Nucleophile-dependent regioselective reaction of (S)-4-benzyl-2- fluoroalkyl-1,3-oxazolines

Article abstract of DOI:10.1021/jo400073d

Nucleophile-dependent regioselectivities in the nucleophilic reaction of (S)-4-benzyl-2-fluoroalkyl-1,3-oxazoline to different types of fluorinated compounds were investigated experimentally and theoretically. The ring opening of (S)-4-benzyl-2-bromodifluoromethyl-1,3-oxazoline by arenethiolates exclusively occurred at the C5 position of the 1,3-oxazoline ring, whereas completely different regioselectivity was observed for a unimolecular radical nucleophilic substitution (S_RN1) at the terminal bromine atom of the CF₂Br group when arenolates were employed as the nucleophiles. The reaction of (S)-4-benzyl-2-trifluoromethyl-1,3-oxazoline with nucleophiles such as arenethiols, arenols, and TMSCl underwent nucleophilic ring opening in a regiospecific way, while the use of TMSCF₃ was determined to proceed through nucleophilic addition to the C=N bond.

Full text of DOI:10.1021/jo400073d

Article
pubs.acs.org/joc
Nucleophile-Dependent Regioselective Reaction of (S)‑4-Benzyl-2-
Fluoroalkyl-1,3-Oxazolines
Haizhen Jiang,*,†,‡ Liuming Yan,† Minjun Xu,† Wenjun Lu,† Yeshan Cai,† Wen Wan,† Jianhua Yao,‡
Shaoxiong Wu,§ Shizheng Zhu,*,‡ and Jian Hao*,†,‡
†Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, People’s Republic of China
‡Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, People’s Republic of China
§Emory NMR Research Center, Emory University, 201 Dowman Drive, Atlanta, Georgia, 30322, United States
S
* Supporting Information
ABSTRACT: Nucleophile-dependent regioselectivities in the
nucleophilic reaction of (S)-4-benzyl-2-fluoroalkyl-1,3-oxazo-
line to different types of fluorinated compounds were
investigated experimentally and theoretically. The ring opening
of (S)-4-benzyl-2-bromodifluoromethyl-1,3-oxazoline by are-
nethiolates exclusively occurred at the C5 position of the 1,3-
oxazoline ring, whereas completely different regioselectivity
was observed for a unimolecular radical nucleophilic substitution (SRN1) at the terminal bromine atom of the CF2Br group when
arenolates were employed as the nucleophiles. The reaction of (S)-4-benzyl-2-trifluoromethyl-1,3-oxazoline with nucleophiles
such as arenethiols, arenols, and TMSCl underwent nucleophilic ring opening in a regiospecific way, while the use of TMSCF3
was determined to proceed through nucleophilic addition to the CN bond.
various types of fluorinated compounds. Herein, we report our
studies on the nucleophilic reaction of chiral 2-trifluoromethyl-
and 2-bromodifluoromethyl-1,3-oxazolines, which generates the
corresponding biologically significant trifluorinated and gem-
difluorinated compounds. Specifically, we discovered nucleo-
phile-dependent regioselective reactions of ring opening at the
C5 position (path a) vs unimolecular radical nucleophilic
substitution (SRN1) to the terminal bromine atom of the CF2Br
group (path b) of (S)-4-benzyl-2-bromodifluoromethyl-1,3-
oxazoline (1a) and ring opening through cleavage of the C5−
O1 bond (path a) vs nucleophilic addition to the CN bond
(path c) of (S)-4-benzyl-2-trifluoromethyl-1,3-oxazoline (1b)
(Scheme 1).
INTRODUCTION
■
Heterocycles based on 1,3-oxazolines have received much
attention in the past few decades, since they are the core
skeletons of many biologically active products and natural
products1 and are of value in organic synthesis.2 Diverse
chemical transformations can be realized using 1,3-oxazoline
heterocycles as the synthetic intermediates,3 including ring-
opening4 and nucleophilic addition reactions5 and functional
group conversion on the 1,3-oxazoline ring. Moreover,
regiocontrolled ring-opening reactions of 1,3-oxazoline con-
stitute useful tools for the preparation of carboxamide targets.
For example, the ring opening of (S or R)-4-methyl-2-alkyl-1,3-
oxazoline by thiophenol is known as an important process
toward the synthesis of biologically significant chiral secondary
carboxamides through cleavage of the C5−O1 bond of 1,3-
oxazoline.6 However, in comparison with ring opening at the
C5 position, nucleophilic addition to the CN bond of 1,3-
oxazolines has few precedents.7 Additionally, the regioselectiv-
ity between ring opening at C5 and addition to the CN bond
of 1,3-oxazolines is susceptible to several factors such as the
substrate, the type of nucleophile, and the solvent.8 Moreover,
fluorinated groups can greatly alter reaction properties.9
Therefore, the study of the regioselectivity of nucleophilic
reactions of chiral 2-fluoroalkyl-1,3-oxazolines comprise a
challenging topic for fundamental research. On the other
hand, considering the importance of organofluorine com-
pounds in medicines, agricultural chemicals, and electronic
materials,10 the reaction of fluorinated 1,3-oxazolines with
different nucleophiles would be intriguing for the formation of
RESULTS AND DISCUSSION
■
Our initial experiments on the reaction of 2-bromodifluor-
omethyl-1,3-oxazoline (1a)11 with phenolate disclosed that a
gem-difluoromethylene-linked 1,3-oxazoline-contaning phenyl
ether (2aa) could be obtained exclusively. The reaction was
carried out in a 1:1.1:2 1a:PhOH:NaH molar ratio in DMF at
80 °C. The results were similar to those of 2-bromodifluor-
omethylbenzoxazole with arenethiolates and arenolates.12 This
reaction did not undergo ring opening as reported for the
reaction of phenylthiolate and 2-alkyl-1,3-oxazoline.4 Intrigued
by this finding, we further explored the reactions of 1a,b with
Received: January 14, 2013
Published: April 9, 2013
© 2013 American Chemical Society
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opening involving an SN2-type nucleophilic attack of
thiophenolate at the C5 position of 1a, along with the
unexpected 5 (15%) and a small amount of disulfide (Table 1,
entry 8, Scheme 2). No gem-difluoromethylene-linked product
2a was detected. However, other arenethiols, such as 4,6-
dimethylpyrimidine-2-thiol and benzothiazole-2-thiol, also
underwent a ring opening by nucleophilic attack of
arenethiolates at the C5 position of the oxazoline ring and
led to the formation of the corresponding optically active
secondary carboxamides 3a as the only detectable regioisomer
(Table 1, entries 9 and 10).
Scheme 1. Selective Reaction of 1 with Different
Nucleophiles
The structure of 5 was confirmed by X-ray diffraction studies
as well as 1H NMR, 13C NMR, and 19F NMR analysis.
Compound 5 (32% isolated yield) was the only isolated
fluorine-containing product, along with a large amount of the
disulfide as byproduct with no detectable 3ah by 19F NMR,
when the amount of thiophenol was increased (1:3.1
1a:thiophenol molar ratio). The formation of compound 5 is
presumed to proceed via the attack of thiophenolate at the C5
position of 1a to form the ring-opening product bromodi-
fluoromethyl carboxamide (3ah), which reacted further with
excess thiophenolate via the SRN1 reaction pathway on the
bromodifluoromethyl group to generate 5 (Scheme 2). This
speculation is consistent with the observation that the isolated
ring-opening product 3ah was transformed into 5 in the
presence of thiophenol in NaH/DMF at 80 °C (Scheme 2).
