A facile access to aliphatic trifluoromethyl ketones via photocatalyzed cross-coupling of bromotrifluoroacetone and alkenes

Abstract

Biological molecules incorporating trifluoromethyl ketones (TFMKs) have emerged as reversible covalent inhibitors, aiding in the management and treatment of inflammatory diseases, cancer, and respiratory conditions. TFMKs, renowned for their versatile binding properties and adaptability, are pivotal in the rational design of novel drugs for diverse diseases. The photocatalytic insertion of alkenes, abundant feedstocks, into the α-carbon of trifluoromethylacetone represents a highly effective and atom-economical method for synthesizing valuable TFMKs. However, these processes typically necessitate high-energy photoirradiation (λ > 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. In our study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor under mild conditions. Aliphatic trifluoromethyl ketones or the corresponding bromo-substituted products can be obtained by selecting an appropriate photocatalyst and solvent. Comprehensive experimental investigations, including cyclic voltammetry, Stern–Volmer quenching studies, and kinetic isotope effects, corroborate the synthesis of trifluoroacetonyl radical species from bromotrifluoroacetone under photoredox conditions. Further, we demonstrate the efficient synthesis of an oseltamivir derivative bearing a trifluoromethylketone moiety, which shows promising biological activity. Hence, this methodology will streamline the direct introduction of trifluoromethyl ketone into biological target molecules during drug discovery.

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Introduction

Trifluoromethyl ketones (TFMKs) are valuable synthetic intermediates¹ and have been extensively used in pharmaceuticals and biological targets. The carbonyl group of TFMK is susceptible to nucleophilic attack owing to the adjacent trifluoromethyl group exhibiting a strong electron-withdrawing property.² Biological molecules with TFMK functional groups in aqueous solutions comprise gem-diol in equilibrium, targeting enzymatic catalytic sites or non-catalytic residues to form reversible covalent bonds (Fig. 1A). As the equilibria composition acts as potential enzyme inhibitors, numerous biologically active TFMKs have been developed as reversible covalent inhibitors toward phospholipase A2,³ histone deacetylase,⁴ human leukocyte elastase,⁵ and more⁶ (Fig. 1B). Consequently, TFMKs may serve as potentially privileged motifs in the rational drug design of reversible covalent inhibitors.

Fig. 1 Efficient approaches for synthesizing aliphatic trifluoromethyl ketones.

Traditional methods to access TFMKs predominantly include the stoichiometric trifluoromethylation of carbonyl compounds;^1,7 however, these reactions are limited by a narrow substrate scope and low regioselectivity. An alternative approach, the oxidation of α-trifluoromethyl alcohol, requires large quantities of oxidants and multiple steps.⁸ Two strategies using trifluoromethylation and trifluoroacetylation reactions have been primarily developed, as illustrated in recent reports (Fig. 1C). For instance, the oxidative trifluoromethylation of an aldehyde with (bpy)Cu(CF₃)₂ occurs in the presence of silane; however, it requires stoichiometric metal species.⁹ Further, deoxytrifluoromethylation using carboxylic acids has been reported.¹⁰ Recently, several remarkable catalytic methods have been reported to access TFMKs. Katayev et al. reported trifluoroacetylation of alkenes using trifluoracetic anhydride (TFAA) and Ir photocatalysts via the generation of a trifluoroacetyl radical, yielding the corresponding CF₃-enones.¹¹ However, owing to its instability, the trifluoroacetyl radical collapsed rapidly into carbon monoxide and the CF₃ radical. Further, the hydrotrifluoroacetylation of electron-poor olefins, mediated by the decarboxylation of masked acyl reagents via photocatalysis has been successfully demonstrated; this method effectively generates TFMKs from the resulting products.¹² To the best of my knowledge, the most noteworthy recent advance in this area is the report by Shu of the radical alkylation between alkyl bromides and TFAA using an Ir photocatalyst in the presence of silane and 2,6-dipropoxypyridine, thus, providing access to various aliphatic TFMKs.¹³

