Diastereoselective Hydrosilylation of N-(tert-Butylsulfinyl)imines Catalyzed by Zinc Acetate

Article abstract of DOI:10.1002/ejoc.201501318

An efficient zinc-catalyzed diastereoselective hydrosilylation of N-(tert-butylsulfinyl)imines has been developed that does not require the use of ligands or noble metals. A variety of N-(tert-butylsulfinyl)imines were reduced by this protocol in the presence of a catalytic amount of zinc acetate (5 mol-%) to provide the corresponding secondary amines in high yields with excellent diastereoselectivities (up to 98 % de). This experimentally simple catalytic procedure is easily applicable to the synthesis of both aromatic and aliphatic amines by using triethoxysilane as an efficient hydrogen source.

Full text of DOI:10.1002/ejoc.201501318

DOI: 10.1002/ejoc.201501318
Full Paper
Asymmetric Hydrosilylation
Diastereoselective Hydrosilylation of N-(tert-Butylsulfinyl)imines
Catalyzed by Zinc Acetate
Anna Adamkiewicz[a] and Jacek Mlynarski*[a,b]
Abstract: An efficient zinc-catalyzed diastereoselective hydro- provide the corresponding secondary amines in high yields
silylation of N-(tert-butylsulfinyl)imines has been developed that with excellent diastereoselectivities (up to 98 % de). This experi-
does not require the use of ligands or noble metals. A variety mentally simple catalytic procedure is easily applicable to the
of N-(tert-butylsulfinyl)imines were reduced by this protocol in synthesis of both aromatic and aliphatic amines by using tri-
the presence of a catalytic amount of zinc acetate (5 mol-%) to ethoxysilane as an efficient hydrogen source.
Introduction
starting material. This strategy could provide chiral imines, and
the well-studied enantiomerically pure N-(tert-butylsulfinyl)-
imines,[7] as versatile intermediates in the asymmetric synthesis
of chiral primary amines on laboratory and industrial scales. The
electron-withdrawing N-tert-butylsulfinyl substituent not only is
a powerful chiral-directing group but also can activate an imine
for the addition of many different classes of nucleophiles. More-
over, this group can be easily removed from a product under
mild acidic conditions to obtain the chiral primary amine with
its stereogenic center intact.[8]
The catalytic enantio- and diastereoselective hydrosilylation[1]
of imines is one of the most powerful methods for the synthesis
of chiral amines, which are widely found in natural products
and biologically active compounds. In general, two methods
have been developed to synthesize enantiomerically pure
amines from ketimines through asymmetric reduction. The first
involves the use of chiral substrates to induce chirality, whereas
the second employs optically pure catalysts for the transfer of
chirality.[2] Both approaches with their advantages and draw-
backs are still developed as complementary strategies.
Many efficient catalysts based on transition metals (mostly
Ti, Rh, Ru, Re)[3] have been applied to the hydrosilylation of
imines by using safe and inexpensive hydrosilanes as stoichio-
metric reducing agents. In recent years, however, these noble
metal complexes have been successively replaced by less ex-
pensive and more environmentally friendly zinc-based chiral
catalysts.[4] The use of a zinc-amine complex to catalyze enan-
tioselective hydrosilylations of aryl-alkyl ketones was developed
by Mimoun.[5] This convenient method can be extended to the
reduction of imines and is now used as a practical synthesis for
optically active amines through the reduction of the carbon-
nitrogen double bond.[6] However, the syntheses of active zinc
catalysts require the use of unstable and hazardous dialkylzinc
compounds, which makes the method less convenient for an
industrial large-scale application.
Strategies for the diastereoselective reduction of N-(tert-but-
ylsulfinyl)imines have been achieved by using several reducing
agents. The most versatile, a one-pot method for the synthesis
and Ti(OEt)4-mediated NaBH4 reduction of (tert-butylsulfinyl)-
imines was developed by Ellman.[9,10] Later, various hydrogen
sources such catecholborane,[11] diisobutylaluminum hydride
(DIBAL-H), lithium tri-sec-butylborohydride (L-selectride), and
NaBH4 were used as convenient hydrogen sources for the re-
duction step.[12] The particularly convenient NaBH4-mediated
reduction required, however, a threefold excess amount of re-
ducing agent and still required some attention in terms of effi-
ciency and stereoselectivity.[12c] An alternative reduction ap-
proach for electronically deficient imines by using diethylzinc
in the presence of Ni(acac)2 (acac = acetylacetonate) was devel-
oped by Quin.[13] Finally, other methods for the asymmetric
transfer hydrogenation to chiral imines have been developed,
but they require the use of a ruthenium complex and careful
screening for an efficient metal-ligand combination.[14]
An alternative pathway based on the diastereoselective re-
duction of chiral imines still deserves much attention, as it
could be executed on a large scale and provide higher enantio-
purity as the result of a chiral auxiliary incorporated into the
Surprisingly, in spite of broad interest in asymmetric hydro-
silylations of carbonyl compounds, a similar protocol had never
been applied to the diastereoselective reduction of imines. We
would like to close this gap and reveal an attractive alternative
for the highly diastereoselective hydrosilylation of N-(tert-butyl-
sulfinyl)imines to chiral secondary amines promoted by a cata-
lytic amount of zinc acetate. Our objectives were to achieve a
high reaction efficiency and diminish possible contamination
by using a smaller amount of reducing agent than that of previ-
ous protocols. We herein disclose our investigation into the re-
[a] Faculty of Chemistry, Jagiellonian University,
Ingardena 3, 30-060 Krakow, Poland
E-mail: jacek.mlynarski@gmail.com
www.jacekmlynarski.pl
[b] Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501318.
