Synthesis of Novel Crown Ether-Squaramides and Their Application as Phase-Transfer Catalysts

This work presents the synthesis of six new phase-transfer organocatalysts in which the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether. Four chiral skeletons, namely hydroquinine, quinine, cinchonine (cinchonas), and α-d-glucopyranoside were responsible for the asymmetric construction of an all-carbon quaternary stereogenic center in α-alkylation and Michael addition reactions of malonic esters. We investigated the effects of these different chiral units and that of crown ethers with different sizes on catalytic activity and enantioselectivity. During extensive parameter investigations, both conventional and emerging green solvents were screened, providing valuable α,α-disubstituted malonic ester derivatives with excellent yields (up to 98%).


Introduction
Investigating the creation of quaternary stereogenic centers is essential in organic synthesis as it poses a challenge to organic chemists due to the possible steric repulsion between the groups around the stereocenter. In the last decade, the synthesis of chiral α,α-disubstituted malonates has gained considerable attention [1,2]. These compounds can be applied in the preparation of α,α-disubstituted amino acids, as they can undergo chemoselective transformations if their carboxylic acid moieties are protected with different groups, e.g., through Curtius rearrangement [3]. A decade ago, a new method involving enantioselective phase-transfer catalytic double α-alkylation of malonates was developed for the construction of chiral quaternary carbon centers, applying tert-butyl diphenylmethyl α-alkylmalonates as starting materials [1]. This method was later extended in numerous publications by examining a broad substrate scope [3][4][5][6]. Moreover, similar phase-transfer catalytic reactions, such as the α-benzoyloxylation of tert-butyl methyl α-alkylmalonates [7] and the Michael addition reaction of tert-butyl methyl α-benzylmalonate to acrylates, have also been elaborated [2]. In all of these papers, quaternary ammonium salts were applied as phase-transfer catalysts (PTCs) in the enantioselective α-alkylation of malonates, while chiral macrocycle PTCs remain a rather neglected tool for these asymmetric reactions.
Phase-transfer catalysis is one of the most efficient asymmetric synthetic methods, which is also inexpensive and sustainable as it involves simple procedures and mild reaction conditions. Thanks to these advantages, phase-transfer catalysis is particularly suitable for industrial applications [8].
The most common types of asymmetric phase-transfer catalysts are chiral quaternary ammonium and phosphonium salts, but chiral crown ether derivatives and other macrocycles emerge as alternatives despite their cumbersome and costly synthesis [9][10][11]. Crown ethers are neutral ligands that can complex and transport alkali metal cations into the organic phase. This crown ether-metal cation complex plays the same role as the quaternary onium cation, but crown ethers work with a different mechanism, called cation-binding catalysis, during which the entire reacting ion pair is transported into the organic phase, not just the anion [12]. The most conspicuous benefits that help crown ether derivatives to stand out from other catalysts are as follows: they are usually more resistant to strong bases, and the cation is usually more accessible than the positively charged nitrogen or phosphorus atom in ammonium or phosphonium salts; consequently, a stronger interaction can take place with the reactive anion. Furthermore, crown ethers are more effective in extracting inorganic salts from their solid form [13].
In asymmetric phase-transfer catalysis, introducing hydrogen bond donor units into catalysts has recently attained broad application [14]. The most common of those units include the hydroxyl group, amide, (thio)urea and squaramide. In the case of quaternary onium salts, there are many examples for the installation of these units into catalyst scaffold [15][16][17][18][19][20]. However, in crown ether derivatives, only hydroxyl groups are frequently used as ancillary components capable of forming hydrogen bonds.
Squaramides are highly effective double hydrogen bond donor units due to their rigid, aromatic four-membered ring [21]. There are a few examples in which a squaramide unit was connected indirectly to crown ether derivatives [22][23][24][25][26][27]. However, these ligands have only been applied for ion pair transport so far.
Herein, we present the synthesis of novel chiral crown ether-squaramide phasetransfer organocatalysts, and the catalytic performance of these new derivatives were tested in the synthesis of α,α-disubstituted malonates. The effects of different chiral units and various cavity sizes of crown ethers on catalytic activity and enantioselectivity were investigated. In these catalysts, the squaramide unit is directly linked to the nitrogen atom of an aza-crown ether; thus, one amino group of the squaramide unit is tertiary. This means that the squaramide unit serves as a linker and a single hydrogen bond donor unit [28,29]. By applying this catalyst design, we have anticipated that one NH group and the cation complexed by the crown ether can form secondary interactions of sufficient strength during the catalysis.

