Bifunctional AgOAc/ThioClickFerrophos catalyzed asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides to nitroalkenes

Article abstract of DOI:10.1016/j.tet.2015.08.002

AgOAc/ThioClickFerrophos (TCF) complex catalyzed the 1,3-dipolar cycloaddition of azomethine ylides (glycine imino ester) to nitroalkenes. The corresponding endo-cycloadducts (88:12-98:2 endo/exo) were afforded in good yields with high enantioselectivitie

Full text of DOI:10.1016/j.tet.2015.08.002

Tetrahedron xxx (2015) 1e5
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Tetrahedron
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Bifunctional AgOAc/ThioClickFerrophos catalyzed asymmetric
1,3-dipolar cycloaddition reaction of azomethine ylides to
nitroalkenes
Midori Kimura, Yukiko Matsuda, Akihiro Koizumi, Chihiro Tokumitsu, Yuichiro Tokoro,
*
Shin-ichi Fukuzawa
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyou-ku, Tokyo, 112-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
AgOAc/ThioClickFerrophos (TCF) complex catalyzed the 1,3-dipolar cycloaddition of azomethine ylides
(glycine imino ester) to nitroalkenes. The corresponding endo-cycloadducts (88:12e98:2 endo/exo) were
afforded in good yields with high enantioselectivities, up to 98% ee, without addition of external amine.
AgOAc/TCF works as a bifunctional (Lewis acid and base) catalyst.
Received 25 June 2015
Received in revised form 24 July 2015
Accepted 1 August 2015
Available online xxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Silver acetate
P,S-Ligand
Nitroalkene
Cycloaddition
Azomethine ylide
1. Introduction
There has previously been success in controlling the stereo-
chemistry at the 4- and 5-positions of pyrrolidine in cycloaddition
The asymmetric 1,3-dipolar cycloaddition of azomethine ylides
to activated alkenes provides a beneficial method for the synthesis
of highly substituted pyrrolidines, which can lead to discovery of
new biologically active compounds. Chiral metal complexes have
been developed for catalyzing this reaction,1 with various activated
alkenes like acrylates and maleimides, employed as good dipolar-
ophiles. Nitroalkenes are also good dipolarophiles, affording bi-
ologically interesting nitro-containing pyrrolidines.2 The 1,3-
dipolar cycloaddition of glycine imino ester 1 with 2-substituted-
1-nitroethene 2 potentially affords up to eight diastereomers of
a pyrrolidine ring bearing four stereogenic centers. While it appears
difficult to generate a single isomer out of eight possible di-
astereoisomers, the use of the (E)-nitroethene can fix the stereo-
conjunction between the 3- (R2) and 4-positions (NO2) in a trans
conformation. The groups at the 5-position (R1, from the sub-
stituent of the imino group) and 2-position (the ester group) are
usually arranged cis to each other, with an exception involving
catalysis by a solid-supported imidazoline-aminophenol/Ni(OAc)2
complex (Fig. 1).3 Thus, the focus of stereoselectivity is simplified to
the 4- and 5-positions, with two diastereoisomers (exo and endo)
possible; epimers of exo and endo isomers can be excluded.4
of azomethine ylide to a nitroalkene was achieved using CuClO4/
FeSulphos,5 CuPF6/Segphos,6 CuClO4/Taniaphos,7 Cu(OTf)2/chiral
phosphoramidite,8 and CuClO4/Imidazolium-FcPHOX.9 Oh et al.
prepared an exo-pyrrolidine ring via consecutive Michael addition
of glycine imino ester to a nitroalkene and intramolecular Mannich
reaction with a CuOAc/brucine-derived amino alcohol complex.10
Waldman et al. first reported the asymmetric reaction of a cyclic
azomethine ylide to a nitroalkene affording exo-cycloadducts as the
major product,11 while endo-selective cycloaddition has been ach-
ieved using Cu(OTf)2/PyBidine complex.12 Hou et al. succeeded in
switching the endo/exo-selectivity in the CuClO4/FcPHOX complex-
catalyzed reaction by tuning the electron density of the phosphine
moiety.13 Cossio et al. also succeeded in endo/exo-switching in the
* Corresponding author. Tel.: þ81 3 3817 1916; fax: þ81 3 3817 1895; e-mail
Fig. 1. exo and endo Isomers in the 1,3-dipolar cycloaddition of azomethine ylide with
nitroalkene.
address: orgsynth@kc.chuo-u.ac.jp (S.-i. Fukuzawa).
