Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2024 Feb 15;4(2):807–815. doi: 10.1021/jacsau.3c00794

Enantioselective Desymmetrization of Trifluoromethylated Tertiary Benzhydrols via Hydrogen-Acceptor-Free Ir-Catalyzed Dehydrogenative C–H Silylation: Decisive Role of the Trifluoromethyl Group

Yoshihiko Yamamoto 1,*, Ryu Tadano 1, Takeshi Yasui 1
PMCID: PMC10900501  PMID: 38425931

Abstract

graphic file with name au3c00794_0008.jpg

Although the trifluoromethyl (CF3) group is one of the most important fluorinated groups owing to its significant ability to modulate pharmacological properties, constructing trifluoromethylated stereogenic centers in an enantioselective manner has been a formidable challenge. Herein, we report the development of the enantioselective desymmetrization of trifluoromethylated benzhydrols via intramolecular dehydrogenative silylation using Ir catalysts with chiral pyridine-oxazoline (PyOX) ligands. The produced benzoxasilol was transformed into several unsymmetrical benzhydrols via iododesilylation and subsequent transition-metal-catalyzed cross-coupling reactions. Moreover, the same Ir catalyst system was used for the kinetic resolution of unsymmetrical trifluoromethylated benzhydrols.

Keywords: asymmetric catalysis, C−H functionalization, fluorine, iridium catalyst, silane

Introduction

The trifluoromethyl (CF3) group is among the most important fluorinated groups owing to its ability to modulate pharmacological properties, such as membrane permeability, electrostatic/hydrophobic interactions with target receptors, and metabolic stability.1 Accordingly, diverse methodologies have been developed to efficiently synthesize trifluoromethylated compounds; however, the synthesis of complex molecules, bearing CF3 groups on tertiary or quaternary sp3 carbons, has not been extensively investigated.2 In particular, the enantioselective construction of trifluoromethylated stereogenic centers, which are found in bioactive compounds, such as reverse transcriptase inhibitors (efavirenz and its analogues)3 and neurokinin-1 receptor antagonist CJ-17,493 (Figure 1a),4 has been a formidable challenge.5 Two strategies have been developed to enantioselectively construct trifluoromethylated tertiary alcohol motifs; the first involves the asymmetric additions of a nucleophile to a trifluoromethyl ketone, and the second involves the asymmetric trifluoromethylation of ketones (Figure 1a, inset scheme). In addition to these strategies that use conventional nucleophilic addition chemistry, the enantioselective desymmetrization of trifluoromethylated tertiary alcohols is a powerful method because optically active products can be obtained by catalytically differentiating enantiotopic groups remote from the trifluoromethylated Csp3 center. Therefore, we investigated the enantioselective desymmetrization of trifluoromethylated benzhydrol 1 (Figure 1b). Our method has significant synthetic advantages; first, benzhydrol substrates can be prepared from readily available starting materials, and second, various optically active trifluoromethylated benzhydrols are accessible by transforming benzoxasilol products 3. The latter is significant in terms of drug discovery because chiral 1,1-diarylmethane motifs are found in a diverse range of bioactive compounds.6

Figure 1.

Figure 1

Open in a new tab

Background and our reaction design for catalytic desymmetrization of trifluoromethylated benzhydrols. (a) Bioactive compounds with trifluoromethylated tertiary stereogenic carbons and three methods for constructing trifluoromethylated tertiary alcohol motifs. (b) Our Ir-catalyzed enantioselective desymmetrization involving trifluoromethylated benzhydrols. (c) Previous Ir-catalyzed desymmetrization involving tertiary benzhydrol.

As a relevant example, Wang and co-workers recently reported the enantioselective desymmetrization of trifluoromethylated (isocyanomethylene)dibenzenes.7 Although this method affords various 1,3-diaryl-1H-isoindole derivatives in high yields and enantioselectivities, an alternative method for accessing divergent optically active trifluoromethylated tertiary benzhydrols remains elusive. Although Hartwig and co-workers developed the Rh- or Ir-catalyzed enantioselective desymmetrization of benzhydrols via intramolecular dehydrogenative silylation, tertiary benzhydrols have not yet been investigated as substrates.8 Moreover, the reaction of trifluoromethylated benzhydrols is challenging because the bulky and highly electron-withdrawing trifluoromethyl group strongly impacts the reactivity and selectivity of the enantioselective desymmetrization reaction. In fact, Zhang et al. demonstrated that the Ir-catalyzed enantioselective desymmetrization of a tertiary benzhydrol derivative produced a racemic product in low yield (Figure 1c).9 Therefore, we carefully optimized the reaction parameters, including the substrate silyl moiety, precatalysts, and chiral ligands, and found that Ir catalysts with chiral pyridine-oxazoline (PyOX) ligands are effective even in the absence of the hydrogen acceptor usually required for efficient dehydrogenative transformations (Figure 1b).

