One-pot asymmetric reductive amination of ketones induced by polyfluoroalkanesulfinamide

Article abstract of DOI:10.1016/j.jfluchem.2015.01.019

Using chiral 2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide as the auxiliary, an efficient one-pot procedure for the asymmetric reductive amination of ketones was achieved in the presence of sodium borohydride. Both aromatic and aliphatic ketones reacte

Full text of DOI:10.1016/j.jfluchem.2015.01.019

Accepted Manuscript
Title: One-pot Asymmetric Reductive Amination of Ketones
Induced by Polyfluoroalkanesulfinamide
Author: Kai Yang Jin-Tao Liu
PII:
S0022-1139(15)00045-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.01.019
FLUOR 8507
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
3-11-2014
21-1-2015
24-1-2015
Please cite this article as: K. Yang, J.-T. Liu, One-pot Asymmetric Reductive Amination
of Ketones Induced by Polyfluoroalkanesulfinamide, Journal of Fluorine Chemistry
(2015), http://dx.doi.org/10.1016/j.jfluchem.2015.01.019
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

A
highly diastereoselective
reductive amination
of ketones using
2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide as auxiliary was developed. Both
aromatic and aliphatic ketones reacted well under the reaction conditions, giving the
corresponding amination products in good yields with excellent diastereoselectivities.
O
S
O
S
O
S
Ti(OEt)4
(4.0 equiv)
NaBH4
(2.0 equiv)
O
CF2CF2Cl
HN
N
CF2CF2Cl
+
NH2
ClF2CF2C
R
Et2O, -78 o
5-14 h
C
Cyclohexane
2 (2.0 equiv) 80 oC, 12-36 h
R
R
1
4
3
up to 82% yield
up to >95:5 dr
1
Page 1 of 17

Research highlights:
The
reductive
amination
of
ketones
using
2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide as auxiliary was investigated.
The amination products were obtained in good yields with excellent
diastereoselectivities.
2-Chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide afforded better diastereoselectivities
for aliphatic and (E)-α,β-unsaturated ketones.
2
Page 2 of 17

One-pot Asymmetric Reductive Amination of Ketones Induced
by Polyfluoroalkanesulfinamide
Kai Yang, Jin-Tao Liu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032
China
jtliu@sioc.ac.cn
Abstract
Using chiral 2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide as the auxiliary, an
efficient one-pot procedure for the asymmetric reductive amination of ketones was
achieved in the presence of sodium borohydride. Both aromatic and aliphatic ketones
reacted well to give the corresponding sulfinyl amides in good yields with excellent
diastereoselectivities.
Keywords:
2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide/ ketimine/ ketone/ reductive
amination/ diastereoselectivity
3
Page 3 of 17

1. Introduction
α-Branched amines are key elements of many potent pharmaceuticals, asymmetric
catalysts and materials such as unnatural biopolymers.[1] A large number of methods
have been developed to prepare chiral α-branched amines via the addition of carbon
nucleophiles to aldimines[2] and asymmetric reductions of ketimines.[3] Among them
one-pot reductive amination of ketones is one of the most efficient methods towards
the synthesis of α-branched amines, avoiding the isolation of imine intermediates. The
reduction of N-sulfinyl imines was first reported by Cozzi[4] and later studied by
Ellman[5]. Ellman’s group also reported the first general one-pot method for the
asymmetric
synthesis
of
pre-protected
α-branched
amines
from
2-methylpropane-2-sulfinamide[6] and the corresponding ketones. In 2004, Ellman and
Kochi reported an isolated example of the stereoselective reduction of a
N-tert-butylsulfinyl ketimines bearing a α-stereocenter to provide either amine
diastereomer.[7] These conditions could also be applied to the reduction of ketimines
with a β-stereocenter.[8] Encouragingly, Andersen and co-workers found that, with the
choice of appropriate metal hydride reagent, either diastereomer could be obtained by
the reduction of the corresponding N-tert-butylsulfinyl ketimines.[9] Since then, the
reduction of N-tert-butylsulfinyl ketimines has attracted much attention[10] and has
been applied to the synthesis of many drug candidates.[11] In addition, the scope of
one-pot reduction method was expanded to include biologically relevant cyclic
substrates. However, the achievement of high diastereoselectivities for the reductive
amination of α,β-unsaturated ketones and aliphatic ketones is still a challenge.
Recently, our group developed
polyfluoroalkanesulfinamide, which was applied successfully in many asymmetric
reactions such as Strecker reaction,[12] three component aza Diels-Alder reaction[13]
a
novel fluorinated chiral auxiliary,
,
aminoallylation of aldehydes[14] and asymmetric vinylogous Mannich reaction.[15]
Using this kind of fluorinated auxiliary, Ellman’s group also developed an asymmetric
intermolecular addition of non-acidic C-H bonds for the first time.[16] Among various
polyfluoroalkanesulfinamides
investigated
in
our
previous
work,
4
Page 4 of 17

