A Facile Synthesis of New L-Proline-Based Trifluoromethyl Oxazole Derivatives Using Microwave Irradiation and Conventional Method

Article abstract of DOI:10.1002/jhet.2666

Cyclization reaction of l-proline with trifluoroacetimidoyl chlorides has been developed as an efficient strategy for the synthesis of trifluoromethyl oxazole derivatives by two methods: (a) in the presence of K₂CO₃ as a base in acet

Full text of DOI:10.1002/jhet.2666

Month 2016
A Facile Synthesis of New L-Proline-Based Trifluoromethyl Oxazole
Derivatives Using Microwave Irradiation and Conventional Method
Mahin Ramezani and Ali Darehkordi*
Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
*
E-mail: adarehkordi@yahoo.com; darehkordi@mail.vru.ac.ir
Received November 29, 2015
DOI 10.1002/jhet.2666
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Cyclization reaction of L-proline with trifluoroacetimidoyl chlorides has been developed as an efficient
strategy for the synthesis of trifluoromethyl oxazole derivatives by two methods: (a) in the presence of
K CO as a base in acetonitrile at room temperature and (b) in the presence of K CO as a base in acetonitrile
2 3 2 3
using microwave irradiation, in one pot reaction. The microwave irradiation has been found to be the most
efficient method. High yields and short reaction times were obtained for both electron-releasing and electron-
withdrawing substituted N-aryltrifluoroacetimidoyl chloride derivatives by microwave irradiation.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
of new piperazinylquinolone, which displayed good anti-
bacterial activities [12,13]. N-Aryltrifluoroacetimidoyl ha-
lides are the most useful trifluoromethylated synthetic
blocks among fluorine compounds [14], because these
compound have potentially active sites, such as C–N dou-
Oxazolidone is a heterocyclic organic compound that is
particularly attractive because it is known to be the core
structural unit of compounds widely used in pharmaceuti-
cal agents such as antibacterial [1], antiallergy [2], immu-
nosuppressant [3], and synthetic chemistry [4]. N-Aryl
oxazolidones have attracted a great deal of attention as a
new class of orally active synthetic antibacterial agents
with activity against gram-positive and anaerobic bacteria
ble bonds, halogens, N-aryl, and CF groups [15,16].
3
Microwave irradiation (MWI) has been an available
method in organic synthesis and chiral oxazolines, which
has been applied in heterocycle chemistry and cycloaddi-
tion reaction [17,18]. Microwave irradiation has certain
benefits over conventional heating such as the acceleration
of reaction rate, milder reaction conditions, higher yield,
lower energy consumption, enhancement of the selectivity
of reaction, and easier workup. Although there are many
methods for the preparation of oxazole compounds, and
the synthesis of different oxazole triflouromethylated
derivatives have been reported in literature [19–22], we did
not see any reports for synthesis of aryl-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one derivatives. Con-
tinuing our studies [12,13], we now report the synthesis of
aryl-3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-
one derivatives using the reaction of trifluoroacetimidoyl
chloride derivatives with L-proline by two methods: (a) in
the presence of K CO as a base in acetonitrile at room
[
5]. It is known that the introduction of fluorine atom into
organic compounds greatly changes their biological activi-
ties [6]. Thus, development of effective methods for the
contraction of fluorinated oxazolidone frame work could
be of interest in organic synthesis and pharmacological
agents [7].
Recently, organofluorine compounds have attracted
huge interest in the pharmaceutical and agrochemical in-
dustries [8]. In particular, trifluoroacetimidoyl chloride-
substituted molecules have become a subject of intense in-
vestigation [9], because fluorinated building blocks exhibit
interesting biological activity [10]. Trifluoromethylated
compounds have attracted considerable attention due to
the influence of fluorine atoms, they often furnish organic
molecules with unique properties that cannot be attainted
using any other element [11]. In our previous paper, aryl
trifluoroacetimidoyl chlorides were used for the synthesis
2
3
temperature and (b) in the presence of K CO as a base
2
3
in acetonitrile using microwave irradiation, in one pot reac-
tion. We did not see any report for the synthesis of these
©
2016 Wiley Periodicals, Inc.

M. Ramezani and A. Darehkordi
Vol 000
compounds in the literatures. We hope these compounds to
be useful for biological activities.
main product. Under these conditions, in addition to the re-
action of imidoyl chlorides 1a with L-proline, in the pres-
ence of NaH, three molecules of acetonitrile were
condensed to produce compound 3 (Scheme 1) [26]. The
single-crystal X-ray analyses confirm the structure of the
RESULTS AND DISCUSSION
2
,6-dimethylpyrimidin-4-amine (3).
