Introduction

The incorporation of CF3 groups possessing strong hydrophobic and electron-withdrawing properties to an organic molecule can significantly improve its lipophilicity, bioavailability, metabolic stability, and binding selectivity1,2,3,4. Therefore, incorporation a CF3 group into a molecule is now quite a generalized paradigm in design of new drugs and functional materials with improved properties5,6,7,8,9,10,11, which has inspired great interest in the development of new trifluoromethylation methods through difunctionalization of alkenes. While alkene 1,2-difunctionalization has been well explored12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28, the remote 1,n-difunctionalization of alkenes is significantly more challenging and has gained considerable attentions29,30,31,32,33,34,35,36. The elegant 1,n-difunctionalization methods that have been developed to assemble structurally diverse scaffolds are mainly from the following two aspects: (1) The radical fluoroalkylation of alkenes and subsequent intramolecular 1,n-migration (Fig. 1a, 1)37,38,39,40,41,42,43,44,45,46; (2) The merger of radical addition to alkenes, hydrogen atom transfer (HAT) and remote C-H functionalization(Figs. 1a, 2)47,48,49,50,51,52,53. Despite significant progress, the development of new aspects of alkene 1,n-difunctionalizations continues to be of major significance.

Fig. 1: Design of photocatalyzed remote-difunctionalization of alkenes.
figure 1

a Remote 1,n-difunctionalization of unactivated alkenes. b Umpolung reactivity of α-carbonyl carbon through multiple-step transformation. c This work: photocatalyzed remote 1,5-difunctionalization of alkenes.

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Meanwhile, direct introducing a nucleophilic functional group onto α-carbon of amides or esters for access to α-nucleophile-substituted acid derivatives would be valuable. However, such a transformation is hard to achieve because it needs an umpolung of the α-carbon. As a consequence, multiple-step access to α-electrophilic reactivity has attracted considerable interest (Fig. 1b): (1) Activation of the α-carbon atom by introducing a good leaving group27,54,55,56,57,58; (2) The oxidation of enamine intermediates by a stoichiometric oxidant59,60; (3) The oxidative functionalization of the carbonyl groups with hypervalent iodine reagents, pyridine-N-oxides, or sulfoxides61,62. In contrast, access to α-carbonyl carbocations from α-carbon radicals would be a valuable method for umpolung of the α-carbon of carbonyl compounds which enables an unusual α-nucleophilic addition to amides or esters. However, the oxidation of α-carbonyl radicals to α-carbonyl carbocations under mild conditions, especially without the participation of a strong protonic acids or strong oxidants, is very challenging and remains less explored63,64,65,66. Within our research on photocatalysis66, we wondered whether it would be viable to merge a photocatalytically triggered free radical clock67,68,69,70,71,72,73,74,75 and a photocatalytically generated α-carbonyl carbocation in a single transformation (Fig. 1c). Thus, we envisioned that the substrate assembled a free radical clock moiety at α-carbon would be triggered off by an addition of CF3 radical generated in situ through the photocatalytic fragmentation of UR to the C = C bond to furnish radical species Int-1, followed by a selective β-fragmentation of cyclopropane generate a α-carbo radical Int-2. The subsequent photocatalytic oxidation of Int-2 resulted in a α-carbonyl carbocation Int-3, followed by a nucleophilic α-addition process to reach the remote 1,5-difunctionalization. As a consequence of our efforts, herein, we report on an unprecedented photocatalyzed three-component remote 1,5-difunctionalization of alkenes, involving tandem CF3 radical addition/radical clock cleavage/umpolung of α-carbonyl carbon/nucleophilic α-addition processes and featuring high regioselectivity and ample substrate scope (Fig. 1c). The resulting products bear a tetrasubstituted α-carbon center which have profound applications in construction of numerous natural products and pharmaceutically relevant molecules76,77,78,79. Access to such compounds usually needs multi-step transformations.

Results

Optimization study

The substrates amides or esters that were assembled with a radical clock moiety could be readily prepared through the reactions with 1,4-dibromobut-2-ene in the presence of NaH80,81. We initiated our studies of the remote alkenes 1,5-difunctionalization of N-phenyl amide A1 with UR and MeOH as the model substrates in N2 atmosphere (Table 1). After extensive screening of different reaction parameters (see SI, Table S1), the optimized reaction conditions were found to be in dichloroethane (DCE) with Ru(bpy)3Cl2 as a catalyst, leading to the expected product 1 in 73% yield (entry 1, Table 1). Some essential findings were listed below: (1) Control experiments confirmed the necessity of all the components for this transformation as no conversion of A1 was observed in the absence of either light irradiation or Ru(bpy)3Cl2 (entries 2,3, Table 1). (2) A slightly lower yield (60%) of 1 was obtained in air (entry 4). (3) Switching to other solvents, such as dioxane, DCM, THF, and DMSO, led to diminished yields (entries 5−8, Table 1). While using solvent MeCN gave a comparable yield to DCE (entry 9, Table 1). (4) Other commercial metal-core photocatalysts such as Ru(bpy)3(PF6)2, fac-Ir(ppy)3, Ir[dF(ppy)2dtbpy]PF6, and organic photocatalysts such as Eosin Y, and 4CzIPN, furnished the desired product in yields of 47%, 59%, 22%, and 17%, respectively (entries 10−14, Table 1). The CF3+ reagent TT-CF3 exhibited a lower reactivity, while a Togni’s reagent I-CF3 showed an unreactivity to this transformation (entries 15-16, Table 1).

Table 1 Optimization of the Reaction Conditionsa
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Substrate scope

To demonstrate the substrates scope of this remote 1,5-trifluoromethyl-alkoxylation of alkenes, a variety of δ,ε-unsaturated amides or esters were explored under the standard reaction conditions and satisfactory results were achieved (Fig. 2). However, other such unsaturated compounds, such as ketones or nitriles, gave no desired products. Meanwhile, during the reactions involving substrates A2 and A15, the corresponding by-products dienes 2’ and 15’ were formed in yields of 7% and 6%, respectively. First, various amides were explored using MeOH as a nucleophile and the corresponding α-methoxy-ε-trifluoromethyl γ,δ-unsaturated amides (1−25) were obtained in good to high yields. The reactions of α-aryls substituted N-phenyl amides bearing various electron-withdrawing groups (EWGs) and electron-donating groups (EDGs) at the α-benzene ring underwent well to afford corresponding products (2−9) in yields of 60%-82%. The electronic nature of the groups at N-benzene ring showed no significant effect on the reactivity. While the substrate with a p-chloro group showed a higher yield than those with o-, m-chloro groups (8 vs 6 and 7). Subsequently, the variation of the amide groups was also explored (A10-A25). The amides containing various N-aryl amino groups and N-alkyl amino groups were good substrates to this reaction, and the desired products were obtained in yields of 62%−83% (10−25). Various of amides bearing diverse EDGs and EWGs at N-aryl moiety gave similar yields of 64%−73% (14−21). The substrates bearing o-, m-, and p-methoxyl group at N-aryl moiety afforded corresponding products in yields of 65%, 68%, and 69%, respectively (19−21). Therefore, the electronic nature of the groups and the sites at N-benzene ring showed a slight effect on the reactivity (14−21). To our delight, the X-ray crystal structure of 18 was confirmed (for details, see SI), indicating the E-form double bond in the products. Furthermore, the N-alkyl amides (A22-A25) were also subjected to the standard reaction conditions, and these substrates were found suitable with comparable yields to N-aryl amides. Next, the ester substrates including methyl ester and phenyl ester were examined, affording the desired products (26 and 27) in yields of 69%, and 62%, respectively. Notably, the reactions of complex amides/esters derived from Baclofen, Aspartame, and Estrone, also underwent well to generate the corresponding amides/esters (28−30) in yields of 58%, 73% and 74%, respectively, thus suggesting the broad application potential of this protocol in late-stage functionalization on complex biorelevant molecules.

Fig. 2: Scope of the trifluoromethyl-alkoxylation.
figure 2

Reaction conditions: Amides or esters (0.2 mmol), UR (0.4 mmol), ROH (2.0 mmol), Ru(bpy)3Cl2 (0.5 mol%), in DCE (2.0 mL), N2, a.t., 455-460 nm blue LED, isolated yield. aAlong with some unidentical complex by-products. b62% of eliminated product 2,4-dieneamide was obtained.

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Finally, the reactivities of other primary, secondary, and tertiary alcohols as nucleophile substrates were also explored (Fig. 2, 31−35). The reactions of A1 with ethanol, benzyl alcohol, cyclobutylmethanol, and isoproanol underwent well to afford the corresponding products 31−34 in yields of 62%, 50%, 47%, and 50%, respectively. While the desired product (35) was not obtained when tertiary butanol was used, whereas, the elimination reaction occurred to give a 2,4-dieneamide product in 62% yield. The bulky tert-butanol inhibits nucleophilic addition so that the elimination reaction is favorable.

The analogical fluorination normally uses more expensive and hazard electrophilic reagents such as selectfluor, DAST, XeF2, and PhIF2, etc. The remote 1,5-trifluoromethyl-fluorination of alkenes allows the concurrent formation of a α-C − F bond and a ε-C − CF3 bond, which may significantly modulate the properties of the molecules4, thus rendering it a valuable methodology in biomolecules synthesis. Although they are highly desirable in view of the increasing demands for polyfluorinated compounds in various research fields, the direct and efficient 1,5-trifluoromethyl-fluorination method of alkenes has not been realized. Inspired by the above results of the 1,5-trifluoromethyl-alkoxylations, this general protocol was extended to the remote trifluoromethyl-fluorination. After screening of different reaction parameters (see SI, table S2), to our delight, the fluorine source Et3N·3HF exhibited a good reactivity to yield 36 in a better yield of 79%, thus the Et3N·3HF was used as the fluorine nucleophile for the subsequent remote trifluoromethyl-fluorination (Fig. 3, 36−54). First, various α-aryl substituted amides bearing diverse EWGs and EDGs were subjected to conduct the 1,5-trifluoromethyl-fluorination, and found suitable with good to excellent yields (37−44). The reaction of the substrate bearing a strong EDG at α-aryl moiety afford the corresponding product (40) in a lower yield of 54% along with some of unidentical complex byproducts, which might be contributed to the strong electron donating nature of the p-OMe group that makes the reaction messy. Next, the variation of the amide groups was also examined, and it was found that the amides containing various N-aryl and N-alkyl amino groups were good substrates to this transformation, and the desired products were obtained in yields of 60%−83% (45−52). To our satisfaction, the reactions of an ester substrate and a complex substrate derived from a dipeptide Aspartame afforded the corresponding products (53, 54) in yields of 77%, and 62%, respectively.

Fig. 3: Scope of the trifluoromethyl-fluorination.
figure 3

Reaction conditions: Amides or esters (0.2 mmol), UR (0.4 mmol), Et3N·3HF (1.0 mmol), Ru(bpy)3Cl2 (0.5 mol%), in DCE (2.0 mL), N2, a.t., 455-460 nm blue LED, isolated yield. aAlong with some unidentical complex by-products.

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Remote 1,5-trifluoromethyl-chlorination of δ,ε-unsaturated amides/esters might afford the corresponding α-chloro and ε-CF3-containing amides/esters, which are also very important synthetic intermediates. The resulting reactive α-C-Cl bond might be useful for performing further synthetic elaborations via many transformations such as elimination, reduction, and substitution to construct other biologically important Cα-tetrasubstituted amides or esters. Therefore, such a remote 1,5-trifluoromethyl-chlorination attracted a great deal of our interest (Fig. 4, 55−82). Similarly, after screening of different reaction parameters (see SI, table S3), the chlorine source nBu4NCl (TBACl) exhibited an excellent reactivity to yield 55 in a yield of 80%, thus the TBACl was used as the chlorine nucleophile for the subsequent remote trifluoromethyl-chlorination (56−82). To our delight, the reactions of δ,ε-unsaturated amides bearing diverse α-aryl substituents and N-aryl/alkyl groups underwent well to form the desired products (56−77) in good to excellent yields, indicating a better reactivity than the above trifluoromethyl-alkoxylations and trifluoromethyl-fluorinations. Notably, the acyl acetamides incorporated with a radical clock were also suitable substrates afforded the corresponding products (78, 79) in satisfactary yields. Furthermore, the reactions of complex substrates derived from Aspartame, Baclofen, and Estrone, also underwent well to generate the desired products (80−82) in yields of 70%, 59% and 68%, respectively. It is worth noted that the perfluoroalkane sulfonyl chloride C4F9SO2Cl proved viable for the efficient remote 1,5-difunctionalization (83), indicating a significant application perspective of this methodology in synthesis of polyfluorinated functional materials.

Fig. 4: Scope of the trifluoromethyl-chlorination.
figure 4

Reaction conditions: Amides or esters (0.2 mmol), UR (0.4 mmol), TBACl (0.8 mmol), Ru(bpy)3Cl2 (0.5 mol%), in DCM (4.0 mL), N2, a.t., 455−460 nm blue LED, isolated yield. aAlong with some unidentical complex by-products.

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Additionally, gram-scale reactions using A1 with HOMe or TBACl as nucleophiles were successfully performed under the optimized conditions producing corresponding products 1, and 55 in yields of 74%, and 81%, respectively (Fig. 5a), exemplifying the practicability and scalability of this protocol.

Fig. 5: Preliminary mechanistic studies.
figure 5

a Gram-scale reactions. b Control experiments.

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Mechanistic studies

To rationalize these reaction pathways, control experiments were carried out (Fig. 5b). The reaction without of light or Ru(II) catalyst did not afford the product 1, and the substrate A1 could be almost quantitatively recovered (Fig. 5b). The light and photocatalyst are necessary to this remote 1,5-difunctionalization.

Stern-Volmer luminescence quenching showcased that the excited state [Ru(bpy)32+]* was quenched by A1 and UR (for details, see SI, Page S16). The reaction in the presence of radical trapping reagent TEMPO could be completely inhibited, and the TEMPO additive TEMPO-A was detected by MS (Figs. 6a, 1). When another radical trapping reagent BHT was used, the reaction could also be obviously inhibited and afforded a BHT trapping adduct 84 in yield of 43% (Figs. 6a, 2). These results indicated that the radicals·CF3 and Int-2 might be involved in the reaction process. To gain more insight into the mechanism, the reaction by using a base K2CO3 instead of the nucleophile was conducted and the diene product 85 was obtained in 74% yield (Figs. 6a, 3), which might be generated through an elimination of the α-carbonyl carbocation Int-3. Therefore, the possible mechanism demonstrated in Fig. 6b is rational. The role of Ru(bpy)3Cl2 as a photoredox catalyst enabled the umpolung of α-carbonyl carbon to realize the unusual nucleophilic α-addition. The reduction potential of UR (-0.25 V vs SCE)82 is compatible with the reduction step using the excited-state Ru(bpy)32+ (E1/2(II/III)* = -0.81 V vs SCE)82, thus generating the desired UR radical specie. The resultant UR radical anion could collapse to generate an electrophilic CF3 radical, which would be well-suited to add regioselectively to the unsaturated amide A1 forming the radical Int-1, and triggered off the radical clock to generate the α-radical Int-2. Subsequently, the strong oxidative Ru(III) (E1/2(II/III) = 1.29 V vs SCE)14 could oxidize the α-radical to α-carbocation Int-3, thus enabled the unusual α-nucleophilic addition, generating the 1,5-difunctionalization product 1. In addition, we employed DFT to calculate the relative Gibbs free energies for two main conformations Int-1a and Int-1b of radical intermediate Int-1, which might transform to the radical intermediates E-form Int-2 and its Z-form isomer, respectively (see the Supporting Information for computational details). The difference of 2.8 kcal/mol explained why the E-form product is predominant (Fig. 6b).

Fig. 6: Preliminary mechanistic studies.
figure 6

a Mechanism studies. b Possible mechanism.

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Discussion

In summary, we have developed a first photocatalyzed three-component remote 1,5-difuncunctionalization of unsaturated amides or esters containing a radical clock moiety with Umemoto reagent and oxygen- or halogen-nucleophiles through the triggered off radical clock by trifluoromethyl radical and photocatalytically generated α-carbonyl carbocation. This regioselective and umpolung strategy enables the rapid access to diverse biologically important CF3-containing amides or esters that bear a tetrasubstituted α-carbon center. Access to such structures usually needs multiple-step transformations. The novel methodology is characterized by mild conditions, broad substrates scope, excellent regioselectivity.

Methods

General procedure for trifluoromethyl-alkoxylation

In a 25 mL Shrek tube with a magnetic stirring bar, the amide/ester substrates A1-35 (0.2 mmol, 1.0 equiv), Ru(bpy)3Cl2 (0.5 mol%), and UR (0.4 mmol) were successively added. The reaction tube was placed under vacuum and backfilled with N2 three times, and followed by addition of MeOH (2.0 mmol), DCE (2 mL) via syringe. The tube was sealed and protected by parafilm. The reaction tube was placed away from the blue LEDs (455−460 nm) about 2.5 cm and stirred for 1 h (monitored by TLC) under blue LEDs, then the tube was removed from the light source. The reaction mixture was treated with water (10 mL) and the resulted mixture was extracted with dichloromethane (10 mL × 3). The resulting solution was concentrated under vacuum and the residue was purified by column chromatography on silica gel to afford the corresponding products.

General procedure for trifluoromethyl-fluorination

In a 25 mL Shrek tube with a magnetic stirring bar, the substrates A36-54 (0.2 mmol, 1.0 equiv), Ru(bpy)3Cl2 (0.5 mol%) and UR (0.4 mmol) were successively added. The reaction tube was placed under vacuum and backfilled with N2 three times, and followed by addition of Et3N·3HF (1.0 mmol), DCE (2.0 mL) via syringe. The tube was sealed and protected by parafilm. The reaction tube was placed away from the blue LEDs (455−460 nm) about 2.5 cm and stirred for 1 h (monitored by TLC) under blue LEDs, then the tube was removed from the light source. The reaction mixture was treated with saturated aqueous NaHCO3 (10 mL), then water (10 mL) was added, the resulted mixture was extracted with dichloromethane (10 mL × 3). The combined organic layers were concentrated by rotary evaporator and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to afford the corresponding products.

General procedure for trifluoromethyl-chlorination

In a 25 mL Shrek tube with a magnetic stirring bar, the substrates A55-83 (0.2 mmol, 1.0 equiv), Ru(bpy)3Cl2 (0.5 mol%) TBACl (0.8 mmol) and UR (0.4 mmol) were successively added. The reaction tube was placed under vacuum and backfilled with N2 three times, and followed by addition of DCM (4.0 mL) via syringe. The tube was sealed and protected by parafilm. The reaction tube was placed away from the blue LEDs (455−460 nm) about 2.5 cm and stirred for 1 h (monitored by TLC) under blue LEDs, then the tube was removed from the light source. The reaction mixture was treated with water (10 mL) and the resulted mixture was extracted with dichloromethane (10 mL × 3). The combined organic layers were concentrated by rotary evaporator and the residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as the eluent to afford the corresponding products.