New derivatives of 6-phenylcomanic acid

Article abstract of DOI:10.1007/s11172-009-0162-8

Ethyl 6-phenylcomanic acid with hydrazine hydrate and hydroxylamine gives 4-oxo-6-phenyl-4H/-pyran-2-carbohydrazide and 4-oxo-6-phenyl-4H-pyran-2- carbohydroxamic acid, whereas 6-phenylcomanic acid with ammonia in aqueous DMSO gives 4-hydroxy-6-phenylpico

Full text of DOI:10.1007/s11172-009-0162-8

Russian Chemical Bulletin, International Edition, Vol. 58, No. 6, pp. 1248—1252, June, 2009
1248
New derivatives of 6ꢀphenylcomanic acid
B. I. Usachev,a D. L. Obydennov,a M. I. Kodess,b G.ꢀV. Röschenthaler,c and V. Ya. Sosnovskikha
aA. M. Gorky Ural State University,
51 prosp. Lenina, 620083 Ekaterinburg, Russian Federation.
Fax: +7 (343) 261 5978. Eꢀmail: Boris.Usachev@mail.ru
bI. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22/20 ul. S. Kovalevskoi, 620041 Ekaterinburg, Russian Federation
cSchool of Engineering and Science, Jacobs University of Bremen,
P.O. Box 750 561, Dꢀ28725 Bremen, Germany
Ethyl 6ꢀphenylcomanic acid with hydrazine hydrate and hydroxylamine gives 4ꢀoxoꢀ
6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarbohydrazide and 4ꢀoxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarbohydroxamic acid,
whereas 6ꢀphenylcomanic acid with ammonia in aqueous DMSO gives 4ꢀhydroxyꢀ
6ꢀphenylpicolinic acid, converted further to its ethyl ester and hydrazide. The reaction of
6ꢀphenylcomanic acid with phenylhydrazine gives rise to 3ꢀ(1,5ꢀdiphenylꢀ1Hꢀpyrazolꢀ3ꢀyl)ꢀ
2ꢀ(2ꢀphenylhydrazono)propionic acid, which by the Fischer reaction was converted to
3ꢀ(1,5ꢀdiphenylꢀ1Hꢀpyrazolꢀ3ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxylic acid.
Key words: 6ꢀphenylcomanic acid and its derivatives, 4ꢀhydroxyꢀ6ꢀphenylpicolinic acid
and its derivatives, phenylhydrazine, Fischer indole synthesis.
tant heterocycles. However, literature data on chemical
properties of these compounds are extremely scarce. There
is only described7 the reaction of ethyl 6ꢀphenylcomanoate
with ammonia and shown that in EtOH at room temperaꢀ
ture the reaction proceeds only at the ester group to yield
4ꢀoxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxamide, whereas for
the deeper transformation to 6ꢀ(4ꢀethylphenyl)ꢀ4ꢀhydroxyꢀ
pyridineꢀ2ꢀcarboxamide, more prolonged heating of the
reaction mixture at 110—120 °C is required. There is no
literature information on the reactions of 6ꢀphenylꢀ
comanic acid itself with nucleophiles.
In the last years, an increasing interest to the synthesis
of 4ꢀoxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxylic (6ꢀphenylꢀ
comanic) acid derivatives is observed, which together with
other representatives of 2ꢀphenylꢀ4ꢀpyrone derivatives are
used in therapeutic practice as nonsteroid inhibitors of
cyclooxygenaseꢀ2 enzyme, influencing the level of prosꢀ
taglandins in tissues.1 Earlier, 6ꢀphenylcomanic acid
has been obtained by cyclodehydrobromination of ethyl
5,6ꢀdibromoꢀ2,4ꢀdioxoꢀ6ꢀphenylhexanoate upon proꢀ
longed reflux with AcOK in anhydrous ethanol with
subsequent acid hydrolysis of ethyl 6ꢀphenylcomanoate
thus formed,2,3 as well as by cyclodehydration of 6ꢀpheꢀ
nylꢀ2,4,6ꢀtrioxohexanoic acid on heating in DMSO,4 and
by condensation of 4ꢀphenylbutꢀ3ꢀynꢀ2ꢀone with diethyl
oxalate in the presence of EtONa (see Ref. 5). However,
no product yields were reported in Refs 2 and 3, whereas
in Patent 6, there was described the synthesis of
6ꢀphenylcomanic acid derivatives substituted at the
aromatic ring from the corresponding ethyl 5,6ꢀdibromoꢀ
2,4ꢀdioxoꢀ6ꢀarylhexanoates under the action of 1,5ꢀdiꢀ
azabicyclo[4.3.0]nonꢀ5ꢀene, but again without the yields.
