1. Introduction

Dienamides are a structural motif prevalent in numerous biologically related molecules and are also key reactive intermediates in the synthesis of some small-molecule natural products[1-3]. For instances, hexadienamide 1 was reported to undergo a pivotal Pd-catalyzed bis-cyclization in the stereocontrolled synthesis of indole alkaloid spirotryprostatin B[4]. Dienamide 2, detected in valproic acid (VPA)-treated rats, is a glycine-conjugated metabolite of VPA[5]. Butadiene-imide derivative T-2639, showed inhibitory potency on the production of plasminogen activator inhibitor-1, is a promising antithrombotic drug candidate (Fig. 1)[6]. On the other hand, the CF₃-substituted quaternary carbon center, particularly CF₃-substituted tertiary alcohol, are common subunits in some bioactive molecules with appealing pharmacological activity[7], and their preparation methods have gained increasing interest among the synthetic community[8]. Though sorts of approaches for assembling dienamides have been documented[9-14], including metalcatalyzed diene-coupling reactions and Wittig olefination with α, β-unsaturated aldehydes, new methods enabling the expedient synthesis of CF₃-bearing dienamides remain highly desirable and would prove valuable for screening bioactive dienamide-containing molecules as potential pharmceuticals.

In 2014, we developed a phosphine-promoted tandem vinylogous addition/lactonization/Wittig reaction between MBH carbonates and aryl trifluoromethyl ketones, and a series of trifluoromethylated vinyl butenolide products were obtained with controllable chemoselectivity (Scheme 1)[15, 16]. In this context, the in situ generated butenolides act as electrophilic alkene in a traditional phosphine-catalyzed [3 + 2] cycloaddition with MBH carbonate or allenoate (vide infra) to produce bicyclic lactones. In the continuing work, we found that treatment of the resulting reaction mixture with secondary alkylamine and an amidine-type base led to direct amidation of the lactone smoothly[17], giving trifluoromethylated dienamides with a tertiary alcohol moiety in a one-pot operation. Herein, we unveiled the outcome of this investigation.

2. Results and discussion

The reaction was first conducted with phenyl trifluoromethyl ketone 3a, allylic carbonate 4 and PPh₃ in CH₂Cl₂ at r.t. for 8 h to produce butenolide compound as previously described [16c]. Then the in situ formed butenolide and cyclic secondary amine morpholine were reacted in the presence of a stoichiometric amount of 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU), the direct aminolysis product 5a was obtained uneventfully with satisfying chemical yield. A selection of bases, including Et₃N, DABCO, 4-dimethylaminopyridine and K₂CO₃/tetrabutylammonium bromide, was evaluated and bicyclic amidine base DBU offered the best reaction efficiency (Table 1, entries 1–5). Either the use of amine and ketone in a 4:1 stoichiometry or raising the loading of DBU to 2 equiv. produced 5a in slightly improved yield, while decreasing the amount of morpholine or DBU employed markedly reduced the process efficiency (Table 1, entries 6–9). Solvent screening revealed that reactions worked in Et₂O or CHCl₃ as well, and CH₂Cl₂ was identified as medium of choice (Table 1, entries 10–16). Typically, with a ketone/carbonate ratio of 4:1 in the presence of 100 mol% of PPh₃ in CH₂Cl₂, 2 equiv. of DBU, the one-pot tandem reaction/aminolysis sequence with morpholine proceeded smoothly at ambient temperature to afford the corresponding dienamide 5a in 73% yield.

The scope of the tandem reaction was examined with various amines and trifluoromethyl ketones outlined in Table 2. Several secondary alkylamines, cyclic or linear, were found to be viable amine reagents, providing dienamide products with moderate to good isolated yields (Table 2, entries 1–5). More sterically demanding dibutylamine still delivered target, albeit with a diminished yield. N-Methyl or Ts aniline, with less nucleophilicity in comparison to aliphatic counterpart, was ineffective under the typical reaction conditions (some intractable polar compounds were observed). In addition, using morpholine or diethylamine, a range of different aryl substituted ketones competently engaged in the one-pot tandem reaction (Table 2, entries 6–14). The presence of electron-donating or -withdrawing substituents at different position of phenyl ring in CF₃ ketones seemingly had a negligible influence on the chemical yield, and a range of densely functionalized dienamides were obtained in modest yields generally.

Furthermore, the isolated butenolide intermediate can also couple with simple allenoate via a conventional phosphine catalyzed [3 +2] cycloaddition, affording bicyclic lactones with moderate yield and E/Z selectivity (Eq. (1)).

(1)

A plausible reaction mechanism is proposed as shown in Scheme 2. Initially, the nucleophilic phosphine converts MBH carbonate to allylic phosphorus ylide via a well-defined S_N2' addition/deprotonation process. The zwitterion A undergoes γ-addition/lactonization/deprotonation/Wittig olefination successive transformations to furnish butenolide intermediate. Amidines, as non-nucleophilic bases, have also been shown to function as nucleophilic catalysts in a wide range of reactions (including amidations)[18]. The nucleophilic DBU displaces the alkoxy moiety of butenolide to generate N-acyl DBU intermediate B, which undergoes the addition-elimination process with secondary alkylamine to afford dienamide 6. Alternatively, nucleophilic secondary alkylamines would react with lactone intermediate directly to furnish aminolysis product using DBU as a nonnucleophilic base.

3. Conclusion

In conclusion, we have developed a one-pot protocol involving sequential phosphine-promoted tandem reaction and DBU-promoted amidation reaction, which afford trifluoromethylated dienamides possessing tertiary alcohol moiety in moderate to good yields at room temperature. This method provides a costeffective and step-economical approach to access trifluoromethylated dienamides with structural complexity from readily accessible reagent and starting materials under ambient and metal-free reaction conditions.

4. Experimental

The allylic carbonate 4 was prepared according to a known procedure [16c]. Amine, CF₃ ketones and base reagents used in this work were purchased from commercial suppliers and were used without further purification. ¹H, ¹⁹F and ¹³C NMR were recorded on Bruker 600 MHz spectrometers in CDCl₃ solution, using TMS as an internal standard. HRMS were performed using electrospray ionization (ESI) with Waters Synapt G2 Si.

General procedure for the preparation of dienamide products: Triphenylphosphine (0.05 mmol) was added to a stirred solution of trifluoromethyl ketone 3 (0.2 mmol) and carbonate 4 (0.05 mmol) in CH₂Cl₂ (1 mL) in one portion. The resulting mixture was magnetically stirred at r.t. and monitored by TLC. After the reaction was complete (around 8 h), DBU (0.1 mmol) and alkylamines (0.2 mmol) was added sequentially and stirred for another 10 h. After completion of reaction as indicated by TLC, the crude mixture was concentrated and directly purified by flash column chromatography (petroleum ether/EtOAc, 3:1-1:1) to give the desired product 5 with indicated yields.

Acknowledgment

This work was supported by the National Natural Science Foundation of China (No. 21302034), and the Fundamental Research Funds for the Central Universities (No. 2013HGQC0028).