Nucleophilic difluoromethylation of N,N-acetals with TMSCF 2SO2Ph reagent promoted by trifluoroacetic acid: A facile access to α-difluoromethylated tertiary amines

Article abstract of DOI:10.1016/j.jfluchem.2012.05.018

A protocol for the synthesis of difluoromethylated tertiary amines by nucleophilic difluoromethylation of N,N-acetals using TMSCF₂SO ₂Ph reagent is developed. The reaction proceeds smoothly in 1,4-dioxane using K₂CO₃ as the initiator. A key feature of the reaction is that the in situ generated iminiums (from N,N-acetals and CF₃COOH) could be fluoroalkylated in an efficient way.

Full text of DOI:10.1016/j.jfluchem.2012.05.018

Journal of Fluorine Chemistry 143 (2012) 161–166
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Nucleophilic difluoromethylation of N,N-acetals with TMSCF2SO2Ph reagent
promoted by trifluoroacetic acid: A facile access to
tertiary amines
a-difluoromethylated
*
Weizhou Huang, Chuanfa Ni, Yanchuan Zhao, Bing Gao, Jinbo Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling Road, 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 protocol for the synthesis of difluoromethylated tertiary amines by nucleophilic difluoromethylation
of N,N-acetals using TMSCF2SO2Ph reagent is developed. The reaction proceeds smoothly in 1,4-dioxane
using K2CO3 as the initiator. A key feature of the reaction is that the in situ generated iminiums (from
N,N-acetals and CF3COOH) could be fluoroalkylated in an efficient way.
Received 19 April 2012
Received in revised form 14 May 2012
Accepted 15 May 2012
Available online 23 May 2012
ß 2012 Elsevier B.V. All rights reserved.
Dedicated to Professor David O’Hagan on
the occasion of his receipt of the ACS Award
for Creative Work in Fluorine Chemistry
2012.
Keywords:
(Phenylsulfonyl)difluoromethylation
Difluoromethylation
Nucleophilic fluoroalkylation
N,N-acetals
Amines
1. Introduction
groups led by Qing [11] and Li [12] have developed an oxidative
trifluoromethylation of tertiary amines via iminium cation
Fluoroalkyl amines are of great interest in bioorganic and
medical chemistry research due to the profound change of the
basicity of the amine functionality imposed by the fluoroalkyl
group [1–3]. Since the first nucleophilic synthesis of enantiomeri-
intermediates based on the fourth method [11,12]. However, all
the research has focused on the synthesis of trifluoromethylated or
perfluorinated tertiary amines. The synthesis of difluoromethy-
lated tertiary amines using various difluoromethylating agents
[13–15] is also of great importance, since CF2H group could act as
lipophilic hydrogen bond donor and alcohol isostere [16,17].
Recently, we reported the difluoromethylation of C55N bonds in
heterocycles under the activation of alkylation reagents (Eq. (1)),
which can be applicable for the synthesis of difluoromethylated
tertiary amines such as 1 [18]. As our continuing effort on the
synthesis of potentially useful difluoromethylated tertiary amines
such as 4, we investigated the use of N,N-acetals 6 as iminium
cation precursors (Eq. (2)). In this article, we wish to report our
results on the difluoromethylation of N,N-acetals promoted by
Me3SiCl or trifluoroacetic acid.
cally pure
a-trifluoromethylated primary amines with Ruppert–
Prakash reagent (TMSCF3) in 2001 [4,5], numerous works have
been devoted to developing efficient methods for the synthesis of
structure-diverse fluoroalkylated primary and secondary amines
[6–8]. Only in recent years, attention has been paid to the direct
synthesis of fluoroalkylated tertiary amines by nucleophilic
fluoroalkylation of iminium cation intermediates [6]. The com-
monly used methods for the generation of iminum cations in
fluoroalkylation reactions include: (1) alkylation of imines [9], (2)
protonation of enamines [10], (3) condensation of aldehydes and
N-trimethylsilylamines in the presence of TMSOTf [9], and (4)
oxidation of tertiary amines [11,12]. Dilman and co-workers have
exploited the first three methods for transferring trifluoromethyl
or other fluorinated groups to iminium cations [9,10]. The research
N
N+
R
N
(1)
R
CF2Y
* Corresponding author. Tel.: +86 21 54925174; fax: +86 21 64166128.
