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. 2026 Jan 9;12(2):eadz1874. doi: 10.1126/sciadv.adz1874

Three-component synthesis of β-thio tertiary alkylamines from simple alkenes via SH2 homolytic substitution

Hongyu Wang 1,2,†, Ting Wang 3,†, Yang Li 1,2,†, Qianyu He 1,†, Wenxuan Ma 2, Xinyu Guan 2, Yifei Li 2, Yongli Bao 1, Yongyun Zhao 1,*, Qian Zhang 2, Neil Vasdev 4,5, Chao Zheng 4,5,*, Junkai Fu 1,2,*
PMCID: PMC12787521  PMID: 41512059

Abstract

Alkene difunctionalization via electrophilic aminyl radical cations offers a straightforward route to complex tertiary alkylamines widely occurring in biologically active molecules. However, only a limited variety of third reaction components have been hitherto introduced because of the challenges in capturing transient C(sp3)-centered radical intermediates under acidic conditions, and structurally specific alkenes are usually required. Herein, we report a copper-catalyzed three-component aminothiolation reaction, enabling the first incorporation of S-based functionalities across simple alkenes to synthesize β-thio tertiary alkylamines. This protocol works well for both aryl and unactivated alkenes with a broad functional group compatibility and is applicable to ─SCF3, ─SCN, and ─SBz groups. Mechanistic investigations reveal a key bimolecular homolytic (SH2) substitution process that efficiently traps the nascent C(sp3)-centered radical intermediates in acidic media and facilitates the C─S bond formation with high regioselectivity and even primary enantiocontrol. The introduced S-based functionality can improve the performance of pharmaceuticals such as Fentora.

Three-component aminothiolation of simple alkenes is reported to construct β-thio tertiary alkylamines via an SH2 mechanism.

INTRODUCTION

Tertiary alkylamines represent ubiquitous structural motifs in pharmaceuticals, alkaloids, and agrochemicals, with about 60% of aliphatic amines falling into this category (1, 2). The favorable physiological properties and the ability to interfere with neurotransmission pathways have driven unremitting efforts toward their synthesis (3–5). When an additional functional group is located in the vicinity of the nitrogen center, the characteristics of targeted molecules can be substantially altered. For example, an adjacent bivalent sulfur group can modulate the molecular conformation through intramolecular noncovalent interaction between the low-lying C─S σ* orbital and the lone pair electrons of the adjacent nitrogen atom (6). This feature renders β-thio tertiary alkylamine moieties core structures in many drugs (e.g., tiphen, diprophen, and tiamulin) and bidentate ligands (7–11). Traditional methods to β-thio tertiary alkylamines mainly rely on the ring opening of aziridinium or thiiranium intermediates (12–14). However, these reactions require specially engineered precursors. Moreover, given that both the thio and amino groups are poor leaving groups, the reactions are kinetically controlled, resulting in difficulties in regiocontrol and making the process unpredictable (Fig. 1A).

Fig. 1. Synthesis of β-thio tertiary alkylamines.

Fig. 1.

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(A) Traditional methods to β-thio tertiary alkylamines. (B) Alkene difunctionalization via ARCs for the synthesis of β-functionalized tertiary alkylamines. (C) Three-component aminothiolation of simple alkenes via an SH2 homolytic substitution to synthesize β-thio tertiary alkylamines (this work).

