Among the countless reactions developed throughout the history of organic chemistry, carbon–carbon bond formation reactions are very special, as such reactions create the framework for organic molecules to build on and for functional groups to be attached to. Thus, the development of methods for forming C–C bonds plays a central role in the design and synthesis of organic matter: molecules and materials.¹  Historically, nucleophilic additions, substitutions, and Friedel–Crafts type reactions formed the pillars of methods to connect two simpler molecules via the formation of a C–C bond in acyclic structures.²  The development of pericyclic reactions³  laid the foundation for synthesizing cyclic structures. Over the past four decades, transition metal catalyses via cross-coupling and metathesis have overcome some limitations of the classical reactions, e.g., nucleophilic substitutions involving sp² carbon centers, and have greatly increased the efficiency of C–C bond formations, especially those involving arenes and alkenes, in modern organic chemistry.⁴  Their importance is attested by the awarding of Nobel Prizes in both 2005 and 2010.⁵ 

However, in spite of the great success of both classical C–C bond formation methods and the modern extraordinary achievements of transition metal catalysis, state-of-the-art C–C bond formation reactions must use pre-functionalized starting materials, which require extra steps (sometimes multiple steps) to synthesize. In many cases, during the core C–C bond formation processes, the pre-formed functional groups are simultaneously ‘lost’. The necessity of these repetitive pre-functionalization and defunctionalization steps plus the associated isolations and purifications, ultimately diminishes the overall material efficiency in the synthesis of complex organic molecules and increases chemical waste. The reduction in efficiency is aggravated with an increase in the complexity of molecules, as exemplified by the E-factor of Sheldon.⁶  To reduce the number of steps involved and increase the efficiency in synthetic chemistry, we must explore new frontiers of chemical reactions, in which various chemical bonds in widely available natural resources, petroleum, natural gas, biomass, N₂, CO₂, O₂, water, and others can be selectively transformed directly without affecting other bonds and without the need for excessive pre-activations. As part of this effort, the transition metal catalyzed C–H bond activation and subsequent C–C bond formations have, thus, attracted much interest in recent years.⁷  Outstanding achievements have been made in this area and many complex compounds can be made much more rapidly. However, these reactions still require at least one functionalized partner in order to generate the desired C–C bond formation products.

Historically, the copper-mediated oxidative homodimerization of alkynes (the Eglinton reaction), an first reported over a century ago, represents the earliest success of directly generating a C–C bond from two C–H bonds.⁸  The reaction requires a stoichiometric quantity of Cu(OAc)₂ as both mediator and oxidant. The Glaser–Hay coupling modified such oxidative homodimerization of alkynes by using a catalytic Cu(I) catalyst with oxygen as the terminal oxidant.⁹  On the other hand, the oxidative homodimerization of electron-rich arenes has also become highly successful in generating arene dimers and polymers for a wide range of applications: from fine chemicals and pharmaceuticals to electronic materials.¹⁰  Both types of reaction, however, are limited to homodimerizations and are beyond the present book.

In synthetic chemistry, what is very challenging and highly desirable is the selective formation of two different C–H bonds from two completely different compounds (or two chemically different sites within a molecule). As C–H bonds are generally relatively inert, compared to all other bonds in organic molecules, such cross-oxidative couplings involving only C–H bonds in the presence of, and without affecting other more reactive bonds, would be unthinkable within classical chemical knowledge.

Prior to the concept of cross-dehydrogenative-coupling (CDC), Moritani and Fujiwara developed the oxidative formation of Heck-type reaction products directly from arenes and alkenes, instead of aryl halides and alkenes, by using palladium as the catalyst.¹¹  This type of reaction is now referred to as the “Moritani–Fujiwara reaction”. Although one can argue that an alkene is still a functional group, this is an early example of formal generation of a C–C bond from two different C–H bonds by removing two hydrogen atoms oxidatively. Since Chapter 2 is devoted entirely to this type of reaction, this chapter will only touch on them briefly.

