Synthesis of carvone-derived 1,2,3-triazoles study of their antioxidant properties and interaction with bovine serum albumin

Article abstract of DOI:10.3390/molecules23112991

Natural L-carvone was utilized as a starting material for an efficient synthesis of some terpenyl-derived 1,2,3-triazoles. Chlorination of carvone, followed by nucleophilic substitution with sodium azide resulted in the preparation of 10-azidocarvone. Sub

Full text of DOI:10.3390/molecules23112991

molecules
Article
Synthesis of Carvone-Derived 1,2,3-Triazoles Study of
Their Antioxidant Properties and Interaction with
Bovine Serum Albumin
1
,
1
1
1
Armen S. Galstyan * , Armen I. Martiryan , Karine R. Grigoryan , Armine G. Ghazaryan ,
1
1
2,
Melanya A. Samvelyan , Tariel V. Ghochikyan and Valentine G. Nenajdenko *
1
Faculty of Chemistry, Yerevan State University, 1 Alex Manoogian Str., Yerevan 0025, Armenia;
armart@ysu.am (A.I.M.); kara@ysu.am (K.R.G.); armghazaryan@ysu.am (A.G.G.);
msamvelyan@ysu.am (M.A.S.); ghochikyan@ysu.am (T.V.G.)
Department of Chemistry, M.V. Lomonosov Moscow State University, 119991 Moscow, Russia
2
*
Correspondence: a_galstyan@ysu.am (A.S.G.); nenajdenko@gmail.com (V.G.N.);
Tel.: +374-91-85-35-16 (A.S.G.); +7-495-939-22-76 (V.N.G.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 19 October 2018; Accepted: 14 November 2018; Published: 16 November 2018
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: Natural L-carvone was utilized as a starting material for an efficient synthesis of some
terpenyl-derived 1,2,3-triazoles. Chlorination of carvone, followed by nucleophilic substitution with
sodium azide resulted in the preparation of 10-azidocarvone. Subsequent CuAAC click reaction
with propargylated derivatives provided an efficient synthetic route to a set of terpenyl-derived
conjugates with increased solubility in water. All investigated compounds exhibit high antioxidant
activity, which is comparable with that of vitamin C. It was also found that serum albumin and the
terpenyl-1,2,3-triazoles hybrids spontaneously undergo reversible binding driven by hydrophobic
interactions, suggesting that serum albumin can transport the target triazoles.
Keywords: carvone; 1,2,3-triazole; click chemistry; acetylene; antioxidant activity; bovine
serum albumin
1
. Introduction
Natural compounds play a significant role in the design of new drugs and prevention of various
diseases [
are of natural origin [
1
]. Thus, more than 60% of current drugs for the treatment of cancer and infectious diseases
]. Terpenoids are one of the largest classes of chiral natural compounds, which
2
includes more than 23,000 compounds. Many terpene derivatives are widely used in perfumes, playing
the role of cosmetic products and food additives [3]. However, medicine is not less important area of
application of terpenes, since the majority of compounds of this class exhibits pronounced biological
®
activity. For example, the antimalarial drug artemisinin and the anticancer drug paclitaxel (Taxol ) are
the two most prominent members of the class of terpenes used in medicine (Figure 1).
O HO
Ac
O
H
Ph
O
O
O
NH
O
O
H
O
Ph
H
O
H
O
O
O
OH
O
OH
Ac
O
Ph
Figure 1. Structures of artemisinin and Taxol®.
Molecules 2018, 23, 2991; doi:10.3390/molecules23112991
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2991
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Annual sales of terpenic derivatives in the world are estimated at about $20 billion [
4]. The scope
of terpenes is constantly expanding; therefore, terpenoids will play an increasingly important role as
therapeutic and prophylactic agents for human diseases.
Monoterpenes–C H compounds and their derivatives are the simplest type of terpenoids. They
10
16
are the basis of essential oils, floral aromas and perform plant protective functions [5,6]. Despite the fact
that these are small and fairly simple molecules, a number of monoterpenes have an antitumor effect,
demonstrating not only the ability to prevent the formation or progression of cancer, but the ability
to reduce existing malignant tumors [7]. Most abundant in nature are terpenoids having menthane
skeleton (Figure 2). For example, limonene is the most common monocyclic monoterpene found
in nature. It can be found in a variety of trees and grasses (for example, Mentha spp.). Limonene
is an important component of the peel of oranges and lemons, as well as the essential oil of cumin.
The limonene fragment can be found in the structure of many drugs [7–11]. Carvone, the main
monoterpene of cumin seed. It has been shown that carvone oil prevents chemically induced carcinoma
of the lung [12]. In addition, carveol has chemoprophylactic activity against breast cancer during
the initiation phase [13]. Perillyl alcohol, a hydroxylated limonene analog, exhibits chemopreventive
activity against chemically induced liver cancer [14] and tumor recurrences in animal models [15].
Figure 2. Some menthane-derived monoterpenoids.
Nowadays, one of the most promising synthetic trends for expanding molecular complexity
from a given scaffold have been the “click” reactions. “Click” reactions are a class of efficient, fast,
universal, and selective reactions that are characterized by high yields and simple isolation of products.
