Formation and cyclization of N′-(benzoyloxy)benzenecarboximidamides

Article abstract of DOI:10.1134/S1070428011120153

The formation of N′-(benzoyloxy)benzenecarboximidamides and their subsequent cyclization to 3,5-disubstituted 1,2,4-oxadiazoles in different solvents were studied. A probable reaction mechanism was proposed on the basis of the obtained results.

Full text of DOI:10.1134/S1070428011120153

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 12, pp. 1874–1877. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © P.A. Tsiulin, V.V. Sosnina, G.G. Krasovskaya, A.S. Danilova, S.V. Baikov, E.R. Kofanov, 2011, published in Zhurnal Organicheskoi
Khimii, 2011, Vol. 47, No. 12, pp. 1838–1841.
Formation and Cyclization
of N′-(Benzoyloxy)benzenecarboximidamides
P. A. Tsiulin, V. V. Sosnina, G. G. Krasovskaya, A. S. Danilova,
S. V. Baikov, and E. R. Kofanov
Yaroslavl State Technical University, Moskovskii pr. 88, Yaroslavl, 150023 Russia
e-mail: kofanover@ystu.ru
Received April 2, 2011
Abstract—The formation of N′-(benzoyloxy)benzenecarboximidamides and their subsequent cyclization to
3,5-disubstituted 1,2,4-oxadiazoles in different solvents were studied. A probable reaction mechanism was
proposed on the basis of the obtained results.
DOI: 10.1134/S1070428011120153
Compounds containing a 1,2,4-oxadiazole ring are
active components of medical agents used for the treat-
ment of asthma, ischemia, and Parkinson’s disease.
There are published data on antibacterial, anti-inflam-
matory, and anticancer properties of such compounds
[1]. Therefore, studies on the formation of 1,2,4-oxa-
diazoles with a view to improve the existing methods
of their synthesis and develop new more efficient
procedures constitute an important problem.
droxyamidines (Scheme 1, a). Here, the slow reaction
step is the transformation of zwitterion into 3,5-disub-
stituted 4,5-dihydro-1,2,4-oxadiazol-5-ol via proton
transfer from the nitrogen atom to oxygen. In the
presence of strong bases [3, 4] 3,5-disubstituted
1,2,4-oxadiazoles are formed from O-acyl-N′-hydroxy-
amidines according to path b (Scheme 1).
We examined [5–8] the formation of a series of
3,5-disubstituted 1,2,4-oxadiazoles (Scheme 2) and
determined the rate constants k (k1 + k2) for the reac-
tion I→III and the rate constants for the cyclization of
preliminarily synthesized compound II (k2). The latter
was obtained by reaction of N′-hydroxybenzimidamide
Several possible ways (a, b) for the formation of
1,2,4-oxadiazoles from N′-hydroxyamidines have been
proposed. Ooi and Wilson [2] described a scheme for
the reaction of carboxylic acid chlorides with N′-hy-
Scheme 1.
H2N
HO
R
H2N
R
R
O
R'
N
+
–H2O
N
N
R'
Cl
N
O
R'
O
O
(a)
(b)
H
R
R
Slow
H
N
HN
R'
–O
R'
N
N
HO
O
O
O
–O
R'
HO
R'
O
O
N
O
O
N
R'
B–
N
N
N
H+
R'
N
N
N
R
R
R
R
H
H
B–
H
B–
H
1874

