Enantioselective synthesis of α-silylamines by meerwein-ponndorf- verley-type reduction of α-silylimines by a chiral lithium amide

Article abstract of DOI:10.1021/jo500441a

Meerwein-Ponndorf-Verley-type reduction of N-tosylsilylimines with chiral lithium amide 2 affords α-silylamines in high enantioselectivity. Since the enantioselectivity observed was inconsistent with our previously proposed chairlike six-membered transition structure, we performed density functional theory (DFT) calculations on transition states leading to (S)- and (R)-7a and (S)- and (R)-7e using an N-phenylsulfonyl derivatives 12 and 13 as model systems. Results of the calculations showed that the structures are considerably deformed from the chairlike form with steric repulsions between the 1′-methylene group and the imine-carbon substituents playing an important role in the control of the enantioselectivity.

Full text of DOI:10.1021/jo500441a

Article
pubs.acs.org/joc
Enantioselective Synthesis of α‑Silylamines by Meerwein−Ponndorf−
Verley-Type Reduction of α‑Silylimines by a Chiral Lithium Amide
Yasuhiro Kondo,† Michiko Sasaki,*,† Masatoshi Kawahata,‡ Kentaro Yamaguchi,‡ and Kei Takeda†
†Department of Synthetic Organic Chemistry, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi,
Minami-Ku, Hiroshima 734-8553, Japan
‡Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193, Japan
S
* Supporting Information
ABSTRACT: Meerwein−Ponndorf−Verley-type reduction of N-tosylsilylimines with
chiral lithium amide 2 affords α-silylamines in high enantioselectivity. Since the
enantioselectivity observed was inconsistent with our previously proposed chairlike six-
membered transition structure, we performed density functional theory (DFT)
calculations on transition states leading to (S)- and (R)-7a and (S)- and (R)-7e using
an N-phenylsulfonyl derivatives 12 and 13 as model systems. Results of the
calculations showed that the structures are considerably deformed from the chairlike
form with steric repulsions between the 1′-methylene group and the imine-carbon
substituents playing an important role in the control of the enantioselectivity.
imines as substrates, Skrydstrup found some sulfinimine
substrates with α-protons to be tolerated under the addition
conditions.12
Fifteen years ago, we reported an enantioselective
Meerwein−Ponndorf−Verley (MPV)-type reduction of acylsi-
lanes13 by chiral lithium amide 2,14 in which hydride transfer
occurs enantioselectively from a stereogenic carbon atom
adjacent to a nitrogen atom of a chiral lithium amide to a
carbonyl carbon atom (1 → 3) (Scheme 1). The method was
recently applied to the enantioselective synthesis of silox-
INTRODUCTION
■
Introducing silicon into bioactive compounds has attracted
considerable interest in medicinal chemistry in view of
potentially induced changes in conformations, lipophilicity,
bonding property, and electronic nature.1 One of the major
applications for silicon-containing molecules is their use as a
carbon isostere, in which, for example, silicon-based amino
acids can act as an active tetrahedral intermediate of a protease
inhibitor.2,3 From that of point of view, enantioselective
synthesis of α-silylamines has recently attracted considerable
attention.4 Although there have been many reports5 on the
synthesis of racemic α-silylamines since the first preparation by
Speier and Sommer in 1951,6 only a few methods for
enantioselective synthesis of these compounds are available.
The first report of an enantioselective synthesis of α-silylamines
was by Tacke and Hengelsberg,7 who used enzymatic
hydrolysis of rac-N-acyl-α-silylamines, derived from alkylation
followed by amination of dimethylphenylsilylmethyl chloride.
The reaction of enantioenriched α,β-epoxysilanes with sodium
azide followed by LiAlH4 was used for the preparation of α-
silylamines bearing a β-hydroxy group by Bassindale and co-
workers.8 Picard and Fortis also reported the synthesis of an α-
silylamine by reduction of the corresponding α-silyliminium
chloride using lithium borohydride and diethyl tartrate.9
Although this method is applicable to aliphatic nonconjugated
silylamines, the yield (43%) and enantioselectivity (60% ee) are
moderate. A retro aza-Brook rearrangement (N to C) in Boc-
protected N-silyl allyl, benzyl, or propargylamines in the
presence of (−)-sparteine provides the corresponding α-
silylamines in >90% ee as reported by Sieburth.10 Scheidt and
co-workers reported the synthesis of α-silylamines by the
addition of silyl anions to chiral tert-butanesulfinimines.11
Although this method was originally limited to non-enolizable
Scheme 1. Enantioselective Reduction of Acylsilane Using
Chiral Lithium Amide
Received: February 24, 2014
Published: March 30, 2014
© 2014 American Chemical Society
3601
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
Table 1. Syntheses of N-Tosylimine
a
entry
6
R
SiR3
time
yield (%)
1
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
Ph
SiMe3
1 h
67
74
57
56
97
83
55
79
73
46
62
71
2
SiMe2But
SiMe2Ph
SiMePh2
SiMe2But
SiMe2But
SiMe2But
SiMe2But
SiMe2But
SiMe2But
SiMe2But
SiMe2But
2 h then reflux 2.5 h
7 h
3
4
38 h then reflux 3 h
reflux 7 h
5
TMSCC-
6
PhCC-
14 h then reflux 8 h
b
7
6g
6h
6i
Ph(CH2)3CC-
TMSCHCH-
tBuCHCH-
reflux 8 h
8
2 h
9
3 h
10
11
12
6j
PhCHCH-
4 h
6k
6l
3-MeOC6H4CHCH-
2-ClC6H4CHCH-
21 h
3.5 h
a
b
NMR spectroscopies indicated the presence of only one isomer in every case, double-bond geometries of which were not determined. The
reaction was performed using TsNH2 (4.0 equiv) and Ti(OEt)4 (4.0 equiv) in THF.
yallenes 4 in combination with a Brook rearrangement.15 We
envisaged this chemistry could be applicable to the
enantioselective preparation of α-silylamines using α-silylimines
that are readily available from the corresponding acylsilanes.
Enantioslelective MPV-type reduction of α-silylimines is
unprecedented, although there is one example for ketimines
using (BINOL)AlIII/2-propanol.16,17
The best result was obtained with lithium amide 2 as in the case
of acylsilanes, suggesting an important role of the nitrogen
atom of piperazine. The absolute configurations of 7a−d were
determined on the basis of X-ray analysis of 7a. The fact that
benzaldehyde was obtained with 9 suggests that not the
methyne hydrogen on the stereogenic carbon atom but the
methylene hydrogen was used for hydride transfer. The inverse
addition of the imine to a solution of 2 resulted in lowering the
chemical yield and enantioselectivity (entry 4). The use of THF
as a solvent is crucial to the success of the reaction; toluene and
Et2O resulted in recovered starting material and racemization,
respectively (entries 5 and 6). The reaction proceeded with
high selectivity even at 0 °C, and lowering the reaction
temperature to −100 °C led to improvement in enantiose-
lectivity to 99:1 but at the expense of chemical yield (entries 7
and 8). A prolonged reaction time or the use of additional
amounts of lithium amide 2 (2.4 equiv) at −100 °C did not
improve the chemical yield (entries 9 and 10). Occurrence of
significant racemization with an excess amount of 2 (entries 4
and 10) indicates the possibility of deprotonation of 7a by the
base. Also, the possibility of intra- and/or intermolecular
proton transfer from an α-silyl carbon atom to a nitrogen atom
before quenching, leading to an α-silyl benzyl carbanion, cannot
be ruled out. However, the fact that enantioenriched 7a (er =
99:1) did not racemize upon treatment with 2 at −80 °C makes
these possibilities unlikely (Scheme 2). While TBS derivative
6b gave the product with same enantiomeric ratio as that in the
case of 6a, introduction of a phenyl group on the silyl group
caused a decline in enantioselectivity. This may reflect a change
in E/Z geometry of the imine moiety (vide infra) (Table 3,
entries 11−13). Another possibility for the partial racemization
is that the resulting lithium amide 7a′ acts as a nonselective
reducing agent. To test the feasibility of the process,
dimethylphenylsilyl derivative 6c was treated with 7a′, which
was generated from 7a by deprotonation. In this reaction and
the reaction using the opposite combination of trimethylsilyl
and dimethylphenylsilyl groups, hydride transfer was not
observed. Consequently, a decrease in enantioselectivity with
an excess amount of a base might be due to other factors such
as a nonselective hydride transfer from aggregated species.
