An efficient synthesis of 2-Alkylthio-5-phenylmethylidene-4H-imidazolin-4-ones

Article abstract of DOI:10.1081/SCC-120018686

2-Alkylthio-5-phenylmethylidene-4H-imidazolin-4-ones 5 were synthesized by S-alkylation of thioimidazolinones 4, which were obtained via cyclization of carbodiimides 2 with Na₂S/HOAc. The direct reaction of carbodiimides 2 with butylthiol could not give 2-butylthio-4H-imidazolin-4-ones 3.

Full text of DOI:10.1081/SCC-120018686

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Efficient Synthesis of 2-Alkylthio- 5-
phenylmethylidene-4 H -imidazolin-4-ones
Ming-Wu Ding , Yong Sun & Zhao-Jie Liu
To cite this article: Ming-Wu Ding , Yong Sun & Zhao-Jie Liu (2003) An Efficient Synthesis of
2-Alkylthio- 5-phenylmethylidene-4 H -imidazolin-4-ones, Synthetic Communications, 33:8,
1267-1274, DOI: 10.1081/SCC-120018686
To link to this article: http://dx.doi.org/10.1081/SCC-120018686
Published online: 15 Aug 2006.
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 8, pp. 1267–1274, 2003
An Efficient Synthesis of 2-Alkylthio-
5-phenylmethylidene-4H-imidazolin-4-ones
*
Ming-Wu Ding, Yong Sun, and Zhao-Jie Liu
Institute of Organic Synthesis, Central China Normal
University, Wuhan, P.R. China
ABSTRACT
2-Alkylthio-5-phenylmethylidene-4H-imidazolin-4-ones 5 were syn-
thesized by S-alkylation of thioimidazolinones 4, which were
obtained via cyclization of carbodiimides 2 with Na2S/HOAc.
The direct reaction of carbodiimides 2 with butylthiol could not give
2-butylthio-4H-imidazolin-4-ones 3.
Key Words: 4H-Imidazolin-4-ones; Aza-Wittig reaction; Alkylation;
Synthesis.
*Correspondence: Ming-Wu Ding, Institute of Organic Synthesis, Central China
Normal University, Wuhan, 430079, P.R. China; E-mail: ding5229@yahoo.com.cn.
1267
DOI: 10.1081/SCC-120018686
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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Ding, Sun, and Liu
4H-Imidazolin-4-ones are important heterocycles having biological
and pharmaceutical activities, especial some 2-alkylthioimidazolinones.[1–3]
Since a new mitochondrial respiratory inhibitor RPA407213 was found
to show high fungicidal activities, many other 2-alkylthioimidazolinones
were synthesized to evaluate their fungicidal activities.[4–6]
Most of the 2-alkylthioimidazolinones reported are 5,5-disubstituted
types. They were generally synthesized from corresponding amino acetic
acid[6,7] (Sch. 1). However, 5-arylidene-2-alkylthioimidazolinones cannot
be prepared by this general method for the corresponding starting
material needed are unstable vinyl amino acetic acid. Recently, we are
interested in the synthesis of biologically active imidazolinones via
tandem aza-Wittig reaction.[8–10] Here we wish to report a new efficient
synthesis of 5-arylidene-2-alkylthio-imidazolinones from the stable
vinyliminophosphorane 1.
The easily accessible vinyliminophosphorane 1 reacted with aromatic
isocyanates to give carbodiimides 2, which reacted with Na2S/HOAc to
give directly 4 in 70–79% yields. S-Alkylation of 4 with alkyl halides in
presence of solid potassium carbonate provided 2-alkylthio-5-phenyl-
methylidene-4H-imidazolin-4-ones 5 in satisfactory yields. When the
active alkylating reagents (RI, BrCH2COR) were used, the alkylation
could be carried out at room temperature. When other alkylating reagents
were applied, the alkylation should be carried out at 50–60ꢀC (see Table 1).
Attempts to prepare 2-butylthio-4H-imidazolin-4-ones 3 by direct reaction
of carbodiimide 2 with butylthiol in presence or absence of solid potassium
carbonate or sodium hydroxide were unsuccessful (Sch. 2).
Scheme 1.

