Reductive Amination of Ketones or Amination of Alcohols over Heterogeneous Cu Catalysts: Matching the Catalyst Support with the N‐Alkylating Agent

Abstract

The perfect match: Supported Cu catalysts can be used for the synthesis of aromatic secondary amines. The choice of catalyst support is tunable according to the alkylating agent that is used. The goals of improved sustainability and cost-competitiveness in fine-chemicals synthesis can be achieved by increasing the selectivity (and hence yield) of the reactions and by reducing the lead time of the entire production process by introducing multifunctional processes.1 In this context, the direct reductive amination (DRA) of aldehydes and ketones, that is, reactions in which the carbonyl compound and the amine are mixed with an appropriate reducing agent without prior formation of the intermediate imine, is a highly attractive procedure in the synthesis of primary, secondary, or tertiary amines.2 However, this reaction is not straightforward. Water is produced during the in situ formation of the imine, which means that the reducing agent has to be stable in the presence of water. This limitation is why some preparation methods involve the use of drying agents, such as molecular sieves3, 4 or TiCl4,5 to bind water. Moreover, imine formation is acid-catalyzed; therefore, the reducing agent must also be stable under acidic conditions. Finally, the rate of reduction of the carbonyl compound must be slower than that of imine formation.6 To meet these requirements, NaBH3CN and NaBH(OAc)3 have been widely used. However, NaBH3CN is highly toxic; thus, the disposal of byproducts and contamination of the products are an issue and it requires the use of a fivefold excess of the amine and long reaction times with aromatic ketones. NaBH(OAc)3 is less toxic but flammable, it reacts with water, and it has several limitations with aromatic, α,β-unsaturated, and sterically hindered ketones.7 Other boron-based systems, such as α-picoline-borane, have shown the same limitations.8 Recently, homogeneous Fe-based systems9 and Leuckardt-type DRA reactions with the formate derivatives of aldehydes and aliphatic ketones have also been reported.10 A Lewis acid, Zn(ClO4)2⋅6 H2O, in combination with a hydride donor, such as the InCl3/Et3SiH system, has been proposed.11 However, in this case, aromatic ketones again displayed very low reactivity. Interestingly, fairly good yields were obtained for the amination of acetophenone by uniformly adsorbing the carbonyl compound and the amine onto the surface of activated silica gel, stirring the mixture until complete formation of the imine had occurred, and then adding a solution of ZnBH4.12 Furthermore, Zn(OTf)2, in combination with poly(methylhydrosiloxane) (PMHS) as a hydride source, was reported to be an useful system for the amination of aldehydes.13 Some drawbacks of these methods are related to the use of Lewis acids that cannot easily be recovered and reused. Moreover, the use of common hydride donors results in the production of large amounts of waste and inorganic salts that require time-consuming work-up and costly purification procedures. Conversely, the use of molecular hydrogen would lead to notable advantages in terms of efficiency. Heterogeneous catalytic hydrogenation reactions can be employed, of which, Raney Ni and Pd/C are the most-used catalysts, but they can give a mixture of products if the as-produced amine competes with the reactant amine in the carbonyl-condensation step. Therefore, a large excess of primary amine is required to give preferential formation of the secondary amine.14 Sulfide catalysts, in particular platinum- and rhodium–sulfide catalysts, are used to minimize the reduction of the carbonyl group into an alcohol and to avoid hydrodehalogenation. These catalysts are much-less active than nonsulfide catalysts and require, for their economic use, elevated temperatures and pressures (50–180 °C, 20–135 atm H2; 1 atm=101.3 kPa).15 Moreover, serious limitations arise when other reducible or hydrogenolyzable functional groups are present in the substrate. In particular, the reactions of primary amines with acetophenone require a very selective catalyst because the aromatic ketone is readily hydrogenolyzed into ethylbenzene. N-phenyl-α-methylbenzylamine, which is useful as an antioxidant, was obtained in 6 % yield from acetophenone and aniline over a Pt/C catalyst by using a large (15:1) excess of aniline under 30–50 atm pressure of H2. To improve the yield to 94 %, 35 % by weight of a platinum–sulfide catalyst was used under