Enantioselective Benzylation and Allylation of α-Trifluoromethoxy Indanones under Phase-Transfer Catalysis

The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both enantiomers of α-benzyl-α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction of α-trifluoromethoxy indanones to give the allylation products in moderate yield with good enantioselectivity (up to 76% ee).

In contrast to the requirement of OCF 3 -containing drug candidates in medicinal chemistry, the synthesis of OCF 3 -containing organic compounds is relatively problematic. The OCF 3 unit is traditionally synthesized from its chlorinated precursor, the trichloromethoxy (OCCl 3 ) moiety, by a chlorine/fluorine exchange reaction under harsh reaction conditions [30][31][32][33][34][35]. The OCF 3 anion is unstable and decomposes rapidly into difluorophosgene (O=CF 2 ) and a fluoride anion (F − ), which can make nucleophilic trifluoromethylation difficult [36]. The electrophilic trifluoromethylation of hydroxyl compounds is another strategy, but the method is somewhat limited. While the synthesis of OCF 3 -containing organic compounds has improved dramatically over the last five years [37][38][39][40][41][42], a method that can be used to construct a chiral "C*-OCF 3 " unit is still extremely scarce. This should be one of the reasons of no pharmaceuticals with chiral, aliphatic "C*-OCF 3 " unit reported. In 2017, Tang and co-workers reported the enantioselective bromo-trifluoromethoxylation of olefins by trifluoromethyl arylsulfonate (TFMS) under silver catalysis in the presence of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH; Scheme 1a) [43]. Later, Shen and co-workers reported a method to construct chiral trifluoromethoxyl compounds by the Ni-catalyzed enantioselective Suzuki-Miyaura coupling of secondary benzyl bromides in good to high enantioselectivity (Scheme 1b) [44]. We developed a strategy for the synthesis of chiral, non-racemic α-OCF 3 -ketones with a tetrasubstituted carbon center via a Pd-catalyzed enantioselective Tsuji-allylation reaction with high enantioselectivity (Scheme 1c) [45,46]. Very recently, Liu and co-workers reported the Pd-catalyzed enantioselective intramolecular trifluoromethoxylation reaction of alkenes using CsOCF 3 to furnish OCF 3 -compounds with a chiral stereogenic center (Scheme 1d) [47]. While these methods have broad substrate scopes with high enantioselectivity, all the methods require transition metal catalysts. Herein, we report the first example of constructing molecules with an OCF 3 chiral center under non-metallic, organocatalytic conditions. The α-OCF 3 indanones react with benzyl bromides in the presence of a cinchona alkaloid-derived chiral phase-transfer catalyst (PTC) to afford enantioenriched α-benzyl-α-OCF 3 indanones in high yield with up to 57% ee. Access to both (R)-and (S)-enantiomers of α-benzyl-α-OCF 3 indanones can be controlled by the catalysts. The method was expanded to the enantioselective allylation reaction with allyl bromide to provide α-allyl-α-OCF 3 indanones with up to 76% ee (Scheme 1e).  [43]. Later, Shen and co-workers reported a method to construct chiral trifluoromethoxyl compounds by the Ni-catalyzed enantioselective Suzuki-Miyaura coupling of secondary benzyl bromides in good to high enantioselectivity (Scheme 1b) [44]. We developed a strategy for the synthesis of chiral, non-racemic α-OCF3-ketones with a tetrasubstituted carbon center via a Pd-catalyzed enantioselective Tsuji-allylation reaction with high enantioselectivity (Scheme 1c) [45,46]. Very recently, Liu and co-workers reported the Pd-catalyzed enantioselective intramolecular trifluoromethoxylation reaction of alkenes using CsOCF3 to furnish OCF3-compounds with a chiral stereogenic center (Scheme 1d) [47]. While these methods have broad substrate scopes with high enantioselectivity, all the methods require transition metal catalysts. Herein, we report the first example of constructing molecules with an OCF3 chiral center under nonmetallic, organocatalytic conditions. The α-OCF3 indanones react with benzyl bromides in the presence of a cinchona alkaloid-derived chiral phase-transfer catalyst (PTC) to afford enantioenriched α-benzyl-α-OCF3 indanones in high yield with up to 57% ee. Access to both (R)-and (S)-enantiomers of α-benzyl-α-OCF3 indanones can be controlled by the catalysts. The method was expanded to the enantioselective allylation reaction with allyl bromide to provide α-allyl-α-OCF3 indanones with up to 76% ee (Scheme 1e).
The substrate scope of the enantioselective benzylation of α-OCF 3 indanones 1 using a catalyst, CN-4, under the same reaction conditions furnished (−)-3 ((S)-3) with an opposite configuration in similar yield and up to 50% ee (Scheme 3). The absolute stereochemistry of the (+)-3 was temporality assigned to be (R) based on the results for the enantioselective allylation of 1 with allyl bromide (2i) as discussed below (see the later part of this paper, Scheme 4).   It should be noted that the method could be applied for the enantioselective allylation of α-OCF 3 indanones 1 with allyl bromide (2i) under CN-4 or CD-4 catalysis. The desired (+)-and (−)-α-allyl-α-OCF 3 indanones 3ai were obtained in moderate yield with up to 70% ee and 76% ee, respectively (Scheme 4). The absolute configurations of 3ai were determined to be the (R)-configuration for (+)-3ai and the (S)-configuration for (−)-3ai by comparing to the optical rotation of reported (S)-3ai ([α] 25 D = −22.5) [45]. The higher enantioselectivity with allylic substrates is most likely due to the less steric hindrance than benzyl bromides.

General Information
All reagents were used as received from commercial sources, unless specified otherwise. All reactions were performed in oven-dried glassware under a positive pressure of nitrogen. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica-gel (60-F254) (Kenilworth, NJ, USA). The TLC plates were visualized with UV light (254 nm) (Tokyo, Japan) and p-Anisaldehyde in ethanol/heat. Column chromatography was carried out on a column packed with silica-gel 60N spherical neutral size 63-210 μm or 40-63 μm. The 1 H-NMR (300 MHz), 19 F-NMR (282 MHz) and 13 C-NMR (126 MHz) spectra for solution in CDCl3 were recorded on a Bruker Avance 500 (Karlsruhe, Germany), Varian Mercury 300 (Palo Alto, CA, USA). Chemical shifts (δ) are expressed in ppm downfield from tetramethylsilane (δH = 0.00 ppm) or tetramethylsilane (δC = 0.00 ppm) or hexafluorobenzene (δF = −162.20 ppm). Optical rotations were measured with a Horiba SEPA-300 operating at 589 nm (Kyoto, Japan). Mass spectra were recorded on an LCMS-2020EV (ESI-MS) system (Shimadzu Corporation, Kyoto, Japan). High resolution mass spectrometry (HRMS) was recorded on a Waters Synapt G2 HDMS (ESI-MS) (Milford, MA, USA). The wave numbers (ν) of recorded IR-signals are quoted in cm −1 on a JASCO FT/IR-4100 spectrometer (Tokyo, Japan). HPLC analyses were performed on a JASCOLC-2000 Plus series (Tokyo, Japan) using 4.6 × 250 mm CHIRALCEL ® series or CHIRALPAK series (Tokyo, Japan). The melting point was recorded on a BUCHI M-565 (Flawil, Switzerland). All solvents were dried and distilled before use. The 1 H, 13 C and 19 F-NMR spectra of compounds 3 and HPLC data of compounds 3 are available in the Supplementary Material.

