Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2026 Apr 17;148(16):16882–16893. doi: 10.1021/jacs.6c00567

Enabling Fluoroalkyl-Sulfonylalkylation and Fluoroalkyl-Halogenation of Alkenes and Alkynes via Photoredox Catalysis

Supuni I N Hewa Inaththappulige 1, Ayush Acharya 1, Nipuna D D Z Agampodi 1, Harshvardhan Singh 1, Ramesh Giri 1,*
PMCID: PMC13135463  NIHMSID: NIHMS2168480  PMID: 41994882

Abstract

We describe a versatile photocatalytic approach for inter- and intramolecular fluoroalkyl-sulfonylalkylation of carbon–carbon bonds in activated and unactivated alkenes and alkynes. This protocol employs fluoroalkyl sulfinate salts as bifunctional reagents to introduce fluoroalkyl and SO2 groups and alkyl bromides to intercept the ensuing sulfonyl intermediates in a process that creates one C­(sp3)-C­(sp3) and two C­(sp3)-S bonds in one step. This method is applicable for the fluoroalkyl-sulfonylalkylation of both alkenes and alkynes bearing a diverse set of functional groups and unsaturated gaseous hydrocarbons. The robustness of the method is also demonstrated by the late-stage diversification of steroids, alkaloids, and pharmaceuticals. Mechanistic insights reveal a photoredox-mediated sequential process involving fluoroalkyl radical addition, SO2 incorporation, and subsequent SN2-type displacement. Notably, the same reaction condition can be extended to achieve iodo- and bromo-trifluoromethylation via a halogen atom transfer mechanism by utilizing alkyl iodides and bromoacetyl bromides, respectively, in place of general alkyl bromides.

graphic file with name ja6c00567_0019.jpg

graphic file with name ja6c00567_0017.jpg

Introduction

Fluorine and sulfur, which are ranked as the fifth and seventh most abundant elements in medicines, play a crucial role in regulating various biological processes. − They affect metabolic pathways, therapeutic efficacy, and lipophilicity, and function as bioisosteres to modify the pharmacological properties of drugs. − Additionally, organosulfur compounds modified with fluorine exhibit remarkable stability and resistance to oxidation. Therefore, fragments bearing these atoms are prevalent in a number of drugs, − agrochemicals, , and organic materials , (Scheme ). Traditionally, the F- and S-containing fragments are introduced into molecules independently, requiring different sets of methods in multistep processes with a variety of reagents. For example, the fluoroalkyl motifs are introduced from precursors such as CF3I, , CF3SO2Cl, − Togni’s reagent, , Umemoto’s reagent, Hu’s reagent, , and CF3SO2Na by utilizing redox agents, thermal, photoirradiation, or electrochemical methods. − Sulfonylation frequently requires synthetic procedures such as the alkylation of sulfinate salts, , the oxidation of thiol groups, , the Friedel–Crafts-type sulfonation of arenes, , and radical SO2 insertion strategies. −

1. Some Important Molecules Containing C­(sp3)-SO2 and C­(sp3)-Fluoroalkyl Moieties.

1

Open in a new tab

Difunctionalization of carbon–carbon unsaturated bonds is an important strategy to engineer complex molecules rapidly using simple organic feedstock. − In this regard, simultaneous introduction of fluoroalkyl and sulfonyl groups across carbon–carbon multiple bonds would offer an expeditious route to access complex F- and S-containing molecules from readily accessible starting materials. , Nevertheless, achieving such a reaction remains challenging. − The difficulty arises because the conditions, catalysts, or reagents required for introducing one functional group are generally not compatible with those needed for the other (Scheme a). For example, generating fluoroalkyl radicals (Scheme a.1.i) from their sources typically requires extreme conditions such as high temperatures or strong oxidizing agents like TBPB (tert-butyl peroxybenzoate), tert-butyl hydroperoxide (tBuOOH), and potassium persulfate (K2S2O8). − In addition, under these oxidizing conditions, the subsequent alkyl sulfinate anions (Scheme a.1.ii), which have a very low one-electron oxidation potential (+0.5 V vs SCE), − can undergo radical decomposition to the original alkyl radicals with the extrusion of SO2 − in a reverse process that is counterproductive to capturing SO2 crucial for sulfone formation. , The reversal activity could also increase the concentration of secondary alkyl radicals and promote the formation of undesired side products. ,

2. Challenges for Introducing C­(sp3)-SO2 and C­(sp3)-Fluoroalkyl Moieties and Current Work.

2

Open in a new tab

This transformation involves formation of three bonds in a single operation via photooxidation of CF3SO2Na, radical addition to the alkene, and trapping with electrophiles (Scheme a.2). But attempting to achieve this can lead to numerous byproducts along with the desired product (Scheme a.2). In particular, bifunctional reagents such as CF3SO2Cl can lead to alternative reaction pathways that diverge from intended transformation. For instance, Reiser and co-workers reported a visible light-mediated copper-catalyzed carbosulfonylation of alkenes that proceeds via photoreduction of CF3SO2Cl, followed by radical addition to the alkene, and subsequent trapping with nucleophiles such as alcohols or amines. ,, In contrast, CF3SO2Cl can also undergo SO2 extrusion to furnish CF3 radicals, thereby promoting chloroalkylation pathways instead as demonstrated by Han, Reiser, and Das groups. ,, Additionally, the Akita group developed fluoroalkyl-sulfonylation of olefins using CF3SO2Na where the of RSO2 – anions were intercepted and trapped by alkyl iodides in a one-pot fashion.

Furthermore, previous studies have shown fluoroalkyl radicals may engage in competing reaction pathways, − generating side products through hydrogen atom transfer (HAT), HAT followed by oxidation, and bis-fluoroalkylation. A further challenge emerges when α-bromoesters are used as the alkyl sources in the reaction. In such cases, existing methods are not suitable, mainly due to catalysts, particularly Ir photocatalysts and organophotocatalysts like 4CzIPN, tend to undergo oxidative quenching in the presence of α-haloesters. , This pathway favors carbobromination of alkenes, yielding predominantly γ-halogenated carbonyl compounds over the desired reaction. Despite these challenges, we report a mild and selective approach for the simultaneous introduction of fluoroalkyl, sulfonyl, and alkyl groups across the vicinal carbons on unactivated alkenes and alkynes in one step. This method enables access to a series of acyclic sulfones, cyclic γ-sultines, and cyclic sulfones with fluoroalkyl groups that hold promise in various application fields. Interestingly, this protocol can be tuned to enable iodo and bromo trifluoromethylation by utilizing iodoesters and bromoacetyl bromides, respectively, under similar reaction conditions (Scheme b).

Results and Discussion

In our studies, we examined the reaction of 4-phenylbutene (1) with methyl α-bromoacetate (2) and sodium trifluoromethanesulfinate (CF3SO2Na, Langlois reagent) using different photocatalysts (PCs) in MeCN under 440 nm blue LED (Table , entries 1–4). Among the PCs evaluated, 2 mol % Ru­(bpz)3(PF6)2 furnished the difunctionalized product 3 in 75% yield under nitrogen (entry 1). Product 3 was formed as a single regioisomer with the incorporation of CF3 to the terminal carbon and the sulfonylalkyl group to the internal carbon of the alkene. The reaction can be conducted in air, but the product yield decreased slightly (entry 2). [Ir­{dF­(CF3)­ppy}2(bpy)]­(PF6), Ir­(dtbbpy)­(ppy)2PF6, eosin Y–Na, fac-Ir­(ppy)3, or 4-CzIPN did not afford the desired product except trace amounts of hydroalkylation 4. When fac-Ir­(ppy)3 was used, carbobrominated product 5 was formed in 52% yield without desired product 3. Moderate yields of product 3 were observed when 9-mesityl-10-phenylacridinium tetrafluoroborate (MPAT) and Ru­(bpy)3(PF6)2 were used as catalysts (entry 5). Unlike the Langlois reagent, (CF3SO2)2Zn was ineffective as a donor of CF3 and SO2 (entry 6). The product yield was also considerably diminished when MeCN was replaced with DMF, DMA, DMSO, DCM, or DCE (entry 7). Two mol % Ru­(bpz)3(PF6)2 loading at 1.5 equiv of α-bromoacetate (2) and 2 equiv of CF3SO2Na remained optimal since reducing their concentrations to 1.0 mol % or 1 equiv each also reduced the product yield (entries 8–10). Similarly, the product was formed in best yield at 440 nm since no light, ambient light, or the use of lights with wavelengths higher or lower than 440 nm also decreased the product yield (entries 11–13).

