Synthesis of benzoic acids containing a 1,2,4-oxadiazole ring

Article abstract of DOI:10.1007/s11172-015-0833-6

A new approach to the synthesis of 4and 3-(5-R-1,2,4-oxadiazol-3-yl)benzoic acids via a selective oxidation of 5-R-3-tolyl-1,2,4-oxadiazoles with air oxygen in the presence of a catalytic system based on cobalt acetate was suggested. This synthesis allowed us to obtain the products in higher yields and with shorter sequence of steps as compared to the known procedures.

Full text of DOI:10.1007/s11172-015-0833-6

Russian Chemical Bulletin, International Edition, Vol. 64, No. 1, pp. 142—145, January, 2015
142
Synthesis of benzoic acids containing a 1,2,4ꢀoxadiazole ring
G. G. Krasouskaya,a A. S. Danilova,a S. V. Baikov,b A. V. Kolobov,a and E. R. Kofanova
aYaroslavl State Technical University,
88 Moskovskii prosp., 150023 Yaroslavl, Russian Federation.
Eꢀmail: kofanover@ystu.ru
bK. D. Ushinsky Yaroslavl State Pedagogical University,
108 ul. Respublikanskaya, 150000 Yaroslavl, Russian Federation
A new approach to the synthesis of 4ꢀ and 3ꢀ(5ꢀRꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzoic acids via
a selective oxidation of 5ꢀRꢀ3ꢀtolylꢀ1,2,4ꢀoxadiazoles with air oxygen in the presence of a cataꢀ
lytic system based on cobalt acetate was suggested. This synthesis allowed us to obtain
the products in higher yields and with shorter sequence of steps as compared to the known
procedures.
Key words: 1,2,4ꢀoxadiazole, catalytic oxidation, methylarenes, benzoic acids.
Benzoic acids with the attached 1,2,4ꢀoxadiazole
agents.8,9 Therefore, we supposed that the methyl group in
the aromatic ring conjugated with the 1,2,4ꢀoxadiazole
ring can be selectively oxidized. With this approach, the
steps of introduction and removal of protecting groups
can be avoided (pathway II in Scheme 1).
Catalytic liquidꢀphase oxidation with air oxygen is one
of the efficient and feasible processes, corresponding to
the principles of "green chemistry", and at present is widely
used in chemical industry and laboratory synthesis.10,11
system and their derivatives are of great importance for
medicinal chemistry due to a wide range of useful biologiꢀ
cal properties.1—4 For example, 3ꢀ[5ꢀ(2ꢀfluorophenyl)ꢀ
1,2,4ꢀoxadiazolꢀ3ꢀyl]benzoic acid is an active substance
of the Ataluren agent used for elimination of the conseꢀ
quences of nonsense mutations.5 Besides, benzoic acid
derivatives under consideration are used to develop liquid
crystalline materials, sensors, and optical devices.6,7
Compounds of this series are commonly synthesizꢀ
ed by a sequence of reactions (pathway I) shown in
Scheme 1.1—6 Earlier, we have shown that alkyl and cycloꢀ
alkyl groups at position 5 of 1,2,4ꢀoxadiazole ring (exꢀ
cept the isopropyl group) are stable to various oxidizing
Results and Discussion
We studied a model oxidation reaction of 5ꢀmethylꢀ3ꢀ
pꢀtolylꢀ1,2,4ꢀoxadiazole (1a) to acid 2a with air oxygen in
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0142—0145, January, 2015.
1066ꢀ5285/15/6401ꢀ0142 © 2015 Springer Science+Business Media, Inc.