Eur. J. Org. Chem. 2016, 1060–1065
1060
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
duction of optically pure sulfinyl imines and present our initial 1 equiv., the hydrosilylation reaction led to lower yields and
results on the stereoselectivity of the reaction performed by more surprisingly to a lower stereoselectivity. The same tend-
using a silane as the reducing agent.
ency was observed for the three other sulfinyl imines 1b–1d.
On the basis of this finding, we maintained the use of 2 equiv.
of silane and 5 mol-% of zinc acetate for our further studies.
Results and Discussion
Table 2. Hydrosilylation of N-(tert-butylsulfinyl)imine 1a–1d by using less tri-
To optimize the reduction of optically pure sulfinyl imines in
terms of reaction yield and stereoselectivity, sulfinyl imine (SS)-
1a was subjected to the hydrosilylation reaction with various
combinations of zinc salts and silanes. Among the silanes, tri-
ethoxysilane proved to be optimal, and we thus decided to
screen zinc salts to promote the hydrosilylation of the N-(tert-
butylsulfinyl)imines with (EtO)3SiH as the hydrogen source. This
part of our optimization study was again performed by using
optically pure imine 1a as the model substrate and 2 equiv. of
(EtO)3SiH in the presence of 5 mol-% of various zinc salts in dry
tetrahydrofuran (THF) as the solvent. Initial studies revealed
that zinc acetate was the most promising Lewis acid for this
hydrosilylation, as it was superior to the other Lewis acids. To
our delight, the reaction promoted by zinc acetate was both
efficient and stereoselective resulting in the formation of (SS,S)-
2a with a diastereomeric excess (de) value of 91 % (Table 1,
Entry 2). Zinc chloride furnished N-(tert-butylsulfinyl)imine 2a in
lower yield with a modest selectivity (Table 1, Entry 3).
ethoxysilane.[a]
Entry Imine
R
x
y
% Yield[b]
% de[c]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
Ph
Ph
Ph
Ph
1
2.5
5
5
5
5
5
5
5
2
2
1
2
1
2
1
2
1
2
56
68
32
80
55
72
52
66
36
72
82
84
90
91
91
98
91
94
91
94
4-O2NC6H4
4-O2NC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
10
5
[a] Reagents and conditions: 1 (0.5 mmol), Zn(OAc)2 (x mol-%), and (EtO)3SiH
(y equiv.) in THF (2 mL) at room temp. for 72 h. [b] Isolated yield after silica
gel chromatography. [c] Determined by HPLC analysis.
Table 1. Hydrosilylation of N-(tert-butylsulfinyl)imine 1a by using various zinc
salts, solvents, and silanes.[a]
Finally, we examined the scope of the reaction by using vari-
ous aromatic (Table 3, Entries 1–9 and 12) and aliphatic (Table 3,
Entries 10 and 11) N-(tert-butylsulfinyl)imines under the opti-
mized reaction conditions for the hydrosilylation protocol. The
results are summarized in Table 3. In all cases, the reduction of
the aromatic sulfinyl imines afforded the corresponding amines
with good de values (87–98 %). To our delight, the reductions
of the electron-neutral, electron-poor, and electron-rich aro-
matic N-(tert-butylsulfinyl)imines 1a–1i were achieved in good
yields with excellent diastereoselectivities in most cases
(Table 3, Entries 1–9). All meta- and para-substituted arylimines
performed well under the optimized reaction conditions to pro-
vide diversely substituted N-(tert-butylsulfinyl)amines. Aliphatic
ketimines were reduced equally well to give the desired pro-
ducts 2j and 2k in good yields but with lower diastereoselectiv-
ities (Table 3, Entries 10 and 11). The 1-naphthyl-substituted
imine 1l was reduced with the same efficiency as the aceto-
phenone-derived imines (Table 3, Entry 12).
The highest diastereoselectivities were observed for the 4-
nitro- and 3-hydroxy-substituted amines (Table 3, Entries 2 and
7) but also by using many of the other para-substituted aceto-
phenone-derived imines (Table 3, Entries 3, 4, and 6). On the
basis of these results, we can conclude that this hydrosilylation
protocol is almost equally efficient for the asymmetric reduction
of imines with either an electron-withdrawing or electron-do-
nating group attached to the aromatic ring.
Entry LA[b]/ZnL2
Solvent
Silane
% Yield[c]
% de[d]
1
–
THF
THF
THF
THF
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
(EtO)3SiH
PMHS[b]
–
80
56
–
68
trace
36
–
–
91
36
–
90
–
2
3
4
5
6
7
8
9
Zn(OAc)2
ZnCl2
[b]
Zn(OTf)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
DCM[b]
toluene
CH3CN
DME[b]
THF
90
–
–
20
–
–
10
11
12
THF
THF
THF
(EtO)2MeSiH
(C6H5)2SiH2
(CH3)2PhSiH
78[e]
–
–
–
[a] Reagents and conditions: 1 (0.5 mmol), ZnL2 (5 mol-%), and silane
(2.0 equiv.) in solvent (2 mL) at room temp. for 72 h. [b] LA = Lewis acid,
OTf = trifluoromethanesulfonate, DCM = dichloromethane, DME = 1,2-di-
methoxyethane, PMHS = polymethylhydrosiloxane. [c] Isolated yield after sil-
ica gel chromatography. [d] Determined by HPLC analysis. [e] After 5 d.
