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Article

Ag/Pyridine Co-Mediated Oxidative Arylthiocyanation of Activated Alkenes

by
De-Long Kong
,
Jian-Xun Du
,
Wei-Ming Chu
,
Chun-Ying Ma
,
Jia-Yi Tao
and
Wen-Hua Feng
*
Department of New Drug Research and Development, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(10), 2727; https://doi.org/10.3390/molecules23102727
Submission received: 10 October 2018 / Revised: 19 October 2018 / Accepted: 19 October 2018 / Published: 22 October 2018
(This article belongs to the Section Organic Chemistry)
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Versions Notes

Abstract

:
An efficient Ag/pyridine co-mediated oxidative arylthiocyanation of activated alkenes via radical addition/cyclization cascade process was developed. This reaction could be carried out under mild conditions to provide biologically interesting 3-alkylthiocyanato-2-oxindoles in good to excellent yields. Mechanistic studies suggested a unique NCS• radical addition path and clarified the dual roles of catalytic pyridine as base and crucial ligand to accelerate the oxidation of Ag(I) to Ag(II), which is likely oxidant responsible for the formation of NCS• radical. These mechanistic results may impact the design and refinement of other radical based reactions proceeding through catalytic oxidations mediated by Ag(I)-pyridine/persulfate. The chemical versatility of thiocyanate moiety was also highlighted via SCN-tailoring chemistry in post-synthetic transformation for new S-C(sp3/sp2/sp), S-P, and S-S bonds constructions. The protocol provides an easy access to many important bioisosteres in medicinal chemistry and an array of sulfur-containing 2-oxindoles that are difficult to prepare by other approaches.

Graphical Abstract

1. Introduction

Alkyl thiocyanates constitutes a key structural feature of a vast number of natural products and pharmaceuticals with a broad spectrum of biological activities (Figure 1). For example, the compound 4-phenoxyphenoxyethyl thiocyanate possesses great antiproliferative and antiparasitic activity [1]. The natural products psammaplin B, 9-thiocyanatopupukeanane, and fasicularin have been evaluated as a histone deacetylase (HDAC) enzyme inhibitor, antimicrobial agent, and cytotoxic agent, respectively [2,3,4]. Further, alkyl thiocyanates also serve as safe cyanating agents and versatile synthetic intermediates for the assembly of functionalized heterocycles and sulfur-based compounds [5,6,7,8,9]. Therefore, their synthetic importance has prompted considerable interest in developing operative construction methodologies for this motif.
So far, the reported approaches for the preparation of alkyl thiocyanates mainly focused on the nucleophilic [10,11,12,13] and electrophilic [14,15,16] substitution of prefunctionalized alkyl substrates with appropriated thiocyanation reagent and the direct thiocyanation of alkyl C–H bonds via oxidative functionalization [17,18,19,20,21,22,23]. However, in these transformations, only a C–S bond is formed. In contrast, the 1,2-difunctionalization of alkenes comprising a cascade thiocyanation and β-functionalization is more appealing from a synthetic perspective because of its high economy of steps and atoms. In recent years, many metal-free and transition-metal-catalyzed transformations such as thiocyanooxygenation [24,25,26,27], dithiocyanation [28,29], thiocyanophosphinoylation [30], thiotrifluoromethylation [31], and thiocyanoamination [32] have been developed (Scheme 1). In spite of these significant advances, arylthiocyanation of alkenes via 1,2-difunctionalization remains relatively unexplored. Especially, the cascade oxidative coupling/cyclization of functionalized alkenes with thiocyanate salts to access structurally diverse heterocycles, which is one of the most important and promising areas in synthetic and medicinal chemistry, are still far less developed. Herein, we would like to report the silver-mediated oxidative arylthiocyanation of alkenes via a radical addition/cyclization cascade process.
Considering the ubiquitous existence and unique biological activity of 2-oxindoles, N-arylacrylamides were chosen as the platform to realize C–H functionalization and C–S and C–C bond formation in one pot to produce the valuable 3-alkylthiocyanato-2-oxindoles. During the course of our studies, Chen and co-workers reported a very similar method which required not only an elevated temperatures (100 °C), but a large excess of oxidants and stoichiometric amounts of strong base Cs2CO3 [33], while, we found that only a slightly excess of the oxidants and catalytic amount of pyridine already could promote the C-H thiocyanation of N-arylacrylamides at 75 °C, making such a protocol easy to handle and scalable. Notably, in contrast to other oxindole syntheses, the resulting products, substituted 2-oxindoles with an appended SCN group, can be used to create further molecular complexity and diversity around the privileged scaffold of 2-oxindoles or can be applied for bioorthogonal transformation under physiological conditions [34,35,36,37].

