Practical synthesis of functionalized 2-thioxoimidazolidine derivatives

Article abstract of DOI:10.1080/00397910701316987

High-yielding syntheses of an unpublished series of 2-thioxo-imidazolidin- 4-ones 6 bearing an N-ethoxycarbonyl and amidyl moieties an N1 and C5, respectively, are reported. These derivatives were obtained by intramolecular cyclization of 3-ethylhydrazinoacetate 3,4-dihydro maleimides 4 in the presence of ethyl or phenylisothiocyanate 2 under neutral conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701316987

This article was downloaded by: [Moskow State Univ Bibliote]
On: 06 February 2014, At: 03:31
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
Practical Synthesis of Functionalized
2‐Thioxoimidazolidine Derivatives
Samia Bouzroura a , Lamouri Hammal a , Bellara Nedjar‐Kolli a , Fadila
Balegroune b , Malika Hamadène b & Sophie Poulain c
a Laboratory of Applied organic Chemistry , Houari Boumediene University
of Sciences and Technology , Algiers, Algeria
b Laboratory of Cristallography , USTHB , Algiers, Algeria
c Sophia Antipolis University , UMR 6001, Nice, France
Published online: 28 Jan 2008.
To cite this article: Samia Bouzroura , Lamouri Hammal , Bellara Nedjar‐Kolli , Fadila Balegroune , Malika
Hamadène & Sophie Poulain (2008) Practical Synthesis of Functionalized 2‐Thioxoimidazolidine Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:3, 448-455, DOI: 10.1080/00397910701316987
To link to this article: http://dx.doi.org/10.1080/00397910701316987
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
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. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 38: 448–455, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701316987
Practical Synthesis of Functionalized
2-Thioxoimidazolidine Derivatives
Samia Bouzroura,1 Lamouri Hammal,1 Bellara Nedjar-Kolli,1
2
Fadila Balegroune, Malika Hamadene, and Sophie Poulain
2
3
`
1Laboratory of Applied organic Chemistry, Houari Boumediene
University of Sciences and Technology, Algiers, Algeria
2Laboratory of Cristallography, USTHB, Algiers, Algeria
3Sophia Antipolis University, UMR 6001, Nice, France
Abstract: High-yielding syntheses of an unpublished series of 2-thioxo-imidazolidin-4-
ones 6 bearing an N-ethoxycarbonyl and amidyl moieties an N1 and C5, respectively, are
reported. These derivatives were obtained by intramolecular cyclization of 3-ethylhy-
drazinoacetate 3,4-dihydro maleimides 4 in the presence of ethyl or phenylisothio-
cyanate 2 under neutral conditions.
´
Keywords: arylisothiocyanates, imidazolidin-2-thione, maleimides, thioxoimida-
zolidinones
INTRODUCTION
Since the first thioxo-hydantoin or 2-thioxo-imidazolidin-4-one ring was
prepared in 1890 by Klason,[1] a large set of imidazolidine derivatives have
been synthesized, showing a wide range of biological activities such as antic-
onvulsant,[2] hypnotic or sedative,[3] antibacterial,[4] and herbicidal activity.[5]
Many syntheses of thioxo-hydantoine ring starting from isothiocyanates and
carbohydrates[4,6] have been described. Other methods such as solid-phase
synthesis[7] and microwave-assisted synthesis[8] have also been reported.
Received in the U.K. August 4, 2006
Address correspondence to Bellara Nedjar-Kolli, LCOA, USTHB, BP 3, El-Alia,
Bab-Ezzouar, 16111, Algiers, Algeria. E-mail: okollidz@yahoo.fr
448

Functionalized 2-Thioxoimidazolidine Derivatives
449
Table 1. Physicochemical data of the compounds 4a–d and 6a–h
Compounds
R
R0
Time (h)
Yield (%)
Mp (8C)
4a
4b
4c
4d
6a
6b
6c
6d
6e
6f
H
/
/
/
/
4
3
3
2
2
3
3
4
1
3
3
3
75
70
81
84
60
69
70
75
60
65
60
70
/
80
CH3
C2H5
C6H5
H
75
165
142
155
145
172
215
150
135
203
C2H5
C2H5
C2H5
C2H5
C6H5
C6H5
C6H5
C6H5
CH3
C2H5
C6H5
H
CH3
C2H5
C6H5
6g
6h
In this article, we report the full data on a synthetic procedure to prepare a
series of 2-thioxo-imidazolidin-4-ones bearing an ethoxycarbonyl and an
amidyl side chain in the N1 and C5 positions, respectively. These unprece-
dented compounds (Table 1) are obtained starting from commercially
available N-aryl or N-alkyl maleimides 1, ethylhydrazinoacetate 2, and
ethyl or phenylisothiocyanate 3 as starting materials.