In recent years, alkene difunctionalization via electrophilic aminyl radical cations (ARCs) has emerged as a promising platform for the synthesis of β-functionalized tertiary alkylamines, which enables rapid buildup of molecular architectures through constructing two sequential C─N and C─X bonds across abundant feedstocks in a single operation (15–17). This umpolung radical approach tactically avoids the use of stoichiometric transition metals required in an ionic pathway because of the strong chelation properties of Lewis basic dialkylamines (Fig. 1B) (18–21). Despite significant advancements in the past decade, the introduced third reaction components are restricted to halide atoms (22–27) as well as O-based (28–30), N-based (31–33), and C-based (34–36) functionalities. The major challenge lies in effectively trapping the transient C(sp3)-centered radical intermediates generated upon ARC addition under acidic conditions (37), which would otherwise decompose or undergo reverse radical addition (30, 38). This obstacle is particularly pronounced for unactivated alkenes lacking of p-π–conjugated systems (39). To overcome these challenges, several representative reaction models have been successively developed, including intramolecular cyclization or functional-group migration in two-component reactions (22, 28, 30–32, 34–36), reductive elimination of an auxiliary-stabilized Cu(III) intermediate (23, 25), and nucleophilic ring opening of aziridinium intermediates (24, 26, 33). However, these models require structurally specific alkenes or suffer from selectivity issues. Consequently, there is a compelling need to introduce a broader array of functionalities across simple alkenes in a regio- and stereoselective manner, aiming to create structurally diverse β-functionalized tertiary alkylamines (40). [Of note, Beller and co-workers successfully introduced a carbonyl group in amino-difunctionalization of simple alkenes for the synthesis of β-amino acid derivatives (40).]

Bimolecular homolytic (SH2) substitution presents a fundamental step in radical chemistry (41–43). Recent advances have shown that the combination of outer-sphere SH2 mechanisms with transition metal catalysis provides a robust synthetic tool in capturing transient C(sp3)-centered radical species (44, 45), thereby facilitating the construction of myriad C─C (46–54) or C─X (55–59) bonds. This chemistry enables an application of N-centered radicals, such as primary aminyl, amidyl, and azidyl radicals in multicomponent alkene difunctionalizations including aminochlorination (60), aminoazidation (61), diazidation (62–66), and recent aminoalkylation reactions (67). Drawing inspiration from these contributions, we hypothesized that the nascent C(sp3)-centered radical intermediates upon addition of ARCs to alkenes may be intercepted by a transition metal complex through the SH2 process. This proposal holds promise for expanding the third components in a three-component alkylaminative difunctionalization of simple alkenes and provides a strategic means to regio- and stereocontrol. Significant challenges arise from the precise control over the rate constants of multiple elementary steps to maintain an orderly catalytic cycle under acidic conditions, particularly for the effective capture of a nascent C(sp3)-centered radical intermediate by an in situ–formed metal complex before reverse radical addition.

Herein, by using easily prepared O-benzoylhydroxylamines as an amino source and commercially available metal sulfides as a thio source, a three-component aminothiolation reaction is reported using copper catalysis (68), smoothly converting simple aryl and unactivated alkenes into the corresponding β-thio tertiary alkylamines (Fig. 1C). This reaction is initiated from an electrophilic addition of ARCs to alkenes, followed by a key SH2 mechanism to install ─SCF3, ─SCN, and ─SBz groups with high regioselectivity and even primary enantioselectivity (69–71). The success of the SH2 process is attributed to an efficient formation of copper-sulfide active species in situ, as well as the low homolytic bond dissociation energy of the Cu(II)─S bond (~34 kcal/mol) that drives the SH2 process before reverse radical addition (72). These S-based functionalities can significantly affect the bioactivity of target N-containing molecules (73, 74), as demonstrated by the ─SCF3 group (75–79), whose incorporation eventually improves the antitumor activity of the drug Fentora. This work broadens the diversity of alkylaminative difunctionalization of simple alkenes with the first introduction of S-based functionalities, opening the door to a broader scope of transformations and previously unexplored chemical space.

