Alkylthio derivatives of the aminoketene S,N-acetals of heterocyclic β-dicarbonyl compounds: One stage synthesis and properties

Article abstract of DOI:10.1023/A:1021253231158

Treatment of phenyl isothiocyanate with heterocyclic β-dicarbonyl compounds gave novel aminoketene S,N-acetals, whose alkylation using haloalkanes has been studied.

Full text of DOI:10.1023/A:1021253231158

Chemistry of Heterocyclic Compounds, Vol. 38, No. 9, 2002
ALKYLTHIO DERIVATIVES
OF THE AMINOKETENE S,N-ACETALS
OF HETEROCYCLIC β-DICARBONYL
COMPOUNDS: ONE STAGE
SYNTHESIS AND PROPERTIES
M. O. Lozinskii and V. V. Shelyakin
Treatment of phenyl isothiocyanate with heterocyclic β-dicarbonyl compounds gave novel aminoketene
S,N-acetals, whose alkylation using haloalkanes has been studied.
Keywords: 1,3-dimethyl-2,4,6-(1H,3H,5H)-pyrimidinetrione, haloalkanes, isothiocyanates, N-methyl-
morpholine, tetrahydrofuran-2,4-dione.
Aminoketene S,N-acetals, obtained from derivatives of cyanoacetic and other CH-acids with
isothiocyanates, have found widespread use in the synthesis of functionalized heterocycles [1-6], including
those with antitumor activity [7].
In a continuation of our work studying the synthetic potential of heterocyclic β-dicarbonyl compounds
as synthons for preparing biologically active molecules [8, 9] we have investigated the nucleophilic addition of
1,3-dimethyl-2,4,6-(1H,3H,5H)-pyrimidinetrione (1) and tetrahydrofuran-2,4-dione (2) to phenyl isothiocyanate
(3) in the presence of an organic base in DMF at 25°C. This reaction occurs via a stage of formation of betaine
intermediates 4, 5. The regioselective alkylation of the latter by the haloalkanes 6a-g leads to the formation of
alkylation products exclusively at the sulfur atom (7a-g, 8) in high yields (see Table 1).
The 1H NMR spectra of compounds 7a-g show signals for the SCH2 and NH group protons at 2.95-3.82
and 11.89-13.82 ppm, as well as signals for the protons of the aryl substituents. The signals for the NH group
protons are strongly shifted and this is likely due to the formation of a stable, intramolecular hydrogen bond
between the NH and C=O groups in the compounds 7a-g, 8 (characteristic of a betaine type structure [10, 11]).
Thus in the case of compound 8 we have separated a stable Z-isomer because of the unsymmetrical structure of
the molecule 5. Oxidation of compound 7b in chloroform using m-chloroperbenzoic acid (9) gives the sulfone
10 which has been characterized by us from the presence of sulfone absorption bands at 1330 and 1150 cm-1 in
the IR spectrum. An X-ray structural study of derivatives of this class of compound will be additionally
published.
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094; e-mail:
shk@janus.net.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1233-1236, September,
2002. Original article submitted December 3, 2001.
0009-3122/02/3809-1077$27.00©2002 Plenum Publishing Corporation
1077

TABLE 1. Characteristics of the Synthesized Compounds 7 and 8
Found, %
——————
δ
Chemical shift, , ppm
IR spectrum,*2
νC=O
Com-
Empirical
formula
Yield,
%
Calculated, %
mp, °С*
, cm-1
pound
2СН3–N
(s, 6Н)
S–CH2–
Ar (m)
(s, 2Н)
–NH
С
Н
Cl
N
S
(br. s, 1Н)
C14H15N3O3S
C20H18ClN3O3S
C20H19N3O3S
C20H18ClN3O3S
C20H18ClN3O3S
C20H17Cl2N3O3S
C12H11NO3S
55.00
55.07
4.90
4.95
13.40
13.76
10.70
10.50
153-154
202-203
195-196
197-199
203-204
229-230
162-163
1630, 1710
1628, 1700
1630, 1700
1625, 1700
1610, 1710
1605, 1700
1710, 1755
3.25
3.18
3.17
3.18
3.18
3.18
–
2.95
3.80
3.74
3.78
3.76
3.82
2.34
7.31-7.40
13.82
13.63
13.55
13.51
13.50
13.41
11.89
93
90
87
89
92
96
56
7a
7b
7c
7d
7f
(5Н)
57.70
4.36
8.58
8.52
10.30
7.80
7.44-7.53
57.76
4.32
10.10
7.71
(9Н)
63.03
62.98
5.25
5.02
10.10
11.02
8.51
8.40
7.26-7.43
(10Н)
57.70
4.36
8.59
8.52
10.26
7.77
7.20-7.34
57.76
4.32
10.10
7.71
(9Н)
58.66
57.76
4.72
4.32
8.61
10.14
10.10
7.91
7.71
7.17-7.33
8.52
(9Н)
53.57
3.74
15.53
15.75
9.41
7.20
7.37-7.54
7g
8*3
53.34
3.80
9.33
7.12
(8Н)
57.71
57.82
4.36
4.45
5.54
5.62
12.67
12.86
7.56-7.62
(5Н)
_______
* Solvent for crystallization: acetonitrile (7a-g) and methanol (8).
*2 The absorption for the NH group did not appear due to the formation of the intramolecular bond.
3
δ
* Chemical shift of the CH2 ring fragment (s, 2H) = 4.43 ppm.

