Synthesis of poly-functionalized pyrazoles under Vilsmeier-Haack reaction conditions

Article abstract of DOI:10.24820/ark.5550190.p010.934

Synthesis of 1,3-disubstituted 5-chloro-1H-pyrazole-4-carbaldehydes was achieved by formylation of the corresponding 5-chloro-1H-pyrazoles under Vilsmeier-Haack conditions.

Full text of DOI:10.24820/ark.5550190.p010.934

The Free Internet Journal
for Organic Chemistry
Paper
Archive for
Arkivoc 2019, part v, 0-0
Organic Chemistry
to be inserted by editorial office
Synthesis of poly-functionalized pyrazoles
under Vilsmeier-Haack reaction conditions
Aleksandr V. Popov,* Valentina A. Kobelevskaya, Ludmila I. Larina, and Igor B. Rozentsveig
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy
of Sciences, Irkutsk, 664033, Russia
E-mail: popov@irioch.irk.ru
With thanks to Professor Galina G. Levkovskaya for her great scientific interest
Received 03-17-2019
Abstract
Accepted 06-06-2019
Published on line 07-03-2019
Synthesis of 1,3-disubstituted 5-chloro-1H-pyrazole-4-carbaldehydes was achieved by formylation of the
corresponding 5-chloro-1H-pyrazoles under Vilsmeier-Haack conditions.
Keywords: Pyrazoles, 5-chloropyrazoles, pyrazole-4-carbaldehydes, Vilsmeier-Haack reaction, formylation
DOI: https://doi.org/10.24820/ark.5550190.p010.934
Page 1
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
Introduction
The pyrazole core is a privileged structural motif of the modern drugs and bioactive natural compounds. This
heterocycle and its derivatives are important building blocks for organic, bioorganic, pharmaceutical and
supramolecular chemistry as well as materials science.1-9 In fact, the pyrazole ring ranks 44th in a frequency
among 351 ring systems found in currently marketed drugs.10 The incorporation of functional groups into the
pyrazolic architecture attracts considerable interest because this modification opens the possibility for further
transformations. These poly-functionalized heterocyclic systems have shown promising applications in the
search of new biologically active candidates for drug discovery as well as polydental ligand systems. Among
them the pyrazoles bearing a halogen atom and formyl group are of particular interest.11
Thus, halopyrazoles show a diverse range of biological activity.12 Moreover, the introduction of a halogen
atom into the pyrazole ring represents often a first step in the synthesis of hard-to-reach derivatives. Many of
the metal-catalyzed carbon-carbon coupling reactions, such as Sonogashira, Heck−Mizoroki, Stille, Negishi, and
Suzuki−Miyaura are based on halopyrazoles.13-16 On the other hand, 4-formylpyrazoles are currently used for
the preparation of nitronylnitroxyl pyrazole-containing ligands, which are promising building blocks in design
of new heterospin magnetics,17 as well as diverse heteropolycyclic derivatives.18 It is worth mentioning that
the poly-condensed heterocyclic ring system, which was synthesized from 5-chloro-1H-pyrazole-4-
carbaldehyde, exhibited potent anti-inflammatory and analgesic activities. In this case, the incorporation of
pyrazole nucleus to quinoxaline moiety caused significant biologically activities.19
Generally, the methods for synthesis of formyl(halo)pyrazoles can be divided into two groups. The first
approach presupposes the use of polyfunctional starting materials in cascade assembly of the heterocyclic
core. The second one is based on the incorporation of the functional group into previously prepared pyrazoles.
The modification of the existing heterocyclic system seems to be a more convenient approach to target
compounds.
The methods for preparation of halo-substituted formyl pyrazoles, to the best of our knowledge, have
rarely been reported. One of the approaches to 3/5-chloro (or 5-bromo)-4-formyl pyrazole derivatives is based
13,20,21
on pyrazolones which undergo haloformylation under Vilsmeier-Haack reaction.
Taking into account
that pyrazolones are produced by refluxing of hydrazines with 1,3-dicarbonyl compounds,22 this method was
extended only for derivatives obtained from the most available representatives of 1,3-diketones or β-
ketoesters.13 In addition, the pyrazolones were often obtained in low yields.23,24
Other pathways to target compounds are based on the reaction of 3-halo-1H-pyrazoles with
organometallics25 or diazonium derivatives.26 However, low availability of the starting materials as well as high
laboriousness are disadvantages of these approaches. Thus, a straightforward approach to functionalized
pyrazoles from available initial reagents is of interest. Herein, we report a general and efficient method for the
synthesis of halo-substituted formylpyrazoles by simple formylation of corresponding halopyrazoles.
Results and Discussion
Our aim was to formylate 1,3-disubstituted 5-chloro-1H-pyrazoles 1 under Vilsmeier-Haack conditions to yield
the corresponding 5-chloro-1H-pyrazole-4-carbaldehydes 2 (Scheme 1). Most of the starting materials were
readily prepared by base-catalyzed condensation of dichlorovinyl ketones with hydrazines (Scheme 2).27-30 An
important advantage of this method is highly selective formation of 5-chloropyrazoles.
Page 2
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
Scheme 1. The general approach for preparation of 5-chloro-1H-pyrazole-4-carbaldehydes.
Moreover, since dichlorovinyl ketones can be obtained from readily available reagents (vinylidene chloride
and acyl chlorides31-34), synthesis of a series of 3-substituted pyrazoles 1 a priori could be easily accessible.
Scheme 2. Simple and efficient method for preparation of 5-chloro-1H-pyrazoles.
First, we sought the optimal reaction conditions using 1-methyl-3-propyl-5-chloro-1H-pyrazole (1a; R =
Pr, R’ = Me) (Sheme 1) as a model compound and the results are shown (Table 1). When reaction was carried
out at 70°C, no products were observed at all (Entry 1). The best results were obtained when the pyrazole 1a
was treated with excess of DMF and POCl3 at 120°C. For instance, using a 5-fold excess of DMF and 2-fold
excess of POCl3 at 120°C for 2 h gives carbaldehyde 2a in 55% yield instead of 32% only for 2-fold excess of the
same reagents (Entries 2, 3).
The use of excess of POCl3 leads to increasing amounts of chloroiminium ions, the key intermediates of
the Vilsmeier-Haack reaction, and therefore favors the formation of target pyrazole. The excess of DMF
ensures homogeneity of the process and solvates the released hydrogen chloride. The yield of 2a is not
increased when more than 6 and 4 equivalents of DMF and POCl3 are used. At this ratio of reagents, a further
increase in the reaction time does not affect the yield of the target product (Entries 7, 8). The use of
microwave assistance did not favor the formation of target pyrazole 2a (Entries 4, 5). Thus, the optimum
conditions of the process are heating the mixture of 5-chloropyrazole 1a with 6 equivalents of DMF and 4
equivalents of POCl3 at 120°C for 1 h. Under such conditions, yield of the target 1H-pyrazole-4-carbaldehyde
2a reached 67% (Entry 7).
