Chiral Bifunctional Thioureas and Squaramides Grafted into Old Polymers of Intrinsic Microporosity for Novel Applications

We have prepared different polymeric chiral bifunctional thioureas and squaramides by modification of the very well-known polymers of intrinsic microporosity (PIM), specifically PIM-1 and PIM-CO-1, to be used as recoverable organocatalysts. The installation of the chiral structures into the polymers has been done in two or three steps in high yields. The catalytic activity of the resulting materials has been proved in the stereoselective nitro-Michael addition and in a cascade process, which allows the synthesis of enantioenriched 4H-chromene derivatives. Squaramide II and thiourea III have been used in six cycles maintaining their activity.


Introduction
Since the discovery of polymers of intrinsic microporosity (PIMs) fifteen years ago [1], a great deal of work has been developed around their applications in physicochemical processes [2][3][4].PIMs are characterized by their lack of rotational freedom along the polymeric chain, which confer a lot of void space, and consequently, interconnected pores along their structures.
The most classical way to obtain PIMs employs the co-polymerization of bis-catechol derivatives with perhalobenzenes activated with electron withdrawing groups to form a dibenzodioxin linkage [21].Interestingly, only the archetypal PIM-1 [12] has been subjected to additional modifications based on the transformation of the nitrile groups.This group has been converted into carboxylic acids [22,23], thioamides [24], amidoximes [25], tetrazoles [26,27], and amides [28] and has been reduced to diamines [29], but all these transformations have been directed to the synthesis of modified PIM-1 to get improvement in gas permeation and in diffusion processes.On the other hand, some other types of polymers, such as chiral helical polymers [30] or copolymers [31] with different pendant substituents [32] have been successfully used as catalysts in enantioselective Rauhut-Currier [33] or aldol [34] reactions.
Our interest in the preparation of recoverable and reusable catalysts that are able to promote enantioselective reactions [35][36][37][38] led us to consider the synthesis of PIMs decorated with chiral thioureas and squaramides and to study their ability to act as organocatalysts in these kinds of transformations.
We selected the most studied PIM-1 as the starting material for the direct synthesis of thioureas derived from L-valine or cyclohexanediamine, and L-valine-derived squaramide.As an alternative, PIM-CO-100 [39], which differs from PIM-1 in the nature of the contortion unit, was selected for the synthesis of two different thioureas and one squaramide.We report here the synthesis of these materials and their use as organocatalysts in some of the most commonly studied stereoselective transformations.

Characterization Techniques
Elemental analysis of the starting PIMs, their corresponding modifications, and final catalysts were determined using a LECO CHNS-932 at the Elemental Analysis Center of the Complutense University of Madrid (Madrid, Spain).Infrared spectra were carried out using a Perkin-Elmer spectrum One FT-IR spectrometer (PerkinElmer, Madrid, Spain and spectra was reported in frequency of absorption (only the structurally most important peaks are given).Microstructural morphology of the catalysts was observed by environmental scanning electron microscopy (ESEM) in low vacuum mode (FEI Quanta 200 FEG) at the UM-PCUVa (Valladolid Spain).Samples for atomic force microscopy (AFM) were prepared on mica by placing a solution of the catalyst in N,N-dimethylformamide (DMF).AFM was performed in air at 25

General Procedure for Asymmetric Reactions
2.4.1.General Procedure for Stereoselective Nitro-Michael Addition 1,3-Dicarbonyl compound 5a-c (0.6 mmol, 2.0 equiv.) was added to a mixture of trans-βnitrostyrene 6 (0.3 mmol) and the corresponding catalyst (I-VI) (5 mol %, calculated on the basis of its effective functionalization given in mmol g −1 ).The reaction was stirred at room temperature in a Wheaton vial until consumption of the starting material (monitored by TLC).The catalyst was filtered off and washed with dichlorometane (3 × 0.5 mL).The solvent was removed from the filtrate under reduced pressure, and the residue was purified by flash chromatography on silica gel with hexane/EtOAc (from 20:1 to 8:1) as the eluent to afford the corresponding pure Michael adduct 7a-c.Racemic reference samples were prepared using 1,4-diazabicyclo[2.2.2]octane (DABCO) as a base in the same conditions as that for the asymmetric reaction.

Recyclability of the Grafted PIM's Catalysts in the Asymmetric Reactions
The catalysts II and III, used in the recyclability studies were recovered by filtration when the reaction was finished, washed with dichloromethane and methanol, and dried under vacuum until a constant weight.These materials were used directly for the next cycle.

Polymerization, Post-Modification, and Structural Characterization of PIMs
The synthesis and post-modifications of well-defined PIMs, subsequent Amine-PIMs, and grafted PIM's catalysts were monitored by infrared spectroscopy.As an example, Figure 1 compares IR spectra of the PIM-1 (black), amine-PIM-1 (red), isothiocyanate-PIM-1 (green), and catalyst I (blue).It is clear that all the CN groups in starting PIM-1 have been reduced to amine groups because the absorption at 2241 cm −1 is not present, and a characteristic broad band of amine at 3200-3500 cm −1 has appeared.The peak at 2046 cm −1 corresponds to the isothiocyanate group in the isothiocyanate-PIM-1 polymer, and the stretching vibration of C-N at 1533 cm −1 confirms the presence of the thiourea substituents in I.In addition, the thermal behavior in relation to the chemical modifications of the PIM-1 that produced the final grafted catalysts I-III was investigated with TGA.
Figure 2 shows TGA thermograms.It is well-known that PIM-1 powder polymer have an extraordinarily high thermal stability of above 400 • C with a single-step decomposition pattern [28,29].However, the nitrile replacement with thiourea or squaramide groups resulted in a decrease in the thermal stability.PIM-1 and the catalysts I-III gradually conveyed approximately until 4% of weight loss at low temperatures between 50 and 150 • C was attributed to the loss of volatiles, and as temperature was ramped up to 300 • C for catalyst II and up to 220 • C for thioureas I-III, the weight loss became more dramatic due to the decomposition of the thiourea and squaramide groups amongst other thermal degradation processes that could also occur at temperatures ramped up to 450 • C. Furthermore, the microstructural morphology of the polymers was observed by ESEM.As an example, some micrographs of the starting PIM-1, Amine-PIM-1, and catalyst III are showed in Figure 3. Inspection of these images reveals the intrinsic porosity of the materials and the observation that subsequent modifications such as dissolution and swelling in different solvents, changes in the chemical composition, and resulting alterations in surface energy, amongst others, might contribute to enhancing the surface roughness.These changes can be useful in improving the catalytic activity of the grafted PIM's catalysts.In light of these results, AFM was used to observe the morphology of the catalyst III.The section image shows pore size between 15 and 40 nm (Figure 3e, right), and additionally, the 3D representation clearly shows microporous structure, indicating that the modification of the starting PIMs does not disturb their characteristic intrinsic microporosity.

Evaluation of Catalytic Activity
The ability of the grafted PIMs (I-VI) to promote stereoselective transformations was first explored in the nitro-Michael addition and is one of the most widely studied organocatalyzed reactions [46].The reaction was carried out in neat conditions by stirring a mixture of trans-β-nitrostyrene 6 (1 equivalent) with pronucleophiles 5a-c (2 equivalents) and the corresponding catalyst (0.05 equivalents) at room temperature (Scheme 2).The catalytic efficiency of all the polymers was tested in the reaction of trans-β-nitrostyrene with diethyl malonate 5a (entries 1-6 in Table 1).These data show that the reactions promoted by catalysts derived from PIM-1 (I-III) are more enantioselective than those catalyzed by polymers derived from PIM-CO-1 (IV-VI) (compare entries 1-3 versus 4-6).The more acidic 2,4-pentanedione 5b reacted faster than 5a with excellent enantioselectivity in the reactions catalyzed by squaramides II and V (entries 8 and 9) but moderate enantioselection in the presence of thioureas I and VI (entries 7 and 10).Tertiary nucleophile 5c also reacted very fast, leading to the addition product 7c in good diastereoselection but moderate enantioselectivity (entries 11-14).To test the recyclability of the catalysts, we selected the reaction of diethyl malonate 5a with trans-β-nitrostyrene 6 catalyzed by thiourea III (entries 15-19 in Table 1) and the reaction of 2,4-pentanedione 5b catalyzed by squaramide II (entries 20-24 in Table 1) in the described reaction conditions.For each cycle, the catalyst was recovered by filtration, washed, dried under vacuum, and used in the next reaction.The results summarized in Table 1 demonstrate that both the activity and the enantio-discrimination were maintained along six cycles, showing that insignificant deterioration of the catalysts occurred.Additionally, both the IR spectra and analytical data of the recovered catalysts are coincident with those of the starting materials. 1H NMR spectra of the final mixtures showed that the transformation was complete for each cycle, and the variations in the isolated chemical yields could be attributed to the efficiency of the flash chromatography in each case.The obtained results are comparable to those obtained with thioureas and squaramides supported on different polymeric materials [43].
The 2-amino-4H-chromenes as biological active compounds [47] lets us consider the synthesis of enantioenriched 2,3,4-trisubstituted 4H-chromenes by using I-VI as organocatalysts following a cascade process related to others previously described [48].The reaction of 2-hydroxynitrostyrene (8) with malononitrile (9) proceeded smoothly in CH 2 Cl 2 , leading to a very good 2-amino-3-cyano-4-nitromethyl-4H-chromene (10) yield (Scheme 3) but to an unfortunately moderate enantioselectivity (Table 2).The stereogenic center was formed in the first step of the process (Michael addition of 9 to 8), then the cyclization of the addition product, followed by a prototropic displacement in the intermediate lead to the 4H-chromene 10.As observed for the nitro-Michael reactions described above, the reactions catalyzed by I-III and derived from PIM-1 were more enantioselective than those promoted by IV-VI and prepared from PIM-CO-1.

Conclusions
We have prepared six novel polymeric organocatalysts by grafting two very well-known polymers of intrinsic microporosity (PIM-1 and PIM-CO-100).Interestingly, the polymers conserve their microporous structure after the described modifications.
The organocatalytic activity of these polymers has been tested in the stereoselective nitro-Michael addition and in a cascade nitro-Michael-cyclization process leading to trisubstituted 4H-chromenes.We have also demonstrated that these polymers are recoverable and reusable as organocatalysts.The present study provides a novel application of modified PIMs for catalytic asymmetric transformations, and more work remains to be done to improve their catalytic activity in different stereoselective transformations.

Figure 1 .
Figure 1.Fourier transform infrared spectroscopy (FTIR) spectra of PIM-1, Amine-PIM-1, isothiocyanate-PIM-1, and catalyst I. 1 H NMRand 13 C NMR spectroscopy were employed to confirm the chemical structure of the soluble the starting PIMs in CDCl 3 (see Supplementary Materials, and the results of the elemental analysis of the starting and modified PIMs indicated that the transformations occurred in high yields.

Table 1 .
Nitro-Michael addition of different nucleophiles to trans-β-nitrostyrene a .Determined by 1 HNMR in the reaction mixture.d Determined by HPLC on a chiral column.e The provided configuration corresponds to the major diastereoisomer.f Cycles 2-6 for entry 3. g Cycles 2-6 for entry 8. c
a Yields correspond to pure isolated compounds; b Determined by HPLC on a chiral column.