Versatile access to benzhydryl-phenylureas through an unexpected rearrangement during microwave-enhanced synthesis of hydantoins

Article abstract of DOI:10.1021/ol035282x

(Equation presented) A new access to benzhydryl-phenylureas is described. These new interesting urea derivatives were obtained by reaction of substituted benzils with substituted phenylureas under microwave irradiation. Phenylthiourea, when reacted with benzil, gave 3-phenyl-thiohydantoin. Moreover, benzylurea, as phenethylurea, gave the corresponding 3-substituted hydantoin derivatives, demonstrating that only phenylurea derivatives can result in benzhydryl-phenylureas under the applied conditions. This new reaction proved to be an easy access to substituted 1-benzhydryl-3-phenyl-ureas.

Full text of DOI:10.1021/ol035282x

ORGANIC
LETTERS
2
003
Vol. 5, No. 20
599-3602
Versatile Access to
3
Benzhydryl-Phenylureas through an
Unexpected Rearrangement during
Microwave-Enhanced Synthesis of
Hydantoins
Giulio G. Muccioli, Johan Wouters, Jacques H. Poupaert,†
†
‡,§
‡
|
⊥
Bernadette Norberg, Wolfgang Poppitz, Gerhard K. E. Scriba, and
Didier M. Lambert*,
†
Unit e´ de Chimie Pharmaceutique et de Radiopharmacie, Ecole de Pharmacie,
Facult e´ de M e´ decine, UniVersit e´ catholique de LouVain, AVenue E. Mounier 73,
UCL-CMFA 7340, B-1200 Bruxelles, Belgium, Laboratoire de Chimie Mol e´ culaire
Structurale, Facult e´ des Sciences, Facult e´ s UniVersitaires Notre Dame de la Paix,
Rue de Bruxelles, 61, 5000 Namur, Belgium, Department of Inorganic and Analytical
Chemistry, UniVersity of Jena, August-Bebel-Strasse 2, 07743 Jena, Germany,
and Department of Pharmaceutical Chemistry, UniVersity of Jena, Philosophenweg 14,
D-07743 Jena, Germany
lambert@cmfa.ucl.ac.be
Received July 11, 2003
ABSTRACT
A new access to benzhydryl-phenylureas is described. These new interesting urea derivatives were obtained by reaction of substituted benzils
with substituted phenylureas under microwave irradiation. Phenylthiourea, when reacted with benzil, gave 3-phenyl-thiohydantoin. Moreover,
benzylurea, as phenethylurea, gave the corresponding 3-substituted hydantoin derivatives, demonstrating that only phenylurea derivatives
can result in benzhydryl-phenylureas under the applied conditions. This new reaction proved to be an easy access to substituted 1-benzhydryl-
3-phenyl-ureas.
In the course of the investigation of Biltz’s synthesis of
phenytoin, we have developed a microwave-enhanced syn-
thesis in order to obtain phenytoin and N-3 alkyl phenytoin-
related compounds in high yields and short reaction times
starting from benzil and alkylurea by using an unmodified
1
domestic microwave oven. The use of microwaves in
2
chemical synthesis, which was first reported by Gedye and
3
4
Giguere in 1986, has become a widely used method.
†
Universit e´ catholique de Louvain.
Facult e´ s Universitaires Notre Dame de la Paix.
Present address: IRMW, av. E. Gryzon 1, 1070 Brussels, Belgium.
Department of Inorganic and Analytical Chemistry, University of Jena.
(1) Muccioli, G. G.; Poupaert, J. H.; Wouters, J.; Norberg, B.; Poppitz
W.; Scriba, G. K. E.; Lambert, D. M. Tetrahedron 2003, 59, 1301-1307.
(2) (a) Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Labege,
L.; Rousell, J. Tetrahedron Lett. 1986, 27, 279-282. (b) Gedye, R.; Smith,
F.; Westaway, K. Can. J. Chem. 1987, 66, 17-26.
‡
§
|
⊥
Department of Pharmaceutical Chemistry, University of Jena.
1
0.1021/ol035282x CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/09/2003

