International Journal of Experimental Spectroscopic Techniques

Characterization of the Structure of 9-([1-{(4-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)methyl}-1H-1,2,3-triazol-4-yl]methyl)-9H-carbazole Using 2D 1H-15N HMBC Experiment

Aouine Younas1, Hassane Faraj1, Anouar Alami1*, Abdelilah El Hallaoui1 and Mohamed Akhazzane2

1Laboratoire de Chimie Organique Fès, Faculté des Sciences Dhar El Mahraz, Université Sidi Mohamed Ben Abdellah, Morocco
2Centre Universitaire Régional d'Interface (CURI), Université Sidi Mohamed Ben Abdellah, Fès, Morocco

*Corresponding author

Anouar Alami, Laboratoire de Chimie Organique Fès, Faculté des Sciences Dhar El Mahraz, Université Sidi Mohamed Ben Abdellah, Morocco, Tel: +212-661 796 480, Fax: +212-535 733 171, E-mail: [email protected]

Int J Exp Spectroscopic Tech, IJEST-1-008, (Volume 1, Issue 2), Review Article

Received: January 27, 2016
Accepted: May 09, 2016
Published: May 12, 2016

Citation: Younas A, Faraj H, Alami A, Hallaoui AE, Akhazzane M (2016) Characterization of the Structure of 9-([1-{(4-methyl- 2-phenyl-4,5-dihydrooxazol-4-yl)methyl}-1H-1,2,3-triazol-4-yl]methyl)-9H-carbazole Using 2D 1H-15N HMBC Experiment. Int J Exp Spectroscopic Tech 1:008.

Copyright: © 2016 Younas A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Abstract


The title compound, 9-([1-{(4-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)methyl}-1H-1,2,3-triazol-4-yl]methyl)-9H-carbazole was synthesized in high yield by 1,3-dipolar cycloaddition reaction of 4-(azidomethyl)-4-methyl-2-phenyl-4,5-dihydrooxazole and 9-(prop-2-ynyl)-9H-carbazole in toluene at reflux. The structure of this product was established on the basis of NMR spectroscopy (1H, 13C, 15N and 2D 1H-15N HMBC) in addition to the elemental analysis and MS data.

Keywords


1,2,3-triazole, Oxazoline, 1,3-dipolar cycloaddition, 1H-15N correlation

Introduction


1,2,3-Triazoles are an important class of heterocycles due to their wide range of applications as synthetic intermediates and pharmaceuticals [1,2]. Several therapeutically interesting 1,2,3-triazoles have been reported, including anti-HIV agents, antimicrobial, anticancer, antibacterial, antifungal, anti-tubercular compounds [3,4], corrosion inhibitors [5], β3-selective adrenergic receptor agonists [6], kinase inhibitors [7,8] and other enzyme inhibitors [9,10]. The 1,2,3-triazole moiety is also present in a number of drugs, for example, the β-lactam antibiotic tazobactam [11] and the cephalosporin cefatrizine [12]. In addition to this, the heterocycle 2-oxazoline has drawn tremendous attention due to their extensive applications in chemistry, biochemistry and pharmacology [13-16]. This heterocycle is found in the structure of many biologically active natural products [17]. It is also known as important intermediates in organic transformations [18].

Materials and Methods


1H NMR spectra were recorded on a Bruker Avance™ 400 spectrometer and Bruker Avance 300 spectrometer respectively at 400.13 MHz and 300.13 MHz (Faculty of Chemistry of Strasbourg, University of Strasbourg - France and Centre Universitaire Régional d'Interface, Sidi Mohamed Ben Abdellah University, Fez - Morocco). Chemical shifts (δ) are given in ppm. The residual solvent proton peak was used as reference for calibration (DMSO-d6: 2.50 ppm and CDCl3: 7.26 ppm). The coupling constants J are given in Hz. Peaks are described as singlet (s), doublet of doublets (dd) and multiplet (m). 13C NMR spectra were recorded on a Bruker Avance™ 400 spectrometer and Bruker Avance 300 spectrometer respectively at 100.62 MHz and 75.47 MHz. All spectra were measured under broadband decoupled conditions. The residual solvent peaks were taken as reference (DMSO-d6: 39.43 and CDCl3: 77.08 ppm). 15N NMR spectra were recorded on a Bruker Avance™ 400 spectrometer at 40.55 MHz. 2D NMR spectra were also recorded on a Bruker Avance™ 400 spectrometer. All spectra were recorded at 25°C. The reaction was followed by TLC. TLC analyses were carried out on 0.25mm thick precoated silica gel plates (Merck Fertigplatten Kieselgel 60F254) and spots were visualized under UV light or by exposure to vaporized iodine. The purification was performed by column chromatography on silica gel columns 60 Merck (Kieselgel 60F254 Merck Fertigplatten) using ether/hexane 4:1 as eluant.

