Practical Deoxygenation of Oxazole N-Oxides by PCl 3/Collidine

Article abstract of DOI:10.1055/s-0037-1610278

A new chemoselective method for the synthesis of 2-aryl-1,3-oxazoles by deoxygenation of the corresponding N-oxides has been developed. As the deoxygenation reagent, a previously unknown complex of collidine with phosphorus trichloride in a 2:1 ratio has

Full text of DOI:10.1055/s-0037-1610278

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
psp
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V. Z. Shirinian et al.
PSP
Synthesis
Practical Deoxygenation of Oxazole N-Oxides by PCl3/Collidine
Valerii Z. Shirinian*a
Cl–
O
O
Ilya A. Lonshakovb
Alexey V. Zakharova
Andrey G. Lvova
OH
N+
Me
Me
PCl3/collidine
N
Me
Ar
Me
Ar
O
O
Mikhail M. Krayushkina
Functional group tolerant
Novel inexpensive reduction agent
15 examples
up to 86% yield
a N. D. Zelinsky Institute of Organic Chemistry, Russian
Academy of Sciences, 47 Leninsky prosp., 119991 Moscow,
Russian Federation
b Mendeleev University of Chemical Technology of Russia,
Miusskaya Sq. 9, 125047 Moscow, Russian Federation
shir@ioc.ac.ru
Received: 16.07.2018
Accepted after revision: 23.08.2018
Published online: 21.09.2018
but many are limited by side reactions or reduction of the
ring substituents and may require tedious procedures.9,10a,11
In addition, chemoselective deoxygenation of N-oxides
comprising sensitive to the reduction of functional groups
such as nitro, carbonyl, cyano, halogens, etc. remains an im-
portant limiting factor. Hence, the development of effective
chemoselective reagents for the deoxygenation of hetero-
cyclic N-oxides remains in demand.
Deoxygenation of N-oxazole oxides I obtained from acy-
clic precursors,1a as one of the key stages in the synthesis of
II, is actively used for the development of biologically ac-
tive12 and photoactive compounds13 (Scheme 1).
DOI: 10.1055/s-0037-1610278; Art ID: ss-2018-z0479-psp
Abstract A new chemoselective method for the synthesis of 2-aryl-
1,3-oxazoles by deoxygenation of the corresponding N-oxides has been
developed. As the deoxygenation reagent, a previously unknown com-
plex of collidine with phosphorus trichloride in a 2:1 ratio has been
used. The developed method enabled the preparation of a wide range
of 2-aryl-1,3-oxazoles comprising various functional groups in good
yields. The advantage of this reagent is its tolerance to nitro, methyl,
hydroxyl, formyl, and acetyl groups, and double bonds. Due to chemo-
selectivity and availability of reagents, the method may be used for de-
oxygenation of N-oxides of other heterocyclic compounds (thiazole,
pyridine, quinoline, etc.).
O–
N+
R2
R1
R2'
R1'
Key words deoxygenation, N-oxides, azoles, phosphorus trichloride,
collidine, chemoselective, oxazoles
[Deoxygenation agent]
N
acyclic
precursors
R3
R3'
O
O
I
II
Heterocyclic N-oxides occupy a prominent place in the
chemistry of heterocyclic compounds, as well as in organic
synthesis and medicinal chemistry.1 They are embedded in
many molecules of natural and pharmaceutical signifi-
cance, for example, in alkaloids, chemotherapeutic agents,
antibiotics, psychotropic drugs, etc.1c Heterocyclic N-oxides
are potential pollutants of soils and aquatic environments
because of their widespread uses as antibiotics, pesticides,
and other chemical industrial products.2 Also N-oxides of
heterocyclic compounds are intermediates in the synthesis
of heteroaromatic compounds (oxazole, imidazole, thiazole,
etc.),3,4 substrates for C–H functionalization,5,6 1,3-dipolar
cycloaddition,7 radical processes,8 etc.
Among all the listed chemical properties of heterocyclic
N-oxides, the most important is deoxygenation, which is
widely used not only in the synthesis of heteroaromatic
compounds (azoles and azines),1a,9 but also in the utiliza-
tion of pharmaceutical waste.2 Various methods of deoxy-
genation of heterocyclic N-oxides have been developed,10
[Deoxygenation agent] =
Specific
Simple
(additional functionalization)
– POCl3 (chlorination)
– Ac2O (acetylation)
(without additional
functionalization)
– Zn, AcOH
– H2, Raney nickel
– P(OPh)3
– PCl3 (chlorination)
This work: [Deoxygenation agent] = PCl3/collidine
Scheme 1 Deoxygenation of azole-N-oxides
Various reagents can be used for the deoxygenation of
oxazole N-oxides. They can be divided into two groups.