Benzoic acids with 1,2,4ꢀoxadiazole cycle
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
143
Scheme 3
solution of acetic acid (Scheme 2). The liquidꢀphase oxiꢀ
dation with oxygen can be catalyzed by different systems,11
among which systems based on cobalt(II) salts are more
efficient and easy available.11 In the present work, we studꢀ
ied several systems containing Co(AcO)2. Sodium bromide
was used as a second component. In a number of cases,
special promoting additives were used. The data obtained
are given in Table 1.
Scheme 2
i. [O], Co(AcO)2, NaBr, AcOH, 95 C.
As it is seen from Table 2, for most substrates the reacꢀ
tion proceeded selectively and acids 2b—g were obtained
in good yields. However, the oxidation of compound 1h
gave rise to 2ꢀcyanobenzoic acid (3) only. The formation
of the latter can be described by Scheme 4.
Initially, the methyl group of the aromatic ring is oxiꢀ
dized. Then, probably, due to the intramolecular hydroꢀ
gen bond the carboxy group facilitates the oxidation of the
methyl group at position 5 of the heterocycle. The formed
compound 4 is prone to decarboxylation.12 The resulting
1,2,4ꢀoxadiazole 5 is also unstable and disintegrates folꢀ
lowing the mechanism of retro 1,3ꢀdipolar cycloaddition.13
In conclusion, a convenient method for the preparaꢀ
tion of benzoic acids containing a 1,2,4ꢀoxadiazole fragꢀ
ment and aliphatic, aromatic, and heterocyclic substituꢀ
Independent of the catalyst, the methyl group of the
aromatic ring exclusively underwent the oxidation. Three
catalytic systems (see Table 1, entries 2, 4, 9) showed
comparable results, and we have chosen the catalyst conꢀ
sisting of Co(AcO)2 and NaBr for further studies.
No oxidation with this catalytic system took place at
~20 C (see entry 10), but already at 45 C the yield of acid 2a
was 67%, whereas an increase in the reaction time to 11 h at
95 C allowed us to obtain the target acid 2a in 94% yield.
The selected conditions were used to oxidize a series of
compounds 1b—h (Scheme 3). The results are given in
Table 2.
Table 1. Catalytic oxidation of compound 1a with air oxygen in a solution of acetic acida
Entry
Amount of components of catalytic
system/mmol
Yield of product 2a
(%)
Co(AcO)2
NaBr
Special additivesb
1
2
3
4
5
6
7
8
0.65
1.3
0.65
1.3
1.3
0
1.3
0.13
0.13
1.3
1.3
1.3
0.65
1.3
1.3
1.3
1.3c
1.3
1.3
0
—
—
29
87
31
85
0
0.65 (Mn(AcO)2)
0.13 (Mn(AcO)2)
—
1.3 (Mn(AcO)2)
130 (TFA)
0.013 (Mn(AcO)2), 1.3 (NHPI)
0
0
35
86
0
67
94
9
0
0.013 (Mn(AcO)2), 1.3 (NHPI), 3.9 (HNO3)
10d
11e
12f
1.3
1.3
1.3
—
—
—
a Reaction time 9 h, 95 C.
d 25 C.
b TFA is trifluoroacetic acid, NHPI is Nꢀhydroxyphthalimide.
e 45 C.
c A 40% aqueous hydrobromic acid was a source of bromine ions (Br–).
f 11 h.

144
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
Krasouskaya et al.
Scheme 4
ents at position 5 was developed. This method can be
easily scaled, since it uses an inexpensive and safe oxidant,
air oxygen. The catalytic system components are also
available and can be regenerated. The target product can
be isolated by common filtration without additional puriꢀ
fication.
Experimental
H and 13C NMR spectra were recorded on a Bruker
DRXꢀ500 spectrometer in DMSOꢀd6, mass spectra were obtained
on a GC/MS Perkin—Elmer Clarus 500 instrument, ionization
by electron impact. IR spectra were recorded on a Spectrum
1
Table 2. Oxidation of compounds 1b—h with air oxygen in solution of acetic acid*
Starting compound Product
Yield (%)
(1b)
(2b)
90
(1c)
(1d)
(1e)
(1f)
(2c)
(2d)
(2e)
(2f)
86
81
75
90
(1g)
(1h)
(2g)
(3)
85
82
* Reaction time 11 h, 95 C; AcOH : 1a—h : Co(AcO)2 : NaBr = 698 : 13 : 1.3 : 1.3 (mmol).