We subsequently studied the role of solvent and the appro-
priate amount of triethoxysilane to employ in the reaction. Us-
ing CH2Cl2, toluene, or acetonitrile under similar reaction condi-
This imine reduction took place chemoselectively in the pres-
tions resulted in decreased yields and diastereoselectivities of ence of an ester function (Table 3, Entry 13), but the observed
the desired product 2a (Table 1). We then decided to examine diastereoselectivity was lower (75 %) than those from reduc-
a possible decrease in the loading of the reducing agent tions of aryl imines derived from ketones. Notably, the reduc-
(Table 2). When the amount of triethoxysilane was reduced to tion of acetophenone under the catalytic system for this proto-
Eur. J. Org. Chem. 2016, 1060–1065
www.eurjoc.org
1061
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 3. Scope of diastereoselective hydrosilylation of N-(tert-butylsulfinyl)-
tigmine, an acetylcholinesterase inhibitor used to treat mild to
moderate dementia of people with Alzheimer's or Parkinson's
disease (Scheme 1).[15] 4-Chloro-substituted amine 2d is a key
intermediate in the synthesis of the agricultural fungicide ca-
propamid, which is a useful to control rice blast fungus.[16] The
1-naphthyl moiety of amine 2l can be found in cinacalcet, part
of the calcimimetics class of compounds, which are useful for
the treatment of secondary hyperparathyroidism in patients
with chronic kidney disease and hypocalcaemia in patients with
parathyroid carcinoma.[17]
imines.[a]
Entry
Imine
RL
RS
% Yield[b]
% de[c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Ph
80
72
68
72
85
82
68
82
75
80
70
78
54
91
98
94
94
87
94
95
91
92
73
64
93
75
4-O2NC6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-F3CC6H4
3-HOC6H4
3-BrC6H4
Ph
CH2CH2Ph
CH=CHPh
1-naphthyl
CO2Et
Scheme 1. Chiral amine structure found in pharmaceuticals and biologically
active compounds.
9
10
11
12
13[d]
1j
1k
1l
Conclusions
1m
In summary, we have developed an efficient method for the
diastereoselective hydrosilylation of N-(tert-butylsulfinyl)imines
promoted by zinc acetate. This approach affords the corre-
sponding secondary amines from aromatic and aliphatic sulfin-
ylimines in high yields (up to 85 %) with excellent diastereo-
selectivities (up to 98 % de). Moreover, both diastereoisomers
can be simply prepared in high optical purity by using an imine
with the suitable absolute configuration of the sulfur atom. This
method employs a smaller amount of a gentle and neutral
hydrogenating agent (2 equiv. of triethoxysilane) than required
by convenient NaBH4-mediated reductions previously de-
scribed. This efficient catalytic procedure provides an attractive
synthetic method for some amines that are versatile chiral
building blocks to several biologically active and pharmaceuti-
cal compounds.
[a] Reagents and conditions: 1 (0.5 mmol), Zn(OAc)2 (5 mol-%), (EtO)3SiH
(2 equiv.) in THF (2 mL) at room temp. for 72 h. [b] Isolated yield after silica
gel chromatography. [c] Determined by HPLC analysis. [d] Reaction per-
formed in THF (2 mL) at 4 °C for 72 h.
col, that is, Zn(OAc)2 (5 mol-%) and triethoxysilane (2 equiv.),
took place smoothly at room temp. to deliver a racemic alcohol.
This parallel experiment shows that the reduction of imines
cannot be performed in the presence of a ketone function.
In all cases, the stereoselective reduction of optically pure
sulfinyl imines (SS)-1 resulted in the preferential formation of
the corresponding (SS,S)-2 diastereomer. Such an origin of
asymmetric induction is similar to a NaBH4-promoted reduction.
In agreement with earlier reports,[12] we propose that the reac-
tions proceed through a closed transition state, in which zinc
coordinates to the sulfinyl oxygen and participates in the deliv-
ery of the hydride (Table 3). Previously, Anderson and co-work-
ers proposed such a six-membered cyclic-like transition state
(TS), in which a boron atom interacted with the oxygen of a
sulfinyl group.[12c] In this catalytic system, the zinc hydride re-
ducing agent, which is generated from zinc acetate and tri-
ethoxysilane, delivers hydrogen to the carbon of the imine in
a similar manner, resulting in the same sense of asymmetric
induction. Under this scenario, (SS)-sulfinyl imines would furnish
the observed (SS,S)-2 sulfinamide products through the six-
membered TS depicted in Table 3.
