Reactions of 2-arylhydrazonoacetamidoximes with orthoesters

Article abstract of DOI:10.1007/s11172-011-0139-2

The reactions of 2-arylhydrazono-2-carbamoylacetamidoximes with orthoesters afford either 3-arylhydrazono-1,2,4-oxadiazoles or 1,2,3-triazoles, depending on the reactant structure.

Full text of DOI:10.1007/s11172-011-0139-2

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 889—895, May, 2011
889
Reactions of 2ꢀarylhydrazonoacetamidoximes with orthoesters*
N. P. Belskaya,a A. V. Koksharov,a S. G. Lesogorova,a P. A. Slepukhin,b and V. A. Bakuleva
aUral Federal University named after the First President of Russia B. N. Eltsyn,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Eꢀmail: belska@mail.ustu.ru
bI. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation
The reactions of 2ꢀarylhydrazonoꢀ2ꢀcarbamoylacetamidoximes with orthoesters afford either
3ꢀarylhydrazonoꢀ1,2,4ꢀoxadiazoles or 1,2,3ꢀtriazoles, depending on the reactant structure.
Key words: hydrazones, amidoximes, 1,2,3ꢀtriazoles, 1,2,4ꢀoxadiazoles, orthoesters,
heterocyclization.
We have earlier1,2 shown that the reaction of 2ꢀarylꢀ
hydrazonoꢀ2ꢀcyanoacetamides 1 with orthoesters 2 is
a convenient method for the construction of the 1,2,4ꢀ
triazine system (Scheme 1). This reaction can afford
2,5ꢀdihydrotriazinones 3 or 2,3,4,5ꢀtetrahydrotriazinoꢀ
nes 4, depending on the substitution pattern in the amide
fragment.
compounds. Hydrazones containing amidoxime function
along with the amide fragment seemed to be an interesting
object for the study. Aminoximes are reactive compounds
involved in a wide range of chemical transformations
affording various oxygenꢀ and nitrogenꢀcontaining heteroꢀ
cycles.3 Alkylꢀ and arylamidoximes are the most studied
representatives of this type of compounds. No reactions of
hydrazones containing the amidoxime groups with orthoꢀ
esters were studied earlier. Therefore, the purpose of the
present work is to study the reactions of arylhydrazono
amidoximes with orthoesters and to determine regularities
of this reaction at various structures of the starting reacꢀ
tants and conditions of the process.
Scheme 1
Hydrazones with amidoxime group 5a—h were synꢀ
thesized by the reaction of arylhydrazonocyanoacetamides
1a—h with hydroxylamine hydrochloride in the presence
of a base (Scheme 2).
Scheme 2
i. Xylene.
1: R1 = Ar, NR2R3 = H, Alk; 2: R4 = H (a), Me (b), Et (c);
3: R1 = Ar, R4 = H, Me, Et; 4: R1 = Ar, R2 = Alk
1, 5: R1 = 4ꢀClC6H4, NR2R3 = NHMe (a), NHEt (b), cycloꢀC6H11NH (c),
NHBn (d), pyrrolidinꢀ1ꢀyl (e); R1 = 4ꢀMeOC6H4, NR2R3 = NHMe (f),
NHBn (g), pyrrolidinꢀ1ꢀyl (h)
We supposed that the introduction of additional funcꢀ
tional fragments into a molecule of hydrazonoacetamides 1
can change the reaction mechanism or cyclization direcꢀ
tion and can result in the formation of other heterocyclic
The IR spectra of hydrazone derivatives 5a—h exhibit
intense absorption bands of stretching vibrations of the NH
and OH bonds in a region of 3300—3500 cm–1 and the
absorption band corresponding stretching vibrations of the
1
С=О bond at 1670 cm–1. The Н NMR spectra of comꢀ
* Dedicated to Academician V. N. Charushin on the occasion of
his 60th birthday.
pounds 5 contain two sets of signals of the protonꢀconꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 869—875, May, 2011.
1066ꢀ5285/11/6005ꢀ889 © 2011 Springer Science+Business Media, Inc.

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Belskaya et al.
taining groups in a ratio of 1 : 1 or 3 : 2, which can be
the result of formation of two geometrical isomers relative
to the С=N bond of the hydrazone group or amidoxime
fragment.
C=O bond of the formyl substituent. The 1Н NMR specꢀ
tra of 2,5ꢀdihydroꢀ1Hꢀ1,2,3ꢀtriazoles 7 in DMSOꢀd6 soꢀ
lution contain signals of protons of the aromatic ring and
the substituent in the amide fragment and two broad sigꢀ
nals of the protons N(1)H and С(7)Н of tautomeric form A
(Scheme 4) and two broad signals from N(6)H and С(7)Н
corresponding to tautometric form В. In the 1Н NMR
spectrum of 1,2,3ꢀtriazole 7a in CDCl3, the signals of the
protons N(6)H and С(7)Н are presented by the AB system.
The reaction of arylhydrazono amidoximes 5 with triꢀ
ethyl orthoformate was carried out in DMF at room temꢀ
perature in the presence of catalytic quantities of boron
trifluoride etherate (Scheme 3). Two types of compounds
were formed (TLC), which were separated by fractional
crystallization from ethanol. Based on the analysis of
the spectral data for one of them, we proposed the strucꢀ
ture of 2ꢀarylhydrazonoꢀ2ꢀ(1,2,4ꢀoxadiazolꢀ4ꢀyl)acetꢀ
amide 6a—c, whose formation is the result of heteroꢀ
cyclization involving nucleophilic centers of the amidꢀ
oxime group.
Scheme 4
Scheme 3
The 13С NMR spectrum of each triazole 7a—c contain
two broadened signals for each carbon atom С(4), С(5),
and С(7)Н of the formyl residue. The detection of the 1Н
and 13C NMR spectra at 30 and 100 °С showed that these
double signals are brought together and form one signal.
This confirms the presence of a dynamic process in the
structure of compounds 7, which is due to the tautomeric
transformation between two forms.
