Insights for diastereoselectivity in synthesis of 2,3-dihydropyrroles by photochemical ring contraction of 1,4-dihydropyridines

doi:10.1016/j.tetlet.2020.152797

Tetrahedron Letters

Volume 65, 16 February 2021, 152797

https://doi.org/10.1016/j.tetlet.2020.152797 Get rights and content

Highlights

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Synthesis 2,3-dihydropyrroles by the photochemical ring contraction.
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The chiralities of 2,3-dihydropyrroles and 1,4-dihydropyridines have stereoconvergence.
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Readily available starting materials, metal-free and easy to handle procedures.

Abstract

Strategies by introducing chiral auxiliaries into the photoreactive substrate 1,4-dihydropyridines, an interesting diastereoselectivity of 2,3-dihydropyrroles in the process of photochemical ring contraction was observed. The diastereoselectivity of (2R,3R) and (2S,3S)-2,3-dihydropyrroles was related to the phenyl group and the chirality of C-4 in 1,4-dihydropyridines and similar to that of 1,4-dihydropyridines. The yields and diastereomeric excess of all obtained products supporting the experimental data were compared and discussed in theoretical calculations. A concise theoretical study was used to explain the diastereoselectivity observed in the photochemical ring contraction of 1,4-dihydropyridines to 2,3-dihydropyrroles.

Graphical abstract

Introduction

Dihydropyrroles and its derivatives are nitrogen-containing five-membered heterocyclic compounds and have unique biological activities in biomedicine, natural products, pesticides, materials and dyes, etc. [1], [2], [3]. The synthesis strategies of dihydropyrrole and its derivatives, mainly including cycloadditions and ring closures, as well as the combining multiple components and the asymmetric catalysis, have attracted the attention of researchers [4]. The 2,3-dihydropyrroles with high diastereoselectivity were synthesized via a photochemical ring contraction of 1,4-dihydropyridines by Yan's group [5]. It was found to be a simpler and convenient method to synthesize (2R,3R) and (2S,3S)-2,3-dihydropyrrole (dr > 20:1). The above 1,4-dihydropyridines were symmetric in structures, the reason that they can decide the diastereoselectivity of (2R,3R) and (2S,3S)-2,3-dihydropyrroles was the geometry characteristic of 1,4-dihydropyridine. Motivated by the previous works, how the asymmetric 1,4-dihydropyridines could make an impact on the photochemical ring contraction. The stereoselectivity of asymmetric 1,4-dihydropyridines to 2,3-dihydropyrroles will be discussed in details (Scheme 1). The asymmetric 1,4-dihydropyrides with the different ester (such as ethyl and chiral auxiliaries) were synthesized by the Hantzsch reaction [6]. And they were irradiated by LED light (410 nm) under air atmosphere. The structures of the asymmetric 1,4-dihydropyridines and 2,3-dihydropyrroles were determined by ¹H NMR, ¹³C NMR, HRMS and single crystal X-ray diffraction crystallographic analysis. A density functional theory (DFT) calculation was performed to compare and discuss the formation and diastereoselectivitis of (2R,3R) and (2S,3S)-2,3-dihydropyrroles.

Section snippets

Synthesis of asymmetric 1,4-dihydropyridines 2 by Hantzsch reaction

The asymmetric 1,4-dihydropyridines 2 were synthesized by the Hantzsch reaction of benzaldehyde, methyl 3-aminobarboxylate and acetoacetic ester 1 (Scheme 2) [5], [7], [8]. The compound 1 were obtained by the transesterification reported by Olfa et al. in about 80% yield [9]. The chiral auxiliaries (d-menthol, Cinchonine and Quinine) were introduced into acetoacetic ester 1 and resulted in the diastereoisomer of 1,4-dihydropyridines 2. When compounds 1 were condensated with benzaldehyde and

Synthesis of 2,3-dihydropyrrole 3 by photochemical ring contraction

The 1,4-dihydropyridine 2 was irradiated in 80% ethanol solvent by the LED light (410 nm) under air atmosphere (Scheme 3), and the results were listed in Table 2. The overall yields of compounds 3 were about 48.7% ~70.1% except compound 3 g (R = NO₂) (entry 8). The substituents R on the benzene ring had no significant effect on the yields of the compounds 3, and the introduction of chiral auxiliaries also had no significant effect on the yields of compounds 3 (entry 3–6). Without a chiral

Proposition of mechanism and theoretical calculations

Based on the photooxidation and rearrangement mechanism of singlet oxygen, the possible mechanism of compounds 3 was proposed via the key intermediate of M which was formed by the singlet oxygen attacking the double bonds of 1,4-dihydropyridine [14], [15], [16], [17]. Compound (4R)–2c was selected for the discussion of mechanism and stereochemical process (Scheme 4). First, singlet oxygen is generated by LED irradiation with the O₂ for the singlet oxygen is the lowest electronic excited state.

Conclusions

In summary, a series of asymmetric 1,4-dihydropyridines emerged by chiral auxiliary of d-menthol were synthesized in the yields of about 80% with a diastereomeric ratio of 59:41 to 70:30. The diastereoisomeric 1,4-dihydropyridines gave the (2R,3R) and (2S,3S)-2,3-dihydropyrroles stereospecifically by the photochemical ring contraction in the yields of about 55% with a diastereomeric ratio of 64:36 to 70:30. The diastereoselectivity of the 2,3-dihydropyrroles was stereoconvergent and caused

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

This work was supported by the Beijing Natural Science Foundation [grant numbers 2192004].

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Citation Excerpt :
Meanwhile, the photocleavage reaction is the best strategy to remove the protective group, which can selectively remove the protective group in high yield, so that the parent molecule was free from undesired reactions [40,41]. To date, the theoretical and experimental studies on the photochemical reactions of the analogues of 4H-pyran have mainly focused on the [2 + 2] photocycloaddition reaction of 1,4-cyclohexadienes, 1,4-dihydropyridines, 1,4-dihydropyrazines, and 4H-thiopyrans [42–50]. The photochemical reactions of 1,4-dihydropyridine are mainly [2 + 2] photocycloaddition reaction (Fig. 2A), ring contraction reaction (Fig. 2B), and aromatization (Fig. 2C).
In this article, we have investigated the photochemical reactions of 4-aryl-4H-pyran and found that the structural symmetry had a significant influence on its photochemical behavior. When symmetric 4-aryl-4H-pyran was used, such as diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylate, mainly underwent [2 + 2] photocycloaddition reaction. While asymmetric 4-aryl-4H-pyran, such as 2-amino-3-cyano-4-aryl-4H-pyrans, mainly underwent photocleavage reactions. To speculate the reaction mechanism, density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations were carried out at the B3LYP-D3/def2TZVP//B3LYP-D3/6-31G(d) level. The results showed that diethyl 2,6-dimethyl-4-aryl-4H-pyran-3,5-dicarboxylate underwent a two-step [2 + 2] photocycloaddition to give 3,9-dioxatetraasterane derivatives via an intermolecular and an intramolecular reaction. And the 2-amino-3-cyano-4-aryl-4H-pyran underwent a ring cleavage to produce the conjugated diene derivatives. To explain the different photochemical behaviors of 4-aryl-4H-pyrans, electron spin density, frontier molecular orbitals (FMOs) analysis, electron-hole analysis and root-mean-square-deviation (RMSD) analysis were performed.
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View full text

Insights for diastereoselectivity in synthesis of 2,3-dihydropyrroles by photochemical ring contraction of 1,4-dihydropyridines

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis of asymmetric 1,4-dihydropyridines 2 by Hantzsch reaction

Synthesis of 2,3-dihydropyrrole 3 by photochemical ring contraction

Proposition of mechanism and theoretical calculations

Conclusions

Declaration of Competing Interest

Acknowledgment

Bioorg. Med. Chem. Lett.

Tetrahedron Lett.

Tetrahedron Lett.

J. Chin. Chem. Lett.

Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions

Tetrahedron

A new class of linear tetrapyrroles: acetylenic 10,10a-didehydro-10a-homobilirubins

J. Org Chem.

Total synthesis of (−)-spirotryprostatin B: synthesis and related studies

J. Am. Chem. Soc.

Condensationprodukte aus Aldehydammoniak und Ketoniartigen Verbindungen

Chemische Berichte

Concise synthesis of enantiopure α-trifluoromethyl alanines, diamines, and amino alcohols via the strecker-type reaction

J. Org Chem.

General and efficient transesterification of β-keto esters with various alcohols using Et3N as a Brønsted base additive

Synth. Commun.

An efficient synthesis of enantiomerically pure (R)-pipecolic acid, (S)-proline, and their N-alkylated derivatives

J. Org Chem.

General and efficient transesterification of β-keto esters with various alcohols using Et₃N as a Brønsted base additive