The aromatic ene reaction

Abstract

The ene reaction is a pericyclic process in which an alkene with an allylic hydrogen atom (the ene donor) reacts with a second unsaturated species (the enophile) to form a new product with a transposed π-bond. The aromatic ene reaction, in which the alkene component is embedded in an aromatic ring, has only been reported in a few (four) instances and has proceeded in low yield (≤6%). Here, we show efficient aromatic ene reactions in which a thermally generated aryne intermediate engages a pendant m-alkylarene substituent to produce a dearomatized isotoluene, itself another versatile but rare reactive intermediate. Our experiments were guided by computational studies that revealed structural features conducive to the aromatic ene process. We proceeded to identify a cascade comprising three reactions: (1) hexadehydro-Diels-Alder (for aryne generation), (2) intramolecular aromatic ene and (3) bimolecular Alder ene. The power of this cascade is evident from the structural complexity of the final products, the considerable scope, and the overall efficiency of these multistage, reagent- and by-product-free, single-pot transformations.

Figure 1. Structural delineation and previous example of an aromatic ene reaction

a, The minimal structural elements for an aromatic ene reaction: a potent enophile and an arene bearing a benzylic C–H bond as an ene donor. This transformation is rare because it requires the energetically demanding formation of a dearomatized isotoluene species (cf. 2). b, The only reported aromatic ene reactions involve the use of the highly energetic o-benzyne (3) in the role of enophile, which engages one of the alkylbenzenes toluene (1), ethylbenzene, cumene, or mesitylene as the ene donor. The intermediate isotoluene 4 was invoked to account for formation of product 5. Yields are marginal in part because products arising from [4+2] cycloaddition between 3 and the π-system in arene 1 are formed competitively.

Figure 2. Arynes as enophiles reacting with various types of ene donor

a, An alkene (an Alder ene reaction)^,,. b, An alkyne (a propargylic ene reaction)^,. c, An arene donor bearing a suitably disposed benzylic hydrogen atom (an aromatic ene reaction, this work).

Figure 3. Competition between aromatic ene and aromatic Diels-Alder pathways

a, Computed (DFT) energetics of possibilities for the bimolecular reaction between toluene (1) and o-benzyne (3) leading to the aromatic ene product 4 (an isotoluene) vs. the Diels-Alder adducts 21a and 21b. b, Computed energetics of the analogous competitions for the tethered substrates 22 leading to the intramolecular ene product 23 vs. the [4+2] adduct 24; the potential energy surface is portrayed for the case where n = 2 and the comparative values of the ΔG_TS are tabulated in the inset. c, Experimental results for the series of related HDDA substrates 26a-c; the first and last give, exclusively, the Diels–Alder products 28a and 28c whereas 26b gives only the aromatic ene product 27b.

Figure 4. Studies giving insight to a) the importance of reaction conditions and b/c) the mechanism of the HDDA//aromatic ene reactions

a, Attempted aromatic ene reaction of the aryne 34 generated by elimination of HBr from the aryl bromide 33 shows an advantage of use of the reagent-free conditions of the HDDA reaction as the method for aryne formation. b, A pair of complementary deuterium-labeling experiments strongly implicate the intermediacy of the isotoluene 39. c, The cis-addition of carbon and deuterium across the maleic anhydride π-bond (see Supplementary Information for a discussion of the ¹H NMR-based assignment of the structure 41-d₃) provides strong mechanistic evidence for the concerted nature of the bimolecular (Alder) ene reaction.