Trifluoromethylated compounds are of particular inter-
est, as the strong electron-withdrawing effect of the CF3
group contributes to a number of biologically important
molecular properties [19,23].
Further attempts were made to improve the yields. First,
the reaction was carried out in the presence of K CO in
2
3
acetonitrile at ambient temperature under an N atmo-
2
sphere for 8–12h. It afforded the corresponding products
2a–j in good yields (70–82%) (Scheme 2, Table 1). In this
reaction, chlorine atom of the trifluoroacetimidoyl chloride
is replaced by pyrrolidine ring to give the substitution
products, and then cyclization occurs by COO– group.
After optimizing conditions (ambient temperature, ace-
tonitrile as a solvent, and K CO ), in order to improve
Also CF -substituent, acting as a stabilizing polar group
3
in oxazoline ring and prevent the ring from opening be-
cause of its strong electron-withdrawing effect. In this re-
search, to increase the interesting and remarkable
biological activities of oxazolones, we required the synthe-
sis of the oxazolones-annulated trifluoromethyl derivative
with the following structure (Scheme 1).
Therefore, in order to synthesize stable and biologically
active oxazole derivatives, we selected L-proline as a
nucleophile in the cyclization reaction with trifluoro-
acetimidoyl chlorides under mild conditions.
2
3
the yields and decrease the reaction time, we used the
microwave-assisted method for the synthesis of aryl-
3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-
one (2a–j), in the presence of K CO3 in acetonitrile
2
(Scheme 2). L-Proline-based trifluoromethyl oxazole com-
pounds were synthesized by microwave irradiation (MW)
as well as conventional stirring with potassium carbonate
in acetonitrile as solvent.
We synthesized the new aryl-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-ones (2a–j)(Scheme1,
Table 1) derivatives under microwave irradiation as well as
the conventional method. However, as shown in Table 1,
using microwave irradiation normally preceded in improved
yields compared with the previous method, and with the ob-
vious advantage of a faster and more convenient operation. A
possible reaction mechanism is illustrated in Scheme 3.
Trifluoroacetimidoyl chlorides (1a–j) have been prepared
by refluxing a mixture of trifluoroacetic acid and primary
amines in carbon tetrachloride in the presence of triethylamine
and triphenylphosphine by one pot reaction [24,25].
In an initial study, we examined the reaction of
acetymidoyl chloride (1a) with L-proline in the presence
of NaH in acetonitrile under ambient temperature. In this
case, the purification of products is difficult, and the ob-
tained yields are low. After the purification and identifica-
1
13
tion of the product by IR, H-NMR, C-NMR, and X-ray,
,6-dimethylpyrimidin-4-amine (3) was obtained as the
2
Scheme 1. Reaction of acetymidoyl chlorides with L-proline in the presence of NaH in acetonitrile under ambient temperature.
2 3
Scheme 2. Synthesis of various aryl-3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one in acetonitrile in present of K CO as a base using
microwave irradiation and conventional method.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
A Facile Synthesis of New L-Proline-Based Trifluoromethyl Oxazole Derivatives Using
Microwave Irradiation and Conventional Method
Table 1
Synthesis of various aryl-3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one.
b
Condition A stirring at room temperature
Condition B MWI (50°C, 400 W)
a
a
Entry
1
R
1
Product
Base
K CO
Time (h)
12
Yield (%)
64
Time (min)
20
Yield (%)
H
2
3
69
2
3
4
p-NO
2
K
2
CO
3
8
82
77
76
20
20
20
95
92
85
p-Cl
K
2
CO
3
8
p-CH
3
K
2
CO
3
12
5
o-CF
3
K
2
CO
3
8
88
20
90
6
o-F
K
2
CO
3
8
82
20
86
(
Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Ramezani and A. Darehkordi
Vol 000
Table 1
(Continued)
b
Condition A stirring at room temperature
Condition B MWI (50°C, 400 W)
a
a
Entry
7
R
1
Product
Base
Time (h)
8
Yield (%)
80
Time (min)
20
Yield (%)
m-NO
2
K
K
K
K
2
CO
CO
CO
CO
3
92
8
m-CF
3
2
3
8
70
89
75
20
20
20
87
98
88
9
Bis-m(CF
3
)
2
3
8
10
o-p-CH
3
2
3
12
a
Isolated yields after purification by plate chromatography.