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2-Alkylthio-5-phenylmethylidene-4H-imidazolin-4-ones
1269
Table 1. Preparation of 2-alkylthio-4H-imidazolin-4-ones 5 by alkylation of 4.
Compounds
Ar
Ph
R
Condition
Yield (%)a
5a
5b
5c
5d
5e
5f
n-BuBr
n-PrBr
i-PrBr
60ꢀC/4 h
50ꢀC/6 h
50ꢀC/10 h
50ꢀC/8 h
r.t./3 h
79
73
68
70
77
68
88
83
83
70
70
81
63
78
72
59
Ph
Ph
Ph
Ph
n-C6H13Br
MeI
EtI
Ph
Ph
r.t./2 h
5g
5h
5i
PhCH2Cl
ClCH2CN
50ꢀC/3 h
50ꢀC/2 h
50ꢀC/2 h
50ꢀC/3 h
r.t./2 h
Ph
Ph
ClCH2COOEt
ClCH2CONH2
BrCH2COOMe
BrCH(Me)COOEt
BrCH2COPh
MeI
5j
Ph
Ph
5k
5l
Ph
Ph
50ꢀC/2 h
r.t./2 h
r.t./5 h
50ꢀC/2 h
50ꢀC/2 h
5m
5n
5o
5p
3-Cl-Ph
3-Cl-Ph
3-Cl-Ph
ClCH2COOEt
BrCH(Me)COOEt
aIsolated yields based on 4.
Scheme 2.

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Ding, Sun, and Liu
Scheme 3.
The formation of 4 can be rationalized in terms of an initial
nucleophilic addition of Na2S/HOAc to give the intermediate 6 which
directly cyclized to give 4 in presence of excess basic Na2S (Sch. 3).
EXEPERIMENTAL
Melting points were uncorrected. MS were measured on a HP5988A
spectrometer. IR were recorded on a PE-983 infrared spectrometer.
NMR were taken on a Varian XL-200 spectrometer. Elementary analysis
were taken on a CHN 2400 elementary analysis instrument.
Preparation of Intermediate 4
To a solution of vinyliminophosphorane 1 (5 mmol) in dry methylene
dichloride (15 mL) was addedaromatic isocyanate (5 mmol) undernitrogen
at room temperature. After the reaction mixture was stand for 4–6 h, the
solvent was removed off under reduced pressure and ether/petroleum
ether (1:2, 20 mL) was added to precipitate triphenylphosphine oxide.
Filtered, the solvent was removed to give carbodiimide 2, which was
used directly without further purification. To the solution of 2 prepared
above in CH3CN (15 mL) was added Na2S/9H2O (4.8 g, 20 mmol) and
HOAc (0.57 mL, 10 mmol). The mixture was stirred for 2–3 h at room
temperature and filtered, the filtrate was condensed and the residual
was recrystallized from methylene dichloride/petroleum ether to give
intermediate 4.
4a (Ar¼Ph). Yield 79%, yellow crystals, m.p. 207–208ꢀC, H NMR
1
(CDCl3, 200 MHz) ꢀ 8.99 (s, 1H, N-H), 7.49–7.22 (m, 10H, Ar-H), 6.80
(s, 1H, ¼CH); IR (cmÀ1), 3217 (N-H), 1744 (C¼O), 1645 (C¼C); MS
(m/z), 280 (Mþ, 5%), 136 (17%), 117 (100%).
4b (Ar¼3-Cl-Ph). yield 70%, yellow crystals, m.p. 244–245ꢀC,
1H NMR (CDCl3, 200 MHz) ꢀ 8.84 (s, 1H, N-H), 7.60–7.22 (m, 9H,

