4-Acyl-2H-thiopyran-3,5(4H,6H)-diones: Synthesis, oxidation, and reaction with amines

Article abstract of DOI:10.1023/B:RUJO.0000019742.81245.f7

Acylation of 2H-thiopyran-3,5(4H,6H)-dione and 2-methyl-2H-thiopyran-3, 5(4H,6H)-dione with acetyl chloride or propionyl chloride afforded the corresponding 4-acyl-2H-thiopyran-3,5(4H,6H)-diones. Oxidation of 4-acetyl-2H-thiopyran-3,5(4H,6H)-dione with m-chloroperoxybenzoic acid gave 4-acetyl-2H-thiopyran-3,5(4H,67H)-dione 1-oxide. 4-Acyl-2H-thiopyran-3,5(4H,6H)- diones and 4-acetyl-2H-thiopyran-3,5(4H,6H)-dione 1-oxide reacted with pyrrolidine, allylamine, and p-anisidine, resulting in formation of the corresponding 4-aminomethylene derivatives.

Full text of DOI:10.1023/B:RUJO.0000019742.81245.f7

Russian Journal of Organic Chemistry, Vol. 39, No. 12, 2003, pp. 1772 1776. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 12, 2003,
pp. 1844 1847.
Original Russian Text Copyright
2003 by Zheldakova, Budnikova, Rubinova, Rubinov.
4-Acyl-2H-thiopyran-3,5(4H,6H)-diones:
Synthesis, Oxidation, and Reaction with Amines
T. A. Zheldakova, M. V. Budnikova, I. L. Rubinova, and D. B. Rubinov
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Kuprevicha 5/2, Minsk, 220141 Belarus
e-mail: rubinov@iboch.bas-net.by
Received March 13, 2003
Abstract Acylation of 2H-thiopyran-3,5(4H,6H)-dione and 2-methyl-2H-thiopyran-3,5(4H,6H)-dione with
acetyl chloride or propionyl chloride afforded the corresponding 4-acyl-2H-thiopyran-3,5(4H,6H)-diones.
Oxidation of 4-acetyl-2H-thiopyran-3,5(4H,6H)-dione with m-chloroperoxybenzoic acid gave 4-acetyl-2H-
thiopyran-3,5(4H,6H)-dione 1-oxide. 4-Acyl-2H-thiopyran-3,5(4H,6H)-diones and 4-acetyl-2H-thiopyran-
3,5(4H,6H)-dione 1-oxide reacted with pyrrolidine, allylamine, and p-anisidine, resulting in formation of the
corresponding 4-aminomethylene derivatives.
Heterocyclic -diketones of the thiopyran series,
specifically 2H-thiopyran-3,5(4H,6H)-diones I, have
been studied to a considerably lesser extent than six-
membered alicyclic -diketones (1,3-cyclohexanedi-
ones). However, some thiopyran-3,5-dione derivatives
were found to exhibit herbicide [1 2], antitumor, and
antiapoptose activity [3] and to regulate permeability
of cell membranes [4]. A procedure for the synthesis
of thio analogs of steroids possessing antiphlogistic
properties was proposed on the basis of thiopyran-
3,5-diones [5].
(thiotetronic acid) [6] and 3-acyldihydro-2H-thio-
pyran-2,4(3H)-dione series [7] can be used in the
synthesis of N,S-dihetero analogs of steroids. While
extending studies in this line, we have developed
a simple procedure for the preparation of 4-acyl-2H-
thiopyran-3,5(4H,6H)-diones and examined some their
chemical properties. The initial compounds, 2H-thio-
pyran-3,5-(4H,6H)-dione (Ia) and 2-methyl-2H-thio-
pyran-3,5-(4H,6H)-dione (Ib), were synthesized by
the procedure described in [8]. Acylation of diketones
Ia and Ib with acetyl chloride and propionyl chloride
in the presence of pyridine gave mixtures of regio-
isomeric enol esters IIa IId and IIIa IIId which
We previously showed that -tricarbonyl com-
pounds of the 3-acyl-2,4(3H,5H)-thiophenedione
Scheme 1.
I, R1 = H (a), Me (b); II IV, R1 = H, R2 = Me (a); R1 = H, R2 = Et (b); R1 = R2 = Me (c); R1 = Me, R2 = Et (d).
1070-4280/03/3912-1772$25.00 2003 MAIK Nauka/Interperiodica

4-ACYL-2H-THIOPYRAN-3,5(4H,6H)-DIONES:
1773
Scheme 2.
