Facile synthesis of 2-alkylthio-3-alkyl-5-phenylmethylidene-4H-imidazol-4- ones

Article abstract of DOI:10.1080/00397910500514071

2-Alkylthio-3-alkyl-5-phenylmethylidene-4H-imidazol-4-ones 6 were synthesized by N-alkylation and S-alkylation of 2-thioxo-5-phenylmethylidene-4- imidazolidinone 5, which was obtained via cyclization of vinyl isothiocyanate 4 with excess ammonium hydroxid

Full text of DOI:10.1080/00397910500514071

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Facile Synthesis of
2‐Alkylthio‐3‐alkyl‐5‐phenylmethylidene‐4H‐imid
Li‐Ping Gao a , Ming‐Wu Ding b & Yong Sun a
a Department of Chemistry , Yunyang Teachers College , Danjiangkou, China
b Institute of Organic Synthesis, College of Chemistry , Central China Normal
University , Wuhan, China
Published online: 24 Feb 2007.
To cite this article: Li‐Ping Gao , Ming‐Wu Ding & Yong Sun (2006) Facile Synthesis of
2‐Alkylthio‐3‐alkyl‐5‐phenylmethylidene‐4H‐imidazol‐4‐ones, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 36:9, 1185-1191
To link to this article: http://dx.doi.org/10.1080/00397910500514071
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Synthetic Communicationsw, 36: 1185–1191, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500514071
Facile Synthesis of 2-Alkylthio-3-alkyl-5-
phenylmethylidene-4H-imidazol-4-ones
Yong Sun and Li-Ping Gao
Department of Chemistry, Yunyang Teachers College, Danjiangkou,
China
Ming-Wu Ding
Institute of Organic Synthesis, College of Chemistry, Central China
Normal University, Wuhan, China
Abstract: 2-Alkylthio-3-alkyl-5-phenylmethylidene-4H-imidazol-4-ones
6
were
synthesized by N-alkylation and S-alkylation of 2-thioxo-5-phenylmethylidene-4-imi-
dazolidinone 5, which was obtained via cyclization of vinyl isothiocyanate 4 with
excess ammonium hydroxide (28% NH3 in water).
Keywords: Alkylation, aza-Wittig reaction, 4H-imidazol-4-ones, synthesis
4H-Imidazol-4-ones are important heterocycles with biological and pharma-
ceutical activities,[1–3] and some 2-alkylthioimidazolones show significant
fungicidal activities.[4–6] Until now, many of the new derivatives of imidazo-
lones have been synthesized to evaluate their biological and pharmaceutical
activities.
However, most of the reported 2-alkylthioimidazolones are of the 5,5-
disubstituted type and were generally synthesized from corresponding
a-amino acetic acid[6,7] (Scheme 1). Regretably, 5-arylmethylidene-2-alkylthioi-
midazolones cannot be prepared by this general method because the correspond-
ing starting material needed would be unstable vinyl amino acetic acids.
We are interested in the synthesis of new imidazolone derivatives,
especially 5-arylmethylidene-imidazolones, via tandem aza-Wittig reaction,
Received in Japan August 11, 2005
Address correspondence to Yong Sun, Department of Chemistry, Yunyang
Teachers College, Danjiangkou 442700, China. E-mail: sunyong376111@yahoo.
com.cn
1185

