Reaction of O-alkyl-N-substituted iminothiocarbonates with bromoacetyl bromide. A general method for the synthesis of 3-substituted 1,3-thiazolidine-2,4-diones

Article abstract of DOI:10.1135/cccc19960432

Reaction of sodium salts of O-methyl-N-substituted iminothiocaibonates with bromoacetyl bromide represents a new general method for preparation of 3-substituted 1,3-thiazolidine-2,4-diones in good yields and high purity. The structure of the synthesized products has been confirmed by ¹H NMR, ¹³C NMR, IR and mass spectroscopy as well as by independent synthesis.

Full text of DOI:10.1135/cccc19960432

432
Imrich, Bernat, Kristian, Busova, Hocova:
REACTION OF O-ALKYL-N-SUBSTITUTED IMINOTHIOCARBONATES
WITH BROMOACETYL BROMIDE. A GENERAL METHOD FOR THE
SYNTHESIS OF 3-SUBSTITUTED 1,3-THIAZOLIDINE-2,4-DIONES
Jan IMRICH, Juraj BERNAT, Pavol KRISTIAN*, Tatiana BUSOVA and Slavka HOCOVA
Department of Organic Chemistry,
P. J. Safarik University, 041 67 Kosice, Slovak Republic
Received July 19, 1995
Accepted November 9, 1995
Reaction of sodium salts of O-methyl-N-substituted iminothiocarbonates with bromoacetyl bromide
represents a new general method for preparation of 3-substituted 1,3-thiazolidine-2,4-diones in good
yields and high purity. The structure of the synthesized products has been confirmed by 1H NMR,
13C NMR, IR and mass spectroscopy as well as by independent synthesis.
Key words: Isothiocyanates; Iminothiocarbonates; 1,3-Thiazolidine-2,4-diones.
In our previous communication1 we studied the reaction of sodium salts of N-(9-acridinyl)-
iminothiocarbonates with alkyl bromoacetates which proceeded under formation of the
corresponding spiro[dihydroacridine-9(10H),4′-thiazolines]. The unusual course of this
reaction prompted us to investigate the analogous reaction with bromoacetyl bromide.
As starting compounds we used 9-isothiocyanatoacridines 1a–1c which on addition of
sodium methoxide afforded sodium salts of O-methyl-N-(9-acridinyl)iminothiocarbo-
nates2 2a–2c. In principle, reaction of these salts with bromoacetyl bromide can afford
two structural isomers: thiazolidines 4a–4c or oxathiolanes 5a–5c (Scheme 1), provided
that the sulfur atom in compounds 2 is preferentially alkylated (in accord with the
literature3) and not acylated (the acyl carbon atom is a harder acid). Intramolecular
cyclization of the intermediates 3a–3c, involving the imine nitrogen and proceeding
with simultaneous loss of methyl bromide, leads to thiazolidinediones 4a–4c, whereas
analogous cyclization, involving the methoxy oxygen, affords the isomeric 2-imino-
1,3-oxathiolan-5-ones 5a–5c.
Proton NMR, 13C NMR and mass spectra have unequivocally shown that the reaction
affords exclusively the corresponding thiazolidine-2,4-diones 4a–4c in high yields and
purity. These compounds were also synthesized by Turkevich4 by reaction of 9-chloro-
* The author to whom correspondence should be addressed.
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433
acridines with potassium salt of 1,3-thiazolidine-2,4-dione. The published melting points
differed substantially from our values and therefore we tried to exclude the possibility
of a different crystalline modification. However, crystallization of compound 4a from
aqueous ethanol (as described in ref.4) did not change the melting point of our com-
pound. It seems thus that the higher melting point of our compound is due to its higher
purity. This, together with good yields and relatively facile preparation of the starting
reactants, led us to extend the method to the synthesis of various types of N-substituted
1,3-thiazolidine-2,4-diones. Although there are many methods of preparation of such
derivatives, no one is generally applicable (cf. refs5–10).
