DOI: 10.1002/cctc.201100255 The Catalytic Amination of Alcohols Sebastian Bhn, Sebastian Imm, Lorenz Neubert, Min Zhang, Helfried Neumann, and Matthias Beller*[a] In this Minireview, the synthesis of amines by the amination of amines are produced in bulk by the chemical industry with alcohols, by means of the so-called borrowing hydrogen meth- this synthetic method. In particular, the recent progress apply- odology, is presented. Compared to other synthetic methodol- ing organometallic catalysts based on iridium, ruthenium, and ogies for the synthesis of amines, these transformations are other metals will be discussed. Notable recent achievements highly attractive because often alcohols are readily available include the conversion of challenging substrates such as diols, starting materials, some of them on a large scale from renewa- the development of recyclable catalysts, milder reaction tem- ble sources. In addition, the amination of alcohols produces peratures, and the direct alkylation of ammonia or its equiva- water as the only by-product, which makes the process poten- lents with alcohols. tially environmentally benign. Already today, lower alkyl Introduction The importance of amines Scheme 1. Amination of alcohols with ammonia. Amines are of significant importance for the chemical industry, but also for numerous biological processes. For instance, amino acids and nucleotides constitute essential biological production of lower alkyl amines (Scheme 1).[13] One reason for building blocks and numerous bioactive compounds such as its large scale use is the availability of many alcohols by indus- vitamins, hormones, alkaloids, neurotransmitters, or natural trial processes such as hydroformylation/reduction of olefins toxics contain amino groups.[1] It is, therefore, not surprising, (e.g. 1-propanol, 1-butanol, 2-ethylhexanol), hydration of ole- that numerous amines and their derivatives find application as fins (2-propanol, ethanol), fermentation of sugars (ethanol), or agrochemicals, pharmaceuticals, or food additives. direct production from synthesis gas (methanol). In addition, Since the Haber–Bosch process was implemented in the the amination of alcohols affords water as the only by-product, early 20th century, ammonia has been available on a large scale which is by far less problematic than the salt waste generated and, today, more than 100 million tons are synthesized annual- in the amination of alkyl or aryl halides. ly, consuming 1–2% of the worldwide produced energy![2] The Notably, the reaction temperature and pressure for the in- impact of ammonia for the chemistry of amines arises from dustrial processes using ammonia vary significantly, depending the simple fact that almost every nitrogen atom in synthetic on the substrates and the catalysts. For example, methanol compounds either directly or indirectly comes from ammonia. and ammonia are reacted together at 350–5008C and 15– Although only a minority of the produced ammonia is em- 30 bar using aluminum-based heterogeneous catalysts.[14] ployed in the synthesis of structurally diverse amines, that still Today more than 1 million tons of methylamines are produced results in several million annual tons of amine products.[3] The according to this method. Other heterogeneous catalysts for various applications of these synthetic amines include their alcohol amination are based on tungsten, chromium, nickel, use as solvents, agrochemicals, pharmaceuticals, detergents, cobalt, iron, and copper. Applying such catalysts to current in- fabric softeners, flotation agents, corrosion inhibitors, anti- dustrial processes usually results in a mixture of primary, sec- static additives, lubricants, polymers, varnishes, and dyes.[4] ondary, and tertiary amines. However, the ratio of products can Owing to their importance, a variety of procedures for their be tuned by reaction parameters, such as residence time and synthesis, such as Hofmann alkylation,[5] Buchwald–Hartwig[6] excess of ammonia. In analogy to ammonia, primary or secon- and Ullmann[7] reactions, hydroamination,[8] hydroaminomethy- dary amines can be employed in these transformations to lation,[9] reduction of nitriles,[10] and nitro[11] compounds, or re- obtain secondary or tertiary amines. ductive amination[12] have been developed in the last century. [a] S. Bhn, S. Imm, L. Neubert, Prof. Dr. M. Zhang, Dr. H. Neumann, Prof. Dr. M. Beller Amination of alcohols Leibniz-Institut fr Katalyse an der Universitt Rostock e.V. Among the various known procedures to prepare amines, the Albert-Einstein-Str. 29a, 18059 Rostock (Germany) Fax: (+ 49)381-1281-51113 reaction of ammonia with alcohols is of special industrial im- E-mail: [email protected] portance as it constitutes the most common method for the Homepage: www.catalysis.de ChemCatChem 2011, 3, 1853 – 1864 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1853 M. Beller et al. So far, to the best of our knowledge, no homogeneously also known as the hydrogen auto transfer process.