Comparison between Conventional and Nonconventional Methods for the Synthesis of Some 2-Oxazolidinone Derivatives and Preliminary Investigation of Their Inhibitory Activity Against Certain Protein Kinases

Article abstract of DOI:10.1134/S1070428019070248

A series of propargyl and allyl carbamates were prepared directly from propargyl and allyl alcohols and phenyl or cyclohexyl isocyanate or indirectly by generating the isocyanates in situ from the corresponding Cbz-protected amines. The obtained carbamate

Full text of DOI:10.1134/S1070428019070248

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 7, pp. 1061–1069. © Pleiades Publishing, Ltd., 2019.
Comparison between Conventional and Nonconventional
Methods for the Synthesis of Some 2-Oxazolidinone Derivatives
and Preliminary Investigation of Their Inhibitory Activity
Against Certain Protein Kinases
S. Zianea,*, M. M. Mazaria, A. M. Safera, A. Sad El Hachemi Amara, S. Ruchaudb,
B. Baratteb, and S. Bachb
a Université Oran 1 Ahmed Ben Bella, Laboratoire de Synthèse Organique Appliquée, Département de Chimie,
Faculté des sciences exactes et appliquées, Oran, Algeria
*e-mail: saidaz37@yahoo.com
b Station biologique de Roscoff, Roscoff, France
Received January 27, 2019; revised March 23, 2019; accepted May 16, 2019
Abstract—A series of propargyl and allyl carbamates were prepared directly from propargyl and allyl alcohols
and phenyl or cyclohexyl isocyanate or indirectly by generating the isocyanates in situ from the corresponding
Cbz-protected amines. The obtained carbamates underwent intramolecular nucleophilic cyclization in presence
of cesium hydroxide monohydrate as a base catalyst under conventional and ultrasonic irradiation conditions to
give the corresponding substituted 4-(benzylidene)methylidene-2-oxazolidinones in good to excellent yields.
The use of ultrasonic irradiation provided remarkably improved yield of the cyclization products and signif-
icant shortening of the reaction time. In some cases the reaction was highly stereoselective, and (Z)-4-ben-
zylideneoxazolidinones were formed as a single stereoisomer. A series of biological tests were performed to
evaluate the inhibitory potential of all synthesized compounds against some protein kinases.
Keywords: Propargyl carbamates, allyl carbamates, isocyanates, intramolecular cyclization, 3-phenyl-1,3-
oxazolidin-2-ones, ultrasonic activation, protein kinase inhibition.
DOI: 10.1134/S1070428019070248
Oxazolidinones represent an important class of
widely used organic compounds with a wide variety of
applications in many fields, including agriculture
[1, 2], organic synthesis [3–5], and medicinal chem-
istry [6]. Oxazolidinone derivatives have received
significant attention due to their broad spectrum of
biological activities like antimicrobial [7], anti-inflam-
matory [8], antifungal [9], anticonvulsant [10], anti-
tubercular [11], and anticancer [12]. Various methods
are available for the synthesis of methylidene-1,3-
oxazolidin-2-ones, such as base-catalyzed cyclization
of vinyl or propargyl carbamates, and only a limited
number of publications on the synthesis of 4-methyli-
deneoxazolidinones have been reported. In recent
years, the use of ultrasound has become more wide-
spread and has been used more and more frequently in
organic synthesis. The use of ultrasound allows good
dispersion of the reactants into the reaction solution,
thus ensuring optimal interaction between them [13].
In fact, reactions carried out under ultrasonic irradia-
tion often ensure higher yields, better selectivity, and
shorter reaction times in comparison with traditional
stirring methods [14, 15]. In order to extend the ap-
plication scope of ultrasound irradiation in the syn-
thesis of heterocyclic compounds, herein we report the
synthesis of 4-methylidene(benzylidene)oxazolidi-
nones from the corresponding carbamates starting from
internal acetylenic alcohols as potential substrates in
presence of cesium hydroxide monohydrate as a base
catalyst under conventional and ultrasonic irradiation
conditions. A series of biological tests were performed
to evaluate the inhibitory potential of all synthesized
compounds against some protein kinases.
Initially, a number of propargyl and allyl carba-
mates were synthesized according to reported proce-
dures [16–18]. Propargyl alcohols 1a–1j and allyl al-
cohols 2a and 2b reacted with commercially available
phenyl or cyclohexyl isocyanate in THF containing
1061

ZIANE et al.
1062
Scheme 1.
R1
R2
R1
R2
R3
Et3N, solvent, 70°C, 12 h
+
R4NCO
H
R3
O
N
R4
OH
1a–1j
O
3a–3j
O
Et3N, solvent, 70°C, 12 h
Ph
+
PhNCO
R
OH
R
O
N
H
2a, 2b
4a, 4b
1, 3, R1 = H (a, b, j), Ph (c), 4-ClC6H4 (d), 4-O2NC6H4 (e), 4-FC6H4 (f), 4-CNC6H4 (g), 2,4-(MeO)2C6H3 (h), 2-MeOC(O)C6H4 (i);
R2 = R3 = H (a, c–j), Me (b); 3, R4 = Ph (a–i), Cy (j); 2, 4, R = H (a), Me (b).
Scheme 2.
(1) 2-Chloropyridine (3 equiv)
Tf2O (1.5 equiv), CH2Cl2
room temp., 1 h
(2) 1a–1j or 2a, 2b, Et3N (3 equiv)
O
room temp., 1 h
R
3a–3j, 4a, 4b
N
O
Ph
R = Ph, Cy
H
one or two drops of triethylamine under reflux for 12 h
(Scheme 1) to give the corresponding carbamates in
good to excellent yields (76–99%; Table 1). Alter-
natively, the synthesis of carbamates from propargyl
alcohols and Cbz-protected amines at room tempera-
ture with in situ generation of intermediate isocyanates
(Scheme 2) afforded moderate yields, in most cases
due to incomplete conversion of the alcohol. Further-
more, the products required additional purification; the
only exception was the reaction with 3-phenylprop-2-
yn-1-ol (1c) in which the yield was fairly good. The
reaction proceeded quite rapidly (2 h) as compared to
the first procedure.