The standard “click” of chemistry for today is the formation of 1,2,3-triazoles catalyzed by copper
salts (I) in the reaction of azides and terminal alkynes (CuAAC) [16–20]. Although 1,2,3-triazole
fragment is generally absent in natural compounds, synthetic molecules containing 1,2,3-triazole
cycles represent a wide class of physiologically active substances exhibiting various types of biological
activity, for example, antibacterial, antiallergic, antiviral, antifungal properties [21,22]. Apparently,
the pharmacological activity of compounds containing 1,2,3-triazole groups is due to the structural and
electronic similarity of the 1,2,3-triazole fragment and the amide group. The 1,2,3-triazole fragment can
be considered as a conformationally constrained bioisostere of the amide group. Greater stability of the
1,2,3-triazole scaffold under physiological conditions, led to the widespread use of the “click” reaction
as an effective method for the synthesis of various biologically active compounds in drug design.
The triazole fragment is an important pharmacophoric unit, and a large number of drugs containing this
heterocycle are known (Figure 3). Due to the commercial success of some pharmaceutical preparations
based on the triazole ring, many pharmaceutical companies and academic groups have shown interest
in developing new methods for synthesizing triazole compounds and screening their biological
activity [23,24]. For example, antifungal drugs containing triazole rings are known: itraconazole,
fluconazole, voriconazole [25], antiviral drug ribavirin and murbritinib (used to treat breast, bladder,
kidney and prostate cancer). Ribavirin is a drug for the treatment of viral infections such as herpes
and hepatitis [26,27].

Molecules 2018, 23, 2991
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Cl
F
N
O
Cl
N
N
N
N
N
N
O
O
N
N
N
OH
F
N
N
O
F
N
1
. Itraconazole
2. Voriconazole
O
N
F
H N
2
N
HO
N
F
N
N
O
N
N N
N
N
O
N
N
N
OH OH
OH
O
3
. Mubritinib
4
. Ribavirin
5. Fluconazole
Figure 3. Some triazole-derived drugs.
2
. Results and Discussion
This study is devoted to the synthesis of carvone-derived 1,2,3-triazoles 4a
–i prepared according
to the strategy outlined in Scheme 1. We proposed that due to the presence of the enone fragment in
the structure, such conjugates would behave as antioxidants. On the other hand, the triazole and amine
moieties will play an auxiliary role of improving water solubility of these molecules. 10-Azido-carvone
was chosen as a key building block to study copper-catalyzed azide alkyne cycloaddition (CuAAC).
A number of propargylated amino derivatives 3 were studied as alkyne partners for this reaction. They
can be prepared using standard alkylation of NH-derivatives with propargyl bromide (Scheme 1) [28].
O
i
O
6
7%
Cl
2
N
N
N
N
O
ii
7
0%
O
4a-i
up to 84%
R-(-)-carvone
1
iv
iii
N
HN
3
a-i
N3
1
0-N -Car.
3
◦
Scheme 1. Reagents and conditions: i–Ca(OCl) , CO , DCM/H O, 0 C; ii—NaN , MeCN or DMSO;
2
2
2
3
iii—3-bromoprop-1-yne, EtOH or MeCN, base; iv—Et N, CuBr or CuI (5 mol%), MeCN or DMSO,
3
◦
6
0 C.
To achieve this goal, L-carvone (
1
) was chlorinated using calcium hypochlorite
−
CO system to
2
provide 10-chlorocarvone ( ) [29]. Subsequent treatment of
2
2
with sodium azide resulted in synthesis
of 10-azidocarvone. We decided to utilize synthetically attractive one-pot protocol to avoid isolation
and purification of this intermediate product. For this aim, chloride 2 was treated with sodium azide
in DMSO or acetonitrile to yield 10-azido-carvone, which was used without isolation in model CuAAC
reaction with N-propargylmorpholine 3a. It was found that the in the case of DMSO as a solvent the
yield of model conjugate 4a is moderate. However, with acetonitrile as a solvent and copper iodide as
a catalyst, the isolated yield was improved significantly. For example, 4a was obtained in up to 78%
yield within a reasonable reaction time (10 h) using only 5 mol % of copper iodide (Table 1). Probably,
such observation can be explained by formation of the complex of copper iodide with final products.

Molecules 2018, 23, 2991
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Table 1. Optimization of synthesis of 4a.
◦
Isolated Yield a
Entry
Solvent
Catalyst (mol%)
Time, h
Temp., C
1.
2.
3.
4.
5.
6.
DMSO
DMSO
MeCN: DMSO—1:1
MeCN
CuBr(10)
CuI(10)
CuI(10)
CuI (10)
CuI (10)
CuI (5)
5
5
8
8
10
10
65
65
60
60
60
39
48
56
69
71
78
MeCN
MeCN
60
a
◦
Conditions: 10-chlorocarvone (1 mmol), solvent (3 mL), NaN
N-propargylmorpholine.
3
(1.2 mmol), 60 C 10 h, Et
3
N (1.2 mmol), CuHal,
Next, the reaction with a number of propargylated amines and amides was investigated. To our
delight, the corresponding triazole derived carvone conjugates were isolated in up to 84% yield.
The efficient procedure provided as crystalline compounds. Their structure was confirmed by
4
4
combination of spectroscopic methods (see SI). As a result, this part of study gave as a family of
carvone derivatives 4 with variable amino- (amido) substituents in the triazole ring (Table 2).
Table 2. Synthesis of terpenyl-1,2,3-triazoles 4a–i.