[19,23] Here, catalyzed alcohol amination is employed on industrial scale, the alcohol is activated by oxidation to give an aldehyde or but significant academic work has been performed in recent ketone, which then undergoes a condensation reaction with years. In this respect, a number of additional nitrogen nucleo- the amine nucleophile. Subsequent hydrogenation of the re- philes, such as sulfonamides,[15] amides,[16] or carbamides,[16b] sulting imine with the initially generated hydrogen yields the have been also studied in their reactions with alcohols. After a desired amine product. The terms borrowing hydrogen and short mechanistic and historical introduction, the recent devel- hydrogen auto transfer relate to the fact, that the catalyst “bor- opments in the field of N-alkylation reactions with alcohols by rows” hydrogen and “auto” transfers it to the modified (ami- the borrowing hydrogen methodology will be given. The two nated) aldehyde or ketone. The mechanism of this process is most important catalyst metals for such transformations, iridi- related to a transfer hydrogenation reaction, but has an impor- um and ruthenium, shall be discussed in more detail, while an tant advantage. In contrast to the hydrogenation of an imine overview is given concerning other catalyst metals. Applica- using an alcohol as a hydrogen donor, the oxidized alcohol is tions of ammonia or its equivalents will also be discussed. no longer waste, but acts as a substrate. Thus, a much higher atom economy[24] is achieved. The overall transformation essentially involves a reductive Mechanistic considerations amination as one part. When comparing reductive amination By 1901, the alkylation of aniline with sodium alkoxides had and alcohol amination, it should be noted that in reductive been described.[17] This represents the first coupling of amines aminations side reactions, such as aldol condensation, can with alcohols and proves that alcohol amination does not nec- easily occur, owing to the high concentration of the reactive essarily require a transition metal catalyst. In fact, the necessary aldehyde. By employing alcohols via borrowing hydrogen in- hydrogen transfer can be catalyzed by base in a Meerwein– stead, the corresponding aldehyde is only present in small Pondorf–Verley-type reaction.[18] Unfortunately, these transfor- amounts, since it is generated and consumed in situ, conse- mations usually require high temperatures (>2008C) or very quently, such side reactions can be diminished. long reaction times.[19] In addition, N-alkylation reactions with Depending on substrates and conditions, identification of alcohols can be catalyzed by acid. Such SN type alcohol amina- the exact operating reaction mechanism of an alcohol amina- tions usually require benzylic, propargylic, or allylic alcohols,[20] tion can be very challenging. Here, deuteration experiments but a very recent example demonstrates that even non-activat- may help to distinguish between acid- or base-catalyzed alco- ed alcohols, such as 1-octanol 1 or 2-undecanol, can be con- hol aminations and those proceeding by a borrowing hydro- verted with aniline 2 to give the N-alkyl anilines (e.g. 3)in gen mechanism. Furthermore, the presence of intermediates good yields;[21] an interesting example is shown in Scheme 2. such as ketones or imines indicates oxidation and suggests a borrowing hydrogen mechanism. Additional informa- tion may result from the substrate scope of a given protocol, as tertiary alcohols cannot be oxidized and another amination mechanism must take place. Brief historical introduction Scheme 2. S alcohol amination using an iron catalyst by Saito. N Heterogeneous catalysts for alcohol amination have been known since the first half of the twentieth cen- Although the reaction temperature is high (2008C), some allylic tury,[25] but no homogeneously catalyzed version was alcohols have been successfully converted at 1008C. reported before 1981, when Grigg and co-workers applied Another possible activation pathway for alcohol amination is [RhH(PPh3)4] for the N-alkylation of pyrrolidine and primary the so-called borrowing hydrogen methodology[22] (Scheme 3) amines, such as butylamine 6, with primary alcohols (e.g. 5) (Scheme 4).[26] In addition, they demonstrated that ruthenium- Scheme 4. Rhodium-catalyzed N-alkylation of amines by Grigg. and iridium-based catalysts were active for such transforma- tions. At the same time, Watanabe et al. reported the N-alkyla- tion of aniline 2 with simple alcohols, such as 1-propanol 8 [27]