Through the development of a one pot synthesis of fused substituted heteroaryl-lactones involving a Metal/Halogen Exchange reaction as key step, the reactivity of various mono- or bimetallic reagents (organolithiums, Grignard reagents and lithium organomagnesiate complexes) was explored to aim high chemoselectivity and efficiency starting from sensitive substrates.

Abstract

Herein we disclose an efficient one-pot route to a wide range of 3-substituted fused pyridinyl-lactones, so called aza-phthalides. The developed strategy involves a Metal/Halogen Exchange (MHE) reaction as key step, followed by an electrophile trapping using various carbonyl derivatives and a subsequent lactonization. To promote the MHE reaction with high chemoselectivity, our investigations have particularly focused on the nature of mono- or bimetallic derivatives as metalation reagents including organolithiums, Grignard reagents and lithium organomagnesiate complexes, and highlighted the positive salt effect on reactional sequence. An extension to fused heteroaryl-lactones (benzothienyl-, benzofuranyl- and naphthofuranyl scaffolds) was explored.

An iron-catalyzed, visible light-driven, dioxygen mediated decarboxylative oxygenation of carboxylic acids is disclosed. The catalytic system based on naturally existing Mohr salt and simple di(2-picolyl)amine ligand is readily available and inexpensive. The applicability of the method was demonstrated through the efficient and selective synthesis of a range of ketones, aldehydes and amides including drug derivatives. Based on experimental investigations, a hypothetical mechanism was proposed.

Starting from the easily prepared 1-(pyridin-2-yl)- or 1-(4-chloropyridin-2-yl)ethan-1-ones bearer of different substituents (cyclohexyl, phenyl, pyridin-2-yl) in the position 2, the corresponding primary pyridinic ethanamines have been synthesized in very high enantiomeric excesses (ee ≥ 97%). The strategy involves a highly enantioselective ketoreductase (KRED) catalyzed reduction, mesylation of the resulting optically active alcohol followed by nucleophilic substitution with azide anion and, finally, reduction of the azide function. Some of these pyridinic amines obtained in such manner are precursors of biologically active compounds such as Ontazolast.

Various synthetic methodologies towards sulfur-containing alkynes are developed including C(sp)−S coupling, thiolation, S-alkynylation, trifluoromethylthiolation, and so on. In this review, the approaches to synthesize alkynyl sulfides over the last three years, as well as to form alkynyl trifluoromethyl sulfides and alkynylthiocyanates, are highlighted.

Abstract

Sulfur-containing alkynes, are important starting materials and intermediates in organic reactions. Some of sulfur-containing alkynes display interesting bioactivities and are potentially applied as drugs. Various synthetic methodologies towards sulfur-containing alkynes have been developed, including C(sp)−S coupling, thiolation, S-alkynylation, trifluoromethylthiolation, etc. In this review, the approaches towards alkynyl sulfides in recent 3 years, as well as to form alkynyl trifluoromethyl sulfides and alkynylthiocyanates were highlighted. Firstly, the property and application of alkynes were introduced. After presenting the superiority of sulfur-containing alkynes, their synthetic methods were classified and presented in details. According to different kinds of sulfur-containing alkynes, synthetic methodologies for alkynyl sulfides, alkynyl trifluoromethyl sulfides and alkynylthiocyanates were summarized and the proposed reaction mechanisms were demonstrated if available.

A simple and straightforward method is developed for the enantioselective synthesis of indol-3-yl-piperidine. The reaction proceeds through a proline-catalyzed direct Mannich reaction between glutaraldehyde and C3-indolyl-imines, followed by intramolecular reductive cyclization as an overall [4+2] annulation in one-pot fashion. A series of indol-3-yl-piperidine have been accessed with good yields (up to 71%) and high enantioselectivity (up to >99% ee).

One-pot, scalable procedures converting benzylic or aliphatic alcohols to various N-functionalized amines are reported in 38-83% overall yields. These multi-step conversions are relatively economic and involve the oxidative formation of acid chloride intermediates and the Curtius rearrangement of acyl azides. Notable aspects of economy include: (1) the use of a relatively green solvent (chlorobenzene) that tolerates both ionic and radical reactions, without the need for rigorously dry or O2-free conditions; (2) the use of minimal amounts of trichloroisocyanuric acid (TCCA) as a cheap and green chlorinating agent to oxidize the alcohol starting materials and then transform the aldehyde intermediates to acid chlorides under photoirradiation for azide addition; (3) the efficient capture of isocyanate intermediates by alcohol or azide nucleophiles providing N-protected anilines or N-protected alkylamines, respectively, the latter of which was employed in the synthesis of an anti-dementia drug, memantine hydrochloride, over two purification steps.

Sulfoxonium ylides as the safe carbene precursors are firstly used in Sommelet-Hauser rearrangement reactions for the synthesis of sulfur/selenium-containing compounds. The present reaction highlights the advantages of mild condition and broad substrate scope.

Abstract

Rhodium-catalyzed Sommelet-Hauser rearrangement derived from α-thioesters/α-selenoesters and sulfoxonium ylides has been developed for the synthesis of various sulfur/selenium-containing ortho-substituted aromatic compounds in medium to excellent yields (39 examples; up to 97 %). Sulfoxonium ylides as the safe carbene precursors are firstly used in Sommelet-Hauser rearrangement reactions, which is superior to traditional diazo compounds. The present reaction has the advantages of mild condition, safety and broad substrate scope, which afford a unique method for the synthesis of sulfur/selenium-containing compounds with a tertiary carbon center.

The first stereoselective total synthesis of euolutchuol C is demonstrated using a biomimetic cationic polyene cyclization, and its absolute structure is established. Four potential stereoisomers of euolutchuol C were synthesized to confirm the structure as an aromatic abietane diterpenoid consisting of a 15(S)-stereogenic center. Asymmetric Sharpless dihydroxylation was employed to build the chiral epoxide, while CBS-reduction was utilized to obtain enantiomerically pure benzylic alcohols. A convergent approach is used to synthesize euolutchuol C in seven longest linear steps resulting in an overall yield of 23 %.

Abstract

The first stereoselective total synthesis of euolutchuol C using a biomimetic cationic polyene cyclization is demonstrated, and its absolute structure has been established. Four potential stereoisomers of euolutchuol C were synthesized to confirm the structure as an aromatic abietane diterpenoid consisting of 15(S)-stereogenic center. Asymmetric Sharpless dihydroxylation was employed to construct the chiral epoxide, while CBS-reduction was utilized for enantiomerically pure benzylic alcohols. A convergent approach is used to synthesize euolutchuol C in seven longest linear steps to give an overall yield of 23 %.

For the first time, an effective method for the synthesis of spirocyclic camphor- and fenchone-based 1,3,4-oxadiazolines has been developed. The influence of the terpene scaffold on the reaction stereoselectivity was studied. The proposed method allows obtaining of spirocyclic products with a wide structural diversity, stereoselectively and in good yields.

Abstract

For the first time, an effective method for the synthesis of spirocyclic camphor- and fenchone-based 1,3,4-oxadiazolines has been developed. The influence of the molecular structure of the terpene substrate on the reaction stereoselectivity was studied. The structural features of the target products were studied using NMR spectroscopy and X-ray diffraction analysis. The proposed method allows obtaining of spirocyclic products with a wide structural diversity, stereoselectively and in good yields.

1,3-Oxathiolan-5-ones are a hitherto very poorly studied class of sulfur heterocycles some of which have been shown to be important precursors for HIV drugs or bioactive, anticarcinogenic compounds. We have developed a novel and effective process for the direct generation of this structural motif in a (3+2)-cycloaddition of thioketones and acetylenedicarboxylic acid. The cycloadducts were obtained with complete regioselectivity and up to >99 % yield. The heterocyclic motif was confirmed by X-ray diffraction analysis.

Abstract

Herein, we report a novel protocol for the direct synthesis of 1,3-oxathiolan-5-ones based on the (3+2)-cycloaddition between thioketones and acetylenedicarboxylic acid. The products were obtained in a one-pot reaction within short reaction times and in typically very good yields. The product structure was confirmed by X-ray diffraction analysis.