Efficient 2-amino-2-thiazolin-4-ones or 2-iminothiazolidin-4-ones formation from thioureas and maleimides under solvent-free conditions

Article abstract of DOI:10.3987/COM-07-11012

A facile method for the construction of 2-thiazolin-4-one or thiazolidin-4-one structure is described. Condensation reactions of thiourea (1a) and maleimides (2) under solvent-free conditions gave 2-amino-2-thiazolin-4-ones (3) via Michael-type reaction, while similar reactions of N-substituted thioureas (1b-d) with 2 afforded 2-iminothiazolidin-4-ones (4). Since the solvent-free reactions of 1 with 2a afforded 3 in good yields, the synthetic method was found to be effective from the viewpoint of green chemistry.

Full text of DOI:10.3987/COM-07-11012

HETEROCYCLES, Vol. 71, No. 5, 2007
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HETEROCYCLES, Vol. 71, No. 5, 2007, pp. 1053 - 1058. © The Japan Institute of Heterocyclic Chemistry
Received, 29th January, 2007, Accepted, 19th March, 2007, Published online, 20th March, 2007. COM-07-11012
EFFICIENT 2-AMINO-2-THIAZOLIN-4-ONES OR 2-IMINOTHIAZOLI-
DIN-4-ONES FORMATION FROM THIOUREAS AND MALEIMIDES
UNDER SOLVENT-FREE CONDITIONS
Tetsuro Shimo,a Yuki Matsuda,a Tetsuo Iwanaga,b Teruo Shinmyozu,b and
Kenichi Somekawaa*
aDepartment of Applied Chemistry and Chemical Engineering, Faculty of
Engineering, Kagoshima University, Korimoto 1-21-40, Kagoshima 890-0065,
Japan
bInstitute for Materials Chemistry and Engineering (IMCE) and Department of
Molecular Chemistry, Graduate School of Sciences, Kyushu University, Hakozaki,
6-10-1, Fukuoka 812-8581, Japan
Abstract – A facile method for the construction of 2-thiazolin-4-one or
thiazolidin-4-one structure is described. Condensation reactions of thiourea (1a)
and maleimides (2) under solvent-free conditions gave 2-amino-2-thiazolin-
4-ones (3) via Michael-type reaction, while similar reactions of N-substituted
thioureas (1b-d) with 2 afforded 2-iminothiazolidin-4-ones (4). Since the
solvent-free reactions of 1 with 2a afforded 3 in good yields, the synthetic
method was found to be effective from the viewpoint of green chemistry.
2-Thiazoline and thiazolidine derivatives have been reported to exibit pharmacological and biological
activities, respectively. For example some 2-thiazoline derivatives present interesting anti-HIV1 and

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HETEROCYCLES, Vol. 71, No. 5, 2007
anti-canser2 activities, while thiazolidine derivatives show insecticidal3 and fungisidal4 activities. The
classical synthesis of these compounds has been carried out in solution reactions between thioureas and
maleimides or maleic anhydride, and so on5 except microwave-assisted solvent-free synthesis.6 In
continuation of our studies related to the development of the solid-state organic synthesis,7 we report here
a simple and efficient synthetic method for 2-amino-2-thiazolin-4-ones or 2-iminothiazolidin-4-ones
under solvent-free conditions.
A mixture of crystals of 1a (0.20 mmol) and N-methylmaleimide (2b) (0.20 mmol) in a mortar was
ground for 10 min with a pestle. The powder was kept at 60 °C in the glass-tube oven for 24 h. The
reaction mixture was washed with acetone and filtered to give 3ab in 59% yield (Scheme 1). Similar
reaction of N, N’-diphenylthiourea (1c) (0.20 mmol) with maleimide (2a) (0.20 mmol) afforded 4ca in
77% yield. The results of the similar reactions of 1a-d with 2a-c were summerized in Table 1. Since
O
O
R1HN
R1HN
4
R1
3
O
∆
O
N
R2
+
O
C S
N
N
O
2
5
1
H2N
2
R1N
NH
R
S
NHR2
,
S
1a: R1=H
2a: R2=H
3aa: R2=H
4ba: R1=Et, R2=H
1
2
2
1
2
1b
2b
3ab
: R =Et
: R =Me
: R =Me
4bb
: R =Et, R =Me
1c: R1=Ph
2c: R2=Ph
3ac: R2=Ph
4ca: R1=Ph, R2=H
Scheme 1
products 3ab and 4ca were recrystallized from ethanol to give single crystals, the structures of 3ab
(Figure 1)8 and 4ca (Figure 2)9 were established by X-Ray crystallographic analyses as 2-amino-2-
thiazolin-4-one-5-N-methylacetamide and (Z)-2-(N-phenylimino)-3-phenylthiazolidin-4-on-5-acetamide,
respectively. It was found that the pairs of 3ab were linked together to form planar tricyclic dimers by
pairs of intermolecular hydrogen bonds between amino proton and nitrogen in the 2-thiazoline ring with
H···N distance of 2.12 Å (Figure 3). The assignment of the same structures (3 and 4) to other
1
2-thiazolin-4-ones and thiazolidin-4-ones were based on their H NMR, IR and MS spectra that were
analogous to those of 3ab and 4ca.10 Since intermolecular hydrogen bonds were found in 3ab as

HETEROCYCLES, Vol. 71, No. 5, 2007
1055
mentioned above the chemical shifts of the amino protons at the 2-thiazoline ring were observed at
lower-field (δ 8.69 and 8.90), whose chemical shifts also appeared to 3aa and 3ac. On the other hand, the
amino protons of amido group for 4ca were observed at higher-field (δ 7.46 and 7.54). Similar chemical
shifts were also observed to 4ba and 4bb.
Table 1 Reactions of Thioureas (1) with Maleimides (2) in the Solid Statea and in Solution.b
yield(%)c in the solid state
yield(%)c in solution
thiourea
maleimide
3 or 4
95 (3aa)
15 (3aa)d
59 (3ab)
0d
recovered 2
5
3 or 4
96 (3aa)
100 (3aa)e
98 (3ab)
100 (3ab)e
97 (3ac)
99 (3ac)e
94 (4ba)
86 (4ba)e
98 (4bb)
93 (4bb)e
98 (4ca)
35 (4ca)e
recovered 2
1a
2a
2
0 e
2
85 d
41
2b
2c
2a
2b
2a
100 d
74
0 e
1
26 (3ac)
0d
100 d
5
1 e
6
1b
1c
95 (4ba)
30 (4ba)d
51 (4bb)
0d
70 d
49
14 e
2
100 d
23
7 e
2
77 (4ca)
0d
100 d
65 e
aEquimolar mixture of 1 and 2 was heated at 60 °C for 24 h. bEquimolar ethanol solution (0.1 M)
of 1 and 2 was heated at 60 °C for 24 h. cEstimated from NMR analyses based on total integral
between 2 and 3 (or 4). dEquimolar mixture of 1 and 2 was left at room temperature for 7d.
eEquimolar ethanol solution (0.1 M) of 1 and 2 was left at room temperature for 7d.
Since the solvent-free reactions of 1a-c with 2a
(60 °C, 24h) afforded 3aa, 3ab, and 3ac in good
yields (Table 1), the synthetic method was found
to be effective from the viewpoint of green
Figure 1 ORTEP drawing of 3ab.
Figure 2 ORTEP drawing of 4ca.

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HETEROCYCLES, Vol. 71, No. 5, 2007
chemistry. It was inferred that the molecular packings between 1a-c and 2a were similar structures to 1:1
complex crystals between 2-pyrones and maleimide using non-covalent interactions which had given
highly selective [2+2] cycloadducts quantitatively by photoirradiation in the solid state.7 The decrease in
reactivity of 1a with 2b or 2c compared to that of 1a with 2a in the solid state was estimated to be caused
by the lack of additional intermolecular hydrogen bond like N-H (2a)···O=C observed in the 1:1 complex
crystals between 2-pyrones and 2a. The reaction mechanism was considered to proceed via Michael
addition of the sulfur of 1 to 2 to afford 4 which tautomerized to give 3 in the case of 1a (R1= H) (Scheme
2). It was estimated that the activation
H
O
O
N
H
H
energies of the reactions between 1a and 2a-c
were relatively lower than the similar Michael
addition containing hetero atom because the
reactions in ethanol proceeded to give 3aa,
3ab, and 3ac quantitatively at 60 °C and even
at room temperature.
HCH
N
S
N
N
S
N
H3CNH
O
O
H
3ab
Figure 3 Intermolecular hydrogen bonds in 3ab.
R1
..
N
H
..
R1
R1HN
R2
O
O
O
O
N
C
S
N
C
H
R2
S
N
H
O
R1N
1
O
H
2
R1
N
O
1, 3-H shift
O
R1N
N
2
NH
R
S
R1=H
H2N
NHR2
S
4
3
Scheme 2
REFERENCES AND NOTES
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HETEROCYCLES, Vol. 71, No. 5, 2007
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2. G. Pattenden, C. Boden, and T. Ye, Synlett, 1995, 417.
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K. Naumann, and W. Steinke, Ger. (East) DD 241,844, 1987 (Chem. Abstr., 1987, 107, 91901m).
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7. T. Obata, T. Shimo, M. Yasutake, T. Shinmyozu, M. Kawaminami, R. Yoshida, and K. Somekawa,
Tetrahedron, 2001, 57, 1531; T. Shimo, T. Uezono, T. Obata, M. Yasutake, T. Shinmyozu, and K.
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Heterocycles, 2004, 63, 1541; W. Wang, T. Shimo, T. Shinmyozu, T. Iwanaga, and K. Somekawa,
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8. X-Ray crystal data for 3ab (C6H9N3O2S); T=113 K, Mo-Kα (Rigaku RAXSIS-RAPID imaging plate
diffractometer, λ=0.71069 Å), crystal dimensions 0.48 x 0.40 x 0.20 mm3 (a colorless block crystal),
a=14.1282 (4), b=4.6976 (2), c=15.6902 (4) Å, β= 108.567 (1)°, monoclinic, space group P21/c (#14),
Z=4, µMoKα=2.96 cm-1, Mr=187.22, V=987.15 (5) Å3, anode power 50 KV x 32 mA, ρcalc=1.260 g/cm3,
2θmax=55.0°, F (000)=392.00. 9060 reflections measured, 1860 observed (I > 3.00σ (I)), number of
parameters 162. The structure was solved by direct method and was refined on SIR 92.10 Data were
corrected for Lorentz polarizations. The data/parameter ratio was 11.48. R=0.026, Rw=0.037,
GOF=1.25, max/min residual density +0.26/-0.17 eÅ-3. 4ca (C17H15N3O2S); T=123K, crystal
dimensions 0.17 x 0.04 x 0.41 mm3 (a colorless platelet crystal), a=4.6757 (8), b=9.502 (2), c=34.392
(6) Å, β=90.117 (7)°, monoclinic, space group P21/c (#14), Z=4, µMoKα=2.25 cm-1, Mr=325.38,
V=1527 (1) Å3, ρcalc=1.414 g/cm3, F (000)=680.00. 25391 reflections measured, 3486 observed (All,

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HETEROCYCLES, Vol. 71, No. 5, 2007
2σ <54.97°), number of parameters 208. The structure was solved by direct method and was refined on
SIR 97.11 The data/parameter ratio was 16.76. R=0.072, Rw=0.146, GOF=1.39, max/min residual
density +0.57/-0.62 eÅ-3. All calculations were performed using the teXsan crystallographic software
package of Molecular Structure Corporation.
9. All the new compounds gave the correct analytical and MS data. Selected spectral data are given below.
3aa: mp 244-245 °C; 1H NMR (DMSO-d6) δ 2.37 (1H, dd, J=16.0, 11.6 Hz), 2.98 (1H, dd, J=16.0, 3.2
Hz), 4.24 (1H, dd, J=11.6, 3.2 Hz), 7.00, 7.48 (each 1H, s), 8.72, 8.94 (each 1H, s). IR (KBr) 3440,
3350, 3200, 1718, 1680, 1650 cm-1. 3ab: mp 219-220 °C; 1H NMR (DMSO-d6) δ 2.35 (1H, dd, J=16.0,
11.6 Hz), 2.55 (3H, d, J=4.4 Hz), 2.94 (1H, dd, J=16.0, 3.2 Hz), 4.23 (1H, dd, J=11.6, 3.2 Hz), 7.91
1
(1H, s), 8.69, 8.90 (each 1H, s). IR (KBr) 3310, 1675, 1635 cm-1. 3ac: mp 257-259 °C; H NMR
(DMSO-d6) δ 2.69 (1H, dd, J=16.4, 11.0 Hz), 3.26 (1H, dd, J=16.4, 3.4 Hz), 4.39 (1H, dd, J=11.4, 3.4
Hz), 7.05 (1H, Ph), 7.30, 7.48 (each 2H, Ph), 8.79, 9.00 (each 1H, s), 10.12 (1H, s). IR (KBr) 3280,
3210, 1670 cm-1. 4ba: mp 186- 187 °C; 1H NMR (DMSO-d6) δ 1.06, 1.15 (each 3H, t, J=7.0 Hz), 2.56
(1H, dd, J=16.4, 10.0 Hz), 2.98 (1H, dd, J=16.4, 3.6 Hz), 3.22, 3.61 (each 2H, q, J=7.0 Hz), 4.36 (1H,
dd, J=10.0, 3.6 Hz), 7.05, 7.49 (each 1H, s). ΙR (KBr) 3380, 1710, 1670 cm-1. 4bb: mp 137-140 °C; 1H
NMR (DMSO-d6) δ 1.05, 1.16 (each 3H, t, J=7.2 Hz), 2.55 (3H, d, J=3.6 Hz), 2.56 (1H, dd, J=16.0,
10.0 Hz), 2.97 (1H, dd, J=16.0, 3.2 Hz), 3.22, 3.53 (each 2H, q, J=7.2 Hz), 4.40 (1H, dd, J=10.0, 3.2
Hz), 7.96 (1H, s). ΙR (KBr) 3330, 1700, 1640 cm-1. 4ca: mp 233-236 °C; 1H NMR (DMSO-d6) δ 2.85
(1H, dd, J=16.6, 10.0 Hz), 3.05 (1H, dd, J=16.6, 3.2 Hz), 4.55 (1H, dd, J=10.0, 3.2 Hz), 6.85, 7.09,
7.32, 7.42, 7.51 (each 2H, Ph), 7.46, 7.54 (each 1H). ΙR (KBr) 3420, 3170, 1705, 1660, 1635 cm-1.
10. A. Altomare, M. C. Burla, M. Camalli, M. Cascarano, C. Giacovazzo, A. Guagliardi, and G. Polidori,
J. Appl. Cryst., 1994, 27, 435.
11. A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, and A. G. G.
Moliterni, G. Polidori, and R. Spagna, J. Appl. Cryst., 1999, 32, 115.