Synthesis and some transformations of functionally substituted lactones

Article abstract of DOI:10.1134/S1070428011060133

Reactions of functionally substituted unsaturated five- and six-membered cyanolactones with α- and β-hydroxy ketones in the presence of sulfuric acid gave substituted 2-oxofuran- and 2-oxopyran-3-carboxamides. Hydrolysis of some keto amides thus obtained

Full text of DOI:10.1134/S1070428011060133

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 6, pp. 910–913. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © A.A. Avetisyan, A.G. Alvandzhyan, T.A. Kostanyan, M.M. Bidar, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47,
No. 6, pp. 893–896.
Synthesis and Some Transformations of Functionally
Substituted Lactones
A. A. Avetisyan, A. G. Alvandzhyan, T. A. Kostanyan, and M. M. Bidar
Erevan State University, ul. A. Manukyana 1, Erevan, 375025 Armenia
e-mail: organkim@sun.ysu.am
Received May 6, 2009
Abstract—Reactions of functionally substituted unsaturated five- and six-membered cyanolactones with
α- and β-hydroxy ketones in the presence of sulfuric acid gave substituted 2-oxofuran- and 2-oxopyran-
3-carboxamides. Hydrolysis of some keto amides thus obtained afforded the corresponding carboxylic acids,
and reactions with hydrazines and semicarbazides led to hydrazones and semicarbazones at the side-chain
oxo group.
DOI: 10.1134/S1070428011060133
Unsaturated lactone fragment is a structural unit of
many natural and synthetic biologically active com-
pounds [1–4], and synthesis of the latter constitutes
an important problem in contemporary organic chem-
istry. The present article reports on the results of our
study on the Ritter reaction [5, 6] in the series of
2,5-dihydro-2-oxofuran-3-carbonitriles and 5,6-dihy-
dro-2-oxopyran-3-carbonitriles, which gave rise to new
functionally substituted derivatives.
pinacolone reacted with benzonitrile in the presence of
trifluoromethanesulfonic acid, yielding protonated
4-tert-butyl-4-methyl-2,6-diphenyl-4H-1,3,5-oxadi-
azine, and that pivalophenone failed to react under
similar conditions. This was rationalized by insuf-
ficient reactivity of hydroxycarbenium ions formed by
protonation of ketones toward weakly nucleophilic
nitriles. Luk’yanov and Borodaev [10] succeeded in
developing a procedure for generation of acyloxy-
carbenium ions in mixtures of ketones with nitriles and
performing the Ritter reaction with ketones [11].
However, reactions of nitriles with hydroxy ketones,
i.e., compounds containing both hydroxy and oxo
group in a single molecule, were not reported at all.
The Ritter reaction of aldehydes with nitriles in the
presence of an acid is known to give bisacylamides [7].
Under analogous conditions, ketones undergo self-con-
densation and subsequent transformation into acyl-
amino ketones [8]. Afanas’eva et al. [9] showed that
Scheme 1.
O
Me
CN
Me
NH
R3
Me
+
Me
Me
OH
R1
R2
R1
R2
R3
Me
O
O
O
O
Ia–Ic
IIa, IIb
IIIa–IIIf
Me
Me
O
R3
Me
CN
O
Me
Me
N
+
Me
OH
H
R3
Me
Me
Me
Me
O
O
O
IIa, IIb
Id
IIIg, IIIh
I, R1 = R2 = Me (a); R1 = Me, R2 = Et (b); R1R2 = (CH2)5 (c); II, R3 = MeC(O)CH2 (a), MeC(O) (b); III, R1 = R2 = Me, R3 = MeC(O)CH2
(a), MeC(O) (d); R1 = Me, R2 = Et, R3 = MeC(O)CH2 (b), MeC(O) (e); R1R2=(CH2)5, R3 = MeC(O)CH2 (c, g), MeC(O) (f, h).
910

SYNTHESIS AND SOME TRANSFORMATIONS OF FUNCTIONALLY SUBSTITUTED
911
In the present work we examined reactions of
5,5-disubstituted 4-methyl-2-oxo-2,5-dihydrofuran-3-
carbonitriles Ia–Ic and 4,6,6-trimethyl-2-oxo-5,6-dihy-
dro-2H-pyran-3-carbonitrile (Id) with some tertiary
keto alcohols. The effects of different factors on the
reaction course were studied, and optimal conditions
were found. The reactions readily occurred upon
mixing the initial reactants in benzene solution at 0°C
in the presence of sulfuric acid, and the products were
the corresponding oxo amides IIIa–IIIh (Scheme 1).
