Enantiocontrol in Radical Coupling Reactions: A Catalytic [1,2]-Rearrangement of Allylic Ammonium Ylides

Abstract

The [1,2]-rearrangement of ammonium ylides is a fascinating reaction that has captivated the mechanistically inclined for almost a century. Allylic migration of these ylides is dominated by a thermally allowed concerted [2,3]-rearrangement, with the [1,2]-process usually absent or a minor pathway. As such, development of a [1,2]-selective reaction within allylic systems is an uphill battle. Decades of mechanistic insights have not settled the debate on the true pathway for [1,2]-rearrangement, with a C–N homolysis step followed by a radical coupling within a solvent cage commonly accepted. Herein, we describe our journey through the development of such a process and opine on the broader context in which this chemistry may currently rest.

Keywords

Radical coupling - Rearrangement - Enantioselective organocatalysis - Ylide - Solvent cage - Recombination - Ammonium ylide

1

Introduction

Ammonium ylides bearing an allylic or benzylic substituent may undergo either [2,3]-sigmatropic rearrangement or [1,2]-rearrangement. These processes are synthetically appealing as at least one new stereogenic center can be accessed in a single step under mild reaction conditions from readily available starting materials, generating molecular complexity ([Fig. 1]).[1] For benzylic ammonium ylides, the [1,2]-rearrangement (referred to as the Stevens rearrangement)[2] and the [2,3]-process (referred to as the Sommelet–Hauser rearrangement)[3] often show co-occurrence. This has been attributed to similarly high activation barriers in both processes— the [1,2]-rearrangement proceeding through homolytic C–N bond scission, whereas the [2,3]-rearrangement demands an unfavorable dearomatization step.[3b] [4] Nonetheless, with judicious choice of reaction conditions and the nature of the substrate, either pathway can be favored.[5] Alternatively, allylic rearrangements are heavily biased toward the thermally allowed [2,3] process,[6] with a stepwise radical mechanism[7] often proposed for the minor [1,2]-rearrangement pathway to obey the conservation of orbital symmetry.[8] Hence, selective access to allylic [1,2]-products is not straightforward. [1,2]-Rearrangements can be favored when the [2,3]-rearrangement is geometrically unfeasible, such as in the ring-expansion of azetidines.[9] For oxonium and iodonium ylides generated from carbenes, selectivity can be dictated by use of distinct ligands or metals,[10] a concept yet to be translated to ammonium ylide processes. Given that noncyclic allylic [1,2]-rearrangements of ammonium ylides are scarce and almost always constitute the minor reaction pathway, understanding its mechanism has been challenging. Moreover, factors that influence the ratio of rearrangement products have seldom been studied systematically.[6a] [11] We begin our journey by highlighting some key studies that have shed light on the factors that impact the ratio of rearrangement products.

Fig. 1 Common rearrangement pathways of allylic onium ylides.

2

[1,2]- vs. [2,3]-Rearrangement

It has been observed that higher reaction temperatures favor [1,2]-rearrangement,[7f] [12] consistent with increasing entropy in the first step of a dissociative mechanism.[4b] [13] Increased steric bulk at the ylidic or allylic terminal carbon also leads to a greater proportion of the minor [1,2]-product,[4b] [7d] [11a] [12a] [14] whereas substitution at the internal allylic carbon reduced the rate for both rearrangement pathways leading to elimination products.[12a] For example, 1 undergoes selective [2,3]-rearrangement to 5, irrespective of temperature, while the more substituted salt 2 generates a mixture of products (4 and 6) with its proportions depending on the temperature. It was also found that less basic ylides (7 vs. 8) tend to favor [1,2]-rearrangement and may constitute the major product ([Fig. 2b], left).[13a] Intrigued by the fact that similar solvent and substituent effects were observed for competing [1,2]- and [2,3]-processes,[7d] [7e] Singleton and coworkers investigated the seeming parity of these processes.[13b] [15] By probing the effect of charge stabilization in benzylic ammonium ylides 9, it was argued that ‘naked’ ylides favor [1,2]-rearrangement (10), whereas [2,3]-rearrangement (11) is favored in H-bond- or solvation-stabilized ylides ([Fig. 2b], right). Both factors indicate that the relative stability of the ylide goes hand in hand with the propensity for C–N bond homolysis. Balancing these factors to obtain a synthetically useful allylic [1,2]-rearrangement is tricky, with development of a catalytic and enantioselective version an even greater challenge.

Fig. 2 Factors that affect [1,2]- vs. [2:3]-rearrangement selectivity of ammonium ylides.

