Recyclable iron(ii) caffeine-derived ionic salt catalyst in the Diels–Alder reaction of cyclopentadiene and α,β-unsaturated N-acyl-oxazolidinones in dimethyl carbonate

Iron(ii) triflate was used in combination with caffeine-derived salts as recyclable catalysts for the Diels–Alder reaction run in dimethyl carbonate (DMC) as a green solvent. The catalyst was prepared as an ionic salt from a xanthinium salt and Fe(OTf)2. Various substrates including α,β-unsaturated carbonyl and N-acyloxazolidinone derivatives were reacted with cyclopentadiene using this recyclable catalyst. The use of a low catalyst loading (1 mol%) afforded high yields (up to 99%) of the corresponding cycloadducts. The recycling and the efficiency of the catalyst were demonstrated for several runs.


Introduction
The Diels-Alder reaction is among the most powerful C-C bond forming transformations in synthetic chemistry. 1 a,b-Dicarbonyl derivatives have been used as dienophiles in the Diels-Alder reaction 2 ever since the introduction of N-acyloxazolinones as dienophiles 30 years ago by Evans. 3 The reaction between a,b-unsaturated oxazolidinones and cyclopentadiene became a benchmark reaction 4 to evaluate the catalytic activity of various metal Lewis acid catalysts, such as Mg, 5 Cu, 6 Sc, 7 Ti, 8 Ln, 2 Ni, 9 Pd, 10 Fe, 11 and Cr. 12 Much progress was made through the development of more efficient Lewis acids and ligands. [1][2][3][4][5][6][7][8][9][10][11][12] However, the use of large quantities of some of these catalysts to mediate this transformation, in addition to their limiting prices, render them difficult to use, thus creating a need for additional recyclable catalysts. 13 Various approaches include heterogeneous catalysis, 14 or replacing the reaction solvent by ionic liquids (ILs), which were originally used toward improved stereoselectivity. 14, 15 Ionic liquids have received considerable attention as new powerful reaction media and emerged as a potential alternative to conventional organic solvents. 16 Furthermore, the combination of ionic liquids or ionic salts with transition metals has been reported as a promising area, and their scope of applicability is extending. 17 An immobilized catalytic system of [bmim] [FeCl 4 ] was developed for aryl Grignard cross-coupling via a liquid-liquid biphasic process, in which FeCl 3 was trapped in the ionic liquid. 18 A similar system involving a Bi(OTf) 3 -trapped caffeine-derived salt (xanthinium salt) in a Diels-Alder reaction, in which the combined xanthinium-Bi III mixture of salts was recycled without loss of efficiency over several runs. 19 However, one drawback of these methods was the use of dichloromethane as a solvent. In fact, the most commonly used solvents in Diels-Alder reactions are, among others, dichloromethane, chloroform, toluene, diethyl ether, and water. Hence, in order to develop a Diels-Alder reaction run in greener conditions, we were interested in seeking appropriate environmentally-benign solvents. Although ILs have many advantages, their high prices and waste disposal during large scale applications limit their widespread use, not to mention their adverse environmental impact in their life cycle assessment (LCA). 20 Beside ILs, other ecofriendly solvents have also been studied. 21 Dimethyl carbonate (DMC), which has been assessed as a green alternative to replace easily-ammable organic compounds (VOC) as solvents, 22 appeared promising to use. It is environmentally benign and scores low on LCA scales. 23 In the context of our research on iron catalysis and ionic liquids, 24 a combination of a caffeine derivative, an iron salt, and dimethyl carbonate is disclosed herein.
Iron has attracted considerable attention on its ecofriendliness, natural abundance, inexpensive price, and its promising applications in organic synthesis. 25 Fe(OTf) 2 was already used with an ionic liquid ethylmethylimidazolium bis-triimide in an aziridination reaction. 26 Also, Fe II /Fe III -derived catalysts have been used in the Diels-Alder reaction, including asymmetric versions. 4a,27 Moreover, many other examples of Fe II /Fe III -catalyzed Diels-Alder reactions were reported in homogeneous and heterogeneous catalysis. 28 Caffeine, as one of the methylxanthines, is a green, natural, abundant, and biodegradable compound that can be further alkylated into xanthinium salts. 29 These xanthinium salts have been used for the preparation of NHC-metal complexes in medicinal and organometallic chemistry. 30 As already mentioned, a caffeine-derived ethylxanthinium salt was already used as an ionic solid in a 10 : 1 ratio to Bi(OTf) 3 $4H 2 O and recycled as a combined ionic salt. 18,19 The recycling of this catalyst was easily performed aer its precipitation from heptane; however, the reaction was run in CH 2 Cl 2 and only a few dienophiles were disclosed. 18,19 Alkylated caffeines, Nmethyl-and N-ethyl-substituted xanthinium salts were obtained with NTf 2 À , I À , and PF 6 À anions (Scheme 1). 18,19,30b-g Next, the xanthiniums were mixed with Fe(OTf) 2 or Fe(OTf) 3 in acetone (Scheme 1). The ratio of the xanthiniums to Fe II /Fe III salts was examined in a range of 2 : 1 to 10 : 1. For ratios 7 : 1 to 10 : 1, the iron salt was completely solubilized. A 10 : 1 ratio was used to ensure that there was no loss of the catalyst during the recycling process. Acetone and heptane were used to prepare catalysts C1, C2, C3, and C4. These catalysts were tested conjointly with Fe(OTf) 2 and Fe(NTf 2 ) 2 in the Diels-Alder reaction of cyclopentadiene and 3-acryloyl-1,4-oxazolidin-2-one, chosen as the model reaction.