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2-Alkylthio-5-phenylmethylidene-4H-imidazolin-4-ones
1271
Ar-H), 6.81 (s, 1H, ¼CH); IR (cmÀ1), 3223 (N-H), 1745 (C¼O), 1642
(C¼C); MS (m/z), 314 (Mþ, 3%), 224 (5%), 168 (12%), 117 (53%),
77 (99%), 45 (100%).
General Preparation of 2-Alkylthio-4H-imidazolin-4-Ones 5
A mixture of 4 (4 mmol), alkyl halide (5 mmol) and solid potassium
carbonate (1.11 g, 8 mmol) in CH3CN (30 mL) was stirred for 2–10 h
at room temperature or 50–60ꢀC and filtered, the filtrate was condensed
and the residual was recrystallized from methylene dichloride/petroleum
ether to give 2-alkylthio-4H-imidazolin-4-ones 5.
5a. Yellow crystals, m.p. 121–122ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.17–7.22 (m, 10H, Ar-H), 6.99 (s, 1H, ¼CH), 3.31 (t, 2H, SCH2,
J ¼ 7.3 Hz), 1.86–1.44 (m, 4H, CH2CH2), 0.99 (t, 3H, CH3, J ¼ 7.3 Hz);
IR (cmÀ1), 1728 (C¼O), 1635 (C¼C); MS (m/z), 337 (Mþ þ 1, 2%), 280
(10%), 136 (37%), 117 (100%); Anal. calcd. for C20H20N2OS: C, 71.40;
H, 5.99; N, 8.33. Found: C, 71.36; H, 5.73; N, 8.48.
5b. Yellow crystals, m.p. 125–126ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.16–7.21 (m, 10H, Ar-H), 6.99 (s, 1H, ¼CH), 3.29 (t, 2H, SCH2,
J ¼ 7.3 Hz), 1.92–1.81 (m, 2H, CH2), 1.08 (t, 3H, CH3, J ¼ 7.3 Hz);
IR (cmÀ1), 1723 (C¼O), 1635 (C¼C); MS (m/z), 323 (Mþ þ 1, 3%),
280 (10%), 136 (51%), 117 (100%); Anal. calcd. for C19H18N2OS:
C, 70.78; H, 5.63; N, 8.69. Found: C, 70.84; H, 5.72; N, 8.57.
5c. Yellow crystals, m.p. 146–147ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.15–7.20 (m, 10H, Ar-H), 6.99 (s, 1H, ¼CH), 4.21–4.14 (m, 1H,
SCH), 1.50 (d, 6H, 2CH3, J ¼ 6.8 Hz); IR (cmÀ1), 1721 (C¼O), 1632
(C¼C); MS (m/z), 323 (Mþ þ 1, 9%), 280 (19%), 204 (22%), 136
(43%), 117 (100%); Anal. calcd. for C19H18N2OS: C, 70.78; H, 5.63;
N, 8.69. Found: C, 70.60; H, 5.85; N, 8.74.
5d. Yellow crystals, m.p. 71–72ꢀC, 1H NMR (CDCl3, 200 MHz)
ꢀ 8.16–7.21 (m, 10H, Ar-H), 6.99 (s, 1H, ¼CH), 3.30 (t, 2H, SCH2,
J ¼ 7.3 Hz), 1.91–0.87 (m, 11H, (CH2)4CH3); IR (cmÀ1), 1718 (C¼O),
1636 (C¼C); MS (m/z), 365 (Mþ þ 1, 2%), 318 (4%), 281 (18%), 136
(18%), 117 (66%), 32 (100%); Anal. calcd. for C22H24N2OS: C, 72.49;
H, 6.64; N, 7.69. Found: C, 72.45; H, 6.77; N, 7.62.
5e. Yellow crystals, m.p. 153–155ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.16–7.27 (m, 10H, Ar-H), 7.00 (s, 1H, ¼CH), 2.67 (s, 3H, SCH3);
IR (cmÀ1), 1720 (C¼O), 1633 (C¼C); MS (m/z), 295 (Mþ þ 1, 20%),
248 (6%), 150 (72%), 135 (54%), 116 (34%), 77 (100%); Anal.
calcd. for C17H14N2OS: C, 69.36; H, 4.79; N, 9.52. Found: C, 69.15;
H, 4.69; N, 9.63.

