Efficacious and rapid metal- and solvent-free synthesis of enantiopure oxazolines

Article abstract of DOI:10.1016/j.tetasy.2014.08.010

A rapid and efficient synthesis of oxazolines was performed starting from various nitriles using microwave irradiation combined to metal- and solvent-free conditions to afford high to quantitative yields of the targeted heterocycles.

Full text of DOI:10.1016/j.tetasy.2014.08.010

Tetrahedron: Asymmetry 25 (2014) 1275–1279
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficacious and rapid metal- and solvent-free synthesis
of enantiopure oxazolines
Rym Hassani a, Alexandre Requet b, Sylvain Marque b, Anne Gaucher b, Damien Prim b,
Yakdhane Kacem a, Béchir Ben Hassine a,
⇑
a Laboratoire de Synthèse Organique, Asymétrique et Catalyse Homogène, Faculté des sciences de Monastir, Avenue de l’Environnement, 5019 Monastir, Tunisia
b University of Versailles Saint-Quentin-en-Yvelines, Institut Lavoisier de Versailles, UMR CNRS 8180, 45, avenue des Etats-Unis, 78035 Versailles, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid and efficient synthesis of oxazolines was performed starting from various nitriles using micro-
wave irradiation combined to metal- and solvent-free conditions to afford high to quantitative yields
of the targeted heterocycles.
Received 25 June 2014
Accepted 19 August 2014
Available online 12 September 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
from nitriles. In this context, oxazolines can be obtained by Witte
and Seeliger’s15 procedure involving nitriles and aminoalcohols in
Optically active oxazoline derivatives have attracted a great
deal of attention due to their high efficiency and versatility as pro-
tecting groups,1,2 chiral auxiliaries,3 and ligands for asymmetric
catalysis.4 The latter area has witnessed an exponential develop-
ment due to the first independent reports by Corey and Evans in
1991.5 Since then, mono or bisoxazolines have appeared as privi-
leged ligands in the expanding field of enantioselective transfor-
mations6 that not only generated progresses in mechanistic
aspects but also extensive efforts of the scientific community to
design new oxazoline-based catalytic systems and facilitate the
preparation of this key heterocycle.
In addition, the development of catalytic enantioselective trans-
formations paved the way for the preparation of enantiopure oxaz-
oline derivatives. Therefore, various procedures have been
reported in order to synthesize oxazoline derivatives from carbox-
aldehydes,7 carboxylic acid derivatives,8,9 or nitrile precursors.10–13
In spite of the potential utility of the aforementioned routes, many
of these methods involve expensive or metallic reagents, strongly
acidic or harsh conditions, require long reaction times, and need
a large amount of organic solvents. Such parameters appear now-
adays as severe drawbacks. Therefore, to avoid these limitations,
the development of new and efficient alternatives combining high
yields, short reaction times, and green conditions (mild, practical,
metal-free, solvent free, and non-conventional activation methods)
is highly desirable.
the presence of catalytic amounts of metal salts. Most commonly,
oxazolines are obtained through either a two-step condensation/
cyclization sequence starting from nitriles in the presence of metal
salts,16–18 or strong Bronsted acids19 or by stepwise formation of
the corresponding imidates20 followed by cyclization. Initially lim-
ited to mononitrile substrates, this methodology has been since
revisited by several groups in order to improve the efficiency of
the transformation. Indeed, catalytic amounts of ZnCl2 or Zn(OTf)2
in refluxing chlorobenzene or toluene under anhydrous condi-
tions,16 Cd(OAc)2-mediated condensation of a large excess of ami-
noalcohols for prolonged reaction times (4–5 days in refluxing
chlorobenzene),21 account for the optimum experimental condi-
tions. Several heterogeneous or biopolymer-based catalysts such
as Dowex-50W-hydrogen ion exchange resin,22 natural Kaolinitic
Clay,23 silica sulfuric acid (SSA) under ultrasonic irradiation or
refluxing conditions,24 tungstophosphoric acid (H3PW12O40),25 cel-
lulose sulfuric acid (CSA),26 and trichloroisocyanuric acid (TCCA)27
and more recently, Fe3O4 supported Pd(0) nanoparticles
(Pd/Fe3O4)28 and S/Co(NO3)2 under thermal or MW conditions,29
have been also reported.
