Highly enantioselective Pd-catalyzed asymmetric hydrogenation of activated imines

Article abstract of DOI:10.1021/jo0700878

(Chemical Equation Presented) Pd/bisphosphines complexes are highly effective catalysts for asymmetric hydrogenation of activated imines in trifluoroethanol. The asymmetric hydrogenation of N-diphenylphosphinyl ketimines 3 with Pd(CF₃CO₂)/(S)-SegPhos indicated 87-99% ee, and N-tosylimines 5 could gave 88-97% ee with Pd-(CF₃CO ₂)/(S)-SynPhos as a catalyst. Cyclic N-sulfonylimines 7 and 11 were hydrogenated to afford the useful chiral sultam derivatives in 79-93% ee, which are important organic synthetic intermediates and structural units of agricultural and pharmaceutical agents.

Full text of DOI:10.1021/jo0700878

Supporting Information
Highly Enantioselective Pd-Catalyzed Asymmetric Hydrogenation of Activated
Imines
You-Qing Wang, Sheng-Mei Lu, Yong-Gui Zhou*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian
116023, The People’s Republic of China.
ygzhou@dicp.ac.cn
Table of Contents.
General and Materials………………………………………………………………………….. S1
The preparation of imines (3, 5, 7)………………………………………………………. …… S2
General procedure for the synthesis of N-sulfonylimines (11) and the date of characterization
for all new compounds………………………………………………………. ……………… S3-5
The procedure for asymmetric hydrogenation and preparation of Pd complex ………… S5-6
The date of characterization for all products of hydrogenation reaction………. ……… S6-10
The procedure for removing the Bn group of 12i and date of characterization for 13…S10-11
The experimental details of non linear effects………………………………………………. S11
Reference ……………………………………………………………………………………… S12
Copy of NMR and HRMS spectrum for all new compounds and products of hydrogenation
reaction …………………………………………………………………………………… S13-142
Copy of HPLC for racemic and chiral compounds…………………………………….S143-202
General:
techniques or in an nitrogen-filled glovebox, unless otherwise noted. H
using standard Schlenk
1
with
JASCO P-1010 polarimeter. Flash column chromatography was performed on silica gel (200-300
mesh).
Materials: Commericially available reagents were used throughout without further purification
2
other than those detailed below. THF and Et O were distilled
Methylene chloride was distilled over calcium hydride.
were purchased from Aldrich without further purification. SynPhos was
1
prepared according to the literature.
The preparation of imines
S1

OH
R
P(O)Ph2
Ph PCl, Et N
N
2
3
N
petroleum ether/CH Cl , -40¡æ
Ar
2
2
Ar
R
3
2
N-Diphenylphosphinyl imines (3): It was prepared according to the literatures. Imines 3 all are
3
known
compounds.
Representative
spectroscopic
dates
are
following:
):
1
N-(1-Phenylethylidene)-diphenylphosphinamide (3a): White solid, H NMR (400 MHz, CDCl
3
=
2.97 (d, J = 2.0 Hz, 3H), 7.43-7.50 (m, 9H), 7.98-8.00 (m, 4H), 8.08-9.10 (m, 2H).
Ts
O
1) p-toluenesulfinamide, Ti(OEt) , CH Cl
4 2 2
N
R1
R2
2) m-CPBA, CH Cl2
2
R1
R2
5
General procedure for the synthesis of N-tosyl imines (5): It was prepared according to the
4
modified procedures reported in the literature. To a Schlenck flask equipped with a condenser
were charged with the corresponding ketone (5 mmol), racemic p-toluenesulfinamide (1.552 g, 10
mmol) and Ti(OEt)
-4 days and monitored by TLC. 20 mL CH
solution was filtered through anhydrous Na
4
(3.2 mL, 15 mmol) in 50 mL CH
OH and a few drops of NaHCO
SO and washed with EtOAc. The solvent was
2
Cl
2
. The solution was heated under reflux for
2
3
3
were added. Then the
2
4
removed in vacuo and the crude product was purified by column chromatography using petroleum
ether and EtOAc to obtain the corresponding p-tolylsulfinimine.
2 2
In a dried flask, to a stirred solution of the corresponding p-tolylsulfinimine in CH Cl was added
dry m-CPBA (monitored by TLC) at room temperature (the reaction can be carried out in the air
without special handling). When the reaction was completed, the solution was concentrated in
vacuo. The residue was dissolved in Et
over anhydrous Na SO , and concentrated to give a residue which was quickly purified by column
chromatography using petroleum ether and EtOAc to give the corresponding N-tosyl imines (5)
2 3
O, washed with saturated solution of NaHCO twice, dried
2
4
4
,5
(
>90%
purity).
Representative
spectroscopic
dates
are
following:
1
(E)-1-Phenyl-N-tosylethanimine (5a): White solid, H NMR (400 MHz, CDCl
3
): = 2.45 (s, 3H),
2
4
.99 (s, 3H), 7.35 (d, J = 8.2 Hz, 2H), 7.39-7.43 (m, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.89-7.94 (m,
H).
O2
S
NH
O2
S
N
RLi or RMgX
THF
7
O
R
6
N-Sulfonylimines (7): It was prepared from the saccharin according to the literatures.
6a
1
3
-Methyl-1,2-benzisothiazole 1,1-Dioxide (7a): White solid, H NMR (400 MHz, CDCl
3
):
=
=
2
.68 (s, 3H), 7.69-7.79 (m, 3H), 7.91-7.93 (m, 1H).
6
c
1
3
-Butyl-1,2-benzisothiazole 1,1-Dioxide (7b): White solid, H NMR (400 MHz, CDCl
3
):
0
3
.99 (t, J = 7.3 Hz, 3H), 1.49-1.54 (m, 2H), 1.84-1.91 (m, 2H), 2.96-2.99 (m, 2H), 7.70-7.75 (m,
H), 7.90-7.92 (m, 1H).
6
b
1
3
3
-Benzyl-1,2-benzisothiazole 1,1-Dioxide (7c): White solid, H NMR (400 MHz, CDCl ): =
4
.30 (s, 2H), 7.30-7.32 (m, 1H), 7.35-7.36 (m, 4H), 7.58-7.70 (m, 3H), 7.89 (d, J = 7.4 Hz, 1H).
S2