Developing green chemistry methods¹²  for chemical syntheses has been an objective of our laboratory over the past two decades. Over the years, we have explored various unconventional chemical reactions that could potentially simplify syntheses, decrease overall waste and maximize resource utilization. In our early studies, we focused on developing Grignard-type reactions in aqueous media in order to simplify protection–deprotection processes involved in organic synthesis, especially carbohydrates.¹³  This led to the success of virtually all types of Barbier–Grignard reactions in water, as well as the synthesis of various natural products, both by us and many others. Since water is analogous to protonic functional groups such as hydroxyls, acids, and amines, these water-tolerant reactions allow a drastic reduction in the number of transformations in those syntheses by eliminating the protection and deprotection steps. Nevertheless, the pre-generation of organic halides and the requirement of stoichiometric quantities of metal will still lead to stoichiometric waste.

As an aspirational endeavor, we then shifted our attention to explore Barbier–Grignard type and other nucleophilic addition reactions by using C–H bonds as surrogates for organometallic reagents, to simplify the halogenation–dehalogenation process and to avoid the utilization of a stoichiometric amount of metal for such reactions. Furthermore, we would like to explore such reactions in water, combining the advantages of both simplifying the protection–deprotection processes as well as avoiding halogenation–dehalogenation processes. Our efforts have been highly fruitful. Among them, our laboratory has pioneered a wide range of direct catalytic additions of terminal alkynes to various electrophiles in water¹⁴  and the most well-known one is the so-called “aldehyde–alkyne–amine coupling”, often in water.¹⁵ 

The success of the above encouraged us to explore the ultimate question in 2003: can we generate C–C bonds selectively from two different C–H bonds of any type without having to convert either one into a pre-synthesized functional group in the first place, possibly even in water? The success of such reactions could potentially lead to chemical transformations beyond functional group-based transformations—a potential tool for the next generation of synthetic chemists. A general scheme for such a process would involve two different types of C–H bonds in any setting, and would form a C–C bond at the specific desirable sites by an overall formal loss of H₂ either in the form of an H₂ molecule or through the use of an oxidant (Scheme 1.1). To help our understanding, we termed these reactions CDCs. Despite the use of “dehydrogenative” in the name, the term is not limited to the generation of H₂ molecules. The CDC reaction has become one of the most active areas of research and extensive progress has been made in all aspects of such reactions. This introductory chapter will only discuss briefly the early evolution of such reactions.

As a starting point, we chose the formation of C–C bonds from α-sp³ C–H bonds of nitrogen in amines, and alkynyl sp C–H bonds to generate propargylic amines. This choice was based on three reasons: (1) propargylic amines are of great pharmaceutical interest and are synthetic intermediates for various nitrogen compounds;¹⁶  (2) the sp³ C–H bond α to nitrogen in amines can be readily activated to generate iminium ions via single-electron-transfer (SET) processes, or by transition metals as described by Leonard¹⁷  and Murahashi;¹⁸  and (3) the aldehyde–alkyne–amine coupling (A³) reactions to afford propargyl amines described earlier, proceed via the formation of the same intermediate (Scheme 1.2). We reasoned that the CDC of the sp³ C–H α to nitrogen with a terminal alkyne should thus occur readily under oxidative conditions.

In the early 1990s, Miura observed the formation of a small amount of the alkynylation product in a complex product mixture when reacting amines with alkynes in the presence of CuCl₂ and oxygen; no further investigation was made.¹⁹  As a prototype for the concept of the selective CDC reaction, we found that the desired CDC reaction product was obtained in good yield and high selectivity with the combination of a copper catalyst and tert-butyl hydroperoxide (TBHP) as the terminal oxidant. Various copper salts such as CuBr, CuBr₂, CuCl, and CuCl₂ were all effective for this transformation. Various alkynes were reacted with dimethylaniline derivatives to give the alkynylation products in 12–82% yields (Scheme 1.3)²⁰  and aromatic alkynes often provided better yields than aliphatic alkynes. The reactions tolerated various functional groups such as alcohols and esters.

As a potential synthetic application of CDCs, we found that various p-methoxyphenyl glycine amides could be directly alkynylated with phenylacetylene readily at room temperature (Scheme 1.4).²¹  By hydrogenating the alkyne and removal of PMP, this methodology provides a versatile method for synthesizing homophenylalanine derivatives, an important synthon in many angiotensin-converting enzyme inhibitors.²²  A series of direct and site-selective peptide functionalizations was also realized by using CDC reactions (Scheme 1.5).²³ 

The asymmetric synthesis of organic compounds is another major effort in modern organic chemistry. With our earlier high success it was intriguing to see if it is possible to achieve enantioselective C–C bond formations based on the direct reaction of prochiral CH₂ groups via CDC. Indeed, asymmetric alkynylation of tetrahydroisoquinolines (THIQs) to generate optically active C1-substituted derivatives was realized by using a copper salt together with pybox 1, among others (Figure 1.1), as the chiral ligand. Both Cu(I) and Cu(II) were found to be effective catalysts, although slightly higher enantioselectivities were observed with Cu(I) catalysts (Scheme 1.6). The catalytic asymmetric CDC alkynylation also proceeded in water and without a solvent, however both the yields and the enantioselectivities were decreased.

