Next Article in Journal
The Effects of Ceric Ammonium Nitrate in the Oxidation of 2-Benzyl-1,4-dimethoxybenzene Derivatives
Previous Article in Journal
The Crystal Structures of Some Bromo-Derivatives of the DPPH Stable Free Radical
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molbank
Volume 2024
Issue 3
10.3390/M1881
molbank-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 thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Short Note

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

by
Donka N. Tasheva
* and
Vesela M. Mihaylova
Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University “St. Kliment Ohridski”, 1 J. Bourchier Blvd., 1164 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Molbank 2024, 2024(3), M1881; https://doi.org/10.3390/M1881
Submission received: 19 August 2024 / Revised: 6 September 2024 / Accepted: 9 September 2024 / Published: 11 September 2024
(This article belongs to the Section Organic Synthesis and Biosynthesis)
Browse Figures
Review Reports Versions Notes

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, 1H-1H COSY, and high-resolution mass spectrometry (HRMS).

Graphical Abstract

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 non-proteinogenic α-amino acids and their derivatives [2,3,4]. O’Donnell Schiff bases have been used for the synthesis of unnatural α-amino acids by alkylation reactions [5,6,7,8,9], aldol reactions [10,11,12], and Michael additions [13,14,15,16,17,18,19,20].
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 this work is to continue our research on the reaction of 2-((diphenylmethylene)amino)acetonitrile with enones, especially with chalcone containing a thiophene ring for the synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3) as a precursor of the corresponding non-proteinogenic α-amino acid–a derivative of 3-(2-thienyl)alanine (Tia) that is modified in the side chain.
It is described that Tia, as a synthetic analogue of phenylalanine, activates the enzyme phenylalanine hydroxylase (PAR) and helps reduce serum L-Phe levels in individuals with phenylketonuria [21].
Synthetic peptides containing Tia in their structure have shown to be potent antagonists of bradykinin receptors [22]. The therapeutic potential of targeting bradykinin receptor antagonists is related to the possibility of their use in the treatment of COVID-19 and inflammatory diseases [23]. For these reasons, compound 3, as a precursor of the corresponding amino acid, has gained our attention due to its potential applications in the biochemistry and medicine sectors.
We should note that, recently, Lee et al. [20] reported the asymmetric synthesis of 5-phenyl-3-(thiophen-2-yl)-3,4-dihydro-2H-pyrrole-2-carbonitrile via the corresponding 5-oxonitrile, which was not isolated and characterized.

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 a diastereoisomeric ratio of 95:5 (1H NMR) was observed for the crude product 3 (Supplementary Materials, Figure S2). 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, 1H NMR, 13C NMR, 1H-1H COSY, and HRMS. In the 1H NMR spectrum, the two protons of the methylene group were nonequivalent, with a 55 Hz chemical shift difference and coupling constants of 2J = 17.6 Hz, 3J = 4.6 Hz (H4a) and 2J = 17.6 Hz, 3J = 8.9 Hz (H4b), calculated from the two observed doublets of doublets. Assignment of the protons from the 2-thienyl group was performed through analysis using 1H-1H COSY. A rel-(2R,3S)-configuration for the major diastereoisomer of oxonitrile 3 was assigned based on a comparison between the proton NMR spectrum of this compound and the proton NMR spectra of oxonitriles, previously reported by us [15] (Figure 1 and Table 1).

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 chalcone 2 [24] were prepared according to literature procedures. The reaction and purity of the final compound were monitored by thin-layer chromatography (TLC) on silica gel aluminium plates Kieselgel 60 F254 (Merck), using petroleum ether/acetone (6:1 v/v) as an eluent. Melting points were determined on a Boetius micromelting point apparatus and were uncorrected. Infrared spectra (FT-IR) were 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 13C. Chemical shifts (δ) are reported in parts per million (ppm). 1H NMR spectra were referenced to the tetramethylsilane (TMS) as an internal standard, and the 13C NMR spectrum was calibrated according to the carbon atom signal of CDCl3 (δ = 77.0 ppm). Coupling constants (J) were measured in hertz (Hz). High-resolution mass spectra (HRMS) were obtained with a Q Exactive hybrid quadrupole-Orbitrap mass spectrometer (Thermo Scientific Co., Waltham, MA, USA) equipped with a TurboFlow® LC system, as well as a heated electrospray model, HESI II, on IonMax® (Thermo Scientific Co., Waltham, MA, USA).

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

An aqueous solution of sodium hydroxide (33% NaOH, 0.75 mL, 8.4 mmol), cooled at 0 °C, 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), 642 (νC-S) cm−1. 1H NMR (500.13 MHz, CDCl3) δ (ppm): 3.76, (dd, 1H, 2J = 17.6 Hz, 3J = 4.6 Hz, CH2CO), 3.87 (dd, 1H, 2J = 17.6 Hz, 3J = 8.9 Hz, CH2CO), 4.32–4.35 (m, 1H, CH-C4H3S), 4.55 (d, 1H, 3J = 4.4 Hz, CHCN), 6.90 (dd, 1H, 3J = 5.0 Hz, 3J = 3.6 Hz, thiophene H-4′), 6.93–6.95 (m, 3H, thiophene H-3′ and aromatics), 7.14 (d, 1H, 3J = 5.0 Hz, thiophene H-5′), 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). 13C 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.

4. Conclusions

In conclusion, the procedure presented here is a simple and efficient route for the preparation of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile. The reaction proceeds with high yield and diastereoselectivity.

Supplementary Materials

Figure S1: FT-IR spectrum of compound 3 (KBr); Figure S2: 1H NMR spectrum of crude product (CDCl3); Figure S3: 1H NMR spectrum of compound 3 (CDCl3); Figure S4: 13C NMR spectrum of compound 3 (CDCl3); Figure S5: 1H-1H COSY spectrum of compound 3 (CDCl3); Figure S6: HRMS ESI spectrum of compound 3; Figure S7: HRMS ESI-MS/MS spectrum of compound 3; Figure S8: 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 was 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

  1. 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. [Google Scholar]
  2. 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. [Google Scholar] [CrossRef] [PubMed]
  3. Nájera, C.; Sansano, J.M. Catalytic Asymmetric Synthesis of α-Amino Acids. Chem. Rev. 2007, 107, 4584–4671. [Google Scholar] [CrossRef] [PubMed]
  4. Shirakawa, S.; Maruoka, K. Recent Developments in Asymmetric Phase-Transfer Reactions. Angew. Chem. Int. Ed. 2013, 52, 4312–4348. [Google Scholar] [CrossRef] [PubMed]
  5. 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. [Google Scholar] [CrossRef]
  6. Meyer, N.; Werner, F.; Opatz, T. One-Pot Synthesis of Polysubstituted Pyrrolidines from Aminonitriles. Synthesis 2005, 6, 945–956. [Google Scholar] [CrossRef]
  7. 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. [Google Scholar] [CrossRef]
  8. 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. [Google Scholar] [CrossRef]
  9. 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. [Google Scholar] [CrossRef]
  10. Dryanska, V. Phase-Transfer Catalyzed Additions. VI. Reaction of N-Diphenylmethyleneaminoacetonitrile with Aromatic Aldehydes. Synth. Commun. 1990, 20, 1055–1061. [Google Scholar] [CrossRef]
  11. 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. [Google Scholar] [CrossRef]
  12. 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. [Google Scholar] [CrossRef] [PubMed]
  13. 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. [Google Scholar] [CrossRef]
  14. Meyer, N.; Opatz, T. A Short Synthesis of Polysubstituted Pyrrolidines via α-(Alkylideneamino)nitriles. Synlett 2004, 5, 787–790. [Google Scholar] [CrossRef]
  15. 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. [Google Scholar] [CrossRef]
  16. 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. [Google Scholar] [CrossRef]
  17. 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. [Google Scholar] [CrossRef]
  18. 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. [Google Scholar] [CrossRef]
  19. Timofeeva, D.S.; Ofial, A.R.; Mayr, H. Nucleophilic reactivities of Schiff base derivatives of amino acids. Tetrahedron 2019, 75, 459–463. [Google Scholar] [CrossRef]
  20. 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. [Google Scholar] [CrossRef]
  21. Stokka, A.J.; Flatmark, T. 3-(2-Thienyl)-L-Alanine as a Competitive Substrate Analogue and Activator of Human Phenylalanine Hydroxylase. In Chemistry and Biology of Pteridines and Folates, 1st ed.; Milstien, S., Kapatos, G., Levine, R.A., Shane, B., Eds.; Springer: Boston, MA, USA, 2002; pp. 109–113. [Google Scholar] [CrossRef]
  22. Whalley, E.T.; Nwator, I.A.; Stewart, J.M.; Vavrek, R.J. Analysis of the receptors mediating vascular actions of bradykinin. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1987, 336, 430–433. [Google Scholar] [CrossRef]
  23. Rex, D.A.B.; Vaid, N.; Deepak, K.; Dagamajalu, S.; Prasad, T.S.K. A comprehensive review on current understanding of bradykinin in COVID-19 and inflammatory diseases. Mol. Biol. Rep. 2022, 49, 9915–9927. [Google Scholar] [CrossRef] [PubMed]
  24. Li, J.-T.; Yang, W.-Z.; Wang, S.-X.; Li, S.-H.; Li, T.-S. Improved synthesis of chalcones under ultrasound irradiation. Ultrason. Sonochemistry 2002, 9, 237–239. [Google Scholar] [CrossRef] [PubMed]
Molbank 2024 m1881 sch001
Scheme 1. Synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3) obtained as a racemate.
Scheme 1. Synthesis of rel-(2R,3S)-2-((diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile (3) obtained as a racemate.
Molbank 2024 m1881 sch001
Molbank 2024 m1881 g001
Figure 1. General formula of oxonitriles.
Figure 1. General formula of oxonitriles.
Molbank 2024 m1881 g001
Table 1. Selected 1H NMR spectral data for compound 3 and substituted oxonitriles (CDCl3).
Table 1. Selected 1H NMR spectral data for compound 3 and substituted oxonitriles (CDCl3).
Compd.Ar1Ar2δ (H4a),
ppm		3J (H3-H4a),
Hz		δ (H4b),
ppm		3J (H3-H4b),
Hz
3 aC4H3SC6H53.764.63.878.9
3 bC4H3SC6H53.597.73.85–3.91- d
a,cC6H5C6H53.744.83.859.1
b,cC6H5C6H53.638.1 4.005.4
a,c4-ClC6H4C6H53.715.2 3.828.6
a,c4-CH3C6H4C6H53.695.43.798.5
a major diastereoisomer. b minor diastereoisomer. c oxonitriles, previously reported by us [15]. d 3J (H3-H4b) could not be measured in 1H NMR spectrum of crude product.
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

Tasheva, D.N.; Mihaylova, V.M. rel-(2R,3S)-2-((Diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile. Molbank 2024, 2024, M1881. https://doi.org/10.3390/M1881

AMA Style

Tasheva DN, Mihaylova VM. rel-(2R,3S)-2-((Diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile. Molbank. 2024; 2024(3):M1881. https://doi.org/10.3390/M1881

Chicago/Turabian Style

Tasheva, Donka N., and Vesela M. Mihaylova. 2024. "rel-(2R,3S)-2-((Diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile" Molbank 2024, no. 3: M1881. https://doi.org/10.3390/M1881

APA Style

Tasheva, D. N., & Mihaylova, V. M. (2024). rel-(2R,3S)-2-((Diphenylmethylene)amino)-5-oxo-5-phenyl-3-(thiophen-2-yl)pentanenitrile. Molbank, 2024(3), M1881. https://doi.org/10.3390/M1881

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