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. 2022 Mar 8;13(12):3539-3548.
doi: 10.1039/d1sc06422c. eCollection 2022 Mar 24.

Synergistic Brønsted/Lewis acid catalyzed aromatic alkylation with unactivated tertiary alcohols or di- tert-butylperoxide to synthesize quaternary carbon centers

Aaron Pan  1 , Maja Chojnacka  1 , Robert Crowley 3rd  1 , Lucas Göttemann  1 , Brandon E Haines  2 , Kevin G M Kou  1
Affiliations

Synergistic Brønsted/Lewis acid catalyzed aromatic alkylation with unactivated tertiary alcohols or di- tert-butylperoxide to synthesize quaternary carbon centers

Aaron Pan et al. Chem Sci. .

Abstract

Dual Brønsted/Lewis acid catalysis involving environmentally benign, readily accessible protic acid and iron promotes site-selective tert-butylation of electron-rich arenes using di-tert-butylperoxide. This transformation inspired the development of a synergistic Brønsted/Lewis acid catalyzed aromatic alkylation that fills a gap in the Friedel-Crafts reaction literature by employing unactivated tertiary alcohols as alkylating agents, leading to new quaternary carbon centers. Corroborated by DFT calculations, the Lewis acid serves a role in enhancing the acidity of the Brønsted acid. The use of non-allylic, non-benzylic, and non-propargylic tertiary alcohols represents an underexplored area in Friedel-Crafts reactivity.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Bioactive molecules bearing all-carbon quaternary carbon centers.
Scheme 1
Scheme 1. Synergistic iron/TFA-catalyzed tert-butylation of phenol using peroxide reagents with and without an acid co-catalyst.
Scheme 2
Scheme 2. Scope of tert-butylation of phenolic, aryl ether, and thiophene derivatives. [a] Reaction conditions: arene 1 (0.2 mmol), DTBP (2, 0.2 mmol), FeCl3 (10 mol%), TFA (0.15 mmol), DCE (0.8 mmol), 50 °C, 2 h. [b] Reaction conditions: arene 1 (0.2 mmol), DTBP (2, 0.2 mmol), FeCl3 (10 mol%), HCl(aq) (0.15 mmol), DCE (0.8 mmol), 50 °C, 2 h. [c] FeCl3 (20 mol%), 18 h. [d] FeCl3 (1 equiv.), HCl(aq) (0.15 mmol), 48 h. [e] 2-tert-Butyl-5-fluorophenol isolated in 5% yield.
Scheme 3
Scheme 3. Proposed pathways for the decomposition of DTBP (2). (a) Fe(iii) initiated pathway. (b) Fe(ii) initiated pathway.
Fig. 2
Fig. 2. Plots of initial rates with respect to (a) [3-tert-butylphenol 1f] indicating approximate first-order dependence, [DTBP 2] = 0.13 M, [FeCl3] = 0.012 M, [TFA] = 0.094 M; (b) [DTBP 2]0.5 indicating half-order dependence [1f], = 0.12 M, [FeCl3] 0.012 M, [TFA] = 0.094 M; (c) [TFA] suggestive of zero-order dependence [1f], = 0.12 M, [DTBP 2] = 0.13 M, [FeCl3] = 0.012 M; (d) [FeCl3]2 indicating second-order dependence [1f], = 0.12 M, [DTBP] = 0.13 M, [TFA] = 0.094 M. Each data point was measured in triplicate.
Scheme 4
Scheme 4. Scope of dual Brønsted/Lewis acid catalyzed, C(sp2)–C(sp3) coupling between phenolic and tertiary alcohol derivatives. [a] 2 equiv. 11a, 48 h.
Fig. 3
Fig. 3. Plots of the normalized time scale method for determining catalyst order; blue = 0.0062 M FeCl3, orange = 0.0094 M FeCl3, grey = 0.013 M FeCl3.
Scheme 5
Scheme 5. Scope of dual Brønsted/Lewis acid-catalyzed, C(sp2)–C(sp3) coupling of arene and tertiary alcohol derivatives. [a] 10 mol% HBr. [b] 75 mol% HCl. [c] Isolated as a 2.6 : 1 mixture of product/starting material.
Fig. 4
Fig. 4. (a) Late-stage tert-alkylation of natural products. Conditions: FeCl3 (5 mol%), tert-alcohol (1.1 equiv.), HCl (75 mol%), PhCl, 100 °C. (b) tert-Alkylation of indoles. Conditions: FeBr3 (5 mol%), tert-butanol (1 equiv.), HBr (15 mol%), DCE, 50 °C. [a] Isolated together with 14% N-methyl-3,5-di-tert-butylindole (see ESI†).
Scheme 6
Scheme 6. (a) Fate of the alcohol. (b) Probing for a radical vs. polar pathway.
Fig. 5
Fig. 5. Free energy profile computed using DFT calculations for the course of ionization of t-BuOH in the presence of the FeCl3/HCl acid pair and FeCl3.
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