenovb@mail.ru
A new method of introducing the 1H-indol-3-yl(phenyl)methyl residue into some CH
acids was developed.
Key words: α-phenyl-nor-gramine, pentane-2,4-dione, ethyl malonate, ethyl 3-oxo-
butanoate.
The benzohydryl residue is contained in some medi-
caments. It is also known that replacement of a phenyl
NHMe
R
R´
1
O
O
fragment in spasmolytin by indol-3-yl affords a less toxic
analog exhibiting a different spectrum of biological ac-
tivity and enhanced local anesthetic effect.2
K CO , EtOH
2
3
N
H
In the present work, the condensation of α-phenyl-
nor-gramine with β-dicarbonyl compounds was described
for the first time. The condensation products are poten-
tial intermediates for the synthesis of heterocyclic com-
pounds containing the indol-3-yl(phenyl)methyl residue.
Previously, the alkylation of β-dicarbonyl compounds
R
R´
R
R´
O
O
O
O
or
with gramine3 and its quaternary ammonium salts
,4
5,6
was described. The use of nor-gramine and α-phenyl-
nor-gramine for these purposes remains unknown so far.
α-Phenyl-nor-gramine was only transformed into 2-(1H-
N
N
H
H
7
1, 2
3
indol-3-yl)-2-phenylacetonitrile by condensation with
potassium cyanide.
1: R = R´ = OEt; 2: R = R´ = Me; 3: R = Me, R´ = OEt
It turned out that α-phenyl-nor-gramine7 smoothly
reacts with β-dicarbonyl compounds containing an ac-
tive methylene group. Products (1—3), in which the
methylamino residue is replaced by a corresponding
β-dicarbonyl radical, were obtained in good yields in
that evolves is removed from the reaction mixture by a
flow of an inert gas and hence the products of its
reaction with β-dicarbonyl compounds were not de-
tected.
ethanol in the presence of K CO . The methylamine
2
3
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 521—522, March, 2001.
066-5285/01/5003-543 $25.00 © 2001 Plenum Publishing Corporation
1

5
44
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Semenov and Smushkevich
1
H NMR spectra recorded in CDCl revealed several
Ind); 5.10 (d, 1 H, CHCHAc2, J = 12.1 Hz); 4.64 (d, 1 H,
3
CHCHAc ); 2.06 (s, 3 H, Me ); 1.93 (s, 3 H, Me). MS,
specific features of the target products. Compound 3 is a
mixture of diastereomers in a ratio of 95 : 5; the major
2
+
+
m/z (Irel (%)): 305 [M] (8), 262 [M – Ac] (14), 206
IndCHPh]+ (70). Found (%): C, 78.87; H, 6.18; N, 4.39.
[
(
R*,R*)-diastereomer can be isolated by crystallization
C20H19NO . Calculated (%): C, 78.66; H, 6.27; N, 4.59.
8
2
from 95% ethanol. The diastereotopic ethoxycarbonyl
groups in compound 1 are magnetically nonequivalent,
giving two sets of signals. The same reason explains why
the 1H NMR spectrum of compound 2 shows different
signals from two acetyl groups. The compounds ob-
Ethyl 2-[1H-indol-3-yl(phenyl)methyl]-3-oxobutanoate (3),
yield 71%, m.p. 162—163 °C (from EtOH). 1H NMR, δ for
(R*,R*)-isomer: 7.99 (br.s, 1 H, NH); 7.54 (dd, 1 H, H(4)Ind
,
J = 7.7 and 1.5 Hz); 7.19 (d, 1 H, H(2)Ind, J = 2.20 Hz);
7.03 —7.34 (m, 8 H, Ph and Ind); 5.09 (d, 1 H, CHPh,
J = 12.1 Hz); 4.50 (d, 1 H, CHC(3)H, J = 12.1 Hz); 3.98 (q,
tained, especially 2, are capable of being enolized, but
no enol tautomers were detected by 1H NMR spec-
troscopy.
2 H, CH2CH3, J = 7.13 Hz); 2.04 (s, 3 H, COMe); 0.97 (t,
+
3
2
H, Me, J = 7.1 Hz). MS, m/z (Irel (%)): 335 [M] (5),
92 [M – COMe]+ (1), 206 [IndCHPh]+ (86). Found (%):
C, 75.31; H, 6.19; N, 4.09. C21H21NO . Calculated (%):
3
Experimental
C, 75.20; H, 6.31; N, 4.18.
