Laboratoire de Synthèse Organique

Abstract With the description of more and more complex one‐ and two‐dimensional NMR experiments comes the need to develop methods to make a comprehensive interpretation of the various different experiments that can be carried out on the same sample or series of related samples. We present some examples of modelling one‐ and two‐dimensional solid‐state NMR spectra of I = ½ spin and quadrupolar nuclei, using laboratory‐developed software that is made available to the NMR community. Copyright © 2001 John Wiley & Sons, Ltd.

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness. The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector. Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.

Nitrogen-centred radicals hold much promise as useful synthetic intermediates. Even though their popularity is still extremely limited and very far from matching that of carbon radicals, the recent development of various routes allowing their generation under mild conditions and a better appreciation of their reactivity thanks to the increased availability of absolute rate constants should encourage their use. It is hoped that this tutorial review will help increase the awareness of synthetic chemists and help revive the interest in these forgotten species.

Hyperbranched polymers (HPs) are highly branched three-dimensional (3D) macromolecules. Their globular and dendritic architectures endow them with unique structures and properties such as abundant functional groups, intramolecular cavities, low viscosity, and high solubility. HPs can be facilely synthesized via a one-pot polymerization of traditional small molecular monomers or emerging macromonomers. The great development in synthetic strategies, from click polymerization (i.e., copper-catalyzed azide-alkyne cycloaddition, metal-free azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, thiol-ene/yne addition, Diels-Alder cycloaddition, Menschutkin reaction, and aza-Michael addition) to recently reported multicomponent reactions, gives rise to diverse HPs with desirable functional/hetero-functional groups and topologies such as segmented or sequential ones. Benefiting from tailorable structures and correspondingly special properties, the achieved HPs have been widely applied in various fields such as light-emitting materials, nanoscience and technology, supramolecular chemistry, biomaterials, hybrid materials and composites, coatings, adhesives, and modifiers. In this review, we mainly focus on the progress in the structural control, synthesis, functionalization, and potential applications of both conventional and segmented HPs reported over the last decade.

The development of more sustainable materials with a prolonged useful lifetime is a key requirement for a transition towards a more circular economy. However, polymer materials that are long-lasting and highly durable also tend to have a limited application potential for re-use. This is because such materials derive their durable properties from a high degree of chemical connectivity, resulting in rigid meshes or networks of polymer chains with a high intrinsic resistance to deformation. Once such polymers are fully synthesised, thermal (re)processing becomes hard (or impossible) to achieve without damaging the degree of chemical connectivity, and most recycling options quickly lead to a drop or even loss of material properties. In this context, both academic and industrial researchers have taken a keen interest in materials design that combines high degrees of chemical connectivity with an improved thermal (re)processability, mediated through a dynamic exchange reaction of covalent bonds. In particular vitrimer materials offer a promising concept because they completely maintain their degree of chemical connectivity at all times, yet can show a clear thermally driven plasticity and liquid behavior, enabled through rapid bond rearrangement reactions within the network. In the past decade, many suitable dynamic covalent chemistries were developed to create vitrimer materials, and are now applicable to a wide range of polymer matrices. The material properties of vitrimers, however, do not solely rely on the chemical structure of the polymer matrix, but also on the chemical reactivity of the dynamic bonds. Thus, chemical reactivity considerations become an integral part of material design, which has to take into account for example catalytic and cross-reactivity effects. This mini-review will aim to provide an overview of recent efforts aimed at understanding and controlling dynamic cross-linking reactions within vitrimers, and how directing this chemical reactivity can be used as a handle to steer material properties. Hence, it is shown how a focus on a fundamental chemical understanding can pave the way towards new sustainable materials and applications.

Covalent organic frameworks (COFs) are a class of crystalline porous organic polymers assembled by connecting organic building units via covalent bonds. They are characterized as extended two-dimensional (2D) or three-dimensional (3D) frameworks with precise spatial structures and building block distribution. A key feature of COFs is their inherent porosity originating from their well-ordered nanopores which are designable, tunable and modifiable through pore engineering. This review describes the pore engineering of 2D COFs based on their framework topologies. It begins with a brief summary of the pore design principles of 2D COFs which are composed of uniform micropores or mesopores. Then the state-of-the-art progress achieved in a new branch of 2D COFs, that is, heteropore COFs, which possess multiple-pore skeletons and thus exhibit hierarchical porosity, is comprehensively reviewed, including their design strategies, synthesis, characterization, properties and applications. In the last part, personal perspectives on this emerging class of 2D polymers with complex structures and hierarchical porosity are discussed.

