2019 Volume 2 Issue 4
INEOS OPEN, 2019, 2 (4), 124–129
Journal of Nesmeyanov Institute of Organoelement Compounds
Rhodium Complexes with Chiral Cyclopentadienyl Ligands for Catalytic Synthesis of Dihydroisoquinolones from Aryl Hydroxamic Acids and Alkenes
a Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, ul. Vavilova 28, Moscow, 119991 Russia
Corresponding author: E. A. Trifonova, e-mail: email@example.com
Received 1 July 2019; accepted 22 August 2019
During the last ten years, cyclopentadienyl rhodium complexes have been extensively used for the C–H activation of aromatic compounds with various directing groups. However, the application of chiral rhodium catalysts for such enantioselective transformations has long remained an underdeveloped area. In this short review, we highlight recent results that demonstrate high potential of this field. In particular, we provide a comparative analysis of the available chiral rhodium complexes and their performances in the catalytic enantioselective annulation of aryl hydroxamic acids with alkenes. The current limitations and objectives for further development are also discussed.
Key words: asymmetric catalysis, C–H activation, cyclopentadienyl ligands, rhodium.
Transition-metal-catalyzed functionalization of C–H bonds, including enantioselective transformations, has attracted a lot of attention over the past decade . In recent years, cyclopentadienyl rhodium complexes have been extensively used for the C–H activation of aromatic compounds with various directing groups . They have opened new, direct pathways for synthesis of valuable molecules, such as drugs , polycyclic compounds, and fluorophores . Although most of the research has been concerned with commercially available catalyst [(C5Me5)RhCl2]2, considerable attention has been also paid to the complexes with other cyclopentadienyl ligands, which provide a control over the selectivity of various transformations . Despite the high potential, the corresponding enantioselective transformations have been studied to a much lesser extent because of the limited number of accessible and efficient chiral Rh(III) catalysts, on the one hand, and a limited understanding of the chiral induction process in these reactions, on the other hand . This field has been highlighted in several recent reviews; the last one was published in 2017 [1, 6]. This short review focuses on the latest advances with special emphasis on the synthesis of chiral rhodium catalysts and their applications for a particular reaction, namely, the formation of dihydroisoquinolones from aryl hydroxamic acids and alkenes. Such focus allows for the benchmarking and direct comparison of various catalysts.
2. Achiral synthesis of dihydroisoquinolones via rhodium-catalyzed CH-activation
In 2011 Fagnou et al.  and Glorius et al.  independently showed that [(C5Me5)RhCl2]2 promotes the reaction of aryl hydroxamates 1 with alkenes 2 to give isomeric dihydroisoquinolones 3 and 4 (Scheme 1). In this process, a hydroxamic acid moiety CONHOR acts both as a directing group for the catalyst, which controls the regioselectivity of CH-activation , and as an internal oxidant, which regenerates the active Rh(III) species. In the proposed catalytic cycle , the first step involves the coordination of starting hydroxamate 1 with Rh(III) catalyst I, affording intermediate II. Then, the carboxylate-assisted concerted metalation–deprotonation results in metallacyclic intermediate IV. The subsequent coordination of an olefin leads to species V, and the migratory insertion of the alkene into the C–Rh bond produces seven-membered metalacycle VI. Finally, the reductive elimination leads to the formation of the C–N bond of product VII, and the reoxidation of the catalytic species from Rh(I) to Rh(III) occurs via cleavage of the N−O bond . The details of this last step are not fully clear yet; some researchers assume the involvement of Rh(V) intermediates .
The coordination of the olefin by rhodium with formation of fluxional intermediate V is believed to be a regio- and enantiodetermining step of the catalytic cycle. The regioselectivity of the olefin association is controlled both by the steric bulk of the Cp moiety and N–Ox substituent [5a, 5d, 11]. Classical catalyst [(C5Me5)RhCl2]2 selectively provides 3-substituted products 3 only if styrenes, acrylic esters [7, 8], dimethylallylamine, or acrolein diethyl acetal  are used as alkenes. At the same time, the reactions of aryl hydroxamates with simple alkyl-substituted terminal alkenes have very low regioselectivities, while the more hindered 1,1- or 1,2-disubstituted alkenes do not react at all. The access to opposite 4-substituted product isomer 4 is limited .
In order to gain control over the selectivity of the reaction, various substrates and rhodium catalysts have been tested. Recently, Rovis [5a], Patman , and our group  have shown that the catalysts with sterically demanding cyclopentadienyl ligands provide 4-substituted dihydroisoquinolones (4) with high regioselectivity. However, achieving both the regio- and enantioselective transformation with the same catalyst is challenging. Therefore, to avoid the formation of complex mixtures of regioisomers, the enantioselective versions of this reaction have been mostly studied for styrenes, acrylates, and symmetrically substituted strained alkenes.