E-mail addresses: jinbohu@sioc.ac.cn, jinbohu@mail.sioc.ac.cn (J. Hu).
1
2
3
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.05.018

162
W. Huang et al. / Journal of Fluorine Chemistry 143 (2012) 161–166
X
X
N
X
N
N+
(2)
Ar
N
Ar
CF2Y
Ar
X
4
5
6
Scheme 1.
2. Results and discussion
fluoroalkylated amine 4f in 67% yield using the above optimized
reactant ratio (Scheme 1). Moreover, TFA proved to be a general
activation reagent for all N,N-acetals tested, including morpholine-
and piperidine-derived ones.
At the onset of our investigation, we synthesized a series of
N,N-acetals 6 by condensation of aromatic aldehydes with dialkyl
amines, such as piperidine, morpholine and dimethylamine
according to known methods [19–21]. All the N,N-acetals were
purified by recrystallization. With a series of N,N-acetals in hand,
we carried out the nucleophilic (phenylsulfonyl)difluoromethy-
lation of N,N-acetal 6a (derived from benzaldehyde and piperi-
dine) with TMSCF2SO2Ph (7) (Table 1). It was found that no
expected fluoroalkylation reaction took place in the presence of a
Lewis base initiator in DMF (entry 1). Some previous reports have
pointed out that a Lewis acid such as trimethylsilyl chloride
(TMSCl) could promote the formation of iminiun cation species
from N,N-acetals [21–23]. Therefore, we tried the fluoroalkyla-
tion using TMSCl as an activator. After N,N-acetal 6a was treated
with TMSCl (1.5 equiv.) in dimethoxyethane (DME) at room
temperature for 10 min, subsequent addition of TMSCF2SO2Ph (7)
(1.5 equiv.) and K2CO3 (1.5 equiv.) resulted in the formation of
the desired product 4a in 57% yield (entry 2). Inspired by this
result, we further optimized the reaction parameters such as
solvents, initiators and reactant ratios (entries 2–8). It was found
that DME was the optimal solvent and a combination of 6a, 7,
TMSCl and K2CO3 in a ratio of 1:1.5:2:3 gave 4a in a good yield
(84%, see entry 3).
However, in the case of N,N-acetal 6f derived from morpholine,
no expected product was detected using the optimized conditions
(as shown in entry 3, Table 1). It was reported that a similar
alkylation of N,N-acetal 6f in the presence of TMSCl was also not
efficient [21]. We then aimed at seeking a more effective activator
(than TMSCl) to ensure the efficient formation of the iminium
species from 6f. After a screening of several Brønsted acids,
trifluoroacetic acid (TFA) was found to be the optimal acid due to
its strong acidity and low oxidizing ability. Under the activation of
TFA, the difluoromethylation of N,N-acetal 6f in DMF gave the
A further optimization of the reaction conditions using 3
equivalents of K2CO3 showed that the reaction between piperi-
dine-derived N,N-acetal 6a and 7 was significantly influenced by
both solvent and the reactant ratio (Table 2). When 1.5 equivalents
of 7 and 2 equivalents of TFA were employed and among several
solvents that were tested, the reaction in 1,4-dioxane gave much
higher yield (69%) (entries 1–4). Further studies showed that a
combination of 2 equivalents of 7 and 1.5 equivalents of TFA gave
4a in excellent yield (92%) (entry 8). However, the Lewis base
initiator had little influence on the reaction, and both K2CO3 and KF
gave similar results (entries 4–7). To identify the reactive
intermediates in this reaction, the reaction mixture of N,N-
acetal 6a with TFA was characterized by NMR. When 6a was
treated with 1.5 equivalents of CF3COOH in DMSO-d6 at room
temperature for 10 min, the 1H NMR showed the disappearance
of the peak corresponding to the PhC–H proton of 6a (
d = 3.63)
and the appearance of a new peak at = 10.06, which was
d
assigned to the methine proton of the iminium cation B [23].
