Exo-Selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides with alkylidene malonates catalyzed by AgOAc/TF-BiphamPhos

Article abstract of DOI:10.1039/b919625k

The first exo-selective asymmetric 1,3-dipolar cycloaddition of alkylidene malonates with azomethine ylides catalyzed by AgOAc/TF-BiphamPhos has been reported in good yields and good to excellent enantio-/diastereoselectivities.

Full text of DOI:10.1039/b919625k

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exo-Selective asymmetric 1,3-dipolar cycloaddition of azomethine ylides
with alkylidene malonates catalyzed by AgOAc/TF-BiphamPhosw
Zhi-Yong Xue, Tang-Lin Liu, Zhou Lu, He Huang, Hai-Yan Tao and Chun-Jiang Wang*
Received (in College Park, MD, USA) 21st September 2009, Accepted 21st January 2010
First published as an Advance Article on the web 5th February 2010
DOI: 10.1039/b919625k
The first exo-selective asymmetric 1,3-dipolar cycloaddition
of alkylidene malonates with azomethine ylides catalyzed by
AgOAc/TF-BiphamPhos has been reported in good yields and
good to excellent enantio-/diastereoselectivities.
Lewis acids and TF-BiphamPhos as chiral ligands in the
presence of triethylamine at room temperature (Table 1).
The reaction was finished in 3 h with Cu(CH3CN)4BF4/
TF-BiphamPhos 1a in DCM at room temperature, and
exo-4aa was achieved as the sole product with 82% yield
and 19% ee, which was different from the endo-preference
while using maleates, maleimides and acrylates as dipolarophiles.13
Encouraged by this result, we screened various copper(I/II) and
silver(I) metals, which are known to be suitable precursors for
1,3-dipolar cycloaddition. Both CuI and CuII salts combined
with TF-BiphamPhos 1a afforded less than 20% ee although
excellent exo-selectivities and high reactivities were achieved
(Table 1, entries 1–3). Silver(I) salts gave better results than
copper salts in terms of the yield and enantioselectivity, and
the exclusive exo-adduct 4aa was achieved with 39% ee when
AgOAc/1a complex was used as the catalyst (Table 1, entries
4–6). Subsequently, AgOAc was selected as the metal catalyst
for ligand screening. The catalytic activities of ligands 1a and
1b were found to be superior to those of ligands 1c and 1d
(Table 1, entries 6–9), and further ligand tuning revealed that
TF-BiphamPhos 1e bearing two bromines at the 3,30-positions
of the TF-BIPHAM backbone was the most effective chiral
ligand and provided exo-4aa exclusively in high yield and
67% ee (Table 1, entry 10). These results demonstrated the
importance of the steric and electronic effects of the ligands on
the enantioselectivities. Other commercially available chiral
ligands were also tested in this transformation: 50% ee was
observed for the exo-product 4aa when BINAP/AgOAc complex
was used as the catalyst; while Monophos produced very low
enantioselectivities when AgOAc or Cu(CH3CN)4BF4 were
chosen as the metal precursor (Table 1, entries 11–14).
Five-membered nitrogen heterocycles, especially highly substituted
pyrrolidines feature widely in pharmaceuticals, natural
alkaloids and organocatalysts and are also useful building
blocks in organic synthesis.1 The catalytic asymmetric 1,3-dipolar
cycloaddition of azomethine ylides to electron-deficient
alkenes provides an efficient approach for constructing such
structures.2 Since the pioneering work of Grigg and Allway3
employing stoichiometric amounts of chiral metal complex
and the first catalytic asymmetric version reported by Zhang
et al.4 using the AgI/xylyl-FAP system, much attention has
been paid to developing enantioselective catalytic protocols
for the reaction over the past decade. Asymmetric 1,3-dipolar
cycloadditions have been reported using chiral metal
complexes such as AgI,4,5 ZnII,6 CuI/II 7 NiII,8 CaII,9 and
,
organocatalysts10 to generate stereochemically complex
products with moderate to high enantio-/diastereoselectivities.
