One-Pot Ozonolytic Synthesis of Isoniazid Derivatives from (–)-α-Pinene and Δ3-Carene

Article abstract of DOI:10.1134/S1070428018010165

Optically active isoniazid derivatives containing a cyclopropane or cyclobutane fragment have been synthesized by ozonolysis of (+)-Δ³-carene and (–)-α-pinene, followed by treatment of the ozonolysis products with isonicotinic acid hydrazide.

Full text of DOI:10.1134/S1070428018010165

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 1, pp. 146–148. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © Yu.V. Legostaeva, L.R. Garifullina, I.S. Nazarov, G.Yu. Ishmuratov, 2018, published in Zhurnal Organicheskoi Khimii, 2018,
Vol. 54, No. 1, pp. 145–146.
SHORT
COMMUNICATIONS
One-Pot Ozonolytic Synthesis of Isoniazid Derivatives
from (–)-α-Pinene and Δ3-Carene
Yu. V. Legostaeva,* L. R. Garifullina, I. S. Nazarov, and G. Yu. Ishmuratov
Ufa Institute of Chemistry, Russian Academy of Sciences, pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
*e-mail: legostaevayuv@yandex.ru
Received July 5, 2017
Abstract—Optically active isoniazid derivatives containing a cyclopropane or cyclobutane fragment have been
synthesized by ozonolysis of (+)-Δ3-carene and (–)-α-pinene, followed by treatment of the ozonolysis products
with isonicotinic acid hydrazide.
DOI: 10.1134/S1070428018010165
An important approach to the design of new medi-
cines is based on the introduction of a pharmacophoric
group into the target molecule. Isoniazid (1, isonico-
tinic acid hydrazide) is utilized in almost all schemes
for the prophylactics and treatment of tuberculosis.
However, this drug is toxic (LD50 178 mg/kg) [1];
therefore, a topical problem is search for new com-
pounds possessing a high tuberculostatic activity in
combination with low toxicity [2]. It is known that the
general toxicity can be reduced via attachment of the
isoniazid fragment to various scaffolds, e.g., by the
synthesis of acylhydrazones from isoniazid (1) and
various carbonyl compounds [1–3].
isolation of intermediate carbonyl compounds. In this
way, from natural monoterpenes, (+)-Δ3-carene (2) and
(–)-α-pinene (3) we obtained in good yields optically
active acylhydrazones 4 and 5 containing cyclopropane
and cyclobutane fragments. Analogous approach was
applied by us previously to accomplish direct trans-
formations of alkenes, including terpenes 2 and 3, into
tosylhydrazones [4] and semicarbazones [5].
Probable biological activity of compounds 4 and 5
was estimated using PASS (Prediction of Activity
Spectra for Substances) computer program which is
based on structure–activity relation analysis for a vast
training set [6]. It was found that the probability of
antitubercular, antimycobacterial, and antiviral activity
of acylhydrazones 4 and 5 is lower than for isoniazid
(1) and that the probability of antibacterial activity is
comparable (Table 1).
Herein we describe a procedure for the synthesis of
isoniazid derivatives from alkenes by ozonolysis of the
latter in methanol at 0°C and subsequent treatment of
the resulting peroxides with excess isoniazid without
O
Me
(1) O3, MeOH, 0°C
(2) Isoniazid (1)
Me
N
O
N
H
N
N
Me
Me
Me
N
H
N
Me
2
4
Me
N
H
N
N
N
(1) O3, MeOH, 0°C
(2) Isoniazid (1)
H
N
O
N
Me
Me
Me
O
Me
Me
3
5
146

ONE-POT OZONOLYTIC SYNTHESIS OF ISONIAZID DERIVATIVES
147
Table 1. Prediction of biological activity of compounds 4 and 5 and isoniazid (1) using PASS computer programa
1
4
5
Activity
Pa
Pi
Pa
Pi
Pa
Pi
Antitubercular
0.813
0.801
0.613
0.377
0.003
0.004
0.017
0.036
0.538
0.505
0.408
0.373
0.009
0.018
0.103
0.037
0.524
0.514
0.485
0.448
0.010
0.017
0.057
0.022
Antimycobacterial
Antiviral (Picornavirus)
Antibacterial
a
Pa stands for the probability of a given activity, and Pi stands for the probability of inactivity.
Yield 87%, Rf 0.08 (petroleum ether–ethyl acetate,
1:1), [α]D20 = –14° (c = 0.192, CHCl3). IR spectrum
Acylhydrazones 4 and 5 (general procedure).
An ozone–oxygen mixture was bubbled through
a solution of 3.3 mmol of terpene 2 or 3 in 20 mL of
anhydrous methanol at 0°C until 4 mmol of ozone was
absorbed. The mixture was purged with argon,
10.9 mmol of isoniazid (1) was added at 0°C, and the
mixture was stirred at room temperature until perox-
ides were no longer detected by starch–iodine test. The
solvent was distilled off, the residue was dissolved in
chloroform, the solution was washed with brine, dried
over Na2SO4, and evaporated, and the residue was
purified by chromatography on silica gel using petro-
leum ether–tert-butyl methyl ether (10:1 to 1:1) and
then methanol as eluents.
1
(KBr): ν 1601 cm–1 (C=N). H NMR spectrum
(CDCl3), δ, ppm: 1.10 s (3H, CH3), 1.15 s (3H, CH3),
1.60–1.70 m (2H, 4-H), 1.85 s (3H, CH3C=N), 1.90–
2.05 m (1H, 1-H), 2.10–2.35 m (2H, CH2), 2.50–
2.70 m (1H, 3-H), 7.40–7.60 m (4H, Harom), 7.70–
7.80 m (1H, CH=N), 8.40–8.70 m (4H, Harom),
10.10 br.s (2H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 18.29 q (CH3C=N), 22.48 q (CH3), 24.22 t (C4),
26.70 q (CH3), 30.43 d (C1), 34.59 t (CH2), 43.44 s
(C2), 49.14 d (C3), 121.32 d and 121.53 d (4C, CHarom),
139.95 s (2C, Carom), 153.27 d (CH=N), 150.16 d and
150.33 d (4C, CHarom), 162.41 s (C=N), 162.91 s (2C,
C=O). Mass spectrum: m/z 407 (Irel 100%): [M + H]+.
Found, %: C 65.10; H 6.39; N 20.63. C22H26N6O2. Cal-
culated, %: C 65.01; H 6.45; N 20.68. M 406.48.
(E)-N′-{1-[(1S,3R)-2,2-Dimethyl-3-{(E)-2-[2-(pyr-
idine-4-carbonyl)hydrazinylidene]ethyl}cyclo-
propyl]propan-2-ylidene}pyridine-4-carbohydra-
zide (4). Yield 63%, Rf 0.08 (petroleum ether–ethyl
acetate, 1:1), [α]D20 = –5° (c = 1.1, CHCl3). IR spectrum
The IR spectra were recorded on a Shimadzu IR
Prestige-21 spectrometer. The 1H and 13C NMR spectra
were measured on a Bruker AM-500 spectrometer at
500.13 and 126.76 MHz, respectively, using tetra-
methylsilane as internal standard. The mass spectra
were obtained on a Shimadzu LCMS-2010 EV instru-
ment. Silica gel (70–230 mesh; Lancaster, UK) was
used for column chromatography. The ozonizer effi-
ciency was 40 mmol O3/h.
1
(KBr): ν 1599 cm–1 (C=N). H NMR spectrum
(CDCl3), δ, ppm: 0.75–0.90 m (2H, 1-H, 3-H), 0.95 s
(3H, CH3), 1.05 s (3H, CH3), 2.15 s (3H, CH3CH),
2.20–2.35 m (4H, CH2), 7.50–7.70 m (4H, Harom),
7.45 m (1H, CH=N), 8.40–8.70 m (4H, Harom),
9.25 br.s (2H, NH). 13C NMR spectrum (CDCl3), δC,
ppm: 14.55 q (CH3), 19.10 s (C2), 20.04 q (CH3),
23.01 d (C1), 23.23 d (C3), 29.17 q (CH3), 29.86 t
(CH2C=N), 32.86 t (CH2), 121.24 d and 121.35 d (4C,
CHarom), 139.90 s (2C, Carom), 149.22 d (CH=N),
150.14 d and 150.29 d (4C, CHarom), 163.34 s (C=N),
164.34 s (2C, C=O). Mass spectrum: m/z 407
(Irel 100%) [M + H]+. Found, %: C 65.12; H 6.40;
N 20.61. C22H26N6O2. Calculated, %: C 65.01; H 6.45;
N 20.68. M 406.48.
This study was performed using the equipment of
the Chemistry Joint Center, Ufa Institute of Chemistry,
Russian Academy of Sciences.
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