Reactions of alkyl 3-amino-5-aryl-2-benzoyl-5-oxopent-2-enoates with hydrazine

Article abstract of DOI:10.1007/s11172-006-0402-0

Reactions of alkyl 3-amino-5-aryl-2-benzoyl-2-oxopent-2-enoates with hydrazine were accompanied by debenzoylation and isomerization to give 3-amino-5-aryl-5-oxopent-3-enohydrazides, which underwent cyclization in the presence of an excess of hydrazine int

Full text of DOI:10.1007/s11172-006-0402-0

Russian Chemical Bulletin, International Edition, Vol. 55, No. 7, pp. 1220—1223, July, 2006
1220
Reactions of
alkyl 3ꢀaminoꢀ5ꢀarylꢀ2ꢀbenzoylꢀ5ꢀoxopentꢀ2ꢀenoates with hydrazine
A. V. Vasilyev, S. V. Baranin, P. A. Belyakov, and V. A. Dorokhovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328. Eꢀmail: vador@ioc.ac.ru
Reactions of alkyl 3ꢀaminoꢀ5ꢀarylꢀ2ꢀbenzoylꢀ2ꢀoxopentꢀ2ꢀenoates with hydrazine were
accompanied by debenzoylation and isomerization to give 3ꢀaminoꢀ5ꢀarylꢀ5ꢀoxopentꢀ3ꢀ
enohydrazides, which underwent cyclization in the presence of an excess of hydrazine into
5(3)ꢀarylpyrazolꢀ3(5)ꢀylacetohydrazides.
Key words: hydrazine, 3ꢀaminoꢀ5ꢀarylꢀ5ꢀoxopentꢀ3ꢀenohydrazides, pyrazolꢀ3(5)ꢀylꢀ
acetohydrazides, diphenylboron chelate, pyrazoles, heterocyclization.
Earlier,1 we have developed a method for the synthesis
gously, with correction for possible participation of the
carbonyl group of the aroylmethyl fragment in this transꢀ
formation.
Unexpectedly, treatment of alcoholic solutions of
compounds 1a—d with an excess of hydrazine hydrate at
20 °C for 30 min gave 3ꢀaminoꢀ5ꢀarylꢀ5ꢀoxopentꢀ3ꢀ
enohydrazides 4a—d in 73—83% yields (Scheme 2, pathꢀ
way a), while cyclization into pyrazolecarboxylic acids of
the type 2 (pathway b) as with compounds 2 did not
occur. Nor were other byꢀproducts detected.
of alkyl 3ꢀaminoꢀ5ꢀarylꢀ2ꢀbenzoylꢀ5ꢀoxopentꢀ2ꢀenoates
(1), which exist in solutions as an equilibrium mixture of
the Eꢀ and Zꢀisomers1 (Scheme 1). Compounds 1 can be
used as reagents for heterocyclic synthesis: when refluxed
in xylene, they transform into 4ꢀaminoꢀ6ꢀarylꢀ3ꢀbenzoylꢀ
pyranꢀ2ꢀones; on heating with ammonium acetate in
AcOH, they undergo cyclization into alkyl 4ꢀaminoꢀ6ꢀ
arylꢀ2ꢀphenylpyridineꢀ3ꢀcarboxylates.1
Here we studied reactions of esters 1 with hydrazine.
It is known2—4 that aminomethylidene derivatives of ethyl
benzoylacetate (2) react with hydrazines to give substiꢀ
tuted ethyl pyrazoleꢀ4ꢀcarboxylates 3 (see Scheme 1). The
formation of the pyrazole ring of products 3 involves the
enaminone fragment of compounds 2. Cyclization of comꢀ
pounds 1 with hydrazine could be expected to occur analoꢀ
Scheme 2
Scheme 1
Ar = Ph (a), 4ꢀClC6H4 (b), 4ꢀMeC6H4 (c), 4ꢀMeOC6H4 (d)
Reaction conditions: 30 min, 20 °C.
Thus, hydrazinolysis of esters 1a—d is accompanied
by debenzoylation and a migration of the double bond.
Compounds 4a—d are white crystalline solids which
are poorly soluble in most organic solvents (e.g., in diꢀ
oxane and chloroform). Their structures were confirmed
R1, R2, R3 = H, Me
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1175—1177, July, 2006.
1066ꢀ5285/06/5507ꢀ1220 © 2006 Springer Science+Business Media, Inc.