Surprisingly, other N-bromodifluoracyl β-thioamides such as
3ai and 3aj could not undergo the SRN1 reaction with
thiophenolate and arenolates. In addition, the SRN1 products
2a could not continue ring-opening reactions with arenols and
arenethiols under the same conditions stated above.
nucleophiles, including other arenols and arenethiols, as well as
the reactions of 1b with TMSCl and TMSCF3.
Under the reaction conditions for phenol (see above), the
reactions of other arenols and arenethiols with (S)-4-benzyl-2-
bromodifluoromethyl-1,3-oxazoline (1a) were studied. The
results are summarized in Table 1. As expected, the reactions
employing arenolates provided gem-difluoromethylene-linked
phenyl ethers 2a as the only detectable product in 65−78%
isolated yields (Table 1, entries 1−7). The results showed that
the reactivity of arenols did not display obvious variation arising
from the steric and electronic effects of substituents. The
reaction is proposed to undergo a unimolecular radical
nucleophilic substitution (SRN1) process.12,13 It is interesting
to note that 3-hydroxypyridine could also be employed in this
SRN1 process and reacted with 1a to give 2ae in 73% yield
(Table 1, entry 5). This result is distinct from the previous
report12 under similar reaction conditions. In the case of
thiophenol under reaction conditions similar to those shown
above in a 1:1.1:2 1a:PhSH:NaH molar ratio in DMF at 80 °C,
the optically active (S)-N-bromodifluoracyl β-thioamide 3ah
was obtained in 79% yield, which was thought to arise from ring
The distinction in the reaction of 1a with arenolates and
arenethiolates was attributed to the different nucleophilicities
and reducibilities of the nucleophilic anion. The displacement
of bromine from 1a by arenolates via an SRN1 mechanism,
Table 1. Reaction of 1a with Arenethiols and Arenols
a
b
Isolated yield. 15% of product 5 and some disulfide observed.
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Scheme 2. Formation of Compound 5
rather than the general SN2 substitution reaction, is possibly
due to the relatively high reducibility and low nucleophilicity of
arenolates as compared to arenethiolates. This process may
involve a transfer of one electron (ET) from arenolate to 1a to
form the radical anion of 1a, followed by the cleavage of the C−
Br bond and departure of the bromide anion to give a free
radical species which combined with ArO−, yielding a new
radical anion precursor of 2a. Afterward, the radical anion
precursor of 2a underwent an intermolecular ET with 1a to
provide the gem-difluoromethylene-linked 1,3-oxazoline-con-
taning aryl ether 2a as a single regioisomer and radical anion of
1a which turns on the chain cycling13 (Scheme 3). The radical
Table 2. Influences of Inhibition Conditions on SRN1
Reactions
a
entry
reaction conditions
temp (°C)
time (h)
yield (%)
b
1
2
3
4
5
6
lab. ill.
80
0.25/2/10
56/78/84
31/42
38/75/81
18/39
62
lab. ill.
in dark
in dark
room temp 0.25/10
80 0.25/2/10
room temp 0.25/10
lab. ill., p-DNB (20 mol %) 80
10
lab. ill., HQ (20 mol %) 80
10
70
a
19F NMR yield using benzotrifluoride as an internal standard (1:1
Scheme 3. SRN1 Process for 2a
b
benzotrifluoride:1a molar ratio). lab. ill. = laboratory illumination.
nucleophilicity caused the arenethiolates to attack at the C5
position of the 1,3-oxazoline ring to proceed via nucleophilic
ring opening.
We also attempted to examine the reaction of 2-
trifluoromethyl-1,3-oxazoline (1b) with different nucleophiles.
Initially, the reactions with arenethiolates and arenolates were
carried out with a 1:1.1:2 1b:ArXH:NaH molar ratio in DMF at
80 °C as mentioned above. It was found that the reactions
yielded the ring-opening products 3b by nucleophilic attack at
the C5 position of 1,3-oxazolines in both cases, which were
different from the reaction with 1a. Arenethiolates only
provided the desired ring-opening products 3b in relatively
high yields (Table 4, entries 6 and 7, procedure B), while
arenolates showed lower efficiency to give ring-opening
products 3b along with a small amount of trifluoromethylated
acetamide product 6 (Table 4, entries 1−5, procedure B). The
structure of 6 was confirmed by X-ray diffraction studies, which
may arise from nucleophilic attack of hydroxide anion. Thus,
further optimization studies were performed to improve the
yields of the desired ring-opening products 3b for the reaction
of 2-trifluoromethyl-1,3-oxazoline (1b) with phenol as the
model substrate. A screen of bases revealed that t-BuOK was
optimal, which provided a higher yield of the desired product
3ba and a lower yield of byproduct 6 (Table 3, entries 1−6).
The reaction did not work well in THF (Table 3, entries 7 and
17) but became much more efficient in dry DMF (entry 13 vs
11). After scanning of the reactant ratio, an optimal yield of 3ba
(97% 19F NMR yield) was eventually observed when the
reaction proceeded in dry DMF at 80 °C for 12 h with a
1.2:1.0:1.1 1b:PhOH:t-BuOK molar ratio (Table 3, entry 13).
The byproduct 6, which could also be obtained in the absence
of PhOH using NaH or t-BuOK as base and dry DMF as
solvent (entries 18 and 19), was the ring-opening product
derived from nucleophilic attack of the hydroxide anion. We
reasoned that hydroxide is most likely from the impurities of
NaH or t-BuOK.
anion of 1a should be stabilized by delocalization of the extra
electron obtained from PhO− into the conjugated oxazoline
moiety, as confirmed by density functional theory (DFT)
calculations (Figure S4 in the Supporting Information).
In order to gain deeper insight the mechanism, radical
inhibition experiments such as addition of p-dinitrobenzene or
hydroquinone (HQ) to the reaction mixture, as well as
reactions in the dark and at room temperature, were carried out
in a 1:1.1 1a:2-methylphenol molar ratio. As shown in Table 2,
the yield was obviously decreased at room temperature as
compared with that at 80 °C (entry 2 vs 1 and 4 vs 3), and the
presence of the radical scavenger p-dinitrobenzene or free
radical inhibitor hydroquinone (HQ) significantly suppressed
the reaction (entries 5 and 6). Additionally, the reaction rate in
the dark was also slower than that under laboratory illumination
during the first 0.25 h. However, when the reaction was run for
an additional 2−9 h, similar yields of the product 2af were
obtained in the dark and under laboratory illumination
conditions (entry 3 vs 1). All these observations support the
S
RN1 mechanism.
On the other hand, although the reducibility of arenethiolates
is somewhat weaker than that of arenolates, their strong
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lone pair on nitrogen attacked TMSCl and broke the Si−Cl
bond.15 The resulting chloride subsequently attacked the C5
position of 1,3-oxazoline, resulting in the formation of ring-
opening product 7 (Scheme 4). Surprisingly, when 1a reacted
with TMSCF3 or TMSCl, the reaction results were too
complicated to analyze.
To explain the selectivity of the substitution reaction of (S)-
4-benzyl-2-fluoroalkyl-1,3-oxazolines with PhOH and PhSH as
summarized in Scheme 5, DFT calculations were performed at
the B3LYP/6-311+G(d)//SDD level of theory.
