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Utilization of CO2 as C1 Building Block for Catalytic Methylation Reactions Yuehui Li, Xinjiang Cui, Kaiwu Dong, Kathrin Junge, and matthias Beller ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02715 • Publication Date (Web): 09 Dec 2016 Downloaded from http://pubs.acs.org on December 9, 2016

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ACS Catalysis

Utilization of CO2 as C1 Building Block for Catalytic Methylation Reactions Yuehui Li, Xinjiang Cui, Kaiwu Dong, Kathrin Junge and Matthias Beller* Leibniz-Institut für Katalyse e.V. Albert-Einstein-Str. 29a, 18059 Rostock, Germany

ABSTRACT. Developing new synthetic approaches for benign CO2 utilization are of current interest. In this respect, reductive alkylations using N- or C-based nucleophiles to give the corresponding methyl amines and (hetero)arenes are investigated intensively. Crucial points for such benign methylations are the choice of suitable homogeneous or heterogeneous catalyst systems. In this article, selective activation of the substrates and the use of acidic co-catalysts are highlighted.

KEYWORDS. Carbon dioxide, Methylation, Reduction, Catalysis, Amines

1. INTRODUCTION Methylations constitute the most important form of alkylation reactions, which are widely used in organic synthesis, life science applications and material science. 1 For example, the incorporation of a methyl group into (hetero)arenes improved the IC50 (half maximal inhibitory concentration) value of drug candidates by more than 100-fold and is known as the so-called ‘magic methyl effect’ in drug development research.2 Due to the fundamental importance of this

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transformation, the development of more benign and efficient methodologies continues to attract synthetic chemists in both industry and academia. Nevertheless, the most common methods to create methyl group are using toxic reagents such as formaldehyde, methyl iodide, dimethyl sulfate, methyl trifluoromethansulfonate, trimethyloxonium tetrafluoroborate (Meerwein salt) or diazomethane etc. 3 . Furthermore, trimethyl orthoformate,

4

dimethyl carbonate,

5

DMSO

(dimethyl sulfoxide),6 methyl radical sources,7 are known to be used as methylation reagent, too. To date, more sustainable methylation reagents such as CH3OH8and HCO2H9 are only scarcely applied in the synthesis of functionalized products. Hence, the development of new and improved catalytic methods especially the usage of green gas CO2 as the methylation agent is highly desired. Among the different C1 building blocks - formic acid, formaldehyde, carbon monoxide, methanol, methane and carbon dioxide - the latter reagents (CH4 and CO2) remained unexplored for alkylation reactions despite their abundant availability. In case of carbon dioxide the selection of a suitable reductant is the key to realize sustainable methylations. For long time, it´s use as an inexpensive and nontoxic C1 feedstock is appealing for the production of value-added bulk and fine chemicals.10 Today, the major chemical application of CO2 is the industrial production of urea on >100 Mio. ton-scale (Bosch-Meiser process). In addition, carbonates, polycarbonates and salicylic acid (Kolbe-Schmitt synthesis) and some fine chemicals are produced on a commercial scale. On the other hand, in basic research CO2 is used to functionalize alkenes, alkynes, allenes, organohalides, organometallic reagents or carbon nucleophiles to generate carboxylic acids (and their derivatives).11 Meanwhile, several approaches to reduce CO2 were developed using different types of reductants, mainly boranes, silanes and H2. 12,

10f

Here, the products could be formic acid or


2

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formates (2-electron reduction process), formaldehyde (4-electron reduction), MeOH or methoxides (6-electron reduction), or even CH4 (8-electron reduction). 13 For such reductions, transition metal catalysts based on Rh,13e Ir,13h Ru,13c,13j and Yb pair Zr(IV)/B(C6F5)3

13g

13l

as well as frustrated Lewis

and metal-free NHC carbenes (N-heterocyclic carbenes)

13f

were

developed. Beyond these direct reductions to give C1-products, more recently it has been demonstrated that reductive domino sequences of CO2 permit the preparation of sophisticated building blocks and fine chemicals. More specifically, the use of modern CO2 reduction catalysts in the presence of suitable nucleophiles allowed for new reductive methylation methodologies (Scheme 1).