http://dx.doi.org/10.1016/j.tet.2015.08.002
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kimura, M.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.08.002

2
M. Kimura et al. / Tetrahedron xxx (2015) 1e5
Table 1
CuPF6/chiral ferrocene pyrrolidine ligand-catalyzed reaction by al-
ternating ligand stereochemistry.14
Optimization of reaction solventa
Despite the success of copper-complex-catalyzed diastereo- and
enantio-selective cyclization reactions, development of highly
stereoselective cycloadditions of azomethine ylides to nitroalkenes
remains challenging. There had been no reports of a successful
asymmetric silver-catalyzed cycloaddition of imino esters to
nitroalkenes with high diastereo- and enantio-selectivities before
the recent work by Xu and co-workers.15 They developed a new
chiral phosphine, based on non-biaryl atropisomers, and achieved
exo-selective cycloaddition using the AgF complex.16
Entry
Solvent
Yield (%)b
endo/exoc
ee (%) (endo)d
1
2
DOX
THF
THF
DOX
DME
Et2O
CH2Cl2
CH2Cl2
toluene
74
61
64
42
60
62
43
36
39
94:6
92:8
91:9
95:5
90:10
94:6
72:28
65:35
96:4
96
96
91
91
95
88
95
91
75
3e
4f
5
6
7
8e,g
9
a
1a (0.20 mmol), 2a (0.22 mmol), AgOAc (0.01 mmol, 5.0 mol %), (R,Sp)-TCF
In our series of studies on 1,3-dipolar cycloadditions of azome-
thine ylides catalyzed by silver/ThioClickFerrophos (TCF, a chiral
P,S-ferrocene ligand) complex, we have reported that the reaction
(0.011 mmol, 5.5 mol %), solvent (2.0 mL): rt, 10 h.
b
Isolated yield of the endo-isomer.
c
Determined by 1H NMR.
d
with
b-nitrostyrene afforded a mixture of endo- and exo-cyclo-
Determined by HPLC (Daicel Chiralpak AS-H).
adducts (65:35 endo/exo) in low yield (36%).17 Although enantio-
selectivity in the endo-isomer was high (91% ee), we abandoned
optimization of the reaction, concluding that the catalyst was not
suitable for the reaction with nitroalkenes because of poor dia-
stereoselectivity and low yield. Later we found that, in the reaction
of a ketimine ester with a nitroalkene, AgOAc/TCF gave the cyclo-
adduct in good yield under base-free conditions, or the Michael
adduct in the presence of base.18 We suspected that the base-free
conditions could be essential for successful cycloaddition to nitro-
alkenes, and chose to re-examine the reaction. It was indeed found
that AgOAc/TCF works as a bifunctional catalyst,19 giving endo-
cycloadducts, both diastereo- and enantioselectively, in good yields
under base-free conditions. In this paper, we report the optimiza-
tion of reaction conditions and scope of substrates.
e
Et3N (20 mol %) was added.
f
Imino tert-butyl ester 1a0 was used.
g
Data from the literature.17
cycloaddition of ketimine esters with nitroalkenes, imino tert-butyl
ester was a better azomethine ylide source than the corresponding
methyl ester. However, the methyl ester was better suited in this
reaction as an aldimine ester.
Having established optimal reaction conditions for the cyclo-
addition of imino ester 1a to nitroalkene 2a, the scope of the re-
action was examined using different imino esters 1be1k in the
reaction with 2a. The results are summarized in Table 2.
All reactions afforded the endo-isomer (3aae3ka) as the major
product, in ratios ranging from 88:12e96:4 endo/exo. Yields were
always high for aryl substrates bearing electron-donating groups,
with ee values for endo-adducts ranged from 94 to 97% (Table 2,
entries 2e5). The position of the methyl group slightly affected the
reaction; the more sterically hindered o-methyl group gave the
endo-isomer in high yield with good ee, as did the m- and p-
substituted substrates. Moderate yields of endo-isomers were ob-
tained in reactions with halogen-substituted aryl substrates (Table
2, entries 6e8). The 1-napthyl ester, 1i, and the heteroaryl imino
esters (2-thienyl; 1j) were also appropriate substrates, achieving
good yields of endo-adducts with up to 91% ee (Table 2, entry 10).
The reaction with alkyl imino esters such as 1k afforded low
product yields, but exhibited high endo-selectivity and enantiose-
lectivity (Table 2, entry 11).
2. Results and discussion
We first optimized the reaction conditions in the model reaction
of imino methyl ester 1a and b-nitrostyrene 2a using 5 mol % of
AgOAc/TCF catalyst (Scheme 1). The reactions were carried out at
room temperature for 10 h, with various solvents, in the absence or
presence of base; results are shown in Table 1.20 The endo/exo-
isomer ratio was determined by 1H NMR integration of the methyl
group peak. Enantiomeric excess was determined by chiral HPLC.
