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Papers by Haitham Elleuch

Al(OiPr)3 as an Effective Catalyst for the Enhancement of Meerwein−Ponndorf−Verley (MPV) Reductions of Morita-Baylis-Hillman (MBH) cyclic alcohols

Journal of molecular structure, Jun 1, 2024

Carbonyl reductions using NaBH4 are generally high-yielding and highly selective processes common... more Carbonyl reductions using NaBH4 are generally high-yielding and highly selective processes commonly used in organic synthesis and the pharmaceutical industry. However, the reaction is exothermic, and the stability of the NaBH4 solution is limited, resulting in long reaction times. In this work, effcient reductions of MBH alcohols with CeCl3/NaBH4 in MeOH are reported . Furthemore in this method, aluminum isopropoxide and isobutanol are employed as proton sources in a transfer process. This approach exhibits impressive selectivity and high yields, resulting in the desired formation of bidentate allylic alcohol.

An efficient one-pot synthesis of benzofurans from functionalized tetrahydronaphtalenes

Tetrahedron, May 1, 2024

A simple, rapid and highly regioselective approach has been achieved for the cyclization of tetra... more A simple, rapid and highly regioselective approach has been achieved for the cyclization of tetrahydronaphthalenes (THN) using α-bromoketones, resulting in the synthesis of benzo[b]furans with high yields. The reaction occurred in DMF in the presence of K2CO3, operating at a temperature of 80 ◦C. The yields of this reaction range from 61 % to 93 %.

Antiplatelet Activity and Toxicity Profile of Novel Phosphonium Salts Derived from Michael Reaction

European Journal of Pharmaceutical Sciences, Dec 31, 2023

In this work, fve novel phosphonium salts derived from the Michael reaction were screened for the... more In this work, fve novel phosphonium salts derived from the Michael reaction were screened for their antiplatelet activity. Our fndings revealed that compounds 2a, 2b, 2c, and 2d signifcantly inhibit platelet aggregation triggered by ADP or collagen (P < 0.001). Notably, compound 2c inhibited the arachidonic acid pathway (P <0.001). Moreover, the selected compounds reduce CD62-P expression and inhibit GPIIb/IIIa activation. The interactions of the active compounds with their targets, ADP and collagen receptors, P2Y12 and GPVI respectively were investigated in silico using molecular docking studies. The results revealed a strong affnity of the active compounds for P2Y12 and GPVI. Additionally, cytotoxicity assays on platelets, erythrocytes, and human embryonic kidney HEK293 cells showed that compounds 2a, 2c and 2d were non-toxic even at high concentrations. In summary, our study shows that phosphonium salts can have strong antiplatelet power and suggests that compounds 2a, 2c and 2d could be promising antiplatelet agents for the management of cardiovascular diseases.

Selection of electron-deficient substances as antifungal candidates

Mycological Progress

A new class of bioactive compounds synthesized from Morita-Baylis–Hillman adducts (MBH) showed an... more A new class of bioactive compounds synthesized from Morita-Baylis–Hillman adducts (MBH) showed antioxidant and antimelanogenesis activities.Therefore, the present researchwork explores the relationship between antifungal activity and the responsible chemical function of MBH adducts and their derivatives (alcohols, acetates, phosphonates and hydrazono phosphonates). It was against the phyto-pathogenic fungiAspergillus niger, Fusarium oxysporum, Penicillium occitanis, Trichoderma reesei, Stachybotrys microspora, Fusarium solani,Trichoderma parceramosum, Fusarium aethiopicum, Alternaria alternata and Aspergillus favus using the agar difusion method. Our results showed that acetates exhibited varying degrees of antifungal activity against several fungi tested, while single alcohol revealed a weaker activity. The fve-membered ring derivative was the most potent with an inhibition zone diameter of 4.75 ±0.21, 6.1±0.14, 4.35±0.21, 3.9±0.14, 4.54±0.11, 3.55 ± 0.07, 3 ± 0, 3.2 ± 0.2, 5.36 ± 0.26 and 5.06 ± 0.5 cm against F. oxysporum, T. parceramosum, S. microspora, T. reesei, F. solani, P. occitanis, A. niger, F. aethiopicum, A. alternataand A. favus, respectively. Compared to the positive control, i.e., the nystatin, the most tested compounds exhibited moderate to strong growth inhibitory efects, depending on the radical group. The originality of this work is that several adducts were evaluated, for the frst time. Acetates or alcohols with fve and six-membered rings exhibited good antifungal activity. Linear or cyclic molecules coupled to fve carbons generally carried an antifungal activity. The fve-membered carbon acetates have thus been proven to be the most efective derivatives.

