Enantioselective Synthesis of 2, 2, 3-Trisubstituted Indolines via

Letter Cite This: Org. Lett. 2018, 20, 4536−4539

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Enantioselective Synthesis of 2,2,3-Trisubstituted Indolines via Bimetallic Relay Catalysis of α‑Diazoketones with Enones Jian Yang, Chaoqi Ke, Dong Zhang, Xiaohua Liu,* and Xiaoming Feng* Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China

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S Supporting Information *

ABSTRACT: An efficient asymmetric intramolecular trapping of ammonium ylides of α-diazoketones with enones to synthesize indoline derivatives was realized. A Rh(II)/chiral N,N′-dioxide−Sc(III) complex bimetallic relay catalytic system was established. A series of optically active 2,2,3-trisubstituted indolines were obtained in high yields (up to 99%), good enantioselectivities (up to 99% ee), and excellent diastereoselectivities (up to >19:1 dr) under mild reaction conditions.

C

Scheme 1. Intramolecular Trapping Ammonium Ylides with Enones

hiral indoline skeletons are widespread in a number of natural products and biologically active compounds.1 The development of a novel protocol for the efficient synthesis of enantiomerically enriched indoline derivatives remains a hot topic in synthetic organic chemistry. Significant progress has been made through several strategies, such as kinetic resolution of 2-substituted indoline,2 intramolecular coupling,3 hydrogenation of substituted indole,4 and miscellaneous transformations of indole.5 Nevertheless, highly diastereo- and enantioselective construction of 2,2,3-trisubstituted indoline derivatives is rare. Asymmetric catalytic cascade reactions have become a powerful tool to rapidly and efficiently construct complicated molecules from simple reactants.6 To realize cascade transformations, cooperative catalytic systems, including bimetallic catalysis, metallic-organocatalysis, and organo-organocatalysis, have been proven to be useful and efficient strategies. Each catalyst component performs its own functions separately and consonantly in each reaction step.7 The former two strategies have been successfully applied in several asymmetric cascade reactions via trapping of the active onium ylides and zwitterions formed in situ from the reaction of α-diazoester with a nucleophile.8 For example, Hu’s group has utilized the intramolecular trapping of ammonium ylides with carbonyl compounds or enones for diastereoselective synthesis of trisubstituted indolines (Scheme 1, eq 1). Nevertheless, it seems hard to achieve satisfactory reactivity and enantioselectivity with combined common Rh(II)/chiral Brønsted acid after much effort.9 Our group has engaged in developing asymmetric transformations catalyzed by chiral N,N′-dioxide−metal complexes.10 Enones can undergo conjugate addition with a variety of nucleophiles in the presence of chiral N,N′-dioxide−metal complexes.11 We became interested in developing efficient bimetallic catalytic systems, which combine a transition metal salt with a chiral Lewis acid complex,12 to realize the asymmetric cascade reaction in Scheme 1, eq 1 for the © 2018 American Chemical Society

synthesis of trisubstituted indoline. However, previous screening of the cocatalysts9b showed that the general Lewis acids, such as ZnCl2, Mg(OTf)2, and Sc(OTf)3, could not yield the desired product. To realize the enantioselective version of this cascade reaction via chiral Lewis acid cooperative catalysis, two methods are available. One includes using a stronger chiral Lewis acid, and the other one, increasing the nucleophilicity of the ammonium ylides. We plan to use α-diazoketone instead of α-diazoester, which bears a stronger electron-withdrawing carbonyl group, benefiting the formation of a free ylide or enol intermediate13 with less steric hindrance and stronger nucleophilicity (Scheme 1, eq 2). In this context, we reported our efforts in developing highly efficient Rh(II) and chiral N,N′-dioxide−Sc(III) complex cocatalyzed intramolecular trapping of ammonium ylides of α-diazoketones with enones. Received: June 13, 2018 Published: July 19, 2018 4536

DOI: 10.1021/acs.orglett.8b01744 Org. Lett. 2018, 20, 4536−4539

Letter

Organic Letters The corresponding optically active 2,2,3-trisubstituted indolines were obtained in high yields, good enantioselectivities, and excellent diastereoselectivities under mild reaction conditions. We initially chose 2-aminophenyl-substituted enone 1a and 1-diazo-1-phenylpropan-2-one 2a as the model substrates to optimize the reaction conditions (Table 1). However, we

L-PrPr3 with a three-carbon linkage (Table 1, entry 8 vs entry 7), affording the indoline 3a in 84% ee. Furthermore, the addition of 5 Å molecular sieves and adjustment of the ratio of Sc(OTf)3 to L2-PrPr3 (1:1.2) resulted in the optimal outcome, and the product 3a could be obtained in 88% yield, 90% ee, and >19:1 dr (Table 1, entries 9 and 10). With the optimized reaction conditions in hand, we turned to evaluating the substrate scope of this protocol. A variety of 2-aminophenyl-substituted enones 1 were investigated. As shown in Table 2, enones 1 with different substituents on the phenyl ring of R1 could be smoothly converted to the corresponding products. The electron-donating substituted enones 1f−1i gave slightly higher enantioselectivity than the electron-withdrawing substituted enones 1b−1e. The desired indolines 3b−3i were generated in 72−94% yields with 81−

Table 1. Optimization of the Reaction Conditionsa

Table 2. Substrates Scope of 2-Aminophenyl-Substituted Enonesa entry

metal salt

ligand

yieldb (%)

drc

eed (%)

1 2 3 4 5 6 7 8 9e 10f

− Ni(OTf)2 Zn(OTf)2 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3

− L-PrPr2 L-PrPr2 L-PrPr2 L-RaPr2 L-PiPr2 L-PrPr3 L2-PrPr3 L2-PrPr3 L2-PrPr3

trace 69 34 85 60 75 87 90 89 88

− >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1

− 20 3 60 55 −7 83 84 88 90

a

Unless otherwise noted, all reactions were performed by addition of 2a (0.2 mmol) in THF (0.5 mL) via a syringe to the mixture of 1a (0.1 mmol), Rh2(OAc)4 (1 mol %), and metal salt/ligand (1:1, 10 mol %) in THF (1.0 mL) at 25 °C for 10 min. After completion of the addition, the reaction mixture was stirred at 25 °C for 2 h. bIsolated yield. cDetermined by chiral HPLC and 1H NMR. dDetermined by chiral HPLC. e5 Å MS (20 mg) was added. fSc(OTf)3/L2-PrPr3 (1:1.2, 10 mol %).

found that the major product was the N−H insertion product 5a and only a trace amount of the target indoline product 3a was detected in the presence of Rh2(OAc)4 without a Lewis acid cocatalyst. It indicates that Rh2(OAc)4 could slightly induce the unasymmetric nucleophilic addition step (Table1, entry 1). Next, different metal salts coordinating with L-proline derived ligand L-PrPr2 were investigated. Several metal salts (see the Supporting Information for details), such as Ni(OTf)2 and Zn(OTf)2, could promote the reaction in moderate yield with excellent diastereoselectivity, but the enantioselectivity was poor (Table 1, entries 2 and 3). The desired product 3a was obtained in 85% yield with 60% ee and >19:1 dr when Sc(OTf)3/L-PrPr2 was used (Table 1, entry 4). Next, we used Sc(OTf)3 to explore different chiral N,N′-dioxide ligands. A survey of the amino acid backbone showed that L-proline derived L-PrPr2 was more competent than L-ramipril derived L-RaPr2 and L-pipecolic acid derived L-PiPr2 in terms of enantioselectivity and reactivity (Table 1, entry 4 vs entries 5 and 6). To our delight, the ligand L-PrPr3 with more steric hindrances significantly benefited the improvement of the enantioselectivity (Table 1, entry 7 vs entry 4). Ligand L2PrPr3, which has a two-carbon linkage was slightly superior to

a

Sc(OTf)3/L2-PrPr3 (1:1.2, 10 mol %), Rh2(OAc)4 (1 mol %), 5 Å MS (20 mg), 2 (0.2 mmol), and 1 (0.1 mmol) in THF (1.5 mL) at 25 °C for 2 h. bIsolated yield. cDetermined by chiral HPLC analysis. All dr value were up to >19:1 detected by 1H NMR.

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DOI: 10.1021/acs.orglett.8b01744 Org. Lett. 2018, 20, 4536−4539

Letter

Organic Letters

observation implied that this reaction did not conduct a sequential N−H insertion/Michael addition pathway.14 The generation of an ammonium ylide intermediate in situ is much preferable for the intramolecular nucleophilic addition. When we subjected methyl 2-diazo-2-phenylacetate to the standard reaction conditions instead of α-diazoketone 2a, the corresponding indoline product 6a was isolated in 40% yield with 11% ee (Scheme 2). It implied that the coordination of

91% ee (Table 2, entries 1−9). Heteroaromatic substituted 1j and 1k, as well as ring-condensed 1l and 1m, were also suitable substrates, affording the related products 3j−3m in good results (81−94% yields, 77−92% ee) (Table 2, entries 10−13). It was noteworthy that enones 1n−1p bearing alkyl acyl substituents also successfully underwent the reaction to provide the desired products 3n−3p, albeit the enantioselectivity decreased slightly (76−99% yields, 73−82% ee) (Table 2, entries 14−16). Enones 1q−1v with a substituted β-aryl group were all tolerated well, resulting in 66−98% yields and 73−95% ee (Table 2, entries 17−22). To our delight, 1indanone derived substrate 1w could undergo this reaction smoothly and afforded the desired product 3w containing three adjacent stereocenters with excellent results (81% yield, 95% ee) (Table 2, entry 23). It was worth noting that only one diastereomer was detected in these cases. The absolute configuration of the product 3r was determined to be (2S,3R) according to X-ray crystal structural analysis (CCDC 1844834). Next, we examined the reaction of 2-aminophenylsubstituted enone 1t with various α-diazoketones 2, with results listed in Table 3. It was found that the electronic nature

Scheme 2. Control Experiment

N,N′-dioxide L2-PrPr3 with Sc(OTf)3 increased the Lewis acidity of the cocatalyst; thus, the reaction could be performed smoothly. The decreased enantioselectivity might result from the formation of a Rh(II)-bonded enolate intermediate (Scheme 1, TS A), which brings steric hindrance and reduces the nucleophilicity. Based on the previous work,11 the X-ray crystal structure of the product 3r, and the N,N′-dioxide−Sc(III) complex,10 a possible enantioselective catalytic model for the cascade reaction was proposed (Figure 1). Initially, the Rh(II) complex

Table 3. Substrate Scope of α-Diazoketonesa

Figure 1. Proposed enantioselective catalytic model.

promotes the decomposition of diazoketone 2a and the formation of the free ammonium ylide intermediate.13a Next, the intermediate coordinates to one site of the chiral L2PrPr3−Sc(III) catalyst with the oxygen of the enone unit. The steric hindrance of one amide subunit of the ligand shields the β-Si-face of the enone, and the phenyl group of the diazoketone is far from the β-aryl group of the enone to reduce the steric hindrance (TS B′ and TS B′′). Next, intramolecular nucleophilic addition occurs via the transition state as in Figure 1, followed by a proton transfer to give the corresponding (2S,3R)-product 3r. In all these cases, only trans-diastereomers were identified. The oxygen anion of the enolate intermediate could not coordinate to Sc(III) due to the steric hindrance shown in TS B′′; thus, the corresponding (2R,3R)-diastereomer was not observed. In conclusion, we have developed an efficient asymmetric catalytic synthesis of 2,2,3-trisubstiuted indolines via intramolecular trapping of ammonium ylides with enones. The use

a

The reaction conditions were the same as those in Table 2. bIsolated yield. cDetermined by chiral HPLC analysis. All dr value were up to >19:1 detected by 1H NMR.

and position of the substituents on the aryl group of αdiazoketones 2b−2h had a limited influence on the enantioselectivity (93−97% ee) but dramatically varied the yield (78−96% yields) (Table 3, entries 1−7). The reaction was also tolerable to diazoketones with different alkyl acyl substituents, including ethyl, n-butyl, isobutyl, and cyclopropyl groups. The corresponding products 4ti−4tl were obtained in moderate to good yield (67−87% yields) with high enantioselectivity (94−99% ee) (Table 3, entries 8−11). To explore the mechanism of this catalytic reaction, we carried out several control experiments. The reaction of the N−H insertion product 5a could not be converted into indoline 3a under the standard reaction conditions. The 4538

DOI: 10.1021/acs.orglett.8b01744 Org. Lett. 2018, 20, 4536−4539

Letter

Organic Letters of α-diazoketone instead of α-diazoester improved the reactivity and enantioselectivity. A bimetallic relay catalytic system of the Rh(II)/chiral N,N′-dioxide−Sc(III) complex showed high efficiency. A range of chiral 2,2,3-trisubstituted indolines was obtained in high yield, good enantioselectivity, and excellent diastereoselectivity. We are currently extensively studying the use of the bimetallic catalyst system for other asymmetric reactions.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01744. Experimental procedures, full spectroscopic data for all new compounds, and copies of 1H, 13C NMR, and HPLC spectra (PDF) Accession Codes

CCDC 1844834 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiaohua Liu: 0000-0001-9555-0555 Xiaoming Feng: 0000-0003-4507-0478 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21625205 and 21332003) for financial support. REFERENCES

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DOI: 10.1021/acs.orglett.8b01744 Org. Lett. 2018, 20, 4536−4539