Moreover, the aromatic hydrogens shifted downfield (from
d
= 7.15–7.40 to d = 7.60–7.80), which was in accordance with
the deshielding effect caused by the positive charge at the
iminium cation. Based on theses findings, the reaction pathway
is depicted in Scheme 2.
Using the conditions shown in Table 2, entry 8 as standard, we
investigated the difluoromethylation of various N,N-acetals 6 with
reagent 7 (Table 3). In all cases, (phenylsulfonyl)difluoromethy-
lated cyclic and acyclic tertiary amines 4 were obtained in
moderate to excellent isolated yields. Both aromatic aldehyde- and
heteroaromatic aldehyde-derived acetals (such as 6k) were found
to be viable substrates for the current reaction. In general, the
morpholine-derived acetals afforded the products in relatively
Table 1
Table 2
Difluoromethylation of N,N-acetal 6a promoted by TMSCl.
Difluoromethylation of N,N-acetal 6a promoted by CF3COOH.
Entry
1
Solvent
DMF
Initiator
6a:7:TMSCl:initiator
Yield (%)a
0
Entry
Solvent
Initiator
6a:7:TFA:initiator
Yield (%)a
K2CO3,
NaOAc, or KF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
KF
1:1.5:0:1.5
1
2
3
4
5
6
7
8
DMF
K2CO3
K2CO3
K2CO3
K2CO3
KF
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
1:2:2:3
52
32
9
2
3
4
5
6
7
8
DME
DME
CH2Cl2
THF
1:1.5:1.5:1.5
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
1:1.5:2:3
57
84
0
DMSO
CH3CN
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
69
69
86
82
92
45
54
46
77
DMF
DME
DME
K2CO3
KF
1:2:2:3
K2CO3
1:2:1.5:3
a
a
Determined by 19F NMR.
Determined by 19F NMR.

W. Huang et al. / Journal of Fluorine Chemistry 143 (2012) 161–166
163
Scheme 2.
lower yields than the piperidine-derived ones, which is probably
due to the incomplete conversion of the former ones to the
iminium species.
To demonstrate the synthetic utility of the obtained (phenyl-
sulfonyl)difluoromethylated amines 4, the reductive desulfonyla-
tion was conducted with Mg/HOAc/NaOAc in a DMF-based system
[24]. As is exemplified in Scheme 3, amine 4a could be smoothly
transformed into difluoromethylated cyclic tertiary amine 8a in
94% yield.
Scheme 3.
Table 3
Difluoromethylation of various N,N-acetals 6 promoted by CF3COOH.
a
2 equiv of CF3COOH was used.

164
W. Huang et al. / Journal of Fluorine Chemistry 143 (2012) 161–166
column chromatography (petroleum ether/ethyl acetate, 2.5:1) to
give 4a (168 mg, 92% yield).
4.1.1. 1-(2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethyl)piperidine
(4a)
Scheme 4.
Considering that a chiral Brønsted acid may promote an asym-
White solid. mp: 81–83 8C. IR (KBr): 2935, 2813, 1584, 1449,
metric mode in our fluoroalkylation reaction [25], we tried the
activation of N,N-acetal 6a with the readily available (1S)-(+)-10-
camphorsulfonic acid. However, when the reaction was conducted
in DMF, the (phenylsulfonyl)difluoromethylated amine 4a was
obtained as a racemic mixture in only 19% yield (Scheme 4).