We envisaged that the insertion of alkenes, which are abundant feedstocks, into the α-carbon of trifluoromethylacetone via photocatalysis¹⁴ can be a powerful tool for synthetic transformations; this approach offers a highly effective and atom-economical strategy for preparing structurally valuable TFMKs. A C–C bond coupling between olefins and photoactivated acetone resulted in the formation of methyl ketone.¹⁵ Li et al. reported silver-catalyzed carbofluorination of alkenes with acetone via atom transfer radical addition (ATRA) reactions in aqueous solutions.¹⁶ However, these processes require high energy photoirradiation (λ > 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. Although photoredox catalytic radical addition of the common α-bromo acetophenone to unactivated olefins has been achieved,¹⁷ the alkylation of α-bromo alkyl ketone derived radicals in this area is less studied. In this study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor (Fig. 1D). Further, we propose that capturing a putative carbon radical with hydrogen- or bromine radicals results in hydrogenation and bromination products, respectively. This reaction facilitates a direct and modular synthesis of various aliphatic TFMKs, including pharmaceutical ingredients, offering several advantages such as tolerance for diverse functional groups, absence of metals and bases, and broad applicability.

Results and discussion

A readily available reagent, bromotrifluoroacetone (1), has been widely used for synthesizing heteroarene with substituted trifluoromethyl groups;¹⁸ however, studies on its utilization as a radical precursor of 1 are limited. We optimize the reaction parameters using pent-4-en-1-yl benzoate (2a) as a reaction partner and photocatalyst under irradiation from blue LEDs at 470 nm and room temperature (Table 1). The reaction of 1 using 2,4,5,6-tetrakis(diphenylamino)isophthalonitrile (4DPAIPN) [E_1/2(PC⁺/PC*) = −1.28 V vs. SCE]^14b,19 as the photocatalyst in 1,4-dioxane affords a mixture of product 3a and corresponding carbobrominated product 4a in 33% and 11% ¹⁹F NMR yields, respectively (entry 1). Further, the effect of the solvent on the photo-catalyzed cross-coupling between bromotrifluoroacetone (1) and substrate 2a (entries 2–5) was analyzed. Tetrahydrofuran (THF) is an excellent solvent, yielding 3a as the primary product (entry 4). In contrast, a carbobromination reaction of 2a with 1 is observed in the MeCN solvent, yielding the product 4a with high chemoselectivity (entry 5). Further, screening of photocatalysts including 3DPA2FBN [E_1/2(PC⁺/PC*) = −1.38 V vs. SCE],²⁰ 4CzIPN [E_1/2(PC⁺/PC*) = −1.04 V vs. SCE],^14b,19 and [Ir[dF(CF₃)ppy]₂(dtbbpy)]PF₆ [E_1/2(Ir⁺/Ir*) = −0.89 V vs. SCE]^14b,19 was performed using THF as a solvent under optimized conditions. A notable achievement is obtained with 3DPA2FBN, resulting in a 75% isolated yield of product 3a (entry 7). A similar result is obtained with 4CzIPN (entry 8); however, the Ir catalyst exhibits less reactivity and chemoselectivity (entry 9). Control experiments reveal that photocatalyst and light are required for this transformation (entry 10). We further optimized the photocatalysts for chemoselective formation of the target product 4a using MeCN as a solvent (entries 11–14). Among photocatalysts, 3DPA2FBN offers the most promising chemoselectivity and 72% isolated yield of 4a by extending the irradiation time to 8 h (entry 11).

Table 1 Optimization of the reaction conditions

Entry	Photocatalyst	Solvent	Yield (isolated) (3a/4a)%^a
a Yields determined by ^19F NMR spectroscopy using benzotrifluoride as an internal standard. b Reaction conditions: 1 (0.45 mmol), 2a (0.3 mmol), photocatalyst (1 mol%), solvent (500 μL), 12 W blue LEDs, room temperature (rt), 3 h. c  1 (0.6 mmol). d For 8 h. PC = photocatalyst, MTBE = tert-butyl methyl ether.
1^b	4DPAIPN	1,4-Dioxane	33/11
2^b	4DPAIPN	MTBE	22/6
3^b	4DPAIPN	MeOH	0/0
4^b	4DPAIPN	THF	48/5
5^b	4DPAIPN	MeCN	0/63 (63)
6^c	4DPAIPN	THF	60/13
7^c	3DPA2FBN	THF	77 (75)/12
8^c	4CzIPN	THF	72/12
9^c	Ir[(dFCF3)ppy]2(dtbbpy)PF6	THF	39/13
10^c	No PC/no light	THF	0/0
11^c^,^d	4DPAIPN	MeCN	0/75 (72)
12^c^,^d	3DPA2FBN	MeCN	4/49
13^c^,^d	4CzIPN	MeCN	13/57
14^c^,^d	Ir[(dFCF3)ppy]2(dtbbpy)PF6	MeCN	5/70

