Hf(OTf)4-Catalyzed Three-Component Synthesis of N-Carbamate-Protected β-Amino Ketones

Hafnium(IV) triflate (Hf(OTf)4) has been identified as a potent catalyst for the direct three-component synthesis of β-carbamate ketones. This new method, featuring a low catalyst loading, fast reaction rate, and solvent-free conditions, provided facile access to a diversity of carbamate-protected Mannich bases. A mechanistic investigation indicated that the three-component reaction proceeds via sequential aldol condensation and aza-Michael addition, but not the Mannich-type pathway.


Introduction
β-Amino ketones, commonly known as Mannich bases, represent an important class of synthetic scaffold [1][2][3][4][5] that has been widely employed in the synthesis of pharmaceutical agents [6][7][8] and natural products [9,10]. Without a doubt, the Mannich reaction [11] is one of the most effective approaches to synthesize β-amino carbonyl compounds. It is widely accepted that the mechanism of the Mannich reaction involves the condensation of aldehyde and amine and the subsequent addition of ketone [1][2][3][4][5]. Currently, a huge number of synthetic methods have been reported for the catalyzed three-component Mannich reaction based on arylamine and alkylamine substrates [12][13][14]. Among various Mannich bases, β-carbamate ketones are of high synthetic value, because the facile removal of carbamate protecting groups offers easy access to β-primary amino ketones. However, it has been reported that the replacement of amine substrates with less reactive carbamates under the same Mannich reaction conditions typically results in significantly lowered yields [15,16].
To date, only a few catalytic systems, including AuCl 3 -PPh 3 [17], Bi(OTf) 3 [15], I 2 [18], FeCl 3 ·6H 2 O/Me 3 SiCl [19], H 3 PW 12 O 40 [20], Me 2 S + BrBr − [21], and PPh 3 Br 2 [22], have been developed to enable direct one-pot, three-component synthesis of β-carbamate ketones from aldehydes, ketones, and carbamates. However, these methods are limited by drawbacks, such as slow reaction rate, low to moderate yields, high catalyst loading, and use of stinky, corrosive, or expensive catalysts. Whilst the catalytic mechanisms of Me 2 S + BrBr − and PPh 3 Br 2 have not been studied, those of the other methods have simply been described as Mannich-type reactions without substantial evidence regarding the formation of key aldimine intermediates. Since it is known that aldimine is extremely hard to form directly from aldehyde and carbamate [23,24], the proposed Mannich reaction-based mechanisms of these reactions are disputable. The true underlying reaction pathways of these carbamatebased three-component reactions still need to be elucidated.

as a highly
Molecules 2022, 27, 1122 2 of 8 reactive catalyst for the Mannich reaction [31] inspired our further exploration of its application in the one-pot synthesis of β-carbamate-protected Mannich bases. Herein, we report the development of a novel Hf(OTf) 4 -catalyzed three-component reaction of aldehydes, ketones, and carbamates for the efficient synthesis of β-carbamate ketones. An experimentbased mechanistic investigation was also conducted to reveal the underlying mechanism of this three-component reaction.

Results and Discussion
In the preliminary experiments, we tested the catalytic reactivity of a series of Lewis acids of Group IVB transition metals. The reaction of 1.0 equiv of acetophenone, 1.0 equiv of benzaldehyde, and 1.5 equiv of benzyl carbamate (Cbz-NH 2 ) in CH 3 CN was performed in the presence of 10 mol% of Lewis acid catalyst at ambient temperature. The results listed in Table 1 showed that most of these catalysts, including ZrCl 4 , bis(cyclopentadienyl)zirconium dichloride (ZrCp 2 Cl 2 ), ZrOCl 2 , Zr(NO 3 ) 4 , ZrO(NO 3 ) 2 , hafnium acetylacetonate (Hf(acac) 4 ), and bis(cyclopentadienyl)hafnium dichloride (HfCp 2 Cl 2 ), were ineffective in this one-pot, three-component synthesis of β-carbamate ketone 1. Only Hf(OTf) 4 and HfCl 4 exhibited moderate catalytic activity. However, this is significantly lower than that observed in the Mannich reaction under similar conditions [31]. such as the selective anomeric deacetylation of peracetylated saccharides [26], the Biginelli reaction [27], and the synthesis of fluorinated benzimidazolines [28] and pyrimido [2,1b] [1,3]benzothiazoles [29,30]. Our recent identification of Hf(OTf)4 as a highly reactive catalyst for the Mannich reaction [31] inspired our further exploration of its application in the one-pot synthesis of β-carbamate-protected Mannich bases. Herein, we report the development of a novel Hf(OTf)4-catalyzed three-component reaction of aldehydes, ketones, and carbamates for the efficient synthesis of β-carbamate ketones. An experiment-based mechanistic investigation was also conducted to reveal the underlying mechanism of this three-component reaction.

