Rapid (≤25 °C) cycloisomerization of anhydride-tethered triynes to benzynes - origin of a remarkable anhydride linker-induced rate enhancement

Abstract

The hexadehydro-Diels-Alder (HDDA) reaction is a cycloisomerization between a conjugated diyne and a tethered diynophile that generates ortho-benzyne derivatives. Considerable fundamental understanding of aryne reactivity has resulted from this body of research. The multi-yne cycloisomerization substrate is typically pre-formed and the (rate-limiting) closure of this diyne/diynophile pair to produce the isomeric benzyne generally requires thermal input, often requiring reaction temperatures of >100 °C and times of 16-48 h to achieve near-full conversion. We report here that diynoic acids can be dimerized and that the resulting substrate, having a 3-atom anhydride linker (i.e., O[double bond, length as m-dash]COC[double bond, length as m-dash]O), then undergoes HDDA cyclization within minutes at or below room temperature. This allows for the novel in situ assembly and cyclization of HDDA benzyne precursors in an operationally simple protocol. Experimental kinetic data along with DFT computations are used to identify the source of this surprisingly huge rate acceleration afforded by the anhydride linker: >10⁷ faster than the analogous multi-yne having, instead, a CH₂OCH₂ ether linker.

Fig. 1. (a) Reports of the tetradehydro-Diels–Alder (TDDA) reaction of phenylpropiolic acid. (b) A classical Diels–Alder reaction (c). A hexadehydro-Diels–Alder (HDDA) reaction to form an ortho-benzyne (and its subsequent trapping). (d) Facile formation of a carboxylic acid anhydride mediated by methanesulfonyl chloride.

Fig. 2. Our first example of in situ, MsCl-promoted condensation of the diynoic acid 10a (1.0 equiv.) to form an anhydride, which underwent rapid HDDA cycloisomerization. The intermediate electrophilic benzyne 12 was immediately trapped by a THF solvent molecule and the oxonium ion 13 was ring-opened by chloride ion.

Fig. 3. (a) Furan trapping of the in situ-generated benzyne 12 derived from 10a. A variety of (b) substituted diynoic acids 10b–h (blue) and (c) benzyne trapping agents (green) are compatible with the in situ anhydride formation/HDDA cyclization conditions.

Fig. 4. Facile condensations of the phthalic anhydride moiety in 14a/c with aniline, propargylamine, glycine methyl ester, and mono-boc diamines give imides 25a–f. ^aGlycine methyl ester hydrochloride was used. ^bYield is of the deprotected primary amine following subsequent Boc removal (TFA, rt, 30 min).

Fig. 5. (a) Generic representation of the preparation of mixed anhydrides using the acid chloride 26 to produce more varied product structure motifs. (b) Examples include unsymmetrical anhydride HDDA substrates of both tetrayne (f, h) and triyne (i–k) classes. ^a2.5 equiv. of 10k used to minimize the amount of 14b that was competitively formed.

Fig. 6. (a) The reaction used to measure the half-life of HDDA cyclization of the anhydride intermediate 29a. (b) In situ NMR data showing competitive formation and cyclization of the anhydride 29a. (c) COPASI simulation of the first 90 min of data shown in panel b.

Fig. 7. Large rate enhancement (red) for the HDDA cyclization of the triyne 29a having an anhydride tether compared to the rates of substates 29b–d having ester or ether tethers.

Fig. 8. (a) Distortion/interaction analysis performed on the series of tethered triynes 29a–d. (b) Experimental half-lives and DFT^a-computed parameters^b separating the energetic contributions from the triyne vs. those from the tether components to the overall barrier height for the initial, rate-limiting C–C bond formation in each of the triynes 29a–d. ^a[(U)B3LYP-GD3BJ/6-311+G(d,p), SMD: chloroform]. ^bΔE^‡ = E_31‡ − E₃₂‖ΔE^‡_total = E_34‡ – (E₃₂ + E₃₃)‖ΔE^‡_dist = (E_32dist + E_33dist) − (E₃₂ + E₃₃)‖ΔE^‡_int = ΔE^‡_total − ΔE^‡_dist‖ΔE^‡_teth = ΔE^‡ − ΔE^‡_total.

Fig. 9. Computed^a enthalpic change for a series of homodesmotic reactions showing the unique favorability (−1.8 kcal mol⁻¹) afforded by conversion of the acyclic to cyclic anhydride compared to the unfavorable enthalpies of cyclization for the ether and ester analogs (+4.5 and +3.8 kcal mol⁻¹, respectively). ^a[(MN15/6-311++G(d,p), SMD : water].

Fig. 10. Tetradehydro-Diels–Alder (TDDA) reactions of propiolic acid chloride-derived anhydride- and imide-linked TDDA substrates 2 and 37. The imide cyclizes faster than the anhydride.