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. 2026 Feb 17;148(8):8621–8633. doi: 10.1021/jacs.5c20464

Potassium Bisulfite’s Role in Developing a Robust Platform for Enantioenriched N‑Alkylpyridinium Salts as Piperidine Precursors

Jake D Selingo †, Jacob R King †, Barbara Pio ‡, Andrew J Neel §, Yu-Hong Lam ∥, Robert S Paton †, Matthew L Maddess ⊥,*, Andrew McNally †,*
PMCID: PMC12964407  PMID: 41700116

Abstract

Piperidines are prominent scaffolds in medicinal chemistry. However, methods that incorporate chiral N-alkyl substituents on piperidine remain limited. Here, we report a platform for the synthesis of enantioenriched N-(α-chiral)­alkylpyridinium salts from commercially available pyridines and enantiopure primary amines; the resulting pyridinium salts serve as versatile precursors to stereoenriched N-(α-chiral)­alkylpiperidines via established reduction protocols. We discovered potassium metabisulfite as a reaction additive that significantly enhanced the robustness of the pyridinium formation reaction. Mechanistic and computational studies reveal that potassium metabisulfite deconjugates Zincke imines, enabling a lower-energy polar cyclization pathway to pyridinium formation compared to a pericyclic one. We performed high-throughput experimentation that demonstrated a broad scope for both coupling partners, providing a robust, general platform for generating libraries of piperidine precursors relevant to medicinal chemistry.

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Introduction

Piperidines are abundant components of bioactive molecules, represented in 20 different drug classes and ranking as the second most common N-heterocycle in FDA-approved pharmaceuticals. − They are frequent targets of Structure Activity Relationship (SAR) studies, which can be challenging due to the lack of general methods for functionalizing their sp 3-hybridized framework and the limited commercial availability of chiral piperidine building blocks. In particular, accessing piperidines with N-enantioenriched carbon-bearing groups, as depicted in Figure A, is surprisingly challenging. − Most modern methods for asymmetric C–N bond formation employ ketones, alkenes, or chiral organohalides and are more broadly applicable to primary amines compared to piperidines. ,− Instead, practitioners commonly rely on more robust, unselective C–N bond-forming reactions, followed by chiral resolutions. − Here, we report an orthogonal approach to piperidine N-functionalization using enantioenriched N-(α-chiral)­alkylpyridinium salts as key precursors. The process operates via a pyridine ring-opening, ring-closing sequence that couples abundant pyridines and enantiopure primary amines from commercial sources or pharmaceutical libraries. − Well-established pyridinium reduction reactions or functionalization-reduction sequences can access the corresponding stereoenriched N-(α-chiral)­alkylpiperidines. ,,−

1.

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(A) Examples of pharmaceuticals and clinical candidates containing stereoenriched N-(α-chiral)­alkylpiperidines. (B) Common strategies for enantioenriched N-alkylpyridinium salt synthesis and limitations. (C) This work: enantioenriched N-(α-chiral)­alkylpyridinium salts synthesis via NTf-Zincke imine intermediates with the discovery of potassium metabisulfite and elucidation of its mechanistic role.

The lack of a robust, general platform for synthesizing N-alkylpyridinium salts limits their use in synthesis, − biology, − materials, and as precursors to N-alkylpiperidines for drug discovery. Existing methods include reactions of pyrylium salts with amines and S N 2 alkylations of pyridines (Figure B). , The scarcity of pyrylium salt precursors and the poor reactivity of pyridines in S N 2 reactions with more hindered electrophiles restrict these approaches. Alternatively, the classic Zincke reaction could be a platform that couples two abundant feedstocks, pyridines and enantiopure primary amines, and incorporates the stereochemistry of the amine into the pyridinium product. ,− However, existing reports show that only a narrow set of pyridines function in this approach, with minimal demonstration of functional groups appended directly to the pyridine, and it does not tolerate 2-position substituents. Similarly, the scope of primary amines remains underexplored. Recently, Xiao reported a rhodium-catalyzed asymmetric transfer hydrogenation of N-ethylpyridinium salts with enantiopure amines that is highly efficient to access certain classes of piperidine with good levels of stereocontrol. Rather than targeting specific classes of piperidines, our goal was to develop a general method that enables broad variation of both C-substituents and N-groups.

