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Letter Cite This: Org. Lett. 2018, 20, 7137−7140

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Catalytic Asymmetric Mannich Type Reaction with Tri-/Difluoro- or Trichloroacetaldimine Precursors Yang’en You†,‡ and Sanzhong Luo*,†,‡,§ †

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Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡ University of Chinese Academy of Sciences, Beijing 100490, China § Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing 100875, China S Supporting Information *

ABSTRACT: A highly efficient catalytic asymmetric Mannich type reaction of CF3-, CF2H-, or CCl3-acetaldimine precursors by a chiral primary amine is presented. This protocol provides facile access to chiral CF3-, CF2H-, or trichloroethyl amines in excellent yields and high enantioselectivity (up to 99% yield, up to >99% ee).

T

he trifluoroethyl amine motif exists widely in biologically active compounds, showing antirheumatic and anticancer activities.1,2 This trifluoroethyl amine motif has also emerged as a remarkable surrogate of the natural peptide bond in the area of peptide mimics (Scheme 1).2c,d In view of the synthetic utility, significant efforts have been devoted to the synthesis of chiral trifluoroethyl amines by asymmetric hydrogenation or arylation reactions.3−6 Deng and co-workers reported an elegant transamination strategy for the synthesis of chiral trifluoroethyl amines from trifluoromethyl ketimines.4b−d As a fundamental C−C bond formation reaction, the Mannich

reaction has been widely explored as a straightforward approach for the synthesis of chiral amines.5 However, such an asymmetric Mannich strategy remains surprisingly underdeveloped for the reaction with trifluoromethyl aldimines. Only chiral trifluoromethyl aldimines were examined with limited scope.6 The primary difficulty is the instability of trifluoromethyl aldimines, which has limited the exploration of their synthetic applications. Herein, we report trifluoromethyl N,O-acetals (NOAc) as stable and readily available precursors of trifluoromethyl aldimines.7,8 The chiral primary amine catalyst was identified to promote effectively the asymmetric Mannich type reaction with trifluoromethyl aldimine precursors. The current catalysis enables not only the reactions with trifluoromethyl aldimines but also difluoromethyl, trichloromethyl, as well as multifluoroalkyl aldimines with good activity and high enantioselectivity. The N,O-acetal imine precursors were readily synthesized from the corresponding aldehydes. In most cases, the acetals were obtained as crystalline bench-stable solid compounds (Scheme 1, see also the Supporting Information).8,9 We began our study by testing the reaction of pentane-2,4-dione with CF3-reagent 2a in the presence of our primary amine catalyst.7,10 To our delight, in the presence of 20 mol % of our primary amine catalyst A, the reaction of 1a and 2a in chloroform at room temperature proceeded smoothly to afford the desired product 3a in 13% yield and >99% ee (Table 1, entry 1). The addition of acid additive such as m-nitrobenzoic acid led to a serious reduction in enantioselectivity (Table 1, entry 2). Further increasing the temperature (Table 1, entries 3 and 4) led to faster reactions while maintaining enantioselectivity. Chloroform was found to be the optimal solvent in terms of both activity and stereoselectivity (Table 1, entries 5− 8). On the basis of these findings, the optimal reaction

Scheme 1. Catalytic Asymmetric Mannich-Type Reaction of Trifluoromethyl Aldimines

Received: September 26, 2018 Published: November 8, 2018 © 2018 American Chemical Society

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DOI: 10.1021/acs.orglett.8b03083 Org. Lett. 2018, 20, 7137−7140

Letter

Organic Letters Table 1. Screening and Optimizationa

Scheme 2. Substrate Scope with CF3-N,O-acetalsa

entry

temp (°C)

solvent

yieldb (%)

eec (%)

1 2d 3 4 5 6 7 8 9e

23 23 40 60 60 60 60 60 60

CHCl3 CHCl3 CHCl3 CHCl3 PhMe CH3CN MeOH THF CHCl3

13 16 35 71 18 56 59 19 65

>99 13 >99 >99 95 99 99 97 99

a

General conditions: 1a (0.12 mmol), 2a (0.10 mmol), amine catalyst (20 mol %) in solvent (0.20 mL) under air for 48 h. bYield of isolated product after flash chromatography. cee determined by HPLC on a chiral stationary phase. dWith m-NO2C6H4CO2H (20 mol %) added. e 10 mol % of amine catalyst was used.

conditions were obtained as a combination of amine catalyst A/HOTf with 1a and 2a in chloroform at 60 °C, providing 3a with 71% isolated yield and >99% ee. The catalyst loading could be further decreased to 10 mol % with similar performance (Table 1, entry 9). Under the optimized reaction conditions, we next explored the substrate scope of the reaction. The results are summarized in Scheme 2. First, the effect of the amine protection (Scheme 2, entries 1−6) was investigated by testing with pentane-2,4dione in the presence of our chiral primary amine catalyst. Different protection groups (Boc, Fmoc, CO2Me) were all well tolerated, and their corresponding products 3b−d were obtained in excellent yields and enantioselectivity. Simple acyl protection groups such as acetyl or benzoyl could also be applied with high ee and good yields (3e and 3f). The scopes of β-ketocarbonyls were next evaluated. The reactions of both alkyl and aryl ketones with 2a proceeded well to give the desired Mannich adducts with good yields and high enantioselectivity (Scheme 2, entries 7−12). Aryl ketones reacted sluggishly, but still with excellent enantioselectivity (3h and 3l). Moreover, α-unsubstituted and unsymmetric 1,3diketones gave the Mannich products 3i−l in almost 1:1 dr due to readily enolizable α-carbon, and both diastereoisomers were obtained with excellent enantioselectivity. α-Unsubstituted β-ketoesters were well tolerated in this reaction (Scheme 2, entries 13−15) and gave the desired products 3m−o in 1:1 dr and excellent enantioselectivity for both diastereoisomers. α-Unsubstituted β-ketoamides (Scheme 2, entries 16 and 17) could also be applied to give the desired adducts 3p and 3q in excellent yield with 63:33 dr and 77:23 dr, and again, both diastereoisomers were obtained with excellent enantioselectivity. The use of simple ketones such as acetone and cyclohexanone has also been examined, unfortunately, showing no reaction under the current conditions.11 We further tried the reaction of N-aryl and N-aliphatic amide containing free N−H (Scheme 2, entries 18−22), and to our delight, the desired products 3r−v were obtained with high diastereoselectivity and excellent enantioselectivity. Notably, the desired Mannich-type reaction in these cases

