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 is discussed, showcasing the reactivity in the context of bifunctional platform and its potential for innovation in the field.

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.

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. R = acyl, sulfonyl, alkyl, aryl or allyl; X = H, Cl, Br, I or OCOOCH₃.

Scheme 3.

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

Scheme 4.

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

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.

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.

Scheme 7.

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

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.

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.

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.

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) Reference b) Reference .

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.

Scheme 14.

Ir catalyzed amination of π-nucleophiles with N-Aminopyridinium Salts.

Scheme 15.

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

Scheme 16.

Synthesis of γ-butyrolactones via aza-pinacol rearrangement.

Scheme 17.

Alkenes functionalization for the synthesis of substituted imidazolines and oxazolidines.

Scheme 18.

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

Scheme 19.

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

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.

Scheme 21.

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

Scheme 22.

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

Scheme 23.

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

Scheme 24.

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

Scheme 25.

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

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.

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.

Scheme 28.

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

Scheme 29.

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

Scheme 30.

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

Scheme 31.

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

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.

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.

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.

Scheme 35.

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

Scheme 36.

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

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.

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.

Scheme 39.

Application of N-aminopyridinium ylides as directing groups for metal-catalyzed a) sp C–H functionalization and b) sp C–H functionalization.

Scheme 40.

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

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.