Beyond Wittig Olefination: Phosphorus Ylide as a Ring-Expansion Reagent for Dibenzocycloheptanone Synthesis

Abstract

We report an unprecedented transformation between phenanthrene-9,10-diones and phosphorus ylide, where methylenetriphenylphosphane exhibits dual reactivity patterns, enabling both olefination and ring expansion to construct seven-membered carbocycles in moderate to good yields. This process proceeds through initial Wittig olefination followed by an unusual alkenyl group 1,2-migration pathway from either an oxaphosphetane or betaine intermediate. Mechanistic studies, including deuterium-labeling experiments and isolation of key intermediates, support a pathway involving conformationally controlled ring expansion.

Ylides are neutral dipolar molecules that contain a negatively charged atom directly bonded to a positively charged heteroatom (typically P, S, N, or As). These versatile reagents or intermediates are widely used in organic synthesis, with several ylide-mediated transformations recognized as name reactions. The reactivity of ylides fundamentally depends on their dipolar structure, ,, particularly the electronic and steric properties of the positively charged heteroatom. Three prominent ylide-mediated transformations exemplify their synthetic utility: (1) The phosphorus ylides would react with the aldehydes or ketones to form alkenes, which is now known as the Wittig reaction. (2) The Corey–Chaykovsky reaction, which utilizes dimethylsulfonium methylide, is usually used for epoxide synthesis from carbonyl compounds; and (3) The Büchner–Curtius–Schlotterbeck reaction, involving diazo compounds, enables achieving one-carbon homologation of carbonyls.

Mechanistically, all of the above three reactions share a common initial step: nucleophilic 1,2-addition of the ylidic carbon to the carbonyl group, forming the same type of alkoxy anion intermediate. However, the subsequent fate of the resulting intermediates is mostly dictated by the nature of the positively charged heteroatom group (Scheme a). In phosphonium ylides, the strong phosphorus–oxygen affinity promotes the formation of four-membered oxaphosphetane intermediates, which decompose to alkenes driven by the formation of a stable phosphine oxide (for the concerted mechanism, see the discussion below). Sulfonium ylides undergo an intramolecular S _N 2 displacement to generate epoxides, since dimethylsulfane is regarded as a better leaving group than triphenylphosphine. In contrast, diazo compounds, due to their compact structure, favor 1,2-migration pathways by adopting a proper conformation with good orbital overlap for the migration step, although epoxide formation can occur as a competing process.

1. Strategies for the Transformation of Carbonyls.

As discussed above, phosphorus ylides are well-established synthetic intermediates characterized by their high oxygen affinity, manifested in the formation of phosphine oxide during Wittig olefination reactions. While this classical reactivity pattern is well-documented, phosphorus ylides have not been observed to participate in Corey–Chaykovsky-type or Büchner–Curtius–Schlotterbeck-type transformations. On the other hand, the synthesis of seven-membered rings, particularly the 6,7-dihydro-5H-dibenzo­[a,c]­[7]­annulene scaffold found in various natural products and bioactive molecules, including allocolchicine and metasequirin B, etc., remains challenging due to inherent ring strain. In this paper, we describe a cascade reaction between phenanthrene-9,10-diones and methylenetriphenylphosphane that enables the rapid synthesis of β,γ-unsaturated cyclic ketones via an unprecedented olefination–ring-expansion sequence, converting planar substrates into three-dimensional molecular architectures in a single operation (Scheme b). In this transformation, methylenetriphenylphosphane serves dual roles: (1) one equivalent acts as a conventional phosphorus ylide, attacking a carbonyl group to form a CC double bond with concurrent release of phosphine oxide. (2) A second equivalent of methylenetriphenylphosphane exhibits unprecedented reactivity reminiscent of diazomethane, inserting an sp³-hybridized methylene unit between the carbonyl group and CC bond and liberating one molecule of Ph₃P.

Our original attempt is to prepare structurally rigid diene 3a from phenanthrene-9,10-dione 1a via Wittig olefination. However, the treatment of 1a with 10 equiv of Ph₃PCH₂, in situ prepared from methyltriphenylphosphonium bromide and n-BuLi in THF, did not give the anticipated diene 3a, instead leading to an unexpected discovery by forming 2a in 77% yield (Table , entry 1). The structure of 2a, unambiguously confirmed by NMR and single-crystal X-ray diffraction (CCDC 2471711), revealed two key transformations: the formation of a CC double bond via Wittig olefination and incorporation of a methylene unit through ring expansion, generating a novel seven-membered ring system. Systematic optimization of reaction conditions revealed that reducing the loading of the Wittig reagent to 8 or 5 equiv maintained good product yield (entries 2–3). However, further reduction to 3.0 equiv resulted in a significant drop in yield, while reduction to 1.0 equiv almost fully suppressed product formation (entries 4–5). Solvent screening demonstrated the crucial role of reaction medium: THF proved optimal, while 1,4-dioxane afforded a moderate yield (38%, entry 6). Other common organic solvents, including toluene, CH₂Cl₂, DMSO, and DMF, failed to produce the desired product 2a (entries 7–10). Sulfur ylide precursor trimethylsulfonium iodide (Me₃S⁺I^–) was also evaluated under identical reaction conditions; however, no target product was detected (entry 11).