the same conditions.16 Two-step procedures that involved the separation of the imine in the presence of a dehydrating agent were preferred. The use of Rh complexes as homogeneous catalysts has also been reported under H2 pressure (50 atm).17, 18 We have long been interested in devising highly selective heterogeneous catalytic processes for the reduction of olefins and carbonyl groups in pharmaceutical intermediates.19 We are also interested in the design of multifunctional catalysts, which contain both acidic and hydrogenation sites, that would allow us to shorten the number of steps in a synthetic pathway.20 Recently, we also reported the acidic activity of a CuO/SiO2 catalyst, which allowed us to perform the alcoholysis of epoxides under very mild conditions.21 Herein, we report that, in its reduced form, the Cu/SiO2 catalyst can effectively promote the direct reductive amination of aromatic ketones without the need for any additive or dehydrating agent. This catalyst has the advantages of being a non-noble-based system, heterogeneous, and active under very mild experimental conditions, thus affording a highly efficient reaction procedure, both in terms of waste-reduction and with regard to safety concerns. Table 1 shows the results that were obtained in the reaction of p-methoxyacetophenone with aniline at 100 °C and 1 atm of H2 over various pre-reduced copper catalysts. Entry Catalyst[a] t [h] Conversion [%] DRA product [%] Imine [%] Alcohol [%] 1 no catalyst 24 – – – – 2 Cu/SiO2Al2O3 2 100 96 1 – 3 Cu/SiO2TiO3 6 100 97 1 0.5 4 Cu/Al2O3 5 86 25 – 75 5 Cu/SiO2 2.5 98 88 2 6 6 Cu/Aerosil 2 100 84 – 5 It is apparent that the catalyst that is supported on acidic silica–alumina shows excellent activity and selectivity in this reaction, thereby resulting in an atom efficiency of 92.6 %. This result is in agreement with what was observed in the direct etherification reaction. That is, we have previously reported that this catalyst is able to convert p-methoxyacetophenone into 1-(4-methoxyphenyl)-ethyl-2-propyl ether within 1 h at 80 °C through a one-step reaction with 2-propanol.20 A similar catalyst that was prepared by using silica–titania as the support also gave excellent results, albeit in longer reaction times (Table 1, entry 3). On the contrary, Cu/Al2O3 afforded a very low yield of the amine owing to its high activity for reducing aromatic ketones;22 this result shows that the choice of catalyst is not trivial. However, the performance of Cu/SiO2 was only slightly poorer, with a selectivity of 88 % for the amine and 6 % for the alcohol. This material was active in its unreduced native form as a Lewis acid catalyst for the alcoholysis of epoxides21 and very active when reduced in the selective hydrogenation of, for example, 4-(6-methoxy-2-naphtyl)-3-buten-2-one into nabumetone.19 This result prompted us to look for a possible synergy of these two active sites in the DRA of aromatic ketones. Analogous results were obtained with nonporous silica (Table 1, entries 5 and 6). Interestingly, in the absence of hydrogen, only the imine was formed, but conversion was very low on both the Cu/SiO2Al2O3 and the Cu/SiO2 catalysts. This result clearly shows that the hydrogenation step drags the reaction towards completion, thus overcoming the low activity of the catalysts in forming the imine under these conditions (Figure 1 and the Supporting Information, Figure S2). Increase in conversion owing to the hydrogenation step after a reaction time of 2 h. Owing to the ease of preparation and the availability of the support, we chose the Cu/SiO2 catalyst to investigate the substrate scope of this reaction (Table 2). The use of a 3:1 amine/ketone molar ratio allows us to avoid dialkylation and to obtain the highest selectivity for the desired DRA product (see the Supporting Information, Table S2). Entry Substrate Amine t [h] Conversion [%] DRA product [%] Imine [%] Alcohol [%] 1 5 97 80 9.0 9.1 2 12 100 93 (86)[b] 3.88 0.6 3 11 100 92 1.6 0.1 4 4 100 98 – – 5 5.5 100 88 (83)[b] 2.66 3.1 6 9 99.1 86 4.56 6.6 7 24 81.6 69 25.5 1.6 8 24 93 75 – 21 9 20 40 86 2 12 10 20 65 8.5 – 77 11 20 45 22 1.6 75.4 12[c] 20 79 51 – 46 13 24 96 28 – 28.9 14 20 72 – 95 1.25 15 24 72.4 5.4 88.5 5.4 16 12 93.3 13.5 79.5 0.73 17 0.5 24 100 100 – – 100 100 – – Very high yields of the amine were obtained for electron-rich aromatic ketones and aromatic amines (Table 2, entries 1–6). Among the aliphatic amines that were considered, only morpholine gave an acceptable yield of the desired product; in the other examples, hydrogenation of the ketone into the alcohol