Table 3. Optimization of Ring-Opening Reaction of 1b
yield of 3ba yield of 6
a
a
entry
base
NaH
1b:PhOH:base
solvent
DMF
(%)
(%)
b
b
1
2
3
4
5
6
7
1:1.1:2
35 (21 )
28 (22 )
KOH
1:1.1:1.1
1:1.1:1.1
1:1.1:1.1
1:1.1:1.1
1:1.1:0
DMF
DMF
DMF
DMF
DMF
THF
34
10
17
63
0
22
2
K2CO3
NaOCH3
t-BuOK
PhO− and PhS− are as known as strong reductants and
should be capable of transferring one electron to 1,3-oxazoline
1 (Scheme 3). However, from the electron affinity energies
(−154.5 and 1.8 kJ/mol for 1a,b, respectively), it was
concluded that 2-bromodifluoromethyl-1,3-oxazoline 1a could
undergo one-electron reduction when reacting with PhO− or
PhS−, while 2-trifluoromethyl-1,3-oxazoline 1b could not
undergo the same process. 1a accepted one electron from
PhO−, which led to C−Br bond weakening (the C−Br bond
distance stretched from 2.005 Å for 1a to 2.825 Å for its radical
anion; Figure 1), then the C−Br bond is broken to give the free
radical, followed by single-electron transfer to form the SRN1
product 2aa (Scheme 3). On the other hand, 1a had a much
lower LUMO energy than 1b (>50% difference) (Figure 2).
Thus, 1a had a higher tendency to accept an electron from the
1
10
0
t-BuOK
1:1.1:1.1
0
0
(dry)
8
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
1:1:1
DMF
DMF
DMF
DMF
DMF
DMF
68
78
78
93
9
26
20
10
13
8
9
1:1.1:2.2
1:2:2.2
10
11
12
13
1.2:1:1.1
1.5:1:1.1
1.2:1:1.1
c
98
97
(dry)
14
15
16
17
t-BuOK
NaH
1.2:1:1
1.2:1:2
2:1:2
DMF
DMF
DMF
THF
(dry)
DMF
(dry)
DMF
(dry)
70
81
74
0
8
21
14
0
NaH
HOMO of the nonbonding electron pair of PhO− for the SRN
1
NaH
1.2:1:2
reaction. However, for 1b and its hypothetical radical anion, no
significant structural changes were observed (Figure 1),
indicating that the C−F bond could not be weakened. As 1b
had a relatively high LUMO energy, it could not carry out the
18
19
t-BuOK
1.2:0:1
1.2:0:2
0
0
6
NaH
29
a
19F NMR yield using benzotrifluoride as an internal standard (1:1
S
RN1 reaction, preferring to execute ring opening.
b
benzotrifluoride:PhOH molar ratio). Isolated yield based on 1b.
The reaction of 1a with PhO− proceeded by a single-electron
c
transfer to form the SRN1 product, while the reaction with PhS−
took place by a ring-opening process. The different behaviors in
the two reactions were difficult to legitimately explain using the
energies of PhS− and PhO− because of their similarity in
energies such as the ionization energies and the HOMO
energies. Through the study of the reaction mechanism, we
found that the reason for the regioselective reaction pathways
of 1a in the presence of PhO− and PhS− could be appraised
from the reverse reaction. The hypothetical SRN1 product 10
could undergo a reverse reaction: 10 had an electron affinity
energy of −57.8 kJ/mol and could be readily reduced by PhS−.
Meanwhile, the C−S bond was weakened during this reduction
and the length of the C−S bond was stretched from 1.84 to
2.62 Å (Figure 3). Therefore, PhS− could be substituted by Br−
reversibly to regenerate the bromodifluoromethylated 1,3-
oxazoline 1a. Thus, the ring-opening reaction of 1a had a
priority due to the strong nucleophilicity of PhS−. However,
2aa displayed an electron affinity energy of −23.3 kJ/mol and
should be difficult to reduce. In addition, the C−O bond was
not significantly weakened in the radical anion of 2aa, which
thus did not undergo the reverse reaction.
With 20% residual substrate 1b.
With the optimized reaction conditions in hand, a series of
arenethiolates and arenolates were examined in the ring-
opening reaction with 2-trifluoromethyl-1,3-oxazoline (1b). For
procedure A shown in Table 4, the yields of trifluoromethylated
acetamide products 3b were significantly improved. The
formation of byproduct 6 was obviously suppressed. However,
the reaction with an electron-poor arenolate such as 4-
nitrophenol required a long reaction time, and only 47% of
conversion of the substrate was observed after 60 h (Table 4,
entry 2, procedure A).
When other nucleophiles such as TMSCl and TMSCF3 were
applied in the reaction with 2-trifluoromethyl-1,3-oxazoline
(1b), we found that the reaction with TMSCl still provided the
ring-opening product 7 in 77% yield. Remarkably, using
TMSCF3 as nucleophile, the product 8 was obtained in 68%
yield (Scheme 4). The reaction was proposed to proceed via
nucleophilic addition to the CN bond of 1,3-oxazoline to
generate the isolable intermediate 9, which then converted into
product 8 in DMF. The distinction in the reaction of 1b with
TMSCF3 and TMSCl was possibly caused by the different
performance of chloride and CF3 groups. Owing to the
difficulty of breaking the Si−CF3 bond, a catalytic amount of
KF was needed as an initiator to cleave the Si−CF3 bond and
generate the CF3 anion. The addition of the resulting CF3
anion to the C2 position of 1,3-oxazoline then occurred
followed by the attack of N− at TMSCF3, forming intermediate
9 and the CF3 anion, which turns on the cycle (Scheme 4).14
The fiinal deprotection of amine of 9 provided 8. In contrast,
the Si−Cl bond was relatively easily broken, and the electron
CONCLUSION
■
In conclusion, the reactions of (S)-4-benzyl-2-fluoroalkyl-1,3-
oxazolines (1) with different nucleophiles were studied. (S)-4-
Benzyl-2-bromodifluoromethyl-1,3-oxazoline (1a) reacted with
arenethiols to provide biologically interesting, optically active
fluoromethylated secondary carboxamides through a nucleo-
philic ring-opening process at the C5 position of 1,3-oxazoline,
while when arenols were used as the nucleophiles, gem-
difluoromethylene-linked, 1,3-oxazoline-contaning phenyl
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Table 4. Reaction of 1b with Arenethiols and Arenols
a
b
Procedure A: 1.2:1.0:1.1 1b:PhXH:t-BuOK reactant molar ratio. Procedure B: 1:1.1:2 1b:ArXH:NaH reactant molar ratio. Isolated yield in
c
procedure A based on PhXH; isolated yield in procedure B based on 1b. With residue of 1b.
Scheme 4. Selective Reactions of 1b
Scheme 5. Reaction of 1 with Phenol and Thiophenol
ethers 2 as the only regioisomer were obtained via a
unimolecular radical nucleophilic substitution reaction (SRN1)
with the terminal bromine atom of the CF2Br group. The
reaction of (S)-4-benzyl-2-trifluoromethyl-1,3-oxazoline (1b)
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311+G(d)//SDD level of theory as implemented in the program suite
of GAUSSIAN 2003.