Scheme 1. Methylation of nitrogen- and carbon-based nucleophiles with CO2 In this perspective article, we summarize the latest developments in this area. Particular focus is given on catalytic methylations of amines with CO2 in the presence of silanes or hydroboranes (Section 2) or H2 (Section 3.1). In addition, recent advancements on related green hydrogenative processes are highlighted. Complementary to homogeneous organometallic complexes, also the


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use of heterogeneous catalysts based on both noble and non-noble metals are discussed for such transformations. When starting our own work in this area around 2012, we believed four aspects to be critical for the development of efficient and selective methylation reactions using CO2: (1) Activation of CO2: An inherent problem of using CO2 for synthesis is its high thermodynamic stability and the difficulty to transform the robust C-O to C-X bonds (X = N, C). Strategies to overcome this limitation include using strong reductants in the presence of organometallic complexes or Lewis bases. As an example NHC carbenes promote the addition of silver hydrides 14 and silanes15 to CO2 producing formates and MeOH, respectively. Here, the formation of the thermodynamically favored Si-O bonds is the driving force of the overall process. In case of nitrogen nucleophiles, the methylation might take place via different intermediates due to easy formation of carbamates (Scheme 2). Similar reactions with “weak” carbon nucleophiles to form desired C-C bonds are more difficult.

Scheme 2. Different pathways for methylation of amines with CO2

(2) Development of more efficient catalysts for reducing in situ-generated formamides or carbamates with “green” hydrogen. Considering the competition of different possible reductions: a) hydrogenation (HCONR2 to CH3NR2) and b) hydrogenolysis (HCONR2 to CH3OH + R2NH)


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the development of selective catalysts is crucial. Particularly basic conditions have to be avoided to prevent the unwanted hydrogenolysis pathway. (3) Chemoselectivity: Alkylation of functionalized substrates having more than one nucleophilic reaction site is a highly interesting task for advanced organic synthesis. For example, methylation of N-H bonds in the presence of O-H bonds and/or other reducible groups (ester, olefin etc.) represent challenging tasks. (4) Multiple methylation reactions: Applying traditional active methylation reagents often diand polyalkylations occur and tedious purification of the product mixture is necessary. Using a combination of reductants/CO2 this problem might be avoided by catalyst control.

2. HYDROSILANES OR HYDROBORANES AS REDUCTANTS Hydrosilanes. In the past decade, several groups reported the reduction of CO2 to formates in the presence of silanes. 16 Meanwhile, related catalytic deoxygenative reduction of amides to amines with hydrosilanes was developed, too. These latter reactions have been performed in the presence of catalytic amounts of transition metal complexes17 such as Ru, Pt, Fe or Zn as well as metal-free catalysts18 such as boronic acids or tris(pentafluorophenyl)borane. Combining these two processes it should be possible to synthesis the methylated amines using CO2 as the methylation agent. Indeed, in 2013, Cantat and co-workers 19 and our group 20 independently reported the first examples of reductive methylation of amines with CO2. In both cases, hydrosilanes were used as the terminal reductant, while Zn-NHC carbene complexes and in situ formed Ru-phosphine complexes were used as the catalysts, respectively (Scheme 3). Screening


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the combination of Zn(II) salts with different neutral ligands, such as phosphines, amine ligands and NHCs Cantat and co-workers observed that the modest activity of bare Zn salts can be promoted by addition of NHC ligands. Best results were obtained using PhSiH3 as the reductant, and 1,3-bis(2,6-diisopropylphenyl)-imidazolium (1, IPr) as the ligand. Under the optimized conditions with 1 to 5 bar CO2 at 100 °C, 19 different amines were tested as the substrates and many amines are smoothly methylated. It is notable that selective monomethylation of primary amines was achieved, too. However, the N-methyl amines were normally not avoided to further react with CO2/H2 to form dimethylamines which decreased the selectivity to N-methyl amines. Thus, it is still challenging for the synthesis of mono-methlylated amine using CO2/H2 as methylation agent.

