Hydroaminoalkylation for the Catalytic Addition of Amines to Alkenes or Alkynes: Diverse Mechanisms Enable Diverse Substrate Scope

Abstract

Hydroaminoalkylation is a powerful, atom-economic catalytic reaction for the reaction of amines with alkenes and alkynes. This C–H functionalization reaction allows for the atom-economic alkylation of amines using simple alkenes or alkynes as the alkylating agents. This transformation has significant potential for transformative approaches in the pharmaceutical, agrochemical, and fine chemical industries in the preparation of selectively substituted amines and N-heterocycles and shows promise in materials science for the synthesis of functional and responsive aminated materials. Different early transition-metal, late transition-metal, and photoredox catalysts mediate hydroaminoalkylation by distinct mechanistic pathways. These mechanistic insights have resulted in the development of new catalysts and reaction conditions to realize hydroaminoalkylation with a broad range of substrates: activated and unactivated, terminal and internal, C–C double and triple bonds with aryl or alkyl primary, secondary, or tertiary amines, including N-heterocyclic amines. By deploying select catalysts with specific substrate combinations, control over regioselectivity, diastereoselectivity, and enantioselectivity has been realized. Key barriers to widespread adoption of this reaction include air and moisture sensitivity for early transition-metal catalysts as well as a heavy dependence on amine protecting or directing groups for late transition-metal or photocatalytic routes. Advances in improved catalyst robustness, substrate scope, and regio-/stereoselective reactions with early- and late transition-metal catalysts, as well as photoredox catalysis, are highlighted, and opportunities for further catalyst and reaction development are included. This perspective shows that hydroaminoalkylation has the potential to be a disruptive and transformative strategy for the synthesis of selectively substituted amines and N-heterocycles from simple amines and alkenes.

Remote and Proximal Hydroaminoalkylation of Alkenes Enabled by Photoredox/Nickel Dual Catalysis

“…9d In addition, the HAA of internal alkenes is also underexplored due to the less polarized and more sterically hindered nature of the olefins. 1,7 Thus, it is highly desirable to develop novel catalytic HAA strategies to achieve α-selectivity and accommodate unactivated alkenes and sterically congested alkenes.…”

The Catalytic Synthesis of N-Aryl Indoles Featuring an Alternative Disconnection. Hydroaminoalkylation for a Telescoped Reaction Sequence

“…The regioselectivity realized using early transition metals results in the synthesis of β-methylated amines, and offers the ability to leverage the “magic methyl effect”, which can improve IC 50 values 100-fold in drug candidates . Late transition metal catalyzed hydroaminoalkylation requires the use of either directing or protecting groups, in comparison to the early transition-metal catalyzed variant that uses unprotected secondary amines, generates no side products and requires no cocatalysts or additives . Here, we show that hydroaminoalkylation enables an alternative bond-disconnection strategy in the assembly of N -aryl indoles, thereby expanding the pool of potential starting materials.…”

“…30 Late transition metal catalyzed hydroaminoalkylation requires the use of either directing or protecting groups, in comparison to the early transition-metal catalyzed variant that uses unprotected secondary amines, generates no side products and requires no cocatalysts or additives. 17 Here, we show that hydroaminoalkylation enables an alternative bond-disconnection strategy in the assembly of N-aryl indoles, thereby expanding the pool of potential starting materials. Styrene and aniline precursors can be used in hydroaminoalkylation as a key step for the catalytic and telescoped synthesis of N-aryl indoles (Scheme 2).…”

“…Hydroaminoalkylation is a reaction that catalytically adds a C sp 3 H bond α to an amine nitrogen across an alkene (Scheme ). − Hydroaminoalkylation is catalyzed by early transition metals, − late transition metals, − and photoredox catalysis , to generate two regioisomers: branched and linear (SI for mechanism). While photoredox catalysis is favored for the hydroaminoalkylation of conjugated alkenes, , unactivated substrates can undergo hydroaminoalkylation with late transition metals to favor the linear product and early transition metals afford the branched product.…”

“…Early transition-metal hydroaminoalkylation catalysts bearing 1,3 - N,O -chelating ligands are state-of-the-art catalysts that can be used with diverse amine and alkene/alkyne substrates in short reaction times, from minutes to hours, at reaction temperatures ranging from room temperature to 160 °C. ,,− In situ generated hydroaminoalkylation catalysts assembled from ureate ligand salts and Ta­(CH 2 SiMe 3 ) 3 Cl 2 are reactive for transformations with saturated N -heterocycles, dialkyl amines, and N -alkyl anilines. − …”