Novel 2-thioxohydantoin ketene dithioacetals: Versatile intermediates for synthesis of methylsulfanylimidazo-[4,5-c]pyrazoles and methylsulfanylpyrrolo-[1,2-c]imidazoles

Article abstract of DOI:10.1081/SCC-120005435

The novel 2-thioxohydantoin ketene S,S-acetals 3a,b were prepared by the reaction of 2-thioxohydantoins 1a,b with carbon disulfide, followed by alkylation with methyl iodide of the produced sodium dithiolate salts 2a,b. The reaction of compounds 3a,b with nucleophiles afforded different fused methylsulfanylimidazoles.

Full text of DOI:10.1081/SCC-120005435

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NOVEL 2-THIOXOHYDANTOIN KETENE DITHIOACETALS:
VERSATILE INTERMEDIATES FOR SYNTHESIS OF
METHYLSULFANYLIMIDAZO- [4,5-C]PYRAZOLES AND
METHYLSULFANYLPYRROLO- [1,2-C]IMIDAZOLES
Galal H. Elgemeie a , Ahmed H. Elghandour b , Hosny A. Ali b & Ahmed M. Hussein b
a Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
b Department of Chemistry, Faculty of Science, Cairo University (Bani Suef Branch), Bani
Suef, Egypt
Version of record first published: 18 Oct 2011.
To cite this article: Galal H. Elgemeie, Ahmed H. Elghandour, Hosny A. Ali & Ahmed M. Hussein (2002): NOVEL 2-
THIOXOHYDANTOIN KETENE DITHIOACETALS: VERSATILE INTERMEDIATES FOR SYNTHESIS OF METHYLSULFANYLIMIDAZO- [4,5-
C]PYRAZOLES AND METHYLSULFANYLPYRROLO- [1,2-C]IMIDAZOLES, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:14, 2245-2253
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 14, pp. 2245–2253, 2002
NOVEL 2-THIOXOHYDANTOIN KETENE
DITHIOACETALS: VERSATILE
INTERMEDIATES FOR SYNTHESIS
OF METHYLSULFANYLIMIDAZO-
[4,5-c]PYRAZOLES AND
METHYLSULFANYLPYRROLO-
[1,2-c]IMIDAZOLES
Galal H. Elgemeie,1, Ahmed H. Elghandour,2
*
Hosny A. Ali,2 and Ahmed M. Hussein2
1Chemistry Department, Faculty of Science, Helwan
University, Helwan, Cairo, Egypt
2Department of Chemistry, Faculty of Science, Cairo
University (Bani Suef Branch), Bani Suef, Egypt
ABSTRACT
The novel 2-thioxohydantoin ketene S,S-acetals 3a,b were
prepared by the reaction of 2-thioxohydantoins 1a,b with
carbon disulfide, followed by alkylation with methyl iodide
of the produced sodium dithiolate salts 2a,b. The reaction
of compounds 3a,b with nucleophiles afforded different
fused methylsulfanylimidazoles.
*Corresponding author. E-mail: rughe@rusys.eg.net
2245
DOI: 10.1081/SCC-120005435
Copyright & 2002 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

