Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags

The effect of the presence of fluorous tags in bisoxazoline ligands on the stereoselectivity of the cobalt-catalyzed asymmetric Henry reaction was investigated. In contrast to the stereoselectivity obtained with conventional nonfluorous ligands, using bisoxazoline bidentate ligands featuring two fluorous tags in adjacent positions on the aromatic ring yielded a reversed stereoselectivity. The stereoselectivity also reversed when the fluorous tags were replaced with alkyl chains of equivalent length, albeit to a considerably lesser degree, highlighting the effect of the fluorous tags.

BOX ligands bearing fluorous tags are particularly interesting because they repel water and polar organic compounds while exhibiting a strong mutual affinity [19] among fluorous molecules.These ligands, which have been used in asymmetric reactions including allylic alkylation [20], cyclopropanation [21], and the Henry reaction [22], can be selectively isolated and recovered from reaction mixtures via solid-phase extraction using fluorous silica gel [23] or liquid-phase extraction using fluorous solvents [24].By incorporating a fluorous tag into the BOX ligand for the first time in asymmetric Henry reactions, Cai et al. achieved high stereoselectivity and recovery [22].Our study involves the use of BOX ligands incorporating two fluorous tags at different positions on the ligand in asymmetric Henry reactions.
Previously, we achieved the first asymmetric epoxidation of an isolated carbon-carbon double bond using an iron salen complex incorporating a fluorous tag at the 3,3 -position of the salen ligand [25].Apart from its recycling ability, this complex exhibits a unique characteristic stemming from the two fluorous tags; namely, the conformational fixation via intramolecular stacking between neighboring fluorous tags forms a distorted asymmetric structure and creates a unique catalytic reaction field.We postulated that the introduction of two adjacent fluorous tags on freely rotatable substituents in BOX ligands could lock the coordination in place through a stacking between the tags, which would lead to different reactivity and stereoselectivity compared with conventional catalysts.Therefore, we synthesized a series of BOX ligands containing two fluorous tags and investigated their reactivity and stereoselectivity in the asymmetric Henry reaction [26], which is a useful carbon-carbon bond formation reaction.Here, we describe an asymmetric Henry reaction using BOX bidentate ligands 1a-1d with two fluorous tags introduced in spatially adjacent positions and pincer-type BOX tridentate ligand 1e (Figure 1).For bisoxazoline catalysts, fluorous tag catalysts via flexible benzyl spacers (1a and 1b) and more rigid aryl-type fluorous catalysts (1c and 1d) were investigated.Ligands with freely rotating methylene groups (1a and 1b) and ligands with rigid aromatic planar ring structures (1c and 1d) have different steric environments, potentially resulting in significant differences in stereoselectivity.
lead to different reactivity and stereoselectivity compared with conventional catalysts Therefore, we synthesized a series of BOX ligands containing two fluorous tags and investigated their reactivity and stereoselectivity in the asymmetric Henry reaction [26 which is a useful carbon-carbon bond formation reaction.Here, we describe a asymmetric Henry reaction using BOX bidentate ligands 1a-1d with two fluorous tag introduced in spatially adjacent positions and pincer-type BOX tridentate ligand 1 (Figure 1).For bisoxazoline catalysts, fluorous tag catalysts via flexible benzyl spacers (1 and 1b) and more rigid aryl-type fluorous catalysts (1c and 1d) were investigated.Ligand with freely rotating methylene groups (1a and 1b) and ligands with rigid aromatic plana ring structures (1c and 1d) have different steric environments, potentially resulting i significant differences in stereoselectivity.

