Elsevier

Tetrahedron

Volume 76, Issue 41, 9 October 2020, 131502
Tetrahedron

Switching the reactivity of cyanomethylpyridinium salts in the 1,3-cycloaddition conditions with alkyl propiolates to cyanoindolizines or cyanoazaindolizinyl-indolizines

https://doi.org/10.1016/j.tet.2020.131502Get rights and content

Highlights

  • [3 + 2] Cycloaddition methodology optimization to directly obtain 3-cyanoindolizines 3 or 2:1 azaindolizine-indolizine adducts 4.

  • Access to a portfolio of rare 3-cyanoindolizines 3.

  • New 2:1 azaindolizine-indolizine adducts 4 (secured by X-Ray): ethyl or methyl 3-(3-cyanoimidazo[1,2-a]pyridin-2-yl)indolizine-1-carboxylates.

  • Heating-facilitated 1-cyanomethylpyridinium salt dimerization.

  • Functionalization of 3-cyanoindolizines 3.

Abstract

A particular reactivity of 1-cyanomethylpyridinium salts was revealed in the [3 + 2] cycloaddition conditions with alkyl propiolates. Cycloadducts 3 were obtained in reactions carried out at room temperature while refluxing in CH3CN provided unexpected ethyl or methyl 3-(3-cyanoimidazo[1,2-a]pyridin-2-yl)indolizine-1-carboxylates 4. The structure of the new 2:1 azaindolizine-indolizine adducts was secured by X-ray analysis. Methodological efforts have enabled the adjustment of the reactivity towards the formation of 3-cyanoindolizines 3 or cyanoazaindolizine-indolizines 4. A mechanism for the formation of azaindolizine-indolizines was proposed. A portfolio of rare cyanoindolizines and cyanoazaindolizine-indolizines has been successfully obtained.

Introduction

Only few representatives of cyanoindolizines were reported in the literature and they demonstrated very diverse and promising therapeutic potential. The main active derivatives are regrouped in Fig. 1. 1-Cyanoindolizine A displayed in vitro antiproliferative activity on Hep-G2 cell lines [1] (Fig. 1). Derivative B [2], decorated in the same way, disrupted the migration and proliferation of PC3 prostate tumor cells by preventing protein-protein interaction in which the endothelial vascular growth factor (VEGF) is involved (Fig. 1). Indolizine C incorporating a cyano group at position 7 is a potential anti-inflammatory agent, cyclooxygenase (COX)-2 inhibitor [3] (Fig. 1). 2-Cyanoindolizine D is effective against Gram-positive and Gram-negative bacterial strains, with increased potency on Bacillus subtilis UC564 and Vibrio cholera 7201 (Fig. 1) [4]. Antibacterial activity has also been reported for 3-cyanoindolizine E on Mycobacterium tuberculosis (Fig. 1) [5]. 2-Cyanoindolizine F was reported as non-nucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI) [6,7]. The indolizine showed very strong picomolar inhibitory activity toward wild-type HIV-1 (EC50 (WT HIV1) = 0.38 nM [6], Fig. 1) and excellent low nanomolar enzymatic activity against HIV with reverse transcriptase (RT) variants containing the K101P mutation (enzyme EC50 (RT (K101P) = 1.9 nM [7], Fig. 1). 3-Cyanoindolizine G decorated with a salicylic acid moiety is a xanthine oxidase inhibitor in the nanomolar range (Fig. 1) with potential application to reduce the production of uric acid (gouty tophus, gout arthritis or other diseases caused by hyperuricemia) [8].

Our group recently discovered 3-acetylindolizine derivative H with excellent potential to inhibit the cell growth of cancer cell lines, especially MDA-MB-435 melanoma cells (GI50 = 1.8 nM) [9]. In an endeavor to enrich the structure-activity relationships information in this series and to provide additional insights into their anticancer potential, we were interested in the synthesis of a portfolio of compounds bearing a cyano group in position 3 of the indolizine as a withdrawing isostere of the acetyl unit (Fig. 1). The new study mainly focused on the synthesis of key intermediates 3-cyanoindolizines 3 (target compounds, Fig. 1), essential for a future access to the designed phenothiazine-indolizine hybrids. Unexpectedly, some by-products were detected in the crude of this traditional [3 + 2] cycloaddition of cyanomethylpyridinium salt with alkyl propiolate. These new compounds have been isolated and their structure elucidated as cyanoazaindolizinyl-indolizines. A straightforward synthetic pathway was developed which allowed to tune the reactivity and obtain either classical cyanoindolizines or the cyanoazaindolizinyl-indolizines.

