Avoiding hot-spots in Microwave-Assisted Pd/C catalysed reactions by using the biomass derived solvent γ-Valerolactone

Herein, we report the use of γ-valerolactone as a new biomass-derived reaction medium for microwave assisted organic synthesis. The interaction of this solvent with microwaves and its heating profile under microwave irradiation has been fully characterized for the first time, demonstrating its stability and the applicability in microwave assisted Pd/C catalysed reactions avoiding the arcing phenomena frequently observed in these conditions. The use of γ-valerolactone demonstrated to be compatible with aliphatic and aromatic amines in the hydrogen transfer Pd/C mediated synthesis of benzimidazoles

Smoothened-antagonists reverse homogentisic acid-induced alterations of Hedgehog signaling and primary cilium length in alkaptonuria

Alkaptonuria (AKU) is an ultra-rare genetic disease, in which the accumulation of a toxic metabolite, homogentisic acid (HGA) leads to the systemic development of ochronotic aggregates. These aggregates cause severe complications mainly at the level of joints with extensive degradation of the articular cartilage. Primary cilia have been demonstrated to play an essential role in development and the maintenance of articular cartilage homeostasis, through their involvement in mechanosignaling and Hedgehog signaling pathways. Hedgehog signaling has been demonstrated to be activated in osteoarthritis (OA) and to drive cartilage degeneration in vivo. The numerous similarities between OA and AKU suggest that primary cilia Hedgehog signaling may also be altered in AKU. Thus, we characterized an AKU cellular model in which healthy chondrocytes were treated with HGA (66μM) to replicate AKU cartilage pathology. We investigated the degree of activation of the Hedgehog signaling pathway and how treatment with inhibitors of the receptor Smoothened (Smo) influenced Hedgehog activation and primary cilia structure. The results obtained in this work provide a further step in the comprehension of the pathophysiological features of AKU, suggesting a potential therapeutic approach to modulate AKU cartilage degradation processes through manipulation of the Hedgehog pathway

Micellar catalysis for sustainable hydroformylation

It is here reported a fully sustainable and generally applicable protocol for the regioselective hydroformylation of terminal alkenes, using cheap commercially available catalysts and ligands, in mild reaction conditions (70 °C, 9 bar, 40 min). The process can take advantages from both micellar catalysis and microwave irradiation to obtain the linear aldehydes as the major or sole regioisomers in good to high yields. The substrate scope is largely explored as well as the application of hydroformylation in tandem with intramolecular hemiacetalization thus demonstrating the compatibility with a broad variety of functional groups. The reaction is efficient even in large scale and the catalyst and micellar water phase can be reused at least 5 times without any impact in reaction yields. The efficiency and sustainability of this protocol is strictly related to the in situ transformation of the aldehyde into the corresponding Bertagnini’s salt that precipitates in the reaction mixture avoiding organic solvent mediated purification steps to obtain the final aldehydes as pure compounds

Metal Catalysis with Microwaves in Organic Synthesis: a Personal Account

In the last 25 years, the influence of microwave (MW) irradiation in chemical synthesis has intrigued chemists for the exceptional results obtained in shortening reaction times. Inspired by recent papers that demonstrate the existence of a non-thermal effect in some MW assisted reactions, we examine herein a series of reactions catalysed by homogeneous and heterogeneous metals occurring under MW irradiation. The review contains examples of hydroformylation, hydrogenation (including enantioselective versions with 98 % ee), hydrogenolysis, hydrogen transfer and borrowing hydrogen reactions carried out under MWs and metal catalysis. An increase in the influence of MW irradiation was often observed in reactions performed with heterogeneous catalysts such as Pd/C. In these cases, a “microwave catalysis” can be possible. The increase in the (apparent) reaction rate requires the contribution of MW irradiation that modifies the catalyst surface, driving the reaction progress as occurring in other kinds of catalysis

Stereoselective Synthesis of N1-6-Methyluridine and Related 2-Substituted Analogues

Coupling reaction of 2-substituted-6-methyl-4(3H)-pyrimidinones (la,b) with I-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (ABR) afforded the corresponding N1-2,6-disubstituted nucleosides (2a,b) without any trace of the N3-isomer. The 2-methylthio-6-methyl derivative (2b) has then proved to be a key intermediate for the synthesis of N1-6-methyluridine (4) and the corresponding N1-2-amino-6-metyhl derivative (5), suggesting the possibility to obtain different 2,6-disubstituted derivatives by means of methylthio nucleophilic substitution. A successful solid phase application was also shown