RESULTS

Screening of the reaction conditions

Our optimization studies began by using 4-tert-butylstyrene 1a as the model substrate and AgSCF3 as the thio source. After screening various reaction parameters, we found that treatment of 1a with 4-benzoyloxymorpholine 2a and AgSCF3 using 10 mol % CuSCN as the catalyst, 15 mol % 6,6′-dimethyl-2,2′-dipyridyl (L1) as the ligand, and 2.5 equiv of CsBr as the additive under acidic conditions [1.5 equiv of trifluoroacetic acid (TFA)] in 1,2-dichloroethane (DCE) at 80°C afforded the desired β-thio tertiary alkylamine 3a in a 70% isolated yield (Fig. 2, entry 1). Ligand screening (for details, see part 2.1 in the Supplementary Materials) showed that replacing L1 with 2,2′-dipyridyl (L2, 10% yield) or 4,4′-dimethyl-2,2′-dipyridyl (L3, 19% yield) markedly reduced the yields, suggesting the importance of the steric effect of methyl groups on the reaction efficiency. Similarly, the 1,10-phenanthroline derivative bearing C2 and C9 methyl groups (L4) gave a moderate yield of 56%, along with a 10% yield of two-component amino oxygenation by-product 3a′. This by-product, which has been independently reported by Wang and co-workers (28, 29) and Beller and co-workers (40), is likely generated via a mechanism involving either a Cu(III) or an aziridinium intermediate, competing with the SH2 pathway (for a detailed discussion, see part 2.2 in the Supplementary Materials). Other ligands, e.g., tridentate L5, oxazoline L6, and diphosphine L7, showed very low reactivity.

Fig. 2. Selected optimization results.

Fig. 2.

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Standard reaction conditions A: TFA (0.30 mmol) was added into a mixture of 1a (0.20 mmol), 2a (0.40 mmol), AgSCF3 (0.40 mmol), CuSCN (0.02 mmol), L1 (0.03 mmol), and CsBr (0.50 mmol) in DCE (2.0 ml), and the reaction was stirred at 80°C for 3 hours under a N2 atmosphere. Yields were determined via 1H nuclear magnetic resonance analysis using dibromomethane as the internal standard. [a] Isolated yield. h, hours; N.D., not determined.

Switching the transition metal catalyst to CuI, CuCN, or Cu(acac)2 resulted in inferior yields, while a mixture of desired product 3a and by-product 3a′ was obtained in the presence of Cu(CH3CN)4PF6 (entries 2 to 5). A marked reduction in yield to 46% was observed when the copper catalyst loading was lowered to 5 mol % (entry 6). Notably, the use of nucleophilic NH4SCF3 or CsSCF3 as an alternative trifluoromethylthiolation reagent failed to give 3a; instead, 1,2-amino oxygenation by-product 3a′ dominated the reaction outcome, underscoring the importance of AgSCF3 for the success of this reaction (entries 7 and 8). Other alkali halides could also promote the reaction, wherein the employment of KBr and CsI gave slightly decreased yields down to 52 and 65%, respectively, while the reaction with ZnBr2 led to a low yield of 15% (entries 9 to 11). The addition of a Brønsted acid has been demonstrated to benefit ARC formation (16). Unfortunately, in addition to TFA, other commonly used acids (e.g., HClO4 and HOAc) showed very low or no reactivity (entries 12 and 13). Further screening of reaction solvents revealed that DCE was the most effective one compared to CHCl3 and toluene, and dioxane made a huge negative impact on the reaction efficiency (entries 14 to 16). The addition of CsBr can react with AgSCF3 to form the Cs[AgSCF3]Br complex, which then undergoes transmetalation with a copper catalyst to in situ form L1CuSCF3 (80, 81). This process is considered to benefit the subsequent SH2 process. In the absence of CsBr, the incorporation of the trifluoromethylthio moiety was sluggish, resulting in a trace amount of 3a along with a 25% yield of by-product 3a′ (entry 17). Moreover, the reaction did not proceed without either the copper catalyst or external ligand L1 (entry 18).