Experimental Section
General Methods: All starting materials and reagents were ob-
tained from commercial sources and used as received unless other-
wise noted. All solvents were freshly distilled prior to use. Optical
rotations were measured at room temperature with a digital pola-
rimeter. High resolution mass spectra were recorded with an ESI-
MS-TOF. Infrared spectra were recorded on a Fourier transform infra-
red [attenuated total reflectance (ATR) FTIR] spectrometer. The 1H
NMR spectroscopic data were recorded with a spectrometer that
operated at 600 MHz, and CDCl3 was used as the NMR solvent. Data
are reported in the following order: chemical shifts in parts per
million (ppm) with tetramethylsilane as the internal standard, multi-
plicity [s (singlet), d (doublet), t (triplet), q (quartet), dd (double
of doublets), m (multiplet), br. (broad)], coupling constants (in Hz),
integration, and assignment. The 13C NMR spectroscopic data were
recorded at 151 MHz with complete proton decoupling. Chemical
An important application of our method would be its use for
the synthesis of pharmaceuticals or biologically active com-
pounds. Several primary amines that are drug and herbicide
precursors can be easily obtained by a simple desulfinylation of
the N-(tert-butylsulfinyl)amines (Scheme 1). 3-Hydroxy-substi-
tuted amine 2g is a desired substrate for the synthesis of rivas- shifts are reported in ppm, and the deuterated solvent was used as
Eur. J. Org. Chem. 2016, 1060–1065
www.eurjoc.org
1062 © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
the internal standard. HPLC analysis was performed with a UV de- 114.1, 55.4, 55.3, 53.3, 22.7, 22.6 ppm. IR: ν = 3215, 2970, 1510,
˜
tector (221 nm).
1248, 1045 cm–1. [α]D25 = +20.4 (c = 1.0, CHCl3), 94 % de.
Preparation of N-(tert-Butylsulfinyl)imines: N-(tert-Butylsulf-
inyl)imines 1a,[18] 1b,[18] 1c,[19] 1d,[18] 1e,[18] 1f,[12c] 1h,[20] 1i,[21]
1j,[12c] 1k,[22] 1l,[18] and 1m[23] were prepared by condensation of
the appropriate ketone (1.2 equiv.) with (Ss)-(–)-2-methyl-2-prop-
anesulfinamide (1.0 equiv.) and Ti(OEt)4 (2 equiv.) in THF according
to the literature.[14a]
(SS)-N-[(S)-1-(4-Chlorophenyl)ethyl]-2-methylpropane-2-sulf-
inamide (2d):[14b] Colorless oil (94 mg, 72 %). 1H NMR (600 MHz,
CDCl3): δ = 7.32 (d, J = 8.7 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 2 H), 4.52
(qd, J = 6.6, 3.1 Hz, 1 H), 3.38 (d, J = 2.0 Hz, 1 H), 1.49 (d, J = 6.6 Hz,
3 H), 1.23 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 142.5, 133.5,
128.9, 128.0, 55.6, 53.5, 22.8, 22.6 ppm. IR: ν = 3195, 2979, 1494,
˜
1045, 824, 783 cm–1. [α]D25 = +34.9 (c = 1.0, CHCl3), 94 % de.
(SS)-N-[1-(3-Hydroxyphenyl)ethylidene]-2-methylpropane-2-
sulfinamide (1g): A mixture of 3′-hydroxyacetophenone (1.47 g,
10.80 mmol, 1.2 equiv.), Ti(OEt)4 (3.77 mL, 18.00 mmol, 2 equiv.),
and (Ss)-(–)-2-methyl-2-propanesulfinamide (1.09 g, 9.00 mmol,
1.0 equiv.) in anhydrous THF (20 mL) was heated to reflux for 24 h
under argon. Upon completion of the reaction, the mixture was
cooled to room temperature and poured into an equal volume of
water that was rapidly stirred. The resulting suspension was filtered
through a plug of Celite, and the filter cake was washed with EtOAc.
The filtrate was transferred to a separatory funnel, and the organic
layer was washed with brine. The brine layer was extracted with a
small volume of EtOAc (1×), and the combined organic portions
were dried with anhydrous Na2SO4, filtered, and concentrated. The
crude product was purified by column chromatography on silica
gel (hexane/ethyl acetate, 4:1). The volatiles were removed under
reduced pressure to give the pure product (1.62 g, 75 %) as a white
(SS)-2-Methyl-N-[(S)-1-(4-methylphenyl)ethyl]propane-2-sulf-
inamide (2e): Colorless oil (102 mg, 85 %). 1H NMR (600 MHz,
CDCl3): δ = 7.24 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 7.8 Hz, 2 H), 4.52
(qd, J = 6.5, 2.7 Hz, 1 H), 3.37 (s, 1 H), 2.34 (s, 3 H), 1.49 (d, J =
6.5 Hz, 3 H), 1.23 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 141.2,
137.5, 129.4, 126.5, 55.4, 53.6, 22.8, 22.6, 21.1 ppm. IR: ν = 3199,
˜
2971, 2917, 1515, 1053, 815 cm–1. HRMS (ESI-TOF): calcd. for
C13H21NNaOS [M + Na]+ 262.1242; found 262.1240. [α]D25 = +47.3
(c = 1.0, CHCl3), 87 % de.