V, R1 = H, R2 = Me, R3R4 = (CH2)4 (a); R1 = H, R2 = Et, R3R4 = (CH2)4 (b); R1 = R2 = Me, R3R4 = (CH2)4 (c); R1 = R3 = H,
R2 = Me, R4 = CH2CH CH2 (d); R1 = R3 = H, R2 = Et, R4 = CH2CH CH2 (e); R1 = R2 = Me, R3 = H, R4 = CH2CH CH2 (f);
R1 = R3 = H, R2 = Me, R4 = p-MeOC6H4 (g); R1 = R2 = Me, R3 = H, R4 = p-MeOC6H4 (h); VII, R2 = Me, R3 = H, R4 =
CH2CH CH2 (a); R2 = Me, R3 = H, R4 = p-MeOC6H4 (b).
were subjected (without isolation) to O C-isomeriza-
tion to the target 4-acylthiopyran-3,5-diones IVa IVd
by the action of 4-dimethylaminopyridine (DMAP)
(Scheme 1).
Va Vh was also confirmed by the IR and mass
spectra and elemental analyses.
The presence of a sulfur atom in molecules of com-
pounds IV and V makes it possible to extend the
range of their synthetic transformations. It is known
[10] that -diketones of the thiopyran series can be
oxidized to the corresponding sulfoxides by the action
of peroxybenzoic acid. -Triketones derived from
cyclohexane react with m-chloroperoxybenzoic acid to
give a complex mixture of products which are difficult
to identify [11]. Therefore, the results of oxidation
of -triketones IV and V could not be predicted.
By reaction of 4-acetyl-2H-thiopyran-3,5(4H,6H)-di-
one (IVa) with m-chloroperoxybenzoic acid in chloro-
form in 0 C we obtained sulfoxide VI whose IR,
1H NMR, and mass spectra were consistent with the
assumed structure. Like triketones IV, sulfoxide VI
reacted with allylamine and p-anisidine to afford
the corresponding enamino derivatives at the acetyl
carbonyl group (compounds VIIa and VIIb). The
product obtained by oxidation of enamine Va with
m-chloroperoxybenzoic acid was identical in physical
properties to sulfoxide VIIa.
We also made an attempt to effect the reaction with
amines at the ring carbonyl group. This is usually
achieved via transformation of -triketones into
methyl enol ethers [9]. However, treatment of both
4-acyl-2H-thiopyran-3,5(4H,6H)-diones IVa IVd and
sulfoxide VI with methylating agents, such as diazo-
methane in diethyl ether or dimethyl sulfate in the
presence of potassium carbonate, resulted in formation
of a complex mixture of compounds, from which we
failed to isolate the desired products.
Triketones IVa IVd are completely enolized, as
1
follows from the presence in their H NMR spectra of
a characteristic downfield signal at 18 ppm, which
belongs to proton of the enol hydroxy group
(H-chelate moiety; structure A). Unsymmetrical -tri-
ketones IVc and IVd give rise to a double set of
1
signals in the H NMR spectra due to equilibrium
between two enol forms A and B. The IR spectra of
triketones IVa and IVb contain a strong absorption
1
band at 1670 1680 cm , corresponding to the con-
jugated carbonyl group, and a very strong band in the
1
region 1550 1570 cm , which belong to stretching
vibrations of the chelating carbonyl group and con-
jugated double bond. Unsymmetrical triketones IVc
and IVd additionally showed in the IR spectra a weak
1
carbonyl absorption at 1720 cm due to non-enolized
C O group.
We planned to use the resulting -triketones of the
thiopyran series in the synthesis of Schiff bases [6, 7].
Therefore, we examined their reactions with amines.
Like -triketones of the cyclohexane series [9], 4-acyl-
2H-thiopyran-3,5-(4H,6H)-diones IVa IVd readily
reacted with pyrrolidine, allylamine, and p-anisidine
to give compounds Va Vh having an exocyclic
1
enamino group (Scheme 2). The H NMR spectra of
compounds Va Vh contained signals from protons in
the substituents at the nitrogen atom, but no enol
proton signal at 18 19 ppm was present. Instead,
a broadened signal from the NH proton appeared at
12 13 ppm. The structure of enamino diketones
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 12 2003

1774
ZHELDAKOVA et al.
EXPERIMENTAL
4-Acetyl-2-methyl-2H-thiopyran-3,5(4H,6H)-di-
one (IVc). Yield 5.00 g (90%). Oily substance. IR
1
1
The IR spectra were recorded on a UR-20 spec-
trometer from samples prepared as KBr pellets (solid
substances) or thin films (liquids). The 1H NMR
spectra were recorded on a Bruker AT-200 instrument
from solutions in chloroform-d containing TMS as
internal reference. The mass spectra were measured
on an MKh-1320 mass spectrometer. The melting
points were determined on a Boetius device. The
progress of reactions and the purity of products were
monitored by TLC on Silufol UV-254 or Alufol UV-
254 plates; spots were visualized under UV light with
subsequent spraying with a solution of iron(III)
chloride. Silica gel 5/40 m (elutriated) was used for
column chromatography.