Table 1. Yields of propargyl and allyl carbamates 3a–3j, 4a,
and 4b and but-3-yn-1-yl phenylcarbamate directly from the
corresponding isocyanates (method a) and from Cbz-pro-
tected amines (method b)
The yields of carbamates 3a, 3b, and 3j (Table 1)
were slightly higher due to the high reactivities of
terminal propargylic alcohols compared to internal
ones [19]. The required internal propargylic alcohols
1c–1i were prepared by the Sonogashira coupling with
the corresponding aryl iodides in the presence of
triethylamine [20, 21]. It may be inferred that the pres-
ence of an electron-donating group in the benzene ring
led to a slight decrease of the yield of carbamates (3d,
3f, 3h). Propargylic alcohols containing an electron-
withdrawing substituent on the benzene were con-
verted into carbamates 5e, 5g, and 5i with relatively
higher yields. Allyl carbamates 4a and 4b were ob-
tained in good yields (82 and 76%, respectively) by
refluxing phenyl isocyanate with allylic alcohols 2a
and 2b for 12 h (Scheme 1). The reaction of Cbz-
protected amines with allylic alcohols in anhydrous
methylene chloride (Scheme 2) provided 66% of 4a
and 63% of 4b. But-3-yn-1-yl phenylcarbamate
derived from homopropargylic alcohol was synthe-
sized with an excellent yield (95%).
Yield, %
Compound no.
method a
99
method b
91
3a
3b
3c
3d
3e
3f
94
80
93
70
90
56
94
63
91
54
3g
3h
3i
93
61
90
50
94
62
3j
88
71
4a
4b
82
66
76
63
But-3-yn-1-yl
phenylcarbamate
95
94
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

COMPARISON BETWEEN CONVENTIONAL AND NONCONVENTIONAL METHODS
1063
Scheme 3.
O
O
R1
Ph
CsOH·H2O (0.1 equiv), DMF, r.t.
(a) 20–120 min (conventional)
(b) ultrasound, 10 s to 26 min
R2
O
O
R3
N
Ph
N
Ph
+
H
R3
87–99% (a); 90–99% (b)
O
N
R2
R1
5a–5h
O
R1
6c, 6g
3a–3i
3, 5, 6, R1 = H (a, b), Ph (c), 4-ClC6H4 (d), 4-O2NC6H4 (e), 4-FC6H4 (f), 4-CNC6H4 (g), 2,4-(MeO)2C6H4 (h);
2-MeOC(O)C6H4 (i); R2 = R3 = H (a, c–i), Me (b).
Intramolecular cyclization of carbamates is a well-
documented method for the synthesis of oxazolidin-2-
one derivatives. Initially, the cyclization of 3-phenyl-
prop-2-yn-1-yl phenylcarbamate (3c) was chosen as
a model reaction (Scheme 3). The effect of various
bases like pyridine, 4-dimethylaminopyrdine (DMAP),
cesium carbonate, lithium hydroxide monohydrate, and
cesium hydroxide monohydrate was thoroughly inves-
tigated, and various solvents were screened. A solution
of carbamate 3c in an appropriate solvent was treated
with 0.1 equiv of a base, and the progress of the
reaction was monitored by TLC. It was found that
inorganic bases such as Cs2CO3 provided the target
product 5c in a moderate yield (68%) as a mixture of
Z and E isomers (reaction time 18 h). In the presence
of LiOH·H2O, the yield of 5c was 82%. Organic bases
such as pyridine and DMAP were found to be inef-
fective. Cesium hydroxide monohydrate proved to be
the most active base catalyst ensuring an excellent
yield of 4-benzylidene-3-phenyloxazolidin-2-one (5c,
up to 93%); the reaction was accompanied by the
formation of isomeric 2,3-dihydrooxazole 6c with the
endocyclic double bond. Furthermore, the reaction
time in the presence of CsOH·H2O (2 h) was 9 times
shorter than in the presence of Cs2CO3 (18 h), and
15 times shorter than in the presence of LiOH·H2O
(30 h). The solvent optimization studies showed that
polar aprotic solvents were the most suitable for the
cyclization. Having optimized the conditions for the
synthesis of 5c, we next investigated the synthesis of
a variety of 4-methylene(benzylidene)oxazolidinones
(Scheme 3, Table 2).
In general, propargyl carbamates 3a–3h were
smoothly converted to the corresponding oxazolidin-2-
ones in very good to excellent yields (Table 2). How-
ever, the cyclization of 3i was an exception, and no
reaction occurred because of its steric hindrances even
under severe conditions (DMF, 90°C, 72 h); the use
of excess CsOH·H2O resulted in the hydrolysis of 3i
to the corresponding amine. Carbamates derived from
terminal propargylic alcohols 3a and 3b underwent
complete cyclization within 30 min to provide the
desired 4-methylidene-3-phenyloxazolidin-2-one (5a)
and 5,5-dimethyl-4-methylidene-3-phenyloxazolidin-
2-one (5b) in 99 and 87% yield, respectively. Carba-
mates 3d and 3f having an electron-donating group on
Table 2. Synthesis of 4-methylidne(benzylidene)oxazolidin-2-ones under conventional and ultrasound irradiation conditions
Reaction time, min
Yield,a % (ratio E-5/Z-5/6)
Compound no.
conventional method
ultrasonic irradiation
conventional method
ultrasonic irradiation
5a
030
030
120
025
020
022
020
028
72 h
10
11
99
99
5b
87
94
5c,b 6c
E-5d, Z-5d
E-5e, Z-5e
E-5f, Z-5f
E-5g, Z-5g, 6g
5h
26
93 (80:20)
92 (58:42:0)
90 (50:50:0)
93 (53:47:0)
92 (41:41:18)
88 (0:100:0)
–
94 (0:100:0)
96 (60:40:0)
92 (53:47:0)
98 (58:42:0)
92 (42:38:20)
90 (0:100:0)
–
06
10 s
04
12 s
12
5i
8 h
a
Yields of isolated products after column chromatography
Isomer mixture, Z/E ratio 60:40.
b
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

ZIANE et al.