Compared with the sp³ C–H bond adjacent to nitrogen, the sp³ C–H bond adjacent to oxygen is much less reactive. In our initial attempt to effect such CDC reactions, only the addition of an sp³ C–H bond across an alkyne was observed, and this was via a radical process.²⁴  Subsequently, we found that a silver-catalyzed oxidative coupling of terminal alkynes and benzylic ethers using 2.5 mol% silver triflate, and 1.5 equiv. of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in a mixture of 4:1 toluene:chlorobenzene at 120 °C successfully provided the alkynylation of benzylic ether derivatives via the CDC process (Scheme 1.7).²⁵  However, poor yields were obtained with acyclic methyl benzyl ether.

More recently, we demonstrated the first alkynylation of benzylic C–H bonds not adjacent to a heteroatom with 1 mol% of a CuOTf–toluene complex in the presence of 1.5 equiv. of DDQ. Various alkynes were successfully coupled with diphenylmethane derivatives (Scheme 1.8).²⁶  Aromatic alkynes were smoothly converted and the use of electron-rich derivatives resulted in a slightly improved yield, rationalized by the nucleophilicity of the substrates. However, aliphatic alkynes (i.e., n-hexyne) did not give the corresponding CDC product under standard conditions. The mechanism was proposed to proceed via the generation of radical intermediates, which were converted into a benzylic cation in the presence of DDQ through two successive SET steps. The resulting hydroquinone subsequently then abstracted the acidic proton from the alkyne to form the copper acetylide, which added to the benzylic cation to afford the desired product.

The proposed iminium intermediate in the CDC-type alkynylation implies that other C–H based pronucleophiles, besides terminal alkynes, can also couple with an α-sp³ C–H bond of a nitrogen in amines via the same process. Thus, we examined electron-rich arenes as one such nucleophile via a cross-dehydrogenative Friedel–Crafts type arylation. Indole derivatives were coupled with N-aryl-THIQs under the CuBr/TBHP system to produce the desired CDC reaction product in good-to-excellent yields (Scheme 1.9).²⁷  It is worth noting that the reaction was not sensitive to moisture or air, and that the desired product was obtained in reasonable yield even when the reaction was carried out in water under an atmosphere of air. The reactions selectively occurred at the C3-position of the indoles, if both the C2- and C3-positions of the indoles were unoccupied, and the C2-substituted products were obtained when the C3-position of the indoles was substituted.

2-Naphthol is another electron-rich aromatic compound which can also lead to sp³–sp² CDC-type products. Thus, a new type of Betti base was formed via the CDC reaction of N-phenyl-THIQ with 2-naphthol derivatives under our CuBr/TBHP system with a small amount of homocoupled 2,2´-binaphthol (BINOL) (Scheme 1.10).²⁸  Subsequently, the scope of cross-dehydrogenative Friedel–Crafts type arylations was significantly improved by the development of highly efficient catalyst systems, and an intramolecular Cu-catalyzed aerobic synthesis of functionalized cinnolines via a Friedel–Crafts-type CDC arylation was reported by Zhang et al.²⁹ 

We then investigated the CDC reaction between α-sp³ C–H bonds of nitrogen in THIQs and sp² C–H bonds of electron-deficient alkenes. The reaction generated the Morita–Baylis–Hillman (MBH) reaction product by using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst (Scheme 1.11). Another common MBH catalyst, triphenylphosphine, was found to be nearly ineffective due to the generation of triphenylphosphine oxide during the reaction.

