Enantioselective Intermolecular C-H Functionalization of Primary Benzylic C-H Bonds Using ((Aryl)(diazo)methyl)phosphonates.

Catalyst-controlled C-H functionalization using donor/acceptor carbenes has been shown to be an efficient process capable of high levels of site control and stereocontrol. This study demonstrated that the scope of the donor/acceptor carbene C-H functionalization can be extended to systems where the acceptor group is a phosphonate. When using the optimized dirhodium catalyst, Rh2(S-di-(4-Br)TPPTTL)4, ((aryl)(diazo)methyl)phosphonates undergo highly enantioselective (84-99% ee) and site-selective (>30:1 r.r.) benzylic C-H functionalization. The phosphonate group is much more sterically demanding than the previously studied carboxylate ester group, leading to much higher selectivity for a primary site versus more sterically crowded positions. The effectiveness of this methodology has been demonstrated by the late-stage primary C-H functionalization of estrone, adapalene, (S)-naproxen, clofibrate, and gemfibrozil derivatives.

Photoinduced carbamoylation reactions: unlocking new reactivities towards amide synthesis.

The preparation of amide-containing compounds is among the most interesting and challenging topics for the synthetic community. Such relevance is given by their reactive aspects explored in the context of organic synthesis and by the direct application of these compounds as pharmaceuticals and useful materials, and their key roles in biological structures. A simple and straightforward strategy for the amide moiety installation is the use of carbamoyl radicals - this nucleophilic one-electron intermediate is prone to undergo a series of transformations, providing a range of structurally relevant derivatives. In this review, we summarize the latest advances in the field from the perspective of photoinduced protocols. To this end, their synthetic applications are organized accordingly to the nature of the radical precursor (formamides through HAT, 4-substituted-1,4-dihydropyridines, oxamic acids, and N-hydroxyphthalimido esters), the mechanistic aspects also being highlighted. The discussion also includes a recent approach proceeding via photolytic C-S cleavage of dithiocarbamate-carbamoyl intermediates. By exploring fundamental concepts, this material aims to offer an understanding of the topic, which will encourage and facilitate the design of new synthetic strategies applying the carbamoyl radical.

Carbamoylation of Azomethine Imines via Visible-Light Photoredox Catalysis.

A versatile and robust photocatalytic methodology to install the amide functional group into azomethine imine ions is described. This protocol is distinguished by its broad scope and mild reaction conditions, which are well suited for the preparation of structurally complex compounds in the form of amino acids, peptides, and small drug-like molecules. Moreover, the generated pyrazolidinone core could be easily converted into ß-alanine analogues.

Photocatalyzed Intramolecular [2+2] Cycloaddition of N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides.

N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides are converted into natural product inspired scaffolds via iridium photocatalyzed intramolecular [2+2] photocycloaddition. The protocol has a broad substrate scope, whilst operating under mild reaction conditions. Tethering four components forming a trisubstituted cyclobutane core builds rapidly high molecular complexity. Our approach allows the design and synthesis of a variety of tetrahydrocyclobuta[c]quinolin-3(1H)-ones, in yields ranging between 20-99 %, and with excellent regio- and diastereoselectivity. Moreover, it was demonstrated that the intramolecular [2+2]-cycloaddition of 1,7-enynes-after fragmentation of the cyclobutane ring-leads to enyne-metathesis-like products.

Visible-Light-Mediated α-Amino Alkylation of Azomethine Imines: An Approach to N-(ß-Aminoalkyl)pyrazolidinones.

Herein, a mild and robust photocatalytic protocol for the combination of amino and pyrazolidinone functionalities through a radical α-amino alkylation of azomethine iminium ions is demonstrated. This method presents a high functional group tolerance providing direct access to a large family of N-(ß-aminoalkyl)pyrazolidinones in good to excellent yields, including the late-stage incorporation of the pyrazolidinone moiety to pharmaceutical ingredients. We propose a plausible scenario for the C-C bond-forming step which involves radical addition followed by a spin-center-shift event.

Photoinduced deaminative strategies: Katritzky salts as alkyl radical precursors.

Primary amines are one of the most predominant functional groups found in organic molecules. These entities help form the chemical architecture of natural products, bioactive molecules, synthetic building blocks and catalysts. Due to their ubiquitous presence, the development of strategies for the construction of C-C or C-X bonds through deaminative processes is of high importance. Deaminative methods offer new possibilities on the retrosynthetic rationale, and enable late-stage-functionalization of complex structures. As a result of the recent development of photoinduced processes, a variety of photo-mediated deaminative protocols employing 2,4,6-triphenyl-pyridinium salts - Katritzky Salts - as activating agents have been recently realized. This review covers the most recent developments of deaminative strategies by using Katritzky Salts as alkyl radical reservoirs, with particular concern on photoinduced processes applied to organic synthesis.

Synthesis of (Z)-ß-halo α,ß-unsaturated carbonyl systems via the combination of halotrimethylsilane and tetrafluoroboric acid.

A convenient and broadly applicable method for the hydrohalogenation of ynones is described, by the combination of halotrimethylsilanes and tetrafluoroboric acid. Practically, one equivalent of HX (Brønsted acid) and BF3 (Lewis acid) is smoothly generated, which activates the carbonyl compounds. Through this protocol, 42 examples of (Z)-ß-halovinyl carbonyl compounds (Cl, Br and I) were obtained, in good yields and high stereoselectivity having 2-MeTHF as a solvent.

Stereoselective Synthesis of Fused Vinylcyclopropanes by Intramolecular Tsuji-Trost Cascade Cyclization.

A stereoselective intramolecular Tsuji-Trost cascade cyclization of (homo)allylic vicinal diacetates with a pendant ß-ketoamide or related carbon nucleophile to give γ-lactam-fused vinylcyclopropanes is reported. In addition to two new rings, the products contain three new C-C stereocenters (two of which are quaternary) with a 9:1 dr. Moreover, the reaction proceeds in >94% enantiospecificity with optically enriched starting materials, using an inexpensive carbohydrate as the source of chirality.

Organocatalyzed Asymmetric Vinylogous Addition of Oxazole-2(3H)-thiones to α,ß-Unsaturated Ketones: An Additive-Free Approach for Diversification of Heterocyclic Scaffold.

A straightforward organocatalyzed asymmetric addition of oxazole-2(3H)-thiones to α,ß-unsaturated ketones is described. This additive-free Michael reaction in the presence of chiral cinchonine-derived primary amines as catalysts has proven to be highly effective for a wide range of cyclic and acyclic enones, leading to the Michael adducts in very good yields and excellent enantioselectivities. The absolute configuration (R) of compound 5j was unambiguously assigned by X-ray diffraction analysis. Furthermore, experimental and theoretical studies were performed and a mechanism is presented and discussed for this novel reaction.

Asymmetric synthesis of new γ-butenolides via organocatalyzed epoxidation of chalcones.

γ-Butenolides have been recognized as an important structural framework in a number of natural products and medicinally important agents. In this work we describe a new metal-free sequential strategy for the asymmetric synthesis of substituted γ-butenolides having epoxychalcones as the advanced intermediate. Using the optimized reaction conditions, we were able to carry out the three-step sequence, epoxidation, olefination and hydrolysis, with only one single chromatographic purification of the final product, furnishing new enantiomerically enriched γ-butenolides in moderate overall yield and good enantiomeric excess.