Terpenyl-1,2,3-triazol eY si eld, %
Terpenyl-1,2,3-triazol eY si eld, %
4
a
78
4f
4g
4h
65
4
b
79
73
63
84
4
c
4
d
79
81
4i
76
4
e

Molecules 2018, 23, 2991
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With these new compounds in hand, we decided to study the antioxidant properties of the
•
synthesized terpenyl-1,2,3-triazoles
4
. For this aim the interaction with HO radicals in the presence of
the competitive acceptor 4-nitroso-N,N-dimethylaniline (PNDMA) was studied [30–32]. The initiation
•
−3
−1
of HO radicals was carried out by photolysis of H O (10 mol
·
L
) under the action of UV radiation
2
2
•
(λ
= 313 nm with the use of a special filter). The rate of initiation of HO radicals (Figure 4a–f) was
determined by the change in PNDMA absorption (A440). It was found that compounds 4a
better water-solubility and their antioxidant properties were investigated. Below are given the kinetic
data of the effect of 4a different concentrations on the optical density of PNDMA, depending on the
–e have
–
e
time of irradiation (Figure 4a–e).
D
D
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.7
0.6
0.5
0.4
0.3
0.2
4
2
4
3
3
2
1
1
6
0
.1
.0
0
t, min
t,min
0
1
2
3
4
5
6
7
8
9
10 11 12 13
0
1
2
3
4
5
7
8
9
10 11 12 13
(
b)
(
a)
D
D
0
.7
.6
.5
.4
.3
.2
.1
.0
0.7
0.6
0.5
0.4
0.3
0
0
0
0
0
0
0
0
.2
0.1
.0
3
2
1
4
3
2
1
4
9 10 11 12
0
t, min
t, min
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
9
10 11 12 13
(
d)
(
c)
tg
0.10
α
D
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.08
4
4
d
0.06
4b
0.04
0.02
0.00
3
2
1
4e
4c
4
a
-
4
t, min
C10 , mol/L
0
1
2
3
4
5
6
7
8
9
10 11 12 13
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2
(
e)
(f)
Figure 4.
(
a
) compound 4a; (
b
) compound 4b; (
c
) compound 4c; (
d
) compound 4d; (e) compound
4
e
. Dependence of optical density of PNDMA vs the time of UV irradiation (
λ
= 313 nm) at various
concentrations of compounds 4a
concentration: compounds 4a–e.
–e; (f) dependence of rate of PNDMA discoloring (in units) vs the

Molecules 2018, 23, 2991
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were calculated by the
−1 −1
(1)
•
The constants of the interaction rate of HO radicals with 4a–e
Equation (1) [31,32]:
10
kOH + P = 1.25 × 10 ([PNDMA]/[P]) × [(W /W ) − 1], mol
s
L
1
2
−1
−1
•
where 1.25
is the concentration of 4a
presence of 4a respectively. The rate constants are shown in Table 3. As one can see from Table 3,
×
1010 mol
s
L is the constant of the interaction rate of HO radicals with PNDMA, [P]
–
e, W and W are rates of PNDMA discoloring in distilled water and in the
1
2
–
e
all the compounds tested exhibit significant antioxidant activity. Moreover compound 4b is slightly
inferior to the known antioxidant ascorbic acid used as a control compound.
Table 3. The rate constants for the reaction.
•
Rate Constant HO + 4a–e
Tested Compound
−
1
(M s
)
9
9
9
9
9
9
4
a
1.155 × 10
4.483 × 10
1.359 × 10
0.104 × 10
0.407 × 10
9.450 × 10
4
b
4
c
4
d
4
e
Ascorbic acid (control)
The transport of active aglycones of drugs is known to be carried out by various interactions with
the proteins. The most abundant protein in the blood plasma is the transport protein serum albumin
(
up to 60%) which can reversibly bind various endogenous and exogenous compounds [33
reveal possibility of such binding, fluorescence spectroscopy was used for model compound 4e with
the bovine serum albumin (BSA). The thermodynamic parameters ( H, S and G) can be used to
propose the binding mode. For the typical hydrophobic interactions, both H and S are positive,
while negative H and S result from the hydrogen bond formation and van der Waals forces,
and electrostatic interactions are responsible for the cases when H < 0 and S > 0 [36]. The value
–35]. To
∆
∆
∆
∆
∆
∆
∆
∆
∆
3
6
−1
of binding constant (K ) for transport protein ligand interaction in the range of10 –10 M indicate
b
the reversibility of binding [37]. The results obtained for BSA-4e system are summarized in Table 4.
Negative values of
∆G show that the binding process proceeds spontaneously. The positive values of
∆
H and ∆S show that the stability of the BSA-4e system is due mainly to hydrophobic interactions.
Table 4. The values of thermodynamic parameters for BSA binding with 4e at 298 and 308 K.
−
1
−1
−1
−1 −1
K
T, K
K , M
N
∆H, kJ mol
7.989
∆G, kJ mol
∆S, J mol
292.86
b
2.40·× 103
2
3
98
08
1.001 ± 0.079
1.061 ± 0.066
−19.283
−22.212
6
5.85·× 103
The distance between the protein and the ligand can be calculated using the theory of resonance
energy transfer (Foerster theory) [38]. Average distance between BSA-4e decreases in the range of
2–8 nm and the energy transfer efficiency increases when the temperature was increased from 298 K to
308 K (Table 5). However, such interactions of BSA with 4e are not very strong. Thus, the transport of
4e can be performed by serum albumin-BSA.
Table 5. The values of the overlap integral, the energy transfer efficiency, the Forster radius and the
distance between the BSA and 4e.