In addition to the sp³ C–H bond adjacent to nitrogen, sp³ C–H/sp² C–H CDC reactions have also been successful adjacent to oxygen. We discovered a palladium-catalyzed coupling of N-heterocycles with simple alcohols initiated by dicumyl peroxide (Scheme 1.12).³⁰ 

Subsequently, the radical coupling of benzothiazoles, benzoxazoles and benzimidazoles with alcohols or ethers in the presence of excess TBHP was reported by He et al.³¹ 

Allylic compounds as well as diphenylmethanes have also been disclosed as substrate classes for CDC-type arylations.³²  A PdCl₂-catalyzed cross-dehydrogenative allylation reaction of indole derivatives was introduced by the group of Bao in 2009 using DDQ as the stoichiometric oxidant (Scheme 1.13). Shi also reported a FeCl₂-catalyzed benzylation reaction of electron-rich arenes with diphenylmethanes (Scheme 1.14).³² 

The cross-dehydrogenative synthesis of oxindole derivatives via intramolecular cyclization of acetanilide radicals was independently explored by the groups of Kündig³³  and Taylor³⁴  in 2009. Phenylacetic acid anilides were converted into the corresponding heterocycles in the presence of stoichiometric quantities of copper salts. In 2010, the group of Taylor also succeeded in developing a Cu(OAc)₂-catalyzed aerobic variant.³⁵  The absence of basic additives and performing the reaction in a non-polar, high-boiling-point solvent such as mesitylene was the key to achieve a catalytic turnover (Scheme 1.15). Recently, Li extended this strategy to the synthesis of various 3-alkylated oxindole derivatives.³⁶ 

Two procedures have independently been introduced to allow a formal CDC of sp² C–H bonds with α-sp³ C–H bonds of carbonyl groups, via the generation of an unsaturated intermediate that is subsequently coupled with an arene or an olefin.³⁷  The group of Hong developed two complementary Pd(OTFA)₂-catalyzed protocols for the arylation and olefination of a series of chromanones and dihydroquinolinones (Scheme 1.16).³⁷ 

Among all the potential CDC reactions, the reaction with simple alkanes (without any functional groups) is the most challenging. Among the many methods for the direct transformation of alkane C–H bonds, Fenton chemistry³⁸  and the Gif process³⁹  are the classical methods and allow the conversion of aliphatic C–H bonds into C–O bonds under mild conditions by using peroxides catalyzed by various iron catalysts. We hypothesized that these classical processes might be intercepted by carbon-based reactive intermediates and thus diverted to form C–C bonds. Our first success came with 1,3-dicarbonyl compounds (to be discussed Section 1.4). Another possibility is the alkyl–aryl CDC coupling. As a first step to model the coupling of an arene with a radical intermediate during the reaction of alkane C–H bonds, we reacted 2-phenylpyridine with dicumyl peroxide (with the objective of producing a methyl radical in situ) with 10 mol% Pd(OAc)₂ as the catalyst at 130 °C under an atmosphere of nitrogen; the reaction generated mono-methylation and bis-methylation products efficiently.⁴⁰  Other peroxides and palladium catalysts could also be used, but generated lower yields of the methylation products. When benzo[h]quinoline was used for the reaction, 76% of the mono-methylation product was obtained. Other substituted aromatic compounds such as acetanilides were also effective in this transformation, generating the methylation product in moderate yields. The mechanism of the reaction was proposed to proceed via a methylpalladium species (generated from the fragmentation of the peroxide), which underwent a nitrogen-assisted aryl C–H activation followed by reductive elimination to give the methylation product (Scheme 1.17, top). The success of this methylation gave us hope for CDC reactions involving simple alkanes. Thus, we reacted 2-phenylpyridine with cyclooctane in the presence of tert-butyl peroxide (TBP) under palladium-catalyzed reaction conditions, however the reaction only gave a trace (<1%) amount of the desired product. We then examined other transition metal catalysts and found that a 42–75% yield of the corresponding CDC products was obtained between various 2-arylpyridines and cycloalkanes by using 10 mol% [Ru(p-cymene)Cl₂]₂ as the catalyst, and TBHP as the hydrogen acceptor, at 135 °C for 16 h under an atmosphere of air (Scheme 1.17, bottom).⁴¹ 

The mechanism of this CDC was proposed to involve a ruthenium-catalyzed aryl C–H activation⁴²  followed by an H–alkyl exchange mediated by the peroxide most likely via an alkyl radical intermediate as in the palladium-catalyzed methylation reaction. Then, reductive elimination of this intermediate generated the arene–cycloalkane coupling product and re-generated the active ruthenium catalyst (Scheme 1.18). A large negative kinetic isotope effect was observed using deuterated starting materials. The results suggested that the ruthenium-catalyzed aryl C–H activation is a fast equilibrium and the H–alkyl exchange is the rate-limiting step.

