A facile one-pot synthesis of 2-fluoroalkyl 1,3-imidazolines and 1,3-oxazolines through imidoyl halide intermediates

Article abstract of DOI:10.1016/j.tet.2012.01.086

A facile one-pot procedure has been developed for the synthesis of 1,3-imidazolines and 1,3-oxazolines bearing fluorinated alkyl groups at the 2-position. The reaction involves the condensation of N-monosubstituted ethane-1,2-diamines or 2-aminoethanols with a fluorinated carboxylic acid in the presence of PPh₃/CX₄. The proposed mechanism is that the amide intermediates were initially formed, and then converted to the imidoyl halide intermediates in the presence of PPh₃/CX₄, followed by rapid intramolecular cyclization to 1,3-diazoline products. This protocol allows for the synthesis of 2-bromodifluoromethyl-1,3-imidazoline, a useful CF₂Br-heterocyclic building block, which can be used for the synthesis of gem-difluoromethylene linked compounds.

Full text of DOI:10.1016/j.tet.2012.01.086

Tetrahedron 68 (2012) 2858e2863
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A facile one-pot synthesis of 2-fluoroalkyl 1,3-imidazolines and 1,3-oxazolines
through imidoyl halide intermediates
,
a
a
a
a
b
,
a,b,
*
Haizhen Jiang a , Lan Sun , Shijie Yuan , Wenjun Lu , Wen Wan , Shizheng Zhu , 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
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile one-pot procedure has been developed for the synthesis of 1,3-imidazolines and 1,3-oxazolines
bearing fluorinated alkyl groups at the 2-position. The reaction involves the condensation of N-mono-
substituted ethane-1,2-diamines or 2-aminoethanols with a fluorinated carboxylic acid in the presence
of PPh3/CX4. The proposed mechanism is that the amide intermediates were initially formed, and then
converted to the imidoyl halide intermediates in the presence of PPh3/CX4, followed by rapid intra-
molecular cyclization to 1,3-diazoline products. This protocol allows for the synthesis of 2-
bromodifluoromethyl-1,3-imidazoline, a useful CF2Br-heterocyclic building block, which can be used
for the synthesis of gem-difluoromethylene linked compounds.
Received 25 October 2011
Received in revised form 14 January 2012
Accepted 31 January 2012
Available online 8 February 2012
Keywords:
1,3-Imidazolines
1,3-Oxazolines
Ó 2012 Elsevier Ltd. All rights reserved.
Imidoyl halides
gem-Difluoromethylene
Intramolecular cyclization
1. Introduction
1,3-oxazolines. In refluxing CCl4 or in toluene at 90 ꢀC in the
presence of 3 equiv of CBr4, Ph3P, and excess Et3N, N-mono-
1,3-Imidazoline and 1,3-oxazoline heterocycles are basic skele-
tons of many important biologically active compounds, natural
products, and organomaterials.1 It has been reported that their
biological activities are greatly enhanced by a substituent at the 2-
position,2 especially 2-fluorinated alkyl groups.3 Therefore, there
has been great interest in developing syntheses of 1,3-diazolines
bearing fluorinated alkyl groups at the 2-position. However, only
a few examples have been reported for the synthesis of 2-
substituted ethane-1,2-diamines or 2-amino-3-phenylpropanol
condense with fluorinated carboxylic acids to generate 2-
fluoroalkyl-1,3-imidazolines or 2-fluoroalkyl-1,3-oxazolines, re-
spectively (Scheme 1, Table 1). The reactions were carried out in
a one-pot process with good to excellent isolated yields. The pos-
tulated mechanism of this tandem process was supported experi-
mentally by isolation of the fluorinated amide intermediates 2,
which then converted to imidoyl halide intermediates 20 in the
presence of PPh3/CX4, followed by rapid intramolecular cyclization
to the desired products 3.
fluoroalkyl-1,3-imidazolines
or
2-fluoroalkyl-1,3-oxazolines.
These include the reaction of trifluoroacetate with ethane-1,2-
diamine, intramolecular cyclization using Ph3P and N-(2-
azidoethyl)-trifluoroacetamide, and cyclocondensation of tri-
fluorothioacetamide with ethane-1,2-diamine.4 Thus, novel and
general synthetic methods for 2-fluoroalkyl-1,3-imidazolines or
1,3-oxazolines are highly desirable.
H
R
N
R
F
R
1
NH
R
1
N
R
F
R
1
2
1
N
Y
PPh / CX
Et N
PPh / CX
3
4
3
3
4
R
F
O
X
Et N
COOH,
R
3
F
Et
N
65%-85%
YH
R
YH
R
3
YH
R
R
3
1
2'
2
Fluorinated imidoyl halides are sophisticated and multifunc-
tional fluorine-containing building blocks that have versatile ap-
plications for the synthesis of biologically interesting fluoroalkyl
compounds.5 Our group has previously reported the synthesis of 2-
fluoroalkyl-benzo-1,3-diazoles through fluorinated imidoyl chlo-
ride intermediates.6 In this paper, we report our recent results on
the synthesis of 2-fluoroalkyl-1,3-imidazolines and 2-fluoroalkyl-
X=Cl, Br
Y= N; R= Me, Et, Ph, Bn; R = H
1
Y= O; R= /; R = Bn
1
R
F
= CF , HCF , C F , BrCF
3
2
3
7
2
Scheme 1. The synthesis of 2-fluoroalkyl substituted 1,3-imidazolines and 1,3-
oxazolines.
