Study on the tandem synthesis of optically active 2-substituted 4 (or 5)-phenyl-1,3-oxazolines

Article abstract of DOI:10.1016/j.tet.2012.12.078

Optically active (S)-2-aryl-4 (or 5)-phenyl-1,3-oxazolines and (S)-2-fluoroalkyl-4-phenyl-1,3-oxazolines were synthesized from a tandem one-pot reaction of (S)-2-amino-2-phenylethanol with a corresponding carboxylic acid in toluene at 90 °C in the presence of PPh₃/CBr₄ and excess Et₃N. The use of aromatic carboxylic acids were determined to proceed through N-(2-bromo-1-phenyl-ethyl)-arylamides 5 and N-aroyl aziridine intermediates 6, which resulted in the formation of (S)-2-aryl-4-phenyl-1,3- oxazolines and (S)-2-aryl-5-phenyl-1,3-oxazolines, respectively. Concurrently, the reaction with fluorinated aliphatic carboxylic acid substrates proceeded via N-(2-hydroxy-1-phenyl-ethyl)-fluoroalkyl amide intermediates 8, which were converted into N-(2-bromo-1-phenyl-ethyl)-fluoroalkyl amide intermediates 9, and then into (S)-2-fluoroalkyl-4-phenyl-1,3-oxazolines as final products. Reaction mechanisms that mainly passed through the formation of aziridine intermediates 6 in the reaction with aromatic carboxylic acids and the formation of fluoroalkyl amide intermediates 8 and 9 in the reaction with fluorinated aliphatic carboxylic acid were proposed. The acidities of the carboxylic acids that were employed were found to play a key role in the selective formation of various intermediates during this reaction.

Full text of DOI:10.1016/j.tet.2012.12.078

Tetrahedron 69 (2013) 2150e2156
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study on the tandem synthesis of optically active 2-substituted
4 (or 5)-phenyl-1,3-oxazolines
,
b
,
a
a
a
c
Haizhen Jiang a , Wenjun Lu , Yeshan Cai , Wen Wan , Shaoxiong Wu ,
*
,
a,b,
*
Shizheng Zhu b , Jian Hao
*
a Department of Chemistry, Shanghai University, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
c Emory NMR Research Center, Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Optically active (S)-2-aryl-4 (or 5)-phenyl-1,3-oxazolines and (S)-2-fluoroalkyl-4-phenyl-1,3-oxazolines
were synthesized from a tandem one-pot reaction of (S)-2-amino-2-phenylethanol with a correspond-
ing carboxylic acid in toluene at 90 ꢀC in the presence of PPh3/CBr4 and excess Et3N. The use of aromatic
carboxylic acids were determined to proceed through N-(2-bromo-1-phenyl-ethyl)-arylamides 5 and N-
aroyl aziridine intermediates 6, which resulted in the formation of (S)-2-aryl-4-phenyl-1,3-oxazolines
and (S)-2-aryl-5-phenyl-1,3-oxazolines, respectively. Concurrently, the reaction with fluorinated ali-
phatic carboxylic acid substrates proceeded via N-(2-hydroxy-1-phenyl-ethyl)-fluoroalkyl amide in-
termediates 8, which were converted into N-(2-bromo-1-phenyl-ethyl)-fluoroalkyl amide intermediates
9, and then into (S)-2-fluoroalkyl-4-phenyl-1,3-oxazolines as final products. Reaction mechanisms that
mainly passed through the formation of aziridine intermediates 6 in the reaction with aromatic car-
boxylic acids and the formation of fluoroalkyl amide intermediates 8 and 9 in the reaction with fluori-
nated aliphatic carboxylic acid were proposed. The acidities of the carboxylic acids that were employed
were found to play a key role in the selective formation of various intermediates during this reaction.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 November 2012
Received in revised form 23 December 2012
Accepted 31 December 2012
Available online 8 January 2013
Keywords:
5-Phenyl-1,3-oxazolines
2-Fluoroalkyl-4-phenyl-1,3-oxazolines
Tandem synthesis
Aromatic carboxylic acids
Fluorinated carboxylic acids
1. Introduction
a tandem reaction for the synthesis of optically active 2-aryl or
fluoroalkyl-4 (or 5)-phenyl-1,3-oxazolines (Scheme 1), and explore
Optically active 1,3-oxazoline heterocycles are a fundamental
motif present in many bioactive molecules, natural products, and
organomaterials.1 In addition, 1,3-oxazoline heterocycles are ver-
satile chiral ligands.2 Many methods have been developed for the
synthesis of 1,3-oxazoline;3 however, most of these methods suffer
from having complicated procedures, being multistep reactions and
using harmful solvents or result in low yields.4 Aziridines are im-
portant organic synthetic intermediates.5 N-substituted aziridines
have been used extensively for ring-opening, ring-expansion and
cycloaddition chemical transformations because of the presence
of inherent ring-strain.6 Recently, we reported that N-aroyl azir-
idines generated in situ from the reaction of (S)-2-amino-3-
phenylpropanol with various aromatic carboxylic acids in the
presence of PPh3/CBr4 could be transformed into the optically ac-
tive (S)-4-benzyl-1,3-oxazolines or (S)-5-benzyl-1,3-oxazolines via
ring-opening of the aziridines and subsequent cyclization.7 This
synthetic methodology was demonstrated to be an effective tan-
dem reaction process for the synthesis of optically active 4 or 5-
benzyl-1,3-oxazoline. As part of our ongoing studies, we present
the reason for the selective formation of different products as
various types of carboxylic acids were employed.
Ph
O
N
O
Ar
Ar
+
R
= Ar
= R
1
N
3
Ph
OH
NH
3'
Ph P/CBr
3
Et N
3
4
Minor
Major
+
R COOH
1
Ph
2
O
1
2
R
1
F
R
F
N
4
Ph
Scheme 1. Synthesis of 4 (or 5)-phenyl-1,3-oxazolines.
2. Results and discussion
As previously reported,7 the tandem reaction of (S)-2-amino-3-
phenylpropanol with various aromatic acids in the presence of
PPh3/CBr4 provided (S)-4-benzyl-1,3-oxazolines as the major
products and unexpectedly produced (S)-5-benzyl-1,3-oxazoline as
minor products. However, the use of (S)-2-amino-2-phenylethanol
* Corresponding authors. E-mail address: hzjiang@shu.edu.cn (H. Jiang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.078

H. Jiang et al. / Tetrahedron 69 (2013) 2150e2156
2151
and naphthalene-2-carboxylic acid resulted in the opposite distri-
bution of products: (S)-5-phenyl-1,3-oxazoline (3a) was the major
product, while (S)-4-phenyl-1,3-oxazoline (3a0) was the minor
product (entry 1, Table 1). In addition, the reaction of (S)-2-amino-
2-phenylethanol with trifluoroacetic acid resulted in the formation
of (S)-2-trifluoromethyl-4-phenyl-1,3-oxazoline (4k) (entry 11,
Table 1) as the only product. The interesting experimental results
prompted us to further investigate the tandem reaction and explore
the transformation process.
The reaction was performed in the presence of 3 equiv of PPh3/
CBr4 in toluene at 90 ꢀC via a one-pot process. The reaction of the-
various aromatic carboxylic acids with (S)-2-amino-2-phenylethanol
Table 1
The reaction of (S)-2-amino-2-phenylethanol with aromatic (or fluorinated) carboxylic acids
Entry
1
R1COOH (2)
pKa
Product (3, 30, or 4)
Time (h)
2
Yielda (%) (3, 30, or 4)
Ph
O
O
N
COOH
4.17
62, 28
N
Ph
2a
3a'
3a
Ph
O
O
COOH
COOH
2
3
4.19
4.14
6
8
48, 29
62, 31
N
N
2b
Ph
3b'
3b
Ph
O
O
F
F
N
N
2c
F
Ph
3c'
3c
O
Ph
COOH
O
NO2
NO2
4
5
3.42
4.47
8
62, 31
45, 31
N
Ph
N
O2N
2d
3d
3d'
Ph
COOH
O
O
OCH3
OCH3
10
N
N
H3CO
2e
Ph
3e'
3e
Ph
O
O
COOH
N
N
Ph
6
3.51
14
53, 24
O
O
O
2f
3f
3f'
Ph
Ph
O
O
O
O
O
S
7
8
3.16
3.51
14
8
49, 21
42, 23
COOH
2g
2h
N
N
Ph
3g'
3g
O
N
S
N
O
N
S
N
COOH
Ph
3h
3h'
Ph
O
O
N
COOH
Cl
F
Cl
F
9
3.24
1.6
13
20
19, 34
43, 20
N
Ph
Cl
N
2i
2j
3i
3i'
F
F
F
F
F
F
F
F
Ph
O
O
N
F
F
COOH
F
10
N
Ph
F
F
3j
3j'
O
CF3
11
12
13
CF3COOH 2k
HCF2COOH 2l
0.5
1.3
42
55
61
42
65
N
Ph
4k
O
CF2H
N
Ph
4l
O
CF2Br
BrCF2COOH 2m
CH3COOH 2n
0.2
18
42
N
Ph
4m
b
14
4.75
/
/
a
Isolated yields.