Triazoles 7 are formed in the monocyclic variant of the
Boulton—Katritzky rearrangement (MRH) of 1,2,4ꢀoxaꢀ
diazoles 6.4—9 These transformations are characteristic of
compounds capable of forming pentalene structures in
which all the three heteroatoms (in our case, N—N—O)
involved in the rearrangement are almost linear. The
Eꢀisomer of 1,2,4ꢀoxadiazoles 6 has a favorable spatial
configuration for this rearrangement to occur, for which
pentalene transition state A can be formed (Scheme 5) due
to the nucleophilic attack of the amine nitrogen atom of
the hydrazone group to the cyclic nitrogen atom N(2).
ZꢀIsomer
EꢀIsomer
i. R3 = H; HC(OEt)3, BF3•OEt2, DMF, 20 °C
6, 7: R1 = 4ꢀClC6H4, NR2R3 = NHMe (a), NHEt (b),
cycloꢀC6H11NH (c)
As compared to the 1Н NMR spectra of starting comꢀ
pounds 5a—c, no changes in position and multiplicity of
the signals caused by resonance of the protons of the
NHꢀhydrazone group and NHꢀalkylamide group are obꢀ
Scheme 5
1
served in the Н NMR spectra of compounds 6a—c, but
the oneꢀproton singlet is present at δ 9.5—9.7 correspondꢀ
ing to the signal of the proton of the C(5)Hꢀoxadiazole
cycle and signals of the protons of the NH2 and NOH
groups are absent.
The structure of 2ꢀarylꢀ5ꢀformyliminoꢀ2,5ꢀdihydroꢀ
1Нꢀ1,2,3ꢀtriazoleꢀ4ꢀalkylcarboxamides 7a—c was ascribed
1
to minor products on the basis of the data of Н and 13С
NMR spectroscopy, IR spectroscopy, mass spectrometry,
and elemental analysis.
Unlike the IR spectra of oxadiazoles 6a—c, the abꢀ
sorption spectra of 1,2,3ꢀtriazoles 7a—c display a band at
1710 cm–1 characteristic of stretching vibrations of the

Reaction of amidoximes with orthoesters
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
891
The Zꢀisomer is not involved in this rearrangement
and, most likely, at room temperature is isolated as hydrꢀ
azoneꢀcontaining oxadiazole 6. It can be assumed that on
heating the Zꢀisomer can be transformed into the Eꢀisoꢀ
mer and then rearranged.
O(2)
C(18)
N(4)
N(3)
C(1)
C(2)
Indeed, reflux of compound 6а in orthoester excess
gave the same compound 7a (Scheme 6).
O(3)
C(3)
C(13)
N(2)
C(14)
C(15)
N(1)
N(5)
C(10)
C(5)
C(12)
C(17)
Scheme 6
C(9)
C(8)
O(1)
C(11)
C(4)
C(16)
C(6)
C(7)
Fig. 1. General view of molecule 7f and the numeration of atoms
accepted in structural experiments.
The Xꢀray diffraction results show that compound 7f
crystallize in the centrosymmetric symmetry space group.
The bond lengths and bond angles of the compounds are
close to standard values. The aryl substituent of triazole
lies almost in the heterocycle plane, and the angle beꢀ
tween the rootꢀmeanꢀsquare planes is 6.5(2)°. At the same
time, the phenyl substituent of the benzyl fragment is unꢀ
folded almost perpendicularly to the triazole plane (the
angle between the rootꢀmeanꢀsquares is 89.0(2)°). Except
for the atoms of the phenyl ring, the deviation of the atꢀ
oms from the rootꢀmeanꢀsquare plane of the azole cycle
does not exceed 0.305(2) Å (deviation of the О(2) atom of
the terminal carbonyl group), and the molecule as a whole
can be considered planar. The crystal packing is characꢀ
terized by the presence of planar dimers formed by interꢀ
molecular hydrogen bonds N(4)H(4)..O(2) [–x, –y + 1,
–z – 1] between the formamide fragments (Table 1).
In addition to this, intermolecular hydrogen bonds
N(5)H(5)...O(3) [x, –y + 3/2, z + 1/2] occur between the
amide fragments binding the molecules into polymer
chains in which the planes of the triazole rings are orientꢀ
ed relatively to each other at an angle of 75.0(2)° and the
phenyl substituents are oriented almost in parallel (the
dihedral angle between the rings is 10.9(2)°, and the disꢀ
tance between the centroids С(5)С(6)С(7)С(8)С(9)—
С(10)...С(5)С(6)С(7)С(8)С(9)С(10) [x, –y + 3/2, z + 1/2]
is 4.605(2) Å).
R1 = 4ꢀClC6H4
The hydrazone group and amide fragment interact with
triethyl orthoformate much more slowly and, hence, no
cyclic products corresponding to tetrahydrotriazines 8 are
formed involving these moieties.
The study of the temperature effect on the yield and
duration of the reaction of arylhydrazono amidoximes with
triethyl orthoformate showed that raising the temperaꢀ
ture to 50 °C shortens the duration time to 3 h, and
5ꢀformyliminoꢀ1,2,3ꢀtriazoles 7 grow as the only prodꢀ
ucts (Scheme 7).
Scheme 7
The molecular packing contains no pronounced π—πꢀ
contacts. As a result, the molecular packing has a compliꢀ
cated motif in which the ladderꢀparquet packing of zones
of polar contacts of the triazole fragments is supplementꢀ
ed by the stack packing of the nonpolar aryl substituents.
Hydrazonoacetamidoximes 1e,h containing the N,Nꢀdiꢀ
substituted carbamoyl group at the carbon atom of the
hydrazone group react with orthoesters in different manꢀ
ner: their heating with triethyl orthoformate affords prodꢀ
ucts of intramolecular cyclization, viz., aminoisoxazoles
9a,b (Scheme 8).
7: R1 = 4ꢀClC6H4, R2 = Me (a), Bn (d); R1 = 4ꢀMeOC6H4,
R
2 = Me (e), Bn (f)
The Xꢀray diffraction data for 2,5ꢀdihydroꢀ1Нꢀ1,2,3ꢀ
triazole 7f confirmed the structure of the compounds conꢀ
sidered (Fig. 1).

