Palladium-Catalyzed Synthesis of Alkylated Amines from Aryl Ethers

Research Article pubs.acs.org/acscatalysis

Palladium-Catalyzed Synthesis of Alkylated Amines from Aryl Ethers or Phenols Xinjiang Cui, Kathrin Junge, and Matthias Beller* Leibniz-Institut für Katalyse e.V. Albert-Einstein-Str. 29a, 18059, Rostock, Germany S Supporting Information *

ABSTRACT: Synthesis of alkylated amines is an important and attractive task in organic chemistry. Herein, we demonstrate a general protocol to produce alkylated amines via the catalytic coupling of amines with aromatic ethers or phenols. This transformation is performed in the presence of a heterogeneous palladium catalyst, and the key to its success is the use of a Lewis acid (LA) co-catalyst. This method shows broad substrate scope and a variety of phenols, including lignin-derived fragments, can be converted to the desired products smoothly. Preliminary mechanistic investigations reveal that this straightforward domino transformation occurs via a hydrogenolysis/reduction/condensation/reduction process. KEYWORDS: catalysis, amines, N-alkylation, ethers, esters

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INTRODUCTION The activation of phenols and related conventionally considered inert ethers constitutes a challenge for modern catalyst development. So far, research in this area has mainly been focused on the utilization of sulfonated substrates,1 esters,2 and other preactivated derivatives.3 However, some influential reports, including transition-metal-mediated activation of C−O bonds, have been recently disclosed.4 Notable examples for the activation of aromatic ethers include the study of iso-borylation of aromatic ethers in the work of Martin and co-workers5 and direct replacement of aromatic methoxy groups with bifunctional nucleophiles forming C−C and C− Si bonds, as reported by Rueping and co-workers.6 Despite these achievements, to the best of our knowledge, no catalytic cross coupling of amines with ethers with the generation of Nalkylated amines is known. N-alkylated amines are important intermediates for pharmaceuticals and fine chemicals and constitute building blocks for numerous organic syntheses.7 Decades of research has been focused on the development of general and efficient methodologies for the generation of alkylated amines.8 Hence, there exist many general methodologies for the synthesis of alkylated amines including the traditional coupling of amines with halogenated molecules, reductive amination of aldehydes or ketones,9 self-coupling of amines,10 hydroamination8a,11 and Nalkylation of alcohols.12 Recently, the direct coupling of phenol and amines forming alkylated amines using sodium formate as hydrogen source also was reported by Li and co-workers13 (see Scheme 1). Despite all these important progresses, the efficient synthesis of alkylated amines, especially with cyclohexyl groups, continues to attract the interest of catalysis researchers. Inspired by recent studies on selective C−O cleavage reactions of highly oxygenated compounds,14 we assumed that phenol, which is an important alkylating agent with amines, © XXXX American Chemical Society

Scheme 1. (i) Coupling of Amines with Phenols by Li and Co-workers and (ii) Our Approach for the Synthesis of Alkylated Amines

might be formed by the hydrogenolysis of the aryl ethers, which are abundant motifs in lignocellulosic biomass (Scheme 1). In this respect, herein, we demonstrate a general method for the synthesis of cycloalkyl amines via direct coupling of amines with aryl ethers and phenols using molecular H2. Initially, we studied the reductive coupling of dodecylamine (1a) and benzyl phenyl ether (2a), because 2a is an abundant structural part in lignin. Using commercially available Pd/C as a catalyst, this transformation proceeded already at 1 bar of hydrogen at 60 °C and the desired product 3a formed in 37% yield (Table 1, entry 1). It has been reported that strong Lewis acids (LA) showed beneficial effects in the catalytic hydrogenolysis of C−O bonds.15 Hence, eight different metal triflates were added to the reaction mixture to promote the reactivity. To our delight, in the presence of Hf(OTf)4, 3a was generated Received: June 15, 2016 Revised: October 6, 2016

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ACS Catalysis

As shown in Table 2, various aliphatic amines with different chain length (C4 to C18) were all effective for this trans-

Table 1. Reductive Amination of Benzyl Phenyl Ether: Variation of Reaction Conditionsa

Table 2. Direct Reductive Coupling of Amines with Benzyl Phenyl Ethera entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

LA

solvent

yield (%)

Hf(OTf)4 Al(OTf)3 Zn(OTf)2 Ga(OTf)3 Bi(OTf)3 In(OTf)3 Fe(OTf)2 Sn(OTf)2 TfOH Hf(OTf)4 Hf(OTf)4 Hf(OTf)4 Hf(OTf)4 Hf(OTf)4 Hf(OTf)4 Hf(OTf)4 Hf(OTf)4

p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene p-xylene toluene THF 1,4-dioxane ethyl acetate H2O p-xylene p-xylene p-xylene