1064
the aromatic ring were successfully converted into
Z/E-isomeric oxazolidinones 5d and 5f with excellent
yields (92 and 93%) in 25 and 22 min, respectively.
The Z and E isomers of all compounds 5 were sepa-
rated and isolated in the pure state; they were iden-
tified by the presence of the olefinic C=CH proton
signal as a triplet at δ 4.04–5.70 ppm in the case of the
Z isomers and as a singlet in the case of the E isomers.
Protons of the two methyl protons on C5 resonated as
a doublet. Carbamates 3e and 3g bearing an electron-
withdrawing group reacted slightly faster (in 20 min),
but no stereoselectivity was observed, and the desired
Z/E-oxazolidinones were obtained in excellent yields
(90 and 92%, respectively) after column chromatog-
raphy. In the cyclization of 3g, we isolated isomer 6g
with the endocyclic double bond as a minor product in
18% yield. 3-(2,4-Dimethoxyphenyl)prop-2-yn-1-yl
phenylcarbamate 3h yielded the corresponding oxa-
zolidinone 5h with a very good conversion (88%) and
exclusive formation of the Z isomer.
irradiation conditions, and the Z isomer of 5c was
obtained as a single stereoisomer in 94% yield. The
reaction time decreased down to 10 and 12 s for car-
bamates 3e and 3g, respectively. We also noticed
a slight increase in selectivity toward the more stable E
isomer. Our efforts to accomplish the cyclization of
but-3-yn-1-yl phenylcarbamate were unsuccessful. All
isolated compounds were characterized by physical
and spectral data, as well as by comparison with
authentic samples.
Tyrosine kinase inhibitors belong to a new thera-
peutic family called “targeted therapy” [22, 23]. Thus
targeted therapies have a greater specificity of action
toward tumor cells and allow obtaining broader thera-
peutic indexes and, consequently, less toxicity. Indeed,
there are several approaches to targeted therapy,
including monoclonal antibodies and tyrosine and
serine–threonine kinase inhibitors. In this work, we
have been particularly interested in the second ap-
proach (tyrosine kinase inhibitors). We conducted
a series of biological tests to evaluate the inhibitory
potential of all synthesized compounds toward CMGC
group kinases like cyclin-dependent kinases
Hs_CDK2/CyclinA, Hs_CDK5/p25, Hs_CDK9/
CyclinT, Hs_PIM1, Hs_HASPIN, CDK-like kinases
(Mm_CLK1), dual-specificity tyrosine phosphoryla-
The cyclization of carbamates 3a–3i was also
accomplished under ultrasonic (US) irradiation, other
conditions being equal. In all cases, the reaction was
complete in a shorter time. For example, the cycliza-
tion time of 3c was reduced significantly from 120 min
under conventional method to 26 min under US
Table 3. Inhibitory activity (% inhibition) of the synthesized compounds against some protein kinases at a concentration
of 10 mM
CDK2/
CyclinA
CDK9/
CyclinT
Comp. no.
CDK5/p26
GSK3β
PIM1
HASPIN
CLK1
DYRK1A
3a
07
00
08
00
10
00
00
00
36
00
02
00
00
37
00
00
03
00
00
00
16
00
00
00
00
05
12
01
00
00
05
40
09
07
09
06
17
44
29
28
31
23
21
22
11
29
40
30
30
20
31
18
30
00
06
75
19
24
19
49
16
41
11
35
38
40
31
36
03
24
69
49
15
00
00
00
00
40
00
00
07
00
15
32
12
18
00
10
21
36
00
31
09
23
00
13
16
22
00
18
36
16
35
27
13
05
46
13
00
58
00
02
05
43
00
00
04
05
18
08
00
00
00
00
12
11
09
61
06
00
06
43
04
02
00
01
05
02
00
00
00
00
07
18
3c
3d
3e
3j
3i
3g
4b
Z-5c
6c
E-5d
Z-5d
E-5e
Z-5e
E-5g
Z-5g
6g
Z-5h
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

COMPARISON BETWEEN CONVENTIONAL AND NONCONVENTIONAL METHODS
1065
Table 4. IC50 values (μM) of carbamate 3c and 4-benzyl-3-
phenyl-1,3-oxazol-2(3H)-one 6g against GSK3β and PIM1
protein kinases
tion-regulated kinase 1A(Hs_ DYRK1A), and glyco-
gen synthase kinase (GSK3β).
Initially, the synthesized compounds were tested at
a final concentration of 10 μM, and those exhibiting
less than 50% inhibition at 10 μM were considered to
be inactive. The results given in Table 3 showed that
only two compounds have an inhibitory activity
greater than 50%, namely carbamate 3c toward
GSK3β, CLK1, and DYRK1A and dihydrooxazole 6g
toward GSK3β. Subsequently, the IC50 values of these
two compounds were determined from the dose–
response curves using Sigma Plot software (Table 4).
IC50, μM
Gini coeffi-
Comp. no.
cient
Hs_GSK3β
Hs_PIM1
3c
6g
9.19
3.30
>10
>10
0.473
0.463
tively. The IR spectra were measured from thin films
for liquids and from KBr pellets for solids. Ultrasound-
assisted reactions were performed using a T660/H
ultrasonic tank with a frequency of 35 kHz. The high-
resolution mass spectra were obtained using a Waters
Q/Tof Premier micro mass HAB 213 spectrometer
with an ESI source. The melting points were measured
on a Kofler hot stage.
The IC50 values are in the micromolar range for
4-benzyl-3-phenyloxazol-2(3H)-one (6g, 3.3 μM)
toward GSK3β and greater than 10 μM toward PIM1
which gives a selectivity coefficient of 0.463 (Gini
coefficient [24] which allows objective ranking of
compounds in terms of their overall selectivity at
a pharmacologically relevant concentration). Carba-
mate 3c is less active toward GSK3β (IC50 = 9.19) and
almost inactive toward PIM1, and it has been shown to
be a little more selective (Gini coefficient 0.473). We
remind that nonselective inhibitors are characterized
by Gini values close to zero and that highly selective
compounds exhibit Gini values close to 1.
