organic chemistry

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RESEARCH ARTICLE

Cite this: DOI: 10.1039/c7qo00229g

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Asymmetric synthesis of CF3- and indole-containing tetrahydro-β-carbolines via chiral spirocyclic phosphoric acid-catalyzed aza-Friedel–Crafts reaction† En Xie, Abdul Rahman and Xufeng Lin

*

Received 23rd March 2017, Accepted 16th April 2017

An enantioselective aza-Friedel–Crafts alkylation reaction of indoles with 1-trifluoromethyl-3,4-dihydro-

DOI: 10.1039/c7qo00229g

vides a facile route to 1-trifluoromethyl-1-indole-substituted tetrahydro-β-carbolines featuring a CF3containing quaternary stereocenter in considerable yields and good enantioselectivities.

rsc.li/frontiers-organic

β-carbolines catalyzed by a chiral spirocyclic phosphoric acid has been realized. This methodology pro-

β-Carbolines are a class of pharmacologically important compounds within the indole alkaloids and are found in nature very frequently.1 In particular, C1-substituted tetrahydroβ-carbolines are valuable structural units in biologically active natural products and pharmaceutical agents (Fig. 1), and have a wide range of pharmacological properties, including KSP inhibitory, antihelminthic, antimalarial, antiviral and antitumor activities.2 Accordingly, many efforts have been devoted to the synthesis of C1-substituted optically active tetrahydroβ-carbolines. The most popular synthetic routes utilize the diastereospecific Pictet–Spengler reactions.3 Asymmetric transfer hydrogenation using Noyori-type catalysts has been applied to synthesize chiral tetrahydro-β-carbolines.4 Notably, the organocatalytic asymmetric Pictet–Spengler reaction has offered a powerful method of accessing a chiral tetrahydro-β-carboline skeleton in a direct manner.5 Although C1-disubstituted tetrahydro-β-carbolines are found in biologically active compounds,

Fig. 1

Selected bioactive compounds.

Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details. CCDC 1539496. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7qo00229g

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the catalytic enantioselective synthesis of structurally diverse tetrahydro-β-carbolines featuring a quaternary stereocenter at the C1 position is still challenging. Because of trifluoromethylated organic compounds with a great diversity of superior biological properties mainly due to the improved chemical and metabolic stability, lipophilicity, and membrane permeability of the parent molecules, the incorporation of a CF3 group in the target molecule is an useful modification in medicinal chemistry.6 Currently, some biologically active molecules with a CF3-containing cyclic quaternary stereocenter, such as efavirenz, CJ-17493 and fluoroartemisinin, have shown the HIV reverse transcriptase inhibitor, the NK-1 receptor antagonist and antimalarial agents, respectively.7 On the other hand, the indole structure is present in drugs currently available on the market, drug candidates under development.8 Therefore, tetrahydro-β-carboline derivatives with a CF3- and indole-containing quaternary stereocenter at the C1 position are interesting targets for medicinal chemistry research. However, catalytic asymmetric synthesis of these compounds is unprecedented. Recently, with our interest in the enantioselective synthesis of heterocyclic compounds with a CF3-containing quaternary stereocenter, we have identified chiral spirocyclic phosphoric acid (SPA) catalysis9 as a tactical tool to activate trifluoromethylated ketoimines for asymmetric reactions.10 Herein, we report to extend this catalysis pattern to the enantioselective aza-Friedel–Crafts reaction11 of indoles with 1-trifluoromethyl3,4-dihydro-β-carbolines for an unprecedented synthesis of tetrahydro-β-carbolines with a CF3- and indole-containing quaternary stereocenter. Initially, 1-trifluoromethyl-3,4-dihydro-β-carbolines were synthesized according to the procedure illustrated in Scheme 1. The amidation reaction of tryptamines with trifluoroacetic anhydride (TFFA) catalyzed by 4-dimethylaminopyridine

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Scheme 1

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Synthesis of 1-trifluoromethyl-3,4-dihydro-β-carbolines.

(DMAP) gave the corresponding trifluoroacetamides. Subsequent cyclization of the trifluoroacetamides in the presence of trifluoromethanesulfonic acid (TfOH) and phosphoryl chloride in reflux toluene produced 1-trifluoromethyl-3,4-dihydroβ-carbolines (1) in moderate yields. We then examined the model reaction between 1-trifluoromethyl-3,4-dihydroβ-carboline (1a) and indole (2a) to study the asymmetric azaFriedel–Crafts reaction. The desirable reaction was completed smoothly in toluene at room temperature in the presence of 5 mol% SPA catalyst (S)-4a to afford 1-trifluoromethyl-1-indolesubstituted tetrahydro-β-carboline (3a) in 90% yield with 75% ee (Table 1, entry 1). Then we screened chiral SPAs (4b–h) with various substituents at the 6,6′-positions, and found that all the reactions proceeded smoothly to afford the desired product (3a) in good yield with variable enantiocontrol (Table 1, entries 2–8). Among these catalysts, 4a provided the best results in terms of yield and enantioselectivity. Furthermore, when a BINOL-based phosphoric acid12 (R)-5 with the 3,3′-bis(3,5-bis-trifluoromethylphenyl) moiety was

Table 1

Optimization of reaction conditionsa

Entry

Cat.

Solvent

Temp. (°C)

Yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

4a 4b 4c 4d 4e 4f 4g 4h 5 4a 4a 4a 4a 4a 4a 4a

Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene t BuOMe CH2Cl2 CHCl3 ClCH2CH2Cl m-Xylene Toluene Toluene

25 25 25 25 25 25 25 25 25 25 25 25 25 25 0 −20

90 85 75 88 89 85 87 80 87 65 85 87 73 89 81 62

75 13 21 32 29 5 10 42 66 22 30 69 25 74 86 74

a

Reactions were performed with 1a (0.05 mmol), 2a (0.06 mmol), catalyst (5 mol%) in 1 mL solvent for 24 h. b Isolated yields. c Determined by chiral HPLC analysis.

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used as a catalyst, good yield (87%) was obtained and only moderate enantioselectivity (66% ee) was observed (Table 1, entry 9). The following study suggested that the behavior of solvent more dramatically affected the stereoselectivity (Table 1, entries 10–14). The use of CHCl3 and m-xylene as a solvent provided 69% ee and 74% ee respectively. Whereas, ee diminished obviously in tBuOMe, CH2Cl2 or CH2ClCH2Cl, but with good yields. Subsequent optimization with respect to temperature indicated that the temperature influenced the catalytic activity and enantiocontrol (Table 1, entries 15 and 16), and the best temperature was 0 °C for this model reaction (81% yield, 86% ee). With the above-mentioned optimized reaction conditions in hand, the substrate scope of the reaction was then tested by varying the substituents on both the β-carbolines and indoles. As summarized in Table 2, good yields were obtained almost in all entries. Various indole derivatives were involved in this

Table 2

Study of the reactiona

a Reactions were performed with 1a (0.05 mmol), 2a (0.06 mmol), and (S)-4a (5 mol%) in 1 mL toluene for 24 h. Yields given are of the isolated products. ees were determined by chiral HPLC. b At 25 °C. c 98% ee was obtained after one recrystallization.


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aza-Friedel–Crafts reaction. Indoles with an electron-withdrawing (Cl, Br) or electron-donating (Me, OMe) substituent on the aryl group afforded the products in high enantioselectivities (Table 2, 3b–3g). In addition, the 7-Cl-indole and 7-Me-indole gave an excellent ee value of 91% and 92% respectively (Table 2, 3b and 3e), and the enantioselectivity decreased to 75% while the 7-OMe-indole or 5-Me-indole was employed (Table 2, 3d and 3g). Subsequently, various β-carboline derivatives starting from different tryptamines were used to expand the scope of the reaction. A range of β-carbolines bearing different substituents on the aryl group, including electron-donating and electronwithdrawing groups, smoothly participated in the reaction process with high efficiency and good to excellent enantioselectivity (Table 2, 3h–3r). The excellent level of stereocontrol was obtained in some cases, such as 3k (91% ee), 3l (91% ee), 3m (90% ee), and 3q (90% ee). The product 3m is a crystalline compound, and the ee value could be easily increased to 98% by one simple recrystallization (Table 2, 3m). It is noteworthy that the absolute configuration (S) of the quaternary stereogenic center in 3m was determined by X-ray crystallographic analysis (Fig. 2). To further demonstrate that this protocol is readily practical, we next carried out scale-up of the experiment using 5 mol % of catalyst (S)-4a (Scheme 2). The reaction of 1a (1.4 g) with 2e (0.8 g) proceeded to give the product 3e (1.78 g) in 82% yield with excellent enantioselectivity (92% ee) within 2 days, and the ee value could be increased to 95% easily after a simple recrystallization. It is noteworthy that most of the catalyst 4a was recovered by a single separation using column chromatography and it was reuseable without diminishing yield and ee. The effect of the trifluoromethyl group13 was then evaluated under the optimized reaction conditions. When 3,4-dihydroβ-carboline or 1-phenyl-3,4-dihydro-β-carboline was treated with indole, no corresponding product was observed even under reflux. On the basis of these experiments, we suspect that the introduction of a trifluoromethyl group into the 1-position of 3,4-dihydro-β-carbolines increases the reactivity

Fig. 2

X-ray crystal structure of compound 3m.

Research Article

Fig. 3 Proposed transition state for the reaction of 1a with indole using catalyst 4a.

in the aza-Friedel–Crafts reaction due to the strong electronwithdrawing effect. On the other hand, 1-Boc-indole as a nucleophile was reacted with 1a under the optimized protocol for 24 h, and no desired adduct was detected, and this suggests that a hydrogen-bonding interaction happening between the indole NH moiety and the catalyst phosphoryl oxygen atom plays a key role in the reactivity of indole. From this consideration, the assumed transition state for the enantioselective aza-Friedel–Crafts reaction using 4a is shown in Fig. 3. We believe that the chiral phosphoric acid plays a bifunctional role in activating both the 1-trifluoromethyl-3,4dihydro-β-carboline electrophile and the indole nucleophile by hydrogen-bonding. In particular, the electrophilicity of β-carboline 1 is activated through both the strong electronwithdrawing effect of the trifluoromethyl group and hydrogen bonding interactions with a phosphoric acid. In this model, indole attacks trifluoromethylated ketoimine from the Re face preferentially, leading to an S-configuration adduct, which is in agreement with the observed good reactivity and stereocontrol. In conclusion, we developed a highly enantioselective chiral spirocyclic phosphoric acid catalyzed aza-Friedel–Crafts reaction of 1-trifluoromethyl-3,4-dihydro-β-carbolines with indoles. This protocol provides a facile and efficient access to functionalized tetrahydro-β-carbolines with a CF3- and indole-containing quaternary stereocenter in good yields and good to excellent enantioselectivities, and involves a simple scalable experimental procedure. Introduction of a trifluoromethyl group at the 1-position of 3,4-dihydro-β-carbolines increases the reactivity in the enantioselective aza-Friedel–Crafts reaction due to the strong electron-withdrawing effect. Extension of this catalytic system to other useful nucleophiles is underway in our laboratory.

Acknowledgements We appreciate the National Natural Science Foundation of China (21572200) and the Fundamental Research Funds for the Central Universities for financial support.

References Scheme 2 Gram-scale experiment for the asymmetric aza-Friedel– Crafts reaction.


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