Silver-mediated synthesis of 1,4-dihydropyridine sulfones via [4 + 2] cyclization of N-allenylsulfonamides and enaminones with a 1,3-sulfonyl shift

Abstract

This study outlines the development of an innovative tandem reaction involving [4 + 2] cyclization with 1,3-sulfonyl migration from N-allenylsulfonamides and enaminones, expanding the scope of synthetic methodologies for multifunctional 1,4-dihydropyridine derivatives. The outlined approach furnishes a broad spectrum of sulfonyl-substituted 1,4-dihydropyridine derivatives with good to excellent yields, which can be subsequently converted into diverse sulfonyl-substituted compounds such as pyridine, tetrahydropyridine, and piperidine derivatives through simplified operation. The methodological advancements achieved in this research not only demonstrate the versatility and applicability of the synthesized derivatives across varied substrates and conditions but also present promising potential for the development and diversification of unsymmetrical 1,4-dihydropyridine sulfones.

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Introduction

(Hydro)pyridine sulfone derivatives are important structural frameworks found in many biologically active molecules.¹ Some representative examples include the 5-HT₆ receptor antagonist intepirdine,² neutrophil elastase inhibitor alvelestat,³ CXCR2 antagonist danirixin,⁴ and active structure RWJ 22108⁵ (Fig. 1). Among these N-heterocycles, the synthesis of 1,4-dihydropyridines (1,4-DHPs) has attracted wide attention in view of their feasibility for further functional modification.⁶ For their preparation, the Hantzsch condensation proves to be an effective method leading to symmetrical 1,4-DHPs.⁷ In order to enrich the structure of 1,4-DHPs and better regulate their activities, recent efforts have focused on the synthesis of unsymmetrical structures tethered by a functional group,⁸ such as β-sulfonylation of piperidine⁹ and [4 + 2] annulation of N-tosylated α,β-imides and aldehydes (Scheme 1a).¹⁰ Despite advancements, constructing unsymmetrical 1,4-DHPs with active groups remains a high-priority objective.

Fig. 1 Selected examples of biologically active (hydro)pyridine sulfones.

Scheme 1 Design of [4 + 2] cyclization of N-allenylsulfonamides and enaminones with a 1,3-sulfonyl shift.

Concurrently, enaminones bearing the active carbonyl and amino groups show unique reactivities in organic transformations,¹¹ especially for the installation of N-heterocycles through C–H activation.¹² Nevertheless, reports on the synthesis of 1,4-DHPs from enaminones are still scarce (Scheme 1b).¹³ Hence, it is still of great significance to construct functionalized 1,4-DHPs with enaminones. Inspired by the interesting N- to C-sulfonyl migration,¹⁴ we envisage that [4 + 2] cascade cyclization of N-allenylsulfonamides¹⁵ and enaminones with a 1,3-sulfonyl shift may be achieved for the synthesis of 1,4-dihydropyridine sulfones (Scheme 1c). If successful, a diversity of functionalized pyridine, tetrahydropyridine, and piperidine derivatives containing a sulfone group can be obtained through simple conversion.

Herein, we describe an Ag-promoted tandem reaction involving 1,3-sulfonyl migration/[4 + 2] cycloaddition to synthesize 1,4-dihydropyridine sulfones. This approach employs the easily prepared N-allenylsulfonamides and enaminones as the raw materials, showcasing the advantages of wide substrate scope and easy derivatization to pyridine, tetrahydropyridine and piperidine substituted with a sulfonyl group.

Results and discussion

To validate this hypothesis, we initiated our synthetic exploration by investigating the reaction between enaminone 1a and N-allenylsulfonamide 2a (Table 1). Employing [Cp*RhCl₂]₂ as a catalyst and AgOAc as the additive in DCE at 100 °C for 12 hours resulted in the formation of the desired 1,4-dihydropyridine sulfone 3a with an 86% yield¹⁶ (entry 1). Interestingly, we observed that the reaction could also proceed without [Cp*RhCl₂]₂ (entry 2), but no product formation occurred without AgOAc (entry 3). Subsequently, we tested various additives including copper acetate, silver carbonate, and silver trifluoroacetate, but these led to either no product or products in low yields (entries 4–6). Reducing the quantity of silver acetate to 1.0 equivalent yielded only 65% of the product (entry 7). Temperature proved crucial and lowering it to 80 °C resulted in only a trace amount of 3a (entry 8). Attempts with different solvents such as acetonitrile and 1,4-dioxane could not improve the yield (entries 9 and 10). Thus, the optimized conditions are identified as follows: enaminones reacting with 1.5 equivalents of N-allenylsulfonamides in DCE at 100 °C for 12 hours, facilitated by 2.0 equivalents of silver acetate.

Table 1 Optimization of the reaction conditions^a

Entry	Additive (equiv.)	Solvent	T (°C)	Yield^b (%)
a Reaction conditions: enaminone 1a (0.4 mmol, 1.0 equiv.), N-allenylsulfonamide 2a (0.6 mmol, 1.5 equiv.), additive, and solvent (1.5 mL) at a specified temperature for 12 h. b Isolated yields based on 1a. c [Cp*RhCl2]2 (2.0 mol%).
1^c	AgOAc (2.0)	DCE	100	86
2	AgOAc (2.0)	DCE	100	88
3	—	DCE	100	0
4	Cu(OAc)2 (2.0)	DCE	100	Trace
5	Ag2CO3 (2.0)	DCE	100	30
6	AgTFA (2.0)	DCE	100	28
7	AgOAc (1.0)	DCE	100	65
8	AgOAc (2.0)	DCE	80	Trace
9	AgOAc (2.0)	MeCN	100	80
10	AgOAc (2.0)	1,4-Dioxane	100	21

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This reaction exhibited remarkable versatility. Both aromatic and alkyl-substituted, linear and cyclic enaminones led to a diverse array of 1,4-dihydropyridine sulfones 3a–q, with yields ranging from 40–92% (Scheme 2). X-ray crystallography validated the structure of 3a. For phenyl-substituted enaminones, every isomer, ortho-, meta-, and para-substituted, responded well, with the para-substituted forms outperforming due to presumed lower steric hindrance (1fvs.1b, 1d, 1hvs.1c, 1e). Electron-donating groups such as methyl in the ortho position (1b) performed better than those in the meta position (1d), whereas electron-withdrawing groups such as fluorine showed an inverse relationship. Various aromatic substituents and alkyl groups also demonstrated compatibility, delivering products 3l–p in 43–81% yields. Notably, cyclic enaminone 1q proved to be an effective substrate, achieving the target tetrahydroquinolin-5(1H)-one 3q in 40% yield. The versatility and compatibility of the substrates underscored the broad applicability of this methodology.

Scheme 2 Scope of enaminones. Reaction conditions: enaminone 1 (0.4 mmol, 1.0 equiv.), N-allenylsulfonamide 2a (0.6 mmol, 1.5 equiv.), AgOAc (0.8 mmol, 2.0 equiv.), DCE (1.5 mL), 100 °C, and 12 h. Isolated yields based on 1.

Next, the scope of N-allenylsulfonamides was expanded under the optimized reaction conditions (Scheme 3). First, different N-sulfonyl groups were investigated, and it was found that simple phenyl 2b, fused naphthyl 2c, alkyl 2d, and dimethylamino 2e substituted sulfonyl groups could successfully migrate to produce various 1,4-dihydropyridine sulfones 3r–u in 56–78% yields. Then, a variety of N-substituents such as methyl 2a, easily removable benzyl 2f and p-methoxybenzyl 2g, functionalized trifluoroethyl 2h, chiral secondary carbon chain 2i, and aromatic ring 2j have also been studied and can be well converted into the desired products 3a, 3s, 3v–y. Finally, internal N-allenylsulfonamide 2k has also been attempted, and it is gratifying that 4-substituted 1,4-dihydropyridine 3z has also been isolated in a yield of 21%.

Scheme 3 Scope of N-allenylsulfonamides. Reaction conditions: enaminone 1a (0.4 mmol, 1.0 equiv.), N-allenylsulfonamide 2 (0.6 mmol, 1.5 equiv.), AgOAc (0.8 mmol, 2.0 equiv.), DCE (1.5 mL), 100 °C, and 12 h. Isolated yields based on 1a.

Given the multifunctional nature of unsymmetrical 1,4-dihydropyridine sulfones, characterized by unsaturated structures, diverse double bonds, and carbonyl groups, we delved deeper into exploring the potential diversification of these compounds. Initially, a 5 mmol scale reaction yielded N-benzyl-protected 3r in 81% yield. Subsequent conversions of 3r and 3v are outlined in Scheme 4. Triethylsilane selectively reduced the sulfonyl group-bearing double bond in trifluoroacetic acid (TFA)¹⁷ to yield tetrahydropyridine sulfone 4a in 82% yield (Scheme 4(i)). Remarkably, treatment of 3r with N,N-diethylaminosulfur trifluoride (DAST) in air at room temperature¹⁸ resulted in deoxofluorinated, debenzylated, and dehydrocyclized pyridine 4b (Scheme 4(ii)). Replacing the N-substituent of 1,4-dihydropyridine sulfone with p-methoxybenzyl facilitated the synthesis of pyridine 4c, achieving 79% yield in TFA in air at room temperature¹⁹ (Scheme 4(iii)). Finally, the reaction of 3v with N-chlorosuccinimide (NCS), followed by the addition of borane, resulted in chlorinated piperidine 4d in 67% yield⁹ (Scheme 4(iv)).

Scheme 4 Diversification of 1,4-dihydropyridine sulfones. Reaction conditions: (i) 1,4-dihydropyridine sulfone 3r (0.5 mmol, 214.5 mg) and Et₃SiH (3.0 equiv.) in TFA (1.5 mL) in air at r.t. for 12 h. (ii) 1,4-Dihydropyridine sulfone 3r (0.5 mmol, 214.5 mg) and DAST (1.5 mmol, 3.0 equiv.) via a syringe in CHCl₃ (1.5 mL) in air at r.t. for 24 h. (iii) 1,4-Dihydropyridine sulfone 3v (0.5 mmol, 229.6 mg) in TFA (1.5 mL) in air at r.t. for 24 h. (iv) 1,4-Dihydropyridine sulfone 3v (0.5 mmol, 229.6 mg) and NCS (0.6 mmol, 1.2 equiv.) in THF (1.5 mL) in air at r.t. for 1.0 h and then BH₃ (1.0 M, 1.0 mL) in air at r.t. for 3 h. Isolated yields.

To investigate whether a 1,3-sulfonyl shift occurred first, enaminone 1 was omitted from the reaction system, revealing no detection of any 2-tosylprop-2-en-1-imine derivative (Scheme 5a). Consequently, based on the observed results and relevant reports,²⁰ a proposed reaction process for the formation of 1,4-dihydropyridine sulfones is illustrated in Scheme 5b. With the assistance of AgOAc, the addition of enaminone 1 to N-allenylsulfonamide 2, accompanied by a 1,3-sulfonyl shift, produced zwitterionic species A. This was followed by intramolecular nucleophilic cyclization yielding tetrahydropyridine B containing an N,N-dimethyl group. Ultimately, 1,4-dihydropyridine sulfone 3 was formed through the elimination of dimethylamine, facilitated by the assistance of silver acetate.

Scheme 5 Proposed process for the formation of 1,4-dihydropyridine sulfones.

Conclusions

In conclusion, we have successfully developed an efficient and practical tandem reaction strategy involving [4 + 2] cyclization with 1,3-sulfonyl migration from N-allenylsulfonamides and enaminones, contributing significantly to the synthesis of multifunctional compounds. This approach has enabled the synthesis of a diverse array of sulfonyl-substituted 1,4-dihydropyridine derivatives in good to excellent yields. These derivatives present vast possibilities for further conversion into structurally diverse compounds such as sulfonyl-substituted pyridine, tetrahydropyridine, and piperidine derivatives through simple operation. The systematic synthetic exploration carried out in this study has demonstrated substantial versatility and applicability across varying substrates and conditions, underlining the potential for further exploration and diversification of unsymmetrical 1,4-dihydropyridine sulfones. The continuation of constructing functionalized 1,4-dihydropyridines through multi-component cascade reactions and their applicability in drug synthesis are the current focal points of ongoing investigations in our laboratory.

Author contributions

S. Zhou, S.-F. Dong, X. Zhang, and S.-Y. Zhang performed the experiments. S. Zhou analyzed the experimental data. J.-S. Tian conceived the project and drafted the paper. J.-S. Tian and T.-P Loh supervised the project and reviewed the paper.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge the Fundamental Research Funds for the Central Universities (G2020KY0501, D5000210701), the Natural Science Basic Research Plan of Shaanxi Province (2023-JC-YB-109), and the grant of MOE-Tier 1 (M4012045.110 RG12/18-(S)) for the generous financial support.

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, characterization of the synthesized compounds, NMR spectra, and X-ray crystallographic data of 3a. CCDC 2186305. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo01681a

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