The absolute configuration of endo-isomer 3aa was determined as
(2S, 3R, 4S, 5S) by comparing optical rotation and HPLC retention
time with reported compounds.10,13 The reaction in 1,4-dioxane
(DOX) in the absence of base gave 79% isolated yield of endo-
product. The endo-isomer was produced selectively (94:6 endo/exo)
with high enantioselectivity (96% ee) (Table 1, entry 1). The re-
actions in tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), and
diethyl ether yielded the endo-isomer preferentially, again with
high ee, but in lower yields (Table 1, entries 2, 5, and 6). The re-
action in THF in the presence of triethylamine had a lower yield
than its base-free counterpart, but showed no significant change in
diastereo- or enantio-selectivity (Table 1, entry 3). Dichloro-
methane and toluene were not suitable solvents, affording poor
yields under even base-free conditions (Table 1, entries 7e9). Thus,
DOX was the solvent of choice. In our previous study on the
Table 2
Scope of glycine imino esters 1 in cycloaddition with nitroalkene 2aa
Entry
R1
Yield (%)b
endo/exoc
ee (%) (endo)d
1
2
3
4
5
6
7
8
Ph, 1a
3aa, 70
3ba, 74
3ca, 86
3da, 71
3ea, 82
3fa, 67
3ga, 80
3ha, 51
3ia, 80
3ja, 80
3ka, 47
94/6
96/4
95/5
96/4
94/6
94/6
95/5
94/6
96/4
91/9
88/12
96
94
96
97
97
96
96
96
86
91
93
o-MeC6H4, 1b
m-MeC6H4, 1c
p-MeC6H4, 1d
p-MeOC6H4, 1e
p-FC6H4, 1f
p-ClC6H4, 1g
p-BrC6H4, 1h
1-Naphtyl, 1i
2-thienyl, 1j
Cy, 1k
9
10
11
a
1 (0.20 mmol), 2a (0.22 mmol), AgOAc (0.01 mmol, 5.0 mol %), (R,Sp)-TCF
(0.011 mmol, 5.5 mol %), solvent (2.0 mL): rt, 10 h.
b
Isolated yield of the endo-isomer.
c
Determined by 1H NMR.
Scheme 1. The 1,3-dipolar cycloaddition of glycine imino ester 1a with
2a.
b-nitrostyrene
d
Determined by HPLC (Daicel Chiralpak AS-H or IB).
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M. Kimura et al. / Tetrahedron xxx (2015) 1e5
3
The substrate scope for nitroalkenes was also examined under
4. Experimental section
4.1. General
optimized conditions (Table 3). Reactions of imino ester 1a with
various (E)-2-aryl-1-nitroalkenes, with o- or p-substituents on the
phenyl ring, proceeded with endo-selectivities of 89:11e98:2 and
enantioselectivities of 80e98%. Nitroalkenes with non-alkyl sub-
stituents on the aromatic ring also gave the endo-adduct as the
major product, although the electronic properties of these sub-
stituents caused a reduction in diastereo- and enantio-selectivity.
The ferrocenyl 1g and heteroaryl substrate such as 2-furyl nitro-
alkene 1h could be used, giving corresponding endo-adducts with
high enantioselectivities (Table 3, entries 6e7).
1H and 13C NMR spectra recorded with a Varian Mercury 300 or
400 MHz using CDCl3 as a solvent. The chemical shifts are reported
in
d units downfield from (SiMe4) and are referenced to CHCl3 as an
internal standard (
d
¼0.00 ppm for 1H,
d
¼77.16 ppm for 13C). All
coupling constants (J) are absolute values and are expressed in Hz.
Enantiomeric excesses were determined by chiral HPLC analysis on
the Chiralpak columns. The GCeMS analyses were carried out with
an Agilent 5975B/6890N instrument equipped with a capillary
column (helium as the carrier gas). Endo/exo ratios of cycloadducts
were determined by integration of the methyl ester signals of 1H
NMR. Preparative TLC was conducted on a 20 cm square glass sheet
coated with a 1 mm thick layer of silica gel. AgOAc was purchased
from Wako Chemicals Inc. ThioClickFerrophos was prepared by the
literature method.21 Nitroalkene 2a was purchased from TCI Com-
pany. Nitroalkenes 2beg were prepared according to literature
procedures.22 Dry 1,4-dioxane (DOX) was purified by distillation
after the pre-drying with LiAlH4.
Table 3
Scope of nitroalkenes 2 in cycloaddition with imino ester 1aa
Entry
R2
Yield (%)b
endo/exoc
ee (%)d (endo)
1
2
3
4
5
6
7
o-MeC6H4, 2b
p-MeC6H4, 2c
p-MeOC6H4, 2d
p-ClC6H4, 2e
p-BrC6H4, 2f
Fc, 2g
3ab, 81
3ac, 60
3ad, 64
3ae, 40
3af, 60
3ag, 80
3ah, 50
97/3
93/7
90/10
93/7
90/10
98/2
97
98
97
90
80
95
91
4.2. General procedure for the asymmetric 1,3-dipolar cyclo-
addition 3
2-furyl, 2h
89/11
The following provide a typical experimental procedure of
asymmetric 1,3-dipolar cycloaddition of azomethine ylide with
nitroalkenes. All reactions were carried out under nitrogen atmo-
sphere with oven-dried glassware. In a 20 mL Schlenk tube con-
taining a stirring bar, AgOAc (1.66 mg, 0.01 mmol), (R,Sp)-TCF
(6.92 mg, 0.011 mmol) were dissolved in dry 1,4-dioxane (2.0 mL)
and stirred at room temperature for 30 min. Then, 1a (35.4 mg,
0.20 mmol) and 2a (32.8 mg, 0.22 mmol) were added successively.
The resulting mixture was stirred at the same temperature for 10 h
and then filtered through Celite and concentrated in vacuo. The
residue was isolated by PTLC (n-hexane/EtOAc¼3/1) to afford 3aa
as yellow oil.
a
1a (0.20 mmol), 2 (0.22 mmol), AgOAc (0.01 mmol, 5.0 mol %), (R,Sp)-TCF
(0.011 mmol, 5.5 mol %), solvent (2.0 mL): rt, 10 h.
b
Isolated yield of the endo-isomer.
c
Determined by 1H NMR.
d
Determined by HPLC (Daicel Chiralpak AS-H or IB).