Results and Discussion

Initial Optimization

Based on a report by Hartwig et al.,8a we initially investigated the Rh-catalyzed intramolecular dehydrogenative silylation of hydrosilane 2a, which was obtained by the silylation of benzhydrol 1a (Table S1, Supporting Information). The reaction of 2a was performed in THF at 80 °C in the presence of 2.5 mol % [RhCl(cod)]2, 5 mol % rac-BINAP, and norbornene (NBE, 1.2 equiv); however, these conditions afforded 3a in only 24% yield (determined by 19F NMR spectroscopy) and 2a mostly remained unreacted (entry 1). The yield of 3a significantly improved when less-polar hydrocarbon solvents (toluene and cyclohexane) were used (entries 4 and 5). Several chiral phosphine ligands were screened in cyclohexane (CyH; Figure S1, Supporting Information). Because 3a is unsuitable for chiral high-performance liquid chromatography (HPLC) analysis, its enantioselectivity was determined after its conversion into more polar diol 4a via Tamao oxidation. Almost no asymmetric induction was observed using bisphosphine ligands, such as BINAP, SEGPHOS, Phanephos, Chiraphos, Me-ferrocelane, and Josiphos. In addition, tBu-Phox, MOP, and Monophos were ineffective ligands.

Therefore, Ir catalysis was investigated by performing the reaction of 2a using 5 mol % [IrOMe(cod)]2 and 11%11mol% chiral PyOX ligand because this type of chiral nitrogen ligand is readily available (Figure 2).10 Although the use of PyOX-type ligand L1 afforded 3a as a racemate in low yield (31%), PyOX ligand L2 bearing an indane-fused oxazoline moiety afforded a better yield (57%) albeit with a low enantiomeric ratio (57:43). Enantioselectivity improved (er 16:84) using quinoline-oxazoline ligand L3, although 3a was produced in a lower yield (38%). In contrast, the symmetrical bis(oxazoline)-type ligand L4 was ineffective.

Figure 2.

Figure 2

Open in a new tab

Ir-catalyzed intramolecular dehydrogenative silylation of 2a.

Having obtained promising results, we next examined several reaction parameters for the Ir/PyOX-catalyzed intramolecular dehydrogenative silylation of 2a (Figure 2 and Table 1). PyOX ligand L2 was used in this optimization study, as its pyridine ring can be further modified to improve enantioselectivity. The desired product 3a was obtained in 78% yield along with small amounts of 2a and desilylation byproduct 1a using a combination of [IrOMe(cod)]2 and L2 (Table 1, entry 1). A similar result was obtained using [IrOMe(cod)]2/L2 in the absence of NBE, showing that the hydrogen acceptor is unnecessary (entry 2). [IrCl(cod)]2, the precursor of [IrOMe(cod)]2, was used as a less expensive iridium source; however, a lower conversion of 2a was observed (entry 3). Interestingly, a higher conversion of 2a was obtained when NBE was omitted from the reaction by using [IrCl(cod)]2 (entry 4). No trace of 1a was observed in the absence of [IrCl(cod)]2, which suggests that the Ir catalyst is involved in the desilylation of 2a (entry 5). As adventitious water can promote desylilation, the reaction was conducted in the presence of a small amount of H2O (5 μL), which led to a significantly lower conversion of 2a, with an increased amount of 1a observed (entry 6). This result implies that H2O deactivates the catalyst. Therefore, MS3A was used to improve the catalytic efficiency by removing adventitious water from the reaction mixture (entry 7); gratifyingly, desilylation was effectively suppressed and the yield of 3a increased to 94%, despite the lower catalyst loading (2.5 mol %). In contrast, 2a was hardly consumed under similar conditions at 45 °C (entry 8). Therefore, an elevated reaction temperature (80 °C) is necessary for efficient reaction (see below). Moreover, the Ir-catalyzed dehydrogenative silylation of diethylsilane 2a(Et) was found to be inefficient, as the corresponding product was formed in less than 15% yield, which indicates that the smaller dimethylsilyl group is optimal.

Table 1. Optimization of the Reaction Conditions for the Ir/L2-Catalyzed Reaction of 2a.

entry X additive 3a/2a/1aa 4a erb
1 OMe NBE (1.2 equiv) 78/4/4 57:43
2 OMe   79/4/4 58:42
3 Cl NBE (1.2 equiv) 28/50/8 57:43
4 Cl   65/25/7 58:42
5     0/97/0  
6 Cl H2O (5 μL) 22/57/21 ND
7c Cl MS3A (20 wt %) 94/4/trace 58:42
8c,d Cl MS3A (20 wt %) 9/86/3 ND
Open in a new tab
a

Determined by 19F NMR analysis of crude mixture.

b

Determined after conversion of 3a into 4a using chiral HPLC (ND: not determined).

c

[IrCl(cod)]2, 2.5 mol %; PyOX, 5.5 mol %; reaction time, 5 h.

d

Reaction was performed at 45 °C for 24 h.

The optimal ligand was identified by examining several PyOX-type ligands under the optimized conditions (Figure 2). PyOX ligands L5–L7, each bearing a substituent at position 6, exhibited similarly high efficiencies (83–98% yields, er 6:94–5:95). However, L8, with a bulky tert-butyl substituent, was ineffective. An additional methyl substituent at the 4-position in L9 had almost no impact, whereas the use of 3-methyl analog L10 resulted in almost no enantioselectivity. These results clearly demonstrate the importance of the substituents at position 6 of the pyridine ring. Finally, tetrahydroquinoline-based ligand L11, which was reported by Shi et al., was found to be an effective ligand under our conditions; however, slightly lower enantioselectivity (8:92) was observed. Accordingly, L6, bearing an ethyl substituent at the 6-position, was determined to be the optimal ligand because it afforded the best yield and enantioselectivity.

