Umpolung Reactions of α-Tosyloximino Esters in a Flow System

Article abstract of DOI:10.1055/s-0040-1707265

An umpolung reaction of α-tosyloximino esters in a flow system is disclosed. Tandem N, N-dialkylations with two different Grignard reagents gave the desired N, N-dialkylated products in moderate to good yields. In addition, a tandem N, N, C-trialkylation of an α-tosyloximino ester with three different Grignard reagents has been successfully achieved to afford the desired N, N, C-trialkylated product in moderate yield.

Full text of DOI:10.1055/s-0040-1707265

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–G
cluster
A
Integrated Synthesis Using Continuous-
K. Ota et al.
Cluster
Synlett
Umpolung Reactions of -Tosyloximino Esters in a Flow System
Kazuki Otaa
Shinya Fukumotoa
Taiki Iwasea
Isao Mizotaa
Makoto Shimizu*a,b
Iwao Hachiya*a
R1
R2
N
R
CO2Et
TsO
R
N,N-dialkylated
product
11 examples
up to 71% yield
N
N-monoalkylation
N,N,C-trialkylation
CO2Et
R1
R
R2
α-tosyloximino ester
N
M1
M2
M3
M4
CO2Et
a Department of Chemistry for Materials, Graduate School of
Engineering, Mie University, Tsu, Mie 514-8507, Japan
hachiya@chem.mie-u.ac.jp
b School of Energy Science and Engineering, Nanjing Tech Uni-
versity, Nanjing 211816, Jiangsu Province, P. R. of China
mshimizu@chem.mie-u.ac.jp
R3
N,N,C-trialkylated
product
R2MgBr
oxidant
R3MgBr
R1MgBr
1 example
57% yield
= micromixer
M
N,N-dialkylation
Published as part of the Cluster
Integrated Synthesis Using Continuous-Flow Technologies
Corresponding Author
Iwao Hachiya
Received: 20.07.2020
Accepted after revision: 03.08.2020
Published online: 03.09.2020
temperature of –78 °C problems were encountered in intro-
ducing a second substituent onto the imino nitrogen atom
to give an N,N-dialkylated amino ester (Scheme 1a). In
N,N,C-trialkylations of (Z)-tosyloximino esters, N,N,C-trial-
kylated -amino acid derivatives with two identical substit-
uents on the amino nitrogen were obtained (Scheme 1b). In
2015, we reported that N,N,C-trialkylated -amino acid de-
rivatives with two different alkyl substituents on the nitro-
DOI: 10.1055/s-0040-1707265; Art ID: st-2020-u0409-c
Abstract An umpolung reaction of -tosyloximino esters in a flow
system is disclosed. Tandem N,N-dialkylations with two different Gri-
gnard reagents gave the desired N,N-dialkylated products in moderate
to good yields. In addition, a tandem N,N,C-trialkylation of an -tosylox-
imino ester with three different Grignard reagents has been successful-
ly achieved to afford the desired N,N,C-trialkylated product in moderate
yield.
(a) Domino N,N-dialkylation using (E)-nosyloximino ester
p-NsO
Et
R
Key words umpolung, tosyloximino esters, tandem, alkylation,
Grignard reagents, flow reactor
EtMgBr in Et2O (2.0 equiv)
toluene, –78 °C, 30 min
RMgX (2.0 equiv)
N
N
DME, –78 °C to rt, 1 h
Ph
CO2Et
Ph
CO2Et
p-Ns = 4-O2NC6H4SO2
up to 60%
Natural products, pharmaceuticals, and the basic skele-
tons of other important biologically active compounds fre-
quently include nitrogen-containing organic moieties.
