Bino, M. Ardon and E. Shirman Lafrance, C. Rowley, T. Woo and K. Fagnou CS1 maint: Multiple names: authors list link. Categories : CS1 maint: Multiple names: authors list Pages with broken file links Organometallic chemistry Carbon-carbon bond forming reactions.
Cookies help us deliver our services. By using our services, you agree to our use of cookies. Namespaces Home Page Discussion. Views Read View source View history Help. 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.
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.
The Glaser—Hay coupling modified such oxidative homodimerization of alkynes by using a catalytic Cu I catalyst with oxygen as the terminal oxidant. 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.
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 methods 12 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. 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. The success of the above encouraged us to explore the ultimate question in 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 H 2 either in the form of an H 2 molecule or through the use of an oxidant Scheme 1. To help our understanding, we termed these reactions CDCs. 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.
In the early s, 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 CuCl 2 and oxygen; no further investigation was made.
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. 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 CH 2 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. 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 sp 3 C—H bond adjacent to nitrogen, the sp 3 C—H bond adjacent to oxygen is much less reactive. In our initial attempt to effect such CDC reactions, only the addition of an sp 3 C—H bond across an alkyne was observed, and this was via a radical process. Various alkynes were successfully coupled with diphenylmethane derivatives Scheme 1.
However, aliphatic alkynes i. 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.
Thus, we examined electron-rich arenes as one such nucleophile via a cross-dehydrogenative Friedel—Crafts type arylation. 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.
Another common MBH catalyst, triphenylphosphine, was found to be nearly ineffective due to the generation of triphenylphosphine oxide during the reaction. We discovered a palladium-catalyzed coupling of N-heterocycles with simple alcohols initiated by dicumyl peroxide Scheme 1. 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. Allylic compounds as well as diphenylmethanes have also been disclosed as substrate classes for CDC-type arylations.
Shi also reported a FeCl 2 -catalyzed benzylation reaction of electron-rich arenes with diphenylmethanes Scheme 1. Phenylacetic acid anilides were converted into the corresponding heterocycles in the presence of stoichiometric quantities of copper salts.
In , the group of Taylor also succeeded in developing a Cu OAc 2 -catalyzed aerobic variant. Recently, Li extended this strategy to the synthesis of various 3-alkylated oxindole derivatives. 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 chemistry 38 and the Gif process 39 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. Another possibility is the alkyl—aryl CDC coupling. 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.
The success of this methylation gave us hope for CDC reactions involving simple alkanes. The mechanism of this CDC was proposed to involve a ruthenium-catalyzed aryl C—H activation 42 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.
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.
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. 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.
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. Several Pd-catalyzed intramolecular CDC cyclizations have been developed that involve the connection of alkyl sp 3 C—H bonds with the sp 2 C—H bonds of heterocycles Scheme 1.
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. By using magnetic Fe 2 O 3 nanoparticles, highly efficient aerobic coupling of N -arylated THIQs with nitroalkanes was obtained under neat conditions with oxygen as the terminal oxidant. 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. 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. 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. In this reaction, InCl 3 is proposed to further activate DDQ by increasing its oxidative potential while the copper catalyst activates the malonates Scheme 1. 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.
The mechanism for the coupling is proposed in Scheme 1. Finally, the enolate attacks the benzoxy cation to generate the CDC product. The Tsuji—Trost palladium-catalyzed allylic alkylation Scheme 1.
The direct utilization of an allylic C—H bond rather than an allylic functional group would be more desirable. 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. The RO radical then reacts with the cyclohexane to give a cyclohexyl radical. Over the past few decades, substantial research has led to the introduction of efficient procedures that allow for the selective connection of two sp 2 C—H bonds.
Direct arylations and oxidative olefinations date back to the pioneering investigations of van Helden and Verberg, 60 and Fujiwara and Moritani 61 as well as other contributors 62 who demonstrated that aromatic C—H bonds are efficiently activated for coupling with a second sp 2 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. The groundbreaking work of Shue, 63 de Vries and van Leeuwen 64 and others 65 on oxidative olefinations and the contributions of Lu, 66 Fagnou, 67 DeBoef 68 and others 69 on direct arylations laid the foundation for the development of an impressive number of transition-metal-catalyzed selective cross-dehydrogenative sp 2 C—H couplings. The addition of free sp 2 C radicals to aromatic compounds followed by a formal single electron oxidation step represents a third strategy for cross-dehydrogenative sp 2 C—C bond formations.
This research area dates back to the pioneering studies of Fenton, Gif and others. 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. 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.
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 Cheng 75 and Li. 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.
In ensuing contributions, phenyl oximes, 77 anilides 78 and 2-phenylbenzothiazoles 79 have been successfully opened up as substrates. The group of Yu proposed a mechanism 78 a for the acylation of pivaloyl anilides Scheme 1.
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 complex 80 or a dimeric Pd III species 81 which are generated by a rate-determining C—H palladation step.
Reductive elimination liberates the product and closes the catalytic cycle. In , the groups of Deng and Li demonstrated that various aliphatic and benzyl alcohols could serve as aldehyde surrogates in this reaction Scheme 1.
The alcohols are oxidized in situ into the corresponding aldehydes, which are subsequently converted into aryl ketones. The utilization of ortho -phenoxy benzaldehydes allowed the group of Li to establish an intramolecular xanthone synthesis Scheme 1.
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. Under optimized reaction conditions Scheme 1. 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.
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. 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 , the group of Wang introduced a tert -butyl perbenzoate mediated amidation of thiazoles and oxazoles with a series of formamides Scheme 1.
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.
Scheme 1. Corey and X. McQuillin , D. Parker and G. Ritleng , C. Sirlin and M. Pfeffer , Chem. Dyker Angew. Chen , S. Schlecht , T. Semple and J. Ackermann Top. Eglinton and A. Galbraith , Chem. Glaser Ber. Hay J. Sarhan and C. Bolm , Chem. Moritani and Y. Fujiwara , Tetrahedron Lett. Li and B. Trost , Proc. Li Chem. Li and T. Li Acc. Wei , J. Mague and C.
Li , Proc. Wei , Z. Li and C. Yoo , L. Zhao and C. Nakamura , T. Kamakura , M. Ishikura and J. Biellmann , J. Leonard and G. Leubner , J. Murahashi , N. Komiya and H. Terai , Angew. Murata , K. Termoto , M. Muira and M. Nomura , J. Li and Z. Li , Pure Appl. Li , Angew. Wyvratt Clin. Beak , W. Zajdel and D. Reitz , Chem. Zhang and C. Li , Tetrahedron Lett. Correia and C.
Li , Adv. Bohle and C. This reaction proceeds through electrophilic substitution. Coupling reaction: In this reaction, arene diazonium salt reacts with aromatic amino compound in acidic medium or a phenol in alkaline medium to form brightly coloured azo compounds.
The reaction generally takes place at para position to the hydroxy or amino group. If para position is blocked, it occurs at ortho position and if both ortho and para positions are occupied, than no coupling takes place.
Question Papers. Question Papers Textbook Solutions MCQ Online Tests 9.
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