3ꢀAminoꢀ5ꢀarylꢀ5ꢀoxopentꢀ3ꢀenohydrazides
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1221
Scheme 4
by spectroscopic data. For instance, the mass spectra of
compounds 4a—d contain molecular ion peaks [M]+.
1
The H NMR spectra of hydrazides 4a—d show singlets
at δ 3.05—3.06 for the methylene protons, singlets at
δ 5.70—5.75 for the HC= proton, and signals for five
NH protons. The position of the double bond was derived
from NOE and 1H—13C heteronuclear correlation exꢀ
periments for compound 4a. For instance, irradiation of
the CH2 protons at δ 3.05 caused NOE only with the
proton HC(4) (δ 5.75). In contrast, irradiation of the
proton at δ 5.75 (HC(4)) caused NOE with both the
CH2 protons (δ 3.05) and the orthoꢀprotons of the phenyl
substituent (δ 7.84—7.78), which matches structure 4
but excludes the isomeric pentꢀ2ꢀene structure
ArC(O)CH2C(NH2)=CHC(O)NHNH2.
Ar = Ph (a), 4ꢀClC6H4 (b)
Reaction conditions: 72 h, 20 °C.
Therefore, the reactions of hydrazine with esters 1a—d
and related esters 2 yield essentially different products.
Apparently, this is due to initial isomerization of comꢀ
pounds 1 in the presence of such a strong base as hydrꢀ
azine (Scheme 3) into an intermediate containing an
aminovinyl carbonyl fragment probably stabilized by an
intramolecular hydrogen bond N—H...O. Obviously, this
will significantly lower the probability of replacement of
the NH2 group but favor deacylation (cf. the deacylation
of ethyl 2ꢀbenzoylacetoacetate in the presence of hydrꢀ
azine5). Ultimately, debenzoylated ester transforms into
hydrazide 4.
peaks [M]+. Their 1H NMR spectra (DMSOꢀd6) show
characteristic signals for the HC(4) protons of the pyrazole
ring at δ 6.50 and for the CH2 protons at δ ~3.50. The
1H NMR data for pyrazole 5a agree with previously reꢀ
ported6 data for this compound obtained from methyl
3ꢀhydroxyꢀ5ꢀphenylthiopheneꢀ2ꢀcarboxylate and hydrꢀ
azine.
The presence of the enaminone fragment and the funcꢀ
tional NHNH2 group in compounds 4 makes them promꢀ
ising synthetic reagents and tetradentate ligands. Earlier,1
with esters 1 as starting material, we have obtained
diphenylboron chelates with the B atom coordinated
through the N and O atoms of the enamino carbonyl
fragment.
Scheme 3
A reaction of hydrazide 4a with an excess of butoxy(diꢀ
phenyl)borane under analogous conditions gave a
binuclear boron chelate formulated as structure 6
(Scheme 5). With one equivalent of the borylating reꢀ
agent, we isolated the same complex 6 and unreacted
hydrazide 4a.
Scheme 5
Substantially longer treatment of esters 1a,b with an
excess of hydrazine hydrate at room temperature gave
5(3)ꢀarylpyrazolꢀ3(5)ꢀylacetohydrazides 5a,b as cyclizaꢀ
tion products from compounds 4 (Scheme 4). The best
route to pyrazoles 5 proved to be treatment of hydrazides
4 with an excess of hydrazine hydrate at room temperaꢀ
ture for 72 h. Attempted acceleration of the reaction by
heating failed because of resinification at elevated temꢀ
peratures.
Chelate 6 is a yellow crystalline solid which is well
soluble in most organic solvents and stable when stored in
air and in solutions. Data from physicochemical methods
(including mass spectrometry and 1H and 11B NMR specꢀ
troscopy) are consistent with structure 6. Its mass specꢀ
trum show characteristic features of mass spectra of
fourꢀcoordinate boron chelates: the peak [M]+ is absent
and the highestꢀmass peak corresponds to the [M – Ph]+
Compounds 5a,b are colorless crystalline solids which
are moderately soluble in ethanol and benzene. The
mass spectra of these compounds contain molecular ion

