Catalyst-Free, Fluoride-Free Visible-Light Alder-ene Reaction of Bicyclobutanes with Cyclohexynes

Shashank Shrotriya and Akkattu T. Biju at the Indian Institute of Science, Bangalore report a photochemical Alder-ene reaction between bicyclo[1.1.0]butanes (BCBs) and transient cyclohexynes that proceeds without a photocatalyst, without fluoride, and at ambient temperature. The reaction assembles skipped dienes bearing an all-carbon quaternary center in a single step and was performed in the EvoluChem™ PhotoRedOx Box throughout.

Exploiting Dual Strain Release with BCBs and Cyclohexynes

Bicyclo[1.1.0]butanes (BCBs) have become central building blocks in modern synthetic chemistry, prized for their high ring strain (66.3 kcal/mol) and the structural diversity accessible through release of that strain. BCBs participate in a broad array of annulation, cycloaddition, and ene-type reactions. Despite this versatility, one reactive partner had remained largely unexplored: cyclohexynes.

Cyclohexynes are strained alkynes that sit in an intermediate strain category – more reactive than unstrained linear alkynes, but less extreme than arynes. This intermediate reactivity makes them compelling partners for a dual strain-release manifold, but their use has been hampered by two practical issues: generation requires stoichiometric fluoride or strong base, and the resulting intermediates decompose rapidly before productive trapping can occur.

The Biju group’s solution was photochemical. Using a peroxide-based cyclohexyne precursor developed by Shi and co-workers, they found that irradiation at 427 nm generates cyclohexyne slowly enough to suppress competing decomposition pathways, while the high dilution conditions (0.025 M in MTBE) ensure that the BCB acts as an efficient trap. The result: a catalyst-free, fluoride-free, ambient-temperature Alder-ene reaction that assembles skipped dienes bearing an all-carbon quaternary center with broad functional group tolerance.

Standard Conditions

Several features of these conditions are noteworthy. MTBE was optimal among all solvents screened – polar solvents (MeCN, acetone, THF) gave substantially lower yields (21–41%). The low concentration (0.025 M) is critical: dilution suppresses bimolecular decomposition of cyclohexyne while favoring productive capture by the BCB. The wavelength was also finely optimized – 427 nm outperformed 390 nm, 440 nm, 365 nm, and 254 nm, suggesting a specific match between the absorption of the photochemical peroxide precursor and the irradiation wavelength. Elevated temperature (50 °C) was detrimental, confirming that the photochemical pathway is distinct from thermal reactivity.

Mechanism: Concerted Alder-ene, Not Radical

The reaction mechanism was investigated through a series of controls and isotopic labeling experiments:

Light requirement: No product formed in the absence of light, even at 50 °C, ruling out thermally driven pathways.

Stepwise vs. concerted: Isolated cyclobutene 7a (the product of BCB isomerization) did not react under the standard conditions with the cyclohexyne precursor, excluding a stepwise pathway via cyclobutene.

Radical quenching: TEMPO completely inhibited product formation. BHT significantly suppressed yield (33% with BHT vs. 77% without). Notably, HRMS confirmed TEMPO reacted with in situ-generated cyclohexyne directly, suggesting radical character arises from the cyclohexyne itself under irradiation rather than from a chain process.

D-labeling: Using d₄-BCB 1a′ (92% D incorporation), the product 3a′ was obtained with 92% deuterium incorporation at the cyclohexene position, with no H/D exchange observed even in the presence of 2.0 equiv of D₂O or H₂O. This is consistent with direct deuterium transfer in a concerted Alder-ene process.

Light on/off: Product formation proceeded during irradiation periods and ceased during dark intervals, confirming continuous photochemical activation is required.

Strain selectivity: When BCB was exposed simultaneously to in situ-generated cyclohexyne and the unstrained electron-poor alkyne DMAD, only the cyclohexyne-derived product 3a was observed (62% yield; no DMAD product 9). Strain alone is the decisive factor.

Together, these data are consistent with a concerted Alder-ene mechanism involving direct deuterium transfer from BCB to cyclohexyne, proceeding through a photochemically generated cyclohexyne intermediate rather than a persistent radical chain.

Substrate Scope

With the optimized conditions, the Biju group demonstrated broad generality across both BCB and cyclohexyne partners. For BCBs bearing aryl substituents, electron-donating, electron-neutral, and halogen groups at para- and meta-positions were all tolerated, giving skipped dienes 3a–3k in 52–77% yield. Ortho-substituted BCBs (“3l, 54%”) and disubstituted aryl rings (“3m, 78%; 3n, 56%”) were also accommodated. Beyond aryl-substituted BCBs, naphthyl (3o, 68%), vinyl (3p, 65%), and a range of ester groups (phenyl, benzyl, isopropyl, tert-butyl, cyclohexyl – 3q–3u) were all productive. Amide and heterocyclic motifs (pyrazole amide 3z, Weinreb amide 3aa) were compatible at 49–51% yield.

On the cyclohexyne side, monosubstituted cyclohexyne precursors gave 3ab–3ae in 48–73% yield (as inseparable regioisomeric mixtures), while 3,3-dimethyl cyclohexyne afforded 3af/3af′ in 71% yield. Monosubstituted BCBs (1ac–1ae) were not reactive under these conditions.

Extension to Benzynes

The photochemical approach was extended to benzyne generation using o-diazonium carboxylic acid 4a as a precursor, which undergoes photochemical extrusion to generate benzyne upon 365 nm irradiation. The EvoluChem PhotoRedOx Box equipped with the EvoluChem™ HCK1012-01-029 365 nm LED was used for these reactions. Irradiation of BCB 1a with 4a in MeCN at 365 nm for 12 h gave aryl cyclobutene 5a in 96% yield – a substantially higher yield than the cyclohexyne variant, reflecting the higher strain energy of benzyne. The scope included differentially substituted BCBs (5a–5e), a pyrazole-derived BCB (5f, 79%), and a gemfibrozil-derived BCB (5g, 81%), all with high efficiency under mild, fluoride-free conditions.

Skeletal Remodeling to Tetralines

The skipped diene products serve as versatile platforms for further synthesis. Treatment of 3a with catalytic elemental sulfur (0.30 equiv) in DMSO at 140 °C (open air) furnished tetraline 6a in 86% yield. This transition-metal-free oxidative skeletal remodeling proceeds via thermal 4π-electrocyclic ring-opening of the cyclobutene, followed by intramolecular cyclization and aromatization. DMSO acts as both solvent and auxiliary oxidant, with sulfur as the terminal oxidant.

The tetraline scope is excellent: substituted examples (“6b–6h, 88–97%”), naphthyl (6i, 89%), benzyl ester (6j, 96%), and gemfibrozil-derived skipped diene (6k, 85%) all furnished tetralines in high yields. A deuterium-labeled analogue afforded 6a′ with complete deuterium retention, confirming the atom-economical nature of the cascade.

Late-Stage Diversification of Bioactive Molecules

The practical value of the method is further illustrated by its application to biologically relevant substrates. BCB esters derived from geraniol, L-menthol, and gemfibrozil all participated in the Alder-ene reaction to give the corresponding skipped dienes 3w–3y (54–71% yield), demonstrating that the protocol tolerates the structural complexity of drug-derived frameworks. For the gemfibrozil-derived skipped diene, the tetraline remodeling cascade also proceeded successfully (6k, 85%).

The Equipment Used