Stereoselective synthesis of β-amino acid derivatives by asymmetric mannich reaction in flow

Article abstract of DOI:10.1246/bcsj.20170194

A continuous flow synthesis of β-amino acid derivatives has been demonstrated using an asymmetric Mannich reaction. An enolate of tert-butyl acetate was successfully prepared in 10s at room temperature in a flow reactor, and the desired β-amino acid derivatives were stereoselectively obtained within a short residence time (40 s) in moderate-to-good yields. Sequential Nalkylation of the Mannich product in the flow reactor was also achieved in the presence of DMPU that provided N-alkylated β-amino acid derivatives in good yields.

Full text of DOI:10.1246/bcsj.20170194

Advance Publication Cover Page
Stereoselective Synthesis of β-Amino Acid Derivatives
by Asymmetric Mannich Reaction in Flow
Masahito Yoshida, Koji Umeda, and Takayuki Doi*
Advance Publication on the web July 27, 2017
doi:10.1246/bcsj.20170194
© 2017 The Chemical Society of Japan

Stereoselective Synthesis of β-Amino Acid Derivatives by Asymmetric Mannich
Reaction in Flow
Masahito Yoshida, Koji Umeda, and Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail: <doi_taka@mail.pharm.tohoku.ac.jp>
Takayuki Doi received his Ph.D. from Tokyo Institute of Technology in 1991. After his postdoctoral research under the
guidance of Professor Gilbert Stork at Columbia University, he joined the groups of Professor Keiji Yamamoto in 1993
and Professor Takashi Takahashi in 1996 as an Assistant Professor. He was appointed to Associate Professor in 2001 and
he has been a Full Professor at Tohoku University since 2008. He received Incentive Award in Synthetic Organic
Chemistry, Japan in 2000 and The Pharmaceutical Society of Japan Award for Divisional Scientific Promotion in 2013.
Abstract
<Previous work>ꢀ
A continuous flow synthesis of β-amino acid derivatives
O
O
O
O
O
OLi
O
OH
LiHMDS
H
STrt
∗
has been demonstrated using an asymmetric Mannich reaction.
An enolate of tert-butyl acetate was successfully prepared in 10
s at room temperature in a flow reactor, and the desired
β-amino acid derivatives were stereoselectively obtained within
a short residence time (40 s) in moderate-to-good yields.
Sequential N-alkylation of the Mannich product in the flow
reactor was also achieved in the presence of DMPU that
provided N-alkylated β-amino acid derivatives in good yields.
O
N
O
N
O
N
STrt
Ph
Ph
Ph
THF
–40 °C, 150 s
THF
Ph
Ph
Ph
–40 °C, 7.5 s
β-Hydroxy acid derivative
85% yield (S:R = 78:22)
Acetamide derivative
Enolate
<This work>ꢀ
M
O
O
O
R3O
R3
Enolate
Acetate derivative
R1
S
Mixer 1
O
HN
O
Base
R1
R3O
R2
Mixer 2
S
N
O
β-Amino acid derivative 1
Imine 2
(R1: tBu or p-tol)
R2
H
1. Introduction
β-Amino acid derivatives are recognized as important
building blocks in the structure of natural products and other
biologically active molecules.1 Several approaches for the
synthesis of β-amino acid derivatives have been reported, for
instance, the Arndt–Eistert homologation of α-amino acids and
an asymmetric Mannich reaction.2 In particular, the Mannich
reaction using a chiral auxiliary has been widely utilized to
prepare a variety of β-amino acid derivatives from chiral imine
derivatives and the corresponding esters.3 Sufficient formation
of an enolate from ester is essential to obtain a Mannich
Figure 1. Outline for the Synthesis of β-Amino Acid
Derivatives 1 by an Asymmetric Mannich Reaction in a Flow
System
2. Results and Discussion
In order to avoid the Claisen condensation of an acetate
derivative during the enolate formation, we chose steric
hindered tert-butyl acetate as an ester source. The reaction
conditions for the asymmetric Mannich reaction in the flow
system were investigated, and the results are summarized in
Table 1. A solution of tert-butyl acetate in the indicated solvent
(0.3 M) was dispensed at a flow rate of 1 mL•min−1 into reactor
R1 (Comet-X01)7 by a syringe pump, and a solution of
NaHMDS in Et2O-THF (7:1, 0.25 M, 1 mL•min−1 by a syringe
pump) was mixed at the appropriate temperature. The mixture
was subsequently introduced into reactor R2 (Comet-X01), in
which the chiral imine 2 (0.05 M in the indicated solvent)
reacted with the resulting enolate at a flow rate of 2 mL•min−1
through a precooling Teflon tube (0.5 m). The desired β-amino
acid derivatives 1 were obtained from the outlet of reactor R2
after a conventional work-up. The solvent for the Mannich
reaction in the flow system was initially investigated at −78°C
(T1 and T2), and the use of THF resulted in a low yield (33%)
product in
a high yield without the generation of an
acetoacetate derivative that can be formed by Claisen
condensation. To enable reproducible production of β-amino
acid derivatives by the Mannich reaction, we envisioned the
use of a flow synthesis because flow systems allow a
reproducible synthesis at different scales without further
optimization of the reaction conditions.4 To date, several
research groups have reported a continuous-flow asymmetric
Mannich reaction using organocatalysts.5 However, the
substrates are limited to ketones and alkanals as an acceptor
and iminoglyoxylates as a donor. We have recently achieved a
continuous-flow diastereoselective aldol reaction.6 An enolate
of an acetamide derivative in the flow reactor was successfully
formed within a short residence time (150 s) at –40 °C, and the
resulting enolate smoothly reacted with the aldehydes in 7.5 s
at the same temperature to afford the aldol products in good
yields. Thus, we assumed that the developed flow system could
be applied to a reproducible synthesis of β-amino acid
derivatives 1 by using an asymmetric Mannich reaction of an
enolate of acetate with a variety of imine derivatives 2,3 as
shown in Figure 1.
of β-amino acid derivative 1a with
a
moderate
diastereoselectivity (8:1) (Table 1, entry 1). Conversely, the
reaction performed in toluene afforded 1a in 64% yield, and the
diastereoselectivity was significantly improved (20:1, entry 2).
Notably, the Mannich product 1a was exclusively provided in
44% yield when Et2O was used as the solvent (entry 3).8
Moreover, we found that the yield of 1a was improved to 69%
without a decrease in the diastereoselectivity when the reaction
was performed at 0°C (entry 5), while the reaction at −40°C did
not improve the yield of 1a (entry 4).

