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DOI: 10.1039/C5RA02653A (Communication) RSC Adv., 2015, 5, 26811-26814

Ni-catalyzed asymmetric decarboxylative Mannich reaction for the synthesis of β-trifluoromethyl-β-amino ketones†

Ping Qiana, Yanling Daia, Haibo Meia, Vadim A. Soloshonokcd, Jianlin Han*ab and Yi Pana
aSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, China. E-mail: hanjl@nju.edu.cn; Fax: +86-25-83686133; Tel: +86-25-83686133
bHigh-Tech Research Institute of Nanjing University, Changzhou, 213164, China
cDepartment of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain
dIKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain

Received 11th February 2015 , Accepted 9th March 2015

First published on 9th March 2015

Abstract

A new Ni-catalyzed asymmetric decarboxylative Mannich reaction between (Ss)-N-t-butylsulfinyl-3,3,3-trifluoro-acetaldimine and β-keto-acids was developed, which was carried out at room temperature affording β-trifluoromethyl-β-amino ketones with excellent yields and diastereoselectivities.

Fluorine-containing compounds play an increasingly important role in various chemical industries ranging from life- to material-related sciences.1 In particular, the pharmaceutical industry critically depends on the methodological developments in fluorine chemistry for the design of more selective and potent new drugs.2 One of these areas is the synthesis of polyfunctional fluorinated derivatives possessing keto/hydroxy/amino groups. However, preparation of such structurally complex compounds still remains a significant synthetic challenge.3 Consistent with our continuous research on the preparation of fluorinated amines,4–9 we have developed a method for the synthesis of β-trifluoromethyl-β-amino ketones10 via an asymmetric Mannich reaction between (Ss)-N-t-butylsulfinyl-3,3,3-trifluoro-acetaldimine 1[thin space (1/6-em)]11 and acetophenone derived enolates. This reaction gave moderate yields and diastereoselectivities. Especially, the reaction needs strong base (LDA) and must be performed at low temperature (−78 °C). So, development of a simple and efficient method for the synthesis of chiral β-trifluoromethyl-β-amino ketones becomes highly urgent.12

Decarboxylative Mannich reaction of β-keto acids, which could form in situ the enolates under mild condition13 and easily construct β-amino ketones structures in cascade mode,14 has attracted broad attentions in synthetic chemistry community. Recently, Lu group reported an organocatalytic decarboxylative Mannich reaction of β-keto acids for the synthesis of chiral β-amino ketones at room temperature with moderate enantioselectivities (Scheme 1a).15 Very recently, Ma group developed a Cu-catalyzed decarboxylative Mannich reaction of β-keto acids at −20 °C with excellent enantioselectivities (Scheme 1b).16 However, the asymmetric decarboxylative Mannich reaction of β-keto acids for the synthesis of chiral trifluoromethylated β-amino ketones has never been reported. Herein, we would like to report a Ni-catalyzed asymmetric decarboxylative Mannich reaction of trifluoro-acetaldimine at room temperature for the synthesis of chiral β-trifluoromethyl-β-amino ketones with excellent chemical yields and high diastereoselectivities (Scheme 1c).


image file: c5ra02653a-s1.tif
Scheme 1 Asymmetric decarboxylative Mannich reaction of β-keto acid.

Initially, we chose β-keto acid 2a and imine 1 as model substrates for the reaction condition optimization, and the results were shown in Table 1. We were pleased to find that the reaction could proceed smoothly with CF3COOLi as catalyst in THF at room temperature, affording the desired product 3a with 65% yield and 96[thin space (1/6-em)]:[thin space (1/6-em)]4 diastereoselectivity after 12 h (entry 1). Pd(OAc)2 also worked for this reaction with excellent diastereoselectivity (98[thin space (1/6-em)]:[thin space (1/6-em)]2 dr), but the yield decreased dramatically (35%, entry 2). To further improve the reaction efficiency, several metal triflate salts were examined (entries 3–11). Among the divalent metals, such as Mg (entry 3), Ni (entry 4), Zn (entry 5), Ni-triflate catalyzed reaction gave the best result (96% yield, 98[thin space (1/6-em)]:[thin space (1/6-em)]2 dr, entry 4). Interestingly, a series of trivalent metals also could catalyze the addition reaction with almost complete stereocontrol, however the target product (R)(Ss)-3a was isolated in only moderate yields (24–67%, entries 6–11). Then, several other Ni(II) salt were tried, such as Ni(acac)2 (entry 12), Ni(OAc)2·4H2O (entry 13), NiNO3·6H2O (entry 14) and NiCl2·6H2O (entry 15). However, no improvement was found at all. Solvent also showed great effect on this reaction. The use of 1,4-dioxane (entry 20), diethyl ether (entry 21), chloroform (entry 22) afforded the product (R)(Ss)-3a with good diastereoselectivity but in rather lower chemical yields (51–72%). Finally, we conducted additional experiments to optimize the loading amount of the catalyst (entries 23–24). These experiments showed that decreasing the amount of Ni(OTf)2 catalyst to 10 mol% also could provide the desired product 3a with 92% chemical yield and 99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr when the reaction was prolonged to 24 h.

Table 1 Optimization of decarboxylative Mannich addition reaction conditionsa

image file: c5ra02653a-u1.tif
Entry Catalyst (mol%) Solvent Time (h) Yieldb (%) Drc
a Reaction conditions: 2a (0.16 mmol), imine 1 (0.1 mmol), catalyst, solvent (2 mL), at room temperature.b Isolated yields.c Determined by 19F NMR analysis.
1 CF3COOLi (30) THF 12 65 96[thin space (1/6-em)]:[thin space (1/6-em)]4
2 Pd(OAc)2 (30) THF 12 35 98[thin space (1/6-em)]:[thin space (1/6-em)]2
3 Mg(SO3CF3)2 (30) THF 12 75 99[thin space (1/6-em)]:[thin space (1/6-em)]1
4 Ni(SO3CF3)2 (30) THF 12 96 98[thin space (1/6-em)]:[thin space (1/6-em)]2
5 Zn(SO3CF3)2 (30) THF 12 53 99[thin space (1/6-em)]:[thin space (1/6-em)]1
6 Fe(SO3CF3)3 (30) THF 12 31 99[thin space (1/6-em)]:[thin space (1/6-em)]1
7 In(SO3CF3)3 (30) THF 12 24 96[thin space (1/6-em)]:[thin space (1/6-em)]4
8 Sc(SO3CF3)3 (30) THF 12 40 >99[thin space (1/6-em)]:[thin space (1/6-em)]1
9 La(SO3CF3)3 (30) THF 12 35 96[thin space (1/6-em)]:[thin space (1/6-em)]4
10 Sm(SO3CF3)3 (30) THF 12 60 >99[thin space (1/6-em)]:[thin space (1/6-em)]1
11 Yb(SO3CF3)3 (30) THF 12 67 >99[thin space (1/6-em)]:[thin space (1/6-em)]1
12 Ni(acac)2 (30) THF 12 82 82[thin space (1/6-em)]:[thin space (1/6-em)]18
13 Ni(OAc)2·4H2O (30) THF 12 76 80[thin space (1/6-em)]:[thin space (1/6-em)]20
14 NiNO3·6H2O (30) THF 12 97 97[thin space (1/6-em)]:[thin space (1/6-em)]3
15 NiCl2·6H2O (30) THF 12 85 93[thin space (1/6-em)]:[thin space (1/6-em)]7
20 Ni(SO3CF3)2 (30) 1,4-Dioxane 12 51 >99[thin space (1/6-em)]:[thin space (1/6-em)]1
21 Ni(SO3CF3)2 (30) Ether 12 72 95[thin space (1/6-em)]:[thin space (1/6-em)]5
22 Ni(SO3CF3)2 (30) CHCl3 12 28 97[thin space (1/6-em)]:[thin space (1/6-em)]3
23 Ni(SO3CF3)2 (20) THF 24 94 >99[thin space (1/6-em)]:[thin space (1/6-em)]1
24 Ni(SO3CF3)2 (10) THF 24 92 >99[thin space (1/6-em)]:[thin space (1/6-em)]1

With the optimized reaction conditions in hand, we next proceeded to study the substrate scope of this decarboxylative Mannich addition reaction (Scheme 2). The reaction showed a wide range of β-keto acids scope, and proceeded smoothly to give the corresponding β-trifluoromethyl-β-amino ketones 3a–y in excellent yields (70–99%) and high diastereoselectivities (94[thin space (1/6-em)]:[thin space (1/6-em)]6–>99[thin space (1/6-em)]:[thin space (1/6-em)]1). For the substrates with para-substituted phenyl group 2b–2j, either electronic properties or steric bulk of the substituent had almost no noticeable effect on the diastereoselectivity of the reactions. For example, product 3g, bearing bulky iso-propyl group was also isolated as diastereomerically pure compound in quantitative chemical yield. The reactions with the substrates containing meta-substituted phenyl ring, also could proceed smoothly resulting in a bit lower chemical yields (3k–3m). To have more structurally interesting derivatives, a di-substituted starting β-keto acid 2o was examined in the reaction, and >99[thin space (1/6-em)]:[thin space (1/6-em)]1 diastereoselectivity was obtained along with 98% chemical yield (3o). Naphthyl containing keto-acids 2x,y cleanly reacted with imine 1 affording the target products 3x,y in excellent yields and diastereoselectivity, and the reaction of 2-naphthyl substituted keto-acids 2y gave a little bit better yield and diastereoselectivity (98% yield, >99[thin space (1/6-em)]:[thin space (1/6-em)]1 dr). The reaction could also well tolerate the heterocyclic and ester substituted groups as disclosed by the addition reaction of β-keto acid 2w and 2p, giving the corresponding products 3w,p with excellent results. Finally we examined a series of aliphatic group containing β-keto acids 2q–t. It was noticed that these substrates with alkyl groups also worked very well in the decarboxylative Mannich reactions, yielding the products 3q–t as diastereomerically pure compounds with excellent yields. However, for the substrate with para-NO2 substituted phenyl group 2z, almost no desired product was found even the reaction time was increased to 48 h.


image file: c5ra02653a-s2.tif
Scheme 2 Substrate scope of the asymmetric decarboxylative Mannich addition reactions. (Reaction conditions: 2 (0.16 mmol), imine 1 (0.1 mmol), Ni(OTf)2 (10 mol%), in THF at room temperature for 24 h. Isolated yields. Determined on crude reaction mixtures by 19F NMR analysis).

The next study was to determine the absolute configuration of the major products 3. Throughout the study, we noticed that the major products 3a–y have a different 19F-NMR data as compared with the previously reported (S)(Ss)-β-trifluoromethyl-β-amino ketones obtained from the asymmetric Mannich reaction.10 So, we synthesized the diastereomer (S)(Ss)-3 using the reported method10 and conducted its deprotection to free amine (S)-4 (Scheme 3a). Diastereomeric compound (R)(Ss)-3, obtained in this work, was also deprotected to produce free amino-ketone (R)-4 (Scheme 3c). Finally, the racemic-4 was prepared with the same method for (R)-4 (Scheme 3b). Then, we conducted their detailed analysis by using chiral HPLC (see ESI†), which clearly showed that the compound obtained in the current decarboxylative Mannich system and that from previous Mannich reaction10 are enantiomers (see ESI†), and have opposite absolute configuration. So, the absolute configuration of compound 4 obtained in the current system is assigned as (R), and the absolute configuration of major products 3a–y, were assigned as (R)(Ss) accordingly.


image file: c5ra02653a-s3.tif
Scheme 3 Preparation of enantiomeric free amines (S)-4, (R)-4 and racemic-4 by deprotection of 3.

According to the above results and previous reports,13–16 a plausible mechanistic pathway for this decarboxylative Mannich reaction was proposed in Scheme 4. Initially, catalyst Ni(OTf)2 reacts with β-keto acid 2a to generate intermediate A. Then, intermediate A adds to chiral imine 1 to form intermediate C via the transition state B. In transition state B, the enolate hydrogen is supposed to coordinate with the oxygen of the S–O group. Therefore the enolate O–H bond can be weakened to generate the negative charge on the corresponding carbon, which accelerates the addition step. The intermediate C reacts with starting material 2a affording the intermediate D, along with the formation of intermediate A for the next catalytic cycle. Fortunately, the intermediate D has been detected by HRMS from the reaction mixture. The final step of this reaction is decarboxylation, resulting in the final product 3a with R configuration.


image file: c5ra02653a-s4.tif
Scheme 4 Possible mechanism for the asymmetric decarboxylative Mannich reaction.

Finally, the cyclization derivatization of the obtained β-trifluoromethyl-β-amino ketone product 3a was carried out (Scheme 5). (R)(Ss)-3a undergoes deprotection, aminoacylation and cyclization with phosphorus pentasulfide to give the (R)-2,6-diphenyl-4-(trifluoromethyl)-4H-1,3-thiazine17 6 with good chemical yields. Also, almost no racemation was found during the three-step transformations.


image file: c5ra02653a-s5.tif
Scheme 5 Cyclization derivatization of 3a.

In summary, we developed an asymmetric Ni-catalyzed decarboxylative Mannich reaction of chiral imine for the synthesis of β-trifluoromethyl-β-amino ketone for the first time. The reaction has a broad scope of keto-acid substrates and could be carried out under room temperature with excellent chemical yields and diastereoselectivities. The reaction provides a new and easy way for the preparation of chiral trifluoromethylated β-amino ketones, even for the large-scale preparation.

Acknowledgements

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (no. 21102071 and 21472082). The Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-Huang program (for Han) are also acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, full spectroscopic data for compounds 3–6 and copies of 1H NMR and 13C NMR spectra. See DOI: 10.1039/c5ra02653a
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