N -(2-Pyridylmethyl)imines as azomethine precursors in catalytic asymmetric [3 + 2] cycloadditions

Article abstract of DOI:10.1021/ol102605q

An efficient Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition of N-(2-pyridylmethyl) imines has been developed. In the presence of a Cu(CH ₃CN)₄PF₆/bisoxazoline catalyst system, high levels of enantioselectivity (up to 97% ee) and moderate to high exo selectivity were achieved with a wide variety of substituted dipolarophiles, including maleimides, fumarates, fumarodinitrile, enones, and nitroalkenes. The reaction with unsymmetrically substituted dipolarophiles is completely regioselective.

Full text of DOI:10.1021/ol102605q

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5608-5611
N-(2-Pyridylmethyl)imines as Azomethine
Precursors in Catalytic Asymmetric
[3 + 2] Cycloadditions
Silvia Padilla, Rube´n Tejero, Javier Adrio,* and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
jaVier.adrio@uam.es; juancarlos.carretero@uam.es
Received September 7, 2010
ABSTRACT
An efficient Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition of N-(2-pyridylmethyl) imines has been developed. In the presence of a
Cu(CH3CN)4PF6/bisoxazoline catalyst system, high levels of enantioselectivity (up to 97% ee) and moderate to high exo selectivity were achieved
with a wide variety of substituted dipolarophiles, including maleimides, fumarates, fumarodinitrile, enones, and nitroalkenes. The reaction with
unsymmetrically substituted dipolarophiles is completely regioselective.
In recent years, the catalytic asymmetric 1,3-dipolar cy-
cloaddition of azomethine ylides has witnessed an explosive
growth,1 to become nowadays a very powerful and atom-
economical methodology for the enantioselective synthesis
of pyrrolidines.2 In addition to efficient protocols using Zn,
Ag, Cu, Ni, and Ca chiral complexes,3 several organocatalytic
asymmetric methods have been recently reported.4 Despite
this huge progress, some important scope limitations still
remain, especially with regard to the substitution at the
azomethine precursor. By far, most catatytic asymmetric
procedures, both metal-catalyzed and organocatalytic ap-
proaches, deal with the use of R-iminoesters. To the best of
our knowledge, the only two general exceptions to this trend
have been recently reported by Kobayashi et al. and our group
using R-iminophosphonates5a and R-iminonitriles,5b respec-
tively, in asymmetric Ag-catalyzed [3 + 2] cycloadditions.
The great efficiency of R-iminoesters as azomethine
precursors relies on the high acidity at the enolizable CR
position and the formation of a rigid five membered N,O-
bidentate metalated azomethine. We envisaged that a suitable
coordinating nitrogen heterocycle, such as the 2-pyridyl
group, could also provide sufficient activation and an
appropriate discriminating environment to promote the
asymmetric cycloaddition via formation of a five membered
N,N-bidentate metalated azomethine6 (Scheme 1). A scattered
example of the intramolecular version of this process has
been previously reported using Ag-PHOX complexes.7
Herein we describe a protocol for the intermolecular catalytic
asymmetric [3 + 2] cycloaddition of N-(2-pyridylmeth-
yl)imines with a variety of activated olefins. The resulting
2-pyridyl pyrrolidine adducts hold a great potential as chiral
N,N-ligands and organocatalysts.8
(1) For pioneering references, see: (a) Longmire, J. M.; Wang, B.; Zhang,
X. J. Am. Chem. Soc. 2002, 124, 13400–13401. (b) Gothelf, A. S.; Gothelf,
K. V.; Hazell, R. J.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41,
4236–4238.
As model reaction we chose the cycloaddition of the
pyridyl imine 1a with N-methyl maleimide. After screening
various Cu, Ag and Zn metal sources and a variety of chiral
ligands, the combination of copper salts and bisoxazoline
(2) For recent reviews, see: (a) Stanley, L. M.; Sibi, M. P. Chem. ReV.
2008, 108, 2887. (b) Pellisier, H. Tetrahedron 2007, 63, 3235–3285. (c)
Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106, 4484–4517.
(d) Na´jera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272–
6276.
10.1021/ol102605q  2010 American Chemical Society
Published on Web 11/15/2010

diastereoselectivity (entries 2 and 3). In contrast, a Cu(I) salt
such as Cu(CH3CN)4PF6 proved to be highly exo diastereo-
selective, especially in combination with bisoxazoline ligands
4, 6 and 7 (entries 6-8). Pleasingly, a nearly complete
diastereoselectivity and very high enantioselectivity (97%
ee) was achieved with the tetraphenyl bisoxazoline 7
(85% yield, entry 8). The cycloaddition can be also per-
formed using a lower catalyst loading (3-5 mol % of
Cu(CH3CN)4PF6 and ligand 7), albeit with a significant
erosion of the enantioselectivity (entry 9).