Synthesis of Crown Ether-Squaramide Phase-Transfer Catalysts
We have prepared a series of crown ethers with a squaramide hydrogen bond donor unit (Scheme 1) for catalyzing the α-alkylation reaction of malonates, which may be an important method for obtaining α,α-disubstituted α-amino acid intermediates. Different cinchona alkaloids [quinine (Q), hydroquinine (HQ) and cinchonine (C)] and a D-glucose derivative (G) were chosen as chiral starting materials for the syntheses of the catalysts. Previously, we have shown that the substituent on the nitrogen atom of glucose-based aza-crown ether G influences the catalytic effect [30].
During the synthetic procedures, all compounds were characterized by well-established methods, including HRMS, IR, 1 H and 13 C NMR spectroscopies.

Application of the Catalysts
The catalysts were applied in the asymmetric α-alkylation of tert-butyl methyl αbenzylmalonate [3] (1) under phase-transfer conditions (Scheme 2).
First, we compared the activities and enantioselectivities of the catalysts; these results are shown in Table 1. The catalysts provided good yields except catalysts bearing a 1-aza-18-crown-6 ether macroring (Q6 and C6, Table 1, Entries 5-6), and only poor or no enantioselectivity. The highest enantiomeric excess of (R)-3 was obtained with catalyst C5, which was still as low as 9% (Table 1, Entry 3). In the absence of a base while applying C5 as catalyst, no product was observed according to thin-layer chromatography (TLC) analysis. When 50% aq. NaOH was applied as a base in the absence of a phase-transfer catalyst, the yield was only 33%.  Next, we conducted a parameter study with catalyst C5 to maximize the enantioselectivity. First, we examined the effect of the solvent while applying 50% aq. NaOH or solid NaOH as base ( Table 2). In the case of aqueous NaOH, six different solvents were tested ( Table 2, Entries 1-6); however, only the most suitable solvent (DCM: dichloromethane; Table 2, Entry 7) and two other polar aprotic solvents (MeCN; THF: tetrahydrofuran; Table 2, Entries 8-9) were used with solid NaOH. Dichloromethane proved to be the best solvent in terms of yield and enantiomeric excess by applying 50% aq. NaOH as base ( Table 2, Entry 1, 73% yield, 9% ee). Then, the effect of the quantity of the applied base or its concentration was investigated. By decreasing the quantity of the 50% aq. NaOH from 50 to 25 eq, the yield slightly increased (from 73% to 85%), but the enantiomeric excess did not change. By using 1 eq of 50% aq. NaOH or 50 eq of 30% aq. NaOH, both yield and enantioselectivity declined (from 73% yield and 9% ee to 26-28% yield and <5% ee).
In the next step of the parameter study, we examined the effect of the catalyst quantity (10 or 20 mol%), the reagent quantity (1 or 1.2 eq) and the solvent volume (1.2 or 2.4 mL) ( Table 3). This set of experiments indicated that the application of 10 mol% catalyst, 1.2 eq of allyl bromide and 2.4 mL DCM is the most beneficial as it gave (R)-3 in an increased yield (83%) with a slightly better enantiomeric excess (11%, Table 3, Entry 3). The reaction was also carried out using allyl iodide instead of allyl bromide as a reagent under the same conditions as at the beginning of the study (1 eq reagent, 10 mol% C5 catalyst, 50 eq 50% aq. NaOH base, DCM solvent, 25 • C, 24 h). In this case, a better yield (98% instead of 73%) and a slightly higher, but still low, enantiomeric excess (12% instead of 9%) were obtained. Consequently, we continued the study by applying allyl iodide.
Next, the reaction was carried out at 0 • C as an endeavor to improve enantioselectivity. As increasing the quantity of the reagent to 1.2 eq and decreasing the quantity of the base (50% aq. NaOH) to 25 eq seemed to be able to ameliorate yield and enantiomeric excess, we also varied these conditions in the following experiments (Table 4). By setting a lower reaction temperature, the enantiomeric excess did not improve significantly in any case. Based on these experiments, the yield was found to deteriorate when only 25 eq base is applied, while it does not depend on the temperature and the reagent quantity in the applied ranges. We also conducted the reaction at −78 • C to examine whether the enantioselectivity could be improved by setting a drastically lower reaction temperature, but no product (3) was formed based on TLC analysis. Table 4. Examination of the effect of temperature and quantities of reagent and base in the presence of catalyst C5 a .

