Application of 7-azaisatins in enantioselective Morita-Baylis-Hillman reaction

Article abstract of DOI:10.3762/bjoc.12.33

7-Azaisatin and 7-azaoxindole skeletons are valuable building blocks in diverse biologically active substances. Here 7-azaisatins turned out to be more efficient electrophiles than the analogous isatins in the enantioselective Morita-Baylis-Hillman (MBH) reactions with maleimides using a bifunctional tertiary amine, β-isocupreidine (β-ICD), as the catalyst. This route allows a convenient approach to access multifunctional 3-hydroxy-7-aza-2-oxindoles with high enantiopurity (up to 94% ee). Other types of activated alkenes, such as acrylates and acrolein, could also be efficiently utilized.

Full text of DOI:10.3762/bjoc.12.33

Application of 7-azaisatins in enantioselective
Morita–Baylis–Hillman reaction
Qing He, Gu Zhan, Wei Du and Ying-Chun Chen*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 309–313.
Key Laboratory of Drug-Targeting and Drug Delivery System of the
Ministry of Education, West China School of Pharmacy, Sichuan
University, Chengdu 610041, China
doi:10.3762/bjoc.12.33
Received: 30 November 2015
Accepted: 10 February 2016
Published: 18 February 2016
Email:
Ying-Chun Chen* - ycchen@scu.edu.cn
This article is part of the Thematic Series "Bifunctional catalysis".
Guest Editor: D. J. Dixon
* Corresponding author
Keywords:
7-azaisatins; β-isocupreidine; bifunctional catalysis; maleimide; MBH
© 2016 He et al; licensee Beilstein-Institut.
License and terms: see end of document.
reaction
Abstract
7-Azaisatin and 7-azaoxindole skeletons are valuable building blocks in diverse biologically active substances. Here 7-azaisatins
turned out to be more efficient electrophiles than the analogous isatins in the enantioselective Morita–Baylis–Hillman (MBH) reac-
tions with maleimides using a bifunctional tertiary amine, β-isocupreidine (β-ICD), as the catalyst. This route allows a convenient
approach to access multifunctional 3-hydroxy-7-aza-2-oxindoles with high enantiopurity (up to 94% ee). Other types of activated
alkenes, such as acrylates and acrolein, could also be efficiently utilized.
Introduction
The asymmetric Morita–Baylis–Hillman (MBH) reaction is one by other groups for similar transformations with acrylates or
of the most powerful synthetic methods in organic chemistry, as acrylamides, affording the 3-hydroxyoxindole derivatives with
it directly constructs carbon–carbon bonds in an atom-economi- moderate to excellent stereocontrol [6-12]. Maleimides are also
cal manner and provides densely functionalized molecules good nucleophilic precursors in the MBH reactions and in 2013,
[1-4]. In particular, the direct formation of stereogenic quater- Chimni developed an asymmetric MBH reaction of isatins and
nary carbon centers by enantioselective MBH reactions has maleimides with excellent enantioselectivity [13]. Later, the
been a fascinating and challenging area, because the compati- same group expanded this strategy to isatin-derived ketimines
ble electrophiles are always limited to aldehydes or derivatives under the identical catalytic conditions [14]. Remarkably, these
thereof. Since the first elegant work on the enantioselective reactions were usually promoted by bifunctional catalysts, such
MBH reaction between isatins and acrolein catalyzed by β-iso- as β-ICD, whose C6’-OH group served as a H-bond donor to
cupreidine (β-ICD) was reported by the Zhou group [5], isatin facilitate the proton-transfer step and to stabilize the transition
derivatives, as highly activated electrophiles, have been utilized state in MBH reactions [11-14]. Nevertheless, all these cases
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Beilstein J. Org. Chem. 2016, 12, 309–313.
suffered from low reactivity and long reaction times were
always required (usually > 48 h) for better conversions.
7-Azaisatins bearing an additional nitrogen atom at the 7-posi-
tion of the 2-oxindole scaffold might be better electrophiles
than isatins owing to the electron-withdrawing effect of the
pyridine motif. More importantly, a number of 7-azaisatins and
7-azaoxindoles were shown to exhibit significant anticancer or
TrkA kinase inhibitory activities (Figure 1) [15-17]. This would
render their derivatives as pharmaceutically interesting com-
pounds with high potential. In addition, 7-azaisatins were also
applied in asymmetric synthesis [18,19]. Therefore, with our
Figure 1: Bioactive 7-azaisatins and their derivatives.
continuing interest in the catalytic application of bifunctional at 50 °C after 72 h (Table 1, entry 1). The reaction could be
β-ICD [20-23], herein we report the enantioselective MBH accelerated significantly by increasing the amounts of 2a
reaction of 7-azaisatins with maleimides. A series of 3-hydroxy- (Table 1, entries 2–5), and almost a quantitative yield could be
7-aza-2-oxindoles have been synthesized in good to excellent obtained after 24 h by employing 6 equiv of 2a (Table 1, entry
yields and with moderate to high enantioselectivity in a shorter 5). Other solvents, such as MeCN, THF and CHCl3, were also
time (for most cases, the reaction time is 24 h).
tested but provided inferior results (Table 1, entries 6–8). The
attempt to improve the enantioselectivity by lowering the tem-
perature failed (Table 1, entry 9), and the enantiocontrol was
Results and Discussion
The enantioselective MBH reaction was first investigated with diminished at 70 °C (Table 1, entry 10). On the other hand,
N-methyl-7-azaisatin (1a) and N-phenylmaleimide (2a) in tolu- when α-isocupreine (α-IC) [24,25] was employed as the cata-
ene catalyzed by β-ICD. To our delight, the desired product 3a lyst instead of β-ICD, unfortunately no desired product was ob-
was obtained in 45% yield and with excellent enantioselectivity tained even after 120 h (Table 1, entry 11). Finally, we com-
Table 1: Screening conditions of the enantioselective MBH reaction of 1a and 2a.
Entrya
2a (equiv)
Solvent
Temperature (°C)
Time (h)
Yield (%)b
ee (%)c
1
1.5
3.0
4.0
5.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
2.0
toluene
toluene
toluene
toluene
toluene
MeCN
THF
50
50
50
50
50
50
50
50
rt
72
72
48
48
24
24
24
96
48
24
>120
72
45
66
83
89
98
98
98
90
91
85
–
91
92
92
91
94
86
88
91
91
88
–
2
3
4
5
6
7
8
CHCl3
toluene
toluene
toluene
CHCl3
9
10
11d
12
70
50
rt
90
95
aUnless noted otherwise, reactions were performed with 1a (0.05 mmol), 2a and catalyst (0.01 mmol) in solvent (0.5 mL). bIsolated yield.
cDetermined by HPLC analysis on a chiral stationary phase. dα-IC was used as the catalyst.
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Beilstein J. Org. Chem. 2016, 12, 309–313.
pared the reaction of 7-azaisatin 1a and maleimide 2a under the cluding methoxymethyl (MOM), benzyl (Bn) and 4-chloro-
catalytic conditions developed by Chimni [13]. The reaction phenyl substituents. All of them showed a lower reactivity and
proceeded slowly, but a high yield with an outstanding ee value enantioselectivity than that of the methyl-substituted one, and
could be obtained after 72 h (Table 1, entry 12).
better results were generally obtained in a mixture of THF and
DCM (Table 2, entries 10–12). The C5-phenyl substituted or
With the optimal conditions in hand, next, the substrate scope of halogenated 7-azaisatins could be smoothly applied, although a
the MBH reaction was studied under the catalysis of β-ICD longer reaction time was required for the halogenated sub-
(Table 2). At first, a variety of N-substituted maleimides 2 were strates (Table 2, entries 13–15).
explored in the reaction with 7-azaisatin 1a in toluene. Male-
imides bearing an electron-rich N-aryl ring generally afforded To further assess the high electrophilicity of 7-azaisatins in
the corresponding 3-hydroxy-7-aza-2-oxindoles in high yields MBH reactions, more activated alkenes were explored with 1a.
and with excellent enantioselectivity (Table 2, entries 2–4) Methyl and ethyl acrylates afforded products 3p and 3q, respec-
while good results were obtained in a mixture of THF and DCM tively, with comparable results to Wu’s work [7], albeit in a
for a maleimide with an electron-deficient N-aryl group because shorter time (24 h vs 2–3 d). Notably, the MBH reaction of
of better solubility (Table 2, entry 5). In addition, N-alkylated acrolein and 7-azaisatin 1a was carried out under the same
maleimides provided the desired products in good yields conditions as described in Zhou’s work [5], providing the
(Table 2, entries 6–9), while only moderate enantioselectivity highly enantio-enriched product 3r in an excellent yield after
was observed for products 3h and 3i (Table 2, entries 8 and 9). 1.5 h. The reaction with 1a was much more efficient, as it took
7-Azaisatins with different N-protecting groups were also 4 d to afford the product 5 in a high yield by using N-methyl-
applied to the MBH reaction with N-phenylmaleimide (2a), in- isatin (4) as the substrate (Scheme 1).
Table 2: Substrate scope of the enantioselective MBH reaction.
Entrya
R1
R2
R
Time (h)
Yield (%)b
ee (%)c
1
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Cl
Br
1a, Me
1a,Me
2a, Ph
24
24
24
24
24
24
24
24
24
24
48
96
24
48
48
3a, 98
3b, 87
3c, 88
3e, 90
3d, 87
3f, 84
3g, 86
3h, 86
3i, 84
94
90
92
79
92
89
89
66
61
91
87
71
92
85
88
2
2b, 4-MePh
2c, 4-MeOPh
2e, 2,4,6-MePh
2d, 4-ClPh
2f, Me
3
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1a, Me
1b, MOM
1c, Bn
4
5d
6
7
2g, Bn
8
2h, n-Bu
2i, cyclohexyl
2a, Ph
9
10d
11d
12d
13d
14
15
3j, 92
2a, Ph
3k, 93
3l, 37
1d, 4-ClPh
1e, Me
1f, Me
2a, Ph
2a, Ph
3m, 88
3n, 81
3o, 82
2a, Ph
1g, Me
2a, Ph
aUnless otherwise noted, all reactions were performed with 1 (0.1 mmol), 2 (0.6 mmol) and β-ICD (0.02 mmol) in toluene (1.0 mL) at 50 °C. bIsolated
yield. cDetermined by HPLC analysis on a chiral stationary phase. The absolute configuration of the chiral products was assigned by analogy to
Chimni’s work [13]. dIn a mixture of THF and DCM (0.5/0.5 mL).
311

Beilstein J. Org. Chem. 2016, 12, 309–313.
Scheme 1: Further exploration with 7-azaisatin 1a and comparison with the previous work by Zhou [5].
Conclusion
Acknowledgements
In summary, we have developed an efficient and enantioselec- We are grateful for financial support from the NSFC
tive Morita–Baylis–Hillman reaction between 7-azaisatins and (21125206, 21572135, and 21321061).
maleimides and other activated alkenes in the presence of the
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