Enantioselective Reaction of 2H-Azirines with Phosphite Using Chiral Bis(imidazoline)/Zinc(II) Catalysts

Article abstract of DOI:10.1002/anie.201704133

The first highly enantioselective nucleophilic addition reaction of phosphites with 2H-azirines has been developed. The reaction was applied to various 3-substituted 2H-azirines using novel chiral bis(imidazoline)/Zn^II catalysts to afford produ

Full text of DOI:10.1002/anie.201704133

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Title: Enantioselective Reaction of 2H-Azirines with Phosphite Using
Chiral Bis(imidazoline)-Zn(II) Catalysts
Authors: Shuichi Nakamura and Daiki Hayama
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10.1002/anie.201704133
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Reaction of 2H-Azirines with Phosphite Using Chiral
Bis(imidazoline)-Zn(II) Catalysts**
Shuichi Nakamura,*,[a,b] Daiki Hayama[a]
Dedication ((optional))
Abstract: The first highly enantioselective nucleophilic addition
reaction of phosphites with 2H-azirines has been developed. The
reaction was applied to various 3-substituted 2H-azirines using novel
chiral bis(imidazoline)/Zn(II) catalysts to afford products in good yield
with high enantioselectivity. The Transformation of the optically
active aziridines obtained showed that 2H-azirines act as α,β- or β,β-
dicarbocationic amine synthons.
Chiral aziridines can react with some nucleophiles to give chiral
amines, therefore aziridines act as valuable building blocks in
organic chemistry.[1] Futheromore, aziridines are an important
class of synthetic targets, because they often exhibit a broad
range of biological activities,[2] such as Mitomycin C,[3]
Azicemicin A,B,[4] and Miraziridine A[5] (Figure 1).
Figure 2. Synthetic methods for chiral aziridines
However, enantioselective reactions of nucleophiles with 2H-
azirines have been far less explored due to the lower reactivity
of 2H-azirines.
Somfai and co-workers first reported the
enantioselective reaction of 2H-azirines with Grignard reagents
using a stoichiometric amount of (−)-sparteine as chiral additives
to give products (up to 17% ee).[8] Recently, Zhang and co-
workers reported the one example of the enantioselective
reaction of azirine with pyrazole using chiral organocatalyst with
moderate enantioselectivity (77% ee).[9] Although there are
pioneering studies, there are no other reports on the highly
enantioselective nucleophilic addition reaction to 2H-azirines.[10]
In addition, obtained aziridines also accept reactions with other
nucleophiles, allowing 2H-azirines to act as α,β- or β,β-
dicarbocationic amine synthons (Figure 3).
H2N
R
OH
O
O
N
O
H3CO
HO
H
O
HO
H2N
H3C
OCH3
NH
H
N
H3CO
OH OH
O
O
Mitomycin C
Azicemicin A: R = CH3
Azicemicin B: R = H
O
O
N
OH
O
O
H
H
N
N
HO
N
OH
H
N
H
O
O
H
NH
NH2
Miraziridine A
HN
Figure 1. Biologically active compounds containing aziridine
Therefore, an intense research effort has been made to the
develop an efficient asymmetric synthesis of chiral aziridines.
Until now, three types of enantioselective syntheses of aziridines
were developed; 1) enantioselective methylene insertion
reaction to imines, 2) enantioselective aziridination reaction to
olefins and 3) enantioselective cyclization of β-substituted
amines (Figure 2a).[6] On the other hand, one of the efficient
methods for the synthesis of optically active aziridines would be
the catalytic enantioselective nucleophilic addition of some
nucleophiles with 2H-azirines (Figure 2b).[7]
Figure 3. Enantioselective reaction with 2H-azirines and the synthetic utility of
aziridines
On the other hand, optically active α- or β-amino phosphonic
acids and their derivatives are also useful chiral building blocks
for the preparation of pharmaceutical targets.[11] From this point
of view, we recently reported the enantioselective reactions of
ketimines with phosphites[12] and the enantioselective reaction of
aziridines with phosphites.[13] We herein report the first highly
enantioselective reaction of phosphites with 2H-azirines using
our original chiral catalysts (Scheme 1).
