Saleem and Tepe
JOCNote
TABLE 1. Scope of the Solvent
SCHEME 1. Proposed Mechanism of Triazoline Formation
solvent
MeCN
DCM
C6H6
THF
Et2O
yield (%)
1
2
3
4
5
94
75
22
26
15
and thiazoles for the synthesis of this triazoline motif.
Anderson and Watt9 have demonstrated the generation of
a triazoline adduct along with a Michael-type addition
product upon the reaction of imidazopyridine with azodi-
carboxylates. Similarly, Tsuge and co-workers10 have uti-
lized azodicarboxylate compounds with N-[(trimethylsilyl)
methyl] iminium triflates to synthesize the imidazolines and
triazolines.
Herein, we report the reaction of the oxazolones with azodi-
carboxylates leading to the formation of 1,2,4-triazolines in
excellent yields at room temperature. Initially, 4-methyl-2-phe-
nyloxazol-5(4H)-one (1)5 was reacted with diethyl azodicarboxy-
late (DEAD) in dichloromethane at room temperature. The
progress of the reaction was monitored by TLC. TLC
indicated the disappearance of 1 from the reaction medium
in 9 h, at which point the product was isolated and identified
to be desired cycloadduct 2 in good yields (Table 1, entry 2).
The reaction was subsequently carried out in a range of
solvents including acetonitrile, benzene, diethyl ether, and
tetrahydrofuran for a period of 9 h at room temperature
(Table 1). Acetonitrile was found to be the superior solvent
for this reaction. Further examination of the reaction pro-
gress in the optimum solvent, acetonitrile, (data not shown)
revealed that compound 1 was quantitatively converted into
compound 2 in 11 h (Table 2). Additional monitoring of
reaction for 24 h did not cause any degradation of the
product or decrease in the yield.
The scope of the reaction was evaluated (Table 2) for
commercially available azodicarboxylate compounds and the
range of the substituents on the oxazolone. Although the
diisopropyl azodicarboxylate (DIAD) is sterically more de-
manding than DEAD, the reaction with DIAD proceeded
smoothly, leading to the excellent yield of the triazoline product
3 (Table 2, entry 2). Similarly, 4-phenyl-1,2,4-triazoline-3,5-
dione (PTAD) also rendered the triazoline product 4 in ex-
cellent yield (Table 2, entry 3). It should be noted that product 4
was prepared as the TMS methyl ester for ease of purification.
Different oxazolones were prepared from N-acyl amino acids,
using trifluoroacetic anhydride as dehydrating agent (see Sup-
porting Information) and were subsequently evaluated for their
reactivity. Different aromatic groups incorporated at the R1
position included a phenyl, p-methoxy phenyl, p-fluoro phenyl,
or p-nitro phenyl moiety. The reaction of the oxazolones with
azodicarboxylates proceeded in very good yields for p-methoxy
phenyl and p-fluoro phenyl moieties (Table 2, entries 5 and 6). As
anticipated, the reaction proceeded significantly more slowly
when the oxazolones were substituted by the electron-withdraw-
ing p-nitro phenyl group (Table 2, entry 4). Switching to a less
polar solvent such as dichloromethane increased the yield in this
case. The reaction was also amendable to changes at the R2
position in most cases. The R2 position was substituted with R2
being a methyl, benzyl, or isopropyl (Table 2, entries 1, 7-9),
which all provided the triazoline product in very good yields.
However, the reaction proceeded more slowly in the presence of
bulky groups such as an isopropyl group and required more time
for completion (24 h).
Additional structural confirmation was established by X-ray
crystallography. The crystals of compound 14 (Table 2, entry 8)
were grown from dichloromethane-hexanes solution and ana-
lyzed by single crystal X-ray crystallography (as shown in
Figure 2 in Supporting Information).
The reaction is believed to proceed via electrophilic attack
of oxazolone to azodicarboxylate leading to the formation of
dipolar intermediate A. This intermediate then undergoes
ring opening, generating nitrilium intermediate B. This
intermediate leads to the cycloadduct upon nucleophilic
attack by the other nitrogen of azodicarboxylate via a 5-
endo-dig-type ring closure (Scheme 1). Although no detailed
mechanistic studies were performed, this mechanism is con-
sistent with all products observed.
Although little is known about the biological properties of
triazolines, the 1,2,4-triazole moiety constitutes the core
structure of a wide range of compounds that have antiviral,
anticancer, anti-inflammatory, and anticonvulsant properties.11
In addition, this core is part of antiviral, antiasthmatic,
antifungal, antibacterial, and hypotonic drugs.12 The 1,2,4-
triazolines produced in this reaction were found to be
excellent precursors to prepare the triazoles.
The triazolines prepared herein were readily converted
into their corresponding triazoles, after decarboxylation and
(11) (a) Todoulou, O. G.; Papadaki-Valiraki, A. E.; Ikeda, S.; De Clercq,
E. Eur. J. Med. Chem. 1994, 29, 611. (b) Bekircan, O.; Kahveci, B.; Kucuk,
M. Turk. J. Chem. 2006, 30, 29. (c) Tandon, M.; Barthwal, J. P.; Bahalla,
T. N.; Bhargava, K. P. Indian J. Chem. 1981, 20B, 1017. (d) Gulerman, N.;
Rollas, S.; Kiraz, M.; Ekinci, A. C.; Vidin, A. Farmaco 1997, 52, 691.
(12) (a) De Clercq, E. J. Clin. Virol. 2004, 30, 115. (b) Naito, Y.;
Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.; Nishimura, H.; Sugiura,
M.; Fukaya, C.; Kagitani, Y. J. Med. Chem. 1996, 39, 3019. (c) Collin, X.;
Sauleau, A.; Coulon, J. Bioorg. Med. Chem. Lett. 2003, 13, 2601. (d)
Papakonstantinou-Garoufalias, S.; Pouli, N.; Marakos, P.; Chytyroglou-
Ladas, A. Farmaco 2002, 57, 973. (e) Hester, J. B.; Rudzik, A. D.; Kamdar,
B. V. J. Med. Chem. 1971, 14, 1078.
(9) Anderson, D. J.; Watt, W. J. Heterocycl. Chem. 1995, 32, 1525.
(10) Tsuge, O.; Hatta, T.; Tashiro, H.; Maeda, H. Heterocycles 2001, 55,
243.
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