5,5-Diaryl and 5-alkyl-3-phenyl-4-imidazolidones: A novel synthesis

Article abstract of DOI:10.1002/jhet.165

(Chemical Equation Presented) Synthesis of 5,5-diaryl and 5-alkyl-3-phenyl-4-imidazolidones has been reported by reductive desulfurization of 5,5-diaryl and 5-alkyl-3-phenyl-2-thiohydantoins with nickel boride.

Full text of DOI:10.1002/jhet.165

September 2009
5,5-Diaryl and 5-Alkyl-3-phenyl-4-imidazolidones:
A Novel Synthesis
1007
Jitender M. Khurana,* Arpita Agrawal, and Geeti Bansal
Department of Chemistry, University of Delhi, Delhi 110007, India
*E-mail: jmkhurana1@yahoo.co.in
Received October 14, 2008
DOI 10.1002/jhet.165
Published online 2 September 2009 in Wiley InterScience (www.interscience.wiley.com).
Synthesis of 5,5-diaryl and 5-alkyl-3-phenyl-4-imidazolidones has been reported by reductive desul-
furization of 5,5-diaryl and 5-alkyl-3-phenyl-2-thiohydantoins with nickel boride.
J. Heterocyclic Chem., 46, 1007 (2009).
INTRODUCTION
with nickel boride in dry methanol at ambient tempera-
ture. The nickel boride was prepared in situ from anhy-
drous nickel chloride and sodium borohydride. Reac-
tions were carried out under varying conditions by
changing solvents and molar ratio of substrate to nickel
boride to optimize conditions for quantitative
desulfurization.
Compounds containing an imidazole ring are well-
known in living systems. A number of 4-imidazolidone
derivatives display a wide range of biological properties
including anti-convulsant [1], anti-depressant [2],
anti-inflammatory [3], anti-viral [4], anti-tumor [5], etc.
4-imidazolidones can be prepared by multistep synthesis
involving reagents which are difficult to handle [6].
Although sodium and amyl alcohol [7], sodium amal-
gam [8], H2 pressure on Pd-charcoal catalyst [9], and
Raney nickel [10] have been reported as dethiating
agents for 2-thiohydantoins, the yields range from low
to moderate. However, the synthesis of 4-imidazolidones
by reductive desulfurization of 2-thiohydantoins has not
received attention. Reductive desulfurization of 2-thio-
hydantoins would obviously provide an alternate and
convenient method of synthesis of 4-imidazolidones.
Nickel boride [11] has been reported as a convenient
and efficient reagent for reductive desulfurization of
benzimidazoline-2-thiones, 2-thiobarbituric acids [12],
2-thioxo-4-3H-quinazolinones [13], and 2-thioxo-5H-
pyrano[23-d]pyrimidines [14]. In view of its versatility
and ease of handling, we decided to explore its applica-
tion for the desulfurization of 5,5-diaryl, 5-alkyl-3-phe-
nyl and 5-alkyl-2-thiohydantoins.
The 5,5-diaryl-2-thiohydantoins underwent complete
reductive desulfurization to give the corresponding
5,5-diaryl-4-imidazolidones in high yields [Eq. (1)] and
were identified by their spectral data. The sulfur
by-product of these reactions is hydrogen sulfide gas. A
number of new 4-imidazolidones have been synthesized
in this manner. All the 4-imidazolidones showed a dis-
tinct peak at d 4.4–4.5 for two protons due to
ANHACH2ANRA group. IR showed a peak at ꢀ1680–
1750 cmꢁ1 due to ACOANR group. No 4-imidazolidi-
nones (double bond between 1-2 positions or 2-3
positions) were formed under these conditions. These
results are listed in Table 1.