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Belskaya et al.
Table 1. Hydrogen bonds with H...A < r(A) + 2.000 Å and angle D—H—A > 110°
D—H
d/Å
Angle
D—H—A
/deg
A
D—H
H...A
D...A
N(4)—H(4)
N(4)—H(4)
N(5)—H(5)
0.852(15)
0.852(15)
0.835(14)
2.273(15)
2.322(15)
2.150(15)
3.029(2)
2.908(2)
2.887(2)
148(1)
126(1)
147(1)
O(2) [–x, –y + 1, –z – 1]
O(3)
O(3) [x, –y + 3/2, z + 1/2]
Scheme 8
ture. The results obtained make it possible to perform the
target synthesis of various types of azoles by the variation
of the structure of the starting reactants or temperature
conditions of the process.
Experimental
1
Н and 13С NMR spectra were obtained on Bruker WМꢀ250
and Bruker AVANCE II 400 instruments (250.13 and 400.00 MHz
1
for Н and 100.00 MHz for 13С) in DMSOꢀd6 or CDCl3 soluꢀ
9: R1 = 4ꢀClC6H4 (a), 4ꢀMeOC6H4 (b)
tions using Me4Si as an internal standard. IR spectra were meaꢀ
sured on a Bruker Alpha FTꢀIR spectrometer (NPVO, ZnSe).
Mass spectra were recorded on a Varian МAТ 311A instrument
at an ionization energy of 70 eV. The reaction course and indiꢀ
vidual character of the synthesized substances were monitored
by TLC on Sorbfil UVꢀ254 plates in ethyl acetane—hexane (1 : 1),
chloroform—acetone (30 : 1), and chloroform—hexane—acetone
(5 : 4 : 1) systems. DMF was purified according to a standard
procedure. Arylhydrazonocyanacetamides were synthesized acꢀ
cording to a method described previously.1,2
The reaction of arylhydrazonoamidoximes 5a,d,f,g with
triethyl orthoacetate 2b and triethyl orthopropionate 2c
(Scheme 9) afford only 1,2,4ꢀoxadiazoles 11a—f, and the
alkylation of the hydrazone nitrogen atom occurs along
with heterocyclization.
Scheme 9
3ꢀAminoꢀ3ꢀhydroxyiminoꢀ2ꢀarylhydrazonoꢀNꢀalkylpropanꢀ
amides 5 (general procedure). A solution of NH2OH•HCl (0.25 g,
3.6 mmol) and NaHCO3 (0.3 g, 3.6 mmol) in water (20 mL) was
added to a suspension of hydrazone 1 (3 mmol) in DMF (50 mL),
and the mixture was stored for 4.5—5 h at 60 °C, cooled, and
diluted with water. The precipitate was filtered off and recrystalꢀ
lized from EtOH.
3ꢀAminoꢀ2ꢀ(4ꢀchlorophenylhydrazono)ꢀ3ꢀhydroxyiminoꢀNꢀ
methylpropanamide (5a). The yield was 0.62 g (78%), m.p.
170—171 °C. IR, ν/cm–1: 1670 (СО); 3310, 3350, 3430, 3440,
3510 (NH, OH). 1H NMR (DMSOꢀd6), δ: 2.75 (d, 3 H, NHCH3,
J = 4.9 Hz); 5.58, 6.70 (both s, 2 H, NH2); 7.36—7.40 (m, 4 H, Ar);
8.20, 9.40 (both q, 1 H, NHMe, J = 4.9 Hz); 10.07, 10.19 (both s,
1 H, OH); 13.24, 13.40 (both s, 1 H, NH). A mixture of Еꢀ and Zꢀisoꢀ
mers in a ratio of 1 : 1. Found (%): C, 44.78; H, 4.56; N, 25.84.
C10H12ClN5O2. Calculated (%): C, 44.54; H, 4.48; N, 25.97.
3ꢀAminoꢀ2ꢀ(4ꢀchlorophenylhydrazono)ꢀNꢀethylꢀ3ꢀhydroxyꢀ
iminopropanamide (5b). The yield was 0.75 g (88%), m.p.
140—141 °C. IR, ν/cm–1: 1665 (СО); 3310, 3340, 3445, 3550
(NH, OH). 1H NMR (DMSOꢀd6), δ: 1.28 (t, 3 H, CH2CH3,
J = 6.9 Hz); 4.22 (dq, 2 H, NHCH2Me, J = 7.0 Hz, J = 5.5 Hz);
5.56, 6.68 (both s, 2 H, NH2); 7.35—7.41 (m, 4 H, Ar); 8.33
(t, 1 H, NHCH2, J = 5.5 Hz); 10.05, 10.17 (both s, 1 H, OH);
13.23, 13.38 (both s, 1 H, NH). A mixture of Еꢀ and Zꢀisomers
in a ratio of 1 : 1. Found (%): C, 46.65; H, 4.63; N, 24.43.
C11H14ClN5O2. Calculated (%): C, 46.57; H, 4.97; N, 24.68.
3ꢀAminoꢀ2ꢀ(4ꢀchlorophenylhydrazono)ꢀNꢀcyclohexylꢀ3ꢀhydrꢀ
oxyiminopropanamide (5c). The yield was 0.76 g (75%), m.p.
11: R1 = 4ꢀClC6H4, R4 = Me, R2 = Me (a), Bn (b);
R
4 = Et, R2 = Me (c); R1 = 4ꢀMeOC6H4, R4 = R2 = Me (d),
Bn (e); R4 = Et, R2 = Bn (f)
The structure of compounds 11a—f was confirmed by
spectral methods and elemental analysis.
Thus, the studies showed that arylhydrazonoamiꢀ
doximes 5 are very reactive compounds. Unlike arylhydrꢀ
azonoacetamides 1, they undergo intramolecular cyclizaꢀ
tion or react with orthoesters already at room temperaꢀ

Reaction of amidoximes with orthoesters
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
893
160—161 °C. IR, ν/cm–1: 1670 (СО); 3310, 3350, 3430, 3440,
3510 (NH, OH). 1H (DMSOꢀd6), δ: 1.22—1.95 (m, 10 H,
5 CH2); 3.72—3.84 (m, 1 H, CH); 5.59, 6.69 (both s, 2 H, NH2);
7.34—7.42 (m, 4 H, Ar); 8.35 (d, 1 H, NHCH, J = 7.2 Hz);
10.09, 10.17 (both s, 1 H, OH); 13.22, 13.38 (both s, 1 H, NH).
A mixture of Еꢀ and Zꢀisomers in a ratio of 2 : 3. Found (%):
C, 53.26; H, 5.87; N, 20.82. C15H20ClN5O2. Calculated (%):
C, 53.33; H, 5.97; N, 20.73.
3ꢀAminoꢀNꢀbenzylꢀ2ꢀ(4ꢀchlorophenylhydrazono)ꢀ3ꢀhydroxyꢀ
iminopropanamide (5d). The yield was 0.82 g (82%), m.p.
152—153 °С. IR, ν/cm–1: 1680 (СО); 3300, 3345, 3570 (NH,
OH). 1H NMR (DMSOꢀd6), δ: 4.15, 4.49 (both d, 2 Н, NHСН2,
J = 6.4 Hz); 5.52, 6.61 (both s, 2 H, NH2); 7.12—7.37 (m, 9 H,
Ar); 8.57, 10.14 (both t, 1 H, NHCH2, J = 6.4 Hz); 9.90, 10.06
(both s, 1 H, NOH); 13.56, 13.87 (both s, 1 H, NH). A mixture
of Еꢀ and Zꢀisomers in a ratio of 1 : 1. MS, m/z (Irel (%)): 345 [М]+
(25). Found (%): C, 55.39; H, 4.59; N, 20.81. C6H16ClN5O2.
Calculated (%): C, 55.58; H, 4.66; N, 20.25.
2ꢀ(4ꢀChlorophenylhydrazono)ꢀNꢀhydroxyꢀ3ꢀoxoꢀ3ꢀ(pyrrolꢀ
idinꢀ1ꢀyl)propanamidine (5e). The yield was 0.74 (80%), m.p.
185—186 °С. 1H NMR (DMSOꢀd6), δ: 1.85—1.90 (m, 4 H,
CH2); 3.23—3.28 (m, 2 H, CH2); 3.43—3.50 (m, 2 H, CH2);
5.27, 6.28 (both s, 2 H, NH2); 7.12 (d, 2 H, Ar, J = 8.4 Hz);
7.30—7.45 (m, 2 H, Ar); 9.69, 9.99 (both s, 1 H, NOH); 12.43,
15.78 (both s, 1 H, NH). A mixture of Еꢀ and Zꢀisomers in a ratio
of 1 : 5. MS, m/z (Irel (%)): 309 [М]+ (46). Found (%): C, 50.55;
H, 5.27; N, 22.70. C13H16ClN5O2. Calculated (%): C, 50.41;
H, 5.21; N, 22.61.
3ꢀAminoꢀ3ꢀhydroxyiminoꢀ2ꢀ(4ꢀmethoxyphenylhydrazono)ꢀNꢀ
methylpropanamide (5f). The yield was 0.60 g (75%), m.p.
135—136 °С. 1H NMR (DMSOꢀd6 + CCl4), δ: 2.77 (d, 3 H,
NHCH3, J = 4.8 Hz); 3.74 (s, 3 H, OMe); 5.45 (s, 1 H, NH2);
6.60 (br.s, 1 H, NH2); 6.83, 7.24, 6.83, 7.27 (two АА´ХХ´ sysꢀ
tems, 4 H, Ar, J = 8.5 Hz); 7.83, 9.00 (both q, 1 H, NHMe,
J = 4.8 Hz); 9.75, 9.88 (both s, 1 H, NOH); 13.37, 13.85 (both s,
1 H, NH). A mixture of Еꢀ and Zꢀisomers in a ratio of 2 : 3. MS,
m/z (Irel (%)): 265 [М]+ (58). Found (%): C, 49.72; H, 5.66;
N, 26.54. C11H15N5O3. Calculated (%): C, 49.81; H, 5.70; N, 26.40.
3ꢀAminoꢀNꢀbenzylꢀ3ꢀhydroxyiminoꢀ2ꢀ(4ꢀmethoxyphenylꢀ
hydrazono)propanamide (5g). The yield was 0.70 g (68%), m.p.
105—106 °С. 1H NMR (DMSOꢀd6 + CCl4), δ: 3.74 (s, 3 H,
OMe); 4.43, 4.48 (both d, 2 Н, СН2, J = 6.4 Hz); 5.51, 6.60
(both s, 2 H, NH2); 6.84 (d, 2 H, Ar, J = 9.2 Hz); 7.17—7.33
(m, 7 H, Ar); 8.53, 10.10 (both t, 1 H, NHСH2, J = 6.4 Hz); 9.81,
9.95 (both s, 1 H, NOH); 13.48, 13.88 (both s, 1 H, NH).
A mixture of Еꢀ and Zꢀisomers in a ratio of 2 : 3. MS, m/z (Irel (%)):
341 [М]+ (31). Found (%): C, 59.57; H, 5.50; N, 20.80.
C17H19N5O3. Calculated (%): C, 59.81; H, 5.61; N, 20.52.
NꢀHydroxyꢀ2ꢀ(4ꢀmethoxyphenylhydrazono)ꢀ3ꢀoxoꢀ3ꢀ(pyrrolꢀ
idinꢀ1ꢀyl)propionamidine (5h). The yield was 0.64 g (70%), m.p.
190—191 °С. 1H NMR (DMSOꢀd6), δ: 1.87—1.91 (m, 4 H,
CH2); 3.24—3.29 (m, 2 H, CH2); 3.42—3.50 (m, 2 H, CH2);
3.72, 3.73 (both s, 3 H, OMe); 5.12, 5.94 (both s, 2 H, NH2);
6.75, 7.04, 6.84, 7.19 (two АА´ХХ´ systems, 4 H, Ar, J = 9.2 Hz);
9.36, 10.03 (both s, 1 H, NOH); 9.86, 12.89 (both s, 1 H, NH).
