Photoinduced activation of alkyl chlorides.

In recent years, the activation of unactivated alkyl chlorides through light-induced processes has emerged as a promising field in radical chemistry, and has led to new transformations in organic synthesis. Direct utilization of alkyl chlorides as C(sp3)-hybridized electrophiles enables the facile construction of carbon-carbon and carbon-heteroatom bonds. Furthermore, recent studies in medicinal chemistry indicate that their presence is associated with high levels of success in clinical trials. This review summarizes the recent advances in the photoinduced activation of unactivated alkyl chlorides and discusses the mechanistic aspects underlying these reactions. We anticipate that this review will serve as a valuable resource for researchers in the field of unactivated chemical bond functionalization, and inspire considerable developments in organic chemistry, drug synthesis, materials science and other related disciplines.

Trinuclear Gold-Catalyzed 1,2-Difunctionalization of Alkenes.

Activated alkyl halides have been extensively explored to generate alkyl radicals with Ru- and Ir- photocatalysts for 1,2-difunctionalization of alkenes, but unactivated alkyl bromides remain challenging substrates due to their strong reduction potential. Here we report a three-component 1,2-difunctionalization reaction of alkenes, unactivated alkyl bromides and nucleophiles (e.g., amines and indoles) using a trinuclear gold catalyst [Au3 (tppm)2 ](OTf)3 . It can achieve the 1,2-aminoalkylation and 1,2-alkylarylation readily. This protocol has a broad reaction scope and excellent functional group compatibility (>100 examples with up to 96 % yield). It also affords a robust formal [2+2+1] cyclization strategy for the concise construction of pyrrolidine skeletons under mild reaction conditions. Mechanistic studies support an inner-sphere single electron transfer pathway for the successful cleavage of inert C-Br bonds.

Divergent Reaction of Indoline-derived Azadienes with α-Bromohydroxamates: Synthesis of Spiro-indolinepyrrolidinones and Indoline-fused Diazepinones.

A divergent reaction of indoline-derived azadienes with α-bromohydroxamates for the selective synthesis of spiro-indolinepyrrolidinones and indoline-fused diazepinones was disclosed. This reaction sequence involved an initial formation of five-membered spirocyclic products followed by an intramolecular ring-opening and ring expansion to produce seven-membered diazepinones. We demonstrated that controlling the reaction time could modulate the reaction pathway for formation of different molecular frameworks for the same set of substrates. Based on the experimental results, the reaction mechanism was also discussed and proposed to explain the phenomena observed in the process.

A rearrangement of saccharin-derived cyclic ketimines with 3-chlorooxindoles leading to spiro-1,3-benzothiazine oxindoles.

An unusual rearrangement of saccharin-derived cyclic ketimines (SDCIs) and 3-chlorooxindoles has been developed to provide a series of spiro-1,3-benzothiazine oxindoles. The reaction features simple manipulations, short reaction times, mild reaction conditions and inexpensive reagents. It is the first example where SDCIs serve as a ring-opening reagent in organic synthesis.

A [4+3] annulation of benzofuran-derived azadienes and α-bromohydroxamates for the synthesis of benzofuran-fused 1,4-diazepinones.

A Cs2CO3-mediated formal [4+3] cycloaddition involving benzofuran-derived azadienes (BDAs) and α-bromohydroxamates to afford benzofuran-fused 1,4-diazepinones is established. This is the first example of using BDAs for the construction of seven-membered dinitrogen-fused heterocycles. This strategy not only enriches the chemistry of BDAs but also provides an interesting class of bioisosteres of 1,4-benzodiazepine.

A Role for Isatin Azomethine Imines as a Dipolarophile in Cycloaddition Reactions.

An unusual [2 + 3] cycloaddition of isatin azomethine imines (AIs) and in situ generated azaoxyallyl cations has been developed. It is the first example where AIs serve as the [C,O] 2-atom synthon in organic synthesis. This work not only reveals a new role of isatin AIs in cycloaddition reaction but also provides an efficient access to unprecedented spiroheterocycle compounds.

Regio- and Diastereoselective Spirocyclopropanation of Benzofuran-Derived Azadienes through 1,4-Addition-Induced Dearomatization Reaction under Mild Conditions.

A Cs2CO3-mediated [2 + 1] cycloaddition of benzofuran-derived azadienes (BDAs) with bromomalonate by using a dearomatization strategy has been developed. Through this process, BDAs serve as a potential 2-atom synthon in the construction of a range of functionalized spirocyclopropane derivatives, such as spirobenzofuran-2-cyclopropanes and spiroindane-2-cyclopropanes.

DABCO-mediated [3+3] cycloaddition of azomethine imines with in situ generated nitrile oxides from hydroximoyl chlorides.

A novel cross 1,3-dipolar cycloaddition between azomethine imines with in situ generated nitrile oxides has been developed. This is the first example of employing a reaction partner containing two heteroatoms in the [3+3] cycloaddition involving azomethine imines. This strategy not only provides structurally diverse N,O-heterocycles but also greatly enriches the chemistry of azomethine imines and nitrile oxides.