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Home > Palladium(II)-Initiated Catellani-Type Reactions
Palladium(II)-Initiated Catellani-Type Reactions
Palladium(II)-Initiated Catellani-Type Reactions
Hong-Gang Cheng, Shuqing Chen, Ruiming Chen, and Qianghui Zhou
1.Introduction
The selective, modular, and efficient assembly of molecular complexity represents one of the most challenging yet fascinating directions in modern synthetic organic chemistry.[1] Therein, the transition-metal-catalyzed C@H function- alization of arenes is among the most attractive strategies.[2] As it can be used to construct carbon–carbon or carbonheteroatom bonds in a direct and selective manner, various game-changing disconnection strategies for organ- ic synthesis have thus been provided. Over decades, this field has attracted much attention from both academic and industrial laboratories.
In this context, Pd/norbornene (NBE) cooperative catalysis, namely the Catellani reaction, is one of the most promising approaches. It utilizes the synergistic interplay of palladium and NBE catalysis to facilitate sequen- tial ortho C@H functionalization and ipso termination of aryl halides. Since the pioneering work by the groups of Catellani[3] and Lautens,[4] this chemis- try has attracted considerable atten- tion from the organic synthesis com- munity. Over more than twenty years of development, it has become a pow- erful strategy for the expeditious synthesis of highly substituted arenes, which are difficult to access through traditional cross-coupling reactions.[5]
As shown in Scheme 1, in traditional Catellani-type reactions, aryl halides (mainly aryl iodides) are used as the substrates, and a Pd0 catalyst is required to generate the arylpalladium(II) species A, which can undergo carbopalla- dation with NBE to form intermediate B. A subsequent ortho C@H activation leads to the formation of the key aryl norbornylpalladacycle C (ANP). Then, oxidative addition of an electrophile 2 (E-X) to C generates PdIV species D, which delivers norbornylpalladium(II) species E upon reductive elimination. If the R group is a hydrogen atom, a second ortho C@H activation will occur, following the same procedure. Otherwise, because of increased steric interactions between the palladium center and the two ortho substituents, in addition to the lack of a b-hydrogen atom syn to palladium in intermediate E, a retro-carbopalladation to regenerate NBE will take place to provide arylpalladium(II) species F, which undergoes a traditional cross-coupling reaction with the terminating reagent 3 (T-Y) to afford the polysubstituted arene 4 and regenerate the Pd0 species catalyst.[6]
According to the above proposed mechanism, it can be surmised that this kind of reaction may also be initiated by a PdII catalyst to form the common arylpalladium(II) species from suitable starting materials that are different from aryl halides. Indeed, owing to the efforts of Bach, Yu, and others, a suite of elegant PdII-initiated Catellani-type reactions have been developed in the past few years (Scheme 2). Different from the conventional Catellani reaction, this PdII/NBE cooperative catalysis proceeds with completely different substrates and a different reaction mechanism, and thus the reaction conditions are significantly different or even orthog- onal. This emerging concept of PdII/NBE cooperative catal- ysis has tremendously advanced Catellani-type reactions, therefore opening a new avenue for future developments in this field. Although there have been several elegant reviews and accounts published for Pd/NBE cooperative catalysis,[5] one focusing on these emerging PdII-initiated Catellani-type reactions are still lacking yet highly desired. In this context, we have comprehensively summarized the recent advances and breakthroughs in this direction in this Minireview, hoping to inspire future studies and promote new developments in this field. This Minireview was divided into Sections accord- ing to the type of substrate interacting with the PdII catalyst, including NH-indoles and NH-pyrroles, arenes with a direct- ing group, as well as aryl boronic acids and their derivatives.
2.C2 Functionalization of NH-Indoles and NH- Pyrroles
Indoles and pyrroles are two important classes of hetero- cycles. Although considerable efforts have been made in the direct C@H functionalization of indoles and pyrroles, the regioselective C2 functionalization of these heterocycles remains a challenge.
Recently, a direct C2 functionalization (mainly alkylation and arylation) of NH-indoles and NH-pyrroles was realized by PdII/NBE cooperative catalysis. The Bach group initiated this research and made major contributions.[5j] In this Section, we have summarized the C2 functionalization of NH-indoles and NH-pyrroles by PdII/NBE cooperative catalysis. The contents discussed have been catalogued according to the functionalization reagents employed.
2.1.C2 Alkylation of NH-Indoles
Studies in this direction were initiated by Bach and co- workers in 2011, who developed reactions between NH- indoles and primary alkyl halides (bromides or iodides) that selectively generate C2-alkylated indoles under cooperative PdII/NBE catalysis (Scheme 3).[7,8] By making use of this facile transformation, an array of structurally diverse 2-alkylindoles were synthesized in moderate to excellent yields.
For 3-substituted NH-indoles, a modified procedure was required, involving more reactive alkyl iodide reagents, a more polar solvent, and air atmosphere (Scheme 3). For electron-deficient NH-indoles, a weaker base such as KHCO3 or K2HPO4 was required so as to prevent direct N-alkylation of the indoles. Lastly, it was found that the addition of water dramatically accelerated this process.
