One-pot synthesis of phenytoin analogs

Article abstract of DOI:10.1023/B:RUJO.0000034975.03943.bb

A series of phenytoin analogs (5,5-diphenylimidazolidine-2,4-dione or 5,5-diphenyl-hydantoin) were synthesized in 65-75% yield from the corresponding substituted benzils. The same products were also obtained directly from α-hydroxy ketones via one-pot procedure.

Full text of DOI:10.1023/B:RUJO.0000034975.03943.bb

Russian Journal of Organic Chemistry, Vol. 40, No. 3, 2004, pp. 377–382. From Zhurnal Organicheskoi Khimii, Vol. 40, No. 3, 2004,
pp. 406–411.
Original English Text Copyright © 2004 by Mahmoodi, Emadi.
One-Pot Synthesis of Phenytoin Analogs*
N. O. Mahmoodi and S. Emadi
Organic Research Laboratory, Department of Chemistry, University of Guilan, Rasht, 1914, Iran
e-mail: mahmoodi@guilan.ac.ir
Received December 25, 2002
Abstract—A series of phenytoin analogs (5,5-diphenylimidazolidine-2,4-dione or 5,5-diphenyl-
hydantoin) were synthesized in 65–75% yield from the corresponding substituted benzils. The same products
were also obtained directly from α-hydroxy ketones via one-pot procedure.
5,5-Diphenylimidazolidine-2,4-dione or 5,5-di-
phenylhydantoin (PHT) is an antiepileptic drug [1]. In
the recent publication [2], the design and synthesis of
new antiepileptic targets for neuronal voltage-sensitive
sodium channel (NVSC) have been extensively con-
sidered. Study of these model hydantoin derivatives
could provide an important knowledge and predict
how to enhance binding site to NVSC [3]. Structural
information about phenytoin binding site is scanty [3].
The exact location of these sites and structure require-
ments for optimal binding have not yet been deter-
mined. According to the results of recent studies,
5,5-diphenylhydantoin inhibits binding of human
immunodeficiency virus (HIV) to lymphocytes [4],
affects hepatic thyroxine [5], selectively enhances
vincristine cytotoxicity [6], affects myocardial contrac-
tivity and hemodynamics [7], and reduces pesticide
residue in human adipose tissue [8].
In the present article specific attention is given to
the novel synthesis of phenytoin analogs. The
Scheme 1.
R'
O
O
HN
O
NH2CONH2, EtOH
R
NH
IIa–IIe
H2O, NaOH, 2–3 h
O
R'
O
R
R'
Ia–Ie
OH
IIIa–IIIe
R
I–III, R = R' = H (a), R = R' = Me (b), R = Me2N, R' = H (c), R = R' = MeO (d), R = MeO, R' = H (e).
O
HN
O
NH
R
R'
XIV
* The original article was submitted in English.
1070-4280/04/4003-0377 © 2004 MAIK “Nauka/Interperiodica”

MAHMOODI, EMADI
378
Scheme 2.
Ar
Ar'
HO
HN
OH
HO
HN
Ar'
–O
KOH, H2O
urea, reflux
OH–
Ar
Ar'
NH
Ar
II
N
HN
N
–H2O
O
O
O
V
VI
VII
NaOH, urea,
H2O, reflux
NaOH, H2O, EtOH
urea, reflux
Ar
N
R
O
Ar'
NaOH, urea
H2O, EtOH
reflux
COOH
OH
HN
III
O–
VIII
R'
IV
NaOH, urea, H2O, EtOH, reflux
H+
I
Bucherer–Bergs procedure is one of the general
methods which are usually used for the synthesis of
hydantoin [9, 10], in particular for the preparation of
5-substituted hydantoin derivatives containing a non-
aromatic or one phenyl group [2]. Several procedures
for the synthesis of new hydantoin-like compounds
were described previously [10–16]. However, a few
studies have been reported on the preparation of
unsymmetrically substituted hydantoins, e.g., Ic and
Ie, and almost no published data are available on the
synthesis of spiro hydantoins like XIV [17a].
Some symmetrical and unsymmetrical α-diketones,
such as IIa–IIf and XII, were prepared from the
corresponding α-hydroxy ketones IIIa–IIIf and XI by
oxidation with ammonium nitrate in the presence of
copper(II) acetate in acetic acid (Scheme 3) according
to the known procedure [18]. Compound XI was
oxidized with CuSO4 in pyridine [19]. Initial
Scheme 3.
O
Co(OAc)2, NH4NO3
O
H2O–AcOH, reflux
O
O
O
O
HO
O
IIIf
IIf
If
IIf + NH2CONH2
+
CHO
COOH
O
O
IX
X
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