2. Results and discussion
The reaction of 2-amino-3-phenylpropanol with various non-
* Corresponding authors. E-mail addresses: hzjiang@shu.edu.cn (H. Jiang),
zhusz@mail.sioc.ac.cn (S. Zhu), jhao@staff.shu.edu.cn (J. Hao).
fluorinated aromatic acids in the presence of PPh3/CBr4 or PPh3/
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.086

H. Jiang et al. / Tetrahedron 68 (2012) 2858e2863
2859
Table 1
Synthesis of 2-fluoroalkyl 1,3-imidazolines and 1,3-oxazolines
Entry
X
Y
RF
pKa (RFCOOH)
R
R1
Product 3
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
Cl
Cl/Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl/Br
Cl/Br
Cl/Br
Cl/Br
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
CF3
CF3
CF3
CF3
0.5
0.5
0.5
0.5
0.5
1.3
1.3
1.9
1.9
0.2
0.2
0.5
0.5
0.2
1.3
1.9
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
12
18/8
18
3
3
18
18
18
18
db
85/88c
82
72
65
81
77
80
75
Bn
Ph
Et
Me
Bn
Ph
Bn
Ph
Bn
Ph
CF3
HCF2
HCF2
C3F7
C3F7
BrCF2
BrCF2
CF3
9
10
11
12
13
14
15
16
18
18
70
68
cis or trans-1,2-Diaminocyclohexane
120
24/8
24/8
24/10
24/8
db
CF3
d
d
d
d
Bn
Bn
Bn
Bn
63/71c
61/73c
21/50c
48/61c
BrCF2
HCF2
C3F7
a
Isolated yield.
b
c
The product was not observed.
The reaction was carried out in toluene with 3 equiv of CBr4/PPh3 at 90 ꢀC.
CCl4 has been demonstrated to proceed through an N-aroyl azir-
idine and a noncyclized amide intermediate (Scheme 2, path b) to
provide 4-benzyl-1,3-oxazolines and the isomeric 5-benzyl-1,3-
oxazolines.7 However, when 2-amino-3-phenylpropanol (or N-
monosubstituted ethane-1,2-diamines) and fluorinated carboxylic
acids were used, only 2-fluoroalkyl-4-benzyl-1,3-oxazolines (or 2-
fluoroalkyl-1,3-imidazolines) were observed through 19F NMR
analysis and isolated. This result revealed that the mechanism of
reaction with fluorinated carboxylic acids differs from that of non-
fluorinated aromatic acids. In order to study the differing reaction
mechanisms, we attempted to capture the reaction intermediates.
Fortunately, the amide intermediates 2 were successfully isolated
from the reaction mixture of N-aryl ethane-1,2-diamines or 2-
amino-3-phenylpropanol reacted with the fluorinated carboxylic
acids in the presence of PPh3 and excess Et3N in refluxing CCl4
(Table 2). The structure of the amide intermediate 2m was further
confirmed by X-ray diffraction study (Fig. 1). In addition, 2-
fluoroalkyl-1,3-diazolines were obtained only when PPh3 and an
excess triethylamine was added to the isolated amide 2 in refluxing
CCl4. On the other hand, the reaction of N-aryl ethane-1,2-diamines
or 2-amino-3-phenylpropanol with the same equivalent of PPh3
and excess Et3N in refluxing CCl4 provided amide as the only
product. Those experimental facts confirmed that the reaction
Fig. 1. X-ray diffraction of the amide intermediate 2m.
proceeded through the other intermediate besides the amide in-
termediate 2, which was deduced to be imidoyl halide in-
termediate 20 according to Uneyama’s research.8 The final products
3 could be from imidoyl halide 20 rapid intramolecular cyclization
(Scheme 2, path a). The selective formation of imidoyl halide in-
termediate in Path a or N-aroyl aziridine and noncyclised amide
intermediate in Path b could depend on the acidity of carboxylic
acid. Because of high acidity of fluorinated carboxylic acids (pKa
0.2e1.9), amidation of the amino group of 2-amino-3-
phenylpropanol or N-aryl ethane-1,2-diamines was easier than
halogenation of hydroxyl or amino group in the presence of PPh3/
9
CX4. This made it much easier to form the amide intermediate 2
rather than N-aroyl aziridine or noncyclised amide. On the other
hand, due to the strong electron withdrawing effect of fluoroalkyl
group, this amide may preferentially give the imidoyl halide 20
through the conversion of the imino alcohol of the amide tautomer
in the presence of PPh3/CX4 (Scheme 3) rather than the direct
formation of five-membered 1,3-diazolines from amide in-
termediate 2 intramolecular cyclization. Owing to the electrophi-
licity of the C]N double bond and the nucleophilicity of the N-
substituted amino group or hydroxyl group, the imidoyl halide
easily undergo the intramolecular cyclization to form the desired
imidazolines or oxazolines 3 (Scheme 3).
Scheme 2. Mechanism of formation of 2-fluoroalkyl 1,3-imidazolines and 1,3-
oxazolines (3).