Results and Discussion
In the preliminary experiments, we tested the catalytic reactivity of a series of Lewis acids of Group IVB transition metals. The reaction of 1.0 equiv of acetophenone, 1.0 equiv of benzaldehyde, and 1.5 equiv of benzyl carbamate (Cbz-NH2) in CH3CN was performed in the presence of 10 mol% of Lewis acid catalyst at ambient temperature. The results listed in Table 1 showed that most of these catalysts, including ZrCl4, bis(cyclopentadienyl)zirconium dichloride (ZrCp2Cl2), ZrOCl2, Zr(NO3)4, ZrO(NO3)2, hafnium acetylacetonate (Hf(acac)4), and bis(cyclopentadienyl)hafnium dichloride (HfCp2Cl2), were ineffective in this one-pot, three-component synthesis of β-carbamate ketone 1. Only Hf(OTf)4 and HfCl4 exhibited moderate catalytic activity. However, this is significantly lower than that observed in the Mannich reaction under similar conditions [31]. In the following research, the effects of solvent on the Hf(OTf)4-catalyzed three-component synthesis of 1 were explored. The experimental results ( Table 2, Entry 1-4) showed that Hf(OTf)4 exhibited similar moderate catalytic activities in CH2Cl2, toluene, and THF with an even slower reaction rate, whereas Hf(OTf)4 was totally ineffective in DMF. Interestingly, under solvent-free conditions, the reaction time was remarkably shortened to 8 h and the yield of 1 was improved to 82%. The elevation of reaction temperature from 20 to 80 °C further shortened the reaction time to 30 min and increased the yield to 91%. However, the yield of 1 dropped when the temperature increased to 100 °C due to the generation of polar by-products ( In the following research, the effects of solvent on the Hf(OTf) 4 -catalyzed threecomponent synthesis of 1 were explored. The experimental results ( Table 2, Entry 1-4) showed that Hf(OTf) 4 exhibited similar moderate catalytic activities in CH 2 Cl 2 , toluene, and THF with an even slower reaction rate, whereas Hf(OTf) 4 was totally ineffective in DMF. Interestingly, under solvent-free conditions, the reaction time was remarkably shortened to 8 h and the yield of 1 was improved to 82%. The elevation of reaction temperature from 20 to 80 • C further shortened the reaction time to 30 min and increased the yield to 91%. However, the yield of 1 dropped when the temperature increased to 100 • C due to the generation of polar by-products (Table 2, Entry 6-7). In addition, the amount of Hf(OTf) 4 catalyst was also optimized. The experimental results showed that when as little as 2 mol% Hf(OTf) 4 was used, the reaction could still afford 1 in an excellent yield (90%) within 2 h. However, further reducing the amount of Hf(OTf) 4 to 1 mol% caused an incomplete reaction and a drop in yield. In a control experiment, when Hf(OTf) 4 was replaced by TfOH, the reaction under the same conditions only afforded a trace amount of 1, confirming the catalytic role of Hf(OTf) 4 . Table 2. Effects of solvent, temperature, and amount of catalyst loading on the three-component synthesis of 1 1 . catalyst was also optimized. The experimental results showed that when as little as 2 mol% Hf(OTf)4 was used, the reaction could still afford 1 in an excellent yield (90%) within 2 h. However, further reducing the amount of Hf(OTf)4 to 1 mol% caused an incomplete reaction and a drop in yield. In a control experiment, when Hf(OTf)4 was replaced by TfOH, the reaction under the same conditions only afforded a trace amount of 1, confirming the catalytic role of Hf(OTf)4. With the optimized conditions, the substrate scope of the Hf(OTf)4-catalyzed direct synthesis of β-carbamate ketones was explored. The data in Table 3 showed that this new approach tolerated a variety of substituents on both acetophenone and benzaldehyde substrates at different positions. It also maintained a good catalytic efficacy in the synthesis of ethyl carbamate products. As shown in Table 3, a range of β-carbamate carbonyl compounds 1-20 were obtained in 75-91% yields in 2-4 h under solvent-free conditions. It was noted that the reactions with p-nitrobenzaldehyde were relatively slower and lower-yielding. This is in accordance with the previous reports that nitro-containing benzaldehydes are typically less reactive substrates in this three-component reaction [17,19,20,32].
Multicomponent reactions (MCRs), which employ three or more reactants to yield a product derived from all the starting materials in a one-pot manner, have long been recognized as a powerful tool to enrich molecular diversity in natural product synthesis and medicinal chemistry [33][34][35]. However, the revelation of the reaction mechanisms of MCRs, which is crucial for condition optimization and the manipulation of stereochemistry outcomes, has always been a challenging task due to the multiple potential reaction pathways and the difficulty of capturing key intermediates [35][36][37]. To elucidate the reaction pathway for the three-component synthesis of β-carbamate ketones, we separately tested the reactivity of each component to another under solvent-free conditions. As shown in Scheme 1A and 1B, Cbz-NH2 does not react with either acetophenone or benzal- With the optimized conditions, the substrate scope of the Hf(OTf) 4 -catalyzed direct synthesis of β-carbamate ketones was explored. The data in Table 3 showed that this new approach tolerated a variety of substituents on both acetophenone and benzaldehyde substrates at different positions. It also maintained a good catalytic efficacy in the synthesis of ethyl carbamate products. As shown in Table 3, a range of β-carbamate carbonyl compounds 1-20 were obtained in 75-91% yields in 2-4 h under solvent-free conditions. It was noted that the reactions with p-nitrobenzaldehyde were relatively slower and lower-yielding. This is in accordance with the previous reports that nitrocontaining benzaldehydes are typically less reactive substrates in this three-component reaction [17,19,20,32].
