Next Article in Journal
Large-Scale Profiling of Coding and Long Noncoding Transcriptomes in the Hippocampus of Mice Acutely Exposed to Vaporized CBD or THC
Previous Article in Journal
The 3D Language of Cancer: Communication via Extracellular Vesicles from Tumor Spheroids and Organoids
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 15
10.3390/ijms26157105
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Facile Synthesis of Polysubstituted Pyridines via Metal-Free [3+3] Annulation Between Enamines and β,β-Dichloromethyl Peroxides

by
Yangyang Ma
1,
Hua Zhang
2,
Zhonghao Zhou
3,*,
Chenyang Yang
1,
Wenxiao Chang
1,
Mohan Li
1,
Yapei Zheng
1,
Weizhuang Zhang
4,
Huan Yue
1,
Changdong Chen
1,
Ming La
1 and
Yongjun Han
1,*
1
School of Chemical & Environmental Engineering, Pingdingshan University, Pingdingshan 467000, China
2
College of Medicine, Pingdingshan University, Pingdingshan 467000, China
3
School of Material Science and Engineering, Dalian Jiaotong University, Dalian 116028, China
4
Malaga School of Engineering, Pingdingshan University, Pingdingshan 467000, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(15), 7105; https://doi.org/10.3390/ijms26157105
Submission received: 20 June 2025 / Revised: 10 July 2025 / Accepted: 17 July 2025 / Published: 23 July 2025
(This article belongs to the Section Physical Chemistry and Chemical Physics)
Browse Figures
Versions Notes

Abstract

Our work introduces a facile and efficient metal-free [3+3] annulation approach for the synthesis of polysubstituted pyridines via the reaction between β-enaminonitriles and β,β-dichloromethyl peroxides. This strategy operates under mild conditions, demonstrating broad substrate scope and excellent functional group tolerance. Mechanistic investigations suggest that the reaction proceeds through a Kornblum–De La Mare rearrangement followed by SNV-type C-Cl bond cleavage and intramolecular cyclization/condensation. By circumventing the need for transition metal catalysts or radical initiators, our method offers practical utility in organic synthesis and provides a new avenue for the rapid construction of complex pyridine scaffolds.

1. Introduction

The pyridine heterocyclic framework demonstrates exceptional functional versatility across pharmaceutical, agrochemical, and materials science applications (Figure 1), which arises from its synergistic interplay of electronic delocalization and nitrogen-centered acidity/basicity [1,2,3,4]. This structural feature enables nitrogen to mediate hydrogen bonding, metal coordination, and redox-active transformations and other key mechanistic determinants that underpin its biological activity and technological utility [5]. Consequently, the development of efficient synthetic methodologies for accessing polysubstituted pyridines remains a cornerstone of organic chemistry. In general, there are mainly three intermolecular annulation strategies to assemble various polysubstituted pyridines [1,2,3,4] (Scheme 1): (1) Cyclocondensation of 2,4-dienone derivatives with amines, which activates the dienone’s conjugated π-system with amine nitrogen to form pyridines, though regiocontrol demands precise reaction conditions (path a) [6,7,8,9]. Although this method represents a classical approach for synthesizing pyridines, it is often limited by poor functional group compatibility and demanding reaction conditions. (2) [3+2+1] Annulation of β-substituted-α,β-unsaturated ketones/aldehydes with nitrogen sources and secondary carbonyl compounds, enabling sequential nucleophilic/electrophilic additions but often requiring stoichiometric additives or elevated temperatures (path b) [10,11,12,13,14,15,16]. [3+2+1] Annulation offers modular assembly but typically requires transition metals or radical initiators, which may complicate scalability. And (3) [3+3] annulation of α,β-unsaturated alkynes with enamines, leveraging alkyne triple bonds and enamine enolates for cycloaddition, albeit frequently relying on transition metal catalysts or radical initiators, limiting scalability (path c) [17,18,19,20,21,22,23,24,25,26].
Organic peroxides have attracted widespread attention due to their unique bioactive properties and oxidative capabilities in the fields of biochemistry, pharmaceuticals, and food chemistry [27,28]. Meanwhile, owing to their distinctive reactivity, organic peroxides have been further utilized as key intermediates in organic synthesis, playing a crucial role in enabling various transformations, such as the synthesis of ketones, alcohols, and epoxides [29,30,31]. β,β-Dihaloperoxides as a special peroxide compound exhibit notable advantages including facile synthetic accessibility [32,33,34,35], superior chemical stability [30], and exceptional chemoselectivity [36,37,38,39,40,41] in reactive processes. These attributes render them valuable synthetic building blocks that are extensively utilized in diverse organic transformations and strategic bond-forming reactions [32,33,34,35,36,37,38,39,40,41]. In this context, our work introduces a facile, metal-free [3+3] annulation strategy for the synthesis of polysubstituted pyridines via the reaction of β-enaminonitriles with β,β-dichloromethyl peroxides (Scheme 1d). This approach circumvents the need for transition metals, operates under mild conditions, and demonstrates broad substrate tolerance, offering a practical alternative to existing methods.