1186
Y. Sun, L.-P. Gao, and M.-W. Ding
Scheme 1.
and some of them have been shown potential fungicidal activities.[8–19] In the
present work we report a new efficient synthesis of some new 2-alkylthio-3-
alkyl-5-phenylmethylidene-4H-imidazol-4-ones derivatives from the stable
vinyliminophosphorane 3.
The vinyliminophosphorane 3 can be easily prepared according to the
following procedure: azide 1 was condensed with benzaldehyde in the
presence of sodium ethoxide to give vinyl azide 2 in 58% yield. A Staudinger
reaction of 2 with Ph3P gave vinyliminophosphorane 3 in 82% yield
(Scheme 2).
The vinyliminophosphorane 3 reacted with carbon disulfide to give vinyl
isothiocyanate 4. The reaction of 4 with excess ammonium hydroxide (28%
NH3 in water) took place smoothly at room temperature to give the yellow
crystals 2-thioxo-5-phenylmethylidene-4-imidazolidinone 5 in 92% yield
(Scheme 3).
S-Alkylation and N-alkylation of 5 with excess alkyl halides in
presence of solid potassium carbonate provided 2-alkylthio-3-alkyl-5-
phenylmethylidene-4H-imidazol-4-ones 6 in satisfactory yields (Scheme 4).
When the active alkylating reagents (RI, BrCH2COR) were used, the alky-
lation could be carried out at room temperature. When other alkylating
reagents were applied, the alkylation should be carried out at 50–708C
(see Table 1).
The formation of 5 can be rationalized in terms of an initial nucleophilic
addition of ammonia to give the intermediate 7, which directly cyclized to
give 5 (Scheme 5).
EXPERIMENTAL
Melting points are uncorrected. MS were measured on a Finnigan Trace MS
spectrometer. IR were recorded on a PE-983 infrared spectrometer as KBr
Scheme 2.

2-Alkylthio-3-alkyl-5-phenylmethylidene-4H-imidazol-4-ones
1187
Scheme 3.
pellets with absorption in centimeters21. NMR were taken on a Varian
Mercury 400 spectrometer, and resonances are given in parts per million
(ppm) (d) relative to TMS. Elementary analyses were taken on a Vario EL
III elementary analysis instrument. CS2 is poisonous, and a good hood
should be used.
Preparation of Vinyliminophosphorane 3
A solution of ethyl azidoacetate 1 (33.5 g, 260 mmol) and benzaldehyde
(13.8 g, 130 mmol) in dry ethanol (30 mL) was added dropwise to a well-stirred
solution containing sodium (6.0 g, 260 mmol) in dry ethanol (160 mL) at
2108C under nitrogen. The reaction mixture was stirred at 08C for 4 h.
After this, it was poured into aqueous 30% ammonium chloride (240 mL),
and the formed solid was separated by filtration, washed with water
(30 mL), and dried to give vinyl azide 2, yield 16.4 g (58%).
A solution of the azide 2 (16.3 g, 75 mmol) in dry CH2Cl2 (40 mL) was
added dropwise to a solution of Ph3P (19.6 g, 75 mmol) in dry CH2Cl2
(60 mL) at room temperature and stirred for 4 h. The solvent was removed
under reduced pressure, and the residual was recrystallized from methylene
dichloride/petroleum ether (1 : 2) to give vinyliminophosphorane 3: yield
27.7 g (82%), mp 148–1508C (lit.[20] 1498C).
Preparation of 2-Thioxo-5-phenylmethylidene-4-imidazolidinone 5
Excess carbon disufide (5 mL) was added to a solution of vinyliminophos-
phorane 3 (2.25 g, 5 mmol) in dry methylene dichloride (15 mL). After
Scheme 4.