The observed behavior of the carbonyl group is con-
sistent with published data [11]. Elevated temperature
induces tarring.
trophenylhydrazine to give the corresponding hydra-
zones Va, Vb, Ve–Vg, and Vi and semicarbazones Vc,
Vd, and Vh in almost quantitative yield (Scheme 3).
EXPERIMENTAL
The IR spectra were recorded on a Specord 75IR
1
spectrometer. The H NMR spectra were measured on
a Varian Mercury-300 instrument at 300 MHz using
hexamethyldisiloxane as internal reference. Thin-layer
chromatography was performed on Silufol UV-254
plates.
5,5-Dialkyl-4-methyl-2-oxo-2,5-dihydrofuran-3-
carboxamides IIIa–IIIf and 4,6,6-trimethyl-2-oxo-
5,6-dihydro-2H-pyran-3-carboxamides IIIg and
IIIh (general procedure). Concentrated sulfuric acid,
5 ml, was added dropwise at ~0°C to a suspension of
0.01 mol of substituted 2,5-dihydro-2-oxofuran-3-car-
bonitrile Ia–Ic or 4,6,6-trimethyl-2-oxo-5,6-dihydro-
2H-pyran-3-carbonitrile (Id) and 0.011 mol of hydroxy
ketone IIa or IIb in 15 ml of anhydrous benzene. The
mixture was stirred for 5 h and poured into 100 ml of
cold water (~5°C), the organic phase was separated,
the aqueous phase was neutralized with a solution of
sodium hydrogen carbonate, and the precipitate was
filtered off, dried, and recrystallized from aqueous
alcohol (1:1).
The product structure was confirmed by both spec-
tral methods and chemical transformations. Hydrolysis
of amides IIIa and IIId with 20% sulfuric acid gave
4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-carboxylic
acid (IV) (Scheme 2) whose physical constants coin-
cided with those reported in [12].
Scheme 2.
O
Me
Me
COOH
O
NH
R3
H2O, H2SO4
Me
Me
Me
Me
Me
Me
O
O
O
IIIa, IIId
IV
N-(1,1-Dimethyl-3-oxobutyl)-4,5,5-trimethyl-2-
oxo-2,5-dihydrofuran-3-carboxamide (IIIa). Yield
1.73 g (65%), mp 105–106°C, Rf 0.66 (acetone–ben-
zene, 1:1). IR spectrum, ν, cm–1: 3340 (NH), 1740
(C=O, lactone), 1720 (C=O, ketone), 1640 (C=O,
The presence of an oxo group in the side chain of
amides IIIa–IIIh makes it possible to synthesize their
new derivatives which could attract some interest.
Compounds IIIa, IIIc, IIId, and IIIf–IIIh reacted
with hydrazine hydrate, semicarbazide, and 2,4-dini-
1
amide). H NMR spectrum, δ, ppm: 1.48 s (6H, CH3),
2.00 s (6H, CH3), 2.25 s (3H, CH3), 2.32 s (2H, CH2),
2.60 s (3H, COCH3), 8.50 br.s (1H, NH). Found, %:
C 62.71; H 7.61; N 5.52. C14H21NO4. Calculated, %:
C 62.92; H 7.87; N 5.24.
Scheme 3.
O
Me
Me
NH
R4NHNH2
Me
IIIa, IIIc, IIIe, IIIf
NNHR4
( )n
Me
N-(1,1-Dimethyl-3-oxobutyl)-5-ethyl-4,5-dimeth-
yl-2-oxo-2,5-dihydrofuran-3-carboxamide (IIIb).
Yield 1.97 g (70%), mp 111–112°C, Rf 0.65 (acetone–
benzene, 1:1). IR spectrum, ν, cm–1: 3315 (NH), 1740
(C=O, lactone), 1718 (C=O, ketone), 1638 (C=O,
amide). Found, %: C 63.98; H 8.08; N 4.69.
C15H23NO4. Calculated, %: C 64.06; H 8.19; N 4.98.
