Radical thioesterification via nickel-catalysed sensitized electron transfer

Multi-catalytic reaction modes have attracted widespread attention in synthetic chemistry. The merger of nickel catalysis with photoredox catalysis has offered a powerful platform for synthesis of molecules with attractive properties. Nonetheless, the conceptual development of nickel-catalysed, sensitized electron transfer is of pivotal relevance, but is still greatly limited. Here we describe the development of a radical cross-thioesterification process by nickel-catalysed sensitized electron transfer. The strategy can produce diverse methyl thioesters, which are not only found in natural products, materials and pharmaceuticals but also are widespread precursors in synthetic chemistry and biological processes. This catalytic mode features high chemoselectivity, good functional group tolerance and excellent scalability. Perhaps more important was the finding that various drugs and amino acids were successfully functionalized in this system. Experimental studies, nanosecond transient spectroscopic analysis, and density functional theory calculations reveal that the merger of photocatalytic electron transfer, energy transfer and nickel catalysis plays an essential role in this radical thioesterification reaction. The combination of nickel-catalysis and sensitized electron transfer is underdeveloped. Now, a nickel-catalysed sensitized electron transfer method for the synthesis of methyl thioesters from carboxylic acids is reported. Mechanistic investigations reveal that the merger of photocatalytic electron transfer, energy transfer and nickel catalysis plays an essential role in this thioesterification reaction.

Multi-catalytic reaction modes have attracted widespread attention in synthetic chemistry.The merger of nickel catalysis with photoredox catalysis has offered a powerful platform for synthesis of molecules with attractive properties.Nonetheless, the conceptual development of nickel-catalysed, sensitized electron transfer is of pivotal relevance, but is still greatly limited.Here we describe the development of a radical cross-thioesterification process by nickel-catalysed sensitized electron transfer.The strategy can produce diverse methyl thioesters, which are not only found in natural products, materials and pharmaceuticals but also are widespread precursors in synthetic chemistry and biological processes.This catalytic mode features high chemoselectivity, good functional group tolerance and excellent scalability.Perhaps more important was the finding that various drugs and amino acids were successfully functionalized in this system.Experimental studies, nanosecond transient spectroscopic analysis, and density functional theory calculations reveal that the merger of photocatalytic electron transfer, energy transfer and nickel catalysis plays an essential role in this r ad ic al t hi oe st er ifi cation reaction.
The development of effective and logical strategies that sustainably access valuable and challenging molecules from simple feedstocks is one of the central tenets of modern synthetic chemistry, as well as relentless pursuit of chemists.Methyl thioesters not only are found in natural products and drug molecules but also represent important synthetic precursors in biosyntheses, such as the native chemical ligation reactions towards increasingly large polypeptides and proteins (Fig. 1a) [1][2][3][4][5][6] .Classical approaches to forging methyl thioester moieties generally rely on multistep syntheses or substitution reactions between electrophilic acyl compounds with either nucleophilic sodium methylthiolate or methyl mercaptan [7][8][9] .Nonetheless, these methods are plagued by the undesirable chemical properties of these two nucleophiles (Fig. 1b).Specifically, the handling of gaseous methyl mercaptan is not operationally straightforward, and sodium methylthiolate hydrolyses in moist air to the former compound.In addition to require of non-ideal reagents, other synthetic challenges such as extra preparatory steps of the starting materials, narrow functional group compatibility and harsh reaction conditions have severely curbed the efficient construction of valuable methyl thioesters through classical methods [10][11][12][13][14] .To address these liabilities, the Wu group successfully developed a palladium-catalysed carbonylation-thiomethylation of aryl halides with CO and thioesters 15 .In summary, reported methods can form limited thioesters, but methyl thioesters remain challenging to synthesize.Thus, broadly substrate-compatible, easy-to-operate and biocompatible strategies for methyl thioesters are yet underdeveloped but in high demand.
Over the past decade, radical reactions triggered by photocatalysis have provided a powerful and efficient platform for the construction of challenging molecules  . In ths field, the combination of transition metal catalysis for bond formation with photoinduced electron-and/or energy transfer processes has attracted increasing attention (Fig. 1c) [39][40][41] .Nickel-catalysed, photoinduced electron transfer (ET) strategies have been deeply investigated and successfully applied to synthetic chemistry [42][43][44][45][46][47][48][49][50] .Moreover, the amalgamation of energy transfer catalysis Article https://doi.org/10.1038/s44160-023-00353-z to form nickel complex (II).In this system, an active phosphorus radical cation might be generated via photocatalytic ET, as described by Doyle and co-workers 61 .Subsequently, nucleophilic attack of carboxylic acids produces the intermediate III.Then, acyl nickel complex (IV) would be obtained via the interaction of intermediate II with III. Furthr reductive elimination of IV would forge the desired product.Herein we describe the successful merger of a nickel-catalysed, energy transfer and ET for the radical thiomethyl esterification of carboxylic acids (Fig. 1e).

