Cp∗Ir-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines

doi:10.1016/j.tet.2007.11.083

Tetrahedron

Volume 64, Issue 8, 18 February 2008, Pages 1943-1954

This paper is dedicated to the memory of the late Professor Yoshihiko Ito

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Abstract

A versatile and highly atom economical catalytic system consisting of [Cp^∗IrCl₂]₂/NaHCO₃ (Cp^∗=pentamethylcyclopentadienyl) for the N-alkylation of amines with primary and secondary alcohols as alkylating reagents has been developed. For example, the reaction of equimolar amounts of aniline and benzyl alcohol in the presence of [Cp^∗IrCl₂]₂ (1.0 mol % Ir) and NaHCO₃ (1.0 mol %) in toluene at 110 °C gives N-benzylaniline in 94% yield. The present catalytic system is applicable to the N-alkylation of both primary and secondary amines, and only harmless water is produced as co-product. A wide variety of secondary and tertiary amines can be synthesized with high atom economy under mild and less-toxic conditions. One-pot sequential N-alkylation leading to tertiary amines bearing three different substituents is also described.

Graphical abstract

Introduction

The development of versatile and efficient methods for the synthesis of amines has still been an active area of research,1, 1(a), 1(b) because a variety of amines play an important role in many fields of organic chemistry including such as biological, medicinal, agrochemical, dyes, and polymer chemistry. In recent years, a number of transition metal catalyzed reactions for the synthesis of amines, such as hydroamination of alkenes or alkynes,2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i) and amination of aryl halides,3, 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k) have been developed. On the other hand, there have been a couple of traditional methods for the synthesis of amines: the N-alkylation with alkyl halides4, 4(a), 4(b), 4(c) and the reductive amination with carbonyl compounds.5, 5(a), 5(b), 5(c), 5(d) However, these conventional reactions suffer disadvantages as follows; (1) the use of alkyl halides or strong reducing reagents is undesirable from an environmental point of view and (2) these reactions generate equimolar amounts of wasteful salts as co-products.

The N-alkylation of amines with alcohols (Scheme 1) is an attractive candidate for the synthesis of amines because, (1) it does not generate any harmful and/or wasteful co-products (only H₂O as co-product), (2) alcohols are more readily available than corresponding halides or carbonyl compounds in many cases, and (3) if the reaction proceeds efficiently by the employment of equimolar amounts of starting materials, extremely high atom economical system⁶ can be realized. Although several catalytic systems for the N-alkylation of amines with alcohols have been studied using ruthenium7, 7(a), 7(b), 7(c), 7(d), 7(e), 7(f), 7(g), 7(h), 7(i), 7(j), 7(k), 7(l) and other transition metal catalysts,8, 9, 9(a), 9(b), 10, 10(a), 10(b) most of them require a high reaction temperature (>150 °C) and/or an excess use of alcohols to obtain high yields of the product. Additionally, applicable amines and alcohols are relatively restricted; there have been no reports on the efficient systems for the N-alkylation with secondary alcohols.11, 11(a), 11(b)

In the course of our studies on the chemistry of pentamethylcyclopentadienyl (Cp^∗) iridium complexes,¹² we found their high catalytic activities toward hydrogen transfer reactions including the Oppenauer-type oxidation of alcohols,13, 13(a), 13(b), 13(c) carbon–nitrogen bond formations,14, 14(a), 14(b) and carbon–carbon bond formations.¹⁵ In this paper, we wish to report a full account of Cp^∗Ir-catalyzed N-alkylation of primary and secondary amines with primary and secondary alcohols.¹⁶ As described below, a variety of amines can be synthesized in atom economical manner under mild and less-toxic conditions.

Section snippets

Reaction of aniline with benzyl alcohol: optimization of the reaction conditions

Initially, we studied the reaction of aniline with benzyl alcohol as a model reaction. The reaction was carried out using equimolar amounts of aniline and benzyl alcohol in toluene (0.1 mL) in the presence of [Cp^∗IrCl₂]₂ as catalyst (1.0 mol % Ir) and base (1.0 mol %) at 110 °C for 17 h.¹⁷ The results are summarized in Table 1. In each reaction, mono-alkylated N-benzylaniline was formed selectively; no formation of di-alkylated N,N-dibenzylaniline was observed. When the reaction was carried out

General

All reactions and manipulations were carried out under an atmosphere of argon by means of standard Schlenk techniques. ¹H and ¹³C NMR spectra were recorded on JEOL A-500 and EX-270 spectrometers. Gas chromatography (GC) analyses were performed on a GL-Sciences GC353B gas chromatograph with a capillary column (GL-Sciences TC-17) and on a Shimadzu GC-14A gas chromatograph with a capillary column (Shimadzu CBP1-M25-025). High-performance liquid chromatography (HPLC) analysis was performed with a

Acknowledgements

We thank Mr. Y. Kida for his valuable technical assistance.

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Cp∗Ir-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines

Abstract

Graphical abstract

Introduction

Section snippets

Reaction of aniline with benzyl alcohol: optimization of the reaction conditions

General

Acknowledgements

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Chem. Rev.

Chem.—Eur. J.

Angew. Chem., Int. Ed.

J. Am. Chem. Soc.

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Chem.—Eur. J.

J. Am. Chem. Soc.

Org. Lett.

Org. Lett.

Inorg. Synth.

Tetrahedron

Tetrahedron

J. Org. Chem.

Tetrahedron

Tetrahedron

Org. Lett.

J. Chem. Soc., Perkin Trans. 1

J. Am. Chem. Soc.

Tetrahedron

J. Org. Chem.

Tetrahedron

Green Chem.

Angew. Chem., Int. Ed. Engl.

Tetrahedron Lett.

J. Org. Chem.

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Acc. Chem. Res.

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Organometallics

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Cp^∗Ir-catalyzed N-alkylation of amines with alcohols. A versatile and atom economical method for the synthesis of amines