2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide (CTFSA, 1) is a promising one due
to its easy availability and high performance. In this paper, we report the one-pot
reductive amination of ketones induced by CTFSA.
2. Results and Discussion
In our preliminary investigation, ketimine 3a was prepared from
2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide (1) and methylphenyl ketone 2a. The
o
reaction of 3a and NaBH4 was carried out at -78 C in tetrahydrofuran (THF).
Gratefully, the stereoisomers 4a and 4a' were obtained in a total yield of 75% with a
ratio of >95:5 as shown by the 19F NMR spectrum of the reaction mixture (Table 1,
entry 1). Much lower yields were obtained in dichloromethane (DCM) or n-hexane
(entries 2-3). Using methanol as solvent, the overall yield of isomers was improved to
95%, but the diastereoselectivity decreased to 90:10 (entry 4). When ethyl ether was
used as solvent, 90% yield and excellent diastereoselectivity (>95:5) were achieved
(entry 5). Considering the higher diastereoselectivity, Et2O was chosen as the solvent
o
for this reduction reaction. When carrying out the reaction at -40 C, only 86% yield
was obtained (entry 6). Adding Ti(OEt)4 as additive, the yield could be improved to
94% in 6 h with excellent diastereoselectivity (entry 7). In our previous work,[12b]
cyclohexane was the best solvent for the preparation of ketimine. However,
cyclohexane could not be used at low temperature because its melting point is 6.5 oC.
Therefore, we tried to run the reductive reaction in a mixed solvent of cyclohexane
o
and Et2O at -78 C, and gratefully the reaction worked well without any erosion in
yield and stereoselectivity (entry 8).
Table 1. Reduction of sulfinyl ketimine 3a under different conditions
O
S
O
S
O
S
CF2CF2Cl
+
N
NaBH4 (2.0 equiv)
solvent, temp, time
HN
Ph
CF2CF2Cl
CF2CF2Cl
HN
Ph
Ph
3a
4a
4a'
Entrya
Solvent
Temp (oC)
Time (h)
Yield (%)b
Dr (4a:4a')b
5
Page 5 of 17

1
2
THF
-78
-78
-78
-78
-78
-40
-78
-78
8
8
8
6
7
4
6
8
75%
45%
13%
95%
90%
80%
94%
93%
>95:5
>95:5
>95:5
90:10
>95:5
>95:5
>95:5
>95:5
DCM
n-Hexane
MeOH
3
4
5
Et2O
6
Et2O
7c
8c
Et2O
Cyclohexane/Et2O(1:2)
a Reactions were carried out with 2.0 equiv of NaBH4 on a 0.25 mmol scale in 1.0 mL of solvent. b
Determined by 19F NMR spectra of the crude reaction mixtures with PhCF3 as internal standard. c
Ti(OEt)4 (2.0 equiv) was added.
Based on the above results, the one-pot reductive amination of ketones was then
investigated. Ketones (2, 2.0 equiv) was firstly treated with 1 in the presence of 4.0
o
equiv of Ti(OEt)4 in cyclohexane at 80 C.[12b] After the reaction was completed, the
reaction mixture was cooled to room temperature. Then anhydrous ether was added.
o
After cooling the mixture to -78 C, NaBH4 (2.0 equiv) was added in one portion
under nitrogen atmosphere. As shown in Table 2, both electron-deficient and
electron-rich aromatic ketones (2a-h) underwent this reductive amination to yield the
desired products (4a-h) in moderate to good yields with excellent
diastereoselectivities (65-80% yield, 94:6~>95:5 dr, entries 1-8). Good result was
obtained with (E)-α,β-unsaturated ketone 2i, giving only 1,2-adduct in 82% yield with
>95:5 dr (entry 9). Moreover, aliphatic ketones (2j-k) also reacted well and gave the
corresponding products (4j-k) in good yields with high diastereoselectivities (entries
10-11). It was reported that the asymmetric reductive amination reactions of 2i and 2k
induced by 2-methylpropane-2-sulfinamide gave the corresponding products with
90:10
and
83:17
dr,[6]
respectively,
indicating
that
2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide was more effective for the amination
reaction of aliphatic and α,β-unsaturated ketones.
6
Page 6 of 17