1335, 1164, 989, 725, 615, 549 cmÀ1. 1H NMR:
d 8.03 (d, J = 8.1 Hz,
2H), 7.70 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.8 Hz, 2H), 7.32–7.35 (m,
5H), 4.61 (dd, J = 28.2 Hz, 6.0 Hz, 1H), 2.62 (t, J = 7.5 Hz, 2H),
2.282.34 (m, 2H), 1.26–1.55 (m, 4H), 1.16–1.24 (m, 2H). 19F NMR:
d
À95.2 (dd, J = 237.7 Hz, 7.3 Hz, 1F), À108.7 (dd, J = 238.3 Hz,
27.4 Hz, 1F). 13C NMR:
d
135.3, 134.5, 130.4, 130.2, 129.4, 128.9,
3. Conclusion
128.6, 128.2, 123.9 (t, J = 292.8 Hz), 68.5 (dd, J = 25.8 Hz, 16.1 Hz),
51.5, 25.5, 23.6. MS (ESI, m/z): 366.2 ([M+H]+). Anal. Calcd. for
In conclusion, we have developed a new protocol for the
synthesis of difluoromethylated tertiary amines by nucleophilic
difluoromethylation of N,N-acetals derived from aromatic alde-
hydes using fluoroalkyl silane reagent TMSCF2SO2Ph. The reaction
proceeds smoothly in 1,4-dioxane using K2CO3 as the initiator. A
key feature of the reaction is the fluoroalkylation of the iminium
cations that are in situ generated from N,N-acetals in the presence
of trifluoroacetic acid.
C
19H21F2NO2S: C, 62.45; H, 5.79; N, 3.83; Found: C, 62.55; H, 5.83;
N, 3.63.
4.1.2. 1-(1-(4-Bromophenyl)-2,2-difluoro-2-(phenylsulfonyl)-
ethyl)piperidine (4b)
4. Experimental
All reactions were carried out in oven-dried glassware under a
nitrogen atmosphere. DME was freshly distilled over sodium and
stored under nitrogen atmosphere. DMF was distilled from CaH2.
N,N-acetals were prepared according to the reported procedure
[19–21]. Me3SiCF2SO2Ph reagent was prepared according to our
previous report [24]. Commercially available chemicals were used
without further purification. Column chromatography was per-
formed on silica gel 300–400 (0.038–0.048 mm). 1H, 13C, and 19F
White solid. mp: 116–118 8C. IR (KBr): 2936, 2856, 2821, 1588,
1448, 1331, 1162, 986, 722, 613, 571 cmÀ1 1H NMR:
. d 8.02 (d,
J = 7.8 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.8 Hz, 2H), 7.49 (d,
J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 4.58 (dd, J = 27.0 Hz, 6.9 Hz,
1H), 2.59 (t, J = 7.5 Hz, 2H), 2.30 (t, J = 6.9 Hz, 2H), 1.32–1.54 (m,
NMR spectra were recorded in CDCl3, chemical shifts (d) are given
4H), 1.18–1.26 (m, 2H). 19F NMR:
d
À95.7 (d, J = 237.7 Hz, 1F),
in ppm and spin–spin coupling constants (J) are given in Hz. 1H
À108.6 (dd, J = 237.7 Hz, 25.4 Hz, 1F). 13C NMR:
d 135.0, 134.6,
NMR chemical shifts were determined relative to internal (CH3)4Si
131.7, 131.4, 130.4, 128.9, 128.5, 123.7 (dd, J = 302.1 Hz, 291.5 Hz),
122.9, 68.0 (dd, J = 25.8 Hz, 16.2 Hz), 51.4, 25.6, 23.7. MS (ESI, m/z):
444.4 ([M+H]+). Anal. Calcd. for C19H20BrF2NO2S: C, 51.36; H, 4.54;
N, 3.15; Found: C, 51.47; H, 4.61; N, 2.99.
(TMS) at
CDCl3
7.26. 13C NMR chemical shifts were determined relative to
internal TMS at
0.0. 19F NMR chemical shifts were determined
relative to CFCl3 at 0.0. Mass spectra were obtained on a mass
d 0.0 or to the signal of a residual protonated solvent:
d
d
d
spectrometer. High-resolution mass data were recorded on a high-
resolution mass spectrometer in the EI or ESI mode. Melting points
are uncorrected.
4.1.3. 1-(2,2-Difluoro-1-(4-fluorophenyl)-2-(phenylsulfonyl)-
ethyl)piperidine (4c)
4.1. Typical procedure for the reaction of N,N-acetals (6) with
TMSCF2SO2Ph (7)
Under a nitrogen atmosphere, into a 1,4-dioxane (3 mL)
solution of N,N-acetal 6a (129 mg, 0.5 mmol) in 25-mL Schlenk
flask was added CF3COOH (85.5 mg, 0.75 mmol) dropwise. After
the reaction mixture was stirred for 10 min at room temperature,
TMSCF2SO2Ph (7) (264 mg, 1.0 mmol) and K2CO3 (207 mg,
1.5 mmol) were added subsequently. After stirring at room
temperature for 1 h, the reaction mixture was quenched with
water (20 mL) and extracted with ethyl acetate (3 Â 15 mL). The
combined organic phase was washed with saturated NaCl solution
(15 mL), and dried by anhydrous MgSO4. After the removal of the
solvent under reduced pressure, the residue was purified by flash
White solid. mp: 86–88 8C. IR (KBr): 2938, 2856, 2826, 1606,
1509, 1330, 1163, 985, 867, 724, 684, 612, 518 cmÀ1 1H NMR:
. d
8.02 (d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.2 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H),
7.27–7.31 (m, 2H), 7.02–7.08 (m, 2H), 4.60 (dd, J = 27.0 Hz, 6.3 Hz,
1H), 2.57–2.63 (m, 2H), 2.27–2.33 (m, 2H), 1.30–1.55 (m, 4H),
1.18–1.26 (m, 2H). 19F NMR:
d
À95.6 (dd, J = 238.0 Hz, 3.4 Hz, 1F),
À108.7 (dd, J = 237.7 Hz, 28.8 Hz, 1F), À113.5 (s, 1F). 13C NMR:
d

W. Huang et al. / Journal of Fluorine Chemistry 143 (2012) 161–166
165
162.7 (d, J = 248.2 Hz), 135.1, 134.6, 131.9 (dd, J = 8.2 Hz, 2.3 Hz),
130.4, 128.9, 125.5, 123.8 (dd, J = 302.0 Hz, 292.3 Hz), 115.2 (d,
J = 21.2 Hz), 67.9 (dd, J = 25.8 Hz, 16.0 Hz), 51.4, 25.6, 23.7. MS (ESI,
m/z): 384.3 ([M+H]+). Anal. Calcd. for C19H20F3NO2S: C, 59.52; H,
5.26; N, 3.65; Found: C, 59.58; H, 5.47; N, 3.50.
J = 8.1 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.37–
7.39 (m, 3H), 7.29–7.34 (m, 2H), 4.62 (dd, J = 27.6 Hz, 5.7 Hz, 1H),
3.51–3.68 (m, 4H), 2.67–2.73 (m, 2H), 2.42–2.48 (m, 2H). 19F NMR:
d
À94.8 (dd, J = 238.8 Hz, 4.5 Hz, 1F), À108.4 (dd, J = 238.5 Hz,
27.1 Hz, 1F). 13C NMR:
d
134.9, 134.7, 130.3, 130.2, 129.0, 128.9,
128.8, 128.4, 123.7 (dd, J = 299.8 Hz, 290.2 Hz), 68.2 (dd,
J = 26.2 Hz, 16.2 Hz), 66.6, 50.3. MS (ESI, m/z): 368.4 ([M+H]+).
Anal. Calcd. for C18H19F2NO3S: C, 58.84; H, 5.21; N, 3.81; Found: C,
58.71; H, 5.38; N, 3.70.