Discussion


In this paper, we examine the 1,3-dipolar cycloaddition reaction between 4-(azidomethyl)-4-methyl-2-phenyl-4,5-dihydrooxazole and 9-(prop-2-ynyl)-9H-carbazole in 5 mL of toluene at reflux with constant stirring during 72 hours (Scheme) [19]. Two regioisomers (1) and (2) were obtained in an 80:20 ratio, the major isomer was found to elute second.

Scheme: Synthesis of two regioisomers (1) and (2).

According to the literature data and the results obtained by the various members of our team [20-23], the 1,3-dipolar cycloaddition reaction between alkynes and azides leads to two regioisomers with different proportions, where the 1,4-isomer is generally more prominent than 1,5-isomer. The assignment of structures to triazoles isomers is essentially based on 1H NMR and 13C NMR spectroscopic study [24-26].

In simple cases where signals of triazole's protons are well resolved and are not covered by other signals of the spectrum, we observed that the triazolic proton C5-H is more deshielded than the proton C4-H [20].

On one hand, the spectroscopic study by 13C NMR, conducted in the laboratory [20,27] shows that the tertiary carbon C4 of 1,2,3-triazole ring of the 1,5-isomer is more deshielded than the tertiary carbon C5 of the 1,4-isomer.

In our case, 1H NMR spectra (at 300 MHz) showed that the signals corresponding to triazole's protons are covered by other signals of the aromatic protons. So, to support the proposed structures to their corresponding products, a thorough spectroscopic study was carried out on the regioisomers (1) and (2).

The comparative study of 1H NMR spectra at 300.13 MHz of the two regioisomers (Figure 1 and Figure 2) shows that the protons of methylene group located between the carbazole ring and the triazole ring are less apart in the isomer (1) than in the isomer (2). It is the same for protons of methylene oxazoline, which shows that the two methylene groups do not have the same environment this is due to the steric hindrance of the carbazole that lies just below the rest of the molecule the isomer (2).

The comparison of 13C NMR spectra of these regioisomers shows the deshielding of the tertiary carbon (123.24 ppm) located in position 4 of 1,2,3-triazole ring of the minor product (2) with respect to the tertiary carbon (120.32 ppm) located in position 5 of 1,2,3-triazole ring of the major product (1) (Table 1) consistent with the literature [24-26].

Table 1. Chemical shifts of tertiary (Ct) and quaternary (Cq) carbon atoms.

On the other hand, the comparison between the 1H NMR spectrum (at 400 MHz) in DMSO (Figure 3) of major product (1) and the crude product (mixture of two regioisomers (1) + (2)) allowed us to locate so specifies the signals corresponding to the triazole's proton C4-H (7.91 ppm) and C5-H (7.90 ppm) of the two regioisomers.

It is found that the C4-H is slightly deshielded compared to C5-H contrary to what is described in the literature, including the work done in our laboratory. The opposite phenomenon is due to the anisotropic effect of the carbazolic ring: the proton C4-H of minor regioisomer is located in the precession cone of the aromatic ring. While in the case of the major regioisomer, the C5-H proton does not undergo the same effect.

Compound (1)

White solid; mp = 146-148°C; Rf = 0.25(ether). δH(ppm, CDCl3, 300.13 MHz): 1.41(3H, CH3, s); 4.01-4.49(2H, CH2(4,5-dihydrooxazole), AB, J = 9.0 Hz); 4.35-4.46(2H, CH2-triazole, AB, J = 14.03 Hz); 5.45-5.57(2H, CH2-carbazole, AB, J = 16.8 Hz); 7.19-8.06(9Harom + H5-1,2,3-triazole, m). δC(ppm, CDCl3, 75.47 MHz): 24.87; 37.98; 57.08; 70.80; 75.18; 120.32(Ct); 144.32(Cq); 119.41-134.64 (18Carom); 162.97. MS-EI: [M]+ = 421. Elemental analysis: calcd.: C 74.10; H 5.46; N 16.62; Found: C 73.84 ; H 5.14 ; N 16.38.

Compound (2)

White solid; mp = 208-210°C; Rf = 0.35(ether). δH(ppm, CDCl3, 300.13 MHz): 1.57(3H, CH3, s); 4.53(2H, CH2(4,5-dihydrooxazole), AB, J = 9.0Hz); 4.55(2H, CH2-triazole, dd, J1 = 14.39 Hz, J2 = 14.45 Hz); 5.73(2H, CH2-carbazole, AB, J = 17.1 Hz); 7.15-8.11(9Harom + H4-1,2,3-triazole, m). δC(ppm, CDCl3, 75.47 MHz): 25.61; 37.64; 55.56; 71.60; 75.05; 123.24(Ct); 140.20(Cq); 119.78-133.46 (18Carom); 162.68. MS-EI: [M]+ = 421. Elemental analysis: calcd.: C 74.10; H 5.46; N 16.6; Found: C 74.14 ; H 5.38 ; N 16.65.