Scheme 1
Table 1. Reaction Conditions for the Model Reaction
ligands provided the best results9 (Table 1). The reaction
using Cu(OTf)2 and ligand 3 (10 mol %) as catalyst system,
in the presence of Et3N as base (CH2Cl2, rt), afforded a
mixture of exo/endo pyrrolidines 2a with low yield and
enantioselectivity (entry 1). Better enantioselectivities were
obtained with bisoxazolines 5 and 7, albeit with poor
entry metal source L* exo/endoa yield(%)b ee (exo)(%)c
1
2
3
4
5
6
7
8
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
3
5
7
3
5
4
6
7
7
34/66
40/60
65/35
66/34
75/25
>98/<2
>98/<2
>98/<2
>98/<2
30
45
60
68
72
70
62
51
77
95
20
6
40
50
d
CuPF6
CuPF6
CuPF6
CuPF6
d
d
(3) For selected recent references, Cu-catalysts, see: (a) Robles-Mach´ın,
R.; Gonza´lez-Esguevillas, M.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2010,
75, 233–236. (b) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato,
H. J. Am. Chem. Soc. 2010, 132, 5338–5339. (c) Kim, H. Y.; Shih, H.-Y.;
Knabe, W. E.; Oh, K. Angew. Chem., Int. Ed. 2009, 48, 7420–7423. (d)
Filippone, S.; Maroto, E. E.; Mart´ın-Domenech, A.; Suarez, M.; Mart´ın,
N. Nature Chem. 2009, 1, 578–582. (e) Hernandez-Toribio, J.; Go´mez
Arraya´s, R.; Mart´ın-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393–
396. (f) Lo´pez-Pe´rez, A.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed.
2009, 48, 340–343. (g) Lo´pez-Pe´rez, A.; Adrio, J.; Carretero, J. C. J. Am.
Chem. Soc. 2008, 130, 10084–10085. (h) Wang, C.-J.; Liang, G.; Xue, Z.-
Y.; Gao, F. J. Am. Chem. Soc. 2008, 130, 17250–17251. (i) Fukuzawa,
S.-I.; Oki, H. Org. Lett. 2008, 10, 1747–1750. (j) Yan, X.-X.; Peng, Q.;
Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem.,
Int. Ed. 2006, 45, 1979–1983. Ag-catalysts: (k) Shimizu, K.; Ogata, K.;
Fukuzawa, S.-i. Tetrahedron Lett. 2010, 51, 5068–5070. (l) Oura, I.;
Shimizu, K.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2010, 12, 1752–1755.
(m) Xue, Z.-Y.; Liu, T.-L.; Lu, Z.; Huang, H.; Tao, H.-Y.; Wang, C.-J.
Chem. Commun. 2010, 46, 1727–1729. (n) Yu, S.-B.; Hu, X.-P.; Deng, J.;
Wang, D.-Y.; Duan, Z.-C.; Zheng, Z. Tetrahedron: Asymmetry 2009, 20,
621–625. (o) Wang, C.-J.; Xue, Z.-Y.; Liang, G.; Zhou, L. Chem. Commun.
2009, 2905–2907. (p) Na´jera, C.; de Gracia Retamosa, M.; Sansano, J. M.;
de Cozar, J. M.; Coss´ıo, F. P. Tetrahedron: Asymmetry 2008, 19, 2913–
2933. (q) Na´jera, C.; de Gracia Retamosa, M.; Sansano, J. M. Angew. Chem.,
Int. Ed. 2008, 47, 6055–6058. Zn-catalysts (r) Dogan, O.; Koyuncu, H.;
Garner, P.; Bulut, A.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8, 4687–
4690. Ni-catalysts (s) Arai, T.; Yokoyama, N.; Mishiro, A.; Sato, H. Angew.
Chem., Int. Ed. 2010, 49, 7895–7898. (t) Shi, J.-W.; Zhao, M.-X.; Lei, Z.-
Y.; Shi, M. J. Org. Chem. 2008, 73, 305–308. Ca-catalysts (u) Tsubogo,
T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 13321–13332.
d
d
CuPF6
85
97
d
CuPF6
76e (66)f
91e (88)f
a Determined by 1H NMR. b Isolated yield. c Determined by HPLC.
d CuPF6 ) Cu(CH3CN)4PF6. e 5 mol % of catalyst. f 3 mol % of catalyst.