O2
S
OH
MeSO NHBoc/LDA
1) PCC, CH
2
Cl
2
O
2
N
SO NHBoc
2
2
R
o
R
THF, -78 C to rt
2) TFA, Reflux
R
9
10
11
General procedure for the synthesis of N-sulfonylimines (11): N-Sulfonylimines 11 were
prepared from corresponding substituted oxiranes 9 according to the procedures reported in the
7
8
literature. The known compounds oxiranes 9d, 9f, 9g were synthesized according to the literature.
9
MeSO
2
NHBoc was synthesized from MeSO
2
NH
2
and (Boc)O
2
according to the literature. PCC
1
0
was synthesized from pyridine and CrO
3
according to the literature.
O
ArOH
O Conditions: 2N NaOH for 9d, 9f, 9g
NaH/DMF for 9e
Cl
ArO
9
[(4-Trifluoromethyl-phenoxy)methyl]oxirane (9e): To a solution of 4-trifluoromethylphenol
(4.053 g, 25 mmol) in dry DMF (50 ml) was added NaH (1.000g, 25 mmol, 60% dispersion in
mineral oil) and the reaction mixture was stirred for 30 min at rt. After the epichlorohydrin was
o
added, the reaction was stirred for 5h at 30 C. The water (100 ml) was added, and the mixture was
extracted with ether (40 ml × 3). The combined organic layer was washed with 1 N NaOH (80 ml ×
1
2 4
) and dried with anhydrous Na SO . Evaporation of solvent and purification of the residue by
column chromatography (petroleum ether/EtOAc = 20:1) gave 9e as a colorless oil (2.294 g, 42%).
1
H NMR (400 MHz, CDCl
3
): = 2.76-2.78 (m, 1H), 2.91-2.93 (m, 1H), 3.35-3.39 (m, 1H), 3.96
(
dd, J = 5.8, 11.0 Hz, 1H), 4.30 (dd, J = 2.8, 10.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8
1
3
Hz, 2H); C NMR (100 MHz, CDCl
3
): = 44.7, 50.1, 69.1, 114.8, 123.6 (q, J = 32 Hz), 124.6 (q, J
+
=
269 Hz), 127.1 (d, J = 3 Hz), 161.1; HRMS Calculated for C10
9
H O
2
F
3
(M ) 218.0555, found:
2
18.0553.
1
tert-Butyl-N-[(3-hydroxynonyl)-sulfonyl]-carbamate (10c): Yellow oil, H NMR (400 MHz,
3
CDCl ): = 0.87-0.90 (m, 3H), 1.28-1.35 (m, 7H), 1.47-1.49 (m, 3H), 1.51 (s, 9H), 1.86-1.90 (m,
1
3
1
H), 2.03-2.06 (m, 1H), 3.52-3.60 (m, 2H), 3.75-3.77 (m, 1H); C NMR (100 MHz, CDCl
3
):
=
1
4.1, 22.6, 25.5, 28.0, 29.2, 30.5, 31.8, 37.4, 49.9, 69.9, 84.3, 150.0; HRMS Calculated for
+
C
10
H
20NO
4
S [M – C
4
H
9
O] 250.1113, found: 250.1122.
tert-Butyl-N-[(3-hydroxy-4-phenoxy-butyl)-sulfonyl]-carbamate (10d): Yellow oil, Yield:
1
8
6%, H NMR (400 MHz, CDCl
3
): = 1.51 (s, 9H), 2.09-2.17 (m, 2H), 3.61-3.71 (m, 2H), 3.89 (dd,
J = 6.6, 9.3 Hz, 1H), 4.01 (dd, J = 3.6, 9.4 Hz, 1H), 4.16-4.18 (m, 1H), 6.90 (d, J = 8.4 Hz, 2H),
1
3
6
.98 (t, J = 7.3 Hz, 1H), 7.27-7.32 (m, 2H); C NMR (100 MHz, CDCl
3
): = 27.2, 28.0, 49.7, 68.2,
+
7
1.4, 84.5, 114.7, 121.5, 129.7, 150.1, 158.4; HRMS Calculated for C15
H23NO
6
S (M ) 345.1246,
found: 345.1250.
tert-Butyl-N-[(3-hydroxy-4-(4-trifluoromethyl-phenoxy)-butyl)-sulfonyl]-carbamate (10e):
1
White solid, Yield: 79%, H NMR (400 MHz, CDCl
3
): = 1.50 (s, 9H), 2.09-2.19 (m, 2H),
3
6
6
.63-3.70 (m, 2H), 3.95 (dd, J = 6.5, 9.3 Hz, 1H), 4.03 (dd, J = 3.7, 9.4 Hz, 1H), 4.19-4.21 (m, 1H),
1
3
3
.96 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H); C NMR (100 MHz, CDCl ): = 27.2, 28.1, 49.9,
8.1,71.8, 84.8, 114.7, 123.8 (q, J = 33 Hz), 124.5 (q, J = 270 Hz), 127.2 (d, J = 3 Hz), 150.0,160.9;
+
HRMS Calculated for C16
H
22NO
6
F
3
NaS [M + Na] 436.1018, found: 436.1031.
tert-Butyl-N-[(3-hydroxy-4-(4-methyl-phenoxy)-butyl)-sulfonyl]-carbamate (10f): Yellow oil,
1
Yield: 54%, H NMR (400 MHz, CDCl
3
): = 1.50 (s, 9H), 2.05-2.14 (m, 2H), 2.28 (s, 3H), 2.71 (br,
1H), 3.59-3.69 (m, 1H), 3.86 (dd, J = 6.6, 9.4 Hz, 1H), 3.96 (dd, J = 3.7, 9.4 Hz, 1H), 4.11-4.13 (m,
S3

13
1
H), 6.78-6.81 (m, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.55 (br, 1H); C NMR (100 MHz, CDCl
3
):
=
2
0.7, 27.2, 28.1, 49.9, 68.3, 71.8, 84.7, 114.7, 130.2, 130.9, 150.0, 156.3; HRMS Calculated for
+
C
16
H
25NO
6
S (M ) 359.1403, found: 359.1405.
tert-Butyl-N-[(3-hydroxy-4-(2-methyl-phenoxy)-butyl)-sulfonyl]-carbamate (10g): Yellow
1
oil, H NMR (400 MHz, CDCl
3
): = 1.49 (s, 9H), 2.07-2.19 (m, 2H), 2.22 (s, 3H), 3.60-3.69 (m,
2
H), 3.88-3.92 (m, 1H), 3.96-4.16 (m, 1H), 4.16-4.18 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 6.87-6.90
1
3
(m, 1H), 7.12-7.16 (m, 2H); C NMR (100 MHz, CDCl
3
): = 16.4, 27.3, 28.1, 49.9, 68.4, 71.5,
+
84.6, 111.4, 121.3, 126.9, 127.1, 131.0, 150.0, 156.4; HRMS Calculated for C16
H25NO
6
S (M )
3
59.1403, found: 359.1412.
tert-Butyl-N-[(3-hydroxy-4-(naphthalen-2-yloxy)-butyl)-sulfonyl]-carbamate (10h): White
1
solid, Yield: 75%, H NMR (400 MHz, CDCl
3
): = 1.51 (s, 9H), 2.14-2.21 (m, 2H), 2.54 (d, J = 4.6
Hz, 1H), 3.65-3.74 (m, 2H), 4.02 (dd, J = 6.7, 9.3 Hz, 1H), 4.13 (dd, J = 3.5, 9.4 Hz, 1H), 4.23-4.24
1
3
(
m, 1H), 7.09-7.16 (m, 3H), 7.34-7.38 (m, 1H), 7.44-7.47 (m, 1H), 7.72-7.78 (m, 3H); C NMR
(
100 MHz, CDCl
3
): = 27.3, 28.2, 50.1, 68.3, 71.7, 84.8, 107.3, 118.7, 124.2, 126.8, 127.0, 127.9,
+
1
29.5, 129.9, 134.6, 149.8, 156.4; HRMS Calculated for C19
95.1410.
tert-Butyl-N-[(3-hydroxy-4-(benzyloxy)-butyl)-sulfonyl]-carbamate (10i): Yellow oil,
NMR (400 MHz, CDCl
Hz, 1H), 3.48-3.53 (m, 2H), 3.55-3.58 (m, 1H), 3.93-3.94 (m, 1H), 4.54 (s, 2H); C NMR (100
MHz, CDCl ): = 27.2, 28.1, 49.8, 68.5, 73.6, 84.4, 128.0, 128.1, 128.7, 137.7, 150.1.
H
25NO
6
S (M ) 395.1403, found:
3
1
H
3
): = 1.48 (s, 9H), 1.92-2.00 (m, 2H), 2.85 (br, 1H), 3.37 (dd, J = 6.8, 9.5
13
3
7
1
3
=
3
-Phenyl-4,5-dihydro-isothiazole 1,1-Dioxide (11a): White solid, H NMR (400 MHz, CDCl
3
):
3.43-3.47 (m, 2H), 3.66-3.70 (m, 2H), 7.51-7.55 (m, 2H), 7.64-7.68 (m, 1H), 8.02-8.04 (m, 2H).
7
1
-Methyl-4,5-dihydro-isothiazole 1,1-Dioxide (11b): White solid, H NMR (400 MHz,
): = 2.34 (s, 3H), 3.19-3.23 (m, 2H), 3.25-3.29 (m, 2H).
-n-Hexyl-4,5-dihydro-isothiazole 1,1-Dioxide (11c): White solid, H NMR (400 MHz, CDCl
0.88-0.91 (m, 3H), 1.31-1.38 (m, 6H), 1.70-1.74 (m, 2H), 2.53-2.57 (m, 2H), 3.17-3.20 (m, 2H),
CDCl
3
1
3
3
):
=
1
3
3
1
.23-3.26 (m, 2H); C NMR (100 MHz, CDCl
3
): = 14.2, 22.6, 25.5, 28.9, 31.5, 35.8, 36.9, 44.2,
+
85.5; HRMS Calculated for C S [M - C
7
H
12NO
2
2
H
5
] 174.0589, found: 174.0585.
1
3
-(Phenoxy-methyl)-4,5-dihydro-isothiazole 1,1-Dioxide (11d): White solid, Yield: 60%, H
NMR (400 MHz, CDCl ): = 3.27-3.31 (m, 2H), 3.39-3.43 (m, 2H), 4.99 (s, 2H), 6.92 (d, J = 8.5
3
1
3
Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 7.32-7.36 (m, 2H); C NMR (100 MHz, CDCl
3
): = 34.3, 43.6,
+
6
7.7, 114.6, 122.7, 130.2, 157.4, 182.1; HRMS Calculated for C10
H
11NO
3
S (M ) 225.0460, found:
2
25.0460.
3
-[(4-Trifluoromethyl-phenoxy)methyl]-4,5-dihydro-isothiazole 1,1-Dioxide (11e): White
1
3
solid, Yield: 65%, H NMR (400 MHz, CDCl ): = 3.30-3.34 (m, 2H), 3.40-3.43 (m, 2H), 5.04 (s,
13
2
H), 7.01 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, d-DMSO): = 33.9,
4
3.6, 67.2, 115.2, 115.8, 121.8, 122.1, 123.1, 125.8, 127.0, 160.3, 182.8; HRMS Calculated for
+
C
11
H
10NO
3
SF
3
(M ) 293.0333, found: 293.0335.
3
-[(4-Methyl-phenoxy)methyl]-4,5-dihydro-isothiazole 1,1-Dioxide (11f): White solid, Yield:
1
5
2
6
2
4%, H NMR (400 MHz, CDCl
3
): = 2.30 (s, 3H), 3.26-3.29 (m, 2H), 3.37-3.41 (m, 2H), 4.96 (s,
1
3
3
H), 6.80-6.82 (m, 2H), 7.12 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl ): = 20.7, 34.3, 43.6,
7.8, 114.5, 130.6, 132.1, 155.4, 182.5; HRMS (EI) Calculated for C11
H
13NO
3
S: 239.0616, found:
39.0620.
1
3
-[(2-Methyl-phenoxy)methyl]-4,5-dihydro-isothiazole 1,1-Dioxide (11g): White solid,
H
S4