4.1.4. 1-(1-(2-Chlorophenyl)-2,2-difluoro-2-(phenylsulfonyl)-
ethyl)piperidine (4d)
4.1.7. 4-(1-(4-Bromophenyl)-2,2-difluoro-2-(phenylsulfonyl)-
ethyl)morpholine (4g)
White solid. mp: 92–94 8C. IR (KBr): 2935, 2856, 2814, 1449,
1330, 1163, 992, 764, 727, 618, 568, 553 cmÀ1. 1H NMR:
d 8.04 (d,
J = 7.8 Hz, 2H), 7.71 (t, J = 7.8 Hz, 1H), 7.52–7.60 (m, 3H), 7.44–7.47
(m, 1H), 7.21–7.31 (m, 2H), 5.48 (dd, J = 26.4 Hz, 7.5 Hz, 1H), 2.69
(t, J = 7.5 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 1.39–1.55 (m, 4H), 1.21–
White solid. mp: 162–164 8C. IR (KBr): 2967, 2865, 1582, 1455,
1.29 (m, 2H). 19F NMR:
(dd, J = 235.2 Hz, 24.8 Hz, 1F). 13C NMR:
d
À95.6 (dd, J = 236.6 Hz, 7.3 Hz, 1F), À108.2
136.1, 135.0, 134.6,
1335, 1162, 1009, 816, 722, 615, 559 cmÀ1 1H NMR:
. d 7.99 (d,
d
J = 8.1 Hz, 2H), 7.74 (t, J = 7.2 Hz, 1H), 7.60 (t, J = 8.1 Hz, 2H), 7.52 (d,
J = 8.1 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.60 (dd, J = 26.4 Hz, 6.6 Hz,
131.0, 130.4, 130.1, 129.7, 128.9, 128.2, 126.1, 123.9 (dd,
J = 302.5 Hz, 292.8 Hz), 62.6 (dd, J = 26.2 Hz, 16.2 Hz), 51.7, 25.8,
23.8. MS (ESI, m/z): 400.4 ([M+H]+). Anal. Calcd. for
1H), 3.54–3.69 (m, 4H), 2.66–2.71 (m, 2H), 2.41–2.50 (m, 2H). 19
F
NMR:
d
À95.4 (dd, J = 238.5 Hz, 5.9 Hz, 1F), À108.2 (dd,
134.9, 134.6, 131.70,
J = 238.6 Hz, 26.3 Hz, 1F). 13C NMR:
d
C19H20ClF2NO2S: C, 57.07; H, 5.04; N, 3.50; Found: C, 57.03; H,
5.29; N, 3.31.
131.65, 130.3, 129.1, 127.8, 123.38 (dd, J = 299.3 Hz, 290.3 Hz),
123.35, 67.6 (dd, J = 25.8 Hz, 16.1 Hz), 66.5, 50.3. MS (ESI, m/z):
446.3 ([M+H]+). Anal. Calcd. for C18H18BrF2NO3S: C, 48.44; H, 4.07;
N, 3.14; Found: C, 48.77; H, 4.21; N, 2.97.
4.1.5. 1-(2,2-Difluoro-1-(2-methoxyphenyl)-2-(phenylsulfonyl)-
ethyl)piperidine (4e)
4.1.8. 4-(1-(2,4-Dichlorophenyl)-2,2-difluoro-2-(phenylsulfonyl)-
ethyl)morpholine (4h)
Orange solid. mp: 103–105 8C. IR (KBr): 2931, 2809, 1600, 1493,
1335, 1152, 1003, 837, 769, 607, 519 cmÀ1 1H NMR:
. d 8.04 (d,
J = 8.1 Hz, 2H), 7.68 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.40 (d,
J = 7.8 Hz, 1H), 7.28–7.34 (m, 1H), 6.89–6.95 (m, 2H), 5.46 (dd,
J = 30.0 Hz, 6.0 Hz, 1H), 3.82 (s, 3H), 2.58 (t, J = 7.5 Hz, 2H), 2.35–
Colorless oil. IR (film): 2962, 2860, 1586, 1449, 1334, 1161,
1117, 1014, 875, 756, 585 cmÀ1. 1H NMR:
d 8.01 (d, J = 7.5 Hz, 2H),
2.40 (m, 2H), 1.26–1.53 (m, 4H), 1.16–1.23 (m, 2H). 19F NMR:
d
7.74 (t, J = 6.6 Hz, 1H), 7.60 (t, J = 7.2 Hz, 2H), 7.51 (s, 1H), 7.46 (d,
J = 8.1 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.46 (dd, J = 24.9 Hz, 7.8 Hz,
À95.4 (dd, J = 235.2 Hz, 4.2 Hz, 1F), À108.5 (dd, J = 236.8 Hz,
30.2 Hz, 1F). 13C NMR:
d
158.2, 135.7, 134.3, 130.5, 130.4, 129.6,
1H), 3.56–3.70 (m, 4H), 2.71–2.79 (m, 2H), 2.56–2.64 (m, 2H). 19
F
128.8, 124.6 (dd, J = 298.8 Hz, 289.2 Hz), 119.7, 118.8, 110.8, 58.6
(dd, J = 26.3 Hz, 15.7 Hz), 55.6, 51.7, 25.8, 23.9. MS (ESI, m/z): 396.1
([M+H]+). Anal. Calcd. for C20H23F2NO3S: C, 60.74; H, 5.86; N, 3.54;
Found: C, 60.72; H, 6.01; N, 3.48.
