Recent trends in catalytic sp³ C–H functionalization of heterocycles

Abstract

In this mini-review, we attempt to highlight gaps in existing techniques for sp3 C–H activation adjacent to heterocycles.

Site‐Selective Pyridylic C−H Functionalization by Photocatalytic Radical Cascades

“…Nitrogen‐containing heteroarenes are widely found in numerous natural products, [1] agrochemicals, [2] and bioactive molecules, [3] and are considered especially useful in drug development [4] . The selective installation of functional groups with different substitution patterns at the heterobenzylic position over heterocyclic cores is of significant interest in synthetic [5–13] and medicinal chemistry [14, 15] . However, because alkyl pyridines have relatively high p K a values (p K a =ca.…”

Direct, Catalytic α-Alkylation of N-Heterocycles by Hydroaminoalkylation: Substrate Effects for Regiodivergent Product Formation

“…The ability to selectively C–H functionalize N -heterocycles allows for the rapid generation of complex amine products from simple starting materials in one catalytic step. According to a recent minireview of catalytic C–H functionalization of heterocycles, less than 8% of reports disclose the ability to C–H functionalize saturated N -heterocycles and most demand the use of protected amine substrates . Current literature to react saturated amine heterocycles is dominated by Csp 3 –Csp 2 arylation − or Csp 3 –Csp cyanation/alkynylation. , Photocatalytic cross-coupling can realize the α-C–H alkylation of protected saturated amines with activated electrophiles, such as aldehydes or alkyl halides, − or the stoichiometric α-alkylation of unprotected N -heterocycles can be achieved by the addition of organometallic nucleophiles to transiently generated imines. , These methods require activated alkylating agents that result in the generation of stoichiometric amounts of waste.…”

Recent Advances in Transition-Metal-Free Late-Stage C-H and N-H Arylation of Heteroarenes Using Diaryliodonium Salts

“…Because small changes can have a huge impact on bioactive profile, this approach offers unique opportunities for the generation of new drug-like analogs of lead structures without extra synthetic steps or resorting to de novo synthesis [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. While various reviews on C–H functionalization of heteroarenes have been already published [ 18 , 19 , 20 , 21 , 22 ], they are mainly focused on transition metal catalysis. In the quest for mild and sustainable late-stage functionalization, transition-metal-free diversification appears as a rewarding tool to build new functionalized heteroarene derivatives onto their established bioactive framework [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”