En Route to Intermolecular Cross-Dehydrogenative Coupling (CDC

Subscriber access provided by Nottingham Trent University

Perspective

En Route to Intermolecular Cross-Dehydrogenative Coupling (CDC) Reactions Chia-Yu Huang, Hyotaik Kang, Jianbin Li, and Chao-Jun Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01704 • Publication Date (Web): 23 Aug 2019 Downloaded from pubs.acs.org on August 23, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

En Route to Intermolecular Cross-Dehydrogenative Coupling (CDC) Reactions Chia-Yu Huang‡, Hyotaik Kang‡, Jianbin Li and Chao-Jun-Li* Department of Chemistry and FRQNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke St. W., Montreal, Quebec H3A 0B8, Canada

Scheme 1. The Concept of CDC

ABSTRACT: Cross-coupling reaction between two C–H bonds has become a fundamental strategy in synthetic organic chemistry. With the increasing importance in green chemistry, atom economy, and step economy, its development has sky-rocketed within the last twenty years, with the term “cross-dehydrogenative coupling (CDC)” popularized and progressed by the group of Li and others to describe direct Y–Z bond formations from Y–H and Z–H bonds under oxidative conditions. Among all types of CDC reactions, the C–C bond formations are of prime importance in building up the molecular complexity but their categorization currently remains disarray due to a wide diversity, resulting in frequent display in separate topics. In this perspective, a contemporary categorization via C–H activation strategies are presented herein, which could be vital for future CDC designs. With this mechanism-based categorization and discussion, we wish that this minireview will help more synthetic chemists gain insight into the design of CDC reactions and inspires more ideas on this topic.

INTRODUCTION

Despite the significance and diversity of CDC reactions, there is a surprising lack of reviews focusing on the different design strategies of CDC reactions. Instead, it frequently appeared in reviews regarding other topics such as radical reaction,10 metal catalysis,11 photochemistry,12 and electrochemistry.13 In addition, the current library of CDC reviews8a, 14 categorized reactions by carbon hybridizations instead of a mechanistic perspective. This display of CDC posed to be unflattering and difficult to demonstrate the versatility in C–H activation/functionalization due to its unkempt nature. As a result, a more modern way to present the topic “CDC” is necessary. In this regard, we believed that separating the coupling partners apart and focusing on their respective C–H activation pathway illustrates a clear, comprehensible picture while spotlighting the fundamentals in CDC designs. Since this minireview only focuses on C–H/C–H couplings, in the following paragraphs all the CDC refers to “C–C cross-dehydrogenative-coupling” unless otherwise noted.

GENERAL DESIGN STRATEGIES

The C–C bond is one of the most abundant, versatile and important types of bond in nature.1 Over the past century, numerous strategies such as nucleophilic addition,2 nucleophilic substitution,3 FriedelCrafts reaction,4 Cope rearrangement,5 and pericyclization6 have been well utilized to construct C–C bonds. Likewise, various transition metal-catalyzed cross-couplings of C–X/C–X and C–H/C– X, where X = (pseudo)halides or metals, have also been well established in synthetic designs.7 These methods have greatly enriched chemists’ toolbox to tackle diverse challenges; however, from the perspectives of green chemistry, atom economy and step economy, protocols that can avoid prefunctionalization of the starting materials are still highly desirable. As a result, the concept of “cross dehydrogenative coupling (CDC)”8 arouse in these years because (1) no prefunctionalization is required, improving step economy and reducing the wastes; (2) high atom efficiency is gained by formal removal of the molecular hydrogen; (3) direct C–H activation/functionalization would be highly desirable for late-stage functionalizations (Scheme 1). Delightfully, a boost in efforts have been devoted to CDC reactions, and fruitful developments have been observed from their potential applications in pharmaceuticals, agrochemicals, and organic materials.9

CDC involves the dehydrogenative connection of two C–H bonds. By overcoming the activation energy and forming active intermediates, coupling partners are connected. Yet, the potential diversity of chemical bonds in one molecule make this an intrinsically challenging topic, especially in late-stage functionalizations. For a rationally designed CDC reaction, it should manage to tackle this challenge when targeting two specific C–H bonds and meanwhile preserving other functional groups. The activation of a C–H bond could be accomplished through more than one way, but not all of them are applicable in CDC. Taking the activation of C(sp3)–H on quinaldine (2-methylquinoline) as an example, there are generally three known methods to achieve it: (1) direct deprotonation by a strong base, (2) hydrogen atom abstraction to generate a benzylic radical, and (3) Lewis acid (LA)assisted tautomerization (Scheme 2). For the purpose of CDC, the first method would potentially compromise the functional group tolerance as well as the subsequent formal dehydrogenative process; therefore, it is rarely considered in CDC design. The second method generates a benzylic radical for the additions. Nonetheless, in the case of C(sp2)–C(sp3) CDC15, it would be difficult to reform a double bond after radical addition to an olefin regardless of

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Scheme 2. C(sp3)–H activations of quinaldine

achieving C(sp3)–C(sp3) CDC via diradical coupling. This makes the second strategy more suitable for redox-neutral functionalizations but less employed for CDC16. The last strategy utilizes imineenamine tautomerization, where the latter nucleophilic intermediate could be accessed under mild conditions and embedded in the coupling events in the presence of electrophilic partners, like iminium ion.17 As such, it is an ideal way to achieve an efficient C(sp3)–C(sp3) CDC (see Scheme 15 for an example). An underlying challenge with any given molecule is the presence of multiple reactive C–H sites, which would cause the regioselectivity issues when linking two C-H species. With a judicious choice of activation systems and fine-tuned conditions, the subtle differences on either electronics or sterics in one specific substrate could be differentiated, therefore, pinpointing the desired regioselective outcome. Taking again quinaldine, for example, it can undergo tautomerization assisted by Lewis acid. As a result of this two-electron process, the benzylic site could now be associated with the tetrahydroisoquinoline (THIQ) -derived iminium to give the -C-H functionalization product (Scheme 3a).17 On the contrary, when it is subjected to single-electron transfer conditions, for instance, treated with benzoyl peroxide (BPO) with trifluoroacetic acid (TFA) in tetrahydrofuran (THF) at 80 °C, the THF radical is efficiently generated through hydrogen atom abstraction would act as a nucleophile to attack the protonated heteroarene, affording a C(sp2)– C(sp3) bond on C-4 position. (Scheme 3b, see Schemes 5 and 6 for examples).18 Scheme 3. C(sp3)–H activations of quinaldine

Aforementioned examples have revealed two important questions in CDC designs: how to activate the C–H bonds, and how to link the C–H species. These are unnecessarily restricted to quinaldine but also to a broad scope of C-H substrates in the CDC realm. More importantly, it emphasizes the importance of selecting an appropriate activation mode during the CDC design, as it could affect the functional group tolerance, guide the regioselective outcome and ultimately determine the fate of the reaction. Gladly, credited to the predecessor’s contribution and successes, many strategies toward C–H activations have been developed, and after referring to a substantial amount of literature related to CDC, the crucial intermediate generation steps in CDC designs, in our per-

Page 2 of 16

spective, can be categorized into six types; (a) hydrogen atom abstraction, (b) -heteroatom-driven hydride removal, (c) tautomerization, (d) single-electron alkene/arene oxidation, (e) in situ C–H functionalization, and (f) metal-catalyzed C–H activation, as illustrated in Scheme 4. By identifying the intermediates generated from each strategy, it is easier to show the potential coupling partners from their electronic properties and give a rational CDC design. As a result, the following sections will be correspondingly divided based on these six types. It should be noted that a CDC reaction could contain more than one activation type due to the presence of two C–H substrates. To be concise and comprehensible, reactions with different conditions but in a mechanistically analogous manner might be omitted, and those involving other bond formations or cleavages will also be excluded. We hope that this minireview will give a clear overview of the reaction designs in CDCs and inspire new thoughts for chemists to come up with more efficient and sustainable chemistry reactions from the mechanistic aspect. Scheme 4. Different approaches to generate active intermediates for CDCs

C–H ACTIVATION ABSTRACTIONS

STRATEGIES:

HYDROGEN

ATOM

Regarding C–H acidity of different carbon hybridizations, to deprotonate a C(sp3)–H is the most difficult; however, due to the high porbital character of C(sp3) in comparison with the others, it turns out to be the easiest one to undergo C–H homocleavage. Hydrogen atom abstraction (HAA) is probably the most intuitive way to activate C(sp3)–H and formyl C(sp2)–H bonds. Because of the strong bond dissociation energy of C–H, a potent oxidant for HAA is a requisite in each design. The dehydrogenative Minisci reaction is a good example which strongly depends on the hydrogen atom abstractor The Minisci reaction, pioneered by Minisci in 1971,19 is a specific type of reaction that couples radical species and electron-deficient heteroarenes, and /its dehydrogenative version is an important method to couple heteroarenes and hydrocarbons.20 From the mechanistic aspect, Lewis acid was generally added to lower the heteroarene’s electron density. At the same time, a carbon-centered radical generated through HAA nucleophilically attacks the heteroarene. The generated radical cation intermediate then rearomatized to form the desired acid-coordinated product (Scheme 5). Due to its mechanistic simplicity and the reagents accessibility, the dehydrogenative Minisci reaction is one of the most popular methods in heteroarene functionalizations. Scheme 5. The concept of dehydrogenative Minisci reactions


Page 3 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The key step in this reaction is the generation of the carbon-centered radical, as a result, most of the strategies focused on the exploration of efficient radical generators and milder, greener protocols. Early works exploited heating to decompose peroxides18, 19b, 21 or persulfates22 and generate an oxy radical for HAA processes, which were not ideal for safety concerns and substrate tolerance. As a result, recent works combined photochemistry to achieve couplings at ambient temperature. In 2015, the group of MacMillan introduced the photoredox catalyst [Ir(dF(CF3)ppy))2(dtbbpy)]PF6 (Ir-PC) to efficiently decompose the persulfate oxidant at room temperature with compact fluorescent lamp (CFL) as the light source (Scheme 6).23 The Ir(III) catalyst was excited to its triplex state under light irradiation, transferring an electron to the persulfate and then generating a sulfate radical anion for HAA. The carbon-centered radical species generated could couple with the heteroarene, followed by single-electron oxidation by Ir(IV) and rearomatized to afford the protonated product. Scheme 6. Photocatalyst-assisted dehydrogenative Minisci reaction

Scheme 7. Alternative hydrogen atom abstractors and oxidants for dehydrogenative Minisci reactions

(Scheme 9a).32 The allyl compound was oxidized by DDQ via two stages of single-electron transfers (SETs) to form an allylic carbocation, which then coupled with enolized diketone to form the product. In the following year, a DDQ-mediated CDC between indoles and diarylpropenes using PdCl2 as the catalyst in MeCN at 0 °C was reported (Scheme 9b).33 Li et al in 2015 likewise demonstrated the coupling of oxindoles and electron-rich arenes using oxygen as a clean oxidant with catalytic FeBr3 (Scheme 9c).34 The benzylic radical generated from oxindole in the presence of oxidant (Fe(III) or O2) was sequentially oxidized to the benzylic carbocation intermediate. The arene then coupled with the cation species through Scheme 8. CDC of oxindoles and styrenes

In addition to using peroxide/persulfate to perform the HAA, other elegant designs were developed to generate different hydrogen atom abstractors for the couplings (Scheme 7). For example, Antonchick et al used NaN3 and (bis(trifluoroacetoxy)iodo)benzene (PIFA) to generate azide radical and iodine-centered radical for HAA at room temperature.24 No external acid source was needed in this reaction since PIFA released TFA to protonate the heteroarene. The group of MacMillan exploited an Ir(III) photocatalyst-thiol dual-catalyst system, in which the generated thiyl radical was used for HAA.25 Wang et al employed excessive N-hydroxysuccinimide (NHS) and (NH4)2S2O8 to generate the N-centered radical cation.26 Ryu’s group employed decatungstate photocatalyst TBATD as both photosensitizer and hydrogen atom abstractor for the reaction under solar light irradiation, while K2S2O8 was added to reactivate the catalyst.27 Li et al also used UV light to generate chlorine radical from CH2Cl2.28 Recently, Lei’s group discovered Selectfluor could be homolytically cleaved under blue light to form an N-centered radical cation as the hydrogen atom abstractor.29 Taking the advantages of visible light-sensitive, volatile, and oxidizing properties of diacetyl (2,3-butanedione), Li et al utilized diacetyl as a peroxide/persulfate surrogate under visible light excitation.30 These modern designs also provide alternative HAA strategies for other C–H functionalizations and CDC reactions. Other than the Minisci reaction, Liu et al in 2015 used 20 mol% of I2 to catalyze the coupling of oxindoles and styrenes via HAA (Scheme 8).31 The proposed mechanism involves the iodine-mediated oxindole and iodine radical generations, followed by the reaction of the generated benzylic radical with the styrene and HI elimination to form the alkenylated product. The I2 was regenerated via oxidation of HI under air. Carbon-centered radicals could be nucleophilic or electrophilic depending on the substituent. If a radical is further oxidized to a carbocation, it becomes more electrophilic with the potential to explore more coupling chemistry. Bao et al in 2008 reported a metalfree dehydrogenative allylic alkylation using DDQ as the oxidant

Scheme 9. Functionalizations of 1,3-diarylpropenes



the nucleophilic attack and aromatized to give the arylated oxindole.