Spectral study of phosphonium salts synthesized from Michael acceptors

Phosphorus, Sulfur, and Silicon and the Related Elements

The synthesis of new phosphonium salts derived from Michael acceptors via a one-pot reaction proc... more The synthesis of new phosphonium salts derived from Michael acceptors via a one-pot reaction process and the study of their NMR characteristics is described. The simple and rapid 1,4 addition of triphenylphosphine to the Michael acceptors in the presence of HBr (48%) (5 equivalents) was carried out at room temperature to give the corresponding phosphonium salts with excellent yields

New Morita-Baylis-Hillman (MBH) phosphonium salts from alcohols to the synthesis of 2-alkenyl- and 2-alkylidenecyclohexenones

Journal of Molecular Structure

In previous work, a new class of synthesized bioactive compounds of Morita-Baylis-Hillman adducts... more In previous work, a new class of synthesized bioactive compounds of Morita-Baylis-Hillman adducts (MBH) showed an antioxidant and anti melanogensis activity [17–23]. Accordingly, in the present work the relationship between antifungal activity and the responsible chemical function of MBH adducts and their derivatives (alcohols, acetates, phosphonates and hydrazono phosphonates) was investigated against plant pathogenic fungi Aspergillus niger, Fusarium oxysporum, Penicillium occitanis, Trichoderma reesei, Stachybotrys microspora, Fusarium solani, Trichoderma parceramosum, fusarium aethiopicum, Alternaria alternata and Aspergillus flavus using the agar diffusion method. Results showed acetates displayed varying degrees of antifungal activity against several fungi tested, while just one alcohol compound showed lower activity. The derivative with five carbon (2g) was the most powerful with an inhibitor growth zone diameter of 4.75 ÷ 0.21, 6.1 ± 0.14, 4.35 ± 0.21, 3.9 ± 0.14, 4.54 ± 0.1...

Direct nucleophilic substitutions of allylic alcohols with 1,3-dicarbonyl compounds: Synthetic design, mechanistic aspects and applications

Tetrahedron, 2022

The nucleophilic allylic substitutions have become one of the most powerful tools for the constru... more The nucleophilic allylic substitutions have become one of the most powerful tools for the construction of carbon-carbon and carbon-heteroatom bonds in organic chemistry. This review focuses on the main previous reports dealing with the evolution of the direct nucleophilic substitutions of simple allylic alcohols or diversely functionalized ones (i.e., Morita-Baylis-Hillman alcohols) with 1,3-dicarbonyl compounds, under the catalysis of a variety of transition metals (Pd, Ir, Ru, Rh, Cu, Ni, Fe, Co, Au, Ag, Pt, W) and rare earth metals (Sc, La, Yb) complexes under activators-free conditions or in the presence of activators, as well as Lewis/Brønsted acids, and organocatalysts. In each synthetic process, a mechanistic aspect is proposed, along with a comparison of the observed regioselectivity in Pd-catalyzed allylic alkylations with that of other metals. Finally, numerous applications to the synthesis of complex molecules and natural products, are presented.

Arkivoc, 2017

An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylami... more An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylamine, and hydrazine derivatives with a series of γ-keto allyl phosphonates in the presence of p-toluene sulfonic acid (PTSA), is described herein. All the synthesized compounds are obtained in 76-98% yields and fully characterized.

Bioorganic Chemistry, 2018

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radi... more Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic fields. We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to find out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10-50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

Bioorganic chemistry, 2018

The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encourage... more The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity. As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives.

Beilstein Journal of Organic Chemistry, 2016

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both... more An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.

Synthetic Communications, 2016

Under mild, transition-metal-free conditions, a simple protocol for the preparation of functional... more Under mild, transition-metal-free conditions, a simple protocol for the preparation of functionalized allylic amines from the reaction of Morita-Baylis-Hillman (MBH) bromides with amines, is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et 3 N in aqueous acetone solution and at room temperature, affords the corresponding functionalized allyl amines in moderate to good yields (45-87%). The reaction is rapid and carried out at room temperature.