Substrate Scope

We next investigated the substrate scope of Ir-catalyzed asymmetric dehydrogenative silylation under the identified optimal conditions and subsequent Tamao oxidation in a telescoping manner (Figure 3). The dehydrogenative silylation of p-tolyl-substituted hydrosilane 2a under standard conditions produced crude 3a (96% 19F NMR yield), which was directly subjected to Tamao oxidation to afford diol 4a in 88% yield over two steps with a high enantiomeric ratio (5:95). Similarly, diols 4c–e, bearing tert-butyl, phenyl, or methoxy substituents at the para-positions of the phenyl rings, were obtained in 88–96% yields with high enantiomeric ratios (4:96–3:97). Silane 2b devoid of substituents on its phenyl rings, and silanes 2f–h, bearing halogens at the para-positions, afforded the corresponding diols 4b and 4f–h, respectively, with high enantiomeric ratios, albeit in lower two-step yields (53–73%). Silanes 2i–k with meta-substituted phenyl rings and 2-naphthyl derivative 2l were also compatible with this telescoping method, with dehydrogenative silylation proceeding with high enantioselectivity (er 5:95–3:97); however, the Tamao oxidation of 3j–l afforded the corresponding diols in moderate yields (40–52%). In contrast, o-tolyl derivative 2m failed to afford 4m under the same conditions, whereas the use of 5 mol % [IrOMe(cod)]2 and 11 mol % L6 in the presence of NBE under harsh conditions (2-MeTHF, 120 °C, sealed tube) produced 5m in 67% yield through dehydrogenative silylation via benzylic C–H activation.11 A CF2H group was also compatible as 4n was obtained in 91% yield with an enantiomeric ratio of 7:93. The introduction of a bulkier C2F5 group led to lower yields of both intermediate 3o (71%) and final product 4o (56%), although a higher enantiomeric ratio (2:98) was obtained compared to that of 4b (5:95). Moreover, substrate 2p bearing a CF2CO2Et group afforded benzoxasilol 3p in 93% yield, which was directly used to determine the enantiomeric ratio (2:98). Bis(3-indolyl) and dialkenyl methanol derivatives were also subjected to dehydrosilylation; however, the former exhibited no reactivity, and the latter led to partial decomposition.

Figure 3.

Figure 3

Open in a new tab

Substrate scope of Ir-catalyzed asymmetric dehydrogenative silylation, followed by Tamao oxidation. Yields of isolated products over two steps are indicated along with enantiomeric ratios (er) determined by chiral HPLC analysis (red, nd: not determined). Crude yields of benzoxasilols 3 determined by 19F NMR spectroscopy are indicated in parentheses (blue).

Mechanistic Investigations

Based on the kinetic isotope effects (KIEs) observed in related Ir-catalyzed desymmetrization involving benzhydrol derivatives, Hartwig and Shi proposed a plausible catalytic cycle in the presence of NBE (R = H, Figure 4a).8b The oxidative addition (O.A.) of the silane substrate is reversible because no KIE was observed. The catalytic cycle starts with the insertion of NBE into iridium hydride species I followed by the O.A. of a hydrosilane substrate to generate alkyl hydride species II. Subsequent reductive elimination (R.E.) of norbornane from II is considered to be the rate-determining step.8b The resultant coordinatively unsaturated silyliridium(I) species III undergoes O.A. with the ortho C–H bond of a phenyl substituent to produce Ir(III) metallacyclic intermediate IV. The final R.E. event regenerates Ir(I) hydride I with the concomitant formation of a benzoxasilol product. In contrast to the previous methods,8 no hydrogen acceptor is required for the dehydrogenative silylation of the trifluoromethylated benzhydrol derivatives in this study. Therefore, an alternative catalytic cycle that operates in the absence of NBE needs to be considered (Figure 4b). The reaction of a chloroiridium(I) precatalyst with the hydrosilane substrate produces iridium(I) hydride I,12 which undergo facile O.A. of the hydrosilane substrate to generate Ir(III) dihydride species V.13,14 The subsequent ortho C–H O.A. of Ir(III) dihydride species V, which is the rate- and enantioselectivity-determining step, produces Ir(V) metallacyclic intermediate VI. A 1:1 mixture of 2b and 2b-d10 was allowed to react under the standard conditions for 1 h (Figure 4c). The 19F NMR spectrum of the crude reaction mixture revealed that benzoxasilol products 4b and 4b-d9 were formed in a 3.3:1 ratio, which suggests that the C–H activation step has an unignored effect on the overall reaction rate. Facile reductive elimination of H2 generates Ir(III) metallacyclic intermediate IV that then undergoes O.A. with another silane substrate and subsequent R.E. of the benzoxasilol product.15

Figure 4.

Figure 4

Open in a new tab

Mechanistic proposal. (a) Plausible catalytic cycle in the presence of NBE. (b) Alternative catalytic cycle in the absence of NBE. (c) Reaction with deuterated substrate 2b-d10.

