Reactions of 2-Mono- and 2,6-Disubstituted 4-Pyrones with Phenylhydrazine as General Method for the Synthesis of 3-(N-Phenylpyrazolyl)Indoles

Article abstract of DOI:10.1007/s10593-014-1603-3

Phenylhydrazine reacted regioselectively with 6-substituted 4-pyrone-2-carboxylic acids (or esters) in protic and aprotic solvents, leading to phenylhydrazones of 3-(3-R-1-phenylpyrazol-5-yl)- or 3-(5-R-1-phenylpyrazol-3-yl)pyruvic acids (or esters), resp

Full text of DOI:10.1007/s10593-014-1603-3

DOI 10.1007/s10593-014-1603-3
Chemistry of Heterocyclic Compounds, Vol. 50, No. 10, January, 2015 (Russian Original Vol. 50, No. 10, October, 2014)
REACTIONS OF 2-MONO- AND 2,6-DISUBSTITUTED 4-PYRONES
WITH PHENYLHYDRAZINE AS GENERAL METHOD FOR THE
SYNTHESIS OF 3-(N-PHENYLPYRAZOLYL)INDOLES
1
1
1
*
D. L. Obydennov , B. I. Usachev , and V. Ya. Sosnovskikh
Phenylhydrazine reacted regioselectively with 6-substituted 4-pyrone-2-carboxylic acids (or esters) in
protic and aprotic solvents, leading to phenylhydrazones of 3-(3-R-1-phenylpyrazol-5-yl)- or 3-(5-R-
1-phenylpyrazol-3-yl)pyruvic acids (or esters), respectively. 6-Di(tri)fluoromethylcomanic acids (or
esters) reacted analogously, forming the corresponding phenylhydrazones with RF group in the side
chain. The obtained phenylhydrazones underwent Fischer reaction under acidic conditions, forming the
respective 3-(N-phenylpyrazolyl)indoles. In contrast to comanic acid and its ester, the reactions of
2-substituted 4-pyrones occurred non-selectively and gave mixtures of regioisomeric pyrazoles with
phenylhydrazone group in the side chain or 3-(N-phenylpyrazolyl)indoles. A mechanism was proposed
to explain the effect of solvent on the course of reaction.
Keywords: comanic acid, indoles, phenylhydrazine, pyrazoles, 4-pyrones, Fischer reaction, regio-
selectivity.
3-(Pyrazolyl)indoles containing two pharmacophore fragments, indole and pyrazole rings, may possess
diverse biological activity and thus attract the attention of researchers [1-7]. Methods for the synthesis of these
heterocycles have been based on cross-coupling reactions [1-14] as well as on the interaction of polycarbonyl
compounds with hydrazines [15, 16]. 4-Pyrones can be viewed as masked triketones, enabling their application
in the synthesis of 3-(pyrazolyl)indoles.
Prior to our work in this area [17-21], the only such examples known were reactions of unsubstituted
-pyrone with arylhydrazines [22], and 2,6-dimethyl--pyrone with phenylhydrazine [23], leading to
arylhydrazones of 2-(N-phenylpyrazol-5-yl)acetaldehyde, products of attack by the more nucleophilic primary
amino group at the С-2 atom with subsequent recyclization to a pyrazole and addition of a second arylhydrazine
molecule. The interaction of 2-mono- and 2,6-disubstituted unsymmetrical -pyrones with phenylhydrazine
theoretically could produce
a
mixture of four regioisomeric phenylhydrazones of 2-oxoethyl-
N-phenylpyrazoles, but our study showed that the reaction proceeded quite selectively in most cases, and its
products could be used in Fischer synthesis of 3-(pyrazolyl)indoles [17-21].
_______
*To whom correspondence should be addressed, e-mail: dobydennov@mail.ru.
1Institute of Natural Sciences, Ural Federal University named after the First President of Russia B. N. Yeltsin,
51 Lenina Ave., Yekaterinburg 620000, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1510-1527, October, 2014.
Original article submitted July 10, 2014; revision sabmitted August 11, 2014.
1388
0009-3122/15/5010-1388©2015 Springer Science+Business Media New York

Taking into account the high biological activity of some 3-(pyrazolyl)indoles [1-7] and also in order to
develop a general method for their preparation, in the current work we studied the interaction of
phenylhydrazine with a wide range of substituted -pyrones under various conditions and generalized all
available results for this reaction. We should note that our previous investigations in this direction were devoted
mainly to trifluoromethylated derivatives of 4-pyrone-2-carboxylic (comanic) acid [18, 19, 21], which did not
allow to make any general conclusions about the effect of substituents and solvent on the regiochemistry of
products.
The first stage of this study concerned the interaction of phenylhydrazine with comanic (1а), 6-methyl-
comanic (1b), chelidonic (1с), and 6-phenylcomanic (1d) acids, as well as with monoethyl ester of chelidonic
acid (1e). We established that these reactions, depending on the nature of solvent and рН of the medium,
occurred with the formation of regioisomeric pyrazoles 2 or 4, which could undergo Fischer reaction under
acidic conditions, forming the indoles 3 and 5, respectively. Performing the reaction with phenylhydrazine
hydrochloride in protic solvents in the presence of acid (method A) gave mainly phenylhydrazones of 3-(N-
phenylpyrazol-5-yl)pyruvic acid 2, but reaction with phenylhydrazine itself in aprotic solvents (method B)
produced phenylhydrazones of 3-(N-phenylpyrazol-3-yl)pyruvic acid 4 (Scheme 1). In a range of cases
(compounds 2b,c, 4b,d,e) the reaction did not stop at the stage of intermediate hydrazone 2 or 4, but gave
directly the indoles 3 or 5.
Scheme 1
Method A: PhNHNH2·HCl, H+
Ph
Ph
R
R
protic solvent
HN
HN
N
N
Method B: 1) PhNHNH2
aprotic solvent; 2) H+
CO2H
CO2H
N
N
Ph
N
N
4a,c [4b,d,e]
Ph
2a [2b,c]
H+
O
H+
R
R
R
O
1a–e
CO2H
H+
H+
Ph
N
N
N
N
a R = H,
Ph
CO2H
3a–c
b R = Me,
c R = CO2H,
d R = Ph,
CO2H
5a–e
N
N
H
H
e R = CO2Et
We used the example of comanic acid (1a) to study the effect of reaction conditions on the
regioselectivity of the process in more detail. It was found that performing the reaction under the conditions of
method А (PhNHNH2·HCl, water, 60°C, 0.1 ml of conc. HCl (experiment 1, Table 1)) gave 81% yield of
isomeric mixture Е-2а+Z-2a+E-4a in 86:5:9 ratio, from which the Е-hydrazone 2а was isolated in pure form
with 47% yield by recrystallization from a toluene–ethanol mixture. As shown by further study, the majority of the
obtained hydrazones had Е-configuration, which was supported by data of X-ray structural analysis (see below).
When using phenylhydrazine as base (H2O, ~20°C (experiment 2, Table 1)), the Е-hydrazone 2а was formed in
lower yield (18%) [17]. When refluxing in 70% AcOH with added HCl (method C), this compound underwent
Fischer reaction, giving the expected indole 3а. Refluxing of pyrone 1а with PhNHNH2·HCl in 70% aqueous
AcOH formed the indole 3a directly (method A, yield 50% (experiment 3, Table 1)) [17], while refluxing with
PhNHNH2 in dioxane followed by addition of HCl gave the indole 5a (method B, yield 35% (experiment 5,
Table 1)). Performing the reaction in dioxane without addition of HCl gave a 63% yield of hydrazone mixture
E-4а+Z-4а+Z-2а+E-2а (51:18:18:13) (experiment 4, Table 1), which explained the rather low yield of indole 5а
under those conditions.
1389

