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Rel-(2R, 3S)-2-((Diphenylmethylene)amino)-5-Oxo-5-Phenyl-3-(Thiophen-2-Yl)pentanenitrile

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27 August 2024

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27 August 2024

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Abstract
The reaction of 2-((diphenylmethylene)amino)acetonitrile with (E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one was performed by using 33% NaOH in CH3CN for 30 min at 0°C. The main product - rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile was isolated and characterized by IR, 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS).
Keywords: 
Subject: Chemistry and Materials Science  -   Organic Chemistry

1. Introduction

Non-proteinogenic α-amino acids play an important role in biological systems, which determines the importance of developing synthetic routes for their synthesis [1]. Imines of glycine esters and aminoacetonitrile are useful building blocks for the synthesis of nonproteinogenic α-amino acids and their derivatives [2-4]. O'Donnell Schiff bases have been used for the synthesis of unnatural α-amino acids by alkylation reactions [5-9], aldol reactions [10-12] and Michael additions [13-20].
In our previous work we reported the reaction of 2-((diphenylmethylene)amino)acetonitrile and several arylmethyleneacetophenones in aqueous conditions. The substituted 2-amino-5-oxonitriles obtained were converted to 3,5-diaryl-3,4-dihydro-2H-pyrrole-2-carbonitriles [15].
The aim of present work is the reaction of 2-((diphenylmethylene)amino)acetonitrile with chalcone, containing heterocyclic ring for synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile.

2. Results and Discussion

The synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3) was performed by the Michael reaction of 2-((diphenylmethylene)amino)acetonitrile (1) and (E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one (2) under the conditions previously described by us (33% NaOH in CH3CN at 0°C) [15] for 30 min (Scheme 1).
The reaction proceeds with high diastereoselectivity and the diastereoisomeric ratio 95:5 (1H NMR) was observed for the crude product 3. The major diastereoisomer was isolated with 83% yield after the recrystallization of crude crystalline product from ethyl acetate-methanol. The structure of compound 3 was confirmed by IR and 1H NMR, 13C NMR and HRMS. A rel-(2R,3S)-configuration for the major diastereoisomer of oxonitrile 3 was assigned based on a comparison between the proton NMR spectra of this compound and the proton NMR spectra of oxonitriles, previously reported by us [15].

3. Materials and Methods

3.1. General

All starting chemicals were purchased from Acros Organics and Fisher Scientific GmbH. The nitrile Schiff base 1 [5] and chalcones 2 [21] were prepared according to literature procedures. Reaction and purity of the final compound was monitored by thin-layer chromatography (TLC) on silica gel aluminium plates Kieselgel 60 F254 (Merck), using petroleum ether/acetone (6:1 v/v) as eluent. Melting points were determined on a Boetius micromelting point apparatus and were uncorrected. Infrared spectrum (FT-IR) was acquired on a Nicolet 6700 FT-IR Thermo Scientific infrared spectrophotometer. NMR spectra were recorded in CDCl3, on a Bruker Avance III HD 500, operating at 500.13 MHz for 1H and at 125.76 MHz for 13С. Chemical shifts (δ) are reported in parts per million (ppm) and were referenced to the tetramethylsilane (TMS) as an internal standard. Coupling constants (J) were measured in hertz (Hz). High-resolution mass spectra (HRMS) was obtained with Q Exactive hybrid quadrupole-Orbitrap mass spectrometer (Thetmo Scientific Co, USA) equipped with TurboFlow® LC system, heated electrospray model HESI II on IonMax® (Thetmo Scientific Co, USA).

3.2. Synthesis of rel-(2R,3S)-2-((Diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile

Cooled to 0°C aqueous sodium hydroxide (33% NaOH, 0.75 mL) was added to a cooled (0°C) solution of 2-((diphenylmethylene)amino)acetonitrile (0.55 g, 2.5 mmol) and (E)-1-phenyl-3-(thiophen-2-yl)prop-2-en-1-one (0.54 g, 2.5 mmol) in 1.25 mL CH3CN. The reaction mixture was stirred for 30 min at 0°C. Water (50 mL) was added and the crystalline product 3 was filtered, washed with water to neutral and dried. The crude product was recrystallized from ethyl acetate-methanol. Yield: 83% (0.90 g)
White crystals, m.p.: 154-156˚C (ethyl acetate-methanol). IR (KBr): 2235 (νCN), 1690 (νC=O), 1623 (νC=N), 1595, 1578, 1489, 1446 (νC=C), 764, 695 (γC-H) сm-1. 1H NMR (500.13 MHz, CDCl3) δ (ppm): 3.76, 3.87 (2dd, 2H, 2J = 17.6 Hz, 3J = 8.9 Hz, 3J = 4.6 Hz, CH2CO), 4.32-4.35 (m, 1H, CНC4H3S), 4.55 (d, 1H, 3J = 4.4 Hz, CНCN), 6.90 (dd, 1H, 3J = 5.0 Hz, 3J = 3.6 Hz, aromatic), 6.93-6.95 (m, 3H, aromatics), 7.14-7.15 (m, 1H, aromatic), 7.36-7.39 (m, 2H, aromatics), 7.42-7.48 (m, 6H, aromatics), 7.55-7.59 (m, 1H, aromatic), 7.67-7.69 (m, 2H, aromatics), 7.96-7.98 (m, 2H, aromatics). 13С NMR (125.76 MHz, CDCl3) δ (ppm): 40.59, 41.19, 57.98, 118.18, 124.73, 126.07, 126.72, 127.13, 128.14, 128.27, 128.67, 128.92, 129.24, 129.31, 131.41, 133.35, 135.01, 136.68, 138.30, 141.95, 174.84, 196.91. HRMS (ESI): calculated for C28H22N2OS [M+H]+ m/z 435.1526, found 435.1545.

Supplementary Materials

Figure S1: FT-IR spectrum of compound 3; Figure S2: 1H NMR spectrum of compound 3; Figure S3: 13C NMR spectrum of compound 3; Figure S4: HRMS of compound 3; Figure S5: HRMS/ESI-MS2 spectrum of compound 3; Figure S6: HRMS/ESI-MS2: proposed structure of the fragment ions of compound 3.

Author Contributions

Conceptualization, D.N.T. and V.M.M.; methodology, V.M.M.; writing—original draft preparation, D.N.T. and V.M.M.; writing—review and editing, D.N.T. and V.M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

This work is financially supported by the Sofia University "St. Kl. Ohridski" Scientific Fund (grant 80-10-14/2020).

Conflicts of Interest

The authors declare no conflicts of interest.

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Preprints 116396 sch001
Scheme 1. Synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3).
Scheme 1. Synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3).
Preprints 116396 sch001
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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