1. Reaction Condition Optimization .

entry	wittig reagent (x equiv)	solvent	yield/%
1	10.0	THF	77%
2	8.0	THF	63%
3	5.0	THF	80%
4	3.0	THF	22%
5	1.0	THF	NR
6	5.0	1,4-Dioxane	38%
7	5.0	Toluene	ND
8	5.0	CH2Cl2	ND
9	5.0	DMSO	ND
10	5.0	DMF	ND
11	10.0	THF	ND

^aReaction conditions: The Wittig reagent was prepared in situ by the addition of n-BuLi (2.5 M in hexanes, x equiv) to a mixture of CH₃PPh₃Br (x equiv) in THF (0.25 M) at 0 °C for 30 min. Subsequently, 1a (0.10 mmol) and solvent (1 mL) were added to the above Wittig reagent at 0 °C and stirred at 40 °C for 3 h.

^bMe₃S⁺I^– was used instead of CH₃PPh₃Br.

Having established optimal conditions, we systematically investigated the substrate scope of this ring-expansion transformation (Scheme ). The reaction exhibits a broad tolerance for substituents at various positions of the phenanthrene-9,10-dione core. Substitution at the 3,6-positions was well-tolerated, though yields were moderately decreased with dimethyl (2b) and dibromo (2c) groups. Various 3,6-diaryl substituents (2d-2k) demonstrated comparable reactivity to that of the parent system. Notably, 4,5-disubstitution, which is also adjacent to the biaryl axis, enhanced reaction efficiency, with dimethyl (2l), dichloro (2m), dimethoxy (2n), and various poly-substituted variants (2r-2u) delivering the corresponding cycloheptane derivatives in good yields. These biaryl structures with 4,5-disubstitution displayed a significant rotational barrier: for an example, optically active 2u (CCDC 2471713) can be obtained by preparative HPLC on a chiral station (see Supporting Information for details). The 2,7-positions proved amenable to both dibromo (2o) and diaryl substitution (2p-2q) without a significant impact on reaction efficiency. The unsymmetrical substrate 1v gave an inseparable mixture of regioisomers 2v and 2v′ in a decent overall yield.

2. Substrate Scope.

Several structural limitations were identified: The nitrogen-containing analogue 1,10-phenanthroline-5,6-dione 1w yielded only decomposition products. The reaction proved to be specific to the phenanthrene-9,10-dione framework, as indoline-2,3-dione (1x) and its derivative (1y) failed to undergo ring expansion. Additionally, 2,7-di-tert-butylpyrene-4,5-dione (1z), a close analogue to phenanthrene-9,10-dione, proved unreactive, likely due to increased ring strain in the potential product 2z imposed by the rigid pyrene system. These results suggest that successful ring expansion requires appropriate conformational flexibility to accommodate the newly formed seven-membered ring.

Tropone and dibenzotropone derivatives are significant structural motifs in materials science, particularly due to their partial aromaticity and the ability to form tropylium ions, important nonbenzenoid aromatic species. We demonstrated that the cyclic β,γ-unsaturated ketones 2 undergo base-mediated isomerization to form thermodynamically stable dibenzo-cycloheptenones 4 (Scheme ). Treatment with aqueous NaOH in THF efficiently converted compounds 2a, 2c, and 2d to their corresponding dibenzotropone derivatives (4a, 4c, and 4d) in 81%, 60%, and 78% yields, respectively. The structure of 4c was unambiguously confirmed through single-crystal X-ray diffraction analysis (CCDC 2471714). For the more sterically constrained substrate 2l, potassium bis­(trimethylsilyl)­amide (KHMDS) proved superior to aqueous NaOH or t-BuOK in promoting the isomerization to dibenzotropone 4l, delivering 66% yield.

3. Synthesis of Dibenzo-cycloheptenone 4 .

Careful analysis of the reaction revealed that triphenylphosphine can be an associated byproduct. Under standard conditions, triphenylphosphine was isolated in 87% yield (Scheme ). Methyltri­(p-tolyl)­phosphonium bromide exhibited slightly lower reactivity compared to that of methyltriphenylphosphonium bromide, resulting in the isolation of compound 2a in a reduced yield (62%). Nevertheless, tri­(p-tolyl)­phosphine was isolated in high yield, confirming that the reaction mechanism involves the release of free phosphine structures.