Page 3
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
Table 1. Optimization of the reaction conditions (ratio of the 3 reactants, temperature, duration of reaction)
for the conversion of 1-methyl-3-propyl-5-chloro-1H-pyrazole (1a; R = Pr, R’ = Me) into 1-methyl-3-propyl-5-
chloro-1H-pyrazole-4-carbaldehyde (2a; R = Pr, R’ = Me) (Scheme 1)
Entry
Molar ratioa
1a : DMF : POCl3
1 : 2 : 2
T, °C
Time, h
Conversion Yieldb of
of 1a, %
4
2a, %
trace
32
1
2
3
4c
5c
6
7
8
9
10
70
7
7
2
1
2
2
1
2
1
2
1 : 2 : 2
1 : 5 : 2
1 : 5 : 2
1 : 5 : 2
1 : 5 : 3
1 : 6 : 4
1 : 6 : 4
1 : 6 : 4
120
120
120
140
120
120
120
140
120
51
74
55
62
45
9
82
trace
61
92
67
95
65
89
66
1 : 6 : 5
87
64
a 2 mmol of 1a were used in screening of the reaction conditions.
b Yield of the isolated product.
c Under microwave activation
Under the selected optimized conditions, the various 5-chloropyrazoles 1b-r were examined (Table 2).
The experiments suggested that the reaction result is dependent on the substrate structure. To our delight,
like model compound 1a, a total conversion of starting 5-chloro-1,3-dialkyl-substituted pyrazoles 1b,d,e,m,n
(Entries 2,4,5,13,14) was achieved after refluxing at 120°C for 1-2.5 h. In contrast, 1-aryl and 3-aryl substituted
pyrazoles 1f-1l needed much more time to complete the reaction (Entries 6-12).
Page 4
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
Table 2. Preparation of 1,3-disubstituted 5-chloro-1H-pyrazole-4-carbaldehydes 2 by formylation of the
corresponding 5-chloro-1H-pyrazoles 1 under Vilsmeier-Haack conditions (Scheme 1)a
Compound
number
Entry
R
R’
Time (h) b
Yield, %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
Pr
Pr
Pr
Pr
Me
Pr
Me
Ph
Me
Pr
-CH2CH2Cl
1
1
8
67
65
58
55
61
54
52
50
56
55
53
46
66
59
4
Bn
Bn
Ph
Ph
Me
Me
Me
Me
2.5
2.5
14
14
10
10
10
10
14
1
1
2
14
14
2
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
4-NO2-C6H4
Me
CH2Cl
-CHClCH3
Pr
Me
Me
Me
Me
2,4-(NO2)2-C6H3
Me
d
d
no reaction
no reaction
no target product
CF3
Pr
e
t-Bu
a All reactions were carried out on a 2.00 mmol scale.
b The time for full conversion of 5-chloro-1H-pyrazole was monitored by TLC.
c All yields refer to isolated and purified products.
d The starting pyrazoles were isolated in quantitative yield.
e Conversion of the starting pyrazole was 100% and 1H-pyrazole-4-carbaldehyde was not formed.
We concluded that the aromatic substituents, being more electron-withdrawing than the alkyl groups,
prevent the formylation of 5-chloropyrazoles. This is especially evident for the nitrophenyl-substituted
derivative 1l (Entry 12).
It should be noted that only a single example of formylation of 5-chloropyrazole 1g with the POCl3/DMF
system was reported.35 Our attempts to reproduce this experiment under the conditions described failed. In
contrast, the application of optimal conditions found in our study allowed us to prepare the target formylated
pyrazole in moderate yield (Entry 7).
We hypothesized that such yields of pyrazoles 2f,g can be explained by formation of by-products. In fact,
when the reaction of substrate 1f with DMF and POCl3 was conducted under optimal conditions, the target
pyrazole 2f (52%) was isolated together with a minor amount of heterocycle 3 (6%). Its formation seems to be
the result of the reaction of initial substrate 1f with formaldehyde which was generated in situ in small
quantity under long heating of DMF (Scheme 3).
Page 5
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
Scheme 3. Hydroxymethylation of 5-chloro-1-phenyl-3-propyl-1H-pyrazole 1f.
Formylation of 5-chloro-1-(2-hydroxyethyl)-3-propylpyrazole 1c is accompanied by substitution of the
hydroxyl group by chlorine atom to afford 5-chloro-1-(2-chloroethyl)-3-propyl-1H-pyrazole-4-carbaldehyde 2c
in 58% yield (Entry 3).
An unexpected result was obtained when 5-chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole 1o was
treated with DMF and POCl3 under optimal conditions. In this case the formylated pyrazole 2o is a minor
product while the pyrazole 5 was isolated in 72% yield. We assumed that the latter compound was formed in
one-pot tandem reaction sequence via elimination of the hydrogen chloride30 and following formylation of
vinyl moiety of intermediate A, as we have described in our previous work36. The target pyrazole 2o undergoes
also dehydrochlorination under reaction conditions to afford 5-chloro-1-methyl-3-vinyl-1H-pyrazole-4-
carbaldehyde 4 in 7% yield (Scheme 4).
Scheme 4. Reactions of 5-chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole 1o under Vilsmeier-Haack conditions.
The reaction’s scope is quite broad but pyrazoles 1p-r bearing strong electron-withdrawing groups on
benzene ring or bulky moiety showed a low reactivity. Thus, the conversion of 1p,q achieved only 5% after
refluxing of the mixture for a long time (entries 16,17). Finally, with pyrazole 1r the dealkylation reaction was
observed: only a mixture of tautomers 6 was isolated (Scheme 5). This heterocycle does not afford formylated
pyrazole under selected conditions.37
Page 6
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
Scheme 5. Dealkylation of 1-(tert-butyl)-5-chloro-3-propyl-1H-pyrazole 1p.
Conclusions
An efficient method for the synthesis of previously unknown or hardly accessible 4-formylpyrazoles containing
also a chlorine atom in position 5 has been developed. A number of different 5-chloro-4-formylpyrazoles
bearing diverse substitution patterns can be synthesized by this method. The simplicity of execution, ready
availability of starting materials and importance of the prepared pyrazoles make this procedure attractive for
synthetic chemists. The method supplements the known approaches to halo-substituted formylpyrazoles and
opens further routes to a variety of pyrazole derivatives, promising for the study of reactivity and possessing
numerous valuable properties.
Experimental Section
1
General. The Н, 13С and 15N NMR spectra were recorded in CDCl3 solutions at room temperature on Bruker
1
DPX-400 and AV-400 spectrometers (400.13, 100.61 and 40.56 MHz, respectively). Н, 13С and 15N Chemical
shifts (δ in ppm) were measured with accuracy of 0.01, 0.02 and 0.1 ppm, respectively, and referred to TMS
1
(1Н, 13С) and nitromethane (15N). The assignment of H and 13C signals in spectra was performed using 2D
heteronuclear correlation HMBC-gp and HSQC-gp 13C-1H methods. The values of the δ 15N were obtained
through the 2D 1H-15N HMBC-gp experiment. Coupling constants (J in Hz) values approaches to 0.1 Hz.