Herein we report the one pot preparation of 2-oxazolines start-
ing from nitriles using an equimolar amount of various aminoalco-
hols under microwave, metal-free, and solvent-free reaction
conditions.
During our studies devoted to the incorporation of nitriles in
various molecular architectures and their reactivity toward nucle-
ophiles,14 we became interested in the preparation of oxazolines
2. Results and discussion
In continuation of our studies concerning the application of use-
ful synthetic microwave methods,30 we describe herein a simple,
efficient, and high-yielding microwave-mediated procedure for
the synthesis of 2-oxazoline derivatives by the reaction of nitriles
⇑
Corresponding author. Tel.: +216 73500279; fax: +216 73500278.
E-mail address: bechirbenhassine@yahoo.fr (B.B. Hassine).
http://dx.doi.org/10.1016/j.tetasy.2014.08.010
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1276
R. Hassani et al. / Tetrahedron: Asymmetry 25 (2014) 1275–1279
with 2-aminoalcohols. In order to find the optimum reaction con-
ditions, we screened different molar ratios of substrates and cata-
lyst, at various temperatures and in different polar and non-polar
solvents. It is noteworthy that solvent-free conditions were not
only beneficial in reagents’ cost but also more efficient than condi-
tions including a solvent.
Using microwave irradiation at 150 °C in the absence of any cat-
alyst and any solvent, the reaction was completed in only 1 h
affording the expected oxazoline. From both an economical and
efficiency point of view, to the best of our knowledge, our method
afforded a better overall compromise by comparison with known
reported procedures. To further investigate the beneficial effect
of the microwave-assisted construction of oxazolines the following
series of condensations were performed using various aminoalco-
hols. In order to extend the scope of our methodology, we focused
on the preparation of oxazoline derivatives from various aromatic
and heterocyclic nitriles. Seventeen enantiopure oxazolines were
prepared using different 2-aminoalcohols under microwave, sol-
vent-free conditions as shown in Scheme 1.
These reactants were successfully used in our earlier work
devoted to the synthesis of oxazolines. The synthesis of oxazolines
2 was accomplished by using an alternate method. All targeted
oxazolines were characterized by TOF-MS and NMR techniques.
Most importantly, the specific rotation and HPLC data of these
products confirmed full conservation of stereochemical informa-
tion, thus evidencing the presence of one single enantiomer. The
enantiomeric purity was unequivocally established by HPLC using
a chiral OJ-H column (heptane/2-propanol, 95:5, 1.0 mL/min,
30 °C).
The reaction of 2-cyanoquinoline with (L)-valinol gave the
(S)-(À)-4-isopropyl-2-(2-quinoline)oxazoline 2g with an enantiomeric
purity of >99% as determined by comparison of the specific rota-
tion with a literature value.31 The oxazoline 2g was obtained in
73% yield and high purity (ee >99% at tR = 14.245 min starting from
(D)-valinol; ee >99% at tR = 12.865 min starting from (L)-valinol
and for racemic valinol area = 49.57% at tR = 12.933 min and
area = 50.43% at tR = 14.250 min). This sequence has been proven
to be highly amenable to parallel, semi-automated methods of
synthesis.
We next moved from heterocyclic substrates to benzo- and
naphtho-nitrile starting materials. As shown in Figure 1, our
method was again successful within this series. We were thus able
to prepare the corresponding (S)-4-benzyl-2-(naphthalen-1-yl)-
4,5-dihydrooxazole 2m and (S)-4-isopropyl-2-(naphthalen-1-yl)-
4,5-dihydrooxazole 2n in 76% and 70% yields, respectively, from
naphthalenecarbonitrile under microwave activation at 240 °C for
100 min. Some derivatives such as chloro- and fluorobenzene were
also tested. In these cases, an increase of the temperature from
210 °C to 240 °C for 4-chlorobenzonitrile and from 180 °C to
240 °C for 4-fluorobenzonitrile respectively ensured complete con-
version of the starting material leading to high yields of 2q and 2o.