Below are the characteristic signals of the minor (R*,S*)-dia-
1
stereomer. H NMR, δ: 5.05 (d, 1 H, CHPh, J = 12.1 Hz); 4.49
1
H NMR spectra were recorded on a Bruker WM-250
(
d, 1 H, CHC(3)H, J = 12.1 Hz); 3.96 (q, 2 H, CH CH ,
2 3
spectrometer in CDCl3 with Me Si as the internal standard.
Mass spectra (EI) were recorded on a Finnigan MAT SSQ-710
spectrometer (ionizing voltage 70 eV).
4
J = 7.1 Hz); 2.14 (s, 3 H, COMe); 0.99 (t, 3 H, Me,
J = 7.1 Hz).
Reaction of nor-gramine with CH-acids (general proce-
dure). A solution of potassium carbonate (0.1 g) in 1 mL of
water and a CH acid (0.625 mmol) were added to a boiling
solution of α-phenyl-nor-gramine (1.0 g, 0.42 mmol) in 10 mL
of 95% EtOH. The reaction mixture was refluxed in a flow of an
inert gas until the starting compound disappeared (monitored by
TLC using Silufol UV-254 plates and EtOAc—CCl4 (1 : 4)).
Cooling to ∼ 20 °C gave a white precipitate, which was filtered
off and recrystallized from 95% EtOH.
References
1
2
. M. D. Mashkovskii, Lekarstvennye preparaty [Medicaments],
Khar´kov, 1997, 1, 215 (in Russian).
. K. A. Zaitseva, V. N. Rusinova, Yu. I. Smushkevich, N. N.
Suvorov, and M. D. Mashkovskii, Khim.-Farm. Zh.,
973, 10, 17.
. D. A. Lyttle and D. L. Weisblat, J. Am. Chem. Soc., 1949,
1, 3079.
4. M. Nettekoven and M. Priorz, Tetrahedron Lett., 1955,
6, 1425.
. H. R. Snyder, J. Am. Chem. Chem. Soc., 1944, 66, 350.
. A. Albertson, J. Am. Chem. Soc., 1944, 66, 500.
. V. N. Rusinova, Yu. I. Smushkevich, O. V. Telenkova,
M. V. Vasin, and N. N. Suvorov, Khim. Geterotsikl. Soedin.,
1
3
7
Ethyl 2-[1H-indol-3-yl(phenyl)methyl]malonate (1), yield
6%, m.p.165—167 °C (from EtOH). 1H NMR, δ: 8.00 (br.s,
H, NH); 7.55 (dd, 1 H, H(4)Ind, J = 7.7 and 1.5 Hz); 7.29
3
1
3
5
6
7
(
dd, 1 H, H(7)Ind, J = 7.7 and 1.5 Hz); 7.18 (d, 1 H, H(2)Ind,
J = 2.2 Hz); 7.02—7.36 (m, 7 H, Ph and Ind); 5.08 (d, 1 H,
CHPh, J = 12.1 Hz); 4.28 (m, 1 H, PhCHCH); 4.01 (q, 2 H,
CH CH , J = 7.1 Hz); 3.97 (q, 2 H, CH CH , J = 7.1 Hz);
2
3
2
3
1
974, 2, 211 [Chem. Heterocycl. Comp., 1974, 2, 211 (Engl.
1
.00 (t, 3 H, Me); 0.98 (t, 3 H, Me). MS, m/z (I (%)): 365
rel
M]+ (42), 320 [M – OEt]+ (2), 292 [M – COOEt]+ (5), 206
IndCHPh]+ (100). Found (%): C, 72.51; H, 6.24; N, 3.63.
Transl.)].
[
[
8. B. B. Semenov, Yu. I. Smushkevich, G. V. Grintselev-
Knyazev, and M. Yu. Antipin, Izv. Akad. Nauk, Ser. Khim.,
C22H23NO . Calculated (%): C, 72.31; H, 6.34; N, 3.83.
4
2
001, 543 [Russ. Chem. Bull., Int. Ed., 2001, 50, 571].
3
-[1H-Indol-3-yl(phenyl)methyl]pentane-2,4-dione (2),
yield 71%, m.p. 150—152 °C (from EtOH). 1H NMR, δ: 8.08
br.s, 1 H, NH); 7.53 (dd, 1 H, H(4)Ind, J = 7.7 and 1.5 Hz);
.12 (d, 1 H, H(2)Ind, J = 2.2 Hz); 7.05—7.31 (m, 8 H, Ph and
(
7
Received April 28, 2000;
in revised form February 7, 2001