As starting compounds for all the types of derivatives served the corresponding
alkyl, arylalkyl and aryl isothiocyanates, mostly commercially available. In this manner
we prepared ten products of which the 3-(1-naphthyl) derivative 4j was synthesized for
H3C O
C SNa
H3C O
S
S
C
N
R
CH2
C
CH3ONa
BrCH2COBr
O
N
R
N
Br
R
3
1
2
S
S
O
R
N
N
R
O
O
O
5
4
1-5
R
1-5
R
a
b
c
d
e
f
9-acridinyl
4-methoxyphenyl
4-bromophenyl
4-chlorophenyl
1-naphthyl
g
h
i
2-chloro-9-acridinyl
4-methyl-9-acridinyl
methyl
j
phenyl
1-naphthylmethyl
SCHEME 1
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Imrich, Bernat, Kristian, Busova, Hocova:
the first time. The structure of derivative 4g has been confirmed also by an independent
synthesis: reaction of the corresponding amine with carbon disulfide gave 3-(4-bromo-
phenyl)-1,3-thiazolidine-2-thion-4-one which on reaction with mesitylnitrile oxide was
converted into the dioxo derivative 4g.
EXPERIMENTAL
Spectral measurements. Proton NMR spectra were measured on a Tesla BS 587 spectrometer (Tesla
Brno, 80 MHz) in deuteriochloroform (compounds 4b–4j) or in deuteriochloroform–hexadeuteriodi-
methyl sulfoxide (5 : 1) (compound 4a) with tetramethylsilane as internal standard, 13C NMR spectra
were taken on a Tesla BS 567 instrument (Tesla Brno, 25 MHz) in deuteriochloroform (4c–4e, 4g–4j)
or in deuteriochloroform–hexadeuteriodimethyl sulfoxide (4b, 4f), again with tetramethylsilane as
standard. Compound 4a was measured in hexadeuteriodimethyl sulfoxide and the signals were
referenced to the solvent peak at 39.39 ppm. The chemical shifts are given in ppm (δ-scale). Infrared
spectra were recorded on a Specord 75 IR instrument (Zeiss, Jena) in chloroform. Elemental analyses
were performed on a Perkin–Elmer CHN 2400 analyzer, mass spectra were taken on an SSQ 710
Finnigan spectrometer (direct inlet, Ee = 70 eV, T = 150 °C, Ie = 200 µA).
Chemicals. Methyl and ethyl isothiocyanate were commercial products (Aldrich). 4-Methoxyphenyl,
4-bromophenyl and 4-chlorophenyl isothiocyanates were prepared by the thiophosgene method according
to the literature11–12. Analogously were synthesized also 1-naphthyl isothiocyanate13 and 1-naphthyl-
methyl isothiocyanate14. 9-Isothiocyanatoacridine and 4-methyl-9-isothiocyanatoacridine were ob-
tained by reflux of the corresponding substituted 9-chloroacridines with AgSCN in toluene15.
2-Chloro-9-isothiocyanatoacridine was obtained by reaction of 2,9-dichloroacridine with KSCN at
room temperature in a mixture of dichloromethane and water in the presence of tetrabutylammonium
iodide16.
General Procedure for Preparation of 3-Substituted 1,3-Thiazolidine-2,4-diones 4a–4j
Solid sodium methoxide (1.62 g, 30 mmol) was added in portions to a stirred solution of isothio-
cyanate 1 (10 mmol) in anhydrous ether (30 ml). The reaction was monitored by TLC (benzene–
acetone 5 : 2). The precipitate was filtered off, washed with ether and dried at room temperature. The
obtained sodium salt of O-methyl-N-substituted iminothiocarbonate 2 (10 mmol) was suspended under
nitrogen in dichloromethane (25 ml) and a solution of bromoacetyl bromide (1.31 ml, 15 mmol) in
dichloromethane (10 ml) was slowly added under stirring. After stirring overnight, the solid was col-
lected on filter and washed with small amount of dichloromethane. The filtrate was concentrated, the
oily residue was mixed with small amount of ether and the obtained crystals were crystallized from
an appropriate solvent (charcoal).
3-(9-Acridinyl)-1,3-thiazolidine-2,4-dione (4a): m.p. 230–233 °C (chloroform–hexane), reported4
1
m.p. 138–140 °C (ethanol–water); yield 85%. IR spectrum: 1 768, 1 713, 1 692 (C=O). H NMR spec-
trum: 4.59 s, 2 H (CH2); 7.54–7.97 m, 6 H (ArH); 8.32 m, 2 H (ArH). 13C NMR spectrum: 171.53
(2-C=O); 171.20 (4-C=O); 35.40 (5-CH2); 122.67 (C-1′,8′); 127.69 (C-2′,7′); 130.92 (C-3′,6′); 129.28
(C-4′,5′); 135.36 (C-9′); 122.67 (C-8′a,9′a); 148.61 (C-4′a,10′a). Mass spectrum, m/z (%): 294 (100)
[M+•] 220 (50) [M+• – SCOCH2].
3-(2-Chloro-9-acridinyl)-1,3-thiazolidine-2,4-dione (4b): m.p. 241–244 °C (chloroform–hexane), re-
ported4 m.p. 182–185 °C (ethanol–water); yield 82%. IR spectrum: 1 765, 1 692 (C=O). 1H NMR
spectrum: 4.44 s, 2 H (CH2); 7.62–7.95 m, 5 H (ArH); 8.23–8.43 m, 2 H (ArH). 13C NMR spectrum:
169.80 (2- and 4-C=O); 34.53 (5-CH2); 120.30 (C-1′); 133.59 (C-2′); 131.65 (C-3′); 130.94 (C-4′);
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129.26 (C-5′); 130.68 (C-6′); 128.10 (C-7′); 121.65 (C-8′); 134.19 (C-9′); 122.92 and 123.10 (C-8′a,9′a);
146.58 (C-4′a); 148.41 (C-10′a).
3-(4-Methyl-9-acridinyl)-1,3-thiazolidine-2,4-dione (4c): m.p. 180–184 °C (chloroform–hexane),
1
reported4 m.p. 195–197 °C (ethanol–water); yield 78%. IR spectrum: 1 765, 1 700 (C=O). H NMR
spectrum: 4.39 s, 2 H (CH2); 7.48–7.92 m, 6 H (ArH); 8.39 m, 1 H (ArH); 2.97 s, 3 H (CH3). 13C NMR
spectrum: 169.80 (2-C=O); 169.95 (4-C=O); 34.60 (5-CH2); 119.71 (C-1′); 128.00 and 128.07 (C-2′,7′);
130.38 and 130.46 and 130.53 (C-3′,5′,6′); 138.26 (C-4′); 121.65 (C-8′); 135.24 (C-9′); 122.84 and
123.22 (C-8′a,9′a); 148.23 and 148.53 (C-4′a,10′a); 18.70 (CH3).
3-Methyl-1,3-thiazolidine-2,4-dione (4d): m.p. 33–35 °C (ether), reported17 m.p. 36–39 °C; yield
1
68%. IR spectrum: 1 745, 1 682, 1 674 (C=O). H NMR spectrum: 3.99 s, 2 H (CH2); 3.11 s, 3 H
(CH3). 13C NMR spectrum: 171.74 (2-C=O); 171.48 (4-C=O); 33.82 (5-CH2); 27.92 (CH3).
3-Phenyl-1,3-thiazolidine-2,4-dione (4e): m.p. 143–145 °C (chloroform–hexane), reported18 m.p.
1
143–145 °C; yield 82%. IR spectrum: 1 763, 1 702, 1 680 (C=O). H NMR spectrum: 4.11 s, 2 H
(CH2); 7.15–7.67 m, 5 H (ArH). 13C NMR spectrum: 170.88 (2-C=O); 170.59 (4-C=O); 33.78 (5-CH2);
132.89 (C-1 of phenyl); 127.25 (2 × C-2 of phenyl); 129.41 (2 × C-3 of phenyl); 129.26 (C-4 of
phenyl). Mass spectrum, m/z (%): 193 (69) [M+•], 119 (100) [C6H5NCO], 91 (30) [C6H5N], 74 (24)
[SCH2CO].
3-(4-Methoxyphenyl)-1,3-thiazolidine-2,4-dione (4f): m.p. 164–165 °C (chloroform–ether), re-
1
ported19 m.p. 166 °C; yield 87%. IR spectrum: 1 762, 1 692 1 684 (C=O). H NMR spectrum: 4.09 s,
2 H (CH2); 6.92–7.24 m, 4 H (ArH); 3.83 s, 3 H (CH3O). 13C NMR spectrum: 170.55 (2-C=O);
170.06 (4-C=O); 32.96 (5-CH2); 124.71 (C-1 of phenyl); 127.73 (2 × C-2 of phenyl); 113.70 (2 × C-3
of phenyl); 158.98 (C-4 of phenyl); 54.61 (CH3O).
3-(4-Bromophenyl)-1,3-thiazolidine-2,4-dione (4g): m.p. 160–163 °C (chloroform–ether), re-
1
ported20 m.p. 163 °C; yield 81%. IR spectrum: 1 764, 1 707, 1 688 (C=O). H NMR spectrum: 4.11 s,
2 H (CH2); 7.16 m, 2 H (ArH); 7.61 m, 2 H (ArH). 13C NMR spectrum: 170.51 (2-C=O); 170.14
(4-C=O); 33.78 (5-CH2); 131.73 (C-1 of phenyl); 128.78 (2 × C-2 of phenyl); 132.62 (2 × C-3 of
phenyl); 123.29 (C-4 of phenyl).
3-(4-Chlorophenyl)-1,3-thiazolidine-2,4-dione (4h): m.p. 142–145 °C (chloroform–ether), re-
1
ported19 m.p. 145 °C; yield 74%. IR spectrum: 1 760, 1 708, 1 683 (C=O). H NMR spectrum: 4.12 s,
2 H (CH2); 7.22 m, 2 H (ArH); 7.46 m, 2 H (ArH). 13C NMR spectrum: 170.62 (2-C=O); 170.25
(4-C=O); 33.78 (5-CH2); 131.21 (C-1 of phenyl); 128.56 (2 × C-2 of phenyl); 129.68 (2 × C-3 of
phenyl); 135.31 (C-4 of phenyl).
3-(1-Naphthyl)-1,3-thiazolidine-2,4-dione (4i): m.p. 154–156 °C (chloroform–ether), reported21
m.p. 194 °C; yield 71%. IR spectrum: 1 761, 1 684, 1 679 (C=O). 1H NMR spectrum: 4.12, 4.16
split signal, 2 H (CH2); 7.22–7.64 m, 5 H (ArH); 7.82–8.02 m, 2 H (ArH). 13C NMR spectrum:
170.70 (2- and 4-C=O); 34.08 (5-CH2); 134.49 (C-1′); 121.54, 125.38, 126.73, 126.73, 127.51,
128.74, 130.50 (CH carbons); 129.45, 129.56 (quaternary carbons).
3-(1-Naphthylmethyl)-1,3-thiazolidine-2,4-dione (4j): m.p. 84–86 °C (chloroform–hexane); yield
75%. For C14H11NO2S (257.3) calculated: 65.35% C, 4.31% H, 5.44% N; found: 65.18% C, 4.20% H,
5.41% N. IR spectrum: 1 757, 1 695, 1 687 (C=O). 1H NMR spectrum: 3.90 s, 2 H (CH2); 7.29–7.65 m,
4 H (ArH); 7.75–7.91 m, 2 H (ArH); 8.23 m, 1 H (ArH); 5.22 s, 2 H (ArCH2). 13C NMR spectrum:
171.56 (2-C=O); 171.26 (4-C=O); 43.11 (ArCH2); 33.63 (5-CH2); 133.86, 131.28, 130.12 (quaternary
carbons); 123.40, 125.19, 125.91, 126.69, 126.72, 127.58, 128.78, 129.00 (CH carbons).
Alternative Synthesis of 3-(4-Bromophenyl)-1,3-thiazolidine-2,4-dione (4g)
A solution of mesitylnitrile oxide22 (322 mg, 2 mmol) in anhydrous acetonitrile (20 ml) was added
dropwise under nitrogen to a stirred solution of 3-(4-bromophenyl)-1,3-thiazolidine-2-thion-4-one23
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Imrich, Bernat, Kristian, Busova, Hocova:
(288 mg, 1 mmol) in anhydrous acetonitrile (40 ml). The reaction mixture was stirred at room tem-
perature for 1 h and the solvent was evaporated. The residue was washed with hexane (50 ml), dried
and crystallized from chloroform–ether. The melting point and physicochemical data of the product
were identical with those of the compound prepared from 4-bromophenyl isothiocyanate (vide supra).
The authors are indebted to the Grant Agency for Science of the Slovak Republic for the finantial
support and to Dr V. Kovalcik (Chemical Institute of Slovak Academy of Sciences, Bratislava) for the
mass spectroscopic analyses.
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