One-pot asymmetric synthesis of α-trifluoromethylated amines from α-trifluoromethyl ketones

Article abstract of DOI:10.1016/j.tet.2010.09.047

Diastereoselective reduction of (Rs)-N-tert-butanesulfinyl α-trifluoromethyl ketimines formed in situ from the corresponding α-trifluoromethyl ketones and N-tert-butanesulfinamide has been achieved, and either diastereomer of N-tert-butanesulfinyl α-trifl

Full text of DOI:10.1016/j.tet.2010.09.047

Tetrahedron 66 (2010) 8933e8937
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Tetrahedron
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One-pot asymmetric synthesis of
from -trifluoromethyl ketones
a-trifluoromethylated amines
a
,
,
,
b
,
a
,
,
*
Jian Xu a y, Zhen-Jiang Liu b y, Xian-Jin Yang a , Li-Min Wang b, Guan-Long Chen a, Jin-Tao Liu b
*
a Laboratory for Advanced Materials, Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling 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:
Received 3 July 2010
Received in revised form 11 September 2010
Accepted 14 September 2010
Available online 18 September 2010
Diastereoselective reduction of (Rs)-N-tert-butanesulfinyl
a-trifluoromethyl ketimines formed in situ
from the corresponding
either diastereomer of N-tert-butanesulfinyl
a
-trifluoromethyl ketones and N-tert-butanesulfinamide has been achieved, and
-trifluoromethyl amines was obtained in good yields with
a
excellent diastereoselectivities (up to 99:1 dr) using NaBH4 and L-Selectride as the reductants,
respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
a
-Trifluoromethylated amine
Trifluoromethyl ketone
N-tert-Butanesulfinamide
Asymmetric synthesis
1. Introduction
to develop a more practical and general method suitable for the
rapid synthesis of chiral a-trifluoromethyl amines.
Trifluoromethyl-containing compounds have gained growing
interest in the field of agrochemistry, pharmaceutical industry, and
materials science during the past decades1 because the intro-
duction of a trifluoromethyl group with strong electron-with-
drawing ability can lead to significant changes in the physical,
chemical, and biological properties of the molecules. Among such
Recently, much attention has been paid to the synthesis of chiral
CF3-substituted N-sulfinyl imines and their applications in the
diastereoselective synthesis of trifluoromethyl amine derivatives.7
During our studies on the reactions of CF3-containing ketones,8 we
have synthesized a new class of chiral CF3-substituted
a,b-un-
saturated N-tert-butanesulfinyl ketimines and explored their pre-
liminary applications in the asymmetric synthesis of either
diastereomer of trifluoromethyl allylic amines.9 As part of our on-
going research in the development of practical methods for the
compounds enantiomerically pure a-trifluoromethyl amines have
attracted considerable attention since these chiral synthons are
important and common subunits in the synthesis of chiral fluori-
nated pharmaceuticals and agrochemicals.1a,b,d Based on its prime
importance in the drug industry, a variety of methodologies have
been developed for their asymmetric synthesis,2e6 such as nucle-
ophilic trifluoromethylation of N-(tert-butylsulfinyl)-imines,3 ad-
dition of organometallic reagents to chiral trifluoromethyl imines
or analogues,4 reduction of enantiopure trifluoromethyl imines5a,b
or catalytic asymmetric reduction of prochiral trifluoromethyl
ketimines5c and so on.6 However, most of them have suffered from
some drawbacks, like for instance, only one enantiomer obtained,
or restricted by the availability of organometallic derivatives, or
having a narrow substrate scope. Therefore, there is still desirable
synthesis of chiral
one-pot approach for the asymmetric synthesis of either (Rs, R) or
(Rs, S) isomer of N-tert-butanesulfinyl -trifluoromethyl amines by
the diastereoselective reduction of (Rs)-N-tert-butanesulfinyl
trifluoromethyl ketimines, which are generated in situ from
a-CF3 amines, we herein wish to report a facile
a
a
-
the condensation of
a-trifluoromethyl ketones and (Rs)-N-tert-
butanesulfinamide.
2. Results and discussion
We began our investigation with the NaBH4-mediated one-pot
reductive amination of 2,2,2-trifluoroacetophenone (1a) according
to the conditions previously reported by Ellman and co-workers for
the one-pot reductive amination of ketones with N-tert-butane-
sulfinamide.10 Condensation of 1a with 2 in dry THF in the presence
of 2.5 equiv of Ti(Oi-Pr)4 under reflux for 24 h,11 followed by in situ
reduction with 3.0 equiv of NaBH4 at ꢀ78 ꢁC for 3 h afforded the
* Corresponding authors. E-mail addresses: yxj@ecust.edu.cn (X.-J. Yang), jtliu@
mail.sioc.ac.cn (J.-T. Liu).
y
Contributed equally to this work.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.047

8934
J. Xu et al. / Tetrahedron 66 (2010) 8933e8937
a
-trifluoromethyl sulfinamide 3a in 52% yield and with a diaster-
With the two optimized reaction conditions in hand (Table 2,
entries 1 and 7), a variety of -trifluoromethyl ketones were
employed as the substrate to explore the scope of the one-pot re-
ductive amination procedures and test the generality of the reversal
in diastereofacial selectivity upon using NaBH4 versus L-Selectride.