TABLE 1. Synthesis of Pyrazoles 2, 4, 7 and Indoles 3, 5, 8 from Pyrones
1 and 6
Expe-
riment
Conditions*
(method)
Conditions
(method)
Pyrone
Pyrazole
Yield, %
Indole Yield, %
1
2
3
4
PhNHNH2·HCl,
H2O, 0.1 ml HCl,
60°C, 8 h (A)
81
47
―
―
―
67 [17]
50 [17]
―
1а
Е-2а+Z-2a+
+ E-4a (86:5:9)
E-2а
PhNHNH2, H2O,
~20°C, 18 h (B)
E-2a
18 [17] 70% AcOH,
0.15 ml HCl,
1a
1a
1а
3a
Δ, 1 h (C)
PhNHNH2·HCl,
70% AcOH,
Δ, 4 h (A)
―
―
―
3a
PhNHNH2, dioxane, E-4а+Z-4а+
63
―
―
Δ, 8 h (B)
+ Z-2а+E-2а
(51:18:18:13)
―
5
PhNHNH2, dioxane,
Δ, 6 h, then 0.75 ml
HCl, Δ, 2 h (B)
―
―
―
―
35
1а
5a
6
7
PhNHNH2·HCl,
EtOH, Δ, 24 h (A)
―
21
5
1b
1b
3b
5b
5b
PhNHNH2, dioxane, E-4b
Δ, 4 h (B)
32
AcOH–HCl
(12:1), Δ,
4 h (C)
―
36
8
PhNHNH2·HCl,
5 ml H2O–HCl 4:1,
Δ, 1 h (A)
―
―
48
1c
1d
1e
6a
6b
6c
3c+5c
(53:47)
5с
18
9
PhNHNH2, dioxane, E-4d
Δ, 2.5 h (B)
20 [20] AcOH,
0.25 ml HCl,
68 [20]
5d
Δ, 4 h (C)
10
11
12
13
PhNHNH2, dioxane, E-4e
Δ, 4 h (B)
13
5 ml AcOH,
0.15 ml HCl,
Δ, 4 h (C)
42
58
5e
8a
8b
8c
PhNHNH2·HCl,
EtOH, ~20°C, 24 h,
60°C, 3 h (A)
PhNHNH2·HCl,
EtOH, 60°C,
24 h (A)
31 (E) 4 ml AcOH,
8 (Z) 0.15 ml HCl,
Δ, 4 h (C)
7a
E-7b
E-7c
9
PhNHNH2
HCl, EtOH, Δ,
24 h (A)
18
(from 6b)
PhNHNH2·HCl,
EtOH, 60°C,
8 h (A)
40
4 ml AcOH,
0.3 ml HCl,
Δ, 4 h (C)
43
_______
*Standard load of reactants: 1.5 mmol of 4-pyrone 1а-е, 6а-с and
3.3 mmol of PhNHNH2 (either salt or base).
In the case of 6-methylcomanic acid (1b) under the conditions of method A (PhNHNH2·HCl, ethanol,
refluxing for 24 h (experiment 6, Table 1)), the major product was indole 3b (yield 21%), while indole 5b was
also isolated from the reaction mixture as by-product by recrystallization from ethanol (yield 5%). The
intermediate hydrazone 2b was detected in the reaction mixture as Z- and Е-isomers in 64:36 ratio after
refluxing for 1 h during this experiment. Performing the reaction in refluxing dioxane gave the hydrazone E-4b
(method B, yield 32% (experiment 7, Table 1)), from which the indole 5b was obtained in 36% yield.
The reaction of chelidonic acid (1c) with phenylhydrazine hydrochloride in water with added HCl
(method A) was non-selective and gave 48% yield of a 53:47 mixture of two indoles 3c and 5c, which were
regioisomers at the pyrazole ring. The indole 5с was isolated from this mixture in 18% yield, using its different
solubility in ethanol (experiment 8, Table 1). The acid 3с was previously obtained by hydrolysis of 3-(3-ethoxy-
1390

carbonyl-1-phenylpyrazol-5-yl)trifluoroacetone phenylhydrazone in the presence of KOH [18]. The diacid 1с
did not react with phenylhydrazine in aprotic solvents. Reactions of 6-phenylcomanic acid (1d) and monoethyl
chelidonate (1e) with phenylhydrazine hydrochloride also occurred non-selectively and resulted in complex
mixtures, from which individual products could not be isolated. At the same time, the interaction of these acids
with phenylhydrazine in dioxane (method B), gave phenylhydrazones of 3-(N-phenylpyrazol-3-yl)pyruvic acids
E-4d,e, albeit in low yields (13-20%). These compounds were converted to 3-(pyrazolyl)indoles 5d,e by refluxing in
acetic acid with added HCl (experiments 9 [20], 10, Table 1).
The reactivity of ethyl esters 6а-с was found to be lower than that of comanic acids 1a-c, as they
practically did not react with phenylhydrazine under the conditions of method B (in dioxane or toluene) or gave
complex mixtures of products in ethanol. However, the reactions of esters 6a,c with phenylhydrazine
hydrochloride in ethanol (method A) occurred sufficiently regioselectively and produced the expected major
products, phenylhydrazones 7a,c of 3-(N-phenylpyrazol-5-yl)pyruvic acid, which in acetic acid with added HCl
were converted to 3-(N-phenylpyrazol-5-yl)indoles 8a,c in 43-58% yields (Scheme 2; experiments 11, 13, Table
1). The less reactive ethyl ester of 6-methylcomanic acid (6b) gave directly the indole 8b (18% yield) upon
refluxing with PhNHNH2·HCl in ethanol, and the pyrazole 7b (isolated in only 9% yield due to incomplete
conversion of the starting ester) at 60°C (experiment 12, Table 1).
Scheme 2
R
Ph
O
N
R
HN
N
N
Method A
Ph
CO2Et
8a–c
CO2Et
N
or
N
R
O
6a–c
CO2Et
Method B
Ph
7a–c
N
H
a R = H, b R = Me, c R = CO2Et
It should be noted that we observed a clear relationship during this stage of investigation, where the side
chain of phenylhydrazone always contained a carboxyl group, regardless of the reaction conditions. In addition,
the use of phenylhydrazine in the form of hydrochloride in protic solvent (method A) gave predominantly the
3-R-1-phenylpyrazole, while the reaction with phenylhydrazine in the base form in aprotic solvent (method B)
led to 5-R-1-phenylpyrazole. In order to determine the general applicability of these observations, we extended
our study by including 6-[tri(di)fluoromethyl]comanic acids 9a,c and their esters 9b,d, as well as monosubstituted
-pyrones 14a-c. At first, we set out to establish the location of tri(di)fluoromethyl group (further in text – RF
group) of phenylhydrazone – either at the side chain or at the pyrazole ring, and the possible solvent effects on
the regiochemistry of product, which were observed in the case of comanic acid derivatives. Besides that, the
possibility of preparing 3-(N-phenylpyrazolyl)indoles containing RF group also attracted our interest, which
would allow to recommend the reaction of -pyrones with phenylhydrazine as a general method for the
preparation of these potentially biologically active compounds.
We found that, in contrast to comanic acids 1a-e and their esters 6a-c, the -pyrones 9a-d containing an RF
group reacted with phenylhydrazine and produced hydrazones with RF group instead of CO2R in the side chain
(Scheme 3). As expected, under the conditions of method А the major products were 1-Ph-3-CO2R-pyrazoles 10a-d,
while 1-Ph-5-CO2R-pyrazoles 12a-d were produced under the conditions of method B (Table 2). We should note
that the reactions were smoother and more selective when RF = CF3. The second major difference was that the
products formed could not be indolized in acetic acid in the presence of HCl. Nevertheless, targeted search for more
suitable conditions of Fischer reaction showed that treatment of CF3-hydrazones 10a,b and 12a,b with a mixture of
МеSO3H and P2O5 (method D) gave the desired 3-(N-phenylpyrazolyl)-2-trifluoromethylindoles 11a,b and 13a,b in
40-73% yields (experiments 1-4, Table 2) [19], while CHF2-phenylhydrazones 10c,d and 12c,d only produced
intractable resins under these conditions as well. It should be noted that introducing an RF group into the pyrone
1391

ring increased the reactivity of not only comanic acids, but also their ethyl esters, which, unlike compounds 6a-
c, reacted with phenylhydrazine both in protic and aprotic media, producing 1-Ph-3-CO2Et-pyrazoles 10b,d and
1-Ph-5-CO2Et-pyrazoles 12b,d, respectively, as the major products.
Scheme 3
Ph
Ph
O
RO2C
RO2C
HN
HN
N
N
RF
RF
N
N
Ph
N
N
RF
O
9a–d
CO2R
12a–d
Ph
10a–d
+
PhNHNH2
CO2R
CO2R
a R = H, RF = CF3,
b R = Et, RF = CF3,
c R = H, RF = CHF2,
d R = Et, RF = CHF2
Ph
N
N
N
N
Ph
CF3
CF3
N
H
N
H
11a,b
13a,b
TABLE 2. Synthesis of Pyrazoles E-10a-d, E-12a-d and Indoles 11a,b,
13a,b from Pyrones 9a-d
Expe-
riment
Conditions
(method)
Pyrone
Conditions* (method)
Pyrazole Yield, %
Indole Yield, %
1
2
3
4
5
6
7
8
PhNHNH2·HCl,
64 [19] MeSO3H, P2O5,
60°C, 6 h (D)
45 [19]
73 [19]
40 [19]
65 [19]
―
9a
9a
9b
9b
9c
9с
9d
9d
10a
12a
10b
12b
12c
11a
13a
11b
13b
―
10% HCl, 10 min (A)
PhNHNH2, dioxane,
Δ, 1.5 h (B)
30 [19] MeSO3H, P2O5,
60°C, 6 h (D)
PhNHNH2, EtOH,
~20°C, 2 days (B)
PhNHNH2, toluene,
Δ, 12 h (B)
58 [19] MeSO3H, P2O5,
60°C, 6 h (D)
34 [19] MeSO3H, P2O5,
60°C, 6 h (D)
PhNHNH2, dioxane,
0.1 ml HCl, 60°C, 3 h (B)
PhNHNH2·HCl, H2O,
50°C, 16 h (A)
31
―
―
―
―
10с+12c 68
―
―
(1:1)*2
PhNHNH2, EtOH,
~20°C, 2 days (B)
PhNHNH2, toluene,
~20°C, 4 days (B)
22
12
―
―
10d
―
―
12d
_______
*Standard load of reagents: 1.5 mmol of 4-pyrone 9а-d and 3.3 mmol of
PhNHNH2 (as salt or base).
*2Besides compounds 10с and 12c, the mixture contained ~20% of the
regioisomer with CHF2 group in the pyrazole ring.
Monosubstituted 4-pyrones 14а-с, obtained by decarboxylation of the respective comanic acids [24, 25],
reacted with phenylhydrazine showing little regioselectivity. Thus, reaction of 2-phenyl-4-pyrone (14a)
with PhNHNH2·HCl in refluxing ethanol for 24 h (method A) allowed to isolate 25% yield of the indole 17а,
1392