1. Reaction Parameter Optimization .

graphic file with name ja6c00567_0006.jpg

entry variation from the standard condition yield of 3 (%)
1 None 75 (70)
2 under open air 63
3 Ir(dtbbpy)(ppy)2PF6 or Ir(dFCF3ppy)(bpy)2PF6 instead of Ru(bpz)3(PF6)2 0
4 Eosin Y–Na, fac-Ir(ppy)3 or 4CzIPN instead of Ru(bpz)3(PF6)2 0
5 MPAT or Ru(bpy)3(PF6)2 instead of Ru(bpz)3(PF6)2 55, 51
6 (CF3SO2)2Zn instead of CF3SO2Na 0
7 DMF, DMA, DMSO, DCM or DCE instead of MeCN trace
8 1 equiv of 2 46
9 1 equiv of CF3SO2Na 32
10 1.0 mol % of Ru(bpz)3(PF6)2 44
11 390 nm LED 38
12 467 nm LED 57
13 ambient light or dark instead of blue LED 0
Open in a new tab
a

Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), CF3SO2Na (2.0 equiv), photocatalyst (1–5 mol %), solvent (0.1 M), ambient temperature (AT), 12 h, 440 nm blue LED, N2. Yields were determined by 1H NMR using the crude mixture and tetrachloroethane as the internal standard. See the SI for details.

With the optimized conditions established, we proceeded to explore the scope of the reaction with regard to alkenes, fluoroalkyl salts, and alkyl bromides (Table ). First, we examined the scope of unactivated alkenes using CF3SO2Na and alkyl α-bromoacetate or α-bromo-N,N-dimethylacetamide as coupling reagents. As shown in Table A, terminal unactivated alkenes containing ether, ketone, and ester were compatible with the reaction condition affording their products in good yields (6–8). Esters containing heterocycles, such as the one derived from 2-furoate (9), and functional groups that are sensitive to radical conditions, like alkyl bromide (10) and trialkylsilyl (11), that are present in alkenes were also well tolerated in the reaction. The reaction worked well with alkenes bearing tertiary amide derived from morpholine (12) and amine protected by phthalimide (13). An alkene bearing a Boc-protected amine with an active hydrogen (NH) (14) furnished the product in a good yield. In addition, alkenes containing active alcoholic hydrogens (OH), such as those in primary alcohols (15), and acidic OH in phenols (16) also served as substrates in the reaction. More importantly, the current reaction condition was applicable to internal alkenes, which are typically more challenging than terminal alkenes because of their low polarization and steric congestion for difunctionalization. For example, the internal acyclic alkene in 3-hexene (17) and the internal cyclic alkenes in cyclopentene, cyclooctene, and norbornene (18–20) were readily difunctionalized affording their products in good yields. Moreover, the reaction condition could be extended to difunctionalize the 1,1-disubstituted alkene in 3-methylene-1-cyanocyclobutane (21) and the internal alkene in cyclic skipped diene (22). In the skipped diene, the additional alkene was preserved during the reaction. Stereoselectivity of this reaction is solely substrate dependent. The linear internal alkenes predominantly resulted in anti-addition due to steric effects (17). Five- and six-membered rings favor anti-addition due to steric constraints and rigidity (18, 20, and 22), , while cyclic octene being more flexible produced both anti- and syn-addition products resulting in diastereomers (19). 1,1-Disubstituted alkenes with an existing diastereotopic carbon center generate the product (21) with low diastereoselectivity owing to the balance of steric and electronic effects. Activated alkenes, such as styrenes, dienes, and α,β-unsaturated carbonyls, were unreactive (See the Supporting Information for details).

2. Scope of the Reaction in Alkene, Alkyne, Alkyl Halide, and Fluoroalkyl-SO2Na .

graphic file with name ja6c00567_0007.jpg

graphic file with name ja6c00567_0008.jpg

Open in a new tab
a

Reaction conditions: alkene (1.0 equiv), alkyl bromide (1.5 equiv), CF3SO2Na (2.0 equiv), Ru­(bpz)3(PF6)2 (2 mol %), MeCN (0.1 M), 12 h, 440 nm blue LED, N2, AT, in vials; isolated yields are reported. The dr ratio was determined based on the 1H NMR analysis of the crude reaction mixture and GC. See the Supporting Information for details.

Second, we explored the reaction with alkynes (Table B). The difunctionalization reaction could be performed with aliphatic and aromatic alkynes, as well as internal alkynes. For example, the reaction of CF3SO2Na and alkyl α-bromoacetate or α-bromo-N,N-dimethylacetamide with 4-phenyl-1-butyne, 1-dodecyne, and 3-cyclohexyl-1-propyne generated their alkyne-difunctionalized products (23–25) in good yields. The regiochemistry was similar to that of the alkene with the addition of CF3 to the terminal carbon and the sulfonylalkyl group to the internal carbon of the alkyne. Similarly, the terminal alkyne in 4-ethynylanisole (26) and the internal alkyne in 4-octyne (27) were also difunctionalized to afford their products in good yields. The reaction of terminal alkynes yielded anti-addition products as a single configurational stereoisomer. The internal alkyne also generated the product (27) in high stereoselectivity. − The high stereoselectivity is likely due to the steric and electronic effects, which stabilize intermediates or transition states favoring anti-addition. − Thermodynamically more stable E-isomer was thus obtained as the major stereoisomer.

Next, we examined the scope of the reaction in alkyl halides and sulfinate salts (Table C). The reaction showed a broad scope in terms of alkyl halides and worked well with benzyl halides and allyl halides in addition to α-halocarbonyls. As shown in Table C, the alkene in 4-phenylbutene (1) could be readily difunctionalized with CF3SO2Na using the alkyl, benzyl, and phenyl esters of α-bromoacetic acid (28–30). α-Bromoketones, such as α-bromopinacolone and α-bromoacetophenone, could also serve as alkyl sources, enabling the formation of the difunctionalized products (31–32) in good yields. Likewise, the reaction furnished good to excellent yields of products (33–34) when α-bromo-N,N-dimethylacetamide was used. More importantly, the reaction was compatible with a primary α-bromoamide containing two active hydrogens (NH2) (35). Additionally, the α-bromocarbonyls could be readily replaced with benzyl bromide, 3-methoxybenzyl bromide, and allyl bromide as alkyl halides, and the corresponding trifluoromethyl-sulfonylalkylated products (36–38) could be obtained in good yields. During our studies, we also integrated HCF2SO2Na as a fluoroalkyl source. To our delight, this reagent was similarly effective and furnished the difluoromethylsulfonylalkylated product (34) in excellent yield. Finally, the reaction could be conducted in large scales (5 mmol) at a slightly longer reaction time (16 h) but without compromising yields, as demonstrated for the reaction of 4-phenylbutene 1 with CF3SO2Na and α-bromo-N,N-dimethylacetamide affording the product 33 in 80% yield (1.40 g).

Reactions of unsaturated gaseous hydrocarbons, particularly ethylene and acetylene, struggle for difunctionalization since they are completely unpolarized. − In addition, the presence of reactive radicals also causes these unsaturated hydrocarbons to undergo polymerization. Gratifyingly, our difunctionalization method was applicable to ethylene, acetylene, and other terminal and internal gaseous alkenes (Table D). Acetylene gas generated trans-alkenes featuring CF3 and SO2CH2CO2R as two strongly electron-withdrawing groups upon reaction with CF3SO2Na and α-bromoesters (39–40). Similarly, ethylene could be reacted with CF3SO2Na along with α-bromoacetic acid ester and amide and benzyl bromides to afford the corresponding products (41–45) in good yields. In particular, ethylene could be difunctionalized with CF3SO2Na using heterocyclic benzyl bromides, such as 8-quinolinylmethyl bromide and 5-(trifluoromethyl)-2-furylmethyl bromide and introduce heterocycles to trifluoromethylsulfonylated products (44–45). Additional gaseous alkenes containing terminal and internal alkenes, such as 1-propene, 1-butene, and 2-butene, could be difunctionalized with CF3SO2Na and α-bromoesters or benzyl bromides (46–49). The structure of the trifluoromethyl-sulfonylalkylated product 48 was determined by single-crystal X-ray crystallography, further confirming the regiochemistry.

Furthermore, we evaluated alkenes attached to natural products and pharmaceuticals containing heterocyclic motifs as a way to showcase the method’s synthetic application to complex molecular architectures (Table E). Under the standard conditions, alkenes tethered to steroids, such as estrone and dehydrocholesterol, successfully reacted to yield the desired products (50–51) in good yields. Pleasingly, alkenes attached to the pharmaceutical diclofenac containing chlorinated diarylamine and the alkaloid theobromine bearing a complex heterocycle were also readily difunctionalized, affording the products (52–53) in good yields.

