Multiple C-H Activation Enabled Modular Construction of Densely Functionalized Sulfur-Contained Arenes
Modular construction of multiple functionalized arenes from abundant feedstocks, stands as an unremitting pursue goal in synthetic chemistry, which would accelerate the discovery of new drugs an advanced materials. Herein, by using multiple C-H activation strategy, through judicious choice of versatile imidate ester as the key directing group, expedi-ent delivery of molecular libraries of densely functionalized sulfur-contained arenes. Further synthetic application was demonstrated by multiple C-H modification of fused arenes and pharmaceuticals such as Ibuprofen, and concise con-struction of biologically active molecules, Madam dihydrochloride and Bipenamol, was also achieved.
Introduction<!>Results and discussion<!>Scheme 5. Concise construction of sulfur contained molecular libraries via C-H activation.<!>Scheme 8. Synthetic applications.<!>Conclusions<!>Conflicts of interest<!>A. General information-----------------------------------------------------------------------S2<!>E. Analytical data for the obtained products-<!>S3<!>Synthesis of multiple functionalized thioethers 5:<!>4) General procedure for the synthesis of ortho-thioether aryl nitriles 8:<!>5) General procedure for the synthesis of thioethers 9:<!>Synthetic applications 1) Sequential C-H sulfenylation and C-H arylation: synthesis of dibenzo[b,d]thiophene-4-carbonitrile 15<!>Synthesis of intermediate 17:<!>Synthesis of Bipenamol 18:<!>D. Preliminary mechanism studies:<!>Figure S9. Conversion of 9a to 8a<!>4-Iodo
<p>The exploration of rapid construction of poly-functionalized molecules in concise manner, provided a new arena for advanced materials and drugs discovery. In this context, expedient delivery of densely substituted arenes, which serve as one most frequently occurred structural skeletons in chemical community, held great synthetic promise in various field. 1 Towards this end, catalytic cascade reaction, such as Catellani-type reaction, using aryl halides or borons, has emerged as one reliable strategy for quick access to molecular complexiety. 2  In pursuing for practicality of the overall process, multiple C-H activation which features step-economy and would provide new retro-synthetic insight, would be highly desirable for the direct introduction of multiple functionality into molecules. However, formidable challenges 3 (Scheme 1) remained in this field although C-H activation has been witnessed great advancement in the past decades: 1) elusive control of site-selectivity, which often led to the formation of difunctionalization byproducts; 2) coordinative saturation, and thus, deactivation of metal catalyst, might be observed, which derived from the intrinsic directing group and the first introduced functionality; 3) moreover, steric and electronic influence, caused by the first C-H functionalization intermediate.</p><p>To increase the synthetic utility of the overall process, the use of weak coordination directing groups, which are readily available and transformable groups, would be also beneficial for the second C-H activation process. 4 With the above principle in mind, herein, we developed a multiple C-H activation strategy enabled polysubstituted arenes delivery, by using easily modifiable imidate ester as the key directing group. The synthetic application of this transformation was demonstrated by late-stage modification of materials and pharmaceuticals via multiple C-H activation, and enabled concise construction of Bipenamol and key structural skeletons of biologically active molecules. Considering the synthetic versatile nitrile and thioether functionality, this transformation would serve as one arsenal for the modular construction of molecular libraries of multiple functionalized arenes.</p><!