Recent Advances in the Organocatalytic Enantioselective Synthesis of Functionalized -Lactones

This Focus Review highlights recent developments in the organocatalytic enantioselective synthesis of -lactone derivatives. Owing to the importance of -lactones as a heterocyclic motif that is present in a variety of natural products and biologically active molecules, several catalytic methods have been developed for the synthesis of these compounds in their enantiomerically pure form. Organocatalytic methods that employ N-heterocyclic carbenes (NHCs), cinchona alkaloids, isothioureas, 4-dimethylaminopyridine (DMAP) derivatives, and phosphines have allowed the highly enantioselective synthesis of -lactones from cheap and readily available starting materials. Moreover, the inherent strain in the four-membered ring of -lactones has also been utilized in further synthetic transformations, thus making -lactones a versatile intermediate in organic synthesis

A Method for the Analysis of Free Carbenes Present after NHC-Organocatalyzed Transformations

In N-heterocyclic carbene (NHC) based organocatalysis, usually, the free carbene is generated in situ by treatment of the azolium salt with a base. Described herein is a method for the analysis of the NHC present in the reaction flask after the NHC-organocatalyzed reaction. For this, the reaction mixture was treated with elemental sulfur after the reaction and the thus-formed thiourea/thione derivative was isolated. Common NHC-catalyzed transformations such as benzoin reactions, Stetter reactions, homoenolate annulation reactions, and reactions proceeding via the ,-unsaturated acylazolium intermediate have been studied. The results indicate that after the reactions, 28-84% of the initial carbenes exist in the free form

Recent advances in molecular rearrangements involving aryne intermediates

This Feature Article is aimed at highlighting the recent developments in the transition-metal-free molecular rearrangements involving arynes. The chemistry of arynes has shown incredible developments especially in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions in the last three decades. The rapid growth in this field is mainly due to the development of mild methods for the generation of arynes. One aspect of the recent developments in the chemistry of arynes involves the molecular rearrangements proceeding via this electrophilic intermediate. The molecular rearrangements have provided direct access to a library of valuable molecules, which cannot be accessed in a single step through other synthetic routes. Herein, we present a concise account on the developments that occurred in this field over the last three decades

Uncovering the Neglected Similarities of Arynes and Donor-Acceptor Cyclopropanes

Arynes and donor-acceptor (D-A) cyclopropanes are two classes of strained systems having the potential for numerous applications in organic synthesis. The last two decades have witnessed a renaissance of interest in the chemistry of these species primarily because of the mild and robust methods for their generation or activation. Commonly, arynes as easily polarizable systems result in 1,2-disubstitution, whereas D-A cyclopropanes as polarized systems lead to 1,3-bisfunctionalization thereby showing striking similarities. Transformations with 1,2- and 1,3-dipoles afford cyclic structures. With arynes, emerging four-membered rings as intermediates might react further, whereas the analogous five-membered rings obtained from D-A cyclopropanes are most often the final products. However, there are a few cases where these intermediates behave surprisingly differently. This Minireview highlights the parallels in reactivity between arynes and D-A cyclopropanes thereby shedding light on the neglected similarities of these two reactive species

NHC-Catalyzed 3+3] Annulation of Thioamides and Modified Enals for the Enantioselective Synthesis of Functionalized Thiazinones

N-Heterocyclic carbene (NHC)-catalyzed 3 + 3] annulation of thioamides with modified enals allowing the enantioselective synthesis of functionalized 1,3-thiazin-4-ones is reported. The NHC generated from the chiral triazolium salt was optimal and the reaction is initiated by the thia-Michael addition to catalytically generated alpha,beta-unsaturated acylazolium intermediates derived from 2-bromoenals, followed by intramolecular cyclization. This operationally simple procedure offers a straightforward and rapid access to target compounds in moderate to good yields and enantiomeric ratio values

Employing Arynes for the Generation of Aryl Anion Equivalents and Subsequent Reaction with Aldehydes

Arynes are highly reactive intermediates, which are utilized for the electrophilic arylation of various X-H bonds (X = O, N, S etc.). Herein, a new synthetic strategy is demonstrated, where arynes are converted into aryl anion equivalents by treatment with phosphines and a base. The addition of phosphines to arynes form the phosphonium salts, which in the presence of a carbonate base generates the aryl anion equivalent. Subsequent addition of the aryl anions with aldehydes afforded the secondary alcohols

Transition-Metal-Free Thioamination of Arynes Using Sulfenamides

The insertion of arynes into the S-N sigma-bond of sulfenamides allowing the synthesis of o-sulfanylaniline derivatives with reasonable functional group compatibility is presented. The aryne generated from 2-(trimethylsilyl)aryl triflates using CsF in DME was the key for the success of this transition-metal-free thioamination reaction, which involves new C-N and C-S bond formations in a single step under mild conditions. Moreover, the synthetic potential of this method was demonstrated by the synthesis of the antidepressant drug vortioxetine

N-Heterocyclic Carbene-Catalyzed Michael-Michael-Lactonization Cascade for the Enantioselective Synthesis of Tricyclic delta-Lactones

Enantioselective synthesis of tricyclic delta-lactones with three contiguous stereocenters has been demonstrated by the N-heterocyclic carbene (NHC)-catalyzed functionalization of benzylic C(sp(3))-H bonds. The NHC-catalyzed reaction of enals with dinitrotoluene derivatives under oxidative conditions proceeds via the chiral alpha,beta-unsaturated acylazoliums and produces the delta-lactones in good yields and excellent diastereoselectivity and enantioselectivity. This mild and atom-economic cascade reaction takes place in a Michael/Michael/lactonization sequence and tolerates a broad range of functional groups

N‑Heterocyclic Carbene-Catalyzed Aza-Michael–Mannich–Lactamization Cascade for the Enantioselective Synthesis of Pyrazoloquinolin-3-ones

The enantioselective synthesis of functionalized pyrazoloquinolin-3-ones via N-heterocyclic carbene-catalyzed cascade reaction of α-bromoenals with 2-aminoaryl N-tosyl hydrazones is reported. The in situ-generated α,β-unsaturated acylazoliums underwent an aza-Michael–Mannich–lactamization sequence to afford the tricyclic products bearing three contiguous stereocenters, including a sterically demanding quaternary stereocenter with high enantioselectivity. The unprotected amine-triggered aza-Michael pathway over the competing amidation pathway is noteworthy