Letter pubs.acs.org/OrgLett
Application of a Heterogeneous Chiral Titanium Catalyst Derived from Silica-Supported 3‑Aryl H8‑BINOL to Enantioselective Alkylation and Arylation of Aldehydes Junichiro Akai, Satoshi Watanabe, Kumiko Michikawa, and Toshiro Harada* Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan S Supporting Information *
ABSTRACT: A 3-aryl H8-BINOL was grafted on the surface of silica gel using a hydrosilane derivative as a precursor, and the resulting silica-supported ligand (6 mol %) was employed in the enantioselective alkylation and arylation of aldehydes in the presence of Ti(OiPr)4. The reactions using Et2Zn, Et3B, and aryl Grignard reagents all afforded the corresponding adducts in high enantioselectivities and yields. The silicaimmobilized titanium catalyst could be reused up to 14 times without appreciable deterioration of the activity.
T
enantioselective carbonyl addition reactions.10 Despite the recent development of efficient polymer-supported catalysts,11 with very few exceptions,11e reported immobilized catalysts have been developed and evaluated for the reaction of diorganozincs, particularly Et2Zn. The high activity of the chiral titanium catalysts derived from 3-aryl-H8-BINOLs 1a,b prompted us to immobilize them on solid supports in anticipation of developing a practical method for the enantioselective alkylation and arylation using conventional organometallic reagents other than diorganozincs. Herein, we report a preliminary result of the study along these lines, which demonstrates the potential of silica-supported 3-aryl-(SSA-)H8BINOL (R)-5 in practical use. Silica was chosen as supports because of the high mechanical strength, thermal stability, and chemical robustness.12,7c Although the reaction of alkoxysilyl precursors is commonly used to bind an organic moiety on the silica surface, purification of the precursors is often hampered by the instability toward hydrolysis. We adopted surface functionalization of silica by Si− H activation through catalysis by B(C6F5)3, reported recently by Shimada and co-workers,13 because the method is not only rapid and efficient but also has an advantage that requisite hydrosilyl precursors can be fully purified by silica gel column chromatography.14 Thus, 3-aryl-H8-BINOL (R)-4 bearing a hydrosilyl group was prepared starting from pinacol borate ester (R)-215 (Scheme 2). The palladium-catalyzed cross-coupling reaction with 1allyl-3-bromo-5-tert-butylbenzene followed by exchange of the hydroxy protecting group gave bis-TMS ether derivative (R)-3 in 89% yield. Iridium-catalyzed hydrosilylation16 of (R)-3 with HSiMe2Cl and subsequent reduction of the chorodimethylsilyl group afforded (R)-4 in 77% yield after purification with silica gel chromatography.13 Grafting of (R)-4 was performed by
he catalytic enantioselective addition of organometallic reagents to aldehydes is one of the most straightforward methods for the synthesis of enantioenriched chiral secondary alcohols.1 Although relatively less reactive diorganozinc reagents2 were previously used in the reaction, the scope of the nucleophiles has been recently expanded to other organometallic reagents,3 including more reactive, hence, more difficult to be tamed, Grignard4 and organolithium5 reagents, by the development of highly active chiral catalyst systems. Recent reports from this laboratory have revealed the remarkably high activity of chiral titanium catalysts derived from BINOLs, such as DPP-H8-BINOL 1a and DTBP-H8BINOL 1b, bearing a sterically demanding aryl group at the 3 position, enabling the use of a variety of organometallic reagents (RM; M = MgX, Li, ZnX, BR′2, AlMe2) in the enantioselective addition to aldehydes at less than 5 mol % catalyst loadings (Scheme 1). Immobilization of chiral molecular catalysts on solid supports has been an active area of research to enhance the practicality by simplifying separation and recycling process.7 Since the pioneering work by Fréchet8 and Soai,9 a variety of chiral ligands have been grafted on polymers and silicas for the Scheme 1. Enantioselective Addition of Organometallic Reagents Catalyzed by 3-Aryl-H8-BINOL-Derived Chiral Titanium Catalysts
Received: May 29, 2017 Published: June 21, 2017 © 2017 American Chemical Society
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Organic Letters
proceeded faster than those reported previously, which required overnight or longer reaction time at 0 °C.10 In accord with the previous reports of chiral titanium catalysts immobilized on silica,18,14a,b the exclusion of free silanols on the surface of silica by capping with a trialkylsilyl group was essential to achieve high enantioselectivity. Thus, the use of SSA-H8-BINOL without EtMe2Si capping resulted in significantly lower conversion and selectivity. The possibility of recovery and reuse of the silicaimmobilized catalyst was examined in the reaction of 6a with Et2Zn at 6 mol % catalyst loading (Table 1). In this experiment,
Scheme 2. Preparation of SSA-H8-BINOL (R)-5
Table 1. Recycling Experiment for Enantioselective Ethylation of Aldehyde 6a Using Et2Zna cycle
conversionb (%)
ee (%)
1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th
91 96 90 94 86 91 87 86 84 85
96 96 95 95 94 94 92 92 90 90
a Reactions were carried out at 0 °C for 2 h under the conditions shown in Scheme 2 with 6 mol % of SSA-H8-BINOL (R)-5 on a 0.5 mmol scale. bDetermined by 1H NMR (500 MHz) analysis.