2. Results and Discussions

We first examined the reaction between β,β-dichloromethyl peroxide (1a, Table S1) and 3-aminocrotononitrile (2a) in the presence of KOH as the base and MeCN as the solvent; the desired pyridine 3a was obtained in 55% yield, while 31% of the β,β-dichloromethyl peroxide remained unreacted (entry 1, Table 1). Subsequently, in screening with organic bases such as NEt3 and DIPEA (entry 2 and 3), no target product was observed under these conditions, with the starting materials remaining largely unreacted. Replacing organic bases with inorganic such as K3PO4 and Cs2CO3 (entry 4 and 5) similarly failed to effectively promote the reaction, whereas NaOH exhibited a reaction efficiency comparable to that of KOH (entry 6). Various solvents were tested in the reaction, including DMF, DMSO, THF, MeOH, EA, and DCM, among which highly polar solvents DMSO and DMF exhibited superior reactivity. This likely stems from the enhanced solubility of the base in high-polarity solvents. When KOH was employed as the base and DMSO as the solvent, elevating the reaction temperature afforded the target product 3a in 73% yield.
With the optimized conditions established, the scopes of substrates 1 and 2 were investigated (Table 2). Representative results are summarized in Table 2. β,β-dichloromethyl peroxides 1 bearing a variety of functional groups (R = aryl), including both the electron-donating (CH3, tBu, and OCH3) and electron-withdrawing (Cl, Br, and F) groups, reacted smoothly with 3-aminocrotononitrile 2a. The target products 3a–3k were obtained in moderate to good yields regardless of the substitution position (ortho-, meta-, or para-) on the benzene ring. As expected, an additional π-extended system such as naphthalene (3l) was also applicable to this transformation. Similarly, the 2,3,5,6- tetrasubstituted product 3m was obtained in 63% yield. When the methyl of 2a is replaced with a phenyl (2b), the target product 3n can be obtained with 72%. Moreover, substitution of the cyanomethyl group in 2a with other electron-withdrawing substituents, such as ketone (2c) or ester (2d), yielded the desired products 3o (64%) and 3p (67%), respectively.
We further performed 1.0 mmol scale experiments under the modified reaction conditions and the desired product 3a was obtained in 63% yield (Table 2). And the synthesized 3-cyanopyridine can be utilized in further chemical transformations, such as hydrolysis and Hofmann rearrangement, which have been demonstrated by Dai and colleagues [42].
On the basis of the results presented above and reports in the literature, a plausible mechanism for this [3+3] annulation reaction was proposed (Scheme 2) [37,38,39]. The base-mediated Kornblum–De La Mare rearrangement of peroxide 1 and the further elimination of one molecule of HCl affords the key β-chloro enone B. Concurrently, β-enamine bearing electron-withdrawing groups (2) undergoes base-induced deprotonation, resulting in the generation of a resonance-stabilized carbon anion D. Then, SNV-type C−Cl bond cleavage of B with the carbanion of D preferentially and readily produces the intermediate E. Subsequent intramolecular cyclocondensation via F leads to the formation of the desired product 3.

3. Materials and Methods

3.1. General Information

1H NMR spectra were recorded on a Bruker (Massachusetts, USA) 400/600 MHz spectrometer and the chemical shifts were reported in parts per million (δ) relative to internal standard TMS (0 ppm) for CDCl3. The peak patterns are indicated as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; m, multiplet; q, quartet. The coupling constants, J, are reported in Hertz (Hz). 13C NMR spectra were obtained at 100 MHz and 150 MHz and referenced to the internal solvent signals (the central peak is 77.0 ppm in CDCl3) and to the internal solvent signals (the central peak is 39.9 ppm in DMSO). CDCl3 and DMSO were used together as the NMR solvent. APEX II (Bruker Inc., Karlsruhe, Germany) was used for ESI-MS and EI-MS. IR spectra were recorded by means of a Bruker Tensor 27 infrared spectrometer. Flash column chromatography was performed over silica gel 200–300. All reagents were weighed and handled in air at room temperature. All chemical reagents were purchased from Alfa (Shanghai, China), Acros (Shanghai, China), Aldrich (Shanghai, China), TCI (Shanghai, China), Energy (Shanghai, China), and J&K (Shanghai, China) and used without further purification.