In both cases, our method was again superior to the literature
reported procedures in terms of yields, number of steps, and con-
venience.32,33 Finally, cyclopropylcarbonitrile and pyruvonitrile
were tested in order to extend our methodology to chiral
R2
R1
OH
R2
R1
O
solvent-free
CN
+
R
R
150°C, 1h
67% - 99%
N
2a-o
NH2
Scheme 1.
In the azine series, pyrazin-, pyridine-, and quinoline-2-carbo-
nitriles were subjected to the aforementioned conditions. Various
aminoalcohols including
L
-phenylalaninol,
L-phenylglycinol,
L
-valinol, -alaninol, and 1-amino-2-propanol afforded the corre-
L
sponding oxazolines 2a–g in yields ranging from 73% to 98%. These
reaction conditions were also successfully applied to 5-chlorothio-
phene-2-carbonitrile which could be converted into the corre-
sponding oxazolines 2h and 2i in 95–98% yields.
N
O
O
N
R2
N
O
N
N
N
R1
N
2a, R1 = CH2Ph, (95%)
, R1 = Ph, (98%)
2b
2c, R1 = iPr, (83%)
2f, (82%)
2g, 73%
, R1 = Me, (91%)
2d
, R1 = H; R2 = Me, (82%)
2e
OH
*
OCH3
O
N
O
Cl
O
S
N
N
R1
2h, R = Ph, (98%)
2i, R = iPr, (95%)
2j, (67%)
2k, (75%)
F
Cl
O
O
N
O
N
R
N
2o,
2m,
2n,
at 180°C for 60min : ( 68%)
at 240°C for 100min: (93%)
R= PhCH2 : (76%)
R= isPr : (70%)
2l, at 210°C : (75%)
at 240°C for 100min :quantitative yield
Figure 1. General conditions: nitrile substrate (1 equiv), aminoalcohol (1.1 equiv), solvent-free conditions, MW. 150 °C and 1 h except for oxazolines 2l, 2m, 2n, 2o that
require 240 °C for 100 min.

R. Hassani et al. / Tetrahedron: Asymmetry 25 (2014) 1275–1279
1277
oxazolines bearing new substituents. The former reacted smoothly
with -valinol affording the unprecedented enantiopure 1-cyclo-
an Anton Paar Monowave 300 apparatus. All of the reactions
under microwave irradiation were conducted in a glass vial G4
(TM 0.5–2 mL filling volume, sealed with PTFE-coated silicone
septa). Microwave heating was carried out with a single mode
cavity Discover Microwave Synthesizer, producing continuous
irradiation with IR temperature control. The optimized reaction
conditions required heating at 150 °C for 60 min, except for
entries 2m, n, q, and o which required 100 min at 240 °C for
oxazoline formation.
L
propyloxazoline 2j in a fair 67% yield. Surprisingly pyruvonitrile
did not afford the expected oxazoline under our reaction
conditions. As shown in Figure 1, 1-methoxy-1-[(S)-4-phenyl-4,5-
dihydrooxazol-2-yl]ethanol 2k was obtained in 75% yield. The
latter was obtained under classical experimental conditions but
required a methanol uptake of the crude material during treatment
that plausibly causes the installation of a methoxy moiety at the
a
-oxazolyl carbon center.37
To investigate the effect of the microwave for the condensation
4.2. General procedure for the synthesis of the 4-substituted-
oxazolines 2a–o
of various nitriles, we had originally hoped that the bis-nitrile
could be converted into a bis-oxazoline, and we attempted the
cyclization reaction with 2.2 equiv of aminoalcohol at 150 °C for
1 h. However, we examined the reaction of the 1,2-dicyanobenzene
The synthesis of (S)-4-phenyl-2-(pyrazin-2-yl)-4,5-dihydroox-
azole 2b is representative.