Synthesis, spectroscopic characterization and solution behavior of new tin tetrachloride adducts with γ-keto allyl phosphonates

Journal of Molecular Structure, 2017

Abstract Four new octahedral complexes of the type [SnCl 4 L 2 ] (L = γ-keto allyl phosphonate) (... more Abstract Four new octahedral complexes of the type [SnCl 4 L 2 ] (L = γ-keto allyl phosphonate) ( 1 – 4 ) were prepared and characterized by multinuclear ( 1 H, 13 C, 31 P and 119 Sn) NMR, IR spectroscopy and elemental analysis. The NMR data show, as expected, that these complexes exist in solution as mixtures of cis and trans isomers. More importantly, the solution structure was confirmed by 119 Sn NMR spectra which show two triplets corresponding to the two isomers. In addition, the solution behavior of these complexes in the presence of excess ligand was studied by variable temperature NMR using the coalescence temperature method. The metal-ligand exchange activation energies were therefore determined and found to be in the range 57–60 kJ/mol. The effect of remote substituents on the metal-ligand interaction was studied and compared with closely related tin-phosphoryl complexes.

Synthesis of a Series of γ-Keto Allyl Phosphonates

The Journal of Organic Chemistry, 2016

Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid convers... more Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid conversion of cyclic Morita-Baylis-Hillman (MBH) acetates into the corresponding γ-keto allyl phosphonates in 70-93% yields is described herein. This allylic nucleophilic substitution works well with primary and secondary acetates bearing, at the β'-position, linear or branched alkyl groups and aryl groups.

Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line, 2019

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radi... more Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic felds.
We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to fnd out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-
oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10–50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

Transition-metal-free nucleophilic allylic substitutions of Morita–Baylis–Hillman bromides with aliphatic and aromatic amines, 2016

A simple protocol for the preparation of functionalized allylic amines under mild, transition-met... more A simple protocol for the preparation of functionalized allylic amines under mild, transition-metal-free conditions from the reaction of Morita–Baylis–Hillman (MBH) bromides with amines is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et3N in aqueous acetone solution and at room temperature affords the corresponding functionalized allyl amines in moderate to good yields (45–87%). The reaction is rapid and carried out at room temperature.

First DMAP mediated direct conversion of Morita–Baylis–Hillman alcohols into γ ketoallylphosphonates, 2016

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both... more An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.
Beilstein J. Org. Chem. 2016, 12, 2906–2915.

Potential antioxidant activity of Morita-Baylis-Hillman adducts, 2018

The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encourage... more The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity.
As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives.

Synthesis, spectroscopic characterization and solution behavior of new tin tetrachloride adducts with g-keto allyl phosphonates, 2017

Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were pre... more Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were prepared and characterized by multinuclear (1H, 13C, 31P and 119Sn) NMR, IR spectroscopy and elemental analysis.
The NMR data show, as expected, that these complexes exist in solution as mixtures of cis and trans isomers. More importantly, the solution structure was confirmed by 119Sn NMR spectra which show two triplets corresponding to the two isomers. In addition, the solution behavior of these complexes in the presence of excess ligand was studied by variable temperature NMR using the coalescence temperature method. The metal-ligand exchange activation energies were therefore determined and found to be in the range 57e60 kJ/mol. The effect of remote substituents on the metal-ligand interaction was studied and compared with closely related tin-phosphoryl complexes.
1127 (2017) 169-174

Al(OiPr)3 as an Effective Catalyst for the Enhancement of Meerwein−Ponndorf−Verley (MPV) Reductions of Morita-Baylis-Hillman (MBH) cyclic alcohols

Journal of molecular structure, Jun 1, 2024

Carbonyl reductions using NaBH4 are generally high-yielding and highly selective processes common... more Carbonyl reductions using NaBH4 are generally high-yielding and highly selective processes commonly used in organic synthesis and the pharmaceutical industry. However, the reaction is exothermic, and the stability of the NaBH4 solution is limited, resulting in long reaction times. In this work, effcient reductions of MBH alcohols with CeCl3/NaBH4 in MeOH are reported . Furthemore in this method, aluminum isopropoxide and isobutanol are employed as proton sources in a transfer process. This approach exhibits impressive selectivity and high yields, resulting in the desired formation of bidentate allylic alcohol.

An efficient one-pot synthesis of benzofurans from functionalized tetrahydronaphtalenes

Tetrahedron, May 1, 2024

A simple, rapid and highly regioselective approach has been achieved for the cyclization of tetra... more A simple, rapid and highly regioselective approach has been achieved for the cyclization of tetrahydronaphthalenes (THN) using α-bromoketones, resulting in the synthesis of benzo[b]furans with high yields. The reaction occurred in DMF in the presence of K2CO3, operating at a temperature of 80 ◦C. The yields of this reaction range from 61 % to 93 %.

