Scope and limitations of reductive amination catalyzed by half-sandwich iridium complexes under mild reaction conditions

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Highlights

  • Half-sandwich Ir complexes show excellent chemoselectivity under optimized reaction conditions.

  • Reactions could be performed at 37 °C under air.

  • A variety of natural and unnatural amino acids could be synthesized.

Abstract

The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of <1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).

Introduction

Primary amines are ubiquitous in nature (e.g., in amino acids, nucleic acids, and alkaloids) and are key components in numerous synthetic products such as dyes, pharmaceuticals, and agrochemicals [1], [2], [3], [4]. Because of their central importance to both life and industry, the synthesis of 1° amines is a major focus in modern organic chemistry. Conventional methods for the synthesis of 1° amines include reduction of nitrile/amide/nitro groups [5], alkylation of ammonia [6], and hydroamination of alkenes [7]. One of the most attractive methods to prepare 1° amines is reductive amination (RA) of aldehydes and ketones because it can be performed under mild reaction conditions and tolerates a broad range of functional groups (Scheme 1) [8]. The RA process involves condensation between carbonyl compounds with ammonia to generate imine intermediates that are subsequently reduced using a hydride donor. Unfortunately, a common competing side reaction is the reduction of the starting carbonyl compound to the corresponding alcohol.

The selection of suitable hydride reagents and reaction conditions are important factors in determining the efficiency and selectivity of RA reactions. The most common reductants used for this application are sodium cyanoborohydride (NaBH3CN) [9], sodium triacetoxyborohydride (NaBH(OAc)3) [10], organosilanes [11], [12], and other similar reagents (Scheme 2) [13], [14], [15]. Such reagents, however, can give poor chemoselectivity and generate potentially non-innocent byproducts (e.g., cyanide and boron-containing species are toxic to cells in biological applications). RA of aldehydes/ketones could also be achieved using metal catalysts in the presence of alkyl amines and hydrogen gas to give 2° amines (hydrogenation) [16], [17] or ammonium formate to give 1° amines (Leuckart-Wallach reaction) [18]. A disadvantage of the former is the use of flammable gas and a disadvantage of the latter is the requirement for high temperatures (>120 °C).

One of the earliest examples of using organometallic catalysts for transfer hydrogenative reductive amination was reported by Ogo/Watanabe and co-workers in 2001, who used pentamethylcyclopentadienyl (Cp*) iridium catalysts and ammonium formate in water to convert aldehydes and ketones to 1° amines [19]. Ogo and Fukuzumi also discovered that Cp*Ir complexes were capable of furnishing α-amino acids from α-keto acids using excess ammonium formate (20 equiv. relative to substrate) in aqueous solutions (pH = 5.0–6.5) at 80 °C [20]. In 2002, Kitamura and co-workers showed that [Cp*RhCl2]2 in combination with HCOONH4 was highly effective for the chemoselective synthesis of 1° amines from ketones in methanol [21]. In 2003, Kadyrov and co-worker achieved the asymmetric RA of aromatic ketones by taking advantage of ruthenium catalysts in the presence of chiral ligands and ammonium formate in ammonia/methanol solutions [22]. Lastly, Xiao and co-workers developed cyclometallated Cp*Ir complexes that efficiently provided 2° or 3° amines from ketones, 1° or 2° amines, and azeotropic mixtures of formic acid/triethylamine [23]. The synthesis of 1° amines was also achieved [24]. Although the examples above demonstrate the remarkable progress made in catalytic amine synthesis in recent years, some of the methods required high temperatures (≥80 °C) and have poor chemoselectivity in water. RA in aqueous solutions is particularly challenging because water is unfavorable for the formation of imines, which are key reaction intermediates (Scheme 1) [25].

Because our research group is interested in biocompatible chemistry, we were intrigued by the prospect of applying transfer hydrogenative RA in biological systems [26], [27], [28]. A seminal report by McFarland and Francis in 2005 showed that lysozymes could be alkylated via reductive amination between lysine side chains and carbonyl containing substrates using [Cp*Ir(bipyridine)OH2]2+ catalysts in the presence of sodium formate [29]. This example was noteworthy because the reactions were carried out under physiologically relevant conditions (pH 7.4 aqueous buffer, 37 °C) and were as efficient as classical protein conjugation methods such as lysine acylation or reductive amination using sodium cyanoborohydride. Given our previous success in demonstrating that [Cp*Ir(N-phenyl-2-pyridinecarboxamidate)Cl] (Ir1) is capable of promoting intracellular transfer hydrogenation [30], we wanted to assess whether such complexes could also mediate transfer hydrogenative RA to afford 1° amines under mild reaction conditions. Recently, Kuwata, Watanabe, and co-workers reported a study showing that Ir1 and related complexes could be used with very low catalyst loading (e.g., substrate/catalyst ratio of up to 20,000) to achieve efficient transfer hydrogenative RA [31]. Unfortunately, these reactions were performed at temperatures ≥60 °C in methanol, which are not suitable conditions for biological environments. In the present work, we report on the scope and limitations of transfer hydrogenative reductive amination using organoiridium complexes in both methanol and water at 37 °C. Our studies showed that iridium-catalyzed RA reactions could proceed with excellent selectivity for a variety of carbonyl substrates in polar organic solvents; however, catalyst loading below 1.0 mM is not sufficient to achieve appreciable reaction rates for practical synthesis in aqueous media.

Section snippets

Catalyst screening

Pentamethylcyclopentadienyl iridium complexes are attractive catalysts because they are air and water stable, can be easily prepared, and show excellent transfer hydrogenation activity [19], [26], [32]. To determine whether such catalysts could be employed for synthetically challenging applications, such as in reactions involving thermally sensitive substrates or inside living environments, we evaluated a series of Ir complexes in open air and mild temperatures. Our studies focused primarily on

Conclusion

In summary, we have shown that [Cp*Ir(N-phenyl-2-pyridinecarboxamidate)Cl] and related complexes are excellent catalysts for converting aldehydes and ketones to 1° amines using HCOONH4 as both the hydride and nitrogen donor. This work has expanded upon other studies by demonstrating that aqueous transfer hydrogenative RA could be carried out at mild temperatures (37 °C) and in many cases, with excellent selectivity of amine over alcohol products. A broad range of substrates was tolerated,

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We are extremely grateful to the Welch Foundation (Grant No. E-1894) and National Institute of General Medical Sciences of the NIH (Grant No. R01GM129276) for financial support.

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