Scheme 1. Reaction of Benzil Derivatives (1) with Phenylurea
Derivatives (2a)
Table 1. Yields after Recrystallization (Ethanol) of the
-Benzhydryl-3-phenylureas (3a-d) Obtained from Substituted
1
Benzil (1) and Phenylurea (2a) under Microwave-Assisted
Conditions
compound
X
yield
3
3
3
3
a
b
c
H
F
Cl
Br
59%
50%
48%
50%
d
Moreover, a growing number of papers report the use of
household microwave ovens to speed-up chemical reactions.
5
under classical reflux conditions (thermal heating).11 Even
under these conditions, the resulting products were the
1-benzhydryl-3-phenylurea derivatives, proving that the
microwaves are not responsible for obtaining these com-
pounds. Nevertheless, it is noteworthy that the yields were
slightly lower under the reflux conditions compared to the
microwave-assisted conditions (data not shown).
In the early 1990s, Bose and co-workers described the
microwave-induced organic reactions enhancement (MORE)
method, where reactions are carried out in unsealed vessels
in unmodified domestic microwave ovens using selected
solvents.6
Herein, we wish to report that an unexpected reaction
yielding 1-benzhydryl-3-phenylurea (3, X ) H), instead of
Since only 5.5 min of actual transfer energy (total pulse
time) was necessary during the microwave procedure,
compared to the 4 h requested for the thermal one, to obtain
similar yields, we can assume that the reaction in the
microwave procedure is 40 times faster than the thermal one.
As an open system was used for the microwave procedure,
this rate enhancement was not due to higher temperatures
reached during this procedure. This acceleration effect on
reactions conducted under microwave irradiation was already
shown in the early 1990s. X-ray analysis of compound 3c
was carried out in order to confirm that the obtained
compounds were 1-benzhydryl-3-phenylurea derivatives
(Figure 1). All compounds have NMR spectral data consis-
tent with their proposed structure.
7
3,5,5′-triphenylhydantoin, has been obtained from benzil (1,
X ) H) and phenylurea (2a, X ) H) in DMSO-aqueous
KOH under microwave irradiation. Although unexpected, this
reaction turned out to be an excellent method for obtaining
benzhydryl-phenylurea derivatives (3-8) (Scheme 1), which
may represent a new template for medicinal chemistry
applications. To the best of our knowledge, only two authors
have reported the synthesis of such derivatives. Their
1
2
procedures are hampered either by a long reaction time (over
8
1
8 h) or by poor flexibility with respect to the substitution
9
of the phenyl rings.
Thus, we report an easy, rapid, and original pathway to
this type of compounds.
Several para-halogenated benzils (1, X ) F, Cl, or Br)
have been reacted10 with phenylurea as examples of this
reaction to assess whether the deactivating effect of the
halogens has an influence on the resulting compounds. Apart
from a slightly reduced yield, the halogens had no effect on
the reaction (Table 1).
To assess whether these products were obtained as a result
of any “microwave effect”, the reactions were carried out
(
3) Giguere, R. J.; Bray, T. L.; Duncan, S. M.; Majetich, G. Tetrahedron
Lett. 1986, 27, 4945-4948.
4) Two interesting reviews dealing with microwave-assisted chemistry
(
are: Larhed, M.; Hallberg, A. Drug DiscoVery Today 2001, 6, 406-416.
Lidstr o¨ m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 571,
9
225-9283.
(
5) (a) Kappe, O. C.; Kumar, D.; Varma, R. S. Synthesis 1999, 10, 1799-
Figure 1. ORTEP diagram of compound 3c.
1
7
803. (b) Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Synthesis 2002, 1,
5-78. (c) Campbell, L. J.; Borges, L. F.; Heldrich, F. J. Bioorg. Med.
Chem. Lett. 1994, 4, 2627-2630. (d) Stadler A.; Kappe, C. O. J. Chem.
Soc., Perkin Trans. 2 2000, 1363-1368.
Another part of the investigation was the possibility of
substituting the phenyl ring of the phenylurea with halogens.
(6) (a) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Shah, M.; Raju, V. S.;
Bari, S. S.; Newaz, S. S.; Banik, B. K.; Chaudhary, A. G.; Barakat, K. J.
J. Org. Chem. 1991, 56, 6968-6970. (b) Banik, B. K.; Manhas, M. S.;
Kaluza, Z.; Barakat, K. J.; Bose, A. K. Tetrahedron Lett. 1992, 33, 3603-
(10) General Procedure for the Microwave-Assisted Method. To a
solution of 3 g of benzil (14.3 mmol) and 1.94 g of phenylurea (28.6 mmol)
in 25 mL of DMSO was added 25 mL of 1.2 M aqueous KOH under stirring.
Following an initial 90 s, 750W microwave irradiation, the mixture was
stirred for 5 min. Additional 30 s pulses were applied at 6, 9, 12, 15, 18,
21, 24, 30 min. Between pulses the mixture was stirred. After the completion
of the sequence, the mixture was poured onto cold water, the resulting
precipitate was filtered, dried, and recrystallized from a suitable solvent.
All microwave irradiations were carried out in an open system.
3
606. (c) Bose, A. K.; Jayaraman, M.; Okawa, A.; Bari, S. S.; Robb, E.
W.; Manhas, M. S. Tetrahedron Lett. 1996, 37, 6989-6992. (d) Bose, A.
K.; Manhas, M. S.; Ganguly, S. N.; Sharma, A. H.; Banik, B. K. Synthesis
2
002, 1578-1591.
(
7) Also termed 3,5,5′-triphenylimidazolidine-2,4-dione.
(8) Henneuse, C.; Boxus, T.; Tesolin, L.; Pantano, G.; Marchand-
Brynaert, J. Synthesis 1996, 4, 495-501.
(9) Schramm, H. W. Sci. Pharm. 1991, 59, 115-122.
3600
Org. Lett., Vol. 5, No. 20, 2003