[a]
[b]
Prof. Shuichi Nakamura, Daiki Hayama
Department of Life Science and Applied Chemistry, Graduate
School of Engineering, Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Fax: (+)81-52-735-5245
E-mail: snakamur@nitech.ac.jp
Frontier Research Institute for Material Science, Nagoya Institute of
Technology
Scheme 1. Asymmetric synthesis of aziridines having a phosphonyl group via
the reaction of 2H-azirines with phosphites
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
The reaction of 2H-azirine 1a with diphenyl phosphite 2 (1.3
equiv.) was carried out in the presence of 12 mol% of various
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10.1002/anie.201704133
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COMMUNICATION
ligands 3 and 10 mol% of Et2Zn. The results are shown in Table
1.
from cyclohexanediamine showed good enantioselectivity (entry
6),[14] although the reaction using a similar catalyst 3e derived
from 1,2-diphenylethylene-1,2-diamine gave product 4a as an
almost racemic form (entry 5). To improve enantioselectivity, the
substituent on the chiral ligand was examined (entries 7-9). As
a result, the reaction using catalyst 3h having a 2,4,6-
trimethylbenzenesulfonyl group on nitrogen in imidazoline and a
tert-butyl group on the phenol group afforded product 4a in high
yield with high enantioselectivity (89%, er = 88:12, entry 8). The
reaction at a lower reaction temperature and lower concentration
of reaction solution improved the yield and enantioselectivity
slightly (entries 10 and 11). The reaction of 1a with diphenyl
tert-butyldimethylsilyl phosphite [TBSOP(OPh)2] instead of
diphenyl phosphite did not afford any product (entry 12).
Table 1. Enantioselective reaction of azirine 1a with diphenyl phosphite 2
using various chiral catalysts 3a-i[a]
Having established the suitable reaction conditions, the
nucleophilic reaction of various azirines 1a-o with diphenyl
phosphite 2 using 3h/Et2Zn was examined (Table 2).
Table 2. Enantioselective reaction of various azirines 1a-o with phosphite using
3h/Et2Zn[a]
Entry
3
Time [h]
Yield [%]
78
Enantiomeric ratio[b]
Entry
1
1
R
Time [h]
48
Yield [%]
93
Er[b]
1a
Ph
97: 3
1
3a
3b
3c
3d
3e
3f
1
50:50
64:36
75:25
66:34
52:48
82:18
86:14
88:12
79:21
95: 5
97: 3
-
2
1b
1c
1d
1e
1f
4-CH3C6H4
3-CH3C6H4
3,5-(CH3)2C6H3
3-Ph-C6H4
4-CH3OC6H4
3-CH3OC6H4
4-FC6H4
72
83
97
91
99
95
99
87
91
92
81
96
83
91
78
96: 4
96: 4
97: 3
95: 5
94: 6
96: 4
93: 7
94: 6
94: 6
94: 6
96: 4
98: 2
96: 4
90:10
2
1
80
3
24
3
0.25
1
85
4
24
4
81
5
72
5
12
4
87
6
7[c]
72
6
78
1g
1h
1i
24
7
3g
3h
3i
3
90
8
120
96
8
4
89
9
3-FC6H4
9
5
95
10[c]
11[c,d]
12[c,d,e]
3h
3h
3h
24
48
48
94
10
11[c]
12
13
14
15[c]
1j
2-FC6H4
120
120
36
1k
1l
1-naphthyl
2-naphthyl
2-thienyl
93
-
1m
1n
1o
24
[a] Reaction conditions; 2H-azirine 1a (0.1 mmol), 2 (1.3 equiv.), Et2Zn (10
mol%), 3 (12 mol%), and MS 4A (50 mg) were used. The reaction was
carried out in CH2ClCH2Cl (0.2 M). [b] Enantiomeric ratio was determined by
HPLC analysis using a chiral column. [c] The reaction was carried out at −25
oC. [d] The reaction was carried out in CH2ClCH2Cl (0.1 M) and MS 4A (100
mg) was used. [e] TBSOP(OPh)2 was used as a phosphite.
3-thienyl
96
PhCH=CH
48
[a] Reaction conditions; 2H-azirine 1a (0.1 mmol), 2 (1.3 equiv.), Et2Zn (10
mol%), 3 (12 mol%), and MS 4A (100 mg) were used. The reaction was carried
out in CH2ClCH2Cl (0.1 M) at -25 oC. [b] Enantiomeric ratio was determined by
HPLC analysis using a chiral column. [c] The reaction was carried out in
CH2ClCH2Cl (0.2 M) and MS 4A (50 mg) was used.
Initial catalyst screening revealed that BINOL 3a was an
active catalysts, but exhibited no enantioselectivity (entry 1).
Although the reaction using chiral BINOL catalyst 3b having one
chiral imidazoline group at the 3-position gave product 4a with
low enantioselectivity, chiral bis(imidazoline)-BINOL catalyst 3c
afforded 4a with moderate enantioselectivity (entries 2 and 3).
The reaction using chiral BINOL-bis(imidazoline) catalyst 3d
derived from chiral cyclohexanediamine gave product 4a with
slightly lower enantioselectivity (entry 4). On the other hand, the
reaction using chiral phenol-bis(imidazoline) catalyst 3f derived
The reaction of azirines 1b-g having electron-donating groups
such as methyl, methoxy, or phenyl groups in the meta or para
position gave corresponding products 4b-g in good to moderate
yield with high enantioselectivity (yield 83-99%, er=93:7-97:3,
entries 2-7). The reaction of electron-deficient azirines 1h-j
having fluoro groups were tolerable in this reaction condition to
give products 4h-j with good enantioselectivity (entries 8-10).
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10.1002/anie.201704133
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COMMUNICATION
Azirines 1k-n having 1- or 2-naphthyl or a heteroaryl group, such
as 2 or 3-thienyl groups, also afforded products 4k-n in 81-96%
yield with 94:6-98:2 er (entries 11-14).
The reaction of
conjugated ketimine 1o gave product 4o with good
enantioselectivity without generating any conjugation addition
product (entry 15). After the reaction, most of catalyst 3h could
be recovered by column chromatography, and recovered
catalyst could be used in the reaction to afford product 4a in
94% yield with 97:3 e.r. We also examined the reaction of
dimethylazirine 1p with 2 using catalyst 3h.[15] The reaction
proceed slowly to give the product 4p in moderate yield with
high enantioselectivity (Scheme 2). These results are the first
example of a highly enantioselective reaction of azirines with
nucleophiles.
Scheme 4. Enantioselective reaction of azirine 1a with
imidazoline catalyst 3j.
2 using mono-
In addition, the reaction of 1a with diphenyl phosphite gave
products in good yield with good enantioselectivity, although the
reaction with TBSOP(OPh)2 did not afford any product (Table 1,
entry 12). Based on these results, the proposed catalytic cycle
for the hydrophosphinylation of azirine 1a with diphenyl
phosphite is shown in Figure 4. Diethylzinc reacts with a
hydroxy group of chiral ligand 3h to afford complex A. Then the
azirine coordinates to the zinc cation of complex A to afford
complex B, which coordinates and activates diphenyl phosphite
2.[18] The activated phosphite attacks the imino carbon of azirine.
Subsequently, the adduct-complex undergoes protonation and
decomplexation to give the product and regenerated complex A.
In order to clarify the assumed reaction mechanism, we
Scheme 2. Enantioselective reaction of dimethylazirine 1p with 2 using bis-
imidazoline catalyst 3h
We next examined the ring-opening reaction of obtained
aziridine 4a (Scheme 3a). The reaction of 4a with hydrogen
bromide in water under sonication gave β-bromo-α-
aminophosphonate 5 in high yield (85%). The bromo group in 5
can be removed by using Bu3SnH and AIBN[16] to give α-
aminophosphonate 6 without the loss of enantiopurity. The
absolute configuration of 6 was assigned as (S), based on the
value of the specific rotation for 6 reported in the literature.[12a]
On the other hand, the transformation of 3,5-dinitrobenzoylated
aziridine 7 prepared from 4a using BF3∙OEt2 afforded oxazoline
compound 8, which could be converted to chiral aminoalcohols
(Scheme 3b).[17] These reactions implied that azirines act as
α,β- or β,β-dicarbocationic amine synthons.
conducted
spectroscopic analysis for the reaction mixture of 1a, 3h, Et2Zn
showed dimer of complex A (cation mode, calcd for
a
spectroscopic analysis.
The ESI-Mass
a
+
+
C92H126N11O10S4Zn2 as dimer complex A+2CH3CN+NH4 :
1800.7, found: 1800.7). This signal supports our proposed
reaction mechanism.
N
Ph
R2
R2
R2
R1
N
R1
R1
N
R1
R1
N
R1
N
N
Et2Zn
N
N
O
N
N
OH
N
Zn
N
O
N
Et
N
Zn
Et
Et-H
complex B
complex A
Ph
a)
Bu3SnH (3.0 eq.)
AIBN (0.3 eq.)
h (365 nm)
H
(PhO)2(O)P
Ph
N
HBr
(PhO)2(O)P NH2
(PhO)2(O)P NH2
Ph
R2
Br
H2O
rt, 30 min
(Sonication)
Ph
THF, -5 oC, 12 h
R1
N
R1
O
H
OR
OR
P
(PhO)2(O)P
Ph
N
4a:er = 96:4
5: 85%, er = 96: 4
6: 91%,er = 96: 4
N
H
N
O
N
N
Zn
Ph
NO2
H
O
P
b)
Et
OR
O
NO2
O2N
O
NO2
(1.2 eq.)
RO
complex C
BF3Et2O
(5.0 eq.)
NO2
Cl
H
O
(PhO)2(O)P
Ph
N
TEA (4.0 eq.)
NO2
Figure 4. Assumed reaction mechanism for the enantioselective reaction of
azirine 1a with diphenyl phosphite 2 using 3h
(PhO)2(O)P
N
CH2Cl2, 0 °C
12 h
CHCl3, -70 °C
12 h
N
(PhO)2(O)P
Ph
8: 93%, er = 95:5
Ph
4a: er = 97:3
7: 95%, er = 97:3
From the above consideration and absolute stereochemistry
of the product, the assumed transition state for the reaction of
azirine 1a with 2 is shown in Figure 5. A nitrogen from
imidazoline and an oxygen on the phenol group in 3h
coordinates to zinc(II) in a tetrahedral manner, and another
imidazoline moiety makes a hydrogen bond with the hydroxyl
group in phosphite. The phosphite approaches the Re-face of
azirine, thereby avoiding steric repulsion, to give the (R)-isomer
of 4a.
Scheme 3. Ring-opening reaction of chiral aziridine 4a using HBr and removal
of bromide from 6, and oxazoline formation reaction of 4a
In order to clarify the reaction mechanism, the reaction using
mono-imidazoline catalyst 3j was carried out (Scheme 4). The
reaction gave product 4a in high yield but with low
enantioselectivity (92%, 61:39 er). This result clearly showed
the superiority of the bis-imidazoline catalyst 3h over the mono-
imidazoline catalyst (Table 1, entry 11).
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10.1002/anie.201704133
Angewandte Chemie International Edition
COMMUNICATION
tBu
N
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SO2Mes
N
SO2Mes
N
[7]
N
Et
S
O
Zn
N
H
O
P
OPh
OPh
Zn
Ph
N
Re-face
[8]
[9]
O
P
O
H
(PhO)2(O)P
Ph
N
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Zhang, X. Liu, X. Feng, Angew. Chem. Int. Ed. 2016, 55, 10098; Angew.
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4a
Figure 5. Proposed transition state of the reaction of azirine 1a with 2 using
3h. H atoms have been omitted for clarity.
In conclusion, we developed a highly enantioselective reaction
of azirines with phosphite. The reaction was screened for a
broad range of azirines. This approach is the first example of a
highly enantioselective reaction of azirines with nucleophiles.
The obtained aziridines can be converted to chiral tetra-
substituted amines and oxazolines. We believe that the concept
described here will open doors to the asymmetric reaction of
azirines. Further studies are in progress to study the potential of
these catalytic systems for other processes and enantioselective
reaction of azirines.
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research
on Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from MEXT (26105727) and Uehara Memorial
Foundation.
Keywords: asymmetric synthesis · azirine · imidazoline ·
aziridine
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Angewandte Chemie International Edition
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[15] We also examined the reaction of alkyl-substituted azirines (R = hexyl
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Layout 2:
COMMUNICATION
Shuichi Nakamura,* Daiki Hayama
Et2Zn (10 mol%)
tBu
Ligand (12 mol%)
H
O
Page No. – Page No.
N
MS 4A
(PhO)2(O)P
R
N
MesSO2
N
SO2Mes
+
P
N
OPh
OPh
H
ClCH2CH2Cl
R
Enantioselective Reaction of 2H-
Azirines with Phosphite Using Chiral
Bis(imidazoline)-Zn(II) Catalysts
N
OH
N
up to 99% yield
up to 98: 2 er
(1.3 eq.)
Ligand
The first highly enantioselective nucleophilic addition reaction of phosphites with
2H-azirines has been developed. The reaction was applied to various 3-substituted
2H-azirines using novel chiral bis(imidazoline)/Zn(II) catalysts to afford products in
good yield with high enantioselectivity. The Transformation of the optically active
aziridines obtained showed that 2H-azirines act as α,β- or β,β-dicarbocationic
amine synthons.
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