As summarized in Table 3, all the one-pot reductive aminations of
eomeric ratio of 98:2 (Table 1, entry 1). To achieve better results, the
effect of the solvent was then surveyed. As shown in Table 1, using
Et2O instead of THF as the solvent, the yield of 3a could be dra-
matically improved to 85% without any loss in the diastereomeric
ratio (3a/4a¼98:2, entry 2). When n-hexane was used as the sol-
vent, the reaction gave similar yield and diastereoselectivity as
using THF (entry 3). Other solvents, such as toluene, CH2Cl2, and
a
both
went smoothly and afforded the corresponding
amines from 1 in good to excellent yields as well as high diaster-
a
-trifluoromethyl aryl and
a
-trifluoromethyl alkyl ketones
a
-trifluoromethyl
CH3CN furnished the a-trifluoromethyl sulfinamides 3a and 4a in
moderate selectivity but gave lower yields (entries 4e6).
eoselectivities. a-Trifluoromethyl aryl ketones containing both
Table 1
Solvent screen for the NaBH4-mediated one-pot reductive amination of 1a
O
S
O
Ti(Oi-Pr)4
NaBH4
S
S
S
NH2
+
N
O
HN
F3C
O
+
HN
F3C
O
Sol., reflux
20-24h
F3C
Ph
Sol., Temp.
3h
F3C
Ph
Ph
Ph
4a
2
1a
3a
Entrya
Solvent
Temp (ꢁC)
Yieldb (%)
3a/4ac
1
2
3
4
5
6
THF
Et2O
n-hexane
Toluene
CH2Cl2
ꢀ78
52
85
98:2
98:2
98:2
82:18
71:29
60:40
ꢀ78
ꢀ78
54
ꢀ78
34d
31d
45d
ꢀ78
CH3CN
ꢀ30 to ꢀ40
a
All reductions were performed using 3.0 equiv of NaBH4 in the appropriate solvent for 3 h.
Isolated yield of 3a in two steps unless otherwise noted.
b
c
Diastereomeric ratios were determined by 19F NMR of the crude reaction mixture.
d
The overall yield of 3a and 4a in two steps. Determined by 19F NMR of the crude reaction mixture.
Encouraged by the above results, we then examined a series of
electron-donating and electron-withdrawing substituents at the
para position proved to be excellent substrates in both systems,
giving 90e96% de (entries 1e8). It is worth to be mentioned that
both systems gave even better diastereoselectivities (dr up to 99:1)
metal hydrides to test the possibility of stereoselectivity reversal
using ether as the solvent.9,10a,12 The results were promising, as
revealed inTable 2. When DIBAL-H was used instead of NaBH4 as the
reductant, a slight improvement in diastereoselectivity (3a/4a¼
99:1) was observed but in a lower yield (entry 2). Catecholborane
was less reactive and only 14% overall yield of 3a and 4a was
obtained after 3 h (entry 3). NaBH3CN and LiBH4 exhibited poor
levels of diastereoselection in favor of isomer 3a (entries 4e5). We
were gratified to find the reversal of the diastereofacial selectivity
when LiBHEt3 was used as the reducing agent (entry 6). More
excitingly, performing the reduction with L-Selectride resulted in
the opposite stereoisomer 4a in good yield with high diaster-
eoselectivity (4a/3a¼98:2, entry 7).13
for a-trifluoromethyl alkyl ketones (entries 9e12). Thus, with two
different reduction systems, the opposite stereocontrol could be
easily achieved. The absolute configuration of product 3a and 3d, 4a
and 4d was unequivocally assigned as (Rs, R) and (Rs, S) by cleaving
the sulfinamide with HCl and examining the optical rotation of the
known salts. By analogy, the absolute configuration of products
3bec, eef, and 4bec, eef is tentativelyassigned as (Rs, R) and (Rs, S).
On the basis of the diastereoselectivity observed (Table 3), the
rationale of the reversal in diastereofacial selectivity upon changing
reductant from NaBH4 to L-Selectride may be explained via a cyclic
Table 2
The one-pot reductive amination of 1a with various reducing agents
O
S
O
Reducing agent
Ti(Oi-Pr)4
S
S
S
NH2
+
N
O
HN
F3C
O
+
HN
F3C
O
Et2O, reflux
20-24h
F3C
Ph
Et2O, -78oC
3h
F3C
Ph
Ph
Ph
4a
2
1a
3a
Entrya
Reducing agent
Yieldb (%)
3a:4ac
1
2
3
4
5
6
7
NaBH4
85 (3a)
46d
98:2
99:1
98:2
72:28
80:20
18:82
2:98
DIBAL-H
Catecholborane
NaBH3CN
LiBH4
LiBHEt3
L-Selectride
14d
40 (3a)
58 (3a)
43d
78 (4a)
a
All reductions were performed using 3.0 equiv of reducing agent in Et2O at ꢀ78 ꢁC for 3 h.
