A Base-Promoted Reductive Coupling Platform for the Divergent Defluorofunctionalization of Trifluoromethylarenes

Abstract

We report a trifluoromethylarene reductive coupling method that dramatically expands the scope of difluorobenzylic substructures accessible via C–F bond functionalization. Catalytic quantities of a Lewis base, in conjunction with a disilane reagent in formamide solvent, leads to the replacement of a single trifluoromethyl fluorine atom with a silylated hemiaminal functional group. The reaction proceeds through a difluorobenzyl silane intermediate that can also be isolated. Together, these defluorinated products are shown to provide rapid access to over 20 unique difluoroalkylarene scaffolds.

Graphical Abstract

The α,α-difluorobenzylic substructure (ArCF₂R) is often studied in pharmaceutical and agrochemical research as a means to modulate bioavailability and metabolic stability, amongst other potential benefits of fluorine incorporation.¹ A key feature of an aromatic difluoroalkyl substituent is the structural modularity possible via the R group, allowing further optimization of a compound’s desired properties. The challenge of exploring this chemical space lies in the lack of general methods to access derivatives from a single precursor, typically requiring the synthesis of a unique reagent for each target of interest.² For example, carbonyl deoxyfluorination^3,4 and cross-coupling⁵ reactions are commonly used to access such motifs, but these routes first require access to the carbonyl or RCF₂X coupling partner, respectively.⁶ Therefore, a method that can access valuable α,α-difluorobenzylic frameworks in a diversifiable fashion could greatly accelerate investigation of this substructure.⁷

The C–F functionalization of trifluoromethylarenes is an ideal route to α,α-difluorobenzylic compounds due to the wide availability of trifluoromethylarenes and their prevalence in late-stage settings.⁸ The impact of such methodology hinges on the ability to access α,α-difluorobenzylic derivatives that reflect the structural diversity found in bioactive compounds (Figure 1).⁹ A major challenge for the single C–F substitution of a trifluoromethyl group is the fact that the C–F bonds become weaker as defluorination proceeds¹⁰, typically resulting in overfunctionalization.¹¹ Early efforts to address this challenge using electrochemical¹² and metal¹³ reducing conditions are either limited to simple trifluoromethylbenzenes or are unselective. Recent reports by König, Jui, and Gouverneur use photoredox catalysis to achieve monoselective C–F reduction and hydroalkylation on a wide range of trifluoromethylarenes.¹⁴ An alternative strategy reported by Young employs frustrated Lewis pairs to form C–F substituted pyridinium and phosphonium salts, primarily used as electrophilic difluorobenzylic reagents.^15,16 Despite these impressive advancements, there is still the need for a unified method that accesses a greater breadth of α,α-difluorobenzylic substructures from trifluoromethylarenes.

Figure 1.

Goals for defluorofunctionalization methodology.

Our group recently reported a fluoride-initiated protocol for the selective defluoroallylation of trifluoromethylarenes using allyltrimethylsilane coupling partners (Figure 2a).^17,18 While practical, this reaction can only access difluoroalkyl substituents that map onto the allyl coupling fragment. To address this limitation, we herein report the development of a base-initiated, silane-mediated, reductive coupling platform of trifluoromethylarenes (Figure 2b). This method expands the C–F transformations accessible from trifluoromethylarenes by providing a versatile silylated hemiaminal synthon that possesses the reactivity of both an aldehyde and an iminium ion. The identification of a difluorobenzyl silane as the key intermediate for the reductive coupling reaction also allowed for its isolation and use as a general difluorobenzylic pronucleophile.

Figure 2.

Overview of base-promoted ArCF₃ functionalization.

