Next Article in Journal
N-Benzo[c][1,2,5]thiazol-4-yl-3-trifluoromethylbenzamide
Previous Article in Journal
2,6-Bis[4-(4-butylphenyl)-1H-1,2,3-triazol-1-yl]-9-dodecyl-9H-purine

Molbank 2019, 2019(3), ; https://doi.org/10.3390/M1074

Short Note
4-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl]-4-methyl-2-phenyl-4,5-dihydrooxazole
1
Doctoral Training “Bioactive Molecules, Health and Biotechnology”, Center of Doctoral Studies “Sciences and Technology’’, Faculty of Sciences Dhar Mahraz, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco
2
Organic Chemistry Laboratory (LCO), Faculty of Sciences Dhar El Mahraz, Sidi Mohammed Ben Abdellah University, Fez 30000, Morocco
3
Organic Chemistry Laboratory (LCO), Faculty of Sciences, Ibn Zohr University, P.B 8106, Cité Dakhla, Agadir 80060, Morocco
*
Author to whom correspondence should be addressed.
Received: 30 June 2019 / Accepted: 16 July 2019 / Published: 19 July 2019

Abstract

:
The compound, 4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-4-methyl-2-phenyl-4,5-dihydrooxazole 2 was prepared in high yield, through nucleophilic substitution reaction of the O-tosyl oxazoline derivative 1, by heating in dimethyl sulfoxide (DMSO) and in presence of KOH as base. The structure of the synthesized compound was established on the basis of NMR spectroscopy (1H, 13C), MS data and elemental analysis.
Keywords:
oxazoline; pyrazole; N-alkylation; 2D NMR

1. Introduction

Five-membered heterocycles are a very important class of molecules because of their wide range of applications in various fields. Pyrazole is the core of this family of heterocycles and it is associated with different biological activities, such as: antimycobacterial [1], inflammatory [2], anticancer [3,4], antimicrobial [5], antibacterial [6], anti-tubercular [7]. It is also used as a herbicide, fungicide [8] and insecticide [9]. In addition to its biological profile, pyrazole is also used as a precursor in organic synthesis.
In the continuation of our research concerning heterocyclic amino acids and their precursors [10,11,12,13,14], we described in this short note our results concerning the synthesis of a new pyrazole compound, 4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-4-methyl-2-phenyl-4,5-dihydrooxazole, an oxazolinic precursor of heterocyclic amino acids via nucleophilic substitution reaction of the (4-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)methyl-4-methylbenzenesulfonate and the 3,5-dimethyl-1H-pyrazole. The title compound was characterized by spectroscopic techniques, such as 1D and 2D NMR spectroscopy, mass spectrometry (MS) and elemental analysis.

2. Results

This paper is dedicated to the synthesis of the precursor of 3-(pyrazol-1-yl)-alanine. Our synthesis strategy is based on the nucleophilic substitution of the O-tosyl group present in the oxazoline ring 1 with pyrazole nucleus. The starting (4-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)methyl-4-methylbenzenesulfonate 1 was prepared in two steps, from the commercially available 2-amino-2-methyl propan-1,3-diol in first time, then followed by tosylation in the presence of pyridine according to the method recommended by El Hajji [15]. The O-tosylated oxazoline 1 thus obtained was subjected under the action of pyrazole using a superbase (KOH-DMSO) in order to synthesize the new biheterocyclic compound 2 (Scheme 1). The use of a super base (KOH-DMSO) proved necessary to realize the substitution of -OTs group by pyrazole.
The structure of the product obtained was established on the basis of standard spectroscopic methods (1D, 2D NMR), mass spectrometry and elemental analysis.
The 1H-NMR spectrum of compound 2 recorded in chloroform presents, in addition to the signals attributed to aromatic and aliphatic protons, two singlets at 1.36 and 2.18 ppm corresponding successively to the methyl groups CH3 (12) and CH3 (3’). It shows that the 2 methyl radicals of the pyrazole nucleus are not equivalent. The methyl in position 3 is more deblinded than that in position 5; this is due to its different chemical environment. The 1H-NMR also shows a doublet between 2.266 and 2.268 ppm with a coupling constant J = 0.60Hz, corresponding to the methyl group CH3 (5’) which explains the correlation observed with C4-H proton in the homonuclear NMR-2D spectrum (Figure 1). It presents also a quartet between 4.07 and 4.2 ppm attributed to -CH2-N protons with a coupling constant in the order of J = 14.40Hz. The -CH2-O protons of the oxazoline ring are chemically non-equivalents since they are in α of asymmetric carbon and resonate as an AB system (centered between 4.04 ppm and 4.94 ppm) with a coupling constant in the order of J = 8.70 Hz. On the other side, the NMR-13C spectrum of compound 2, shows in particular three signals at 11.60, 13.46 and 25.10 ppm attributed to the carbons of the methyl groups -CH3 and a signal at 59.95 ppm corresponding to the carbon C6-N of the pyrazole-oxazoline junction. The asymmetric C7 carbon of the oxazoline ring resonates around 71.90 ppm with no correlation observed in the heteronuclear NMR-2D spectrum (Figure 2). Likewise, a signal to 163.65 ppm attributed to the C10 quaternary carbon of the oxazoline ring also represents no correlation. The heteronuclear NMR spectrum (Figure 2) shows also that there is a correlation between the two doublets of the AB system and the 75.79 ppm signal corresponding to the carbon C8-O of oxazoline ring, and the CH2-N protons are correlated with the 59.56 ppm signal corresponding to the carbon C6-N of the pyrazole-oxazoline. This finding is in perfect agreement with the difference in the electronegativity of the oxygen atom and that of nitrogen. The definite assignment the chemical shifts of protons and carbons are shown in the Table 1 below.

3. Materials and Methods

The solvents used have been purified using standard techniques. Commercial reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA). The melting point was determined using a Kofler Bench device. The NMR spectra (1D and 2D) were recorded in deuterated chloroform on an AM 300 Bruker spectrometer (300.13 MHz for proton and 75.47 MHz for carbon 13) at the Cité d’Innovation of Mohammed Ben Abdallah University in Fez. Chemical displacements are given in ppm and coupling constants in Hz. The reactions were monitored by TLC on silica gel plates (Fertigplatten Kieselgel, 60F254) and the plates were visualized under a UV lamp (250–365 nm). Mass spectra were recorded on a PolarisQ Ion Trap GC/MSn Mass Spectrometer (City of Innovation, USMBA-Fez, Morocco). Elemental analysis was performed with Flash 2000 EA 1112, Thermo Fisher Scientific-Elemental Analyzer (CNRST-Rabat, Morocco).
To (0.762 g, 7.94 mmol) of 3,5-dimethyl-1H-pyrazole (1.2 eq.) in 15 mL of DMSO, (0.891 g, 15.88 mmol) of potassium hydroxide (2.4 eq.) is added in small portions (KOH). The mixture is left shaking for one hour at 80 °C, and then we add drop by drop for 20 min, (2.284 g, 6.62 mmol) of the O-tosylated oxazoline 1 diluted in 10 mL of DMSO. Once the addition is complete, the reaction is maintained at the same temperature (80 °C) for 24 h, and as soon as the reaction is completed, 200 mL of water is added to the reaction mixture and then extracted by dichloromethane (6 × 30 mL). Then, the organic layer is washed with water (3 × 20 mL), dried and concentrated. The resulting oil is purified by column chromatography of silica gel (ethyl acetate/hexane).
Yield = 82% (White solid); m.p. = 161–163 °C. 1H-NMR (CDCl3, δH ppm): 1.36 (s, 3H, CH3-Oxaz), 2.18 (s, 3H, CH3(3′)), 2.266–2.268 (d, 3H, CH3(5′), J = 0.60 Hz), 4.096–4.2 (q, 2H, CH2-N, J = 14.40 Hz), 4.04–4.93 (2H, CH2-Oxaz, AB, J = 8.70 Hz), 5.69 (s, 1H, C4-H), 7.35–7.90 (m, 5Harom). 13C-NMR (CDCl3, δC ppm): 11.60 (CH3(5′)), 13.46 (CH3(3′)), 25.10 (CH3-Oxaz), 55.95 (CH2-N), 71.90 (C7), 75.79 (CH2-Oxaz), 105.06 (C4), 127.70–131.31 (6Carom), 140.25 (C5), 147.55 (C3), 163.65 (C10). MS m/z (%) = 270.14 [M+1] (100). Calcd. for C16H19N3O (%): C, 71.35; H, 7.11; N, 15.60; Found (%): C 71.16, H 7.11, N 14.94. The supporting 13C-NMR, 1H-NMR, 1H-1H NMR, 1H-13C NMR, mass spectra and elemental analysis are presented in the Supplementary Materials file.

4. Conclusions

The synthesis of 4-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-4-methyl-2-phenyl-4,5-dihydrooxazole was performed by N-alkylation reaction with good yield. The structure of the product was confirmed by the usual spectroscopic methods.

Supplementary Materials

The following are available online, Figure S1: 13C-NMR spectrum of compound 2, Figure S2: 1H-NMR spectrum of compound 2, Figure S3: Homonuclear 1H-1H spectrum of compound 2, Figure S4: Heteronuclear 1H-13C spectrum of compound 2, Figure S5: 1H-1H correlation spectroscopy identifies coupling between protons in compound 2, Figure S6: 1H-13C 2D correlation spectroscopy identifies coupling between protons and carbons in compound 2, Figure S7: Mass spectrum of compound 2, Figure S8: Elemental analysis of compound 2.

Author Contributions

S.H. performed the experiments; H.F., A.A. conceived and designed the experiments; A.A. supervise the research activity; A.A., Y.A. Analyzed the data and wrote the paper. All authors read and approved the final manuscript.

Funding

This research received no external funding.

Acknowledgments

This work was supported by Sidi Mohammed Ben Abdellah University (USMBA).

Conflicts of Interest

The authors declared that they have no conflict of interest as regards this work.

References

  1. Takate, S.J.; Shinde, A.D.; Karale, B.K.; Akolkar, H.; Nawale, L.; Sarkar, D.; Mhaske, P.C. Thiazolyl-pyrazole derivatives as potential antimycobacterial agents. Bioorg. Med. Chem. Lett. 2019, 29, 1199–1202. [Google Scholar] [CrossRef] [PubMed]
  2. Hassan, G.S.; Abdel Rahman, D.E.; Abdelmajeed, E.A.; Refaey, R.H.; Alaraby Salem, M.; Nissan, Y.M. New pyrazole derivatives: Synthesis, anti-inflammatory activity, cycloxygenase inhibition assay and evaluation of mPGES. Eur. J. Med. Chem. 2019, 171, 332–342. [Google Scholar] [CrossRef] [PubMed]
  3. Ran, F.; Liu, Y.; Zhang, D.; Liu, M.; Zhao, G. Discovery of novel pyrazole derivatives as potential anticancer agents in MCL. Bioorg. Med. Chem. Lett. 2019, 29, 1060–1064. [Google Scholar] [CrossRef] [PubMed]
  4. Shi, J.B.; Tang, W.J.; Qi, X.B.; Li, R.; Liu, X.H. Novel pyrazole-5-carboxamide and pyrazole–pyrimidine derivatives: Synthesis and anticancer activity. Eur. J. Med. Chem. 2015, 90, 889–896. [Google Scholar] [CrossRef] [PubMed]
  5. Sayed, G.H.; Azab, M.E.; Anwer, K.E.; Raouf, M.A.; Negm, N.A. Pyrazole, pyrazolone and enaminonitrile pyrazole derivatives: Synthesis, characterization and potential in corrosion inhibition and antimicrobial applications. J. Mol. Liq. 2018, 252, 329–338. [Google Scholar] [CrossRef]
  6. Prasath, R.; Bhavana, P.; Sarveswari, S.; Ng, S.W.; Tiekink, E.R.T. Efficient ultrasound-assisted synthesis, spectroscopic, crystallographic and biological investigations of pyrazole-appended quinolinyl chalcones. J. Mol. Struct. 2015, 1081, 201–210. [Google Scholar] [CrossRef]
  7. Xu, Z.; Gao, C.; Ren, Q.-C.; Song, X.-F.; Feng, L.-S.; Lv, Z.-S. Recent advances of pyrazole-containing derivatives as anti-tubercular agents. Eur. J. Med. Chem. 2017, 139, 429–440. [Google Scholar] [CrossRef] [PubMed]
  8. Lamberth, C. Pyrazole Chemistry in Crop Protection. Heterocycles 2007, 71, 1467–1502. [Google Scholar] [CrossRef]
