Decarboxylative thiolation of redox-active esters to free thiols and further diversification

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.

internal alkenes are tolerated in the reaction. The product alkyl thiols can be easily converted into other sulfur containing compounds by established reactions. A reasonable mechanism is proposed based on preliminary quenching studies. The manuscript provides a potentially useful addition to the growing class of redox-active ester decarboxylative thiolation reactions. Access to alkyl thiols without deprotection may have value to end-users in certain cases.
The manuscript title, abstract, and introduction discuss the reaction in the context of "diversityoriented synthesis" and drug discovery. The paper describes a functional group interconversion on relatively simple substrates. In my opinion there is no direct connect to these fields, or at least not any more than prototypical functional group interconversions. The products generated have little structural diversity compared to modern pharmaceuticals or lead compounds. The introduction provides almost no context on the state-of-the-art in thiolation. The authors state SN2 reactions have limitations, however these limitations can be overcome by SN1 processes, epoxide opening reactions, Mitsonobu reactions, or conjugate thiolations (among others). In this light, the introduction, framing of the work, and referencing should be significantly revised.
In terms of the merit of the work with respect to thiolation and decarboxylation methodology, my opinion is the work is not suitable for publication in Nature Communications. The scope of substrates examined is narrow. Poor yields for tertiary substrates are observed for non-biased substrates. The strategy for acid activation and capture is well established. Due to the technical nature of the advance this manuscript reports, it is better suited for publication in a journal such as Org. Lett. or Chem. Eur. J.
Reviewer #3 (Remarks to the Author): In this work, Liao and coworkers developed a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox active esters to free thiols is developed based on the abundant carboxylic acid feedstock, and the arylthioamides have been identified as an effective sulfur donor and crucial to this thiolation reaction. Importantly, this transformation provides a convenient and green channel for the preparation of free thiols and could be further in-situ diversification allows for a rapid and general access to various pharmaceutically compounds such as sulfide, disulfide, thiocyanide, and thioselenide. However, there are still some issues that need to be resolved before being published. Therefore, I recommend this manuscript publish in nature commucation after minor revised are needed.
1. For different activities of sulfur donors, the author should give corresponding explanations. 2. In Figure 2, the yields of some free thiols products are relatively low, what's the main byproduct? 3. If the carboxylic acid is used directly as the starting material, the corresponding product can be obtained by decarboxylation thiolation, or can the "one-pot" method be used to achieve this transformation? 4. Based on the speculated reaction mechanism, which step is the rate-determining step? 5. The "RSC Adv. 2016,6, 70335" should be cited in mechanism proposed. 6. The "J. Org. Chem. 1962, 27, 93-95" should be cited in introduction. 7. The figure S 7-9 should be provided the stern-volmer plots.

Dear Reviewers,
We have revised the manuscript and supplementary information accordingly. Thank you very much for the comments and suggestions. Below are our point-by-point responses: Reviewer #1: Liao and co-workers described the invention of a visible light-mediated decarboxylative thiolation of alkyl redox-active esters to free thiols under the concept of diversity-oriented synthesis. The decarboxylative access to free thiols under a photoredox radical conditions is a challenging reaction. The optimization of the reaction was focused on choice of sulfur donor, and good yield was finally achieved under mild reaction conditions by suppressing the competing formation of hydrodecarboxylation products. The reaction scope is wide with primary, secondary, and tertiary acids, and the yields are reasonable good. The transformation of natural carboxylic acids and drugs to thiols was also demonstrated. The authors further extended the method to the synthesis of disulfides, sulfides, thiocyanide, thioselenide via in-situ trapping of the free thiols. Based on control experiments, fluorescence titrations, and key intermediate trappings, a plausible mechanism was proposed. The decarboxylative thiolation of alkyl redox-active esters to free thiols is new. In fact, the transformations of carboxylic acids to disulfides, thiocyanide, and thioselenide etc. demonstrated in this paper are also new methods. In my opinion, this work can attract considerable interest as 1) the visible-light mediated decarboxylative transformation is a very hot research area, and 2) the method affords a new and useful method for the thesis of various important sulfur-containing compounds with diverse structure, which could be of interest to labs of chemical biology and drug discovery. Overall, this work represents a new and significant contribution to both areas of photo-induced decarboxylative transformations and thiol/thiol-derivative synthesis. The authors lay out a well-organized paper that defines the challenges, significances, and advances clearly, and the conclusion is well supported by the results. I am therefore supportive of publishing this paper in Nature communication after minor revisions. Figure 1A, in the structure of Rpn13, the thiol group (-SH) is disconnected from the protein. It can be shown as yellow dot (?): -SH, as I saw there are several thiol residues in this protein.

