Intramolecular Hydroalkoxylation/Reduction and Hydroamination/Reduction of Unactivated Alkynes Using a Silane-Iodine Catalytic System

Article abstract of DOI:10.1055/s-0036-1588436

A transition-metal-free silane-iodine catalytic system comprising I ₂ and Et ₃ SiH promotes intramolecular hydroalkoxylation/reduction and hydroamination/reduction of unactivated alkynes. This system allows the reaction to proceed at room temperature affording 2,4- and 2,5-disubstituted pyrrolidines as well as a 2,3-disubstituted tetrahydrofuran with high diastereoselectivity..

Full text of DOI:10.1055/s-0036-1588436

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
special topic
A
en
S. Fujita et al.
Special Topic
Synthesis
Intramolecular Hydroalkoxylation/Reduction and Hydroamina-
tion/Reduction of Unactivated Alkynes Using a Silane–Iodine
Catalytic System
Silane–iodine catalytic system
Shoji Fujita
Masatoshi Shibuya*
Yoshihiko Yamamoto
0
0
0
0
0-
0
0
2
1-
8
3
0
0-
0
8
2
cat. I2, Et3SiH, H2O
CH2Cl2, r.t.
XH
X
22 examples
up to 96% yield
R
0
0
0
0
0-
0
0
1
8-
5
4
4
6-
3
2
4
R
H
H
Department of Basic Medicinal Sciences, Graduate School
of Pharmaceutical Sciences, Nagoya University, Furo-cho
Chikusa, Nagoya, 464-8601, Japan
X = O, NSO2Ar
O
H
Ts
N
Ts
N
m-shibu@ps.nagoya-u.ac.jp
Published as part of the Special Topic Modern Cyclization
Strategies in Synthesis
cis/trans = 1:7
cis/trans = 10:1
cis/trans = 23:1
High diastereoselectivity
Received: 31.03.2017
Accepted after revision: 02.05.2017
Published online: 24.05.2017
duce saturated heterocycles. Herein, we describe our devel-
opment of a silane–iodine system for the intramolecular
hydroalkoxylation/reduction and hydroamination/reduc-
tion of unactivated alkynes.
DOI: 10.1055/s-0036-1588436; Art ID: ss-2017-c0212-st
Abstract A transition-metal-free silane–iodine catalytic system com-
prising I2 and Et3SiH promotes intramolecular hydroalkoxylation/reduc-
tion and hydroamination/reduction of unactivated alkynes. This system
allows the reaction to proceed at room temperature affording 2,4- and
2,5-disubstituted pyrrolidines as well as a 2,3-disubstituted tetrahydro-
furan with high diastereoselectivity.
We previously reported a silane–iodine catalytic system
that uses I2 and PhSiH3 for the intramolecular hydroalkoxyl-
ation of unactivated alkenes.9a The reaction of monoalkyl-
and 1,2-dialkyl-substituted unactivated alkenes efficiently
proceeded at room temperature using this catalytic system.
Alkyne 1a also underwent the desired hydroalkoxylation in
the presence of a catalytic amount of I2 and a stoichiometric
amount of PhSiH3, followed by reduction to produce 1c in
86% yield (Scheme 1a).13 On the other hand, 2a underwent
a reaction in which most of the starting material was recov-
ered with a small amount of iodoketone 2d produced by the
iodinative ring opening of 2b′ (Scheme 1b). Similar results
were obtained with the reaction of several γ-hydroxy-
alkynes. In our previous study, we paid attention to the low
nucleophilicity of the conjugated bases of TfOH and Tf2NH
to prevent iodinative ring opening. This led to the develop-
ment of the Brønsted acid–silane catalytic system for the
hydroalkoxylation/reduction and hydroamination/reduc-
tion of unactivated alkynes.13 Although this method was
applicable to a variety of alkyne substrates, it required an
elevated temperature of 60 °C (Scheme 1c). Because the re-
action of 1a using I2 and PhSiH3 proceeds even at room tem-
perature, we surmised that if iodinative ring opening is
suppressed when using the iodine–silane system, intramo-
lecular hydrofunctionalization/reduction of various alkynes
would occur without the need of an elevated temperature.
