Unnatural amino acids (UAAs) are key building blocks with widespread application across several scientific fields. Therefore, it is highly attractive to develop straightforward and simple methodologies capable of granting quick access to these species. Herein we report a light‐mediated protocol for the synthesis of UAA via radical decarboxylative processes. This methodology, which employs readily available and abundant starting materials – such as carboxylic and α‐keto acids – proceeds under very mild reaction conditions and shows a high functional group tolerance. In addition, the products of the radical reaction can be readily derivatized to grant rapid access to complex UAAs.
Thioethers are highly prevalent functional groups in organic compounds of natural and synthetic origin but remain remarkably underexplored as starting materials in desulfurative transformations. As such, new synthetic methods are highly desirable to unlock the potential of the compound class. In this vein, electrochemistry is an ideal tool to enable new reactivity and selectivity under mild conditions. Herein, we demonstrate the efficient use of aryl alkyl thioethers as alkyl radical precursors in electroreductive transformations, along with mechanistic details. The transformations proceed with complete selectivity for C(sp3)−S bond cleavage, orthogonal to that of established transition metal‐catalyzed two‐electron routes. We showcase a hydrodesulfurization protocol with broad functional group tolerance, the first example of desulfurative C(sp3)−C(sp3) bond formation in Giese‐type cross‐coupling and the first protocol for electrocarboxylation of synthetic relevance with thioethers as starting materials. Finally, the compound class is shown to outcompete their well‐established sulfone analogues as alkyl radical precursors, demonstrating their synthetic potential for future desulfurative transformations in a one‐electron manifold.
In recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp3-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a novel and powerful approach for the light-mediated B-alkyl Suzuki−Miyaura cross-coupling between alkyl boranes and aryl bromides. Alkyl boranes can be easily generated via hydroboration from readily available alkenes, exhibiting excellent regioselectivity and enabling the selective transfer of a diverse range of primary alkyl fragments onto the arene ring. This methodology eliminates the need for expensive catalytic systems and sensitive organometallic compounds, operating efficiently at room temperature within just 30 minutes. Interestingly, our mechanistic studies reveal an unexpected mechanistic scenario that operates through transmetalation rather than alkyl radical formation, setting it apart from established metallaphotoredox protocols. Moreover, we demonstrate the advantageous translation of the present protocol to continuous-flow conditions, enhancing scalability, safety, and overall efficiency of the method. This versatile approach offers significant potential for accelerating drug discovery efforts by enabling the introduction of complex aliphatic fragments in a straightforward and reliable manner.
Herein, the use of aryl alkyl thioethers as precursors for C-centered alkyl radicals is demonstrated for desulfurative C-H and C-C bond formation under electroreductive conditions. The transformations occur with complete selectivity for C(sp3)-S bond cleavage, orthogonal to that of transition metal-catalyzed two-electron routes. Experimental and theoretical studies provide mechanistic insights that serve as a steppingstone for future use of thioethers as efficient radical precursors that can outcompete their established sulfone analogues.
Herein, the use of aryl alkyl thioethers as precursors for C-centered alkyl radicals is demonstrated for desulfurative C-H and C-C bond formation under electroreductive conditions. The transformations occur with complete selectivity for C(sp3)-S bond cleavage, orthogonal to that of transition metal-catalyzed two-electron routes. Experimental and theoretical studies provide mechanistic insights that serve as a steppingstone for future use of thioethers as efficient radical precursors that can outcompete their established sulfone analogues.
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