Interestingly, we also found that using Ru₃(CO)₁₂ in combination with 1,4-bis(diphenylphosphino)butane (DPPB) in the presence of di-TBP provided the para-selective CDC reaction of arenes and cycloalkanes.⁴³  A wide range of arenes were functionalized with simple cycloalkanes (Scheme 1.19). Both electron-withdrawing groups (EWG) and electron-donating groups (EDG) on the arene partner were suitable for this reaction to give the coupling product in good yields and high para-selectivity, even with chelating ortho-directing substituents. The ring size has a dramatic influence on the reaction yield, with the lowest yield obtained with cyclopentane. No kinetic isotope effect (k_H/k_D=1.00) was observed when using chlorobenzene-d₅ as the substrate, which suggests the possibility of a radical mechanism. The regioselectivity was rationalized by the stabilization of the radical intermediate by both electron-donating and electron-withdrawing groups through frontier molecular orbital (FMO) interactions.⁴⁴  Recently, the ruthenium-catalyzed CDC was modified to functionalize nucleotides.⁴⁵ 

In subsequent efforts, we succeeded in introducing significantly improved variants of the Minisci reaction. Pyridine-N-oxide proved to be reactive enough to undergo radical alkylation with cyclic hydrocarbons even in the absence of an activator (Scheme 1.20).⁴⁶ 

Several Pd-catalyzed intramolecular CDC cyclizations have been developed that involve the connection of alkyl sp³ C–H bonds with the sp² C–H bonds of heterocycles (Scheme 1.21):⁴⁷  the group of Fagnou introduced an aerobic cyclization of N-pivaloyl pyrroles; the group of Yu disclosed a one-pot sequence for the synthesis of functionalized 2-pyrrolidinones that starts with an intramolecular olefination of the pivaloyl amides, followed by a 1,4-conjugate addition step; and the group of Sanford provided an intramolecular aerobic Pd-catalyzed synthesis of various 2,3-dihydroindolizinium salts.

The success of the sp³ C–H/sp C–H and sp³ C–H/sp² C–H couplings led us to explore the possibility of the even more challenging CDC reaction between sp³ C–H and sp³ C–H bonds. We started with the reaction of an α-sp³ C–H bond of nitrogen in amines with nitroalkanes, which would provide aza-Henry-type reaction products. Using CuBr as the catalyst and TBHP as the terminal oxidant, various β-nitroamine derivatives were generated by this new methodology (Scheme 1.22).^48a 

Dialkyl malonates are another type of important synthon with relatively reactive sp³ C–H bonds, and can thus react with THIQs similarly in the presence of 5 mol% CuBr and TBHP at room temperature to give the CDC products, β-diester amine derivatives, in high yields (Scheme 1.23).^48b  Using malononitrile as the pronucleophile generated β-dicyano-THIQs under standard reaction conditions. Meldrum's acid can also be used as the pronucleophile, with which the CDC reaction of free 1,2,3,4-THIQ is possible. A subsequent major achievement, by Sodeoka and co-workers, was the CDC reaction of malonate with N-Boc-protected THIQ asymmetrically using a chiral palladium catalyst together with DDQ as the dehydrogenating reagent to generate the desired product in 86% enantiomeric excess (ee) (Scheme 1.24).^48c 

Peroxide is potentially hazardous in large-scale reactions and replacing peroxides with molecular oxygen would offer a safer and more atom-economical process. We found that, in water, molecular dioxygen (or even simply air atmosphere) can efficiently serve as the hydrogen acceptor for the CDC reaction. Both the nitroalkane reaction and the malonate reaction gave the corresponding CDC products in excellent yields catalyzed by CuBr under an oxygen atmosphere in water (Scheme 1.25).⁴⁹  As a green chemistry effort, we also investigated recoverable heterogeneous nanoparticles as catalysts in aza-Henry-type CDC reactions. By using magnetic Fe₂O₃ nanoparticles, highly efficient aerobic coupling of N-arylated THIQs with nitroalkanes was obtained under neat conditions with oxygen as the terminal oxidant.⁵⁰  The nanoparticle catalysts easily separated from the reaction mixture with a magnet and could be re-used without significant loss of reactivity.

