Asymmetric Friedel-Crafts Alkylation of Indole with Chalcones Catalyzed by Chiral Phosphoric Acids

The reaction of indole with chalcones, to give Michael-type adducts, was found to occur with good efficiency (up to 98% yield) and moderate enantioselectivity (up to 52% e.e.) in the presence of a chiral BINOL-based phosphoric acid. Furthermore, the alkylation products can be obtained in much higher e.e.s after one only crystallization.


Introduction
The indole moiety represents the main structural feature of a variety of unnatural and natural bioactive products, such as the indole alkaloids [1,2]. In recent years particular attention has been paid to the enantioselective alkylation of indoles with α,β-unsaturated carbonyl compounds [3,4] since the corresponding Michael-type adducts could be considered valuable key-intermediates for the construction of chiral indole architectures.

OPEN ACCESS
With regards to chiral Bronsted Acids, good efficiency but rather poor levels of enantioselectivity were observed in the F.C. alkylation of indoles with chalcones when a camphor-based Bronsted acid was used [10], while improved enantiomeric excesses (up to 56% e.e.) were obtained through the use of the H 8 -BINOL-based phosphoric acid of type 1 [11,12] (R= 4-ClC 6 H 4 ) (Scheme 1, Figure 1).
Taking into account that the different steric and electronic effects of the above cited substituents were found exert a deep influence, both on efficiency and enantioselectivity, we decided to investigate the catalytic properties of the BINOL-derivatives 2a (R= SiPh 3 ), and 2b (R=4-NO 2 C 6 H 4 ), bearing substituents with different electronic and steric properties, in the F.C. alkylation of indole with chalcones.

Results and Discussion
Initially chalcone 4a (R 1 =R 2 =H; Ar=Ph) was chosen as a representative substrate and was submitted to reaction with indole 3 under the conditions reported in Table 1 and Scheme 2. Based on the results reported in Table 1, dichloromethane proved a superior solvent with respect to toluene (compare entries 1 and 2), while the organocatalyst 2b gave better results than 2a, both in terms of yield and enantioselectivity, provided that more dilute solutions of chalcones 4 were used (compare entries 3, 4 and 5).   A lower organocatalyst loading (entries 6 and 7) caused a dramatic drop of the yields and a slight decrease of the e.e.s. It has to be noted that the e.e. of compound 5a, obtained in entry 5 (52% e.e.) could be enhanced significantly (72% e.e.) by one only crystallization from Et 2 O. The general scope of the procedure was then checked by submitting indole 3 to treatment with a set of chalcones 4 under the optimized conditions of entry 5, Table 1. As reported in Table 2, the alkylation of indole was found to take place in moderate to high yields (up to 98%) with variously substituted chalcones while a moderate level of enantioselectivity could be observed for most of the reported starting materials. However, and very interestingly, in several cases the e.e.s of the Michael-type adducts 5 could be again enhanced noticeably (up to 98%) by recrystallization. More simple α,β-unsaturated ketones, such as benzylidene acetone, gave much less satisfactory results since the corresponding alkylation product was isolated in only 15% yield and 30% e.e.

General
All chemicals were purchased from Sigma-Aldrich and used without any further purification. TLC was performed on silica gel 60 F 254 0.25 mm on glass plates (Merck) and non-flash chromatography was performed on silica gel (0.063-0.200 mm) (Merck). All 1 H-and 13 C-NMR spectra were recorded with a DRX 400 MHz Bruker instrument (400.135 MHz for 1 H and 100.03 MHz for 13 C), using CDCl 3 (δ=7.26 ppm in 1 H-NMR spectra and δ=77.0 ppm in 13 C-NMR spectra) as solvent. 1 H data are reported as follows: chemical shift (δ in ppm), multiplicity (s singlet, d doublet, t triplet, dd doublet of doublets, m multiplet) and coupling costant (J in Hz). Optical rotations were measured on a JASCO DIP-1000 polarimeter operating at the sodium D line at room temperature. Concentration is given in g/100 mL. IR spectra were recorded on a Bruker spectrometer. The HPLC analyses were performed with Waters Associates equipment (Waters 2487 Dual λ absorbance Detector) using a CHIRALPAK AD-H column with hexane/isopropyl alcohol mixtures (composition and flow rate as indicated). HPLC methods were calibrated with the corresponding racemic mixtures. Mass spectrometry analysis was carried out using an Waters 4 micro quadrupole electrospray spectrometer. The elemental analyses were calculated with FLASH EA 1112 Thermo equipment. Melting points were determined with an Electrothermal 9100 apparatus. The known compounds have been identified by comparison of spectral data with those reported [8,11].The absolute configureurations of the optically active compounds 5a was determined on the basis of the measured optical rotation compared with literature values [8,11].

Typical experimental procedure
To a mixture of chalcone (0.125 mmol) and catalyst (0.0125 mmol) 1.2 eq. of indole (0.15 mmol) were added and stirred in dry dichloromethane (0.75 mL) at room temperature. The reaction was monitored by TLC analysis. After 48 hours a saturated aqueous NaHCO 3 solution (0.75 mL) was added dropwise and the organic layer was extracted in CH 2 Cl 2 , dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel in gradient elution with petroleum pther/ethyl acetate to give the pure product.

Conclusions
In conclusion, we have developed a Michael-type reaction of indole leading to variously substituted chalcones by using chiral Bronsted Acid 2b as catalyst. The reaction proceeds with good efficiency and moderate enantioselectivity. The possibility to obtain the alkylation products in much higher e.e.s (up to 98%) after only a single recrystallization provides a practical method to synthesize highly enantiopure 2-indole derivatives.