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We determined the substrate scope of this transformation using the optimized reaction conditions (Table 1, entry 7; Fig. 2). This photocatalytic process tolerates a variety of functional groups, including sensitive ones such as ester, alcohol, acid, and boronate ester in unactivated alkenes, affording the corresponding target products (3a–l) in moderate to high yields. The photo-catalyzed functionalization of 2a was performed on a 2.4 mmol scale by increasing the irradiation time, yielding the product 3a in 66% yield. Alkene substrates (2m–o) with various substitute patterns, including bromine and ether group, undergo the cross-coupling reactions, yielding alkyl TFMKs (3m–o) as major products and bromo-substituted products in relatively low ratios (4m–o). These reaction conditions affect the reactivity and chemoselectivity of alkene substrates containing the amide moiety. When 4CzIPN is used as a photocatalyst instead of 3DPA2FBN, the substrate 2p converts into hydro- and bromo-products with 59% yield in a 1 : 1 ratio. Under identical conditions, the related substrate 2q containing a phthalimide group chemoselectively transforms into the corresponding TFMK 3q in 64% yield. Further experiments display good functional group compatibility with 1,2-disubstituted alkenes (2r and 2s) and cyclooctene (2t), affording the desired products (3r–u) in moderate yields. This photocatalytic reaction using 3DPA2FBN and 4CzIPN applies to biologically relevant ibuprofen 2u, naproxen 2v, and estrone derivatives 2w, affording the desired products (3u–w) in 91%, 66%, and 36% yields, respectively.

Fig. 2 Substrate scope of alkene partners. Isolated yield is given for each compound. Reaction conditions: 1 (2.0 eq.), 2 (0.3 or 0.50 mmol), photocatalyst (1 mol%), THF, rt, 3 h. ^a Run on 2.4 mmol scale (isolated yield). Reaction was performed with 4CzIPN (1 mol%) at rt for ^b 8 h and ^c 22 h.

Next, we investigated the substrate scope of carbobromination of 1 under the optimized reaction conditions (Table 1, entry 11; Fig. 3). The reaction tolerates a broad array of functional groups, including ester (4a–f), alcohol (4g), aryl (4h), ether (4j), acid (4k), ether (4o), and amides (4p, 4y). Their desired products are obtained in moderate to high yields; however, the yield of the product (4q) containing a phthalimide moiety is low. This protocol with 2a is scaled up to 2.4 mmol, which affords the product 4a in 85% yield. Cycloalkenes (2t and 2aa) and 1,2-disubstituted alkenes (2s, and 2z) are compatible, resulting in the desired products with moderate to high yields. Finally, tetraphenylethylene (TPE) derivative 2ab is tolerated, affording the corresponding product 4ab in 56% yield.

Fig. 3 Substrate scope of photocatalyzed carbobromination of alkene partners. The isolated yield is given for each compound. Reaction conditions: 1 (2.0 eq.), 2 (0.3 mmol), photocatalyst (1 mol%), MeCN, rt, 8 h. ^a Run on 2.4 mmol scale (isolated yield). ^b Reaction was performed at rt for 20 h.

Mechanistic experiments were conducted to gain insight into the mechanism of this transformation under standard conditions. The reduction of bromotrifluoroacetone 1via 3DPA2FBN in THF-d₈ under blue LED irradiation affords the product [D]5 in 36% ¹⁹F NMR yield (Fig. 4A (1)). The reaction of 2a in THF-d₈ leads to the formation of product 3a in 54% yield with 53% deuterium incorporation (Fig. 4A (2)). Hence, trifluoroacetonyl radical is synthesized from 1via a single electron transfer followed by hydrogen trapping using THF. Moreover, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl TEMPO, a radical scavenger, completely impedes the basic conditions (Fig. 4A (3)). When the photocatalytic reaction of 2,2-diallyl malonate 6 is performed under standard conditions, two cyclized products, 7a and 7b, are obtained in 26% yield, as confirmed by NMR and electrospray ionization mass spectrometry (ESI-MS) analyses (Fig. 4A (4)).

Fig. 4 (A) Mechanistic experiments. (B) Cyclic voltammetry experiments. (C) Stern–Volmer quenching of 3DPA2FBN (PC*) by 1. (D) Proposed reaction pathway.