Initial benzyl phenylcarbamate and benzyl cyclo-
hexylcarbamate were synthesized according to the
procedure described in [25].
General procedures for the preparation of car-
bamates. a. Phenyl or cyclohexyl isocyanate
(1.1 mmol) was added to a solution of alcohol 1a–1j,
2a, or 2b (1 mmol) in anhydrous THF under a nitrogen
atmosphere, and one or two drops of triethylamine
were introduced via a syringe. The resulting homo-
geneous mixture was refluxed for 12 h. The mixture
was cooled and extracted with methylene chloride
(3×15 mL), the combined extracts were dried over
Na2SO4 and evaporated under reduced pressure, and
the residue was purified by flash column chromatog-
raphy using ethyl acetate–hexane (2:8) as eluent.
In conclusion, a number of propargyl and allyl car-
bamates have been synthesized and shown to readily
undergo intramolecular nucleophilic cyclization in the
presence of cesium hydroxide monohydrate as a base
catalyst under conventional and ultrasonic irradiation
conditions to give the corresponding substituted
4-methylene(benzylidene)oxazolidin-2-ones. Ultra-
sonic irradiation provides a remarkable improvement
in the yield of the cyclization products and significant
shortening of the reaction times in comparison to the
conventional method. The reaction was highly stereo-
selective in some cases to afford Z-isomeric oxazolidi-
nones as a single stereoisomer. Furthermore, the two
Gini indices for carbamate 3c and 4-benzyl-3-phenyl-
oxazol-2(3H)-one (6g) indicated their moderate kinase
selectivity representing an encouraging start-point for
further optimization.
b. Benzyl phenylcarbamate or benzyl cyclohexyl-
carbamate (1.0 mmol) and 2-chloropyridine
(3.0 mmol) were dissolved in anhydrous methylene
chloride (4 mL), and trifluoromethanesulfonic anhy-
dride (1.5 mmol) was added dropwise over a period of
5 min. The mixture was stirred for 1 h at room tem-
perature, alcohol 1a–1j, 2a, or 2b (3.0 mmol) was
added, and triethylamine (3.0 mmol) was then added.
The mixture was stirred until the reaction was com-
plete and diluted with methylene chloride, and the
organic layer was washed with brine and water, dried
over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chroma-
tography using ethyl acetate–hexane (1:9) as eluent.
EXPERIMENTAL
All chemicals were purchased commercially and
were used without further purification. Anhydrous sol-
vents were used for the reactions. Merck silica gel (60–
120 and 100-200 mesh) was used for column chroma-
3-(4-Chlorophenyl)prop-2-yn-1-yl phenylcarba-
mate (3d). Yield 90 (a), 56% (b); yellow solid,
mp 144–147°C. IR spectrum, ν, cm–1: 3307 (N–H),
1
tography. The H and 13C NMR spectra were recorded
1
1696 (C=O). H NMR spectrum, δ, ppm: 7.34–7.40 m
on a Jeol spectrometer at 400 and 100 MHz, respec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

ZIANE et al.
1066
(4H, Harom), 7.25–7.33 m (4H, Harom), 7.05–7.12 t (1H,
104.02, 98.59, 85.78, 83.32, 56.03, 55.68, 54.13. Mass
spectrum, m/z: 329.1502 [M + NH4]+, 334.1059
[M + Na]+. Calculated: M + NH4 329.1358, M + Na
334.1156.
H
arom, J = 7.07 Hz), 6.82 s (1H, NH), 4.99 s (1H, CH2).
13C NMR spectrum, δC, ppm: 152.82, 137.68, 135.33,
133.36, 129.35, 128.92, 124.04, 120.81, 119.02, 85.85,
84.34, 53.69. Mass spectrum, m/z (Irel, %): 303.0906
(100) [M + NH4]+, 308.0451 (18) [M + Na]+.
Methyl 2-[3-(phenylcarbamoyloxy)prop-2-yn-1-
yl]benzoate (3i). Yield 94 (a), 62% (b); pale greenish
solid, mp 60–62°C. IR spectrum, ν, cm–1: 3331 (N–H),
1716 (C=O). 1H NMR spectrum, δ, ppm: 7.95–7.93 d.d
(1H, Harom, J = 7.83, 1.29 Hz), 7.57–7.55 d.d (1H,
3-(4-Nitrophenyl)prop-2-yn-1-yl phenylcarba-
mate (3e). Yield 94 (a), 63% (b); white solid, mp 153–
155°C. IR spectrum, ν, cm–1: 3339 (N–H), 1705
1
Harom, J = 7.65, 0.96 Hz), 7.46–7.35 m (4H, Harom),
(C=O). H NMR spectrum, δ, ppm: 8.20–8.16 m (2H,
7.32–7.28 t (2H, Harom, J = 8.47 Hz), 7.08–7.05 t (1H,
Harom), 7.60–7.58 m (2H, Harom), 7.42–7.40 d (2H,
H
arom, J = 7.55 Hz), 6.98 s (1H, NH), 5.06 s (2H, CH2),
H
arom, J = 7.41 Hz), 7.34–7.30 t (2H, Harom, J =
3.90 s (3H, CH3). 13C NMR spectrum, δC, ppm:
167.08, 152.82 ,137.73, 134.07, 132.08, 131.74,
130.46, 129.14, 128.48, 123.73, 122.78, 118.87, 88.26,
85.30, 53.78, 52.31. Mass spectrum, m/z (Irel, %):
310.1087 (100) [M + H]+, 332.0902 (79.5) [M + Na]+.
7.32 Hz), 7.12–7.08 t (1H, Harom, J = 7.10 Hz), 6.80 s
(1H, NH), 5.04 s (2H, CH2). 13C NMR spectrum, δC,
ppm: 151.29, 146.25, 136.17, 131.45, 127.98, 127.76,
122.75, 122.39, 117.63, 87.30, 83.38, 51.96. Mass
spectrum, m/z (Irel, %): 297.0892 (45) [M + H]+,
314.1142 (100) [M + NH4]+, 319.0713 (18) [M + Na]+.