Results and Discussions
Scheme 1 outlines the synthetic pathway for bidentate ligands 1a and 1b.Firs methylation of 4-iodo-L-phenylalanine 2 afforded 3, which was Boc-protected to yield compound 4. Subsequently, the introduction of C4F9 and C8F17 fluorous tags was achieve via Ullmann coupling, resulting in intermediates 5a and 5b, respectively.After este reduction and removal of the Boc group, compounds 7a and 7b were obtained.Th synthesis culminated with the condensation with dimethylmalonyl chloride and subsequent cyclization, furnishing oxazoline ligands 1a and 1b bearing the C4F9 and C8F tags, respectively.Ligands 1c and 1d were synthesized following the reaction pathway outlined i Scheme 2. (S)-2-Phenylglycinol 9 was iodinated to obtain compound 10.Afte

Results and Discussions
Scheme 1 outlines the synthetic pathway for bidentate ligands 1a and 1b.First, methylation of 4-iodo-L-phenylalanine 2 afforded 3, which was Boc-protected to yield compound 4. Subsequently, the introduction of C 4 F 9 and C 8 F 17 fluorous tags was achieved via Ullmann coupling, resulting in intermediates 5a and 5b, respectively.After ester reduction and removal of the Boc group, compounds 7a and 7b were obtained.The synthesis culminated with the condensation with dimethylmalonyl chloride and subsequent cyclization, furnishing oxazoline ligands 1a and 1b bearing the C 4 F 9 and C 8 F 17 tags, respectively.
Therefore, we synthesized a series of BOX ligands containing two fluorous tags and investigated their reactivity and stereoselectivity in the asymmetric Henry reaction [26], which is a useful carbon-carbon bond formation reaction.Here, we describe an asymmetric Henry reaction using BOX bidentate ligands 1a-1d with two fluorous tags introduced in spatially adjacent positions and pincer-type BOX tridentate ligand 1e (Figure 1).For bisoxazoline catalysts, fluorous tag catalysts via flexible benzyl spacers (1a and 1b) and more rigid aryl-type fluorous catalysts (1c and 1d) were investigated.Ligands with freely rotating methylene groups (1a and 1b) and ligands with rigid aromatic planar ring structures (1c and 1d) have different steric environments, potentially resulting in significant differences in stereoselectivity.