Table 2 One-pot reductive amination of ketones
1. Ti(OEt)4 (4.0 equiv)
O
O
S
O
S
cyclohexane
O
S
80 oC, time 1
CF2CF2Cl
+
HN
CF2CF2Cl
HN
+
NH2
ClF2CF2C
R
2. NaBH4 (2.0 equiv)
Et2O, -78 oC, time 2
R
1
R
(2.0 equiv)
2
4
4'
Entrya 2, R
Time 1/Time 2 (h)
Product
4a, 4a'
4b, 4b'
4c, 4c'
4d, 4d'
4e, 4e'
4f, 4f'
Yield (%)b
73 (85)
75 (86)
77 (80)
69 (87)
71 (78)
65
Drc (4:4')
1
2
2a, C6H5
24/9
12/7
24/8
24/8
24/8
12/7
24/9
36/9
36/14
12/9
12/5
>95:5
>95:5
94:6
2b, p-CF3C6H4
2c, p-FC6H4
3
4
2d, p-ClC6H4
2e, p-BrC6H4
2f, m-CF3C6H4
2g, p-MeC6H4
2h, p-MeOC6H4
2i,C6H5CH=CH
2j,(CH3)2CHCH2
2k, n-Bu
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
92:8
5
6
7
4g, 4g'
4h, 4h'
4i, 4i'
73 (77)
75 (81)
82 (93)
76 (80)
78 (83)
8
9
10
11
4j, 4j'
4k, 4k'
a Reaction conditions: 1) 1 (0.25 mmol), 2 (0.5 mmol), Ti(OEt)4 (1.0 mmol), cyclohexane (1 mL),
o
80 C; 2) NaBH4 (0.5 mmol), Et2O (2.0 mL), -78 oC. b Isolated yield, yield in parentheses was
determined by 19F NMR spectroscopy using PhCF3 as internal standard. c Determined by 19F NMR
spectra of the crude reaction mixture.
7
Page 7 of 17

O
S
O
S
N
CF2CF2Cl
NaBH4 (2.0 equiv)
CF2CF2Cl
HN
Me
Ti(OEt)4 (2.0 equiv)
Et2O, -78 oC, 86%
4a
(Ss, Sc)-
de = 97.6 %
(S)-3a
ee = 97.8 %
NH
3 Cl
1M HCl/MeOH (1:1)
50 oC, 2 h, 97%
5
(S)-
[]D25 = -4.4 (c 4.0, MeOH)
ref. 17: []D25 = -4.6 (c 4.0, MeOH, 99% ee)
Scheme 1. The synthesis of (S)-5
To determine the configuration of major products, optically pure 4a (97.6% de,
determined by HPLC) was prepared from ketimine (S)-3a (97.8% ee). Treatment of
4a with 1 M HCl in MeOH at 50oC afforded 1-phenylethylamine hydrochloride 5 in
high yield (97% yield). Comparisons to optical data for previously reported S-5
revealed compound 5 generated herein to bear the S-configuration (Scheme 1).[17]
Therefore, the stereochemistry of 4a was assigned to be (Ss, Sc), and accordingly, the
major products in Table 2 are putatively assigned to be syn-confinguration.
3. Conclusion
In summary, we have presented a highly diastereoselective reductive amination of
ketones using 2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide as auxiliary. Both
aromatic and aliphatic ketones reacted well under the reaction conditions, giving the
corresponding amination products in good yields with excellent diastereoselectivities.
Compared with tert-butylsulfinyl, this auxiliary afforded better diastereoselectivities
for aliphatic and (E)-α,β-unsaturated ketones.
4. Experimental
8
Page 8 of 17

4.1. General
Unless otherwise mentioned, solvents and reagents were purchased from
commercial sources and used as received. 1H and 13C NMR spectra were recorded on
a Bruker AM-300 and AM-400 (100 MHz) spectrometer with TMS as internal
standard. 19F NMR spectra were taken on a Bruker AM-300 (282 MHz) spectrometer
using CFCl3 as external standard. IR spectra were obtained with a Nicolet AV-360
spectrophotometer. The mass analyzer type was FTICR-MS used for the HRMS
measurements.
4.2. Procedure for the synthesis of racemic 1[12a]
To
a
flask containing neat HMDS (0.075 mol) was added
o
2-chloro-1,1,2,2-tetrafluoroethanesulfinyl chloride (0.075 mol) dropwise at 0 C.
After addition, stirring was continued for 2 h at room temperature. The mixture was
concentrated under reduced pressure, followed by the addition of of saturated aqueous
NH4Cl solution (50 mL) at room temperature. After stirring for 2 h, the resulting
mixture was extracted with Et2O (30 mL × 4) and the extract was dried over
anhydrous Na2SO4. After concentration, the residue was purified by flash column
chromatography on silica gel (EtOAc/petroleum ether 1/5) to give 1.
1
Compound 1: H NMR (300 MHz, CDCl3): δ 4.96 (s, 2H); 19F NMR (282 MHz,
CDCl3): δ -67.27~-67.32 (m, 2F), -119.74 (d, JFF = 243.6 Hz, 1F), -122.47 (d, JFF =
243.6 Hz, 1F); 13C NMR (100 MHz, CDCl3): δ 122.4 (tt, J = 298.4, 33.4 Hz), 116.3
(ddt, J = 306.0, 302.0, 35.1 Hz); HRMS (EI) calcd for C2H2ClF4NOS (M+) 198.9482,
found 198.9480.
4.3. Procedure for the synthesis of (S)-1
n-BuLi (2.64 mL, 2.5 M in hexane) was added dropwise to the solution of
o
(S)-4-phenyl-oxazolidin-2-one (6 mmol) in THF (30 mL) at -78 C under nitrogen
atmosphere. After addition, the mixture was stirred for 0.5 h. Then
2-chloro-1,1,2,2-tetrafluoroethanesulfinyl chloride (19.8 mmol) in 10 mL of THF was
9
Page 9 of 17

