Catalytic asymmetric α-amination of β-keto esters and β-keto amides with a chiral N,N′-dioxide–copper(I) complex

Xiao Xiao , Lili Lin *, Xiangjin Lian , Xiaohua Liu and Xiaoming Feng *
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People's Republic of China. E-mail: xmfeng@scu.edu.cn

Received 8th March 2016 , Accepted 27th April 2016

First published on 9th May 2016


The highly efficient asymmetric α-amination of β-keto esters and β-keto amides was realized by using a chiral N,N′-dioxide/Cu(I) complex. Under mild reaction conditions, a series of corresponding chiral α-amino dicarbonyl compounds were obtained in excellent yields (up to 98%) with excellent enantioselectivities (up to 95% ee).


Introduction

Optically active amino acids are distributed widely in natural products and medicines, exhibiting important biological or medicinal activities.1 The asymmetric α-amination of 1,3-dicarbonyl compounds with azodicarboxylates is an efficient and simple strategy to construct optically active α-amino carbonyl compounds bearing a quaternary stereocenter.2 Therefore, this reaction has gained much attention.3–7 Since the pioneer work of Jørgensen and co-workers6b using a copper(II)-box catalyst to accomplish this transformation, different catalytic systems, including metal complexes,3,6 organocatalysts4 and phase-transfer catalysts,5 have recently been reported. However, most of these studies are concentrated on β-keto esters. The reports on the α-amination of β-keto amides are relatively rare7 although the amino group is useful for their further easy manipulation,8 due to the lower acidity of the α-hydrogen.9 So, developing new catalytic systems, efficient not only for the enantioselective α-amination of β-keto esters but also for that of β-keto amides, is still necessary and meaningful.

Copper, with mild Lewis acidity, has been proved to be particularly effective at activating the nitrogen atom.6,10 Several chiral copper(II) complexes have been applied in α-amination reactions.6 The application of copper(I) complexes in α-amination reactions needs to be developed. On the other hand, chiral N,N′-dioxides, developed by our group, have been proved to be efficient ligands or organocatalysts in various asymmetric transformations.11 Herein, we describe our efforts in developing an N,N′-dioxide/Cu(I) complex catalytic system for the enantioselective α-amination of β-keto esters as well as β-keto amides.

Results and discussion

Initially, we investigated several copper salts complexing with a L-pipecolic acid derived ligand L-PiEt2 to promote the α-amination of the β-keto ester 1c using commercially available diethyl azodicarboxylate 2a as the amination reagent in CH2Cl2 at 35 °C. As shown in Table 1, the L-PiEt2–Cu(OTf)2 complex provided the product in good yield but moderate enantioselectivity (73% yield, 46% ee; Table 1, entry 1), while the L-PiEt2–CuOTf·(C7H8)0.5 complex provided the product in excellent yield and good enantioselectivity (90% yield, 74% ee, Table 1, entry 2). Since Cu(I) afforded the product with better results than Cu(II) did, the counterion of Cu(I) was then screened. When CuCl, CuBr and CuI were used, the ee value was further improved (Table 1, entries 3–5) though the yield decreased a little, and CuI gave the highest yield and ee (89% yield and 90% ee). Encouraged by these results, the efficiency of CuI with other N,N′-dioxide ligands was explored (Fig. 1). It was showed that the reactivity and enantioselectivity were closely dependent on both the substituent R of the amide moiety and the chiral backbone of the ligand. Increasing the steric hindrance of the R group from methyl to isopropyl (Table 1, entries 5–7) led to an obvious increase in the yield and ee value. But the more hindered ligand L-PiPr3 derived from 2,4,6-triisopropylaniline didn't give better results (Table 1, entry 8). Besides, L-pipecolic acid derived L-PiPr2 was superior to L-proline-derived L-PrPr2 and L-ramipril-derived L-RaPr2 in enantioselectivity (Table 1, entry 7 vs. entries 9 and 10).
image file: c6qo00095a-f1.tif
Fig. 1 Ligands screened in this study.
Table 1 Screen of Lewis acids and N,N′-dioxide ligandsa

image file: c6qo00095a-u1.tif

Entry Metal Ligand Yieldb (%) eec (%)
a Unless otherwise noted, all reactions were performed with L/metal (1.1[thin space (1/6-em)]:[thin space (1/6-em)]1, 10 mol%), 1c (0.1 mmol), and 2a (0.12 mmol, 20 μL) in CH2Cl2 (0.5 mL) at 35 °C for 24 hours. b Isolated yield. c Determined by chiral HPLC analysis (Chiralcel IA).
1 Cu(OTf)2 L-PiEt 2 73 46
2 CuOTf·(C7H8)0.5 L-PiEt 2 90 74
3 CuCl L-PiEt 2 82 80
4 CuBr L-PiEt 2 80 87
5 CuI L-PiEt 2 89 90
6 CuI L-PiMe 2 82 91
7 CuI L-PiPr 2 96 95
8 CuI L-PiPr 3 83 91
9 CuI L-PrPr 2 88 68
10 CuI L-RaPr 2 97 87


With the optimized conditions in hand, the substrate scope of the reaction was evaluated, and the results are summarized in Table 2. When 1-tetralone-derived β-keto esters were investigated, the ee values of the products increased gradually with the increase of the steric hindrance of the R2 group located on the ester side and the yields were maintained (Table 2, entries 1–3). When the R2 group was varied from methyl, ethyl to adamantyl, the ee value increased from 80%, 86% to 95%. The 1-tetralone-derived β-keto esters, bearing electron-donating groups at different positions on the phenyl ring (Table 2, entries 4–6), could transform into the corresponding products in excellent yield and high ee values (91–98% yield and 90–94% ee). Next, the scope of azodicarboxylates 2 was tested, with the increase of the steric hindrance of the R3 group located on the ester side (Table 2, entry 3 vs. entries 7 and 8), both the yield and the ee value decreased obviously. When the R3 group was changed from ethyl, isopropyl to tert-butyl, the yield decreased from 96%, 95% to 76% and the ee value decreased from 95%, 90% to 82%. Dibenzyl azodicarboxylate 2d was also a suitable substrate, which was converted to the corresponding product 3cd in 98% yield and 90% ee value (Table 2, entry 9).

Table 2 Substrate scope of the catalytic asymmetric α-amination of β-keto estersa

image file: c6qo00095a-u2.tif

Entry R1, R2, R3 Product Yieldb (%) eec (%)
a Unless otherwise noted, all reactions were performed with L-PiPr2/CuI (1.1[thin space (1/6-em)]:[thin space (1/6-em)]1, 10 mol%), 1 (0.1 mmol), and 2 (0.12 mmol) in CH2Cl2 (0.5 mL) at 35 °C for 24 hours. b Isolated yield. c Determined by chiral HPLC analysis.
1 H, Me, Et 3aa 94 80
2 H, Et, Et 3ba 92 86
3 H, Ad, Et 3ca 96 95
4 5-MeO, Ad, Et 3da 91 90
5 6-MeO, Ad, Et 3ea 98 94
6 7-MeO, Ad, Et 3fa 95 94
7 H, Ad, i-Pr 3cb 95 90
8 H, Ad, t-Bu 3cc 76 82
9 H, Ad, Bn 3cd 98 90


After investigation of the β-keto esters, we then turn our attention to the more challenging 1-tetralone-derived β-keto amides (Table 3). The amides with a more hindered 1-adamantyl or tert-butyl substituent on the nitrogen atom could give better results (90–96% yield, 87–92% ee; Table 3, entries 1–6). In terms of azodicarboxylates, generally, compared to diethyl azodicarboxylate 2a and dibenzyl azodicarboxylate 2d, the diisopropyl azodicarboxylate 2b afforded the products in lower yields with lower enantioselectivities. Next, the influence of substituents on 1-tetralone-derived β-ketone amides was tested. The amides, bearing electron-donating groups at different positions on the phenyl ring, could transform into the corresponding products in high yields and high ee values (89–93% yield and 90–94% ee, Table 3, entries 7–10). Besides, the 1-indanone-derived β-keto amide 4g and 1-benzosuberanone-derived β-keto amide 4h were also examined with the same catalytic system. However, the enantioselectivities were very poor since only racemic 5ga and 5ha with 0% and 25% ee, respectively, were obtained (Table 3, entries 11 and 12).

Table 3 Substrate scope of the catalytic asymmetric α-amination of β-keto amidesa

image file: c6qo00095a-u3.tif

Entry n, R3, R4, R5 Product Yieldb (%) eec (%)
a Unless otherwise noted, all reactions were performed with L-PiPr2/CuI (1.1[thin space (1/6-em)]:[thin space (1/6-em)]1, 10 mol%), 4 (0.1 mmol), 2 (0.12 mmol) in CH2Cl2 (0.5 mL) at 35 °C for 24 hours. b Isolated yield. c Determined by chiral HPLC analysis. d The reaction time was 48 hours.
1 1, Et, Ad, H 5aa 95 90
2 1, i-Pr, Ad, H 5ab 90 87
3 1, Bn, Ad, H 5ad 96 90
4 1, Et, t-Bu, H 5ba 96 92
5 1, i-Pr, t-Bu, H 5bb 90 88
6 1, Bn, t-Bu, H 5bd 94 90
7d 1, Et, t-Bu, 5-MeO 5ca 90 90
8d 1, Et, t-Bu, 6-MeO 5da 93 92
9d 1, Et, t-Bu, 7-MeO 5ea 92 92
10d 1, Et, t-Bu, 5,7-Me2 5fa 89 94
11d 0, Et, t-Bu, H 5ga 82 0
12d 2, Et, t-Bu, H 5ha 87 25


For the purpose of examining the synthetic potential of the catalytic system, a gram-scaled synthesis of 3cd was performed (Scheme 1). As shown in Scheme 1, under the optimized reaction conditions (Table 2, entry 9), 2 mmol 1c reacted with 1.2 equivalents of 2d smoothly, giving 1.20 g (95% yield) of the desired product 3cd with 90% ee.


image file: c6qo00095a-s1.tif
Scheme 1 Scaled-up version of the catalytic asymmetric amination reaction.

Conclusions

In summary, we have developed a highly efficient N,N′-dioxide/Cu(I) complex catalytic system for the asymmetric α-amination of β-keto esters and β-keto amides by using dialkyl azodicarboxylates as amination reagents. A series of corresponding chiral α-amino dicarbonyl compounds were obtained in excellent yields (up to 98%) and excellent enantioselectivities (up to 95% ee) under mild reaction conditions. The synthetic potential of this methodology was also demonstrated by the excellent results obtained on a gram scale.

Acknowledgements

We appreciate the National Natural Science Foundation of China (no. 21321061 and 21372162) for financial support.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00095a

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