Visible-Light-Mediated Radical Truce–Smiles Rearrangement via Arylazo Sulfones

Abstract

We present a photocatalyst-free, visible-light-mediated Truce–Smiles rearrangement (TSR) for the selective difunctionalization of olefins by exploiting photoactivatable arylazo sulfones as sulfonyl radical precursors. This method efficiently affords β-sulfonyl-α-arylpropamides in high yields with excellent stereoselectivity. Furthermore, by incorporating a readily available chiral amino acid auxiliary (α-tert-butyl-leucine), we successfully developed a stereoselective variant of the TSR reaction, delivering optically enriched α-arylpropamides with excellent diastereoselectivity (up to 20:1 dr). DFT calculations provided detailed insight into the key factors governing reactivity and selectivity, particularly the contrasting behaviors of N-alkyl and N-aryl acrylamides. Overall, this work provides a sustainable and practical method for constructing sulfonylated aryl compounds under mild and catalyst-free conditions.

Vicinal radical difunctionalization of alkenes is a powerful strategy for incorporating two functional moieties across CC bonds, enabling the straightforward construction of complex molecular structures. − Recent advancements in this area have been driven by the application of visible-light photocatalysis, − which has significantly enhanced the versatility and potential of these transformations. Traditional strategies focus on photocatalyzed three-component reactions, where an excited photocatalyst generates an FG₁ ^· radical via electron − or energy transfer from a suitable precursor (I, Scheme a). − Such an intermediate is then trapped by olefin II, and the radical adduct IV then couples with FG₂-Y to afford the target product III (Scheme a). On the other hand, alternative methodologies rely on FG₁ ^· radical that undergoes addition to form IV’, followed by 1,4-aryl migration via the formation of a Meisenheimer radical intermediate V (Scheme b). − Such an approach is efficient for the selective incorporation of both aryl and heteroaryl groups at the internal positions of CC bonds. In particular, radical desulfonylative aryl group migration, which belongs to the so-called Truce–Smiles rearrangement (TSR), has benefited from significant advancements through the earlier work of Stephenson, − Greaney, , Wu, Nevado, − and along with more recent developments contributed by others. − Such proposals have greatly expanded the scope of difunctionalization processes, enabling the synthesis of β-(hetero)­arylethylamides, which serve as key precursors to β-(hetero)­arylacetic acids, privileged pharmacophores commonly found in bioactive compounds. − Despite these remarkable advancements, many current methods rely on the use of external photocatalysts, ,, which, while effective, are often expensive and challenging to recover and reuse. Therefore, the development of a photocatalyst-free approach would represent a significant step forward, reducing costs, streamlining the reaction process, and improving overall sustainability.

1. Photocatalyzed Difunctionalization of Alkenes.

As part of our interest in the radical TSR , and the chemistry of arylazo sulfones, − we aimed to develop a photocatalyst-free TSR system relying solely on photoactive arylazo sulfones. , Upon direct visible light irradiation, these compounds can generate three distinct intermediates, namely sulfonyl (RSO ₂ ^· ), − aryldiazenyl radical (Ar–N ₂ ^· ), − and, upon nitrogen loss, aryl (Ar ^· ) radicals − (FG_s ^· in Scheme c). An obvious difficulty in such an approach is the possible competitive addition of each of these radicals to N-(arylsulfonyl)­acrylamide 2 and the trapping of intermediate radicals IV’ by other radicals rather than the desired 1,4-aryl migration, leading to multiple difunctionalized byproducts (such as compounds 4–6, Scheme c).

As part of the design considerations for this photocatalyst-free TSR system, radical addition to N-(arylsulfonyl)-acrylamides might be influenced by polarity-matching effects between radicals and alkenes. − Under this model, moderate-to-weak nucleophilic aryl radicals , would be expected to react preferentially with the electron-deficient acrylamide rather than with the electrophilic sulfonyl radical. However, it should be noted that philicity criteria do not always correlate perfectly with reactivity, as they represent only one factor among others (such as solvent effects, hydrogen bonding, orbital interactions, and thermodynamics) that govern reaction outcomes. Indeed, Wu and co-workers reported the addition of sulfonyl radicals to acrylamides while aryl radicals were generated. In our previous work, we also observed that radical additions do not strictly follow polarity rules, with sulfonyl radicals reacting preferentially even with less electron-rich styrenes. In both cases, regio- and chemoselectivity could be achieved by adjusting the reaction conditions. We therefore believe that, through careful optimization, sulfonyl radical addition − can be selectively promoted, enabling the exclusive formation of compound 3. This strategy will provide an efficient route for the introduction of sulfone motifs, which are widely present in pharmaceuticals and agrochemicals. −

