Well-Defined Phosphine-Free Iron-Catalyzed N-Ethylation and N

Letter Cite This: Org. Lett. 2018, 20, 5985−5990

pubs.acs.org/OrgLett

Well-Defined Phosphine-Free Iron-Catalyzed N‑Ethylation and N‑Methylation of Amines with Ethanol and Methanol Alexis Lator,† Sylvain Gaillard,† Albert Poater,*,‡ and Jean-Luc Renaud*,† †

Normandie Université, LCMT, ENSICAEN, UNICAEN, CNRS, 6 boulevard du Maréchal Juin, 14000 Caen, France Departament de Química, Institut de Química Computacional i Catàlisi (IQCC), Universitat de Girona, c/Ma Aurèlia Capmany 69, 17003 Girona, Catalonia, Spain

‡

Org. Lett. 2018.20:5985-5990. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/05/18. For personal use only.

S Supporting Information *

ABSTRACT: An iron(0) complex bearing a cyclopentadienone ligand catalyzed N-methylation and N-ethylation of aryl and aliphatic amines with methanol or ethanol in mild and basic conditions through a hydrogen autotransfer borrowing process is reported. A broad range of aromatic and aliphatic amines underwent mono- or dimethylation in high yields. DFT calculations suggest molecular hydrogen acts not only as a reducing agent but also as an additive to displace thermodynamic equilibria.

A

methane, dimethyl sulfate, or diazomethane, palladium-formaldehyde reductive amination, or reduction of carbamates with a stoichiometric amount of hydride reagents.1b However, the low selectivity (due to the formation of overalkylated products), the employment of toxic and hazardous chemicals, and the simultaneous production of waste are not in agreement with an environmentally friendly process. In recent years, several efficient strategies have been developed for the creation of nitrogen−carbon bonds and greener strategies for Nmethylation. Transition metal-catalyzed small-molecules activation such as carbon dioxide,2 carbonate,3 or formic acid4 are among these recent developments. A hydrogen autotransfer or borrowing hydrogen strategy for methylation is also a powerful strategy.5 Advantages of this approach is the use of easy-tohandle methanol, as a source of methylating agent, and the formation of water as a unique byproduct. Based on a simplified mechanism, this one-pot sequence involved a methanol oxidation step, followed by a condensation of the amine and reduction of the iminium intermediate. Following such a strategy, methanol could be considered as a convenient and sustainable alkylating agent for amine methylation. However, dehydrogenation of methanol is more energetically demanding compared to other alcohols (ΔH = +84 kJ.mol‑1 for methanol vs ΔH = +68 kJ.mol‑1 for ethanol). So the use of methanol as a methylating agent is still a challenging reaction, and few examples have been reported so far.6−9 Efficient catalysts for N-methylation of amines with methanol are often based on precious and noble metal-based complexes such as iridium6 and ruthenium.7 However, due to

lkylation of amines, notably N-methylation, is a vibrant field of investigation for pharmaceuticals and industrials, due to their high bioactivity and importance in nature (Adrenaline) and medicine (antidepressant, anti-Parkinsonian, painkiller) (Figure 1). Industrial synthesis of N-methylamines mainly involved formaldehyde via Eschweiller−Clarke type reactions.1a On the other hand, academic researchers prefer a traditional stoichiometric methylating agent such as iodo-

Figure 1. Bioactive molecules bearing a N-methyl or N-ethyl amine moiety. © 2018 American Chemical Society

Received: July 3, 2018 Published: September 20, 2018 5985

DOI: 10.1021/acs.orglett.8b02080 Org. Lett. 2018, 20, 5985−5990

Letter

Organic Letters economic pressure and engagement in the development of more sustainable processes, the replacement of these noble metals by Earth-abundant ones becomes a challenging and attractive topic. In 2016, Beller and Sortais reported the first non-noble metal catalyst, involving a PNP pincer type manganese complex, for monomethylation of anilines in the presence of a (sub-) stoichiometric amount of a base at 100− 120 °C (Figure 2).8 Liu reported a combination of a cobalt(II)

In our ongoing research on iron-catalyzed reduction of polarized CC and CX bonds,14,15 we recently presented several electron-rich (cyclopentadienone) iron tricarbonyl complexes which are highly active in alkylation of both aliphatic and aromatic ketones (Fe1, Figure 2).16 Based on in silico predictions and experimental works, we highlighted the role of the base both in the dehydrogenation step (decreasing the barrier of activation) and in the reduction step.15 We report herein that our complex Fe1 is also an active complex for the methylation and ethylation of amine derivatives in basic conditions. We highlighted recently that the dehydrogenation of ethanol and isopropanol in basic medium in the presence of Fe1 was more facile than the hydrogen cleavage.15 Preliminary studies with ethanol as an alkylating reagent in the presence of cesium carbonate (10 mol %) and complex Fe1 (2 mol %) at 90 °C confirmed this result. N-Ethyl anisidine 3a was obtained in 40% conversion. Changing the base to cesium hydroxide and increasing the temperature to 110 °C led to a full conversion and a 97% isolated yield (Scheme 1). In these conditions, no Scheme 1. N-Ethylation of Anilines and Some Aliphatic Aminesa