How can both rearrangements arise when the [2,3]-process is intuitively kinetically favored? Singleton’s answer is that both rearrangements pass through the same transition state at a secondary saddle point (TS-I) and then diverge at the valley ridge inflection (VRI).[16] Rearrangement of 12 (the ylide derived from 2) showed that the [1,2]-rearrangement product 4 is formed from significantly greater intermolecular reaction (18%) than the [2,3]-rearrangement product 6 (5%). The calculated degree of C–N bond homolysis to radicals 13 and 14 is exceptionally low compared to the experimentally observed rearrangement ratio. Calculations from the [2,3]-transition state TS-I showed homolysis results across a range of potential energy surfaces, giving predicted mixtures of [1,2]- and [2,3]-rearrangement in all cases. This indicates that bifurcation occurs from a common transition state TS-I and is dictated by dissociative linear motion between C and N. On the VRI, either continued linear motion will ultimately lead to fragmentation and recombination to the [1,2]-product or C–C bond formation to the [2,3]-product.

3

Stereocontrol in Radical Coupling

Early studies have shown remarkable stereoretention of enantioenriched substrates undergoing the [1,2]-rearrangement process,[7b] [17] implying that recombination must be faster (≈30 times) than diffusion or torsion/rotation of the fragments.[18] Schöllkopf first proposed that a solvent caged radical pair is involved, explaining the observation of an apparent intramolecular process.[19] Ollis and Sutherland showed that the solvent cage effect is reinforced by solvent (micro)viscosity, while polarity of the solvent had little effect.[7f] [18a] [20] Enantiopure benzylic ammonium ylide 15 revealed >99% enantiospecificity can be obtained if intermolecular rearrangement is minimized, while increased crossover led to loss of enantiopurity ([Fig. 3a]).[7f] This enantiospecific radical coupling is a remarkable stereochemical outcome. A planar, sp²-hybridized benzylic radical (17) reacts with stereocontrol because it has been formed from a chiral ylide, fleetingly retaining ‘memory-of-chirality’. This may explain why success in [1,2]-rearrangements of enantiopure ammonium salts has so far been limited, often due to competing [2,3]-rearrangement or loss of enantiopurity.[21]

Fig. 3 Examples of stereocontrolled radical coupling.

Stereocontrolled coupling of two radicals is a challenge due to both their high reactivity and propensity to undergo inversion.[22] Recently, three main tools, namely metal catalysis, organocatalysis, and biocatalysis have enabled significant progress. Prochiral radicals complexed to a chiral metal complex can be facially discriminated ([Fig. 3b]),[23] while chiral nickel complexes can capture pyramidal radicals with stereoselectivity before formal radical coupling.[24] Organocatalytic approaches include the use of chiral amines and NHCs, which exploit catalyst-bound radicals ([Fig. 3c]),[25] and noncovalent strategies include ion-pair catalysis[26] and H-bonding interactions.[27] Photobiocatalysis, an emerging field in which photochemical reactions are promoted enzymes, seeks to achieve stereocontrol of radicals within the confines of an active site.[28] If radicals are formed in close proximity, they may react on the picosecond time scale[7f] [29] and with exceptional stereoselectivity.[30] This alleviates the problem of the persistent radical effect, where efficient intermolecular radical couplings only take place between a persistent radical and a transient one.[31] The active site of an enzyme can be likened to a chiral solvent cage, protecting radicals from diffusion and loss of stereochemical information. Parallels can be drawn between the stereoretentive Stevens rearrangement and a recently disclosed photobiocatalytic radical coupling ([Fig. 3d]).[30a] The planar benzylic radical 17 is generated from an enantiopure carboxylic acid within the active site and reacts immediately with inversion of configuration. Furthermore, a Stevens-type biocatalytic rearrangement was developed, which enabled the enantioselective ring-expansion of aziridinium ylides.[32]

4

Enantioselective [1,2]-Rearrangement of Allylic Ammonium Ylides

The first stepping stone was the development of an enantioselective isothiourea-catalyzed [2,3]-rearrangement of allylic ammonium ylides, which was enabled by an aryloxide rebound strategy to promote catalyst-turnover ([Fig. 4a]).[33] In situ formation of the ammonium ylides triggered selective [2,3]-rearrangement with high levels of enantio- and diastereocontrol, guided by the isothiourea catalyst’s stereodirecting group, with transition state TS-II proposed to explain the stereochemical outcome. The chiral isothiourea catalyst binds to the substrate via acylation by the electron-poor aryl ester group. The scope of the protocol was demonstrated, which succeeded particularly well with cinnamyl derivatives. Introduction of a fluorine atom at the distal vinylic position necessitated higher reaction temperatures, but excellent stereocontrol could still be achieved.^35c It was during the study of the scope and limitations of these methodologies that the [1,2]-rearrangement product was detected, specifically when an additional methyl group at the allylic terminus was introduced within the cinnamyl fragment. This encouraged us to consider that if both rearrangements pass through the same [2,3]-transition state, then disfavoring the [2,3]-process through increased steric congestion, alongside decreasing ylide stability and increasing the reaction temperature, may promote C-N homolysis and subsequent radical coupling ([Fig. 4b]).