NMR:
d
À96.0 (dd, J = 237.7 Hz, 8.8 Hz, 1F), À107.5 (dd,
136.7, 135.5, 135.0, 134.2,
J = 237.4 Hz, 26.8 Hz, 1F). 13C NMR:
d
131.5, 130.4, 130.0, 129.1, 126.7, 126.1, 123.4 (dd, J = 300.9 Hz,
292.5 Hz), 66.6, 61.8 (dd, J = 25.1 Hz, 16.2 Hz), 50.5. MS (ESI, m/z):
436.1 ([M+H]+). HRMS (ESI): calcd. for C18H18Cl2F2NO3S+ ([M+H]+):
436.0347; Found: 436.0349.
4.1.6. 4-(2,2-Difluoro-1-phenyl-2-(phenylsulfonyl)ethyl)morpholine
(4f)
4.1.9. 4-(2,2-Difluoro-1-(4-methoxyphenyl)-2-(phenylsulfonyl)-
ethyl)morpholine (4i)
White solid. mp: 102–104 8C. IR (KBr): 2958, 2835, 1582, 1449,
1339, 1162, 1116, 829, 724, 623, 558 cmÀ1 1H NMR:
. d 8.01 (d,

166
W. Huang et al. / Journal of Fluorine Chemistry 143 (2012) 161–166
4 h followed by adding water (20 mL). The reaction mixture was
White solid. mp: 109–111 8C. IR (KBr): 2956, 2865, 2835, 1609,
1512, 1331, 1258, 1163, 876, 729, 622, 557 cmÀ1 1H NMR:
8.00
extracted with EtOAc (15mL Â 3), and the combined organic phase
was washed with saturated brine (20 mL), then dried over MgSO4.
After the removal of EtOAc, the crude product was purified by silica
gel column chromatography using petroleum ether/ethyl acetate
(25:1) as eluent to give product 8a (106 mg, 94% yield).
.
d
(d, J = 7.5 Hz, 2H), 7.71 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.24
(d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.56 (dd, J = 27.3 Hz,
6.3 Hz, 1H), 3.81 (s, 3H), 3.50–3.68 (m, 4H), 2.64–2.71 (m, 2H),
2.41–2.48 (m, 2H). 19F NMR:
(dd, J = 238.3 Hz, 24.8 Hz, 1F). 13C NMR:
d
À95.1 (d, J = 238.0 Hz, 1F), À108.3
160.0, 134.9, 134.7,
d
4.2.1. 1-(2,2-Difluoro-1-phenylethyl)piperidine (8a)
131.5, 130.3, 129.0, 123.8 (dd, J = 298.4 Hz, 289.0 Hz), 120.8, 113.8,
67.6 (dd, J = 25.9 Hz, 16.1 Hz), 66.5, 55.2, 50.3. MS (ESI, m/z): 398.2
([M+H]+). Anal. Calcd. for C19H21F2NO4S: C, 57.42; H, 5.33; N, 3.52;
Found: C, 57.45; H, 5.32; N, 3.37.
4.1.10. 2,2-Difluoro-N,N-dimethyl-1-phenyl-2-(phenylsulfonyl)-
ethanamine (4j)
Colorless oil. IR (film): 2935, 2852, 2809, 1454, 1389, 1136,
1102, 1072, 1057, 998, 868, 702 cmÀ1
.