1
which contained 16% of the regioisomeric indole 18a according to Н NMR spectrum (Scheme 4, Table 3,
experiment 1); this reaction could not be stopped at the stage of phenylhydrazone intermediate. In the case of
2-trifluoromethyl- and 2-difluoromethyl-4-pyrones 14b,c the optimum reaction conditions were heating for 1 h in
phenylhydrazine at 120°C (method B, experiments 2, 3, Table 3). In both cases this led to a mixture of two
regioisomeric pyrazoles E-15b+E-16b and E-15c+E-16c, which were separated by recrystallization from
ethanol. The Fischer indolization could be accomplished only for СF3-substituted hydrazones 15b and 16b in
the presence of МеSO3H and P2O5 (method D), and resulted in the synthesis of 2-CF3-indoles 17b, 18b
(experiment 2, Table 3).
Scheme 4
Ph
Ph
O
HN
HN
N
N
(from 14b,c)
R
R
+ PhNHNH2
N
+
N
Ph
N
N
O
R
16b,c
Ph
15b,c
14a–c
(from 16b)
(from 15b)
(from 14a)
MeSO3H 60°C
P2O5 6 h
MeSO3H 60°C
P2O5 6 h
N
Ph
N
N
N
N
N
Ph
Ph
CF3
17b
Ph
Ph
+
N
N
CF3
18b
H
N
H
N
H
17a
N
Ph
N
a R = Ph, b R = CF3, c R = CHF2
H
18a
The structures of all obtained compounds were confirmed by elemental analysis, IR spectra, as well as
1Н, 13C, and 19F NMR spectroscopy. Besides that, the regio- and stereochemistry of phenylhydrazones 4b (Fig. 1)
1
and 12b [19] was reliably established by X-ray structural analysis. The Н NMR spectra of pyrazoles 2, 4, 7,
TABLE 3. Synthesis of Pyrazoles 15b,c, 16b,c and Indoles 17, 18a,b
from Pyrones 14a-c
Experi-
ment
Conditions*
(method)
Pyrone
Pyrazole
Yield, %
Conditions
Indole Yield, %
1
2
3
PhNHNH2·HCl,
EtOH, Δ, 24 h (A)
―
―
―
25
14a
14b
14c
17a+18a
(84:16)
PhNHNH2,
120°C, 1 h (B)
15b+16b 16 (15b) [19] MeSO3H, P2O5,
65 [19]
60 [19]
17b
18b
―
60°C, 6 h (D)
21 (16b) [19]
15c+16c 18 (15c)
13 (16c)
PhNHNH2,
120°C, 1 h (B)
―
―
_______
*Standard load of reagents: 1.5 mmol of 4-pyrone 14а-с and 3.3 mmol of
PhNHNH2 (as salt or base).
10, 12, 15, 16 (in DMSO-d6) contained a downfield signal of NH proton in the region of 9.91-10.43 ppm, which
indicated Е-configuration of the phenylhydrazone fragment, confirmed by X-ray structural analysis. The
Z-phenylhydrazones were observed in crude products 2а,b and 4а, while only the hydrazone Z-7a was isolated
in pure form with 8% yield. This hydrazone featured an NH proton involved in the formation of intramolecular
1393

hydrogen bond with ester group and gave a more downfield 1H NMR signal at 11.88 ppm (Fig. 2), which was in
a good agreement with the literature data for Z-phenylhydrazone of 3-(pyrazolyl)pyruvic acid [18].
1
The Н NMR spectral analysis of the synthesized compounds allowed to identify a range of trends
useful for establishing the regiochemistry of 3-(1-phenylpyrazolyl)indoles (Table 4).
Fig. 1. The molecular structure of phenylhydrazone E-4b with atoms represented by thermal vibration ellipsoids
of 50% probability.

NH = 11.88–12.25 ppm

NH = 10.27–10.37 ppm
R
N
Ph
Ph
N
NH
Ph
O
R
R
.
HN
CH3
.
O
N
N
.
CO2R1
N
N
OR1
Z-2a–c, Z-7a
N
N
N
O
H
Ph
Ph
8a–c
E-2a,b, E-7a
Fig. 2. Geometric isomers of phenylhydrazones 2a-c and 7а, and the non-planar structure of 3-(N-phenyl-
pyrazol-5-yl)indoles 8a-c.
1
1) The most characteristic H NMR signal for regioisomeric N-phenylpyrazoles with E-phenylhydrazone
fragment was that of the Н-4 proton in the pyrazole ring (H-4 Pz). This signal was shifted downfield by 0.24-
0.38 ppm when going from compounds 2a,b, 10a-d, and 15b,c to compounds 4a,b, 12a-d, and 16b,c. At the
same time, the chemical shift of methylene group practically did not change and depended only on the nature of
substituent in the side chain, for example, δСН was 4.02-4.05 ppm for CF3-hydrazones, and 3.88-3.93 ppm for
2
CHF2-hydrazones.
2) In the N-phenylpyrazoles 2a,b, 7a with Z-phenylhydrazone fragment, compared to the corresponding
E-isomers, the Н-4 Pz proton signals were shifted downfield by 0.25-0.29 ppm, while the signals of methylеne
protons – upfield by 0.13-0.18 ppm.
3) When comparing indoles to phenylhydrazones, the signal of Н-4 Pz was always shifted downfield in
the case of indoles due to the deshielding effect of adjacent indole fragment. Thus, Δδ was 0.62-0.69 ppm for
3-(N-phenylpyrazol-5-yl)indole-2-carbonic acids 3 and their esters 8, obtained from compounds E-2 and E-7,
1394

respectively, while Δδ was 0.93-1.04 ppm for the regioisomeric products 5, obtained from phenylhydrazones
E-4, which was explained by the more planar conformation of heterocyclic rings in the latter compounds. In the
case of 3-(N-phenylpyrazol-5-yl)-2-trifluoromethylindoles 11a,b, 17b, this value was close to Δδ of indoles 3, 8
and was equal to 0.50-0.62 ppm. At the same time, Δδ = 0.36-0.41 ppm for regioisomeric indoles 13a,b, 18b,
despite their planar structure, apparently due to the effect of substituent at the indole ring position 2.
4) The chemical shift of Н-4 Pz strongly depended on the substituent at the indole ring position 2 in the
regioisomeric pairs of 3-(N-phenylpyrazol-5-yl)- and 3-(N-phenylpyrazol-3-yl)indoles. This difference was
0.68-0.73 ppm in the case of indole-2-carboxylic acids 3a-c and 5a-c, while for 2-CF3-indoles 11a,b and 13a,b,
17b and 18b Δδ was 0.12-0.18 ppm, and for 2-phenylindoles 17a and 18a Δδ was -0.20 ppm.
5) Another important signal in 3-(N-phenylpyrazol-3-yl)indoles 5, 13 and 18 was the downfield doublet
of indole proton Н-4 Ind at 8.10-8.31 ppm (J = 7.9-8.3 Hz), which was linked to the deshielding effect of the
planar pyrazole ring. This signal allowed to easily distinguish regioisomeric indoles, because the pyrazole
fragment deviated from the molecular plane due to steric hindrance in 3-(N-phenylpyrazol-5-yl)indoles 3, 8, 11,
17 and thus shielded the Н-4 Ind proton, shifting its signal upfield by ~0.9 ppm to the region of 7.20-7.40 ppm.
In this case, the most downfield signal was that of indole Н-7 proton, which was observed as doublet at
7.44-7.51 ppm (J = 8.1-8.3 Hz).
6) The non-planar conformation and hindered rotation of heterocyclic rings in 3-(N-phenylpyrazol-
5-yl)indoles resulted in non-equivalent methylene protons of ethoxycarbonyl group in ethyl esters 8a-c,
observed as unresolved ABX3 system at 3.85-4.20 ppm (Fig. 2). The chemical shifts of these protons pointed to
the presence of ester group in indole, instead of pyrazole ring, because the methylene protons gave quartets with
J = 7.1 Hz at 4.36 and 4.23-4.24 ppm in the cases of 5-(indol-3-yl)-N-phenylpyrazole-3-carboxylic acid and
3-(indol-3-yl)-N-phenylpyrazole-5-carboxylic acids 11b, 5e, 13b, respectively.
7) The spin-spin coupling constant between the pyrazole ring protons was larger (JH-4,H-5 = 2.1-2.6 Hz)
in 3-monosubstituted N-phenylpyrazoles 4a, 5a, 16b,c, and 18a,b, compared to 5-monosubstituted N-phenyl-
pyrazoles 2a, 3a, 7a, 8a, 15b,c, and 17a,b (JH-3,H-4 = 1.1-1.8 Hz), making it a convenient indicator for
establishing the regiochemistry of these compounds.
The obtained results allowed to reach some general conclusions. First of all, reactions of 2-mono- and
2,6-disubstituted 4-pyrones with phenylhydrazine produced phenylhydrazones of (2-oxoethyl)-N-phenyl-
pyrazoles, containing a relatively electron-donating substituent (RD) in the pyrazole ring and a relatively
electron-withdrawing substituent (RA) in the hydrazone fragment of the starting -pyrone I. Thus, 6-substituted
comanic acids and their esters, where CO2R is the most electron-withdrawing group, formed ethoxycarbonyl-
hydrazones, while fluorine-containing derivatives with stronger electron-withdrawing RF group than СO2R [26]
gave RF-hydrazones. Secondly, reaction in protic solvents in the presence of acid gave mainly 1-phenyl-3-RD-
pyrazoles II, while 1-phenyl-5-RD-pyrazoles III were formed in aprotic solvents. Based on the obtained
experimental data and taking into account that the primary amino group of phenylhydrazine is the more
nucleophilic center, the general scheme of the process could be presented in the following way (Scheme 5).
Scheme 5
Ph
Ph
O
RD
RD
HN
HN
N
N
i
ii
RA
RA
N
N
Ph
RD
O
RA
N
N
III
Ph
I
II
RD – more electron-donating substituent, RA – more electron-accepting substituent; i – protic solvent, ii – aprotic solvent
1395

