N-Amino pyridinium salts in organic synthesis

Abstract

C–N bond forming reactions hold immense significance to synthetic organic chemistry. In pursuit of efficient methods for the introduction of nitrogen in organic small molecules, myriad synthetic methods have been developed, and methods based on both nucleophilic and electrophilic aminating reagents have received sustained research effort. In response to continued challenges – the need for substrate prefunctionalization, the requirement for vestigial N-activating groups, and the need to incorporate nitrogen in ever more complex molecular settings – the development of novel aminating reagents remains a central challenge in method development. N-Aminopyridinums and their derivatives have recently emerged as a class of bifunctional aminating reagents, which combine N-centered nucleophilicity with latent electrophilic or radical reactivity by virtue of the reducible N–N bond, with broad synthetic potential. Here, we summarize the synthesis and reactivity of N-aminopyridinium salts relevant to organic synthesis. The preparation and application of these reagents in photocatalyzed and metal-catalyzed transformations are discussed, showcasing the reactivity in the context of bifunctional platform and its potential for innovation in the field.

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1 Introduction

Amines and other nitrogen-containing functional groups are ubiquitous in biologically active natural products, synthetic intermediates, and fine chemicals, and thus are central to modern drug discovery programs.¹ As a result, the development of efficient, step- and atom-economical methods for the incorporation of nitrogen into organic small molecules has been the focus of sustained and ongoing research effort. The resulting suite of C–N bond-forming methods that has been developed can be categorized by the philicity of the nitrogen precursor: nucleophilic amine precursors (i.e., functionally N⁻ sources),^2–4 such as sulfonamides, carboxamides, aryl and alkylamines engage in amination chemistry with pre-oxidized, electrophilic compounds such as organohalides (Scheme 1a), and electrophilic amine precursors (i.e., functionally N⁺ sources),⁵ such as iminoiodinanes, azides, hydroxylamine derivatives, and nitro compounds, which engage in amination chemistry with nucleophilic substrates including C–H bonds and olefins (Scheme 1b). Nitrogen-centered radical intermediates are also an emerging class of reactive nitrogen species that are finding applications in organic synthesis.⁶

Scheme 1 Amination reactions can be categorized according to the philicity of the nitrogen precursors, either (a) nucleophilic or (b) electrophilic. (c) N-Aminopyridiniums are bifunctional amine precursors that combine N-centered nucleophilicity with electrophilic or radical chemistry accessible via N–N cleavage.

Application of nucleophilic amine precursors requires pre-functionalized coupling partners (Scheme 1a). For example, transition metal-catalyzed C–N cross-coupling methods involve reaction of aryl- or alkenyl (pseudo)halides with amines under optimal catalytic conditions.^2,7–10 Fine tuning of the steric and/or electronic properties of the ancillary ligands used in these reactions provides the opportunity to fine tune catalyst activity and thus the classes of substrates that will engage in coupling (e.g., to achieve cross-coupling of aryl chlorides).^8,11 In all cases, the requisite halide or pseudohalide functionality needs to be introduced prior to the transformation.

Electrophilic and radical nitrogen intermediates provide the opportunity to effect amination of nucleophilic substrates, including olefins, organometallic reagents, and C–H bonds (Scheme 1b).^12–14 An array of electrophilic reagents have been developed, with hydroxylamine derivatives, organoazides, and iminoiodinane reagents all featuring prominently in developed electrophilic amination methods. While each of these reagent classes has numerous attractive attributes, each face significant draw backs: as examples, access to hydroxylamine derivatives often requires pre-functionalized starting materials and multiple synthetic steps;^15,16 and, access to iminoiodinane typically requires N-sulfonyl derivatives,¹⁷ which can enable C–H amination, but require harsh deprotection conditions that can limit product diversification.^18,19

Bifunctional reagents are compounds that display two reactive sites (e.g., a reagent that displays both a site of nucleophilicity and a site of electrophilicity) or display one mode of reactivity and serve as a precursor to another (e.g., a reagent that simultaneously displays a site of nucleophilicity and a site of latent radical character).²⁰ Bifunctional reagents are attractive because access to orthogonal reactivity modes within the same reagent can enable rapid structural elaboration. N-Aminopyridiniums exemplify bifunctionality in that they can serve as synthetic lynchpins due to their inherent N-centered nucleophilicity and the presence of a reducible N–N bond that provides the opportunity for depyridylative N-centered radical generation or metal-catalyzed coupling (Scheme 1c). As such, the bifunctionality of N-aminopyridinium salts renders that diversifiable amine equivalents. Despite the potential opportunities, N-aminopyridinium derivatives have only recently begun to garner significant interest as bifunctional reagents in amination chemistry.

This review will discuss the emerging chemistry of N-aminopyridinium reagents in organic synthesis. Preparative methods will be presented and categorized based on the respective starting materials. We then discuss application of N-aminopyridinium reagents in synthesis and have organized the discussion to first describe photocatalyzed transformations before discussing recent progress in metal catalyzed transformations. Together, the discussion of synthesis and application of N-aminopyridinium intermediates in synthesis serves to highlight the reactivity of this bifunctional platform and to begin to illuminate future directions for innovation with these reagents.

2 Synthesis of N-aminopyridinium derivatives

N-Aminopyridinium reagents can be accessed by (1) N-amination of pyridine derivatives using electrophilic aminating reagents (i.e., formal sources of NH₂⁺ equivalents), (2) condensation of hydrazine (or hydrazide) with pyrylium salts, or (3) elaboration of the N-valences of simple N-aminopyridinium reagents (Scheme 2).