2246
ELGEMEIE ET AL.
Key Words: Ketene dithioacetals; Methylsulfanylimidazo-
pyrazoles; Methylsulfanylpyrroloimidazoles; Unsaturated
nitriles; Heterocycles
Recent reports from this laboratory have described the synthesis of
certain methylsulfanylpyrazolo[1,5-ꢀ]pyrimidine ring system as mercapto-
purine analogues via the reaction of cyanoketene dithioacetals with
amino-substituted azoles.[1–3] We report here a novel and convenient
method for the synthesis of fused imidazoles carrying a methylsulfanyl
group. Derivatives of these ring systems are interesting because they are
sulfanylpurine analogues and as such may have useful properties as anti-
metabolites in purine biochemical reactions. The novel 2-thioxohydantoin
ketene dithioacetals 3 were chosen as the key intermediates.
Thus, it has been found that reaction of 2-thioxohydantoin derivatives
1a,b with carbon disulfide in the presence of sodium ethoxide gives the cor-
responding sodium dithiolate derivatives 2a,b in high yields. The latters on
treatment with methyl iodide give the novel 2-thioxohydantoin ketene
dithioacetals 3a,b (Chart 1). The structures of 3 have been established on
the basis of their elemental analysis and spectral data. Thus, structure 3a is
supported by its mass spectrum which showed a molecular formula
C6H8N2OS3 (Mþ220) and 1H NMR spectrum contained two signals at
ꢁ ¼ 2.43 and 2.45 ppm, which are assignable to two methylsulfanyl groups
and two singlet bands at ꢁ ¼ 11.76 and 12.16 ppm assignable to two NH
groups. The 13C NMR spectrum was characterized by two signals at
ꢁ ¼ 17.31 and 17.77 ppm corresponding to two SCH3 carbons. Also, salts 2
reacted with benzoyl chloride and phenacyl bromide to yield the correspond-
ing alkylating products 4 and 5, respectively (Chart 1). The structures of 4
and 5 were established and confirmed on the basis of their elemental analysis
and spectral data. The 2-thioxohydantoin ketene dithioacetals 3 bearing
latent functional substituents were found useful for the synthesis of fused
methylsulfanylimidazole derivatives. Thus, it has been found that the reac-
tion of ketene dithioacetals 3 with substituted hydrazines in refluxing ethanol
containing a catalytic amount of piperidine gives the corresponding 4-
methylsulfanylimidazo-[5,4-c]pyrazoles 6a–d in good yields (Chart 2). The
structures of 6 were established and confirmed for the reaction products on
1
the basis of their elemental analysis and spectral data (MS, IR, H NMR).
The analytical data for 6a indicated a molecular formula C5H6N4S2 (Mþ 186)
and 1H NMR revealed a singlet band at ꢁ ¼ 2.49 ppm, assignable to a SCH3
group. When compounds 3 were subjected to the reaction with cyanothioa-
cetamide in refluxing ethanol containing a catalytic amount of piperidine, the
corresponding 7-methylsulfanyl-3-thioxopyrrolo[1,2-c]imidazol-1-ones
were obtained (Chart 2), the structures of which are established on the
7

NOVEL 2-THIOXOHYDANTOIN KETENE DITHIOACETALS
2247
basis of spectral evidence. Thus, compound 7a showed the presence of a CN
absorption in its IR at 2221 cmꢀ1 whilst its mass spectrum was compatible
with the molecular formula C8H5N3OS3 (Mþ 255). The formation of 7 from
the reaction of 3 and cyanothioacetamide is assumed to proceed via initial
Michael addition of the active methylene group of cyanothioacetamide to the
exocyclic double bond of 3. The Michael adducts cyclized smoothly via
CH3SH and NH3 elimination. Similarly, compounds 3 reacted with malono-
nitrile in refluxing ethanol containing a catalytic amount of piperidine to give
the corresponding 5-amino-7-methylsulfanyl-3-thioxopyrrolo[1,2-c]imida-
zoles 8 (Chart 2). The structures of 8 were established and confirmed on
1
the basis of their elemental analysis and spectral data (MS, IR, H NMR,
and 13C NMR). The analytical data for 8b revealed a molecular formula
1
C14H10N4OS2 (Mþ 314). H NMR spectroscopy was used to confirm this
structure. Thus, it revealed a singlet band at ꢁ ¼ 2.49 ppm assignable to a
SCH3 group, a multiplet band at ꢁ ¼ 7.41–7.55 ppm for a phenyl group and a
broad singlet at ꢁ ¼ 8.79 ppm assignable to an amino group. The formation
of 8 from the reaction of 3 and malononitrile is assumed to proceed via the
intermediacy of acyclic Michael adducts, which cyclize via CH3SH elimin-
ation and addition to the cyano group to yield the final stable diazapentalene
analogues 8. The course of the reaction between 3 and malononitrile
prompted us to investigate this reaction between 2-thioxohydantoin 1 and
bis[(methylthio)methylene]malononitrile 9 under the same conditions. The
products obtained were shown to be the same as those obtained from the
reaction of 3 with malononitrile by their melting points and spectral data to
give the pyrrolo[1,2-c]imidazoles 8.[4]
EXPERIMENTAL
All melting points are uncorrected on a Gallenkamp melting point
apparatus. The IR spectra were recorded (KBr disk) on a Perkin Elmer
11650 FT-IR instrument. The 1H NMR spectra were measured on a
Varian 400 MHz spectrometer for solutions in (CD3)2SO using Si(CH3)4
as an internal standard. Mass spectra were recorded on a Varian MAT
112 spectrometer. Analytical data were obtained from the Microanalytical
Data Center at Cairo University.
Sodium Dithiolate Derivatives (2a,b)
A mixture of 2-thioxohydantoin derivatives 1a,b (0.01 mole) and
sodium ethoxide (0.02 mole) in ethanol (30 mL) was boiled under reflux