TABLE 4. The Characteristic 1Н NMR Signals of Regioisomeric
Pyrazoles and Indoles
Pyrazole
H-4 Pz
CH2
Indole
H-4 Pz
Н-4 Ind
5.94 (d, J = 1.6)
4.02
3.84
3.96
3.81
3.88
4.03
3.81
3.97
―
6.56 (d, J = 1.6)
7.32 (d, J = 8.2)
E-2a
Z-2a
3a
6.19 (d, J = 1.1)
E-2b
Z-2b
Z-2c
5.74
6.36
7.33 (d, J = 8.1)
3b
6.01
6.66
6.97
7.36 (d, J = 8.4)
8.30 (d, J = 8.2)
3c
5a
E-4a
Z-4a
6.27 (d, J = 2.3)
7.24 (d, J = 2.5)
6.30 (d, J = 2.3)
E-4b
Z-4b
4c
E-4d
E-4e
6.05
7.09
8.20 (d, J = 8.3)
5b
―
―
―
7.66
8.18 (d, J = 8.2)
8.31 (d, J = 8.3)
8.19 (d, J = 8.2)
7.39 (d, J = 8.1)
5c
5d
5e
8a
6.42
4.07
4.05
4.04
3.91
3.98
4.05
4.05
4.05
3.91
3.93
4.02
4.03
3.91
3.92
―
overlapped
7.71
6.78
E-7a
Z-7a
5.96 (d, J = 1.6)
6.59 (d, J = 1.1)
6.25
E-7b
E-7c
5.74
6.38
7.40 (d, J = 8.2)
7.40 (d, J = 8.1)
7.26–7.36
7.27–7.35
―
8b
8c
6.36
7.05
E-10a
E-10b
E-10c
E-10d
E-12a
E-12b
E-12c
E-12d
15a
E-15b
E-15c
16a
E-16b
E-16c
6.46
7.08
11a
11b
―
6.51
7.11
6.44
―
6.47
―
―
―
6.84
7.20
8.10 (d, J = 8.1)
8.09 (d, J = 8.1)
―
13a
13b
―
6.88
7.24
6.78
―
―
6.82
―
―
―
6.44 (d, J = 1.8)
7.20-7.30 (m)
17a
17b
17c
18a
18b
18c
6.11 (d, J = 1.8)
6.06 (d, J = 1.7)
―
4.03
3.91
―
6.61 (unresolved d) 7.20-7.36 (m)
―
6.24 (d, J = 2.6)
6.79 (d, J = 2.5)
―
―
8.11 (d, J = 7.9)
8.19 (d, J = 8.1)
―
6.38 (d, J = 2.1)
6.30 (d, J = 2.4)
4.02
3.88
Scheme 6
I
II
H+
i
PhNHNH2 –H2O, –H+
RD
PhNHNH2
RD
OH
OH
O+
H
RD
RA
RA
N
+
+
O
N
NHPh
+O
O
RD
O
RA
RA
N
H
H
N
N
Ph
A
H
H
D
C
Ph
B
PhNHNH2
NNHPh
O
RD
RA
Ph
PhNHNH2
RA
RA
I
III
ii
–H2O
O
N
N
RD
O
RD
O
H
H
N
N
NH HN
N
N
H
H
Ph
Ph
Ph
E
F
G
1396

Quantum-chemical calculations have been used to demonstrate [27] that the course of 4-pyrone and
2-methyl-4-pyrone reaction with ammonia depends on the polarity of medium, where the reaction in polar
solvent proceeds through unstable charged intermediates A-D, while in non-polar solvent – through the stable
cyclic enones E. The possible mechanism of reaction between 4-pyrones and phenylhydrazine, which accounts
for the calculated data and explains our obtained results, is presented in Scheme 6.
The protonation of carbonyl oxygen atom in polar solvent in the presence of acid leads to pyrilium
intermediate A, which is attacked by the primary amino group of phenylhydrazine at the С-6 atom, where the
electron-donating substituent RD is located, and gives the addition product B, stabilized by conjugation of its
diene fragment with the electron-withdrawing group RA. Subsequent opening of the pyrone ring to the
intermediate С is accompanied by the formation of pyrazole D, which reacts with the second phenylhydrazine
molecule and gives the final 3-RD-1-phenylpyrazole II. In aprotic medium, the phenylhydrazine NH2 group
attacked the more electrophilic С-2 atom bearing the electron-withdrawing group RA, leading to the cyclic
enone E, which reacted at keto group with a second phenylhydrazine molecule, giving the intermediate F. The
latter opened to dihydrazone G, which then cyclized to the regioisomeric 5-RD-1-phenylpyrazole III (Scheme
6). We explained the higher reactivity of comanic acids 1, compared to their esters 6, with the specific
properties of CO2H group, which was apparently coordinated through intermolecular hydrogen bond with the
phenylhydrazine molecule, and directed its attack towards the C-2 atom bearing the carboxyl group.
Thus, we have demonstrated a regioselective reaction of comanic acid derivatives with phenyl-
hydrazine, giving pyrazoles that, regardless of the conditions, were always substituted in the phenylhydrazone
side chain with the most electron-withdrawing group of the starting 4-pyrone. The regiochemistry of pyrazole
ring was determined by reaction conditions, mainly by the nature of solvent. The use of protic solvent gave mainly
phenylhydrazones of 5-(2-oxoethyl)-1-phenyl-3-R-pyrazoles, while phenylhydrazones of 3-(2-oxoethyl)-1-phenyl-
5-R-pyrazoles were obtained in aprotic solvents. These compounds could be converted by Fischer reaction
under acidic conditions to 3-(3-R-1-phenylpyrazol-5-yl)indoles and 3-(5-R-1-phenylpyrazol-3-yl)indoles,
respectively, providing a general method for the preparation of these important heterocyclic compounds.
EXPERIMENTAL
IR spectra were recorded on IKS-29 (KBr pellets, compounds E-12c, E-12d), Perkin-Elmer Spectrum
1
13
BX-II, and Nicolet 6700 with ATR accessory instruments (the rest of compounds). Н and C NMR spectra
were acquired on a Bruker Avance II spectrometer (400 and 100 MHz, respectively) in DMSO-d6, with TMS as
1
internal standard. The following abbreviations were used in reporting Н NMR spectra of phenylhydrazones 2,
4, 7, 10, 12, 15 and 16: Ph – phenyl ring at the hydrazone fragment, Ph' – phenyl ring at the pyrazole fragment.
The pyrazole ring protons were denoted as H Pz, the indole ring protons – as H Ind. Elemental analysis was
performed on a PE 2400 automated analyzer. Melting points were determined on a Stuart SMP30 apparatus.
Reaction of 4-Pyrones with Phenylhydrazine.
Method A. A mixture of 4-pyrone (1.5 mmol) and PhNHNH2·HCl (3.3 mmol) in protic solvent (H2O,
EtOH, AcOH) was heated for several hours.
Method B. A mixture of 4-pyrone (1.5 mmol) and PhNHNH2 (3.3 mmol) in aprotic solvent (dioxane,
toluene) was heated for several hours.
Cyclization of Phenylhydrazones to Indoles by the Action of Acids.
Method C. A solution of phenylhydrazone (0.50 mmol) in AcOH was refluxed with added HCl, the
reaction mixture was then diluted with water, the precipitate that formed was filtered off, and recrystallized from
a suitable solvent.
Method D. A reaction mixture, containing trifluoromethyl-substituted phenylhydrazone (0.48 mmol),
MeSO3H (1.0 g, 10.40 mmol), and P2O5 (0.17 g, 1.20 mmol) was heated for 6 h at 60°C, followed by addition
of Н2О (10 ml), the precipitate was filtered off, dried, and recrystallized from a suitable solvent.
1397