FORMATION AND CYCLIZATION OF N′-(BENZOYLOXY)BENZENECARBOXIMIDAMIDES
1875
Scheme 2.
OH
O
Ph
O
N
N
N
k1
k2
Ph
O
NH2
+
PhC(O)Cl
N
NH2
R
R
R
I
II
III
R = H, O2N, Br, Me, MeO.
(I) with benzoyl chloride in toluene at 80°C. The rate
constants were determined following accumulation of
final product III.
imidamide (I) on the reaction rate and determined the
corresponding rate constants (Table 2). It is seen that
the cyclization is favored by electron-donating substit-
uents (cationic transition state). Presumably, the small
absolute value of ρ is related to a weak effect of the
substituent on the carbonyl carbon atom in II and to
the fact that elimination of water molecule from
O-benzoyl derivative II occurs almost synchronously
with its formation [10].
The acylation with benzoyl chloride was carried out
using equimolar amounts of the reactants, the initial
concentration of amidine I being 0.49 M. According to
the IR data, compound II is formed immediately after
mixing solutions of N′-hydroxybenzimidamide and
benzoyl chloride in pyridine at 100°C, and the initial
reactants are consumed completely. The IR spectra of
samples of the reaction mixture contained absorption
bands at 1733, 1251, and 1090 cm–1, which are typical
of esters, while no band at 1774 cm–1 (νC=O in ben-
zoyl chloride) was present.
The reaction was also performed in other solvents:
1,4-dioxane, toluene, and acetic acid. The correspond-
ing values of k and k2 are given in Table 3. The reac-
tion in acetic acid was slow (Table 3), and the yield of
III was 6.3% (20 min, 100°C); in pyridine, the yield of
III was 24.3%, other conditions being equal. Under
analogous conditions the cyclization of O-benzoyl
The following values were obtained in pyridine at
100°C: k = 2.44 ×10–4 ±1.1 ×10–5 (R2 = 0.97), k2 =
2.40×10–4±1.4×10–5 s–1 (R2 = 0.99). The linear rela-
tion between the logarithm of the current concentration
of III and reaction time (R2 = 0.97–0.99) indicates that
the process conforms to first-order kinetics. We also
determined the rate constants for the formation of com-
pound III at different molar reactant ratios (100°C).
Table 1. Activation parameters for the formation of com-
pound III (cI = 0.49 M, I–BzCl ratio 1:1, pyridine)
Temperature, K ∆H≠, J/mol A×10–13, s–1 ∆S≠, J mol–1 K–1
368
373
378
383
115783.12
115741.57
115700.02
115700.02
1.04
1.15
1.21
1.02
–5.71
–5.01
–4.71
–6.20
Ratio I–BzCl
k×104, s–1 (R2 = 0.99)
2:1
1:1
1:2
2.58±0.07 2.44±0.11 2.17±0.16
∆S≠av. = –5.41 J mol–1 K–1; Ea = 118.84±1.217 kJ/mol
A conclusion can be drawn that intramolecular
cyclization of II is the rate-determining stage and that
it is described by first-order kinetic equation. The ac-
tivation parameters were estimated from the tempera-
ture dependence of k (lnk—1/T, R2 = 0.99) in pyridine
at 95–110°C (Table 1).
(R2 = 0.985), ∆H≠av = 115.72 kJ/mol
Table 2. Logarithms of rate constants k and correlation
parameters with substituent constants σ (100°C, pyridine)
R
logk
σ+
σ–
σ
The preexponential factor suggests first order of the
reaction. The entropy of activation indicates insignif-
icant difference in the structures of the transition state
and product III, which may be illustrated by compar-
ing the structures of II and III. The cyclization rules
out the possibility for rotation about the N–O and O–C
bonds in molecule II [9].
H
–3.59
0.00
0.79
0.00
1.27
0.00
0.79
O2N –3.77
Br
–3.65
–3.50
0.15
0.23
0.23
Me
–0.30–
–0.17–
–0.17–
MeO –3.38
–0.76–
–0.27–
–0.27–
We also estimated the effect of substituents in the
para position of the benzene ring of N′-hydroxybenz-
ρ = –0.255 (R2 = 0.98) R2 = 0.75 R2 = 0.88
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