Evaluation of the reaction conditions
To evaluate this multi-catalytic hypothesis, 4-phenylbutyric acid (1) and DMDS (2) were chosen as reaction partners.Pleasingly, after extensive optimization, 95% yield of thiomethyl ester (3) could be obtained with NiBr 2 (diglyme) and Ir[dF(CF 3 )ppy 2 (dtbbpy)][PF 6 ] [Ir-F] as co-catalysts, triphenylphosphine (PPh 3 ) and pyridine as additives (Fig. 2a, entry 1).It is worth mentioning that no decarboxylation by-product was observed in this reaction system, which shows high chemoselectivity 62,63 .The effect of other essential reaction parameters was further investigated (Fig. 2a).Noteworthily, the reaction yield dropped substantially in the absence of nickel catalyst (Fig. 2a, entry 2).Similarly, no desired product was observed without either photocatalyst or irradiation under visible light (Fig. 2a, entry 3).Further screening revealed that PPh 3 plays an essential role in this transformation (Fig. 2a, entry 4).In addition, 80% yield of product was obtained in the absence of pyridine (Fig. 2a, (EnT) with nickel catalysis has offered new opportunities for organic cross-coupling reactions (Fig. 1c).Energy transfer-mediated nickel catalysis for the construction of C-O and C-C bonds was pioneered by the groups of MacMillan 51 and Molander 52 , respectively.Intriguingly, successful combination of photoinduced energy transfer process (EnT) with ET process by Xiao 53 , König 54 , Gilmour 55 , Weaver 56 and their co-workers paved the way to new radical reaction scenarios (Fig. 1c).So far, only a few examples that operate through ET/nickel catalysis followed by single electron transfer (SET) have been reported by Rueping 57 and Chu 58 , successfully enabling the generation of tri-substituted alkenes via a three-component cross-coupling reaction (Fig. 1c).In this type of reactions, energy transfer from excited photocatalysts often plays a role in the last step, enabling alkene isomerizations 57,58 .Nevertheless, more attractive roles for energy transfer in multi-catalytic mode remain to be exploited.For instance, energy transfer with a photosensitizer can promote chemical bond cleavage 17,59,60 , which offers more possibilities for constructing functional molecules.
Considering the importance and abundance of carboxylic acids in nature and the easy availability of dimethyl disulfide (DMDS), construction of thiomethyl esters from these two starting materials is an attractive strategy.In this Article, to address the synthetically challenging methyl thioesterification of carboxylic acids, we envisioned that merging energy transfer with ET could offer a cooperative manifold with nickel catalysis.According to the hypothesis, we designed a possible catalytic process (Fig. 1d).Thiomethyl radical, formed from DMDS via photocatalytic energy transfer 60

Article
https://doi.org/10.1038/s44160-023-00353-zentry 5).Increasing the amount of PPh 3 did not affect the reaction yield, while the yield dropped substantially when less PPh 3 was used (Fig. 2a, entries 6 and 7).Moreover, changing the amount of DMDS had no obvious effect on the reaction efficiency (Fig. 2a, entries 8 and 9).Higher or lower amount of the nickel catalyst led to low reaction yields (Fig. 2a, entries 10 and 11).Additionally, other nickel catalysts could also work for this protocol, albeit with lower efficiency (Fig. 2a, entries 12 and 13).

Sensitivity assessment
A condition-based sensitivity screening approach was carried out (Fig. 2b) 64 , which demonstrates that the reaction of synthesizing compound 3 is sensitive to high oxygen concentration, low temperature and water content.Pleasingly, good efficiency of this transformation was observed at high temperature and light intensities (Supplementary Section 4).

Additive-based robustness screen
The robustness and the functional group tolerance of this radical two-component thioesterification protocol were investigated by applying an intermolecular additive-based screening method 65 .Most of the examined additives could be well tolerated, and high reaction yields were observed.These findings highlight the remarkable mildness and tolerance of our methodology (Fig. 2c and Supplementary Section 5).

Mechanistic investigations
To provide mechanistic details to support the proposed catalytic cycle, Stern-Volmer luminescence quenching experiments were carried out.As shown in Fig. 3a, the excited photocatalyst could be quenched by either the PPh 3 or DMDS (2), which supports our hypothesis.Additionally, UV/Vis absorption experiments were Article https://doi.org/10.1038/s44160-023-00353-zalso performed (Supplementary Fig. 5).Then, this multi-catalytic process was completely inhibited in the presence of TEMPO (tetramethylpiperidine-1-oxyl), revealing that a radical process might be involved (Fig. 3b).Thiomethyl radical was trapped by the (2-cyclopropylallyl)benzene ( 4), and no acyl radical 8 was observed.This probe experiment further suggests the intermediacy of radical

Article
https://doi.org/10.1038/s44160-023-00353-z in this system (Fig. 3c).Subsequently, control experiments show that the sulfur radical could be formed from DMDS (2) in absence of nickel catalyst or PPh 3 (Fig. 3c).Furthermore, various triplet sensitizers were evaluated (Fig. 3d).The yield of the methylthiolated product correlates to the triplet energy rather than the redox potential of the photocatalysts, which means that the production of thiomethyl radicals from disulfides is probably promoted by EnT 60,66 .

Transient absorption spectroscopic studies
Nanosecond transient electronic absorption spectroscopy (ns-TEAS) was employed to obtain further insight into the kinetics of the initial activation of PPh 3 and DMDS (2) by the [Ir-F] (Fig. 3 and Supplementary Section 6.7).The ns-TEAS results of the sole as well as mixtures of [Ir-F] with DMDS 2, [Ir-F] with PPh 3 , and [Ir-F] with DMDS 2 and PPh 3 in Ar-saturated MeCN upon excitation at λ exc = 387 nm are displayed in Fig. 3. Global and target analysis of the data was performed using the python package KiMoPack, which yielded the species-associated difference spectra (SADS, bottom panel) 67 .The pure [Ir-F] (Fig. 3e) exhibits a broad excited state absorption band peaking at λ probe = 465 nm, which is ascribed to the triplet metal-to-ligand charge-transfer/ ligand-centred ( 3* MLCT/LC) state of the photocatalyst 60 .Addition of 2 to the solution (Fig. 3f) leads to a notable shortening of the 3* MLCT/ LC lifetime and to the formation of a second species with distinct absorption peaks at λ probe = 400, 440 nm that has previously been assigned to the triplet state of 2 ( 3* 2), which is generated from triplettriplet energy transfer 60,68 .The mixture of [Ir-F] and PPh 3 (Fig. 3g) shows the accelerated depletion of the 3* MLCT/LC state of the photosensitizer in favour of a species with a broad absorption band centred at λ probe = 520 nm indicates the excited state ET leading to the formation of the radical cation PPh 3 +⦁ as well as to the reduction of the ([Ir-F] II ) photosensitizer [67][68][69][70][71] .The mixture of all three compounds (Fig. 3h) mostly resembles the photodynamics resulting from excited state ET between the [Ir-F] and 2. However, some superimposed triplet-triplet energy transfer contribution caused by the interaction of the photocatalyst with PPh 3 can be identified from the decomposed spectra.In summary, the ns-TEAS results provide evidence that the initial activation of the PPh 3 to PPh 3 +⦁ is due to one-electron oxidation from the 3* MLCT/LC state of the photocatalyst and that the previously observed TTEnT between the photocatalyst and the disulfide (2) also occurs in the presence of PPh 3 .