3
−1
T, K
I, cm L × mol
E
R , nm
r, nm
0
−
14
14
2
3
98
08
1.79 × 10
0.019
0.043
3.778
3.782
7.27
7.06
1.80 × 10−

Molecules 2018, 23, 2991
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3
. Materials and Methods
3
.1. General Information
1H- and 13C-NMR spectra were recorded on a Mercury-300 MHz instrument (Varian, Palo Alto,
CA, USA) in DMSO-CCl mixture (1:3) or on an AVANCE 400 MHz spectrometer (Bruker, Billerica,
4
MA, USA) in CDCl . Chemical shifts (
δ
) in ppm are reported as quoted relative to the residual
3
1
13
1
signals of chloroform-d (7.26 for H-NMR and 77.16 for C-NMR) or DMSO-d (2.50 for H-NMR
6
and 39.52 for 13C-NMR) as internal references. The coupling constants (J) are given in Hertz. ESI-MS
spectra were measured with a MicroTof instrument (Bruker Daltonics, Billerica, MA, USA). TLC
analysis was performed on Xtra SIL G/UV254 plates (Macherey-Nagel, Düren, German). All reagents
were of reagent grade and were used as such or distilled prior to use. Compounds
2
and 3a
–i were
synthesized according to the procedure described in [28,29]. Melting points were determined on
a Boetius micro-heating stage and a SMP10.
◦
20
(
[
5R)-5-(3-chloroprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one. Yield 67%, b.p. 110–116 C/1 Torr,
n
1.5285,
D
20
α] −44.05 (C 2.17 DCM).
D
◦
20
1
4
-(Prop-2-yn-1-yl)morpholine (3a). Yield 53%, b.p. 71–72 C/15 Torr,
n
1.4741. H-NMR (300 MHz,
D
DMSO/CCl —1/3)
δ
3.63–3.56 (m, 4H, OCH ), 3.22 (d, J = 2.5 Hz, 2H, NCH2
C
≡
CH), 2.51 (t, J = 2.5 Hz,
4
2
13
1
7
H,
≡
CH), 2.49–2.44 (m, 4H, NCH2).
C-NMR (75 MHz, DMSO/CCl —1/3)
δ
78.0(C≡CH),
4
3.9(C≡CH), 65.8 (OCH ), 51.3 (NCH ), 46.4(NCH C≡).
2
2
2
◦
20
1.4799. 1H-NMR
1-Methyl-4-(prop-2-yn-1-yl)piperazine (3b). Yield 49%, b.p. 74 C/12 Torr,
n
D
(
300 MHz, DMSO/CCl —1/3) 3.20 (d, J = 2.5 Hz, 2H, NCH2
δ
C
≡
CH), 2.55–2.42 (m, 5H, NCH2,
4
13
≡
CH), 2.42–2.21 (m, 4H, NCH ), 2.18 (s, 3H, NCH ). C-NMR (75 MHz, DMSO/CCl —1/3)
δ
2
3
4
7
8.4(C≡CH), 73.5(C≡CH), 54.2(NCH ), 50.8(NCH ), 46.1(NCH C≡), 45.4(NCH ).
2
2
2
3
◦
20
1
1
-(Prop-2-yn-1-yl)pyrrolidine (3c). Yield 41%, b.p. 42–43 C/17 Torr,
DMSO/CCl —1/3) 3.33 (d, J = 2.4 Hz, 2H, NCH2
CH), 1.82–1.70 (m, 4H, CH2). 13C-NMR (75 MHz, DMSO/CCl —1/3)
n
1.4590. H-NMR (300 MHz,
D
δ
C CH), 2.58–2.50 (m, 4H, NCH ), 2.38
≡
4
2
(
t, J = 2.4 Hz, 1H,
≡
δ
78.9(C≡CH),
4
7
2.7(C≡CH), 51.2(NCH ), 41.8(NCH C≡), 23.2(CH ).
-(Prop-2-yn-1-yl)piperidine (3d). Yield 50%, b.p. 55–57 C/12 Torr,
2
2
2
◦
20
1
1
n
1.4706. H-NMR (300 MHz,
D
DMSO/CCl —1/3) 3.18 (d, J = 2.4 Hz, 2H, NCH2
δ
C
≡
CH), 2.48–2.35 (m, 5H-NCH2,
≡
CH), 1.62–1.50
4
13
(
m, 4H, CH ), 1.47–1.33 (m, 2H, CH ).
C-NMR (75 MHz, DMSO/CCl —1/3)
δ
78.6(C≡CH),
2
2
4
7
3.2(C≡CH), 52.1(NCH ), 46.9(NCH C≡), 25.2(CH ), 23.4(CH ).
2
2
2
2
◦
20
1.4791. 1H-NMR (300 MHz,
1-(Prop-2-yn-1-yl)azepane (3e). Yield 55%, b.p. 71–72 C/15 Torr,
n
D
DMSO/CCl —1/3) 3.28 (d, J = 2.4 Hz, 2H, NCH2
δ
C
≡
CH), 2.66–2.57 (m, 4H, NCH ), 2.35 (t, J = 2.4 Hz,
4
2
13
1
5
H,
≡
CH), 1.69–1.54 (m, 8H, (CH ) ).
C-NMR (75 MHz, DMSO)
δ
79.6(C≡CH), 72.3(C≡CH),
2
4
4.0(NCH ), 47.4(NCH C≡), 27.8(CH ), 26.2(CH ).
2
2
2
2
◦
20
1
1
-(Prop-2-yn-1-yl)pyrrolidine-2,5-dione (3f). Yield 64%, b.p. 127 C/2 Torr,
n
1.5124. H-NMR (300 MHz,
D
DMSO/CCl —1/3)
C-NMR (75 MHz, DMSO/CCl —1/3)
δ
4.13 (d, J = 2.5 Hz, 2H, NCH ), 2.69 (s, 4H, CH C=O), 2.60 (t, J = 2.5 Hz, 1H,
≡
CH).