Microwave irradiation.
b
Scheme 3. A possible mechanism for the synthesis of aryl-3-
trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one.
The yields of these reactions were generally excellent. It is
important to note that the presence of an electron-withdrawing
group had no effect on the yield. Under the optimized condi-
tions, various acetymidoyl chlorides with electron-donating
or electron-withdrawing groups reacted to give the
corresponding aryl-3-(trifluoromethyl)tetrahydropyrrolo[1,2-
c]oxazol-1(3H)-one products in excellent yields (Table 1).
(
Synthesis
of
various
aryl-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one.
The reaction
of trifluoroacetimidoyl chlorides (1a–j) with L-proline in
the presence of K CO3 in acetonitrile using both
2
microwave irradiation and conventional method gave
an isomeric mixture of two diastereomers, (3R,7aR)-3-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
A Facile Synthesis of New L-Proline-Based Trifluoromethyl Oxazole Derivatives Using
Microwave Irradiation and Conventional Method
1
(
arylamino)-3-(trifluoromethyl)tetrahydropyrrolo[1,2-
corresponding to the C¼O moiety. The H-NMR spectrum
of 2g showed a signal at δ 10.89 corresponding to the NH
group, a signal at δ 8.31, a doublet at δ 7.93 (J= 7.8 Hz), and
a doublet at δ 7.87 (J= 8.1 Hz), due to the aromatic protons.
c]oxazol-1(3H)-one and (3S,7aR)-3-(arylamino)-3-
(
(
trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
Scheme 1).
The generality of this method was investigated by utili-
1
Also the H-NMR spectrum of 2g showed two multiplets at
zation of ten various acetymidoyl chlorides in the reaction
to furnish corresponding trifluoromethyl oxazole deriva-
tives in good to excellent yield. The reaction of 1a, 1b,
δ 4.77–4.84 and δ 4.57–4.60 corresponding to the –CH
(two diastereotopic CH) and three multiplets at δ 3.57–
3.74, δ 2.23–2.29, and δ 1.82–1.85, corresponding to the
13
1
c, 1e, 1g, 1h, and 1i with L-proline in acetonitrile gave
an diastereomeric mixture (3R/3S,7aR)-3-(phenylamino)-
-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
pyrrolidine ring protons. The C-NMR spectrum of 2g
showed downfield signal at δ 170.50 ppm for the carbonyl
group and at δ 22.70, 25.70, 29.50, and 62.2 ppm for the
3
1
9
(2a, 2a′) for 1a, (3R/3S,7aR)-3-(4-nitrophenylamino)-3-
(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
(2b, 2b′) for 1b, (3R/3S,7aR)-3-(4-chlorophenylamino)-3-
(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
(2c, 2c′) for 1c, (3R/3S,7aR)-3-(trifluoromethyl)-3-(2-
three CH and CH carbons, respectively. The F-NMR
2
spectrum of 2g in dimethyl sulfoxide (DMSO) showed
two peaks at δ ꢀ76.94 and ꢀ76.96 for the CF group.
3
(
1
trifluoromethyl)phenylamino) tetrahydropyrrolo[1,2-c]oxazol-
(3H)-one(2e, 2e′) for 1e, (3R/3S,7aR)-3-(3-nitro-
CONCLUSION
phenylamino)-3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]
oxazol-1(3H)-one (2g, 2g′) for 1g, (3R/3S,7aR)-3-
In conclusion, we have successfully synthesized a series of
new aryl-3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-
(3H)-one derivatives using different 2, 2, 2-trifluoro-N-
(trifluoromethyl)-3-(3-(trifluoromethyl)phenylamino) tetrahy-
1
dropyrrolo[1,2-c]oxazol-1(3H)-one (2h, 2h′) for 1h,
and (3R/3S,7aR)-3-(3, 5-bis(trifluoromethyl)phenylamino)-3-
arylacetimidoyl chlorides under mild conditions. In addition
to its efficiency, simplicity, and mild reaction conditions, this
method provides high yields of trifluoromethyl oxazole.
Therefore, this protocol is efficient and may open up a new
area for the synthesis of trifluoromethylated oxazoles.
Further studies including the pharmacological activities in
this area are being carried out in our laboratory.