If tetra-coordinated transition state could be proposed as shown
in Fig. 2 based on the absolute configuration of the endo-cyclo-
adduct, the azomethine ylide would coordinate to silver atom with
the preferred orientation where the nitrogen atom is oriented trans
to the phosphine group (the oxygen atom is oriented trans to the
sulfur atom). A reverse orientation in which the nitrogen atom is
trans to the sulfur atom would not be preferred because of the steric
repulsion between the phosphine phenyl group and the substituent
(R1) of the azomethine ylide. The nitroalkene would come from the
si face of the azomethine ylide avoiding the bulky tert-butylthio
group, thus affording the endo-(2S, 3R, 4S, 5S)-configured adduct.
4.2.1. 3aa (R1¼Ph). Yellow oil; 45.6 mg, 70% yield. 1H NMR
d
7.43e7.24 (m, 10H), 5.27 (dd, J¼3.6, 6.5 Hz, 1H), 4.90 (m, 1H), 4.21
(dd, J¼3.6, 7.5 Hz, 1H), 4.15 (m, 1H), 3.79 (s, 3H), 3.35 (br s, 1H); 13
C
NMR
d 172.1, 138.9, 134.7, 129.7, 134.7, 129.6, 129.5, 128.5, 127.9,
126.8, 97.4, 68.2, 67.8, 55.8, 53.0; HPLC: Daicel Chiralpak AS-H
(hexane/2-propanol¼70/30, 0.7 mL/min, 220 nm); tR¼21.9 min
27
(major), tR¼30.4 min (minor); [
a]
¼ꢀ29.2 (c¼0.11, CHCl3); HRMS
D
(ESI) calcd for C18H19N2O4 [MþH]þ327.1345, found: 327.1347.
4.2.2. 3ba (R1¼o-MeC6H4). Yellow oil; 50.4 mg, 74% yield. 1H NMR
d
7.43e7.15 (m, 9H), 5.33 (dd, J¼3.5, 6.6 Hz, 1H), 5.00 (dd, J¼6.6,
10.7 Hz, 1H), 4.27 (dd, J¼3.5, 7.7 Hz, 1H), 4.09 (t, J¼8.0 Hz, 1H), 3.79
(s, 3H), 3.32 (t, J¼10.2 Hz, 1H), 2.38 (s, 3H); 13C NMR
d 171.6, 138.7,
135.3, 132.2, 130.5, 129.3, 128.5, 128.0, 127.4, 126.5, 125.0, 95.5, 67.2,
64.9, 55.3, 52.6,15.4; HPLC: Daicel Chiralpak AD-H column (hexane/
Fig. 2. Plausible transition structure of the reaction.
2-propanol¼70/30, 0.7 mL/min, 220 nm); tR¼13.7 (minor),
25
tR¼18.2 min (major); [
a
]
¼ꢀ4.89 (c¼0.11, CHCl3). HRMS (ESI) calcd
D
3. Conclusion
for C19H20N2NaO4 [MþNa]þ 363.1321, found: 363.1303.
AgOAc/ThioClickFerrophos (TCF) complex is an effective bi-
functional catalyst for the 1,3-dipolar cycloaddition of azomethine
ylides to nitroalkenes under base-free conditions. The corre-
sponding endo-cycloadducts were afforded preferentially
(88:12e98:2 endo/exo) with high enantioselectivities (up to
98% ee). Substituents on the nitroalkene 2-aryl group had little
effect on the stereochemistry and product yield.
4.2.3. 3ca (R1¼m-MeC6H4). White oil; 58.5 mg, 86% yield. 1H NMR
d
7.44e7.13 (m, 9H), 5.27 (dd, J¼3.3, 6.5 Hz, 1H), 4.87 (dd, J¼6.5,
11.3 Hz, 1H), 4.20 (dd, J¼3.3, 7.4 Hz, 1H), 4.14 (dd, J¼7.4, 8.8 Hz, 1H),
3.82 (s, 3H), 3.36 (t, J¼10.7 Hz, 1H), 2.35 (s, 3H); 13C NMR
d 171.7,
138.6, 138.4, 134.2, 129.4, 129.2, 128.5, 128.0, 127.4, 127.1, 123.4, 97.0,
67.8, 67.5, 55.5, 52.6, 21.4; HPLC: Daicel Chiralpak AS-H (hexane/2-
propanol¼70/30, 0.7 mL/min, 220 nm); tR¼16.6 (major),
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4
M. Kimura et al. / Tetrahedron xxx (2015) 1e5
25
tR¼21.7 min (minor); [
a
]
D
¼ꢀ35.3 (c¼0.09, CHCl3); HRMS (ESI)
125.4, 96.3, 67.1, 63.4, 54.7, 52.8; HPLC: Daicel Chiralpak IB (hexane/
calcd for C19H21N2O4 [MþH]þ 341.1501, found: 341.1506.
2-propanol¼95/5, 0.7 mL/min, 220 nm); tR¼12.2 min (minor),
26
tR¼13.5 min (major); [
a]
¼þ12.9 (c¼0.01, CHCl3); HRMS (ESI)
D
4.2.4. 3da (R1¼p-MeC6H4). Yellow solid, mp¼115e117 ꢁC; 48.3 mg,
calcd for C16H17N2O4S [MþH]þ 333.0909, found: 333.0900.
71% yield. 1H NMR
d
7.34e7.07 (m, 9H), 5.17 (dd, J¼3.5, 6.5 Hz, 1H),
4.80 (m, 1H), 4.13 (dd, J¼3.5, 7.4 Hz, 1H), 4.08 (m, 1H), 3.72 (s, 3H),
4.2.11. 3ka (R1¼Cy). Yellow oil; 31.2 mg, 47% yield. 1H NMR
3.25 (m, 1H), 2.25 (s, 3H); 13C NMR
d
171.8, 138.6, 138.5, 131.3, 129.4,
d
7.41e7.19 (m, 5H), 5.07 (d, J¼4.9 Hz, 1H), 3.96 (s, 2H), 3.78 (s, 1H),
129.3, 128.0, 127.5, 126.3, 97.1, 67.7, 67.4, 55.4, 52.6, 21.1. HPLC:
2.27 (m, 1H), 2.88 (br s, 1H), 1.04e2.11 (m, 11H); 13C NMR
d 171.9,
Daicel Chiralpak AS-H (hexane/2-propanol¼70/30, 0.7 mL/min,
139.7, 129.4, 128.1, 127.5, 95.3, 71.5, 68.4, 57.1, 52.7, 38.5, 31.5, 31.1,
26
220 nm); tR¼19.3 (major), tR¼18.2 min (minor); [
a
]
¼ꢀ42.9
26.2, 25.8, 25.6; HPLC: Daicel Chiralpak IB (hexane/2-propanol¼95/
D
(c¼0.12, CHCl3); HRMS (ESI) calcd for C19H20KN2O4 [MþK]þ
5, 1 mL/min, 220 nm); tR¼6.53 min (major), tR¼7.16 min (minor);
27
379.1060, found: 379.1056.
[a
]
¼ꢀ48.4 (c¼0.05, CHCl3); HRMS (ESI) calcd for C18H24N2NaO4
D
[MþNa]þ 355.1634, found: 355.1634.
4.2.5. 3ea (R1¼p-MeOC6H4). Yellow oil; 58.4 mg, 82% yield. 1H NMR
d
7.41e7.28 (m, 7H), 6.88 (d, J¼8.0 Hz, 1H), 5.23 (dd, J¼3.6, 6.5 Hz,
4.2.12. 3ab (R2¼o-MeC6H4). Yellow oil; 55.1 mg, 81% yield. 1H NMR
1H), 4.88 (dd, J¼6.5, 11.0 Hz, 1H), 4.22 (dd, J¼3.4 Hz, 7.4 Hz, 1H), 4.13
d
7.37e7.23 (m, 9H), 5.14 (dd, J¼3.4, 6.5 Hz, 1H), 4.94 (dd, J¼6.5,
(t, J¼8.6 Hz, 1H), 3.80 (s, 3H), 3.81 (s, 3H), 3.28 (t, J¼9.8 Hz, 1H); 13
C
10.9 Hz, 1H), 4.55 (dd, J¼3.4, 7.0 Hz, 1H), 4.21 (dd, J¼7.0, 8.5 Hz, 1H),
NMR
d
171.8, 159.8, 138.6, 129.6, 128.1127.7, 127.5, 126.3, 114.1, 97.1,
3.81 (s, 3H), 3.38 (t, J¼9.2 Hz, 1H), 2.35 (s, 3H); 13C NMR
d 172.1,
67.4, 67.4, 67.3, 55.2, 52.6. HPLC: Daicel Chiralpak AD-H (hexane/2-
137.1, 134.4, 131.1, 130.7, 129.1, 128.8, 127.9, 127.1, 126.5, 126.0, 97.2,
67.8, 67.2, 52.7, 51.0, 19.9. HPLC: Daicel Chiralpak AS-H (hexane/2-
propanol¼70/30, 0.7 mL/min, 220 nm); tR¼29.3 (major),
26
tR¼41.9 min (minor); [
a
]
¼ꢀ29.1 (c¼0.12, CHCl3); HRMS (ESI)
propanol¼70/30, 0.7 mL/min, 220 nm); tR¼19.0 (minor),
D
27
calcd for C19H20KN2O5 [MþK]þ 395.1009, found: 395.1023.
tR¼22.0 min (major); [
a]
¼ꢀ23.4 (c¼0.13, CHCl3); HRMS (ESI)
D
calcd for C19H21N2O4 [MþH]þ 341.1501, found: 341.1503.
4.2.6. 3fa (R1¼p-FC6H4). Yellow oil; 46.1 mg, 67% yield. 1H NMR
d
7.53e7.02 (m, 9H), 5.25 (dd, J¼3.8, 6.6 Hz, 1H), 4.89 (m, 1H), 4.23
4.2.13. 3ac (R2¼p-MeC6H4). Yellow oil; 40.8 mg, 60% yield. 1H NMR
(dd, J¼3.8, 7.5 Hz, 1H), 4.14 (m, 1H), 3.80 (s, 3H), 3.24 (m, 1H); 13C
d 7.55e7.06 (m, 9H), 5.20e5.30 (m, 1H), 4.90e4.92 (m, 1H),
NMR
d
171.7, 162.8 (d, J¼250 Hz), 138.3, 130.4, 129.3, 128.4, 128.2 (d,
4.11e4.19 (m, 2H), 3.81 (s, 3H), 2.37 (s, 3H); 13C NMR
d 171.8, 138.0,
J¼11.4 Hz), 127.5, 115.7 (d, J¼21.7 Hz), 96.8, 67.1, 66.8, 54.9, 52.7;
135.6, 130.0, 129.6, 128.7, 127.9, 127.3, 126.4, 87.2, 67.8, 67.5, 55.2,
HPLC: Daicel Chiralpak AS-H (hexane/2-propanol¼70/30, 0.7 mL/
52.6, 21.1; HPLC: Daicel Chiralpak AS-H (hexane/2-propanol¼70/
27
min, 220 nm); tR¼28.5 (major), tR¼36.7 min (minor); [
a
]
¼ꢀ41.2
30, 0.7 mL/min, 220 nm); tR¼20.8 (major), tR¼25.9 min (major);
D
27
(c¼0.12, CHCl3); HRMS (ESI) calcd for C18H17FNaN2O4 [MþNa]þ
[a
]
¼ꢀ35.2 (c¼0.06, CHCl3); HRMS (ESI) calcd for C19H21N2O4
D
367.1070, found: 367.1079.
[MþH]þ 341.1501, found: 341.1550.
4.2.7. 3ga (R1¼p-ClC6H4). White solid, mp¼126e127 ꢁC; 57.7 mg,
4.2.14. 3ad (R2¼p-MeOC6H4). Yellow oil; 45.6 mg, 64% yield. 1H
80% yield. 1H NMR
d
7.51e7.26 (m, 9H), 5.26 (dd, J¼3.8, 6.6 Hz, 1H),
NMR
d
7.43e7.25 (m, 5H), 7.23 (d, J¼8.0 Hz, 2H), 6.93 (d, J¼8.0 Hz,
4.89 (dd, J¼6.6, 10.3 Hz,1H), 4.23 (dd, J¼3.8, 7.5 Hz,1H), 3.81 (s, 3H),
2H), 5.24 (dd, J¼3.3, 6.5 Hz, 1H), 4.90 (dd, J¼6.5, 11.1 Hz, 1H),
3.26 (t, J¼9.8 Hz,1H); 13C NMR
d 171.6,138.2,134.7,133.1,129.3,128.9,
128.2, 127.9, 127.5, 96.7, 67.1, 66.8, 55.0, 52.7. HPLC; Daicel Chiralpak
4.11e4.19 (m, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.35 (m, 1H); 13C NMR
d 172.0, 159.5, 134.7, 130.7, 128.9, 128.9, 128.8, 126.7, 114.8, 97.4, 67.8,
AS-H(hexane/2-propanol¼70/30, 0.7mL/min, 220nm);tR¼22.1min
67.6, 55.5, 55.0, 52.8. HPLC: Chiralpak AS-H (hexane/2-
27
(major), tR¼30.4 min (minor); [
a
]
¼ꢀ27.6 (c¼0.12, CHCl3); HRMS
propanol¼80/20, 1.0 mL/min, 220 nm); tR¼31.1 (major),
D
26
calcd for C18H18ClN2O4 [MþH]þ 361.0955, found: 361.0969.
tR¼39.2 min (minor); [
a]
¼ꢀ34.9 (c¼0.08, CHCl3); HRMS (ESI)
D
calcd for C19H21N2O5 [MþH]þ 357.1451, found: 357.1455.
4.2.8. 3ha (R1¼p-BrC6H4). White solid, mp¼132e134 ꢁC; 41.3 mg,
51% yield. 1H NMR
d
7.50e7.23 (m, 9H), 5.25 (dd, J¼3.8, 6.6 Hz, 1H),
4.2.15. 3ae (R2¼p-ClC6H4). Yellow oil; 28.9 mg, 40% yield. 1H NMR
4.87 (dd, J¼6.6, 10.2 Hz, 1H), 4.22 (dd, J¼3.8, 7.5 Hz, 1H), 4.13 (t,
d
7.51e7.26 (m, 9H), 5.26 (dd, J¼3.8, 6.6 Hz, 1H), 4.89 (dd, J¼6.6,
J¼8.1 Hz, 1H), 3.79 (s, 3H), 3.24 (t, J¼9.6 Hz, 1H); 13C NMR
d
171.6,
10.3 Hz, 1H), 4.23 (dd, J¼3.8, 7.5 Hz, 1H), 3.81 (s, 3H); 13C NMR
138.2, 133.7, 131.9, 129.3, 128.2, 128.2, 127.5, 122.8, 96.6, 67.1, 66.8,
54.9, 52.7; HPLC: Daicel Chiralpak AS-H column (hexane/2-
d 171.6,137.0,134.5,134.2,129.6,129.0,129.0,128.9,126.6, 96.6, 67.7,
67.4, 54.6, 52.9; HPLC: Chiralpak IB (hexane/2-propanol¼95/5,
propanol¼70/30, 0.7 mL/min, 220 nm); tR¼42.6 (major),
1.0 mL/min, 220 nm); tR¼32.6 (minor), tR¼36.2 min (major);
27
27
tR¼55.8 min (minor); [
a
]
D
¼ꢀ47.1 (c¼0.12, CHCl3); HRMS (ESI)
[a
]
¼ꢀ28.4 (c¼0.12, CHCl3); HRMS (ESI) calcd for C18H18ClN2O4
D
calcd for C18H18BrN2O4 [MþH]þ 405.0450, found: 405.0444.
[MþH]þ 361.0955, found: 361.0949.
4.2.9. 3ia (R1¼1-C8H9). Yellow solid, mp¼85e88 ꢁC; 60.2 mg, 80%
4.2.16. 3af (R2¼p-BrC6H4). Yellow oil; 48.6 mg, 60% yield. 1H NMR
yield. 1H NMR
d
7.91e7.67 (m, 4H), 7.28e7.67 (m, 8H), 5.65 (d,
d
7.54 (d, J¼8.5 Hz, 2H), 7.47e7.33 (m, 5H), 7.18 (d, J¼8.5 Hz, 1H),
J¼6.2 Hz, 1H), 5.54 (dd, J¼3.2, 6.1 Hz, 1H), 4.35 (dd, J¼3.0, 7.3 Hz,
5.24 (dd, J=4.1, 6.4 Hz, 1H), 4.89 (d, J¼7.0 Hz, 1H), 4.17e4.20 (m, 1H),
1H), 4.15 (d, J¼7.3 Hz,1H), 3.80 (s, 3H); 13C NMR
d
171.8,139.0,133.6,
4.07e4.10 (m, 1H), 3.81 (s, 3H); 13C NMR
d
171.6, 137.5, 134.4, 132.6,
130.7, 129.5, 129.4, 128.2, 127.7, 126.9, 126.0, 125.5, 123.7, 121.8, 96.6,
67.1, 64.1, 55.4, 52.8. HPLC: Daicel Chiralpak IB (hexane/2-
129.4, 129.0, 128.9, 126.6, 122.3, 96.8, 68.1, 67.8, 54.7, 52.9; HPLC:
Chiralpak IB (hexane/2-propanol¼95/5, 1.0 mL/min, 220 nm);
27
propanol¼90/10, 0.8 mL/min, 220 nm); tR¼15.0 min (minor),
tR¼15.9 (minor), tR¼20.2 min (major); [
a]
¼ꢀ36.9 (c¼0.10, CHCl3);
D
tR¼22.5 min (major); [
a
]
D
¼þ46.3 (c¼0.05, CHCl3); HRMS (ESI)
HRMS (ESI) calcd for C18H17BrKN2O4 [MþK]þ 443.0009, found:
27
calcd for C22H20KN2O4 [MþK]þ 415.1060, found: 415.1047.
443.0031.
4.2.10. 3ja (R1¼2-thienyl). Yellow oil; 53.2 mg, 80% yield. 1H NMR
4.2.17. 3ag (R2¼C10H9Fe). Yellow solid, mp¼152e154 ꢁC; 82.5 mg,
d
7.43e7.26 (m, 7H), 6.99e7.07 (m, 1H), 5.27 (dd, J¼4.1, 6.5 Hz, 1H),
80% yield. 1H NMR
d 7.37e7.32 (m, 5H), 5.26 (m, 1H), 4.75 (d,
5.12 (d, J¼6.5 Hz, 1H), 4.26 (dd, J¼4.1, 7.4 Hz, 1H), 4.14 (m, 1H), 3.80
J¼5.5 Hz, 1H), 4.26 (m, 4H), 4.23 (s, 5H), 4.12 (m, 1H), 4.03 (m, 1H),
(s, 3H); 13C NMR
d
171.6,138.2,137.5,129.4,128.2,127.6, 127.4, 125.8,
2.91 (s, 3H); 13C NMR
d
172.3, 134.2, 128.9, 126.4, 96.8, 87.2, 69.0,
Please cite this article in press as: Kimura, M.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.08.002

M. Kimura et al. / Tetrahedron xxx (2015) 1e5
5
ꢀ
2. Najera, C.; Sansano, J. M. Curr. Top. Med. Chem. 2014, 14, 1271 and references are
cited therein.
68.5, 67.9, 67.8, 67.6, 66.1, 52.8, 51.0; HPLC: Chiralpak IB (hexane/2-
propanol¼95/5, 1.0 mL/min, 220 nm); tR¼24.2 (minor), tR¼35.5 min
3. Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H. Angew. Chem., Int. Ed. 2010, 49, 7895.
4. Recently, Oh et al. reported that an epimerization of the endo cycloadduct
proceeded on treatment with triethylamine to afford the corresponding epi-
endo cycloadduct Li, J.-Y.; Kim, H. Y.; Oh, K. Org. Lett. 2015, 17, 1288.
27
(major);
[
a
]
¼96.1 (c¼0.10, CHCl3); HRMS (ESI) calcd for
D
C
22H23FeN2O4 [MþNa]þ 437.0827, found 457.0839.
ꢀ
5. (a) Cabrera, S.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 16394;
4.2.18. 3ah (R2¼2-furyl). Yellow oil; 30.0 mg, 50% yield. 1H NMR
ꢀ
(b) Cabrera, S.; Arrayas, R. G.; Martín-Matute, B.; Cossío, F. P.; Carretero, J. C.
Tetrahedron 2007, 63, 6587.
6. Gonzalez-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun. 2012, 2149.
7. Lia, Q.; Dinga, C.-H.; Lib, X.-H.; Weissensteinerc, W.; Hou, X.-L. Synthesis 2012,
d
7.44e7.30 (m, 6H), 6.39e6.37 (m, 2H), 6.30 (d, J¼3.2 Hz, 2H), 5.34
(dd, J¼3.0, 6.1 Hz,1H), 4.86 (m, 1H), 4.30 (dd, J¼3.0, 6.7 Hz, 1H), 4.20
(m, 1H), 3.79 (s, 3H), 3.31 (m, 1H); 13C NMR
d
171.4, 150.9, 143.1,
265.
ꢀ
~
ꢀ
134.0, 128.9, 128.2, 126.5, 110.9, 108.0, 94.2, 67.7, 64.9, 52.9, 49.0.
8. Castello, L. M.; Najera, C.; Sansano, J. M.; Larranaga, O.; de Cozar, A.; Cossío, F. P.
Org. Lett. 2013, 15, 2902.
HPLC: Daicel Chiralpak IB (hexane/2-propanol¼95/5, 1.0 mL/min,
9. Dai, L.; Xu, D.; Dong, X.; Zhou, Z. Tetrahedron: Asymmetry 2015, 26, 350.
10. Kim, H. Y.; Li, J.-Y.; Kim, S.; Oh, K. J. Am. Chem. Soc. 2011, 133, 20750.
11. Narayan, R.; Bauer, J. O.; Strohmann, C.; Antonchick, A. P.; Waldmann, H. Angew.
Chem., Int. Ed. 2013, 52, 12892.
12. Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am. Chem. Soc. 2010,
132, 5338.
27
220 nm); tR¼17.9 (minor), tR¼19.9 min (major); [
a
]
¼ꢀ35.1
D
(c¼0.11, CHCl3); HRMS (ESI) calcd for C16H16N2O5 [MþNa]þ
339.0957, found: 339.0950.
Acknowledgements
13. Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew.
Chem., Int. Ed. 2006, 45, 1979.
ꢀ
~
ꢀ
14. Castello, L. M.; Najera, C.; Sansano, J. M.; Larranaga, O.; de Cozar, A.; Cossío, F. P.
This study was financially supported by a Grant-in-Aid, No.
25410053, for scientific research from the Japan Society for the
Promotion of Science (JSPS).
Adv. Synth. Catal. 2014, 356, 3861.
15. Silver-catalyzed non-asymmetric reaction of azomethine ylide with nitroalkene
has been reported where high diastereoselectivity is achieved Grigg, R.; Kilner,
C.; Sarker, M. A. B.; de la Cierva, C. O.; Dondas, H. A. Tetrahedron 2008, 64, 8974.
16. Bai, X.-F.; Song, T.; Xu, Z.; Xia, C.-G.; Huang, W.-S.; Xu, L.-W. Angew. Chem., Int.
Ed. 2015, 54, 5255.
Supplementary data
17. Shimizu, K.; Ogata, K.; Fukuzawa, S. Tetrahedron Lett. 2010, 51, 5068.
18. Imae, K.; Konno, T.; Ogata, K.; Fukuzawa, S. Org. Lett. 2012, 14, 4410.
19. For a review of AgOAc bifunctional catalysis (base-free conditions) Chen, Q.-A.;
Wang, D.-S.; Zhou, Y.-G. Chem. Commun. 2010, 4043 Chen, Q.-A.; Zeng, W.;
Wang, D.-S.; Zhou, Y.-G. Synlett. 2009, 2236, and our related paper, Watanabe,
S.; Tada, A.; Tokoro, Y.; Fukuzawa, S. Tetrahedron Lett. 2014, 55, 1306.
20. Careful analysis of the 1H NMR spectrum of the crude product revealed the
presence of minor amount of epi-endo isomer (less than exo isomer).
21. Oura, I.; Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2010, 12, 1752.
22. Worral, D. E. Org. Synth. 1929, 9, 66.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.08.002.
References and notes
1. For reviews, (a) Adrio, J.; Carretero, J. C. Chem. Commun. 2014,12434; (b) Adrio, J.;
Carretero, J. C. Chem. Commun. 2011, 47, 6784; (c) Zhang, W. Chem. Lett. 2013, 42,
ꢀ
676; (d) Pandy, G.; Banerjee; Garde, S. R. Chem. Rev. 2006,106, 4484; (e) Najera, C.;
Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272.
Please cite this article in press as: Kimura, M.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.08.002