Table 2
Synthesis of fluorinated amide intermediates 2
Entry
Y
RF
R1
R
Product 2
1
2
3
4
N
N
N
O
CF3
H
H
H
Bn (S)
Bn
Bn
Ph
d
2b
2f
2g
2m
HCF2
HCF2
CF3

2860
H. Jiang et al. / Tetrahedron 68 (2012) 2858e2863
YH
R
YH
R
YH
N
R
Table 3
Ph3P/CCl4
Et3N
Ph3P/CCl4
The static energy of the conformations
Cl
RFCOOH
+
R1
R1
C
OPPh3
R1
NH2
NHCORF
Entry
Conformation
The static energy (kcal/mol)a
RF
1
2
1
2
3
4
5
6
4
5
6
7
8
3l
ꢁ217526.9
ꢁ741407.7
ꢁ741406.6
ꢁ741402.3
ꢁ1265284.2
ꢁ452235.4
R
Y
YH
R
X
..
Et3N
-PPh3O
Et3N
RF
N
R1
N
R1
RF
2'
3
Scheme 3. The formation of the imidoyl halide intermediate 20.
a
Calculation method: B3LYP/6-31G (d).
This transformation was initially carried out in refluxing CCl4.
It was later found that the reaction proceeded even faster and
with higher isolated yields by heating in toluene with only 3 equiv
of CBr4.
F C
3
O
Cl
CF
3
N
NH
NH
-500092.8
NH
When (S)-2-amino-3-phenylpropanol was the substrate, 2-
fluoroalkyl-4-benzyl-1,3-oxazolines were successfully obtained as
the only product after being treated with 3 equiv of CBr4, Ph3P, and
excess Et3N in toluene at 90 ꢀC (entries 13e16, Table 1). N-Mono-
substituted ethane-1,2-diamines smoothly underwent the trans-
formation. When N-substituted groups were donor groups with
little steric hindrance (such as N-methyl or N-ethyl), the reaction
proceeded more rapidly (Table 1, entries 4 and 5). The formation of
the amide and the imidoyl chloride and subsequent cyclization
reaction happened almost simultaneously according to TLC analy-
sis, so the corresponding amide intermediates were not isolated. In
contrast, when aryl groups are attached to the nitrogen atom, N-(2-
phenylamino-ethyl)-acetamide (2g) was formed in the first 1e2 h,
which could be isolated by column chromatography, and sub-
sequently converted slowly to the imidazoline in the following
9e10 h. This synthetic methodology was suitable for a series of N-
monosubstituted ethylenediamines for the preparation of 2-
fluoroalkyl imidazolines in good yield (Table 2). However, ethane-
1,2-diamine failed to generate the expected 2-trifluoromethyl-
imidazoline (Table 1, entry 1). According to 19F NMR studies, the
chemical shift was only ꢁ75.66 ppm after stirring for 12 h. This
suggests that both amino groups may form amides (2a). Un-
fortunately, we were unable to obtain this amide (2a). 2-
Trifluoromethyl-imidazoline 3a was also not observed. The free
rotation about the CeC single bond of ethane-1,2-diamine may be
the reason for without any 3a. The two amino groups of ethane-1,2-
diamine will be most stable in a staggered conformation, and for-
mation of an amide or imidoyl chloride on one end should not
sterically hinder reaction at the other end. However, 1,2-
diaminobenzene has two amino groups constrained in close
proximity and steric hindrance prevents the formation of an imi-
doyl chloride on both amino groups. Thus, it can be successfully
converted to 2-trifluoromethyl-benzimidazole under the same re-
action conditions, as shown in our previous research.7 To our sur-
prise, cis or trans-1,2-diaminocyclohexane, whose amino groups
are also held in close proximity, failed to produce the expected
product, even after a reaction time of 120 h. Although 19F NMR
suggested the ready formation of the amide, the amide in-
termediate failed to be isolated and the expected product was not
observed. Therefore, the B3LYP/6-31G (d) calculation method was
used to calculate the static energy of the reactants and products of
the reaction with trans-1,2-diaminocyclohexane through thermo-
dynamic analysis in order to help explain why the reaction had
failed. The formation of imidoyl chlorides (8), (5) or (6) is facile due
to their lower static energy than trans-1,2-diaminocyclohexane
(Table 3, Scheme 4). However, if 1,3-imidazoline (3l) was to be
formed, the five atoms must be in the same plane (Scheme 4), thus
distorting the conformation of the cyclohexane ring. This is shown
in conformation 7, whose formation is more difficult because of the
higher static energy (ꢁ741402.3 kcal/mol). Moreover, even if con-
formation 7 is present in the reaction system, it would be difficult to
form the intramolecular cyclic product 3l due to its much higher
2
2
CF
Cl
3
5
H
N
C
-741407.7
C
NH
2
NH
2
C
NH
CF
3
2
O
4
H
7
N
Cl
-217526.9
HN
CF
3
-741402.3
O
CF
3
NH
2
NH
NH
NH
H
2
6
C
N
CF
-500088.0
3
-741406.6
C
CF
3
C
N
-782711.8
O
H
3 l
F C
3
-452235.4
Cl
Cl
N
N
F C
3
8
-1265284.2
Scheme 4. Postulated conformation of cyclohexane amide and imidoyl chlorides.
energy. This could explain why the intramolecular cyclic product 3l
was difficult to formation.