RESULTS AND DISCUSSION
Recyclization reactions of N-substituted maleimides 1 have been described
when they are reacted with binucleophiles such as ethylenediamines[9] or
thiourea.[10] The reaction includes addition of an amino group (in the first
case) or a mercapto group (in the second case) at the active double bond of
maleimide and opening of the imide ring with transamidation relative to the
free amino group of the binucleophilic substrate.
In this work, the title compounds were synthesized in two steps: first,
treatment of 1 with ethylhydrazinoacetate 2 proceeded smoothly in
refluxing and yielded by filtration product 4 in high purity. Second, derivative
4 was subsequently transformed into 2-thioxo-imidazolidin-4-one 6 by
reaction with alkyl or phenylisothiocyanate 3.
Formation of products 4 can be explained by the Michael addition in a
1,4-fashion of the most reactive amino group on the active double bond of
maleimide. These compounds contain two nucleophilic centers (i.e., Na and
Nb); however, the neutral conditions of the reaction could not promote inter-
action of Nb with isothiocyanate 3 according the reaction of Jacobsen,[11]
which occurs in basic conditions.
Opening of the maleimide ring by internal nucleophilic attack of the Na
yielded a single 2-thioxo-imidazolidin-4-one 6. This procedure affords a

450
S. Bouzroura et al.
Scheme 1. Synthetic route to compounds 6.
regiospecific way of access to derivatives 6. The reaction mechanism could be
rationalized as shown in Scheme 1.
It is most likely that the condensation of 1 with ethylhydrazinoacetate 2
takes place initially to afford 4. Nucleophilic addition of Na to isothiocyanate
3 could afford the intermediate 5, which could undergo further transformation
to provide either 1,3-thioxo-imidazolidine 7 (path 2) or 2-thioxo-imidazolidin-
4-one 6 (path 1) depending on whether nitrogen [12] or sulfur[13] of the thiour-
eido moiety acts as the nucleophile. It should be noted that the intramolecular
cyclization reaction of 5 to 6 results from the harder nucleophile nitrogen
attack on the hard electrophile center, the carbonyl group, according to
Pearson’s HSAB (hard and soft acids and bases) rules. The carbonyl group
leading to 7 would not promote a similar reaction involving the soft nucleo-
phile, the sulfur with the hard electrophile (Figure 1).
Because the spectral data (e.g., NMR, IR, MS, and elemental analysis)
were not conclusive, X-ray crystallographic analysis was conducted to
verify path 1 prevails to produce 2-thioxo-imidazolidin-4-one 6.
In summary, a series of functionalized 2-thioxo-imidazolidin-4-ones 6
were synthesized by the sequential reaction of maleimides 1, ethylhydrazinoa-
cetate 2, and then isothiocyanate 3 through intermediate 4. All these
compounds were obtained with good yields, thus rendering these approaches
adaptable to high-throughput combinatorial syntheses.
EXPERIMENTAL
Melting points were determined with a Buchi 512 apparatus and are uncor-
rected. Nuclear magnetic resonance spectra were obtained with a Bruker

Functionalized 2-Thioxoimidazolidine Derivatives
451
Figure 1. ORTEP plots of compound 6h.
AC 2 at 300 MHz; chemical shifts are reported in d (ppm) from internal tetra-
methylsilane (TMS). IR spectra in Nujol were recorded on a Perkin Elmer, and
mass spectra were recorded on a Nermag R10-10C mass spectrometer.