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1272
Ding, Sun, and Liu
5f. Yellow crystals, m.p. 127–128ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.16–7.27 (m, 10H, Ar-H), 6.99 (s, 1H, ¼CH), 3.32 (q, 2H, SCH2,
J ¼ 7.3 Hz), 1.47 (t, 3H, CH3, J ¼ 7.3 Hz); IR (cmÀ1), 1721 (C¼O), 1630
(C¼C); MS (m/z), 309 (Mþ þ 1, 10%), 280 (7%), 248 (3%), 204 (7%),
136 (53%), 117 (50%), 32 (100%); Anal. calcd. for C18H16N2OS: C, 70.10;
H, 5.23; N, 9.08. Found: C, 70.32; H, 5.18; N, 9.26.
5g. Yellow crystals, m.p. 184–185ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.19–7.19 (m, 15H, Ar-H), 7.03 (s, 1H, ¼CH), 4.55 (s, 2H, SCH2Ph);
IR (cmÀ1), 1730 (C¼O), 1634 (C¼C); MS (m/z), 371 (Mþ þ 1, 1%), 167
(3%), 116 (8%), 77 (61%), 32 (100%); Anal. calcd. for C23H18N2OS:
C, 74.57; H, 4.90; N, 7.56. Found: C, 74.63; H, 4.78; N, 7.74.
5h. Yellow crystals, m.p. 174–175ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.15–7.21 (m, 10H, Ar-H), 7.11 (s, 1H, ¼CH), 4.04 (s, 2H, SCH2CN);
IR (cmÀ1), 2258 (CN), 1726 (C¼O), 1627 (C¼C); MS (m/z), 320 (Mþ þ 1,
10%), 280 (4%), 175 (15%), 144 (24%), 135 (100%), 116 (77%); Anal.
calcd. for C18H13N3OS: C, 67.69; H, 4.10; N, 13.16. Found: C, 67.62;
H, 4.32; N, 13.21.
5i. Yellow crystals, m.p. 147–148ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.13–7.22 (m, 10H, Ar-H), 7.02 (s, 1H, ¼CH), 4.24 (q, 2H, COOCH2,
J ¼ 7.2 Hz), 4.05 (s, 2H, SCH2COO), 1.30 (t, 3H, CH3, J ¼ 7.3 Hz);
IR (cmÀ1), 1737 (COOEt), 1722 (C¼O), 1634 (C¼C); MS (m/z), 367
(Mþ þ 1, 9%), 294 (14%), 248 (5%), 135 (37%), 116 (92%), 77
(100%); Anal. calcd. for C20H18N2O3S: C, 65.56; H, 4.95; N, 7.64.
Found: C, 65.43; H, 4.74; N, 7.83.
5j. Yellow crystals, m.p. 225–227ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.08–7.22 (m, 10H, Ar-H), 7.08 (s, 1H, ¼CH), 5.51 (s, 2H, NH2),
3.91 (s, 2H, SCH2CO); IR (cmÀ1), 3305, 3261 (N-H), 1709 (C¼O),
1678 (CONH2), 1630 (C¼C); MS (m/z), 338 (Mþ þ 1, 2%), 280 (2%),
193 (2%), 135 (7%), 116 (26%), 77 (32%), 32 (100%). Anal. calcd.
for C18H15N3O2S: C, 64.08; H, 4.48; N, 12.45. Found: C, 64.30;
H, 4.37; N, 12.63.
5k. Yellow crystals, m.p. 161–163ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.13–7.22 (m, 10H, Ar-H), 7.02 (s, 1H, ¼CH), 4.04 (s, 2H, SCH2COO),
3.79 (s, 3H, CH3); IR (cmÀ1), 1737 (COOMe), 1724 (C¼O), 1637 (C¼C);
MS (m/z), 353 (Mþ þ 1, 12%), 294 (14%), 248 (4%), 208 (8%), 135
(44%), 116 (75%), 32 (100%); Anal. calcd. for C19H16N2O3S: C, 64.76;
H, 4.58; N, 7.95. Found: C, 64.63; H, 4.56; N, 8.12.
5l. Yellow crystals, m.p. 111–113ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.13–7.21 (m, 10H, Ar-H), 7.00 (s, 1H, ¼CH), 4.65 (q, 1H,
SCHCOO, J ¼ 7.7 Hz), 4.24–4.18 (m, 2H, COOCH2), 1.69 (d, 3H,
CHCH3, J ¼ 7.7 Hz), 1.24 (t, 3H, OCH2CH3, J ¼ 7.7 Hz); IR (cmÀ1),
1739 (COOEt), 1723 (C¼O), 1635 (C¼C); MS (m/z), 381 (Mþ þ 1, 1%),