Antiplatelet Activity and Toxicity Profile of Novel Phosphonium Salts Derived from Michael Reaction

European Journal of Pharmaceutical Sciences, Dec 31, 2023

In this work, fve novel phosphonium salts derived from the Michael reaction were screened for the... more In this work, fve novel phosphonium salts derived from the Michael reaction were screened for their antiplatelet activity. Our fndings revealed that compounds 2a, 2b, 2c, and 2d signifcantly inhibit platelet aggregation triggered by ADP or collagen (P < 0.001). Notably, compound 2c inhibited the arachidonic acid pathway (P <0.001). Moreover, the selected compounds reduce CD62-P expression and inhibit GPIIb/IIIa activation. The interactions of the active compounds with their targets, ADP and collagen receptors, P2Y12 and GPVI respectively were investigated in silico using molecular docking studies. The results revealed a strong affnity of the active compounds for P2Y12 and GPVI. Additionally, cytotoxicity assays on platelets, erythrocytes, and human embryonic kidney HEK293 cells showed that compounds 2a, 2c and 2d were non-toxic even at high concentrations. In summary, our study shows that phosphonium salts can have strong antiplatelet power and suggests that compounds 2a, 2c and 2d could be promising antiplatelet agents for the management of cardiovascular diseases.

Selection of electron-deficient substances as antifungal candidates

Mycological Progress

A new class of bioactive compounds synthesized from Morita-Baylis–Hillman adducts (MBH) showed an... more A new class of bioactive compounds synthesized from Morita-Baylis–Hillman adducts (MBH) showed antioxidant and antimelanogenesis activities.Therefore, the present researchwork explores the relationship between antifungal activity and the responsible chemical function of MBH adducts and their derivatives (alcohols, acetates, phosphonates and hydrazono phosphonates). It was against the phyto-pathogenic fungiAspergillus niger, Fusarium oxysporum, Penicillium occitanis, Trichoderma reesei, Stachybotrys microspora, Fusarium solani,Trichoderma parceramosum, Fusarium aethiopicum, Alternaria alternata and Aspergillus favus using the agar difusion method. Our results showed that acetates exhibited varying degrees of antifungal activity against several fungi tested, while single alcohol revealed a weaker activity. The fve-membered ring derivative was the most potent with an inhibition zone diameter of 4.75 ±0.21, 6.1±0.14, 4.35±0.21, 3.9±0.14, 4.54±0.11, 3.55 ± 0.07, 3 ± 0, 3.2 ± 0.2, 5.36 ± 0.26 and 5.06 ± 0.5 cm against F. oxysporum, T. parceramosum, S. microspora, T. reesei, F. solani, P. occitanis, A. niger, F. aethiopicum, A. alternataand A. favus, respectively. Compared to the positive control, i.e., the nystatin, the most tested compounds exhibited moderate to strong growth inhibitory efects, depending on the radical group. The originality of this work is that several adducts were evaluated, for the frst time. Acetates or alcohols with fve and six-membered rings exhibited good antifungal activity. Linear or cyclic molecules coupled to fve carbons generally carried an antifungal activity. The fve-membered carbon acetates have thus been proven to be the most efective derivatives.

Spectral study of phosphonium salts synthesized from Michael acceptors

Phosphorus, Sulfur, and Silicon and the Related Elements

The synthesis of new phosphonium salts derived from Michael acceptors via a one-pot reaction proc... more The synthesis of new phosphonium salts derived from Michael acceptors via a one-pot reaction process and the study of their NMR characteristics is described. The simple and rapid 1,4 addition of triphenylphosphine to the Michael acceptors in the presence of HBr (48%) (5 equivalents) was carried out at room temperature to give the corresponding phosphonium salts with excellent yields

New Morita-Baylis-Hillman (MBH) phosphonium salts from alcohols to the synthesis of 2-alkenyl- and 2-alkylidenecyclohexenones

Journal of Molecular Structure

In previous work, a new class of synthesized bioactive compounds of Morita-Baylis-Hillman adducts... more In previous work, a new class of synthesized bioactive compounds of Morita-Baylis-Hillman adducts (MBH) showed an antioxidant and anti melanogensis activity [17–23]. Accordingly, in the present work the relationship between antifungal activity and the responsible chemical function of MBH adducts and their derivatives (alcohols, acetates, phosphonates and hydrazono phosphonates) was investigated against plant pathogenic fungi Aspergillus niger, Fusarium oxysporum, Penicillium occitanis, Trichoderma reesei, Stachybotrys microspora, Fusarium solani, Trichoderma parceramosum, fusarium aethiopicum, Alternaria alternata and Aspergillus flavus using the agar diffusion method. Results showed acetates displayed varying degrees of antifungal activity against several fungi tested, while just one alcohol compound showed lower activity. The derivative with five carbon (2g) was the most powerful with an inhibitor growth zone diameter of 4.75 ÷ 0.21, 6.1 ± 0.14, 4.35 ± 0.21, 3.9 ± 0.14, 4.54 ± 0.1...

