Decatungstate‐Mediated C(sp³)–H Heteroarylation via Radical‐Polar Crossover in Batch and Flow

Abstract

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp 3 )-H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical-polar crossover concept to access the direct net-oxidative C(sp 3 )-H heteroarylation. The present methodology demonstrates a high functional group tolerance (40 examples) and is scalable when using continuous-flow reactor technology. The developed protocol is also amenable to the late-stage functionalization of biologically relevant molecules such as stanozolol, (À)ambroxide, podophyllotoxin, and dideoxyribose.Photocatalytic hydrogen atom transfer (HAT) is witnessing an ever-growing interest from the synthetic community as a versatile strategy for the late-stage functionalization of C(sp 3 )ÀH bonds. [1][2][3] In this activation mode, the excited state of a photocatalyst can be conveniently exploited to cleave C(sp 3 ) À H bonds to obtain carbon-centered radicals. By exploiting inherent electronic and steric properties of the parent molecule and by tuning the reaction conditions, these nucleophilic radicals can be obtained with high regioselectiv-ity, thus obviating the need to use any directing or activating groups (Scheme 1 a).Amongst the different HAT photocatalysts, the decatungstate anion (W; [W 10 O 32 ] 4À ) has proven to be an ideal candidate owing to its unique selectivity, robustness and ease of preparation. [4,5] The excited state of W (W*) can be readily obtained upon exposure to UV-A light (l > 365 nm) and has been used for the activation of C(sp 3 )ÀH bonds within a wide variety of hydrogen donors such as ethers, aldehydes, amides and even alkanes. In most cases, the fleeting radical intermediates were used to forge CÀC, [6] CÀF, [7] and CÀO [8] bonds. In contrast, only a handful of examples demonstrate the formation of C À N bonds. [9] These examples mainly rely on the trapping of the radical with a suitable Michael acceptor, e.g., diisopropyl azodicarboxylate (DIAD), delivering the corresponding hydrazides. Despite its synthetic utility to Scheme 1. a) Photocatalytic hydrogen atom transfer (HAT) enables the conversion of CÀH bonds in complex biologically active molecules. b) Established mechanism for the formation of CÀN bonds via TBADT-mediated HAT. c) Proposed approach to realize the regioselective CÀH bond heteroarylation through combination of decatungstateenabled HAT and Radical-Polar Crossover (RPC).

Mo2C as Pre-Catalyst for the C-H Allylic Oxygenation of Alkenes and Terpenoids in the Presence of H2O2

“…This result was in line with the literature reporting non-bonding interactions (steric effects) [73] between a large group (i.e., phenyl) and an incoming decatungstate reactive intermediate (wO) in the C-H activation pathway [61]. Thus, the corresponding hydrogen atom abstraction (HAT) from the lone-selectivity where this steric interaction must be negligible provides a reasonable explanation for the observed side-selectivity with TBADT [74][75][76][77]. In contrast, the Mo 2 C-catalyzed twix-selectivity (100% yield of 6a') reflects a complete change in mechanism with that proposed via the HAT mechanism [78][79][80][81] (Scheme 5).…”

Accelerated and Scalable C(sp3)–H Amination via Decatungstate Photocatalysis Using a Flow Photoreactor Equipped with High-Intensity LEDs

“…It should be further noted that this two-step flow protocol enables access to pyrazoles bearing unactivated alkanes, which could not be prepared using our direct decatungstate-mediated C(sp 3 )–H azolation. 33 In addition, by adding 2-formylbenzoic acid derivatives ( D , E ) instead, the corresponding phthalazinones ( 34 – 37 , 55–69%) could be obtained by means of this streamlined flow process ( Scheme 3 A). Finally, we also demonstrated that the protected hydrazines can be readily converted to the corresponding primary amines via hydrogenation ( 38 , 87%) ( Scheme 3 B).…”

Ni‐Catalyzed Cross‐Coupling of 2‐Iodoglycals and 2‐Iodoribals with Grignard Reagents: A Route to 2‐C‐Glycosides and 2’‐C‐Nucleosides

“…and others, either by a NIS‐mediated addition of nitrogen‐based nucleophiles [19] or an epoxidation of the double bond followed by a ring opening [20] . N ‐glycosylation of glycals was recently achieved by photoredox catalysis [21] . However, to the best of our knowledge, N ‐glycosylation of C2‐alkylated glycals is unknown.…”