RESULTS AND DISCUSSION
In this article, we report a convenient synthesis of
5,5-diaryl and 5-alkyl-3-phenyl-4-imidazolidones by
reductive desulfurization of 5,5-diaryl-2-thiohydantoins
(Ia–i) and 5-alkyl-3-phenyl-2-thiohydantoins (IIIa–e)
The reactions carried out in ethanol, THF, and
DMF were sluggish and showed the formation of
C
V
2009 HeteroCorporation

1008
J. M. Khurana, A. Agrawal, and G. Bansal
Vol 46
Table 1
Reactions of 5,5-diaryl-2-thiohydantoin with nickel boride in dry methanola at ambient temperature.
Molar ratio
S:NiCl2:NaBH4
Run
Substrate (S)
Reaction time (min)
Product (P)
Yield (%)
1.
2.
3.
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ih
Ih
Ii
1:8:8
1:8:8
1:10:10
1:5:5
1:6:6
1:6:6
1:10:10
1:8:8
5
15
30
45
120
150
5
10
5
5
6 h
5,5-diphenyl-4-imidazolidone (IIa)
5,5-di(p-anisyl)-4-imidazolidone (IIb)
5,5-di(p-tolyl)-4-imidazolidone (IIc)
5,5-di(o-tolyl)-4-imidazolidone (IId)
5,5-di(p-chlorophenyl)-4-imidaolidone (IIe)
5,5-di(o-chlorophenyl)-4-imidazolidone (IIf)
5,5-di(p-bromophenyl)-4-imidazolidone (IIg)
5,5-di(m-bromophenyl)-4-imidazolidone (IIh)
5,5-di(m-bromophenyl)-4-imidazolidone (IIh)
5,5-di(m-bromophenyl)-4-imidazolidone (IIh)
–
94 [15]
89 [10a]
89
4.
88
89
86
87
84
86
5.
6.
7.
8.
9.
10.
11.
1:10:10
1:15:15
1:20:20b
82
c
–
a 5 mL of dry methanol was used for 0.1 g of substrate.
b Reaction started with 1:10:10 molar ratio of S:NiCl2:NaBH4 and another lot of 10:10 NiCl2:NaBH4 was added after 2 h.
c Incomplete reaction.
complex mixture of products, unlike the reactions in
dry methanol. Therefore, dry methanol was the solvent
of choice in these reactions. Reaction of 5,5-diphenyl-
2-thiohydantoin (Ia) with sodium borohydride alone in
1:8 molar ratio yielded a mixture of products, whereas
starting material was recovered on reaction with
nickel chloride alone (molar ratio 1:8) under these
conditions. This confirms that the reductive desulfur-
izations are proceeding due to nickel boride generated
in situ.
Nickel boride showed high selectivity toward desul-
furization because it did not affect the carbonyl group
and also no dehalogenated products were obtained in the
Therefore, we conclude that nickel boride is an
efficient reagent for the reductive desulfurization of 5,5-
diaryl-2-thiohydantoins (I) and 5-alkyl-3-phenyl-2-thio-
hydantoins (III) and provides a convenient route for
synthesis of 4-imidazolidones (II and IV) in high yields.
reactions of Ie–h. Reaction of 5,5-di(m-bromophenyl)-2-
thiohydantoin (Ih) in high-molar ratios also did not
show any debromination (Table 1) as only 82 and 86%
of 5,5-di(m-bromophenyl)-4-imidazolidone (IIh) was iso-
lated in runs 9 and 10, respectively. 3,5,5-Triphenyl-2-
thiohydantoin (Ii) did not undergo any reaction and
starting material was recovered unchanged even after
using high-molar ratios (run 11). This could be due to
steric hindrance of the 3-phenyl groups, which prevents
reaction on the surface of catalyst.
EXPERIMENTAL
Starting materials. Methanol (S.D. Fine) was used after
drying by the reported procedure [17]. Nickel (II) chloride
hexahydrate (Thomas Baker Chemicals) was dried by heating
in a crucible till golden yellow, it was then allowed to cool at
room temperature and stored over calcium chloride in a dessic-
cator. Sodium borohydride (E. Merck) was used in all the
reactions. Thiourea (S.D. Fine) was used as such for the prepa-
ration of starting materials. Benzils were prepared from the
corresponding hydrobenzoins by oxidation with NBS [18].