added. After stirring for 3 h, the mixture was allowed to warm to room temperature.
Solvent was removed, and the residue was purified by flash column chromatography
on
silica
gel
(EtOAc/petroleum
ether
1/7).
(Rs,
Sc)-4-Phenyl-N-(2-chloro-1,1,2,2-tetrafluoroethanesulfinyl)oxazolidin-2-one
was
obtained as a white solid.
A solution of (Rs, Sc)-4-phenyl-N-(2-chlorotetrafluoroethanesulfinyl)oxazolidin
-2-one (0.5 mmol) in CH2Cl2 (7 mL) was added slowly to a solution of LiHMDS (1.0
mmol) in CH2Cl2 (3 mL) in 3 h at -78 oC under nitrogen atmosphere. After addition,
saturated NH4Cl (aq) (5 mL) was added. The resulting mixture was extracted with
CH2Cl2 (10 mL × 3) and the extract was dried over anhydrous Na2SO4. After
concentration, the residue was purified by flash column chromatography on silica gel
(EtOAc/petroleum ether 1/5) to give (S)-1.
Compound (S)-1: yield 72%; white solid; [α]20D = -15.5 (c = 1.0, CHCl3, 99% ee) [12]
.
4.4. Typical procedure for the reductive amination of ketones 2
To a solution of 2-chloro-1,1,2,2-tetrafluoroethane-1-sulfinamide 1 (0.25 mmol)
and titanium (IV) ethoxide (1.0 mmol) in cyclohexane (1.0 mL) was added ketone 2
o
(0.5 mmol). The mixture was stirred at 80 C under nitrogen atmosphere and
monitored by TLC. After the reaction was completed, the mixture was cooled to room
temperature. Then anhydrous ether (2.0 mL) was added, and the resulting mixture was
o
cooled to -78 C. NaBH4 (0.5 mmol) was added in one portion under nitrogen
o
atmosphere. The mixture was stirred at -78 C and monitored by TLC or 19F NMR.
After reaction, saturated aqueous NH4Cl solution (5.0 mL) was added slowly, and the
resulting mixture was warmed to room temperature and filtered through celite. The
filter cake was washed with EtOAc. The aqueous phase was extracted with EtOAc
(5.0 mL×3), and the combined organic phase was dried over anhydrous Na2SO4. After
concentration, the residue was subjected to flash column chromatography (silica gel,
EtOAc/petroleum ether: 1/10). The desired products 4 and alcohol byproducts could
be easily separated. Results are given in Table 2.
10
Page 10 of 17

4.4.1. Compound 4a: 73%; Colorless oil. IR (film): 3242, 2976, 2929, 1650, 1603,
1453, 1261, 1115, 1017, 909, 803, 699 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.40-7.30
(m, 5H), 4.79-4.78 (m, 1H), 4.72-4.69 (m, 1H), 1.59 (d, J = 6.4 Hz, 3H). 19F NMR
(376 MHz, CDCl3): δ -66.10 to -67.17 (m, 2F), -116.88 (dd, JFF = 233.8, 3.0 Hz ,1F),
-120.35 (dd, JFF = 233.8, 6.0 Hz, 1F). 13C NMR (100 MHz, CDCl3): δ 142.1, 129.0,
128.3, 126.3, 122.2 (tt, JC-F = 298.6, 33.5 Hz), 116.4 (tt, JC-F = 306.9, 36.1 Hz), 54.8,
23.6. ESI-MS (m/z, %): 320.9 (100) [M+NH4]+; HRMS (ESI) Calcd for
C10H11ClF4NOS [M+H]+ requires 304.0181, found 304.0181.
(Ss, Sc)-4a: 97.6% ee; [α]25D = -33.5 (c = 1.0 in CHCl3, λ = 589 nm).
4.4.2. Compound 4b: 75%; Colorless oil. IR (film): 3300, 2926, 1657, 1621, 1445,
1327, 1262, 1116, 1017, 804, 735, 697 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.64-7.62
(d, J = 8.0 Hz, 2H), 7.47-7.45 (d, J = 8.4 Hz, 2H), 4.92-4.90 (d, J = 5.2 Hz, 1H),
4.79-4.76 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -62.70 to
-62.79 (m, 3F), -66.75 to -66.83 (m, 2F), -116.88 (dd, J = 233.8, 3.0 Hz, 1F), -120.35
13
(dd, J = 233.8, 5.6 Hz, 1F). C NMR (100 MHz, CDCl3): δ 146.0, 130.5 (t, J = 33.2
Hz), 127.0, 126.8 (t, J = 235.4 Hz), 126.0 (t, J = 3.8 Hz), 122.1 (tt, JC-F = 298.6, 33.6
Hz), 116.4 (tt, JC-F = 305.6, 35.0 Hz), 54.1, 23.8. ESI-MS (m/z, %): 388.9 (100)
[M+NH4]+; HRMS (ESI) Calcd for C11H10ClF7NOS [M+H]+ requires 372.0054,
found 372.0055.
4.4.3. Compound 4c: 77%; Colorless oil. IR (film): 3231, 2981, 1606, 1512, 1230,
1
1127, 1015, 908, 835, 798 cm-1. H NMR (400 MHz, CDCl3): δ 7.32-7.29 (m, 2H),
7.07-7.02 (m, 2H), 4.86-4.84 (d, J = 4.4 Hz, 1H), 4.70-4.67 (m, 1H), 1.56 (d, J = 6.4
Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -66.18 to -67.23 (m, 2F), -113.71 to -113.78
(m, 1F), -117.65 (dd, J = 232.3, 3.0 Hz, 1F), -119.54 (dd, J = 232.3, 3.0 Hz, 1F). 13C
NMR (100 MHz, CDCl3): δ 162.5 (d, J = 245.4 Hz), 137.9 (d, J = 2.7 Hz), 128.1 (d, J
= 8.8 Hz), 115.8 (d, J = 21.3 Hz), 54.1, 23.7. ESI-MS (m/z, %): 338.9 (100)
[M+NH4]+; HRMS (ESI) Calcd for C10H10ClF5NOS [M+H]+ requires 322.0086,
found 322.0085.
11
Page 11 of 17