1222
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
Vasil´ev et al.
1
N, 16.62. C12H15N3O3. Calculated (%): C, 57.82; H, 6.07;
N, 16.86. MS, m/z: 249 [M]+. 1H NMR (DMSOꢀd6), δ: 3.04 (s,
3 H, CH2); 3.81 (s, 3 H, MeO); 4.33 (br.s, 2 H, H2N—N); 5.70
(s, 1 H, HC=); 7.57 (br.s, 1 H, NH); 6.97, 7.79 (both d, 2 H each,
C6H4, J = 8.5 Hz); 9.22 (br.s, 1 H, NH); 9.89 (br.s, 1 H, NH).
5(3)ꢀPhenylpyrazolꢀ3(5)ꢀylacetohydrazide (5a). Hydrazine
hydrate (1.5 g, 24 mmol) was added to a suspension of hydrazide
4a (0.44 g, 2 mmol) in ethanol (5 mL). The reaction mixture was
kept at 20 °C for 72 h. The solvent and the excess hydrazine were
removed in vacuo and the residue was recrystallized from ethaꢀ
nol (4 mL). The yield of pyrazole derivative 5a was 0.28 g (65%),
m.p. 164—165 °C.* Found (%): C, 60.98; H, 5.57; N, 25.94.
ion. The H NMR spectrum (in DMSOꢀd6) of chelate 6
contains broadened singlets for the NH protons at δ 10.18
and for the NH2 protons at δ 8.65 (cf. the chemical shift of
the amino group in the starting hydrazide 4a (δ 4.30)) and
singlets at δ 6.10 (HC(4)) and 3.75 (CH2).
Experimental
1
H and 13C NMR spectra were recorded on a Bruker
WMꢀ250 instrument (250.13 and 62.9 MHz, respectively)
with Me4Si as the internal standard. 11B NMR spectra were
recorded on a Bruker ACꢀ200P instrument (64.21 MHz) with
BF3•Et2O as the internal standard. IR spectra were recorded on
a Specord Mꢀ82 instrument. Mass spectra were recorded on a
Kratos MSꢀ30 instrument (EI, 70 eV, ionization chamber temꢀ
perature 250 °C, direct inlet probe). Elemental analysis was
carried out at the laboratory for microanalysis of the N. D.
Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences.
C11H12N4O. Calculated (%): C, 61.10; H, 5.59; N, 25.91. MS,
m/z: 216 [M]+. IR (KBr), ν/cm–1: 3320, 3230 br, 3130 (NH),
3040—2800 (NH, CH), 1650, 1624, 1532 (C=O, C=N, C=C).
1H NMR (DMSOꢀd6), δ: 3.40 (s, 2 H, CH2); 4.20 (br.s, 2 H,
H2N—N); 6.50 (s, 1 H, HC(4)); 7.20—7.80 (m, 5 H, Ph); 9.20
(br.s, 1 H, NH); 12.90 (br.s, 1 H, NH).
5(3)ꢀ(4ꢀChlorophenyl)pyrazolꢀ3(5)ꢀylacetohydrazide (5b) was
obtained analogously from hydrazide 4b. The yield was 70%,
m.p. 170—171 °C. Found (%): C, 52.63; H, 4.50; Cl, 14.25;
N, 22.37; C11H11ClN4O. Calculated (%): C, 52.70; H, 4.42;
Ethyl 3ꢀaminoꢀ5ꢀarylꢀ2ꢀbenzoylꢀ5ꢀoxopentꢀ2ꢀenoates 1a—d
were prepared as described earlier.1
Cl, 14.14; N, 22.35. MS, m/z: 251 [M]+. IR (KBr), ν/cm–1
:
3ꢀAminoꢀ5ꢀoxoꢀ5ꢀphenylpentꢀ3ꢀenohydrazide (4a). Hydrꢀ
azine hydrate (5.00 g, 80 mmol) was added to a solution of
ester 1a (3.40 g, 10 mmol) in ethanol (10 mL). After 30 min,
the solution was triturated with a glass rod. The resulting preꢀ
cipitate was filtered off, washed with ethanol (2×3 mL), and
dried in vacuo. The yield of hydrazide 4a was 1.70 g (78%),
m.p. 153—155 °C (decomp.). Found (%): C, 59.98; H, 6.08;
N, 19.20. C11H13N3O2. Calculated (%): C, 60.26, H, 5.98;
N, 19.17. MS, m/z: 219 [M]+. 1H NMR (DMSOꢀd6), δ: 3.05 (s,
2 H, CH2); 4.30 (br.s, 2 H, H2N—N); 5.75 (s, 1 H, HC=);
7.30—7.50 (m, 3 H, 3 H arom.); 7.66 (br.s, 1 H, NH); 7.78—7.84
(m, 2 H, 2 H arom.); 9.23 (br.s, 1 H, NH); 10.00 (br.s, 1 H,
NH). 13C NMR (DMSOꢀd6), δ: 40.88 (C(2)); 90.56 (HC(4));
126.69, 128.33, 130.76, 140.01 (Ph); 161.73 (C(3)); 166.92
(C(1)); 187.13 (C(5)). The signals were assigned from HMBC