RESULTS AND DISCUSSION
■
On application of the MPV-type reduction for acylsilanes to
imines, several issues were recognized: (1) less electrophilic
reactivity of silylimines in comparison with silylketones and (2)
possibility of the occurrence of an aza-Brook rearrangement18
in the reduction product before quenching. Taking into account
the electron-withdrawing nature of a sulfonyl group capable of
stabilizing the developing anion in the hydride transfer and
convenient availability of starting materials, we chose N-
tosylsilylimine 6 as a substrate, which can be prepared by the
reaction of acylsilanes with tosylamine in the presence of
triethylamine and TiCl4 (Table 1).
At the outset, we examined the feasibility of hydride transfer
to 6a from LDA14,19 and found that the reaction can proceed
over a wide range of temperatures with no products resulting
from an aza-Brook rearrangement being detected (Table 2).
Having demonstrated the possibility of the desired MPV-type
reduction of an N-tosylsilylimine, we then proceeded to
examine enantioselective variants using enantioenriched
known lithium amides including 2 (Table 3, entries 1−3).
Table 2. Reduction of N-Tosylimine Using LDA
entry
T (°C)
yield (%)
1
2
3
4
0
−40
−80
54
66
73
a
−100
17
a
54% of starting material was recovered.
3602
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
Table 3. Reduction of N-tosylimines Using Chiral Lihium Amide
entry
2, 8−10
6
SiR3
T (°C)
solvent
yield (%)
0
er
sm (%)
1
2
3
8
9
2
2
2
2
2
2
2
2
2
2
2
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
SiMe3
−80
−80
−80
−80
−80
−80
0
THF
THF
THF
THF
toluene
Et2O
THF
THF
THF
THF
THF
THF
THF
b
SiMe3
65
50:50
93:7
SiMe3
76
50
0
7
36
78
69
c
4
SiMe3
82:18
5
SiMe3
6
SiMe3
7
48:52
97:3
7
SiMe3
65
58
53
59
68
71
53
8
SiMe3
−100
−100
−100
−80
−80
−80
99:1
28
19
29
9
SiMe3
93:7
10
11
12
13
SiMe3
78:22
92:8
SiMe2But
SiMe2Ph
SiMePh2
75:25
84:16
15
a
All reactions were performed using 1.2 equiv of lithium amide except for entry 10 (2.4 equiv) and for 30 min except for entry 9 (180 min).
Benzaldehyde (21%) was obtained as a byproduct. Inverse addition of 6a to a cooled solution of 2.
b
c
Scheme 2. Possibility for Partial Racemization via Deprotonation of 7 by 2 or Reduction of 6 by Reduction Product 7′
The same type of hydride transfer reaction can be applied to
α,β-unsaturated imines 6e−l to give the corresponding amines
7e−l in good to excellent enantioselectivity (Table 4). The
absolute configurations of 7e−l were determined on the basis
of X-ray analysis of 7e. In the case of β-aryl-substituted
derivatives, enamine 10, a product that can arise from the
above-mentioned proton transfer followed by an allylic and
then a C-to-N lithio migration, was formed as a byproduct.
Regarding the enantioselectivity observed in the MPV-type
reduction of a carbonyl group by chiral lithium amides, we have
previously rationalized this by invoking a model of a chairlike
six-membered transition state (early transition state), in which
the silyl and the chelated piperazinylmethyl groups occupy an
axial position.14 The results obtained with 6a−d and 6e−l,
however, were inconsistent with those expected from the model
as shown in Scheme 3. Thus, the axial/equatorial preference of
the silyl group is reversed between chairlike transition states
11a and 11e, leading to (S)-7a and (R)-7e, respectively. The
results indicate that in the chairlike model, phenyl and tert-
butyldimethylsilyl groups must each occupy an axial position,
respectively. Considering results showing that the extents of the
enantioselectivities observed with 7a,b and 7e−l are almost the
same despite differences in the relative sizes of the two
substituents in the imine carbon atom (Ph vs SiMe3 and RC
C vs TBS), the chairlike model does not seem appropriate.
Also, a distinct structural difference between N-tosyl imines and
acylsilanes or ketones that potentially affects the enantiose-
lectivity should be the presence of E/Z geometry concerning
the N-tosyl group in imines. The geometries of E- and Z-6a and
6e were optimized at the B3LYP level with the 6-31G(d) basis
set, and it was found that E-isomers were more stable than the
Z-isomer (6a, 0.54 kcal/mol; 6e, 3.81 kcal/mol). There have
been some reports20,21 suggesting that N-sulfonylimines are
configurationally unstable even at low temperatures, and in fact,
there was no peak separation in each case when 1H NMR of 6a
and that of 6e were measured at room temperature. The fact
Table 4. Reduction of N-Tosylimines Using Chiral Lihium
Amide 2
7
10
6
yield
(%)
yield
(%)
yield
(%)
entry
6
R
er
1
2
3
4
5
6
7
8
6e
6f
TMSCC-
91
84
58
90
77
67
60
27
88:12
91:9
97:3
99:1
99:1
99:1
97:3
97:3
PhCC-
6g
6h
6i
Ph(CH2)3CC-
TMSCHCH-
tBuCHCH-
6j
PhCHCH-
22
18
31
6k
6l
3-MeOC6H4CHCH-
2-ClC6H4CHCH-
20
3603
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
Scheme 3. Chair-Like Six-Membered Transition State Models of the Reduction
Table 5. B3LYP/6-31G* Optimized Geometries of Transition-State Structures of Reduction of 12 and Their relative Energies
TS-A
TS-B
TS-C
TS-D
G°298 (au)
−2389.049 91
−2389.040 30
−2389.039 51
−2389.044 92
G°rel (kcal/mol)
0.0
6.0
6.5
3.1
that the degree of enantioselectivity is not affected by the
reaction temperature (Table 3, entries 3, 7, and 8) also
indicates that the configuration of N-tosylimine in the ground
state is not an important factor to control the enantioselectivity.
To obtain information on the origin of the observed
enantioselectivities, we performed density functional theory
(DFT) calculations on transition states leading to (S)-7a and
(R)-7a using a N-phenylsulfonyl derivative 12 as a model
system, assuming that the reduction proceeds by a concerted
hydride transfer in a six-membered ring transition state.22 Two
transition structures for each, corresponding to the (Z)- and
(E)-imines in a ground state, TS-A−TS-D, were located at a
B3LYP/6-31+G* level. These calculations account for the
enantioselectivity observed by showing that TS-A leading to
(S)-7a is the most stable (Table 5).23 The fact that the
conformation of the imine in the most stable TS-A is Z suggests
that E-to-Z isomerization can occur under the reaction
conditions. Apparent differences between the calculated
structures and the previously proposed ones in Scheme 3 are
deformation from a chairlike six-membered ring in which the
lithium atom coordinates to the sulfone oxygen atom rather
than the imine nitrogen and increase in the double-bond
character of the C1-nitrogen bond. The latter is likely to be a
major factor in determining the enantioselectivity because it
causes a steric interaction between the 1′-methylene group and
the imine-carbon substituents. Thus, the selectivity results from
a balance of steric repulsions of the imine carbon substituents
with C2 and C1′.
A similar analysis can be applied to 6e (N-phenylsulfonyl
derivative 13), in which the two substituents on the imine
carbon atom are different in their bulkiness in comparison with
those for 6a (Table 6). Thus, in TS-C leading to 7e, calculated
to be the most stable, a much bulkier TBS group is preferably
disposed at a position to avoid steric repulsions with 1′-
methylene and the Ts group occupies the same side as the
much less bulky silylethynyl group.
3604
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
Table 6. B3LYP/6-31G* Optimized Geometries of Transition-State Structures of Reduction of 13 and Their Relative Energies
TS-A
TS-B
TS-C
TS-D
G°298 (au)
−2360.649 46
−2360.651 12
−2360.662 81
−2360.660 27
G°rel (kcal/mol)
8.4
7.3
0.0
1.6
experiments. Mass spectra (HRMS) were obtained on an Orbitrap
mass spectrometer.
CONCLUSION
■
Preparation of Acylsilanes. Compounds 5a,24 5b,25 5c,26 5e,27
5f,28 5g,15 5h,29 5i,30 5j,31 and 5k32 were prepared according to
literature procedures.
We have developed a new and efficient method for the
enantioselective formation of α-silylamine by Meerwein−
Ponndorf−Verley-type reduction of N-tosylsilylimines with
lithium amide 2. A rationale for the excellent enantioselectivity
of the hydride transfer was offered on the basis of analysis of
transition state models obtained from DFT calculations.