(
(
trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
2i, 2i′) according to the H-NMR spectra. Also, when 1d,
1
1
f, and 1j trifluoroacetimidoyl chloride derivatives were
employed, corresponding trifluoromethyl oxazole com-
pounds as a diastereomeric mixture were obtained. In these
reactions, we could not obtain diastereomeric ratio, be-
1
cause the H-NMR spectrum of the compounds 2d, 2f,
and 2j showed three multiplet signals at δ, 4.12–4–15,
EXPERIMENTAL
4
.23–4.25, and 3.55–3.57 ppm, respectively, correspond-
ing to the H HCNCOO group.
Each of the two diastereomers, (2a, 2a′), (2b, 2b′), (2c,
General. All manipulations were carried out under a
nitrogen atmosphere; all reactions were performed with
magnetic stirring in flame-dried glassware with dry and
distilled solvents. Chemicals and solvents were purchased
from Merck AG and Aldrich Chemical companies
2
c′), (2d, 2d′), (2e, 2e′), (2fc, 2fc′), (2g, 2g′), (2h, 2h′),
(
2i, 2i′), and (2j, 2j′), showed the same Rf value on thin-
1
layer chromatography (TLC). However, the H-NMR
spectrum of the mixture showed the H HCNCOO signal
as two singlets at δ major = 5.63, δ minor = 4.11ppm for
(
Merck and Aldrich Representation in Tehran). Melting
points were determined with a Barnstead electrothermal
Dubuque, IA). IR spectra (KBr, Neat) were obtained on
(
2a, 2a′); δ major = 4.14, δ minor =4.04 ppm for (2b, 2b′);
(
δ major= 4.79, δ minor= 4.24ppm for (2c, 2c′); δ ma-
jor =4.92, δ minor = 4.70ppm for (2e, 2e); δ major =4.80,
δ minor = 4.58ppm for (2g, 2g′); δ major =4.96, δ
minor = 4.80ppm for (2h, 2h′); and δ major= 6.61, δ
minor = 5.55ppm for (2i, 2i′), which is characteristic of
trifluoromethyl oxazoles. The Fourier transform IR,
a Thermo Scientific, Nicolet iS10 Fourier transform IR
spectrometer (Thermo Fisher Scientific, Waltham, MA).
ETHOS 1 Advanced Microwave Digestion System
(Milestone, Italy) was used for the synthesis of
compounds. The H-NMR and C-NMR spectra were
recorded by a Bruker DRX-400 or -300 AVANCE
spectrometer at 400 or 300 and 100 or 75MHz (Bruker,
1
13
19
1
13
F-NMR, H-NMR, C-NMR, correlation spectroscopy,
and heteronuclear multiple bond correlation spectra and
elemental analysis confirmed the structures of the
products.
Billerica, MA), respectively, using Me Si as an internal
standard (chemical shifts in δ, ppm). F-NMR spectra
were taken on Brucher AM-300 (282MHz) spectrometer
4
1
9
The IR spectrum of (3R/S, 7aR)-3-(3-nitrophenylamino)-3-
using CFCl as external standard. Element analyses
3
(
(
trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
(CHN) were performed with a EuroVector EuroEA3000
CHNSO analyzer (EuroVector, Milan). Merck silica-gel
60F254 plates were used for analytical TLC.
ꢀ
ꢀ
1
1
2g) showed absorption bands at 3433 and 3408 cm
,
,
corresponding to –NH stretching, and at 1719 cm
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Ramezani and A. Darehkordi
Vol 000
General procedure for the synthesis of 3-aryl-3-
trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one
diastereotopic CH–C¼O), 7.95–7.98 (dd, 4H, J=8.0,
2.4Hz, Ar), 8.29–8.32 (dd, 4H, J=8.0, 2.4Hz, Ar), 11.82
(
19
derivatives.
described as follows. Method A: a mixture of L-proline
1mmol) and calcium carbonate (2mmol) in dry acetonitrile
10mL) was stirred at room temperature for 20 min. Imidoyl
1mmol) in dry acetonitrile (10mL) was added dropwise to
A representative experimental procedure is
(br, 2H, NH). F (282.2 MHz, DMSO): δ=ꢀ73.91 (3F,
CF ). Anal. Calcd. for C H F N O : C, 47.14; H, 3.65;
3
13 12 3 3 4
(
(
(
N, 12.69%. Found: C, 47.12; H, 3.67; N, 12.65%.
