The Michael donor-acceptor reactivity of curcumins in the synthesis of diverse multi-functional scaffolds.

Curcumin is a key constituent of turmeric with a variety of biological activities. From a chemical point of view, curcumin contains different functional groups that can undergo multiple transformations such as Michael addition, cycloaddition, click reaction, polymerisation, etc. Among these, Michael-type reactions under benign conditions constitute a captivating domain of curcumin's reactivity. To the best of our knowledge, no review focusing on the Michael donor-acceptor reactivity of curcumins has been published to date. Herein, we have compiled the chemistry of curcumins with respect to their chemical synthesis, biosynthesis, and involvement in chemical transformations, especially in Michael additions with advances in mechanistic aspects and understanding.

Hauser-Kraus Annulation Initiated Multi-Cascade Reactions for Facile Access to Functionalized and Fused Oxazepines, Carbazoles and Phenanthridinediones.

The Hauser-Kraus (H-K) annulation of N-unsubstituted 3-olefinic oxindoles with 3-nucleophilic phthalides triggers a cascade of ring expansion and ring contraction reactions through several regioselective steps in one pot. While oxazepines were isolated in the presence of stoichiometric amounts of base at room temperature, carbazoles and phenanthridinediones were the products in the presence of excess base and microwave irradiation. Mechanistic studies guided by stepwise reactions and control experiments revealed that the isolable oxazepine intermediate, formed via ring expansion of the H-K adduct, is the key precursor to carbazole and phenanthridinedione via decarboxylative regioselective cyclizations.

His1-tagged DM or DDM detergent micelles are reversibly conjugated by nickel ions.

Specific conjugation of decyl ß-D-maltoside (DM) or dodecyl ß-D-maltoside (DDM) detergent micelles is accomplished between pH 7.0-8.5 in the presence of an amphiphilic analog of the amino acid histidine, bound to a 10-carbon hydrocarbon chain (His1-C10) and Ni2+ ions. Following addition of 10-15 wt% PEG-6000 as precipitant, phase separation in the form of oil-rich globules (30-600 µm) is observed by light microscopy. Other divalent cations: Zn2+, Fe2+, Cu2+ lead to dark precipitates rather than colorless globules; while Mg2+, Ca2+ do not promote any phase separation at all. Even in the absence of precipitant, dynamic light scattering (DLS) measurements demonstrate that DM micelles (hydrodynamic size ~ 6 nm) or DDM micelles (8 nm) self-associate into larger particles (9 nm and 411 nm for DM; 10 nm and 982 nm for DDM) in the presence of His1-C10 and nickel ions. Micellar conjugation is partially reversible in the presence of water soluble 50 mM EDTA, histidine or imidazole chelators. Cryo-transmission electron microscopy (cryo-TEM) imaging revealed the formation of non-uniformly dense detergent aggregates for both DM and DDM micelles in the presence of precipitant. The possible utility of such His1-tagged DM or DDM micelles for promoting crystallization of integral membrane proteins is discussed.

Recent advances in the synthetic applications of Morita-Baylis-Hillman and Rauhut-Currier adducts of nitroalkenes.

The Morita-Baylis-Hillman (MBH) and Rauhut-Currier (RC) adducts of nitroalkenes are important synthetic intermediates in organic synthesis. This review discusses the applications of different MBH and RC adducts of nitroalkenes such as MBH alcohols, acetates, bromides and hydrazinonitroalkenes as well as ketoalkylnitroalkenes in the synthesis of complex molecules including carbocycles and heterocycles. It also covers the mechanistic aspects, including the key intermediates and the reaction pathways. Early reports on MBH and RC reactions of nitroalkenes and applications of the products were covered in previous reviews. The present review covers the reports that appeared in the timeline of 2015-2023.

Catalyst- and Base-Free Synthesis of Morita-Baylis-Hillman and Rauhut-Currier Adducts of ß-Aminonitroalkenes.