(Е)-2-(Phenylhydrazono)-3-(1-phenyl-1H-pyrazol-5-yl)propionic acid (E-2a) was obtained according to
method A from pyrone 1a in H2O (4 ml) with the addition of conc. HCl (0.1 ml) by heating for 8 h at 60°C. The
precipitate that formed (0.389 g, 81%) was a 86:5:9 mixture of three isomers Е-2а+Z-2a+E-4a and gave the
acid E-2a in 0.226 g (47%) yield after recrystallization from a toluene–EtOH mixture. White powder. Mp
214-215°C (mp 215°C [17]). Spectral characteristics(IR and 1Н NMR spectra) matched the literature data [17].
3-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-2-(phenylhydrazono)propionic acid (2b) was not isolated in
pure form. A mixture of E-2b and Z-2b isomers was found in the product obtained according to method А by
refluxing pyrone 1b in 25% EtOH (9 ml) for 1 h. After the reaction was complete, the mixture was diluted with
water, the precipitate was filtered off, and recrystallized from aqueous EtOH. This product had the mass of
0.155 g and consisted of indole 3b (41%) as well as Е- and Z-phenylhydrazones 2b (59%) in 36:64 ratio.
1Н NMR spectrum, δ, ppm (J, Hz): E-2b isomer: 2.14 (3Н, s, СН3); 3.96 (2H, s, CH2); 5.74 (1H, s, H-4 Pz);
6.87-7.63 (10H, m, Н Ph); 10.28 (1H, s, NH); the СO2H signal was not observed; Z-2b isomer: 2.18 (3Н, s,
СН3); 3.81 (2H, s, CH2); 6.01 (1H, s, H-4 Pz); 6.91 (1H, t, J = 7.2, H-4 Ph); 7.11 (2H, d, J = 7.2, H-2,6 Ph);
7.22-7.63 (7H, m, Н Ph, Н Ph'); 12.11 (1H, s, NH); the СO2H signal was not observed.
3-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1H-indole-2-carboxylic acid (3b) was obtained according to
method А by refluxing pyrone 1b in EtOH (6.5 ml) for 24 h. After cooling of the reaction mixture, the
precipitate that formed was filtered off, yielding 0.024 g (5%) of compound 5b as by-product. The filtrate was
diluted with water, the precipitate was recrystallized from toluene, giving the acid 3b. Yield 0.100 g (21%). Gray
1
powder. Mp 254-255°C. IR spectrum, ν, cm-1: 3425, 3268, 1686, 1664, 1499. H NMR spectrum, δ, ppm (J,
Hz): 2.32 (3H, s, CH3); 6.36 (1H, s, H-4 Pz); 7.06 (1H, t, J = 7.6, H-4 Ph); 7.08-7.16 (3H, m, Н-5 Ind, Н-2,6
Ph); 7.21 (2H, t, J = 7.5, H-3,5 Ph); 7.28 (1H, t, J = 7.6, H-6 Ind); 7.33 (1H, d, J = 8.1, Н-4 Ind); 7.46 (1H, d,
J = 8.3, Н-7 Ind); 11.98 (1H, s, NH); 12.60-13.20 (1H, br. s, CO2H). Found, %: C 69.11; H 5.08; N 12.32.
C19H15N3O2·0.75H2O. Calculated, %: C 68.97; H 5.03; N 12.70.
Mixture of (Е)- and (Z)-2-(phenylhydrazono)-3-(1-phenyl-1H-pyrazol-3-yl)propionic acids (E-4a)
and (Z-4a) and (Z)- and (Е)-2-(phenylhydrazono)-3-(1-phenyl-1H-pyrazol-5-yl)propionic acids (Z-2a) and
(E-2a) was obtained according to method B by refluxing pyrone 1a in dioxane (6 ml) for 8 h. After evaporation
of dioxane, the residue was treated with 10% aqueous HCl (6 ml), the aqueous phase was decanted, the resinous
residue was washed with water, dissolved in EtOH, treated with water, and the product that crystallized was
filtered off. Yield 0.303 g (63%). Gray powder. Mp 110-120°C. The product was a 51:18:18:13 mixture of
isomers E-4a+Z-4a+Z-2a+E-2a. 1H NMR spectrum, δ, ppm (J, Hz): E-4a isomer: 4.03 (2H, s, CH2); 6.27 (1H, d, J
= 2.3, H-4 Pz); 6.85 (1H, t, J = 6.9, H-4 Ph); 7.15-7.60 (7H, m, Н-3,5 Ph, Н Ph'); 7.75 (1H, d, J = 7.6, Н-2,6 Ph');
8.25 (1H, d, J = 2.3, H-5 Pz); 10.10 (1H, s, NH); 11.50-13.50 (1H, br. s, CO2H); Z-4a isomer: 3.81 (2H, s, CH2);
6.30 (1H, d, J = 2.3, H-4 Pz); 6.60-7.90 (10H, m, Н Ph, Н Ph'); 8.21 (1H, d, J = 2.3, H-5 Pz); 11.50-13.50 (2H,
br. s, NH, CO2H); Z-2a isomer: 3.84 (2H, s, CH2); 6.19 (1H, d, J = 1.1, H-4 Pz); 6.60-7.90 (11H, m, Н-5 Pz, Н
Ph, Н Ph'); 12.25 (1H, s, NH); 11.50-13.50 (1H, br. s, CO2H). The spectrum of E-2a isomer was identical to that
described above.
(Е)-3-(5-Methyl-1-phenyl-1H-pyrazol-3-yl)-2-(phenylhydrazono)propionic acid (Е-4b) was
obtained according to method B from pyrone 1b by refluxing in dioxane (4 ml) for 4 h. The reaction mixture
was diluted with Н2О (6 ml) with the addition of conc. HCl (0.3 ml), the precipitate was filtered off and
recrystallized from aqueous EtOH. Yield 0.204 g (32%). Light-brown crystals. Mp 114-115°C. IR spectrum, ν,
1
cm-1: 3247, 2924, 1665, 1583, 1498. H NMR spectrum, δ, ppm (J, Hz): 2.28 (3Н, s, СН3); 3.97 (2H, s, CH2);
6.05 (1H, s, H-4 Pz); 6.89 (1H, unresolved t, H-4 Ph); 7.10-7.57 (9H, m, H Ph, H Ph'); 10.22 (1H, s, NH); 12.06
(1Н, s, СO2H). Found, %: C 66.13; H 5.43; N 16.08. C19H18N4O2·0.5H2O. Calculated, %: C 66.46; H 5.58;
N 16.32.
(E)-3-[5-(Ethoxycarbonyl)-1-phenyl-1H-pyrazol-3-yl]-2-(phenylhydrazono)propionic acid (E-4e)
was obtained according to method B from pyrone 1е by refluxing in dioxane (3 ml) for 3 h. The reaction
mixture was diluted with water with the addition of conc. HCl (0.3 ml), the aqueous layer was decanted, toluene
was added to the residue, the precipitate was filtered off, and recrystallized from toluene. Yield 0.077 g (13%).
1398