(
3R/3S,7aR)-3-(4-Chlorophenylamino)-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2c, 2c′).
The
this mixture. The reaction mixture was then stirred at room
temperature and monitored by TLC (EtOAc/n-hexane). After
the completion of the reaction at 8–12h, the solvent was
removed under reduced pressure. The crude product was
purified by TLC plates (silica-gel, appropriate EtOAc/hexane)
to give a diastereomer mixture of (3S,7aR) and (3R,7aR)
product was purified by TLC plates (n-hexane/EtOAc, 1:3)
to give product as a yellow oil, which was found to be a
mixture of two diastereomers 80:20; diastereomer ratio as
1
calculated from their H-NMR integrals CHC¼O signal, δ
major=4.79, δ minor=4.24; with the same Rf (n-hexane/
ꢀ
1
EtOAc, 1:3). IR (thin film): 3335, 1704, and 1598cm .
1
3-aryl-3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-
H-NMR (400MHz, DMSO): δ=1.27–1.35 (m, 4H, CH2),
1
(3H)-one.
1
4
4
2
.98–2.01 (m, 4H, CH ), 2.26–2.29 (m, 4H, CH ), 4.24,
2 2
Method B: A mixture of L-proline (1mmol), calcium car-
.79 (m, 2H, diastereotopic CH–C¼O), 7.31–7.33 (dd,
H, J=8.0, 2.40Hz, Ar), 7.42–7.53 (dd, 4H, J=8.0,
bonate (2 mmol), and imidoyl (1 mmol) in dry acetonitrile
10 mL) was charged in a pressure-tight microwave tube con-
1
3
(
.40Hz, Ar), 8.67, 8.73 (br, 2H, NH).
C-NMR
taining a stirring bar. The reaction mixture was submitted to
microwave irradiation for 20min at 50°C, with an irradiation
power of 400 W. The progress of the reaction was monitored
by TLC. After completion of the reaction, the solvent was re-
moved under reduced pressure. The crude product was puri-
fied by TLC plates (silica-gel, appropriate EtOAc/hexane) to
give a diastereomer mixture of (3S,7aR) and (3R,7aR) 3-aryl-
(
9
100MHz, DMSO): δ= 24.61, 36.8, 55.6, 75.7, 76.1, 95.3,
19
5.4, 126.2, 126.4, 128.9, 131.1, 134.3, 170.9 (C¼O).
F
(
282.2MHz, DMSO): δ =ꢀ77.04 (3F, CF ). Anal. Calcd.
3
for C H ClF N O : C, 48.69; H, 3.77; N, 8.74%. Found:
13
12
3 2 2
C, 48.65; H, 3.80; N, 8.72%.
(
3R/3S,7aR)-3-(p-Tolylamino)-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2d, 2d′).
The
3-(trifluoromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one.
product was purified by TLC plates (n-hexane/EtOAc, 1:1)
to give product as yellow oil, which was found to be a
mixture of two diastereomers with the same Rf (n-hexane/
(
3R/3S,7aR)-3-(Phenylamino)-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2a, 2a′).
The product was purified by TLC plates (n-hexane/
EtOAc, 1:1) to give product as a yellow oil, which was
found to be a mixture of two diastereomers 56:44;
ꢀ
1
EtOAc, 1:1). IR (thin film): 3449, 1697, and 1516cm .
1
H-NMR (400MHz, DMSO): δ=0.86–0.89 (m, 2H, CH2),
1
2
.23 (S, 3H, CH ), 1.27–1.31 (m, 2H, CH ), 2.09–2.27 (m,
3 2
1
diastereomeric ratio as calculated from their H-NMR
H, CH ), 4.12–4.15 (m, 2H, CH–C¼O, diastereotopic
2
integrals CHC¼O signal, δ major= 5.63, δ minor = 4.11;
protons) 7.14–7.16 (m, 2H, Ar), 7.66–7.73 (m, 2H, Ar),
1
23.4, 24.6, 36.8, 55.6, 95.3, 95.4, 124.8, 124.5, 129.3,
1
1
13
with the same Rf (n-hexane/EtOAc, 1:1). H-NMR
0.37 (br, NH). C-NMR (100MHz, DMSO): δ=20.6,
(
400 MHz, DMSO): δ= 1.14–1.29 (m, 6CH , 12H), 4.11,
2
19
5
7
.63 (m, 2H, diastereotopic CH–C¼O), 7.07 (m, 2H, Ar),
.31–7.50 (m, 5H, Ar), 7.62 (m, 1H, Ar), 7.82 (m, 2H,
29.1, 132.9, 135.4, 171.0 (C¼O).