Herein, we present a versatile photocatalyst-free radical TSR by exploiting arylazo sulfones 1 as sulfonyl radical precursors upon light activation. By carefully optimizing the reaction conditions, we achieved highly chemoselective addition of the sulfonyl radicals to alkenes, leading to a broad range of β-sulfonyl-α-arylpropamides 3 in moderate to excellent yields. Importantly, incorporation of the chiral auxiliary α-tert-butyl-leucine into 2 enabled the development of a stereoselective protocol, affording compounds 3 with excellent diastereoselectivity. It should be mentioned that this strategy represents the first stereoselective, photocatalyst-free TSR process, offering a complementary and sustainable strategy within the realm of photocatalyzed desulfonylative aryl migration chemistry.

In the beginning, we investigated the desulfonylative radical TSR between N-(4-tolyl)-N-tosylacrylamide (2a) and 1-(4-methoxyphenyl)-2-(methylsulfonyl)­diazene (1a) in CH₃CN under visible light irradiation at 427 nm (Table ). Notably, the reaction proceeded smoothly, yielding a single TSR adduct 3a, which resulted from the addition of the sulfonyl radical − to the acrylamide (entry 1). The presence of water as an additive again exclusively led to the sulfonylated TSR product 3a, albeit in a lower yield (entry 2). Various solvents, including CH₂Cl₂, THF, and acetone (entries 3 to 5), were tested, but none outperformed CH₃CN. We also evaluated irradiation at different wavelengths. Light at 456 and 440 nm slightly improved the yield (entries 6 and 7), whereas 390 nm resulted in a reduced efficiency of the process (entry 9). Reducing the amount of 2a decreased the reaction efficiency (entry 10), while incorporating a buffering agent (NaHCO₃) did not significantly impact the yield, but it produced a cleaner crude reaction mixture (entry 11). , The conditions described in the latter entry, which facilitate the purification process, were chosen to further optimize the reaction. The effect of the aromatic substituent on arylazo sulfone was thus investigated (entries 12–14). However, arylazo sulfones bearing electron-rich aryl groups such as 4-(N,N-diethylamino)­phenyl and 3,4,5-trimethoxyphenyl, did not produce the desired TSR product (entries 12 and 13). In contrast, excellent yields of 3a were achieved when sulfone was substituted with a 4-tolyl group (1d, entry 14). Further experiments pointed out the positive effect of NaHCO₃, which led to comparable yields in both CH₂Cl₂ and CH₃CN, in contrast to TSR with 1a (entries 14, 15).

1. Optimization of Visible-Light-Mediated Radical TSR .

entry	1 (X eq)	light, nm	solvent	3a yield (%)
1	1a (2)	427	CH3CN	65
2	1a (2)	427	CH3CN/H2O	42
3	1a (2)	427	CH2Cl2	37
4	1a (2)	427	THF	62
5	1a (2)	427	acetone	25
6	1a (2)	456	CH3CN	78
7	1a (2)	440	CH3CN	90, 68
8	1a (2)	405	CH3CN	80
9	1a (2)	390	CH3CN	41
10	1a (1)	440	CH3CN	30
11	1a (2)	456	CH3CN	71,
12	1b (2)	456	CH3CN	0
13	1c (2)	456	CH3CN	0
14	1d (2)	456	CH3CN	90,
15	1d (2)	456	CH2Cl2	91,
16	1d (2)	(−)	CH2Cl2	0

^aReaction conditions: 2a (0.10 mmol) in 2.0 mL of solvent in the presence of the chosen amount of 1, irradiated for 20 h.

^bYields refer to chromatographically pure TSR product 3a.

^cGC yields (based on the consumption of 2a).