IR spectra were recorded on a Bruker Vertex-70 instrument. MS analyses were recorded on a Shimadzu GCMS-
QP5050A instrument (ionization potential 70 eV). Column and thin-layer chromatography were carried out on
commercial available SiO2 (Sigma-Aldrich).
Commercially available acyl chlorides, vinylidene chloride and hydrazines of the company Sigma-Aldrich were
used. Alkyl hydrazines were distilled before reactions. Synthesis of 2,2-dichlorovinylketones and pyrazoles 1a,
g-j, l-r was presented in previous work.27-34 Pyrazoles 1b-f,k are described here for the first time.
3,3-Dichloro-1-(4-fluorophenyl)prop-2-en-1-one. A solution of a 4-fluorobenzoyl chloride (4.758 g, 30 mmol)
in CH2Cl2 (50 mL) and AlCl3 4 (4.0 g, 30 mmol) was shaken for 20 min at -5°C. Then vinylidene chloride (3.490
g, 36 mmol) was added dropwise over a period of 20 min to avoid the temperature exceeding of 0°C. After
that, the reaction mass was stirred for 4 h at rt, poured upon ice. An organic layer was separated and a water
layer was extracted with CH2Cl2 (3×50 mL). The collected organic layer were dried over MgSO4 and evaporated
under reduced pressure. The residual mass was dissolved in diethyl ether (30 mL), treated with triethylamine
(3.036 g, 30 mmol) at -5°C for 10 min and kept to rt, filtered and evaporated. The crude product was purified
by silica gel column chromatography to give 3,3-dichloro-1-(4-fluorophenyl)prop-2-en-3-one, 4.995 g (76%),
Rf=0.70 (trichloromethane), colorless needles, m.p. 29°C.[Lit.38 29-29.9°C]1H NMR (400.13 MHz, CDCl3): δ 7.96-
Page 7
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
7.93 (m, 2H), 7.22 (s, 1H), 7.17-7.13 (m, 2H) ppm. 13C NMR (100.61 MHz, CDCl3) δ 185.0, 166.0 (d, 1JC,F 256.0
4
3
2
Hz), 135.6, 133.2 (d, JC,F 2.4 Hz), 131.1 (d, JC,F 9.6 Hz), 123.8, 116.0 (d, JC,F 22.0 Hz) ppm. Anal. calcd. for
С9H5Cl2FO: С, 49.35; H, 2.30; Cl, 32.37. Found %: С, 49.24; H, 2.32; Cl, 32.45.
General procedure for the synthesis of 1H-pyrazoles (1). A triethylamine (2 mmol) was added to a solution of
dichlorovinylketone (2 mmol) in diethyl ether (10 mL) under cooling with ice-water bath. After that a
hydrazine (2 mmol) was added dropwise for 20 min. In the synthesis of N-methylpyrazole 1k 2 equiv (4 mmol)
of dimethylhydrazine was used without using of triethylamine. The reaction mixture was stirred for 1.5 h at
room temperature. The reaction mixture was filtered off and diethyl ether was evaporated. Individual
pyrazoles usable for further purposes without additional purification were obtained.
5-Chloro-1,3-dipropyl-1H-pyrazole (1b). The general procedure was followed using triethylamine (2 mmol),
1,1-dichlorohex-1-en-3-one (2 mmol) and propylhydrazine (2 mmol), reaction time: 1.5 h, 344 mg (92%),
yellow oil. IR (film): 3186, 3123, 2963, 2875, 1724, 1516, 1461, 773 cm-1. 1H NMR (400.13 MHz, CDCl3):  5.95
(s, 1H), 4.01 (t, 2H, J 7.2 Hz), 2.52 (t, 2H, J 7.6 Hz), 1.81 (m, 2H), 1.61 (m, 2H), 0.93 (t, 3H, J 7.3 Hz), 0.89 (t, 3H,
J 7.4 Hz) ppm. 13C NMR (100.61 MHz, CDCl3):  152.8, 126.4, 102.8, 50.2, 30.6, 23.2, 22.7, 13.7, 10.9 ppm. Anal.
calcd. for С9H15ClN2: С, 57.91; H, 8.10; Cl, 18.99; N, 15.01. Found %: С, 57.81; H, 8.06; Cl, 19.06; N, 15.07.
2-(5-chloro-3-propyl-1H-pyrazol-1-yl)ethan-1-ol (1c). The general procedure was followed using triethylamine
(2 mmol), 1,1-dichlorohex-1-en-3-one (2 mmol) and 2-hydrazineylethan-1-ol (2 mmol), reaction time: 1.5 h,
328 mg (87%) orange oil. IR (film): 3326, 3131, 2958, 2873, 1516, 1463, 775 cm-1. 1H NMR (400.13 MHz, CDCl3):
 6.03 (s, 1H), 4.17 (t, 2H), 3.98 (t, 2H), 2.54 (t, 2H, J 7.5 Hz), 1.64 (m, 2H), 0.95 (t, 3H, J 7.4 Hz) ppm. 13C NMR
(100.61 MHz, CDCl3):  153.6, 127.3, 103.2, 61.4, 49.9, 30.6, 22.5, 13.8 ppm. Anal. calcd. for С8H13ClN2O: С,
50.93; H, 6.95; Cl, 18.79; N, 14.85. Found %: С, 51.01; H, 6.93; Cl, 18.70; N, 14.90.
1-Benzyl-5-chloro-3-propyl-1H-pyrazole (1d). The general procedure was followed using triethylamine (2
mmol), 1,1-dichlorohex-1-en-3-one (2 mmol) and benzylhydrazine (2 mmol), reaction time: 1.5 h, 418 mg
(89%), orange oil. IR (film): 3127, 3063, 2959, 2873, 1708, 1574, 1457, 724 cm-1. 1H NMR (400.13 MHz, CDCl3):
 7.25-7.39 (m, 5H), 6.12 (s, 1H), 5.36 (s, 2H), 1.64 (t, 2H, J 7.6 Hz), 1.72 (m, 2H), 1.02 (t, 3H, J 7.3 Hz) ppm. 13C
NMR (100.61 MHz, CDCl3):  153.3, 136.2, 128.6, 127.7, 127.1, 126.3, 103.6, 52.3, 30.5, 22.6, 13.7 ppm. Anal.
calcd. for С13H15ClN2: С, 66.52; H, 6.44; Cl, 15.10; N, 11.93. Found %: С, 66.62; H, 6.42; Cl, 15.06; N, 11.90.
1-Benzyl-5-chloro-3-methyl-1H-pyrazole (1e). The general procedure was followed using triethylamine (2
mmol), 4,4-dichlorobut-3-en-2-one (2 mmol) and benzylhydrazine (2 mmol), reaction time: 1.5 h, 343 mg
(83%), orange oil. IR (film): 3128, 3033, 2932, 1605, 1518, 1451, 776 cm-1. 1H NMR (400.13 MHz, CDCl3):  7.25-
7.38 (m, 5H), 6.08 (s, 1H), 5.32 (s, 2H), 2.30 (s, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):  148.6, 136.2, 128.5,
127.7, 127.1, 127.0, 104.4, 52.3, 13.9 ppm. Anal. calcd. for С11H11ClN2: С, 63.93; H, 5.36; Cl, 17.15; N, 13.55.