Table 2. Yields after Recrystallization of Some
-Benzhydryl-3-phenylureas (4-8) Obtained from Benzil (1)
Scheme 2. Reaction of Benzil (1) with Phenylthiourea (2b)
Leading to the 3,5,5′-Triphenyl-2-thioxo-imidazolidin-4-one
1
and Substituted Phenylurea (2a, X ) H) under Microwave
Irradiation
compound
X
X′
yield
4
5
6
7
8
H
H
Cl
Br
Br
Cl
I
Br
Br
I
52%
45%
47%
48%
43%
phenylthiourea (2b) resulted in 3,5,5′-triphenyl-2-thioxo-
imidazolidin-2-one (11) as shown in Scheme 2.
This substitution did not affect the reaction as illustrated in
Scheme 1 and Table 2.
To investigate how benzylurea and phenethylurea would
react with benzil derivatives under these conditions, benzil
13
Summarizing the results, only phenylurea (2a), possibly
substituted, when reacted with a benzil derivative will yield
the 1-benzhydryl-3-phenylurea derivative (3-8). Neither
benzylurea nor phenylthiourea will give a benzhydryl deriva-
tive. This could be interesting for an understanding of the
reaction mechanism, which has not yet been elucidated.
Nevertheless, on the basis of the present results, we propose
a mechanism (Scheme 3) involving the condensation of
(1, X ) H), 4,4′-difluorobenzil (1, X ) F), 4,4′-dibromoben-
zil (1, X ) Br), and 4,4′-dimethoxybenzil (1, X ) OMe)
were reacted with the urea derivatives.
Scheme 3. Proposed Mechanism for the Synthesis of
1
-Benzhydryl-3-phenylurea (3a) from Benzil (1) and Phenylurea
a
(2b)
Figure 2. Structure of 3-benzyl-5,5′-diphenylhydantoins (9a-d)
and 3-phenethyl-5,5′-diphenylhydantoins (10a-c).
a
As shown in Figure 2, the reaction products were always
the corresponding 3-benzyl-5,5′-diphenylhydantoins (9a-
d) or 3-phenethyl-5,5′-diphenylhydantoins (10a-c). The
First condensation step is followed by a benzilic rearrangement
and then by a decarboxylation leading to 3a.
3
-benzyl-5,5′-phenylhydantoins and 3-phenethyl-5,5-phenyl-
benzil (1) and phenylurea (2a), followed by a benzilic
rearrangement. The subsequent decarboxylation step results
in the final compound (3a).
hydantoins that have been synthesized are listed in Table 3.
A common bioisosteric replacement in medicinal chem-
istry is the substitution of an oxygen atom by a sulfur.
Reaction under microwave irradiation of benzil (1) with
The initial condensation step is identical with the first step
in the synthesis of the 5,5′-diphenylhydantoin derivatives,
but the intramolecular nucleophilic attack by the nitrogen
bearing the phenyl, resulting in a five-membered ring and
Table 3. 3-Benzyl- and 3-Phenethyl-hydantoins Synthesized
from Benzil Derivative (1) and either Benzylurea or
Phenethylurea under Microwave Irradiation
14
then the hydantoin, is replaced by the nucleophilic attack
by a hydroxide ion leading to a carboxylate. It is likely that
the phenylthiourea gives the 2-thio-hydantoin compound (11)
due to its more acidic proton, compared to the phenylurea
one, which promotes the cyclization pathway.
compound
X
yield
9
9
9
9
0a
0b
0c
a
b
c
H
F
Br
OMe
H
60%
54%
50%
56%
64%
55%
57%
(11) General Procedure for the Classical Method. As used for 9, but
the reacting mixture was refluxed over a period of 4 h instead of receiving
the microwave pulse sequence.
d
1
1
1
(12) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei, K.;
Cl
OMe
Urbanczyk-Lipokwska, Z. Heterocycles 1990, 30, 741-744.
(13) Also termed 3,5,5′-triphenyl-2-thio-hydantoin.
(14) Hayward, R. C. J. Chem. Educ. 1983, 60, 512.
Org. Lett., Vol. 5, No. 20, 2003
3601

Acknowledgment. G.M. is very indebted to “Fonds pour
Supporting Information Available: Procedures for the
la formation a` la Recherche dans l’Industrie et l’Agriculture
synthesis of benzil and urea derivatives and full characteriza-
1
13
(FRIA)”, Belgium, for the award of a research fellowship.
tion for synthesized compounds (IR, H NMR, C NMR,
MS, elemental analysis). This material is available free of
charge via the Internet at http://pubs.acs.org.
This work was partially funded by a FRSM grant from the
Belgian National Fund for Scientific Research and by a FSR
grant from the Universit e´ catholique de Louvain.
OL035282X
3602
Org. Lett., Vol. 5, No. 20, 2003