Asymmetric Synthesis of Chiral Primary Amines by Ruthenium

Communication Cite This: J. Am. Chem. Soc. 2018, 140, 2024−2027

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Asymmetric Synthesis of Chiral Primary Amines by RutheniumCatalyzed Direct Reductive Amination of Alkyl Aryl Ketones with Ammonium Salts and Molecular H2 Xuefeng Tan,† Shuang Gao,† Weijun Zeng,† Shan Xin,† Qin Yin,*,†,‡ and Xumu Zhang*,† †

Department of Chemistry, Southern University of Science and Technology, Shenzhen 518000, People’s Republic of China Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518000, People’s Republic of China

‡

S Supporting Information *

Scheme 1. Representative Strategies for Transition MetalCatalyzed ARA

ABSTRACT: A ruthenium/C3-TunePhos catalytic system has been identified for highly efficient direct reductive amination of simple ketones. The strategy makes use of ammonium acetate as the amine source and H2 as the reductant and is a user-friendly and operatively simple access to industrially relevant primary amines. Excellent enantiocontrol (>90% ee for most cases) was achieved with a wide range of alkyl aryl ketones. The practicability of this methodology has been highlighted by scalable synthesis of key intermediates of three drug molecules. Moreover, an improved synthetic route to the optimal diphosphine ligand C3-TunePhos is also presented.

C

hiral amines are prevalent structural units in a large number of pharmaceutical drug molecules, agrochemicals, and commodity chemicals. Therefore, efficient synthetic routes toward chiral amines have attracted tremendous attention.1 Transition metal-catalyzed reductive amination represents a step-economic and efficient strategy by directly converting carbonyl compounds into amines in the presence of amine sources and reductants.2 However, compared to numerous studies on asymmetric imine reduction,3 only limited success has been achieved regarding asymmetric reductive amination (ARA), partly due to the incompatibility of transition-metal hydrides with ketones. Another factor that cannot be ignored lies in coordination of the amine to the metal catalyst, often resulting in its inhibition.4 To enhance the catalytic efficiency, some special amines such as aryl amines,5 benzylamines6 or others7 were used as amine sources, but these furnish secondary amines. An additional synthetic operation to remove the aryl or benzyl substituents is thus required to liberate the synthetically more versatile primary amine (eq 1, Scheme 1). Asymmetric reductive amination for the direct synthesis of chiral primary amines from ketones and ammonia or its equivalents is highly desirable but still underdeveloped. In 2005, Takasago company patented an asymmetric reductive amination of β-keto esters with NH4OAc to provide chiral β-amino esters.8 After that, several works using a similar strategy have been reported, including the application of different ligands such as ClMeOBIPHEP9 and segphos.10 The syntheses of top-selling drug sitagliptin,11 (S)-3-amino-4-methoxy-butan-1-ol12 as well as methyl (3R)-3-aminobutyrate13 via this methodology were © 2018 American Chemical Society

also documented. In all cases, a functional group such as ester or amide in the β-position is necessary to ensure high efficiency (eq 2, Scheme 1). In comparison, Kadyrov’s group reported a ruthenium-catalyzed enantioselective reductive amination of simple aryl ketones via transfer hydrogenation. However, the formation of undesired formylated amine could not be avoided, thus requiring an additional hydrolysis step to achieve the primary amine product (eq 3, Scheme 1).14 Despite the abovementioned state-of-the-art, a highly efficient and enantioselective asymmetric reductive amination of simple aryl ketones with ammonia or its equivalents using molecular H2 has remained rare15 and is a formidable challenge to be overcome (eq 4, Scheme 1). Herein, we report our recent efforts toward asymmetric reductive amination of simple ketones with ammonium salts utilizing molecular H2 as the reducing reagent. We commenced our study by testing the performance of various combinations of ruthenium precatalysts and different chiral diphosphine ligands in the reaction of model substrate acetophenone (5a) and ammonium salts under 55 bar of H2. Received: December 6, 2017 Published: January 29, 2018 2024

