Elsevier

Applied Catalysis A: General

Volume 478, 20 May 2014, Pages 241-251
Applied Catalysis A: General

Reinvestigating Raney nickel mediated selective alkylation of amines with alcohols via hydrogen autotransfer methodology

https://doi.org/10.1016/j.apcata.2014.04.009Get rights and content

Highlights

  • New application of Raney nickel (R-Ni) for N-alkylation of amines using alcohol.

  • R-Ni prepared and characterized as autohydrogen transfer agents.

  • Scope of reaction explored with different amines and alcohols.

  • Optimized conditions applied to synthesis of pharmaceutical actives.

Abstract

An efficient, cost-effective use of Raney nickel (R-Ni) a widely used industrial catalyst for N-alkylation using alcohols is highlighted here. The work describes the scope and capability of R-Ni in hydrogen autotransfer reactions enabling its widespread use in the Chemical and Pharmaceutical industry. R-Ni of W4, T4, and W7 grades were prepared and evaluated for alkylation of amines. The best activity and selectivity for mono alkylation of amines were obtained using W4 R-Ni at 1:4 moles of amine to alcohol in xylene at reflux. T4 R-Ni also showed ability to form stable imines. The prepared R-Ni was also recycled and reused for N-alkylation reaction. The optimized methodology was applied for synthesis of Active Pharmaceutical ingredients Piribedil and Mepyramine. The simplicity and wide substrate scope makes this method a preferred Hydrogen Auto-transfer protocol for the alkylation of amines.

Introduction

Synthesis of organic amines forms the crux of industrial organic chemistry. The Csingle bondN bond is the most prevalent moiety in intermediates and active pharmaceutical ingredients. The synthesis of this moiety is extensively achieved by N-alkyl/aryl substitution reactions. These reactions comprise upto 57% of the total reactions conducted in the R & D process chemistry departments of the top four drug companies [1]. Conventionally these reactions have been executed by SN2 reaction of amines with alkyl halides or by reduction of secondary amines [2]. The use of toxic reagents and complex work-up procedures in these conventional methods leads to generation of high levels of waste and has other environmental drawbacks.

Hydrogen autotransfer methodology is a shift toward sustainable chemistry along with removal of hazardous practices in amine synthesis. The reaction allows the use of easily available starting materials and giving back an ecologically benign byproduct. It is a type of a domino reaction where catalyst based dehydrogenation occurs, followed by condensation and finally hydrogenation of the condensed molecule takes place by replacing the removed hydrogen. The catalyst in these reactions acts as a hydrogen acceptor as well as donor [3].

Several catalytic systems have been developed for this reaction, dominated by the use of expensive homogeneous transition metals. Amongst them the use of ruthenium [4], [5], [6] is prominent followed by iridium [7], [8], [9], palladium [10], [11], [12], and platinum [13], [14], [15]. In recent years heterogeneous systems like silicon, alumina, copper and its derivatives [16] have also been investigated. Raney nickel (R-Ni) prepared from nickel and aluminum alloy is an effective catalyst for reductive transformations of organic compounds. This remarkable hydrogenation ability of R-Ni is well documented, but the dehydrogenation capability is less known and under-utilized. The use of R-Ni as hydrogen autotransfer catalyst was first reported for alkylation of aliphatic amines with primary alcohols. The reaction was reported in low boiling alcohol as solvent which resulted in very low yields [17]. Following this, R-Ni has been reported for alkylation of aromatic amines where the results indicated that the rate of reaction was dependent on the concentration of catalyst and also the formation of aldehyde vapors confirmed that the reaction follows the hydrogen autotransfer reaction [18], [19]. The reports on alkylation of heterocyclic amines using R-Ni showed low yields of product [20], whereas reports on the alkylation of sulfonamides in alcoholic solvents showed a brief study on the reaction kinetics and on the probable reaction mechanism [21]. Although the literature does mention experiments and results using R-Ni but little or no elaboration has been mentioned on the used catalyst, its method of preparation, its nature, and characteristics. The literature also reports limited substrate scope and application of R-Ni as Hydrogen autotransfer catalyst.

In this paper, we would like to fill up the gaps and short falls of previous literature, along with further scientific addition to R-Ni mediated alkylation of amines using alcohol. The work sequentially deals with preparation and characterization of different grades of R-Ni as agents for hydrogen autotransfer reaction. The prepared three grades were tested for their activity. The paper further discusses optimization of reaction conditions for a model reaction. Additionally the study establishes scope of reaction with different amines and alcohols. The major focus of this work includes selective monoalkylation of amines to prepare secondary amines with absence of tertiary amine formation. The prepared R-Ni was recycled and reused for N-alkylation reaction. Finally the conditions have been applied for synthesis of Pharmaceutical Actives like Piribedil and Mepyramine.

Section snippets

Preparation and characterization of R-Ni

R-Ni [22] of three grades, i.e. T4, W4, and W7 previously reported in the literature were selected for the study. The grades varied in the degree of leaching of aluminum from nickel–aluminum (50:50) alloy (Ni–Al alloy).

Conclusion

The current work has demonstrated a new role for R-Ni, an old widely used reduction catalyst. The identification of W4 as the specific grade of R-Ni in the same reaction that is capable of both dehydrogenation and hydrogenation was unexpected. In addition it also suggests that R-Ni can also be used for selective dehydrogenation of alcohols to aldehydes. The ability of T4 R-Ni to form stable imines and lacking the efficiency to undergo hydrogenation was also an outcome in this work. The neutral

General methods

All reactions were carried out in oven-dried glassware. TLC with aluminum foil backed plates coated with 0.2 mm layers of silica gel 60 F254 (E. Merck, Darmstadt, Germany) were used to monitor reactions where appropriate. Visualization of these plates was done by a 254 nm UV light and/or KMnO4 or ninhydrin (1%) dip followed by gentle warming. Organic layers were routinely evaporated using Equitron Roteva, 8703.RVR.000 rotary evaporator. Where necessary, further drying was facilitated by high

Acknowledgments

The authors thank Ambernath Organics Pvt. Ltd. (grant no. 022-42504000) for sponsoring the project and Monarch catalyst Pvt. Ltd. for catalyst characterization.

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