Found %: С, 63.80; H, 5.34; Cl, 17.22; N, 13.64.
5-chloro-1-phenyl-3-propyl-1H-pyrazole (1f). The general procedure was followed using triethylamine (2
mmol), 1,1-dichlorohex-1-en-3-one (2 mmol) and phenylhydrazine (2 mmol), reaction time: 1.5 h, 353 mg
(80%), yellow oil. IR (film): 3121, 2058, 2959, 2870, 1597, 1523, 1453, 763 cm-1. 1H NMR (400.13 MHz, CDCl3): 
7.58-7.35 (m, 5H), 6.21 (s, 1H), 2.64 (t, 2H, J 7.6 Hz), 1.72 (m, 2H), 1.01 (t, 3H, J 7.3 Hz) ppm. 13C NMR (100.61
MHz, CDCl3):  154.3, 138.3, 128.8, 127.8, 126.7, 124.8, 105.3, 30.6, 22.5, 13.8 ppm. Anal. calcd. for С12H13ClN2:
С, 65.31; H, 5.94; Cl, 16.06; N, 12.69. Found %: С, 65.40; H, 5.96; Cl, 16.00; N, 12.64.
5-Chloro-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (1k). The general procedure was followed using 3,3-
dichloro-1-(4-fluorophenyl)prop-2-en-1-one (2 mmol) and 1,1-dimethylhydrazine (4 mmol), reaction time: 1.5
1
h, 345 mg (82%), beige solid, m.p. 50-52 °C. IR (film): υ 3125, 3058, 2944, 2877, 1658, 1603, 1497, 779 cm-1. H
NMR (400.13 MHz, CDCl3):  7.72-7.69 (m, 2H), 7.11-7.07 (m, 2H), 6.45 (s, 1H), 3.89 (s, 3H) ppm. 13C NMR
Page 8
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
(100.61 MHz, CDCl3):  162.7 (d, 1JC,F 247.3 Hz), 149.9, 129.0 (d, 4JC,F 2.8 Hz), 128.2, 127.0 (d, 3JC,F 8.4 Hz), 115.5
(d, 2JC,F 21.6 Hz), 101.5, 36.2 ppm. Anal. calcd. for С10H8ClFN2: С, 57.02; H, 3.83; Cl, 16.83; N, 13.30. Found %: С,
56.85; H, 3.84; Cl, 16.87; N, 13.34.
General procedure for the synthesis of 1H-pyrazole-4-carbaldehydes (2). POCl3 (4 equiv.) was added to DMF
(6 equiv.) at 0 °C. After 10–15 min, pyrazole (1.0 equiv.) was added to the reaction mixture, which was then
stirred at 120°C until the pyrazole was completely consumed (based on TLC analysis). The reaction was
quenched with water and was neutralized with a saturated solution of Na2CO3 to pH~7. The mixture was
extracted with chloroform (3 times). The combined organic layers were dried with Mg2SO4, and filtered. The
solvent was removed under vacuum and the residue was purified by silica gel column chromatography (diethyl
ether/hexane) to afford the 1H-pyrazole-4-carbaldehyde.
5-Chloro-1-methyl-3-propyl-1H-pyrazole-4-carbaldehyde (2a). The general procedure was followed using 5-
chloro-1,3-dimethyl-1H-pyrazole 1a (2 mmol), reaction time: 1 h, 250 mg (67%) orange oil, Rf 0.33 (diethyl
ether/hexane, 1:1 v/v). IR (film): 2961, 2931, 2873, 1682, 1510, 1470, 772 cm-1. 1H NMR (400.13 MHz, CDCl3): 
9.85 (s, 1H), 3.83 (s, 3H), 2.81 (t, 2H, J 7.3 Hz), 1.67 (m, 2H), 0.97 (t, 3H, J 7.0 Hz) ppm. 13C NMR (100.61 MHz,
CDCl3):  183.2, 154.9, 133.6, 115.8, 35.9, 29.8, 21.8, 13.8 ppm. 15N NMR (40.56 MHz, CDCl3):  -75.8, -180.7
ppm. MS (EI, 70 eV): m/z (%) 186 (98, [M+]), 171 (85), 157 (81), 130 (100), 76 (45). Anal. calcd. for С8H11ClN2O:
С, 51.48; H, 5.94; Cl, 19.00; N, 15.01. Found %: С, 51.62; H, 5.95; Cl, 18.95; N, 14.98.
5-Chloro-1,3-dipropyl-1H-pyrazole-4-carbaldehyde (2b). The general procedure was followed using 5-chloro-
1,3-dipropyl-1H-pyrazole (1b, 2 mmol), reaction time: 1 h, 279 mg (65%), orange oil, Rf 0.30 (diethyl
ether/hexane, 1:1 v/v). IR (film): 2964, 2934, 2875, 1683, 1521, 1469, 776 cm-1. 1H NMR (400.13 MHz, CDCl3): 
9.86 (s, 1H), 4.08 (t, 2H, J 7.2 Hz), 2.82 (t, 2H, J 7.7 Hz), 1.83-1.93 (m, 2H), 1.64-1.73 (m, 2H), 0.92-0.98 (m, 6H)
ppm. 13C NMR (100.61 MHz, CDCl3):  183.3, 154.9, 133.1, 115.6, 50.5, 29.9, 22.8, 21.9, 13.8, 10.9 ppm. 15N
NMR (40.56 MHz, CDCl3):  -77.4, -169.2 ppm. MS (EI, 70 eV): m/z (%) 214 (76, [M+]), 199 (50), 186 (45), 179
(60), 158 (100), 143 (55). Anal. calcd. for С10H15ClN2O: С, 55.94; H, 7.04; Cl, 16.51; N, 13.05. Found %: С, 51.82;
H, 7.06; Cl, 16.56; N, 13.03.
5-Chloro-1-(2-chloroethyl)-3-propyl-1H-pyrazole-4-carbaldehyde (2c). The general procedure was followed
using 2-(5-chloro-3-propyl-1H-pyrazol-1-yl)ethanol (1c, 2 mmol), reaction time: 8 h, 273 mg (58%), colorless
needles, m.p. 77-79 °C, Rf 0.16 (diethyl ether/hexane, 1:2 v/v). IR (film): 2962, 2933, 2872, 1682, 1522, 1464,
1
778 cm-1. H NMR (400.13 MHz, CDCl3):  9.88 (s, 1H), 4.43 (t, 2H, J 6.4 Hz), 3.91 (t, 2H, J 6.1 Hz), 2.83 (t, 2H, J
7.8 Hz), 1.64-1.73 (m, 2H), 0.96 (t, 3H, J 7.3 Hz) ppm. 13C NMR (100.61 MHz, CDCl3):  183.2, 155.7, 134.4,
115.9, 49.7, 41.4, 29.9, 21.6, 13.7 ppm. 15N NMR (40.56 MHz, CDCl3)  -78.5, -176.8 ppm. MS (EI, 70 eV): m/z
(%) 234 (60, [M+]), 219 (62), 206 (60), 178 (100), 157 (56), 143 (52), 63 (88). Anal. calcd. for С9H12Cl2N2O: С,
45.98; H, 5.14; Cl, 30.16; N, 11.91. Found %: С, 46.10; H, 5.14; Cl, 30.08; N, 11.90.
1-Benzyl-5-chloro-3-propyl-1H-pyrazole-4-carbaldehyde (2d). The general procedure was followed using 1-
benzyl-5-chloro-3-propyl-1H-pyrazole (1d, 2 mmol), reaction time: 2.5 h, 289 mg (55%), orange powder, mp 35
°C, Rf 0.47 (diethyl ether/hexane, 1:1 v/v). IR (film): υ 3066, 2962, 2932, 2873, 1683, 1521, 1463, 775 cm-1. 1H
NMR (400.13 MHz, CDCl3):  9.88 (s, 1H), 7.25-7.37 (m, 5H), 5.33 (s, 2H), 2.85 (t, 2H, J 7.7 Hz), 1.67-1.76 (m,
2H), 0.98 (t, 3H, J 7.4 Hz) ppm. 13C NMR (100.61 MHz, CDCl3):  183.2, 155.2, 134.8, 133.4, 128.9, 128.3, 127.5,
116.1, 52.7, 29.8, 21.8, 13.8 ppm. 15N NMR (40.56 MHz, CDCl3):  -75.6, -170.4 ppm. MS (EI, 70 eV): m/z (%)
262 (23, [M+]), 91 (100), 65 (34), 130 (100), 76 (45). Anal. calcd. for С14H15ClN2O: С, 64.00; H, 5.75; Cl, 13.49; N,
10.66. Found %: С, 64.18; H, 5.77; Cl, 13.53; N, 10.62.
1-Benzyl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (2e). The general procedure was followed using 1-
benzyl-5-chloro-3-methyl-1H-pyrazole (1e, 2 mmol), reaction time: 2.5 h, 286 mg (61%), orange powder, m.p.
Page 9
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
101-102 °C, Rf 0.30 (diethyl ether/hexane, 1:2 v/v). IR (film): 3062, 2961, 2849, 1681, 1526, 1460, 765 cm-1. 1H
NMR (400.13 MHz, CDCl3):  9.87 (s, 1H), 7.25-7.37 (m, 5H), 5.30 (s, 2H), 2.47 (s, 3H) ppm. 13C NMR (100.61
MHz, CDCl3):  183.2, 151.0, 134.8, 133.5, 128.7, 128.2, 127.4, 116.3, 52.5 ppm. 15N NMR (40.56 MHz, CDCl3): 
-75.5, -170.4 ppm. MS (EI, 70 eV): m/z (%) 234 (15, [M+]), 199 (11), 91 (100), 65 (17). Anal. calcd. for
С12H11ClN2O: С, 61.42; H, 4.72; Cl, 15.11; N, 11.94. Found %: С, 61.35; H, 4.75; Cl, 15.07; N, 11.98.
5-Chloro-1-phenyl-3-propyl-1H-pyrazole-4-carbaldehyde (2f). The general procedure was followed using 5-
chloro-1-phenyl-3-propyl-1H-pyrazole (1f, 2 mmol), reaction time: 14 h, 269 mg (54%), light brown needles,
m.p. 151-152 °C, Rf 0.23 (diethyl ether/hexane, 1:8 v/v). IR (film): υ 3064, 2951, 2923, 2854, 1675, 1525, 1462,
766 cm-1. 1H NMR (400.13 MHz, CDCl3): δ 9.97 (s, 1H), 7.45-7.56 (m, 5H), 2.90 (t, 2H, J 7.6 Hz), 1.70-1.79 (m,
2H), 1.00 (t, 3H, J 7.3 Hz) ppm. 13C NMR (100.61 MHz, CDCl3): δ 183.6, 155.7, 136.9, 133.4, 129.2, 129.0, 125.1,
116.9, 29.8, 21.6, 13.8 ppm. 15N NMR (40.56 MHz, CDCl3): δ -73.0, -165.3 ppm. MS (EI, 70 eV): m/z (%) 248 (45,
[M+]), 220 (41), 192 (82), 133 (35), 77 (100). Anal. calcd. for С13H13ClN2O: С, 62.78; H, 5.27; Cl, 14.25; N, 11.26.
Found %: С, 62.60; H, 5.25; Cl, 14.20; N, 13.30.
5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (2g). The general procedure was followed using 5-
chloro-3-methyl-1-phenyl-1H-pyrazole (1g, 2 mmol), reaction time: 14 h, 230 mg (52%), dark red needle, m.p.
142-143 °C, Rf 0.17 (diethyl ether/hexane, 1:5 v/v). IR (film): 3065, 2927, 1676, 1527, 1469, 764 cm-1. 1H NMR
(400.13 MHz, CDCl3):  9.97 (s, 1H), 7.46-7.55 (m, 5H), 2.54 (s, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):  183.8,
151.7, 136.8, 133.4, 129.2, 129.1, 125.1, 117.3, 13.8 ppm. 15N NMR (40.56 MHz, CDCl3):  -72.9, -165.1 ppm.
MS (EI, 70 eV): m/z (%) 220 (93, [M+]), 219 (100), 155 (22), 77 (63), 51 (50). Anal. calcd. for С11H9ClN2O: С,
59.88; H, 4.11; Cl, 16.07; N, 12.70. Found %: С, 59.73; H, 4.09; Cl, 16.10; N, 12.73.
5-Chloro-1-methyl-3-phenyl-1H-pyrazole-4-carbaldehyde (2h). The general procedure was followed using 5-
chloro-1-methyl-3-phenyl-1H-pyrazole (1h, 2 mmol), reaction time: 14 h, 221 mg, (50%) beige oil, Rf 0.50
1
(diethyl ether/hexane, 1:1 v/v). IR (film): 3062, 2946, 1683, 1502, 1448, 779 cm-1. H NMR (400.13 MHz,
CDCl3):  9.92 (s, 1H), 7.72-7.73 (m, 2H), 7.43-7.45 (m, 3H), 3.90 (s, 3H) ppm. 13C NMR (100.61 MHz, CDCl3): 
183.3, 153.3, 133.1, 130.9, 129.2, 128.6, 128.4, 115.3, 36.2 ppm. 15N NMR (40.56 MHz, CDCl3)  -75.0, -176.7
ppm. MS (EI, 70 eV): m/z (%) 220 (100, [M+]). Anal. calcd. for С11H9ClN2O: С, 59.88; H, 4.11; Cl, 16.07; N, 12.70.
Found %: С, 59.71; H, 4.10; Cl, 16.08; N, 12.75.
5-Chloro-1-methyl-3-(4-methylphenyl)-1H-pyrazole-4-carbaldehyde (2i). The general procedure was followed
using 5-chloro-1-methyl-3-(4-methylphenyl)-1H-pyrazole (1i, 2 mmol), reaction time: 14 h, 263 mg (56%),
beige powder, mp 105-107 °C, Rf 0.33 (diethyl ether/hexane, 1:1 v/v). IR (film): 3058, 2920, 1673, 1492, 1451,
830 cm-1. 1H NMR (400.13 MHz, CDCl3)  9.95 (s, 1H), 7.62-7.64 (m, 2H), 7.27-7.29 (m, 2H), 3.94 (s, 3H), 2.42 (s,
3H) ppm. 13C NMR (100.61 MHz, CDCl3):  183.6, 153.6, 139.4, 133.0, 129.2, 128.6, 128.4, 115.3, 36.2 ppm. 15N
NMR (40.56 MHz, CDCl3):  -75.8, -177.8 ppm. MS (EI, 70 eV): m/z (%) 234 (100, [M+]), 219 (66), 116 (28), 91
(23), 76 (19). Anal. calcd. for С12H11ClN2O: С, 61.41; H, 4.72; Cl, 15.11; N, 11.94. Found %: С, 61.52; H, 4.71; Cl,
15.08; N, 11.93.
3-(4-Bromophenyl)-5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde (2j). The general procedure was followed
using 3-(4-bromophenyl)-5-chloro-1-methyl-1H-pyrazole (1g, 2 mmol), reaction time: 10 h, 330 mg (55%), light
yellow needles, mp 74-76 °C, Rf 0.23 (diethyl ether/hexane, 1:2 v/v). IR (film): 3076, 2945, 1684, 1499, 1446,
1
834, 778 cm-1. H NMR (400.13 MHz, CDCl3):  9.94 (s, 1H), 7.69-7.71 (m, 2H), 7.59-7.61 (m, 2H), 3.95 (s, 3H)
ppm. 13C NMR (100.61 MHz, CDCl3):  183.0, 151.8, 134.3, 131.6, 130.2, 130.0, 123.7, 115.4, 36.4 ppm. 15N
NMR (40.56 MHz, CDCl3):  -74.6, -177.1 ppm. MS (EI, 70 eV): m/z (%) 298 (70, [M+]), 219 (53), 109 (29), 76
(42), 50 (18). Anal. calcd. for С11H8BrClN2O: С, 44.11; H, 2.69; Br, 26.67; Cl, 11.84; N, 9.35. Found %: С, 44.07; H,
2.68; Cl, 11.88; N, 9.32.
Page 10
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
5-Chloro-3-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (2k). The general procedure was followed
using 5-chloro-3-(4-fluorophenyl)-1-methyl-1H-pyrazole (1k, 2 mmol), reaction time: 10 h, 253 mg (53%),
peach powder, m.p. 226-227 °C; Rf 0.37 (diethyl ether/hexane, 1:1 v/v). IR (film): 3076, 2945, 1684, 1499,
1
1446, 778 cm-1. H NMR (400.13 MHz, CDCl3):  9.93 (s, 1H), 7.78-7.81 (m, 2H), 7.13-7.17 (m, 2H), 3.95 (s, 3H,
CH3) ppm. 13C NMR (100.61 MHz, CDCl3):  183.0, 163.4 (d, 1JC,F 249.3 Hz), 151.9, 134.1, 130.5 (d, 3JC,F 8.4 Hz),
4
2
127.1 (d, JC,F 3.2 Hz), 115.4 (d, JC,F 21.6 Hz), 115.2, 36.2 ppm. 15N NMR (40.56 MHz, CDCl3):  -75.4, -177.4
ppm. MS (EI, 70 eV): m/z (%) 238 (100, [M+]), 203 (27), 175 (20), 156 (41), 131 (18), 107 (40), 95 (32), 76 (54).
Anal. calcd. for С11H8ClFN2O: С, 55.36; H, 3.38; Cl, 14.86; F, 7.96, N, 11.74. Found %: С, 55.45; H, 3.39; Cl, 14.80;
N, 11.75.
5-Chloro-1-methyl-3-(4-nitrophenyl)-1H-pyrazole-4-carbaldehyde (2l). The general procedure was followed
using 5-chloro-1-methyl-3-(4-nitrophenyl)-1H-pyrazole (1m, 2 mmol), reaction time: 14 h, 244 mg (46%), beige
powder, mp 171-172 °C; Rf 0.23 (diethyl ether/hexane, 1:1 v/v). IR (film): 3106, 3080, 2922, 2850, 1688, 1519,
1
1345, 778 cm-1. H NMR (400.13 MHz, CDCl3):  9.97 (s, 1H), 8.29-8.31 (m, 2H), 8.08-8.10 (m, 2H), 3.99 (s, 3H)
ppm. 13C NMR (100.61 MHz, CDCl3):  182.6, 149.9, 148.2, 137.4, 135.7, 129.5, 123.6, 115.8, 36.6 ppm. 15N
NMR (40.56 MHz, CDCl3):  -8.1, -69.9, -176.3 ppm. MS (EI, 70 eV): m/z (%) 265 (100, [M+]), 248 (16), 218 (33),
107 (29), 76 (27), 50 (15). Anal. calcd. for С11H8ClN3O3: С, 49.73; H, 3.04; Cl, 13.35; N, 15.82. Found %: С, 49.81;
H, 3.03; Cl, 13.30; N, 15.77.
5-Chloro-1,3-dimethyl-1H-pyrazole-4-carbaldehyde (2m). The general procedure was followed using 5-chloro-
1,3-dimethyl-1H-pyrazole (1l, 2 mmol), reaction time: 1 h, 209 mg (66%), orange needles, mp 67-68 °C, Rf 0.38
1
(diethyl ether/hexane, 2:1 v/v). IR (film): 2937, 1682, 1528, 1476, 771 cm-1. H NMR (400.13 MHz, CDCl3): 
9.95 (s, 1H), 3.81 (s, 3H), 2.44 (s, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):  183.3, 150.8, 133.6, 116.2, 35.8,
13.6 ppm. 15N NMR (40.56 MHz, CDCl3):  -77.0, -180.5 ppm. MS (EI, 70 eV): m/z (%) 158 (54, [M+]), 157 (100).
Anal. calcd. for С6H7ClN2O: С, 45.44; H, 4.45; Cl, 22.36; N, 17.66. Found %: С, 45.29; H, 4.44; Cl, 22.41; N, 17.61.
5-Chloro-3-(chloromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (2n). The general procedure was followed
using 5-chloro-3-(chloromethyl)-1-methyl-1H-pyrazole (1n, 2 mmol), reaction time: 1 h, 228 mg (59%), white
powder, mp 105-106 °C, Rf 0.20 (diethyl ether/hexane, 1:1 v/v). IR (film): 2927, 2858, 1671, 1517, 1482, 769
cm-1. 1H NMR (400.13 MHz, CDCl3):  9.90 (s, 1H), 4.78 (s, 2H), 3.89 (s, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):
 182.5, 149.4, 134.1, 115.7, 36.9, 36.3 ppm. 15N NMR (40.56 MHz, CDCl3):  -70.1, -178.4 ppm. MS (EI, 70 eV):
m/z (%) 193 (43, [M+]), 192 (80), 191 (59), 157 (100), 156 (50), 76 (41). Anal. calcd. for С6H6Cl2N2O: С, 37.33; H,
3.13; Cl, 36.73; N, 14.51. Found %: С, 37.20; H, 3.14; Cl, 36.75; N, 14.49.
5-Chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (2o). The general procedure was followed
using 5-chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole (1o, 2 mmol), reaction time: 2 h, 17 mg (4%); Rf 0.27
1
(diethyl ether/hexane, 1:2 v/v). H NMR (400.13 MHz, CDCl3):  9.92 (s, 1H), 5.58 (q, J 6.9 Hz, 1H), 3.88 (s, 3H),
1.88 (d, J 6.9 Hz, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):  182.6, 150.0, 134.2, 114.8, 49.4, 36.3, 23.1 ppm.
15N NMR (40.56 MHz, CDCl3):  -72.3, -179.4 ppm.
(5-chloro-1-phenyl-3-propyl-1H-pyrazol-4-yl)methanol (3). The general procedure was followed using 5-
chloro-1-phenyl-3-propyl-1H-pyrazole (1f, 2 mmol), reaction time: 14 h, 30 mg, (6%), yellow oil, Rf 0.40 (diethyl
1
ether/hexane, 1:8 v/v). IR (film): 3062, 2960, 2929, 2869, 1551, 1502, 1464, 1423, 761, 693 cm-1. H NMR
(400.13 MHz, CDCl3):  7.54-7.56 (m, 1H), 7.46-7.50 (m, 2H), 7.39-7.42 (m, 2H), 4.57 (s, 2H), 2.71 (t, J 7.8 Hz,
2H), 1.75-1.81 (m, 2H), 1.04 (t, J 7.3 Hz, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):  153.1, 138.2, 129.0, 128.2,
127.0, 124.9, 114.2, 29.1, 22.3, 16.1, 13.8 ppm. 15N NMR (40.56 MHz, CDCl3):  -76.0, -169.1 ppm. MS (EI, 70
eV): m/z (%) 233 [100], 205 [64], 77 [84], 51 [66]. Anal. calcd. for С13H15ClN2O: С, 62.28; H, 6.03; Cl, 14.14; N,
11.17. Found %: С, 62.18; H, 6.02; Cl, 14.18; N, 11.21.
Page 11
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
5-chloro-3-ethenyl-1-methyl-1H-pyrazole-4-carbaldehyde (4). The general procedure was followed using 5-
chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole (1o, 2 mmol), reaction time: 2 h, 24 mg (7%), Rf 0.27 (diethyl
1
ether/hexane, 1:2 v/v). H NMR (400.13 MHz, CDCl3):  9.90 (s, 1H), 7.04 (dd, J 11.3, 17.7 Hz, 1H), 6.22 (dd, J
17.7, 1.0 Hz, 1H), 5.50 (dd, J 11.3, 1.0 Hz, 1H), 3.88 (s, 3H) ppm. 13C NMR (100.61 MHz, CDCl3):  183.0, 150.0,
133.9, 126.3, 119.8, 115.4, 36.2 ppm. 15N NMR (40.56 MHz, CDCl3):  -78.8 , -179.4 ppm.
(2E)-3-(5-chloro-1-methyl-1H-pyrazol-3-yl)prop-2-enal (5). The general procedure was followed using 5-
chloro-3-(1-chloroethyl)-1-methyl-1H-pyrazole (1o, 2 mmol), reaction time: 2 h, 246 mg (72%), white powder,
mp 68-70°С, Rf 0.15 (diethyl ether/hexane, 1:2 v/v). IR (film): 3134, 2851, 2827, 1672, 1633, 1504, 974, 786
1
cm-1. H NMR (400.13 MHz, CDCl3): δ 9.87 (d, J 7.8 Hz, 1H), 7.37 (d, J 15.9 Hz, 1Н), 6.59 (dd, J 7.8, 15.9 Hz, 1Н),
6.52(s, 1Н), 3.90 (s, 3Н) ppm. 13C NMR (100.61 MHz, CDCl3):  193.4, 146.9, 143.4, 129.5, 129.2, 104.0, 36.6
ppm. 15N NMR (40.56 MHz, CDCl3):  -66.1, -175.6 ppm. MS (EI, 70 eV) m/z %: 170 (20, [M+]), 142 (100), 141
(53), 107 (22), 81 (32). Anal. calcd. for C7H7ClN2O: C, 49.28; H, 4.14; Cl, 20.78; N, 16.42. Found %: C, 49.16; H,
4.16; Cl, 20.73; N, 16.47.
5(3)-Chloro-3(5)-propyl-1H-pyrazole (6). The general procedure was followed using 1-tert-butyl-5-chloro-3-
propyl-1H-pyrazole (1p, 2 mmol), reaction time: 2 h, 252 mg (87%), yellow oil, Rf 0.20 (diethyl ether/hexane,
1:1 v/v). IR (film): 3186, 3141, 2965, 2871, 1576, 1462, 1368, 798 cm-1. 1H NMR (400.13 MHz, CDCl3):  6.00 (s,
1H), 2.69 (t, 2H, J 7.6 Hz), 1.67 (m, 2H), 0.98 (t, 3H, J 7.3 Hz) ppm. 13C NMR (100.61 MHz, CDCl3):  146.6,
139.7, 102.7, 27.8, 22.4, 13.6 ppm. 15N NMR (40.56 MHz):  -101.3, -178.3 ppm. MS (EI, 70 eV): m/z (%) 144
(47, [M+]), 116 (100), 115 (92). Anal. calcd. for С6H9ClN2: С, 49.84; H, 6.27; Cl, 24.52; N, 19.37. Found %: С,
50.00; H, 6.28; Cl, 24.46; N, 19.30.
Acknowledgements
The spectral and analytical data were obtained using the equipment of the Baykal Analytical Center for
Collective Use SB RAS.
Supplementary Material
Copies of spectra of compounds are provided in the supplementary material file available on the Publisher’s
web site.
References
1. Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman.
http://dx.doi.org/10.1039/c6nj03181a
New J. Chem. 2017, 41, 16.
2. Ardiansah, B. Asian J. Pharm. Clin. Res. 2017, 10, 45.
http://dx.doi.org/10.22159/ajpcr.2017.v10i12.22065
3. Kumar V.; Sareen, V.; Khatri, V.; Sareen, S. Int. J. Applied Res. 2016, 2, 461.
4. Vicentini, C.B.; Romagnoli, C.; Andreotti, E.; Mares, D. J. Agric. Food. Chem. 2007, 55, 10331.
http://dx.doi.org/10.1021/jf072077d
Page 12
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
5. Giornal, F.; Pazenok, S.; Rodefeld, L.; Lui, N.; Vors, J.-P.; Leroux, F.R. J. Fluor. Chem. 2013, 152, 2.
http://dx.doi.org/10.1016/j.jfluchem.2012.11.008
6. Lei. P.; Zhang, X.; Xu, Y.; Xu, G.; Liu, X.; Yang, X.; Zhang, X.; Ling, Yun. Chem. Cent. J. 2016, 10, 40.
http://dx.doi.org/10.1186/s13065-016-0186-8
7. Halсrow, M.A. Dalton Trans. 2009, 2059.
http://dx.doi.org/10.1039/b815577a
8. Potapov, A.S.; Chernova, N.P.; Ogorodnikov, V.D.; Petrenko, T.V.; Khlebnikov, A.I. Beilstein J. Org. Chem.
2011, 7, 1526.
http://dx.doi.org/10.3762/bjoc.7.179
9. Bianchi, L.; Carloni-Garaventa, A.; Maccagno, M.; Pani, M.; Petrillo, G.; Scapolla, C.; Tavani, C. Tetrahedron
2015, 71, 7550.
http://dx.doi.org/10.1016/j.tet.2015.08.014
10. Taylor,
http://dx.doi.org/10.1021/jm4017625
11. Abdel-Wahab, B.F.; Khidre,
http://dx.doi.org/10.3998/ark.5550190.0012.103
R.D.;
MacCoss,
M.; Lawson,
A.D.G.
J. Med. Chem.
A.A. Arkivoc
2014,
2011,
57,
(i),
5845.
196.
R.E.;
Farahat,
12. Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011, 15, 1423.
http://dx.doi.org/10.2174/138527211795378263
13. Janin Y.L. Chem. Rev. 2012, 112, 3924.
http://dx.doi.org/10.1021/cr200427q
14. Fuestro, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984.
http://dx.doi.org/10.1021/cr2000459
15. Bourrain, S.; Ridgill, M.; Collins, I. Synlett 2004, 5, 795.
http://dx.doi.org/10.1055/s-2004-820020
16. Rodriguez-Franco, M.I; Dorronsoro, I.; Martinez, A. Synthesis 2001, 11, 1711.
http://dx.doi.org/10.1055/s-2001-16768
17. Ovcharenko, V.; Fokin, S.; Chubakova, E.; Romanenko, G.; Bogomyakov, A.; Dobrokhotova, Zh.; Lukzen, N.;
Morozov, V.; Petrova, M.; Petrova, M.; Zueva, E.; Rozentsveig, I.; Rudyakova, E.; Levkovskaya, G.; Sagdeev,
R. Inorg. Chem. 2016, 55, 5853.
http://dx.doi.org/10.1021/acs.inorgchem.6b00140
18. Papernaya, L.K.; Shatrova, A.A.; Albanov, A.I.; Levkovskaya, G.G.; Rozentsveig, I.B. Arkivoc 2016, (v), 142.
http://dx.doi.org/10.3998/ark.5550190.p009.709
19. Abu-Hashem A.A.; Gouda M.A.; Badria F.A. Eur. J. Med. Chem. 2010, 45, 1976.
https://doi.org/10.1016/j.ejmech.2010.01.042
20. Gouda M. A.; Abu-Hashem A.A.; Saad, H.H.; Elattar K.M. Res. Chem. Intermed. 2016, 42, 2119.
https://doi.org/10.1007/s11164-015-2139-6
21. Paul, S.; Gupta, M.; Gupta, R. Synlett. 2000, 8, 1115.
https://doi.org/10.1055/s-2000-6747
22. Sumathy, A.; Gowrishankar, N. L.; Krishnan, A; Prakash, M; Muhsin, T.; Naseena, U.; Poornima, G. World J.
of Pharmacy and Pharmaceutical Sciences 2018, 7, 574.
https://doi.org/10.20959/wjpps20185-11603
23. Butler, D.E.; DeWald, H.A. J. Org. Chem. 1971, 36, 2542.
https://doi.org/10.1021/jo00816a037
24. Buchi, J.; Ursprung, R.; Lauener, G. Helv. Chim. Acta 1949, 32, 984.
Page 13
©ARKAT USA, Inc

Arkivoc 2018, v, 0-0
Popov, A. V. et al.
https://doi.org/10.1002/hlca.19490320347
25. Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11, 3326.
https://doi.org/10.1021/ol901208d
26. Hamatake, R.K.; Chen, H.; Raney, A.; Allan, M.; Lang, S. Patent WO 2006033995, 2006.
27. Bozhenkov, G.V.; Savosik, V.A.; Larina, L.I.; Klyba, L.V.; Zhanchipova, E.R.; Mirskova, A.N.; Levkovskaya, G.G.
Russ. J. Org. Chem. 2008, 44, 1014.
https://doi.org/10.1134/S1070428008070129
28. Bozhenkov, G.V.; Savosik, V.A.; Larina, L.I.; Klyba, L.V.; Zhanchipova, E.R.; Mirskova, A.N.; Levkovskaya, G.G.
Russ. J. Org. Chem. 2008, 44, 1194.
https://doi.org/10.1134/S1070428008080150
29. Rudyakova, E.V.; Savosik, V.A.; Evstaf’eva, I.T.; Kondrashov, E.V.; Levkovskaya, G.G. Russ. J. Org. Chem.
2009, 45, 705.
https://doi.org/10.1134/S1070428009050108
30. Levkovskaya, G.G.; Kobelevskaya, V.A.; Rudyakova, E.V.; Khanh, Q. Ha.; Samultsev, D.O.; Rozentsveig, I. B.
Tetrahedron 2011, 67, 1844.
https://doi.org/10.1016/j.tet.2011.01.028
31. Levkovskaya, G.G.; Atavin, A.S.; Mirskova, A.N. Zh. Org. Khim. 1973, 9, 318. Chem. Abstr. 1973, 78,
159137g.
32. Mirskova, A.N.; Levkovskaya, G.G.; Kalikhman, I.D.; Voronkov, M.G. Zh. Org. Khim. 1979, 15, 2301. Chem.
Abstr. 1980, 92, 128792b.
33. Levkovskaya, G.G.; Mirskova, A.N.; Kalikhman, I.D.; Voronkov, M.G. Zh. Org. Khim. 1984, 21, 634. Chem.
Abstr. 1984, 101, 90823b.
34. Levkovskaya, G.G.; Bozhenkov, G.V.; Larina, L.I.; Evstaf’eva, I.T.; Mirskova, A.N. Russ. J. Org. Chem. 2001,
37, 644.
https://doi.org/10.1023/A:1012483314133
35. Barreiro, E.J.; Camara, C.A.; Verli, H.; Brazil-Mas, L.; Castro, N.J.; Cintra, W.M.; Aracava, Y.; Rodrigues, C.R.;
Fraga, C.A.M. J. Med. Chem. 2003, 46, 1144.
https://doi.org/10.1021/jm020391n
36. Popov, A.V.; Kobelevskaya, V.A.; Larina, L.I.; Levkovskaya, G.G. Mendeleev Commun. 2017, 27, 178.
https://doi.org/10.1016/j.mencom.2017.03.024
37. Badalyan, K.S.; Akopyan, A.E.; Attaryan, H.S.; Astratyan, G.V. Russ. J. Gen. Chem. 2014, 84, 793.
https://doi.org/10.1134/S1070363214040331
38. Kamigata, N.; Udodaira, K.; Yoshikawa, M.; Shimizu, T. J. Organomet. Chem. 1998, 552, 39.
https://doi.org/10.1016/S0022-328X(97)00497-X
Page 14
©ARKAT USA, Inc