ONE-POT SYNTHESIS OF PHENYTOIN ANALOGS
379
Scheme 4.
NMe2
NMe2
O
O
Urea, NaOH
EtOH
CuSO4, pyridine, H2O
OH
O
Me
Me
XII
XI
α hydroxy ketones were obtained by the benzoin
condensation [20]. We recently reported on enantio-,
regio-, and stereoselective reduction of several α-di-
ketones and aliphatic, aromatic, and prochiral β-di-
ketones and β-keto esters in the presence of
S. Cerevisiae [17b, 17c]. The yields, melting points,
and spectral parameters of the synthesized compounds
are collected in table. One-pot reactions of substituted
benzils IIa–IIf and XII or benzoins IIIa–IIIf and XI
with urea in aqueous ethanol in the presence of sodium
hydroxide afforded the desired phenytoin derivatives
Ia–Ie in 65–75% yield (Scheme 1).
Scheme 2 shows the generally accepted mecha-
nism of the transformation of benzoins III into diaryl-
hydantoins I. Benzilic acid IV could be formed as
intermediate by the action of NaOH and urea on
compounds II and III in aqueous ethanol. The syn-
thesis of benzilic acid from benzoin was reported in
[25]. On the other hand, the condensation of benzoin
with urea is known to afford 4,5-diphenyl-2,3-dihydro-
1H-imidazol-2-one. We have still no rigorous proofs
that acid IV is the key intermediate in the formation of
5,5-diphenylhydantoin. The main difference between
the proposed mechanism (see intermediates IV–VIII
in Scheme 2) and those reported in [22, 26] consists of
facile rearrangement of initially formed benzilic acid,
followed by hydantoin ring closure. There is some
analogy between the benzoin–benzilic acid rearrange-
ment and migration of the aryl group in intermediate
product VII by the action of alkali, which was reported
in [27, 28].
unchanged initial compound XII (Scheme 4). Under
analogous conditions, dimethylamino-substituted ben-
zoin XI was completely converted into benzil XII.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Bruker FT 80 MA2 and Bruker DRX 500 Avance
spectrometers from solutions in CDCl3, acetone-d6, or
DMSO-d6 using tetramethylsilane as internal refer-
ence. The IR spectra were measured on a Shimadzu
Model 470 instrument. The high-resolution mass
spectra were obtained on a Fisons Trio-1000 mass
spectrometer. The melting points were determined
using a Mettler Fp5 melting point apparatus and are
uncorrected. The yields refer to products purified by
recrystallization or by column or thin-layer chromatog-
raphy (central cuts). The products were identified by
comparing their NMR and IR spectral data (see table),
GLC and TLC parameters, and melting points with
those of authentic samples.
2-Hydroxy-l,2-di-p-tolylethanone (IIIb). A 250-
ml round-bottom flask was charged with 50 ml of 96%
ethanol and 30 ml (30.9 g, 25 mmol) of p-methyl-
benzaldehyde (purified by vacuum distillation), a solu-
tion of 2.5 g (38.3 mmol) of KCN in 25 ml of distilled
water was added, and the mixture was stirred for 3 h
on heating under reflux. The progress of the reaction
was monitored by TLC. The unreacted initial aldehyde
was removed by steam distillation. The orange oily
liquid was dissolved in 30 ml of ethanol, and the
solution was left to stand for crystallization. The crude
product was repeatedly (3–4 times) crystallized from
96% ethanol. Yield 16.5 g (55%), white powder,
mp 86–88°C; published data [24]: mp 86–88°C.
We failed to obtain the corresponding substituted
hydantoin If by condensation of furil IIf with urea in
alkaline solution (Scheme 3). Under these conditions,
rearrangement of IIf into furilic acid (by analogy with
the transformation of benzil into benzilic acid [29]) did
not occurr, and the products were 2-furaldehyde IX
and 2-furoic acid X (Scheme 3).
1,2-Di-p-tolyl-1,2-ethanedione (IIb). A 250-ml
round-bottom flask was charged with 10 g (40 mmol)
of compound IIIb, 0.3 g (1.5 mmol) of Cu(OAc)2·
H2O, 10 g (125 mmol) of ammonium nitrate, and
60 ml of 80% acetic acid. The mixture was heated at
the boiling point for 2 h with stirring. The solution was
cooled, and the precipitate was filtered off, dissolved
Likewise, purified 1-(4-dimethylaminophenyl)-2-p-
tolylethane-1,2-dione (XII) failed to react with urea
and NaOH in aqueous ethanol under reflux (reaction
time 7–8 h). After appropriate treatment, we isolated
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

