Asymmetric construction of 3-vinylidene-pyrrolidine derivatives containing allene moiety via Ag(i)/TF-BiphamPhos-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with diethyl 2-(3,3-diphenylpropa-1,2-dienylidene) malonate

Article abstract of DOI:10.1039/c1ob05291h

Catalytic asymmetric 1,3-dipolar cycloaddition of various azomethine ylides with diethyl 2-(3,3-diphenylpropa-1,2-dienylidene)malonate has been developed successfully with good to excellent enantioselectivity for the effcient construction of 3-vinylidene-pyrrolidine derivatives containing a unique allene moiety.

Full text of DOI:10.1039/c1ob05291h

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 3622
www.rsc.org/obc
COMMUNICATION
Asymmetric construction of 3-vinylidene-pyrrolidine derivatives containing
allene moiety via Ag(I)/TF-BiphamPhos-catalyzed 1,3-dipolar cycloaddition
of azomethine ylides with diethyl 2-(3,3-diphenylpropa-1,2-dienylidene)
malonate†‡
Zhi-Yong Xue,a Xin Fanga and Chun-Jiang Wang*a,b
Received 23rd February 2011, Accepted 21st March 2011
DOI: 10.1039/c1ob05291h
Catalytic asymmetric 1,3-dipolar cycloaddition of various
azomethine ylides with diethyl 2-(3,3-diphenylpropa-1,2-
dienylidene)malonate has been developed successfully with
good to excellent enantioselectivity for the effcient con-
struction of 3-vinylidene-pyrrolidine derivatives containing
a unique allene moiety.
occasionally as dienophiles in many reactions.5 However, those
compounds have seldom been employed as dipolarophiles in the
asymmetric 1,3-dipolar cycloaddition of azomethine ylides.6 To
the best of our knowledge, only one recent example reported
by Gong7 has showed that 2,3-allenoates could be employed
as dipolarophiles in the organocatalytic asymmetric 1,3-dipolar
cycloaddition of in situ-formed azomethine ylides, which provided
3-methylenepyrrolidines derivatives containing a C–C double
bond in high diastereo-/enantioselectivity. This methodology has
also been applied by the same group for the kinetic resolution of
racemic 2,3-allenoates with excellent performances.8
Recently, we reported that Ag(I)/TF-BiphamPhos complexes
exhibited excellent results in the asymmetric 1,3-dipolar cy-
cloaddition of azomethine ylides with alkylidene malonate as
dipolarophile.9,10 Encouraged by those achievements, we envi-
sioned that the 1,2-dienylidene-malonate could be employed as
dipolarophiles in the asymmetric 1,3-dipolar cycloaddition for the
construction of 3-vinylidene-pyrrolidine derivatives11 containing
a unique allene moiety (Scheme 1). 3-Vinylidene-pyrrolidine
derivatives are undoubtedly important building block in synthetic
chemistry considering that the allene core structures have resulted
in excellent regio- and stereoselectivities for many nucleophilic
and electrophilic reactions.12 Herein, we reported the first catalytic
asymmetric version of 1,3-dipolar cycloaddition of various azome-
thine ylides to easily accessible diethyl 2-(3,3-diphenylpropa-1,2-
dienylidene) malonate13 with high yield and good to excellent
enantioselectivity.
