β-Silicon effect enables direct HAT for enantioconvergent couplings of α-silyl alcohols

The direct activation of R–H bonds via hydrogen atom transfer (HAT) provides an atom-economical route to radical intermediates for constructing molecular complexity. Yet this strategy is fundamentally constrained by bond dissociation energies (BDEs). The O–H bonds of common alcohols are simply too strong to be cleaved directly by HAT under conventional conditions. Consequently, a general, redox-neutral method for direct O–H activation that circumvents substrate-specific redox potentials or metal pre-activation has remained an elusive goal.

The research group of Professor Xiao Shen at Wuhan University has long been dedicated to radical and carbene chemistry involving organosilicon reagents, with a particular focus on harnessing the β-silicon effect for selective bond constructions. In earlier work, the team leveraged this effect to achieve site-selective C–H functionalization (Nat. Synth. 2025, 4, 188). Now, in a recent publication in National Science Review, they have extended the β-silicon strategy to enable a photoinduced direct HAT process on the O–H bond of α-silyl alcohols, thereby developing an enantioconvergent radical-relay coupling reaction.

The key insight is computational: the calculated O–H BDE of a representative α-silyl alcohol is only 89.2 kcal/mol—roughly 11.5 kcal/mol lower than that of its non-silylated counterpart. This bond-weakening effect, arising from the β-silyl substitution, renders direct HAT thermodynamically accessible. To realize this paradigm, the team employs thioxanthone (TXT) as an efficient HAT photocatalyst. Under mild, redox-neutral conditions, photoexcited TXT abstracts the weakened O–H hydrogen, generating an alkoxy radical that rapidly undergoes a radical Brook rearrangement to produce a nucleophilic carbon radical. This carbon radical is then intercepted by a nickel catalyst in an enantioconvergent cross-coupling with either acyl chlorides or aryl bromides, delivering chiral acyloins and alcohols with high yields and excellent enantioselectivities (Figure 1).

A particularly telling result underscores the power of this approach. Substrates bearing high oxidation potentials—such as trifluoromethyl-substituted α-silyl alcohols—were completely inert under the authors' previously reported SET/PCET conditions (Angew. Chem. Int. Ed. 2025, 64, e202507789). In sharp contrast, these same substrates performed smoothly under the new HAT protocol, affording the desired product in 84% yield. This direct experimental comparison validates that the direct HAT paradigm operates independently of substrate redox potentials, unlocking chemical space that was previously inaccessible.

The synthetic utility of this method is further enhanced by its operational simplicity (Figure 2). α-Silyl alcohol substrates are readily prepared via nucleophilic addition of silyllithium reagents to aldehydes. After a simple work-up, the crude material can be used directly in the coupling step without column chromatography. Both acylation and arylation proceed efficiently under this one-pot, two-step protocol, delivering products in good yields and enantioselectivities. The reaction is also scalable: a 2 mmol-scale run provided product 3a in 72% yield with 96% ee, without erosion of enantioselectivity.

To showcase the practical value of this strategy in complex synthesis, the team conducted a series of downstream transformations. The chiral acyloin products serve as versatile intermediates, enabling selective deoxyfluorination, diastereoselective reduction, Wittig olefination, and vinylation—all while preserving stereochemical integrity. These derivatizations highlight the potential of this method in pharmaceutical and natural product synthesis.

Mechanistic investigations provide strong support for the proposed direct HAT pathway (Figure 3). A radical clock experiment using a cyclopropane-bearing substrate produced the ring-opened product, confirming the generation of an oxygen-centered radical intermediate. Cyclic voltammetry measurements showed that the oxidation potentials of the α-silyl alcohols are significantly higher than the excited-state reduction potential of TXT, ruling out a single-electron-transfer pathway. ¹H NMR titration experiments revealed hydrogen-bonding interactions between TXT and the substrate, which likely facilitate the HAT event.   

Density functional theory calculations further corroborate this picture: the O–H BDE of the α-silyl alcohol is substantially lower than that of the reduced photocatalyst intermediate INT2, and the computed activation barrier for the HAT step is only 4.4 kcal/mol. Based on these experimental and computational data, a comprehensive catalytic cycle has been proposed, integrating the HAT event, radical Brook rearrangement, and nickel-catalyzed cross-coupling.

The corresponding authors of this work are Professor Xiao Shen and Dr. Xiaoqian He from Wuhan University. The co-first authors are Dr. Chenyu Jin and Dr. Yunhong Niu, also at Wuhan University. This research was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China. Theoretical calculations were performed on the supercomputing system at the Supercomputing Center of Wuhan University.

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