HAT Lessons Help Hydrogen Hop, Skip, and Jump

Abstract

Nagib and Rajanbabu share a clever approach to remote desaturation triggered by metal-catalysed hydrogen atom transfer (mHAT) to an alkene, followed by intramolecular 1,6-HAT, and terminated via mHAT. This method both realizes a valuable synthetic transformation and provides multiple lessons for the design of HAT-mediated reactions.

Selective functionalization of Csp³–H bonds has emerged as a powerful tool for the late-stage diversification of organic molecules.¹ Despite this promise, it is extremely challenging to facilitate this process in a highly efficient, regio- and chemo-selective fashion due to the relative similarity and inertness of alkyl Csp³–H bonds. Hydrogen atom transfer (HAT) abstraction, or the homolytic cleavage of a C–H bond by removal of the hydrogen atom (H•) fragment, has emerged as a relatively efficient means of activating Csp³–H bonds and allowing subsequent functionalization by generating versatile carbon-centered radical intermediates. However, regioselectivity remains a challenge in HAT reactions, with intermolecular abstraction often leading to a mixture of C–H activation products. One recent approach to overcoming this regioselectivity issue has been via intramolecular 1,n-Hydrogen Atom Transfer (HAT) using radical chaperones, where the abstracting species is temporarily tethered to the substrate, allowing the tether geometry to control which Csp³–H bond is activated. This approach has allowed for various Csp³–H bond functionalizations to be achieved with exquisite regioselectivity; however, mild methods to generate the intramolecular abstractor to perform HAT are limited.^2,3

Nagib, Rajanbabu, and co-workers have made exciting progress on this problem through design of a vinyl sulfonyl radical chaperone that allows selective remote desaturation of amines via a triple HAT pathway (Figure, center).⁴ The reaction is initiated by metal-catalysed HAT (mHAT) from a cobalt salen hydrogen atom donor to the vinylsulfonyl group to produce an α-sulfonamide radical which can then undergo a selective 1,6-HAT to transpose the radical to a remote site.^5,6 Computational studies suggest that this unusual 1,6-HAT, as opposed to 1,5-HAT, regiochemistry results from the elongated C-S-N bonds in the sulfonamide.⁷ Finally, abstraction of the hydrogen atom adjacent to the transposed radical by the cobalt mHAT catalyst allows for alkene formation at a remote site while regenerating the cobalt hydrogen atom donor. Critically, the mHAT steps are exceptionally mild and functional group-tolerant, allowing for this method to be used to synthesize functionally-dense molecules including unnatural amino acids and desaturated analogues of active pharmaceutical ingredients and natural products.^5,8 From a synthetic stangpoint, this method is a unique and exceptionally-mild entry into the stepwise cooperative HAT (cHAT) desaturation manifold with much promise for late stage molecule diversification.⁹

Figure. A Metal-Catalyzed Hydrogen Atom Transfer (mHAT) Reaction Developed by Nagib and Rajanbabu [14] Allows Remote Desaturation of Vinyl Sulfonamides.

The catalytic system proceeds via three successive HAT steps whose study provides four useful lessons for the design of effective HAT reactions.

In addition to the preparative value of the overall remote desaturation reaction, this report is notable for four major lessons in HAT reaction design (Figure):

1. Chaperone design can prevent unproductive mHAT isomerization prior to 1,6-HAT.

Cobalt salen catalysts have been shown to readily perform terminal alkene isomerization under mHAT conditions, selectively producing subterminal alkenes in high yield via an mHAT/retro-mHAT cascade.^6,10 Not only are these subterminal, internal alkenes less reactive than terminal alkenes to mHAT, but they also present a regioselectivity issue for subsequent radical generation via mHAT, especially for 1,2-disubstituted alkenes. This competitive isomerization has impeded using simple alkenes with allylic hydrogen atoms to perform remote functionalization via an mHAT/intramolecular HAT cascade.

The Nagib and Rajanbabu team show this unproductive isomerization side reaction can be suppressed by ensuring there are no allylic hydrogen atoms in the chaperone. Thus, the formed radical has no choice but to react via 1,6-HAT.

2. Careful tuning of chaperone functionality can enable both kinetically- and thermodynamically-competent 1,6 HAT using Csp³ radicals.

HAT processes are influenced by both thermodynamic (bond energy) and kinetic (polarity) factors, with a favorable match in both categories required for efficient reaction.^2,9 Previous approaches to C–H functionalization have taken advantage of the strong X–H bonds and high electronegativity of heteroatoms (especially oxygen and nitrogen) to drive HAT from weaker and more electron-rich Csp³–H bonds.¹ Alternatively, Csp² radicals can also serve as efficient abstractors due to the high strength of Csp²–H bonds, providing a thermodynamic match, and higher s-character, providing a polarity match for Csp³–H activation.² However, abstraction of C–H bonds by Csp³ radicals has proven challenging due to the similar bond strengths and electronic characters between both hydrogen atom donor and abstractor, preventing favorable matching in both categories.

This report shows how these challenges can be overcome through careful chaperone design, revealing a sulfonamide adjacent to the carbon-centered radical abstractor provides a strong polarity match with the target alkyl Csp³–H bonds while keeping HAT thermodynamically-feasible through similar bond strengths, with both properties interrogated computationally. This design was supported by comparison with four unsuccessful chaperones having a mismatch in either one or both thermodynamic and kinetic properties.

3. Alkene isomerization ability of cobalt mHAT catalyst can impact regioselectivity of remote desaturation products.

The authors show that most desaturation reactions selectively produce the γ,δ-alkene over the β,γ-alkene; however, in cases where the γ,δ-alkene would be terminal and not sterically encumbered, a switch in regioselectivity is observed.

Based on the known ability of cobalt Salen catalysts to isomerize terminal alkenes to sub-terminal alkenes under mHAT conditions, it was theorized that this selectivity might be due to isomerization of the γ,δ-alkene to the β,γ-alkene in these cases.^6,10 This reactivity was confirmed by subjecting pure γ,δ-alkene product to the reaction conditions, producing a mixture of both alkene regioisomers favoring β,γ-alkene in analogy to the parent desaturation reaction. This result demonstrates how tandem mHAT isomerization can be used to access new products.

4. Steric effects can play a major role in regioselectivity of final HAT performed by mHAT catalyst.

The Ohio State team observed a variation in γ,δ-alkene versus β,γ-alkene regioselectivity that appeared to trend with local steric environment. Toward interrogating this effect, a series of desaturation substrates with increasing steric demand were subjected to the reaction conditions. Intriguingly, the authors found that γ,δ-alkene selectivity increases dramatically with larger substituents, demonstrating steric encumbrance to be a key factor in this reaction.

It is not yet clear how much of this effect is due to impacting the regioselectivity of the initial desaturation event and how much is from impeding mHAT alkene isomerization, though both effects likely contribute. This series of experiments clearly demonstrate how modifying steric encumbrance can be used to control mHAT reactivity, a valuable lesson for reaction design.

Together, this comprehensive study introduces a streamlined method for remote desaturation of alkyl amines while also serving as a platform to gain fundamental insight into HAT steps. The lessons from this study will be invaluable for the design of future reactions enabled by HAT.