Among nitrogen-containing compounds, -amino acids and
their derivatives, including amino esters and amino alco-
hols, have attracted considerable attention. Consequently,
there has been a considerable desire to develop reactions
that efficiently synthesize compounds with various substit-
uents on both the nitrogen and the carbon atoms at the -
positions of -amino acid moieties. -Imino esters are
among the most useful nitrogen-containing starting mate-
rials for the synthesis of various natural and nonnatural -
amino acid derivatives.1,2
We have previously reported that the N-alkylation reac-
tion of -imino esters with Grignard reagents proceeds
smoothly to give the N-alkylated products,3 and that N,N-
dialkylations and N,N,C-trialkylations of -sulfoximino es-
ters give the corresponding -amino acid derivatives.4
There are some limitations on these reactions; for example,
the use of an (E)-nosyloximino ester was needed for the
synthesis of N,N-dialkylated -amino acid derivatives hav-
ing two different substituents on the amino nitrogen. How-
ever, when reaction was conducted at the extremely low
(b) Domino N,N,C-trialkylation using (Z)-tosyloximino ester
Et
Et
OTs
N
EtMgBr in Et2O (2.2 equiv)
toluene, 30 °C, 15 min
N
OMgBr
OEt
Ph
Ph
CO2Et
Et
N
Et
Et
Et
DBDMH (0.6 equiv)
EtCN, 30 °C, 15 min
RMgBr (2.0 equiv)
30 °C, 15 min
N
Br
CO2Et
Ph
R
CO2Et
Ph
DBDMH = 1,3-dibromo-5,5-
dimethylhydantoin
up to 74%
(c) Domino N,N,C-trialkylation using (Z)-p-toluoyloximino ester
1. EtMgBr (2.2 equiv)
toluene, –78 °C, 30 min
Et
n-Pr
2. PhCO2H (0.75 equiv)
toluene, –78 to 30 °C, 15 min
N
OCO(p-MeC6H4)
N
OMgBr
OEt
Ph
3. n-PrMgBr (1.75 equiv)
30 °C, 30 min
Ph
CO2Et
Et
n-Pr
Et
n-Pr
Br
N
R
DBDMH (0.6 equiv)
CH2Cl2, 30 °C, 15 min
RMgBr (2.0 equiv)
30 °C, 15 min
N
Ph
CO2Et
Ph
CO2Et
up to 64%
Scheme 1 Previous tandem N,N-dialkylation and N,N,C-trialkylation re-
actions
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Ota et al.
Cluster
Synlett
gen atom could be synthesized by using -N-p-toluoyloxi-
mino esters as highly efficient starting -imino esters
(Scheme 1c).5
First, we screened the reaction conditions for N-mono-
ethylation of the -tosyloximino ester (E)-1a by using a
Comet X-01 micromixer (Figure S1).8,9 The results are sum-
marized in Table 1. A solution of (E)-1a in toluene and a
solution of ethylmagnesium bromide (EtMgBr) in toluene–
diethyl ether were mixed by using the Comet X-01 at vari-
ous temperatures. When the reaction was carried out at
room temperature, the desired N-monoethylated product 2
was obtained in 37% yield, accompanied by the diethylated
product 3a in 18% yield (Table 1, entry 1). Lower reaction
temperatures gave better yields (entries 2–5). Although the
best yield (70%) was obtained at –78 °C, we continued to ex-
amine the effects of various concentrations of EtMgBr at the
milder temperature of –40 °C (entries 6–10). The use of 1.4
equivalents of EtMgBr slightly improved the yield (entry 7).
The use of the isomer (Z)-1a was then examined under sev-
eral reaction conditions, but the desired monoethylated
product 2 was not obtained (entries 11–13).
Flow systems can provide conditions different from
those of batch processes conducted in flasks. A reaction
field in micro-space can increase the efficiency of heat ex-
change, permitting better control of the reaction tempera-
ture than in a batch reaction. In addition, because tandem
reactions can be easily carried out, it becomes possible to
use unstable intermediates and to synthesize products effi-
ciently and rapidly.6,7 Here, we report N,N-dialkylation, and
N,N,C-trialkylation reactions of -tosyloximino esters in a
flow system; this has such advantages as high efficiency
and rapid heat transfer compared with conventional batch
reactions (Scheme 2).