Isolated yield of 3a or 4a in two steps unless otherwise noted.
b
c
Diastereomeric ratios were determined by 19F NMR of crude reaction mixture.
d
The overall yield of 3a and 4a in two steps. Determined by 19F NMR of crude reaction mixture.

J. Xu et al. / Tetrahedron 66 (2010) 8933e8937
8935
Table 3
The one-pot reductive amination of 1 with NaBH4 and L-Selectride
O
S
O
Ti(Oi-Pr)4, Et2O, reflux
Ti(Oi-Pr)4, Et2O, reflux
S
S
R
NH2
HN
F3C
O
HN
F3C
O
+
then NaBH4, -78oC
then L-Selectride, -78oC
F3C
R
R
2
3
1
4 (Rs, S)
(Rs, R)
Entrya
R
Reductant
NaBH4
L-Selectride
NaBH4
L-Selectride
NaBH4
L-Selectride
NaBH4
L-Selectride
NaBH4
L-Selectride
NaBH4
Product
Yieldb (%)
drc
1
2
3
4
5
6
7
8
Ph (1a)
Ph (1a)
3a
4a
3b
4b
3c
4c
3d
4d
3e
4e
3f
85
78
78
68
72
70
66
60
69
68
79
84
98:2
98:2
95:5
96:4
97:3
96:4
98:2
96:4
99:1
99:1
99:1
99:1
4-MeOC6H4 (1b)
4-MeOC6H4 (1b)
4-MeC6H4 (1c)
4-MeC6H4 (1c)
4-BrC6H4 (1d)
4-BrC6H4 (1d)
C6H5(CH2)3 (1e)
C6H5(CH2)3 (1e)
n-C8H17 (1f)
9
10
11
12
n-C8H17 (1f)
L-Selectride
4f
a
All reductions were performed using 3.0 equiv of NaBH4 or L-Selectride in Et2O at ꢀ78 ꢁC for 3 h.
Isolated yield of 3aef or 4aef in two steps.
b
c
Diastereomeric ratios were determined by 19F NMR of the crude reaction mixture.
transition state in the former reduction (NaBH4) and an open
a-trifluoromethyl ketones and N-tert-butanesulfinamide took place
transition state in the latter case (L-Selectride) as previously pro-
posed by Andersen and co-workers12c (Scheme 1). Although the
steric hindrance of CF3 group is similar to phenyl and between
readily to give either diastereomer of the tert-butanesulfinyl-pro-
tected trifluoromethylated amines in good yields and with excellent
diastereoselectivities by simply choosing the appropriate reducing
agents. Further studies on the application of this method in the
preparation of CF3-containing natural product analogues are in
progress in our laboratory.
those of Pr and Bu,14 high diastereoselectivities were observed in
all the cases examined (Table 3). These results indicated that the
electronic effect of the CeF bond in the CF3 group might play an
important role in achieving high diastereoselectivities in both re-
duction systems. The electrostatic repulsion15 of the lone pairs
between the sulfur atom and the fluorine atom makes CF3 group be
far away from the sulfur atoms in both systems. Therefore TS-A is
more stable than TS-B in the six-membered chairlike models under
the NaBH4 reduction and TS-D is more favored than TS-C in the
open transition state under the L-Selectride reduction. Hence, the
six-membered transition state in which the sulfinyl oxygen par-
ticipates in the delivery of hydride in the NaBH4 system gives (Rs,
R)-3 as the major product, while an open transition state in the
L-Selectride system affords the major product (Rs, S)-4.
i
t
4. Experimental section
4.1. General experimental methods
Unless otherwise mentioned, solvents, and reagents were pur-
chased from commercial sources and used as received. Et2O and
THF were freshly distilled over Na/benzophenone. Melting points
were measured on a Melt-Temp apparatus and uncorrected. 1H
NMR spectra were recorded on Bruker AM-300 or Mercury 300
(300 MHz) spectrometers with TMS as internal standard. 19F NMR
spectra were recorded on Bruker AM-300 or Mercury 300
(282 MHz) spectrometers with CFCl3 as an external standard. 13C
NMR spectra were recorded on Bruker 300 (75.5 MHz) or DPX-400
(100.7 MHz) spectrometers. IR spectra were obtained with a Nicolet
AV-360 spectrophotometer. Mass spectra were taken on a HP5989A
spectrometer. High-resolution mass data were obtained on a high-
resolution mass spectrometer in the EI or MALDI mode.
S
N
O
L
-
S
e
H 4
l
e
c
B
a
t
r
i
d
F3C
R
N
e
H-M
O
H
M
CF3
t-Bu
N
S
R
S
closed T.S.
closed T.S.
open T.S.
open T.S.
