A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

Abstract

•Switchable, base-controlled reincorporation/release of SO2•Highly chemoselective and scalable photoinduced protocol•Gaseous alkenes were well tolerated•Broad substrate scope and application to functionalization of high value-added molecules Control of selectivity is a centrally important issue in radical chemistry. In this field, switching product selectivity in the radical difunctionalization of alkenes, stemming from the same starting material, remains greatly challenging owing to the high reactivity and instability of radical species and their intrinsic reactivity patterns. Herein, a switchable, base-controlled reincorporation/release of SO2 in photocatalyzed radical difunctionalization of alkenes has been described, offering a selective route toward a series of otherwise difficult-to-obtain γ-trifluoromethylated ketones and trifluoromethylated sulfonyl ketones. With this, we could address a key challenge in radical chemistry and not only understand but also utilize the base-switchable chemoselectivity. We believe that this method would have diverse applications across the many fields of chemistry, from drug and pharmaceutical research to material chemistry. Control of selectivity is a pivotal challenge in radical chemistry owing to the high reactivity and instability of radical species. Herein, a switchable, base-controlled strategy toward the reincorporation/release of SO2 in photocatalyzed radical difunctionalization of alkenes has been described. By this chemodivergent strategy, a variety of valuable, otherwise difficult-to-access γ-trifluoromethylated ketones and trifluoromethylated sulfonyl ketones can be selectively furnished from the same starting materials. This method features high chemoselectivity, a broad substrate scope, excellent functional group tolerance, and facile scale-up and was applied in a one-pot synthetic procedure. Evaluation of the reaction conditions and mechanistic studies indicate that the choice of base can invert the chemoselectivity of the reaction, demonstrating control over a challenging radical selectivity pattern. Control of selectivity is a pivotal challenge in radical chemistry owing to the high reactivity and instability of radical species. Herein, a switchable, base-controlled strategy toward the reincorporation/release of SO2 in photocatalyzed radical difunctionalization of alkenes has been described. By this chemodivergent strategy, a variety of valuable, otherwise difficult-to-access γ-trifluoromethylated ketones and trifluoromethylated sulfonyl ketones can be selectively furnished from the same starting materials. This method features high chemoselectivity, a broad substrate scope, excellent functional group tolerance, and facile scale-up and was applied in a one-pot synthetic procedure. 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The potential challenges for this switchable concept include: (1) in the SO2-reincorporation process, the low concentration of generated SO2 may be insufficient to react with the high-energy, short-lived radical intermediates, which are also produced in low concentrations; (2) the generated SO2 may be attacked by radical species,40Sarver P.J. Bissonnette N.B. MacMillan D.W.C. Decatungstate-catalyzed C(sp3)–H sulfinylation: rapid access to diverse organosulfur functionality.J. Am. Chem. Soc. 2021; 143: 9737-9743Google Scholar interfering in the case of desired SO2 release and leading to low chemoselectivity. The construction of valuable motifs for medicinal and agrochemical applications stands among the most important real-world challenges faced by synthetic chemists. In this regard, γ-trifluoromethylated ketones and trifluoromethylated sulfonyl ketones are important building blocks (Figure 1C).41Kisselev A.F. van der Linden W.A. Overkleeft H.S. 