Figure 2. Previous works in hydrogen autotransfer methylation using methanol.

salt and a tetraphosphine ligand for the monomethylation of anilines and secondary aliphatic amines, and dimethylation of primary aliphatic amines in the presence of a catalytic amount of K3PO4 at 140 °C (Figure 2).9 However, even if these complexes paved the way to more sustainable processes, they are based on expensive phosphorus ligands. Alkylation of amines and ketones via the borrowing hydrogen strategy has also been demonstrated in the presence of the (cyclopentadienone) iron tricarbonyl complexes Fe2 and Fe3 (Figure 2).10−12 However, methylation has been scarcely investigated, due to the higher enthalpy of dehydrogenation for methanol compared to higher alcohols.13

a

General conditions: amine (0.5 mmol), Fe1 (2 mol %), CsOH (10 mol %), EtOH (1 mL) for 16 h. bYield was based on isolated product.

preactivation of the complex (under UV-A irradiation or with Me3NO to remove a CO ligand) was required and the active species was generated via a Hieber-type reaction.17 Functional groups such as nitrile, acetal, or ether were tolerated in this reaction affording compounds 3a-e in good yields (73−99%, Scheme 1). Benzylamine type derivatives also underwent ethylation in excellent yields (4a-b, f-g, 73−98%) as highlighted in Scheme 1. Secondary aliphatic amines were 5986


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Scheme 2. N-Methylation of Various Anilines Bearing Different Functional Groupa

ethylated with ethanol in good to excellent yield, while primary amines were dialkylated, as already observed with noble metals and with the in-situ generated cobalt complex.8 Having demonstrated the feasibility of the ethylation of amines, we wondered whether methanol, the less reactive alcohol for dehydrogenation, could be a C1-alkylating reagent. As a model reaction, the methylation of anisidine 1a in methanol was optimized in the presence of 10 mol % of a base and 2 mol % of Fe1 (Table 1). Again, cesium hydroxide Table 1. N-Methylation of Anisidinea

entry

catalyst

base

conv. (%)b

c

Fe1 Fe1 Fe1 Fe1 Fe1 Fe2 Fe3

Cs2CO3 CsOH CsOH CsOH CsOH CsOH CsOH

9 >99 70 63 58 35 0

1 2 3d 4e 5f 6 7 a

General conditions: anisidine (0.5 mmol), catalyst (2 mol %), base (10 mol %), solvent (1 mL) for 16 h. bConversion was determined by 1 H-NMR. cCatalyst was activated under UV-A (400−315 nm) irradiation for 30 min. dFor 8 h. e5 mol % of iron complex. f1 mol % of iron complex.

provided enhanced conversions compared to cesium carbonate (entries 1 and 2, Table 1). Shortening the reaction time to 8 h led to a decrease of the conversion (entries 2 and 3, Table 1). Finally, deviation of the catalyst loading or the nature of the complex provided lower conversions (entries 4−7, Table 1). With the optimized alkylation conditions in hand, we delineated the scope of the methylation by modifying the nature of the substituent on the aromatic ring (Scheme 2). Both electron-donating and electron-withdrawing substituents were tolerated in this alkylation, and the N-methyl anilines 5 were isolated in moderate to excellent yields (58−99%, Scheme 2). Alkylation of the halogen-substituted anilines gave the methylated anilines 5d-g in excellent yields without any reduction of the carbon−halogen bonds (Scheme 2). Other functionalities, such as reducible functionalities (nitrile, ketone), an acetal or a styrene fragment, remained also inert in these conditions. Heteroaromatic derivatives were also tolerated, and the methylated amines 5j-k were isolated in 94−99% yields. Noticeably, chemoselective methylation was obtained with 4-amino-acetophenone and 4-amino-benzophenone. The corresponding 4-N-methylamino-acetophenone 5n and 4-N-methylamino-benzophenone 5l were obtained in 77% and 96% yields, respectively (Scheme 2). Neither alkylation in the α-position to the ketone nor reduction of the ketone was observed. To increase the interest of this procedure and demonstrate its versatility, the scope was extended to aliphatic amines (Scheme 3). Initial attempts, using the previous reaction conditions with benzylamine, did not deliver any methylated product, even by raising the temperature up to 140 °C (see Supporting Information (SI), entries 1−4, Table S2). Such a result is in sharp contrast with the ethylation procedure but

a General conditions: aryl amine (0.5 mmol), Fe1 (2 mol %), CsOH (10 mol %), MeOH (1 mL) for 16 h. bYield was based on isolated product.