R1
R2
N
TsO
R
N
R
CO2Et
N-monoalkylation
N,N,C-trialkylation
N,N-dialkylated
product
CO2Et
R1
R
R2
N
M1
M2
M3
M4
CO2Et
R3
R2MgBr
N,N,C-trialkylated
product
oxidant
R3MgBr
R1MgBr
= micromixer
M
N,N-dialkylation
Scheme 2 Tandem N,N-dialkylation and N,N,C-trialkylation reactions in
a flow system
Table 1 Optimization of the N-Monoethylation of -Tosyloximino Ester 1a
temp. (°C)
TsO
Ph
Φ = 2 mm, 100 cm
20 s
OTs
N
N
P1
9.5 mL/min
or
Ph
CO2Et
CO2Et
(E)-1a
0.02 M in toluene
(Z)-1a
M1
Comet X-01
Et
Et
Et
R1
N
N
+
Φ = 2 mm
20 cm
2.0 s
Ph
CO2Et
Ph
CO2Et
2
3a
P2
9.5 mL/min
EtMgBr
X x M in toluene–Et2O
0.02
Entry
E/Z
Temp (°C)
EtMgBr (equiv)
Yield (%)
2 (Z/E)
3a
1a
16
1
2
3
4
5
6
7
8
9
E
E
E
E
E
E
E
E
E
rt
1.0
1.0
1.0
1.0
1.0
1.2
1.4
1.6
1.8
37 (83:17)
34 (88:12)
51 (92:8)
58 (89:11)
70 (90:10)
56 (89:11)
61 (91:9)
49 (92:8)
41 (93:7)
18
4
0
12
8
–20
–40
–78
–40
–40
–40
–40
10
6
9
10
5
10
9
17
22
37
3
1
0
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

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K. Ota et al.
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Entry
E/Z
Temp (°C)
EtMgBr (equiv)
Yield (%)
2 (Z/E)
3a
40
1a
10
11
12
13
E
–40
–40
–40
rt
2.0
1.0
2.0
2.2
23 (85:15)
0
Z
Z
Z
0
0
0
3
90
4
95
52
41
Because the starting material (E)-1a was recovered in
some cases, we next examined the use of two connected
Comet X-01 micromixers to increase the mixing efficiency
(Figure 1).
The results are summarized in Table 2. The formation of
the diethylated product 3a increased and (E)-1a was not re-
covered (entries 2–6). Benzoic acid (BzOH) was examined
as an additive to quench excess EtMgBr and to activate (E)-
1a. A solution of (E)-1a containing BzOH in toluene and a
solution of EtMgBr in toluene–diethyl ether were mixed by
using the two connected Comet X-01 micromixers. The use
of 2.0 equivalents of EtMgBr and 0.5 equivalents of BzOH
gave the desired N-monoethylated product 2 in the best
yield of 69% (entry 9).9
Tandem N,N-dialkylations with two different Grignard
reagents were next examined. The reaction conditions were
screened by using ethyl and propyl Grignard reagents. The
results are summarized in Table 3. The use of 2.0 equiva-
lents of EtMgBr, 0.5 equivalents of BzOH, and 2.0 equiva-
lents of PrMgBr gave the desired N-ethyl N-propyl product
3b in the best yield of 71% (entry 3).10,11
Figure 1 Connected Comet X-01 micromixers
Table 2 Optimization of the N-Monoethylation of -Tosyloximino Ester (E)-1a in Two Connected Comet X-01 Micromixers
TsO
–40 °C
N
Φ = 2 mm, 100 cm
20 s
Ph
CO2Et
(E)-1a
P1
9.5 mL/min
0.02 M in toluene
+
M1
Comet X-01 x 2
Et
Et
Et
R1
N
N
PhCO2H
0.02 X y M in toluene
+
Φ = 2 mm
20 cm
2.0 s
Ph
CO2Et
Ph
CO2Et
2
3a
P2
9.5 mL/min
EtMgBr
X x M in toluene–Et2O
0.02
Entry
EtMgBr (equiv)
BzOH (equiv)
Yield (%)
2 (Z/E)
3a
(E)-1a
1
2
3
4
5
6
7
8
9
1.0
1.2
1.4
1.6
1.8
2.0
1.2
1.4
2.0
–
56 (94:6)
67 (89:11)
60 (95:5)
57 (93:7)
48 (90:10)
40 (93:7)
36 (92:8)
44 (89:11)
69 (92:8)
8
13
0
–
12
20
22
30
38
3
–
0
–
0
–
0
–
0
0.5
0.5
0.5
27
23
0
4
15
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

