Facile synthesis of 2-alkylthio-5,5-dimethyl-4H-imidazol-4-ones

Article abstract of DOI:10.1080/00397910600772959

The isothiocyanate 3, obtained from aza-Wittig reaction of iminophosphorane 2 with CS₂, reacts with phenylhydrazine to give thiosemicarbazide 4. Reactions of 4 with alkyl halides in the presence of K₂CO ₃ directly provided

Full text of DOI:10.1080/00397910600772959

Synthetic Communicationsw, 36: 2921–2925, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600772959
Facile Synthesis of 2-Alkylthio-5,5-dimethyl-
4H-imidazol-4-ones
Ju-Zhen Yuan, Jia-Jia Wei, and Ming-Wu Ding
Key Laboratory of Pesticide and Chemical Biology,
Ministry of Education, College of Chemistry, Central China Normal
University, Wuhan, China
Abstract: The isothiocyanate 3, obtained from aza-Wittig reaction of iminophosphor-
ane 2 with CS2, reacts with phenylhydrazine to give thiosemicarbazide 4. Reactions of
4 with alkyl halides in the presence of K2CO3 directly provided 2-alkylthio-4H-
imidazol-4-ones 6 in good yields.
Keywords: Aza-Wittig reaction, 4H-imidazol-4-one, isothiocyanate, synthesis
The derivatives of 4H-imidazol-4-one have shown good biological and
pharmaceutical activities.[1–3] Some of them exhibited good antibacterial,
antifungal, and angiotensin antagonistical activities.[4–6] Since a novel mito-
chondrial respiratory inhibitor, 5-methyl-5-phenyl-2-methylthio-3-phenyla-
mino-3,5-dihydroimidazol-4-one (Fenamidone), was found to show high
fungicidal activity, many other 2-methylthioimidazolone derivatives have
been synthesized to evaluate their fungicidal activities.[7–11] They were
generally prepared from the corresponding amino acetic acid[8,9]
(Scheme 1). However, the highly toxic thiophosgene was used to transfer
amino acetic acid into isothiocyanate by the synthetic route.
Recently, we became interested in the synthesis of biologically active
imidazolones via tandem aza-Wittig reaction.[12–17] Here we report a facile
Received in R.O.C. January 24, 2006
Address correspondence to Ming-Wu Ding, Key Laboratory of Pesticide and
Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan, 430079, China. E-mail: mwding@mail.ccnu.edu.cn
2921

2922
J.-Z. Yuan, J.-J. Wei, and M.-W. Ding
Scheme 1.
synthesis of 2-alkylthio-3-phenylamino-4H-imidazol-4-ones 6 from the azide
1 without using the highly toxic thiophosgene.
Iminophosphorane 2, obtained from azide 1 with triphenylphosphine,
reacted with excess carbon disulfide to give isothiocyanate 3. Then isothio-
cyante 3 was allowed to react with phenylhydrazine to provide thiosemicarba-
zide 4, which was further treated with alkyl halide in the presence of K2CO3 to
give 2-alkylthio-3-phenylamino-4H-imidazol-4-ones 6 (Scheme 2). The
formation of 6 can be rationalized in terms of an initial cyclization of thiose-
micarbazide 4 to give 2-thioxo-4-imidazolidinone 5, which was subsequently
alkylated with alkyl halide to give 6 in presence of K2CO3.
The structures of 6 have been characterized spectroscopically. For
1
example, the H NMR spectrum in 6a shows the singlet of NH at 6.11 ppm
as wide absorption and SCH2 at 3.12–3.15 ppm as a triplet. The absorption
of 5,5-2CH3 appears at 1.43 ppm as a singlet. The mass spectrum of 6a
shows molecule ion peak at m/z ¼ 291 with 100% abundance.
EXPERIMENTAL
Melting points are uncorrected. MS were measured on Finnigan Trace MS
spectrometer. 1H NMR spectra were recorded in CDCl3 on a Varian
Mercury 400 spectrometer, and resonances are given in parts per million
(ppm) (d) relative to TMS. Elemental analyses were performed on a Vario
EL III elementary analysis instrument. Ethyl 2-azido-isobutylate 1 was
Scheme 2.

2-Alkylthio-5,5-dimethyl-4H-imidazol-4-ones
2923
obtained quantitatively by the reaction of ethyl 2-bromo-isobutylate with
sodium azide (1.5 equiv.) in dry CH3CN at 808C for 2 days.
Preparation of Iminophosphorane 2
Triphenylphosphine (2.62 g, 10 mmol) in dry CH3CN (10 mL) was added
dropwise to a solution of azide 1 (1.89 g, 12 mmol) in dry CH3CN (20 mL)
at 608C under an argon atmosphere. After the reaction mixture was stirred
for 2 h at 808C, the solvent was removed under reduced pressure, and the
residue was then recrystallized from petroleum ether to give iminophosphor-
ane 2 (87%). Mp 55–578C. 1H NMR (CDCl3, 400 MHz): d 7.75–7.38
(m, 15H, Ar-H), 3.69 (q, J ¼ 7.2 Hz, 2H, CH2), 1.38 (s, 6H, 2CH3), 1.04
(t, J ¼ 7.2 Hz, 3H, CH3). MS (m/z, %): 392 (Mþ, 76), 375 (99), 258 (90),
179 (92), 105 (100), 91 (29). Anal. calcd. for C24H26NO2P: C, 73.64;
H, 6.69; N, 3.58. Found: C, 73.58; H, 6.60; N, 3.67.
Preparation of Thiosemicarbazide 4
Excess carbon disulfide (5 mL) was added to a solution of iminophosphorane
2 (1.96 g, 5 mmol) in dry methylene chloride (15 mL). After the reaction
mixture was refluxed for 48 h under a dry argon atmosphere, the solvent
was removed under reduced pressure, and ether/petroleum ether (1 : 2,
20 mL) was added to precipitate triphenylphosphine sulfide, which was
removed by filtration. The filtrate was evaporated to give isothiocyanate 3,
which was used directly without further purification. To a solution of the
crude 3 in diethyl ether (15 ml) was added phenylhydrazine (0.54 g,
5 mmol). The mixture was allowed to stir for 0.5 h at room temperature and
1
was filtered to give thiosemicarbazide 4 (78%). Mp 127–1288C. H NMR
(CDCl3, 400 MHz): d 7.64 (s, 1H, NH), 7.36 (s, 1H, NH), 7.31–6.86
(m, 5H, Ar-H), 6.11 (s, 1H, PhNH), 4.14 (q, J ¼ 7.2 Hz, 2H, CH2), 1.69
(s, 6H, CH3), 1.27 (t, J ¼ 7.2 Hz, 3H, CH3).
General Preparation of 2-Alkylthio-4H-imidazol-4-ones 6
A mixture of thiosemicarbazide 4 (0.28 g, 1 mmol), alkyl halide (1.2 mmol),
and solid potassium carbonate (0.28 g, 2 mmol) in CH3CN (15 ml) was stirred
for 3–5 h at room temperature or 40–608C and was filtered. The filtrate was
condensed, and the residue was recrystallized from diethyl ether/petroleum
ether (1 : 3) to give 2-alkylthio-3-phenylamino-4H-imidazol-4-ones 6.
Data
6a. White crystals, mp 118–1198C. 1H NMR (CDCl3, 400 MHz): d 7.28–6.72
(m, 5H, Ar-H), 6.11 (s, 1H, NH), 3.13 (t, J ¼ 7.2 Hz, 2H, SCH2), 1.71–1.43

2924
J.-Z. Yuan, J.-J. Wei, and M.-W. Ding
(m, 10H, 2CH2 and 2CH3), 0.94 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m/z, %): 291
(100, Mþ), 263 (21), 249 (44), 247 (71), 148 (28). Anal. calcd. for
C15H21N3OS: C, 61.82; H, 7.26; N, 14.42. Found: C, 61.87; H, 7.21; N, 14.50.
6b. White crystals, mp 165–1678C. 1H NMR (CDCl3, 400 MHz) d 7.28–6.73
(m, 5H, Ar-H), 6.18 (s, 1H, NH), 2.51 (s, 3H, SCH3), 1.43 (s, 6H, 2CH3). MS
(m/z, %): 249 (57), 221 (34), 206 (89), 176 (100), 148 (65), 91 (57). Anal.
calcd. for C12H15N3OS: C, 57.81; H, 6.06; N, 16.85. Found: C, 57.90;
H, 6.00; N, 16.91.
6c. White crystals, mp 162–1648C. 1H NMR (CDCl3, 400 MHz) d 7.28–6.72
(m, 5H, Ar-H), 6.16 (s, 1H, NH), 3.15 (q, J ¼ 7.2 Hz, 2H, SCH2), 1.44 (s, 6H,
2CH3), 1.40–140 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m/z, %): 263 (54), 235 (24),
220 (81), 192 (24), 176 (100), 91 (83). Anal. calcd. for C13H17N3OS: C, 59.29;
H, 6.51; N, 15.96. Found: C, 59.21; H, 6.54; N, 15.90.
1
6d. White crystals, mp 82–838C. H NMR (CDCl3, 400 MHz) d 7.28–6.72
(m, 5H, Ar-H), 6.08 (s, 1H, NH), 3.12 (t, J ¼ 7.2 Hz, 2H, SCH2), 1.73–
1.28 (m, 14H, 4CH2 and 2CH3), 0.88 (t, J ¼ 7.2 Hz, 3H, CH3). MS
(m/z, %): 319 (13), 275 (37), 175 (100), 147 (79), 91 (50). Anal. calcd. for
C17H25N3OS: C, 63.91; H, 7.89; N, 13.15. Found: C, 63.77; H, 7.95; N, 13.20.
6e. White crystals, mp 147–1488C. 1H NMR (CDCl3, 400 MHz) d 7.39–6.69
(m, 10H, Ar-H), 6.06 (s, 1H, NH), 4.34 (s, 2H, SCH2), 1.44 (s, 6H, 2CH3). MS
(m/z, %): 325 (82), 297 (12), 282 (78), 175 (99), 147 (96), 90 (100). Anal.
calcd. for C18H19N3OS: C, 66.43; H, 5.88; N, 12.91. Found: C, 66.61;
H, 5.81; N, 12.95.
6f. White crystals, mp 124–1268C. 1H NMR (CDCl3, 400 MHz): d 7.28–6.73
(m, 5H, Ar-H), 6.11 (s, 1H, NH), 3.10 (t, J ¼ 7.2 Hz, 2H, SCH2), 1.76–1.73
(m, 2H, CH2), 1.42 (s, 6H, 2CH3), 1.03 (t, J ¼ 7.2 Hz, 3H, CH3). MS (m/z,
%): 277 (50), 248 (14), 234(97), 192(46), 175(99), 147(99), 91(100). Anal.
calcd. for C14H19N3OS: C, 60.62; H, 6.90; N, 15.15. Found: C, 60.43;
H, 6.98; N, 15.01.
6g. White crystals, mp 138–1408C. 1H NMR (CDCl3, 400 MHz) d 7.29–6.76
(m, 5H, Ar-H), 6.15 (s, 1H, NH), 3.94 (s, 2H, SCH2), 3.77 (s, 3H, OCH3), 1.39
(s, 6H, 2CH3). MS (m/z, %): 307 (48), 279(19), 264(80), 204(45), 176(100),
148(76). Anal. calcd. for C14H17N3O3S: C, 54.71; H, 5.57; N, 13.67. Found:
C, 54.82; H, 5.51; N, 13.72.
6h. White crystals, mp 143–1458C. 1H NMR (CDCl3, 400 MHz) d 7.28–6.72
;;
(m, 5H, Ar-H), 6.18 (s, 1H, NH), 3.88 (s, 2H, SCH2), 2.24 (s, 1H2 CH), 1.42
(s, 6H, 2CH3). MS (m/z, %): 273 (67), 245 (47), 230 (97), 175 (100), 148 (98).

2-Alkylthio-5,5-dimethyl-4H-imidazol-4-ones
2925
Anal. calcd. for C14H15N3OS: C, 61.51; H, 5.53; N, 15.37. Found: C, 61.59;
H, 5.58; N, 15.32.
ACKNOWLEDGMENT
We gratefully acknowledge financial support of this work by the Natural
Science Foundation of Hubei Province (Project No. 2006ABB016).
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