(SS)-2-Methyl-N-{(S)-1-[4-(trifluoromethyl)phenyl]ethyl}-
propane-2-sulfinamide (2f):[12c] Colorless oil (120 mg, 82 %). 1H
NMR (600 MHz, CDCl3): δ = 7.61 (d, J = 8.1 Hz, 2 H), 7.48 (d, J =
8.2 Hz, 2 H), 4.61 (qd, J = 6.6, 3.5 Hz, 1 H), 3.45 (d, J = 2.6 Hz, 1 H),
1.53 (d, J = 6.6 Hz, 3 H), 1.24 (s, 9 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 148.0, 130.2 (q, J = 32.4 Hz), 127.0, 125.8 (q, J = 3.5 Hz),
1
solid; m.p. 149–150 °C. H NMR (600 MHz, CDCl3): δ = 7.69 (s, 1 H),
123.1 (q, J = 272.2 Hz), 55.7, 53.8, 22.8, 22.6 ppm. IR: ν = 3237, 2981,
˜
7.43–7.32 (m, 2 H), 7.22 (t, J = 7.9 Hz, 1 H), 7.01 (ddd, J = 8.1, 2.4,
0.7 Hz, 1 H), 2.68 (s, 3 H), 1.32 (s, 9 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 177.9, 156.8, 139.7, 129.5, 119.6, 119.2, 114.3, 57.4, 22.4,
1619, 1323, 1050, 835 cm–1. [α]D25 = +35.3 (c = 1.0, CHCl3), 94 % de).
(SS)-N-[(S)-1-(3-Hydroxyphenyl)ethyl]-2-methylpropane-2-sulf-
20.31 ppm. IR: ν = 3157, 1596, 1577, 1299, 1018, 786 cm–1. HRMS
1
˜
inamide (2g): White solid (82 mg, 68 %); m.p. 135–136 °C. H NMR
(ESI-TOF): calcd. for C12H17NNaO2S [M + Na]+ 262.0878; found
262.0872.
(600 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.16 (t, J = 7.8 Hz, 1 H), 6.82–
6.75 (m, 3 H), 4.42 (qd, J = 6.6, 3.7 Hz, 1 H), 3.58 (d, J = 3.4 Hz, 1 H),
1.47 (d, J = 6.6 Hz, 3 H), 1.26 (s, 9 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 157.1, 145.2, 129.9, 117.3, 115.1, 113.9, 55.9, 54.8, 22.9,
General Procedure for the Zinc-Catalyzed Hydrosilylation of N-
(tert-Butylsulfinyl)imines 2a–2m: A solution of zinc acetate
(4.6 mg, 0.025 mmol) in anhydrous THF (2 mL) was stirred at room
temperature for 10 min. Subsequently, triethoxysilane (0.185 mL,
1.00 mmol, 2.0 equiv.) and the appropriate N-(tert-butylsulfinyl)-
imine (0.5 mmol, 1.0 equiv.) were added in 15 min intervals, and
the resulting mixture was stirred at room temperature for 72 h un-
der argon. Upon the complete consumption of the starting materi-
als, the reaction mixture was directly purified by column chroma-
tography on silica gel (hexane/ethyl acetate, 1:1). The volatiles were
removed under reduced pressure to give pure 2a–2m.
22.7 ppm. IR: ν = 3275, 3078, 2972, 1589, 1285, 1013, 788 cm–1
.
˜
HRMS (ESI-TOF): calcd. for C12H19NNaO2S [M + Na]+ 264.1034; found
264.1028. [α]D25 = +24.2 (c = 1.0, CHCl3), 95 % de).
(SS)-N-[(S)-1-(3-Bromophenyl)ethyl]-2-methylpropane-2-sulf-
inamide (2h): White solid (125 mg, 82 %); m.p. 84–85 °C. 1H NMR
(600 MHz, CDCl3): δ = 7.50–7.48 (m, 1 H), 7.43–7.41 (m, 1 H), 7.29–
7.27 (m, 1 H), 7.22 (dd, J = 9.8, 5.8 Hz, 1 H), 4.51 (qd, J = 6.6, 3.1 Hz,
1 H), 3.41 (d, J = 2.1 Hz, 1 H), 1.50 (d, J = 6.6 Hz, 3 H), 1.24 (s, 9
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 146.3, 131.0, 130.4, 129.7,
125.4, 122.8, 55.6, 53.6, 22.8, 22.6 ppm. IR: ν = 3147, 2954, 1569,
˜
(SS)-2-Methyl-N-[(S)-1-phenylethyl]propane-2-sulfinamide
1430, 1045, 964, 698 cm– 1 . HRMS (ESI-TOF): calcd. for
C12H18BrNNaOS [M + Na]+ 326.0190; found 326.0174. [α]D25 = +25.7
(c = 1.0, CHCl3), 91 % de.
1
(2a):[13] Colorless oil (90 mg, 80 %). H NMR (600 MHz, CDCl3): δ =
7.36–7.28 (m, 5 H), 4.55 (qd, J = 6.6, 2.8 Hz, 1 H), 3.42 (br. s, 1 H),
1.51 (d, J = 6.5 Hz, 3 H), 1.24 (s, 9 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 144.1, 128.8, 127.8, 126.6, 55.5, 53.9, 22.8, 22.6 ppm. IR:
(SS)-2-Methyl-N-[(S)-1-phenylpropyl]propane-2-sulfinamide
ν = 3211, 2974, 1454, 1363, 1052, 761, 698 cm–1. [α]D25 = +56.1 (c =
1
(2i):[13] Colorless oil (90 mg, 75 %). H NMR (600 MHz, CDCl3): δ =
˜
1.0, CHCl3), 91 % de.