No desired product was observed.
b

2152
H. Jiang et al. / Tetrahedron 69 (2013) 2150e2156
resulted in2-aryl-1,3-oxazolines withthe retentionof stereochemical
configuration in excellent overall yields (Table 1). The aromatic car-
boxylic acids with electron-withdrawing groups resulted in com-
paratively higher yields (entry 3, 4) than aromatic carboxylic acids
with electron-donating groups (entry 5). When perfluorinated ben-
zoic acid was used, the reaction provided 2-pentafluorophenyl-5-
To clarify the results of the tandem reactions using (S)-2-amino-
2-phenylethanol with various carboxylic acids, isolation, and iden-
tification of the reaction intermediates were attempted by per-
forming the reaction of different carboxylic acids with 1 equiv of (S)-
2-amino-2-phenylethanol and 3 equiv of PPh3/CBr4 in toluene, un-
der a nitrogen atmosphere. The reaction with naphthalene-2-
carboxylic acid was performed at room temperature for 10 min,
and then heated at 90 ꢀC. The intermediate (S)-1-(2-naphthoyl)-2-
phenylaziridine (6a, Scheme 2) was observed after 0.5 h by TLC,
and it was isolated in 16% yield as a white solid7 that could be
completely converted into product of (S)-5-phenyl-1,3-oxazolines
(3a) with the retention of stereochemical configuration, under the
reaction conditions described above. Other intermediates with the
general structure of 6 were observed by GCeMS analysis of the re-
action mixtures (e.g., pentafluorophenyl-(2-phenyl-aziridin-1-yl)-
methanone (6j) (Mþ: 313, base peak m/z: 195)). Moreover, the ex-
periments demonstrated that pentafluorophenyl-(2-phenyl-azir-
idin-1-yl)-methanone (6j) could be completelyconverted into (S)-5-
phenyl-1,3-oxazoline (3j, Mþ: 313, base peak m/z: 207). This tandem
reaction combines three steps in a one-pot process: the formation of
N-aroyl aziridine intermediate 6 in the presence of PPh3/CBr4, the
subsequent ring-opening reaction of 6 at the arylmethyl carbon by
a Brꢁ nucleophile generated from PPh3/CBr4,8 followed by intra-
molecular nucleophilic cyclization (Scheme 2, path a). The config-
uration of the stereogenic center of the products was retained
because inversion of the stereogenic center occurred twice during
the ring-opening of the N-aroyl aziridine intermediate and the ring
closure that formed the product in this tandem transformation. The
retention of the configuration was also demonstrated by the mea-
surement of enantiomeric purity. For example, the enantiomer ex-
cess value (ee%) of (S)-5-phenyl-1,3-oxazoline 3a was 99.5%. The
minor product, (S)-4-phenyl-1,3-oxazoline, could be obtained from
the intramolecular ring closure of a noncyclized amide intermediate
(5, Scheme 2) in the presence of Et3N.7 Although the noncyclized
phenyl-1,3-oxazoline
and
2-pentafluorophenyl-4-phenyl-1,3-
oxazoline in 43% and 20% yield, respectively (entry 10). Addition-
ally, the 5-phenyl-1,3-oxazolines were the major products for all re-
actions that used aromatic carboxylic acids. Further experiments
demonstrated that aromatic heterocyclic acids that contained either
nitrogen (N), oxygen (O) or sulfur (S) could be employed in this
tandem reaction to obtain optically active 1,3-oxazolines (entries 7, 8,
and 9).
To expand the application of this tandem one-pot reaction,
several fluorinated aliphatic carboxylic acids were used as re-
actants. The reaction of trifluoroacetic acid with (S)-2-amino-2-
phenylethanol, performed in the presence of PPh3/CBr4 in toluene
at 90 ꢀC with excess Et3N, resulted in one product 4k (entry11, Table
1), which was observed as a singlet at ꢁ69.97 ppm in the 19F NMR
spectrum of the reaction mixture. This result suggested that the
procedure of reaction with fluorinated aliphatic carboxylic acids is
different from a reaction with aromatic carboxylic acids and aro-
matic heterocyclic acids. A variety of techniques (e.g., 1H NMR, 13
C
NMR, 19F NMR, GCeMS, and HPLC) were used to determine that the
fluorinated product was (S)-2-trifluoromethyl-4-phenyl-1,3-
oxazoline with the retention of stereochemical configuration (99%
ee). Other fluorinated aliphatic carboxylic acids (e.g., difluoroacetic
acid and bromodifluoroacetic acid) provided the formation of
similar (S)-2-fluoroalkyl-4-phenyl-1,3-oxazoline products in mod-
erate yields (Table 1, entries 12 and 13). However, the use of non-
fluorinated aliphatic carboxylic acids did not result in the desired
2-alkyl-4 (or 5)-phenyl-1,3-oxazolines under the same reaction
conditions (Table 1, entries 14).
OH
NH
R
2
1
Ph P/CBr
3
4
R COOH
F
path b
ArCOOH
path a
R = Ph
Et N
3
OH
OH
Br
OH
R
NH
Ph
N
10
R
F
Ph
NHCOR
2
F
8
Et N
3
Ph P/CBr
3
4
CBr
Ph P
4
3
Br
NH
O
C
+
k
Br
OH
Br
R
O
R
N
Ar
H
5
Ph
Ph
N
H
R
F
Ar
O
Ph
N
R
"
F
N
"
Br
a
N
t
t
9
a
c
"O" attack
Et N
Et N
3
3
R
6
O
O
Et N
Ph P/CBr
3
3
4
R
F
Ar
N
N
R
R = Bn
Ref. 7
R = Ph
4
(Minor)
3'
H
N
Bn
O
O
Ar
Ar
+
Ar
H
N
N
Minor
Bn
O
Br
Ph
Major
7
Et N
3
Ph
O
Ar
N
(Major)
3
Scheme 2. The proposed mechanism for the formation of the various products.

H. Jiang et al. / Tetrahedron 69 (2013) 2150e2156
2153
amide intermediate 5 in the reaction mixture of (S)-2-amino-2-
phenylethanol with perfluorinated benzoic acid was not observed
after 2 h by GCeMS, the minor product ofþ2-pentafluorophenyl-4-
phenyl-1,3-oxazoline (3j0) was found (M : 313, base peak m/z:
283). The formation of the N-aroyl aziridine intermediate 6 may be
easier than the direct ring closure of the noncyclized amide in-
termediate 5 in the reaction system; therefore, the 5-phenyl-1,3-
oxazoline 3 was obtained as the major product.
intermediate 5, there was the competition of the O or N to attack
the brominated carbon for cyclization into the five-membered ring
product or three-membered ring N-aroyl aziridine intermediate.