F3C
R
HN
F3C
O
N
R
t-Bu
O
A
C
4.2. General procedure for the one-pot reductive amination
of 1 with NaBH4
3 (Rs, R)
H-M
S
O
H
Trifluoromethyl ketones 1 (0.4 mmol) were added to a solution
of (R)-2 (0.5 mmol) and Ti(Oi-Pr)4 (1.0 mmol) in Et2O (4 mL) at
room temperature. The reaction mixture was stirred under reflux
and the reaction was monitored by 19F NMR. After the reaction was
complete, the mixture was cooled to room temperature and then to
ꢀ78 ꢁC NaBH4 (1.2 mmol) was added dropwise, and the resulted
mixture was stirred at ꢀ78 ꢁC for 3 h (monitored by TLC). After
reaction, the mixture was quenched with saturated NaCl solution
(5 mL) at ꢀ78 ꢁC and then warmed to room temperature while
being rapidly stirred. The resulting suspension was filtered through
a plug of Celite, and the filter cake was washed with EtOAc. The
filtrate was washed with saturated NaCl solution. The aqueous layer
M
HN
F3C
O
R
CF3
t-Bu
N
S
R
F3C
N
R
t-Bu
O
4 (Rs, S)
B
D
Scheme 1. Proposed transition state for the one-pot reductive amination of 1.
3. Conclusions
In summary, we have developed a facile protocol for the asym-
metric synthesis of either stereoisomer of
amines. The diastereoselective reduction of -trifluoromethyl N-tert-
butanesulfinyl ketoimines formed in situ from the corresponding
a-trifluoromethylated
a

8936
J. Xu et al. / Tetrahedron 66 (2010) 8933e8937
was extracted with EtOAc (10 mLꢂ3). The combined organic solu-
tion was dried over Na2SO4. After the removal of volatile solvents
under vacuum, the crude product was further purified by column
chromatography on silica gel to give product 3.
(CDCl3):
d
125.30 (q, J¼283.1 Hz), 57.99 (q, J¼29.6 Hz), 56.90, 31.65,
29.12, 29.03, 28.94, 25.18, 22.49, 22.40, 13.90; EIMS (m/z, %): 316
(Mþþ1, 6.09) 259 (Mþꢀ Buþ1, 2.70), 57 (100.00); HRMS (EI) calcd
t
for C14H28F3NOS [Mþ]: 315.1844; found: 315.1833.
4.2.1. (Rs,R)-N-(2,2,2-Trifluoro-1-phenylethyl)-tert-butanesulfina-
4.3. General procedure for the one-pot reductive amination
of 1 with L-Selectride
mide (3a). Colorless viscous oil, yield 85%; FT-IR (film, cmꢀ1):
n
3196, 2962, 2930, 2872, 1495, 1366, 1265, 1173, 1125, 1073, 693; 1H
NMR (CDCl3):
d
7.46e7.40 (m, 5H), 4.94e4.81 (m, 1H), 3.90 (s, 1H),
Trifluoromethyl ketones 1 (0.4 mmol) were added to a solution
of (R)-2 (0.5 mmol) and Ti(Oi-Pr)4 (1.0 mmol) in Et2O (4 mL) at
room temperature. The reaction mixture was stirred under reflux
and the reaction was monitored by 19F NMR. After the reaction was
completed, the mixture was cooled to room temperature and then
to ꢀ78 ꢁC. A solution of L-Selectride (1.2 mL, 1.2 mmol, 1.0 M so-
lution in THF) was added slowly, and the resulted mixture was
stirred at ꢀ78 ꢁC for 3 h (monitored by TLC). After reaction, the
mixture was quenched with saturated NaCl solution (5 mL) at
ꢀ78 ꢁC and then warmed to room temperature while being rapidly
stirred. The resulting suspension was filtered through a plug of
Celite, and the filter cake was washed with EtOAc. The filtrate was
washed with saturated NaCl solution. The aqueous layer was
extracted with EtOAc (10 mLꢂ3). The combined organic solution
was dried over Na2SO4. After the removal of volatile solvents under
vacuum, the crude product was further purified by column chro-
matography on silica gel to give product 4.
1.24 (s, 9H); 19F NMR (CDCl3):
d
ꢀ74.33 (d, J¼7.1 Hz, 3F); 13C NMR
(CDCl3):
d
131.67, 129.70, 129.26, 128.73, 124.47 (q, J¼281.8 Hz),
60.52 (q, J¼30.4 Hz), 56.35, 22.31; EIMS (m/z, %): 280 (Mþþ1, 4.29),
223 (Mþꢀ Buþ1, 9.94), 159 (17.29), 57 (100.00); HRMS (EI) calcd for
t
C12H16F3NOS [Mþ]: 279.0905; found: 279.0901.
