The β-alkylation of secondary alcohols with primary alcohols consists of the alkylation of a secondary alcohol in the beta position using a primary alcohol as alkylating agent (Scheme 2.14). Most of the efforts dealing with the design of effective catalysts for this process concern the preparation of highly active catalysts that selectively afford the formation of the -alkylated alcohols, with minimum production of the related ketones, which are often obtained as undesired side-products of the reaction.
+ [cat.] +
Scheme 2.14 β-Alkylation of secondary alcohols with primary alcohols
The most widely accepted mechanism for this reaction is the one shown in Scheme 2.15.84 In the first step of the process, both alcohols (primary and secondary) are oxidised to form an aldehyde (i) and a ketone (ii) together with the metal-dihydride [M]-(H)2. Subsequently, the base catalyzes an aldol condensation between the aldehyde and the ketone to form an α,β-unsaturated ketone (iii). Finally, the dihydride [M]-(H)2 reduces the C=C and C=O double bonds of the α,β-unsaturated ketone (iii) by donation of its two hydrogens, with subsequent formation of the final β-alkylated alcohol (iv).
Scheme 2.15 Mechanism of β-alkylation of secondary alcohols with primary alcohols 2.3.1.2 Alkylation of ammonia with primary alcohols
The inexpensive chemical ammonia is one of the most desirable substrates for the formation of nitrogen-containing organic molecules, despite its lack of reactivity in most catalytic reactions.85
A particular important class of nitrogen-containing molecules, amines, are produced in a 100,000 t/y worldwide scale, being of significant importance for bulk chemistry and also high-value intermediates in organic synthesis.86 Other important applications of amines include their use in pharmaceutical industry, and the manufacture of solvents, plastics, surfactants, textiles, cosmetics, toiletries, hydrazines, dyes and agrochemicals.87
Traditionally, amines are synthesised by alkylation of ammonia or amines with conventional alkylating agents, such as alkyl halides. However, over-alkylations commonly lead to mixtures of primary, secondary, tertiary amines as well as quaternary ammonium salts (Scheme 2.16).88 This over-alkylation makes the purification process tedious, expensive and far from being a green process due to the toxicity issues associated with alkyl halides and waste formation.
NH3 R-X
Scheme 2.16 Over-alkylation of amines
Compared to the well-known classical N-alkylation of amines with alkyl halides, an atom economically and environmentally attractive method is the alkylation of amines with primary alcohols, which is governed by a Borrowing-Hydrogen89 process.
Scheme 2.17 shows the proposed general mechanism for this reaction.67,90 The first step of the mechanism implies the in situ dehydrogenation of the primary alcohol to the corresponding aldehyde (i), generating a metal-dihydride [M]-(H)2. Then, a nucleophilic attack of the amine to the carbonyl intermediate (i) takes place, forming the imine (ii) and releasing H2O. Finally, the dihydride [M]-(H)2 reduces the imine by donation of its two hydrogen atoms, achieving the corresponding alkylated amine (iii).
Scheme 2.17 Alkylation of amines with primary alcohols
This is an attractive and promising alternative to traditional alkylating procedures due to several reasons: a) it is a safe and non-toxic procedure, b) water is generated as the only by-product, c) alcohols are inexpensive and more readily available than the corresponding toxic alkyl halides, and d) the selectivity of the reaction can be controlled by the catalyst. Moreover, this reaction also has the advantage of favouring the selective production of secondary amines, because a primary amine can more
easily react with the aldehyde. In contrast, traditional alkylation tends to give over-alkylation because the secondary amine is more reactive than the primary with the alkyl halide.
Considering the increasing attention given to Green Chemistry as well as to economic reasons, the use of ammonia as an alternative route to amines has gained attention in the scientific community. All the transformations using ammonia as substrate to produce nitrogen-containing molecules, have been extensively reviewed.85, 91-92 In the case of the alkylation of ammonia with alcohols, many alkylamines are prepared on large scale by the reaction of an alcohol with ammonia, normally using heterogeneous catalysts under extreme conditions, such as high pressures and temperatures.87,91 The use of homogeneous catalysts for this reaction is an interesting alternative, which should allow a more selective coupling of alcohols with ammonia under milder conditions.
The first alkylation of ammonia with alcohols catalysed by a homogeneous catalyst was reported by Fujita and co-workers in 2007.93 The article showed that [IrCp*Cl2]2
catalyzes the multiple alkylation of ammonium acetate with benzylic and aliphatic alcohols forming tertiary amines. Later, Milstein and Gunanathan achieved the alkylation of pressurised ammonia with alcohols using a ruthenium complex with a PNP pincer ligand (2.8, in Scheme 2.18).94 In this case, the primary amines were obtained with high selectivity and good yields.
N P Ru P
Cl H O
2.8
Scheme 2.18 Ru-catalyst 2.8
Shortly thereafter, Mizuno and co-workers reported that nitriles could also be obtained by a ruthenium catalysed reaction between alcohols and ammonia.95 Beller
96-97 and Vogt98 independently reported preparative procedures for the formation of primary amines by means of ruthenium-catalysed amination of secondary alcohols with ammonia. Although the efficiency and selectivity of these reactions were
excellent, the requirement of ammonia in the gaseous or liquid state limits the synthetic utility of these approaches.
Recently, exceptional results in Borrowing-Hydrogen processes have been achieved.
For instance, β-alkylation of secondary alcohols with primary alcohols using copper103 and iron104 complexes as catalysts, have been reported. An efficient and green aldehyde-catalysed transition metal-free dehydrative C-alkylation method for preparation of useful long chain alcohols, using primary alcohols and methyl carbinols as substrates, has also been described.105 Additionally, extraordinary outcomes for the N-alkylation of amines with alcohols by using Borrowing-Hydrogen methodology have recently been reported by Martín-Matute, based on an iridium complex with an alcohol/alkoxide-tethered NHC, which is able to catalyze the reaction at temperatures as low as 50ºC.106 The most spectacular result achieved in this topic corresponds to the enantioselective amination of alcohols using a chiral Ir complex in cooperation with a chiral phosphoric acid, reported by Zhao and co-workers.107
Bearing in mind all these previous results, we focused our attention on the development of new challenging Borrowing-Hydrogen processes, using 'IrCp*' complexes as catalysts, with ligands that could participate in the catalytic cycle. As previously mentioned, our group has experience in β-alkylation of secondary alcohols with primary alcohols, hence we decided to start our studies by testing the efficiency of our catalysts in this reaction, to further extend our studies to a more challenging Borrowing-Hydrogen process, such as the alkylation of ammonia with primary alcohols.
In the next section, we will present firstly the synthesis of our new 'IrCp*' complexes with non-spectator ligands, followed by the catalytic results obtained in the β-alkylation of secondary alcohols with primary alcohols, and in the β-alkylation of ammonia with primary alcohols. The catalytic activity of our new 'IrCp*' compounds will be compared with that of [IrCp*Cl2]2 and Shvo's catalyst.