O
O
HN
O
O
Me
Me
O
R–CH2–Br
B
N
N
S
+
O
Ph–NCS
+
6a–g
3
N
O
N
Me
1
N
Me
Me
H
4
O
HN
O
Me
N
S
R
O
N
Me
7a–g
O
O
HN
O
HN
MeI
B
O
3
+
S
O
S Me
O
+
O
O
O
N
Me
O
H
2
8
5
O
Cl
OOH
O
HN
O
HN
O
Me
O
Me
O
9
N
S
N
S
O
O
O
Cl
CHCl3
N
Me
N
Me
Cl
10
7b
B = N-methylmorpholine, 6, 7 a R = H, b R = 2-Cl–C6H4, c R= Ph, d R = 3-Cl–C6H4,
f R = 4-Cl–C6H4, g R = 3,4-Cl2–C6H3
EXPERIMENTAL
1
IR spectra were recorded on a UR-20 spectrophotometer for KBr tablets. H NMR Spectra were taken
on a Bruker VXR-300 (300 MHz) instrument for solutions in DMSO-d6 with TMS as internal standard.
Monitoring of the course of the reaction and the purity of the materials was carried out using TLC on Silufol
UV-254 plates (eluent acetone–hexane, 3:5).
The parameters for the synthesized compounds 7a-g, 8 are given in Table 1.
1079

5-[1-Alkylthio-1-(phenylamino)methylidene]-1,3-dimethylhexahydro-2,4,6-pyrimidinetrione (7a-g)
(General Method). Mixture of compound 1 (1.56 g, 10 mmol), phenyl isothiocyanate 3 (1.35 g, 10 mmol), and
N-methylmorpholine (1.01 g, 10 mmol) in DMF (20 ml) was stirred for 2 h at 25°C and a precipitate of
compound 4 was formed The haloalkane 6a-g (10 mmol) was added to the reaction mass and it was stirred until
full solution of the precipitated compound 4 occurred. The product was then allowed to stand for 40 min at
25°C, diluted with water (25 ml), and the precipitated material was filtered off and washed with methanol.
3-[(Z)-1-Methylthio-1-(phenylamino)methylidene]tetrahydro-2,4-furandione (8). A mixture of
compound 2 (1.00 g, 10 mmol), phenyl isothiocyanate (1.35 g, 10 mmol), and N-methylmorpholine (1.01 g,
10 mmol) in DMF (10 ml) was stirred for 24 h at 25°C. Methyl iodide (1.41 g, 10 mmol) was added to the
solution obtained and the product was stirred for 40 min at 25°C, after which it was diluted with water (20 ml)
and the precipitate formed was filtered off.
5-[1-(2-Chlorobenzylsulfonyl)-1-phenylaminomethylidene]-1,3-dimethylhexahydro-2,4,6-pyrimidine-
trione (10). Acid 9 (0.45 g, 0.24 mmol) was added to a suspension of compound 7b (1.0 g, 0.24 mmol) in
chloroform (15 ml) which was cooled to 10°C. The mixture was left to stand at room temperature for 8 h. The
chloroform solution was evaporated on a water bath to give the product which was recrystallized from methanol.
1
Yield 0.61 g (56.6%); mp 124-125°C. IR spectrum, ν, cm-1: 1330, 1150, 1710, 1630, 1650. H NMR spectrum,
δ, ppm: 3.16 (6H, s, 2CH3–N); 3.56 (2H, s, CH2); 7.40-7.53 (9H, m, aromatic protons); 13.71 (1H, br. s, NH).
Found, %: C 53.52; H 3.89; Cl 7.86; N 9.27: S 7.07. C20H18ClN3O5S. Calculated, %: C 53.63; H 4.05; Cl 7.92;
N 9.38; S 7.16.
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