Bicyclo1.1.1pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp3-rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of ...1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to 1.1.1propellane to afford iodo-BCPAs; the newly formed C–I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.
The possibility of finding novel disconnections for the efficient synthesis of organic molecules has driven the interest in developing technologies to directly functionalize C–H bonds. The ubiquity ...of these bonds makes such transformations attractive, while also posing several challenges. The first, and perhaps most important, is the selective functionalization of one C–H bond over another. Another key problem is inducing reactivity at sites that have been historically unreactive and difficult to access without prior inefficient prefunctionalization. Although remarkable advances have been made over the past decade toward solving these and other problems, several difficult tasks remain as researchers attempt to bring C–H functionalization reactions into common use. The functionalization of sp3 centers continues to be challenging relative to their sp and sp2 counterparts. Directing groups are often needed to increase the effective concentration of the catalyst at the targeted reaction site, forming thermodynamically stable coordination complexes. As such, the development of removable or convertible directing groups is desirable. Finally, the replacement of expensive rare earth reagents with less expensive and more sustainable catalysts or abandoning the use of catalysts entirely is essential for future practicality. This Account describes our efforts toward solving some of these quandaries. We began our work in this area with the direct arylation of N-iminopyridinium ylides as a universal means to derivatize the germane six-membered heterocycle. We found that the Lewis basic benzoyl group of the pyridinium ylide could direct a palladium catalyst toward insertion at the 2-position of the pyridinium ring, forming a thermodynamically stable six-membered metallocycle. Subsequently we discovered the arylation of the benzylic site of 2-picolonium ylides. The same N-benzoyl group could direct a number of inexpensive copper salts to the 2-position of the pyridinium ylide, which led to the first description of a direct copper-catalyzed alkenylation onto an electron-deficient arene. This particular directing group offers two advantages: (1) it can be easily appended and removed to reveal the desired pyridine target, and (2) it can be incorporated in a cascade process in the preparation of pharmacologically relevant 2-pyrazolo1,5-apyridines. This work has solved some of the challenges in the direct arylation of nonheterocyclic arenes, including reversing the reactivity often observed with such transformations. Readily convertible directing groups were applied to facilitate the transformation. We also demonstrated that iron can promote intermolecular arylations effectively and that the omission of any metal still permits intramolecular arylation reactions. Lastly, we recently discovered a nickel-catalyzed intramolecular arylation of sp3 C–H bonds. Our mechanistic investigations of these processes have elucidated radical pathways, opening new avenues in future direct C–H functionalization reactions.
Bicyclo1.1.1pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes,
-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the ...synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions,
triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo1.1.1.0
pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/
-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.
Photoredox catalysis has transformed the landscape of radical-based synthetic chemistry. Additions of radicals generated through photoredox catalysis to carbon–carbon π-bonds are well-established; ...however, this approach has yet to be applied to the functionalization of carbon–carbon σ-bonds. Here, we report the first such use of photoredox catalysis to promote the addition of organic halides to the carbocycle 1.1.1propellane; the product bicyclo1.1.1pentanes (BCPs) are motifs of high importance in the pharmaceutical industry and in materials chemistry. Showing broad substrate scope and functional group tolerance, this methodology results in the first examples of bicyclopentylation of sp 2 carbon–halogen bonds to access (hetero)arylated BCPs, as well as the functionalization of nonstabilized sp 3 radicals. Substrates containing alkene acceptors allow the single-step construction of polycyclic bicyclopentane products through unprecedented atom transfer radical cyclization cascades, while the potential to accelerate drug discovery is demonstrated through late-stage bicyclopentylations of natural productlike and druglike molecules. Mechanistic investigations demonstrate the importance of the photocatalyst in this chemistry and provide insight into the balance of radical stability and strain relief in the reaction cycle.
Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper ...historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.
Bicyclo1.1.1pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is ...highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to 1.1.1propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of 1.1.1propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.
A versatile Cu‐catalyzed direct CH alkenylation of N‐iminopyridinium ylides, compatible with several different copper sources (including a penny), provides a powerful and inexpensive method for the ...synthesis of functionalized pyridine derivatives. Chemoselective functionalization of halide‐containing compounds allows the synthesis of alkenyl pyridines containing reactive tethers for further functionalization.
Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such ...as bicyclo1.1.1pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.
1,3‐Disubstituted bicyclo1.1.1pentanes (BCPs) are important motifs in drug design as surrogates for p‐substituted arenes and alkynes. Access to all‐carbon disubstituted BCPs via cross‐coupling has to ...date been limited to use of the BCP as the organometallic component, which restricts scope due to the harsh conditions typically required for the synthesis of metallated BCPs. Here we report a general method to access 1,3‐C‐disubstituted BCPs from 1‐iodo‐bicyclo1.1.1pentanes (iodo‐BCPs) by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This chemistry represents the first general use of iodo‐BCPs as electrophiles in cross‐coupling, and the first Kumada coupling of tertiary iodides. Benefiting from short reaction times, mild conditions, and broad scope of the coupling partners, it enables the synthesis of a wide range of 1,3‐C‐disubstituted BCPs including various drug analogues.
1,3‐C‐disubstituted bicyclo1.1.1pentanes (BCPs) are accessed from 1‐iodo‐BCPs by direct iron‐catalyzed cross‐coupling with aryl and heteroaryl Grignard reagents. This represents the first general use of iodo‐BCPs as cross‐coupling electrophiles, and the first Kumada coupling of tertiary iodides in general. Benefiting from short reaction times, mild conditions, and broad scope, it enables the synthesis of a wide range of BCPs including drug analogues.
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