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Open AccessCCS ChemistryRESEARCH ARTICLES25 Nov 2024

Intermolecular Crosslinking of Phenols and Alkyl Amines with Formaldehyde in Hexafluoroisopropanol (HFIP) for Conjugation: A Multipartner Bridging Model for HFIP Promotion

    https://doi.org/10.31635/ccschem.024.202404848

    Crosslinking different biorelevant molecules (BMs) through their endogenous nucleophilic groups in one step could provide streamlined methods for their conjugation. Previously, we discovered that the phenol side chain of tyrosine and the amino side chain of lysine in peptides can be intramolecularly crosslinked via a methylene linker using a simple formaldehyde (HCHO) reagent in hexafluoroisopropanol (HFIP) solvent. Herein, we report that HCHO-mediated crosslinking between various phenols and alkyl amines could proceed intermolecularly in HFIP under mild conditions. This new protocol offers a simple, versatile, and robust method for crosslinking various BMs with a small-footprint linker and high atom economy. Unlike previous HFIP activation models that involve interactions with only one reaction partner, we propose that HFIP aggregates act as versatile bridging templates, bringing together two reaction partners through combinations of weak bonding interactions such as H-bonding, cation-dipole, and C–H/π interactions, in a multipartner activation mode.

    Introduction

    Conjugation chemistry plays a key role in developing modern biopharmaceuticals and biochemical probes such as peptide/antibody-drug conjugates, proteolysis targeting chimera (PROTAC), and advanced imaging agents.1–3 Despite significant progress, there is still a high demand for broadly applicable and user-friendly conjugation methods.4–20 Biorelevant molecules (BMs), such as peptides and small-molecule drugs, primarily display nucleophilic groups (-NH, -OH, and, to a lesser extent, -SH) on their surfaces, which can react with various electrophilic reagents for conjugation. However, crosslinking two native BMs typically requires specially designed bifunctional linkers bearing two different electrophilic groups to necessitate a two-step installation procedure. The ability to directly crosslink two different BMs through their endogenous nucleophilic handles in one step could significantly streamline the conjugation process (Scheme 1a).21–31 The Betti reaction, a special case of the Mannich reaction, can crosslink phenol and amino groups via a methylene linker between carbon and nitrogen atoms (C/N) using a simple formaldehyde (HCHO) reagent.32–34 HCHO-mediated crosslinking of various nucleophiles occurs naturally in living systems; however, these processes usually proceed with moderate reactivity and high promiscuity.35–44 Notably, Francis and coworkers45,46 reported a bioconjugation protocol for labeling the phenol group of tyrosine (Tyr) residues in proteins with HCHO and electron-enriched arylamine reagents under near-physiological conditions (Scheme 1b). However, this reaction exhibited moderate efficiency and required a large excess of HCHO and aryl amine reagents to achieve good conversions. Interestingly, alkyl amines showed little reactivity in the labeling reaction. Recently, we discovered that the HCHO-mediated intramolecular C/N crosslinking between the Tyr and the alkyl amine side chain of lysine (Lys) could proceed efficiently and selectively at room temperature (rt) in hexafluoroisopropanol (HFIP) solvent.47 This method enabled the stapling of native peptides with a small footprint methylene linker and high atom economy (Scheme 1c).48–51 Herein, we report that the HCHO-mediated intermolecular C/N methylene crosslinking between various phenols and alkyl amines could proceed smoothly in HFIP solvent under mild conditions (Scheme 1d). This new protocol offers a simple, versatile, and robust method for crosslinking various BMs such as peptides, small molecule drugs, and fluorophores through their endogenous phenol and amine moieties.51–74 Mechanistically, we propose that HFIP aggregates act as self-assembled bridges for bringing together two reaction partners, promoting the intermolecular reaction in a pseudo-intramolecular fashion through a multipartner activation mode.75–96

    Scheme 1

    Scheme 1 | Crosslinking phenols and alkyl amines with HCHO for conjugation of BMs.

