Organocatalytic, Enantioselective Friedel–Crafts Reaction of Indoles in

Letter Cite This: Org. Lett. 2018, 20, 2190−2194

pubs.acs.org/OrgLett

Organocatalytic, Enantioselective Friedel−Crafts Reaction of Indoles in the Carbocyclic Ring and Electron-Rich Phenols Jin-Yu Liu,† Xie-Chao Yang,† Hong Lu,† Yu-Cheng Gu,‡ and Peng-Fei Xu*,† †

State Key Laboratory of Applied Organic Chemistry, School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, People’s Republic of China ‡ Syngenta Jealott’s Hill International Research Centre, Bracknell, Berks RG42 6EY, United Kingdom S Supporting Information *

ABSTRACT: An efficient method has been successfully developed to achieve the asymmetric C−H functionalization of indoles in the carbocyclic ring via organocatalysis, and a variety of tetrahydropyranoindoles were synthesized in good yields with excellent stereoselectivities. Further study on thermodynamic calculations indicated that the process was promoted by generating more thermodynamically stable products. This strategy, together with traditional C-3 functionalization of hydroxyindoles, could realize the switchable, regiodivergent asymmetric modification of indoles.

D

conditions, or using transition metals as catalysts.10 For example, Yu and co-workers have developed the first example of C-6 functionalization of indolines using a U-shaped nitrile template attached to the N-1 position of indoline via a sulfonamide linkage.10f Consequently, the enantioselective Friedel−Crafts reaction of indoles in the carbocyclic ring under mild conditions to modify indoles is still one of the most challenging tasks for synthetic chemists. With our ongoing interest in the exploration of practical asymmetric organocatalysis11 and the hydroxy group,12 we envisioned that the stereoselective and enantioselective Friedel−Crafts reaction of indoles might be achieved through cascade reactions involving the hydroxyl group (Scheme 1). Notably, the hydroxyl group was not only used as the directing group,13 but also served as the nucleophilic group. Together with the traditional approaches for the C-3 functionalization of hydroxyindole,14 this method could realize the switchable regiodivergent asymmetric modification of indoles. The study was initiated by testing the model reaction of 4hydroxyindole (1a) and (E)-2-nitroallylic acetate15 (2a) in the presence of bifunctional thiourea I in DCE (1 mL) at 30 °C. The expected cycloaddition product 3aa was successfully produced in low yield, but with an encouraging level of stereoselectivity (Table 1, entry 1). Notably, the addition of

espite the rapid development of asymmetric catalysis in recent decades, switchable chemodivergent, regiodivergent or diastereodivergent synthesis is still a long-standing and challenging issue to be addressed.1 To date, besides the process achieved by metal catalysis,2 organocatalysis has emerged as a powerful strategy for activating divergent positions of a single starting material by adjusting substrates or readily tunable conditions.1e,3 Particularly, activating conventionally inactive sites has proved to be an efficient method to achieve switchable, regiodivergent synthesis.3 Therefore, organocatalytic, enantioselective functionalization of inactive sites of a substrate is one option to achieve switchable, regiodivergent synthesis. Over the past decades, indole frameworks have been extensively exploited, because of their enormous potential and widespread applications as pharmaceutical agents, synthetic scaffolds, and chelating agents.4 In addition, a multitude of natural products with biological activities or medicinal value contain the indole scaffold.5 Hence, more and more attention has been paid to the synthesis and modifications of indole derivatives.6 However, the majority of attention has been focused on the asymmetric functionalization of indoles in the azole ring, including the C-3,7 C-2,7f,g,8 and N-17g,9 positions, because of their high nucleophilic reactivities. Some methods have been reported to realize the C−H functionalization of indoles in the carbocyclic ring, but these strategies required the presence of directing or blocking groups in the azole ring, or harsh © 2018 American Chemical Society

Received: February 11, 2018 Published: March 29, 2018 2190

DOI: 10.1021/acs.orglett.8b00503 Org. Lett. 2018, 20, 2190−2194

Letter

Organic Letters Scheme 1. Proposed Enantioselective Long-Range C−H Functionalization

Figure 1. Bifunctional catalysts investigated in the reaction.

Table 1. Optimization of the Reaction Conditions

entrya e

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20f 21f,g 22f,g,h 23f,g,h,i

catalyst

solvent

yieldb (%)

drc

eed (%)

I I II III IV V VI VII VIII IX X XI XII X X X X X X X X X X

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE CH2Cl2 CHCl3 THF toluene CH3CN chlorobenzene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

6 20 16 16 24 16 trace NR 48 52 62 52 30 67 60 trace 58 NR 42 75 78 80 86

>20:1 >20:1 >20:1 >20:1 15:1 10:1

75 75 80 −22 8 5

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

90 92 99 96 −87 >99 98

>20:1

90

>20:1 >20:1 >20:1 >20:1 >20:1

97 >99 >99 >99 >99

inhibited the reaction (Table 1, entries 16 and 18). Further reaction condition optimizations demonstrated that the optimal conditions were 50 °C, 0.25 mL DCE, and 1.5 equiv of substrate 2a (Table 1, entries 20−22). Finally, the addition of 4 Å MS also improved the reaction yield, probably because of its dehydration ability (Table 1, entry 23). To prove the generality of this method, we performed the reactions using various hydroxyindoles as the substrate (3aa− 3da).17 (See Scheme 2.) All of the reactions proceeded Scheme 2. Scope of the Asymmetric C−H Functionalization with Different Hydroxyindoles

smoothly to afford the corresponding products, albeit with either lower yields or lower stereoselectivities in some cases. Moreover, substituted 4-hydroxyindole and 4-hydroxycarbazole also gave satisfactory results (3ea−3ga). With the optimal reaction conditions established, the cascade reactions of 4-hydroxyindole and (E)-2-nitroallylic acetates with different electronic and steric properties were investigated (see Scheme 3). The reactions proceeded smoothly to afford the products in good yields with excellent diastereoselectivities and enantioselectivities. The electronic properties of substrates had no pronounced effects on the stereoselectivities, but had noticeable influences on the yields. Generally, substrates 2 with electron-withdrawing substituents gave more satisfactory yields than those with electron-donating substituents, probably because of the higher electrophilicities of the substrates 2 with electron-withdrawing substituents (see Scheme 3, 3ab and 3ac versus 3ad, 3ae versus 3af, 3ag versus 3ah). In addition, the steric influence of the substituents of the substrates 2 was not obvious (see Scheme 3, 3aj and 3ak), and heterocyclic, substituted allyl acetates were well-tolerated (Scheme 3, 3al and 3am). A variety of substrates 2 with alkyl substituents were also tested. However, the results were unsatisfactory. Interestingly, electron-rich phenols such as 3,5-dimethoxyphenol and β-naphthol also reacted to produce the desired products with satisfactory results under slightly different

a

Conditions: reactions were performed with 1a (0.1 mmol), 2a (0.1 mmol), K2HPO4 (0.1 mmol), and the catalyst (20 mol %) in DCE (1 mL) at 30 °C for 24 h. For detailed experimental procedures, see the Supporting Information. bIsolated yield. cDiastereomeric ratio. Determined by 1H NMR analysis of the crude products. dEnantiomeric excess. Determined by chiral-phase HPLC analysis eNo K2HPO4. fUnder 50 °C. g0.5 mL of DCE was used. h0.15 mmol of 2a was used. i50 mg of 4 Å MS was added.

K2HPO4 to neutralize the acid generated in the reaction offered more-satisfactory results (Table 1, entry 2). Various tertiary amine−hydrogen bond donor bifunctional organocatalysts were then examined (see Figure 1), and bifunctional squaramide X turned out to be the best catalyst for this reaction (Table 1, entries 3−13). Squaramides were more effective than thioureas for the reaction, possibly due to the significantly greater distance between the donor hydrogens16 (Table 1, entries 2−8 versus entries 9−13). However, catalysts VII and VIII with large steric hindrance did not promote the reaction (Table 1, entries 7 and 8). Next, different solvents were screened, and CH2Cl2 was found to be optimal (Table 1, entries 14−19). Notably, THF and MeCN, as hydrogen bond acceptors, 2191

DOI: 10.1021/acs.orglett.8b00503 Org. Lett. 2018, 20, 2190−2194

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Organic Letters Scheme 3. Scope of the Asymmetric Functionalization between 4-Hydroxyindole 1a and Differently Substituted Substrates 2

Figure 2. Proposed reaction mechanism.

In summary, we have developed a practical and efficient approach for asymmetric C−H functionalization of indoles in the carbocyclic ring via organocatalysis, and a series of tetrahydropyranoindoles were obtained in moderate to high yields with excellent stereoselectivities. The cascade reactions also proceeded smoothly on large scale, further proving their synthetic value.19 The control experiments and thermodynamic calculations demonstrated that C-3 functionalization of this system needed to overcome higher Gibbs free energies.20 Particularly, together with previous asymmetric C-3 functionalization of hydroxyindoles, the strategy realized the switchable, regiodivergent modification of indoles.

18

conditions (see Scheme 4, 5aa and 5ab). We then explored the reactions between 3,5-dimethoxyphenol and (E)-2-nitroScheme 4. Scope of the Reaction of Other Electron-rich Phenols

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00503. Details on experimental procedure, characterization data, and HPLC data of all compound derivatives (PDF) Accession Codes

CCDC 1590159 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 data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

allylic acetates with different electronic and steric properties. Again, substrates 2 with either electron-withdrawing or electron-donating groups afforded the products in good yields with excellent stereoselectivities in all cases (see Scheme 4, 5ba−5fa), and the steric hindrance of the substituents of substrates 2 did not affect the reactions (see Scheme 4, 5ga and 5ha). In addition, heterocyclic-substituted allyl acetates were also well-tolerated (Scheme 4, 5ia and 5ja). The absolute configuration of the product 5ca was determined to be (3S, 4R) by X-ray crystallography. Based on our experimental results and previous reports, a plausible catalytic cycle is outlined (see Figure 2). First, the 4hydroxyindole 1a and (E)-2-nitroallylic acetate 2a are synergistically activated by the bifunctional squaramide X to generate the reactive transition state A. Then, the transition state A undergoes an asymmetric Friedel−Crafts reaction with the concurrent release of acetic acid to form the intermediate B. Finally, the intermediate B affords desired product 3aa with the regeneration of the catalyst through an intramolecular cyclization process.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Peng-Fei Xu: 0000-0002-5746-758X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the NSFC (Nos. 21632003 and 21572087), the Key program of Gansu province (No. 17ZD2GC011) and the “111” program from the MOE of P. R. China for financial 2192

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Organic Letters

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support. We also gratefully acknowledge a Syngenta Postgraduate Fellowship awarded to J.-Y.L.

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Organic Letters 81, 4340. (h) Liu, J.-Y.; Zhao, J.; Zhang, J.-L.; Xu, P.-F. Org. Lett. 2017, 19, 1846. (16) (a) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. (b) Rombola, M.; Sumaria, C. S.; Montgomery, T. D.; Rawal, V. H. J. Am. Chem. Soc. 2017, 139, 5297. (17) The regioselectivities of 5-hydroxyindole and 6-hydroxyindole were perfect, probably because of the obvious difference of nucleophilic reactivities between two sites. (18) For more details on screening conditions and experimental procedures, see the Supporting Information (Section S6). (19) For details on the derivatizations of the chiral products, see the Supporting Information (Section S9). (20) The control experiments and thermodynamic calculation demonstrated that the free hydroxy group and oxa-Michael reaction occurring in the second step are crucial to reactivity. For details on the control experiments and thermodynamic calculation, see the Supporting Information (Section S25).

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