Based on our recent research interest in the development of hydrogenation transfer reactions(Liu et al., 2019; Shao et al., 2020; Shao et al., 2022), we conducted studies on Guerbet catalysis using our previously reported manganese pincer-type complexes. Standard reaction conditions employed a 10 mL vial containing 6 mmol benzylic alcohol 1a, 1 mmol ethanol 2, 1 equiv. NaOEt as the base, and 0.5 mol% Mn precatalyst. After the reaction mixture was heated to 140 oC for 16 h, the product distribution was determined by GC using biphenyl as an internal standard (Table S1, Supporting Information). Higher activity was observed when cyPNP-Mn(I) complex [Mn]-II (entry 2) was used instead of iPrPNP-Mn(I) complex [Mn]-I (entry 1). Analysis of the reaction products (entry 2) exhibited 97% conversion of ethanol and a high yield (85% GC yield and 77% isolated yield) for the production of phenylpropanol 3a, which is consistent with Guerbet coupling of benzylic alcohol with EtOH. In addition, the evolved gas during the reaction process was collected and the H2 was detected by GC as a result of dehydrogenation of the alcohols. Meanwhile, the mainly byproduct 4 also can be determined with 4% yield, which was generated via the homocoupling of ethanol. The PhPNP-Mn(I) complex [Mn]-III afforded a lower yield of 3a than [Mn]-I and [Mn]-II (entry 3). In contrast, only 21% yield was afforded using Mn(I) complexes supported by the bulkier tBuPNP ligand ([Mn]-IV) (entry 4). The reactivities of other Mn salts were also studied under similar conditions. Mn complexes, MnCl2 and Mn(CO)5Br, failed to catalyse the reaction (entries 5 and 6), and there was no reaction in the absence of the Mn catalyst (entry 19), indicating the importance of the Mn catalysts and the supporting pincer ligands. Furthermore, the effects of various bases such as NaOH, NaOCH3, and tBuONa was examined, and the yields of 3a were 76, 78, and 62%, respectively (entries 7–9). Moreover, the weakly basic Na2CO3 did not react (entry 10).
Next, we investigated the influence of temperature, amount of base, ratio between 1a and ethanol, and other reaction parameters. A lower temperature (120°C) resulted in a decreased yield, whereas very similar results were obtained at an increased temperature (165°C) (entries 11 and 12). Moreover, a reduced amount of the base (0.8 equiv. of NaOEt) afforded a lower yield, and further increase in the base loading (1.2 equiv. of NaOEt) did not increase the yield of 3a (entries 13 and 14). An increase of the amount of 1a to 7 mmol resulted in a similar yield of 3a, whereas a decrease in the amount of 1a from 6 to 5 mmol resulted in a lower yield (entries 15 and 16). Finally, considering the advantages of cheap and widely available ethanol, excess ethanol was used instead of benzyl alcohol and compared efficient can be obtained when 1 mmol of 1a and 6 mmol of ethanol or 1 mmol of 1a and 8 mmol of ethanol were used in the reaction (entries 17, 18).
With the optimised conditions in hand, we explored the substrate scope of the reaction using the conditions listed in entry 2 of Table 1, with [Mn]-II as the catalyst. First, we observed that a wide range of substituted primary benzylic alcohol derivatives underwent a smooth cross-coupling reaction with ethanol while tolerating several functional groups. As shown in Scheme 1, the corresponding phenylpropanols were obtained in good to excellent yields. Specifically, the electron-donating functionalities such as methyl, methoxy, isopropyl, t-butyl, and methylthio substituents at the p-position on the aryl ring of alcohol were well-tolerated and afforded the expected phenylpropanols 3b − 3f in 75–89% yields. Moreover, alcohols bearing electron-withdrawing halogen substituents, such as 4-chloro, 4-bromo, and 4-iodo, were observed to be excellent coupling partners of ethanol under reductive reaction conditions and selectively furnished products 3g − 3i in moderate to good yields, albeit in reduced yields. Moreover, 4-trifluoromethyl, 4- cyano, and 4-phenyl substituents are suitable for this transformation. In addition, methyl-substituted benzyl alcohols at C-2 and C-3 positions were well tolerated and afforded products 3m and 3m in 83% and 86% yield, respectively (entries 8 and 9). Furthermore, sterically hindered 1-naphthalenemethanol and 2-naphthalenemethanol also successfully reacted with ethanol to afford the desired 3o and 3p in 63 and 76% yields, respectively. Analogously, the catalyst used in this study worked effectively in the coupling of piperonyl alcohol with ethanol and afforded product 3q in a 58% yield. Subsequently, we investigated some of the heterocyclic alcohols such as biomass-based furfuryl alcohol, 2-thiophenemethanol, and 3-pyridinemethanol, whic h smoothly reacted with ethanol and afforded products 3r − 3t in 32 − 74% yield. However, 2-pyridinemethanol 1u substrate was very challenging owing to potential catalyst poisoning, and only afforded product 3u in a 27% yield. Finally, the reaction of the diol substrate, 1,4-benzenedimethanol 1v, afforded the diol product 3v in a 68% yield.
Thereafter, we evaluated the substrate scope of this reaction using aliphatic alcohols as the coupling reagents to access longer-chain aliphatic alcohols (Table S2, Supporting Information). We began our investigation by employing 1-hexanol 4a as the model substrate. However, the reaction of 1-hexanol with ethanol under standard conditions only generated trace of the desired cross-coupling product 5a, along with 0.36 mmol 8a, which was produced by the homocoupling of 4a (entry 2). Meanwhile, the cross-coupling of ethanol with 4a to branched alcohol byproducts 6a, and β-alkylation of 5a with 2 also can be obtained in < 5 yield. Thereafter, the catalytic activity of [Mn]-I to [Mn]-IV was explored again. To our delight, PhPNP-pincer [Mn]-III was observed to be an active catalyst for this transformation with the formation of the desired linear alcohol product 5a in a 33%
yield and branched alcohol 6a in a 5% yield without the assistance of an hydrogen acceptor (entries 1 − 4)(Kobayashi et al., 2020). Therefore, we optimised the reaction of 4a with catalyst [Mn]-III. Under harsh reaction conditions (165°C); a 41% yield of 5a and 7% yield of 6a were obtained using complex [Mn]-III as the catalyst (entry 5).
In light of the activity of the PhPNP-Mn catalytic system in the upgrading of aliphatic alcohols, we investigated the scope and limitations of this cross-coupling reaction using a variety of aliphatic alcohols (Scheme 2). The reaction between chain aliphatic alcohols (1-butyl alcohol 4a and 3-phenyl-1-propanol 4c) and ethanol in the presence of 0.5 mol% of [Mn]-III at 165°C formed the corresponding linear alcohol products 5a and 5c, respectively, in moderate yields (41–47%). Small amounts of branched chain alcohol byproducts 6a and 6c, respectively, were detected in these cases. Encouraged by the high chemoselectivity of the manganese-catalysed upgrading of long-chain aliphatic alcohols, we believe that selective upgrading of branched alcohols with α-carbonyl positions containing tertiary carbons is also promising. However, the corresponding transformation has not yet been reported(Kobayashi et al., 2020). To our delight, branched alcohols with methyl substituents at the β position afforded longer-chain aliphatic alcohol products in 24 and 22% yields (5d and 5e, respectively); these results are less than those of linear substrates. Moreover, the proposed Mn-catalysed protocol could also be applied to the one-step sustainable synthesis of 3-cyclopentyl-1-propanol 5f and 3-cyclohexyl-1-propanol 5g from cyclohexyl- and cyclopentyl-substituted methanol in 36 and 40% yields, respectively.
To further demonstrate the scalability and catalytic efficiency of the proposed reaction system, the gram-scale dehydrogenative coupling of ethanol and benzyl alcohol was tested using 0.03 mol% catalyst loading in a 30 mmol scale (Fig. S1, Supporting Information). To our delight, the desired phenylpropanol product 3a was obtained in a 73% GC yield and 61% isolated yield. The corresponding TON was more than 2000. In view of sustainability and high catalytic efficiency, the proposed method represents a highly practical approach for the synthesis of higher-order linear alcohols.
a Reaction conditions: Unless otherwise specified, reactions were performed on a 6 mol scale of aliphatic alcohols 4, 1 mmol ethanol 2, using 1 equiv. of NaOEt, 0.5 mol% of [Mn]-III at 165 oC for 16 h. The yields were determined by GC using biphenyl as the internal standard. B 2 mmol ethanol 2 was added.
Meanwhile, to further test the stability and recyclability of catalyst, we conducted the catalyst recycling experiment three times (Table S3, Supporting Information). In the argon atmosphere glovebox, [Mn]-II (0.5 mmol, 0.5 mol%), NaOEt (1 mmol, 1 equiv.), benzyl alcohol (6 mmol) and EtOH (1 mmol) were added sequentially to the seal tube equipped with a magnetic stir bar, The reaction mixture was stirred at 140 oC for 16 hours and cooled to room temperature. Then, 1 mmol ethanol and 1 mmol NaOEt was added to the reaction system and the reaction mixture was stirred at 140 oC for another 16 h. After three consecutive reactions, the results of three recycle experiment was shown in Table 3. It illustrated that the Mn catalyst was still active during three recycle, although the reaction efficiency was decreased after each recycle. It further illustrated that the stability of the Mn catalyst should be further increased to ensure the reusability of the catalyst. A further evolution of the Mn-catalysts towards this goal is under way in our lab.
Having established a Mn-catalysed process for upgrading primary alcohols with ethanol, we conducted a mechanistic study by performing a series of control experiments (Fig. S2, Supporting Information). Based on our previous studies of Mn-catalysed alcohol dehydrogenation transformation(Fu et al., 2017; Shao et al., 2018), we hypothesise that the reaction occurs through a Guerbet mechanism, where the acceptorless dehydrogenation of alcohols to aldehydes is one of the key steps. To verify this hypothesis, the reaction using benzaldehyde instead of 1a was tested under standard conditions, and just as we expected, a 58% yield of the target product was obtained (Fig. S2A). Furthermore, acetaldehyde can react with 1a to form the target alkylation product 3a in a 31% yield under similar conditions (Fig. S2B), indicating that the dehydrogenation of alcohols and subsequent aldol condensation are involved in the proposed protocol. Furthermore, the [Mn]-I catalyzed hydrogenation of cinnamaldehyde 9 proceeded smoothly and gave 64% yield for phenylpropanol 3a (Fig. S2C). Conversely, [Mn]-V gave much lower yield for the hydrogenation of cinnamaldehyde 9. The results further imply that the metal − ligand cooperative fashion of the pincer Mn catalysts bearing N − H moieties is essential for the hydrogenation of the key reaction intermediate cinnamaldehyde 9. Furthermore, to demonstrate that the reaction occurred through the borrowed hydrogens from the alcohols, t-butanol was selected as the substrate under standard conditions, and no product was formed (Fig. S2D). In addition, the reaction using 2-phenyl-2-propanol instead of 1a was conducted under standard conditions, and as expected, the target product was not formed (Fig. S2E). These results reveal the hydrogen-borrowing mechanism using the Mn catalyst system.
To gain more mechanistic insights, poisoning experiments were performed in the presence of substoichiometric amounts of PMe3, PPh3 with respect to [Mn]-II and a drop of mercury (Table S4, Supporting Information). No significant inhibition effect was observed in all of these cases, which indicates the homogeneous nature of the manganese catalysis systems. Furthermore, the N-methyl-substituted manganese catalysts [Mn]-V were also used to study the reaction mechanism of the hydrogen transfer process (Fig. S3, Supporting Information). The comparable catalytic activities observed with manganese precatalysts V for the cross-coupling of benzyl alcohol with ethanol and only 8% yield of 3a product were obtained. These results demonstrated that the outersphere hydrogen transfer mechanism was the major reaction pathway and the N-H groups of catalysts II were indispensable in these transformations.
On basis of the results of the mechanistic experiments and previous literature reports(Liu et al., 2019; Shao et al., 2020; Shao et al., 2022), we proposed a plausible reaction mechanism for the dehydrogenative coupling of primary alcohol with ethanol to possible products in Fig. 2. First, the catalytically active species A or A’ were generated from [Mn]-II precatalyst by using sodium ethoxide in the present of alcohols, which then underwent β-H elimination to form the manganese hydride species B and liberate aldehyde D and acetaldehyde, respectively. Next, the aldol condensation of aldehyde D and acetaldehyde led to the formation of α, β-unsaturated aldehyde intermediate E, F or G. It was then reduced by manganese hydride species B to afford the products H, I or J along with the generation of Mn(I)-amido complex C. Finally, the alcoholysis of the Mn(I)-amido complex C regenerated complex A and A’ to complete the catalytic cycle.