was dominant or competitive (Table 2, entries 10–12). Next, we investigated the effect of substitution on the aromatic ketone (Table 3). As a general trend, the reaction is favored by the presence of an electron-donating group on the aromatic ketone. On the other hand, the presence of an electron-withdrawing substituent leads to the formation of the imine, but the subsequent hydrogenation into the secondary amine does not take place under these conditions. The reaction of p-nitroacetophenone affords the imine together with the reduction of the nitro group into the amine. Entry Substrate t [h] Conversion [%] Amine [%] Imine [%] Alcohol [%] 1 2.5 98 88 2 6 2 24 99 76.8 0.7 15.8 3 2.5 24 80 91 0.8 13 88 60 11 26 4 9 80.3 4.8 87 7.1 5 24 73.4 0 88.7 11.2 6 24 91.8[b] 0 49.1 0 7 24 54.8 88.5 – 7.4 8 24 49.8 30.5 52.8 15.5 The electronic effects of substituents on the aromatic ring were confirmed by the reactions of series of o-, m- and p-methoxyacetophenones. The reaction with the ortho isomer was significantly slower than that of the para isomer, owing to steric effects, but still resulted in the formation of the desired secondary amine. On the contrary, with m-methoxyacetophenone, with comparable conversion of the starting material, a mixture of the imine and amine products was obtained. These results suggest that the hydrogenation reaction is strongly influenced by electronic effects, as has already been observed in the reduction of aromatic ketones.22 In turn, the progress of the hydrogenation step influences the formation of the imine, which slows down when the hydrogenation does not take place (Figure 1). Unsubstituted acetophenone gave the imine with fairly good selectivity but failed to give the amine, even after long reaction times (Table 3, entry 3). Moreover, a test reaction on the pure imine showed that this substrate was not hydrogenated under these conditions (see the Supporting Information, Table S3). The effect of water that was formed from the condensation step on the hydrogenation reaction was investigated by adding water in equimolar amounts into the same experiment. No significant influence was observed on the hydrogenation reaction, but hydrolysis took place to a significant extent, presumably owing to the high concentration of water from the beginning of the reaction. It should be emphasized that, with respect to substituted aromatic rings, acetophenone could represent a unique case because the adsorption phenomena for this substrate on heterogeneous systems could be significant, as has already been observed for Pd catalysts.23 The reaction conditions were very mild; in particular, the H2 pressure was only 1 atm. Notably, Pd and Pt catalysts are only active between 5–80 atm H2.24–26 The use of 100 °C as the reaction temperature was due to the slower reaction rate when the catalytic test was performed at 80 °C (see the Supporting Information, Table S2). DRA reactions of aromatic ketones are rare when hydride-donor systems are used. Montmorillonite-supported NaBH4 under microwaves irradiation has afforded good results in the DRA of acetophenone with aniline27 and only one example (1-indanone) was reported with Zn(ClO4)2 as the catalyst and InCl3/Et2SiH as the hydrogen donor.11 Pd-exchanged molybdophosphoric acid that was supported on silica only gave trace amounts of the amine when used in the DRA of ketones28 and only aliphatic ketones were converted by sulfonic acid that was supported on hydroxyapatite-encapsulated Fe2O3 nanocrystallites.29 Moreover, in general, amine–borane was more active with aldehydes and aliphatic ketones.6 Furthermore, for some of the other combinations of substrate and amine, this method was effective for the synthesis of imines (Table 2, entries 14–17). There is a growing interest in finding new synthetic methods for imines, either through the oxidation of amines30–32 or from alcohols and amines.33 CuII salts can be used in the presence of equimolar amounts of KOH with the amine and molecular O2,34 but this method fails with secondary alcohols. The catalytic system has already been widely investigated.35 It is characterized by the presence of a highly dispersed CuO phase on the silica matrix, which is easily reducible into supported metallic Cu [see the temperature-programmed reduction (TPR) analysis in the Supporting Information, Figure S1]. This system is truly heterogeneous, as shown by a hot-filtration test (see the Supporting Information, Figure S3) and the catalyst was reusable up to three times without requiring any treatment or reactivation of the catalyst (Figure 2). Recyclability of the Cu/SiO2 catalyst in the direct reductive amination of p-methoxyacetophenone. As has already been observed in alcoholysis reactions,21 the drop in activity could reasonably be due to a feeble poisoning of the catalyst surface rather than to an actual deactivation. Trace analysis after the catalytic test did not show any contamination of the product with copper. Our procedure involves the use of H2 but does not require any additive, does not produce any waste, and the mild reaction conditions are able to avoid side-reactions, such as dehalogenation (Table 3, entry 4); moreover, this procedure can be proposed as an alternative method for the synthesis of ketimines. Environmental benefits that are due to the use of a heterogeneous system, such as Cu/SiO2, are worth underlining. In particular, the formation of waste to be disposed of is very low compared with other systems: For example, in the case of Zn(ClO4)2⋅6 H2O with InCl3/Et3SiH, the E factor was 2.4, whereas, under our typical reaction conditions (i.e., in the DRA of p-methoxyacetophenone with aniline), the E factor is <0.2.36 For the synthesis of a benzylidene amine, it appears more convenient to start from the corresponding ketone, which is the first intermediate in the functionalization of aromatic compounds by using the Friedel–Crafts acylation reaction. However, the catalytic amination of alcohols by using the so-called “borrowing-hydrogen” methodology has received a lot of attention in the last few years,37 including in the pharmaceutical industry.38 Therefore, we investigated the potential use of Cu/Al2O3 in this reaction. This material was an effective catalyst in the oxidation of a wide series of alcohols, including cyclohexanols and steroidal alcohols, through a transfer-dehydrogenation reaction from the alcohol substrate to styrene under very mild liquid-phase experimental conditions (90 °C, N2 atmosphere). Moreover, this catalyst also showed unusual selectivity: Only secondary and allylic alcohols were dehydrogenated, even in the presence of unprotected primary and benzylic alcohols. Electronic effects and the choice of hydrogen acceptor accounted for the observed selectivity.39a,39b The results for the “borrowing-hydrogen” amination of various alcohols are reported in Table 4. Excellent results were obtained in the n-alkylation of aniline with p-methoxyphenylethanol (24 h, 130 °C, 92 % yield); moreover, cyclooctanol and 3-octanol also gave good results, which showed that their corresponding imines acted as effective hydrogen acceptors. Entry Substrate Conversion [%] DRA product [%] 1 95 97 2 97.1 81.9 3 89.4 84.8 RuII and IrI complexes are able to catalyze the direct alkylation of amines by alcohols under hydrogen-transfer conditions,37 and a Cu(OAc)2/tBuOK system gave good-to-excellent yields in the N-alkylation of aromatic amines with benzylic alcohols within 2 days, although, in the case of 4-chlorobenzyl alcohol, some dehalogenation occurred.40 As far as heterogeneous catalysts are concerned, a Pd/MgO catalyst was active at 180 °C: a 3:1 aniline/alcohol ratio gave about 81 % of the desired amine.41 Cu catalysts require high H2 pressures, high reaction temperatures, and/or stoichiometric amounts of base to obtain good yields.42, 43 Only supported Cu(OH)244 gave good results without the need for additional base at 135 °C. However, none of these systems afforded a high yield of secondary amines from a secondary aliphatic alcohol. This result was due to the unique activity of the Cu/Al2O3 catalyst for the dehydrogenation of secondary alcohols. In conclusion, very simple and truly heterogeneous copper catalysts are effective for the synthesis of secondary amines. This synthesis can take place starting from an aromatic ketone through a one-pot direct-reductive-amination reaction over a slightly acidic, pre-reduced Cu/silica catalyst. This procedure was used to prepare a range of arylbenzylamines in one step under very mild reaction conditions. The catalyst was heterogeneous in nature and no waste was produced. Furthermore, a Cu/Al2O3 system, which was very active in hydrogen-transfer reactions, allowed us to synthesize secondary amines from aromatic or aliphatic secondary alcohols through a “borrowing hydrogen” mechanism. Experimental details are reported in the Supporting Information. The Italian Ministry of Education, University, and Research is acknowledged for financial support through the Project “Ital-NanoNet” (Rete Nazionale di Ricerca sulle Nanoscienze, project No. RBPR05JH2P). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.