2. Results and Discussion

As an easily prepared and stable thiocyanation reagent, AgSCN has been previously used as a SCN radical source [38]. Our study commenced by examining the arylthiocyanation of N-methyl-N-phenylmethacrylamide 1a in the presence of AgSCN (1.5 equiv) in CH3CN at 75 °C (Table 1). The oxidant was found to be crucial for this reaction. As an example, ceric ammonium nitrate (CAN) only afforded the product 2a in 15% yield, while di-tert-butyl peroxide (DTBP), oxone, PhI(OAc), and Selectfluor completely shut down the reaction (entry 1–5). Peroxydisulfate ion (S2O82−, oxidation potential is 2.01 V) have been proven to be a powerful inorganic oxidant in oxidizing Ag(I) to the metastable Ag(II) species (1.98 V), which is the key step in most Ag(I)-mediated oxidative processes [39]. However, no desired product was observed with single K2S2O8 (entry 6). We envisioned that a base could be necessary to capture the proton released in this reaction; thus, several bases were next investigated. However, NaHCO3, Cs2CO3, hexamethylphosphoramide (HMPA) and Et3N all failed to give the desired reaction (entry 7–10). 1,8-Diazabicyclo[5,4,0]undec-7-ene (DBU) slightly increased the yield to 55% (entry 11). Pleasingly, the addition of 1 equiv pyridine significantly improved the efficiency of the reaction and provided 2a in 83% yield (entry 12). Moreover, the reaction can be performed well when catalytic amount pyridine (0.2 equiv) was used, giving 2a in 85% yield, albeit with a longer reaction time (entry 13). As a control experiment, removing K2S2O8 led to no reaction (entry 15).
With the optimized conditions in hand, we then investigated the substrate scope of silver-mediated arylthiocyanation of alkenes (Scheme 2). Several N-substituted substrates bearing methyl, ethyl, isopropyl, phenyl and benzyl were tolerated, affording the desired products 2a–e in good yields. Next, the effect of the substituent in the phenyl ring of N-arylacrylamides was studied. In general, very smooth arylthiocyanation occurred for N-arylacrylamides having substituents at the para and meta as well as ortho positions in the aniline. Substrates with halo-substituents (F, Cl, Br, and I) on the para-position of the N-aryl moiety performed well to produce the thiocyanated 2-oxindoles 2f–i in high yields (85–91%), which offers the potential for further derivatization via cross-coupling reactions. Other electron withdrawing groups such as CF3, CN, Ac, and CO2Me on the para-position of aryl rings were also compatible, affording the corresponding products 2j–n in good to excellent yields (77–93%). In particular, the para-NO2 substituted substrate which is usually inert in radical cyclizations [40], afforded the desired oxindole 2m still with high yields. An obvious negative electronic effect from 4-methoxy on the para-position of the aryl moiety led to only a trace amount of the desired product 2o as determined by LC-MS analysis. While meta-Substituted N-phenylacrylamides with both electron-withdrawing and electron-donating groups could be cyclized smoothly to give a mixture of regioisomers in a good yield (2p–q, ratio = 2:1). To our satisfaction, the ortho-position substituted N-arylacylamides, which usually did not work well in radical cyclizations due to steric effect, afforded the corresponding oxindoles 2r still with good yields. Next, the compatibility of the substituents on the α-position (R2) of the acrylamides was also investigated. Several α-substituents, including CF3, benzyl and ester, were tolerated in the reaction to furnish the desired products 2s–u in good yields. Notably, the reaction can also be carried out successfully with heterocyclic substrates to furnish biologically interesting heterocyclic scaffolds, 7-azaoxindole 2v and 4-azaoxindole 2w in high yields. To document the potential of the method, a gram scale (5 mmol) reaction was performed for the generation of compound 2g. The reaction worked smoothly, giving the corresponding product in 77% yield. The molecular structure of 2g was confirmed by the X-ray crystal analysis (CCDC 1849159, see the Supplementary Materials for details).
The 2-oxindole scaffold is a common motif for many biologically active natural products and pharmaceuticals. 2-Oxindoles with an appended SCN moiety obtained by the presented methodology can be used to create a focused compound library. Therefore, we attempted to explore the post-synthetic transformations of the SCN moiety (Scheme 3). Firstly, an array of unsymmetrical thioethers 3a–h could be efficiently prepared starting from 2g with corresponding Grignard reagent or lithium reagent. In this type of transformation, new C–S bonds that involve Csp3, Csp2, and Csp were constructed, demonstrating the generality of this homologation chemistry. In a particularly noteworthy example, treatment of 2g with ethynylmagnesium chloride/LiCl led cleanly to thioalkyne 4, which was used for further modification through copper-catalyzed azide–thioalkyne cycloadditions (CuAtAC) to generate thiotriazole motif 5, an important amide bond bioisostere in medicinal chemistry. In addition, cycloaddition of 2g with NaN3 led to the generation of thiotetrazole 6, itself a carboxylate bioisotere and important structural motifs existed in a lot of cephalosporins drugs. The hydrolysis reaction of 2g with sulfuric acid furnished thiocarbamate 7 in good yield. Furthermore, the valuable trifluoromethylthiole-containing oxindole 8 was achieved upon treatment of 2g with TMSCF3 and CsF, providing a facile method for accessing the interesting trifluoromethylthiole-containing oxindoles. Notably, biologically highly relevant phosphonothioates (9a–b), which have been identified as enzymatically stable phosphate analogues, could also be easy prepared via base promoted nucleophilic substitution of H-phosphine oxides and H-phosphinates on thiocyanates. Clearly, this reaction provides an easily access to S-P(O) bond-containing 2-oxindoles, which have never been explored before. Finally, symmetrical disulfide 10 was prepared in the presence of a base via reductive dimerization of 2g. The base might promote the formation of a nucleophilic thiolate anion which could attack another thiocyanate to give symmetrical disulfide. It is worth pointing out that the aryl chloride functionality of 2g remains totally untouched in all of these derivatization reactions, which enable further elaboration via cross-coupling chemistry. These representative transformations clearly demonstrate the potential molecular diversity that can be created starting from the SCN appended oxindoles.
To gain insight into mechanistic details of this reaction, several control experiments were performed (see the Supplementary Materials for details). The desired transformation was completely inhibited when 1 equiv 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT, a well-known radical scavenger) was added into the present reaction system. Replacement of AgSCN with CuSCN or KSCN in the standard reaction conditions led to no product, while AgNO3/KSCN gave a yield of 15%, which indicated silver was crucial to this transformation to understand the role of pyridine in this reaction, a stage reaction was carried out. In this experiment, we found that stirring of AgSCN/K2S2O8/pyridine mixture in CH3CN at 75 °C for 1 h led to a formation of catalytic silver–pyridine complexes [41,42], which could react with 1a without free pyridine to give 2a in 68% yield. This experiment suggested pyridine functioned not only as a base but also as a possible ligand to accelerate the oxidation of Ag(I) to Ag(II), which was consistent with Bonchev and Aleksiev’s reports that the addition of a suitable nitrogen-containing neutral ligand to Ag(I)/persulfate reactions resulted in a lowering of the potential of the Ag(II)/Ag(I) couple [43,44]. Furthermore, Ag(py)4S2O8 was prepared as an orange solid. Then, treatment of 1a with Ag(py)4S2O8 (0.5 equiv), KSCN(1.5 equiv), and K2S2O8 (1.5 equiv) in CH3CN at 75 °C for 2 h led to the formation of 2a in 56% isolated yield. In this experiment, a quick reduction of orange-Ag(II) to colorless-Ag(I) was observed at the beginning of the reaction which suggested that Ag(II) should be the active species to oxidize NCS− to NCS• radical.
On the basis of the experimental results and previous reports [45,46,47,48,49,50], a plausible mechanism is proposed as depicted in Scheme 4. Pyridine coordination to Ag(I) is followed by persulfate oxidation, resulting a Ag(II)–pyridine complex. The oxidation of the thiocyanate anion by Ag(II)–pyridine complex generates an electrophilic SCN radical, which then attacks the C=C bond of 1a to afford corresponding alkyl radical intermediate A, followed by cyclization to give the aryl radical B. Another single-electron transfer from intermediate B to an additional 1 equiv of Ag(II) generates intermediate C, which affords product 2a by β-H elimination.

3. Materials and Methods

3.1. General Information

All reagents used were obtained commercially and used without further purification unless indicated otherwise. Column chromatography was carried out on silica gel (300–400 grad). TLC analysis was performed on pre-coated, glass-backed silica gel plates and visualized with UV light. 1H-NMR and 13C-NMR spectra were obtained on a 400 MHz (Varian, Palo Alto, CA, USA) and 500 MHz (Bruker-Biospin, Billerica, MA, USA) NMR spectrometer in the deuterated solvents and chemical shifts are reported in ppm form with tetramethylsilane as the internal standard. Multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quintet), and m (multiplet), and coupling constants (J) are reported in Hertz. High resolution mass spectra (HRMS) is recorded using electrospray ionization (ESI) (Thermo Scientific, TSQ Fortis, MA, USA) equipped with a quadrupole mass analyzer. X-ray structures were determined on an X-ray diffraction meter (Bruker-Biospin, Billerica, MA, USA). Melting points were measured on a Beijing Tech X-4 apparatus without correction (Tech X-4, Beijing, China). All the substrates 1 were synthesized according to the literature, and the NMR spectroscopy were consisted with reported data [51].

