Manganese‐Catalyzed β‐Methylation of Alcohols by Methanol

Abstract We report an earth‐abundant‐metal‐catalyzed double and single methylation of alcohols. A manganese catalyst, which operates at low catalyst loadings and short reaction times, mediates these reactions efficiently. A broad scope of primary and secondary alcohols, including purely aliphatic examples, and 1,2‐aminoalcohols can be methylated. Furthermore, alcohol methylation for the synthesis of pharmaceuticals has been demonstrated. The catalyst system tolerates many functional groups among them hydrogenation‐sensitive examples and upscaling is easily achieved. Mechanistic investigations are indicative of a borrowing hydrogen or hydrogen autotransfer mechanism involving a bimetallic K‐Mn catalyst. The catalyst accepts hydrogen as a proton and a hydride from alcohols efficiently and reacts with a chalcone via hydride transfer.

The borrowing hydrogen [1] or hydrogen autotransfer [2] methodology (BH/HA) is aprominent and intensively investigated example of an alcohol re-functionalization concept. [3,4] The alcohol is catalytically dehydrogenated to ac arbonyl compound via hydride and proton transfer to acatalyst, followed by acondensation reaction with anucleophile and subsequent reduction with the hydrogen (hydride and proton) stored at the catalyst. Alcohols are attractive green and sustainable starting materials for the synthesis of fine and bulk chemicals or agrochemicals and pharmaceuticals [5] since they can be obtained from abundantly available and indigestible biomass namely lignocellulose combining pyrolysis and hydrogenation. [6] Furthermore,e thanol can be obtained via fermentation [7] and methanol via CO 2 hydrogenation. [8] Thed irect hetero-coupling of two alcohols follows the BH/HA concept and exclusively uses alcohols as starting materials.T he replacement of rare metals in key technologies,s uch as catalysis,i so fs imilar importance as the saving of our fossil carbon resources.R ecent progress in manganese-catalyzed (de)hydrogenation catalysis [9] indicates the potential of the third most abundant transition metal of the earth crust [10] to not just replace rare noble metals but to significantly extend their applicability. [11] Methyl-group branching is ah ighly important structural motif in chemistry and biology [12] ranging from synthetic lubricants [13] to more than half of all drug molecules. [14] Thus,B H/HA-based alkylation reactions employing methanol are especially attractive but challenging due to the increased energy of dehydrogenation to form the transient carbonyl compound. DH for methanol is + 84 kJ mol À1 whereas DH for ethanol is only + 68 kJ mol À1 . [15] Herein, we report that an earth-abundant metal catalyst can mediate the double and single methylation of alcohols efficiently.W ed eveloped aM nc atalyst that operates at low catalyst loadings (0.1 mol %) and short reaction times (3 h) at temperatures usually used for methanol-based alkylation reactions.O ur catalyst system has ab road scope.T he single methylation of secondary carbon atoms and the double methylation of primary carbon atoms of alcohols,i ncluding purely aliphatic examples,isobserved. Furthermore,methylation of 1,2-aminoalcohol for the synthesis of pharmaceuticals has been demonstrated. Thec atalyst system tolerates many functional groups among them hydrogenation-sensitive examples,like an iodide and aC =Cdouble bond, and permits easy upscaling.M echanistic investigations are indicative of ab orrowing hydrogen or hydrogen autotransfer mechanism involving ab imetallic K-Mn catalyst. Thec atalyst accepts ahydride and aproton from alcohols and reacts with chalcone via hydride transfer.
Them ethylation of alcohols employing methanol has been demonstrated using noble metal catalysts [17] (Figure 1) and we first described the methanol-based methylation of 1phenylethanol as part of our Mn-catalyzed multi-component pyrimidine synthesis. [18] Parallel to the finalization of our manuscript, Morrill/Williams and co-workers elegantly demonstrated the Fe-catalyzed methylation of secondary bcarbon atoms of alcohols. [16] Their catalyst system is inefficient in the double methylation of primary b-carbon atoms of alcohols.Moreover,the alkylation of alcohols by alcohols has been shown for af ew earth-abundant metal catalysts [19] and the Mn-catalyzed methylation of substrates other than alcohols has been shown recently. [20] We investigated the double methylation of 1-phenyethanol by methanol as ab enchmark reaction to optimize the reaction conditions.F irst, different earth-abundant metal catalysts were tested at conditions commonly used for methanol-based alkylation reactions.I ti ss hown that manganese(I) complexes containing at riazine backbone significantly outperform other 3d-metal-based precatalysts ( Table 1, entries 1-9). Catalytic performance can be further enhanced by changing the isopropyl substituent on the phosphorous atoms to phenyl substituents.O verall, the highest performance was achieved using precatalyst [Mn-IIIa],w hich gave the desired product in 63 %y ield (Table 1, entry 4). Having established the most active precatalyst, the reaction conditions were then optimized one factor at atime (precatalyst loading, solvent, base,a mount of base,t emper- has not yet been reported in literature and was characterized by standard NMR techniques,e lemental analysis,a nd IR spectroscopy. Thel atter revealed signals typically associated with three carbonyl ligands.T his was confirmed by X-ray crystal structure analysis (Figure 2), which shows that the central manganese atom is meridionally coordinated by the P,N,P ligand and three further carbonyl ligands,which form aslightly distorted octahedral coordination pattern. Contrary to the isopropyl ([Mn-III])a nd cyclohexyl ([Mn-IIIb])a nalogues, the resulting positive charge on the manganese complex is compensated by the bromide counter ion, which is not bound to the manganese center.