with the (
L
)-valinol to afford the 1,2-bis((S)-4-isopropyl-4,5-dihy-
Pyrazin-2-carbonitrile (15.3 mg, 0.145 mmol, 1 equiv) was
drooxazol-2-yl)benzene 3 in quantitative yield under solvent-free
conditions at 150 °C for 1 h (Scheme 2).
mixed
with
L
-(+)-(
a
)-phenylglycinol (22 mg,
0.160 mmol,
1.1 equiv) in the G4 vial in a Monowave 300 vessel. The resulting
mixture was irradiated using the closed vessel mode at 150 °C
for 60 min. The reaction mixture was quenched with ethyl acetate
and filtered by silica. The filtrate was dried over magnesium sul-
fate, and concentrated by evaporation under vacuum to give the
OH
corresponding
(S)-4-phenyl-2-(pyrazin-2-yl)-2-oxazoline
2b
NH2
(32.2 mg, 0.143 mmol, 98% yield, entry 2b).
solvent-free
O
O
N
N
150°C, 1h
quant.
4.2.1. (S)-4-Phenyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole 2b
98%; Yellow oil; [a]
(CDCl3, 300 MHz): d = 9.37 (s, 1H), 8.70 (s, 1H), 7.34 (m, 5H),
D = À43.5 2.6 (c 1.3, CHCl3). 1H NMR
NC
CN
3
5.50 (dd, 1H; J 10.14 Hz, J 8.76 Hz), 4.92 (dd, 1H; J 10.24 Hz, J
8.61 Hz), 4.41 (t, 1H;
J
8.61 Hz) ppm. 13C NMR (CDCl3,
Scheme 2.
75 MHz): d = 162.0, 147.1, 146.4, 145.5, 144.2, 142.4, 141.2,
128.8, 127.9, 126.7, 75.3, 70.4 ppm. TOFMS ES+ for C13H11N3O
theoretical [M+H]+: 226.0980; measured [M+H]+: 226.0972. IR-
TF (KBr pellets, cmÀ1): 702.3; 1022.9; 1517.7; 1652.8; 2930.5;
3374.4.
The yield of isolated bis-oxazoline was either higher or compa-
rable to that reported in the literature using solvents and catalytic
amounts of various metallic salts.35 Nevertheless, we aim to test
other bisnitriles and to extend this methodology by optimizing
the experimental conditions.
4.2.2. (S)-4-Isopropyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole 2c
83%; Colorless oil;
[a
]D = À38
2
(c 0.8, CHCl3). 1H NMR
3. Conclusion
(CDCl3, 300 MHz): d = 9.26 (s, 1H), 8.67 (s, 1H), 4.53 (m, 1H),
4.21 (m, 2H), 1.90 (m, 1H), 1.07 (d, 3H; J 3.75 Hz), 0.96 (d, 3H;
J 3.75 Hz) ppm. 13C NMR (CDCl3, 75 MHz): d = 160.7, 146.1,
145.2, 144.1, 142.6, 73.1, 70.9, 32.7, 18.9, 18.1 ppm. TOFMS ES+
for C10H13N3O theoretical [M+H]+: 192.1137; measured [M+H]+:
192.1128. IR-TF (KBr pellets, cmÀ1): 668.4; 1020.6; 1533.8;
1675.5; 2963.4; 3390.4.
The reported method proved to be rapid and efficient in con-
verting nitriles into 2-oxazolines in high yields. Unlike some of
the previously reported methods, our microwave closed vessel
technique requires short reaction times, avoids the use of solvents
and of any catalysts. A simple work-up procedure, general applica-
bility, high yields, and mild reaction conditions have made this
approach distinctly superior to the many other protocols reported
earlier.
