Transition-Metal Free Chemoselective Hydroxylation and Hydroxylation–Deuteration of Heterobenzylic Methylenes

Abstract

We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41–76% yields. Using DMSO-d 6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.

Iodine-Promoted Controlled and Selective Oxidation of (Aryl)(Heteroaryl)Methanes

“…Silica gel for column chromatography (particle size 100−200 mesh) was purchased from SRL India. 1 H, 13 C, and 19 F NMR spectra were recorded on a Bruker 400 MHz instrument. Chemical shifts were recorded in parts per million (ppm) relative to tetramethylsilane (TMS) (δ 0.00), chloroform (7.26 ppm), or DMSO (2.50 ppm).…”

“…1 H NMR splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), m (multiplet), quint (quintet), etc. 13 C NMR spectral values were reported relative to CDCl 3 (77.16 ppm) and DMSO-d 6 (39.52 ppm). FT-IR spectra were recorded on a JASCO spectrometer and are reported in frequency of absorption (cm −1 ).…”

“…151 mg, 70% yield; white solid; mp 118−120 °C; R f = 0.10 (hexane/ethyl acetate = 4:1); FTIR (neat) ν (cm −1 ) 909, 1112, 1594, 2925, 3384; 1 H NMR (400 MHz, CDCl 3 ) δ 8.55−8.58 (m, 1H), 7.62 (td, J 1 = 1.6 Hz, J 2 = 7.6 Hz, 1H), 7.26−7.30 (m, 2H), 7.17 (4-(Methylthio)phenyl)(pyridin-2-yl)methanol (3g). 171 mg, 74% yield; brown solid; mp 62−64 °C; R f = 0.09 (hexane/ethyl acetate = 4:1); FTIR (neat) ν (cm −1 ) 762, 1048, 1190, 1593, 2919, 3373; 1 H NMR (400 MHz, CDCl 3 ) δ 8.54 (d, J = 3.6 Hz, 1H), 7.61 (t, J = 6.0 Hz, 1H), 7.28 (d, J = 6.8 Hz, 2H), 7.16−7.23 (m, 3H), 7.14 (d, J = 6.4 Hz, 1H), 5.71 (s, 1H), 5.26 (s, 1H), 2.44 (s, 3H); 13…”

“…In particular, a unique oxidative system as 5 Very recently, Li and co-workers described a transition-metal-free chemoselective hydroxylation of benzylpyridine derivatives using a superstoichiometric quantity of strong inorganic base, potassium tert-butoxide, under aerobic oxidation reaction conditions (Scheme 1b). 13 In the view of developing a methodology with a significantly different activation mode under a distinct mechanism, herein, we report our recent efforts to selectively oxidize the heterobenzylic C (sp3) −H bond to C (sp3) −OH with a novel iodine/silane catalytic system based on halogen bond (XB) catalysis, which has been recently employed to activate several C−hetero bonds. 14−26 During our previous work, 5 we merely observed that 30 mol % of iodine can lead to the oxidation of 2-benzylpyridine 2a to give 31% yield of phenyl(pyridin-2-yl)methanol 3a in DMSO at 100 °C along with the 43% of ketone 4a (Table 1, entry 1).…”

Base-Mediated Anti-Markovnikov Hydroamidation of Vinyl Arenes with Arylamides

“…On the basis of the preceding mechanistic studies, , we put forth a reasonable mechanistic hypothesis as described in Scheme . The mechanism is initiated by the generation of dimesyl radical B via a single electron transfer (SET) from dimesyl anion A . Then amide 1 is induced by a dimesyl radical B in the presence of base to form amidoyl radical species C .…”