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. 2023 Dec 15;88(24):16783-16789.
doi: 10.1021/acs.joc.3c01281. Epub 2023 Nov 30.

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes

Enrico Lunghi  1 , Pietro Ronco  1 , Federico Della Negra  2 , Beatrice Trucchi  2 , Massimo Verzini  2 , Daniele Merli  1 , Emanuele Casali  1 , C Oliver Kappe  3   4 , David Cantillo  3   4 , Giuseppe Zanoni  1
Affiliations

Electrifying Friedel-Crafts Intramolecular Alkylation toward 1,1-Disubstituted Tetrahydronaphthalenes

Enrico Lunghi et al. J Org Chem. .

Abstract

In this work, we successfully employed electrochemical conditions to promote a Hofer-Moest, intramolecular Friedel-Crafts alkylation sequence. The reaction proceeds under mild conditions, employing carboxylic acids as starting materials. Notably, the electrochemical process performed in batch was adapted to a continuous flow electrolysis apparatus to provide a significant improvement. This catalyst-free, electrochemical approach produces an array of tetrahydronaphthalenes that could be used for API synthesis.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Optimized Flow Recirculation Procedure
Conditions: 2b (0.2 mmol), 2,4,6-collidine (0.4 mmol), nBu4NPF6 (0.1 mmol), 14:1 DCM/HFIP (10.7 mL), undivided flow cell, 10 mA, 2.3 F/mol, (+)Cgr|SS(−), 5 mL/min, flow recirculation mode, 3.30 h for 0.4 mmol.
Scheme 2
Scheme 2. Scope of the Electrochemical Decarboxylative Cycloalkylation
Conditions: 2b (0.2 mmol), solvent (10.7 mL), constant current electrolysis. Batch: 10 mL IKA ElectraSyn 2.0 vial, 7.5 mA, 2.1 F/mol. Flow: 10 mA, 2.3 F/mol, 5 mL/min recirculation.
Figure 1
Figure 1
Optimization of the electrolysis parameters in a flow electrolysis cell operating in single-pass mode.
Figure 2
Figure 2
(a) Radical trapping experiment, (b) carbocation trapping experiment, and (c) suggested mechanism for the electrochemical decarboxylative cycloalkylation.
Figure 3
Figure 3
Electronic free energy profile (kilocalories per mole) for both the cyclization and the elimination reactions [SMD(DCM)-wB97XD/def2TZVP//SMD(DCM)-M06-2x/6-31+g(d,p)].
See this image and copyright information in PMC

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