Comparison between Conventional and Nonconventional
Methods for the Synthesis of Some 2-Oxazolidinone
Derivatives and Preliminary Investigation of Their
Inhibitory Activity Against Certain Protein Kinases

S Ziane, M M Mazari, A M Safer, A Sad El Hachemi Amar, S Ruchaud, Blandine Baratte, S Bach

<figure><img src="image_1.png" /></figure>

To cite this version:

S Ziane, M M Mazari, A M Safer, A Sad El Hachemi Amar, S Ruchaud, et al.. Comparison between Conventional and Nonconventional Methods for the Synthesis of Some 2-Oxazolidinone Derivatives and Preliminary Investigation of Their Inhibitory Activity Against Certain Protein Kinases. Russian Journal of Organic Chemistry / Zhurnal Organicheskoi Khimii, 2019, 55 (7), pp.1061 - 1069. 10.1134/s1070428019070248. hal-03867403

HAL Id: hal-03867403

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Submitted on 23 Nov 2022

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Comparison between Conventional and Nonconventional
Methods for the Synthesis of Some 2-Oxazolidinone Derivatives
and Preliminary Investigation of Their Inhibitory Activity
Against Certain Protein Kinases

S. Zianeª,*, M. M. Mazariª, A. M. Saferª, A. Sad El Hachemi Amarª, S. Ruchaudᵇ,
B. Baratteᵇ, and S. Bachᵇ

Received January 27, 2019; revised March 23, 2019; accepted May 16, 2019

**Abstract**—A series of propargyl and allyl carbamates were prepared directly from propargyl and allyl alcohols and phenyl or cyclohexyl isocyanate or indirectly by generating the isocyanates *in situ* from the corresponding Cbz-protected amines. The obtained carbamates underwent intramolecular nucleophilic cyclization in presence of cesium hydroxide monohydrate as a base catalyst under conventional and ultrasonic irradiation conditions to give the corresponding substituted 4-(benzylidene)methylidene-2-oxazolidinones in good to excellent yields. The use of ultrasonic irradiation provided remarkably improved yield of the cyclization products and significant shortening of the reaction time. In some cases the reaction was highly stereoselective, and (Z)-4-benzylideneoxazolidinones were formed as a single stereoisomer. A series of biological tests were performed to evaluate the inhibitory potential of all synthesized compounds against some protein kinases.

**Keywords:** Propargyl carbamates, allyl carbamates, isocyanates, intramolecular cyclization, 3-phenyl-1,3-oxazolidin-2-ones, ultrasonic activation, protein kinase inhibition.

DOI: 10.1134/S1070428019070248

Oxazolidinones represent an important class of widely used organic compounds with a wide variety of applications in many fields, including agriculture [1, 2], organic synthesis [3–5], and medicinal chemistry [6]. Oxazolidinone derivatives have received significant attention due to their broad spectrum of biological activities like antimicrobial [7], anti-inflam-matory [8], antifungal [9], anticonvulsant [10], anti-tubercular [11], and anticancer [12]. Various methods are available for the synthesis of methylidene-1,3-oxazolidin-2-ones, such as base-catalyzed cyclization of vinyl or propargyl carbamates, and only a limited number of publications on the synthesis of 4-methylidieneoxazolidinones have been reported. In recent years, the use of ultrasound has become more wide-spread and has been used more and more frequently in organic synthesis. The use of ultrasound allows good dispersion of the reactants into the reaction solution, thus ensuring optimal interaction between them [13].

In fact, reactions carried out under ultrasonic irradiation often ensure higher yields, better selectivity, and shorter reaction times in comparison with traditional stirring methods [14, 15]. In order to extend the application scope of ultrasound irradiation in the synthesis of heterocyclic compounds, herein we report the synthesis of 4-methylidene(benzylidene)oxazolidinones from the corresponding carbamates starting from internal acetylenic alcohols as potential substrates in presence of cesium hydroxide monohydrate as a base catalyst under conventional and ultrasonic irradiation conditions. A series of biological tests were performed to evaluate the inhibitory potential of all synthesized compounds against some protein kinases.