R1
R2
O
O
Va–Vf
Me
O
O
Me
R4NHNH2
Me Me
( )n
N
IIg, IIh
H
Me
Me
NNHR4
O
N-(1,1-Dimethyl-3-oxobutyl)-4-methyl-2-oxo-1-
oxaspiro[4.5]dec-3-ene-3-carboxamide (IIIc). Yield
2.13 g (70%), mp 139–140°C, Rf 0.63 (acetone–ben-
zene, 1:1). IR spectrum, ν, cm–1: 3316 (NH), 1735
(C=O, lactone), 1715 (C=O, ketone), 1640 (C=O,
Vg–Vi
V, R1 = R2 = Me, R4 = H (a), H2NC(O) (c), 2,4-(O2N)2-
C6H3 (e); R1R2 = (CH2)5, R4 = H (b), H2NC(O) (d),
2,4-(O2N)2C6H3 (f); R4 = H (g), H2NC(O) (h), 2,4-(O2N)2-
C6H3 (i); n = 1 (a, b, e, g), 0 (c, d, f, h, i).
1
amide). H NMR spectrum, δ, ppm: 1.20–1.48 m (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

AVETISYAN et al.
912
CH2), 1.52–1.80 m (8H, CH2), 1.84 s (6H, CH3), 2.1 s
(3H, CH3), 2.35 s (2H, CH2), 2.60 s (3H, COCH3),
8.16 br.s (1H, NH). Found, %: C 66.94; H 8.21; N 4.62.
C17H25NO4. Calculated, %: C 66.45; H 8.14; N 4.56.
%: C 63.25; H 7.73; N 5.34. C14H21NO4. Calculated,
%: C 62.49; H 7.87; N 5.24.
4,5,5-Trimethyl-2-oxo-2,5-dihydrofuran-3-car-
boxylic acid (IV). A mixture of 0.01 mol of compound
IIIa or IIId and 10 ml of 20% sulfuric acid was heated
for 4 h at 60°C on a water bath. The mixture was
cooled and poured onto 50 g of crushed ice. After 10 h,
the crystalline material was filtered off, washed with
water, and recrystallized from xylene. Yield 1.17 g
(67%), mp 113°C [12].
N-(1,1-Dimethyl-3-oxopropyl)-4,5,5-trimethyl-2-
oxo-2,5-dihydrofuran-3-carboxamide (IIId). Yield
1.71 g (69%), mp 100–101°C, Rf 0.67 (acetone–ben-
zene, 1:1). IR spectrum, ν, cm–1: 3375 (NH), 1740
(C=O, lactone), 1710 (C=O, ketone), 1645 (C=O,
1
amide). H NMR spectrum, δ, ppm: 1.45 s (6H, CH3),
2.15 s (6H, CH3), 2.5 s (3H, CH3), 2.75 s (3H,
COCH3), 8.40 br.s (1H, NH). Found, %: C 61.52;
H 7.62; N 5.71. C13H19NO4. Calculated, %: C 61.66;
H 7.51; N 5.53.
Hydrazones Va, Vb, and Vg (general proecdure).
Compound IIIa, IIIc, or IIIg, 0.005 mol, was dis-
solved in 10 ml of anhydrous ethanol, 0.5 ml of di-
methylformamide and 2 ml of hydrazine hydrate were
added, and the mixture was heated for 15 min under
reflux and left overnight. The precipitate was filtered
off and recrystallized from water.
N-(1,1-Dimethyl-3-oxopropyl)-5-ethyl-4,5-di-
methyl-2-oxo-2,5-dihydrofuran-3-carboxamide
(IIIe). Yield 1.82 g (71%), mp 107°C, Rf 0.66 (ace-
tone–benzene, 1:1). IR spectrum, ν, cm–1: 3367 (NH),
1736 (C=O, lactone), 1717 (C=O, ketone), 1640 (C=O,
amide). Found, %: C 62.49; H 7.59; N 5.09.
C14H21NO4. Calculated, %: C 62.92; H 7.87; N 5.24.
N-(1,1-Dimethyl-3-hydrazonobutyl)-4,5,5-tri-
methyl-2-oxo-2,5-dihydrofuran-3-carboxamide
(Va). Yield 1.18 g (91%), mp 172–173°C. IR spec-
trum, ν, cm–1: 3260, 3175 (NH); 1755 (C=O, lactone);
1640 (C=O, amide); 1620 (C=N). Found, %: C 59.70;
H 8.23; N 14.43. C14H23N3O3. Calculated, %: C 59.79;
H 8.19; N 14.95.
N-(1,1-Dimethyl-3-oxopropyl)-4-methyl-2-oxo-1-
oxaspiro[4.5]dec-3-ene-3-carboxamide (IIIf). Yield
2.14 g (73%), mp 132–133°C, Rf 0.69 (acetone–ben-
zene, 1:1). IR spectrum, ν, cm–1: 3360 (NH), 1740
N-(1,1-Dimethyl-3-hydrazonobutyl)-4-methyl-2-
oxo-1-oxaspiro[4.5]dec-3-ene-3-carboxamide (Vb).
Yield 1.4 g (88%), mp 167–168°C. IR spectrum, ν,
cm–1: 3260, 3180 (NH); 1735 (C=O, lactone); 1640
(C=O, amide); 1620 (C=N). Found, %: C 63.71;
H 8.59; N 13.31. C17H27N3O3. Calculated, %: C 63.55;
H 8.41; N 13.08.
1
(C=O, lactone), 1645 (C=O, amide). H NMR spec-
trum, δ, ppm: 1.25–1.48 m (2H, CH2), 1.50–1.75 m
(8H, CH2), 1.85 s (6H, CH3), 2.10 s (3H, CH3), 2.70 s
(3H, COCH3), 8.25 br.s (1H, NH). Found, %: C 65.31;
H 7.92; N 4.63. C16H23NO4. Calculated, %: C 65.53;
H 7.85; N 4.78.
N-(1,1-Dimethyl-3-hydrazonobutyl)-4,6,6-tri-
methyl-2-oxo-5,6-dihydro-2H-pyran-3-carboxamide
(Vg). Yield 1.3 g (89%), mp 165°C. IR spectrum, ν,
cm–1: 3260, 3185 (NH); 1750 (C=O, lactone); 1644
(C=O, amide); 1620 (C=N). Found, %: C 61.23;
H 8.16; N 14.30. C15H25N3O3. Calculated, %: C 61.02;
H 8.47; N 14.24.
N-(1,1-Dimethyl-3-oxobutyl)-4,6,6-trimethyl-2-
oxo-5,6-dihydro-2H-pyran-3-carboxamide (IIIg).
Yield 1.81 g (64%), mp 107–108°C, Rf 0.66 (acetone–
benzene, 1:1). IR spectrum, ν, cm–1: 3320 (NH), 1745
(C=O, lactone), 1710 (C=O, ketone), 1645 (C=O,
1
amide). H NMR spectrum, δ, ppm: 1.40 s (6H, CH3),
2.05 m (9H, CH3), 2.66 s (3H, CH3), 2.66 s (3H,
COCH3), 2.83 s (2H, CH2), 8.72 br.s (1H, NH). Found,
%: C 64.41; H 7.91; N 5.16. C15H23NO4. Calculated,
%: C 64.06; H 8.19; N 4.98.
Semicarbazones Vc, Vd, and Vh (general proce-
dure). A mixture of 0.01 mol of amide IIId, IIIf, or
IIIh, 1.1 g (0.01 mol) of semicarbazide hydrochloride,
2.2 g (0.02 mol) of anhydrous sodium acetate, and
10 ml of anhydrous ethanol was heated for 1 h under
reflux (on a water bath). The mixture was cooled and
diluted with 30 ml of water, and the precipitate was
filtered off, washed with water, dried, and recrys-
tallized from ethanol.
N-(1,1-Dimethyl-3-oxopropyl)-4,6,6-trimethyl-2-
oxo-5,6-dihydro-2H-pyran-3-carboxamide (IIIh).
Yield 1.95 g (76%), mp 88–89°C, Rf 0.68 (acetone–
benzene, 1:1). IR spectrum, ν, cm–1: 3340 (NH), 1745
(C=O, lactone), 1710 (C=O, ketone), 1645 (C=O,
1
amide), 1610 (C=C). H NMR spectrum, δ, ppm:
1.60 s (6H, CH3), 2.20 m (9H, CH3), 2.70 s (3H,
COCH3), 3.20 s (2H, CH2), 8.61 br.s (1H, NH). Found,
N-{2-[(Aminocarbonyl)hydrazono]-1,1-dimethyl-
propyl}-4,5,5-trimethyl-2-oxo-2,5-dihydrofuran-3-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 6 2011

SYNTHESIS AND SOME TRANSFORMATIONS OF FUNCTIONALLY SUBSTITUTED
913
carboxamide (Vc). Yield 3 g (94%), mp 145–146°C,
Rf 0.73 (acetone–benzene, 1:1). IR spectrum, ν, cm–1:
3250, 3180 (NH); 1730 (C=O); 1640 (C=O, amide);
1660 (NHCONH2); 1620 (C=N). Found, %: C 54.50;
H 7.42; N 18.48. C14H22N4O4. Calculated, %: C 54.19;
H 7.097; N 18.07.
