Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

An efficient multicomponent reaction of newly designed β-trifluoromethyl β-diazo esters, acetonitrile, and carboxylic acids via an interrupted esterification process under copper-catalyzed conditions has been developed, which affords various unsymmetrical β-trifluoromethyl N,N-diacyl-β-amino esters in good to excellent yields. The reaction features mild conditions, a wide scope of β-amino esters and carboxylic acids, and also applicability to large-scale synthesis, thus providing an efficient way for the synthesis of β-trifluoromethyl β-diacylamino esters. Furthermore, this reaction represents the first example of a Mumm rearrangement of β-trifluoromethyl β-diazo esters.


Introduction
The insertion of fluorine-containing components frequently confers desirable physical and biological properties to organic molecules, and the development of fluorine-containing drugs is an important field of research [1][2][3][4][5][6][7][8][9].It is estimated that 30% of drugs and over 50% of agricultural chemicals contain at least one fluorine atom, among which architectural motifs contain-Scheme 1: Mumm-type rearrangement of diazo compounds.

Results and Discussion
Due to the instability of β-carbonyl diazo compounds and the occurrence of possible side reactions [58][59][60][61], screening of reaction conditions to optimize this conversion and inhibit the occurrence of side reactions was carried out with benzyl 3-amino-4,4,4-trifluorobutanoate (1a) and benzoic acid (3a) as model substrates.The initial reaction of amine 1a and acid 3a in acetonitrile in the presence of diazotization reagent tert-butyl nitrite with CuI (10 mol %) as catalysts for 2.5 h at room temperature proceeded to afford the desired unsymmetrical β-trifluoromethyl diacyl-β-amino ester 4a in 54% yield (Table 1, entry 1).The loading amount of catalyst CuI plays a crucial role in the formation of the desired product 4a.
Increasing the loading amount of CuI, the yield could be raised to 66% when 20 mol % of CuI was used as catalyst (Table 1, entries 2 and 3).However, further increasing the amount of the catalyst led to an obvious decrease in the yield of product 4a (Table 1, entries 4 and 5).Variation on the reaction temperature also afforded the corresponding product 4a but failed to bring any improvement on the reaction outcome (Table 1, entries 6 and 7).Further optimization of the reaction conditions focused on the variation of the amounts of amine 1a and tert-butyl nitrite (Table 1, entries 8-12).Considering the instability of the diazo structure generated from amine 1a, we increased the amount of amine 1a and tert-butyl nitrite to 4 equivalents.Pleasingly, the yield of product 4a was further increased to 74% (Table 1, entry 12).Furthermore, we optimized the reaction time and found that shortening the reaction time resulted in a decreased yield (Table 1, entry 13).Increasing the reaction time to 3 h also did not lead to any better result mainly due to the decomposition of product 4a (Table 1, entry 14).
With the optimized reaction conditions in hand, we next evaluated the substrate scope by using a variety of structurally diverse carboxylic acids 3 to react with β-trifluoromethyl β-amino esters 1.As shown in Scheme 2, all the substituted benzoic acids 3 tested were well tolerated in this reaction, and the corresponding product 4 was successfully prepared at moderate to excellent yields (4a-e, 4h-m, 31-86% yields).The benzoic acids featuring a wide range of functional groups, including alkyl (4a-e), halogen (4h-l), and phenyl (4m), were all suitable substrates for this reaction.However, the benzoic acid with ortho-substituent did not afford the expected product (4f) mainly due to the steric hindrance effect.Notably, substrates with electron-withdrawing groups (4h-l, 76-86% yields) provided better chemical yields in this reaction compared with those containing electron-donating groups (4b-e, 31-84% yields).For the case with a strong electron-donating group (methoxy, 3g) only traces of 4g were produced.Besides benzoic acid, the current Cu-catalyzed reaction was also applicable to other aromatic acid substrates.Using 2-naphthoic and 1-naphthoic acid as substrates, the corresponding products 4n and 4o were produced well with yields of 78% and 54%, respectively.Unfortunately, the tested aliphatic acid, such as cyclohexanecarboxylic acid, did not work in the system to produce the expected product (4p).In addition, the β-trifluoromethyl β-amino benzyl ester substrates 1 with different ester groups were tried to react with benzoic acid (3a) to further extend the substrate range.To our delight, both the amines with electron-donating groups (4q and 4r) and electron-withdrawing groups (4s and 4t) could generate the target products with moderate to good yields (46-71%).We also tried another nitrile substrate, such as cyclopropyl acetonitrile, which yielded only very small amounts of the expected product (4u).To gain insight into the mechanism of this reaction, several control experiments were performed.First, the reaction was conducted under the optimized conditions without the addition of CuI.The conversion of the starting substrates to the desired product 4a was decreased and only 14% yield of 4a was obtained (Scheme 3a).However, as shown in entry 1 of Table 1, 54% yield product 4a was produced by this reaction in the presence of 10 mol % CuI.These results demonstrate that copper catalysis plays a crucial role in the generation of the desired product 4a.Moreover, we performed this reaction without the addition of tert-butyl nitrite (Scheme 3b).The final goal of this work is the examination of the scale-up applicability of this three-component tandem reaction (Scheme 5).To our delight, the reaction also proceeded smoothly when the amount of β-trifluoromethyl β-amino ester 1a was increased ten-fold to 988.8 mg.The corresponding β-tri-Scheme 5: Scale-up synthesis.
fluoromethyl diacylamino ester 4a was obtained in 58% chemical yield.This result indicates the wide synthesis utility of the reactions reported in this work.

Conclusion
In summary, a series of new β-trifluoromethyl β-diazo esters have been designed, which are applied for the first time in a cascade reaction through an interrupted esterification with nitrile ylides as the key intermediates under copper-catalysis conditions.Varieties of unsymmetric trifluoromethyl diacyl β-amino esters can be easily constructed with good chemical yields.The reaction is conducted under mild conditions and shows good applicability to different series of substrates, which provides an efficient way for the preparation of unsymmetric trifluoromethyl diacyl β-amino esters.

Experimental
General procedure for copper-catalyzed multicomponent reaction of β-amino esters Into a flask were added amines 1 (0.4 mmol), acids 3 (0.1 mmol), CuI (20 mol %), and CH 3 CN (2 mL).Then, the mixture was stirred at room temperature under a nitrogen atmosphere and t-BuONO (0.4 mmol) was added dropwise.Stirring was continued at room temperature for 2.5 h and the solvent was removed in vacuum.Products 4 were purified on a TLC plate of 20 cm × 20 cm using petroleum ether/ethyl acetate 7:1 (v/v) as eluent.

Scheme 2 :
Scheme 2: Substrate scope study of this Cu-catalyzed reaction.
The expected threecomponent tandem reaction did not occur, and the target 4a was not observed with almost all of the starting amine 1a remaining.This result indicates the reaction proceeds through the diazo intermediate.