Triphenylphosphine catalyzed domino reaction of dialkyl acetylenedicarboxylate with 3-aryl- 2-benzoylcyclopropane-1,1-dicarbonitrile

In recent years, nucleophilic phosphine-catalyzed reactions have attracted much research effort and have emerged as highly efficient synthetic tools for diverse carbocycles and heterocycles [1, 2]. In these reactions, an addition of trialkylphosphine to electron-deficient alkene or alkyne generates a reactive 1,3-dipole, which is in turn captured by suitable substrates to undergo a wide variety of cyclizations and annulations to give versatile carbocyclic and heterocyclic systems [3–6]. In these transformations, many electrophiles and nucleophiles have been successfully utilized [7–9]. We envisioned that the donor-acceptor cyclopropane can participate in the phosphine catalyzed reactions because the cyclopropane ring could open to give reactive dipolar intermediates via cleavage of σ-1,2-bond upon thermolysis or under catalysis by Lewis acids [10, 11]. With this background and in continuation of our aim to develop new phosphine catalyzed multicomponent reactions in organic synthesis [12, 13], herein we wish to report the preliminary results of triphenylphosphine catalyzed domino reaction of a acetylenedicarboxylates and 3-aryl-2-benzoylcyclopropane-1,1-dicarbonitriles. In view of our previous study of the phosphine-catalyzed domino reactions of acetylenedicarboxylate [13, 14], we initially used dimethyl acetylenedicarboxylate (1.0 mmol), 3-phenyl-2-benzoylcyclopropane-1,1-dicarbonitrile (1.0 mmol) and triphenylphosphine for a model reaction. The reaction proceeded very smoothly at room temperature in 1,2-dimethoxyethane to give a product of 80% yield. Spectral and structural analysis showed that the product is cyclopropyl-substituted 2,5-dihydrofuran-3-carboxylate 1a, which indicated that the cyclopropane ring did not open and only the carbonyl group took part in the reaction to form the dihydrofurane ring. When the reaction was performed in refluxing 1,2-dimethoxyethane for an extended period of time, and using excess amount of triphenylphosphine, compound 1a was still obtained as the main product. Though the phosphine-catalyzed reaction of electron-deficient alkynes with carbonyl compounds has been described in the literature to give diverse acyclic and cyclic compounds [14, 15], there are no reports on phosphine catalyzed synthesis of 2,5-dihydrofuran-3-carboxylate. Thus, we explored the substrate scope of the new phosphine-catalyzed reaction by using various aryl and benzoyl substituted cyclopropanes. The results are summarized in Table 1. In all cases, 2,5-dihydrofuran-3-carboxylates 1a-n were produced in satisfactory yields. Diethyl acetylenedicarboxylate can also be used in the reaction to give high yields of products.

Table 1

Synthesis of cyclopropyl-substituted 2,5-dihydrofuran- 3-carboxylates.^a

Compound	R	Ar	Ar′	Yield (%)b
1a	Me	C6H5	C6H5	80
1b	Me	C6H5	p-CH3C6H4	84
1c	Me	C6H5	m-CH3C6H4	71
1d	Me	C6H5	p-t-BuC6H4	64
1e	Me	C6H5	m-ClC6H4	79
1f	Me	p-ClC6H4	C6H5	72
1g	Me	p-ClC6H4	m-CH3C6H4	78
1h	Me	p-ClC6H4	p-ClC6H4	66
1i	Me	p-ClC6H4	p-BrC6H4	77
1j	Et	C6H5	C6H5	70
1k	Et	C6H5	m-CH3C6H4	72
1m	Et	C6H5	p-CH3C6H4	70
1l	Et	C6H5	m-ClC6H4	67
1n	Et	p-ClC6H4	m-CH3C6H4	74

^aReaction conditions: acetylenedicarboxylate (1.0 mmol), substituted cyclopropane (1.0 mmol) and triphenylphosphine (1.0 mmol) in DME (10.0 mL), rt, 5 h; ^bisolated yields.

The racemic cyclopropyl-substituted 2,5-dihydrofuran-3-carboxylates 1a-n were fully characterized by IR, HRMS, ¹H NMR and ¹³C NMR and the structures were confirmed by X-ray diffraction analysis of single crystal structures for compounds 1a (Figure 1) and 1b (Figure 2). In the ¹H NMR spectra of 1a-n, the two protons in the cyclopropyl unit are displayed as two doublets at about δ 3.40 and δ 4.15 with a coupling constant J = 8.8 Hz, which suggests a trans-configuration [16]. From Figures 1 and 2, it can be clearly seen that the cyclopropane ring is present in the molecules. The phenyl group and the dihydrofuryl moiety at the cyclopropyl function are in the trans-configuration.

Figure 1

X-ray structure of the compound 1a.

Figure 2

X-ray structure of the compound 1b.

A reaction mechanism (Scheme 1) is proposed which takes into account known triphenylphosphine catalyzed reactions of electron-deficient alkynes [13–15]. Initially, the addition of triphenylphosphine to acetylenedicarboxylate results in the generation of 1,3-dipolar intermediate product A (Scheme 1). Nucleophilic addition of the 1,3-dipole A to the carbonyl group of the benzoyl group of the acylcyclopropane affords the intermediate adduct B. In the third step, intramolecular attack of negative oxygen atoms on the terminal ester function causes a release of alkoxide and generates the 5-oxo-2,5-dihydrofuran-3-carboxylate ester C with a triphenylphosphanyl cation β to the ester at position 3. This cyclization is accompanied by elimination of the alkoxide ion. Finally, the addition-elimination of the alkoxide to the β-triphenylphosphoranyl-substituted α,β-unsaturated ester produces the cyclopropyl-substituted 2,5-dihydrofuran-3-carboxylate 1.

Scheme 1

The proposed mechanism.