Electron deficient borane-mediated hydride abstraction in amines: stoichiometric and catalytic processes
The manipulation of amino C–H bonds has garnered significant interest from the synthetic community due to its inherently high atom, step and redox economy. This Tutorial Review summarises the ability of boranes to mediate hydride abstraction from α-amino and γ-amino conjugated C–H bonds. Borane-mediated hydride abstraction results in the generation of reactive iminium hydridoborate salts that participate in a variety of stoichiometric and catalytic processes. The reactions that have utilised this unusual reactivity include those that manipulate amino scaffolds (including dehydrogenation, racemisation, isomerisation, α- and β-functionalisation, and C–N bond cleavage) and those that use amine-based reagents (transfer hydrogenation, and alkylation) (Chem. Soc. Rev., 2021, 50, 3720-3737). [link]
B(C6F5)3-Catalyzed Direct C3 Alkylation of Indoles and Oxindoles
Owing to their intrinsic Lewis acidity, borane catalysts have found numerous applications in synthesis and are traditionally used to activate polarized bonds. Triaryl boranes can also activate unpolarized bonds, such as H–H and Si–H bonds. In a similar vein, we considered if boranes could also be used to cleave heterolytically C(sp3)–H bonds and unveil new approaches to challenging transformations
The direct C3 alkylation of indoles and oxindoles is a challenging transformation and only a few direct methods exist. Utilizing the underexplored ability of triaryl boranes to mediate the heterolytic cleavage of α-nitrogen C–H bonds in amines, in a collaborative research effort with the Pulis and Melen labs, we have developed a catalytic approach for the direct C3 alkylation of a wide range of indoles and oxindoles using amine based alkylating agents. We also employed this borane-catalyzed strategy in an alkylation-ring opening cascade (ACS Catal., 2020, 10, 4835-4840) [link].
FLP-Catalyzed Transfer Hydrogenation of Silyl Enol Ethers
Silyl enol ethers have often served as a test bed for the development of novel FLP catalytic systems. In contrast to imines and N-heterocycles, which can serve the role of the Lewis base within an FLP-type system, the lower basicity of silyl enol ethers necessitates an additional Lewis base for dihydrogen activation and subsequent hydrogenation.
In a collaborative research effort with the Melen lab, we developed the first catalytic transfer hydrogenation of silyl enol ethers. This metal free approach employs tris(pentafluorophenyl)borane and 2,2,6,6-tetramethylpiperidine (TMP) as a commercially available FLP catalyst system and naturally occurring γ-terpinene as a dihydrogen surrogate. A variety of silyl enol ethers undergo efficient hydrogenation, with the reduced products isolated in excellent yields (29 examples, 82% average yield) (Angew. Chem. Int. Ed., 2018, 57, 12356-12359) [link].
Frustrated Lewis Pair (FLP)-Catalyzed Hydrogenation of Aza-Morita-Baylis-Hillman Adducts and Sequential Organo-FLP Catalysis
Over the past 10 years there has been a surge or research into frustrated Lewis pairs (FLPs). Of particular interest is the ability of FLPs to activate hydrogen for metal-free hydrogenation processes. Despite intensive research efforts, the substrate scope of FLP-catalyzed hydrogenation is somewhat narrow and applications of FLP catalysis in wider organic synthesis remain scarce. FLP-catalyzed hydrogenations of electron-deficient olefins are particularly challenging, often requiring the use of specialized Lewis acidic boranes, out with B(C6F5)3.
In a collaborative research effort with the Melen lab, we developed a metal-free diastereoselective FLP-catalyzed hydrogenation of aza-Morita-Baylis-Hillman (aza-MBH) adducts, accessing a diverse range of stereodefined β-amino acid derivatives in excellent isolated yields (28 examples, 89% average yield, up to 90:10 d.r.). Furthermore, the first example of sequential organo-FLP catalysis has been developed. An initial organocatalyzed aza-MBH reaction followed by in situ FLP formation and hydrogenation of the electron deficient α,β-unsaturated carbonyl compounds can be performed in one-pot, using DABCO as the Lewis base in both catalytic steps (ACS Catal., 2017, 7, 7748-7752) [link].