Microwave-assisted intramolecular huisgen cycloaddition of azido alkynes derived from α-amino acids

The intramolecular version of the Huisgen cycloaddition is a potentially useful reaction for the stereocontrolled preparation of 1,5-disubstituted and 1,4,5-trisubstiututed triazoles. When α-azido propargyl esters derived from α-amino acids are submitted to [3 + 2] cycloaddition, the expected 4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-ones are not formed; rather, an oligomeric cyclic polyester is obtained via a prevailing intermolecular cycloaddition. We have discovered that propargyl α-azido amides undergo metal-free intramolecular Huisgen cycloaddition in MeCN/H2O under microwave dielectric heating. This reaction provides access to new condensed triazoles that can be considered as conformationally constrained peptidomimetics. Moreover, the following microwave-assisted lactam ring opening provides 1,4-disubstituted and 1,4,5-trisubstituted triazole amino acids. The same kind of compounds are obtained from the ester cycloadduct by reaction with primary amines in the presence of AlMe3. In order to interpretate this unpredictable behavior, an ab initio study of the reaction pathway was undertaken using GAMESS(US) at the B3LYP/6-31G** level of theory. Different relaxed potential energy profiles were obtained for esters and amides, suggesting that the cis-arrangement of the-CO=N-could account for the amide reactivity

In Water Markovnikov Hydration and One-Pot Reductive Hydroamination of Terminal Alkynes under Ruthenium Nanoparticle Catalysis

In the presence of Shvo's catalyst [2,3,4,5-tetraphenyl-1,3-cyclopentadien-1-ol, ruthenium(II) complex], a small quantity of aniline and TGPS-750-M surfactant, terminal alkynes were hydrated under microwave (MW) dielectric heating in water as solvent with high conversion and good yield. The reaction gives the Markovnikov product exclusively, unlike that commonly observed with ruthenium complexes. Under the influence of MWs, Ru nanoparticles embedded in the nanomicelle environment were formed, acting as the effective hydration catalyst. Introducing sodium formate in the aqueous phase and using a stoichiometric amount of amines, the Ru nanoparticle nanomicelle catalyst gave the first example of one-pot single-step hydroamination of alkynes with the formation of the corresponding secondary amines. The reaction is characterized by low environmental impact as TGPS-750-M is required in low amount, and organic solvents employed only for product separation or catalyst recycling

A general approach to substituted benzimidazoles and benzoxazoles via heterogeneous palladium catalyzed hydrogen transfer with primary amines

The synthesis of benzimidazoles starting from o-phenylenediamines and amines in the presence of palladium on charcoal as catalyst is reported. Under microwave dielectric heating it is possible to use a tertiary, a secondary, and even a primary amine as the substrate for a palladium mediated process to get 2-substituted or 1,2-disubstituted benzimidazoles, depending on the nature of the o-phenylendiamine employed. Primary amines are the most suitable reagents for the atom economy of the overall process that resulted to be general as several different substituted benzimidazoles were obtained in good yield. Benzoxazoles can be also prepared starting from primary amines and o-aminophenol. The reaction is also highly selective as no (poly)-alkylated phenylendiamines or cross-contaminated benzimidazoles are obtained starting from N-monoalkylphenylen-diamines. This behavior was interpreted as a scarce aptitude to dehydrogenation of the methylene bonded to the aromatic NH of N-alkyl-arylamines. The experiments carried out consent to draw an almost complete picture of the reaction pathways occurring during the process. The catalyst can be recycled several times and, although far from optimal performances, catalyst TON = 90 is encouraging for further large scale optimization protocols. In addition, palladium on charcoal catalyzed microwave assisted reaction of o-phenylendiamine gives tertiary amines de-alkylation and transformation into the secondary one

An improved synthesis of α,β-unsaturated nitrones relevant to the stephacidins and analogs thereof

A new method is reported for the synthesis of the α,β-unsaturated nitrone moiety characteristic of the stephacidin/avrainvillamide family of bioactive prenylated indole alkaloids. Application to the synthesis of stephacidin analogs and a potential biological probe are showcased.A new method is reported for the synthesis of the α,β-unsaturated nitrone moiety characteristic of the stephacidin/avrainvillamide family of bioactive prenylated indole alkaloids. Application to the synthesis of stephacidin analogs and a potential biological probe are showcased. © 2009 Elsevier Ltd. All rights reserved