3
NMR (400 MHz, CDCl ): = 2.27 (s, 3H), 3.27-3.31 (m, 2H), 3.42-3.45 (m, 2H), 4.99 (s, 2H), 6.77
13
(
3
d, J = 8.5 Hz, 1H), 6.94-6.97 (m, 1H), 7.16-7.20 (m, 2H); C NMR (100 MHz, CDCl ): = 16.4,
3
4.4, 43.6, 67.7, 111.0, 122.3, 126.9, 127.4, 131.5,155.5, 182.4; HRMS Calculated for C11
H
13NO
3
S
+
(M ) 239.0616, found: 239.0619.
3
-[(Naphthalen-2-yloxy)methyl]-4,5-dihydro-isothiazole 1,1-Dioxide (11h): Gray solid, Yield:
1
5
4%, H NMR (400 MHz, CDCl
3
): = 3.28-3.31 (m, 2H), 3.43-3.46 (m, 2H), 5.11 (s, 2H), 7.13 (d,
J = 2.5 Hz, 1H), 7.18 (dd, J = 2.6, 8.9 Hz, 1H), 7.40-7.42 (m, 1H), 7.47-7.51 (m, 1H), 7.75-7.82 (m,
1
3
3
1
2
H); C NMR (100 MHz, CDCl
3
): = 34.4, 43.7, 67.7, 107.3, 118.2, 124.9, 127.2, 127.3, 127.9,
+
29.8, 130.5, 134.4, 155.3, 182.0; HRMS Calculated for C14
H
13NO
3
S (M ) 275.0616, found:
75.0618.
1
3
-(Benzyloxy-methyl)-4,5-dihydro-isothiazole 1,1-Dioxide (11i): Yellowish solid, H NMR
(
3
400 MHz, CDCl ): = 3.19-3.23 (m, 2H), 3.26-3.30 (m, 2H), 4.42 (s, 2H), 4.62 (s, 2H), 7.32-7.40
13
(m, 5H); C NMR (100 MHz, CDCl
3
): = 34.3, 43.6, 69.6, 74.0, 128.2, 128.6, 128.9, 136.6, 183.3;
+
HRMS Calculated for C11
H
13NO [M - SO
2
] 175.0997, found: 175.1008.
Typical procedure for asymmetric hydrogenation of imines: (S)-SegPhos (2.9 mg, 0.0048
mmol) and Pd(CF CO (1.3 mg, 0.004 mmol) were placed in a dried Schlenk tube under nitrogen
3
2 2
)
atmosphere, and degassed anhydrous acetone was added. The mixture was stirred at r.t. for 1 h. The
solvent was removed under vacuum to give the catalyst. This catalyst was taken into a glove box
filled with nitrogen and dissolved in dry TFE. To the mixture of imine (0.2 mmol) and 4A MS (50
mg if it was added) was added this catalyst solution, and then the mixture was transferred to an
autoclave. The autoclave was stirred under directed condition (oil bath temperature was showed if
it was heated). After release of the hydrogen, the autoclave was opened and the reaction mixture
1
was evaporated. Conversion was directly determined by H NMR spectroscopy. The enantiomeric
excess was determined by HPLC after purification on silica gel using petroleum ether and EtOAc.
3
Observingly, containing 1% Et N should be utilized, otherwise the remains on silica gel resulted in
lower isolated yield for purification of N-(diphenylphosphinyl)amines. The absolute configuration
was determined by comparison of rotation sign with literature data or by analogue.
A large scale experiments on the asymmetric hydrogenation of 11d (SCHEME 2 in text):
3 2 2
(S)-SegPhos (60.4 mg, 0.099 mmol) and Pd(CF CO ) (29.9 mg, 0.09 mmol) were placed in a dried
Schlenk tube under nitrogen atmosphere, and degassed anhydrous acetone (8 ml) was added. The
mixture was stirred at r.t. for 2 h. The solvent was removed under vacuum to give the catalyst. This
catalyst was taken into a glove box filled with nitrogen and dissolved in dry TFE (16 ml). To the
mixture of 11d (1.014 g, 4.5 mmol) was added this catalyst solution, and then the mixture was
transferred to an autoclave. The autoclave was stirred at rt for 20 h. After release of the hydrogen,
the autoclave was opened and the reaction mixture was evaporated. The residue was purified by
flash column chromatography (petroleum ether / EtOAc: 1/1) to give 12d (1.013 g, yield 99%, 93%
ee). The obtained 12d was recrystallized from 10 ml EtOH/H
738 mg, yield 72%, >99% ee).
Racemates of aryl glycine 2f were prepared by the reduction of the corresponding imines under 1
atm H with 5% Pd/C at rt for 20 min. Racemates of N-(diphenylphosphinyl)amines 4 were
prepared by the reduction of the corresponding imines using NaBH in THF. Racemates of 2a,
N-tosylamines 6 and sultams 8, 12, 14 were prepared by the reduction of the corresponding imines
using NaBH in MeOH.
2
O (3/2, V/V) to give the white solid
(
2
4
4
S5

