Synthesis of Diaryl Hydroxyl Dicarboxylic Acids from Amino Acids

Herein we report a unique method for preparing diaryl hydroxyl dicarboxylic acids in a diastereospecific manner. The three-component reaction occurs between amino acid, aromatic aldehyde, and primary alcohol in alkaline solutions under microwave-assisted conditions. The dicarboxylic acids are isolated as sodium salts in high yields (up to 77%) by direct precipitation from the reaction solution. The experimental results suggest that the diastereospecificity originates from a [3,3]-sigmatropic rearrangement followed by a sodium-assisted hydride transfer. As further shown, the previously unreported dicarboxylic acids are easily turned into corresponding delta-lactones.Peer reviewe

Titanium isopropoxide-mediated cis-selective synthesis of 3,4-substituted butyrolactones from CO2

We report a Ti(OiPr)4-mediated multicomponent reaction, which produces 3,4-substituted cis-d-lactones from alkyl magnesium chloride, benzaldehyde and CO2. The key intermediate, titanacyclopropane, is formed in situ from Ti(OiPr)4 and a Grignard reagent, which enables 1,2-dinucleophilic reactivity that is used to insert carbon dioxide and an aldehyde. An alternative reaction route is also described where a primary alkene is used to create the titanacyclopropane. A computational analysis of the elementary steps shows that the carbon dioxide and the aldehyde insertion proceeds through an inner-sphere mechanism. A variety of cisbutyrolactones can be synthesized with up to 7 : 1 diastereoselectivity and 77% yield

Dual Nickel Photocatalysis for O-Aryl Carbamate Synthesis from Carbon Dioxide

We report the use of dual nickel photocatalysis in the synthesis of O-aryl carbamates from aryl iodides or bromides, amines, and carbon dioxide. The reaction proceeded in visible light, at ambient carbon dioxide pressure, and without stoichiometric activating reagents. Mechanistic analysis is consistent with a Ni(I- III) cycle, where the active species is generated by the photocatalyst. The rate-limiting steps were the photocatalyst-mediated reduction of Ni(II) to Ni(I) and subsequent oxidative addition of the aryl halide. The physical properties of the photocatalyst were critical for promoting formation of O-aryl carbamates over various byproducts. Nine new phthalonitrile photocatalysts were synthesized, which exhibited properties that were vital to achieve high selectivity and activity.Peer reviewe

One‐Step Synthesis of 3,4‐Disubstituted 2‐Oxazolidinones by Base‐Catalyzed CO2 Fixation and Aza‐Michael Addition

2-Oxazolidinones are saturated heterocyclic compounds, which are highly attractive targets in modern drug design. Herein, we describe a new, single-step approach to 3,4-disubstituted 2-oxazolidinones by aza-Michael addition using CO2 as a carbonyl source and 1,1,3,3-tetramethylguanidine (TMG) as a catalyst. The modular reaction, which occurs between a gamma-brominated Michael acceptor, CO2 and an arylamine, aliphatic amine or phenylhydrazine, is performed under mild conditions. The regiospecific reaction displays good yields (av. 75 %) and excellent functional-group compatibility. In addition, late-stage functionalization of drug and drug-like molecules is demonstrated. The experimental results suggest a mechanism consisting of several elementary steps: TMG-assisted carboxylation of aniline; generation of an O-alkyl carbamate; and the final ring-forming step through an intramolecular aza-Michael addition.Peer reviewe

Mechanistic insights into carbamate formation from CO2 and amines : the role of guanidine-CO2 adducts

Capture of CO2 by amines is an attractive synthetic strategy for the formation of carbamates. Such reactions can be mediated by superbases, such as 1,1,3,3-tetramethylguanidine (TMG), with previous implications that zwitterionic superbase-CO2 adducts are able to actively transfer the carboxylate group to various substrates. Here we report a detailed investigation of zwitterionic TMG-CO2, including isolation, NMR behavior, reactivity, and mechanistic consequences in carboxylation of aniline-derivatives. Our computational and experimental mechanistic analysis shows that the reversible TMG-CO2 zwitterion is not a direct carboxylation agent. Instead, CO2 dissociates from TMG-CO2 before a concerted carboxylation occurs, where the role of the TMG is to deprotonate the amine as it is attacking a free CO2. This insight is significant, as it opens a rational way to design new synthesis strategies. As shown here, nucleophiles otherwise inert towards CO2 can be carboxylated, even without a CO2 atmosphere, using TMG-CO2 as a stoichiometric source of CO2. We also show that natural abundance N-15 NMR is sensitive for zwitterion formation, complementing variable-temperature NMR studies.Peer reviewe

N-Heteroaryl Carbamates from Carbon Dioxide via Chemoselective Superbase−Catalysis: Substrate Scope and Mechanistic Investigation

We report a mild superbase-catalyzed and nitrogen-selective carboxylation of N-heteroaryls, with subsequent alkylation enabling the synthesis of drug-like O-alkyl carbamates in good yields (av. 86%). Our findings suggest a partial revision of the current mechanistic understanding as superbases upon mixing with indoles and azoles generally form uncharged hydrogen-bonded complexes and not ionic salts as previously proposed. However, when these complexes are exposed to CO2, carbamate salts are formed. These can be categorized into two subgroups, stable and fluxional carbamate salts, where the latter undergo fast and reversible CO2 exchange, thus being poor substrates for alkylation. Experiments and DFT calculations indicate that the fluxional behavior is primarily caused by substrate-specific electronic destabilization effects. The degree of destabilization depends on the number of nitrogen atoms within and the functional group substitution on the heterocyclic ring structures. Fluxionality can be compensated for by the use of lower temperatures and/or higher CO2 pressures as both measures stabilize the carbamate salts sufficiently, enabling subsequent alkylation

Enantioselective incorporation of CO2: status and potential

CO2 is a promising and sustainable carbon feedstock for organic synthesis. New catalytic protocols for efficient incorporation of CO2into organic molecules are continuously being reported. However, little progress has been made in the enantioselective conversion of CO2to form enantioenriched molecules. In order to allow CO2to become a versatile carbon source in academia and in the fine chemical and pharmaceutical industries, the development of enantioselective approaches is essential. Here we discuss general strategies for CO2activation and for generation of enantioenriched molecules, alongside selected examples of reactions involving asymmetric incorporation of CO2. The main product classes considered are carboxylic acids and derivatives (C–CO2bonds) and carbonates, carbamates, and polycarbonates (C–OCO bonds). Similarities to asymmetric hydrogenation are discussed, and some strategies for developing novel enantioselective CO2reactions are outlined