Glycine, alanine, isoleucine, phenylalanine, and proline were
obtained from commercial sources. 5,5-Diaryl-2-thiohydantoins
were prepared by the condensation of thiourea and benzils in
the presence of potassium hydroxide [19]. 5-Alkyl-3-phenyl-2-
thiohydantoins were prepared by the reaction of corresponding
amino acids with aniline, triethyl amine, carbon disulphide,
and methyl iodide [20] and 5-alkyl-2-thiohydantoins were
Reactions of 5-alkyl-3-phenyl-2-thiohydantoins
(IIIa–d) also yielded corresponding 5-alkyl-3-phenyl-
4-imidazolidones (IVa–d) in high yields with nickel
boride [Eq. (2)]. Desulfurization of 2-phenyl-1H-
pyrrolo[1,2-c]imidazol-3-thio-1-one (IIIe) with nickel
boride yielded 2-phenyl-1H-pyrrolo[1,2-c]imidazol-1-
one (IVe) with 89% yield. Synthesis of IVe has been
reported by multistep synthesis [16]. Reactions of 2-
thiohydantoin (Va), 5-methyl-2-thiohydantoin (Vb),
and 5-isopropyl-2-thiohydantoin (Vc) were not clear
and mixtures of products were obtained. All the
results are listed in Table 2.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2009
5,5-Diaryl and 5-Alkyl-3-phenyl-4-imidazolidones: A Novel Synthesis
1009
Table 2
Reactions of 5-alkyl-3-phenyl-2-thiohydantoins and 5-alkyl-2-thiohydantoin with nickel boride in dry methanol at ambient temperature.
Molar ratio
S:NiCl2:NaBH4
Run
Substrate (S)
Reaction time (min)
Product (P)
Yield (%)
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
IIIa
IIIb
IIIc
IIId
IIIe
Va
Va
Vb
Vc
Vc
1:10:10
1:10:10
1:10:10
1:5:5
5
5
3-phenyl-4-imidazolidone (IVa)
5-methyl-3-phenyl-4-imidazolidone (IVb)
5-isobutyl-3-phenyl-4-imidazolidone (IVc)
5-benzyl-3-phenyl-4-imidazolidone (IVd)
2-phenyl-1H-pyrrolo[1,2-c]imidazol-1-one (IVe)
72
92
71
85
10
10
15
150
5
60
15
5
1:10:10
1:5:5a
1:3:9
1:5:5
1:5:5
1:10:10
89 [16]
b
–
–
–
–
–
–
b
–
b
–
b
–
b
–
a Reaction started with 1:3:3 molar ratio of S:NiCl2:NaBH4 and second lot of NiCl2:NaBH4 was added after 60 min.
b Starting material disappeared but number of spots were observed on TLC.
prepared by reaction of amino acids with potassium thiocya-
nate in acetic anhydride [21].
IIf: (0.078 g, 86%), mp 142–145ꢃC; IR: NH 3409, C¼¼O
1
1708 cmꢁ1; H NMR: d 4.43–4.50 (t, 2H, H-2), 7.26–7.59 (m,
Reactions of 2-thiohydantoins. In a typical procedure, 5,5-
diphenyl-2-thiohydantoin (Ia) (0.1 g, 0.37315 mmol), anhy-
drous nickel chloride (0.3851 g, 2.9851 mmol), and dry metha-
nol (5 mL) were placed in a 50 mL round-bottomed flask fitted
with a condenser and a CaCl2 guard tube. The flask was
8H, ArAH); MS ESþ for C15H12N2Cl2O (306): 329 (Mþ
þ
Na). Anal. Calcd. for C15H12N2Cl2O: C, 58.87; H, 3.95; N,
9.15. Found: C, 58.88; H, 3.95; N, 9.14.
IIg: (0.08 g, 87%), mp 176ꢃC; IR: NH 3409, C¼¼O 1708
cmꢁ1 1H NMR: d 4.42 (s, 2H, H-2), 7.26–7.59 (m, 8H,
;
mounted over
a
magnetic stirrer. Sodium borohydride
ArAH); MS ESþ for C15H12N2Br2O (394): 395 (Mþ þ1).
Anal. Calcd. for C15H12N2Br2O: C, 45.74; H, 3.07; N, 7.11.
Found: C, 45.72; H, 3.08; N, 7.10.
(0.1135 g, 2.9851 mmol) was added very cautiously while stir-
ring the solution vigorously. The progress of the reaction was
monitored by TLC using petroleum ether-ethyl acetate as elu-
ent. After disappearance of the starting material, the reaction
mixture was filtered through a celite pad (ꢀ1 inch) and
washed with methanol (1 ꢂ 15 mL). The combined filtrate
was diluted with water (ꢀ50 mL) and extracted with ethyl ace-
tate (3 ꢂ 10 mL). The combined extract was dried over anhy-
drous MgSO4, filtered, and concentrated on a rotary evaporator
to give a new product, which was purified by recrystallization
from ethanol and analyzed by mp, IR, NMR, and mass spectra
as 5,5-diphenyl-4-imidazolidone (IIa) (0.0825 g, 94%) mp
182–183ꢃC (lit. mp 183ꢃC) [15]. All other products were syn-
thesized similarly from the corresponding 2-thiohydantoins.
The spectroscopic data of newly synthesized 4-imidazolidones
is listed as follows.
IIh: (0.0796 g, 84%), mp 110–112ꢃC; IR: NH 3173, C¼¼O
1686 cmꢁ1
;
1H NMR: d ꢁ4.43 (s, 2H, H-2), 7.18–7.84 (m,
8H, ArAH); MS ESþ for C15H12N2Br2O (394): 395 (Mþ þ1).
Anal. Calcd. for C15H12N2Br2O: C, 45.74; H, 3.07; N, 7.11.
Found: C, 45.72; H, 3.08; N, 7.11.
IVa: (0.0610 g, 72%), mp 154ꢃC; IR: NH 3155, C¼¼O 1766
1
cmꢁ1; H NMR: d 3.60–3.62 (d, 2H, H-4), 4.74 (s, 2H, H-2),
7.16–7.57 (m, 5H, ArAH); MS ESþ for C9H10N2O (162): 162
(Mþ). Anal. Calcd. for C9H10N2O: C, 66.69; H, 6.22; N,
17.26. Found: C, 66.70; H, 6.22; N, 17.25.
1
IVb: (0.0786 g, 92%); IR: NH 3292, C¼¼O 1714 cmꢁ1; H
NMR: d 1.44–1.46 (d, 3H, 5-CH3), 3.63–3.70 (q, 1H, H-5),
4.80 (s, 2H, H-2), 7.1644–7.5828 (m, 5H, ArAH); MS ESþ
for C10H12N2O (176): 177 (Mþ þ1). Anal. Calcd. for
C10H12N2O: C, 68.21; H, 6.87; N, 15.91. Found: C, 68.21; H,
6.88; N, 15.90.
IIc: (0.08 g, 89%), mp 170ꢃC; IR: NH 3185, C¼¼O 1699
1
cmꢁ1; H NMR: d 2.32–2.35 (2ꢂ CH3, 6H), 4.39 (s, 2H, H-2),
7.12–7.50 (m, 8H, Ar0AH, Ar00AH); MS ESþ for C17H18N2O
(266): 267 (Mþ þ1). Anal. Calcd. for C17H18N2O: C, 76.72;
H, 6.82; N, 10.53. Found: C, 76.73; H, 6.82; N, 10.52.