Benzoic acids with 1,2,4ꢀoxadiazole cycle
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 1, January, 2015
145
RX1 Fourierꢀtransform IR spectrometer in Nujol suspensions using
KBr plates. Melting points were determined on a NAGEMA
PHMKꢀ05 heating stage. Starting 3ꢀtolylꢀsubstituted 1,2,4ꢀoxadiꢀ
azoles 1a—h were synthesized from commercially available nitriles
(Sigma—Aldrich Co.) according to the known procedures.14—16
Oxidation of 4ꢀ and 3ꢀmethylꢀ5ꢀRꢀ1,2,4ꢀoxadiazoles (general
procedure). Oxidation process was carried out in an ideal mixing
reactor. A starting methylarene 1a—h (13 mmol), cobalt acetate
(1.3 mmol), and sodium bromide (1.3 mmol) were dissolved in
glacial acetic acid (40 mL). Then, the solution was heated to
95 C and air was fed to the reactor. The reaction mixture was
allowed to stand for 11 h at 95 C and cooled to ~20 C,
a precipitate formed was filtered.
(Irel (%)): 284 [M]+ (22), 267 (19), 239 (34), 189 (29), 163 (100),
146 (28), 118 (31), 146 (21), 130 (12), 89 (17), 77 (32). 1H NMR,
: 7.51 (t, 2 H, Ar, J = 8.9 Hz); 7.88 (d, 2 H, Ar, J = 8.8 Hz); 8.09
(m, 1 H, Ar); 8.17 (d, 2 H, Ar, J = 8.9 Hz); 8.31 (s, 1 H, Ar); 13.26
(br.s, 1 H, OH). 13C NMR, : 111.7, 117.4, 125.5, 127.8, 129.8,
130.1, 131.1, 131.8, 132.2, 135.8, 161.3, 166.5, 167.4, 172.7.
2ꢀCyanobenzoic acid (3). The yield was 82%, m.p. 210—212 C.
MS (70 eV), m/z (Irel (%)): 147 [M]+ (100), 104 (72), 103 (34),
90 (4), 76 (88), 74 (20),66 (6), 50 (41). 1H NMR, : 7.80 (s, 4 H,
Ar); 11.31 (s, 1 H, OH).
References
4ꢀ(5ꢀMethylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzoic acid (2a). The yield
was 94%, m.p. 225—226 C. IR, /cm–1: 2670 (OH); 1686 (C=O);
1594 (Ar); 1289 (C—O). MS (70 eV), m/z (Irel (%)): 204 [M]+ (78),
187 (3), 163 (100), 146 (31), 118 (14), 102 (5), 90 (9), 88 (9). 1H NMR,
: 2.70 (s, 3 H, Me); 8.11 (s, 4 H, Ar); 13.26 (br.s, 1 H).
13C NMR, : 11.91, 126.99, 129.98, 133.10, 166.51, 166.92, 177.68.
3ꢀ(5ꢀMethylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzoic acid (2b). The
yield was 90%, m.p. 211—112 C. IR, /cm–1: 2675 (OH); 1693
(C=O); 1595 (CAr); 1284 (C—O). MS (70 eV), m/z (Irel (%)):
204 [M]+ (77), 187 (2), 163 (100), 146 (15), 118 (25), 102 (6),
90 (10), 88 (9), 76 (6), 75 (6), 63 (6), 62 (6), 51 (9), 50 (7), 43 (31).
1H NMR, : 2.70 (s, 3 H, Me); 7.71 (t, 1 H, Ar, J = 7.8 Hz); 8.14
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1
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Received April 21, 2014;
in revised form July 25, 2014