Chemodivergent Synthesis of β‑Phosphonyl Carboxylic Acids and Acylphosphine Oxides via Ring-Opening Addition of Cyclopropenone

Abstract

Chemodivergent synthesis offers a robust and efficient platform for streamlining synthetic routes and broadening reaction diversity. Herein, we demonstrate that the reaction of diphenylcyclopropanone with secondary phosphine oxides generates a versatile ketenylphosphorus intermediate, which serves as a pivotal platform for nucleophilic addition. This intermediate readily reacts with water and phosphine oxides, enabling efficient synthesis of structurally diverse β-phosphoryl carboxylic acids and acylphosphine oxides. Mechanistic studies and DFT calculations reveal a pivotal β-ketenyl phosphine oxide intermediate that undergoes selective nucleophilic addition, enabling divergent product formation.

Introduction

β-Carboxyl phosphine oxides represent valuable motifs in natural products and bioactive molecules, while acylphosphine oxides featuring unique photochemical properties serve as a radical initiator in polymer science research and industrial production (Scheme A). − However, β-phosphonyl carboxylic acids have been only scarcely reported, while the synthesis of β-phosphonyl acylphosphine oxides remains unachieved. ,

1. β-Phosphoryl Carboxylic Acids and Acylphosphine Oxides.

Cyclopropenone represents a privileged three-membered synthon that has found important utility in both cycloaddition − and ring-opening addition reactions, − owing to their inherent structural characteristics of pronounced ring strain and electronic polarization. In 1975, Takizawa and co-workers reported the reaction of diphenylcyclopropenone with a phosphine catalyst, which proceeds via an α-phosphonium ylide intermediate to afford ring-opening addition products. Studies taking advantage of the α-phosphonium ylide intermediate with various nucleophiles have emerged, leading to either addition or cyclization products (Scheme B). , In 2025, the Shuli You group achieved a catalytic asymmetric dearomative [3 + 2] cyclization reaction between cyclopropenones and benzimidazoles with a chiral phosphine catalyst. Inspired by these findings, we envisioned that a nucleophilic phosphorus species could serve as a reagent to generate the corresponding α-phosphoryl ylide, which would then be susceptible to nucleophilic attack, thereby enabling the synthesis of a diverse array of phosphorus-containing compounds. Herein, we report a chemodivergent synthesis of β-phosphoryl carboxylic acids and acylphosphine oxides, employing secondary phosphine oxides as the nucleophilic reagent (Scheme C).

Results and Discussion

To initiate our investigation, commercially available diphenylphosphine oxide 1a and diphenylcyclopropenone 2a were selected as model substrates for screening the reaction conditions (Table ). The proposed ring-opening addition product β-phosphoryl carboxylic acid 3a was successfully isolated upon heating at 80 °C in 1,4-dioxane (entry 1), and its structure was unambiguously confirmed by single-crystal X-ray diffraction analysis. To optimize the reaction, we examined the effects of temperature and solvent, finding that deviations from the reaction conditions led to diminished yields (entries 2–8). Notably, a minor byproduct, β-phosphonophosphine oxide 4a was also observed during the optimization process. We speculate that the reaction proceeds via a shared β-ketenyl phosphine oxide intermediate wherein residual water and diphenylphosphine oxide competitively undergo nucleophilic addition, giving rise to the two structurally distinct products. Exclusive formation of 4a was achieved by removing residue water from the reaction system with 4 Å molecular sieve (entry 9). In contrast, the addition of 2.0 equiv of H₂O significantly suppressed the formation of 4a, leading exclusively to β-phosphonyl carboxylic acid 3a (entry 10).

1. Optimization of Reaction Conditions .

entry	variation of standard conditions	yield (%)	dr
1	none	73	>20:1
2	Rt instead of 80 °C	<5	>20:1
3	50 °C instead of 80 °C	28	>20:1
4	toluene instead of 1,4-dioxane	34	>20:1
5	THF instead of 1,4-dioxane	52	>20:1
6	EA instead of 1,4-dioxane	37	>20:1
7	DMF instead of 1,4-dioxane	45	>20:1
8	DMSO instead of 1,4-dioxane	53	>20:1
9	4 Å MS (100 mg) as additive	89	1.9:1
10	H2O (2.0 equiv) as additive	84	>20:1

^aStandard conditions: 1a (0.2 mmol), 2a (0.1 mmol), 1,4-dioxane (1 mL), 80 °C, 23 h.

^bIsolated yield of product 3a.

^cIsolated yield of product 4a.