4.4.4. Compound 4d: 69%; Colorless oil. IR (film): 3223, 2978, 1449, 1377, 1261,
1179, 1080, 907, 748, 692 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.34-7.31 (d, J = 8.0
Hz, 2H), 7.27-7.25 (d, J = 7.2 Hz, 2H), 4.93-4.92 (m, 1H), 4.68-4.65 (m, 1H), 1.55 (d,
J = 6.9 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -66.68 to -66.75 (m, 2F), -117.15 (d,
J = 232.8 Hz, 1F), -119.76 (d, J = 233.8 Hz, 1F). 13C NMR (100 MHz, CDCl3): δ
140.6, 134.1, 129.1, 127.7, 122.1 (tt, JC-F = 298.2, 33.2 Hz), 116.4 (tt, JC-F = 306.0,
35.4 Hz), 54.0, 23.7. ESI-MS (m/z, %): 354.8 (100) [M+NH4]+; HRMS (ESI) Calcd
for C10H10Cl2F4NOS [M+H]+ requires 337.9791, found 337.9791.
4.4.5. Compound 4e: 71%; Colorless oil. IR (film): 3222, 2981, 2932, 1490, 1262,
1171, 1127, 1011, 908, 823, 799 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.5-7.49 (d, J =
8.0 Hz, 2H), 7.26-7.20 (d, J = 8.4 Hz, 2H), 4.68-4.65 (m, 2H), 1.58 (d, J = 6.9 Hz,
3H). 19F NMR (376 MHz, CDCl3): δ -66.14 to -67.20 (m, 2F), -117.54 (dt, J = 231.6,
1.9 Hz, 1F), -119.43 (dt, J = 232.0, 1.9 Hz, 1F). 13C NMR (100 MHz, CDCl3): δ 141.0,
132.2, 128.0, 122.3, 54.1, 23.6. ESI-MS (m/z, %): 400.8 (100) [M+NH4]+; HRMS
(ESI) Calcd for C10H10BrClF4NOS [M+H]+ requires 381.9286, found 381.9283.
4.4.6. Compound 4f: 65%; Colorless oil. IR (film): 3224, 2983, 2935, 1453, 1380,
1
1329, 1266, 1179, 1079, 1016, 905, 802, 703 cm-1. H NMR (400 MHz, CDCl3): δ
7.58-7.50 (m, 4H), 4.96-4.95 (d, J = 5.6 Hz, 1H), 4.80-4.77 (m, 1H), 1.61 (d, J = 6.9
Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -62.73 (s, 3F), -66.75 to -66.83 (m, 2F),
-116.93 (dq, J = 233.6, 3.0 Hz, 1F), -119.85 (dq, J = 233.6, 1.9 Hz, 1F). 13C NMR
(100 MHz, CDCl3): δ 143.2, 131.3 (t, J = 34.2 Hz), 129.7, 129.5, 125.1 (t, J = 3.7 Hz),
123.9 (t, J = 271.1 Hz), 123.1 (t, J = 3.8 Hz), 122.1 (tt, JC-F = 298.2, 33.2 Hz), 116.4
(tt, JC-F = 306.2, 35.3 Hz), 54.1, 23.7. ESI-MS (m/z, %): 388.9 (100) [M+NH4]+;
HRMS (ESI) Calcd for C11H10ClF7NOS [M+H]+ requires 372.0054, found 372.0054.
4.4.7. Compound 4g: 73%; Colorless oil, IR (film): 3230, 2979, 2928, 2872, 1516,
1452, 1377, 1261, 1179, 1016, 950, 908, 797, 603 cm-1. 1H NMR (400 MHz, CDCl3):
12
Page 12 of 17