Substrate scope

With the optimized reaction conditions in hand, we explored the substrate scope of the amino trifluoromethylthiolation reaction. As shown in Fig. 3, a variety of aryl alkenes bearing electronically diverse substituents smoothly underwent the difunctionalization reaction to afford products 3b to 3m. In general, the electronically neutral (─Me, ─iBu, ─Ph, and ─SMe) and donating (─OMe) substituents gave superior yields compared to the electronically deficient (─F, ─Cl, and ─Br) ones, with a strongly electron-withdrawing group (─CF3) providing 3m in only 45% yield. A steric effect was observed for o-methyl-styrene, and the reaction yield decreased to 52% (3e). In addition to monosubstituted styrenes, di- and sterically encumbered trisubstituted styrene derivatives were proved to be competent substrates, giving rise to products 3n to 3t in good yields. The reaction exhibited an excellent functional group tolerance, with halogens (3u and 3v), esters (3w), and azides (3x) all being compatible. The styryl olefin could be selectively difunctionalized in the presence of a carbon-carbon triple bond (3y) or an α,β-unsaturated ester (3z). Moreover, the aminothiolation of 1,1-disubstituted alkenes furnished products 3aa and 3ab bearing tertiary C─S stereocenters. Notably, both acyclic and cyclic internal alkenes effectively participated in the reaction to deliver 3ac to 3af, and the N and S atoms in products 3ae and 3af were installed in an anti-fashion, indicating no coordination between the preinstalled nitrogen atom and the metal-sulfide complex during the C─S bond forming process. Alkenes having other types of aromatic scaffolds (e.g., naphthalene and benzofuran) took part in the reaction to produce 3ag and 3ah, while 1,3-diene was smoothly converted to the 1,2-difunctionalization product 3ai in an acceptable yield of 55%. Delightedly, alkenes derived from biologically active molecules, including estrone (3aj), diacetone-d-galactose (3ak), lithocholic acid (3al), and indometacin (3am), all worked well, and even the free hydroxyl group was tolerated, fully demonstrating the synthetic practicability of this methodology in late-stage functionalization of complex molecules. With regard to the generality of amino sources, both cyclic and acyclic O-benzoylhydroxylamines reacted with 4-tert-butylstyrene 1a to furnish tertiary alkylamines 3an to 3az in moderate to good yields, and various functional groups were compatible including esters, ketals, amides, phenyls, and ethers. Furthermore, secondary alkylamines 3ba and 3bb were obtained, albeit in low yields. For O-benzoylhydroxylamines derived from the drug molecules, e.g., maprotiline and fluoxetine, the corresponding amino trifluoromethylthiolation products 3bc and 3bd were isolated in acceptable yields of 57 and 60%, respectively.

Fig. 3. Substrate scope for the reactions with aryl alkenes.

Fig. 3.

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Standard reaction conditions A: TFA (0.30 mmol) was added into a mixture of alkene 1 (0.20 mmol), O-benzoylhydroxylamine 2 (0.40 mmol), AgSCF3 (0.40 mmol), CuSCN (0.02 mmol), L1 (0.03 mmol), and CsBr (0.50 mmol) in DCE (2.0 ml), and the reaction was stirred at 80°C for 3 hours under a N2 atmosphere. Isolated yield. dr, diastereomeric ratio.

Radical difunctionalization of simple unactivated alkenes has been proven to be challenging because of the lack of a stabilizing p-π conjugation (26, 39). Fortunately, this amino trifluoromethylthiolation reaction works efficiently with various unactivated alkenes, and the regioselectivity observed here is consistent with that for aryl alkenes, suggesting a mechanism different from the aziridinium ring-opening pathway (33). The substrate scope was then explored under slightly modified reaction conditions B, where TFA was replaced by a combination of trifluoroacetic anhydride (TFAA) and hexafluoro-2-propanol (HFIP) (Fig. 4) (82). TFAA is known to provide protic acid through the reaction with the protic HFIP and function as a water scavenger. Simple alkenes with different alkyl chains took part in the reaction to simultaneously introduce morpholine and trifluoromethylthio moieties, resulting in the formation of products 5a to 5e with yields ranging from 72 to 61%. A variety of functional groups, including halogens (5f and 5g), ketones (5h), azides (5i), ethers (5m), esters (5n and 5o), amides (5j and 5k), and even free hydroxyls (5l), were found to be compatible, providing valuable synthetic handles for further manipulations. The reaction preferred terminal olefin (5p) over internal olefin (5p′), with a regioselectivity ratio of 3:1. For cyclohexene, the difunctionalization product 5q was obtained as a single anti-isomer, which is consistent with aforementioned observations for 3ae and 3af in Fig. 3. This protocol was also effective for the aliphatic alkenes sourced from natural products or drug molecules, including l-phenylalanine (5r), ibuprofen (5s), diacetone-d-galactose (5t), and lithocholic acid (5u), with a good tolerance for various functional groups including even free NH group. Further evaluation of O-benzoylhydroxylamines revealed that both cyclic and acyclic dialkylamino moieties could be successfully incorporated across 4-phenyl-1-butene to forge the C─N bonds, delivering products 5v to 5ab in moderate to good yields.