We recently disclosed a protocol for synthesizing N-(hetero)­arylpyridinium salts via NTf-Zincke imine intermediates, and we hypothesized that this pyridine ring-opening, ring-closing strategy could also serve as a general platform to construct enantioenriched N-alkylpyridinium salts using the vast collections of chiral amines (Figure C). Although conceptually simple, we did not achieve this goal until we discovered potassium metabisulfite as a critical additive that markedly enhances reaction generality. This report presents experimental and computational studies of metabisulfite’s effect on the reaction mechanism and its breadth, demonstrated by High-Throughput Experimentation (HTE).

Results and Discussion

Reaction Development

We began our study by developing a one-pot method for converting pyridines to pyridinium salts via NTf-Zincke imine intermediates. Using 2-phenylpyridine, triflic anhydride, collidine, and dibenzylamine in EtOAc, we synthesized 1a and added 1.5 equiv of amine 2a to the same reaction vessel to study the formation of 3a (Table , left). Pyridinium salt 3a did not form at room temperature, and heating the reaction at 50 or 70 °C resulted in low yields (entries 1–3). Notably, increasing the temperature to 120 °C provided minimal yield improvement for 3a and mainly resulted in decomposition of 1a (entry 4). Conditions similar to our previous report, which employ AcOH in EtOAc, did not improve the yield of 3a (entry 5). DABCO provided a significant improvement for pyridinium salt formation (entry 6). However, sulfite additives further increased the yield of 3a, with potassium metabisulfite providing the highest yield (entries 7–9; see Supporting Information Section 2 for additional additives). Reducing the stoichiometry of metabisulfite to one equivalent did not adversely affect the reaction outcome (entry 10). We then extended our study to a small set of other amines using 2b–2d (Table , right). While 2a–2c form pyridiniums in good to excellent yields using the conditions from entry 9, we did not observe product formation with electron-deficient amine 2d. Our previous report demonstrated MeOH can improve the reaction outcome with certain amines, so we employed it as a cosolvent for one-pot N-alkylpyridinium formation. While MeOH did not affect the reaction outcome with 2a or 2b, it improved the pyridinium salt yield with amino alcohol 2c. Notably, including MeOH as a cosolvent enabled pyridinium formation with 2d. These results suggest that including MeOH in the solvent mixture provides a more general set of reaction conditions.

1. Ring-Closing Optimization Study.

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a

Yields calculated by 1H NMR spectroscopy using Ph3CH as an internal standard.

Next, we explored the scope of the one-pot pyridinium salt formation process (Table ). We developed Liquid–Liquid Extraction (LLE) and precipitation methods to isolate the pyridinium salts as the triflate or hexafluorophosphate salts. Salt 3b demonstrated tolerance for enantioenriched 1-phenethylamines in pyridinium formation. The process also accommodated C2-alkyl substituted pyridines, such as 3c derived from amino alcohol (−)-norephedrine. In general, pyridines with C2-alkyl substituents required AcOH and metabisulfite in EtOAc to form pyridinium salts in good yields (see Supporting Information Section 2). Nicotine-derived pyridinium salt 3d formed a single diastereomer from an α-tertiary amino-ester. Salt 3e formed in good yield but partially decomposed under the reaction conditions and the LLE stage. However, we observed a good yield of 3e at shorter reaction times (see Supporting Information Section 6.2). Salts 3d and 3e were unstable under the reaction conditions with potassium metabisulfite, and excluding metabisulfite from the reaction improved the yields for both salts. Pyridinium salts derived from 2,3- and 3,4-disubstituted pyridines containing esters and halides were also accessible and efficiently coupled with fluorinated aminopiperidines and aminocyclopropanes in good yields, respectively (3f and 3g).

2. One-Pot Pyridinium Salt Formation Scope .

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a

Isolated yields are shown.

b

Reaction used 10 equiv of AcOH, 1 equiv of K2S2O5 in EtOAc (0.2 M).

c

K2S2O5 not used in reaction.

d

Reaction ran at 50 °C.

e

Yields calculated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

Nucleophilic Additive Effects in Pyridinium Formation

The next phase of our study focused on the role of potassium metabisulfite as a reaction additive. We investigated the cyclization of isolated Zincke imine 1a with amine 2a independent from the ring-opening byproducts generated in the one-pot pyridinium formation. While EtOAc is necessary for generality in the ring-opening step, we found that using MeOH as the sole reaction solvent with isolated Zincke imines reproduced the yields obtained with potassium metabisulfite in Table (see Supporting Information Section 7.1). In Scheme , we surveyed the reactivity of several sulfite-based reagents and compared them to common acids and bases. The data indicate that potassium metabisulfite, sodium bisulfite, and potassium sulfite all significantly improve the yields of pyridinium salt 3a–NHTf, whereas acid and base additives did not. We postulate that the similar efficiency of these additives implies a common active species, and previous precedent describes that metabisulfite will form an equilibrium with bisulfite anions in the presence of nucleophiles (eq 1). , graphic file with name ja5c20464_0016.jpg

1. Comparison of Nucleophilic and Non-Nucleophilic Reaction Additives for the Recyclization of Isolated 1a .

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a Yields calculated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

There is well-established precedent for bisulfite deconjugating polarized contiguous π-bonds in organic dyes and aromatic rings. − We hypothesized that similar processes were operating in the cyclization of Zincke imines to pyridinium salts. However, other nucleophilic additives, such as DABCO, did not increase the yield of 3a–NHTf, unlike the result reported in entry 5 of Table . This result emphasized the effect of the ring-opening byproducts on the downstream pyridinium formation steps (see Supporting Information Section 7.1). Interestingly, thiophenol did result in a substantial increase in the yield of 3a–NHTf compared to the other acids, bases, and nucleophiles tested. We examined other electronically distinct thiophenols and observed that the nucleophilicity of the sulfur atom (Mayr’s nucleophilicity parameter, N) and the pK a of the S–H bond had positive correlations to the yield of 3a–NHTf (see Supporting Information Section 7.1). , These trends for thiophenol additives and the analogous reactivity to bisulfite additives in pyridinium formation suggested that both the acidity and nucleophilicity of bisulfite are central to its reactivity.

Proposed Mechanisms for Pyridinium Formation and the Role of Bisulfite

To determine bisulfite’s role in the mechanism, we first considered the key steps of pyridinium formation without exogenous additives (Scheme A). We propose that the process begins with a transamination step that incorporates the amine nucleophile into Zincke imine 1 to form 1–(NHR 2 ) 2 . This process is observable by 1H NMR and low-resolution mass spectrometry (LRMS) at early time points of the reaction (vide infra). Next, E/Z-isomerization of the all-trans-configured 1–(NHR 2 ) 2 generates the requisite cis-isomer Int-I, which undergoes a disrotatory 6π-electrocyclization to yield the cyclized Int-II. Elimination of the exocyclic amine produces the product 3.

2. Proposed Mechanisms for Pyridinium Formation without Additives and with Potassium Metabisulfite .

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a Counterions are omitted for clarity.

We then considered potassium bisulfite’s role in promoting pyridinium formation and propose an alternative mechanism in Scheme B. We reasoned that bisulfite protonates 1–(NHR 2 ) 2 to facilitate 1,4-addition of sulfite to the protonated Zincke imine Int-III to generate Int-IV. This deconjugation process with bisulfite would obviate the E/Z-isomerization and 6π-electrocyclization steps outlined in Scheme A, providing an alternative, polar pathway to pyridinium formation. Protonation of the enamine followed by a 6-exo-trig cyclization through Int-V generates Int-VI. Elimination of the amine and subsequent E1cB elimination of bisulfite produces pyridinium 3. Notably, the aromatization process regenerates potassium bisulfite. Using Zincke imine 1a and amine 2a with 20 mol % potassium metabisulfite produced a comparable yield of 3a–NHTf to that obtained with a full equivalent. Other amines, such as 2d, required a full equivalent of potassium metabisulfite to produce high yields of the corresponding salt. Therefore, we continued to use it as a stoichiometric additive for reaction generality (see Supporting Information Section 7.2).

