Organocatalyzed nucleophilic addition of pyrazoles to 2: H -azirines: Asymmetric synthesis of 3,3-disubstituted aziridines and kinetic resolution of racemic 2 H -azirines

Article abstract of DOI:10.1039/c6cc06388h

The first organocatalytic asymmetric nucleophilic addition of arylpyrazoles to 2H-azirines and kinetic resolution of racemic 2H-azirines have been realized. Chiral aziridines were obtained with up to 98% yields and up to 99.9% ee. Meanwhile, simply changing the ratio of reactants, optically active 2H-azirines were recovered in good yields with excellent enantioselectivities.

Full text of DOI:10.1039/c6cc06388h

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Journal Name
COMMUNICATION
Organocatalyzed Nucleophilic Addition of Pyrazoles to 2H-
Azirines: Asymmetric Synthesis of 3,3-Disubstituted Aziridines and
Kinetic Resolution of Racemic 2H-Azirines
Received 00th January 20xx,
Accepted 00th January 20xx
Dong An, Xukai Guan, Rui Guan, Lajiao Jin, Guangliang Zhang and Suoqin Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
H
organocatalyst
The first organocatalytic asymmetric nucleophilic addition of
arylpyrazoles to 2H-azirines and kinetic resolution of racemic 2H-
azirines have been realized. Chiral aziridines were obtained with
up to 98% yields and up to 99.9% ee. Meanwhile, simply changing
the ratio of reactants, optically active 2H-azirines were recovered
in good yields with excellent enantioselectivities.
N
N
N
+
NuH
+
R1
Nu
R1
R2
R1
R2
R2
kinetic resolution
chiral
aziridines
chiral
2H-azirines
(±) 2H-azirines
Scheme 1 Asymmetric nucleophilic addition of nucleophiles
to 2H-azirines via kinetic resolution of racemic 2H-azirines.
Chiral aziridines and azirines are very important synthetic
intermediates in the preparation of many optically active
nitrogen-containing compounds.1 These two kinds of
structures could also be found in many natural products and
pharmaceuticals such as azicemicins, azirinomycins and
dysidazirines (Fig. 1).2 Several of these compounds exhibit
significant biological activities such as antibiotic, antitumor and
other properties.3 Due to their wide synthetic utility and
biological properties, asymmetric synthesis of chiral aziridines
and azirines has attracted considerable attention and has been
extensively investigated since 1980s.4
nucleophilic addition have been limited to two categories:
stereocontrolling by chiral auxiliaries or starting material from
chiral 2H-azirine reagents.5,6d,6e Organocatalytic asymmetric
nucleophilic addition to 2H-azirines has never been reported at
present. On the other hand, the asymmetric synthesis of chiral
2H-azirines are mainly realized by asymmetric Neber
reaction4d,4e and β-elimination of N-substituted aziridines.7
Reports for kinetic resolute of racemic 2H-azirines are rare and
only a few examples could be found.8 To the best of our
knowledge, there is no report for organocatalytic kinetic
resolution of racemic 2H-azirines.
Asymmetric nucleophilic addition to 2H-azirines is one of
the most effective synthetic strategies for the preparation of
chiral aziridines.1a,5 Especially, the addition of nitrogen
heterocycles to 2H-azirines has been extensively researched
since the first report of the nucleophilic addition of pyrazole to
3-phenyl-2H-azirines.6 Methods for the asymmetric
We hypothesized that an asymmetric nucleophilic addition
to 2H-azirines via organocatalytic kinetic resolution of racemic
2H-azirines may afford the optically active aziridines and
azirines simultaneously (Scheme 1), though it is a challenge to
realize both the asymmetric nucleophilic addition and the
kinetic resolution of racemic 2H-azirines in one reaction. A
suitable organocatalyst is needed in order to achieve high
enantioselectivity. As important chiral Brønsted acids, chiral
imidodiphosphoric acids have been successfully used in a
variety of enantioselective reactions.9,10 In this work, we
R
N
OH
H
O
N
COOH
O
HO
H
HO
Azirinomycin
H3CO
N
developed
a new cross type H8-BINOL derived chiral
OH
OH
O
H
C13H27
COOCH3
imidodiphosphoric acid 4e to catalyze the nucleophilic addition
of arylpyrazoles to racemic 2H-azirine carboxylic esters.
To begin the study, we focused on the asymmetric synthesis
of aziridines. In order to obtain aziridines with high yields, 3
Azicemicin A: R = CH3
Azicemicin B: R = H
(R)-(E)-Dysidazirine
Fig
.
1
Natural products and pharmaceuticals containing
aziridine and azirine structures.
equiv of 2H-azirines
because only half of 2H-azirines could undergo the reaction.
H8-BINOL derived imidodiphosphoric acids 4a 4d were
2 were used to react with arylpyrazoles 1,
-
screened in the reaction (Table 1). Among them, catalyst 4a
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Table 1 Optimization of reaction conditions.a
Table 2 Substrate Scope for Racemic 2H-Azirines.a
H
N
COOEt
NH
N
N
COOEt
cat
H
N
N
+
COOEt
COOEt
solvent
Br
3 equiv
Br
(±)-2a
1a
3a
R1
R2
4a: R1=R2=1-naphthyl
4b: R1=R2=2-naphthyl
4c: R1=R2=phenyl
4d: R1=R2=3,5-bis(trifluoromethyl)-phenyl
4e: R1=1-naphthyl, R2=9-anthracenyl
entry
R1
R2
t
yield of ee
(%)b
O
P
OH
P
(h)
18
18
3
(%)c
O
O
O
O
N
1
Methyl
Methyl
Methyl
Methyl
n-C3H7
Ethyl
97 (3a
)
99.9
99.9
99.9
99.9
99.9
99.6
99.9
99.3
97.1
98.0
99.7
99.9
99.5
99.9
99.1
R1
R2
2
Methyl
96 (3b
)
3
Isopropyl 18
98 (3c
)
entry
catalyst sovent
t
yield
ee
(%)c
76
44
54
69
95
93
93
94
90
95
97
4
Benzyl
Methyl
Methyl
Methyl
Methyl
Ethyl
18
36
36
48
48
36
48
48
48
98 (3d
)
(h) (%)b
5
96 (3e
)
6
n-C5H11
n-C6H13
Isobutyl
Benzyl
92 (3f
)
1
4a
4b
4c
4d
4e
4e
4e
4e
4e
4e
4e
toluene
toluene
toluene
toluene
toluene
CH2Cl2
48
48
60
42
12
24
18
32
12
6
74
63
68
76
93
86
81
87
90
96
90
7
86 (3g
)
2
8
93 (3h
91 (3i
89 (3j
91 (3k
93 (3l
)
3
9
)
4
10d
11d
12d
13d
14d
15d
C6H5
Ethyl
)
5
4-BrC6H5
4-ClC6H5
4-CH3C6H5
4-CF3C6H5
3-ClC6H5
Methyl
Methyl
Methyl
Methyl
Methyl
)
6
)
7
CHCl3
144 74 (3m
)
8
EtOAc
36
72
90 (3n
86 (3o
)
9
THF
)
10
11d,e
cyclohexane
cyclohexane: 18
toluene(9:1)
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.3 mmol,
3 equiv), catalyst 4e (10 mol %) in 0.9 mL cyclohexane and 0.1
mL toluene at -20 oC. b Isolated yield. c Determined by HPLC
analysis with Daicel ChiralPak AS-H column. d The reaction was
carried out at 25 oC.
12 d,f
13d,g
14d,g,h
4e
4e
4e
cyclohexane: 30
toluene(9:1)
89
86
97
98
cyclohexane: 48
toluene(9:1)
99
cyclohexane: 18
toluene(9:1)
99.9
further improved to 99% ee as the reaction temperature was
lowered to -20 oC but with a decrease in both the yield and
reaction rate (entries 11-13). We then increased the catalyst
loading of 4e to 10 mol % and obtained the best 97% yield and
99.9% ee in 18 hours (entry 14).
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.3 mmol,
3 equiv), catalyst (5 mol %) in 1.0 mL of solvent. b Isolated yield.
Determined by HPLC analysis with Daicel ChiralPak AS-H
c
column. d The mixed solvent of 0.9 mL cyclohexane and 0.1 mL
toluene. e The reaction was carried out at 0 C. The reaction
0
f
Under the optimized conditions, the scope of racemic 2H-
was carried out at -10 C. g The reaction was carried out at -20
o
azirine carboxylic esters
2 were investigated (Table 2). Azirines
oC. h Catalyst 4e (10 mol %).
with different esters group gave products with excellent yields
(96-98%) and enantioselectivities (99.9% ee’s, entries 1-4). We
next examined azirines with different aliphatic substituents at
C-3 position. The reaction rates and yields were gradually
decreased with the increase of the carbon chain, but the
enantioselectivities were almost unaffected (86-96% yields,
99.6-99.9% ee, entries 1 and 5-7). Among them, the absolute
configuration of product 3e was established by X-ray
crystallography.11 The reactions of isobutyl and benzyl azirines
also proceeded smoothly, affording products with 91-93%
yields and 97-99.3% ee (entries 8 and 9). Azirines with C-3
aromatic substituted groups were subsequently used in the
reaction. The reaction proceeded very slowly at -20 oC. Then
with 1-naphthyl substituents provided better yield (74%) and
enantioselectivity (76% ee, entry 1). The reaction rate
decreased with the consumption of the isomeric 2H-azirines.
For this reason, the reaction proceeded incompletely and
afforded relative low yields. Based on the catalyst 4a, chiral
imidodiphosphoric acid 4e with 1-naphthyl and 9-anthracenyl
substituents was synthetized and used in the reaction. To our
delight, the yield and enantioselectivity were improved
dramatically (93% yield and 95% ee, entry 5). Further
screening of solvents showed that the reaction rate and yield
were significantly improved in cyclohexane (entry 10). The
product 3a was obtained with 96% yield and 95% ee in only 6
hours. In order to avoid the freezing point of solvent as well as
to lower the reaction temperature, a small amount of toluene
was added into the reaction. The enantioselectivity was
o
we increased the reaction temperature to 25 C. The azirines
with electron-withdrawing or electron-donating aromatic
substituents smoothly underwent the reaction and gave
products with high yields and excellent enantioselectivities
2 | J. Name., 2012, 00, 1-3
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Table
3
Substrate Scope for 3-Aryl-1H-Pyrazole-5- Table 4 Substrate Scope for the Kinetic Resolution of Racemic
2H-Azirine Carboxylic Esters.a
Carboxylates.a
entry R1
R2
t
yield of ee
3
(%)b
(%)c
en
try
(±)-2
ee % of 3
ee % of 2
Sc
(
1)
(h)
18
(yield %)b
(yield %)b
1
2
3
4
5
6
7
8
4-Cl (1p
)
)
Ethyl
98 (3p
97 (3q
)
)
99.9
99.9
99.9
99.9
99.6
99.9
99.9
99.1
1
2
99 (48)
3a
98 (49)
2a
909
4-Cl (1q
Isopropyl 18
3-Cl (1r
)
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
18
12
18
12
24
96
97 (3r
)
2-Cl (1s
)
97 (3s
)
99 (48)
3b
99 (48)
2b
1057
1057
1057
844
4-F(1t
2-F (1u
4-CH3 (1v
4-CF3 (1w
)
98 (3t
97 (3u
98 (3v
72 (3w
)
)
)
3
99 (49)
3c
99 (48)
2c
)
)
)
)
4
99 (49)
3d
99 (49)
2d
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.3 mmol,
3 equiv), catalyst 4e (10 mol %) in 0.9 mL cyclohexane and 0.1
mL toluene at -20 oC. b Isolated yield. c Determined by HPLC
analysis with Daicel ChiralPak AS-H column.
5d
6d
7d
8e
99 (48)
3e
97 (48)
2e
N
n-C3H7
COOCH3
99 (48)
3g
99 (49)
2g
1057
55
(entries 10-15). Among them, aromatic azirine with strong
electron-withdrawing 4-CF3 substituent afforded the highest
enantioselectivity and reaction rate (99.9% ee, entry 14). In
contrast, the reaction of electron-rich 4-methyl-phenyl
substituted azirine progressed slowly and resulted in relatively
low yield (74% yield, 99.5% ee, entry 13). It is easy to
understand that azirines with electron- withdrawing groups
are more favorable for the attack of nucleophiles. Azirines with
ortho- and meta-substituents were also tested. The use of
meta-chlorophenyl substituted azirines decreased the reaction
rate and resulted in 86% yield and 99% ee (entry 15). However,
the reaction of ortho-chlorophenyl substituted azirines did not
occur under the same conditions.
88 (49)
3i
94 (45)
2i
99 (42)
3k
97 (48)
2k
844
9e
99 (43)
96 (49)
792
909
3l
2l
10
99 (45)
98 (46)
e
3n
2n
aReaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.18 mmol,
1.8 equiv), catalyst 4e (10 mol %) in 0.9 mL cyclohexane and
0.1 mL toluene at -20 oC, 3d. bThe ee value was determined by
The scope of arylpyrazoles was subsequently examined
(Table 3). Arylpyrazoles with different ester groups gave
almost the same yields and enantioselectivities (entries 1 and
2). The ortho-, meta- and para-substituted arylpyrazoles could
all smoothly proceeded the reaction with excellent yields and
enantioselectivities (97-98% yields, 99.6-99.9% ee, entries 1-6).
Next, arylpyrazoles with electron-withdrawing or electron-
donating groups on the aromatic ring were used in the
reaction, obtaining good to high yield with excellent
enantioselectivities (Table 3, entries 7 and 8). However, the
reaction of arylpyrazole with electron-withdrawing group
progressed very slowly.
HPLC analysis by using a chiral column. Isolated yield based on
racemic
c
. Selectivity factor (s) = ln[(1 - conv)(1 - ee2)]/ln[(1 -
2
conv)(1 + ee2)], conv = ee2/(ee2+ee3). dThe reaction was carried
out at 0 oC, 3d. eThe reaction was carried out at 25 oC, 6d.
were recovered with 48-49% yields and 98-99% ee (The
theoretical yield of recovered
2 was 50%, entries 1-4). Azirines
with different aliphatic substituents at C-3 position were then
tested and recovered with high yields and enantioselectivities
(entries 5-7). Aromatic substituted azirines also gave the
desired products with 42-45% yields and 99% ee’s. The
recovered 2H-azirines were obtained with 46-49% yields and
96-98% ee (entires 8-10). In comparison, in previous reports,
the best result was 73% yield with 93% ee.7
We next investigated the kinetic resolution of racemic 2H-
azirine carboxylic esters via the nucleophilic addition reaction
(Table 4). Arylpyrazoles
1 underwent the reaction with 1.8
equiv of 2H-azirines 2. Aliphatic 2H-azirines with different
Optically active 2H-azirine carboxylic esters are important
synthetic intermediates and could participate in a variety of
organic reactions. We investigated the nucleophilic addition of
esters group reacted smoothly and provided aziridines with
high yields and enantioselectivities. Meanwhile, 2H-azirines
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Journal Name
Jackson, A. K. Miller, S. Hernandez and J. M. Mata, J.
Antibiot. 1971, 24, 42-47; (d) T. F. Molinski and C. M. Ireland,
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3
4
(a) V. Martichonok, C. Plouffe, A. C. Storer, R. Menard and J.
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and S. A. Sieber, Chem. Sci. 2012, 3, 2035-2041.
Scheme 2 Nucleophilic Addition of Arylpyrazole to (R)-2H-
Azirine Carboxylic Ester.
(a) Y. Zhu, Q. Wang, R. G. Cornwall and Y. Shi, Chem. Rev.
2014, 114, 8199-8256; (b) H. Pellissier, Adv. Synth. Catal.
2014, 356, 1899-1935; (c) A. S. Timen, A. Fischer and P.
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H. Verstappen, G. J. A. Ariaans and B. Zwanenburg, J. Am.
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L. Gilchrist, J. Chem. Soc., Perkin Trans. 1, 2002, 2002, 1911-
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Commun. 2004, 2004, 2088-2089; (c) E. Risberg, A. Fischerb
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2005, 70, 8895-8901.
(a) H. Heimgartner, Angew. Chem. Int. Ed. 1991, 30, 238-264;
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D'Hooghe and N. D. Kimpe, Chem. Rev. 2007, 107, 2080-
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L. F. Goncalves, Tetrahedron Letters. 2003, 44, 6277-6279.
5
6
Scheme 3 Nucleophilic Addition of Arylpyrazole to 3-Phenyl-2H-
Azirine.
resolution product (R)-2H-azirine carboxylic ester 2n with
arylpyrazole 1a. Chiral aziridine (2S, 3R)-3n was obtained with
79% yield and 98% ee in the presence of TsOH at 25 oC
(Scheme 2). It is
a straightforward procedure for the
preparation of the enatiomeric aziridine
3.
Preliminary study on the enantioselective nucleophilic
addition of arylpyrazole to 3-phenyl-2H-azirine was also
7
8
(a) F. A. Davis, C.-H. Liang and H. Liu, J. Org. Chem. 1997, 62,
3796-3797; (b) F. A. Davis, H. Liu, C.-H. Liang, G. V. Reddy, Y.
Zhang, T. Fang and D. D. Titus, J. Org. Chem. 1999, 64, 8929-
8935.
(a) T. Sakai, I. Kawabata, T. Kishimoto, T. Ema and M. Utaka,
J. Org. Chem. 1997, 62, 4906-4907; (b) T. Sakai, Y. Liu, H.
Ohta, T. Korenaga and T. Ema, J.Org. Chem. 2005, 70, 1369-
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Angew. Chem. Int. Ed. 2016, 55, 10098-10101; Angew. Chem.
2016, 128, 10252-10255.
For BINOL derived chiral imidodiphosphoric acids, see: (a) I.
Coric and B. List, Nature. 2012, 483, 315-319; (b) Y.-Y. Chen,
Y.-J. Jiang, Y.-S. Fan, D. Sha, Q. Wang, G. Zhang, L. Zheng and
S. Zhang, Tetrahedron: Asymmetry. 2012, 23, 904-909; (c) S.
Liao, I. Coric, Q. Wang and B. List, J. Am. Chem. Soc. 2012,
134, 10765-10768; (d) K. Wu, Y.-J. Jiang, Y.-S. Fan, D. Sha and
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Fan, Y. Gao, Z.-Q. Zhu, L.-Y. Zheng and S.-Q. Zhang, Eur. J.
Org. Chem. 2014, 2014, 301-306; (f) M.-H. Zhuo, Y.-J. Jiang,
performed. The corresponding aziridine
6 was obtained with
62% yield and 77% ee in 6 days (Scheme 3). The result showed
that the catalyst is potentially applicable to the
enantioselective nucleophilic addition of 2H-azirines.
In conclusion, we have developed an organocatalytic
asymmetric nucleophilic addition of 2H-azirines and kinetic
resolution of racemic 2H-azirines. Chiral aziridines and azirines
were obtained with excellent yields and enantioselectivities.
Meanwhile, the enantioselective nucleophilic addition of
arylpyrazole to 2H-azirine was also tested and afforded chiral
aziridine with good yield and enantioselectivity. Further
investigations of other asymmetric reactions involving 2H-
azirines are currently underway in our laboratory.
9
The authors are grateful for the financial support provided
by the National Natural Science Foundation of China (Nos.
21372098 and 20802025), Jilin Provincial Science and
Technology Sustentation Program (Nos. 20150203006GX,
20140307004GX, 201215033 and 20110436).
Y.-S. Fan, Y. Gao, S. Liu and S. Zhang, Org. Lett. 2014, 16
1096-1099.
,
10 For H8-BINOL derived chiral imidodiphosphoric acids, see: (a)
Y.-S. Fan, Y.-J. Jiang, D. An, D. Sha, J. C. Antilla and S. Zhang,
Org. Lett. 2014, 16, 6112-6115; (b) D. An, Z. Zhu, G. Zhang, Y.
Gao, J. Gao, X. Han, L. Zheng and S. Zhang, Tetrahedron:
Asymmetry. 2015, 26, 897-906; (c) K. Wu, M. H. Zhuo, D. Sha,
Y. S. Fan, D. An, Y. J. Jiang and S. Zhang, Chem. Commun.
2015, 51, 8054-8057; (d) M. H. Zhuo, G. F. Liu, S. L. Song, D.
An, J. Gao, L. Zheng and S. Zhang, Adv. Synth. Catal. 2016,
358, 808-815.
Notes and references
1
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Angew. Chem. 1994, 106, 625-646; (b) W. McCoull and F. A.
Davis. Synthesis. 2000, 2000, 1347-1365; (c) X. E. Hu,
11 CCDC 1486543 contains the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
Tetrahedron. 2004, 60, 2701-2743; (d) F. Palacios, A. M. O.
Retana, E. M. Marigorta and J. M. Santos, Eur. J. Org. Chem.
2001, 2001, 2401-2414.
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