CH C=O),
2
4
2
2
13
δ
175.0 (C=O), 77.1(C≡CH), 71.8(C≡CH), 27.7
4
2
6.8 (NCH2).
◦
1
1
-(Prop-2-yn-1-yl)-1H-indole-2,3-dione (3g). Yield 64%, m.p. 162–163 C (EtOH/H O—1/1). H-NMR
2
(
1
300 MHz, DMSO/CCl —1/3)
H
δ
7.66 (td, J = 7.8, 1.4 Hz, 1Harom), 7.57 (ddd, J = 7.4, 1.3, 0.4 Hz,
arom), 7.22–7.12 (m, 2Harom), 4.53 (d, J = 2.5 Hz, 2H, NCH ), 2.81 (t, J = 2.5 Hz, 1H,
CH). 13C-NMR
181.7(C=O), 156.3(NC=O), 149.3(Carom), 137.5(HCarom), 124.2(HCarom),
23.0(HCarom), 117.2(Carom), 110.8(HCarom), 76.1(C≡CH), 73.8(C≡CH), 28.7 (NCH ).
4
≡
2
(
75 MHz, DMSO/CCl —1/3) δ
4
1
2
◦
1
2
-(Prop-2-yn-1-yl)-1H-isoindole-1,3(2H)-dione (3h). Yield 63%, m.p. 146–148 C (EtOH). H-NMR
(
300 MHz, DMSO/CCl —1/3)
δ
7.89–7.84 (m, 2Harom), 7.83–7.78 (m, 2Harom), 4.37 (d, J = 2.5 Hz,
4

Molecules 2018, 23, 2991
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2
H, NCH ), 2.64 (t, J = 2.5 Hz, 1H,
≡
CH). 13C-NMR (75 MHz, DMSO/CCl —1/3)
δ
165.7(C=O),
2
4
1
33.7(HCarom), 131.4(Carom), 122.9(HCarom), 77.2(C≡CH), 72.2(C≡CH), 26.2(NCH ).
2
◦
1
1
-(Prop-2-yn-1-yl)-1H-benzotriazole (3i). Yield 45%, m.p. 62–63 C (PhH/Hex—1/1). H-NMR (300 MHz,
DMSO)
δ
8.00 (dt, J = 8.3, 1.0 Hz, 1Harom), 7.82 (dt, J = 8.3, 1.0 Hz, 1Harom), 7.52 (ddd, J = 8.2, 6.9,
1
1
1
.0 Hz, 1Harom), 7.37 (ddd, J = 8.2, 6.9, 1.0 Hz, 1Harom), 5.58 (d, J = 2.6 Hz, 2H, NCH ), 3.04 (t, J = 2.6 Hz,
2
H,
≡
CH). 13C-NMR (75 MHz, DMSO/CCl —1/3)
δ
145.3(Carom), 132.0(Carom), 126.7(HCarom),
4
23.2(HCarom), 119.1(HCarom), 109.9(HCarom), 75.9(C≡CH), 75.6(C≡CH), 37.1(NCH ).
2
(
5R)-5-(3-azidoprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one (10-N -Car.).
369 mg (2 mmol) of
3
(
5R)-5-(3-chloroprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one, 2 mL of acetonitrile, 156 mg (2.4 mmol)
◦
of sodium azide are placed in a round-bottomed 5 mL flask and heated with stirring for 10 h (60 C).
The mixture was poured into water (30 mL) and extracted with DCM (3 10 mL). The combined
extracts were dried over Na SO , the volatiles were evaporated and the residue was purified via
column chromatography on silica gel using DCM–Hex mixture (1:1) as an eluent. Yield 70%. H-NMR
(
×
2
4
1
a
300 MHz, DMSO/CCl —1/.3)
δ
6.74 (ddq, J = 5.5, 2.7, 1.3 Hz, 1H, HC=), 5.15 (s, J = 4.0 Hz, 1H ,
4
b
a
H C=), 5.09 (s, 1H , H C=), 3.87 (s, 2H, CH N ), 2.93–2.66 (m, 1H , CH C=O), 2.61–2.44 (m, 2H, CH,
CH in carbocycle), 2.43–2.22 (m, 2H, CH in carbocycle), 1.73 (dt, J = 2.6, 1.4 Hz, 3H, CH ). C-NMR
2
2
2
3
2
13
2
2
3
(
75 MHz, DMSO/CCl —1/3) δ 196.5(C=O), 144.7, 142.8, 134.6, 113.4, 53.8, 42.2, 38.4, 30.6, 15.1(CH ).
4
3
3
.2. General Method for the Preparation of Terpenyl-1,2,3-triazoles 4a–i
369 mg (2 mmol) of (5R)-5-(3-chloroprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one, 2 mL of
acetonitrile, 156 mg (2.4 mmol) of sodium azide are placed in a round-bottomed 5 mL flask and
◦
heated with stirring for 10 h (60 C). After cooling, 242 mg (2.4 mmol) of triethylamine, 19 mg
(
0.1 mmol) of CuI and 2.4 mmol of the corresponding propargyl derivative are added to the resulting
◦
mixture. The whole is heated then for 10 h at 60 C and the solvent is distilled off. The cooled mixture
is dissolved in benzene, filtered and hexane is added to the filtrate. The precipitated crystals are filtered
off, washed with hexane and dried.
(
5R)-2-methyl-5-(3-{4-[(morpholin-4-yl)methyl]-1H-1,2,3-triazol-1-yl}prop-1-en-2-yl)cyclohex-2-en-1-one (4a).