7.35–7.27 (m, 5 H), 4.29–4.26 (m, 1 H), 3.40 (d, J = 3.1 Hz, 1 H), 2.08–
2.03 (m, 1 H), 1.79–1.75 (m, 1 H), 1.23 (s, 9 H), 0.79 (t, J = 7.4 Hz, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 142.3, 128.6, 127.8, 127.3,
(SS)-2-Methyl-N-[(S)-1-(4-nitrophenyl)ethyl]propane-2-sulfin-
amide (2b):[14b] Colorless oil (97 mg, 72 %). 1H NMR (600 MHz,
CDCl3): δ = 8.21 (d, J = 8.8 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H), 4.65
(qd, J = 6.6, 4.1 Hz, 1 H), 3.50 (d, J = 3.5 Hz, 1 H), 1.55 (d, J = 6.6 Hz,
3 H), 1.25 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 151.2, 147.5,
60.4, 55.7, 29.3, 22.6, 10.0 ppm. IR: ν = 3199, 2962, 1455, 1059,
˜
698 cm–1. [α]D25 = +82.6 (c = 1.0, CHCl3), 92 % de.
(SS)-2-Methyl-N-[(S)-4-phenylbutan-2-yl]propane-2-sulfinamide
(2j):[12c] Colorless oil (101 mg, 80 %). 1H NMR (600 MHz, CDCl3): δ =
7.30–7.26 (m, 2 H), 7.22–7.18 (m, 3 H), 3.45–3.41 (m, 1 H), 3.11 (d,
127.6, 124.1, 55.9, 53.9, 22.9, 22.6 ppm. IR: ν = 3280, 3057, 2979,
˜
1510, 1349, 1060, 858 cm–1. [α]D25 = +19.9 (c = 1.0, CHCl3), 98 % de.
(SS)-N-[(S)-1-(4-Methoxyphenyl)ethyl]-2-methylpropane-2-sulf- J = 4.5 Hz, 1 H), 2.72–2.70 (m, 2 H), 1.91–1.79 (m, 2 H), 1.23 (d, J =
inamide (2c):[13] Colorless oil (87 mg, 68 %). 1H NMR (600 MHz,
CDCl3): δ = 7.28–7.26 (m, 2 H), 6.89–6.87 (m, 2 H), 4.51 (qd, J = 6.5,
2.6 Hz, 1 H), 3.80 (s, 3 H), 3.35 (s, 1 H), 1.49 (d, J = 6.5 Hz, 3 H), 1.23
6.4 Hz, 3 H), 1.18 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 141.5,
128.5, 128.5, 126.0, 55.3, 51.1, 39.9, 32.1, 22.6, 21.7 ppm. IR: ν =
˜
3135, 2972, 2860, 1603, 1361, 1051, 753, 699 cm–1. [α]D25 = +68.6
(s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 159.2, 136.2, 127.8, (c = 1.0, CHCl3), 73 % de.
Eur. J. Org. Chem. 2016, 1060–1065
www.eurjoc.org
1063
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[3]
a) X. Verdaguer, U. E. W. Lange, M. T. Reding, S. L. Buchwald, J. Am. Chem.
Soc. 1996, 118, 6784; b) N. Langlois, T. P. Dang, H. B. Kagan, Tetrahedron
Lett. 1973, 14, 4865; c) R. Becker, H. Brunner, S. Mahboobi, W. Wiegrebe,
Angew. Chem. Int. Ed. Engl. 1985, 24, 995; Angew. Chem. 1985, 97, 969;
d) Y. Nishibayshi, I. Takei, S. Uemura, M. Hidai, Organometallics 1998, 17,
3420; e) K. A. Nolin, R. W. Ahn, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
12462.
(SS)-2-Methyl-N-[(S)-(2E,3E)-4-phenylbut-3-en-2-yl]propane-2-
1
sulfinamide (2k):[9] Colorless oil (88 mg, 70 %). H NMR (600 MHz,
CDCl3): δ = 7.39–7.24 (m, 5 H), 6.58 (dd, J = 15.9, 8.3 Hz, 1 H), 6.21
(dd, J = 15.9, 7.2 Hz, 1 H), 4.14–4.11 (m, 1 H), 3.24 (d, J = 4.1 Hz, 1
H), 1.39 (d, J = 6.5 Hz, 3 H), 1.23 (s, 9 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 136.5, 132.1, 130.9, 128.6, 127.8, 126.5, 55.5, 53.0, 22.6,
21.4 ppm. IR: ν = 3196, 2959, 1052, 962, 747, 692 cm–1. [α]D25 = +12.3
˜
[4]
[5]
D. Łowicki, S. Baś, J. Mlynarski, Tetrahedron 2015, 71, 133.
(c = 1.0, CHCl3), 64 % de.
a) H. Mimoun, J. Y. de Saint Laumer, L. Giannini, R. Scopelliti, C. Floriani,
J. Am. Chem. Soc. 1999, 121, 6158; for recent examples of a Zn-based
asymmetric hydrosilylation of ketones, see: b) M. Szewczyk, F. Stanek, A.
Bezłada, J. Mlynarski, Adv. Synth. Catal. 2015, 357, 3727; c) D. Łowicki, A.
Bezłada, J. Mlynarski, Adv. Synth. Catal. 2014, 356, 591; d) F. S. Pang, J.
Peng, J. Li, Y. Bai, W. Xiao, G. Lai, Chirality 2013, 25, 275; e) K. Junge, K.
Moller, B. Wendt, S. Das, D. Gordes, K. Thurow, M. Beller, Chem. Asian J.
2012, 7, 314; f) T. Inagaki, Y. Yamada, L. T. Phong, A. Furuta, J.-I. Ito, H.
