A synergistic LUMO lowering strategy using Lewis acid catalysis in water to enable photoredox catalytic, functionalizing C-C cross-coupling of styrenes.

Easily available α-carbonyl acetates serve as convenient alkyl radical source for an efficient, photocatalytic cross-coupling with a great variety of styrenes. Activation of electronically different α-acetylated acetophenone derivatives could be effected via LUMO lowering catalysis using a superior, synergistic combination of water and (water-compatible) Lewis acids. Deliberate application of fac-Ir(ppy)3 as photocatalyst to enforce an oxidative quenching cycle is crucial to the success of this (umpolung type) transformation. Mechanistic particulars of this dual catalytic coupling reaction have been studied in detail using both Stern-Volmer and cyclic voltammetry experiments. As demonstrated in more than 30 examples, our water-assisted LA/photoredox catalytic activation strategy allows for excess-free, equimolar radical cross-coupling and subsequent formal Markovnikov hydroxylation to versatile 1,4-difunctionalized products in good to excellent yields.

An N-Heterocyclic Carbene-Mediated, Enantioselective and Multicatalytic Strategy to Access Dihydropyranones in a Sequential Three-Component One-Pot Reaction.

The multicatalytic generation of 3,5,6-trisubstituted 3,4-dihydropyranones with high enantioselectivity using a highly convergent strategy starting from commercially available precursors is reported. The operationally simple three-step, one-pot protocol merges H-bond and NHC catalysis to provide crucial, reactive ß-unsubstituted enones from nitroalkenes as latent 1,2-biselectrophiles. These intermediates are directly funneled into a further NHC-catalyzed formal hetero-Diels-Alder reaction to deliver manifold chiral C(4)-unsubstituted dihydropyranones (typical ee >98%), allowing aliphatic and heteroaromatic substituents and hence expanding the scope of this Michael addition/lactonization.

Nitroalkenes as Latent 1,2-Biselectrophiles - A Multicatalytic Approach for the Synthesis of 1,4-Diketones and Their Application in a Four-Step One-Pot Reaction to Polysubstituted Pyrroles.

An NHC-catalyzed nitro-Stetter/elimination/Stetter reaction sequence employs nitroalkenes as latent 1,2-dication synthons providing a novel access to highly useful symmetrical and unsymmetrical 2-aryl substituted 1,4-diketone building blocks from commercially available aldehyde precursors. For less activated (aliphatic) aldehydes, a cooperative catalytic strategy has been developed via the merger of NHC and H-bonding catalysis. To further showcase the versatility of our approach, a great variety of these unprecedented 1,4-diketones are used to efficiently synthesize polysubstituted pyrroles-including those with hetaryl substituents-in good to excellent yields in a multicatalytic metal-free, four-step one-pot cascade reaction under mild, yet robust, conditions.

On-chip integration of organic synthesis and HPLC/MS analysis for monitoring stereoselective transformations at the micro-scale.

We present a microfluidic system, seamlessly integrating microflow and microbatch synthesis with a HPLC/nano-ESI-MS functionality on a single glass chip. The microfluidic approach allows to efficiently steer and dispense sample streams down to the nanoliter-range for studying reactions in quasi real-time. In a proof-of-concept study, the system was applied to explore amino-catalyzed reactions, including asymmetric iminium-catalyzed Friedel-Crafts alkylations in microflow and micro confined reaction vessels.

Remote-Stereocontrol in Dienamine Catalysis: Z-Dienamine Preferences and Electrophile-Catalyst Interaction Revealed by NMR and Computational Studies.

Catalysis with remote-stereocontrol provides special challenges in design and comprehension. One famous example is the dienamine catalysis, for which high ee values are reported despite insufficient shielding of the second double bond. Especially for dienamines with variable Z/E-ratios of the second double bond, no correlations to the ee values are found. Therefore, the structures, thermodynamics, and kinetics of dienamine intermediates in SN-type reactions are investigated. The NMR studies show that the preferred dienamine conformation provides an effective shielding if large electrophiles are used. Calculations at SCS-MP2/CBS-level of theory and experimental data of the dienamine formation show kinetic preference for the Z-isomer of the second double bond and a slow isomerization toward the thermodynamically preferred E-isomer. Modulations of the rate-determining step, by variation of the concentration of the electrophile, allow the conversion of dienamines to be observed. With electrophiles, a faster reaction of Z- than of E-isomers is observed experimentally. Calculations corroborate these results by correlating ee values of three catalysts with the kinetics of the electrophilic attack and reveal the significance of CH-π and stacking interactions in the transition states. Thus, for the first time a comprehensive understanding of the remote stereocontrol in γ-functionalization reactions of dienamines and an explanation to the "Z/E-dilemma" are presented. The combination of bulky catalyst subsystems and large electrophiles provides a shielding of one face and causes different reactivities of E/Z-dienamines in nucleophilic attacks from the other face. Kinetic preferences for the formation of Z-dienamines and their unfavorable thermodynamics support high ee values.