Results and Discussions
Scheme 1 outlines the synthetic pathway for bidentate ligands 1a and 1b.First, methylation of 4-iodo-L-phenylalanine 2 afforded 3, which was Boc-protected to yield compound 4. Subsequently, the introduction of C4F9 and C8F17 fluorous tags was achieved via Ullmann coupling, resulting in intermediates 5a and 5b, respectively.After ester reduction and removal of the Boc group, compounds 7a and 7b were obtained.The synthesis culminated with the condensation with dimethylmalonyl chloride and subsequent cyclization, furnishing oxazoline ligands 1a and 1b bearing the C4F9 and C8F17 tags, respectively.As a control ligand, unsubstituted ligand 14 [27] without fluorous synthesized from (S)-2-phenylglycinol 9 via a condensation reaction w malonyl chloride followed by cyclization (Scheme 3).First, the as-synthesized fluorous BOX ligands were investigated as ch the Henry reaction.Using p-nitrobenzaldehyde and nitromethane as subst metal sources were employed in the Henry reaction in the presence of ligan When Cu(OAc)2•H2O was utilized, the reaction proceeded with a 97% conve enantiomeric excess (ee), predominantly yielding the S-aldol addition pro entry 1).In contrast, no reaction occurred when using CuCl2, CuBr2, or Cu(O entries 2-4).Meanwhile, Co(OAc)2 and Zn(OAc)2 gave high conversion ra racemic products (Table 1, entries 5 and 6).Therefore, Cu(OAc)2•H2O was s metal source for subsequent reactions.As a control ligand, unsubstituted ligand 14 [27] without fluorous tags was also synthesized from (S)-2-phenylglycinol 9 via a condensation reaction with dimethyl malonyl chloride followed by cyclization (Scheme 3).As a control ligand, unsubstituted ligand 14 [27] without fluorous tag synthesized from (S)-2-phenylglycinol 9 via a condensation reaction with malonyl chloride followed by cyclization (Scheme 3).First, the as-synthesized fluorous BOX ligands were investigated as chira the Henry reaction.Using p-nitrobenzaldehyde and nitromethane as substrat metal sources were employed in the Henry reaction in the presence of ligand 1 When Cu(OAc)2•H2O was utilized, the reaction proceeded with a 97% conversio enantiomeric excess (ee), predominantly yielding the S-aldol addition produ entry 1).In contrast, no reaction occurred when using CuCl2, CuBr2, or Cu(OT entries 2-4).Meanwhile, Co(OAc)2 and Zn(OAc)2 gave high conversion rates racemic products (Table 1, entries 5 and 6).Therefore, Cu(OAc)2•H2O was sele metal source for subsequent reactions.First, the as-synthesized fluorous BOX ligands were investigated as chiral ligands in the Henry reaction.Using p-nitrobenzaldehyde and nitromethane as substrates, various metal sources were employed in the Henry reaction in the presence of ligand 1a in i PrOH.When Cu(OAc) 2 •H 2 O was utilized, the reaction proceeded with a 97% conversion and 69% enantiomeric excess (ee), predominantly yielding the S-aldol addition product (Table 1, entry 1).In contrast, no reaction occurred when using CuCl 2 , CuBr 2 , or Cu(OTf) 2 (Table 1, entries 2-4).Meanwhile, Co(OAc) 2 and Zn(OAc) 2 gave high conversion rates but nearly racemic products (Table 1, entries 5 and 6).Therefore, Cu(OAc) 2 •H 2 O was selected as the metal source for subsequent reactions.
Next, fluorophobic ( i PrOH and 50% i PrOH aqueous solution) and fluorophilic solvents (THF and FC-72) were employed as reaction media using ligands 1a-d to investigate the solvent effect in the reaction.Although differences in affinity between the fluorinated ligands and solvents were expected to affect the stereoselectivity, no remarkable impact on stereoselectivity was observed in reactions using 1a and 1b.When catalysts (1a and 1b) with fluorous tags via benzyl spacers were used, a moderate level of stereoselectivity was obtained in favor of the formation of S-aldol addition products in all cases.(Table 2, entries 1-7).metal sources were employed in the Henry reaction in the presence of ligand 1a in i PrOH.When Cu(OAc)2•H2O was utilized, the reaction proceeded with a 97% conversion and 69% enantiomeric excess (ee), predominantly yielding the S-aldol addition product (Table 1, entry 1).In contrast, no reaction occurred when using CuCl2, CuBr2, or Cu(OTf)2 (Table 1, entries 2-4).Meanwhile, Co(OAc)2 and Zn(OAc)2 gave high conversion rates but nearly racemic products (Table 1, entries 5 and 6).Therefore, Cu(OAc)2•H2O was selected as the metal source for subsequent reactions.Zn(OAc) 2 96 3 1 Determined by 1 H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chiral highperformance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex: i PrOH = 80:20, 1.0 mL/min). 3The absolute configuration of the aldol adduct was determined by comparison with previously published data [13].
Next, fluorophobic ( i PrOH and 50% i PrOH aqueous solution) and fluorophili solvents (THF and FC-72) were employed as reaction media using ligands 1a-d to investigate the solvent effect in the reaction.Although differences in affinity between th fluorinated ligands and solvents were expected to affect the stereoselectivity, no remarkable impact on stereoselectivity was observed in reactions using 1a and 1b.When catalysts (1a and 1b) with fluorous tags via benzyl spacers were used, a moderate level o stereoselectivity was obtained in favor of the formation of S-aldol addition products in al cases.(Table 2, entries 1-7).
Interestingly, when fluorous ligands 1c and 1d were used as chiral sources, th reverse stereoselectivity was observed even though all ligands 1a-1d exhibited the sam absolute stereochemistry (S,S), favoring the R-aldol addition product with moderat stereoselectivity (Table 2, entries 8-13 vs. entries [1][2][3][4][5][6][7]14).This result suggests that th fluorinated aryl BOX ligands at the 2′ position (1c and 1d) create a distinct asymmetri environment compared with the other ligands used.Although there was no substantia difference in stereoselectivity based on differences in reaction solvent and tag length in either case, the combination of ligand 1c and i PrOH yielded the highest revers stereoselectivity (53% ee) (Table 2, entry 8). 1 Determined by 1 H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chira high-performance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex: i PrOH = 80:20, 1. mL/min). 3 The absolute configuration of the aldol adduct was determined through comparison with previously published data [13].* Represents the asymmetric carbon.
A control experiment was conducted using ligand 19, which is the nonfluorinated version of 1c, under the same conditions.Interestingly, as in the case of fluorinated ligand 1c, a preference for the aldol addition to the R-isomer was observed.However, th stereoselectivity drastically decreased to 14% ee (Table 2, entry 15).These results indicat that the steric bulkiness at the 2′-position on the aryl-type BOX ligand is a factor tha 1 Determined by 1 H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chiral highperformance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex: i PrOH = 80:20, 1.0 mL/min). 3The absolute configuration of the aldol adduct was determined through comparison with previously published data [13].* Represents the asymmetric carbon.
