An enantioselective aza-Friedel-Crafts reaction of 5-aminoisoxazoles with isatin-derived: N -Boc ketimines

Article abstract of DOI:10.1039/d1ob00374g

By employing a chiral phosphoric acid as a catalyst, an enantioselective aza-Friedel-Crafts reaction of 5-aminoisoxazoles with isatin-derived N-Boc ketimines was realized. The reaction provided a wide variety of novel 3-isoxazole 3-amino-oxindoles with good yields (up to 99%) and moderate to good enantioselectivities (up to 99%). The absolute configuration of one product was assigned by X-ray crystal structural analysis and a plausible reaction mechanism was proposed. In addition, a scale-up reaction was performed successfully. Finally, one product was subjected to Suzuki-Miyaura coupling with phenylboronic acid to afford the product in a moderate yield without erosion of the enantioselectivity. This journal is

Full text of DOI:10.1039/d1ob00374g

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An enantioselective aza-Friedel–Crafts reaction of
5-aminoisoxazoles with isatin-derived N-Boc
ketimines†
Cite this: Org. Biomol. Chem., 2021,
19, 3820
Received 26th February 2021,
Accepted 29th March 2021
a,b
Hui Liu,a,b,c Yingkun Yan,a,b,c Min Lia,b,c and Xiaomei Zhang
*
DOI: 10.1039/d1ob00374g
rsc.li/obc
By employing a chiral phosphoric acid as a catalyst, an enantio- ketimines5 have been well developed to deliver various highly
selective aza-Friedel–Crafts reaction of 5-aminoisoxazoles with enantio-enriched 3-aryl 3-amino-oxindoles.
isatin-derived N-Boc ketimines was realized. The reaction provided
Isoxazole derivatives exhibit numerous biological activities,
a wide variety of novel 3-isoxazole 3-amino-oxindoles with good including insecticidal, antibacterial, antibiotic, antiviral, anti-
yields (up to 99%) and moderate to good enantioselectivities (up tumour, antifungal, etc.6 Owing to the significance of isoxa-
to 99%). The absolute configuration of one product was assigned zoles in drug discovery, the construction of novel isoxazole
by X-ray crystal structural analysis and a plausible reaction mecha- derivatives is of great importance.
nism was proposed. In addition, a scale-up reaction was performed
Recently, we disclosed a highly enantioselective dearoma-
successfully. Finally, one product was subjected to Suzuki–Miyaura tive [3 + 2] annulation of 5-aminoisoxazoles with quinone
coupling with phenylboronic acid to afford the product in a mod- monoimines.7 Owing to the good nucleophilicity of 5-amino-
erate yield without erosion of the enantioselectivity.
isoxazoles, we envisioned that they can also be used in asym-
metric Friedel–Crafts reactions.8 In continuation of the
research on asymmetric transformations of 5-aminoisoxazoles,
herein we present the enantioselective aza-Friedel–Crafts reac-
tion of 5-aminoisoxazoles with isatin-derived ketimines. In the
presence of a chiral phosphoric acid catalyst, the reactions pro-
ceeded smoothly to generate a wide range of novel 3-isoxazole-
3-amino-oxindoles with good yields (up to 99%) and moderate
to good enantioselectivities (up to 99%). The absolute con-
figuration of one product was determined by X-ray crystal
structural analysis. Accordingly, a plausible reaction mecha-
nism was proposed. In addition, a scale-up reaction was per-
formed using only 0.5 mol% of the catalyst and a good result
was achieved. Furthermore, one product was used in Suzuki–
Miyaura coupling with phenylboronic acid to afford the
product in a moderate yield with excellent enantioselectivity.
Introduction
Chiral 3,3-disubstituted oxindoles are important structural
motifs in a large number of natural products and pharmaceuti-
cals. Among them, chiral 3-substituted 3-amino-oxindoles rep-
resent pharmaceutically interesting molecules.1 Consequently,
the asymmetric synthesis of chiral 3-substituted 3-amino-oxi-
ndoles has attracted much attention and many efficient strat-
egies for the construction of novel chiral 3-substituted
3-amino-oxindoles have been established.2 Among these strat-
egies, asymmetric reactions of isatin-derived ketimines are
highly efficient and straightforward in the preparation of
diverse chiral 3-substituted 3-amino-oxindoles.3–5 In particu-
lar, the asymmetric aza-Friedel–Crafts reaction of isatin-
derived ketimines with electron-rich arenes4 and asymmetric
addition of arylboronic acids or arylboroxines to isatin-derived
Results and discussion
First, various chiral phosphoric acids were evaluated in the
Friedel–Crafts reaction of N-ethyl-3-phenylisoxazol-5-amine 1a
with isatin-derived tert-butyl(1-ethyl-2-oxoindolin-3-ylidene)car-
bamate 2a in dichloromethane at 0 °C for 2 hours. As can be
seen in Scheme 1, all of the chiral phosphoric acids promoted
the reaction smoothly to provide 3-isoxazole-3-amino-oxindole
3aa in quantitative yields and PA4, which bears a 2-naphthyl
group in the 3,3′ position of BINOL, gave the product 3aa with
aAsymmetric Synthesis and Chiraltechnology Key Laboratory of Sichuan Province,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
China. E-mail: xmzhang@cioc.ac.cn; Fax: (+86)28-85257883; Tel: (+86)28-85257883
bDepartment of Chemistry, Xihua University, China
cGraduate School of Chinese Academy of Sciences, Beijing, China
†Electronic supplementary information (ESI) available. CCDC 2064372 and
2064373. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00374g
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Scheme 1 Evaluation of chiral phosphoric acids. Unless otherwise specified, the reactions were carried out with 0.10 mmol of 1a, 0.15 mmol of 2a
and 10 mol% of PA in 1 mL of dichloromethane at 0 °C for 2 hours. Yields refer to isolated product based on 1a. Enantiomeric excess was determined
by HPLC analysis on a chiral stationary phase.
the highest ee value of 89%. Thus PA4 was determined as the The reaction in acetonitrile delivered a much lower ee value
optimal catalyst and used in the following investigations.
(Table 1, entry 6). Therefore THF was determined as the most
Subsequently, the other conditions were optimized. The favourable solvent for the reaction. When we tried to lower the
results are presented in Table 1. First, various solvents were catalyst loading to 5 mol%, the enantioselectivity remained the
evaluated. Similar outcomes were observed in reactions in di- same (Table 1, entry 7). Further lowering the catalyst loading
chloromethane, chloroform and toluene (Table 1, entries 1–3). to 2 mol% led to a little decrease in the ee value (Table 1, entry
To our delight, MTBE and THF exhibited quantitative yields as 8). When the reaction was conducted at −10 °C for 12 hours, a
well as excellent enantioselectivities (Table 1, entries 4 and 5). little increase in enantioselectivity was observed (Table 1, entry
9). Further lowering the temperature to −30 °C led to an excel-
lent ee value without a decrease in the yield (Table 1, entry 10).
Having established the optimal conditions, the scope of the
enantioselective aza-Friedel–Crafts reaction of 5-aminoisoxa-
Table 1 Optimization of the conditionsa
zoles with isatin-derived N-Boc ketimines was investigated.
The results are presented in Table 2. First, various 5-amino-
isoxazoles were tested in the reaction with isatin-derived N-Boc
ketimine 2a. Generally, 5-aminoisoxazoles with different 3-aryl
substituents were tolerable in the reaction to afford the corres-
ponding 3-isoxazole-3-amino-oxindoles in quantitative yields
with high ee values (Table 2, entries 1–8). However, only mod-
Entry
Solvent
T (°C)
t (h)
Yieldb (%)
eec (%)
erate enantioselectivities were observed with two 3-alkyl-5-
aminoisoxazoles (Table 2, entries 9 and 10). Some 3-phenyl-
isoxazol-5-amines with different N-substituents underwent the
reaction with 2a to give the products with quantitative yields
and good enantioselectivities (Table 2, entries 11–13), in which
N-benzyl substrate 1l exhibited lower enantioselectivity
(Table 2, entry 12). Afterwards, various isatin-derived N-Boc
ketimines were also subjected to the reaction with N-ethyl-3-
phenylisoxazol-5-amine 1a. Ketimines with various electron-
donating and electron-withdrawing groups on the benzene
part were generally tolerated in the reaction and afforded the
corresponding 3-isoxazole 3-amino-oxindoles in quantitative
yields with good ee values (Table 2, entries 14–26).
1
2
3
4
5
6
CH2Cl2
CHCl3
Toluene
MTBE
THF
CH3CN
THF
THF
THF
THF
0
0
0
0
0
0
0
0
2
2
6
6
6
6
12
12
12
12
99
99
99
99
99
99
93
93
95
99
89
89
88
96
96
50
96
94
97
98
7d
8e
9d
10d
−10
−30
a Unless otherwise specified, the reactions were carried out with
0.10 mmol of 1a, 0.15 mmol of 2a and 10 mol% of PA4 in 1 mL of the
solvent. b Yield of the isolated product based on 1a. c Enantiomeric
excess was determined by HPLC analysis on a chiral stationary phase.
d 5 mol% of PA4 was used. e 2 mol% of PA4 was used.
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Table 2 Substrate scope of the enantioselective aza-F–C reaction of 5-aminoisoxazoles 1 with isatin-derived N-Boc ketimines 2a
Entry
3
t (h)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
3aa (R5 = H)
12
12
12
12
12
12
99
98
99
97
95
99
98
96
98
99
97
91
3ba (R5 = 4-F)
3ca (R5 = 4-Cl)
3da (R5 = 3-Cl)
3ea (R5 = 4-Br)
3fa (R5 = 4-OMe)
7
8
3ga (X = O)
3ha (X = S)
12
12
99
99
95
96
9
10
3ia (R1 = i-Pr)
3ja (R1 = Me)
60
12
99
99
53
69
11
12
13
3ka (R2 = Me)
3la (R2 = Bn)
3ma (R2 = allyl)
12
12
12
99
99
99
98
88
96
14
15
16
17
18
3ab (R3 = Cl)
3ac (R3 = Br)
3ad (R3 = Me)
3ae (R3 = OMe)
3af (R3 = NO2)
24
12
12
12
12
92
99
88
99
94
95
97
98
96
92
19
20
21
3ag (R3 = F)
3ah (R3 = Cl)
3ai (R3 = Br)
12
12
12
98
99
99
98
94
96
22
23
24
25
3aj (R3 = Cl)
3ak (R3 = Br)
3al (R3 = Me)
3am (R3 = CF3)
12
12
12
12
99
99
95
98
92
97
98
88
26
3an
12
99
96
27
28
29
30
3ao (R4 = Me)
3ap (R4 = Bn)
3aq (R4 = Boc)
3ar (R4 = H)
12
12
40
24
99
99
94
84
96
98
92
83
a Unless otherwise specified, the reactions were carried out with 0.10 mmol of 1, 0.15 mmol of 2, and 5 mol% of PA4 in 1 mL of THF at −30 °C.
b Yield of the isolated product based on 1. c Enantiomeric excess was determined by HPLC analysis on a chiral stationary phase. d The absolute
configuration of 3ca was determined by X-ray analysis and the absolute configurations of the other products were assigned by analogy.
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Fig. 1 X-ray crystal structure of (S)-3ca.
Furthermore, some ketimines with different 1-substituents
were also used in the reaction with 1a. Good results were
obtained with 1-methyl, 1-benzyl and N-Boc ketimines
(Table 2, entries 27–29). However, the reaction of N–H keti-
mine 2r with 1a delivered an obviously lower yield and lower
enantioselectivity (Table 2, entry 30).
Scheme 3 Scale-up synthesis of 3aa and Suzuki–Miyaura cross coup-
ling of 3ac with phenylboronic acid.
The absolute configuration of 3ca was determined as (S) by
X-ray crystal structural analysis9 (Fig. 1). Consequently, the
other products can be assigned absolute configurations by
analogy.
coupling with phenylboronic acid to afford compound 4 in a
moderate yield without erosion of the ee value (Scheme 3).
Based on the absolute configuration of product 3ca, a
plausible reaction mechanism was proposed. As outlined in
Scheme 2, first, bifunctional phosphoric acid activated both
isoxazole 1c and isatin-derived N-Boc ketimine 2a. In addition,
maybe the arene–arene interaction between the aromatic
systems of the two substrates could stabilize the transition
state. Thus isoxazole 1c attacked ketimine 2a from the Si-face
to generate the intermediate (S)-A which underwent aromatiza-
tion immediately to give 3-isoxazole 3-amino-oxindole (S)-3ca.
To illustrate the synthetic utility of this methodology, in the
presence of 0.5 mol% of PA4, a scale-up enantioselective F–C
reaction of 1a with 2a was performed. The reaction provided
(S)-3aa with an excellent yield and enantioselectivity.
Moreover, product 3ac was subjected to Suzuki–Miyaura cross
Conclusions
In conclusion, we have developed an efficient enantioselective
Friedel–Crafts reaction of 5-aminoisoxazoles with isatin-
derived N-Boc ketimines catalyzed by a chiral phosphoric acid.
The reactions provided novel 3-isoxazole 3-amino-oxindoles
with good yields (up to 99%) and moderate to good enantio-
selectivities (up to 99%). This transformation has a broad sub-
strate scope and the reaction could be scaled up successfully.
The absolute configuration of one product was determined as
S by X-ray crystal structural analysis and a plausible reaction
mechanism was proposed. Moreover, Suzuki–Miyaura coupling
of one product with phenylboronic acid was performed and
the phenylated product was obtained in a moderate yield
without loss of the enantioselectivity.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21672208) and the start-
up fund for recruited talent of Xihua University (Z201098).
Notes and references
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Scheme 2 Plausible reaction mechanism.
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