Title: Copper-Catalyzed Benzylic C–H Bond Thiocyanation: Enabling Late-Stage Diversifications
Abstract: Open AccessCCS ChemistryCOMMUNICATION1 Aug 2021Copper-Catalyzed Benzylic C–H Bond Thiocyanation: Enabling Late-Stage Diversifications Chao Jiang, Pinhong Chen and Guosheng Liu Chao Jiang State Key Laboratory of Organometallic Chemistry, Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author , Pinhong Chen State Key Laboratory of Organometallic Chemistry, Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 Google Scholar More articles by this author and Guosheng Liu *Corresponding author: E-mail Address: [email protected] State Key Laboratory of Organometallic Chemistry, Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 Chang-Kung Chuang Institute, East China Normal University, Shanghai 200062 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.020.202000435 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The rapid growth of using C–H bond as cross-coupling partners is reshaping the landscape of organic synthesis. C(sp3)–H functionalization via hydrogen atom transfer (HAT) represents the most compelling strategy in this avenue. Here, we demonstrate an efficient method for benzylic C–H bond thiocyanation via copper-catalyzed radical relay. The reaction exhibits broad substrate scope and exquisite benzylic selectivity with C–H substrates as limiting reagents. In addition, the benzyl thiocyanates are readily converted to other pharmaceutically important motifs, including isothiocyanate, thiourea, and others, highlighting the broad utility of this method. Download figure Download PowerPoint Introduction Advances in C–H functionalization have enriched the organic synthesis toolbox.1–5 Specifically, selective functionalization of the ubiquitous benzylic C–H bond in organic molecules has a broad impact, ranging from upgrading feedstock alkylarenes for functional molecule synthesis to late-stage modifications of complex pharmaceuticals and bioactive structures (Scheme 1a).6–18 For instance, approximately 30% of the top-selling drugs contain at least one (hetero)benzylic C–H bond, and the selective functionalization of these C–H bonds could potentially change their metabolic stabilities and regulate bioactivities. Information gathered by the Njardarson group with data from DrugTopics & Pharmacompass. (see Ref. [19] for details). However, differentiating between individual C–H bonds for selective functionalization represents a key challenge. Bond cleavage through hydrogen atom transfer (HAT) dominates the realm of selective benzylic C–H functionalization because of the relatively low C–H bond strength (<90 kcal/mol).20 Apparent constraints must be overcome to expand the utility of these methods, such as using large excess of C–H substrates and restricted functional group diversity.21–25 Recently, our group26–31 and others32–37 have developed a copper-catalyzed radical relay strategy for selective benzylic C(sp3)–H bond functionalization with N–F reagents (e.g., N-fluorobenzenesulfonimide [NFSI]) as oxidant that features high site selectivity and uses C–H substrates as limiting reagents (Scheme 1b). Many functional groups have been incorporated by varying the nucleophiles, highlighting the efficacy of this approach. Scheme 1 | (a–c) Copper-catalyzed benzylic C–H bond functionalization via radical relay. Download figure Download PowerPoint The prevalence of sulfur-containing scaffolds in natural products and drugs has stimulated recent interest in methodology development for forging C–S bonds,38–42 especially from C–H substrates that are suitable for late-stage functionalization.43–53 Benzyl thiocyanates are an important core motif in bioactive molecules, such as those that could be used as immunomodulators (Scheme 1c).54,55 They are also versatile synthetic intermediates in other prominent pharmacophores and functional molecules: isothiocyanate, a core structure of compounds that show promising activity as inhibitors of N-acylethanolamine acid amidase (NAAA)56,57; thioureas that find extensive utility in medicinal chemistry,58 and organocatalyst (Scheme 1c).59–61 