Investigation into Zincke Imine Deconjugation

Next, we investigated the deconjugation of Zincke imines with bisulfite additives (Scheme , top). Despite the arguments presented thus far, we did not observe 1a–SO 3 K when we treated 1a with potassium metabisulfite in MeOH at 70 °C (see Supporting Information Section 7.3). Nevertheless, we assumed these species may transiently form in low concentrations and examined the deuteration of 1a in CD3OD at 70 °C to study the deconjugation phenomenon independent of pyridinium formation (Scheme , bottom). , Importantly, isotope incorporation did not occur without additives after 2 h. Brønsted acids, such as AcOH and pyridinium p-toluenesulfonate (PPTS), afforded varying degrees of deterium incorporation, but both reactions were indiscriminate between the C3- and C5-positions of d -1a. However, potassium metabisulfite, sodium bisulfite, and thiophenol all furnished high isotope incorporation of d- 1a with considerable selectivity for the C5-position (see Supporting Information Section 7.4 for additional additives). We postulate that this outcome may arise from intermediate 1a–SO 3 K, as the more reactive N-dialkyl enamine would deuterate the C5-carbon preferentially over the C3-position within the N-triflyl enamine.

3. Hypothesis for Zincke Imine Deconjugation and Comparison of Additives in the Deuteration of 1a .

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a Deuterium incorporation calculated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

b tr = trace.

Experimental Investigation of Mechanistic Steps with Potassium Metabisulfite

We then studied how bisulfite additives affect the mechanism of pyridinium salt formation using the reaction of Zincke imine 1a and isopropylamine as a model system (Scheme ). At room temperature, we observed an initial transamination event that formed a collection of new Zincke imines ( transaminated –1a) that are structurally similar by 1H NMR spectroscopy but distinguishable by LCMS analysis (Scheme A). It is conceivable that potassium metabisulfite accelerates this transamination step by deconjugating Zincke imine 1a. Yet, at a 2-h time point, we saw minimal difference compared to a control reaction without the additive. We did, however, observe minor amounts of pyridinium salt 3h when bisulfite was present.

4. Investigation of Potassium Metabisulfite Effects on the Mechanism of Pyridinium Salt Formation .

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a Yields calculated using 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

b Yields calculated using 1H NMR spectroscopy using 1,3,5-trimethylbenzene as an internal standard.

In Scheme B, we prolonged the previous reaction with potassium metabisulfite at room temperature for 18 h and observed two distinct intermediates as well as appreciable amounts of pyridinium product 3h. We separated the two new polar products from 3h and isopropylamine, and structure elucidation using NMR spectroscopy and High-Resolution Mass Spectrometry (HRMS) supported the structures for monobisulfite adduct 4a and bis-bisulfite adduct 4b. Importantly, resubjecting 3h to the reaction conditions does not decompose the salt nor form 4a or 4b, suggesting that 3h forms irreversibly, and it is not the origin of 4a or 4b (see Supporting Information Section 7.6).

We hypothesized that 4a and 4b may form through the mechanism proposed in Scheme B via exchange of the exocyclic amine in Int-VI with methanol or bisulfite, respectively. Therefore, we examined their reactivity for pyridinium formation by subjecting the crude reaction mixture containing 3h, 4a, and 4b to various conditions (Scheme C). Stirring the reaction mixture for an additional 24 h equilibrates 4a to 4b, but neither of the intermediates convert to 3h. However, heating the reaction to 70 °C for 24 h forms 3h exclusively, explaining why we do not observe either of these intermediates under the optimized reaction conditions. Acids tested in Scheme C also convert 4a and 4b to 3h at room temperature. We suspect that acids promote the elimination of methanol and bisulfite from 4a and 4b, thereby facilitating the final aromatization step of the mechanism. The results of this study suggest that bisulfite may alter the reaction pathway for pyridinium formation via deconjugated Zincke imine and pyridinium intermediates that enable a distinct cyclization mechanism, as evidenced by 4a and 4b.

Computational Investigation

We next employed density functional theory (DFT) to investigate the reaction mechanism with and without bisulfite additives at the ωB97M-V/def2-TZVPP//M06-2X­(D3)/6-31+G­(d,p) level of theory in methanol (Figure ). Quantum chemical calculations were performed with Gaussian 16 revision C.01 and Orca 6.0.0. , For full details of computations and references see Supporting Information. Importantly, in the proposed mechanism without bisulfite, the rate-limiting step is the disrotatory 6π-electrocyclization of Int-VIII through TS5 (ΔG‡ = 23.9 kcal/mol; see Supporting Information Section 7.7.2). Based on the initial configuration of Int-VIII, the disrotatory motion generates the syn conformation in TS5 and results in steric strain between the N-isopropyl and exocyclic amine substitutents. Therefore, we investigated our hypothesis regarding bisulfite’s role in the cyclization, with our computed energy surface starting from transaminated-Zincke imine Int-VII, since this step occurs independently of bisulfite (vide supra). After protonation of Int-VII (ΔG = −6.4 kcal/mol), potassium sulfite undergoes facile 1,4-addition to Int-VIII via TS1, generating the addition intermediate Int-IX (ΔG‡ = 12.7 kcal/mol, ΔG = −10.9 kcal/mol). Int-IX is protonated to generate Int-X (ΔG = −17.5 kcal/mol), which undergoes rapid 6-exo-trig cyclization via TS2 to produce cyclic Int-XI (ΔG‡ = 5.8 kcal/mol, ΔG = 2.3 kcal/mol). Notably, the steric strain present in TS5 is absent in TS2, as the N-isopropyl substituent is preferentially anti to the exocyclic amine, providing a facile polar cyclization. Following proton transfer, Int-XI converts to the more thermodynamically favored Int-XII (ΔG = −12.3 kcal/mol), which eliminates isopropylamine through TS3 to form iminium Int-XIII as the rate-determining step (ΔG‡ = 19.9 kcal/mol, ΔG = 10.1 kcal/mol). Interestingly, we found Int-XIII to be an intermediary species in the formation of 3h, as well as the off-pathway intermediates 4a and 4b (see Supporting Information Section 7.7.5). The remaining E1cB sequence from Int-XIII generates 3h; this sequence commences with deprotonation of Int-XIII to produce Int-XIV (ΔG = −12.8 kcal/mol). Then, Int-XIV eliminates KSO3 – through TS4 to produce 3h (ΔG‡ = 17.7 kcal/mol, ΔG = −4.6 kcal/mol). The low-energy barrier for cyclization via TS2 supports our hypothesis that bisulfite enables a facile polar cyclization process, and the rate-determining amine elimination via TS3 demonstrates its role in reducing the overall kinetic barrier for pyridinium formation through a distinct mechanism.

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Proposed mechanism for the reaction pathway with potassium bisulfite (bold) and without (dashed line). Gibbs energy surface computed at the ωB97M-V/def2-TZVPP,CPCM­(methanol)//M06-2X­(D3)/6-31+G­(d,p), PCM­(methanol) level of theory. Counterions are omitted for clarity.

Influence of Zincke Imine Substitution Patterns on Pyridinium Formation

Next, we systematically investigated the effects of potassium metabisulfite with other Zincke imine substitution patterns using amine 2a as a representative nucleophile (Scheme ). There was a significant impact on 3a formation with metabisulfite, yet 3i and 3j formed in near quantitative yields without it. Pyridiniums with methyl groups at the C3-position were higher yielding with potassium metabisulfite in the reaction, and a larger effect was observed with an additional C2-phenyl group (3k and 3l). Potassium metabisulfite did not impact the yield of 2,4-disubstituted 3m; however, it did significantly improve the formation of 2,5-disubstituted 3n. These results suggest that the Zincke imine substitution pattern has a significant impact on pyridinium formation, showing that metabisulfite is not always necessary or effective in improving the reaction outcome. We suspect that C2-substituents on the Zincke imine can impede pyridinium formation; however, large substituents and/or substitution patterns that generate steric repulsion with coplanar substituents in the all trans-Zincke imine configuration, such as a C2-phenyl group interacting with a C4-methyl group in salt 3m, promote pyridinium formation without involving metabisulfite (Figure ).

5. Potassium Metabisulfite Effects with Different Zincke Imine Substitution Patterns .

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a Yields calculated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

b Counterions are omitted for clarity.

3.

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Hypothesis for steric interactions that promote pyridinium formation.

HTE Screening

We then used HTE to assess the compatibility of a set of Zincke imines with an extensive range of chiral amines. We selected 48 enantioenriched (α-chiral)­amines 2a–2av from the Merck & Co., Inc., Rahway, NJ, USA compound library, shown in Figure , and synthesized 12 substituted Zincke imines (1a–1l). ,, First, we performed a control screen using Zincke imine 1a and amines 2a–2av without potassium metabisulfite (Table ; see Supporting Information 8.2 for further details). We observed that most products did not form without the additive, and none formed in a yield of ≥20%. However, Zincke imines 1a–1l were all successful in forming pyridinium salts under the reaction conditions with potassium metabisulfite, underscoring the importance of the additive for reaction robustness. Additionally, 37 out of the 48 amines were successful in forming ≥20% pyridinium product with at least three Zincke imines. These examples demonstrate that the reaction tolerates various amine classes, spanning from simple aliphatic amines to more complex (hetero)­benzylic amines, β-aryl amines, amino alcohols, amino heterocycles, protected diamines, and amino esters. Notably, most of the salts generated in this study retain the stereochemistry of the chiral amine. Pyridinium salts derived from heterobenzylic amines and ∝-amino esters epimerize under the reaction conditions to different degrees (see Supporting Information Section 8.4). Although the bulk of the amines were successful in pyridinium formation, 2e, 2j, 2o, 2v, 2ae, 2ag, 2ah, 2am, 2as, 2at, and 2au formed <20% product with most of the Zincke imines tested. Our analysis of these reaction wells indicated this was often due to product decomposition under the reaction conditions or a poor transamination process, as evidenced by UPLC-MS detection of the parent pyridine and corresponding elimination byproducts, or the unreacted Zincke imine, respectively (see Supporting Information 8.5). The bottom of Table presents examples of pyridiniums formed in the HTE screen. These representative examples demonstrate the method’s robustness across substantial variations in both Zincke imine and amine coupling partners, enabling access to libraries of diverse piperidine precursors.

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Scope enantioenriched (α-chiral)­amines (2a–2av) explored in high-throughput experimentation. Successful amines formed ≥ 20% product with at least 3 Zincke imines. Yields calculated by UPLC-MS-CAD analysis with noscapine as an external calibrant.

3. High-Throughput Experimentation for Pyridinium Salt Formation .

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a

12 × 48 screen: 7.5 μmol 1a–1l, 11.25 μmol 2a–2av, 15 μmol K2S2O5, 0.2 M in MeOH.

b

Yields calculated by UPLC-MS-CAD analysis with noscapine as an external calibrant.

c

Counterions are omitted for clarity.

HTE Validations and Reaction Improvements

Next, we validated the UPLC-CAD yields using quantitative 1H NMR analysis and isolated the products on preparative scale (Table ). Although pyridiniums generally formed in higher yields on a larger reaction scale, the UPLC-CAD analysis provided reasonable estimates of reaction outcomes (see Supporting Information Section 8.3 for additional validations). Isolation via LLE and precipitation readily accessed the pyridinium salt products formed in the HTE screen on preparative scale (3o–3t).

4. Preparative Scale 1H NMR Validations of Pyridinium Salts Formed in HTE Screening .

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a

Isolated yields on 1.5 mmol scale are shown.

b

Yields in parentheses calculated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

c

HTE yields calculated by UPLC-MS-CAD with noscapine as an external calibrant.

We then addressed some of the limitations observed in the HTE with adjustments to the reaction conditions. First, running the reaction at 50 °C instead of 70 °C improves the yields of pyridinium salts sensitive to elimination, such as 3o–NHTf (Scheme A). Additional studies in Supporting Information Section 8.5 show general improvement for other pyridinium salts prone to elimination, including salts derived from β-amino esters. However, we still did not see pyridinium salt formation using amines 2e and 2o, even at room temperature. Second, Scheme B demonstrates that amino sugar 2ae will form pyridinium salts without potassium metabisulfite at a lower temperature and shorter time (3e–NHTf). Removing this additive is therefore an option when using sensitive amines and Zincke imines without C2-substituents (vide supra). Third, adding acid and heating the reaction after the recyclization step can improve pyridinium salt formation with electron-deficient amines, such as 3u in Scheme C, as well as amino alcohols and diamines, potentially by promoting the aromatization step of the reaction mechanism (see Supporting Information Section 8.5 for additional examples). Fourth, employing the amine as the limiting reagent can improve yields for pyridiniums with C2-alkyl substituents, such as 3v, and provides practitioners with an alternate protocol when using valuable amines (Scheme D).

6. Reaction Improvements for Forming Pyridinium Salts .

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a Yields calculated by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

Synthetic Applications

We next examined the robustness of one-pot pyridinium formation using 2-phenylpyridine and amine 2a (Scheme A). Without needing to modify the reaction or isolation protocol, we obtained salt 3a in high yield and 99% purity (see Supporting Information Section 9.1.). Furthermore, we demonstrated the synthetic utility for late-stage convergent coupling of complex pyridine and amine fragments (Scheme B). To this end, we performed the selective ring-opening of etoricoxib to couple the resulting Zincke imine with linagliptin under the one-pot conditions developed for C2-alkyl pyridines. Notably, LLE and precipitation provided salt 3af in modest yield, demonstrating the breadth of this strategy in various synthetic stages for pharmaceutical development. Lastly, we demonstrated proof-of-concept for stereoenriched N-alkylpiperidine formation by subjecting three of the pyridinium salts generated in this study to platinum dioxide-catalyzed reduction (Scheme C). We observed that the pyridinium N-substituent can modestly influence the diastereoselectivity when C2- groups are present (5a and 5b). Alternatively, C3-substituted pyridinium salts do not exhibit the same stereocontrol by the N-substituent, such as 5c, which forms in good yield as a nearly 1:1 mixture of diastereomers. There are several other approaches to improving diastereocontrol during pyridinium salt reductions, including exploiting ligand effects in metal-catalyzed reductions, regent-based additions, and the use of designed N-substituents. ,,,

7. Synthetic Applications for Enantioenriched N-Alkylpyridinium Salt Formation .

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a Isolated yields are shown.

Conclusions

In summary, we have developed a robust platform for synthesizing enantioenriched N-alkylpyridinium salts as N-(α-chiral)­alkylpiperidine precursors. Mechanistic investigations revealed that potassium metabisulfite enhances the scope and yield of pyridinium salt formation through a distinct cyclization mechanism. This understanding led to additional improvements in reaction yields for select amines and could have implications in other classes of heterocycle-forming reactions. We employed HTE to assess diverse Zincke imine and enantioenriched amine collections in pyridinium formation and demonstrated their use as piperidine precursors. This strategy can generate diverse and complex libraries for SAR studies and will be directly applicable to medicinal chemists for accessing new piperidine chemical space.

Supplementary Material

ja5c20464_si_001.pdf (20.3MB, pdf)

Acknowledgments

We gratefully acknowledge the National Science Foundation (NSF) Grant Opportunities for Academic Liaison with Industry (GOALI) grant (CHE-2155215) and a generous award from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We also acknowledge Eric Phillips and Qiao Lin for their contributions to the project. R.S.P. acknowledges support from the NSF (CHE-2400056) and computational resources from the Alpine high-performance computing resource jointly funded by the University of Colorado Boulder, the University of Colorado Anschutz, and Colorado State University, and ACCESS through allocation TG-CHE180056. We dedicate this paper to Professor Steven V. Ley in celebration of his 80th birthday.

Glossary

Abbreviations

SAR

structure–activity relationship

THE

high-throughput experimentation

DNP

2,4-dinitrophenyl

LLE

liquid–liquid extraction

PPTS

pyridinium p-toluenesulfonate

PhOH

phenol

PhSH

thiophenol

HRMS

high-resolution mass spectrometry

NMR

nuclear magnetic resonance

UPLC-MS-CAD

ultraperformance liquid chromatography–mass spectrometry-charged aerosol detection

DFT

density-functional theory

PES

potential energy surface

PCM

polarizable continuum model.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c20464.

  • Experimental procedures and characterization data for all reported compounds, protocols for high-throughput experimentation and details of the analysis methods, and descriptions of computational methods (PDF)

The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the manuscript.

This work was supported by the National Science Foundation (NSF) Grant Opportunities for Academic Liaison with Industry (GOALI) mechanism under award number 2155215 and via a donation from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

The authors declare no competing financial interest.

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