Direct nucleophilic substitutions of allylic alcohols with 1,3-dicarbonyl compounds: Synthetic design, mechanistic aspects and applications

Tetrahedron, 2022

The nucleophilic allylic substitutions have become one of the most powerful tools for the constru... more The nucleophilic allylic substitutions have become one of the most powerful tools for the construction of carbon-carbon and carbon-heteroatom bonds in organic chemistry. This review focuses on the main previous reports dealing with the evolution of the direct nucleophilic substitutions of simple allylic alcohols or diversely functionalized ones (i.e., Morita-Baylis-Hillman alcohols) with 1,3-dicarbonyl compounds, under the catalysis of a variety of transition metals (Pd, Ir, Ru, Rh, Cu, Ni, Fe, Co, Au, Ag, Pt, W) and rare earth metals (Sc, La, Yb) complexes under activators-free conditions or in the presence of activators, as well as Lewis/Brønsted acids, and organocatalysts. In each synthetic process, a mechanistic aspect is proposed, along with a comparison of the observed regioselectivity in Pd-catalyzed allylic alkylations with that of other metals. Finally, numerous applications to the synthesis of complex molecules and natural products, are presented.

Arkivoc, 2017

An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylami... more An efficient protocol involving highly chemoselective reaction of ethane-1,2-dithiol, hydroxylamine, and hydrazine derivatives with a series of γ-keto allyl phosphonates in the presence of p-toluene sulfonic acid (PTSA), is described herein. All the synthesized compounds are obtained in 76-98% yields and fully characterized.

Bioorganic Chemistry, 2018

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radi... more Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic fields. We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to find out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10-50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

Bioorganic chemistry, 2018

The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encourage... more The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity. As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives.

Beilstein Journal of Organic Chemistry, 2016

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both... more An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.

Synthetic Communications, 2016

Under mild, transition-metal-free conditions, a simple protocol for the preparation of functional... more Under mild, transition-metal-free conditions, a simple protocol for the preparation of functionalized allylic amines from the reaction of Morita-Baylis-Hillman (MBH) bromides with amines, is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et 3 N in aqueous acetone solution and at room temperature, affords the corresponding functionalized allyl amines in moderate to good yields (45-87%). The reaction is rapid and carried out at room temperature.

Synthesis, spectroscopic characterization and solution behavior of new tin tetrachloride adducts with γ-keto allyl phosphonates

Journal of Molecular Structure, 2017

Abstract Four new octahedral complexes of the type [SnCl 4 L 2 ] (L = γ-keto allyl phosphonate) (... more Abstract Four new octahedral complexes of the type [SnCl 4 L 2 ] (L = γ-keto allyl phosphonate) ( 1 – 4 ) were prepared and characterized by multinuclear ( 1 H, 13 C, 31 P and 119 Sn) NMR, IR spectroscopy and elemental analysis. The NMR data show, as expected, that these complexes exist in solution as mixtures of cis and trans isomers. More importantly, the solution structure was confirmed by 119 Sn NMR spectra which show two triplets corresponding to the two isomers. In addition, the solution behavior of these complexes in the presence of excess ligand was studied by variable temperature NMR using the coalescence temperature method. The metal-ligand exchange activation energies were therefore determined and found to be in the range 57–60 kJ/mol. The effect of remote substituents on the metal-ligand interaction was studied and compared with closely related tin-phosphoryl complexes.

Synthesis of a Series of γ-Keto Allyl Phosphonates

The Journal of Organic Chemistry, 2016

Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid convers... more Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid conversion of cyclic Morita-Baylis-Hillman (MBH) acetates into the corresponding γ-keto allyl phosphonates in 70-93% yields is described herein. This allylic nucleophilic substitution works well with primary and secondary acetates bearing, at the β'-position, linear or branched alkyl groups and aryl groups.