A facile, base- and catalyst-free synthesis of Morita-Baylis-Hillman and Rauhut-Currier adducts of ß-aminonitroalkenes with different electrophiles such as ethyl glyoxylate, trifluoropyruvate, ninhydrin, vinyl sulfone, and N-tosylazadiene is reported. The products are formed in good to excellent yields at room temperature with a broad substrate scope. The adducts of ninhydrin and ß-aminonitroalkene spontaneously cyclize to fused indenopyrroles. Gram-scale reactions and synthetic transformations of the adducts are also reported here.

Synthesis of Spirolactones and Functionalized Benzofurans via Addition of 3-Sulfonylphthalides to 2-Formylaryl Triflates and Conversion to Benzofuroisocoumarins.

A convenient protocol for the synthesis of spirobenzofuran-isobenzofurans and substituted benzofurans via a modified Hauser-Kraus reaction of 3-sulfonylphthalide with 2-formylaryl triflates is reported here. The initial reaction involved 1,2-addition of phthalide to the formyl group and intramolecular cyclization via substitution of triflate followed by a cascade of rearrangements leading to spirolactone or benzofuran derivatives. The electronic nature of substituents on aryl triflates affected the course and outcome of the reaction. The mechanism was supported by successful characterization of one of the intermediates by mass spectrometry. A medicinally relevant influenza virus type B inhibitor, benzofuroisocoumarin, was synthesized in a single step from the spiro compound, thus demonstrating the synthetic utility of our methodology.

Regio- and stereoselective synthesis of functionalized tetrahydro-benzochromenes and hexahydrochromenochromenones via [4 + 2] annulation of curcumins with nitrochromenes.

A base-mediated regio- and stereoselective synthesis of functionalized tetrahydro-6H-benzo[c]chromenes and hexahydro-1H,6H-chromeno[6,5-c]chromenone is disclosed here. It involves a [4 + 2] annulation via cascade double and triple Michael reactions between curcumins and nitrochromenes in the presence of Cs2CO3 and DBU, respectively, at room temperature, and it offers a diverse array of products as single regio- and diastereomers in excellent yields under mild conditions. Preliminary studies towards developing an enantioselective version under organocatalytic conditions met with only limited success but revealed a potentially interesting kinetic resolution pathway.

Reactions of Sulfonylphthalide with Diverse Activated Imines for the Synthesis of Enaminophthalides, Spiro-isoquinolinones, and Homalicine Natural Products.

The reactivity of the Hauser-Kraus (H-K) donor, 3-sulfonylphthalide, with various activated imines under basic conditions is demonstrated. The reaction of 3-sulfonylphthalide with Boc-protected aldimine provides a rapid access to 1,2-imine adducts and alkylidenephthalides depending upon the stoichiometry of the base. The alkylidenephthalides could be transformed to ketophthalides, a new class of phthalides, on acid hydrolysis, which upon reductive cyclization using Zn/AcOH afforded the natural product homalicine. On the contrary, the Boc-protected isatinimines undergo an efficient H-K annulation to provide spiro-isoquinolinone-oxindoles in excellent yields. However, the corresponding conjugated ketimines afforded Michael adducts, which were converted to the corresponding alkylidenephthalides under TBAF conditions.

Approaches to 1,4-Disubstituted Cubane Derivatives as Energetic Materials: Design, Theoretical Studies and Synthesis.

Novel 1,4-disubstituted cubane derivatives have been designed and selected ones have been successfully synthesized and characterized by various analytical and spectroscopic techniques, including single-crystal X-ray analysis. A detailed computational study at B3LYP/6-311++G(d,p) level of theory revealed that all newly designed 1,4-disubstituted cubane derivatives possess higher densities, higher density-specific impulse and superior ballistic properties when compared to conventional fuels, for example, RP-1. These compounds also exhibit acceptable kinetic and thermodynamic stabilities which were evaluated in terms of their HOMO-LUMO energy gap and bond dissociation energies, respectively, and are superior to TEX and many other compounds containing explosophoric groups. These results provide novel insights into the possible application of cubane-based energetic materials.

