Catalytic asymmetric 1,3-dipolar cycloaddition of α-iminonitriles

Article abstract of DOI:10.1002/chem.200903443

(Figure Presented) Improving the structural scope: A catalytic asymmetric 1,3-dipolar cycloaddition involving α-iminonitriles as azomethine precursors has been developed. In the presence of AgOAc/ Taniaphos as the catalyst system the reaction of α-iminonitriles with dimethyl fumarate and N-methyl maleimide affords 2-cyanopyrrolidines with good endo selectivity and enantioselectivity (68-≥99% ee; see scheme).

Full text of DOI:10.1002/chem.200903443

DOI: 10.1002/chem.200903443
Catalytic Asymmetric 1,3-Dipolar Cycloaddition of a-Iminonitriles
Rocꢀo Robles-Machꢀn, Inꢁs Alonso, Javier Adrio,* and Juan C. Carretero*[a]
Dedicated to Professor Josep M. Ribꢀ on the occasion of his 70th birthday
The 1,3-dipolar cycloaddition of azomethine ylides with
alkenes is one of the most powerful and convergent methods
for the stereoselective synthesis of pyrrolidines,[1] a heterocy-
clic moiety widely present in the structure of natural prod-
ucts, pharmaceuticals[2] and chiral ligands.[3] Improving the
overall chemical and stereochemical efficiency of this reac-
tion, pioneered by Grigg with stoichiometric metal chiral
complexes,[4] a great effort has been devoted in recent years
in the development of catalytic asymmetric protocols. In this
field a wide variety of outstanding chiral complex catalysts
have been reported,[5] mainly AgI,[5f,g,j,m,q–s] CuI[5e,h,i,k,l,o,t–w] and
CuII[5d] catalysts, but also ZnII,[5x] NiII[5n] and CaII[5p] com-
plexes. In addition, several organocatalytic asymmetric
methods have been also developed in the last few years.[6]
Concerning the scope of the catalytic asymmetric 1,3-dipolar
cycloaddition of azomethine ylides, although there is an
ample tolerance with regard to the nature of the dipolaro-
phile (i.e., a,b-unsaturated esters, maleimides, a,b-unsaturat-
ed nitriles, enones, enals, nitroalkenes, vinyl sulfones and
fullerene), the structural variety at the azomethine dipole is
much more limited. By far most catalytic asymmetric ver-
sions reported to date are based on the use of a-iminocar-
bonyl substrates, specifically a-iminoesters. The great effec-
tiveness of a-iminoesters as dipole precursors relies on the
enhanced acidity of the a-position and the formation of a
robust five-membered, N,O-bidentate-metalated, azome-
thine ylide, which facilitates the asymmetric induction from
the chiral ligand. The inherent limitation of this strategy is
the restricted structural versatility with regard to the substi-
tution at C2, always providing pyrrolidines with a C2 car-
boxylate ester substitution.
To access other types of substituted pyrrolidines, a-imino-
nitrile precursors are very appealing, since in the resulting
2-cyanopyrrolidines[7] the cyano group could further act as
leaving group allowing its formal substitution by hydrogen
or by a carbon nucleophile,[8] and thus leading to a wider va-
riety of substituted pyrrolidines. Two decades ago Kane-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
with electron-deficient dipolarophiles, but the catalytic
asymmetric version of this process remained to be devel-
oped. We describe herein the first catalytic asymmetric pro-
cedure for the 1,3-dipolar cycloaddition of a-iminonitriles,
as well as some synthetic applications and a DFT theoretical
study on the presumed nature of the metalated 1,3-dipole.
To evaluate the viability of a-iminonitriles as dipole pre-
cursors in catalytic asymmetric 1,3-dipolar cycloadditions,
we first studied the reaction of N-benzylidenaminoacetoni-
trile (1) with methyl acrylate in the presence of ligand Fesul-
phos (2, 10 mol%). This ligand had proved to be very effi-
cient in the 1,3-dipolar cycloadditions of a-iminoesters with
a wide variety of dipolarophiles (acrylates, maleates, fuma-
rates, maleimides,[5t] enones,[5i] bissulfonylethylenes[5h] and
fullerene[5d]), providing the pyrrolidines usually with high
control of the endo/exo selectivity and enantioselectivity.
However, a very poor reactivity and stereoselectivity was
obtained in the reaction of methyl acrylate with a-iminoni-
trile 1a in the presence of a variety of copper and silver
salts[11] (11% yield and 22% ee for the major adduct[12] as
the best results, Scheme 1). In an attempt to find a more ef-
ficient catalyst system for this reaction we next tested a vari-
ety of ligands,[13] albeit with moderate success. A promising
enantioselectivity was found with AgOAc/Taniaphos (3) as
catalyst system (30% yield, 68% ee for endo-4).
[a] R. Robles-Machꢀn, Dr. I. Alonso, Dr. J. Adrio,
Prof. Dr. J. C. Carretero
Departamento de Quꢀmica Orgꢁnica, Facultad de Ciencias
Universidad Autꢂnoma de Madrid
Cantoblanco 28049 Madrid (Spain)
Fax : (+34)914973966
To improve the efficiency of the process we next applied
this catalyst system to a more reactive dipolarophile, such as
dimethyl fumarate (Table 1). Interestingly, unlike the previ-
ously reported thermal or LDA-mediated reactions, which
give rise to C2/C5 cis/trans mixtures of isomers,[9,10] this cata-
lytic asymmetric reaction provided exclusively the C2/C5
E-mail: javier.adrio@uam.es
juancarlos.carretero@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903443.
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COMMUNICATION
Table 2. AgOAc/Taniaphos-catalysed 1,3-dipolar cycloaddition of a-imi-
nonitriles 1b–n with dimethyl fumarate.
R1
R2
t
Prod- endo/ Yield ee
[h] uct
exo[a] [%][b] [%][c]
1
2
3
4
5
6
7
8
9
m-FC6H4
H
H
H
H
H
H
H
H
H
H
H
Ph
6
5
5b
5c
75/25 74
80/20 61
87/13 35
80/20 44
79/21 45
71
77
79
72
74
98
76
89
84
p-BrC6H4
p-MeOC6H4
o-MeOC6H4
o-MeC6H4
2-thienyl
2-pyridyl
2-furyl
N-Boc-2-pyrryl
(ꢀ99)[d]
Scheme 1. Ag-catalysed 1,3-dipolar cycloaddition of a-iminonitrile 1a
and methyl acrylate with Fesulphos and Taniaphos ligands.
24 5d
24 5e
24 5f
6
5g
25 5h
5i
24 5j
5k
93/7
92
ACHTUNGTRENNUNG
85/15 81
3
93/7
91/9
74
87
ACHTUNGTRENNUNG
Table 1. Optimisation of the reaction conditions.
10 CH=CH-Ph
11 Cy
12 Ph
2
80/20 64
68(96)[d]
24 5l
96 5m
–
–
–
87
85
92/8
91/9
64
59
13 p-FC6H4
p-FC6H4 96 5n
1
[a] By H NMR spectroscopy from the crude reaction mixture [b] In pure
adducts endo-5b–n after column chromatography. [c] By HPLC for endo
5b–n; see Supporting Information for details. [d] ee after recrystallisa-
tion.
Solvent
Base
endo/exo[a]
Yield [%][b]
ee [%][c]
1
2
3
4
THF
Et3N
Et3N
Et3N
Et3N
88/12
88/12
88/12
89/11
89/11
86/14
87/13
85/15
85/15
53
46
44
61
43
76
82
81
57
79
81
73
78
78
79
79
81
78
toluene
CH2Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
5[d]
6
Et3N
DIPEA
K2CO3
NaOAc
NaOAc
ities (entries 6–9). Particularly noticeable was the excellent
control achieved in the case of the 2-thienyl derivative
(entry 6, 92% yield and 98% ee). The cycloaddition also tol-
erates an alkenyl substitution at the imine moiety, although
the enantioselectivity was moderate (entry 10, 68% ee). Un-
fortunately, no cycloaddition was observed in the case of
alkyl-substituted iminonitriles (entry 11). Finally, we also
studied the cycloaddition of a-iminonitriles derived from ke-
timines, which are interesting substrates, since they generate
a quaternary centre at C5 (entries 12 and 13). These imines
are sterically more demanding and, as it was expected, they
showed a lower reactivity (reaction time of 96 h instead of
2–24 h for the aldimine substrates), but pleasingly they re-
acted in a highly endo/exo selective and enantioselective
manner (85–87% ee).
From a practical point of view, it is interesting to note
that the enantiopurity of the major adduct endo-5 can be en-
hanced to 96–ꢀ99% ee by simple recrystallisation with
iPrOH (entries 2, 6, 8 and 10; 45–73% recrystallisation
yields). In addition, the stereochemical and configurational
assignment of (+)-endo-5c was unequivocally established by
X-ray diffraction of a recrystallised sample of endo-5c>
99% ee.[14]
7
8
9[e]
1
[a] By H NMR spectroscopy from the crude reaction mixture [b] In pure
endo-5a after column chromatography. [c] For endo-5a; determined by
HPLC, see Supporting Information for details. [d] Reaction run at 08C.
[e] 5 mol% of catalyst system.
cis-substituted pyrrolidines, mainly as the endo isomer
(endo-5a). After surveying different solvents and bases (en-
tries 1–8), the best results in terms of reactivity and enantio-
selectivity were obtained in Et2O using 20 mol% of NaOAc
as base (81% isolated yield and 81% ee for endo-5a;
entry 8). A reduction in the catalyst loading to 5 mol% re-
sulted in a similar enantioselectivity, albeit with a significant
drop in the reactivity (entry 9).
With these optimal reaction conditions in hand, Table 2
shows the scope of this cycloaddition with regard to the sub-
stitution at the a-iminonitrile. As in the case of the model
reaction, all cycloadditions provided the endo adduct (endo
5b–n) as the major isomer (endo/exo ratio ranging from
75:25 to 93:7), which was readily isolated by standard chro-
matographic purification. In the case of the a-iminonitriles
derived from homoaromatic aldehydes, the enantioselectivi-
ty was rather similar (entries 1–5; 71–77% ee), albeit elec-
tron-deficient aryl iminonitriles provided the corresponding
pyrrolidines with higher yields than electron-rich substrates
(compare entries 1/2 with 3/4). Heteroaryl a-iminonitriles
also proved to be suitable substrates, undergoing the cyclo-
addition with high endo/exo selectivities and enantioselectiv-
To extend this asymmetric protocol to other dipolaro-
philes, we next investigated the 1,3-dipolar cycloaddition of
a-iminonitriles with N-methylmalemide (Scheme 2). The re-
action of 1a or 1g, under similar reaction conditions to
those used with dimethyl fumarate, but using toluene as sol-
vent, afforded the bicyclic pyrrolidine endo-6a or endo-6g
as major isomers[15] in good yields and excellent enantiocon-
trol (>99 and 96% ee, respectively).
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J. C. Carretero, J. Adrio et al.
well as the lower stability of complex II, mainly due to steric
effects, are also comparable with those found in the case of
iminoesters complexes.[5t] The distance between the metal
atom and the nitrile group is significantly longer, which im-
plies a smaller interaction. However, the syn orientation of
this group has a very important stabilizing effect (compare
the stability of complexes I and II with that of III).[20] The
NBO analysis[21] of complex I show a two-electron donation
from the lone pair at Nn (Nn =nitrile N atom) along with the
p-C1=Nn and the p-C1=C2 to the empty 5s AO of AgI.
These combined orbital interactions result in total second-
order perturbation energy of about À4.0 kcalmolÀ1. Besides,
there are two hydrogen bonds that contribute to the stabili-
sation of complex I. One of them is formed between Nn and
the closest H atom of one of the phenyl groups of the PPh2
À
Scheme 2. Catalytic asymmetric 1,3-dipolar cycloaddition of a-imino-
ACHTUNGTRENNUNGnitriles 1a,g with N-methylmaleimide.
The high selectivity for the formation of C2/C5 cis-substi-
tuted pyrrolidines in all the reactions with a-iminonitriles
suggests the participation of syn-metalated 1,3-dipole com-
plexes. However, unlike the well-established syn arrange-
ment in the five-membered, N,O-bidentate-metalated, azo-
methine ylides derived from a-iminoesters, the structure of
the metal-complex ylides derived from a-iminonitriles is un-
clear.[10] To shed some light on this point, a theoretical study
at the DFT (B3LYP)[16] level by using the Gaussian 03 pro-
gram[17,18] was carried out. Fesulphos–AgI complexes with
the azomethine ylide derived from N-benzylidenaminoace-
tonitrile 1a were used as models.[19] Their molecular struc-
tures are shown in Figure 1.
subunit (dACTHNUGTRENUNG(Nn H)=2.40 ꢄ). The second is formed between
Nn and the closest H atom of the nearby cyclopentadienyl
À
ring of ferrocene moiety (d
second-order perturbation energy associated with these sta-
(Nn H)=2.37 ꢄ). The total
bilizing interactions is about À5.0 kcalmolÀ1.
The next step in our study was to understand the origin of
the good enantioselectivity found with Taniaphos. First, to
determine the coordination mode of Taniaphos (3) with sil-
ver(I), we isolated and studied by X-ray diffraction the com-
plex [AgOAc(3)], prepared by treatment of Taniaphos 3
with AgOAc in THF and further recrystallisation in CH2Cl2/
hexane[22] (Figure 2). This complex shows a P,P-bidentate co-
ordination to silver, similar to that found in PtII–Taniaphos
complexes.[23] The eight-membered metallacycle adopts a
relatively rigid boat-like conformation, minimizing the steric
interactions and likely stabilised by p-stacking interactions
between the aromatic rings bonded to both phosphorous
atoms; the distance between the silver and iron atoms is
4.41 ꢄ. Taking the structure of complex [AgOAc(3)] as
starting point, the acetate anion was substituted by the
model azomethine ylide with a coordination mode similar to
that found in the previously studied most stable complex
with Fesulphos (complex I). The resulting structure was fully
optimised giving rise to complex IV (Figure 2) in which the
conformation of the ligand remains almost unaltered (for
Complexes I and II show a syn arrangement of the dipole
moiety with very similar bond lengths around Ag atom. The
À
À
À
P Ag, S Ag and Ni Ag (Ni =imine N atom) distances as
example, dACTHNUGRTNEUNG(Ag···Fe)=4.65 ꢄ) with respect to the X-ray
À
structure. A slight elongation of the P Ag distances was ob-
served. Interestingly, the well-defined steric environment in
complex IV and the fact that the orientation of the azome-
thine ylide moiety is different than in the starting complex I
(dihedral angle C1-C2-Ni-Ag increases from À8.8 to À13.68)
gives rise to a better steric differentiation of its faces. Thus,
in complex IV the approach of the dipolarophile to the
(2Re,4Si)-face of the azomethine would be hindered by a
combination of two effects: 1) the unsubstituted cyclopenta-
dinyl ring of the ferrocene unit blocks the approach of the
À
dipolarophile to C2 (smaller distance Cp C2=3.11 ꢄ) and
2) one of the phenyl groups on P2 blocks the approach to
Figure 1. Molecular structure, representative distances [ꢄ] and relative
energies [kcalmolÀ1, ZPE correction included] of complexes I, II and III.
Spatial representation of the most stable complex I, in which hydrogen
atoms have been omitted for clarity, is also included. Ni and Nn refer to
nitrogen atoms of the imine and nitrile group, respectively.
À
C4 (smaller distance Ph C4=2.76 ꢄ). Consequently, the se-
lective approach of the dipolarophile to the less hindered
(2Si,4Re)-face of the azomethine in complex IV could ex-
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Chem. Eur. J. 2010, 16, 5286 – 5291

Asymmetric Catalysis
COMMUNICATION
2-pyrroline exo-7 with trans configuration at C4–C5, owing
to the epimerisation at C4 under the basic reaction condi-
tions. On the other hand, under milder reaction conditions,
the treatment of pyrrolidine endo-5a with AgBF4 in CH2Cl2
at room temperature selectively afforded the pyrroline
endo-7[25] without epimerisation at C4 (89% yield). Interest-
ingly, the reaction of pyrrolidine endo-6a with AgBF4 in the
presence of indole led, with complete stereoselectivity, to
the C2–C5 trans-2-indolylpyrrolidine[26] 9 (51% yield), likely
by reaction of indole to the least hindered face of the elec-
trophilic iminium intermediate 8.
In conclusion, an efficient protocol for the catalytic asym-
metric 1,3-dipolar cycloaddition of a-iminonitriles has been
developed. This process relies on the use of AgOAc/Tania-
phos as catalyst system, providing 2-cyanopyrrolidines with
good diastereo and enantioselectivity (68–ꢀ99% ee) in the
reaction with activates dipolarophiles, such as fumarates and
maleimides. A combination of X-ray and theoretical DFT
studies has been used to study the plausible coordination
mode of the a-iminonitrile to the Ag/Taniaphos chiral com-
plex. The further elimination or substitution of the cyano
group on the 2-cyanopyrrolidine adducts highlights the ver-
satility of this protocol for the enantioselective synthesis of
substituted pyrrolidines.
Figure 2. Molecular structure and representative distances [ꢄ] around the
metal of crystal complex [AgOAc(3)], studied by X-ray diffraction, and
theoretically studied a-iminonitrile complex IV. Spatial representation is
also included. Hydrogen atoms have been omitted for clarity. Ni and Nn
refer to nitrogen atoms of the imine and nitrile, group respectively.
Experimental Section
Typical procedure for the asymmetric 1,3-dipolar cycloaddition of a-imi-
nonitriles: A solution of 1a (25 mg, 0.17 mmol) in Et2O (1.2 mL), and di-
methyl fumarate (39 mg, 0.26 mmol) were successively added to a mix-
ture of
3 (13.1 mg, 0.019 mmol), AgOAc (2.9 mg, 0.017 mmol) and
NaOAc (2.8 mg, 0.035 mmol) in Et2O (0.5 mL), under nitrogen atmos-
phere. After stirring for 24 h at room temperature, the mixture was fil-
tered through a plug of Celite with the aid of CH2Cl2 (2 mL), and the sol-
vent was removed under reduced pressure. The residue was purified by
silica gel flash chromatography (hexane/EtOAc 3:1) to afford the adduct
endo-5a (34 mg, 81%, white solid). M.p.=85–878C; [a]2D0 =+29.5 (c=
0.20, CH2Cl2), 81% ee.
plain the good enantioselectivity of the cycloaddition in
favour of the pyrrolidines with 2S,5R configuration[24]
From a synthetic point of view, an interesting aspect of
using a-iminonitriles as 1,3-dipoles, compared with a-imi-
noesters, is that in the resulting 2-cyanopyrrolidines the
cyano group can further behave as a leaving group, owing to
the facile formation of an iminium intermediate that can
evolve by conversion into the enamine tautomer or be trap-
ped by an added nucleophile.[8] This is apparent from the
transformations depicted in Scheme 3. As previously report-
ed by Tsuge,[10] the treatment of pyrrolidine endo-5a with a
catalytic amount of DBU in toluene at reflux afforded the
Acknowledgements
This work was supported by the Ministerio de Ciencia e Innovaciꢂn
(MICINN, projects CTQ2006-01121 and CTQ2009-07791), Consejerꢀa de
Educaciꢂn de la Comunidad de Madrid (programme AVANCAT, S2009/
PPQ-1634) and Universidad Autꢂnoma de Madrid (UAM/CAM project
CCG08-UAM/PPQ-4454). R.R. thanks the MICINN for a predoctoral
fellowship. We thank Solvias AG (Dr. H.-U. Blaser) for a generous loan
of chiral ligands (Taniaphos and Solvias ligand kit). A generous alloca-
tion of computer time at the “Centro de Computaciꢂn Cientꢀfica-UAM”
is also acknowledged.
Keywords: asymmetric catalysis
· azomethine ylides ·
cycloaddition · iminonitriles · pyrrolidines
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A
ACHTUNGERTN(NUNG PPh3)Cl] afforded even poorer re-
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on the ligand structure, see Supporting Information for details.
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be obtained free of charge from The Cambridge Crystallographic
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metal: dicoordinated (shown in Figure 2) or monocoordinated (dis-
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À
À
À
tances around the metal in ꢄ: P3 Ag2=2.490, P4 Ag2=2.414, O3
À
Ag2=2.224 and O4 Ag2=3.138). See the Supporting Information
for details. CCDC-752507 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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5290
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 5286 – 5291

Asymmetric Catalysis
COMMUNICATION
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[24] It is worth noting that in the case of the related complex with Fesul-
phos ligand (complex I) there is a less efficient steric shielding be-
tween both faces of the azomethine unit, especially around C2,
which could explain the much lower enantioselectivity obtained with
this ligand.
[25] Racemic endo- and exo-7 have been previously described, see refer-
ences [9a] and [10a], respectively.
[26] See the Supporting Information for the stereochemical assignment
of 9.
Received: December 15, 2009
Published online: March 31, 2010
Chem. Eur. J. 2010, 16, 5286 – 5291
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5291