Procedure a for the Synthesis of Compounds 2, 3, 5, and 6. A 25
mL, three-necked, round-bottom flask was charged with NaH (2
mmol, 60% weight) and 10 mL of dry DMF under a nitrogen
atmosphere. To the stirred suspension was added the arenethiol or
arenol (1.1 mmol). Hydrogen gas was evolved, and the flask became
warm. After the mixture was stirred for 30 min, a clear solution was
obtained. Then the substrate 1 (1 mmol) in 5 mL of DMF was added
dropwise, and the solution was stirred at 80 °C for 8−45 h. The
mixture was poured into 5 mL of ice water and then extracted three
times with 10 mL portions of ethyl acetate. The combined organic
layers were dried over anhydrous MgSO4 and concentrated by rotary
evaporation at reduced pressure. The residue was then purified by
column chromatography (2:1 petroleum ether:ethyl acetate) on basic
aluminum oxide to offer the products 2, 3, 5, and 6.
Figure 1. Bond length changes during the electron affinity reactions:
gray, C; blue, N; red, O; light blue, F; purple, H; brown, Br.
Optimal procedure for the synthesis of products 3b: to a stirred
suspension of t-BuOK (0.054 g, 0.480 mmol) and the arenethiol or
arenol (0.437 mmol) in 2 mL of dry DMF under nitrogen atmosphere
was added dropwise the substrate 1b (0.120 g, 0.524 mmol) in 1 mL
of DMF. Then the solution was stirred at 80 °C. With reference to the
separation processes described above, the products 3b were obtained.
(S)-4-Benzyl-2-(difluorophenoxymethyl)-4,5-dihydrooxazole
25
(2aa): colorless oil; yield 0.20 g, 68%; [α]D = −20.6° (c = 1.36,
CHCl3); 1H NMR (500 MHZ, CDCl3) δ 7.33−7.14 (m, 10H), 4.55−
4.49 (m, 1H), 4.32 (t, J = 9.0 Hz, 1H), 4.12 (t, J = 8.5 Hz, 1H), 3.12
(dd, J = 14.0, 5.5 Hz, 1H), 2.65 (dd, J = 14.0, 8.5 Hz, 1H); 13C NMR
Figure 2. LUMO shapes and energies of 1a (a) and 1b (b).
2
(125 MHz, CDCl3) δ 157.4 (t, JC−F = 38.8 Hz), 149.5, 136.7, 129.5,
1
129.2, 128.6, 126.8, 126.3, 121.9, 115.2 (t, JC−F = 261.3 Hz,), 73.4,
67.5, 40.8; 19F NMR (470 MHz, CDCl3) δ −71.69 (s, 2F); IR (KBr,
cm−1) ν 3065, 3029, 2925, 1687, 1492, 1393, 1197, 1109, 741, 701;
HRMS (EI TOF) calcd for (M+) C17H15F2NO2 303.1071, found
303.1073.
(S)-4-Benzyl-2-(difluoro(4-nitrophenoxy)methyl)-4,5-dihydrooxa-
25
zole (2ab): yellow oil; yield 0.26 g, 76%; [α]D = −18.6° (c = 0.54,
CHCl3); 1H NMR (500 MHZ, CDCl3) δ 8.28 (td, J = 9.5, 2.5 Hz, 2H),
7.41 (d, J = 9.0 Hz, 2H), 7.34 (t, J = 7.0 Hz, 2H), 7.29−7.27 (m, 1H),
7.22 (d, J = 7.0 Hz, 2H), 4.68−4.62 (m, 1H), 4.48 (t, J = 9.0 Hz, 1H),
4.26 (t, J = 8.0 Hz, 1H), 3.21 (dd, J = 14.0, 5.0 Hz, 1H), 2.79 (dd, J =
2
14.0, 8.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 156.9 (t, JC−F
=
Figure 3. Optimized structures for (a) 2aa, (b) 10, (c) the radical
anion of 2aa, and (d) the radical anion of 10: gray, C; blue, N; red, O;
light blue, F; purple, H; yellow, S; brown, Br.
37.5 Hz), 154.4, 145.5, 136.6, 129.3, 128.8, 127.1, 125.6, 121.8, 115.2
(t, 1JC−F = 265.0 Hz), 73.8, 67.7, 40.8; 19F NMR (470 MHz, CDCl3) δ
−72.37 (d, J = 10.2, 2F); IR (KBr, cm−1) ν 3043, 2930, 1688, 1476,
1375, 1235, 1109, 969, 705. Anal. Calcd for C17H14F2N2O4 (348.09):
C, 58.62; H, 4.05; N, 8.04. Found: C, 58.66; H, 3.98; N, 8.01
(S)-4-Benzyl-2-(difluoro(4-methoxyphenoxy)methyl)-4,5-dihy-
drooxazole (2ac): colorless oil; yield 0.22 g, 65%; [α]D25 = −14.6° (c
with arenethiols, arenols, and TMSCl was a ring-opening
pathway through cleavage of the C5−O1 bond, while the use of
TMSCF3 was determined to proceed by nucleophilic addition
to the CN bond to form the product 8. Selective reactions of
(S)-4-benzyl-2-bromodifluoromethyl-1,3-oxazoline (1a) and
(S)-4-benzyl-2-trifluoromethyl-1,3-oxazoline (1b) with phenol
and thiophenol were explained by using density functional
theory (DFT) calculations.
1
= 0.86, CHCl3); H NMR (500 MHZ, CDCl3) δ 7.31 (t, J = 7.5 Hz,
2H), 7.25−7.18 (m, 5H), 6.88−6.84 (m, 2H), 4.59−4.53 (m, 1H),
4.37 (t, J = 9.0 Hz, 1H), 4.17 (t, J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.16
(dd, J = 14.0, 5.5 Hz, 1H), 2.70 (dd, J = 14.0, 8.5 Hz, 1H); 13C NMR
2
(125 MHz, CDCl3) δ 157.7, 157.4 (t, JC−F = 38.8 Hz), 142.6, 136.8,
1
129.1, 128.6, 126.7, 123.2, 115.2 (t, JC−F = 260.0 Hz), 114.3, 73.3,
67.4, 55.4, 40.8; 19F NMR (470 MHz, CDCl3) δ −71.94 (s, 2F); IR
(KBr, cm−1) ν 3050, 2936, 1678, 1485, 1385, 1208, 1088, 950, 696.
Anal. Calcd for C18H17F2NO3 (333.11): C, 64.86; H, 5.14; N, 4.20.
Found: C, 64.92; H, 5.11; N, 4.24.
EXPERIMENTAL SECTION
■
1
General Methods. General Comments. H, 13C, and 19F NMR
(S)-4-Benzyl-2-(difluoro(naphthalen-2-yloxy)methyl)-4,5-dihy-
spectra were recorded on 500 MHz spectrometers. Chemical shifts for
1H NMR spectra are reported in ppm downfield from TMS, chemical
shifts for 13C NMR spectra are reported in ppm relative to internal
chloroform (δ 77.2 ppm for 13C), and chemical shifts for 19F NMR
spectra are reported in ppm downfield from internal fluorotrichloro-
methane (CFCl3). Infrared spectra (IR) were recorded with KBr
pellets. Silica gel (200−400 mesh) was used for flash column
chromatography. Melting points are uncorrected. Optical rotations
were recorded on a highly sensitive polarimeter with a 200 mm cell.
High-resolution mass spectrometry (HRMS) was conducted by TOF
MS with electron impact (EI) ionization at 70 eV. Mass spectra were
obtained using EI. DFT calculations were carried out at the B3LYP/6-
25
drooxazole (2ad): yellow oil; yield 0.23 g, 66%; [α]D = −9.3° (c =
1
1.39, CHCl3); H NMR (500 MHZ, CDCl3) δ 7.85−7.81 (m, 3H),
7.71 (d, J = 1.5 Hz, 1H), 7.53−7.47 (m, 2H), 7.38 (dd, J = 9.0, 2.5 Hz,
1H), 7.30 (t, J = 7.0 Hz, 2H), 7.25−7.22 (m, 1H), 7.17 (d, J = 7.5 Hz,
2H), 4.63−4.57 (m, 1H), 4.42 (t, J = 9.0 Hz, 1H), 4.21 (t, J = 8.0 Hz,
1H), 3.19 (dd, J = 14.0, 5.5 Hz, 1H), 2.68 (dd, J = 14.0, 9.0 Hz, 1H);
2
13C NMR (125 MHz, CDCl3) δ 157.6 (t, JC−F = 38.8 Hz), 147.2,
136.8, 133.7, 131.6, 129.7, 129.3, 128.8, 127.8, 127.8, 126.9, 126.1,
1
121.3, 119.0, 115.5 (t, JC−F = 261.3 Hz), 73.6, 67.7, 40.9; 19F NMR
(470 MHz, CDCl3) δ −71.62 (s, 2F); IR (KBr, cm−1) ν 3023, 2968,
1697, 1456, 1398, 1275, 1088, 926, 712. Anal. Calcd for C21H17F2NO2
4266
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Article
1
(353.12): C, 71.38; H, 4.85; N, 3.96. Found: C, 71.43; H, 4.81; N,
3.98.
26.3 Hz), 136.6, 129.8, 128.7, 127.0, 116.5, 111.8 (t, JC−F = 315.0
Hz), 54.5, 39.6, 32.7, 23.7; 19F NMR (470 MHz, CDCl3) δ −60.63
(dd, 2F); IR (KBr, cm−1) ν 3364, 3084, 3028, 2924, 1699, 1584, 1265,
1115, 964. Anal. Calcd for C17H18BrF2N3OS (429.03): C, 47.45; H,
4.22; N, 9.77. Found: C, 47.67; H, 4.21; N, 9.77.
(S)-3-((4-Benzyl-4,5-dihydrooxazol-2-yl)difluoromethoxy)pyridine
25
(2ae): yellow oil; yield 0.22 g, 73%; [α]D = −10.6° (c = 1.20,
1
CHCl3); H NMR (500 MHZ, CDCl3) δ 8.53 (m, 2H), 7.58 (dd, J =
8.5, 1.0 Hz, 1H), 7.32−7.28 (m, 3H), 7.24−7.21 (m, 1H), 7.18 (d, J =
7.1 Hz, 2H), 4.62−4.56 (m, 1H), 4.41 (t, J = 8.5 Hz, 1H), 4.20 (t, J =
8.0 Hz, 1H), 3.17 (dd, J = 14.0, 5.5 Hz, 1H), 2.71 (dd, J = 14.0, 8.5 Hz,
(S)-N-[2-(Benzothiazol-2-ylsulfanyl)-1-benzylethyl]-2-bromo-2,2-
difluoroacetamide (3aj): pale yellow solid; mp 134.3−135.4 °C; yield
70.34 g, 5%; [α]D25 = −36.9° (c = 1.11, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 9.40 (d, J = 6.0 Hz, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.75 (d, J
= 7.5 Hz, 1H), 7.49−7.46 (m, 1H), 7.38−7.28 (m, 6H), 4.48−4.42 (m,
1H), 3.43 (d, J = 6.0 Hz, 2H), 3.35 (dd, J = 13.5, 4.5 Hz, 1H), 2.95
(dd, J = 13.5, 9.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 168.0,
2
1H); 13C NMR (125 MHz, CDCl3) δ 157.0 (t, JC−F = 38.8 Hz),
147.6, 143.9, 136.6, 129.4, 129.3, 128.8, 126.9, 124.1, 115.2 (t, 1JC−F
=
263.8 Hz), 73.7, 67.6, 40.8; 19F NMR (470 MHz, CDCl3) δ −72.06 (s,
2F); IR (KBr, cm−1) ν 3035, 2916, 1665, 1477, 1385, 1289, 1075, 981,
696; HRMS (EI TOF) calcd for (M+) C16H14F2N2O2 304.1023, found
304.1021.
2
160.3 (t, JC−F = 27.5 Hz), 152.1, 136.7, 135.5, 129.5, 128.9, 127.1,
126.6, 125.0, 121.4, 121.2, 111.9 (t, 1JC−F = 315.0 Hz), 53.8, 39.1, 35.7;
19F NMR (470 MHz, CDCl3) δ −60.27 (s, 2F); IR (KBr, cm−1) ν
(S)-4-Benzyl-2-(difluoro(o-tolyloxy)methyl)-4,5-dihydrooxazole
25
(2af): colorless oil; yield 0.24 g, 75%; [α]D = −25.4° (c = 1.38,
3359, 3064, 3029, 2928, 1697, 1547, 1426, 1134, 1080, 958, 751, 698.
Anal. Calcd for C18H15BrF2N2OS2 (455.97): C, 47.27; H, 3.31; N,
6.13; Found: C, 47.19; H, 3.27; N, 6.15.
1
CHCl3); H NMR (500 MHZ, CDCl3) δ 7.35−7.32 (m, 2H), 7.30−
7.24 (m, 3H), 7.24−7.16 (m, 4H), 4.64−4.58 (m, 1H), 4.41 (t, J = 9.0
Hz, 1H), 4.21 (t, J = 8.0 Hz, 1H), 3.20 (dd, J = 14.0, 5.3 Hz, 1H), 2.74
(dd, J = 14.0, 8.5 Hz, 1H), 2.36 (s, 3H); 13C NMR (125 MHz, CDCl3)
(S)-2,2,2-Trifluoro-N-(1-phenoxy-3-phenylpropan-2-yl)acetamide
(3ba): white solid; mp 124.7−126.2 °C; yield 0.13A/0.064B g, 90/20%;
2
25
1
δ 157.7 (t, JC−F = 39.2 Hz), 148.1, 136.9, 131.7, 131.4, 128.7, 126.9,
[α]D = −18.7° (c = 2.00, acetone); H NMR (500 MHz, CDCl3) δ
7.35−7.25 (m, 5H), 7.24−7.22 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H),
6.93−6.91 (m, 2H), 6.78 (d, J = 7.5 Hz, 1H), 4.55−4.49 (m, 1H),
4.00−3.94 (m, 2H), 3.09 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 158.1, 156.9 (q, 2JC−F = 36.3 Hz), 136.4, 129.7, 129.4, 128.9,
1
126.8, 122.2, 115.5 (t, JC−F = 262.7 Hz), 73.5, 67.6, 40.9, 16.4; 19F
NMR (470 MHz, CDCl3) δ −71.10 (dd, J = 183.4, 152.8 Hz, 2F); IR
(KBr, cm−1) ν 3063, 3029, 2929, 1685, 1494, 1393, 1172, 1120, 749,
702. Anal. Calcd for C18H17F2NO2 (317.12): C, 68.13; H, 5.40; N,
4.41. Found: C, 68.07; H, 5.34; N, 4.37.
1
127.2, 121.8, 115.8 (q, JC−F = 286.3 Hz), 114.6, 66.6, 51.0, 36.9; 19F
NMR (470 MHz, CDCl3) δ −75.83 (s, 3F); IR (KBr, cm−1) ν 3318,
3106, 2911, 1706, 1589, 1560, 1246, 1208, 1179, 880, 754, 703, Anal.
Calcd for C17H16F3NO2 (323.11): C, 63.15; H, 4.99; N, 4.33. Found:
C, 63.07; H, 4.86; N, 4.22.
(S)-4-Benzyl-2-((2,6-dimethylphenoxy)difluoromethyl)-4,5-dihy-
drooxazole (2ag): colorless oil; yield 0.26 g, 78%; [α]D25 = −9.5° (c =
1.20, CHCl3); 1H NMR (500 MHZ, CDCl3) δ 7.35 (t, J = 7.5 Hz, 2H),
7.26 (dd, J = 18.8, 7.3 Hz, 3H), 7.0 (s, 3H), 4.67−4.61 (m, 1H), 4.42
(t, J = 9.0 Hz, 1H), 4.22 (t, J = 8.0 Hz, 1H), 3.22 (dd, J = 14.0, 5.3 Hz,
1H), 2.78 (dd, J = 14.0, 8.5 Hz, 1H), 2.40 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 157.9 (t, 2JC−F = 39.3 Hz), 146.9, 136.9, 132.8, 129.4,
128.7, 126.9, 126.5, 116.2 (t, 1JC−F = 264.2 Hz), 73.5, 67.5, 40.9, 17.2;
19F NMR (470 MHz, CDCl3) δ −69.82 (dd, J = 164.5, 152.9 Hz, 2F);
(S)- N-[1-Benzyl-2-(4-nitrophenoxy)ethyl]-2,2,2-trifluoroaceta-
mide (3bb): pale yellow solid; mp 183.2−184.3 °C; yield 0.052A/
25
1
0.018B g, 32/5%; [α]D = −4.4° (c = 1.10, acetone); H NMR (500
MHz, CDCl3) δ 8.24−8.21 (m, 2H), 7.34−7.27 (m, 3H), 7.19−7.17
(m, 2H), 6.98−6.95 (m, 2H), 6.59 (d, J = 8.0 Hz, 1H), 4.60−4.54 (m,
1H), 4.11−4.03 (m, 2H), 3.13−3.05 (m, 2H); 13C NMR (125 MHz,
CD3COCD3) δ 164.3, 157.2 (q, 2JC−F = 36.3 Hz), 142.4, 138.0, 129.8,
IR (KBr, cm−1) ν 3063, 3028, 2931, 1686, 1474, 1390, 1160, 1113,
773, 702. Anal. Calcd for C19H19F2NO2 (317.12): C, 68.87; H, 5.78;
N, 4.23. Found: C, 68.84; H, 5.71; N, 4.21.
1
129.0, 127.2, 126.3, 116.7 (q, JC−F = 286.3 Hz), 115.5, 69.6, 51.9,
(S)-N-(1-Benzyl-2-phenylsulfanylethyl)-2-bromo-2,2-difluoroace-
36.8; 19F NMR (470 MHz, CDCl3) δ −75.82 (s, 3F); IR (KBr, cm−1)
ν 3311, 3121, 2923, 1700, 1593, 1562, 1503, 1332, 1264, 1179, 884,
756, 701. Anal. Calcd for C17H15F3N2O4 (368.09): C, 55.44; H, 4.11;
N, 7.61. Found: C, 55.38; H, 4.03; N, 7.57.
tamide (3ah): pale yellow solid; mp 118.6−119.5 °C; yield 0.32 g,
25
79%; [α]D = +25.1° (c = 1.21, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 7.39−7.37 (m, 2H), 7.33−7.29 (m, 4H), 7.27−7.22 (m,
2H), 7.17−7.15 (m, 2H), 6.30 (d, J = 7.5 Hz, 1H), 4.37−4.30 (m,
1H), 3.14−3.06 (m, 2H), 3.01 (d, J = 6.5 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 159.5 (t, 2JC−F = 27.5 Hz), 136.2, 134.9, 130.2, 129.4,
(S)- N-[1-Benzyl-2-(4-methoxyphenoxy)ethyl]-2,2,2-trifluoroace-
tamide (3bc): white solid; mp 145.3−146.0 °C; yield 0.12A/0.098B
g, 80/28%; [α]D25 = −16.6° (c = 2.01, acetone); 1H NMR (500 MHz,
CDCl3) δ 7.33−7.22 (m, 5H), 6.87−6.85 (m, 4H), 6.83 (s, 1H),
4.51−4.46 (m, 1H), 3.94−3.88 (m, 2H), 3.78 (s, 3H), 3.08 (d, J = 7.5
Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 156.9 (q, 2JC−F = 36.3 Hz),
1
128.8, 127.1, 127.1, 111.5 (t, JC−F = 315.0 Hz), 51.3, 38.7, 37.1; 19F
NMR (470 MHz, CDCl3) δ −60.74 (s, 2F); IR (KBr, cm−1) ν 3382,
3049, 2942, 1669, 1527, 1441, 1276, 1078, 970, 715; HRMS (EI TOF)
calcd for (M+) C17H16BrF2NOS 399.0104, found 399.0101.
1
154.6, 152.3, 136.5, 129.4, 128.9, 127.2, 115.9 (q, JC−F = 286.3 Hz),
(S)-N-(1-Benzyl-2-phenylsulfanylethyl)-2,2-difluoro-2-phenylsul-
115.7, 114.9, 67.5, 55.8, 51.1, 36.9; 19F NMR (470 MHz, CDCl3) δ
−75.83 (s, 3F); IR (KBr, cm−1) ν 3357, 3146, 2925, 1696, 1550, 1514,
1352, 1255, 1240, 1174, 910, 827, 768, 720, 694. Anal. Calcd for
C18H18F3NO3 (353.12): C, 61.19; H, 5.13; N, 3.96. Found: C, 61.11;
H, 5.06; N, 3.84.
fanylacetamide (5): pale yellow solid; mp 97.0−97.6 °C; yield 0.064
25
1
g, 15%; [α]D = +11.5° (c = 1.14, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.59 (d, J = 7.0 Hz, 2H), 7.45−7.42 (m, 1H), 7.38−7.35 (m,
4H), 7.32−7.21 (m, 6H), 7.11 (d, J = 7.0 Hz, 2H), 6.28 (d, J = 8.0 Hz,
1H), 4.31−4.24 (m, 1H), 3.01−2.84 (m, 4H); 13C NMR (125 MHz,
CDCl3): δ161.1 (t, 2JC−F = 27.5 Hz), 136.8, 136.4, 135.1, 130.6, 130.0,
(S)-N-[1-Benzyl-2-(naphthalen-2-yloxy)ethyl]-2,2,2-trifluoroace-
tamide (3bd): white solid; mp 127.3−129.0 °C; yield 0.13A/0.07B g,
1
25
1
129.5, 129.4, 129.3, 128.8, 127.1, 126.9, 125.0, 122.3 (t, JC−F = 287.5
78/19%; [α]D = −14.8° (c = 1.02, acetone); H NMR (500 MHz,
CDCl3) δ 7.83−7.81 (m, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.51−7.47 (m,
1H), 7.42−7.39 (m, 1H), 7.35−7.22 (m, 6H), 7.10 (d, J = 2.0 Hz,
1H), 6.88 (d, J = 8.5 Hz, 1H), 4.63−4.57 (m, 1H), 4.11−4.06 (m,
2H), 3.14 (d, J = 7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 157.0
Hz), 50.7, 38.4, 36.7; 19F NMR (470 MHz, CDCl3) δ −82.46 (s, 2F);
IR (KBr, cm−1) ν 3412, 3060, 3028, 2951, 1676, 1540, 1478, 1441,
1214, 1059, 987; HRMS (EI TOF) calcd for (M+) C23H21F2NOS2
429.1033, found 429.1032. Anal. Calcd for C23H21F2NOS2 (429.55):
C, 64.31; H, 4.93; N, 3.26. Found: C, 64.16; H, 5.018; N, 3.207.
(S)-N-[1-Benzyl-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethyl]-2-
bromo-2,2-difluoro-acetamide (3ai): white solid; mp 145.3−146.0
2
(q, JC−F = 36.3 Hz), 156.1, 136.4, 134.5, 129.9, 129.4, 129.0, 127.8,
1
127.2, 127.0, 126.9, 124.2, 118.5, 115.9 (q, JC−F = 286.3 Hz), 107.2,
66.7, 51.0, 37.0; 19F NMR (470 MHz, CDCl3) δ −75.75 (s, 3F); IR
(KBr, cm−1) ν 3420, 3102, 2927, 1704, 1557, 1259, 1176, 875, 837,
759, 744, 701. Anal. Calcd for C21H18F3NO2 (373.12): C, 67.55; H,
4.86; N, 3.75. Found: C, 67.48; H, 4.79; N, 3.71.
25
1
°C; yield 0.34 g, 78%; [α]D = −33.5° (c = 1.15, CHCl3); H NMR
(500 MHz, CDCl3) δ 8.49 (d, J = 5.5 Hz, 1H), 7.34 (dd, J = 8.5, 1.0
Hz, 2H), 7.27 (t, J = 7.0 Hz, 3H), 6.76 (s, 1H), 4.36−4.29 (m, 1H),
3.36 (dd, J = 10.0, 5.0 Hz, 1H), 3.22 (dd, J = 13.5, 4.0 Hz, 1H), 3.17
(S)-N-[1-Benzyl-2-(pyridin-3-yloxy)ethyl]-2,2,2-trifluoroacetamide
(dd, J = 15.0, 3.5 Hz, 1H), 2.94 (dd, J = 13.5, 8.5 Hz, 1H), 2.38 (s,
(3be): white solid; mp 134.2−136.3 °C; yield 0.11A/0.038B g, 78/12%;
2
25
1
6H); 13C NMR (125 MHz, CDCl3) δ 171.3, 167.5, 160.0 (t, JC−F
=
[α]D = −5.4° (c = 0.91, acetone); H NMR (500 MHz, CDCl3) δ
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Article
8.31 (d, J = 3.0 Hz, 1H), 8.24 (d, J = 4.5 Hz, 1H), 7.32−7.14 (m, 8H),
4.57−4.51 (m, 1H), 4.05−3.97 (m, 2H), 3.09 (d, J = 8.5 Hz, 2H); 13C
1b (0.8 mmol) in 2 mL of dry DMF was added under a nitrogen
atmosphere. To the stirred suspension was added TMSCF3 (2.0
mmol), and then the mixture was stirred at room temperature for 1 h.
The mixture was poured into 5 mL of water and then extracted three
times with 10 mL portions of ethyl acetate. The combined organic
layers were washed with saturated brine and then were dried over
anhydrous MgSO4 and concentrated by rotary evaporation at reduced
pressure. The residue was then purified by column chromatography
(petroleum ether) to yield 162 mg of the product 8.
2
NMR (125 MHz, CDCl3) δ 157.1 (q, JC−F = 37.5 Hz), 154.5, 143.0,
138.1, 136.2, 129.3, 129.1, 127.4, 124.2, 121.2, 115.9 (q, 1JC−F = 286.3
Hz), 67.2, 50.9, 36.8; 19F NMR (470 MHz, CDCl3) δ −75.71 (s, 3F);
IR (KBr, cm−1) ν 3390, 3034, 2929, 1704, 1575, 1475, 1287, 1112,
1054, 883, 798, 703, 613; HRMS (EI TOF) calcd for (M+)
C16H15F3N2O2 324.1086, found 324.1085.
(S)-N-(1-Benzyl-2-phenylsulfanylethyl)-2,2,2-trifluoroacetamide
(3bf): pale yellow solid; mp 48.1−49.6 °C; yield 0.13A/0.16B g, 89/
(S)-4-Benzyl-2,2-bis(trifluoromethyl)oxazolidine (8): yellow oil;
25
1
25
yield 0.16 g, 70%; [α]D = −2.2° (c = 0.82, CHCl3); 1H NMR
46%; mp 48.1−49.6 °C; [α]D = +6.6° (c = 1.05, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.38−7.36 (m, 2H), 7.33−7.24 (m, 6H), 7.23−
7.14 (m, 2H), 6.48 (s, 1H), 4.39−4.32 (m, 1H), 3.16 (dd, J = 14.5, 7.5
Hz, 2H), 3.08 (dd, J = 12.0, 5.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 156.7 (q, 2JC−F = 37.5 Hz), 136.2, 134.8, 130.3, 129.4, 129.3,
(500 MHz, CDCl3) δ 7.36 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H),
7.22 (d, J = 7.5 Hz, 2H), 4.26 (dd, J = 7.0 Hz, J = 6.8 Hz, 1H), 3.93−
3.86 (m, 1H), 3.81 (dd, J = 7.1 Hz, J = 8.0 Hz, 1H), 2.93 (dd, J = 7.0,
13.5 Hz, 1H), 2.82 (dd, J = 6.5, 13.5 Hz, 1H), 2.67 (d, J = 6.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 137.2, 128.9, 128.8, 127.0, 122.1 (q,
1
128.9, 127.3, 127.2, 115.7 (q, JC−F = 286.3 Hz), 51.2, 42.4, 38.6; 19F
NMR (470 MHz, CDCl3) δ −75.99 (s, 3F); IR (KBr, cm−1) ν 3367,
3041, 2933, 1670, 1543, 1429, 1266, 1078, 968, 701. Anal. Calcd for
C17H16F3NOS (339.09): C, 60.16; H, 4.75; N, 4.13. Found: C, 60.06;
H, 4.68; N, 4.10.
1
1JC−F = 288.3 Hz), 121.9 (q, JC−F = 287.1 Hz), 91.5−92.5 (m), 74.3,
58.8, 39.1; 19F NMR (470 MHz, CDCl3) δ −79.61 (q, J = 8.5 Hz, 3F),
−79.77 (q, J = 8.5 Hz, 3F); IR (KBr, cm−1) ν 3382, 3031, 1604, 1498,
1216, 1131, 757, 702. Anal. Calcd for C12H11F6NO (299.07): C, 48.17;
H, 3.71; N, 4.68. Found: C, 48.01; H, 3.65; N, 4.53.
(S)- N-[1-Benzyl-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)ethyl]-
2,2,2-trifluoroacetamide (3bg): white solid; mp 149.3−151.0 °C;
Procedure for the Synthesis of 9. A 25 mL, three-necked, round-
bottom flask was charged with KF (0.2 mmol), and then a mixture of
the substrate 1b (0.8 mmol) and TMSCF3 (2.0 mmol) in 2 mL of
superdry DMF was added under a nitrogen atmosphere. The mixture
was stirred at room temperature for 1 h and then was concentrated by
rotary evaporation at reduced pressure. The residue was then purified
by column chromatography to offer the intermediate 9.
25
1
yield 0.13A/0.26B g, 78/58%; [α]D = +42.2° (c = 2.55, acetone); H
NMR (500 MHz, CDCl3) δ 8.66 (d, J = 5.5 Hz, 1H), 7.37−7.27 (m,
5H), 6.77 (s, 1H), 4.40−4.33 (m, 1H), 3.34 (dd, J = 9.5, 15.0 Hz, 1H),
3.24 (td, J = 3.5, 13.5 Hz, 2H), 2.96 (dd, J = 8.5, 13.5 Hz, 1H), 2.39 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 171.3, 167.6, 157.2 (q, JC−F
=
2
1
36.3 Hz), 136.7, 129.7, 128.8, 127.1, 116.6, 116.0 (q, JC−F = 286.3
Hz), 54.4, 39.4, 32.8, 29.8, 23.7; 19F NMR (470 MHz, CDCl3) δ
−75.88 (s, 3F); IR (KBr, cm−1) ν 3399, 3110, 2925, 1703, 1587, 1563,
1534, 1341, 1264, 1223, 1183, 880, 752, 724, 700. Anal. Calcd for
C17H18F3N3OS (369.11): C, 55.27; H, 4.91; N, 11.38. Found: C,
55.17; H, 4.87; N, 11.25.
(S)-N-Trimethylsilanyl-4-benzyl-2,2-bis(trifluoromethyl)-
oxazolidine (9): pale yellow solid; mp 41−43 °C; [α]D25 = −12.3° (c =
1.20, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.36 (t, J = 7.0 Hz, 2H),
7.28 (dd, J = 7.0, 6.5 Hz, 1H), 7.22 (d, J = 7.5 Hz, 2H), 4.03 (d, J = 8.0
Hz, 1H), 3.95−3.93 (m, 1H), 3.86 (t, J = 7.0 Hz, 1H), 3.00 (d, J = 13.5
Hz, 1H), 2.80 (t, J = 13.0 Hz, 1H), 0.40 (s, 9H); 13C NMR (125 MHz,
(S)-N-(1-Benzyl-2-hydroxyethyl)-2,2,2-trifluoroacetamide (6):
white solid; mp 172.3−173.0 °C; [α]D25 = −18.1° (c = 2.02, acetone);
1H NMR (500 MHz, CDCl3) δ 7.34−7.31 (m, 2H), 7.28−7.25 (m,
1
CDCl3) δ 138.4, 129.1, 128.9, 126.8, 122.5 (q, JC−F = 291.3 Hz),
1
121.8 (q, JC−F = 286.3 Hz), 94.2−93.7 (m), 71.0, 63.3, 41.7, 1.4; 19F
NMR (470 MHz, CDCl3) δ −75.14 (q, J = 8.9 Hz, 3F), −76.47 (q, J =
8.9 Hz, 3F); IR (KBr, cm−1) ν 3031, 1604, 1496, 1208, 1136, 843, 746,
702. Anal. Calcd for C15H19F6NOSi (371.11): C, 48.51; H, 5.16; N,
3.77. Found: C, 48.48; H, 5.13; N, 3.69.
1H), 7.23−7.21 (m, 2H), 6.61 (s, 1H), 4.27−4.21 (m, 1H), 3.74−3.67
(m, 2H), 2.99−2.92 (m, 2H), 1.71 (s, 1H); 13C NMR (125 MHz,
DMSO) δ 156.4 (q, 2JC−F = 36.3 Hz), 138.8, 129.4, 128.6, 126.6, 116.4
(q, 1JC−F = 286.3 Hz), 62.8, 54.4, 36.3; 19F NMR (470 MHz, CDCl3) δ
−75.90 (s, 3F); IR (KBr, cm−1) ν 3400, 3109, 2936, 1699, 1561, 1225,
1207, 1179, 877, 751, 727, 701. Anal. Calcd for C11H12F3NO2
(247.08): C, 53.44; H, 4.89; N, 5.67. Found: C, 53.37; H, 4.82; N,
5.49.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and CIF files giving experimental details,
characterization data (including 1H, 13C, and 19F NMR spectra)
for the compounds synthesized, information of single-crystal
XRD, and information and the results of the theoretical
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org. CCDC 876227 also contains
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB21EZ, U.K. (fax: +44 1223
336033).
Procedure for the Synthesis of 7. A 25 mL, three-necked, round-
bottom flask was charged with THF (2 mL) and the substrate 1b (0.88
mmol) under a nitrogen atmosphere. To the stirred suspension was
added TMSCl (3.14 mmol). This mixture was stirred at room
temperature for 2 h and was then poured into 5 mL of water and
extracted three times with 10 mL portions of ethyl acetate. The
combined organic layers were washed with saturated brine and then
were dried over anhydrous MgSO4 and concentrated by rotary
evaporation at reduced pressure after filtering. The residue was then
purified by column chromatography (20:1 petroleum ether:ethyl
acetate) to yield 178 mg of the product 7.
N-((S)-3-Chloro-1-phenylpropan-2-yl)-2,2,2-trifluoroacetamide
(7): white solid; mp 89−90 °C; yield 0.18 g, 77%; [α]D25 = −1.6° (c =
1
0.90, CHCl3); H NMR (500 MHz, CDCl3) δ 7.36−7.33 (m, 2H),
7.30−7.23 (m, 3H), 6.53 (s, 1H), 4.50−4.45 (m, 1H), 3.68 (dd, J =
11.5, 4.0 Hz, 1H), 3.56 (dd, J = 11.5, 3.5 Hz, 1H), 3.04−2.96 (m, 2H);
AUTHOR INFORMATION
Corresponding Author
*E-mail: hzjiang@shu.edu.cn (H.J.); zhusz@mail.sioc.ac.cn
(S.Z.); jhao@staff.shu.edu.cn (J.H.).
■
2
13C NMR (125 MHz, CDCl3) δ 156.7 (q, JC−F = 36.8 Hz), 135.6,
1
129.2, 129.0, 127.4, 115.6 (q, JC−F = 286.0 Hz), 51.5, 45.4, 37.1; 19F
NMR (470 MHz, CDCl3) δ −75.91 (s, 3F); IR (KBr, cm−1) ν 3301,
3074, 1701, 1606, 1495, 1227, 1175, 754, 699; MS (EI) m/z (%)
Notes
265(1) (M+), 154 (15) (M+ − H2NCOCF3), 152 (46) (M+
−
The authors declare no competing financial interest.
H2NCOCF3), 91 (100) (PhCH2). Anal. Calcd for C11H11ClF3NO
(265.05): C, 49.73; H, 4.17; N, 5.27. Found: C, 49.63; H, 4.09; N,
5.24.
ACKNOWLEDGMENTS
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21072127, 21032006,
■
Procedure for the Synthesis of 8. A 25 mL, three-necked, round-
bottom flask was charged with KF (0.2 mmol), and then the substrate
4268
dx.doi.org/10.1021/jo400073d | J. Org. Chem. 2013, 78, 4261−4269

The Journal of Organic Chemistry
Article
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21072216, 21172141), the Science Foundation of Shanghai
Municipal Commission of Sciences and Technology
(10JC1405600), and the Ministry of Science and Technology
of China (Nos. 2010CB12610, 2011BAE06B05). We thank the
Laboratory for Microstructures of Shanghai University for
structural analysis.
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