New Class of Electrophiles in Palladium/Norbornene Cooperative Catalysis: Sulfenamide-Enabled Ortho Thiolation of Aryl Iodides

Renhe Li1, Yun Zhou1,2, Ki-Young Yoon1, Zhe Dong3* and Guangbin Dong1* 1Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States 2Department of Applied Chemistry, China Agricultural University, Beijing 100193, China 3 Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544 (USA)

*Correspondence: [email protected] (Z. D.), [email protected] (G. D.)

Dedicated to Professor Mark Lautens on the occasion of his 60th birthday

Abstract: To expand the synthetic platform of the palladium-norbornene cooperative catalysis, here we report a general ortho thiolation of aryl and heteroaryl iodides using sulfenamides as a new class of electrophiles. The sulfenamides derived from a ε-tbutyl-lactam were found most efficient to introduce various aryl and methyl sulfur groups at the arene ortho position. The ipso functionalization is achieved through Heck or Suzuki termination. This reaction also provides a convenient access to the corresponding aryl sulfoxides and sulfones via selective oxidation of the ortho thiolation products.

Palladium/norbornene (Pd/NBE) cooperative catalysis,1 originally discovered by Catellani,2 has emerged as a useful tool for preparing polysubstituted arenes.[3] Compared to the conventional arene functionalization, this approach enables simultaneous functionalization of arene vicinal positions regioselectively using simple aryl halides as substrates (Scheme 1a). Specifically, through forming an aryl-NBE-palladacycle (ANP) intermediate, a nucleophile and an electrophile are coupled at the arene ipso and ortho positions, respectively. While the scope of nucleophiles in this reaction is broad,1 finding suitable electrophiles that can participate in the Catellani reaction nevertheless remains a formidable challenge,1f,4 because the electrophile must react with ANP selectively in the presence of Pd(0) species and has to be compatible with the nucleophile and NBE. Currently, the scope of electrophiles is mainly limited to carbon5 and nitrogen6-based reagents. In 2017, the Yu group used aryl chlorosulfates for a directed Pd(II)-catalyzed meta chlorination of arenes;7 however, compatibility of this reagent with Pd(0) catalysts could be a concern.8 More recently, Zhang9 and Cheng10 independently reported an interesting ortho silyation with disilanes; unfortunately, NBE cannot be extruded in this reaction. Hence, it would be attractive if a new element, besides C and N, could be introduced at the arene ortho position in the Pd(0)- catalyzed Catellani reaction.

Stimulated by this challenge, we turned our attention to the use of sulfur-based electrophiles. Aromatic sulfur compounds are commonly found in drugs (Scheme 1b)11 agrochemicals,12 organic electronics13 and polymers14. Aryl sulfides often serve as versatile intermediates to access the coresponding sulfoxides,15 sulfones16 and benzothiophenes.17 Common ways to prepare aryl sulfides heavily rely on nucleophilic aromatic substitution18 and cross-coupling reactions19 between aryl halides and thiols. Both methods form C−S bonds at the ipso position of aryl halides; thus, the position of the installed sulfur moiety is restricted by the position of the halide. On the other hand, C−H thiolation offers an attractive approach to prepare aryl sulfides from unactivated arenes;20 however, control of site-selectivity generally requires use of directing groups21 or electron-rich arenes.22 Herein, we describe an alternative method for regioselectively preparing functionalized aryl sulfides via Pd/NBE-catalyzed ortho thiolation of aryl iodides, which is enabled by a new class of sulfenamide electrophiles (Scheme 1c).

Scheme 1. Pd/NBE cooperative catalysis. Eneg: electronegativity.

Compared to other ortho functionalizations, ortho thiolation exhibits its unique challenges. First, many electrophilic sulfur based compounds, such as PhSSPh or PhSCl, readily react with Pd(0),23 therefore preventing arene functionalization. Second, thiolates (RS-) are known as strong ligands for soft Pd species; thus, decomposition of the thiolating agent would likely generate RS- that could lead to direct ipso thiolation.24 Hence, developing a stable but also reactive electrophilic thiolating agent would be a key for realizing the ortho thiolation reaction. Based on our prior efforts on developing the ortho amination reaction,6 sulfenamides25 were anticipated to be a suitable electrophile for the Pd/NBE catalysis for two reasons (Scheme 1d): 1) the electronegativity (Eneg, Pauling scale) difference between N and S matches well with that between O and N;26 2) analogous to the ortho amination, the amide carbonyl could serve as a directing moiety to facilitate selective reactions with ANP. Thus, we hypothesized that sulfenamides could show similar stability and reactivity as O-benzoyl hydroxylamines.

To test our hypothesis, a range of sulfenamide-based thiolating agents were examined with 2-iodotoluene (1a) as the standard substrate, and the ipso position was functionalized via Heck termination with acrylate 2a (Table 1). As a control experiment, PhSSPh S1, previously used in Pd-catalyzed C−H thiolation,21a,21b gave almost no desired product with a low conversion of 1a. In contrast, various sulfenamides indeed afforded the desired ortho thiolation product (4a). First, neither imide- or amine-derived sulfenamides (S2 and S3) were as effective as amide-based ones. In particular, the lactam-derived sulfenamides (S11-S20) were found most reactive. Interestingly, the six, seven and eight-membered sulfenamides (S12-S14) gave significantly improved yields compared to the five-membered one (S11). Use of more strained or benzofused lactams (S15-S18) gave inferior results. Surprisingly, increasing the bulkiness around the lactam nitrogen with an adjacent isopropyl group significantly enhanced the yield (S19). Ultimately, the optimal result was obtained using the t-butyl-substituted sulfenamide S20.

Table 1. Thiolating Reagents effect on Pd/NBE-catalyzed ortho thiolation of aryl iodide.a

a Unless otherwise noted, the reaction was run with 1 (0.15 mmol), 2 (0.30 mmol), sulfur electrophile (0.30 mmol), Pd(OAc)2 (0.015 mmol), P(2- furyl)3 (0.0375 mmol), NBE (0.075 mmol), Cs2CO3 (0.30 mmol) and CuTC (0.03 mmol) in ethyl acetate (3.0 mL) at 105 °C for 12 h. The yield was determined by 1H-NMR using 1,3,5-trimethoxylbenzene as the internal standard. CuTC: Copper(I) thiophene-2-carboxylate.

To understand these counterintuitive results in terms of the role of the bulk substituent, X-ray crystal structures of S11-S14, S19 and S20 analogue (3c)27 were obtained (Figure 1).28 A clear trend is that increasing the steric hindrance around the amide moiety elongated the N−S bond, which correlates to the performance of these reagents. Hence, the t-butyl group in S20 weakened the N−S bond, thereby making it more reactive. It is noteworthy that adding copper(I) thiophene-2-carboxylate (20 mol%) enhanced the yield, which may serve as a thiolate scavenger (for full control experiments, see supporting information Table S1).

Figure 1. X-ray structures of representative sulfenamides.

Table 2. The aryl iodide scope of the ortho thiolation.a

aAll reactions were run on a 0.20 mmol scale. With the optimized conditions in hands, the aryl iodide scope was examined first. Different substituents at the ortho position of aryl iodides were tolerated, including methyl (4a), methoxy (4b), MOM ether (4c), 4- bromobenzyl ether (4d), acetate and silyl-protected benzyl alcohols (4e and 4f) and an estrone derivative (4g). In addition, a broad range of functional groups, such as aryl chloride (4h), aryl bromide (4i), Weinreb amide (4j), dialkyl aniline (4k), carbamate (4l), fluoride (4m) and Vitamin E moiety (4n). Importantly, the reaction is suitable for a variety of heteroarenes and polycyclic arenes, including quinoline derivative (4o, 4p), indole (4q), thiophene (4r), naphthalene (4s), phenanthrene(4t) and pyrene (4u).

Next, the scope of the thiolating agents and the olefin coupling partners was explored (Table 3). Besides PhS-, other aryl sulfur groups that contain electron-donating or withdrawing groups could be introduced at the ortho position in good to excellent yields. Notably, the ortho-substituted aryl sulfide (5h) still afforded a high yield of product. While it was challenging to prepare the corresponding alkyl thiolating agents based on the tBu-substituted lactam, use of simple ε-lactam-derived sulfenamide 6 nevertheless delivered the desired methylthiolated product (5k) in moderate efficiency. In addition to tBu acrylate, other acrylates and acrylamides (5l-5o) were also competent coupling partners for ipso functionalization.

Table 3. The sulfenamide and olefin scope of the ortho thiolation.a

aAll reactions were run on a 0.20 mmol scale.

The reaction is scalable: a high yield was still obtained on a gram scale (Eq. 1). Besides aryl sulfides, the corresponding sulfoxides and sulfones could be conveniently accessed through selective oxidation of the ortho thiolation product (Scheme 2). In addition to Heck coupling, preliminary success was obtained with Suzuki quenches to install an aryl group at the ipso position (Eq. 2).

Scheme 2. Access to sulfoxides and sulfones.

In summary, a new class of electrophiles, sulfenamides, is discovered for the Pd/NBE catalysis, which enables ortho thiolation of a wide range of aryl and heteroaryl iodides. The broad substrate scope and high chemoselectivity could make this method attractive for complex molecule synthesis. The substituent effect observed in tuning the sulfenamide reactivity could have implications beyond this work. Efforts on expanding the reaction scope and understanding the detailed mechanism of the C–S bond formation are underway.

Acknowledgements

Financial supports from the University of Chicago and NIGMS (1R01GM124414-01A1) are acknowledged. Z.Y. is supported by a CSC fellowship. We thank Mr. Jianchun Wang for helpful discussions.

Keywords: thiolation • sulfenamide • sulfide • palladium/norbornene catalysis • arene functionalization

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27. All attmepts to crystallize S20 are not successful at current stage.

28. CCDC: 1906766 (S11), CCDC: 1906767 (S12), CCDC: 1906768 (S13), CCDC: 1906770 (S14) CCDC: 1906771 (S19),CCDC: 1906769 (3c) and CCDC 1906772 (4e) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the CambridgeCrystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.