F (282.2MHz,
DMSO): δ=ꢀ77.01 (3 F, CF ). Anal. Calcd. for
3
1
3
Ar), 8.00, 8.33 (br, 2H, NH). C-NMR (100MHz,
C H F N O : C, 56.00; H, 5.04; N, 9.33%. Found: C,
14 15 3 2 2
DMSO): δ= 25.1, 31.8, 37.9, 56.5, 114.7, 125.3, 126.5,
5
6.04; H, 5.10; N, 9.35%.
1
9
1
(
27.5, 129.1, 129.3, 129.4, 135.9, 173.2 (C¼O).
F
(
3R/3S,7aR)-3-(Trifluoromethyl)-3-(2-(trifluoromethyl)
282.2 MHz, DMSO): δ =ꢀ77.04, ꢀ76.87 (6 F, CF ).
3
phenylamino)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2e,
2e′). The product was purified by TLC plates (n-hexane/
EtOAc, 2:1) to give pure product as a white solid. Mp 99–
102°C, which was found to be a mixture of two
diastereomers 71:29; diastereomer ratio as calculated from
their 1H-NMR integrals CHC¼O signal, δ major=4.92, δ
minor= 4.70; with the same Rf (n-hexane/EtOAc, 2:1). IR
Anal. Calcd. for C H F N O : C, 54.55; H, 4.58; N,
1
3 13 3 2 2
9
.79%. Found: C, 54.52; H, 4.53; N, 9.75%.
(
3R/3S,7aR)-3-(4-Nitrophenylamino)-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2b, 2b′).
The
product was purified by TLC plates (n-hexane/EtOAc, 2:1)
to give product as a pale white solid. Mp 141–143°C,
ꢀ
1 1
which was found to be a mixture of two diastereomers
(KBr): 3378 and 1702cm . H-NMR (400MHz, DMSO):
δ=1.41–3.98 (m, 6CH , 12H), 4.70, 4.92 (m, 2H,
1
6
6:33; diastereomer ratio as calculated from their H-NMR
2
integrals CHC¼O signal, δ major=4.14, δ minor=4.04;
diastereotopic CH–C¼O), 7.36–7.77 (m, 8H, Ar), 9.38,
13
with the same Rf (n-hexane/EtOAc, 2:1). IR (KBr): 3325,
9.98 (br, 2H, NH). C-NMR (100 MHz, DMSO): δ =24.4,
ꢀ
1
1
1
743, and 1621cm
.
H-NMR (300MHz, DMSO):
36.8, 56.1, 94.4, 121.2, 124.6, 127.5, 129.1, 129.2, 130.2,
1
9
δ=1.03–1.07 (m, 4H, CH ), 1.18–1.30 (m, 4H, CH ),
132.6, 132.8, 134.0, 171.2 (C¼O).
F (282.2MHz,
2
2
2
.07, 2.33, 2.67, 3.16 (m, 4H, CH ), 4.04, 4.14 (m, 2H,
2
DMSO): δ=ꢀ58.75, ꢀ77.92 (6 F, 2CF ). Anal. Calcd. for
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
A Facile Synthesis of New L-Proline-Based Trifluoromethyl Oxazole Derivatives Using
Microwave Irradiation and Conventional Method
1
C H F N O : C, 47.47; H, 3.41; N, 7.91%. Found: C,
70:30; diastereomer ratio as calculated from their H-NMR
1
4 12 6 2 2
4
7.45; H, 3.38; N, 7.90%,
integrals CHC¼O signal, δ major=6.61, δ minor=5.55;
ꢀ
1
(
3R/3S,7aR)-3-(2-Fluorophenylamino)-3-(trifluoromethyl)
with the same Rf. IR (KBr): 3420, 1725, and 1559cm .
1
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2f, 2f′).
The
H-NMR (300MHz, DMSO): δ=1.05–3.35 (m, 6CH
,
2
productwaspurifiedbywashingwithn-hexanetogiveproduct
12H), 5.55–6.61 (m, 2H, diastereotopic CH–C¼O),
19
as a yellow oil, which was found to be a mixture of two
7.22–7.68 (m, 6H, Ar), 8.98 (br, 2H, NH). F-NMR
(376MHz, DMSO): δ=ꢀ73.39, 70.00 (6F, 2CF ). Anal.
