Metamorphosis of HOSA: from consumable nitrogen donors to transient directing hubs for switchable divergent synthesis

Abstract

For decades, hydroxylamine-O-sulfonic acid (HOSA) was relegated to the periphery of organic synthesis as a rudimentary, consumable electrophilic aminating agent. Recently, the strategic exploitation of its highly polarized N–O bond and exceptional sulfate leaving group has triggered renewed methodological interests, elevating HOSA from a static nitrogen donor to a dynamic “multifunctional reagent” and a “tunable directing group.” This comprehensive review systematically decodes this paradigm shift across three distinct operational dimensions. First, in metal-free transformations, we elucidate how HOSA leverages its Umpolung reactivity and endogenous thermodynamic driving force to orchestrate profound skeletal reorganizations—such as cascade Beckmann and Lossen rearrangements—while unveiling its concealed identity as a non-consumable zwitterionic organocatalyst. Second, we critically evaluate its significant methodological advancements in transition-metal catalysis, where HOSA emerges as a versatile transient directing group (TDG), dictating precise spatial topologies for remote C–H activation and driving highly programmable, switchable divergent catalytic manifolds. Finally, we highlight HOSA's disruptive impact on industrial-scale pharmaceutical manufacturing, showcasing its unparalleled capacity to truncate classical synthetic routes and definitively eradicate genotoxic impurities in the commercial production of blockbuster drugs. By bridging fundamental physical organic insights with multi-kilogram industrial triumphs, this review firmly establishes HOSA as a premier, sustainable feedstock propelling the next generation of precision organic synthesis.

This review summarizes HOSA’s updated synthetic applications in metal-free catalysis, transition-metal-catalyzed remote C–H activation, and sustainable pharmaceutical manufacturing.

1. Introduction

The rational design of heteroatom-transfer reagents remains a central pillar in the evolution of precision organic synthesis. Historically, the installation of nitrogenous pharmacophores—which constitute the indisputable cornerstone of modern chemical biology and account for the vast majority of FDA-approved small-molecule drugs^1,2—necessitated reagents that occupy the perilous extremes of the reactivity-stability continuum. These range from hyper-reactive, explosive azides and diazo compounds to highly toxic cyanides and hydrazines.^3,4 The contemporary mandate for sustainable and scalable pharmaceutical manufacturing, heavily guided by the foundational principles of green chemistry,⁵ strictly precludes the use of such perilous progenitors in modern processes.⁶ Consequently, the strategic development of bench-stable, atom-economical reagents capable of dictating complex bond-forming trajectories via programmed activation pathways has emerged as a paramount objective for the synthetic community, prompting extensive exploration into various nitrogenous scaffolds, including O-substituted hydroxylamines.⁷

Hydroxylamine-O-sulfonic acid (HOSA)—an inexpensive, water-soluble inorganic salt that was systematically popularized as a highly versatile reagent in classic foundational literature⁸—perfectly embodies this chemical ideal. Featuring a highly polarized N–O bond adjacent to a superlative sulfate leaving group, HOSA pairs a masked electrophilic nitrogen center with an intrinsic thermodynamic driving force for bond cleavage, granting it the inherent capacity to overcome formidable activation barriers. While previous synthetic overviews—including a broader 2018 survey of O-substituted hydroxylamines and a recent 2024 HOSA-specific review⁹—have provided timely phenomenological summaries of its amination utility, the existing literature predominantly treats this reagent as a static, consumable nitrogen donor. This superficial perspective severely neglects the profound conceptual metamorphosis HOSA has undergone within modern catalytic architectures. A comprehensive, mechanism-driven framework that elucidates HOSA's transition from a simple aminating agent to a dynamic “multifunctional reagent” and a “tunable directing group”¹⁰ remains conspicuously absent.

To fully appreciate the modern synthetic paradigm of HOSA, it is instructive to examine its historical trajectory and profound impact on the synthesis of bioactive architectures (Fig. 1). Synthesized over a century ago, HOSA was long perceived as a specialized, rudimentary electrophilic nitrogen source, primarily utilized in classical atom-transfer protocols such as the amination of carbanions, organoboranes, and simple nucleophiles. However, its unique molecular choreography gradually propelled it into the realm of complex skeletal rearrangements and cascade transformations. Over the past few decades, the strategic utility of HOSA has matured exponentially, culminating in its contemporary application as a sophisticated transient directing scaffold capable of orchestrating switchable, redox-neutral C–H functionalizations.

Fig. 1. Historical timeline illustrating the evolutionary metamorphosis of hydroxylamine-O-sulfonic acid (HOSA) and representative bioactive nitrogen-containing molecules synthesized via HOSA-mediated methodologies.

Beyond its methodological elegance, the practical mandate for developing HOSA-centered chemistry is deeply intertwined with its capacity to access structurally diverse, nitrogen-containing privileged medicinal frameworks. The utilization of HOSA has enabled streamlined, highly atom-economical pathways toward numerous bioactive targets, effectively bypassing the logistical and environmental liabilities of multi-step classical sequences. Prominent examples include the multi-kilogram industrial synthesis of the endothelin receptor antagonist clazosentan, where HOSA facilitates a direct, regulatory-compliant sulfonamidation step. Furthermore, HOSA-mediated transformations have provided efficient access to complex heterocyclic cores found in potent antiviral and oncology agents, as well as the streamlined assembly of the clinical anti-anemia drug roxadustat. By unifying historical reactivity with modern coordination-driven catalysis, HOSA has solidified its status as an indispensable asset in pharmaceutical manufacturing.

This comprehensive review is specifically engineered to bridge this fundamental mechanistic void. We postulate that the true broad synthetic utility of HOSA lies not merely in its atom-transfer capability, but in its unparalleled proficiency to manipulate reaction microenvironments and orchestrate complex catalytic manifolds. To systematically decode this paradigm shift, we categorize the recent milestones based on HOSA's evolving mechanistic identities rather than traditional reaction types.

Our analysis commences at the foundational level of metal-free polar networks. Here, we delve into HOSA's Umpolung reactivity and its role as a thermodynamic engine, meticulously exploring how the synchronous extrusion of its sulfate moiety drives profound skeletal reorganizations—including cascade Lossen and Beckmann rearrangements. Complementing these cleavage-driven pathways, we also unveil HOSA's concealed identity as a non-consumable, zwitterionic organocatalyst, demonstrating its capacity to orchestrate green multicomponent assemblies without N–O bond fragmentation.

Ascending from these intrinsic polar reactivities, we critically dissect HOSA's significant methodological advancement in transition-metal catalysis. In this domain, HOSA completely sheds its identity as a passive reagent and emerges as a transient directing group (TDG). We examine its extraordinary “multi-role” capacity to function simultaneously as an in situ structural navigator for ortho-C–H activation, a precise spatial topology controller for remote meta-functionalization, and an endogenous redox-neutral oxidant. Particular emphasis is placed on highly programmable catalytic networks where HOSA dictates the switchable, divergent assembly of entirely distinct heterocyclic scaffolds from identical precursors.

To bridge the chasm between methodological innovation and practical utility, we elevate the discourse to the rigorous arena of industrial-scale pharmaceutical manufacturing. By critically analyzing multi-kilogram industrial case studies—such as the radical step-truncation in the total synthesis of roxadustat and the total eradication of genotoxic impurities (GTIs) in the commercial routes for cenerimod and clazosentan—we unequivocally demonstrate HOSA's transformative dominance in overcoming the most rigorous late-stage manufacturing bottlenecks.

Ultimately, this review seeks to provide synthetic chemists with a definitive, physically and organically grounded blueprint, redefining HOSA as a premier, sustainable engine for driving the next generation of complex molecular assembly.

2. Metal-free transformation: umpolung reactivity, skeletal reorganizations, and zwitterionic catalysis

The synthetic utility of HOSA in metal-free transformations is fundamentally driven by its highly polarized N–O bond and the exceptional leaving ability of the sulfate moiety. This structural feature endows HOSA with unique Umpolung reactivity, enabling it to function as a potent electrophilic nitrogen source. To systematically illustrate these methodologies, this section is organized into three distinct mechanistic paradigms. The discussion begins with direct electrophilic aminations and aziridinations governed by the inherent Umpolung reactivity. It then transitions to complex skeletal reorganizations and ring expansions triggered by sulfate extrusion, before concluding with recent advancements in zwitterionic organocatalysis that facilitate highly selective cascade assemblies.

2.1. Electrophilic amination and umpolung reactivity

In 2012, based on foundational investigations with the late Nobel laureate Herbert C. Brown, Sanjay V. Malhotra reported a seminal study on metal-free polar amination. By employing hydroxylamine-O-sulfonic acid (HOSA) as a direct electrophilic nitrogen source, the authors developed a highly efficient one-step route to primary amines from B-chlorodialkylboranes (R₂BCl). Conducted in tetrahydrofuran (THF) at 60 °C, this protocol exhibited broad substrate compatibility, covering linear alkyls, cyclic alkyls including cyclohexyl and cyclopentyl, and sterically hindered chiral alkyl groups such as the isopinocampheyl moiety obtained from α-pinene. These transformations delivered consistently high isolated yields between 72% and 94% (Scheme 1).¹¹ Beyond its synthetic utility, this work represented a notable improvement in step and atom economy. In contrast, conventional aminations of trialkylboranes only made use of one alkyl group, giving rise to considerable carbon-source waste.

Scheme 1. Synthesis of primary amines (RNH₂) from chlorodialkylboranes (R₂BCl).

The Brown group discovered that introducing a chlorine atom to the boron center (R₂BCl) intrinsically enhanced its Lewis acidity via a strong inductive effect. Under thermal activation at 60 °C, this heightened acidity effectively lowered the energy barrier for the 1,2-metallate rearrangement, facilitating the successive and efficient transfer of both alkyl groups from the boron center to the nitrogen atom provided by HOSA. This milestone contribution established HOSA as a robust, green electrophilic aminating reagent for main-group element transformations. By employing strategic molecular design—specifically the modulation of Lewis acidity via chloro-substitution—the authors successfully addressed the long-standing challenge of low alkyl-transfer efficiency in organoborane chemistry. This method provides a textbook paradigm for the rapid conversion of readily available olefins into high-value hindered and chiral primary amines via a hydroboration–amination cascade.