reflects the lower reactivity of methanol. In a recent contribution, Hong reported a ruthenium-catalyzed methylation of amines with methanol under hydrogen pressure and demonstrated that hydrogen pressure was necessary to allow selective dehydration over dehydrogenation of the hemiaminal intermediate.7g Following this line, methylation of benzylamine in the presence of Fe1 was achieved (full conversion, 95% isolated yield, Scheme 3). Deviation of these reaction conditions (hydrogen pressure, temperature or reaction time) did not allow methylation of benzylamine (see SI, entries 5−8, Table S1). To delineate the scope of this alkylation, various primary and secondary alkyl amines were evaluated (Scheme 3). The reactivity of both types of amines is similar, and good to excellent yields were obtained. As monoalkylation occurs with aniline, chemoselective methylation of an amino-indole was obtained (6j: 83% yield). Gratifyingly, (chiral) amino-alcohols provided the corresponding methylated amines in high yields (6g: 87% and 6h: 88%, Scheme 3). To provide a mechanistic framework consistent with our experiments, DFT calculations were undertaken (Figure 3) and both amines were considered (aniline as model for aromatic amines and methylamine for alkyl amines). If the organic steps 5987


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are first studied, the condensation between aniline and formaldehyde generated in situ (vide infra) is a metal free two-step reaction, which is thermodynamically neutral (2.5 and 0.0 kcal.mol‑1, respectively) but highly kinetically energy demanding with energy barriers of 29.4 and 39.6 kcal.mol‑1, respectively (see Figure S66 in the SI). The latter is the ratedetermining step in the overall catalytic cycle, and the solvent assists both steps. The same process occurs with methylamine. However, the rate-determining step is then 7.7 kcal.mol‑1 kinetically less demanding (see Tables S89 to S91 in the SI). Regarding the iron catalytic cycle, the initial Hieber’s type activation required two steps. A barrierless addition of the hydroxide on one CO ligand is followed by a hydride formation. The latter requested a quite energy-demanding barrier (34.1 kcal.mol‑1; see also Figure S67a in the SI for the transition state I−II). Overall, this activation is highly exergonic ( 29.7 kcal.mol‑1). Despite the relatively high stability of II, methanol interacts with the FeH···OCs moiety leading to the release of CsOMe with a kinetic cost of 31.4 kcal.mol‑1 (see Figure S67b in the SI for the transition state II−III) and the unexpected formation of the intermediate [Fe(CO)2(cyclopentadienone)(η2-H2)] III. Two possible pathways have then been examined. Either, a hydrogen release could liberate the unsaturated intermediate VI with an energy barrier of 9.5 kcal.mol‑1, or a hydrogen cleavage, assisted by a methanol molecule, could generate the intermediate IV, overcoming a transition state with an energy barrier of 19.1 kcal.mol‑1 (see Figure S67c in the SI for the transition state III−IV). Regarding these pathways, the indirect way is 9.6 kcal.mol‑1 more expensive than the direct hydrogen release. In other words, hydrogen pressure could drive the equilibrium (III to VI) to the formation of IV, and consequently to the

Scheme 3. N-Methylation of Various Primary and Secondary Aminesb

a

General conditions: amine (0.5 mmol), Fe1 (2 mol %), CsOH (10 mol %), MeOH (1 mL) for 16 h. bYield was based on isolated product.

Figure 3. Energy profile for Fe1-catalyzed methylation of amines (Gibbs free energies in solvent in kcal.mol‑1; in red, relative energy for transition states; R = Ph, Me (R = Ph for the energy values included here)). 5988


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Organic Letters reduction of the imines.14,18 Dehydrogenation of methanol could occur then via barrierless interactions between the ketone function of VI and the cesium cation in CsOMe. The release of formaldehyde from the iron center is again barrierless. Finally, reduction of the imine function is a concerted mechanism with an energy barrier of 19.7 kcal.mol‑1 for aniline derivatives (see Figure S67d in the SI) and 23.1 kcal.mol‑1 for alkylamine derivatives (see Table S84 in the SI). All these results highlight both an easier condensation of alkylamines and a lower reducibility of the corresponding imines. Finally, the methylated amine coordinated the iron center but can dissociate easily to regenerate VI. In conclusion, we have developed a general ethylation and methylation procedure for a broad range of aliphatic and aromatic amines using ethanol or methanol as an alkylating reagent in the presence of a well-defined bifunctional iron complex. This alkylation process provided alkylated amines in high yields, in the presence of other reducible functionalities. Both DFT calculations and experimental work unveil some key features in this process: the lower reactivity of alkylamines compared to anilines, the role of the hydrogen pressure and of the base, and finally the participation of the solvent in the synthesis of some intermediates.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02080. Preparation details, optimization conditions, NMR spectra, computational details, DFT calculations (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Albert Poater: 0000-0002-8997-2599 Jean-Luc Renaud: 0000-0001-8757-9622 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the “Ministère de la Recherche et des Nouvelles Technologies”, Normandie Université, CNRS, and the LABEX SynOrg (ANR11-LABX-0029). A.P. thanks the Spanish MINECO for a project CTQ2014-59832-JIN, and the EU for a FEDER fund (UNGI08-4E-003).

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Well-Defined Phosphine-Free Iron-Catalyzed N-Ethylation and N

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