D
K. Ota et al.
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Synlett
Table 3 Optimization of the Tandem N,N-Dialkylation of -Tosyloximino ester (E)-1a
TsO
–40 °C
N
Φ = 2 mm, 100 cm
20 s
Ph
CO2Et
(E)-1a
P1
9.5 mL/min
0.02 M in toluene
+
M1
Comet X-01 x 2
M2
Et
n-Pr
R1
R2
N
PhCO2H
0.02 X y M in toluene
Comet X-01
Ph
CO2Et
Φ = 2 mm
5 cm
0.5 s
Φ = 2 mm
20 cm
1.3 s
3b
9.5 mL/min
P2
9.5 mL/min
Et
Et
n-Pr
n-Pr
EtMgBr
x M in toluene–Et2O
N
N
0.02
X
n-PrMgBr
0.04 M in DME–Et2O
Ph
CO2Et
3a
Ph
CO2Et
3c
Entry
EtMgBr (equiv)
BzOH (equiv)
Yield (%)
3b
3a
3c
1
1.6
1.8
2.0
2.2
2.0
2.0
2.0
2.0
2.0
2.5
2.5
0.5
0.5
0.5
0.5
1.0
0.7
0.6
0.4
0.3
1.0
1.5
49
62
71
58
50
57
61
65
61
63
54
5
4
3
0
6
2
12
3
6
4
10
7
5
13
6
15
9
0
7
5
8
9
0
9
16
8
1
10
11
5
12
14
With the optimized reaction conditions in hand, we
used a variety of second Grignard reagents and -tosyloxi-
mino esters 1 in the tandem N,N-dialkylation (Scheme 3).
Methyl Grignard reagent as the second nucleophile did not
give the desired product 3d, as previously reported.3 The
use of primary benzyl Grignard reagent afforded the prod-
uct 3e in 52% yield. Secondary alkyl (isopropyl and cyclo-
hexyl) Grignard reagents gave the corresponding products
3f and 3g in yields of 60 and 46%, respectively. The use of
tert-butyl Grignard reagent afforded product 3h in a lower
yield of 21% as a result of steric hindrance. The scope of the
aromatic group was next examined. -Tosyloximino esters
(E)-1b–d containing tolyl groups gave the desired products
3i–k in moderate yields. -Tosyloximino esters (E)-1e and
1f, with electron-withdrawing and electron-donating
groups respectively, gave the corresponding products 3l
and 3m in yields of 63 and 43%, respectively.
porting Information, Figure S2).9 The results are summa-
rized in Table 4. The use of 1.2 equivalents of DBDMH and
2.5 equivalents of BnMgBr afforded the desired N-ethyl N-
propyl C-benzyl product 4 in the best yield of 57% (entry 6).
Based on our previous study,5 a plausible reaction
mechanism for the N-mono-, N,N-di-, and N,N,C-trialkyla-
tions of -tosyloximino ester (E)-1a is shown in Scheme 4.
The addition of the first Grignard reagent gives (Z)-2
through either an addition–elimination reaction (path a) or
an SN2 reaction (path b). With regard to the role of benzoic
acid, we presume that it coordinates to the tosyloxy group
of intermediate A or B to facilitate its elimination. (Z)-2
might isomerize to (E)-2 in the presence of benzoic acid or
bromomagnesium tosylate. The addition of the second Gri-
gnard reagent gives the magnesium enolate D via the five-
membered intermediate C. The magnesium enolate D is hy-
drolyzed to afford the N,N-dialkylated product 3. Oxidation
of the magnesium enolate D with DBDMH generates the
iminium salt E, which undergoes an addition reaction with
the third Grignard reagent to give the N,N,C-trialkylated
product 4.
Finally, we examined the tandem N,N,C-trialkylation of
-tosyloximino ester 1a with three different Grignard re-
agents. Effects of the number of equivalents of 1,3-dibro-
mo-5,5-dimethylhydantoin (DBDMH) as an oxidant and of
BnMgBr as the third nucleophile were examined (see Sup-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
K. Ota et al.
Cluster
Synlett
TsO
R
–40 °C
N
1b: R = o-tolyl
1c: R = m-tolyl
1d: R = p-tolyl
1e: R = 4-ClC6H4
1f: R = 4-MeOC6H4
Φ = 2 mm, 100 cm
20 s
CO2Et
(E)-1
P1
9.5 mL/min
0.02 M in toluene
+
M1
Comet X-01 x 2
M2
Et
R2
R1
R2
N
PhCO2H
0.01 M in toluene
Comet X-01
R
CO2Et
Φ = 2 mm
5 cm
0.5 s
Φ = 2 mm
20 cm
1.3 s
3
9.5 mL/min
R2MgBr
P2
9.5 mL/min
EtMgBr
0.04 M in toluene–Et2O
0.04 M in DME–Et2O
Et
N
Et
Me
Et
Et
Et
Et
N
N
Ph
CO2Et
N
N
N
Ph
CO2Et
Ph
CO2Et
Ph
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
3b, 71% (79%)a
3d, 0% (0%)a
3e, 52% (64%)a,b
3f, 60% (72%)a
3g, 46% (39%)a
3h, 21% (21%)a,c
Et
N
Et
Et
N
Et
Et
N
N
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
MeO
Cl
3j, 49%
3m, 43%
3i, 45%
3k, 56%
3l, 63%
Scheme 3 Tandem N,N-dialkylations of various -tosyloximino esters (E)-1. a Yield previously obtained under batch conditions.5 b BnMgBr (0.05 M) was
used. c t-BuMgCl (0.05 M) in DME–THF was used.