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2-Alkylthio-5-phenylmethylidene-4H-imidazolin-4-ones
1273
308 (2%), 280 (2%), 136 (6%), 116 (18%), 44 (100%); Anal. calcd. for
C21H20N2O3S: C, 66.30; H, 5.30; N, 7.36. Found: C, 66.17; H, 5.58;
N, 7.19.
5m. Yellow crystals, m.p. 202–203ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.09–7.03 (m, 15H, Ar-H), 6.96 (s, 1H, ¼CH), 4.77 (s, 2H, SCH2COPh);
IR (cmÀ1), 1721 (C¼O), 1694 (COPh), 1634 (C¼C); MS (m/z), 399
(Mþ þ 1, 1%), 294 (3%), 135 (6%), 116 (12%), 105 (71%), 32 (100%);
Anal. calcd. for C24H18N2O2S: C, 72.34; H, 4.55; N, 7.03. Found:
C, 72.38; H, 4.37; N, 7.26.
5n. Yellow crystals, m.p. 157–159ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.15–7.21 (m, 9H, Ar-H), 7.00 (s, 1H, ¼CH), 2.70 (s, 3H, CH3);
IR (cmÀ1), 1716 (C¼O), 1637 (C¼C); MS (m/z), 329 (Mþ þ 1, 2%),
184 (4%), 170 (4%), 116 (6%), 44 (100%); Anal. calcd. for
C17H13ClN2OS:C,62.10;H,3.98;N,8.52.Found:C,62.26;H,3.74;N,8.64.
5o. Yellow crystals, m.p. 139–140ꢀC, H NMR (CDCl3, 200 MHz)
1
ꢀ 8.12–7.19 (m, 9H, Ar-H), 7.02 (s, 1H, ¼CH), 4.24 (q, 2H, COOCH2,
J ¼ 7.2 Hz), 4.05 (s, 2H, SCH2COO), 1.30 (t, 3H, CH3, J ¼ 7.3 Hz);
IR (cmÀ1), 1730 (COOEt), 1718 (C¼O), 1636 (C¼C); MS (m/z), 401
(Mþ þ 1, 1%), 328 (1%), 154 (1%), 116 (5%), 31 (100%); Anal. calcd.
for C20H17ClN2O3S: C, 59.92; H, 4.27; N, 6.99. Found: C, 59.73;
H, 4.17; N, 7.21.
5p. Yellow crystals, m.p. 91–93ꢀC, 1H NMR (CDCl3, 200 MHz)
ꢀ 8.12–7.21 (m, 9H, Ar-H), 7.01 (s, 1H, ¼CH), 4.65 (q, 1H, SCHCOO,
J ¼ 7.3 Hz), 4.28–4.13 (m, 2H, COOCH2), 1.70 (d, 3H, CHCH3,
J ¼ 7.7 Hz), 1.28 (t, 3H, OCH2CH3, J ¼ 7.3 Hz); IR (cmÀ1), 1742
(COOEt), 1716 (C¼O), 1636 (C¼C); MS (m/z), 415 (Mþ þ 1, 7%), 342
(15%), 314 (10%), 250 (5%), 144 (25%), 116 (100%); Anal. calcd. for
C21H19ClN2O3S: C, 60.79; H, 4.62; N, 6.75. Found: C, 60.53; H,
4.83; N, 6.67.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support of this work by the
Natural Science Foundation of China (Project No. 20102001).
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Ding, Sun, and Liu
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Received in Japan February 18, 2002