The hexadehydro-Diels-Alder reaction

Abstract

Arynes (aromatic systems containing, formally, a carbon-carbon triple bond) are among the most versatile of all reactive intermediates in organic chemistry. They can be 'trapped' to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of benzynes-through a hexadehydro-Diels-Alder reaction-with their in situ elaboration into structurally complex benzenoid products. In the hexadehydro-Diels-Alder reaction, a 1,3-diyne is engaged in a [4+2] cycloisomerization with a 'diynophile' to produce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.

Figure 1. Diels-Alder reactions of varying oxidation states

a, Generic benzyne generation (2 to 1) and trapping (1 to 3). Most commonly, G/X = H/halogen, CO₂⁻/N₂⁺, halogen/halogen, or TMS/OTf. b–e, Prototypes of Diels–Alder reactions differing in the oxidation levels of the reactant pairs and products: classic Diels–Alder (b), didehydro-Diels–Alder (c), tetradehydro-Diels–Alder (TDDA) (d), and hexadehydro-Diels–Alder (HDDA, this work, e) reactions. [TMS = trimethylsilyl, OTf = trifluoromethanesulfonate, Nu = nucleophile, El = electrophile]

Figure 2. Mechanistic rationale, substrate synthesis, and mild conditions for our initial two HDDA reactions

a, Serendipitous observation of the HDDA reaction: cyclization of ketone 14 to putative benzyne (red) intermediate 16/16′ and subsequent trapping by the pendant silyl ether gave a hexasubstituted benzenoid (blue), the indenone 15. b, Synthesis of 21 (via convergent coupling of 18 with 19, addition of an ethynyl unit to 20, and oxidation) and its facile, high-yielding conversion to the tetracyclic benzenoid (blue) 22. [TBS = tert-butyldimethylsilyl]

Figure 3. Examples of intramolecular trapping of HDDA-generated benzynes

Benzenoid (bold black bonds) synthesis via the HDDA cycloaddition has considerable substrate scope with respect to the nature of i) the poly-yne tether (red) and ii) the intramolecular trapping moiety (blue). [Ac = acetyl, Ts = p-toluenesulfonyl, o-DCB = 1,2-dichlorobenzene]

Figure 4. Examples of intermolecular trapping of HDDA-generated benzynes

Bimolecular trapping reactions of benzyne 24 to give adducts 25a–f [trapping agent (and amount); yield following purification]. [THF = tetrahydrofuran]

Figure 5. Computed free energy changes for a representative HDDA-initiated cascade

Free energies of reaction [M06-2X/6-31+G(d, p)] for the aryne-generating (26 to 27) and tert-butanol (^tBuOH) trapping (27 to 28) stages highlight the favorable thermodynamics associated with both the triyne cycloisomerization and aryne trapping events.