Cyclic sulfones and sultines are sulfur-containing heterocycles with application in medicine and materials, making their synthesis essential. , This method could also employ alkene-tethered alkyl bromides or α-bromocarbonyls as starting materials for an intramolecular process to generate a variety of fluoroalkyl-decorated cyclic sulfones (Table ). The reaction was applicable for the formation of five- and six-membered cyclic sulfones (54–57) by the interception of SO2 during the cyclization of 5-bromo-1-pentene, diethyl 2-allyl-2-(bromomethyl)­malonate, and 6-bromo-1-hexene, respectively. The structure of sulfone 56 was also confirmed by single-crystal X-ray crystallography. Both CF3SO2Na and HCF2SO2Na were amenable as a source of SO2 and fluoroalkyls. Similarly, N-allyl-α-bromoacetamide could be cyclized with the incorporation of SO2 to generate thiomorpholin-3-one 1,1-dioxide (58). However, 4-bromo-1-butene underwent intramolecular cyclization through O rather than S following SO2 insertion. As a result, 4-bromo-1-butene generated five-membered γ-sultines predominantly as trans-isomers (59–60) as the major product instead of four-membered sulfones. Likewise, 4-bromo-1-butyne could also be cyclized with CF3SO2Na to form a γ-sultine with an exocyclic alkene (61). ,, The reaction of 5-bromo-2-methylpent-2-ene (62) furnished the sulfone product 65 in which CF3 was added to the alkenyl carbon proximal to the alkyl bromide in an apparent regioreversal process. This reversed addition arose from the preference to generate a 3° (63) over a 2° radical and the ultimate cyclization of the intermediate 64 to create a 5-membered (65) over a 4-membered heterocycle.

3. Scope of the Cyclization Reaction ,

graphic file with name ja6c00567_0009.jpg

graphic file with name ja6c00567_0010.jpg

Open in a new tab
a

Reaction conditions: Alkyl bromide (1.0 equiv), CF3SO2Na (2.0 equiv), Ru­(bpz)3(PF6)2 (2 mol %), MeCN (0.1 M), 12 h, 440 nm blue LED, N2, AT, in vials; isolated yields are reported.

b

The dr ratio was determined based on the 1H NMR analysis of the crude reaction mixture and GC. See the Supporting Information for details.

The process of intercepting sulfonyl anions, which are generated in situ through photoredox catalysis, could be utilized to synthesize a range of sulfur­(VI)-containing molecules, such as alkyl and aryl sulfones, sulfonamides, and sulfonyl halides, by a two-step, one-pot protocol upon reaction with diverse electrophiles without having to purify reaction intermediates (Table ). Treating the in situ-generated sulfonyl anion with a base and secondary alkyl iodide allowed for the generation of alkyl sulfones 66 in moderate yields. When diphenyliodonium trifluoromethanesulfonate and 2-bromothiazole were used, aryl sulfones 67–68 were obtained in good to moderate yields. This method could also be applied to the synthesis of sulfonamides for creating medicinally significant substituted sulfonamides (69–70). Sulfonyl fluorides, involved in sulfur­(VI)-fluoride exchange (SuFEx) click chemistry, , are garnering increasing interests in drug discovery and materials research. This method also facilitated the concurrent integration of CF3 and sulfonyl fluoride (71), and CF3 and sulfonyl chloride (72) into unactivated alkenes in high yields, providing a versatile method essential for pharmacokinetic investigations. −

4. In Situ Interception of Sulfonyl Anion for Diverse Derivatization .

graphic file with name ja6c00567_0011.jpg

graphic file with name ja6c00567_0012.jpg

Open in a new tab
a

Reactions were run at a 0.50 mmol scale. All yields are isolated. For the detailed reaction conditions, see the Supporting Information. The percentage numbers are the yields of isolated products.

b

Alkyl iodide, K2CO3, MeCN, 60 °C.

c

Diphenyliodonium trifluoromethanesulfonate, DMF, 110 °C.

d

2-bromothiazole, DMSO, 110 °C.

e

HSOA, NaOAc,H2O.

f

Morpholine, SO2Cl2, THF, 0 °C to rt.

g

NFSI, DIPEA, DCM.

h

SO2Cl2, THF, 0 °C to rt.

In addition to developing the method, we have also conducted preliminary mechanistic studies to deduce the working underpinnings of the fluoroalkyl-sulfonylalkylation reaction and proposed a possible mechanism, as illustrated in Scheme . Initially, the excited-state photocatalyst Ru­(bpz)3 2+ (E II*/I = +1.45 V vs SCE in MeCN) accepts a single electron from CF3SO2Na and generates •CF3 with the concomitant release of SO2. , The resulting •CF3 then adds to an alkene, generating a stabilized sec-alkyl radical (73). The alkyl radical 73 subsequently captures SO2 to form a sulfonyl radical (74), which then accepts an electron from the reduced photocatalyst Ru­(bpz)3 + to produce a sulfonyl anion (75) and regenerate photocatalyst Ru­(bpz)3 2+. Finally, the sulfonyl anion 75 reacts with alkyl bromides off-cycle by nucleophilic substitution to yield the final product 76.

3. Proposed Catalytic Cycle.

3

Open in a new tab

In the intramolecular setting, the reaction preferentially afforded five- and six-membered cyclic sultines and sulfones even with unactivated alkyl bromides whereas the intermolecular reactions failed under the same condition unless it was heated at 60 °C in the presence of a base (66). This discrepancy may arise from the intrinsic enthalpy and entropic advantages of intramolecular cyclization. This rationale also explains the preference for 4-bromo-1-butene and butyne to yield five-membered sultine (79) over four-membered sulfone (80). In the 5-bromo-1-pentene case, the reaction favored a five-membered sulfone (81) over the six-membered product (82). This specific kinetically favored selectivity for five-membered rings could be due to the added thermodynamic stability, resulting from an optimal balance between angle strain and entropy.

We conducted a series of experiments to deduce the presence of radical and anionic intermediates (Scheme ). The Stern–Volmer quenching studies revealed fluorescence quenching with fluoroalkyl sulfinates but not with α-bromoesters, indicating the formation of •CF3 (Scheme D). The presence of •CF3 and the subsequent sec-alkyl radical 73 was confirmed by HRMS/LCMS and 19F NMR as their 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-adducts 83 and 84 from the standard reaction (Scheme A). , The addition of TEMPO completely suppressed the difunctionalization reaction and led to the formation of these radical intermediates. In addition, the sec-alkyl radical 73 and the SO2-captured sulfonyl radical 74 also underwent dimerization to generate their dimers 87 and 88, as confirmed by HRMS/GCMS, when n-PrBr was used as an unreactive alkyl halide (Scheme A). We have gathered further evidence for the presence of the sec-alkyl radical 73 in the reaction by radical clock experiments and a chiral racemic probe. The vinylcyclopropyl (89) and 1,6-heptadienyl (91) radical clocks yielded the ring-opened product 90 and the cyclized product 92 (Scheme B), respectively. Similarly, the reaction of chiral racemic allylic ether (93) generated two diastereomers with barely any stereocontrol (dr, 1.2:1) (Scheme C). These experiments support the proposed free-radical mechanism. Light on/off experiments and quantum yield measurements indicated that the reaction did not involve radical chain propagation but rather followed a closed photoredox catalytic cycle (see the Supporting Information for details). ,

4. Mechanistic Studies: (A) Radical Trapping and Dimerization Experiments, (B) Radical Clock Experiment, (C) Chiral Racemic Probe, (D) Stern–Volmer Quenching Studies, (E) Reactivity of Iodo Compounds under Standard Conditions, (F) Three-Way Competition Experiment with α-Bromo and α-Chloro Substrates, (G) Three-Way Competition Experiment with α-Bromo and α-Iodo Substrates, (H) Reactivity Trend of Activated α-Bromo Compounds, and (I) Reactivity with Molecular Iodine and Bromine, See the Supporting Information for Details.

4

Open in a new tab

During our mechanistic studies, we observed that when switching the α-bromoester with α-chloroester, it resulted in lower yield of product 3 to 31% (see the Supporting Information). In contrast, when bromo α-ester was replaced with iodo α-ester (97) rather than anticipated carbosulfonylation, it resulted in fluoroalkyl iodination of alkene (95) in 70% yield (Scheme E). Remarkably, this reactivity pattern was consistent when other iodo-compounds were used such as benzyl iodide (98), methyl iodide (MeI, 100), or trifluoroethyl iodide (ICH2CF3, 99), albeit in varying yields. To better understand this preference for iodofluoroalkylation over carbosulfonylation, we investigated the relative reactivity and selectivity of radical intermediate 73 by conducting a series of crossover competition experiments. In three-way competitive experiments, between the α-bromo ethyl ester and α-chloro methyl ester, the reaction predominantly resulted as expected from α-bromo ester undergoing effective SN2 nucleophilic addition (Scheme F). The crossover between α-bromo ethyl ester and α-iodo methyl ester primarily yielded iodotrifluoromethylated products (95) as the major species (Scheme G).