Initially, a number of propargyl and allyl carbamates were synthesized according to reported procedures [16–18]. Propargyl alcohols **1a–1j** and allyl alcohols **2a** and **2b** reacted with commercially available phenyl or cyclohexyl isocyanate in THF containing

<footnote>ª Université Oran 1 Ahmed Ben Bella, Laboratoire de Synthèse Organique Appliquée, Département de Chimie, Faculté des sciences exactes et appliquées, Oran, Algeria
*e-mail: saidaz37@yahoo.com</footnote>

<footnote>ᵇ Station biologique de Roscoff, Roscoff, France</footnote>
Scheme 1.

<figure><img src="image_2.png" /></figure>

1, 3, R¹ = H (a, b, j), Ph (c), 4-ClC₆H₄ (d), 4-O₂NC₆H₄ (e), 4-FC₆H₄ (f), 4-CNC₆H₄ (g), 2,4-(MeO)₂C₆H₃ (h), 2-MeOC(O)C₆H₄ (i); R² = R³ = H (a, c-j), Me (b); 3, R⁴ = Ph (a-i), Cy (j); 2, 4, R = H (a), Me (b).

Scheme 2.

<figure><img src="image_3.png" /></figure>

one or two drops of triethylamine under reflux for 12 h (Scheme 1) to give the corresponding carbamates in good to excellent yields (76–99%; Table 1). Alternatively, the synthesis of carbamates from propargyl

<table><caption>**Table 1.** Yields of propargyl and allyl carbamates **3a–3j**, **4a**, and **4b** and but-3-yn-1-yl phenylcarbamate directly from the corresponding isocyanates (method *a*) and from Cbz-protected amines (method *b*)</caption><thead><tr><th rowspan="2">Compound no.</th><th colspan="2">Yield, %</th></tr><tr><th>method a</th><th>method b</th></tr></thead><tbody><tr><td>3a</td><td>99</td><td>91</td></tr><tr><td>3b</td><td>94</td><td>80</td></tr><tr><td>3c</td><td>93</td><td>70</td></tr><tr><td>3d</td><td>90</td><td>56</td></tr><tr><td>3e</td><td>94</td><td>63</td></tr><tr><td>3f</td><td>91</td><td>54</td></tr><tr><td>3g</td><td>93</td><td>61</td></tr><tr><td>3h</td><td>90</td><td>50</td></tr><tr><td>3i</td><td>94</td><td>62</td></tr><tr><td>3j</td><td>88</td><td>71</td></tr><tr><td>4a</td><td>82</td><td>66</td></tr><tr><td>4b</td><td>76</td><td>63</td></tr><tr><td>But-3-yn-1-yl phenylcarbamate</td><td>95</td><td>94</td></tr></tbody></table>

alcohols and Cbz-protected amines at room temperature with *in situ* generation of intermediate isocyanates (Scheme 2) afforded moderate yields, in most cases due to incomplete conversion of the alcohol. Furthermore, the products required additional purification; the only exception was the reaction with 3-phenylprop-2-yn-1-ol (1c) in which the yield was fairly good. The reaction proceeded quite rapidly (2 h) as compared to the first procedure.

The yields of carbamates **3a**, **3b**, and **3j** (Table 1) were slightly higher due to the high reactivities of terminal propargylic alcohols compared to internal ones [19]. The required internal propargylic alcohols **1c–1i** were prepared by the Sonogashira coupling with the corresponding aryl iodides in the presence of triethylamine [20, 21]. It may be inferred that the presence of an electron-donating group in the benzene ring led to a slight decrease of the yield of carbamates (**3d**, **3f**, **3h**). Propargylic alcohols containing an electron-withdrawing substituent on the benzene were converted into carbamates **5e**, **5g**, and **5i** with relatively higher yields. Allyl carbamates **4a** and **4b** were obtained in good yields (82 and 76%, respectively) by refluxing phenyl isocyanate with allylic alcohols **2a** and **2b** for 12 h (Scheme 1). The reaction of Cbz-protected amines with allylic alcohols in anhydrous methylene chloride (Scheme 2) provided 66% of **4a** and 63% of **4b**. But-3-yn-1-yl phenylcarbamate derived from homopropargylic alcohol was synthesized with an excellent yield (95%).