Fig. 4 (a) Previous work on an isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides. (b) Starting hypothesis to obtain a [1,2]-selective rearrangement.

With this precedent, our recent study of a catalytic enantioselective [1,2]-rearrangement of allylic ammonium ylides commenced.[34] Using an ammonium salt bearing a trisubstituted allylic group, a clear trend was observed in which increased reaction temperature led to increased preference for the [1,2]-rearrangement, with concurrent decrease in enantioselectivity ([Fig. 5a]). A reaction temperature of 50 °C was selected as a compromise between maximizing [1,2]-selectivity and enantiocontrol (84:16 rr, 91:9 er). In stark contrast, the cinnamyl group undergoes essentially exclusive [2,3]-migration under these conditions (<5:95 rr). Increasing the size of the cis-substituent of the allyl group from methyl to ethyl, isopropyl and phenyl lead to sequentially better [1,2]-selectivity and lower enantioselectivity ([Fig. 5b]). The effect of different nitrogen substituents is less intuitive. Use of cyclic salts generally resulted in better [1,2]-rearrangement preference, but a morpholinyl salt is a clear exception. The acyclic dimethylammonium salt preference for [2,3]-rearrangement can be overridden in the migration of a diphenyl-substituted allyl group ([Fig. 5c]).

Fig. 5 Study of temperature and structural variation on reaction selectivity for rearrangement of allylic ammonium salts. Blue/red bars indicate [1,2]/[2,3]-rearrangement ratio.

Our real interest lay in understanding the mechanism, enantioselectivity, and the factors that dictate the ratio of rearrangement products. Firstly, crossover experiments established that a significant portion of [1,2]-rearrangement product formation occurs through an intermolecular process (32% for diphenyl substituted allyl migration) ([Fig. 6]). Inclusion of TEMPO in [1,2]-selective rearrangements gave two interesting results. The trapping of allylic radicals confirmed their intermediacy, while no trapping was observed under the same conditions for [2,3]-selective substrates, which was further supported by EPR spectroscopy. Secondly, concurrent increase in the enantiomeric ratio of the [1,2]-rearrangement was observed. Crossover experiments with TEMPO revealed that trapping of allylic radicals totally suppresses intermolecular formation of the product and resulted in increased [1,2]-product enantiopurity. A direct link between intramolecularity and stereocontrol was established that echoed the seminal findings of Ollis on benzylic [1,2]-migrations ([Fig. 3a]).[18] [19] To probe the root cause of this link, the enantiomeric mixtures of products from the crossover experiments were separated using chiral stationary phase preparative HPLC. Each purified enantiomer was then subjected to quantitative[13]C NMR analysis, which revealed that the major enantiomer is mostly formed via intramolecular reaction, whereas the minor enantiomer appears to be formed from ≈1:1 mixture of intra- and intermolecular processes. This means that enantiodifferentiation is different for intramolecular and intermolecular product formation.

Fig. 6 Key crossover and radical trapping experiments.

Fig. 7 A simplified version of the proposed catalytic cycle of the isothiourea-catalyzed [1,2]-rearrangement of allylic ammonium ylides. Units of Gibbs free energies are kcal/mol.

With the aid of calculations, an overall picture of the catalytic process and origin of rearrangement selectivity was proposed. After acylation of the catalyst with 19a, deprotonation forms the key catalyst-bound ammonium ylide 23a. The ensuing lowest energy pathway was found to be C–N bond homolysis from the Re-face of the ylide, in which a 1,5-O···S chalcogen interaction ensures a co-planar conformation (TS-III).

From the Re-face of the ylide, both the Re- and Si-face of the allylic fragment are available. The search for transition-state structures from a preorganized ylide in an exo-like conformation, in which the allyl’s Si-face is directed toward the ylide, gave preferential C–N bond homolysis (TS-II, +17.3 kcal/mol). Conversely, an endo-like concerted [2,3]-rearrangement TS was located from the allyl’s Re-face (+18.9 kcal/mol), which leads to the major diastereoisomer of the [2,3]-product. From the chiral radical pair 24a (+10.6 kcal/mol) several pathways are feasible. Radical coupling of the sterically hindered C3 position of the allylic fragment leads to the minor diastereoisomer of the [2,3]-rearrangement product (+13.0 kcal/mol), whereas coupling with the less hindered C1 leads to [1,2]-rearrangement (+11.9 kcal/mol). In both cases, the barrier to C–C formation is very low, reflecting a rapid bond-forming event (radical-clock-determined rate constant >10¹¹ s⁻¹). Diffusion of the radicals may occur, which may then lead to recombination of radicals 25 and 26a via transition states that are not immediately accessible from the preorganized [2,3]-like radical complex 24a. That is to say that rapid coupling from 24a to the [1,2]-27a intermediate occurs with little geometrical reorganization, and since C–N homolysis from the Si-face of the ylide is unfeasible, this ‘intramolecular’ process is highly stereoselective. On the other hand, diffused radicals have no ‘memory-of-chirality’ of the ylide from which they were formed, and thus may approach the catalyst-bound radical with greater geometric freedom. Rebound of the aryloxide results in turnover of the isothiourea catalyst and reformation of the ester moiety within the [1,2]-rearrangement product 20a.[35]

5

Conclusions

Biasing the rearrangement of allylic ammonium ylides toward [1,2]-migration over the [2,3]-rearrangement is difficult. Why should spontaneous thermal bond homolysis take place when a perfectly reasonable concerted, thermally allowed, 6π pericyclic process is available? Singleton’s hypothesis of a shared transition state was an inspiring explanation, which echoes the increasingly invoked bifurcation of reaction pathways on potential energy surfaces, in which a single transition state, or saddle-point, can lead to multiple products.[13] [15] [16] From our joint experimental and computational study, it can be concluded that C–N bond homolysis in allylic ammonium ylides proceeds via a transition state that closely resembles the concerted [2,3]-rearrangement. With an isothiourea catalyst to control enantioselectivity, nonclassical H-bonding interactions with the halide counterion were invoked to rationalize control over the allylic endo/exo-preference leading to rearrangement selectivity. In the broader context of stereoselective radical coupling reactions, our study showcases a rare example of enantioselective catalysis facilitated by the solvent cage effect, in which suppressing diffusion of a geminate chiral radical pair is vital to attaining enantiocontrol.

Will Hartley

Will studied chemistry at the University of Sheffield (UK) and was guided on research projects by Prof. Joseph P. A. Harrity and Prof. Patrick W. Fowler FRS. He moved to the University of St. Andrews (UK) within the CRITICAT CDT scheme, obtaining his PhD under the supervision of Prof. Andrew D. Smith. His thesis was focused on the development of organocatalytic [1,2]-rearrangements. After joining Prof. Paolo Melchiorre at ICIQ (Spain) in 2020, he was awarded an MSCA European Fellowship to study the photochemical activation of organocatalytic intermediates. Since 2023, he has been carrying out research in the SintCarb Group at Universitat Rovira i Virgili (Spain), with an interest in new synthetic reagents for application in catalysis and photochemistry.

Kevin Kasten

Kevin grew up in Berlin and obtained his undergraduate degree at the Humboldt-Univeristät zu Berlin under the final guidance of Priv. Doz. Reiner Mahrwald and Prof. Stefan Hecht. He obtained his PhD at the University of St. Andrews under the supervision of Prof. Andrew D. Smith on the subject of organocatalyzed pericyclic processes. After a postdoctoral project with Peter O’Brien at the University of York investigating the lithiation-trapping of oxygen- and sulfur-containing heterocycles, he returned to St. Andrews to improve the understanding of substituent effects on HyperBTM derivatives. He is now working on organocatalytic processes involving boron at the University of St. Andrews with Prof. Andrew D. Smith.

Andrew D. Smith

Andy gained a D. Phil (supervised by Prof. Steve Davies) in 2000 from Jesus College, University of Oxford followed by postdoctoral studies with Prof. Davies. In October 2005, Andy was appointed as a Royal Society URF within the School of Chemistry at the University of St Andrews, was promoted to Reader in 2010, and Professor in 2012. He was awarded the RSC Merck Prize in 2014 and RSC Charles Rees Award in 2018. Research within the ADS group is directed toward the development of catalytic enantioselective reactions and developing a mechanistic understanding of these processes.

Contributorsʼ Statement

A.D.S.: Writing – review & editing. K.K.: Writing – original draft. W.H.: Writing – original draft.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

The authors acknowledge all coworkers in the ADS group, particularly Dr. Mark Greenhalgh (now University of Warwick), who were part of interesting discussions around this topic.

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Publication History

Received: 21 July 2025

Accepted after revision: 14 September 2025

Accepted Manuscript online:
15 September 2025

Article published online:
03 November 2025