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On the one hand, K2CO3 can enable the reincorporation of the in situ generated SO2 to access trifluoromethylated sulfonyl ketones; alternatively, release of SO2 could be achieved via the replacement of K2CO3 with KOH, and a series of γ-trifluoromethylated ketones were successfully obtained with high selectivity. Due to the low bond dissociation energy of the O–S bond, enol triflates could undergo desulfurization-fragmentation, followed by formal addition over multiple bonds of enol triflates to generate α-trifluoromethylated ketones in a catalytic manifold.46Kawamoto T. Sasaki R. Kamimura A. Synthesis of α-trifluoromethylated ketones from vinyl triflates in the absence of external trifluoromethyl sources.Angew. Chem. Int. Ed. Engl. 2017; 56: 1342-1345Google Scholar,48Su X. Huang H. Yuan Y. Li Y. Radical desulfur-fragmentation and reconstruction of enol triflates: facile access to α-trifluoromethyl ketones.Angew. Chem. Int. Ed. 2017; 56: 1338-1341Google Scholar,49Liu S. Jie J. Yu J. Yang X. Visible light induced trifluoromethyl migration: easy access to α-trifluoromethylated ketones from enol triflates.Adv. Synth. Catal. 2018; 360: 267-271Google Scholar In principle, enol triflates can be divided into three components, namely the trifluoromethyl group, SO2, and the ketone moiety. To evaluate the hypothesized switchable use of enol triflate as bifunctional or trifunctional reagents to generate distinct products from the same alkene feedstocks, phenyl enol triflate (1a) was used as a functional reagent and 1-hexene (2a) served as the radical acceptor (Figure 2). While no product was observed when PhCO2Na and NEt3 were used as additives (entries 1 and 4), other different additives (entries 2 and 3) allowed 3a and 4a to be simultaneously obtained. Interestingly, satisfactory yields and good selectivity for 4a were observed when K2CO3 was used as the additive (entry 5). In stark contrast, upon replacement of K2CO3 with KOH, no 4a was detected, while 3a was obtained in 66% yields (entry 6). Further screening showed that [Ir(ppy)2(dtbbpy)][PF6] could slightly increase the yield toward 3a (entry 7). Noteworthy, base plays an essential role toward the formation of 3a and 4a, and none of the desired products was observed in the absence of base (entries 8 and 9). Similarly, neither 3a nor 4a was obtained without the irradiation of visible light (entries 10 and 11). Additionally, we also examined the solvent effect for this reaction (see Table S3 for details).50Hu X.-Q. Qi X. Chen J.-R. Zhao Q.-Q. Wei Q. Lan Y. Xiao W.-J. Catalytic N-radical cascade reaction of hydrazones by oxidative deprotonation electron transfer and TEMPO mediation.Nat. Commun. 2016; 7: 11188Google Scholar By applying a condition-based sensitivity-screening approach (Figure 3),51Pitzer L. Schäfers F. Glorius F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations.Angew. Chem. Int. Ed. Engl. 2019; 58: 8572-8576Google Scholar we discovered that the reaction toward compound 3a is sensitive to high oxygen concentration and low substrate concentration, while being generally tolerant toward different temperatures and light intensities (Figure 3; see also Table S1 and Figure S2 for details). Subsequently, we examined the substrate scope with regard to the construction of γ-trifluoromethylated ketones with the optimal condition. As shown in Figure 2, simple alkenes, such as 1-hexene (3a), decene (3b), 4-methylpent-1-ene (3c), and allylcyclohexane (3d), were amenable to this two-component difunctionalization protocol. Moreover, functional groups including ester (3e and 3l), ether (3f), ketone (3g), succinimide (3i), phosphate ester (3j), and polyfluoroalkyl (3k) groups were well tolerated in this transformation, affording the desired products with good chemoselectivity. Subsequently, long chain alkenes featuring biaryl (3m), aryl (3n), and heteroaryl (3o) groups reacted smoothly with 1a, offering the corresponding products in moderate yields (49%–65%). As for the 1,2-disubstituted alkenes, longer reaction times provided moderate yields with 2-pentene and 3-hexene as substrates, respectively (3p-3r). Pleasingly, when α-methyl substituted alkenes (3s-3u) were used as radical acceptors (Figure 3), the products that contain quaternary carbon centers were obtained in good yields. Disubstituted alkenes with larger steric hindrance could also be successfully converted to trifluoromethylated compounds in moderate yields (3v-3x). Importantly, trisubstituted alkene, such as 2-methylbut-2-ene, reacted smoothly with 1a to form the desired product in 60% yield (3y). Despite the prohibitive