1188
Y. Sun, L.-P. Gao, and M.-W. Ding
Table 1. Preparation of 2-alkylthio-3-alkyl-5-phenylmethylidene-4H-
imidazol-4-ones 6 by S-alkylation and N-alkylation of 5
Compounds
RX
Condition
Yield (%)a
6a
6b
6c
6d
6e
6f
MeI
EtBr
rt/2 h
78
72
69
65
45
88
74
79
87
508C/5 h
608C/6 h
608C/7 h
708C/8 h
508C/3 h
508C/3 h
rt/2 h
n-PrBr
n-BuBr
s-BuBr
PhCH2Cl
6g
6h
6i
ClCH2COOEt
BrCH2COOMe
BrCH2COPh
rt/2 h
aIsolated yields based on 5.
the reaction mixture was refluxed for 28 h, the solvent was removed under
reduced pressure, and ether/petroleum ether (1 : 2, 20 mL) was added to pre-
cipitate triphenylphosphine sulfide, which was removed by filtration. The
filtrate was evaporated to give vinyl isothiocyanate 4, which was used
directly without further purification. Excess ammonium hydroxide (28%
NH3 in water) (2 mL, 30 mmol) was added to a solution of crude 4
prepared previously in CH3CN (15 mL). The mixture was allowed to
stand for 2 h at room temperature, and the precipitated solid was
collected, washed with water and ethanol, and recrystallized from ethanol
to give 5.
2-Thioxo-5-phenylmethylidene-4-imidazolidinone 5: yield 92%, yellow
1
crystals, mp 272–2748C, H NMR (DMSO-d6, 400 MHz) d12.40 (s, 1H,
O55CN-H), 12.16 (s, 1H, C55CN-H), 7.76–7.37 (m, 5H, Ph-H), 6.50
(s, 1H, 55CH); IR (cm21), 3320 (O55CN-H), 3241 (C55CN-H), 1722
(C55O), 1651 (C55C); MS (m/z), 204 (Mþ, 100%), 167 (2%), 149 (12%),
144 (2%), 132 (1%), 127 (4%), 117 (95%), 102 (3%), 89 (26%), 62 (16%),
39 (44%). Elemental anal. calcd. for C10H8N2OS: C, 58.82; H, 3.92; N,
13.73. Found: C, 59.10; H, 3.99; N, 14.00.
Scheme 5.

2-Alkylthio-3-alkyl-5-phenylmethylidene-4H-imidazol-4-ones
1189
General Preparation of 2-Alkylthio-3-alkyl-5-phenylmethylidene-
4H-imidazol-4-ones 6
A mixture of 5 (0.82 g, 4 mmol), excess alkyl halide (16 mmol), and solid
potassium carbonate (2.22 g, 16 mmol) in CH3CN (30 mL) was stirred for
2–8 h at room temperature (50–708C) and filtered. The filtrate was
condensed, and the residual was recrystallized from methylene dichloride/
