Jonathan M. J. Williams

Metal-catalysed approaches to amide bond formation

Amongst the many ways of constructing the amide bond, there has been a growing interest in the use of metal-catalysed methods for preparing this important functional group. In this tutorial review, highlights of the recent literature have been presented covering the key areas where metal catalysts have been used in amide bond formation. Acids and esters have been used in coupling reactions with amines, but aldehydes and alcohols have also been used in oxidative couplings. The use of nitriles and oximes as starting materials for amide formation are also emerging areas of interest. The use of carbon monoxide in the transition metal catalysed coupling of amines has led to a powerful methodology for amide bond formation and this is complemented by the addition of an aryl or alkenyl group to an amide typically using palladium or copper catalysts.

Ruthenium-Catalyzed N-Alkylation of Amines and Sulfonamides Using Borrowing Hydrogen Methodology

The alkylation of amines by alcohols has been achieved using 0.5 mol % [Ru(p-cymene)Cl(2)](2) with the bidentate phosphines dppf or DPEphos as the catalyst. Primary amines have been converted into secondary amines, and secondary amines into tertiary amines, including the syntheses of Piribedil, Tripelennamine, and Chlorpheniramine. N-Heterocyclization reactions of primary amines are reported, as well as alkylation reactions of primary sulfonamides. Secondary alcohols require more forcing conditions than primary alcohols but are still effective alkylating agents in the presence of this catalyst.

The Give and Take of Alcohol Activation

Catalysts make alcohols more reactive by taking away hydrogen to create carbonyl compounds and then returning the hydrogen to the final products. Alcohols are relatively common starting materials for chemical reactions, even though they are quite unreactive. For example, reactions that would substitute another functional group (a nucleophile) for OH often fail because the hydroxide group (HO−) is difficult to displace—it is a poor leaving group. Alcohols are usually activated by turning the hydroxide into a better leaving group, either by protonating the alcohol or by converting it into a sulfonate or halide. However, both of these activation methods have some disadvantages (1). The acidic environment required for protonating the alcohol also protonates and deactivates the incoming nucleophile, especially amines. Conversion of the alcohol into a sulfonate or halide can lead to toxicity problems; many alkyl halides and alkyl sulfonates are mutagenic.

Amidines, isothioureas, and guanidines as nucleophilic catalysts

Over the last ten years there has been a huge increase in development and applications of organocatalysis in which the catalyst acts as a nucleophile. Amidines and guanidines are often only thought of as strong organic bases however, a number of small molecules containing basic functional groups have been shown to act as efficient nucleophilic catalysts. This tutorial review highlights the use of amidine, guanidine, and related isothiourea catalysts in organic synthesis, as well as the evidence for the nucleophilic nature of these catalysts. The most common application of these catalysts to date has been in acyl transfer reactions, although the application of these catalysts towards other reactions is an increasing area of interest. In this respect, amidine and guanidine derived catalysts have been shown to be effective in catalysing aldol reactions, Morita-Baylis-Hillman reactions, conjugate additions, carbonylations, methylations, silylations, and brominations.

Ruthenium-Catalyzed Oxidation of Alcohols into Amides

The synthesis of secondary amides from primary alcohols and amines has been developed using commercially available [Ru(p-cymene)Cl(2)](2) with bis(diphenylphosphino)butane (dppb) as the catalyst.

Synthesis of benzazoles by hydrogen-transfer catalysis.

Transition-metal-catalyzed hydrogen-transfer reactions have been used for the conversion of alcohols into benzimidazoles and aldehydes into benzoxazoles and benzothiazoles.

Iridium-catalysed amine alkylation with alcohols in water

Amines have been directly alkylated with alcohols using 1 mol% [Cp*IrI(2)](2) catalyst in water in the absence of base or other additives.

Borrowing Hydrogen Methodology for Amine Synthesis under Solvent-Free Microwave Conditions

Application of microwave heating to the Borrowing Hydrogen strategy to form C-N bonds from alcohols and amines is presented, removing the need for solvent and reducing the reaction times while still yielding results comparable with those using thermal heating.

Transamidation of Primary Amides with Amines Using Hydroxylamine Hydrochloride as an Inorganic Catalyst

Metal-free catalysis: A method for the transamidation of primary amides with primary or secondary amines provides access to secondary and tertiary amides, by utilizing catalytic quantities of hydroxylamine hydrochloride to activate the chemically robust primary amide group (see scheme). A mechanism of primary amide activation through a hydrogen-bonding complex is proposed.

Selective Ruthenium‐Catalyzed N‐Alkylation of Indoles by Using Alcohols

Indoles constitute important heterocyclic systems in nature. Based on the broad structural diversity and due to their biological activity, indoles have become an important component in several current pharmaceutical drugs. Hence, the development of improved synthetic methodologies for the generation of the indole core, as well as functionalization reactions on the aromatic ring system continue to be of significant interest to organic chemists. Among the numerous known bioactive indoles, various N-alkylated derivatives are known. The classical approach for the introduction of these alkyl chains involves treatment of the indole with base and an alkyl halide. A drawback of these reactions is the quantitative formation of waste salts. Clearly, this disadvantage can be overcome by using easily available alcohols as a more benign alkyl source. However, so far, the N-alkylation of indoles with alcohols has only been investigated in the presence of Raney nickel. More recently, Grigg and co-workers demonstrated that simple alcohols can be used for selective C-3-alkylation of indoles. This reaction is based on the so-called “borrowing hydrogen” methodology. Thereby, an alcohol or amine is initially dehydrogenated, then undergoes a functionalization reaction, and finally is rehydrogenated. Applications of this elegant methodology have been developed by the groups of Yus, Fujita, Grigg, Kempe, and us. Based on our ongoing interest in the synthesis of novel indoles and the activation of alcohols, we became interested in the selective N-alkylation of this important class of natural products. At the start of our investigations we studied the reaction of indole with hexanol as a model system. In general, this alkylation might result in N-, C-, and dialACHTUNGTRENNUNGkylated products (Scheme 1).