4.2.2. (Rs,R)-N-(2,2,2-Trifluoro-1-(4-methoxyphenyl)ethyl)-tert-bu-
tanesulfinamide (3b). Colorless viscous oil, yield 78%; FT-IR (film,
cmꢀ1):
n
3209, 2962, 2910, 2871, 1615, 1518, 1466, 1366, 1253, 1172,
1126, 1073, 829, 732, 585; 1H NMR (CDCl3):
d
7.29 (d, J¼8.7 Hz, 2H),
6.86 (d, J¼8.7 Hz, 2H), 4.83e4.68 (m, 1H), 3.84 (s, 1H), 3.75 (s, 3H),
1.24 (s, 9H); 19F NMR (CDCl3):
d
ꢀ74.70 (d, J¼5.6 Hz, 3F); 13C NMR
(CDCl3):
d
160.57, 130.58, 123.32, 114.13, 124.55 (q, J¼281.5 Hz),
59.85 (q, J¼30.4 Hz), 56.16, 55.17, 22.31; EIMS (m/z, %): 310 (Mþþ1,
5.26), 253 (Mþꢀ Buþ1, 6.01), 189 (100.00), 57 (84.83); HRMS(EI)
t
calcd for C13H18F3NO2S [Mþ]: 309.1010; found: 309.1012.
4.2.3. (Rs,R)-N-(2,2,2-Trifluoro-1-p-tolylethyl)-tert-butanesulfina-
4.3.1. (Rs,S)-N-(2,2,2-Trifluoro-1-phenylethyl)-tert-butanesulfina-
mide (4a)3a. White solid, yield 78%; mp 139e141 ꢁC; FT-IR (KBr,
mide (3c). Colorless viscous oil, yield 72%; FT-IR (film, cmꢀ1):
n
3198, 2960, 2929, 2870, 1458, 1365, 1266, 1172, 1126, 1075, 811, 728,
cmꢀ1):
n
2995, 2964, 1498, 1460, 1365, 1265, 1155, 1123, 1058, 1014,
930, 761, 702; 1H NMR (CDCl3):
7.47e7.36 (m, 5H), 4.90e4.76 (m,
1H), 3.70 (s,1H),1.24 (s, 9H); 19F NMR (CDCl3):
ꢀ73.29 (d, J¼7.1 Hz,
3F); 13C NMR (CDCl3):
133.68, 129.70, 129.12, 127.90, 124.58 (q,
670; 1H NMR (CDCl3):
d
7.32 (d, J¼7.2 Hz, 2H), 7.22 (d, J¼7.2 Hz, 2H),
d
4.80e4.85 (m, 1H), 3.84 (s, 1H), 2.38 (s, 3H), 1.24 (s, 9H); 19F NMR
d
(CDCl3):
d
ꢀ74.50 (d, J¼7.1 Hz, 3F); 13C NMR (CDCl3):
d
139.55,
d
129.34, 129.05, 128.60, 124.48 (q, J¼281.7 Hz), 60.19 (q, J¼30.2 Hz),
J¼281.1 Hz), 61.35 (q, J¼30.9 Hz), 58.89, 22.28; EIMS (m/z, %): 223
56.16, 22.20, 21.05; EIMS (m/z, %): 294 (Mþþ1, 1.52), 237
(Mþꢀ Buþ1, 7.80), 159 (13.71), 57 (100.00); HRMS (EI) calcd for
t
t
t
(Mþꢀ Buþ1, 12.76), 173 (36.95), 57 (100.00); HRMS (EI) calcd for
C8H7F3NOS [Mþꢀ Bu]: 222.02000; found: 222.0193.
C13H18F3NOS [Mþ]: 293.1061; found: 293.1073.
4.3.2. (Rs,S)-N-(2,2,2-Trifluoro-1-(4-methoxyphenyl)ethyl)-tert-bu-
tanesulfinamide (4b). White solid, yield 68%; mp 164e167 ꢁC; FT-IR
4.2.4. (Rs,R)-N-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-tert-buta-
nesulfinamide (3d). Colorless viscous oil, yield 66%; FT-IR (film,
(KBr, cmꢀ1):
n
3247, 3116, 2989, 2966, 2906, 1616, 1519, 1467, 1365,
1263, 1183, 1121, 1058, 812, 711, 528; 1H NMR (CDCl3):
7.28 (d,
J¼8.1 Hz, 2H), 6.85 (d, J¼8.1 Hz, 2H), 4.88e4.64 (m, 1H), 3.54 (s, 1H),
3.76 (s, 3H), 1.18 (s, 9H); 19F NMR (CDCl3):
ꢀ73.52 (d, J¼7.3 Hz, 3F);
13C NMR (CDCl3):
160.40, 129.20, 125.78, 114.54, 124.69 (q,
cmꢀ1):
n
3198, 2962, 2929, 2872, 1493, 1366, 1266, 1175, 1126, 1075,
d
728, 670; 1H NMR (CDCl3):
d
7.56 (d, J¼7.5 Hz, 2H), 7.32 (d, J¼7.5 Hz,
2H), 4.75e4.94 (m, 1H), 3.85 (s, 1H), 1.24 (s, 9H); 19F NMR (CDCl3):
d
d
ꢀ74.41 (d, J¼6.5 Hz, 3F); 13C NMR (CDCl3):
d
135.78, 132.06,
d
130.53, 127.59, 124.16 (q, J¼281.6 Hz), 59.98 (q, J¼31.0 Hz), 56.55,
J¼281.4 Hz), 60.84 (q, J¼30.9 Hz), 56.84, 55.29, 22.31; EIMS (m/z, %):
t
t
22.24; EIMS (m/z, %): 357 (Mþ, 2.40), 301 (Mþꢀ Buþ1, 1.82), 237
310 (Mþþ1, 0.78), 253 (Mþꢀ Buþ1, 3.13), 189 (51.20), 57 (100.00);
(10.46), 57 (100.00); HRMS (EI) calcd for C12H15BrF3NOS [Mþ]:
357.0010; found: 357.0017.