Due to the fact that 6ꢀphenylcomanic acid has three
electrophilic centers (C(2) and C(6) atoms and C=O
group), the reactions of both the acid itself and its derivaꢀ
tives with nucleophilic reagents could serve as a valuable
source for the preparation of a whole number of imporꢀ
Results and Discussion
Recently,8 we have developed the synthesis of 6ꢀ(triꢀ
fluoromethyl)comanic acid and some of its derivatives.
It was shown that ethyl 6ꢀ(trifluoromethyl)comanoate
already at 0 °C easily reacts with aqueous ammonia at the
ester group giving rise to the corresponding amide, whereas
upon short heating with the same reagent, the reaction
proceeds further and leads to 4ꢀhydroxyꢀ6ꢀ(trifluoroꢀ
methyl)pyridineꢀ2ꢀcarboxamide in almost quantitative
yield. At the same time, treatment of ethyl 6ꢀ(trifluoroꢀ
methyl)comanoate with hydrazine and hydroxylamine is
accompanied by cleavage of the pyrone ring and formaꢀ
tion of a complex mixture of products. In this connection,
it was of interest to compare reactivities of 6ꢀ(trifluoroꢀ
methyl)ꢀ and 6ꢀphenylcomanic ethyl esters.
* Dedicated to Academician O. N. Chupakhin on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1213—1217, June, 2009.
1066ꢀ5285/09/5806ꢀ1248 © 2009 Springer Science+Business Media, Inc.

6ꢀPhenylcomanic acid and its derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1249
Scheme 1
We found that ethyl 5,6ꢀdibromoꢀ2,4ꢀdioxoꢀ6ꢀphenylꢀ
hexanoate upon treatment with diisopropylamine in
DMSO at 0 °C for 30 min easily undergoes cyclodehydroꢀ
bromination to form ethyl 6ꢀphenylcomanoate 1 (74%),
which upon reflux in 20% aq. HCl smoothly hydrolyzes
to 6ꢀphenylcomanic acid 2 (94%). The starting ethyl
5,6ꢀdibromoꢀ2,4ꢀdioxoꢀ6ꢀphenylhexanoate is available
compound and can be easily obtained by condensation
of benzylideneacetone and diethyl oxalate with subsequent
bromination of the thus forming ethyl (E)ꢀ2,4ꢀdioxoꢀ
6ꢀphenylhexꢀ5ꢀenoate.2 The reaction of ethyl 6ꢀphenylꢀ
comanoate 1 with ammonia even under drastic enough
conditions (heating in ethanol at 60 °C for 24 h in a sealed
tube) does not affect the pyrone ring and stops at the stage
of 4ꢀoxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxamide 3 (79%),7
whereas the recyclization to 4ꢀhydroxyꢀ6ꢀphenylpyridineꢀ
2ꢀcarboxamide 4 (83%) was successful only on heating
ester 1 or amide 3 with ammonia in DMSO at 110 °C for
12 h in a sealed tube. Hydrazine hydrate and hydroxylꢀ
amine react with ester 1 at ∼20 °C for 0.5—1 h only at the
ester group, giving the earlier undescribed hydrazide 5
(90%) and hydroxamic acid 6 (48%). To sum up, as it
has been expected the reactions with Nꢀnucleophiles
(Scheme 1) indicate the higher stability of the pyrone ring
conjugated with the phenyl substituent in ethyl 6ꢀphenylꢀ
comanoate 1 as compared to the pyrone ring in ethyl
6ꢀ(trifluoromethyl)comanoate.8
was obtained only on reflux of ester 8 in excess 65% aq.
hydrazine hydrate for 1 h without addition of a solvent.