3-carboxamide (Vf). Yield 3.76 g (93%), mp 161–
162°C, Rf 0.71 (acetone–benzene, 1:1). IR spectrum,
ν, cm–1: 3330, 3220 (NH); 1730 (C=O); 1640 (C=O,
amide); 1615 (C=N). Found, %: C 55.51; H 5.70;
N 14.17. C22H27N5O7. Calculated, %: C 55.82; H 5.71;
N 14.80.
N-{2-[(2,4-Dinitrophenyl)hydrazono]-1,1-di-
methylpropyl}-4,6,6-trimethyl-2-oxo-5,6-dihydro-
2H-pyran-3-carboxamide (Vi). Yield 3.21 g (88%),
mp 203–204°C. IR spectrum, ν, cm–1: 3330, 3215
(NH); 1730 (C=O); 1640 (C=O, amide); 1615 (C=N).
Found, %: C 53.67; H 5.41; N 15.73. C20H25N5O7. Cal-
culated, %: C 53.69; H 5.59; N 15.65.
N-{2-[(Aminocarbonyl)hydrazono]-1,1-dimethyl-
propyl}-4-methyl-2-oxo-1-oxaspiro[4.5]dec-3-ene-
3-carboxamide (Vd). Yield 3.24 g (89%), mp 149–
150°C, Rf 0.71 (acetone–benzene, 1:1). IR spectrum,
ν, cm–1: 3250, 3180 (NH); 1756 (C=O); 1665
(NHCONH2); 1642 (C=O, amide); 1620 (C=N).
Found, %: C 58.45; H 7.23; N 16.41. C17H26N4O4. Cal-
culated, %: C 58.89; H 7.43; N 16.00.
REFERENCES
N-{2-[(Aminocarbonyl)hydrazono]-1,1-dimethyl-
propyl}-4,6,6-trimethyl-2-oxo-5,6-dihydro-2H-pyr-
an-3-carboxamide (Vh). Yield 2.97 g (95%), mp 169–
170°C. IR spectrum, ν, cm–1: 3250, 3180 (NH); 1750
(C=O, lactone); 1670 (NHCONH2); 1640 (C=O,
amide); 1615 (C=N). Found, %: C 55.43; H 7.23;
N 17.13. C15H24N4O4. Calculated, %: C 55.56; H 7.41;
N 17.28.
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2,4-Dinitrophenylhydrazones Ve, Vf, and Vi
(general procedure). Concentrated sulfuric acid, 2 ml,
was added to 1.98 g of 2,4-dinitrophenylhydrazine,
3 ml of water was added dropwise under stirring, and
20 ml of ethanol was then added to the warm solution.
Compound IIIa, IIIb, or IIIh, 0.01 mol, was added to
the freshly prepared solution, and the mixture was left
overnight. The precipitate was filtered off and recrys-
tallized from dioxane.
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N-{3-[(2,4-Dinitrophenyl)hydrazono]-1,1-di-
methylbutyl}-4,5,5-trimethyl-2-oxo-2,5-dihydro-
furan-3-carboxamide (Ve). Yield 3.48 g (95%),
mp 157–158°C. IR spectrum, ν, cm–1: 3335, 3220
(NH); 1740 (C=O); 1640 (C=O, amide); 1615 (C=N).
Found, %: C 53.40; H 5.82; N 15.63. C20H25N5O7. Cal-
culated, %: C 53.69; H 5.59; N 15.66.
1986, vol. 22, p. 510.
11. Borodin, S.V., Shibaeva, N.V., Zubkova, O.V., Knya-
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Khim., 1989, vol. 25, p. 2416.
N-{2-[(2,4-Dinitrophenyl)hydrazono]-1,1-di-
12. Avetisyan, A.A., Tatevosyan, G.E., and Dangyan, M.T.,
methylpropyl}-4-methyl-2-oxaspiro[4.5]dec-3-ene-
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