In order to remove any ambiguity and irrevocably confirm the structure of each of two regioisomers, we studied the structure of the major compound (1) by 15N NMR.

The 15N NMR spectrum (at 40.55 MHz) of the compound (1) has five signals corresponding to five nitrogen atoms in the molecule (Figure 4). The assigning each signal to its corresponding nitrogen atom is carried out based on the 2D 1H-15N HMBC experiment that have been used in the characterization of 1,2,3-triazole derivatives [27].

The interaction 1H-15N has allowed us to make the following observations (Table 2 and Figure 5):

Table 2. Listing of 15N NMR spectral data for (1) in DMSO-d6, including results obtained by heteronuclear multiple bond coherence shift-correlated (HMBC).

- Correlation between aromatic system protons of carbazole ring, the protons of the methylene group attached to the carbazole ring and nitrogen whose chemical shift is 118.93 ppm, allowing us to assign this signal to nitrogen N-5.

- Correlation between the three methyl protons, the two protons of the methylene group linked to the triazole nucleus and nitrogen whose chemical shift is 236.02 ppm, which justifies the attribution of this signal to the oxazoline cycle nitrogen N-1.

- Interaction between the methylene protons related to the triazole ring, the triazolic proton C5-H and the nitrogen whose chemical shift is 244.37 ppm. This signal is assigned to the nitrogen N-2 situated in position 1 of the 1,2,3-triazole ring.

- Correlation between the methylene protons related to the carbazole ring, the triazolic proton C5-H and nitrogen whose chemical shift is 351.35 ppm. This enables to assign the signal corresponding to the nitrogen N-4 located in position 3 of the 1,2,3-triazole ring.

- Interaction between the methylene protons related to the triazole ring, the triazolic proton C5-H and nitrogen whose chemical shift is 364.27 ppm. The corresponding signal is attributed to the nitrogen N-3 situated in position 2 of the 1,2,3-triazole ring.

The assignment of each signal to its nitrogen atom is based on the correlation 1H-15N (Figure 6). Indeed, analysis of the different correlations presented in the 1H-15N HMBC NMR spectrum of the major compound (1), we can assign accurately to each nitrogen; the corresponding chemical shift. Hence, the identification of this compound has been confirmed.

On the basis of this spectroscopic study, we can conclude, then, for the substrates and conditions probed here, the 1,4-isomer was found to be the major isomer. Therefore, the allocation of each structure to its corresponding compound is well established.


Figures




Figure 1: 1H NMR spectrum in CDCl3 (aliphatic moiety) of compound (1).





Figure 2: 1H NMR spectrum in CDCl3 (aliphatic moiety) of compound (2).





Figure 3: 1H NMR spectrum of major isomer (in red) and of crude product (in blue).





Figure 4: 15N NMR spectrum of compound (1) in DMSO-d6.





Figure 5: 2D 1H-15N HMBC of compound (1) in DMSO-d6.





Figure 6: Assignment of each signal to its nitrogen atom.




References


  1. Fan WQ, Katritzky AR (1996) 1,2,3-Triazoles. In: Katritzky AR, Rees CW, Scriven EFV, Comprehensive Heterocyclic Chemistry II. (Eds.), Pergamon Press, New York, NY, USA 4: 1-126.

  2. Katritzky AR, Zhang Y, Singh SK (2003) 1,2,3-Triazole formation under mild conditions via 1,3-dipolar cycloaddition of acetylenes with azides. Heterocycles 60: 1225-1239.

  3. Agalave SG, Maujan SR, Pore VS (2011) Click chemistry: 1,2,3-triazoles as pharmacophores. Chem Asian J 6: 2696-2718.

  4. Ganesh A (2013) Potential biological activity of 1,4-sustituted-1H-[1,2,3]triazoles. Int J Chem Sci 11: 573-578.

  5. González-Olvera R, Espinoza-Vázquez A, Negrón-Silva GE, Palomar-Pardavé ME, Romero-Romo MA, et al. (2013) Multicomponent Click Synthesis of New 1,2,3-Triazole Derivatives of Pyrimidine Nucleobases: Promising Acidic Corrosion Inhibitors for Steel. Molecules 18: 15064-15079.

  6. Brockunier LL, Parmee ER, Candelore MR, Cascieri MA, Colwell LF, et al. (2000) Human β3-adrenergic receptor agonists containing 1,2,3-triazole-substituted benzenesulfonamides. Bioorg Med Chem Lett 10: 2111-2114.

  7. Pande V, Ramos MJ (2005) Structural basis for the GSK-3beta binding affinity and selectivity against CDK-2 of 1-(4-aminofurazan-3yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives. Bioorg Med Chem Lett 15: 5129-5135.

  8. Olesen PH, Sørensen AR, Ursø B, Kurtzhals P, Bowler AN, et al. (2003) Synthesis and in vitro characterization of 1-(4-aminofurazan-3-yl)-5-dialkylaminomethyl-1H-[1,2,3]triazole-4-carboxylic acid derivatives. A new class of selective GSK-3 inhibitors. J Med Chem 46: 3333-3341.

  9. Krasinski A, Radic Z, Manetsch R, Raushel J, Taylor P, et al. (2005) In situ selection of lead compounds by click chemistry: target-guided optimization of acetylcholinesterase inhibitors. J Am Chem Soc 127: 6686-6692.

  10. Mocharla VP, Colasson B, Lee LV, Roeper S, Sharpless BK, et al. (2005) In situ click chemistry: Enzyme-generated inhibitors of carbonic anhydrase II. Angew Chem Int Ed Engl 44: 116-120.

  11. Micetich RG, Maiti SN, Spevak P, Hall TW, Yamabe S, et al. (1987) Synthesis and β-lactamase inhibitory properties of 2β-[(1,2,3-triazol-1-yl)methyl]-2α-methylpenam-α-carboxylic acid 1,1-dioxide and related triazolyl derivatives. J Med Chem 30: 1469-1474.

  12. Actor P, Uri JV, Phillips L, Sachs CS, Zajac JRG, et al. (1975) Laboratory studies with cefatrizine (SK + F 60771), a new broad-spectrum orally-active cephalosporin. J Antibiot 28: 594-601.

  13. Gant TG, Meyers AI (1994) The chemistry of 2-oxazolines. Tetrahedron 50: 2297-2360.

  14. Frump JA (1971) Oxazolines. Their preparation, reactions, and applications. Chem Rev 71: 483-505.

  15. Grimmett MR (1996) 3.02 – Imidazoles. In: Katritzky AR, Rees CW, Scriven EFV, Comprehensive Heterocyclic Chemistry. (Eds.), Pergamon Press, Oxford, UK 3: 77-220.

  16. Gilman AG, Goodman LS (2001) The Pharmacological Basis of Therapeutics. 10th Ed, McGraw-Hill, New York, NY, USA.

  17. Greenhill JV, Lue L (1993) In: Ellis GP, Luscombe DK, Progress in Medicinal Chemistry. (Eds.), Elsevier, New York, NY, USA 3: 170-180.

  18. Puntener K, Hellman MD, Kuester E, Hegedus LS (2000) Synthesis and Complexation Properties of Poly(ethylene glycol)-Linked Mono- and Bis-dioxocyclams. J Org Chem 65: 8301-8306.

  19. Aouine Y, Faraj H, Alami A, El Hallaoui A, Elachqar A, et al. (2008) Synthesis of new triheterocyclic compounds, precursors of biheterocyclic Aminoacids. J Mar Chim Hétérocycl 7: 44-49.

  20. El Hajji S (1992) Thèse de Doctorat d'État, Faculté des Sciences DM, Fès.

  21. Elachqar A, El Hallaoui A, Roumestant ML, Viallefont Ph (1994) Synthesis of heterocyclic α-aminophosphonic acids. Synthetic Communications 24: 1279-1286.

  22. Achamlale S, Elachqar A, El Hallaoui A, El Hajji S, Alami A, et al. (1998) Synthesis of biheterocyclic α-aminophosphonic acid derivatives. Phosphorus, Sulfur and Silicon 140: 103-111.

  23. Zaid F, el Hajji S, el Hallaoui A, Elachqar A, Alami A, et al. (1998) Synthesis of heterocyclic alpha-aminoaldehyde and alpha-aminoacid analogues of histidine. Prep Biochem Biotechnol 28: 155-165.

  24. Tsypin GI, Timofeeva TN, Mel'nikov VV, Gidaspov BV (1977) Structure and reactivity of aliphatic azido compounds. Isomeric composition of the products from cycloaddition of aliphatic azides to acetylene derivatives. Zh Org Khim 13: 2275-2281.

  25. Lehetet G (1970) Thèse de troisième cycle, Rennes.

  26. Tsypin GI, Mel'nikov VV, Timofeeva TN, Gidaspov BV (1977) Structure and reactivity of aliphatic azido compounds, kinetics of the cycloaddition of alkylazides to acetylene derivatives. Zh Org Khim 13: 2281-2283.

  27. Bednarek E, Modzelewska-Banachiewicz B, Cyrański MK, Sitkowski J, Wawer I (2001) The 1H, 13C and 15N NMR study on 5-carboxymethyl-1,2,4-triazole and 5-oxo-1,2,4-triazine derivatives. J Mol Struct 562: 167-175.