All reactions were performed at 60 °C in 0.20 mL of CHCl3 with 1 (0.12 mmol), 2 (0.10 mmol), chiral amine A/HOTf (20 mol %), 48 h. Yield of isolated product. ee determined by HPLC analysis.

a

precipitated from the reaction solution, and we could obtain the essentially pure adducts by simple filtration and washing in almost quantitative yields. α-Substituted β-ketocarbonyls have also been examined (Scheme 2, entries 23−26), and the reactions showed generally lower reactivity possibly because of steric effects in this reaction. The desired Mannich adducts bearing contiguous quaternary and tertiary stereocenters could be obtained with excellent diastereoselectivity and enantoise7138

DOI: 10.1021/acs.orglett.8b03083 Org. Lett. 2018, 20, 7137−7140

Letter

Organic Letters Scheme 3. Substrate Scope with CF2H-N,O-acetalsa

lectivity (3w and 3z). The reaction also worked well with cyclic ketoesters to give the expected adducts as single stereoisomers (3x and 3y). Encouraged by the high efficiency of CF3-containing N,Oacetals in asymmetric Mannich-type reactions, we further examined the CCl3- and C2F5-containing N,O-acetals reagents, and the expected Mannich-type reactions also provided straightforward approaches to access CCl3- and C2F5-functional molecules.12 The desired products 4a−d were obtained with high enantioselectivity but moderate yields (Figure 1).

Figure 1. Substrate scope with CCl3- and C2F5-N,O-acetals and X-ray crystal structure of 4a.

The unreacted N,O-acetals could be quantitatively recovered. By X-ray crystallographic analysis, the absolute configuration of 4a was established as S. The configuration of 3w was determined by NMR analysis.13 The difluoroethyl amine group exhibited similar biological potency as trifluoroethyl amine, while these difluoro alterations could more positively affect the oral bioavailability compared with their trifluoro counterparts.14 Bearing this in mind, we also examined the reactions with difluoromethyl aldimines, for which a catalytic asymmetric Mannich type reaction remains undeveloped. CF2H-N,O-acetals 2k were first synthesized. As shown in Scheme 3, both alkyl and aryl diketones (Scheme 3, entries 1−3) reacted smoothly to give the desired adducts with good yields and high enantioselecivity (5a−c). α-Unsubstituted and unsymmetric 1,3-diketones (Scheme 3, entries 4−6) gave the desired products 5d−f in low dr due to the easy enolization of the α-carbon but good enantioselectivity for both diastereoisomers. β-Ketoesters and ketoamides also worked well in this reaction (Scheme 3, entries 7−11), and the desired products 5g−k were obtained with good yields and enantioselectivity. To evaluate the practicality of this catalytic asymmetric Mannich-type reaction, gram-scale reactions of 2a and 2h were carried out. As shown in Scheme 4A, in the presence of 10 mol % of catalyst A, the desired products were obtained with similar outcomes and the chiral primary amine catalyst could be quantitatively recovered by concentrating the aqueous solution after workup. The transformations of 3a were conducted as shown in Scheme 4B. Compound 3a could be condensed with hydroxylamine and hydrazines, leading to their corresponding pyrazoles (6a and 6b) and oxazole (7a) in excellent yields. The decarboxylation of 3n was tested, and the desired product 8 was obtained with 76% yield. There was little erosion of enantioselectivity observed during these transformations.

All reactions were performed at 60 °C in 0.20 mL of CHCl3 with 1 (0.12 mmol), 2k (0.10 mmol), chiral amine A/HOTf (20 mol %), 48 h. Yield of isolated product. ee determined by HPLC analysis. a

Scheme 4. (A) Gram-Scale Reactions and (B) Transformations of the Products

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DOI: 10.1021/acs.orglett.8b03083 Org. Lett. 2018, 20, 7137−7140

Letter

Organic Letters In summary, we have developed the first catalytic asymmetric Mannich type reactions of β-ketocarbonyls with CF3 -, CF2 H-, CCl3 -, and C 2 F5 -containing N,O-acetals (NOAcs) by chiral primary amine catalysis. This reaction provides a facile and efficient access to trifluoro- or difluoroethyl amine and trichloroethyl amines in good yields and with high enantioselectivity.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03083. Experimental procedures, characterization data, copies of NMR spectra, and HPLC chart (PDF) Accession Codes

CCDC 1863303 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sanzhong Luo: 0000-0001-8714-4047 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Natural Science Foundation of China (21390400, 21521002, 21572232, and 21672217), the Chinese Academy of Science (QYZDJ-SSW-SLH023), and Tsinghua University for financial support. S.L. is supported by the National Program of Top-notch Young Professionals.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03083 Org. Lett. 2018, 20, 7137−7140