Simple deoxygenation agents affect only the N-oxide frag-
ment, by ‘splitting off’ the oxygen atom. Specific deoxygen-
ation agents affect adjacent functional groups. For the de-
oxygenation of oxazole N-oxides, zinc in acetic acid,14 triph-
enyl phosphite,14a and hydrogen with Raney nickel15 were
used. The reaction of oxazole N-oxides with POCl3 or acetic
anhydride is accompanied by additional functionalization
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
V. Z. Shirinian et al.
PSP
Synthesis
of the substrate (chlorination or O-acylation).13,16 In the
presence of chlorine-sensitive functional groups, the deox-
ygenation by PCl3 leads to the formation of a mixture of two
products.13 Along with deoxygenated oxazoles, the chlori-
nated product is also formed.
Oxazoles comprising the acetyl group (compound 2) at
position 4, acquired great importance in the chemistry of
photoactive compounds (Scheme 2). These compounds
were used to synthesize the photochromic derivatives of
cyclopentenone,13a,17,18 cyclopentene,19 and cyclohexen-
one,20 which found application, in particular, for the devel-
opment of photoswitchable organic field-effect transis-
tors.21 Also, oxazoles 2 were used for the preparation of
photoactive diarylethenes, undergoing a photoinduced re-
arrangement reaction, which is promising preparative
method for the synthesis of polyaromatic compounds.22
genate the pyridine N-oxide without reduction of the nitro
group. The reaction proceeds under mild conditions in high
yields. On the other hand, the chlorinating properties of
this reagent are also well known.25,26 In particular, it was
shown that the deoxygenation by phosphorus trichloride of
the oxazole N-oxide comprising the methyl group at posi-
tion 4 is accompanied by side-chain chlorination.15 This re-
agent, to our best knowledge, was not used for the deoxy-
genation of oxazole N-oxides comprising acetyl group.
In continuation of our work on the development of pho-
toactive compounds of the azole series, we have studied the
deoxygenation of the oxazole N-oxides by phosphorus tri-
chloride. Oxazole-N-oxide 1a was used as a model com-
pound (Scheme 3). Initially, we have tested the method de-
scribed in the literature,20 where, as noted above, a chemo-
selective deoxygenation of pyridine N-oxide was carried
out in high yield (92%). However, the deoxygenation of 1a
with phosphorus trichloride under similar conditions led to
failure (Table 1, entry 1). The desired oxazole was isolated
only in trace amounts (about 7%). We suggest that the rea-
son for this result is probably the use of oxazole N-oxide hy-
drochloride as a substrate, in contrast to the deoxygenation
of the pyridine N-oxide where a free oxide was used. In or-
der to introduce into the reaction just the free N-oxide of
oxazole, we carried out the reaction in the presence of pyri-
dine.
Cl-
O
O
OH
N+
Me
Me
Zn
N
Ar2
N
Ar1
Me
Ar1 AcOH
Me
O
O
Me
photoactive
Ar1
O
1
2
O
O
diarylethenes
Me
Me
Me
Me
O
O
N
N
Me
Me
O
O
CF3
O
Cl–
OH
N+
O
3a (28%)
3b (53%)
Me
Me
PCl3/Py
solvent
Scheme 2 Oxazoles bearing acetyl group in the synthesis of photo-
active diarylethenes
N
Me
Ph
Me
Ph
O
O
1a
2a
In these studies, oxazoles 2 were prepared by a standard
method, the deoxygenation of N-oxides 1 by zinc in acetic
acid. Yields of desired oxazoles varied from 30 to 40%. The
disadvantage of this method is the need to keep a low tem-
perature when the addition of zinc (the reaction tempera-
ture should not exceed 40 °C), otherwise uncontrolled heat-
ing of the reaction mass occurs to form by-products, which
significantly complicates the purification of the target com-
pounds.
However, maintaining the temperature did not prevent
the formation of oxazoles with a reduced carbonyl group.
Thus, we have obtained the products with the reduced car-
bonyl group 3a,b even when the temperature is not raised
over 40 °C. Also, the disadvantage of zinc/acetic acid as a
deoxygenation agent is the sensitivity to certain functional
groups in the aromatic ring (Ar1), in particular, the nitro
group. In this connection, it became necessary to develop a
new convenient method for the deoxygenation of oxazole
N-oxide using an alternative chemoselective reagent.
Analysis of literature has shown that one of the effective
chemoselective reagents for the deoxygenation of hetero-
cyclic N-oxides comprising a nitro group is phosphorus tri-
chloride.23,24 In the reported work,20 it was shown that
phosphorus trichloride is able to chemoselectively deoxy-
Scheme 3 Model reaction
Table 1 Optimization of Reagents Ratio
Entry
1a/PCl3/pyridine
Solvent
Temp (°C)
2a Yield (%)