◦
20
1
Yield 78%, m.p. 81–82 C, [α]D
NCH), 6.69 (ddd, J = 5.8, 2.6, 1.4 Hz, 1H, HC=CCO), 5.13 (s, 1H , H C=), 5.06 (s, 1H , H C=), 5.04
(
−
31.65 (C 1.15 DCM). H-NMR (400 MHz, CDCl ) δ 7.47 (s, 1H,
3
a
b
2
2
a
a
d, J = 15.8 Hz, 1H , H C=C-CH2N), 4.93 (d, J = 15.3 Hz, 1H , H C=C-CH2N), 3.75–3.68 (m, 4H,
2
2
O(CH2CH ) NCH ), 3.67 (s, 2H, O(CH CH ) NCH2), 2.65–2.43 (m, 7H, CH C=O, O(CH2CH ) N, CH
2 2
2
2
2 2
2
2 2
3
1
in carbocycle), 2.42–2.18 (m, 2H, CH in carbocycle), 1.76 (dt, J = 2.5, 1.3 Hz, 3H, CH ). C-NMR
2
3
(
4
75 MHz, DMSO/CCl —1/3) δ: 196.5 (C=O), 145.6, 143.0, 142.9, 134.5, 123.1, 113.3, 65.9, 52.9, 52.6, 52.5,
4
2.1, 37.9, 30.4, 15.1. HRMS (ESI) m/z: [M + H] Calcd for C H N O 317.1978, Found 317.1972.
17 25 4 2
+
+
(
5R)-2-methyl-5-(3-{4-[(4-methylpiperazin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}prop-1-en-2-yl)cyclohex-2-en-1-
◦
20
1
one (4b). Yield 79%, m.p. 117 C, [α]D
(
5
−
38.79 (C 1.044 DCM). H-NMR (400 MHz, CDCl )
δ
7.45
3
b
a
s, 1H, NCH), 6.67 (ddd, J = 5.7, 2.7, 1.4 Hz, 1H, HC=CCO), 5.10 (s, 1H , =CH ), 5.04 (s, 1H , =CH ),
2
2
a
b
.01 (d, J = 15.5 Hz, 1H , H C=C-CH2N), 4.90 (d, J = 15.2 Hz, 1H , H C=C-CH2N), 3.66 (s, 2H,
2
2
CH2N(CH CH ) NCH ), 2.65–2.30 (m, 12H, CH and CH in carbocycle, CH N), 2.25 (s, J = 7.6 Hz, 4H,
2
2 2
3
2
2
13
CH in carbocycle, NCH ), 1.74 (dt, J = 2.5, 1.3 Hz, 3H, CH ). C-NMR (101 MHz, CDCl3)
δ
198.5
2
3
3
(
C=O), 145.2, 145.1, 143.8, 135.8, 122.6, 115.5, 55.1, 54.0, 53.4, 53.0, 46.1, 42.8, 38.3, 31.2, 15.7. HRMS (ESI)
+
+
m/z: [M + H] Calcd for C H N O 330.2294, Found 330.2293.
18
28
5
(
5R)-2-methyl-5-(3-{4-[(pyrrolidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}prop-1-en-2-yl)cyclohex-2-en-1-one (4c).
◦
20
1
Yield 73%, m.p. 69–70 C, [α]D
NCH), 6.67 (ddd, J = 5.7, 2.6, 1.3 Hz, 1H, HC=CCO), 5.11 (s, 1H , =CH ), 5.05 (s, 1H , =CH ), 5.02
−
29.6 (C 1.066 DCM). H-NMR (400 MHz, CDCl ) δ 7.47 (s, 1H,
3
a
b
2
2
(
d, J = 15.4 Hz, 1H, H C=C-CH2N), 4.92 (d, J = 15.2 Hz, 1H, H C=C-CH2N), 3.77 (s, 2H, CH2N(CH ) ),
2 2 2 4
2
.64–2.52 (m, 2H, CH C=O, 4H, N(CH2CH ) ), 2.47 (m, 1H, CH in carbocycle), 2.36 (m, 1H, CH in
2 2 2 2
carbocycle), 2.29–2.17 (m, 1H, CH in carbocycle), 1.83–1.76 (m, 4H, N(CH2CH2)2), 1.76–1.71 (m, 3H,
2

Molecules 2018, 23, 2991
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CH ). 13C-NMR (101 MHz, DMSO)
δ
198.6 (C=O), 146.7, 145.2, 143.8, 135.8, 122.2, 115.5, 54.2, 54.0, 51.0,
3
+
+
4
2.8, 38.3, 31.3, 23.6, 15.7. HRMS (ESI) m/z: [M + H] Calcd for C H N O 301.2028, Found 301.2026.
17 25 4
(
5R)-2-methyl-5-(3-{4-[(piperidin-1-yl)methyl]-1H-1,2,3-triazol-1-yl}prop-1-en-2-yl)cyclohex-2-en-1-one (4d).