Diphenylmethylbenzoylsilane (5d).31 To a cooled (−80 °C)
solution of 2-phenyl-1,3-dithiane (934 mg, 4.76 mmol) in THF (20
mL) was added a solution of n-BuLi (1.83 M in hexane, 2.86 mL, 5.23
mmol). After 2 h of stirring at the same temperature, a solution of
Ph2MeSiCl (1.2 mL, 1.33 g, 5.71 mmol) in THF (6 mL) was added.
After being allowed to warm to 0 °C over 30 min, the reaction mixture
was diluted with saturated aqueous NH4Cl solution (30 mL) and
extracted with Et2O (30 mL × 3). The combined organic phases were
washed with saturated brine (30 mL), dried, and concentrated. The
residual oil was subjected to column chromatography (silica gel, 50 g;
elution with hexane/CH2Cl2 = 4:1) to give methyldiphenyl(2-phenyl-
1,3-dithian-2-yl)silane (1.77 g, 95%). To a cooled (ice−water) solution
of the above compound (807 mg, 2.06 mmol) in acetone (21 mL) and
H2O (630 μL) was added NBS (1.83 g, 10.3 mmol). After being
stirred at room temperature for 30 min, the reaction mixture was
diluted with 15% aqueous Na2S2O3 (10 mL) and extracted with Et2O
(30 mL × 3). The combined organic phases were washed with H2O
(30 mL × 3) and saturated brine (30 mL), dried, and concentrated.
The residual oil was subjected to column chromatography (silica gel,
10 g; elution with hexane/Et2O = 20:1) to give 5d (164 mg, 26%).
1-(tert-Butyldimethylsilyl)-3-(trimethylsilyl)prop-2-yn-1-one
(5e). To a cooled (ice−water) solution of 1-(tert-butyldimethylsilyl)-3-
EXPERIMENTAL SECTION
■
General Methods. All moisture-sensitive reactions were per-
formed under a positive pressure of nitrogen. Anhydrous MgSO4 was
used for drying all organic solvent extracts in work-up unless otherwise
indicated, and removal of the solvents was performed with a rotary
evaporator. Dry solvents and reagents were obtained by using standard
procedures. Thin-layer chromatography was performed on precoated
glass-backed silica gel 60 F-254 plates. For routine chromatography,
the following adsorbents were used: silica gel 60N of particle size 63-
210 μm or 40−50 μm. Liquid chromatography under medium
pressures (MPLC) was carried out using prepacked columns (22 mm
× 100 mm (5 μm silica gel) or 22 mm × 300 mm (10 μm silica gel)).
1H NMR spectra (500 MHz) were taken in CDCl3 with reference to
CHCl3 (δ 7.26). 13C NMR spectra (125 MHz) were measured in
1
CDCl3 with reference to CHCl3 (δ 77.2). The assignment of H and
13C NMR spectra was based on H−H decoupling and HMQC
3605
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
(trimethylsilyl)prop-2-yn-1-ol32 (568 mg, 2.34 mmol) in acetone (9.4
mL) was added Jones reagent (1.94 M, 1.45 mL, 2.81 mmol). After 10
min of stirring at the same temperature, i-PrOH (1 mL) was added to
the reaction mixture, which was diluted with saturated aqueous
NaHCO3 solution (10 mL) and extracted with Et2O (10 mL × 3).
The combined organic phases were washed with H2O (10 mL × 3)
and saturated brine (10 mL), dried, and concentrated. The residual oil
was subjected to column chromatography (silica gel, 20 g, elution with
hexane/Et2O = 30:1) to give 5e (479 mg, 85%) as an orange oil. Rf =
0.52 (hexane/Et2O = 3:1); IR (NaCl) 2953, 2931, 2889, 2858, 1637,
1581 cm−1; 1H NMR (CDCl3) δ 0.34 (6H, s), 0.98 (9H, s), 6.84 (1H,
d, J = 16.5 Hz), 7.28−7.34 (2H, m), 7.43 (1H, dd, J = 7.8, 1.2 Hz),
7.65 (1H, dd, J = 7.6 Hz, 2.1), 7.88 (1H, d, J = 16.5 Hz); 13C NMR
(CDCl3) δ −5.5, 16.9, 26.8, 127.3, 127.3, 130.3, 131.3, 133.3, 134.6,
135.6, 139.0, 236.1; HRMS-APCI (m/z) [M + H]+ calcd for
C15H21OClSi 281.1123, found 281.1126.
(CDCl3) δ 0.14 (6H, s), 0.90 (9H, s), 2.41 (3H, s), 7.18−7.20 (2H,
m), 7.24 (2H, d, J = 8.3 Hz), 7.35−7.39 (3H, m), 7.74 (2H, d, J = 8.3
Hz); 13C NMR (CDCl3) δ −5.8, 17.9, 21.7, 26.8, 125.1, 127.6, 128.2,
129.2, 129.4, 138.6, 140.8, 143.5, 205.3; HRMS-ESI (m/z) [M + Na]+
calcd for C20H27NO2SSi 396.1424, found 396.1427.
N-((Methyldiphenylsilyl)(phenyl)methylene)-p-toluenesulfo-
namide (6d). Pale yellow oil. 56% yield, 133 mg (from 164 mg of
5d); Rf = 0.44 (hexane/Et2O = 3:2); IR (NaCl) 3065, 3024, 2965,
2922, 1595, 1551 cm−1; 1H NMR (CDCl3) δ 0.74 (1H, brs), 2.42 (3H,
s), 7.07 (2H, d, J = 7.4 Hz), 7.21−7.26 (4H, m), 7.28−7.35 (5H, m),
7.40−7.44 (2H, m), 7.48 (4H, d, J = 7.1 Hz), 7.72 (2H, d, J = 8.2 Hz);
13C NMR (CDCl3) δ −4.1, 21.7, 125.9, 127.7, 128.0, 128.2, 129.5,
129.6, 130.3, 132.5, 135.4, 138.3, 143.6, 202.0; HRMS-ESI (m/z) [M
+ Na]+ calcd for C27H25NO2SSi 478.1268, found 478.1267.
N-(1-(tert-Butyldimethylsilyl)-3-(trimethylsilyl)prop-2-yn-1-
ylidene)-p-toluenesulfonamide (6e). Off-white plates (CH2Cl2/
hexane). 97% yield, 852 mg (from 538 mg of 5e); mp = 65.0−66.0 °C;
Rf = 0.34 (hexane/Et2O = 3:1); IR (KBr) 2967, 2930, 2897, 2859,
1596, 1555; 1H NMR (CDCl3) d 0.22 (s, 6H), 0.24 (9H, s), 0.91 (9H,
s), 2.43 (3H, s), 7.29 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz); 13C
NMR (CDCl3) δ −6.7, −0.7, 17.9, 21.8, 26.6, 100.5, 128.1, 128.3,
129.5, 137.1, 144.0, 184.6; HRMS-ESI (m/z) [M + Na]+ calcd for
C19H31NO2SSi2 416.1506, found 416.1500.
(E)-1-(tert-Butyldimethylsilyl)-3-(2-chlorophenyl)prop-2-en-
1-one (5l). To a cooled (ice−water) suspension of NaH (60%, 157
mg, 3.91 mmol) in THF (14 mL) was added a solution of HWE
reagent (1.14 g, 4.27 mmol) in THF (13 mL). The reaction mixture
was allowed to warm to room temperature and was stirred for 10 min.
The mixture was cooled to 0 °C, and then 2-chlorobenzaldehyde (0.40
mL, 3.56 mmol) was added. After being stirred at room temparature
for 1.5 h, the reaction mixture was diluted with saturated aqueous
NH4Cl solution (30 mL) and extracted with Et2O (30 mL × 3). The
combined organic phases were washed with saturated brine (30 mL),
dried, and concentrated. The residual oil was subjected to column
chromatography (silica gel, 50 g; elution with hexane/AcOEt = 15:1)
to give 5l (957 mg, 96%) as an orange oil. Rf = 0.52 (hexane/Et2O =
N-(1-(tert-Butyldimethylsilyl)-3-phenylprop-2-yn-1-ylidene)-
p-toluenesulfonamide (6f). Pale yellow needles (CH2Cl2/hexane).