Five-membered nitrogen heterocycles, especially the highly sub-
stituted pyrrolidines are observed widely in pharmaceuticals,
natural alkaloids, organocatalysts and also useful building blocks
in synthetic chemistry.1 The catalytic asymmetric 1,3-dipolar cy-
cloaddition of azomethine ylides generated from readily available
imino esters and electron-deficient alkenes provides an efficient
approach and powerful diversity-oriented synthesis (DOS)2 for
the construction of the type of structures.3 Much attention has
been paid to develop enantioselective catalytic protocols for 1,3-
dipolar cycloaddition since the first report in 2002.4 During the last
decade, asymmetric 1,3-dipolar cycloadditions have been reported
using chiral metal-complexes and organocatalysts to generate
stereochemically complex pyrrolidine derivatives with moderate
to high enantio-/diastereoselectivities.3 Although various meth-
ods have been developed for this transformation, most of the
electron-deficient alkenes applied in 1,3-dipolar cycloaddition of
azomethine ylides are limited to a-unsaturated compounds such
as maleates, fumarates, maleimides, acrylates, nitroalkenes and
vinyl phenyl sulfones,3 proving pyrrolidine derivatives substituted
with saturated C–C chemical bond. Cumulene derivatives have
attracted much attention in organic chemistry due to their high
unique reactivities serving as nucleophiles, electrophiles, and
aCollege of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
430072, China. E-mail: cjwang@whu.edu.cn; Fax: +86-27-68754067
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, 354 Fenglin Road, Shanghai, 200032, China
† Electronic supplementary information (ESI) available: Experimental
section. CCDC reference numbers 809653. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1ob05291h
Scheme
1 Proposed asymmetric synthesis of 3-vinylidence-pyrro-
lidines via 1,3-dipolar cycloaddition of azomethine yildes using diethyl
2-(3,3-diphenylpropa-1,2-dienylidence)malonate as the dipolarophiles.
‡ Crystal data for (2R,5R)-5: C40H36BrNO7, Mr = 722.60, T = 293 K,
Initially, the reaction of N-benzylidene glycine methyl ester
3a with diethyl 2-(3,3-diphenylpropa-1,2-dienylidene) malonate
2 was investigated under the previous reported optimal re-
action conditions for asymmetric 1,3-dipolar cycloaddition of
Orthorhombic, space group P212121, a = 13.323(2), b = 15.987(3), c =
3
˚
˚
17.448(3) A, V = 3716.3(11) A , Z = 4, 4470 reflections measured, 3536
unique (Rint = 0.0503) which were used in all caclculations. The final wR2 =
0.1444 (all data). Flack c = 0.008(18). CCDC 809653 (5).
3622 | Org. Biomol. Chem., 2011, 9, 3622–3624
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
alkylidene malonates, and the representative results are sum-
marized in Table 1. To our delight, this reaction was finished
in 30 min with 3 mol% AgOAc/TF-BiphamPhos 1a and 15
mol% K2CO3 powder in CH2Cl2 at room temperature, and the
1,3-dipolar cycloaddition reaction selectively occurs on the C2-3
double bond to afford the cycloadduct 4a containing an allene
moiety with 89% yield and 86% ee (Table 1, entry 1). Only
moderate enantioselectivity was obtained when switching the
metal precursor from AgOAc into Cu(CH3CN)4BF4 (Table 1,
entry 2). The experimental results disclosed that the corresponding
active intermediate generated from silver(I) cation, chiral ligand
and the in situ-formed azomethine ylide has more appropriate
interaction with the dipolarophile cumulene diester, which af-
fords higher asymmetric inducing capability (Table 1, entries
1 and 2). Encouraged by these results, the reaction conditions
described in entry 1 were chosen for subsequent screening of
other TF-BiphamPhos ligands with different substituents either
on the phenyl ring of diaryl phosphine group or on the chiral
backbone. It was found that the enantioselectivity in this 1,3-
dipolar cycloaddition was greatly affected by the properties of the
substitutes. Although no difference was observed when the phenyl
group on the phosphorous atom of ligand 1a was replaced by xylyl
group (1b), much lower asymmetric induction and catalytic ability
were obtained by ligand 1c and 1d containing strongly electron-
withdrawing 3,5-bis(trifluoromethyl)-phenyl group and the bulky
cyclohexyl group on the phosphorus atom, respectively (Table
1, entries 3–5). Gratifyingly, ligand 1e bearing two bromines at
the 3,3¢-positions of the TF-BIPHAM backbone was the most
effective chiral ligand affording the cycloadduct 4a in high yield
and 90% ee (Table 1, entry 6). To examine the effect of solvent,
the reaction of 2 with 3a in the presence of AgOAc/(S)-TF-
BiphamPhos (1e) was performed in DCM, THF, ether, ethyl
acetate, toluene and CH3CN, and dichloromethane was found
to be the best solvent in terms of the yield and enantioselectivity
(Table 1, entries 6–11). Reducing the temperature to 0 ◦C in DCM
led to full conversion in 60 min with 93% ee (Table 1, entry
12), but further lowering the temperature could not improve the
enantioselectivity (Table 1, entry 13).