4.2.3. (S)-4-Benzyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole 2a
95%; Colorless oil; [
a
]
D = À18.5 2.2 (c 1.035, CHCl3). 1H NMR
(CDCl3, 300 MHz): d = 9.27 (s, 1H), 8.68 (s, 1H), 7.28 (m, 5Haromat),
4.71 (m, 1H), 4.48 (td, 1H; J 9.2 Hz), 4.26 (td, 1H; J 5.2 Hz), 3.30
(ddd, 1H; J 13.6 Hz, J 5.2 Hz), 2.81 (ddd, 1H; J 13.6 Hz, J 8.8 Hz)
ppm. 13C NMR (CDCl3, 75 MHz): d = 161.3, 146.3, 145.2, 144.1,
142.5, 137.4, 129.2, 128.6, 126.7, 72.5, 68.2, 41.4 ppm. TOFMS ES+
for C14H13N3O theoretical [M+H]+: 240.1137; measured [M+H]+:
240.1137. IR-TF (KBr pellets, cmÀ1): 699.5; 1021.5; 1533.7;
1652.8; 2921.1; 3362.9.
4. Experimental
4.1. General comments
Unless otherwise noted, all starting materials were obtained
from commercial suppliers and used without purification. NMR
spectra were recorded on 300 MHz and 200 MHz Bruker spec-
trometers. Chemical shifts were reported in ppm relative to the
residual solvent peak (7.27 ppm for CHCl3) for 1H spectra and
(77.00 ppm for CDCl3) for 13C spectra. High Resolution Mass
spectroscopy data were recorded on an Autospec Ultima
(Waters/Micromass) device with a resolution of 5000 RP at 5%.
Thin-layer chromatography (TLC) was carried out on aluminum
sheets precoated with silica gel 60 F254. The chromatographic
analysis was performed on a chiral OJ-H column. A mobile phase
of heptane/2-propanol [95:5] was used with a flow rate of
1.0 mL/min at 30 °C. Microwave irradiations were realized using
4.2.4. (S)-4-Methyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole 2d
91%; Yellow oil; [
a
]
D = À41.9 2.4 (c 1.135, CHCl3).1H NMR
(CDCl3, 300 MHz): d = 9.24 (s, 1H), 8.66 (s, 2H), 4.58 (m, 1H), 4.48
(dd, 1H; J 15.87 Hz, J 8.01 Hz), 4.06 (m, 1H), 1.40 (dd, 3H; J
6.48 Hz, J 1.2 Hz) ppm. 13C NMR (CDCl3, 75 MHz): d = 160.8,
146.2, 145.1, 144.1, 142.5, 74.0, 62.5, 21.1 ppm. TOFMS ES+ for
C8H10N3O theoretical [M+H]+: 164.0824; measured [M+H]+:
164.0821. IR-TF (KBr pellets, cmÀ1): 668.3; 1020.7; 1531.8;
1652.8; 2975.8; 3392.9.

1278
R. Hassani et al. / Tetrahedron: Asymmetry 25 (2014) 1275–1279
4.2.5. (S)-5-Methyl-2-(pyrazin-2-yl)-4,5-dihydrooxazole 2e
82%; Yellow oil; [
D = +23 4 (c 0.8, CHCl3). 1H NMR (CDCl3,
4.2.12. (S)-2-(4-Chlorophenyl)-4-isopropyl-4,5-dihydrooxazole
2l
a
]
300 MHz): d = 9.41 (s, 1H), 8.77 (d, 1H; J 2.16 Hz), 8.55 (d, 1H; J
1.11 Hz), 4.08 (m, 1H), 3.69 (m, 1H), 3.38 (m, 1H), 1.29 (dd, 3H; J
6.36 Hz, J 0.99 Hz) ppm. 13C NMR (CDCl3, 75 MHz): d = 163.8,
147.3, 145.1, 144.4, 142.5, 67.3, 46.8, 21.0 ppm. TOFMS ES+ for
C8H10N3O theoretical [M+H]+: 164.0824; measured [M+H]+:
164.0821. IR-TF (KBr pellets, cmÀ1): 668.4; 1024.7; 1533.8;
1653.1; 2975.8; 3392.9.
