Sulfenamide-enabled ortho thiolation of aryl iodides via palladium/norbornene cooperative catalysis

Poly-substituted aromatic sulfur compounds are widely found in pharmaceuticals, agrochemicals and organic materials. However, the position that a sulfur moiety can be introduced to is largely restricted to a pre-functionalized site; otherwise, use of electronically biased substrates or auxiliary groups that direct catalysis is required. Here we report a general ortho thiolation of common aryl and heteroaryl iodides via palladium-norbornene cooperative catalysis. Using this approach, an aryl or alky sulfur moiety can be site-selectively introduced at the arene ortho position without using sterically or electronically biased substrates. The arene ipso functionalization is simultaneously achieved through Heck, Suzuki or Sonogashira termination. The reaction is enabled by a unique class of electrophiles in palladium-norbornene cooperative catalysis, which are sulfenamides derived from seven-membered lactams. The broad substrates scope and high chemoselectivity could make this method attractive for synthesis of complex sulfur-containing aromatic compounds.

1. In support information, page S3, entrys 6-7. The reaction of ligand is extremely harsh. When triphenylphosphine derivatives were used as ligands, the yield of the product was only 2-3%. Therefore, readers may be interested in the effects of more electron-rich ligands and Buchwald ligands, such as P(Cy)3, P(tBu)3HBF4 and X-Phos.
2. Heck reaction is very valuable as the terminal proccess of Catellani reaction, but the scope of olefin substrates is relatively narrow. Can styrene derivatives be used as substrates for termination process?
3. Please unify the all template of MestReNova in support information (NMR Spectrum). For example, the chemical shifts on page S41 are black and they are blue on page S52. 4. The author is inspired by the carbonyl group in the leaving group (benzoic acid) of the orthoamination reagent. ACS Catal. 2018, 8, 12, 11827-11833 describes the coordination mode of leaving group and palladium after ortho-amination and it should be cited.
Reviewer #2 (Remarks to the Author): Dong and co-workers described a novel Pd/norbornene-catalyzed ortho-C-H thiolation of aryl and heteroaryl iodides for the facile preparation of polysubstituted aromatic sulfur compounds. This transformation was enabled by a new class of sulfenamide electrophiles derived from sevenmembered lactams, which was designed based on inspiration from their previous research on ortho-C-H aminations. Interestingly, it's found that the bulky substituent around the nitrogen of the sulfenamides can significantly enhance the thiolation efficiency, which was owing to the elongated N-S bond as revealed by X-ray crystallographic analysis. This ortho-C-H thiolation is compatible with various ipso functionalization, including Heck, Suzuki or Sonogashira termination. This scalable procedure has broad substrate scope and high chemoselectivity, which make it attractive for synthesis of diversified sulfur-containing aromatic compounds, including aryl sulfoxides and sulfones (via a following selective oxidation). Thus, this work represents important progress in the development of new Catellani-type reactions. The SI is of good quality for the characterization of new compounds.
The reviewer has also noticed that a related work by Gu was recently published in Org Lett. (DOI: 10.1021/acs.orglett.9b00923). However, this doesn't dilute the novelty of this work considering the completely different thiolation reagent used and the much broader scope of aryl iodides and termination methods. Therefore, I recommend the publication of the present manuscript in Nature Communications after addressing the following minor points.

1.
The aforementioned manuscript by Gu should be cited and discussed in the main text.

2.
The authors may think about recycling the cyclic amide product to regenerate the thiolation reagent, which will be attractive especially for large scale opearation.

3.
The gram-scale preparation procedure of 5n should be included in SI 4. The quality of NMR spectra of compounds 4i-j and 4l should be improved.
Reviewer #3 (Remarks to the Author): Recommendation: Publish after minor revisions noted. Comments: Dong, Dong and co-workers discovered a new type of electrophiles (t-butyl-substituted sulfenamide) to realize ortho thiolation of aryl and heteroaryl iodides in Catellani reaction. The substituent effect was observed in tuning the sulfonamide reactivity: bulky substituent around the nitrogen can significantly enhance the electrophilicity of the sulfenamides. This manuscript presents a useful strategy to synthesize sulfur-containing aromatic compounds from simple aryl iodides and sulfonamides. The products were well characterized. I would like to suggest this manuscript publish in Nature Communication after minor changes.
1) Did the authors try to use other more bulky substituents on sulfonamide except ipr and tBu?
2) It is interesting to note that, ortho-unsubstituted aryl iodides must be used the current methodology. Thus, how about using ortho-unsubstituted aryl iodide in the reaction?
3) Did the authors try to use 5 mol% of palladium sources? I would suggest the authors give this information in SI, even it gave low conversion. The suggestions and comments from the three reviewers have been well received and appreciated. Here are our responses to these constructive comments:

4) Some important references which using new types of electrophilic reagents in the
1. Re: referee 1 (a) Original comments: "In support information, page S3, entrys 6-7. The reaction of ligand is extremely harsh. When triphenylphosphine derivatives were used as ligands, the yield of the product was only 2-3%. Therefore, readers may be interested in the effects of more electron-rich ligands and Buchwald ligands, such as P(Cy)3, P(tBu)3HBF4 and X-Phos." This is a great suggestion. In the revised SI (Supplementary Table 1), the results of using more electron-rich ligands, such as P(Cy)3, P(tBu)3HBF4 and XPhos, have been added into the table of the control experiments.

(b) Original comments: "Heck reaction is very valuable as the terminal proccess of Catellani reaction, but the scope of olefin substrates is relatively narrow. Can styrene derivatives be used as substrates for termination process?"
We appreciate this excellent suggestion. The use of styrene as the termination reagent has been attempted. Unfortunately, the reaction only gave a complex mixture with trace product. In the revised SI, we added a Supplementary Figure (9) of "Less successful and Unsuccessful Substrates" to clarify the limitation of the reaction scope.
(c) Original comments: "Please unify the all template of MestReNova in support information (NMR Spectrum). For example, the chemical shifts on page S41 are black and they are blue on page S52." We also appreciate this suggestion very much. The template of the NMR spectra has been unified in the revised SI.
(d) Original comments: "the author is inspired by the carbonyl group in the leaving group (benzoic acid) of the ortho-amination reagent. ACS Catal. 2018, 8, 12, 11827-11833 describes the coordination mode of leaving group and palladium after orthoamination and it should be cited." We fully agree with the reviewer's suggestion. The aforementioned paper has been cited as ref 30.