DMSO-catalysed late-stage chlorination of (hetero)arenes

Mechanistic Insights for Dimethyl Sulfoxide Catalyzed Aromatic Chlorination Reactions

“…In pure O=SMe 2 solution, such barrier can be further enhanced due to even stronger trapping of SMe 2 OH + , eventually inhibiting efficient NsCl activation. These results are consistent with the almost inhibited catalysis in DMSO solution [9] . In cases of substrates with basic amine functional group, the amine group may act as proton shuttle instead but this will not change the crucial role of the S‐site of DMSO as efficient Cl + shuttle.…”

“…Facile α‐deprotonation of O=SClMeCH 2 Cl + with the coexisting anion Ns − may lead to another ylide O=SClMeCHCl that can also easily abstract Cl + from NsCl to initialize efficient electrophilic Cl + transfer to nucleophilic substrates (along with further methyl chlorination of O=SMeCH 2 Cl, see ESI). Note that the sizable overall barrier of 24.1 kcal/mol (via TS1 ) found for the formation of by‐product O=SMeCH 2 Cl along with the catalytic sulfoxonium O=SClMe 2 + is consistent with the slow methyl chlorination of O=SMe 2 with NsCl observed in experiment, [9] thus providing further support to our DFT‐computed reaction mechanism.…”

“…In contrast, direct Cl + transfers from NsCl to the substrate PoH is 23.3 kcal/mol endergonic to form the separated arenium PoHCl + (along with anion Ns − ) thus prevented by a sizable barrier. For comparison, the direct Cl + transfers from 1,3‐dichloro‐5,5‐dimethylhydantoin (DhCl 2 ) to PoH is 4.7 kcal/mol less endergonic to form the separated arenium PoHCl + (see ESI), consistent with the experimentally observed [9] higher electrophilic chlorination reactivity of DhCl 2 without catalyst.…”

“…As shown in Figure 1, the initial chloronium Cl + transfer from NsCl to O=SMe 2 may be directed by the moderately strong intermolecular N−Cl⋅⋅⋅S and N−Cl⋅⋅⋅O non‐covalent (halogen bond) interactions. Despite 2.5 kcal/mol stronger N−Cl⋅⋅⋅O than N−Cl⋅⋅⋅S halogen bond is involved, the Cl + transfer to the O‐site of O=SMe 2 is endergonic by 50.3 kcal/mol in chloroform solution thus highly unlikely, in sharp contrast to the recent mechanistic proposal with the O ‐chloro sulfonium SMe 2 OCl + as key intermediate for electrophilic Cl + transfer [9] . On the other hand, the Cl + transfer from NsCl to the more polarisable S‐site of O=SMe 2 is only 20.5 kcal/mol endergonic to form the S ‐chloro sulfoxonium O=SClMe 2 + , which after a methyl α‐deprotonation with separated anion Ns − over a free energy barrier of 24.1 kcal/mol (via transition structure TS1 ) may lead to the meta‐stable ylide O=SClMeCH 2 (along with stable succinimide NsH) that is still 2.4 kcal/mol higher in free energy.…”

“…Recently, the guanidine‐based Palau'chlor reagent [7] and non‐symmetric iodanes [8] have been proven useful for the late‐stage chlorination of various bioactive molecules and natural products. Efficient and practical late‐stage chlorination of (hetero)arenes, drugs, natural products and peptides has also been achieved using dimethyl sulfoxide (DMSO, or O=SMe 2 ) as a novel catalyst and N ‐chlorosuccinimide (NsCl) as a cheap chlorinating reagent under neutral conditions in chloroform solution at room temperature [9] . The O ‐chloro sulfonium SMe 2 OCl + was proposed as the key intermediate for electrophilic Cl + ‐transfer, which can be further trapped by concentrated O=SMe 2 into stable Cl + ‐bound dimer (SMe 2 O) 2 Cl + that may inhibit the catalysis (Scheme 1).…”