DOI: 10.1021/jacs.7b12898 J. Am. Chem. Soc. 2018, 140, 2024−2027

Communication

Journal of the American Chemical Society Table 1. Reaction Condition Optimizationa

From an initial screening of diverse diphosphine ligands, C3TunePhos (4), a derivative of the Cn-TunePhos (n = 0−6) series developed by our group in 2000,16 emerged as optimal regarding enantiocontrol. Existing procedures17 to synthesize these privileged ligands suffer from long synthetic routes and limited possibilities for derivatization. An improved and divergent preparation to five C3-TunePhos derivatives 4a−4e is shown in Scheme 2 (for details, see the Supporting Information). Scheme 2. Improved Synthetic Route to C3-TunePhosa

Entry

Ru cat.

Yield (%)

ee (%)

1 2 3 4 5 6 7a 8 9 10

RuCl2(4a)(DMF)n RuCl2(4b)(DMF)n RuCl2(4c)(DMF)n RuCl2(4d)(DMF)n RuCl2(4e)(DMF)n Ru(OAc)2(4e) Ru(OAc)2(4e) Ru(OAc)2(4a) Ru((R)-BINAP)(OAc)2 Ru((R)-SegPhos)(OAc)2

90 88 87 93 94 92 96 93 92 92

78 74 76 89 94 97 96 75 65 67

a

Reaction conditions: acetophenone 5a (0.2 mmol), NH4OAc (0.4 mmol), [Ru] (1 mol %), TFE (0.4 mL), H2 (55 bar), 80 °C, 24 h. The pressure refers to the actual value at 80 °C. The free amine 6a was obtained after neutralizing its corresponding acetate salt with a base. The ee values were determined by chiral HPLC after sample acylation. b Reaction was carried out with 0.5 mol % catalyst loading at 100 °C. TFE = trifluoroethanol.

a Reaction conditions: (a) (2R,4R)-pentane-2,4-diol, DIAD, Ph3P, 81%; (b) n-BuLi; then CuCN; then p-benzoquinone, one pot, 55%; (c) KOH, then NaNO2 and KI, 40% over two steps; (d) n-BuLi, ClPAr2, 37−61%.

5b−g) and electron-withdrawing substituents (F, Cl, Br, CF3 as in 5h−5o) on the benzene ring were tolerated, and the reactivity and selectivity were high throughout. The heteroaromatic ketone 5q reacted with decreased enantiomeric excess probably due to a weak coordination effect of the oxygen atom. Besides methyl ketone, ethyl ketone 5r demonstrated comparable reactivity and selectivity, providing 6r in 78% yield and 97% ee. It is worth mentioning that catalyst Ru(OAc)2(4e) showed very low reactivity toward 1-benzosuberone (5s), whereas good conversion and enantiocontrol of 5s could be achieved by using Ru(OAc)2 (4a) as catalyst. Unfortunately, the dialkyl ketone 5t was not a suitable substrate for this catalytic system, and poor yield and enantiocontrol were obtained (20% ee, 6t). To demonstrate the significance and practicality of this methodology, scale-up syntheses of key intermediates of drug molecules, including Tecalcet hydrochloride, Cinacalcet, and Rivastigmine were performed (Scheme 3). Tecalcet hydrochloride and Cinacalcet are drugs that act as a calcimimetic and used to treat secondary hyperparathyroidism, the former currently in Phase II clinical trials18 and the latter sold by Amgen under the trade name of Sensipar in North America and Australia, and of Mimpara in Europe.19 The critical synthon to Tecalcet hydrochloride is (R)-1-(3-methoxyphenyl)ethyl amine (6g), which could be easily accessed under standard conditions with high enantioselectivity (94% ee) and TON up to 500 (eq 1, Scheme 3). Similarly, the key chiral motif (R)-1-(naphth-1yl) ethyl amine in Cinacalcet could be efficiently synthesized with high enantioselectivity (up to 98% ee) and promising efficacy of S/C up to 1000 (eq 2, Scheme 3). The gram-scale syntheses of these two key intermediates reveal the potential of practical industrial application. Rivastigmine, sold under the trade name of Exelon, is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson’s disease.20 As shown in eq 3 of Scheme 3, the key intermediate to (R)Rivastigmine was directly synthesized via reductive amination of 5v with high efficiency.21

With these C3-TunePhos ligands in hand, further condition optimization was conducted to improve the reaction efficiency and selectivity, including the screening of the ruthenium source, solvent, additive, ammonium salt, substrate concentration, reaction temperature as well as hydrogen pressure with the standard substrate acetophenone (5a) (Tables S1−S6). Finally, the combination of 1 mol % Ru(OAc)2(4e) as catalyst, trifluoroethanol (TFE) as solvent, two equivalents of ammonium acetate as amine source, 0.5 M substrate concentration, 55 bar of H2 at 80 °C stood out, providing the corresponding primary amine 6a in 92% yield and 97% ee (entry 6, Table 1). It is noteworthy that excellent conversion is obtained when TFE is used as solvent, and possible reason is that TFE facilitates the formation of imine intermediate.9 The formation of secondary alcohol could be inhibited through choosing suitable ammonium salts in TFE (see Tables S2 and S3 for details). Interestingly, we did not observe the formation of secondary amine arising from double reductive aminations. A comparison of C3-TunePhos 4a with commercially available diphosphine ligands binap and segphos is summarized in Table 1 (entry 8 vs entries 9 and 10), This demonstrates the superiority of C3-TunePhos in this reaction. When the reaction temperature was increased from 80 to 100 °C, similar results were obtained in the presence of only 0.5 mol % catalyst loading (entry 7). Further substrate scope investigation was then carried out at 100 °C with 0.5 mol % of catalyst. The absolute configuration of the product 6a was established by comparison of its optical rotation with that reported in literature (see the Supporting Information for details). Under the optimal reaction conditions, a wide range of simple aryl ketones were subjected to this direct reductive amination procedure. In most cases, the ketones could be transformed into the corresponding primary amines with excellent enantioselectivities and moderate to high yields (Table 2). Both electron-donating (Me, tBu or MeO as in 2025

DOI: 10.1021/jacs.7b12898 J. Am. Chem. Soc. 2018, 140, 2024−2027

Communication

Journal of the American Chemical Society

molecular H2. The use of ammonia acetate as an amine source and H2 as reductant constitutes a facile and user-friendly approach to versatile primary amines, which can be easily derived into more valuable amine products. This reaction features broad substrate scope, good functional group compatibility and excellent enantiocontrol (up to 98% ee). Key intermediates of three drugs can be easily accessed in gram scale from commercially available ketones, which showcases the potential of practical usage. In addition, an improved synthetic route to the optimal diphosphine ligand C3-TunePhos was also developed.

Table 2. Substrate Scope

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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/jacs.7b12898. Detailed experimental procedures, spectral data, and analytical data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Xuefeng Tan: 0000-0002-6121-1499 Qin Yin: 0000-0003-3534-3786 Xumu Zhang: 0000-0001-5700-0608 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to a start-up fund from Southern University of Science and Technology, Shenzhen Science and Technology Innovation Committee (No. KQTD20150717103157174) and National Natural Science Foundation of China (No. 21432007) for financial support. We greatly acknowledge Professor Martin Oestreich (Technische Universität Berlin) for proofreading the paper.

a

Reaction condtions: ketone 5 (0.2 mmol), NH4OAc (0.4 mmol), Ru(OAc)2(4e) (0.5 mol %), TFE (0.4 mL), H2 (57 bar), 100 °C, 24 h. The pressure refers to the actual value at 100 °C. The free amines 6a-t were obtained after neutralizing their corresponding acetate salts with a base. The ee values were determined by chiral HPLC after sample acylation. bRu(OAc)2(4a) was used instead of Ru(OAc)2(4e). cThe ee was determined by chiral HPLC after sample tosylation.

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Scheme 3. Scale-up Syntheses of Key Intermediates of Drug Molecules

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DOI: 10.1021/jacs.7b12898 J. Am. Chem. Soc. 2018, 140, 2024−2027