Interestingly, no reaction was observed under the optimal
conditions shown in entry 8 when the phenyl, 3-pyridyl or
4-pyridyl substituted imines (1b-d) were used instead of
1a, proving the key role of the 2-pyridyl unit as efficient
activating group in the formation of the metalated azomethine
intermediate10 (Scheme 2).
Given the high reactivity of the phenyl imine 1a, we next
examined the scope of this asymmetric transformation with
regard to the substitution at the imine11 (Table 2). In all cases
only the exo isomer was isolated (62-86% yield) and an
excellent enantiocontrol was achieved from aryl and het-
eroaryl substituted imines regardless of the nature of the
substituents (89-97% ee, entries 1-7). As expected, the
(4) For selected organocatalytic asymmetric versions of this reaction,
see: (a) Liu, Y.-K.; Liu, H.; Du, W.; Yue, L.; Chen, Y.-C. Chem.sEur. J.
2008, 14, 9873–9877. (b) Xue, M.-X.; Zhang, X.-M.; Gong, L.-Z. Synlett
2008, 691–694. (c) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem.
Soc. 2008, 130, 5652–5654. (d) Ibrahem, I.; R´ıos, R.; Vesely, J.; Co´rdova,
A. Tetrahedron Lett. 2007, 48, 6252–6257. (e) Vicario, J. L.; Reboredo,
S.; Bad´ıa, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168–5170. (f)
Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett. 2005, 7, 4569–4572.
(5) (a) Yamashita, Y.; Guo, X.-X.; Takashita, R.; Kobayashi, S. J. Am.
Chem. Soc. 2010, 132, 3262–3263. (b) Robles-Mach´ın, R.; Alonso, I.; Adrio,
J.; Carretero, J. C. Chem.sEur. J. 2010, 16, 5286–5291.
(8) See for example: (a) Xu, D.-Z.; Shi, S.; Wang, Y. Eur. J. Org. Chem.
2009, 4848–4853. (b) Comba, P.; Lang, C.; Lopez de Laorden, C.;
Muruganantham, A.; Rajaraman, G.; Wadepohl, H.; Zajaczkowski, M.
Chem.sEur. J. 2008, 14, 5313–5328. (c) Ishii, T.; Fujioka, S.; Sekiguchi,
Y.; Kotsui, H. J. Am. Chem. Soc. 2004, 126, 9558–9559. (d) Dickerson,
T. J.; Janda, K. D. J. Am. Chem. Soc. 2002, 124, 320–321.
(6) For the non asymmetric thermal 1,3-dipolar cycloaddition of N-(2-
pyridylmethyl)imines, see: Grigg, R.; Donegan, G.; Gunaratne, H. Q. N.;
Kennedy, D. A.; Malone, J. F.; Sridharan, V.; Thianatanagul, S. Tetrahedron
1989, 45, 1723–1746.
(9) See Supporting Information for catalyst optimization studies.
(10) For a recent example on the use of the 2-pyridine unit as activating
group in asymmetric metal catalyzed reactions, see: Rupnicki, L.; Saxena,
A.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 10386–10387.
(7) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431–1436.
Org. Lett., Vol. 12, No. 24, 2010
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Scheme 2
Table 3. Reaction with other Dipolarophiles
2-pyridyl imine 1l afforded the meso compound 2l in 90%
yield (entry 8). Interestingly, challenging substrates such as
R,ꢀ-unsaturated (entry 9) and alkyl substituted imines (entry
10) proved also to be suitable partners in the cycloaddition,
albeit with a lower enantioselectivity (68-74% ee). The
absolute and relative configuration of pyrrolidine exo-2g was
unequivocally established by X-ray diffraction.12
Table 2. Catalytic Asymmetric [3 + 2] Cycloaddition of
2-Pyridyl Imines 1e-n with N-Methyl Maleimide
entry
R
product
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
10
(p-OMe)C6H4
(m-Me)C6H4
(p-Br)C6H4
(o-F)C6H4
(p-NO2)C6H4
2-Thienyl
2-Furyl
2-pyridyl
Ph-CH)CH
Cy
2e
2f
2g
2h
2i
2j
2k
2l
78
83
86
78
62
83
72
90
78
79
90
94
92
94
97
95
89
-
2m
2n
68
74
a Determined by 1H NMR in the crude mixture. b Isolated yield of pure
exo adduct after silica gel chromatography. c ee of exo adduct determined
by HPLC. d ee of exo adduct after recrystallization.
a Isolated yield. b Determined by HPLC.
To extend the synthetic scope of this procedure, a wide
variety of trans substituted dipolarophiles were next explored
in the cycloaddition of imines 1 under the optimal Cu-
catalyzed reaction conditions (Table 3). The reactions of
diactivated symmetrical dipolarophiles such as dimethyl
fumarate, dibenzoylethylene, and fumarodinitrile, occurred
with a moderate exoselectivity13 (45-63% yield in isolated
exo isomer) and good enantioselectivities ranging from 72%
to 91% ee (entries 1-4). Interestingly, the ee of the major
pyrrolidine exo adduct can be further enhanced to very high
levels by simple recrystallization (Table 3, values in paren-
theses).
Gratifyingly, the reaction with unsymmetrically substituted
alkenes such as nitroalkenes14 and enones15 (adducts 11 and
12) was completely regioselective, leading to the regioisomer
having the activating group contiguous to the pyridyl unit
(11) Typical procedure for asymmetric [3 + 2] cycloadditions: (3aS,
4S, 6R, 6aR)-2-methyl-4-phenyl-6-(2-pyridyl)-octahydropyrrolo[3,4-c]pyr-
role-1,3-dione (exo-2a): To a solution of bisoxazoline ligand 7 (12.4 mg,
0.027 mmol) and Cu(CH3CN)4PF6 (10.1 mg, 0.027 mmol) and Et3N (5.3
µL, 0.041 mmol) in CH2Cl2 (0.5 mL), under nitrogen atmosphere, at room
temperature, a solution of imine 1a (79.4 mg, 0.41 mmol) in CH2Cl2 (0.5
mL) and N-methylmaleimide (30.0 mg, 0.27 mmol) in CH2Cl2 (0.5 mL)
were successively added. The mixture was stirred overnight and filtered
through a plug of Celite with the aid of CH2Cl2 (5.0 mL). The organic
layer was washed with NH3 5% (aq) (2 × 10 mL) and the combined organic
layers were dried over MgSO4 and evaporated. The resulting residue was
purified by silica gel flash chromatography (hexane-EtOAc 1:2) to afford
exo-2a (70.5 mg, 85%, white solid).
(13) By analogy with the 1,3-dipolar cycloaddition of R-iminoes-
ters, exo refers to the pyrrolidine adduct with trans stereochemistry at
C2-C3.
(14) For catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
ylides with nitroalkenes, see: refs 3b and 3j.
(12) See Supporting Information for details of the X-ray structure of
exo-2g, exo-10g, and exo-11g. CCDC 784831, CCDC 784832, and CCDC
784833 contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif.
(15) For the use of enones as dipolarophiles, see refs 3e and 3l.
5610
Org. Lett., Vol. 12, No. 24, 2010

(1,2-disubstitution). The cycloaddition of (E)-ꢀ-nitrostyrene
took place with moderate exo selectivity and high enanti-
oselectivity (entries 5 and 6, 96% and 86% ee, respectively),
whereas the reaction with trans-chalcone led only to the exo
isomer, also with high enantioselectivity (92% ee, entry 7).
It is interesting to note that the regioselectivity of the
cycloaddition with N-(2-pyridylmethyl)imines is opposite to
that observed in the reaction with the usual R-iminoesters,
which provide the pyrrolidine adducts with 1,3-disubstitution
between the ester moiety and the activating group at the
dipolarophile. The absolute and relative configuration of the
bromine-containing pyrrolidines exo-10g and exo-11g was
unequivocally established by X-ray diffraction.12
of dipolarophiles under mild reaction conditions. The exten-
sion of this enantioselective Cu-catalyzed 1,3-dipolar cy-
cloaddition to other heterocycle containing azomethine ylides
is underway.
Acknowledgment. This work is dedicated to Professor
Carmen Na´jera on the occasion of her 60th birthday.
Financial support from the Ministerio de Ciencia e Innova-
cio´n (MICINN, project CTQ2009-07791), Consejer´ıa de
Educacio´n de la Comunidad de Madrid (programme AVAN-
CAT; S2009/PPQ-1634) and Universidad Auto´noma de
Madrid/Comunidad de Madrid (UAM/CAM project CCG08-
UAM/PPQ-4454) is greatly appreciated. S.P. thanks the
MICINN for a predoctoral contract.
In summary, we have described that N-(2-pyridylmeth-
yl)imines can be used as efficient azomethine precursors in
catalytic asymmetric [3 + 2] cycloadditions. Employing
Cu(CH3CN)4PF6/bisoxazoline 7 as a chiral catalyst system,
high enantioselectivities (up to 97% ee) and moderate to high
exo-selectivities have been accomplished for a wide variety
Supporting Information Available: Experimental pro-
cedures, characterization data for new compounds, and copies
of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL102605Q
Org. Lett., Vol. 12, No. 24, 2010
5611