  9. Lahm, G.P.; Cordova, D.; Barry, J.D. New and selective ryanodine receptor activators for insect control. Bioorg. Med. Chem. 2009, 17, 4127–4133. [Google Scholar] [CrossRef] [PubMed]
  10. Aouine, Y.; Faraj, H.; Alami, A.; El Hallaoui, A.; Elachqar, A.; El Hajji, S.; Kerbal, A.; Labriti, B.; Martinez, J.; Rolland, V. Synthesis of new triheterocyclic compounds, precursors of biheterocyclic amino acids. J. Mar. Chim. Heterocycl. 2008, 7, 44–49. [Google Scholar]
  11. Aouine, Y.; Faraj, H.; Alami, A.; El Hallaoui, A.; Elachqar, A.; Kerbal, A. Simple and efficient synthesis of racemic 2-(tert-Butoxycarbonylamino)-2- methyl-3-(1H-1,2,4-triazol-1-yl)propanoic acid, a new derivative of β-(1,2,4-Triazol-1-yl)alanine. Molecules 2011, 16, 3380–3390. [Google Scholar] [CrossRef] [PubMed]
  12. Aouine, Y.; Faraj, H.; Alami, A.; El Hallaoui, A.; Elachqar, A.; El Hajji, S.; Labriti, B.; Kerbal, A. Triheterocyclic compounds, oxazolinic precursors of biheterocyclic amino acids, Part II: Phenothiazine derivatives and structural study of regioisomers through 1H-15N 2DNMRHMBC. J. Mar. Chim. Heterocycl. 2014, 13, 39–47. [Google Scholar]
  13. Aouine, Y.; Alami, A.; El Hallaoui, A. N,N-dibenzyl-1-(1-[(4-methyl-2-phenyl-4,5-dihydrooxazol- 4-yl)methyl)] -1H-1,2,3-triazol-4-yl)methanamine. Molbank 2014, 2014, M819. [Google Scholar] [CrossRef]
  14. Boukhssas, S.; Aouine, Y.; Faraj, H.; Alami, A.; El Hallaoui, A.; Bekkari, H. Synthesis, Characterization, and Antibacterial Activity of Diethyl 1-((4-Methyl-2-phenyl-4,5-dihydrooxazol-4-yl)methyl)-1H-1,2,3-triazole-4,5-dicarboxylate. J. Chem. 2017, 2017, 4238360. [Google Scholar] [CrossRef]
  15. Atmani, A.; El Hallaoui, A.; El Hajji, S.; Roumestant, M.L.; Viallefont, P. From Oxazolines to Precursors of Aminoacids. Synth. Commun. 1991, 21, 2383–2390. [Google Scholar] [CrossRef]
Scheme 1. Synthesis strategy for compound 2.
Scheme 1. Synthesis strategy for compound 2.
Molbank 2019 m1074 sch001
Figure 1. 1H-1H correlation spectroscopy identifies coupling between protons in compound 2.
Figure 1. 1H-1H correlation spectroscopy identifies coupling between protons in compound 2.
Molbank 2019 m1074 g001
Figure 2. 1H-13C 2D correlation spectroscopy identifies coupling between protons and carbons in compound 2.
Figure 2. 1H-13C 2D correlation spectroscopy identifies coupling between protons and carbons in compound 2.
Molbank 2019 m1074 g002
Table 1. (300.13 MHz) and 13C (75.47 MHz) NMR spectral data for compound 2 in CDCl3, including results obtained by homonuclear 2D shift-correlated and heteronuclear 2D shift-correlated HSQC (1JCH). Chemical shifts (δ in ppm) and coupling constants (J in Hz).
Table 1. (300.13 MHz) and 13C (75.47 MHz) NMR spectral data for compound 2 in CDCl3, including results obtained by homonuclear 2D shift-correlated and heteronuclear 2D shift-correlated HSQC (1JCH). Chemical shifts (δ in ppm) and coupling constants (J in Hz).
PositionδHδCCorrelation H-HCorrelation C-H
3-147.55--
3′2.18 (s)13.463H3′–3H3′C3′–3H3′
45.69 (s)105.061H4–1H4C4–1H4
5-140.25--
5′2.266–2.268 (d, J = 0.60)11.603H5′–3H5′; 3H5′–1H4C5′–3H5′
64.096–4.2 (q, J = 14.40)55.952H6–2H6C6–2H6
7-71.90--
84.042–4.939 (AB, J = 8.70)75.792H8–2H8C8–2H8
10-163.65--
121.36 (s)25.103H12–3H12C12–3H12
13–187.35–7.90 (m)127.70–131.115Harom–5Harom5Carom–5Harom

© 2019 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/).
Back to TopTop