Further, cyclic voltammetry (CV) was performed to understand the redox properties of 1 (Fig. 4B). Two higher reduction potentials (E_red) at −0.30 and −0.60 V vs. Ag/AgNO₃ compared with those of phenacyl bromide as a known radical precursor²¹ (E_red = −0.95 and −1.28 V vs. Ag/AgNO₃, Fig. S12†) and a high oxidation potential (E_ox) at 0.73 V vs. Ag/AgNO₃ in MeCN are observed. The two reduction peaks are attributed to the readily initial reduction of the C–Br bond owing to the trifluoromethyl ketone and a second reduction of mesolytically cleaved carbon radical for ˙CH₂COCF₃/⁻CH₂COCF₃.²² The oxidation potential suggests oxidation of the resultant bromide anion to the corresponding bromine radical. Moreover, Stern–Volmer quenching studies reveal an efficient quenching of the excited T₁-state of photocatalyst (PC*) by 1 (Fig. 4C). Hence, we propose that the catalytic cycle is initiated via a single electron reduction of 1 by PC*, affording a trifluoroacetonyl radical.

Based on these data and previous reports,²³ a plausible mechanistic pathway for this transformation is elucidated (Fig. 4D). The catalytic cycle on the oxidative quenching cycle is initiated by a single electron transfer (SET) reduction of 1 (E_red = −0.30 V) using the excited state of catalysts, i.e., 3DPA2FBN [E_1/2(PC⁺/PC*) = −1.38 V vs. SCE],²⁰ leading to a trifluoroacetonyl radical A, a bromide ion, and the corresponding oxidized photocatalysts. Subsequently, the radical addition of A to alkenes leads to a putative carbon radical intermediate B, followed by hydrogen atom abstraction from THF to give the product 3. PC⁺ [E_1/2(PC⁺/PC) = 1.30 V vs. SCE] oxidizes the THF α-radical,²⁰ which restores the ground state of PC, producing an oxonium ion that could be trapped by a bromide ion affording α-bromo-THF.

Then, we performed control experiments to elucidate the mechanism of carbobromination. The Stern–Volmer quenching studies reveal the higher ability of 1 to quench the excited state of 4DPAIPN in MeCN compared with that of 3DPA2FBN in THF (Fig. 5A). The presence of TEMPO under the basic conditions of carbobromination leads to a low yield of 16% for 4a (Fig. 5B (1)). The reaction of 2,2-diallyl malonate 6 using 4DPAIPN in MeCN results in the formation of the cyclized product 7b along with a trace quantity of bromo-substituted product 8a, and its exact mass was determined by high-resolution mass spectrometry (HRMS) analysis (Fig. 5B (2)). Hence, we propose the ATRA reaction²⁴ as a plausible mechanistic pathway to bromo-substituted product 4 (Fig. 5C). The initial SET of 1 by the excited state of 4DPAIPN [E_1/2(PC⁺/PC*) = −1.28 V]^14b,19 leads to C–Br bond cleavage, inducing the formation of radical A and PC⁺ [E_1/2(PC⁺/PC) = 1.34 V].^14b,19 Subsequent radical addition of A to alkene results in the formation of carbon-centered radical B. The oxidation of B by PC⁺ under standard conditions releases the ground state of PC and the carbocation intermediate C that undergoes nucleophilic bromine substitution. Alternatively, a halogen-atom transfer (XAT) reaction of 1 as a bromine source to lead the radical chain propagation could be a proposed pathway for affording the product 4.

Fig. 5 Mechanistic studies (A) Stern–Volmer quenching of 4DPAIPN (PC*) by 1. (B) Control experiments. (C) Proposed reaction mechanism.

We accomplished a series of synthetic transformations of 4a on biologically valuable compounds (Fig. 6A). The efficient intramolecular cyclopropanation of 4a with cesium carbonate provides the product 9a with an 80% yield. The heterocyclization of o-phenylenediamine leads to a biologically relevant compound 9b. Additionally, the transformation of 4a using a nucleophilic reaction partner, NaN₃, leads to the azide product 9c in 55% yield. Finally, the antiviral drug oseltamivir derivative 2ac exhibiting multiple functional groups is used for this transformation with chloroform as a co-solvent owing to its poor solubility, affording 10 in 31% yield (Fig. 6B). Condensations of oseltamivir phosphate and acid 3i gave a TFMK folding oseltamivir derivative (11) in 62% yield.