Table 1. Investigation of the Reaction Conditions for the Asymmetric Mannich Reaction in a Flow System
t-Butyl acetate
(0.3 M)
1.0 mL/min
p-tol
T1
T2
R1
R2
S
O
HN
O
NaHMDS/
Et2O-THF
(0.25 M)
RT1
RT2
RT3
O
R
β-Amino acid derivative 1
1a: R = Ph
1b: R = CH2CH2Ph
p-tol
Imine 2
(0.05 M)
1.0 mL/min
S
O
N
2.0 mL/min
R
H
Entry Imine Solvent T1 (°C) T2 (°C)
RT1 (s)
RT2 (s)
300
RT3 (s)
Product Yield (%)a
dr
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2b
THF
−78
−78
−78
−40
0
30
30
30
30
30
30
30
30
1a
1a
1a
1a
1a
1a
1b
1b
33
64
44
44
69
87
80
73
8:1
Toluene
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
300
300
300
300
20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
rt
rt
rt
rt
rt
rt
−78
200
100
−78
−78
−78
−78
–78
200
30
10
10
10
10
100
60
30
0
9
2b
2b
2b
2b
Et2O
Et2O
Et2O
Et2O
30
30
10
30
1b
1b
1b
1b
81
80
59
49
>20:1
>20:1
>20:1
>20:1
10
11
0
12
rt
0
aIsolated yield
The above observation indicated that a higher temperature is
required to generate an enolate or to perform the Mannich
reaction in a flow reactor. To investigate the effect of
temperature, we attempted the Mannich reaction at −78°C by
using an enolate generated at room temperature. The enolate
formed in the residence time RT1 (200 s) was introduced into
the next reactor to react with imine 2a at −78°C for 30 s after
passing through a precooling coiled tube for the indicated
residence time (Table 1, RT2). Interestingly, the yield of 1a
increased to 93% (entry 6, RT2, 100 s). The reaction with
imine 2b also proceeded to afford the corresponding 1b in 80%
yield with high diastereoselectivity (entry 7). Therefore, room
temperature is crucial for enolate generation to provide the
Mannich product 1 in a desirable yield. Having the good
conditions for the enolate generation, we further investigated
the residence time RT1 for the enolate formation and RT2 for
precooling. We found that RT1 and RT2 could be reduced
without affecting the yield of 1b (entries 8–10). In particular,
the enolate was smoothly generated in 10 s and the Mannich
reaction proceeded in 30 s without precooling (entry 10). To
our delight, the desired 1b was stereoselectively obtained in 40
s in 80% yield. On the other hand, a decrease in the yield of 1b
was observed either reducing the residence time for the
Mannich reaction (RT3: 10 s, entry 11) or performing the
Mannich reaction at room temperature (T2: rt, entry 12).9
After determining the good reaction conditions for the
stereoselective synthesis of β-amino acid derivatives (Table 1,
entry 10), we investigated the substrate scope of imine 2 in the
asymmetric Mannich reaction (Table 2). First of all, the
reaction using imine 2a was re-investigated under the
optimized condition as mentioned in Table 1. Imine 2a was
completely consumed as well as entry 6 in Table 1, and the
desired 1a was afforded in 93% yield. Further, note that the
Mannich reaction was performed in the continuous flow system
for 4 min leading to 122 mg of 1a (85% yield, 1.83 g•h–1). A
slightly lower yield of 1a was observed by extension of the
operation time. As a hydrolysate of 1a was found in the
resulting mixture, we assumed that the hydrolysis of the ester
moiety in 1a would partially occur at the time of quenching
with saturated aqueous NH4Cl (entry 1). The reaction using
imines 2c–2e derived from benzaldehyde derivatives proceeded
smoothly to provide 1c–1e in good yields without any influence
of the substituent on the aromatic ring (entries 2–4). Moreover,
imines 2f–2h prepared from cinnamaldehyde derivatives were
tolerant in the Mannich reaction, and the corresponding
products 1f–1h were afforded in acceptable yields (71–89%,
entries 5–7). However, a decrease in the yields of the Mannich
products of 1i and 1j was observed in the reaction with alkyl
imine derivatives 2i and 2j (entries 8 and 9). Conversely, the
reaction with imine 2k derived from pivalaldehyde was
smoothly performed to obtain the corresponding 1k in 85%
yield (entry 10), resulting in the finding that the existence of
acidic α-protons in the imine derivatives causes
a
decomposition or a decrease in the yield of the corresponding
Mannich products.
Table 2. Substrate Scope of Imine 2 in the Asymmetric
Mannich Reaction in a Flow System
t-Butyl acetate
(0.3 M)
1.0 mL/min
p-tol
rt
–78 °C
30 s
R1
10 s
Imine 2
R2
S
O
HN
O
NaHMDS/
Et2O-THF
(0.25 M)
O
R
β-Amino acid derivative 1
p-tol
1.0 mL/min
S
(0.05 M)
2.0 mL/min
O
N
R
H
Entry Imine
R
Product Yield (%)a
(dr)b
1
2
2a
2c
1a
93 (85)c, d
(>20:1)
80
1c
(>20:1)

successfully found the good conditions for sequential
N-alkylation in the flow system, the reactions with several
reactants were performed as follows. A methyl group was
readily installed on a nitrogen atom by the N-alkylation in the
flow system to afford 3b in 72% yield, while the reaction with
ethyl iodide was not complete within 120 s and the desired 3c
was provided in 28% yield with a recovery of the Mannich
product 1a in 55% yield (entries 5 and 6). The N-alkylation
using allyl bromide proceeded smoothly, leading to the
allylated 3d (65%, entry 7); therefore, less hindered and
reactive alkylating reagents were tolerated for the sequential
N-alkylation in a flow system to provide the corresponding 3 in
moderate-to-good yields.
3
2d
2e
2f
1d
1e
1f
79
Cl
(>20:1)
77
4
F3C
(>20:1)
89
5
(>20:1)
84
6
2g
2h
2i
1g
1h
1i
MeO
(>20:1)
71
7
Table 3. Synthesis of N-Alkylated β-Amino Acid
Derivatives 3 by Sequential Mannich-N-Alkylation in a
Flow System
Cl
(>20:1)
51
8
t-Butyl acetate
(0.3 M)
1.0 mL/min
(>20:1)
55
rt
–78 °C
R2
T °C
RT
p-tol
R1
R3
S
O
RN
O
9
2j
1j
NaHMDS/
Et2O-THF
(0.25 M)
30 s
10 s
O
Ph
β-Amino acid derivative 3
(>20:1)
85
p-tol
Imine 2a
(0.05 M)
2.0 mL/min
3a: R=Bn, 3b: R=Me
3c: R=Et, 3d: R=Allyl
Reactant (0.5 M)
R-X (X = Br or I)
1.0 mL/min
S
O
N
10
2k
1k
Ph
H
aIsolated yield, bDetermined by crude 1H NMR, cOperated for 4
Entry R-X
T
RT Additive Product Yield
min, dA hydrolysate of 1a was observed in 5% yield.