3. Chiral rhodium catalysts
The asymmetric reaction requires a suitable chiral Rh(III) catalyst. Since all three coordination sites of the (C5R5)Rh fragment are occupied during the catalytic cycle , the chiral moiety can be placed only in the cyclopentadienyl ligand. In 2012 Ward and Rovis et al. [16a] and Cramer and co-workers [17, 18] have reported the first examples of enantioselective reactions of hydroxamic acids with alkenes. Ward and Rovis et al. have used a achiral rhodium catalyst with a biotin tag in combination with the biochemically engineered streptavidin proteins. The chiral environment has been created by binding streptavidin to the biotin fragment (Scheme 2). In this supramolecular assembly, a sort of artificial metalloenzyme is created. A specific engineered glutamic acid residue of the streptavidin acts as the carboxylate cofactor for the carboxylate-assisted CH-activation step of the reaction. Due to the regioselectivity problems mentioned above, the reaction scope is limited to electron-withdrawing alkenes, such as acrylates, which produce 3-substituted dihydroisoquinolones 5a–d in yields ranging from 30 to 95% with enantiomeric excesses of 12–86%. Although the idea is elegant, the methodology faces many limitations: the modification of the chiral environment is possible only by the molecular biology techniques and is probably necessary for each new reaction type. Solubility of the substrates and regeneration of the catalyst may also be problematic.
At the same time, the Cramer group has developed  a series of mannitol-derived cyclopentadienyl ligands with C2 symmetry and used their rhodium(I) complexes for asymmetric synthesis of dihydroisoquinolones from Boc-substituted hydroxamic acid and alkenes with enantiomeric excesses of 84–93% (Scheme 3). The C2-symmetric Cp ligand creates a well-defined chiral pocket and controls the chirality at the metal center, although the methyl groups have rather small steric influence. In the reaction mixture, the Rh(I) catalyst precursor is oxidized to Rh(III) with dibenzoyl peroxide (Scheme 3). The use of dibenzoyl peroxide as an oxidant in combination with the Rh(I) catalyst precursor is convenient, because it generates an exact amount of carboxylate for the concerted metalation–deprotonation step, in contrast to excess of CsOAc, which is typically used in an achiral version of this reaction. Boc-Protected hydroxamate 6 proved to be superior to other acyl derivatives in terms of the enantioselectivity. Additionally, virtually traceless decomposition of the released tert-butylcarbonic acid into tert-butanol and carbon dioxide does not increase the acidity of the reaction media, which could slow down the reaction. This problem was indeed observed in the case of O-pivaloyl-substituted substrates, where an equimolar amount of PivOH is formed in the course of the reaction.
More recently Cramer et al.  developed a mild protocol for in situ generation of chiral Rh catalysts in the reaction mixture using the C2-symmetric Cp ligands, previously reported by his group, in combination with [(COD)Rh(OAc)]2 as a Rh(I) catalyst precursor (Scheme 4). The enantioselective formation of dihydroisoquinolone 7g by this in situ approach proceeded with the yield and enantioselectivity similar to those provided by the preformed cyclopentadienyl rhodium catalyst. This methodology allows one to modify a catalyst structure more rapidly, which is important for a fast catalyst screening and development of novel enantioselective transformations.
Although mannitol-derived cyclopentadienyl complexes were effective for the target reaction, the stereoinducing ability of these ligands was not sufficient in many other rhodium-catalyzed processes . Therefore, Cramer and coworkers have developed the binaphthyl-based family of cyclopentadienyl ligands (Scheme 5). The rhodium complexes of these ligands were successfully employed in a closely related transformation of annulation of aryl hydroxamates with allenes . Somewhat lengthy preparations of these cyclopentadienyl ligands  still limit their widespread application in organic synthesis.
Very recently Cramer et al. have reported the application of this ligand family for the synthesis of chiral cobalt (III) complexes . These new complexes catalyze the annulation of N-chlorobenzamides with alkenes, giving dihydroisoquinolones 10 with impressive enantiomeric excesses up to 99% and high regioselectivities (Scheme 6). To the best of our knowledge, this is the first and the only one example of an asymmetric transformation catalyzed by chiral Cpx cobalt(III) complexes. The observed values of enantio- and regioselectivities outperform those provided by the corresponding rhodium(III)-based methods for this reaction type, presumably, because of the shorter Co–ligand distances, which results in the more effective steric control. The use of HFIP as a solvent allowed the authors to avoid harsh conditions (elevated temperatures and high catalyst loadings), which are typically used in many other cobalt-catalyzed reactions . Noteworthy, challenging substrates, such as alkyl alkenes, also react with high regio- and enantioselectivities, producing 3-substituted dihydroisoquinolones 10d,e. This promising results show great potential for the development of other cobalt-catalyzed enantioselective reactions.