A mixture of Еꢀ and Zꢀisomers in a ratio of 1 : 3. MS, m/z (Irel (%)):
305 [М]+ (20). Found (%): C, 54.95; H, 6.25; N, 22.98.
C14H19N5O3. Calculated (%): C, 55.07; H, 6.27; N, 22.94.
Reactions of arylhydrozonoacetamidoximes 5 with orthoesters
(general procedures). Method A. Triethyl orthoformate (2 mL)
and 1—2 droplets of BF3•OEt2 were added to a solution of amidꢀ
oxime 5 (1.0 mmol) in DMF (10 mL). The reaction mixture was
stored for 20—24 h at ~20 °C and diluted with 100 mL of water,
and the precipitate was filtered off and crystallized from EtOH.
After crystallization, the filtrate was diluted with water, and the
precipitate that formed was filtered off.
Method B. Triethyl orthoformate (2 mL) and 1 droplet of
BF3•OEt2 were added to a solution of amidoxime 5 (1.0 mmol)
in DMF (10 mL). The reaction mixture was stored for 3—4 h at
50 °C and diluted with water. The precipitate that formed was
filtered off and recrystallized from ethanol.
2ꢀ(4ꢀChlorophenylhydrazono)ꢀNꢀmethylꢀ2ꢀ(1,2,4ꢀoxadiazolꢀ
3ꢀyl)acetamide (6а). Method A, the yield was 0.14 g (50%), m.p.
110—111 °С. IR, ν/cm–1: 1680 (CO); 3330, 3370 (NH). 1H NMR
(DMSOꢀd6), δ: 2.78, 2.87 (both d, 3 H, NHCH3, J = 4.8 Hz);
7.30, 7.37 (AA´XX´ system, 4 H, Ar, J = 8.5 Hz); 8.31, 8.37
(both q, 1 H, NHMe, J = 4.8 Hz); 9.57, 9.67 (both br.s, 1 H,
CH); 13.58 (br.s, 1 H, NH). Found (%): C, 47.11; Н, 3.73;
N, 25.34. C11H10ClN5O2. Calculated (%): C, 47.24; Н, 3.60;
N, 25.04.
2ꢀ(4ꢀChlorophenylhydrazono)ꢀNꢀethylꢀ2ꢀ(1,2,4ꢀoxadiazolꢀ3ꢀ
yl)acetamide (6b). Method A, the yield was 0.19 g (65%), m.p.
135—136 °С. IR, ν/cm–1: 1640 (CO); 2845, 2930 (CH); 3210,
3280, 3315 (NH). 1H NMR (DMSOꢀd6), δ: 1.21 (t, 3 H,
CH2CH3, J = 7.0 Hz); 3.37 (dq, 2 H, NHCH2CH3, J = 7.1 Hz,
J = 5.1 Hz); 7.29, 7.39 (AA´XX´ system, 4 H, Ar, J = 9.2 Hz);
8.43 (t, 1 H, NHCH2, J = 5.1 Hz); 9.48 (s, 1 H, CH); 14.00
(s, 1 H, NH). Found (%): C, 48.93; Н, 3.85; N, 24.57.
C12H12ClN5O2. Calculated (%): C, 49.07; Н, 4.12; N, 23.84.
2ꢀ(4ꢀChlorophenylhydrazono)ꢀNꢀcyclohexylꢀ2ꢀ(1,2,4ꢀoxadiꢀ
azolꢀ3ꢀyl)acetamide (6с). Method A, the yield was 0.25 g (72%),
m.p. 115—116 °С. IR, ν/cm–1: 1630 (CO); 2850, 2930 (CH);
3210, 3280, 3310 (NH). 1H NMR (DMSOꢀd6), δ: 1.24—1.93
(m, 10 H, CH2); 3.83—3.91 (m, 1 H, CH); 7.32, 7.36 (AA´BB´
system, 4 H, Ar, J = 9.2 Hz); 8.39 (d, 1 H, NHCH, J = 7.3 Hz);
9.57 (s, 1 H, CH); 13.98 (br.s, 1 H, NH). Found (%): C, 55.49;
Н, 5.10; N, 20.3. C15H18ClN5O2. Calculated (%): C, 55.25;
Н, 5.22; N, 20.14.
2ꢀ(4ꢀChlorophenyl)ꢀ5ꢀformyliminoꢀNꢀmethylꢀ2,5ꢀdihydroꢀ
1Нꢀ1,2,3ꢀtriazoleꢀ4ꢀcarboxamide (7а). Method A, the yield was
0.08 (30%); method B, the yield was 0.19 (68%), m.p. 230—231 °С.
IR, ν/cm–1: 1650, 1710 (CO); 3060, 3100 (CH); 3280, 3380,
3500 (NH). 1H NMR (CDCl3), δ: 3.04 (d, 3 H, NHCH3, J = 5.2
Hz); 6.73, 6.83 (both br.q, 1 H, NHMe, J = 5.2 Hz); 7.47, 7.95
(AA´XX´ system, 4 H, Ar, J = 8.7 Hz); 8.52 and 9.17 (s and d,
1 H, CHO, J = 10.8 Hz); 9.03 and 9.68 (br.d and br.s, 1 H, NH,
J = 10.8 Hz). Found (%): C, 47.12; H, 3.55; N, 24.88.
C11H10ClN5O. Calculated (%): C, 47.24; H, 3.60; N, 25.04.
2ꢀ(4ꢀChlorophenyl)ꢀNꢀethylꢀ5ꢀformyliminoꢀ2,5ꢀdihydroꢀ1Нꢀ
1,2,3ꢀtriazoleꢀ4ꢀcarboxamide (7b). Method A, the yield was 0.60
g (20%), m.p. 172—173 °С. IR, ν/cm–1: 1650, 1710 (CO); 2850,
2920, 2980 (CH); 3380; 3280 (NH). 1H NMR (Т = 373 K,
DMSOꢀd6), δ: 1.19 (t, 3 H, CH2CH3, J = 7.2 Hz); 3.36 (dq, 2 H,
NHCH2CH3, J = 7.2 Hz, J = 5.3 Hz); 7.60, 8.00 (AA´XX´
system, 4 H, Ar, J = 8.9 Hz); 8.26 (s, 1 H, СHО); 8.73 (t, 1 H,
NHCH2, J = 5.3 Hz); 9.71 (s, 1 H, NH). 1H NMR (Т = 303 K,
DMSOꢀd6), δ: 1.17 (t, 3 H, CH2CH3, J = 7.2 Hz); 3.34 (dq, 2 H,
CH2CH3 J = 7.2 Hz, J = 5.3 Hz); 7.67, 8.02 (AA´XX´ system,
4 H, Ar, J = 8.9 Hz); 8.74 (br.t, 1 H, NHCH2, J = 5.3 Hz); 8.44
and 8.92 (br.s and br.s, 1 H, СHО); 9.94 and 10.37 (br.s and br.s,
1 H, NH). 13С NMR (Т = 373 K, DMSOꢀd6), δ: 13.8 (Me); 33.0
(СН2); 119.8; 129.0; 132.2; 137.1 (Сarom); 131.1 (С(5)triaz); 144.5

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Belskaya et al.
(С(4)triaz); 159.1 (СО); 159.9 (СНО). 13С NMR (Т = 313 K,
DMSOꢀd6), δ: 14.6 (Me); 33.4 (СН2); 120.0; 129.9, 132.5; 137.3
(Сarom); 130.9, 131.88 (br.s, С(5)triaz); 144.1, 145.5 (br.s, С(4)triaz);
159.4 (СО); 159.4, 162.1 (br.s, СНО). Found (%): C, 48.92;
H, 4.02; N, 23.75. C12H12ClN5O2. Calculated (%): C, 49.07;
H, 4.12; N, 23.84.
7.49, 7.78 (AA´XX´ system, 4 H, Ar, J = 9.2 Hz); 8.10 (q, 1 H,
NHMe, J = 4.8 Hz). Found (%): C, 52.02; H, 5.11; N, 21.42.
C14H16ClN5O2. Calculated (%): C, 52.26; H, 5.01; N, 21.77.
NꢀBenzylꢀ2ꢀ[2ꢀ(4ꢀchlorophenyl)ꢀ2ꢀethylhydrazono]ꢀ2ꢀ(5ꢀ
methylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)acetamide (11b). Method A, the
yield was 0.32 g (80%), m.p. 142—143 °С. 1H DMSOꢀd6), δ:
1.30 (t, 3 H, CH2CH3, J = 7.2 Hz); 2.37 (s, 3 H, Me); 4.20 (q, 2 H,
CH2CH3, J = 7.2 Hz); 4.50 (d, 2 H, NHCH2, J = 6.0 Hz); 7.00,
7.20 (AA´BB´ system, 4 H, Ar, J = 8.5 Hz); 7.30—7.48 (m, 5 H,
Ph); 8.63 (t, 1 H, NHCH2, J = 6.0 Hz). Found (%): C, 60.28;
H, 5.37; N, 17.35. C20H20ClN5O2. Calculated (%): C, 60.38;
H, 5.07; N, 17.60.
2ꢀ[2ꢀ(4ꢀChlorophenyl)ꢀ2ꢀethylhydrazono]ꢀ2ꢀ(5ꢀethylꢀ1,2,4ꢀ
oxadiazolꢀ3ꢀyl)ꢀNꢀmethylacetamide (11c). Method A, the yield
was 0.21 g (63%), m.p. 72—73 °С. 1H NMR (DMSOꢀd6), δ: 1.10
(t, 3 H, CH2CH3, J = 7.3 Hz); 1.27 (t, 3 H, CH2CH3, J = 7.0 Hz);
2.72 (q, 2 H, CH2CH3, J = 7.3 Hz); 2.79 (d, 3 H, NHCH3,
J = 4.7 Hz); 4.24 (q, 2 H, CH2CH3, J = 7.0 Hz); 7.61, 7.76 (AA´XX´
system, 4 H, Ar, J = 8.6 Hz); 8.45 (q, 1 H, NHMe, J = 4.7 Hz).
13С NMR (DMSOꢀd6), δ: 14.3 (Me), 19.3 (Me), 26.2 (Me), 63.7
(CH2), 125.4, 129.5, 132.7, 136.1, 155.0, 155.1, 159.7, 171.1
(CO). Found (%): C, 53.52; H, 5.11; N, 20.40. C15H18ClN5O2.
Calculated (%): C, 53.65; H, 5.40; N, 20.86.
2ꢀ(4ꢀChlorophenyl)ꢀNꢀcyclohexylꢀ5ꢀformyliminoꢀ2,5ꢀdihydroꢀ
1Нꢀ1,2,3ꢀtriazoleꢀ4ꢀcarboxamide (7c). Method A, the yield was
1
0.07 g (20%), m.p. 115—116 °С. H (DMSOꢀd6), δ: 1.24—1.93
(m, 10 H, 5 CH2); 3.73—3.83 (m, 1 H, CH); 7.32, 7.36 (AA´BB´
system, 4 H, Ar, J = 9.2 Hz); 8.39 (d, 1 H, NHCH, J = 7.3 Hz);
8.65, 9.57 (both br.s, 1 H, CHО); 10.15, 13.98 (both br.s, 1 H,
NH). MS, m/z (Irel (%)): 347 [М]+ (6). Found (%): C, 55.35;
H, 5.30; N, 20.15. C16H18ClN5O2. Calculated (%): C, 55.25;
H, 5.22; N, 20.14.
NꢀBenzylꢀ2ꢀ(4ꢀchlorophenyl)ꢀ5ꢀformyliminoꢀ2,5ꢀdihydroꢀ
1Нꢀ1,2,3ꢀtriazoleꢀ4ꢀcarboxamide (7d). Method B, the yield was
1
0.25 g (70%), m.p. 153—154 °С. H NMR (DMSOꢀd6), δ: 4.50
(d, 2 H, NHCH2, J = 6.0 Hz); 7.00—7.37 (m, 5 H, Ph); 7.34,
7.39 (AA´BB´ system, 4 H, Ar, J = 8.8 Hz); 8.35, 9.09 (both br.s,
1 H, CHО); 9.60 (br.t, 1 H, NHСH2, J = 6.0 Hz); 10.30, 10.80
(both br.s, 1 H, NH). MS, m/z (Irel (%)): 355 [М]+ (6). Found (%):
C, 57.35; H, 3.50; N, 19.45. C17H14ClN5O2. Calculated (%):
C, 57.39; H, 3.97; N, 19.68.
5ꢀFormyliminoꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀNꢀmethylꢀ2,5ꢀdihydroꢀ
1Нꢀ1,2,3ꢀtriazoleꢀ4ꢀcarboxamide (7e). Method B, the yield was
0.19 g (70%), m.p. 121—122 °С. 1H NMR (DMSOꢀd6), δ: 3.04
(d, 3 H, NHCH3, J = 4.3 Hz); 3.84 (s, 3 H, OMe); 7.05, 7.95
(AA´BB´ system, 4 H, Ar, J = 8.8 Hz); 8.40 (br.q, 1 H, NHCH3,
J = 4.3 Hz); 8.95, 9.35 (both br.s, 1 H, СH); 9.50, 9.75 (both
br.s, 1 H, NH). MS, m/z (Irel (%)): 275 [М]+ (10). Found (%):
C, 52.33; H, 4.50; N, 25.34. C12H13N5O3. Calculated (%):
C, 52.36; H, 4.76; N, 25.44.
2ꢀ[2ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀethylhydrazono]ꢀNꢀmethylꢀ2ꢀ(5ꢀ
methylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)acetamide (11d). Method A, the
yield was 0.23 g (72%), m.p. 124—125 °С. IR, ν/cm–1: 1670
1
(CO); 2945, 2985 (CH); 3330 (NH). H NMR (DMSOꢀd6), δ:
1.30 (t, 3 H, CH2CH3, J = 7.2 Hz); 2.35 (s, 3 H, Me); 2.80 (d, 3 H,
NHCH3, J = 4.7 Hz); 3.80 (s, 3 H, OMe); 4.20 (q, 2 H, CH2CH3,
J = 7.2 Hz); 7.45, 7.75 (AA´XX´ system, 4 H, Ar, J = 9.0 Hz);
8.05 (br.q, 1 H, NHMe, J = 4.7 Hz). Found (%): C, 56.72;
H, 6.15; N, 22.27. C15H19N5O3. Calculated (%): C, 56.77;
H, 6.03; N, 22.07.
NꢀBenzylꢀ5ꢀformyliminoꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ2,5ꢀdihydroꢀ
1Нꢀ1,2,3ꢀtriazoleꢀ4ꢀcarboxamide (7f). Method B, the yield was
0.22 g (63%), m.p. 123—124 °С. H NMR (DMSOꢀd6), δ: 3.84
NꢀBenzylꢀ2ꢀ(5ꢀmethylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)ꢀ2ꢀ[2ꢀ(4ꢀmethꢀ
oxyphenyl)ꢀ2ꢀethylhydrazono]acetamide (11e). Method A, the
yield was 90%, m.p. 142—143 °С. IR, ν/cm–1: 1675 (CO); 2930,
1
1
(s, 3 H, OMe); 4.49 (d, 2 H, NHCH2, J = 7.5 Hz); 7.05, 7.94
(AA´XX´ system, 4 H, Ar, J = 9.3 Hz); 7.18—7.32 (m, 5 H, Ph);
8.40, 8.95 (both br.s, 1 Н, CH); 9.01 (br.t, 1 Н, NHCH2, J = 7.5 Hz);
9.55, 10.25 (both br.s, 1 H, NH). MS, m/z (Irel (%)): 351 [М]+ (5).
Found (%): C, 61.48; H, 4.10; N, 19.53. C18H17N5O3. Calcuꢀ
lated (%): C, 61.53; H, 4.88; N, 19.93.
3ꢀAminoꢀ4ꢀ(4ꢀchlorophenylhydrazono)ꢀ4Hꢀisoxazolꢀ5ꢀone
(9а). Method A, the yield was 0.17 g (72%), m.p. 124—125 °С.
1H NMR (DMSOꢀd6), δ: 6.09 (br.s, 2 H, NH2); 7.28, 7.41
(AA´XX´ system, 4 H, Ar, J = 7.0 Hz); 12.27 (br.s, 1 H, NH). MS,
m/z (Irel (%)): 238 [М]+ (1). Found (%): C, 45.33; H, 3.00; N, 23.25.
C9H7ClN4O2. Calculated (%): C, 45.30; H, 2.96; N, 23.48.
3ꢀAminoꢀ4ꢀ(4ꢀmethoxyphenylhydrazono)ꢀ4Hꢀisoxazolꢀ5ꢀone
(9b). Method A, the yield was 0.19 g (83%), m.p. 198—199 °С.
1H NMR (DMSOꢀd6), δ: 3.77 (s, 3 H, OMe); 6.07 (br.s, 2 H,
NH2); 6.91, 7.61 (AA´BB´ system, 4 H, Ar, J = 8.8 Hz); 12.25
(br.s, 1 H, NH). MS, m/z (Irel (%)): 234 [М]+ (83). Found (%):
C, 51.33; H, 4.43; N, 23.75. C10H10N4O3. Calculated (%):
C, 51.28; H, 4.30; N, 23.92.
2970 (CH); 3345 (NH). H NMR (DMSOꢀd6), δ: 1.29 (t, 3 H,
CH2CH3, J = 7.0 Hz); 2.35 (s, 3 H, Me); 3.83 (s, 3 H, OMe); 4.22
(q, 2 H, CH2CH3, J = 7.0 Hz); 4.47 (d, 2 H, NHCH2, J = 5.8 Hz);
6.98, 7.60 (AA´XX´ system, 4 H, Ar, J = 8.8 Hz); 7.20—7.38
(m, 5 H, Ph); 8.62 (t, 1 H, NHCH2, J = 5.8 Hz). MS, m/z (Irel (%)):
393 [М]+ (78). Found (%): C, 64.44; H, 5.70; N, 17.54.