(°C) (s)
(%)a, b
0 (93)
35
After successfully establishing a flow system for the
stereoselective synthesis of β-amino acid derivatives, we
investigated the synthesis of N-alkylated β-amino acid
derivatives for a further application of this flow system.
Focusing on the intermediate 4 generated by the Mannich
reaction in the flow reactor, as shown in Scheme 1, we assumed
that the anionic intermediate 4 was sufficiently nucleophilic to
readily react with an alkyl halide, leading to the desired
N-alkylated derivative 3.10
1
2
BnBr
0
0
120
-
3a
3a
BnBr
120 DMPU
(58)
53
3
4
5
6
BnBr
BnBr
MeI
EtI
rt
rt
rt
rt
120 DMPU
150 DMPU
120 DMPU
120 DMPU
3a
3a
3b
3c
50
72
28
p-tol
p-tol
p-tol
O
R-X
(X = Br or I)
S
S
S
(55)
65
O
O
N
O
O
RN
O
N
O
O
R1
Intermediate 4
O
R1
N-Alkylated derivative 3
R1
Imine 2
H
Mannich reaction
in flow
7
AllylBr rt
120 DMPU
3d
aIsolated Yield, bYield of recovered 1a in the parenthesis.
Scheme 1. Synthetic Plan for N-Alkylated ββ-Amino Acid
Derivatives 3 in a Flow System
3. Conclusion
We have demonstrated a continuous-flow stereoselective
synthesis of β-amino acid derivatives by an asymmetric
Mannich reaction using optically active sulfinimines. An
enolate of tert-butyl acetate successfully formed in 10 s at room
temperature in the flow reactor, and the asymmetric Mannich
reaction with the resulting enolate proceeded smoothly within
First, benzyl bromide was subjected at 0°C as an
electrophile for the sequential N-alkylation after the Mannich
reaction performed at −78°C in the flow system; however, the
N-alkylated product 3a was not observed (Table 3, entry 1), but.
the Mannich product 1a was obtained in 93% yield. Therefore,
we further investigated the reaction conditions such as the
requirement of an additive. Note that the addition of DMPU11
was essential to promote the N-alkylation and that the
corresponding 3a was obtained in 35% yield accompanied with
the Mannich product 2a recovered in 58% yield (entry 2). Then,
we assumed that a higher temperature was required to promote
the N-alkylation of the resulting sulfonamide moiety. As
expected, the reaction in the flow reactor was smoothly
conducted at room temperature and the corresponding 3a was
afforded in 53% yield (entry 3). Conversely, the yield of 3a
was not improved by an extension of the residence time
because the sulfonamide moiety in the resulting 3a was
partially eliminated under the reaction conditions, leading to
the formation of tert-butyl cinnamate (entry 4). As we
30
s at −78°C to afford β-amino acid derivatives in
moderate-to-good yields with high diastereoselectivity.
Moreover, we found that the developed flow system could be
operated continuously, leading to the formation of the
corresponding Mannich product at the rate of 1.83 g•h−1. For a
further application of the flow system, the synthesis of
N-alkylated β-amino acid derivatives was investigated.
Continuous-flow N-alkylation of the resulting Mannich product
was smoothly performed in the presence of DMPU to afford
N-alkylated β-amino acid derivatives in good yields. This is the
first example of a continuous-flow stereoselective synthesis of
β-amino acid derivatives by a Mannich reaction using an
enolate prepared from an acetate derivative in a flow reactor.

We are currently applying this method to a study on the
synthesis and the structure–activity relationship of biologically
active natural products, and the results will be reported in due
course.
2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 166.0,
141.6, 141.5, 140.1, 129.6, 128.4, 128.2, 126.1, 124.5, 37.2,
31.2, 21.33, 21.30; IR (CHCl3) 3023, 2924, 1619, 1497, 1455,
1098, 1072, 809, 700 cm−1; [α]D24 +229 (c 0.950, CHCl3) [lit.14
20
[α]D
+196 (c 1.37, CHCl3)]; HRMS(FAB) calcd for
4. Experimental
C16H18NOS [M+H]+ 272.1109, found 272.1115.
Generals. All commercially available reagents were used
as received. Dry THF and CH2Cl2 (Kanto Chemical Co.) were
obtained by purchasing commercially available pre-dried,
oxygen-free formulations. All reactions were monitored by
thin-layer chromatography carried out on 0.2 mm E. Merck
silica gel plates (60F-254) with UV light, visualized by
p-anisaldehyde solution, phosphomolybdic acid solution.
Column chromatography and flash column chromatography
were carried out with silica gel 60 N (Kanto Chemical Co.
100-210 µm) and silica gel 60 N (Kanto Chemical Co. 40-50
(S)-N-(p-Methylbenzylidene)-p-toluenesulfinamide
(2c):
Yield: 60 % (0.597 g, 2.32 mmol), white solid; Melting point:
1
96–99 °C [lit.15 mp 100–102 °C], H NMR (400 MHz, CDCl3)
δ 8.71 (s, 1H), 7.74 (d, 2H, J = 8.0 Hz), 7.63 (d, 2H, J = 8.3
Hz) 7.24−7.31 (m, 4H), 2.39−2.40 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 160.5, 143.4, 142.0, 141.6, 131.4, 129.8, 129.6,
124.8, 21.7, 21.4; IR (Solid) 3030, 2953, 2922, 1599, 1566,
1494, 1452, 1304, 1210, 1173, 1103, 1073, 1040, 1017, 982,
26
25
809, 714, 702 cm−1; [α]D +77.7 (c 1.13, CHCl3) [lit.15 [α]D
+67 (c 0.50, CHCl3)]; HRMS(EI) calcd for C15H15NOS [M]+
1
µm), respectively. H NMR spectra (400 MHz and 600 MHz)
257.0874, found 257.0864.
