Bifunctional AgOAc/ThioClickFerrophos complex-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with aryl- and alkylidene malonates

Article abstract of DOI:10.1016/j.tetlet.2013.12.101

AgOAc/ThioClickFerrophos complex-catalyzed 1,3-dipolar cycloaddition of glycine imino ester, the precursor of azomethine ylide, with aryl- and alkylidene malonates afforded the corresponding exo-cycloadducts, that is, proline ester derivatives in high yie

Full text of DOI:10.1016/j.tetlet.2013.12.101

Tetrahedron Letters 55 (2014) 1306–1309
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Tetrahedron Letters
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Bifunctional AgOAc/ThioClickFerrophos complex-catalyzed
asymmetric 1,3-dipolar cycloaddition of azomethine ylides
with aryl- and alkylidene malonates
⇑
Sayo Watanabe, Atsuo Tada, Yuichiro Tokoro, Shin-ichi Fukuzawa
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, Tokyo, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
AgOAc/ThioClickFerrophos complex-catalyzed 1,3-dipolar cycloaddition of glycine imino ester, the
precursor of azomethine ylide, with aryl- and alkylidene malonates afforded the corresponding exo-cyc-
loadducts, that is, proline ester derivatives in high yields with high enantiomeric excess (up to 99% ee).
The reactions proceeded smoothly under base-free conditions demonstrating the bifunctional catalysis of
the silver complex.
Received 11 November 2013
Revised 11 December 2013
Accepted 25 December 2013
Available online 27 January 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylide
Cycloaddition
Alkylidene malonate
Chiral phosphine
Ferrocene ligand
The asymmetric 1,3-dipolar cycloaddition of glycine imino
ester, the precursor of azomethine ylide, with electron-deficient al-
kenes may afford diverse optically active proline derivatives that
may lead to the discovery of antiviral drugs.1 For example, a pro-
line derivative acts as the inhibitor of hepatitis C virus (HCV) poly-
merase.2 Major interest has been focused on the development of
enantioselective catalysts for the asymmetric 1,3-dipolar cycload-
dition since Zhang and co-workers succeeded for the first time in
developing the catalytic version of this reaction.3 Among a number
of catalysts, the copper4 and silver5 phosphine complexes are par-
ticularly effective for this reaction. Diverse electron-deficient al-
kenes such as acrylates, maleates, and maleimides have been
extensively investigated as the dipolarophiles for this reaction.
On the other hand, aryl- and alkylidene malonates have been rarely
studied as the dipolarophiles, even though they have been inten-
sively employed as good Michael acceptors in asymmetric conju-
gate additions.6 Aryl- and alkylidene malonates can be replaced
for cinnamates and crotonates, which cannot react as the dipolaro-
philes to afford the corresponding 3-aryl- and alkyl-substituted
proline derivatives. Wang and co-workers used arylidene malo-
nates 2 for the first time as the dipolarophiles for the enantioselec-
tive 1,3-dipolar cycloaddition with azomethine ylides 1 catalyzed
by the silver(I)/TF-BiphamPhos catalyst system.7 Subsequently,
Deng and co-workers reported that a copper(II)/imino alcohol
complex can be used as an efficient catalyst for the reaction result-
ing in high diastereo- and enantioselectivities.8 Both the catalysts
afforded exo-cycloadducts 3, where the 2-ester and 3-aryl groups
are trans to each other, exclusively with high enantioselectivity
(Scheme 1).
We previously reported the highly enantioselective 1,4-conju-
gate addition of diphenylmethyleneamino ester 4 to arylidene
malonates 2 catalyzed by the AgOAc/ThioClickFerrophos (chiral
ferrocenyl P,S-ligand; ThioClickFerrophos is abbreviated as TCF)
catalyst system and obtained syn-1,4-adducts 5 (2-aryl-3-imino-
1,1,3-triesters) diastereoselectively (Scheme 2).9 Inspired by the
success in this conjugate addition, we applied the AgOAc/TCF
atalyst system to the reaction of benzylidene amino esters 1, the
precursor of azomethine ylides, with arylidene malonates 2. The
1,3-dipolar cycloaddition reactions proceeded smoothly in the ab-
sence of a base, such as triethylamine, to afford the corresponding
exo-cycloadducts in good yields with high enantioselectivities. In
the previous Letters, the silver and copper catalysts required a
base, whereas base is not essential for the function of AgOAc/TCF
catalyst system, which works as a bifunctional catalyst (Lewis acid
and base).10 In this study, we report the bifunctional catalysis of
AgOAc/t-BuTCF catalyst system and the substrate scope with re-
spect to both azomethine ylides 1 and arylidene malonates 2.
First, AgOAc/t-BuTCF (R = t-Bu, 5 mol %) catalyst system was
tested in the model reaction of methyl 2-phenyleneamino acetate
1 (R1 = Ph) and diethyl benzylidene malonate 2 (R2 = Ph) under
the similar conditions (room temperature, 15 h in THF) as the
⇑
Corresponding author. Tel.: +81 3 3817 1916; fax: +81 3 3817 1895.
E-mail address: orgsynth@kc.chuo-u.ac.jp (S.-i. Fukuzawa).
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.101

S. Watanabe et al. / Tetrahedron Letters 55 (2014) 1306–1309
1307
Table 2
Substrate scope of azomethine ylides 1a
Scheme 1. 1,3-Dipolar cycloaddition of azomethine ylides
arylidene malonates 2.
1 with alkyl- and
Entry
R1 in 1
Product
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
10
C6H5
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
90
95
95
90
93
83
91
70
75
60
98
99
99
96
98
98
94
85
93
99
p-MeC6H4
o-MeC6H4
p-MeOC6H4
p-CF3C6H4
p-ClC6H4
p-BrC6H4
1-C10H7
2-Thienyl
c-C6H11
3ja
Scheme 2. 1,4-Conjugate addition of glycine imino ester 4 to aryl- and alkylidene
malonates 2.
a
Reaction conditions:
1 (0.20 mmol), 2 (0.24 mmol), AgOAc (0.010 mmol,
5 mol %), TCF (0.011 mmol, 5.5 mol %), Et2O (3.0 mL); rt, 15 h.
b,c
Same as Table 1.
previous conjugate addition to 4. The reaction proceeded smoothly
and afforded exo-cycloadduct 3aa exclusively in 82% yield with
95% ee; the 1H NMR spectrum of 3aa was identical to the reported
compound. The optimization of solvent showed that diethyl ether
was the optimal solvent resulting in the best enantiomeric excess
(98% ee) with an excellent yield (99%) at room temperature for
15 h. The reaction proceeded smoothly in the absence of an exter-
nal base such as triethylamine. Although the addition of triethyl-
amine improved the yield of the product to some extent, it
resulted in a lower enantioselectivity. Other TCF variations such
as EtTCF (R = Et) and PhTCF (R = Ph) resulted in lower enantioselec-
tivities. From the optimization experiments, as shown in Table 1,
the optimized reaction conditions were determined as follows:
diethyl ether as the solvent and t-BuTCF as the ligand under
base-free conditions.
Next, the substrate scope of the reaction was investigated with
respect to imino esters 1 and arylidene malonates 2 to determine
the effectiveness of AgOAc/t-BuTCF catalyst system. Because of
the advantage of the bifunctional activity of AgOAc/t-BuTCF cata-
lyst, the reactions were usually carried out in the absence of a base.
Tables 2 and 3 summarize the substrate scope of imino esters 1 and
arylidene malonates 2, respectively. As shown in Table 1, the
Table 3
Substrate scope of arylidene malonates 2a
Entry
R2 in 2
Product
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
9
p-MeC6H4
o-MeC6H4
p-MeOC6H4
p-CF3C6H4
p-ClC6H4
p-BrC6H4
1-C10H7
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
95
95
85
98
95
85
99
99
90
97
95
95
94
97
96
88
97
87
2-Thienyl
c-C6H11
3aj
a–c
Same as Table 2.
reaction of dimethyl benzylidene malonate 1a with the phenyl
derivatives of the imino ester with electron-donating (p-Me, p-
OMe, and o-Me) and electron-withdrawing (p-Cl, p-Br, and p-CF3)
substituents afforded the corresponding exo-cycloadducts in good
to excellent yields with high enantioselectivities; the electronic
nature and position of the substituent did not affect the yield
and enantioselectivity. The relative and absolute configuration of
the cycloadduct were determined by the X-ray crystallography
Table 1
Optimization of 1,3-dipolar cycloadditiona
analysis of 3fa (Flack
v
= À0.07(6)); the configuration of 3fa was
determined as exo-(2S,3S,5S) (Fig. 1). The 1-naphthyl derivative
of the imino ester also reacted with 2 and afforded the correspond-
ing product in a good yield with 85% ee. A heteroaryl imino ester
such as a thienyl derivative could be used as the substrate even
though it could be coordinated to silver and might affect the
enantioselectivity; the cycloadduct was obtained in 75% yield with
99% ee. Thus, the substituent had a limited effect on the reaction.
The reaction of the cyclohexyl derivative afforded the correspond-
ing product in a low yield (18% yield) with low catalyst loading
(3 mol %), and 20 mol % of the catalyst was required to obtain a rea-
sonable yield.7 For the AgOAc/TCF-catalyzed reaction, 5 mol % of
the catalyst afforded the cyclohexyl derivative in a moderate yield
(60% yield).
Entry
L
Solvent
Yieldb (%)
Eec (%)
1
2
3
t-BuTCF
t-BuTCF
t-BuTCF
t-BuTCF
t-BuTCF
EtTCF
THF
DME
1,4-Dioxane
Et2O
Et2O
82
88
80
90
99
84
93
95
92
97
98
95
62
66
4
5d
6
Et2O
Et2O
7
PhTCF
a
Reaction conditions:
5 mol %), TCF (0.011 mmol, 5.5 mol %), solvent (3.0 mL); rt, 15 h.
1 (0.20 mmol), 2 (0.24 mmol), AgOAc (0.010 mmol,
b
Isolated yield.
Determined by HPLC (Daicel Chiralpak IA).
Et3N (18 mol %) was added.
c
d

1308
S. Watanabe et al. / Tetrahedron Letters 55 (2014) 1306–1309
afforded the corresponding exo-cycloadducts exclusively in high
yields with high enantioselectivities (up to 99% ee). The substrate
scopes with respect to both azomethine ylides and arylidene mal-
onates were diverse, and the reaction was hardly affected by the
electronic nature of the substituent on the substrates. Further,
diverse proline esters could be prepared by this method.
Acknowledgments
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). We thank Professor Makoto Yamashita
and Dr. Katsunori Suzuki of Chuo University for X-ray diffraction
analysis of compound 3fa.
Figure 1. X-ray structure of 3fa.
Supplementary data
In the case of arylidene malonates 2, the substituent effect was
hardly observed on the reaction. Regardless of the electronic nat-
ure and position of the substituent, the corresponding exo-cycload-
ducts were obtained in excellent yields (>95%) with excellent
enantioselectivities (>95% ee). The reaction of 2-thienylidene and
1-naphthylidene malonates also afforded the corresponding ad-
ducts in excellent yields and enantioselectivities. Interestingly,
the reaction of cyclohexylidene malonate proceeded smoothly in
the absence of a base and afforded the corresponding product in
an excellent yield (90% yield, 87% ee), whereas the addition of a
base (Cs2CO3) was essential in the conjugate addition of glycine
imino ester 4 to 2.
Supplementary data (full experimental procedures, the charac-
terization data for novel compounds, and the crystallographic data
for 3fa are provided in a CIF file (CCDC 959135)) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.12.101.
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