Scheme 2 General methods for synthesis of N-aminopyridinium salts: (a) electrophilic amination of pyridine derivatives with hydroxylamine reagents, (b) condensation of pyrylium salts and hydrazines, and (c) elaboration of N-valences of N-aminopyridinium reagents by substitution reactions. R¹ = acyl, sulfonyl, alkyl, aryl or allyl; X = H, Cl, Br, I or OCOOCH₃.

2.1 From electrophilic aminating reagents

N-Aminopyridinium iodide 1a, which can be synthesized from hydroxyl-O-sulfonic amine (HOSA) and pyridine, was the first N-aminopyridinium salt reported and is currently commercially available (Scheme 3).²¹ The counteranion of N-aminopyridinium salts can easily be exchanged by sequential deprotonation with K₂CO₃ to generate the pyridinium ylide followed by protonation with the appropriate acid source (i.e., HX). Various other pyridine derivatives also engage in N-amination chemistry with HOSA to afford the corresponding aminopyridinium salts, however in general, low yields of the corresponding N-aminopyridinium salts have been obtained.

Scheme 3 Synthesis of N-aminopyridinium salts by reaction of pyridine with HOSA.

N-Aminopyridinium salts derived from less reactive pyridine derivatives can be accessed using mesitylsulfonyl hydroxylamine (MSH) in place of HOSA (Scheme 4).^22–25 In addition to providing access to a broader scope of pyridine derivatives, additional N-heteroarenes, such as pyridazine and quinoline, also undergo efficient N-amination with MSH.

Scheme 4 Synthesis of N-aminopyridinium salts 2 by reaction of substituted pyridine derivatives with mesitylsulfonyl hydroxylamine (MSH).

Other electrophilic aminating reagents, such as H₂NOTs and O-(2,4-dinitrophenyl)hydroxylamine 4 (DPH), have also been used in the nitrogen transfer to pyridine.^26,27 In 2003, Charette reported the efficient synthesis of a family of N-aminopyridinium salts 5 featuring a variety of pyridine substitution patterns using DPH as the electrophilic aminating reagent (Scheme 5a). In 2021, Gao reported a postsynthetic N-amination of bipyridine linkers within a Zr(IV)-based MOF using H₂NOTs as the electrophilic aminating reagent to yield 6 (Scheme 5b).

Scheme 5 (a) N-Aminopyrdinium salts 5 were synthesized using DPH. (b) Postsynthetic modification of Zr(IV)-bpy UiO-67 type MOF with H₂NOTs results in amination of the bipyridyl spacer.

2.2 From hydrazines

Condensation of pyrylium salts with hydrazines (or hydrazides) can also provide access to N-aminopyridinium salts (Scheme 6). Substitution of the 2,4,6-positions of the pyrylium salts can be necessary to prevent unwanted nucleophilic addition of hydrazines at these positions: for example, aminopyridinium salt 8 was synthesized using 2,4,6-trimethyl pyrylium perchlorate 7 (Scheme 6a).²⁸ In contrast, treatment of triphenylpyrylium salt 9 under similar conditions is not efficient due to undesired formation of 7-membered ring 10 with an endocyclic N–N bond (Scheme 6b).²⁹ To overcome this challenge, a two-step protocol was employed based on initial reaction of pyrylium salt 9 with 2-aminopyridine to afford pyridinium salt 11 followed by subsequent hydrazinolysis to form the desired N-aminopyridinium salt 12 (Scheme 6c).³⁰ Condensation of unsubstituted pyrylium salts with simple hydrazine has not been reported to our knowledge, however, Studer et al. reported the reaction of unsubstituted pyrylium salt 13 with N-aminophthalimide 14 to afford N-aminopyridinium salt 15 (Scheme 6d).³¹

Scheme 6 (a) Synthesis of 8 by condensation of 2,4,6-trimethylpyrylium salt 7 and hydrazine. (b) Treating 2,4.6-triphenyl pyrylium salt 9 directly with hydrazine resulted in undesired product 10, but (c) the desired N-aminopyridinium salt 12 can still be accessed via hydrazinolysis of 11. (d) Preparation of N-aminophthalimide derived N-aminopyridinium salt.

Several N-alkyl or N-acyl aminopyridinium salts have been synthesized by condensation of pyrylium salts with mono- or di-substituted hydrazines. For example, Taylor et al. reported the synthesis of a series of N-carbamoyl pyridinium salts 18via hydrazine condensation chemistry (Scheme 7).^32–34 The resulting compounds displayed structure-dependent optical properties, which were leveraged for application in photolabeling of proteins.

Scheme 7 Hydrazine carboxylates 17 is converted to N-aminopyridinium salts 18via condensation with pyrylium salts 16 with varying para-substituents.

2.3 Via derivatization of N-aminopyridiniums

N-Amino pyridiniums engage in nucleophilic substitution reactions, such as N-sulfonylation, -acylation, or -alkylation in the presence of appropriate electrophiles to afford new N-functionalized N-aminopyridinium reagents (Scheme 8a).^35–39 Relatedly, Alvarez-Builla et al. demonstrated that pyridinium ylides, generated by deprotonation of N-aminopyridinium 1a, are sufficiently nucleophilic to engage in nucleophilic aromatic substitution (S_NAr) with heteroaryl halides (Scheme 8b).^40,41N-Arylation with substrates less prone to S_NAr chemistry has been demonstrated via Pd-catalyzed cross-coupling (Scheme 8c). In a related metal-catalyzed coupling reaction, Evans et al. demonstrated that the amine valence could be elaborated via Rh-catalyzed amination of allyl carbonates 22 to access pyridinium allylamines 23 (Scheme 8d).⁴²

Scheme 8 Elaboration of N-valence of N-aminopyridniums can be carried out by (a) nucleophilic substitution with acyl, sulfonyl and alkyl halides, (b) nucleophilic aromatic substitution with N-heterohaloarenes 20, (c) Pd-catalyzed cross-coupling, and (d) Rh-catalyzed reaction with allyl carbonates 22.