Theoretically, iodo α-ester ought to be more SN2-active due to its superior leaving group ability and lower C–I bond dissociation energy (BDE). , However, the divergence of the SN2 product formation with iodo α-ester can be rationalized to the preference of sec-alkyl radical 73 to undergo halogen atom transfer (XAT) over SO2 addition, furnishing the iodotrifluoromethylated product (95). In this scenario, α-Bromoesters exhibit a balanced reactivity supporting efficient SN2 but avoid XAT. In contrast, α-chloroesters display poor reactivity due to the strong C–Cl bond and sluggish leaving group ability, limiting both SN2 and XAT pathways.

Scheme a outlines the proposed catalytic cycle for the iodotrifluoromethylation of alkenes. Following initial radical formation, similar to the carbosulfonylation mechanism, the secondary alkyl radical (73) undergoes XAT with an iodinated species (109), forming an acyl radical (111). This intermediate regenerates the photocatalyst and subsequently undergoes protonation to yield ketone 112, as verified by crude NMR and deuterium-labeling experiments. A control experiment with I2 and CF3SO2Na produced diiodinated product 108, indicating no in situ I2 formation and supporting the XAT pathway via iodine radicals (Scheme I). The observed XAT preference is attributed to favorable C–I bond formation and polarity matching between the nucleophilic radical (73) and electrophilic iodine. Given the importance of iodides in downstream transformations, the development of single-step methods for incorporating both iodine and CF3 groups is well justified. The new optimized conditions for iodotrifluoromethylation of alkenes demonstrate compatibility with both alkene and alkyne substrates (Table ).

5. Proposed Catalytic Cycle (a) Iodotrifluoromethylation and (b) Bromotrifluoromethylation of Alkenes.

5

Open in a new tab

5. Scope of Iodotrifluoromethylation of Alkenes and Alkynes .

graphic file with name ja6c00567_0013.jpg

graphic file with name ja6c00567_0014.jpg

Open in a new tab
a

Reaction conditions: Alkene or alkyne (1.0 equiv), 97 (1.5 equiv), CF3SO2Na (2.5 equiv), Ru­(bpz)3(PF6)2 (2 mol %), MeCN (0.1 M), AT, 12 h, 440 nm blue LED, in vials; isolated yields are reported. The dr ratio was determined based on the 1H NMR analysis of the crude reaction mixture and GC. See the Supporting Information for details.

As we progressed testing other activated α-bromoester analogues, when highly activated α,α-dibromo esters (103) with alkenes were used, the reaction selectively generated bromotrifluoromethylated alkenes (Scheme H). To our surprise, bromoacetyl bromide (105) and bromoacetyl chloride (106) enabled this outcome, even without the need for a photocatalyst. In addition, we also observed that under dark conditions, the same reagents led to the dibrominated product (107). This may be because the fluoroalkyl radical generation is suppressed in dark, and conventional electrophilic dibromination dominates. Similarly, external addition of Br2 led predominantly to dibromination, as seen with I2, underscoring the importance of the need for radical initiation to prevent unselective electrophilic halogenation. The proposed catalytic pathway involves generation of CF3 • radicals from CF3SO2Na upon irradiation which eventually added to the alkene to form the alkyl radical intermediate (73). The resulting alkyl radical undergoes halogen atom transfer with bromoacetyl bromide, completing the reaction (Scheme b). Overall, this condition shows that intermediate 73 exhibits distinct reactivity in the presence of different reagents, leading to variation in the product preference.

All other trifluoromethylation reactions reported here require a photocatalyst. However, the bromotrifluoromethylation reaction does not. This is likely because other haloesters (103 and 97) can undergo oxidative quenching and form carbohalogenation products without incorporating the CF3 group. Therefore, rapid CF3 radical generation via a photocatalyst is necessary to favor the desired product and suppress the side reactions. In contrast, bromoacetyl bromide is not known to undergo carbohalogenation, and thus, bromotrifluoromethylation is the major product formed under light. To support this, control experiments show that direct photolysis of CF3SO2Na can generate radicals in the absence of a catalyst, as seen by the 14% yield of the hydrotrifluoromethylated product (see the Supporting Information for details). This process may be facilitated by the presence of oxygen in air, which could serve as an oxidant to promote SET. This methodology was well extended to catalyst-free bromotrifluoromethylation across a range of internal and terminal alkenes and alkynes (Table ).

6. Scope of Bromotrifluoromethylation of Alkenes and Alkynes .

graphic file with name ja6c00567_0015.jpg

graphic file with name ja6c00567_0016.jpg

Open in a new tab
a

Reaction conditions: Alkene or alkyne (1.0 equiv), 105 (1.5 equiv), CF3SO2Na (2.0 equiv), MeCN (0.1 M), AT, 12 h, 440 nm blue LED, in vials; isolated yields are reported. The dr ratio was determined based on the 1H NMR analysis of the crude reaction mixture and GC. See the Supporting Information for details.

Conclusion

In summary, we have established a practical method for efficiently inducing visible-light-mediated intermolecular and intramolecular fluoroalkyl-sulfonylalkylation of alkenes and alkynes. Mechanistic studies reveal that the reaction proceeds through a sequential process involving the addition of fluoroalkyl radicals, the incorporation of SO2, and subsequent SN2-type reactions. This approach demonstrates a wide range of applicability, producing a variety of acyclic sulfones, cyclic γ-sultines, and cyclic sulfones with fluoroalkyl groups, predominantly with high stereoselectivity and regioselectivity. The generality of this protocol is further evident by its capacity to perform iodo- and bromo-trifluoromethylation under the same reaction condition using structurally distinct precursors, iodoesters, and bromoacetyl bromides.

Supplementary Material

ja6c00567_si_001.pdf (7.1MB, pdf)

Acknowledgments

We gratefully acknowledge the NIH NIGMS (R35GM133438) and The Pennsylvania State University (PSU) for support of this work. The X-ray instrument was funded by the NIH SIG S10 grants (1S10OD028589-01 and 1S10RR023439-01). We thank Dr. Christy George at the NMR facility at PSU for helping with the assignment of regio- and stereochemistry. We would also like to acknowledge the Huck Institutes’ Proteomics and Mass Spectrometry Core Facility (RRID:SCR_024462).

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.6c00567.

  • Experimental procedures and characterization data for all compounds. CCDC numbers 2419235, 2419238, 2419234, and 2419232 for compounds 21, 40, 48, and 56 contain the supplementary crystallographic data for this paper (PDF)

The authors declare no competing financial interest.

References

  1. Ilardi E. A., Vitaku E., Njardarson J. T.. Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery. J. Med. Chem. 2014;57:2832–2842. doi: 10.1021/jm401375q. [DOI] [PubMed] [Google Scholar]
  2. Müller K., Faeh C., Diederich F.. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science. 2007;317:1881–1886. doi: 10.1126/science.1131943. [DOI] [PubMed] [Google Scholar]
  3. Minghao F., Bingqing T., Steven H. L., Xuefeng J.. Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry. Curr. Top. Med. Chem. 2016;16:1200–1216. doi: 10.2174/1568026615666150915111741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Kohlhepp S. V., Gulder T.. Hypervalent iodine­(iii) fluorinations of alkenes and diazo compounds: new opportunities in fluorination chemistry. Chem. Soc. Rev. 2016;45:6270–6288. doi: 10.1039/C6CS00361C. [DOI] [PubMed] [Google Scholar]
  5. Ni C., Hu J.. The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations. Chem. Soc. Rev. 2016;45:5441–5454. doi: 10.1039/C6CS00351F. [DOI] [PubMed] [Google Scholar]
  6. Zhao C., Rakesh K. P., Ravidar L., Fang W. Y., Qin H. L.. Pharmaceutical and medicinal significance of sulfur (S­(VI))-Containing motifs for drug discovery: A critical review. Eur. J. Med. Chem. 2019;162:679–734. doi: 10.1016/j.ejmech.2018.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Tshepelevitsh S., Kütt A., Leito I.. Theoretical Study on Fluorinated Derivatives of Sulfolane, Cyclopentanone, and Gamma-Butyrolactone. Molecules. 2023;28:7770. doi: 10.3390/molecules28237770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Wang Q., Han J., Sorochinsky A., Landa A., Butler G., Soloshonok V. A.. The Latest FDA-Approved Pharmaceuticals Containing Fragments of Tailor-Made Amino Acids and Fluorine. Pharmaceuticals. 2022;15:999. doi: 10.3390/ph15080999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Scott, K. A. ; Njardarson, J. T. In Sulfur Chemistry; Jiang, X. , Ed.; Springer International Publishing: Cham, 2019; p 1–34. [Google Scholar]
  10. Bian K.-J., Lu Y.-C., Nemoto D., Kao S.-C., Chen X., West J. G.. Photocatalytic hydrofluoroalkylation of alkenes with carboxylic acids. Nat. Chem. 2023;15:1683–1692. doi: 10.1038/s41557-023-01365-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jeanguenat A., Lamberth C.. Sulfur-based functional groups in agrochemistry. Pest Manag. Sci. 2023;79:2647–2663. doi: 10.1002/ps.7553. [DOI] [PubMed] [Google Scholar]
  12. Ogawa Y., Tokunaga E., Kobayashi O., Hirai K., Shibata N.. Current Contributions of Organofluorine Compounds to the Agrochemical Industry. iScience. 2020;23:101467. doi: 10.1016/j.isci.2020.101467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guo W., Wang D.-Y., Chen Q., Fu Y.. Advances of Organosulfur Materials for Rechargeable Metal Batteries. Adv. Sci. 2022;9:2103989. doi: 10.1002/advs.202103989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Beaufrez J., Guillouet S., Seimbille Y., Perrio C.. Synthesis, Fluorine-18 Radiolabeling, and In Vivo PET Imaging of a Hydrophilic Fluorosulfotetrazine. Pharmaceuticals. 2023;16:636. doi: 10.3390/ph16050636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ni C., Hu M., Hu J.. Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis. Chem. Rev. 2015;115:765–825. doi: 10.1021/cr5002386. [DOI] [PubMed] [Google Scholar]
  16. Choi S., Kim Y. J., Kim S. M., Yang J. W., Kim S. W., Cho E. J.. Hydrotrifluoromethylation and iodotrifluoromethylation of alkenes and alkynes using an inorganic electride as a radical generator. Nat. Commun. 2014;5:4881. doi: 10.1038/ncomms5881. [DOI] [PubMed] [Google Scholar]
  17. Wang D., Mück-Lichtenfeld C., Daniliuc C. G., Studer A.. Radical Aryl Migration from Boron to Carbon. J. Am. Chem. Soc. 2021;143:9320–9326. doi: 10.1021/jacs.1c04217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lin J.-S., Wang F.-L., Dong X.-Y., He W.-W., Yuan Y., Chen S., Liu X.-Y.. Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines. Nat. Commun. 2017;8:14841. doi: 10.1038/ncomms14841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Oh S. H., Malpani Y. R., Ha N., Jung Y. S., Han S. B.. Vicinal difunctionalization of alkenes: chlorotrifluoromethylation with CF3SO2Cl by photoredox catalysis. Org. Lett. 2014;16:1310–1313. doi: 10.1021/ol403716t. [DOI] [PubMed] [Google Scholar]
  20. Rawner T., Knorn M., Lutsker E., Hossain A., Reiser O.. Synthesis of Trifluoromethylated Sultones from Alkenols Using a Copper Photoredox Catalyst. J. Org. Chem. 2016;81:7139–7147. doi: 10.1021/acs.joc.6b01001. [DOI] [PubMed] [Google Scholar]
  21. Charpentier J., Früh N., Togni A.. Electrophilic Trifluoromethylation by Use of Hypervalent Iodine Reagents. Chem. Rev. 2015;115:650–682. doi: 10.1021/cr500223h. [DOI] [PubMed] [Google Scholar]
  22. Wu F.-P., Yuan Y., Wu X.-F.. Copper-Catalyzed 1,2-Trifluoromethylation Carbonylation of Unactivated Alkenes: Efficient Access to β-Trifluoromethylated Aliphatic Carboxylic Acid Derivatives. Angew. Chem., Int. Ed. 2021;60:25787–25792. doi: 10.1002/anie.202112609. [DOI] [PubMed] [Google Scholar]
  23. Mizuta S., Verhoog S., Engle K. M., Khotavivattana T., O’Duill M., Wheelhouse K., Rassias G., Médebielle M., Gouverneur V.. Catalytic Hydrotrifluoromethylation of Unactivated Alkenes. J. Am. Chem. Soc. 2013;135:2505–2508. doi: 10.1021/ja401022x. [DOI] [PubMed] [Google Scholar]
  24. Zhao Y., Huang W., Zhu L., Hu J.. Difluoromethyl 2-Pyridyl Sulfone: A New gem-Difluoroolefination Reagent for Aldehydes and Ketones. Org. Lett. 2010;12:1444–1447. doi: 10.1021/ol100090r. [DOI] [PubMed] [Google Scholar]
  25. Zhang W., Wang F., Hu J.. N-Tosyl-S-difluoromethyl-S-phenylsulfoximine: A New Difluoromethylation Reagent for S-, N-, and C-Nucleophiles. Org. Lett. 2009;11:2109–2112. doi: 10.1021/ol900567c. [DOI] [PubMed] [Google Scholar]
  26. Li Z., Jiao L., Sun Y., He Z., Wei Z., Liao W.-W.. CF3SO2Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N-Sulfonylimines. Angew. Chem., Int. Ed. 2020;59:7266–7270. doi: 10.1002/anie.202001262. [DOI] [PubMed] [Google Scholar]
  27. Mandal D., Maji S., Pal T., Sinha S. K., Maiti D.. Recent advances in transition metal-mediated trifluoromethylation reactions. Chem. Commun. 2022;58:10442–10468. doi: 10.1039/D2CC04082D. [DOI] [PubMed] [Google Scholar]
  28. Xiao H., Zhang Z., Fang Y., Zhu L., Li C.. Radical trifluoromethylation. Chem. Soc. Rev. 2021;50:6308–6319. doi: 10.1039/D1CS00200G. [DOI] [PubMed] [Google Scholar]
  29. Champagne P. A., Desroches J., Hamel J.-D., Vandamme M., Paquin J.-F.. Monofluorination of Organic Compounds: 10 Years of Innovation. Chem. Rev. 2015;115:9073–9174. doi: 10.1021/cr500706a. [DOI] [PubMed] [Google Scholar]
  30. Furuya T., Kamlet A. S., Ritter T.. Catalysis for fluorination and trifluoromethylation. Nature. 2011;473:470–477. doi: 10.1038/nature10108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Cabrera-Afonso M. J., Lu Z.-P., Kelly C. B., Lang S. B., Dykstra R., Gutierrez O., Molander G. A.. Engaging sulfinate salts via Ni/photoredox dual catalysis enables facile Csp2–SO2R coupling. Chem. Sci. 2018;9:3186–3191. doi: 10.1039/C7SC05402E. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Jin S., Haug G. C., Trevino R., Nguyen V. D., Arman H. D., Larionov O. V.. Photoinduced C­(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group. Chem. Sci. 2021;12:13914–13921. doi: 10.1039/D1SC04245A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Griffin R. J., Henderson A., Curtin N. J., Echalier A., Endicott J. A., Hardcastle I. R., Newell D. R., Noble M. E. M., Wang L.-Z., Golding B. T.. Searching for Cyclin-Dependent Kinase Inhibitors Using a New Variant of the Cope Elimination. J. Am. Chem. Soc. 2006;128:6012–6013. doi: 10.1021/ja060595j. [DOI] [PubMed] [Google Scholar]