Attempted reaction with hydroxylamine under similar
conditions resulted in isolation of only the starting ester 8
(Scheme 2). The structures of all the new products were
1
confirmed by elemental analysis data, H NMR and IR
spectroscopic data.
Scheme 2
Compounds 7—9 are of undoubted interest, since
4ꢀhydroxypicolinic acid derivatives are antiallergic drugs,9
as well as they can be used in the synthesis of 4ꢀ(tetrazoꢀ
lylalkyl)piperidineꢀ2ꢀcarboxylic acids possessing proꢀ
perties of strong antagonists of receptors of Nꢀmethylꢀ
Dꢀasparaginic acid with a short action time.10
We also found that in contrast to the reaction of
ester 1 with hydrazine hydrate, which takes place at
the ester group and gives hydrazide 5, the reaction of
6ꢀphenylcomanic acid 2 with excess phenylhydrazine
(2.2 equiv.) in boiling dioxane takes place with the parꢀ
Treatment of acid 2 with excess aq. ammonia in DMSO
for 24 h at 130 °C in a sealed tube furnished 4ꢀhydroxyꢀ
6ꢀphenylpicolinic acid 7 (90%), the esterification of the
latter in anhydrous ethanol in the presence of HCl (16 h,
110 °C, a sealed tube) gives the earlier undescribed ester 8
(76%). The carbethoxy group in ester 8 has proved less
electrophilic than in ethyl 6ꢀphenylcomanoate 1, which
is confirmed by the fact that the reaction with such strong
nucleophile as hydrazine hydrate on reflux in ethanol
failed. 4ꢀHydroxyꢀ6ꢀphenylpyridineꢀ2ꢀcarbohydrazide 9

1250
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Usachev et al.
Scheme 3
the C(2) and C(4) atoms (the intermediate A) with subꢀ
sequent heterocyclization. It should be noted that in
the reaction of 2 with phenylhydrazine, irrespective of the
ratio of reagents, there is formed only hydrazonopyrazole
ticipation of two phenylhydrazine molecules and involves
the pyrone ring opening, resulting in the isolation of
hydrazonopyrazole of the composition C24H20N4O2 in
20% yield. Taking into account higher nucleophilicity
of the primary NH2 group and depending on the site of
nucleophilic attack (the intermediates A, B, and C), four
alternative structures could have been suggested for this
product, which represent two pairs of regioisomeric
pyrazoles (10, 11 and 12, 13), differing in the structures of
the side chains (Scheme 3).
Scheme 4
The choice of the regioisomeric pair 10, 11 with carꢀ
boxylic group in the side chain has been made based
on the proton decoupled 13C NMR spectra, in which
the most downfield signal at 166.05 ppm, belonging to the
CO2H group, resonates as a triplet with 3J = 3.8 Hz due to
the splitting resulting from the interaction of the carbonyl
carbon with the protons of the CH2 group (confirmed by
the 2D HMBC spectra). In addition, it is known11 that
for Nꢀsubstituted pyrazoles the following correlation
2JC(5,)H(4)
>
2JC(3),H(4), usually holds, which allows us
2
to assign the signals at 148.17 ppm (td, J = 7.8, 4.6 Hz,
bound with the CH2 group according to the HMBC data)
and 143.28 ppm (dt, 2J = 8.0, 3J = 4.0 Hz, bound with the
phenyl according to the HMBC data) to the pyrazole
atoms C(3) and C(5), respectively, therefore, out of 1,5ꢀ
(10) and 1,3ꢀdiphenylpyrazoles (11) we give a preference
to the former. To sum up, the reaction product has the
structure of 1,5ꢀdiphenylpyrazole 10, which confirms the
nucleophilic attack by two phenylhydrazine molecules on

6ꢀPhenylcomanic acid and its derivatives
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
1251
of amide 6 from isobutanol gives no change in the melting point.