In 2022, Powers et al. reported N-substitution of N-aminopyridniums via metal-free amination of C–H bonds (Scheme 9).^39,43 Using DDQ or NIS as the oxidant, two reaction conditions were developed for the C–H amination, showing complementary substrate preferences. In general, the DDQ-promoted condition provided higher yields for the functionalization of electron-rich substrates while the NIS-promoted condition provided higher yields for functionalization of electron-deficient substrates. In addition to functionalization of benzylic C–H bonds, the developed methods also enabled functionalization of tertiary aliphatic C–H bonds, such as those of adamantane, to afford the corresponding pyridinium salts.

Scheme 9 Benzylic C–H amination of 24 with 1b formed N-benzyl substituted aminopyridinium salts 25 provides access to N-functionalized N-aminopyridinium salts from C–H bonds.

Powers et al. also reported nitrogen group transfer reactions between N-aminopyridinium salts and olefinic substrates to access N-pyridinium aziridines 27 (Scheme 10a).⁴⁴ In the presence of catalytic iodide, combination of styrenes, aminopyridinium 12, and iodosylbenzene resulted in pyridinium aziridines. This reaction provided access to N-pyridinium aziridines in modest to good yields for a range of aryl alkene derivatives but was less efficient for the aziridination of aliphatic olefins, such as cyclohexene or allylbenzene (Scheme 10b).

Scheme 10 N-Aminopyridinium salts 12 and 1b in the presence of iodosylbenzene reacted with (a) styrenes and (b) aliphatic alkenes to form pyridinium aziridines 27 and 28.

3 Application of N-aminopyridiniums in photochemical and photoredox chemistry

N-Aminopyridinium reagents have gained increasing prominence as precursors to N-centered radicals via photochemical and photoredox activation of the N–N bond.^6,45 Many of the photochemical reactions of N-aminopyridinum salts, including olefin and arene functionalizations, proceed via the general mechanistic scheme illustrated in Scheme 11.^31,43 Electron transfer from the excited state of an appropriate photocatalyst (PCⁿ) to the N-aminopyridinium reagents 29 results in N–N cleavage to yield an amidyl radical 30, pyridine, and an oxidized photocatalyst (PCⁿ⁺¹). Subsequent reaction of amidyl radical 30 with a suitable radical acceptor 31 results in the formation of a carbon-centered radical (32). Oxidation of radical 32 with PCⁿ⁺¹ generates cationic intermediate 33 and regenerates the photocatalyst (PCⁿ). Depending on the specific reaction conditions, nucleophilic additions to or elimination reactions from the incipient carbocation furnish the ultimate reaction products (34). The stability of the nitrogen-centered radicals that mediate these transformations is highly dependent on the N-substituent: electron-withdrawing substituents are typical and give rise to stable yet reactive radical species. Scheme 12 summarizes available electrochemical data for commonly encountered N-aminopyridinium salts. The electrochemistry of these compounds is typically characterized by one-electron reduction processes, which result in the formation of N-centered radicals. The substitution pattern of the pyridine ring exerts significant influence on the electrochemical properties, with electron-withdrawing substituents promoting easier reduction and electron-donating substituents making it more challenging (Scheme 12). The data rationalize the oft-encountered choice of either fac-[Ir(ppy)₃] (−1.88 V vs. SCE) and Ru(bpy)₃Cl₂ (−0.81 V vs. SCE) as photocatalysts for the activation of N-aminopyridinium salts.⁴⁶

Scheme 11 Generic catalytic cycle for photoredox activation of N-aminopyridinium salts proceeds through the generation and reaction chemistry of N-centered radicals.

Scheme 12 Comparison of reduction potentials of commonly used N-aminopyridnium salts (V vs. SCE), (a) ref. 51 (b) ref. 75.

3.1 Olefin functionalization

Olefins are readily available in bulk quantities from both renewable resources and petrochemical feedstocks and as such selective olefin functionalization reactions have immense value in fine chemical synthesis.^47–49 Given the proclivity of many olefinic substrates to serve as radical acceptors and the ease of N-centered radical generation by reductive cleavage of the N–N bonds of N-aminopyridinium reagents, many olefin difunctionalization reactions have been developed based on these starting materials. Regiospecific 1,2-aminofunctionalization of olefins via radical addition is a well-studied class of reactions with aminohydroxylation,^35,36 aminohalogenation,³⁷ aminothiocyanation³⁸ and aminoazidation⁵⁰ reactions all having been developed (Scheme 13). Akita et al. reported a regiospecific 1,2-aminohydroxylation of olefins using tosyl protected N-aminopyridinium derivative 35 and subsequently extended the method to include N-trifluoroacetyl protected ylides 38 (Scheme 13b). In these reactions, the addition of Sc(OTf)₃ decreases the potential needed to effect N–N cleavage to unveil N-centered radicals via [Ir] photoredox/Sc(OTf)₃ dual catalysis. The method can be utilized to a variety of activated olefins and as well as aliphatic olefins (e.g., 39c) in good yields. Xu et al. developed 1,2-aminofluoroination and aminochlorination of olefins using commercially available hydrogen fluoride-pyridine or hydrogen chloride-pyridine as the nucleophiles, respectively (Scheme 13a). Zhu et al. demonstrated 1,2-aminoisothiocyanation and 1,2-aminoazidation of 1,3-dienes under fac-[Ir(ppy)₃] photoredox catalysis utilizing N-aminopyridinium salts 35 as the amine precursor, TMSNCS and TMSN₃ as the respective nucleophiles. The thiocyanated and the azidated products (i.e., 37f and 37g) can be selectively converted to the free amine leaving the Boc or the tosyl group intact (Scheme 13a).