TSIULIN et al.
1876
Table 3. Apparent rate constants k and k2 in different sol-
vents (100°C, c0I = 0.49 M)
centration of compound III versus time in the cycliza-
tion of amidine II in different solvents.
When the reaction is carried in pyridine, liberated
hydrogen chloride is bound with the solvent, whereas
in toluene and acetic acid initial N′-hydroxybenzimid-
amide molecule takes up liberated HCl (Scheme 3).
Presumably, this is the factor responsible for the lower
reaction rate. Moreover, pyridine is capable of reacting
with benzoyl chloride with formation of active ionic
compound which is a strong acylating agent [9];
therefore, addition of pyridine accelerates the process.
Solvent
k×104, s–1
k2 ×104, s–1
Pyridine
2.44±0.14
–
2.44±0.11
0.30±0.02
12.31±0.510
1.17±0.02
Toluene
Acetic acid
1,4-Dioxane
0.51±0.05
1.02±0.05
derivative II in acetic acid was faster than in pyridine
(Table 3); this means that the rate-determining stage in
acetic acid is the formation of compound II
(Scheme 2). Compound II was formed in toluene, and
N′-hydroxybenzimidamide salt precipitated (Scheme 3).
cI :cPy
k×104, s–1
R2
01:0.25
1:0.5
1.244±0.099
2.066±0.171
2.089±0.229
0.969
0.967
0.943
1:1.2
Scheme 3.
OH
O
Ph
N
N
N
Taking the above into account, we can conclude
that the mechanism of reaction of carboxylic acid
chlorides with N′-hydroxy amidines is determined by
the reaction medium.
+
PhC(O)Cl
HCl
+
HCl
Cl–
O
Ph
Ph
NH2
OH
Ph
NH2
H
OH
H
OH
N
N
In basic medium (pyridine, dioxane) the rate-deter-
mining stage is intramolecular cyclization of N′-(ben-
zoyloxy)benzimidamide (II), which is likely to follow
Scheme 4. Base catalyzes proton transfer in the dehy-
dration stage.
··
··
··
NH2
NH2
Ph
NH2
Ph
H
OH
N
Cl–
Ph
NH2
In acid (acetic acid) and neutral media (toluene) the
rate-limiting step is the formation of compound II. The
higher rate of cyclization in acetic acid is likely to be
determined by protonation of 3,5-diphenyl-4,5-dihy-
dro-1,2,4-oxadiazol-5-ol, which facilitates its subse-
quent transformation into iminium cation (Scheme 4).
The cyclization of II in toluene was slower than in
pyridine. Both reactions in 1,4-dioxane (Table 3)
occurred at a higher rate than in toluene, but they were
slower than in pyridine. Figure shows the plots of con-
cIII, M
1
2
0.12
0.08
0.04
0.00
3
4
Time, s
0
400
800
1200
1600
Cyclization of N′-(benzoyloxy)benzimidamide (II) in (1) glacial acetic acid, (2) pyridine, (3) 1,4-dioxane, and (4) toluene.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011

FORMATION AND CYCLIZATION OF N′-(BENZOYLOXY)BENZENECARBOXIMIDAMIDES
1877
Scheme 4.
N
O
PhMe
O–
Ph
Ph
Ph
N
~H+
O
H
H
O
Ph
N
N
O
O
N
O
N
N
~H+
Pyridine
N
O–
OH
Ph
PyH+
Ph
Ph
Ph
Ph
O
–H2O
N
H
N
H
N
Ph
Ph
NH2
–AcOH
O
N
O
AcOH
OH
Ph
OH2
Ph
Ph
AcO–
Ph
Ph
N
H
N
H
N
AcO–
H
EXPERIMENTAL
(C–O), 1090 (C–O). 1H NMR spectrum, δ, ppm: 6.99 s
(2H, NH2), 7.51 m (5H, Harom), 7.65 t (1H, Harom, J =
7.4 Hz), 7.79 d (2H, Harom, J = 7.7 Hz), 8.20 d (2H,
The IR spectra were recorded on a Perkin–Elmer
Spectrum RX-1 spectrometer from samples dispersed
in mineral oil. The 1H NMR spectra were measured on
a Bruker MSL 300 spectrometer from solutions in
DMSO-d6 using tetramethylsilane as reference. Sol-
vents and auxiliary reagents were prepared according
to the procedures described in [11, 12].
Harom, J = 7.4 Hz).
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N′-(Benzoyloxy)benzimidamide (II). A mixture of
10 g (0.074 mol) of N′-hydroxybenzimidamide and
10.3 g (0.074 mol) of benzoyl chloride in 50 ml of
toluene heated to 80°C was kept for 5 min, the mixture
was filtered while hot, the filtrate was cooled to 20°C
and kept for 2 h at room temperature, and the precip-
itate was filtered off and dried. Yield 4.6 g (26%),
colorless powder, mp 124–125°C. IR spectrum, ν,
cm–1: 3309 (NH2), 1732 (C=O), 1640 (C=N), 1250
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 12 2011