Kinetic Resolution of 2H-Azirines by Asymmetric Imine Amidation

Article abstract of DOI:10.1002/anie.201605251

Highly efficient kinetic resolution of 2H-azirines by an asymmetric imine amidation was achieved in the presence of a chiral N,N′-dioxide/Sc^IIIcomplex, thus providing a promising method to obtain the enantioenriched 2H-azirine derivatives and p

Full text of DOI:10.1002/anie.201605251

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605251
German Edition: DOI: 10.1002/ange.201605251
Asymmetric Catalysis
Kinetic Resolution of 2H-Azirines by Asymmetric Imine Amidation
Haipeng Hu, Yangbin Liu, Lili Lin, Yuheng Zhang, Xiaohua Liu,* and Xiaoming Feng*
Abstract: Highly efficient kinetic resolution of 2H-azirines by
an asymmetric imine amidation was achieved in the presence of
a chiral N,N’-dioxide/ScIII complex, thus providing a promising
method to obtain the enantioenriched 2H-azirine derivatives
and protecting-group free aziridines at the same time. It is rare
to find an example of N1 of an oxindole participating in
a reaction over C3. Moreover, chiral 2H-azirines were
stereospecifically transformed into an unprotected aziridine
and a-amino ketone.
Chiral 2H-azirine frameworks are key intermediates in
organic synthesis and privileged structural units in a number
of natural products and biological compounds.[1,2] The interest
in synthetic methodologies for the preparation of the smallest
unsaturated nitrogen-containing heterocyclic compounds has
increased in the last decades. So far, 2H-azirine can be
synthesized by various methods,[3,4] but their preparation in
a catalytic way is lacking. Besides asymmetric Neber reac-
tions,[4a,d] which are only applicable for the synthesis of 2H-
azirines bearing an ester at the 2-position (Scheme 1a), other
asymmetric strategies are limited. The ester group is indis-
pensable for the enantiodifferentiation during the abstraction
of the methylene protons. And the asymmetric synthesis of
2H-azirines with either aryl or alkyl substituents at the 2/3-
position, without the ester substituent, remains a challenge.
Additionally, aziridines are important building blocks and
widely distributed in many natural products.[5] Despite the
many efficient approaches to aziridines, almost all of the
reported research to date apply to aziridines which do not
always have easily removable N-Ts or N-Boc groups.[5d] Thus,
it is meaningful to develop a catalytic method to atom-
economically deliver protecting-group free chiral aziridines.
We envisioned that the possibility for kinetic resolution
(KR)[6,7] of 2H-azirines by an enantioselective nucleophilic
addition reaction. This strategy could achieve chiral 2H-
azirines and aziridines simultaneously (Scheme 1b, path a).
The idea was investigated by using oxindole derivatives[8] as
nucleophiles in the presence of N,N’-dioxide/scandium(III)
complexes.[9] Surprisingly, we found that the unpredicted
imine amidation[10] product was exclusively obtained rather
Scheme 1. Methods for the synthesis of chiral 2H-azirines. a) Reac-
tions were performed with Sc(OTf)3/L-RaPr2 (1:1, 5 mol%), 1a (0.10
mmol), and 2 (0.10 mmol) in CH2Cl2 (1 mL) at 35 8C for 6 h. b) Used
0.5 mL CH2Cl2. (1a: R1, R2 =Ph). LG=leaving group.
than the expected product arising from reaction at C3 of the
oxindole (Scheme 1b, path b). In general, the C3-position
exhibits stronger nucleophilicity compared to the N1 position
which has been verified by reactions such as Michael,
Mannich, and aldol reactions. For the oxindoles 2a–c, the
nitrogen addition products were exclusively obtained. This
phenomenon could be rationalized by the fact potential
formation of two contiguous quaternary stereocenters
through directly addition at C3 is difficult because of the
steric repulsion between the substituents on the carbon
center. The diastereoselectivity for the products 3aa and
3ab was 1:1 because the C3-position of the oxindole is easily
racemized via an enolate intermediate. Therefore, 3,3-dime-
thylindolin-2-one (2c) was selected as the nucleophile to
realize the KR process.
[*] H. P. Hu, Y. B. Liu, Dr. L. L. Lin, Y. H. Zhang, Prof. Dr. X. H. Liu,
Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
E-mail: liuxh@scu.edu.cn
Initially, the reaction of 2,3-diphenyl-2H-azirine (1a) and
3,3-dimethylindolin-2-one (2c) were employed in the model
reaction to optimize the reaction conditions. Several metal
salts coordinating to the chiral N,N’-dioxide L-RaPh were
tested in CH2Cl2 at 358C for 6 hours. Only the scandium(III)
complex could promote the reaction, though the desired
product was obtained with poor results (Table 1, entry 1).
Then, a series of ligands were tested (entries 2–6). It was
found that the steric hindrance at the amide of the ligand
xmfeng@scu.edu.cn
Prof. Dr. X. M. Feng
Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin), Tianjin 300071 (China)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605251.
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Table 1: Optimization of reaction conditions.[a]
by using ent-L-RaPr2 (entry 13). In
all cases, the d.r. value of 3a was
over 19:1.
With the optimized reaction
conditions established, various rac-
emic 2H-azirines were tested
(Table 2). Satisfyingly, 2H-azirines
containing either electron-with-
drawing or electron-donating sub-
stituents on the 4-position of the
phenyl ring (R1) were smoothly
converted into the corresponding
products 3b–h in good yields and
Entry
Ligand
Solvent
1a
3a
s[d]
excellent
(entries 2–8).
enantioselectivities
Meanwhile, the
Yield [%][b]
ee [%][c]
<5
7
17
15
6
77
<5
98
90
95
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
L-RaPh
L-RaMe2
L-RaEt2
L-RaPr2
L-PiPr2
L-PrPr2
L-RaPr2
L-RaPr2
L-RaPr2
L-RaPr2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
THF
67
83
77
82
90
29
95
15
32
46
31
16
20
12
5
62
trace
83
67
49
45
37
65
96
70
33
73
20
40
93
–
2
6
unreacted 1b–h were recovered in
yields of 43–52% with 94–99% ee.
Although substituents on the 3/2-
position of the phenyl group 1i/1j
and disubstituted 1k exhibited
lower reactivities (entries 9–11),
the results were still satisfying
after prolonging the reaction time
and increasing the catalyst loading
to 10 mol%. The compounds 1l and
1m, having a fused ring and naph-
thyl substitutent, respectively, also
underwent the KR process with the
corresponding s factors of 354 and
100 (entries 12 and 13). Although
alkyl groups on the 3-position of the
57
6
4
–
5
7
toluene
10
toluene/Et2O
(v/v, 4:1)
toluene/Et2O
(v/v, 4:1)
toluene/Et2O
(v/v, 4:1)
toluene/Et2O
(v/v, 4:1)
103
11[e]
12[f]
13[g]
L-RaPr2
49
49
50
98
98
49
50
50
94
94
149
149
149
L-RaPr2
ent-L-RaPr2
À98
À94
[a] Unless otherwise noted, all reactions were performed with Sc(OTf)3/ligand (1:1, 5 mol%), 1a
(0.10 mmol), and 2c (0.10 mmol) in solvent (0.5 mL) at 358C for 6 h. [b] Yield of isolated product.
[c] Determined by chiral-phase HPLC analysis. [d] Selectivity factors s, calculated according to the
following equations: s=ln[(1ÀC)(1—ee1)]/ ln[(1ÀC)(1+ee1)], C=(ee1)/(ee1 +ee3). [e] The reaction was
carried out with 2c (0.10 mmol), metal/ligand (1:1.2, 5 mol%), 1a (0.10 mmol), toluene (0.4 mL), Et2O
(0.1 mL) at 358C for 5.5 hours. [f] The reaction was performed with 0.5 mol% catalyst for 23 hours.
2H-azirine
were
compatible
(entries 14 and 15), the substrate
1n, having a methyl group gave low
s factor. In comparison, 1o, having
a more bulky benzyl substituent
resulted in an improved s factor of
41. Next, R2 was varied (entries 16–
20), and the reaction was unbiased
1
[g] The reaction was run for 5.5 hours. The d.r. value of 3a was over 19:1 as detected by H NMR
spectroscopy. THF=tetrahydrofuran.
affected the enantioselectivities of recovered 1a and product
3aa. Improving the steric hindrance from a 2,6-dimethyl to
2,6-diisopropyl group resulted in an increase of the s factors
from 2 to 57 (entries 2–4). Subsequently, l-pipecolic-acid-
derive L-PiPr2 and l-proline-derived L-PrPr2 were investi-
gated (entries 5 and 6), but no better result was obtained. To
further improve the reaction results, various solvents were
screened. When Et2O was used (entry 7), the recovered 1a
was obtained in 95% yield with less than 5% ee. Fortunately,
the reaction rate was improved in both THF and toluene in
spite of the decrease in the s factors (entries 8 and 9).
Additionally, when the mixed solvent of Et2O and toluene
(v/v, 1:4) was added, both the s value and reactivity were
greatly improved (entry 10). Finally, by adjusting the ratio of
metal to ligand to 1:1.2, and the s factors increased up to 149.
The unreacted 1a was recovered in 49% yield with 98% ee,
and 3a was formed in 49% yield with 94% ee (entry 11).
Gratifyingly, the catalyst loading could be reduced to
0.5 mol% without affecting the results (entry 12). As
expected, ent-1a and ent-3a were formed enantioselectively
toward electronic properties, as excellent enantioselectivities
were obtained for both the desired products 3p–s (92–95%
ee) and the recovered 1p–s (93–96% ee). The reaction of rac-
1t, having an alkyl group in the 2-position of the 2H-azirine,
gave the recovered 1t in 78% ee with 20% yield. The absolute
configuration of the product 3q was determined to be (2S, 3S)
by X-ray crystallography analysis.[11]
Next, the synthetic potential of the recovered 2H-azirines
was investigated. In the presence of NaBH4, 1q was converted
to into the unprotected aziridine 1qa in 90% yield with
excellent diastereo- and enantioselectivity (Scheme 2a).
Additionally, when 1a was treated with NaOMe, the nucle-
ophilic imine addition delivered the intermediate A, which
was sequentially protected by BzCl and hydrolyzed with HCl
(6n, aq.) to give the a-amino ketone 4 (Scheme 2b).
Based on the X-ray structure of the N,N’-dioxide/ScIII
complex[9a] and the absolute configuration of the product
3q, a transition state for the KR process was proposed
(Figure 1). In TS-1, the oxindole preferentially attacked (S)-
1 from the Re face of the 2H-azirine via imine formation
2
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Table 2: Substrate scope for kinetic resolution of 2H-azirines.[a]
Entry
R1
R2
t [h]
Conv
[%][d]
1a
3a
s[d]
Yield [%][b]
ee [%][c]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Ph
4-FC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5.5
7.0
4.5
3.0
2.5
4.5
5.5
7.0
51
52
52
52
54
52
49
51
51
37
55
49 (1a)
47 (1b)
45 (1c)
43 (1d)
50 (1e)
50 (1 f)
52 (1g)
50 (1h)
47 (1i)
65 (1j)
47 (1k)
98
99
97
97
94
96
96
97
98
57
93
50 (3a)
53 (3b)
53 (3c)
52 (3d)
47 (3e)
47 (3 f)
46 (3g)
48 (3h)
51 (3i)
30 (3j)
49 (3k)
94
93
90
91
81
90
99
95
96
99
76
149
145
80
89
33
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-C6H5C6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
3,5-Me2C6H3
74
790
165
226
355
24
12.0
168.0
72.0
10[e]
11[e]
12
Ph
7.0
49
43 (1l)
94
47 (3l)
98
354
13
2-naphthyl
Me
C6H5CH2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9.0
1.0
0.6
5.0
5.5
9.5
5.5
17.0
51
71
56
49
49
50
51
76
44 (1m)
19 (1n)
44 (1o)
55 (1p)
54 (1q)
50 (1r)
48 (1s)
20 (1t)
97
64
>99
93
92
95
96
78
56 (3m)
60 (3n)
55 (3o)
40 (3p)
44 (3q)
47 (3r)
52 (3s)
67 (3t)
92
30
78
95
94 (S,S)
95
92
100
3
41
133
106
146
94
14[f]
15
16
4-FC6H4
4-ClC6H4
4-MeC6H4
4-MeO2CC6H4
C6H4CH2CH2
17[g]
18
19
20
25
4
[a] The reactions were carried out with 2 (0.10 mmol), metal/ligand (1:1.2, 5 mol%) in CH2Cl2 (0.5 mL) at 358C for 0.5 h, then CH2Cl2 was removed.
And 1 (0.10 mmol) and solvent (0.5 mL) were added. [b] Yield of isolated product. [c] Determined by chiral-phase HPLC analysis. [d] Selectivity factors
s, calculated according to the following equations: s=ln[(1ÀC)(1Àee1)]/ln[(1ÀC)(1+ee1)], C=(ee1)/(ee1 +ee3). [e] 10 mol% catalyst was used. [f] The
reaction was carried out at 08C. [g] The configuration of 3q was determined by X-ray crystallography analysis. The d.r. values of 3 were all over 19:1 as
1
detected by H NMR spectroscopy.
because of the reduced steric bulk, thus delivering the
corresponding S,S-configured product 3, and is in accordance
with the observed experiment result. The (R)-1 is disfavored
since there is steric repulsion between the phenyl group of the
2H-azirine and oxindole.
In summary, we have presented the first kinetic resolution
of 2H-azirines by an asymmetric imine amidation under mild
reaction conditions, thus achieving selectivity factors of up to
790. A series of chiral 2H-azirines and protecting-group free
Scheme 2. Transformations of 2H-azirines. Bz=benzoyl.
aziridines were formed with excellent results (up to > 99% ee
and 99% ee, > 19:1 d.r.). Meanwhile, this is the first example
of N1 of oxindole participating in a reaction instead of C3.
Further studies on 2H-azirines and aziridines are under way.
Acknowledgments
We appreciate the National Natural Science Foundation of
China (Nos. 21572136, 21321061, 21432006) for financial
support.
Keywords: asymmetric catalysis · enantioselectivity ·
Figure 1. Proposed transition state.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
heterocycles · kinetic resolution · scandium
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2166.
[11] CCDC 1480937 (3q) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre. For more
data see the Supporting Information.
Received: May 29, 2016
Published online: && &&, &&&&
4
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
H. P. Hu, Y. B. Liu, L. L. Lin, Y. H. Zhang,
X. H. Liu,* X. M. Feng*
&&&& — &&&&
Kinetic Resolution of 2H-Azirines by
Asymmetric Imine Amidation
The s factor: The title reaction was
achieved in the presence of the chiral
N,N’-dioxide/ScIII complex. The method
provided a promising approach for
obtaining the enantioenriched 2H-azirine
derivatives and protecting-group free
aziridines with excellent results (up to
>99% ee and 99% ee, >19:1 d.r.).
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!