Scheme 13 (a) Regiospecific three-component difunctionalization of olefins under photoredox catalysis. (b) Aminohydroxylation of olefins with N-aminopyridinium ylides by dual [Ir]/Sc(OTf)₃ catalysis.

In 2019, Gryko et al. developed a visible-light induced amination reaction for silyl enol ethers 40 with tosyl, Boc or trifluoroacetyl protected N-aminopyridinium salts 35 leading to α-amino carbonyl compounds (Scheme 14).⁵¹ The reactivity of the N-centered radicals is very much dependent on the EWG: N-tosyl and N-Boc proved to be the best while N-Cbz protected salts were found to be less reactive.

Scheme 14 Ir catalyzed amination of π-nucleophiles with N-aminopyridinium salts.

In 2022, Xu et al. reported an organic photoredox catalyzed 1,2-aminoheteroarylation of unactivated alkenes 43via migratory radical rearrangement using Cz-NI as the photocatalyst (Scheme 15).⁵² This reaction provides efficient entry to a family of distal amino ketones under mild conditions. A variety of substrates, including aliphatic olefins, as well as a diverse set of migrating groups were tolerated. Mechanistic experiments suggest the transformation proceeds via sequential additional of an N-centered radical to the olefinic substrate followed by trapping by the migrating group.

Scheme 15 1,2-Aminoheteroarylation of unactivated olefins to access distal amino ketones via migratory radical rearrangement.

In 2017, Xu et al. developed an aza-pinacol rearrangement reaction that combines N-sulfonylated aminopyridinium salts 45 and cyclopropylidenes 46 under the action of Ir photocatalysis to access iminocyclobutanes 47 (Scheme 16).⁵³ The reaction was proposed to proceed through a nitrogen radical-initiated ring expansion mechanism and the transformation provides ready access to γ-butyrolactones with all-carbon quaternary centers.

Scheme 16 Synthesis of γ-butyrolactones via aza-pinacol rearrangement.

3.2 Synthesis of heterocycles from olefins

Access to N-heterocycles is a core challenge in synthetic chemistry due to the ubiquity of this motif in pharmaceutically relevant molecular scaffolds.^54,55 Different classes of nitrogen containing heterocycles can be synthesized utilizing N-centered radicals derived from N-aminopyridiniums. Most of these transformations are proposed to proceed via carbocation intermediates which engage in intramolecular trapping reactions to generate the desired ring.

In 2017 Xu et al. developed an Ir-catalyzed photoredox functionalization of tosyl protected N-aminopyridinium salt 48 and alkene 49 to access oxazolidine and imidazoline derivatives (Scheme 17).⁵⁶ This method results in formal [3 + 2] annulation via the intermediacy of nitrogen-centered radicals. Because the reaction solvent in these transformations also serves as a trapping agent, switching the solvents allowed derivatives of oxazolidines 50 and imidazolines 51 to be obtained.

Scheme 17 Alkenes functionalization for the synthesis of substituted imidazolines and oxazolidines.

Subsequently, Xu et al. extended the aforementioned olefin functionalization chemistry to achieve the stereospecific aziridination of alkenes using N-sulfonyaminopyridinium salts 45 (Scheme 18).⁵⁷ This approach allowed the synthesis of aziridines bearing various functional groups with excellent diastereoselectivity.

Scheme 18 Stereospecific synthesis of substituted aziridines by combination of N-sulfonyl N-aminopyridiniums and olefinic substrates under the action of Ir photocatalysis.

In 2021, Shi et al. disclosed a visible-light driven photoredox reaction between cycloalkanol-substituted 1H-indenes 53 or styrenes 54 with N-sulfonyl N-aminopyridinium salts 45 (Scheme 19).⁵⁸ This transformation was proposed to proceed via a radical addition/semipinacol rearrangement cascade initiated by addition of a photogenerated N-centered radical to the olefinic substrate. The observed reaction products are ultimately generated via a semipinacol rearrangement of an intermediate benzylic carbocation.

Scheme 19 Semipinacol rearrangement using N-aminopyridinium salts for the synthesis of β-amino (spiro)cyclic ketones.

In 2022, Powers et al. described olefin carboamination to form tetrahydroisoquinolines from N-benzyl-N-aminopyridinium reagents and styrenyl substrates under photoredox activation (Scheme 20a). Complementary spectroscopic studies provided evidence for photoredox-mediated generation of a transient amidyl radical, which was trapped and characterized (by both X-band EPR spectroscopy and high-resolution APCI-MS) as its adduct with N-tert-butyl-α-phenylnitrone (PBN).⁴³ The synthetic chemistry accessible under these conditions was extended to the formal aza-Rubottom oxidation of silyl enol ethers to access α-aminated products of carbonyls 60 (Scheme 20b) and the C–H amination of Boc protected indole 61 (Scheme 20c), both of which were possible due to the facility of N-centered radical trapping by the relevant substrates.

Scheme 20 Diversification of N-centered radicals derived from benzyl C–H aminopyridylation. (a) Synthesis of tetrahydroisoquinoline derivatives from styrenes. (b) Functionalization of silyl enol ethers. (c) C–H amination of heterocycles.