  34. Shaabani A., Mirzaei P., Naderi S., Lee D. G.. Green oxidations. The use of potassium permanganate supported on manganese dioxide. Tetrahedron. 2004;60:11415–11420. doi: 10.1016/j.tet.2004.09.087. [DOI] [Google Scholar]
  35. Falconnet A., Arndt J.-D., Hashmi A. S. K., Schaub T.. Triflic-Acid-Catalyzed Friedel-Crafts Reaction for the Synthesis of Diaryl Sulfones. Eur. J. Org. Chem. 2022;2022:e202200477. doi: 10.1002/ejoc.202200477. [DOI] [Google Scholar]
  36. Neale A. J., Rawlings T. J., McCall E. B.. The internuclear cyclizations of aromatic sulphonyl chlorides. Tribenz (b, d, f) oxepin and tribenzo (b, d, f) thiepin. Tetrahedron. 1965;21:1299–1313. doi: 10.1016/S0040-4020(01)98289-4. [DOI] [Google Scholar]
  37. Pedersen P. S., Blakemore D. C., Chinigo G. M., Knauber T., MacMillan D. W. C.. One-Pot Synthesis of Sulfonamides from Unactivated Acids and Amines via Aromatic Decarboxylative Halosulfonylation. J. Am. Chem. Soc. 2023;145:21189–21196. doi: 10.1021/jacs.3c08218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Magre M., Cornella J.. Redox-Neutral Organometallic Elementary Steps at Bismuth: Catalytic Synthesis of Aryl Sulfonyl Fluorides. J. Am. Chem. Soc. 2021;143:21497–21502. doi: 10.1021/jacs.1c11463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Emmett E. J., Hayter B. R., Willis M. C.. Palladium-Catalyzed Three-Component Diaryl Sulfone Synthesis Exploiting the Sulfur Dioxide Surrogate DABSO. Angew. Chem., Int. Ed. 2013;52:12679–12683. doi: 10.1002/anie.201305369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Chen Y., Murray P. R. D., Davies A. T., Willis M. C.. Direct Copper-Catalyzed Three-Component Synthesis of Sulfonamides. J. Am. Chem. Soc. 2018;140:8781–8787. doi: 10.1021/jacs.8b04532. [DOI] [PubMed] [Google Scholar]
  41. Nagornîi D., Raymenants F., Kaplaneris N., Noël T. C.. sp3)–H sulfinylation of light hydrocarbons with sulfur dioxide via hydrogen atom transfer photocatalysis in flow. Nat. Commun. 2024;15:5246. doi: 10.1038/s41467-024-49322-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Dhungana R. K., Shekhar K. C., Basnet P., Giri R.. Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins. Chem. Rec. 2018;18:1314–1340. doi: 10.1002/tcr.201700098. [DOI] [PubMed] [Google Scholar]
  43. Badir S. O., Molander G. A.. Developments in Photoredox/Nickel Dual-Catalyzed 1,2-Difunctionalizations. Chem. 2020;6:1327–1339. doi: 10.1016/j.chempr.2020.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Derosa J., Apolinar O., Kang T., Tran V. T., Engle K. M.. Recent developments in nickel-catalyzed intermolecular dicarbofunctionalization of alkenes. Chem. Sci. 2020;11:4287–4296. doi: 10.1039/C9SC06006E. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Qi X. X., Diao T. N.. Nickel-Catalyzed Dicarbofunctionalization of Alkenes. ACS Catal. 2020;10:8542–8556. doi: 10.1021/acscatal.0c02115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wickham L. M., Giri R.. Transition Metal (Ni, Cu, Pd)-Catalyzed Alkene Dicarbofunctionalization Reactions. Acc. Chem. Res. 2021;54:3415–3437. doi: 10.1021/acs.accounts.1c00329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Castanheiro T., Besset T.. Regioselective difunctionalization of alkenes with CF2FG Moieties. J. Fluor. Chem. 2024;277:110296. doi: 10.1016/j.jfluchem.2024.110296. [DOI] [Google Scholar]
  48. Zhu S., Zhao X., Li H., Chu L.. Catalytic three-component dicarbofunctionalization reactions involving radical capture by nickel. Chem. Soc. Rev. 2021;50:10836–10856. doi: 10.1039/D1CS00399B. [DOI] [PubMed] [Google Scholar]
  49. Kim M., You E., Kim J., Hong S.. Site-Selective Pyridylic C–H Functionalization by Photocatalytic Radical Cascades. Angew. Chem., Int. Ed. 2022;61:e202204217. doi: 10.1002/anie.202204217. [DOI] [PubMed] [Google Scholar]
  50. Petek N., Brodnik H., Reiser O., Štefane B.. Copper- and Photoredox-Catalyzed Cascade to Trifluoromethylated Divinyl Sulfones. J. Org. Chem. 2023;88:6538–6547. doi: 10.1021/acs.joc.2c02422. [DOI] [PubMed] [Google Scholar]
  51. Zhang T., Rabeah J., Das S.. Red-light-mediated copper-catalyzed photoredox catalysis promotes regioselectivity switch in the difunctionalization of alkenes. Nat. Commun. 2024;15:5208. doi: 10.1038/s41467-024-49514-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Tanaka S., Nakayama Y., Konishi Y., Koike T., Akita M.. Fluoroalkanesulfinate Salts as Dual Fluoroalkyl and SO2 Sources: Atom-Economical Fluoroalkyl-Sulfonylation of Alkenes and Alkynes by Photoredox Catalysis. Org. Lett. 2020;22:2801–2805. doi: 10.1021/acs.orglett.0c00789. [DOI] [PubMed] [Google Scholar]
  53. Li H., Zhang Y., Yang X., Deng Z., Zhu Z., Zhou P., Ouyang X., Yuan Y., Chen X., Yang L., Liu M., Shu C.. Synthesis of Multifluoromethylated γ-Sultines by a Photoinduced Radical Addition–Polar Cyclization. Angew. Chem., Int. Ed. 2023;62:e202300159. doi: 10.1002/anie.202300159. [DOI] [PubMed] [Google Scholar]
  54. Bagal D. B., Kachkovskyi G., Knorn M., Rawner T., Bhanage B. M., Reiser O.. Trifluoromethylchlorosulfonylation of Alkenes: Evidence for an Inner-Sphere Mechanism by a Copper Phenanthroline Photoredox Catalyst. Angew. Chem., Int. Ed. 2015;54:6999–7002. doi: 10.1002/anie.201501880. [DOI] [PubMed] [Google Scholar]
  55. Hou X., Liu H., Huang H.. Iron-catalyzed fluoroalkylative alkylsulfonylation of alkenes via radical-anion relay. Nat. Commun. 2024;15:1480. doi: 10.1038/s41467-024-45867-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wang H., Bellotti P., Zhang X., Paulisch T. O., Glorius F.. A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes. Chem. 2021;7:3412–3424. doi: 10.1016/j.chempr.2021.10.007. [DOI] [Google Scholar]
  57. Liu Y., Wu H., Guo Y., Xiao J.-C., Chen Q.-Y., Liu C.. Trifluoromethylfluorosulfonylation of Unactivated Alkenes Using Readily Available Ag­(O2CCF2SO2F) and N-Fluorobenzenesulfonimide. Angew. Chem., Int. Ed. 2017;56:15432–15435. doi: 10.1002/anie.201709663. [DOI] [PubMed] [Google Scholar]
  58. Ghosh P., Mondal S., Hajra A.. Metal-Free Trifluoromethylation of Indazoles. J. Org. Chem. 2018;83:13618–13623. doi: 10.1021/acs.joc.8b02312. [DOI] [PubMed] [Google Scholar]
  59. Deb A., Manna S., Modak A., Patra T., Maity S., Maiti D.. Oxidative Trifluoromethylation of Unactivated Olefins: An Efficient and Practical Synthesis of α-Trifluoromethyl-Substituted Ketones. Angew. Chem., Int. Ed. 2013;52:9747–9750. doi: 10.1002/anie.201303576. [DOI] [PubMed] [Google Scholar]
  60. Chu L., Qing F.-L.. Oxidative Trifluoromethylation and Trifluoromethylthiolation Reactions Using (Trifluoromethyl)­trimethylsilane as a Nucleophilic CF3 Source. Acc. Chem. Res. 2014;47:1513–1522. doi: 10.1021/ar4003202. [DOI] [PubMed] [Google Scholar]