Fig. 4. Substrate scope for the reactions with unactivated alkenes.

Fig. 4.

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Standard reaction conditions B: TFAA (0.60 mmol) and HFIP (1.0 ml) were added into a mixture of alkene 4 (0.20 mmol), O-benzoylhydroxylamine 2 (0.40 mmol), AgSCF3 (0.40 mmol), CuSCN (0.02 mmol), L1 (0.03 mmol), and CsBr (0.50 mmol) in DCE (2.0 ml), and the reaction was stirred at 80°C for 3 hours under a N2 atmosphere. Isolated yield.

After investigating the incorporation of the ─SCF3 group, we sought to test other S-based functionalities to further expand the scope of this alkene aminative difunctionalization reaction (Fig. 5). The ─SCN group was chosen for initial exploration. Under reaction conditions similar to those adopted for the ─SCF3 group, simple alkenes reacted smoothly with 4-benzoyloxymorpholine 2a and AgSCN, furnishing vicinal thiocyano tertiary alkylamines 6a to 6d in moderate yields. Then, we examined the installation of the ─SBz group. Replacing the silver salt with KSBz and omitting alkali halide improved the reaction efficiency, allowing the installation of both the ─SBz group and morpholine moiety across the simple alkenes (59). Alkenes bearing electronically neutral (─tBu), rich (─OMe), and deficient (─CF3) substituents all reacted efficiently, giving rise to the desired products 7a to 7c.

Fig. 5. Extension of S-based functionalities.

Fig. 5.

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(A) Introduction of the SCN unit. (B) Introduction of the SBz unit.

Mechanistic studies

A series of experimental studies were conducted to investigate the reaction mechanism (Fig. 6). The addition of 2,2,6,6-tetramethyl-1-piperidinyloxy or butylated hydroxytoluene as a radical scavenger completely suppressed the formation of the desired product 3a, and adduct 8 was isolated in a 42% yield in the case of butylated hydroxytoluene (Fig. 6A). A radical clock experiment with cyclopropylvinyl substrate 9 led to the formation of fused arene 10, implying a radical ring opening of the cyclopropyl group followed by intramolecular trapping (Fig. 6B). Together, these findings suggested the involvement of a N-centered radical in the reaction. Competing reactions under standard conditions A or B were then carried out in the presence of 5.0 equiv of methanol. The anticipated products 3a and 5a were obtained in slightly lower yields of 65 and 62%, respectively, without the observation of methoxylation by-products 11 or 12, indicating that the C─S bond formation does not proceed via a carbocation or aziridinium intermediate (Fig. 6C) (24). To further support this nonionic pathway, the known compound 13 (33) was first reacted with silver salt to generate aziridinium intermediate 14 in situ, which has been detected by ESI-MS (electrospray ionization mass spectrometry) analysis (83). As expected, no ring-opening products 5a or 5a′ were obtained upon treatment of 14 with AgSCF3 under standard reaction conditions B. A test of aziridinium intermediate 14 with the prefabricated (L1)CuSCF3 complex also failed to produce desired products 5a or 5a′. Directly performing the reaction of 13 under standard reaction conditions B excluding alkene and amine precursor did not give any desired aminothiolation products 5a or 5a′, with 80% of starting material 13 recovered. Moreover, the treatment of known β-bromoamine 15 with the standard reaction conditions B excluding alkene and amine precursor offered no desired product 5q, with 65% of substrate 15 being recovered. These results show that β-haloamine cannot be a possible intermediate in the alkene aminothiolation reaction (Fig. 6D). Moreover, replacing CuSCN, AgSCF3, CsBr, and ligand L1 with the stoichiometric (L1)CuSCF3 complex (84) pre-prepared from an equimolar mixture of CuI, AgSCF3, and L1 afforded the desired product 3a in a 45% yield, demonstrating that the (L1)CuSCF3 complex likely acts as the active species in this reaction and serves as an ─SCF3 donor to forge the C─S bond. The reaction with a combination of stoichiometric CuSCF3 and ligand L1 gave an inferior yield of 26%, suggesting that a fast generation of the (L1)CuSCF3 complex benefits the reaction efficiency (Fig. 6E). In addition, the electronic effects of the substituents (such as 4-Me, 4-F, 4-Cl, and 4-CF3) on the reaction rate of styrene derivatives were assessed using Hammett studies. The good linear correlation (R2 = 0.97) between log(KX/KH) and σ values of the respective substituents, along with a negative slope (ρ = −1.44) in the Hammett plot, reveals that the reaction likely proceeds through a highly electrophilic transition state (Fig. 6F). It should be mentioned that when a chiral ligand was used in replacement of racemic L1, primary enantiomeric ratios were observed (for details, see part 2.3 of the Supplementary Materials). Enantiocontrol remains a long-standing challenge in ARC-involved alkene difunctionalization, with the only example reported by Liu and co-workers (32) in a two-component asymmetric diamination of alkenes. Our preliminary findings showed that when a box-type chiral L1* was used at room temperature (30°C), product 3a was obtained in a 52% yield with a moderate enantiomeric ratio of 65:35 (Fig. 6G). These results indicate that the C─S bond–forming step involves a chiral transition metal complex, which is crucial for achieving the challenging stereoselective formation of C─S bonds (59).

Fig. 6. Control experiments.

Fig. 6.

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(A) Radical trapping experiment. (B) Radical clock experiment. (C) Competing reactions. (D) Exploring the possibility of aziridinium or β-haloamine intermediate. rt, room temperature. (E) Reaction with a stoichiometric copper complex. (F) Hammett plot. (G) Primary enantiocontrol using a chiral ligand. er, enantiomeric ratio.

To gain a deeper understanding of the reaction mechanism, density functional theory calculations were performed (Fig. 7). The reaction begins with a binding between active species (L1)Cu(I)SCF3 demonstrated in Fig. 6E and the 2a-TFA complex observed by 1H nuclear magnetic resonance (see part 2.4 of the Supplementary Materials), resulting in the formation of the N-coordinated Cu(I)-hydroxylamine intermediate (INT1) while releasing TFA. Next, the cleavage of the N─O bond occurs via an inner-sphere (85, 86), cyclic transition state TS1OSS (for a discussion of an outer-sphere pathway, see fig. S9). This process involves homolysis of the N─O bond and a single electron transfer from the Cu(I) center to the OBz group, generating the Cu(II)-coordinated nitrogen radical intermediate INT2OSS [Mulliken spin populations: p(Cu) = 0.566, p(N) = −0.760]. Subsequent release of the L1Cu(II)(SCF3)(OBz) complex from INT2OSS yields the free nitrogen-centered radical (INT3), as confirmed by radical trapping/clock experiments shown in Fig. 6 (A and B). The nitrogen-centered radical INT3 can add directly to alkene 1a via TS2′ with a relative free energy of 18.0 kcal/mol. Alternatively, in the presence of TFA, protonation of a nitrogen-centered radical may occur first to form an electrophilic ARC (INT4, dN─H = 1.13 Å, dO─H = 1.41 Å), which is exergonic by 6.9 kcal/mol. Subsequent addition of INT4 to the alkene proceeds via TS2 with a significantly lower free energy of 6.6 kcal/mol, showing that electrophilic ARC formation can effectively facilitate the radical addition to alkene (87), leading to the C(sp3)-centered radical intermediate INT5. Notably, the moderate energy barrier (ΔG≠ = 21.4 kcal/mol) also indicates the potential for reverse radical addition from INT5 to a high-energy ARC (INT4), which would slowly decompose (38). Therefore, rapid capture of the C(sp3)-centered radical INT5 is crucial to drive the reaction forward. With regard to the final C─S bond formation between INT5 and the L1Cu(II)(SCF3)(OBz) complex, there are three potential pathways (88): (i) sequential single electron transfer, leading to a carbocation followed by ion-type C─S bond formation, (ii) SH2 substitution, and (iii) reductive elimination of a Cu(III) intermediate. The carbocation path can be first ruled out by experimental evidence from competing reactions and aziridinium trapping experiments in Fig. 6 (C and D). Further evaluations on the basis of computational results show that the Cu(II)-mediated outer-sphere SH2 pathway via TS3OSS is 3.2 kcal/mol more favorable than the reductive elimination process via TS3-RE. In addition, this SH2 step has a lower energy barrier (ΔG≠ = 16.8 kcal/mol) compared to the reverse radical addition from INT5 to INT4 (ΔG≠ = 21.4 kcal/mol), effectively driving the reaction toward the desired product. Overall, the density functional theory calculations highlight the important roles of TFA and (L1)Cu(I)SCF3 active species in promoting ARC formation and mediating the SH2 substitution to forge the C─S bond, thereby making the entire reaction process kinetically feasible (ΔG≠ = 20.9 kcal/mol).