1
2
1:2:0
1:1:1
1:2:1
1:2:2
1:3:3
1:5:10
1:6:4.5
1:4:2
1:6:3
1:8:4
toluene
toluene
CHCl3
50
50
60
50
50
50
80
50
50
50
<5
10
23
10
<7
0
3
4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5
6
7
10
25
42
30
8
9
10
Indeed, the reaction in the presence of pyridine has re-
sulted in an increase, albeit insignificant, in the yield of the
desired product. Further studies showed that the yields are
strongly dependent on the ratio of reagents, and the opti-
mal ratio was a three-fold excess of the reagent in the ratio
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
V. Z. Shirinian et al.
PSP
Synthesis
PCl3/Py = 2:1. It can be assumed that as the deoxygenation
agent in this process is not free phosphorus trichloride, but
its adduct with pyridine. Analysis of the literature data
showed that the complex of pyridine with phosphorus tri-
chloride is not known, but the physicochemical characteris-
tics of the complex of phosphorus pentachloride with 2,2′-
bipyridyl/[PCl4*L]+Cl– = 1:1 and ([PCl4*L]+Cl6– = 2:1 were de-
scribed.27 And in the solution the most stable complex
structures correspond to a ratio of 2:1. Perhaps, in this case
the deoxygenation agent is a complex of phosphorus tri-
chloride with pyridine in the ratio ([PCl2*Py]+PCl4– = 2:1. In
all likelihood, the stability of such a complex depends
strongly on temperature and storage time. Therefore, pro-
longed heating (above 8 h) of the reaction mixture with one
portion (PCl3/Py = 2:1) did not result in an increase in the
yield of the desired product. The best results were obtained
in the addition of three portions of this mixture in a 2:1 ra-
tio portionwise, every 2 hours (Table 1, entry 9). However,
these results have been disappointing and yields of desired
product did not exceed 42%. We assumed that the yields de-
pend on the stability of the complex, and the nature of the
ligand (pyridine) can influence it. For this reason, to in-
crease the stability of the pyridine- phosphorus trichloride
complex and increase the yields of the deoxygenation prod-
ucts, we have also tested lutidine (2,6-dimethylpyridine),
collidine (2,4,6-trimethylpyridine), and 2,6-dichloropyri-
dine.
As can be seen from Table 2, the replacement of pyri-
dine with lutidine and collidine resulted in an improve-
ment in the yield of the final product. With 2,6-dichloropy-
ridine, the reaction proceeds very slowly, the conversion of
the N-oxide after heating about 20 hours did not exceed
10–15%. Such results can be explained by the introduction
of methyl substituents leading to an increase the basicity of
the pyridine nitrogen, while chlorine as substituents, in
contrast, reduce it. Thus, we have found that a relatively ef-
fective deoxygenation agent is a complex of phosphorus tri-
chloride with collidine in a 2:1 ratio.
Table 3 Solvent and Temperature Optimizationa
Entry
Solvent (temp)
Yield (%)
1
2
3
4
5
6
7
benzene (50 °C)
CH2Cl2 (reflux)
CH2Cl2 (reflux)
CHCl3 (reflux)
toluene (50 °C)
toluene (r.t.)
55
68
60
50
57
30
22
toluene (reflux)
a Reagent ratio: 2:1; number of portions: 3.
We tested various solvents including toluene, benzene,
dichloromethane, dichloroethane, and chloroform, and at
different temperatures (20–110 °C). Dichloromethane was
found to be the most suitable solvent for this process. The
best results were obtained by adding the reagents in a 2:1
ratio portionwise at reflux (40 °C) every 2 hours (for a total
of three portions). Yields of the target oxazole exceeded
68%. It was found that the optimum process temperature is
40–50 °C, an increase in temperature leads to an increase of
resinification process, and a decrease up to room tempera-
ture leads to a great slowdown of the reaction. The optimal
reaction time is 6–7 hours. The complex of collidine-phos-
phorus trichloride is stable at a temperature of 40–50 °C for
2–3 hours. This complex in the form of a white powder was
isolated from the diethyl ether solution by cooling to –5 °C.
However, due to its high hygroscopicity and instability, it
was not possible to characterize it. The developed deoxy-
genation method was used for the synthesis of oxazoles
with various aromatic substituents in the second position.
Different functional groups were used as substituents on
the peripheral benzene ring, including nitro, dialkylamino
groups, as well as halogen substituents. Particularly note-
worthy is the chemoselective deoxygenation of nitro deriv-
atives in high yields. The desired oxazoles were obtained in
good yields in the range of 59–86% (Scheme 4).
Table 2 Optimization of Reaction Conditionsa
The deoxygenation of some oxazole N-oxides (3-
NO2C6H4, 4-NO2C6H4, and 4-CF3C6H4) was accompanied by
the formation of 4-chloroacetyloxazole derivatives 3c,d,m
(Figure 1). We failed to separate these by-products by col-
umn chromatography, and predicted their structures by 1H
NMR spectrum (see S18 in Supporting Information). To pu-
rify the target oxazoles from the by-product, the reaction
mixture prior to purification by column chromatography
was treated with morpholine.
Entry
Ligand
Solvent
Yield (%)
1
2
3
4
pyridine
2,6- lutidine
toluene
toluene
toluene
toluene
42
49
57
15
2,4,6-collidine
2,6-dichloropyridine
a Ratio of PCl3/ligand = 2:1, three portions every 2 h.
O
Cl
To further optimize the reaction conditions of the deox-
ygenation of oxazole N-oxides, we tested various solvents
and temperatures (Table 3).
NO2
N
CF3
9% (m)
Me
Ar
NO2
O
3c,d,m
7% (c)
5% (d)
Figure 1 Side products 3c,d,m
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
V. Z. Shirinian et al.
PSP
Synthesis
O
Cl–
OH
N+
O
Me
Me
Me
PCl3/collidine
CH2Cl2 (abs)
N
Ar
Me
Ar
O
O
2b–p
1b–p
Ar =
Cl
Br
NO2
NO2
NO2
Cl
Cl
F
NO2
Cl
78% (b)
69% (c)
OMe
65% (d)
67% (e)
79% (f)
69% (g)
65% (h)
78% (i)
S
S
Me
N
OMe
CF3
O
OMe
76% (j)
86% (k)
75% (l)
59% (m)
84% (n)
86% (o)
67% (p)
Scheme 4 Scope of the reaction
1H and 13C NMR spectra of samples in deuterated solvents were re-
corded at 293 K (300 MHz for 1H, 75 MHz for 13C). Melting points
were recorded by using a melting point apparatus and are not cor-
rected. Mass spectra were obtained on a mass spectrometer (70 eV)
with direct sample injection into the ion source. High-resolution
mass spectra were obtained on a TOF mass spectrometer with an ESI
source. All chemicals and anhydrous solvents were purchased from
commercial sources and used without further purification. Column
chromatography was performed by using silica gel 60 (70–230 mesh).
TLC analysis was conducted on silica gel 60 F254 plates. N-Oxides were
synthesized from the corresponding aldehydes according to litera-
ture.[14a] Compounds 2a,i,j,m were described previously.[28]
The developed method for the deoxygenation of oxazole
derivatives was tested for the imidazole N-oxides compris-
ing nitro group (Scheme 5). The reaction was carried out
under analogous conditions and the oxides of the nitro-
substituted imidazoles were chemoselectively deoxygenat-
ed in good yields.
O
O
Me
O
N+
Me
N
PCl3/collidine
CH2Cl2 (abs)
Me
Ar
Me
Ar
N
N
Ph
Ph
Compounds 3a,b were obtained in experiments with uncontrolled
warming during fast addition of zinc to a solution of the correspond-
ing oxazole N-oxides in AcOH.
4a–c
5a–c
Cl
NO2
Ar =
Deoxygenation of Oxazole N-Oxides 1 and Imidazole N-Oxides 4 by
PCl3/Collidine; General Procedure
NO2
NO2
75% (b)
63% (a)
65% (c)
PCl3 (1.576 mmol, 0.14 mL) was dissolved in anhyd CH2Cl2 (4 mL) and
2,4,6-trimethylpyridine (0.788 mmol, 0.11 mL) was added. The solu-
tion was stirred for 30 min at r.t. and was cooled to 0 °C. Then, the
respective oxazole N-oxide 1 or imidazole N-oxide 4 (0.8 mmol) was
added portionwise and the mixture was heated to reflux. After 2 and
4 h, additional portions of PCl3 (1.576 mmol, 0.14 mL) and 2,4,6-
trimethylpyridine (0.788 mmol, 0.11 mL) were added. Total time of
reaction was 6 h. The reaction mixture was poured onto crushed ice
(100 mL), extracted with CH2Cl2 (2 × 50 mL), the combined organic
extracts were washed with H2O (100 mL), and evaporated in vacuum
[For oxazoles 2c,d,m the residue was dissolved in 1% solution of mor-
pholine in CH2Cl2 (10 mL) and stirred for 4 h. The solution was
washed with H2O, dried (MgSO4), and concentrated]. The residue was
purified by flash chromatography.
Scheme 5 Deoxygenation of N-oxide of imidazole derivatives
To summarize, we have investigated various conditions
for the deoxygenation of oxazole N-oxides using the com-
plex of phosphorus trichloride with pyridine derivatives. A
new chemoselective method of the synthesis of 2-aryl-1,3-
oxazoles by the deoxygenation of the corresponding N-ox-
ides is presented. As a deoxygenation agent, a previously
unknown complex of collidine with phosphorus trichloride
in a 2:1 ratio was designed. The developed method allowed
the synthesis of a wide range of 2-aryl-1,3-oxazoles com-
prising various functional groups. It was shown that the
method developed is also applicable for chemoselective de-
oxygenation of nitroimidazole derivatives. The proposed
deoxygenation agent, due to its tolerance to many function-
al groups (nitro, methyl, hydroxyl, formyl, acetyl groups,
and double bonds), have the potential to be used to reduce
the N-oxides of other heterocyclic systems, including thi-
azole, pyridine and quinoline.
1-[5-Methyl-2-(2-nitrophenyl)-1,3-oxazol-4-yl]ethanone (2b)
White powder; yield: 0.154 g (78%); mp 101–103 °C.