In a comprehensive evaluation of HOSA as a multidimensional polar transformation reagent, its profound capability to construct challenging heteroatom–heteroatom bonds warrants particular emphasis. In 2012, Keith Jones and co-workers disclosed an elegant, metal-free, one-pot strategy utilizing HOSA for the direct assembly of N-aryl-[3,4-d]pyrazolopyrimidines—privileged core scaffolds in modern anticancer drug discovery. This protocol entirely circumvents the traditional reliance on highly toxic and unstable hydrazine derivatives for N–N bond formation. Instead, the cascade operates smoothly at ambient temperature utilizing a remarkably benign biphasic aqueous system (H₂O/CH₂Cl₂) with sodium hydroxide as the sole promoter. The methodology exhibits excellent substrate compatibility, translating structurally diverse precursors directly into complex fused heterocyclic architectures via a streamlined one-pot operation. The cascade proceeds with yields up to 51%—a highly pragmatic efficiency for pharmaceutical library synthesis considering the multi-step nature of the in situ condensations and cyclizations (Scheme 2).

Scheme 2. HOSA-mediated, one-pot, metal-free synthesis of N-aryl-[3,4-d]pyrazolopyrimidines.

Mechanistically, this transformation pushes the conceptual limits of HOSA as an electrophilic nitrogen source (Scheme 3).¹² In the critical sequence of the cascade, the pendant aldehyde initially condenses with HOSA to form an electron-deficient O-sulfonyloxime intermediate with exceptionally high E-diastereoselectivity. Subsequently, driven by the profound electron-withdrawing nature and superlative leaving-group ability of the –OSO₃H moiety, the oxime nitrogen becomes highly electrophilic. This electrophilic center is rapidly intercepted via intramolecular nucleophilic attack by the ortho-aniline NH group. Expulsion of the sulfate anion cleanly furnishes the N–N bond, sealing the pyrazole ring. This compelling research addresses the conventional paradigm that HOSA is strictly reserved for “carbon amination.” It unequivocally demonstrates that the highly polarized HOSA-derived intermediates can serve as robust electrophilic targets for other heteroatoms to forge synthetically demanding N–N linkages. Furthermore, the deployment of benign, biphasic aqueous conditions offers a highly step-economical and scalable platform for the rapid elaboration of medicinal chemistry libraries.

Scheme 3. Mechanism of constructing N–N bonds via intramolecular nucleophilic attack using electron-deficient hydroxylamine derivatives.

In 2015, the research group of J. Adam McCubbin published a foundational study in The Journal of Organic Chemistry, detailing the direct, transition-metal-free translation of arylboronic acids into primary anilines. In classical Buchwald–Hartwig or Ullmann cross-couplings, the direct installation of an unprotected primary amino group (–NH₂) frequently encounters severe challenges, including catalyst poisoning and intractable over-arylation. Circumventing these formidable catalytic obstacles, the authors elegantly leveraged HOSA as a highly reactive, electrophilic ‘+NH₂’ equivalent. Operating under exceedingly mild conditions—at room temperature within a basic aqueous biphasic medium (NaOH/MeCN)—the protocol cleanly executed the amination of diverse arylboronic acids (Scheme 4).¹³ The methodology exhibited excellent compatibility with electron-rich and sterically encumbered aryl scaffolds and was further highlighted by a streamlined one-pot procedure converting aryl bromides to anilines via transient boronate esters, drastically elevating its synthetic utility.

Scheme 4. Substrate scope for the metal-free amination of arylboronic acids to primary anilines.

At the fundamental physical organic level, this transformation efficiently adheres to the classical 1,2-metallate rearrangement pathway (Scheme 5). In a basic aqueous environment, the arylboronic acid initially coordinates with HOSA, generating a critical tetravalent boronate complex. Subsequently, the electron-rich aryl group acts as an internal nucleophile, undergoing a stereospecific 1,2-migration from the boron center to selectively attack the highly electrophilic nitrogen atom of HOSA, which is heavily polarized by the adjacent sulfate group. Driven by the synchronous extrusion of this superior sulfate leaving group, the transiently high-energy N–O bond is cleaved, irreversibly forging the stable C–N bond, which upon hydrolysis liberates the target primary aniline.

Scheme 5. Proposed modes of aryl B–N migration.

This investigation possesses irreplaceable strategic value in the historical evolution of synthetic methodologies. It not only establishes a supremely green and cost-effective paradigm for assembling ubiquitous aniline motifs in medicinal chemistry but also provides the quintessential mechanistic archetype for the kinetic limitations unraveled nearly a decade later. Because the rate-determining step (1,2-migration) of this reaction heavily relies on the nucleophilic migratory aptitude of the arene, HOSA inevitably encounters a profound kinetic barrier (as discussed in the 2024 studies) when confronted with highly electron-deficient substrates. This decade-spanning mechanistic corroboration masterfully completes the physical organic portrait of HOSA within metal-free systems.

In 2015, the research group of Gustavo Moura-Letts reported an exceptionally elegant multicomponent cascade strategy, seamlessly forging highly substituted diaziridine architectures from simple ketones or aldehydes, primary amines, and HOSA, facilitated by a weak inorganic base (Scheme 6).¹⁴ Diaziridines represent a class of fundamentally important yet synthetically challenging high-strain N–N heterocycles, where traditional protocols often struggle to balance overall yield with stringent stereocontrol. In contrast, this metal-free paradigm not only exhibits outstanding substrate universality—gracefully accommodating a diverse array of sterically encumbered and electronically biased aliphatic or aromatic precursors—but remarkably establishes three stereocenters in a single chemical step, delivering the targeted pure stereoisomers with superlative diastereoselectivity. In dissecting the physical organic mechanism of this three-component cascade, the authors elucidated a sequential bond-forming trajectory fundamentally driven by precise polarity matching. Initially, the ketone or aldehyde undergoes classical dehydrative condensation with the primary amine to in situ generate a transient imine intermediate. Subsequently, capitalizing on its intense electrophilicity derived from the exceptional sulfate leaving group, HOSA accurately intercepts this transient imine.

Scheme 6. Substrate adaptability of synthetic diaziridines.

Within a mildly basic microenvironment, the imine nitrogen executes a nucleophilic attack on HOSA, and concomitant with sulfate anion extrusion, this critical electrophilic amination step rapidly yields a high-energy N-amino intermediate. Immediately following this event, the intermediate undergoes an extremely rapid intramolecular nucleophilic addition and cyclization, forcefully overcoming the immense internal ring strain to irrevocably lock the three-membered core framework.

This cascade assembly efficiently underscores the formidable prowess of HOSA as an ultimate nitrogen-transfer reagent. It not only cleverly circumvents the utilization of transition-metal catalysts but, through the meticulous kinetic orchestration between the in situ-generated imine and the highly reactive electrophilic aminating agent, establishes a highly atom-economical and operationally benign green synthetic paradigm for accessing stereochemically complex heterocyclic pharmaceutical precursors.

In 2017, the collaborative efforts of the McCubbin and Tranmer groups yielded a methodological upgrade of profound engineering elegance. Abandoning conventional prolonged room-temperature stirring and standard thermal activation, they creatively integrated sonication and microwave-assisted technologies into the HOSA-mediated polar amination manifold. This physical-field-driven strategy not only drastically curtailed reaction times but also successfully expanded the substrate scope to include potassium aryltrifluoroborates—precursors celebrated for their superior bench stability and industrial operational advantages. Under the intense acoustic cavitation effect generated by ultrasound or the targeted dielectric heating of microwaves, these trifluoroborate salts gracefully underwent translation into primary anilines (Scheme 7).¹⁵

Scheme 7. Scope of amination reaction using microwave and ultrasound processing for potassium aryltrifluoroborates.

Even more striking is the profoundly accelerated reaction kinetics observed when this dual-energy activation paradigm was applied to classical arylboronic acids (Scheme 8). Under precise microwave irradiation, the formidable activation energy barrier of the rate-determining 1,2-metallate migration step—which typically requires hours or overnight stirring to surmount—was instantaneously overcome, driving the reaction to absolute completion within a mere 15 minutes. The physical-field-induced acceleration clearly indicates, from a physical organic perspective, that under sufficient and high-density energy inputs, the HOSA system can readily overcome the intrinsic kinetic barrier associated with electron-deficient or sterically hindered arenes during nucleophilic migration. This contribution not only equips modern high-throughput pharmaceutical synthesis with an “on-demand” protocol for primary aniline construction but also perfectly exemplifies modern green chemistry by employing unconventional physical energy sources to accelerate electron transfer and bond reorganization, thereby entirely supplanting reliance on expensive and highly toxic transition-metal catalysts.

Scheme 8. Comparison of amination reactions using room temperature, sonication, and microwave processing for arylboronic acids.

In 2020, driven by a “continuous search for novel electron-withdrawing groups (EWG)” to engineer sophisticated “push–pull chromophores”, Daniel T. Gryko and co-workers at the Polish Academy of Sciences reported an elegant two-step, one-pot cascade strategy. This work expanded the operational dimensionality of HOSA from fundamental polar bond formations to complex multicomponent reactions (MCRs), underscoring its profound utility as a highly versatile synthetic linchpin. By utilizing aromatic aldehydes, HOSA, and diethyl acetylenedicarboxylate, the protocol efficiently assembled esters of 4-(arylmethylene)-5-oxo-4,5-dihydroisoxazole-3-carboxylic acids (Scheme 9).¹⁶

Scheme 9. Universality of HOSA-involved synthesis of isoxazole-5-one substrates.