1H NMR, δ: 6.87 (d, 1 H, H(3), J = 2.3 Hz); 7.10 (d, 1 H, H(5),
J = 2.3 Hz); 7.53—7.63 (m, 3 Harom); 8.09—8.14 (m, 2 Harom);
8.20 (s, 1 H, NH); 8.31 (s, 1 H, NH).
10, whereas the use of smaller amounts of phenylhydrꢀ
azine only reduces the yield of 10 and contaminates it
with unreacted acid 2.
Upon reflux in acetic acid containing several drops
of concentrated HCl, phenylhydrazone 10 is converted
by the Fischer reaction to indole 14, the structure of
which (Scheme 4) was inferred from the structure of 10
and confirmed by the proton decoupled 13C NMR spectral
data and 2D HSQC and HMBC experiments. Selected
crossꢀpeaks in the 2D HMBC spectrum: (NH, C(2)),
(NH, C(3a)), (NH, C(7a)), (NH, C(3)), (H(4), C(3)),
(H(7), C(5)), (H(7), C(3a)), (H(5), C(7)), (H(5), C(3a)),
(H(4´), C(3´)), (H(4´), C(5´)).
In conclusion, we have developed simple and inexꢀ
pensive methods for the preparation of 6ꢀphenylcomanic
acid and its new derivatives, which are of interest as the
starting reactants for the synthesis of compounds with
biological activity.
4ꢀHydroxyꢀ6ꢀphenylpyridineꢀ2ꢀcarboxamide (4). Ester 1
(2.2 g, 9.0 mmol) was heated with 25% aq. NH3 (7 mL) in
DMSO (35 mL) in a sealed tube for 12 h at 110 °C. Then, the
reaction mixture was mixed with water (100 mL), followed by
addition of 85% aq. formic acid (10 mL) with stirring.
A precipitate formed after a while was filtered off, washed with
water, and dried. The yield was 1.60 g (83%), light brown crystals
with m.p. 225—227 °C (Ref. 7: m.p. 225—226 °C). 1H NMR, δ:
7.41 (d, 1 H, H(3), J = 2.2 Hz); 7.44 (d, 1 H, H(5), J = 2.2 Hz);
7.43—7.51 (m, 3 Harom); 7.64 (br.s, 1 H, NH); 8.21 (br.s, 1 H,
NH); 8.17—8.21 (m, 2 Harom); 11.04 (br.s, 1 H, OH).
4ꢀOxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarbohydrazide (5). Ester 1
(0.27 g, 1.1 mmol) was dissolved in ethanol (5 mL), followed by
addition of 67% aq. hydrazine hydrate (0.27 g). After 30 min, a
precipitate formed was filtered off and washed with ethanol
(5 mL). The yield was 0.23 g (90%), light yellow crystals with
m.p. 223—224 °C. Recrystallization from isobutanol gives
no change in the melting point. Found (%): C, 62.69; H, 4.26;
N, 11.85. C12H10N2O3. Calculated (%): C, 62.60; H, 4.38;
N, 12.17. IR, ν/cm–1: 3310, 3237, 1679, 1651, 1590, 1497.
1H NMR, δ: 4.78 (br.s, 2 H, NH2); 6.80 (d, 1 H, H(3), J = 2.3 Hz);
7.07 (d, 1 H, H(5), J = 2.3 Hz); 7.52—7.62 (m, 3 Harom);
8.10—8.14 (m, 2 Harom); 10.32 (br.s, 1 H, NH).
NꢀHydroxyꢀ4ꢀoxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxamide (6).