C21H23N5O3. Calculated (%): C, 64.11; H, 5.89; N, 17.80.
NꢀBenzylꢀ2ꢀ[2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀethylhydrazono]ꢀ2ꢀ(5ꢀ
ethylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)acetamide (11f). Method A, the yield
was 0.35 g (90%), m.p. 142—143 °С. IR, ν/cm–1: 1670 (CO);
2945, 2985 (CH); 3335 (NH). 1H NMR (DMSOꢀd6), δ: 1.18
(t, 3 H, CH2CH3, J = 7.0 Hz); 1.30 (t, 3 H, CH2CH3, J = 6.9 Hz);
2.72 (q, 2 H, CH2CH3, J = 7.0 Hz); 3.79 (s, 3 H, OMe); 4.23
(q, 2 H, CH2CH3, J = 7.0 Hz); 4.48 (d, 2 H, NHCH2,
J = 6.0 Hz); 7.00, 7.58 (AA´XX´ system, 4 H, Ar, J = 9.2 Hz);
7.18—7.57 (m, 5 H, Ar); 8.55 (t, 1 H, NHCH2, J = 6.0 Hz). MS,
m/z (Irel (%)): 407 [М]+ (50). Found (%): C, 64.72; H, 6.38;
N, 17.25. C22H25N5O3. Calculated (%): C, 64.85; H, 6.18; N, 17.19.
Xꢀray diffraction study of compound 7f was carried out acꢀ
cording to a standard procedure on an Xcalibur 3 diffractometer
equipped with a CCD detector (λ(MoꢀКα) = 0.71073 Å, graphꢀ
ite monochromator, 295(2) K, ω scan mode, scanning increꢀ
ment 1°, time of frame measurement 20 s). A piece of colorless
crystal 0.48×0.31×0.19 mm in size was used, and no absorption
correction was applied because it is negligible. The structure was
2ꢀ[2ꢀ(4ꢀChlorophenyl)ꢀ2ꢀethylhydrazono]ꢀNꢀmethylꢀ2ꢀ(5ꢀ
methylꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)acetamide (11a). Method A, the
yield was 0.20 g (87%), m.p. 125—126 °С. IR, ν/cm–1: 1680
1
(CO); 2980, 2940 (CH); 3340 (NH). H NMR (DMSOꢀd6), δ:
1.32 (t, 3 H, CH2CH3, J = 7.0 Hz); 2.39 (s, 3 H, Me); 2.82
(d, 3 H, NHCH3, J = 4.8 Hz); 4.26 (q, 2 H, CH2CH3, J = 7.0 Hz);

Reaction of amidoximes with orthoesters
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
895
solved by a direct method and refined by the leastꢀsquares methꢀ
od in the anisotropic fullꢀmatrix approximation for nonꢀhydroꢀ
gen atoms using the SHELXTL97 program package.11 The hyꢀ
drogen atoms of the C—H bonds were added to the geometricalꢀ
ly calculated positions and included into refinement in the isoꢀ
tropic approximation with dependent thermal parameters in the
riding model, while the hydrogen atoms of the N—H groups
were refined in the isotropic approximation. According to the
Xꢀray diffraction results, crystal 7f is monoclinic, space group
P21/s, a = 14.374(3) Å, b = 14.1218(17) Å, c = 8.6374(6) Å,
β = 96.323(10)°, V = 1742.7(4), Z = 4, empirical formula
C18H17N5O3, dcalc = 1.339 g cm–3, μ = 0.095 mm–1, F(000) = 736.
At scanning angles 2.78° < θ < 26.38°, 13 115 reflections
were collected, of which 3457 were independent reflections
(Rint = 0.0335), 1665 with I > 2σ(I), completeness for θ = 26.38°
is 97%. The final parameters are R1 = 0.0350, wR2 = 0.0499 (for
reflections with I > 2σ(I)), R1 = 0.1029, wR2 = 0.0541 (for all
2. N. P. Belskaya, E. E. Zvereva, L. A. Babushkina, V. A. Bakuꢀ
lev, Khim. Geterotsikl. Soedin., 2000, 1224 [Chem. Heteroꢀ
cycl. Compd. (Engl. Transl.), 2000, 36, 1066].
3. Y. Tanabe, M. Nagaosa, Y. Nishii, Heterocycles, 1995, 41,
2033.
4. H. M. ElꢀMatar, S. M. Riyadh, M. H. Elnagdi, Arkivoc,
2007, 13, 53.
5. S. M. AlꢀMousawi, M. S. Moustafa, M. H. Elnagdi, J. Chem.
Res., 2007, 515.
6. H. M. ElꢀMatar, S. M. Riyadh, M. H. Elnagdi, Arkivoc,
2007, 13, 53.
7. A. Bottoni, V. Frenna, C. Z. Lanza, G. Macaluso, D. Spinelli,
J. Phys. Chem. A, 2004, 108, 1731.
8. F. D´Ana, F. Ferroni, V. Frenna, S. Guernelli, C. Z. Lanza,
G. Macaluso, V. Pace, G. Petrillo, D. Spinelli, R. Spisani,
Tetrahedron, 2005, 61, 167.
9. B. Cosimelli, V. Frenna, S. Guernelli, C. Z. Lanza, G. Maꢀ
caluso, G. Petrillo, D. Spinelli, J. Org. Chem., 2002,
67, 8010.aa
reflections) at the goodnessꢀofꢀfit S = 1.000. The residual elecꢀ
–3
tron density is ρmax/ρmin = 0.122/–0.126 e•Å
.
10. A. J. Gordon, R. A. Ford, The Chemist´s Companion, A Wileyꢀ
Interscience—John Wiley and Sons, New York—Lonꢀ
don—Toronto, 1972.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 10ꢀ03ꢀ
96084_r_uralꢀa).
11. G. M. Sheldrick, Acta Crystallogr., Sect. A, 2008, 64, 112.
References
1. N. P. Belskaia, E. E. Zvereva, W. Dehaen, V. A. Bakulev,
J. Chem. Res., 2000, (M) No. 12, 1365; (S) No. 12, 551.
Received February 14, 2011;
in revised form April 25, 2011