With the optimized reaction conditions at hand and the precatalyst characterized, we started to investigate the substrate scope of our catalyst system using arange of differently substituted 1-arylethanols (Table 2). Theyields are similar for meta-o rpara-substituted isomers as shown for methyl (m: 94 % B5 and p:8 9% B6)a nd methoxy groups (m:9 2% B3 and p:9 6% B4). As light decrease in yield, possibly due to steric reasons was observed for the ortho-methoxy-substituted isomer (o:4 5% B2). Halide-substituted 1-phenyletha-nols are swiftly converted to the corresponding products in yields up to 80 %f or B8.A fter modifying the reaction conditions to 0.3 mol %catalyst loading (same temperature and reaction time), the 3'-F,3 '-Br, and 3'-I analogs could also be obtained in synthetically useful yields (B7, B9,and B10,respectively). Theproducts containing electron-withdrawing CF 3 group (74 % B11)o re lectron-donating groups like tert-butyl (80 % B12)a nd 1-pyrrolidinyl (56 % B14)w ere easily obtained in high yields.N aphthyl ethanols could be methylated in attractive yields of 79 %f or B15 and 96 %for B16.Heterocyclic moieties like 3-pyridine and ferrocene appear to be tolerated, giving the corresponding products in 72 % B17 and 76 % B18 yields,r espectively.G ratifyingly,t he synthesis is easily scaled up,w hich was demonstrated by synthesizing B4 on a4 7.6 mmol scale yielding 7.46 g( 87 %) product after distillation. After finding ab road substrate scope for the double methylation, we were interested in the mono methylation of secondary carbon atoms.W es howed for three examples  (B19-B21)that the methylation of secondary b-carbon atoms ( Table 3) is possible in similarly attractive yields and became interested in the methylation of more challenging substrates, which gave the products B22-B24 in 65 to 91 %yields.After synthesizing the ephedrine derivative B26 in 84 %y ield, we became interested whether the secondary amine functionality found in ephedrine itself would also be tolerated. Fortunately,t he catalyst system did indeed tolerate this functional group,l eading to the synthesis of ephedrine (B25)f rom commercially available 2-(methylamino)-1-phenylethan-1-ol in 80 %yield using 0.5 mol %catalyst loading. This experiment was easily scaled up to produce 5.97 g( 76 %) of ephedrine B25.Furthermore,the catalyst is able to methylate ap urely aliphatic amino alcohol (68 % B27). Eventually,we showcase three examples (B28-B30)i ncluding an aliphatic unsaturated one (B30) where the catalyst system methylates primary alcohols in very good to excellent yields.
Purely aliphatic 2-octanol and alicyclic dodecanol were methylated in reasonable yields after increasing the catalyst loading, methanol amount, and reaction time, giving the corresponding products B31 and B32 in 73 % yield and 61 %y ield, respectively (Scheme 1).
To gain insight into the reaction mechanism, as eries of control experiments was conducted. In analogy to our previously published results, [22] we postulate [Mn-IIIaH]K 2 to be the active species in the hydride-transfer step of the reaction sequence.T ov erify this assumption, we synthesized [Mn-IIIaH]K 2 from [Mn-IIIaH]H 2 by deprotonation with ap otassium base (Scheme 2, experiment A). Next, we showed that the active species [Mn-IIIaH]K 2 is formed under similar-to-catalysis conditions by comparing the 31 PNMR spectra and the hydride signal in the 1 HNMR spectra (experiment B). Using the in situ-generated [Mn-IIIaH]K 2 ,weset out to investigate the reactivity towards unsaturated compounds.F irst, we investigated the stoichiometric reaction of [Mn-IIIaH]K 2 [a] Reaction conditions: 0.5 mol %p recatalyst (5 mmol), KO t Bu (1 mmol, 112 mg), A1 (1 mmol, 121 mL), MeOH (3 mmol, 122 mL), diglyme (2 mL), 140 8 8C(oil bath), 20 h. Yields of B1 and C1 were determined by GC-analysis using n-decanea saninternal standard.
with (E)-chalcone.T oour surprise,atroom temperature using only 1equiv of [Mn-IIIaH]K 2 the C=Cb ond was quantitatively converted almost immediately,y ielding 1,3-diphenylpropan-1-one (experiment C  [22] We conclude that the catalyst is stable at 140 8 8Ca sl ong as it is kept busy by alcohol dehydrogenation and ketone hydrogenation, which means doing BH/HA. In summary,w er eport that an earth-abundant catalyst permits the general methylation of alcohols by methanol. Our Mn-based catalyst system permits the efficient single methylation of secondary carbon atoms and the double methylation of primary carbon atoms of primary and secondary alcohols,including purely aliphatic examples,and operates at low catalyst loadings (0.1 mol %) and short reaction times (3 h) at temperatures usually used for methanol-based alkylation reactions.M any functional groups among them hydrogenation-sensitive examples are tolerated, and upscaling is easily accomplished. Mechanistic investigations revealed that our novel bimetallic K-Mn catalyst follows the borrowing hydrogen or hydrogen autotransfer mechanism. During the revision of our manuscript two related manuscripts appeared. [23]