62 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 62±63$
Microwave-assisted Heterogeneous Benzil±Benzilic
Acid Rearrangement$
Hui-Ming Yu,a Same-Ting Chen,a Min-Jen Tseng,a Shui-Tein Chena
and Kung-Tsung Wang*a,b
aInstitute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan
bDepartment of Chemistry, National Taiwan University, Taipei, 10098, Taiwan
A new procedure for carrying out the benzil±benzilic acid rearrangement in the solid state has been developed which
provides a new route to synthesize the pharmacologically interesting anticonvulsant dilantin.
Some simple benzilic acid derivatives show pronounced
pharmacological activity,2 for example the sodium salt of
5,5'-diphenylhydantoin, the anticonvulsant Dilantin. In 1838
von Liebig1 described the hydroxide ion induced transform-
ation of benzil, an a-diketone, into benzilic acid, the salt
of an a-hydroxy acid. In this hydroxide ion-catalyzed
rearrangement reaction, the favoured solvents are water and
aqueous ethanol. Heterogeneous conditions with hydroxide
ion in organic solvents have also been employed.3 The
reactions may take up to 4 days when conducted at room
temperature or 10 min to 24 h under re¯ux. Recently,
Toda et al.4 have developed a method for carrying out the
benzil±benzilic acid rearrangement in the solid state at 80 8C
(giving 0±95% yield in 0.1 h to 6 h) and some reactions
were found to proceed more quickly than in solution.
We report here the solid state microwave-enhanced benzil±
benzilic acid rearrangement.5
If powdered KOH and benzil are ground together with a
pestle and mortar, and irradiated in a domestic microwave
over, they burnt due to the tendency of KOH to adsorb
the microwave energy. Therefore, two drops of water were
added to the KOH crystals to dissolve them, then benzil
was added and the mixture ground with a pestle to form
a milky material. Some Celite was added to absorb the
milky material and it was ground again. The resulting solid
<?show mixture was transferred to a Te¯on beaker and
irradiated in a household microwave oven for 15 s ®rst and
then for 10 s intervals for the indicated times (Table 1). The
benzil rearrangement reactions proceeded safely using this
sample preparation procedure. The results are outlined in
Table 1.
was dicult to dissolve in common organic solvents prob-
ably due to the eect of its lattice energy.
In conclusion, the benzil±benzilic acid rearrangement
reaction using microwave-irradiation not only shortens the
reaction time but also increases yields. In addition the
simple reaction protocol of microwave-irradiation also
provides an advantage over the traditional heating method
in organic solvents.
Experimental
Methanol, ethyl acetate, methylene chloride, diethyl ether, and
dimethylformamide (HPLC grade and reagent grade) were obtained
from a local supplier, the ALPS Chem. Co. (Taiwan). Potassium
hydroxide, Celite, hydrochloric acid, and anhydrous sodium sulfate
were purchased from Fluka A. G. (Switzerland). A Tatung micro-
wave oven (model TMO-110, Tatung Co., Taipei, Taiwan) with
adjustable power level was used for microwave irradiation. NMR
spectra were taken on a Bruker AM-400 and chemical shifts of
the 1H NMR spectra were referenced to solvent peaks. J values
are in Hz. TLC was performed on silica gel G pre-coated plates
(E. Merck, Germany), HPLC was run on an Alcott 760-HPLC
pump (Japan) with a Soma 3701 UV-Detector (Japan) and data
collected on a Hewlett-Packard HP 3394A Integrator (USA).
General Procedures for Microwave-assisted Solid State Reaction.Ð
To solid KOH (0.56 g, 10 mmol) was added water (0.1 ml) and the
resulting solution allowed to stand for 2 min to dissolve the KOH.
Powdered benzil (0.42 g, 2 mmol) was added to the KOH and the
mixture was well-ground with a pestle to form a milky material.
Then to this mixture, Celite (5 ml) was added and the resulting mix-
ture was ground again. The ®nal mixture was irradiated in a dom-
estic microwave oven (70% of full power) for 15 s ®rst and then
three times for 10 s (compound 1, ®ve times; compound 2, ®ve
times; compound 3, four times; compound 4, three times; compound
5, eleven times and once for 15 s). Diethyl ether (5 ml) was added to
the mixture, which was stirred for a while, ®ltered and the mixture
acidi®ed to pH 1.5 with 3 M HCl (25 ml) and then extracted with
ethyl acetate (100 ml). The organic phase was dried over MgSO4
and concentrated to give benzilic acid 1 as a white solid. Compound
1 (0.393 g, 86% yield), mp 146±148 8C (lit.,6 mp 150±153 8C); ꢀH
(400 MHz, [2H6]DMSO) ꢀH 7.35±7.24 (10 H, m), 3.38 (1 H, br).
In a similar procedure, compounds 2±5 were synthesized. Their
yields and physical data are: compound 2 (0.642 g, 95% yield), mp
163±164 8C; dH (400 MHz, [2H6]DMSO) 7.87 (4 H, d, J 7.0), 6.85
(4 H, d, J 7.0), 3.71 (6 H, s), 3.38 (1 H, br); compound 3 (0.476 g,
93% yield), mp 127±128 8C; dH (400 MHz, [2H6]DMSO) 7.33±7.11
(8 H, m), 3.41 (1 H, br), 2.26 (6 H, s); compound 4 (0.585 g,
Generally, without microwave irradiation, the benzil
derivatives with electron-donating groups took a long time
to complete the rearrangement reaction at 80 8C in the
solid state; for example the para-methoxy derivative gives
only 32% yield after 6 h.4 In contrast, under microwave
irradiation, there was not much dierence between electron-
donating and withdrawing groups on benzil; both reactions
gave satisfactory yields in a very short time (<1 min in
most cases). In entry 5 the reason for the low yield from
4,4'-dibromobenzil is not clear. However, this compound
Table 1 Microwave-assisted heterogeneous benzil±benzilic acid rearrangements Ar1C(:O)C(:O)Ar2 4 Ar1C(OH)(CO2H)Ar2
Entry
Ar1
Ar2
Irradiation time/s
Isolated yield (%)
Mp/8C
1
2
3
4
5
C6H5
C6H5
45
65
55
45
86
95
93
98
56
146±148
163±164
127±128
135±136
216±218
p-MeC6H4
p-MeOC6H4
o-ClC6H4
p-BrC6H4
p-MeC6H4
p-MeOC6H4
o-ClC6H4
p-BrC6H4
145
*To receive any correspondence.
98% yield), mp 135±136 8C (lit.,6 mp 136±138 8C); dH (400 MHz,
[2H6]acetone) 7.49±7.31 (8 H, m), 3.40 (1 H, br); compound 5
(0.429 g, 56% yield), mp 216±218 8C; dH (400 MHz, [2H6]DMSO)
7.50 (4 H, d, J 6.9), 7.30 (4 H, d, J 6.9).
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).