    Experimental Methods

    All commercial materials were used as received unless otherwise noted. Flash chromatography was performed using Silica gel (200–300 mesh) purchased from Qingdao Haiyang Chemical Co., Ltd. (Shandong, China) Fmoc-protected amino acids and coupling reagents N,N’-diisopropylcarbodiimide (DIC) and ethyl (hydroxyimino)cyanoacetate (Oxyma) were purchased from Shanghai Haohong Scientific Co. Ltd. (Shanghai, China). Rink amide MBHA (MBHA: bmethylbenzhydryl amine) resin (0.634 mmol/g) was purchased from GL Biochem (Shanghai, China). HFIP solvent (99.5%, Energy Chemical Co. Ltd., Shanghai, China), N,N-diisopropylethylamine (DIPEA; 99.5%; Energy Chemical), and HCHO (37% wt % in H2O; Energy Chemical) were used in the intermolecular crosslinking of phenols and alkyl amines with HCHO. Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) analyses were performed with a Dionex UltiMate 3000 connected to a Thermo Scientific MSQ PLUS mass spectrometer using Thermo Scientific Hypersil GOLD C18 (1.9 μm, 2.1 × 100 mm) (Thermo Fisher Scientific, Waltham, Massachusetts, USA) or Agilent TC-C18 (5 μm, 4.6 × 250 mm) (Agilent Technologies Inc., Santa Clara, California, USA). Linear gradients using A: H2O (0.1% HCOOH) and B: MeCN (0.1% HCOOH) over varying periods. High-resolution mass spectra (HRMS) were recorded on a Thermo Q Exactive Focus (Thermo Fisher Scientific, Waltham, Massachusetts, USA) using electrospray ionization (ESI). Semi-preparative high-performance liquid chromatography (HPLC) was carried out on a Dionex UltiMate 3000 using a Thermo Scientific Hypersil GOLD C18 (5 μm, 21.2 × 150 mm) preparative column (Thermo Fisher Scientific, Waltham, Massachusetts, USA). Nuclear magnetic resonance (NMR) spectra were recorded on Bruker AVANCE AV 400 instruments (Bruker, Billerica, Massachusetts, USA) and all NMR experiments were reported in units, parts per million (ppm), using residual solvent peaks (chloroform (δ = 7.26 ppm) or TMS (δ = 0.00 ppm) for 1H NMR, chloroform (δ = 77.16 ppm) for 13C NMR) as the internal reference. Multiplicities are recorded as follows: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, td = triplet of doublets, br s = broad singlet, m = multiplet. UV–vis spectra were recorded on a Cary 100 spectrophotometer (Agilent Technologies Inc., Santa Clara, California, USA). Steady-state fluorescence measurements were recorded on a Cary Eclipse fluorescence spectrometer (Agilent Technologies Inc., Santa Clara, California, USA).

    Results and Discussion

    As shown in Scheme 2a, our investigation commenced with the crosslinking of the model tetrapeptide 1, which has a free Lys side chain, and para-cresol 2 using aq. HCHO (37 wt % in H2O). The amino peptide starting material 1 was prepared as a trifluoracetic acid (TFA) salt using standard solid-phase peptide synthesis procedures (see Supporting Information Figure S1). The N-terminus of 1 was capped with a 2-naphthyl group (NA) to enhance the UV detection sensitivity. The reaction of 1 with 1.5 equiv of 2 and 3.0 equiv of HCHO, along with 3.0 equiv of DIPEA base, in HFIP at rt for 2 h gave the desired 2-hydroxybenzyl amine (2-HBA, also called Hobamine) product 1-2 in 93% yield based on liquid chromatography-mass spectrometry (LC-MS) analysis (standard conditions [ A], see LC trace 1). N,N-dialkylation side product 1-2-a, generated via the reaction of secondary amine 1-2 with HCHO and 2, was also formed in 5% LC yield. Prolonging the reaction time from 2 to 24 h led to an increased formation of 1-2-a (35%, see Supporting Information Figure S2 for details). Notably, reducing the amount of 2 from 1.5 to 1.1 equiv gave 1-2 in comparable yield (91%) and suppressed the formation of 1-2-a to less than 2% (see LC trace 2 and Supporting Information Table S2). Reducing the amount of HCHO from 3.0 to 2.0 equiv slightly diminishes the yield of 1-2 to 90% (see Supporting Information Table S3). Side products 1-2-c and 1-2-d featuring an aminal methylene linkage, and o,o′-dialkylation side product 1-2-b were not detected. As seen in our HCHO-mediated intramolecular C/N crosslinking of Tyr and Lys, the HFIP solvent was crucial for the success of the intermolecular reaction of 1 and 2.47–49 Trifluoroethanol solvent gave a 16% yield of 1-2 under otherwise identical conditions, while other organic solvents such as MeOH, CH3CN, and dimethylformamide (DMF) did not produce any 1-2. The reaction of 1 and 2 in phosphate-buffered saline (PBS) at pH 7.3 also failed to generate any 1-2 (see LC trace 3). The reaction in mixed solvents of HFIP/H2O (1:1) gave a trace amount of 1-2 (2%) (see Supporting Information Table S1). DIPEA base was mainly used to neutralize the residual TFA in starting material 1. The reaction of 1 and 2 without any base yielded about 50% of 1-2 (see Supporting Information Table S4). Our previous work showed that primary alkyl amines, when treated with HCHO in HFIP, could undergo intermolecular hydrogen transfer with HCHO or formaldimines to form N-methylation side products such as 1-b and other dehydrogenation side products.48,49 Product 1-b was not detected (>1%) for the reaction of 1 and 2 under the standard conditions. Product 1-2, containing the 2-HBA linkage, showed no signs of decomposition after being dissolved in aqueous buffer (pH 3–9) for 3 days at rt. (see Supporting Information Table S5 and Figure S45 for details).

    Scheme 2

    Scheme 2 | HCHO-mediated labeling of Lys side chains in peptides with phenols. Reactions were conducted on a 0.01 mmol scale. LC yields were estimated based on the UV absorption of peptide-related peaks in LC traces. HPLC-isolated yields were shown in braces. (a) 35% of 1-2-a along with 60% of 1-2 was formed after 24 h. (b) A mixture of regioisomers was obtained. (c) Around 10% of N,N-dialkylation side product was formed. (d) About 10% of 1 remained unconsumed after 2 h; extending the reaction time to 24 h resulted in a more complex mixture of products. (e) 1.1 equiv of ArOH was used. (f) A small amount (∼5%) of the N-methylation product of the amine reactant was observed. (g) 1.1 equiv of 11 was used. (h) A single regio-isomer of the product was observed using LC-MS. (i) 1.3 equiv of Ar was used. (k) an unknown peak with a MW of 24+24Da was detected. ND, not detected; NR, no reaction;

    As shown in Scheme 2b, model peptide 1 could react with various phenol partners to give the corresponding oHBA products with different efficiency and selectivity under HCHO-mediated conditions in HFIP. (1) The aminomethylation reaction of phenols can occur at both the ortho and para positions of the OH group, with the ortho position being considerably more favored. For example, the reaction with plain phenol 3 gave the products 1-3 as a 3:1 mixture of ortho and para isomers in a 91% combined LC yield (see Supporting Information Figures S3 and S47–S49 for NMR spectra of isolated isomers). Phenols with both ortho positions blocked, such as 2,6-dimethylphenol 6, reacted but with reduced efficiency (see 1-6 and Supporting Information Figure S6). (2) Generally, electron-rich phenols exhibited high reactivity, whereas phenols bearing electron-withdrawing groups displayed diminished reactivity and selectivity. Extending the reaction time usually could increase yields for low-reactivity substrates; however, it also could lead to the increased formation of competing side products, such as N-methylation products of amines (e.g., 1-b) (see Supporting Information Figures S4 and S5). For example, the reaction of p-chlorophenol 4 for 2 h formed product 1-4 in 65% LC yield, which increased to 73% after 24 h ( Supporting Information Figure S4). A small amount of 1-a (typically around 5%) was observed for reactions of low-yielding substrates (see 1-6, 1-18 and Supporting Information Figures S6 and S14). (3) For many electron-rich phenol substrates (e.g., 13, 14, 19, 20), the use of 1.1 equiv of phenol was sufficient to give the desired products in high yield along with the added benefit of suppressing the formation of N,N-dialkylation side products ( Supporting Information Figures S9–S10 and S15–S16). (4) The phenolic OH group was critical for achieving high reactivity. For instance, in contrast to phenols 3 and 6, their methyl ether analogs 8 and 7 did not produce any corresponding aminomethylation products. Similarly, 1,3-dimethoxybenzene 9 and N,N-dimethylaniline 10, despite their electron-donating substituents, did not yield any desired alkylation products. However, 1,3,5-trimethoxylbenzene 11, an exceptionally electron-rich arene, reacted well to give the 1,3,5-trimethoxybenzyl amine product 1-11 in near quantitative yield ( Supporting Information Figures S7 and S51). (5) The aminomethylation reactions of phenols bearing two different ortho C–H bonds usually gave a mixture of regioisomers. However, the reactions of some phenols proceeded with a strong preference for one of the ortho C–H bonds. For example, the alkylation of ethinylestradiol 19 produced 1-19 as a 1:1 mixture of i- and ii-substituted regioisomers (See Supporting Information Figures S15 and S55–S57). The reaction of 2-naphthol 13 selectively occurred at the C1 position ( 1-13) (See Supporting Information Figures S9 and S52). Interestingly, the reaction of fluorescein 22 and d-luciferin 21 (see LC trace 4, 5 and Supporting Information Figures S17–S18 and S58–S59) selectively occurred at the Ci position. (6) A range of phenol-containing functional molecules such as bioactive compounds and fluorophores, could be readily installed onto the Lys side chains of peptides under standard conditions. For example, acetaminophen 16, tolterodine 17, ezetimibe 18, and γ-tocopherol 20 reacted with 1 to give the corresponding crosslinked products in good to excellent yield. Functional groups such as alkyne ( 19), alcohol ( 18), and carboxylic acid ( 21) were well tolerated (See Supporting Information Figures S12–S17). As shown in Scheme 2c, the efficient and regioselective reaction of fluorescein 22 enabled a new way of labeling peptides with the classic fluorophore through a nonconventional linking site. The reaction of cyclic peptide drug atosiban 24 with 22 yielded 24-22 with high yield and selectivity (see LC trace 5 and Supporting Information Figures S22).

