Letter pubs.acs.org/OrgLett
Nickel-Catalyzed Enantioselective Hydrogenation of β‑(Acylamino)acrylates: Synthesis of Chiral β‑Amino Acid Derivatives Xiuxiu Li,† Cai You,† Shuailong Li,† Hui Lv,*,†,‡ and Xumu Zhang*,†,§ †
Key Laboratory of Biomedical Polymers, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China ‡ Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China § Department of Chemistry, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China S Supporting Information *
ABSTRACT: The nickel-catalyzed asymmetric hydrogenation of β-(acylamino)acrylates has been developed, affording chiral βamino acid derivatives with excellent yields (95−99% yield) and enantioselectivities (97−99% ee). With the Ni−Binapine system, high enantioselectivities (98−99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of β-alkyl and β-aryl β-(acylamino)acrylates. The synthesis of chiral β-amino acid derivatives on a gram scale has also been achieved with 0.2 mol % catalyst loading.
A
easy task in asymmetric hydrogenation, even if the precious metals are employed.7 To date, there are only a handful of catalytic systems can work well for the asymmetric hydrogenation of Z/E isomeric mixtures of β-(acylamino)acrylates (Scheme 1a).7a−h In the first-row metal-catalyzed asymmetric (transfer) hydrogenation, the catalytic systems that can complete this task have not appeared. Herein, we report the first nickel-catalyzed asymmetric hydrogenation of Z/E mixture of β-(acylamino)acrylates with excellent yields (95−99% yield) and enantioselectivities (97−99% ee, Scheme 1b).
symmetric hydrogenation of alkenes is one of the most dominant and well-established methods for the synthesis of enantiopure compounds. It has found multiple applications in many pharmaceuticals and biologically active molecules.1 Typically, these asymmetric hydrogenation methods rely on precious metal compounds based on rhodium, ruthenium, or iridium.2 Excellent stereoselectivity can be achieved by a judicious choice of suitable phosphorus ligands, and the catalyst loading can be lowered for an industrial scale. However, these heavy metal compounds are seriously contaminating the environment, and their reserves in the Earth’s crust are exhausted. By contrast, catalysts containing first-row transition elements offer potential advantages in cost and sustainability. Recently, replacing these expensive and toxic elements with more abundant and environmentally compatible metals such as iron, cobalt, and nickel has drawn a great deal of attention.3 Although some examples of iron-,4 cobalt-5 and nickelcatalyzed6 asymmetric (transfer) hydrogenation of CC, CO, and CN bonds were reported, the hydrogenation of Z/E isomeric mixtures of olefins, an important reflection of catalytic systems’ compatibility, has never been studied. Since both (Z)- and (E)-isomeric substrates are formed simultaneously in most synthetic protocols, the development of a catalytic system that can tolerate both isomeric substrates is essential. This is especially important in the situation where the (Z)- and (E)-substrates cannot be easily separated and only their mixture can be employed as the starting material. The tolerance of both isomers of β-(acylamino)acrylates is not an © 2017 American Chemical Society
Scheme 1. Asymmetric Hydrogenation of Z/E Isomeric Mixtures of β-(Acylamino)acrylates
Received: August 5, 2017 Published: September 11, 2017 5130
DOI: 10.1021/acs.orglett.7b02417 Org. Lett. 2017, 19, 5130−5133
Letter
Organic Letters
enantioselectivities and bad conversions were obtained (Table 1, entries 5−8). Inspired by these promising results, we investigated the solvent effects in the presence of a 5 mol % Ni(OAc)2/(S)Binapine complex, as summarized in Table 2. Solvent screening
We began the initial investigation with the asymmetric hydrogenation of methyl (Z)-3-acetamido-3-phenyl acrylate 1a to optimize the reaction conditions. Without any additives, a variety of diphosphine ligands (Figure 1) developed by our
Table 2. Solvent Screening for Ni-Catalyzed Asymmetric Hydrogenation of (Z)-1aa
entry
solvent
convb(%)
eec (%)
1 2 3 4 5 6 7d
MeOH CF3CH2OH CH2Cl2 toluene 1,4-dioxane THF CF3CH2OH
93 >99 trace trace trace trace >99
92 99
99
a
Unless otherwise mentioned, all reactions were carried out with a Ni(OAc)2/(S)-Binapine/substrate ratio of 1:1.1:20, in 1 mL of solvent, at 50 °C, under hydrogen (50 atm) for 24 h. bDetermined by 1H NMR spectroscopy. cDetermined by HPLC analysis using a chiral stationary phase. dCarried out with a Ni(OAc)2/(S)-Binapine/ substrate ratio of 1:1.1:100.
Figure 1. Structures of the phosphine ligands for hydrogenation of (Z)-1a.
group and some commercially available chiral ligands were examined, as summarized in Table 1. The evaluation of ligands
showed that this reaction proceeded smoothly in alcoholic solvents (entries 1 and 2), and CF3CH2OH was found to give full conversion with 99% ee. However, when nonprotonic solvents were used, only trace conversions were detected (entries 3−6). Full conversion with unchanged ee value was also obtained when the reaction was carried out in CF3CH2OH with 1 mol % catalyst loading (entry 7). With an optimized set of conditions in hand, we explored the substrate scope and generality of this catalytic reaction (Scheme 2). First, the substituent on the ester group was changed from methyl to ethyl. However, the result indicated that this change of the substrate has almost no impact on this reaction (2b). Many functional groups, such as methyl (2c), methoxy (2d), halides (2e−g), and trifluoromethyl (2h), at the para position of the phenyl group are compatible with this transformation. Substrates with meta- or ortho-substitution on the phenyl group are also tolerated, and excellent ee values were obtained (2i and 2j). Moreover, good yields and excellent enantioselectivities were obtained with substrates containing other aromatic fragments, including thiophenes, furans, and naphthalenes (2k−n). Notably, when the aryl substituent was changed to an alkyl group, such as methyl, excellent enantioselectivity (98% ee) was also achieved (2o). Since both Z and E isomeric substrates are formed simultaneously and it is difficult to obtain a single isomer in most cases, asymmetric hydrogenation of their Z/E mixtures is crucial for the synthesis of chiral β-amino acid derivatives. Based on this idea, we used the Z/E isomeric mixture as the substrate directly to investigate the compatibility of this catalytic system, as summarized in Scheme 3. To our delight, when the hydrogenation of the 1:1 Z/E isomeric mixture (1a) was conducted, the results were almost the same as that of pure (Z)-1a. Next, substrates bearing heterocyclic rings and alkyl groups were also tested, and excellent yields (96−98%) with excellent enantioselectivities (98−99% ee) were obtained. These results declare that this nickel-catalyzed system can
Table 1. Ligand Screening for Ni-Catalyzed Asymmetric Hydrogenation of (Z)-1aa
entry
ligand
convb (%)
eec (%)
1 2 3 4 5 6 7 8
(S)-Binapine (Rc,Sp)-DuanPhos (S,S)-Me-DuPhos (R,R)-QuinoxP* (S)-BINAP (S)-SegPhos JosiPhos WalPhos
93 18 trace 19 33 trace 25 23
92 53 73 11 −9 rac
a
All reactions were carried out with a Ni(OAc)2/ligand/substrate ratio of 1:1.1:20, in 1 mL of methanol, at 50 °C, under hydrogen (50 atm) for 24 h. bDetermined by 1H NMR spectroscopy. cDetermined by HPLC analysis using a chiral stationary phase. The absolute configuration was assigned by comparing the sign of the optical rotation of the product 2a, methyl (R)-3-acetamido-3-phenylpropanoate, with that reported in the literature; see ref 6b.
revealed (S)-Binapine to be superior to all others tested, and it is notable that the Ni−(S)-Binapine catalytic system is efficient for the asymmetric hydrogenation of the Z isomer of 1a (Table 1, entry 1, 93% conversion and 92% ee). The use of (Rc,Sp)DuanPhos, (S,S)-DuPhos, and (R,R)-QunioxP* showed low conversions with poor to moderate enantioselectivities (Table 1, entries 2−4). Chiral biarylbisphosphorus ligands with axial chirality or chiral ferrocenyl structures, such as (S)-BINAP, (S)SegPhos, JosiPhos and WalPhos, were also investigated, but low 5131
DOI: 10.1021/acs.orglett.7b02417 Org. Lett. 2017, 19, 5130−5133
Letter
Organic Letters Scheme 2. Ni-Catalyzed Asymmetric Hydrogenation of (Z)β-(Acylamino)acrylates.a
Scheme 4. Gram-Scale Reaction for the Nickel-Catalyzed Asymmetric Hydrogenation of 1b
method provides a concise route to the synthesis of β-amino acids, which are versatile precursors in chemical synthesis. More importantly, with this Ni−Binapine system, high enantioselectivities (98−99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of β-alkyl and β-aryl β-(acylamino)acrylates. Further investigation on asymmetric hydrogenation of alkenes bearing unprotected NH2 is underway in our laboratory.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02417. Experimental details and characterization data (PDF)
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a
Unless otherwise mentioned, all reactions were carried out with a Ni(OAc)2/(S)-Binapine/substrate ratio of 1:1.1:100, in 1 mL of CF3CH2OH, at 50 °C, under hydrogen (50 atm) for 24 h. bYield of the isolated product. cDetermined by HPLC analysis using a chiral stationary phase.
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Scheme 3. Ni-Catalyzed Asymmetric Hydrogenation of Z/E Isomeric Mixtures of β-(Acylamino)acrylatesa
Hui Lv: 0000-0003-1378-1945 Xumu Zhang: 0000-0001-5700-0608 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Grant Nos. 21402145, 21432007, and 21372179), the Youth Chen-Guang Science and Technology Project of Wuhan City (2015071704011640), the Fundamental Research Funds for Central Universities (2042017kf0177), the Important Sci-Tech Innovative Project of Hubei Province (2015ACA058), and the “111” Project of the Ministry of Education of China.
a
Unless otherwise mentioned, all reactions were carried out with a Ni(OAc)2/(S)-Binapine/substrate ratio of 1:1.1:100, in 1 mL of CF3CH2OH, at 50 °C, under hydrogen (50 atm) for 24 h. b Determined by 1H NMR spectroscopy. cYield of the isolated product. dDetermined by HPLC analysis using a chiral stationary phase.
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REFERENCES
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