Next, the scope and generality of this novel 1,3-dipolar cycload-
dition of diethyl 2-(3,3-diphenylpropa-1,2-dienylidene) malonate 2
with a series of representative imino esters 3 derived from glycinate
were investigated under the optimized experimental conditions.
As shown in Table 2, a variety of aromatic aldehydes derived
imino esters, which bear electron-rich (Table 2, entries 2 and 3),
electron-neutral (Table 2, entries 1 and 9), and electron deficient
groups (Table 2, entries 4–8) on the aryl rings, reacted smoothly
with 2-(3,3-diphenylpropa-1,2-dienylidene) malonate 2 to afford
the corresponding cycloadducts (4a–4j) in high yields (82–92%)
and good enantioselectivities (90–93%) at 0 ◦C within 1–2 h. It
is noteworthy that comparable excellent performance was still
achieved for the sterically hindered ortho-chloro-substituted imino
ester 3e in terms of enantioselectivity and reactivity (Table 2, entry
5), which demonstrated that the substitution pattern of the arene
Table 1 Screening studies of the asymmetric 1,3-dipolar cycloaddition
of azomethine ylide 3a with diethyl 2-(3,3-diphenylpropa-1,2-dienyli-
dene)malonate 2a
Table 2 Substrate scope of AgOAc/(S)-1e-catalyzed asymmetric 1,3-
dipolar cycloaddition of azomethine ylides
3 with diethyl 2-(3,3-
diphenylpropa-1,2-dienylidene)malonate 2a
Entry
R1
R2
4
Yield (%)b
90
Ee (%)c
1
2
3
4
5
6
7
8
Ph (3a)
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
93
90
92
93
92
90
91
93
91
90
91
88
93
95
96
96
Entry
L
[M]
Solvent T/◦C Time (min) Yieldb (%) Eec (%)
p-Me-Ph (3b)
m-Me-Ph (3c)
p-Cl-Ph (3d)
o-Cl-Ph (3e)
m-Cl-Ph (3f)
p-Br-Ph (3g)
p-CF3-Ph (3h)
2-Naphthyl (3i)
2-Furyl (3j)
PhCH CH (3k)
Cyclohexyl (3l)
Ph (3m)
92
90
85
90
88
89
88
85
82
85
82
88
85
85
82
1
2
3
4
5
6
7
8
1a AgOAc DCM rt
1a CuBF4 DCM rt
1b AgOAc DCM rt
1c AgOAc DCM rt
1d AgOAc DCM rt
1e AgOAc DCM rt
30
60
30
30
30
30
30
30
30
30
30
60
60
89
75
85
73
68
91
90
63
68
81
52
90
87
86
59
86
23
65
90
33
68
29
21
30
93
90
9
1e AgOAc THF
1e AgOAc Et2O
rt
rt
10
11
12
13d
14d
15d
16d
9
1e AgOAc EtOAc rt
1e AgOAc PhMe rt
1e AgOAc MeCN rt
10
11
12
13
p-Cl-Ph (3n)
p-Br-Ph (3o)
p-Br-Ph (3p)
1e AgOAc DCM
0
1e AgOAc DCM -20
a All reactions were carried out with 0.23 mmol of 2 and 0.40 mmol of
3a in 2 mL solvent. CuBF4 = Cu(CH3CN)4BF4. b Isolated yield. c Ee was
determined by chiral HPLC analysis.
a All reactions were carried out with 0.23 mmol of 2 and 0.40 mmol of
3a in 2 mL DCM. b Isolated yield. c Ee was determined by chiral HPLC
analysis. d The reactions were carried out in 24h.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3622–3624 | 3623
©

View Article Online
had little effect on the selectivity of the reaction. Additionally,
heteroaromatic 2-furyl imino ester 3j was also a viable substrate
as condensed-ring imino ester 3i and a-unsaturated imino ester 3k
(Table 2, entries 9-11). Remarkably, the less reactive imino ester
3l derived from aliphatic cyclohexanecarbaldehyde also work in
this transformation to give 88% ee (Table 2, entry 12). Notably,
imino esters (3m–3p) derived from a-substituted amino acids, such
as alanine and 2-phenylglycine, have also proven to be excellent
substrates for this reaction, producing the desired 3-vinylidene-
pyrrolidines bearing a nitrogen-substituted quaternary stereogenic
centre14 with high reactivity and excellent enantioselectivity (Table
2, entries 13–16).
To determine the relative and absolute configuration of cy-
cloadduct 4o, the derived amide 5 was synthesized via highly
efficient and simple benzoylation protocol (Fig. 1). A X-ray
analysis of the crystal of 5 revealed (2R,5R) configuration
for the two stereogenic centers around the N atom therefore
also for the corresponding moiety in 4o (Fig. 1). The abso-
lute configuration of all other cycloadducts was assigned by
analogy.
SRFDP (20090141110042), and the Fundamental Research Funds
for the Central Universities.
Notes and references
1 (a) S. G. Pyne, A. S. Davis, N. J. Gates, J. Nicole, J. P. Hartley, K.
B. Lindsay, T. Machan and M. Tang, Synlett, 2004, 2670; (b) In
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural ProductsL. M. Harwood and R. J. Vickers,
A. Padwa, W. Pearson, ed.; Wiley & Sons, New York, 2002; (c) J. P.
Michael, Nat. Prod. Rep., 2008, 25, 139.
2 S. L. Schreiber, Science, 2000, 287, 1964.
3 For excellent reviews about 1,3-dipolar cycloaddition reactions of
azomethine ylides, see: (a) L. M. Stanley and M. P. Sibi, Chem. Rev.,
2008, 108, 2887; (b) G. Pandey, P Banerjee and S. R. Gadre, Chem.
Rev., 2006, 106, 4484; (c) T. M. V. D. Pinho e Melo, Eur. J. Org. Chem.,
2006, 2873; (d) M. Bonin, A. Chauveau and L. Micouin, Synlett, 2006,
2349; (e) C Na´jera and J. M. Sansano, Angew. Chem., Int. Ed., 2005,
44, 6272; (f) I. Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765;
(g) I. Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765; (h) V.
Nair and T. D. Suja, Tetrahedron, 2007, 63, 12247; (i) B. Engels and M.
Christl, Angew. Chem., Int. Ed., 2009, 48, 7968; (j) M. Alvarez-Corral,
M. Munoz-Dorado and I. Rodrıguez-Garcıa, Chem. Rev., 2008, 108,
3174; (k) M. Naodovic and H. Yamamoto, Chem. Rev., 2008, 108, 3132;
(l) V. Nair and T. D. Suja, Tetrahedron, 2007, 63, 12247.
4 (a) J. M. Longmire, B. Wang and X. Zhang, J. Am. Chem. Soc., 2002,
124, 13400For the early report on the stoichiometric amount of chiral
catalyst, see: (b) R. Grigg, Tetrahedron: Asymmetry, 1995, 6, 2475; (c) P.
Allway and R. Grigg, Tetrahedron Lett., 1991, 32, 5817; (d) Z Zhang,
S.-B. Yu, X.-P. Hu, D.-Y. Wang and Z. Zheng, Org. Lett., 2010, 12,
5542.
5 (a) T. Furuta, T. Asakawa, M. Iinuma, S. Fujii, K. Tanaka and T. Kan,
Chem. Commun., 2006, 3648; (b) T. Asakawa, M. Iinuma, T. Furuta,
S. Fujii, T. Kan and K. Tanaka, Chem. Lett., 2006, 35, 512; (c) P.-H.
Liu, L. Li, J. A. Webb, Y. Zhang and N. S. Goroff, Org. Lett., 2004, 6,
2081; (d) N. Suzuki, Y. Fukuda, C. E. Kim, H. Takahara, M. Iwasaki,
M. Saburi, M. Nishiura and Y. Wakatsuki, Chem. Lett., 2003, 32, 16;
(e) N. Suzuki, M. Nishiura and Y. Wakatsuki, Science, 2002, 295, 660;
(f) G. Dyker, S. Borowski, G. Henkel, A. Kellner, I. Dix and P. G. Jones,
Tetrahedron Lett., 2000, 41, 8259.