^dNaHCO₃ (2 equiv).

^ePerformed away from light.

With the optimal reaction conditions in hand (entry 15), we explored this visible-light-mediated desulfonylative radical TSR using different arylazo sulfones 1 and various N-(arylsulfonyl)­acrylamides 2a–u (Scheme ). Both alkyl and aryl sulfones were successfully incorporated, leading to the corresponding sulfonylated TSR products 3 in yields ranging from moderate to almost quantitative. The electronic effects of the aromatic substituents of the sulfones had a minimal impact on the reaction outcome, as comparable yields were obtained for para-substituted aryl groups (Scheme and ), including methyl, bromo, chloro, fluoro, methoxy, or nitro (see, for example, 3i vs 3j, or 3l vs 3o). Furthermore, arylazo sulfones containing a 2-naphthyl substituent reacted cleanly with acrylamides, giving rise to product 3ac in satisfactory yields. However, while sulfones 1 bearing a more electron-rich substituent, such as the tolyl group, delivered the TSR products (3k–3l) mostly in high yields, substrates with a strongly electron-withdrawing nitro group exhibited a lower efficiency (3m–3n). In any case, the best yields were generally achieved with alkyl sulfones (3p-3x, up to 99%).

2. Scope of the Photocatalyst-Free TSR .

^a General reaction conditions: 1 (0.20 mmol, 2 equiv), 2 (0.10 mmol), and NaHCO₃ (0.20 mmol, 2 equiv) in 2.0 mL of CH₂Cl₂ at rt for 20 h. Yields refer to chromatographically pure TSR product 3. Ms: mesyl; Ns: nosyl, Ts: tosyl.

4. Scope of the Diastereoselective Photocatalyst-Free TSR and Auxiliary Cleavage .

^a General reaction conditions: 1 (0.08 mmol) and 2 (0.12 mmol, 1.5 equiv) in 1.0 mL of CH₂Cl₂ at 0 °C for 20 h. Yields refer to chromatographically pure TSR product 3. ^a0.8 mmol of 1r and 1.2 mmol of 2w. ^bDetermined by chiral HPLC versus racemic. ^cEnantiomeric purity of the major diastereoisomer. Ms: mesyl; Ns: nosyl, Ts: tosyl.

We next examined the influence of the N-aryl moiety on acrylamides 2 and found that the reaction proceeded efficiently in the presence of substituents such as methyl (see, among the other products, 3e), methoxy (3u), tert-butyl (3s), and halogens (see, among the others, 3f–3l), regardless of their position (para, meta, or ortho, 3c, 3y, and 3z). Electron-withdrawing groups such as cyano (3v), ester (3w), or nitro (3x) were also tolerated. Pleasingly, N-aryl amide bearing both cyano and trifluoromethyl groups produced biologically relevant bicalutamide derivative (3ae) in high yields. Additionally, α-substituted N-(arylsulfonyl)­acrylamides reacted smoothly with 1 to deliver sulfonylated TSR products 3ab–3ae bearing a quaternary carbon center with high yields. Further studies on the migrating aryl group in N-(arylsulfonyl)­acrylamides 2 showed that substrates with both electron-donating groups (OMe, 3d) and electron-withdrawing groups (CF₃, 3af) were tolerated, leading to propamides in moderate to good yields. Heteroaromatic rings such as pyridine (3ad), as well as ortho-substituted aryl bromide (3z), also underwent the 1,4-migration effectively.

We next turn our attention to the study of a stereoselective variant of this photocatalyst-free TSR reaction. − Asymmetric TSR reactions have been limited, mainly due to the challenges in controlling chirality in the transient radical Meisenheimer intermediate V (Scheme ) during aryl migration. ,− ,,, Nevado’s work − with a traceless chiral sulfoxyl auxiliary on the nitrogen of acrylamide marked a significant advance in this area. Last year, our group disclosed an efficient asymmetric photocatalytic TSR reaction using the readily available chiral auxiliary α-tert-butyl-leucine and thus we evaluated its potential in the present catalyst-free TSR reaction. As this approach requires N-alkylated acrylamides, we initially subjected an acrylamide bearing a tert-butyl group on the nitrogen atom to the established conditions (Scheme a). Unexpectedly, the reaction failed under these optimized conditions, resulting in a complex mixture and minor amounts of the desired TSR product 3ah, as determined by crude ¹H NMR analysis. Performing the reaction with the chiral auxiliary-derived acrylamide 2v led to a similar outcome.

