Quinones are common stoichiometric reagents in organic chemistry. Para-quinones with high reduction potentials, such as DDQ and chloranil, are widely used and typically promote hydride abstraction. In recent years, many catalytic applications of these methods have been achieved by using transition metals, electrochemistry, or O2 to regenerate the oxidized quinone in situ. Complementary studies have led to the development of a different class of quinones that resemble the ortho-quinone cofactors in copper amine oxidases and mediate the efficient and selective aerobic and/or electrochemical dehydrogenation of amines. The latter reactions typically proceed by electrophilic transamination and/or addition-elimination reaction mechanisms, rather than hydride abstraction pathways. The collective observations show that the quinone structure has a significant influence on the reaction mechanism and has important implications for the development of new quinone reagents and quinone-catalyzed transformations.

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Quinone-Catalyzed Selective Oxidation of Organic Molecules

In 1989, the reaction of vinyl magnesium halides with ortho-substituted nitroarenes leading to indoles was discovered. This reaction is now frequently reported as the “Bartoli reaction” or the “Bartoli indole synthesis” (BIS). It has rapidly become the shortest and most flexible route to 7-substituted indoles, because the classical indole syntheses generally fail in their preparation. The flexibility of the Bartoli reaction is great as it can be extended to heteroaromatic nitro derivatives and can be run on solid support. This review will focus on the use of the Bartoli indole synthesis as the key step in preparations of complex indoles, which appeared in the literature in the last few years.

Applications of Bartoli indole synthesis

The palladium-catalyzed Suzuki–Miyaura reaction of multiply halogenated, electron-rich and electron-deficient heteroarenes is one of the most reliable and environmentally friendly tools for installing a wide range of non-functionalized and functionalized carbon substituents onto heteroaromatic systems with exquisite chemo- and site-selectivity. For substrates with different halogen groups the chemoselectivity of the Suzuki–Miyaura reactions has been found to be dependent on the reactivity difference between the halogens. However, the hardest achievement of selectivity in Suzuki–Miyaura monocouplings involving polyhalogenated heteroarenes with identical halogen atoms has been shown to be dominated by steric and electronic effects and the presence of directing groups at positions neighbouring the reaction sites. Moreover, in the case of symmetrically substituted dihaloheteroarenes with identical halogen atoms, highly selective monocoupling reactions have often been achieved only after a careful optimization of reaction parameters including the catalyst precursor, base, solvent, and the molar ratio between electrophile and organoboron reagent. This critical review with 341 references covers developments on the chemo- and site-selective Suzuki–Miyaura monocoupling reactions of polyhalogenated heteroarenes with different or identical halogen atoms. It also includes the synthesis of polysubstituted heteroarenes, not easily accessible by other means, via consecutive monocoupling reactions and/or a more synthetically valuable approach involving one-pot polycoupling reactions.

Selective Palladium-Catalyzed Suzuki–Miyaura Reactions of Polyhalogenated Heteroarenes

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized at the cellular level by abnormal accumulation of cholesterol and other lipids in lysosomal storage organelles. Lysosomal acid lipase (LAL) has been recently identified as a potential therapeutic target for NPC. LAL can be specifically inhibited by a variety of 3,4-disubstituted thiadiazole carbamates. An efficient synthesis of the C(3) oxygenated/C(4) aminated analogues has been developed that furnishes the products in high yields and high degrees of purity. Common intermediates can also be used for the synthesis of the C(3) carbon substituted derivatives. Herein we tested various thiadiazole carbamates, amides, esters, and ketones for inhibition of LAL. In addition, we tested a diverse selection of commercially available non-thiadiazole carbamates. Our studies show that, among the compounds examined herein, only thiadiazole carbamates are effective inhibitors of LAL. We present a mechanism for LAL inhibition by these compounds whereby LAL transiently carbamoylates the enzyme similarly to previously described inhibition of acetylcholinesterase by rivastigmine and other carbamates as well as acylation of various lipases by orlistat.

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Thiadiazole Carbamates: Potent Inhibitors of Lysosomal Acid Lipase and Potential Niemann−Pick Type C Disease Therapeutics

Chinone sind gebrauchliche, stochiometrisch eingesetzte Reagentien in der organischen Chemie. para-Chinone mit hohem Reduktionspotential wie DDQ und Chloranil werden verbreitet angewendet und fordern normalerweise die Hydridabstraktion. In den letzten Jahren wurden viele katalytische Anwendungen dieser Methoden entwickelt, wobei das oxidierte Chinon in situ mithilfe von Ubergangsmetallen, O2 oder Elektrochemie regeneriert wird. Erganzende Studien haben zur Entdeckung einer anderen Klasse von Chinonen gefuhrt, die den ortho-Chinon-Cofaktoren in Kupfer-Amin-Oxidasen ahneln und effiziente und selektive aerobe und/oder elektrochemische Dehydrierungen von Aminen vermitteln. Letztgenannte Reaktionen laufen gewohnlich uber elektrophile Transaminierungs- und/oder Additions-Eliminierungs-Reaktionsmechanismen anstelle von Hydridabstraktionspfaden ab. Die gesammelten Beobachtungen zeigen, dass die Chinonstruktur einen signifikanten Einfluss auf den Reaktionsmechanismus ausubt und somit bedeutende Auswirkungen auf die Entwicklung neuer Chinonreagentien und Chinon-katalysierter Umwandlungen hat.

Chinon‐katalysierte, selektive Oxidation organischer Moleküle

Novel approaches towards the LTD4/E4 antagonist, LY290154

The ring opening of 3,4-dichloro-1,2,5-thiadiazole with metal amides. A new synthesis of 3,4-disubstituted-1,2,5-thiadiazoles

3,4-Dichloro- and 3-chloro-4-halogeno-1,2,5-thiadiazoles (halogeno-: bromo- and iodo-) are involved in Pd-catalyzed cross-coupling reactions under Stille and Suzuki conditions. As a result, by using the commercially available 3,4-dichloro-1,2,5-thiadiazole as substrate, several 3-alkyl-, 3-alkenyl-, 3-alkynyl-and 3-aryl-4-chloro-1,2,5-thiadiazoles can easily be prepared. However, these reactions through direct desymmetrization of the 3,4-dichloro-1,2,5-thiadiazole always occur with side-reactions resulting from the concurrent decomposition of the heterocyclic ring of the starting material. These problems are resolved by involving, in these Pd-catalyzed cross-coupling reactions, the more reactive and selective 3-bromo-4-chloro- and 3-chloro-4-iodo-1,2,5-thiadiazole. These new dihalogeno-1,2,5-thiadiazoles can easily be prepared, via diazotization reaction followed by halogen substitution, from the 3-amino-4-chloro-1,2,5-thiadiazole.

The palladium-catalyzed cross-coupling reactions of 3-chloro-4-halogeno-1,2,5-thiadiazoles

Disclosed are processes for resolving chiral (2S) and (2R) benzopyrans, racemizing benzopyrans, and recycling racemized benzopyrans to increase yield of a desired enantiomer to provide purified or substantially purified bicyclic amino substituted benzopyran derivatives. Such benzopyran derivatives are preferably chromans which can be coupled with benzoyl derivatives via an amide bond to produce potent platelet aggregation inhibitors.

Method for resolving chiral (2s) and (2r) chromanes

Disclosed are processes for coupling amino substituted 2-chromanyl derivatives and benzoyl derivatives via an amide bond, and intermediates for producing platelet aggregation inhibitors and for producing potent platelet aggregation inhibitors. Also disclosed are processes for producing such compounds from chiral intermediates to provide desired enantiomers, and methods for using the compounds as platelet aggregation inhibitors.

Hugo Gorissen

Papers

Novel approaches towards the LTD4/E4 antagonist, LY290154

The ring opening of 3,4-dichloro-1,2,5-thiadiazole with metal amides. A new synthesis of 3,4-disubstituted-1,2,5-thiadiazoles

The palladium-catalyzed cross-coupling reactions of 3-chloro-4-halogeno-1,2,5-thiadiazoles

Method for resolving chiral (2s) and (2r) chromanes

Process for the preparation of benzoyl substituted bicyclic compounds and chiral benzopyran derivatives