A recyclable fluorous organocatalyst for Diels-Alder reactions.

Over the past decade, much interest has been devoted to the development of highly efficient organocatalysts for a variety of reactions, and the pace of growth in this field of chemistry has been breathtaking.1–3 However, the need for high loading and separation of the organocatalyst from the product are still the issues need to be addressed in this area.4,5 Fluorous organocatalysts are of high interest because they are soluble in common reaction solvents, yet they can be easily separated from the reaction mixture for subsequent reuse.6,7 Recently, enantioselective Michael additions have been achieved with fluorous pyrrolidine derivatives as recyclable catalysts.8 Chiral imidazolidinone 1 (Scheme 1) is a well-known enantioselective catalyst for many different chemical transformations2c such as Diels-Alder,9a,9b Michael addition,10a 1,3-dipolar addition,10b and Friedel-Crafts alkylation reactions.10c Although polymer-supported chiral imidazolidinones have been known for several years,11,12 there is no reported fluorous variant to date. Described in this paper is a recyclable fluorous imidazolidinone organocatalyst which has comparable yields and enantioselectivities to the standard organocatalyst. It can be recovered by fluorous solid-phase extraction (F-SPE)6 and has significant better yield and purity than that of standard catalyst recovered by acid-base extraction. Scheme 1 The chiral imidazolidinone 1 and its fluorous variant 2. The only structural difference between the fluorous catalyst 2 and the original imidazolidinone 1 is that the fluorous tag13 (p-C8F17CH2CH2-C6H4-) is attached to the N-methyl group. Since the single fluorous tag is away from the functional group for catalytysis,9 it was hypothesized that this design would not affect the activity of the catalyst. A simple three-step synthesis for the fluorous chiral imidazolidinone 2 is shown in Scheme 2.14 N-Fmoc-amide 3 was obtained by an amide coupling reaction of Fmoc-Phe-OH with a fluorous amine. Subsequent de-protection with piperidine gave aminoamide 4. Treatment of 4 with excess amount of acetone in DMF with microwave irradiation gave the fluorous organocatalyst 2. The overall yield of the three-step synthesis was 66%. Fluorous compound 2 is a stable white solid, and it was kept on bench for weeks without sign of decomposition. A typical Diels-Alder reaction of acrolein and cyclohexadiene was conducted using either standard imidazolidinone 1 or its fluorous variant 2 as the catalyst (Table 1). We first carried out the Diels-Alder reaction with the normal imidazolidinone catalyst by following the literature procedures.9 Acrolein (100 μL, 1.5 mmole) and cyclohexadiene (48 μL, 0.5 mmole) were added into a solution of 1·HCl salt (14 mg, 0.05 mmole) with 2 mL CH3CN-H2O (95:5, v:v). The mixture was stirred for 40 h at 25 °C. An acid-base extraction was utilized to separate the product and recover the organocatalyst.15 Thus, a 0.05M HCl aqueous solution was added to the reaction mixture. The solution was extracted with diethyl ether three times. The organic phases were combined, washed with aqueous NaHCO3, dried and concentrated to give the product 5. The acidic phase was neutralized and extracted with diethyl ether to provide 7.8 mg (65%) of recovered 1. Although the product yield (82%) and ee (88.4%) were comparable to the reported data,9 the recovery of the organocatalyst 1 under the procedures described above was moderate and its purity was only 74% (Table 1, Entry 1). This purity is not sufficient for direct reuse of the recovered catalyst. Moreover, for some reactants (e.g. substance with -OH), the acid-base extraction approach might disturb the functional group in the final product. Table 1 The Diels-Alder reaction of acrolein and cyclohexadiene catalyzed by either the organic imidazolidinone 1 or its fluorous variant 2. The fluorous imidazolidinone 2 catalyzed reactions were then performed with wet solvents and under aerobic atmosphere, same to the reaction conditions described above without much effort of modification.16 After the reaction mixture was stirred for 40 h at room temperature, 0.1 g of MP-carbonate was added and the mixture was shaken for 30 min to free the amine 2. After filtration, the solution was concentrated and then loaded onto a 0.5 g endcapped FluoroFlash® silica gel cartridge for F-SPE.14 The cartridge was first eluted with CH3CN-H2O (65:35) for product 5, then with THF containing 1% Et3N for fluorous catalyst 2. Concentration of the THF fraction gave the fluorous catalyst 2 in good recovery (84%) and excellent purity (99%). The purity was assessed by GC and 1H NMR analyses (Figure 1). The chiral GC of the major Endo products from both organic catalyst 1 and fluorous catalyst 2 are shown in Figure 2. While the yields, endo:exo ratios and high enantioselectivities of the product were comparable to those of the control experiment showing the similar catalytic activity of the two catalysts, the recovery of the fluorous catalyst 2 is much more efficient and its purity was good enough for direct reuse (Table 1, Entries 1 and 2). Figure 1 1H NMR spectrum of the fluorous chiral imidazolidinone 2 after recovery by F-SPE. Figure 2 Chiral GC (Bodman Chiraldex Γ-TA column, 90 °C, 23 psi) chromatograms of the Diels-Alder products. Left: from organic imidazolidinone 1; Right: from fluorous imidazolidinone 2. To probe the scope of both diene and dienophile (α, β-unsaturated aldehydes) as the reaction components for the fluorous reactions and separations, four other Diels-Alder reactions were conducted (Table 2).16 We found that variation on olefin substituents did not decrease in yield, endo:exo ratios and enantioselectivity (Table 2, Entry 1, Me; Entry 4, Pr) comparing to the control experiments using standard imidazolidinone 1 (Table 2, Entry 2, M,; Entry 5, Pr). Meanwhile, similar stereoselectivity and yield were achieved using the recovered fluorous organocatalyst 2 (Table 2, Entry 1, and Entry 3 with recovered 2). The result confirms the quality of recovered fluorous imidazolidinone catalyst. Furthermore, the [4+2] cycloaddition between acrolein and two acyclic dienes also gave high yields and enantioselectivities (Table 2, Entries 6 and 7). Thus, the generality of the fluorous imidazolidinone 2 as an efficient recyclable organo-catalyst for Diels-Alder reactions has been clearly demonstrated Table 2 Diels-Alder reactions of different dienophiles and dienes catalyzed by the chiral fluorous imidazolidinone 2 as well as two control experiments catalyzed by the standard organocatalyst 1. In addition, a Diels-Alder reaction between acrolein and cyclohexadiene with fluorous organocatalyst 2 was also carried out at gram scale (Table 2, Entry 8).16 The consistent results between the small scale reactions shown in Table 1 and the gram scale reaction is a good indicator that fluorous catalyst has good potential for scale up reactions. In summary, a simple procedure for preparation of a chiral fluorous imidazolidinone catalyst 2 was developed. While the fluorous organocatalyst 2 provides consistently high enantioselectivities in Diels-Alder reactions of dienes and α,β-unsaturated aldehydes, the fluorous catalyst can readily be recovered from the reaction mixture by F-SPE with excellent purity. The recovered fluorous organocatalyst is ready for reuse.