This metal-free protocol boasts remarkable modularity; by systematically varying the substituents on the aldehyde precursor—particularly by incorporating electron-rich aryl or expanded heteroaryl scaffolds such as carbazole or phenothiazine—the electronic architecture of the resulting chromophores can be meticulously tailored. Although the isolated yields range from 11% to 43%, such efficiencies are highly commendable given the profound structural complexity generated via multiple sequential bond-forming and bond-breaking events in a single pot. Crucially, these synthesized isoxazol-5-one scaffolds function as quintessential donor–acceptor (D–A) systems, exhibiting intense UV/vis absorption characteristics in the 350–450 nm range. To elucidate the fundamental logic of this cascade, the authors proposed an exquisite, continuous four-step sequential pathway (see Scheme 10).

Scheme 10. Proposed multi-group cascade reaction mechanism.

Within this intricate network, HOSA operates as a highly practical, “water-soluble, and inexpensive hydroxylamine equivalent”. Initially, in a basic aqueous medium (NaOH), the first equivalent of the aromatic aldehyde rapidly condenses with HOSA to in situ generate the requisite oxime. Upon the addition of diethyl acetylenedicarboxylate, the oxime functions as a nucleophile, undergoing a robust oxa-Michael addition to the electron-deficient alkyne to afford an intermediate. This event is immediately followed by spontaneous intramolecular cyclization, accompanied by the extrusion of ethanol, which constructs the core N–O heterocycle yielding the isoxazol-5-one framework. The defining architectural step of this cascade is a terminal Knoevenagel condensation; because the active methylene group is flanked by potent electron-withdrawing groups and possesses high C–H acidity, it undergoes rapid condensation with a second equivalent of the aromatic aldehyde. This terminal dehydration event completes the extended π-conjugated network, delivering the final push–pull target.

Ultimately, this pioneering research irrevocably demonstrates that HOSA transcends its traditional role as a simple aminating agent; it acts as a precise “multifunctional reagent” capable of orchestrating sophisticated sequences to seamlessly forge advanced functional materials endowed with tailored photophysical properties.

In 2021, a research team led by Allen Y. Hong from Genentech reported a highly pragmatic, metal-free synthetic strategy in Tetrahedron Letters, successfully leveraging HOSA to achieve the direct N-amination of lactams, thereby efficiently assembling semi-saturated polycyclic 1,2,4-triazole scaffolds—architectures of immense pharmaceutical potential. While conventional triazole syntheses frequently depend on heavily pre-functionalized substrates or highly toxic hydrazine derivatives, this protocol ingeniously commences from ubiquitous and inexpensive lactams. Through a streamlined two-step cascade, it executes a significant advance toward complex three-dimensional polycyclic systems (Scheme 11).¹⁷ The strategy exhibits excellent accommodating capacity for lactams of varying ring sizes; whether employing five-membered, six-membered, or more intricate fused-ring precursors, the system smoothly translates them into the corresponding polycyclic triazole derivatives.

Scheme 11. Triazole formation substrate scope.

From a fundamental physical organic perspective, this transformation clearly demonstrates the distinct advantages of HOSA in polar N–N bond construction: in the presence of a strong base like sodium hydride, the lactam is first deprotonated to generate a highly nucleophilic amide anion. This electron-rich species rapidly attacks the amine nitrogen of HOSA—markedly electron-deficient due to the adjacent strong electron-withdrawing sulfate group—and the concurrent extrusion of the excellent sulfate leaving group enables electrophilic amination to proceed instantaneously to cleanly form the critical N-amino lactam intermediate. Subsequently, this intermediate undergoes highly efficient dehydrative condensation and cyclization with an introduced iminoacetate, specifically ethyl 2-ethoxy-2-iminoacetate. This concerted sequence irreversibly locks the newly formed N–N bond within the highly conjugated aromatic heterocyclic framework while endowing the target product with a highly functionalized ester handle, thereby priming the scaffold for downstream medicinal chemistry elaboration.

Emanating from a premier industrial research institution, this methodology strips away the constraints of complex transition-metal catalytic systems, maximizing the synthetic potential of HOSA as a pure electrophilic aminating reagent. It unequivocally demonstrates to the synthetic community that by relying solely on the fundamental principles of polarity matching, HOSA possesses the profound capability to drive the rapid construction of highly strained, semi-saturated modern pharmacophores, thereby providing an irreplaceable green synthetic tool for the discovery of novel pharmaceutical lead compounds.

In 2022, the research group of Petr Cankař reported a methodology for synthesizing unsymmetrical 1,1′-bibenzimidazoles via the formation of a key N–N bond. The strategy involves the N-amination of benzimidazole substrates using HOSA, pre-assembling a 1-aminobenzimidazole intermediate equipped with a primary amino group. Building upon this critical nitrogenous building block, the authors designed and demonstrated a highly concise and efficient two-step derivatization route (Scheme 12).¹⁸ In the initial step of the sequence, the HOSA-derived 1-aminobenzimidazole acts as a nucleophile to undergo a classical nucleophilic aromatic substitution (S_NAr) with 1-fluoro-2-nitrobenzene in a mild basic environment (K₂CO₃, DMF), effectively connecting the two independent aromatic scaffolds in high yields. Subsequently, the system enters the reductive cyclization phase. Employing an iron powder and glacial acetic acid (Fe/AcOH) catalytic system, the nitro group on the intermediate is effectively reduced to an amino group, immediately triggering an in situ intramolecular cyclization. This contiguous chemical process not only smoothly constructs the second benzimidazole core but also efficiently establishes the overall rigid architecture of the target unsymmetrical bibenzimidazole without the intervention of precious metals. This synthetic route, utilizing mild conditions and inexpensive reagents, fully demonstrates that the pre-installation of a nitrogen anchor via HOSA can significantly streamline the otherwise highly complex de novo synthesis of heteroaromatic rings.

Scheme 12. Synthetic route to asymmetric bisbenzimidazole.

In 2024, the research team led by Hao Wang and Gong Chen at Nankai University disclosed a conceptually disruptive paradigm that entirely eschews transition metals. By relying solely on inexpensive HOSA as the ultimate aminating agent, they successfully achieved the direct, metal-free N–H aziridination of unactivated olefins. The mechanistic key to unlocking this elusive transformation lies in the strategic deployment of a 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) solvent system. Within this highly specific microenvironment, the reaction proceeds smoothly at 50 °C upon the simple addition of an organic base such as piperidine or pyridine, completely bypassing all metal-mediated redox pathways. This metal-free protocol boasts astonishing substrate generality and synthetic robustness. Even with exceptionally challenging unactivated alkenes, the system exhibits excellent substrate compatibility (Scheme 13),¹⁹ effortlessly translating mono-, di-, and even sterically encumbered tri- and tetra-substituted double bonds into high-value N–H aziridines. Such indiscriminate reactivity toward sterically congested olefins is exceedingly rare, even among state-of-the-art transition-metal-catalyzed systems. Simultaneously, it is compatible with most functional groups (Scheme 14).

Scheme 13. Investigation of functional group compatibility.

Scheme 14. Investigation of functional group compatibility.

At the fundamental mechanistic level, this research profoundly illuminates how sophisticated solvent networks can efficiently substitute the activation roles traditionally reserved for metal catalysts (Scheme 15). In this protocol, HFIP transcends its role as a mere inert medium; empowered by its formidable hydrogen-bond-donating capability, it acts as a “pseudo-metallic Lewis acid.” Facilitated by the organic base, the amine nitrogen of HOSA approaches the electron-rich double bond. Concurrently, the extensive hydrogen-bonding network of HFIP intensely solvates and activates the intrinsic sulfate leaving group of HOSA. This potent hydrogen-bond tug-of-war induces severe polarization of the otherwise recalcitrant N–O bond. Driven by the concerted nucleophilic attack from the alkene and the facilitated extrusion of the sulfate anion, an exceptionally clean polar transfer occurs. This orchestrates the stereospecific closure of the three-membered ring entirely free from the intervention of any organometallic intermediates. This milestone investigation not only propels the utility of HOSA in metal-free polar bond formations to unprecedented heights but also serves as an exquisite paradigm in physical organic chemistry. It unequivocally demonstrates that by precisely orchestrating hydrogen-bonding solvent networks, an inexpensive and benign inorganic aminating reagent can surmount formidable activation barriers to execute the complex assembly of highly strained heterocycles—a feat previously thought to be the exclusive domain of noble-metal catalysis.

Scheme 15. Proposed mechanism.

2.2. Condensation, rearrangement, and polar cleavage: metal-free cyanation, esterification, and C–C bond cleavage

In 2022, the research group of John R. Falck reported a metal-free transformation strategy with profound synthetic depth. Utilizing only HOSA and simple triethylamine (Et₃N), they successfully achieved the chemoselective C–C bond cleavage of benzylic and allylic alcohols, translating them directly into high-value anilines or nitriles (Scheme 16). This reaction system is remarkably streamlined, entirely obviating the need for exogenous oxidants or transition-metal catalysts. For acyclic alcohols, the system undergoes exhaustive cleavage to furnish the corresponding primary amines or nitriles. Furthermore, when applied to cyclic benzylic or allylic alcohols possessing higher topological complexity, the reaction exhibits exceptional ring-opening bis-functionalization capabilities. It simultaneously introduces nitrogen atoms at both termini of the cleaved molecular framework, forging complex nitrogenous heterocycles or unsymmetrical bifunctional products in a single operation.

Scheme 16. Substrate adaptability of synthetic amines and nitriles.

At the physical organic level, this transformation unveils the profound potential of HOSA in driving complex rearrangement pathways (Scheme 17).²⁰ According to the proposed mechanism, the cascade sequence initiates with the activation of the benzylic or allylic alcohol to generate a transient carbocation. Subsequently, rather than acting as an oxidant, HOSA functions as a nucleophile, directly intercepting this carbocation to form a critical N-alkylated O-sulfate intermediate. Driven by the basic microenvironment (Et₃N) and the superlative leaving ability of the intrinsic sulfate moiety, this intermediate undergoes a Stieglitz-type rearrangement or fragmentation. The expulsion of the sulfate group directly triggers the cleavage of the adjacent carbon–carbon bond and the concomitant 1,2-migration of the aryl (or allyl) group. This process cleanly severs the intrinsically stable C(sp²)–C(sp³) bond.

Scheme 17. Plausible bis-functionalization mechanism.

Ultimate hydrolysis or elimination of the resulting intermediates delivers the final aniline (Scheme 17B) or nitrile (Scheme 17A) products. This synthetic route highlights the chemical capacity of HOSA to act sequentially as a nucleophilic aminating reagent and a rearrangement initiator in a one-pot protocol, providing a highly atom-economical, metal-free solution for the precise late-stage degradation and selective nitrogen insertion of complex pharmaceutical scaffolds.

In 2025, Ashirwad Divedi and Jawahar L. Jat reported a sophisticated metal-free catalytic protocol that ingeniously exploits the multifaceted reactivity of hydroxylamine-O-sulfonic acid (HOSA) to facilitate the direct transformation of aldehydes and alcohols into high-value esters. Operating within a thermal range of 70 °C to 110 °C, this one-pot system utilizes a precisely tuned solvent environment—optimally an alcohol/water mixture at a 9 : 1 ratio—which functions concurrently as the reaction medium and the coupling partner. Remarkably, the transformation proceeds efficiently with a loading of 2.0 equivalents of HOSA, entirely circumventing the conventional reliance on expensive transition-metal catalysts or external stoichiometric oxidants. This methodology demonstrates formidable substrate generality, seamlessly accommodating a diverse array of aromatic aldehydes bearing both electron-donating and electron-withdrawing groups. Furthermore, it effectively converts challenging aliphatic, polycyclic, and heteroaromatic aldehydes, including scaffolds containing thiophene, furan, pyridine, and tosyl-protected indole moieties (Scheme 18).²¹

Scheme 18. Investigation of the universality of aldehyde substrates in HOSA-mediated direct esterification reactions.

The catalytic system also exhibits broad compatibility with various alcohols, ranging from simple primary alcohols to complex unsaturated derivatives and even phenol under additive-assisted conditions (Scheme 19). Mechanistically, through rigorous control experiments and intermediate trapping followed by high-resolution mass spectrometry (HRMS), the authors elucidated an exquisitely designed cascade pathway (Scheme 20). The sequence initiates with the nucleophilic condensation of the aldehyde with HOSA to generate an in situ oxime intermediate. Subsequently, driven by the intrinsic polarization of the N–O bond and the superior leaving ability of the sulfate group, a spontaneous Beckmann rearrangement occurs, transforming the oxime into a crucial nitrile species while synchronously liberating sulfuric acid (H₂SO₄) into the medium. This in situ-generated acid then acts as a potent Brønsted acid catalyst to activate the nitrile, facilitating subsequent nucleophilic attack by the alcohol to afford a highly reactive, transient imidate intermediate. Finally, the imidate undergoes selective hydrolysis, mediated by the trace moisture present in the system, to release the target ester.

Scheme 19. Expansion of alcoholic companion drugs and regulatory preparation of the commercial drug nicoboxil.

Scheme 20. Self-supply cascading reaction mechanism based on HOSA triple roles.

This seminal work fundamentally addresses the inherent limitations of classical esterification methodologies—such as the Tishchenko reaction or noble-metal-catalyzed oxidative esterification—which are often plagued by restricted substrate scope, use of toxic reagents, and poor atom economy. Within this framework, HOSA uniquely assumes a “triple-role” as an aminating agent, a rearrangement initiator, and a latent catalyst precursor. The robustness of this protocol is further underscored by its successful 10 mmol scale-up (achieving 91% yield) and its direct implementation in the gram-scale synthesis of nicoboxil, a commercial pharmaceutical agent utilized for musculoskeletal pain management. Consequently, this method establishes a highly step-economical and industrially viable metal-free platform for modern sustainable organic synthesis.

In the expanding landscape of metal-free polar transformations, HOSA stands out for its remarkable ability to drive the assembly of C–N triple bonds (nitriles) through profound dehydrative pathways. In 2016, Gustavo Moura-Letts and co-workers disclosed a highly sustainable, direct cyanation strategy that aligns closely with green chemistry principles by avoiding highly toxic classical cyanide sources, such as KCN and CuCN, as well as harsh dehydrating conditions to facilitate the simple reaction of aldehydes with HOSA in a mildly acidic aqueous medium containing stoichiometric acetic acid at 50 °C. Notably, the authors showed that this transformation proceeds smoothly even in common household vinegar, and this environmentally benign approach boasts broad substrate compatibility—for aliphatic aldehydes and conjugated enals, the system delivers the corresponding nitriles in excellent yields (86–95%) (Scheme 21). Furthermore, the reaction exhibits profound tolerance toward diverse electronic variations on aromatic scaffolds (Scheme 22). Electron-rich, electron-deficient, and heteroaromatic aldehydes (e.g., pyridyl) are seamlessly converted to aryl nitriles in superb yields. Notably, the operational simplicity is highlighted by the fact that the majority of products require only simple extraction, entirely circumventing the need for chromatographic purification.

Scheme 21. HOSA-mediated metal-free dehydration cyanation of aliphatic compounds with conjugated aldehydes.

Scheme 22. Investigation of substrate universality for aromatic and heteroaromatic aldehydes.

Mechanistically, the authors proposed a highly efficient elimination pathway driven by the unique leaving group ability of HOSA, ruling out the sluggish conventional “oxime formation–dehydration” sequence (Scheme 23).²² The condensation of the aldehyde with HOSA rapidly generates a highly reactive O-sulfonyloxime intermediate. Facilitated by the mildly acidic aqueous environment, this transient species undergoes either an intermolecular base-mediated elimination (mechanism A) or a concerted syn-elimination (mechanism B), expelling a sulfate anion and forging the highly stable C N triple bond. This work not only provides a highly sustainable platform for synthesizing high-value nitriles but also elucidates HOSA's fundamental potential for “one-shot dehydrative cyanation.” This robust in situ nitrile-forming capability laid the crucial mechanistic groundwork for subsequent cascade transformations—such as the divergent esterification developed by Jat in 2025 (discussed in Section 2.4)—which elegantly utilizes these transient nitriles to intercept alcoholic nucleophiles.

Scheme 23. Possible elimination mechanism of HOSA-driven formation of nitrile compounds.

2.3. Lossen rearrangement-driven cascade cyclization

In 2018, building upon their profound expertise in microwave-assisted organic synthesis, the Tranmer group reported an exceptionally elegant metal-free, one-pot strategy that successfully harnessed HOSA to completely subvert this highly perilous synthetic paradigm. Utilizing inexpensive and readily available benzoyl chloride derivatives as starting materials, the protocol efficiently translates them into diverse N,N′-disubstituted phenylureas and N-aryl carbamates under precise microwave heating (Scheme 24).²³ This reaction not only entirely obviates the reliance on highly toxic reagents but also exhibits outstanding functional group compatibility. Whether deploying various primary or secondary amines to construct symmetrical or unsymmetrical urea scaffolds, or introducing alcoholic solvents to lock in the carbamate architectures, the system consistently delivers the target products in high yields within remarkably brief reaction times.

Scheme 24. Broad substrate scope.

Concealed beneath this highly efficient transformation lies an exquisite cascade mechanism and formidable physical organic driving force (Scheme 25). In the initial phase of the reaction sequence, benzoyl chloride reacts rapidly with HOSA, acting as a nucleophile, to in situ generate the critical O-sulfonylhydroxamate intermediate. This intermediate serves as the “energetic core” of the entire system: the intrinsic sulfate group of HOSA metamorphoses into an outstanding leaving group. Catalyzed by a weak base and the thermal effects of microwave irradiation, this intermediate undergoes deprotonation. Subsequently, the aryl group executes a decisive 1,2-migration synchronous with the extrusion of the sulfate anion, instantaneously completing a classical Lossen rearrangement. This rearrangement process safely and in situ liberates the highly reactive transient isocyanate species within the reaction vessel.

Scheme 25. Proposed mechanism via Lossen rearrangement.

Ultimately, amine or alcohol nucleophiles rapidly intercept this high-energy transient species, cleanly executing an addition reaction to irreversibly lock the final urea or carbamate framework. This investigation holds far-reaching strategic significance in synthetic methodology. It efficiently demonstrates that the ubiquitous sulfate group of HOSA can be deployed not only to drive simple electrophilic aminations but also as a formidable “thermodynamic engine” to forcefully drive complex skeletal rearrangements. Through an astute “generate-and-trap” strategy, HOSA confines the formation of highly hazardous chemical intermediates to the microscopic reaction cycle, thereby furnishing a versatile and green synthetic technology with immense potential for industrial-scale pharmaceutical implementation.

2.4. Beckmann rearrangement and heterocycle remodeling

In 2026, the research group of Jyoti Kaushik disclosed a highly eco-friendly, one-pot synthetic route in the Journal of Molecular Structure. Operating within a pristine aqueous medium, this protocol utilizes HOSA and a mild Zn(ii) Lewis acid catalyst to cleanly translate relatively simple triketone precursors into complex pyrrolo-annulated azepinone scaffolds—architectures endowed with potent monoamine oxidase-A (MAO-A) inhibitory activity and profound antidepressant potential. The most significant facet of this synthetic trajectory is its ability to telescope multiple bond-cleavage, ring-expansion, and annulation events into a singular operational sequence, entirely avoiding the isolation of any transient intermediates (Scheme 26).²⁴

Scheme 26. Beckmann rearrangement of pyrrolo annulated analogues of dimedone.

Delving deeply into the mechanistic rationale and molecular evolution of this exquisite synthetic route, the entire transformation operates as a thermodynamically and kinetically synchronized “domino effect.” The sequence initiates with the selective condensation of HOSA with the least sterically encumbered and most reactive carbonyl of the triketone precursor, in situ generating a high-energy O-sulfonyloxime intermediate. At this juncture, the Zn(ii) Lewis acid plays a pivotal dual role: it not only activates the substrate carbonyls but coordinates with the oxime, significantly attenuating the activation energy barrier for the ensuing migration. Subsequently, the critical skeletal remodeling occurs: driven by the forceful extrusion of the intrinsic sulfate moiety of HOSA—an excellent leaving group—the substrate undergoes a stereospecific Beckmann rearrangement. The carbon–carbon bond positioned anti-periplanar to the cleaving N–O bond migrates seamlessly onto the electron-deficient nitrogen atom, instantaneously expanding the original ring into a highly coveted seven-membered azepinone core. However, this cascade route does not stop there. Within this newly expanded intermediate, the nascent nitrogen atom and the residual dicarbonyl units are spatially preorganized in close spatial proximity for annulation. Propelled by the continuous thermodynamic driving force of the system, the molecule immediately undergoes a spontaneous intramolecular dehydrative cyclization (analogous to a Paal–Knorr synthesis). This irreversibly “zips up” the molecular framework, efficiently forming the fused five-membered pyrrole ring. This efficient synthetic route elevates HOSA from a mere aminating reagent to an immensely powerful “molecular sculptor,” vividly demonstrating its pinnacle mastery in driving tandem ring-expansion and annulation cascades.

2.5. HOSA as a zwitterionic green organocatalyst

In the aforementioned metal-free networks, the synthetic utility of HOSA is fundamentally tethered to the irreversible cleavage of its highly polarized N–O bond—functioning effectively as a stoichiometric, consumable reagent. However, a comprehensive portrait of HOSA would be glaringly incomplete without acknowledging its latent capacity to act as an intact, non-consumable organocatalyst.

In 2016, the Zolfigol team unveiled another highly potent, concealed identity of HOSA—serving as a highly efficient, green, and task-specific pure acidic catalyst. In a hallmark study, HOSA entirely shed its conventional “aminating reagent” guise. Operating under efficiently environmentally benign solvent-free conditions, it successfully drove the three-component condensation between aromatic aldehydes and two equivalents of dimedone, culminating in the high-yield synthesis of biologically privileged 1,8-dioxo-octahydroxanthene derivatives (Scheme 27). This protocol exhibited outstanding universality across a diverse array of substituted aromatic aldehydes, featuring remarkably straightforward operational procedures devoid of cumbersome downstream purification. Consequently, it seamlessly amalgamated the inherently high atom economy of multicomponent reactions with the green catalytic attributes of HOSA.

Scheme 27. Synthetic route for xanthenes.

In probing the fundamental mechanism underpinning this highly efficient operation, the authors directed their focus toward the exceptionally unique molecular architecture of HOSA (Scheme 28).²⁵ In the solid state or under solvent-free molten conditions, HOSA predominantly exists in a highly polarized zwitterionic form. This distinctive structural feature endows HOSA with dual acidic catalytic sites. In the initial phase of the catalytic cycle, the acidic protons (or Lewis acidic sites) of HOSA precisely activate the carbonyl oxygen of the aromatic aldehyde, profoundly augmenting its electrophilicity. Subsequently, the first molecule of dimedone, residing in its enol tautomeric form, executes nucleophilic attack on the activated carbonyl. Following dehydration, this yields the critical Knoevenagel condensation intermediate. Subsequently, HOSA continues to exert its formidable acidic catalytic efficacy by activating the olefinic double bond of this intermediate, thereby guiding the second molecule of dimedone to undergo a classical Michael addition. Ultimately, driven by continuous proton transfer facilitated by HOSA, the addition adduct undergoes a seamlessly smooth intramolecular cyclization and dehydration sequence, irrevocably locking the core xanthene framework and liberating HOSA to initiate the subsequent catalytic turnover.

Scheme 28. Plausible catalytic mechanism for xanthenes.

This investigation has profound methodological implications. It unequivocally demonstrates that the synthetic value of HOSA is not strictly confined to its role as a specialized electrophilic nitrogen donor. Leveraging its non-toxic, inexpensive, and highly water-soluble nature, alongside its intrinsic, highly polar zwitterionic network, HOSA possesses the undeniable capability—within the broader context of green chemistry—to function as a highly industrially viable, recoverable small organic molecule catalyst, adept at orchestrating complex multicomponent scaffold assemblies that heavily rely on synergistic acid/base catalysis.

Despite the synthesis of diverse structures via metal-free pathways, these transformations frequently require elevated temperatures or generate stoichiometric inorganic by-products—challenges that warrant the critical evaluation presented in the final section of this review.

3. Transition-metal catalysis: synergistic N–O bond activation and transient directing architectures

The integration of transition-metal catalysis has fundamentally redefined the synthetic capabilities of HOSA. By synergistically merging the intrinsic polar reactivity of the N–O bond with the precise coordinative demands of high-valent metals, HOSA transcends its traditional role as a simple aminating reagent. Within these catalytic regimes, it effectively functions both as an internal redox agent via rapid sulfate extrusion and as an in situ molecular anchor. To systematically navigate this paradigm, this section outlines the methodologies based on the evolving functional role of HOSA and the structural complexity of the resulting assemblies. The discussion begins with reactions centered on direct synergistic N–O bond activation for targeted C–N bond formation. It then delves into the strategic implementation of HOSA as a transient directing group (TDG) to orchestrate site-selective ortho-C–H functionalizations and heterocycle annulations, before concluding with advanced programmable catalytic networks that leverage HOSA for condition-driven divergent synthesis.

3.1. Direct functionalization via metal-mediated N–O bond cleavage

In 2017, the group of László Kürti reported a formidable breakthrough in the Rh-catalyzed aziridination of unactivated olefins, marking a transformative shift in the utilization of HOSA. Prior to this work, the community relied heavily on reagents such as O-(2,4-dinitrophenyl)hydroxylamine (DPH). However, the inherent drawbacks of DPH—including its explosive nitro-organic nature and the generation of toxic, difficult-to-remove 2,4-dinitrophenol by-products—severely hampered its adoption in large-scale industrial applications. To address these critical shortcomings, Kürti and co-workers strategically introduced HOSA as an inexpensive, non-explosive, and highly water-soluble electrophilic nitrogen precursor. Employing a remarkably low catalyst loading (1–2 mol%) of Rh₂(esp)₂ or Rh₂(OAc)₄, the protocol facilitates efficient aziridination at ambient temperature in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) with pyridine as the optimal base. The methodology demonstrates broad substrate scope and excellent stereospecificity. A diverse range of olefins—including mono-, 1,1-di-, 1,2-di-, and even sterically demanding tri-substituted unactivated alkenes—are smoothly converted into their corresponding N–H or N-alkyl aziridines in excellent yields (Scheme 29).²⁶ Furthermore, the system exhibits extraordinary chemoselective precision in the context of late-stage functionalization. When applied to substrates containing both electron-rich aryl rings and unactivated double bonds, the highly reactive Rh-nitrenoid intermediate selectively undergoes alkene amination, completely bypassing the competing aryl C–H amination pathways. This robustness was further validated by the high diastereoselective transformation of complex steroidal scaffolds, such as cholesterol derivatives, within a mere 2.5 h reaction window. This seminal contribution establishes a green, safe, and atom-economical paradigm for aziridine synthesis. By utilizing HOSA, the protocol generates benign, water-soluble inorganic sulfates as the sole by-product, thereby simplifying purification and aligning with the principles of green chemistry. Mechanistically, this work solidifies the role of HOSA as an ideal precursor for metallanitrenoid species, representing the zenith of its utility as a standalone amination reagent in transition-metal-catalyzed transformations.

Scheme 29. Rh-catalyzed stereospecific N–H and N-alkyl aziridination of unactivated olefins using HOSA.

In 2019, Shu-Li You and co-workers reported a milestone Rh-catalyzed polar amination strategy, utilizing HOSA as an inexpensive and safe electrophilic nitrogen source to achieve the direct aminative dearomatization of naphthols. Catalyzed by a low loading of Rh₂(esp)₂ in a mild trifluoroethanol/water co-solvent system, the protocol efficiently disrupts the aromaticity of naphthols to deliver a series of high-value, unprotected α-amino-β-naphthalenone derivatives (Scheme 30).²⁷ The system exhibits excellent functional group tolerance, enabling the translation of flat, two-dimensional aromatic precursors into three-dimensional (3D) complex architectures in moderate to good yields. To further underscore the synthetic practicality and industrial viability of this dearomatization paradigm, the authors executed gram scale scale-up operation (Scheme 31). Remarkably, HOSA retained strong aminating reactivity even at a 6.5 mmol scale, furnishing the target dearomatized product in 68% isolated yield (0.76 g) with no discernible drop in catalytic performance. The resulting α-amino-β-naphthalenone scaffolds act as versatile 3D building blocks for constructing complex pharmaceutical frameworks, and the dearomatized product can be easily reduced to the corresponding cis-amino alcohol in 91% yield with excellent diastereoselectivity (dr > 20 : 1). The primary amine could also be smoothly protected to yield the corresponding Boc-protected derivative, effectively priming the scaffold for subsequent peptide coupling. This seminal work elevates the operational ceiling of HOSA within transition-metal networks. By synergizing with a rhodium catalyst, HOSA completely circumvents the traditional reliance on highly toxic and explosive azide reagents for dearomatization. The liberated high-energy metallanitrenoid possesses the strong driving force necessary to overcome aromatic stabilization energy, establishing a highly atom-economical and pragmatic platform for the rapid construction of complex 3D pharmacophores in modern drug discovery.

Scheme 30. HOSA-mediated 2-naphthylamine-amination dearomatization substrate scope.

Scheme 31. HOSA-mediated dearomatization scale-up reaction.

In 2019, Sailu Munnuri, John R. Falck, Jawahar L. Jat, and co-workers disclosed an exceptionally efficient Cu(OTf)₂-catalyzed protocol that uses HOSA to facilitate the mild Beckmann rearrangement of ketones into secondary amides, operating under remarkably benign conditions (ambient temperature to 70 °C) with CsOH H₂O as the base in a strategically selected fluorinated solvent system (TFE/DCM). This metallacatalytic system featured a broad substrate scope and excellent functional group tolerance, with a diverse range of substrates—including aryl alkyl ketones and sterically demanding cyclic aliphatic ketones such as cyclohexanone derivatives and fused polycyclic systems—undergoing smooth ring-expansion or linear rearrangement to afford the corresponding secondary amides or lactams in moderate to excellent yields (up to 91%) (Scheme 32).²⁸ Notably, the synthetic robustness of this strategy was demonstrated by the late-stage derivatization of architecturally complex natural products and steroidal scaffolds, including (+)-nootkatone and estrone, confirming its significant utility in complex molecule functionalization.

Scheme 32. Substrate scope and application of complex molecules for HOSA-mediated Beckmann rearrangement catalyzed by Cu(OTf)₂.

From a mechanistic standpoint, the authors delineated the synergistic interaction between the transition metal center and HOSA (Scheme 33). The cascade initiates with the condensation of the ketone and HOSA to in situ generate a highly reactive O-sulfonyloxime intermediate. Subsequently, Cu(OTf)₂ intervenes as a potent Lewis acid, specifically coordinating to this intermediate. This strategic metallation profoundly attenuates the N–O bond dissociation energy, thereby precipitously lowering the activation barrier for the ensuing alkyl migration (the Beckmann rearrangement step). Concomitant with the expulsion of the sulfate leaving group, the nascent nitrilium ion intermediate undergoes rapid hydration—facilitated by adventitious moisture—and subsequent tautomerization to deliver the thermodynamically favored secondary amide. This pioneering work fundamentally transcended the strict historical constraints of the classical Beckmann rearrangement, which traditionally necessitated highly corrosive superacids or highly toxic promoters.

Scheme 33. Synergistic mechanism of copper-catalyzed HOSA-mediated Beckmann rearrangement.

Within this rationally designed catalytic system, HOSA efficiently manifests its dual competency as a “green” nitrogen precursor and a carrier of an excellent intrinsic leaving group. The strategic integration of a Lewis acidic metal center not only unleashes the latent reactivity of HOSA but also establishes a highly chemoselective and step-economical paradigm for amide synthesis. Crucially, this foundational study paved the way for the subsequent integration of HOSA into more sophisticated transition-metal architectures.

In 2024, Kai Cheng and co-workers disclosed a highly pragmatic palladium-catalyzed multicomponent cross-coupling strategy, successfully expanding the operational territory of HOSA into the efficient construction of sulfur–nitrogen (S–N) bonds. Avoiding hazardous gaseous precursors, this protocol ingeniously utilizes thiourea dioxide (TUD) as a benign, bench-stable solid substitute for sulfur dioxide. In synergy with HOSA serving as the ultimate solid electrophilic nitrogen source, this system orchestrates the direct, one-pot translation of aryl iodides into primary sulfonamides (Scheme 34).²⁹ In this meticulously designed catalytic system, the reaction exemplifies an elegant strategy of polarity matching and sequential transfer (Scheme 35). Initially, the Pd(0) catalyst undergoes classical oxidative addition to the aryl iodide. Subsequently, the in situ generated sulfur dioxide (released from TUD) rapidly inserts into the transient Pd–C bond, which, following reductive elimination, yields a critical aryl sulfinate intermediate. Endowed with pronounced nucleophilicity, this sulfinate species immediately engages in a polar interaction with the HOSA molecule. Capitalizing on its signature electrophilic aminating nature, HOSA readily undergoes nucleophilic attack by the sulfinate. Accompanied by the facile extrusion of the ubiquitous sulfate leaving group, the S–N linkage is irrevocably forged, liberating the terminal primary sulfonamide. This methodology not only boasts commendable substrate scope but has also been successfully implemented in the rapid late-stage functionalization and structural elaboration of blockbuster drug scaffolds, including derivatives of sulpiride, venetoclax, and furosemide. Such robust downstream utility provides compelling evidence for the immense potential of HOSA-mediated multicomponent reactions in industrial-scale pharmaceutical synthesis.

Scheme 34. Reaction scope of the amino-sulfonylation of aryl iodide derivatives.

Scheme 35. Proposed mechanism for the amino-sulfonylation of aryl iodide derivatives.

In 2024, the research group of Edgar Haak reported a synthetically valuable methodology that successfully combines ruthenium-catalyzed redox isomerization with the transformative properties of HOSA to convert propargyl alcohols directly into α,β-unsaturated nitriles (Scheme 36).³⁰ Under transition-metal catalysis, propargyl alcohols typically favor the classical Meyer–Schuster rearrangement or redox isomerization. The core of this reaction system lies in the introduction of a specific diaminocyclopentadienone ruthenium complex, which effectively controls the chemoselectivity of the system. With the participation of HOSA as both a nitrogen source and a dehydrating agent, the standard thermodynamic isomerization pathway is successfully redirected toward dehydrative cyanation. This protocol operates under relatively mild conditions and exhibits good functional group compatibility, delivering a variety of aryl- and alkyl-substituted target products in high yields. Furthermore, the reaction demonstrates excellent stereoselectivity, predominantly favoring the formation of the thermodynamically more stable (E)-olefin configuration. This study provides a highly atom-economical synthetic route for the highly efficient, one-pot construction of high-value nitrogenous triple-bonded scaffolds from simple alcohol starting materials.

Scheme 36. Formation of unsaturated nitriles from terminal propargyl alcohols.

3.2. Remote C–H functionalization and spatial topology control

In 2020, the research group of John R. Falck achieved a landmark breakthrough in this arena, ingeniously coupling inexpensive, earth-abundant iron(iii) chloride (FeCl₃) with HOSA within a hexafluoro-2-propanol (HFIP) microenvironment to execute the exquisitely regioselective meta-C–H amination of aryl picolinates. This paradigm not only completely eliminates the need for precious metals such as palladium or rhodium to achieve the transformation but also proceeds under remarkably mild conditions (0–40 °C). It seamlessly accommodates a vast array of highly functionalized, complex arene substrates and has been efficiently implemented in the late-stage site-selective modification of complex pharmaceutical architectures (Scheme 37).³¹

Scheme 37. Directed C–H meta-amination of picolinates.

In dissecting the fundamental physical organic mechanism underpinning this remarkable meta-selectivity, the authors unveiled a sophisticated outer-sphere delivery mechanism, profoundly distinct from traditional inner-sphere migratory insertions. Within this precise catalytic network, the picolinate moiety on the substrate initially acts as a robust bidentate ligand, firmly anchoring the high-spin iron catalytic center. Concurrently, HOSA is activated by the iron center, inducing severe polarization or homolytic cleavage of its fragile N–O bond to generate a highly electrophilic or radical-character nitrogen species. The true geometric marvel manifests at this exact juncture: dictated by the rigid complex architecture formed between the iron center and the picolinate ligand, the activated HOSA species is topologically suspended directly above the meta position of the aromatic ring. This macroscopic conformational control, functioning as a “molecular crane,” forcefully reaches over the proximal ortho space, guiding the highly reactive amino species to execute electrophilic attack or radical abstraction-recombination exactly at the meta C–H bond. The HFIP solvent further stabilizes this highly structured transition state through its extensive hydrogen-bonding network, facilitating the extrusion of the sulfate leaving group and ultimately installing a highly coveted primary amino group onto the complex arene with high selectivity.

This investigation propels the operational dimensionality of HOSA into unprecedented realms of spatial and stereogeometric control. It decisively demonstrates to the synthetic community that by rationally engineering the spatial topology of directing groups in tandem with the unique coordination geometries of earth-abundant metals, HOSA possesses a profound capacity to overcome the traditional ortho-centric limitations of organometallic chemistry, emerging as the ultimate solution for solving the long-standing synthetic challenge of precise remote C–H functionalization.

3.3. HOSA as a transient directing group (TDG) for ortho-C–H activation

While HOSA has been historically established as a highly efficient bonding reagent in classical polar transformations, its synthetic utility has experienced a profound conceptual leap within the realm of transition-metal-catalyzed C–H functionalization. In this domain, HOSA has emerged as an extraordinarily potent in situ transient directing group (TDG). This strategic evolution elegantly bypasses the synthetically taxing requirement for the pre-installation and subsequent removal of static directing groups, seamlessly fusing the intrinsic electrophilicity of HOSA with the rigorous coordinative demands of high-valent transition metals. To systematically illustrate this paradigm shift, the following subsections will categorize these methodologies based on the nature of the coupling partners. We will first examine the cascade annulations driven by the classical insertion of 2-carbon synthons (such as alkynes and activated alkenes) for the assembly of diverse N-heterocycles. Subsequently, we will explore the recent structural leap involving the integration of 1-nitrogen synthons (dioxazolones) via distinct nitrenoid insertion pathways, showcasing the synergistic construction of complex quinazoline architectures.

3.3.1. Unified assembly via 2-carbon synthon insertion (alkynes and analogues)

In a series of foundational reports starting from 2020, the research groups of Ravikumar, Chen, Zeng, and co-workers systematically reconceptualized the operational dimensionality of HOSA within rhodium-catalyzed C–H functionalization paradigms (Scheme 38).^32–34,36 These protocols utilized HOSA to execute one-pot C–H/N–O cascade annulations between aryl ketones and alkynes (or activated analogues such as methyl propiolate), enabling the sustainable construction of pharmaceutically privileged isoquinoline, indole, and aza-polycyclic aromatic hydrocarbon (N-PAH) scaffolds.

Scheme 38. Unified synthesis of isoquinolines and N-PAHs via alkyne insertion and proposed reaction mechanism.

The mechanistic sophistication of these systems lies in HOSA's multifaceted structural properties and its ability to orchestrate an endogenous redox-neutral catalytic cycle. From a physical organic perspective, while stoichiometric transition-metal additives (e.g., AgOAc, Ag₂CO₃, and Cu(OAc)₂) are routinely employed in these protocols, their primary function is not to act as terminal oxidants for catalytic turnover. Rather, these silver or copper salts are crucial for the in situ activation of the precatalyst—typically executing halide abstraction from the dimeric [Cp*RhCl₂]₂ to generate the highly coordinatively unsaturated and electrophilic cationic Rh(iii) active species—or functioning as Lewis acidic promoters to facilitate substrate coordination.

However, the fundamental reoxidation of the metal center is exclusively driven by HOSA. The catalytic cascade initiates with the rapid, reversible dehydrative condensation of the aryl ketone with HOSA, generating a transient O-sulfonyloxime. This species acts as a precise molecular anchor. Its oxime nitrogen selectively coordinates to the cationic Rh(iii) center, forcibly directing the metal into spatial proximity with the ortho-C–H bond. Mechanistic depth is further revealed through kinetic isotope effect (KIE) studies across these methodologies; parallel or intermolecular competition experiments frequently yield significant k_H/k_D values (typically >2.0), corroborating that the irreversible ortho-C–H metalation to form the rigid five-membered rhodacycle is the turnover-limiting step (TLS).

Following metalation, the 2-carbon synthon (alkyne or propiolate) coordinates and undergoes a regioselective migratory insertion into the Rh–C bond. The terminal phase unveils the critical electronic role of HOSA during the C–N bond-forming reductive elimination, in which the highly polarized N–O bond of the HOSA framework cleaves synchronously, driven by the exceptional leaving ability of the sulfate moiety (SO₄²⁻). This spontaneous departure effectively acts as an endogenous electron transfer event, rapidly reoxidizing the low-valent Rh(i) back to its active Rh(iii) state. Standard control experiments utilizing radical scavengers (TEMPO or BHT) typically exhibit no reaction inhibition or radical trapping products, firmly ruling out single-electron transfer (SET) pathways and validating this concerted, two-electron organometallic cascade.

3.3.2. Synergistic dual-nitrogen integration via nitrenoid insertion

Advancing significantly beyond the classical insertion of 2-carbon synthons, the chemical space accessible via HOSA-TDG chemistry has been dramatically expanded by the strategic incorporation of 1-nitrogen synthons. In 2026, the collaborative teams of Zhang, Chen, and She disclosed a methodological breakthrough of profound atom economy by ingeniously amalgamating HOSA with dioxazolones under rhodium catalysis (Scheme 39).³⁵ This one-pot cascade efficiently orchestrates the precise, regioselective assembly of quinazoline architectures—core pharmacophores found in blockbuster anticancer drugs such as gefitinib and lapatinib.

Scheme 39. Synergistic dual-nitrogen integration via dioxazolones and proposed reaction mechanism.

Delving into the microscopic reaction pathway, this transformation diverges fundamentally from the aforementioned alkyne insertions. Following the initial condensation and the formation of the directing five-membered rhodacycle derived from the HOSA-O-sulfonyloxime, the secondary coupling partner—dioxazolone—enters the coordination sphere. Rather than undergoing a simple migratory insertion, the dioxazolone is activated by the Rh(iii) center to undergo rapid decarboxylation (extruding CO₂). This generates a highly reactive, electrophilic rhodium–nitrenoid (Rh N) intermediate.

This transient nitrenoid species subsequently inserts into the adjacent Rh–C bond. Concomitant with the final intramolecular C–N bond formation, the fragile N–O bond of the HOSA framework is forced to cleave. This “targeted dual-nitrogen detonation” mechanism permanently and simultaneously integrates two independently sourced nitrogen atoms—one originating from HOSA and the other from the dioxazolone—into the nascent six-membered heteroaromatic ring. By leveraging HOSA as both a directing navigator and an internal electron acceptor, this methodology efficiently liberates the complex quinazoline product without relying on harsh terminal oxidants.

3.4. Diverse TDG behavior of HOSA and switchable divergent synthesis

Within the chemical space of transient directing groups (TDGs), expanding the structural diversity of accessible scaffolds from simple precursors remains a primary objective. While the preceding sections detailed targeted assemblies via alkyne and nitrenoid insertions, this section explores catalytic networks utilizing alkenes, such as allylic alcohols and α,β-unsaturated ketones. In these systems, the reactivity of HOSA can be modulated by the specific metal catalyst and solvent microenvironment, allowing it to function either as a classical transient directing group or as a reagent that induces in situ skeletal rearrangement.

In 2026, the research group of Zeng reported an efficient one-pot synthetic route to quinoline derivatives starting from acetophenones and allylic alcohols (Scheme 40).³⁷ In this transformation, the allylic alcohol serves as a two-carbon synthon. The reaction proceeds through the rapid condensation of acetophenone with HOSA to form an O-sulfonyloxime, which directs the subsequent Ru-catalyzed ortho-C–H metalation. Following olefin coordination and migratory insertion, the intermediate undergoes β-hydride elimination and reductive elimination, ultimately affording the quinoline core in moderate to good yields across a variety of substituted substrates.

Scheme 40. Condition-controlled divergent synthesis of quinolines and isoquinolines.

Expanding on the application of alkene coupling partners, Zeng, Yang, and co-workers independently disclosed a divergent catalytic network utilizing α,β-unsaturated ketones (Scheme 40).³⁸ By fine-tuning the transition-metal catalyst, solvent, and temperature, this system enables the condition-dependent synthesis of either isoquinoline or quinoline derivatives from the same class of starting materials. The divergence originates from the distinct mechanistic pathways dictated by the catalytic microenvironment:

Trajectory (A): The Rh-Catalyzed TDG pathway (Isoquinolines). When the system employs the rhodium precatalyst [Cp*RhCl₂]₂ with Ag₂CO₃ and AcOH in a mixed solvent (MeOH/MeCN/DCE) at 80 °C, HOSA functions strictly as a TDG. The in situ-generated O-sulfonyloxime directs exclusive ortho-C–H activation. Following the migratory insertion of the enone and subsequent β-hydride elimination, the sulfate moiety departs, triggering N–O bond cleavage and concurrent cyclization to yield the isoquinoline scaffold (Scheme 41).

Scheme 41. Plausible mechanism for the programmable bidirectional catalytic network.

Trajectory (B): The Ru-Catalyzed Beckmann Pathway (Quinolines). Conversely, shifting to a ruthenium catalyst ([RuCl₂(p-cym)]₂) with AgSbF₆ and Cu(OAc)₂ at 120 °C induces a fundamental switch in HOSA's reactivity. Under these thermodynamic conditions, the O-sulfonyloxime undergoes an acid-promoted Beckmann rearrangement, converting the acetophenone into an N-phenylacetamide intermediate. This newly formed amide serves as a robust static directing group for Ru-catalyzed ortho-C–H metalation. Subsequent enone insertion, isomerization, and deacetylation furnish the quinoline product.

In summary, these studies demonstrate that a TDG can function beyond a temporary coordinating anchor, serving as a condition-dependent divergent point. By selectively accessing HOSA's dual reactivity—directing group coordination versus skeletal rearrangement—this strategy provides a practical approach for divergent organic synthesis. It effectively improves the step economy and structural diversity in the late-stage functionalization of complex molecules.

While these transition-metal-catalyzed methods demonstrate high efficiency, they exhibit a pronounced mechanistic reliance on specific coordination sites. Furthermore, the development of generalized enantioselective protocols for these transient networks remains a formidable frontier, which is systematically analyzed in the concluding section.

4. HOSA drives iterative advancements in green pharmaceutical manufacturing processes

In the grand narrative of modern pharmaceutical manufacturing, beyond the relentless pursuit of ultimate step economy, process safety and green chemistry metrics serve as life-or-death red lines determining whether a synthetic route can genuinely scale to tonnage production. Constructing high-value pharmacophores via traditional cyanation invariably necessitates reliance on highly toxic cyanide salts, such as sodium cyanide or copper(i) cyanide, and undesirable dipolar aprotic solvents. In plant-scale operations, this undeniably represents a perilous “severe safety hazard.” In 2023, Gabriel Schäfer and Tony Fleischer from Idorsia Pharmaceuticals (Switzerland) disclosed a process-remodeling endeavor of profound industrial revolutionary significance: they successfully deployed HOSA to pioneer a second-generation green manufacturing process for 3-ethyl-4-hydroxy-5-methylbenzonitrile, the pivotal building block of the S1P receptor modulator cenerimod. Dissecting the first-generation commercial route for this drug, the authors noted it was plagued by a classical sequence of Sandmeyer hydroxylation and highly hazardous cyanation steps. The operations were laboriously complex, yielding a dismal overall efficiency hovering between 40 and 45%. More critically, its process mass intensity (PMI) was alarmingly high at 210, branding it a quintessential “high-pollution, low-efficiency” archaic process. To completely shatter these technical shackles, the R&D team executed an audacious foundational route reconstruction: they totally abandoned all highly toxic cyanide sources. Instead, they opted for a para-selective formylation strategy to pre-install a single-carbon unit, subsequently deploying HOSA to orchestrate a highly efficient non-classical nitrile formation (Scheme 42).³⁹

Scheme 42. Safe conversion of aldehydes to nitriles.

In this radically streamlined core transformation, the aldehyde intermediate undergoes condensation and dehydration driven by HOSA, being efficiently and safely converted in situ into the target nitrile. This HOSA-centric “aldehyde-to-nitrile” non-toxic conversion strategy not only achieves a qualitative leap in process safety but, leveraging its exceptionally mild reaction conditions and straightforward workup, drastically elevates the overall yield while precipitously slashing the PMI pollution index. This authentic, multi-kilogram battle-tested case from the frontlines of the pharmaceutical industry forcefully declares to both the academic and industrial communities that the application boundary of HOSA has long transcended mere methodological curiosities in the laboratory. As an exceptionally inexpensive, secure, and potent substitute for toxic cyanide/nitrogen sources, it is aggressively redefining the green manufacturing benchmarks for blockbuster, high-value pharmacophores worldwide.

Within the highly regulated landscape of modern active pharmaceutical ingredient (API) manufacturing, the absolute eradication of potential genotoxic impurities (GTIs) constitutes an insurmountable regulatory red line. When constructing the ubiquitous sulfonamide pharmacophore, the textbook paradigm invariably dictates the oxidation of a thiol to a sulfonyl chloride, followed by an aqueous ammonia quench. However, this highly reactive and electrophilic chlorinated intermediate is notoriously prone to deleterious side reactions, frequently spawning carcinogenic impurities that terrify the pharmaceutical industry. In 2023, the Gabriel Schäfer team once again demonstrated profound industrial acumen, reporting a conceptually novel process engineered to resolve the multi-kilogram production bottleneck of 5-methyl-2-pyridinesulfonamide, the critical regulatory starting material for the endothelin receptor antagonist clazosentan. In meticulously dissecting the original commercial route of this pivotal building block, the authors astutely pinpointed its fatal flaws: the traditional sulfonyl chloride trajectory not only necessitated excruciatingly difficult aqueous workups—culminating in a dismal overall yield of merely 29%—but, perilously, led to the formation of a highly genotoxic benzyl chloride impurity. To completely eliminate this compliance issue, the R&D team discarded the entrenched “chlorination followed by nucleophilic substitution” dogma. Instead, they innovatively deployed an “electrophilic amination” strategy centered precisely around HOSA. The thiophenol substrate was initially and selectively oxidized under mild conditions to a sulfinate salt intermediate. Subsequently, without the need for isolation, HOSA was precisely introduced into the cascade system (Scheme 43).⁴⁰

Scheme 43. Novel electrophilic amination for the synthesis of clazosentan building block (kilogram-scale production route).

Within this transformation of profound physical organic elegance, the sulfinate salt acts as a robust nucleophile, launching an aggressive attack on the exceptionally electron-deficient nitrogen center of HOSA. Driven by the irreversible extrusion of the superlative sulfate leaving group, the highly coveted amino moiety (–NH₂) is cleanly and efficiently “grafted” onto the sulfur atom, generating the target sulfonamide in a single, remarkably safe step. This radically remodeled synthetic network not only fundamentally precludes the intervention of any chlorinating agents—thereby entirely obliterating the chemical space for genotoxic impurity formation—but also spectacularly catapults the overall yield of this regulatory starting material to 69%. This protocol has been successfully scaled up to multi-kilogram quantities under the most rigorous industrial standards, exhibiting impeccable thermodynamic stability while completely circumventing the need for cumbersome chromatographic purification. This significant mass-production benchmark unequivocally proves to the entire pharmaceutical enterprise that HOSA is not merely a tool in academia for forging novel chemical bonds; it is the ultimate barrier-breaker for reconstructing green, compliant manufacturing processes and overcoming the barriers of traditional toxic and carcinogenic routes in modern pharmaceutical production.

In 2026, the Xianwen Zeng team propelled the HOSA-mediated transient directing strategy to the zenith of modern pharmaceutical application by achieving the radically streamlined total synthesis of the blockbuster antianemic drug roxadustat. As the world's first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), roxadustat features a core isoquinoline pharmacophore that traditionally imposes a formidable synthetic barrier in commercial manufacturing. The conventional cross-coupling and annulation trajectory dictates an agonizingly protracted 9-step linear sequence. This not only consumes exorbitant temporal, solvent, and purification costs but also severely dilutes the overall yield to a mere 26.2%. This quintessential low-efficiency paradigm constitutes a critical bottleneck restricting the production capacity of high-value pharmaceuticals. Given that the microscopic mechanistic intricacies of HOSA-directed precise isoquinoline assembly under rhodium catalysis have been delineated previously, the Zeng team audaciously transposed this “direct annulation” foundational approach onto the skeletal disconnection of this complex pharmaceutical molecule. Abandoning the convoluted precursor pre-assembly endemic to traditional routes, they initiated the sequence directly from inexpensive commodity chemicals. Leveraging HOSA's intelligent directing and intrinsic nitrogen-donating capabilities, the system operates with surgical precision to lock in the core scaffold of roxadustat in a single step within one reaction vessel (Scheme 44).

Scheme 44. Comparison of the commercial (a) and HOSA-enabled (b) synthetic routes for roxadustat.

This direct skeletal disconnection strategy comprehensively eliminates the previously protracted intermediate isolation and protecting-group manipulations. Significantly, it compresses the agonizing 9-step commercial route down to a truly concise 3 steps to deliver the final drug. Even more remarkably, while reducing the number of operational steps by two-thirds, the overall yield of this total synthetic route was significantly improved to 60.9%. This landmark investigation irrefutably proves to the global community that HOSA is by no means a mere “reagent toy” confined to academia for proof-of-concept studies. It has demonstrably acquired the significant practical dominance to subvert traditional synthetic paradigms, substantially reduce the manufacturing costs of high-value pharmaceuticals, and forcefully reshape the modern global pharmaceutical supply chain.

5. Limitations, challenges, and future perspectives

While hydroxylamine-O-sulfonic acid (HOSA) has driven significant advances from classical aminating protocols to sophisticated transient directing group (TDG) networks, its broader translational impact in complex molecule synthesis remains hindered by several fundamental chemical and operational barriers.

A primary limitation lies in the harsh reaction conditions frequently required for classical HOSA-mediated transformations, which severely compromise functional group compatibility. A concrete example is the classical Friedel–Crafts aromatic C–H amination, which necessitates stoichiometric quantities of strong Lewis acids such as aluminum trichloride and elevated temperatures ranging from 95 °C to 105 °C. Such aggressive conditions preclude the presence of sensitive structural motifs, including acetals and esters. Furthermore, these homogeneous reactions predominantly generate stoichiometric sulfate waste and rely heavily on toxic polar aprotic solvents, thereby diminishing the overall atom economy and environmental sustainability of the process.

Although transition-metal-catalyzed TDG strategies represent a major methodological advancement, the substrate scope of HOSA remains narrowly restricted. Currently, HOSA-TDG chemistry is exclusively tethered to carbonyl compounds, specifically aldehydes and ketones. The methodology has not yet been successfully translated to other ubiquitous functional groups such as free amines, alcohols, or carboxylic acids. Additionally, HOSA-directed C–H activation is presently limited to proximal positions, leaving remote functionalization entirely unresolved. Another formidable challenge is the development of asymmetric cascades. Because HOSA is inherently achiral and its in situ-generated O-sulfonyloxime intermediates exhibit high conformational flexibility, rigorous stereocontrol is difficult to achieve. Consequently, highly enantioselective variants are scarce, which fundamentally limits the utility of HOSA in the late-stage functionalization of chiral pharmaceutical intermediates.

Addressing these fundamental bottlenecks requires transitioning from condition-heavy processes to sustainable and precisely controlled catalytic networks. Future methodologies must prioritize milder activation modes. Integrating HOSA chemistry with photoredox or electrochemical activation offers a pathway to generate active nitrogen-centered radicals under ambient conditions, thereby avoiding harsh exogenous oxidants and improving functional group tolerance. To overcome the stereocontrol barrier, the design of novel rigidifying chiral transition-metal ligands or dual organo-metal synergistic catalytic systems will be essential.

From an engineering and safety perspective, HOSA is highly hygroscopic and decomposes violently at temperatures exceeding 120 °C. Implementing continuous-flow technology for the in situ generation and immediate consumption of HOSA could mitigate these inherent handling hazards. Moreover, the development of solid-state supported variants, such as the recently synthesized rice husk ash-supported catalyst Si@OSA-Dir,⁴¹ provides a viable practical solution for catalyst recovery and stable industrial application.

Beyond organic methodology, the unique physicochemical profile of HOSA is driving innovations in materials science and environmental engineering. Recent investigations have successfully repurposed HOSA as a multifunctional defect-passivating additive in perovskite solar cells, which improved the power conversion efficiency by 15% and doubled operational stability.⁴² In the field of environmental remediation, HOSA has been utilized as a sulfonating agent to synthesize algal biosorbents, thereby increasing the adsorption capacity for strontium ions from seawater with exceptional selectivity.⁴³ These interdisciplinary applications underscore the broader technological potential of HOSA, provided that its fundamental chemical limitations in synthesis can be systematically resolved.

6. Conclusions

The developmental course of hydroxylamine-O-sulfonic acid (HOSA) mirrors the overall advancement of modern organic synthetic methods. Having evolved from a conventional electrophilic aminating reagent to a multifunctional platform for complex molecule assembly, HOSA has seen a substantial extension of its application scope. As outlined in this review, such progress stems from in-depth insights into its physical organic properties and the rational construction of catalytic systems.

Under metal-free conditions, HOSA displays distinct dual reactivity: its Umpolung nature and the thermodynamic driving force from N–O bond cleavage enable Lossen and Beckmann-type skeletal rearrangements, while its zwitterionic character allows it to serve as a recyclable organocatalyst for green heterocyclic synthesis. In transition-metal-catalyzed systems, HOSA features behavior-switchable dual roles: it can act as a transient directing group (TDG) to facilitate ortho-C–H activation, or induce skeletal rearrangement under controlled solvent and temperature conditions, providing a tunable strategy for the divergent construction of polysubstituted nitrogen-containing heterocycles.

Furthermore, HOSA has demonstrated prominent industrial translation potential in the late-stage functionalization and total synthesis of complex pharmaceutical molecules. Addressing the rigorous demands of the pharmaceutical industry for step economy, safety, and green chemistry, HOSA-based methodologies offer viable and pragmatic solutions. For instance, in the total synthesis of roxadustat, HOSA-mediated one-pot transformations substantially streamlined the previously cumbersome multi-step operations, significantly enhancing the overall yield. In the synthesis of the core building blocks for cenerimod and clazosentan, HOSA successfully replaced highly toxic cyanating agents and effectively avoided the generation of genotoxic impurities associated with traditional chlorination processes, enabling safe and efficient kilogram-scale scale-up.

In conclusion, through the precise modulation of reaction microenvironments and metal catalysts, this classical inorganic reagent has been revitalized in modern synthetic chemistry. From fundamental polar transformation mechanisms to industrial-scale pharmaceutical applications, HOSA provides organic chemists with a highly efficient and green synthetic tool. As its microscopic reaction mechanisms are further elucidated, HOSA is anticipated to play a crucial role in more challenging chemical transformations, continuing to enrich the toolbox of precision organic synthesis.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.