100%; Yellow oil; 1H NMR (CDCl3, 200 MHz): d = 7.90 (d, 2H; J
8.6 Hz), 7.38 (d, 2H; J 8.6 Hz), 4.37–4.47 (m, 1H), 4.04–4.20 (m,
2H), 1.82–1.92 (m, 1H), 1.03 (d, 3H; J 6.8 Hz), 0.93 (d, 3H; J
6.8 Hz) ppm. 13C NMR (CDCl3, 75 MHz): d = 162.5, 137.3, 129.6,
128.5, 126.4, 72.6, 70.3, 32.8, 18.9, 18.0 ppm. Data in agreement
with the literature.33
4.2.13. (S)-4-Benzyl-2-(naphthalen-1-yl)-4,5-dihydrooxazole 2m
4.2.6. (S)-4-Phenyl-2-(pyridin-2-yl)-4,5-dihydrooxazole 2f
82%; Yellow oil; 1H NMR (CDCl3, 300 MHz): d = 8.75 (d, 1H; J
4.6 Hz), 8.18 (d, 1H; J 7.8 Hz), 7.78–7.85 (m, 1H), 7.29–7.47 (m,
5H), 5.42–5.52 (m, 1H), 4.87–4.96 (m, 1H), 4.40 (t, 1H; J 8.4 Hz)
ppm. Data in agreement with the literature.17
76%; Colorless oil; [a]
D = +14 1.9 (c 0.75, CHCl3). 1H NMR
(CDCl3, 200 MHz): d = 9.06 (dd, 1H; J 8.32 Hz, J 1.14 Hz), 8.10 (dd,
1H; J 7.24 Hz, J 1.28 Hz), 7.98 (d, 1H; J 8.64 Hz), 7.89 (dd, 1H; J
7.4 Hz, J 1.8 Hz), 7.54 (m, 3H), 7.31 (m, 5H), 4.78 (m, 1H), 4.44 (t,
1H, J 8.6 Hz), 4.24 (dd, 1H; J 8.48 Hz, J 7.28 Hz), 3.35 (dd, 1H; J
13.72 Hz, J 5.08 Hz), 2.90 (dd, 1H; J 13.72 Hz, J 8.48 Hz) ppm. 13C
NMR (CDCl3, 75 MHz): d = 163.9, 138.0, 133.7, 131.9, 131.1,
130.7, 129.3, 128.9, 128.5, 128.4, 127.2, 126.5, 126.4, 126.0,
124.6, 70.8, 68.6, 41.9 ppm. TOFMS ES+ for C20H18NO theoretical
[M+H]+: 288.1388; measured [M+H]+: 288.1390. IR-TF (KBr pellets,
cmÀ1): 702.3; 777.4; 996.9; 1125.4; 1191.8; 1510.9; 1642.5;
2923.4; 3060.0.
4.2.7. (S)-4-Isopropyl-2-(quinolin-2-yl)-4,5-dihydrooxazole 2g
73%; Colorless oil; 1H NMR (CDCl3, 300 MHz): d = 8.27 (d, 1H; J
8.4 Hz), 8.23 (s, 2H), 7.84 (d, 2H; J 8.1 Hz), 7.77–7.72 (m, 1H), 7.59
(t, 1H; J 7.5 Hz), 4.64–4.56 (m, 1H), 4.36–4.17 (m, 2H), 2.03–1.90
(m, 1H), 1.08 (d, 3H; J 6.8 Hz), 0.97 (d, 3H; J 6.8 Hz) ppm. Data in
agreement with the literature.31
4.2.8. (S)-2-(5-Chlorothiophen-2-yl)-4-phenyl-4,5-dihydrooxazole
4.2.14. (S)-4-Isopropyl-2-(naphthalen-1-yl)-4,5-dihydrooxazole
2h
2n
98%; Yellow oil; [a]
D = +6.4 3.1 (c 0.44, CHCl3). 1H NMR (CDCl3,
70%; Yellow oil; [a]
D = À63.6 1.9 (c 0.75, CHCl3). 1H NMR
300 MHz): d = 7.54 (d, 1H; J 3.93 Hz), 7.32 (m, 5H), 6.95 (d, 1H; J
4.02 Hz), 5.38 (dd, 1H; J 8.16 Hz, J 9.87 Hz), 4.81 (dd, 1H; J
8.46 Hz, J 9.99 Hz), 4.30 (t, 1H; J 8.23 Hz) ppm. 13C NMR (CDCl3,
75 MHz): d = 159.5, 141.7, 135.2, 130.3, 128.8, 128.3, 127.8,
127.0, 126.7, 75.3, 70.0 ppm. TOFMS ES+ for C13H11NOSCl theoret-
ical [M+H]+: 264.0250; measured [M+H]+: 264.0250. IR-TF (KBr
pellets, cmÀ1): 698.9; 1034.0; 1250.3; 1437.4; 1533.9; 1646.1;
2921.4; 3028.7.