3.2. General Procedures for the Synthesis of β,β-Dichloromethyl Peroxides 1

A 25 mL round-bottom flask equipped with a magnetic stir bar was charged with CuI (1.9 mg, 1.0 mol%), alkene (1.0 mmol), CHCl3 (2.5 mL), acetone (2.5 mL), DIPEA (870 uL, 5.0 eq.), and 70% aqueous TBHP (650 μL, 5.0 eq.) in the order listed. The flask was placed in a water bath and allowed to stir at room temperature for 2–5 h. The resulting mixture and the solvent were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the peroxides 1a–1m (isolated yields: 83–91%) [24].

3.3. General Procedures for the Synthesis of Pyridines 3

To a Schlenk tube were added KOH (0.6 mmol), 2 (0.4 mmol), dichloromethyl-peroxides (1a–1r) (0.2 mmol), and DMSO (2.0 mL) at room temperature and the resulting solution was stirred for 5 h. The resulting mixture and the solvent were evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: ethyl acetate/petroleum ether) to give the polysubstituted pyridines (3a–3p).
2-Methyl-6-(p-tolyl)nicotinonitrile (3a). (32.4 mg, 78%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 2.82 (s, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 159.7, 140.7, 140.5, 134.9, 129.7, 127.3, 117.5, 116.9, 106.5, 23.9, 21.4; HRMS (ESI) calcd for C14H13N2+ [M+H+]: 209.1073; found: 209.1066.
6-(4-(Tert-butyl)phenyl)-2-methylnicotinonitrile (3b). (36.5 mg, 73%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 2.83 (s, 3H), 1.36 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.5, 159.8, 153.8, 140.5, 135.0, 127.2, 126.0, 117.5, 117.1, 106.5, 34.9, 31.2, 23.9; HRMS (ESI) calcd for C17H19N2+ [M+H+]: 251.1543; found: 251.1534.
6-(4-Methoxyphenyl)-2-methylnicotinonitrile (3c). (34.9 mg, 71%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 8.03–8.01 (m, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.02–7.00 (m, 2H), 3.87 (s, 3H), 2.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 161.5, 159.3, 140.5, 130.2, 128.9, 117.6, 116.4, 114.4, 106.0, 55.4, 23.9; HRMS (ESI) calcd for C14H13N2O+ [M+H+]: 247.0842; found: 247.0832.
2-Methyl-6-phenylnicotinonitrile (3d). (27.5 mg, 78%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.53–7.47 (m, 3H), 2.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 159.8, 140.7, 137.7, 130.4, 129.0, 127.4, 117.4, 117.3, 107.0, 23.9; HRMS (ESI) calcd for C13H11N2+ [M+H+]: 195.0917; found: 195.0912.
6-(4-Chlorophenyl)-2-methylnicotinonitrile (3e). (31.9 mg, 70%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.7, 158.4, 140.8, 136.7, 136.1, 129.2, 128.7, 117.2, 117.1, 107.3, 23.9; HRMS (ESI) calcd for C13H10ClN2Na+ [M+H+]: 229.0527; found: 229.0519.
6-(4-Bromophenyl)-2-methylnicotinonitrile (3f). (34.8 mg, 64%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 7.94–7.91 (m, 3H), 7.64–7.62 (m, 3H), 2.83 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 161.7, 158.5, 140.8, 136.5, 132.2, 128.9, 125.1, 117.2, 117.0, 107.3, 23.9; HRMS (ESI) calcd for C13H10BrN2+ [M+H+]: 273.0022; found: 273.0032.
6-(4-Fluorophenyl)-2-methylnicotinonitrile (3g). (26.3 mg, 62%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 8.07–8.04 (m, 2H), 7.93 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 8.6 Hz, 2H), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3 (d, J = 251.7 Hz), 161.7, 158.6, 140.8, 133.8, 129.4 (d, J = 8.6 Hz), 117.3, 117.0, 116.0 (d, J = 21.9 Hz), 23.9; 19F NMR (564 MHz, CDCl3) δ −110.4 (s, 1F); HRMS (ESI) calcd for C13H10FN2+ [M+H+]: 213.0832; found: 213.0818.
6-(2-Chlorophenyl)-2-methylnicotinonitrile (3h). (33.2 mg, 73%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.3); white solid; 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.61–7.59 (m, 1H), 7.50–7.48 (m, 1H), 7.42–7.37 (m, 2H), 2.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 159.5, 139.8, 137.8, 132.1, 131.5, 130.6, 130.4, 127.3, 122.1, 117.1, 107.7, 23.8; HRMS (ESI) calcd for C13H10ClN2+ [M+H+]: 229.0527; found: 229.0520.