Thus far, the methods described in this section have largely relied on N-sulfonyl-N-aminopyridinium derivatives. N-Carbonyl derivatives have also found application in heterocycle synthesis. Yu et al. demonstrated that vinyl arenes react with benzoamidyl radicals derived from N-aminopyridinium salts 63 to form dihydrooxazoles 64. In contrast, under similar conditions aliphatic olefins afford dihydroisoquinolones 65via formal [4 + 2] annulation (Scheme 21).⁵⁹ The observed product selectivities were based on carbocation stability: in case for the vinyl arene substrates, the benzylic carbocation intermediate would be sufficiently stable to undergo intramolecular enolate trapping; in the case of aliphatic alkenes, [4 + 2] annulation is more feasible due to lack of stability of the carbon centered radical.

Scheme 21 Visible-light driven [3 + 2]/[4 + 2] annulation reactions of alkenes for the synthesis of dihydrooxazoles and dihydroisoquinolones.

In 2020, Zhao et al. prepared isoquinolone derivatives (68) from benzoyl protected N-aminopyridiniums 66 and alkynes via a deaminative [4 + 2] annulation (Scheme 22).⁶⁰ Na₂[EosinY] was used as the photocatalyst and a broad range of isoquinolones could be prepared from this method. In this reaction, the photogenerated N-centered radical adds to the alkyne 67 and undergoes the annulation to afford the desired products 68.

Scheme 22 Synthesis of isoquinolones by visible-light induced deaminative [4 + 2] annulation reaction.

In 2022, Yang and Xia et al. reported a deaminative [3 + 2] annulation method for the synthesis of γ-lactams (Scheme 23) that was initiated by reductive cleavage of the N–N bond of 69.⁶¹ Following the general mechanism described in Scheme 11, the N-centered radical generated from the triphenyl N-aminopyridinium derivative 69 adds to styrene 49 to generate the carbon-centered radical, which undergoes further intramolecular 5-exo-trig cyclization followed by oxidation to the benzylic carbocation. Product 70 is delivered by trapping the incipient carbocation with solvent.

Scheme 23 Deaminative [3 + 2] annulation method for the synthesis of γ-lactams.

Yu et al. subsequently developed a visible light mediated 1,2-amidoarylation of arylacrylamides to synthesize amidated oxindoles with N-aminopyridinium salts 71 under the action of fac-Ir(ppy)₃ photocatalysis. This method allows a variety of substituted arylacrylamides 72 and N-aminopyridinium salts to be converted to oxindole derivatives in good yields (Scheme 24).⁶²

Scheme 24 Visible light promoted 1,2-amidoarylation of arylacrylamides provides entry to a family of amidated oxindoles using N-aminopyridinium salts.

3.3 C–H amination chemistry

In 2015, Studer et al. disclosed one of the first examples of N-aminopyridinium salts as a N-centered radical precursor.³¹ This report described regioselective amidation of heteroarenes 77 and substituted arenes 74 using N-aminopyridinium reagents under the action of Ru(bpy)₃Cl₂ photoredox catalyst (Scheme 25). The requisite N-centered radicals were generated by oxidative quenching of the Ru(bpy)₃²⁺ excited state with the N-aminopyridiniums 15 and 76, which resulted in N–N cleavage. The N-arylation chemistry is most efficient with electron-rich arenes, such as 1,3,5-trimethoxy benzene. In 2021, Li et al. developed a similar transformation under aqueous conditions using 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-tetrakis(9H-carbazol-9-yl) isophthalonitrile) as an organic photocatalyst and demonstrated rate accelerations in the presence of anionic surfactants. The electrostatic interaction between positively charged N-aminopyridiniums and negatively charged surface of micelles were credited for the observed accelerations.⁶³

Scheme 25 C–H amination of arenes and heterocycles via N-centered radicals generated from N-aminopyridinium intermediates.

Taylor et al. leveraged the abovementioned C–H amination strategy to develop a photobioconjugation process that operates directly on native peptides or protein structures using N-carbamoyl pyridinium salts. This strategy delivers the carbamate group from 18 into tryptophan (Trp)-containing peptides or proteins 79, such as melittin, daptomycin, glucagon, and lysozyme. The reaction proceeds with excellent selectivity for tryptophan, features short reaction times, and does not require catalysts or organic solvent. In contrast to the visible light-mediated aromatic C–H amidation reported by Studer group,³¹ tryptophan functionalization did not require photocatalysts, as tryptophan readily participates in photoinduced electron transfer under short-UV region. Mechanistic studies indicated that a donor–acceptor interaction of Trp with the pyridinium salts facilitated Trp modification (Scheme 26a).³²

Scheme 26 (a) Catalyst-free amination of tryptophan 79 in proteins under UV light in aqueous solution with N-aminopyridinium salts, (b) in situ protein modification via visible light mediated amination with modified N-aminopyridinium salt 81.

The same group extended these studies in 2022 by developing a donor–acceptor pyridinium salt scaffold to enables PET (photo-induced electron transfer) -driven Trp modification in proteins using visible light. To achieve Trp modification under visible light irradiation, the optical properties of the pyridinium starting materials were modified by varying the para-substituent. Enrichment of modified tryptophan containing proteome lysates and live cell cultures demonstrated that N-aminopyridinium salts are suitable for chemoproteomic profiling (Scheme 26b).⁶⁴

3.4 Pyridine functionalization

Pyridine derivatives are prevalent heterocycles in bioactive compounds and thus methods to selectively prepare functionalized pyridine scaffolds are of significant interest. Site selective functionalization of pyridines can be a challenge because unbiased pyridines have more than one reactive site and direct functionalization reactions often result in mixtures of regioisomeric and/or over-functionalized products.

