An efficient synthesis of double 2-alkylthio-5-phenylmethylidene-4H- imidazol-4-ones

Article abstract of DOI:10.1081/SCC-200046481

Double 2-alkylthio-5-phenylmethylidene-4H-imidazol-4-ones 6 were synthesized by S-alkylation of double 2-thioxo-5-phenylmethylidene-4- imidazolidinone 5, which was obtained via cyclization of vinyl isothiocyanate 4 with ethylenediamine.

Full text of DOI:10.1081/SCC-200046481

This article was downloaded by: [Brown University]
On: 16 June 2013, At: 03:03
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
An Efficient
Synthesis of Double
2
‐Alkylthio‐5‐phenylmethylidene‐4
a b
Yong Sun & Ming‐Wu Ding
a
Department of Chemistry, Yunyang Teachers
College, Danjiangkou, 442700, P.R. China
b
Institute of Organic Synthesis, College of
Chemistry, Central China Normal University, Wuhan,
P.R. China
Published online: 05 Aug 2006.
To cite this article: Yong Sun & Ming‐Wu Ding (2005): An Efficient Synthesis of Double
2
‐Alkylthio‐5‐phenylmethylidene‐4H‐imidazol‐4‐ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:1,
1-47
4
To link to this article: http://dx.doi.org/10.1081/SCC-200046481
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.

The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

w
Synthetic Communications , 35: 41–47, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200046481
An Efficient Synthesis of Double
-Alkylthio-5-phenylmethylidene-4H-
imidazol-4-ones
2
Yong Sun
Department of Chemistry, Yunyang Teachers College, Danjiangkou,
P.R. China
Ming-Wu Ding
Institute of Organic Synthesis, College of Chemistry, Central China
Normal University, Wuhan, P.R. China
Abstract: Double 2-alkylthio-5-phenylmethylidene-4H-imidazol-4-ones 6 were syn-
thesized by S-alkylation of double 2-thioxo-5-phenylmethylidene-4-imidazolidinone
5, which was obtained via cyclization of vinyl isothiocyanate 4 with ethylenediamine.
Keywords: 4H-Imidazol-4-ones, aza-Wittig reaction, alkylation, synthesis
4H-Imidazol-4-ones are important heterocycles having bactericidal, antiin-
flammatory, and angiotensin II antagonistical activities.
[1–4]
Some of them
appear in a variety of biologically active molecules in which a common
[5–7]
structural unit is a derivatized 2-alkylthio-4H-imidazol-4-one moiety.
However, most of the 2-alkylthioimidazolones reported are of the 5,5-disub-
stituted type and were generally synthesized from corresponding a-amino
[7,8]
acetic acid (Scheme 1). Regrettably, 5-arylmethylidene-2-alkylthioimida-
zolones cannot be prepared by this general method for the corresponding
Received in Japan February 23, 2004
Address correspondence to Yong Sun, Department of Chemistry, Yunyang
Teachers College, Danjiangkou 442700, P.R. China. E-mail: sunyong6111@sina.com

42
Y. Sun and M.-W. Ding
Scheme 1.
starting material needed would be unstable vinyl amino acetic acids. Recently,
we are interested in the synthesis of biologically active imidazolones via
[
9–13,15,16]
tandem aza-Wittig reaction.
Here we wish to report a new
efficient synthesis of some new double 5-arylmethylidene-2-alkylthioimidazo-
lone 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 presence
of sodium ethoxide to give vinyl azide 2 in 58% yield. Staudinger reaction
of 2 with Ph P gave vinyliminophosphorane 3 in 82% yield.
3
The vinyliminophosphorane 3 reacted with carbon disulfide to give vinyl
isothiocyanate 4. The reaction of 4 with ethylenediamine took place smoothly
at room temperature to give the yellow crystal double 2-thioxo-5-phenyl-
methylidene-4-imidazolidinone 5 in 87% yield (Scheme 2).
S-Alkylation of 5 with alkyl halides in presence of solid potassium
carbonate provided double 2-alkylthio-5-phenylmethylidene-4H-imidazol-4-
ones 6 in satisfactory yields (Scheme 3). When the active alkylating
reagents (RI, BrCH COR) were used, the alkylation could be carried out
2
at room temperature. When other alkylating reagents were applied, the
alkylation should be carried out at 50 ꢀ 608C (see Table 1).
The formation of 5 can be rationalized in terms of an initial nucleophilic
addition of ethylenediamine to give the intermediate 7, which directly
cyclized to give 5 (Scheme 4).
Scheme 2.