><p>To commence our study for the concise construction of densely functionalized arenes via multiple C-H activation, in our continuous research endeavor towards weak coordination enabled C-H activation, 5 readily available and modifiable imidate esters were selected, which has demonstrated to be traceless directing groups in C-H activation. This multiple C-H activation cascade was inspired by our initial finding that switchable selectivity in C-H sulfenylation 6 was observed that nitrile substituted aryl thioether 8a was obtained when using Cu(II) salt as the additive under Rh(III) catalysis, 7 while thioether product 9a was obtained as the major product with imidate ester remained intact (Scheme 2). Notably, when conducting this multicomponent reaction by successive addition of imidate 1, disulfide 3 and styrene 2, led to no desired multiple C-H activation product 4, 8 while only C-H sulfenylation product 8n was obtained as the major product. It was speculated that this transformation might proceed via C-H activation of aryl imidate esters, affording to the 5membered rhodacycle A, which assisted the generation of C-H sulfenylated product 9b by addition of electrophilic disulfide 3. Further interaction of thioether and intrinsic imidate imidate group led to the over-coordination of the rhodium catalyst, and thus, no catalytic reactivity of Rh(III) species B was exhibited when further addition of styrene 2 into the standard conditions. Finally, ortho thioether substituted aryl nitrile product 8n was obtained, with the treatment of base to the intermediate 9b or B. Scheme 2. Imidate esters enabled multiple C-H activation.</p><p>The above observations encourage us to investigate this multiple C-H activation cascade in details, as summarized in Table 1, Rh(III) exhibited optimal result for the poly-functionalized arenes 4 delivery, with the assistance of Cu(II) salt. Further investigation of reaction conditions indicated that Ru(II) could also serve as the catalyst, albeit in moderated yield (entry 2), while Ir(III), Pd(II) and Ni(II) complexes showed no catalytic activity for this multiple C-H activation (entries [3][4][5]. Control experiments indicated that Rh(III) catalyst, AgNTf played pivotal roles in this multiple C-H activation cascade, and only trace amount of poly-substituted arene product 4a was obtained without them (entries 6-7). Dramatic decreased efficiency was observed in the sequential C-H activation, when N-Boc-L-Leu-OH was replaced by HOAc or PivOH (entries 8-9). Cu(II) salt was also crucial for this transformation, since no desired product 4a was isolated in the absence of it, and only trace amount of 4a was isolated when using molecular oxygen as the terminal oxidant (entries 10-11). Intriguingly, when direct use of phenthiol instead of disulfide 3a in this transformation (entry 12), the desired product could also be obtained. Lower the reaction temperature was detrimental for the formation of the multiple functionalized arene product 4a. When using acetone or t BuOH as the solvent instead of DCE, only trace amount of product 4a was obtained (entry 14). Notably, other common directing groups such as ketone (1a-1), ester (1a-2), amide (1a-3),  exhibited no catalytic efficiency in this multiple C-H activation reaction.  With the optimal condition in hand, we further explored the substrate scope in this multiple C-H activation for the production of poly-functionalized arenes 4 (Scheme 3). Intriguingly, further exploration of this sequential C-H activation revealed that when using Ag(I) instead of Cu(II) salt in multiple C-H activation, polyfunctionalized arene product 5 were obtained, with imidate ester functionality remained intact. Further assessment of substrates indicated that an array of aryl imidate esters, including methyl (4e, 5f), methoxyl (4f), fluoro (4c) and chloro (5c) substituents, could be compatible. For disulfides coupling partners, substituted aryl disulfides (4a, 4b) including poly-substituted (5b), and even steric hindered disulfides (5a) could well participate in this sequential C-H activation. Olefins (4a, 4d) including halides substituted styrenes (5d, 5e) could serve as suitable substrates, which provide opportunity for further decoration of the obtained densely functionalized products via cross-couplings.</p><p>Inspired by above results, we are delighted to find that sequential introduction of C-C double bond and heterocycles could be achieved via multiple cross-dehydrogenative coupling (CDC) strategy (Scheme 4-3). 