6-(2,5-Dimethylphenyl)-2-methylnicotinonitrile (3i). (29.3 mg, 66%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.4); white solid; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.19–7.12 (m, 3H), 2.82 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.1, 161.2, 140.0, 138.7, 135.7, 132.7, 131.1, 130.1, 130.0, 121.2, 117.3, 106.7, 23.9, 20.9, 19.7; HRMS (ESI) calcd for C15H15N2+ [M+H+]: 223.1230; found: 223.1224.
2-Methyl-6-(m-tolyl)nicotinonitrile (3j). (26.3 mg, 63%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.4); white solid; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 780 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 2.84 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 160.0, 140.6, 138.7, 137.7, 131.2, 128.9, 128.1, 124.5, 117.4, 106.8, 23.9, 21.5; HRMS (ESI) calcd for C14H13N2+ [M+H+]: 209.1073; found: 209.1068.
6-(3-Chlorophenyl)-2-methylnicotinonitrile (3k). (33.7 mg, 74%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.4); white solid; 1H NMR (400 MHz, CDCl3) δ 8.07–8.06 (m, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.92–7.89 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.46–7.41 (m, 2H), 2.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 158.2, 140.9, 139.4, 135.2, 130.3, 130.2, 127.6, 125.4, 117.4, 117.1, 107.6, 23.9; HRMS (ESI) calcd for C13H10ClN2+ [M+H+]: 229.0527; found: 229.0519.
2-Methyl-6-(naphthalen-2-yl)nicotinonitrile (3l). (34.6 mg, 71%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.5); white solid; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.15 (dd, J = 1.8 Hz, 8.6 Hz, 1H), 7.95 (d, J = 8.1 Hz, 3H), 7.89–7.87 (m, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.57–7.53 (m, 2H), 2.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 159.6, 140.7, 134.9, 134.3, 133.3, 129.0, 128.8, 127.8, 127.6, 127.4, 126.7, 124.3, 117.5, 117.4, 106.9, 24.0; HRMS (ESI) calcd for C17H13N2+ [M + H+]: 245.1073; found: 245.1063.
2,5-Dimethyl-6-phenylnicotinonitrile (3m). (26.2 mg, 63%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.5); white solid; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.50–7.41 (m, 4H), 2.76 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.6, 158.5, 142.1, 139.2, 128.9, 128.8, 128.5, 128.4, 117.3, 107.2, 23.3, 19.5; HRMS (ESI) calcd for C14H13N2+ [M+H+]: 209.1073; found: 209.1065.
2-Phenyl-6-(p-tolyl)nicotinonitrile (3n). (38.8 mg, 72%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:20, Rf = 0.5); white solid; 1H NMR (400 MHz, CDCl3) δ 8.08–8.03 (m, 5H), 7.76 (d, J = 8.2 Hz, 1H), 7.57–7.50 (m, 3H), 7.31 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 159.7, 142.4, 141.0, 137.6, 134.7, 130.2, 129.7, 129.0, 128.6, 127.4, 118.4, 117.4, 104.7, 21.5; HRMS (ESI) calcd for C19H15N2+ [M+H+]: 271.1230; found: 271.1219.
1-(2-Methyl-6-(p-tolyl)pyridin-3-yl)ethan-1-one (3o). (28.8 mg, 64%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:30, Rf = 0.4); white solid; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 2.84 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 158.7, 158.6, 139.9, 138.0, 135.6, 130.4, 129.6, 127.2, 116.9, 29.3, 25.4, 21.4; HRMS (ESI) calcd for C15H16N2O+ [M+H+]: 226.1226; found: 226.1218.
Methyl 2-methyl-6-(p-tolyl)nicotinate (3p). (32.3 mg, 67%). Isolated by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1:30, Rf = 0.4); white solid; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 3.93 (m, 3H), 2.91 (s, 3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 160.0, 159.2, 139.9, 139.3, 135.7, 129.6, 127.2, 122.9, 117.0, 52.1, 25.3, 21.4; HRMS (ESI) calcd for C15H16NO2+ [M+H+]: 242.1176; found: 242.1165.

4. Conclusions

In summary, we have developed a simple and efficient method for the synthesis of pyridines under a metal-free [3+3] annulation strategy of β,β-dichloromethyl peroxides and β-enaminonitriles. With this protocol, a series of polysubstituted pyridines were afforded in moderate to good yields under ambient conditions. The operational simplicity and good functional group compatibility would render this protocol a useful tool in organic synthesis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms26157105/s1.