IVc: (0.0624 g, 71%), mp 113ꢃC; IR: NH 3284, CAO 1689
1
cmꢁ1; H NMR: d 0.98–1.02 (t, 6H, H-c), 1.47–1.50 (m, 1H,
H-b), 1.85–1.90 (m, 2H, H-a), 3.60–3.63 (d, 1H, H-4), 4.79 (s,
2H, H-2), 7.35–7.57 (m, 5H, ArAH); MS ESþ for C13H18N2O
(218): 219 (Mþ þ1). Anal. Calcd. for C13H18N2O: C, 71.58;
H, 8.32; N, 12.84. Found: C, 71.58; H, 8.33; N, 12.82.
IId: (0.078 g, 88%), mp 150ꢃC; IR: NH 3216, C¼¼O 1710
1
cmꢁ1; H NMR: d 1.99 (s, 3H, CH3), 2.04 (s, 3H, CH3), 4.55
(s, 2H, H-2), 7.11–7.36 (m, 8H, ArAH); MS ESþ for
C17H18N2O (266): 267 (Mþ þ1). Anal. Calcd. for C17H18N2O:
C, 76.72; H, 6.82; N, 10.53. Found: C, 76.72; H, 6.83; N,
10.52.
IVd: (0.0750 g, 85%), mp 140ꢃC; IR: NH 3283, CAO 1682
cmꢁ1 1H NMR: d 3.08–3.24 (m, 2H, ACH2Ph), 3.89 (s, 1H,
;
H-5), 4.53–4.71 (dd, J ¼ 7.2 Hz, 2H, H-2), 7.13–7.52 (m,
10H, ArAH); MS ESþ for C16H16N2O (252): 253 (Mþ þ1).
Anal. Calcd. for C16H16N2O: C, 76.22; H, 6.40; N, 11.11.
Found: C, 76.23; H, 6.40; N, 11.10.
IIe: (0.082 g, 89%), mp 140ꢃC; IR: NH 3308, CAO 1683
1
cmꢁ1; H NMR: d 4.43 (s, 2H, H-2), 7.29–7.36 (m, 4H, 20, 60,
200 and 600-H), 7.49–7.52 (d, J ¼ 8.68 Hz, 2H, 3" and 5"-H),
7.56–7.59 (d, J ¼ 8.44 Hz, 2H, 30 and 50-H); MS ESþ for
C15H12N2Cl2O (306): 307 (Mþ þ1). Anal. Calcd. for
C15H12N2Cl2O: C, 58.87; H, 3.95; N, 9.15. Found: C, 58.87;
H, 3.96; N, 9.15.
IVe: (0.0775 g, 89%), mp 90ꢃC; IR: C¼¼O 1692 cmꢁ1
;
1H
NMR: d 1.82–1.91 (m, 2H, H-6), 2.18–2.25 (q, 2H, H-7),
2.66–2.74 (q, 1H, H-8), 3.24–3.31 (m, 1H, H-8), 3.91–3.95 (t,
1H, H-5), 4.56–4.59 (d, J ¼ 8.29 Hz, 1H, H-2), 4.99–5.02 (d,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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J. M. Khurana, A. Agrawal, and G. Bansal
Vol 46
[8] Granacher, C.; Mahler, M. Helv Chim Acta 1927, 10, 246.
[9] Pfeiffer, U.; Riccaboni, M. T.; Erba, R.; Pinza, M. Liebigs
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J ¼ 8.29, 1H, H-2), 7.14–7.59 (m, 5H, ArAH); MS ESþ for
C12H14N2O (202): 203 (Mþ þ1). Anal. Calcd. for C12H14N2O:
C, 71.31; H, 6.98; N, 13.86. Found: C, 71.31; H, 6.98; N,
13.86.
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Acknowledgments. A. Agrawal is grateful to CSIR, New Delhi,
India for the award of senior research fellowship.
[11] Khurana, J. M.; Gogia, A. Org Prep Proced Int 1997, 29, 1.
[12] Khurana, J. M.; Kukreja, G.; Bansal, G. J Chem Soc Perkin
Trans 1 2002, 1, 2520.
[13] Khurana, J. M.; Kukreja, G. J Heterocycl Chem 2003, 40,
667.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet