Russ.Chem.Bull., Int.Ed., Vol. 50, No. 7, July, 2001
1263
(4-Oxo-4,5,6,7-tetrahydroindol-3-yl)acetic acids
the 1H NMR spectra. Among the compounds obtained,
the methylene protons are nonequivalent in 2e, 3h, and
2u. In other cases, these protons manifest themselves as
singlets. This cannot be explained by hindered rotation
about the CN (NN) bond, which gives rise to a
center of asymmetry in the molecule and changes the
CH2X group from enantiotopic to diastereotopic,11 be-
cause the aforesaid splitting is not observed for many
other compounds 2 and 3 containing different substitu-
ents in position 2. It should be noted that such an effect
is absent in structurally related compounds 3e and 2h.
Thus, we developed a new method for the synthesis
of N-substituted 3-(2,2,2-trichloroethyl)-4,5,6,7-tetra-
hydroindol-4-ones and N-substituted 2-(4-oxo-(4,5,6,7-
tetrahydroindol-3-yl)acetic acids with potential biologi-
cal activity.
for 8 h. The solution was cooled and added dropwise to water
(40 mL) with stirring. The precipitate that formed was filtered
off and recrystallized from ethanol or aqueous ethanol.
3-(2,2,2-Trichloroethyl)-2,6,6-trimethyl-1-(4-methyl-
3-chlorophenyl)-4,5,6,7-tetrahydro-1H-indol-4-one (2a).
13C NMR, δ: 192.8 (C=O); 142.3 (C(1-Ar)); 136.5 (C(7a));
135.2 (C(3-Ar)); 133.8 (C(2)); 132.0 (C(2-Ar)); 131.2 (C(4a));
127.2 (C(6-Ar)); 126.5 (C(5-Ar)); 117.2 (C(4-Ar)); 110.5 (C(3));
101.9 (CCl3); 52.2 (C(5)); 48.3 (C(7)); 35.9 (C(6)); 34.8
(CH2CCl3); 27.9 (2 CH3); 19.3 (4-CH3C6H4); 11.6 (CH3).
Synthesis of compounds 3 (general procedure). A mixture
of trichloroethyl derivative 2 (5 mmol) and 93% H2SO4 (8 mL)
was heated with stirring to 6070 °C. Then oleum (∼30%,
1 mL) was added, and heating was continued at 90100 °C for
34 h until vigorous evolution of HCl ceased. The reaction
mixture was cooled and slowly poured into 40 mL of cold
water. The precipitate that formed was filtered off, dissolved in
an excess of 20% KOH, and washed with ether (3½10 mL).
Then the aqueous solution was acidified with dilute HCl, and
the precipitate that formed was isolated, dried, and recrystal-
lized from aqueous ethanol or chromatographed in ethyl ac-
etatehexane (3 : 1).
Experimental
1
H and 13C NMR spectra were recorded on Bruker WM-250
[2,6,6-Trimethyl-(4-methyl-3-chlorophenyl)-4-oxo-4,5,6,7-
tetrahydro-1H-indol-3-yl)acetic acid (3a). 13C NMR, δ: 193.0
(C=O); 172.4 (COOH); 141.7 (C(7a)); 136.1 (C(1-Ar)); 135.4
(C(3-Ar)); 133.7 (C(4a)); 131.9 (C(2-Ar)); 128.4 (C(2)); 127.6
(C(6-Ar)); 126.3 (C(5-Ar)); 116.7 (C(4-Ar)); 111.2 (C(3));
52.0 (C(5)); 35.8 (C(7)); 34.9 (C(6)); 30.2 (CH2COOH); 28.0
(2 CH3); 19.2 (4-CH3C6H4)); 9.7 (CH3).
and Bruker AM-300 instruments in DMSO-d6 with Me4Si as
the internal standard. The melting points were determined on
a Boetius microscope stage and are uncorrected. Col-
umn chromatography was carried out on Aldrich silica gel
(60100 mesh).
2-(1-Acetyl-3,3,3-trichloropropyl)-3-hydroxy-5,5-dimethyl-
cyclohex-2-en-1-one (1a). Potassium hydroxide (3.2 g, 58 mmol)
and dimedone (8 g, 58 mmol) were dissolved successively in
35 mL of MeOH. 3,5,5,5-Tetrachloropentan-2-one (12.78 g,
58 mmol) was added dropwise with vigorous stirring. The
solution became turbid, and a precipitate was formed within
1015 min. The reaction mixture was stirred for 36 h and
concentrated in vacuo. The residue was diluted with EtOH
(80 mL) and brought to boiling. Water (∼50 mL) and dilute
HCl (pH 56) were added dropwise until the precipi-
tate dissolved. Cooling gave compound 1a (14.3 g, 79%),
m.p. 191 °C. Found (%): C, 47.39; H, 5.13; Cl, 32.02.
C13H17Cl3O3. Calculated (%): C, 47.66; H, 5.23; Cl, 32.46.
1H NMR, δ: 11.1 (s, 1 H, OH); 4.05 (dd, 1 H, CH, J = 6.5,
3.0 Hz); 3.73 (dd, 1 H, HCHCCl3, J = 15.3, 3.0 Hz); 2.75 (dd,
1 H, HCHCCl3, J = 15.3, 6.5 Hz); 2.30 (s, 4 H, 2 CH2); 1.92
(s, 3 H, COCH3); 1.04 (s, 6 H, 2 CH3).
2-(1-Acetyl-3,3,3-trichloropropyl)-3-hydroxycyclohex-2-en-
1-one (1b). Potassium hydroxide (3.75 g, 67 mmol) and cyclo-
hexane-1,3-dione (7.47 g, 66.6 mmol) were dissolved succes-
sively in 45 mL of MeOH. 3,5,5,5-Tetrachloropentan-2-one
(14.93 g, 66.6 mmol) was added dropwise with vigorous stirring.
The solution became turbid, and a precipitate was formed
within 1015 min. The reaction mixture was stirred for 96 h
and worked up as described above. The yield of compound 1b
was 8.38 g (42%), m.p. 164166 °C. Found (%): C, 44.48;
H, 4.37; Cl, 35.40. C11H13Cl3O3. Calculated (%): C, 44.10;
H, 4.37; Cl, 35.50. 1H NMR, δ: 11.2 (s, 1 H, OH); 4.06 (dd,
1 H, CH, J = 6.7, 3.2 Hz); 3.69 (dd, 1 H, HCHCCl3, J = 15.3,
3.2 Hz); 2.77 (dd, 1 H, HCHCCl3, J = 15.3, 6.7 Hz); 2.40 (s,
4 H, 2 CH2); 1.90 (s, 5 H, CH2 + CH3).
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Synthesis of compounds 2 (general procedure). A mixture
of ketone 1a or 1b (10 mmol) and the corresponding amine
(10 mmol) or hydrazine was refluxed in 15 mL of glacial AcOH
Received September 18, 2000;
in revised form March 20, 2001