Although various methods have been developed for this
transformation, most of the electron-deficient alkenes applied
in the 1,3-dipolar cycloadditions of azomethine ylides are
limited to maleates, fumarates, maleimides, acrylates, nitro-
alkenes and vinyl phenyl sulfones.3–10 However, alkylidene
malonates, which have been employed successfully in many
asymmetric Michael addition reactions,11 have not yet been
applied as dipolarophiles in the asymmetric 1,3-dipolar
cycloadditions of azomethine ylides. To the best of our
knowledge, only limited racemic examples have been reported
involving alkylidene malonates as the dipolarophile so far.12
An enantioselective version of this transformation may not
only diversify the existing asymmetric 1,3-dipolar cycloaddition
of azomethine ylides but also be valuable in the synthesis of
bioactive pyrrolidines. In this communication, we report the
first catalytic asymmetric version of the 1,3-dipolar cycloaddition
of azomethine ylides to various alkylidene malonates with high
diastereoselectivity and good to high enantioselectivity.
Having established the optimal ligand and metal precursor,
the effect of the ester functional group of the alkylidene
malonates 2 was investigated to further improve the enantio-
selectivity for this novel asymmetric 1,3-dipolar cycloaddition
(Table 2). The ester functional group of 2 has a significant
influence on the reactivity and enantioselectivity. By changing
the ester moiety of the alkylidene malonates from an ethyl (2a)
to a phenyl group (2c), the enantioselectivity of the corres-
ponding adducts improved from 67% ee to 78% ee, respectively
(Table 2, entries 1 and 3). When the ethyl group was replaced
by the sterically hindered tert-butyl group (2d), the enantio-
selectivity of the exo-adduct 4da was improved to 82% ee at
the expense of reaction rate (Table 2, entry 4). Fortunately, the
yield of 4da could be improved remarkably through switching
the organic base Et3N for K2CO3, and the enantioselectivity
was unchanged (Table 2, entry 5). Reducing the temperature
from room temperature to 0 1C or ꢀ20 1C did not improve the
enantioselectivity (Table 2, entries 6 and 7), and carrying out
Initially, the asymmetric 1,3-dipolar cycloaddition of
N-benzylidene glycine methyl ester 3a with diethyl benzylidene
malonate 2a was examined using different metal salts as
College of Chemistry and Molecular Sciences, Wuhan University,
430072, China. E-mail: cjwang@whu.edu.cn; Fax: +86-27-68754067
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 739450, 747638 and 761891. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
b919625k
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Table 1 Asymmetric 1,3-dipolar cycloaddition of diethyl benzylidene
malonate 2a with azomethine ylide 3aa
exo-adducts (4da–4dg) exclusively in high yields (69–98%)
and good enantioselectivities (78–86%) (Table 3, entries
1–8). It appears that the position and the electronic properties
of the substituents on the aromatic rings have very limited
effect on the enantioselectivities. Iminoesters from a- or
b-naphthylaldehyde also work well in this transformation
producing the exo-4dh and 4di with 82% and 80% ee, respectively
(Table 3, entries 9 and 10). Notably, the iminoester 3j from
aliphatic cyclohexanecarbaldehyde was tolerated in this
reaction, and the corresponding adduct could be obtained in
80% yield and remarkably 99% ee, although the catalyst
loading should be improved to 20 mol% probably due to
the lower reactivity of 3j (Table 3, entries 11 and 12). For the
dipolarophile partner, both electron-rich (2e) and electron-
deficient (2f) benzylidene malonates gave the exo-adducts in
high yields and good enantioselectivities (Table 3, entries 13
and 14). Alkylidene malonates with alkyl substitution (2g–2j)
proved to be excellent dipolarophiles in this transformation
affording the exo-adducts with good yields and 82–83% ee
(Table 3, entries 15–18). Iminoesters 3k and 3l derived
from (ꢂ)- or (S)-alanine were also tolerated in this reaction
producing exo-4fk bearing a nitrogen-substituted quaternary
stereogenic center with almost the same enantioselectivity due
to the in situ-formed same azomethine ylide (Table 3, entries
19 and 20). To our delight, most of the adducts are solid, and
enantiopure compounds can be easily obtained by direct
crystallization of the crude products from petroleum ether
(Table 3, entries 9 and 14).