Page 4 of 16

Scheme 11. Different approaches toward formal hydride removal followed by functionalizations

C–H ACTIVATION STRATEGIES: -HETEROATOM-DRIVEN HYDRIDE REMOVALS Although C(sp3)–H activation could be accomplished through HAA, the regioselectivity could be problematic due to subtle activation energy differences between C(sp3)–H bonds. Despite this, if the C(sp3)–H bond is adjacent to an electron-rich heteroatom, for instance, nitrogen, the reaction could regioselectively occur at this position via formal hydride removal to generate an active iminium ion intermediate, with the C(sp3) character restored after electrophilic addition to a nucleophile. Inspired by the Ru-catalyzed iminium generation pioneered by Murahashi et al35 and the “cation pool”-enabled two-step coupling developed by Yoshida et al,36 Li et al in 2004 used N,N-dimethylanilines and terminal alkynes as the coupling partners with 5 mol% of CuBr and 1 equiv of TBHP at 100 °C to afford propargylic amines (Scheme 10a).37 The method performed not only with N,Ndimethylanline derivatives but also bioactive THIQ substrate. It was postulated that the copper catalyst played two separate roles, one was the generation of the imine-type complex through the activation of the C(sp3)–H bond adjacent to the nitrogen in the presence of TBHP, and the other was the C(sp)–H activation of the terminal alkyne to generate the copper acetylide. Subsequently, the coupling of the two species yielded the propargylic amine and regenerate the catalyst. Soon later, they showed that the strategy could achieve enantioselective alkynylation of THIQ by using CuOTf as the catalyst, 2,6-bis[(4S)-4-phenyl-2-oxazolinyl]pyridine ((S,S)-Ph-pybox) as the chiral ligand at mild reaction conditions, which gave 11-72% of different alkynylated THIQs with 5-74% ee (Scheme 10b).38 Scheme 10. Cu-catalyzed propargylic aminations

system. More related works before 2014 have been well summarized in the literature.8c, 48a, 49 Hydrogen evolution is the goal for CDC since its byproduct dihydrogen is green and easily removable. In 2013, Wu et al reported a novel THIQ indolation with graphene-supported RuO2 (G-RuO2) and eosin Y as the catalysts in water under visible light irradiation (Scheme 12a).50 The reaction is external oxidant-free because hydrogen gas evolution is involved. In the proposed mechanism, eosin Y was excited by light and oxidized the THIQ through singleelectron oxidation. The formed THIQ radical cation lost one electron to G-RuO2 and generated an iminium ion intermediate upon deprotonation. The intermediate reacted with nucleophilic indole to give the coupling product. The elegance of this design is that eosin Y was restored via SET from eosin Y•– to G-RuO2, and the G-RuO2 could be reactivated once it reacted with water and proton to generate hydrogen gas. Expanding on this established hydrogen evolution design, the group of Wu later replaced ruthenium with more economical Co(III) catalyst, Co(dmgH)2Cl2 and green LED as the light source to achieve the same transformation (Scheme 12b).51 Apart from the single-electron oxidation pathway to obtain those electrophilic intermediates, ionic pathways were developed by the groups of Li and García Mancheño. As demonstrated by Li and coworkers in 2009, the trisubstituted amine was alkynylated in the Scheme 12. CDC of THIQs and indoles with H2 evolution

Their success pioneered new roads toward dehydrogenative C(sp3)–H functionalizations, and the number of -functionalization protocols that have been developed based on the outlined iminium ion generation strategy showed the broad applicability of this strategy (Scheme 11). In addition to amine substrates, benzylic ethers/39thioethers40 were demonstrated to be practical, and oxidants such as DDQ,39a, 39b SO2Cl2/O2,41 PhI(OAc)2,42 I2,43 metal or organic photocatalysts39c, 44 and others45 were also developed lately. Nucleophiles such as nitromethane,42-44, 46 indole,45c, 47 dicarbonyl,39-40, 44b, 45c and others45a, 48 were shown to be effective in this


Page 5 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


presence of 5 mol% of CuI and 1.1 equiv of diethyl azodicarboxylate (DEAD) at room temperature and gave moderate to excellent yields (64-90%) of the corresponding propargylic amines (Scheme 13a).52 A tentative DEAD-mediated multiple deprotonation mechanism was proposed to generate the Cu(I) acetylide and iminium ion, which coupled to the desired product. Another instance reported by García Mancheño et al coupled THIQ or isochroman derivatives with dicarbonyl compounds with 10 mol% of Fe(OTf)2 and 1.2 equiv of TEMPO salt (T+BF4-) and provided moderate to good yields (40-85%) of the alkylated products (Scheme 13b).53 Suggested by the radical quenching experiment, an ionic generation pathway for iminium or oxonium ion was proposed to go through formal hydride transfer to the oxygen on the TEMPO salt, while Fe(II) only participated in the coordination-assisted tautomerization of the dicarbonyl compound as the reaction still proceeded by replacing the metal catalyst with acid to facilitate the dicarbonyl tautomerization.

Scheme 14. Enantioselective CDC of esters and THIQs

Scheme 13. Ionic pathways for -hydride removal

eventually determine the enantioselectivity. The organocatalyst turnover was promoted by the nucleophilic attack of the 4nitrophenoxid. With the advantages of bearing vicinal carbonyls and a phenyl group, the C3 C–H functionalization of oxindoles can go through tautomerizations to generate a nucleophilic enol species under mild conditions. An example was demonstrated by Wang et al in 2012 using an enzyme, laccase from Pleurotus ostreatus (15 U), as an environment-friendly oxidase to couple oxindoles and catechol derivatives at room temperature in moderate to good yields (52-87%) (Scheme 15).55 The reaction mechanism involved the oxidation of catechol to ortho-quinone in the presence of laccase and oxygen, which was attacked by the 2-hydroxyindole tautomerized from the oxindole and rearomatized to give the 3-aryloxindole. Scheme 15. Enzyme-enabled CDC of oxindoles and catechols

C–H ACTIVATION STRATEGIES: TAUTOMERIZATIONS The outlined approach is commonly observed in synthesis when a C(sp3)–H is adjacent to an electron-withdrawing group such as ketone, ester, amide or nitro group, which facilitates the generation of a nucleophilic C(sp2) center from C(sp3)–H, as shown in some C(sp3)–C(sp3) bond-building strategies presented in the previous chapter. Despite its conceptual simplicity, the tautomerization could be a crucial step in the reaction design. In 2018, Smith and co-workers designed a one-pot, two-step enantioselective CDC of esters and THIQs by taking advantage of keto-enol tautomerization (Scheme 14).54 The iminium salts were generated in situ from THIQs with 0.5 mol% of the redox photocatalyst Ru(bpy)3Cl2 (Ru-PC) and 1.5 equiv of CBrCl3 under blue light, which were then subjected to react with 1.5 equiv of the esters, 5 mol% of the chiral isothiourea organocatalyst (OC*), 1 equiv of tetrabutylammonium 4-nitrophenoxide (TBAPNP) and 1.5 equiv of iPr2NEt in THF at -10 °C. Amine reagents were then added to react with the ester intermediates to obtain isolable amides. Moderate to excellent yields (51-96%) of the products were obtained with 56:44-79:21 dr and 76:24-99.5:0.5 er. The reaction protocol represents the organocatalyst, isothiourea proceeds through N-acylation with the active aryl ester species to form an acyl ammonium intermediate. Enolization of this intermediate led to an ammonium enolate which was conformationally locked due to the nO to σ*C−S interaction between the enolate O and the catalyst S. This would

As mentioned previously, recent studies showed that the C(sp3)– H activation of quinaldine could be simply enabled through enamination with the aid of a Lewis56 or Bronsted acid (BA).57 Inspired by these results, Yang and his group in 2014 developed a C(sp3)–C(sp3) dehydrogenative coupling between quinaldines and THIQs (Scheme 16).17 The reaction was conducted with 5 mol% of Cu(OTf)2 and 25 mol% of pivalic acid (PivOH) in dichloroethane (DCE) at 60 °C under O2 atmosphere, and moderate to excellent yields (54-90%) of the coupling products were obtained. Two concerted pathways occurred during the reaction: one being the Bronsted acid-assisted tautomerization of quinaldine to generate an enamine nucleophile and the other showed THIQ oxidation in the presence of Cu(II) and O2 to form an iminium ion as the electrophile. Coupling of the two species eventually gave the product.



Page 6 of 16

bonyl group was assisted by Fe(III) generated in situ and the chelating imidazole group, which could be removed to yield acid derivatives (18b).63

Scheme 16. CDC of quinaldines and THIQs

Scheme 18. Dehydrogenative benzylic functionalizations with dicarbonyl or amino acid derivatives

MeCN could be a promising cyanomethylation source for its readily accessibility and modest toxicity; however, it is generally considered as an inert organic solvent for its high pKa value (31.3 in DMSO). Most of the cyanomethylation strategies required halogenated acetonitrile for SN2 reactions58 or acetonitrile radical for radical additions59. Until Shen and co-workers in 2016 successfully showed that MeCN could be tautomerized to perform nucleophilic addition to THIQ through CDC (Scheme 17).60 The cyanomethylation of THIQs was conducted with 20 mol% of CuCl2, 1.5 equiv of TEMPO, 1 equiv of Cs2CO3 in MeCN at 120 °C under N2. As the mechanism proposed, Cu(I) was oxidized to Cu(II) and acted as a Lewis acid to coordinate with MeCN to facilitate the tautomerization in the presence of the base. Meanwhile, the THIQ was oxidized by Cu(I) and TEMPO to form an iminium salt, which subsequently coupled with tautomerized MeCN to form the alkylated product. The reactions produced a broad spectrum of products in poor to good yields (37-87%), and interestingly, when isobutyronitrile or pentanenitrile was used, N-amidations instead of alkylations of the THIQ were observed. Scheme 17. Cu-catalyzed cyanomethylation of THIQs

C–H ACTIVATION STRATEGIES: ALKENE/ARENE OXIDATIONS

SINGLE-ELECTRON

In the presence of a strong oxidant, electron-rich alkenes or arenes could lose an electron to form a radical cation and function as an electrophile. Thereby, the alkene/arene single-electron oxidation are routinely followed by the coupling with nucleophiles; however, most of them are, again, alkenes and arenes. As a result, the ability to selectively oxidize one of the substrates while preventing overoxidation and homocoupling is a long-lasting topic64 (Scheme 19). Scheme 19. Single-electron oxidation of alkenes/arenes followed by CDC