Ester 1 (2.0 g, 8.2 mmol) and Et2O (10 mL) were added to a
solution of hydroxylamine hydrochloride (0.63 g, 9.1 mmol)
in water (10 mL). Solid KOH (1.01 g, 0.018 mol) was added
portionꢀwise over 30 min to the mixture obtained with thorough
stirring and cooling in an iceꢀwater bath. Then, the mixture was
stirred for another 1 h, the ethereal layer containing a small
amount of the starting substrate and organic impurities was
separated, whereas a 20% aq. HCl was added dropwise to the
aqueous layer with stirring and cooling to obtain рH 2—3.
A colorless precipitate formed was filtered off, washed with cold
water (5 mL), dried, and recrystallized from EtOH. The filtered
crystals were washed with toluene to remove traces of the startꢀ
ing ester 1. The yield was 0.90 g (48%), colorless crystals
with m.p. ∼200 °C (decomp.). Found (%): C, 62.05; H, 4.07;
N, 5.75. C12H9NO4. Calculated (%): C, 62.34; H, 3.92; N, 6.06.
IR, ν/cm–1: 3225—3090, 2860, 1690, 1639, 1607, 1584, 1574,
1498. 1H NMR, δ: 6.79 (d, 1 H, H(3), J = 2.3 Hz); 7.08 (d, 1 H,
H(5), J = 2.3 Hz); 7.53—7.62 (m, 3 Harom); 8.08—8.12 (m,
2 Harom); 9.61 (s, 1 H, NH); 11.78 (s, 1 H, OH).
Experimental
IR spectra were recorded on a PerkinꢀElmer Spectrum BXꢀII
spectrometer in KBr pellets. 1H and 13C NMR spectra were
recorded on a Bruker DRXꢀ400 spectrometer (400 and 100 MHz,
respectively) in DMSOꢀd6 with Me4Si as an internal standard.
Mass spectrum of compound 8 was obtained on a Finnigan
MAT 8200 instrument (EI, 70 eV). Elemental analysis was
performed on a PE 2400 Series II automatic analyzer. Ethyl
5,6ꢀdibromoꢀ2,4ꢀdioxoꢀ6ꢀphenylhexanoate was obtained according
to the procedure described earlier.2
Ethyl 4ꢀoxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxylate (1). Diisoꢀ
propylamine (9.80 g, 0.097 mol) was added dropwise to a solution
of ethyl 5,6ꢀdibromoꢀ2,4ꢀdioxoꢀ6ꢀphenylhexanoate (19.64 g,
0.048 mol) in freshly distilled DMSO (80 mL) with stirring and
cooling with icy water. The turned dark reaction mixture
was stirred for another 30 min, followed by addition of water
(100 mL), a yellow precipitate formed was filtered off and
recrystallized from toluene—hexane (1 : 2), preliminary passing
a hot solution through silica gel (20 cm3), to obtain the product
(8.71 g, 74%) with m.p. 118—119 °C (Ref. 3: m.p. 119 °C).
1H NMR (CDCl3), δ: 1.44 (t, 3 H, Me, J = 7.1 Hz); 4.47 (q,
2 H, OCH2, J = 7.1 Hz); 6.87 (d, 1 H, H(3), J = 2.3 Hz); 7.13
(d, 1 H, H(5), J = 2.3 Hz); 7.49—7.58 (m, 3 Harom); 7.85—7.88
(m, 2 Harom).
4ꢀOxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxylic acid (2). Ester 1
(13.0 g, 0.053 mol) was refluxed in 20% aq. HCl (100 mL) for
1 h with vigorous stirring, the reaction mixture was cooled, a
precipitate was filtered off and washed with water. The yield was
10.86 g (94%), light yellow crystals with m.p. 237—239 °C (Ref. 2:
m.p. 237 °C). 1H NMR, δ: 6.90 (d, 1 H, H(3), J = 2.3 Hz);
7.13 (d, 1 H, H(5), J = 2.3 Hz); 7.55—7.62 (m, 3 H, arom.);
7.96—8.00 (m, 2 Harom); 13.5—15.5 (br.s, 1 H, OH).