Entry Ligand
[M]
Time/h Yield (%)b Ee (%)c
d
1
2
3
4
5
6
7
8
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(R)-BINAP
(R)-BINAP
CuBF4
Cu(OTf)2
CuBr
3
3
3
3
3
3
3
5
5
5
8
8
5
5
82
89
65
85
79
87
83
85
74
88
65
85
52
62
19
15
13
33
31
39
32
25
11
67
19
50
11
7
AgSbF6
AgClO4
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
CuBF4
AgOAc
9
10
11
12
13
14
(S)-Monophos CuBF4
(S)-Monophos AgOAc
a
The reactions were carried out with 0.23 mmol of 2a and 0.45 mmol
b
c
of 3a in 2 mL DCM at room temperature. Isolated yield. Determined
d
by chiral HPLC analysis. CuBF4 = Cu(CH3CN)4BF4.
The relative configuration of 4dh was assigned as exo
and the absolute configuration of 4fd and 4fk achieved by
AgOAc/(R)-TF-BiphamPhos 1e was unequivocally deter-
mined as (2S,3S,5S) by X-ray diffraction analysis (see ESIw).z
Those of other adducts were deduced on the basis of
these results. Based on the relative and absolute configuration
of 4dh, 4fd and 4fk, the high exo-selectivity observed in the
AgOAc/TF-BiphamPhos catalyzed asymmetric 1,3-dipolar
cycloaddition reaction can be rationalized from the
proposed tetracoordinated complex5b shown in Fig. 1. The
in situ-formed azomethine ylide is coordinated to the metallic
center and oriented in such a transition state because
of the steric repulsion between the phenyl group in the ylide
and the phenyl ring on the phosphorus atom of the chiral
ligand, and the high steric congestion imposed by the
latter effectively blocks the dipolarophile approach from
the Re (CQN) face of the azomethine ylide and forms the
exo-(2R,3R,5R) product through Si face attack (See ESI for
more informationw).
the reaction at room temperature provided the best results
(Table 2, entry 5).
The scope and generality of this catalytic system with regard
to iminoester and alkylidene malonate were investigated under
the optimized experimental conditions. As shown in Table 3, a
wide array of iminoesters derived from aromatic aldehydes,
which bear electron-rich, electron-neutral, or electron-deficient
groups on the phenyl ring, reacted smoothly with di-tert-butyl
2-benzylidene malonate 2d to afford the corresponding
Table 2 Asymmetric 1,3-dipolar cycloaddition of various benzylidene
malonate esters 2 with azomethine ylide 3aa
In conclusion, we have successfully developed the first
catalytic enantioselective 1,3-dipolar cycloaddition of various
alkylidene malonates with azomethine ylides. The highly
efficient AgOAc/TF-BiphamPhos catalytic system exhibited
the best performance, providing exo-adducts of poly-
substituted pyrrolidine derivatives in good yields, excellent
diastereoselectivities, and good enantioselectivities (78–99% ee).
Further investigation of the mechanism and the reaction
scope are ongoing in our laboratory and will be reported in
due course.
Entry
R
2
Base
T/1C Time/h
4
Yield (%)b Ee (%)c
1d
2d
3d
4d
5e
6e
7e
Et
2a Et3N
rt
rt
rt
5
5
5
4aa 88
4ba 90
4ca 90
4da 14
4da 85
4da 89
4da 80
67
65
78
82
82
78
74
Bn 2b Et3N
Ph 2c Et3N
t-Bu 2d Et3N
t-Bu 2d K2CO3
t-Bu 2d K2CO3
rt 48
rt
0
3
6
t-Bu 2d K2CO3 ꢀ20 12
a
b
c
d
See Table 1. See Table 1. See Table 1. 15 mol% Et3N.
2 eq. K2CO3.
This work was supported by the National Natural Science
Foundation of China, SRFD and Wuhan University.
e
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Table
3
Asymmetric 1,3-dipolar cycloaddition of alkylidene
Flack w = 0.008(12). CCDC 747638 (4dh), CCDC 739450 (4fd),
CCDC 761891 (4fk).
malonates 2 with azomethine ylides 3 catalyzed by AgOAc/1ea
1 For a recent review about 1,3-dipolar cycloaddition reactions of
azomethine ylides, see: L. M. Stanley and M. P. Sibi, Chem. Rev.,
2008, 108, 2887.
2 L. M. Harwood and R. J. Vickers, in Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and
Natural Products, ed. A. Padwa and W. Pearson, Wiley & Sons,
New York, 2002.
Entry 2 R1
3
R2
R3
4
Yield (%)b Ee (%)c
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1
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
2d Ph
3a Ph
3a Ph
H
H
H
H
H
H
H
H
4da 83
4da 85
4db 88
4dc 81
4dd 81
4de 88
4df 69
4dg 98
81
82
84
83
86
85
78
80
2d
3
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3b p-Me-Ph
3c m-Me-Ph
3d p-MeO-Ph
3e p-F-Ph
3f o-Cl-Ph
3g m-Cl-Ph
3h 1-Naphthyl H 4dh 80
3i 2-Naphthyl H 4di 74
3j Cy
3j Cy
4
5
6
7
8
9
10
11
12e
13
14
15g
16
17
18
82 (99)f
80
99
H
H
H
H
H
H
H
H
4dj 18
4dj 80
4ed 94
4fd 84
4ga 85
4ha 85
4ia 87
4ja 80
99
78
2e p-MeO-Ph 3d p-MeO-Ph
2f p-Br-Ph
2g Et
2h Et
2i Bu
2j i-Bu
3d p-MeO-Ph
3a Ph
3a Ph
3a Ph
3a Ph
82 (99)f
82
83
82
82
19h,i 2f p-Br-Ph
20h,j 2f p-Br-Ph
3k Ph
3l Ph
Me 4fk 72
Me 4fk 70
76 (99)f
72
a
b
See Table 1. See Table 1. See Table 1. (S)-TF-BiphamPhos was
c
d
e
f
used. 20 mol% catalyst was used. Data in parentheses were obtained
g
after simple recrystallization. Diethyl 2-propylidene malonate was
h
i
used as the dipolarophile. 10 mol% catalyst was used. (ꢂ)-Alanine
j
derived 3k was used as the iminoester. (S)-Alanine derived 3l was used
as the iminoester.
8 J.-W. Shi, M.-X. Zhao, Z.-Y. Lei and M. Shi, J. Org. Chem., 2008,
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Fig. 1 Proposed transition state leading to exo-adducts.
Notes and references
z Crystal data for racemic exo-4dh: C32H37NO6, Mr = 531.63,
ꢀ
T = 293 K, triclinic, space group P1, a = 10.0784(12), b =
12.2383(14), c = 12.8767(15) A, V = 1463.4(3) A3, Z = 2, 8636
reflections measured, 5649 unique (Rint = 0.0136) which were used in
all calculations. The final wR2 = 0.1176 (all data). For (2S,3S,5S)-4fd:
C29H36BrNO7, Mr = 590.50, T = 293 K, orthorhombic, space group
P212121, a = 9.7742(8), b = 15.7902(13), c = 18.9829(16) A, V =
2929.8(4) A3, Z = 4, 16 920 reflections measured, 5717 unique (Rint
=
0.0328) which were used in all calculations. The final wR2 = 0.1127
(all data), Flack w = 0.013(9). For (2S,3S,5S)-4fk: C29H36BrNO6,
Mr = 574.50, T = 293 K, orthorhombic, space group P212121,
a = 11.202(2), b = 11.863(2), c = 22.167(5) A, V = 2945.5(10) A3,
Z = 4, 17 768 reflections measured, 6077 unique (Rint = 0.0285)
which were used in all calculations. The final wR2 = 0.1460 (all data),
13 (a) C.-J. Wang, G. Liang, Z.-Y. Xue and F. Gao, J. Am. Chem.
Soc., 2008, 130, 17250; (b) C.-J. Wang, Z.-Y. Xue, G. Liang and
Z. Lu, Chem. Commun., 2009, 2905.
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