Results and discussion
Initially, Fe(OTf) 2 and catalyst C1 were studied in dichloromethane. The ratio of diene to dienophile was set to 7 : 1. The yields and stereoselectivities obtained with Fe(OTf) 2 ( Table 1, entry 1) and catalyst C1 in CH 2 Cl 2 were similar (entry 2). The same yield and endo/exo selectivity were obtained in dimethyl carbonate at room temperature (entry 3) and even at 2 C (melting point of DMC, entry 4). Then, an optimization study was performed by lowering the ratio of reactants from 7 : 1 to 5 : 1 (entry 5) until 2 : 1, and a quantitative yield together with a slightly higher endo/exo ratio was obtained (entry 6). This result was even better than our previous study using Fe III catalyst in DMC (76% yield). 24e The other three catalysts C2, C3, and C4 were tested in the same conditions as in entry 6. Catalysts C2 and C3 led to low yields of 3a (entries 7 and 8). Using the Fe(OTf) 3 derived catalyst C4, the yield reached 97%, whereas the endo/exo ratio decreased to 90 : 10 (entry 9). Three control experiments were consequently performed (entries 10, 11, and 12). The yield dropped to 34% without using a catalyst (entry 10). While Fe(OTf) 2 led to a lower yield than when using catalyst C1 (entry 11). A quantitative yield was obtained when using Fe(NTf 2 ) 2 alone (entry 12). Compared to Fe(OTf) 2 , catalyst C1 was shown to be more efficient in terms of yield and stereoselectivity. Although Fe(NTf 2 ) 2 alone was as efficient as catalyst C1, it was not recyclable from the reaction media. Similarly, Fe(OTf) 2 was also lost during work-up (entries 1 and 11). On the contrary, catalyst C1 could be recycled aer the addition of heptane and ltration. Since no detectable difference was observed among the results obtained with C1 and Fe(NTf 2 ) 2 , it was hypothesized that OTf À and NTf 2 À can readily exchange within the catalytic system (entries 2 and 12). The reaction using gram scale of 2a was tested as well, and a quantitative yield was obtained (entry 13).
To explore the scope of the reaction solvent, a few green solvents were selected and compared with CH 2 Cl 2 and THF ( Table 2). CH 2 Cl 2 afforded the lowest endo/exo selectivity, while THF led to a moderate yield and good endo/exo selectivity (entries 1 and 2). Me-THF resulted in an even lower yield than THF, but with a high stereoselectivity (entry 3). N-Methyl pyrrolidinone (NMP) was found less suitable due to its high boiling point, resulting in a difficult separation from the reaction product (entry 4). Cyclopentyl methyl ether (CPME), ethyl acetate, and methyl tert-butyl ether (MTBE) led to good results (entries 5, 6, and 7). Of all the solvents tested, DMC was selected for its polarity close to CH 2 Cl 2 . 31 It provided a high endo/exo ratio combined with an excellent yield (entry 8) and was thus chosen for the next part of the study.
Scheme 1 Synthetic routes of chiral dihydroquinoxalinones. To investigate the recoverability of the catalyst, recycling tests were performed using C1. Table 3 highlights the reaction yields and the mass of recycled catalyst aer each of the 5 runs of the reaction. Firstly, 1 mol% catalyst was used for ve runs, and aer each run, heptane was added to the reaction mixture to precipitate the catalyst. Then, aer ltration through a cotton-plugged pipet, the catalyst was recollected and washed with acetone, and was nally recycled aer evaporation. Using 1 mol% of C1, the yields of both the product and the recycled catalyst slightly decreased over the 5 runs. 32 However, when the catalyst loading was increased to 2 mol%, all of the catalyst was recycled aer each run, and the reaction yield was maintained at the same level. According to 1 H and 19 F NMR analysis, the chemical composition of the catalyst resulted unchanged (or mostly unchanged) aer recovery (see ESI †).
Finally, given the results above, the optimized conditions were applied to various dienophiles in the Diels-Alder reaction (Scheme 2). The general procedure was run as follows: cyclopentadiene was added into a solution of the catalyst and the dienophile in dimethylcarbonate. Aer the given time, heptane was added into the solution to precipitate the catalyst for recycling. 3-Crotonyl-oxazolidinone (2b) required a longer time than substrate acryloyl-oxazolidin-2-one (2a) but afforded a slightly higher stereoselectivity of 3b. Instead of a CH 3 group, a b-CF 3 to the carbonyl group led to higher endo/exo selectivity and high yield (3c). However, low solubility of cinnamoyl oxazolidinone resulted in a very low yield (3d). 33 2-Alkenoyl pyridines were explored as bidentate dienophiles that can chelate to the metal center through both the pyridine and the carbonyl lone pairs. 6a Here, the objective was to use them as substrates in the developed conditions (3e-h). High yields and high endo/exo ratios were obtained. The stereoselectivity decreased when using cinnamoyl pyridine N-oxide (2h), probably due to the weaker coordination of the oxide with iron than that with pyridine. Being similar on the cinnamoyl part, benzylidene acetone (2i) and acryloyl chloride (2j) were chosen to get a comparison with the bidentate dienophiles 2d and 2e. Benzylidene acetone showed a good reactivity with a higher endo/exo ratio (3i). Using acryloyl chloride, a moderate yield (60%, 3j) was obtained. Neat conditions were efficiently used with methyl acrylate at very low  catalyst loading (0.1 mol%), and high yield (90%), and selectivity were obtained (77 : 23 endo/exo, 3k), which was even better than some obtained results using ionic liquids, but low yield was obtained for methyl propiolate. 34 While keeping the dicarbonyl group, acryloyl 2-pyrrolidinone led to a 95% yield and a 83 : 17 endo/exo selectivity (3l). Without the second carbonyl group, the yield dropped to 25% when using acryloyl amide (2m), which revealed the importance of the oxazolidin-2-one or pyridine group to obtain a good conversion. Finally, cyclohexa-1,3-diene was selected to react with 3-acryloyl-1,4-oxazolidin-2one, but this diene led to a slower reaction rate. A 20% yield and 77 : 23 endo/exo ratio were obtained for 4a.
In order to shed light on the nature of the catalyst, the interaction between xanthinium and Fe(OTf) 2 in the catalyst was studied by UV-vis, FTIR, 1 H, 13 C, and 19 F NMR, and HRMS techniques (see ESI † for more details). As shown in Fig. 1, aer mixing xanthinium and Fe(OTf) 2 together, the 19 F NMR signal of OTf À shied from À56.9 ppm to À73.4 ppm, which is comparable to the chemical shi of unbound OTf À in Fe 2+ complexes (À69.7 ppm, 35 À78.96 ppm, 36 and À79.59 ppm 37 ). Since the OTf À signal shied to high eld (i.e. became more electron-enriched), the counterpart (Fe 2+ ) was considered more electron-decient, thus more Lewis acidic for the activation of dienophiles. The increase of Lewis acidity of Fe(II) in C1 thus led to higher yield (Table 1, entry 6 vs. entry 11). On the other hand, the NTf 2 À is a non-coordinating anion, so the 19 F signal of NTf 2 À (À80.0 ppm) did not considerably change. According to the changes observed by FTIR, 19 F NMR, and HRMS, the interaction between xanthinium and Fe(OTf) 2 has been highlighted and provides evidence for anion metathesis. 37 DFT calculations (B3LYP/6-31G/LANL2DZ level in gas phase) were run to shed light on the changes of Gibbs free energy and Mulliken charges of Fe(II) aer the ion exchanges. According to the calculations, the anion exchange in C1 is favored (DG ¼ À22.2 kcal mol À1 ), which is supported by the 19 F NMR change and HRMS, allowing a qualitative evaluation of C1-C4 (see ESI † for more details).