Calcd. for C15 : C, 42.67; H, 2.63; N, 6.63%.
1
diastereomers with the same Rf (n-hexane/EtOAc, 1:3). H-
3
NMR (400 MHz, CDCl ): δ = 1.40–3.13 (m, 3CH , 12H),
H F N O
11 9 2 2
Found: C, 42.62; H, 2.60; N, 6.60%.
3
2
4
6
.23–4–26(m,2H,CH–C¼O,diastereotopicprotons),6.76–
1
3
.87 (m, 8H, Ar), 7.84 (br, 2H, NH). C-NMR (100MHz,
(3R/3S,7aR)-3-(2, 4-Dimethylphenylamino)-3-(trifluoromethyl)
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2j, 2j′). The product
was purified by washing with n-hexane to give product as a
solid. Mp 148–150°C, which was found to be a mixture of
two diastereomers with the same Rf. IR (KBr): 3432 and
CDCl ):δ =23.74,38.73,45.13,68.16,114.91,118.09(CF ,
3
3
q,JC-F = 286Hz),123.13,123.98,128.80,130.88,143.76(C-
CF , q, J = 32Hz), 153.29 (C–F, d, J =240 Hz), 175.53
3
C-C-F
(
9
C¼O).Anal.Calcd.forC H F N O :C,51.32;H,3.98;N,
1
3 12 4 2 2
ꢀ
1 1
.21%.Found:C,51.30;H,3.95;N,9.18%.
1725 cm . H-NMR (400 MHz, DMSO): δ=1.24–1.93 (m,
H, CH ), 2.17, 2.30 (s, 6H, CH ), 3.32–3.46 (m, 8H,
4
(
3R/3S,7aR)-3-(3-Nitrophenylamino)-3-(trifluoromethyl)
2
3
2
CH ), 3.55–3.56 (m, 2H, CH–C¼O, diastereotopic protons),
tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (2g, 2g′). The
product was purified by TLC plates (n-hexane/EtOAc, 1:3)
to give pure product as a yellow oil, which was found to be
a mixture of two diastereomers 81:19; diastereomer ratio as
2
13
7
(
1
.02–7.20 (m, 6H, Ar), 9.26 (m, 2H, NH). C-NMR
100MHz, DMSO): δ= 17.3, 20.5, 26.8, 28.0, 43.8, 82.2,
19.1, 121.85 (CF , q, J = 27 8Hz), 126.1, 126.5, 127.2,
3
C-F
1
130.4, 131.9, 137.0, 145.7, 171.8. Anal. Calcd. for
calculated from their H-NMR integrals CHC¼O signal, δ
C H F N O : C, 57.32; H, 5.45; N, 8.91%. Found: C,
major= 4.80, δ minor= 4.58; with the same Rf (n-hexane/
15 17 3 2 2
ꢀ
1 1
57.30; H, 5.40; N, 8.81%.
EtOAc, 1:3). IR (thin film): 3408 and 1719cm . H-NMR
(
400MHz, DMSO): δ =1.83 (m, 2H, CH ), 2.00 (m, 2H,
2
CH ), 3.62 (m, 2H, CH ), 4.58, 4.80 (m, 2H, diastereotopic
2
2
Acknowledgments. We gratefully acknowledge the Vail-e-Asr
University of Rafsanjan Faculty Research Grant for financial
support.
CH–C¼O), 7.62 (d, 1H, J=7.8Hz, Ar), 7.86–7.94 (dd, 2H,
13
J= 8.1, 7.8Hz, Ar), 8.87 (m, 1H, Ar), 10.75 (br, NH). C-
NMR (100MHz, DMSO): δ= 22.7, 25.7, 29.5, 62.2, 108.2,
1
15.3, 120.1, 126.9, 129.8, 132.4 (q, J
=43.0Hz),
C-C-F
19
1
37.4, 147.8, 170.5 (C¼O). F-NMR (376 MHz, DMSO):
REFERENCES AND NOTES
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4
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[
(
3R/3S,7aR)-3-(Trifluoromethyl)-3-(3-(trifluoromethyl)
[
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1
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14 12 6 2 2
[
47.43; H, 3.35; N, 7.87%.
(
3R/3S,7aR)-3-(3,5-bis(Trifluoromethyl)phenylamino)-3-
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[
2
(
(
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M. Ramezani and A. Darehkordi
Vol 000
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