1 Introduction

1,5-Diketones are useful precursors to various substituted anilines [1] and heterocyclic compounds including pyridine derivatives [2–5], dihydropyridines [5,6], and pyrazolo[1,5-a] pyrimidines [7]. Moreover, 1,5-diketones with abstractable γ-hydrogen atoms were shown to be highly photoactive cage molecules for the release of fragrances [8]. These dicarbonyl compounds were also used for the synthesis of bicyclic ethers via their annulation reaction with bis (trimethylsilyl) enol ethers [9] and pinacol coupling through their reductive dimerization [10].

Michael addition of ketone enolates or their surrogates onto α,β-enones is one of the common methods for the synthesis of 1,5-diketones [11–13]. These compounds can also be prepared by a cross-coupling reaction of aryl methyl ketones with either aromatic aldehydes [14] or acetohydrazones [15], as well as by dimerization of α,β-enones in the presence of a quaternary ammonium salt as a phase-transfer catalyst [16]. In addition, the cross-metathesis of olefins was found to be a rapid access to such dicarbonyl derivatives [1,3]. In another synthetic protocol, Zard et al. reported a free radical approach for the synthesis of 1,5-diketones from alkenylacylphosphonates and keto-xanthates [2].

On the other hand, during the last decades, the nucleophilic behavior of enamines has been explored in palladium-catalyzed nucleophilic substitution of allylic compounds. Indeed, the reaction of allylic acetates with enamines worked well in the presence of Pd(II)/metallocene-based ligands, affording the corresponding allylation products [17]. Such a nucleophilic allylic substitution was used to prepare γ,δ-unsaturated ketones through the reaction of allylic benzotriazoles with enamines under the action of Pd(0)/PPh₃ in the presence of ZnBr₂ [18].

Furthermore, it was shown that the one-pot reaction of functionalized acyclic Morita–Baylis–Hillman (MBH) acetates with various enamino β-ketoesters in the presence of NaH afforded a series of trisubstituted 2-pyridones [19,20]. Nevertheless, it is worth noting that up to now, no Pd-catalyzed nucleophilic reaction of enamines with acyclic or cyclic MBH adducts has been reported. In our previous studies on the MBH chemistry, we have reported a Pd-free Tsuji-Trost–type reaction of MBH alcohols or acetates with β-dicarbonyl compounds, affording γ,δ-unsaturated 1,5-diketones [21,22]. In continuation of our interest in the allylic substitution of MBH derivatives with various nucleophiles [23,24], we report herein the first examples of a Pd-catalyzed allylic nucleophilic substitution of both cyclic and acyclic MBH adducts, as functionalized allylic substrates, with ketoenamines, providing a new series of saturated and γ,δ-unsaturated 1,5-dicarbonyl compounds.

2 Results and discussion

For this purpose, we have initially prepared the enamines 2a–c in 60–70% yields (Table 1) from the reaction of cyclic ketones 1a–c with morpholine using conventional reaction conditions [25].

Next, upon treatment of the enamine 2a with the MBH acetate 3a [21], at room temperature (rt), under solvent-free conditions, and without any additive, the starting materials were recovered within 48 h (Table 2, entry 1). The same result was also obtained when toluene was used as a solvent in the same reaction at rt or at reflux for 72 h (Table 2, entries 2 and 3). Interestingly, in dichloromethane at rt, the 1,5-dicarbonyl compound 4a was obtained, within 72 h, but in only 30% yield (Scheme 1, Table 2, entry 4). To improve the reaction yield and reduce the reaction time, our subsequent experiment was conducted in refluxing dichloromethane. Under these conditions, the 1,5-keto ester 4a was produced in the same yield within 72 h (Scheme 1, Table 2, entry 5).

Taking into account the low yields of the compound 4a and long reaction times recorded in the previous preliminary attempts, we therefore decided to explore a new synthetic approach for 4a under catalytic conditions. In this context, we reacted, under the established conditions, the enamine 2a (5 equiv) with the MBH acetate 3a (1 equiv) in the presence of Pd(OAc)₂ (0.04 equiv)/PPh₃ (0.16 equiv) and ZnBr₂ (2.66 equiv) as a Lewis acid in refluxing dichloromethane. The conversion of the substrate 3a was complete within 6 h, yielding exclusively, after hydrolysis of the reaction mixture, the unsaturated 1,5-keto ester 4a in 70% yield (Scheme 1, Table 3, entry 1). Under the same conditions, the allylic nucleophilic substitution of the substrate 3a was also successfully performed with enamines 2b and 2c, affording similarly the corresponding S_N2 and/or S_N2′-type products 4b and 4c in 80 and 68% yield, respectively (Scheme 1, Table 3, entries 2 and 3).

Next, to establish the substrate scope, we selected the cyclic MBH derivatives 3b–d bearing three different leaving groups (LG = OAc, OMe, OEt), and we explored their behavior toward the nucleophilic enamines 2. First, upon treatment of allylic acetate 3b or allylic ethers 3c and 3d with enamine 2a, under the previous conditions (MBH adduct (1 equiv), ketoenamine (5 equiv), Pd(OAc)₂ (0.04 equiv), PPh₃ (0.16 equiv), and ZnBr₂ (2.66 equiv) in CH₂Cl₂), the reaction worked well. Nevertheless, the expected S_N2-type product 4d was not isolated but we exclusively obtained the same compound 5d, in 75–80% yields (entries 4–6). This derivative was presumably formed through an in situ intramolecular Michael addition on the enone moiety of its precursor 4d (Scheme 2, Table 3, entries 4–6). The best yield (80%) and the shorter reaction time (24 h) were achieved with the allylic acetate 3b that was found to be the most reactive.

It is noteworthy that the monitoring of the reaction progress by thin layer chromatography, from the beginning of our experiment, showed only the formation of the compound 5d with no trace of its precursor 4d (Table 3, entries 4–6), suggesting that the conversion of this intermediate into 5d was kinetically faster than that of substrates 3b–d into the intermediate 4d.

Correlatively, an interesting example on Michael–Stork addition of enamine 2a to allenyl ketones and esters was previously reported by Lepore et al. [26]. They showed that a Michael addition onto the title substrates provided an iminium ion intermediate, which could further undergo hydrolysis to afford the 1,4-adducts 6. Alternatively, the corresponding enamines can undergo an intramolecular cyclization to yield the bicyclic compounds 7 (Scheme 3).

Furthermore, we explored the scope of this allylic nucleophilic substitution reaction involving the five-membered MBH acetate 3e with enamines 2a–c. Under the previous conditions (Pd(OAc)₂/ZnBr₂), adducts 5e–g were exclusively obtained in 57–64% yields (Scheme 2, Table 3, entries 7–9).

Finally, the nucleophilic allylic substitution of substrates 3b–d with six-membered enamines 2b and 2c has been investigated (Scheme 2, Table 3, entries 10–15). We observed that these substrates did not have the same behavior toward the five-membered enamine 2a (vide supra) and the six-membered enamines 2b and 2c (Scheme 2, Table 3, entries 10–15). Indeed, the reaction with enamine 2a gave exclusively the adduct 5d (Scheme 2, Table 3, entries 4–6), whereas the use of 2b and 2c gave predominantly adducts 5h and 5i along with their corresponding precursors 4h and 4i (Scheme 2, Table 3, entries 10–15) in high overall yields.

Compounds 5h and 5i and the corresponding precursors 4h and 4i were easily separated by column chromatography (petroleum ether/ether = 60:40) and fully characterized. Polycyclic compounds 5d–i were unequivocally elucidated by ¹H NMR and high-resolution mass spectra (HRMS).

It is notable that, under the catalysis of both Pd(0) and ZnBr₂, we did not observe any S_N2′ product along with the S_N2-type products 4d–i using cyclic MBH adducts 3b–e and enamines 2a–c. We believe that this allylic substitution is under thermodynamic control, affording exclusively the α-products [27,28].

To explain the formation of the 1,5-dicarbonyl compounds 4 and 5, we propose an initial departure of the leaving group on adducts 3, which would be assisted by the Lewis acid ZnBr₂ [29–31]. Indeed, the resulting intermediate 7 undergoes an oxidative addition to Pd(0) to form a cationic Π–allyl Pd(II) complex 8 (i) that is further attacked by the enamines 2, yielding an iminium intermediate 9 (ii). After that, there is either the hydrolysis of the intermediate 9 to give the δ-diketones 4 (iii), or alternatively the carbanion derived from the tautomeric form 9′ of 9 undergoes an intramolecular Michael addition on the enone moiety to finally provide, after hydrolysis, the δ-diketones 5 (iv) (Scheme 4).

3 Conclusion

We have reported the first examples of an efficient ZnBr₂-promoted Pd-catalyzed allylic substitution reactions of cyclic and acyclic MBH adducts with cyclic ketoenamines in refluxing dichloromethane. These reactions afford a series of S_N2-type unsaturated 1,5-dicarbonyl compounds, which can further undergo an intramolecular Michael addition on the enone moiety, yielding the corresponding 1,4-adducts. All the newly synthesized compounds were isolated in moderate to good yields and fully characterized.

4 Experimental section