Entry
Temperature

Reagent Quantity (eq)
Base Quantity (eq) Yield b (%) ee c (%) Furthermore, the use of other bases did not improve the outcome: with 2 eq Na 2 CO 3 in THF or MeCN solvent, there was no product at 0 • C, and by applying 50% aq. NaOH base in the cases of Q6 and C6, and 50% aq. KOH in the cases of Q5, HQ5, C5 and G5 catalysts (to examine the effect of both bases with each catalyst), enantioselective alkylation occurred only with C5 catalyst at 0 • C (17% ee, but only 47% yield, with 50% aq. KOH).

Proposed Mechanism
Based on our previous research, we propose a mechanism for the α-alkylation reaction of tert-butyl methyl α-benzylmalonate (1) in the presence of our crown ether-squaramide catalysts. According to our preceding study, the Na + ion of multiple monosaccharide-based aza-crown ethers' Na + complexes can be coordinated by a substrate's carbonyl group [37]. In our other work, we have found that it is possible that only one NH group of a cinchonabased organocatalyst's squaramide unit forms a hydrogen bond with a substrate's carbonyl group [29]. Extending these results to our catalysts, we suggest that after the deprotonation of malonate 1 by the hydroxide ion, the phase-transfer catalyst coordinates the malonate anion in a way that one carbonyl of the malonate binds to the Na + ion and the other to the NH group of the squaramide (Scheme 4). Then, the nucleophilic α-carbon of the malonate attacks the allyl halide, either directly on the electrophilic saturated carbon or in a conjugate addition on the unsaturated carbon, resulting in allylic rearrangement. Naturally, in the case of the applied unsubstituted allyl halides, the product is the same in both cases. Thus, the halide anion leaves, and an allyl group is built into the substrate. Scheme 4. Proposed transition state for the α-alkylation reaction of tert-butyl methyl α-benzylmalonate (1) with catalyst C5. R 1 , R 2 = tert-butyl or methyl.