  61. Ji Y., Brueckl T., Baxter R. D., Fujiwara Y., Seiple I. B., Su S., Blackmond D. G., Baran P. S.. Innate C-H trifluoromethylation of heterocycles. Proc. Natl. Acad. Sci. U. S. A. 2011;108:14411–14415. doi: 10.1073/pnas.1109059108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Sarver 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;143:9737–9743. doi: 10.1021/jacs.1c04722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Carson Ii W. P., Sarver P. J., Goudy N. S., MacMillan D. W. C.. Photoredox Catalysis-Enabled Sulfination of Alcohols and Bromides. J. Am. Chem. Soc. 2023;145:20767–20774. doi: 10.1021/jacs.3c08216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Meyer A. U., Straková K., Slanina T., König B.. Eosin Y (EY) Photoredox-Catalyzed Sulfonylation of Alkenes: Scope and Mechanism. ChemEur. J. 2016;22:8694–8699. doi: 10.1002/chem.201601000. [DOI] [PubMed] [Google Scholar]
  65. Corpas J., Kim-Lee S.-H., Mauleón P., Arrayás R. G., Carretero J. C.. Beyond classical sulfone chemistry: metal- and photocatalytic approaches for C–S bond functionalization of sulfones. Chem. Soc. Rev. 2022;51:6774–6823. doi: 10.1039/D0CS00535E. [DOI] [PubMed] [Google Scholar]
  66. Gianatassio R., Kawamura S., Eprile C. L., Foo K., Ge J., Burns A. C., Collins M. R., Baran P. S.. Simple Sulfinate Synthesis Enables C-H Trifluoromethylcyclopropanation. Angew. Chem., Int. Ed. 2014;53:9851–9855. doi: 10.1002/anie.201406622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Haut F.-L., Mega R. S., Estornell J. V., Martin R.. Catalytic Photoinduced Intramolecular Decarboxylative and Desulfonylative sp Allylation Enabled by Sulfinate Salts. Angew. Chem., Int. Ed. 2023;62:e202304084. doi: 10.1002/anie.202304084. [DOI] [PubMed] [Google Scholar]
  68. Xu S., Zhang W., Li C., Li Y., Zeng H., Wang Y., Zhang Y., Niu D.. Generation and Use of Glycosyl Radicals under Acidic Conditions: Glycosyl Sulfinates as Precursors. Angew. Chem., Int. Ed. 2023;62:e202218303. doi: 10.1002/anie.202218303. [DOI] [PubMed] [Google Scholar]
  69. Nambo M., Maekawa Y., Crudden C. M.. Desulfonylative Transformations of Sulfones by Transition-Metal Catalysis, Photocatalysis, and Organocatalysis. ACS Catal. 2022;12:3013–3032. doi: 10.1021/acscatal.1c05608. [DOI] [Google Scholar]
  70. Wang Z., Zhang Z., Zhao W., Sivaguru P., Zanoni G., Wang Y., Anderson E. A., Bi X.. Synthetic exploration of sulfinyl radicals using sulfinyl sulfones. Nat. Commun. 2021;12:5244. doi: 10.1038/s41467-021-25593-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Xu P., Fan W., Chen P., Liu G.. Enantioselective Radical Trifluoromethylation of Benzylic C–H Bonds via Cooperative Photoredox and Copper Catalysis. J. Am. Chem. Soc. 2022;144:13468–13474. doi: 10.1021/jacs.2c06432. [DOI] [PubMed] [Google Scholar]
  72. Pham L. N., Olding A., Ho C. C., Bissember A. C., Coote M. L.. Investigating Competing Inner- and Outer-Sphere Electron-Transfer Pathways in Copper Photoredox-Catalyzed Atom-Transfer Radical Additions: Closing the Cycle. Angew. Chem., Int. Ed. 2025;64:e202415792. doi: 10.1002/anie.202415792. [DOI] [PubMed] [Google Scholar]
  73. Maiti R., Nath A., Guimarães A. B. R., Bagnich S., Köhler A., Maseras F., Das S.. Mechanistic Insights into the Light-Driven Difunctionalization of Alkenes with a Sulfonyl-Based Reagent: A Catalyst-Free Approach. J. Am. Chem. Soc. 2025;147:38021–38032. doi: 10.1021/jacs.5c08562. [DOI] [PubMed] [Google Scholar]
  74. Li X.-T., Lv L., Wang T., Gu Q.-S., Xu G.-X., Li Z.-L., Ye L., Zhang X., Cheng G.-J., Liu X.-Y.. Diastereo- and Enantioselective Catalytic Radical Oxysulfonylation of Alkenes in β,γ-Unsaturated Ketoximes. Chem. 2020;6:1692–1706. doi: 10.1016/j.chempr.2020.03.024. [DOI] [Google Scholar]
  75. Tilby M. J., Dewez D. F., Pantaine L. R. E., Hall A., Martínez-Lamenca C., Willis M. C.. Photocatalytic Late-Stage Functionalization of Sulfonamides via Sulfonyl Radical Intermediates. ACS Catal. 2022;12:6060–6067. doi: 10.1021/acscatal.2c01442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Long T., Zhu C., Li L., Shao L., Zhu S., Rueping M., Chu L.. Ligand-controlled stereodivergent alkenylation of alkynes to access functionalized trans- and cis-1,3-dienes. Nat. Commun. 2023;14:55. doi: 10.1038/s41467-022-35688-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Liu Q., Wang X., Gu X., Dai H., Huang Z., Zhao Y.. Visible-Light-Induced Difunctionalization of 3-Butenoic Acid with Bromodifluoromethyl Heteroarylsulfones. Org. Lett. 2024;26:6449–6453. doi: 10.1021/acs.orglett.4c02277. [DOI] [PubMed] [Google Scholar]
  78. De Vos D., Cunha A. V., Jei B. B., Maes B. U. W.. Hydrosulfonylation of Unactivated Alkenes Involving Sulfonyl Radical Generation via Photocatalytic Activation of Symmetrical Disulfones by an Energy Transfer Mimicry. ACS Catal. 2024;14:12282–12296. doi: 10.1021/acscatal.4c02866. [DOI] [Google Scholar]
  79. Zhu L., Wang L.-S., Li B., Fu B., Zhang C.-P., Li W.. Operationally simple hydrotrifluoromethylation of alkenes with sodium triflinate enabled by Ir photoredox catalysis. Chem. Commun. 2016;52:6371–6374. doi: 10.1039/C6CC01944G. [DOI] [PubMed] [Google Scholar]
  80. Zhao L., Li P., Zhang H., Wang L.. Photoinduced synthesis of α-trifluoromethylated ketones through the oxidative trifluoromethylation of styrenes using CF3SO2Na as a trifluoromethyl reagent without an external photoredox catalyst. Org. Chem. Front. 2019;6:87–93. doi: 10.1039/C8QO01079J. [DOI] [Google Scholar]
  81. Yang B., Xu X.-H., Qing F.-L.. Copper-Mediated Radical 1,2-Bis­(trifluoromethylation) of Alkenes with Sodium Trifluoromethanesulfinate. Org. Lett. 2015;17:1906–1909. doi: 10.1021/acs.orglett.5b00601. [DOI] [PubMed] [Google Scholar]
  82. Singh H., Tak R. K., Poudel D. P., Giri R.. Catalytic Photoredox Carbobromination of Unactivated Alkenes with α-Bromocarbonyls via the Mechanistically Distinct Radical-Addition Radical-Pairing Pathway. ACS Catal. 2024;14:6001–6008. doi: 10.1021/acscatal.4c00955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Wallentin C.-J., Nguyen J. D., Finkbeiner P., Stephenson C. R. J.. Visible Light-Mediated Atom Transfer Radical Addition via Oxidative and Reductive Quenching of Photocatalysts. J. Am. Chem. Soc. 2012;134:8875–8884. doi: 10.1021/ja300798k. [DOI] [PubMed] [Google Scholar]
  84. Corpas J., Mauleón P., Arrayás R. G., Carretero J. C.. Transition-Metal-Catalyzed Functionalization of Alkynes with Organoboron Reagents: New Trends, Mechanistic Insights, and Applications. ACS Catal. 2021;11:7513–7551. doi: 10.1021/acscatal.1c01421. [DOI] [Google Scholar]
  85. Li Y., Shi H., Yin G.. Synthetic techniques for thermodynamically disfavoured substituted six-membered rings. Nat. Rev. Chem. 2024;8:535–550. doi: 10.1038/s41570-024-00612-3. [DOI] [PubMed] [Google Scholar]
  86. Chan L., Hutchison G. R., Morris G. M.. Understanding Ring Puckering in Small Molecules and Cyclic Peptides. J. Chem. Inf. Model. 2021;61:743–755. doi: 10.1021/acs.jcim.0c01144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Adhikari K., Vanermen M., Da Silva G., Van den Wyngaert T., Augustyns K., Elvas F.. Trans-cyclooctene-a Swiss army knife for bioorthogonal chemistry: exploring the synthesis, reactivity, and applications in biomedical breakthroughs. EJNMMI Radiopharm. Chem. 2024;9:47. doi: 10.1186/s41181-024-00275-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Lu Q.-T., Du Y.-B., Xu M.-M., Xie P.-P., Cai Q.. Catalytic Asymmetric Aza-Electrophilic Additions of 1,1-Disubstituted Styrenes. J. Am. Chem. Soc. 2024;146:21535–21545. doi: 10.1021/jacs.4c04852. [DOI] [PubMed] [Google Scholar]
