Enantioselective Friedel–Crafts Alkylation Reaction of Indoles

Letter Cite This: ACS Catal. 2019, 9, 6903−6909

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Enantioselective Friedel−Crafts Alkylation Reaction of Indoles with α‑Trifluoromethylated β‑Nitrostyrenes Catalyzed by Chiral BINOL Metal Phosphate Ignacio Ibáñez,† Mio Kaneko,† Yuto Kamei,‡ Ryosuke Tsutsumi,‡ Masahiro Yamanaka,*,‡ and Takahiko Akiyama*,† †

Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan Department of Chemistry, Faculty of Science, Rikkyo University, 3-41-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan

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‡

S Supporting Information *

ABSTRACT: An efficient enantioselective Friedel−Crafts alkylation reaction of indoles with α-CF3-substituted β-nitrostyrenes is disclosed. The key to success is the use of a chiral calcium BINOL bis(phosphate) complex as a Lewis acid catalyst. The reaction gives access to a wide variety of optically active indoles bearing trifluoromethylated all-carbon quaternary stereocenter (up to 20 examples) in high yields (up to 99%) with excellent enantioselectivities (up to 98%) under mild reaction conditions. Nonactivated α-alkyl-β-nitrostyrenes also participated in the Friedel− Crafts alkylation reaction successfully.

KEYWORDS: Indole, Friedel−Crafts alkylation, nitroalkene, metal chiral phosphate, quaternary carbon center

T

Scheme 1. Examples of the Friedel-Crafts Alkylation Reaction of Indole with Nitroalkene and Present Work

rifluoromethyl-containing compounds have received extensive attention in pharmaceutical, agrochemical, and materials sciences in the past decade, because of the influence of the fluorinated group to modify the chemical reactivity, stability, and bioactivity.1 The development of new, efficient, and practical methods for the introduction of fluorinated moieties into organic compounds is a topic of current interest. Among the reported methods for the synthesis of fluorinated compounds, the formation of chiral CF3-bearing all-carbon quaternary stereocenters is very important in organic chemistry.2 However, the construction of fluorinated quaternary stereocenters continues to pose a challenge, because of the highly congested nature of the CF3-substituted carbon, which usually leads to decreased reactivity and low enantioselectivity. In the past decade, the enantioselective Friedel−Crafts alkylation reaction of indoles with activated alkenes has proven to be one of the most straightforward methods for the synthesis of chiral aromatic derivatives bearing a benzylic allcarbon quaternary stereocenter.3,4 Therefore, the development of a novel asymmetric Friedel−Crafts alkylation reaction that would furnish a trifluoromethylated all-carbon quaternary stereocenter is mandatory.5 Jia et al. reported the first enantioselective Friedel−Crafts reaction of α-trifluoromethylated β-nitrostyrenes with indoles catalyzed by a Ni(II) perchlorate-bisoxazoline complex (Scheme 1a),5a which required extended time to achieve high catalytic efficiency. Meggers recently reported limited examples of chiral Ir© XXXX American Chemical Society

catalyzed reaction in the pursuit of CF3- and alkyl-bearing allcarbon quaternary stereocenters.4f As part of our continued interest in the chiral phosphoric acid catalysis,6 we already reported enantioselective Friedel−Crafts alkylation reaction of indole with nitrostyrene by means of chiral phosphoric acid Received: May 15, 2019 Revised: June 29, 2019 Published: July 2, 2019 6903

DOI: 10.1021/acscatal.9b01811 ACS Catal. 2019, 9, 6903−6909

Letter

ACS Catalysis (Scheme 1b).3c,4d We wish to report herein enantioselective Friedel−Crafts alkylation reaction of N-H indole with αtrifluoromethylated β-nitrostyrene, using chiral calcium BINOL bis(phosphate) as the catalyst (Scheme 1c). We also found that our protocol could be extended to enantioselective Friedel−Crafts alkylation reaction of indole with α-alkylsubstituted β-nitrostyrene. At the outset, we investigated the Friedel−Crafts reaction of (E)-1-phenyl-1-trifluoromethyl-2-nitroethene (1a) and indole (2a) as model substrates (Table 1). Primary results showed