2
treating with a suspension of amorphous silica (480 m /g) in dry CH2Cl2 in the presence of B(C6F5)3 (6 mol %) at room temperature for 5 min. After filtration, washing, and drying, free silanol groups present on the surface of the resulting grafted silica were capped with Me2(Et)SiH under similar conditions to furnish SSA-H8-BINOL (R)-5, which was estimated to contain 0.069−0.101 mmol/g (depending on the runs) of the (R)-H8BINOL unit by the elemental analysis of samples before and after capping. The catalytic activity and enantioselectivity of an immobilized titanium catalyst derived from SSA-H8-BINOL (R)-5 was evaluated first in the enantioselective ethylation of pchlorobenzaldehyde (6a) with Et2Zn (3 equiv) and Ti(OiPr)4 (1.4 equiv) in CH2Cl2 at 0 °C (Scheme 3). The reaction with 2
the supernatant solution was withdrawn with a syringe after each run. The residual silica was washed with CH2Cl2 in a similar manner and used in the next run. Following this method, we managed successfully to run up to 10 cycles keeping high conversion (84−96%) and enantioselectivity (90−96% ee). The result demonstrates the robustness of the present silica immobilized catalyst for multiple uses even at relatively low catalyst loadings. We have reported that Et 3 B can be used in the enantioselective ethylation of aldehydes.6j It was revealed that the present silica-immobilized titanium catalyst also exhibited high performance in the reaction of Et3B (Table 2). Thus, in the presence of (R)-5 (6 mol %), treatment of 1naphthaldehyde (6b) with Et3B (3 equiv) and Ti(OiPr)4 (3 equiv) in THF at 60 °C for 3 h gave the ethyl adduct (R)-7b enantioselectively (96% ee) in 85% yield (entry A1). The performance of the silica-immobilized catalyst paralleled with a homogeneous catalyst derived from DTBP-H8-BINOL (R)-1b (2 mol %) (entry B). The immobilized titanium catalyst generated in entry A1 were reused in recycling experiments (entries A2−A10), demonstrating that high product yields (81−89%) and selectivities (93−98% ee) were entirely maintained up to the tenth cycle. After the tenth cycle, SSAH8-BINOL 5 was recovered by filtration of the hydrolyzed immobilized titanium catalyst. Thus, recovered ligand again exhibited its original performance as shown by the 11−14th cycles (entries A11−A14). The high activity and durability of the immobilized chiral titanium catalyst derived from (R)-5 was further exploited in the enantioselective arylation of aldehydes using Grignard reagents (Table 3). Addition of the mixed reagent of PhMgBr (8a) (2 equiv) and Ti(OiPr)4 (3.3 equiv) to a CH2Cl2 solution of aldehyde 6b and Ti(OiPr)4 (1.7 equiv) in the presence of
Scheme 3. Enantioselective Ethylation of Aldehyde 6a Using Et2Zn
mol % of immobilized ligand (R)-5 attained 77% conversion after 2 h to give the ethylation product (R)-7a (91% ee) as a sole product. Although the conversion and enantioselectivity were inferior to those observed in the reaction with the corresponding soluble ligand, DTBP-H8-BINOL (R)-1b (2 mol %),17 high conversion (91%) and enantioselectivity (96% ee) were obtained in the reaction employing 6 mol % of the immobilized ligand. It should be noted that the reaction 3633
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(R)-5 (6 mol %) at 0 °C for 3 h, and additional 1 h stirring afforded the phenyl adduct (R)-9ba in 85% yield and 94% ee (entry A1). The high enantioselectivity (88−95% ee) and yield (85−99%) of 9ba were maintained up to the tenth cycle as shown by a recycle experiment (entries A1−10). The practicality of the present heterogeneous catalyst system was further demonstrated by recycling experiments in which the same immobilized catalyst was used in different combinations of aldehydes and Grignard reagents. Thus, a recycling experiment was conducted for the reaction of benzaldehyde (6c) and p-ClC6H4MgBr (8b) (entries B1−B4) and for the reaction of 6b and 8b (entries B5 and B6). These six reactions were carried out in this order by using the same immobilized titanium catalyst, prepared in entry B1, without hydrolysis to the silica-supported ligand (R)-5, leading to the enantioselective formation of the p-chlorophenyl adducts (S)9cb (85−90% ee) and (R)-9bb (88 and 89% ee) in high yields. In a similar manner, enantioenriched diarylmethanols (S)-9cc (90 and 91% ee), (R)-9da (91% ee), and (R)-9ea (91% ee) were obtained in high yields by the reaction of the corresponding aldehyde 6c−e and Grignard reagents 8a,c through a recycling experiment in entries C1−C6. In summary, we have developed a robust silica-supported 3aryl H8-BINOL ligand for the catalytic enantioselective alkylation and arylation of aldehydes. The heterogeneous titanium catalyst derived from the silica-supported ligand exhibited high activity and enantioselectivity at 6 mol % loading not only in the reaction using Et2Zn but also, for the first time, in the reaction using Et3B and aryl Grignard reagents. The synthetic potential of the catalyst was further indicated by the fact that it could be reused up to 14 times without appreciable deterioration of the activity.
Table 2. Enantioselective Ethylation of Aldehyde 6b Using Et3Ba
entry
yield (%)
ee (%)
A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11b A12 A13 A14 Bc
85 85 83 81 88 81 85 88 82 89 84 82 85 84 91
96 96 96 95 93 96 96 98 96 95 94 96 95 94 95
a
Unless otherwise noted, reactions were carried out with aldehyde 6 (0.5 mmol), Et3B (3 equiv), Ti(OiPr)4 (3 equiv), and (R)-5 (6 mol %) in THF at 60 °C for 3 h. bLigand (R)-5, recovered in entry A10, was employed. cEt3B (1.5 equiv) and (R)-1b (2 mol %) were used.
Table 3. Enantioselective Arylation of Aldehydes Using Aryl Grignard Reagentsa
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ASSOCIATED CONTENT
S Supporting Information *
entry
aldehyde (R1)
ArMgBr (R2)
product
yield (%)
ee (%)
A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 B1 B2 B3 B4 B5 B6 C1 C2 C3 C4 C5 C6
6b (1-naphthyl) 6b 6b 6b 6b 6b 6b 6b 6b 6b 6c (Ph) 6c 6c 6c 6b (1-naphthyl) 6b 6c (Ph) 6c 6d (m-MeOC6H4) 6d 6e (p-CNC6H4) 6e
8a (H) 8a 8a 8a 8a 8a 8a 8a 8a 8a 8b (p-Cl) 8b 8b 8b 8b (p-Cl) 8b 8c (p-F) 8c 8a (H) 8a 8a (H) 8a
9ba 9ba 9ba 9ba 9ba 9ba 9ba 9ba 9ba 9ba 9cb 9cb 9cb 9cb 9bb 9bb 9cc 9cc 9da 9da 9ea 9ea
85 91 99 93 83 86 91 99 96 99 90 99 90 92 92 90 91 92 86 85 88 94
94 95 89 89 93 95 92 92 90 88 90 89 89 85 88 89 91 90 91 91 91 91
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01625. Experimental procedures and characterization of products (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Toshiro Harada: 0000-0002-9818-5386 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by KAKENHI (No. 15K05500) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan.
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REFERENCES
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