In 2017 Antonchick, Waldmann and co-workers described the synthesis of a large series of rhodium complexes with new chiral cyclopentadienyl ligands (JasCp), which were obtained by the catalytic enantioselective cycloadditions of imino esters to fulvenes (Scheme 7) . These complexes have been applied in the reaction of aryl hydroxamates with alkenes. Various styrenes, even those with the heterocyclic substituents, are tolerated in this enantioselective transformation. Desired 3-substituted products 10 were obtained in 50–93% yields and with enantiomeric excesses of 87–93%. The chiral JasCp ligands can be synthesized in three steps on a gram scale from commercially available starting materials, and their structures can be adjusted by means of flexible enantioselective [6+3]-cycloaddition reactions. However, the procedures are somewhat complicated; for example, the final purification of the ligands is often carried out by chiral preparative HPLC. The coordination of rhodium sometimes occurred on both sides of the optically pure cyclopentadienyl ligand, giving a mixture of two diastereomeric complexes. These are apparently unstable in solution on air, so they have been separated by column chromatography under inert atmosphere at –40 °C. Despite these complications, recently Antonchik and coworkers used rhodium complexes with JasCp ligands for the enantioselective synthesis of axially chiral 4-arylisoquinolones from aryl hydroxamates tethered with naphthyl-substituted alkynes .
In 2018 we developed  new planar-chiral rhodium catalyst [(C5H2tBu2CH2tBu)RhI2]2 (14-R, Scheme 8) with the sterically demanding cyclopentadienyl ligand, which can be obtained starting from commercially available [(cod)RhCl]2 and tert-butylacetylene. The route for synthesis of catalyst 14-R is based on [2+2+1]-cyclotrimerization of tert-butylacetylene in the metal coordination sphere with formation of a fulvene . Subsequent addition of a hydride to the coordinated fulvene converted it into the substituted cyclopentadienyl ligand, and, finally, the oxidation with I2 gave desired catalyst [(C5H2tBu2CH2tBu)RhI2]2. Pure enantiomers of the catalyst were obtained by separation of its diastereomeric adducts with natural proline. Apart from the simple synthesis, this approach has two strategic advantages: 1) it gives access to complexes with planar chirality, which cannot be obtained from free chiral cyclopentadienyl ligands; 2) it simultaneously gives both enantiomers of the catalyst. Noteworthy, despite the success of planar-chiral complexes in other catalytic reactions , apparently, before this work they have not been used for enantioselective CH-activation. Possible addition of other nucleophiles to fulvene complex (±)-11 provides an opportunity for modification of the catalyst structure, but, except for the only one example , the modification of this catalyst has not been reported yet.
Catalyst 14-R promoted the enantioselective reaction of aryl hydroxamic acids with strained alkenes, giving dihydroisoquinolones in high yields (up to 97%) with good stereoselectivities (up to 95% ee) (Scheme 9). The selectivity of annulation of hydroxamates with olefins in the presence of 14-R can be explained by the less hindered approach of an alkene to one of the sides of the proposed metallacyclic intermediate (Fig. 1) [5d, 7].
a prepared from isolated Boc-derivative of acid; the yields are given for the second (catalytic) step
On the other hand, acyclic terminal alkenes reacted smoothly with the Boc derivative of 15 to give 4-substituted dihydroisoquinolones 16k–m in excellent yields of 89–97% and with high regioselectivities (>15:1; Scheme 9). However, the enantioselectivities were moderate in this case (45–47% ee), apparently because of insufficient steric interactions between the incoming alkene and the cyclopentadienyl ligand.
In overall, among all the ligand families developed so far, Cramer's C2-symmetrical cyclopentadienes seem to be the most promising class, despite their somewhat lengthy preparation. Other ligands were used in a small number of reactions and further research is needed to clarify their potential. The most general problem, however, is an insufficient understanding of the correlation between the ligand structure and the enantioselectivity of the CH-activation reactions.
In this short review, we have highlighted recent developments regarding the synthesis of chiral rhodium catalysts and their increasing importance as tools for asymmetric catalysis. We hope this record serves not only to introduce readers to this emerging field, but also to inspire future research efforts towards the synthesis of novel chiral catalysts with cyclopentadienyl ligands.
This work was supported by the Russian Science Foundation, project no. 17-73-20144, and the Ministry of Science and Higher Education of the Russian Federation.
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