Multicomponent reactions (MCRs), which employ three or more reactants to yield a product derived from all the starting materials in a one-pot manner, have long been recognized as a powerful tool to enrich molecular diversity in natural product synthesis and medicinal chemistry [33][34][35]. However, the revelation of the reaction mechanisms of MCRs, which is crucial for condition optimization and the manipulation of stereochemistry outcomes, has always been a challenging task due to the multiple potential reaction pathways and the difficulty of capturing key intermediates [35][36][37]. To elucidate the reaction pathway for the three-component synthesis of β-carbamate ketones, we separately tested the reactivity of each component to another under solvent-free conditions. As shown in Scheme 1A,B, Cbz-NH 2 does not react with either acetophenone or benzaldehyde alone in the presence of 2 mol% of Hf(OTf) 4 at 80 • C, which excluded the possibility of a Mannich-type reaction mechanism. On the other hand, simply heating benzaldehyde and acetophenone at 80 • C without Hf(OTf) 4 caused no reaction (Scheme 1C). However, the addition of Hf(OTf) 4 dramatically promoted the aldol condensation to afford chalcone in a high yield (90%, 2 h). This result is in agreement with the precedents of metal Lewis acid-catalyzed aldol condensation [38][39][40]. In the next stage, we tested the reaction between Cbz-NH 2 and chalcone in the presence or absence of Hf(OTf) 4 (Scheme 1D). The experimental results showed that the two components did not react in the absence of a catalyst. In contrast, Hf(OTf) 4 catalyzed the highly efficient conversion to 1 (99%, 1 h). This result is supported by the previous reports on the catalytic aza-Michael addition of carbamates to enones [32,[41][42][43]. Taken together, it is proposed that the Hf(OTf) 4 -catalyzed three-component reaction proceeds via sequential aldol condensation and aza-Michael addition to afford the desired β-carbamate ketones (Scheme 2). Hf(OTf) 4 exerts catalytic effects on both steps. This is perhaps because the Hf(IV) strongly activates the carbonylcontaining substrates, including benzaldehyde, acetophenone, and chalcone, in both steps (Scheme 2), as has been demonstrated in previous research [27,31,32,44]. Lewis acid-catalyzed aldol condensation [38][39][40]. In the next stage, we tested the reaction between Cbz-NH2 and chalcone in the presence or absence of Hf(OTf)4 (Scheme 1D). The experimental results showed that the two components did not react in the absence of a catalyst. In contrast, Hf(OTf)4 catalyzed the highly efficient conversion to 1 (99%, 1 h). This result is supported by the previous reports on the catalytic aza-Michael addition of carbamates to enones [32,[41][42][43]. Taken together, it is proposed that the Hf(OTf)4-catalyzed three-component reaction proceeds via sequential aldol condensation and aza-Michael addition to afford the desired β-carbamate ketones (Scheme 2). Hf(OTf)4 exerts catalytic effects on both steps. This is perhaps because the Hf(IV) strongly activates the carbonylcontaining substrates, including benzaldehyde, acetophenone, and chalcone, in both steps (Scheme 2), as has been demonstrated in previous research [27,31,32,44]. Lewis acid-catalyzed aldol condensation [38][39][40]. In the next stage, we tested the reaction between Cbz-NH2 and chalcone in the presence or absence of Hf(OTf)4 (Scheme 1D). The experimental results showed that the two components did not react in the absence of a catalyst. In contrast, Hf(OTf)4 catalyzed the highly efficient conversion to 1 (99%, 1 h). This result is supported by the previous reports on the catalytic aza-Michael addition of carbamates to enones [32,[41][42][43]. Taken together, it is proposed that the Hf(OTf)4-catalyzed three-component reaction proceeds via sequential aldol condensation and aza-Michael addition to afford the desired β-carbamate ketones (Scheme 2). Hf(OTf)4 exerts catalytic effects on both steps. This is perhaps because the Hf(IV) strongly activates the carbonylcontaining substrates, including benzaldehyde, acetophenone, and chalcone, in both steps (Scheme 2), as has been demonstrated in previous research [27,31,32,44]. Lewis acid-catalyzed aldol condensation [38][39][40]. In the next stage, we tested the reaction between Cbz-NH2 and chalcone in the presence or absence of Hf(OTf)4 (Scheme 1D). The experimental results showed that the two components did not react in the absence of a catalyst. In contrast, Hf(OTf)4 catalyzed the highly efficient conversion to 1 (99%, 1 h). This result is supported by the previous reports on the catalytic aza-Michael addition of carbamates to enones [32,[41][42][43]. Taken together, it is proposed that the Hf(OTf)4-catalyzed three-component reaction proceeds via sequential aldol condensation and aza-Michael addition to afford the desired β-carbamate ketones (Scheme 2). Hf(OTf)4 exerts catalytic effects on both steps. This is perhaps because the Hf(IV) strongly activates the carbonylcontaining substrates, including benzaldehyde, acetophenone, and chalcone, in both steps (Scheme 2), as has been demonstrated in previous research [27,31,32,44]. Table 3. Hf(OTf)4-catalyzed three-component synthesis of β-carbamate ketones 1-20.