9 With the assistance of PivOH under Rh(III) catalysis, two C-C bonds were constructed through sequential aryl C-H/alkenyl C-H bond and aryl C-H/heteroaryl C-H bond activation, affording to multiple functionalized arenes. Thiophenes (7a), benzothiophenes (7b) could act as suitable electron-rich heterocycles, and participate in this multiple cross-dehydrogenative coupling smoothly. Notably, biaryl nitriles were widely used liquid crystal materials, and considering the readily transformable functionality contained in the products, this methodology could provide an expedient procedure for rapid construction of molecular libraries of multiple functionalized arenes, which might find synthetic value in pharmaceuticals, agrochemicals and material science.</p><p>Multiple functionalized sulfur-contained molecules 10 serve as key skeletons occurred in pharmaceuticals, pesticides and advanced materials (Scheme 5), which have stimulated continuous research endeavor towards their concise delivery. Of note, Ullmann-type reaction that utilized aryl halides with sulfenylation reagents under metal, photo-and electronic catalysis, has been demonstrated to be a reliable tactics. Direct C-H sulfenylation has emerged as one promising strategy for the selective introduction of S-contained functionality, nevertheless, the use of readily available and transformable directing group would facilitate rapid construction of functionalized sulfur molecular libraries.</p><p>Herein, divergent C-H sulfenylation with tunable selectivity was achieved, assisted by versatile imidate esters, which enabled modular construction of S-containing molecular libraries. Great functional group compatibility of this transformation enabled latestage modification of bioactive molecules and advanced materials, significantly, expedient construction of pharmaceuticals, such as bipenamol and key skeleton of madam, were also achieved.</p><!><p>With the optimal condition for this tunable C-H sulfenylation with readily transformable imitates, 11 we first explored the synthetic generality for the production of 1,2-thiobenzonitriles, 12 and great functional group tolerance was exhibited (Scheme 6). Widely used functionality in pharmaceuticals and materials, such as fluoro (8b) and trifluoromethyl (8f), could be well tolerated. Halides including chloro (8c), bromo (8d), and even iodo (8e), were compatible, holding great synthetic potential for further decoration of thioether products via cross-coupling reactions. Substrates bearing readily transformable groups, eg., nitro (8g), benzyl chloride (8i), and widely used as directing group, methoxyl (8h), could participate in this tunable C-H sulfenylation smoothly. Heterocycles and fused ring system could be well serve as suitable substrates in this regioselective C-H sulfenylation, notably, directing effect outcome the intrinsic electronic effect. For instance, C3-H sulfenylation of This journal is © The Royal Society of Chemistry 20xx</p><p>Please do not adjust margins Please do not adjust margins thiophene (8j), without the observation of C2-H activation product; C3-H sulfenylation of naphthalene (8k), and C6-H sulfenylation of indole (8l) took place with great regioselectivity.</p><p>For disulfides partners, both aromatic and aliphatic disulfides were suitable substrates in this regioselective C-H sulfenylation. Ester (8m), methoxyl (8o), fluoro (8p), chloro (8r), bromo (8q) were well tolerated, affording to the desired 1,2-thiobenzonitriles in good yield. Notably, no obvious steric effect was observed as for disulfides, ortho-substituted and even 2,6-disubstituted disulfides could serve as suitable sulfenylation reagents (8r, 8s, 8t). Heterocycles and fused arenes such as thiophene (8u), naphthalene (8v) substituted disulfides, could be well tolerated. Aliphatic such as benzyl (8w) and pentyl (8x) disulfides also served as suitable sulfenylation reagents. Scheme 6. Tunable C-H sulfenylation enabled by imidates.</p><p>Intriguingly, the use of Ag(I) salt under Rh(III) catalysis switched the chemoselectivity to that of Cu(II) salt, and led to formation of thioether products 9. Functional groups including fluoro (9f), chloro (9d), bromo (9c), ester (9e) were well compatible. Heteroaryl and naphthalene substituted imidate esters (9g, 9h) could also afford the desired products with good efficiency. This transformation could also enable late-stage modification of biologically active molecules, eg., plotlitazone analogue (9i).