Abstract Although isocyanide‐based multicomponent reactions (MCRs), introduced in 1921 by Passerini, largely predominate nowadays in the construction of widely diverse heterocycles, one of the first substrate classes involved in a MCR was that of 1,3‐dicarbonyl derivatives, with Hantzsch’s dihydropyridine synthesis appearing as early as 1882. The aim of this microreview is to present an overview of the great synthetic potential of MCRs involving the specific reactivity of easily accessible 1,3‐dicarbonyl derivatives and to stress their more recent utilisation for the development of new and useful methodologies valuable for the selective construction of highly functionalised small organic molecules of high synthetic and biological value. After a short general introduction, we present chronologically the different methodologies developed on the bases of the reactivity of 1,3‐dicarbonyl systems towards many other substrates involved in a variety of synthetic pathways, including Knoevenagel condensations, Michael and Mannich reactions, cyclodehydrations, electrocyclisations, cycloadditions and metal‐promoted transformations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Although justly considered as a cumbersome component in artificial photosystems, these simple molecules are a “necessary evil” to drive photo-induced reactions aiming at producing high added value molecules by photo-induced reduction of low energy value substrates. This review first presents the specifications of sacrificial electron donors. Then the various families of sacrificial donors used from the early 1970s to nowadays are reviewed, such as aliphatic and aromatic amines, benzyl-dihydronicotinamide (BNAH), dimethylphenylbenzimidazoline (BIH), ascorbic acid, oxalate and finally thiols. Experimental conditions (pH, solvent) are immensely versatile but important trends are given for adequate operation of a three-component system. Although literature abounds with various, very different artificial photosystems, we will realize that virtually the same sacrificial donors are used over and over again.

Transition-metal catalysed C-N bond activation has attracted much attention and become one of the most promising bond disconnection and formation strategies that encompass a broad spectrum of applications in many reactions. In this tutorial review, efficient strategies for catalytic cleavage of C(sp)-N, C(sp(2))-N and C(sp(3))-N bonds and their applications in new C-C and C-N bond formation reactions are summarized.

Abstract Starburst‐Dendrimere sind dreidimensionale, hoch geordnete oligomere und polymere Verbindungen, die ausgehend von kleinen Molekülen – „Initiatorkernen”︁ wie Ammoniak oder Pentaerythrit – durch eine sich ständig wiederholende Reaktionsfolge entstehen. Bei den Synthesen, bei denen Schutzgruppentechniken von entscheidender Bedeutung sind, werden diskrete Entwicklungsstufen – „Generationen”︁ – durchlaufen, deren Größe, Gestalt und Oberflächenchemie durch die Aufbauschritte und die Synthesebausteine kontrolliert werden können. Mit den Starburst‐Dendrimeren und verwandten Verbindungen können einige Eigenschaften von Micellen und Liposomen nachgeahmt werden, aber auch solche von Biomakromolekülen und noch komplizierteren aber gleichfalls hoch geordneten Bausteinen biologischer Systeme. Vielerlei Anwendungen dieser neuen Verbindungsklasse sind denkbar, insbesondere im Bereich der Nachahmung großer Biomoleküle (Arzneimitteltransport, Impfstoffe). Dieser neue Zweig der „Supramolekularen Chemie”︁ dürfte der Organischen wie der Makromolekularen Chemie neue Impulse geben.

The high-affinity binding of triatiated imipramine to platelet membranes was compared in samples from 16 untreated depressed women and 21 age-matched controls of the same sex. The maximal binding in the depressed group was significantly lower than that of the controls, although the affinity constants were similar. These results suggest that binding of tritiated imipramine in human platelets may represent a biochemical index of depression, possibly reflecting similar changes in the brain.

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.

Abstract This microreview focuses on recent applications of the ring‐closing metathesis reaction (RCM) to construct piperidine and pyrrolidine cores for the total synthesis of natural alkaloids. The most recent examples are described, from simple piperidine alkaloids to complex pentacyclic structures such as (+)‐tabersonine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Abstract The use of free radical reactions in organic synthesis has witnessed an extraordinary development in recent years. When properly conceived, radical processes often exhibit many of the properties desired by synthetic organic chemists, such as flexibility, mildness, and selectivity. Unfortunately, the number of synthetically useful radical‐generating systems is still limited, and most applications have relied on tin hydride chemistry. Secondary O ‐alkyl‐ S ‐methyl xanthates, for example, eact with tributyltin hydride to give the corresponding alkane (the Barton‐McCombie reaction). It was, however, found that the isomeric O ‐methyl‐ S ‐alkyl xanthates undergo cleavage of the weaker carbon–sulfur bond and that a chain reaction can be sustained without tin or other heavy metals. A variety of synthetically interesting free radicals can thus be produced and captured, the last propagating step being a reversible transfer of the xanthate group. S ‐Propargyl xanthates represent a special class. Their radical chemistry can be easily overshadowed by hitherto unknown but equally interesting nonradical behavior. Upon heating, a thermal [3,3] sigmatropic rearrangement occurs to give the allenyl isomer, which is in equilibrium with a novel betaine structure. This species is at the heart of a number of new transformations, including formal [3+2] cycloadditions, formation of esters with inversion in the case of secondary alcohols, conversion into 1,3‐dithiol‐2‐ones, generation of cisoid dienes, carbon, carbon‐carbon bond formation through reaction with acid chlorides etc. This account provides a brief description of this original radical and nonradical chemistry of xanthates, an old family of compounds that still harbors many mysteries.

Nitrogen-, phosphorus-, and sulfur-containing palladacycles, typically containing four- or six-electron donor anionic metallated ligands, are emerging as a new family of organometallic catalyst precursors. These thermally and air-stable complexes are easy to handle and their synthesis is often straightforward. Palladacycles are now being successfully exploited in catalytic reactions ranging from classical hydrogenations to enantioselective aldol-type condensations. The main recent achievements pertaining to their use in homogeneous organometallic catalysis are outlined herein.

The urgent need for clean and renewable energy drives the exploration of effective strategies to produce hydrogen. Semiconductor-based photocatalytic hydrogen production technology is one of the ideal processes for direct solar energy conversion and storage that has been widely studied. The development of highly efficient photocatalysts is essential for the cost-effective and large-scale production of hydrogen. CdS-based semiconductor photocatalysts have attracted significant attention due to their unique advantages, including strong visible light absorption capacity, suitable band edge levels and excellent electronic charge transfer. However, unlike TiO2 with good photostability, the intrinsic drawback of photocorrosion of CdS-based semiconductors significantly challenges their durable application in photocatalysis. This review focuses on recent advances in material design and strategies for improving the anti-photocorrosion of CdS-based photocatalysts for applications in photocatalytic overall water splitting to produce hydrogen. Moreover, brief prospective development and challenges in the synthesis of anti-corrosion CdS-based photocatalysts are also presented.

In recent years, radical C-C bond cleavage reactions have been increasingly understood and used to perform transformations that complement traditional ionic processes. However, to date radical C-C bond cleavage/functionalization reactions have not been the subject of a dedicated review. Herein we summarize the most recent and significant developments in the radical activation and functionalization of carbon-carbon bonds, with an emphasis on both synthetic outcomes and reaction mechanisms, and highlight how these radical C-C bond cleavage reactions enable challenging transformations.

Focal cerebral ischemia was induced by occlusion of the middle cerebral artery in rats. The volumetric assessment of infarcted tissue, 2 days following occlusion, was calculated from the examination of eight preselected coronal sections. Five differing rat strains were examined. A small and variable infarcted volume was seen in Wistar-Kyoto rats; Sprague-Dawley rats had a relatively large, but still variable, infarcted volume. Of the normotensive rat strains, the most reproducible volume of infarcted tissue was seen in Fischer-344 rats; also the absolute value of the infarcted volume did not vary from one series to another in this strain. Chronic arterial hypertension, studied in both normal and stroke-prone spontaneously hypertensive rats, was associated with significantly larger infarction volumes. Age does not change the volume of necrosis: Fischer-344 rats were studied at 3, 9, and 20 months of age, and no significant differences were noted between these ages. Experimental diabetes was induced by the administration of streptozotocin 3 days prior to middle cerebral artery occlusion. Severe hyperglycemia (greater than 400 mg/dl) was associated with a considerably increased volume of infarction. The variability of the resultant lesion is high in the most commonly studied strains, but our results suggest that, for studies in normotensive rats, the use of the Fischer-344 strain produces a standardized and repeatable infarction that may be significantly modified by experimental interventions. Age is not a factor that affects the occlusion-induced infarction; in contrast, both chronic arterial hypertension and experimental diabetes aggravate the histological consequences of middle cerebral artery occlusion in the rat. We conclude that quantitative histological evaluation of infarct size allows a meaningful assessment of the gravity of focal cerebral ischemia.

Inhibition of the binding of [3H]imipramine and inhibition of the uptake of [3H]serotonin and [3H]norepinephrine by a series of antidepressants and other drugs were studied in the rat hypothalamus. No correlation was found between the potencies of these drugs for the inhibition of [3H]imipramine binding and the inhibition of [3H]norepinephrine uptake. There was, however, a highly significant correlation between the potencies of these drugs for the inhibition of [3H]serotonin uptake. These results suggest that high-affinity [3H]imipramine binding might be associated with the mechanism of serotonin uptake in the brain.

EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.