2248
ELGEMEIE ET AL.
for 15 min. Then cooled and carbon disulphide (0.01 mole) was added.
The reaction mixture was warmed at 50ꢁC for 15 min. The solvent
was evaporated and the resulting precipitated product was filtered off and
recrystallized from ethanol.
2a: Yellow; m.p. > 300ꢁC; from ethanol; yield. 68%; ꢂmax/cmꢀ1 (KBr)
3384, 3250 (NH), 1713 (CO); found: C, 20.00; H, 1.02; N, 11.34%; calcd for
C4H2N2OS3Na2 (236); C, 20.33; H, 0.84; N, 11.86%.
2b: Yellow; m.p. > 300ꢁC; from ethanol; yield. 73%; vmax/cmꢀ1 (KBr)
3316, 3122 (NH), 1690 (CO); found: C, 38.11; H, 2.01; N, 8.65%; calcd for
C10H6N2OS3Na2 (312): C, 38.46; H, 1.92; N, 8.97%.
2-Thioxo-4-bis(methylsulfanyl)methylidene-
(3H)-imidazolin-5-ones (3a,b)
A cold solution of the sodium salts 2a,b (0.01 mole) in methanol
(30 mL) was treated with methyl iodide (0.02 mole). The solution was stirred
for 10 min at room temperature. The formed solid product was filtered off
and recrystallized from ethanol.
3a: Yellow; m.p. 248ꢁC; from ethanol; yield, 77%; ꢂmax /cmꢀ1 (KBr);
3417–3134 (2NH), 1714 (CO); ꢁH [(CD3)2SO]: 2.40 (s, 3H, SCH3); 2.45
(s, 3H, SCH3); 11.76 (s, 1H, NH ); 12.16 (s, 1H, NH); 13C NMR: 17.31
(SCH3); 17.77 (SCH3); 128.89 (C-6); 130.02 (C-4); 161.06 (C-2); 174.72
(C-5); m/z (220); found: C, 32.50; H, 3.71; N, 12.70%; calcd for
C6H8N2OS3 (220): C, 32.72; H, 3.63; N, 12.72%.
3b: Orange; m.p. 202ꢁC; from ethanol; yield, 85.34%; ꢂmax/cmꢀ1 (KBr)
3155, 3124 (NH), 1720 (CO); ꢁH [(CD3)2SO]: 2.05 (s, 3H, SCH3); 2.51 (s, 3H,
SCH3); 7.32–7.52 (m, 5H, C6H5); 12.24 (s, 1H, NH); 13C NMR: 17.36
(SCH3); 17.97 (SCH3); 127.37–128.88 (Phenyl-C); 131.99 (C-6); 133.48
(C-4); 159.12 (C-2); 174.31 (C-5); mlz (296); found: C, 48.81; H, 3.98;
N, 9.54%; calcd for C12H12N2OS3 (296): C, 48.64; H, 4.05; N, 9.45%.
2-Thioxo-4-bis(benzoylsulfanyl)methylidene-
(3H)imidazolin-5-ones (4a,b)
To a solution of sodium salts 2a,b (0.01 mole) in methanol (20 mL),
benzoyl chloride (0.02 mole) was added. The reaction mixture was stirred
at room temperature for 30 min and then poured over cold water. The
produced solid product was filtered and recrystallized from the appropriate
solvent.

NOVEL 2-THIOXOHYDANTOIN KETENE DITHIOACETALS
2249
4a: Yellow; m.p.>300ꢁC; from ethanol; yield, 87%; ꢂmax/cmꢀ1 (KBr);
3400–3150 (2NH), 1730 (CO), 1650 (2CO); ꢁH [(CD3)2SO]: 7.12–7.87 (m,
10H, 2C6H5); 9.56 (s, 1H, NH), 12.11 (s, 1H, NH); found: C, 54.33; H, 3.20;
N, 6.85%; calcd for C18H12N2O3S3 (400): C, 54.00; H, 3.00; N, 7.00%.
4b: Yellow; m.p. 285ꢁC; from ethanol–DMF; yield, 92%; ꢂmax/cmꢀ1
(KBr), 3320 (NH), 1730 (CO), 1680, 1650 (2CO); ꢁH [(CD3)2SO]: 7.40–8.02
(m, I5H, 3C6H5); 13.14 (s, 1H, NH); found: C, 60.00; H, 3.41; N, 5.75%;
calcd for C24H16N2O3S3 (476): C, 60.50; H, 3.36; N, 5.88%.
2-Thioxo-4-bis(benzoylmethylsulfanyl)methylidene-
(3H)-imidazolin-5-ones (5a,b)
A mixture of sodium salts 2a,b (0.01 mole) and phenacyl bromide
(0.02 mole) was dissolved in methanol (20 mL). The reaction mixture was
refluxed for 15 min, then poured over cold water. The solid precipitate was
filtered and recrystallized from ethanol.
5a: Yellow; m.p.>300ꢁC; from ethanol; yield, 87%; ꢂmax/cmꢀ1 (KBr)
3210–3131 (NH), 1720 (CO), 1660 (2CO); ꢁH [(CD3)2SO]: 2.92 (s, 4H, 2
SCH2); 7.11–7.87 (m, 10H, 2C6H5); 9.86 (s, 1H, NH), 11.00 (s, 1H, NH);
m/z (428); found: C, 56.17; H, 3.06; N, 6.82; calcd for C20H16N2O3S3 (428):
C, 56.07; H, 3.74; N, 6.54%.
5b: Yellow; m.p.>300ꢁC; from ethanol; yield, 85%; ꢂmax/cmꢀ1 (KBr)
3260, 3220 (NH), 1725 (CO), 1680, 1640 (2CO); ꢁH (CD3)2SO]: 3.04 (s, 4H, 2
SCH2; 7.36–7.93 (m, 15H, 3C6H5); 11.12 (s, 1H, NH); found: C, 62.01; H,
3.54; N, 5.72%; calcd for C26H20N2O3S3 (504): C, 61.90; H, 3.97; N, 5.55%.
4-Methylsulfanylimidazo[4,5-c]pyrazoles (6a–d)
General Procedure
A mixture of 3a,b (0.01 mole) and hydrazine hydrate or phenyl-
hydrazine (0.01 mole) was boiled under reflux in ethanol (30 mL), containing
a catalytic amount of piperidine for 3 h. The solution mixture was left to cool,
and the product which separated was collected and recrystallized from the
appropriate solvent.
6a: Colorless; m.p. 230ꢁC; from ethanol; yield, 55%; ꢂmax/cmꢀ1, 3330,
3276, 3157 (3NH); ꢁH [(CD3)2SO]: 2.49 (s, 3H, SCH3); 6.58 (s, 1H, NH); 7.58
(s, 1H, NH); 8.50 (s, 1H, NH); m/z (186); found: C, 32.01; H, 3.42; N,
29.88%; calcd for C5H6N4S2 (186): C, 32.25; H, 3.22; N, 30.11%.

2250
ELGEMEIE ET AL.
6b: Yellow; m.p.>300ꢁC; from ethanol–DMF; yield, 68%; ꢂmax/cmꢀ1
(KBr), 3460, 3200 (2 NH); ꢁH [(CD3)2SO]: 2.52 (s, 1H, SCH3); 7.06–7.58 (m,
5H, C6H5); 7.63 (s. 1H, NH); 7.77 (s, 1H, NH); found: C, 50.54; H, 3.94; N,
21.02%; calcd for C11H10N4S2 (262): C, 50.38; H, 3.81; N, 21.37%.
6c: Buff; m.p. 252ꢁC; from DMF; yield, 64%; ꢂmax/cmꢀ1 (KBr), 3309,
3238 (NH, NH); ꢁH [(CD3)2SO]: 2.49 (s. 3H, SCH3); 7.11–7.32 (m, 5H, C6H5);
7.47 (s, 1H, NH); 8.73 (s, 1H, NH); mIz (262); found: C, 49.98; H, 4.01; N,
21.05%; calcd for C11H10N4S2 (262): C, 50.38; H, 3.81; N, 21.37%.
6d: Yellow; m.p.>285ꢁC; from ethanol–DMF; yield. 74%; ꢂmax/cmꢀ1
(KBr). 3210 (NH); ꢁH [(CD3)2SO]: 2.61 (s, 3H, SCH3); 7.00–7.95 (m, 10H,
2C6H5); 8.22 (s, 1H, NH); found: C, 60.44; H, 3.97; N, 16.81%; calcd for
C17H14N4S2 (338): C, 60.35; H, 4.14; N, 16.56%.
5-Mercapto-2,3-dihydro-7-methylsulfanyl-3-thioxo-1H-
pyrrolo[1,2-c]imidazol-1-ones (7a,b)
A solution of dithioacetals 1a,b (0.01 mole) and cyanothioacetamide
(0.01 mol) in ethanol (30 mL) and a few drops of piperidine was refluxed for
3 h, cooled, the precipitate was then filtered off and recrystallized from the
appropriate solvent.
7a: Brown; m.p.>300ꢁC; from DMF; yield, 68%; ꢂmax/cmꢀ1 (KBr)
3466, 3355 (NH), 2221 (CN), 1714 (CO); ꢁH [(CD3)2SO]: 2.60 (s, 3H,
SCH3); 8.22 (s, 1H, NH), 11.98 (s, 1H, SH); m/z (253); found: C, 38.00;
H, 1.58; N, 16.91%; calcd for C8H5N3OS3 (255): C, 37.65; H, 1.96;
N, 16.47%.
7b: Brown; m.p.>300ꢁC; from DMF; yield, 71%; ꢂmax/cmꢀ1 (KBr)
2219 (CN), 1715 (CO); ꢁH [(CD3)2SO]: 2.41 (s, 3H, SCH3); 7.46–8.12
(m, 5H, C6H5); 11.98 (s, 1H, SH); found: C, 50.10; H, 3.10; N, 12.36%;
calcd for C14H9N3OS3 (331): C, 50.76; H, 2.72; N, 12.69%.
5-Amino-6-cyano-7-methylsulfanyl-
3-thioxo-1H-pyrro1o[1,2-c]imidazol-1-ones (8a,b)
Method a: A mixture of compounds 3a,b (0.01 mole) and malononitrile
(0.01 mole) was boiled under reflux in ethanol (30 mL) containing a catalytic
amount of piperidine for 4 h. The product precipitated was collected and
recrystallized from the appropriate solvent.
Method b: Bis[(methylthio)methylene]malononitrile 9 (0.01 mol) and
three drops of piperidine were added to a stirred suspension of the imida-

NOVEL 2-THIOXOHYDANTOIN KETENE DITHIOACETALS
2251
Chart 1.

2252
ELGEMEIE ET AL.
Chart 2.
zolidines 1 (0.01 mol) in ethanol (50 mL). The mixture was refluxed for 5 h
and then allowed to cool. The solid precipitate was isolated by suction and
recrystallized from the appropriate solvent.
8a: Yellow; m.p. 290–292ꢁC; from DMF; yield, 87%; ꢂmax/cmꢀ1 (KBr)
3450–3320 (NH, NH2); 2220 (CN); 1715 (CO); ꢁH [(CD3)2SO]: 2.66 (s, 3H,
SCH3); 8.79 (s, br, 2H, NH2), 11.20 (s, br, 1H, NH); m/z (238); found: C,
40.48; H, 2.58; N, 23.85%; calcd for C8H6N4OS2 (238): C, 40.34; H, 2.52;
N, 23.53%.
8b: Yellow; m.p. 298–300ꢁC; from ethanol–DMF; yield, 91%;
ꢂ
max/cmꢀ1 (KBr) 3377–3226 (NH, NH2); 2216 (CN); 1716 (CO); ꢁH
[(CD3)2SO]: 2.79 (s, 3H, SCH3); 7.41–7.55 (m, 5H, C6H5); 8.79 (s, br, 2H,
NH2); 13C NMR: 16.56 (SCH3); 109.89 (CN); 113.58 (C-7); 128.80–129.27

NOVEL 2-THIOXOHYDANTOIN KETENE DITHIOACETALS
2253
(phenyl-C); 132.43 (C-6); 137.62 (C-8), 148.72 (C-5); 154.53 (C-3); 169.68
(C-1); m/z (314); found: C, 53.32; H, 2.99; N, 17.98; calcd for C14H10N4OS2
(314): C, 53.50; H, 3.18; N, 17.83%.
REFERENCES
1. Elgemeie, G.H.; El-Ezbawy, S.E.; Ali, H.A.; Mansour, A.K. Bull.
Chem. Soc. Jpn. 1994, 67, 738.
2. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Hussein, A.M.
J. Chem. Research (S) 1997, 256.
3. Elgemeie, G.H.; Elghandour, A.H.; Elzanate, A.M.; Ahmed, S.A.
J. Chem. Soc., Perkin Trans. 1 1997, 3285.
4. Elgemeie, G.H.; Ali, H.A.; Elzanate, A.M. J. Chem. Research (S),
1996, 340.
Received in the UK May 21, 2001