◦
20
1
Yield 79%, m.p. 80–81 C, [α]D
NCH), 6.67 (ddd, J = 5.8, 2.6, 1.4 Hz, 1H, HC=CCO), 5.12 (s, 1H , H C=), 5.06 (s, 1H , H C=), 5.02
(
−
35.04 (C 1.036 DCM). H-NMR (400 MHz, CDCl ) δ 7.46 (s, 1H,
3
a
b
2
2
a
b
d, J = 15.4 Hz, 1H , H C=C-CH2N), 4.92 (d, J = 15.2 Hz, 1H , H C=C-CH2N), 3.64 (s, 2H, CH2N(CH ) ),
2 2 2 5
2
.65–2.30 (m, 8H, CH2C=O, N(CH2CH ) CH , CH and CH in carbocycle), 2.29–2.16 (m, 1H CH in
2 2 2 2 2
carbocycle), 1.75 (dt, J = 2.3, 1.2 Hz, 3H, CH ), 1.61–1.52 (m, 4H, N(CH2CH ) CH ), 1.46–1.36 (m, 2H,
3
2 2
2
13
N(CH CH ) CH2). C-NMR (75 MHz, DMSO/CCl —1/3) δ 196.4 (C=O), 145.6, 143.8, 142.9, 134.4,
22.7, 113.3, 53.4, 52.5, 42.1, 37.9, 30.4, 25.3, 23.7, 15.1. HRMS (ESI) m/z: [M + H] Calcd for C H N O
2
2 2
4
+
+
1
18
27
4
3
15.2185, Found 315.2182.
(
5R)-2-methyl-5-(3-{4-[(azepan-1-yl)methyl]-1H-1,2,3-triazol-1-yl}prop-1-en-2-yl)cyclohex-2-en-1-one (4e).
◦
20
1
Yield 81%, m.p. 89–90 C, [α]D
6
1
−
21.6 (C 1.000 DCM). H-NMR (400 MHz, CDCl ) δ 7.46 (s, 1H, NCH),
3
a
b
.66 (ddd, J = 5.7, 2.6, 1.4 Hz, 1H, HC=CCO), 5.11 (s, 1H , H C=), 5.05 (s, 1H , H C=), 5.02 (d, J = 15.6 Hz,
2
2
a
b
H , CH =C-CH2N), 4.92 (d, J = 15.2 Hz, 1H , CH =C-CH2N), 3.79 (s, 2H, CH2N(CH ) ), 2.68–2.60
2 2 2 6
(
m, 4H, N(CH2CH CH ) ), 2.60–2.29 (m, 4H, CH and CH in carbocycle), 2.29–2.04 (m, 1H, CH
2 2 2 2 2
13
in carbocycle), 1.74 (dt, J = 2.4, 1.2 Hz, 3H, CH ), 1.68–1.51 (m, 8H, N(CH2CH CH ) ). C-NMR
3
2
2 2
(
2
101 MHz, CDCl3)
δ 198.6 (C=O), 146.9, 145.3, 143.8, 135.8, 122.4, 115.4, 55.6, 54.0, 53.6, 42.8, 38.3, 31.3,
+
+
8.1, 27.0, 15.7. HRMS (ESI) m/z: [M + H] Calcd for C H N O 329.2341, Found 329.2339.
19
29
4
1
-[(1-{2-[(1R)-4-methyl-5-oxocyclohex-3-en-1-yl]prop-2-en-1-yl}-1H-1,2,3-triazol-4-yl)methyl]pyrrolidine-2,5
◦
20
1
-dione (4f). Yield 65%, m.p. 127–128 C, [α]D
−
23.2 (C 1.61 DCM). H-NMR (400 MHz, CDCl )
δ
b
3
a
7
.56 (s, 1H, NCH), 6.68 (ddd, J = 5.6, 2.6, 1.4 Hz, 1H, HC=CCO), 5.13 (s, 1H , H C=), 5.06 (s, 1H ,
2
a
b
H C=), 5.00 (d, J = 15.2 Hz, 1H , CH =C-CH2N), 4.90 (d, J = 15.2 Hz, 1H , CH =C-CH2N), 4.79 (s, 2H,
2
2
2
CH2N-C=O), 2.74 (s, 4H, CH C(O)N), 2.61–2.43 (m, 3H, CH and CH in carbocycle), 2.37–2.18 (m,
2
2
13
2
H, CH and CH in carbocycle), 1.76–1.74 (m, 3H, CH ). C-NMR (101 MHz, CDCl3)
δ
198.5(C=O),
2
3
1
76.7(C=O), 144.9, 143.8, 142.6, 135.8, 123.2, 115.8, 54.1, 42.8, 38.2, 33.8, 31.2, 29.8, 28.3, 15.7. HRMS (ESI)
+
+
m/z: [M + H] Calcd for C H N O 329.1614, Found 329.1610.
17
21
4
3
1
-[(1-{2-[(1R)-4-methyl-5-oxocyclohex-3-en-1-yl]prop-2-en-1-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indole-2,3-
◦
20
1
dione (4g). Yield 63%, m.p. 144–145 C, [α]D
−
23.1 (C 1.6(6) DCM). H-NMR (400 MHz, CDCl ) δ 7.58
3
(
s, 1H, NCH), 7.53–7.44 (m, 2Harom), 7.16 (d, J = 8.3 Hz, 1Harom), 7.02 (t, J = 7.5 Hz, 1Harom), 6.57 (ddd,
a
b
J = 5.7, 2.6, 1.3 Hz, 1H, HC=CCO), 5.03 (s, 1H , H C=), 4.95 (s, 1H , H C=), 4.92 (s, 2H, CH2N-C=O),
4
1
2
2
a
b
.91 (d, J = 15.6 Hz, 1H , CH =C-CH2N), 4.85 (d, J = 15.2 Hz, 1H , CH =C-CH2N), 2.54–2.47 (m,
2
2
a
b
H , CH in carbocycle), 2.47–2.40 (m, 1H , CH in carbocycle), 2.40–2.30 (m, 1H, CH in carbocycle),
2 2
.29–2.19 (m, 1H , CH in carbocycle), 2.19–2.07 (m, 1H , CH in carbocycle), 1.69–1.58 (m, 3H, CH ).
a
b
2
2
2
3
13
C-NMR (101 MHz, CDCl3)
δ
198.4(C=O), 183.1(C=O), 158.0, 150.2, 144.6, 143.7, 142.3, 138.7, 135.7,
+
1
25.4, 124.2, 123.1, 117.6, 115.9, 111.5, 54.1, 42.7, 38.2, 35.5, 31.1, 15.7. HRMS (ESI) m/z: [M + H] Calcd
+
for C H N O 377.1614, Found 377.1609.
