Three
types of dirhodium tetrakis(triarylcyclopropanecarboxylate)
complexes were generated and shown to adopt disparate high-symmetry
structures. These catalysts were evaluated in the intermolecular C–H
functionalization of an array of terminally substituted n-alkanes and displayed various site-selectivity as a function of
catalyst and substrate structure, which could be correlated through
quantitative relationships.
A new chiral dirhodium tetracarboxylate catalyst, Rh( S-2-Cl-5-BrTPCP), has been developed for C-H functionalization reactions by means of donor/acceptor carbene intermediates. The dirhodium catalyst contains four ( S)-1-(2-chloro-5-bromophenyl)-2,2-diphenylcyclopropane-1-carboxylate ligands, in which all four 2-chloro-5-bromophenyl groups are on the same face of the catalyst, leading to a structure, which is close to C symmetric. The catalyst induces highly site selective functionalization of remote, unactivated methylene C-H bonds even in the presence of electronically activated benzylic C-H bonds, which are typically favored using earlier established dirhodium catalysts, and the reactions proceed with high levels of diastereo- and enantioselectivity. This C-H functionalization method is applicable to a variety of aryl and heteroaryl derivatives. Furthermore, the potential of this methodology was illustrated by sequential C-H functionalization reactions to access the macrocyclic core of the cylindrocyclophane class of natural products.
A mild method for accessing diazo
compounds via aerobic oxidation
of hydrazones is described. This catalytic transformation employs
a Cu(OAc)2/pyridine catalyst and molecular oxygen from
ambient air as the terminal oxidant, generating water as the sole
byproduct and affording the desired diazo compounds within minutes
at room temperature. A broad array of electronically diverse aryldiazo
esters, ketones, and amides can be accessed. Pyridine dramatically
enhances the rate of the reaction by solubilizing the copper catalyst
and serving as the Brønsted base in the turnover-limiting proton-coupled
oxidation of hydrazone by copper(II). Insights gained from mechanistic
studies led to expansion of the scope of this method to include diaryl
hydrazones, delivering diaryl diazomethane derivatives, which cannot
be accessed via established diazo transfer methods. The products of
this method may be employed in rhodium carbene catalysis without isolation
of the diazo intermediate to afford cyclopropane products in good
yield with high enantioselectivity.
A scalable flow reactor is demonstrated for enantioselective and regioselective rhodium carbene reactions (cyclopropanation and C-H functionalization) by developing cascade reaction methods employing a microfluidic flow reactor system containing immobilized dirhodium catalysts in conjunction with the flow synthesis of diazo compounds. This allows the utilization of the energetic diazo compounds in a safe manner and the recycling of the dirhodium catalysts multiple times. This approach is amenable to application in a bulk-scale synthesis employing asymmetric C-H functionalization by stacking multiple fibers in one reactor module. The products from this sequential flow-flow reactor are compared with a conventional batch reactor or flow-batch reactor in terms of yield, regioselectivity, and enantioselectivity.
Leveraging congested catalyst scaffolds has emerged as a key strategy for altering innate substrate site-selectivity profiles in C−H functionalization reactions. Similar to enzyme active sites, optimal small molecule catalysts often feature reactive cavities tailored for controlling substrate approach trajectories. However, relating three-dimensional catalyst shape to reaction output remains a formidable challenge, in part due to the lack of molecular features capable of succinctly describing complex reactive site topologies in terms of numerical inputs for machine learning applications. Herein, we present a new set of descriptors, "Spatial Molding for Approachable Rigid Targets" (SMART), which we have applied to quantify reactive site spatial constraints for an expansive library of dirhodium catalysts and to predict site-selectivity for C−H functionalization of 1-bromo-4-pentylbenzene via donor/acceptor carbene intermediates. Optimal site-selectivity for the terminal methylene position was obtained with Rh 2 (S-2-Cl-5-MesTPCP) 4 (30.9:1 rr, 14:1 dr, 87% ee), while C−H functionalization at the electronically activated benzylic site was increasingly favored for Rh 2 (TPCP) 4 catalysts lacking an ortho-Cl, Rh 2 (S-PTAD) 4 , and Rh 2 (S-TCPTAD) 4 , respectively. Intuitive global site-selectivity models for 25 disparate dirhodium catalysts were developed via multivariate linear regression to explicitly assess the contributing roles of steric congestion and dirhodium-carbene electrophilicity in controlling the site of C−H functionalization. The workflow utilizes spatial classification to extract descriptors only for reactive catalyst conformers, a nuance that may be widely applicable for establishing close correspondence between ground-state model systems and transition states. Broader still, SMART descriptors are amenable for delineating salient reactive site features to predict reactivity in other chemical and biological contexts.
Rhodium‐catalyzed C−H insertions and cyclopropanations of donor/acceptor carbenes have been used for the synthesis of positional analogues of methylphenidate. The site selectivity is controlled by the catalyst and the amine protecting group. C−H functionalization of N‐Boc‐piperidine using Rh2(R‐TCPTAD)4, or N‐brosyl‐piperidine using Rh2(R‐TPPTTL)4 generated 2‐substitited analogues. In contrast, when N‐α‐oxoarylacetyl‐piperidines were used in combination with Rh2(S‐2‐Cl‐5‐BrTPCP)4, the C−H functionalization produced 4‐susbstiuted analogues. Finally, the 3‐substituted analogues were prepared indirectly by cyclopropanation of N‐Boc‐tetrahydropyridine followed by reductive regio‐ and stereoselective ring‐opening of the cyclopropanes.
Rhodium(II)-catalyzed reactions between isopropyl acetate and trichloroethyl aryldiazoacetates result in the formation of oxirane intermediates that ring open under the reaction conditions to form tertiary alcohols. When the reaction is catalyzed by the dirhodium tetrakis(triarylcyclopropanecarboxylate) complex, Rh( S-2-Cl,4-BrTPCP), the tertiary alcohols are formed with good asymmetric induction (80-88% ee).
Recent developments in controlled C-H functionalization transformations continue to inspire new retrosynthetic disconnections. One tactic in C-H functionalization is the intermolecular C-H insertion reaction of rhodium-bound carbenes. These intermediates can undergo highly selective transformations through the modulation of the ligand framework of the rhodium catalyst. This work describes our continued efforts toward differentiating C-H bonds in the same molecule by judicious catalyst choice. Substituted cyclobutanes that exist as a mixture of interconverting conformers and possess neighboring C-H bonds within a highly strained framework are the targets herein for challenging the current suite of catalysts. Although most C-H functionalization tactics focus on generating 1,2-disubstituted cyclobutanes via substratecontrolled directing-group methods, the regiodivergent methods discussed in this paper provide access to chiral 1,1-disubstituted and cis-1,3-disubstituted cyclobutanes simply by changing the catalyst identity, thus permitting entry to novel chemical space.
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