(S)-N-(p-Chlorobenzylidene)-p-toluenesulfinamide
and 13C NMR spectra (100 MHz and 150 MHz) were recorded
on JEOL JNM-AL400 and JEOL ECA600 spectrometers in the
indicated solvent. Chemical shifts are reported in units parts per
(2d):
Yield: 63 % (0.677 g, 2.44 mmol), white solid; Melting point:
106–110 °C [lit.13 mp 116–118 °C], 1H NMR (400 MHz,
CDCl3) δ 8.71 (s, 1H), 7.78 (d, 2H, J = 8.9 Hz), 7.62 (d, 2H, J
= 8.2 Hz), 7.43 (d, 2H, J = 8.9 Hz), 7.31 (d, J = 8.2 Hz), 2.40 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 141.8, 141.5, 138.8,
132.3, 130.7, 129.8, 129.2, 124.7, 21.4; IR (Solid) 2921, 1608,
1
million (ppm) relative to tetramethylsilane (0.00 ppm for H),
chloroform (7.26 ppm for 1H), methanol (3.30 ppm for 1H),
chloroform-d (77.0 ppm for 13C) and methanol-d3 (49.0 ppm
for 13C) when internal standard is not indicated. Multiplicities
are reported by the following abbreviations: s; singlet, d;
doublet, t; triplet, q; quartet, dd; double doublet, dt; double
triplet, ddt; double double triplet, m; multiplet, br; broad, J;
coupling constants in Hertz. Mass spectra and high-resolusion
mass spectra were measured on JEOL JMS-DX303 (for EI),
MS-AX500 (for FAB), and ThermoScientificTM ExactiveTM
Plus Orbitap Mass Spectrometer (for ESI). IR spectra were
recorded on a JASCO FTIR-8400. Only the strongest and/or
structurally important absorption are reported as the IR data
afforded in cm-1. Melting points were measured on Round
Science RFS-10, and are uncorrected. Optical rotations were
measured with a JASCO P-1010 polarimeter.
1592, 1566, 1489, 1405, 1104, 1087, 1014, 825, 809, 669 cm−1;
28
[α]D
+15.6 (c 0.975, CHCl3); HRMS(EI) calcd for
C14H12ClNOS [M]+ 277.0328, found 277.0330.
(S)-N-(p-Trifluoromethylbenzylidene)-p-toluenesulfinamide
(2e): Yield: 37 % (0.446 g, 1.43 mmol), white solid; Melting
point: 100–102 °C [lit.16 99–101 °C], 1H NMR (400 MHz,
CDCl3) δ 8.79 (s, 1H), 7.96 (d, 2H, J = 8.0 Hz), 7.71 (d, 2H, J
= 8.3 Hz), 7.63 (d, 2H, J = 8.3 Hz), 7.32 (d, 2H, J = 8.0 Hz),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 141.9,
141.2, 136.7, 133.8 (q, J = 32.7 Hz), 129.9, 129.7, 125.8 (q, J =
3.6 Hz), 124.9, 124.7, 122.2, 21.4; IR (Solid) 1607, 1574, 1411,
24
1324, 1170, 1120, 1104, 1065, 838, 809 cm−1; [α]D +87.4 (c
20
1.06, CHCl3) [lit.16 [α]D +86.2 (c 1.15, CHCl3)]; HRMS(EI)
General
procedure
for
the
synthesis
of
calcd for C15H12F3NOS [M]+ 311.0592, found 311.0591.
(S)-N-p-toluenesulfinylimine 2. To
a
solution of
(S)-N-{(E)-3-Phenylpropenylidene}-p-toluenesulfinamide
(2f): Yield: 82 % (0.855 g, 3.17 mmol), white solid; Melting
point: 114–117 °C [lit.17 mp 114–115 °C], 1H NMR (400 MHz,
CDCl3) δ 8.53 (d, 1H, J = 9.2 Hz), 7.60 (d, 2H, J = 8.2 Hz),
7.52 (dd, 2H, J = 6.5, 2.9 Hz), 7.38−7.39 (m, 3H), 7.24−7.33
(m, 3H), 7.05 (dd, 1H, J = 15.8, 9.2 Hz), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 161.5, 146.8, 141.9, 141.7, 134.9,
130.3, 129.8, 128.9, 127.9, 125.1, 124.6, 21.4; IR (Solid) 3056,
1625, 1579, 1568, 1490, 1449, 1162, 1153, 1093, 1070, 998,
p-tol-sulfinamine12 (3.87 mmol, 1.0 equiv) in dry
dichloromethane (7.7 mL, 2 mL/mmol) was added aldehyde
(3.87 mmol, 1.0 equiv), Ti(OEt)4 (19.4 mmol, 5.0 equiv) at
room temperature under argon. After being stirred at reflux
temperature for 3 h, the reaction mixture was poured into water.
The mixture was filtered through a buchner funnel, and wash
with dichloromethane. The filtrate was extracted with
dichloromethane. The organic layer was washed with water,
brine and dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by column chromatography on silica
28
960, 809, 751, 704, 690 cm−1; [α]D +334 (c 0.980, CHCl3)
20
[lit.17 [α]D +337 (c 1.49, CHCl3)]; HRMS(EI) calcd for
gel
(5%
ethyl
acetate
in
hexane)
to
give
C16H15NOS [M]+ 269.0874, found 269.0872.
(S)-N-(p-toluenesulfinyl)imine 2.
(S)-N-Benzylidene-p-toluenesulfinamide (2a): Yield: 91%
(S)-N-{(E)-3-(p-Methoxyphenyl)propenylidene}-p-toluenesu
lfinamide (2g): Yield: 76 % (0.881 g, 2.94 mmol), yellow
solid; Melting point: 119–120 °C, 1H NMR (400 MHz, CDCl3)
δ 8.50 (d, 1H, J = 9.3 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.46 (d, 2H,
J = 7.3 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.20 (d, 1H, J = 15.6 Hz),
6.91−6.95 (m, 3H), 3.84 (s, 3H), 2.39 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 161.7, 161.4, 146.7, 142.1, 141.6, 129.8, 129.6,
127.6, 124.6, 123.3, 114.4, 55.3, 21.4; IR (Solid) 3030, 2998,
2956, 2840, 1626, 1602, 1578, 1569, 1513, 1315, 1307, 1299,
1265, 1180, 1153, 1096, 1070, 1022, 989, 954, 860, 821, 808,
(0.856 g, 3.52 mmol), white solid; Melting point: 79–82 °C
1
[lit.13 mp 77−78 °C]; H NMR (400 MHz, CDCl3) δ 8.75 (s,
1H), 7.85 (d, 2H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.3 Hz)
7.43−7.51 (m, 3H), 7.31 (d, 2H, J = 8.0 Hz), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.6, 141.8, 141.7, 133.9, 132.5,
129.8, 129.5, 128.8, 124.8, 21.4; IR (Solid) 3058, 1604, 1573,
1494, 1450, 1216, 1099, 1071, 809, 758, 721, 690 cm−1; [α]D
28
+96.1 (c 1.17, CHCl3) [lit.13 [α]D +120 (c 0.45, CHCl3)];
27
HRMS(EI) calcd for C14H13NOS [M]+ 243.0718, found
243.0728.