6 For an recent report on phosphine-mediated [3 + 2] cycloaddition
reactions of ethyl 5,5-diarylpenta-2,3,4-trienoates with arylmethyl-
idenemalononitriles and N-Tosylimines, see: X.-Y. Guang and M. Shi,
J. Org. Chem., 2009, 74, 1977.
7 J. Yu, L. He, X.-H. Chen, J. Song, W.-J. Chen and L.-Z. Gong, Org.
Lett., 2009, 11, 4946.
8 J. Yu, W.-J. Chen and L.-Z. Gong, Org. Lett., 2010, 12, 4050.
9 Z.-Y. Xue, T.-L. Liu, Z. Lu, H. Huang, H.-Y. Tao and C.-J. Wang,
Chem. Commun., 2010, 46, 1727.
Fig. 1 X-Ray Structure of (2R, 5R)-5.
10 For other research work based on chiral TF-BIPHAM backbone from
this lab, see: (a) C.-J. Wang, F. Gao and G. Liang, Org. Lett., 2008, 10,
4711; (b) C.-J Wang, G. Liang, Z.-Y. Xue and F. Gao, J. Am. Chem.
Soc., 2008, 130, 17250; (c) C.-J. Wang, Z.-Y. Xue, G. Liang and Z.
Lu, Chem. Commun., 2009, 2905; (d) G. Liang, M.-C Tong and C.-J.
Wang, Adv. Synth. Catal., 2009, 351, 3101; (e) G. Liang, M.-C. Tong,
H.-Y. Tao and C.-J. Wang, Adv. Synth. Catal., 2010, 352, 1851; (f) T.-L.
Liu, Z.-Y. Xue, H.-Y Tao and C.-J. Wang, Org. Biomol. Chem., 2011,
9, 1980; (g) T.-L. Liu, Z.-L. He, H.-Y. Tao, Y.-P. Cai and C.-J. Wang,
Chem. Commun., 2011, 47, 2616.
11 For the early examples on the synthesis of 3-vinylidene-pyrrolidine
derivatives via other methods, see: (a) H. Hiemstra, P. F. Hendrikus, S.
Sander and W. N. Speckamp, Tetrahedron Lett., 1985, 26, 3151; (b) D.
Damour, J. Pornet and L. Miginiac, Tetrahedron Lett., 1987, 28, 4689.
12 S. Ma, Chem. Rev., 2005, 105, 2829.
13 (a) K. W. Ratts and R. D. Partos, J. Am. Chem. Soc., 1969, 91, 6112;
(b) N. R. Browne, R. F. C. Brown, F. W. Eastwood and G. D. Fallon,
Aust. J. Chem., 1987, 40, 1675.
14 (a) Quaternary Stereocenters: Challenges and Solution for Organic
SynthesisJ. Christoffers and A. Baro, ed.; WILEY-VCH, Weinheim,
2005; (b) J. Christoffers and A. Baro, Angew. Chem., Int. Ed., 2003,
42, 1688; (c) B. M. Trost and C. Jiang, Synthesis, 2006, 369; (d) C. J.
Douglas and L. E. Overman, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
5363.
In summary, we have found that AgOAc/TF-BiphamPhos
complex is an efficient catalyst for the highly enantioselective
1,3-dipolar cycloaddition of azomethine ylides with diethyl 2-
(3,3-diphenylpropa-1,2-dienylidene) malonate as the novel dipo-
larophile for the construction of 3-vinylidene-pyrrolidine deriva-
tives containing a unique allene moiety. Excellent reactivity,
enantioselectivity, and structural scope were uniformly observed
for various azomethine ylides, especially derived from amino
esters other than glycinate. The ready availability of the starting
materials and the great importance of the enantiopure products
make the current methodology particularly interesting in synthetic
chemistry. Further investigations of the scope and synthetic
application of this methodology are ongoing, and the results will
be reported in due course.
This work was supported by National Natural Science Foun-
dation of China (20702039, 20972117), 973 (2011CB808600),
3624 | Org. Biomol. Chem., 2011, 9, 3622–3624
This journal is
The Royal Society of Chemistry 2011
©