General Methods
Chemical reagents and solvents were purchased from Leyan-Shanghai Haohong Scientific Co. Ltd., Shanghai, China. Reactions were monitored by TLC plates coated with Scheme 2. Proposed reaction mechanism for Hf(OTf) 4 -catalyzed three-component reaction.

General Methods
Chemical reagents and solvents were purchased from Leyan-Shanghai Haohong Scientific Co., Ltd., Shanghai, China. Reactions were monitored by TLC plates coated with 0.25 mm silica gel 60 F 254 and visualized by UV irradiation (254 nm). Flash column chromatography employed silica gel (particle size 32-63 µm, Qingdao Haiyang Chemicals, Qingdao, China). NMR spectra were acquired on an AV-400 instrument (Bruker BioSpin, Faellanden, Switzerland) with chemical shifts reported in ppm and referenced to CDCl 3 . IR spectra were obtained with a Vertex-70 instrument (Bruker Optics, Billerica, MA, USA). High-resolution mass spectra were obtained with a Dalton micrOTOF-Q II spectrometer (Bruker Optics, Billerica, MA, USA) and reported as m/z. Melting points were determined with an X-4 digital melting point apparatus and uncorrected (Tech Instrument, Beijing, China). The characterization data of known compounds 1-9, 11, and 13-17 are in agreement with previous reports [17,18,20,23,32,45] and listed in the Supplementary Materials. The characterization spectra of new compounds 10, 12, 18-20 are also provided in the Supplementary Materials.

Conclusions
In summary, we developed a Hf(OTf) 4 -catalyzed one-pot method for the synthesis of β-carbamate-protected Mannich bases directly from the reaction of aldehydes, ketones, and carbamates. Compared to the previously reported catalytic systems, this new method only requires 2 mol% catalyst and affords a diversity of β-carbamate ketones under solventfree conditions in excellent yields within only 2-4 h. Our experimental results based on sequential bimolecular reactions show that the Hf(OTf) 4 -catalyzed three-component reaction should not be categorized as a Mannich or Mannich-type reaction. The replacement of amine with much less reactive carbamate radically changes the reaction pathway to sequential aldol condensation and aza-Michael addition.