Quaternary Ammonium Ion-Tethered (Ambient-Temperature) HDDA Reactions

Abstract

The hexadehydro-Diels-Alder (HDDA) reaction converts a 1,3-diyne bearing a tethered alkyne (the diynophile) into bicyclic benzyne intermediates upon thermal activation. With only a few exceptions, this unimolecular cycloisomerization requires, depending on the nature of the atoms connecting the diyne and diynophile, reaction temperatures of ca. 80-130 °C to achieve a convenient half-life (e.g., 1-10 h) for the reaction. In this report, we divulge a new variant of the HDDA process in which the tether contains a central, quaternized nitrogen atom. This construct significantly lowers the activation barrier for the HDDA cycloisomerization to the benzyne. Moreover, many of the ammonium ion-based, alkyne-containing substrates can be spontaneously assembled, cyclized to benzyne, and trapped in a single-vessel, ambient-temperature operation. DFT calculations provide insights into the origin of the enhanced rate of benzyne formation.

Figure 1.

(a) Hypothesis: Tertiary amines I are alkylated in situ to produce ammonium ions III, which cyclize to reactive benzynes IV enroute to trapped products V. (b) DFT free energies and geometries for the analogous reactions of the model6 tetrayne ammonium bromide substrate 1-N⁺ leading to the benzyne 3-N⁺ vs. the hydrocarbon analog 1-C to 3-C. [(U)B3LYP/6-311+G(d,p), SMD: CDCl₃]

Figure 2.

(a) One pot, room temperature formation of ammonium ion 6-Br and the in situ production of 7a and 8a involving cyclization of 6-Br to benzyne VI and trapping by bromide ion to proceed via zwitterions VII and VIII. (b) Alternative generation of ammonium ion 6-Br (from pre-formed 9), its conversion by anion exchange to 6-BF₄, and room temperature trapping reactions with furan (to 10a) and methanol (to 11a,b). (c) ¹H NMR spectrum of the reaction in CDCl₃ after 7 days at rt for conversion of 6-BF₄ + furan (2.0 equiv) to 10a; insets show the progress of reaction as reflected by the acetate methyl group resonances and from which the half-life of ca. 30 h is determined.

Figure 3.

(a) Formation of 7a/8a accompanied by the neutral rearrangement products 12 and 13, the latter pair from the ammonium ylide intermediate IX. (b) Variation in product ratios among 7a-H/D, 8a-H/D, 12, and 13 depending on the reaction solvent and conditions. (c) Schematic for the formation of the six products observed in CDCl₃.

Figure 4.

(a) Variation of the 2° amines used in the one-pot assembly, cyclization, and bromide ion trapping reactions leading to aryl bromides 7a-g and 8a-g. (b) A different type of HDDA pathway when strained (small ring) amines 4h and 4i are used. ^aReagents and conditions: 5 (2.0 mmol), amine (1.0 mmol), CHCl₃ (2.0 mL), rt (unless otherwise indicated), 3 days or overnight (see SI). Isolated yields are indicated. ^b100 °C, 5 h.

Figure 5.

^a Effect of ring-size of the ammonium ion on the rate of the HDDA cyclization reaction. ^a[17]₀ = ca. 0.3 M in CDCl₃, furan (2 equiv), rt.

Figure 6.

Contrasting and complementary behavior of tetraynes 6 having either (a) a BF₄^– or (b) a Br^– counterion. ^aReagents and conditions: 6-BF₄ (1.0 mmol), or 6-Br (1.0 mmol), CH₃OH (or CD₃OD) (2 mL), rt, 24 to 48 h. Isolated yields are indicated.

Figure 7.

Demonstrations of neutralization of the ammonium ion by hydroxide ion-promoted intramolecular dealkylation reactions: (a) Ethylene oxide extrusion or (b) intramolecular ring-opening by a pendant alcohol hydroxy group.

Figure 8.

(a) A two-phase reaction mixture allows for exchange of the nucleophilic bromide anion with the non-participating tetrafluoroborate counterion, leading to preferential formation of the furan adduct 10a. (b) Use of 5-OMs allows for efficient in situ trapping of the benzyne intermediate by the external agent (furan, giving 10a-OMs) because the mesylate counterion is an innocent bystander.