Interestingly, when fluorous ligands 1c and 1d were used as chiral sources, the reverse stereoselectivity was observed even though all ligands 1a-1d exhibited the same absolute stereochemistry (S,S), favoring the R-aldol addition product with moderate stereoselectivity (Table 2, entries 8-13 vs. entries [1][2][3][4][5][6][7]14).This result suggests that the fluorinated aryl BOX ligands at the 2 position (1c and 1d) create a distinct asymmetric environment compared with the other ligands used.Although there was no substantial difference in stereoselectivity based on differences in reaction solvent and tag length in either case, the combination of ligand 1c and i PrOH yielded the highest reverse stereoselectivity (53% ee) (Table 2, entry 8).
A control experiment was conducted using ligand 19, which is the nonfluorinated version of 1c, under the same conditions.Interestingly, as in the case of fluorinated ligand 1c, a preference for the aldol addition to the R-isomer was observed.However, the stereoselectivity drastically decreased to 14% ee (Table 2, entry 15).These results indicate that the steric bulkiness at the 2 -position on the aryl-type BOX ligand is a factor that reverses the stereoselectivity.Introducing a fluorous tag at the 2 -position does not substantially affect the reaction result, but it does affect the stereoselectivity more than the corresponding nonfluorous alkyl substituent.Note that ligand 19 was synthesized using the route depicted in Scheme 4.
Molecules 2023, 28, x FOR PEER REVIEW 5 of 16 reverses the stereoselectivity.Introducing a fluorous tag at the 2′-position does not substantially affect the reaction result, but it does affect the stereoselectivity more than the corresponding nonfluorous alkyl substituent.Note that ligand 19 was synthesized using the route depicted in Scheme 4. Next, pincer-type fluorinated ligand 1e, which was synthesized using the route depicted in Scheme 5, was applied to the present reaction.Briefly, iodinated compound 15 was first protected with Boc and then the C4F9 tag was introduced via the Ullmann reaction, forming intermediate 20.Under acidic conditions, both the TBS and Boc groups were simultaneously removed, and the subsequent condensation reaction with 2,6pyridinedicarbonyl dichloride yielded 22. Finally, ligand 1e was synthesized through a ring-closure reaction using DAST.Furthermore, unsubstituted ligand 24 [28] was synthesized as a control ligand via condensation and cyclization reactions with 2,6pyridinedicarbonyl dichloride using (S)-2-phenylglycinol 9 as the substrate (Scheme 6).Table 3 shows the results of asymmetric Henry reactions using pincer-type ligands 1e and 2. The combination of 1e and Co(OAc)2 afforded the R-addition product with slightly higher stereoselectivity than that obtained when using Cu(OAc)2•H2O or Zn(OAc)2 (Table 3, entries 1-3).
Solvent effects were investigated using a 50% i PrOH aqueous solution, THF, and FC-72 as reaction solvents (Table 3, entries 4-6).The reaction proceeded quantitatively in a Next, pincer-type fluorinated ligand 1e, which was synthesized using the route depicted in Scheme 5, was applied to the present reaction.Briefly, iodinated compound 15 was first protected with Boc and then the C 4 F 9 tag was introduced via the Ullmann reaction, forming intermediate 20.Under acidic conditions, both the TBS and Boc groups were simultaneously removed, and the subsequent condensation reaction with 2,6-pyridinedicarbonyl dichloride yielded 22. Finally, ligand 1e was synthesized through a ring-closure reaction using DAST.Furthermore, unsubstituted ligand 24 [28] was synthesized as a control ligand via condensation and cyclization reactions with 2,6-pyridinedicarbonyl dichloride using (S)-2-phenylglycinol 9 as the substrate (Scheme 6).
Molecules 2023, 28, x FOR PEER REVIEW 5 reverses the stereoselectivity.Introducing a fluorous tag at the 2′-position does substantially affect the reaction result, but it does affect the stereoselectivity more than corresponding nonfluorous alkyl substituent.Note that ligand 19 was synthesized u the route depicted in Scheme 4. Next, pincer-type fluorinated ligand 1e, which was synthesized using the r depicted in Scheme 5, was applied to the present reaction.Briefly, iodinated compo 15 was first protected with Boc and then the C4F9 tag was introduced via the Ullm reaction, forming intermediate 20.Under acidic conditions, both the TBS and Boc gro were simultaneously removed, and the subsequent condensation reaction with pyridinedicarbonyl dichloride yielded 22. Finally, ligand 1e was synthesized throu ring-closure reaction using DAST.Furthermore, unsubstituted ligand 24 [28] synthesized as a control ligand via condensation and cyclization reactions with pyridinedicarbonyl dichloride using (S)-2-phenylglycinol 9 as the substrate (Scheme Table 3 shows the results of asymmetric Henry reactions using pincer-type liga 1e and 2. The combination of 1e and Co(OAc)2 afforded the R-addition product w slightly higher stereoselectivity than that obtained when using Cu(OAc)2•H2O Zn(OAc)2 (Table 3, entries 1-3).
Solvent effects were investigated using a 50% i PrOH aqueous solution, THF, and Next, pincer-type fluorinated ligand 1e, which was synthesized using the route depicted in Scheme 5, was applied to the present reaction.Briefly, iodinated compound 15 was first protected with Boc and then the C4F9 tag was introduced via the Ullmann reaction, forming intermediate 20.Under acidic conditions, both the TBS and Boc groups were simultaneously removed, and the subsequent condensation reaction with 2,6pyridinedicarbonyl dichloride yielded 22. Finally, ligand 1e was synthesized through a ring-closure reaction using DAST.Furthermore, unsubstituted ligand 24 [28] was synthesized as a control ligand via condensation and cyclization reactions with 2,6pyridinedicarbonyl dichloride using (S)-2-phenylglycinol 9 as the substrate (Scheme 6).Table 3 shows the results of asymmetric Henry reactions using pincer-type ligands 1e and 2. The combination of 1e and Co(OAc)2 afforded the R-addition product with slightly higher stereoselectivity than that obtained when using Cu(OAc)2•H2O or Zn(OAc)2 (Table 3, entries 1-3).
Table 3 shows the results of asymmetric Henry reactions using pincer-type ligands 1e and 2. The combination of 1e and Co(OAc) 2 afforded the R-addition product with slightly higher stereoselectivity than that obtained when using Cu(OAc) 2 •H 2 O or Zn(OAc) 2 (Table 3, entries 1-3).50% i PrOH aqueous solution but with little stereoselectivity.Using THF resulted in better stereoselectivity, and the target product was obtained with an optical purity of 42% ee.The reaction did not proceed when the fluorous solvent FC-72 was used.
The R-product was predominantly obtained in experiments conducted in THF with pincer-type ligand 24 lacking fluorous tags.However, the stereoselectivity was lower (8% ee) than when using fluorous 1e (Table 3, entry 5 vs. entry 7).This suggests that introducing the fluorous tags into the pincer-type ligand enhances the stereoselectivity of this reaction. 1Determined by 1 H Nuclear magnetic resonance (NMR) of the crude product. 2 Determined by chiral high-performance liquid chromatography (HPLC) (Chiralpak IA-3 column, hex: i PrOH = 80:20, 1.0 mL/min). 3The absolute configuration of the aldol adduct was determined through comparison with previously published data [13].* Represents the asymmetric carbon.

Materials and Reagents
All the laboratory chemicals were purchased from Tokyo Chemical Industry Co., Ltd.(Tokyo, Japan), FUJIFILM Wako Pure Chemical Corporation (Richmond, VA, USA), Sigma-Aldrich Co. LLC (St. Louis, MO, USA), and Kanto Chemical Co., Inc. (Tokyo, Japan) and used without further purification unless otherwise stated.Solvents were removed using rotary evaporation under reduced pressure using a water bath at 40 °C-50 °C.Nonvolatile compounds were dried in vacuo at 0.01 mbar.All reactions were stirred magnetically and monitored using thin-layer chromatography using silica gel plates.Purification by chromatography was performed on silica gel 60 N (spherical, neutral, 63-210 µm, Kanto Chemical Co., Inc.).

Entry
Solvent effects were investigated using a 50% i PrOH aqueous solution, THF, and FC-72 as reaction solvents (Table 3, entries 4-6).The reaction proceeded quantitatively in a 50% i PrOH aqueous solution but with little stereoselectivity.Using THF resulted in better stereoselectivity, and the target product was obtained with an optical purity of 42% ee.The reaction did not proceed when the fluorous solvent FC-72 was used.
The R-product was predominantly obtained in experiments conducted in THF with pincer-type ligand 24 lacking fluorous tags.However, the stereoselectivity was lower (8% ee) than when using fluorous 1e (Table 3, entry 5 vs. entry 7).This suggests that introducing the fluorous tags into the pincer-type ligand enhances the stereoselectivity of this reaction.

Materials and Reagents
All the laboratory chemicals were purchased from Tokyo Chemical Industry Co., Ltd.(Tokyo, Japan), FUJIFILM Wako Pure Chemical Corporation (Richmond, VA, USA), Sigma-Aldrich Co. LLC (St. Louis, MO, USA), and Kanto Chemical Co., Inc. (Tokyo, Japan) and used without further purification unless otherwise stated.Solvents were removed using rotary evaporation under reduced pressure using a water bath at 40 • C-50 • C. Nonvolatile compounds were dried in vacuo at 0.01 mbar.All reactions were stirred magnetically and monitored using thin-layer chromatography using silica gel plates.Purification by chromatography was performed on silica gel 60 N (spherical, neutral, 63-210 µm, Kanto Chemical Co., Inc.).

General Procedure for the Henry Reaction
A mixture of the ligand (0.012 mmol) and the metal salt (0.011 mmol) was stirred in a solvent (328 µL) at room temperature for 1 h.Aldehyde (0.22 mmol) and MeNO 2 (2.19 mmol) were added to the reaction mixture, which was then stirred at room temperature for 22 h.The reaction mixture was concentrated.The conversion was determined by 1 H NMR analysis of the crude product.The ee of the product was determined with HPLC of the crude product.

Table 2 .
Asymmetric Henry reaction using fluorous ligands

1a-d and control ligand 14. Entry Ligand Solvent Conv. (%) 1 ee (%) 2 Config. 3
Introducing a fluorous tag at the 2′-position does not substantially affect the reaction result, but it does affect the stereoselectivity more than the corresponding nonfluorous alkyl substituent.Note that ligand 19 was synthesized using the route depicted in Scheme 4.