</p><p>The exploration of catalytic systems that could distinguish one specific C-H bond in complex molecules remained a formidable challenge, 13 we thus further investigated the competing coordination of multiple functionalized arenes, and imidate ester showed directing priority to ester (8y), ketone (9j) and phenol ester (8z), while N-heterocycle pyrazole overrides imidate ester (9k). Notably, site-selective C-H sulfenylation of probenecid analogue took place exclusively (8za), with C-H bonds proximal to sulfonamide and ester remained intact. This site-specific C-H functionalization of multiple functionalized arenes would provide valuable synthetic insight into late-stage modification of complex pharmaceuticals.</p><p>Further synthetic application by late-stage modification of materials and pharmaceuticals (Scheme 7) indicated that orthoselective C-H sulfenylation of 4'-(hexyloxy)-[1,1'-biphenyl]-4carbonitrile proceed smoothly (10a), which was one important liquid crystal molecule. Pharmaceuticals such as ibuprofen (10b), and natural product L-Menthol (10c) could be readily modified via regioselective C-H sulfenylation, while estrone (10d) could be well decorated with nitrile and thioether functionality. Considering the widely utility of nitriles and thioethers in biologically active molecules, this transformation might provide valuable insight into the advanced materials and new drug discovery. Scheme 7. Late-stage modification of material molecules and pharmaceuticals.</p><p>The readily transformable nitrile and thioether groups in the obtained products could serve as a versatile platform for the rapid construction of functionalized sulfur molecular libraries (Scheme 8). Benzo[b]thiophene skeleton could be readily introduced via crosscoupling of halides to give 11, oxidation of thioether afforded to diaryl sulfone 12. The versatile aryl nitrile group underwent hydrolysis to afford carboxylic acid 13, and could be easily reduced to benzyl amine 14 (Scheme 8-1). Sequential C-H activation served as a reliable arena for the expedient delivery of functionalized molecules in a selective manner, in this context, functionalized dibenzo[b,d]thiophene 15 could be accessed via a sequential imidate enabled ortho C-H sulfenylation followed by intramolecular C-H arylation (Scheme 8-2). Further synthetic utility was demonstrated by concise delivery of Madam dihydrochloride analogue 16 via ortho C-H sulfenylation with primary amine substituted disulfide (Scheme 8-3). Significantly, Bipenamol, an antidepressant, could be concisely accessed from commercial available thiosalicylic acid via ortho C-H sulfenylation of aryl imidate ester, followed by selective reduction with LiAlH4, with a total 72% yield in two steps (Scheme 8-4).</p><!><p>To shed some mechanistic insight into this transformation, some control experiments were performed (Scheme 9). Experimental observations indicated that the use of 2 equivalent of Cu(II) salt assisted the conversion of 9a to 8a, which might due to the more Lewis acidity of Ag(I) to that of Cu(II) (Scheme 9-1). Radical trapping experiments that with the addition of stoichiometric TEMPO or 1,4dinitrobenzene led to no obvious effect of the transformation between 1a and 3a to afford 8a (Scheme 9-2). Scheme 9. Mechanistic studies.</p><p>Inspired by the related precedent literature, and the experimental observation, a tentative mechanism was proposed (Scheme 10). First, with the assistance of mono-N-protected amino acid (MPAA), 6i, 14  Notably, when disulfides 3 were subjected into reaction prior to terminal olefins 2, C-H sulfenylation took place to give 9. However, the overcoordination of imidate ester and thioether group to Rh(III) led to deactivation of Rh(III) catalyst, and thus, no second C-H activation proceed. Scheme 10. Proposed Mechanism.</p><!><p>In summary, by judicious choice of versatile imidate esters as the key directing groups, multiple C-H activation was developed, leading to poly-functionalized arenes. Significantly, dual crossdehydrogenative coupling between imidate esters, terminal olefins and heterocycles, via sequential C-H activation, was also achieved under Rh(III) catalysis. The use of Ag(I) or Cu(II) salt switched the selectivity in C-H sulfenylation of synthetically valuable imidate esters, which facilitated the rapid construction of various Scontaining molecular libraries. Further synthetic application was demonstrated by late-stage modification of pharmaceuticals and advanced materials, as well as expedient construction of biologically active molecules. This sequential C-H activation strategy might provide valuable insight into expedient delivery of highly functionalized pharmaceuticals and materials.</p><!><p>There are no conflicts to declare. This journal is © The Royal Society of Chemistry 20xx</p><p>Please do not adjust margins Please do not adjust margins Technology and GDUT Analysis and Test Center for the HRMS analysis. E-mail: xwli@gdut.edu.cn</p><!><p>B. General procedure- -------------------------------------------------------------------------S3 C. Synthetic applications ---------------------------------------------------------------------S5 ------------------------------------------- --------------------------------------------------------------------------------S32 S2</p><!><p>A. General Information 1 H and 13 C NMR spectra were recorded on BRUKER DRX-400 spectrometer using CDCl3 as solvent and TMS as an internal standard. Chemical shifts for 1 H NMR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet).</p><p>Multiplicities were given as: s (singlet); d (doublet); t (triplet); q (quartet); dd (doublets of doublet); dt (doublets of triplet); dq (doublets of quartet). Coupling constants are reported as a J value in Hz. Carbon nuclear magnetic resonance spectra ( 13 C NMR) are reported as δ in units of parts per million (ppm) downfield from SiMe4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.0, triplet). Gas chromatograph mass spectra were obtained with a SHIMADZU model GCMS-QP 5000 spectrometer.</p><p>HRMS was carried out on a MAT 95XP (Thermo).</p><!><p>B. General procedure:</p><p>1) General procedure for the synthesis of arylimidates:  A round bottom flask was charged with 1% H2O2 (1 mmol) and I2 (0.01 mmol). The thiol (1 mmol) was added to the solution at room temperature with vigorous stirring. The reaction was monitored by TLC (nhexane:ethyl acetate 15:3). After the completion of the reaction, the products were filtered off and dried or extracted with ethyl acetate (3 × 5 mL). Then the combined organic phases were washed with water (2 × 4 mL), separated, and dried with anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the corresponding disulfides.</p><p>3) General procedure for the three component synthesis of multiple functionalized thioethers: synthesis of multiple functionalized thioethers 4:</p><p>An oven-dried 10 mL Schlenk Tube was charged with imidates 1 (0.1 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008 mmol), N-Boc-L-Leu-OH (15 mol%) and in sequence, followed by addition of terminal alkenes 2 (0.15 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h. And then, Cu(OAc)2·H2O (2.0 equiv.), disulfides 3 (0.15 mmol) in DCE (0.5 mL) was inserted into the reaction system through syringe for another 12 hours. After that, the reaction S5 mixture was diluted with CH2Cl2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired products 4.</p><!><p>An oven-dried 10 mL Schlenk Tube was charged with imidates 1 (0.1 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008 mmol), N-Boc-L-Leu-OH (15 mol%) in sequence, followed by addition of terminal alkenes 2 (0.15 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h; And then, AgOAc (1.2 equiv.), disulfides 3 (0.15 mmol) in DCE (0.5 mL) was inserted into the reaction system through syringe for another 12 hours. After that, the reaction mixture was diluted with CH2Cl2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired products.</p><!><p>An oven-dried 10 mL Schlenk Tube was charged with imidates 1 (0.10 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008 mmol) and Cu(OAc)2·H2O (2.0 equiv.) in sequence, followed by addition of disulfides 3 (0.15 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h and then diluted with CH2Cl2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired products 8.</p><!><p>An oven-dried 10 mL Schlenk Tube was charged with imidates 1 (0.10 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008 mmol) and AgOAc (1.2 equiv.) in sequence, followed by addition of disulfides 3 (0.15 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h and then diluted with CH 2 Cl 2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired products 9.</p><!><p>Product 8t was obtained through standard conditions via Rh(III) catalysis: An oven-dried 10 mL Schlenk Tube was charged with imidates 1a (0.10 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008mmol), Cu(OAc)2·H2O (2.0 equiv.) in sequence, followed by addition of disulfides 3i (0.15 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h and then diluted with CH2Cl2 and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired product 8t.</p><p>With product 8t (0.3 mmol), PdCl2(PPh3)2 (0.006 mmol), KOPiv (2 equiv.) in DMA (N,N-dimethyl acetamide) (1 mL) in an oven-dried Schlenk tube under 140 o C, and the reaction was conducted for 12 hours. After reaction finished, the solution was washed with brine (20 mL × 2), and extracted with ethyl acetate (20 mL × 2), and obtained solution was concentrated and purification of the residue by silica gel column chromatography afforded the desired product 15 (Figure S6). 2) Rapid synthesis of Madam dihydrochloride analogue 16:</p><p>An oven-dried 10 mL Schlenk Tube was charged with imidates 1a (0.1 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008 mmol) and AgOAc (1.2 equiv.) in sequence, followed by addition of disulfides 3o (0.20 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h. After that, the reaction mixture was diluted with CH2Cl2 and filtered through diatomite.</p><p>Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired product 16 (Figure S7). 3) Expedient delivery of Bipenamol:</p><!><p>An oven-dried 10 mL Schlenk Tube was charged with imidates 1a (0.1 mmol), [RhCp*Cl2]2 (0.002 mmol), AgNTf2 (0.008 mmol) and Cu(OAc)2·H2O (2.0 equiv.) in sequence, followed by addition of disulfides 3n (0.15 mmol) in DCE (1.0 mL) through syringe. The resulting reaction mixture was stirred at 100 º C for 12 h. After that, the reaction mixture was diluted with CH2Cl2 and filtered through diatomite.</p><p>Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired product 17.</p><!><p>To a round bottle was added product 17 (0.2 mmol) in THF (2 mL), which was further added LiAlH4 (4 equiv.), the obtained solution was heated to 120 o C for 10 minutes. After the reaction was cooled to room temperature, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate and filtered through diatomite. Removing the solvent in vacuo and purification of the residue by silica gel column chromatography afforded the desired product 18 (Figure S8).</p><!><p>To obtain some insight into this multiple cascade reaction, we conducted the following experiments:</p><p>1) Conversion of thioether product 9a to 8a (Figure S9):</p><p>To elucidate the role of metal salts such as AgOAc and Cu(OAc) 2 •H 2 O for the generation of imidate ester or nitrile substituted thioethers, first, we found that product 8a could be obtained in high efficiency under standard conditions. Control experiments revealed that Cu(OAc)2•H2O was crucial for the conversion of product 9a to 8a, while air or AgOAc exhibited low conversion.</p><p>These observations indicated that Cu(II) salt was essential for the generation of nitrile substituted aryl thioethers. It was speculated that silver exhibited stronger Lewis acidity, which might favor the imidate ester functionality remained intact, while Cu(II) salt might promote the release of ethol moiety from the corresponding imidate ester products.</p><!><p>2) To gain some insight into this transformation that if radical process was involved, some radicalscavenger studies were conducted.</p><p>Procedure: To a 25 mL Schlenk tube equipped with a magnetic stirring bar was added the substrate 1a (0.1 mmol), [RhCp*Cl2]2 (2.5 mg, 0.002 mmol), AgNTf2 (0.008 mmol) and Cu(OAc)2·H2O (2.0 equiv.) in sequence under N2 atmosphere, followed by addition of disulfide PhSSPh 3a (25.0 mg, 0.15 mmol) in DCE (1.0 mL) through syringe. The tube was capped, and heated to 100 °C for 12 h. After cooled to room temperature, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo to afford crude product, which was analyzed with 1 H NMR using CH2Br2 as the internal standard.</p><p>. The results revealed that radical or an electron scavenger TEMPO and 1,4-dinitrobenzene showed no significant inhibition for the generation of the desired thioether product 8a. These experiments indicated that single-electron transfer (SET) pathway might not be involved in this transformation (Figure S10). For the multiple C-H activation reactions, a tentative mechanism was proposed (Figure S12).  2, 144.2, 142.2, 139.4, 134.3, 133.7, 133.4, 132.3, 130.6, 126.9, 125.8, 123.3, 122.0, 34.7 2, 145.7, 144.2, 142.2, 140.8, 134.3, 133.7, 133.4, 133.3, 133.1, 132.7, 132.3, 129.4, 127.3, 126.9, 125.8, 125.2, 123.3, 122.1, 118.0, 115.9, 111.1, 34.7, 31.2, 28.6, 15.3 2H),4H),1H),7.27 (d,J = 8.0 Hz,2H),7.22 (d,J = 16.0 Hz,1H),7.16 (dd,J = 2.4 Hz,9.6 Hz,1H),6.41 (dd,J = 2.4 Hz,8.8 Hz,1H),2.42 (s,3H),1.34 (s,9H). 13 C NMR (100 MHz, CDCl3) δ 152. 7, 148.7, 144.8, 140.5, 135.2, 134.9, 132.9, 130.9, 129.7, 128.6, 127.1,   125.8, 122.3, 115.3, 113.2, 112.9, 108.7, 108.5, 34.8, 31.2, 21.3. 19   3, 133.9, 132.3, 130.5, 128.8, 127.1, 124.0, 122.0, 113.5, 21.2 2, 133.9, 133.4, 130.5, 128.4, 126.9, 125.7, 123.4, 123.2, 108.5, 105.4, 34.7, 31.2 21.9, 21.3. HRMS (ESI-TOF) m/z: [M + H] + Calcd for C27H28NS: 398.1937, Found: 398.1941.  4, 152.3, 146.1, 143.8, 139.3, 134.5, 133.6, 130.5, 126.9, 125.8, 123.4, 113.4, 107.1, 55.5, 31.2, 29.7 3, 143.9, 136.3, 135.4, 134.3, 133.5, 131.2, 130.6, 129.3, 129.3, 128.5, 126.5, 125.6, 124.5, 121.6, 62.1), 34.6, 31.3, 21.8, 14.3 3, 137.8, 136.7, 135.9, 135.5, 134.3, 133.8, 131.2, 130.5, 130.3, 129.7, 129.3, 126.5, 125.6, 124.5, 123.2, 62.1, 34.6, 31.2, 19.6, 19.4, 14.2 7, 138.8, 138.1, 137.1, 135.4, 133.5, 132.4, 130.4, 129.2, 128.7, 127.8, 126.6, 125.7, 123.2, 122.8, 62.2, 34.7, 31.2, 7, 135.6, 134.4, 133.5, 130.3, 129.5, 128.8, 127.9, 125.6, 124.7, 124.3, 62.8, 20.9, 14.5.  136.0, 134.4, 131.8, 130.3, 129.8, 129.4, 128.2, 125.7, 124.7, 124.3, 121.7, 62.8, 20.9, 14.4 8, 1315, 131,5, 130.5, 126.6, 126.0, 125.6, 123.9, 95.2, 62.9, 34.6, 31.3, 21.5, 14.3 4, 151.0, 141.8, 134.9, 134.0, 132.1, 131.7, 131.1, 129.6, 129.4, 128.1, 127.9, 127.4, 126.5, 125.6, 124.9, 124.8, 124.1, 62.7, 31.2, 29.6, 20.9, 14.4 160.6, 151.1, 142.0, 140.5, 137.7), 136.4, 133.4, 130.8, 130.2, 129.3, 127.6, 127.1, 125.4, 121.1, 118.8, 114.6, 104.8, 64.8, 64.5, 61.2, 45.1, 44.9, 34.7), 31.2, 30.1, 29.6, 28.5, 22.3, 21.6, 21.4, 18.3, 14.6.  7.64-7.55 (m, 2H), 755-7.49 (m, 4H), 7.44-7.38 (m, 4H), 7.29-7.24 (m, 2H), 7.23-7.20 (m, 1H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl3) 152.0, 140.7, 133.4, 133.3, 133.2, 133.1, 130.0, 132.6, 127.2, 126.8, 125.7, 125.0, 123.2, 118.0, 111.0, 34.7, 31. 7.55-7.50 (m, 4H), 7.46 (s, 1H), 7.43-7.39 (m, 3H), 7.29-7.26 (m, 2H), 7.24-7.23 (m, 1H), 1.34 (s, 9H). 13 C NMR (100 MHz, CDCl3) 152. 1, 152.0, 141.4, 140.7, 133.2, 133.1, 132.7, 127.3, 126.9, 125.7, 125.1, 123.2, 118.0, 111.1, 34.7, 31.2 7.49-7.46 (m, 2H), 7.43-7.38 (m, 4H), 7.28-7.25 (m, 1H), 7.13 (dd, J = 0.4 Hz, 8.0 Hz, 1H). 13 C NMR (100 MHz, CDCl3) δ 142. 3, 133.6, 133.5, 132.9, 131.8, 129.9, 129.7, 128.9, 126.4, 116.9, 112.9.  134.8,130.2,130.0,129.8,116.2,115.5 (d,J = 26 Hz),113.7 (d,J = 23 Hz), 107.  3, 1398, 134.4, 133.4, 130.1, 129.8, 129.7, 128.5, 126.5, 116.1, 110. 1, 134.4, 134.3, 131.5, 130.1, 129.7, 129.4, 128.2, 127.7, 116.2, 110.6.  2, 134.4, 134.3, 131.5, 130.5, 130.1, 129.7, 129.4, 128.2, 116.2, 110.6. HRMS (ESI-TOF) m/z: [M + H] + Calcd for C13H9INS:</p><!><p>337.9495, Found: 337.9498.  7.48-7.45 (m, 4H), 7.23 (s, 1H). 13 C NMR (100 MHz, CDCl3) δ 145. 1,134.8 (q,J = 34 Hz),134.4,134.1,130.2,129.9,125.3 (q, J = 4.0 Hz), 122.6 (q, J = 4.0 Hz), 122.7 (q, J = 272.0 Hz), 121. 4, 115.7, 115.0.  2, 147.3, 135.0, 134.5, 133.4, 130.5, 128.6, 124.3, 122.2, 120.1, 116.0, 115.1. HRMS (ESI-TOF) m/z: [M + H] + Calcd for C13H9N2O2S: 257.0379, Found: 257.0383.</p>