Fig. 6 (A) Synthetic transformation of TFMK 4a. (B) Synthesis of TFMK-folding oseltamivir derivatives (10 and 11). (C) Profile of anti-influenza activity for 2ac, 10, 11 and oseltamivir. CV staining determined a 50% effective concentration (EC₅₀) against the A/WSN/33 virus. EC₅₀ values were calculated from two independent experiments. Compound 10 exhibited promising antiviral activity (EC₅₀ = 0.46 ± 0.09 μM) against the A/WSN/33 virus compared with that of oseltamivir phosphate (EC₅₀ = 0.43 ± 0.15). Substrate 2ac and compound 11 did not exhibit antiviral activity at 10 μM concentration. (D) Crystal structure (PDB code: 6HP0) of NA (gray) and the binding structure of 10 (blue) from docking simulations. Ary293, ILE427, and Lys432 in the cavity of NA are illustrated with some key NA residues (pink).

Influenza viruses cause acute respiratory illnesses in humans during seasonal epidemics worldwide, resulting in hundreds of thousands of deaths annually.²⁵ Influenza-A viruses (IAVs) possess a surface glycoprotein, neuraminidase (NA), an exosialidase that cleaves the glycosidic linkages between the sialic acid and the host glycoconjugate.²⁶ Its activity facilitates the viral movement that releases the progeny viruses from the host cells. As a selective neuraminidase inhibitor, oseltamivir has been used worldwide to prevent the spread of influenza infections.²⁷ The TFMK-holding oseltamivir derivative with a bromo atom (10) and that without the bromo atom (11) are assayed in vitro against the A/WSN/33 virus (Fig. 6C). Compound 10 exhibits potent antiviral activity equivalent to that of the parent compound oseltamivir, with a half-effective concentration (EC₅₀) of 0.46 ± 0.09 μM. In comparison, the inhibitory effect of alkene substrate 2ac and compound 11 could not be observed even at 10 μM. The oseltamivir structure comprises the ethyl ester prodrug of oseltamivir carboxylate, which can convert to its active form by esterases.²⁸ These results suggest that the bromo atom and TFMK of the compound 10 contribute to the inhibition of the neuraminidase enzymatic activity. Next, we performed the docking simulation of the acid form of 10 with the crystal structure of neuraminidase from H1N1 influenza virus (PDB code: 6HP0)²⁹ using AutoDockVina (Fig. 6D). The binding mode of the most reasonable structure obtained from the docking calculation revealed a hydrogen bonding interaction between the acid moiety and Arg293. Additionally, we observe that the TFMK moiety is located in the cavity of a nucleophilic amino acid Lys432 and a hydrophobic amino acid ILE427. Bromo substitute on the alkyl chain of compound 10 might assist the TFMK moiety to orient toward the cavity. These computational findings agree with the inhibitory activity observed experimentally.

Conclusions

In this study, we have demonstrated a metal- and base-free, visible light photocatalyzed cross-coupling between bromotrifluoroacetone and unactivated alkenes, providing direct access to aliphatic TFMKs, including the biologically relevant derivatives. The protocol is carried out under mild conditions with the appropriate choice of photocatalyst and solvent, providing chemoselectively aliphatic TFMKs and the corresponding bromo-substituted products, exhibiting remarkably broad functional group tolerance. This methodology successfully facilitated the synthesis of an oseltamivir derivative featuring an aliphatic TFMK exhibiting potential anti-influenza activity. Hence, the photocatalyzed radical addition of bromotrifluoroacetone offers a streamlined approach for synthesizing TFMK derivatives, which can be pivotal in the design of reversible covalent enzyme inhibitors for drug development. We are currently investigating the applications of our methodology toward the synthesis of biological targets incorporating TFMKs, and photoredox-catalyzed C–H alkylation of arenes.

Author contributions

The synthesis of aliphatic trifluoromethyl ketones was carried out by S. M. The docking studies were carried out by T. I. The biological data were evaluated by T. Y. and M. I. The characterization and data curation were made by S. M. and T. I. S. M., T. I. and M. I. were responsible for financial resource. The manuscript was written through contributions of S. M. and T. I. All authors have given approval to the final version of the manuscript.

Data availability

Experimental procedures and characterization data for all the products can be found in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This study was supported financially by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers 21K07704 (S. M.) and 23K28190 (T. I.)), and AMED (grant numbers JP23fk0108657 and JP24fk0108657 (S. M. and M. I.)).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ob01247j

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