(CDCl3, 300 MHz): d = 9.13 (d, 1H; J 8.55 Hz), 8.10 (d, 1H; J
7.23 Hz), 7.97 (d, 1H; J 5.19 Hz), 7.89 (d, 1H; J 8.13 Hz), 7.56 (m,
3H), 4.48 (dd, 1H; J 7.92 Hz, J 9 Hz), 4.25 (m, 2H), 1.98 (m, 1H),
1.14 (d, 3H ; J 6.75 Hz), 1.04 (d, 3H ; J 9.75 Hz) ppm.13C NMR
(CDCl3, 75 MHz): d = 163.3, 133.7, 131.7, 131.2, 128.9, 128.4,
127.2, 126.4, 126.0, 124.7, 124.6, 73.3, 69.3, 32.9, 19.0, 18.3 ppm.
TOFMS ES+ for C14H13N3O theoretical [M+H]+: 240.1388; measured
[M+H]+: 240.1392. IR-TF (KBr pellets, cmÀ1): 777.7; 1025.3;
1123.1; 1359.2; 1465.2; 1590.5; 1652.6; 2958.5; 3050.2.
4.2.9. (S)-2-(5-Chlorothiophen-2-yl)-4-isopropyl-4,5-dihydrooxazole
2i
4.2.15. (S)-2-(4-Fluorophenyl)-4-isopropyl-4,5-dihydrooxazole
2o
95%; Yellow oil; [
a
]
D = À36.9 4 (c 0.8, CHCl3). 1H NMR (CDCl3,
200 MHz): d = 7.57 (d, 1H; J 2.72 Hz), 6.92 (d, 1H; J 3.98 Hz), 4.45
(m, 1H), 4.16 (m, 2H), 1.89 (m, 1H), 1.02 (d, 3H; J 6.58 Hz), 0.93
(d, 3H; J 10.02 Hz) ppm. 13C NMR (CDCl3, 75 MHz): d = 158.7,
133.6, 130.7, 127.1, 71.8, 70.9, 32.5, 18.7, 17.9 ppm. TOFMS ES+
for C10H13NOSCl theoretical [M+H]+: 230.0406; measured
[M+H]+: 230.0405. IR-TF (KBr pellets, cmÀ1): 668.3; 803.1;
1042.2; 1276.4; 1436.7; 1538.3; 1646.0; 2875.3; 2965.9.