Scheme 3. First examples for N-methylation with CO2 and silanes

In order to investigate the mechanism of this transformation control experiments were carried out, which clearly show that CO2 needs to be activated by amines. Specifically, in the absence of amines, no reduction of CO2 occurred even after 20 h at 100 °C. Hence, the authors proposed an initial reductive amidation of CO2 to yield formamide, which is further reduced by Zn-catalyzed hydrosilylation. Although, the detailed role of NHC ligands is not clear, their coordination to the


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Zn centre should stabilize the active species.21 Later on, a related transformation was reported using fluoro-functionalized polymeric NHC carbene-Zn(II) complexes for the formlyation and methylation of amines with CO2 and silanes. 22 Compared to the original work of the Cantat group, lower temperature (80 °C) was used with the same catalyst loading (5 mol% Zn). Although a high conversion was obtained for N-methyl aniline derivatives, the reaction gave a mixture of products containing mainly formamides and only minor amounts of methylated products. Reductive N-methylation using carbon dioxide is also promoted by ruthenium phosphine complexes. More specifically, we observed best results in the presence of the electron-rich phosphine cataCXium A (2, di(1-adamantyl)-n-butylphosphine). To our delight, aromatic and aliphatic, secondary and primary amines were smoothly methylated. Complementary to the work of the group of Cantat, dimethylation occurred when primary amines were used. From a synthetic point of view it is interesting that selective N-methylation of amino alcohols took place and ephedrine was transformed to N-methyl ephedrine in good yield (73%) with high selectivity. The proposed key intermediates such as formamides, ureas were observed by control experiments using different diamines. In addition, the reduction of formamide and ureas was shown under the reaction conditions. Consequently, two possible reaction pathways were proposed (Scheme 4): One reaction pathway, similar with the Zn-catalyzed reductive methylations, involves the formation of formamide intermediates followed by reduction to the desired methylated products. The other one proceeds via formation of ureas, which can also be reduced to N-methyl amines.


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Scheme 4. Proposed reaction pathways for catalytic N-methylation with CO2 and silanes

Later, also Fe-catalyzed hydrosilylation of CO2 were achieved. In this case, it was found that the ligand effect is crucial. Only in the presence of the tetradentate phosphine tris[2(diphenylphosphino)ethyl]phosphine (3), [Fe(acac)2] (acac = acetylacetonate) efficiently promoted the desired transformation of CO2 (1 bar) with PhSiH3 (1 equiv.). Applying 10 mol% of this catalyst at 100 °C methylation of aniline derivatives proceeded smoothly (Table 1).23 Comparing the activity of all three catalyst systems, the iron complexes seem to be less active. Table 1, Fe catalyzed formylation of various amines with CO2 and PhSiH3

R1 H N 4

H N

+ R2

CO2

1 eq. 5 N H

THF, RT, 18h N

O

N

R1

N

N

O

6

7

> 95%

O

H N

O

N 8

H R2 O

O

45%

5

70%

N

PhSiH3

+

1 bar

O

H N

O

Fe(acac) 3 + PPh3

> 95%

H N

O

O

Cl 24%

9

8%

O

10

65%

11

62%


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Most recently, another study focussing on base metal catalysis, disclosed the Ni(0)-catalyzed N-methylation of primary and secondary aliphatic amines with CO2 and silanes. 24 Using diphosphines

as

ligand,

namely

1,2-bis(diisopropylphophino)ethane

or

1,2-

bis(dicyclohexylphophino)ethane, led to best results. In the model reaction with benzyl amine, heating to 100 °C was necessary to get full conversion. Unfortunately, several products were generated: N-methylbenzyl amine, N-methyl-N,N’-dibenzylurea, N,N’-dibenzylformimidamide, N,N’-dibenzylurea, N-benzylformamide, and benzyl isocyanate. However, under modified conditions (1 mol% of [Ni(cod)2]/diphosphine in the presence of 4 equivalents of PhSiH3) improved results and selective monomethylation of six different amines was achieved. When lower amounts of PhSiH3 (2 equiv.) were used, the reaction allowed the synthesis of monomethylated ureas in good yields. Aniline showed the lowest reactivity in this protocol. In contrast, the previous reports by the groups of Cantat and Beller showed a comparably high reactivity for aromatic amines and proposed a facile reduction of the corresponding formamide intermediates. However, in the procedure of García and co-workers the formation of the formamide is more difficult and the rate-determining step is probably different. Reduction of CO2 with PhSiH3 in the presence of the Ni/diphosphine catalysts gave no conversion which indicates that the corresponding silyl formate (R3SiOCOH) or methoxysilane (R3SiOCH3) are unlikely to be formed during methylation reactions. On the basis of the experimental results, the proposed mechanism includes consecutive methylation of N–H bonds from CO2 and hydrosilanes. In the initial step, oxidative addition of PhSiH3 to Ni(0) yields the active Ni-H species, which reacts with carbamic acids formed from CO2 and amine substrates. Along with silanols, the resulting formamide intermediates will be further reduced to the desired methylated products. Meanwhile, electrophilic isocyanates may be formed from either


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dehydration of carbamic acids or dehydrogenation of formamide intermediates. Once formed isocyanates react with 1 equiv. of amines (primary or methylated secondary amines) to generate the corresponding N-methyl ureas. Disubstituted ureas might be further reduced to yield amidines (Scheme 5).

Scheme 5. Proposed mechanism for Ni-catalyzed N-methylation with CO2 and silanes

It should be noticed that reductive methylation of amines was also achieved using organic carbonates as the C1 source.25 Dialkyl carbonates were used for methylation of amines using well-defined half-sandwich iron-NHC complexes. Photoactivation of the iron carbonyl precatalyst [CpFe(CO)2(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazolium, 12) with visible light irradiation is essential for reactivity. In the presence of excess amounts of PhSiH3 (5 equiv.) and dimethyl or diethyl carbonate (as C1 source and solvent) at 100 °C a variety of amines including aliphatic and aromatic substrates were smoothly converted to the corresponding methylated amines in 54-98% yields (17 examples). Initially, photoactivation leads to decarbonylation and the resulting 16-electron Fe species reacts with hydrosilanes to form the active Fe-H species.26 Control experiments with methyl N-methyl-N-phenylcarbamate (13) or N,N’-dimethyl-N,N’-diphenylurea (14) indicated that formation of urea intermediates


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from CO2 and amines followed by reduction to methylated products is favoured compared to the direct reduction of carbamate intermediates. Remarkably, using the right choice of silane and solvent allowed for metal-free N-methylation with CO2. In this respect, the reaction of nucleophilic NHC ligands with CO2 to give imidazolium carboxylates is well known. Reduction of these adducts also led to formates. 27 Based on these observations, an elegant metal-free catalytic reduction methylation of amines using CO2 was developed by Das et al.28 employing an NHC carbene (5 mol%) as catalyst and diphenylsilane (3-4 equiv.) as the reducing agent. Specifically, using IMes (12) in DMF, high chemoselectivity under ambient conditions was achieved for the N-methylation of both aromatic and aliphatic amines, producing the corresponding N-methylated amines in high yields (Scheme 6). This methodology proved to be quite general and tolerates a broad range of functional groups (FGs), such as nitrile, nitro, alkenyl, alkyl, ester, ether and even ketones.

Scheme 6. Chemoselective metal-free N-methylation with CO2

In addition, the carbene catalyst was found to be useful for the straightforward synthesis of Nmethyl-substituted natural products and bio-active compounds. For instance, a two-step synthesis of Naftifine (23), an antifungal drug for the topical treatment of infections, from naphthalen-1-


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ylmethanamine (20) and cinnamyl alcohol (21) was achieved with an overall yield of 58% (Scheme 7).

Scheme 7. Two-step synthesis of Naftifine including methylation with CO2 Recently, Dyson et al.28b demonstrated methylation of different amines catalyzed by a bioinspired effective and cheap thiazolium carbene complex in the presence of PMHS. Moreover, by simply changing the reaction temperature, the reaction product (N-formylation versus N-methylation) can be obtained selectively. The catalyst shows a broad substrate scope and thereby has high application in CO2 fixation reactions. In 2015, Cantat and co-workers29 described a novel catalytic transformation to produce aminal derivatives using CO2 as starting material under metal-free conditions. This reaction proceeded via a four-component pathway. The organo-catalysts were able to balance the reactivity of CO2 to promote the selective formation of two C−N and two C−H bonds. In this transformation, a broad substrate scope was well tolerant and good to excellent yields were obtained. In addition, instead of the amine reagents by other nucleophiles, such as malonates, could efficiently replace the amine reagents. Challenging formation of C−C bonds from CO2 was realized with good yield.


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Hydroboranes. Alternatively to hydrosilanes, hydroboranes were less intensively studied for the reduction of CO2. Compared to the recently developed organometallic catalysts based on Ni, Ru, Cu, frustrated Lewis pairs and metal free N-heterocyclic carbene for hydroboration of CO2, 30

the most efficient system to date was discovered by Guan and co-workers in 2010.31a Using

nickel(II)-PCP pincer-type complexes in combination with catecholborane (25, catBH) TOF up to 495 h-1 at 25 °C were achieved for the reduction of CO2 to methanol derivatives. Meanwhile, organocatalysts based on phosphino-borane, nitrogen–boranes or nitrogen bases were applied to the hydroboration of CO2 by Fontaine et al. and Cantat et al. For example, Cantat and coworkers attained TONs and TOFs up to 648 and 33 h-1 respectively at room temperature for reduction of CO2 to methoxyboranes using 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (26, MTBD) as catalyst. Formate and acetal intermediates were detected in these reactions and it was proposed that MTBD promotes the reduction of CO2 through the activation of the hydroborane reagent based on detailed DFT (density functional theory) calculations and experimental findings. Based on these results, later on the same group reported the first metal-free catalytic system for methylation of amines with carbon dioxide in the presence of hydroboranes. 32 Interestingly, using silanes (PhSiH3 or Ph2SiH2) under the same conditions only formamide was obtained, which is explained by solvent effects. Among the investigated catalysts, proazaphosphatrane superbases proved to be the most active compounds

in

the

reductive

N-methylation

with

CO2

and

9-BBN

(27,

9-

borabicyclo[3.3.1]nonane) (Scheme 8). Wthin 15 minutes at 90 °C, the reaction of diphenylamine (28) with CO2 and 4 equiv. of 9-BBN afforded N-methyldiphenylamine (29) in up to 93% yield under the catalysis of 1.0 mol% VBiBu (31c). Notably, this phosphorus basecatalyzed methodology offers a broad substrate scope for both aromatic and aliphatic secondary


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amines as well as primary anilines (27 examples, 33-99% yields). With respect to chemoselectivity, good functional group tolerance was obtained for phenol and some ester groups.

Scheme 8. Metal-free methylation of diphenylamine 28 with CO2 and 9-BBN

Based on mechanistic studies, the possible reaction pathways for the catalytic methylation of N-methyl aniline (32) in the presence of 9-BBN were postulated (Scheme 9). Initially, CO2 is reduced to a formoxyborane intermediate HCOOBBN (35), which is transformed to N-phenyl formamide 36 as no nucleophilic substitution of CH3OBBN (35) with amines occurred. Meanwhile, N-methyl aniline reacts with 9-BBN to dehydrogenatively form the borylamine intermediate 33. Deoxygenative reduction of 36 leads to the desired methylamine product 37. It should be pointed out that the two competing routes to 35 and 37 determine the final efficiency of methylation. Applying a higher reaction temperature (>60 °C) favours formamide formation. Several control experiments supported the above proposal.


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ACS Catalysis

Scheme 9. Proposed reaction pathways for methylation of N-methylaniline 32 with CO2 and 9BBN

3. HYDROGEN AS THE REDUCTANT From the economic and sustainable points of view, hydrogen is a far better choice of reductant than hydrosilanes or hydroboranes. In addition to the direct hydrogenation of CO2 to formic acid derivatives, methanol, or methane, reductive domino transformations using CO2 are highly desirable for the production of both fine and bulk chemicals. In recent years especially methylation reactions have been developed with both homogeneous and heterogeneous systems aside from the original discovery by Baiker and co-workers in the 1990s (Scheme 10).33

Scheme 10. N-Methylation of amines using CO2 and H2

3.1. Homogeneous Catalysis. Recently, several research groups developed new homogeneous catalysts for the hydrogenation of CO2 to methanol.34 In this context, the discovery


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of the deoxygenative hydrogenation of amides to amines by Cole-Hamilton et al. in 2007, 35 inspired the development of hydrogenative methylation with carbon dioxide. Hence, in 2013 Klankermayer/Leitner and co-workers36 and our group37 reported independently the methylation of amines with CO2 as the C1 source and H2 as the reductant. Both reported catalyst systems used ruthenium as the metal centre and the so-called triphos (1,1,1-tris(diphenylphosphinomethyl, 38) ligand (Scheme 11). Mechanistic investigations proposed a sequential formylation/amide reduction pathway (Scheme 12).

NH2

R1 CO2 + H2 20 bar

60 bar

[Ru]/acid

+ 1

H N

R

THF

CH3 CH3 or N N 1 R H R1 CH3 CH3 N R1 R2

2

R

Klankermayer & Leitner PPh2 Ph2P Ph2P Ru 2.5 mol%

HNTf2

150 oC

5 mol%

10-48h

14 examples, 27-99% yield, aromatic amines

[Ru(triphos)(tmm)] Beller Ru(acac)3 + 1 mol%

PPh2 PPh2 PPh2

MSA or LiCl 140 oC 1.5 mol% 24h or 7.5 mol%

33 examples, 40-99% yield, aromatic and aliphatic amines

2 mol%

Scheme 11. Methylation of aromatic amines with CO2 and H2

Scheme 12. Proposed reaction pathway for the Ru/triphos-catalyzed methylation of aromatic amines


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In

their report,

Klankermayer/Leitner and

co-workers

used

a

defined

complex

[Ru(triphos)(tmm)] (tmm = trimethylenemethane) with Brønsted acid co-catalysts, such as trifluoromethanesulfonylimide (HNTf2), methanesulfonic acid (MSA), or p-toluenesulfonic acid (p-TsOH), which allowed methylation of aromatic amines in excellent yields (14 examples, 2799 yields). Interesting synthetic applications of this methodology were depicted by the sequential reduction/methylation reactions of indole (39) and acetanilide (41) for preparation of 1methylindoline (40) and the unsymmetrical N-ethyl-N-methylaniline (42) (Scheme 13; 69-70% yields). After this initial discovery, the same group developed the ruthenium-catalyzed reductive methylation of imines using carbon dioxide and molecular hydrogen.38 Under similar conditions with [Ru(triphos)(tmm)] as the catalyst, imines as well as the in situ formed imines from amines and aldehydes were successfully reduced and methylated sequentially to desired N-methyl amines in good to excellent yields. Notably, this atom efficient methodology was applied to the preparation of the antifungal agent butenafine in one step.

Scheme 13. Sequential hydrogenation-reductive methylation reactions In the catalytic system developed by Beller and co-workers, methylations of both aromatic and aliphatic amines with CO2 and H2 were achieved. An in situ formed complex from stable Ru(acac)3 and triphos was able to catalyze the desired methylation of amines in the presence of


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either Brønsted or Lewis acids. Being comparable with the system mentioned above, aromatic amines were all successfully methylated under similar conditions. However, almost no reaction occurred when aliphatic amines were used as the substrates and only

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