Tandem Hock and Friedel-Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

Abstract

The Hock cleavage, which is compatible with tandem processes, was applied to the synthesis of 1-aryltetralines through a one-pot transformation from readily available benzyl(prenyl)malonate substrates. After the photooxygenation of the prenyl moiety, the resulting hydroperoxide was directly engaged in a Hock cleavage by adding a Lewis acid. The presence of an aromatic nucleophile in the reaction mixture and that of a benzyl moiety on the substrate resulted in tandem Friedel-Crafts reactions to form the 1-aryltetraline products. These compounds share a close analogy to the cyclolignan natural products. Experimental observations and a DFT study support the involvement of an aldehyde intermediate during the Friedel-Crafts reactions, rather than an oxocarbenium.

Keywords: 1-aryltetralines; Friedel–Crafts reaction; Hock rearrangement; oxidative cleavage; tandem reactions.

Scheme 1

The Hock rearrangement: (a) General mechanism (substituents are omitted); (b) Example of previous tandem process; (c) Objective of this work.

Scheme 2

One-pot conversion of substrate 1 into dihydronaphthalene 4.

Scheme 3

One-pot conversion of substrate 1 into 1-aryltetraline structure 6, and the proposed mechanism for its formation.

Figure 1

X-ray crystallographic structure of product 6 (CCDC 2301977). The structure shows one disordered ethyl ester group (backward).

Scheme 4

Free-energy profile of the hypothesized [1,5]-sigmatropic hydrogen shift between 7 and 7’, (IEFPCM(CH₂Cl₂)-M06/6-311++G(2d,2p)//M06/6-31G(d,p) level of theory).

Figure 2

Examples of cyclolignan natural products [–27].

Scheme 5

Scope of substrates and aromatic nucleophiles in the one-pot transformation. ^aNot determined (mixture with unidentified products).