Yellowish crystals. Mp 203-204°C. IR spectrum, ν, cm-1: 3270, 2874, 1732, 1666, 1568. 1H NMR spectrum, δ,
ppm (J, Hz): 1.13 (3H, t, J = 6.6, OCH2СН3); 4.05 (2H, s, CH2); 4.15 (2H, q, J = 6.6, OCH2CH3); 6.78 (1H, s,
H-4 Pz); 6.89 (1H, t, J = 6.2, H-4 Ph); 7.20-7.60 (9H, m, H Ph, H Ph'); 10.23 (1H, s, NH); 12.11 (1H, br. s,
13
CO2H). C NMR spectrum, δ, ppm (J, Hz): 14.3 (qt, J = 127.1, J = 2.6, OCH2СН3); 23.7 (t, J = 129.3, CH2);
61.0 (m, OCH2CH3); 111.9 (dt, J = 179.9, J = 3.0, C-4); 114.4 (dm, J = 162.3, C-2,6 Ph); 121.3 (dt, J = 160.6,
J = 7.1, C-4 Ph); 126.0 (dt, J = 162.8, J = 6.0, C-2,6 Ph'); 128.4 (dt, J = 162.3, J = 8.7, C-4 Ph'); 128.6 (dd,
J = 162.1, J = 8.0, C-3,5 Ph); 129.1 (dd, J = 159.3, J = 8.0, C-3,5 Ph'); 131.9 (m, С=N); 134.0 (d, J = 7.8, C-5);
140.3 (t, J = 8.0, C-1 Ph); 144.5 (m, C-1 Ph'); 148.3 (td, J = 7.8, J = 4.2, C-3); 158.6 (t, J = 3.1, C=O); 166.3 (t,
J = 3.5, C=O). Found, %: C 64.40; H 5.20; N 14.44. C21H20N4O4. Calculated, %: C 64.28; H 5.14; N 14.28.
3-(1-Phenyl-1H-pyrazol-3-yl)-1H-indole-2-carboxylic acid (5a) was obtained from pyrone 1а in
dioxane (9 ml) according to method B. The reaction mixture was refluxed for 6 h, then treated with H2O
(1.5 ml) and conc. HCl (0.75 ml), and refluxed for another 2 h. The obtained solution was cooled, diluted with
H2O (20 ml), the residue was filtered off and recrystallized from EtOH. Yield 0.159 g (35%). Gray powder.
1
Mp 269-270°C (mp 270°C [17]). Spectral characteristics (IR and Н NMR spectra) corresponded to the
literature data [17].
3-(5-Methyl-1-phenyl-1H-pyrazol-3-yl)-1H-indole-2-carboxylic acid (5b) was obtained according to
method C from phenylhydrazone E-4b by refluxing in AcOH (6 ml) with the addition of conc. HCl (0.5 ml)
over 4 h. After the reaction was complete, the mixture was treated by addition of Н2О (10 ml), the precipitate
was filtered off and dried. Yield 0.058 g (36%). Yellow crystals. Mp 279-280°C. IR spectrum, ν, cm-1: 3268, 1664,
1
1559, 1492. H NMR spectrum, δ, ppm (J, Hz): 2.46 (3H, d, J = 0.6, CH3); 7.09 (1H, q, J = 0.6, H-4 Pz); 7.17
(1H, td, J = 7.6, J = 0.9, Н-5 Ind); 7.32 (1H, td, J = 7.7, J = 1.0, Н-6 Ind); 7.49 (1Н, tt, J = 7.3, J = 1.5, Н-4 Ph);
7.52 (1H, d, J = 8.2, Н-7 Ind); 7.61 (2H, t, J = 7.8, Н-3,5 Ph); 7.68 (2H, dd, J = 8.5, J = 1.2, Н-2,6 Ph); 8.20
(1H, d, J = 8.3, Н-4 Ind); 11.96 (1H, s, NH); 14.20-15.20 (1H, br. s, CO2H). Found, %: C 70.69; H 4.49;
N 13.03. C19H15N3O2·0.33H2O. Calculated, %: C 70.58; H 4.88; N 13.00.
3-(5-Carboxy-1-phenyl-1H-pyrazol-3-yl)-1H-indole-2-carboxylic acid (5c) was obtained according to
method A from pyrone 1c by refluxing in Н2О (6 ml) with adding conc. HCl (1.5 ml), over 1 h. The white
precipitate that formed was a mixture of two regioisomeric indoles 3c (53%) and 5с (47%). The combined yield
was 0.25 g (48%). The obtained mixture was stirred for 5 min at room temperature in EtOH (5 ml). The
precipitate of pure compound 5с was filtered off. Yield 0.094 g (18%). White powder. Mp 305-306°C.
IR spectrum, ν, cm-1: 3261, 1719, 1671, 1561. 1H NMR spectrum, δ, ppm (J, Hz): 7.08 (1H, td, J = 7.6, J = 0.5,
Н-5 Ind); 7.25 (1H, td, J = 7.6, J = 0.9, Н-6 Ind); 7.44-7.49 (2Н, m, H-7 Ind, H-4 Ph); 7.52 (2H, t, J = 7.5,
Н-3,5 Ph); 7.57 (2H, d, J = 7.6, Н-2,6 Ph); 7.65 (1H, s, Н-4 Pz); 8.18 (1H, d, J = 8.2, Н-4 Ind); 11.82 (1H, s,
NH); 12.00-15.00 (2H, br. s, 2CO2H). Found, %: C 63.63; H 3.46; N 11.63. C19H13N3O4·0.5H2O. Calculated, %:
C 64.04; H 3.96; N 11.79.
3-[5-Ethoxycarbonyl-1-phenyl-1H-pyrazol-3-yl]-1H-indole-2-carboxylic acid (5e) was obtained
according to method C from phenylhydrazone Е-4e by refluxing in AcOH (5 ml) with adding conc. HCl
(0.15 ml) over 4 h. After the reaction was complete, the mixture was stored for 24 h, the crystals that formed
were filtered off and washed with water. Yield 0.080 g (42%). Yellowish crystals. Mp 264-265°C. IR spectrum,
ν, cm-1: 3293, 2984, 1733, 1665, 1556. 1H NMR spectrum, δ, ppm (J, Hz): 1.19 (3H, t, J = 7.1, ОCH2СH3); 4.23
(2H, q, J = 7.1, ОCH2СH3); 7.12 (1H, t, J = 7.5, Н-5 Ind); 7.30 (1H, td, J = 7.2, J = 0.7, Н-6 Ind); 7.46-7.55
(2Н, m, H-7 Ind, H-4 Ph); 7.55 (2H, t, J = 7.3, Н-3,5 Ph); 7.61 (2H, d, J = 7.1, Н-2,6 Ph); 7.71 (1H, s, Н-4 Pz);
8.19 (1H, d, J = 8.2, Н-4 Ind); 11.96 (1H, s, NH); 13.30-13.50 (1H, br. s, CO2H). Found, %: C 67.25; H 4.49;
N 11.35. C21H17N3O4. Calculated, %: C 67.19; H 4.56; N 11.19.
Ethyl (Е)-2-(phenylhydrazono)-3-(1-phenyl-1H-pyrazol-5-yl)propionate (Е-7а) was obtained
according to method A from pyrone 6a by stirring in EtOH (5 ml) at room temperature for 24 h and then for
additional 3 h at 60°C temperature. The reaction mixture was diluted with water, the precipitate was filtered off
and recrystallized from toluene. Yield 0.162 g (31%). Colorless crystals. Mp 153-154°C. IR spectrum, ν, cm-1:
3216, 3006, 1697, 1597. 1H NMR spectrum, δ, ppm (J, Hz): 1.20 (3H, t, J = 7.1, ОСН2СН3); 4.04 (2H, s, CH2);
1399