petroleum ether to give 2-alkylthio-3-alkyl-5-phenylmethylidene-4H-
imidazol-4-ones 6.
Data
6a: yellow crystals, mp112–1148C, 1H NMR (CDCl3, 400 MHz) d8.15–7.34
(m, 5H, Ph-H), 6.94 (s, 1H,55CH), 3.14 (s, 3H, NCH3), 2.72 (s, 3H, SCH3); IR
(cm21), 1719 (C55O), 1638 (C55C); MS (m/z), 232 (Mþ, 84%), 217 (3%),
199 (7%), 187 (17%), 171 (2%), 160 (2%), 149 (1%), 142 (19%), 130
(9%), 116 (30%), 102 (6%), 87 (100%), 72 (24%), 62 (18%), 55 (13%), 46
(14%), 41 (24%). Anal. calcd. for C12H12N2OS: C, 62.07; H, 5.17; N,
12.07. Found: C, 61.81; H, 5.44; N, 12.33.
6b: yellow crystals, mp 150–1528C, 1H NMR (CDCl3, 400 MHz) d8.15–7.26
(m, 5H, Ph-H), 6.93 (s, 1H, 55CH), 3.64 (q, 2H, J ¼ 7.6 Hz, NCH2CH3), 3.37
(q, 2H, J ¼ 7.2 Hz, SCH2CH3), 1.52 (t, 3H, J ¼ 7.6 Hz, NCH2CH3), 1.26
(t, 3H, J ¼ 7.2 Hz, SCH2CH3); IR (cm21), 1721 (C55O), 1640 (C55C); MS
(m/z), 260 (Mþ, 2%), 231 (7%), 203 (4%), 189 (1%), 171 (3%), 160 (3%),
144 (5%), 130 (3%), 116 (100%), 102 (15%), 89 (81%), 59 (88%), 44
(28%). Anal. calcd. for C14H16N2OS: C, 64.62; H, 6.15; N, 10.77. Found:
C, 64.88; H, 5.90; N, 11.05.
1
6c: yellow crystals, mp 75–768C, H NMR (CDCl3, 400 MHz) d8.15–7.34
(m, 5H, Ph-H), 6.92 (s, 1H, 55CH), 3.55 (t, 2H, J ¼ 7.6 Hz, NCH2CH2CH3),
3.33 (t, 2H, J ¼ 7.6 Hz, SCH2CH2CH3), 1.87 (m, 2H, NCH2CH2CH3), 1.69
(m, 2H, SCH2CH2CH3), 1.10 (t, 3H, J ¼ 7.2 Hz, NCH2CH2CH3), 0.94 (t, 3H,
J ¼ 7.2 Hz, SCH2CH2CH3); IR (cm21), 1719 (C55O), 1637 (C55C); MS (m/
z), 288 (Mþ, 3%), 259 (8%), 255 (5%), 245 (11%), 231 (6%), 203 (7%), 199
(4%), 186 (5%), 171 (4%), 160 (11%), 144 (14%), 130 (10%), 117 (100%),
102 (28%), 89 (48%), 77 (26%), 43 (38%). Anal. calcd. for C16H20N2OS: C,
66.67; H, 6.94; N, 9.72. Found: C, 66.91; H, 7.17; N, 10.00.
1
6d: yellow crystals, mp 37–398C, H NMR (CDCl3, 400 MHz) d8.16–7.26
(m, 5H, Ph-H), 6.92 (s, 1H, 55CH), 3.59 (t, 2H, J ¼ 7.6 Hz,
NCH2CH2CH2CH3), 3.36 (t, 2H, J ¼ 7.2 Hz, SCH2CH2CH3), 1.86–1.34
(m, 8H, NCH2CH2CH2CH3 and SCH2CH2CH2CH3), 1.03–0.86 (m, 6H,
NCH2CH2CH2CH3 and SCH2CH2CH2CH3); IR (cm21), 1720 (C55O), 1633