MS substantially improved both yield and enantioselectivity (Table 1, entry 7). Under the optimal reaction conditions, we explored the scope of this protocol over a wide range of substituted nitrostyrenes and indoles, and the results are summarized in Scheme 2. Nitrostyrenes bearing electron-donating (products 4ba and 4ca), electron-withdrawing (products 4da and 4ea), and heteroaromatic (product 4fa) groups afforded the corresponding Friedel−Crafts adducts in high yields and with excellent enantioselectivities by means of 5 mol % of Ca[3]2. The present Friedel−Crafts alkylation reaction of

Table 1. Optimization of Reaction Conditions

Scheme 2. Chiral Calcium BINOL Bis(phosphate)Catalyzed Friedel−Crafts Alkylation Reaction of Indoles with Nitroalkenesa

entry

catalyst

reaction temperature, T [°C]

1 2 3 4 5 6c 7d

3 Sr[3] Na[3] Mg[3]2 Ca[3]2 Ca[3]2 Ca[3]2

RT RT RT RT RT 40 40

reaction time, t [h]

yielda [%]

enantiomeric excess, eeb [%]

48 24 24 24 24 24 24

0 trace 45 23 66 72 96

− − 27 27 94 90 97

a

Yield of isolated product. bEnantiomeric excess was determined by chiral HPLC analysis. c5 mol % of Ca[3]2. d5 Å molecular sieves (MS) were used.

that the use of BINOL phosphoric acids (Table 1, entry 1) did not promote the Friedel−Crafts reaction, in contrast to the previously reported analogous reaction employing nonfluorinated nitroalkenes.3c,d,4d The absence of reactivity may be ascribed to the presence of the strong electron-withdrawing CF3 group, which decreases the basicity of the conjugated nitro moiety, thereby impeding efficient coordination with the catalyst. Then, we turned our attention to the use of chiral metal BINOL phosphate complexes as the catalyst. In recent years, chiral alkali and alkaline-earth organophosphates have emerged as effective catalysts for several important organic transformations.7 To our delight, chiral metal BINOL phosphate proved to be a catalyst of choice for this transformation, rather than the corresponding chiral-free BINOL phosphoric acid (Table 1, entries 3−5). We reasoned that metal phosphates might create a better chiral environment and, indeed, calcium salt catalyst 3 provided the corresponding Friedel−Crafts adduct in high yield and with high enantioselectivity (Table 1, entry 5).8,9 Furthermore, as we had reported previously, the addition of molecular sieves (MS) had a beneficial effect on the chiral phosphoric acid-catalyzed Friedel−Crafts reaction of indole with β-monosubstituted nitroalkenes.3c,e,4d In that sense, we found that the use of 5 Å

a

Reactions were performed with 1 (0.138 mmol) and 2 (0.276 mmol) in toluene (0.5 mL). bYield of isolated product. cEnantiomeric excess was determined by chiral HPLC analysis.

6904

DOI: 10.1021/acscatal.9b01811 ACS Catal. 2019, 9, 6903−6909

Letter

ACS Catalysis trifluoromethylated nitrostyrenes is independent of the electronic nature of the electrophile. Furthermore, the reaction could be extended to α-alkyl substituted nitrostyrenes; quantitative yields were obtained using substrates 1g and 1h (products 4ga and 4ha), despite the slight decrease in the enantioselectivity. The effect of indole substituents was also examined. Excellent enantioselectivities were achieved with indoles bearing either electron-withdrawing or electrondonating groups at C6 and C7. The reaction with 6chloroindole afforded 4ah in a low yield and moderate enantioselectivity. In addition, we also examined the effect of the fluorine group at the β-position of the nitroalkene. Perfluoroalkylated and difluoroalkylated moieties were well-tolerated and the reported Friedel−Crafts alkylation reaction occurred in good yields and excellent enantioselectivities (Figure 1).

Scheme 4. Chiral Calcium BINOL Bis(phosphate)Catalyzed Friedel−Crafts Alkylation Reaction of Indoles with β-Alkyl β-Aryl Nitroalkenesa

Figure 1. Effect of fluorinated alkane moiety.

The absolute configuration of product 4ck was determined to be S by single-crystal X-ray structure analysis (Figure 2).

Figure 2. Single-crystal X-ray analysis of product 4ck.

Next, we studied the Friedel−Crafts alkylation reaction of βmethyl-β-nitrostyrene (5a) under the optimal reaction conditions (Scheme 3) and found that geometrical isomers Scheme 3. Nucleophile and Alkene Geometry Evaluation a

Reactions were performed with 1 (0.138 mmol) and 2 (0.276 mmol) in toluene (0.5 mL). bYield of isolated product. cEnantiomeric excess (ee) was determined by chiral HPLC analysis.

was then examined using α-ethyl-β-nitrostyrenes as model substrates. Good to moderate yield and high enantioselectivity were obtained when electron-withdrawing groups were placed in the aromatic ring. In addition, substituents on the indole nucleophile were well-tolerated. Interestingly, lower yield and selectivities were obtained for product 6la, indicating that the presence of a strong electron-donating group has a negative effect on the reactivity, promoting a competitive isomerization reaction of the starting nitroalkene. In addition, the absolute stereochemistry of methyl and ethyl derivatives (6a and 6b) was determined to be R by the X-ray analysis of 7a and 7b (see Figures S1 and S2 in the Supporting Information).12 The absolute stereochemistry of the remaining compounds was surmised by analogy. To gain a deeper insight into the origin of the high stereocontrol in (E)-nitroalkene, density functional theory

exhibited different reactivity.10 Interestingly, whereas (Z)-5a provided the Friedel−Crafts adduct in high yield and with high enantioselectivity, (E)-5a gave low enantioselectivity. This indicates that high enantioselectivity is dependent critically on the geometric configuration of nitroalkene, regardless of the type of β-substituent (vide infra). The high yield and enantioselectivity that was obtained when (Z)-5a was used as starting material motivated us to explore the use of nonactivated α-alkyl-substituted β-nitrostyrenes as suitable substrate for the Friedel−Crafts alkylation reactions by means of chiral calcium phosphate (see Scheme 4).11 The presence of several alkyl groups was evaluated, and good selectivities were obtained in every case, although the yield decreased when a bulky group was attached. The scope 6905

DOI: 10.1021/acscatal.9b01811 ACS Catal. 2019, 9, 6903−6909

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ACS Catalysis

Ca cation (Figure 3a). In sharp contrast, a large steric repulsion exists between the phenyl group of 1a and the 3,3′groups of Ca(3)2 in TSminor. Such a repulsive interaction deforms the coordination structure of the Ca-phosphate moiety (monodentate coordination), significantly destabilizing TSminor (see Figure 3b). In the cases of 4ah and 4ai resulting in lower enantioselectivities (recall Scheme 2), the Cl atom and the methyl group are located in sterically more-crowded region in TSmajor, compared to TSminor, inducing a significant steric clash in TSmajor. Such structural changes would destabilize TSmajor to decrease the energy difference between TSmajor and TSminor (see Figure S4 in the Supporting Information). We also investigated the DFT calculation of the reaction with (Z)α-methyl-β-nitrostyrene (5a) and found similar TS (Figure S5 in the Supporting Information).19 Using (E)-5a would make the position of the phenyl group away from the 3,3′-groups of Ca(3)2, removing a probematic steric interaction. In order to clarify the role of MS in the Friedel−Crafts alkylation reaction, we evaluated this transformation by employing MS of different sizes (see the Supporting Information). We found that the reaction did not proceed in the absence of MS, and the use of 4 Å MS did not promote the reaction efficiently. Although previous studies proposed the use of MS to remove traces of water in the catalyst,9d the results obtained showed that the presence of MS is critical.20 To conclude, for the purpose of evaluating the effect of the observed competitive isomerization reaction, we conducted the Friedel−Crafts reaction in the absence of indole (reaction 1 in Scheme 5). Compound 8 was isolated in 95% yield as a

(DFT) calculation was conducted [PCM(toluene)-M06-2x/631G*].13,14 Although the precise nature of the active catalyst remains unknown, catalytically active monomeric species [Ca(3)2] have been proposed in the literature.7e,15−17 Based on these experimental analyses and previous DFT calculations,18 monomeric TS models leading to the major Senantiomer (TSmajor) and the minor R-enantiomer (TSminor) of (E)-α-trifluoromethyl-β-nitrostyrene (1a) were investigated (see Figure 3). Alkaline-earth metal (e.g., Ca) phosphate can

Scheme 5. Evaluation of the Competitive Isomerization Reaction

Figure 3. Three-dimensional (3D) structures and relative energies (Gibbs free energies are shown in italic font) of (a) TSmajor and (b) TSminor of the reaction with 1a. [PCM(toluene)-M06-2x/6-31G*].

mixture of E/Z isomers and was employed as the starting material under the optimized chiral calcium BINOL bis(phosphate) Friedel−Crafts reaction (reaction 2 in Scheme 5) to give desired Friedel−Crafts adduct 6la in 15% yield and 36% ee. In summary, a highly enantioselective Friedel−Crafts alkylation reaction of indoles with α-CF3-substituted βnitrostyrenes was achieved. The chiral calcium BINOL bis(phosphate) complex was revealed to be an efficient Lewis acid catalyst for this transformation. The mild and versatile procedure provides straightforward access to highly interesting chiral aromatic derivatives bearing a CF3-benzylic all-carbon quaternary stereocenter. A wide range of α-CF3-βnitrostyrenes and indoles were found to be suitable substrates. Molecular sieves as additives were evaluated, and the 5 Å size gave the best results. Further studies are underway to uncover the specific role of MS in the Friedel−Crafts reaction.

act as a bifunctional catalyst, simultaneously activating 1a and 2a on the metal center (Lewis acidic site) and one phosphoryl oxygen (Brønsted basic site), respectively. This is consistent with the fact that no reaction was observed when N-methylprotected indole (2j) was used as the substrate (4aj, Scheme 2). TSmajor is 2.8 kcal/mol (3.6 kcal/mol for Gibbs free energy) more stable than TSminor, in good agreement with the experimentally observed stereoselectivity. In all TS structures, the benzene ring moiety of 2a is located out of the cavity constructed by Ca(3)2. Furthermore, CF3 group has no effective interaction with any part of 1a and Ca(3)2. These structural features of TS are consistent with the fact that (Z)5a also achieved high enantioselectivity (recall Scheme 3). The phenyl group of 1a is located at the empty space constructed by the 3,3′-groups of Ca(3)2 in TSmajor, which allows the strong bidentate coordination of the phosphate anion to the 6906

DOI: 10.1021/acscatal.9b01811 ACS Catal. 2019, 9, 6903−6909

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ACS Catalysis

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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/acscatal.9b01811. Experimental procedures and spectral data for all new compounds (PDF) Crystallographic data for 4ck (CIF) Crystallographic data for 7a (CIF) Crystallographic data for 7b (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (M. Yamanaka). *E-mail: [email protected] (T. Akiyama). ORCID

Ryosuke Tsutsumi: 0000-0001-7785-8257 Masahiro Yamanaka: 0000-0001-7978-620X Takahiko Akiyama: 0000-0003-4709-4107 Funding

The authors acknowledge a Grant-in-Aid for Scientific Research on Innovative Areas, “Advanced Transformation Organocatalysis”, from MEXT, Japan, as well as Grants-in-Aid for Scientific Research from JSPS (17H03060, 15K05506, 17KT0011), and MEXT-Supported Program for the Strategic Research Foundation at Private Universities. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Masamichi Miyagawa (Gakushuin University) and Dr. Koya Inomata (AIST, Gakushuin University) for X-ray structural analysis.

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REFERENCES

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ACS Catalysis

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Awata, A.; Kamiya, K.; Ishibashi, M.; Arai, M. Catalytic Asymmetric Synthesis of Mixed 3,3-Bisindoles and their Evaluation as Wnt Signaling Inhibitors. Angew. Chem., Int. Ed. 2013, 52, 2486−2490. (h) Li, G.; Liu, H.; Wang, Y.; Zhang, S.; Lai, S.; Tang, L.; Zhao, J.; Tang, Z. The Catalytic Enantioselective Synthesis of Tetrahydroquinolines Containing All-Carbon Quaternary Stereocenters via the Formation of Aza-ortho-xylylene with 1,2-Dihydroquinoline as a Precursor. Chem. Commun. 2016, 52, 2304−2306. (i) Zhang, Y.; Zhang, S. X.; Fu, L. N.; Guo, Q. X. Highly Efficient Atom-Economic Synthesis of Chiral Bis(indolyl)methanes Bearing Quaternary Stereogenic Carbon Centers. ChemCatChem 2017, 9, 3107−3110. (j) Abozeid, M. A.; Sairenji, S.; Takizawa, S.; Fujita, M.; Sasai, H. Enantioselective Synthesis of Tetrahydrocyclopenta[b]indole bearing a Chiral Quaternary Carbon Center via Pd(II)−SPRIX-catalyzed C− H Activation. Chem. Commun. 2017, 53, 6887−6890. (5) For selected examples of enantioselective Friedel−Crafts reactions to afford quaternary trifluoromethylated stereocenters, see: (a) Gao, J.-R.; Wu, H.; Xiang, B.; Yu, W.-B.; Han, L.; Jia, Y.-X. Highly Enantioselective Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters via Nickel-Catalyzed Friedel−Crafts Alkylation Reaction. J. Am. Chem. Soc. 2013, 135, 2983−2986. (b) Huang, Y.; Tokunaga, E.; Suzuki, S.; Shiro, M.; Shibata, N. Enantioselective Friedel−Crafts Reaction of β-Trifluoromethylated Acrylates with Pyrroles and Its Application to the Synthesis of Trifluorinated Heliotridane. Org. Lett. 2010, 12, 1136−1138. (c) Blay, G.; Fernandez, I.; Munoz, M. C.; Pedro, J. R.; Vila, C. Synthesis of Functionalized Indoles with a Trifluoromethyl-Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel− Crafts Alkylation with β-Trifluoromethyl-α,β-enones. Chem. - Eur. J. 2010, 16, 9117−9122. (d) Lin, J.-H.; Xiao, J.-C. The Asymmetric Friedel−Crafts Reaction of Indoles with Fluoroalkylated Nitroalkenes Catalyzed by Chiral Phosphoric Acid. Eur. J. Org. Chem. 2011, 2011, 4536−4539. (f) Wang, W.; Lian, X.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Highly Enantioselective Yttrium(III)-catalyzed Friedel−Crafts Alkylation of β-Trichloro(trifluoro)methyl Arylenones with Indoles. Chem. Commun. 2011, 47, 7821−7823. (g) Wen, L.; Shen, Q.; Wan, X.; Lu, L. Enantioselective Friedel−Crafts Alkylation of Indoles with Trifluoroethylidene Malonates by Copper−Bis(oxazoline) Complexes: Construction of Trifluoromethyl-Substituted Stereogenic Tertiary Carbon Center. J. Org. Chem. 2011, 76, 2282−2285. (h) Shibatomi, K.; Narayama, A.; Abe, Y.; Iwasa, S. Practical Synthesis of 4,4,4-Trifluorocrotonaldehyde: a Versatile Precursor for the Enantioselective Formation of Trifluoromethylated Stereogenic Centers via Organocatalytic 1,4-Additions. Chem. Commun. 2012, 48, 7380−7382. (i) Wu, H.; Liu, R.-R.; Jia, Y.-X. Asymmetric Friedel− Crafts Alkylation Reaction in the Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters. Synlett 2014, 25, 457−460. (6) For a seminal work of chiral phosphoric acid catalysis, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Enantioselective Mannich-Type Reaction Catalyzed by a Chiral Brønsted Acid. Angew. Chem., Int. Ed. 2004, 43, 1566−1568. (b) Uraguchi, D.; Terada, M. Chiral Brønsted Acid-Catalyzed Direct Mannich Reactions via Electrophilic Activation. J. Am. Chem. Soc. 2004, 126, 5356−5357. For reviews, see: (c) Akiyama, T. Stronger Brønsted Acids. Chem. Rev. 2007, 107, 5744−5758. (d) Terada, M. Chiral Phosphoric Acids as Versatile Catalysts for Enantioselective Transformations. Synthesis 2010, 2010, 1929−1982. (e) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Complete Field Guide to Asymmetric BINOLPhosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2014, 114, 9047−9153. (f) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Addition and Correction to Complete Field Guide to Asymmetric BINOL-Phosphate Derived Brønsted Acid and Metal Catalysis: History and Classification by Mode of Activation; Brønsted Acidity, Hydrogen Bonding, Ion Pairing, and Metal Phosphates. Chem. Rev. 2017, 117, 10608−10620. (7) For reviews on chiral alkaline earth metal catalysis, see: (a) Yamashita, Y.; Tsubogo, T.; Kobayashi, S. Chiral Alkaline-Earth 6908

DOI: 10.1021/acscatal.9b01811 ACS Catal. 2019, 9, 6903−6909

Letter

ACS Catalysis phoramides and Their Calcium Salts-Highly Acidic and Effective Brønsted Acids. Chem. - Eur. J. 2010, 16, 13116−13126. (16) For a review, see: Harder, S. From Limestone to Catalysis: Application of Calcium Compounds as Homogeneous Catalysts. Chem. Rev. 2010, 110, 3852−3876. (17) For an example of monomeric structure of Ca complex, see: Mashima, K.; Sugiyama, H.; Kanehisa, N.; Kai, Y.; Yasuda, H.; Nakamura, A. Diene Complexes of Calcium and Strontium: First Crystal Structures of Calcium- and Strontium-Diene Complexes, M(2,3-dimethyl-1,4-diphenyl-1,3-butadiene)(THF)4 (M = Ca and Sr). J. Am. Chem. Soc. 1994, 116, 6977−6978. (18) (a) Simón, L.; Paton, R. S. The True Catalyst Revealed: The Intervention of Chiral Ca and Mg Phosphates in Brønsted Acid Promoted Asymmetric Mannich Reactions. J. Am. Chem. Soc. 2018, 140, 5412−5420. (b) Hirata, T.; Yamanaka, M. DFT Study of Chiral Phosphoric Acid Catalyzed Enantioselective Friedel−Crafts Reaction of Indole with Nitroalkene: Bifunctionality and Substituent Effect of Phosphoric Acid. Chem. - Asian J. 2011, 6, 510−516. (19) For details regarding the calculation, see the Supporting Information. (20) Recently, it has been reported that additional metal cations could be leaked from the MS and played an active role in the catalytic process, see: Hatano, M.; Nishikawa, K.; Ishihara, K. Enantioselective Cycloaddition of Styrenes with Aldimines Catalyzed by a Chiral Magnesium Potassium Binaphthyldisulfonate Cluster as a Chiral Brønsted Acid Catalyst. J. Am. Chem. Soc. 2017, 139, 8424−8427.

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DOI: 10.1021/acscatal.9b01811 ACS Catal. 2019, 9, 6903−6909