705 cm−1; [α]D +240 (c 1.05, CHCl3) [lit.18 [α]D +170 (c
1.00, CHCl3)]; HRMS(EI) calcd for C17H17NO2S [M]+
299.0980, found 299.0983.
22
25
(S)-N-3-(Phenylpropylidene)-p-toluenesulfinamide
(2b):
Yield: 68 % (0.714 g, 2.63 mmol), colorless oil; 1H NMR (400
MHz, CDCl3) δ 8.28 (t, 1H, J = 4.4 Hz), 7.50 (d, 2H, J = 8.3
Hz), 7.17−7.26 (m, 9H), 2.94 (t, 2H, J = 7.6 Hz), 2.79−2.84 (m,
(S)-N-{(E)-3-(p-Chlorophenyl)propenylidene}-p-toluenesulfi
namide (2h): Yield: 57 % (0.670 g, 2.21 mmol), white solid;
Melting point: 117–120 °C, 1H NMR (400 MHz, CDCl3) δ 8.51

(d, 1H, J = 9.3 Hz), 7.59 (d, 2H, J = 8.0 Hz), 7.43 (d, 2H, J =
8.5 Hz), 7.36 (d, 2H, J = 8.5 Hz), 7.31 (d, 2H, J = 8.0 Hz), 7.19
(d, 1H, J = 15.9 Hz), 7.01 (dd, J = 15.9, 9.3 Hz), 2.39 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 161.1, 145.1, 141.8, 141.7,
136.2, 133.4, 129.9, 129.2, 129.0, 126.0, 124.5, 21.4; IR (Solid)
3048, 2920, 1625, 1577, 1489, 1407, 1156, 1096, 1071, 809,
710, 677 cm−1; [α]D27 +227 (c 0.650, CHCl3); HRMS(EI) calcd
for C16H14ClNOS [M]+ 303.0485, found 303.0484.
CDCl3) δ 170.0, 142.4, 141.3, 140.4, 129.5, 128.6, 127.9, 127.3,
125.3, 81.4, 55.0, 43.3, 27.9, 21.3; IR(CHCl3) 3181, 2976,
23
1730, 1455, 1366, 1150, 1089, 1056, 810, 700 cm−1; [α]D
+53.3 (c 0.615, CHCl3); HRMS(ESI) calcd for C20H25NO3SNa
[M+Na]+ 382.1447, found 382.1436.
tert-Butyl
(R)-5-phenyl-3-{(S)-p-toluenesulfinylamino}pentanoate
(1b): Yield: 80 % (31.0 mg, 0.08 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.3 Hz), 7.22−7.28
(m, 7H), 4.73 (d, 1H, J = 9.0 Hz), 3.63−3.67 (m, 1H),
2.69−2.85 (m, 2H), 2.53−2.59 (m, 2H), 2.41 (s, 3H), 1.86−2.02
(m, 2H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.8,
142.5, 141.3, 141.2, 129.5, 128.5, 128.4, 125.9, 125.4, 81.2,
52.4, 41.6, 37.3, 32.3, 28.1, 21.3; IR (CHCl3) 3191, 2976, 2929,
(S)-N-Propylidene-p-toluenesulfinamide (2i): Yield: 44 %
(0.333 g, 1.70 mmol), colorless oil; 1H NMR (400 MHz,
CDCl3) δ 8.25 (t, 1H, J = 4.4 Hz), 7.56 (d, 2H, J = 8.0 Hz),
7.30 (d, 2H, J = 8.0 Hz), 2.47−2.55 (m, 2H) 2.40 (s, 3H), 1.16
(t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 167.9,
141.8, 141.5, 129.6, 129.4, 125.2, 124.5, 29.2, 21.3, 9.4; IR
(CHCl3) 2973, 2935, 2877, 1620, 1491, 1450, 1418, 1376, 1349,
22
1725, 1367, 1149, 1089, 1056, 810, 700 cm−1; [α]D +42.2 (c
22
1094, 1072, 809, 624 cm−1; [α]D +354 (c 1.04, CHCl3) [lit.13
1.20, CHCl3); HRMS(ESI) calcd for C22H29NO3SNa [M+Na]+
410.1760, found 410.1749.
19
[α]D
+341.1 (c 1.105, CHCl3)]; HRMS(EI) calcd for
C10H13NOS [M]+ 195.0718, found 195.0723.
tert-Butyl
(R)-
(S)-N-(2-Methylpropylidene)-p-toluenesulfinamide
(2j):
3-(p-methylphenyl)-3-{(S)-p-toluenesulfinylamino}propanoa
te (1c): Yield: 80 % (29.9 mg, 0.08 mmol), colorless oil; H
Yield: 82 % (0.664 g, 3.17 mmol), colorless oil; 1H NMR (400
MHz, CDCl3) δ 8.14 (d, 1H, J = 4.6 Hz), 7.56 (d, 2H, J = 8.3
Hz), 7.30 (d, 2H, J = 8.3 Hz), 2.64−2.72 (m, 1H), 2.40 (s, 3H),
1.15 (d, 3H, J = 4.6 Hz), 1.14 (d, 3H, J = 4.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 171.1, 141.8, 141.5, 129.6, 129.4, 125.2,
124.5, 34.5, 21.3, 18.7, 18.6; IR (CHCl3) 2966, 2929, 2871,
1
NMR (400 MHz, CDCl3) δ 7.60 (d, 2H, J = 8.3 Hz), 7.28−7.32
(m, 4H), 7.18 (d, 2H, J = 7.8 Hz), 4.95 (d, 1H, J = 4.6 Hz),
4.81−4.84 (m, 1H), 2.72 (dd, 2H, J = 6.6, 3.7 Hz), 2.41 (s, 3H),
2.35 (s, 3H) 1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.1,
142.4, 141.2, 137.6, 137.3, 129.4, 129.2, 127.3, 125.2, 81.3,
54.7, 43.3, 27.8, 21.3, 21.1; IR (CHCl3) 3171, 2976, 1726,
2360, 1617, 1491, 1457, 1095, 1072, 809 cm−1; [α]D +291 (c
22
20
23
1.30, CHCl3) [lit.17 [a]D +387 (c 2.1, CHCl3)]; HRMS(EI)
1367, 1150, 1090, 1055, 951, 810 cm−1; [α]D +47.0 (c 1.37,
calcd for C11H15NOS [M]+ 209.0874, found 209.0875.
CHCl3); HRMS(ESI) calcd for C21H27NO3SNa [M+Na]+
396.1604, found 396.1595.
(S)-N-(2,2-Dimethylpropylidene)-p-toluenesulfinamide (2k):
Yield: 53% (0.458 g, 2.05 mmol), white solid; Melting point:
tert-Butyl
(R)-
1
69–74 °C [lit.17 mp 73–75 °C], H NMR (400 MHz, CDCl3) δ
3-(p-chlorophenyl)-3-{(S)-p-toluenesulfinylamino}propionat
1
8.08 (s, 1H), 7.55 (d, 2H, J = 8.3 Hz), 7.29 (d, 2H, J = 8.3 Hz),
2.40 (s, 3H), 1.13 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.4,
142.2, 141.5, 129.7, 124.7, 37.7, 26.5, 21.4; IR (Solid) 2969,
2930, 2903, 2867, 1932, 1618, 1593, 1495, 1477, 1463, 1364,
1342, 1300, 1209, 1202, 1086, 1072, 1040, 1013, 971, 963, 921,
855, 818, 799, 780, 703, 630 cm−1; [α]D23 +274 (c 1.07, CHCl3)
e (1d): Yield: 79 % (31.1 mg, 0.079 mmol), colorless oil; H
NMR (400 MHz, CDCl3) δ 7.58 (d, 2H, J = 8.3 Hz), 7.29−7.32
(m, 6H), 5.04 (d, 1H, J = 4.9 Hz), 4.80−4.83 (m, 1H), 2.71 (d,
2H, J = 6.1 Hz), 2.41 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 169.7, 142.1, 141.5, 139.0, 133.7, 129.5, 128.78,
128.77, 125.2, 81.6, 54.2, 43.1, 27.9, 21.3; IR (CHCl3) 3186,
2977, 2924, 1726, 1491, 1450, 1367, 1257, 1151, 1090, 1056,
[lit.17 [α]D +371 (c 1.94, CHCl3)]; HRMS(EI) calcd for
20
C12H17NOS [M]+ 223.1031, found 223.1031.
1014, 810 cm−1; [α]D +57.3 (c 1.01, CHCl3); HRMS(ESI)
24
calcd for C20H24ClNO3SNa [M+Na]+ 416.1058, found
416.1046.
General procedure for the synthesis of β-amino acid
derivatives 1 by the Mannich reaction in Flow: The flow
system was established with a syringe pump (HII-10B, Techno
applications®), teflon tube, the flow reactor (Comet X-01-T,
Techno applications®). Before use, the flow system was flushed
with Et2O and dried under vacuum. A solution of NaHMDS
(0.25 M) in Et2O was loaded into a teflon sample tube, and a
solution of tert-butyl acetate (0.3 M) in Et2O was loaded into
another teflon sample tube. Both two sample solutions were
pumped at a flow rate of 1 mL/min, and mixed in the reactor
(Comet X-01-T) at room temperature. The output of the reactor
was connected with another reactor (Comet X-01-T) to mix
with a solution of imine 2 in Et2O (0.05 M, 2 mL/min) at
–78 °C. The resulting mixture was collected for 60 s and
quenched with saturated aqueous NH4Cl, and the aqueous layer
was extracted with ethyl acetate. The organic layer was washed
with brine, and dried over MgSO4, filtered and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (20% ethyl acetate in hexane) to give Mannich
product 1.
tert-Butyl
(R)-3-{(S)-p-toluenesulfinylamino}-3-{p-(trifluoromethyl)ph
enyl}propanoate (1e): Yield: 77 % (32.9 mg, 0.077 mmol),
colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.56−7.62 (m, 6H),
7.32 (d, 2H, J = 8.0 Hz), 5.14 (d, 1H, J = 5.4 Hz), 4.88 (m, 1H),
2.76 (d, 2H, J = 6.3 Hz), 2.42 (s, 3H), 1.32 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 169.7, 144.7, 141.9, 141.6, 129.8 (q, J =
32.1 Hz), 129.6, 127.7, 125.5 (q, J = 4.2 Hz), 125.3, 81.7, 54.4,
42.9, 27.8, 21.3; IR (CHCl3) 3181, 2979, 2924, 1727, 1368,
1325, 1161, 1125, 1068, 842, 810 cm−1; [α]D +73.5 (c 0.900,
21
CHCl3); HRMS(ESI) calcd for C21H24F3NO3SNa [M+Na]+
450.1321, found 450.1311.
tert-Butyl
(R)-5-phenyl-3-{(S)-p-toluenesulfinylamino}-4-pentenoate
(1f): Yield: 89 % (34.3 mg, 0.089 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.63 (d, 2H, J = 8.0 Hz), 7.29−7.35
(m, 7H), 6.66 (d, 1H, J = 15.9 Hz), 6.23 (dd, 1H, J = 15.9, 7.2
Hz), 4.83 (d, 1H, J = 5.9 Hz), 4.40−4.42 (m, 1H), 2.62 (d, 2H, J
= 6.1 Hz), 2.41 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.1, 142.3, 141.3, 136.3, 132.5, 129.5, 128.7, 128.5,
127.8, 126.5, 125.4, 81.4, 53.5, 41.9, 28.0, 21.3; IR (CHCl3)
3191, 2971, 2924, 1727, 1366, 1156, 1093, 1087, 1056, 962,
tert-Butyl
(R)-3-phenyl-3-{(S)-p-toluenesulfinylamino}propanoate
(1a): Yield: 93% (33.4 mg, 0.093 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, 2H, J = 8.0 Hz), 7.26−7.43
(m, 7 H), 5.00 (d, 1H, J = 4.6 Hz), 4.86 (m, 1H), 2.75 (d, 2H, J
= 6.3 Hz), 2.41 (s, 3H), 1.32 (s, 9H); 13C NMR (100 MHz,
809, 694 cm−1; [α]D +96.2 (c 0.980, CHCl3); HRMS(ESI)
23
calcd for C22H27NO3SNa [M+Na]+ 408.1604, found 408.1594.
tert-Butyl

(R)-5-(p-methoxyphenyl)-3-{(S)-p-toluenesulfinylamino}-4-p
entenoate (1g): Yield: 84 % (34.9 mg, 0.084 mmol), colorless
oil; H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J = 8.0 Hz),
use, the flow system was flushed with Et2O and dried under
vacuum. A solution of NaHMDS (0.25 M) in Et2O-THF (7:1)
was loaded into a teflon sample tube, and a solution of
tert-butyl acetate (0.3 M) in Et2O was loaded into another
teflon sample tube. Both two sample solutions were pumped at
a flow rate of 1 mL/min, and mixed in the reactor (Comet
X-01-T) at room temperature. The output of the reactor was
connected with another reactor (Comet X-01-T) to mix with a
solution of imine 2a in Et2O (0.05 M, 2 mL/min) at −78 °C.
The output of the reactor was connected with another reactor
(T-shaped mixer) to react with an alkylating reagent (0.5 M
solution in DMPU-Et2O (1:1)). The resulting mixture was
collected for 60 s and quenched with saturated aqueous NH4Cl,
and the aqueous layer was extracted with ethyl acetate. The
organic layer was washed with brine, and dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (20% ethyl acetate in
hexane) to give N-alkylated product 3.
1
7.26−7.34 (m, 4H), 6.85 (d, 2H, J = 8.5 Hz), 6.61 (d, 1H, J =
15.9 Hz), 6.08 (dd, 1H, J = 15.9, 7.3 Hz), 4.81 (d, 1H, J = 5.6
Hz), 4.38−4.40 (m, 1H), 3.80 (s, 3H), 2.60 (d, 2H, J = 6.1 Hz),
2.41 (s, 3H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.1,
159.4, 142.3, 141.2, 132.1, 129.5, 129.1, 127.7, 126.4, 125.4,
113.9, 81.3, 55.2, 53.6, 42.1, 28.0, 21.3, 21.2; IR (CHCl3) 3202,
2971, 2929, 1724, 1607, 1510, 1366, 1297, 1250, 1152, 1034,
814, 625 cm−1; [α]D23 +103 (c 1.45, CHCl3); HRMS(ESI) calcd
for C23H29NO4SNa [M+Na]+ 438.1710, found 438.1701.
tert-Butyl
(R)-
5-(p-chlorophenyl)-3-{(S)-p-toluenesulfinylamino}-4-penten
oate (1h): Yield: 71 % (29.8 mg, 0.071 mmol), colorless oil;
1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J = 8.0 Hz),
7.29−7.31 (m, 6H), 6.60 (d, 1H, J = 15.9 Hz), 6.22 (dd, 1H, J =
15.9, 7.1 Hz), 4.86 (d, 1H, J = 5.9 Hz) 4.35−4.41 (m, 1H), 2.60
(d, 2H, J = 5.9 Hz), 2.41 (s, 3H), 1.40 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 170.0, 142.0, 141.3, 134.7, 133.5, 131.2,
129.54, 129.53, 128.7, 127.7, 125.4, 81.4, 53.3, 41.8, 28.1, 28.0,
tert-Butyl
(R)-{N-benzyl-N-(S)-p-toluenesulfinyl}amino-3-phenylprop
anoate (3a): Yield: 53% (23.8 mg, 0.053 mmol), yellow oil; 1H
NMR (400 MHz, CDCl3) δ 7.69 (d, 2H, J = 8.3 Hz), 7.20−7.41
(m, 10H), 6.96 (d, 2H, J = 7.6 Hz), 4.71 (t, 1H, J = 7.8 Hz) 4.05
(d, 1H, J = 15.1 Hz), 3.62 (d, 1H, J = 15.1 Hz), 3.15 (dd, 1H, J
= 15.9, 8.5 Hz), 2.85 (dd, 1H, J = 15.9, 7.1 Hz), 2.39 (s, 3H),
1.33 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.5, 141.2,
141.0, 138.3, 136.3, 129.5, 129.0, 128.6, 128.5, 128.4, 128.3,
128.2, 127.9, 127.5, 127.3, 126.4, 126.1, 80.9, 60.2, 47.2, 41.7,
27.9, 21.3; IR (CHCl3) 3023, 2976, 2924, 1728, 1494, 1455,
21.3; IR (CHCl3) 3190, 2976, 2929, 1725, 1490, 1367, 1152,
23
1089, 1058, 809 cm−1; [α]D
+100 (c 1.67, CHCl3);
HRMS(ESI) calcd for C22H26ClNO3SNa [M+Na]+ 442.1214,
found 442.1203.
tert-Butyl
(R)-3-{(S)-p-toluenesulfinylamino}pentanoate
(1i): Yield: 51 % (15.9 mg, 0.051 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, 2H, J = 8.3 Hz), 7.29 (d,
2H, J = 8.3 Hz), 4.61 (d, 1H, J = 8.3 Hz), 3.52−3.57 (m, 1H),
2.50 (d, 2H, J = 5.6 Hz), 2.41 (s, 3H), 1.64−1.71 (m, 2H), 1.41
(s, 9H) 0.99 (t, 3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ
170.9, 142.5, 141.1, 129.4, 125.5, 81.0, 53.9, 41.1, 28.5, 28.0,
21.3, 10.4; IR (CHCl3) 3208, 2973, 2929, 2871, 1726, 1455,
1366, 1250, 1158, 1089, 1057, 811 cm−1; [α]D23 +64.7 (c 0.700,
CHCl3); HRMS(ESI) calcd for C16H25NO3SNa [M+Na]+
334.1447, found 334.1438.
23
1367, 1149, 1090, 1068, 813, 754, 698 cm−1; [α]D +10.7 (c
1.31, MeOH); HRMS(ESI) calcd for C27H31NO3SNa [M+Na]+
472.1917, found 472.1909.
tert-Butyl
(R)-{N-methyl-N-(S)-p-toluenesulfinyl}amino-3-phenylprop
anoate (3b): Yield: 72% (26.9 mg, 0.072 mmol), colorless oil;
1H NMR (400 MHz, CDCl3) δ 7.46−7.51 (m, 4H), 7.38 (m,
2H), 7.27−7.31 (m, 3H), 5.02 (dd, 1H, J = 7.7, 7.7 Hz), 3.17
(dd, 1H, J = 15.9, 7.7 Hz), 2.99 (dd, 1H, J = 15.9, 7.7 Hz), 2.39
(s, 3H), 2.25 (s, 3H), 1.37 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 169.7, 140.9, 140.7, 139.0, 129.5, 128.5, 127.9, 127.7,
126.2, 81.1, 63.6, 39.8, 28.0, 27.9, 21.2; IR (CHCl3) 2976,
2929, 1728, 1455, 1367, 1261, 1151, 1089, 1067, 813, 700
tert-Butyl
(R)-4-methyl-3-{(S)-p-toluenesulfinylamino}pentanoate (1j):
1
Yield: 55 % (17.9 mg, 0.055 mmol), colorless oil; H NMR
(400 MHz, CDCl3) δ 7.61 (d, 2H, J = 8.3 Hz), 7.29 (d, 2H, J =
8.3 Hz), 4.57 (d, 1H, J = 8.5 Hz), 3.45−3.49 (m, 1H), 2.57 (dd,
2H, J = 5.6, 1.5 Hz), 2.40 (s, 3H), 1.94−1.97 (m, 1H), 1.42 (s,
9H) 0.97−0.99 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 171.1,
142.8, 141.1, 129.4, 125.3, 81.0, 58.6, 39.1, 31.9, 28.0, 21.3,
22
cm−1; [α]D +46.4 (c 0.610, CHCl3); HRMS(ESI) calcd for
C21H27NO3SNa [M+Na]+ 396.1604, found 396.1596.
tert-Butyl
19.0, 18.6; IR (CHCl3) 3202, 2965, 2929, 1726, 1367, 1156,
23
1089, 1058, 810 cm−1; [α]D
+68.3 (c 1.16, CHCl3);
(R)-{N-ethyl-N-(S)-p-toluenesulfinyl}amino-3-phenylpropan
oate (3c): Yield: 28% (10.9 mg, 0.028 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, 2H, J = 8.0 Hz), 7.52 (d,
2H, J = 8.0 Hz), 7.37 (m, 2H), 7.27−7.30 (m, 3H), 4.93 (t, 1H,
J = 7.7 Hz), 3.15 (m, 1H), 2.93−2.98 (m, 2H), 2.60 (m, 1H),
2.40 (s, 3H), 1.38 (s, 9H), 0.81 (t, 3H, J = 7.2 Hz); 13C NMR
(100 MHz, CDCl3) δ 169.8, 141.0, 140.8, 139.1, 129.3, 128.6,
127.9, 127.8, 126.5, 126.2, 81.0, 60.0, 41.8, 41.4, 38.1, 27.9,
21.3, 14.4, 13.8; IR(CHCl3) 2975, 2929, 1728, 1455, 1367,
HRMS(ESI) calcd for C17H27NO3SNa [M+Na]+ 348.1604,
found 348.1595.
tert-Butyl
(R)-4,4-dimethyl-3-{(S)-p-toluenesulfinylamino}pentanoate
(1k): Yield: 85 % (28.9 mg, 0.085 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.62 (d, 2H, J = 8.4 Hz), 7.29 (d,
2H, J = 8.4 Hz), 4.63 (d, 1H, J = 8.8 Hz), 3.55 (ddd, J = 8.8,
5.6, 5.6 Hz, 1H), 2.64 (dd, 1H, J = 16.0, 5.6 Hz), 2.52 (dd, 1H,
J = 16.0, 5.6 Hz), 2.40 (s, 3H), 1.45 (s, 9H) 0.97 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 171.4, 143.3, 141.0, 129.4, 125.2,
81.1, 62.1, 38.1, 35.7, 27.9, 26.6, 21.3; IR (CHCl3) 3197, 2972,
19
1148, 1087, 1066, 809, 700 cm−1; [α]D +48.5 (c 0.910,
CHCl3); HRMS(ESI) calcd for C22H29NO3SNa [M+Na]+
470.1760, found 470.1753.
24
1731, 1366, 1152, 1090, 1065, 809 cm−1; [α]D +95.8 (c 1.08,
tert-Butyl
CHCl3); HRMS(ESI) calcd for C18H29NO3SNa [M+Na]+
362.1760, found 362.1750.
(R)-{N-allyl-N-(S)-p-toluenesulfinyl}amino-3-phenylpropan
oate (3d): Yield: 65% (25.2 mg, 0.065 mmol), colorless oil; 1H
NMR (400 MHz, CDCl3) δ 7.60 (d, 2H, J = 7.8 Hz), 7.50 (d,
2H, J = 7.8 Hz), 7.38 (m, 2H), 7.30−7.35 (m, 3H), 5.46 (m, 1H),
4.91−5.02 (m, 3H), 3.51 (dd, 1H, J = 15.5, 4.8 Hz), 3.22 (dd,
1H, J = 16.2, 9.1 Hz), 3.07 (dd, 1H, J = 15.5, 8.3 Hz), 2.92 (dd,
1H, J = 16.2, 6.7 Hz), 2.40 (s, 3H), 1.38 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 169.7, 141.1, 141.0, 138.8, 134.2, 129.4, 128.6,
General Procedure for the synthesis of tert-butyl
(R)-3-[{(S)-N-alkyl-N-p-toluenesulfinyl}amino]-5-phenylpen
tanoate 3 in Flow: The flow system was established with a
syringe pump (HII-10B, Techno applications®), Teflon tube,
the flow reactor (Comet X-01-T, Techno applications®). Before

127.98, 127.96, 126.5, 118.5, 81.0, 60.2, 46.5, 41.5, 27.9, 21.3;
IR (CHCl3) 2977, 2924, 1729, 1367, 1149, 1090, 1069, 813,
700 cm−1; [α]D22 +22.5 (c 0.550, CHCl3); HRMS(ESI) calcd for
C23H29NO3SNa [M+Na]+ 422.1760, found 422.1749.
Marteinez-Ripoll, I. Fonseca, I. André, A. Rodríquez,
Chem. Eur. J. 2003, 9, 2867.
15. T. Akindele, Y. Yamamoto, M. Maekawa, H. Umeki, K.
Yamada, K. Tomioka, Org. Lett. 2006, 8, 5729.
16. M. E. Scott, W. Han, M. Lautens, Org. Lett. 2004, 6,
3309.
Acknowledgement
This work was supported by JSPS KAKENHI
‘Middle-Molecular Strategy’ (JP15H05837) and was partially
supported by the Platform Project for Supporting Drug
Discovery and Life Science Research funded by Japan Agency
for Medical Research and Development (AMED).
17. F. A. Davis, R. E. Reddy, J. M. Szewczyk, G. V. Reddy,
P. S. Portonovo, H. Zhang, D. L. Fanelli, R. T. Reddy, P.
Zhou, P. J. Carroll, J. Org. Chem. 1997, 62, 2555.
18. S. Morales, F. G. Guijaro, J. L. G. Ruano, M. B. Cid, J.
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