Elemental analyses were performed at the National High School of
Chemistry in Toulouse (France).
All chemicals were obtained from Aldrich or Acros Organics and were
used without further purification.
General Procedure for the Synthesis of Products 4
Ethylhydrazinoacetate 2 was added (0.01 mol) to a solution of maleimide 1
(0.01 mol) in ethanol (25 ml). The resulting mixture was refluxed. After
cooling down to room temperature, the white precipitate was collected by fil-
tration and washed with a small amount of cold ethyl ether and dried in air to
yield 4.
Data
4a. ethyl-2-(2,5dioxotetrahydro1-H-3-pyrrolyl) hydrazine carbamate. Yield:
1
75%, oil; H NMR (300 MHz, CDCl3) d 1.19 (t, J ¼ 7 Hz, 3H), 2.3 (dd,
J ¼ 13 Hz, J ¼ 4 Hz, 1H), 2.8 (dd, J ¼ 13 Hz, J ¼ 4 Hz, 1H), 4.10 (dd,
J ¼ 13 Hz, J ¼ 8 Hz, 1H), 4.39 (q, J ¼ 7 Hz, 2H), 5 (s, 1H), 7.35 (s, 1H),
10.5 (s, 1H); 13C NMR (300 MHz, CDCl3) d 14.81, 34.99, 59.51, 62.24,
158.35, 177.27, 178.71. Anal. calcd. for C7H11N3O4: C, 41.79; H, 5.51; N,
20.89; O, 31.81. Found: C, 41.40; H, 5.37; N, 20.65. MS m/z 201, 97 (22)
and 156 (15).

452
S. Bouzroura et al.
1
4b. Yield: 70%, mp 808C; H NMR (300 MHz, CDCl3) d 1.22 (t, J ¼ 7 Hz,
3H), 2.6 (dd, J ¼ 13 Hz, J ¼ 4 Hz, 1H), 2.8 (dd, J ¼ 13 Hz, J ¼ 4 Hz, 1H),
2.95 (s, 3H), 4.10 (dd, J ¼ 13 Hz, J ¼ 8 Hz, 1H), 4.15 (q, J ¼ 7 Hz, 2H),
4.4 (s, 1H), 6.65 (s, 1H); 13C NMR (300 MHz, CDCl3) d 11.59, 14.0, 34.50,
58.06, 62.22, 158.90, 177.10, 178.01. Anal. calcd. for C8H13N3O4: C,
44.65; H, 6.09; N, 19.53; O, 29.74. Found: C, 44.55; H, 5.95; N, 19.20. MS
m/z 215, 169 (40), and 127 (12).
4c. Yield: 81%, mp 758C; 1H NMR (300 MHz, DMSO-d6) d 1.02 (t, J ¼ 7 Hz,
3H), 1.15 (t, J ¼ 7 Hz, 3H), 2.42 (dd, J ¼ 13 Hz, 4 Hz, 1H), 2.84
(dd, J ¼ 13 Hz, J ¼ 4 Hz, 1H), 4.0 (q, J ¼ 7 Hz, 2H), 4.05 (q, J ¼ 7 Hz,
2H), 4.10 (dd, J ¼ 13 Hz, J ¼ 8 Hz, 1H), 5.2 (s, 1H), 8.6 (s, 1H);
13C NMR (300 MHz, DMSO-d6) d 13.54, 15.40, 33.59, 34.78, 57.84, 60.91,
157.69, 176.16, 176.62, Anal. calcd. for C9H15N3O4: C, 47.16; H, 6.60; N,
18.33; O, 27.92. Found: C, 47.01; H, 6.30; N, 18.00. MS m/z 229, 183
(21), 141 (9).
4d. Yield: 84%, mp 1658C; 1H NMR (300 MHz, DMSO-d6) d 1.20
(t, J ¼ 7 Hz, 3H), 2.6 (dd, J ¼ 13 Hz, J ¼ 4 Hz, 1H), 3.0 (dd, J ¼ 13 Hz,
J ¼ 4 Hz, 1H), 4.10 (dd, J ¼ 13 Hz, J ¼ 8 Hz, 1H), 4.2 (q, J ¼ 7 Hz, 2H),
5.38 (s, 1H), 7.15 (m, 5H), 8.66 (s, 1H); 13C NMR (300 MHz, DMSO-d6) d
15.35, 35.50, 58.06, 61.18, 127.57, 129.06 – 129.57 – 134, 158.35, 175.64,
176.15. Anal. calcd. for C13H15N3O4: C, 56.31; H, 5.45; N, 15.15; O, 23.08.
Found: C, 56.17; H, 5.25; N, 15.00. MS m/z 277, 231 (6), 189, (54).
General Procedure for the Synthesis of Compounds 6
A solution of derivative 4 (0.01 mol) in ethanol was refluxed with ethyl or
phenyl isothiocyanate 3. After evaporation of the solvent under reduced
pressure, the crude reaction product was dissolved in a minimum of ethyl
ether and stirred for 1 h. The precipitate was separated by filtration and recrys-
tallized from ethanol.
Data
6a, ethyl N-5-(amino-2-oxoethyl)-3-ethyl-4-oxo-2-thioxo-1-imidazolidinyl
carbamate. Yield: 60%, mp 1428C; IR (Nujol, cm21) 3270, 3360, 1750,
1
1737, 1640, 1140; H NMR (300 MHz, DMSO-d6) d 1.09 (t, J ¼ 7 Hz, 3H),
1.19 (t, J ¼ 7 Hz, 3H), 2.70(d, J ¼ 4 Hz, 2H), 3.77 (q, J ¼ 7 Hz, 2H), 4.1
(q, J ¼ 7 Hz, 2H), 4.41 (t, J¼ 4 Hz, 1H), 6.92–7 (s, 2H), 10.1 (s, 1H); 13C
NMR (300 MHz, DMSO-d6) d 12.61, 14.84, 36.90, 33.75, 59.66, 61.81,
155.39, 169.87, 172.13, 184.44. Anal. calcd. for C10H16N4O4S: C, 41.66; H,
5.59; N, 19.43; O, 22.20; S, 11.12. Found: C, 41.30; H, 5.47; N, 19.31; MS
m/z 288, 231 (42).

Functionalized 2-Thioxoimidazolidine Derivatives
453
6b. Yield: 65%, mp 1558C; IR (Nujol, cm21) 3286, 3195, 1748, 1742, 1638,
1135; 1H NMR (300 MHz, DMSO-d6) d 1.11 (t, J ¼ 7 Hz, 3H), 1.19
(t, J ¼ 7 Hz, 3H), 2.54 (d, J ¼ 4.5 Hz, 3H), 2.71 (d, J ¼ 4 Hz, 2H), 3.73
(q, J ¼ 7 Hz, 2H), 4.23 (q, J ¼ 7 Hz, 2H), 4.40 (t, J ¼ 4 Hz, 1H), 7.9
(t, 1H), 10.05 (s, 1H); 13C NMR (300 MHz, DMSO-d6) d 12.74, 14.83,
25.98, 33.82, 36.93, 60, 61.80, 155.37, 172.02, 179.62, 184.43. Anal. calcd.
for C11H18N4O4S: C, 43.70; H, 6.00; N, 18.53; O, 21.17; S, 10.61. Found:
C, 43.61; H, 5.98; N, 18.33. MS m/z 302, 244 (32).
6c. Yield: 60%, mp 1458C; IR (Nujol, cm21) 3284, 3195, 1748, 1750, 1638,
1135; 1H NMR (300 MHz, DMSO-d6) d 0.98 (t, J ¼ 7 Hz, 3H), 1.10
(t, J ¼ 7 Hz, 3H), 1.19 (t, J ¼ 7 Hz, 3H), 2.69 (d, J ¼ 4 Hz, 2H), 3.05
(q, J ¼ 7 Hz, 2H), 3.77 (q, J ¼ 7 Hz, 2H), 4.09 (q, J ¼ 7 Hz, 2H), 4.43
(t, J ¼ 4 Hz, 1H), 7.90 (t, 1H), 10.05 (s, 1H); 13C NMR (300 MHz, DMSO-d6)
d 12.74, 14.83, 25.98, 33.82, 36.93, 39.05, 60, 61.80, 155.37, 168, 172, 184.
Anal. calcd. for C12H20N4O4S: C, 45.56; H, 6.37; N, 17.71; O, 20.23; S, 10.14.
Found: C, 45.48; H, 6.20; N, 17.40. MS m/z 316, 244 (12).
6d. Yield: 55%, mp 1728C; IR (Nujol, cm21) 3285, 3241, 1739, 1742, 1677,
1135; 1H NMR (300 MHz, DMSO-d6) d1.14 (t, J ¼ 7 Hz, 3H), 1.19
(t, J ¼ 7 Hz, 3H), 2.98 (d, J ¼ 4 Hz, 2H), 3.79 (q, J ¼ 7 Hz, 2H), 4.09
(q, J ¼ 7 Hz, 2H), 4.50 (t, J ¼ 4 Hz, 1H), 7.31 (m, 5H), 10.06 (s, 1H), 10.1
(s, 1H); 13C NMR (300 MHz, DMSO-d6) d 12.75, 14.80, 34.67, 37.0, 57.92,
61.82, 139–129.14 – 128.78 – 129.32, 155.37, 166.7, 172, 184. Anal.
calcd. for C16H20N4O4S: C, 52.73; H, 5.53; N, 15.37; O, 17.56; S, 8.80.
Found: C, 52.65; H, 5.41; N, 15.20. MS m/z 364, 306 (12).
6e. Yield: 60%, mp 2158C; IR (Nujol, cm21) 3280, 3358, 1734, 1757, 1680,
1157; 1H NMR (300 MHz, DMSO-d6) d 1.2 (t, J ¼ 7 Hz, 3H), 2.85 (d,
J ¼ 4 Hz, 2H), 4.1 (q, J ¼ 7 Hz, 2H), 4.60 (t, J ¼ 4 Hz, 1H), 7–7.3 (s, 2H),
7.5 (m, 5H), 10.26 (s, 1H); 13C NMR (300 MHz, DMSO-d6) d 14.88, 34.05,
60.20, 61.83, 134.35 – 129.32 – 129 – 129.22, 155.41, 170.08, 172.03, 184.
Anal. calcd. for C14H16N4O4S: C, 49.99; H, 4.79; N, 16.66; O, 19.03; S, 9.53.
Found: C, 49.77; H, 4.53; N, 16.50. MS m/z 336, 319 (10), 101 (20).
6f. Yield: 65%, mp 1508C; IR (Nujol, cm21) 3280, 3396, 1737, 1756, 1654,
1
1166; H NMR (300 MHz, DMSO-d6) d 1.1 (t, J ¼ 7 Hz, 3H), 2.08 (s, 3H),
3.13 (d, J ¼ 4 Hz, 2H), 4.10 (t, J ¼ 4 Hz, 1H), 4.13 (q, J ¼ 7 Hz, 2H), 7.55
(m, 5H), 10.14 (s, 2H), 10.30 (s, 1H); 13C NMR (300 MHz, DMSO-d6) d
14.87, 26.06, 34.09, 60.25, 61.83, 134.40 – 128.54 – 129 – 129.23, 155.41,
168.32, 171.91, 184.44. Anal. calcd. for C15H18N4O4S: C, 51.42; H, 5.18; N,
15.99; O, 18.26; S, 9.15. Found: C, 51.30; H, 5.02; N, 15.87. MS m/z 350,
101 (36).

454
S. Bouzroura et al.
6g. Yield: 60%, mp 1358C; IR (Nujol, cm21) 3262, 3358, 1706, 1753, 1675,
1157; 1H NMR (300 MHz, DMSO-d6) d 1.02 (t, J ¼ 7 Hz, 3H), 1.24
(t, J ¼ 7 Hz, 3H), 2.8 (d, J ¼ 4 Hz, 2H); 3.1 (q, J ¼ 7 Hz, 2H), 4.20 (q,
J ¼ 7 Hz, 2H), 4.63 (t, J ¼ 4 Hz, 1H), 7.55 (m, 5H), 10.14 (d, 1H), 10.30
(s, 1H); 13C NMR (300 MHz, DMSO-d6) d 14.98, 25.32, 34.20, 55.39,
60.29, 61.83, 134.37 – 129.34 – 129.22, 155.39, 167.53, 171.89, 184.39.
Anal. calcd. for C16H20N4O4S: C, 52.73; H, 5.53; N, 15.37; O, 17.50; S,
8.80. Found: C, 52.65; H, 5.30; N, 15.25. MS m/z 350, 101 (36).
6h. Yield: 65%, mp 203 8C; IR (Nujol, cm21) 3260, 3357, 1706, 1737, 1674,
1145; 1H NMR (300 MHz, DMSO-d6) d 1.18 (t, J ¼ 7 Hz, 3H), 3.13
(d, J ¼ 4 Hz, 2H), 4.11 (q, J ¼ 7 Hz, 2H), 4.75 (t, J ¼ 4 Hz, 1H), 7.55
(m, 10H), 10.14 (d, 1H), 10.30 (s, 1H); 13C NMR (300 MHz, DMSO-d6) d
14.98, 35.29, 57.94, 61.86, 134.33 – 128.98 – 128.74 – 127.37, 139.36 –
129.36 – 129.43 – 129.31, 155.43, 167.01, 171.84, 184.36. Anal. calcd. for
C20H20N4O4S: C, 56.31; H, 5.45, N, 15.15; O, 23.08; S, 8.80. Found: C,
56.21; H, 5.34; N, 15.12. MS m/z 412, 292 (20), 273 (48).
˚
¯
Crystal data for 6h: C20H20N4O4S, M ¼ 412.46, triclinic P 1 a ¼ 7.9636(8) A,
˚
˚
b ¼ 9.1477(8) A, c ¼ 14.1448(16) A, a ¼ 94.53(0.87)8, b ¼ 90.47(1.1)8,
3
˚
g ¼ 101.41(0.9)8, V ¼ 1006.6 A , Z ¼ 2. Reflections (3521:1751 independent,
Rint ¼ 0.1299), were collected at room temperature using an Enraf-Nonius
FR590 Kappa CCD diffractometer. The structure was solved by direct
methods and refined, using Shelxs and Shelxl respectively,[14] available in the
Wings package.[15] Parameters (323) were refined using the least squares
method on F2.[16] Analytical absorption corrections were applied using a
program available in the Wings package.[15] Largest electron density residue
is 0.148 eA23, R1 [for I . 2s(I)] ¼ 0.0565, and wR2 (all data) ¼ 0.1104 with
R1 ¼ SjFoj 2 jFcj/SjFoj and wR2 ¼ w(Sw (F2o 2 F2c)2/Sw(Fo2)2)0.5
.
Crystallographic data (excluding structure factors) for the structure
reported in this article have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication CCDC no. 613040.
Copies of the data can be obtained free of charge upon application to
CCDC, 12 Union Road, Cambridge CB1 1EZ, UK (Fax: þ44-1223/336-
033; e-mail: deposit@ccdc.cam.ac.uk).
REFERENCES
1. Klason, P. An apparatus for preparing chloride. P. Chem. Ztg. 1890, 14, 543.
2. Karali, N.; Gursoy, A.; Terzioglu, N.; Ozkirimli, S.; Ozer, H.; Ekinci, A. C. A.
Synthesis and preliminary CNS depressant activity evaluation of new
3-[(3-substituted-5-methyl-4-thiazolidinon-2-ylidene) hydrazono]-1H-indolinones
and 3-[(2-thioxo-3-substituted-4,5-imidazolidine-dion-1-yl)imino]-1H-2-indoli-
nones. Arch. Pharama. Med. Chem. 1998, 331, 254.

Functionalized 2-Thioxoimidazolidine Derivatives
455
3. Chaudari, S. K.; Verma, M.; Chatuvedi, A.; Parmar, S. S. Substituted thiazoli-
dones: Selective inhibition of nicotinamide adenine dinucleotide–dependent oxi-
dations and evaluation of their CNS [central nervous system] activity. J. Pharma.
Sci. 1975, 64, 615.
4. Albuquerque, J. F. C.; Rocha Filh, J. A.; Brandao, S. S. F.; Lima, M. C. A.;
Ximenes, E. A.; Galdino, S. L.; Pitta, I. R.; Chantegrel, J.; Perrissin, M.;
Luu-Duc, C. Synthesis and antimicrobial activity of substituted imidazolidine-
dione and thioxo imidazolidines. Il Farmaco 1999, 54, 77–82.
5. Nakajima, M.; Itoi, K.; Takamatsu, Y.; Kinoshita, T.; Okazaki, T.; Kawakubo, K.;
Shindou, M.; Homna, T.; Toujigamori, M.; Haneishi, T. Hydantocidin: A new
compound with herbicidal activity from streptomyces hygroscopicus.
J. Antibiotic. 1991, 44 (3), 293–300.
6. Fuents, M.; Salameh, B. A. B.; Angeles Pradera, M.; De Cordoba, F. J. F.; Gash, C.
Stereocontrolled synthesis of thiohydantoin spironucleosides from sugar spiroace-
tals. Tetrahedron 2006, 62, 97–111.
7. Severinsen, R.; Lau, J. F.; Bondensgaard, K.; Hansen, B. S.; Begtrup, M.;
Ankersen, M. Parallel solid-phase synthesis of disubstituted (5-biphenyltetrazolyl)
hydantoins and thiohydantoins targeting the growth hormone secretagogue
receptor. Bioorg. Med. Chem. Lett. 2004, 14, 317–320.
8. Lin, M. J.; Sun, C. M. Microwave-assisted traceless of thiohydantoin. Tetrahedron
Lett. 2003, 44, 8739–8742.
9. Abelman, M. M.; Fisher, K. J.; Doerffler, M. E.; Edwards, P. J. The synthesis of
2-ketopiperazine acetic acid esters and amides from ethylenediamines with
maleates and maleimides. Tetrahedron Lett. 2003, 44, 1823.
10. Takido, T.; Tamura, S.; Sato, K.; Kamijo, H.; Nakazava, T.; Hata, T.; Seno, M.
Synthesis of hexahydooxoepithiopyridinedicarboximides by reaction of thioa-
mides with N-substituted amaleimides. J. Heterocycl. Chem. 1998, 35 (2),
437–443.
11. Jacobsen, N.; Toelberg, J. A simple synthesis of 3-substituted 1-amino-2-thioxo-4-
imidazolidinones (1-aminothiohydantoins). Synthesis 1986, 7, 559–561.
12. (a) Zeng, R. S.; Zou, J. P.; Zhi, S. J.; Chen, J.; Shen, Q. Novel synthesis of 1-aroyl-
3-aryl-4-substituted imidazole-2-thiones. Org. Lett. 2003, 5, 1657–1659;
(b) Ojima, I.; Inaba, S. I. A convenient synthesis of 1,3 dimethyl (5H,7H)
imidazo (4,5-d) pyrimidine-2,4,6-trithione and its unusual character. Tetrahedron
Lett. 1979, 20, 817–820.
13. (a) Katritzky, A. R.; Cai, X.; Rogovoy, B. V. Solid phase synthesis and application
of trisubstituted thioureas. J. Comb. Chem. 2003, 5, 392–399; (b) Bramley, S. E.;
Dupplin, V.; Goberdhan, D. G. C.; Meakins, G. D. Hantzsch thiazole synthesis
under acidic conditions: Change of regioselectivity. J. Chem. Soc., Perkin
Trans. 1, 1987, 639–643.
14. Sheldrick, G. M. Phase annealing in SHELX-90: Direct methods for larger
structures. Acta Cryst. 1990, A46, 467–473.
15. Farrugia, J. L. Wings software package. J. App. Crys. 1999, 32, 837–838.
16. Sheldrick, G. M. SHELX-97: Program for Crystal Structure Refinement;
University of Goettingen, 1997.