83% yield, 366 mg (from 270 mg of 5f); mp = 70.5−71.0 °C; Rf = 0.50
(hexane/Et2O = 2:1); IR (KBr) 2948, 2929, 2897, 2855, 2170, 1509
1
cm−1; H NMR (CDCl3) δ 0.30 (6H, s), 0.96 (9H, s), 2.41 (3H, s),
7.30 (2H, d, J = 8.3 Hz), 7.41 (2H, dd, J = 7.7, 7.7 Hz), 7.47 (1H, tt,
7.7, 1.2 Hz), 7.57 (2H, dd, J = 7.7, 1.2 Hz), 7.90 (1H, d, J = 8.3 Hz);
13C NMR (CDCl3) δ −6.6, 18.0, 21.8, 26.6, 87.7, 118.3, 121.2, 128.1,
1
3:1); IR (NaCl) 2953, 2931, 2889, 2858, 1637, 1581 cm−1; H NMR
(CDCl3) δ 0.34 (6H, s), 0.98 (9H, s), 6.84 (1H, d, J = 16.5 Hz), 7.28−
7.34 (2H, m), 7.43 (1H, dd, J = 7.8, 1.2 Hz), 7.65 (1H, dd, J = 7.6 Hz,
2.1), 7.88 (1H, d, J = 16.5 Hz); 13C NMR (CDCl3) δ −5.5, 16.9, 26.8,
127.3, 127.3, 130.3, 131.3, 133.3, 134.6, 135.6, 139.0, 236.1; HRMS-
APCI (m/z) [M + H]+ calcd for C15H21OClSi 281.1123, found
281.1126.
128.8, 129.6, 131.3, 133.0, 137.3, 144.0, 183.5; HRMS-ESI (m/z) [M
+ Na]+ calcd for C22H27NO2SSi 420.1424, found 420.1421.
N-(1-(tert-Butyldimethylsilyl)-6-phenylhex-2-yn-1-ylidene)-
p-toluenesulfonamide (6g). Pale yellow oil. Rf = 0.29 (hexane/
Et2O = 5:1); IR (NaCl) 3061, 3027, 2952, 2931, 2893, 2859, 2189,
1600, 1515 cm−1; 1H NMR (CDCl3) δ 0.24 (6H, s), 0.94 (9H, s), 1.93
(2H, tt, J = 7.1. 7.6 Hz), 2.41 (3H, s), 2.57 (2H, t, J = 7.1 Hz), 2.77
(2H, t, J = 7.6 Hz), 7.19−7.22 (3H, m), 7.28−7.32 (4H, m), 7.86 (2H,
d, J = 8.3 Hz); 13C NMR (CDCl3) δ −6.7, 17.7, 20.2, 21.7, 26.5, 29.6,
34.9, 80.6, 122.1, 126.2, 127.9, 128.6, 128.7, 129.4, 137.6, 141.1, 143.7;
HRMS-ESI (m/z) [M + Na]+ calcd for C25H33NO2SSi 462.1894
found 462.1894.
Representative Procedure for the Preparation of N-
Silylimine (6i). To a cooled solution of acylsilane (325 mg, 1.44
mmol), TsNH2 (294 mg, 1.72 mmol), and Et3N (881 μL, 6.32 mmol)
in CH2Cl2 (7.2 mL) was added TiCl4 (1.0 M in CH2Cl2, 1.44 mL, 1.44
mmol). After 3 h of stirring at room temperature, saturated aqueous
NaHCO3 (10 mL) was added. The mixture was filtered through a plug
of Celite, and the filtrate was extracted with CH2Cl2 (20 mL × 2). The
combined organic phases were washed with H2O (10 mL) and
saturated brine (10 mL), dried, and concentrated. The residual oil was
subjected to column chromatography (silica gel, 30 g; elution with
hexane/CH2Cl2/Et2O = 40:20:1) to give 6i (397 mg, 73%).
Preparation of N-Silylimine (6g). To a solution of asylsilane
(493 mg, 1.72 mmol) and TsNH2 (1.18 g, 6.88 mmol) in THF (5.7
mL) was added Ti(OEt)4 (1.44 mL, 1.57 g, 6.88 mmol). The mixture
was heated to reflux for 8 h. After cooling to room temperature,
saturated aqueous NaHCO3 (10 mL) was added. The mixture was
filtered through a plug of Celite, and the filtrate was extracted with
AcOEt (10 mL × 2). The combined organic phases were dried and
concentrated. After the residue was passed through a pad of silica gel
eluting with hexane/CH2Cl2/Et2O = 5:5:1, the residual oil was
subjected to column chromatography (silica gel, 30 g; elution with
hexane/Et2O = 5:1) to give 6g (419 mg, 55%)
N-(2E)-1-(tert-Butyldimethylsilyl)-3-(trimethylsilyl)-
allylidene)-p-toluenesulfonamide (6h). Orange oil. 79% yield, 877
mg (from 682 mg of 5h); Rf = 0.47 (hexane/Et2O = 5:1); IR (NaCl)
1
2956, 2931, 2894, 2859, 1599, 1515; H NMR (CDCl3) δ 0.17 (9H,
s), 0.21 (6H, s), 0.89 (9H, s), 2.43 (3H, s), 6.64 (1H, d, J = 19.5 Hz),
7.56 (1H, d, J = 19.5 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3
Hz); 13C NMR (CDCl3) δ −4.3, −1.7, 17.6, 21.7, 26.9, 127.3, 129.5,
139.2, 142.2, 143.4, 149.8, 199.8; HRMS-ESI (m/z); [M + Na]+ calcd
for C19H33NO2SSi2 418.1663, found 418.1659.
N-((E)-1-(tert-Butyldimethylsilyl)-4,4-dimethylpent-2-en-1-
ylidene)-p-toluenesulfonamide (6i). Pale yellow oil. Rf = 0.28
(hexane/Et2O = 8:1); IR (NaCl) 2959, 2932, 2860, 1623, 1513 cm−1;
1H NMR (CDCl3) d 0.23 (6H, s), 0.89 (9H, s), 1.12 (9H, s), 6.58
(1H, d, J = 16.1 Hz), 7.24 (1H, d, J = 16.1 Hz), 7.29 (2H, d, J = 8.3
Hz), 7.84 (2H, d, J = 8.3 Hz); 13C NMR (CDCl3) d −3.8, 17.5, 21.7,
27.0, 28.7, 35.0, 126.3, 127.2, 129.5, 139.5, 143.2, 162.2, 198.7; HRMS-
ESI (m/z) [M + Na]+ calcd for C20H33NO2SSi 402.1894, found
402.1898.
N-(Phenyl(trimethylsilyl)methylene)-p-toluenesulfonamide
(6a). Colorless needles (CH2Cl2/hexane). 67% yield, 2.45 g (from
1.99 g of 5a); mp = 112.0−113.0 °C; Rf = 0.43 (hexane/AcOEt = 5:1);
1
IR (KBr) 3358, 3260, 2965, 1740, 1550 cm−1; H NMR (CDCl3) δ
N-((E)-1-(tert-Butyldimethylsilyl)-3-phenylallylidene)-p-tol-
uenesulfonamide (6j). Pale yellow needles (CH2Cl2/hexane). 46%
yield, 512 mg (from 687 mg of 5j); mp = 105.0−105.5 °C; Rf = 0.39
(hexane/Et2O = 3:1); IR (KBr) 2952, 2928, 2887, 2857, 1613 cm−1;
1H NMR (CDCl3) δ 0.32 (6H, s), 0.94 (9H, s), 2.43 (3H, s), 7.29−
7.34 (3H, m), 7.41−7.42 (3H, m), 7.58−7.59 (2H, m), 8.07 (1H, d, J
= 16.3 Hz); 13C NMR (CDCl3) δ −3.7, 17.7, 21.7, 27.0, 127.1, 127.6,
128.7, 129.2, 129.5, 131.1, 135.0, 139.3, 143.3, 147.3, 197.1; HRMS-
0.07−0.41 (9H, brs), 2.40 (3H, s), 7.14−7.29 (4H, brm), 7.33−7.29
(3H, m), 7.71−7.82 (2H, br); 13C NMR (CDCl3) δ −2.2 (br), 21.7,
125.0 (br), 127.7, 128.2, 129.2−129.8 (br), 205.8; HRMS-ESI (m/z)
[M + Na]+ calcd for C17H21NO2SSi 354.0955, found 354.0957.
N-(Phenyl(trimethylsilyl)methylene)-p-toluenesulfonamide
(6b). Colorless needles (CH2Cl2/hexane). 74% yield, 634 mg (from
508 mg of 5b); mp = 69.5−70.0 °C; Rf = 0.48 (hexane/AcOEt = 5:1);
IR (KBr) 3055, 2959, 2927, 2890, 2856, 1597, 1548; 1H NMR
3606
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
ESI (m/z) [M + Na]+ calcd for C22H29NO2SSi 422.1581, found
422.1583.
