Fluorene-Based Multicomponent Reactions
TL;DR: The implementation of fluorene and fluorenone moieties via the isocyanide-based multicomponent reactions and their incorporation in diverse and complex derivatives that can be further utilized are demonstrated.
Abstract: Fluorene and fluorenone are privileged structures with extensive utility in both materials science and drug discovery Here, we describe syntheses of those moieties through isocyanide-based multicomponent reactions (IMCRs) and the incorporation of the products in diverse and complex derivatives that can be further utilized We performed six different IMCRs, based on the dual functionality of 9-isocyano-9H-fluorene, and we describe 23 unprecedented adducts
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TL;DR: In this paper , an environmentally friendly benign and practical protocol for the highly diastereo and chemo selective synthesis of some novel derivatives of 6-amino-4-aryl-3-oxo-2,3,3a,4-tetrahydro-1H-pyrazolo[3,4b]pyridine-5-carbonitrile via a one-pot three-component reaction between arylaldehydes, malononitrile and 3amino, 1H pyrazolone-5(4H)-one in the presence of acetic acid as a catalyst and aqueous green medium at the ambient temperature.
3 citations
TL;DR: A multicomponent reaction (MCR)‐based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping is demonstrated.
Abstract: Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage‐gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)‐based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single‐crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three‐component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.
3 citations
TL;DR: In this paper , a mild and facile two-step access towards complex, polycyclic dibenzothiazepine derivatives via multicomponent reaction chemistry is demonstrated, and the peculiar butterfly conformation is observed and studied.
2 citations
TL;DR: 2D distant but 3D closely related scaffolds, which can be of high interest in exploiting chemistry space on a receptor, are achieved in moderate to good yields by reacting various substituted ethanones or terminal alkynes with Ugi-4CR intermediates via an ammonia-Ugi- 4CR/Copper(I)-catalyzed annulation sequence reaction.
Abstract: We achieved a divergent synthesis of isoquinolin-2(1H)-yl-acetamides (16 examples, up to 90% yields) and regioselective isoindolin-2-yl-acetamides (14 examples, up to 93% yields) in moderate to good yields by reacting various substituted ethanones or terminal alkynes with Ugi-4CR intermediates via an ammonia-Ugi-4CR/Copper(I)-catalyzed annulation sequence reaction. The same intermediate thus gives 2D distant but 3D closely related scaffolds, which can be of high interest in exploiting chemistry space on a receptor. The scopes and limitations of these efficient sequence reactions are described, as well as gram-scale synthesis.
1 citations
TL;DR: This work demonstrates a rapid synthesis of unprecedented benzoxepanes from readily available starting materials in one step via a Passerini multicomponent reaction, obtaining a single-crystal X-ray structure, revealing a butterfly conformation, combined with useful structural features.
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TL;DR: MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures, however, this requires that the chemist learns the "language" of M CRs, something that this review wishes to stimulate.
Abstract: Multicomponent reactions (MCRs) are fundamentally different from two-component reactions in several aspects. Among the MCRs, those with isocyanides have developed into popular organic-chemical reactions in the pharmaceutical industry for the preparation of compound libraries of low-molecular druglike compounds. With a small set of starting materials, very large libraries can be built up within a short time, which can then be used for research on medicinal substances. Due to the intensive research of the last few years, many new backbone types have become accessible. MCRs are also increasingly being employed in the total synthesis of natural products. MCRs and especially MCRs with isocyanides offer many opportunities to attain new reactions and basic structures. However, this requires that the chemist learns the “language” of MCRs, something that this review wishes to stimulate.
3,619 citations
TL;DR: It is demonstrated that saturation correlates with solubility, an experimental physical property important to success in the drug discovery setting, and both complexity and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs.
Abstract: The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations,...
2,396 citations
TL;DR: This paper presents a new approach to drug design called “combinatorial biosynthesis and drug discovery through nanofiltration”, which combines the efforts of a single investigator with those of a number of other scientists.
Abstract: Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, … 7, where most of the atoms of the starting materials are incorporated in the final product.1 Several descriptive tags are regularly attached to MCRs (Fig. 1): they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2 Therefore MCRs are often a useful alternative to sequential multistep synthesis.
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Figure 1
Above: multistep syntheses can be divergent (sequential) or convergent; below: in analogy MCR reactions are convergent and one or two component reactions are divergent or less convergent.
1,840 citations
TL;DR: It is shown that visible light can activate diarylketones to abstract a benzylic hydrogen atom selectively and the scope and efficiency of this new C-H fluorination method are significantly better than those of the existing methods.
Abstract: We report herein an operationally simple method for the direct conversion of benzylic C–H groups to C–F. We show that visible light can activate diarylketones to abstract a benzylic hydrogen atom selectively. Adding a fluorine radical donor yields the benzylic fluoride and regenerates the catalyst. The selective formation of mono- and difluorination products can be achieved by catalyst control. 9-Fluorenone catalyzes benzylic C–H monofluorination, while xanthone catalyzes benzylic C–H difluorination. The scope and efficiency of this new C–H fluorination method are significantly better than those of the existing methods. This is also the first report of selective C–H gem-difluorination.
422 citations
TL;DR: The principle of chemical ligation of reactive partners (see reaction scheme) has been employed to find a new, highly efficient synthesis of fused 3-aminoimidazoles.
Abstract: When general and reliable, multicomponent reactions are among the most powerful tools in modern drug discovery. The principle of chemical ligation of reactive partners (see reaction scheme) has been employed to find a new, highly efficient synthesis of fused 3-aminoimidazoles.
384 citations