4. Isolation of Free Phosphines.

^a The yields were calculated based on the limited substrate 1a.

As demonstrated in Scheme , the introduction of 4,5-disubstituents enhanced the reaction efficacy. This improvement can be attributed to the increased distortion of the substrates. For comparison, 1a was inert at 20 °C, whereas the reaction proceeded smoothly when 1l was used as the substrate (Scheme a). At 20 °C, only 2l was detected in the reaction mixture containing both 1a and 1l in the same flask. At an elevated temperature (40 °C), both 2a and 2l formed, with 2l as the major product. Deuterium-labeling experiments by either using Ph₃PCD₂ or quenching with D₂O revealed that both methylene groups originate from the Wittig reagent. Enolate may be generated under these basic conditions since α-deuterium was lost when CD₃PPh₃Br was used (Scheme b). While direct isolation of enone 5a proved in vain, treating 1a with methyltriphenylphosphonium bromide and K₃PO₄ yielded compound 6a (CCDC 2471718), a hetero-Diels–Alder product formed from two molecules of enone 5a (Scheme c). We hypothesized that K₃PO₄ gradually generates reactive CH₂PPh₃, and the resulting low concentration of the Wittig reagent prevents the reaction between 5a and the Wittig reagent, thus leading to dimerization of 5a to give spiro-compound 6a. This mechanistic proposal was further validated by introducing 2,3-dimethyl-1,3-butadiene as a trapping agent for enone 5a, which led to the successful isolation of compounds 7 (CCDC 2486634) and 8 in 58% and 22% yields, respectively.

5. Control Experiments.

The most intriguing aspect of this reaction is its mechanism (Scheme a). It is tentatively proposed that the reaction of enone 5a with Wittig reagent first forms an oxaphosphetane (OPA) Int-1 via a concerted [2 + 2] cycloaddition (path A). Notably, this OPA intermediate does not undergo retro-[2 + 2] cycloaddition to release triphenylphosphine oxide and furnish diene 3a, likely due to the strong 1,4-strain in 3a. Instead, this key intermediate Int-1 undergoes a converted ring expansion via cleavage of the P–O and C–P bonds to release triphenylphosphine and deliver 2a. The second mechanistic possibility involves the initial 1,2-addition of the ylide to the carbonyl group to form a betaine intermediate, Int-2 (path B). Although OPAs are the preferred intermediates over betaines in Wittig reactions, especially in the absence of Li⁺ species. However, in our system, the ylide generated by the use of n-BuLi outperformed other bases (see the Supporting Information, Table S1), consistent with accessible betaine Int-2 formation. Subsequently, the alkoxide promotes ring expansion to build a seven-membered carbocycle with a concomitant release of PPh₃. Notably, the newly formed β,γ-enone2a is deprotonated by the Wittig reagent to give Int-3, which suppresses further olefination. Upon workup, Int-3 would give the kinetically controlled product 2a. In contrast, treatment of 2a with NaOH generates H₂O, making the deprotonation reversible, therefore giving a thermal, dynamically controlled product 4a, an α,β-unsaturated ketone. With 4,5-disubstituents, there is a more distorted betaine, i.e., Int-5, is formed (Scheme b). This species more readily adopts a trans-parallel conformation between the C_(a)-C_(b) and C_(c)-P bonds. This conformation may also rationalize the preferential migration of the alkenyl group over the aryl group.

6. Proposed Reaction Mechanism.

In summary, we have discovered an unprecedented ring-expansion transformation of phenanthrene-9,10-diones mediated by methylenetriphenylphosphane, providing efficient access to synthetically valuable dibenzocycloheptanones. This transformation reveals a previously unknown reactivity pattern of phosphorus ylides, where they can exhibit behavior reminiscent of diazo compounds in promoting ring expansion through 1,2-migration. The seven-membered carbocycle forms either via a concerted migration/ring expansion of the OPA intermediate or through an alkoxide-promoted elimination/migration of the betaine intermediate. This new transformation not only provides a practical approach to accessing structurally rigid seven-membered carbocycles, potentially valuable for the synthesis of natural products and bioactive molecules, but also expands the potential new synthetic utility of phosphorus ylides beyond their classical reactivity.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01138.

• Experimental procedures, characterization of products, and spectroscopic data (PDF)

Z.G. and L.D. directed this project. L.L. conceived the idea and discovered this reaction. L.L. and H.Z. performed the experiments and characterized the compounds. X.X., Z.G., and L.L. cowrote the manuscript.

The authors declare no competing financial interest.