11
2 2 3 2
Preparation of complex PdCl -(S)-SYNPHOS: PdCl (CH CN) (77.8 mg, 0.3 mmol) was
suspended in 5 mL of benzene. (S)-SYNPHOS (287 mg, 0.45mmol) was added and the mixture
was stirred at room temperature. The yellow precipitate was collected by filtration and washed with
Et
Preparation of complex Pd(OTf)
SYNPHOS)][Cl]
and dissolved in CH
2
O, and dried in vacuo: yield of [Pd((S)- SYNPHOS)][Cl]
2
1
242 mg (99%).
2
2
-(S)-SYNPHOS:
The orange powder [Pd((S)-
2
(0.210 g, 0.257 mmol) was placed into a Schlenk flask equipped with a stirbar
Cl (16 mL). Then, 0.159 g (0.620 mmol) of AgOTf was added, and the
2
2
resulting solution was stirred under nitrogen for 20 h at room temperature. The precipitate was
filtered, and the filtrate was reduced in volume to about 3 mL in vacuo. Then 5 ul (0.334 mmol) of
distilled water was added, followed by the addition 12 mL of Et
collected by filtration and washed with Et O and was dried in vacuo: yield of [Pd((S)-
SYNPHOS)(H O)][OTf] 254 mg (93%).
2
O. The yellow precipitate was
2
2
2
1
3
1
4
-Methoxy-N-(1-phenylethyl)benzenamine (2a): Yellow oil, H NMR (400 MHz, CDCl
1.50 (d, J = 6.8 Hz, 3H), 3.69 (s, 3H), 4.40-4.42 (m, 1H), 6.46-6.48 (m, 2H), 6.68-6.70 (m, 2H),
.22-7.25 (m, 1H), 7.29-7.37 (m, 4H); HPLC (Chiralcel OD-H column, hexane/iPrOH 97/3, 1.0 mL
3
):
=
7
-1
min , 254 nm): t
Ethyl 2-(4-methoxyphenylamino)-2-phenylacetate (2f): Yellow oil, H NMR (400 MHz,
CDCl ): = 1.20 (t, J = 7.2 Hz, 3H), 3.70 (s, 3H), 4.10-4.26 (m, 2H), 5.00 (s, 1H), 6.55 (d, J = 8.8
Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 7.28-7.36 (m, 3H), 7.48-7.50 (m, 2H); HPLC (Chiralcel OJ-H
1 2
= 10.3 min (R), t = 11.4 min (S).
1
4
1
3
-1
1 2
column, hexane/iPrOH 70/30, 1.0 mL min , 254 nm): t = 21.2 min, t = 24.1 min.
2
,3
26
N-(1-Phenyl-ethyl)-diphenylphosphinamide (4a): White solid, 95% ee (R), [ ]
D
= +38.3
1
(
c 0.54, EtOH); H NMR (400 MHz, CDCl
3
): = 1.58 (d, J = 6.7 Hz, 3H), 3.17 (dd, J = 5.9, 9.1 Hz,
1
H), 4.36-4.43 (m, 1H), 7.26-7.45 (m, 11H), 7.80-7.85 (m, 2H), 7.89-7.93 (m, 2H); HPLC
-1
(Chiralpak AS-H column, hexane/iPrOH 80/20, 1.0 mL min , 254 nm): t
1 2
= 12.9 min (R), t = 24.4
min (S).
3
N-[1-(4-Methylphenyl)ethyl]-diphenylphosphinamide (4b): White solid, 97% ee (S),
8
1
[
]
D
= -66.5 (c 1.08, MeOH); R
f
= 0.22 (PE/EtOAc, 2:1); H NMR (400 MHz, CDCl
3
): = 1.56 (d,
J = 6.8 Hz, 3H), 2.34 (s, 3H), 3.14-3.17 (m, 1H), 4.32-4.39 (m, 1H), 7.15 (dd, J = 8.0, 20.4 Hz, 4H),
.37-7.48 (m, 6H), 7.81-7.91 (m, 4H); HPLC (Chiralpak AS-H column, hexane/iPrOH 80/20, 1.0
7
-1
1 2
mL min , 254 nm): t = 11.4 min (R), t = 15.8 min (S).
3
N-[1-(4-Methoxylphenyl)ethyl]-diphenylphosphinamide (4c): White solid, 96% ee (S),
8
1
[
]
D
= -66.4 (c 1.30, MeOH); H NMR (400 MHz, CDCl
3
): = 1.55 (d, J = 6.7 Hz, 3H), 3.12 (dd, J
=
5.9, 9.4 Hz, 1H), 3.80 (s, 3H), 4.31-4.41 (m, 1H), 6.85 (d, J = 8.7Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H),
7
.37-7.48 (m, 6H), 7.81-7.91 (m, 4H); HPLC (Chiralpak AS-H column, hexane/iPrOH 80/20, 1.0
-1
1 2
mL min , 254 nm): t = 15.9 min (R), t = 26.8 min (S).
3
N-[1-(4-Fluorophenyl)ethyl]-diphenylphosphinamide (4d): White solid, 94% ee (S),
8
1
[
]
D
= -41.9 (c 1.04, MeOH); H NMR (400 MHz, CDCl
3
): = 1.55 (d, J = 6.8 Hz, 3H), 3.11 (dd, J
=
5.9, 9.2 Hz, 1H), 4.35-4.42 (m, 1H), 6.98 (t, J = 8.7 Hz, 2H), 7.23-7.25 (m, 2H), 7.36-7.37 (m,
2
H), 7.44-7.46 (m, 4H), 7.78-7.81 (m, 2H), 7.88-7.92 (m, 2H); HPLC (Chiralpak AS-H column,
-1
hexane/iPrOH 80/20, 1.0 mL min , 254 nm): t
1
= 10.0 min (R), t
2
= 27.0 min (S).
3
N-[1-(4-Chlorophenyl)ethyl]-diphenylphosphinamide (4e): White solid, 94% ee (S),
8
1
[
]
D
3
= -73.4 (c 1.14, MeOH); H NMR (400 MHz, CDCl ): = 1.55 (d, J = 6.8 Hz, 3H), 3.17 (dd, J
S6