Interestingly, we found that the CuBr-catalyzed aza-Henry-type CDC reaction also proceeds well in ionic liquids under an oxygen atmosphere. The catalyst-containing ionic liquid can be re-used without loss of reactivity after extraction of the product with diethyl ether. Since ionic liquids are highly polar and excellent media for conducting electricity,⁵¹  we subsequently demonstrated that the CDC of N-phenyltetrahydroisoquinoline with nitromethane is also feasible under electrochemical conditions.⁵²  The reaction was performed with a large-area Pt electrode in an electrochemical H-cell using the ionic liquid [BMIm][BF₄] as the solvent and triethylamine to trap the protons generated. The reaction furnished the product in 80% chemical yield and 93% Faradaic yield.

The subsequent phenomenal work by Stephenson and others on using photo-oxidation catalysts in cross-dehydrogenative aza-Henry reactions which permit the use of visible light as a primary oxidant are covered in detail in a separate chapter in this book. Many other variations of this reaction have also been reported.

With the initial success of amines, we began to explore the functionalization of the α-C–H bond of oxygen in ethers, which is more challenging due to the former's higher oxidation potential. Thus, a stronger oxidant than TBHP or molecular oxygen would be required. A good choice is DDQ, which is known to react with benzyl ether to generate oxonium ions. Thus, the CDC reaction of an sp³ C–H bond adjacent to an oxygen atom with an sp³ C–H bond in pronucleophiles proceeds efficiently to give β-diester ethers in the presence of DDQ by using a combination of indium and copper as catalysts. In this reaction, InCl₃ is proposed to further activate DDQ by increasing its oxidative potential while the copper catalyst activates the malonates (Scheme 1.26).⁵³ 

However, the In/Cu/DDQ reaction system is limited to CDC reactions between benzyl ethers and relatively reactive malonate; and simple ketones do not react. To our surprise then, we found that in the absence of any metal catalyst, a CDC reaction between benzyl ethers and simple ketones mediated by DDQ proceeds efficiently (Scheme 1.27).⁵⁴ 

The mechanism for the coupling is proposed in Scheme 1.28 in which an SET from the benzyl ether to DDQ generates a radical cation and a DDQ radical anion. The radical oxygen of the DDQ radical anion then abstracts an H atom from the radical cation and generates a benzoxy cation, and the anionic oxygen of the DDQ radical anion abstracts an α-hydrogen from the ketone to generate an enolate. Finally, the enolate attacks the benzoxy cation to generate the CDC product.

The Tsuji–Trost palladium-catalyzed allylic alkylation (Scheme 1.29) is an important reaction in modern organic synthesis.⁵⁵  However, in general, a carboxylate (or another leaving group) is required at the allylic position. The direct utilization of an allylic C–H bond rather than an allylic functional group would be more desirable. Trost and co-workers reported the formation of an allylic alkylation from an allylic sp³ C–H in two steps in the late 1970s, directly using allylic C–H bonds to form π-allyl palladium complexes.⁵⁶  However, this reaction was stoichiometric with respect to Pd(II), as it served as both the catalyst and the oxidant because the in situ re-oxidation of the reduced Pd(0) to Pd(II) is difficult.

To explore the direct Tsuji–Trost CDC reaction, we found that by using a combination of CuBr (2.5 mol%) and CoCl₂ (10 mol%) as a catalyst, various 1,3-dicarbonyl compounds reacted smoothly with cyclohexene by directly using allylic sp³ C–H and methylenic sp³ C–H bonds (Scheme 1.30).⁵⁷ 

When cycloheptatriene was reacted with 2,4-pentadione, the corresponding tropylacetylacetone was obtained in 41% isolated yield. If cyclopentadiene was used, the major product obtained was a dihydrofuran derivative due to the further transformation of the alkylation product in situ (Scheme 1.31).

To explore the CDC reaction of benzylic C–H bonds, diphenylmethane was reacted with benzoylacetone. We found that FeCl₂ in combination with TBP (instead of TBHP) is an effective catalyst in this case, giving the corresponding CDC products cleanly in good yields (Scheme 1.32).⁵⁸ 

Various activated methylene substrates were reacted with cyclohexane, cyclopentane, cycloheptane, cyclooctane, norbornane, and adamantane to give the corresponding CDC products in good yields in most cases by using 10 mol% FeCl₂·4H₂O as the catalyst and TBP the oxidant at 100 °C for 12 h under an atmosphere of nitrogen (Scheme 1.33).⁵⁹  A mechanism analogous to the Gif process was proposed. This mechanism involves an Fe(II)-catalyzed decomposition of the peroxide to give an Fe-enolate and an RO radical. The RO radical then reacts with the cyclohexane to give a cyclohexyl radical. The cyclohexyl radical then reacts with the enolate to form the alkylated β-ketoester and the re-generated Fe(II) for further reactions (Scheme 1.34).

Over the past few decades, substantial research has led to the introduction of efficient procedures that allow for the selective connection of two sp² C–H bonds. Direct arylations and oxidative olefinations date back to the pioneering investigations of van Helden and Verberg,⁶⁰  and Fujiwara and Moritani⁶¹  as well as other contributors⁶²  who demonstrated that aromatic C–H bonds are efficiently activated for coupling with a second sp² C–H bond in the presence of stoichiometric quantities of Pd salts. However the products were usually obtained as isomeric mixtures in moderate yields (Scheme 1.35).

The groundbreaking work of Shue,⁶³  de Vries and van Leeuwen⁶⁴  and others⁶⁵  on oxidative olefinations and the contributions of Lu,⁶⁶  Fagnou,⁶⁷  DeBoef⁶⁸  and others⁶⁹  on direct arylations laid the foundation for the development of an impressive number of transition-metal-catalyzed selective cross-dehydrogenative sp² C–H couplings. Notably, the Fujiwara–Moritani reaction is also commonly termed the “oxidative Mizoroki–Heck reaction”.^70–72  Progress in this area has been extensively reviewed and will thus only be briefly mentioned here, notwithstanding their great importance.

The addition of free sp² C radicals to aromatic compounds followed by a formal single electron oxidation step represents a third strategy for cross-dehydrogenative sp² C–C bond formations. This research area dates back to the pioneering studies of Fenton, Gif and others.⁷²  The first cross-dehydrogenative acylation of protonated nitrogen-containing heterocycles with aromatic and aliphatic aldehydes was introduced by the group of Minisci in the late 1960s (Scheme 1.36).⁷³ 

The reaction is mediated by a combination of TBHP and stoichiometric quantities of FeSO₃ in strongly acidic media. Electron-deficient substrates proved to be far more reactive than their corresponding electron-rich derivatives and consequently, over-acylation was frequently observed. The acylation occurs preferentially in the ortho- and para-positions for pyridine derivatives and thus complements the scope of Friedel–Crafts-type acylations.⁷⁴  The authors proposed a reaction mechanism that starts with the generation of a tert-butoxy radical which subsequently abstracts the hydrogen atom from the carbonyl group of the aldehyde (Scheme 1.37).

The resulting nucleophilic acyl radical adds onto the protonated heterocycle and the resulting heterocyclic radical is reduced by the Fe(II) salt into the corresponding dihydropyridine derivative that is subsequently oxidized into the corresponding products. The use of a TBHP/Ti(III) redox system allowed for the isolation and characterization of the dihydropyridine intermediate.^34j 

Efficient procedures for the cross-dehydrogenative synthesis of aryl ketones have been introduced by complementing the radical acylation with transition-metal-catalyzed activation of aromatic C–H bonds. The first cross-dehydrogenative Pd-catalyzed acylation of 2-phenylpyridines was developed independently by the groups of Cheng⁷⁵  and Li.⁷⁶  The latter demonstrated that various aliphatic, alicyclic and some aromatic aldehydes are smoothly converted in the presence of 5 mol% of Pd(OAc)₂ in combination with 1.5 equiv. of TBHP at 120 °C under an air atmosphere (Scheme 1.38).

The reaction conditions proved to be remarkably mild and even highly sensitive substrates such as (E)-croton aldehyde could be converted into the corresponding aryl ketone. The procedure is also applicable for the arylation of naturally occurring aldehydes, and this has been demonstrated by the coupling of enantiomerically pure (S)-citronellal. The group of Cheng developed a complementary Pd(OAc)₂-catalyzed aerobic protocol that is highly efficient for the acylation of 2-phenylpyridine derivatives with electron-rich, electron-deficient and heterocyclic aromatic aldehydes (Scheme 1.39).⁷⁵ 

In ensuing contributions, phenyl oximes,⁷⁷  anilides⁷⁸  and 2-phenylbenzothiazoles⁷⁹  have been successfully opened up as substrates. The group of Yu proposed a mechanism^78a  for the acylation of pivaloyl anilides (Scheme 1.40) on the basis of deuterium labeling experiments (k_H/k_D=3.6 for the C–H palladation), a Hammett correlation study with a series of meta-substituted pivaloyl anilides, and the studies of Li et al. with pre-formed Pd complexes.⁷⁶ 

The reaction starts with the thermal generation of tert-butoxy radicals that subsequently abstract a hydrogen atom from the carbonyl group of the aldehyde. The generated acyl radicals oxidize the palladacycles into either a Pd(IV) complex⁸⁰  or a dimeric Pd(III) species⁸¹  which are generated by a rate-determining C–H palladation step. Reductive elimination liberates the product and closes the catalytic cycle.

In 2011, the groups of Deng and Li demonstrated that various aliphatic and benzyl alcohols could serve as aldehyde surrogates in this reaction (Scheme 1.41). The alcohols are oxidized in situ into the corresponding aldehydes, which are subsequently converted into aryl ketones.⁸² 

The utilization of ortho-phenoxy benzaldehydes allowed the group of Li to establish an intramolecular xanthone synthesis (Scheme 1.42).⁸³  The oxidative cyclization was efficiently mediated by a RhCl₃/PPh₃ catalyst system in chlorobenzene at 160 °C.

The scope of this procedure was recently improved by the group of Studer with the introduction of ferrocene as a radical chain initiator (Scheme 1.43).⁸⁴ 

Under optimized reaction conditions (Scheme 1.43) various 2-phenoxy- as well as 2-phenylbenzaldehydes were smoothly converted into the corresponding cyclic ketones in the presence of only 1 mol% ferrocene. Other Fe salts such as FeCl₂, Fe(OAc)₂ and FeSO₄ have also been shown to initiate the reaction but unreliable variations in yield were observed. The TBHP is best added in two batches to ensure reproducible results. The authors proposed a mechanism in which the Fe catalyst initiates a radical chain reaction by generating a tert-butoxy radical that subsequently abstracts the hydrogen atom from the aldehyde (Scheme 1.44).

The resulting acetyl radical adds onto the adjacent arene ring and the resulting aryl radical is oxidized into the corresponding product by a second molecule of peroxide.

Based on the studies of Gottschalk and Neckers in 1985,⁸⁵  the group of Lei developed a radical Cu-catalyzed cross-dehydrogenative olefination reaction that gives direct access to α,β-unsaturated ketones (Scheme 1.45).⁸⁶ 

Various aromatic and heteroaromatic aldehydes were coupled with styrenes in the presence of catalytic quantities of CuCl₂ and TBHP at 80 °C. The procedure is remarkably selective, and the products detected arise from the acylation of the α,β-unsaturated ketone or radical polymerization of double bonds. The mechanism proceeds via the Cu-assisted generation of an acyl radical that adds onto the double bond of the olefin. Oxidation by the Cu catalyst and proton elimination yields the product and re-generates the Cu-catalyst.

In parallel contributions, two metal-free acylation reactions have been reported. In 2011, the group of Wang introduced a tert-butyl perbenzoate mediated amidation of thiazoles and oxazoles with a series of formamides (Scheme 1.46).⁸⁷  The groups of Qu and Guo recently applied our method of the di-TBP mediated alkylation to various purines and purine glycosides with cycloalkanes.⁸⁸ 

As an endeavor to explore novel chemical reactions and to search new tools for more efficient chemical synthesis and green chemistry, a new concept in forming C–C bonds, cross-dehydrogenative-coupling, evolved. Representative examples illustrated in this chapter have shown that various C–C bonds can be generated directly from C–H and C–H bonds under oxidative conditions. This concept is continuing to evolve and many fascinating examples are being reported. These reactions will lay the foundation for the next generation of synthetic chemists with an eye on green chemistry.

I am indebted to my colleagues, whose names are cited in the references, and who made this research possible. I also thank the Canada Research Chair (Tier I) Foundation, the CFI, NSERC, and the (US) NSF-EPA Joint Program for a Sustainable Environment for their partial support of this research.