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Cross-dehydrogenative coupling enables enantioselective access to CF3-substituted all-carbon quaternary stereocenters

Xiaoguang Pan a, Zehua Wangb, Linglong Kanb, Ying Maoa, Yasheng Zhua and Lei Liu*ab
aSchool of Pharmaceutical Sciences, Shandong University, Jinan 250012, China. E-mail:
bSchool of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China

Received 20th November 2019 , Accepted 9th January 2020

First published on 29th January 2020

A cross-dehydrogenative coupling strategy for enantioselective access to acyclic CF3-substituted all-carbon quaternary stereocenters has been established. By using catalytic DDQ with MnO2 as an inexpensive terminal oxidant, asymmetric cross coupling of racemic δ-CF3-substituted phenols with indoles proceeded smoothly, providing CF3-bearing all-carbon quaternary stereocenters with excellent chemo- and enantioselectivities. The generality of the strategy is further demonstrated by efficient construction of all-carbon quaternary stereocenters bearing other polyfluoroalkyl and perfluoroalkyl groups such as CF2Cl, C2F5, and C3F7.


Enantiopure molecules bearing a trifluoromethyl-containing stereogenic center often possess desirable properties.1 Therefore, practical and robust approaches for their enantioselective synthesis are highly attractive.2 On the other hand, the catalytic enantioselective construction of all-carbon quaternary stereocenters remains one of the great challenges in organic chemistry.3 In this context, enantioselective construction of acyclic CF3-substituted all-carbon quaternary centers is particularly daunting.4–7 Since the seminal work by Shibata, current strategies are restricted to 1,4-conjugate addition to β,β-disubstituted CF3-enones or nitroolefins (Scheme 1a),4 and two isolated methods including substitution of a propargyl electrophile (Scheme 1b),5 and hydrohydroxymethylation of CF3-bearing allenes (Scheme 1c).6 All of these methods rely on reactive functional groups, and extra steps are usually involved for their incorporation. Developing a strategically different C–H functionalization approach for enantioselective construction of CF3-bearing all-carbon quaternary centers is highly desirable.
image file: c9sc05894j-s1.tif
Scheme 1 Overview of enantioselective access to acyclic CF3-substituted all-carbon quaternary stereocenters.

Enantioselective cross-dehydrogenative coupling (CDC) of two easily accessible C–H substrates represents a straightforward and economical approach in organic synthesis.8 Existing studies predominantly focused on C–H bonds adjacent to a heteroatom.9,10 But surprisingly, asymmetric CDC involving functionalization of acyclic benzylic C–H bonds has rarely been explored.11,12 Elegant works from the groups of Cozzi and Gong reported enantioselective CDC of 3-arylmethylindoles with aldehydes11a and malonates.11b In addition, CDC technology for enantioselective construction of all-carbon quaternary stereocenters has remained elusive.13 Recently, our group disclosed a chiral imidodiphosphoric acid catalyzed asymmetric CDC of 2,2-diarylacetonitriles with (hetero)arenes, furnishing triarylmethanes bearing all-carbon quaternary stereocenters with excellent enantioselectivity.13c Given the importance of optically active hetero-di- and hetero-triarylmethanes in chemistry, biology, material science, and medicine,14 we decided to explore the asymmetric CDC of racemic p-hydroxybenzyl CF3 moieties with heteroarenes for construction of these motifs containing CF3-substituted all-carbon quaternary stereocenters (Scheme 1d).

Three main challenges might obstruct the reaction design. First, regioselective oxidation of Cδ–H bond adjacent to strong electron-withdrawing CF3 group is difficult to achieve, which might be accompanied by competitive oxidation of Cα–H bond to 1,2-benzoquinones.15 Second, even if the expected oxidation proceeded smoothly, the CDC reaction might still be precluded by the potential incompatibility of electron-rich heteroarenes with strongly oxidative conditions. Third, the oxidized intermediate is expected to be highly unstable δ-CF3-substituted para-quinone methide (p-QM).16 Effective and enantioselective addition to highly congested CF3-substituted carbon of reactive p-QM intermediate under strongly oxidative conditions is substantially challenging.17–19

Results and discussion

Initially, chiral phosphoric acid catalyzed asymmetric CDC of p-hydroxybenzyl CF3 1a with indole 2a was selected as a model reaction for optimization (Table 1).20 To explore a suitable oxidation system, the reaction involving an initial oxidation of 1a followed by 3a catalyzed nucleophilic addition of 2a was conducted in a two-step, one-pot manner. As expected, efficient oxidation of 1a proved to be challenging. Common reagents for phenol oxidation, such as K3Fe(CN)6, (NH4)2S2O8, Ag2O, PhI(OAc)2, and MnO2, proved to be futile (entries 1 and 2, Table 1). Reaction with DDQ provided expected 4a in 10% yield with 26% ee, though the majority of 1a (83%) was recovered (entry 3, Table 1). Increasing the loading of DDQ did not improve oxidation conversion (entry 4, Table 1). We envisioned that oxidation of 1a with DDQ might be a reversible process, and adopting a DDQ-catalyzed oxidation system might be beneficial for breaking the equilibrium and driving the oxidation process. A screen of terminal oxidants towards metal oxides revealed that use of DDQ (25 mol%) as catalyst and MnO2 as stoichiometric oxidant furnished a complete and clean oxidation, and the CDC process afforded 4a in 70% yield with 55% ee (entries 5–7, Table 1).21 Reversal of the procedure by adding all the components prior to oxidation gave an inferior result (entry 8, Table 1). Optimization of chiral phosphoric acid catalysts identified 3c to be optimal (entries 7 and 9–12, Table 1). K2CO3 as a basic additive proved to be beneficial for improving the enantiocontrol (entry 13, Table 1). Increasing the loading of 2a was beneficial to the reaction by slowing down the nucleophilic addition process, and 4a was isolated in 86% yield with 93% ee (entry 14, Table 1).
Table 1 Optimization of the reaction conditionsa

image file: c9sc05894j-u1.tif

Entry Oxidant Catalyst Yieldb (%) eec (%)
a Reaction conditions: 1a (0.1 mmol) and oxidant (0.12 mmol) in CH2Cl2 at 60 °C for 8 h, followed by 2a (0.1 mmol), 3 (5 mol%), 3 Å molecular sieves (20 mg) at −78 °C for 1 h.b Yield of isolated product.c Determined by chiral HPLC analysis.d K3Fe(CN)6, (NH4)2S2O8, Ag2O, and PhI(OAc)2 as oxidant.e 2.0 equiv. of DDQ used.f 25 mol% DDQ with 3.0 equiv. of terminal oxidant.g 2a and 3a added before oxidation.h 2.0 equiv. of K2CO3 as additive.i 2a (0.3 mmol) used. n.d. = not determined.
1d Oxidant 3a <5 n.d.
2 MnO2 3a <5 n.d.
3 DDQ 3a 10 26
4e DDQ 3a 12 21
5f DDQ/FeCl3 3a <5 n.d.
6f DDQ/Mn(OAc)3 3a 45 39
7f DDQ/MnO2 3a 70 55
8f,g DDQ/MnO2 3a 32 9
9f DDQ/MnO2 3b <5 n.d.
10f DDQ/MnO2 3c 78 85
11f DDQ/MnO2 3d <5 n.d.
12f DDQ/MnO2 3e 36 41
13f,h DDQ/MnO2 3c 83 88
14f,h,i DDQ/MnO2 3c 86 93
image file: c9sc05894j-u2.tif

The scope of asymmetric CDC of δ-CF3-δ-alkynyl substituted 1 with 2a was investigated (Scheme 2). In general, substrates bearing a wide range of electronically varied aryl acetylenes with different substitution patterns were tolerated, affording respective hetero-diarylmethanes 4a–4g, 4j, and 4k in good yields with excellent ee. Polyarene naphthalene substituted acetylene 1h and thiophene substituted 1i proved to be competent coupling partners. δ-Alkyl acetylene-containing 1l–1p were also compatible with the asymmetric CDC process, furnishing corresponding 4l–4p in 66–73% yields with up to 93% ee. The process exhibited a good functional group tolerance, with common functionalities like halides (4d and 4e), primary alcohol (4n), propargyl chloride (4o), and silyl group (4p) well tolerated for further manipulation.

image file: c9sc05894j-s2.tif
Scheme 2 Scope of δ-alkynyl-substituted substrates for CF3-containing hetero-diarylmethanes. aReaction with 3b (5 mol%) and 2a (1.1 equiv.) without K2CO3 additive. bAsymmetric nucleophilic addition of 2a was performed at 0 °C.

Asymmetric CDC of a variety of δ-aryl substituted 5 with 2a proceeded smoothly, affording respective CF3-bearing hetero-triarylmethanes 6a–6f with 90–97% ee (Scheme 3). To our knowledge, this is the first example of direct and asymmetric construction of CF3-substituted tri-arylmethanes.5

image file: c9sc05894j-s3.tif
Scheme 3 Scope of δ-aryl-substituted substrates for CF3-containing hetero-triarylmethanes. aReaction with 2a (1.1 equiv.).

The substituent effect of indoles was next evaluated (Scheme 4). A broad range of indoles 2 bearing either electron-donating or -withdrawing groups at different positions (C4, C5, C6, and C7) on aryl rings participated in the CDC process, furnishing corresponding 7a–7h in 75–88% yields with 90–96% ee. Additionally, C2-substituted indoles proved to be competent components, as demonstrated by the generation of 7i in 70% yield with 92% ee. Besides indole moieties, 2-substituted pyrroles were also identified to be suitable coupling partners in asymmetric CDC reaction, as illustrated by the formation of 9 in 65% yield with 93% ee (Scheme 5). While the scope of 2-substituted pyrroles was not exclusively explored, the result afforded a proof-of-concept for the modularity of the method for asymmetric preparation of diversely functionalized hetero-diarylmethanes bearing CF3-substituted all-carbon quaternary stereocenters.

image file: c9sc05894j-s4.tif
Scheme 4 Scope of the indole components.

image file: c9sc05894j-s5.tif
Scheme 5 Asymmetric CDC with 2-substituted pyrrole. a1.0 equiv. of 8 used.

The generality of the CDC approach is further demonstrated by enantioselective construction of all-carbon quaternary stereocenters bearing other polyfluoroalkyl or perfluoroalkyl groups, such as CF2Cl (11a), C2F5 (11b), and C3F7 (11c) (Scheme 6).

image file: c9sc05894j-s6.tif
Scheme 6 Enantioselective access to other polyfluoroalkyl-bearing all-carbon quaternary stereocenters.

The synthetic utilities of the method were next examined (Scheme 7). The phenolic hydroxyl group in 4a was removed through triflation followed by hydrogenation affording 12 in 86% yield (Scheme 7a). Phenol 4a can also undergo triflation followed by palladium-catalyzed cross-coupling reaction, furnishing biaryl 13 efficiently (Scheme 7b). Notably, the ee values of the products remain highly reserved in these processes.

image file: c9sc05894j-s7.tif
Scheme 7 Representative product transformations.

Control experiments were performed to gain further insights into the mechanism (Scheme 8). Upon completion of oxidation of 1a, δ-CF3-δ-alkynyl-substituted p-QM 14 was isolated in 11% yield (Scheme 8a). The low yield might be ascribed to the poor stability of δ-CF3-substituted p-QM compound. Subjecting 14 to standard CDC conditions in the absence of oxidation elements furnished 4a with comparable yield and ee to those observed in the one-pot process, thus indicating the intermediacy of p-QM 14 (Scheme 8b). No invertible reaction was observed for 14 and 2,3-dichloro-4,5-dicyanohydroquinone (DDQH2), the reduction product of DDQ (Scheme 8c). The asymmetric 1,6-conjugate addition to 14 was not influenced by introducing stoichiometric amount of acidic DDQH2 (Scheme 8d). K2CO3 was found to be beneficial for improving the enantiocontrol (entry 13, Table 1). Accordingly, chiral potassium-organophosphate 3f was prepared in situ for real catalyst identification (Scheme 8e). No enantioselective catalytic reactivity was observed for 3f, implying that 3c but not 3f should be the real catalyst, and the hydroxyl group in chiral phosphoric acid is requisite. No reaction was observed for p-methoxybenzyl CF3 15, indicating the significance of the hydroxyl moiety in the in situ formation of p-QM intermediate (Scheme 8f). According to the above experiments, a plausible mechanism was recommended (Scheme 8g). Racemic p-hydroxybenzyl CF3 moiety 1a might be oxidized by catalytic amount of DDQ, giving p-QM 14 together with the generation of DDQH2. Stoichiometric MnO2 as terminal oxidant proved to be crucial to the complete oxidation of 1a to 14 by converting DDQH2 to DDQ for the catalytic cycle.21 Chiral phosphoric acid 3c catalyzed asymmetric 1,6-conjugate addition of indole 2a to 14 yielding expected 4a.22 Asymmetric CDC of 1a with N-methyl protected indole 19 provided inferior ee to unprotected 2a, implying that the N–H moiety might act as a hydrogen bond donor (Scheme 8h). A plausible transition state was proposed in Scheme 8i, in which chiral phosphoric acid acts as a bifunctional role for activation of both coupling partners and remote stereocontrol by hydrogen bonding. p-QM intermediates can be generated in situ through chiral phosphoric acid catalyzed dehydration of p-hydroxybenzyl alcohols.17 Accordingly, δ-CF3-substituted p-hydroxybenzyl alcohol 21 was subjected to the CDC condition without oxidation elements (Scheme 8j). However, no reaction was observed even at an elevated temperature, thus demonstrating the uniqueness of the oxidation strategy in generating unstable δ-CF3-substituted p-QM intermediates.

image file: c9sc05894j-s8.tif
Scheme 8 Control experiments and the proposed mechanism.


In summary, CDC strategy for enantioselective construction of CF3-substituted all-carbon quaternary stereocenters has been established for the first time. By using catalytic DDQ with MnO2 as an inexpensive terminal oxidant, asymmetric cross-coupling of racemic p-hydroxybenzyl CF3 moieties with indoles and pyrroles proceeded smoothly, providing acyclic CF3-bearing all-carbon quaternary centers with excellent chemo- and enantioselectivity. The generality of the strategy is further demonstrated by efficient formation of all-carbon quaternary centers bearing other polyfluoroalkyl and perfluoroalkyl groups such as CF2Cl, C2F5, and C3F7. We envisioned that the strategically different approach described here will provide an attractive platform for enantioselective access to all-carbon quaternary stereocenters bearing diverse perfluoroalkyl groups that are otherwise difficult to be prepared by existing methods.

Conflicts of interest

There are no conflicts to declare.


We gratefully acknowledge the National Science Foundation of China (21722204 and 21971148), Fok Ying Tung Education Foundation (151035), and Youth Interdiscipline Innovative Research Group of Shandong University (2020QNQT009).

Notes and references

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Electronic supplementary information (ESI) available. See DOI: 10.1039/c9sc05894j
These authors contributed equally.

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