Time for a round-up of this week’s #Reactionoftheday. On offer this time we have an aryl borane catalyst for dehydrative amide synthesis, a carbonyl to sulfur swap by double C-C bond activation, a method for amination of boronic acids, a copper-catalysed amination of aryl halides with ammonia, and finally a transition-metal-free method for the insertion of alkynes into unfunctionalized amines.
Aryl borane as a catalyst for dehydrative amide synthesis
M. Sawant et al, J. Org. Chem. 2025, 90, 2271−2277
https://doi.org/10.1021/acs.joc.4c02652
While amide synthesis can be considered a well-established transformation, with a vast array of protocols available, many standard methods rely on stoichiometric coupling reagents. These reagents often generate large volumes of waste, are costly, and involve thermally unstable activated intermediates. Such drawbacks become especially significant when considering scale-up. Catalytic approaches offer a more sustainable alternative by reducing waste and improving atom economy.
Among these, Lewis-acidic boron derivatives-first introduced by Yamamoto and Ishihara in the 1990’s-have proven to be effective catalysts for amide bond formation. A notable advancement in this area was reported by Mane and Sawant, who described the use of tris(pentafluorophenyl)borane monohydrate, B(C₆F₅)₃·H₂O, a highly electrophilic and Lewis-acidic aryl borane, in catalytic dehydrative amidation reactions.
This catalyst is commercially available, which enhances its practical utility. In their method, equimolar amounts of carboxylic acid and amine substrates, along with 12.5 mol% of the borane catalyst, are azeotropically heated in toluene. A broad substrate scope is demonstrated-over 35 examples-including aliphatic, aromatic, and heterocyclic acids and amines. Notably, the method is effective even with challenging substrates such as benzoic acids and anilines, affording the corresponding amides in moderate to good yields.
Mechanistic insight was provided via 1919F NMR studies, which confirmed that the catalyst remains intact under the reaction conditions. This rules out its degradation to bis(pentafluorophenyl)borinic acid or pentafluorophenylboronic acid.
One limitation of the current protocol is that the catalyst is not recovered at the end of the reaction-an issue likely to be addressed in future refinements of the process.
- Large-scale amidations in process chemistry: practical considerations for reagent selection and reaction execution: J. Magano, Org. Process Res. Dev. 2022, 26, 1562–1689
- Tris(pentafluorophenyl)borane and beyond: modern advances in borylation chemistry: R. Melen et al, Inorg. Chem. 2017, 56, 8627–8643
- Boronic acid catalysis: D. Hall, Chem. Soc. Rev., 2019, 48, 3475-3496
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Carbonyl-to-sulfur swap enabled by sequential double carbon-carbon bond activation
G. Dong et al., Science 2025, 10.1126/science.adx2723
Sulfur, in various oxidation states, is a common heteroatom in pharmaceuticals and agrochemicals—second only to oxygen and nitrogen. Despite its prevalence, efficient methods for the direct replacement of carbon with sulfur remain limited. Existing strategies often suffer from low yields and rely on toxic reagents such as mercury.
A recent Science publication from the Dong group reports a novel and efficient two-step carbonyl-to-sulfur atom swap strategy. This approach employs a rationally designed N’-alkyl-hydrazomide (NAHA) to activate C–C bonds in alkyl ketones through the formation of a pre-aromatic intermediate. Sulfur is introduced via p-toluenesulfonyl disulfide (Ts–S–Ts), which mediates a radical cascade involving both intermolecular and intramolecular trapping of alkyl radicals by the central sulfur atom.
The hydrazomide activating reagent features an aryl halide moiety. In the second step, halogen abstraction is achieved using a silicon or tin-based radical species, followed by intramolecular triazole attack in a redox-neutral transformation.
The method demonstrates broad substrate compatibility, tolerating a range of functional groups including esters, alkynes, and amines. It has been successfully applied to the late-stage functionalization of complex bioactive molecules such as steroids and drugs, providing access to thioethers from both linear and cyclic scaffolds.
NAHA reagents offer a powerful platform for skeletal editing of sp³-rich molecules and present opportunities for the development of new sulfur analogs in medicinal and synthetic chemistry.
- Analysis of us FDA-approved drugs containing sulfur atoms: J. Njardarson et al, Top. Curr. Chem. 2018, 376, 5
- Olefination via Cu-mediated dehydroacylation of unstrained ketones: G. Dong et al, J. Am. Chem. Soc. 2021, 143, 20042–20048
- Single-atom logic for heterocycle editing: R. Sarpong et al, Nat. Synth. 2022, 1, 352–364
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Rapid and general amination of aryl boronic acids and esters using o‑(diphenylphosphinyl)hydroxylamine (DPPH)
R. Liu et al, Org. Lett. 2024, 26, 9847−9851
https://doi.org/10.1021/acs.orglett.4c03625
Efficient methods for preparing electron-deficient (hetero)aryl anilines are limited. This paper by the Liu group describes a operationally simple method for synthesizing primary anilines from (hetero)aryl boronic acids and esters using commercially available O-(diphenylphosphinyl)hydroxylamine (DPPH) under mild, metal-free conditions. The transformation occurs efficiently at room temperature (DPPH, KOH, CH3CN) with high functional group tolerance and is particularly effective for electron-deficient substrates—an area where existing methods often struggle. The reaction proceeds via a proposed mechanism involving a 1,2-aryl shift from boron to nitrogen, followed by hydrolysis. Experimental data, including a Hammett study, reveal that the reaction rate is largely insensitive to the electronic properties of the aryl group, distinguishing it from similar transformations. The DPPH reagent also works with boronic esters and heterocycles, including challenging nitrogen-containing compounds.
- Metal-free direct transformation of aryl boronic acid to primary amines: V. Verma et al, J. Org. Chem. 2022, 27, e202200508
- Reductive molybdenum-catalyzed direct amination of boronic acids with nitro compounds: S. Suarez-Pantiga et al, Angew. Chem. Int. Ed. 2019, 131, 2151-2155
- Aminative Suzuki–Miyaura coupling: R. Liu et al, Science 2024, 383, 1019-1024
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Cu-catalyzed coupling of aryl halides utilizing ammonia and hydroxypicolinamide ligands
I. Hotham et al, Org. Process Res. Dev. 2025, 29, 1554–1559
https://doi.org/10.1021/acs.oprd.5c00101
The standard go-too method for coupling ammonium salts and ammonia or ammonia surrogates with aryl halides is palladium catalysis. Copper catalysis has become much more competitive over the past few years, driven largely by the development of activating ligands. A recent paper by Hotham and a team at Pfizer describes a detailed investigation into the Cu-catalysed coupling of aryl halides with ammonia and primary amines using hydroxypicolinamide ligands, in particular the the dimethoxy picolinamide scaffold (DMPS). The ligand family was previously applied to Cu-mediated C–N and C–O bond formation; here, its utility is extended to amination using either aqueous or anhydrous ammonia. The DMPS ligand was identified using a comprehensive ligand screen focusing on optimal conversion and selectivity for C–N coupling over competing hydroxylation. Further optimisation yielded a high yielding reaction with low Cu loading (1-2 mol%). The protocol tolerates a wide range of (hetero)aryl bromides and iodides, including electron-rich, electron-deficient, and sterically hindered substrates, as well as various functional groups. Selective activation of aryl iodides over other halides was observed under mild conditions (25 °C). The system was shown to be applicable to other small primary amines and was demonstrated on multigram scale with minimal pressure build-up, The paper suggeststhat electronic and steric features of the DMPS ligand contribute to its efficacy, potentially through secondary coordination effects. This represents an operationally simple approach to aryl amines via Cu-catalysed C–N coupling.
- Cu-mediated Ullmann-type cross-coupling and industrial applications in route design, process development, and scale-up of pharmaceutical and agrochemical processes: D. Ma et al, Org. Process Res. Dev. 2022, 26, 1690–1750
- Palladium-catalyzed amination of aryl halides with aqueous ammonia and hydroxide base enabled by ligand development: J. Hartwig et al, J. Am. Chem. Soc. 2024, 146, 19414–19424
- Cu-catalyzed couplings of heteroaryl primary amines and (hetero)aryl bromides with 6-hydroxypicolinamide ligands: R. Singer et al, Org. Process Res. Dev. 2019, 23, 1538–1551
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Modular alkyl growth in amines via the selective insertion of alkynes into C–C bonds
C. Wang et al, Nat. Chem. 2025, 10.1038/s41557-025-01849-1
https://doi.org/10.1038/s41557-025-01849-1
Amines are one of the most ubiquitous functional groups in bioactive natural products, pharmaceuticals, agrochemicals and catalysts. However, synthesis of medium sized cyclic (8-11) and macrocyclic (>12) amines is difficult and compounded by low availability as off-the-shelf commercial materials.
A recent paper by Wang et al published in Nature Chemistry reports a borane-catalysed method for selective alkyne insertion into C(sp³)–C(sp³) bonds of amines, enabling ring expansion of cyclic amines and chain elongation of acyclic analogues. The method utilizes a catalytic combination of tris(pentafluorophenyl)borane and TMSOTf to generate reactive enamine intermediates from unfunctionalized amines. These intermediates undergo regioselective [2+2] cycloaddition with electrophilic alkynes, followed by strain-driven electrocyclic ring opening to yield expanded-ring or elongated-chain amines.
The transformation is compatible with an array of cyclic and acyclic tertiary amines and alkynes bearing electron-withdrawing groups, including esters, nitriles, and sulfonyl groups. It proceeds without the need for pre-activation or leaving groups and is tolerant of diverse functional groups, enabling late-stage functionalization of complex drug molecules. Mechanistic studies, including isotopic labelling and DFT calculations, suggest that hydrogen transfer and zwitterionic intermediates govern the stereochemical outcomes and thermodynamic product distribution.
The methodology grants access to both medium-sized and macrocyclic amines, directly addressing the synthetic challenges associated with these privileged motifs. The modular approach is amenable to iterative homologation, allowing controlled growth of C–C frameworks. This strategy constitutes a rare example of C–C bond functionalization via catalytic enamine intermediates, expanding the synthetic toolbox for amine diversification and expansion of chemical space.
- Ring-expansion reactions in the synthesis of macrocycles and medium-sized rings: W. Unsworth et al, Chem. Eur. J. 2017, 23, 8780-8799
- A happy medium: the synthesis of medicinally important medium-sized rings via ring expansion: W. Unsworth et al, Chem. Sci., 2020, 11, 2876-2881
- Skeletal editing through direct nitrogen deletion of secondary amines. M. Levin et al, Nature 2021, 593, 223–227