    As outlined in Scheme 3a, the HCHO-mediated intermolecular phenol/amine crosslinking reaction was utilized to attach various alkyl amines onto the Tyr side chain of short peptides. For example, the reaction of tetrapeptide NA-Leu-Gly-Tyr-Ala-NH2 25 with 2 equiv of primary amine Amlodipine 26, 3.0 equiv of HCHO, and 3.0 equiv of DIPEA in HFIP at rt for 24 h gave product 26-25 in excellent LC yield (conditions [ B]) (See Supporting Information Figure S24). In general, larger phenols such as Tyr-containing peptides, showed lower reactivity than smaller phenol substrates, such as p-cresol 2, and their reactions typically required longer time (12–48 h). The reaction of sterically hindered primary amines such as Memantine 28 also worked well (see 28-25 and Supporting Information Figure S26). The reaction of 25 with unprotected phenylalanine 30 through the electronically deactivated α-NH2 group gave 30-25 in moderate yield (70%) ( Supporting Information Figure S28). The reaction of 25 with Atosiban 24 gave 24-25 in 78% LC yield along with 20% of unreacted 25 (see LC trace 6) ( Supporting Information Figure S23). Drug molecules containing six-membered cyclic secondary amines such as Ciprofloxacin 32, Amoxapine 33, and Paroxetine 34 exhibited excellent reactivity and reacted well with 25 to give the corresponding products in high LC yield (>90%) even with a slightly reduced amount of amine partners (1.5 equiv) (see Supporting Information Figures S30–S32). The reaction of acyclic secondary amine Duloxetine 35 (3 equiv) gave 35-25 in 90% LC yield ( Supporting Information Figure S33). In contrast to alkyl amines, primary and secondary aryl amines such as aniline 36 and N-methyl aniline 37 did not yield any desired C/N crosslinked products. We suspected that the resonance effect of the corresponding N-aryl formaldimines might reduce their reactivity toward electrophilic attack by phenol. As exemplified by 40-18, two nonpeptide compounds, N-(4-aminobutyl)biotinamide 40 and Ezetimibe 18, were crosslinked to give a biotin-tagged Ezetimibe in 84% LC yield at a slightly elevated temperature (50 °C, see LC trace 7 and Supporting Information Figure S36). Paroxetine 34 was installed onto the Tyr side chain of N-Ac oxytocin 41 to give 34-41 in excellent LC yield (see LC trace 8 and Supporting Information Figures S37 and S38). As demonstrated by 38-2, the imidazole side chain of histidine (His) could be reasonably well tolerated (Scheme 3b and see Supporting Information Figure S34). The indole side chain of tryptophan (Trp) can undergo crosslinking with Lys via an N-CH2-N linker, though with lower efficiency compared to Tyr-Lys crosslinking. For example, the reaction of Ciprofloxacin 32 with tripeptide Ac-Tyr-Gly-Trp-NH2 39 gave Tyr-Lys linked product 32-39 in 73% LC yield, along with 23% of undesired N-CH2-N crosslinked products between the indole side chain and 32 (see Supporting Information Figure S35). Both the guanidine side chain of arginine (Arg) and the thiol side chain of cysteine (Cys) reacted with Lys under HCHO treatment in HFIP, and thus, should be avoided during HCHO-mediated phenol-amine crosslinking. The N-terminal amine group of peptides also exhibited high reactivity with phenols and HCHO. However, crosslinking between the peptide N-terminus and phenols was typically complicated by the facile formation of a 5-membered cyclic aminal between the NH2 and the amide NH, leading to the formation of mixed products.

    Scheme 3

    Scheme 3 | Labeling peptide Tyr side chains with primary and secondary alkyl amines. Reactions were conducted on a 0.01 mmol scale. LC yields were estimated based on the UV absorption of peptide-related peaks in LC traces. HPLC-isolated yields were shown in braces. (a) Unconsumed starting material predominantly accounts for the remaining mass balance of phenols. (b) 3.0 equiv of amine N was used. (c) 1.5 equiv of N was used. (d) 1.1 equiv of 2 was used, and N,N-dialkylation side product 38-2-a was formed in a 24% LC yield. (e) A mixture of undesired N-CH2-N crosslinked products between Trp and 32 was also formed in about 30% combined yields. NR, no reaction;

    As shown in Scheme 4a, the HCHO-mediated phenol/amine crosslinking method can be applied to construct various complex molecular structures. For instance, linear peptide 42, which bears an amide-linked fluorescein tag through its terminal amino caproic acid (Acp) unit, can be cyclized between the phenol moiety of fluorescein and the Lys amino side chain to form a macrocyclic product 43 in excellent yield and selectivity (see LC trace 9) ( Supporting Information Figures S39 and S40). The crosslinking method also worked well on the solid phase. For example, treating Rink Amide resin-bound Acp-Ala-Ala-Lys-Phe 44 with 3 equiv of fluorescein 22 and 10 equiv of HCHO in HFIP solvent at rt, followed by cleavage from the resin with TFA/triisopropylsilane (TIPS)/H2O, yielded compound 45 in good yield (Scheme 4b and see Supporting Information Figures S41 and S42). Notably, the 2-HBA linkage exhibited excellent stability under strongly acidic TFA conditions. Amide coupling of 45 with tetramethylrhodamine succinimidyl ester 46 (TMRM-NHS) in DMF gave product 47 bearing a pair of different fluorophores. Compound 47 underwent fluorescence energy transfer (FRET) between fluorescein and TMRM upon irradiation at the excitation wavelength of fluorescein (491 nm) (see Supporting Information Figures S41 and S43). Finally, the method could be used to crosslink compound 48, an androgen receptor inhibitor, and 49, a von Hippel-Linda (VHL) E3 ligase ligand, to construct a PROTAC molecule 50 in excellent yield (see LC trace 10 in Scheme 4c and Supporting Information Figures S44 and S62–S64).

    Scheme 4

    Scheme 4 | Construction of complex molecular structures via HCHO-mediated phenol/amine crosslinking. Reactions were conducted on a 0.01 mmol scale. LC yields were estimated based on the UV absorption of peptide-related peaks in LC traces. HPLC-isolated yields were shown in braces.

    In our previous report on the HCHO-mediated intramolecular Tyr-Lys stapling, the role of the HFIP solvent was not addressed in detail, as we attributed the reactivity primarily to the proximity effect in the intramolecular setting.47 However, the high reactivity observed in the present intermolecular variant suggests that HFIP played a crucial role in promoting the electrophilic aromatic substitution reaction of phenols with formaldimines or formaldiminium ions. HFIP (pKa = 9.3) had an acidic OH group comparable to phenol (pKa = 10.0) and strong H-bonding ability. Notably, HFIP can readily form aggregates, typically comprising up to 4 or 5 units, which exhibited further enhanced H-bonding capabilities (Scheme 5a).94 The H-bonding interaction with HFIP, usually involving only one of the reaction partners, has been invoked for HFIP’s promoting effect in previous studies.94–96 In a recent discovery, we found that HFIP could promote an unusual intermolecular hydride transfer from alkyl amines to formaldimines or HCHO under mild conditions.49 Mechanistic studies suggested that HFIP aggregates acted as self-assembled bridges, bringing together both alkyl amines and formaldimines through H-bond interactions. This arrangement allowed the intermolecular hydride transfer reaction to proceed in a pseudo-intramolecular fashion via a macrocyclic transition state with a significantly lowered energy barrier. Compared with the previous “single-partner” solvent promotion models, we proposed that HFIP aggregates facilitate the hydride transfer reaction via a “dual-partner” promotion model through a network of H-bonds.

    Scheme 5

    Scheme 5 | Proposal of multipartner solvent activation models for HFIP-promoted intermolecular reactions.

    In addition to H-bonding, recent studies have shown that other types of weak interactions could also contribute to the reaction-promoting effect of HFIP (Scheme 5a). For instance, Qu’s recent study indicated that HFIP stabilized various cationic species through its C–F bonds via dipole/cation interactions.92 Lu and Hua89 and Lu’s group90,91 independently demonstrated that the tertiary C–H bond of HFIP can bind arene substrates via C–H/π interactions. Based on these studies, our prior investigations, and other literature reports, we propose that HFIP aggregates can act as versatile bridging templates, bringing together two reaction partners through various combinations of weak bonding interactions. Figuratively, the HFIP molecule was viewed as a “bird-shaped magnetic block” featuring an O–H head, a pair of CF3 wings, and a C–H foot (Scheme 5a). The sticky OH heads were readily connected via H-bonds to form the backbone of aggregates with varied lengths and shapes. While H-bonding likely provided the most dominant means for binding one of the reaction partners (e.g., b), the binding with the other reaction partner (e.g., a) could vary, including H-bonds, cation/dipole, C–H/π, or other weak interactions.

    As outlined in Scheme 5b, conventional mechanistic models for the Betti reaction (see I or II) involve a kinetically favored H-bond-linked 6-membered transition state, where the phenol aryl plane attacked the nearby imine or iminium carbon. However, due to ring constraints, these 6-membered transition states might not allow optimal orbital interactions for the desired electrophilic attack such as conjugation between the benzene ring and the lone pair electrons of oxygen for enhanced nucleophilicity. In the non-H-bonded model III, HFIP might stabilize the iminium intermediate, and orbital interactions were not conformationally constrained. However, the kinetic challenges might have slowed down the intermolecular reaction. Following the multipartner solvent promotion model, HFIP aggregates, as exemplified by the representative dimer shown in model IV, used H-bonds to bind both the formaldimine and the phenol. The solvent activation of secondary alkyl amines might have adopted a different mode, as the corresponding formaldiminium ion intermediates could not form an H-bond with HFIP. As shown in model V, we proposed that HFIP aggregates interacted with the phenol’s OH group via H-bonding, while the (CF3)2CH moiety engaged with the iminium ion through cation/dipole interactions. Similar to the mechanism proposed for HFIP-promoted electrophilic addition to imines, we suspected that C–H/π interactions might have played an important anchoring role in enhancing the reactivity of nonpolar unsaturated groups such as alkenes and arenes, through analogous multipartner macrocyclic transition states in other HFIP-promoted reaction systems.

    Conclusion

    In summary, we have developed an efficient protocol for the intermolecular Betti reaction of phenols, alkyl amines, and HCHO under mild conditions. The new protocol provides a simple and powerful method for crosslinking two native BMs such as peptides, small molecule drugs, and fluorophores, through their endogenous phenol and amine handles. The HFIP solvent is critical for achieving high intermolecular reactivity. Unlike previous HFIP activation models that involve interactions with only one reaction partner, we propose that HFIP aggregates act as versatile bridging templates, bringing together two reaction partners through combinations of weak bonding interactions in a multipartner activation mode. We anticipate that this crosslinking method will find broad application in conjugation processes and that the bridging solvent activation model can be extended to other reaction systems featuring unusual reactivity enhancements by HFIP solvent.

    Supporting Information

    Supporting Information is available and free of charge at CCS Chemistry; it includes synthetic procedures, additional control experiments, compound characterization, LC-MS trace, and NMR spectra.

    Conflict of Interest

    There is no conflict of interest to report.

    Funding Information

    G.C. thanks the following institutions for financial support of this work: the National Key R&D Programme of China (grant no. 2022YFA1504303), the National Natural Science Foundation of China (grant nos. 92256302 and 22221002), Frontiers Science Center for New Organic Matter, China (grant no. 63181206), and Haihe Laboratory of Sustainable Chemical Transformations, China.

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