Table 4 Optimization of the Tandem N,N,C-Trialkylation of -Tosyloximino Ester (E)-1a
TsO
–40 °C
N
Φ = 2 mm, 100 cm
Ph
CO2Et
(E)-1a
P1
9.5 mL/min
20 s
0.02 M in toluene
+
M1
Comet X-01 x 2
M2
M3
M4
Et
n-Pr
N
R1
R2
R3
R4
PhCO2H
0.01 M in toluene
Comet X-01
Comet X-01
Comet X-01
Ph
CO2Et
Bn
Φ = 2 mm
5 cm
0.5 s
Φ = 2 mm
20 cm
1.3 s
Φ = 2 mm
20 cm
1.0 s
Φ = 2 mm
20 cm
9.5 mL/min
9.5 mL/min
9.5 mL/min
4
0.8 s
P2
9.5 mL/min
EtMgBr
0.04 M in toluene–Et2O
BnMgBr
y M in DME–Et2O
DBDMH
X x M in CH2Cl2
n-PrMgBr
0.04 M in DME–Et2O
0.02
X
0.02
Entry
DBDMH (equiv)
BnMgBr (equiv)
Yield (%) of 4
1
2
3
4
5
6
7
0.6
0.8
1.0
1.2
1.5
1.2
1.2
2.0
2.0
2.0
2.0
2.0
2.5
3.0
0
0
43
47
45
57 (64)a
46
a Yield previously obtained under batch conditions.5
In conclusion, we have investigated the umpolung reac-
tion of -tosyloximino esters in a flow system. Tandem N,N-
dialkylations with two different Grignard reagents gave the
desired N,N-dialkylated products in moderate to good
yields. In addition, the tandem N,N,C-trialkylation of an -
tosyloximino ester with three different Grignard reagents
proceeded successfully to afford the desired N,N,C-trial-
kylated product in moderate yield. The present flow system
is an attractive because one step can be eliminated by si-
multaneous introduction of benzoic acid. Moreover, the
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

F
K. Ota et al.
Cluster
Synlett
R1
R
R2
OEt
TsO
N
N
1) R1MgBr, PhCO2H
OEt
2) R2MgX
3) H2O
R
O
O
1
3
+ PhCO2H
R1MgBr
path a
H2O
R2
O
path b
Br
Br
R1
R
N
N
O
R2
R1
R
N
N
OEt
O
CO2Et
R1
O
Br
H
S
MgX
R1
O
O
O
Mg Br
D
O
Mg Br
OEt
N
S
O
N
Tol
R3MgBr
O
O
Tol
R
O
R
OEt
R2
O
R2
R1
R
B
R1
Mg
X
N
Br
N
CO2Et
O
R
E
SN2 reaction
addition
R3 MgBr
OEt
C
R2MgX
OEt
O
H
S
R1
R1
R
R2
R1
R
PhCO2H
TsOMgBr
O
O
N
N
N
elimination
R1
N
OEt
O
MgBr
R
CO2Et
Tol
R3
O
O
O
O
R
OEt
(Z)-2
(E)-2
4
A
Scheme 4 Plausible reaction mechanism
N,N-dialkylated and N,N,C-trialkylated products are useful
intermediates for syntheses of biologically active com-
pounds, and they can be synthesized at the less extreme
temperature of –40 °C in a shorter time in comparison with
the previously reported batch conditions.
(3) For representative N-alkylations of -imino esters by our group,
see: (a) Shimizu, M.; Niwa, Y. Tetrahedron Lett. 2001, 42, 2829.
(b) Niwa, Y.; Takayama, K.; Shimizu, M. Tetrahedron Lett. 2001,
42, 5473. (c) Niwa, Y.; Takayama, K.; Shimizu, M. Bull. Chem. Soc.