Regio- and stereoselective synthesis of functionalized and fused heterocycles from Morita-Baylis-Hillman adducts of dicyclopentadienone.

An efficient protocol for the Morita-Baylis-Hillman (MBH) reaction of dicyclopentadienone using CTAB has been developed. The MBH adduct was subsequently transformed to its acetate and bromide derivatives. The 1,3-bielectrophilic character of the MBH acetate and bromide was further explored with various 1,3-binucleophiles to construct various oxa-, thia- and aza-heterocycles. These reactions proceed through a cascade double Michael addition of 1,3-binucleophiles to the MBH acetate/bromide under basic conditions. Amenability of these reactions to scale-up and applications of the products in the synthesis of cyclopentenone-fused chromenones and thiopyranoindoles have been demonstrated.

Metal-Free and Regioselective Synthesis of Functionalized α-Carbolines via [3 + 3] Annulation of Morita-Baylis-Hillman Acetates of Nitroalkenes with Iminoindolines.

A facile, metal-free method for the synthesis of substituted α-carbolines from secondary Morita-Baylis-Hillman (MBH) acetates of nitroalkenes is presented. The cascade reaction of MBH acetates with tosyliminoindolines occurs regioselectively to form various α-carbolines with a wide substrate scope. The reaction involves mild conditions, and the products are formed in high yields within a short reaction time. The amenability of the reaction to scale up and synthetic applications of the products have been demonstrated.

Regio- and Stereoselective Synthesis of Dispiro-bisoxindoles via [3+2] Annulation Involving Nitroisatylidene as a Vinylogous Michael Donor.

A cascade [3+2] annulation, involving a γ-selective vinylogous Michael addition of nitroalkylideneoxindoles to various electron deficient alkenes followed by an intramolecular Michael addition, provides access to dispiro-bis-oxindoles and spiro-oxindoles. Up to four contiguous chiral centers, including two quaternary spirocenters, are generated in this high-yield regio- and diastereoselective transformation that also provides a convenient entry into conformationally constrained γ-amino acid derivatives.

Synthesis of ß-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles.

Desulfonylative alkylation of N-tosyl-1,2,3-triazoles under metal-free conditions leading to ß-triazolylenones is reported here. The present study encompasses the synthesis of triazoles with a new substitution pattern in a single step from cyclic 1,3-dicarbonyl compounds and N-tosyl triazole in moderate to high yields. Our synthesis takes place with complete regioselectivity as confirmed by crystallographic analysis which is rationalized by a suitable mechanistic proposal. This method provides an efficient, versatile and straightforward strategy towards the synthesis of new functionalized 1,2,3-triazoles.

Stereoselective Synthesis of Tri- and Tetrasubstituted Olefins via 1,6-Additions of Diazo Compounds and Their Precursors to p-Quinone Methides.

Reactions of para-quinone methides (p-QMs) with α-diazo-ß-ketosulfones and their corresponding esters as well as simple ß-dicarbonyl compounds and ß-ketosulfones have been carried out under basic conditions. While the reaction of diazosulfone with p-QMs afforded trisubstituted olefins via deacylative 1,6-addition and elimination, α-diazo-ß-ketoesters and various active methylene compounds such as 1,3-dicarbonyls and ß-ketosulfones afforded tetrasubstituted olefins via 1,6-addition and aerial oxidation. These simple, environmentally benign, and mechanistically diverse protocols provided the products in moderate to excellent yields and selectivities.

Strategies towards potent trypanocidal drugs: Application of Rh-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulation and nitroalkene reactions for the synthesis of substituted quinones and their evaluation against Trypanosoma cruzi.

Rhodium-catalyzed [2 + 2 + 2] cycloadditions, sulfonyl phthalide annulations and nitroalkene reactions have been employed for the synthesis of 56 quinone-based compounds. These were evaluated against Trypanosoma cruzi, the parasite that causes Chagas disease. The reactions described here are part of a program that aims to utilize modern, versatile and efficient synthetic methods for the one or two step preparation of trypanocidal compounds. We have identified 9 compounds with potent activity against the parasite; 3 of these were 30-fold more potent than benznidazole (Bz), a drug used for the treatment of Chagas disease. This article provides a comprehensive outline of reactions involving over 120 compounds aimed at the discovery of new quinone-based frameworks with activity against T. cruzi.

Synthesis of indenofurans, benzofurans and spiro-lactones via Hauser-Kraus annulation involving 1,6-addition of phthalide to quinone methides.

An unprecedented reactivity of 3-sulfonylphthalide with 2-hydroxyaryl-p-quinone methides (HQMs) is reported here. A cascade of reactions starting with 1,6-addition and Dieckmann cyclization produced a diverse array of indenofurans and benzofurans in high yields, depending on the amount of base used, presumably via a common 8-membered ketolactone intermediate. The indenofurans could be transformed to benzofurans in the presence of excess base via a key spiro-lactone intermediate, which could be characterized via in situ oxidation to a stable spirolactone linked quinone methide, providing crucial evidence for the mechanism of the reaction. The three diverse oxygen heterocycles synthesized by our methodology constitute the core structure of several bioactive compounds including natural products.

Substrate-oriented selectivity in the Mg-mediated conjugate addition of bromoform to electron-deficient alkenes.

The Mg-mediated conjugate addition of bromoform to a variety of electron-deficient alkenes has been investigated. In the case of nitrodienes and dibenzylideneacetones, tribromomethylated products were isolated, whereas spiro-cyclopropanated products were obtained with cyclic dibenzylideneketones and 3-olefinic oxindoles. The spiro-cyclopropyl ketones derived from cyclic dibenzylideneketones were successfully transformed into fused furans via the Cloke-Wilson rearrangement.

Synthesis of Densely Substituted Sulfonylfurans and Dihydrofurans via Cascade Reactions of α-Functionalized Nitroalkenes with ß-Ketosulfones.

The reaction of ß-ketosulfones with different α-functionalized nitroalkenes affords diversely substituted sulfonylfurans and dihydrofurans. Furthermore, ß-ketosulfones react with α-bromonitroalkenes and α-hydrazinonitroalkenes via a cascade Michael addition-cyclization protocol to afford nitrodihydrofurans and hydrazinodihydrofurans, respectively, bearing a key sulfonyl group, in excellent yields with a broad substrate scope. Application of these products has been demonstrated by the synthesis of pyrroles and pyrazoles in good yields. The reaction of ß-ketosulfones with nitroallylic acetates yields tetrasubstituted sulfonyl furans through a cascade SN2'-intramolecular Michael reaction, followed by aromatization. The gram-scale synthesis of a representative example of sulfonylfurans was carried out to demonstrate the synthetic efficiency of the methodology.

Stereoselective synthesis of hydrazinodihydrofurans via cascade Michael addition-substitution involving the reaction of curcumin and other ß-dicarbonyls with α-hydrazinonitroalkenes.

Highly diastereoselective synthesis of 2-hydrazinated 2,3-dihydrofurans in good to excellent yields involving an interrupted Feist-Bénary type reaction by treating a wide variety of 1,3-dicarbonyl compounds, including curcumins, with α-hydrazinated nitroalkenes is reported here. The first ever enantioselective reaction of α-hydrazinonitroalkenes has also been carried out with two selected 1,3-dicarbonyls, dimedone and cyclohexanone by employing an l-t-leucine derived squaramide as the chiral organocatalyst to afford the enantio-enriched 2-hydrazinodihydrofurans as single diastereomers in good yields and with good enantioselectivities.