  89. Flores-Leonar M. M., Azpilcueta C. R., Amador-Bedolla C., Rozenel S. S.. Isomerization reactions with [Ru­(Bpy)­3]­2+ photocatalyst. A DFT study of the factors influencing the energy transfer mechanism supported by experimental data. J. Photochem. Photobiol. A. 2021;414:113224. doi: 10.1016/j.jphotochem.2021.113224. [DOI] [Google Scholar]
  90. Hörmann F. M., Kerzig C., Chung T. S., Bauer A., Wenger O. S., Bach T.. Triplet Energy Transfer from Ruthenium Complexes to Chiral Eniminium Ions: Enantioselective Synthesis of Cyclobutanecarbaldehydes by [2 + 2] Photocycloaddition. Angew. Chem., Int. Ed. 2020;59:9659–9668. doi: 10.1002/anie.202001634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Singh K., Staig S. J., Weaver J. D.. Facile Synthesis of Z-Alkenes via Uphill Catalysis. J. Am. Chem. Soc. 2014;136:5275–5278. doi: 10.1021/ja5019749. [DOI] [PubMed] [Google Scholar]
  92. Zhan Y.-Z., Meng H., Shu W.. Rapid access to t-butylalkylated olefins enabled by Ni-catalyzed intermolecular regio- and trans-selective cross-electrophile t-butylalkylation of alkynes. Chem. Sci. 2022;13:4930–4935. doi: 10.1039/D2SC00487A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Rawner T., Lutsker E., Kaiser C. A., Reiser O.. The Different Faces of Photoredox Catalysts: Visible-Light-Mediated Atom Transfer Radical Addition (ATRA) Reactions of Perfluoroalkyl Iodides with Styrenes and Phenylacetylenes. ACS Catal. 2018;8:3950–3956. doi: 10.1021/acscatal.8b00847. [DOI] [Google Scholar]
  94. Li H., Wang F., Zhu S., Chu L.. Selective Fluoromethyl Couplings of Alkynes via Nickel Catalysis. Angew. Chem., Int. Ed. 2022;61:e202116725. doi: 10.1002/anie.202116725. [DOI] [PubMed] [Google Scholar]
  95. Lü S., Wang Z., Gao X., Chen K., Zhu S.. 1,2-Difunctionalization of Acetylene Enabled by Light. Angew. Chem., Int. Ed. 2023;62:e202300268. doi: 10.1002/anie.202300268. [DOI] [PubMed] [Google Scholar]
  96. Dhungana R. K., Kc S., Basnet P., Giri R.. Transition Metal-Catalyzed Dicarbofunctionalization of Unactivated Olefins. Chem. Rec. 2018;18:1314–1340. doi: 10.1002/tcr.201700098. [DOI] [PubMed] [Google Scholar]
  97. Yu J., Zhang X., Wu X., Liu T., Zhang Z.-Q., Wu J., Zhu C.. Metal-free radical difunctionalization of ethylene. Chem. 2023;9:472–482. doi: 10.1016/j.chempr.2022.10.020. [DOI] [Google Scholar]
  98. Li J., Luo Y., Cheo H. W., Lan Y., Wu J. P.-C.-M.. Nickel-Catalyzed Divergent Difunctionalization of Ethylene. Chem. 2019;5:192–203. doi: 10.1016/j.chempr.2018.10.006. [DOI] [Google Scholar]
  99. Zhang Y., Li H., Yang X., Zhou P., Shu C.. Recent advances in the synthesis of cyclic sulfinic acid derivatives (sultines and cyclic sulfinamides) Chem. Commun. 2023;59:6272–6285. doi: 10.1039/D3CC01238G. [DOI] [PubMed] [Google Scholar]
  100. Huang H.-L., Shi Y.-Q., Ning J.-X., Li S., Song D.-T., Gao F., Ma N.. Recent Advances in the Synthesis of Cyclic Sulfone Compounds with Potential Biological Activity. Molecules. 2024;29:5868. doi: 10.3390/molecules29245868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Andrews J. A., Kalepu J., Palmer C. F., Poole D. L., Christensen K. E., Willis M. C.. Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides. J. Am. Chem. Soc. 2023;145:21623–21629. doi: 10.1021/jacs.3c07974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Lou T. S.-B., Willis M. C.. Sulfonyl fluorides as targets and substrates in the development of new synthetic methods. Nat. Rev. Chem. 2022;6:146–162. doi: 10.1038/s41570-021-00352-8. [DOI] [PubMed] [Google Scholar]
  103. Barrow A. S., Smedley C. J., Zheng Q., Li S., Dong J., Moses J. E.. The growing applications of SuFEx click chemistry. Chem. Soc. Rev. 2019;48:4731–4758. doi: 10.1039/C8CS00960K. [DOI] [PubMed] [Google Scholar]
  104. Tamura T., Kawano M., Hamachi I.. Targeted Covalent Modification Strategies for Drugging the Undruggable Targets. Chem. Rev. 2025;125:1191–1253. doi: 10.1021/acs.chemrev.4c00745. [DOI] [PubMed] [Google Scholar]
  105. Gómez-Palomino A., Cornella J.. Selective Late-Stage Sulfonyl Chloride Formation from Sulfonamides Enabled by Pyry-BF4 . Angew. Chem., Int. Ed. 2019;58:18235–18239. doi: 10.1002/anie.201910895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Werder M., Hauser H., Carreira E. M.. Carbohydrate Sulfonyl Chlorides for Simple, Convenient Access to Glycoconjugates. Org. Lett. 2005;7:1145–1148. doi: 10.1021/ol0502127. [DOI] [PubMed] [Google Scholar]
  107. Pincekova L., Merot A., Schäfer G., Willis M. C.. Sandmeyer Chlorosulfonylation of (Hetero)­Aromatic Amines Using DABSO as an SO2 Surrogate. Org. Lett. 2024;26:5951–5955. doi: 10.1021/acs.orglett.4c01908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Schultz D. M., Sawicki J. W., Yoon T. P.. An improved procedure for the preparation of Ru­(bpz)3(PF6)2 via a high-yielding synthesis of 2,2’-bipyrazine. Beilstein J. Org. Chem. 2015;11:61–65. doi: 10.3762/bjoc.11.9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Bell J. D., Murphy J. A.. Recent advances in visible light-activated radical coupling reactions triggered by (i) ruthenium, (ii) iridium and (iii) organic photoredox agents. Chem. Soc. Rev. 2021;50:9540–9685. doi: 10.1039/D1CS00311A. [DOI] [PubMed] [Google Scholar]
  110. Kirby, A. J. Adv. Phys. Org. Chem.; Gold, V. , Bethell, D. , Eds.; Academic Press: 1980; Vol. 17, p 183–278. [Google Scholar]
  111. Gilmore K., Alabugin I. V.. Cyclizations of Alkynes: Revisiting Baldwin’s Rules for Ring Closure. Chem. Rev. 2011;111:6513–6556. doi: 10.1021/cr200164y. [DOI] [PubMed] [Google Scholar]
  112. Li Y., Studer A.. Transition-Metal-Free Trifluoromethylaminoxylation of Alkenes. Angew. Chem., Int. Ed. 2012;51:8221–8224. doi: 10.1002/anie.201202623. [DOI] [PubMed] [Google Scholar]
  113. Liu G., Shen H., Wang Z.. Access to All-Carbon Quaternary Centers by Photocatalytic Fluoroalkylation of α-Halo Carbonyl Compounds. Org. Lett. 2024;26:1863–1867. doi: 10.1021/acs.orglett.4c00041. [DOI] [PubMed] [Google Scholar]
  114. Cismesia M. A., Yoon T. P.. Characterizing Chain Processes in Visible Light Photoredox Catalysis. Chem. Sci. 2015;6:5426–5434. doi: 10.1039/C5SC02185E. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Reiß B., Hu Q., Riedle E., Wagenknecht H.-A.. The Dependence of Chemical Quantum Yields of Visible Light Photoredox Catalysis on the Irradiation Power. ChemPhotoChem. 2021;5:1009–1019. doi: 10.1002/cptc.202100090. [DOI] [Google Scholar]
  116. Blanksby S. J., Ellison G. B.. Bond Dissociation Energies of Organic Molecules. Acc. Chem. Res. 2003;36:255–263. doi: 10.1021/ar020230d. [DOI] [PubMed] [Google Scholar]
  117. Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds; CRC Press, 2002. [Google Scholar]
  118. Ramkumar N., Raiskuma A. P., Baumane L., Belyakov S., Traskovskis K., Veliks J.. Monofluoromethyl Radical Mediated Halogen-Atom Transfer. J. Am. Chem. Soc. 2025;147:25950–25959. doi: 10.1021/jacs.5c08589. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ja6c00567_si_001.pdf (7.1MB, pdf)

Articles from Journal of the American Chemical Society are provided here courtesy of American Chemical Society

RESOURCES