Prop-2-yn-1-yl cyclohexylcarbamate (3j). Yield
88 (a), 71% (b); yellow solid, mp 69–61°C. IR spec-
3-(4-Fluorophenyl)prop-2-yn-1-yl phenylcarba-
mate (3f). Yield 91 (a), 54% (b); yellow solid,
mp 119–121°C. IR spectrum, ν, cm–1: 3319 (N–H),
trum, ν, cm–1: 3284 (N–H), 1704 (C=O). H NMR
1
spectrum, δ, ppm: 4.71 s (1H), 4.67 d (1H, J =
2.25 Hz), 3.56–3.45 m (1H), 2.48–2.63 t (1H, J =
2.27 Hz), 1.96–1.91 m (2H), 1.73–1.57 m (3H), 1.42–
1.11 m (5H). 13C NMR spectrum, δC, ppm: 154.53,
78.36, 74.49, 52.05, 50.02, 33.31, 25.58, 24.74.
1
1698 (C=O). H NMR spectrum, δ, ppm: 7.46–7.39 m
(4H, Harom), 7.33–7.29 m (2H, Harom), 7.10–7.04 m
(1H, Harom), 7.03–6.97 m (2H, Harom), 6.78 s (1H, NH),
5.00 s (2H, CH2). 13C NMR spectrum, δC, ppm:
164.23, 161.44, 152.68, 137.55, 133.93, 129.20,
123.87, 118.85, 116.00, 85.68, 82.84, 53.59. Mass
spectrum, m/z (Irel %): 241.1452 (100) [M – CO]+,
287.1211 (12) [M + NH4]+, 292.0757 (72) [M + Na]+.
But-2-en-1-yl phenylcarbamate (4a). Yield 76
(a), 63% (b); white solid, mp 78–80°C. IR spectrum, ν,
cm–1: 3301 (N–H), 1721 (C=O). 1H NMR spectrum, δ,
ppm: 7.42–7.39 d (2H, Harom, J = 8.52 Hz), 7.11–
7.05 m (1H, Harom), 6.72 s (1H, NH), 5.93–5.82 m and
5.72–5.61 m (1H each, CH=CH), 4.64–4.61 d.t (2H,
CH2, J = 6.46, 1.00 Hz), 1.78–1.75 m (3H, CH3).
13C NMR spectrum, δC, ppm: 153.45, 137.93, 131.59,
125.22, 123.42, 118.74, 66.00, 17.89. Mass spectrum:
m/z 192.0946 [M + NH4]+. C11H17N2O2. Calculated:
M + NH4 192.0988.
3-(4-Cyanophenyl)prop-2-yn-1-yl phenylcarba-
mate (3g). Yield 93 (a), 61% (b); white solid,
mp 138–140°C. IR spectrum, ν, cm–1: 3325 (N–H),
1
1705 (C=O). H NMR spectrum, δ, ppm: 7.53–7.51 m
(2H, Harom), 7.45–7.43 m (2H, Harom), 7.34–7.32 d
(2H, Harom, J = 7.93 Hz), 7.33–7.25 t (1H, Harom, J =
7.35 Hz), 6.82 s (1H, NH), 4.96 s (1H, CH2). 13C NMR
spectrum, δC, ppm: 151.45, 136.35, 131.34, 131.01,
128.12, 125.99, 122.88, 117.78, 117.27, 111.17, 86.62,
83.77, 52.14. Mass spectrum, m/z (Irel, %): 294.1244
(64) [M + NH4]+, 299.0798 (88) [M + Na]+, 575.1694
(100) [2M + Na]+.
General procedure for the cyclization of carba-
mates 3a–3h. a. Conventional method. Cesium hy-
droxide monohydrate (0.1 mmol) was added to a solu-
tion of carbamate 3a–3h (1 mmol) in DMF (2 mL),
and the mixture was stirred at room temperature until
the initial compound disappeared. The mixture was
diluted with water (20 mL) and extracted with
methylene chloride (3×10 mL), the combined organic
extracts were dried over anhydrous Na2SO4 and
evaporated, and the residue was purified by column
chromatography.
3-(2,4-Dimethoxyphenyl)prop-2-yn-1-yl phenyl-
carbamate (3h). Yield 90 (a), 50% (b); pale yellow
solid, mp 163–165°C. IR spectrum, ν, cm–1: 3301
1
(N–H), 1699 (C=O). H NMR spectrum, δ, ppm:
7.40–7.26 m (5H, Harom), 7.09–7.05 t (1H, Harom, J =
7.02 Hz), 6.74 s (1H, NH), 6.45–6.43 d (2H, Harom, J =
10.43 Hz), 5.05 s (2H, CH2), 3.85–3.81 (6H, OCH3).
13C NMR spectrum, δC, ppm: 161.86, 161.79, 152.19,
137.68, 134.98, 129.31, 123.86, 118.94, 105.04,
b. Ultrasonic irradiation method. Carbamate 3a–3h
(1 mmol) was dissolved in DMF (2 mL), CsOH·H2O
(0.1 mmol) was added to the solution, and the resulting
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COMPARISON BETWEEN CONVENTIONAL AND NONCONVENTIONAL METHODS
1067
mixture was irradiated for an appropriate time (TLC).
The mixture was diluted with water (20 mL) and
extracted with methylene chloride (3×10 mL). The
combined organic extracts were dried over anhydrous
Na2SO4 and filtered, the filtrate was rotary evaporated,
and the crude product was purified by column chro-
matography using ethyl acetate–hexane (1:9 for 5a–5g
and 2:8 for 5h).
Harom), 6.55–6.53 m (2H, Harom), 5.60 s (1H, =CH),
5.12 d (2H, CH2, J = 1.96 Hz). 13C NMR spectrum, δC,
ppm: 155.57, 137.89, 133.88, 133.67, 131.91, 130.19,
129.22, 129.18, 128.43, 122.91, 100.53, 67.44. Mass
spectrum, m/z (Irel, %): 286.0635 (100) [M + H]+,
308.0467 (49) [M + Na]+.
(Z)-4-(4-Chlorobenzylidene)-3-phenyl-1,3-oxazo-
lidin-2-one (Z-5d). Yield 42 (a), 40% (b); yellow
solid, mp 131–133°C. IR spectrum, ν, cm–1: 1770
(C=O), 1661 (C=C). 1H NMR spectrum, δ, ppm: 7.57–
7.54 m (2H, Harom), 7.49–7.47 m (1H, Harom), 7.41–
7.38 d.t (2H, Harom, J = 2.53, 8.59 Hz), 7.30–7.27 d.t
4-Benzylidene-3-phenyl-1,3-oxazolidin-2-one (5c,
E/Z). Yield 80% (a), yellow solid, mp 114–116°C. IR
1
spectrum, ν, cm–1: 1771 (C=O), 1669 (C=C). H NMR
spectrum, δ, ppm: 7.55–7.38 m (6H, Harom), 7.32–
7.28 t (2H, Harom, J = 7.71 Hz), 7.18–7.14 t (2H, Harom
,
(2H, Harom, J = 2.54, 4.41 Hz), 6.93–6.89 t (2H, Harom,
J = 7.41 Hz), 7.06–6.62 m (10H, Harom), 5.69 s (E) and
5.64–5.62 t (Z, J = 2.49 Hz) (1H, =CH), 5.37 d
(J = 2.49 Hz) and 5.14 d (J = 2.10 Hz) (2H, CH2).
13C NMR spectrum, δC, ppm: 157.20, 155.70, 137.11,
135.14, 134.82, 133.71, 132.51, 129.99, 128.94,
128.42, 128.37, 127.76, 127.22, 127.16, 126.25,
126.13, 125.93, 101.74, 100.07, 68.26, 67.46. Mass
spectrum, m/z (Irel, %): 252.1026 (100) [M + H]+,
253.1026 (18) [M + 2H]+.
J = 2.66 Hz), 5.60 t (1H, =CH, J = 2.55 Hz), 5.36 d
(2H, CH2, J = 2.42 Hz), 13C NMR spectrum, δC, ppm:
157.01, 134.68, 133.30, 131.74, 131.58, 129.55,
128.63, 127.60, 127.30, 126.21, 98.72, 68.20. Mass
spectrum, m/z (Irel, %): 286.0638 (100) [M + H]+,
287.0638 (18) [M + 2H]+.
(E)-4-(4-Nitrobenzylidene)-3-phenyl-1,3-oxazo-
lidin-2-one (E-5e). Yield 50 (a), 53% (b); yellow
solid, mp 179–181°C. IR spectrum, ν, cm–1: 1778
(C=O), 1674 (C=C). 1H NMR spectrum, δ, ppm: 7.72–
7.70 d (2H, Harom, J = 8.7 Hz), 7.13–7.11 m (3H,
(Z)-4-Benzylidene-3-phenyl-1,3-oxazolidin-2-one
(Z-5c). Yield 94% (b), pale yellow solid, mp 169–
161°C. IR spectrum, ν, cm–1: 1770 (C=O), 1655
H
H
arom), 7.04–7.01 m (2H, Harom), 6.79–6.77 d (2H,
1
(C=C). H NMR spectrum, δ, ppm: 7.58–7.53 m (2H,
arom, J = 8.62 Hz), 5.70 s (1H, =CH), 5.20 d (2H,
H
H
arom), 7.48–7.39 m (3H, Harom), 7.34–7.29 t (2H,
arom, J = 7.56 Hz), 7.20–7.15 t (1H, Harom, J =
CH2, J = 1.91 Hz). 13C NMR spectrum, δC, ppm:
156.66, 145.56, 140.23, 136.09, 134.62, 128.94,
128.83, 128.11, 126.21, 122.37, 97.48, 68.22. Mass
spectrum, m/z (Irel, %): 314.1144 (100) [M + NH4]+,
319.0706 (56) [M + Na]+.
8.06 Hz), 7.00–6.97 m (2H, Harom), 5.66–5.64 t (1H,
=CH, J = 2.56 Hz), 5.39 d (2H, CH2, J = 2.56 Hz).
13C NMR spectrum, δC, ppm: 155.56, 136.83, 135.07,
133.53, 129.95, 128.89, 127.62, 127.12, 126.08,
101.71, 67.62. Mass spectrum, m/z (Irel, %): 269.1303
(16.5) [M + NH4]+, 274.0864 (54) [M + Na]+, 297.1624
(100) [M + 2Na]+.
(Z)-4-(4-Nitrobenzylidene)-3-phenyl-1,3-oxazo-
lidin-2-one (Z-5e). Yield 50 (a), 47% (b); yellow
solid, mp 198–200°C. IR spectrum, ν, cm–1: 1782
(C=O), 1656 (C=C). 1H NMR spectrum, δ, ppm: 8.17–
8.15 m (2H, Harom), 7.59–7.55 m (2H, Harom), 7.51–
7.47 m (1H, Harom), 7.39–7.37 m (2H, Harom), 7.08–
7.05 m (2H, Harom), 5.68–5.66 t (1H, =CH, J =
2.55 Hz), 5.44 d (2H, CH2, J = 2.40 Hz). 13C NMR
spectrum, δC, ppm: 155.37, 145.27, 142.44, 141.42,
133.08, 130.05, 129.50, 127.73, 127.51, 124.41, 99.91,
67.39. Mass spectrum, m/z (Irel, %): 297.0895 (19)
[M + H]+, 314.1149 (100) [M + NH4]+.
4-Benzyl-3-phenyl-1,3-oxazol-2(3H)-one (6c).
Yield 20% (a), pale yellow solid, mp 64–66°C. IR
1
spectrum, ν, cm–1: 1750 (C=O), 1598 (C=C). H NMR
spectrum, δ, ppm: 7.41–7.39 m (3H, Harom), 7.24–
7.18 m (5H, Harom), 7.02–7.00 m (2H, Harom), 6.56 t
(1H, 5-H, J = 1.36 Hz), 3.55 s (2H, 4-CH2). 13C NMR
spectrum, δC, ppm: 155.20, 134.92, 134.02, 133.40,
129.56, 128.84, 128.73, 128.69, 128.58, 127.51,
127.24, 125.06, 30.48. Mass spectrum, m/z (Irel, %):
252.1024 (100) [M + H]+, 274.0862 (11) [M + Na]+.
(E)-4-(4-Fluorobenzylidene)-3-phenyl-1,3-oxazo-
lidin-2-one (E-5f). Yield 53 (a), 58% (b); white solid,
mp 109-111°C. IR spectrum, ν, cm–1: 1779 (C=O),
(E)-4-(4-Chlorobenzylidene)-3-phenyl-1,3-oxazo-
lidin-2-one (E-5d). Yield 58 (a), 60% (b); white solid,
mp 94–96°C. IR spectrum, ν, cm–1: 1779 (C=O), 1681
1
1681 (C=C). H NMR spectrum, δ, ppm: 7.11–7.08 m
(3H, Harom), 7.03–6.98 m (2H, Harom), 6.63–6.53 m
(4H, Harom), 5.65 s (1H, =CH), 5.15 d (2H, CH2, J =
2.17 Hz). 13C NMR spectrum (CDCl3), δC, ppm:
1
(C=C). H NMR spectrum, δ, ppm: 7.12–7.09 m (3H,
H
arom), 7.01–6.97 m (2H, Harom), 6.81–6.80 m (2H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

ZIANE et al.
1068
162.36, 159.93, 155.63, 133.62, 130.02, 128.99,
128.67, 128.59, 127.72, 115.75, 100.81, 67.16. Mass
spectrum, m/z (Irel, %): 270.0935 (100) [M + H]+,
271.0980 (23) [M + 2H]+.
(Z)-4-(2,4-Dimethoxybenzylidene)-3-phenyl-1,3-
oxazolidin-2-one (5h). Yield 88 (a), 90% (b), white
solid, mp 111–113°C. IR spectrum, ν, cm–1: 1771
(C=O), 1685 (C=C). 1H NMR spectrum, δ, ppm: 7.26–
6.94 m (5H, Harom), 6.37–6.34 d (1H, Harom, J =
8.44 Hz), 6.09 d (1H, Harom, J = 2.38 Hz), 5.95–
5.91 d.d (2H, Harom, J = 2.38, 8.44 Hz), 5.60 t (1H,
=CH, J = 2.33 Hz), 5.17 d (2H, CH2, J = 2.19 Hz),
3.66–3.64 (6H, OCH3). 13C NMR spectrum, δC, ppm:
159.77, 157.42, 156.92, 134.59, 132.13, 130.42,
127.89, 126.96, 125.85, 114.89, 103.43, 97.50, 95.49,
68.31, 55.41, 55.14. Mass spectrum, m/z (Irel, %):
312.1239 (100) [M + H]+, 234.1063 (13.5) [M + Na]+.
(Z)-4-(4-Fluorobenzylidene)-3-phenyl-1,3-oxazo-
lidin-2-one (Z-5f). Yield 47 (a), 42% (b); white solid,
mp 129–131°C. IR spectrum, ν, cm–1: 1774 (C=O),
1
1674 (C=C). H NMR spectrum, δ, ppm: 7.56–7.52 m
(2H, Harom), 7.48–7.45 m (1H, Harom), 7.40–7.39 m
(2H, Harom), 7.04–6.95 m (4H, Harom), 5.62–5.60 t (1H,
=CH, J = 2.67 Hz), 5.35 d (2H, CH2, J = 2.66).
13C NMR spectrum, δC, ppm: 162.34, 159.83, 157.06,
132.72, 132.64, 129.84, 128.56, 127.57, 126.06,
114.07, 98.90, 68.28. Mass spectrum, m/z (Irel, %):
241.1452 (100) [M – CO]+, 292.0757 (72.5) [M + Na]+.
Kinase preparations and assays. Kinase activities
were assayed in buffer A (10 mM MgCl2, 1 mM
EGTA, 1 mM DTT, 25 mM Tris–HCl, pH 7.5,
50 μg/mL heparin, 30°C) at a final ATP concentration
of 15 μM. Blank values were subtracted and the activ-
ities were expressed in percent of the maximal activity,
i.e., in the absence of inhibitors. Controls were
performed with appropriate dilutions of DMSO.
The kinase peptide substrates were obtained from
Proteogenix (Oberhausbergen, France).
(E)-4-[(2-Oxo-3-phenyl-1,3-oxazolidin-4-
ylidene)methyl]benzonitrile (E-5g). Yield 41 (a),
42% (b); yellow solid, mp 128–130°C. IR spectrum, ν,
cm–1: 1781 (C=O), 1673 (C=C). 1H NMR spectrum, δ,
ppm: 7.15–7.09 m (5H, Harom), 7.01–6.99 m (2H,
H
arom), 6.74–6.72 d (2H, Harom, J = 8.22 Hz), 5.67 s
(1H, =CH), 5.18 d (2H, CH2, J = 2.12 Hz). 13C NMR
spectrum, δC, ppm: 156.52, 138.11, 135.21, 134.45,
132.66, 130.68, 128.83, 128.00, 126.19, 119.21,
109.08, 97.89, 68.17. Mass spectrum, m/z (Irel, %):
277.0977 (100) [M + H]+, 294.1234 (24.8)
[M + NH4]+, 299.0812 (13) [M + Na]+.
The protein kinase DYRK1A (rat recombinant,
expressed in Escherichia coli as a GST fusion
proteins) was purified by affinity chromatography on
glutathione-agarose and assayed in buffer A
(+0.15 mg/mL BSA) using Woodtide synthetic protein
(KKISGRLSPIMTEQ, 1.5 mg per assay) as a substrate
in the presence of 15 mM [g-33P] ATP (3000 Ci×
mmol–1; 10 mCi/mL) in a final volume of 30 mL. After
incubation for 30 min at 30°C, the reaction was
stopped by harvesting onto P81 phosphocellulose
paper (Whatman) using a Filter Mate harvester
(Packard), and samples were washed with 1% phos-
phoric acid. Scintillation fluid was added, and the
radioactivity was measured in a Packard counter.
CLK1 kinase (mouse recombinant, expressed in E. coli
as GST fusion proteins) was assayed in buffer A
(+ 0 . 1 5 m g / m L B S A ) w i t h R S p e p t i d e
(GRSRSRSRSRSR) (1 mg per assay). GSK-3α/β was
prepared as described previously [26]. CDK5/p25
(human recombinant) was prepared as described in
[27], and the kinase activity was assayed in buffer C
[10 mM MgCl2, 1 mM ethylene glycol bis(2-amino-
ethyl) ether-N,N,N′,N′-tetraacetic acid (EGTA),
1 mM dithiothreitol (DTT), 25 mM Tris–HCl pH 7.5,
50 μg/mL heparin), with 1 mg/mL histone H1. Haspin
kinase domain (HsHaspin-kdaa 470 to 798) encoding
cDNA obtained by RT-PCR was cloned into pGex-
(Z)-4-[(2-Oxo-3-phenyl-1,3-oxazolidin-4-
ylidene)methyl]benzonitrile (Z-5g). Yield 41 (a),
38% (b); pale orange solid, mp 181–183°C. IR spec-
1
trum, ν, cm–1: 1760 (C=O), 1655 (C=C). H NMR
spectrum, δ, ppm: 7.59–7.55 t (4H, Harom, J = 8.06 Hz),
7.51–7.47 m (1H, Harom), 7.39 d (2H, Harom, J =
8.37 Hz), 5.63 t (1H, =CH, J = 2.38 Hz), 5.18 d
(2H, CH2, J = 2.41 Hz). 13C NMR spectrum, δC, ppm:
155.02, 140.20, 139.89, 132.99, 132.51, 129.93,
127.49, 127.21, 118.68, 108.90, 99.92, 67.14, 68.17.
Mass spectrum, m/z (Irel, %): 277.0982 (74) [M + H]+,
294.1255 (50) [M + NH4]+, 299.0799 (100) [M + Na]+.
4-[(2-Oxo-3-phenyl-2,3-dihydro-1,3-oxazol-4-yl)-
methyl]benzonitrile (6g). Yield 18 (a), 20% (b);
orange solid, mp 73–75°C. IR spectrum, ν, cm–1: 1755
(C=O), 1597 (C=C). 1H NMR spectrum, δ, ppm: 7.51–
7.49 d (2H, Harom, J = 8.25 Hz), 7.40 m (3H, Harom),
7.13–7.10 m (2H, Harom), 7.08 d (2H, Harom, J =
8.08 Hz), 6.68 t (1H, 5-H, J = 1.34 Hz), 3.65 s (2H,
4-CH2). 13C NMR spectrum, δC, ppm: 154.97, 140.20,
132.42, 129.72, 129.45, 129.14, 127.44, 118.52,
111.32, 30.45. Mass spectrum, m/z (Irel, %): 277.0982
(100) [M + H]+, 299.0800 (32) [M + Na]+.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

COMPARISON BETWEEN CONVENTIONAL AND NONCONVENTIONAL METHODS
1069
7. Kuo, H.C., Ayer, M.B., Chakravarty, P.K.,
Meinke, P.T., Parsons, W.H., and Tyagarajan, S., US
Patent no. 7348348 B2, 2008.
8. Welstead, W.J., Helsley, G.C., Taylor, C.R., Turn-
bull, L.B., Da Vanzo, J.P., Funderburk, W.H., and
Alphin, R.S., J. Med. Chem., 1973, vol. 16, p. 1129.
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Sternberg, C.G., Campbell, C.L., and Moberg, W.K.,
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and Rethish, B., Eur. J. Med. Chem., 2009, vol. 44,
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11. Vera-Cabrera, L., Gonzalez, E., Rendon, A., Ocampo-
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6P-3. The fusion protein was expressed in Escherichia
coli strain BL21-KRX (Promega, Madison, WI, USA)
and purified by affinity chromatography on gluta-
thione-agarose beads (Sigma). CDK2/CyclinA activity
was assayed with 3 μM Histone H3 (1-21) peptide,
a specific Haspin substrate, (ARTKQTARKS
TGGKAPRKQLA), in buffer E (25 mM MOPS,
pH 7.5, 10 mM MgCl2). CDK9/CyclinT (human,
recombinant) was prepared as described in [27]; its
kinase activity was assayed in buffer B (50 mM
MgCl2, 90 mM NaCl, 30 mM Tris-HCl, pH 7.4) and
buffer D (25 mM MOPS, pH 7.2, 12.5 mM β-glycero-
phosphate, 25 mM MgCl2, 5 mM EGTA, 2 mM
EDTA, 0.25 mM DTT) with 1 mg/mL histone H1.
HsPIM1 (human proto-oncogene, recombinant, ex-
pressed in bacteria) was assayed in buffer B with
0.8 μg/μL of histone H1 (Sigma) as substrate.
FUNDING
13. Ambulgekar, G.V., Samant, S.D., and Pandit, A.B.,
Ultrason. Sonochem., 2005, vol. 12, p. 85.
This study was performed under financial support
by the Ministry of Higher Education and Scientific
Research of Algeria (grant no. 571/PNE/Doctorant/
India/2016-2017).
14. Jadhav, S.A., Sarkate, A.P., Farooqui, M., and
Shinde, D.B., Synth. Commun., 2017, vol. 47, p. 1676.
15. Xu, H., Liao, W.M., and Li, H.F., Ultrason. Sonochem.,
2007, vol. 14, p. 779.
16. Shachat, N. and Bagnell, J.J., J. Org. Chem., 1963,
vol. 28, p. 991.
ACKNOWELEDGMENTS
17. Kim, H.-K. and Lee, A., Org. Biomol. Chem., 2016,
vol. 14, p. 7345.
18. Newton, R. and Savage, G., Aust. J. Chem., 2008,
The authors are grateful to Prof. Dr. Ramesh
Ramapanicker (Indian Institute of Technology,
Kanpur, India) for providing laboratory facilities.
vol. 61, p. 432.
19. Jiang, H.-F. and Zhao, J.W., Tetrahedron Lett., 2009,
vol. 50, p. 60.
CONFLICT OF INTERESTS
No conflict of interests is declared by the authors.
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