Conjugation of the carbonyl group with the aromatic ring would
reduce the nucleophilicity of the oxygen, which would cause the
closure of the five-membered ring to be more difficult than that of
the three-membered ring. Therefore, this tandem one-pot reaction
was suggested to have mainly passed through the formation of
aziridine intermediate 6 in the reaction with aromatic carboxylic
acids. This was also the reason that (S)-5-phenyl-1,3-oxazoline 3
was the major product. On the other hand, for relatively strong
fluorinated aliphatic carboxylic acids (pKa¼0.5e1.3), the formation
of fluorinated amide 8 illustrated that this reaction preferentially
underwent the amidation of amino group of (S)-2-amino-2-
phenylethanol. Subsequently, the hydroxyl group at the sp3-hy-
bridized carbon atom of 8 was halogenated to intermediate 9 in the
presence of PPh3/CX4, rather than the halogenations of the hy-
droxyl group at the sp2-hybridized carbon atom of the imino al-
cohol 10 from the amide 8 tautomer to the imidoyl halide reported
by Uneyama. Finally, intermediate 9 easily underwent intra-
molecular cyclization to form the 2-fluoroalkyl-4-phenyl-1,3-
oxzaline product only.
When fluorinated aliphatic carboxylic acid, such as trifluoroacetic
acid, was used as the substrate, the intermediate 8k was observed by
GCeMS and was isolated from the mixture of the reaction of (S)-2-
amino-2-phenylethanol after 2 h. The intermediate 8k could not be
directly converted into the product 4k in the presence of Et3N. One
possible reason is that the strong electron-withdrawing inductive
effect of the fluoroalkyl group reduced the polarization of the C]O
bond, which caused the attack of the hydroxyl group on the carbonyl
carbon of intermediate 8k to be weak and resulted in the inefficient
formation of the 1,3-diazoline 4k. 2-Trifluoromethyl-4-phenyl-1,3-
diazoline (4k) could be obtained from 8k only when PPh3/CBr4 and
an excess Et3N were added to the isolated amide 8kintolueneat 90 ꢀC.
This result indicates that the desired 1,3-oxazoline 4k should be
transformed via the other intermediate, which was derived from
amide 8k in the presence of Ph3P/CBr4 and excess Et3N. According to
Uneyama’s reports,9 amides were easily converted to imidoyl halides
in the presence of PPh3/CX4. However, the reaction of (S)-2-amino-2-
phenylethanol with trifluoroacetic acidresulted intheformationof an
N-(2-halo-1-phenyl-ethyl)-2,2,2-trifluoro-acetamide (9), which was
different from the imidoyl halide intermediate. GCeMS analysis in-
dicated that there was N-(2-chloro-1-phenyl-ethyl)-2,2,2-trifluoro-
acetamide 9k0 (wherein halo is chloro) (Mþ: 251, t¼9.81 min) and
amide 8k (Mþ: 233, t¼7.38 min) with the generation of product 4k
(Mþ: 215, t¼7.90 min) in the reaction system of (S)-2-amino-2-
phenylethanol with trifluoroacetic acid in the presence of PPh3/CCl4.
The structure of N-(2-chloro-1-phenyl-ethyl)-2,2,2-trifluoro-
acetamide (9k0) was also further confirmed by X-ray diffraction
(Fig. 1). Intermediate 9k (Mþ: 295, t¼10.50 min) was also observed
by GCeMS in the presence of PPh3/CBr4 after reacting for 2 h. N-(2-
Halo-1-phenyl-ethyl)-2,2,2-trifluoro-acetamide (9) was obviously
generated from N-(2-hydroxy-1-phenyl-ethyl)-2,2,2-trifluoro-
acetamide (8k) in the presence of PPh3/CX4 and Et3N. The forma-
tion of N-(2-halo-1-phenyl-ethyl)-2,2,2-trifluoro-acetamide (9)
versus imidoyl halide could depend on the structure of the sub-
strate of 2-hydroxy-ethylamine. Additionally, the isolated N-(2-
chloro-1-phenyl-ethyl)-2,2,2-trifluoro-acetamide (9k0) can easily
be converted into 2-trifluoromethyl-4-phenyl-1,3-oxazoline (4k)
in 94% yield in the presence of NEt3.
3. Conclusions
In summary, the optically active (S)-2-aryl-4 (or 5)-phenyl-1,3-
oxazolines and 2-fluoroalkyl-4-phenyl-1,3-oxazolines were effi-
ciently prepared through a tandem one-pot reaction of (S)-2-
amino-2-phenylethanol with a corresponding aromatic or fluori-
nated aliphatic carboxylic acid in toluene at 90 ꢀC in the presence of
3 equiv of PPh3/CBr4 and excess Et3N. Through the observation or
isolation of reaction intermediates, the reaction with aromatic
carboxylic acids was proposed to proceed via N-(2-bromo-1-
phenyl-ethyl)-arylamide intermediates 5 and N-aroyl aziridine in-
termediates 6. Subsequently, the N-aroyl aziridine intermediates 6
underwent ring-opening in the presence of PPh3/CBr4, which were
followed by rapid intramolecular cyclization to form (S)-2-aryl-5-
phenyl-1,3-oxazolines as the major products, while N-(2-bromo-
1-phenyl-ethyl)-arylamides 5 directly cyclized to form (S)-2-aryl-4-
phenyl-1,3-oxazolines as the minor products. When fluorinated
aliphatic carboxylic acids were used as the substrates, the reaction
first resulted in the formation of the N-(2-hydroxy-1-phenyl-
ethyl)-fluoroalkyl amide intermediates 8, and then converted 8 into
N-(2-halo-1-phenyl-ethyl)-fluoroalkyl amide intermediates 9,
which finally underwent ring closure to form 2-fluoroalkyl-1,3-
oxazolines 4 as the only products.
4. Experimental section
4.1. General methods
4.1.1. General comments. 1H, 13C, and 19F NMR spectra were recor-
ded on 500 MHz spectrometers. Chemical shifts for 1H NMR spectra
are reported in parts per million downfield from TMS, chemical
shifts for 13C NMR spectra are reported in ppm relative to internal
chloroform (d
77.2 ppm for 13C), and chemical shifts for 19F NMR
Fig. 1. An ORTEP plot of the intermediate 9k0 and its packing diagram.
spectra are reported in ppm downfield from internal fluorotri-
chloromethane (CFCl3). Infrared spectra (IR) were recorded with
KBr pellets. Silica gel (200e400 mesh) was used for flash column
chromatography. Melting points are uncorrected. Single-crystal
In the reaction with aromatic carboxylic acids with relatively
weak acidity, halogenation of the hydroxyl group of (S)-2-amino-2-
phenylethanol could occur preferentially, proceeding via amidation
of the amino group in this reaction condition to intermediate 5 or 6
(Scheme 2, path a), because no product of the amidation of amino
group, such as N-(2-hydroxy-1-phenyl-ethyl)-amide, was observed
by GCeMS in the reaction of (S)-2-amino-2-phenylethanol with
perfluorinated benzoic acid after 2 h. Following the formation of
XRD was performed with graphite-monochromatic MoKa radia-
ꢀ
tion (
l
¼0.71073 A) on a Bruker Smart ApexII CCD diffractometer at
T¼273 (2) K. The structures were solved by direct method with
SHELXS-97 program and refined by full matrix least-squares on F2
with SHELXL-97 program. All non-hydrogen atoms were refined
anisotropically, and hydrogen atoms were located and included at

2154
H. Jiang et al. / Tetrahedron 69 (2013) 2150e2156
their calculated position. Optical rotations were recorded on high
sensitive polarimeter with 200 mm cell. The enantiomeric purity
was determined by chiral HPLC (Sino-Chiral AD 0.46ꢂ25 cm col-
umn and n-hexane and isopropylol as mobile phase). Mass spectra
were obtained using ESI or EI. High resolution mass spectra were
obtained using EI at 70 eV.
CCDC 896966 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_-
request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge CB21EZ, UK; fax:
þ44 1223 336033.
