Photoredox-enabled 1,2-dialkylation of α-substituted acrylates via Ireland-Claisen rearrangement.

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland-Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp3)-C(sp3) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors - a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.

Three-Component, Interrupted Radical Heck/Allylic Substitution Cascade Involving Unactivated Alkyl Bromides.

Developing efficient and selective strategies to approach complex architectures containing (multi)stereogenic centers has been a long-standing synthetic challenge in both academia and industry. Catalytic cascade reactions represent a powerful means of rapidly leveraging molecular complexity from simple feedstocks. Unfortunately, carrying out cascade Heck-type reactions involving unactivated (tertiary) alkyl halides remains an unmet challenge owing to unavoidable ß-hydride elimination. Herein, we show that a modular, practical, and general palladium-catalyzed, radical three-component coupling can indeed overcome the aforementioned limitations through an interrupted Heck/allylic substitution sequence mediated by visible light. Selective 1,4-difunctionalization of unactivated 1,3-dienes, such as butadiene, has been achieved by employing different commercially available nitrogen-, oxygen-, sulfur-, or carbon-based nucleophiles and unactivated alkyl bromides (>130 examples, mostly >95:5 E/Z, >20:1 rr). Sequential C(sp3)-C(sp3) and C-X (N, O, S) bonds have been constructed efficiently with a broad scope and high functional group tolerance. The flexibility and versatility of the strategy have been illustrated in a gram-scale reaction and streamlined syntheses of complex ether, sulfone, and tertiary amine products, some of which would be difficult to access via currently established methods.

Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists.

sp3-hybridized attached-rings are common motifs in secondary metabolites and represent tetrahedral equivalents to the biaryl substructures that overpopulate synthetic libraries. Few methods are available that can link fully substituted carbon atoms of two rings with stereocontrol. Here we have developed a stereoselective, heteroselective butenolide coupling that exhibits an unusually fast rate of C-C bond formation driven by exquisite complementarity of the reacting π systems. Heterodimerization generates a compound collection with topological complexity and diverse principal moments of inertia. The special status of the sp3-sp3 attached-ring motif is demonstrated in a high-throughput screen for inhibitors of the cyclic GMP-AMP synthase/stimulator of interferon genes pathway, which recruited these butenolide heterodimers from a field of 250,000 compounds. The driving forces underlying this general attached-ring coupling identify a novel paradigm for the accession of wider natural product chemical space, accelerating the discovery of selective lead compounds.

1,2-Amino Alcohols via Cr/Photoredox Dual-Catalyzed Addition of α-Amino Carbanion Equivalents to Carbonyls.

Herein, we report the synthesis of protected 1,2-amino alcohols starting from carbonyl compounds and α-silyl amines. The reaction is enabled by a Cr/photoredox dual catalytic system that allows the in situ generation of α-amino carbanion equivalents which act as nucleophiles. The unique nature of this reaction was demonstrated through the aminoalkylation of ketones and an acyl silane, classes of electrophiles that were previously unreactive toward addition of alkyl-Cr reagents. Overall, this reaction broadens the scope of Cr-mediated carbonyl alkylations and discloses an underexplored retrosynthetic strategy for the synthesis of 1,2-amino alcohols.

Accelerated Discovery in Photocatalysis by a Combined Screening Approach Involving MS Tags.

Herein we report on the development of an MS tag screening strategy that accelerates the discovery of photocatalytic reactions. By efficiently combining mechanism- and reaction-based screening dimensions, the respective advantages of each strategy were retained, whereas the drawbacks inherent to each screening approach could be eliminated. Applying this approach led to the discovery of a mild photosensitized decarboxylative hydrazide synthesis from mesoionic sydnones and carboxylic acids as starting materials.

Further Insights into Structural Diversity of Phosphorus-Based Decomposition Products in Lithium Ion Battery Electrolytes via Liquid Chromatographic Techniques Hyphenated to Ion Trap-Time-of-Flight Mass Spectrometry.

This study illustrates the high complexity of phosphorus-based decomposition products in thermally treated state-of-the-art lithium ion battery (LIB) electrolytes. Liquid chromatographic techniques hyphenated to ion trap time-of-flight mass spectrometry reveal 122 different organophosphate (OP) and organofluorophosphate (OFP) species, the majority of which are not reported in the literature so far. The application of hydrophilic interaction liquid chromatography and reversed-phase chromatography enables the investigation of the acidic as well as nonacidic spectrum of aging products. Furthermore, the generation of high structure certainty by consideration of (i) mass accuracy of the precursor ions and subsequent MS2/3 fragments, (ii) fragment intensity distribution in the mass spectra, and (iii) retention times in hydrophilic interaction liquid chromatography (HILIC) and reversed-phase (RP) separation allows a target analysis of further work in the LIB electrolyte context. In an ethyl methyl carbonate-based battery electrolyte, 82 OP compounds, 27 OFPs, and 13 cyclic O(F)Ps are identified. Additionally, the formation of 8-membered organo(fluoro)phosphate rings in lithium ion battery electrolytes is reported for the first time. Since the high toxic potential of organo(fluoro)phosphates has emerged interest in safety assessments of electrolytes, the knowledge of possibly formed substances supports further quantification approaches and toxicological assessments compared to nontarget investigations.

Reductive radical-polar crossover: traditional electrophiles in modern radical reactions.

The concept of reductive radical-polar crossover (RRPCO) reactions has recently emerged as a valuable and powerful tool to overcome limitations of both radical and traditional polar chemistry. Especially in case of additions to carbonyl compounds, the synergy of radical and polar pathways is of great advantage since it enables the use of traditional carbonyl electrophiles in radical reactions. The most recent and synthetically important transformations following this line are summarised in the first part of this review. The second part deals with transformations, in which the concept of RRPCO promotes the usage of alkyl halides as electrophiles in radical reactions.

Diastereoselective Allylation of Aldehydes by Dual Photoredox and Chromium Catalysis.

Herein, we report the redox-neutral allylation of aldehydes with readily available electron-rich allyl (hetero-) arenes, ß-alkyl styrenes and allyl-diarylamines. This process was enabled by the combination of photoredox and chromium catalysis, which allowed a range of homoallylic alcohols to be prepared with high levels of selectivity for the anti diastereomer. Mechanistic investigations support the formation of an allyl chromium intermediate from allylic C(sp3)-H bonds and thus significantly extends the scope of the venerable Nozaki-Hiyama-Kishi reaction.