Anti-melanogenesis potential of a new series of Morita-Baylis-Hillman adducts in B16F10 melanoma cell line, 2019

Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radi... more Melanin is a natural polymer pigment which provides skin photoprotection against ultraviolet radiation. An excessive synthesis of melanin leads to hyperpigmentation disorders. Tyrosinase catalyzes the rate limiting steps on melanogenesis. Therefore, tyrosinase inhibitors have potential applications in medicine and cosmetic felds.
We carried out herein the screening of a family of cyclic Morita-Baylis-Hillman adducts (MBH) to fnd out their effects on tyrosinase activity and on melanogenesis in murine melanoma B16F10 cell line. Kinetic analysis of tyrosinase inhibition showed that compounds 1a (2-hydroxymethyl) cyclohex-2-enone) and 3f (diethyl (1-(6-
oxocyclohex-1-en-1-yl) ethyl-phosphonate) were competitive inhibitors, whereas the compound 2b (6-oxocyclohex-1-en-1-yl) ethyl acetate) was a non-competitive one. Additionally we have found that (1a, 2b and 3f) compounds had a strong melanogenesis inhibition effect in isobutylmethylxanthine (IBMX)-treated murine melanoma B16F10 cells when tested at low and non cytotoxic dose (10–50 µM), by attenuating the melanin production, intracellular tyrosinase activity and tyrosinase expression. Thus, we suggest that these compounds could be used as effective skin-whitening agents.

Transition-metal-free nucleophilic allylic substitutions of Morita–Baylis–Hillman bromides with aliphatic and aromatic amines, 2016

A simple protocol for the preparation of functionalized allylic amines under mild, transition-met... more A simple protocol for the preparation of functionalized allylic amines under mild, transition-metal-free conditions from the reaction of Morita–Baylis–Hillman (MBH) bromides with amines is described herein. The treatment of the MBH bromides with various amines in the presence of NaI and Et3N in aqueous acetone solution and at room temperature affords the corresponding functionalized allyl amines in moderate to good yields (45–87%). The reaction is rapid and carried out at room temperature.

First DMAP mediated direct conversion of Morita–Baylis–Hillman alcohols into γ ketoallylphosphonates, 2016

An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both... more An efficient synthesis of a series of γ-ketoallylphosphonates through a direct conversion of both primary and secondary Morita–Baylis–Hillman (MBH) alcohols by trialkyl phosphites with or without DMAP, used as additive, and under solvent-free conditions, is described herein for the first time. Subsequently, a highly regioselective Luche reduction of the primary phosphonate 2a (R = H) gave the corresponding γ-hydroxyallylphosphonate 5 that further reacted with tosylamines in the presence of diiodine (15 mol %) as a catalyst, affording the corresponding SN2-type products 6a–d in 63 to 70% isolated yields. Alternatively, the alcohol 5 produced the corresponding acetate 7 which, mediated by Ce(III), was successfully converted into the corresponding γ-aminoallylphosphonates 8a–d.
Beilstein J. Org. Chem. 2016, 12, 2906–2915.

Potential antioxidant activity of Morita-Baylis-Hillman adducts, 2018

The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encourage... more The wide variety of potent biological activities of Morita-Baylis-Hillman adducts (MBH) encouraged us to synthesize new series of products belonging to this class of compounds, possessing different functionalities and exhibiting potential antioxidant activity.
As part of our on-going program on targeting molecules with antioxidant activity, we describe herein different DPPH (2,2-diphenyl-1-picrylhydrazyl) scavenging activities of MBH alcohols and their derivatives including acetates, phosphonates and hydrazonophosphonates. The obtained results showed that the strongest DPPH radical scavenging activity was observed in the case of hydrazonophosphonates in comparison to the other MBH derivatives.

Synthesis, spectroscopic characterization and solution behavior of new tin tetrachloride adducts with g-keto allyl phosphonates, 2017

Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were pre... more Four new octahedral complexes of the type [SnCl4L2] (L ¼ g-keto allyl phosphonate) (1e4) were prepared and characterized by multinuclear (1H, 13C, 31P and 119Sn) NMR, IR spectroscopy and elemental analysis.
The NMR data show, as expected, that these complexes exist in solution as mixtures of cis and trans isomers. More importantly, the solution structure was confirmed by 119Sn NMR spectra which show two triplets corresponding to the two isomers. In addition, the solution behavior of these complexes in the presence of excess ligand was studied by variable temperature NMR using the coalescence temperature method. The metal-ligand exchange activation energies were therefore determined and found to be in the range 57e60 kJ/mol. The effect of remote substituents on the metal-ligand interaction was studied and compared with closely related tin-phosphoryl complexes.
1127 (2017) 169-174