Jpn. 2002, 75, 1819. (d) Niwa, Y.; Shimizu, M. J. Am. Chem. Soc.
2003, 125, 3720. (e) Mizota, I.; Tanaka, K.; Shimizu, M. Tetrahe-
dron Lett. 2012, 53, 1847. (f) Shimizu, M.; Takao, Y.;
Katsurayama, H.; Mizota, I. Asian J. Org. Chem. 2013, 2, 130.
(g) Shimizu, M.; Kurita, D.; Mizota, I. Asian J. Org. Chem. 2013, 2,
208. (h) Mizota, I.; Matsuda, Y.; Kamimura, S.; Tanaka, H.;
Shimizu, M. Org. Lett. 2013, 15, 4206. (i) Tanaka, H.; Mizota, I.;
Shimizu, M. Org. Lett. 2014, 16, 2276. (j) Tanaka, T.; Mizota, I.;
Umezu, K.; Ito, A.; Shimizu, M. Heterocycles 2017, 95, 830.
(k) Kawanishi, M.; Mizota, I.; Aratake, K.; Tanaka, H.; Nakahama,
K.; Shimizu, M. Bull. Chem. Soc. Jpn. 2017, 90, 395. (l) Mizota, I.;
Nakajima, Y.; Higashino, A.; Shimizu, M. Arabian J. Sci. Eng.
2017, 42, 4249. (m) Nakahama, K.; Suzuki, M.; Ozako, M.;
Mizota, I.; Shimizu, M. Asian J. Org. Chem. 2018, 7, 910.
(n) Mizota, I.; Tadano, Y.; Nakamura, Y.; Haramiishi, T.; Hotta,
M.; Shimizu, M. Org. Lett. 2019, 21, 2663. (o) Shimizu, M.;
Mushika, M.; Mizota, I.; Zhu, Y. RSC Adv. 2019, 9, 23400.
Funding Information
This work was supported by the Japan Society for the Promotion of
Science (JSPS) KAKENHI Grant No. JP18H04402 in Middle Molecular
Strategy and JP17K05860.Japa
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707265. Su
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References and Notes
(4) Hata, S.; Maeda, T.; Shimizu, M. Bull. Chem. Soc. Jpn. 2012, 85,
1203.
(1) For reviews on ,-disubstituted -amino acids and their
peptides, see: (a) Venkatraman, J.; Shankaramma, S. C.;
Balaram, P. Chem. Rev. 2001, 101, 3131. (b) Tanaka, M. Chem.
Pharm. Bull. 2007, 55, 349. (c) Vogt, H.; Bräse, S. Org. Biomol.
Chem. 2007, 5, 406.
(2) For a review on recent advances in applications of -imino
esters in organic synthesis, see: Eftekhari-Sis, B.; Zirak, M. Chem.
Rev. 2017, 117, 8326.
(5) Mizota, I.; Maeda, T.; Shimizu, M. Tetrahedron 2015, 71, 5793.
(6) For representative reviews on flow-microreactor syntheses, see:
(a) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.;
McQuade, D. T. Chem. Rev. 2007, 107, 2300. (b) Ahmed-Omer,
B.; Brandt, J. C.; Wirth, T. Org. Biomol. Chem. 2007, 5, 733.
(c) Watts, P.; Wiles, C. Chem. Commun. 2007, 443. (d) Fukuyama,
T.; Rahman, M. T.; Sato, M.; Ryu, I. Synlett 2008, 151.
(e) Hartman, R. L.; Jensen, K. F. Lab Chip 2009, 9, 2495.
(f) McMullen, J. P.; Jensen, K. F. Annu. Rev. Anal. Chem. 2010, 3,
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
K. Ota et al.
Cluster
Synlett
19. (g) Yoshida, J.-i.; Kim, H.; Nagaki, A. ChemSusChem 2011, 4,
331. (h) Wiles, C.; Watts, P. Green Chem. 2012, 14, 38.
(i) Kirschning, A.; Kupracz, L.; Hartwig, J. Chem. Lett. 2012, 41,
562. (j) McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78,
6384. (k) Elvira, K. S.; Casdevall i Solvas, X.; Wootton, R. C. R.;
deMello, A. J. Nat. Chem. 2013, 5, 905. (l) Pastre, J. C.; Browne, D.
L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849. (m) Baxendale, I. R. J.
Chem. Technol. Biotechnol. 2013, 88, 519. (n) Fukuyama, T.;
Totoki, T.; Ryu, I. Green Chem. 2014, 16, 2042. (o) Gemoets, H. P.
L.; Su, Y.; Shang, M.; Hessel, V.; Luque, R.; Noël, T. Chem. Soc.
Rev. 2016, 45, 83. (p) Cambié, D.; Bottecchia, C.; Straathof, N. J.
W.; Hessel, V.; Noël, T. Chem. Rev. 2016, 116, 10276.
(q) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H.
Chem. Rev. 2017, 117, 11796. (r) Gutmann, B.; Kappe, C. O.
J. Flow Chem. 2017, 7, 65.
Shirahata, T.; Yokoyama, M.; Katsumi, T.; Ito, Y.; Hirata, N.;
Nishino, T.; Makino, K.; Sato, N.; Nagai, T.; Kiyohara, H.; Yamada,
H.; Kaji, E.; Kobayashi, Y. J. Org. Chem. 2017, 82, 6703. (m) Ikawa,
T.; Masuda, S.; Akai, S. Chem. Pharm. Bull. 2018, 66, 1153.
(n) Myachin, I. V.; Orlova, A. V.; Kononov, L. O. Russ. Chem. Bull.
2019, 68, 2126. (o) Arakawa, Y.; Ueta, S.; Okamoto, T.;
Minagawa, K.; Imada, Y. Synlett 2020, 31, 866.
(9) See the Supporting Information for details.
(10) Results with other acids as additives are summarized in Table
S1 of the Supporting Information.
(11) Ethyl [Ethyl(propyl)amino](phenyl)acetate (3b)4; Typical
Procedure
A flow-microreactor system consisting of two connected Comet
X-01 micromixers (M1), a Comet X-01 micromixer (M2), two
pre-cooling units (P1: inner diameter = 2000 m, length = 100
cm; P2: inner diameter: 2 mm, length = 100 cm), and two
Teflon tube reactors (R1: inner diameter = 2 mm, length = 5 cm;
R2: inner diameter = 2 mm, length = 20 cm) was used. The first
flow-microreactor system consisting of the two connected
Comet X-01 micromixers together with P1 and P2 was
immersed in a magnetically stirred constant-temperature bath
at –40 °C. The remainder of the system was at rt. A solution of
-tosyloxyimino ester 1a (0.02 M) and BzOH (0.01 M) in toluene
(9.5 mL/min) [prepared from -tosyloximino ester (E)-1a (138.9
mg, 0.40 mmol), BzOH (24.4 mg, 0.20 mmol), and toluene (20
mL)] was introduced into M1 by using a syringe pump. A 0.04 M
solution of EtMgBr in toluene–Et2O (9.5 mL/min) [prepared
from a 0.93 M solution of EtMgBr (0.86 mL, 0.80 mmol) in Et2O
and toluene (19.14 mL)] was also introduced into M1 by using a
syringe pump, and the mixed solution was passed through R1. A
0.04 M solution of PrMgBr in DME–Et2O (9.5 mL/min), prepared
from a 0.82 M solution of PrMgBr (0.98 mL, 0.80 mmol) in Et2O
and DME (19.02 mL), was introduced into M2 by using a syringe
pump, and the resulting solution was passed through R2. Once a
steady state was reached, the resulting solution (30 mL) was
poured into sat. aq NaHCO3 (10 mL) to quench the reaction. The
resulting mixture was extracted with EtOAc (3 × 20 mL), and the
combined organic layers were washed with brine (15 mL), dried
(Na2SO4), and filtered. The solvents were evaporated in vacuo,
and the residue was purified by preparative TLC [silica gel,
hexane–Et2O (20:1)] three times to give the desired product 3b
[yield: 35.5 mg (71%)], together with the N,N-diethyl product 3a
[yield: 3.0 mg (6%)].
(7) For some selected recent examples of flow-microreactor syn-
theses, see: (a) Fuse, S.; Mifune, Y.; Takahashi, T. Angew. Chem.
Int. Ed. 2014, 53, 851. (b) He, Z.; Jamison, T. F. Angew. Chem. Int.
Ed. 2014, 53, 3353. (c) Nagaki, A.; Takahashi, Y.; Yoshida, J.-i.
Chem. Eur. J. 2014, 20, 7931. (d) Chen, M.; Ichikawa, S.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2015, 54, 263. (e) Fuse, S.;
Mifune, Y.; Nakamura, H.; Tanaka, H. Nat. Commun. 2016, 7,
13491. (f) Nagaki, A.; Takahashi, Y.; Yoshida, J.-i. Angew. Chem.
Int. Ed. 2016, 55, 5327. (g) Seo, H.; Katcher, M. H.; Jamison, T. F.
Nat. Chem. 2017, 9, 453. (h) Mambrini, A.; Gori, D.; Kouklovsky,
C.; Kim, H.; Yoshida, J.-i.; Alezra, V. Eur. J. Org. Chem. 2018, 6754.
(i) Nagaki, A.; Sasatsuki, K.; Ishiuchi, S.; Miuchi, N.; Takumi, M.;
Yoshida, J.-i. Chem. Eur. J. 2019, 25, 4946. (j) Nagaki, A.;
Yamashita, H.; Tsuchihashi, Y.; Hirose, K.; Takumi, M.; Yoshida,
J.-i. Chem. Eur. J. 2019, 25, 13719. (k) Fuse, S.; Masuda, K.; Otake,
Y.; Nakamura, H. Chem. Eur. J. 2019, 25, 15008. (l) Sugisawa, N.;
Otake, Y. N.; Nakamura, H.; Fuse, S. Chem. Asian J. 2020, 15, 79.
(m) Alexandre Baralle, A.; Inukai, T.; Yanagi, T.; Nogi, K.; Osuka,
A.; Nagaki, A.; Yoshida, J.-i.; Yorimitsu, H. Chem. Lett. 2020, 49,
160. (n) Sugisawa, N.; Nakamura, H.; Fuse, S. Chem. Commun.
2020, 56, 4527.
(8) For representative examples of flow-microreactor syntheses
using Comet X-01, see: (a) Tanaka, K.; Fukase, K. Synlett 2007,
164. (b) Tanaka, K.; Motomatsu, S.; Koyama, K.; Tanaka, S.-i.;
Fukase, K. Org. Lett. 2007, 9, 299. (c) Tanaka, K.; Motomatsu, S.;
Koyama, K.; Fukase, K. Tetrahedron Lett. 2008, 49, 2010.
(d) Tanaka, K.; Mori, Y.; Fukase, K. J. Carbohydr. Chem. 2009, 28,
1. (e) Brandt, J.; Elmore, S.; Robinson, R.; Wirth, T. Synlett 2010,
3099. (f) Ishikawa, H.; Bondzic, B. P.; Hayashi, Y. Eur. J. Org.
Chem. 2011, 6020. (g) Uchinashi, Y.; Nagasaki, M.; Zhou, J.;
Tanaka, K.; Fukase, K. Org. Biomol. Chem. 2011, 9, 7243. (h) Sano,
T.; Mizota, I.; Shimizu, M. Chem. Lett. 2013, 42, 995.
(i) Uchinashi, Y.; Tanaka, K.; Manabe, Y.; Fujimoto, Y.; Fukase, K.
J. Carbohydr. Chem. 2014, 33, 55. (j) Pradipta, A. R.; Tsutsui, A.;
Ogura, A.; Hanashima, S.; Yamaguchi, Y.; Kurbangalieva, A.;
Tanaka, K. Synlett 2014, 25, 2442. (k) Doi, T.; Otaka, H.; Umeda,
K.; Yoshida, M. Tetrahedron 2015, 71, 6463. (l) Konishi, N.;
3b
Yellow oil. IR (neat): 1737, 1453, 1372, 1154, 1067 1029, 728,
696 cm–1 1H NMR (400 MHz, CDCl3):  = 7.42–7.40 (m, 2 H),
.
7.34–7.25 (m, 3 H), 4.51 (s, 1 H), 4.25–4.13 (m, 2 H), 2.63 (q, J =
7.3 Hz, 2 H), 2.55–2.44 (m, 2 H), 1.52–1.35 (m, 2 H), 1.24 (t, J =
7.3 Hz, 3 H), 0.98 (t, J = 7.3 Hz, 3 H), 0.81 (t, J = 7.3 Hz, 3 H). 13
C
NMR (100 MHz, CDCl3)  = 172.4, 137.4, 128.7, 128.2, 127.7,
69.1, 60.4, 52.0, 44.3, 20.4, 14.2, 12.3, 11.7. HRMS (EI): m/z [M –
C3H5O2]+ calcd for C12H18N: 176.1434; found: 176.1434.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–G