1190
Y. Sun, L.-P. Gao, and M.-W. Ding
(C55C); MS (m/z), 316 (Mþ, 25%), 287 (6%), 283 (6%), 269 (33%), 259
(8%), 245 (2%), 227 (100%), 218 (6%), 213 (4%), 203 (12%), 199 (5%),
160 (12%), 144 (10%), 130 (7%), 117 (45%), 104 (32%), 89 (21%), 77
(33%), 57 (47%), 41 (68%). Anal. calcd. for C18H24N2OS: C, 68.35; H,
7.59; N, 8.86. Found: C, 68.55; H, 7.80; N, 9.07.
6e: little yellow crystals, mp 165–1678C, 1H NMR (CDCl3, 400 MHz) d8.15–
7.26 (m, 5H, Ph-H), 6.92 (s, 1H, 55CH), 3.57 [m, 1H, NCH(CH3)CH2CH3],
3.34 [m, 1H, SCH(CH3)CH2CH3], 1.84–1.30 [m, 16H, NCH(CH3)CH2CH3
and SCH(CH3)CH2CH3]; IR (cm21), 1721 (C55O), 1636 (C55C); MS (m/
z), 316 (Mþ, 8%), 287 (2%), 283 (2%), 269 (15%), 260 (6%), 243 (3%),
227 (86%), 217 (8%), 203 (11%), 183 (67%), 171 (7%), 160 (13%), 152
(15%), 144 (12%), 138 (23%), 130 (9%), 116 (60%), 89 (29%), 57 (56%),
41 (100%). Anal. calcd. for C18H24N2OS: C, 68.35; H, 7.59; N, 8.86.
Found: C, 68.09; H, 7.33; N, 9.04.
6f: yellow crystals, mp 142–1448C, 1H NMR (CDCl3, 400 MHz) d8.18–7.25
(m, 15H, Ph-H), 7.02 (s, 1H, 55CH), 4.77 (s, 2H, NCH2Ph), 4.57 (s, 2H,
SCH2Ph); IR (cm21), 1715 (C55O), 1636 (C55C); MS (m/z), 384 (Mþ,
1%), 293 (2%), 203 (15%), 160 (14%), 144 (10%), 130 (6%), 121 (3%),
116 (20%), 91 (100%), 89 (54%), 65 (18%). Anal. calcd. for C24H20N2OS:
C, 75.00; H, 5.21; N, 7.29. Found: C, 75.13; H, 4.99; N, 7.50.
6g: little yellow crystals, mp 108–1098C, 1H NMR (CDCl3, 400 MHz)
d8.13–7.27 (m, 5H, Ph-H), 7.01 (s, 1H, 55CH), 4.38 (s, 2H, NCH2), 4.28–
4.22 (m, 4H, NCH2COOCH2CH3 and SCH2COOCH2CH3), 4.13 (s, 2H,
SCH2), 1.32–1.28 (m, 6H, NCH2COOCH2CH3 and SCH2COOCH2CH3);
IR (cm21), 1739 (COOEt), 1736 (COOEt), 1720 (C55O), 1639 (C55C);
MS (m/z), 376 (Mþ, 94%), 331 (24%), 302 (83%), 299 (3%), 289 (15%),
286 (2%), 273 (10%), 257 (12%), 245 (66%), 229 (49%), 215 (43%),
201 (16%), 188 (6%), 174 (8%), 160 (16%), 144 (16%), 130 (83%),
128 (8%), 116 (100%), 102 (35%), 89 (39%), 72 (70%). Anal. calcd.
for C18H20N2O5S: C, 57.45; H, 5.32; N, 7.45. Found: C, 57.70; H, 5.18; N, 7.69.
6h: little yellow crystals, mp 127–1288C, 1H NMR (CDCl3, 400MHz) d8.14–
7.26 (m, 5H, Ph-H), 7.02 (s, 1H, 55CH), 4.40 (s, 2H, NCH2), 4.30 (s, 3H,
NCH2COOCH3), 4.24 (s, 3H, SCH2COOCH3), 4.15 (s, 2H, SCH2); IR (cm21),
1740 (COOMe), 1738 (COOMe), 1717 (C55O), 1637 (C55C); MS (m/z), 348
(Mþ, 88%), 317 (29%), 289 (78%), 275 (21%), 246 (7%), 243 (17%), 231
(54%), 230 (33%), 216 (49%), 202 (11%), 174 (5%), 160 (21%), 144 (10%),
131 (57%), 116 (100%), 102 (8%), 89 (45%), 59 (21%). Anal. calcd. for
C16H16N2O5S: C, 55.17; H, 4.60; N, 8.05. Found: C, 54.91; H, 4.85; N, 8.33.
6i: yellow crystals, mp 169–1718C, 1H NMR (CDCl3, 400 MHz) d8.16–7.27
(m, 15H, Ph-H), 7.03 (s, 1H, 55CH), 4.69 (s, 2H, NCH2), 4.35 (s, 2H, SCH2);

2-Alkylthio-3-alkyl-5-phenylmethylidene-4H-imidazol-4-ones
1191
IR (cm21), 1721 (C55O), 1700 (COPh), 1695 (COPh), 1640 (C55C); MS
(m/z), 440 (Mþ, 10%), 335 (16%), 321 (24%), 230 (46%), 216 (57%), 202
(9%), 160 (17%), 144 (15%), 130 (23%), 119 (11%), 116 (46%), 105
(69%), 89 (100%). Anal. calcd. for C26H20N2O3S: C, 70.91; H, 4.54; N,
6.36. Found: C, 71.13; H, 4.71; N, 6.61.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the Natural
Science Foundation of Hubei Education Commission of China (Project No.
D200560003) and the Natural Science Foundation of China (Project No.
20102001).
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