3. Visible-Light-Mediated Radical TSR with N-Alkylated Acrylamides .

^a Reaction conditions: (a) 1 (0.20 mmol, 2 equiv), 2 (0.10 mmol), and NaHCO₃ (0.20 mmol, 2 equiv) in 2.0 mL of CH₂Cl₂ at rt for 20 h. Crude NMR. (b) 1 (0.08 mmol) and 2 (0.12 mmol, 1.5 equiv) in 1.0 mL of CH₂Cl₂ at 0 °C for 20 h. Yields refer to chromatographically pure TSR product 3.

To address these disappointing results, the reaction conditions were reoptimized by varying the solvent, reagent ratio, and temperature (see the Supporting Information). Through optimization, we identified that the process needed to be performed at a lower temperature (0 °C) with an inverse reagent ratio of 1 and 2 (from 2:1 to 1:1.5) to achieve a cleaner outcome. Nevertheless, under such conditions, we isolated a mixture of two inseparable products in a ratio of 2:1, containing, along with the desired compound 3ah, also the tosylated derivative 3ai. Curiously, arylazo sulfone 1d does not directly release a tosyl radical, which would explain the formation of 3ai. We suggested that this radical species can arise from the trapping of the tolyl radical (in turn obtained via photolysis of 1d) by SO₂ released during the desulfonative TSR reaction (a detailed description of the process is available in Scheme and in the related text). ,− Accordingly, efforts were undertaken to suppress the competitive formation of 3ai. Optimization through fine-tuning of conditions did not allow avoiding the competitive reaction and consistently produced sulfonylated mixtures (Supporting Information).

5. Proposed Mechanism of the Visible-Light-Mediated TSR.

A straightforward yet effective solution was found by employing an arylazo sulfone bearing the same aryl group (e.g., Ar¹ = 4-tolyl for 1h) on both the sulfonyl unit and the nitrogen in order to obtain the desired TSR product via two convergent pathways. This strategy enabled the clean formation of the tosylated TSR product 3ai, isolated in 66% yield (Scheme b). While this approach does not exclude the competitive pathway, it remains attractive because it makes use of both the aryl radical (Ar·) from arylazo sulfone 1 and the SO₂ released during the desulfonative step. Indeed, the combination of these two fragments converges to the same final product formed by the initially released ArSO₂ ^· radical, thereby enhancing the overall resource efficiency of the transformation. By following the same approach with other pseudosymmetrical arylazo sulfones (bearing two identical Ar groups), a representative set of TSR products bearing N-tBu (3ai-3ak) was obtained in high yields.

Diastereoselective photocatalyst-free TSR involving chiral auxiliary α-tert-butyl-leucine-derived acrylamides was subsequently evaluated under the new reaction conditions (Scheme ). Pleasingly, the reaction proceeded effectively with enantioenriched acrylamide 2v and arylazo sulfone 1h yielding β-4-tosyl-α-tolylpropamide 3al in 76% yield with excellent diastereoselectivity (16:1 dr). A range of arylazo sulfones reacted smoothly with acrylamide 2 independently of the nature and the position of the aromatic substituents and TSR products 3al to 3aw were obtained in 44–76% yield, and a diastereomeric ratios ranging from 9:1 to 20:1. It should be noticed that the TSR proceeded without any loss of enantiopurity of the chiral auxiliary, as confirmed by the HPLC-determined stereochemical purity of the major β-arylpropamide 3ai (see Supporting Information). In contrast, but consistent with our previous studies, reactions involving α-substituted acrylamides resulted in the formation of 3ax in a very low yield, along with a nearly 1:1 diastereomeric ratio under our reaction conditions (0 °C or rt).

As mentioned earlier, the use of pseudosymmetrical arylazo sulfones with identical aryl groups prevents the formation of an in situ competing recombinant (SO₂ + Ar¹ vs Ar²SO₂) sulfonyl radical but limits product formation to arylsulfonyl propanamides. Nevertheless, we succeeded in synthesizing the related methylsulfonylated product, compound 3ay, from 4-tolylazo methylsulfone, thereby broadening the scope. Modification of the reaction conditions did not fully suppress the tosylated byproduct, but we were able to favor the desired product 3ay, which was separable from 3al, leading to a 65% isolated yield with 16:1 dr. The absolute configuration of compound 3ar was established based on X-ray crystallographic data. This allowed us to determine that diastereoselective induction followed our previous observation, where amino acid (R) induced an (S) stereochemistry of the newly formed chiral center.

We also demonstrated that the chiral auxiliary can be removed via a concise multistep procedure. This involves selective hydrolysis of the ester to form the carboxylic acid, followed by acyl azide formation and a Curtius rearrangement, with the final hydrolysis of the hemiaminal occurring in situ. , As such, compound 7 was obtained from compound 3al in an unoptimized yield of 41% over the sequence; importantly, chiral information was preserved (initial dr = 16:1 = 94:6 to e.r = 93:7).

Afterward, we conducted several control experiments to probe the reaction mechanism. We first observed that the reaction did not proceed in the absence of light, with the starting materials being fully recovered (Table , entry 16). Additionally, the use of 4 equiv of TEMPO completely inhibited the reaction for the formation of 3a, and the product resulting from the trapping of the methyl sulfonyl radical by TEMPO has been detected by LC-MS analyses (see the Supporting Information). Finally, a quantum yield (Φ) value of 0.014 was measured (λ = 456 nm) for the formation of TSR product 3a, indicating that a radical chain mechanism could probably be excluded as the primary pathway for the reaction (see the Supporting Information).

From these investigations, we propose a reasonable mechanism outlined in Scheme . Upon visible-light irradiation, excited arylazo sulfone generates, after homolytic cleavage of the N–S bond and N₂ loss, sulfonyl (R ¹ SO ₂ ^· ) and aryl (Ar ^1· ) radicals (path a). The R ¹ SO ₂ ^· intermediate then couples with acrylamide 2 (path b), producing a radical intermediate B, which undergoes intramolecular radical addition onto the aromatic ring to form the Meisenheimer intermediate [B’] (path c). − Subsequently, consecutive 1,4-aryl migration and extrusion of SO₂ occur through C, giving rise to the amidyl radical D (paths d and e). ,− ,,, In the final step, D abstracts a hydrogen atom from the medium and affords the final derivative 3 (path f). To probe the origin of this hydrogen, path f was further investigated using deuterated solvents (see the Supporting Information, Table S3). The reaction of 2a with arylazo sulfone 1a in CH₃CN or DCM in the presence of a small amount of D₂O resulted in partial deuterium incorporation, consistent with rapid proton exchange between the amido group of 3a and traces of water. In contrast, nearly complete incorporation (∼90%) was observed when CD₃CN was combined with D₂O, indicating that the hydrogen atom in the final product predominantly originates from the reaction medium. On the other hand, the aryl radical (Ar ^1· ) generated from 1 can trap SO₂, released during the main pathway (path e), forming the sulfonyl radical Ar ¹ SO ₂ ^· (path a’). The latter competes with R ¹ SO ₂ ^· in reacting with the acrylamide, leading to the formation of the undesirable minor TSR product 3′ (path b’ to f’) alongside the desired major product 3.

The competitive SO₂ insertion pathway was observed in the case of N-alkyl acrylamides, where a low reaction temperature furnished the best results. Nevertheless, competition was also present at room temperature with such reagents (Scheme a), contrary to the room temperature reaction performed with N-aryl acrylamides. Density functional theory (DFT) calculations were therefore undertaken to shed light on the reactivity difference between N-arylated and N-alkylated precursors (Scheme ). As such, DFT calculations at the B3LYP-D3­(BJ)/def2-SV­(P) level were conducted and complemented with DLPNO–CCSD­(T)/def2-TZVP calculations to ascertain the quality. A preliminary conformational search, done with the CREST software, was initially undertaken on model compounds 2 _Ph and 2tBu, and the best conformer was taken as a starting point for the following computations. During this conformational search, we also found that the s-cis conformer of 2 _Ph is 2.49 kcal.mol^–1 more stable than the s-trans one (at the B3LYP-D3­(BJ) level, DLPNO–CCSD­(T) gave a similar value (see the Supporting Information), while the opposite is found in the case of compound 2 _tBu, which favored the s-trans conformer by 8.08 kcal.mol^–1 (Scheme A). Subsequent DFT computations revealed major dissimilarity between these two reagents, critical to understand the reactivity and competitive pathway (Scheme B). Indeed, while both conformers converged with a limited energy difference to intermediate B _ph and B _tBu following initial sulfonyl radical addition, a marked difference appeared when reaching respective transition-state TS_B’C _Ph and TS_BC _tBu , key for the ipso-attack leading to aryl migration. The reactive conformer B _tBu is s-trans and thus, with a proper orientation to perform the aryl transfer, an energy barrier of only 6.82 kcal.mol^–1 allows reaching directly TS_BC _tBu . For Ph-derived amide radical B _ph , an isomerization from s-cis to s-trans is first needed (ΔΔG = +1.10 kcal·mol^–1). It gives rise to noncovalent interactions (π–π stacking), clearly observed in intermediate B’ _Ph (Supporting Information, Figure S10), which needs to be subsequently discharged to reach TS_B’C _Ph , and this accounts for the large observed energy barrier of 14.57 kcal·mol^–1.

6. DFT Study for Radical TSR via Arylazo Sulfones .

^a (A) Conformers of 2_Ph/2 _tBu and (B) energy profiles and key TS for aryl migration.

A second major difference was also observed during the calculation. The product of aryl transfer C _Ph essentially evolved in a barrierless energetic pathway (less than 0.2 kcal.mol^–1) to intermediate D _Ph by releasing SO₂. This is in sharp contrast to the calculated pathway for N-tBu, where a barrier of 7.26 kcal.mol^–1 for the loss of SO₂ was found. Specific stabilizing interactions between the t-Bu group and the SO₂ moiety, through dispersion interactions, in intermediate C _tBu (Supporting Information, Figure S9) account for this difference during the SO₂ release.

Overall, these calculations fully explain the divergent behavior of acrylamides: N-alkyl acrylamides can proceed at lower temperatures, while N-aryl derivatives, which follow a more energetic pathway, require room temperature conditions. In addition, SO₂ reincorporation (a competitive pathway in Scheme ) is a direct consequence of the slow homolysis rate of the N-SO₂ bond, which is effective in the case of N-alkylated substrates. Indeed, a slow release of SO₂ will allow time for aryl radicals to intercept it and generate the competing ArylSO₂ radical. Such behavior would also be favored by lower (0 °C) temperature, which influenced the concentration of dissolved gaseous SO₂. ,

In conclusion, we developed a versatile visible-light-mediated and (photo)­catalyst-free radical TSR for the desulfonylative functionalization of N-sulfonylated acrylamides by using arylazo sulfones. This method provides an effective strategy for the selective installation of sulfonyl and aryl groups, affording β-sulfonyl-α-arylpropamides in moderate to excellent yields. Through careful optimization, we also achieved stereoselective synthesis of these products by incorporating chiral auxiliaries such as α-tert-butyl-leucine, enabling high diastereoselectivity. The method represents a sustainable and operationally simple alternative to traditional photocatalytic systems, avoiding the use of external catalysts. In addition, the stereoselective approach enhances atom economy through the dual utilization of both the aryl radical and the SO₂ byproduct. Detailed mechanistic investigations, supported by DFT calculations, revealed key conformational and energetic factors that govern the reaction outcome. In particular, the distinct reactivity profiles of N-alkylated versus N-arylated acrylamides were attributed to differences in conformational stability and transition-state energetics during the aryl migration step, providing a clear rationale for the observed selectivity.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c00919.

• Experimental details, experimental procedure, characterization data (¹H, ¹³C, ¹⁹F NMR, and HRMS data), copies of NMR spectra of new compounds, details of computational methods, optimized Cartesian coordinates along with electronic energy and frequency, and references related to the computational section (PDF)

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L.D.T., L.N., and E.M.-I. contributed equally to this work.

The authors declare no competing financial interest.