93%; Yellow oil; 1H NMR (CDCl3, 300 MHz): d = 7.92–7.98 (m,
2H), 7.04–7.27 (m, 2H), 4.35–4.42 (m, 1H), 4.04–4.15 (m, 2H),
1.81–1.87 (m, 1H), 1.02 (d, 3H; J 6.9 Hz), 0.91 (d, 3H; J 6.6 Hz)
ppm. 13C NMR (CDCl3, 75 MHz): d = 166.2, 162.9, 162.4, 130.5,
124.1, 115.4, 115.1, 72.6, 70.2, 32.8, 18.8, 18.0 ppm. Data in agree-
ment with the literature.33
4.3. General one-pot procedure for the synthesis of 4-substituted-
bis-oxazolines
4.2.10. (S)-2-Cyclopropyl-4-phenyl-4,5-dihydrooxazole 2j
67%; Yellow oil; [a]
D = +25.3 3.5 (c 0.6, CHCl3). 1H NMR (CDCl3,
200 MHz): d = 7.30 (m, 5H), 5.15 (dd, 1H; J 7.86 Hz, J 10 Hz), 4.58
(dd, 1H; J 8.34 Hz, J 10 Hz), 4.06 (t, 1H; J 8.1 Hz), 1.77 (m, 1H),
0.99 (m, 4H) ppm. 13C NMR (CDCl3, 75 MHz): d = 170.0, 142.6,
128.6, 127.4, 126.5, 74.9, 69.3, 8.5, 7.3, 7.0 ppm. TOFMS ES+ for
The synthesis of 1,2-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-
yl)benzene 3 is representative. A G4 vial in a Monowave 300 vessel
was charged with phthalonitrile (37.2 mg, 0.290 mmol, 1 equiv)
C
12H14NO theoretical [M+H]+: 188.1075; measured [M+H]+:
mixed with
(L)-valinol (65.8 mg, 0.638 mmol, 2.2 equiv). The
188.1072. IR-TF (KBr pellets, cmÀ1): 701.3; 1030.4; 1172.1;
1250.1; 1405.3; 1455.3;1540.3; 1646.1.
resulting mixture was irradiated using the closed vessel mode at
150 °C for 60 min. The reaction mixture was quenched with ethyl
acetate and filtered through silica. The filtrate was dried over mag-
nesium sulfate, and concentrated by rota-evaporation under vac-
uum to give the corresponding 1,2-bis((S)-4-isopropyl-4,5-
dihydrooxazol-2-yl)benzene 1a (87 mg, 0.289 mmol, 100% yield)
as a colorless oil.
4.2.11. 1-((S)-4-Isopropyl-4,5-dihydrooxazol-2-yl)-1-
methoxyethanol 2k
75%; Yellow oil; [
a
]
D = À51.5 2.4 (c 1.18, CHCl3). 1H NMR
(CDCl3, 200 MHz): d = 5.83 (br s, 1H), 4.18 (m, 1H), 4.01 (m, 2H),
2.06 (s, 3H), 2.00 (s, 3H), 1.80 (m, 1H), 0.95 (d, 3H; J 4.38 Hz),
0.92 (d, 3H; J 2.42 Hz) ppm. 13C NMR (CDCl3, 75 MHz): d = 171.1,
170.1, 64.4, 53.4, 29.4, 20.8, 19.2, 18.5 ppm. TOFMS ES+ for
C9H18NO3 theoretical [M+H]+: 188.1287; measured [M+H]+:
188.1281. IR-TF (KBr pellets, cmÀ1): 607.0; 1037.4; 1236.0;
1539.2; 1646.1; 2967.4; 3081.9.
4.3.1. 1,2-Bis((S)-4-Isopropyl-4,5-dihydrooxazol-2-yl)benzene 1a
100%; Yellow oil; 1H NMR (CDCl3, 300 MHz): d = 7.76 (dd, 1H; J
6 Hz, J 3.6 Hz), 7.47 (dd, 1H; J 6 Hz, J 3.3 Hz), 4.34–4.43 (m, 1H),
4.05–4.14 (m, 2H), 1.86–1.92 (m, 1H), 1.05 (d, 3H; J 6.9 Hz), 0.96
(d, 3H; J 6.6 Hz) ppm. Data in agreement with literature.16

R. Hassani et al. / Tetrahedron: Asymmetry 25 (2014) 1275–1279
1279
16. Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173.
Acknowledgments
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The authors are grateful to the DGRS (Direction Generale de la
Recherche Scientifique) of the Tunisian Ministry of Higher Educa-
tion, Scientific Research and Information and Communication
Technologies, the CNRS, the University of Versailles Saint
Quentin-en-Yvelines, France, and ANR (ANR-11-BS07-030-01),
France, for the financial support.
19. Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J.
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