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

Donka Nikolova Tasheva; Vesela Mihaylova Mihaylova

doi:10.20944/preprints202408.1953.v1

Submitted:

27 August 2024

Posted:

27 August 2024

You are already at the latest version

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:

2-((diphenylmethylene)amino)acetonitrile

;

Michael addition

;

non-proteinogenic aminoacids

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.

References

Hunt, S. The Non-Protein Amino Acids. In Chemistry and Biochemistry of the Amino Acids, 1st ed.; Barrett, G.C. Ed.; Chapman and Hall: London, UK, 1985; pp. 55–85.
O'Donnell, M.J. The Enantioselective Synthesis of α-Amino Acids by Phase-Transfer Catalysis with Achiral Schiff Base Esters. Acc. Chem. Res. 2004, 37, 506–517. [CrossRef]
Nájera, C.; Sansano, J.M. Catalytic Asymmetric Synthesis of α-Amino Acids. Chem. Rev. 2007, 107, 4584–4671. [CrossRef]
Shirakava, S.; Maruoka, K. Recent Developments in Asymmetric Phase-Transfer Reactions. Angew. Chem. Int. Ed. 2013, 52, 4312–4348. [CrossRef]
O’Donnell, M. J.; Polt, R. L. A mild and efficient route to Schiff base derivatives of amino acids. J. Org. Chem. 1982, 47, 2663–2666. [CrossRef]
Meyer, N.; Werner, F.; Opatz, T. One-Pot Synthesis of Polysubstituted Pyrrolidines from Aminonitriles. Synthesis 2005, 6, 945–956. [CrossRef]
He, W.; Wang, Q.; Wang, Q.; Zhang, B.; Sun, X.; Zhang, S. Synthesis of Novel Chiral Phase-Transfer Catalysts and Their Application to Asymmetric Synthesis of α-Amino Acid Derivatives. Synlett 2009, 8, 1311–1314. [CrossRef]
Waser, M.; Gratzer, K.; Herchl, R.; Müller, N. Design, synthesis, and application of tartaric acid derived N-spiroquaternary ammonium salts as chiral phase-transfer catalysts. Org. Biomol. Chem. 2012, 10, 251–254. [CrossRef]
Schettini, R.; De Riccardis, F.; Della Sala, G.; Izzo, I. Enantioselective Alkylation of Amino Acid Derivatives Promoted by Cyclic Peptoids under Phase-Transfer Conditions. J. Org. Chem. 2016, 81, 2494–2505. [CrossRef]
Dryanska, V. Phase-Transfer Catalyzed Additions. VI. Reaction of N-Diphenylmethyleneaminoacetonitrile with Aromatic Aldehydes. Synth. Commun. 1990, 20, 1055–1061. [CrossRef]
Dryanska, V.; Tasheva, D. Phase-transfer catalyzed additions. VII. Preparation of 3-aryl-3-arylamino-2-(N-diphenylmethyleneamino)propanenitriles. Synth. Commun. 1992, 22, 63–71. [CrossRef]
Ooi, T.; Kameda, M.; Taniguchi, M.; Maruoka, K. Development of Highly Diastereo- and Enantioselective Direct Asymmetric Aldol Reaction of a Glycinate Schiff Base with Aldehydes Catalyzed by Chiral Quaternary Ammonium Salts. J. Am. Chem. Soc. 2004, 126, 9685–9694. [CrossRef]
Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Michael Addition and Alkylation of 2-Azaallyl Anions Derived from N-(1-Cyanoalkyl)imines, and Stereoselective Cyclization of Imine Esters or Ketones Leading to 1-Pyrrolines. Bull. Chem. Soc. Jpn. 1987, 60, 3347–3358. [CrossRef]
Meyer, N.; Opatz, T. A Short Synthesis of Polysubstituted Pyrrolidines via α-(Alkylideneamino)nitriles. Synlett 2004, 5, 787–790. [CrossRef]
Tasheva, D.; Petrova, A.; Simova, S. Convenient Synthesis of Some Substituted 5-Oxonitriles under Aqueous Conditions: Synthesis of 3,4-Dihydro-2H-pyrrole-2-carbonitriles. Synth. Commun. 2007, 37, 3971–3979. [CrossRef]
Ma, T.; Fu, X.; Kee, C.W.; Zong, L.; Pan, Y.; Huang, K.-W.; Tan, C.-H. Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions. J. Am. Chem. Soc. 2011, 133, 2828–2831. [CrossRef]
Nie, J.; Hua, M.-Q.; Xiong, H.-Y.; Zheng, Y.; Ma, J.-A. Asymmetric Phase-Transfer-Catalyzed Conjugate Addition of Glycine Imine to Exocyclic α,β-Unsaturated Ketones: Construction of Polycyclic Imines Containing Three Stereocenters. J. Org. Chem. 2012, 77, 4209–4216. [CrossRef]
Konno, T.; Watanabe, S.; Takahashi, T.; Tokoro, Y.; Fukuzawa, S. Silver/ThioClickFerrophos Complex as an Effective Catalyst for Asymmetric Conjugate Addition of Glycine Imino Ester to Unsaturated Malonates and α-Enones. Org. Lett. 2013, 15, 4418–4421. [CrossRef]
Timofeeva, D. S.; Ofial, A. R.; Mayr, H. Nucleophilic reactivities of Schiff base derivatives of amino acids. Tetrahedron 2019, 75, 459–463. [CrossRef]
Lee, H.; Nam, H.; Lee, S.Y. Enantio- and Diastereoselective Variations on α-Iminonitriles: Harnessing Chiral Cyclopropenimine-Thiourea Organocatalysts. J. Am. Chem. Soc. 2024, 146, 3065−3074. [CrossRef]
Li, J.-T.; Yang, W.-Z.; Wang, S.-X.; Li, S.-H.; Li, T.-S. Improved synthesis of chalcones under ultrasound irradiation. Ultrason. Sonochem. 2002, 9, 237–239. [CrossRef]

Scheme 1. Synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3).

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.

© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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.