Based on this idea, we optimized the reaction conditions
using an iodine reagent and a silane reagent, and found that
the combination of I2 and Et3SiH efficiently promoted the
desired reaction at room temperature; 2a was subjected to
hydroalkoxylation/reduction using I2 (10 mol%) and Et3SiH
(2.0 equiv) in CH2Cl2 at room temperature, affording 2c in
Key words iodine, silane, hydroalkoxylation, hydroamination, unacti-
vated alkyne
Oxygen- and nitrogen-containing heterocycles are im-
portant structural components of biologically active com-
pounds. A particularly attractive approach for the synthesis
of these heterocycles is the intramolecular hydroalkoxyl-
ation and hydroamination of carbon–carbon multiple
bonds, because such reactions allow the construction of
these heterocyclic structures by atom-economical cy-
cloisomerization from acyclic unsaturated compounds.1–3
A
variety of transition-metal complexes have been developed
as efficient catalysts for the hydroalkoxylation and hy-
droamination of unactivated alkynes and alkenes.4–7 Several
transition-metal-free methods for unactivated alkenes have
also been reported,8–10 but the same for unactivated alkynes
have rarely been reported.11 One reason that has prevented
the development of a transition-metal-free method for
alkynes is the inherent instability of a vinyl cation interme-
diate.12 Recently, we found that an unactivated alkyne is
electrophilically activated by a Brønsted acid, and reported
a Brønsted acid–silane catalytic system for the hydroalkox-
ylation and hydroamination of unactivated alkynes.13 Under
the reaction conditions, the exo-cyclic enol ether/enamine
formed readily generates an oxocarbenium/iminium inter-
mediate, which was effectively reduced by Et3SiH to pro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
S. Fujita et al.
Special Topic
Synthesis
termolecular attack of H2O or the remaining starting mate-
rials on the alkyne moiety did not occur. Alkyne 5a, with no
substituent on the linker between the hydroxy group and
alkyne, produced 5c in low yield. The fact that the reactions
of alkynes 8a–11a, bearing one substituent on the linker,
proceeded efficiently suggests that at least one substituent
is required for intramolecular hydroalkoxylation. In the re-
action of internal alkyne 6a, product 6c was selectively
formed in 87% yield together with a trace amount of the
six-membered ether. The cyclization of δ-hydroxyalkyne 7a
also proceeded efficiently to provide six-membered ether
7c in 90% yield. The 2,4- and 2,5-disubstituted tetrahydro-
furans 9c–11c were formed in high yields (80–81%) with
moderate selectivity; these results are similar to those ob-
tained using the Brønsted acid–silane catalytic system.13 On
the other hand, 2,3-disubstituted tetrahydrofuran 8c was
formed with a higher diastereoselectivity (cis/trans = 1:7.0)
than that obtained using the Brønsted acid–silane catalytic
system (cis/trans = 1:5.3).
13
a) Hydroalkoxylation of alkyne 1a using I2 and PhSiH3
H
OH
O
5 mol% I2, 1.0 equiv PhSiH3
H
H
Ph
Ph
CH2Cl2, r.t., 7 h
Ph
Ph
1a
1c (86%)
Reaction pathway
H
OH
O
O
O
Si–H
– H
H
H
H
H
H
H
a
b
b'
c
13
b) Reaction of alkyne 2a using I2 and PhSiH3
OH
5 mol% I2, 1.0 equiv PhSiH3
CH2Cl2, r.t., 24 h
I
O
H
O
2a
2d (9%)
I
5
Next, N-protected aminoalkynes were subjected to the
standard conditions (Table 2). The reactions of tosylamide
12a and nosylamide 13a proceeded efficiently at room tem-
perature to afford the desired products 12c and 13c in high
yields, but the reactions of carbamate 14a and benzamide
15a resulted in recovery of the starting materials. These re-
sults are similar to those obtained using the Brønsted acid–
silane catalytic system.13 Not only alkynes 16a and 17a
with gem-dialkyl substituents on the linker between the N
atom and the alkyne, but also alkyne 19a, with no substitu-
ent on the linker, underwent the desired reaction to provide
the corresponding products in high yields. Due to the low
solubility of 18a in dichloromethane, the reaction of 18a
was slow; 18c was obtained in 44% yield after 24 hours
along with 39% recovery of 18a. The use of 20 mol% of I2
slightly improved the yield to 66%. Internal alkyne 20a un-
derwent the desired reaction to provide 20c in 93% yield
without the production of the N-Ts six-membered amine.