3.2. General Procedure for Arylthiocyanation of Acrylamides 1

Acrylamides 1 (0.2 mmol), K2S2O8 (81 mg, 0.3 mmol) and AgSCN (50 mg, 0.3 mmol) were combined in an oven-dried sealed tube. The vessel was evacuated and backfilled with N2 (this process was repeated a total of 3 times), and CH3CN (3 mL) and pyridine (3.5 μL, 0.04 mmol) were added via syringe. The tube was then sealed with a Teflon lined cap and placed into a preheated oil bath at 75 °C with vigorous stirring. After 8 h, the reaction mixture was cooled to room temperature and filtered through a plug of silica (eluted with EtOAc). The filtrate was concentrated, and the product was purified by column chromatography on silica gel (petroleum ether/EtOAc) to give product 2.
1,3-Dimethyl-3-(thiocyanatomethyl)indolin-2-one (2a). Yield 38 mg (83%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.38 (td, J = 7.7, 1.3 Hz, 1H), 7.29 (m, 1H), 7.15 (td, J = 7.6, 1.0 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 3.45–3.33 (m, 2H), 3.26 (s, 3H), 1.51 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.4, 143.5, 129.9, 129.5, 123.6, 123.3, 111.6, 108.8, 48.6, 40.8, 26.5, 22.7. HRMS (ESI): calcd. for C12H13N2OS ([M + H]+) 233.0749, found 233.0739.
1-Ethyl-3-methyl-3-(thiocyanatomethyl)indolin-2-one (2b). Yield 42 mg (84%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.35 (td, J = 7.8, 1.3 Hz, 1H), 7.30–7.23 (m, 1H), 7.12 (td, J = 7.6, 1.0 Hz, 1H), 6.92 (d, J = 7.8 Hz, 1H), 3.96–3.67 (m, 2H), 3.48–3.31 (m, 2H), 1.48 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ177.0, 142.6, 130.1, 129.4, 123.7, 123.1, 111.6, 108.9, 48.5, 40.9, 35.1, 22.8, 12.7. HRMS (ESI): calcd. for C13H15N2OS ([M + H]+) 247.0899, found 247.0898.
1-Isopropyl-3-methyl-3-(thiocyanatomethyl)indolin-2-one (2c). Yield 41 mg (79%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.33 (td, J = 7.7, 1.5 Hz, 1H), 7.26 (dd, J = 8.0, 1.7 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.63 (dt, J = 14.2, 7.1 Hz, 1H), 3.45–3.27 (m, 2H), 1.50 (dd, J = 7.0, 4.0 Hz, 6H), 1.46 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.1, 142.3, 130.3, 129.2, 123.8, 122.7, 111.6, 110.5, 48.3, 44.4, 41.1, 22.9, 19.5, 19.5. HRMS (ESI): calcd. for C14H17N2OS ([M + H]+) 261.1056, found 261.1054.
1-Benzyl-3-methyl-3-(thiocyanatomethyl)indolin-2-one (2d). Yield 44 mg (71%), colorless oil.1H-NMR (400 MHz, CDCl3) δ 7.36–7.23 (m, 7H), 7.17–7.05 (m, 1H), 6.81 (dq, J = 1.5, 0.7 Hz, 1H), 5.05–4.86 (m, 2H), 3.45 (q, J = 9.3 Hz, 2H), 1.55 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.6, 142.6, 135.5, 129.8, 129.4, 128.9, 127.9, 127.4, 123.6, 123.3, 111.6, 109.9, 48.7, 44.2, 40.8, 23.2. HRMS (ESI): calcd. for C18H17N2OS ([M + H]+) 309.1056, found 309.1052.
3-Methyl-1-phenyl-3-(thiocyanatomethyl)indolin-2-one (2e). Yield 52 mg (88%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.58–7.51 (m, 2H), 7.46–7.40 (m, 3H), 7.37–7.27 (m, 2H), 7.19 (dt, J = 7.6, 1.1 Hz, 1H), 6.89 (td, J = 1.4, 0.7 Hz, 1H), 3.55–3.43 (m, 2H), 1.63 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.0, 143.6, 134.1, 129.8, 129.6, 129.4, 128.5, 126.6, 123.8, 123.8, 111.4, 110.2, 48.9, 41.2, 23.2. HRMS (ESI): calcd. for C17H15N2OS ([M + H]+) 295.0899, found 295.0896.
5-Fluoro-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2f). Yield 45 mg (90%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.16–6.95 (m, 1H), 6.85 (dd, J = 8.4, 4.1 Hz, 1H), 3.37 (s, 1H), 3.25 (s, 2H), 1.50 (s, 2H).13C-NMR (100 MHz, CDCl3) δ 177.1, 159.6 (d, J = 241.1 Hz), 139.5, 131.5 (d, J = 8 Hz), 115.8 (d, J = 23.5 Hz), 111.9 (d, J = 24.8 Hz), 111.2, 109.4 (d, J = 8.1 Hz), 49.1, 40.5, 26.7, 22.7. HRMS (ESI): calcd. for C12H12N2OFS ([M + H]+) 251.0648, found 251.0654.
5-Chloro-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2g). Yield 47 mg (88%), pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.3, 2.1 Hz, 1H), 7.32–7.26 (m, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.37 (s, 2H), 3.25 (s, 3H), 1.51 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 176.9, 142.1, 131.6, 129.4, 128.7, 124.2, 111.2, 109.8, 48.9, 40.5, 26.7, 22.7. HRMS (ESI): calcd. for C12H12N2OClS ([M + H]+) 267.0353, found 267.0354.
5-Bromo-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2h). Yield 52 mg (85%), pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 3.37 (d, J = 1.0 Hz, 2H), 3.24 (s, 3H), 1.51 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 176.8, 142.56, 132.3, 132.0, 126.9, 115.9, 111.2, 110.2, 48.8, 40.5, 26.7, 22.7. HRMS (ESI): calcd. for C12H12N2OBrS ([M + H]+) 310.9848, found 310.9856.
5-Iodo-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2i). Yield 65 mg (91%), pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.69 (dd, J = 8.2, 1.7 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 3.36 (d, J = 1.3 Hz, 2H), 3.23 (s, 3H), 1.49 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 176.6, 143.3, 138.3, 132.4, 132.4, 111.2, 110.8, 85.6, 48.7, 40.5, 26.6, 22.7. HRMS (ESI): calcd. for C12H12N2OIS ([M + H]+) 358.9709, found 358.9710.
1,3-Dimethyl-3-(thiocyanatomethyl)-5-(trifluoromethyl)indolin-2-one (2j). Yield 56 mg (93%), pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.72–7.64 (m, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.40 (s, 2H), 3.30 (s, 3H), 1.54 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.3, 146.5, 130.5, 127.3, 127.3, 125.8, 125.5, 120.8, 120.8, 110.9, 108.6, 48.7, 40.3, 26.8, 22.7. HRMS (ESI): calcd. for C13H12N2OF3S ([M + H]+) 301.0617, found 301.0616.
1,3-Dimethyl-2-oxo-3-(thiocyanatomethyl)indoline-5-carbonitrile (2k). Yield 41 mg (80%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.70 (dd, J = 8.2, 1.6 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.38 (s, 2H), 3.29 (s, 3H), 1.52 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.1, 147.4, 134.7, 131.1, 127.1, 118.8, 110.7, 109.3, 106.6, 48.7, 40.1, 26.8, 22.7. HRMS (ESI): calcd. for C13H12N3OS ([M + H]+) 258.0695, found 258.0699.
5-Acetyl-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2l). Yield 43 mg (79%), pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 8.02 (dd, J = 8.2, 1.8 Hz, 1H), 7.91 (d, J = 1.7 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.41 (s, 2H), 3.30 (s, 3H), 2.59 (s, 3H), 1.52 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 196.6, 177.7, 147.8, 132.7, 131.3, 130.3, 123.6, 111.1, 108.3, 48.6, 40.3, 26.8, 26.5, 22.8. HRMS (ESI): calcd. for C14H15N2O2S ([M + H]+) 275.0848, found 275.0844.
1,3-Dimethyl-5-nitro-3-(thiocyanatomethyl)indolin-2-one (2m). Yield 41 mg (74%), white solid. 1H-NMR (400 MHz, CDCl3) δ 8.36 (dd, J = 8.7, 2.2 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 8.7 Hz, 1H), 3.43 (s, 2H), 3.34 (s, 3H), 1.57 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.5, 149.2, 143.9, 130.7, 126.7, 119.7, 110.5, 108.5, 48.9, 39.9, 27.0, 22.8. HRMS (ESI): calcd. for C12H12N3O3S ([M + H]+) 278.0593, found 278.0581.
Methyl 1,3-dimethyl-2-oxo-3-(thiocyanatomethyl)indoline-5-carboxylate (2n). Yield 44 mg (77%), white solid. 1H-NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 8.2, 1.7 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.39 (s, 2H), 3.28 (s, 3H), 1.51 (s, 3H).13C-NMR (100 MHz, CDCl3) δ 177.7, 166.5, 147.6, 132.1, 130.0, 125.3, 124.8, 111.0, 108.4, 52.3, 48.5, 40.4, 26.8, 22.7. HRMS (ESI): calcd. for C14H14N2O3SNa ([M + Na]+) 313.0617, found 313.0620.
1,3,4-Trimethyl-3-(thiocyanatomethyl)indolin-2-one (2p).Total yield 34 mg (70%, 2p/2p’ = 2:1). 1H-NMR (400 MHz, CDCl3) δ 7.31–7.26 (m, 1H), 6.93–6.89 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H), 3.67–3.44 (m, 2H), 3.25 (s, 3H), 2.41 (s, 3H), 1.56 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.5, 144.0, 135.2, 129.4, 125.8, 123.7, 111.0, 106.5, 49.6, 38.6, 26.6, 21.5, 18.4. HRMS (ESI): calcd. for C13H15N2OS ([M + H]+) 247.0899, found 247.0898.
1,3,6-Trimethyl-3-(thiocyanatomethyl)indolin-2-one (2p′). Total yield 34 mg (70%, 2p/2p′ = 2:1). 1H-NMR (400 MHz, CDCl3) δ 7.16 (d, J = 7.5 Hz, 1H), 6.95 (ddd, J = 7.6, 1.5, 0.8 Hz, 1H), 6.75–6.73 (m, 1H), 3.38 (s, 2H), 3.24 (s, 3H), 2.41 (d, J = 0.7 Hz, 3H), 1.48 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.7, 143.5, 139.8, 127.0, 126.6, 123.3, 111.78, 109.7, 48.40, 41.0, 26.5, 22.8, 22.0. HRMS (ESI): calcd. for C13H15N2OS ([M + H]+) 247.0899, found 247.0898.
4-Chloro-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2q). Total yield 48 mg (90%, 2q/2q’ = 2:1). 1H-NMR (400 MHz, CDCl3) δ 7.33 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 7.7 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 3.41 (d, J = 13.3 Hz, 1H), 3.27 (s, 3H), 1.62 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 176.9, 145.5, 131.5, 130.8, 124.6, 124.1, 110.5, 107.4, 50.52, 37.08, 26.80, 20.91. HRMS (ESI): calcd. for C12H12N2OClS ([M + H]+) 267.0353, found 267.0354.
6-Chloro-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2q′). Total yield 48 mg (90%, 2q/2q′ = 2:1). 1H-NMR (400 MHz, CDCl3) δ 7.21 (d, J = 7.8 Hz, 1H), 7.12 (dd, J = 8.0, 1.9 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 3.37 (s, 2H), 3.24 (s, 3H), 1.49 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.4, 144.7, 135.3, 128.3, 126.0, 123.1, 111.4, 109.6, 48.5, 40.5, 26.7, 22.8. HRMS (ESI): calcd. for C12H12N2OClS ([M + H]+) 267.0353, found 267.0354.
7-Chloro-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2r). Yield 38 mg (71%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 8.2, 1.2 Hz, 1H), 7.17 (dd, J = 7.4, 1.2 Hz, 1H), 7.05 (dd, J = 8.2, 7.4 Hz, 1H), 3.62 (s, 3H), 3.37 (s, 2H), 1.49 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.7, 139.5, 132.6, 131.8, 124.0, 122.1, 116.3, 111.3, 48.5, 40.7, 29.9, 23.1. HRMS (ESI): calcd. for C12H12N2OClS ([M + H]+) 267.0353, found 267.0354.
1-Methyl-3-(thiocyanatomethyl)-3-(trifluoromethyl)indolin-2-one (2s). Yield 55 mg (97%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.51 (td, J = 7.8, 1.2 Hz, 1H), 7.44 (dtd, J = 7.5, 1.2, 0.6 Hz, 1H), 7.22 (td, J = 7.6, 1.0 Hz, 1H), 6.98 (dt, J = 7.9, 0.8 Hz, 1H), 3.80–3.63 (m, 2H), 3.30 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 168.9, 145.0, 131.7, 126.0, 125.0, 123.9, 122.2, 120.5, 109.9, 109.4, 56.7 (q, J = 27.1 Hz), 34.3, 27.0. 19F NMR (376 MHz, CDCl3) δ −71.5. HRMS (ESI): calcd. for C12H10N2OF3S ([M + H]+) 287.0460, found 287.0456.
3-Benzyl-1-methyl-3-(thiocyanatomethyl)indolin-2-one (2t). Yield 38 mg (62%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.32–7.28 (m, 1H), 7.21 (ddd, J = 7.5, 1.3, 0.6 Hz, 1H), 7.15–7.06 (m, 4H), 6.88–6.83 (m, 2H), 6.69 (dt, J = 7.9, 0.8 Hz, 1H), 3.63–3.50 (m, 2H), 3.22–3.10 (m, 2H), 3.03 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 176.23, 144.1, 134.2, 130.0, 129.6, 129.2, 127.9, 127.2, 124.6, 122.8, 111.6, 108.6, 54.5, 43.0, 39.4, 26.2. HRMS (ESI): calcd. for C18H17N2OS ([M + H]+) 309.1056, found 309.1052.
(1-Methyl-2-oxo-3-(thiocyanatomethyl)indolin-3-yl)methyl acetate (2u). Yield 44 mg (76%), colorless oil. 1H-NMR (400 MHz, Acetone-d6) δ 7.52–7.48 (m, 1H), 7.40 (td, J = 7.8, 1.3 Hz, 1H), 7.14–7.07 (m, 2H), 4.55 (d, J = 11.0 Hz, 1H), 4.20 (d, J = 11.0 Hz, 1H), 3.82 (d, J = 13.4 Hz, 1H), 3.63 (d, J = 13.4 Hz, 1H), 3.23 (s, 3H), 1.92 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 174.3, 170.1, 144.12, 130.2, 126.0, 124.7, 123.4, 111.2, 109.0, 65.8, 52.2, 36.9, 26.7, 20.7. HRMS (ESI): calcd. for C14H15N2O3S ([M + H]+) 291.0798, found 291.0793.
1,3-Dimethyl-3-(thiocyanatomethyl)-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (2v). Yield 40 mg (87%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 5.1, 1.3 Hz, 1H), 7.28 (dd, J = 8.0, 5.2 Hz, 1H), 7.17 (dd, J = 8.0, 1.3 Hz, 1H), 3.58 (d, J = 13.3 Hz, 1H), 3.37 (d, J = 13.4 Hz, 1H), 3.28 (s, 3H), 1.54 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 176.0, 151.1, 143.6, 139.1, 124.0, 115.0, 110.6, 49.2, 38.7, 26.3, 21.5. HRMS (ESI): calcd. for C11H12N3OS ([M + H]+) 234.0695, found 234.0693.
1,3-Dimethyl-3-(thiocyanatomethyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (2w). Yield 38 mg (82%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 8.29 (ddd, J = 5.3, 1.6, 0.7 Hz, 1H), 7.57 (ddd, J = 7.3, 1.6, 0.7 Hz, 1H), 7.05 (ddd, J = 7.3, 5.3, 0.7 Hz, 1H), 3.46–3.32 (m, 5H), 1.53 (d, J = 0.7 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.2, 156.9, 148.3, 131.5, 124.4, 118.7, 111.4, 48.7, 40.2, 25.7, 22.3. HRMS (ESI): calcd. for C11H12N3OS ([M + H]+) 234.0695, found 234.0693.

3.3. Procedure for Gram-Scale Preparation of 5-Chloro-1,3-dimethyl-3-(thiocyanatomethyl)indolin-2-one (2g)

Acrylamides 1g (1.05g, 5 mmol), K2S2O8 (1.70 g, 7.5 mmol) and AgSCN (1.24 g, 7.5 mmol) were combined in an 50 mL oven-dried sealed tube. The vessel was evacuated and backfilled with N2 (this process was repeated a total of 3 times), and CH3CN (30 mL) and pyridine (79 μL, 1 mmol) were added via syringe. The tube was then sealed with a Teflon lined cap and placed into a preheated oil bath at 75 °C with vigorous stirring. After 12 h, the reaction mixture was cooled to room temperature and filtered through a plug of silica (eluted with EtOAc). The filtrate was concentrated, and the product was purified by column chromatography on silica gel (petroleum ether/EtOAc, 10:1) to give product 2g (1.05g, 77%) as a yellow solid.

3.4. General Procedure for Preparation of Compounds 3a–g

To a solution of 2g (53 mg, 0.2 mmol) in dry THF (3 mL) at 0 °C under N2 was added corresponding Grignard reagent RMgBr (0.6 mmol in THF, 3 equiv), dropwise, via syringe. The reaction was allowed to warm to room temperature, stirred for 2–3 h, whereupon TLC analysis indicated that the reaction was complete. Following quenching [saturated NH4Cl (aq)], and extraction (EtOAc, 2 x), the crude product was dried (Na2SO4), filtered and evaporation. Flash chromatography over silica gel (petroleum ether/EtOAc, 10:1) then yielded the corresponding product 3a–g.
5-Chloro-3-((ethylthio)methyl)-1,3-dimethylindolin-2-one (3a). Yield 49 mg (91%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.24 (d, J = 6.6 Hz, 2H), 6.84–6.66 (m, 1H), 3.19 (s, 3H), 3.06–2.86 (m, 2H), 2.37 (qd, J = 7.3, 3.9 Hz, 2H), 1.39 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 179.1, 142.2, 134.7, 128.2, 127.9, 123.7, 108.0, 49.5, 39.7, 27.9, 26.4, 22.9, 14.9. HRMS (ESI): calcd. for C13H17NOClS ([M + H]+) 270.0714, found 270.0712.
5-Chloro-3-((hexylthio)methyl)-1,3-dimethylindolin-2-one (3b). Yield 49 mg (75%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.29–7.25 (m, 2H), 6.78 (d, J = 8.8 Hz, 1H), 3.22 (s, 3H), 3.10–2.81 (m, 2H), 2.36 (td, J = 7.4, 1.5 Hz, 2H), 1.49–1.39 (m, 5H), 1.32–1.17 (m, 7H), 0.86 (t, J = 7.0 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 179.1, 142.2, 134.8, 128.2, 128.0, 123.7, 109.0, 49.6, 40.1, 34.0, 31.4, 29.7, 28.4, 26.4, 22.9, 22.6, 14.1. HRMS (ESI): calcd. for C17H25NOClS ([M + H]+) 326.1345, found 326.1348.
5-Chloro-3-((cyclohexylthio)methyl)-1,3-dimethylindolin-2-one (3c). Yield 61 mg (96%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.32–7.24 (m, 2H), 6.77 (dd, J = 8.1, 0.6 Hz, 1H), 3.21 (s, 3H), 3.02 (d, J = 12.8 Hz, 1H), 2.88 (d, J = 12.8 Hz, 1H), 2.49–2.39 (m, 1H), 1.90–1.50 (m, 5H), 1.41 (s, 3H), 1.28–1.11 (m, 5H). 13C-NMR (100 MHz, CDCl3) δ 179.2, 142.1, 134.7, 128.1, 127.9, 123.7, 109.0, 49.4, 45.2, 38.0, 33.9, 33.6, 26.4, 26.1, 25.7, 22.8. HRMS (ESI): calcd. for C17H23NOClS ([M + H]+) 324.1183, found 324.1187.
5-Chloro-3-((cyclopropylthio)methyl)-1,3-dimethylindolin-2-one (3d). Yield 47 mg (85%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.29–7.24 (m, 2H), 6.80–6.76 (m, 1H), 3.23 (s, 3H), 3.04 (d, J = 1.2 Hz, 2H), 1.54 (tt, J = 7.3, 4.3 Hz, 1H), 1.43 (s, 3H), 0.79–0.67 (m, 2H), 0.49–0.33 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ 179.1, 142.2, 134.8, 128.2, 127.9, 123.8, 109.0, 49.6, 41.6, 26.4, 23.1, 14.3, 9.5, 8.6. HRMS (ESI): calcd. for C14H17NOClS ([M + H]+) 282.0714, found 282.0717.
5-Chloro-1,3-dimethyl-3-((vinylthio)methyl)indolin-2-one (3e). Yield 51 mg (95%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.16 (dd, J = 16.9, 9.9 Hz, 1H), 5.10–4.99 (m, 2H), 3.18 (s, 3H), 3.09 (s, 2H), 1.43 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 178.6, 142.1, 134.2, 132.7, 128.4, 128.1, 123.9, 112.4, 109.1, 49.2, 40.1, 26.5, 22.7. HRMS (ESI): calcd. for C13H15NOClS ([M + H]+) 268.0557, found 268.0551.
5-Chloro-1,3-dimethyl-3-((phenylthio)methyl)indolin-2-one (3f). Yield 51 mg (81%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.22 (dd, J = 8.3, 2.1 Hz, 1H), 7.20–7.14 (m, 5H), 7.05 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 3.37 (s, 2H), 3.20 (s, 3H), 1.42 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 178.6, 142.1, 135.6, 133.9, 130.9, 128.8, 128.2, 128.0, 126.9, 124.1, 109.0, 49.7, 42.8, 26.5, 23.0. HRMS (ESI): calcd. for C17H17NOClS ([M + H]+) 318.0714, found 318.0716.
3-((Benzo[d][1,3]dioxol-5-ylthio)methyl)-5-chloro-1,3-dimethylindolin-2-one (3g). Yield 65 mg (91%), pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ 7.19 (dd, J = 8.5, 2.0 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.79–6.72 (m, 1H), 6.66–6.52 (m, 3H), 5.92 (dd, J = 4.0, 2.4 Hz, 2H), 3.27 (d, J = 2.9 Hz, 2H), 3.21 (s, 3H), 1.37 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 178.7, 147.7, 147.5, 142.2, 133.9, 128.1, 127.9, 127.5, 126.5, 124.0, 112.9, 108.9, 108.9, 101.4, 50.1, 44.5, 26.5, 23.2. HRMS (ESI): calcd. for C18H17NO3ClS ([M + H]+) 362.0612, found 362.0605.

3.5. Procedure for the Preparation of 5-Chloro-1,3-dimethyl-3-((((trimethylsilyl)ethynyl)thio)methyl)indolin-2-one (3h)

To a solution of trimethylsilacetylene (60 mg, 0.6 mmol) in dry THF (2 mL) at 0 °C under N2 was added n-BuLi (0.4 mL of a 1.6 M solution in hexanes, 0.6 mmol) dropwise and the resulting reaction mixture was stirred for 0.5 h. A solution of 2g (53 mg, 0.2 mmol) in THF (1 mL) was slowly added, via syringe, and the reaction was allowed to warm to room temperature, stirred for 2 h, and then quenched (saturated aq. NH4Cl), extracted (EtOAc, 2×) and dried (Na2SO4). Purification by flash chromatography (petroleum ether/EtOAc, 10:1) yielded the desired product 3h. Yield 48 mg (71%), colorless oil.1H-NMR (400 MHz, CDCl3) δ 7.32 (d, J = 2.1 Hz, 1H), 7.28 (ddd, J = 8.3, 2.1, 0.5 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 3.24–3.10 (m, 5H), 1.46 (s, 3H), 0.11 (s, 9H). 13C-NMR (100 MHz, CDCl3) δ 177.9, 142.1, 133.3, 128.5, 128.0, 124.5, 109.2, 100.7, 93.7, 49.3, 43.3, 26.5, 22.6, −0.07. HRMS (ESI): calcd. for C16H21NOClSSi ([M + H]+) 338.0796, found 338.0791.

3.6. Procedure for the Preparation of 5-Chloro-3-((ethynylthio)methyl)-1,3-dimethylindolin-2-one (4)

To a solution of 2g (53 mg, 0.2 mmol) and LiCl (24 mg, 0.6 mmol) in dry THF (3 mL) at 0 °C under N2 was added ethynylmagnesium chloride (1.2 mL of a 0.5 M solution in THF, 0.6 mmol), dropwise, via syringe. The reaction was allowed to warm to room temperature and stirred for 2 h, Upon completion of the reaction, saturated NH4Cl (aq) was added and extraction (EtOAc, 2 x). The crude product was dried (Na2SO4), filtered and evaporation. Flash chromatography over silica gel (petroleum ether/EtOAc, 10:1) then yielded the product 5-Chloro-3-((ethynylthio)methyl)-1,3-dimethylindolin-2-one (4). Yield 32mg (65%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.31–7.29 (m, 1H), 7.29 (s, 1H), 6.82–6.78 (m, 1H), 3.22 (s, 3H), 3.19 (d, J = 3.4 Hz, 2H), 2.62 (s, 1H), 1.47 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.9, 142.2, 133.1, 128.6, 128.1, 124.5, 109.2, 82.0, 73.7, 49.3, 42.6, 26.6, 22.7. HRMS (ESI): calcd. for C13H13NOClS ([M + H]+) 266.0401, found 266.0396.

3.7. Procedure for the Preparation of Triazole 3-(((1-benzyl-1H-1,2,3-triazol-4-yl)thio)methyl)-5-chloro-1,3-dimethylindolin-2-one (5)

To a solution of 4 (26 mg, 0.1 mmol) in CH2Cl2/H2O (2:1, 2 mL) at room temperature was added CuSO4·5H2O (1.5 mg, 0.01 mmol) and sodium ascorbate (4 mg, 0.02 mmol). The reaction mixture was stirred for 1 h at room temperature and the solvents were removed under reduced pressure. Column chromatography of the residue (petroleum ether/EtOAc, 1:1) provided triazole 3-(((1-benzyl-1H-1,2,3-triazol-4-yl)thio)methyl)-5-chloro-1,3-dimethylindolin-2-one (5). Yield 35 mg (91%), white solid. 1H-NMR (400 MHz, Methanol-d4) δ 7.40 (s, 1H), 7.39–7.31 (m, 3H), 7.30–7.23 (m, 3H), 7.03 (d, J = 2.1 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.55–5.35 (m, 2H), 3.53 (d, J = 13.8 Hz, 1H), 3.25 (d, J = 13.8 Hz, 1H), 3.15 (s, 3H), 1.33 (s, 3H). 13C-NMR (100 MHz, Methanol-d4) δ 179.1, 142.3, 139.0, 134.8, 133.8, 128.7, 128.3, 128.0, 127.9, 127.6, 126.6, 123.4, 109.6, 53.7, 50.1, 41.4, 25.3, 22.0. HRMS (ESI): calcd. for C20H20N4OClS ([M + H]+) 399.1046, found 399.1041.

3.8. Procedure for the Preparation of 3-(((1H-tetrazol-5-yl)thio)methyl)-5-chloro-1,3-dimethylindolin-2-one (6)

Compound 2g (53 mg, 0.2 mmol), ZnBr2 (45 mg, 0.2 mmol, 1 equiv.) and NaN3 (32 mg, 0.5 mmol, 2.5 equiv.) were combined in a mixed solvent [H2O/iPrOH (1:1, 3 mL)] and refluxed for 1 h. Upon completion of the reaction, the mixture was diluted with EtOAc. The solvent was then removed under vacuo. Column chromatography of the residue (petroleum ether/EtOAc, 1:1) provided tetrazole 6. Yield 55 mg (90%), white solid. 1H-NMR (400 MHz, Methanol-d4) δ 7.27–7.21 (m, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.85 (d, J = 13.7 Hz, 1H), 3.63 (d, J = 13.7 Hz, 1H), 3.17 (s, 3H), 1.41 (s, 3H). 13C-NMR (126 MHz, Methanol-d4) δ 178.7, 154.4, 142.2, 132.9, 128.5, 128.1, 123.7, 109.8, 49.8, 39.3, 25.5, 21.7. HRMS (ESI): calcd. for C12H13N5OClS ([M + H]+) 310.0529, found 310.0531.

3.9. Procedure for the Preparation of S-((5-chloro-1,3-dimethyl-2-oxoindolin-3-yl)methyl) carbamothioate (7)

Compound 2g (53 mg, 0.2 mmol) and 1mL 95% sulfuric acid was stirred for 2 h at room temperature. Upon completion of the reaction, the mixture was diluted with EtOAc and cooled water. The solvent was then removed under vacuo. The residue was purified by column chromatography on silica gel (petroleum/EtOAc, 1:1) to give the corresponding products 7. Yield 40 mg (71%), white solid. 1H-NMR (400 MHz, Methanol-d4) δ 7.37 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 8.3, 2.2 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 3.48 (d, J = 13.6 Hz, 1H), 3.29 (d, J = 13.6 Hz, 1H), 3.22 (s, 3H), 1.42 (s, 3H).13C-NMR (100 MHz, Methanol-d4) δ 179.5, 168.0, 142.0, 134.1, 128.1, 127.9, 123.8, 109.4, 49.2, 35.4, 25.3, 21.5. HRMS (ESI): calcd. for C12H13N2OClSNa ([M + Na]+) 307.0284, found 307.0288.

3.10. Procedure for the Preparation of 5-chloro-1,3-dimethyl-3-(((trifluoromethyl)thio)methyl)indolin-2-one (8)

A mixture of 2g (53 mg, 0.2 mmol) and CsF (30 mg, 0.2 mmol) was dissolved in MeCN (3 mL) and cooled to 0 °C. Then trifluoromethyltrimethylsilane (56.8 mg, 0.4 mmol) was added at once via syringe and the mixture was stirred at room temperature for 2 h. The resulting mixture was filtered through a short pad of celite and extracted with EtOAc. The resulting organic solution was washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (petroleum ether/EtOAc, 5:1) to give the corresponding product 8. Yield 55 mg (90%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.29 (dd, J = 8.3, 2.1 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 3.29 (d, J = 0.5 Hz, 2H), 1.46 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.5, 141.8, 132.7, 131.9, 128.9, 128.3, 123.7, 109.4, 47.8, 36.2 (t, J = 2.1 Hz), 26.5, 22.6. 19F NMR (376 MHz, CDCl3) δ −41.1 (s). HRMS (ESI): calcd. for C12H12ONClF3S ([M + H]+) 310.0275, found 310.0276.

3.11. General Procedure for the Preparation of Compounds 9a–b

To a solution of 2g (52 mg, 0.2 mmol) and H-P(O)(R2)2 (diphenylphosphine oxide or diethyl phosphite 0.3 mmol) in toluene (2 mL) at room temperature was added DBU (45 mg, 0.3 mmol). The reaction mixture was stirred for 3 h at room temperature and the solvents were removed under reduced pressure. Column chromatography of the residue (petroleum ether/EtOAc, 4:1) provided corresponding products 9a–b.
((5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)methyl) diphenylphosphinothioate (9a). Yield 76 mg (87%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.82–7.75 (m, 2H), 7.73–7.66 (m, 2H), 7.53–7.39 (m, 6H), 7.23–7.19 (m, 2H), 6.74–6.69 (m, 1H), 3.18 (s, 3H), 1.39 (s, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.8, 141.8, 133.3, 132.8, 132.7, 132.7, 132.7, 131.8, 131.7, 131.6, 131.6, 131.5, 128.9, 128.8, 128.8, 128.7, 128.6, 128.3, 124.2, 109.1, 48.5, 48.4, 35.6, 35.6, 23.0. HRMS (ESI): calcd. for C23H22NO2ClSP ([M + H]+) 442.0792, found 442.0784.
((5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)methyl) O,O-diethyl phosphorothioate (9b). Yield 57 mg (76%), colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.36–7.25 (m, 2H), 6.79 (d, J = 8.3 Hz, 1H), 4.17–3.87 (m, 4H), 3.30 (d, J = 11.2 Hz, 2H), 3.21 (d, J = 1.2 Hz, 3H), 1.44 (d, J = 1.4 Hz, 3H), 1.33 (td, J = 7.1, 0.9 Hz, 3H), 1.25 (td, J = 7.1, 0.9 Hz, 3H). 13C-NMR (100 MHz, CDCl3) δ 177.9, 142.1, 133.3, 128.6, 128.3, 124.2, 109.2, 63.8 (m), 48.9 (d, J = 6.7 Hz), 37.5 (d, J = 3.8 Hz), 16.0 (dd, J = 11.6, 7.4 Hz). HMS (ESI): calcd. for C15H22NO4ClSP ([M + H]+) 378.0683, found 378.0690.

3.12. Procedure for the Preparation of 3,3′-(disulfanediylbis(methylene))bis(5-chloro-1,3-dimethylindolin-2-one) (10)

To a solution of Et2NH (0.6 mmol) in dry THF (2 mL) at 0 °C under N2 was added n-BuLi (0.4 mL of a 1.6 M solution in hexanes, 0.6 mmol) dropwise and the resulting reaction mixture was stirred for 0.5 h. A solution of 2g (53 mg, 0.2 mmol) in THF (1 mL) was slowly added, via syringe, and the reaction was allowed to warm to room temperature, stirred for 3 h, and then quenched (saturated aq. NH4Cl), extracted (EtOAc, 2×) and dried (Na2SO4). Purification by flash chromatography (petroleum ether/EtOAc, 3:1) yielded the desired product 10.
3,3′-(Disulfanediylbis(methylene))bis(5-chloro-1,3-dimethylindolin-2-one)(10). Yield 89 mg (83%), white solid. 1H-NMR (400 MHz, CDCl3) δ 7.30–7.22 (m, 3H), 7.19–7.17 (m, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 3.20 (d, J = 3.0 Hz, 6H), 3.13 (d, J = 13.4 Hz, 1H), 3.07–2.97 (m, 2H), 2.88 (d, J = 13.4 Hz, 1H), 1.35 (s, 6H). 13C-NMR (100 MHz, CDCl3) δ 178.3, 178.3, 142.2, 142.1, 133.7, 133.6, 128.4, 128.4, 128.0, 127.9, 124.1, 124.0, 109.2, 109.2, 49.4, 49.3, 48.7, 48.1, 26.5(4), 26.5(2), 23.1, 22.9. HRMS (ESI): calcd. for C22H23N2O2Cl2S2 ([M + H]+) 481.0578, found 481.0586.

4. Conclusions

In summary, we have developed an efficient arylthiocyanation of activated alkenes under mild conditions leading to biologically interesting 3-alkylthiocyanato-2-oxindoles, which was practical and straightforward to construct the C–C and C–SCN bonds in one pot, and was of broad functional group compatibility. Mechanistic studies suggested a unique NCS• radical addition path and clarified the dual roles of catalytic pyridine as base and crucial ligand to accelerate the oxidation of Ag(I) to Ag(II). Around the privileged 2-oxindole core, we demonstrate the versatility of the thiocyanate moiety in post-synthetic transformations for constructing new S-C(sp3/sp2/sp), S-P, and S-S bonds, which provides an easy access to many important bioisosteres in medicinal chemistry and an array of sulfur-containing 2-oxindoles that are difficult to prepare by other approaches. This protocol will likely open up new vistas to chemical biology community for exploiting the rich chemical potential of the SCN moiety. Further work to achieve effective thiocyanation with catalytic amount of silver are underway.

Supplementary Materials

The following are available online, general methods, X-ray crystallography details for oxindole 2g, mechanistic studies, and 1H-NMR and 13C-NMR spectra of all products.

Author Contributions

D.-L.K. and W.-H.F. conceived and designed the experiments. D.-L.K., J.-X.D. and W.-M.C. performed the experiments. D.-L.K. wrote the manuscript. C.-Y.M. and J.-Y.T. revised the manuscript. All authors read and approved the final manuscript.

Funding

Financial support was provided by CAMS Innovation Fund for Medical Sciences (CIFMS) (CAMS-2017-I2M-1-011 and CAMS-2016-I2M-1-002).

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 1–10 are available from the authors.
Molecules 23 02727 g001 550
Figure 1. Representative bioactive alkyl thiocyanates.
Figure 1. Representative bioactive alkyl thiocyanates.
Molecules 23 02727 g001
Molecules 23 02727 sch001 550
Scheme 1. Difunctionalization of alkenes with thiocyanation.
Scheme 1. Difunctionalization of alkenes with thiocyanation.
Molecules 23 02727 sch001
Molecules 23 02727 sch002 550
Scheme 2. Scope of Activated Alkenes a. a Reaction conditions: 1a (0.2 mmol, 1 equiv), AgSCN (1.5 equiv), K2S2O8 (1.5 equiv), pyridine (0.2 equiv) in CH3CN (2.5 mL) at 75 °C for 8 h. b 0.5 equiv portion pyridine was used. c The yield of gram scale reaction (5 mmol) is given in parenthesis.
Scheme 2. Scope of Activated Alkenes a. a Reaction conditions: 1a (0.2 mmol, 1 equiv), AgSCN (1.5 equiv), K2S2O8 (1.5 equiv), pyridine (0.2 equiv) in CH3CN (2.5 mL) at 75 °C for 8 h. b 0.5 equiv portion pyridine was used. c The yield of gram scale reaction (5 mmol) is given in parenthesis.
Molecules 23 02727 sch002
Molecules 23 02727 sch003 550
Scheme 3. Derivatizations of 2g via SCN-Tailoring Chemistry a. a Reaction conditions: (a) RMgBr or TMSC≡CLi, THF, 0 °C–rt, 2 h; (b) H2SO4, rt, 2 h; (c) Et2NH, n-BuLi, 0 °C–rt, 3 h; (d) TMSCF3, CsF, CH3CN, rt, 2 h; (e) HC≡CMgCl, LiCl, THF, 0 °C–rt, 2 h; (f) BnN3, CuSO4, Na ascorbate, DCM/H2O = 3:1, rt, 1 h; (g) NaN3, ZnBr2, i-PrOH/H2O = 1:1, reflux; 1 h) H-P(O)(R2)2, DBU, toluene, rt, 3 h.
Scheme 3. Derivatizations of 2g via SCN-Tailoring Chemistry a. a Reaction conditions: (a) RMgBr or TMSC≡CLi, THF, 0 °C–rt, 2 h; (b) H2SO4, rt, 2 h; (c) Et2NH, n-BuLi, 0 °C–rt, 3 h; (d) TMSCF3, CsF, CH3CN, rt, 2 h; (e) HC≡CMgCl, LiCl, THF, 0 °C–rt, 2 h; (f) BnN3, CuSO4, Na ascorbate, DCM/H2O = 3:1, rt, 1 h; (g) NaN3, ZnBr2, i-PrOH/H2O = 1:1, reflux; 1 h) H-P(O)(R2)2, DBU, toluene, rt, 3 h.
Molecules 23 02727 sch003
Molecules 23 02727 sch004 550
Scheme 4. Proposed mechanism.
Scheme 4. Proposed mechanism.
Molecules 23 02727 sch004
Table
Table 1. Optimization of the Reaction Conditions a.
Table 1. Optimization of the Reaction Conditions a.
Molecules 23 02727 i001
EntryOxidantBase (equiv.)Yield b (%)
1DTBPnone0
2Oxonenone0
3PhI(OAc)none0
4selectfluornonetrace
5CANnone15
6K2S2O8none0
7K2S2O8NaHCO3 (1)0
8K2S2O8Cs2CO3 (1)trace
9K2S2O8HMPA (1)0
10K2S2O8Et3N (1)0
11K2S2O8DBU (1)55
12K2S2O8pyridine (1)83
13 cK2S2O8Pyridine (0.2)85
14 cK2S2O8Pyridine (0.1)64
15nonePyridine (0.2)0
aReaction conditions: 1a (0.2 mmol), AgSCN (0.3 mmol), oxidant (1.5 equiv) and base in CH3CN (2.5 mL) at 75 °C for 2 h. b Isolated yields. c 8 h.

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Kong, D.-L.; Du, J.-X.; Chu, W.-M.; Ma, C.-Y.; Tao, J.-Y.; Feng, W.-H. Ag/Pyridine Co-Mediated Oxidative Arylthiocyanation of Activated Alkenes. Molecules 2018, 23, 2727. https://doi.org/10.3390/molecules23102727

AMA Style

Kong D-L, Du J-X, Chu W-M, Ma C-Y, Tao J-Y, Feng W-H. Ag/Pyridine Co-Mediated Oxidative Arylthiocyanation of Activated Alkenes. Molecules. 2018; 23(10):2727. https://doi.org/10.3390/molecules23102727

Chicago/Turabian Style

Kong, De-Long, Jian-Xun Du, Wei-Ming Chu, Chun-Ying Ma, Jia-Yi Tao, and Wen-Hua Feng. 2018. "Ag/Pyridine Co-Mediated Oxidative Arylthiocyanation of Activated Alkenes" Molecules 23, no. 10: 2727. https://doi.org/10.3390/molecules23102727

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