Hong et al. developed site-selective C4 acylation method of pyridines by combination of N-aminopyridinium salts 84 and aldehydes 85 under Ir photoredox catalysis (Scheme 27a).⁶⁵ The proposed mechanism of this transformation is illustrated in Scheme 27a and proceeds via SET (single electron transfer) from the excited state of the photocatalyst to 84, followed by cleavage of the N–N bond to unveil amidyl radical 87. Hydrogen atom abstraction (HAA) from aldehyde 85 by 87 generates the acyl radical 88. The acyl radical 88 is then trapped by the N-aminopyridinium salts 84 at the C4 position to provide 89. Finally, deprotonation and homolytic N–N cleavage affords the observed C4 acylated pyridines (86). The scope of C4 functionalization was extended by utilizing cyclopropanols as the precursors of β-keto radicals (Scheme 27b).⁶⁶ Similar to the mechanism depicted in Scheme 27a, the β-keto radicals are generated from the N-centered radicals 87 and eventually add to the C4 position of N-aminopyridinium salts to afford β-pyridylated carbonyls 92.

Scheme 27 (a) Visible light mediated C4 acylation method of pyridinium derivatives. (b) Visible light mediated C4 functionalization of pyridinium salts with cyclopropanols as β-keto radical precursors.

The N-centered radicals released from N-aminopyridinium salts can also participate in remote C(sp³)–H activation reactions, for example, to pyridylate the δ-position of sulfonamides and carboxamides (Scheme 28a)⁶⁷via the formation of carbon centered radical. In a related protocol, N-aminopyridinium salts 96 have been used for various C–H and X–H (X = P, Si) pyridylation reactions using anthraquinone as the photocatalyst (Scheme 28b).⁶⁸ Here, the anthraquinone excited state engages in HAA to generate carbon-centered radicals, which adds to the C4 position of the N-aminopyridinium salts 96 to ultimately provide the substituted pyridines 98, similar to the mechanism provided in Scheme 27a.

Scheme 28 (a) Remote C(sp³)–H pyridylation of sulfonamide and carbamoyl protected N-aminopyridinium salts. (b) C4 selective direct C–H pyridylation of unactivated alkanes.

The abstraction of weak Si–H bond in 103 was further demonstrated by the formation of a light-absorbing electron donor acceptor (EDA) complex of N-aminopyridinium salts 84, similar to the phenomenon highlighted in tryptophan functionalization illustrated in Scheme 26. This strategy offers photocatalyst free, facile, and environmentally benign photochemical transformations as well as expands the synthetic utility of N-aminopyridinium derivatives. A diverse set of alkyl bromides have been pyridylated to get C4 alkylated pyridines 100 utilizing this approach (Scheme 29).⁶⁹ In this transformation, EDA complex 101 undergoes an intramolecular SET to trigger the formation of a bromine radical, which, in presence of (TMS)₃SiH leads to the formation of silyl radical 104. Silyl radical 104 then abstracts the bromine atom from alkyl bromide to afford alkyl radical 105 which adds to the C4 position of N-aminopyridinium salts to ultimately provide C4 alkylated pyridines 100.

Scheme 29 Visible light mediated photocatalyst free site selective C4 alkylation of pyridiniums with alkyl bromides mediated by EDA complexes.

1,4-Dihydropyridine 106 can also form the EDA complexes with N-aminopyridinium salts (Scheme 30).⁷⁰ Single-electron oxidation of 106 generates carbon-centered radical 105 which is subsequently trapped by N-aminopyridiniums (84) to deliver C4 functionalized pyridines including alkyl, acyl and carbamoyl groups.

Scheme 30 Site selective C4 alkylation of pyridiniums with 1,4-dihydropyridine assisted N-aminopyridinium EDA complexes.

In 2019, Hong et al. reported olefin 1,2-aminopyridylation utilizing N-sulfonylated aminopyridiniums as precursors to N-centered radicals (Scheme 31).⁷¹ Similar to the mechanism illustrated in Scheme 27a, this reaction is proposed to proceed via the intermediacy of N-centered radical 87, which upon addition to the electron-rich olefin generates C-centered radical 110. Addition of 110 to the C4 position of the N-aminopyridinium salts provide 111 which undergoes deprotonation followed by homolytic N–N cleavage give the desired aminopyridylated product 109.

Scheme 31 Visible light-mediated alkene aminopyridylation method using N-aminopyridinium salts.

The Hong group have also developed an olefin hydropyridylation method in both Markovnikov and anti-Markovnikov fashion by in situ generation of alkyl bromides.⁷² In presence of air, anti-Markovnikov bromination proceeds via radical pathway (Scheme 32a). In contrast, under anaerobic conditions, with tetrabutylammonium bromide (TBAB) as an additive result in Markovnikov addition which operates via116 (Scheme 32b). The in situ generated alkyl bromides 114 and 116 produce the alkyl radicals similarly as shown in Scheme 29 and the respective alkyl radicals find N-aminopyridinium salts at C4 position to obtain branched and linear C4 alkylated pyridines.

Scheme 32 (a) Anti-Markovnikov olefin hydropyridylation yields linear alkyl pyridines. (b) Markovnikov olefin hydropyridylation yields branched alkyl pyridines. Regioisomeric ratio (linear/branched products) (>20 : 1 if not denoted). (c) Visible light mediated NHC catalyzed enantioselective C4 alkylation of pyridinium salts utilizing pivalate based N-aminopyridinium EDA complexes and enones.

The same group have further achieved visible light mediated enantioselective hydropyridylation of enones utilizing pivalate based N-aminopyridinium EDA complex (Scheme 32c).⁷³ NHC bound homoenolate radical 121 directs the C4 addition of N-aminopyridinium salts from a particular direction yielding enantio-enriched C4-alkylated pyridines 119.

1,3-Aminopyridylated bicyclo[1.1.1]pentane (BCP) derivatives can also be accessed through the photochemistry of N-aminopyridinium EDA complexes. Photolysis of the EDA complex that forms between N-aminopyridinium salts 84 and acetate anion (similar EDA complex was illustrated in Scheme 29) results in introduction of amino and 4-pyridyl groups at the 1,3-positions of propellane (Scheme 33a).⁷⁴ On the other hand, the EDA complexes formed between N-aminopyridinium salts 84 with sulfinate anion 124 participated in a visible light mediated three component olefin difunctionalization reaction (Scheme 33b).⁷⁵ Interestingly, the reaction proceeds via a two-electron pathway in the absence of visible light resulting an efficient pyridine C4 sulfonylation reaction to yield 126 (Scheme 33b).

Scheme 33 (a) Visible light mediated 1,3-aminopyridylation of [1.1.1] propellane with pyridinium salts. (b) One electron and two electron reaction pathways of sulfonyl pyridylation and sulfonation of pyridinium salts respectively with sulfinates as radical precursors.

In addition to the extensive progress in selective pyridine functionalization at the 4-position utilizing N-aminopyridinium salts, N-aminopyridinium ylide 127 can also engage in a diverse set of C2-functionalizations. N-Aminopyridinium ylides undergo oxidative SET with the excited state of an appropriate photocatalyst to afford pyridinium radical cation 129. The radical cation 129 can engage in 1,3-dipolar cycloaddition with a broad range of olefins to provide adducts 131.⁷⁶ Subsequent deprotonation, N–N cleavage, and finally reductive SET results in ortho-selective olefin aminopyridylation via a non-classical radical process (Scheme 34a). The scope has been extended further to develop an ortho-selective aminopyridylation method of ketones through a double umpolung approach (Scheme 34b).⁷⁷

Scheme 34 (a) Visible light mediated C2-selective functionalization of pyridinium ylides by radical based 1,3-dipolar cycloaddition with olefins. (b) Photocatalytic ortho-selective aminopyridylation of methyl ketones.

Apart from functionalizing the C4 and C2 position, pyridylic C–H bonds also undergo diversification via intermolecular radical trapping to yield a broad range of pyridylic fluoroalkylated scaffolds 138 and 139 (Scheme 35).⁷⁸ In presence of olefins the reaction carries forward in a cascade fashion where the olefins traps the fluoroalkyl radicals to afford alkyl radicals which upon SO₂ addition make sulfonyl radicals. Subsequently the sulfonyl radicals trap the activated pyridylic C–H center to obtain β-fluoroalkylsulfonylated heteroarenes 138.

Scheme 35 Photocatalytic pyridylic C–H fluoroalkylation and cascade reactions with olefins to provide pyridylic fluoroalkylated scaffold and β-fluoroalkylsulfonylated heteroarenes respectively.

4 Metal-catalyzed transformations of N-aminopyridiniums

4.1 Synthesis of nitrogen rich heterocycles

In addition to the photochemical methods for the synthesis of nitrogen containing heterocycles from N-aminopyridinium salts described in section 3.2, transition metal-catalyzed methods have also been developed to access this class of products. In 2010, Charette et al. described the synthesis of 2-substituted pyrazolo[1,5-a]pyridines 142 by combining N-aminopyridinium salts 140 with iodoolefins under the action of Pd catalysis (Scheme 36).⁷⁹ The products were obtained in good yields, the reaction was broadly functional group tolerant, and the transformation was proposed to proceed through a sequential alkenylation/cyclization route.

Scheme 36 Pd-catalyzed synthesis of 2-substituted pyrazolo[1,5-a]pyridines through an alkenylation/cyclization cascade.

Davies et al. reported a regioselective gold-catalyzed intermolecular [3 + 2] cycloaddition across electronically biased π systems using N-aminopyridinium ylide 143. The protocol gives straightforward access to highly substituted and functionalized 1,3-oxazoles which employs 143 as chemoselective 1,3-N,O-dipole equivalents (Scheme 37a).⁸⁰ Davies et al. later extended the gold-catalyzed ynamide-nitrenoid strategy for the synthesis of imidazo-fused oxo-substituted heterocycles starting from pyridinium N-(heteroaryl)-aminides 21. These reactions show good regioselectivity with (hetero)aryl-, vinyl-, and alkyl-ynamides as well as 3-alkynyl indoles to access different types of important heteroaromatic scaffolds and also accommodate a range of useful functional groups including aldehydes, alkenes, free and acylated indoles, furan, thiophene, nitro, aryl halides, and alkyl chlorides (Scheme 37b).^41,81 Mechanistically, these reactions are proposed to proceed through activation of the alkyne 144 by the Au catalyst followed by nucleophilic addition of ylide 143 or 21 to afford 148 (Scheme 37c). Cyclization to 150 can be envisioned after elimination of pyridine (via 4π-electrocyclization), which goes through 149 transition state. Elimination of the gold-catalyst from 150 then yields the product and closes the catalytic cycle.

Scheme 37 (a) Synthesis of 2,4,5-trisubstituted oxazoles by Au-catalyzed formal [3 + 2] cycloaddition. (b) Au-catalyzed synthesis of oxo-functionalised 4-aminoimidazolyl fused compounds by intermolecular annulation reactions. (c) General mechanistic cycle for Au-catalyzed annulation reactions via N-aminopyridinium ylides.

In 2020, Tabolin et al. described a method for the synthesis of 3-fluoro- and 3-nitro-pyrazolo[1,5-a]pyridines from N-aminopyridnium salts 2 and nitroolefins promoted by Cu salts (Scheme 38).⁸² Although the method required stoichiometric quantities of copper salts, the developed transformation efficiently provides access to pharmaceutically attractive pyrazolopyridine derivatives 152 and 154.

Scheme 38 Copper-mediated oxidative [3 + 2]-annulation of nitroalkenes and N-aminopyridinium to synthesize 3-fluoro- and 3-nitro-pyrazolo[1,5-a]pyridines.

4.2 Transition metal-catalyzed functionalization

The use of directing groups in metal-catalyzed C–H functionalization reactions provides an opportunity to exert high levels of positional selectivity. Daugulis et al. demonstrated N-aminopyridinium ylides 155 to be an efficient directing group for palladium-catalyzed β-arylation and alkylation of sp³ C–H bonds in carboxylic acid derivatives (Scheme 39a).²³ Following the C–H functionalization, the pyridinium moiety was removed through reductive N–N cleavage with either Zn or Mg to yield primary amides. The N–N bonds can also be cleaved through BF₃·Et₂O-promoted methanolysis to produce methyl esters. These investigators subsequently extended the use of N-aminopyridinium ylides as directing groups to achieve Cu(OAc)₂ promoted sulfenylation, selenylation, and amination of sp² C–H bonds with aryl and alkyl disulfides, diphenyl diselenides as well as with a diverse set of nitrogen-containing heterocycles (Scheme 39b).^83,84

Scheme 39 Application of N-aminopyridinium ylides as directing groups for metal-catalyzed (a) sp³ C–H functionalization and (b) sp² C–H functionalization.

In 2020, Daugulis et al. reported that N-iminopyridinium ylides 159 can also serve as monodentate directing groups for cobalt-catalyzed annulation of sp² C–H bonds with internal alkynes (Scheme 40).²⁴ The developed annulation reaction is compatible with heterocyclic substrates, including furan, thiophene, pyridine, pyrrole, pyrazole, and indole functionalities. The method exhibits poor selectivity and lower yields in the case of unsymmetrical alkynes. Mechanistically, the transformation is proposed to proceed via chelation assisted C–H activation to give the cobaltacycle 162. Ligand exchange followed by migratory insertion forms the seven-membered cobaltacycle 163. Intramolecular C–N bond formation gives the desired product 160 and releases pyridine 164 along with Co(III) catalyst 161 (Scheme 40).

Scheme 40 N-Iminopyridinium ylide directed cobalt-catalyzed coupling of sp² C–H bonds with alkynes.

In 2022, Powers et al. disclosed a Ni-catalyzed cross-coupling reaction to access N-aryl aziridines and N-aryl benzyl amines from the corresponding N-aminopyridinium derivatives (Scheme 41a).^39,44 The low-lying pyridinium-centered LUMO of the N-aminopyridinium starting materials provided the opportunity to leverage first-row metal catalysts to engage these compounds as electrophiles in Ni-catalyzed cross-coupling with a variety of boronic acids. The developed methods proved effective for both electron-donating and electron-withdrawing aryl substituents in 25, 27 and 165. Furthermore, this method was compatible with application in complex settings such as those relevant to pharmaceutical derivatization. In the context of N-pyridinium aziridines, ring-opening chemistry with various nucleophiles provided 1,2-difunctionalization products, which also engaged in the abovementioned Ni-catalyzed cross-coupling reaction (Scheme 41b). The two-step sequence of either C–H N-aminopyridylation or olefin aziridination followed by Ni-catalyzed cross coupling highlights the bifunctionality of N-aminopyridium as both nucleophile and latent electrophile in producing nitrogen containing value added products.

Scheme 41 (a) Ni-catalyzed cross-coupling platform via N-aminopyridiniums, derived from aziridines and benzylic C–H bonds. (b) Ring-opening of N-pyridinium aziridines with various nucleophiles provides 1,2-difunctionalization products.

5. Conclusions

This review explored the use of N-aminopyridinium salts and derivatives thereof as reagents in organic synthesis. The synthesis of these reagents is expanding, offering more opportunities to uncover their unique reactivity patterns. These reagents can act as efficient nitrogen centered radical precursors, electrophiles in cross-coupling chemistry, and directing groups for C–H functionalization reactions. The bifunctionality in N-aminopyridinium motifs makes them a unique N-atom source which is in some cases superior to the traditional aminating reagents. Although significant progress has been made in this field, potential problems further remain to be explored to make this class of compounds as a generalized lynchpin for amine synthesis. (1) There are not a lot of report to utilize the innate bifunctionality of the N-aminopyridinium reagents, more research in this space is required. This strategy of N-atom lynchpin can be extrapolated to other heteroatoms; thus, more reagents should be discovered accordingly. (2) There are very few examples of asymmetric synthesis using these molecules; further development is required to either incorporate asymmetry in the pyridinium moiety or to discover an asymmetric catalysis solution. (3) For the N-centered radical chemistry, in most of the cases, an EWG is required which makes the transformation slightly less attractive, the requirement of these stabilizing groups should be obliviated to broaden the scope.

Author contributions

All authors participated in literature surveying, manuscript writing, and editing.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors gratefully acknowledge support from the Welch Foundation (A-1907) and the National Institutes of Health (R35GM138114).

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