Enols were considered nucleophilic in ionic reactions from the aspect of enol conjugation; however, once enols are coordinated with Lewis acid such as metal cations to localize C-C double bond, these electron-deficient alkenes can act as electrophiles and trap nucleophilic alkyl radicals to construct new C-C bonds. This reversed property of enols was utilized by Li et al in 2007 to achieve a novel CDC between dicarbonyl compounds and diarylmethanes (Scheme 18a).61 The optimal reaction conditions used 10 mol% of FeCl2·4H2O and 2 equiv of di-tert-butyl peroxide (DTBP) in diarylmethane solvents at 80 °C under N2. The tentative mechanism started with the SET between Fe(II) and DTBP to generate Fe(III) and tert-butoxy radical, which were followed by coordination with enolized dicarbonyl and HAA from diarylmethane, respectively. The formed Fe(III)-acetylacetonate complex further reacted with diarylmethyl radical to yield the product with the release of Fe(II). 40-87% of the coupling products were obtained from diarylmethane by this method, and other benzylic substrates such as tetralin and indane are also effective. Soon after, the protocol was extended to the CDC with unactivated cycloalkanes at 100 °C.62 In a mechanistically similar work, in 2018 Yazaki and Ohshima reported the coupling of monocarbonyl compounds and toluene derivatives was accomplished with catalytic FeCl2, phosphine oxide ligand (4OMe-Ph)3PO and DTBP at 80 °C. The tautomerization of the car-

A series of metal-free arene-arene CDCs were developed by Kita and co-workers to achieve homo/heterocoupling of arenes such as thiophene, pyrrole, naphthalene, and others.65 An attractive feature of their methodology is that hypervalent iodine such as PIFA and PhI(OH)OTs was used as the key oxidant to activate arenes and selectively couple with another electron-rich arene under metalfree conditions. Early adaptations required stoichiometric amounts of hypervalent iodine as the oxidant to mediate the coupling; but in 2013, they reported the first catalytic protocol using solely 5 mol% Scheme 20. Hypervalent iodine-catalyzed heterocoupling of anilines and arenes


Page 7 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of the iodide(I) as the preoxidant and 1.5 equiv of the co-oxidant mCPBA to couple anilines and arenes at room temperature (Scheme 20).66 With the optimized conditions, reactions gave moderate to excellent yields (50-99%) of C2-arylated anilines, and unlike usual C–N couplings, the method provided the first C–C coupling between anilines and nucleophilic arenes. Electrochemistry is being established as a powerful tool in organic synthesis for its ability to directly donate or withdraw electrons from the reaction system in the absence of external redox reagents. An increasing number of synthetic chemists have started their excavations into the combination of conventional chemistry and electrochemistry for its cleanliness and atom efficiency of reactions.13, 67 In the previous arene-arene heterocoupling, it is difficult to avoid homocouplings and overoxidation of the biaryl product. To tackle these issues, Yoshida et al in 2012 reported a heterocoupling of arenes under metal- and oxidant-free conditions by applying the concept “radical-cation pool” (Scheme 21).64 This method controlled selectivity by two-step reactions; in the reaction setup, the initial arene was electrolyzed in the anodic chamber to generate the unstable organic radical cation at -78 °C, in which the second arene was added as a nucleophile at -90 °C afterward. Generally, good reactivity (70-92%) were shown for biaryls bearing functional groups such as halide, alkyl, ester, and sulfonamide. However, 4 equiv of the organic radical cation source was necessary for this reaction due to the formation of the dimer complex, that took part in the terminal single-electron oxidation process. Scheme 21. Radical-cation pool-enabled heterocoupling of arenes

Due to phenol’s electron-rich property and its presence of a hydroxy group, depending on the reaction conditions, formal singleelectron oxidation of phenolic arenes could be accomplished either through HAA or stepwise proton and electron transfers from the hydroxy group.68 These pathways allow various nucleophilic functionalizations of phenols, and one type of valuable product is biphenol. Biphenol structures are found in various natural products, pharmaceutical molecules, and are also important ligands in organic synthesis.69 The homo CDC of phenols could be traced back to 1968,70 and has been achieved following the concept of radical cation formations using oxidants such as NO2+,71 Fe(III),72 Cu(I),73 Co(II),74 and others.75 The heterocoupling of phenols is, however, challenging due to the competing side reactions such as the formation of Pummerer ketones, homocoupled biphenols, and quinones. In 2014, Kozlowski et al reported a metal-catalyzed hetero CDC coupling of phenols assisted by the salen-derived ligand Salen-Cy (Scheme 22a).76 In their investigations, metals such as Ru, V, Cu, and Cr all worked for the heterocoupling, while the Cr(III) catalyst Cr-Salen-Cy was especially good for para-ortho regioselectivity. The proposed mechanism involving the oxidation of 2 equiv of Cr-Salen-Cy by 0.5 equiv of oxygen to form a Cr(IV)– O–Cr(IV) species, which could react with phenol to generate a Cr(IV)-phenolate complex. The carbon radical, which was formed from the phenolate via SET to the Cr metal center, could react with another phenol to give the product, and the Cr(III) catalyst was regenerated during the rearomatization process.

Scheme 22. Biphenol synthesis via CDC of phenols

In addition to ortho-para biphenol couplings, Jeganmohan et al in 2015 used persulfate K2S2O8 as the oxidant to couple two phenols in TFA. By adding a catalytic amount of the ionic Bu4N+·HSO3- to stabilize the radical cation intermediate, the orthoortho heterocoupled products were obtained in 33-82% (Scheme 22b).69 In 2018, Lei et al exploited 3 mol% of Acr+-Mes ClO4- and 10 mol% of Co(III) catalyst [Co(dmgH)2(4-NMe2py)Cl] to fulfill CDC between electron-rich arenes and styrenes at room temperature under visible light irradiation with the evolution of hydrogen gas as the byproduct (Scheme 23).77 In the proposed mechanism, the light-excited acridinium ion oxidized the electron-rich arenes to form an aryl radical cation, which coupled with the styrene to generate a distonic radical cation. Further deprotonations and singleelectron oxidation would give an alkenylated alkene. It was also possible that the alkene oxidation happened first and then coupled with an arene. On the other hand, the cobalt catalyst was crucial for both the oxidation of acridinium salt and the hydrogen evolution step. The reaction gave moderate to excellent yields (34-99%) of the coupling products, and heteroarenes such as pyrrole, furan, and thiophene were tolerable in this system. Scheme 23. CDC of arenes and styrenes with H2 evolution

C–H ACTIVATION STRATEGIES: FUNCTIONALIZATIONS

IN

SITU

C–H

In situ C–H functionalization means to generate active non-C–H species from C-H substrates for cross-coupling reactions in one-pot, avoiding tedious sequential additions and purifications as shown in



Scheme 24. Since the in situ-formed coupling partners are no longer C–H substrates, they might even present different reactivity and properties from the original ones. Scheme 24. The concept of in situ C–H functionalization-enabled CDC

The Glaser coupling is a well-established reaction which couples two-terminal alkynes to generate diynes in the presence of transition metal catalysts (will be discussed in the later section). Considering the formation of metal acetylides, electron-deficient alkyne substrates would give better coupling efficiency and yields. A novel Glaser-type coupling was introduced by Fan et al78 in 2010 in which a bromodicarbonyl compound was used to assist the coupling with catalytic CuI at room temperature (Scheme 25). In their proposed mechanism, a half equivalent of the terminal alkyne was oxidized to bromoalkyne by the bromodicarbonyl compound, and this active species coupled with another half equivalent of terminal alkyne in the presence of the copper catalyst. Interestingly, relatively good yields (65-99%) were obtained from electron-rich substrates while most of the electron-deficient substrates gave no reactivity, which the result was opposite to other direct Glaser couplings.

Page 8 of 16

2-methylmalonate, and the thiophene could not have a strong electron-withdrawing group such as chloro or ester group on it. Radical-mediated remote C–H functionalization is a largely unexplored but intriguing topic these years for its possibility to precisely activate inert C(sp3)–H bonds through 1,n-HAT which n ≥ 5.80 Such functionalizations normally required a weak heteroatom– heteroatom bond on the alkyl substrate that could homocleave to generate a heteroatom radical to perform the remote HAA from its own alkyl chain, and prefunctionalizations are sometimes needed. Zhu and his team in 2018 combined dehydrogenative Minisci alkylation with the 1,5-HAT concept to achieve remote heteroarylation of alkylalcohols using PIFA as both oxidant and acid source, which no prefunctionalization of the alcohols was needed (Scheme 27).81 Supported by the mechanistic studies, the PIFA efficiently reacted with an alcohol to form a metastable dialkoxyphenyliodane intermediate, which decomposed under irradiation to generate an oxy radical. 1,5-HAT occurred through a six-membered cyclic transition state gave a carbon-centered radical at the C4 position, followed by Minisci alkylation to give the coupling product. The protocol produced 33-90% of the coupling products including medium- to macrocyclic alcohols and complex heterocycles. Scheme 27. Remote dehydrogenative C(sp3)–H heteroarylations

Scheme 25. Bromodicarbonyl-assisted Glaser-type reaction

C–H ACTIVATION STRATEGIES: METAL-CATALYZED C–H ACTIVATIONS In situ C–H functionalization can be used for metal-free Minisci alkylation of thiophenes with trisubstituted malonate derivatives, which was demonstrated by the group of Yamaguchi and Itoh in 2017 (Scheme 26).79 The optimal reaction conditions used 20 mol% of I2 as the catalyst in basic solution under air with visible light irradiation. The proposed mechanism involved the in-situ C– H iodination of the malonate, which then homocleaved into iodine radical and malonate radical upon light irradiation. These radicals then coupled with thiophene to afford a 1,2-dihydrothiophene intermediate, which rearomatized after losing a HI in basic conditions. The HI was oxidized into I2 in the presence of O2 and reentered the catalytic cycle. The reaction afforded 45-83% yields of the corresponding products; however, the protocol was limited to the tertiary alkyl sources bearing three electron-withdrawing groups as no product was observed with diethyl malonate or diethyl Scheme 26. CDC of thiophenes and trisubstituted malonates

Transition metal-catalyzed C–H activation is the most applied method among the aforementioned. Its strength is the ability to convert strong C–H bonds into weaker and reactive C–M bonds. Since the first metal-catalyzed C–H activation reported by Volhard in 1892,82 it has been explored and progressed for more than a hundred year; mechanisms such as -bond metathesis, oxidative addition, electrophilic activation, and others were studied in detail,83 and some of them have been applied in CDC designs. Since there are a great number of reviews related to metal-catalyzed C–H functionalizations by types of metal, mechanism or reaction,11b, 11c, 84 the purpose of this review will focus elsewhere. Here, we would like to demonstrate a few representative CDC examples involving transition metal-catalyzed C–H activations. The Glaser coupling is one of the oldest Cu-mediated C(sp)– C(sp) homo-dehydrogenative coupling,85 and Glaser-Hay coupling is its catalytic version which significantly influences the later diyne syntheses (Scheme 28).86 From the mechanistic aspect, with the assistant of copper- interaction between copper salt and terminal alkyne, the copper acetylide was formed. Two copper acetylide then Scheme 28. Simplified mechanism of Glaser-Hay coupling


Page 9 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


coupled together and underwent reductive elimination to give the diyne. Although the generally accepted mechanism for the Glasertype couplings was the one proposed by Bohlmann et al,87 the real mechanism is still under debate; as a result, the detailed mechanism for the acetylide-acetylide coupling step is not provided here. Due to the substrate simplicity, later advances of Glaser-type couplings mainly focused on the development of greener, efficient and milder reaction conditions, exploration of new catalytic systems, or achieving selective heterocoupling of two alkyne species. Several reviews have discussed these advances.88 Among them, asymmetric Glaser coupling between two alkyne species is the most challenging because the competing homocoupling of more reactive alkyne substrate was considered to afford low yields of heterocoupling products. A few methods showed limited scopes of heterocoupling reactions and more than 2 equiv of an alkyne substrate was added to suppress the homocoupling of the limiting alkyne, as shown by teams of Hua89 and Corma.90 In 2016, Yin and Zhou made a breakthrough in selective heterocoupling of terminal alkynes in CHCl3/1,4-dioxane using 5 mol% of Cu power and 20 mol% of TMEDA as the catalysts (Scheme 29).91 The molar ratio of two starting alkynes was 1 to 1.3, and the selectivity toward heterocoupling was predominant in all the cases (hetero:homo=5:1 to 30:1). In the mechanistic studies, the in situ formed cupric catalyst was essential for the selectivity based on both electronic and steric effects. These results not only negate the belief that homocouplings are exclusively more favored in Glaser-type reaction, but also provided a general method for asymmetric Glaser-type coupling.