steric hinderance, tetrasubstituted alkenes such as 2,3-dimethylbut-2-ene could be transformed into the product containing two quaternary carbon centers in 31% yield after 36 h of irradiation (3z). To evaluate the utility of this protocol, the functionalization of complex alkenes was also examined. For instance, monosubstituted alkenes containing the commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen and indometacin proved compatible with this protocol (3aa and 3af). The modification of other drug analogs, such as chloroxylenol (3ab), 2,4-D (3ac), diprogulic acid (3ae) and ciprofibrate (3ag), was successfully achieved. Pleasingly, a series of amino-acid derivatives were well tolerated, offering compounds 3ad and 3ah-3aj in moderate to good yields. These results demonstrate the potential application of this photochemical strategy in the modification of pharmaceutically relevant motifs. Furthermore, disubstituted alkenes containing segments of drug and amino derivatives were also tested, providing desired products which contain quaternary carbon centers in good yields (3ak-3ao). The chemical transformation of gaseous molecules into high-added-value target products is an attractive, yet challenging target.29Li J. Luo Y. Cheo H.W. Lan Y. Wu J. Photoredox-catalysis-modulated, nickel-catalyzed divergent difunctionalization of ethylene.Chem. 2019; 5: 192-203Google Scholar,52Tang S. Wang D. Liu Y. Zeng L. Lei A. Cobalt-catalyzed electrooxidative C-H/N-H [4+2] annulation with ethylene or ethyne.Nat. Commun. 2018; 9: 798Google Scholar Hence, to further benchmark the utility of this protocol, challenging gaseous alkenes, such as propene and ethylene, were used as radical acceptors to react with various enol triflates (Figure 4). A series of aromatic enol triflates could successfully react with propene, offering desired products in moderate to good yields. In addition to electron-withdrawing functional groups, such as halogens (3aq and 3ar), nitrile (3as), sulfone (3at), trifluoromethyl (3au), and ester (3av and 3ay), which were well tolerated, enol triflates containing electron-donating groups were also amenable to this protocol, reacting smoothly with propene to yield the corresponding products in 67% (3aw) and 62% (3ax), respectively. Furthermore, ethylene proved to be a feasible radical acceptor to yield γ-CF3 ketone 3az in a 26% yield. We speculated that the low stability of the carbon-centered radical formed after addition of trifluoromethyl radical to ethylene accounted for the low yield (Figure 4, 3az). By applying a condition-based sensitivity-screening approach to investigate the reaction for the construction of compound 4a (Figure 5),51Pitzer L. Schäfers F. Glorius F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations.Angew. Chem. Int. Ed. Engl. 2019; 58: 8572-8576Google Scholar we found this SO2-reincorporation protocol to be sensitive to high water content, increased temperature, and high oxygen concentrations (Figure 5; see also Table S2 and Figure S3 for details). Then, we examined the substrate scope for the synthesis of trifluoromethylated sulfonyl ketones via the reincorporation of SO2. First, various aromatic enol triflates could react successfully with 1-hexene (1a) to offer the corresponding products in moderate yields by incorporation of generated SO2 in the final molecules (4b-4f). Additionally, the scope of this strategy could be extended to propene (4g), showing satisfactory applicability. When long chain alkenes were submitted to the standard conditions, moderate to good yields and high selectivity could be observed (4h-4j). Alkenyl alkyl halides, such as 10-chloronon-1-decene (4k), 6-iodo-1-hexene (4l) and 5-bromo-1-pentene (4m) could also be amenable to this protocol. Moreover, alkenes containing fused rings and heterocycles were compatible with this protocol, thus demonstrating the good functional-group tolerance of this strategy. For instance, thiophene (4q), pyridine (4r), quinoline (4s), cyclic amide (4t), naphthalene (4u), benzothiazole (4v), etc., were tolerated. It is worth mentioning that disubstituted alkenes, such as cyclohexene (4w) and trans-2-pentene (4x and 4y), delivered moderate yields through the reincorporation of SO2. Unfortunately, only trace amounts of the desired product were observed when 2-methylbut-2-ene and 2,3-dimethylbut-2-ene were used as reaction substrates. Importantly, alkenes containing amino-acid derivatives were also investigated (4z-4ab): leucine (4z) and valine derivatives (4aa) could furnish the desired trifluoromethylated sulfonyl compounds in 61% and 64% yields, respectively. Additionally, a dipeptide was also successfully used to access the corresponding sulfonyl product (4ab). To further evaluate the utility of this SO2-reincorporation protocol, we tested the compliance of alkenes containing drug molecule derivatives (4ac-4ae). Notably, the multiple functionalization of these compounds could be smoothly achieved with the use of K2CO3 as the base. In order to streamline the present protocol, we observed that carbotrifluoromethylation and carbononafluorobutylation products (3ba-3be) were successfully synthesized via a telescoped one-pot synthesis from alkenes, ketones, and sulfonic anhydride as starting materials. Analogously, this one-pot strategy was also smoothly applied to the construction of trifluoromethylated/nafluorobutylated sulfonyl ketones (4a, 4af, and 4ag). These results further highlight the strategic application of this base-controlled reincorporation/release of SO2 approach in synthetic chemistry, avoiding the requirement of isolating reactive enol triflates (Figure 6A). To evaluate the scalability of this photochemical protocol, the reactions were carried out on a larger scale (Figure 6B). Notably, 1.37 g (66% yield) of 3a could be obtained starting from 7 mmol of phenyl enol triflate in the presence of KOH. Additionally, the reincorporation of SO2 could also be scaled up with the use of K2CO3 as base, allowing the synthesis of 1.48 g of 4a (63% yield). To gain more insight on the reaction mechanism, various mechanistic experiments were performed (Figure 7). The reactions toward 3a and 4a were significantly inhibited by the radical scavenger, such as butylated hydroxytoluene (BHT) or 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), thus suggesting a radical process (for details, see supplemental information). Additionally, radical probe experiments provided further evidence of the radical process (Figure 7A). When 2aa was used as a radical acceptor, product 3bf, which resulted from β-fragmentation of cyclobutylmethyl radical, was afforded in 66% yield. Similarly, the ring-opening product was obtained in 30% with the use of 2ab as the radical acceptor. Subsequently, Stern-Volmer fluorescence-quenching experiments revealed that the excited state ∗IrIII was effectively quenched by 1a, rather than by 2a (Figure 7B). Moreover, when external K2S2O5 was added to the reaction, in the absence of any base, a 60% yield of desired product was obtained (Figure 7C). This result suggested that K2S2O5, which was generated from the reaction between the SO2 with K2CO3, might be the intermediate in the SO2-reincorporation process.53Meng Y. Wang M. Jiang X. Multicomponent reductive cross-coupling of an inorganic sulfur dioxide surrogate: straightforward construction of diversely functionalized sulfones.Angew. Chem. Int. Ed. Engl. 2020; 59: 1346-1353Google Scholar,54For details, see supplemental information. Chemical equation of the reactions of SO2 with KOH and K2CO3, SO2 + 2KOH → K2SO3 + H2O and 2SO2 + K2CO3 → K2S2O5 + CO2 On the other hand, in the release of SO2, the generated SO2 would be consumed by excessive KOH to form K2SO3, which could not offer SO2 source and, thus, selectively offered γ-trifluoromethylated ketones (for details, see supplemental information).54For details, see supplemental information. Chemical equation of the reactions of SO2 with KOH and K2CO3, SO2 + 2KOH → K2SO3 + H2O and 2SO2 + K2CO3 → K2S2O5 + CO2 For details, see supplemental information. Chemical equation of the reactions of SO2 with KOH and K2CO3, SO2 + 2KOH → K2SO3 + H2O and 2SO2 + K2CO3 → K2S2O5 + CO2 For details, see supplemental information. Chemical equation of the reactions of SO2 with KOH and K2CO3, SO2 + 2KOH → K2SO3 + H2O and 2SO2 + K2CO3 → K2S2O5 + CO2 Additionally, cyclic voltammetry (CV) was performed to study the redox potential of the reaction substrates (1a and 2a), as shown in Figure 7D. No obvious oxidation potential peak was observed for 1a and 2a before 1.5 V versus SCE (saturated calomel electrode). Similarly, no obvious reduction potential peak of these substrates (1a and 2a) was detected before −1.8 V versus SCE (Figure 7D). According to the literature and the results of CV,12Prier C.K. Rankic D.A. MacMillan D.W.C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis.Chem. Rev. 2013; 113: 5322-5363Google Scholar,15Strieth-Kalthoff F. James M.J. Teders M. Pitzer L. Glorius F. Energy transfer catalysis mediated by visible light: principles, applications, directions.Chem. Soc. Rev. 2018; 47: 7190-7202Google Scholar,55Teders M. Henkel C. Anhäuser L. Strieth-Kalthoff F. Gómez-Suárez A. Kleinmans R. Kahnt A. Rentmeister A. Guldi D. Glorius F. The energy-transfer-enabled biocompatible disulfide–ene reaction.Nat. Chem. 2018; 10: 981-988Google Scholar species 1a and 2a could neither be oxidized nor reduced by the excited state ∗[Ir(ppy)2(dtbbpy)][PF6] (E1/2(M∗/M−) = + 0.66 V versus SCE; E1/2(M+/M∗) = −0.96 V versus SCE) and ∗fac-Ir(ppy)3 (E1/2(M∗/M−) = + 0.31 V versus SCE; E1/2(M+/M∗) = −1.73 V versus SCE), which excludes the possibility of redox process of this protocol via electron transfer. To evaluate the interaction between reaction substrates with photosensitizers, various photosensitizers with different properties were tested. As shown in Figures 7E and 7F, the yields of the products (3a and 4a) correlate to the triplet energy of the photosensitizers rather than the redox potentials. Furthermore, when the reaction was carried out in the presence of the triplet quenchers, a sharp decrease of yield was observed (see Tables S4 and S5 for details). Therefore, the abovementioned results support an energy-transfer process to be a plausible mechanism underlying the present difunctionalization of alkenes. Finally, the quantum yield of the reaction was determined to be 2.1, which suggested that this reaction might involve a radical chain process (see supplemental information for details). Based on the mechanistic studies, we propose a radical chain mechanism for this switchable reincorporation/release of SO2 strategy (Figure 8). Trifluoromethyl carbon-centered radical, which is generated from the enol triflate via the photoinduced catalysis, would attack the alkenes to form new carbon-centered radical (I). Subsequently, two different reaction pathways can selectively take place via the control of base. In pathway A, intermediate I would react with enol triflate to form II, which would undergo fragmentation to yield the desired product, along with the re-formation of CF3 radical that initiates the chain process again and generation of SO2. In this scenario, the generated SO2 would be consumed by excess KOH via an acid-base reaction, therefore preventing SO2 incorporation to selectively access γ-trifluoromethylated ketones. On the other hand, in the presence of K2CO3, intermediate III would be formed through the reaction between I and in situ generated K2S2O5. Then the sulfur-centered radical III could add to the enol triflate to selectively form the trifluoromethylated sulfonyl ketones. Simultaneously, the generated SO2 from the enol triflate, can be trapped by K2CO3 to newly generate K2S2O5. In summary, this base-controlled photochemical strategy features high chemoselectivity, a broad substrate scope (88 examples), excellent functional group tolerance, and facile scalability and was applied in a one-pot synthetic procedure. Trifluoromethylated sulfonyl ketones and γ-trifluoromethylated ketones could be selectively obtained from the same starting materials by switching the commercially available bases. Various alkenes, ranging from gaseous alkenes (propene and ethylene) to mono-, di-, tri-, and tetrasubstituted ones were successfully functionalized. We investigated the essential role played by the base in controlling the selectivity, therefore offering a switchable strategy for the reincorporation and release of SO2 in a radical chemistry manifold. Therefore, beyond synthetic chemistry, we anticipate that this switchable photochemical protocol would have diverse applications across the many fields of chemistry, from drug and pharmaceutical research to material chemistry.