While elucidating the details of the reaction mechanism requires further research, we used computational techniques to gain insight into the C–H activation step (Figure 5a). Density functional theory (DFT) calculations at the SMD (THF) M06/SDD–6-311+G(d,p)//B3LYP-D3(BJ)/LanL2DZ–6-31G(d) level of theory (for details, see the Supporting Information) afforded Ir(III) dihydride complex S-1, which has a square pyramidal geometry with a silyl ligand at the apical position, as the starting point. Geometrical isomerization of S-1 leads to the less-stable dihydride complex S-2 in which the silyl ligand is cis to the ligand oxazolyl moiety; S-2 further evolves into the slightly more stable intermediates Int-1R and Int-1S via C–O bond rotation. The transition states for O.A. of the ortho C–H bonds were located as TS-1R and TS-1S, with activation barriers of 15.2 and 19.1 kcal/mol from Int-1R and Int-1S, respectively. The formations of Ir(V) trihydride intermediates Int-2R and Int-2S are endergonic (12.9 and 17.0 kcal/mol, respectively). While the transition states for the subsequent H2 reductive elimination (TS-2R and TS-2S) were located, their Gibbs energies were lower than those of Int-2R and Int-2S, respectively; consequently, reductive elimination of H2 from Int-2R and Int-2S is barrierless, which leads to the exergonic (9.4 and 8.7 kcal/mol) formation of Ir(III) σ-H2 complexes Int-3R and Int-3S, respectively. Although the C–H activation steps leading to Ir(III) σ-H2 complexes are endergonic and reversible, facile extrusion of H2 gas from the reaction solutions at elevated temperatures renders the overall reaction irreversible.

Figure 5.

Figure 5

Open in a new tab

Computational studies. (a) DFT analysis of the C–H activation step. (b) NCI analyses of TS-1R and TS-1S.

The energetic span between S-1 and TS-1R (25.0 kcal/mol) is lower than that between S-1 and TS-1S (27.3 kcal/mol); hence, the (R) enantiomer is predicted to be favored. This result was corroborated by the X-ray diffraction (XRD) study of a product (see below). The enantiomeric ratio was theoretically determined to be (R):(S) = 96:4 at 80 °C from the difference in the activation barriers associated with TS-1R and TS-1S (ΔΔG‡ = 2.3 kcal/mol), which is in good agreement with the experimentally observed enantiomeric ratio of 95:5. TS-1R and TS-1S were subjected to noncovalent interaction (NCI) analysis.16 The green regions reveal π–π interactions between the benzene rings in the ligand and substrate (highlighted) in these TSs (Figure 5b). The π–π interactions are expected to be more efficient in TS-1R than in TS-1S because the distance between the two benzene rings is shorter in the former. Accordingly, TS-1R is favored over TS-1S, leading to the (R)-enantiomer being the major product. These analyses reveal that the ligand indenyl moiety plays an important role in stabilizing each TS. In fact, the C–H activation that proceeds from the face opposite to the ligand indenyl moiety is disfavored because the energetic span between S-1 and TS-3R or TS-3S is +31.7 and +28.7 kcal/mol, respectively (Figure S2, Supporting Information).

The influence of the C6 substituent of the PyOX ligands on the enantioselectivity is noteworthy (Figure 2). We located the C–H activation TSs involving L2 without the C6 substituent [TS-1R-(H) and TS-1S-(H)] and L5 with the methyl group at the 6-position [TS-1R-(Me) and TS-1S-(Me)], and their geometries were compared with those of TS-1R and TS-1S (Figure S3, Supporting Information). As a general trend, the Ir–N(Py) distances (l1) are longer than those of Ir–N(Ox) (l2) in these TSs. The difference between l1 and l2 decreased in the order TS-1R/TS-1S > TS-1R-(Me)/TS-1S-(Me) ≫ TS-1R-(H)/TS-1S-(H) because of the steric repulsion of the C6 alkyl groups of L6 and L5. Moreover, the same trend was found in the distance between the benzene rings in the PyOX ligand and substrate. These results qualitatively correlate with the experimentally observed order of enantioselectivity. However, the theoretical enantiomeric ratio (94:6) based on the energy difference between TS-1R-(H) and TS-1S-(H) (ΔΔG‡ = +1.96 kcal/mol) is much larger than that observed experimentally (58:42). Therefore, further investigation is needed to elucidate the role of the C6 substituents.

Although the above C–H activation step from the Ir(III) dihydride intermediate (Int-1R) is facile, an alternative C–H activation step involving an Ir(I) species generated via H2 reductive elimination from Int-1R is conceivable. However, the activation barrier of the H2 reductive elimination from Int-1R (ΔG‡ = +36.0 kcal/mol) is too high to overcome under the experimental conditions (Figure S4a, Supporting Information). The final R.E. of the benzoxasilol product from Ir(III) metallacyclic intermediate (Int-4R) proceeds with a resonable activation barrier of ΔG‡ = +23.9 kcal/mol (Figure S4b, Supporting Information); however, the R.E. step involving Ir(V) metallacyclic intermediate (Int-10R), which is generated via the O.A. of the hydrosilane substrate to Int-4R, was found to be barrierless (Figure S4c, Supporting Information). These results support the proposed Ir(III)/Ir(V) catalytic cycle as outlined in Figure 4b.17

To shed light on the role of the CF3 group, several control experiments were conducted (Figure 6). The reaction of trifluoromethylated benzhydrol derivatives 2a hardly proceeded under the conditions reported by Shi et al. (Figure 6a). Because ligand L11 was efficient under our conditions, an elevated reaction temperature is required for benzhydrol substrates bearing the bulky CF3 group. We assumed that the elevated reaction temperature facilitated the C–H activation step by extrusion of H2 from the reaction solution to the gas phase. In fact, the reaction of 2a performed in a sealed tube under our conditions resulted in diminished substrate conversion (Figure 6b). Then, nonfluorinated benzhydrols were subjected to Ir-catalyzed asymmetric dehydrogenative silylation and subsequent Tamao oxidation (Figure 6c). Secondary benzhydrol derivative 2q (R = H) exhibited low conversion (56%), with an enantiomeric ratio of 15:85 observed after Tamao oxidation, which is lower than that of the corresponding CF3-substituted analogue 4b (5:95). The CF3 group is comparable in size to the ethyl and isopropyl groups rather than the methyl group.18 Indeed, the van der Waals volume of the CF3 group (39.8 Å3) is closer to that of an ethyl group (38.9 Å3) than that of a methyl group (21.6 Å3), and the A value of the CF3 group (2.10 kcal/mol) is similar to that of an isopropyl group (2.15 kcal/mol), while those of the methyl and ethyl groups are smaller (1.70 kcal/mol). Consistent with these data, higher enantiomeric ratios were obtained in the reactions of tertiary benzhydrol derivatives 2r (R = Et, er 8:92) and 2s (R = iPr, er 1:99) than that of 2q, although the conversions of less than 63% were observed. In striking contrast, methoxymethyl-containing benzhydrol derivative 2t was converted into 4t in 68% yield over two steps, with a moderate enantiomeric ratio of 11:89 observed. These results highlight the importance of a heteroatom γ to the siloxy group in this Ir-catalyzed dehydrogenative silylation. We evaluated changes in Gibbs energies for the transformations of silanes 2 into benzoxasilols 3 and H2 (Figure 6d). The transformation of 2b (R = CF3) into 3b and H2 was calculated to be slightly exergonic (−0.5 kcal/mol), while that of 2r (R = Et) into 3r and H2 is endergonic by 2.5 kcal/mol, and the transformation of 2t (R = CH2OMe) into 3t and H2 was determined to be less endergonic (1.2 kcal/mol). These thermodynamic data are in good qualitative agreement with the observed reaction efficiencies: 2b > 2t ≫ 2r. We also hypothesize that the coordinating groups assist silane O.A. by placing the Si–H bond in close proximity to the Ir center (Figure 6d, inset scheme).

Figure 6.

Figure 6

Open in a new tab

Control experiments. (a) Reaction of 2a under Hartwig and Shi’s conditions. (b) Reaction of 2a under our conditions using a sealed tube. (c) Reactions of nonfluorinated benzhydrol derivatives. (d) Change in Gibbs energies for the transformations of 2 into 3 and H2.

Synthetic Applications

To demonstrate the synthetic potential of our method, we divergently transformed 3a into a representative product. According to a previous report,8a3a was treated with NIS or NBS in the presence of AgF (excess) in acetonitrile at room temperature to afford the desired iodide 6a or bromide 6b in high yields without significant erosion of the enantiomeric ratio (Figure 7a), after which 6a was subjected to transition-metal-catalyzed cross-coupling reactions (Figure 7b). The Suzuki–Miyaura coupling of 6a with p-anisylboronic acid (7) afforded the biaryl product 8 in 67% yield. The Sonogashira–Hagihara coupling of 6a with 1-ethynyl-4-methoxybenzene (9) produced (Z)-benzylidenephthalan derivative 10 in 73% yield via 5-exo cyclization of the initially formed diarylalkyne intermediate.19 In addition to these C–C coupling reactions, Ullmann coupling of 6a with p-toluidine (11) afforded diarylamine derivative 12 in 88% yield. Importantly, enantiomeric purity was maintained in all coupling reactions. The phenol moiety of 4a was tosylated using p-tosyl chloride and Et3N to afford 13 in 94% yield with an intact enantiomeric ratio (Figure 7c). Because good-quality single crystals of 13 were obtained, their absolute configuration was determined to be (R) by XRD.20

Figure 7.

Figure 7

Open in a new tab

Synthetic applications. (a) Halodesilylation of 3a. (b) Transition-metal-catalyzed transformations of iodide 6a into chiral trifluoromethylated benzhydrol derivatives. (c) Preparation of tosylate 13 and its crystal structure. (d) Kinetic resolution of unsymmetrical benzhydrol derivatives. Relative rate krel was determined using the equation: krel = ln[1 – c(1 + eep)]/ ln[1 – c(1–eep)] (c: conversion based on product yields, eep: product enantiomeric excess).

Finally, we briefly investigated the kinetic resolution of unsymmetrical substrates 2u–x using the Ir/PyOX catalyst system (Figure 7d). Because o-tolyl derivative 2m did not undergo dehydrogenative silylation under the standard conditions, benzhydrol derivative 2u bearing o-tolyl and phenyl substituents was subjected to Ir-catalyzed dehydrogenative silylation for 13 h. After Tamao oxidation, phenol derivative 4u was obtained in 34% yield with a moderate enantiomeric ratio of 11:89. In contrast, a benzhydrol derivative bearing an o-methoxyphenyl substituent failed to undergo dehydrogenative silylation. Therefore, we examined benzhydrol derivatives bearing 3,5-disubstituted phenyl substituents as substrates. Dehydrogenative silylation of 2v bearing 3,5-xylyl substituent was conducted for 4 h, and the subsequent Tamao oxidation afforded phenol derivative 4v in 43% yield with a higher enantiomeric ratio of 96:4. 3,5-Dimethoxyphenyl derivative 2w and 3,5-dichlorophenyl derivative 2x were also compatible with the kinetic resolution conditions; the corresponding products 4w and 4x were produced in 40% and 47% yields, respectively, and with moderate enantiomeric purities (er = 88:12 and 87:13, respectively).

Conclusions

We successfully realized the enantioselective desymmetrization of trifluoromethylated benzhydrols via intramolecular dehydrogenative silylation using Ir catalysts and chiral PyOX ligands. No hydrogen acceptor was required for the present enantioselective desymmetrization of trifluoromethylated benzhydrols, unlike previous Rh- or Ir-catalyzed methods, which require norbornene as the hydrogen acceptor. The mechanism responsible for differentiating the enantiotopic aryl ortho C–H bonds was examined using DFT calculations. The produced benzoxasilol can be transformed into several unsymmetrical benzhydrols via iododesilylation, followed by transition-metal-catalyzed cross-coupling reactions. Moreover, the same Ir/PyOX catalyst system was applied to the kinetic resolution of unsymmetrical trifluoromethylated benzhydrols.

Methods

Representative Procedure for Sequential Intramolecular Dehydrogenative Silylation/Tamao–Fleming Oxidation

A solution of silyl ether 2a (67.6 mg, 0.200 mmol), [IrCl(cod)]2 (3.4 mg, 0.00506 mmol), PyOX ligand L6 (2.9 mg, 0.0110 mmol), and MS3A (0.2 g) in dry THF (1 mL) was degassed at −90 °C and then stirred at 80 °C for 5 h under an Ar atmosphere. The volatile materials were evaporated in vacuo, and the obtained crude product was filtered through a short-pass silica gel column (hexane/AcOEt, 10/1). The crude yield of 3a (96%) was evaluated by 19F NMR using trifluorotoluene as an internal standard.

To crude 3a were added KHCO3 (62.8 mg, 0.627 mmol), KF (37.0 mg, 0.637 mmol), MeOH (0.5 mL), THF (0.5 mL), and aq. H2O2 (ca. 34.5%, 0.2 mL, ca. 2 mmol), and the mixture was stirred at room temperature for 12 h. The reaction was quenched by adding portion-wise Na2S2O3·5H2O (0.3 g). The mixture was stirred at room temperature for 30 min. The mixture was filtered through a pad of Celite, and insoluble materials were washed with ether (10 mL). The solvents were evaporated in vacuo, and the obtained crude product was purified by silica gel column chromatography (hexane/AcOEt, 98:2–94:6) to afford 4a (52.2 mg, 88%, er 5:95) as a colorless oil.

Acknowledgments

This research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED under Grant Number JP23ama121044) and JSPS KAKENHI (Grant Number JP 22K05110). Computations were performed using the Research Center for Computational Science, Okazaki, Japan (Project: 22-IMS-C242, 23-IMS-C125). R.T. acknowledges the Interdisciplinary Frontier Next-Generation Researcher Program of the Tokai Higher Education and Research System.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.3c00794.

  • Experimental details; characterization data for all new compounds; DFT calculation data; and HPLC and NMR charts (PDF)

  • X-ray crystallographic data for 13 (CIF)

Author Contributions

CRediT: Yoshihiko Yamamoto conceptualization, data curation, project administration, writing-original draft; Ryu Tadano data curation, investigation, writing-review & editing; Takeshi Yasui validation, writing-review & editing.

The authors declare no competing financial interest.

Supplementary Material

au3c00794_si_001.pdf (16.6MB, pdf)
au3c00794_si_002.cif (23.9KB, cif)

References

  1. a Müller K.; Faeh C.; Diederich F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881–1886. 10.1126/science.1131943. [DOI] [PubMed] [Google Scholar]; b Purser S.; Moore P. R.; Swallow S.; Gouverneur V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320–330. 10.1039/B610213C. [DOI] [PubMed] [Google Scholar]
  2. Selected reviews:; a Ma J.-A.; Cahard D. Strategies for nucleophilic, and radical trifluoromethylations. J. Fluorine Chem. 2007, 128, 975–996. 10.1016/j.jfluchem.2007.04.026. [DOI] [Google Scholar]; b Liu H.; Gu Z.; Jiang X. Direct Trifluoromethylation of the C–H Bond. Adv. Synth. Catal. 2013, 355, 617–626. 10.1002/adsc.201200764. [DOI] [Google Scholar]; c Zhu W.; Wang J.; Wang S.; Gu Z.; Aceña J. L.; Izawa K.; Liu H.; Soloshonok V. A. Recent advances in the trifluoromethylation methodology and new CF3-containing drugs. J. Fluorine Chem. 2014, 167, 37–54. 10.1016/j.jfluchem.2014.06.026. [DOI] [Google Scholar]; d Barata-Vallejo S.; Postigo A. New Visible-Light-Triggered Photocatalytic Trifluoromethylation Reactions of Carbon–Carbon Multiple Bonds and (Hetero)Aromatic Compounds. Chem. - Eur. J. 2020, 26, 1065–11084. 10.1002/chem.202000856. [DOI] [PubMed] [Google Scholar]; e Aradi K.; Kiss L. Carbotrifluooromethylations of C–C Multiple Bonds (Excluding Aryl- and Alkynyltrifluoromethylations). Chem. - Eur. J. 2023, 29, e202203499 10.1002/chem.202203499. [DOI] [PubMed] [Google Scholar]; f Kawamura S.; Barrio P.; Fustero S.; Escorihuela J.; Han J.; Soloshonok V. A.; Sodeoka M. Evolution and Future of Hetero- and Hydro-Trifluoromethylations of Unsaturated C–C bonds. Adv. Synth. Catal. 2023, 365, 398–462. 10.1002/adsc.202201268. [DOI] [Google Scholar]
  3. a Li S.; Ma J.-A. Core-structure-inspired asymmetric addition reactions: enantioselective synthesis of dihydrobenzoxazinone- and dihydroquinazolinonne-based anti-HIV agents. Chem. Soc. Rev. 2015, 44, 7439–7448. 10.1039/C5CS00342C. [DOI] [PubMed] [Google Scholar]; b Bastos M. M.; Costa C. C. P.; Bezerra T. C.; de C da Silva F.; Boechat N. Efavirenz a nonnucleoside reverse transcriptase inhibitor of first-generation: Approaxhes based on its medicinal chemistry. Eur. J. Med. Chem. 2016, 108, 455–465. 10.1016/j.ejmech.2015.11.025. [DOI] [PubMed] [Google Scholar]
  4. Shishido Y.; Wakabayashi H.; Koike H.; Ueno N.; Nukui S.; Yamagishi T.; Murata Y.; Naganeo F.; Mizutani M.; Shimada K.; Fujiwara Y.; Sakakibara A.; Suga O.; Kusano R.; Ueda S.; Kanai Y.; Tsuchiya M.; Satake K. Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist ‘CJ-17,493′. Bioorg. Med. Chem. 2008, 16, 7193–7205. 10.1016/j.bmc.2008.06.047. [DOI] [PubMed] [Google Scholar]
  5. a Ma J.-A.; Cahard D. Update 1 of: Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions. Chem. Rev. 2008, 108, PR1–PR43. 10.1021/cr800221v. [DOI] [PubMed] [Google Scholar]; b Huang Y.-Y.; Yang X.; Chen Z.; Verpoort F.; Shibata N. Catalytic Asymmetric Synthesis of Enantioenriched Heterocycles Bearing a C–CF3 Stereogenic Center. Chem. - Eur. J. 2015, 21, 8664–8684. 10.1002/chem.201500361. [DOI] [PubMed] [Google Scholar]; c He X.-H.; Ji Y.-L.; Peng C.; Han B. Organocatalytic Asymmetric Synthesis of Cyclic Compounds Bearing a Trifluoromethylated Stereogenic Center: Recent Developments. Adv. Synth. Catal. 2019, 361, 1923–1957. 10.1002/adsc.201801647. [DOI] [Google Scholar]
  6. Ameen D.; Snape T. J. Chiral 1,1-diaryl compounds as important pharmacophores. Med. Chem. Commun. 2013, 4, 893–907. 10.1039/c3md00088e. [DOI] [Google Scholar]
  7. Wang J.; Li L.; Chai M.; Ding S.; Li J.; Shang Y.; Zhao H.; Li D.; Zhu Q. Enantioselective Construction of 1H-Isoindoles Containing Tri- and Difluoromethylated Quaternary Stereogenic Centers via Palladium-Catalyzed C–H Bond Imidoylation. ACS Catal. 2021, 11, 12367–12374. 10.1021/acscatal.1c03682. [DOI] [Google Scholar]
  8. a Lee T.; Wilson T. W.; Berg R.; Ryberg P.; Hartwig J. F. Rhodium-Catalyzed Enantioselective Silylation of Arene C–H Bonds: Desymmetrization of Diarylmethanols. J. Am. Chem. Soc. 2015, 137, 6742–6745. 10.1021/jacs.5b03091. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Su B.; Zhou T.-G.; Li X.-W.; Shao X.-R.; Xu P.-L.; Wu W.-L.; Hartwig J. F.; Shi Z.-J. A Chiral Nitrogen Ligand for Enantioselective, Iridium-Catalyzed Silylation of Aromatic C–H bonds. Angew. Chem., Int. Ed. 2017, 56, 1092–1096. 10.1002/anie.201609939. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Su B.; Hartwig J. F. Development of Chiral Ligands for the Transition-Metal-Catalyzed Enantioselective Silylation and Borylation of C–H Bonds. Angew. Chem., Int. Ed. 2022, 61, e202113343 10.1002/anie.202113343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Zhang H.; Zhao D. Synthesis of Silicon-Stereogenic Silanols Involving Iridium-Catalyzed Enantioselective C–H Silylation Leading to a New Ligand Scaffold. ACS Catal. 2021, 11, 10748–10753. 10.1021/acscatal.1c03112. [DOI] [Google Scholar]
  10. Yang G.; Zhang W. Renaissance of pyridine-oxazolines as chiral ligands for asymmetric catalysis. Chem. Soc. Rev. 2018, 47, 1783–1810. 10.1039/C7CS00615B. [DOI] [PubMed] [Google Scholar]
  11. Ru-catalyzed intramolecular benzylic C–H silylation has been reported:; Zuo Z.; Xu S.; Zhang L.; Gan L.; Fang H.; Liu G.; Huang Z. Cobalt-Catalyzed Asymmetric Hydrogenation of Vinylsilanes with a Phosphine–Pyridine–Oxazoline Ligand: Synthesis of Optically Active Organosilanes and Silacycles. Organometallics 2019, 38, 3906–3911. 10.1021/acs.organomet.9b00067. [DOI] [Google Scholar]
  12. The generation of hydridoiridium(I) species from chloroiridium(I) complexes and hydrosilanes has been proposed, see:; a Song L.-J.; Ding S.; Wang Y.; Zhang X.; Wu Y.-D.; Sun J. Ir-Catalyzed Regio- and Stereoselective Hydrosilylation of Internal Thioalkynes: A Combined Experimental and Computational Study. J. Org. Chem. 2016, 81, 6157–6164. 10.1021/acs.joc.6b00854. [DOI] [PubMed] [Google Scholar]; b Srinivas V.; Nakajima Y.; Sato K.; Shimada S. Iridium-Catalyzed Hydrosilylation of Sulfur-Containing Olefins. Org. Lett. 2018, 20, 12–15. 10.1021/acs.orglett.7b02940. [DOI] [PubMed] [Google Scholar]; c Zhang X.; Gao C.; Xie X.; Liu Y.; Ding S. Thioether-Facilitated Iridium-Catalyzed Hydrosilylation of Steric 1,1-Disubstituted Olefins. Eur. J. Org. Chem. 2020, 2020, 556–560. 10.1002/ejoc.201901513. [DOI] [Google Scholar]
  13. a Harrod J. F.; Gilson D. F. R.; Charles R. Oxidative addition of silicon hydrides to hydridocarbonyltris(triphenylphosphine)iridium(I). Can. J. Chem. 1969, 47, 2205–2208. 10.1139/v69-358. [DOI] [Google Scholar]; b Chalk A. J. A New Synthesis of Silyliridium Hydrides. J. Chem. Soc. D 1969, 1207–1208. 10.1039/c29690001207. [DOI] [Google Scholar]
  14. Two pairs of hydride signals were observed when the stoichiometric reaction of [IrCl(cod)]2 (1 equiv), L6 (2 equiv), and 2b (2 equiv) in THF-d8 at 80 °C was monitored by 1H NMR spectroscopy (see, Supporting Information).
  15. Trace amounts of H2 was detected when the catalytic reaction of 2b in THF-d8 under the standard conditions was monitored by 1H NMR spectroscopy (see, Supporting Information).
  16. Johnson E. R.; Keinan S.; Mori-Sánchez P.; Contreras-García J.; Cohen A. J.; Yang W. Revealing Noncovalent Interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506. 10.1021/ja100936w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. A similar Ir(III)/Ir(V) catalytic cycle was also proposed for a related dehydrogenative silylation:; Zhang M.; Liang J.; Huang G. Mechanism and Origins of Enantioselectivity of Ir-Catalyzed Intramolecular Silylation of Unactivated C(sp3)–H Bonds. J. Org. Chem. 2019, 84, 2372–2376. 10.1021/acs.joc.9b00117. [DOI] [PubMed] [Google Scholar]
  18. Meanwell N. A. Fluorine and Fluorinated Motifs in the Design and Application of Bioisosters for Drug Design. J. Med. Chem. 2018, 61, 5822–5880. 10.1021/acs.jmedchem.7b01788. [DOI] [PubMed] [Google Scholar]
  19. A related tandem reaction, leading to (Z)-1-benzylidene-1,3-dihydroisobenzofurans, was reported:; Zanardi A.; Mata J. A.; Peris E. Domino Approach to Benzofurans by the Sequential Sonogashira/Hydroalkoxylation Couplings Catalyzed by New N-Heterocyclic-Carbene-Palladium Complexes. Organometallics 2009, 28, 4335–4339. 10.1021/om900358r. [DOI] [Google Scholar]
  20. Deposition number 2310281 (for 13) contains the supporting crystallographic data for this paper.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au3c00794_si_001.pdf (16.6MB, pdf)
au3c00794_si_002.cif (23.9KB, cif)

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES