Synthesis and Catalytic Activity of Bifunctional Phase-Transfer Organocatalysts Based on Camphor

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of β-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate. α-Fluorination and chlorination of β-keto esters proceeded with full conversion and low enantioselectivities (up to 29% ee). Similarly, the Michael addition of a glycine Schiff base with methyl acrylate proceeded with full conversion and up to 11% ee. The new catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined.


Introduction
Since the seminal contributions of Wynberg [1], Dolling [2], and O'Donnell [3] in the 1970s and 1980s, in which chiral quaternary ammonium salts based on Cinchona alkaloids were used as catalysts for enantioselective epoxidations and α-alkylations of prochiral substrates, the use of chiral quaternary ammonium salts as phase-transfer catalysts (PTCs) has been successfully demonstrated in a multitude of asymmetric organic transformations and now represents an established fundamental catalysis principle in asymmetric organocatalysis [4][5][6][7][8]. In addition to Cinchona alkaloid-based PTCs, other chiral backbones have also been successfully used to access high-performance catalysts. A group of highly efficient binaphthyl-based ammonium salts was introduced by Maruoka (the so-called Maruoka catalysts) [9,10], which have since established themselves as the second most privileged class of chiral ammonium salt PTCs, alongside Cinchona alkaloids ( Figure 1). Over the years, efficient chiral quaternary ammonium salts based on tartaric acid [11,12], α-amino acids [13,14], trans-cyclohexane-1,2-diamine [15], and others [16] have been developed. Many of the developed quaternary ammonium salts, especially catalysts based on Cinchona alkaloids and some Maruoka-type catalysts, possess a hydrogen-bonding donor in the form of a OH group, which leads to improved catalytic properties [17]. The incorporation of (thio)urea-containing hydrogen bond donors in catalysts based on Cinchona alkaloids, and, in particular, in catalysts based on amino acids and cyclohexane-1,2-diamine, contributed significantly to the diversification of the available catalysts and extended the scope of catalyzed asymmetric transformations [13,15,18,19].  [20].
Camphor is one of nature's most privileged scaffolds, readily available in both enantiomeric forms. In addition, camphor undergoes a variety of interesting chemical transformations that functionalize, at first sight, inactive positions [21,22], allowing the synthesis of structurally and functionally very different products [23][24][25][26][27], thus making camphor a desirable starting material. The first reports on the application of camphor-derived organocatalysts date back to 2001. Camphor-derived phase-transfer organocatalysts were employed to catalyze the α-alkylation of a glycine Schiff base with enantioselectivities up to 39% ee ( Figure 1) [20]. Since then, several types of camphor-based organocatalysts have been reported, exhibiting covalent or noncovalent activation modes, both those with a camphor backbone as the sole chiral fragment and those in which the camphor backbone is covalently linked to a chiral amino acid, usually proline, via a suitable spacer [28].
As part of our ongoing study of camphor-based diamines as potential organocatalyst scaffolds [29], we reported the synthesis of 1,3-diamine-based bifunctional squaramide organocatalysts prepared from camphor and their application as efficient catalysts in Michael additions of 1,3-dicarbonyl compounds and pyrrolones as nucleophiles to trans-βnitrostyrene derivatives [30,31]. Extending this work, we report here the synthesis of a new type of 1,3-diamine-based bifunctional quaternary ammonium salt phase-transfer organocatalyst ( Figure 1) and its evaluation in the electrophilic α-functionalization of β-keto ester and the alkylation of a glycine-derived Schiff base with methyl acrylate.

Synthesis
Camphor-derived endo-diamines 1a,b and exo-diamines 2a were prepared in four steps from commercially available (1S)-(+)-10-camphorsulfonic acid (Scheme 1) [29,30]. Camphorsulfonic acid was transformed into 10-iodocamphor in an Apple-type reaction, followed by nucleophilic substitution with pyrrolidine or dimethylamine in dimethyl sulfoxide. The thus formed tertiary amines were transformed into the corresponding oximes. Camphor is one of nature's most privileged scaffolds, readily available in both enantiomeric forms. In addition, camphor undergoes a variety of interesting chemical transformations that functionalize, at first sight, inactive positions [21,22], allowing the synthesis of structurally and functionally very different products [23][24][25][26][27], thus making camphor a desirable starting material. The first reports on the application of camphor-derived organocatalysts date back to 2001. Camphor-derived phase-transfer organocatalysts were employed to catalyze the α-alkylation of a glycine Schiff base with enantioselectivities up to 39% ee ( Figure 1) [20]. Since then, several types of camphor-based organocatalysts have been reported, exhibiting covalent or noncovalent activation modes, both those with a camphor backbone as the sole chiral fragment and those in which the camphor backbone is covalently linked to a chiral amino acid, usually proline, via a suitable spacer [28].
As part of our ongoing study of camphor-based diamines as potential organocatalyst scaffolds [29], we reported the synthesis of 1,3-diamine-based bifunctional squaramide organocatalysts prepared from camphor and their application as efficient catalysts in Michael additions of 1,3-dicarbonyl compounds and pyrrolones as nucleophiles to transβ-nitrostyrene derivatives [30,31]. Extending this work, we report here the synthesis of a new type of 1,3-diamine-based bifunctional quaternary ammonium salt phase-transfer organocatalyst ( Figure 1) and its evaluation in the electrophilic α-functionalization of β-keto ester and the alkylation of a glycine-derived Schiff base with methyl acrylate.

Synthesis
Camphor-derived endo-diamines 1a,b and exo-diamines 2a were prepared in four steps from commercially available (1S)-(+)-10-camphorsulfonic acid (Scheme 1) [29,30]. Camphorsulfonic acid was transformed into 10-iodocamphor in an Apple-type reaction, followed by nucleophilic substitution with pyrrolidine or dimethylamine in dimethyl sulfoxide. The thus formed tertiary amines were transformed into the corresponding oximes. The final oxime reduction with sodium in isopropanol gave a mixture of the corresponding major endo-diamines 1a,b and minor exo-diamines 2a, separable by column chromatography.
The final oxime reduction with sodium in isopropanol gave a mixture of the corresponding major endo-diamines 1a,b and minor exo-diamines 2a, separable by column chromatography.
Next, the primary amino group of diamines 1a,b and 2a was Boc-protected, yielding 3a,b and 4a, respectively. In the following step, we introduced the benzyl group to the tertiary amine (benzyl groups have been very successfully established as useful motives for numerous quaternary ammonium salt phase-transfer catalysts [4][5][6][7][8]). Alkylation with benzyl bromide thus gave the quaternary ammonium salts 5a,b and 6a. Potassium carbonate was added to ensure complete conversion. They were subsequently Boc-deprotected with trifluoroacetic acid or aqueous hydrogen iodide, furnishing ammonium salts 7a,b and 8a, respectively (Scheme 1).
Finally, the ammonium salts 7a,b and 8a were reacted with aromatic iso(thio)cyanates 9 and squaramate 10 to give the quaternary trifluoroacetate ammonium salts I, IV, VI, VII, and IX. The quaternary iodide ammonium salts II, V, and VIII were formed from the corresponding trifluoroacetates I, IV, and VII, respectively, via anion metathesis with excess NaI in dichloromethane (Scheme 2). The quaternary iodide ammonium salts III and X were formed directly from the iodide ammonium salt 7b and the corresponding isothiocyanate. The catalysts thus formed have either (thio)urea or squaramide hydrogen bond donors (Supplementary Materials). Scheme 1. Synthesis of camphor-derived endo-7a,b and exo-quaternary ammonium salts 8a.
Next, the primary amino group of diamines 1a,b and 2a was Boc-protected, yielding 3a,b and 4a, respectively. In the following step, we introduced the benzyl group to the tertiary amine (benzyl groups have been very successfully established as useful motives for numerous quaternary ammonium salt phase-transfer catalysts [4][5][6][7][8]). Alkylation with benzyl bromide thus gave the quaternary ammonium salts 5a,b and 6a. Potassium carbonate was added to ensure complete conversion. They were subsequently Boc-deprotected with trifluoroacetic acid or aqueous hydrogen iodide, furnishing ammonium salts 7a,b and 8a, respectively (Scheme 1).
Finally, the ammonium salts 7a,b and 8a were reacted with aromatic iso(thio)cyanates 9 and squaramate 10 to give the quaternary trifluoroacetate ammonium salts I, IV, VI, VII, and IX. The quaternary iodide ammonium salts II, V, and VIII were formed from the corresponding trifluoroacetates I, IV, and VII, respectively, via anion metathesis with excess NaI in dichloromethane (Scheme 2). The quaternary iodide ammonium salts III and X were formed directly from the iodide ammonium salt 7b and the corresponding isothiocyanate. The catalysts thus formed have either (thio)urea or squaramide hydrogen bond donors (Supplementary Materials).

Structure Determination
The intermediates 3-8 were characterized by 1 H-and 13 C-NMR, IR, and HRMS. Compounds 1a and 2a were characterized by 1 H-NMR. Phase-transfer catalysts I-X have been fully characterized. The structures of the thioureas III and VI-Br (the bromide analog of the compound VI) were determined by single-crystal X-ray analysis ( Figure 2). In both structures, the endo-stereochemistry was confirmed at the C-2 chiral center. The conformational differences in the two structures in the solid state are shown in Figure 3. The main differences are due to the conformation of the benzyl group and the arylthiourea structural elements. Scheme 2. Synthesis of camphor-derived phase-transfer organocatalysts.

Structure Determination
The intermediates 3-8 were characterized by 1 H-and 13 C-NMR, IR, and HRMS. Compounds 1a and 2a were characterized by 1 H-NMR. Phase-transfer catalysts I-X have been fully characterized. The structures of the thioureas III and VI-Br (the bromide analog of the compound VI) were determined by single-crystal X-ray analysis ( Figure 2). In both structures, the endo-stereochemistry was confirmed at the C-2 chiral center. The conformational differences in the two structures in the solid state are shown in Figure 3. The main differences are due to the conformation of the benzyl group and the arylthiourea structural elements.
The endo-stereochemistry at the C-2 chiral center of compounds III-X was further confirmed by NOESY measurements based on the cross-peak between the methyl group and the exo-H(2) proton ( Figure 4). Similarly, the exo-stereochemistry at the C-2 chiral center of compounds I and II was in line with the cross-peak between the methyl group and the exo-H-N proton observed in the NOESY spectra (Supplementary Materials).  The endo-stereochemistry at the C-2 chiral center of compounds III-X was further confirmed by NOESY measurements based on the cross-peak between the methyl group and the exo-H(2) proton ( Figure 4). Similarly, the exo-stereochemistry at the C-2 chiral center of compounds I and II was in line with the cross-peak between the methyl group and the exo-H-N proton observed in the NOESY spectra (Supplementary Materials).
Finally, the stereochemistry at the C-2 chiral center can be correlated on the basis of the multiplicity of the H-C(3)-endo proton (He) (Figure 4). Exclusively in the endo-isomes of compounds 1, 3, 5, 7, and III-X, the H-C(3)-endo proton appears as a doublet of doublet between 0.67 and 1.35 ppm (Table S7 in Supplementary Materials).  The endo-stereochemistry at the C-2 chiral center of compounds III-X was further confirmed by NOESY measurements based on the cross-peak between the methyl group and the exo-H(2) proton ( Figure 4). Similarly, the exo-stereochemistry at the C-2 chiral center of compounds I and II was in line with the cross-peak between the methyl group and the exo-H-N proton observed in the NOESY spectra (Supplementary Materials).
Finally, the stereochemistry at the C-2 chiral center can be correlated on the basis of the multiplicity of the H-C(3)-endo proton (He) (Figure 4). Exclusively in the endo-isomes of compounds 1, 3, 5, 7, and III-X, the H-C(3)-endo proton appears as a doublet of doublet between 0.67 and 1.35 ppm (Table S7 in Supplementary Materials).

Organocatalytic Activity
First, the organocatalytic activity of camphor-derived phase-transfer organocatalysts I-IX was tested in electrophilic functionalizations of β-keto ester 9 (Scheme 3). Details of  Finally, the stereochemistry at the C-2 chiral center can be correlated on the basis of the multiplicity of the H-C(3)-endo proton (H e ) ( Figure 4). Exclusively in the endo-isomes of compounds 1, 3, 5, 7, and III-X, the H-C(3)-endo proton appears as a doublet of doublet between 0.67 and 1.35 ppm (Table S7 in Supplementary Materials).

Organocatalytic Activity
First, the organocatalytic activity of camphor-derived phase-transfer organocatalysts I-IX was tested in electrophilic functionalizations of β-keto ester 9 (Scheme 3). Details of the optimization reactions can be found in the Supporting Information. The asymmetric α-fluorination of β-keto ester 9 with N-fluorobenzenesulfonimide (NFSI) proceeded under complete conversion and gave the product 10 with low enantioselectivity (87% yield and up to 29% ee). The best result was obtained with the catalyst VIII in toluene in the presence of K 3 PO 4 . In contrast, up to 86% ee has been reported in the literature for the α-fluorination of β-keto ester 9 with NFSI [15,32]. Similarly, the α-chlorination of 9 with N-chlorosuccinimide (NCI) gave product 11 in complete conversion and a meager 7% ee when squaramide PTC IX was used (for comparison, up to 80% ee has been reported in the literature when using alternative catalyst scaffolds [33]). Disappointingly, both the α-hydroxylation [34] of 9 with tosylimine 12/H 2 O 2 and the ring opening of arylaziridine 14 [35] with 9 did not give the expected products 13 and 16, respectively. In both cases, no conversion was observed. Finally, the asymmetric Michael addition of glycine Schiff base 16 to methyl acrylate (17) was investigated, with up to 90% ee reported in the literature [36]. Catalyst V gave the expected product 18 with full conversion but low enantioselectivity (11% ee).

Materials and Methods
Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical-grade anhydrous Na2SO4. Melting points were determined on a Kofler micro hot stage. The NMR spectra were obtained on a Bruker Avance DPX 300 and Bruker Avance III 300 at 300 MHz for 1 H nucleus, Bruker

Materials and Methods
Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical-grade anhydrous Na 2 SO 4 . Melting points were determined on a Kofler micro hot stage. The NMR spectra were obtained on a Bruker Avance DPX 300 and Bruker Avance III 300 at 300 MHz for 1 H nucleus, Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) at 500 MHz for 1 H and 126 MHz for 13 C nucleus, and Bruker Ascend 600 (Bruker, Billerica, MA, USA) at 600 MHz for 1 H and 151 MHz for 13 C nucleus, using DMSO-d 6 and CDCl 3 , with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA, USA), and IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA). CD spectra were recorded on a J-1500 Circular Dichroism Spectrophotometer (JASCO corporation, Tokyo, Japan). Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size:

Benzylation of Tertiary Amines-General Procedure 2 (GP2)
To a stirred mixture of tertiary amine 3 or 4 and K 2 CO 3 (1.1 equivalents) in anhydrous DMF was added benzyl bromide (1.1 equivalents). The resulting reaction mixture was stirred at 25 • C for 24 h. DMF was evaporated in vacuo and the residue was purified by column chromatography (CC). The fractions containing product 5 or 6 were combined and the volatiles were evaporated in vacuo.    13

Synthesis of Phase-Transfer Bifunctional Catalysts-General Procedure 4 (GP4)
Amine 7 or 8 was dissolved in anhydrous CH 2 Cl 2 , the appropriate electrophile was added (1.2-1.4 equivalents), and the reaction mixture was stirred for 16 h at room temperature. The volatiles were evaporated in vacuo. The residue was purified by column chromatography (CC). The fractions containing product I-X were combined and the volatiles were evaporated in vacuo.

Trifluoroacetate Anion Exchange-General Procedure 5 (GP5)
The column was packed with NaI (5 g) and conditioned with ethyl acetate. The trifluoroacetate phase-transfer catalyst was dissolved in ethyl acetate and applied to the NaI column. The fractions containing the product were combined and the volatiles were evaporated in vacuo. Based on the 19 F NMR spectra (presence of a signal for fluorine from trifluoroacetate anion), the procedure was repeated as necessary.   (17) Degassed solvent (2.5 mL) was added to a mixture of tert-butyl 2-((diphenylmethylene)amino) acetate (16) (0.05 mmol, 14.8 mg), catalyst I, III-V, VII, VIII, or IX (10 mol%), and Cs 2 CO 3 (1.5-10.0 equivalents) in a Schlenk tube at 25 • C or 0 • C; then, methyl acrylate (17) (1.5 equivalents, 6.8 µL) was added. After 24 h at 25 • C or 0 • C, the reaction mixture was filtrated through a plug of anhydrous Na 2 SO 4 and washed with ethyl acetate. The volatiles were evaporated in vacuo. The crude product 18 was purified by column chromatography (Silica gel 60, EtOAc/Heptane = 1:15). Enantiomeric excess (ee) was determined by HPLC (Chiralpak AD-H, n-Hexane/i-PrOH = 95:5, flow rate 0.5 mL/min, λ = 250 nm, 10 • C) after filtration of the reaction mixture through a plug of Na 2 SO 4 .

X-ray Crystallography
Single-crystal X-ray diffraction data were collected on an Agilent Technologies Su-perNova Dual diffractometer with an Atlas detector using monochromated Mo-K α radiation (λ = 0.71073 Å) at 150 K. The data were processed using CrysAlis PRO [37]. Using Olex2.1.2. [38], the structures were solved by direct methods implemented in SHELXS [39] or SHELXT [40] and refined by a full-matrix least-squares procedure based on F 2 with SHELXT-2014/7 [41]. All nonhydrogen atoms were refined anisotropically. Hydrogen atoms were placed in geometrically calculated positions and were refined using a riding model. The drawings and the analysis of bond lengths, angles, and intermolecular interactions were carried out using Mercury [42] and Platon [43]. Structural and other crystallographic details on data collection and refinement for compounds VI-Br and III have been deposited with the Cambridge Crystallographic Data Centre as a supplementary publication under CCDC Deposition Numbers 2204647 and 2204648, respectively. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).

Conclusions
Ten novel quaternary ammonium salt bifunctional phase-transfer organocatalysts based on a chiral (+)-camphor framework were prepared. Starting from camphor-derived 1,3-diamines, catalysts I-X were synthesized in a four-step sequence: Boc protectionbenzylation-Boc deprotection-reaction with iso(thio)cyanate/squaramate. The catalysts prepared bear either a (thio)urea or squaramide hydrogen bond donor and possess either a trifluoroacetate or iodide counteranion. The quaternary iodide ammonium salts II, V, and VIII were formed from the corresponding trifluoroacetates I, IV, and VII, respectively, via anion methathesis with an excess of NaI. The phase-transfer catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined. Their organocatalytic activity was investigated in the electrophilic functionalization of the β-keto ester 9. The α-fluorination and chlorination of β-keto ester 9 proceeded to full conversion, affording the desired products 10 and 11 with low enantioselectivity (up to 29% ee). α-Hydroxylation and ring opening of N-tosylaziridine 14 gave no product. Finally, the Michael addition of glycine Schiff base 16 to methyl acrylate (17) gave the expected product 18 with full conversion and up to 11% ee.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules28031515/s1. Synthesis and characterization data; HPLC data; copies of 1 H-and 13 C-NMR spectra; copies of HRMS reports; structure determination by X-ray diffraction analysis. Figure S1. Applied organocatalysts I-IX. Figure S2. Molecular structure of compound VI-Br. Thermal ellipsoids are shown at 50% probability. Figure S3. Molecular structure of compound III. Thermal ellipsoids are shown at 50% probability. Table S1. Evaluation of organocata-lysts I-IX in the fluorination of β-keto ester 9. Table S2. Further evaluation of organocatalysts III, VIII, and IX in the fluorination of β-keto ester 9. Table S3. Evaluation of organocatalysts II, III, VI-VIII, and IX in the chlorination of β-keto ester 9. Table S4. Evaluation of organocatalysts III, IV, VII, VIII, and IX in the hydroxylation of β-keto ester 9. Table S5. Evaluation of organocatalysts IV, VIII, and IX in the addition of β-keto ester 9 to tosylaziridine 14. Table S6. Evaluation of organocatalysts I, III-V, VII, VIII, and IX in the addition of tert-butyl 2-((diphenylmethylene)amino)acetate (16) to methyl acrylate (17). Table S7. Correlation between the multiplicity of the H-C(3)-endo proton (He) and the endo absolute configuration at the C-2 chiral center of compounds 1a, 3b, 5a, 7a,b, and III-X. Table S8. Crystal data and structure refinement for compound VI-Br. Table S9. Crystal data and structure refinement for compound III.