Following the optimal reaction conditions, we systematically explored the substrate scope of the reaction (Table ). Notably, excellent diastereoselectivities (>20:1) were observed in all cases. Secondary phosphine oxides bearing methyl substituents at the meta- and para-positions of the phenyl ring reacted smoothly and produced 3b–3c in 52–76% yields. The electronic nature of substituents on the aromatic ring was also examined, substrates with electron-donating groups at the para-position furnished products 3d–3e in 77–80% yields, whereas a substrate with a para-fluoro-group provided product 3f in moderate yield (48%). Substrates with a naphthyl or thienyl group also delivered the desired products 3g–3h in 45–66% yields. Additionally, 3,5-disubstituted arenes (methyl or tert-butyl) were compatible, affording products 3i–3j in 33–46% yields. Remarkably, the reaction exhibited particularly high efficiency with alkyl-substituted substrates, yielding products 3k–3l in 69–75%. Subsequently, we evaluated the substrate scope for the synthesis of acylphosphine oxides (Table ). The reaction also proceeds readily, delivering the desired products in moderate to high yields (47–89%). Notably, the diastereoselectivity was largely dependent on the electronic properties of the secondary phosphine oxide: Electron-deficient substrates gave relatively high dr (4g 9.3:1), while the other ones exhibited lower diastereoselectivity (4a–4f, 4h–4j 1.1:1 to 5.0:1). To demonstrate the practicality of the method, gram-scale syntheses were performed under the optimized conditions (Figure ). Both the β-phosphonocarboxylic acid and β-phosphonoylphosphine oxide products were obtained while maintaining reaction efficiency and stereochemical control. Under these conditions, product 3a was obtained in 76% isolated yield (>20:1 dr), while 4a was isolated in 83% yield with 1.2:1 dr.

2. Substrate Scope.

^aReaction conditions: 0.2 mmol 1, 0.1 mmol 2a, and 2.0 equiv. H₂O in 1,4-dioxane (1 mL) at 80 °C.

^bReaction conditions: 0.2 mmol 1, 0.1 mmol 2a, and 4 Å MS (100 mg) in 1,4-dioxane (1 mL) at 80 °C. d.r. were determined by ¹H NMR analysis.

1.

Gram-scale reaction.

Mechanistic studies were carried out using experimental and computational methods (Figure ). To verify the key intermediate, we tested carboxylic acid 5a, a potential 1,4-addition intermediate, with secondary phosphine oxide 2a. Only a trace amount of 3a was formed under standard conditions, ruling out 5a as the intermediate. Subsequently, when product 3a was subjected to the standard conditions, it remained unchanged with no loss of dr, indicating that the reaction is irreversible and that enolization of the product likely did not occur. In stark contrast, the dr of purified product 4a decreased significantly under the standard conditions to 3.4:1, indicating that less-selective tautomerization (enolization–protonation) had occurred. Interestingly, the presence of H₂O in the system markedly suppressed this tautomeric interconversion. We speculate that in the presence of water, 4a exists in an equilibrium between the keto form and the ketal form, which inhibits the keto–enol tautomerization process.

2.

Mechanistic studies.

To elucidate the reaction mechanism under both conditions, we performed DFT calculations (Figure A). The results indicate that the rate-determining step involves the nucleophilic addition of 1a to 2a, in which the lone pair on the phosphorus atom attacks the carbon–carbon double bond, proceeding through transition state TS-1 to form ketene intermediate Int-1. Subsequently, the hydroxy group on phosphorus rapidly tautomerizes to form the phosphine oxide, yielding intermediate Int-2. In the presence of water, DFT studies revealed that Int-2 would be attacked by water and transform to Int-3-O via transition state TS-2-O, which involves two water molecules connected with hydrogen bondings. During the subsequent proton transfer, the transition state with two phenyl groups in an antiperiplanar conformation TS-3-O is favored than that of the syn-periplanar conformation TS-3-O′, leading to the formation of product 3a that is favored both kinetically and thermodynamically. The reaction mechanism leading to product 4 proceeds through the same intermediate Int-2 as in the formation of 3. Under anhydrous conditions, achieved by the addition of molecular sieves, the secondary phosphine oxide in its phosphinic acid form acts as a nucleophile, attacking the ketene moiety of Int-2 to furnish product 4. Because product 4a and its diastereomer 4a′ possess nearly identical stabilities, tautomerization as evidenced by experimental results leads to only modest diastereoselectivity.

3.

DFT calculation and proposed mechanism. (A) DFT calculations were performed at the M06-2X/def2-TZVP/SMD­(1,4-dioxane)// B3LYP-D3/def2-SVP level. (B) Proposed mechanism.

Based on the experimental and computational results, we propose the mechanism depicted in (Figure B). The nucleophilic addition of secondary phosphine oxide to the cyclopropenone generated Int-1, which rapidly tautomerizes to Int-2. From this common intermediate, two distinct pathways emerge: in the presence of water, Int-2 reacts to form Int-3-O, whereas in its absence, the phosphinic acid form of the secondary phosphine oxide attacks to give Int-3-P. Subsequent protonation of these intermediates furnishes final products 3a and 4a, respectively.

Conclusions

In conclusion, we have reported the ring-opening addition of diphenylcyclopropenone with secondary phosphine oxides via β-ketenyl phosphine oxide intermediates, enabling chemodivergent synthesis of β-phosphoryl carboxylic acids and acylphosphine oxides with high atom economy. This study establishes that β-ketenyl phosphine oxide intermediates can be generated in situ through a concerted process of C–C σ-bond cleavage and C–P bond formation. Such a strategy may find broad applications in the synthesis of phosphorus-containing compounds with diverse nucleophiles.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.5c00125.

• Optimization studies, experimental procedures, mechanistic studies, characterization (NMR spectra, HRMS) of all new compounds, and DFT calculations details (PDF)

‡.

S.Z. and J.T. contributed equally to this work.

Q.-W.Z. conceived the project and designed the experiments. S.-Z., Z.H., and S.Z. performed the experimental work, J.T. conducted computational studies. Q.-W.Z., S.Z., J.T., and Z.H. wrote the manuscript.

The authors declare no competing financial interest.