Author Contributions

Synthesis and characterization, Y.M., H.Z., C.Y., M.L. (Mohan Li), W.C. and Y.Z.; Data curation, Y.M., H.Z., C.Y. and Z.Z.; Writing—original draft preparation, W.Z., H.Y. and Y.H.; Writing—review and editing, C.C., Y.M. and Z.Z.; Funding acquisition, Y.M., H.Y., M.L. (Ming La) and Y.H. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Natural Science Foundation of Henan Province of China (242300420568), the Key Scientific Programs of Higher Education of Henan Province of China (No. 24B150024, 25B150026), the Doctoral Scientific Research Foundation of Pingdingshan University (PXY-BSQD-2023002, PXY-BSQD-2023001), and the Science and Technology Development Program of Henan Province (252102240012, 252102240080).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials (Table S1) and 1H and 13C spectra for 3.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Metal-Free Multicomponent Syntheses of Pyridines. Chem. Rev. 2014, 114, 10829–10868. [Google Scholar] [CrossRef]
  2. Li, J.; Gu, A.; Nong, X.-M.; Zhai, S.; Yue, Z.-Y.; Li, M.-Y.; Liu, Y. Six-Membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications. Chem. Rec. 2023, 23, e202300293. [Google Scholar] [CrossRef]
  3. Reza, A.I.; Iwai, K.; Nishiwaki, N. Recent Advances in Synthesis of Multiply Arylated/Alkylated Pyridines. Chem. Rec. 2022, 22, e202200099. [Google Scholar] [CrossRef]
  4. Matthew, D.H. Recent Strategies for the Synthesis of Pyridine Derivatives. Chem. Eur. J. 2010, 16, 12052–12062. [Google Scholar] [CrossRef]
  5. Vitaku, E.; Smith, D.T.; Njardarson, J.T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257–10274. [Google Scholar] [CrossRef]
  6. de Lera, A.R.; Reischl, W.; Okamura, W.H. On the Thermal Behavior of Schiff Bases of Retinal and Its Analogues: 1,2-Dihydropyridine Formation via Six-π-Electron Electrocyclization of 13-Cis Isomers. J. Am. Chem. Soc. 1989, 111, 4051–4063. [Google Scholar] [CrossRef]
  7. Trost, B.M.; Gutierrez, A.C. Ruthenium-Catalyzed Cycloisomerization-6π-Cyclization: A Novel Route to Pyridines. Org. Lett. 2007, 9, 1473–1476. [Google Scholar] [CrossRef]
  8. Resende, D.I.S.P.; Guieu, S.; Oliva, C.G.; Silva, A.M.S. Synthesis of 2,6-Diaryl-1,2-dihydropyridines through a 6π-Electrocyclization of N-Sulfonylazatrienes. Tetrahedron Lett. 2014, 55, 6585–6588. [Google Scholar] [CrossRef]
  9. Varandas, P.A.M.M.; Rocha, D.H.A.; Paz, F.A.A.; Silva, E.M.P.; Silva, A.M.S. One-Pot Synthesis of Isoquinuclidines via 2,6-Diaryl-1,2-dihydropyridines using (E,E)-Cinnamylideneacetophenones as Templates. Synthesis 2018, 50, 1965–1972. [Google Scholar] [CrossRef]
  10. Allais, C.; Constantieux, T.; Rodriguez, J. Use of β,γ-Unsaturated α-Ketocarbonyls for a Totally Regioselective Oxidative Multicomponent Synthesis of Polyfunctionalized Pyridines. Chem. Eur. J. 2009, 15, 12945–12948. [Google Scholar] [CrossRef] [PubMed]
  11. LiØby-Muller, F.; Allais, C.; Constantieux, T.; Rodriguez, J. Metal-free Michael Addition Initiated Multicomponent Oxidative Cyclodehydration Route to Polysubstituted Pyridines from 1,3-Dicarbonyls. Chem. Commun. 2008, 35, 4207–4209. [Google Scholar] [CrossRef] [PubMed]
  12. Lin, L.-C.; Suresh, S.; Lin, K.-W.; Kavala, V.; Yao, C.-F. One-Pot Knoevenagel/Imination/6π-Azaelectrocyclization Sequence for the Synthesis of Disubstituted Nicotinonitriles. J. Org. Chem. 2023, 88, 10298–10305. [Google Scholar] [CrossRef] [PubMed]
  13. Hilf, J.A.; Holzwarth, M.S.; Rychnovsky, S.D. Route to Highly Substituted Pyridines. J. Org. Chem. 2016, 81, 10376–10382. [Google Scholar] [CrossRef] [PubMed]
  14. Lui, E.K.J.; Hergesell, D.; Schafer, L.L. N-Silylenamines as Reactive Intermediates: Hydroamination for the Modular Synthesis of Selectively Substituted Pyridines. Org. Lett. 2018, 20, 6663–6667. [Google Scholar] [CrossRef]
  15. Verma, R.S.; Khatana, A.K.; Vermaa, D.; Tiwari, B. Organocatalytic Access to 3-Pyridylphosphonates from Vinyl Phosphonates and Aldehydes. Chem. Commun. 2024, 60, 5306–5309. [Google Scholar] [CrossRef]
  16. Zhan, Z.Z.; He, J.P.; Jiang, P.B.; Zhang, M.M.; Wang, H.S.; Luo, N.; Huang, G.S. Cu(II)-Catalyzed Synthesis of 2,3,6-Trisubstituted Pyridines from Saturated Ketone and Alkynones/1,3-Dicarbonyl Compounds. ChemistrySelect 2021, 6, 4160–4165. [Google Scholar] [CrossRef]
  17. Erian, A.W. The Chemistry of β-Enaminonitriles as Versatile Reagents in Heterocyclic Synthesis. Chem. Rev. 1993, 93, 1991–2005. [Google Scholar] [CrossRef]
  18. Petrich, S.A.; Hicks, F.A.; Wilkinson, D.R.; Tarrant, J.G.; Bruno, S.M.; Vargas, M.; Hosein, K.N.; Gupton, J.T.; Sikorski, J.A. The Application of Vinylogous Iminium Salts and Related Synthons to the Preparation of Trisubstituted Pyridines. Tetrahedron 1995, 51, 1575–1584. [Google Scholar] [CrossRef]
  19. Katritzky, A.R.; Denisenko, A.; Arend, M. A Simple and Versatile Route to Novel Conjugated β-Enaminonitriles and Their Application for the Highly Regioselective Synthesis of Nicotinonitriles Using a Vilsmeier-type Reagent. J. Org. Chem. 1999, 64, 6076–6079. [Google Scholar] [CrossRef]
  20. Bagley, M.C.; Dale, J.W.; Bower, J. A New Modification of the Bohlmann-Rahtz Pyridine Synthesis. Synlett 2001, 7, 1149–1151. [Google Scholar] [CrossRef]
  21. Risch, N.; Winter, A. The Vinylogous Mannich Reaction: An Efficient Access to Substituted Nicotinonitriles. Synlett 2003, 13, 1959–1964. [Google Scholar] [CrossRef]
  22. Bagley, M.C.; Lin, Z.; Pope, S.J.A. Rapid Synthesis of 3-Cyanopyridine-Derived Chromophores with Two-dimensional Tunability and Solvatochromic Photophysical Properties. Chem. Commun. 2009, 34, 5165–5167. [Google Scholar] [CrossRef]
  23. Sarkar, D.; Rout, N.; Ghosh, M.K.; Giri, S.; Neue, K.; Reuter, H. Atom-Economical Palladium Carbon-Catalyzed de Novo Synthesis of Trisubstituted Nicotinonitriles. J. Org. Chem. 2017, 82, 9012–9022. [Google Scholar] [CrossRef] [PubMed]
  24. Neff, R.K.; Su, Y.L.; Liu, S.Q.; Rosado, M.; Zhang, X.H.; Doyle, M.P. Generation of Halomethyl Radicals by Halogen Atom Abstraction and Their Addition Reactions with Alkenes. J. Am. Chem. Soc. 2019, 141, 16643–16650. [Google Scholar] [CrossRef] [PubMed]
  25. Duan, X.; Sun, R.; Tang, J.; Li, S.; Yang, X.; Zheng, X.; Li, R.; Chen, H.; Fu, H.; Yuan, M. Facile Synthesis of 2-Methylnicotinonitrile through Degenerate Ring Transformation of Pyridinium Salts. J. Org. Chem. 2022, 87, 7975–7988. [Google Scholar] [CrossRef] [PubMed]
  26. Verma, V.; Schafer, L.L. One-Pot Sequential Hydroamination Protocol for N-Heterocycle Synthesis: One Method to Access Five Different Classes of Tri-Substituted Pyridines. J. Org. Chem. 2023, 88, 1378–1384. [Google Scholar] [CrossRef]
  27. Dembitsky, V.M. Bioactive Peroxides as Potential Therapeutic Agents. Eur. J. Med. Chem. 2008, 43, 223–251. [Google Scholar] [CrossRef]
  28. Gandhi, H.; O’Reilly, K.; Gupta, M.K.; Horgan, C.; O’Learyc, E.M.; O’Sullivan, T.P. Advances in the Synthesis of Acyclic Peroxides. RSC Adv. 2017, 7, 19506–19556. [Google Scholar] [CrossRef]
  29. Liu, W.; Li, Y.; Liu, K.; Li, Z. Iron-Catalyzed Carbonylation-Peroxidation of Alkenes with Aldehydes and Hydroperoxides. J. Am. Chem. Soc. 2011, 133, 10756–10759. [Google Scholar] [CrossRef]
  30. Liu, K.; Li, Y.; Zheng, X.; Liu, W.; Li, Z. Synthesis of α-Estere-β-keto Peroxides via Iron-catalyzed Carbonylationeperoxidation of α,β-Unsaturated Esters. Tetrahedron 2012, 68, 10333–10337. [Google Scholar] [CrossRef]
  31. Chen, Y.; Chen, Y.; Lu, S.; Li, Z. Copper-catalyzed Three-component Phosphorylation–peroxidation of Alkenes. Org. Chem. Front. 2018, 5, 972–976. [Google Scholar] [CrossRef]
  32. Chen, Y.; Li, L.; Ma, Y.; Li, Z. Cobalt-Catalyzed Three-Component Difluoroalkylation-Peroxidation of Alkenes. J. Org. Chem. 2019, 84, 5328–5338. [Google Scholar] [CrossRef] [PubMed]
  33. Cai, S.-Z.; Ge, D.; Sun, L.-W.; Rao, W.; Wang, X.; Shen, Z.-L.; Chu, X.-Q. Three-Component Heteroannulation for Tetrasubstituted Furan Construction Enabled by Successive Defluorination and Dual Sulfonylation Relay. Green Chem. 2021, 23, 935–941. [Google Scholar] [CrossRef]
  34. Chu, X.-Q.; Cheng, B.-Q.; Zhang, Y.-W.; Ge, D.; Shen, Z.-L.; Loh, T.-P. Copper-Catalyzed Three-Component Cyclization of Amidines, Styrenes, and Fluoroalkyl Halides for the Synthesis of Modular Fluoroalkylated Pyrimidines. Chem. Commun. 2018, 54, 2615–2618. [Google Scholar] [CrossRef] [PubMed]
  35. Shi, E.; Liu, J.; Liu, C.; Shao, Y.; Wang, H.; Lv, Y.; Ji, M.; Bao, X.; Wan, X. Difunctionalization of Styrenes with Perfluoroalkyl and tertButylperoxy Radicals: Room Temperature Synthesis of (1-(tertButylperoxy)-2-perfluoroalkyl)-ethylbenzene. J. Org. Chem. 2016, 81, 5878–5885. [Google Scholar] [CrossRef]
  36. Chen, Y.; Li, L.; He, X.; Li, Z. Four-Component Reactions for the Synthesis of Perfluoroalkyl Isoxazoles. ACS Catal. 2019, 9, 9098–9102. [Google Scholar] [CrossRef]
  37. Ma, Y.; Chen, Y.; Lv, L.; Li, Z. Regioselective Synthesis of Emission Color-Tunable Pyrazolo [1,5-a]pyrimidines with β,β-Difluoro Peroxides as 1,3-Bis-Electrophiles. Adv. Synth. Catal. 2021, 363, 3233–3239. [Google Scholar] [CrossRef]
  38. Ma, Y.; Lv, L.; Li, Z. β-Perfluoroalkyl Peroxides as Fluorinated C3-Building Blocks for the Construction of Benzo [4,5]imidazo [1,2-a]pyridines. J. Org. Chem. 2022, 87, 1564–1573. [Google Scholar] [CrossRef]
  39. Ma, Y.; Zhang, H.; Du, X.; Fang, S.; Yin, K.; Du, G.; Tian, Z.; Zhou, Z. β,β-Difluoro Peroxides as Fluorinated C2-Building Blocks for the Construction of Functionalized Indolizines. Molecules 2024, 29, 5927. [Google Scholar] [CrossRef]
  40. Ma, Y.; Chen, Y.; Lou, C.; Li, Z. DABCO-Mediated [4+1] Cycloaddition of β,β-Dihalo Peroxides with Sodium Azide toward Isoxazoles. Asian J. Org. Chem. 2020, 9, 1018–1021. [Google Scholar] [CrossRef]
  41. Zheng, X.; Lv, L.; Lu, S.; Wang, W.; Li, Z. Benzannulation of Indoles to Carbazoles and Its Applications for Syntheses of Carbazole Alkaloids. Org. Lett. 2014, 16, 5156–5159. [Google Scholar] [CrossRef]
  42. Dai, X.-J.; Krolikowski, P.; Murray, J.I.; Wei, C.S.; Dornan, P.K.; Rötheli, A.R.; Caille, S.; Thiel, O.R.; Smith, A.G.; Parsons, A.T. Synthesis of Substituted Pyridines via Formal (3+3) Cycloaddition of Enamines with Unsaturated Aldehydes and Ketones. J. Org. Chem. 2022, 87, 8437–8444. [Google Scholar] [CrossRef]
Ijms 26 07105 sch001
Scheme 1. Synthesis of polysubstituted pyridines from α,β-unsaturated enyne ketones.
Scheme 1. Synthesis of polysubstituted pyridines from α,β-unsaturated enyne ketones.
Ijms 26 07105 sch001
Ijms 26 07105 g001
Figure 1. Representative compounds containing a pyridine substructure.
Figure 1. Representative compounds containing a pyridine substructure.
Ijms 26 07105 g001
Ijms 26 07105 sch002
Scheme 2. Proposed reaction mechanisms.
Scheme 2. Proposed reaction mechanisms.
Ijms 26 07105 sch002
Table 1. Optimization studies a.
Table 1. Optimization studies a.
Ijms 26 07105 i001
EntryBaseSolventT (°C)1a Recovery (%) b3a Yield (%) b
1KOHMeCN253155
2NEt3MeCN2587N.D.
3DIPEAMeCN2589N.D.
4K3PO4MeCN2594N.D.
5Cs2CO3MeCN2591trace
6NaOHMeCN253847
7KOHDMSO25trace73
8KOHDMF252269
9KOHTHF255037
10KOHMeOH257016
11KOHEA2590N.D.
12KOHDCM2587N.D.
13KOHDMSO60trace71
14 cKOHDMSO253752
15 dKOHDMSO25trace76
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (0.6 mmol), solvent (2.0 mL), 5 h, and under air. b Reported yields were based on 1a and determined by 1H NMR using CH2Br2 as an internal standard. c 1a (0.2 mmol), 2a (0.4 mmol), base (0.4 mmol), solvent (2.0 mL), 5 h, and under air. d 1a (0.2 mmol), 2a (0.4 mmol), base (0.8 mmol), solvent (2.0 mL), 5 h, and under air.
Table 2. Scope of the substrates a.
Table 2. Scope of the substrates a.
Ijms 26 07105 i002
Ijms 26 07105 i003
a Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), KOH (0.6 mmol), DMSO (2.0 mL), 25 °C, and 5 h unless otherwise noted. Reported yields were the isolated yields. b Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), KOH (3.0 mmol), DMSO (10.0 mL), 25 °C, and 16 h.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ma, Y.; Zhang, H.; Zhou, Z.; Yang, C.; Chang, W.; Li, M.; Zheng, Y.; Zhang, W.; Yue, H.; Chen, C.; et al. Facile Synthesis of Polysubstituted Pyridines via Metal-Free [3+3] Annulation Between Enamines and β,β-Dichloromethyl Peroxides. Int. J. Mol. Sci. 2025, 26, 7105. https://doi.org/10.3390/ijms26157105

AMA Style

Ma Y, Zhang H, Zhou Z, Yang C, Chang W, Li M, Zheng Y, Zhang W, Yue H, Chen C, et al. Facile Synthesis of Polysubstituted Pyridines via Metal-Free [3+3] Annulation Between Enamines and β,β-Dichloromethyl Peroxides. International Journal of Molecular Sciences. 2025; 26(15):7105. https://doi.org/10.3390/ijms26157105

Chicago/Turabian Style

Ma, Yangyang, Hua Zhang, Zhonghao Zhou, Chenyang Yang, Wenxiao Chang, Mohan Li, Yapei Zheng, Weizhuang Zhang, Huan Yue, Changdong Chen, and et al. 2025. "Facile Synthesis of Polysubstituted Pyridines via Metal-Free [3+3] Annulation Between Enamines and β,β-Dichloromethyl Peroxides" International Journal of Molecular Sciences 26, no. 15: 7105. https://doi.org/10.3390/ijms26157105

APA Style

Ma, Y., Zhang, H., Zhou, Z., Yang, C., Chang, W., Li, M., Zheng, Y., Zhang, W., Yue, H., Chen, C., La, M., & Han, Y. (2025). Facile Synthesis of Polysubstituted Pyridines via Metal-Free [3+3] Annulation Between Enamines and β,β-Dichloromethyl Peroxides. International Journal of Molecular Sciences, 26(15), 7105. https://doi.org/10.3390/ijms26157105

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop