Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate was synthesized via Ugi four component (4C) reaction at ambient temperature. The protocol employs a reaction between formaldehyde, furfurylamine, acrylic acid, and ethyl 2-isocyanoacetate. The course of the reaction was found to be high yielding, and the resulting glycine ester derivative was well characterized by elemental analysis, FTIR, NMR spectroscopy, and mass spectrometric techniques. © 2017 by the authors; licensee MDPI, Basel, Switzerland.DE-AC02-05CH11231, DOE, U.S. Department of Energy; MŠMT, Ministerstvo Školství, Mládeže a TělovýchovyMSMT CR-USA Kontakt II [LH14050]; Molecular Foundry, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]; Ministry of Education, Youth and Sports of the Czech Republic - NPU Program I [LO1504

Saha, Nabanita

Shimoga Dinesh, Ganesh

Sáha, Petr

Zuckermann, Ronald N.

Molbank

Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate was synthesized via Ugi four component (4C) reaction at ambient temperature. The protocol employs a reaction between formaldehyde, furfurylamine, acrylic acid, and ethyl 2-isocyanoacetate. The course of the reaction was found to be high yielding, and the resulting glycine ester derivative was well characterized by elemental analysis, FTIR, NMR spectroscopy, and mass spectrometric techniques.DE-AC02-05CH11231, DOE, U.S. Department of Energy; MŠMT, Ministerstvo Školství, Mládeže a TělovýchovyMSMT CR-USA Kontakt II [LH14050]; Molecular Foundry, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]; Ministry of Education, Youth and Sports of the Czech Republic - NPU Program I [LO1504

Institutional repository of Tomas Bata University Library

molbankShort NoteEthyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetateShimoga D. Ganesh 1, Nabanita Saha 1,*, Ronald N. Zuckermann 2 and Petr Sáha 11 Centre of Polymer Systems, University Institute, Tomas Bata University in Zlin, Trˇ. T. Bati 5678, 760 01, Zlin,Czech Republic; icganeshin@gmail.com (S.D.G.); saha@utb.cz (P.S.)2 Biological Nanostructures Facility, Molecular Foundry, Lawrence Berkeley National Laboratory1 Cyclotron Rd.,Berkeley, CA 94720, USA; rnzuckermann@lbl.gov* Correspondence: nabanita@ft.utb.cz; Tel.: +420-576-038-156Academic Editor: Norbert HaiderReceived: 21 September 2016; Accepted: 4 January 2017; Published: 9 January 2017Abstract: Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate was synthesized via Ugifour component (4C) reaction at ambient temperature. The protocol employs a reaction betweenformaldehyde, furfurylamine, acrylic acid, and ethyl 2-isocyanoacetate. The course of the reactionwas found to be high yielding, and the resulting glycine ester derivative was well characterized byelemental analysis, FTIR, NMR spectroscopy, and mass spectrometric techniques.Keywords: FTIR; NMR; peptides; peptoids; Ugi reaction1. IntroductionProteins and peptides have been an important class of biomolecules since the evolution of modernlife. They are the central framework of all biological events governing aspects of structure, transport,and catalytic pathways in nature [1]. Created intricately in a highly specific fashion, the functionsof proteins and peptides in the living system have been a wonder and an inspiration in syntheticchemistry [2].Peptoids are structural isomers of natural peptides where the side chain functionality is joinedto the nitrogen atom of the peptide backbone rather than to the α-carbons (as they are in peptides).This new class of non-natural molecules mimics the natural structure of peptides and has versatilebiological activities, and many of the classic disadvantages of native peptides have been circumventedby their development [3,4]. It should, however, be noted that, because of their remarkable proteolyticstability, exploration leads to a modular drug discovery approach by combinatorial synthesis [5,6].Low-molecular-weight gelators (LMWGs) are small organic compounds that can self-assembleto form fibrous supramolecular structures in aqueous/organic media. Recently, the divergentsynthesis of tripeptoids can be seen as a combinatorial approach to LMWGs by a one-pot Ugimulticomponent reaction from simple starting materials [7,8]. Several organic compounds especiallyamino acids, cholesterols, sugars, and ureas, are classic examples for the design of these LMWGs.Significant efforts have been made by researchers to exploit the spontaneous molecular arrangement ofpeptides/peptoids and their derivatives in aqueous/organic solutions, and to afford nanostructuredhydrogels under specific conditions. These highly hydrated scaffolds have potential applications in 3Dcell culture and tissue engineering [9,10].With concern over the increasing demand for substituted alkyl acrylates, many researchers havedesigned various synthons from aza-Michael addition reactions [11,12] and reported their gelationproperties. The present paper describes the synthesis of an acryl functional tripeptoid with a furanmoiety via Ugi four component (4C) reaction at ambient temperature. Moreover, the reported titlecompound can be utilized as a starting material for the aza-Michael addition reaction.Molbank 2017, 2017, M925; doi:10.3390/M925 www.mdpi.com/journal/molbankMolbank 2017, 2017, M925 2 of 42. Results and DiscussionEthyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate was synthesized via Ugifour component (4C) reaction involving furfurylamine, paraformaldehyde, acrylic acid, and ethyl2-isocyanoacetate at ambient conditions for 30 h, as shown in Scheme 1. The target compound isyellow, naturally oily, insoluble in water and non-polar solvents such as n-hexane, and completelysoluble in dichloromethane, chloroform, methanol, ethanol, and dimethyl sulfoxide.Molbank 2016, 2017, M925  2 of 4 a furan moiety via Ugi four component (4C) reaction at ambient temperature. Moreover, the reported title compound can be utilized as a starting material for the aza-Michael addition reaction. 2. Results and Discussion  Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate was synthesized via Ugi four component (4C) reaction involving furfurylamine, paraformaldehyde, acrylic acid, and ethyl 2-isocyanoacetate at ambient conditions for 30 h, as shown in Scheme 1. The target compound is yellow, naturally oily, insoluble in water and non-polar solvents such as n-hexane, and completely soluble in dichloromethane, chloroform, methanol, ethanol, and dimethyl sulfoxide.  Scheme 1. Synthesis of ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate. The 1H &13C-NMR of the title compound is presented in Figures 1 and 2. The data revealed that the peak at 7.38 δ is for the aromatic proton of the furan ring (12H). The peaks in the range 6.77–6.80 δ corresponds to CH of the acryloyl group [H2C=CH–C(=O)–]. The signals for the aromatic protons of the furan ring (13H, 14H) along with CH2 of the acryloyl group [H2C=CH–C(=O)–] have been attributed to the peaks in the range of 6.34–6.47 δ. The δ value in the range 5.10 corresponds to the CH2 connected to the furan ring (10H). The δ value in the range 4.58–4.71 ascribed to CH2 of the ester functionality (8H). The peak at 3.98 δ and 2.99 δ corresponds to 4H and 6H protons, respectively. Finally, the peak at 1.26–1.27 δ corresponds to methyl protons (9H).   Figure 1. 1H-NMR spectra of the title compound (700 MHz, CDCl3) at room temperature. Scheme 1. Synthesis of ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate.The 1H- &13C-NMR of the title compound is presented in Figures 1 and 2. The data revealed thatthe peak at 7.38 δ is for the aromatic proton of the furan ring (12H). The peaks in the range 6.77–6.80 δcorresponds to CH of the acryloyl group [H2C=CH–C(=O)–]. The signals for the aromatic protonsof the furan ring (13H, 14H) along with CH2 of the acryloyl group [H2C=CH–C(=O)–] have beenattributed to the peaks in the range of 6.34–6.47 δ. The δ value in the range 5.10 corresponds to the CH2connected to the furan ring (10H). The δ value in the range 4.58–4.71 ascribed to CH2 of the esterfunctionality (8H). The peak at 3.98 δ and 2.99 δ corresponds to 4H and 6H protons, respectively.Finally, the peak at 1.26–1.27 δ corresponds to methyl protons (9H).Molbank 2016, 2017, M925  2 of 4 a furan moiety via Ugi four component (4C) reaction at ambient temperature. Moreover, the reported title compound can be utilized as a starting material for the aza-Michael addition reaction. 2. Results and Discussion  Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate was synthesized via Ugi four compo ent (4C) reaction involving furfurylamine, paraformaldehyde, acrylic acid, and ethyl 2-isocyanoacetate at ambient conditions for 30 h, as shown in Scheme 1. The target compound is yellow, naturally oily, insoluble in water and non-polar solvents such as n-hexane, and completely soluble in dichloromethane, chloroform, methanol, ethanol, and dimethyl sulfoxide.  Scheme 1. Synthesis of ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate. The 1H 13 -  of the title co pound is presented in Figures 1 and 2. The data revealed that the peak at 7.38 δ is for the aromatic proton of the furan ring (12H). The peaks in the range 6. 7–6.80 δ corresponds to CH of the acryloyl group [H2C=CH–C(=O)–].     atic protons of the furan ring (13H, 14H) along with CH2 of the acryloyl group [H2 )–] have been attributed to the peaks in the range of 6.34–6.47 δ. The δ value in the range 5.10 corresponds to the CH2 connected to the furan ring (10H). The δ value in the range 4.58–4.71 ascribed to CH2 f t e ester functionality (8H). The pea  at 3.98 δ a  2.99 δ corres o s to 4  and 6H protons, respectively. Finally, the peak at 1.26–1.27 δ corresponds to methyl protons (9 ).   Figure 1. 1H-NMR spectra of the title compound (700 MHz, CDCl3) at room temperature. Figure 1. 1H-N R spectra of t e titl 3) at roo te perature.Molbank 2017, 2017, M925 3 of 4Molbank 2016, 2017, M925  3 of 4  Figure 2. 13C-NMR spectra of the desired compound (176 MHz, CDCl3) at room temperature. 3. Experimental Section  3.1. Materials  Furfurylamine ≥99%, ethyl 2-isocyanoacetate, paraformaldehyde, acrylic acid, aluminum oxide (Ultra dry powder, Type—Neutral), and methanol were procured from Sigma-Aldrich, Prague, Czech Republic. All other chemicals and solvents were of AR grade and used without further purification. Double distilled water was used throughout the study.  3.2. Instrumentaion  The 1H &13C-NMR spectra were recorded on a 700 MHz Bruker Avance III HD spectrometer with a 5 mm dual broad-band probe, a 5 mm dual inverse broad-band probe, and a 1.7 mm triple resonance (1H–13C) probe (Bruker, Leiderdorp, The Netherlands) for multinuclear applications in liquids and solids. Tetramethylsilane (TMS) was used as an internal standard. LCMS measurement was performed on a liquid chromatography system with mass spectrometry detection (Q-TOF)—Agilent ACCURATE MASS 6530 Q TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA). The elemental analysis was carried out on a VARIO EL III Elemental analyzer (Elementar Analysensysteme GmbH, Hanau, Germany), and the results for C, H, and N were within 0.4% of the theoretical values. FTIR analysis was carried out on Nicolet 6700 (ATR, Thermo Scientific, Waltham, Middlesex County, MA, USA) in scanning range 4000–600 cm−1. The resolution was 4 cm−1 with 64 scans, and the measurement was performed with germanium crystal. 3.3. Synthesis of Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate To a 50 mL of round bottomed flask, paraformaldehyde (0.042 g, 1.38mmol) was added to a stirring solution of furfurylamine (100 mg, 1.38 mmol) in methanol (10 mL). The solution was stirred at room temperature for 2 h. Later, acrylic acid (0.1 g, 1.38mmol) was added, followed by ethyl 2-isocyanoacetate (0.156 g, 1.38 mmol). The completion of the reaction was monitored using thin-layer chromatography (TLC) analysis (performed with Merck Kieselgel TLC aluminum oxide 60 F254, neutral TLC plates, Merck Millipore, Bangalore, India). The formation of the product was confirmed by after 30 h. The reaction mixture was diluted with 20 mL of ethyl acetate (EtOAc) and washed with water (15 mL × 4) and, afterwards, a saturated solution of brine (20 mL). The collected Figure 2. 13C- s ectr f t , l3) at room temperature.3. Experimental Section3.1. MaterialsFurfurylamine ≥ , t l -i t t , r f r al ehyde, acrylic acid, aluminum oxide(Ultra dry powder, Type—Neutral), a t l r r c r fr i a- ldrich, Prague,Czech Republic. All other che icals a sol e ts ere of ra e a se ithout furtherpurification. Double distilled water as used throughout the study.3.2. InstrumentaionThe 1H- &13 spectra were recorded on a 700 MHz Bruker Avance III HD spectrometer witha 5 mm dual broad-band probe, a 5 mm dual inverse broad-band probe, and a 1.7 mm triple resonance(1H–13C) probe (Bruker, L iderdorp, The Netherlands) for multinuclear applications in liquids andsolids. Tetramethylsilane (TMS) was used as an internal standard. LCMS measurement was performedon a liquid chromatography system with mass s ectrometry detection (Q-TOF)—Agilent ACCURATEMASS 6530 Q TOF L /MS (Agilent Technologies, Santa Clara, CA, USA). The elemental analysiswas carried out on a VARIO EL III Elemental analyzer (Elementar Analysensysteme GmbH, Hanau,Germany), and the results for C, H, and N were within 0.4% of the theoretical values. FTIR analysiswas carried out on Nicolet 6700 (ATR, Thermo Scientific, Waltham, Middlesex County, MA, USA) inscanning range 4000–600 cm−1. The resolution was 4 cm−1 with 64 scans, and the measurement wasperformed with germanium crystal.3.3. Synthesis of Ethyl({[acryloyl(furan-2-yl ethyl)a ino]acetyl}a ino)acetateTo a 50 mL of round botto ed flask, paraformaldehyde (0.042 g, 1.38 mol) was added toa stirring solution of furfurylamine (100 mg, 1.38 mmol) in methanol (10 mL). The solution wasstirred at room temperature for 2 h. Later, acrylic acid (0.1 g, 1.38mmol) was added, followed byethyl 2-isocyanoacetate (0.156 g, 1.38 mmol). The completion of the reaction was monitored usingthin-layer chromatography (TLC) analysis (performed with Merck Kieselgel TLC aluminum oxide60 F254, neutral TLC plates, Merck Millipore, Bangalore, India). The formation of the product wasconfirmed by after 30 h. The reaction mixture was diluted with 20 mL of ethyl acetate (EtOAc) andMolbank 2017, 2017, M925 4 of 4washed with water (15 mL × 4) and, afterwards, a saturated solution of brine (20 mL). The collectedorganic layer was dried over anhydrous sodium sulfate, and solvent was removed under reducedpressure to collect the crude product (0.385 g). The crude product was passed through neutral aluminausing 45% EtOAc/n-hexane. The desired product was obtained as a yellow oily liquid (0.295 g) ina 72% yield. The supporting FTIR and LCMS spectra are presented in the supplementary material file.13C-NMR (176 MHz, CDCl3): (ppm) 174.92, 171.08, 162.45, 149.15, 143.06, 128.18, 126.95, 110.45, 109.11,61.46, 49.99, 46.35, 41.22, 14.01. Anal. calcd. for C14H18N2O5 (294.303): C, 57.13; H, 6.16; N, 9.52.Found: C, 56.81; H, 5.76; N, 9.58. LCMS (ESI): m/z = 295.127 (Found), 294.303 (Expected for [M + H]+),FTIR (Ge Crystal): 3385, 3180, 2985 cm−1 (-NH Stretch), 1686, 1744 cm−1 (C=O); 1125 cm−1 (C-O-C).Supplementary Materials: LCMS and FTIR spectra for the title compound are available online atwww.mdpi.com/1422-8599/2017/1/M925.Acknowledgments: The work is supported by MŠMT CˇR-USA Kontakt II (LH14050) and the MolecularFoundry, Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy under ContractNo. DE-AC02-05CH11231. This research is also supported in part by a grant from the Ministry of Education,Youth and Sports of the Czech Republic - NPU Program I (LO1504). We also acknowledge Pavel Kucharczyk,Centre of Polymer Systems, University Institute, Tomas Bata University in Zlin, Trˇ. T. Bati 5678, 760 01, Zlin,Czech Republic, for LCMS measurement.Author Contributions: S.D.G. designed the synthesis, carried out the experiments for the title compoundsynthesis, and wrote the article. N.S. and P.S. confirmed the data analysis. R.N.Z. helped in the discussionof the results. All of the above authors have read and approved the final manuscript.Conflicts of Interest: The authors declare no conflict of interest.References1. Gutteridge, A.; Thornton, J.M. Understanding nature’s catalytic toolkit. Trends Biochem. Sci. 2005, 30, 622–629.[CrossRef] [PubMed]2. Reddington, S.C.; Howarth, M. Secrets of a covalent interaction for biomaterials and biotechnology:SpyTag and SpyCatcher. Curr. Opin. Chem. Biol. 2015, 29, 94–99. [CrossRef] [PubMed]3. Simon, R.J.; Kania, R.S.; Zuckermann, R.N.; Huebner, V.D.; Jewell, D.A.; Banville, S.; Ng, S.; Wang, L.;Rosenberg, S.; Marlowe, C.K.; et al. Peptoids: A modular approach to drug discovery. Proc. Natl. Acad.Sci. USA 1992, 89, 9367–9371. 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Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate

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Ethyl({[acryloyl(furan-2-ylmethyl)amino]acetyl}amino)acetate

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