1)
Response: Thank you very much for the comments and suggestion. We have added an arrow to indicate the thiol group. Please see the revised Fig. 1 A. 2) In the substrate scope, reactions of 34 and 40 were performed in CF3CH2OH rather than CH3CN, any comment on choosing this solvent? Response: For these cases (some tertiary acids), a higher thiol/alkane ratio were observed in CF 3 CH 2 OH than that in CH 3 CN, and thus led to slightly better yields. However, in cases of primary and secondary carboxylic acids, using alcoholic solvents led to the some hydrolysis (alcoholysis) of redox active esters and decreased the yield. We have added a comment on these results in the revised manuscript.
3) The reviewer believes that the novelty and the establishment of this transformation could already ensure this paper to be published in a top journal, but still curious about the mechanism: a) what happened without adding DIPEA or with an inorganic base instead of DIPEA? b) how fast is the trapping by sulfur donor or active sulfur-species? May run a reaction with acrylates for comparison, which are often used as Michael acceptors in radical addition reactions. Response: Without adding DIPEA, lower yield was obtained (please see Supplementary Table 3). With an inorganic base, such as K 2 CO 3 , the decarboxylative thiolation could also proceed, but with a lower yield (68%). We observed some disulfide formation. As suggested, we performed a competing experiment with butyl acrylate (2.0 equivalents) as shown below. We found 3 and compound 1 were obtained as the major products, and only a trace amount of compound 2 was detected by GC-MS, which suggests that the rate of trapping by sulfur donor is faster than this Michael acceptor in the radical addition step. We have added these results in the revised Supplementary Information (Supplementary Table 3 & Scheme 1). Many thanks for the suggestion.

Reviewer #2:
In this manuscript Liao and co-workers report a method for the conversion of hydroxyphthalimide-derived alkyl esters to alkyl thiols. The reaction is promoted by a simple photoredox catalysts (Eosin Y) using blue LED irradiation and benzothioamide sulfur donor. A series of simple alkyl esters are demonstrated to undergo the reaction. Esther, aryl bromide, terminal alkyne, and internal alkenes are tolerated in the reaction. The product alkyl thiols can be easily converted into other sulfur containing compounds by established reactions. A reasonable mechanism is proposed based on preliminary quenching studies. The manuscript provides a potentially useful addition to the growing class of redox-active ester decarboxylative thiolation reactions. Access to alkyl thiols without deprotection may have value to end-users in certain cases.
The manuscript title, abstract, and introduction discuss the reaction in the context of "diversity-oriented synthesis" and drug discovery. The paper describes a functional group interconversion on relatively simple substrates. In my opinion there is no direct connect to these fields, or at least not any more than prototypical functional group interconversions. The products generated have little structural diversity compared to modern pharmaceuticals or lead compounds. The introduction provides almost no context on the state-of-the-art in thiolation. The authors state SN2 reactions have limitations, however these limitations can be overcome by SN1 processes, epoxide opening reactions, Mitsonobu reactions, or conjugate thiolations (among others). In this light, the introduction, framing of the work, and referencing should be significantly revised.
In terms of the merit of the work with respect to thiolation and decarboxylation methodology, my opinion is the work is not suitable for publication in Nature Communications. Thank you for your time on evaluating this manuscript, suggestion and understanding.
Reviewer #3: I In this work, Liao and coworkers developed a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox active esters to free thiols is developed based on the abundant carboxylic acid feedstock, and the arylthioamides have been identified as an effective sulfur donor and crucial to this thiolation reaction. Importantly, this transformation provides a convenient and green channel for the preparation of free thiols and could be further in-situ diversification allows for a rapid and general access to various pharmaceutically compounds such as sulfide, disulfide, thiocyanide, and thioselenide. However, there are still some issues that need to be resolved before being published. Therefore, I recommend this manuscript publish in nature commucation after minor revised are needed.