Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

Abstract

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method for the mild generation of alkyl radicals for C–C bond formation. The effect of ring strain on radical reactivity is not well understood, with no studies that address this question systematically. Examples of reactions that involve benzylic radicals are rare, and their reactivity is challenging to harness. This work develops a radical functionalization of benzylic oxetanes and azetidines using visible light photoredox catalysis to prepare 3-aryl-3-alkyl substituted derivatives and assesses the influence of ring strain and heterosubstitution on the reactivity of small-ring radicals. 3-Aryl-3-carboxylic acid oxetanes and azetidines are suitable precursors to tertiary benzylic oxetane/azetidine radicals which undergo conjugate addition into activated alkenes. We compare the reactivity of oxetane radicals to other benzylic systems. Computational studies indicate that Giese additions of unstrained benzylic radicals into acrylates are reversible and result in low yields and radical dimerization. Benzylic radicals as part of a strained ring, however, are less stable and more π-delocalized, decreasing dimer and increasing Giese product formation. Oxetanes show high product yields due to ring strain and Bent’s rule rendering the Giese addition irreversible.

Synthesis of oxetane and azetidine ethers as ester isosteres by Brønsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols

“…3° out of plane to maximize π-conjugation resulting in a flat conformation. As observed in our previous analysis on 3-aryl-3-alkyl-oxetanes, 23 the increased steric requirement of the oxetane ring provokes a switch in conformational preference of the ethereal substituent which lies on the aryl side in oxetane ethers in a quasi -staggered conformation, but on the carbonyl side in benzoate structures.…”

Radical Group Transfer of Vinyl and Alkynyl Silanes Driven by Photoredox Catalysis

“…This can result in a higher activation energy for the formation of such radicals, thereby explaining the longer reaction times. Benzylic radicals, on the other hand, are known to be stabilized by delocalization. , Indeed, we were pleased to observe rapid reactions and high isolated yields at benzylic positions ( 6q – s ). Similarly, reactions at electron-deficient positions also proceeded rapidly and gave high yields ( 6t – v ).…”

“…Benzylic radicals, on the other hand, are known to be stabilized by delocalization. 25,26 Indeed, we were pleased to observe rapid reactions and high isolated yields at benzylic positions (6q−s). Similarly, reactions at electron-deficient positions also proceeded rapidly and gave high yields (6t−v).…”

“…1 H NMR (400 MHz, CDCl 3 , mixture of rotamers) δ 5.89 (1H, dddd, J = 14.8, 11.0, 6.9, 4.5 Hz, CH(CHCH 2 )), 5.31−5.12 (2H, m, CH(CHCH 2 )), 4.24 (1H, dd, J = 3.6, 2.1 Hz, CHOH), 3.61−3.40 (3H, m, 3 × CH 2 ), 3.34 (1H, dt, J = 12.4, 10.5 Hz, CH 2 ), 2.84−2.71 (1H, m, CH(CHCH 2 )), 2.27 (1H, dd, J = 48.5, 3.5 Hz, OH), 1.43 (9H, s, 3 × CH 3 ); 13 42 4-(2-Benzyloxy)propan-2-yl)-1-methyl-2-vinylcyclohexan-1-ol (6e) was synthesized from vinyl silane 4e (0.14 g, 0.30 mmol, 1.0 equiv), [Ir(dtbbpy)(ppy) 2 ]PF 6 (6.3 mg, 7.0 μmol, 2.4 mol %), Bu 3 N (0.14 mL, 0.60 mmol, 2.0 equiv) in MeCN/MeOH 9:1 (3 mL), and HCl 1. 25 2-Methyl-1-phenylbut-3-en-1-ol (6f) was synthesized from vinyl silane 4f (0.10 g, 0.30 mmol, 1.0 equiv), [Ir(dtbbpy)(ppy) 2 ]PF 6 (6.2 mg, 7.0 μmol, 2.2 mol %), Bu 3 N (0.14 mL, 0.59 mmol, 2.0 equiv) in MeCN/MeOH 9:1 (3 mL), and HCl 1.25 M in MeOH (0.50 mL, 0.63 mmol, 2.1 equiv) according to Procedure E. The crude was purified by column chromatography (IPA/CH 2 Cl 2 1%) to afford an inseparable 87:13 diastereomers mixture of 6f (35 mg, 0.22 mmol, 72%) as a colorless oil. Note: the NMR data were extracted f rom the analysis of the inseparable mixture.…”

“…1 H NMR (400 MHz, CDCl 3 , minor) δ 7.45−7.12 (5H, m, ArH), 5.70 (1H, d, J = 8.6 Hz, CHCH 2 ), 5.09−4.93 (2H, m, CHCH 2 ), 4.57 (1H, t, J = 4.3 Hz, CHOH), 2.56 (1H, q, J = 6.8 Hz, CHCH 3 ), 0.99 (3H, d, J = 6.9 Hz, CH 3 ); 13 43 5-Vinyloctan-4-ol (6g) was synthesized from vinyl silane 4g (0.10 g, 0.30 mmol, 1.0 equiv), [Ir(dtbbpy)(ppy) 2 ]PF 6 (6.6 mg, 7.2 μmol, 2.4 mol %), Bu 3 N (0.14 mL, 0.59 mmol, 1.9 equiv) in MeCN/MeOH 9:1 (3 mL), and HCl 1. 25 1-Phenyl-2-vinylpropane-1,3-diol (6h) was synthesized from vinyl silane 4h (0.14 g, 0.30 mmol, 1.0 equiv), [Ir(dtbbpy)(ppy) 2 ]PF 6 (6.8 mg, 7.3 μmol, 2.4 mol %), Bu 3 N (0.14 mL, 0.59 mmol, 1.9 equiv) in MeCN/MeOH 9:1 (3 mL), and HCl 1.25 M in MeOH (0.50 mL, 0.63 mmol, 2.1 equiv) according to Procedure E. The crude was purified by column chromatography (Et 2 O/pentane 20%). A short second column chromatography (IPA/CH 2 Cl 2 1−5%) afforded an inseparable 87:13 diastereomers mixture of 6 h (9.6 mg, 54 μmol, 18%) as a colorless oil.…”