(t, J¼8.5 Hz, 1H, CH2); 13C NMR (125 MHz, CDCl3, ppm):
d 164.8,
142.4, 131.6, 128.8, 128.5, 128.4, 127.7, 127.6, 126.8, 74.9, 70.2; IR
(KBr, cmꢁ1):
695.
n 3028, 2924, 1648, 1605, 1495, 1451, 1361, 1081, 780,
4.2.5. (S)-2-(4-Fluorophenyl)-5-phenyl-1,3-oxazoline (3c). Pale yel-
low solid; mp 55.3e56.1 ꢀC; 0.42 g, 62%; ½a 2D5
ꢁ9.7 (c 1.066, CHCl3);
ꢃ
1H NMR (500 MHz, CDCl3, ppm):
d 8.04e8.00 (m, 2H, ArH),
7.41e7.37 (m, 2H, ArH), 7.35e7.32 (m, 3H, ArH), 7.13e7.10 (m, 2H,
ArH), 5.66 (dd, J¼8.0, 10.0 Hz, 1H, CH), 4.47 (dd, J¼10.0, 14.5 Hz, 1H,
CH2), 3.99 (dd, J¼8.0, 14.5 Hz, 1H, CH2); 19F NMR (125 MHz, CDCl3,
ppm):
d
ꢁ107.97e108.00 (m, 1F); 13C NMR (500 MHz, CDCl3, ppm):
1
3
d
164.9 (d, JCeF¼251.3 Hz), 163.3, 141.0, 130.7 (d, JCeF¼8.8 Hz),
4.2. General procedure for the preparation of (S)-2-aryl-4 (5)-
129.0, 128.5, 125.9, 124.0 (d, 4JCeF¼3.8 Hz), 115.7 (d, 2JCeF¼21.3 Hz),
phenyl-1,3-oxazolines 30and 3
81.4, 63.3; IR (KBr, cmꢁ1):
n 3033, 2936,1653,1605,1509,1412,1225,
1070, 847, 735, 699; HRMS (EI) calcd for (Mþ) C15H12FNO: 241.0903,
found 241.0901.
A 200 mL three-necked flask equipped with a condenser was
charged with Ph3P (2.20 g, 8.4 mmol), Et3N (0.85 g, 8.4 mmol), CBr4
(16.8 g, 8.4 mmol), substrate 1 (3.3 mmol), and aromatic acid 2
(2.8 mmol) in toluene (15.0 mL) under a nitrogen atmosphere. The
solution was stirred for approximately 20 min at room tempera-
ture, then the mixture was heated at 90 ꢀC with stirring for 6e14 h.
The solvent was evaporated under reduced pressure, and the resi-
due was diluted with petroleum ether (60e90 ꢀC) and filtered. The
residual solid Ph3PO and Et3N$HBr was washed with petroleum
ether three times. The filtrate was concentrated, and the residue
was separated by column chromatography (ethyl acetate/petro-
leum ether, 1:8) to afford product 3 and 30. If the mixture was
processed after stirring for 0.5 h at 90 ꢀC, intermediate 6 was ob-
tained by column chromatography (ethyl acetate/petroleum
ether¼1:8).
4.2.6. (S)-2-(4-Fluorophenyl)-4-phenyl-1,3-oxazoline (3c0). Pale yel-
low solid; mp 52.3e54.1 ꢀC; 0.21 g, 31%; ½a 2D5
þ3.3 (c 0.584, CHCl3);
ꢃ
1H NMR (500 MHz, CDCl3, ppm):
d 8.07e8.03 (m, 2H, ArH),
7.38e7.35 (m, 2H, ArH), 7.31e7.28 (m, 3H, ArH), 7.14e7.10 (m, 2H,
ArH), 5.38 (dd, J¼8.5, 10.0 Hz, 1H, CH), 4.80 (dd, J¼8.5, 10.0 Hz, 1H,
CH2), 4.28 (t, J¼8.5 Hz, 1H, CH2); 19F NMR (470 MHz, CDCl3, ppm):
d
d
ꢁ107.76 to ꢁ107.80 (m, 1F); 13C NMR (125 MHz, CDCl3, ppm):
1
3
165.0 (d, JCeF¼246.4 Hz), 164.0, 142.3, 130.9 (d, JCeF¼8.8 Hz),
128.9, 127.8, 126.8, 123.9 (d, 4JCeF¼2.5 Hz), 115.7 (d, 2JCeF¼22.5 Hz),
75.1, 70.2; IR (KBr, cmꢁ1.):
n 3028, 2934, 1646, 1524, 1336, 1066, 976,
846, 700; HRMS (EI) calcd for (Mþ) C15H12FNO: 241.0903, found
241.0903.
4.2.7. (S)-2-(4-Nitrophenyl)-5-phenyl-1,3-oxazoline (3d). Pale yel-
4.2.1. (S)-2-(2-Naphthyl)-5-phenyl-1,3-oxazoline (3a).7 White solid;
low solid; mp 133.1e134.9 ꢀC; 0.47 g, 62%; ½a 2D5
ꢁ19.9 (c 0.762,
ꢃ
0.47 g, 62%, mp 73.2e76.7 ꢀC; ½a D25
ꢃ
þ28.4 (c 0.984, CHCl3); 1H NMR
CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d
8.28 (d, J¼9.0 Hz, 2H,
(500 MHz, CDCl3):
d
8.53 (s, 1H, HAr), 8.12 (dd, J¼8.5,1.5 Hz,1H, HAr),
ArH), 8.18 (d, J¼9.0 Hz, 2H, ArH), 7.42e7.35 (m, 5H, ArH), 5.72 (dd,
7.93e7.87 (m, 3H, HAr), 7.58e7.51 (m, 2H, HAr), 7.41e7.34 (m, 5H,
HAr), 5.73 (dd, J¼10.0, 10.0 Hz, 1H, NCH2), 4.55 (dd, J¼15.0, 10.0 Hz,
1H, NCH2), 4.07 (dd, J¼15.0, 8.0 Hz, 1H, CH); 13C NMR (500 MHz,
J¼8.5, 10.0 Hz, 1H, CH), 4.53 (dd, J¼10.0, 15.0 Hz, 1H, CH2), 4.06 (dd,
J¼8.0, 15.5 Hz, 1H, CH2); 13C NMR (125 MHz, CDCl3, ppm):
d 162.3,
149.7, 140.4, 133.5, 129.4, 129.1, 128.8, 128.6, 125.9, 125.8, 123.7, 81.9,
CDCl3):
d
164.3, 141.2, 134.9, 132.8, 129.1, 129.0, 128.9, 128.5, 128.4,
63.4; IR (KBr, cmꢁ1):
n 3055, 2926, 1644, 1519, 1455, 1251, 1077, 758,
128.0, 127.7, 126.7, 126.0, 125.0, 124.9, 81.3, 63.5; IR (cmꢁ1):
2927, 1641, 1354, 1191, 1062, 962, 761, 699.
n
3033,
700; HRMS (EI) calcd for (Mþ) C15H12N2O3: 268.0848, found
268.0843.
4.2.2. (S)-2-(2-Naphthyl)-4-phenyl-1,3-oxazoline(3a0).7 White solid;
4.2.8. (S)-2-(4-Nitrophenyl)-4-phenyl-1,3-oxazoline (3d0).11a Pale yel-
0.21 g, 28%. Mp 110.6e112.0 ꢀC; ½a D25
ꢃ
ꢁ55.5 (c 1.016, CHCl3); 1H NMR
low solid; mp 88.3e90.1 ꢀC; 0.24 g, 31%; ½a 2D5
þ20.7 (c 1.072, CHCl3);
ꢃ
(500 MHz, CDCl3):
d
8.55 (s, 1H, HAr), 8.14 (dd, J¼8.5, 1.5 Hz, 1H, HAr),
1H NMR (500 MHz, CDCl3, ppm):
d
8.28 (dd, J¼9.0 Hz, 2H, ArH), 8.20
7.94e7.88 (m, 3H, HAr), 7.59e7.52 (m, 2H, HAr), 7.40e7.31 (m, 5H,
HAr), 5.45 (dd, J¼10.0, 10.0 Hz, 1H, OCH2), 4.87 (dd, J¼10.0, 10.0 Hz,
1H, OCH2), 4.35 (t, J¼8.0 Hz, 1H, CH); 13C NMR (500 MHz, CDCl3):
(dd, J¼8.5 Hz, 2H, ArH), 7.39e7.30 (m, 5H, ArH), 5.45 (dd, J¼10.0,
9.0 Hz, 1H, CH), 4.87 (dd, J¼8.5, 10 Hz, 1H, CH2), 4.35 (t, J¼8.5 Hz, 1H,
CH2); 13C NMR (125 MHz, CDCl3, ppm):
d
163.0, 149.7, 141.7, 133.4,
d
165.0, 142.5, 135.0, 132.8, 129.2, 129.1, 128.9, 128.3, 127.9, 127.8,
129.6, 129.0, 128.0, 126.8, 123.7, 75.4, 70.5; IR (KBr, cmꢁ1):
n 3035,
127.7, 127.0, 126.7, 125.1, 125.0, 75.1, 70.4; IR (cmꢁ1):
1642, 1361, 1194, 1064, 757, 694.
n
3026, 2912,
2924,1641,1525,1348,1230,1070, 744, 699; HRMS (EI) calcd for (Mþ)
C15H12N2O3: 268.0848, found 268.0846.