Conclusions
In conclusion, a recyclable ionic salt/iron triate catalyst was prepared from a xanthinium salt and iron(II) triate. This green catalytic system using a caffeine-derived xanthinium-Fe(OTf) 2 complex for the Diels-Alder reaction run in DMC was developed for a large scope of substrates. The xanthinium salt as a solid provides a new way of catalyst immobilization in comparison to ionic liquids. Several green solvents were examined and the recycling of the catalyst was demonstrated for several runs. The use of a caffeine derivative, an iron salt, and dimethyl carbonate represents a major advancement from a green chemistry point of view. Work is in progress on further applications of ionic salt catalysts and will be reported in due course.

General information
All materials are commercially available and were used as received without further purication. Preparation of catalysts C1-C4 The 1,3,7-trimethyl-9-ethylxanthinium bis(triuoromethanesulfonyl)amide (1.26 g, 2.5 mmol) and anhydrous Fe(OTf) 2 (89 mg, 0.25 mmol) were added to a 25 mL oven-dried ask. Acetone (7 mL) was then added into the ask to dissolve the salts, then heptane (15 mL) was added. A brown solution formed at the bottom of the ask. Then, the solvent was slowly evaporated at reduced pressure, and the ask was put under high vacuum overnight. Catalyst C1 was obtained in quantitative yield. Catalysts C2-C4 were prepared according to the same procedure. Characterization data for each catalyst is shown below.  (signal of OTf À was not observed). 19

General procedure for Diels-Alder reaction in DMC
To an oven-dried vial, were added catalyst C1 (27.5 mg, 0.005 mmol) and dienophile 3-acryloyl-1,3-oxazolin-2-one (70.5 mg, 0.5 mmol), then DMC (1 mL) was injected. The solution was stirred for 10 minutes. Aer that, the vial was placed in an ice water bath at 2 C. Then the pre-distilled cyclopentadiene (1 mmol, 66 mg) was injected into the vial. The solution was stirred for 3 hours. Aer the reaction was complete, heptane (5 mL) was added into the solution to precipitate the catalyst (other solvents, such as hexane, petroleum ether and Et 2 O, could also be used for recycling of catalyst). The precipitate of catalyst was recycled (27.5 mg) by ltration. The ltrate was concentrated, and the crude product was puried by silica gel column chromatography using hexanes/EtOAc as the eluent to obtain the product (103 mg, 99% yield). For other substrates, 0.25 mmol of dienophiles and 0.5 mmol of diene were used with 0.0025 mmol (14 mg) of the catalyst, and the crude products were puried by silica gel column chromatography using hexanes/EtOAc as the eluent unless stated otherwise.

General procedure for Diels-Alder reaction under neat conditions
For liquid dienophiles, the reactions were carried out in neat conditions. Typically, to an oven-dried vial, was added catalyst C1 (27.5 mg, 0.005 mmol). The reaction vial was then cooled at 2-3 C using a cryostat. Methyl acrylate (430 mg, 5 mmol) and distilled cyclopentadiene (396 mg, 6 mmol, 1.2 equiv.) were then injected into the vial. The reaction mixture was stirred for 1 day. Then, heptane (5 mL) was added into the vial to precipitate the catalyst, and the crude product was obtained through ltration of cotton-plugged pipet. The ltrate was evaporated and the product was dried under high vacuum for 5-10 minutes. Pure product was obtained without further purication in 90% yield (677 mg). The precipitated catalyst was dissolved by acetone, and ltered through cotton-plugged pipet to be recycled aer evaporation of acetone.