4ꢀOxoꢀ6ꢀphenylꢀ4Hꢀpyranꢀ2ꢀcarboxamide (3). Ester 1
(2.0 g, 8.2 mmol) was heated with 25% aq. NH3 (2.5 mL) in
ethanol (10 mL) in a sealed tube for 24 h at 60 °C. A preciꢀ
pitate formed was filtered off, washed with ethanol (5 mL),
and dried. The yield was 1.4 g (79%), colorless crystals with
m.p. 248—250 °C (Ref. 7: m.p. 247—250 °C). Recrystallization
4ꢀHydroxyꢀ6ꢀphenylpyridineꢀ2ꢀcarboxylic acid (7). Acid 2
(9.0 g, 0.042 mol) was heated with 25% aq. NH3 (22 mL) and
DMSO (140 mL) in a sealed tube for 24 h at 130 °C. Then, the
solvents were evaporated in vacuo, a dry residue was mixed with
20% aq. HCl (15 mL) and the mixture obtained was cooled to
–10 °C. A precipitate formed was filtered off, washed with cold
20% aq. HCl (5 mL), and dried. The yield was 8.10 g (90%),
a colorless powder with m.p. ∼250 °C (decomp.) (Ref. 7:
m.p. 241—242 °C). 1H NMR, δ: 5.0—7.5 (br.s, 2 H, 2 OH);
7.47—7.55 (m, 5 H, H(3), H(5)arom); 8.02—8.06 (m, 2 Harom).
Ethyl 4ꢀhydroxyꢀ6ꢀphenylpyridineꢀ2ꢀcarboxylate (8). A mixꢀ
ture of anhydrous EtOH (200 mL), acid 7 (8.0 g, 0.037 mol),
and concentrated HCl (2 mL) was stirred until a homogeneous
solution was formed, The solution obtained was heated in a

1252
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 6, June, 2009
Usachev et al.
sealed tube for 16 h at 110 °C. Pyridine (3 mL) was added to the
cooled mixture with stirring, the solvent was evaporated in vacuo,
the residue was vigorously shaken with a toluene—Et2O solvent
mixture (1 : 1, 300 mL) and water (20 mL). The upper organic
layer was separated, passed through silica gel (10 cm3), the
solvent excess was evaporated from the filtrate, keeping the bath
temperature under 100—110 °C, the evaporated solvent was
again passed through the same layer of silica gel, the filtrates
were combined. After evaporation of solvents from the combined
filtrate in a hot water bath in vacuo, ester 8 was obtained. The
yield was 6.90 g (76%), a glassy solid compound, transforming
into a viscous liquid on heating. IR, ν/cm–1: 3400—2500, 1725,
1627, 1608, 1580, 1523, 1500. MS (EI, 70 eV), m/z (Irel (%)):
243 [M]+ (23), 199 [M – CO2]+ (12), 171 [M – C3H4O2]+
(100). Found: m/z 243.08989 [M]+. C14H13NO3. Calculated: M
3ꢀ(1,5ꢀDiphenylꢀ1Hꢀpyrazolꢀ3ꢀyl)ꢀ1Hꢀindoleꢀ2ꢀcarboxylic
acid (14). Concentrated HCl (3 drops) was added to a solution
of hydrazone 10 (0.2 g, 0.5 mmol) in AcOH (5 mL), the mixture
was refluxed for 4 h and cooled. A precipitate was filtered off,
sequentially washed with AcOH and water. After recrystallization
from AcOH, indole 14 was obtained (0.13 g, 68%) as colorless
crystals with m.p. 280 °C. IR, ν/cm–1: 3312, 1693, 1678, 1596,
1562, 1536, 1499, 1488. Found (%): C, 75.68; H, 4.38; N, 10.92.
C24H17N3O2. Calculated (%): C, 75.97; H, 4.52; N, 11.08.
1H NMR, δ: 7.16 (ddd, 1 H, H(5), J = 8.4 Hz, 7.0 Hz, 1.1 Hz);
7.31—7.50 (m, 12 H, H(6), H(4´), 2 Ph); 7.53 (d, 1 H, H(7),
J = 8.4 Hz); 8.31 (d, 1 H, H(4), J = 8.3 Hz); 11.97 (s, 1 H, NH);
13.8 (br.s, 1 H, OH). 13C NMR, δ: 109.12 (d, C(4´), J = 179.6
Hz); 111.97 (dd, C(3), J = 5.5 Hz, 2.1 Hz); 112.50 (dd, C(7),
J = 165.1 Hz, 7.4 Hz); 120.66 (dd, C(5), J = 160.4 Hz, 7.8 Hz);
122.90 (dd, C(4), J = 162.5 Hz, 7.3 Hz); 124.67 (d, C(2),
J = 4.3 Hz); 124.94 (dm, C(6), J = 161.3 Hz); 125.04 (ddd,
C(2″), C(6″), J = 163.6 Hz, 7.5 Hz, 5.1 Hz); 126.03 (m, C(3a));
127.82 (dt, C(4″), J = 162.3 Hz, 7.7 Hz); 128.57 (C(4´´´));
128.60 (C(3´´´), C(5´´´)); 128.65 (C(2´´´), C(6´´´)); 129.24 (dd,
C(3″), C(5″), J = 162.8 Hz, 7.5 Hz); 129.83 (m, C(1´´´)); 136.07
(ddd, C(7a), J = 10.2 Hz, J = 7.3 Hz, J = 2.7 Hz); 139.44 (t,
C(1″), J = 8.3 Hz); 142.95 (dt, C(5´), J = 8.3 Hz, J = 4.1 Hz);
146.25 (d, C(3´), J = 4.3 Hz); 162.39 (C=O).
1
243.08954. H NMR, δ: 1.34 (t, 3 H, Me, J = 7.0 Hz); 4.36 (q,
2 H, OCH2, J = 7.0 Hz); 7.42—7.50 (m, 5 H, H(3), H(5)arom);
8.03—8.07 (m, 2 Harom); 11.17 (s, 1 H, OH).
4ꢀHydroxyꢀ6ꢀphenylpyridineꢀ2ꢀcarbohydrazide (9). Ester 8
(0.22 g, 0.9 mmol) in 65% aq. hydrazine hydrate (2 mL) was
refluxed for 1 h. Then, the water and hydrazine hydrate excess
was evaporated, the residue was diluted with water (6 mL), a
colorless precipitate was filtered off, washed with water, dried,
and recrystallized from butanol. The yield was 0.12 g (58%),
colorless crystals with m.p. 222—223 °C. Found (%): C, 63.08;
H, 4.84; N, 18.40. C12H11N3O2. Calculated (%): C, 62.87;
H, 4.84; N, 18.33. IR, ν/cm–1: 3317, 3250, 1666, 1598, 1572,
1517, 1499. 1H NMR, δ: 4.59 (s, 2 H, NH2); 7.37 (d, 1 H, H(3),
J = 2.2 Hz); 7.42 (d, 1 H, H(5), J = 2.2 Hz); 7.43—7.50 (m,
3 Harom); 8.21—8.25 (m, 2 Harom); 9.92 (s, 1 H, NH); 11.05
(br.s, 1 H, OH).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 06ꢀ03ꢀ04004ꢀ
NNIO) and German Research Society (Grant 436 RUS
113/901/0ꢀ1).
References
3ꢀ(1,5ꢀDiphenylꢀ1Hꢀpyrazolꢀ3ꢀyl)ꢀ2ꢀ(2ꢀphenylhydrazono)ꢀ
propionic acid (10). A mixture of 6ꢀphenylcomanic acid 2 (1.0 g,
4.63 mmol) and phenylhydrazine (1.1 g, 10.2 mmol) in dioxane
(20 mL) was refluxed for 2.5 h, the solvent excess was evaporated,
the residue was diluted with 1% aq. NaHCO3 (50 mL). Excess
phenylhydrazine was extracted with toluene (10 mL), the
aqueous layer was separated and mixed with conc. HCl (5 mL).
