Enantioselective 1,3-dipolar cycloaddition of methyleneindolinones and N,N′-cyclic azomethine imines

Article abstract of DOI:10.1039/c3cc41507d

A new chiral bis-phosphoric acid 3l bearing triple axial chirality was synthesized and applied to effect a highly enantioselective 1,3-dipolar cycloaddition reaction between N,N′-azomethine imines and methyleneindolinones for the creation of chiral spiro[pyrazolidin-3,3′- oxindoles] in excellent yields and selectivities. MS experiment and DFT calculation studies prompted us to propose a dual H-bond donor activation mode of bis-phosphoric acid which is different from the traditional phosphoric acid catalysis.

Full text of DOI:10.1039/c3cc41507d

Chemical Communications
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Volume 49 | Number 60 | 4 August 2013 | Pages 6691–6814
ISSN 1359-7345
COMMUNICATION
Liang Hong, Rui Wang et al.
Enantioselective 1,3-dipolar cycloaddition of methyleneindolinones
and N,N′-cyclic azomethine imines
1359-7345(2013)49:60;1-Z

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Enantioselective 1,3-dipolar cycloaddition of
methyleneindolinones and N,N0-cyclic azomethine
imines†
Cite this: Chem. Commun., 2013,
49, 6713
Received 27th February 2013,
Accepted 15th April 2013
a
a
Liang Hong,*a Ming Kai,z Chongyang Wu,z Wangsheng Sun,a Gongming Zhu,a
Guofeng Li,a Xiaojun Yaoa and Rui Wang*ab
DOI: 10.1039/c3cc41507d
www.rsc.org/chemcomm
A new chiral bis-phosphoric acid 3l bearing triple axial chirality both pyrazolidines and spirooxindoles are privileged structural
was synthesized and applied to effect a highly enantioselective 1,3- units in biologically and pharmaceutically active compounds,8
dipolar cycloaddition reaction between N,N0-azomethine imines and the current methodology provides a facile access to novel
methyleneindolinones for the creation of chiral spiro[pyrazolidin-3,30- scaffolds that would greatly benefit drug discovery research
oxindoles] in excellent yields and selectivities. MS experiment and DFT (Fig. 1).
calculation studies prompted us to propose a dual H-bond donor
In view of the fact that binaphthol(BINOL)-derived chiral
activation mode of bis-phosphoric acid which is different from the phosphoric acids have been successfully applied in many
traditional phosphoric acid catalysis.
asymmetric reactions,9–11 we initially screened a representative
range of phosphoric acids derived from the privileged BINOL
1,3-Dipolar cycloadditions (1,3-DCs) are powerful tools for architecture and conditions for the reaction (Table 1, entries 1–7
constructing a variety of five-membered heterocycles in a con- and more details are provided in the ESI†). Unfortunately, none of
vergent manner from relatively simple precursors.1 N,N0-Cyclic these well-investigated catalysts provided a positive effect in terms
azomethine imines are readily accessible, stable compounds2 of either reaction conversion or selectivity. The bis-phosphoric acid
that have been employed as efficient 1,3-dipoles in 1,3-DCs for 3h, which gave a high selectivity in the 1,3-dipolar cycloaddition
synthesis of pyrazolidines.3–5 While major advances have been of azomethine ylides,10 was also examined, and showed slight
made in the area of racemic3 or asymmetric metal-catalyzed4 improvement in efficiency (Table 1, entry 8).
reactions over the past decade, the benign and environmentally
These disappointing results obliged us to explore a new
friendly asymmetric organocatalytic 1,3-DCs involving N,N0-cyclic catalyst to achieve our goal. We realized that in this 1,3-DC
azomethine imines have met with less success.5 Nevertheless, reaction both substrates are H-bond receptors, which cannot be
the enantioselective organocatalytic 1,3-DCs using N,N0-cyclic efficiently activated by a single traditional mono-phosphoric acid,
azomethine imines are still underdeveloped and the exploration as it can only supply one H-bond donor.9 We thus envisioned that
of a complementary method is highly desirable.
We herein designed a 1,3-DC of readily available methyl-
eneindolinones 16,7 and N,N0-cyclic azomethine imines 2 to obtain
enantiomerically pure spiro pyrazolidine oxindoles, as part of our
research program toward the development of enantioselective
construction of spiro cyclic oxindole scaffolds.7 Given the fact that
a Key Laboratory of Preclinical Study for New Drugs of Gansu Province,
School of Basic Medical Sciences, Institute of Biochemistry and Molecular Biology,
School of Life Sciences, Lanzhou University, Lanzhou, 730000, P.R. China.
E-mail: hongl@lzu.edu.cn, wangrui@lzu.edu.cn; Fax: +86-931-891-2567
b State Key Laboratory of Chiroscience and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Kowloon,
Hong Kong. E-mail: bcrwang@polyu.edu.hk
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data of compounds 3l, 4–6, crystallographic details,
details of MS and DFT calculation experiments and copies of HPLC and NMR.
CCDC 904719. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc41507d
Fig. 1 Structures of catalysts studied.
‡ These authors contributed equally to this work.
c
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Table 1 Catalyst screening and evolutiona
Table 2 Scope of the reactiona
Entry
Catalyst Conversionb (%) dr (4aa : 4aa0)b eec (%) (4aa)
Entry 1, R1, R2
2, R3
4, yieldc (%) drb
eed (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
35
42
30
29
32
30
28
42
89
96
68
>99
>99
>99 (93)
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
2 : 1
1 : 1
16 : 1
16 : 1
16 : 1
10
17
rac
rac
5
11
11
39
74
89
5
1
2
3
4
5
6
7
8
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1a, H, Et
1b, 5-Cl, Et
1c, 5-Br, Et
1d, 5-Me, Et
2a, Ph
4aa, 93
4ab, 89
4ac, 92
4ad, 88
16 : 1
15 : 1
20 : 1
10 : 1
10 : 1
98
97
96
98
93
2b, 2-ClC6H4
2c, 2-BrC6H4
2d, 3-BrC6H4
2e, 3-MeOC6H4 4ae, 82
2f, 4-FC6H4
2g, 4-ClC6H4
2h, 4-BrC6H4
2i, 4-MeC6H4
2j, 4-MeOC6H4 4aj, 86
2k, 2-Furyl
2a, Ph
4af, 92
4ag, 93
4ah, 94
4ai, 91
16 : 1 >99
17 : 1 97
20 : 1 >99
20 : 1
14 : 1
14 : 1
7 : 1
6 : 1
16 : 1
9 : 1
9d
10d
11d
12d
13d,e
9
95
94
91
96
98
96
99
97
3j
3k
3l
10
11e
12
13
14
4ak, 68
4ba, 84
4ca, 84
4da, 93
4ea, 87
4fa, 81
4ga, 94
4ha, 92
92
94
98
3l
14d,e,f 3l
2a, Ph
2a, Ph
a
Unless otherwise specified, the reaction was carried out with 1a 15
(0.05 mmol), 2a (0.05 mmol), catalyst 3 (0.005 mmol) in CH2Cl2 16
1e, 5-MeO, Et 2a, Ph
1f, 6-Br, Et
1g, H, Me
1h, H, tBu
2a, Ph
2a, Ph
2a, Ph
6 : 1
18 : 1 >99
14 : 1 98
(1.0 mL) at room temperature for 72 h. Determined using 1H NMR 17
b
c
spectroscopy of the crude mixture. Determined using chiral HPLC on 18
a Chiralcel IA column. The reaction was carried out for 4 h. The
d
e
a
Unless otherwise specified, the reaction was carried out with 1
reaction was carried out on the 0.1 M scale with a 1/2 = 1 : 1.3 ratio.
f
(0.10 mmol), 2 (0.13 mmol), catalyst 3l (0.01 mmol) in CH2Cl2
The reaction was performed at 15 1C, isolated yield is given in the
(1.0 mL) at 15 1C for 4 h. Determined using 1H NMR spectroscopy
b
parentheses.
c
d
of the crude mixture. Isolated yield. For analysis of the ee values of
the products, see the ESI. The reaction was carried out for 12 h.
e
installation of bis-phosphoric acid on one BINOL backbone,
providing two H-bond donors, might lead to new reactivity and
selectivity (Fig. 2).10,11 We therefore synthesized chiral bis-
phosphoric acids 3i–3k from chiral BINOL-derived tetraphenol
and bis-phosphoric acid 3l from the chiral BINOL-derived
tetranaphthol and evaluated their catalytic ability in the model
reaction (Table 1, entries 9–14). To our delight, obvious improve-
ments in reaction conversion (96% conv.) and enantioselectivity
(89% ee) were observed when 3j was used for much shorter reaction
time (Table 1, entry 10). However, the diastereoselectivity was far
away from satisfaction (2 : 1 dr). When 3l was used, the diastereo-
selectivity was greatly improved to 16 : 1 and the combined enantio-
selectivity was the highest obtained thus far in our investigation
(92% ee) (Table 1, entry 12). The influence of substrate concentration
and reaction temperature was investigated next. When conducted in
a 0.1 M at 15 1C, the reaction gave the best results, with 93% isolated
yield, 16 : 1 dr and 98% ee (Table 1, entries 13 and 14).
yields, with good to excellent diastereoselectivities and excellent
enantioselectivities (Table 2). For the reaction with methyleneindo-
linone 1a, a wide range of N,N0-cyclic azomethine imines 2a–2k
were examined. It appeared that the positions and electronic
properties of substituents on aromatic rings had a limited effect
on the efficiency of this process for the aryl-substituted N,N0-cyclic
azomethine imines. The products were obtained in high yields with
excellent diastereoselectivities and enantioselectivities (82–94%
yield, 10 : 1–>20 : 1 dr and 93–>99% ee) (Table 2, entries 1–10).
Particularly, the hetero aryl-substituted azomethine imine 2k could
also participate in the reaction in excellent diastereoselectivities
and enantioselectivities, although a longer reaction time was
required (68% yield, 14 : 1 dr and 91% ee) (Table 2, entry 11).12
Various methyleneindolinones 1 were also tested for the reaction,
and minimal impact on efficiencies, enantioselectivities and dia-
stereoselectivities was observed, regardless of the electronic nature,
bulkiness or positions of the substitution patterns on the methyl-
eneindolinones 1 (81–93% yield, 6 : 1–18 : 1 dr and 96–>99% ee)
(Table 2, entries 12–18).13 The absolute configuration of the
stereogenic centers of compound 4ad was unambiguously
determined by X-ray crystallographic analysis.14
With the optimal reaction conditions established, the scope
of substrates for the asymmetric chiral bis-phosphoric acid 3l
catalyzed 1,3-DC of methyleneindolinones 1 and N,N0-cyclic
azomethine imines 2 was then examined. In general, the
reaction proceeded well to afford the desired products in high
To shed light on the mechanism of this asymmetric 1,3-DC
reaction, the MS and DFT calculation experiments were per-
formed (for details, see the ESI†). The results revealed that the
best transition structure is TS-1 (Fig. 3), wherein both the
methyleneindolinones and azomethine imines are hydrogen
bonded with the OH groups of both phosphoric acid moieties.
The electron deficient dipolarophile methyleneindolinone is
activated by H-bonds with one of the phosphoric acid moieties
and stabilized forward. The 1,3-dipoles may locate on backward
Fig. 2 Activation mode of phosphoric acid.
c
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Fig. 3 Calculated transition state.
by the other OH group of the phosphoric acid moiety. Thus the
two substrates are simultaneously activated by the two OH
groups of this bis-phosphoric acid, which cannot be accessible
by the traditional mono-phosphoric acid catalysts and located
at a proper distance, and the 1,3-dipole attacks from backside
to form N1–C5 and C3–C4 bonds.
In summary, we have developed a chiral bis-phosphoric acid
bearing triple axial chirality and applied it in the asymmetric
1,3-DC of methyleneindolinones 1 and N,N0-cyclic azomethine
imines
2 for the construction of enantiomerically pure
spiro[pyrazolidin-3,30-oxindoles] for the first time. The activation
mode proposed by us according to experimental and calculation
results may open unprecedented opportunities for phosphoric
acid catalyzed asymmetric reactions. The application of this
novel catalyst in other asymmetric transformations is underway
in our laboratory.
We gratefully acknowledge the financial support from NSFC
(20932003, 91213302, 21272102, 21202071), the National S&T
Major Project of China (2012ZX09504001-003) and computing
resources of Gansu Supercomputing Center, Cold and Arid
Environment and Engineering Research Institute of Chinese
Academy of Sciences.
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 6713--6715 6715