Synthesis of Double 2-Alkylthio-5-phenylmethylidene-4H-imidazol-4-ones
43
Scheme 3.
EXEPERIMENTAL
Melting points were uncorrected. MS were measured on a HP5988A spec-
trometer. IR were recorded on a PE-983 infrared spectrometer as KBr
pellets. NMR were taken on a Varian XL-200 spectrometer and resonances
are given relative to TMS. Elementary analysis were taken on a Perkin-
Elmer 2400 CHN Elementary Analysis Instrument. CS is poisonous and a
2
good hood should be used.
Preparation of Vinyliminophosphorane 3
To a well-stirred solution containing sodium (6.0 g, 260 mmol) in dry ethanol
(
160 mL), a solution of ethyl azidoacetate 1 (33.5 g, 260 mmol) and benzal-
dehyde (13.8 g, 130 mmol) in dry ethanol (30 mL) was added dropwise at
108C under nitrogen. The reaction mixture was stirred at 08C for 4 h.
2
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%).
Table 1. Preparation of double 2-alkylthio-4H-imidazol-4-ones 6
by alkylation of 5
a
Compounds
RX
Condition
Yield (%)
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
MeI
EtBr
r.t./3 h
71
62
68
73
61
63
82
76
67
58
508C/5 h
608C/6 h
608C/7 h
608C/10 h
608C/8 h
508C/3 h
508C/2 h
r.t./2 h
n-PrBr
n-BuBr
s-BuBr
n-C H Br
5
11
g
h
i
PhCH
2
Cl
COOEt
BrCH COOMe
ClCH
2
2
j
BrCH
2
COPh
r.t./2 h
a
Isolated yields based on 5.

44
Y. Sun and M.-W. Ding
Scheme 4.
To a solution of Ph P (19.6 g, 75 mmol) in dry CH Cl (60 mL), a solution
3
2
2
of the azide 2 (16.3 g, 75 mmol) in dry CH Cl (40 mL) was added dropwise at
2
2
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%),
[
14]
m.p. 148–1508C (lit., 1498C).
Preparation of Double 2-Thioxo-5-phenylmethylidene-4-
imidazolidinone 5
To a solution of vinyliminophosphorane 3 (2.25 g, 5 mmol) in dry methylene
dichloride (15 mL) was added excess carbon disufide (5 mL). After 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. To a solution of crude 4 prepared pre-
viously in CH CN (15 mL) was added ethylenediamine (0.17 mL,
3
2.5 mmol). The mixture was allowed to stand for 2 h at room temperature
and the precipitated solid was collected and washed with water and ethanol,
recrystallized from methylene dichloride/petroleum ether to give 5.
Double 2-Thioxo-5-phenylmethylidene-4-imidazolidinone 5: yield 87%,
1
yellow crystals, m.p. 277 ꢀ 2788C,
H NMR(DMSO-d6, 200MHz)
d 9.06(s, 2H, N-H), 7.79 ꢀ 7.40(m, 10H, Ph-H), 6.55(s, 2H, 55 CH),
2
1
4
.14(s, 4H, CH CH ); IR(cm ), 3255(N-H), 1718(C 55 O), 1646(C 55 C);
2 2
þ
MS(m/z), 434(M , 88%), 401(2%), 230(49%), 204(32%), 188(12%),
60(39%), 144(7%), 117(100%), 102(13%), 89(43%). Elemental Anal.
Calcd. For C H N O S : C, 60.83; H, 4.15; N, 12.90. Found: C, 61.09; H,
1
2
2 18 4 2 2
3
.98; N, 13.14.