=
5.7, 9.5 Hz, 1H), 4.33-4.40 (m, 1H), 7.24 (dd, J = 8.5, 23.0 Hz, 4H), 7.37-7.47 (m, 6H), 7.79 (dd,
J = 7.0, 12.0, 2H), 7.90 (dd, J = 6.9, 11.9 Hz, 2H); HPLC (Chiralpak AS-H column, hexane/iPrOH
-1
8
1 2
0/20, 1.0 mL min , 254 nm): t = 11.4 min (R), t = 26.3 min (S).
3
N-[1-(3-Methoxylphenyl)ethyl]-diphenylphosphinamide (4f): White solid, 96% ee (S),
8
1
[
]
D
= -52.1 (c 1.32, MeOH); H NMR (400 MHz, CDCl
3
): = 1.57 (d, J = 6.8 Hz, 3H), 3.22 (dd, J
=
5.9, 9.5 Hz, 1H), 3.78 (s, 3H), 4.31-4.39 (m, 1H), 6.82-6.88 (m, 3H), 7.21-7.23 (m, 1H),
7
.36-7.47 (m, 6H), 7.80-7.93 (m, 4H); HPLC (Chiralpak AS-H column, hexane/iPrOH 80/20, 1.0
-1
1 2
mL min , 254 nm): t = 14.5 min (R), t = 29.4 min (S).
3
N-[1-(3-Methoxylphenyl)ethyl]-diphenylphosphinamide (4g): White solid, 99% ee (S),
8
1
[
]
D
= -22.1 (c 1.13, MeOH); H NMR (400 MHz, CDCl
3
): = 1.50 (d, J = 6.8 Hz, 3H), 3.69 (s,
3
H), 3.87 (dd, J = 8.0, 10.5 Hz, 1H), 4.36-4.43 (m, 1H), 6.78-6.82 (m, 2H), 6.97 (s, 1H), 7.19 (t, J =
13
7
.7 Hz, 1H), 7.33-7.38 (m, 6H), 7.72 (dd, J = 7.3, 11.9 Hz, 2H), 7.79 (dd, J = 7.1, 11.8 Hz, 2H);
): = 25.1, 49.6, 55.4, 111.2, 121.0, 128.3 (d, J = 7.0 Hz), 128.5, 131.7,
31.8, 128.1 (d, J = 108.6 Hz), 131.7, 131.8, 132.0 (d, J = 9.3 Hz), 132.8 (d, J = 9.4 Hz), 133.0,
C
NMR (100 MHz, CDCl
3
1
1
3
1
33.1, 133.8 (d, J = 119.7 Hz), 157.0; P NMR (162 MHz, CDCl
3
): = 22.9; HRMS Calculated for
21 2
C H22NO
P (M+1) 352.1461, found 352.1451; HPLC (Chiralpak AS-H column, hexane/iPrOH
-1
8
0/20, 1.0 mL min , 254 nm): t
N-(1-Naphthalen-1-yl-ethyl)-diphenylphosphinamide (4h): White solid; H NMR (400
MHz, CDCl ): = 1.70 (d, J = 6.7 Hz, 3H), 3.35-3.38 (m, 1H), 5.23-5.25 (m, 1H), 7.26-7.27 (m,
H), 7.41-7.51 (m, 7H), 7.62 (m, 1H), 7.74-7.78 (m, 3H), 7.86-7.93 (m, 4H).
1 2
= 11.9 min (R), t = 21.3 min (S).
2
1
3
2
2
,3
N-(1-Naphthalen-2-yl-ethyl)-diphenylphosphinamide (4i): White solid, 93% ee (S),
8
1
[
]
D
= -77.8 (c 1.02, MeOH); H NMR (400 MHz, CDCl
3
): = 1.66 (d, J = 6.7 Hz, 3H), 3.27-3.31
(
m, 1H), 4.51-4.61 (m, 1H), 7.32-7.33 (m, 2H), 7.43-7.48 (m, 7H), 7.65 (s, 1H), 7.80-7.83 (m, 5H),
-1
7
2
.93 (m, 2H); HPLC (Chiralpak AS-H column, hexane/iPrOH 80/20, 1.0 mL min , 254 nm): t
1
=
1.6 min (R), t = 27.7 min (S).
2
3
8
N-(1-Furylethyl)-diphenylphosphinamide (4j): White solid, 87% ee (S), [ ]
D
= -42.1 (c
1
0
1
7
.60, CH
2
Cl
2
); H NMR (400 MHz, CDCl
3
): = 1.60 (d, J = 6.8 Hz, 3H), 3.19 (dd, J = 6.6, 10.3 Hz,
H), 4.38-4.44 (m, 1H), 6.13 (d, J = 3.2 Hz, 1H), 6.28 (dd, J = 1.9, 3.2 Hz, 1H), 7.35 (m, 1H),
.42-7.49 (m, 6H), 7.87-7.95 (m, 4H); HPLC (Chiralpak AS-H column, hexane/iPrOH 80/20, 1.0
-1
1 2
mL min , 254 nm): t = 12.1 min (R), t = 17.0 min (S).
3
8
N-(1-Phenyl-propyl)-diphenylphosphinamide (4k): White solid, 87% ee (S), [ ]
D
= -38.5
1
(c 1.26, MeOH); H NMR (400 MHz, CDCl
3
): = 0.79 (t, J = 7.4 Hz, 3H), 1.80-1.89 (m, 1H),
1
.97-2.04 (m, 1H), 3.25 (dd, J = 6.4, 9.4 Hz, 1H), 4.08-4.11 (m, 1H), 7.14-7.16 (m, 2H), 7.23-7.33
(
m, 5H), 7.42-7.44 (m, 4H), 7.73-7.87 (m, 4H); HPLC (Chiralpak AS-H column, hexane/iPrOH
-1
8
0/20, 1.0 mL min , 254 nm): t
1
= 9.6 min (R), t
2
= 17.7 min (S).
5
15
1
1
-Phenyl-N-tosylethanamine (6a): White solid, 96% ee (S), [ ]
D
= -63.7 (c 0.95, EtOH); H
3
NMR (400 MHz, CDCl ): = 1.43 (d, J = 6.8 Hz, 3H), 2.39 (s, 3H), 4.44-4.48 (m, 1H), 4.77 (d, J =
6
.7 Hz, 1H) 7.09-7.11 (m, 2H), 7.17-7.21 (m, 5H), 7.62 (d, J = 8.2 Hz, 2H); HPLC (Chiralcel OD-H
-1
column, iPrOH/hexane 20/80, 1.0 mL min , 254nm): t
1
= 6.4 min (R), t
2
= 7.4 min (S).
5
15
1
-(4-Fluorophenyl)-N-tosylethanamine (6b): White solid, 96% ee (S), [ ]
D
= -58.2 (c 1.02,
1
EtOH); H NMR (400 MHz, CDCl
3
): = 1.39 (d, J = 6.9 Hz, 3H), 2.39 (s, 3H), 4.42-4.49 (m, 1H),
4
.90 (d, J = 6.6 Hz, 1H), 6.87 (t, J = 8.7 Hz, 2H), 7.05-7.09 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.60
-1
(d, J = 8.2 Hz, 2H); HPLC (Chiralcel OD-H column, iPrOH/hexane 20/80, 1.0 mL min , 254nm):
t
1
= 6.3 min (R), t = 6.9 min (S).
2
S7