A precipitate formed was recrystallized from CCl4. The yield
was 0.37 g (20%), colorless crystals with m.p. 187—189 °C.
Found (%): C, 72.88; H, 4.90; N, 13.93. C24H20N4O2. Calcuꢀ
lated (%): C, 72.71; H, 5.08; N, 14.13. IR, ν/cm–1: 3393, 3321,
1666, 1605, 1579, 1534, 1507, 1494. 1H NMR, δ: 4.07 (s, 2 H,
CH2); 6.42 (s, 1 H, H(4)); 6.90 (tt, 1 H, H(4´), J = 7.3 Hz,
1.2 Hz); 7.18—7.40 (m, 14 Harom); 10.30 (s, 1 H, NH); 12.10
(br.s, 1 H, OH). 13C NMR, δ: 23.65 (t, CH2, J = 130.0 Hz);
107.08 (dt, C(4), J = 175.8 Hz, 2.5 Hz); 113.86 (dt, C(2´),
C(6´), J = 161.4 Hz, 6.1 Hz); 121.00 (dt, C(4´), J = 160.0 Hz,
7.4 Hz); 124.96 (ddd, C(2″), C(6″), J = 164.0 Hz, 7.3 Hz,
5.6 Hz); 127.48 (dt, C(4´´´), J = 162.7 Hz, 7.1 Hz); 128.30 (dm,
2 Carom, J = 162.0 Hz); 128.33 (dm, C(4″), J = 161.0 Hz);
1. US Pat. 0232880, Chem. Abstr., 2001, 135, 257153.
2. W. Borsche, W. Peter, Lieb. Ann. Chem., 1927, 453, 158.
3. G. Soliman, L. Rateb, J. Chem. Soc., 1956, 3663.
4. M. Stiles, J. P. Selegue, J. Org. Chem., 1991, 56, 4067.
5. H. Schiefer, G. Henseke, Angew. Chem., 1965, 77, 547.
6. UK Pat. GB 2123813 A, Chem. Abstr., 1981, 94, 121322.
7. Y. Honma, Y. Sekine, T. Hashiyama, M. Takeda, Y. Ono,
K. Tsuzurahara, Chem. Pharm. Bull., 1982, 30, 4314.
8. B. I. Usachev, I. A. Bizenkov, V. Ya. Sosnovskikh, Izv. Akad.
Nauk, Ser. Khim., 2007, 537 [Russ. Chem. Bull., Int. Ed.,
2007, 56, 558].
9. Y. Honma, K. Oda, T. Hashiyama, K. Hanamoto, H. Nakai,
H. Inoue, A. Ishida, M. Takeda, Y. Ono, K. Tsuzurahara,
J. Med. Chem., 1983, 26, 1499.
10. P. L. Ornstein, D. D. Schoepp, M. B. Arnold, J. D. Leander,
D. Lodge, J. W. Paschal, T. Elzey, J. Med. Chem., 1991, 34,
90.
11. C. B. Vicentini, M. Manfrini, M. Mazzanti, M. Manferdini,
C. F. Morelli, A. C. Veronese, Heterocycles, 2000, 53, 1285.
128.57 (dm, 2 Carom, J = 162.8 Hz); 129.00 (dm, 4 Carom
,
J = 162.2 Hz); 129.88 (m, C(1´´´)); 132.41 (td, C=N, 2J = 6.2 Hz,
3J = 3.4 Hz); 139.58 (tt, C(1″), J = 8.9 Hz, 2.3 Hz); 143.28 (dt,
C(5), 2J = 8.0 Hz, 3J = 4.0 Hz); 144.12 (dtt, C(1´), J = 8.7 Hz,
8.4 Hz, 1.6 Hz); 148.17 (td, C3, 2J = 7.8 Hz, 4.6 Hz); 166.05
(t, C=O, 3J = 3.8 Hz).
Received August 12, 2008;
in revised form November 28, 2008