Synthesis of Double 2-Alkylthio-5-phenylmethylidene-4H-imidazol-4-ones
45
General Preparation of Double 2-Alkylthio-5-phenylmethylidene-
4
H-imidazol-4-ones 6
A mixture of 5 (1.74 g, 4 mmol), alkyl halide (10 mmol) and solid potassium
carbonate (2.22 g, 16 mmol) in CH CN (30 mL) was stirred for 2 ꢀ 10 h at
3
room temperature or 50 ꢀ 608C and filtered, the filtrate was condensed and
the residual was recrystallized from methylene dichloride/petroleum ether
to give double 2-alkylthio-5-phenylmethylidene-4H-imidazol-4-ones 6.
1
6
a. yellow crystals, m.p. 266 ꢀ 2688C, H NMR(CDCl , 200 MHz) d
3
8
2
4
2
.15 ꢀ 7.26(m, 10H, Ph-H), 6.96(s, 2H, 55 CH), 3.89(s, 4H, NCH CH N),
2
2
21
.65(s, 6H, SCH ); IR(cm ), 1716(C 55 O), 1635(C 55 C); MS(m/z),
3
þ
62(M , 84%), 447(3%), 415(6%), 244(56%), 229(28%), 218(15%),
01(7%), 174(7%), 144(12%), 130(29%), 116(100%), 102(12%), 89(42%);
Anal. Calcd. for C H N O S : C, 62.34; H, 4.76; N, 12.12. Found: C,
2
4 22 4 2 2
6
2.38; H, 5.02; N, 12.39.
b. yellow crystals, m.p. 194 ꢀ 1968C, H NMR(CDCl , 200 MHz) d
1
6
3
8
3
1
4
1
.14 ꢀ 7.26(m, 10H, Ph-H), 6.96(s, 2H, 55 CH), 3.86(s, 4H, NCH CH N),
2
2
21
.23(q, 4H, SCH , J ¼ 7.3Hz), 1.34(t, 6H, CH , J ¼ 7.3Hz); IR(cm ),
2
3
þ
717(C 55 O), 1633(C 55 C); MS(m/z), 490(M , 57%), 462(9%), 434(4%),
29(6%), 401(6%), 258(59%), 243(18%), 230(50%), 204(22%), 188(19%),
60(52%), 144(38%), 130(68%), 116(100%), 102(29%), 89(80%); Anal.
Calcd. for C H N O S : C, 63.67; H, 5.31; N, 11.43. Found: C, 63.89; H,
2
6 26 4 2 2
5
.39; N, 11.68.
c. yellow crystals, m.p. 154 ꢀ 1558C, H NMR(CDCl , 200 MHz) d
1
6
3
8
3
1
4
1
.14 ꢀ 7.26(m, 10H, Ph-H), 6.95(s, 2H, 55 CH), 3.87(s, 4H, NCH CH N),
2
2
2
1
.20(t, 4H, SCH ), 1.71(m, 4H, SCH CH ), 0.91(t, 6H, CH ); IR(cm ),
2 2 2 3
þ
717(C 55 O), 1633(C 55 C); MS(m/z), 518(M , 84%), 476(20%), 443(19%),
34(49%), 429(8%), 401(8%), 272(11%), 247(8%), 230(52%), 204(14%),
60(28%), 144(9%), 130(11%), 116(64%), 102(12%), 89(27%), 43(100%);
Anal. Calcd. for C H N O S : C, 64.86; H, 5.79; N, 10.81. Found: C,
8 30 4 2 2
2
6
5.11; H, 6.04; N, 11.09.
d. yellow crystals, m.p. 130 ꢀ 1328C, H NMR(CDCl , 200 MHz) d
1
6
3
8
3
0
7
4
4
.15 ꢀ 7.26(m, 10H, Ph-H), 6.95(s, 2H, 55 CH), 3.86(s, 4H, NCH CH N),
2
2
.20(t, 4H, SCH ), 1.64(m, 4H, SCH CH ), 1.31(m, 4H, CH CH ),
2 2 2 2 3
2
1
þ
.77(t, 6H, CH ); IR(cm ), 1720(C 55 O), 1634(C 55 C); MS(m/z), 546(M ,
3
5%), 513(5%), 499(34%), 490(22%), 457(54%), 443(36%), 434(38%),
15(11%), 397(23%), 230(59%), 204(20%), 160(51%), 116(90%), 89(31%),
1(100%); Anal. Calcd. for C H N O S : C, 65.93; H, 6.23; N, 10.26.
3
0 34 4 2 2
Found: C, 65.72; H, 6.04; N, 10.55.
6
1
e. yellow crystals, m.p. 171 ꢀ 1728C, H NMR(CDCl , 200 MHz) d
3
8
3
0
5
.13 ꢀ 7.26(m, 10H, Ph-H), 6.94(s, 2H, 55 CH), 3.96(m, 2H, SCH)
.84(s, 4H, NCH CH N), 1.68(m, 4H, SCHCH ), 1.35(d, 6H, SCHCH ),
2
2
2
3
2
1
.90(t, 6H, CH CH ); IR(cm ), 1716(C 55 O), 1634(C 55 C); MS(m/z),
2
3
þ
46(M , 69%), 490(33%), 457(33%), 434(80%), 429(18%), 425(10%),

