By hijacking endogenous E3 ligase to degrade protein targets via the ubiquitin-proteasome system, PROTACs (PRoteolysis TArgeting Chimeras) provide a new strategy to inhibit protein targets that were regarded as undruggable before. However, the catalytic nature of PROTAC potentially leads to uncontrolled degradation that causes systemic toxicity issues, limiting the application of PROTAC in the clinic. Here, we introduce a light-inducible switch on PROTACs, thereafter termed as opto-PROTAC, to enable the degradation of protein targets in a spatiotemporal manner. By adding a photolabile caging group on pomalidomide as a parental compound and two additional PROTACs, dBET1 and dALK, we demonstrated light-inducible protein degradation. These opto-PROTACs display no activities in the dark, while the restricted degradation can be induced at a specific time and rate by ultraviolet A irradiation. Our approach provides a generalizable platform for the development of light-controlled PROTACs and enables PROTAC to be a precision medicine. Light induces the uncaging of opto-pomalidomide to mediate degradation of Ikaros zinc finger transcription factorsPomalidomide and its derivatives, such as lenalidomide and thalidomide, are widely used as immunomodulatory drugs for treating Light-induced control of protein destruction by opto-PROTAC. Sci. Adv. 6, eaay5154 (2020).

The copper-assisted radical carbofluorination of unactivated alkenes with fluoride ions is described. With [Cu(L3)F]HO (L3 = 4,4'-di(methoxycarbonyl)-2,2'-bipyridine) as the fluorine source and [Ag(DMPhen)(MeCN)]BF (DMPhen = 2,9-dimethyl-1,10-phenanthroline) as the chloride scavenger, the reaction of unactivated alkenes with CCl in acetonitrile provided the corresponding carbofluorination products in satisfactory yields. The protocol exhibited a wide functional group compatibility and broad substrate scope and could be extended to the use of a variety of activated alkyl chlorides other than CCl. A copper-catalyzed fluorotrifluoromethylation of unactivated alkenes was then successfully developed with CsF as the fluorine source and Umemoto's reagent as the trifluoromethylating agent. A mechanism involving the fluorine atom transfer from Cu(II)-F complexes to alkyl radicals is proposed.

Direct decarboxylative radical allylation of aliphatic carboxylic acids is described. With K2S2O8 as the oxidant and AgNO3 as the catalyst, the reactions of aliphatic carboxylic acids with allyl sulfones in aqueous CH3CN solution gave the corresponding alkenes in satisfactory yields under mild conditions. This site-specific allylation method is applicable to all primary, secondary, and tertiary alkyl acids and exhibits wide functional group compatibility.

The silver-catalyzed Hunsdiecker bromination of aliphatic carboxylic acids is described. With Ag(Phen)OTf as the catalyst and dibromoisocyanuric acid as the brominating agent, various aliphatic carboxylic acids underwent decarboxylative bromination to provide the corresponding alkyl bromides under mild conditions. This method not only is efficient and general but also enjoys wide functional group compatibility. An oxidative radical mechanism involving Ag(II) intermediates is proposed.

In this article, we report the first examples of carbofluorination of unactivated alkenes. Under catalysis by AgNO 3 , the reactions of unactivated alkenes with Selectfluor reagent and active methylene compounds such as acetoacetates or 1,3-dicarbonyls in CH 2 Cl 2 -H 2 O-HOAc solution afforded the corresponding three-component condensation products under mild conditions. Furthermore, with the promotion of NaOAc, the AgOAc-catalyzed carbofluorination of various unactivated alkenes with Selectfluor and acetone proceeded smoothly in aqueous solution at 50°C. The carbofluorination was efficient and highly regioselective, and enjoyed a broad substrate scope and wide functional group compatibility. These formal fluorine atom transfer radical addition reactions provide a convenient entry to structurally divergent, polyfunctional organofluorine compounds as versatile synthetic intermediates.Scheme 1 ATRA versus formal ATRA. † Electronic supplementary information (ESI) available. See

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen-exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal-free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.

The trifluoromethylalkynylation of unactivated alkenes with alkynyl sulfones and Togni's reagent was developed. The reaction was catalyzed by 2,4,6-trimethylpyridine, leading to various β-trifluoromethylated alkynes under metal-free conditions with a broad substrate scope and wide functional group compatibility. A mechanism involving catalytic nonchain radical processes is proposed.

The AgNO3-catalyzed carbofluorination of unactivated alkenes with acetic acid provides an efficient and general route to γ-fluorinated carboxylic acids.