4.2.3. (S)-2,5-Diphenyl-1,3-oxazoline (3b).10 Clear oil; 0.30 g, 48%;
4.2.9. (S)-2-(4-Methoxyphenyl)-5-phenyl-1,3-oxazoline (3e). Pale
½
a 2D5
ꢃ
þ21.2 (c 0.821, CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
yellow oil; 0.32 g, 45%; ½a D25
ꢃ
ꢁ8.2 (c 0.880, CHCl3); 1H NMR
d
8.04e8.01 (m, 2H, ArH), 7.53e7.49 (m, 1H, ArH), 7.46e7.42 (m, 2H,
(500 MHz, CDCl3, ppm): d 7.98e7.95 (m, 2H, ArH), 7.40e7.31 (m, 5H,
ArH), 7.41e7.31 (m, 5H, ArH), 5.67 (dd, J¼8.0, 10.0 Hz, 1H, CH), 4.49
ArH), 6.95e6.92 (m, 2H, ArH), 5.63 (dd, J¼8.0, 10.0 Hz, 1H, CH), 4.46
(dd, J¼10.0, 15.0 Hz, 1H, CH2), 4.00 (dd, J¼8.0, 15.0 Hz, 1H, CH2); 13
C
(dd, J¼10.0, 14.5 Hz, 1H, CH2), 3.97 (dd, J¼8.0, 14.5 Hz, 1H, CH2), 3.85
NMR (125 MHz, CDCl3, ppm):
d
164.0, 141.1, 131.5, 128.8, 128.4,
(s, 3H, OCH3); 13C NMR (125 MHz, CDCl3, ppm):
d 163.8, 162.2, 141.2,
128.3, 127.7, 125.8, 81.1, 63.2; IR (KBr, cmꢁ1):
1605, 1495, 1451, 1256, 1063, 778, 696.
n
3033, 2927, 1651,
130.1, 128.8, 128.3, 125.8, 120.2, 113.8, 81.0, 63.2, 55.4; IR (KBr,
cmꢁ1):
n 3038, 2927, 1651, 1609, 1513, 1255, 837, 763, 700; HRMS
(EI) calcd for (Mþ) C16H15NO2: 253.1103, found 253.1097.
4.2.4. (S)-2,4-Diphenyl-1,3-oxazoline (3b0).11 Clear oil; 0.18 g, 29%;
½
a 2D5
ꢃ
ꢁ22.8 (c 0.690, CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
4.2.10. (S)-2-(4-Methoxyphenyl)-4-phenyl-1,3-oxazoline (3e0). Pale
d
8.07e8.05 (m, 2H, ArH), 7.53e7.50 (m, 1H, ArH), 7.47e7.43 (m, 2H,
yellow solid; mp 99.2e101.5 ꢀC; 0.22 g, 31%; ½a 2D5
þ41.3 (c 1.018,
ꢃ
ArH), 7.39e7.35 (m, 2H, ArH), 7.33e7.28 (m, 3H, ArH), 5.40 (dd,
J¼8.5, 10.0 Hz, 1H, CH), 4.81 (dd, J¼8.5, 10.5 Hz, 1H, CH2), 4.29
CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d 8.01e7.98 (m, 2H, ArH),
7.37e7.34 (m, 2H, ArH), 7.32e7.27 (m, 3H, ArH), 6.96e6.93 (m, 2H,

H. Jiang et al. / Tetrahedron 69 (2013) 2150e2156
2155
ArH), 5.36 (dd, J¼8.0, 10.0 Hz, 1H, CH), 4.77 (dd, J¼8.5, 10.0 Hz, 1H,
CH2), 4.25 (t, J¼8.0 Hz, 1H, CH2), 3.86 (s, 3H, OCH3); 13C NMR
5.0 Hz, 1H, ArH), 7.38e7.35 (m, 2H, ArH), 7.32e7.27 (m, 3H, ArH),
7.11 (dd, J¼4.0, 5.0 Hz, 1H, ArH), 5.37 (dd, J¼8.5, 10.0 Hz, 1H, CH),
4.78 (dd, J¼8.5, 10.0 Hz, 1H, CH2), 4.27 (t, J¼8.5, 10.0 Hz, 1H, CH2);
(125 MHz, CDCl3, ppm):
d 164.6, 162.3, 142.7, 130.3, 128.8, 127.6,
126.8, 120.0, 113.8, 74.8, 70.1, 55.4; IR (KBr, cmꢁ1):
n
3033, 2959,
13C NMR (125 MHz, CDCl3, ppm):
d 160.5, 142.1, 130.8, 130.2, 130.1,
1648, 1608, 1256, 1030, 843, 759, 698; HRMS (EI) calcd for (Mþ)
C16H15NO2: 253.1103, found 253.1101.
128.8, 127.7, 127.6, 126.8, 75.3, 70.3; IR (KBr, cmꢁ1):
n 3028, 2924,
1646, 1432, 1251, 1059, 851, 700; HRMS (EI) calcd for (Mþ)
C13H11NOS: 229.0561, found 229.0562.
4.2.11. (S)-4-(5-Phenyl-1,3-oxazoline-2-yl)-9H-fluoren-9-one
(3f). Pale yellow solid; mp 149.2e151.3 ꢀC; 0.48 g, 53%; ½a 2D5
ꢃ
þ27.3
4.2.17. (S)-2-(6-Chloropyridin-3-yl)-5-phenyl-1,3-oxazoline (3i). Pale
(c 1.018, CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d
8.45 (d,
yellow solid; mp 71.3e72.6 ꢀC; 0.14 g, 19%; ½a 2D5
ꢁ16.3 (c 1.326,
ꢃ
J¼7.5 Hz, 1H, ArH), 7.97 (dd, J¼1.5, 8.0 Hz, 1H, ArH), 7.80 (dd, J¼1.0,
7.5 Hz, 1H, ArH), 7.71e7.69 (m, 1H, ArH), 7.45e7.40 (m, 5H, ArH),
7.39e7.30 (m, 3H, ArH), 5.76 (dd, J¼8.0, 10.0 Hz, 1H, CH2), 4.65 (dd,
J¼10.5, 15.0 Hz, 1H, CH2), 4.19 (dd, J¼8.0, 15.0 Hz, 1H, CH2); 13C NMR
CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d
8.98 (d, J¼2.0 Hz, 1H,
ArH), 8.23 (dd, J¼2.5, 8.5 Hz, 1H, ArH), 7.41e7.39 (m, 3H, ArH),
7.37e7.33 (m, 3H, ArH), 5.69 (dd, J¼8.0, 10.0 Hz, 1H, CH), 4.49 (dd,
J¼10.5, 15.0 Hz, 1H, CH2), 4.02 (dd, J¼8.0, 15.0 Hz, 1H, CH2); 13C NMR
(125 MHz, CDCl3, ppm):
d
193.3, 163.1, 143.8, 143.4, 140.5, 136.3,
(470 MHz, CDCl3, ppm): d 161.3, 154.3, 149.8, 140.4, 138.4, 129.1,
135.6, 135.0, 134.5, 129.6, 129.1, 128.8, 128.7, 126.5, 126.3, 126.1,
128.8, 125.9, 124.3, 122.9, 81.4, 63.2; IR (KBr, cmꢁ1):
n 3028, 2934,
124.2, 124.1, 81.2, 63.4; IR (KBr, cmꢁ1):
n
3060, 2954, 1712, 1651,
1646, 1524, 1336, 1066, 976, 846, 700; HRMS (EI) calcd for (Mþ)
C14H11ClN2O: 258.0560, found 258.0555.
1572, 1241, 1111, 752, 702; HRMS (EI) calcd for (Mþ) C22H15NO2:
325.1103, found 325.1102.
4.2.18. (S)-2-(6-Chloropyridin-3-yl)-4-phenyl-1,3-oxazoline
4.2.12. (S)-4-(4-Phenyl-1,3-oxazolinꢀe-2-yl)-9H-fluoren-9-one
(3i0). Pale yellow solid; mp 66.3e67.1 ꢀC; 0.24 g, 34%; ½a 2D5
þ9.8 (c
ꢃ
a 25
0.578, CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d
8.99 (d, J¼2.5 Hz,
0
(3f ). Pale yellow solid; mp 114.1e115.3 C; 0.22 g, 24%; ½ ꢃD þ7.2 (c
0.856, CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d
8.40 (d, J¼7.5 Hz,
1H, ArH), 8.26 (dd, J¼2.5, 8.5 Hz, 1H, ArH), 7.41e7.35 (m, 3H, ArH),
7.31e7.28 (m, 3H, ArH), 5.40 (dd, J¼8.5, 10.5 Hz, 1H, CH), 4.83 (dd,
J¼8.5, 10.5 Hz, 1H, CH2), 4.31 (t, J¼8.5 Hz, 1H, CH2); 13C NMR
1H, ArH), 7.97 (dd, J¼1.5, 8.0 Hz, 1H, ArH), 7.80 (dd, J¼1.0, 7.5 Hz, 1H,
ArH), 7.70e7.68 (m, 1H, ArH), 7.43e7.37 (m, 5H, ArH), 7.36e7.28 (m,
3H, ArH), 5.57 (dd, J¼8.5, 10.0 Hz, 1H, CH2), 4.90 (dd, J¼8.5, 10.0 Hz,
1H, CH2), 4.39 (t, J¼8.5 Hz, 1H, CH2); 13C NMR (470 MHz, CDCl3,
(470 MHz, CDCl3, ppm):
d 162.0, 154.3, 149.8, 141.7, 138.5, 129.0,
128.0, 126.8, 124.2, 122.8, 75.2, 70.3; IR (KBr, cmꢁ1):
n 3029, 2958,
ppm):
d
193.2, 163.9, 143.7, 143.4, 141.8, 136.5, 135.5, 135.0, 134.4,
1649, 1585, 1368, 1279, 1103, 748, 702; HRMS (EI) calcd for (Mþ)
C14H11ClN2O: 258.0560, found 258.0557.
129.6, 129.0, 128.8, 128.0, 126.8, 126.5, 126.2, 124.2, 124.0, 74.6, 70.8;
IR (KBr, cmꢁ1):
n 3031, 2962, 1709, 1635, 1567, 1493, 1194, 986, 900,
739; HRMS (EI) calcd for (Mþ) C22H15NO2: 325.1103, found
325.1096.
4.2.19. (S)-2-(Perfluorophenyl)-5-phenyl-1,3-oxazoline (3j). Yellow
solid; mp 42.3e43.1 ꢀC; 0.38 g, 43%; ½a 2D5
ꢃ
ꢁ33.9 (c 1.072, CHCl3); 1H
NMR (500 MHz, CDCl3, ppm):
d 7.43e7.35 (m, 5H, ArH), 5.72 (dd,
4.2.13. (S)-2-(Furan-2-yl)-5-phenyl-1,3-oxazoline (3g). Yellow oil;
J¼8.5, 10.0 Hz, 1H, CH), 4.55 (dd, J¼10.0, 15.0 Hz, 1H, CH2), 4.07 (dd,
0.29 g, 49%; ½a 2D5
ꢃ
ꢁ12.8 (c 1.242, CHCl3); 1H NMR (500 MHz, CDCl3,
J¼8.5, 15.0 Hz, 1H, CH2); 19F NMR (470 MHz, CDCl3, ppm):
ꢁ136.74
d
ppm):
d
7.54e7.53 (m, 1H, ArH), 7.37e7.33 (m, 2H, ArH), 7.32e7.28
to ꢁ136.81 (m, 2F), ꢁ149.60 to ꢁ149.69 (m, 1F), ꢁ160.68 to ꢁ160.80
(m, 3H, ArH), 6.98 (d, J¼3.5 Hz, 1H, ArH), 6.47 (dd, J¼1.5, 3.5 Hz, 1H,
ArH), 5.59 (dd, J¼8.0, 10.0 Hz, 1H, CH), 4.43 (dd, J¼10.0, 14.5 Hz, 1H,
CH2), 3.96 (dd, J¼8.0, 15.0 Hz, 1H, CH2); 13C NMR (125 MHz, CDCl3,
(m, 2F); 13C NMR (125 MHz, CDCl3, ppm):
d 154.6e154.5 (m), 145.8
(dddd, J¼255.0, 15.0, 7.5, 3.8 Hz), 142.8 (dm, J¼265.3 Hz), 140.0,
137.9 (dm, J¼251.3 Hz), 129.0, 128.1, 125.8, 104.9 (td, J¼15.0, 3.8 Hz),
ppm):
d
156.4, 145.4, 142.9, 140.4, 128.9, 128.5, 125.9, 114.6, 111.6,
81.8, 63.3; IR (KBr, cmꢁ1):
n 3019, 2974, 1672, 1526, 1359, 1218, 993,
81.3, 62.9; IR (KBr, cmꢁ1):
n
3032, 2939, 1672, 1482, 1262, 1089, 755,
701; HRMS (EI) calcd for (Mþ) C15H8F5NO: 313.0526, found
700; HRMS (EI) calcd for (Mþ) C13H11NO2: 213.0790, found 213.0780.
313.0522; MS (EI): m/z (%) 313 (Mþ, 7), 207 (MþꢁC6H5CHO, 100).
4.2.14. (S)-2-(Furan-2-yl)-4-phenyl-1,3-oxazoline (3g0). Yellow oil;
4.2.20. (S)-2-(Perfluorophenyl)-4-phenyl-1,3-oxazoline (3j0). Yellow
0.13 g, 21%; ½a 2D5
ꢃ
þ28.6 (c 1.315, CHCl3); 1H NMR (500 MHz, CDCl3,
solid; mp 62.3e63.1 ꢀC; 0.18 g, 20%; ½a 2D5
ꢃ
þ28.8 (c 1.072, CHCl3); 1H
ppm):
d
7.56e7.55 (m, 1H, ArH), 7.36e7.33 (m, 2H, ArH), 7.31e7.26
NMR (500 MHz, CDCl3, ppm): d 7.41e7.31 (m, 5H, ArH), 5.47 (t,
(m, 3H, ArH), 7.04 (d, J¼3.5 Hz, 1H, ArH), 6.50 (dd, J¼1.5, 3.5 Hz, 1H,
ArH), 5.38 (dd, J¼8.5, 10.0 Hz, 1H, CH), 4.76 (dd, J¼8.5, 10.0 Hz, 1H,
CH2), 4.25 (t, J¼8.5 Hz, 1H, CH2); 13C NMR (125 MHz, CDCl3, ppm):
J¼9.5 Hz, 1H, CH), 4.83 (dd, J¼8.5, 10.5 Hz, 1H, CH2), 4.32 (t,
J¼8.5 Hz, 1H, CH2); 19F NMR (470 MHz, CDCl3, ppm):
d
ꢁ136.74
to ꢁ136.81 (m, 2F), ꢁ149.64 to ꢁ149.74 (m, 1F), ꢁ160.80 to ꢁ160.92
d
157.0, 145.4, 142.8, 141.8, 128.7, 127.7, 126.7, 114.9, 111.6, 74.8, 70.0;
(m, 2F); 13C NMR (125 MHz, CDCl3, ppm):
d 155.5e155.3 (m), 145.8
IR (KBr, cmꢁ1):
702; HRMS (EI) calcd for (Mþ) C13H11NO2: 213.0790, found 213.0783.
n
3028, 2911, 1662, 1628, 1480, 1171, 1091, 970, 752,
(dm, J¼251.3 Hz), 142.9 (dddd, J¼257.5, 17.5, 8.8, 5.0 Hz), 141.2, 137.9
(dm, J¼252.5 Hz), 129.0, 128.1, 126.7, 104.9 (td, J¼15.0, 3.8 Hz), 75.2,
70.5; IR (KBr, cmꢁ1):
n 3018, 2949, 1680, 1526, 1341, 1212, 1080, 985,
4.2.15. (S)-5-Phenyl-2-(thiophen-2-yl)-1,3-oxazoline
(3h). Yellow
807, 699; HRMS (EI) calcd for (Mþ) C15H8F5NO: 313.0526, found
oil; 0.27 g, 42%; ½a D25
ꢃ
ꢁ21.3 (c 0.721, CHCl3); 1H NMR (500 MHz, CDCl3,
313.0527; MS (EI): m/z (%) 313 (Mþ, 28), 283 (MþꢁCH2O,100).
ppm):
d
7.66 (dd, J¼1.0, 4.0 Hz, 1H, ArH), 7.48 (dd, J¼1.0, 5.0 Hz, 1H,
ArH), 7.42e7.31 (m, 5H, ArH), 7.09 (dd, J¼3.5, 5.0 Hz, 1H, ArH), 5.65
(dd, J¼8.0, 10.0 Hz, 1H, CH), 4.45 (dd, J¼10.0, 14.5 Hz, 1H, CH2), 3.97
4.2.21. (S)-Naphthalen-2-yl-(2-phenyl-aziridin-1-yl)-methanone
(6a).7 White solid; mp 106.1e107.6 ꢀC; 0.12 g, 16%, ½a 2D5
þ150.6 (c
ꢃ
(dd, J¼8.0,15.0 Hz,1H, CH2); 13C NMR (125 MHz, CDCl3, ppm):
d
159.9,
0.336, CHCl3); 1H NMR (500 MHz, CDCl3, ppm):
d 8.53 (s, 1H, HAr),
140.7, 130.5, 130.3, 130.0, 128.9, 128.4, 127.7, 125.8, 81.6, 63.2; IR (KBr,
8.00 (dd, J¼8.5, 1.5 Hz, 1H, HAr), 7.85e7.78 (m, 3H, HAr), 7.57 (td,
J¼7.0,1.5 Hz,1H, HAr), 7.49 (td, J¼8.5,1.0 Hz,1H, HAr), 7.44e7.37 (m,
5H, HAr), 3.53 (dd, J¼6.0, 6.0 Hz, 1H, CH), 3.04 (d, J¼6.0 Hz, 1H,
NCH2), 2.52 (d, J¼3.5 Hz, 1H, NCH2); 13C NMR (125 MHz, CDCl3,
cmꢁ1):
n 3031, 2928, 1648,1524,1432,1251, 1059, 970, 852, 759, 700;
HRMS (EI) calcd for (Mþ) C13H11NOS: 229.0561, found 229.0556.
4.2.16. (S)-4-Phenyl-2-(thiophen-2-yl)-1,3-oxazoline (3h0).12 Yellow
ppm): d 179.3, 137.3, 135.7, 132.6, 130.9, 130.1, 129.6, 129.0, 128.4,
oil; 0.15 g, 23%; ½a D25
ꢃ
þ41.5 (c 0.950, CHCl3); 1H NMR (500 MHz,
128.3, 127.9, 126.8, 126.4, 125.1, 40.6, 35.5; IR (KBr):
n 3055, 2993,
CDCl3, ppm):
d
7.71 (dd, J¼1.0, 4.0 Hz, 1H, ArH), 7.49 (dd, J¼1.0,
1675, 1629, 1391, 1303, 1286, 833, 785, 705; Anal. Calcd for

2156
H. Jiang et al. / Tetrahedron 69 (2013) 2150e2156
C19H15NO (273.12): C 83.49, H 5.53, N 5.12; found C 83.55, H 5.42, N
5.29.
C10H10F3NO2: 233.0664, found 233.0661; MS (ESI): m/z (%) 256
(MþþNaþ).
4.3.5. (S)-N-(2-Chloro-1-phenylethyl)-2,2,2-trifluoroacetamide
(9k0). White solid; mp 100.3e101.5 ꢀC; 1H NMR (500 MHz, CDCl3):
4.3. General procedure for the preparation of 2-fluoroalkyl-
1,3-oxazolines 4
d
7.43e7.36 (m, 3H, ArH), 7.34e7.31 (m, 2H, ArH), 6.90 (s, 1H, NH),
5.41 (dd, J¼5.5, 8.0 Hz, 1H, CH), 3.95e3.86 (m, 2H, CH2); 19F NMR
A 200 mL three-necked flask equipped with a condenser was
charged with Ph3P (2.20 g, 8.4 mmol), Et3N (1.42 g,14.0 mmol), CBr4
(16.8 g, 8.4 mmol), substrate 1 (3.3 mmol), and fluorinated car-
boxylic acid 2 (2.8 mmol) in toluene (15.0 mL) under a nitrogen
atmosphere. The solution was stirred for about 20 min under 0 ꢀC,
then the mixture was heated at 90 ꢀC with stirring for 18e55 h. The
solvent was evaporated under reduced pressure, and the residue
was diluted with petroleum ether (60e90 ꢀC) and filtered. The
residual solid Ph3PO and Et3N$HBr was washed with petroleum
ether three times. The filtrate was concentrated, and the residue
was purified by column chromatography (ethyl acetate/petroleum
ether, 1:8) to afford product 4. If the mixture of Ph3P (2.20 g,
8.4 mmol), Et3N (1.42 g, 14.0 mmol), CCl4 (15 mL), substrate 1
(3.3 mmol), and trifluoroacetic acid 2k (2.8 mmol) in toluene
(15.0 mL) was processed after stirring for 2 h at 90 ꢀC, intermediate
8k and 9k0 were obtained by column chromatography (ethyl ace-
tate/petroleum ether¼1:8).
(470 MHz, CDCl3):
d
ꢁ75.67 (s, CF3); 13C NMR (125 MHz, CDCl3):
2
d
157.1 (q, JCeF¼37.5 Hz), 136.6, 129.2, 128.9, 126.6, 115.8 (q,
1JCeF¼286.3 Hz), 54.8, 46.4; IR (KBr):
n 3327, 3091, 1700, 1554, 1220,
1173, 728, 697, 528 cmꢁ1; HRMS (EI) calcd for (Mþ) C10H9ClF3NO:
251.0325, found 251.0325; MS (EI): m/z (%) 251 (Mþ, 1), 253 (Mþþ2,
0.32), 215 (MþꢁHCl, 53), 202 (MþꢁCH2Cl, 100).
Acknowledgements
This work was financially supported by the National Natural Sci-
ence Foundation of China (Nos. 21072127, 21032006, 21172141) and
the Science Foundation of Shanghai Municipal Commission of Sci-
ences and Technology (10JC1405600). The authors thank Laboratory
for Microstructures of Shanghai University for structural analysis.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.12.078.
4.3.1. (S)-4-Phenyl-2-(trifluoromethyl)-1,3-oxazoline (4k). Pale yel-
low oil; 0.37 g, 61%; ½a D25
ꢃ
ꢁ21.8 (c 1.24, CHCl3); 1H NMR (500 MHz,
CDCl3, ppm):
d 7.42e7.38 (m, 2H, ArH), 7.36e7.32 (m, 1H, ArH),
References and notes
7.26e7.24 (m, 2H, ArH), 5.41 (m,1H, CH), 4.89 (dd, J¼8.5,10.5 Hz,1H,
CH2), 4.40 (t, J¼8.5 Hz, 1H, CH2); 19F NMR (470 MHz, CDCl3, ppm):
1. (a) Onishi, H. R.; Pelak, B. A.; Silver, L. L.; Kahan, F. M.; Chen, M. H.; Patchett, A.
A.; Galloway, S. M.; Hyland, S. A.; Anderson, M. S.; Raetz, C. R. H. Science 1996,
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Am. Chem. Soc. 2003, 125, 1575e1586; (c) Locatelli, M.; Cozzi, P. G. Angew. Chem.,
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H. G.; Jew, S. S. Org. Lett. 2005, 7, 1557e1560; (e) Gant, T. G.; Meyers, A. I. Tet-
d
ꢁ69.97 (s, CF3); 13C NMR (125 MHz, CDCl3, ppm):
d 155.9 (q,
2JCeF¼40.0 Hz), 139.7, 129.1, 128.3, 126.5, 116.5 (q, 1JCeF¼272.5 Hz),
76.6, 69.8; IR (KBr, cmꢁ1):
n 3034, 2913, 1687, 1604, 1399, 1210, 1160,
1126,1083, 762, 700; HRMS (EI) calcd for (Mþ) C10H8F3NO: 215.0558,
found 215.0561; MS (EI): m/z (%) 215 (Mþ), 185 (Mþ-CH2O).
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Angew. Chem., Int. Ed. 2010, 49, 1143e1146; (g) Bettencourt-Dias, A.;
Viswanathan, S.; Rollett, A. J. Am. Chem. Soc. 2007, 129, 15436e15437; (h) H.
Masashi; T. Takao; O. Shinjiro, U.S. Patent 2,007,228,940, 2007.
4.3.2. (S)-2-(Difluoromethyl)-4-phenyl-1,3-oxazoline
(4l). Yellow
oil; 0.23 g, 42%; ½a D25
ꢃ
ꢁ42.7 (c 1.03, CHCl3); 1H NMR (500 MHz,
2. (a) McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151e4202; (b) Hahn, B. T.;
€
Tewes, F.; Frohlich, R.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 1e5; (c) Chai,
CDCl3, ppm):
d 7.40e7.37 (m, 2H, ArH), 7.35e7.31 (m, 1H, ArH),
Z.; Liu, X. Y.; Yu, X. Y.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 2442e2447;
(d) Inoue, M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 1140e1141.
3. (a) Gade, L. H.; Bellemin-Laponnaz, S. Coord. Chem. Rev. 2007, 251, 718e725; (b)
Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. Rev. 2006,106, 3561e3651; (c) Meyers,
A. I. Acc. Chem. Res.1978,11, 375e381; (d) Frump, J. A. Chem. Rev.1971, 71, 483e506.
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7019e7020; (b) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907e910; (c)
Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
1165e1168; (d) Wenker, H. J. Am. Chem. Soc. 1935, 57, 1079e1080.
5. (a) Sureshkumar, D.; Koutha, S. M.; Chandrasekaran, S. J. Am. Chem. Soc. 2005,
127, 12760e12761; (b) Watson, I. D. G.; Yu, L.; Yudin, A. K. Acc. Chem. Res. 2006,
39, 194e206.
7.26e7.24 (m, 2H, ArH), 6.34 (t, J¼53.0 Hz, 1H, CF2H), 5.36e5.31 (m,
1H, CH), 4.80 (dd, J¼9.0, 10.0 Hz, 1H, CH2), 4.31 (t, J¼9.0 Hz, 1H,
CH2); 19F NMR (470 MHz, CDCl3, ppm):
d
ꢁ123.89 (d, J¼52.0 Hz, 2F,
CF2H); 13C NMR (125 MHz, CDCl3, ppm):
d
159.7 (t, 2JCeF¼27.5 Hz),
140.4, 129.0, 128.1, 126.6, 107.23 (t, 1JCeF¼240.0 Hz), 75.8, 69.6; IR
(KBr, cmꢁ1):
n 3033, 2909, 1683, 1604, 1455, 1352, 1113, 1064, 761,
701; HRMS (EI) calcd for (Mþ) C10H9F2NO: 197.0652, found
197.0651.
6. For ringexpansion see: (a) Singh, G. S.; D’hooghe, M.; DeKimpe, N. Chem. Rev. 2007,
107, 2080e2135; (b)Kokotos, C.G.;Aggarwal, V. K.Org.Lett. 2007, 9, 2099e2102; (c)
Brichacek, M.; Lee, D.; Njardarson, J. T. Org. Lett. 2008, 10, 5023e5026; (d)
Schomaker, J. M.; Bhattacharjee, S.; Yan, J.; Borhan, B. J. Am. Chem. Soc. 2007, 129,
1996e2003 For cycloaddition see: (e) Kang, B.; Miller, A. W.; Goyal, S.; Nguyen, S. T.
Chem. Commun. 2009, 3928e3930; (f) Guo, H.; Xu, Q.; Kwon, O. J. Am. Chem. Soc.
2009, 131, 6318e6319 For ring-opening see: (g) Crestey, F.; Witt, M.; Frydenvang,
K.; Stærk, D.; Jaroszewski, J. W.; Franzyk, H. J. Org. Chem. 2008, 73, 3566e3569; (h)
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(i) Wang, Z.; Cui, Y. T.; Xu, Z. B.; Qu, J. J. Org. Chem. 2008, 73, 2270e2274.
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2010, 9, 4227e4236.
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Saha, B.; Nandy, J. P.; Shukla, S. J. Org. Chem. 2002, 67, 7858e7860.
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1993, 58, 32e35.
10. (a) Meyers, A. I.; Hanagan, M. A.; Trefonas, L. M.; Baker, R. J. Tetrahedron 1983,
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42, 7959e7961.
4.3.3. (S)-2-(Bromodifluoromethyl)-4-phenyl-1,3-oxazoline
(4m). Yellow oil; 0.42 g, 65%; ½a D25
ꢃ
ꢁ35.1 (c 0.68, CHCl3); 1H NMR
(500 MHz, CDCl3, ppm): d 7.43e7.39 (m, 2H, ArH), 7.38e7.35 (m, 1H,
ArH), 7.29e7.27 (m, 2H, ArH), 5.44 (dd, 1H, J¼9.0, 10.0 Hz, CH), 4.94
(dd, J¼9.0, 10.0 Hz, 1H, CH2), 4.46 (t, J¼8.5 Hz, 1H, CH2); 19F NMR
(470 MHz, CDCl3, ppm):
d
ꢁ55.22; 13C NMR (125 MHz, CDCl3, ppm):
2
d
159.5 (t, JCeF¼30.0 Hz), 139.9, 129.0, 128.3, 126.5, 109.1 (t,
1JCeF¼301.3 Hz), 76.9, 69.7; IR (KBr, cmꢁ1):
n 3028, 2926, 1670,1398,
1273, 1089, 754, 700; HRMS (EI) calcd for (Mþ) C10H8BrF2NO:
274.9757, found 274.9753.
4.3.4. (S)-2,2,2-Trifluoro-N-(2-hydroxy-1-phenylethyl)acetamide
(8k).13 White solid; mp 154.5e155.3 ꢀC; 1H NMR (500 MHz, CDCl3,
ppm):
d 7.42e7.30 (m, 5H, HAr), 7.12 (s, 1H, NH), 5.13e5.10 (m, 1H,
CH), 4.01e3.94 (m, 2H, CH2), 1.91 (s, 1H, OH); 19F NMR (470 MHz,
11. (a) Kangani, C. O.; Kelley, D. E.; Day, B. W. Tetrahedron Lett. 2006, 47,
6497e6499; (b) Li, Z.; Xu, Q. Tetrahedron Lett. 2009, 50, 6838e6840.
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Chem. Soc., Perkin Trans. 1 1994, 2065e2072.
13. S. M. Wang; H. Y. Sun; D. G. Qin; Z. Nikolovska-Coleska; J. F. Lu; S. Qiu; Y. F.
Peng; Q. Cai, U.S. Patent 20,090,123,480, 2009.
CDCl3, ppm):
d
ꢁ75.65 (s, CF3); 13C NMR (125 MHz, CDCl3, ppm):
2
d
157.1 (q, JCeF¼37.5 Hz), 139.0, 138.9, 128.3, 127.5, 126.8, 116.1 (q,
1JCeF¼286.3 Hz), 64.2, 56.5; IR (KBr, cmꢁ1):
n 3422, 3334, 2959,
1699,1554,1363,1184,1038, 759, 701, 541; HRMS (EI) calcd for (Mþ)