46
Y. Sun and M.-W. Ding
4
1
01(13%), 370(14%), 286(10%), 261(14%), 230(93%), 204(70%), 160(91%),
44(41%), 116(100%), 89(36%), 41(85%); Anal. Calcd. for C H N O S :
3
0 34 4 2 2
C, 65.93; H, 6.23; N, 10.26. Found: C, 66.17; H, 5.98; N, 10.49.
1
6
f. yellow crystals, m.p. 151 ꢀ 1538C, H NMR(CDCl , 200 MHz) d
3
8
.15 ꢀ 7.26(m, 10H, Ph-H), 6.95(s, 2H, 55 CH), 3.86(s, 4H, NCH CH N),
2 2
3
CH CH CH ), 0.78(t, 6H, CH ); IR(cm ), 1715(C 55 O), 1635(C 55 C);
.19(t, 4H, SCH ), 1.66(m, 4H, SCH CH ), 1.30 ꢀ 1.18(m, 8H,
2 2 2
2
1
2
2
3
3
þ
MS(m/z), 574(M , 30%), 541(2%), 527(11%), 503(17%), 471(27%),
4
1
57(11%), 444(7%), 434(20%), 411(10%), 369(13%), 231(29%), 204(11%),
60(21%), 116(37%), 89(14%), 43(100%); Anal. Calcd. for C H N O S :
3
2 38 4 2 2
C, 66.90; H, 6.62; N, 9.76. Found: C, 67.14; H, 6.89; N, 10.01.
1
6
g. yellow crystals, m.p. 198 ꢀ 2008C, H NMR(CDCl , 200 MHz) d
3
8
.20 ꢀ 6.94(m, 22H, Ph-H and 55 CH), 4.35(s, 4H, SCH Ph), 3.83(s, 4H,
þ
2 2
2
2
1
NCH CH N); IR(cm ), 1716(C 55 O), 1634(C 55 C); MS(m/z), 614(M ,
1
1
4
%), 523(1%), 231(1%), 206(2%), 204(1%), 178(3%), 160(3%), 116(12%),
02(3%), 91(100%), 89(10%); Anal. Calcd. for C H N O S : C, 70.36; H,
.89; N, 9.12. Found: C, 70.63; H, 5.18; N, 9.40.
3
6 30 4 2 2
1
6
h. yellow crystals, m.p. 206 ꢀ 2088C, H NMR(CDCl , 200 MHz) d
2
3
8
.10 ꢀ 7.26(m, 10H, Ph-H), 6.97(s, 2H, 55 CH), 4.16(q, 4H, OCH ,
J ¼ 7.3 Hz), 4.02(s, 4H, SCH ), 3.91(s, 4H, NCH CH N), 1.22(t, 6H, CH ,
2 2 2 3
2
1
J ¼ 7.3 Hz); IR(cm ), 1737(COOEt), 1718(C 55 O), 1636(C 55 C); MS(m/z),
þ
6
06(M , 50%), 561(5%), 533(3%), 520(18%), 487(4%), 401(3%), 229(6%),
03(5%), 160(11%), 144(12%), 130(16%), 116(100%), 102(14%), 89(40%);
2
Anal. Calcd. for C H N O S : C, 59.41; H, 4.95; N, 9.24. Found: C,
3
0 30 4 6 2
5
9.45; H, 5.07; N, 8.99.
i. yellow crystals, m.p. 228 ꢀ 2308C, H NMR(CDCl , 200 MHz) d
1
6
3
8
4
1
5
1
.11 ꢀ 7.27(m, 10H, Ph-H), 6.96(s, 2H, 55 CH), 4.15(s, 6H, OCH ),
3
2
.00(s, 4H, SCH ), 3.90(s, 4H, NCH CH N); IR(cm ), 1736(COOMe),
1
2 2 2
þ
719(C 55 O), 1636(C 55 C); MS(m/z), 578(M , 69%), 547(6%), 519(4%),
06(23%), 373(7%), 230(9%), 204(6%), 160(17%), 144(15%), 130(21%),
16(100%), 102(12%), 89(44%); Anal. Calcd. for C H N O S : C, 58.13;
2
8 26 4 6 2
H, 4.50; N, 9.69. Found: C, 57.96; H, 4.77; N, 9.91.
1
6
j. yellow crystals, m.p. 264 ꢀ 2668C, H NMR(CDCl , 200 MHz) d
3
8
.17 ꢀ 7.28(m, 20H, Ph-H), 6.95(s, 2H, 55 CH), 4.32(s, 4H, SCH ),
2
2
1
3
MS(m/z), 670(M , 3%), 565(6%), 551(4%), 230(7%), 204(11%), 160(16%),
.87(s, 4H, NCH CH N); IR(cm ), 1719(C 55 O), 1698(COPh), 1637(C 55 C);
2 2
þ
144(12%), 130(13%), 116(19%), 91(100%). Anal. Calcd. for C H N O S :
38 30 4 4 2
C, 68.06; H, 4.48; N, 8.36. Found: C, 67.97; H, 4.71; N, 8.60.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the Natural
Science Foundation of China (Project No. 20102001) and the Natural