δ 7.23 (d, J = 6.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.68-4.66 (m, 2H), 2.35 (s, 1H),
1.57 (d, J = 6.7 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -66.05 to -67.13 (m, 2F),
-118.04 (dq, J = 233.8, 5.3 Hz, 1F), -119.37 (dq, J = 233.9, 3.4 Hz, 1F). 13C NMR
(100 MHz, CDCl3): δ 139.0, 138.1, 129.7, 126.2, 54.7, 23.5, 21.1. ESI-MS (m/z, %):
350.9 (100) [M+NH4]+; HRMS (ESI) Calcd for C11H13ClF4NO2S [M+H]+ requires
334.0286, found 334.0282.
4.4.8. Compound 4h: 75%; Colorless oil. IR (film): 3239, 2977, 2838, 1613, 1514,
1460, 1249, 1179, 1028, 906, 813, 796, 687 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.25
(d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.73-4.72 (d, J = 3.6 Hz, 1H), 4.66-4.64
(m, 1H), 3.79 (s, 1H), 1.56 (d, J = 6.5 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -66.07
to -67.15 (m, 2F), -117.82 (dd, J = 230.8, 4.1 Hz, 1F), -119.37 (dd, J = 230.8, 4.5 Hz,
1F). 13C NMR (100 MHz, CDCl3): δ 159.5, 134.0, 127.6, 124.3, 122.2 (tt, JC-F = 298.2,
33.1 Hz), 116.4 (tt, JC-F = 305.0, 35.8 Hz), 55.3, 54.4, 23.5. ESI-MS (m/z, %): 350.9
(100) [M+NH4]+; HRMS (ESI) Calcd for C11H13ClF4NO2S [M+H]+ requires 334.0286,
found 334.0282.
4.4.9. Compound 4i: 82%; Colorless oil. IR (film): 3300, 2928, 1666, 1494, 1454,
1
1166, 1124, 1014, 801 cm-1. H NMR (400 MHz, CDCl3): δ 7.31-7.17 (m, 5H), 6.52
(d, J = 15.6 Hz, 1H), 6.14-6.08 (dd, J = 15.0, 6.4 Hz, 1H), 4.54-4.52 (m, 1H),
4.24-4.19 (m, 1H), 1.37 (d, J = 6.8 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -66.61 to
-66.69 (m, 2F), -117.45 (d, J = 232.8 Hz, 1F), -119.83 (dd, J = 232.8, 4.5 Hz, 1F). 13C
NMR (100 MHz, CDCl3): δ 135.9, 131.8, 130.2, 128.7, 128.2, 126.7, 53.5, 22.3.
ESI-MS (m/z, %): 346.9 (100) [M+NH4]+; HRMS (ESI) Calcd for C12H13ClF4NOS
[M+H]+ requires 330.0337, found 330.0331.
4.4.10. Compound 4j: 76%; Colorless oil. IR (film): 3233, 2961, 2873, 1470, 1421,
1388, 1261, 1170, 1125, 1059, 1015, 908, 795, 598 cm-1. 1H NMR (400 MHz, CDCl3):
δ 4.23 (s, 1H), 3.64-3.57 (m, 1H), 1.75-1.68 (m, 1H), 1.52-1.47 (m, 1H), 1.38-1.31 (m,
1H), 1.23 (d, J = 6.6 Hz, 3H), 0.91 (t, J = 6.0 Hz, 6H). 19F NMR (376 MHz, CDCl3): δ
13
Page 13 of 17

-66.12 to -67.16 (m, 2F), -117.92 (d, J = 232.6 Hz, 1F), -120.47 (d, J = 232.6 Hz, 1F).
13C NMR (100 MHz, CDCl3): δ 50.8, 47.7, 24.6, 22.8, 22.4, 22.3. ESI-MS (m/z, %):
283.8 (100) [M+H]+; HRMS (ESI) Calcd for C8H15ClF4NOS [M+H]+ requires
284.0494, found 284.0492.
4.4.11. Compound 4k: 78%; Colorless oil. IR (film): 3237, 2963, 2862, 1461, 1417,
1
1261, 1125, 1013, 908, 801, 684 cm-1. H NMR (400 MHz, CDCl3): δ 4.23-4.14 (m,
1H), 3.57-3.50 (m, 1H), 1.61-1.50 (m, 2H), 1.33-1.31 (m, 4H), 1.24 (d, J = 6.8 Hz,
3H), 0.90 (t, J = 6.0 Hz, 3H). 19F NMR (376 MHz, CDCl3): δ -66.12 to -67.18 (m, 2F),
-117.96 (dq, J = 232.9, 3.0 Hz, 1F), -120.28(dd, J = 232.9, 3.0 Hz, 1F). 13C NMR
(100 MHz, CDCl3): δ 122.3 (tt, JC-F = 297.9, 33.6 Hz), 116.1 (tt, JC-F = 304.4, 34.9
Hz), 52.7, 38.1, 27.8, 22.4, 22.3, 13.9. ESI-MS (m/z, %): 283.8 (100) [M+H]+; HRMS
(ESI) Calcd for C8H15ClF4NOS [M+H]+ requires 284.0494, found 284.0492.
4.4.12. Compound 5a: White solid, mp: 167-169 oC. 1H NMR (400 MHz, CD3OD): δ
7.35-7.47 (m, 5H), 4.43 (q, J = 6.8 Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H). The data
corresponded to that reported in the literature.[17]
4.5. Typical Procedure for the synthesis of (S)-5 from (Ss, Sc)-4a
To a 5.0 mL reaction tube equipped with a reflux condenser were added (Ss, Sc)-4a
(60.4 mg), 1 M HCl (1 mL), and MeOH (1 mL). The mixture was stirred at 50 oC for
2 h. After cooled to room temperature, the mixture was adjusted to pH = 10 with 1 M
NaOH, and then extracted with EtOAc (2 mL×5). Dry hydrogen chloride was
bubbled through the combined organic solution for 5 min, and a white solid
precipitated. Evaporation of the volatile solvent under reduced pressure afforded 30.6
mg (97% yield) of (S)-5: [α]D25 = -4.4 (c 4.0, MeOH) [17]
.
Acknowledgements
14
Page 14 of 17

Financial support from the National Natural Science Foundation of China (No.
21172243) is gratefully acknowledged.
References:
[1] For selective references, see: a) A.G. Dyker and K.R. Lees, Stroke 30 (1999)
1796–1801. b) A.K. Desai and G.T. Grossberg, Expert Rev. Neurother. 5 (2005)
563–580. c) A. Welter, J. Jadot, G. Dardenne, M. Marlier and J. Casimir,
Phytochemistry 15 (1976) 747–749. d) T.M. Wrodnigg, Monatsh. Chem. 133
(2002) 393–426.
[2] For reviews, see: a) S. Kobayashi, Y. Mori, J. S. Fossey, M.M. Salter, Chem. Rev.
111 (2011) 2626-2704. b) G.K. Friestad, A.K. Mathies, Tetrahedron 63 (2007)
2541-2569. c) P. Zhou, B.-C. Chen, F.A. Davis, Tetrahedron 60 (2004)
8003-8030. d) P. Zhou, B.-C. Chen, F.A. Davis, Advances in Sulfur Chemistry;
Rayner, C.M., Ed.; JAL Press: Greenwich, CT, 2000; Vol. 2, p 249. e) D.A.
Cogan, G. Liu, J.A. Ellman, Tetrahedron 55 (1999) 8883-8904. f) F.A. Davis, P.
Zhou, B.-C. Chen, Chem. Soc. Rev. 27 (1998) 13-18. For recent papers about the
addition of carbon nucleophiles to aldimines by chiral sulfinyl group, see: g) S.
Pindi, J. Wu, G. Li, J. Org. Chem. 78 (2013) 4006−4012. h) X. Yu, X. Lu, Adv.
Synth. Catal. 353 (2011) 2805–2813. i) O. Plietzsch, C.I. Schilling, M. Nieger, T.
Muller, S. Bräse, Tetrahedron: Asymmetry 21 (2010) 1474–1479. j) C. Estivill , J.
Mendizabal, A. Virgili, E. Monteagudo, T. Flor, F. Sánchez-Ferrando, A.
Alvarez-Larena, J.F. Piniell, Tetrahedron 65 (2009) 171–176. k) J.T. Reeves, Z.
Tan, M.A. Herbage, Z.S. Han, M.A. Marsini, Z. Li, G. Li, Y. Xu, K.R. Fandrick,
N.C. Gonnella, S. Campbell, S. Ma, N. Grinberg, H. Lee, B.Z. Lu, C.H.
Senanayake, J. Am. Chem. Soc. 135 (2013) 5565−5568. l) M. Blangetti, G. Croce,
A. Deagostino, E. Mussano, C. Prandi, P. Venturello, J. Org. Chem. 76 (2011)
1814–1820. m) C.M. Park, D.J. Jeon, Org. Biomol. Chem. 10 (2012) 2613–2620.
n) N.S.S. Reddy, B.V.S. Reddy, Tetrahedron Lett. 55 (2014) 3157–3159. o) Z.
Han, R. Busch, K.R. Fandrick, A. Meyer, Y. Xu, D.K. Krishnamurthy, C.H.
Senanayake, Tetrahedron 67 (2011) 7035-7041. p) C. Roe, T. Moragas Solá, L.
15
Page 15 of 17

Sasraku-Neequaye, H. Hobbs, I. Churcher, D. MacPherson, R.A. Stockman,
Chem. Commun. 47 (2011) 7491–7493.
[3] References on asymmetric reductions of isolated imines, see: a) K.A. Nolin, R.W.
Ahn, F.D. Toste, J. Am. Chem. Soc. 127 (2005) 12462-12463. b) Q. Yang, G.
Shang, W. Gao, J. Deng, X. Zhang, Angew. Chem. Int. Ed. 45 (2006) 3832-3835.
c) S. Hoffmann, A.M. Seayad, N. List, Angew. Chem. Int. Ed. 44 (2005)
7424-7427. d) H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner, M.
Studer, Adv. Synth. Catal. 345 (2003) 103-151. e) N. Uematsu, A. Fujii, S.
Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 118 (1996) 4916-4917. f)
C.J. Cobley, J.P. Henschke, Adv. Synth. Catal. 345 (2003) 195-201. g) M.C.
Hansen, S.L. Buchwald, Org. Lett. 2 (2000) 713-715. h) J. Qin, G.K. Friestad,
Tetrahedron 59 (2003) 6393-6402. References on Enantioselective
Organocatalytic Reductive Amination of ketones, see: i) R.I. Storer, D.E.
Carrera, Y. Ni, D.W.C. MacMillan, J. Am. Chem. Soc. 128 (2006) 84-86. For
reduction of preformed N-sulfinyl imines, see: j) X. Xiao, H. Wang, Z. Huang, J.
Yang, X. Bian, Y. Qin, Org. Lett. 8 (2006) 139-142. k) D. Guijarro, O. Pablo, M.
Yus, Tetrahedron Lett. 50 (2009) 5386-5388. l) Z.-H. Lu, N. Bhongle, X. Su, S.
Ribe, C.H. Senanayake, Tetrahedron Lett. 43 (2002) 8617–8620.
[4] a) R. Annunziata, M. Cinquini, F. Cozzi, J. Chem. Soc. Perkin Trans. 1 1 (1982)
339-343. b) M. Cinquini, F. Cozzi, J. Chem. Soc. Chem. Commun. (1977)
723-724.
[5] a) J. Tanuwidjaja, H.M. Peltier, J.A. Ellman, J. Org. Chem. 72 (2007) 626-629. b)
A. Watzke, R.M. Wilson, S.J. O’Malley, R.G. Bergman, J.A. Ellman, Synlett
(2007) 2383-2389. c) T. Kochi, T.P. Tang, J.A. Ellman, J. Am. Chem. Soc. 125
(2003) 11276-11282. d) T. Kochi, T. P. Tang, J. A. Ellman, J. Am. Chem. Soc.
124 (2002) 6518-6519.
[6] a) G. Borg, D.A. Cogan, J.A. Ellman, Tetrahedron Lett. 40 (1999) 6709-6712. For
a review on applications of 2-methylpropane-2-sulfinamide, see: b) J.A. Ellman,
T.D. Owens, T.P. Tang, Acc. Chem. Res. 35 (2002) 984-995. c) G.-Q. Lin, M.-H.
Xu, Y.-W. Zhong, X.-W. Sun, Acc. Chem. Res. 41 (2008) 831-840. (d) M.T.
Robak, M.A. Herbage, J.A. Ellman, Chem. Rev. 110 (2010) 3600-3740.
[7] T. Kochi, J.A. Ellman, J. Am. Chem. Soc. 126 (2004) 15652-15653.
[8] H.M. Peltier, J.A. Ellman, J. Org. Chem. 70 (2005) 7342-7345.
16
Page 16 of 17

[9] J.T. Colyer, N.G. Andersen, J.S. Tedrow, T.S. Soukup, M.M. Faul, J. Org. Chem.
71 (2006) 6859-6862.
[10] a) G. Chelucci, S. Baldino, S. Chessa, G.A. Pinna, F. Soccolini, Tetrahedron:
Asymmetry 17 (2006) 3163-3169. b) J.-U. Chung, S.Y. Kim, J.-O. Lim, H.-K.
Choi, S.-U. Kang, H.-S. Yoon, H. Ryu, D.W. Kang, J. Lee, B. Kang, S. Choi, A.
Toth, L.V. Pearce, V.A. Pavlyukovets, D.J. Lundberg, P.M. Blumberg, Bioorg.
Med. Chem. 15 (2007) 6043-6053.
[11] a) Z. Han, S.G. Koenig, H. Zhao, X. Su, S.P. Singh, R.P. Bakale, Org. Process
Res. Dev. 11 (2007) 726-730. b) A. Grajewska, M.D. Rozwadowska,
Tetrahedron: Asymmetry 18 (2007) 557-561. c) A. Watzke, R. M. Wilson, S. J.
O’Malley, R. G. Bergman, J. A. Ellman, Synlett (2007) 2383-2389. d) A. V.
Reddy, S. U. B. Rao, G. L. Narasimha, P. K. Dubey, Synth. Commun. 39 (2009)
1451-1456.
[12] a) L.-J. Liu, L.-J. Chen, P. Li, X.-B. Li, J.-T. Liu, J. Org. Chem. 76 (2011)
4675-4681. (b) K. Yang, L.-J. Liu, J.-T. Liu, J. Org. Chem. 79 (2014) 3215-3220.
[13] P. Li, L.-J. Liu, J.-T. Liu, Org. Biomol. Chem. 9 (2011) 74-77.
[14] L.-J. Liu, J.-T. Liu, Chin. J. Org. Chem. 29 (2011) 2722-2726.
[15] L.-J. Liu, J.-T. Liu, Tetrahedron 70 (2014) 1236-1245.
[16] A. Wangweerawong, R.G. Bergman, J.A. Ellman, J. Am. Chem. Soc. 136 (2014)
8520-8523.
[17] M.V. Rangaishenvi, B. Singaram and H.C. Brown, J. Org. Chem. 56 (1991)
3286-3294.
17
Page 17 of 17