General Information
All reagents were used as received from commercial sources, unless specified otherwise. All reactions were performed in oven-dried glassware under a positive pressure of nitrogen. Solvents were transferred via syringe and were introduced into the reaction vessels though a rubber septum. All reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck silica-gel (60-F254) (Kenilworth, NJ, USA). The TLC plates were visualized with UV light (254 nm) (Tokyo, Japan) and p-Anisaldehyde in ethanol/heat. Column chromatography was carried out on a column packed with silica-gel 60N spherical neutral size 63-210 µm or 40-63 µm. The 1 H-NMR (300 MHz), 19 F-NMR (282 MHz) and 13 C-NMR (126 MHz) spectra for solution in CDCl 3 were recorded on a Bruker Avance 500 (Karlsruhe, Germany), Varian Mercury 300 (Palo Alto, CA, USA). Chemical shifts (δ) are expressed in ppm downfield from tetramethylsilane (δH = 0.00 ppm) or tetramethylsilane (δC = 0.00 ppm) or hexafluorobenzene (δF = −162.20 ppm). Optical rotations were measured with a Horiba SEPA-300 operating at 589 nm (Kyoto, Japan). Mass spectra were recorded on an LCMS-2020EV (ESI-MS) system (Shimadzu Corporation, Kyoto, Japan). High resolution mass spectrometry (HRMS) was recorded on a Waters Synapt G2 HDMS (ESI-MS) (Milford, MA, USA). The wave numbers (ν) of recorded IR-signals are quoted in cm −1 on a JASCO FT/IR-4100 spectrometer (Tokyo, Japan). HPLC analyses were performed on a JASCOLC-2000 Plus series (Tokyo, Japan) using 4.6 × 250 mm CHIRALCEL ® series or CHIRALPAK series (Tokyo, Japan). The melting point was recorded on a BUCHI M-565 (Flawil, Switzerland). All solvents were dried and distilled before use. The 1 H, 13 C and 19 F-NMR spectra of compounds 3 and HPLC data of compounds 3 are available in the Supplementary Material.

Preparation of α-OCF 3 -Substituted Indanones (General Procedure)
All the substrates, α-OCF 3 -indanones 1, were prepared by following a reported procedure [45]. General Procedure: A mixture of the indanone (1.0 equiv) and KOH (3.0 equiv) in MeOH (0.4 M) was stirred for 15 min at 0 • C, and PhI(OAc) 2 (1.1 equiv) was added in 4-5 portions during 5 min. The mixture was stirred at the same temperature for 1 h, then warmed to room temperature and stirred overnight. The mixture was concentrated, dissolved in Et 2 O, washed with NaHCO 3 aq., dried over Na 2 SO 4 and concentrated, then purified by silica-gel column chromatography. The pure product was then dissolved in EtOH (0.3 M), and 3N HCl aq. (1.0 M) was added. After stirring for 0.5 h at room temperature, the resulting mixture was extracted with Et 2 O, and the combined organic layer was washed with sat. NaHCO 3 aq. and brine, then dried over Na 2 SO 4 . The residue can be used without further purification for the next reaction.
A flask was charged with hydroxyketone, AgOTf (3.0 equiv), KF (4.0 equiv) and Selectfluor ® (1.5 equiv) in a nitrogen-filled glovebox. Then ethyl acetate (0.2 M), 2-fluoropyridine (3.0 equiv) and Me 3 SiCF 3 (3.0 equiv) were added successively under an Ar atmosphere. The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of silica-gel and concentrated. The residue was purified by flash silica-gel column chromatography.

Representative Procedure for the Enantioselective Catalytic Phase Transfer Benzylation
A flask was charged with α-OCF 3 -indanone 1 (0.10 mmol, 1.0 equiv), CsOH·H 2 O (0.20 mmol, 2.0 equiv) and cat. 4 (0.010 mmol, 10.0 mol%) in a nitrogen-filled glovebox. Then anhydrous toluene (5.0 mL, 0.02 M) and 2 (0.15 mmol, 1.5 equiv) was added under an Ar atmosphere. The resulting mixture was stirred overnight or 48 h at room temperature. After that, the solvent was removed under reduced pressure and the residue was purified by flash silica-gel column chromatography.

Conclusions
In conclusion, we disclose the organo-catalytic enantioselective benzylation reaction of α-OCF 3 -indanones 1. α-Benzyl-α-OCF 3 -indanones 3 was synthesized in good to high yield with moderate enantioselectivity, up to 57% ee, and both enantiomers of 3 could be accessed by the selection of chiral PTC, CN-4 or CD-4. The method was extended to the enantioselective allylation of 1, and both enantiomers of α-allyl-α-OCF 3 -indanones were also obtained in moderate yield with good ee, as much as 76% ee. To our knowledge, this is the first example of the asymmetric synthesis of trifluoromethoxylated compounds with a stereogenic OCF 3 -carbon center, without the use of transition metals. Extension of this methodology to other OCF 3 ketones is underway, and will be reported in due course [48].