and HMQC data obtained according to Bruker standard proceꢀ
dures.
3ꢀAminoꢀ5ꢀ(4ꢀchlorophenyl)ꢀ5ꢀoxopentꢀ3ꢀenohydrazide (4b)
was obtained analogously from ester 1b. The yield was 83%,
m.p. 160—161 °C (decomp.). Found (%): C, 52.16; H, 4.66;
Cl, 14.02; N, 16.62. C11H12ClN3O2. Calculated (%): C, 52.08;
H, 4.77; Cl, 13.97; N, 16.56. MS, m/z: 254 [M]+. 1H NMR
(DMSOꢀd6), δ: 3.06 (s, 2 H, CH2); 4.30 (br.s, 2 H, H2N—N);
5.71 (s, 1 H, HC=); 7.87 (br.s, 1 H, NH); 7.47, 7.83 (both d,
2 H each, C6H4, J = 8.6 Hz); 9.22 (br.s, 1 H, NH); 9.99
(br.s, 1 H, NH).
3312, 3245, 3136 (NH), 3040—2800 (NH, CH), 1656, 1628,
1536 (C=O, C=N, C=C). 1H NMR (DMSOꢀd6), δ**: 3.50
(br.s, 2 H, CH2); 4.25 (br.s, 2 H, H2N—N); 6.50 (br.s, 1 H,
HC(4)); 7.40, 7.80 (both br.d, 2 H each, C6H4); 9.20 (br.s, 1 H,
NH); 12.80, 13.10 (both br.s, 1 H each, NH).
Bis(diphenylboron) chelate of 3ꢀaminoꢀ5ꢀoxoꢀ5ꢀphenylpentꢀ
3ꢀenohydrazide (6). Butoxy(diphenyl)borane (1.43 g, 6 mmol)
was added to a suspension of hydrazide 4a (0.44 g, 2 mmol) in
THF (5 mL). The reaction mixture was refluxed to complete
dissolution of the hydrazide (15 min) and then kept at 20 °C for
24 h. The solvent was removed in vacuo and the residue was
crystallized from a mixture of benzene (4 mL) and hexane
(2 mL). The crystals were filtered off, washed with benzene—hexꢀ
ane (2 : 1) and hexane (4 mL), and dried in vacuo. The yield of
chelate 6 (in the form of 6•C6H6) was 0.83 g (66%), m.p.
223—225 °C. Found (%): C, 78.56; H, 6.14; B, 3.69; N, 6.62.
C
35H31B2N3O2•C6H6. Calculated (%):C, 78.74; H, 5.96;
B, 3.46; N, 6.72. MS, m/z: 470 [M – Ph]+. IR (KBr), ν/cm–1
:
3236, 3204 (NH), 3050—2800 (NH, CH), 1644, 1616, 1568,
1
1532 vs (C=C, C=N, C=O). H NMR (DMSOꢀd6), δ: 3.75 (s,
2 H, CH2); 6.10 (s, 1 H, HC=); 3.75 (s, 2 H, CH2); 7.90—7.00
(m, 31 H, 5 Ph, PhH); 8.65 (br.s, 2 H, NH2); 10.18 (br.s, 1 H,
NH). 11B NMR, δ: 3.83.
This work was financially supported by the Russian
Academy of Sciences (Program for Basic Research of the
Presidium of the Russian Academy of Sciences "Developꢀ
ment of Methods for the Synthesis of Chemically Pure
Compounds and Creation of Novel Materials", Subproꢀ
gram "Development of the Methodology of Organic Synꢀ
3ꢀAminoꢀ5ꢀ(4ꢀmethylphenyl)ꢀ5ꢀoxopentꢀ3ꢀenohydrazide (4c)
was obtained analogously from ester 1c. The yield was 76%,
m.p. 155—156 °C (decomp.). Found (%): C, 61.58; H, 6.27;
N, 17.93. C12H15N3O2. Calculated (%): C, 61.79; H, 6.48;
N, 18.01. MS, m/z: 233 [M]+. 1H NMR (DMSOꢀd6), δ: 2.33
(s, 3 H, Me); 3.05 (s, 2 H, CH2); 4.30 (br.s, 2 H, H2N—N); 5.72
(s, 1 H, HC=); 7.64 (br.s, 1 H, NH); 7.23, 7.71 (both d,
2 H each, C6H4, J = 8.0 Hz); 9.21 (br.s, 1 H, NH); 9.94
(br.s, 1 H, NH).
* For pyrazole 5a, m.p. 193—194 °C has been reported;6 howꢀ
ever, elemental analysis data for that material are unsatisꢀ
factory.W
** All the signals are broadened because of the tautomeric transꢀ
formations of pyrazole 5b.
3ꢀAminoꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀoxopentꢀ3ꢀenohydrazide
(4d) was obtained analogously from ester 1d. The yield was 76%,
m.p. 145—146 °C (decomp.). Found (%): C, 57.96; H, 6.26;

3ꢀAminoꢀ5ꢀarylꢀ5ꢀoxopentꢀ3ꢀenohydrazides
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 7, July, 2006
1223
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Received May 19, 2006