1H NMR:
d
7.32–7.37 (m,
5H), 6.15 (dt, J = 55.5 Hz, 3.9 Hz, 1H), 3.62–3.73 (m, 1H), 2.43–2.56
(m, 4H), 1.54–1.61 (m, 4H), 1.34–1.43 (m, 2H). 19F NMR:
À120.3
(ddd, J = 283.0 Hz, 55.9 Hz, 9.3 Hz, 1F), À121.7 (ddd, J = 283.2 Hz,
55.9 Hz, 15.8 Hz, 1F). 13C NMR:
134.1, 129.5, 128.2, 128.0, 116.0
d
White solid. mp: 101–103 8C. IR (KBr): 2992, 2952, 2791, 1580,
1456, 1349, 1149, 1075, 714, 594, 534 cmÀ1 1H NMR:
. d 8.00 (d,
J = 7.8 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 7.29–
7.38 (m, 5H), 4.63 (dd, J = 26.7 Hz, 6.6 Hz, 1H), 2.15 (s, 6H). 19F
d
(t, J = 245.5 Hz), 71.5 (t, J = 21.5 Hz), 52.1, 26.1, 24.2. MS (ESI, m/z):
226.2 ([M+H]+). HRMS (ESI): calcd. for C13H18F2N+ ([M+H]+):
226.1402; Found: 226.1406.
NMR:
d
À97.0 (d, J = 241.1 Hz, 1F), À108.8 (dd, J = 238.5 Hz,
135.2, 134.5, 130.4, 130.2, 128.8, 128.68,
27.4 Hz, 1F). 13C NMR:
d
Acknowledgements
128.65, 128.3, 123.8 (dd, J = 300.5 Hz, 292.0 Hz), 67.2 (dd,
J = 25.7 Hz, 15.7 Hz), 41.7. MS (ESI, m/z): 326.2 ([M+H]+). Anal.
Calcd. for C16H17F2NO2S: C, 59.06; H, 5.27; N, 4.30; Found: C, 58.99;
H, 5.61; N, 4.19.
Support of our work by the National Natural Science Foundation
of China (20825209, 20832008) and the National Basic Research
Program of China (2012CB821600) is gratefully acknowledged.
4.1.11. 3-(2,2-Difluoro-2-(phenylsulfonyl)-1-(piperidin-1-yl)-
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White solid. mp: 127–129 8C. IR (KBr): 2939, 2812, 1587, 1337,
1156, 1104, 1009, 715, 608, 533 cmÀ1 1H NMR:
. d 8.62 (dd,
J = 4.5 Hz, 1.2 Hz, 1H), 8.56 (d, J = 1.5 Hz, 1H), 8.03 (d, J = 7.8 Hz,
2H), 7.69–7.76 (m, 2H), 7.60 (t, J = 8.1 Hz, 2H), 7.30–7.34 (m, 1H),
4.65 (dd, J = 26.4 Hz, 7.2 Hz, 1H), 2.59–2.66 (m, 2H), 2.30–2.37 (m,
2H), 1.34–1.58 (m, 4H), 1.19–1.27 (m, 2H). 19F NMR:
d
À95.6 (dd,
J = 239.4 Hz, 7.3 Hz, 1F), À108.0 (dd, J = 240.8 Hz, 29.1 Hz, 1F). 13
C
NMR:
d 150.8, 149.7, 137.1, 134.71, 134.66, 130.3, 128.9, 125.6,
123.5 (dd, J = 301.6 Hz, 291.6 Hz), 123.0, 66.5 (dd, J = 25.4 Hz,
16.6 Hz), 51.3, 25.5, 23.5. MS (ESI, m/z): 367.2 ([M+H]+). Anal.
Calcd. for C18H20F2N2O2S: C, 59.00; H, 5.50; N, 7.65; Found: C,
59.24; H, 5.58; N, 7.49.
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At room temperature, into a DMF (5 mL) solution of 4a (183 mg,
0.5 mmol) was added HOAc/NaOAc (1:1) buffer solution (8 mol/L,
2.5 mL). Magnesium turnings (180 mg, 7.5 mmol) were added in
portions. The reaction mixture was stirred at room temperature for