5
15
1
-(4-Methoxyphenyl)-N-tosylethanamine (6c): White solid, 97% ee (S), [ ]
D
= -65.3 (c 0.75,
1
EtOH); H NMR (400 MHz, CDCl
3
): = 1.40 (d, J = 6.8 Hz, 3H), 2.39 (s, 3H), 3.76 (s, 3H),
4
7
2
.38-4.44 (m, 1H), 4.77 (br, 1H), 6.71-6.74 (m, 2H), 7.00-7.03 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H),
-1
.62 (d, J = 8.0 Hz, 2H); HPLC (Chiralcel OJ-H column, iPrOH/hexane 20/80, 0.8 mL min ,
54nm): t = 22.5 min (S), t = 26.6 min (R).
-(3-Methoxyphenyl)-N-tosylethanamine (6d): Colorless oil, 93% ee (S), [ ]
1
2
5
15
1
D
= -46.5 (c
): = 1.41 (d, J = 6.8 Hz, 3H), 2.38 (s, 3H), 3.69 (s, 3H),
.39-4.46 (m, 1H), 4.98 (d, J = 6.9 Hz, 1H), 6.58 (t, J = 1.9 Hz, 1H), 6.69-6.72 (m, 2H), 7.11 (t, J =
1
1
4
7
2
.02, EtOH); H NMR (400 MHz, CDCl
3
13
.9 Hz, 1H), 7.18 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H); C NMR (100 MHz, CDCl
3
):
=
1.7, 23.7, 53.8, 55.3, 111.9, 113.2, 118.6, 127.3, 129.6, 129.8, 137.8, 143.3, 143.8, 159.8; HPLC
-1
(Chiralcel OD-H column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
2
= 9.2 min (R), t = 10.2
min (S).
1
5
15
1
-(2-Methoxyphenyl)-N-tosylethanamine (6e): White solid, 94% ee (S), [ ]
D
= -33.8 (c 0.90,
1
EtOH); H NMR (400 MHz, CDCl
3
): = 1.45 (d, J = 7.0 Hz, 3H), 2.31 (s, 3H), 3.70 (s, 3H),
4
.50-4.58 (m, 1H), 5.50 (d, J = 9.5 Hz, 1H), 6.61 (t, J = 8.2 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.91
(
dd, J = 1.5, 7.5 Hz, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.06-7.11 (m, 1H), 7.49 (d, J = 8.2 Hz, 2H);
-1
HPLC (Chiralcel OJ-H column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
2
= 13.6 min (S), t =
1
5.5 min (R).
5
15
1
-(Naphthalen-2-yl)-N-tosylethanamine (6f): White solid, 95% ee (S), [ ]
D
= -53.8 (c 1.10,
1
EtOH); H NMR (400 MHz, CDCl
3
): = 1.51 (d, J = 6.8 Hz, 3H), 2.24 (s, 3H), 4.60-4.67 (m, 1H),
4
.90-4.95 (m, 1H), 7.03 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 1.6, 7.7 Hz, 1H), 7.43-7.46 (m, 3H), 7.57
(
d, J = 8.2 Hz, 2H), 7.65-7.67 (m, 2H), 7.73-7.75 (m, 1H); HPLC (Chiralcel OD-H column,
-1
iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
= 10.2 min (R), t
2
= 11.9 min (S).
5
15
1
-Phenyl-N-tosylpropan-1-amine (6g): White solid, 88% ee (S), [ ]
D
= -43.3 (c 0.70, EtOH);
1
3
H NMR (400 MHz, CDCl ): = 0.78 (t, J = 7.4 Hz, 3H), 1.68-1.85 (m, 2H), 2.36 (s, 3H), 4.19 (q, J
=
7.2 Hz, 1H), 4.76 (d, J = 6.5 Hz, 1H), 6.99-7.01 (m, 2H), 7.11 (d, J = 8.1 Hz, 2H), 7.14-7.16 (m,
-1
3
H), 7.53 (d, J = 8.2 Hz, 2H); HPLC (Chiralcel OD-H column, iPrOH/hexane 20/80, 0.8 mL min ,
54nm): t = 6.8 min (R), t = 7.9 min (S).
,3-Dimethyl-N-tosylbutan-2-amine (6h): White solid, 91% ee (S), [ ]
2
1
2
5
15
D
3
= -28.5 (c 0.92,
): = 0.82 (s, 9H), 0.89 (d, J = 6.8 Hz, 3H), 2.43 (s, 3H),
.02-3.09 (m, 1H), 4.12 (d, J = 9.6 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H);
1
EtOH); H NMR (400 MHz, CDCl
3
3
-1
HPLC (Chiralpak AS-H column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
2
= 8.6 min (S), t =
1
1.5 min (R).
6
a, 6c
15
3
-Methyl-1,2-benzisothiazoline 1,1-Dioxide (8a):
White solid, 91% ee (R), [ ]
D
= 23.7 (c
1
0
.90, CHCl
3
); H NMR (400 MHz, CDCl
3
): = 1.62 (d, J = 6.6 Hz, 3H), 4.77 (br, 1H), 4.78-4.81
(
m, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.62-7.66 (m, 1H), 7.78 (d, J = 7.8 Hz,
-1
1
H); HPLC (Chiralcel OD-H column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
= 12.4 min
(
S), t
2
= 15.2 min (R).
6
c
15
3
-Butyl-1,2-benzisothiazoline 1,1-Dioxide (8b): White solid, 90% ee (R), [ ]
D
= 46.6 (c 1.12,
1
CHCl
3
); H NMR (400 MHz, CDCl
3
): = 0.92 (t, J = 7.2 Hz, 3H), 1.36-1.48 (m, 4H), 1.75-1.78 (m,
1H), 1.97-1.99 (m, 1H), 4.67-4.72 (m, 1H), 4.95 (br, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.4
Hz, 1H), 7.62(t, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H); HPLC (Chiralcel OD-H column,
-
1
iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
= 9.2 min (S), t
2
= 16.1 min (R).
6
b, 6c
15
3
-Benzyl-1,2-benzisothiazoline 1,1-Dioxide (8c):
White solid, 88% ee (R), [ ]
D
= 42.3 (c
S8

1
1
1
7
2
.00, CHCl
3 3
); H NMR (400 MHz, CDCl ): = 3.01 (dd, J = 9.6, 13.8 Hz, 1H), 3.28 (dd, J = 4.8,
3.8 Hz, 1H), 4.64 (d, J = 3.4 Hz, 1H), 4.86-4.91 (m, 1H), 7.27-7.37 (m, 6H), 7.55-7.62 (m, 2H),
-1
.80 (d, J = 7.6 Hz, 1H); HPLC (Chiralcel OD-H column, iPrOH/hexane 20/80, 0.8 mL min ,
54nm): t = 15.0 min (S), t = 19.2 min (R).
-Phenyl-1,2-thiazolidine 1,1-Dioxide (12a): White solid, 79% ee (S), [ ]
1
2
1
6
15
D
3
= -30.8 (c 0.46,
): = 2.39-2.41 (m, 1H), 2.75-2.78 (m, 1H), 3.17-3.25 (m, 1H),
.33-3.38 (m, 1H), 4.60 (br, 1H), 4.71-4.76 (m, 1H), 7.32-7.42 (m, 5H); HPLC (Chiralcel OD-H
1
EtOH); H NMR (400 MHz, CDCl
3
3
-1
column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
= 20.9 min (S), t
2
= 25.0 min (R).
30
3
-Methyl-1,2-thiazolidine 1,1-Dioxide (12b): Colorless oil, 88% ee (R), [ ]
D
= 0.4 (c 0.60,
1
CHCl
3
); H NMR (400 MHz, CDCl
3
): = 1.34 (d, J = 6.3 Hz, 3H), 2.03-2.08 (m, 1H), 2.52-2.54 (m,
13
1
H), 3.10-3.18 (m, 1H), 3.21-3.27 (m, 1H), 3.72-3.76 (m, 1H), 4.13 (br, 1H) ; C NMR (100 MHz,
+
3 4 9 2
CDCl ): = 21.5, 32.0, 48.6, 51.1; HRMS Calculated for C H NO S (M ) 135.0354, found
135.0350. Ee of this product was determined by the analysis of products derived by the cinnamyl
bromine.
O2
S
Ph
N
N-Cinnamyl-3-Methyl-1,2-thiazolidine 1,1-Dioxide: To a solution of
2b in THF was added sodium hydride (60% dispersion in mineral oil) at
1
o
0
C. After the reaction mixture was stirred for 30 min at rt, the cinnamyl bromine (2 equiv.) was
introduced. To accelerate the reaction, tetrabutylammonium bromide (TBAB) as PTC was added,
and then the reaction was stirred overnight. The water was added, and the mixture was extracted
2 4
with ether. The organic extracts were dried over Na SO and concentrated. The residue was purified
by column chromatography on silica gel (petroleum ether/EtOAc) to give a colorless oil: 88% ee
1
(
R), H NMR (400 MHz, CDCl
3
): = 1.26-1.29 (m, 3H), 1.97-2.03 (m, 1H), 2.42-2.44 (m, 1H),
3
6
2
1
.04-3.08 (m, 1H), 3.24-3.27 (m, 1H), 3.49-3.52 (m, 1H), 3.79-3.85 (m, 1H), 3.95-3.99 (m, 1H),
.21-6.28 (m, 1H), 6.59 (d, J = 15.9 Hz, 1H), 7.23-7.27 (m, 1H), 7.30-7.34 (m, 2H), 7.37-7.39 (m,
13
H); C NMR (100 MHz, CDCl
3
): = 20.1, 27.5, 45.1, 46.8, 53.2, 124.5, 126.7, 128.2, 128.8,
+
34.2, 136.4; HRMS Calculated for C13
H17NO
2
S (M ) 251.0980, found 251.0973; HPLC
-1
(Chiralcel OJ-H column, iPrOH/hexane 30/70, 0.8 mL min , 254nm): t
1
2
= 19.1 min (S), t = 25.9
min (R).
1
6b
27
3
-Hexyl-1,2-thiazolidine 1,1-Dioxide (12c): White solid, 90% ee (R), [ ]
D
= 8.7 (c 1.02,
1
CHCl
3
); H NMR (400 MHz, CDCl
3
): = 0.85-0.89 (m, 3H), 1.27-1.39 (m, 8H), 1.51-1.63 (m, 2H),
2
4
.02-2.10 (m, 1H), 2.46-2.52 (m, 1H), 3.05-3.13 (m, 1H), 3.17-3.23 (m, 1H), 3.53-3.59 (m, 1H),
13
.36 (br, 1H); C NMR (100 MHz, CDCl
3
): = 14.2, 22.7, 26.2, 29.1, 30.1, 31.8, 36.1, 48.2, 55.5;
+
HRMS Calculated for C
9
H
19NO
2
S (M ) 205.1137, found: 205.1139. Ee of this product was
determined by the analysis of products derived by the cinnamyl bromine.
N-Cinnamyl-3-Hexyl-1,2-thiazolidine 1,1-Dioxide: It was prepared in
O2
S
30
Ph
similar methods of 12b. Colorless oil, 90% ee (R), [ ]
D
= -6.3 (c 1.06,
N
1
CHCl
3
); H NMR (400 MHz, CDCl
3
): = 0.84-0.87 (m, 3H), 1.26-1.37
n-C H
6
13
(
m, 8H), 1.46-1.49 (m, 1H), 1.73-1.79 (m, 1H), 2.01-2.08 (m, 1H),
.37-2.43 (m, 1H), 2.96-3.04 (m, 1H), 3.20-3.27 (m, 1H), 3.37-3.41 (m, 1H), 3.82 (dd, J = 8.1, 15.8
Hz, 1H), 3.98 (dd, J = 5.4, 15.8 Hz, 1H), 6.20-6.27 (m, 1H), 6.58 (d, J = 15.8 Hz, 1H), 7.23-7.27 (m,
2
13
1
4
3
H), 7.30-7.39 (m, 4H); C NMR (100 MHz, CDCl
3
): = 14.2, 22.7, 24.4, 25.0, 29.3, 31.8, 33.6,
+
5.8, 46.8, 57.2, 124.5, 126.7, 128.1, 128.8, 134.3, 136.4; HRMS Calculated for C18
H
27NO
2
S (M )
-1
21.1763, found: 321.1762; HPLC (Chiralcel OJ-H column, iPrOH/hexane 20/80, 0.8 mL min ,
S9

2
54nm): t
1 2
= 11.8 min (S), t = 15.4 min (R).
3
0
3
-Phenoxy-methyl-1,2-thiazolidine 1,1-Dioxide (12d): White solid, 92% ee (S), [ ]
D
= 14.1 (c
): = 2.35-2.38 (m, 1H), 2.59-2.61 (m, 1H), 3.15-3.26 (m,
H), 3.99-4.07 (m, 3H), 4.74 (br, 1H), 6.79 (d, J = 7.9 Hz, 2H), 7.00 (t, J = 7.4 Hz, 1H), 7.28-7.33
1
1
2
3 3
.12, CHCl ); H NMR (400 MHz, CDCl
13
(m, 2H); C NMR (100 MHz, CDCl
3
): = 25.9, 47.5, 53.3, 69.6, 114.7, 121.9, 129.8, 158.1;
+
HRMS Calculated for C10
H13NO
3
S (M ) 227.0616, found: 227.0619; HPLC (Chiralcel OD-H
-1
column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1
= 25.2 min (R), t
2
= 37.4 min (S).
3
-[(4-Trifluoromethyl-phenoxy)methyl]-1,2-thiazolidine 1,1-Dioxide (12e): White solid, 93%
2
7
1
ee (S), [ ]
D 3 3
= 11.1 (c 1.04, CHCl ); H NMR (400 MHz, CDCl ): = 2.35-2.38 (m, 1H), 2.64-2.66
(
m, 1H), 3.14-3.21 (m, 1H), 3.26-3.30 (m, 1H), 4.05-4.11 (m, 3H), 4.75 (d, J = 4.9 Hz, 1H), 6.97 (d,
13
J = 8.7 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H); C NMR (100 MHz, CDCl
3
): = 25.7, 47.4, 53.1, 70.1,
1
14.7, 124.1 (q, J = 32 Hz), 124.4 (q, J = 270 Hz), 127.3 (d, J = 3 Hz), 160.6; HRMS Calculated for
+
C
11
H
12NO
3
SF
0/70, 0.8 mL min , 254nm): t
-[(4-Methyl-phenoxy)methyl]-1,2-thiazolidine 1,1-Dioxide (12f): White solid, 91% ee (S),
3
(M ) 295.0490, found: 295.0497; HPLC (Chiralcel OJ-H column, iPrOH/hexane
-1
3
1 2
= 17.6 min (R), t = 19.6 min (S).
3
2
7
1
[
]
D
3 3
= 11.1 (c 0.93, CHCl ); H NMR (400 MHz, CDCl ): = 2.29 (s, 3H), 2.34-2.37 (m, 1H),
2
2
1
.57-2.60 (m, 1H), 3.15-3.25 (m, 2H), 3.97-4.04 (m, 3H), 4.70 (d, J = 4.7 Hz, 1H), 6.77-6.80 (m,
13
H), 7.09 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, CDCl
32.1, 155.4, 182.5; HRMS Calculated for C11
3
): = 20.7, 34.3, 43.6, 67.8, 114.5, 130.6,
+
H
15NO
3
S (M ) 241.0773, found: 241.0772; HPLC
-1
(
Chiralcel OJ-H column, iPrOH/hexane 30/70, 0.8 mL min , 254nm): t
min (S).
-[(2-Methyl-phenoxy)methyl]-1,2-thiazolidine 1,1-Dioxide (12g): White solid, 92% ee (S),
1 2
= 24.8 min (R), t = 26.4
3
2
7
D
1
[
]
= 13.8 (c 1.14, CHCl
3 3
); H NMR (400 MHz, CDCl ): = 2.22 (s, 3H), 2.34-2.41 (m, 1H),
2
6
6
.60-2.64 (m, 1H), 3.14-3.28 (m, 2H), 4.01-4.03 (m, 3H), 4.82 (br, 1H), 6.78 (d, J = 8.4 Hz, 1H),
13
.88-6.92 (m, 1H), 7.13-7.17 (m, 2H); C NMR (100 MHz, CDCl
3
): = 16.4, 25.9, 47.4, 53.4,
+
9.8, 111.2, 121.5, 126.9, 127.1, 131.1, 156.2; HRMS Calculated for C11
H
15NO
3
S (M ) 241.0773,
-1
found: 241.0781; HPLC (Chiralcel OD-H column, iPrOH/hexane 30/70, 0.8 mL min , 254nm): t
1
=
2
14.1 min (R), t = 17.1 min (S).
3
-[(Naphthalen-2-yloxy)methyl]-1,2-thiazolidine 1,1-Dioxide (12h): White solid, 90% ee (S),
2
7
1
[
]
D
3 3
= 1.9 (c 0.99, CHCl ); H NMR (400 MHz, CDCl ): = 2.35-2.40 (m, 1H), 2.59-2.63 (m,
1
H), 3.15-3.21 (m, 1H), 3.24-3.28 (m, 1H), 4.04-4.07 (m, 1H), 4.10-4.15 (m, 2H), 4.83 (d, J = 5.9
1
3
Hz, 1H), 7.12-7.14 (m, 2H), 7.35-7.38 (m, 1H), 7.44-7.47 (m, 1H), 7.71-7.78 (m, 3H); C NMR
(
100 MHz, CDCl
3
): = 25.9, 47.5, 53.3, 69.8, 107.2, 118.5, 124.3, 126.8, 127.0, 127.9, 129.5,
+
1
29.9, 134.5, 156.0; HRMS Calculated for C14
H
15NO
3
S (M ) 277.0773, found: 277.0778; HPLC
-1
(Chiralcel OD-H column, iPrOH/hexane 30/70, 0.8 mL min , 254nm): t
1 2
= 35.1 min (S), t = 40.7
min (R).
3
0
3
-(Benzyloxy-methyl)-1,2-thiazolidine 1,1-Dioxide (12i): Colorless oil, 86% ee (S), [ ]
D
=
1
1
3
=
0.5 (c 1.12, CHCl
3
); H NMR (400 MHz, CDCl
3
): = 2.19-2.25 (m, 1H), 2.43-2.47 (m, 1H),
.10-3.16 (m, 2H), 3.49-3.52 (m, 1H), 3.57-3.60 (m, 1H), 3.77-3.78 (m, 1H), 4.55 (s, 2H), 4.64 (d, J
13
5.2 Hz, 1H), 7.30-7.38 (m, 5H); C NMR (100 MHz, CDCl
3
): = 26.1, 47.6, 53.9, 71.6, 73.6,
+
128.0, 128.2, 128.8, 137.5; HRMS Calculated for C11
H
15NO
3
S (M ) 241.0773, found: 241.0782;
-
1
HPLC (Chiralcel OD-H column, iPrOH/hexane 20/80, 0.8 mL min , 254nm): t
1 2
= 19.2 min (R), t
=
24.6 min (S).
S10

O2
S
O2
S
HN
H , Pd/C
HN
13
2
BnO
HO
MeOH
1
2i
3
-Hydroxymethyl-1,2-thiazolidine 1,1-Dioxide (13): To a solution of (S)-12i (52mg, 0.22mmol,
6% ee) in MeOH (2 ml) was added 5% Pd/C (104 mg, 50% H O) (the reaction can be carried out
in the air without special handling). The mixture was transferred to an autoclave, was stirred under
0 atm of hydrogen at rt for 4h. After release of the hydrogen, the autoclave was opened and the
reaction mixture was passed on a short silica gel column. The solvent was removedand gave 13 as a
8
2
1
29
1
colorless oil (31 mg, 95%). 86% ee (S), [ ]
D 3 3
= 12.8 (c 0.75, CHCl ); H NMR (400 MHz, CDCl ):
=
2.25-2.35 (m, 1H), 2.37 (br, 1H), 2.45-2.53(m, 1H), 3.09-3.16 (m, 1H), 3.22-3.28 (m, 1H),
13
3
5
.61-3.66 (m, 1H) 3.76-3.81 (m, 2H), 4.77 (br, 1H); C NMR (100 MHz, CDCl
3
): = 25.0, 47.9,
+
5.7, 64.6; HRMS Calculated for C
4
H
9
NO
3
SNa [M + Na] 174.0201, found: 174.0209.
The experimental details of non linear effects:
O2
S
O2
S
Pd(CF CO ) (2 mol%)
(S)-SynPhos (2.4 mol%)
3
2 2
N
HN
PhOCH2
PhOCH2
H2 (600 psi), TFE, rt
1
1d
12d
(
S)-SynPhos solution(3.8 mg/2.0 ml): 19.0 mg (S)-SynPhos in 10.0 ml acetone
R)-SynPhos solution (3.8 mg/2.0 ml): 9.5 mg (R)-SynPhos in 5.0 ml acetone
(
Preparation of catalyst: X ml (S)-SynPhos solution and Y ml (R)-SynPhos solution were placed in
a dried Schlenk tube under nitrogen atmosphere, and stirred for a few minutes. Then Pd(CF CO
1.7 mg, 0.005 mmol) was added and the mixture was stirred at rt for 1h. The solvent was removed
under vacuum to give the corresponding catalyst.
3
2 2
)
(
1
00%
0%
0%
40%
0%
Entry (S)-SynPhos ee
X / Y
12d ee
8
1
2
3
4
5
100%
80%
60%
40%
20%
-
88%
1.80 / 0.20 64%
1.60 / 0.40 47%
1.40 / 0.60 30%
1.20 / 0.80 12%
6
2
Conversion all are >95%
0
%
0
%
20% 40% 60% 80% 100%
ee of ( S) - SynPhos
1
2d ee (Y axis) versus ligand ee (X axis)
for the hydrogenation reaction of 11d using (S)-SynPhos as ligand
S11

Reference
(1) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J-P.; Champion, N.;
Deschaux, G.; Dellis, P. Org. Process Res. Dev. 2003, 7, 399.
(
2) (a) Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270. (b)Masumoto, S.; Usuda, H.;
Suzuki, M.; Kainai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
3) Wang, Y.-Q.; Zhou, Y.-G. Synlett 2006, 1189.
(
(
(
(
4) Ruano, J. L. G.; Alemán, J.; Cid, M. B.; Parra, A. Org. Lett. 2005, 7, 179.
5) Yang, Q.; Deng, J. G.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 3832.
6) (a) Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. Tetrahedron Lett. 1990, 31,
4
117. (b) Ahn, K. H.; Ham, C.; Kim, S.-K.; Cho, C.-W. J. Org. Chem. 1997, 62, 7047. c)
Mao, J. M.; Baker, D. C. Org. Lett. 1999, 1, 841–843.
(7) Freitag, D.; Metz, P. Tetrahedron 2006, 62, 1799.
(
8) Kopka, K.; Wagner, S.; Riemann, B.; Law, M. P.; Puke, C.; Luthra, S. K.; Pike, V. W.;
Wichter, T.; Schmitz, W.; Schober, O.; Schäfers, M. Bioorg. & Med. Chem. 2003, 11, 3513.
9) Neustadt, B. R. Tetrahedron Lett. 1994, 35, 379.
(
(
(
(
(
(
(
10) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 31, 2647.
11) Sanshiro, K. Synthesis of Organometallic Compounds; Wiley: Chichester, 1997, P285.
12) Stang, P. J.; Olenyuk, B.; Arif, A. M. Organometallics 1995, 14, 5281.
13) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem. 2003, 68, 4120.
14) Shang, G.; Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360.
15) Dudykina, S. J. Gen. Chem. USSR 1964, 34, 2294. (Chem. Abstr. 1964, 61, 11960f. CAS:
[93027-83-9])
(16) (a) Lee, J.; Zhong, Y.-L.; Reamer, R. A.; Askin, D. Org. Lett. 2003, 5, 4175. (b)Enders, D.;
Moll, A.; Bats, J. W. Eur. J. Org. Chem. 2006, 1271.
S12

OMe
HN
1
2
a H NMR (CDCl , 400M)
3
S13

OMe
HN
CO Et
2
1
2
f H NMR (CDCl , 400M)
3
S14

P(O)Ph2
HN
1
4
a H NMR (CDCl , 400M)
3
S15

P(O)Ph2
HN
Me
1
4
b H NMR (CDCl , 400M)
3
S16

P(O)Ph2
HN
MeO
1
4
c H NMR (CDCl , 400M)
3
S17

P(O)Ph2
HN
F
1
4
d H NMR (CDCl , 400M)
3
S18

P(O)Ph2
HN
Cl
1
4
e H NMR (CDCl , 400M)
3
S19

P(O)Ph2
HN
MeO
1
4
f H NMR (CDCl , 400M)
3
S20

P(O)Ph2
MeO HN
1
4
g H NMR (CDCl , 400M)
3
S21

P(O)Ph2
MeO HN
4
g 13C NMR (CDCl , 100M)
3
S22

P(O)Ph2
MeO HN
4
g 31P NMR (CDCl , 162M)
3
S23

P(O)Ph2
MeO HN
4
g HRMS
S24

P(O)Ph2
HN
1
4
h H NMR (CDCl , 400M)
3
S25

P(O)Ph2
HN
1
4
i H NMR (CDCl , 400M)
3
S26

P(O)Ph2
HN
O
1
4
j H NMR (CDCl , 400M)
3
S27

P(O)Ph2
HN
1
4
k H NMR (CDCl , 400M)
3
S28

Ts
HN
1
6
a H NMR (CDCl , 400M)
3
S29

Ts
HN
F
1
6
b H NMR (CDCl , 400M)
3
S30