Synthesis of Double 2-Alkylthio-5-phenylmethylidene-4H-imidazol-4-ones
47
Science Foundation of Hubei Education Commission of China (Project No.
003A002).
2
REFERENCES
1
2
. Kumar, A.; Verma, M.; Saxena, A. K.; Shanker, K. Indian J. Chem., Sect B 1988,
7B, 301.
. Bhalla, M.; Naithani, P. K.; Bhalla, T. N.; Saxena, A. K.; Shanker, K. J. Indian
Chem. Soc. 1992, 69, 594.
2
3
4
. Trivedi, B.; Shah, V. H. J. Indian Chem. Soc. 1993, 70, 645.
. Kikuchi, K.; Watanable, T.; Okazaki, T.; Yanagisawa, I.; Inagaki, O JP06279437,
1
994.
. Bascou, J. P.; Gadras, A.; Perez, J.; Emeric, G.; Lacroix, G.; Veyrat, C EP668270,
995.
5
1
6
7
. Emeric, G.; Hutt, J.; Perez, J WO9602538, 1996.
. Lacroix, G.; Peignier, R.; Pepin, R.; Bascou, J. P.; Perez, J.; Schmitz, C
US6002016, 1999.
8
9
. Bascou, J. P.; Lacroix, G.; Gadras, A.; Perez, J EP629616, 1994.
. Ding, M. W.; Xu, Z. F.; Wu, T. J. Synth. Commun. 1999, 29, 1171.
1
1
0. Ding, M. W.; Xu, Z. F.; Liu, Z. J.; Wu, T. J. Synth. Commun. 2001, 31, 1053.
1. Ding, M. W.; Zeng, G. P.; Liu, Z. J. Phosphorus Sulfur and Silicon 2002b, 177,
1
315.
2. Ding, M. W.; Yang, S. J.; Sun, Y.; Liu, Z. J.; Liu, X. P. Heterocycl. Commun.
002a, 8, 493.
1
2
13. Ding, M. W.; Sun, Y.; Liu, Z. J. Synth. Commun. 2003a, 33, 1267.
14. Molina, P.; Pastor, A.; Vilaplana, M. J. Tetrahedron 1993, 49, 7769.
15. Ding, M. W.; Sun, Y.; Yang, S. J.; Liu, X. P.; Liu, Z. J. Synth. Commun. 2003c, 33,
1651.
1
6. Ding, M. W.; Sun, Y.; Liu, X. P.; Liu, Z. J. Chinese J. Chem. 2003b, 21, 577.