SET/HAT flips benzylamine C–H arylation site
PhC(O)SH plus Ir(ppy)3 switches photoredox arylation from N-methyl C–H to the benzylic position, giving 1,1-diarylmethylamines in hours.
Source
Regio- and chemoselective Csp<sup>3</sup>-H arylation of benzylamines by single electron transfer/hydrogen atom transfer synergistic catalysis
Study at a glance
- Design
- Animal / in-vitro — Photoredox SET/HAT synergistic arylation of benzylamines with Ir(ppy)3 and thiobenzoic acid
- N
- Substrate-scope yields 56–98% rather than a single sample N
- Population
- N,N-dimethylbenzylamines and related amines versus aryl nitriles
- Outcome
- PhC(O)SH switches arylation from N-methyl C–H to the benzylic position, giving 1,1-diarylmethylamines
Structured fields used in claim comparison tables when every cited study has a complete layer.
Inspect source passages
SET/HAT flips benzylamine C–H arylation site
These passages occur verbatim in the stored paper text. They support the points listed below; they do not verify every statement in the explanation.
SET-only reaction reaches 95% mass balance in 12 h
With Ir(ppy) 3 (1 mol%) as a photoredox catalyst and K 2 HPO 4 as base, the reaction afforded two compounds, 2a and 3a , in excellent mass balance (95%), though a long reaction time (12 h) was required for completion.
0.5 mol% Ir(ppy)3 and 1 mol% PhC(O)SH give 90% yield of 2a
When we used 0.5 mol% of Ir(ppy) 3 and as little as 1 mol% of PhC(O)SH, the reaction proceeded without difficulty to give 2a in 90% yield (entry 11).
What they did
They coupled N,N-dimethylbenzylamines with terephthalonitrile using Ir(ppy)3. Without a HAT catalyst, the N-methyl product dominated. Adding thiobenzoic acid (or PhC(O)SK) inverted selectivity. CV compared oxidation potentials; scope included cyclic amines and late-stage drugs.
What they found
SET-only: 12 h, 95% mass balance but major product from the 1° N-methyl radical. With 1 mol% PhC(O)SH, benzylic arylation is 91% in 1 h (r.r. >20:1). Down to 0.5 mol% Ir and 1 mol% thiol still gives 90%. Yields 56–98%. BDE: PhC(O)S–H 87.4 vs benzylic C–H 84.9 kcal mol–1. PhC(O)SK Epox = +0.80 V vs SCE, below the amine.
The limits
What it doesn't show
The aryl partner is an electron-poor arene (terephthalonitrile class), not a generic aryl halide. Full kinetic isotope effects and computed BDEs for every substrate are not given. Scale-up beyond millimole flasks is not the focus.
Key terms
- SET catalysis
- Photoredox oxidation of the amine to an aminium radical cation, then deprotonation to an α-amino radical.
- HAT
- Hydrogen-atom transfer from a C–H bond to a thiyl/thiocarboxyl radical.
- Thiobenzoic acid
- PhC(O)SH; its conjugate base oxidizes faster than the amine, generating the HAT catalyst.
- 1,1-Diarylmethylamine
- Ar2CH–NR2 pharmacophore from benzylic C–H arylation.
- Regioselectivity switch
- Same amine, different C–H site depending on SET-only vs SET/HAT.
Flashcards
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Quiz yourself
Without a HAT catalyst, N,N-dimethylbenzylamine is arylated mainly at
Common questions
Without PhC(O)SH, which C–H reacts?
Mostly the N-methyl (less stable 1° α-amino radical), not the benzylic CH2.
How does the thiol invert selectivity?
Thiocarboxylate is oxidized first; the S-radical abstracts the weaker benzylic C–H.
How little catalyst is needed?
0.5 mol% Ir(ppy)3 and 1 mol% PhC(O)SH, 90% yield in ~2 h.
Need excess amine?
No; stoichiometric benzylamine is enough, unlike many α-amino C–H arylations.
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