Introduction of a gem-difluoromethylene moiety into organic
molecules has been shown to enhance potential biological activities
as the CF2 group can confer types of compounds unique polarity
and activity.10 In order to synthesize gem-difluoromethylene linked
molecules, 2-bromodifluoromethyl-1,3-imidazoline, readily avail-
able using our method (entry 10), was tentatively reacted with
phenol in the presence of NaH/DMF through a typical SET mecha-
nism.10d This reaction yielded the gem-difluoromethylene linked
compound 9 in 55% yield (Scheme 5). The application of 2-
bromodifluoromethyl-1,3-imidazoline to other types of reactions
is being explored.
N
N
Bn
3j
N
N
NaH / DMF
PhOH
r.t. 24 h, 55%
CF2Br
CF2O
Bn
9
Scheme 5. Reaction of 2-bromodifluoromethyl 1,3-imidazoline with sodium phenolate.
3. Conclusion
In summary, 2-fluoroalkyl-imidazolines and 2-fluoroalkyl-oxa-
zolines were successfully prepared from N-monosubstituted 1,2-
diamines or 2-aminoethanol and the fluorinated carboxylic acids
in the presence of PPh3/CX4 using a convenient one-pot synthesis.
The reaction mechanism is proposed to go through amide in-
termediates, then converted to imidoyl halide intermediates, fol-
lowed by rapid intramolecular cyclization to 2-fluoroalkyl-1,3-
diazolines. In addition, 2-bromodifluoromethyl-1,3-imidazoline,

H. Jiang et al. / Tetrahedron 68 (2012) 2858e2863
2861
which is readily available using our method, was successfully used
in the synthesis of gem-difluoromethylene linked compounds to be
(470 MHz, CDCl3)
1531, 1186, 762, 721, 697.
d
ꢁ75.85 (s); IR (KBr, cmꢁ1) 3407, 3109, 3081, 1716,
used in biological studies.
4.2.4. N-(2-Benzylamino-ethyl)-2,2-difluoroacetamide (2f). Yellow
4. Experimental section
4.1. General
oil; 1H NMR (500 MHz, CDCl3, ppm)
d 7.37e7.25 (m, 6H), 5.90 (t,
2JHeF¼54.5 Hz, 1H), 3.80 (s, 2H), 3.40 (dd, J¼5.0, 5.0 Hz, 2H), 2.82 (t,
J¼5.0 Hz, 2H), 1.98 (s, 1H); 13C NMR (125 MHz, CDCl3)
d 162.9 (t,
2JCeF¼24.4 Hz), 139.8, 128.7, 128.3, 127.4, 108.7 (t, 1JCeF¼250.3 Hz),
Reactions were generally carried out under nitrogen in an ap-
53.4, 47.2, 38.8; 19F NMR (470 MHz, CDCl3)
d
ꢁ126.36 (d,
propriate round-bottom flask with magnetic stirring. Thin layer
2JHeF¼54.4 Hz). IR (KBr, cmꢁ1) 3416, 3104, 3067, 1693, 1605, 1132,
chromatography (TLC) was performed on silica gel. 1H, 13C, and 19
F
767, 713, 689.
NMR spectra were recorded on a 500 MHz spectrometer. Chemical
l
shifts for H NMR spectra are reported in parts per million down-
4.2.5. 2,2-Difluoro-N-(2-phenylamino-ethyl)-acetamide
field from TMS, chemical shifts for 13C NMR spectra are reported in
ppm relative to internal chloroform (
(2g). Yellow oil; 1H NMR (500 MHz, CDCl3, ppm)
d 7.22e7.18 (m,
d
77.2 ppm for 13C), and
2H), 7.09 (s, 1H), 6.77e6.62 (m, 3H), 5.87 (t, 2JHeF¼54.3 Hz, 1H), 3.98
chemical shifts for 19F NMR spectra are reported in ppm downfield
from internal fluorotrichloromethane (CFCl3). Coupling constants
(J) are given in Hertz (Hz). The terms m, s, d, t, q refer to multiplet,
singlet, doublet, triplet, quartet; br refers to a broad signal. Infrared
spectra (IR) were recorded on an FT-IR spectrometer and absor-
bance frequencies are given at maximum intensity in cmꢁ1. Mass
spectra were obtained using ESI. High resolution mass spectra were
obtained using EI at 70 eV.
(br, 1H), 3.54 (dd, J¼6.0, 5.5 Hz 2H), 3.32 (t, J¼6.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3)
d
163.4 (t, 2JCeF¼25.0 Hz), 147.7, 129.5, 118.1, 113.0,
1
108.5 (t, JCeF¼250.0 Hz), 43.2; 39.0; 19F NMR (470 MHz, CDCl3)
d
ꢁ126.34 (d, 2JHeF¼54.3 Hz). IR (KBr, cmꢁ1) 3405, 3031, 1706, 1601,
1127, 785, 716, 692.
4.2.6. 2,2,2-Trifluoro-N-(1-hydroxymethyl-2-phenyl-ethyl)-acet-
amide (2m). White solid; mp 172.3e176.0 ꢀC. ½a D25
ꢁ18.1 (c 2.021,
ꢂ
CCDC 861104 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 CB2 1EZ, UK; fax:
þ44 1223 336033.
acetone); 1H NMR (500 Hz, CDCl3)
d 7.34e7.21 (m, 5H), 6.61 (br, 1H),
4.27e4.21 (m, 1H), 3.74e3.67 (m, 2H), 2.92e2.99 (m, 2H), 1.71 (s,
1H); 13C NMR (125 MHz, DMSO-d6)
d
156.4 (q, 2JCeF¼35.0 Hz),138.8,
1
129.4, 128.6, 126.6, 116.4 (q, JCeF¼287.5 Hz), 62.8, 54.4, 36.3; 19F
NMR (470 MHz, CDCl3)
d
ꢁ75.89 (s). IR (KBr, cmꢁ1) 3511, 3109, 3063,
1699, 1561, 1225, 1207, 1179, 877, 755, 699, 681.
4.2. General procedure for 1,3-diazolines
4.2.7. N-Benzyl-2-trifluoromethylimidazoline (3b). Yellow oil; 88%;
1H NMR (500 MHz, CDCl3, ppm)
d 7.38e7.25 (m, 5H), 4.39 (s, 2H),
4.2.1. Former procedure. A 200-ml three-necked flask equipped
with a condenser was charged with Ph3P (34.5 g, 132 mmol), Et3N
(excess), CCl4 (21.1 ml, 220 mmol), and fluorinated carboxylic acid
(44 mmol) at 0 ꢀC under nitrogen. After the solution was stirred for
about 10 min (ice water bath), a solution of substrate 1 (53 mmol)
in CCl4 (21.1 ml, 220 mmol) was added dropwise. The mixture was
refluxed under stirring for 3e18 h. The solvent was evaporated
under reduced pressure, and the residue was diluted with petro-
leum ether (60e90 ꢀC) and filtered. The residual solid Ph3PO and
Et3N$HCl was washed with petroleum ether three times. The fil-
trate was concentrated, and the residue was purified by column
chromatography to obtain the product 3. When N-benzylethyle-
nediamine and N-phenylethylenediamine were employed as the
substrates 1 in this reaction, amides 2 could be isolated after stir-
ring for 1e2 h.
3.87 (t, J¼10.5 Hz, 2H), 3.35 (t, J¼10.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3)
d
154.8 (q, 2JCeF¼34.4 Hz), 136.3, 128.9, 128.0, 127.8, 118.3 (q,
1JCeF¼273.1 Hz), 53.1, 51.0, 50.9; 19F NMR (470 MHz, CDCl3)
d
ꢁ66.75 (s); IR (KBr, cmꢁ1) 3032, 2934, 2872, 1628, 1193, 1150, 742,
700; ESI-MS: m/z¼229 [Mþ1]þ.
4.2.8. N-Phenyl-2-trifluoromethylimidazoline (3c). Yellow oil; 82%;
1H NMR (500 MHz, CDCl3, ppm)
d 7.38e7.21 (m, 5H), 4.06e3.94 (m,
2
4H); 13C NMR (125 MHz, CDCl3)
d
153.7 (q, JCeF¼35.6 Hz), 140.0,
129.5, 127.3, 125.7, 118.0 (q, JCeF¼273.8 Hz), 55.6, 53.1; 19F NMR
1
(470 MHz, CDCl3)
d
ꢁ64.83 (s); IR (KBr, cmꢁ1) 3061, 2944, 2875,
1630, 1597, 1497, 1289, 1199, 1148, 764, 697; ESI-MS: m/z¼215
[Mþ1]þ.
4.2.9. N-Ethyl-2-trifluoromethylimidazoline (3d). Yellow oil; 72%;
1H NMR (500 MHz, CDCl3, ppm)
d
3.88 (t, J¼10.0 Hz, 2H), 3.52 (t,
4.2.2. Optimal procedure. A 200-ml three-necked flask equipped
with a condenser was charged with Ph3P (2.20 g, 8.4 mmol), Et3N
(0.85 g, 8.4 mmol), CBr4 (16.8 g, 8.4 mmol), the substrate 1
(3.3 mmol), and fluorinated carboxylic acid (2.8 mmol) in toluene
(15.0 ml) under a nitrogen atmosphere. After the solution was
stirred for about 10 min at room temperature, the mixture was
heated to 90 ꢀC by for 1e3 h with stirring. The solvent was evap-
orated under reduced pressure, and the residue was diluted with
petroleum ether (60e90 ꢀC) and filtered. The residual solid Ph3PO
and Et3N$HCl was washed with petroleum ether three times. The
filtrate was concentrated, and the residue was purified by column
chromatography to obtain product 3.
J¼10.0 Hz, 2H), 3.29 (q, J¼6.4 Hz, 2H),1.18 (t, J¼6.4 Hz, 3H); 13C NMR
2
(125 MHz, CDCl3)
d
154.7 (q, JCeF¼35.0 Hz), 118.0 (q,
1JCeF¼273.1 Hz), 52.7, 50.0, 46.0, 13.3; 19F NMR (470 MHz, CDCl3)
d
ꢁ67.59 (s); IR (KBr, cmꢁ1): 2973, 2936, 2877, 1694, 1186, 1148; ESI-
MS: m/z¼167 [Mþ1]þ.
4.2.10. N-Methyl-2-trifluoromethylimidazoline (3e). Yellow oil; 65%;
1H NMR (500 MHz, CDCl3, ppm)
d
3.87 (t, J¼10.3 Hz, 2H), 3.48 (t,
J¼10.3 Hz, 2H), 2.91 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 153.5 (q,
2JCeF¼35.6 Hz), 117.4 (q, 1JCeF¼261.3 Hz), 53.4, 50.8, 46.5; 19F NMR
(470 MHz, CDCl3)
d
ꢁ64.67 (s); IR (KBr, cmꢁ1) 2970, 2937, 1690,
1208, 1190, 1149, 1116; ESI-MS: m/z¼153 [Mþ1]þ.
4.2.3. N-(2-Benzylamino-ethyl)-2,2,2-trifluoroacetamide(2b). Yellow
4.2.11. N-Benzyl-2-difluoromethylimidazoline (3f). Yellow oil; 81%;
oil; 1H NMR (500 MHz, CDCl3, ppm)
d
8.04 (m,1H), 7.35e7.22 (m, 5H),
1H NMR (500 MHz, CDCl3, ppm)
d 7.36e7.24 (m, 5H), 6.32 (t,
3.71 (s, 2H), 3.31 (dd, J¼6.0, 5.5 Hz, 2H), 2.74 (t, J¼6.0 Hz, 2H), 1.61 (s,
2JHeF¼53.0 Hz, 1H), 4.44 (s, 2H), 3.79 (t, J¼10.3 Hz, 2H), 3.27 (t,
2
1H); 13C NMR (125 MHz, CDCl3)
d
157.4 (q, JCeF¼36.7 Hz), 139.8,
J¼10.3 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 158.5 (t,
128.4,128.0,127.6,116.0 (q,1JCeF¼285.6 Hz), 53.2, 46.9, 39.2; 19F NMR
2JCeF¼25.0 Hz), 136.8, 128.5, 128.1, 127.2, 110.7 (t, 1JCeF¼240.0 Hz),

2862
H. Jiang et al. / Tetrahedron 68 (2012) 2858e2863
53.3, 50.5, 50.3; 19F NMR (470 MHz, CDCl3)
d
ꢁ120.47 (d,
1094, 754, 697. HRMS calcd for (Mþ) C11H10BrF2NO: 288.9914,
found 288.9915.
2JHeF¼53.0 Hz); IR (KBr, cmꢁ1) 3064, 3030, 2940, 2869, 1698, 1623,
1280, 1109, 1054, 739, 700; HRMS calcd for (Mþ) C11H12F2N2:
210.0969, found 210.0973.
4.2.19. (S)-2-Difluoromethyl-4-benzyl-1,3-oxazoline
(3o). Yellow
oil; 50%; 1H NMR (500 MHz, CDCl3):
d
7.34e7.21 (m, 5H), 6.22 (t,
4.2.12. N-Phenyl-2-difluoromethylimidazoline (3g). Yellow oil; 77%;
J¼52.5 Hz, 1H), 4.57e4.51 (m, 1H), 4.38 (t, J¼9.0 Hz, 1H), 4.15 (t,
1H NMR (500 MHz, CDCl3, ppm)
d
7.65e7.13(m, 5H), 6.23 (t,
J¼8.0 Hz, 1H), 3.13 (dd, J¼6.0, 14.0 Hz, 1H), 2.75 (dd, J¼8.0, 14.0 Hz,
2JHeF¼53.0 Hz, 1H), 4.08e3.84 (m, 4H); 13C NMR (125 MHz, CDCl3)
1H); 13C NMR (125 MHz, CDCl3):
d
159.0 (t, JCeF¼27.5 Hz), 137.0,
2
2
d
156.7 (t, JCeF¼24.4 Hz), 139.8, 129.4, 127.3, 123.4, 108.7 (t,
129.2,128.7,126.9,107.2 (t, 1JCeF¼240.0 Hz), 73.1, 67.4, 41.0; 19F NMR
1JCeF¼240.6 Hz), 55.8; 53.7, 19F NMR (470 MHz, CDCl3)
d
ꢁ119.50 (d,
(470 MHz, CDCl3):
d
ꢁ124.20 (d, J¼52.0 Hz); IR (KBr): v 3039, 2944,
2JHeF¼53.0 Hz); IR (KBr, cmꢁ1) 3058, 2946, 2873, 1697, 1600, 1499,
1120, 1059, 696; ESI-MS: m/z¼197 [Mþ1]þ.
1676, 1412, 1231, 1104, 755, 696. HRMS calcd for (Mþ) C11H11F2NO:
211.0809, found 211.0813.
4.2.13. N-Benzyl-2-perfluoropropylimidazoline (3h). Yellow oil;
4.2.20. (S)-4-Benzyl-2-(perfluoropropyl)-1,3-oxazoline (3p). Yellow
80%; 1H NMR (500 MHz, CDCl3, ppm)
d
7.38e7.25 (m, 5H), 4.42 (s,
oil; 61%; 1H NMR (500 MHz, CDCl3):
d 7.33e7.18 (m, 5H), 4.66e4.60
2H), 3.91 (t, J¼10.5 Hz, 2H), 3.33 (t, J¼10.5 Hz, 2H); 13C NMR
(m,1H), 4.43 (t, J¼8.5 Hz, 1H), 4.22 (t, J¼8.5 Hz, 1H), 3.17 (dd, J¼14.0,
2
(125 MHz, CDCl3)
d
154.2 (t, JCeF¼26.3 Hz), 136.5, 128.9, 127.9,
5.5 Hz, 1H), 2.76 (dd, J¼14.0, 8.5 Hz, 1H); 13C NMR (125 MHz,
1
2
127.7, 117.9 (q, t, JCeF¼286.3 Hz, JCeF¼33.7 Hz), 113.3 (t, t,
CDCl3):
d
155.4 (t, 2JCeF¼27.5 Hz), 136.5, 129.4, 128.8, 127.0, 117.6 (q,
1JCeF¼255.6 Hz, JCeF¼31.3 Hz), 108.9 (t, t, q, JCeF¼228.8 Hz,
t, JCeF¼285.0 Hz, JCeF¼33.8 Hz), 109.1 (t, t, JCeF¼256.0 Hz,
2
1
1
2
1
2JCeF¼35.0 Hz, JCeF¼31.3 Hz), 53.5, 51.6, 51.1; 19F NMR (470 MHz,
2JCeF¼31.0 Hz), 108.4 (t, t, q, JCeF¼268.8 Hz, JCeF¼31.3 Hz,
2JCeF¼33.8 Hz), 73.7, 68.0, 40.7; 19F NMR (470 MHz, CDCl3):
2
1 2
CDCl3)
d
ꢁ80.05 (t, J¼11.8 Hz), ꢁ112.05 (q, J¼11.8 Hz), ꢁ125.65 (s);
IR (KBr, cmꢁ1) 3063, 3031, 2850, 1627, 1560, 1187, 1147, 743, 700;
d
ꢁ80.68 (t, J¼9.4 Hz), ꢁ116.70 (m), ꢁ127.14 (s); IR (KBr): v 3021,
ESI-MS: m/z¼329 [Mþ1]þ.
2918, 1669, 1396, 1256, 1084, 731, 693. HRMS calcd for (Mþ)
C13H10F7NO: 329.0651, found 329.0648.
4.2.14. N-Phenyl-2-perfluoropropylimidazoline (3i). Yellow oil; 75%;
1H NMR (500 MHz, CDCl3, ppm)
d
7.36e7.19 (m, 5H), 4.04 (t, J¼10.3 Hz,
2H), 3.85 (t, J¼10.3 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d 153.3 (t,
4.3. N-Benzyl-2-difluoro(phenoxy)methylimidazoline (7)
2JCeF¼25.0 Hz), 141.0, 129.4, 127.5, 126.6, 117.8 (q, t, 1JCeF¼286.3 Hz,
2JCeF¼33.8 Hz), 110.9 (t, t, 1JCeF¼257.5 Hz, 2JCeF¼31.3 Hz),108.4 (t, t, q,
A 25 ml, three-necked, round-bottom flask protected by ni-
trogen was charged with 99.7 mg (4.2 mmol) of NaH (60%) and
10 ml of dry DMF. To the stirred suspension was added 4.2 mmol
phenol. Hydrogen gas was evolved and the flask became warm.
After stirring for 20 min, a clear solution was obtained. Then
200 mg (0.70 mmol) of 3j was added all at once, and the solu-
tion was allowed to stir at the room temperature for the 24 h.
The mixture was poured into 15 ml of ice water, and then
extracted three times with 10 ml portions of CHCl3. The com-
bined organic layers were dried over anhydrous MgSO4 and
concentrated by rotary evaporation at reduced pressure. Com-
pound 7 was obtained as a yellow oil in 55% yield and by column
chromatography (2/1 petroleum ether/ethyl acetate) on basic
2
2
1JCeF¼267.5 Hz, JCeF¼35.0 Hz, JCeF¼33.8 Hz), 56.3, 53.8; 19F NMR
(470 MHz, CDCl3)
d
ꢁ80.12 (t, J¼9.4 Hz), ꢁ109.96 (q, J¼9.4 Hz),
ꢁ125.24 (s); IR (KBr, cmꢁ1) 3064, 2972, 2876, 1623, 1596, 1267, 1230,
1121, 698. ESI-MS: m/z¼315 [Mþ1]þ.
4.2.15. N-Benzyl-2-bromodifluoromethylimidazoline (3j). Yellow oil;
70%; 1H NMR (500 MHz, CDCl3, ppm)
d 7.38e7.29 (m, 5H), 4.47 (s,
2H), 3.87 (t, J¼10.3 Hz, 2H), 3.36 (t, J¼10.3 Hz, 2H); 13C NMR
2
(125 MHz, CDCl3)
d
158.7 (t, JCeF¼25.6 Hz), 136.6, 129.0, 128.0,
127.8, 111.7 (t, 1JCeF¼301.9 Hz), 52.8, 51.7, 51.5; 19F NMR (470 MHz,
CDCl3)
d
ꢁ51.29 (s); IR (KBr, cmꢁ1): 3061, 3031, 2944, 2866, 1614,
1148, 1119, 998, 698; ESI-MS: m/z¼289 [Mþ1]þ.
aluminum oxide: 1H NMR (500 MHz, CDCl3, ppm)
(m, 10H), 4.57 (s, 2H), 3.90 (t, J¼10.3 Hz, 2H), 3.39 (t, J¼10.3 Hz,
d 7.36e6.85
4.2.16. N-Phenyl-2-bromodifluoromethylimidazoline
(3k). Yellow
2
2H); 13C NMR (125 MHz, CDCl3)
d
157.3 (t, JCeF¼35.0 Hz), 149.6,
oil; 68%; 1H NMR (500 MHz, CDCl3, ppm)
d 7.40e7.27 (m, 5H),
4.07e3.95 (m, 4H); 13C NMR (125 MHz, CDCl3)
d
157.8 (t, 2JCeF¼26.3 Hz),
136.7, 129.8, 129.6, 128. 9, 127.9, 126.3, 121.7, 116.7 (t,
1JCeF¼263.8 Hz), 52.3, 51.2, 50.8; 19F NMR (470 MHz, CDCl3)
140.5, 129.5, 127.7, 127.2, 111.7 (t, 1JCeF¼303.8 Hz), 56.8, 52.9; 19F NMR
ꢁ48.46 (s); IR (KBr, cmꢁ1): 3043, 2975, 2872, 1615,
d
ꢁ69.23 (s); IR (KBr, cmꢁ1) 3064, 2942, 2870, 1623, 1593, 1493,
(470 MHz, CDCl3)
d
1199, 1070, 741, 694; HRMS calcd for (Mþ) C17H16F2N2O:
302.1231, found 302.1239.
1591, 1495, 1287, 1147, 699; ESI-MS: m/z¼275 [Mþ1]þ.
4.2.17. (S)-2-Trifluoromethyl-4-benzyl-1,3-oxazoline (3m). Yellow
oil; 71%; 1H NMR (500 MHz, CDCl3):
d 7.33e7.18 (m, 5H), 4.63e4.56
Acknowledgements
(m, 1H), 4.42 (t, J¼9.0 Hz, 1H), 4.21 (t, J¼8.0 Hz, 1H), 3.15 (dd,
J¼14.0, 5.5 Hz, 1H), 2.76 (dd, J¼14.0, 8.0 Hz, 1H); 13C NMR
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21072127, 21032006, 21172141)
and the Science Foundation of Shanghai Municipal Commission
of Sciences and Technology (10JC1405600). The authors thank
Laboratory for Microstructures of Shanghai University for struc-
tural analysis. The authors are very grateful to Professor Wencong
Lu and Liuming Yan for chemical calculation as well as helpful
discussions.
2
(125 MHz, CDCl3):
d
155.3 (dd, JCeF¼40.0 Hz), 136.5, 129.3, 128.8,
127.1, 116.5 (q, 1JCeF¼273.0 Hz), 73.8, 67.7, 40.7; 19F NMR (470 MHz,
CDCl3):
d
ꢁ70.28 (s, 3F). IR (KBr): v 3023, 2925, 1666, 1379, 1215,
1093, 741, 701. HRMS calcd for (Mþ) C11H10F3NO: 229.0714, found
229.0714.
4.2.18. (S)-2-(Bromodifluoromethyl)-4-benzyl-1,3-oxazoline
(3n). Yellow oil; 73%; 1H NMR (500 MHz, CDCl3):
d 7.34e7.20 (m,
5H), 4.67e4.60 (m, 1H), 4.47 (t, J¼9.0 Hz, 1H), 4.27 (t, J¼8.5 Hz, 1H),
3.17 (dd, J¼14.0, 5.0 Hz, 1H), 2.80 (dd, J¼14.0, 8.0 Hz, 1H); 13C NMR
Supplementary data
2
(125 MHz, CDCl3):
d
159.0 (t, JCeF¼30.0 Hz), 136.5, 129.4, 128.9,
127.1, 109.1 (t, 1JCeF¼303.0 Hz), 74.1, 67.7, 40.6; 19F NMR (470 MHz,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.086.
CDCl3):
d
ꢁ55.27 (q, 2F); IR (KBr): v 3028, 2928, 1670, 1398, 1276,

H. Jiang et al. / Tetrahedron 68 (2012) 2858e2863
2863
J.; Zhang, X.; Wang, D.; Yuan, C. J. Fluorine Chem. 1999, 99, 83e85 Reaction with
C-nucleophiles see: (d) Bravo, P.; Cavicchio, G.; Crucianelli, M.; Markovsky, A. L.;
Volonterio, A.; Zanda, M. Synlett 1996, 887e889; (e) Fustero, S.; Navarro, A.;
Pina, B.; Asensio, A.; Bravo, P.; Crucianelli, M.; Volonterio, A.; Zanda, M. J. Org.
Chem. 1998, 63, 6210e6219 Metalehalogen exchange see: (f) Watanabe, H.;
Yan, F.; Sakai, T.; Uneyama, K. J. Org. Chem. 1994, 59, 758e761; (g) Amii, H.;
Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109e1112.
6. Ge, F. L.; Wang, Z. X.; Wan, W.; Lu, W. C.; Hao, J. Tetrahedron Lett. 2007, 48,
3251e3254.
7. Jiang, H. Z.; Yuan, S. J.; Wan, W.; Yang, K.; Deng, H. M.; Hao, J. Eur. J. Org. Chem.
2010, 9, 4227e4236.
8. Tamura, K.; Mizukami, T.; Meada, K.; Watanabe, H.; Uneyama, K. J. Org. Chem.
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