37 55 41 24 26 35 29 0 0 16 33 3 6 18 2 40b 57c 99d/97e/68f

a

Reaction conditions: 0.5 mmol benzyl phenyl ether, 0.5 mmol amine, catalyst (2 mol % Pd), 2 mL p-xylene, 1 bar H2, 60 °C, 5 mol % Hf(OTf)4, 6 h, isolated yields. bGC-yield, fully hydrogenated product in the parentheses.

a

Reaction conditions: 0.5 mmol benzyl phenyl ether, 0.5 mmol docalyamine, catalyst (2 mol % Pd), 2 mL solvent, 1 bar H2, 60 °C, 5 mol % LA, 3 h. The conversion and selectivity were determined by GC-FID using dodecane as a standard. b2.5 mol % LA. c10 mol % LA. d After 6 h. eYield of toluene. fAfter 12 h without triflates.

formation and good to excellent yields were obtained (Table 2, 3b−3f). Branched primary amines gave full conversion, affording the corresponding secondary amines in excellent yields (Table 2, 3g and 3h). Furthermore, both cyclohexylmethylamine and cyclohexyl-ethylamine were converted to the corresponding products in good yields (Table 2, 3i and 3j). Subsequently, transformations of cyclopentanamine and cyclohexanamine proceeded under the optimized conditions and the corresponding products were obtained in 81% and 91% yields, respectively (Table 2, 3k and 3l). In addition, aniline as an example for aromatic amines was studied, which afforded the alkylated aniline in 64% yield (Table 2, 3m). Note that the hydrogenation of the aromatic ring of aniline is significantly slower, compared to the phenol derivative (Scheme S1 in the Supporting Information). Nevertheless, some amounts of fully hydrogenated product (3l) were observed in 26% yield. Next, different benzyl aryl ethers were reacted with dodecylamine (2a) to demonstrate the scope and limitations of this protocol further on (Table 3). Alkyl and aryl substituents on the benzyl part had no strong effect on the reaction rate and product yield (Table 3, entries 1−4). Interestingly, 1,4-bis(phenoxymethyl)benzene converted smoothly to the desired product in 86% yield (Table 3, entry 5). Electron-withdrawing substituents on the benzyl group resulted in higher activity and quantitative yields of the cyclohexylamine were obtained (Table 3, entries 6 and 7). Furthermore, related substrates containing different substituents on the aryl ring were tested. Because the hydrogenation of the phenols from C−O cleavage of these compounds is difficult to convert to the cyclohexanone intermediates under low temperature, the reactions of 1i and 1j proceeded at slightly higher temperature and the corresponding products were obtained in 90% and 87% yields, respectively (Table 3, entries 8 and 9). Using sterically more hindered substrates such as 1k− 1m, cross-coupling products were achieved in moderate yields (Table 3, entries 10−13). Note that the corresponding products are obtained as a mixture of cis/trans isomers (1−

in 55% yield (Table 1, entry 2). Interestingly, other metal triflates such as Al, Ga, Zn, Bi, and In, failed to improve this transformation (Table 1, entries 3−7) and no desired product was obtained in the presence of Sn(OTf)2 and Fe(OTf)2 (Table 1, entries 8 and 9). These results demonstrate the pronounced influence of the Lewis acid in this catalytic transformation. The specific positive role of Hf(OTf)4 is explained by the higher effective charge density (ρ) of hafnium triflate, compared to the other metal ions.16 Notably, TfOH is less active (Table 1, entry 10), suggesting that the overall process is predominantly catalyzed by Lewis acids rather than by Brønsted acids, which may be formed by metal triflate hydrolysis. Performing the reaction in different solvents showed that best activity was obtained in p-xylene (Table 1, entries 11− 15). However, there was no desired product observed in the absence of Hf(OTf)4 and Pd/C. In addition, the model reaction was performed in the presence of different amounts of Hf(OTf)4. A lower yield (40%) of cyclohexylamine was observed when 2.5 mol % of LA was used (Table 1, entry 16). On the other hand, there was no significant improvement when more LA was added (Table 1, entry 17). Gratifyingly, by prolonging the reaction time to 6 h, the desired product was obtained in 99% yield (Table 1, entry 18) and toluene was generated quantitatively. With prolonging the reaction time to 12 h, 3a was formed in 68% yields in the absence of triflates. This result demonstrated the effect of LAs on this transformation. In addition, 1a was successfully transformed to 3a in the scale-up reaction (Scheme S4 in the Supporting Information). Given optimal reaction conditions, we studied the catalytic coupling reactions of benzyl phenyl ether with different amines. 7835

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ACS Catalysis Table 3. Pd-Catalyzed Reductive Coupling of 2a with Benzyl Aryl Ethersa