4.12 (2H, q, J = 7.1, ОСН2CH3); 5.96 (1H, d, J = 1.7, H-4 Pz); 6.93 (1H, t, J = 7.0, J = 1.6, H-4 Ph); 7.24-7.34
(4H, m, Н Ph); 7.44-7.51 (1H, m, H-4 Ph'); 7.56 (1H, d, J = 1.7, H-3 Pz); 7.57-7.62 (4H, m, Н Ph'); 10.37 (1H,
s, NH). Found, %: C 68.80; H 5.77; N 15.98. C20H20N4O2. Calculated, %: C 68.95; H 5.79; N 16.08.
Ethyl (Z)-2-(Phenylhydrazono)-3-(1-phenyl-1H-pyrazol-5-yl)propionate (Z-7а). The toluene filtrate
after isolation of isomer Е-7а was passed through a thin layer of silica gel (approximately 1 cm3), the solvent
was removed by evaporation, the residue was recrystallized from aqueous EtOH. Yield 0.043 g (8%). Colorless
powder. Mp 110-111°C. IR spectrum, ν, cm-1: 3212, 3049, 1676, 1599. 1H NMR spectrum, δ, ppm (J, Hz): 1.13
(3H, t, J = 6.9, OCH2СН3); 3.91 (2H, s, CH2); 4.14 (2H, q, J = 6.9, OCH2СН3); 6.25 (1H, s, H-4 Pz); 6.94 (1H,
t, J = 7.1, H-4 Ph); 7.12 (2H, d, J = 7.4, H-2,6 Ph); 7.27 (2H, t, J = 7.1, H-3,5 Ph); 7.38-7.58 (5H, m, H Ph');
7.60 (1H, s, H-3 Pz); 11.88 (1H, s, NH). Found, %: C 68.09; H 6.00; N 15.38. C20H20N4O2·0.33H2O. Calculated,
%: C 67.78; H 5.88; N 15.81.
Ethyl (E)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-2-(phenylhydrazono)propionate (E-7b) was
obtained according to method A from pyrone 6b by stirring in EtOH (6 ml) at 60°C for 24 h. After cooling, the
reaction mixture was diluted with water, decanted, the resinous residue was treated with 1:1 mixture of hexane–
toluene (6 ml), the precipitate that formed was filtered off and washed with hexane. Yield 0.049 g (9%). Gray
1
powder. Mp 172-173°C. IR spectrum, ν, cm-1: 3171, 2970, 1698, 1585, 1500. H NMR spectrum, δ, ppm
(J, Hz): 1.23 (3H, t, J = 7.1, ОCH2СН3); 2.15 (3H, s, СН3); 3.98 (2H, s, CH2); 4.13 (2H, q, J = 7.1, ОCH2СН3);
5.74 (1H, s, H-4 Pz.); 6.91 (1H, tt, J = 5.6, J = 2.3, H-4 Ph); 7.22-7.32 (4H, m, Н Ph); 7.41 (1H, tt, J = 7.0, J = 1.4,
H-4 Ph'); 7.53 (2H, t, J = 8.2, H-2,6 Ph'); 7.57 (2H, d, J = 7.5, H-3,5 Ph'); 10.29 (1H, s, NH).
Ethyl (E)-3-(3-ethoxycarbonyl-1-phenyl-1H-pyrazol-5-yl)-2-(phenylhydrazono)propionate (E-7c)
was obtained according to method A from pyrone 6с by stirring for 8 h in EtOH (3 ml) at 60°C. The precipitate
that formed was filtered off, washed with H2O, EtOH, and recrystallized from toluene. Yield 0.252 g (40%).
1
Colorless powder. Mp 205-207°C. IR spectrum, ν, cm-1: 3221, 3037, 2975, 2928, 1716, 1669. H NMR
spectrum, δ, ppm (J, Hz): 1.20 (3H, t, J = 7.1, ОCH2СН3); 1.25 (3H, t, J = 7.1, ОCH2СН3); 4.05 (2H, s, CH2);
4.12 (2H, q, J = 7.1, ОCH2СН3); 4.25 (2H, q, J = 7.1, ОCH2СН3); 6.36 (1H, s, H-4 Pz.); 6.92-6.98 (1H, m,
H-4 Ph); 7.24-7.35 (4H, m, Н Ph); 7.53-7.58 (1H, m, H-4 Ph'); 7.60-7.66 (4H, m, Н Ph'); 10.43 (1H, s, NH).
Found, %: C 65.70; H 5.77; N 13.09. C23H24N4O4. Calculated, %: C 65.70; H 5.75; N 13.32.
Ethyl 3-(1-phenyl-1H-pyrazol-5-yl)-1H-indole-2-carboxylate (8а) was obtained according to method
C from phenylhydrazone E-7a by refluxing in AcOH (4 ml) with adding conc. HCl (0.15 ml) over 4 h. After
cooling, the reaction mixture was diluted with water, the precipitate was filtered off and recrystallized from
aqueous AcOH. Yield 0.097 g (58%). Colorless powder. Mp 185-186°C. IR spectrum, ν, cm-1: 3136, 2983,
1
1716, 1500. H NMR spectrum, δ, ppm (J, Hz): 1.04 (3H, t, J = 7.1, ОCH2СН3); 3.85-4.15 (2H, unresolved
ABX3, ОCH2СН3); 6.59 (1H, d, J = 1.1, H-4 Pz); 7.11 (1H, t, J = 7.5, H-4 Ph); 7.14 (2H, d, J = 7.1, H-2,6 Ph);
7.18 (1H, t, J = 6.8, Н-5 Ind); 7.25 (2H, t, J = 7.7, H-3,5 Ph); 7.32 (1H, t, J = 7.7, Н-6 Ind); 7.39 (1H, d, J = 8.1,
Н-4 Ind); 7.50 (1H, d, J = 8.2, Н-7 Ind); 7.83 (1H, d, J = 1.1, H-3 Pz); 12.15 (1H, s, NH). Found, %: C 71.51;
H 5.08; N 12.31. C20H17N3O2·0.25H2O. Calculated, %: C 71.52; H 5.25; N 12.51.
Ethyl 3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-indole-2-carboxylate (8b) was obtained
according to method A from pyrone 6b by refluxing in EtOH (8 ml) for 24 h. After cooling, the reaction
mixture was diluted with water, the precipitate was filtered off, dissolved in refluxing toluene, and passed
through a silica gel layer. The filtrate was evaporated to small volume, the residue was diluted with petroleum
ether, the precipitated crystals were filtered off. Yield 0.093 g (18%). Yellow powder. Mp 158-159°C.
1
IR spectrum, ν, cm-1: 3315, 2982, 1684, 1510. H NMR spectrum, δ, ppm (J, Hz): 1.05 (3H, t, J = 7.0,
ОCH2СН3); 2.33 (3H, s, СН3); 3.85-4.16 (2H, unresolved ABX3, ОCH2СН3); 6.38 (1H, s, H-4 Pz); 7.06-7.17
(4H, m, Н-5 Ind, Н Ph); 7.21 (2H, t, J = 7.5, H-3,5 Ph); 7.31 (1H, t, J = 7.7, H-6 Ind); 7.40 (1H, d, J = 8.2, H-4
Ind); 7.49 (1H, d, J = 8.2, H-7 Ind); 12.15 (1H, br. s, NH). Found, %: C 73.23; H 5.38; N 12.31. C21H19N3O2.
Calculated, %: C 73.03; H 5.54; N 12.17.
Ethyl 3-[3-(ethoxycarbonyl)-1-phenyl-1H-pyrazol-5-yl]-1H-indole-2-carboxylate (8c) was obtained
according to method C from phenylhydrazone E-7c by refluxing in AcOH (4 ml) with adding conc. HCl
1400

(0.3 ml) over 4 h. After cooling, the reaction mixture was diluted with water, the precipitate was filtered off and
recrystallized from aqueous АсОН. Yield 0.087 g (43%). Colorless powder. Mp 167-168°C. IR spectrum, ν,
cm-1: 3337, 2983, 1708, 1509. 1H NMR spectrum, δ, ppm (J, Hz): 1.07 (3H, t, J = 7.1, ОCH2CH3); 1.34 (3H, t,
J = 7.1, ОCH2СН3); 3.91-4.20 (2H, unresolved ABX3, ОCH2CH3); 4.36 (2H, q, J = 7.1, ОCH2СН3); 7.05 (1H, s,
Н-4 Pz); 7.12 (1H, tt, J = 7.6, J = 0.7, H-4 Ph); 7.19 (2H, dd, J = 7.5, J = 1.0, H-2,6 Ph); 7.24-7.31 (3H, m, Н-5
Ind, Н-3,5 Ph); 7.33 (1H, td, J = 8.1, J = 1.0, H-6 Ind); 7.40 (1H, d, J = 8.1, H-4 Ind); 7.50 (1H, d, J = 8.3, H-7
Ind); 12.24 (1H, s, NH). Found, %: C 68.62; H 5.08; N 10.31. C23H21N3O4. Calculated, %: C 68.47; H 5.25;
N 10.42.
5-[3,3-Difluoro-2-(phenylhydrazono)propyl]-1-phenyl-1Н-pyrazole-3-carboxylic acid (E-10c) was
obtained as a mixture with acid E-12с according to method A from pyrone 9с by maintaining for 16 h in a
mixture of H2O (4 ml) and 20% HCl (2 ml) at 50°C. The precipitated mixture contained isomers E-10c and
E-12с in approximately equal amounts. It was filtered off and recrystallized from toluene (20 ml). Yield 0.378 g
1
(68%). Yellow powder. Mp 180-185°С. H NMR spectrum, δ, ppm (J, Hz): isomer E-10c: 3.91 (2H, s, CH2);
6.44 (1H, s, H-4 Pz); 6.48 (1Н, t, J = 54.5, CHF2); 6.88 (1H, tt, J = 7.3, J = 1.1, H-4 Ph); 7.16 (2H, dd, J = 7.5,
J = 1.2, H-2,6 Ph); 7.20-7.66 (7H, m, Н-3,5 Ph, Н Ph'); 10.04 (1H, s, NH); 12.60-13.90 (1H, br. s, СO2H).
Ethyl 5-[3,3-difluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-3-carboxylate (E-10d)
was obtained from pyrone 9d according to method B by maintaining for 48 h in EtOH (10 ml) at 20°C. After the
reaction was complete, the mixture was treated with conc. HCl (1.5 ml), the aqueous layer was decanted, and
toluene (3 ml) was added to the viscous residue. The precipitate that formed was filtered off and recrystallized
from toluene (10 ml). Yield 0.131 g (22%). Beige powder. Mp 186-187°C (mp 186-187°C [28]). Spectral
characteristics(IR, 1Н and 19F NMR spectra) matched the literature data [28].
3-[3,3-Difluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-5-carboxylic acid (E-12c) was
obtained according to method B from pyrone 9с by stirring with dioxane (6 ml) with the addition of conc. HCl
(0.1 ml) over 3 h at 60°C. After cooling, the reaction mixture was treated by adding Н2О (10 ml) and 20% HCl
(1 ml), the precipitate was filtered off and recrystallized from toluene (40 ml). Yield 0.172 g (31%). Light-
yellow powder. Mp 214-215°C. IR spectrum, ν, cm-1: 3448, 3289, 2646, 1703, 1600, 1536. 1H NMR spectrum,
δ, ppm (J, Hz): 3.91 (2H, s, CH2); 6.48 (1Н, t, J = 55.0, CHF2); 6.78 (1H, s, H-4 Pz); 6.85 (1H, tt, J = 7.3,
J = 1.0, H-4 Ph); 7.16 (2H, dd, J = 7.5, J = 1.2, H-2,6 Ph); 7.25 (2H, dd, J = 8.5, J = 7.3, H-3,5 Ph); 7.39-7.49
(5H, m, Н Ph'); 10.02 (1H, s, NH); 13.10-13.50 (1H, br. s, СO2H). Found, %: C 61.55; H 4.27; N 15.30.
C19H16F2N4O2. Calculated, %: C 61.62; H 4.35; N 15.13.
Ethyl 3-[3,3-difluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole-5-carboxylate (Е-12d)
was obtained according to method B from pyrone 9d by maintaining in toluene (4 ml) for 96 h at room
temperature. After removing toluene, the residue was diluted with EtOH (4 ml), the precipitate that formed was
filtered off and recrystallized from toluene (2 ml). Yield 0.072 g (12%). Colorless powder. Mp 117-118°C.
1
IR spectrum, ν, cm-1: 3290, 1740, 1603, 1541, 1529, 1504. H NMR spectrum, δ, ppm (J, Hz): 1.13 (3H, t,
J = 7.1, ОCH2CH3); 3.93 (2H, s, CH2); 4.15 (2H, q, J = 7.1, ОCH2CH3); 6.49 (1Н, t, J = 54.4, CHF2); 6.82 (1H,
s, H-4 Pz); 6.85 (1H, tt, J = 7.3, J = 1.0, H-4 Ph); 7.16 (2H, dd, J = 8.6, J = 1.2, H-2,6 Ph); 7.25 (2H, dd, J = 8.6,
J = 7.3, H-3,5 Ph); 7.40-7.51 (5H, m, H Ph'); 10.01 (1H, s, NH). Found, %: C 63.44; H 5.11; N 14.01.
C21H20F2N4O2. Calculated, %: C 63.31; H 5.06; N 14.06.
5-[3,3-Difluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole (E-15c). A mixture of 2-difluoro-
methyl-4-pyrone 14c (0.153 g, 1.05 mmol) and freshly distilled phenylhydrazine (0.25 g, 2.31 mmol) was
heated for 1 h at 120°C. After cooling, the reaction mixture was treated with EtOH (3 ml), maintained for 1 h at
-25°C, the precipitate that formed was filtered off. Yield 0.063 g (18%). White powder. Mp 207-208°C.
1
IR spectrum, ν, cm-1: 3222, 3186, 3122, 1605, 1595, 1496. H NMR spectrum, δ, ppm (J, Hz): 3.91 (2H, s,
CH2); 6.06 (1Н, d, J = 1.7, Н-4 Pz); 6.46 (1H, t, J = 54.9, СHF2); 6.87 (1Н, tt, J = 7.2, J = 1.1, H-4 Ph); 7.16
(2H, dd, J = 8.4, J = 1.2, H-2,6 Ph); 7.26 (2H, dd, J = 8.6, J = 7.3, H-3,5 Ph); 7.46 (1H, tt, J = 7.2, J = 2.2, H-4
Ph'); 7.54-7.62 (5H, m, Н-3 Pz, Н Ph'); 10.02 (1H, s, NH). Found, %: C 65.33; H 5.18; N 16.54.
C18H16F2N4·0.33H2O. Calculated, %: C 65.05; H 5.05; N 16.86.
1401

3-[3,3-Difluoro-2-(phenylhydrazono)propyl]-1-phenyl-1H-pyrazole (E-16c). The filtrate after isolation
of phenylhydrazone Е-15с was maintained for 24 h at -25°C, the precipitate that formed was filtered off. Yield
0.045 g (13%). White powder. Mp 75-76°C. IR spectrum, ν, cm-1: 3249, 3043, 1597, 1497. 1H NMR spectrum,
δ, ppm (J, Hz): 3.88 (2H, s, CH2); 6.30 (1Н, d, J = 2.4, Н-4 Pz); 6.31 (1H, t, J = 55.6, СHF2); 6.81 (1Н, tt,
J = 7.2, J = 1.1, H-4 Ph); 7.13 (2H, d, J = 7.8, H-2,6 Ph); 7.19 (2H, t, J = 7.1, H-3,5 Ph); 7.25 (1H, tt, J = 7.3,
J = 1.0, H-4 Ph'); 7.44 (2H, t, J = 8.2, H-3,5 Ph'); 7.77 (2H, d, J = 7.7, H-2,6 Ph'); 8.29 (1H, d, J = 2.4, H-5 Pz);
9.91 (1H, s, NH). Found, %: C 66.19; H 5.02; N 16.99. C18H16F2N4. Calculated, %: C 66.25; H 4.94; N 17.17.
2-Phenyl-3-(1-phenyl-1H-pyrazol-5-yl)-1H-indole (17a) and 2-Phenyl-3-(1-phenyl-1H-pyrazol-
3-yl)-1H-indole (18a). A mixture of compounds 17a and 18a in the ratio of 84:16 was obtained according to
method A by refluxing pyrone 14a in EtOH (7 ml) for 24 h. After cooling, the reaction mixture was diluted with
water, the precipitate that formed was filtered off, dissolved in hot toluene, passed through a silica gel layer, the
filtrate was evaporated. Yield 0.126 g (25%). Yellow crystals. Mp 175-180°C. IR spectrum, ν, cm-1: 3164, 1597,
1
1588, 1573, 1510. H NMR spectrum, δ, ppm (J, Hz): isomer 17a: 6.58 (1H, d, J = 1.8, H-4 Pz); 7.02 (1H, td,
J = 7.5, J = 0.9, Н Ph); 7.16 (1H, td, J = 7.6, J = 1.2, Н Ph); 7.26 (2H, d, J = 7.4, Н Ar); 6.95-7.32 (9H, m, Н
Ar); 7.44 (1H, dt, J = 8.1, J = 0.8, H-7 Ind); 7.80 (1H, d, J = 1.8, H-3 Pz); 11.72 (1Н, s, NH); isomer 18a: 6.24
(1H, d, J = 2.6, H-4 Pz); 6.95-7.30 (9H, m, Н Ind, Н Ph); 7.65-7.75 (2H, m, H-2,6 Ph); 7.90 (2H, dd, J = 1.8,
J = 8.7, H-2,6 Ph); 8.11 (1H, d, J = 7.9, H-4 Ind); 8.45 (1H, d, J = 2.6, H-5 Pz); 11.61 (1Н, s, NH).
X-Ray Structural Study of Compound E-4b. Crystals of compound E-4b were grown from 1:1 EtOH–H2O.
The X-ray structural study was performed at room temperature on an Xcalibur-3 diffractometer with CCD-
detector according to standard procedure (λMoKα radiation, graphite monochromator, ω/2θ-scanning). No
correction for absoption was used due to its low value (μ 0.088 mm-1). A fragment of light-brown prismatic
crystal of compound E-4b with dimensions 0.42×0.30×0.18 mm was used for the analysis. The crystal of
compound E-4b (C19H18N4O2·0.5H2O, M 343.38) was monoclinic; a 24.0185(19), b 7.6114(11), c 19.354(3) Å;
β 91.633(10)°; V 3536.8(8) Å3; Z 8; dcalc 1.290 g/cm3; F(000) 1448; space group C2/c. A total of 12968
reflections, including 4297 independent (Rint 0.0265), of which 2110 had I > 2σ(I), were measured over the
range of 2.74 ≤ θ ≤ 28.28°. The structure was solved and refined with full matrix least squares method by F2,
using the SHELXTL software suite [29]. Non-hydrogen atoms were included in the model in anisotropic
approximation. The СН hydrogen atoms were localized by electron density maxima and included in the
refinement in isotropic approximation by the "rider" model with dependent thermal parameters. The final
refinement parameters: R1 0.0351, wR2 0.0750 (by reflections with I > 2σ(I)), R1 0.0836, wR2 0.0801 (by all
reflections) with reliability factor S 1.005. The maxima and minima of residual electron density were
0.135/-0.144 ē·Å-3. The complete X-ray structural data set for compound E-4b was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1011360).
Supplementary information file, containing synthetic procedures and spectral data for compounds Z-2c,
3a,c, E-4d, 5d, E-10a,b, 11a,b, E-12a,b, 13a,b, E-15b, E-16b, 17b, 18b is available to authorized users.
This work received financial support from the Russian Foundation for Basic Research (project
No. 14-03-31925) and the development program at Ural Federal University for the winners of competition
"Young scientists of Ural Federal University".
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