General
Starting materials were purchased from commercially available sources (Sigma-Aldrich, Merck, and Alfa Aesar). Infrared spectra were recorded on a Bruker Alpha-T FT-IR spectrometer (Bruker, Ettlingen, Germany). Optical rotations were measured on a Perkin-Elmer 241 polarimeter (Perkin-Elmer, Waltham, MA, USA) that was calibrated by measuring the optical rotations of both enantiomers of menthol. Silica gel 60 F 254 (Merck) plates were used for TLC. Silica gel 60 (70-230 mesh, Merck) was used for column chromatography. Ratios of solvents for the eluents are given in volumes (mL mL −1 ). Melting points were taken on a Boetius micro-melting point apparatus (VEB Dresden Analytik, Dresden, Germany), and they were uncorrected.
NMR spectra were recorded on a Bruker Avance 500 MHz spectrometer( Bruker, Ettlingen, Germany), (500.13 MHz for 1 H, 125.76 MHz for 13  The broad signals, the non-integer integral values in the 1 H NMR spectra (seen in Supplementary Materials) of compounds and the duplication of some signals in the 1 H and 13 C NMR spectra (e.g., 1 H and 13 C NMR signals of N-methylene groups in aza-crown ether units) of compounds indicate inhibited motions in the molecule. Also, the conformational properties of the molecules resulted in many cases in which not all signals appeared in the NMR spectra due to signal broadening. In these cases, the approximate chemical shift of the above-mentioned signals could be determined based on their HSQC or HMBC correlations. Previous 1 H NMR measurements of similar compounds at higher temperatures showed that not all conformational motion inhibitions were removed.
In the process of structure elucidation, we assigned the 1 H and 13 C NMR signals of the main conformer with the exception of compound G5, in which the chemical shifts of several minor signals were also determined.
The starting points of signal assignment were easily identifiable units of molecules: the methyl and methoxy groups, the terminal olefinic methylene unit, the position 2 in the quinoline ring and the methylidine groups next to nitrogen. The remainder of the molecular structures was elucidated using the same NMR methods mentioned above.
HPLC-MS was performed using a Shimadzu LCMS-2020 (Shimadzu Corp., Kyoto, Japan) device, equipped with a Reprospher (Altmann Analytik Corp., München, Germany) 100 C18 (5 µm; 100 × 3 mm) column and a positive/negative double ion source (DUIS±) with a quadrupole MS analyzer in a range of 50-1000 m/z. The samples were eluted with gradient elution, using eluent A (0.1% HCOOH in H 2 O) and eluent B (0.1% HCOOH in MeCN). The flow rate was set to 1.5 mL min −1 . The initial condition was 5% eluent B, followed by a linear gradient to 100% eluent B by 1.5 min; from 1.5 to 4.0 min, 100% eluent B was retained; and from 4 to 4.5 min, it went back by a linear gradient to 5% eluent B, which was retained from 4.5 to 5 min. The column temperature was kept at room temperature, and the injection volume was 1 µL. The purity of the compounds was assessed by HPLC with UV detection at 215 and 254 nm. High-resolution mass measurements were performed on a Q-TOF Premier mass spectrometer (Waters Corp., Milford, MA, USA). The ionization method was electrospray ionization (ESI) operated in positive ion mode. The enantiomeric excess (ee) values were determined by chiral HPLC with a PerkinElmer Series 200 instrument (PerkinElmer, Waltham, MA, USA). The applied column, eluent, flow rate, column temperature, and detector wavelength are indicated at the corresponding procedure. To the best of our knowledge, the synthesis of C-HSQ has not been reported so far.

General Procedure for the Preparation of Cinchona Alkaloid-Based Catalysts
To a solution of cinchona half squaramide (Q-HSQ or HQ-HSQ or C-HSQ, 0.482 mmol) in methanol (2.1 mL), a solution of aza-crown ether (1-aza-15-crown-5 ether or 1-aza-18crown-6 ether, 0.439 mmol) in methanol (2.1 mL) was added under argon atmosphere. The resulting mixture was warmed up to 60 • C, then it was stirred for 6 h at this temperature. The solvent was removed under reduced pressure, then the crude product was purified by column chromatography (SiO 2 ; DCM:methanol = 10:1) to obtain Q5 or Q6 or HQ5 or C5 or C6. To the best of our knowledge, the synthesis of C6 has not been reported so far.

Conclusions
In conclusion, we have described the synthesis of six new crown ether-squaramide phase-transfer organocatalysts bearing four different chiral units. To the best of our knowledge, this is the first successful direct coupling of squaramide and aza-crown-ether units and the first application of crown ether-squaramides as phase-transfer catalysts. We have tested their performance in the asymmetric α-alkylation of tert-butyl methyl α-benzylmalonate with extensive parameter investigation, after which reaction of the products could be converted to α,α-disubstituted amino acids through Curtius rearrangement. The alkylation reactions afforded the products in excellent yields, but with only low enantiomeric excess values. Thus, despite the low enantioselectivity, the new crown ether-based catalysts can catalyze the often-difficult construction of quaternary carbon centers. With the catalyst having the best enantioselectivity, a Michael addition reaction of tert-butyl methyl α-benzylmalonate was also conducted; however, no enantioselectivity was observed. Based on our results, we anticipate that a linker between the crown ether and the squaramide unit may potentially increase the enantioselectivity of this new type of phase-transfer catalyst, as two NH groups may form stronger hydrogen bonds during catalysis.