metallacycles and increase the research difficulty.98 As the practical templates in synthetic and industrial applications, some impressive results allowed directed-C–H functionalizations using carboxylic acid as a weak coordinating group;99 however, the carboxylic aciddirected CDC is still rare. Biaryl acids are important moieties in polymer syntheses, metalorganic frameworks, and bioactive compounds, while the synthetic methods were limited and cumbersome. Li et al in 2015 reported a practical and efficient synthesis of biaryls acids from aryl acids using rhodium(I) catalyst in water (Scheme 31).9 The proposed mechanism involved Rh(III)-initiated dual cyclometallation which the Rh(III) was generated from the MnO2 oxidation of the Rh(I). Reductive elimination would regenerate the Rh(I) species. 36-90% of the biaryls products were obtained following the standard conditions, and gram-scale synthesis could be performed with only 0.40.6 mol% catalyst loading. Further works allowed asymmetric couplings100 and to conduct the reaction at 100 °C using NaClO2 as the oxidant.101 Scheme 31. Carboxylic acid-directed homocoupling of benzoic acids

Scheme 29. Heterocoupling of terminal alkynes

Aromatic compounds are ubiquitous in nature. They are important solvents and materials in industry and also privileged structural skeleton in pharmaceuticals.92 For these reasons, aromatic C– H activations always receive the most attention from synthetic chemists, and within just a decade, various CDC with arenes such as alkynylation,93 arylation,9, 94 acylation,95 alkenylation96, and alkylation97 have been achieved (Scheme 30). In most of the metal-catalyzed aromatic C–H activations, directing groups are pre-installed on arenes to enhance the metal-C–H interactions through coordination. Functional groups such as alcohol, ketone, and carboxylic acid are naturally abundant; as directing groups for C–H activations, they are functionalizable and easily removable. Despite having these advantages, they were not as popular as N-, P- and S-containing coordinating groups for their relatively weak interaction with metals, which barely form stable Scheme 30. Directed aryl C–H activation for CDC reactions

While a considerable amount of ortho-directed C–H functionalizations were designed, meta-C–H functionalizations have been flourished recently with the assistance of long-reaching coordinating groups. Compared with early non-ortho-selective cross-dehydrogenative couplings102 counted on the electronic and steric natures of the arenes which gave less controllable selectivity, weak directing groups such as nitrile group led to drastic improvement to the site selectivity. In 2012, Yu and co-workers103 reported the first nitrile group directed cross-dehydrogenative meta-C–H alkenylation using Pd(OPiv)2 as the catalyst and Ag2O as the oxidant to couple a series of arenes and conjugated alkenes in good to excellent meta-selectivity (meta:non-meta=75:25 to 100:0) (Scheme 32a). This selectivity was originally explained by the coordination of the linear nitrile with the palladium catalyst which allowed the formation of a macropalladacycle as the intermediate. Later computational studies on this reaction system by Yu, Wu and Houk et al104 suggested that a palladium-silver dimeric complex would lead the palladium center toward the meta-position more favorably. Different substrates bearing a nitrile template were later developed by Tan, Li, and others,105 which have been documented in the literature.96c Other than installing a long-reaching directing group on the arenes, the use of transient directing species was developed to facilitate meta-C–H couplings. Yu and co-workers in 2017 developed a transient ligand-assisted meta-alkenylation of 3-phenylpyridines in the presence of catalytic Pd(OAc)2, Ac-Gly-OH, and an external coordinating template, and stoichiometric amounts of AgBF4 and Cu(OAc)2 were added to the reaction (Scheme 32b).96b In the idealistic reaction process, the 3-phenylpyridine coordinated to the Ag(I) or Cu(II). This metal complex then coordinated with the bissulfonamide template, while the terminal pyridinyl group on the template can coordinate with the Pd(II) catalyst to conduct a meta-



Scheme 32. Meta-directed C–H activations in CDC reactions

C–H activation. The general ratios between meta-/non-meta- adducts were 87/13 to 99/1, and the protocol could even be modified to achieve C5-functionalizations on quinoline derivatives. Combining the aromatic C–H activation and alkyl HAA, dehydrogenative aromatic alkylations could skip the prefunctionalization of alkyl sources. Since the hydrogen atom abstractors such as peroxide and persulfate are also single-electron oxidizers, they could participate in the catalyst regeneration process after reductive elimination, which simplifies the reaction conditions. In 2008, Li et al106 reported a ruthenium-catalyzed CDC between cycloalkanes and arenes with a pyridinyl ortho-directing group (Scheme 33a). The catalyst [Ru(p-cymene)Cl2]2 first activated the aryl C–H bond to form a ruthenacyclic complex, which then reacted with alkanes and peroxide to form the alkylated arenes in 42-80% yields. Later, a para-selective alkylation of arenes was reported in 2011;107 by Scheme 33. Ru-catalyzed ortho-, meta- and para-alkylation of arenes

Page 10 of 16

replacing the catalyst with Ru3(CO)12 and 1,4-bis(diphenylphosphino)butane (dppb), the reaction showed good selectivity (45-96% para-adducts) and reactivity (26-95% yields) toward the aryl para-positions, and arenes bearing weak coordinating groups such as carboxylic, ester and ketone were viable. It is notable that the protocol works in all cases of substituted arenes, and even 2phenylpyridine gave 70% of the para-alkylated product. Another regioselective example was demonstrated by Shi and Zhao’s team (Scheme 33b).108 Using 4 mol% of RuCl2(PPh3)3 as the catalyst, 10 mol% of ferrocene as the electron transferrer and 4 equiv of DTBP as the oxidant, the CDC between 2-phenylpyridines and benzylic substrates took place at the aryl ortho-positions; on the contrary, when the catalyst was replaced by 20 mol% of RuCl3 and 10 mol% of 1,1'-binaphthyl-2,2'-dihydrogen phosphate (BNDHP), the functionalization took place at the meta-position. Transition metal-catalyzed C(sp3)–H activation has been an intriguing topic over the past decade for its high regioselectivity toward remote alkyl functionalizations109 while the substrates are not limited to the active species (for example, C(sp3)–H adjacent to a nitrogen or oxygen atom). Most of the C(sp3)–H arylations required prefunctionalization of arene partners, and it remains challenging to be applied in CDC designs.110 In 2015, Ge et al reported a Cupromoted arylation of unactivated C(sp3)–H bonds using 8quinoylamide as the bidentate coordinating group (Scheme 34a).111 The reaction was optimized with 1 equiv of Cu(OAc)2, 2.5 equiv of DTBP, and 3 equiv of pyridine (py) in DME/dioxane cosolvent at 140-160 °C under N2. According to the results from isotope-labeling experiments, the proposed mechanism starting from a reversible C–H cupration of an arene with aid of a base. Then, the Cu(II) species underwent coordination-assisted ligand exchange with amide. The Cu(II) was oxidized by DTBP to Cu(III) to enable alkyl C–H cleavage and formed a metallacycle. Reductive elimination of this complex would give the product, while the released Cu(I) was oxidized to Cu(II) for further reactions. The method gave moderate to excellent yields (55-93%) of the arylated products, with limitations to sterically less hindered primary alkyl groups only. Later, You’s group reported a Rh(III)-catalyzed pyridinyl-directed alkyl arylation in the presence of 5 mol% of [RhCp*Cl2]2, 20 mol% of AgSbF6, 3 equiv of Ag2O, 30 mol% of AcOH in THF/tBuOH cosolvent at 140 °C (Scheme 34b).112 The method afforded 34-82% of the arylated products and was also viable for the C(sp3)-functionalization of 8-methylquinoline derivatives. Scheme 34. C(sp3)–H activation CDC of ethers/alkanes and alkenes


Page 11 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CONCLUSION Undeniably, the development of CDC has greatly progressed in recent years. Distinguishable changes can be observed in ways chemists strategize cross-coupling reactions toward more efficient and sustainable manners, and we can expect that this trend will continue in the future. Thus far, the CDC between most types of C–H species has been succeeded, exhibiting its versatility and potential in the framework of cross-coupling. Despite this tremendous success, we are still looking forward to furthering efforts on enriching the CDC toolkit, making it a versatile platform for C-H cross-couplings. Particularly, extending the scope to some simple and “light” substrates like alkanes (sp3 C-Hs, e.g., methane), alkenes (sp2 C-Hs, e.g., ethylene) and alkynes (sp C-Hs, e.g., acetylene) would be highly valuable in both academic and industrial settings. Besides, current CDC protocols are seemingly specific to the corresponding one type of reaction(s), which usually hinders its versatility. Hence, it is envisioned that, with the above-mentioned mechanistic insights, designing and developing a unified protocol to accommodate more coupling reactions in the CDC realm would be one of the future pursuits. For the environmental and economic concerns, more efforts would be preferably guided to the exploration of metal-free CDC strategies, as most of the current methods rely on the transition-metal-based catalysts. Regarding the selectivity of modern CDC reactions, most of them have addressed the regioselectivity problem, yet limitations in enantioselective syntheses remain. This limitation is emphasized in pharmaceutical applications. The scalability of CDC protocols in industrial applications should also be taken into concern. Furthermore, incorporation of oxygen as a green and nontoxic oxidant or hydrogen-releasing CDC are even more attractive. From the perspective of these long-term goals, the concept CDC still has a long way to go, but we firmly believe that these obstacles will eventually be solved in an elegant manner.

Chia-Yu Huang obtained his M.Sc. in 2015 at National Taiwan Normal University with Prof. C.-F. Yao in which his research field was heterocycle syntheses. In 2017, he joined the group of Dr. Chao-Jun Li at McGill University for his Ph.D. studies where his current interest is with C-H functionalizations.

Hyotaik Kang obtained his B.Sc. honors in chemistry at the University of Manitoba in 2017. During his undergraduate studies, he was part of the research laboratory of Dr. Rebecca Davis. Following this, he joined the group of Dr. Chao-Jun Li at McGill University where he is currently pursuing his Ph.D. studies with interest in hydrazone chemistry.

AUTHOR INFORMATION Corresponding Author *Email: [email protected]

Author Contributions ‡These authors contributed equally.

Jianbin Li received his B.Sc. (honor) degree in 2016 collaboratively from Sun Yat-sen University and Hong Kong Polytechnic University through a 2+2 joint 4-year study. In the same year, he moved to McGill University and joined Dr. ChaoJun Li’s research group for the direct entry into Ph.D. study. His current research is focusing on developing efficient and green strategies for late-stage functionalization.

ORCID Chia-Yu Huang: 0000-0002-0732-6287 Hyotaik Kang: 0000-0002-6594-6441 Jianbin Li: 0000-0003-4956-7625 Chao-Jun Li: 0000-0002-3859-8824

Notes The authors declare no competing financial interests.

Biographies

Chao-Jun Li completed his B.Sc. in Chemistry at Zhengzhou University and continued his graduate studies to McGill University where he received his M.Sc. in 1988 with T. H Chan and Ph.D. in 1992 with T. H Chan and D. N. Harpp. At Stanford University he joined B. M. Trost for his NSERC post-doctoral fellowship and moved to Tulane University as an assistant professor in 1994 and become a full professor in 2000. He moved to McGill University in



2003 where he was appointed Canada Research Chair (Tier I) in Green Chemistry and is currently E. B. Eddy Professor, Director of CFI Infrastructure for Green Chemistry and Green Chemicals and Co-Director of FRQNT Centre for Green Chemistry and Catalysis. He is an elected Fellow of the Royal Society of Canada (UK) in 2007, the American Association for the Advancement of Science in 2012, Chemical Institute of Canada in 2013, American Chemical Society in 2015 and World Academy of Sciences in 2016.

ACKNOWLEDGMENT We are grateful to the Canada Research Chair Foundation (to C.J.L.), the Canada Foundation for Innovation, the FQRNT Center in Green Chemistry and Catalysis, the Natural Sciences and Engineering Research Council of Canada, and McGill University for supporting our research.

REFERENCES (1) Perry, I. B.; Brewer, T. F.; Sarver, P. J.; Schultz, D. M.; DiRocco, D. A.; MacMillan, D. W. C. Direct arylation of strong aliphatic C–H bonds. Nature 2018, 560, 70-75. (2) Rossiter, B. E.; Swingle, N. M. Asymmetric conjugate addition. Chem. Rev. 1992, 92, 771-806. (3) Fu, G. C. Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A Radical Alternative to SN1 and SN2 Processes. ACS Cent. Sci. 2017, 3, 692-700. (4) Rueping, M.; Nachtsheim, B. J. A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis. Beilstein J. Org. Chem. 2010, 6, 6. (5) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. [3,3]-Sigmatropic rearrangements: recent applications in the total synthesis of natural products. Chem. Soc. Rev. 2009, 38, 3133-3148. (6) Liu, Y.; Doyle, M. P. Michael addition/pericyclization/rearrangement – a multicomponent strategy for the synthesis of substituted resorcinols. Org. Biomol. Chem. 2012, 10, 6388-6394. (7) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition Metal (Pd,Ni,Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-organometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417-1492. (8) (a) Li, C.-J. Cross-Dehydrogenative Coupling (CDC): Exploring C−C Bond Formations beyond Functional Group Transformations. Acc. Chem. Res. 2009, 42, 335-344. (b) Gulzar, N.; Schweitzer-Chaput, B.; Klussmann, M. Oxidative coupling reactions for the functionalisation of C–H bonds using oxygen. Catal. Sci. Technol. 2014, 4, 2778-2796. (c) Girard, S. A.; Knauber, T.; Li, C.-J. The Cross-Dehydrogenative Coupling of Csp3–H Bonds: A Versatile Strategy for C–C Bond Formations. Angew. Chem. Int. Ed. 2014, 53, 74-100. (d) Li, C.-J. Exploration of New Chemical Reactivities for Sustainable Molecular Transformations. Chem 2016, 1, 423-437. (e) Varun, B. V.; Dhineshkumar, J.; Bettadapur, K. R.; Siddaraju, Y.; Alagiri, K.; Prabhu, K. R. Recent advancements in dehydrogenative cross coupling reactions for C–C bond formation. Tetrahedron Lett. 2017, 58, 803-824. (9) Gong, H.; Zeng, H.; Zhou, F.; Li, C.-J. Rhodium(I)-Catalyzed Regiospecific Dimerization of Aromatic Acids: Two Direct C–H Bond Activations in Water. Angew. Chem. Int. Ed. 2015, 54, 57185721. (10) (a) Studer, A.; Curran, D. P. Catalysis of Radical Reactions: A Radical Chemistry Perspective. Angew. Chem. Int. Ed. 2016, 55, 58-102. (b) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Recent Advances in Radical C–H Activation/Radical Cross-Coupling. Chem Rev. 2017, 117, 90169085. (11) (a) Faisca Phillips, A. M.; Pombeiro, A. J. L. Recent Developments in Transition Metal-Catalyzed Cross-

Page 12 of 16

Dehydrogenative Coupling Reactions of Ethers and Thioethers. ChemCatChem 2018, 10, 3354-3383. (b) Funes-Ardoiz, I.; Maseras, F. Oxidative Coupling Mechanisms: Current State of Understanding. ACS Catal. 2018, 8, 1161-1172. (c) Gandeepan, P.; Müller, T.; Zell, D.; Cera, G.; Warratz, S.; Ackermann, L. 3d Transition Metals for C–H Activation. Chem. Rev. 2019, 119, 2192-2452. (12) (a) Sun, C.-L.; Shi, Z.-J. Transition-Metal-Free Coupling Reactions. Chem. Rev. 2014, 114, 9219-9280. (b) Revathi, L.; Ravindar, L.; Fang, W.-Y.; Rakesh, K. P.; Qin, H.-L. Visible Light-Induced C−H Bond Functionalization: A Critical Review. Adv. Synth. Catal. 2018, 360, 4652-4698. (13) Tang, S.; Liu, Y.; Lei, A. Electrochemical Oxidative Crosscoupling with Hydrogen Evolution: A Green and Sustainable Way for Bond Formation. Chem 2018, 4, 27-45. (14) (a) Scheuermann, C. J. Beyond Traditional Cross Couplings: The Scope of the Cross Dehydrogenative Coupling Reaction. Chem. Asian J. 2010, 5, 436-451. (b) Girard, S. A.; Knauber, T.; Li, C. J. The cross-dehydrogenative coupling of C(sp3)-H bonds: a versatile strategy for C-C bond formations. Angew. Chem. Int. Ed. 2014, 53, 74-100. (c) Krylov, I. B.; Vil’, V. A.; Terent’ev, A. O. Cross-dehydrogenative coupling for the intermolecular C–O bond formation. Beilstein J. Org. Chem. 2015, 11, 92-146. (15) Minbaeva, C. K.; Galust'yan, G. G.; Yusupova, V. M.; Il'yasov, E. A. Free Radical Addition of Alkylpyridines to Diethyl Maleate. Zh. Org. Khim. 1992, 28, 395-403. (16) (a) Domasevitch, K. V.; Gerasimchuk, N. N.; Mokhir, A. Organoantimony(V) Cyanoximates: Synthesis, Spectra and Crystal Structures. Inorg. Chem. 2000, 39, 1227-1237. (b) Shouxin, L.; Debin, J.; Yihua, Y.; Xiaoli, Z.; Xia, T.; Jianrong, H. A Practical Procedure for Efficient Synthesis of α-Amino Acids. Lett. Org. Chem. 2009, 6, 156-158. (17) Wang, F.-F.; Luo, C.-P.; Deng, G.; Yang, L. C(sp3)–C(sp3) bond formation via copper/Brønsted acid co-catalyzed C(sp3)–H bond oxidative cross-dehydrogenative-coupling (CDC) of azaarenes. Green Chem. 2014, 16, 2428-2431. (18) Okugawa, N.; Moriyama, K.; Togo, H. Introduction of Ether Groups onto Electron-Deficient Nitrogen-Containing Heteroaromatics Using Radical Chemistry under Transition-MetalFree Conditions. Eur. J. Org. Chem. 2015, 2015, 4973-4981. (19) (a) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. Nucleophilic character of alkyl radicals—VI: A new convenient selective alkylation of heteroaromatic bases. Tetrahedron 1971, 27, 3575-3579. (b) Giordano, C.; Minisci, F.; Vismara, E.; Levi, S. A general, selective, and convenient procedure of homolytic formylation of heteroaromatic bases. J. Org. Chem. 1986, 51, 536-537. (c) Fontana, F.; Minisci, F.; Vismara, E. New general and convenient sources of alkyl radicals, useful for selective syntheses. Tetrahedron Lett. 1988, 29, 19751978. (d) Coppa, F.; Fontaria, F.; Minisci, F.; Pianese, G.; Tortoreto, P.; Zhao, L. A novel radical reaction of alkyl xantates useful for the selective substitution of heteroaromatic bases. Tetrahedron Lett. 1992, 33, 687-690. (20) Duncton, M. A. J. Minisci reactions: Versatile CHfunctionalizations for medicinal chemists. MedChemComm 2011, 2, 1135-1161. (21) (a) Deng, G.; Li, C.-J. Sc(OTf)3-Catalyzed Direct Alkylation of Quinolines and Pyridines with Alkanes. Org. Lett. 2009, 11, 1171-1174. (b) Yuan, J.; Fu, J.; Yin, J.; Dong, Z.; Xiao, Y.; Mao, P.; Qu, L. Transition-metal-free direct C-3 alkylation of quinoxalin-2(1H)-ones with ethers. Org. Chem. Front. 2018, 5, 2820-2828. (22) (a) Xie, Z.; Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.; Wang, L.; Pan, Y. Cu-Catalyzed Cross-Dehydrogenative Coupling Reactions of (Benzo)thiazoles with Cyclic Ethers. Org. Lett. 2013, 15, 4600-4603. (b) Siddaraju, Y.; Lamani, M.; Prabhu, K. R. A Transition Metal-Free Minisci Reaction: Acylation of


Page 13 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Isoquinolines, Quinolines, and Quinoxaline. J. Org. Chem. 2014, 79, 3856-3865. (23) Jin, J.; MacMillan, D. W. C. Direct α-Arylation of Ethers through the Combination of Photoredox-Mediated C–H Functionalization and the Minisci Reaction. Angew. Chem. Int. Ed. 2015, 54, 1565-1569. (24) Antonchick, A. P.; Burgmann, L. Direct Selective Oxidative Cross-Coupling of Simple Alkanes with Heteroarenes. Angew. Chem. Int. Ed. 2013, 52, 3267-3271. (25) Jin, J.; MacMillan, D. W. C. Alcohols as alkylating agents in heteroarene C–H functionalization. Nature 2015, 525, 87. (26) Liu, S.; Liu, A.; Zhang, Y.; Wang, W. Direct Cαheteroarylation of structurally diverse ethers via a mild Nhydroxysuccinimide mediated cross-dehydrogenative coupling reaction. Chem. Sci. 2017, 8, 4044-4050. (27) Quattrini, M. C.; Fujii, S.; Yamada, K.; Fukuyama, T.; Ravelli, D.; Fagnoni, M.; Ryu, I. Versatile cross-dehydrogenative coupling of heteroaromatics and hydrogen donors via decatungstate photocatalysis. Chem. Commun. 2017, 53, 2335-2338. (28) Liu, W.; Yang, X.; Zhou, Z.-Z.; Li, C.-J. Simple and Clean Photo-induced Methylation of Heteroarenes with MeOH. Chem 2017, 2, 688-702. (29) Niu, L.; Liu, J.; Liang, X. A.; Wang, S.; Lei, A. Visible light-induced direct alpha C–H functionalization of alcohols. Nat. Commun. 2019, 10, 467. (30) Huang, C.-Y.; Li, J.; Liu, W.; Li, C.-J. Diacetyl as a “traceless” visible light photosensitizer in metal-free crossdehydrogenative coupling reactions. Chem. Sci. 2019. (31) Huang, H.-Y.; Wu, H.-R.; Wei, F.; Wang, D.; Liu, L. IodineCatalyzed Direct Olefination of 2-Oxindoles and Alkenes via Cross-Dehydrogenative Coupling (CDC) in Air. Org. Lett. 2015, 17, 3702-3705. (32) Cheng, D.; Bao, W. Highly Efficient Metal-Free CrossCoupling by C–H Activation between Allylic and Active Methylenic Compounds Promoted by DDQ. Adv. Synth. Catal. 2008, 350, 1263-1266. (33) Mo, H.; Bao, W. Efficient Palladium-Catalyzed Oxidative Indolation of Allylic Compounds with DDQ via sp3 C–H Bond Activation and Carbon-Carbon Bond Formation Under Mild Conditions. Adv. Synth. Catal. 2009, 351, 2845-2849. (34) Wu, H.-R.; Huang, H.-Y.; Ren, C.-L.; Liu, L.; Wang, D.; Li, C.-J. FeIII-Catalyzed Cross-Dehydrogenative Arylation (CDA) between Oxindoles and Arenes under an Air Atmosphere. Chem. Eur. J. 2015, 21, 16744-16748. (35) (a) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T. Aerobic Ruthenium-Catalyzed Oxidative Cyanation of Tertiary Amines with Sodium Cyanide. J. Am. Chem. Soc. 2003, 125, 15312-15313. (b) Murahashi, S.-I.; Zhang, D. Ruthenium catalyzed biomimetic oxidation in organic synthesis inspired by cytochrome P-450. Chem. Soc. Rev. 2008, 37, 1490-1501. (36) (a) Yoshida, J.-i.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K. Direct Oxidative Carbon−Carbon Bond Formation Using the “Cation Pool” Method. 1. Generation of Iminium Cation Pools and Their Reaction with Carbon Nucleophiles. J. Am. Chem. Soc. 1999, 121, 9546-9549. (b) Yoshida, J.-i.; Suga, S. Basic Concepts of “Cation Pool” and “Cation Flow” Methods and Their Applications in Conventional and Combinatorial Organic Synthesis. Chem. Eur. J. 2002, 8, 26502658. (37) Li, Z.; Li, C.-J. CuBr-Catalyzed Efficient Alkynylation of sp3 C−H Bonds Adjacent to a Nitrogen Atom. J. Am. Chem. Soc. 2004, 126, 11810-11811. (38) Li, Z.; Li, C.-J. Catalytic Enantioselective Alkynylation of Prochiral sp3 C−H Bonds Adjacent to a Nitrogen Atom. Org. Lett. 2004, 6, 4997-4999. (39) (a) Zhang, Y.; Li, C.-J. Highly Efficient CrossDehydrogenative-Coupling between Ethers and Active Methylene

Compounds. Angew. Chem. Int. Ed. 2006, 45, 1949-1952. (b) Zhang, Y.; Li, C.-J. DDQ-Mediated Direct CrossDehydrogenative-Coupling (CDC) between Benzyl Ethers and Simple Ketones. J. Am. Chem. Soc. 2006, 128, 4242-4243. (c) Xiang, M.; Meng, Q.-Y.; Gao, X.-W.; Lei, T.; Chen, B.; Tung, C.-H.; Wu, L.-Z. Reactivity and mechanistic insight into the cross coupling reaction between isochromans and β-keto esters through C–H bond activation under visible light irradiation. Org. Chem. Front. 2016, 3, 486-490. (40) Li, Z.; Li, H.; Guo, X.; Cao, L.; Yu, R.; Li, H.; Pan, S. C−H Bond Oxidation Initiated Pummerer- and Knoevenagel-Type Reactions of Benzyl Sulfide and 1,3-Dicarbonyl Compounds. Org. Lett. 2008, 10, 803-805. (41) Tanoue, A.; Yoo, W.-J.; Kobayashi, S. Sulfuryl Chloride as an Efficient Initiator for the Metal-Free Aerobic CrossDehydrogenative Coupling Reaction of Tertiary Amines. Org. Lett. 2014, 16, 2346-2349. (42) Shu, X.-Z.; Xia, X.-F.; Yang, Y.-F.; Ji, K.-G.; Liu, X.-Y.; Liang, Y.-M. Selective Functionalization of sp3 C−H Bonds Adjacent to Nitrogen Using (Diacetoxyiodo)benzene (DIB). J. Org. Chem. 2009, 74, 7464-7469. (43) Nobuta, T.; Tada, N.; Fujiya, A.; Kariya, A.; Miura, T.; Itoh, A. Molecular Iodine Catalyzed Cross-Dehydrogenative Coupling Reaction between Two sp3 C–H Bonds Using Hydrogen Peroxide. Org. Lett. 2013, 15, 574-577. (44) (a) Condie, A. G.; González-Gómez, J. C.; Stephenson, C. R. J. Visible-Light Photoredox Catalysis: Aza-Henry Reactions via C−H Functionalization. J. Am. Chem. Soc. 2010, 132, 1464-1465. (b) Freeman, D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Functionally Diverse Nucleophilic Trapping of Iminium Intermediates Generated Utilizing Visible Light. Org. Lett. 2012, 14, 94-97. (c) Yoo, W.-J.; Kobayashi, S. Efficient visible lightmediated cross-dehydrogenative coupling reactions of tertiary amines catalyzed by a polymer-immobilized iridium-based photocatalyst. Green Chem. 2014, 16, 2438-2442. (45) (a) Hari, D. P.; König, B. Eosin Y Catalyzed Visible Light Oxidative C–C and C–P bond Formation. Org. Lett. 2011, 13, 3852-3855. (b) Rueping, M.; Zoller, J.; Fabry, D. C.; Poscharny, K.; Koenigs, R. M.; Weirich, T. E.; Mayer, J. Light-Mediated Heterogeneous Cross Dehydrogenative Coupling Reactions: Metal Oxides as Efficient, Recyclable, Photoredox Catalysts in C–C Bond-Forming Reactions. Chem. Eur. J. 2012, 18, 3478-3481. (c) Tanoue, A.; Yoo, W.-J.; Kobayashi, S. Antimony/NHydroxyphthalimide as a Catalyst System for CrossDehydrogenative Coupling Reactions under Aerobic Conditions. Adv. Synth. Catal. 2013, 355, 269-273. (d) Zhi, H.; Ung, S. P.-M.; Liu, Y.; Zhao, L.; Li, C.-J. Phosphorylation of Glycine Derivatives via Copper(I)-Catalyzed Csp3−H Bond Functionalization. Adv. Synth. Catal. 2016, 358, 2553-2557. (e) Odachowski, M.; Greaney, M. F.; Turner, N. J. Concurrent Biocatalytic Oxidation and C–C Bond Formation via Gold Catalysis: One-Pot Alkynylation of NAlkyl Tetrahydroisoquinolines. ACS Catal. 2018, 8, 10032-10035. (46) Li, Z.; Li, C.-J. Highly Efficient Copper-Catalyzed NitroMannich Type Reaction: Cross-Dehydrogenative-Coupling between sp3 C−H Bond and sp3 C−H Bond. J. Am. Chem. Soc. 2005, 127, 3672-3673. (47) Ghobrial, M.; Schnürch, M.; Mihovilovic, M. D. Direct Functionalization of (Un)protected Tetrahydroisoquinoline and Isochroman under Iron and Copper Catalysis: Two Metals, Two Mechanisms. J. Org. Chem. 2011, 76, 8781-8793. (48) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Cu-catalyzed crossdehydrogenative coupling: A versatile strategy for C–C bond formations via the oxidative activation of sp3 C–H bonds. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928. (b) DiRocco, D. A.; Rovis, T. Catalytic Asymmetric α-Acylation of Tertiary Amines Mediated by a Dual Catalysis Mode: N-Heterocyclic Carbene and Photoredox Catalysis. J. Am. Chem. Soc. 2012, 134, 8094-8097.



(49) (a) Gini, A.; Brandhofer, T.; Mancheño, O. G. Recent progress in mild Csp3–H bond dehydrogenative or (mono-) oxidative functionalization. Org. Biomol. Chem. 2017, 15, 12941312. (b) Lakshman, M. K.; Vuram, P. K. Cross-dehydrogenative coupling and oxidative-amination reactions of ethers and alcohols with aromatics and heteroaromatics. Chem. Sci. 2017, 8, 58455888. (50) Meng, Q.-Y.; Zhong, J.-J.; Liu, Q.; Gao, X.-W.; Zhang, H.H.; Lei, T.; Li, Z.-J.; Feng, K.; Chen, B.; Tung, C.-H.; Wu, L.Z. A Cascade Cross-Coupling Hydrogen Evolution Reaction by Visible Light Catalysis. J. Am. Chem. Soc. 2013, 135, 1905219055. (51) Zhong, J.-J.; Meng, Q.-Y.; Liu, B.; Li, X.-B.; Gao, X.-W.; Lei, T.; Wu, C.-J.; Li, Z.-J.; Tung, C.-H.; Wu, L.-Z. CrossCoupling Hydrogen Evolution Reaction in Homogeneous Solution without Noble Metals. Org. Lett. 2014, 16, 1988-1991. (52) Xu, X.; Li, X. Copper/Diethyl Azodicarboxylate Mediated Regioselective Alkynylation of Unactivated Aliphatic Tertiary Methylamine with Terminal Alkyne. Org. Lett. 2009, 11, 10271029. (53) Richter, H.; García Mancheño, O. Dehydrogenative Functionalization of C(sp3)–H Bonds Adjacent to a Heteroatom Mediated by Oxoammonium Salts. Eur. J. Org. Chem. 2010, 2010, 4460-4467. (54) Arokianathar, J. N.; Frost, A. B.; Slawin, A. M. Z.; Stead, D.; Smith, A. D. Isothiourea-Catalyzed Enantioselective Addition of 4-Nitrophenyl Esters to Iminium Ions. ACS Catal. 2018, 8, 11531160. (55) Pietruszka, J.; Wang, C. Laccase-catalyzed 3-Arylation of 3Substituted Oxindoles. ChemCatChem 2012, 4, 782-785. (56) (a) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang, H. Palladium-Catalyzed Benzylic Addition of 2-Methyl Azaarenes to N-Sulfonyl Aldimines via C−H Bond Activation. J. Am. Chem. Soc. 2010, 132, 3650-3651. (b) Komai, H.; Yoshino, T.; Matsunaga, S.; Kanai, M. Lewis Acid Catalyzed Benzylic C−H Bond Functionalization of Azaarenes: Addition to Enones. Org. Lett. 2011, 13, 1706-1709. (c) Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Synthesis of Functionalized Indolizines via Copper-Catalyzed Annulation of 2-Alkylazaarenes with α,β-Unsaturated Carboxylic Acids. Org. Lett. 2012, 14, 957-959. (57) (a) Wang, F.-F.; Luo, C.-P.; Wang, Y.; Deng, G.; Yang, L. Brønsted acid promoted benzylic C–H bond functionalization of azaarenes: nucleophilic addition to aldehydes. Org. Biomol. Chem. 2012, 10, 8605-8608. (b) Niu, R.; Xiao, J.; Liang, T.; Li, X. Facile Synthesis of Azaarene-Substituted 3-Hydroxy-2-oxindoles via Brønsted Acid Catalyzed sp3 C–H Functionalization. Org. Lett. 2012, 14, 676-679. (58) Zhang, J.; Wu, W.; Ji, X.; Cao, S. Perfluorobutyl iodideassisted direct cyanomethylation of azoles and phenols with acetonitrile. RSC Adv. 2015, 5, 20562-20565. (59) (a) Liu, Z.-Q.; Li, Z. Radical-promoted site-specific cross dehydrogenative coupling of heterocycles with nitriles. Chem. Commun. 2016, 52, 14278-14281. (b) Gao, X.; Dong, W.; Hu, B.; Gao, H.; Yuan, Y.; Xie, X.; Zhang, Z. Visible-light induced tandem radical cyanomethylation and cyclization of N-aryl acrylamides: access to cyanomethylated oxindoles. RSC Adv. 2017, 7, 49299-49302. (c) Chang, Q.; Liu, Z.; Liu, P.; Yu, L.; Sun, P. Visible-Light-Induced Regioselective Cyanomethylation of Imidazopyridines and Its Application in Drug Synthesis. J. Org. Chem. 2017, 82, 5391-5397. (d) Wang, K.; Chen, X.; Yuan, M.; Yao, M.; Zhu, H.; Xue, Y.; Luo, Z.; Zhang, Y. Silver-Mediated Cyanomethylation of Cinnamamides by Direct C(sp3)–H Functionalization of Acetonitrile. J. Org. Chem. 2018, 83, 15251531. (60) Zhang, W.; Yang, S.; Shen, Z. Copper-Catalyzed Cyanomethylation of Substituted Tetrahydroisoquinolines with Acetonitrile. Adv. Synth. Catal. 2016, 358, 2392-2397.

Page 14 of 16

(61) Li, Z.; Cao, L.; Li, C.-J. FeCl2-Catalyzed Selective C–C Bond Formation by Oxidative Activation of a Benzylic C–H Bond. Angew. Chem. Int. Ed. 2007, 46, 6505-6507. (62) Zhang, Y.; Li, C.-J. Highly Efficient Direct Alkylation of Activated Methylene by Cycloalkanes. Eur. J. Org. Chem. 2007, 2007, 4654-4657. (63) Tanaka, T.; Hashiguchi, K.; Tanaka, T.; Yazaki, R.; Ohshima, T. Chemoselective Catalytic Dehydrogenative CrossCoupling of 2-Acylimidazoles: Mechanistic Investigations and Synthetic Scope. ACS Catal. 2018, 8, 8430-8440. (64) Morofuji, T.; Shimizu, A.; Yoshida, J.-i. Metal- and Chemical-Oxidant-Free C–H/C–H Cross-Coupling of Aromatic Compounds: The Use of Radical-Cation Pools. Angew. Chem. Int. Ed. 2012, 51, 7259-7262. (65) Kita, Y.; Dohi, T.; Morimoto, K. Hypervalent Iodine Induced Metal-Free C–H Cross Couplings to Biaryls. J. Syn. Org. Chem. Jpn. 2011, 69, 1241-1250. (66) Ito, M.; Kubo, H.; Itani, I.; Morimoto, K.; Dohi, T.; Kita, Y. Organocatalytic C–H/C–H' Cross-Biaryl Coupling: C-Selective Arylation of Sulfonanilides with Aromatic Hydrocarbons. J. Am. Chem. Soc. 2013, 135, 14078-14081. (67) Kärkäs, M. D. Electrochemical strategies for C–H functionalization and C–N bond formation. Chem. Soc. Rev. 2018, 47, 5786-5865. (68) Vairalakshmi, M.; Raj, V.; Sami, P.; Rajasekaran, K. Studies on electron transfer reactions: oxidation of phenol and ringsubstituted phenols by heteropoly 11-tungstophosphovanadate(V) in aqueous acidic medium. Transit. Met. Chem. 2011, 36, 875-882. (69) More, N. Y.; Jeganmohan, M. Oxidative Cross-Coupling of Two Different Phenols: An Efficient Route to Unsymmetrical Biphenols. Org. Lett. 2015, 17, 3042-3045. (70) Dewar, M. J. S.; Nakaya, T. Oxidative coupling of phenols. J. Am. Chem. Soc. 1968, 90, 7134-7135. (71) Tanaka, M.; Nakashima, H.; Fujiwara, M.; Ando, H.; Souma, Y. Synthesis of Binaphthyl Derivatives through Radical Cation Formation. J. Org. Chem. 1996, 61, 788-792. (72) (a) Ding, K.; Yang, W.; Zhang, L.; Yangjie, W.; Matsuura, T. A novel two-phase oxidative coupling of 2-naphthols suspended in aqueous Fe3+ solutions. Tetrahedron 1996, 52, 1005-1010. (b) Li, T.-S.; Duan, H.-Y.; Li, B.-Z.; B. Tewari, B.; Li, S.-H. Novel oxidative coupling of 2-naphthols to 1,1'-bi-2-naphthols catalysed by solid Lewis acids using atmospheric oxygen as oxidant. J. Chem. Soc., Perkin Trans. 1 1999, 291-294. (73) (a) Li, X.; Hewgley, J. B.; Mulrooney, C. A.; Yang, J.; Kozlowski, M. C. Enantioselective Oxidative Biaryl Coupling Reactions Catalyzed by 1,5-Diazadecalin Metal Complexes: Efficient Formation of Chiral Functionalized BINOL Derivatives. J. Org. Chem. 2003, 68, 5500-5511. (b) Esguerra, K. V. N.; Fall, Y.; Petitjean, L.; Lumb, J.-P. Controlling the Catalytic Aerobic Oxidation of Phenols. J. Am. Chem. Soc. 2014, 136, 7662-7668. (74) Jiang, Q.; Sheng, W.; Tian, M.; Tang, J.; Guo, C. Cobalt(II)– Porphyrin-Catalyzed Aerobic Oxidation: Oxidative Coupling of Phenols. Eur. J. Org. Chem. 2013, 2013, 1861-1866. (75) (a) Hwang, D.-R.; Chen, C.-P.; Uang, B.-J. Aerobic catalytic oxidative coupling of 2-naphthols and phenols by VO(acac)2. Chem. Commun. 1999, 0, 1207-1208. (b) Matsushita, M.; Kamata, K.; Yamaguchi, K.; Mizuno, N. Heterogeneously Catalyzed Aerobic Oxidative Biaryl Coupling of 2-Naphthols and Substituted Phenols in Water. J. Am. Chem. Soc. 2005, 127, 6632-6640. (c) Morimoto, K.; Sakamoto, K.; Ohnishi, Y.; Miyamoto, T.; Ito, M.; Dohi, T.; Kita, Y. Metal-Free Oxidative para Cross-Coupling of Phenols. Chem. Eur. J. 2013, 19, 8726-8731. (76) Lee, Y. E.; Cao, T.; Torruellas, C.; Kozlowski, M. C. Selective Oxidative Homo- and Cross-Coupling of Phenols with Aerobic Catalysts. J. Am. Chem. Soc. 2014, 136, 6782-6785. (77) Hu, X.; Zhang, G.; Bu, F.; Luo, X.; Yi, K.; Zhang, H.; Lei, A. Photoinduced oxidative activation of electron-rich arenes:


Page 15 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


alkenylation with H2 evolution under external oxidant-free conditions. Chem. Sci. 2018, 9, 1521-1526. (78) Fan, X.; Li, N.; Shen, T.; Cui, X.-M.; Lv, H.; Zhu, H.-B.; Guan, Y.-H. A mild CuI-catalyzed Glaser-type homo-coupling reaction using α,α-dibromo-β-dicarbonyl compounds as oxidants. Tetrahedron 2014, 70, 256-261. (79) Sudo, Y.; Yamaguchi, E.; Itoh, A. Photo-oxidative CrossDehydrogenative Coupling-Type Reaction of Thiophenes with αPosition of Carbonyls Using a Catalytic Amount of Molecular Iodine. Org. Lett. 2017, 19, 1610-1613. (80) (a) Nechab, M.; Mondal, S.; Bertrand, M. P. 1,n-HydrogenAtom Transfer (HAT) Reactions in Which n ≠ 5: An Updated Inventory. Chem. Eur. J. 2014, 20, 16034-16059. (b) Qin, Q.; Yu, S. Visible-Light-Promoted Remote C(sp3)–H Amidation and Chlorination. Org. Lett. 2015, 17, 1894-1897. (c) Groendyke, B. J.; AbuSalim, D. I.; Cook, S. P. Iron-Catalyzed, Fluoroamide-Directed C–H Fluorination. J. Am. Chem. Soc. 2016, 138, 12771-12774. (d) Chen, D.-F.; Chu, J. C. K.; Rovis, T. Directed γ-C(sp3)–H Alkylation of Carboxylic Acid Derivatives through Visible Light Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 14897-14900. (e) Li, Z.; Wang, Q.; Zhu, J. Copper-Catalyzed Arylation of Remote C(sp3)−H Bonds in Carboxamides and Sulfonamides. Angew. Chem. Int. Ed. 2018, 57, 13288-13292. (f) Kim, I.; Park, B.; Kang, G.; Kim, J.; Jung, H.; Lee, H.; Baik, M.-H.; Hong, S. Visible-Light-Induced Pyridylation of Remote C(sp3)−H Bonds by Radical Translocation of N-Alkoxypyridinium Salts. Angew. Chem. Int. Ed. 2018, 57, 15517-15522. (g) Liu, Z.; Xiao, H.; Zhang, B.; Shen, H.; Zhu, L.; Li, C. Copper-Catalyzed Remote C(sp3)−H Trifluoromethylation of Carboxamides and Sulfonamides. Angew. Chem. Int. Ed. 2019, 58, 2510-2513. (h) Wu, K.; Wang, L.; Colón-Rodríguez, S.; Flechsig, G.-U.; Wang, T. Amidyl Radical Directed Remote Allylation of Unactivated sp3 C−H Bonds by Organic Photoredox Catalysis. Angew. Chem. Int. Ed. 2019, 58, 1774-1778. (81) Wu, X.; Zhang, H.; Tang, N.; Wu, Z.; Wang, D.; Ji, M.; Xu, Y.; Wang, M.; Zhu, C. Metal-free alcohol-directed regioselective heteroarylation of remote unactivated C(sp3)–H bonds. Nat. Commun. 2018, 9, 3343. (82) Volhard, J. Ueber Verbindungen des Thiophens, seiner Homologen und einiger Ketone mit Quecksilberchlorid. Justus Liebigs Ann. Chem. 1892, 267, 172-185. (83) (a) Gensch, T.; Hopkinson, M. N.; Glorius, F.; WencelDelord, J. Mild metal-catalyzed C–H activation: examples and concepts. Chem. Soc. Rev. 2016, 45, 2900-2936. (b) Roudesly, F.; Oble, J.; Poli, G. Metal-catalyzed CH activation/functionalization: The fundamentals. J. Mol. Catal. A: Chem. 2017, 426, 275-296. (84) (a) Labinger, J. A.; Bercaw, J. E. Understanding and exploiting C–H bond activation. Nature 2002, 417, 507-514. (b) Crabtree, R. H. Organometallic alkane CH activation. J. Organomet. Chem. 2004, 689, 4083-4091. (c) Hussain, I.; Singh, T. Synthesis of Biaryls through Aromatic C–H Bond Activation: A Review of Recent Developments. Adv. Synth. Catal. 2014, 356, 1661-1696. (85) Glaser, C. Beiträge zur Kenntniss des Acetenylbenzols. Ber. Dtsch. Chem. Ges. 1869, 2, 422-424. (86) Hay, A. S. Oxidative Coupling of Acetylenes. II. J. Org. Chem. 1962, 27, 3320-3321. (87) (a) Bohlmann, F. S., H.; Inhoffen, E.; Grau, G. Polyacetylenverbindungen, LII. Über den Mechanismus der oxydativen Dimerisierung von Acetylenverbindungen. Chem. Ber. 1964, 97, 794-800. (b) Fomina, L.; Vazquez, B.; Tkatchouk, E.; Fomine, S. The Glaser reaction mechanism. A DFT study. Tetrahedron 2002, 58, 6741-6747. (c) Vilhelmsen, M. H.; Jensen, J.; Tortzen, C. G.; Nielsen, M. B. The Glaser–Hay Reaction: Optimization and Scope Based on 13C NMR Kinetics Experiments. Eur. J. Org. Chem. 2013, 2013, 701-711.

(88) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Acetylenic Coupling: A Powerful Tool in Molecular Construction. Angew. Chem. Int. Ed. 2000, 39, 2632-2657. (b) Shi, W.; Lei, A. 1,3-Diyne chemistry: synthesis and derivations. Tetrahedron Lett. 2014, 55, 2763-2772. (c) Sindhu, K. S.; Anilkumar, G. Recent advances and applications of Glaser coupling employing greener protocols. RSC Adv. 2014, 4, 27867-27887. (89) Zheng, Q.; Hua, R.; Wan, Y. An alternative CuCl–piperidinecatalyzed oxidative homocoupling of terminal alkynes affording 1,3-diynes in air. Appl. Organometal. Chem. 2010, 24, 314-316. (90) Liu, L.; Matsushita, T.; Concepción, P.; Leyva-Pérez, A.; Corma, A. Facile Synthesis of Surface-Clean Monodispersed CuOx Nanoparticles and Their Catalytic Properties for Oxidative Coupling of Alkynes. ACS Catal. 2016, 6, 2211-2221. (91) Su, L.; Dong, J.; Liu, L.; Sun, M.; Qiu, R.; Zhou, Y.; Yin, S.-F. Copper Catalysis for Selective Heterocoupling of Terminal Alkynes. J. Am. Chem. Soc. 2016, 138, 12348-12351. (92) Polêto, M. D.; Rusu, V. H.; Grisci, B. I.; Dorn, M.; Lins, R. D.; Verli, H. Aromatic Rings Commonly Used in Medicinal Chemistry: Force Fields Comparison and Interactions With Water Toward the Design of New Chemical Entities. Front. Pharmacol. 2018, 9, 395-395. (93) (a) Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. CopperCatalyzed Direct Alkynylation of Electron-Deficient Polyfluoroarenes with Terminal Alkynes Using O2 as an Oxidant. J. Am. Chem. Soc. 2010, 132, 2522-2523. (b) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Nickel- and Copper-Catalyzed Direct Alkynylation of Azoles and Polyfluoroarenes with Terminal Alkynes under O2 or Atmospheric Conditions. Org. Lett. 2010, 12, 2358-2361. (c) de Haro, T.; Nevado, C. Gold-Catalyzed Ethynylation of Arenes. J. Am. Chem. Soc. 2010, 132, 1512-1513. (d) Kim, S. H.; Yoon, J.; Chang, S. Palladium-Catalyzed Oxidative Alkynylation of Heterocycles with Terminal Alkynes under Air Conditions. Org. Lett. 2011, 13, 14741477. (e) Jie, X.; Shang, Y.; Hu, P.; Su, W. Palladium-Catalyzed Oxidative Cross-Coupling between Heterocycles and Terminal Alkynes with Low Catalyst Loading. Angew. Chem. Int. Ed. 2013, 52, 3630-3633. (f) Shang, M.; Wang, H.-L.; Sun, S.-Z.; Dai, H.X.; Yu, J.-Q. Cu(II)-Mediated Ortho C–H Alkynylation of (Hetero)Arenes with Terminal Alkynes. J. Am. Chem. Soc. 2014, 136, 11590-11593. (94) (a) Fujiwara, Y.; Moritani, I.; Ikegami, K.; Tanaka, R.; Teranishi, S. Aromatic Substitution of Olefin. X. Formation of Biphenyl Derivatives by Means of Olefin-Palladium Chloride Complexes and Silver Nitrate. Bull. Chem. Soc. Jpn. 1970, 43, 863867. (b) Lee, S. H.; Lee, K. H.; Lee, J. S.; Jung, J. D.; Shim, J. S. Oxidative coupling of methyl benzoate with palladium/heteropolyacid catalysts. J. Mol. Catal. A: Chem. 1997, 115, 241-246. (c) Mukhopadhyay, S.; Rothenberg, G.; Lando, G.; Agbaria, K.; Kazanci, M.; Sasson, Y. Air Oxidation of Benzene to Biphenyl – A Dual Catalytic Approach. Adv. Synth. Catal. 2001, 343, 455-459. (d) Ackerman, L. J.; Sadighi, J. P.; Kurtz, D. M.; Labinger, J. A.; Bercaw, J. E. Arene C−H Bond Activation and Arene Oxidative Coupling by Cationic Palladium(II) Complexes. Organometallics 2003, 22, 3884-3890. (e) Hull, K. L.; Lanni, E. L.; Sanford, M. S. Highly Regioselective Catalytic Oxidative Coupling Reactions: Synthetic and Mechanistic Investigations. J. Am. Chem. Soc. 2006, 128, 14047-14049. (f) Izawa, Y.; Stahl, S. S. Aerobic Oxidative Coupling of o-Xylene: Discovery of 2Fluoropyridine as a Ligand to Support Selective Pd-Catalyzed C– H Functionalization. Adv. Synth. Catal. 2010, 352, 3223-3229. (g) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Copper-Mediated Intermolecular Direct Biaryl Coupling. J. Am. Chem. Soc. 2011, 133, 2160-2162. (h) Zhou, L.; Lu, W. Palladium(II)-Catalyzed Coupling of Electron-Deficient Arenes via C–H Activation. Organometallics 2012, 31, 2124-2127. (i) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M. Copper-Mediated



C–H/C–H Biaryl Coupling of Benzoic Acid Derivatives and 1,3Azoles. Angew. Chem. Int. Ed. 2013, 52, 4457-4461. (95) (a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Palladium-Catalyzed Acylation of sp2 C−H bond: Direct Access to Ketones from Aldehydes. Org. Lett. 2009, 11, 3120-3123. (b) Ma, Y.-N.; Tian, Q.-P.; Zhang, H.-Y.; Zhou, A.-X.; Yang, S.-D. P(O)R2 directed Pd(II)-catalyzed C(sp2)–H acylation. Org. Chem. Front. 2014, 1, 284-288. (96) (a) Le Bras, J.; Muzart, J. Intermolecular dehydrogenative Heck reactions. Chem Rev. 2011, 111, 1170-1214. (b) Zhang, Z.; Tanaka, K.; Yu, J. Q. Remote site-selective C–H activation directed by a catalytic bifunctional template. Nature 2017, 543, 538-542. (c) Mihai, M. T.; Genov, G. R.; Phipps, R. J. Access to the meta position of arenes through transition metal catalysed C–H bond functionalisation: a focus on metals other than palladium. Chem. Soc. Rev. 2018, 47, 149-171. (97) Li, Q.; Hu, W.; Hu, R.; Lu, H.; Li, G. Cobalt-Catalyzed Cross-Dehydrogenative Coupling Reaction between Unactivated C(sp2)–H and C(sp3)–H Bonds. Org. Lett. 2017, 19, 4676-4679. (98) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak Coordination as a Powerful Means for Developing Broadly Useful C–H Functionalization Reactions. Acc. Chem. Res. 2012, 45, 788802. (99) (a) Miao, J.; Ge, H. Palladium-Catalyzed Chemoselective Decarboxylative Ortho Acylation of Benzoic Acids with αOxocarboxylic Acids. Org. Lett. 2013, 15, 2930-2933. (b) Wu, Z.; Chen, S.; Hu, C.; Li, Z.; Xiang, H.; Zhou, X. Palladium-Catalyzed C–H ortho Arylation of Benzoic Acids with Diaryliodonium Salts in Water. ChemCatChem 2013, 5, 2839-2842. (c) Thuy-Boun, P. S.; Villa, G.; Dang, D.; Richardson, P.; Su, S.; Yu, J.-Q. LigandAccelerated ortho-C–H Alkylation of Arylcarboxylic Acids using Alkyl Boron Reagents. J. Am. Chem. Soc. 2013, 135, 17508-17513. (d) Zhu, C.; Zhang, Y.; Kan, J.; Zhao, H.; Su, W. AmbientTemperature Ortho C–H Arylation of Benzoic Acids with Aryl Iodides with Ligand-Supported Palladium Catalyst. Org. Lett. 2015, 17, 3418-3421. (e) Biafora, A.; Krause, T.; Hackenberger, D.; Belitz, F.; Gooßen, L. J. ortho-C−H Arylation of Benzoic Acids with Aryl Bromides and Chlorides Catalyzed by Ruthenium. Angew. Chem. Int. Ed. 2016, 55, 14752-14755. (f) Han, W.-J.; Pu, F.; Li, C.-J.; Liu, Z.-W.; Fan, J.; Shi, X.-Y. Carboxyl-Directed Conjugate Addition of C−H Bonds to α,β-Unsaturated Ketones in Air and Water. Adv. Synth. Catal. 2018, 360, 1358-1363. (100) Zhang, H.; Deng, G.-J.; Li, S.; Li, C.-J.; Gong, H. Nonsymmetrical diarylcarboxylic acids via rhodium(I)-catalyzed regiospecific cross-dehydrogenation coupling of aromatic acids: twofold direct C–H bond activations in water. RSC Adv. 2016, 6, 91617-91620. (101) Liu, Y.; Zhu, Y.; Li, C. J. Mild and highly regioselective synthesis of biaryl acids via Rh(I)-catalyzed cross-dehydrogenative coupling of benzoic acids using sodium chlorite as oxidant. Front. Chem. Sci. Eng. 2018, 12, 3-8. (102) (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Pd(II)-Catalyzed Olefination of Electron-Deficient Arenes Using 2,6Dialkylpyridine Ligands. J. Am. Chem. Soc. 2009, 131, 5072-5074. (b) Wang, X.; Leow, D.; Yu, J.-Q. Pd(II)-Catalyzed para-Selective C–H Arylation of Monosubstituted Arenes. J. Am. Chem. Soc. 2011, 133, 13864-13867. (c) Ye, M.; Gao, G.-L.; Yu, J.-Q. LigandPromoted C-3 Selective C–H Olefination of Pyridines with Pd Catalysts. J. Am. Chem. Soc. 2011, 133, 6964-6967. (103) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 2012, 486, 518. (104) Yang, Y.-F.; Cheng, G.-J.; Liu, P.; Leow, D.; Sun, T.-Y.; Chen, P.; Zhang, X.; Yu, J.-Q.; Wu, Y.-D.; Houk, K. N.

Page 16 of 16

Palladium-Catalyzed Meta-Selective C–H Bond Activation with a Nitrile-Containing Template: Computational Study on Mechanism and Origins of Selectivity. J. Am. Chem. Soc. 2014, 136, 344-355. (105) (a) Lee, S.; Lee, H.; Tan, K. L. Meta-Selective C–H Functionalization Using a Nitrile-Based Directing Group and Cleavable Si-Tether. J. Am. Chem. Soc. 2013, 135, 18778-18781. (b) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.; Wang, P.; Tang, R.-Y.; Movassaghi, M.; Yu, J.-Q. Pd(II)-Catalyzed meta-C–H Olefination, Arylation, and Acetoxylation of Indolines Using a UShaped Template. J. Am. Chem. Soc. 2014, 136, 10807-10813. (c) Li, S.; Cai, L.; Ji, H.; Yang, L.; Li, G. Pd(II)-catalysed meta-C– H functionalizations of benzoic acid derivatives. Nat. Commun. 2016, 7, 10443. (d) Bera, M.; Sahoo, S. K.; Maiti, D. RoomTemperature meta-Functionalization: Pd(II)-Catalyzed Synthesis of 1,3,5-Trialkenyl Arene and meta-Hydroxylated Olefin. ACS Catal. 2016, 6, 3575-3579. (e) Xu, H. J.; Lu, Y.; Farmer, M. E.; Wang, H. W.; Zhao, D.; Kang, Y. S.; Sun, W. Y.; Yu, J. Q. Rh(III)-Catalyzed meta-C–H Olefination Directed by a Nitrile Template. J. Am. Chem. Soc. 2017, 139, 2200-2203. (106) Deng, G.; Zhao, L.; Li, C. J. Ruthenium-catalyzed oxidative cross-coupling of chelating arenes and cycloalkanes. Angew. Chem. Int. Ed. 2008, 47, 6278-6282. (107) Guo, X.; Li, C.-J. Ruthenium-Catalyzed Para-Selective Oxidative Cross-Coupling of Arenes and Cycloalkanes. Org. Lett. 2011, 13, 4977-4979. (108) Li, G.; Li, D.; Zhang, J.; Shi, D.-Q.; Zhao, Y. LigandEnabled Regioselectivity in the Oxidative Cross-coupling of Arenes with Toluenes and Cycloalkanes Using Ruthenium Catalysts: Tuning the Site-Selectivity from the ortho to meta Positions. ACS Catal. 2017, 7, 4138-4143. (109) (a) Li, H.; Li, B.-J.; Shi, Z.-J. Challenge and progress: palladium-catalyzed sp3 C–H activation. Catal. Sci. Technol. 2011, 1, 191-206. (b) Xu, Y.; Dong, G. sp3 C–H activation via exo-type directing groups. Chem. Sci. 2018, 9, 1424-1432. (110) (a) He, G.; Chen, G. A Practical Strategy for the Structural Diversification of Aliphatic Scaffolds through the PalladiumCatalyzed Picolinamide-Directed Remote Functionalization of Unactivated C(sp3)–H Bonds. Angew. Chem. Int. Ed. 2011, 50, 5192-5196. (b) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Stereoselective Synthesis of Chiral α-Amino-βLactams through Palladium(II)-Catalyzed Sequential Monoarylation/Amidation of C(sp3)–H Bonds. Angew. Chem. Int. Ed. 2013, 52, 13588-13592. (c) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. β-Arylation of Carboxamides via Iron-Catalyzed C(sp3)–H Bond Activation. J. Am. Chem. Soc. 2013, 135, 60306032. (d) Aihara, Y.; Chatani, N. Nickel-Catalyzed Direct Arylation of C(sp3)–H Bonds in Aliphatic Amides via BidentateChelation Assistance. J. Am. Chem. Soc. 2014, 136, 898-901. (e) Gu, Q.; Al Mamari, H. H.; Graczyk, K.; Diers, E.; Ackermann, L. Iron-Catalyzed C(sp2)–H and C(sp3)–H Arylation by Triazole Assistance. Angew. Chem. Int. Ed. 2014, 53, 3868-3871. (f) Gao, P.; Guo, W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z. Iridium(III)-Catalyzed Direct Arylation of C–H Bonds with Diaryliodonium Salts. J. Am. Chem. Soc. 2015, 137, 12231-12240. (g) Wang, X.; Yu, D.-G.; Glorius, F. Cp*RhIII-Catalyzed Arylation of C(sp3)–H Bonds. Angew. Chem. Int. Ed. 2015, 54, 10280-10283. (111) Wu, X.; Zhao, Y.; Ge, H. Pyridine-enabled copperpromoted cross dehydrogenative coupling of C(sp2)–H and unactivated C(sp3)–H bonds. Chem. Sci. 2015, 6, 5978-5983. (112) Tan, G.; You, J. Rhodium(III)-Catalyzed Oxidative CrossCoupling of Unreactive C(sp3)–H Bonds with C(sp2)–H Bonds. Org. Lett. 2017, 19, 4782-4785.


En Route to Intermolecular Cross-Dehydrogenative Coupling (CDC

Recommend Documents