Scheme 2. Proposed Reaction Mechanism

experiments showed that cyclohexanone B is a reaction intermediate, whereas cyclohexanol is not observed by gas chromatography (GC) and also showed no activity in this reaction (Scheme S2 in the Supporting Information). We assume B to be easily formed by selective hydrogenation of phenol in the presence of LA, which is in agreement with previous work (Scheme S3 in the Supporting Information).17 Finally, the desired alkylated amine product is formed according to the classic reductive amination (condensation/ reduction) process. According to our mechanistic proposal, the reaction of amines and phenols under similar conditions should be possible. Indeed, as shown in Table 4, simple phenol reacted Table 4. Catalytic Coupling of Amines with Phenolsa

a

Reaction conditions: 0.5 mmol benzyl aryl ether, 0.5 mmol amine, catalyst (2 mol % Pd), 2 mL p-xylene, 1 bar H2, 60 °C, 5 mol % Hf(OTf)4, 6 h, isolated yields. b0.25 mmol. c100 °C. d120 °C.

a

2:1). To our delight, the transformation of 1n, which is the most abundant C−O linkage in lignin (contributing to 45%− 62%), proceeded successfully, forming the desired product in 68% yield (Table 3, entry 14). A preliminary mechanism for this coupling of aryl ethers with amines under ambient pressure of hydrogen is proposed in Scheme 2. Initially, the palladium-catalyzed hydrogenolysis of the substrate leads to the corresponding phenol A. We assume this reaction step is facilitated in the presence of LA. Control

with different aliphatic amines to produce the desired products in 70%−91% yields. In addition, the coupling of phenol with aromatic amines preceded chemoselectively to the corresponding alkylated anilines (see data for 3m, 3t, and 3u in Table 4). Interestingly, dimethylamine, diethylamine, and piperidine succeeded to transform to the corresponding alkylated amines in 68%−84% yields (Table 4, 3v−3x). Similarly, 3y was formed in 76% yield by the cross coupling of 1,2,3,4-tetrahydroisoquinoline and phenol. In addition, the coupling of phenol

Reaction conditions: 0.5 mmol phenol, 0.5 mmol amine, catalyst (2 mol % Pd), 2 mL p-xylene, 1 bar H2, 60 °C, 5 mol % Hf(OTf)4, 6 h, isolated yields. bGC yield. cNMR yields. dAt 100 °C. eAt 120 °C.

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with methyl isonipecotate proceeded smoothly to the desired product 3z in 81% yield without reducing the ester group. In the same way, methyl 3-aminopropanoate was converted to the desired product in 84% yield. By simply increasing the temperature to 100 or 120 °C, p-cresol, 4-methoxyphenol, 3,4-dimethylphenol, and 3-tert-butylphenol were converted to the corresponding products in 76%−87% yields (see data for 3o, 3q, and 3r in Table 4). The general applicability of this catalyst system encouraged us to test its performance in the synthesis of an intermediate of hexylcaine 5a, which is a short-acting local anesthetic drug. To our delight, 4b was obtained in a straightforward manner in 81% isolated yield (Scheme 3). Note that this N-cyclohexyl group is an important motif in numerous other biologically active compounds.

AUTHOR INFORMATION

Corresponding Author

* [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the state of Mecklenburg− Vorpommern and the BMBF. REFERENCES

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Scheme 3. Synthesis of a Pharmaceutical Intermediate

In summary, we have developed, for the first time, the catalytic synthesis of alkylated amines from aryl ethers in the presence of molecular hydrogen. The key to success is the combination of commercial Pd/C with Hf(OTf)4. As shown in Tables 2−4 a series of (cyclo)alkyl amines are obtained in excellent yields at ambient hydrogen pressure. Moreover, phenols are shown to react in a similar manner. We believe this reaction provides inspiration for future research on the direct transformation of oxygenated compounds to higher valued amines.

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EXPERIMENTAL SECTION The general procedure for the amination of amines with benzyl phenyl ether can be described as follows. In a 4 mL glass vial, the catalyst Pd/C (2 mol % Pd), Lewis acid (5 mol %), aryl ether (0.5 mmol), amine (0.5 mmol), and solvent (p-xylene, 2 mL) were combined and a magnetic stirring bar was added. The reaction vials were fitted with a cap and needle and then were placed into a 300 mL autoclave. The autoclave was purged three times with H2 (20 bar) and was then pressurized to 1 bar H2 pressure. The autoclave was placed into an aluminum block and heated to the desired temperature, and the reactions were stirred for 6 h. After completion of the reaction, the autoclave was cooled to room temperature, and the mixture was diluted with ethyl acetate, followed by filtration and analysis of the samples by gas chromatography (GC) and gas chromatography coupled with mass spectroscopy (GC-MS). The isolated product HCl salts are characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectroscopy (HR-MS).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b01687. NMR data; extended data about mechanism study, control experiments, scale-up reaction, and characterization (PDF) 7837

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