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Please enable JavaScript to access the full features of the site or access our non-JavaScript page. Issue 6, From the journal: Chemical Science. This article is part of the themed collection: Most popular organic chemistry articles. This article is Open Access. Please wait while we load your content Something went wrong. It was ultimately established that the combination of Cu OAc 2 , benzoquinone and CH 3 CN gave the best results for this new coupling reaction Scheme Although benzoquinone is a well established oxidant for Pd 0 and promoter for C—C bond formation in a wide range of Pd-catalyzed reactions,[ 62 ] our studies on the formation of cyclopalladated intermediates and their subsequent reaction with organotin reagents revealed an additional role for benzoquinone: promoting C—H activation.
Having established the proof of concept, we moved forward to test if organoboronic acids, the most widely used coupling partners,[ 1 ] could be used for this reaction.
Exploring other directing groups, we were pleased to find that coupling of pyridine substrates with alkylboronic acids was successful Scheme However, rather than optimizing this coupling protocol with 2-phenylpyridine, we sought applications with more synthetically applicable substrates and thus focused our efforts on developing this reaction using a carboxylic acid directing group see Section 6.
As discussed in Section 6. This side reaction becomes predominant if C—H activation of the substrates is not rapid. The aforementioned coupling reactions benefited greatly from the use of electron-rich aryl rings or from the presence of strong coordinating groups to ensure rapid binding of the substrate with the Pd II catalysts.
Typically, nitrogen-containing directing groups are used to aid coordination; however, the presence of such groups severely restricts the substrate scope, preventing potential broad synthetic applications.
Thus, expanding the scope to include simple substrates such as carboxylic acids and alcohols was major hurdle to clear on the way to general applicability. Compared to the classical nitrogen atom-directed cyclopalladation reactions, Pd II insertion into C—H bonds promoted by oxygen atom coordination via CIPE [ 8 ] is rather rare. Considerable difficulties have been met during our effort to promote Pd II insertion into inert C—H bonds in both aliphatic and aryl carboxylic acids.
We hypothesized that the observed lack of reactivity of carboxylic acids with Pd II catalysts was due to the presence of several possible known coordination modes Scheme Subsequent structural studies using X-ray crystallography and 1 H NMR spectroscopy have also provided evidence for the formation of such a structure from toluic acid. Strikingly, the mere use of table salt was sufficient for the promotion of C—H insertion.
This newly discovered mode of reactivity made possible the application of our coupling protocol to substrates without strong directing groups Scheme The use of Ag 2 CO 3 as a stoichiometric oxidant was another major practical drawback. Nonetheless, the ability to use a simple functional group to promote C—H insertion by Pd II was encouraging. Moreover, the C—H insertion intermediates are different from the commonly obtained cyclopalladated complexes in that the latter have unusually high thermodynamic stability.
The stability of such C—H insertion intermediates is beneficial for the C—H activation step but may also cause difficulties for further functionalization. Previous conditions developed by Daugulis[ 36 ] were modified by adding excess NaOAc to improve the yields. Coupling of C—H bonds with substrates without a nitrogen-containing directing group. The versatility and practicality of this coupling reaction was then substantially improved by using potassium aryltrifluoroborates as the coupling partners Table 1.
Although the use of 20 atm of air or O 2 is needed to shorten the reaction time, this coupling reaction could also be performed under 1 atm of air or O 2 with prolonged reaction time. Most importantly, a wide range of functional groups was tolerated. The compatibility with electron-withdrawing groups, such as nitro and acetyl, which are usually deactivating, is valuable in synthesis.
Mechanistically, the reactivity observed with arenes containing both a carboxyl and nitro group renders an electrophilic palladation pathway unlikely. The excellent results obtained with benzoic acid substrates prompted us to test whether this coupling protocol could be applied to phenyl acetic acid substrates as well.
Intriguingly, the removal of the Ag I oxidant was crucial for this reaction to occur. Common functional groups on the aryl boronic acids, including methoxyl, carbonyl, and halo groups, were also tolerated. Currently, the scope of heterocyclic boronic acids is still limited Table 3. As shown for pyridyl boronic acid substrates, 2,6-disubstitution is required to obtain the corresponding product in good yields.
The compatibility with both benzoic acid and phenyl acetic acid substrates makes this aryl—aryl coupling reaction a versatile way to construct biaryl molecules with different carbon skeletons. In addition, benzoic acids and phenyl acetic acids are among the most abundant starting materials in synthesis. The only drawback is the requirement for the presence of a carboxyl group; however, the rich chemical reactivity of carboxyl groups also offers opportunity for a wide range of chemical manipulations to meet synthetic needs.
Furthermore, our ongoing work suggests that other broadly useful substrates are also compatible with this coupling protocol. For instance, triflate-protected phenylalkyl amines, which have recently been found to be reactive substrates for ortho -C—H activation,[ 22 ] similarly undergo successful ortho- coupling under identical conditions.
Further inclusion of a broader range of synthetically useful directing groups will minimize the inherent limitation of directed C—H coupling to a great extent because a particular directing group can be chosen to meet the needs of a desired synthetic application. Intrigued by the drastically enhanced reactivity in C—H activation, we are currently investigating whether a different mechanism is operative in this coupling reaction.
If this pathway were to hold, in theory the electron-rich Ph—Pd—OAc species could be oxidized to a Pd IV intermediate, which could then cleave C—H bonds more efficiently. However, these hypotheses remain pure speculation in the absence of comprehensive mechanistic studies and further structural characterization.
While it is encouraging to see that coupling of electron-rich and hence highly activated olefins, arenes and indoles with organoboron[ 74 ] and organotin[ 75 ] reagents is feasible Scheme 49 , key challenges in this endeavor remain to be addressed. For example, the reaction of Pd II with benzene still requires a large excess of benzene. Additionally, Pd II generally reacts with mono-substituted benzene at the ortho -, meta - and para -positions in an unselective fashion, limiting the potential for synthetic applications.
The solution to both of these problems most likely hinges on an innovative design of a new ligand that will impart an appropriate steric and electronic bias on Pd II so that selective C—H coupling of mono-substituted arenes can be accomplished. Continued efforts to confront the fundamental challenges of coupling unactivated arenes with organometallic reagents regioselectively are expected to yield both novel ligands and improved catalytic systems Scheme Recently, a closely related coupling reaction involving two different arene substrates as the coupling partners has attracted significant attention.
Since the early discovery of Pd II -catalyzed arene—arene coupling,[ 76 ] a great deal of effort has been devoted to eliminating the less desirable arene—arene homocoupling pathway.
The replacement of one of the arene partners by an electron-rich heterocycle substantially improves the selectivity for the heterocoupling reaction Scheme The use of a directing group has also been successfully employed to suppress homocoupling Scheme Additionally, concurrent to these studies, You found that oxazoline was a suitable directing group for this coupling reaction.
Notably, our group has also used oxazoline groups as auxiliaries to achieve C—H coupling with organotin reagents using Cu OAc 2 as the oxidant. Despite recent impressive progress made in sp 3 — sp 3 cross coupling using alkyl halides,[ 82 ] efforts to couple sp 3 C—H bonds with organometallic reagents have been met with numerous problems, likely due to the lack of assistance from an appropriate ligand.
The carboxyl-directed C—H activation inspired us to test structurally analogous hydroxamic acids as substrates Scheme The utility of this coupling reaction was further demonstrated in the alkylation of the hydroxamic acid derived from dehydroabietic acid, a natural product identified as an efficient BK channel opener Scheme Generally, however, diversification of such core structures is difficult because of the lack of reactive chemical functional groups, aside from the carboxylic acid moiety, which is essential for biological activity.
Masking the carboxylic acid as the hydroxamic acid allows for functionalization at the methyl C—H bond, affording a novel class of analogues that could ultimately display improved pharmacokinetic properties.
Despite the remarkable success in developing Pd-catalyzed asymmetric catalysis more generally, studies towards the enantioselective functionalization of C—H bonds via Pd insertion have been largely unsuccessful. Firstly, the relatively high reaction temperatures required in C—H activation reactions make chiral recognition of sp 3 carbon centers challenging.
Secondly, most commonly used chiral ligands are problematic. Typically, effective chiral induction in asymmetric catalysis occurs as a result of the chiral ligands promoting the favored reaction pathway.
However, in the case of C—H insertion processes, these ligands either outcompete the substrate for binding to the Pd II center or deactivate Pd II for cleavage of the desired C—H bond, even if the required L substrate PdX 2 complex is formed.
Our initial efforts focused on desymmetrization of prochiral C—H bonds on geminal aryl or methyl groups. In choosing such systems for early investigation, we envisioned that any insights into the stereoselection model for these substrates would be directly applicable to the desymmetrization of other C—H bonds. In particular, we looked towards desymmetrization of geminal C—H bonds of methylene groups as a long-term goal Scheme 58 , though the reactivity of methylene C—H bonds is usually markedly lower.
Upon further investigation, it was found that a wide range of mono-protected amino acids were effective chiral ligands for this enantioselective coupling reaction Table 4. Of particular importance was the finding that mono- N -protection of the amino acid ligands is crucial for chiral recognition. Analysis by 1 H NMR spectroscopy and X-ray crystallography led us to propose the involvement of a key reactive intermediate B Scheme The interaction between bound substrate and the mono -protected chiral amino acid ligand on the Pd center results in the assembly of an intermediate complex B in which C—H cleavage is not retarded to a noticeable degree.
Contrasting this favorable pre-transition state with the unfavorable pre-transition state formed from A , it is clear that the unfavorable steric interactions in A decrease the efficiency of this pathway, leading to the high enantioselectivity of this process Scheme In hindsight, mono -protection of the nitrogen atom in the amino acid ligands offers a tremendous advantage for chiral control in metal-mediated reactions.
In an effort to expand the scope of this reaction, we explored coupling of prochiral sp 3 C—H bonds. The sensitive response of enantioselectivity to the ligand structure suggests that there is vast opportunity for additional tuning of existing ligand structures, as well as for the design of entirely new ligand architectures to achieve enantioselective C—H activation reactions with more general substrate scope.
To this end, we are currently synthesizing a wide range of chiral amino acid ligands[ 98 ] with the aim of applying this new asymmetric C—C bond forming reaction to broader classes of substrates. Since its initial discovery, this mode of catalysis has been expanded to include a broad range of coupling partners, including organotin, organoboron and organosilicon reagents. Importantly, sp 2 — sp 2 , sp 2 — sp 3 and sp 3 — sp 3 coupling reactions have all been demonstrated. Due to the ubiquity of these functional groups, this catalytic reaction will likely find immediate synthetic applications, especially in the early stages of a synthesis and in medicinal chemistry.
In this context, a number of major challenges must still be overcome before these reactions will find broad applicability. Development of an efficient catalytic system that uses 1 atm of air as the sole oxidant, rather than co-oxidants such as Cu II and Ag I salts, or benzoquinone would make this new process more comparable to conventional cross-coupling reactions in terms of costs and practicality.
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