Fig. 7. Free energy profile for the copper-catalyzed amino trifluoromethylthiolation of alkenes and three-dimensional structures for the key transition states.

Fig. 7.

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All the calculations were performed at the uB3LYP-D3BJ/def2-TZVP, SMD(dichloroethane)//uB3LYP-D3BJ/6-31G(d), SDD (Cu) level using Gaussian 16 software. The subscript OSS represents the open-shell singlet state of the corresponding structure. The irrelevant hydrogen atoms are omitted for clarity in three-dimensional structures. Relative free energies, key distances, and spin populations (p) are given in kcal/mol, angstroms (Å), and atomic units (a.u.), respectively.

CCK-8 assay of the antitumor activity of Fentora derivative

The incorporation of S-based functionalities is known to significantly affect the bioactivity of N-containing molecules (6, 73, 74), among which the introduction of an ─SCF3 group has been shown to enhance cell-membrane permeability owing to high stability, electronegativity, and lipophilicity (π = 1.44) (75–79). Here, to evaluate its effect on the performance of specific N-containing pharmaceuticals, we chose to modify Fentora, an anesthetic used in clinical practice and previously reported with antitumor activity (89, 90). To synthesize the Fentora derivative, an amino trifluoromethylthiolation reaction of styrene and O-benzoylhydroxylamine derived from 4-piperidone ethylene ketal was first conducted, affording β-trifluoromethylthio alkylamine 16 in a 63% yield. The ketal group was then hydrolyzed under acidic conditions to yield the corresponding ketone, which underwent reductive amination with aniline to form secondary amine 18. Final condensation of secondary amine with propionyl chloride furnished Fentora derivative 19, with an ─SCF3 group adjacent to the tertiary alkylamine moiety (Fig. 8). We assessed the antitumor activity of Fentora derivative 19 using the Cell Counting Kit-8 (CCK-8) assay. The results demonstrated that derivative 19 outperformed the parent compound Fentora in inhibiting the proliferation of both HCT116 cells [IC50 (median inhibitory concentration) = 0.12 versus 0.72 μM] and A549 cells (IC50 = 0.18 versus 0.85 μM). This enhanced potency was further evaluated in additional tumor cell lines, including HCT-8, C13K, A2780, and HepG2, and the results were highly consistent with those from the HCT116 and A549 assays. Further studies based on biotin-labeled Fentora derivative 20 revealed that the significant role of the ─SCF3 group in improving the antitumor efficacy of Fentora might be due to the enhancement of cell-membrane permeability (for details, see part 2.5 of the Supplementary Materials).

Fig. 8. Synthesis and subsequent CCK-8 assay of the antitumor activity of Fentora derivative.

Fig. 8.

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DISCUSSION

In summary, a copper-catalyzed three-component aminothiolation of simple alkenes with O-benzoylhydroxylamines and metal sulfides has been developed, allowing for the direct incorporation of ─SCF3, ─SCN, and ─SBz groups across abundant feedstocks to construct structurally diverse β-thio tertiary alkylamines. The broad substrate scope applicable to both aryl and unactivated alkenes, together with an excellent tolerance for various functional groups, renders this methodology a practical tool for the late-stage functionalization of complex natural products and drugs. Mechanistic investigations suggest a radical reaction pathway involving electrophilic addition of ARCs to alkenes and reveal that the in situ generation of a copper-sulfide active species with low homolytic bond dissociation energy contributes to the success of subsequent SH2 homolytic substitution. This SH2 process can mitigate the negative effect of acidic media and effectively trap the nascent C(sp3)-centered radical intermediates to prevent reverse radical addition, thus providing the driving force to forge the C─S bond with high regioselectivity and even primary enantiocontrol. The incorporated S-based functionalities, such as an ─SCF3 group with a potential for enhancing cell-membrane permeability, have eventually improved the antitumor activity of the drug molecule Fentora. We believe that this SH2 mechanism will direct future endeavors in aminative difunctionalization of simple alkenes and inspire further advances in the synthesis of complex tertiary alkylamine scaffolds.

MATERIALS AND METHODS

Standard reaction conditions A

A 10-ml Schlenk tube equipped with a magnetic stir bar was charged with 2a (82.8 mg, 0.40 mmol, 2.0 equiv), AgSCF3 (83.6 mg, 0.40 mmol, 2.0 equiv), CuSCN (2.5 mg, 0.02 mmol, 0.10 equiv), L1 (5.5 mg, 0.03 mmol, 0.15 equiv), CsBr (106 mg, 0.50 mmol, 2.5 equiv), and anhydrous DCE (2.0 ml). The mixture was degassed three times with nitrogen. After that, alkene 1a (32.1 mg, 0.20 mmol, 1.0 equiv) and TFA (23 μl, 0.30 mmol, 1.5 equiv) were added, and the resulting solution was stirred at 80°C for 3 hours. The reaction was quenched with a 1 M aqueous solution of NaOH (3.0 ml) at room temperature and then extracted with DCM (5.0 ml × 3). The combined organic layers were washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluted with petroleum ether (PE)/ethyl acetate (EA) = 10:1 to obtain the desired product 3a as a yellow oil (48.6 mg, 0.14 mmol, 70%).

Acknowledgments

Funding:

We acknowledge the National Natural Science Foundation of China (22371036, 21971034, 22203069, and 22401041), Fundamental Research Funds for the Central Universities (2412024QD020), Jilin Province Scientific and Technological Development Program (20230508107RC), and Canadian Institutes of Health Research (CIHR507113, to C.Z.) for financial support. N.V. thanks the Azrieli Foundation, Canada Foundation for Innovation, Ontario Research Fund, and the Canada Research Chairs Program for support.

Author contributions:

H.W. and Yang Li designed and performed the experiments. T.W. performed the density functional theory calculations. W.M. and X.G. assisted in completing the experiments. Q.H., Y.B., and Y.Z. designed and performed the biological experiments. Yifei Li and Q.Z. analyzed the data. J.F., C.Z., and N.V. directed the project and wrote the manuscript. All the authors were involved in the interpretation of the results presented in the manuscript.

Competing interests:

The authors declare that they have no competing interests.

Data and materials availability:

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials.

Supplementary Materials

This PDF file includes:

Supplementary Text

Figs. S1 to S331

Tables S1 and S2

sciadv.adz1874_sm.pdf (17.7MB, pdf)

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Associated Data

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Supplementary Materials

Supplementary Text

Figs. S1 to S331

Tables S1 and S2

sciadv.adz1874_sm.pdf (17.7MB, pdf)

Data Availability Statement

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials.

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