18
24
5
3
2
1
-[(1-{2-[(1R)-4-methyl-5-oxocyclohex-3-en-1-yl]prop-2-en-1-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-isoindole-
◦
,3(2H)-dione (4h). Yield 84%, m.p. 132 C, [α] –21.3 (C 1.6(6) DCM). H-NMR (400 MHz, CDCl ) δ
D
3
20
1
7
.93–7.80 (m, 2Harom), 7.80–7.66 (m, 2Harom), 7.59 (s, 1H, NCH), 6.73–6.59 (m, 1H, HC=CCO), 5.11 (s,
a
b
a
1H , H C=), 5.05 (s, 1H , H C=), 5.00 (d, J = 14.6 Hz, 1H , CH =C-CH2N), 4.99 (s, 1H, CH2N-C=O),
2 2 2
b
4
.90 (d, J = 15.2 Hz, 1H , CH =C-CH2N), 2.66-2.51 (m, 2H, CH in carbocycle), 2.47 (m, 1H, CH in
2
2
carbocycle), 2.36 (m, 1H, CH in carbocycle), 2.28–2.12 (m, 1H, CH in carbocycle), 1.82–1.63 (m,
2
2
13
3
1
H). C-NMR (101 MHz, CDCl3)
23.6, 123.0, 115.7, 54.1, 42.7, 38.2, 33.2, 31.2, 15.7. HRMS (ESI) m/z: [M + H] Calcd for C H N O
21 21 4 3
δ
198.6(C=O), 167.8(C=O), 144.9, 143.8, 135.8, 134.5, 134.3, 132.1,
+
+
3
77.1614, Found 377.1609.
(
(
5R)-5-(3-{4-[(1H-benzotriazol-1-yl)methyl]-1H-1,2,3-triazol-1-yl}prop-1-en-2-yl)-2-methylcyclohex-2-en-1-one
◦
20
1
4i). Yield 76%, m.p. 104–105 C, [α]D
−
24.0 (C 1.67 DCM). H-NMR (400 MHz, CDCl ) δ 8.04 (dt,
3

Molecules 2018, 23, 2991
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J = 8.4, 0.9 Hz, 1Harom), 7.68 (dt, J = 8.4, 0.9 Hz, 1Harom), 7.50 (s, J = 3.2 Hz, 1H, NCH), 7.47 (ddd,
J = 8.3, 7.0, 1.0 Hz, 1Harom), 7.39–7.34 (m, 1Harom), 6.62 (ddd, J = 5.6, 2.7, 1.3 Hz, 1H, HC=CCO), 5.97 (s,
a
b
a
2
(
H, CH N), 5.09 (s, 1H , H C=), 5.00 (s, 1H , H C=), 4.96 (d, J = 15.4 Hz, 1H , CH =C-CH2N), 4.88
2 2 2 2
b
d, J = 15.2 Hz, 1H , CH =C-CH2N), 2.59–2.47 (m, 2H, CH in carbocycle), 2.45–2.30 (m, 2H, CH in
2 2 2
carbocycle), 2.30–2.11 (m, 1H, CH in carbocycle), 1.75–1.72 (m, 3H, CH ). C-NMR (101 MHz, CDCl3)
13
2
3
δ
198.3(C=O), 144.6, 143.6, 142.8, 135.8, 127.9, 124.3, 123.0, 120.0, 116.0, 110.1, 54.3, 42.7, 38.2, 31.1, 29.8,
+
+
1
5.7. HRMS (ESI) m/z: [M + H] Calcd for C H N O 349.1777, Found 349.1773.
19 21 6
1
13
The H-NMR and C-NMR for all the synthesized compounds as well as details of fluorescence
experiments and BSA binding are available in Supplementary Material.
4
. Conclusions
Efficient synthesis of 1,2,3-triazolyl conjugates of various amines with carvone was developed.
Chlorination of carvone followed by the reaction with sodium azide open excess to 10-azidocarvone.
Its CuAAC with propargylated amines can be performed as a one-pot procedure to give target products
in up to 84% isolated yield. The prepared conjugates demonstrated high antioxidant activity and
spontaneously undergo hydrophobic reversible interaction with serum albumin.
Supplementary Materials: The H-NMR and 13C-NMR for all the synthesized compounds as well as details of
1
fluorescence experiments and BSA binding are available online.
Author Contributions: Conceptualization, A.S.G., T.V.G. and V.G.N. A.S.G., M.A.S. performed experiments on
the synthesize and assay the data. A.I.M. developed and performed the antioxidant activity experiments. K.R.G.
and A.G.G. developed experiments and analyzed the data and fluorescence spectroscopy.
Funding: This work was supported by the RA MES State Committee of Science and Russian Foundation for Basic
Research (RF) in the frames of the joint research project SCS 18RF-020 and RFBR 18-53-05007 accordingly.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of all the compounds 4a–i are available from the authors.
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