Nishiyama, Synlett 2009, 253; for recent examples of an Fe-based asym-
metric hydrosilylation of ketones, see: g) T. Bleith, H. Wadepohl, L. Gade,
J. Am. Chem. Soc. 2015, 137, 2456; h) Z. Zuo, L. Zhang, X. Leng, Z. Huang,
Chem. Commun. 2015, 51, 5073; i) M. Flückiger, A. Togni, Eur. J. Org.
Chem. 2011, 4353; j) S. Hosokawa, J.-I. Ito, H. Nishiyama, Organometallics
2010, 29, 5773.
a) V. Bette, A. Mortreux, D. Savoia, J. F. Carpentier, Adv. Synth. Catal. 2005,
347, 289; b) B. M. Park, S. Mun, J. Yun, Adv. Synth. Catal. 2006, 348, 1029;
c) M. Bandini, M. Melucci, F. Piccinelli, R. Sinisi, S. Tommasi, A. Umani-
Ronchi, Chem. Commun. 2007, 4519; d) B. M. Park, X. Feng, J. Yun, Bull.
Korean Chem. Soc. 2011, 32, 2960; e) J. Gajewy, J. Gawronski, M. Kwit,
Org. Biomol. Chem. 2011, 9, 3863; f) for a review, see: O. Riant, N. Moste-
fai, J. Courmarcel, Synthesis 2004, 18, 2943; for zinc-catalyzed reductions
of amides, see: g) S. Das, D. Addis, S. Zhou, K. Junge, M. Beller, J. Am.
Chem. Soc. 2010, 132, 1770; for zinc-catalyzed reductive aminations, see:
h) S. Enthaler, Catal. Lett. 2011, 141, 55.
(SS)-2-Methyl-N-[(S)-1-(1-naphthyl)ethyl]propane-2-sulfinamide
1
(2l):[24] Colorless oil (107 mg, 78 %). H NMR (600 MHz, CDCl3): δ =
8.23 (d, J = 8.5 Hz, 1 H), 7.88–7.80 (m, 2 H), 7.62–7.47 (m, 4 H), 5.38
(qd, J = 6.4, 1.7 Hz, 1 H), 3.60 (s, 1 H), 1.70 (d, J = 6.5 Hz, 3 H), 1.24
(s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 139.2, 134.0, 130.5,
129.0, 128.5, 126.5, 125.8, 125.44, 123.5, 123.1, 55.5, 49.3, 22.7,
21.8 ppm. IR: ν = 3216, 2976, 1594, 1055, 775 cm–1. [α]D25 = +90.7
˜
(c = 1.0, CHCl3), 93 % de.
(SS)-Ethyl 2-[(S)-1,1-Dimethylethylsulfinamido]-2-phenylacetate
1
(2m):[23] Colorless oil (77 mg, 54 %). H NMR (600 MHz, CDCl3): δ =
7.38–7.32 (m, 5 H), 5.06 (d, J = 4.4 Hz, 1 H), 4.59 (d, J = 4.2 Hz, 1 H),
4.26–4.21 (m, 1 H), 4.16–4.11 (m, 1 H), 1.24 (s, 9 H), 1.20 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.4, 137.3, 128.7,
[6]
128.4, 127.7, 62.2, 60.5, 60.0, 22.6, 14.0 ppm. IR: ν = 3282, 3184,
˜
2980, 1737, 1455, 1292, 1178, 1070, 848 cm–1. [α]D25 = +158.2 (c =
1.0, CHCl3), 75 % de.
Procedure for the Removal of the N-tert-Butylsulfinyl Group of
Representative Compound 2a: The optical purity of compound
2a (Table 3, Entry 1, 91 % de) was confirmed by the optical rotation
of the corresponding chiral amine (1-phenylethylamine) using a
[7]
[8]
polarimeter. To
ethyl]propane-2-sulfinamide (112 mg, 0.5 mmol) in MeOH (0.20 mL)
was added HCl (1.25 ) in MeOH (0.8 mL, 1.0 mmol) at room tem-
a
solution of (SS)-2-methyl-N-[(S)-1-phenyl-
a) J. A. Ellman, T. D. Owens, T. P. Tang, Acc. Chem. Res. 2002, 35, 984; b)
J. A. Ellman, Pure Appl. Chem. 2003, 75, 39; c) P. Zhou, B.-C. Chen, F. A.
Davis, Tetrahedron 2004, 60, 8003; d) G.-Q. Lin, M.-H. Xu, Y.-W. Zhong, X.-
W. Sun, Acc. Chem. Res. 2008, 41, 831; e) F. Ferreira, C. Botuha, F. Chemla,
A. Perez-Luna, Chem. Soc. Rev. 2009, 38, 1162; f) P. Zhou, B.-C. Chen, F. A.
Davis, Tetrahedron 2004, 60, 8003.
a) X. Sun, S. Wang, S. Sun, J. Zhu, J. Deng, Synlett 2005, 2776; b) A.
Kosciolowicz, M. D. Rozwadowska, Tetrahedron: Asymmetry 2006, 17,
1444; c) B. Denolf, S. Mangelinckx, K. W. Toernroos, N. De Kimpe, Org.
Lett. 2006, 8, 3129.
G. Borg, D. A. Cogan, J. A. Ellman, Tetrahedron Lett. 1999, 40, 6709.
J. Tanuwidjaja, J. Peltier, J. A. Ellman, J. Org. Chem. 2007, 72, 626.
C.-H. Zhao, L. Liu, D. Wang, Y.-J. Chen, Eur. J. Org. Chem. 2006, 2977.
a) G. Dutheuil, S. Couve-Bonnaire, X. Pannecoucke, Angew. Chem. Int. Ed.
2007, 46, 1290; Angew. Chem. 2007, 119, 1312; b) Z.-J. Liu, J.-T. Liu, Chem.
Commun. 2008, 5233; c) J. T. Colyer, N. G. Andersen, J. S. Tedrow, T. S.
Soukup, M. M. Faul, J. Org. Chem. 2006, 71, 6859.
M
perature. The mixture was stirred for 30 min and then extracted
with diethyl ether. The aqueous phase was basified with NaOH solu-
tion and extracted again with diethyl ether. The combined organic
phases were dried with Na2SO4 and evaporated under reduced
pressure to give the corresponding (S)-(–)-1-phenylethylamine
(59 mg, 97 %) as a pure pale yellow oil. [α]D25= –30.6, (c = 1.0, CHCl3);
ref.[25] [α]D29= –36.7, (c = 1.02, CHCl3), 99 % ee. All spectroscopic data
are in agreement with previously reported values for the amine
product.[25]
[9]
[10]
[11]
[12]
Supporting Information (see footnote on the first page of this
article): 1H and 13C NMR spectra as well as HPLC analysis of pro-
ducts.
[13]
[14]
X. Xiao, H. Wang, Z. Huang, J. Yang, X. Bian, Y. Qin, Org. Lett. 2006, 8,
139.
Acknowledgments
a) D. Guijarro, O. Pablo, M. Yus, Tetrahedron Lett. 2009, 50, 5386; b) D.
Guijarro, O. Pablo, M. Yus, J. Org. Chem. 2010, 75, 5265; c) D. Guijarro, O.
Pablo, M. Yus, Tetrahedron Lett. 2011, 52, 789; d) O. Pablo, D. Guijarro, G.
Kovacs, A. Lledós, G. Ujaque, M. Yus, Chem. Eur. J. 2012, 18, 1969; e) D.
Guijarro, O. Pablo, M. Yus, Org. Synth. 2013, 90, 338; f) D. Guijarro, O.
Pablo, M. Yus, J. Org. Chem. 2013, 78, 3647; g) O. Pablo, D. Guijarro, M.
Yus, J. Org. Chem. 2013, 78, 9181; h) O. Pablo, D. Guijarro, M. Yus, Eur. J.
Org. Chem. 2014, 75, 7034.
Financial support from the Polish National Science Centre (grant
number NCN 2012/07/B/ST5/00909) is gratefully acknowledged.
Keywords: Asymmetric synthesis · Diastereoselectivity ·
Amines · Hydrosilylation · Zinc
[15]
[16]
[17]
a) C. M. Spencer, S. Noble, Drugs Aging 1998, 13, 391–411; b) C. Bhanja,
S. Jena, J. Chem. Pharm. Res. 2012, 4, 3171.
G. Tsuji, T. Takeda, I. Furusawa, O. Horino, Y. Kubo, Pestic. Biochem. Physiol.
1997, 57, 211.
N. Franceschini, M. S. Joy, A. Kshirsagar, Expert Opin. Invest. Drugs 2003,
12, 1413.
[1] B. Marciniec (Ed.), Hydrosilylation: A Comprehensive Review on Recent Ad-
vances, Springer, The Netherlands, 2009, p. 342–398.
[2] a) T. C. Nugent (Ed.), Chiral Amine Synthesis, Wiley-VCH, Weinheim, Ger-
many, 2010; b) T. C. Nugent, M. El-Shazly, Adv. Synth. Catal. 2010, 352,
753; for a review of the asymmetric hydrogenation of imines and
heteroaromatic compounds, see: c) J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem.
Rev. 2011, 111, 1713; d) Y.-G. Zhou, Acc. Chem. Res. 2007, 40, 1357; for a
review of the asymmetric transfer hydrogenation of imines, see: e) F.
Foubelo, M. Yus, Chem. Rec. 2015, 15, 907.
[18]
[19]
[20]
Q. Chen, C. Yuan, Synthesis 2007, 24, 3779.
D. Zhang, C. Yuan, Chem. Eur. J. 2008, 14, 6049.
Shionogiand Co., Ltd., Patent: EP2147914 A1, 2010.
Eur. J. Org. Chem. 2016, 1060–1065
www.eurjoc.org
1064
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
CCDC 2147914 (for A1) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[23] L. R. Reddy, A. P. Gupta, Y. Liu, J. Org. Chem. 2011, 76, 3409.
[24] V. R. Arava, L. Gorentla, P. K. Dubey, Beilstein J. Org. Chem. 2012, 8, 1366.
[25] Y. Shimizu, H. Morimoto, M. Zhang, T. Ohshima, Angew. Chem. Int. Ed.
2012, 51, 8564; Angew. Chem. 2012, 124, 8692.
[21]
J. A. Sirvent, F. Foubelo, M. Yus, Chem. Commun. 2012, 48, 2543.
[22] T. Guo, R. Song, B. Yuan, X. Chen, X. Sun, G. Lin, Chem. Commun. 2013,
49, 5402.
Received: October 14, 2015
Published Online: January 20, 2016
Eur. J. Org. Chem. 2016, 1060–1065
www.eurjoc.org
1065
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim