Synthesis of Isonicotinic and Salicylic Acids Derivatives from (–)-α-Pinene and (+)-Δ3-Carene

Article abstract of DOI:10.1134/S1070363220110031

Abstract: Optically active cyclobutanediyl- and cyclopropanediylbisalkylidenedihydrazides of isonicotinic and salicylic acids were synthesized when theperoxide products of ozonolysis of (–)-α-pinene and(+)-Δ³-carene were reduced with isonicotin

Full text of DOI:10.1134/S1070363220110031

ISSN 1070-3632, Russian Journal of General Chemistry, 2020, Vol. 90, No. 11, pp. 2038–2042. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Obshchei Khimii, 2020, Vol. 90, No. 11, pp. 1654–1660.
Synthesis of Isonicotinic and Salicylic Acids Derivatives
from (–)-α-Pinene and (+)-Δ3-Carene
Yu. V. Myasoedovaa, E. R. Nurievaa,*, L. R. Garifullinaa, and G. Yu. Ishmuratova
a Ufa Institute of Chemistry, Ufa Federal Research Center of the Russian Academy of Sciences, Ufa, 450054 Russia
*e-mail: eva_lala@bk.ru
Received June 18, 2020; revised June 18, 2020; accepted July 1, 2020
Abstract—Optically active cyclobutanediyl- and cyclopropanediylbisalkylidene dihydrazides of isonicotinic
and salicylic acids were synthesized when the peroxide products of ozonolysis of (–)-α-pinene and (+)-Δ3-carene
were reduced with isonicotinic and salicylic acid hydrazides in methanol, methylene chloride or tetrahydrofuran.
Using QSAR models, high antituberculosis activity in combination with low values of acute toxicity and minimal
inhibitory concentration was predicted for the obtained compounds.
Keywords: (–)-α-pinene, (+)-Δ3-carene, ozonolysis, isonicotinic and salicylic acid hydrazides, diacylhydrazones,
ketoesters, ketoacids
DOI: 10.1134/S1070363220110031
The synthesis of hybrid molecules containing
fragments of natural compounds and pharmacophoric
groups opens the way to a wide range of new compounds
with potential biological activity [1, 2]. Hydrazide and
hydrazone groups are present in many biologically active
compounds exhibiting antibacterial, anti-tuberculosis,
antifungal, antitumor, anti-inflammatory, anticonvulsant,
antiviral, and antiprotozoal activity [3, 4].
structure of organic compounds and biological activity
and toxicity. We used the QSAR (Quantitative Structure-
Activity Relationship) method of analysis, one of the
advantages of which is the identification of various types
of toxicity along with biological activity, including acute
one (LD50) [10].
The QSAR analysis was performed using the OCHEM
version of the expert system. Using training and test
samples, the quantitative probability of anti-tuberculosis
activity (Consensus Anti-TB activity_Model_5 [11]),
the probable minimum inhibitory concentration (M3 T2
ConsensusAnti-TB activity MIC [12]) were calculated, as
well as the probable acute toxicity after oral administration
to mice (LD50 mouse oral ASNN [10]) for both starting
hydrazides 3 and 4 and their derivatives 5–8 (Table 1).
In continuation of studies on the synthesis of new
compounds, in whose molecules monoterpene fragments
are combined with acylhydrazone groups [5–7], we
carried out ozonolysis of (–)-α-pinene 1 and (+)-Δ3-carene
2 with the participation of isonicotinic (3) and salicylic
(4) acids hydrazides. Derivatives of the latter are known
for their wide application in the treatment of tuberculosis
[8].As a result, optically active acylhydrazones 5–8 were
obtained (Scheme 1).
Calculations have shown a significant increase
(up to 91%) in anti-tuberculosis activity in isoniazid
derivatives 5 and 6, as well as a high probability (63–
74%) of the appearance of activity in salicylhydrazide
derivatives 7 and 8. A sharp decrease in the probable
minimum inhibitory concentration (MIC) in compounds
5‒8 we associate, firstly, with the presence of C=N
groups, and secondly, with an increase in the number of
pharmacologically active fragments in the molecule. The
probable acute toxicity of compounds 5–8 is reduced by
1.5–4 times in comparison with the initial hydrazides 3
and 4.
When creating new drugs, an important role is assigned
to the search for compounds that have low toxicity along
with high biological activity. For example, isonicotinic
acid hydrazide 3 is included in almost all schemes for
the prevention and treatment of tuberculosis, but it is
toxic [9], therefore, it remains relevant to reduce the
general toxicity by introducing its fragment into various
structures. In order to predict the properties of synthesized
molecules, it is convenient to use mathematical models
that quantitatively describe the relationship between the
2038

SYNTHESIS OF ISONICOTINIC AND SALICYLIC ACIDS DERIVATIVES
2039
Scheme 1.
The general procedure for the synthesis of compounds
5–8 consisted in the ozonolysis of monoterpenes 1 or
2 in proton-donor (MeOH) or aprotic (DCM, THF)
solvents at 0°С, followed by treatment of the resulting
peroxide ozonolysis products with an excess (3 equiv.) of
hydrazides 3 or 4 and maintaining the reaction mixture at
room temperature until the disappearance of peroxides.
There are two possible directions of the reaction
(Scheme 2): the formation of diacylhydrazones 5–8 or
keto acids/ketoesters 9–12 (the mechanisms of these
reactions have been described in detail in [7]).
Ozonolysis of monoterpenes 1 or 2 in MeOH followed
by treatment of peroxide compounds with an excess
of isonicotinic acid hydrazide 3 leads to the formation
of diacylhydrazones 5 and 6 in 87 and 63% yields,
respectively [6]. The minor formation (up to 10%) of
methyl esters 9 and 10 was recorded. When the peroxides
3 in aprotic solvents (THF, DCM), a significant decrease
in the yields of hydrazones 5 and 6 and the predominant
formation of keto acids 11 and 12 is observed.
Scheme 2.
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MYASOEDOVA et al.
Table 1. Results of calculations of the activity and toxicity of compounds 3–8 using the QSAR prediction procedure
Compounds
5
+
Parameter
3
+
4
–
7
+
6
+
8
+
Quantitative probability of anti-tuberculosis
activitya
(54.0%)
(55.0%)
(91.0%)
(63.0%)
(91.0%)
(74.0%)
Probable minimum inhibitory concentrationb 21.7 mg/kg 9.6 mg/kg 0.256 mg/kg 1.74 mg/kg 0.129 mg/kg 0.871 mg/kg
Probable acute toxicity (LD50)c
585 mg/kg 258 mg/kg 1070 mg/kg 776 mg/kg 849 mg/kg 1020 mg/kg
a Consensus Anti-TB activity_Model_5 [11].
b M3_T2_Consensus Anti-TB activity MIC, 271938 [12].
c When administered orally to mice (per day) (LD50 mouse oral ASNN [10]).
Table 2. Yields of ozonolysis products of (–)-α-pinene 1 and (+)-∆3-carene 2 in the presence of hydrazides 3 and 4 depending
on the solvent used
Product, %
Solvent
Terpene
with hydrazide 3
5 (71%), 9 (10%)
6 (69%), 10 (10%)
5 (24%), 11 (47%)
6 (20%), 12 (52%)
5 (17%), 11 (47%)
6 (21%), 12 (67%)
with hydrazide 4
7 (53%), 9 (5%)
1
2
1
2
1
2
МеОН
8 (52%), 10 (15%)
7 (70%), 11 (16%)
8 (61%), 12 (17%)
7 (67%), 11 (14%)
8 (56%), 12 (19%)
CH2Cl2
THF
The opposite situation is observed when using
salicylic acid hydrazide 4. Hydrazones 7 and 8 are
formed in higher yields when the reaction is carried out
in methylene chloride (Table 2), which is probably due
to the higher reducing ability of salicylic acid hydrazide
4 in comparison with isoniazid 3.
acetonitrile–water, 95:5, flow rate—0.1 mL/min) in the
mode of registration of positive and negative ions. TLC
control was performed on Sorbfil silicagel (Russia).
For column chromatography, SiO2 (70–230 mesh) from
Lancaster (Great Britain) was used.
We used (–)-α-pinene (97%, Acros Organics) and
(+)-∆3-carene (97%). Elemental analysis data for all
compounds were in agreement with the calculated data.
Ozonator productivity is 40 mmol O3/h.
In conclusion, using QSAR models, high anti-
tuberculosis activity was predicted in combination with
low values of acute toxicity and minimum inhibitory
concentration of diacylhydrazones obtained by ozonolysis
of (–)-α-pinene and (+)-Δ3-carene in the presence of
isonicotinic or salicylic acid hydrazides in one-pot
procedure.
The QSAR analysis was performed using the online
version of the OCHEM expert system (https://ochem.
eu) and the Consensus Anti-TB activity_Model_5
model (training sample accuracy 79%±2.0, test sample
accuracy 81%±3.0), M3 T2 Consensus Anti-TB activity
(training sample accuracy 78%±2.0, test sample accuracy
76%±4.0), LD50 mouse oral ASNN (training sample
accuracy 72%±2.0, test sample accuracy 74%±3.0).
Ozonolysis of (–)-α-pinene (1) and (+)-Δ3-carene
(2). An ozone-oxygen mixture was bubbled through a
solution of 0.5 g (3.6 mmol) of alkene 1 or 2 in 20 mL
of the solvent at 0°C until the absorption of 4 mmol
of O3. The reaction mixture was purged with argon.
11.0 mmol of isonicotinic 3 (1.5 g) or salicylic 4 (1.7 g)
acid hydrazide was added at 0°С. The resulting mixture
was stirred at room temperature until the disappearance
of peroxides (control by iodine-starch test). After the
solvent was distilled off, the residue was dissolved in
CHCl3, washed with saturated NaCl solution, dried
EXPERIMENTAL
IR spectra were recorded on an IR Prestige-21
Shimadzu instrument from a thin layer. NMR spectra
were recorded on a Bruker Avance III 500 spectrometer
[operating frequencies 500.13 (1H), 125.76 MHz
(13C)] from CDCl3, internal standard – TMS. GLC was
performed on a Chrom-5 instrument [column length
1.2 m, stationary phase – silicone SE-30 (5%) on a
Chromaton N-AW-DMCS support (0.16–0.20 mm),
operating temperature 50–300°C], the carrier gas is
helium. Optical rotation was measured on a PerkinElmer
241-MC polarimeter. Mass spectra were recorded on an
LCMS-2010 EV (Shimadzu) gas chromatography-mass
spectrometer (sample injection with a syringe, eluent—
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SYNTHESIS OF ISONICOTINIC AND SALICYLIC ACIDS DERIVATIVES
2041
1
with Na2SO4, evaporated and chromatographed (SiO2,
petroleum ether–tert-butyl methyl ether, 20 : 1→1 : 1).
IR spectrum (KBr), ν, cm–1: 1599 (С=N). Н NMR
spectrum (СDCl3), δ, ppm (hereinafter, the numbering of
atoms is arbitrary, see Scheme 1): 0.75‒0.90 m (2Н, Н1,
H3), 0.95 s (3Н, H9), 1.05 s (3Н, H10), 2.15 s (3Н, H6),
2.20‒2.35 m (4Н, Н4, Н7), 7.45 m (1Н, Н8), 7.50–7.70 m
(4Н, H3ʹ,3ʹʹ,6,6ʹʹ), 8.40‒8.70 m (4Н, H4ʹ,4ʹʹ,5ʹ,5ʹʹ), 9.25 br. s
(2Н, 2NH). 13C NMR spectrum (СDCl3), δ, ppm: 14.55
(C6), 19.10 (C2), 20.04 (C10), 23.01 (C1), 23.23 (C3), 29.17
(C9), 29.86 (C7), 32.86 (C4), 121.24 (121.35) (C3ʹ,3ʹʹ,6ʹ,6ʹʹ),
139.90 (C2ʹ,2ʹʹ), 149.22 (C8), 150.14 (150.29) (C4ʹ,4ʹʹ,5ʹ,5ʹʹ),
163.34 (C5), 164.34 (C1ʹ,1ʹʹ). Mass spectrum, m/z (Irel,
%): [M + H]+ 407 (100.0). Found, %: C 65.12; H 6.40;
N 20.61. C22H26N6O2. Calculated, %: C 65.01; H 6.45;
N 20.68. М 406.48.
Ozonolysis in methanol. After chromatography of
the residue (1.59 g) obtained by treatment of α-pinene
1 with isonicotinic acid hydrazide 3, 1.05 g (71%) of
acylhydrazone 5 and 0.07 g (10%) of methyl ester 9 were
isolated. After chromatography of the residue (1.34 g)
obtained fromΔ3-carene, 1.02 g (69%) of acylhydrazone
6 and 0.07 g (10%) of ketoester 10 were isolated.
After chromatography of the residue (1.17 g) obtained
by treatment of α-pinene 1 with salicylic acid hydrazide
4, 0.85 g (53%) of acylhydrazone 7 and 0.04 g (5%) of
ketoester 9 were isolated. After chromatography of the
residue (1.20 g) obtained fromΔ3-carene 2, 0.83 g (52%)
of acylhydrazone 8 and 0.11 g (15%) of methyl ester 10
were isolated.
Nʹ-{(2E)-1-[(1S,3R)-2,2-Dimethyl-3-{(2E)-2-
[2-(pyridin-4-ylcarbonyl)hydrazinylidene]-
ethyl}cyclopropyl]propan-2-ylidene}pyridine-4-
carbohydrazide (6) [6]. White crystals, mp 170‒171°С,
[α]D20 ‒5° (c = 1.1, CH2Cl2), Rf 0.25 (hexane–tert-butyl
methyl ether, 2 : 1). IR spectrum (KBr), ν, cm–1: 1601
(С=N). 1Н NMR spectrum (СDCl3), δ, ppm: 1.10 s (3Н,
H10), 1.15 s (3Н, H9), 1.60‒1.70 m (2Н, Н4), 1.85 s
(3Н, Н6), 1.90‒2.05 m (1Н, Н1), 2.10‒2.35 m (2Н, Н7),
2.50‒2.70 m (1Н, Н3), 7.40‒7.60 m (4Н, H3ʹ,3ʹʹ,6,6ʹʹ),
7.70‒7.80 m (1Н, H8), 8.40‒8.70 m (4Н, H4ʹ,4ʹʹ,5ʹ,5ʹʹ),
10.10 br. s (2Н, 2NH). 13C NMR spectrum (СDCl3), δ,
ppm: 18.29 (C6), 22.48 (C10), 24.22 (C7), 26.70 (C9),
30.43 (C1), 34.59 (C4), 43.44 (C2), 49.14 (C3), 121.32
(121.53) (C3ʹ,3ʹʹ,6ʹ,6ʹʹ), 139.95 (C2ʹ,2ʹʹ), 150.16 (150.33)
(C4ʹ,4ʹʹ,5ʹ,5ʹʹ), 153.27 (C8), 162.41 (C5), 162.91 (C1ʹ,1ʹʹ). Mass
spectrum, m/z (Irel, %): [M + H]+ 407 (100.0). Found, %:
C 65.10; H 6.39; N 20.63. C22H26N6O2. Calculated, %:
C 65.01; H 6.45; N 20.68. М 406.48.
Ozonolysisintetrahydrofuran.Afterchromatography
of the residue (1.43 g) obtained by treatment of α-pinene
1 with isonicotinic acid hydrazide 3, 0.25 g (17%) of
acylhydrazone 5 and 0.32 g (47%) of keto acid 11 were
isolated. After chromatography of the residue (1.33 g)
obtained fromΔ3-carene 2, 0.31 g (21%) of acylhydrazone
6 and 0.45 g (67%) of keto acid 12 were isolated.
After chromatography of the residue (1.52 g) obtained
from α-pinene 1 by treatment with salicylic acid hydrazide
4, 1.07 g (67%) of acylhydrazone 7 and 0.10 g (14%)
of keto acid 11 were isolated. After chromatography of
the residue (1.68 g) obtained from Δ3-carene 2, 0.90 g
(56%) of acylhydrazone 8 and 0.13 g (19%) of keto acid
12 were isolated.
Ozonolysis in DCM. After chromatography of the
residue (1.15 g) obtained by treatment of α-pinene 1
with isonicotinic acid hydrazide 3, 0.36 g (24%) of
acylhydrazone 5 and 0.35 g (52%) of keto acid 11 were
isolated. After chromatography of the residue (1.30 g)
obtained fromΔ3-carene 2, 0.30 g (20%) of acylhydrazone
6 and 0.35 g (52%) of keto acid 12 were isolated.
Nʹ-{(1E)-1-[(1R,3R)-3-{(2E)-2-[2-(2-Hydroxy-
benzoyl)hydrazinylidene]ethyl}-2,2-dimethyl-
cyclobutyl]ethylidene}-2-hydroxybenzohydrazide (7).
Rf 0.30 (hexane–tert-butyl methyl ether, 2 : 1), white
crystals, mp 161‒162°С. [α]D20 5° (с = 0.68, CH2Cl2). IR
spectrum (KBr), ν, cm–1: 3225 (OH), 3062 (NH), 1652,
1645 (С=N). 1Н NMR spectrum (СDCl3), δ, ppm: 0.89 s
(3H, H10), 1.05 s (3H, H9), 1.85 s (3H, H6), 2.10‒2.75 m
(2H, H4), 2.60‒2.75 m (2H, H7), 4.18‒4.39 m (1H, H3),
5.22‒5.31 m (1H, H1), 7.02‒7.16 m (4H, H4ʹ,4ʹʹ,6ʹ,6ʹʹ),
7.37‒7.43 m (4H, H3ʹ,3ʹʹ,5ʹ,5ʹʹ), 7.90 br. s and 8.03 br. s
(2Н, 2NH + 2H, 2OH), 8.18‒8.22 m (1H, H8). 13C NMR
spectrum (СDCl3), δ, ppm: 13.99 (C6), 20.01 (C10), 23.93
(C4), 28.92 (C7), 30.01 (C9), 40.55 (C2), 43.07 (C3), 50.57
(C1), 113.54 (C2ʹ,2ʹʹ), 119.18 (C6ʹ,6ʹʹ), 120.06 (C4ʹ,4ʹʹ), 129.44
(C3ʹ,3ʹʹ), 134.41 (C5ʹ,5ʹʹ), 145.61 (C8), 154.3 (C5), 159.58
(C7ʹ,7ʹʹ), 165.99 (C1ʹ,1ʹʹ). Mass spectrum, m/z (Irel, %):
After chromatography of the residue (1.35 g) obtained
by treatment of α-pinene 1 with salicylic acid hydrazide
4, 1.12 g (70%) of acylhydrazone 7 and 0.11 g (16%)
of keto acid 11 were isolated. After chromatography of
the residue (1.49 g) obtained from Δ3-carene 2, 0.97 g
(61%) of acylhydrazone 8 and 0.12 g (17%) of keto acid
12 were isolated.
Nʹ-{(1E)-1-[(1R,3R)-2,2-Dimethyl-3-{(2E)-2-
[2-(pyridin-4-ylcarbonyl)hydrazinylidene]ethyl}-
cyclobutyl]ethylidene}pyridine-4-carbohydrazide (5)
[6]. Rf 0.25 (hexane–tert-butyl methyl ether, 2 : 1). White
crystals, mp 173‒174°С, [α]D20 ‒14° (c = 0.192, CH2Cl2).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 11 2020

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MYASOEDOVA et al.
[M + H]+ 437 (100.0). Found, %: C 66.03; H 6.46; N
12.83. C24H28N4O2. Calculated, %: C 66.07; H 6.41; N
12.84. М 436.51.
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C 66.03; H 6.46; N 12.83.C24H28N4O2. Calculated, %: C
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FUNDING
https://doi.org/10.1111/cbdd.13188
This work was supported by the Russian Foundation for
Basic Research (project no. 19-33-90083) using the equipment
of the Center for Collective Use “Chemistry” of the Ufa
Institute of Chemistry, Russian Academy of Sciences and the
Regional Center for Collective Use “Agidel” of the Ufa Federal
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CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 11 2020