MAHMOODI, EMADI
Yields, melting points, and IR and NMR spectra of compounds I–III, VI, and VII
380
Comp. Yield,
IR spectrum (KBr),
mp, °C (solvent)
1H and 13C NMR spectra, δ, δC, ppm
no.
%
ν, cm–1
75
292 (96% EtOH); 3270 s, 3200 s, 1770 s, 1H (DMSO): 7.2 m (10H), 8.9 s (1H), 10.7 s (1H)
Ia
13C (DMSO): 75.5 126, 128.4, 129, 143, 160, 170.7
286–295 [21]
1720 s, 1710 s
68
65
228 (96% EtOH); 3200 s, 1720 s
230 [22]
1H (DMSO): 2.5 s (6H), 3.5 s (H2O), 7.4 s (8H), 9.3 s (1H),
Ib
Ic
11.2 s (1H); DMSO–D2O: 2.1 s (6H), 4 s (H2O), 7.2 s
(8H)
13C (DMSO): 20.9, 75.4, 128.3, 129.7, 135.1, 140, 160,
170.6
229 (96% EtOH) 3300 s, 3200 s, 1760 s, 1H (DMSO): 2.8 s (6H), 3.2 s (H2O), 6.6 d (2H), 7 d (2H),
1720 s, 1700 s
7.4 s (5H), 9 s (1H), 10.7 s (1H); DMSO–D2O: 2.9 s
(6H), 4.2 s (H2O), 6.8 d (2H), 7.2 d (2H), 7.5 s (5H)
13C (DMSO): 43.5, 75.5, 113.6, 126, 128.4, 129, 129.3,
132.5, 142, 143, 160, 170.5
–
225
222
3200 s, 1720 s
1H (DMSO): 3.8 s (6H), 6.8 d (4H), 7.2 d (4H), 9 s (1H),
10.8 s (1H)
Id
Ie
13C (DMSO): 56, 75.6, 114.5, 129.3, 135.3, 159.6, 160,
170.7
65
3300 s, 3200 s, 1720 s, 1H (CDCl3): 1.5 s (H2O), 3.7 s (3H), 7 m (9H)
1700 s
13C (CDCl3): 56, 75.4, 114.6, 126, 128.4, 129, 129.4, 135.3,
143, 159.4, 160, 170.7
90
71
93 (96% EtOH);
95 [23]
3070 w, 1650 s
1H (CDCl3): 7.5 m (6H), 8 d.d (4H)
IIa
IIb
13C (CDCl3): 129, 130, 133, 135, 195
103 (96% EtOH); 1660 s
102–104 [24]
1H (CDCl3): 2.3 s (6H), 7.2 d (4H, J = 8.2 Hz), 7.7 d (4H,
J = 8.2 Hz)
13C (CDCl3): 22, 130, 130.1, 131, 146, 194
80
71
75
114–116
(96% EtOH)
1675 s, 1630 s
1H (CDCl3): 3 s (6H), 6.6 d (2H), 7.5 m (3H), 7.9 m (4H)
13C (CDCl3): 40, 111, 121, 129, 130, 132, 134, 134.5, 154,
192, 196
IIc
102–104 [24]
66
3460 m, 1650 s
1650 s, 1585 s
1H (CDCl3): 2.3 s (6H), 7.2 d (4H, J = 8.2 Hz), 7.7 d (4H,
J = 8.2 Hz)
IId
IIea
13C (CDCl3): 22, 130, 130.1, 131, 146, 194
1H (CDCl3): 4 s (3H), 7.1 d (2H), 7.7 m (3H), 8.1 d (4H)
13C (CD3COCD3, 125 MHz): 54.9, 114.1, 125.5, 128.7,
129, 131.6, 132.8, 134.4, 164.8, 192.8, 194.6
75
88
166 (96% EtOH); 1640 s
165–166 [23]
1H (CDCl3): 6.7 d.d (2H), 7.7 d.d (2H), 7.8 d.d (2H)
IIf
137 (96% EtOH) 3400 s, 1665 s
[23]
1H (CDCl3): 4.6 d (1H), 6 d (1H), 7.4 m (8H), 8 d (2H)
13C (CDCl3): 75.4, 128, 129, 129.1, 129.3, 129.6, 133, 134,
139, 199
IIIa
55
40
86–88 (96%
EtOH) [24]
3450 s, 1670 s
1H (CDCl3): 2.3 s (3H), 2.4 s (3H), 4.7 d (1H), 7.2 m (6H),
IIIb
IIIc
7.9 d (2H)
13C (CDCl3): 21, 21.4, 75, 127, 129, 130, 130.2, 137.6, 138,
144, 198
162 (96% EtOH); 3400 s, 1650 s, 1600 s 1H (CDCl3): 2.9 s (6H), 4.7 d (1H, J = 6.1 Hz), 5.8 d (1H,
161–163 [19b]
J = 6.1 Hz), 6.5 d (2H, J = 9.1 Hz), 7.2 m (5H), 7.8 d
(2H, J = 9.1 Hz)
13C (CDCl3, DMSO): 39, 75, 110, 120.4, 127, 127.2, 128,
131, 140.6, 153, 196
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

ONE-POT SYNTHESIS OF PHENYTOIN ANALOGS
IR spectrum (KBr),
381
Table. Contd.
Comp. Yield,
no.
mp, °C (solvent)
1H and 13C NMR spectra, δ, δC, ppm
%
ν, cm–1
54
109 (96% EtOH);
109–110 [24]
3450 s, 1670 s, 1600 s
1H (CDCl3): 2.3 s (3H), 2.4 s (3H), 4.7 d (1H), 6 d
IIId
(1H), 7.2 m (6H), 7.9 d (2H)
13C (CDCl3): 21, 21.5, 75, 127, 129, 130, 130.1, 131,
137.5, 138, 144, 198
21
45
106 (96% EtOH);
105–106 [19b]
3460 m, 1650 s, 1600 s 1H (CDCl3, 80 MHz): 3.9 s (3H), 4.7 d (1H, J = 6 Hz),
6 d (1H, J = 6 Hz), 7 d (2H, J = 9 Hz), 7.4 m (5H),
8 d (J = 9 Hz)
IIIe
IIIf
13C (CD3COCD3, 125 MHz): 54.6, 75.2, 113.3, 126.5,
127, 127.4, 128.2, 130.9, 140.1, 163.5, 197
139 (96% EtOH);
138–139 [23]
3400 s, 1665 s
1H (CDCl3): 4.2 d (1H), 5.8 d (1H), 6.4 d.d (2H), 6.6
d.d (1H), 7.3 d.d (1H), 7.4 d.d (1H), 7.6 d.d (2H),
7.7 d.d (2H)
45
78
120 (96% EtOH)
125
3400 s, 1670 s
3430 s, 1600 s
1H (CDCl3): 2.4 s (3H), 3.2 s (6H), 4.9 d (1H), 6 d
(1H), 6.8 d (2H), 7.4 m (4H), 8 d (2H)
VI
1H (CDCl3): 2.4 s (3H), 3.1 s (6H), 6.6 d (2H), 7.2 d
(2H), 7.8 m (4H)
VII
a
Found: M+ 240.0789; calculated: M 240.0783.
in 96 ethanol, and recrystallized with addition of
charcoal. Yield 7.1 g (71%), pale yellow crystals,
mp 103°C; published data [24]: mp 102–104°C.
boiling point under stirring. It was then cooled, and the
precipitate was filtered off, dissolved in 96% ethanol,
and recrystallized. Yield 4.5 g (75%), yellow crystals,
mp 66°C.
2-Hydroxy-1-(4-methoxyphenyl)-2-phenyl-
ethanone (IIIe). A 250-ml round-bottom flask was
charged with 24.3 ml (27.2 g, 0.2 mol) of p-methoxy-
benzaldehyde (purified by vacuum distillation),
22.2 ml (23.3 g, 0.22 mol) of freshly distilled
benzaldehyde, 100 ml of 96% ethanol, and a solution
of 5 g (77 mmol) of KCN in 30 ml of water. The
mixture was heated for 3 h at the boiling point under
vigorous stirring using a magnetic stirrer. When the
mixture warmed up to the boiling point, it became
homogeneous. The unreacted aldehydes and ethanol
were removed by steam distillation. The orange oily
liquid was dissolved in 50 ml of hot ethanol, and the
solution was left to stand for crystallization. The crude
product was a mixture of benzoin and compound IIIe.
Fractional crystallization from 96% ethanol gave
10.2 g (21%) of compound IIIe as colorless crystals
with mp 106°C; published data [19a]: mp 105–106°C.
The product was repeatedly crystallized until its