Acylation of diketones Ia and Ib. To a solution
of 30 mmol of diketone Ia or Ib in 100 ml of toluene
we added with stirring 2.9 ml (36 mmol) of anhydrous
pyridine and 33 mmol of acetyl or propionyl chloride.
The mixture was stirred for 3 h at room temperature
(until the initial compound disappeared according to
the TLC data), and 50 ml of cold water was added.
The organic layer was separated, washed with
a 1% solution of Na2CO3, dried over magnesium
sulfate, and evaporated on a rotary evaporator. The
residue (O-acyl derivative, 30 mmol) was dissolved in
100 ml of dry toluene, 0.7 g (6 mmol) of 4-dimethyl-
aminopyridine was added, and the mixture was stirred
for 16 20 h (TLC) with protection from atmospheric
moisture. The mixture was then washed with 10%
hydrochloric acid (2 20 ml), the organic phase was
separated, and the aqueous phase was extracted with
toluene (2 20 ml). The combined extracts were
washed with a 10% solution of Na2CO3 and dried
over magnesium sulfate, and the solvent was removed
on a rotary evaporator.
spectrum, , cm : 1720, 1680, 1560. H NMR spec-
trum, , ppm: 1.50 d and 1.60 d (3H, CH3, J =
7.0 Hz); 2.60 s (3H, CH3); 3.48 q and 3.60 q (1H,
CH, J = 7.0 Hz); 3.45 s, 3.48 d, and 3.75 d (2H,
SCH2, J = 18 Hz); 18.2 s and 18.4 s (1H, enol).
Found, %: C 51.67; H 5.56; S 17.34. [M]+ 186.
C8H10O3S. Calculated, %: C 51.60; H 5.41; S 17.22.
2-Methyl-4-propionyl-2H-thiopyran-3,5-(4H,6H)-
dione (IVd). Yield 3.70 g (62%). Oily substance. IR
1
1
spectrum, , cm : 1720, 1680, 1560. H NMR spec-
trum, , ppm: 1.20 t (3H, CH3, J = 7.0 Hz); 1.45 d
and 1.58 d (3H, CH3, J = 7.0 Hz); 3.02 m (2H, CH3);
3.46 s, 3.48 d, and 3.74 d (2H, CH2S, J = 18.0 Hz),
3.47 q and 3.62 q (1H, CH, J = 7.0 Hz); 18.4 s and
18.6 s (1H, enol). Found, %: C 54.07; H 6.16;
S 16.20. [M]+ 200. C9H12O3S. Calculated, %:
C 53.98; H 6.04; S 16.01.
Enamines Va Vh. To a solution of 1 mmol of
-triketone IVa IVd in 25 ml of toluene we added
1.3 mmol of the corresponding amine, and the mixture
was heated for 2 3 h under reflux (TLC). The mixture
was then poured into water and washed with dilute
hydrochloric acid. The organic phase was separated,
and the aqueous phase was extracted with chloroform
(2 10 ml). The extracts were combined with the
organic phase and dried over sodium sulfate, and the
solvent was removed under reduced pressure. The
residue was recrystallized from ethyl acetate hexane.
4-(1-Pyrrolidinoethylidene)-2H-thiopyran-
3,5(4H,6H)-dione (Va). Yield 0.20 g (89%), mp 98
1
1
99 C. IR spectrum, , cm : 1630, 1580, 1550. H
NMR spectrum, , ppm: 2.80 m (4H, CH2CH2CH2),
2.50 s (3H, CH3), 3.30 s (4H, CH2SCH2), 3.72 m
(4H, CH2NCH2). Found, %: C 58.95; H 6.91; N 6.32;
4-Acetyl-2H-thiopyran-3,5(4H,6H)-dione (IVa).
S 14.06. [M]+ 225. C11H15NO2S. Calculated, %:
Yield 4.90 g (95%). Low-melting colorless crystals,
C 58.64; H 6.71; N 6.22; S 14.23.
1
mp 24 25 C (from hexane). IR spectrum, , cm :
1
4-(1-Pyrrolidinopropylidene)-2H-thiopyran-
3,5(4H,6H)-dione (Vb). Yield 0.19 g (78%), mp 65
1675, 1560. H NMR spectrum, , ppm: 2.62 s (3H,
CH3), 3.38 s (2H, CH2), 3.52 s (2H, CH2), 18.2 s
(1H, enol). Found, %: C 48.98; H 4.80; S 18.46.
[M]+ 172. C7H8O3S. Calculated, %: C 48.82; H 4.68;
S 18.62.
1
67 C. IR spectrum, , cm : 1670, 1630, 1580, 1540.
1H NMR spectrum, , ppm: 1.18 t (3H, CH3, J =
7.0 Hz), 2.10 m (4H, CH2CH2CH2), 2.96 q (2H,
CH2CH3, J = 7.0 Hz), 3.30 s (4H, CH2SCH2), 3.82 m
(4H, CH2NCH2). Found, %: C 60.47; H 7.31; N 6.02;
4-Propionyl-2H-thiopyran-3,5(4H,6H)-dione
(IVb). Yield 3.60 g (65%). Oily substance. IR spec-
S 13.26. [M]+ 239. C12H17NO2S. Calculated, %:
C 60.22; H 7.16; N 5.85; S 13.40.
1
1
trum, , cm : 1670, 1560. H NMR spectrum,
,
ppm: 1.20 t (3H, CH3, J = 7.0 Hz), 3.04 q (2H, CH2,
J = 7.0 Hz), 3.40 s (2H, CH2), 3.52 s (2H, CH2),
18.50 s (1H, enol). Found, %: C 51.81; H 5.63;
S 17.02. [M]+ 186. C8H10O3S. Calculated, %:
C 51.60; H 5.41; S 17.22.
2-Methyl-4-(1-pyrrolidinoethylidene)-2H-thio-
pyran-3,5(4H,6H)-dione (Vc). Yield 0.21 g (88%).
1
Oily substance. IR spectrum, , cm : 1630, 1580,
1540. 1H NMR spectrum, , ppm: 1.50 d (3H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 12 2003

4-ACYL-2H-THIOPYRAN-3,5(4H,6H)-DIONES:
1775
CH3CH, J 7.0 Hz), 2.06 m (4H, CH2CH2CH2), 2.46 s
(3H, CH3), 3.36 q (1H, CH, J = 7.0 Hz), 3.28 3.44 m
(2H, CH2S, J = 18.0 Hz), 3.68 m (4H, CH2NCH2).
Found, %: C 60.47; H 7.34; N 5.98; S 13.56.
[M]+ 239. C12H17NO2S. Calculated, %: C 60.22;
H 7.16; N 5.85; S 13.40.
7.00 m (4H, Harom), 14.46 br.s (1H, NH). Found, %:
C 62.02; H 5.98; N 4.62; S 11.16. [M]+ 291.
C15H17NO3S. Calculated, %: C 61.83; H 5.88;
N 4.81; S 11.01.
4-Acetyl-2H-1 4-thiopyran-3,5(4H,6H)-dione
1-oxide (VI). To a solution of 0.17 g (1 mmol) of
triketone IVa in 10 ml of chloroform we added at 0 C
1.1 mmol of m-chloroperoxybenzoic acid, and the
mixture was stirred for 1 h. The solvent was removed
under reduced pressure, and the residue was subjected
to column chromatography on silica gel using chloro-
form as eluent. Yield 0.14 g (75%), mp 83 84 C. IR
4-(1-Allylaminoethylidene)-2H-thiopyran-
3,5(4H,6H)-dione (Vd). Yield 0.20 g (95%), mp 61
1
62 C. IR spectrum, , cm : 3180, 1650, 1585.
1H NMR spectrum, , ppm: 2.42 s (3H, CH3), 3.36 s
(4H, CH2SCH2), 4.16 m (2H, CH2N), 5.25 m (2H,
CH2 ), 5.86 m (1H, CH ), 13.2 br.s (1H, NH).
Found, %: C 57.01; H 6.45; N 6.48; S 15.36.
[M]+ 211. C10H13NO2S. Calculated, %: C 56.85;
H 6.20; N 6.63; S 15.18.
1
1
spectrum, , cm : 1665, 1565. H NMR spectrum,
, ppm: 2.66 s (3H, CH3), 3.78 d (2H, CH2, J =
16.8 Hz), 4.02 d (2H, CH2, J = 16.8 Hz), 13.8 br.s
(1H, OH). Found, %: C 44.57; H 4.35; S 17.18.
[M]+ 188. C7H8O4S. Calculated, %: C 44.67; H 4.28;
S 17.04.
4-(1-(Allylaminopropylidene)-2H-thiopyran-
3,5(4H,6H)-dione (Ve). Yield 0.21 g (93%), mp 50
1
1
52 C. IR spectrum, , cm : 3200, 1650, 1580. H
NMR spectrum, , ppm: 1.22 t (3H, CH3, J = 7.0 Hz),
2.92 q (2H, CH2CH3, J = 7.0 Hz), 3.36 s (4H,
CH2SCH2), 4.12 m (2H, CH2N), 5.26 m (2H, CH2 ),
5.90 m (1H, CH ), 13.16 br.s (1H, NH). Found, %:
C 58.82; H 6.95; N 6.18; S 14.06. [M]+ 225.
C11H15NO2S. Calculated, %: C 58.64; H 6.71;
N 6.22; S 14.23.
Compounds VIIa and VIIb were synthesized from
sulfoxide VI by the procedure described above for
the synthesis of enamines V.
4-(1-Allylaminoethylidene)-2H-1 4-thiopyran-
3,5(4H,6H)-dione 1-oxide (VIIa). Yield 0.18 g
(79%), mp 137 138 C (from ethyl acetate). IR spec-
1
trum, , cm : 1650, 1590, 1470, 1430, 1420, 1375,
4-(1-Allylaminoethylidene)-2-methyl-2H-thio-
pyran-3,5(4H,6H)-dione (Vf). Yield 0.18 g (80%).
Oily substance. IR spectrum, , cm : 3300, 1650,
1360, 1340, 1300, 1270, 1210, 1120, 1110, 1045,
950, 905. H NMR spectrum, , ppm: 2.56 s (3H,
1
1
CH3), 3.72 d (2H, CH2, J = 18.0 Hz), 3.90 d (2H,
CH2, J = 18.0 Hz), 4.12 m (2H, CH2), 5.30 m (2H,
CH2 ), 5.90 m (1H, CH ), 13.34 br.s (1H, NH).
Found, %: C 53.07; H 5.95; N 6.01; S 14.18.
[M]+ 227. C10H13NO3S. Calculated, %: C 52.85;
H 5.77; N 6.16; S 14.11.
1580. 1H NMR spectrum, , ppm: 1.48 d (3H,
CH3CH, J = 7.0 Hz), 2.48 s (3H, CH3), 3.42 q (1H,
CHCH3, J 7.0 Hz), 3.34 d and 3.50 d (2H, SCH2, J =
18.0 Hz), 4.08 m (2H, CH2N), 5.28 m (2H, CH2 ),
5.88 m (1H, CH ), 13.12 br.s (1H, NH). Found, %:
C 58.52; H 6.87; N 6.38; S 14.46. [M]+ 225.
C11H15NO2S. Calculated, %: C 58.64; H 6.71;
N 6.22; S 14.23.
4-[1-(4-Methoxyphenylamino)ethylidene]-2H-
1
4-thiopyran-3,5(4H,6H)-dione 1-oxide (VIIb).
Yield 0.21 g (72%), mp 168 C (decomp.; from ethyl
1
4-[1-(4-Methoxyphenylamino)ethylidene]-2H-
thiopyran-3,5(4H,6H)-dione (Vg). Yield 0.26 g
acetate). IR spectrum, , cm : 1650, 1620, 1590,
1
1580. H NMR spectrum, , ppm: 2.52 s (3H, CH3),
1
(93%), mp 120 121 C. IR spectrum, , cm : 3160,
3.78 d (2H, CH2, J = 16.0 Hz), 3.88 s (3H, OCH3),
3.96 d (2H, CH2, J = 16.0 Hz), 7.02 m (4H, Harom),
14.6 br.s (1H, NH). Found, %: C 57.17; H 5.24;
N 4.85; S 11.01. [M]+ 293. C14H15NO4S. Calculated,
%: C 57.32; H 5.15; N 4.77; S 10.93.
1
1645, 1620, 1580. H NMR spectrum, , ppm: 2.44 s
(3H, CH3), 3.40 s (4H, 2CH2), 3.86 s (3H, OCH3),
7.02 m (4H, Harom), 14.4 br.s (1H, NH). Found, %:
C 60.72; H 5.68; N 5.12; S 11.46. [M]+ 227.
C14H15NO3S. Calculated, %: C 60.63; H 5.45;
N 5.05; S 11.56.
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1
vol. 110, mo. 114681.
0.25 g (85%). Oily substance. IR spectrum, , cm :
1
2. JPN Patent no. 62-298584, 1986; Chem. Abstr., 1988,
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3.50 q (1H, CH, J = 7.0 Hz), 3.42 d and 3.60 d (2H,
SCH2, 3H, CH3, J = 18.0 Hz), 3.84 s (3H, OCH3),
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