HRMS (EI) calcd for C13H18F3NO2S [Mþ]: 309.1010; found: 309.1013.
4.3.3. (Rs,S)-N-(2,2,2-Trifluoro-1-p-tolylethyl)-tert-butanesulfina-
mide (4c). White solid, yield 70%; mp 174e176 ꢁC; FT-IR (KBr,
4.2.5. (Rs,R)-N-(1,1,1-Trifluoro-5-phenylpentan-2-yl)-tert-butane-
sulfinamide (3e). White solid, yield 69%; mp 68e70 ꢁC; FT-IR (KBr,
cmꢀ1):
n
3198, 2971, 2927, 1517, 1458, 1365, 1268, 1156, 1124, 1064,
cmꢀ1):
n
3207, 3029, 2959, 2933, 2870, 1604, 1541, 1498, 1465, 1365,
806, 724, 547; 1H NMR (CDCl3):
d
7.31 (d, J¼8.1 Hz, 2H), 7.10 (d,
1275, 1180, 1163, 1126, 1067, 749, 700; 1H NMR (CDCl3):
d
7.37e7.14
J¼8.1 Hz, 2H), 4.95e4.76 (m, 1H), 3.69 (s, 1H), 2.35 (s, 3H), 1.26 (s,
(m, 5H), 3.77e3.56 (m, 1H), 3.44 (d, J¼9.0 Hz, 1H), 2.66 (t, J¼4.5 Hz,
9H); 19F NMR (CDCl3):
d
ꢀ73.38 (d, J¼6.8 Hz, 3F); 13C NMR (CDCl3):
2H), 2.05e1.80 (m, 2H), 1.78e1.65 (m, 2H), 1.18 (s, 9H); 19F NMR
d
139.56, 130.78, 129.83, 127.78, 124.67 (q, J¼281.6 Hz), 61.16 (q,
t
(CDCl3):
d
ꢀ75.13 (d, J¼7.6 Hz, 3F); 13C NMR (CDCl3):
d
141.14,
J¼30.2 Hz), 56.88, 22.32, 21.13; EIMS (m/z, %): 237 (Mþꢀ Buþ1,
128.36, 128.23, 125.97, 125.24 (q, J¼282.8 Hz), 57.83 (q, J¼29.0 Hz),
7.44), 173 (26.30), 57 (100.00); HRMS (EI) calcd for C9H9F3NOS
56.94, 35.15, 28.71, 26.85, 22.42; EIMS (m/z, %): 265 (Mþꢀ Buþ1,
[Mþꢀ Bu]: 236.0357; found: 236.0365.
t
t
11.18), 217 (2.68), 57 (100.00); HRMS (EI) calcd for C11H14F3NOS
t
[Mþꢀ Buþ1]: 265.0748; found: 265.0755.
4.3.4. (Rs,S)-N-(1-(4-Bromophenyl)-2,2,2-trifluoroethyl)-tert-buta-
nesulfinamide (4d)3a. White solid, yield 60%; mp 164e167 ꢁC; FT-IR
4.2.6. (Rs,R)-N-(1,1,1-Trifluorodecan-2-yl)-tert-butanesulfinamide
(KBr, cmꢀ1):
n 2968, 2928, 1493, 1365, 1265, 1161, 1123, 1058, 1014,
(3f). Colorless viscous oil, yield 79%; FT-IR (film, cmꢀ1):
n
3297,
2958, 2928, 2859, 1468, 1366, 1276, 1168, 1133, 1112, 1066, 940, 885,
847, 795, 693, 580; 1H NMR (CDCl3):
3.72e3.55 (m, 1H), 3.43 (s,
917, 811, 728; 1H NMR (CDCl3):
d
7.56 (d, J¼7.5 Hz, 2H), 7.32 (d,
J¼7.5 Hz, 2H), 4.88e4.72 (m, 1H), 3.56 (s, 1H), 1.24 (s, 9H); 19F NMR
d
(CDCl3):
d
ꢀ73.95 (d, J¼7.1 Hz, 3F); 13C NMR (CDCl3):
d 135.63,
1H), 1.90e1.47 (m, 4H), 1.37e1.26 (m, 10H), 1.25 (s, 9H), 0.88 (t,
132.35, 131.54, 127.54, 123.96 (q, J¼281.1 Hz), 61.35 (q, J¼30.9 Hz),
J¼5.7 Hz, 3H); 19F NMR (CDCl3):
d
ꢀ75.26 (d, J¼6.5 Hz, 3F); 13C NMR
57.25, 22.17; EIMS (m/z, %): 301 (Mþꢀ Buþ1, 0.66), 237 (4.07), 57
t

J. Xu et al. / Tetrahedron 66 (2010) 8933e8937
8937
t
(100.00); HRMS (EI) calcd for C8H6BrF3NOS [Mþꢀ Bu]: 299.9306;
3. (a) Olah, G. A.; Prakash, G. K. S.; Mandal, M. Angew. Chem., Int. Ed. 2001, 40, 589;
(b) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847; (c) Prakash,
G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538; (d) Estivill, C.; Mendi-
found: 299.9304.
