Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes

Abstract

Fosu, Hambira, and colleagues describe the direct C-H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc) 2 . The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included.

Mechanistic Insights for Iodane Mediated Aromatic Halogenation Reactions

“…The reverse conversion from PhICl 2 and HOAc encounters a moderate barrier of 20.7 kcal/mol ( TS2 ) and thus is still possible under ambient conditions. Since the formation of PhI(Cl)OAc from PhI(OAc) 2 is −2.4 kcal/mol more exergonic than the formation of PhICl 2 from PhI(Cl)OAc via formal OAc/Cl ligand exchange with HCl, PhI(Cl)OAc should be thermodynamically favoured and dominate at low HCl molar ratio, though PhICl 2 is eventually reached with excess HCl, fully consistent with experimental results mixing 0.5 and 2.0 equivalent of HCl with PhI(OAc) 2 [11a] …”

“…The second OAc/Cl ligand exchange with AcCl is thus −10.0 kcal/mol exergonic and again irreversible (high reverse barrier of 33.8 kcal/mol). Consistent with experiment, [11a] our DFT calculations indicate that AcCl is less reactive than TMSCl and HCl as electrophilic iodane activator but is more selective for the formation of the desirable PhI(Cl)OAc for further electrophilic atom transfer reactions.…”

“…However, the detailed mechanism of iodane activation and subsequent aromatic substitution reactions still remains controversial. For example, either nucleophiles [11a,12] such as halide anions X − or electrophiles [11a,b,12b] TMSX (X=Cl, Br) seem to be directly involved in ligand exchange with stable iodanes such as PhI(OAc) 2 , followed by direct I−X bond cleavage of either non‐symmetric [11a] or symmetric [11b,12b] iodanes to induce radical [11a,12a] or electrophilic [11b,12b] aromatic substitution reactions. A clear and general mechanistic picture is thus highly desirable for such iodane‐mediated aromatic substitution reactions.…”

“…Excess HCl is often used as protic PhI(OAc) 2 activator in experiment for aromatic chlorination reactions [11a] . As seen in Figure 1B, once generated from HCl activation of PhI(Cl)OAc, the electrophilic iodonium PhICl + may easily transfer Cl + to anisole PhOMe as aromatic substrate, which is −17.5 kcal/mol exergonic and almost barrierless to form the arenium Cl + ⋅ PhOMe and stable PhI.…”

“…Experimentally, other electrophiles such as TMSX (X=Cl and Br) have also been identified as efficient activator of stable iodanes such as PhI(OAc) 2 [11a,b,12b] . As shown in Figure 2A, nucleophilic replacement at the Si‐center of TMSCl with a acetyl C=O group of PhI(OAc) 2 can easily release a chloride anion Cl − , which is only 10.1 kcal/mol endergonic to form the cation PhI(OAc) 2 TMS + .…”