1H NMR (300 MHz, CDCl3): δ = 2.58 (s, 3 H, CH3), 2.68 (s, 3 H, CH3),
7.62–7.74 (m, 2 Harom), 7.87 (d, J = 7.72 Hz, 1 Harom), 7.99 (d, J = 7.62
Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): δ = 12.3, 27.9, 120.8, 124.2, 130.7, 131.3,
132.4, 135.9, 148.6, 154.2, 155.7, 194.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
V. Z. Shirinian et al.
PSP
Synthesis
MS (EI, 70 eV): m/z (%) = 246 (35, [M]+).
1H NMR (300 MHz, CDCl3): δ = 2.61 (s, 3 H, CH3), 2.73 (s, 3 H, CH3),
7.37 (dd, J = 8.49, 1.85 Hz, 1 Harom), 7.55 (d, J = 1.82 Hz, 1 Harom), 7.94
(d, J = 8.48 Hz, 1 Harom).
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,
58.81; H, 4.19; N, 11.32.
13C NMR (75 MHz, CDCl3): δ = 12.4, 27.9, 124.3, 127.3, 131.0, 131.6,
133.4, 135.7, 136.8, 154.9, 155.7, 194.9.
1-[5-Methyl-2-(3-nitrophenyl)-1,3-oxazol-4-yl]ethanone (2c)
MS (EI, 70 eV): m/z (%) = 269 (100), 271 (75, [M]+), 254 (50, [M –
White powder; yield: 0.136 g (69%); mp 192–193 °C.
CH3]+), 234 (15, [M – Cl]+).
1H NMR (300 MHz, CDCl3): δ = 2.63 (s, 3 H, CH3), 2.75 (s, 3 H, CH3),
7.69 (t, J = 8.02 Hz, 1 Harom), 8.33 (d, J = 8.25 Hz, 1 Harom), 8.38 (d, J =
7.79 Hz, 1 Harom), 8.88 (s, 1 Harom).
Anal. Calcd for C12H9Cl2NO2: C, 53.36; H, 3.36; N, 5.19; Cl, 26.25.
Found: C, 54.09; H, 3.56; N, 4.91; Cl, 26.06
13C NMR (75 MHz, CDCl3): δ = 12.4, 27.9, 121.2, 124.9, 128.5, 130.0,
131.8, 136.1, 148.7, 155.3, 156.3, 194.8.
1-[2-(2-Bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethanone (2h)
White powder; yield: 0.145 g (65%); mp 83–85 °C.
MS (EI, 70 eV): m/z (%) = 246 (100, [M]+), 231 (100, [M – CH3]+).
1H NMR (300 MHz, CDCl3): δ = 2.63 (s, 3 H, CH3), 2.73 (s, 3 H, CH3),
7.33 (t, J = 8.37 Hz, 1 Harom), 7.43 (t, J = 7.40 Hz, 1 Harom), 7.73 (d, J =
7.92 Hz, 1 Harom), 7.91 (d, J = 6.40 Hz, 1 Harom).
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,
57.92; H, 4.01; N, 11.16.
13C NMR (75 MHz, CDCl3): δ = 12.4, 27.9, 121.3, 127.4, 128.0, 131.3,
131.4, 134.5, 135.6, 154.8, 157.1, 195.1.
MS (EI, 70 eV): m/z (%) = 279, 281 (100, [M]+), 200 (10, [M – Br]+).
1-[5-Methyl-2-(4-nitrophenyl)-1,3-oxazol-4-yl]ethanone (2d)
Yellow powder; yield: 0.128 g (65%); mp 156–158 °C, (Lit. [29] mp
158 °C).
1H NMR (300 MHz, CDCl3): δ = 2.63 (s, 3 H, CH3), 2.75 (s, 3 H, CH3),
8.23 (d, J = 8.61 Hz, 2 Harom), 8.35 (d, J = 8.53 Hz, 2 Harom).
Anal. Calcd for C12H10BrNO2: C, 51.45; H, 3.60; N, 5.00; Br, 28.53.
Found: C, 52.32; H, 3.97; N, 4.71; Br, 28.42.
13C NMR (75 MHz, CDCl3): δ = 12.4, 27.8, 124.2 (2 C), 127.1 (2 C),
132.3, 136.4, 148.8, 155.7, 156.4, 194.7.
1-[2-(4-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]ethanone (2i)
White powder; yield: 0.136 g (78%); mp 85–87 °C (Lit.[28] mp 84–85
°C)
1H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 2.70 (s, 3 H, CH3),
7.17 (t, J = 8.64 Hz, 2 Harom), 8.05 (dd, J = 8.74, 5.34 Hz, 2 Harom).
MS (EI, 70 eV): m/z (%) = 246 (100, [M]+), 231 (65, [M – CH3]+).
Anal. Calcd for C12H10N2O4: C, 58.54; H, 4.09; N, 11.38. Found: C,
58.62; H, 4.18; N, 11.06.
1-[2-(2-Chloro-5-nitrophenyl)-5-methyl-1,3-oxazol-4-yl]etha-
none (2e)
1-[2-(4-Methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethanone (2j)
White powder; yield: 0.141 g (76%); mp 94–96 °C (Lit.[28] mp 92–94
°C).
1H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 2.69 (s, 3 H, CH3),
3.88 (s, 3 H, CH3), 6.98 (d, J = 8.84 Hz, 2 Harom), 7.98 (d, J = 8.83 Hz, 2
White powder; yield: 0.150 g (67%); mp 208–210 °C.
1H NMR (300 MHz, CDCl3): δ = 2.64 (s, 3 H, CH3), 2.77 (s, 3 H, CH3),
7.73 (d, J = 8.83 Hz, 1 Harom), 8.25 (dd, J = 8.82, 2.67 Hz, 1 Harom), 8.90
(d, J = 2.62 Hz, 1 Harom).
H
arom).
13C NMR (75 MHz, CDCl3): δ = 12.4, 27.9, 125.2, 125.7, 126.9, 132.5,
135.9, 139.1, 146.5, 154.3, 155.6, 194.7.
MS (EI, 70 eV): m/z (%) = 280 (100, [M]+), 265 (70, [M – CH3]+).
1-[2-(2,4-Dimethoxyphenyl)-5-methyl-1,3-oxazol-4-yl]ethanone
(2k)
Anal. Calcd for C12H9ClN2O4: C, 51.35; H, 3.23; N, 9.98; Cl, 12.63.
Found: C, 51.34; H, 3.28; N, 9.88; Cl, 12.60.
White powder; yield: 0.180 g (86%); mp 78–80 °C.
1H NMR (300 MHz, CDCl3): δ = 2.62 (s, 3 H, CH3), 2.70 (s, 3 H, CH3),
3.88 (s, 3 H, CH3), 3.94 (s, 3 H, CH3), 6.57–6.61 (m, 2 Harom), 7.86 (d, J =
8.49 Hz, 1 Harom).
1-[2-(4-Chlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethanone (2f)
White powder; yield: 0.148 g (79%); mp 108–110 °C (Lit. [29] mp 108
°C).
1H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 2.70 (s, 3 H, CH3),
7.45 (d, J = 8.50 Hz, 2 Harom), 7.98 (d, J = 8.50 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): δ = 12.3, 27.9, 125.3, 127.6 (2 C), 129.1 (2
C), 135.8, 136.7, 154.5, 157.6, 195.0.
13C NMR (75 MHz, CDCl3): δ = 12.3, 27.9, 55.5, 56.0, 99.1, 105.2, 109.1,
131.5, 135.3, 153.8, 157.5, 159.0, 162.9, 195.2.
MS (EI, 70 eV): m/z (%) = 261 (100, [M]+), 218 (25, [M – CH3C(O)]+).
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.77;
H, 6.34; N, 5.18.
MS (EI, 70 eV): m/z (%) = 235 (100), 237 (30, [M]+), 220 (50, [M –
1-[5-Methyl-2-(4-morpholin-4-ylphenyl)-1,3-oxazol-4-yl]etha-
none (2l)
CH3]+).
Anal. Calcd for C12H10ClNO2: C, 61.16; H, 4.28; N, 5.94; Cl, 15.04.
Found: C, 61.11; H, 4.30; N, 5.69; Cl, 16.53.
White powder; yield: 0.172 g (75%); mp 177–178 °C.
1H NMR (300 MHz, CDCl3): δ = 2.60 (s, 3 H, CH3), 2.68 (s, 3 H, CH3),
3.26–3.30 (m, 4 H, 2 × CH2), 3.88–3.91 (m, 4 H, 2 × CH2), 6.96 (d, J =
8.84 Hz, 2 Harom), 7.93 (d, J = 8.82 Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): δ = 12.3, 27.9, 48.4 (2 С), 66.6 (2 С), 114.8
(2 С), 118.1, 127.7 (2 С), 135.6, 152.3, 153.7, 158.9, 195.3.
1-[2-(2,4-Dichlorophenyl)-5-methyl-1,3-oxazol-4-yl]ethanone
(2g)
White powder; yield: 0.148 g (69%); mp 64–66 °C.
MS (EI, 70 eV): m/z (%) = 286 (100, [M]+), 228 (40, [M – CH3C(O),
CH3]+).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
V. Z. Shirinian et al.
PSP
Synthesis
Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N, 9.78. Found: C, 67.20;
H, 6.36; N, 9.73.
1-{5-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}ethyl
Acetate (3b)
Yellow viscous oil; yield: 0.133 g (53%); mp 22–24 °C.
1-[5-Methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl]etha-
none (2m)
1H NMR (300 MHz, CDCl3): δ = 1.63 (d, J = 6.7 Hz, 3 H, CH3), 2.06 (s, 3
H, CH3), 2.45 (s, 3 H, CH3), 5.88 (q, J = 6.7 Hz, 1 H, CH–CH3), 7.68 (d,
J = 8.2 Hz, 2 Harom), 8.12 (d, J = 8.2 Hz, 2 Harom).13C NMR (75 MHz, CD-
Cl3): δ = 10.3, 19.2, 21.1, 64.3, 122.0, 125.6 (dd, J = 7.5, 3.7 Hz, 2 C),
126.3 (2 C), 130.6, 131.50 (q, J = 32.7 Hz), 135.9, 146.6, 158.4, 170.4.
White powder; yield: 0.127 g (59%); mp 82–84 °C (Lit.[28] mp 81–82
°C).
1H NMR (300 MHz, CDCl3): δ = 2.62 (s, 3 H, CH3), 2.73 (s, 3 H, CH3),
7.74 (d, J = 8.28 Hz, 2 Harom), 8.17 (d, J = 8.21 Hz, 2 Harom).
MS (EI, 70 eV): m/z (%) = 313 (25, [M]+), 270 (60, [M – CH3C(O)]+), 253
(100, [M – CH3CO2H]+).
1-(5-Methyl-2-naphthalen-1-yl-1,3-oxazol-4-yl)ethanone (2n)
1-[5-Methyl-2-(2-nitrophenyl)-1-phenyl-1H-imidazol-4-yl]etha-
Light green powder; yield: 0.169 g (84%); mp 111–112 °C.
none (5a)
1H NMR (300 MHz, CDCl3): δ = 2.72 (s, 3 H, CH3), 2.78 (s, 3 H, CH3),
7.54–7.62 (m, 2 Harom), 7.69 (t, J = 7.58 Hz, 1 Harom), 7.94 (d, J = 8.07 Hz,
1 Harom), 8.00 (d, J = 8.18 Hz, 1 Harom), 8.20 (d, J = 7.28 Hz, 1 Harom), 9.34
(d, J = 8.60 Hz, 1 Harom).
Yellow powder; yield: 0.160 g (63%); mp 148–150 °C.
1H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 2.70 (s, 3 H, CH3),
7.11 (d, J = 4.73 Hz, 2 Harom), 7.38 (m, 3 Harom), 7.56 (m, 3 Harom), 7.91
(d, J = 8.18 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): δ = 12.3, 28.0, 123.1, 124.9, 126.0, 126.4,
13C NMR (75 MHz, CDCl3): δ = 11.2, 28.0, 117.5, 120.1, 125.2 (2 C),
127.8, 130.2 (2 C), 130.7, 130.5, 131.2, 131.5, 132.8, 141.3, 144.1,
147.9, 191.7.
MS (EI, 70 eV): m/z (%) = 321 (15, [M]+).
HRMS (ESI): m/z [M + H]+ calcd for C18H15N3O3: 322.1186; found:
127.7, 127.8, 128.6, 130.0, 131.5, 134.0, 135.8, 154.0, 158.3, 195.2.
MS (EI, 70 eV): m/z (%) = 251 (100, [M]+), 236 (20, [M – CH3]+).
Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C, 76.52;
H, 5.27; N, 5.37.
322.1180.
1-(5-Methyl-2-thiophen-2-yl-1,3-oxazol-4-yl)ethanone (2o)
Yellowish powder; yield: 0.143 g (86%); mp 88–90 °C.
1-[5-Methyl-2-(4-nitrophenyl)-1-phenyl-1H-imidazol-4-yl]etha-
none (5b)
1H NMR (300 MHz, CDCl3): δ = 2.59 (s, 3 H, CH3), 2.69 (s, 3 H, CH3),
7.12–7.15 (m, 1 Harom), 7.46 (d, J = 4.96 Hz, 1 Harom), 7.68 (d, J = 3.62
Hz, 1 Harom).
Bright-yellow powder; yield: 0.190 g (75%); mp 175–177 °C.
1H NMR (300 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 2.70 (s, 3 H, CH3),
7.24 (dd, J = 6.19, 2.78 Hz, 2 Harom), 7.58 (m, 5 Harom), 8.08 (d, J = 8.83
Hz, 2 Harom).
13C NMR (75 MHz, CDCl3): δ = 11.1, 27.6, 123.5 (2 C), 127.6 (2 C),
128.8 (2 C), 130.0, 130.3 (2 C), 130.4, 135.8, 137.6, 137.9, 143.2, 147.3,
196.2.
13C NMR (75 MHz, CDCl3): δ = 12.3, 27.9, 127.9, 128.1, 128.6, 129.2,
135.6, 153.9, 154.8, 194.9.
MS (EI, 70 eV): m/z (%) = 207 (100, [M]+), 192 (30, [M – CH3]+).
Anal. Calcd for C10H9NO2S: C, 57.95; H, 4.38; N, 6.76; S, 15.47. Found:
C, 57.57; H, 4.21; N, 6.52; S, 15.44.
MS (EI, 70 eV): m/z (%) = 321 (100, [M]+), 306 (50, [M – CH3]+).
HRMS (ESI): m/z [M + H]+ calcd for C18H15N3O3: 322.1186; found:
1-[5-Methyl-2-(5-methylthiophen-2-yl)-1,3-oxazol-4-yl]ethanone
(2p)
322.1189.
Yellow powder; yield: 0.11 g (67%); mp 83–85 °C.
1H NMR (300 MHz, CDCl3): δ = 2.54 (s, 3 H, CH3), 2.57 (s, 3 H, CH3),
2.66 (s, 3 H, CH3), 6.77 (d, J = 3.25 Hz, 1 Harom), 7.46 (d, J = 3.58 Hz, 1
1-[2-(2-Chloro-5-nitrophenyl)-5-methyl-1-phenyl-1H-imidazol-4-
yl]ethanone (5c)
H
arom).
Light-orange powder; yield: 0.182 g (65%); mp 188–190 °C.
13C NMR (75 MHz, CDCl3): δ = 12.2, 15.4, 27.9, 126.3, 126.7, 128.3,
135.4, 143.8, 153.6, 154.9, 195.0.
MS (EI, 70 eV): m/z (%) = 221 (100, [M]+).
1H NMR (300 MHz, CDCl3): δ = 2.49 (s, 3 H, CH3), 2.68 (s, 3 H, CH3),
7.15 (m, 2 Harom), 7.41 (m, 3 Harom), 7.50 (d, J = 8.81 Hz, 1 Harom), 8.15
(dd, J = 8.81, 2.43 Hz, 1 Harom), 8.29 (d, J = 2.39 Hz, 1 Harom).
13C NMR (75 MHz, CDCl3): δ = 11.2, 27.7, 125.4, 127.3 (2 C), 127.7,
129.6, 129.6 (2 C), 130.7, 131.5, 134.5, 136.3, 137.3, 141.3, 141.6,
146.0, 196.0.
MS (EI, 70 eV): m/z (%) = 354 (100, [M – Н]+), 340 (60, [M – CH3]+), 356
(35, [M + Н]+).
HRMS (ESI): m/z [M + H]+ calcd for C18H14ClN3O3: 356.0796; found:
Anal. Calcd for C11H11NO2S: C, 59.71; H, 5.01; N, 6.33; S, 14.49. Found:
C, 59.91; H, 4.99; N, 5.92; S, 14.40.
1-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)ethyl Acetate (3a)
Yellow-green viscous oil, yield: 0.055 g (28%); mp 26–28 °C.
1H NMR (300 MHz, CDCl3): δ = 1.65 (d, J = 6.7 Hz, 3 H, CH3), 2.06 (s, 3
H, CH3), 2.43 (s, 3 H, CH3), 5.89 (q, J = 6.7 Hz, 1 H, CH–CH3), 7.36–7.47
(m, 3 Harom), 7.97–8.05 (m, 2 Harom).
356.0788.
13C NMR (75 MHz, CDCl3): δ = 10.3, 19.3, 21.2, 64.5, 126.2 (2 C), 127.5,
128.6 (2 C), 130.0, 135.3, 145.6, 159.8, 170.4.
HRMS (ESI): m/z [M + H]+ calcd for C14H15NO3: 246.1125; found:
Funding Information
This work was supported by Russian Science Foundation (RSF Grant
246.1129.
14-50-00126).
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
V. Z. Shirinian et al.
PSP
Synthesis
Acknowledgment
Med. Chem. Lett. 2009, 19, 2468. (e) Raval, P.; Jain, M.; Goswami,
A.; Basu, S.; Gite, A.; Godha, A.; Pingali, H.; Raval, S.; Giri, S.;
Suthar, D.; Shah, M.; Patel, P. Bioorg. Med. Chem. Lett. 2011, 21,
3103. (f) Hershberger, P. M.; Peddibhotla, S.; Sessions, E. H.;
Divlianska, D. B.; Correa, R. G.; Pinkerton, A. B.; Reed, J. C.; Roth,
G. P. Beilstein J. Org. Chem. 2013, 9, 900. (g) Shibata, Y.;
Kagechika, K.; Yamaguchi, M.; Yoshikawa, K.; Chiba, K.; Takano,
H.; Akiyama, C.; Ono, M.; Nishi, M.; Kubo, H.; Kobayashi, Y.;
Usui, H. Chem. Pharm. Bull. 2013, 61, 1248. (h) Otake, K.;
Azukizawa, S.; Takeda, S.; Fukui, M.; Kawahara, A.; Kitao, T.;
Shirahase, H. Chem. Pharm. Bull. 2015, 63, 998. (i) Piemontese,
L.; Cerchia, C.; Laghezza, A.; Ziccardi, P.; Sblano, S.; Tortorella, P.;
Iacobazzi, V.; Infantino, V.; Convertini, P.; Dal Piaz, F.; Lupo, A.;
Colantuoni, V.; Lavecchia, A.; Loiodice, F. Eur. J. Med. Chem.
2017, 127, 379. (j) He, S.; Li, K.; Lin, B.; Hu, Z.; Xiao, J.; Hu, X.;
Wang, A. Q.; Xu, X.; Ferrer, M.; Southall, N.; Zheng, W.; Aubé, J.;
Schoenen, F. J.; Marugan, J. J.; Liang, T. J.; Frankowski, K. J. J. Med.
Chem. 2017, 60, 6364.
Authors are grateful to Mr. Filipp Obrezkov (Skoltech) for some initial
experiments.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610278.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G