Cinchona alkaloid amide catalyzed enantioselective formal [2+2] cycloadditions of allenoates and imines: Synthesis of 2,4-disubstituted azetidines

Article abstract of DOI:10.1002/anie.201100706

Mix and go: The quinidine amide 1 catalyzed [2+2] cycloaddition between N-sulfonylimines 2 and alkyl 2,3-butadienoates 3 afforded the R-configured azetidines 4 in excellent yields and enantioselectivities (M.S.=molecular sieve). The S enantiomer was obtained when a quinine amide catalyst, the pseudoenantiomer of 1, was used.

Full text of DOI:10.1002/anie.201100706

Communications
DOI: 10.1002/anie.201100706
Organocatalysis
Cinchona Alkaloid Amide Catalyzed Enantioselective Formal
[2+2] Cycloadditions of Allenoates and Imines: Synthesis of
2,4-Disubstituted Azetidines**
Jean-Baptiste Denis, Gꢀraldine Masson,* Pascal Retailleau, and Jieping Zhu*
Chiral azetidines[1] represent an important class of four-
membered nitrogen heterocycles that have a wide range of
synthetic applications,[1–3] remarkable biological activities,[1,4]
and are prevalent in natural products.[1,5] However, in contrast
to the homologous small-ring saturated nitrogen heterocycles
such as aziridines, pyrrolidines, and piperidines, the synthetic
approaches to enantiomerically enriched azetidines are few in
number and are generally multistep processes.[1,6,7] Among
the different synthetic routes, the formal [2+2] cycloaddi-
tion[8] is certainly one of the most powerful methods for the
construction of the strained four-membered ring. However,
only a few catalytic enantioselective methods have been
developed for a one-step synthesis of azetidines in spite of the
great number of synthetic efforts dedicated to this field.[9]
Recently, an elegant synthesis of 2,4-disubstituted azeti-
dines involving a new DABCO-catalyzed regioselective
[2+2] cycloaddition of N tosylimines with allenoates was
described by Shi and co-workers.[10] While the synthetic
potential of this transformation is self-evident, its enantio-
selective version remains, to the best of our knowledge,
unknown to date.[11] Indeed, the diverse reactivity of allen-
oates[10–16] and the complexity of the mechanism make the
development of the asymmetric version particularly challeng-
ing. In connection with our ongoing project that deals with the
catalytic potential of the cinchona-alkaloid-derived
amides,[17–19] we became interested in examining the reaction
of allenoates with imines in the presence of a chiral tertiary
amine catalyst. Herein, we report the first examples of the
catalytic enantioselective [2+2] cycloaddition between alle-
noates and N sulfonylimines to give enantioenriched 2-
alkylideneazetidines.[20]
We began our studies by examining the reaction of (E)-N-
benzylidene-4-methoxybenzene sulfonamide (2a) with ethyl
2,3-butadienoate (3a) in the presence of 6’-deoxy-6’-benz-
amido-b-isocupreidine (1a; 10 mol%)[17] and molecular
sieves (4 ꢀ) in CH2Cl2 (Table 1). Although the E-azetidine
4a was formed as a major product, no enantioselectivity was
observed (Table 1, entry 1).[21,22] Interestingly, the less-rigid 6’-
Table 1: Enantioselective [2+2] versus the aza-Morita–Baylis–Hillman
(aza-MBH) reaction: Survey of catalytic reaction conditions.[a]
Entry
2
Cat. Solvent
4
Yield ee
5
Yield
[%][b]
ee
[%][b] [%][c,d]
[%][c,d]
1
2
3
4
5
6
7
8
2a 1a
2a 1b
2a 1c
2a 1c
2a 1d
2a 1e
2a 1 f
2a 1c
2a 1c
2a 1c
2a 1c
2a 1c
2b 1c
2c 1c
2a 1g
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene 4a 57
benzene 4a 93
benzene 4a 41[f]
CF3C6H5 4a 52
benzene 4b 75
benzene 4c 81
benzene 4a 69
4a 57
4a 71
4a 77
4a 60[e]
4a 72
4a 57
4a 31
4a 41
<5
89
5a
5a
5a
5a
4a
5a
5a
5a
5a
5a <5
5a
5a
5b <5
5c <5
8
5
5
29
0
25
94
94
80
74
63
90
95
95
94
90
91
91
18[e] 25
3
14
15
5
28
13
15
15
8
[*] J.-B. Denis, Dr. G. Masson, Dr. P. Retailleau, Prof. Dr. J. Zhu
Centre de Recherche de Gif
9
25
10
11
12
13
14
15
n.d.
n.d.
15
n.d.
n.d.
n.d.
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
Fax: (+33)1-6907-7247
5
5
E-mail: masson@icsn.cnrs-gif.fr
ꢀ92[g] 5c <5
Prof. Dr. J. Zhu
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
EPFL-SB-ISIC-LSPN, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9740
[a] Reaction conditions: imine (2a; 0.1 mmol), ethyl 2,3-butadienoate
(3a; 0.2 mmol), 1 (0.01 mmol), c=0.25m, RT, 48 h. [b] Yield of the
isolated product after purification by column chromatography on silica
gel. [c] Determined by HPLC analysis on a chiral stationary phase. [d] R-
enriched 4a. See the Supporting Information for the structure determi-
nation by X-ray crystallographic analysis. [e] Catalyst was used without
drying. [f] Reaction carried out at 08C. [g] S-enriched 4a. Boc=tert-
butyloxycarbonyl, Bn=benzyl, M.S.=molecular sieves, n.d.=not deter-
mined, THF=tetrahydrofuran.
E-mail: jieping.zhu@epfl.ch
[**] Financial supports from CNRS and ICSN are gratefully acknowl-
edged. J.B.D. thanks ANR for a doctoral fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100706.
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Angew. Chem. Int. Ed. 2011, 50, 5356 –5360

Table 2: Enantioselective formal [2+2] cycloaddition with representative
deoxy-6’-benzamido quinidine (1b) gave much better enan-
tioselectivity than 1a (Table 1, entries 1 and 2). Catalyst 1c,
which contains the N-Boc glycinamide unit at C6’, afforded
adduct 4a with even better enantioselectivity (Table 1,
entry 3). However, when the catalyst 1c was not anhydrous,[23]
the proportion of the aza-Morita–Baylis–Hillman (MBH)
product 5a increased (Table 1, entry 4). In contrast, catalysts
1d and 1e, which contain the N-Boc l- and d-phenylalanine
units, respectively, provided inferior results relative to 1c
(Table 1, entries 5 and 6). That the quinidine amides (1b–1e)
provided higher regio- and enantioselectivities than the O-
demethyl quinidine 1 f (Table 1, entry 7) demonstrated the
aromatic N sulfonylimines.[a]
Entry
Ar
3
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
p-ClC6H4 (2d)
p-CNC6H4 (2e)
p-NO2C6H4 (2 f)
p-CF3C6H4 (2g)
naphthyl (2h)
p-MeC6H4 (2i)
m-MeC6H4 (2j)
o-BrC6H4 (2k)
p-MeOC6H4 (2l)
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
85
75
74
79
59
65
80
86
46
58
56
58
72
67
76
92
85
92
86
90
92
94
90
95
94
96
98
97
98
96
ꢀ
ꢀ
superiority of the N H of the amide over the O H group in
this process.[17] The solvent effect was next examined, and
benzene was found to be the best reaction medium. In this
solvent, the formation of the aza-MBH product 5a was
minimized and the azetidine 4a was isolated in 93% yield
with 95% ee (Table 1, entry 10).[10] Lowering the reaction
temperature reduced significantly the yield of 4a and did not
have a positive impact on the enantioselectivity (Table 1,
entry 11). The N-substituent effect was also examined, and it
was found that both N-tosyl and N-mesyl imines were suitable
substrates (Table 1, entries 13 and 14) and led to the
corresponding cycloadducts 4b and 4c with slightly lower
enantioselectivities and yields. As expected, the enantiomer
of 4a was formed with the same efficiency when the quinine-
derived catalyst 1g was employed as a catalyst (Table 1,
entry 15).[22]
9
=
10
11
12
13
14
15
PhCH CH (2m)
m-BrC6H4 (2n)
C6H5 (2o)
m-BrC6H4 (2p)
p-MeC6H4 (2q)
p-CNC6H4 (2r)
[a] Reaction conditions: imine (2; 0.1 mmol), alkyl 2,3-butadienoate (3;
0.2 mmol), 1c (0.01 mmol), benzene (0.4 mL), RT, 48 h. [b] Yield of the
isolated product after purification by column chromatography on silica
gel. [c] Determined by HPLC analysis on a chiral stationary phase. [d] The
1g-catalyzed reaction between 2a and 3a gave the product with the
S configuration.
Having established the optimal reaction conditions for the
formation of the azetidine, we surveyed the scope of the
reaction by varying the structure of sulfonylimines 2 and
allenoates 3. As shown in Table 2, the reaction of ethyl 2,3-
butadienoate (3a) with N-sulfonylimines 2, which are derived
from aromatic aldehydes, afforded cleanly the corresponding
R-configured azetidines in moderate to high yields and
excellent enantioselectivities (entries 1–11). The electronic
properties of the substituents on the phenyl ring did not affect
the enantioselectivity much, but did impact the yield. For
instance, imines bearing both electron-withdrawing and weak
electron-donating substituents afforded the desired products
in excellent yields (Table 2, entries 1–8), while strong elec-
tron-donating substituents, such as the methoxy group, led to
diminished yields (Table 2, entry 9). Ortho, meta, and para
substituents were all well tolerated. The a,b-unsaturated
imine was also a suitable substrate and afforded the corre-
sponding cycloadduct 4m with excellent enantioselectivity
(Table 2, entry 10). Similarly, benzyl 2,3-butadienoate (3b)
reacted with various sulfonylimines under identical reaction
conditions to give the corresponding R-configured azetidines
with excellent enantioselectivities (> 96% ee; Table 2,
entries 12–15).
the azetidine and the aza-MBH adduct are shown in
Scheme 1. Addition of the catalyst 1 to the allenoate 3
would afford the zwitterionic intermediate 6, which might
react with the imine 2 according to two different pathways. In
pathway A, the addition of g-carbanion 6b to the imine would
afford the intermediate 7, which upon a 4-exo-trig cyclization
Mechanistically, the reaction of imines 2 with allenoates 3
in the presence of a Lewis base catalyst can take place
through different pathways, which include the aza-MBH
reaction as well as [3+2] and [2+2] cycloadditions.[24] There-
fore to be synthetically meaningful, the catalytic reaction
conditions should not only be able to determine the enantio-
selectivity but also be able to direct the reaction toward a
single pathway.[10–15] Two competitive pathways that lead to
Scheme 1. Competitive reaction pathways leading to azetidines and
aza-MBH adducts.
Angew. Chem. Int. Ed. 2011, 50, 5356 –5360
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www.angewandte.org
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Communications
solution of N sulfonylimine (2; 0.05 mmol, 1.0 equiv) in anhydrous
benzene (0.2 mL) at room temperature. The reaction mixture was
stirred under an argon atmosphere at room temperature for 48 h. The
reaction was stopped by passing the mixture through a short pad of
silica gel using dichloromethane as the eluent. The filtrate was
concentrated in vacuo and the residue was purified by preparative
thin-layer chromatography (silica gel; eluent: n-heptane/ethyl ace-
tate = 3:2) to afford the corresponding pure azetidine.
would afford 8. Hydride elimination from 8 would produce
the azetidine 4 with concurrent regeneration of the catalyst 1.
In pathway B, the addition of the a-carbanion 6a to the imine
would provide the aza-MBH-type product 5 via intermediates
9 and 10. On the basis of earlier reports[10] and our own
investigations, we believed that the rigidity of the catalyst
structure[18] and the presence of a protic additive can in part
modulate the regiochemical outcome.[25] As the proton-trans-
fer step of the aza-MBH reaction is known to be favored in
the presence of a protic additive,[10,26] the equilibrium favors
pathway A, thus leading to 4 under anhydrous reaction
conditions because of the reduced rate of the aza-MBH
reaction (Table 1, entries 4 and 3). To gain an insight into the
influence of the protic additives on the regioselectivity of the
reaction pathways additional control experiments were car-
ried out. When the reaction of 2a and 3a was performed in
the presence of 1c (0.1 equiv) and a Brønsted acid (b-
naphthol, 2-pyridone, and p-nitrophenol; 0.1 equiv), the yield
of the product 4a decreased (70%!46%) and there was
concurrent formation of the aza-MBH adduct 5a (see the
Supporting Information). Likewise, the same reaction cata-
lyzed by 1a in the presence of b-naphthol and trifluorethanol
afforded the adduct 5a as the major (b-naphthol) and even as
the only product (trifluorethanol; see the Supporting Infor-
mation).[27]
Received: January 27, 2011
Published online: April 28, 2011
Keywords: allenoates · asymmetric synthesis · cycloaddition ·
.
nitrogen heterocycles · organocatalysis
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Figure 1. Possible transition state.
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configured azetidine compounds were produced with similar
efficiency.
Experimental Section
General protocol: Catalyst 1c (2.6 mg, 0.005 mmol, 0.1 equiv), and
alkyl 2,3-butadienoate (3; 0.1 mmol, 2.0 equiv) were added to a
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[21] The E configuration of azetidines 4 was determined by compar-
ison of their spectroscopic data with those described in Ref.
[10a] and [10b]. In addition, an X-ray crystal structure of 4n
corroborated with this assignment.
[22] The absolute configuration was determined by X-ray crystallo-
graphic analysis of an enantiomerically pure sample of 4n (see
the Supporting Information). CCDC 012011 (4n) contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[23] Preparation of anhydrous catalysts: the catalysts were dissolved
in THF and the volatiles were evaporated under reduced
pressure at room temperature. This procedure was repeated
three times.
[27] The control experiments in the presence of 2-pyridone and
trifluoroethanol were suggested by one of the referees.
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