Although the diastereoselectivity of the 2,3-disubstituted
pyrrolidine 21c was low, 2,4- and 2,5-disubstituted pyrroli-
dines 22c–24c were produced with high diastereoselectivi-
ty. The diastereoselectivity for the formation of these com-
pounds was better than that obtained using the Brønsted
acid–silane catalytic system.13 The use of the bulkier silanes
Me2PhSiH and iPr3SiH improved the diastereoselectivity for
22c (cis/trans = 12:1 and 13:1, respectively).
2b'
c) Hydroalkoxylation/reduction of alkynes using Tf2NH and Et3SiH13
Nucleophilicity: I– > Tf2N–
H
O
OH
10 mol% Tf2NH, 2.0 equiv Et3SiH
H
0.2 equiv H2O
H
DCE, 60 °C, 4 h
2c (82%)
2a
d) Hydroalkoxylation/reduction of alkynes using I2 and Et3SiH: This study
Hydride donor ability: Et3SiH > PhSiH3
H
O
OH
10 mol% I2, 2.0 equiv Et3SiH
H
0.2 equiv H2O
H
CH2Cl2, r.t., 2 h
2c (90%)
2a
Scheme 1 Reactions of 1a and 2a using I2–PhSiH3, Tf2NH–Et3SiH, and
I2–Et3SiH
90% yield without the formation of iodoketone 2d (Scheme
1d). This is attributed to the fact that the hydride donor
ability of Et3SiH is higher than that of PhSiH3.14 Next, we ex-
amined the substrate scope of this reaction.
A variety of hydroxyalkynes were efficiently converted
into the corresponding cyclic ethers under the standard
conditions (Table 1). The reaction was compatible with es-
ters (3a and 4a). Diyne 4a selectively afforded propargyl-
substituted tetrahydrofuran 4c in 88% yield. One of the two
alkyne moieties of 4a remained intact. It was noted that in-
Finally, enyne 25a was investigated to examine the pref-
erence of the hydroalkoxylation for an alkene and an
alkyne. As a result, the hydroalkoxylation of the alkene pro-
ceeded faster than that of the alkyne, affording propargyl-
substituted tetrahydrofuran 26 as the major product (Table
3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

C
S. Fujita et al.
Special Topic
Synthesis
Table 1 Substrate Scope of the Hydroalkoxylation/Reductiona
Table 2 Substrate Scope of the Hydroamination/Reductiona
Alkyne
Product
Time (h) Yield (%)b
Alkyne
Product
Time (h) Yield (%)b
R
N
O
OH
NHR
EtO2C
24
85
EtO2C
EtO2C
CO2Et
3a
3c
12a: R = Ts
13a: R = Ns
14a: R = Cbz
15a: R = Bz
12c
13c
14c
15c
1
6
96
87
0
O
OH
BzO
88
dr = 1:1
24
24
19
24
6
BzO
0
4a
4c
Ts
N
NHTs
OH
O
Ph
Ph
2
93
Ph
18c
Ph
16c
5c
5a
16a
Ts
OH
NHTs
O
N
87
dr = 1.2:1
TsHN
18
87
TsHN
17a
17c
6a
6c
Ts
NHTs
N
44 (39)c
O
OH
BzO
dr = 1.2:1
24
19
48
90
BzO
66 (30)c,d
dr = 1.2:1
7c
7a
18a
18c
O
OH
Ts
N
NHTs
81
18
90
93
cis/trans = 1:7.0
C5H11
C5H11
19c
19a
8a
8c
Ts
NHTs
O
N
OH
81
7
3
cis/trans = 4.5:1
9a
9c
20a
20c
O
Ts
OH
NHTs
N
Ph
80
24
94
cis/trans = 6.7:1
4
Ph
cis/trans = 1:2.5
10a
C5H11
21a
C5H11
10c
21c
93
Ts
N
O
NHTs
cis/trans = 10:1
81
95e
OH
24
cis/trans =1.6:1
3
cis/trans = 12:1
92f
cis/trans = 13:1
11c
22a
23a
22c
11a
a Reaction conditions: I2 (10 mol%), Et3SiH (2.0 equiv), H2O (0.2 equiv), CH2-
Ts
N
NHTs
Cl2, r.t.
Ph
b Yield of isolated product.
c Determined by 1H NMR spectroscopy.
79
24
cis:trans = 9.5:1
Ph
23c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

D
S. Fujita et al.
Special Topic
Synthesis
Table 2 (continued)
Alkyne
Hydroalkoxylation/Reduction of Hydroxyalkyne 2a to Tetrahydro-
furan 2c; Typical Procedure
Product
Time (h) Yield (%)b
A solution of I2 (7.6 mg, 0.03 mmol) and Et3SiH (96 μL, 0.6 mmol) in
CH2Cl2 (3 mL) was stirred for 15 min, and then H2O (1.08 μL, 0.06
mmol) and hydroxyalkyne 2a (45.7 mg, 0.3 mmol) were added. After
the reaction mixture was stirred at room temperature for 2 h, it was
quenched with sat. aq Na2CO3, and extracted with Et2O. The organic
layer was washed with brine, dried over MgSO4 and concentrated un-
der reduced pressure. The residue was purified by flash column chro-
matography (SiO2, hexane–EtOAc, 25:1) to give 3-methyl-2-oxa-
spiro[4.5]decane (2c)9a (41.1 mg, 90%) as a colorless oil.
Ts
N
88
3
NHTs
cis/trans = 23:1
24c
24a
a Reaction conditions: I2 (10 mol%), Et3SiH (2.0 equiv), H2O (0.2 equiv),
CH2Cl2, r.t.
b Yield of isolated product.
c Numbers in parentheses are the yields of recovered starting materials.
d I2 (20 mol%) was used.
Diethyl 5-Methyldihydrofuran-3,3(2H)-dicarboxylate (3c)13
e Me2PhSiH (2.0 equiv) was used instead of Et3SiH.
f iPr3SiH (2.0 equiv) was used instead of Et3SiH.
Colorless oil; yield: 38.8 mg (85%).
[5-Methyl-3-(prop-2-yn-1-yl)tetrahydrofuran-3-yl]methyl Benzo-
ate (4c)13
Table 3 Hydroalkoxylation/Reduction of Enyne 25a
Colorless oil; yield: 22.5 mg (88%); dr = 1:1.
10 mol% Reagent
2.0 equiv Et3SiH
0.2 equiv H2O
O
O
OH
3-Ethyl-2-oxaspiro[4.5]decane (6c)4d
Colorless oil; yield: 29.0 mg (87%).
Solvent, Temp., 5 h
Ph
25c
Ph
Ph
3-Methyl-2-oxaspiro[5.5]undecane (7c)13
25a
26
Colorless oil; yield: 30.0 mg (90%).
Reagent
Solvent
Temp
25c (%)
26 (%)
2-Methyl-3-pentyltetrahydrofuran (8c)13
I2
CH2Cl2
DCE
r.t.
30
63
51
29
Colorless oil; yield: 25.3 mg (81%); cis/trans = 1:7.0.
Tf2NH
60 °C
(Ref. 13)
1H NMR (400 MHz, CDCl3): δ (trans isomer) = 3.88–3.75 (m, 2 H), 3.47
(dq, J = 8.0, 6.0 Hz, 1 H), 2.13–2.05 (m, 1 H), 1.65–1.55 (m, 1 H), 1.55–
1.50 (m, 1 H), 1.46–1.16 (m, 8 H), 1.22 (d, J = 6.0 Hz, 3 H), 0.89 (t, J =
6.4 Hz, 3 H).
In conclusion, we have found that the silane–iodine cat-
alytic system comprising I2 and Et3SiH promoted the intra-
molecular hydroalkoxylation/reduction and hydroamina-
tion/reduction of unactivated alkynes at room temperature.
Owing to the lower reaction temperature, a 2,3-disubstitut-
ed cyclic ether, and 2,4- and 2,5-disubstituted pyrrolidines
were formed with higher diastereoselectivity compared to
the products obtained using the Brønsted acid–silane cata-
lytic system. The preference of the hydroalkoxylation for an
alkene and an alkyne is different from the preference ex-
hibited when the Brønsted acid–silane catalytic system is
used.
4-Isopropyl-2-methyltetrahydrofuran (9c)13
Colorless oil; yield: 20.8 mg (81%) ; cis/trans = 4.5:1.
2-Methyl-4-phenyltetrahydrofuran (10c)15
Colorless oil; yield: 26.0 mg (80%); cis/trans = 6.7:1.
2-Isobutyl-5-methyltetrahydrofuran (11c)13
Colorless oil; yield: 23.0 mg (81%); cis/trans = 1.6:1.
Hydroamination/Reduction of N-Ts Aminoalkyne 12a to Pyrroli-
dine 12c; Typical Procedure
Reagents were purchased from commercial suppliers and were used
without purification. Each reaction was performed in a 10 mL round-
bottom flask fitted with a polypropylene cap. Column chromatogra-
phy was performed on silica gel (Cica silica gel 60N, 40–50 μm) using
the solvents specified below. Melting points were obtained using a
A solution of I2 (2.5 mg, 0.01 mmol) and Et3SiH (32 μL, 0.2 mmol) in
CH2Cl2 (1 mL) was stirred for 15 min, and then H2O (0.36 μL, 0.02
mmol) and N-Ts aminoalkyne 12a (30.5 mg, 0.1 mmol) were added.
After the reaction mixture was stirred at room temperature for 1 h, it
was quenched with sat. aq Na2CO3, and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4 and concentrat-
ed under reduced pressure. The residue was purified by flash column
chromatography (SiO2, hexane–EtOAc, 10:1) to give 3-methyl-2-tosyl-
2-azaspiro[4.5]decane (12c)16 (29.4 mg, 96%) as a colorless oil.
1
SRS OptiMelt MPA100 apparatus. H NMR spectra were recorded us-
ing a JEOL ECS400 spectrometer with samples in CDCl3 solution at
25 °C. 1H NMR chemical shifts are reported in terms of chemical shift
(δ, ppm) relative to the singlet at δ 7.26 for chloroform or at δ 0.00 for
tetramethylsilane as the internal standard. Splitting patterns are des-
ignated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet. Coupling constants are reported in Hz. All substrates and prod-
ucts (1c–13c, 16c–25c and 26) are known compounds. The spectral
data of these compounds are consistent with those in the literature.
3-Methyl-2-[(2-nitrophenyl)sulfonyl]-2-azaspiro[4.5]decane
(13c)17
Colorless oil; yield: 29.4 mg (87%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

E
S. Fujita et al.
Special Topic
Synthesis
2-Methyl-4,4-diphenyl-1-tosylpyrrolidine (16c)9a
1H NMR (400 MHz, CDCl3): δ (cis isomer) = 7.71 (d, J = 8.0 Hz, 2 H),
7.30 (d, J = 8.0 Hz, 2 H), 3.73–3.60 (m, 2 H), 2.43 (s, 3 H), 1.80–1.73 (m,
1 H), 1.69–1.42 (m, 5 H), 1.37–1.30 (m, 1 H), 1.33 (d, J = 6.4 Hz, 3 H),
0.94 (t, J = 6.4 Hz, 6 H).
Colorless oil; yield: 41.3 mg (93%).
N-[(3,5-Dimethyl-1-tosylpyrrolidin-3-yl)methyl]-4-methylben-
zenesulfonamide (17c)13
Hydroalkoxylation/Reduction of Enyne 26a to Tetrahydrofurans
25c and 26
White solid; yield: 38.2 mg (87%); dr = 1.2:1; mp 176–177 °C.
A solution of I2 (3.6 mg, 0.014 mmol) and Et3SiH (45 μL, 0.28 mmol) in
CH2Cl2 (1.4 mL) was stirred for 15 min, and then H2O (0.51 μL, 0.028
mmol) and hydroxyalkyne 25a (28.4 mg, 0.14 mmol) were added. Af-
ter the reaction mixture was stirred at room temperature for 1 h, it
was quenched with sat. aq Na2CO3, and extracted with Et2O. The or-
ganic layer was washed with brine, dried over MgSO4 and concentrat-
ed under reduced pressure. The residue was purified by flash column
chromatography (SiO2, hexane–EtOAc, 50:1) to give 4-allyl-2-methyl-
4-phenyltetrahydrofuran (25c)13 (8.4 mg, 30%) and 2-methyl-4-phe-
nyl-4-propargyltetrahydrofuran (26)13 (14.1 mg, 51%) as colorless
oils.
[5-Methyl-3-(prop-2-yn-1-yl)-1-tosylpyrrolidin-3-yl]methyl Ben-
zoate (18c)13
White solid; yield: 18.1 mg (44%); dr = 1.2:1; mp 115–116 °C.
2-Methyl-1-tosylpyrrolidine (19c)18
Colorless oil; yield: 21.5 mg (90%).
3-Ethyl-2-tosyl-2-azaspiro[4.5]decane (20c)13
Colorless oil; yield: 30.0 mg (93%).
2-Methyl-3-pentyl-1-tosylpyrrolidine (21c)13
Colorless oil; yield: 29.0 mg (94%); cis/trans = 1:2.5.
Funding Information
4-Isopropyl-2-methyl-1-tosylpyrrolidine (22c)13
Japan Society for the Promotion of Science, Grant Number:
'JP16K08162', Japan Agency for Medical Research and Development.
Colorless oil; yield: 26.1 mg (93%); cis/trans = 10:1.
a
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1H NMR (400 MHz, CDCl3): δ (cis isomer) = 7.71 (d, J = 8.4 Hz, 2 H),
7.31 (d, J = 8.4 Hz, 2 H), 3.60–3.54 (m, 2 H), 3.01–2.96 (m, 1 H), 2.44 (s,
3 H), 2.09–2.02 (m, 1 H), 1.38 (d, J = 6.0 Hz, 3 H), 1.40–1.11 (m, 3 H),
0.80 (d, J = 6.4 Hz, 3 H), 0.79 (d, J = 6.4 Hz, 3 H).
Acknowledgment
This work was partially supported by JSPS KAKENHI JP16K08162, and
the Platform Project for Supporting in Drug Discovery and Life Science
Research from AMED.
Hydroamination/Reduction of N-Ts Aminoalkyne 22a to Pyrroli-
dine 22c Using Me2PhSiH
A solution of I2 (2.5 mg, 0.01 mmol) and Me2PhSiH (31 μL, 0.2 mmol)
in CH2Cl2 (1 mL) was stirred for 15 min, and then H2O (0.36 μL, 0.02
mmol) and N-Ts aminoalkyne 22a (27.9 mg, 0.1 mmol) were added.
After the reaction mixture was stirred at room temperature for 3 h, it
was quenched with sat. aq Na2CO3, and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4 and concentrat-
ed under reduced pressure. The residue was purified by flash column
chromatography (SiO2, hexane–EtOAc, 20:1) to give 4-isopropyl-2-
methyl-1-tosylpyrrolidine (22c) (26.7 mg, 95%, cis/trans = 12:1) as a
colorless oil.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588436.
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References
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Hannedouche, J. Catal. Sci. Technol. 2015, 5, 2017. (d) Lepori, C.;
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Hydroamination/Reduction of N-Ts Aminoalkyne 22a to Pyrroli-
dine 22c Using iPr3SiH
A solution of I2 (2.5 mg, 0.01 mmol) and iPr3SiH (41 μL, 0.2 mmol) in
CH2Cl2 (1 mL) was stirred for 15 min, and then H2O (0.36 μL, 0.02
mmol) and N-Ts aminoalkyne 22a (27.9 mg, 0.1 mmol) were added.
After the reaction mixture was stirred at room temperature for 3 h, it
was quenched with sat. aq Na2CO3, and extracted with EtOAc. The or-
ganic layer was washed with brine, dried over MgSO4 and concentrat-
ed under reduced pressure. The residue was purified by flash column
chromatography (SiO2, hexane–EtOAc, 20:1) to give 4-isopropyl-2-
methyl-1-tosylpyrrolidine (22c) (25.9 mg, 92%, cis/trans = 13:1) as a
colorless oil.
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2-Methyl-4-phenyl-1-tosylpyrrolidine (23c)19
Colorless oil; yield: 24.8 mg (79%); cis/trans = 9.5:1.
2-Isobutyl-5-methyl-1-tosylpyrrolidine (24c)8a
Colorless oil; yield: 17.0 mg (88%); cis/trans = 23:1.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
S. Fujita et al.
Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F