ꢀ
zabal, J.; Virgili, A.; Monteagudo, E.; Flor, T.; Sanchez-Ferrando, F.; Alvarez-
4.3.5. (Rs,S)-N-(1,1,1-Trifluoro-5-phenylpentan-2-yl)-tert-butane-
sulfinamide (4e). White solid, yield 68%; mp 74e76 ꢁC; FT-IR (KBr,
Larena, A.; Piniella, J. F. Tetrahedron 2009, 65, 171.
ꢀ
4. (a) Truong, V. L.; Menard, M. S.; Dion, I. Org. Lett. 2007, 9, 683; (b) Ishii, A.;
Higashiyama, K.; Mikami, K. Synlett 1997, 1381; (c) Enders, D.; Funabiki, K. Org.
Lett. 2001, 3, 1575; (d) Gosselin, F.; Roy, A.; O’Shea, P. D.; Chen, C.-Y.; Volante, R.
P. Org. Lett. 2004, 6, 641.
cmꢀ1):
n
3219, 3031, 2962, 2871, 1605, 1498, 1456, 1365, 1275, 1180,
1163, 1126, 1058, 750, 696; 1H NMR (CDCl3):
7.37e7.14 (m, 5H),
3.77e3.56 (m, 1H), 3.07 (s, 1H), 2.80e2.55 (m, 2H), 2.10e1.72 (m,
d
€ €
5. (a) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2436; (b) Torok, B.; Prakash,
2H), 1.69e1.44 (m, 2H), 1.23 (s, 9H); 19F NMR (CDCl3):
d
ꢀ75.83 (d,
G. K. S. Adv. Synth. Catal. 2003, 345, 165; (c) Gosselin, F.; O’Shea, P. D.; Roy, S.;
Reamer, R. A.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 355.
J¼7.2 Hz, 3F); 13C NMR (CDCl3):
d 141.03, 128.36, 128.33, 125.89,
6. For other examples for the asymmetric synthesis of
a-trifluoromethylated
amines, see: (a) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N.
Angew. Chem., Int. Ed. 2009, 48, 6324; (b) Wang, Y.; Mosher, H. S. Tetrahedron
Lett. 1991, 32, 987; (c) Soloshonok, V. A.; Ono, T. J. Org. Chem. 1997, 62, 3030; (d)
Ishii, A.; Miyamoto, F.; Higashiyama, K.; Mikami, K. Chem. Lett. 1998, 119; (e)
Jiang, J.; DeVita, R. J.; Doss, G. A.; Goulet, M. T.; Wyvratt, M. J. J. Am. Chem. Soc.
1999, 121, 593; (f) Jiang, J.; Shah, H.; DeVita, R. J. Org. Lett. 2003, 5, 4101; (g) Xu,
W.; Dolbier, W. R., Jr. J. Org. Chem. 2005, 70, 4741.
7. For CF3-substituted N-tert-butylsulfinyl imines, see: (a) see Ref. 5a; (b) Wang,
H.; Zhao, X.-M.; Li, Y.-H.; Lu, L. Org. Lett. 2006, 8, 1379; (c) Kuduk, S. D.; Marco,
C. N. D.; Pitzenberger, S. M.; Tsou, N. Tetrahedron Lett. 2006, 47, 2377 For CF3-
substituted N-p-tolylsulfinyl imines, see: (d) Asensio, A.; Bravo, P.; Crucianelli,
M.; Farina, A.; Fustero, S.; Soler, J. G.; Meille, S. V.; Panzeri, W.; Viani, F.; Vo-
lonterio, A.; Zanda, M. Eur. J. Org. Chem. 2001, 1449; (e) Bravo, P.; Crucianelli, M.;
Vergani, B.; Zanda, M. Tetrahedron Lett. 1998, 38, 7771; (f) Crucianelli, M.; De
Angelis, F.; Lazarro, F.; Malpezzi, L.; Volonterio, A.; Zanda, M. J. Fluorine Chem.
2004, 125, 573; (g) Ruano, J. L. G.; Haro, T.; Singh, R.; Cid, M. B. J. Org. Chem.
2008, 73, 1150.
125.26 (q, J¼288.8 Hz), 58.56 (q, J¼29.6 Hz), 56.65, 34.93, 28.77,
26.30, 22.28; EIMS (m/z, %): 322 (Mþþ1, 0.75), 265 (Mþꢀ Buþ1,
t
14.95), 217 (3.25), 57 (100); HRMS (EI) calcd for C11H14F3NOS
t
[Mþꢀ Buþ1]: 265.0748; found: 265.0760.
4.3.6. (Rs,S)-N-(1,1,1-Trifluorodecan-2-yl)-tert-butanesulfinamide
(4f). Colorless viscous oil, yield 84%; FT-IR (film, cmꢀ1):
n
3209,
2958, 2929, 2860, 1495, 1366, 1276, 1168, 1133, 1111, 1046, 887, 723,
697; 1H NMR (CDCl3):
3.72e3.59 (m, 1H), 3.08 (d, J¼7.2 Hz, 1H),
d
1.67e1.40 (m, 4H), 1.36e1.26 (m, 10H), 1.24 (s, 9H), 0.88 (t, J¼5.7 Hz,
3H); 19F NMR (CDCl3):
d
ꢀ75.94 (d, J¼7.1 Hz, 3F); 13C NMR (CDCl3):
d
124.36 (q, J¼281.1 Hz), 58.75 (q, J¼30.2 Hz), 56.70, 31.74, 29.56,
29.14, 28.05, 24.87, 22.55, 22.33, 13.98; EIMS (m/z, %): 316 (Mþþ1,
1.22), 259 (Mþꢀ Buþ1, 4.02), 57 (100.00); HRMS (EI) calcd for
t
8. (a) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Org. Lett. 2007, 9, 1343; (b) Liu, Z.-J.; Mei, Y.-Q.;
Liu, J.-T. Tetrahedron 2007, 63, 855; (c) Zhao, Y.; Wang, X.-J.; Liu, J.-T. Synlett
2008, 1017; (d) Wang, X.-J.; Zhao, Y.; Liu, J.-T. Synthesis 2008, 3967; (e) Zhang, F.;
Wang, X.-J.; Cai, C.-X.; Liu, J.-T. Tetrahedron 2009, 65, 83.
C14H28F3NOS [Mþ]: 315.1844; found: 315.1857.
9. Liu, Z.-J.; Liu, J.-T. Chem. Commun. 2008, 5233.
Acknowledgements
10. (a) Tanuwidjaja, J.; Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2007, 72, 626; (b)
Borg, G. D.; Cogan, A.; Ellman, J. A. Tetrahedron Lett. 1999, 40, 6709.
11. The synthesis of the chiral CF3-substituted (R)-N-tert-butanesulfinyl ketoimines
has been reported by Lu and co-workers. see Ref. 7b. In their context, they have
pointed out that these CF3-substituted sulfinylketoimines are readily hydro-
lyzed upon prolonged standing on silica gel. We also tried to isolate these ke-
toimines by column chromatography on silica gel, but low to moderate yields
(less than 50% and the product with a large impurity) were obtained. After the
reaction conditions for the condensation of 2,2,2-trifluoroacetophenone with
N-tert-butanesulfinamide were optimized, we found that moderate to good
yields (determined by 19F NMR) can be obtained in several solvents, such as
Et2O (87%), THF (74%), n-hexane (70%), in the presence of 2.5 equiv of Ti(Oi-Pr)4
under reflux for 20e24 h.
12. For the stereoselectivity reversal in hydride reduction of N-tert-butanesulfinyl
imines, see: (a) Reddy, L. R.; Das, S. G.; Liu, Y.; Prashad, M. J. Org. Chem. 2010, 75,
2236; (b) Martjuga, M.; Shabashov, D.; Belyakov, S.; Liepinsh, E.; Suna, E. J. Org.
Chem. 2010, 75, 2357; (c) Colyer, J. T.; Anderson, N. G.; Tedrow, J. S.; Soukup, T.
S.; Faul, M. M. J. Org. Chem. 2006, 71, 6859; (d) Denolf, B.; Leemans, E.; De
Kimpe, N. J. Org. Chem. 2007, 72, 3211; (e) Chelucci, G.; Baldino, S.; Chessa, S.;
Pinna, G. A.; Soccolini, F. Tetrahedron: Asymmetry 2006, 17, 3163; (f) Kochi, T.;
Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124, 6518; (g) Kochi, T.; Tang, T. P.;
Ellman, J. A. J. Am. Chem. Soc. 2003, 125, 11276; (h) Kochi, T.; Ellman, J. A. J. Am.
Chem. Soc. 2004, 126, 15652; (i) Peltier, H. M.; Ellman, J. A. J. Org. Chem. 2005, 70,
7342.
Financial support from the National Natural Science Foundation
of China (No. 20872166), Doctoral Fund of Ministry of Education of
China, and Postdoctoral Fund of China is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.047. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
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