Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry

[Image: see text] Photoinduced chemical transformations have received in recent years a tremendous amount of attention, providing a plethora of opportunities to synthetic organic chemists. However, performing a photochemical transformation can be quite a challenge because of various issues related to the delivery of photons. These challenges have barred the widespread adoption of photochemical steps in the chemical industry. However, in the past decade, several technological innovations have led to more reproducible, selective, and scalable photoinduced reactions. Herein, we provide a comprehensive overview of these exciting technological advances, including flow chemistry, high-throughput experimentation, reactor design and scale-up, and the combination of photo- and electro-chemistry

C(sp3)–H sulfinylation of light hydrocarbons with sulfur dioxide via hydrogen atom transfer photocatalysis in flow

Sulfur-containing scaffolds originating from small alkyl fragments play a crucial role in various pharmaceuticals, agrochemicals, and materials. Nonetheless, their synthesis using conventional methods presents significant challenges. In this study, we introduce a practical and efficient approach that harnesses hydrogen atom transfer photocatalysis to activate volatile alkanes, such as isobutane, butane, propane, ethane, and methane. Subsequently, these nucleophilic radicals react with SO2 to yield the corresponding sulfinates. These sulfinates then serve as versatile building blocks for the synthesis of diverse sulfur-containing organic compounds, including sulfones, sulfonamides, and sulfonate esters. Our use of flow technology offers a robust, safe and scalable platform for effectively activating these challenging gaseous alkanes, facilitating their transformation into valuable sulfinates

Efficient C(sp3)-H carbonylation of light and heavy hydrocarbons with carbon monoxide via HAT photocatalysis in flow

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C-H functionalization at sp3-hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C-H bonds known in Nature, requiring extreme activation conditions that are not tolerant to most organic molecules. To bypass these issues, synthetic chemists rely on prefunctionalized alkyl halides or organometallic coupling partners. However, new synthetic methods that target regioselectively C-H bonds in a variety of different organic scaffolds would be of great added value, not only for the late-stage functionalization of biologically active molecules but also for the catalytic upgrading of cheap and abundant hydrocarbon feedstocks. Here, we describe a general, mild and scalable protocol which enables the direct C(sp3)-H carbonylation of saturated hydrocarbons, including natural products and light alkanes, using photocatalytic hydrogen atom transfer (HAT) and gaseous carbon monoxide (CO). Flow technology was deemed crucial to enable high gas-liquid mass transfer rates and fast reaction kinetics, needed to outpace deleterious reaction pathways, but also to leverage a scalable and safe process

Photocatalytic Late-stage Functionalization of Dehydroalanine-derived Peptides in Batch and Flow

Unnatural amino acids, and their synthesis via the late-stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. In this study, we present a photocatalytic hydroarylation process targeting the electrophilic residue dehydroalanine (Dha). This residue possesses an α,β-unsaturated moiety and can be combined with various arylthianthrenium salts, both in batch and flow reactors. Notably, the flow setup proved instrumental for efficient scale-up, paving the way for the synthesis of unnatural amino acids and peptides in substantial quantities. Our photocatalytic approach, being inherently mild, permits the diversification of peptides even when they contain sensitive functional groups. The readily available arylthianthrenium salts facilitate the seamless integration of Dha-infused peptides with a wide range of arenes, drug blueprints, and natural products, culminating in the creation of unconventional phenylalanine derivatives. The synergistic effect of the high functional group tolerance and the modular characteristic of the aryl electrophile enables efficient peptide conjugation and ligation in both batch and flow conditions