DFT studies
To gain more mechanistic insights, density functional theory (DFT) calculations were performed to investigate the radical methyl thioesterification of carboxylic acids.Firstly, computational studies suggest that the activation of PPh 3 through the single ET from thiomethyl radical is endergonic by 28.9 kcal mol −1 (Supplementary Fig. 11), indicating the SET pathway is thermodynamically unfeasible, which further supports the rationality of activation of PPh 3 by excited state photosensitizer [72][73][74][75] .With the proposal of the activation of PPh 3 and thiomethyl radicals, we paid attention to the detailed reaction pathway of methyl thioesterification of carboxylic acids, especially the C(acyl)-O activation mechanism.
As shown in Fig. 4a, the combination of carboxylate anion with PPh 3 radical cation, which leads to the formation of complex 7, is exergonic by 6.9 kcal mol −1 .The calculated Mulliken atomic spin population reveals that complex 7 is a phosphorus-centred radical species as the phosphorus atom has the largest spin density (0.55).From 7, the C(acyl)-O activation can be achieved through the β-scission of phosphorus radical 7 (via TS-1), which generates the acyl radical 8 and triphenylphosphine oxide.This metal-free pathway requires an activation free energy of 17.8 kcal mol −1 .
In the presence of the nickel catalyst (Fig. 4b), nickel(I) bromide 10 can be used to stabilize the thiomethyl radical by forming a triplet thiomethyl nickel(II) complex 3 11.The corresponding singlet structure is less stable than the triplet structure by 7.8 kcal mol −1 .Subsequently, thiomethyl nickel(II) complex 3 11 can further trap the phosphorus radical 7 and forms a stable doublet nickel complex 12.As shown in Fig. 4b, most of the spin is located at the nickel centre (0.97).Moreover, natural population analysis (NPA) of 12 reveals that the NPA charge of the [Br-Ni-SMe] fragment is −0.97.These results support that the metal centre in complex 12 is nickel(I).We surmise that the SET between thiomethyl nickel(II) complex and phosphorus radical 7 can occur rapidly, thereby resulting in the single-electron reduction of nickel(II) to nickel(I).The energy barrier of the SET 76 between thiomethyl nickel(II) complex and phosphorus radical 7 is only 0.9 kcal mol −1 (Supplementary Section 7), which verifies the facile single-electron reduction of nickel(II) to nickel(I) can occur rapidly.Considering the free energy of nickel(I) complex 12 with respect to 10 is -26.0 kcal mol −1 , we can conclude that the successive trapping of thiomethyl radical and phosphorus radical using nickel(I) bromide 10 is thermodynamically feasible and irreversible.
From 12 (Fig. 4b), the C(acyl)-O activation can be achieved through the C-O oxidative addition to the nickel(I) centre (via TS-2).The activation free energy is 9.9 kcal mol −1 , which is 7.9 kcal mol −1 lower than that of TS-1 in the metal-free C(acyl)-O activation pathway.Subsequent C-S reductive elimination from the acyl nickel(III) complex 13 (via TS-3) is demonstrated to be a barrier-less step.The final ligand exchange with two molecular PPh 3 can release the thiomethyl ester product 3 and regenerate the nickel(I) bromide 10.Besides the metal-free and two-electron oxidative addition mechanisms for C(acyl)-O activation, Ni(I)-mediated radical C(acyl)-O activation mechanism has also been considered in DFT calculation (Fig. 4c).An open-shell singlet transition state TS-4 containing a three-membered cyclic core structure was located.Vibrational frequency calculation and intrinsic reaction coordinate calculation of TS-4 suggest that this process is analogous to nickel(I)-mediated β-scission of phosphorus radical.However, the higher activation free energy (26.2 kcal mol −1 ) indicates this radical pathway is disfavoured.Therefore, the radical methyl thioesterification of carboxylic acids prefers to occur through successive radical trapping with nickel(I) complex, C(acyl)-O oxidative addition, and C-S reductive elimination.The nickel catalyst plays a critical role in tuning the stability and reactivity of different radical species and promoting the C(acyl)-O activation.

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https://doi.org/10.1038/s44160-023-00353-zacids further demonstrate the functional group tolerance of this radical approach (68, 71 and 72, 46-80% yields).γ-Amino acids could also be successfully reacted, and formed the desired product in 55% yield (73), which shows the compatibility of this method with a wide range of amino acids.

Application of product
We next turned our attention to the potential applications of thiomethyl esters (Supplementary Section 9).Compound 61 was submitted to the conditions presented in reported work and provided other valuable compounds [77][78][79] .For examples, 96% yield of compound S-76 could be generated via decarbonylation of compound 61.In addition, alkynylation (S-77, 62% yield) and boronation (S-78, 92% yield) were also successfully achieved using compound 61 as coupling partner, demonstrating that thiomethyl esters are functional synthetic precursors in a series of chemical transformations.

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https://doi.org/10.1038/s44160-023-00353-zvarious drugs and amino acids were successfully functionalized using this system.The facile scalability and the synthetic utility of this radical protocol were demonstrated by the gram-scale synthesis and application of products, respectively.Mechanistically, the successful amalgamation of photoinduced ET, energy transfer and nickel catalysis plays an essential role in this two-component radical deoxysulfurization.Therefore, we anticipate that this combination of multiple catalytic systems would have diverse applications in synthetic chemistry and beyond.

2 Fig. 3 |
Fig. 3 | Mechanistic investigations for the synthesis of thiomethyl esters by this protocol.a, Stern-Volmer fluorescence quenching analysis.b, Radical inhibitor and probe experiments.c, Control experiments.d, Comparison of various triplet sensitizers.e, Transient spectroscopy of [Ir-F].f, Transient rings were introduced in this protocol, and delivered the corresponding products in 60-85% yields.The successful reactions of other β-amino

Fig. 4 |
Fig. 4 | DFT studies for this photochemical nickel-catalysed synthesis of thiomethyl esters.a, Metal-free C(acyl)-O activation through the β-scission of phosphorus-centred radical 7. b, Free energy profile of Ni-promoted radical methyl thioesterification of carboxylic acids.c, Ni(I)-mediated C(acyl)-O activation in phosphorus radical 7. The purple numbers denote the Mulliken

| Development of a strategy for the synthesis of thiomethyl esters. a, Representative
, would react with a nickel catalyst