(3H, s), 0.27 (3H, s), 2.29 (3H, s), 4.14 (1H, d, J = 8.3 Hz), 5.26−5.29
(1H, m), 6.72−6.73 (2H, m), 6.96 (2H, d, J = 8.1 Hz), 6.99−7.02
(3H, m), 7.28−7.31 (4H, m), 7.37−7.42 (1H, m), 7.41 (2H, d, J = 8.1
Hz); 13C NMR (CDCl3) δ −5.6, −4.8, 21.5, 49.9, 125.6, 126.5, 127.3,
127.9, 128.1, 129.1, 130.0, 134.1, 134.5, 137.4, 138.9, 142.8 ; HRMS-
ESI (m/z) [M + Na]+ calcd for C22H25NO2SSi 418.1268, found
418.1261.
N-((E)-1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)-
allylidene)-p-toluenesulfonamide (6k). Yellow prisms (CH2Cl2/
hexane). 62% yield, 462 mg (from 482 mg of 5k); mp = 90.0−91.0 °C;
Rf = 0.30 (hexane/Et2O = 3:1); IR (KBr) 2958, 2926, 2857, 1615,
1588 cm−1; 1H NMR (CDCl3) δ 0.32 (6H, s), 0.94 (9H, s), 2.40 (3H,
s), 3.83 (3H, s), 6.95 (1H, dd, J = 8.3, 1.6 Hz), 7.08 (1H, brs), 7.17
(1H, d, J = 7.6 Hz), 7.29−7.32 (4H, m), 7.88 (2H, d, J = 8.2 Hz), 8.05
(1H, d, J = 16.3 Hz); 13C NMR (CDCl3) δ −3.9, 17.6, 21.6, 26.9, 55.4,
113.3, 116.8, 121.3, 127.0, 127.7, 129.4, 130.1, 136.3, 139.2, 143.3,
147.0, 160.1, 197.0; HRMS-ESI (m/z) [M + Na]+ calcd for
C23H31NO3SSi 452.1686, found 452.1687.
N-((E)-1-(tert-Butyldimethylsilyl)-3-(2-chlorophenyl)-
allylidene)-p-toluenesulfonamide (6l). Yellow prisms (CH2Cl2/
hexane). 71% yield, 662 mg (from 606 mg of 5l); mp = 113.0−114.0
°C; Rf = 0.33 (hexane/Et2O = 3:1); IR (KBr) 2952, 2926, 2885, 2853,
1611, 1503 cm−1; 1H NMR (CDCl3) δ 0.35 (6H, s), 0.95 (9H, s), 2.41
(3H, s), 7.29−7.33 (4H, m), 7.39−7.43 (1H, m), 7.78 (1H, d, J = 16.3
Hz), 7.78−7.80 (1H, m), 7.89 (2H, d, J = 8.0 Hz), 8.07 (1H, d, J =
16.3 Hz); 13C NMR (CDCl3) δ −4.0, 17.6, 21.7, 26.9, 127.1, 127.5,
127.9, 129.1, 129.5, 130.1, 131.7, 133.1, 135.4, 139.1, 142.4, 143.4,
197.2; HRMS-ESI (m/z) [M + Na]+ calcd for C22H28NO2ClSSi
456.1191, found 456.1190.
Representative Procedure for the Reduction of N-Silylimine
(6b). To a cooled (−80 °C) solution of 6b (92.7 mg, 0.248 mmol) in
THF (1.2 mL) was added dropwise a solution of chiral lithium amide
generated from (S)-2,2-dimethyl-N-(2-(4-methylpiperazin-1-yl)-1-
phenylethyl)propan-1-amine (83.4 mg, 0.288 mmol) and n-BuLi
(1.97 M in n-hexane, 151 μL, 0.298 mmol) in THF (1.1 mL) at 0 °C.
The reaction mixture was stirred at the same temperature for 30 min
before the addition of a solution of AcOH (0.5 M in THF, 0.600
mmol). The mixture was diluted with hydrochloric acid (1%, 10 mL)
and extracted with AcOEt (10 mL × 3). The combined organic phases
were successively washed with saturated aqueous NaHCO3 solution (5
mL) and saturated brine (5 mL), dried, and concentrated. The residual
oil was subjected to flash column chromatography (silica gel, 7 g,
elution with hexane/CH2Cl2/Et2O = 20:20:1) to give 7b (54.1 mg,
68%).
N-((Methyldiphenylsilyl)(phenyl)methyl)-p-toluenesulfona-
mide (7d). White prisms (CH2Cl2/hexane). 53% yield, 39 mg (from
73 mg of 6d); mp = 174.0−175.0 °C; Rf = 0.34 (hexane/Et2O = 3:2);
[α]27D −23.8 (c 0.72, CHCl3) (er = 84:16); Chiralpak AD-H (25 cm),
hexane/i-PrOH = 15:1, flow rate 1.00 mL/min, detection at 254 nm,
tR = 10.3 min (major) and 15.8 min (minor), er = 84:16; IR (KBr)
1
3266, 3063, 3022, 2957, 2918, 1597 cm−1; H NMR (CDCl3) δ 0.39
(3H, s), 2.29 (3H, s), 4.57 (1H, d, J = 8.0 Hz), 4.79 (1H, d, J = 8.0
Hz), 6.65 (2H, d, J = 6.7 Hz), 6.94−7.00 (5H, m), 7.30−7.47 (12H,
m); 13C NMR (CDCl3) δ −5.6, 21.5, 48.5, 125.9, 126.9, 127.5, 127.9,
128.2, 128.4, 129.2, 130.2, 130.5, 132.1, 133.0, 135.2, 135.6, 137.5,
138.5, 143.0; HRMS-ESI (m/z) [M + Na]+ calcd for C27H27NO2SSi
480.1424, found 480.1424.
N-(1-(tert-Butyldimethylsilyl)-3-(trimethylsilyl)prop-2-yn-1-
yl)-p-toluenesulfonamide (7e). Colorless plates (CH2Cl2/hexane).
91% yield, 72 mg (from 85 mg of 6e); mp = 161.0−161.5 °C; Rf =
0.50 (hexane/Et2O = 2:1); [α]26D +70.9 (c 1.03, CHCl3) (er = 95:5);
Chiralpak AS-3 (25 cm), hexane/i-PrOH/EtOH = 30:1:1, flow rate
0.40 mL/min, detection at 254 nm, tR = 11.4 min (major) and 13.6
min (minor), er = 95:5; IR (KBr) 3279, 2955, 2935, 2861, 2161, 1734,
1
1600 cm−1; H NMR (CDCl3) δ −0.08 (9H, s), 0.09 (3H, s), 0.11
(3H, s), 0.99 (9H, s), 2.42 (3H, s), 3.80 (1H, d, J = 10.5 Hz), 4.15
(1H, d, J = 10.5 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.1
Hz); 13C NMR (CDCl3) δ −8.0,, −7.5, −0.2, 17.6, 21.7, 27.0, 35.3,
90.3, 103.6, 128.1, 129.7, 137.6, 143.5; HRMS-ESI (m/z) [M + Na]+
calcd for C19H33NO2SSi2 418.1663, found 418.1656.
N-(1-(tert-Butyldimethylsilyl)-3-phenylprop-2-yn-1-yl)-p-tol-
uenesulfonamide (7f). Colorless needles (CH2Cl2/hexane). 84%
yield, 65 mg (from 84 mg of 6f); mp = 135.0−136.0 °C; Rf = 0.44
(hexane/Et2O = 2:1); [α]26 +118.8 (c 1.08, CHCl3) (er = 90:10);
D
Chiralcel OD-H (25 cm), hexane/i-PrOH = 12:1, flow rate 1.00 mL/
min, detection at 254 nm, tR = 5.46 min (minor) and 7.29 min
(major), er = 90:10; IR (KBr) 3290, 3060, 2926, 2853, 1599 cm−1; 1H
NMR (CDCl3) δ 0.15 (3H, s), 0.17 (3H, s), 1.03 (9H, s), 2.31 (3H, s),
4.01 (1H, d, J = 10.7 Hz), 4.27 (1H, d, J = 10.7 Hz), 6.93 (2H, d, J =
8.3 Hz), 7.17−7.25 (5H, m), 7.84 (2H, d, J = 8.3 Hz); 13C NMR
(CDCl3) δ −7.9, −7.3, 17.6, 21.6, 27.0, 34.8, 85.6, 87.2, 123.2, 128.1,
129.7, 129.7, 131.4, 131.4, 137.7, 143.7 ; HRMS-ESI (m/z) [M + Na]+
calcd for C22H29NO2SSi 422.1581, found 422.1574.
N-(Phenyl(trimethylsilyl)methyl)-p-toluenesulfonamide (7a).
Colorless needles (CH2Cl2/hexane). 58% yield, 38 mg (from 73 mg of
6a); mp = 170−171 °C; Rf = 0.34 (hexane/AcOEt = 5:1); [α]27
D
−60.0 (c 0.35, CHCl3); Chiralcel OD-H (25 cm), hexane/i-PrOH =
10:1, flow rate 1.0 mL/min, detection at 254 nm, tR = 7.91 min
(major) and 11.6 min (minor), er = >99:1; IR (KBr) 3284, 2964,
1598; 1H NMR (CDCl3) δ −0.02 (9H, s), 2.29 (3H, s), 3.97 (1H, d, J
= 8.4 Hz), 5.23 (1H, d, J = 8.4 Hz), 6.81 (2H, d, J = 7.1 Hz), 6.97−
7.05 (5H, m), 7.49 (2H, d, J = 8.2 Hz); 13C NMR (CDCl3) δ −3.7,
21.5, 50.4, 125.6, 126.3, 127.4, 128.1, 129.2, 137.7, 139.4, 143.0;
HRMS-ESI (m/z) [M + Na]+ calcd for C17H23O2NSSi 356.1111,
found 356.1114.
N-(1-(tert-Butyldimethylsilyl)-6-phenylhex-2-yn-1-yl)-p-tol-
uenesulfonamide (7g). Colorless prisms (CH2Cl2/hexane). 58%
yield, 43 mg (from 78 mg of 6g); mp = 82.5−83.5 °C; Rf = 0.50
(hexane/Et2O = 2:1); [α]25 +71.3 (c 1.08, CHCl3) (er = 97:3);
D
Chiralcel OD-H (25 cm), hexane/i-PrOH = 10:1, flow rate 1.0 mL/
min, detection at 254 nm, tR = 5.69 min (minor) and 9.38 min
(major), er = 97:3; IR (KBr) 3254, 2951, 2931, 2900, 2854, 1600
N-((tert-Butyldimethylsilyl)(phenyl)methyl)-p-toluenesulfo-
namide (7b). Colorless prisms (CH2Cl2/hexane); mp = 135.5−136.5
°C; Rf = 0.35 (hexane/AcOEt = 5:1); [α]26 −23.0 (c 1.02, CHCl3)
1
cm−1; H NMR (CDCl3) δ 0.08 (3H, s), 0.11 (3H, s), 0.99 (9H, s),
D
(er = 93:7); Chiralcel OD-H (25 cm), hexane/i-PrOH = 8:1, flow rate
1.00 mL/min, detection at 254 nm, tR = 5.99 min (major) and 7.22
min (minor), er = 93:7; IR (KBr) 3476, 3304, 2954, 2927, 2886, 2855,
1.49 (2H, tt, J = 7.2, 7.2 Hz), 1.82 (2H, td, J = 7.2, 2.3 Hz), 2.31 (3H,
s), 2.48 (2H, t, J = 7.2 Hz), 3.78 (1H, dd, J = 10.6, 2.3 Hz), 4.20 (1H,
d, J = 10.6 Hz), 7.09 (2H, d, J = 7.3 Hz), 7.18−7.29 (5H, m), 7.80
(2H, d, J = 8.3 Hz); 13C NMR (CDCl3) δ −8.0, −7.3, 17.4, 18.4, 21.6,
27.0, 30.3, 34.5, 35.0, 78.1, 85.6, 126.2, 128.1, 128.5, 129.4, 129.5,
137.9, 141,7, 143.3; HRMS-ESI (m/z) [M + Na]+ calcd for
C25H35NO2SSi 464.2050, found 464.2048.
1
1599 cm−1; H NMR (CDCl3) δ −0.29 (3H, s), 0.05 (3H, s), 0.90
(9H, s), 2.26 (3H, s), 4.19 (1H, d, J = 8.9 Hz), 4.98−5.05 (1H, brm),
6.78 (2H, d, J = 6.9 Hz), 6.92−7.00 (5H, m), 7.41 (2H, d, J = 8.0 Hz);
13C NMR (CDCl3) δ −8.5, −7.0, 17.5, 21.5, 26.9, 48.0, 125.6, 126.7,
127.4, 128.1, 129.1, 137.9, 139.9, 142.8; HRMS-ESI (m/z) [M + Na]+
calcd for C20H29NO2SSi 398.1581, found 398.1585.
(E)-N-(1-(tert-Butyldimethylsilyl)-3-(trimethylsilyl)allyl)-p-tol-
uenesulfonamide (7h). Colorless prisms (CH2Cl2/hexane). 90%
yield, 69 mg (from 79 mg of 6h); mp = 136.0−137.0 °C; Rf = 0.22
N-((Dimethyl(phenyl)silyl)(phenyl)methyl)-p-toluenesulfo-
namide (7c). Colorless needles (AcOEt/hexane). 71% yield, 41 mg
(from 66 mg of 6c); mp = 151.0−152.0 °C; Rf = 0.33 (hexane/AcOEt
(hexane/Et2O = 5:1); [α]24 +17.5 (c 1.03, CHCl3) (er = >99:1);
D
Chiralcel OD-H (25 + 25 cm), hexane/i-PrOH = 25:1, flow rate 0.30
mL/min, detection at 254 nm, tR = 34.7 min (minor) and 36.3 min
(major), er = >99:1; IR (KBr) 3296, 2958, 2930, 2859, 1600 cm−1; 1H
NMR (CDCl3) δ −0.19 (9H, s), −0.09 (3H, s), −0.02 (3H, s), 0.93
(9H, s), 2.37 (3H, s), 3.77−3.80 (1H, m), 4.84−4.89 (1H, brm), 5.19
= 4:1); [α]25 −25.9 (c 1.03, CHCl3) (er = 68:32); Chiralcel OD-H
D
(25 cm), hexane/i-PrOH = 10:1, flow rate 1.00 mL/min, detection at
254 nm, tR = 7.96 min (major) and 21.9 min (minor), er = 75:25; IR
1
(KBr) 3267, 3063, 3026, 2957, 1595 cm−1; H NMR (CDCl3) δ 0.24
3607
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
(1H, dd, J = 18.9, 1.2 Hz), 5.58 (1H, dd, J = 18.9, 6.7 Hz), 7.20 (2H, d,
J = 8.3 Hz), 7.71 (2H, d, J = 8.3 Hz); 13C NMR (CDCl3) δ −8.2, −7.2,
−1.3, 17.6, 21.6, 27.1, 49.2, 126.7, 127.7, 129.5, 138.6, 143.1, 143.3;
HRMS-ESI (m/z) [M + Na]+ calcd for C19H35NO2SSi2 420.1819,
found 420.1813.
3.38 (2H, d, J = 8.0 Hz), 5.56 (1H, s), 6.35 (1H, t, J = 8.0 Hz), 6.97
(2H, d, J = 7.4 Hz), 7.17−7.24 (5H, m), 7.67 (2H, d, J = 8.3 Hz); 13
C
NMR (CDCl3) δ −4.2, 18.1, 21.7, 26.8, 36.2, 126.2, 128.0, 128.3,
128.5, 129.4, 129.6, 133.5, 137.0, 140.3, 143.7; HRMS-ESI (m/z) [M
+ Na]+ calcd for C22H31NO2SSi 424.1737, found 424.1734.
N-(1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)prop-1-
en-1-yl)-p-toluenesulfonamide (10k). Colorless prisms (CH2Cl2/
hexane). 18% yield, 16 mg (from 89 mg of 6k); mp = 97.0−98.0 °C; Rf
= 0.28 (hexane/Et2O = 2:1); IR (KBr) 3282, 3060, 2961, 2926, 2884,
(E)-N-(1-(tert-Butyldimethylsilyl)-4,4-dimethylpent-2-en-1-
yl)-p-toluenenesulfonamide (7i). Colorless prisms (CH2Cl2/
hexane). 77% yield, 63 mg (from 88 mg of 6i); mp = 136.0−137.0
°C; Rf = 0.32 (hexane/Et2O = 3:1); [α]27D −18.9 (c 1.12, CHCl3) (er
= 94:6); Chiralcel OD-H (25 + 25 cm), hexane/i-PrOH = 20:1, flow
rate 0.50 mL/min, detection at 254 nm, tR = 19.7 min (minor) and
20.8 min (major), er = 99:1; IR (KBr) 3299, 2959, 2830, 2859, 1599
1
2852, 1908, 1598 cm−1; H NMR (CDCl3) δ 0.13 (6H, s), 0.87 (9H,
s), 2.41 (3, s), 3.35 (2H, d, J = 8.0 Hz), 3.78 (3H, s), 5.54 (1H, s), 6.33
(1H, t, J = 8.0 Hz), 6.57−6.58 (2H, m), 6.74 (1H, dd, J = 8.0, 2.3 Hz),
7.15 (1H, dd, J = 8.0, 8.0 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.67 (2H, d, J
= 8.1 Hz); 13C NMR (CDCl3) δ −4.2, 18.1, 21.7, 26.8, 36.2, 55.3,
111.6, 114.1, 120.7, 127.9, 129.4, 129.5, 129.7, 133.5, 137.1, 141.9,
143.8, 159.9; HRMS-ESI (m/z) [M + Na]+ calcd for C23H33NO3SSi
454.1843, found 454.1843.
1
cm−1; H NMR (CDCl3) δ −0.08 (3H, s), −0.01 (3H, s), 0.72 (9H,
s), 0.93 (9H, s), 2.38 (3H, s), 3.64 (1H, dd, J = 8.3, 8.3 Hz), 4.49 (1H,
brd, J = 8.3 Hz), 4.88 (1H, dd, J = 8.3, 15.7 Hz), 5.06 (1H, d, J = 15.7
Hz), 7.22 (2H, d, J = 8.3 Hz), 7.71 (2H, d, J = 8.3 Hz); 13C NMR
(CDCl3) δ −8.1, −7.1, 17.5, 21.6, 27.2, 29.4, 32.7, 46.3, 122.7, 127.7,
129.6, 138.9, 140.2, 143.1; HRMS-ESI (m/z) [M + Na]+ calcd for
C20H35NO2SSi 404.2050, found 404.2060.
N-(1-(tert-Butyldimethylsilyl)-3-(2-chlorophenyl)prop-1-en-
1-yl)-p-toluenesulfonamide (10l). Colorless plates (Et2O/hexane).
31% yield, 27 mg (from 87 mg of 6l); mp = 120.0−120.5 °C; Rf = 0.39
(hexane/Et2O = 2:1); IR (KBr) 3444, 3279, 2953, 2928, 2852, 1597
(E)-N-(1-(tert-Butyldimethylsilyl)-3-phenylallyl)-p-toluene-
sulfonamide (7j). Colorless needles (CH2Cl2/hexane). 67% yield, 56
mg (from 80 mg of 6j); mp = 140.0−140.5 °C; Rf = 0.13 (hexane/
Et2O = 3:1); [α]28D +91.7 (c 1.05, CHCl3) (er = 97:3); Chiralcel OD-
H (25 + 15 cm), hexane/i-PrOH = 20:1, flow rate 0.70 mL/min,
detection at 254 nm, tR = 18.4 min (minor) and 27.9 min (major), er =
1
cm−1; H NMR (CDCl3) δ 0.12 (6H, s), 0.87 (9H, s), 2.43 (3H, s),
3.44 (2H, d, J = 8.0 Hz), 5.59 (1H, s), 6.30 (1H, t, J = 8.0 Hz), 6.91
(1H, d, J = 7.5 Hz), 7.10 (1H, dd, J = 7.5, 7.5 Hz), 7.14 (1H, dd, J =
7.5, 7.5 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.31 (1H, d, J = 7.5 Hz), 7.72
(2H, d, J = 8.1 Hz); 13C NMR (CDCl3) δ −4.3, 18.1, 21.8, 26.8, 33.5,
126.9, 127.6, 128.0, 129.3, 129.4, 129.7, 133.9, 134.7, 137.1, 138.1,
143.9; HRMS-ESI (m/z) [M + Na]+ calcd for C22H30O2NClSSi
458.1347, found 458.1346.
1
97:3; IR (KBr) 3252, 2953, 2931, 2856, 2361, 2337, 1597 cm−1; H
NMR (CDCl3) δ −0.07 (3H, s), 0.06 (3H, s), 0.96 (9H, s), 2.20 (3H,
s), 3.84 (1H, dd, J = 8.4, 8.4 Hz), 4.85−4.92 (1H, brm), 5.69 (1H, dd,
J = 15.9, 8.4 Hz), 5.97 (1H, d, J = 15.9 Hz), 6.98 (2H, d, J = 7.3 Hz),
7.11 (2H, d, J = 8.1 Hz), 7.14 (1H, t, J = 7.3 Hz), 7.21 (2H, dd, J = 7.3,
7.3 Hz), 7.74 (2H, d, J = 8.1 Hz) ; 13C NMR (CDCl3) δ −8.0, −7.1,
17.5, 21.4, 27.1, 46.9, 126.0, 127.0, 127.7, 128.0, 128.4, 128.4, 129.5,
137.1, 138.5, 143.4; HRMS-ESI (m/z) [M + Na]+ calcd for
C22H31NO2SSi 424.1737, found 424.1735.
(E)-N-(1-(tert-Butyldimethylsilyl)-3-(3-methoxyphenyl)allyl)-
p-toluenesulfonamide (7k). Colorless needles (CH2Cl2/hexane).
60% yield, 52 mg (from 89 mg of 6k); mp = 139.0−140.0 °C; Rf =
0.16 (hexane/Et2O = 2:1); [α]27D −24.3 (c 1.25, CHCl3) (er = 97:3);
Chiralcel OD-H (25 + 15 cm), hexane/i-PrOH = 10:1, flow rate 0.70
mL/min, detection at 254 nm, tR = 17.0 min (minor) and 29.4 min
(major), er = 97:3; IR (KBr) 3299, 3029, 2948, 2931, 2890, 2857,
1645, 1604, 1576 cm−1; 1H NMR (CDCl3) δ −0.02 (3H, s), 0.04 (3H,
s), 0.95 (9H, s), 2.23 (3H, s), 3.77 (3H, s), 3.84 (1H, dd, J = 8.3, 8.3
Hz), 4.65−4.70 (1H, brm), 5.67 (1H, dd, J = 15.8, 8.3 Hz), 5.93 (1H,
d, J = 15.8 Hz), 6.50 (1H, brs), 6.58 (1H, d, J = 7.6 Hz), 6.70 (1H, dd,
J = 8.3, 2.5 Hz), 7.10−7.14 (3H, m), 7.72 (2H, d, J = 8.1 Hz); 13C
NMR (CDCl3) δ −8.0, −7.1, 17.5, 21.5, 27.1, 46.9, 55.3, 111.8, 112.3,
118.8, 127.8, 128.3, 128.4, 129.4, 129.6, 138.5, 138.6, 143.5, 159.8;
HRMS-ESI (m/z) [M + Na]+ calcd for C23H33NO3SSi 454.1843,
found 454.1842.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra of all new compounds,
chiral HPLC analyses of compound 7a−l, computational
methods and crystallographic data of (S)-7a and (R)-7e. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: misasaki@hiroshima-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a Grant-in-Aid for
Scientific Research (B) 22390001 (K.T.), a Grant-in-Aid for
Challenging Exploratory Research 2365900700 (K.T.). and a
Grant-in-Aid for Scientific Research (C) 25460015 (M.S.) from
the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), the Hoan Sha Foundation (M.S.), the
Hayashi Memorial Foundation for Female Natural Scientists
(M.S.), the Takeda Science Foundation (M.S.), and the Naito
Foundation Natural Science Scholarship (M.S.). We thank the
staff of Natural Science Center for Basic Research and
Development (N-BARD), Hiroshima University for the use
of their facilities.
(E)-N-(1-(tert-Butyldimethylsilyl)-3-(2-chlorophenyl)allyl)-p-
toluenesulfonamide (7l). Colorless needles (CH2Cl2/hexane). 27%
yield, 23 mg (from 87 mg of 6l); mp = 139.0−140.0 °C; Rf = 0.24
(hexane/Et2O = 2:1); [α]26 +66.9 (c 1.07, CHCl3) (er = 97:3);
D
Chiralcel OD-H (25 + 15 cm), hexane/i-PrOH = 20:1, flow rate 0.70
mL/min, detection at 254 nm, tR = 20.5 min (minor) and 30.2 min
(major), er = 97:3; IR (KBr) 3291, 2952, 2931, 2891, 2856, 1633,
1597 cm−1; 1H NMR (CDCl3) δ 0.00 (3H, s), 0.07 (3H, s), 0.96 (9H,
s), 2.22 (3H, s), 3.85 (1H, dd, J = 8.5, 8.5 Hz), 4.68 (1H, d, J = 8.5
Hz), 5.69 (1H, dd, J = 16.1, 8.5 Hz), 6.36 (1H, d, J = 16.1 Hz), 6.96−
6.98 (1H, m), 7.07−7.11 (2H, m), 7.15 (2H, d, J = 8.1 Hz), 7.26−7.28
(1H, m), 7.74 (2H, d, J = 8.1 Hz) ; 13C NMR (CDCl3) δ −8.0, −7.1,
17.5, 21.4, 27.1, 47.1, 124.6, 126.5, 126.6, 127.8, 128.1, 129.6, 131.2,
132.5, 135.2, 138.1, 143.4; HRMS-ESI (m/z) [M + Na]+ calcd for
C22H30NO2ClSSi 458.1347, found 458.1347.
REFERENCES
■
(1) (a) Franz, A. K.; Wilson, S. O. J. Med. Chem. 2013, 56, 388−405.
(b) Brook, M. A. In Silicon in Organic, Organometallic, and Polymer
Chemistry; Wiley & Sons: New York, NY, 2000; pp 459−479.
(c) Tacke, R.; Linoh, H. In The Chemistry of Organic Silicon
Compounds, Part 2; Patai, S., Rappoport, Z., Eds.; John Wiley &
Sons: Chichester, 1989; pp 1143−1206.
N-(1-(tert-Butyldimethylsilyl)-3-phenylprop-1-en-1-yl)-p-tol-
uenesulfonamide (10j). Colorless plates (CH2Cl2/hexane). 22%
yield, 18 mg (from 80 mg of 6j); mp = 96.5−97.0 °C; Rf = 0.26
(hexane/Et2O = 3:1); IR (KBr) 3276, 2954, 2926, 2891, 2853, 1599
1
cm−1; H NMR (CDCl3) δ 0.13 (6H, s), 0.87 (9H, s), 2.42 (3H, s),
3608
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609

The Journal of Organic Chemistry
Article
(2) (a) Min, G. K.; Hernan
2013, 46, 457−470. (b) Min, G. K.; Skrydstrup, T. J. Org. Chem. 2012,
77, 5894−5906.
́
dez, D.; Skrydstrup, T. Acc. Chem. Res.
selectivity-determining groups was not much different from that of
ones without THF.
(24) Picard, J.-P.; Calas, R.; Dunogues, J.; Duffaut, N.; Gerval, J.;
Lapouyade, P. J. Org. Chem. 1979, 44, 420−424.
(25) Linghu, X.; Nicewicz, D. A.; Johnson, J. S. Org. Lett. 2002, 4,
2957−2960.
(3) (a) Mutahi, M. W.; Nittoli, T.; Guo, L.; Sieburth, S. M. J. Am.
Chem. Soc. 2002, 124, 7363−7375. (b) Sieburth, S. M.; Nittoli, T.;
Mutahi, A. M.; Guo, L. Angew. Chem., Int. Ed. 1998, 37, 812−814.
(c) Sieburth, S. M.; Somers, J. J.; O’Hare, H. K.; Hewitt, G. W. Appl.
Organomet. Chem. 1997, 11, 337−343.
(4) (a) Lazareva, N. F. Russ. Chem. Bull. 2011, 60, 615−632.
(b) Mortensen, M.; Husmann, R.; Veri, E.; Bolm, C. Chem. Soc. Rev.
2009, 38, 1002−1010.
(26) Han, X.-J.; Yao, M.; Lu, C.-D. Org. Lett. 2012, 14, 2906−2909.
(27) Takeda, K.; Yamawaki, K.; Hatakeyama, N. J. Org. Chem. 2002,
67, 1786−1794.
(28) Okada, T.; Oda, N.; Suzuki, H.; Sakaguchi, K.; Ohfune, Y.
Tetrahedron Lett. 2010, 51, 3765−3768.
(29) Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto, Y.; Sato, T.;
Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998, 120, 4947−
4959.
(5) Picardo, J.-P. Adv. Organomet. Chem. 2004, 52, 175−375.
(6) (a) Noll, J. E.; Speier, J. L.; Daubert, B. F. J. Am. Chem. Soc. 1951,
73, 3867−3871. (b) Sommer, L. H.; Rocket, J. J. Am. Chem. Soc. 1951,
73, 5130−5134.
(30) Nowick, J. S.; Danheiser, R. L. J. Org. Chem. 1989, 54, 2798−
2802.
(31) Sakaguchi, K.; Ayabe, M.; Watanabe, Y.; Okada, T.; Kawamura,
K.; Shinada, T.; Ohfune, Y. Tetrahedron 2009, 65, 10355−10364.
(32) Kondo, J.; Shinokubo, H.; Oshima, K. Org. Lett. 2006, 8, 1185−
1187.
(7) Hengelsberg, H.; Tacke, R.; Fritsche, K.; Syldatk, C.; Wagner, F.
J. Organomet. Chem. 1991, 415, 39−45.
(8) Bassindale, A. R.; Taylor, P. G.; Xu, Y. Tetrahedron Lett. 1996, 37,
555−558.
(9) Picard, J.-P.; Fortis, F. Tetrahedron: Asymmetry 1998, 9, 3455−
3460.
(10) Liu, G.; Sieburth, S. M. Org. Lett. 2003, 5, 4677−4679.
(11) Ballweg, D. M.; Miller, R. C.; Gray, D. L.; Scheidt, K. A. Org.
Lett. 2005, 7, 1403−1406.
(12) Nielsen, L.; Lindsay, K. B.; Faber, J.; Nielsen, N. C.; Skrydstrup,
T. J. Org. Chem. 2007, 72, 10035−10044.
(13) (a) Zhang, H.-J.; Priebbenow, D. L.; Bolm, C. Chem. Soc. Rev.
2013, 42, 8540−8571. (b) Qi, H.; Curran, D. P. In Comprehensive
Organic Functional Group Transformations; Katritzky, A. R., Meth-
Cohn, O., Rees, C. W., Moody, C. J., Eds.; Pergamon: Oxford, 1995;
pp 409−431. (c) Cirillo, P. F.; Panek, J. S. Org. Prep. Proced. Int. 1992,
24, 553−582. (d) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc.
Rev. 1990, 19, 147−195. (e) Ricci, A.; Degl’Innocenti, A. Synthesis
1989, 647−660.
(14) Takeda, K.; Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1, 237−
239.
(15) Sasaki, M.; Kondo, Y.; Kawahata, M.; Yamaguchi, K.; Takeda, K.
Angew. Chem., Int. Ed. 2011, 50, 6375−6378.
(16) Graves, C. R.; Scheidt, K. A.; Nguyen, S. T. Org. Lett. 2006, 8,
1229−1232.
(17) For reviews on asymmetric MVP-type reduction, see: (a) Graves,
C. R.; Joseph Campbell, E.; Nguyen, S. T. Tetrahedron: Asymmetry
2005, 16, 3460−3468. (b) Nishide, K.; Node, M. Chirality 2002, 14,
759−767.
(18) Honda, T.; Mori, M. J. Org. Chem. 1996, 61, 1196−1197.
(19) Majewski, M.; Gleave, D. M. J. Organomet. Chem. 1994, 470, 1−
16.
(20) (a) Brown, C.; Hudson, R. F.; Record, K. A. F. J. Chem. Soc.
Perkin II 1978, 822−828. (b) Davis, F. A.; Kluger, E. W. J. Am. Chem.
Soc. 1976, 98, 302−303. (c) Masumoto, S.; Usuda, H.; Suzuki, M.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634−5635.
(21) For a review on the isomerization of CN bond, see: Kessler,
H. Angew. Chem., Int. Ed. 1970, 9, 219−235.
(22) (a) Normand, M.; Kirillov, E.; Roisnel, T.; Carpentier, J.-F.
Organometallics 2012, 31, 5511−5519. (b) Graves, C. R.; Zhou, H.;
Stern, C. L.; Nguyen, S. T. J. Org. Chem. 2007, 72, 9121−9133.
(c) Cohen, R.; Graves, C. R.; Nguyen, S. T.; Martin, J. M. L.; Ratner,
M. A. J. Am. Chem. Soc. 2004, 126, 14796−14803.
(23) All of these transition structures were located using chairlike six-
membered conformations as an initial geometry, in which the amide-
lithium atom coordinates to the imine-nitrogen atom. Attempts to
locate a chairlike six-membered conformation resulted in conversion to
deformed ones. We also calculated energies of the corresponding
transition state structures in which a piperazine acts as a bidentate
ligand to the lithium atom by adopting a boat-like conformation,
showing that they have energies higher than that of TS-A. Although we
also tried to locate transition structures with one THF molecule, the
search failed in some cases. In successful cases, the geometry of the
3609
dx.doi.org/10.1021/jo500441a | J. Org. Chem. 2014, 79, 3601−3609