Mechanistic studies showed that 3-substituted NH-indoles were suitable substrates whereas N-substituted indoles ex- hibited no reactivity at all, indicating the pivotal role of the free NH moiety (Scheme 4 a). Moreover, through careful reaction design, key complex 12 and trapping product 13 were isolated and characterized (Scheme 4 a). Based on these results, a reaction mechanism was put forward (Scheme 4 b). Initially, the free N@H bond of indole 5 is activated by PdII, which is followed by NBE insertion to form complex 15. Cyclopalladation of 15 generates the five-membered pallada- cycle 16. Then, oxidative addition of alkyl bromide to 16 gives the PdIV complex 17, which undergoes reductive elimination to deliver norbornylpalladium(II) intermediate 18. Lastly, NBE expulsion from 18 followed by protolysis of the resulting intermediate 19 affords the final product, 2-alkylindole 7, and regenerates the PdII catalyst.[8]
A number of C2-alkylated tryptophan derivatives 21 were prepared in good yields in a similar process from the N-Boc- protected ethyl ester of (S)-tryptophan (20). Significantly, the reaction proceeded without any loss of the enantiomeric purity inherited from the chiral tryptophan substrate (Scheme 5).[9] It should be noted that this transformation requires air to proceed to prevent reduction of PdII to Pd0, just as for the previously mentioned C3-substituted indole sub- strates.
Recently, Liu[10] and co-workers utilized this strategy for the selective C2 trifluoroethylation of indoles with commer- cially available trifluoroethyl iodide as the alkylating reagent (Scheme 6 a). The reaction displays a wide functional group tolerance, and can even be utilized for the late-stage trifluoroethylation of complex indole derivatives (Sche- me 6 b). Preliminary mechanistic studies show that the unique anionic ligand dibenzoylmethane (dbm) plays a critical role in governing the efficiency of this transformation by accelerating the oxidative addition step of the unreactive trifluoroethyl iodide to the ANP intermediate 16. In addition, DFT calculations suggested that the N@H activation of the indole substrate is involved in the rate-determining step.
Remarkably, the synthetic utility of this selective C2 alkylation strategy of indoles was demonstrated by its application in the efficient synthesis of several complex indole alkaloids, such as ( )-aspidospermidine (Sche- me 7 a),[8a] ( )-goniomitine (Scheme 7 b),[8a] (+)-kopsihaina- nine A (Scheme 7 c),[11] ( )-aspidophylline A (Scheme 7 d),[12] and (+)-strictamine (Scheme 7 e).
2.2.C2 Arylation of NH-Indoles
Based on the success of the selective C2 alkylation of NH- indoles through PdII/NBE cooperative catalysis, the Bach group demonstrated that this chemistry could be extended to C2 arylation by selecting iodobenzene as the coupling partner. However, only one such example was presented in their report in 2011 (Scheme 8 a).[7] Recently, the groups of Xue and Jiang intensively explored this topic, and successfully synthesized a variety of C2-arylated NH-indoles in moderate to excellent yields (Scheme 8 b).[14] It was found that a combi- nation of electron-rich indoles and electron-poor aryl iodides usually led to good results, probably because the correspond- ing ortho C@H activation and oxidative addition steps are facilitate.
2.3.C2 Alkylation of NH-Pyrroles
Aside from indole substrates, Bach and co-workers applied the PdII/NBE cooperative catalysis chemistry to NH-pyrroles for selective C2 alkylation, which used to be a very challenging task. As pyrroles are more electron-rich and less acidic than indoles, initial attempts with such pyrroles, for example, 2-phenylpyrrole, were unsuccessful. However, electron-deficient pyrroles are suitable substrates for this transformation, delivering the corresponding alky- lated pyrroles 39 in moderate to excellent yields.[15] Utilizing this reaction as the key step, a short synthesis of the lipophilic pyrrole natural product mycalazal was realized (Scheme 9).
3.meta-Selective C@H Functionalization of Arenes
Transition-metal-catalyzed site-selective C@H functional- ization has continuously been a highly impactful process in synthetic chemistry.[16] Whereas ortho-selective C@H func- tionalization reactions of arenes have been well developed, meta-selective C@H functionalization remains a challenge. Recently, several elegant strategies have been developed to address this issue,[16g,i,17–19] for example, steric-hindrance- sensitive borylation,[17] ruthenium-catalyzed meta-selective C@H functionalization,[18] and the use of a U-shaped tem- plate.[19] A separate approach using PdII/NBE cooperative catalysis was developed by the groups of Yu, Dong, Zhao, Shi, Ferreira, and others,[20–37] who drew inspiration from the Catellani reaction. As shown in Scheme 10, by taking advantage of the directed ortho palladation and CatellaniQs NBE-mediated insertion/deinsertion, functionalization at the meta position of the arene substrate can be readily achieved. It should be pointed out that in these meta-selective C@H functionalization processes, stoichiometric silver salts are usually needed, which may act as a base for the C@H activation steps, as an oxidant to prevent the formation of Pd0 species, as well as a halogen anion scavenger to promote the formation of PdIV species. Further studies illustrated the use of this strategy in generating derivatives of phenylacetic acid, b-arylethylamines, benzyl amines, anilines, and phenols.
In this Section, we have summarized the meta-selective C@H functionalization of arenes by PdII/NBE cooperative catalysis. The contents are ordered according to the type of functionalization, including alkylation, arylation, chlorina- tion, amination, and alkynylation. Enantioselective meta C@H functionalization co-catalyzed by a chiral NBE-type mediator and PdII will be discussed separately.
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