Therefore, exploring an efficient route to benzyl thiocyanates will not only be of great importance on its own but also provide streamlined access to other valuable skeletons (e.g., isothiocyanates and thiourea). The canonical methods for benzyl thiocyanate synthesis include substitutions of (pseudo)halides with thiocyanating agents and cyanation of thioalcohol derivatives that uniformly require prefunctionalizations.62 Direct benzylic C(sp3)–H thiocyanation should be the most straightforward approach, which, however, remains a challenging task. Herein, we report a novel and general method for thiocyanation of benzylic C–H bonds that is amenable to both simple alkylarenes and complex molecules (Scheme 1c). In addition, benzyl isothiocyanates are readily accessible through Lewis acid–mediated isomerization of related thiocyanates, which also provides the basis for the valuable benzyl thiourea synthesis. It is noteworthy that both benzyl isothiocyanates and thioureas could be obtained in a successive one-pot fashion from associated C–H substrates. Experimental Methods Compound L10 (0.012 mmol, 2.4 mol %) and CuOAc (0.01 mmol, 2 mol %) were dissolved in 1,1,2,2-tetrachloroethane (TCE) (2.0 mL) under an Ar atmosphere in a dried, sealed tube, and the mixture was stirred for 30 min. Then NFSI (0.75 mmol, 1.5 equiv), alkylarene 1 (0.5 mmol, 1.0 equiv), and (Trimethylsilyl)isothiocyanate (TMSNCS) (0.75 mmol, 1.5 equiv) were added sequentially. The reaction mixture was stirred under Ar at room temperature for another 12 h. After reaction completion, the mixture was directly purified by column chromatography on silica gel or Al2O3 with a gradient eluent of petroleum ether and ethyl acetate to provide the desired products 2–3. Experimental details and characterization methods are available in Supporting Information. Results and Discussion The reaction conditions were optimized using 1-ethylnaphthalene ( 1a) for thiocyanation under conditions resembling our recent examples of C(sp3)–H functionalization, but with TMSNCS as the nucleophile in 1,2-dichloroethane (DCE). The initial attempt with 2,2′-bipyridine ( L1, bpy) as ligand led to appreciable product 2a (14%). As part of the systematic optimization, four 4,4′-disubstituted bpys with electronically diverse functionalities were first evaluated ( L2– L6); however, only L4 with two methyl groups provided slightly improved yield of 2a to 17%. Using more sterically hindered 6,6′-disubstituted bpys, in contrast, resulted in substantial improvement. For example, the reaction with L7 afforded 2a in 34% yield, replacement of the Me substituent with tBu ( L8) led to 2a in 49% yield, and the yield was further increased to 79% with the CN-substituted ligand ( L10). Other ligands, such as 1,10-phenanthroline, 2,2′,2′′-terpyridine, 2,2′-diquinoline, and their derivatives, were also surveyed, but none of them proved to be advantageous (see Supporting Information for full optimization data). Although it is not clear yet, we believe that the unique reactivity of L10 may be due to its capability of modulating the steric and electronic nature of copper centers that could promote the benzylic radical thiocyanation (Scheme 1b). The cyano group potentially plays multifunctional roles, such as manipulating the electron density and steric hindrance of bpy as well as serving as a coordinating group to copper.63,64 Using TCE as solvent finally increased the yield of 2a to 94%. A number of control experiments highlighted the importance of each component. For example, utilizing other thiocyanate sources, such as NaSCN, KSCN, and NH4SCN, led to diminished yields (e.g., 48% yield with NaSCN, see Supporting Information for details). The reaction required both ancillary ligand and catalyst precursors (CuOAc) to operate, which corresponds to copper involvement in the catalytic cycle. Remarkably, the catalyst loading could be reduced to 2% without affecting the reaction efficiency (Table 1). Table 1 | Optimization of the Reaction Conditionsab aReactions were conducted on a 0.1 mmol scale. bYields were determined by 1H NMR spectroscopy with MeNO2 as an internal standard. cWith TCE as solvent. dCuOAc (2 mol %), L (2.4 mol %), NFSI (1.5 equiv), TMSNCS (1.5 equiv). eWithout CuOAc and L. DCE = 1,2-dichloroethane. TCE = 1,1,2,2-tetrachloroethane. Efforts then shifted to test a broad collection of alkylarenes under the optimized conditions (Table 2). Alkylnaphthylenes bearing different functional groups on the alkyl chain are tolerated ( 2a– 2e). Diarylmethane derivatives, important pharmaceutical building blocks and common motifs in drug molecules,65–67 yielded products 2f and 2g in 63% and 52% yields, respectively. Simple alkylbenzenes typically exhibited moderate-to-poor reactivities in our previous work, such as benzylic C(sp3)–H cyanation, arylation, and alkynylation, whereas good-to-excellent yields were observed in the present thiocyanation reactions ( 2h– 3a). A series of functional groups, including chloride ( 2b and 2t), bromide ( 2u and 2o), iodide ( 2k), triflate ( 2l), boronic acid pinacol ester (Bpin, 2z), among others, are compatible with the reaction conditions. The tolerance of these versatile functionalities allows further elaboration of the products. The reaction is unlikely electronic or steric sensitive because of the electronically diverse substituents on suitable substrates and the high reactivity of ortho-substituted ethylbenzenes ( 2p and 2q), underlining the efficacy of this chemistry. More importantly, the reaction exhibits exclusive benzylic selectivity. For example, 2r, derived from the benzylic C–H thiocyanation of isobutylbenzene, was afforded as the sole product although the substrate contains both secondary benzylic and tertiary aliphatic C–H bonds. Meanwhile, the benzylic site could also outcompete those positions that are adjacent to diverse functional groups, such as halide ( 2t and 2u), OAc ( 2v), and OMe ( 2y). The remarkable reactivity was then extended to pharmaceutical relevant heterocycles, including benzothiazole ( 3b), benzofuran ( 3c), and thiophene ( 3d), which furnished the desired products in up to 95% yields ( 3b). Table 2 | Scope of Benzylic C–H Thiocyanationab aAll the reactions were conducted on a 0.5 mmol scale. bIsolated yields. cWith CuOAc (0.5 mol %), L10 (0.6 mol %), and substrate concentration of 1.0 M in TCE. Our previous studies on benzylic C(sp3)–H functionalization via copper-catalyzed radical relay focused on secondary C–H bonds that feature low bond strength and relatively high stability of the resulting radical intermediates, whereas the reactions of primary C–H bonds have not been rigorously investigated. The outstanding reactivity obtained with secondary C–H bonds, especially that for simple alkylbenzenes, prompted us to interrogate the benzylic C–H thiocyanation of methylarenes. In addition to 1-methylnaphthalene, various para- and ortho-substituted toluenes were evaluated, affording the desired benzyl thiocyanates ( 3e– 3l) with moderate-to-excellent yields, and most of the results are comparable to that of their ethylbenzene analogues. Methylbenzothiophene provided the related thiocyanate in high yield ( 3m, 89%). Practical laboratory-scale utility was demonstrated through synthesizing 3f and 3m on gram scale (2.26 and 1.79 g, respectively) with catalyst loading as low as 0.5 mol %. (Hetero)benzylic C–H bonds are prevalent in medicinal and bioactive molecules, and these positions are prone to oxidation catalyzed by enzymes during metabolization.68 Selective functionalization of those C–H bonds could potentially tune the metabolic stability of drugs and regulate the bioactivity of lead compounds or drug candidates.5 The feasibility of late-stage benzylic C–H thiocyanation was then tested with a number of pharmaceuticals and related derivatives. Celestolide, a commercial perfume component, gave the thiocyanated product 3n in 82% yield. The reaction took place exclusively at the less sterically hindered benzylic methylene position of homophenylalanine derivatives ( 3o, 59%). Toltrazuril69 underwent selective thiocyanation in 59% yield ( 3p). Benzbromarone acetate, derived from an antihyperuricemic agent (Benzbromarone70–72), afforded the corresponding thiocyanate 3q in 83% yield, and a similar yield (2.16 g, 82%) was obtained on a 5 mmol scale. Ibuprofen methyl ester, bearing distinct C–H bonds (e.g., benzylic and acidic tertiary C–H bond, benzylic secondary C–H bonds, and aliphatic tertiary C–H bond), was converted to 3r as the sole product in 75% yield. In addition, selective thiocyanation of a retinoic acid receptor agonist analog ( 3s),73 the Celecoxib74 (a potent and gastrointestinal safe anti-inflammatory and analgesic agent, 3t), and a Lithocholic acid analog ( 3u) has also been demonstrated with high efficiency. As noted earlier, site selectivity represents a key challenge in C–H functionalization. If the C–H bond cleavage happens through HAT, the site selectivity is determined by the combination of thermodynamic (e.g., bond strength) and kinetic (e.g., steric hindrance and polarity) preference during HAT from the C–H bond to the HAT acceptor (Scheme 1b).a The selectivity between benzylic and nonbenzylic aliphatic C–H bonds in the copper-catalyzed radical relay system, that is, with NFSI as the oxidant and latent HAT acceptor, has been extensively studied; however, the relative reactivity of distinct benzylic C–H bonds (primary, secondary, and tertiary) is much less explored.32,34,35 The impressive reactivity of site-selective hydrogen abstraction toward both secondary and primary benzylic C–H bonds, as well as its potential extension to tertiary C–H bonds, establishes the basis for such comparison. The thiocyanation reactivity follows the sequence of 3° > 2 ° > 1° based on the competition experiments between individual substrates (Scheme 2a) and the site selectivity in certain substrates bearing two types of C–H bonds (Scheme 2b). These results differ from the observations in the literature although the conditions appear to have some resemblance (e.g., copper catalysis and NFSI as oxidant). For example, Ni et al.32 demonstrated that primary benzylic C–H bonds were functionalized preferentially for sulfonimidation in the presence of secondary benzylic C–H bonds, while Suh et al.35 found that secondary benzylic C–H bonds would outcompete tertiary benzylic C–H bonds for azidation. Such distinctions underline the difference in reaction mechanism (e.g., C–H bond cleavage), which merits future efforts for better understanding. Scheme 2 | Investigation of site-selective hydrogen atom abstract (HAA) of substrates with two different benzylic C–H bonds. (a) Intermolecular competition experiment; (b) intramolecular competition experiment. See Supporting Information for details. Download figure Download PowerPoint We then explored the derivation of benzyl thiocyanates. Benzyl isothiocyanates are frequently found in therapeutic agents and related bioactive compounds (Scheme 1c). Surprisingly, benzyl isothiocyanates were obtained directly from certain C–H substrates under the standard thiocyanation conditions, for example, 4-ethylanisole and cumene ( 4a and 4b, Scheme 3a). The formation of benzyl thiocyanate and its subsequent isomerization to isothiocyanate were evident by monitoring the reaction profiles of both 4-ethylanisole and cumene by 1H NMR spectroscopy (see Supporting Information for details).73 These results support the assertion that the benzyl thiocyanates are kinetically controlled and isothiocyanates should be thermodynamically more stable. Although the process took place spontaneously for thiocyanates adjacent to electron-rich aromatics ( 4a)75 or connected to a quaternary benzylic carbon center ( 4b), ZnCl2 proved to be a reliable catalyst for electronically diverse substrates under elevated temperature. For example, isothiocyanate 4c was obtained efficiently from 1a by simply adding ZnCl2 (2.0 equiv) to the preceding thiocyanation reaction mixture with a one-pot, two-step yield of 74% (Scheme 3b, see Supporting Information for detailed procedures). Such reactivity was effectively extended to a number of other substrates giving benzyl isothiocyanates 4d– 4h in good yields (Table 3). Synthetic utility of the present reaction was amplified by streamlined access to benzyl thioureas, common structural motifs in pharmaceuticals, bioactive molecules, and hydrogen-bonding catalysts. The one-pot sequential thiocyanation, isomerization, and condensation with amines or anilines delivered the benzyl thioureas in moderate-to-good yields ( 5a– 5k, Table 3, see Supporting Information for detailed procedures). Examples of the amines and anilines include morpholine, benzylamine, N-isopropylaniline, indoline, and 1,2,3,4-tetrahydroquinoline. The modular and straightforward approach to accessing benzyl thioureas should find broad applications in organic synthesis. Scheme 3 | (a and b) Isothiocyanates synthesis from C–H substrates. Download figure Download PowerPoint Table 3 | One-Pot Synthesis of Benzyl Isothiocyanates and Thioureas from C–H Substratesab aAll the reactions were conducted on a 0.5 mmol scale. bIsolated yields with respect to C–H substrates. cConditions: ZnCl2 (2.0 equiv) at 50 °C for 6 h after thiocyanation without purification. cConditions: Amine/Aniline (2.0 equiv), Et3N (5.0 equiv) at 50 °C for 6–12 h after isothiocyanation without purification (see Supporting Information for detailed procedures). In addition to isothiocyanates and thioureas, the benzylic C(sp3)–H thiocyanation provides a valuable platform for incorporating other functionalities. For example, trifluoromethylthio (SCF3) and difluoromethylthio (SCF2H) groups are attractive units in medicinal chemistry in that compounds containing these groups typically possess distinctive properties (e.g., the high lipophilicity of SCF3 and unique hydrogen binding ability of SCF2H). 76–78 As shown in Scheme 4, with our current method, both SCF3 and SCF2H products were accessed in good yields via tandem thiocyanation and substitution ( 6 and 7) with components that are all commercially available and inexpensive.79–81 5-S-Linked tetrazoles have been employed as activators for DNA and RNA synthesis, making them an important target.82,83 5-S-Benzbromarone-linked tetrazole ( 8) was obtained from ZnCl2-catalyzed condensation of the corresponding thiocyanate with NaN3 in iPrOH. Finally, reductive dimerization of 3m afforded the disulfide 9 in 79% yield. Scheme 4 | Tandem diversification of benzylic C–H bonds. Download figure Download PowerPoint Conclusion We have demonstrated an efficient method for thiocyanation and then diversification of benzylic C–H bonds. Expanding the synthetic utility of the robust copper-catalyzed radical relay approach, this method provides a distinctive route to incorporate various medicinally and synthetically important functionalities, including thiocyanate, isothiocyanate, thiourea, SCF3, and SCF2H, among others. The appeal of this method is also highlighted by the broad substrate scope, diverse functional group tolerance, one-pot derivatization, and applicability to late-stage functionalization. Future efforts will be focused on understanding the mechanism and interrogating the synthetic applications. Footnote a An N-centered radical might coordinate with copper to form a complex that serves as the HAT acceptor, see refs 29 and 30. Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Funding Information The authors are grateful for financial support from the National Nature Science Foundation of China (nos. 21532009, 91956202, 21821002, 21790330, and 21761142010), the Science and Technology Commission of Shanghai Municipality (nos. 19590750400 and 17JC1401200), the strategic Priority Research Program (no. XDB20000000), the Key Research Program of Frontier Science (no. QYZDJSSW-SLH055), and the International Partnership Program (no. 121731KYSB20190016) of the Chinese Academy of Sciences. P.C. also thanks the Youth Innovation Promotion Association CAS (no.2018292). References 1. Giri R.; Shi B. F.; Engle K. M.; Maugel N.; Yu J.-Q.Transition Metal-Catalyzed C–H Activation Reactions: Diastereoselectivity and Enantioselectivity.Chem. Soc. Rev.2009, 38, 3242–3272. Google Scholar 2. Newhouse T.; Baran P. S.If C–H Bonds Could Talk: Selective C–H Bond Oxidation.Angew. Chem. Int. Ed.2011, 50, 3362–3374. Google Scholar 3. Lyons T. W.; Sanford M. 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