melting point (105°C) no longer changed.
1-(4-Dimethylaminophenyl)-2-phenyl-1,2-
ethanedione (IIc). Compound IIIc was synthesized as
described above for IIIe. A 250-ml round-bottom flask
was charged with 14 g (56 mmol) of CuSO4·5H2O,
40 ml (39.2 g, 496 mmol) of pyridine, and 30 ml of
distilled water. The mixture was heated on a water
bath with stirring until it became homogeneous, 5.38 g
(20 mmol) of compound IIIc was added, and the mix-
ture was refluxed for 2 h under stirring. The mixture
was cooled, and the crude product was filtered off,
washed with water, and recrystallized from 96%
EtOH. Yield 4.19 g (78%), yellow crystals, mp 125°C.
5,5-Di-p-tolylimidazolidine-2,4-dione (Ib). A 100-
ml round-bottom flask equipped with a reflux
condenser was charged with 5.95 g (25 mmol) of
compound IIb, 3 g (50 mmol) of urea, 15 ml of 40%
aqueous NaOH, and 70 ml of 96% ethanol. The
mixture was heated for 3 h under reflux with stirring,
cooled to room temperature, and poured into 120 ml of
distilled water. The resulting mixture was vigorously
stirred for 15 min, and the precipitate was filtered off,
and recrystallized from 96% ethanol. Yield 2.41 g
(62%), colorless crystals, mp 225°C.
1-(4-Methoxyphenyl)-2-phenyl-1,2-ethanedione
(IIe). A 250-ml round-bottom flask was charged with
6 g (25 mmol) of compound IIIe, 0.3 g (1.5 mmol) of
Cu(OAc)2·H2O, and 9 g (112 mmol) of ammonium
nitrate, and 70 ml of 80% (by volume) aqueous acetic
acid was added. The mixture was heated for 3 h at the
5-(4-Methoxyphenyl)-5-phenylimidazolidine-2,4-
dione (Ie). A 100-ml round-bottom flask equipped
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 3 2004

MAHMOODI, EMADI
382
13. Sarges, R., Schnuer, R.C., Belletire, J.L., and Peter-
with a reflux condenser was charged with 3 g
(12.5 mmol) of compound IIIe, 1.5 g (25 mmol) of
urea, 9 ml of 30% aqueous NaOH, and 40 ml of 96%
ethanol. The mixture was heated for 3 h under reflux
with stirring, cooled to room temperatury, and poured
into 60 ml of distilled water. The resulting mixture was
vigorously stirred for 15 min and filtered, and con-
centrated hydrochloric acid was added to the filtrate
(on cooling with ice) to strongly acidic reaction. The
colorless precipitate was filtered off and recrystallized
from 96% ethanol. Yield 2.51 g (65%), colorless crys-
tals, mp 222°C.
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