Synthesis of new carboxy lactones and some their transformations

Article abstract of DOI:10.1023/A:1016338226670

Alkylation of 2-ethoxycarbonyl-4-pentanolides with ethyl chloroacetate gave 2-ethoxycarbonyl-2-ethoxycarbonylmethyl-4-pentanolides. Alkaline hydrolysis of the latter afforded 2-carboxymethyl-4-pentanolides which were converted into the corresponding acyl chlorides in high yield by treatment with thionyl chloride in the presence of a catalytic amount of dimethylformamide. Reaction of 2-chloroformylmethyl-4-pentanolides with thiosemicarbazide, followed by treatment with alkali, resulted in formation of 2-(5-mercapto-1,2,4-triazol-3-ylmethyl)-4-pentanolides.

Full text of DOI:10.1023/A:1016338226670

Russian Journal of Organic Chemistry, Vol. 38, No. 3, 2002, pp. 390 393. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 3, 2002,
pp. 411 414.
Original Russian Text Copyright
2002 by Kochikyan, E. Arutyunyan, V. Arutyunyan, Avetisyan.
Synthesis of New Carboxy Lactones
and Some Their Transformations
T. V. Kochikyan, E. V. Arutyunyan, V. S. Arutyunyan, and A. A. Avetisyan
Erevan State University, ul. Aleka Manukyana 1, Erevan, 375049 Armenia
Received April 4, 2001
Abstract Alkylation of 2-ethoxycarbonyl-4-pentanolides with ethyl chloroacetate gave 2-ethoxycarbonyl-
2-ethoxycarbonylmethyl-4-pentanolides. Alkaline hydrolysis of the latter afforded 2-carboxymethyl-4-pentano-
lides which were converted into the corresponding acyl chlorides in high yield by treatment with thionyl
chloride in the presence of a catalytic amount of dimethylformamide. Reaction of 2-chloroformylmethyl-4-
pentanolides with thiosemicarbazide, followed by treatment with alkali, resulted in formation of 2-(5-mer-
capto-1,2,4-triazol-3-ylmethyl)-4-pentanolides.
The present study continues the series of our
systematic investigations in the field of biologically
active substances having a saturated -lactone ring
[1 3]. We previously described [4, 5] a procedure for
preparation of 4-substituted 2-ethoxycarbonyl-4-pen-
tanolides which possess a wide synthetic potential. In
the present communication we report on some trans-
formations leading to carboxylactone esters and
heterocyclic compounds having a lactone ring as sub-
stituent.
when the reaction was carried out in 30% aqueous
sodium hydroxide, first at room temperature and then
on heating for 3 h. The yields of butanolides V and
VI were 80 90% (Scheme 2).
Scheme 2.
It is known that carboxylactones and esters derived
therefrom are used as propellant additives [6] and in
the synthesis of lactone derivatives as lubricant
additives [7, 8], plasticizers [9], etc. Taking the above
into account, 2-ethoxycarbonyl-4-pentanolides I and
II were brought into reaction with ethyl chloroacetate
in the presence of an equimolar amount of sodium
ethoxide in anhydrous ethanol. The reaction gave the
corresponding 2-ethoxycarbonylmethyl derivatives III
and IV (Scheme 1).
V, R = Me; VI, R = H.
Carboxylic acids V and VI were converted into
chlorides VII and VIII by treatment with thionyl
chloride. Products VII and VIII were obtained in
high yields (80 90%) when the reaction was carried
out in dry benzene in the presence of a catalytic
amount of dimethylformamide (Scheme 3).
Scheme 1.
Scheme 3.
VII, R = Me; VIII, R = H.
I, III, R = Me; II, IV, R = H.
Compounds III and IV were then subjected to
alkaline hydrolysis. The best results were obtained
We previously synthesized triazolyl-substituted
lactones which showed a hypotensive effect [10].
1070-4280/02/3803-0390$27.00 2002 MAIK Nauka/Interperiodica

SYNTHESIS OF NEW CARBOXY LACTONES
391
With the goal of obtaining new triazolyl lactones and
studying substituent effect on their pharmacological
properties we examined the reaction of acyl chlorides
VII and VIII with thiosemicarbazide in dry benzene.
These reactions smoothly afforded compounds IX
and X in 76 87% yield (Scheme 4).
crystalline products were determined on a Boetius
device. Initial compounds I and II were synthesized
by the procedure described in [5].
2-Ethoxycarbonyl-2-ethoxycarbonylmethyl-4-
methyl-4-pentanolide (III). A dry four-necked flask
equipped with a mechanical stirrer, reflux condenser,
dropping funnel, and thermometer was charged with
150 ml of anhydrous ethanol and 3.45 g (0.15 mol)
of metallic sodium. When the metal dissolved, the so-
lution was cooled to 20 25 C, and 25.8 g (0.15 mol)
of butanolide I was added. The mixture was stirred for
0.5 h, and 20.2 g (0.165 mol) of ethyl chloroacetate
was added dropwise. The mixture was stirred for 3 h
at 20 25 C and was then heated under reflux until
it became neutral. The solvent was distilled off, and
dilute hydrochloric acid was added to the residue to
pH 2 3. The mixture was extracted with ether, the
extract was washed with water and dried over anhy-
drous magnesium sulfate, the solvent was distilled off,
and the residue was distilled under reduced pressure.
Scheme 4.
IX, R = Me; X, R = H.
Cyclization of thiosemicarbazides IX and X in
16% aqueous sodium hydroxide gave triazolylmethyl-
pentanolides XI and XII (Scheme 5).
Yield 35.9 g (88%), bp 119 120 C (2 mm), nD20
=
,
1.4515, d240 = 1.1239, R 0.7 (A). IR spectrum,
f
1
cm : 1770 (C O, lactone); 1730 (C O, ester); 1183,
1225 (C O C). Found, %: C 57.45; H 7.50.
C13H20O6. Calculated, %: C 57.35; H 7.35.
Scheme 5.
2-Ethoxycarbonyl-2-ethoxycarbonylmethyl-4-
pentanolide (IV) was synthesized as described above
for compound III from 2.3 g (0.1 mol) of metallic
sodium, 20 g (0.1 mol) of pentanolide II, and 13.5 g
(0.11 mol) of ethyl chloroacetate in 100 ml of anhy-
drous ethanol. Yield 20.1 g (78%), bp 118 120 C
(1 mm), n2D0 = 1.4515, d420 = 1.1464, Rf = 0.51 (A).
XI, R = Me; XII, R = H.
1
IR spectrum, , cm : 1770 (C O, lactone); 1733
All the compounds prepared were characterized by
physical constants, elemental analysis data, and
(C O, ester); 1183, 1225 (C O C). Found, %:
C 55.95; H 7.10. C12H18O6. Calculated, %: C 55.81;
H 6.98.
1H and IR spectra, and their purity was proved by
TLC and GLC.
2-Carboxymethyl-4-methyl-4-pentanolide (V).
A three-necked flask equipped with a mechanical
stirrer, reflux condenser, and dropping funnel was
charged with 70 g of 30% aqueous sodium hydroxide;
the solution was cooled, and 40.8 g (0.15 mol) of
pentanolide III was added dropwise. When the
mixture became homogeneous, it was stirred for 1 h
at room temperature and for 3 h at 80 85 C. The
mixture was cooled, acidified with concentrated
hydrochloric acid to pH 1 2, and extracted with ether.
The extract was washed with a small amount of water
and dried over anhydrous magnesium sulfate. The
solvent was distilled off, and the residue was heated
at 250 300 C (12 15 mm), cooled, and recrystallized
from water. Yield 23.2 g (90%), mp 147 149 C. IR
EXPERIMENTAL
The IR spectra of compounds III and IV (prepared
as thin films) and V XII (dispersed in mineral oil)
were recorded on a Nicolet FTIR NEXUS instrument.
The 1H NMR spectra were recorded on a Varian
Mercury-300 spectrometer (300 MHz) in DMSO-d6.
Gas liquid chromatography was performed on
a Varian Model 3600 chromatograph using a DB-5
capillary column (15 m 0.25 mm, film thickness
0.25 m); flame ionization detector (300 C); oven
temperature 180 250 C; carrier gas helium, flow rate
18.9 ml/s. Silufol UV-254 plates were used for TLC,
eluent alcohol benzene hexane (3 : 3 : 10) (A) or
alcohol benzene (1:5) (B). The melting points of
1
spectrum, , cm : 3400 2500 (OH); 1738 (C O,
lactone); 1700 (C O, COOH); 1230, 1183 (C O C).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 3 2002

392
KOCHIKYAN et al.
1
1H NMR spectrum, , ppm: 1.1 1.22 two s (6H,
CH3), 1.86 2.36 two d (2H, CH2, ring), 2.36 2.7
two d (2H, 2-CH2), 2.99 3.11 m (1H, CH), 12.1 br.s
(1H, OH). Found, %: C 55.70; H 7.15. C8H12O4.
Calculated, %: C 55.81; H 6.98.
1630 ( NH2), 1210 (C O C). H NMR spectrum,
, ppm: 1.2 1.23 two s (6H, CH3), 1.46 1.7 d.d (2H,
CH2, ring), 2.23 2.60 m (2H, 2-CH2), 2.85 3.0 m
(1H, CH), 4.45 4.63 m (1H, CH), 7.05 7.85 br.s (2H,
NH2), 8.93 9.85 br.s (2H, NH). Found, %: C 44.20;
H 6.20; N 17.30; S 13.25. C9H15N3O3S. Calculated,
%: C 44.08; H 6.12; N 17.14; S 13.06.
2-Carboxymethyl-4-pentanolide (VI) was syn-
thesized as described above for compound V from
25.8 g (0.1 mol) of pentanolide IV and 46.7 g of
30% aqueous sodium hydroxide. After decarboxyla-
tion, the residue was distilled under reduced pressure.
2-(1-Thiosemicarbazidocarbonylmethyl)-4-pen-
tanolide (X) was synthesized as described above for
compound IX from 6.8 g (0.075 mol) of thiosemi-
carbazide and 6.6 g (0.0375 mol) of chloride VIII
in 40 ml of dry benzene. Yield 6.6 g (76%), mp 199
Yield 12.6 g (80%), bp 144 145 C (1 mm), nD20
=
1.4690. The product crystallized on storage, mp 68
1
69 C (from hexane). IR spectrum, , cm : 3400
200 C (from water), Rf 0.46 (B). IR spectrum,
,
1
2500 (OH); 1738 (C O, lactone); 1700 (C O,
cm : 3425 3100 (NH, NH2), 1750 (C O, lactone),
1690 (C O, amide), 1630 ( NH2), 1210 (C O C).
1H NMR spectrum, , ppm: 1.38 d (3H, CH3), 1.50
1.71 d.d (2H, CH2, ring), 2.2 2.65 m (2H, 2-CH2),
2.9 3.07 m (1H, CH), 4.5 4.67 m (1H, CH), 7.0
7.9 br.s (2H, NH2), 8.9 9.9 br.s (2H, NH). Found, %:
C 41.70; H 5.55; N 18.30; S 13.95. C8H13N3O3S.
Calculated, %: C 41.56; H 5.63; N 18.18; S 13.85.
1
COOH); 1230, 1183 (C O C). H NMR spectrum,
, ppm: 1.27 d (3H, CH3), 1.88 2.40 d.d (2H, CH2,
ring), 2.40 2.67 d (2H, 2-CH2), 2.96 3.15 m (1H,
CH), 4.4 4.65 m (1H, CH), 12.22 br.s (1H, OH).
Found, %: C 53.30; H 6.50. C7H10O4. Calculated, %:
C 53.16; H 6.33.
2-Chloroformylmethyl-4-methyl-4-pentanolide
(VII). A round-bottomed flask was charged with
17.2 g (0.1 mol) of compound V, 50 ml of dry
benzene, 13.1 g (0.11 mol) of thionyl chloride, and
1 ml of dimethylformamide. The mixture was left to
stand for 2 h at room temperature and was then
refluxed for 3 h. The solvent was removed under
reduced pressure, and the residue was distilled at
109 110 C (1 mm). Yield 16.2 g (85%). After distil-
lation, the product crystallized, mp 68 69 C. Found,
%: C 50.50; H 5.65; Cl 18.75. C8H11ClO3. Calcu-
lated, %: C 50.39; H 5.77; Cl 18.64.
2-Chloroformylmethyl-4-pentanolide (VIII) was
synthesized as described above for compound VII
from 15.8 g (0.1 mol) of pentanolide VI, 13.1 g
(0.11 mol) of thionyl chloride, and 1 ml of dimethyl-
formamide in 50 ml of dry benzene. Yield 14.3 g
(81%), bp 97 C (2 mm), n2D0 = 1.4735, d420 = 1.2537.
Found, %: C 47.45; H 5.20; Cl 20.30. C7H9ClO3.
Calculated, %: C 47.59; H 5.10; Cl 20.11.
2-(5-Mercapto-1,2,4-triazol-3-ylmethyl)-4-
methyl-4-pentanolide (XI). A round-bottomed flask
was charged with a 16% aqueous solution of sodium
hydroxide, prepared from 3 g (0.075 mol) of NaOH,
and 7.35 g (0.03 mol) of compound IX. The mixture
was heated for 4 h on a boiling water bath, cooled,
diluted with water, and acidified with hydrochloric
acid to pH 2 3. The precipitate was filtered off,
washed with water, and dried in air. Yield 4.8 g
(71%), mp 262 263 C (from aqueous alcohol, 1:1),
1
Rf 0.52 (B). IR spectrum, , cm : 3290, 3226 (NH);
1734 (C O, lactone); 1590 (C N); 1240 (C O C).
1H NMR spectrum, , ppm: 1.17 1.24 two s (6H,
CH3), 1.8 2.36 d.d (2H, CH2, ring), 2.58 3.08 d.d
(2H, 2-CH2), 3.15 3.35 m (1H, CH), 12.98 s (1H,
NH), 13.1 s (1H, SH). Found, %: C 47.65; H 5.65;
N 18.65; S 14.22. C9H13N3O2S. Calculated, %:
C 47.58; H 5.73; N 18.50; S 14.10.
2-(5-Mercapto-1,2,4-triazol-3-ylmethyl)-4-pen-
tanolide (XII) was synthesized as described above
for compound XI from 4.6 g (0.02 mol) of compound
X and 2 g (0.05 mol) of sodium hydroxide. Yield 3 g
(70%), mp 221 223 C (from water). Rf 0.48 (B).
4-Methyl-2-(1-thiosemicarbazidocarbonyl)-4-
pentanolide (IX). A three-necked flask was charged
with 0.1 g (0.1 mol) of thiosemicarbazide and 40 ml
of dry benzene, and a solution of 9.5 g (0.05 mol)
of chloride VII in 10 ml of dry benzene was added
dropwise. The mixture was stirred for 0.5 h at 20
25 C and was then heated for 4 h under reflux. The
solvent was distilled off, and the residue was cooled
and treated with water. The precipitate was filtered
off, washed with water, and dried. Yield 10.7 g
(87%), mp 204 206 C (aqueous alcohol, 1 : 1),
1
IR spectrum, , cm : 3290, 3226 (NH); 1734 (C O,
lactone); 1590 (C N); 1240 (C O C). 1H NMR
spectrum, , ppm: 1.3 s (3H, CH3), 1.78 2.25 d.d
(2H, CH2, ring), 2.4 2.98 d.d (2H, 2-CH2), 3.07
3.3 m (1H, CH), 4.5 4.63 m (1H, CH), 12.95 s (1H,
NH), 13.0 s (1H, SH). Found, %: C 45.22; H 5.05;
N 19.85; S 15.20. C8H11N3O2S. Calculated, %:
C 45.07; H 5.16; N 19.72; S 15.02.
1
Rf 0.50 (B). IR spectrum, , cm : 3425 3100 (NH,
NH2), 1750 (C O, lactone), 1690 (C O, amide),
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SYNTHESIS OF NEW CARBOXY LACTONES
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