Analysis of the literature revealed that only four 3-cyanoindolizines derivatives of interest (methyl 3-cyanoindolizine-1-carboxylate, methyl 3-cyano-7-methylindolizine-1-carboxylate, ethyl 3-cyanoindolizine-1-carboxylate and 3-cyanoindolizine-1-carboxylic acid) have been described via diverse procedures. Their syntheses are mainly based on [3 + 2] cycloadditions and presented in Scheme 1. Methyl 3-cyanoindolizine-1-carboxylate has been obtained in 71% yield from the cycloaddition reaction of ylide generated in situ from 1-(cyanomethyl)pyridinium bromide with methyl acrylate in the presence of MnO2 used as dehydrogenation agent in DMF at 90 °C (pathway 1, Scheme 1) [10]. The same 3-cyanoindolizine has been constructed in the same way and in the same yield by Wang and co-workers [11] with a modified final workup using aqueous HCl (pathway 2, Scheme 1). The methyl 3-cyano-7-methylindolizine-1-carboxylate has also been isolated in 86% yield by 1,3-dipolar cycloaddition of pyridinium N-ylide to methyl acrylate, followed by internal aromatization mediated by MnO2 (pathway 3, Scheme 1). Now, the ethyl 3-cyanoindolizine-1-carboxylate has also been synthesized mainly through 1,3-cycloaddition reaction but using different catalysts and conditions (pathways 4, 6–9, Scheme 1): i) one-pot reaction of pyridine, bromoacetonitrile and ethyl acrylate in imidazolium-based ionic liquid [Omim]Br used to reinforce the final cycloaddition reaction by the noncovalent interactions between the ionic liquid and substrates at 110 °C (55% yield, pathway 4) [12]; ii) reaction of pyridinium salt with ethyl acrylate in the presence of copper acetate monohydrate and sodium acetate in DMF at 80 °C (55% yield, pathway 6) [13]; iii) reaction of pyridinium salt with ethyl acrylate in the presence of Na2CO3 in DMSO at rt, followed by the oxidation of the intermediate with chloranil and final acid treatment (58%, pathway 7) [14]; iv) iodine-mediated cesium acetate-controlled annulation of ethyl 2-(pyridin-2-yl)acetate with acrylonitrile in DCE at 90 °C (42%, pathway 8) [15]; and v) iodine-catalyzed intermolecular oxidative tandem cyclization reaction of acrylonitrile and ethyl 2-(pyridin-2-yl)acetate under metal-free conditions in the presence of TMEDA and TBHP in NMP at 120 °C (30%, pathway 9) [16]. The only free carboxylic acid in the series of 3-cyanopyridine described in the literature is 3-cyanoindolizine-1-carboxylic acid [8]. The acid has been also obtained by cycloaddition reaction of the same ylide with benzyl acrylate operated in chlorobenzene, followed by internal aromatization induced by MnO2. Resulting benzyl ester was next deprotected to generate free carboxylic acid in reductive conditions (pathway 5, Scheme 1).

Herein we report the synthesis of target 3-cyanoindolizines via oxidant free [3 + 2] cycloaddition reaction between pyridinium N-ylides generated in situ from cyanomethylpyridinium salts and triethylamine, and alkyl propiolates (pathway 10, Scheme 1), in the same way as some reactions of other cycloimmonium salts [17,18].

Section snippets

Results/discussion

In the first attempt to obtain methyl 3-cyanoindolizine-1-carboxylate 3a, a [3 + 2] cycloaddition of the dipolarophile methyl propiolate with the pyridinium N-ylide formed in situ from 1-(cyanomethyl)pyridinium chloride 2a was performed. The target indolizine 3a was obtained in modest 32% yield. A supplementary unexpected product was detected in the crude, purified and corresponded to methyl 3-(3-cyanoimidazo[1,2-a]pyridin-2-yl)indolizine-1-carboxylate 4a, isolated in 20% yield (Scheme 2 and

Conclusion

In summary, the investigation of the [3 + 2] cycloaddition of pyridinium N-ylides obtained from 1-cyanomethylpyridinium salts with alkyl propiolates revealed the formation of expected 3-cyanoindolizines along with original by-products. The structure of these by-products was elucidated and secured by X-Ray analysis as ethyl or methyl 3-(3-cyanoimidazo[1,2-a]pyridin-2-yl)indolizine-1-carboxylates. Experiments were next designed to access either the expected 3-cyanoindolizines 3 or the

Experimental section

Starting materials are commercially available and were used without further purification (suppliers: Carlo Erba Reagents S.A.S., Tokyo Chemical Industry Co. Ltd. and Acros Organics). Melting points were measured on an MPA 100 OptiMelt® apparatus and are uncorrected. Nuclear Resonance Magnetic (NMR) were acquired at 400 MHz for 1H NMR and at 100 MHz for 13C NMR, on a Varian 400-MR spectrometer or at 500 MHz for 1H NMR and at 125 MHz for 13C NMR, on a Bruker Avance III 500 MHz spectrometer with

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.

Acknowledgements

We are grateful for financial support from the ‘Ministerul Educației, Cercetării, Tineretului și Sportului’ (Romania) for the I.-M. M.‘s scholarship. The authors also thank the Integrated Center of Environmental Science Studies in the North East Region (CERNESIM) for providing NMR analysis of compounds (the URL for the website of the center is: http://cernesim.uaic.ro/index.php/en/).

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