This work began with the goal of discovering a single silane reagent that couples with trifluoromethylarenes to generate synthetically versatile difluorobenzylic products. While investigating disilane¹⁹ coupling partners, we observed that catalytic activation of commercially available tris(trimethylsilyl)silane (TTMSS) with Lewis basic salts in DMF generates silylated hemiaminal adduct 2 (Scheme 1). Given that a silylated hemiaminal could potentially serve as a branching point for a wealth of derivatization reactions, we sought to further optimize this reaction. Notably, similar silylated hemiacetal and hemiaminal adducts were proposed as intermediates in Lalic’s dual Pd/Cu-catalyzed selective trifluoromethylarene reduction protocol that is conducted with triphenylsilane in DMF.²⁰ Strong Lewis bases, such as fluoride and alkoxide salts, provide low yields of 2, while carboxylate salts lead to significantly higher yields (entries 1–3). Ultimately, we found 18-crown-6-ligated cesium formate to be the optimal catalyst system (76% yield, entry 4). The reaction proceeds in slightly lower yield without 18-crown-6 (63%, entry 5) or using tetrabutylammonium acetate (69%, entry 6). Other commercial disilanes are less effective at promoting this reaction (entries 7 and 8). Unfortunately, all attempts to isolate product 2 via chromatography resulted in decomposition. Evaluation of other formamides led to the identification of 4-formylmorpholine (4FM) in NMP (1:1 mixture) as a satisfactory substitute for DMF, providing chromatographically stable 3 in 66% isolated yield (Scheme 1b, entry 10). Benzotrifluoride can also be used as a cosolvent (entry 11) and, for some substrates, results in improved yields (vide infra).

Scheme 1. Development of ArCF₃ reductive coupling reaction.

^a Yields determined by ¹H NMR spectroscopy. ^b Yields in parentheses are isolated yields by column chromatography.

Table 1 shows representative trifluoromethylarenes that are amenable to the base-promoted coupling reaction. 1,3-Bis(trifluoromethyl)arenes are effective substrates, including when scaled to 10 mmol (3) or with free phenolic O–H (4) and terminal alkene (5) functional groups. Sulfonamide (6, characterized by X-ray crystallography) and phosphonate ester (7) aryl substituents also sufficiently activate the trifluoromethylarene towards functionalization. Heteroaryl and drug-like trifluoromethylarenes are also effective, including 2-, 3- and 4-trifluoromethylpyridines (8–11), a benzylated aprepitant precursor (12) and a fluoxetine-trifluoromethylpyrimidine derivative (13) that selectively couples at the electron-deficient heteroarene. Under the current reaction conditions, trifluoromethylbenzenes that lack an electron-withdrawing group do not react, while substrates with electrophilic functional groups (e.g. ketone) undergo competitive side reactions with the silane.²¹

Table 1.

Substrate Scope of Trifluoromethylarenes.^a

^aYields are of purified product on a 0.25–1 mmol scale; see Supporting Information for full details.

^bIsolated as adduct with NEt₃.

^cPhCF₃ used in place of NMP.

^dReaction conducted at 80 °C.

^eAdditional base (20 mol%) and TTMSS (1.2 equiv) added after 16 h.

We expected these silylated hemiaminal products to be versatile synthetic intermediates based on their resemblance to reported trifluoromethyl formamide adducts.²² The diversity of difluorobenzylic frameworks accessible from the silylated hemiaminal unit is demonstrated in Scheme 2, with sixteen transformations shown starting from product 3 (prepared on multigram scale). These reactions employ common reagents and require one purification step, with detailed procedures described in the Supporting Information (Section VII, pages S14–25). Numerous reactions can be conducted directly with the silylated hemiaminal (Scheme 2a), including cleavage to a deuterated difluoromethylarene (14), condensation to an oxime (15), condensation-dehydration to a nitrile (16), a Petasis-type styrenylation process (17), oxidation to an amide (18), reduction to a tertiary amine (19), and a Mannich-type addition reaction (20). Conversion of 3 into a hemiacetal is facile with catalytic acid in ethanol without the need for isolation.^23,24 From this intermediate, many transformations are possible (Scheme 2b), including reduction (21), reductive amination (22), Wittig (23, 24), heterocycle condensation (25), Henry (26), oxidation (27), cyanide addition (28) and silylation (29) reactions.

Scheme 2. Synthetic utility of hemiaminal adduct.^a.

^a Isolated product yields; see Supporting Information for full synthetic details for each derivatization reaction.

An additional application of this method is its use for late-stage C–F functionalization via sequenced reductive coupling and derivatization. A series of pharmaceutical derivatives and drug-like structures are shown in Scheme 3 that underwent defluorofunctionalization using one total purification step. This includes trifluoromethylaryl derivatives of apriprazole (30 and 31), fluoxetine (34) and bepotastine (35), as well as an aprepitant precursor (32 and 33) and a trifluoromethylquinoline substrate (36). These examples demonstrate the ability to modify trifluoromethyl substituents of bioactive compounds, as well as the ability to carry the typically inert trifluoromethyl group through multistep syntheses before derivatization.

Scheme 3. Divergent late-stage ArCF₃ C–F functionalization.^a.

^a Isolated product yields starting from trifluoromethylarene; see Supporting Information for full synthetic details for each entry.

Insight into the mechanism of this reductive coupling process first came while varying the reaction conditions. We observed the product identity to be dependent on the solvent used; in NMP, the major product is difluorobenzylsilane 37, and in MeCN, the major product is difluoromethylarene 38 (Figure 3a).²⁵ We reasoned that formation of the benzylsilane (37) and subsequent in situ base-promoted desilylation could explain the solvent dependence.²⁶ Subjection of benzylsilane 37 to cesium formate in MeCN or DMF provides difluoromethylarene 38 or silylated hemiaminal 2, respectively (Figure 3b).²⁷ A profile of the model reaction in DMF shows the concurrent formation of benzylsilane 37 and the silylated hemiaminal 2, and once the trifluoromethylarene has been consumed, the remaining benzylsilane is converted to the silylated hemiaminal (Figure 3c). These observations support defluorosilylation as the key process en route to the formamide addition product 2. Each reaction of this sequence generates an anion (fluoride or oxyanion) that could regenerate the formate anion or propagate silane activation via an anionic chain process, explaining why only catalytic quantities of formate salt are required (Figure 3d).²⁸

Figure 3.

Studies and observations into reaction mechanism. Yields determined by ¹H or ¹⁹F NMR spectroscopy. ^a Under alternative conditions, the yield of 38 is 86% if the reaction is conducted at 80 °C and 80% if CsF is used at rt in place of HCO₂Cs.

Defluorosilylation likely occurs via initial formation of a silicate²⁹ or silyl anion from TTMSS^30,31, and we have obtained evidence that both TMS and HSi(TMS)₂ anions may be generated under the reaction conditions.^32,33 As silyl anions are known to be potent reductants³⁴, bases³⁵ and halophilic nucleophiles³⁶, numerous mechanistic pathways for defluorosilylation seem plausible. Interestingly, when TTMSS is replaced with other disilane reagents (e.g. Si₂Me₆ or Si(TMS)₄) for the model reaction, consumption of the trifluoromethylarene is observed but with little formation of the hemiaminal product.³⁷ These comparisons indicate TTMSS strikes the right balance of Lewis acidity and capability of silyl anion generation to mediate the selective reductive coupling reaction. Details of these control studies and a discussion of possible pathways for the initiation of this reaction are provided in the Supporting Information. Investigations are underway to gain more insight into the defluorosilylation process and to identify disilanes that can activate a wider scope of trifluoromethylarenes.^38,39

The discovery of a defluorosilylation pathway provides an opportunity to expand the scope of accessible C–F coupling products. Use of the α,α-difluorobenzylsilane as a masked carbanion can access derivatives that are challenging to prepare from the hemiaminal intermediates.²⁶ The model defluorosilylation product 37 was first isolated from a reaction conducted in NMP on a 5 mmol scale in 40% yield. From 37, our recently reported fluoride-promoted protocol for benzylsilane cross-coupling to aryl nitriles can be used to generate defluoroarylation products (Scheme 4a).⁴⁰ This route provides an alternative to Zhang’s recently developed light-promoted Pd-catalyzed trifluoromethylarene C–F arylation method.⁴¹

Scheme 4. Isolation and utility of α,α-difluorobenzylsilane.^a.

^a Isolated product yields; see Supporting Information for full synthetic details for each entry. ^b 53% ¹⁹F NMR yield; isolated yield reduced due to coelution with protodesilylated compound 38. ^c 76% ¹H NMR yield; isolated yield reduced due to coelution with protodesilylation side product.

We also sought to show how defluorosilylation could serve as an entry to assembling difluoroalkylarene libraries with minor structural differences (Scheme 4b). Fluoride-activation of 37 promotes facile substitution with alkyl iodides, providing the defluoromethylation product (41), its isotopologues (42 and 43), and the ethyl derivative (44). Substitution using Togni reagent II⁴² provides pentafluoroethyl product 45, thus accomplishing a net extension of a trifluoromethyl substituent into a pentafluoroethyl group.

In summary, this reductive coupling platform expands the scope of α,α-difluorobenzylic substructures accessible from trifluoromethylarenes to better reflect the structural diversity found in bioactive compounds (Figure 1). The reaction leverages the continuous generation of anionic intermediates to propogate a disilane-mediated defluorosilylation and formamide addition sequence. This ensemble allows a trifluoromethyl C–F bond to formally serve as a masked nucleophile, thus delivering new difluoroalkylarene synthetic linchpins.