Synthesis of sulfur-containing sydnones

Article abstract of DOI:10.1023/A:1016065707957

A method for the synthesis of 4-alkylthio- and 4-arylthiosydnones from 4-lithiosydnones and elementary sulfur was proposed.

Full text of DOI:10.1023/A:1016065707957

Russian Chemical Bulletin, International Edition, Vol. 51, No. 5, pp. 899—900, May, 2002
899
Synthesis of sulfurꢀcontaining sydnones
ꢀ
S. N. Lebedev, I. A. Cherepanov, and V. N. Kalinin
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. Eꢀmail: vkalin@ineos.ac.ru
A method for the synthesis of 4ꢀalkylthioꢀ and 4ꢀarylthiosydnones from 4ꢀlithiosydnones
and elementary sulfur was proposed.
Key words: sydnones, metalation, sulfur.
Sydnones, which are representatives of mesoionic
heterocyclic compounds, possess a broad spectrum of
pharmacological activities.1,2 It is known that sulfurꢀconꢀ
taining substituents significantly influence the biological
activity of heterocyclic compounds. However, only a
few number of sydnone derivatives bearing thioalkyl subꢀ
stituents have been described in the literature.
ment with water affords 4ꢀmercaptoꢀ3ꢀphenylsydnone 2,
which reacts with organic halides such as methyl iodide,
propargyl bromide, and ethyl bromoacetate to give the
corresponding sulfides 3—5 and with pivaloyl chloride to
form thioester 6 (Scheme 2).
Scheme 2
Earlier, sulfurꢀcontaining sydnones have been obꢀ
tained by the reactions of 4ꢀlithiosydnone with disulꢀ
fides3 or by the reactions of sulfoxides with 4ꢀnonꢀ
substituted sydnones in the presence of AcCl.4 However,
these methods are of limited utility.
The goal of the present study was to investigate the
method of introduction of alkylꢀ and arylthio substituꢀ
ents in position 4 of the sydnone ring based on the reacꢀ
tions of 4ꢀlithiosydnones with elementary sulfur.
Compound
RX
H2O
MeI
R
H
Me
2
3
4
5
6
7
HC≡CCH2Br
BrCH2CO2Et
ButCOCl
Me3SnCl
HC≡CCH2
CH2CO2Et
ButCO
Me3Sn
Results and Discussion
We found that elementary sulfur is inserted into the
C—Li bond in the reaction with 4ꢀlithiosydnone to give
lithium thiolate 1 (Scheme 1).
Of special note is that thiolate 1 reacts with Me3SnCl
to give product 7 with an S—Sn bond; the Stille reaction
of the latter with pꢀiodonitrobenzene yields sulfide 8
(Scheme 3).
Scheme 1
Scheme 3
Compound 1 shows properties inherent in common
alkaliꢀmetal alkaneꢀ and arenethiolates. Thus its treatꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 826—828, May, 2002.
1066ꢀ5285/02/5105ꢀ899 $27.00 © 2002 Plenum Publishing Corporation

900
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 5, May, 2002
Lebedev et al.
2.67 Hz); 3.53 (d, 2 H, CH2); 7.59—7.85 (m, 5 H, Ph). IR,
ν/cm–1: 1760 (CO).
Experimental
4ꢀEthoxycarbonylmethylthioꢀ3ꢀphenylsydnone (5), yield 64%,
oil. Found (%): C, 51.65; H, 4.58; N, 9.28; S, 10.86.
C12H12N2SO4. Calculated (%): C, 51.42; H, 4.32; N, 9.99;
S, 11.44. H NMR (CDCl3), δ: 1.10 (t, 3 H, Me); 3.30 (s, 2 H,
SCH2); 4.00 (q, 2 H, OCH2); 7.50—7.70 (m, 5 H, Ph). IR,
ν/cm–1: 1758 (CO); 1736 (CO).
3ꢀPhenylꢀ4ꢀpivaloylthiosydnone (6), yield 76%, oil.
Found (%): C, 56.24; H, 5.22; N, 9.28; S, 11.63. C13H14N2SO3.
Calculated (%): C, 56.10; H, 5.07; N, 10.06; S, 11.52. 1H NMR
(CDCl3), δ: 1.00 (s, 9 H, But); 7.60—7.80 (m, 5 H, Ph). IR,
ν/cm–1: 1750 (CO); 1736 (CO).
1
H NMR spectra were recorded on a Bruker WMꢀ400 specꢀ
trometer with Me4Si as the internal standard. IR spectra were
recorded on a Specord Mꢀ80 spectrometer (solutions in CHCl3).
Melting points were determined in glass capillaries in a metalꢀ
lic block. All reactions involving organometallic compounds
were carried out in an atmosphere of dry argon in anhydrous
solvents.
1
3ꢀPhenylsydnone was prepared from Nꢀphenylglycine acꢀ
cording to the known procedure.5
4ꢀMercaptoꢀ3ꢀphenylsydnone (2). A 1.75 M solution of BunLi
(1.9 mL, 3.4 mmol) in hexane was added at –78 °C to a soluꢀ
tion of 3ꢀphenylsydnone (0.5 g, 3.1 mmol) in 50 mL of THF.
The reaction mixture was stirred at –78 °C for 5 min and, after
addition of elementary sulfur (0.1 g), at the same temperature
for 10 min. Then the reaction mixture was warmed to ∼20 °C,
and 2 M HCl (2 mL) was added. The solvent was removed in
vacuo, and the residue was dissolved in CHCl3 and filtered
through a layer of Al2O3 (2×3 cm) with CHCl3 as the eluent.
The eluate was concentrated in vacuo, and the product was
isolated by preparative TLC on silica gel in ether—chloroform
(1 : 1) and recrystallized from a chloroform—ether mixture.
The yield of compound 2 was 0.24 g (40%), m.p. 148—149 °C.
Found (%): C, 49.53; H, 2.84; N, 14.38; S, 16.6. C8H6N2SO2.
Calculated (%): C, 49.48; H, 3.11; N, 14.42; S, 16.51. 1H NMR
(CDCl3), δ: 1.60 (s, 1 H, SH); 7.60—7.80 (m, 5 H, Ph). IR,
ν/cm–1: 1762, 1784 (CO).
3ꢀPhenylꢀ4ꢀtrimethylstannylthiosydnone (7), yield 67%, m.p.
125—127 °C. Found (%): C, 36.53; H, 5.70; N, 7.21; S, 8.36;
Sn, 32.11. C11H14N2SSnO2. Calculated (%): C, 36.39; H, 5.55;
1
N, 7.72; S, 8.83; Sn, 32.69. H NMR (CDCl3), δ: 0.55 (s, 9 H,
SnMe3); 7.55—7.80 (m, 5 H, Ph). IR, ν/cm–1: 1748 (CO).
4ꢀ(4ꢀNitrophenylthio)ꢀ3ꢀphenylsydnone (8). A mixture of
compound 7 (0.3 g, 0.84 mmol), pꢀiodonitrobenzene (0.2 g,
0.84 mmol), LiCl (0.14 g, 3.36 mmol), and Pd(PPh3)4 (0.05 g,
0.042 mmol) in 25 mL of anhydrous benzene was refluxed for
3 h. The reaction mixture was cooled to ∼20 °C, and a satuꢀ
rated solution of KF (10 mL) was added. The organic layer was
decanted, dried with potassium carbonate, and filtered through
a layer of Al2O3 (2×3 cm) with CHCl3 as the eluent. The eluate
was concentrated in vacuo, and the residue was recrystallized
from a chloroform—hexane mixture. The yield of compound 8
was 0.21 g (80%), m.p. 115 °C. Found (%): C, 53.42; H, 2.91;
N, 13.30; S, 9.96. C14H9N31SO4. Calculated (%): C, 53.33;
H, 2.88; N, 13.33; S, 10.17. H NMR (CDCl3), δ: 7.30, 8.15
(dd, 4 H, C6H4, AB system, J = 12 Hz); 7.40—7.76 (m, 5 H,
Ph). IR, ν/cm–1: 1764 (CO).
4ꢀMethylthioꢀ3ꢀphenylsydnone (3). 3ꢀPhenylsydnone
(3.1 mmol) was converted into thiolate 1 as described above.
Methyl iodide (0.23 mL, 3.7 mmol) was added at ∼20 °C, and
the reaction mixture was stirred for 30 min. Water (1 mL) was
added, and THF was removed in vacuo. The residue was disꢀ
solved in CHCl3 and filtered through a layer of Al2O3 (2×3 cm)
with CHCl3 as the eluent; the eluate was concentrated in vacuo.
The product was isolated by preparative TLC and recrystallized
from a chloroform—ether mixture. The yield of compound 3
was 0.4 g (63%), m.p. 101—102 °C (cf. Refs.: m.p. 101—102 °C 3
and 101.5—102 °C 4). Found (%): C, 51.82; H, 3.96; N, 13.46;
S, 15.45. C9H8N2SO2. Calculated (%): C, 51.99; H, 3.87;
References
1. M. Ohta and H. Kato, Nonbenzenoid Aromatics, Ed. J. P.
Snyder, Academic Press, New York, 1969, 117.
2. C. G. Newton and C. A. Ramsden, Tetrahedron, 1982,
38, 2965.
3. T. Fuchigami, C.ꢀS. Chen, T. Nonaka, M.ꢀY. Yen, and
H.ꢀJ. Tien, Bull. Chem. Soc. Jpn., 1986, 59, 483.
4. K. Masuda and T. Okutani, Tetrahedron, 1974, 30, 409.
5. J. B. Earl and A. W. Mackney, J. Chem. Soc., 1935, 899.
1
N, 13.45; S, 15.40. H NMR (CDCl3), δ: 2.20 (s, 3 H, Me);
7.60—7.80 (m, 5 H, Ph). IR, ν/cm–1: 1752 (CO).
Compounds 4—7 were synthesized analogously.
3ꢀPhenylꢀ4ꢀpropargylthiosydnone (4), yield 71%, m.p.
75—76 °C. Found (%): C, 56.64; H, 3.48; N, 11.91; S, 13.91.
C11H8N2SO2. Calculated (%): C, 56.89; H, 3.47; N, 12.06;
S, 13.80. 1H NMR (DMSOꢀd6), δ: 3.20 (t, 1 H, CH, J =
Received September 28, 2001;
in revised form March 5, 2002