José A. Fuentes

On the NH Effect in Ruthenium-Catalysed Hydrogenation of Ketones: Rational Design of Phosphine-Amino-Alcohol Ligands for Asymmetric Hydrogenation of Ketones

The asymmetric hydrogenation of simple ketones, such as acetophenones, has become an important synthetic method as a result of the development of [RuCl2(diphosphine)ACHTUNGTRENNUNG(diamine)] catalysts by Noyori and co-workers. A large range of catalysts of this general type have now been prepared. Their reactivity is quite in contrast to simple MACHTUNGTRENNUNG(diphos)Xn salts that are barely active as catalysts for ketones that cannot chelate to the metal centre. The enhanced reactivity for reduction of simple ketones is proposed to be due to the “bifunctional mechanism” in which the ketone hydrogen bonds to the primary amine terminus of the ligand, activating it to attack by Ru–hydride and controlling stereoselectivity. There are reports that suggest these catalysts are not effective for certain ketones, such as bulky ketones (low reactivity), sterically similar aryl–aryl ketones (low selectivity), some ketones with strongly co-ordinating substituents (low reactivity), and alkyl–alkyl ketones (low selectivity) as well as a range of individual substrates that do not undergo asymmetric reduction readily. The discovery of structurally distinct, new classes of ketone hydrogenation catalyst that deviate from the [RuCl2(diphosphine)(di-primary-amine)] blueprint therefore might present one of the best opportunities to solve these problems; the importance of chiral secondary alcohols requires that methodology exists for every possible type of substrate in order to see this technology widely exploited in industry and more generally in synthesis. We have shown that Ru catalysts derived from P^N^NH2 ligands can hydrogenate some poorly reactive ketones with good enantioselectivity. The initial design of the catalyst envisaged hydrogenation of polar bonds facilitated by the primary amine terminus of the ligand in a co-ordination environment that is more accessible for bulky substrates relative to the Noyori catalysts. Rather than synthesising a very large library of new P^N^NH2 catalysts, we felt that an investigation of catalyst– structure activity relationships might throw up some leads for new catalysts, along with shedding light on some mechanistic issues, since it had not been possible to isolate the reaction intermediates in our previous studies. In this communication, we report some surprising findings from our kinetic experiments and the introduction of phosphino-amino-alcohol ligands for Ru-catalysed hydrogenation. The new achiral ligands, 1–3 can be prepared in one step from commercial starting materials and then converted into complexes of type [RuCl2ACHTUNGTRENNUNG(P^NR1N(R2)2ACHTUNGTRENNUNG(dmso)] by microwave-assisted complexation with [RuCl2ACHTUNGTRENNUNG(dmso)4] in THF at 120 8C (Scheme 1). Complexes 4–7 can be obtained pure by chromatography or recrystallisation and are easily handled in air. We carried out kinetic studies on the hydrogenation of a,a-dimethylpropiophenone, a substrate that was initially re-

Convenient and improved protocols for the hydrogenation of esters using Ru catalysts derived from (P,P), (P,N,N) and (P,N,O) ligands

An improved protocol where a pre-cursor, [Ru(Cl)(2)(NBD)(Py)(2)], is treated with ligands to form [RuCl(2)(bidentate ligand)(diamine)] pre-catalysts for ester hydrogenation is reported. This family of catalysts, as well as a range of ruthenium complexes of tridentate P^N^X (X = NR(2), OH) ligands have been investigated in the hydrogenation of aromatic esters. A range of aromatic esters can be hydrogenated in high yields at temperatures between 30 °C and 100 °C.

Synthesis of organocatalysts using non-covalent chemistry; understanding the reactivity of ProNap, an enamine-type organocatalyst that can self assemble with complementary co-catalysts

A promising but relatively unexplored approach to tuning asymmetric catalysts is to design catalysts that can self-assemble with a family of complementary co-catalysts. In order to study the mechanism of self-assembled enamine catalysts that are tagged with a supramolecular receptor, a new series of more soluble complementary co-catalysts have been developed. The formation of hydrogen-bonded supramolecular pre-catalysts was established by NMR and X-ray crystallography. NMR studies have identified an enamine intermediate in the reactions between the supramolecular organocatalyst ProNap and aldehydes in which the co-catalysts are hydrogen-bonded. The formation of imidazolidinones from ketones is a reversible process that is likely to coincide with formation of trace amounts of the productive enamine intermediate. The equilibrium is reached much faster in the presence of the complementary co-catalysts, explaining the faster initial rates and greater productivity when ketones are used in stoichiometric quantities relative to the Michael acceptor in asymmetric Michael reactions. These imidazolidinones are a parasitic dead-end in the reaction of aldehydes, both for the self-assembled Proline derivatives and for simple Proline-derived amides. Catalysts prepared from (S)-pyrrolidine-3-carboxylic acid are immune to this and high-yielding nitro-Michael reaction using aldehydes can be achieved.

The influence of imine structure, catalyst structure and reaction conditions on the enantioselectivity of the alkylation of alanine methyl ester imines catalyzed by Cu(ch-salen)

Abstract Systematic variation of the substrate structure has shown that the most effective substrates for Cu(ch-salen)-catalyzed asymmetric enolate alkylation reactions carried out under phase-transfer conditions are the para -chlorophenyl imines of amino esters. The other reaction parameters (solvent and stirring speed) have also been optimized. The introduction of substituents onto the aryl rings of the salen ligand was found not to have a beneficial effect on the enantioselectivity of the reaction.

Synthesis, conformational flexibility and preliminary complexation behaviour of α,α′-trehalose-based macrocycles containing thiourea spacers

An efficient synthesis of macrocyclic ligands incorporating two α,α′-trehalose subunits linked through the primary C-6,6′ positions by means of 1,3-thiourea spacers is reported; the Z/E configuration of the N–C(S) bonds is governed by intramolecular hydrogen bonding as well as steric factors.

A supramolecular approach to chiral ligand modification: coordination chemistry of a multifunctionalised tridentate amine-phosphine ligand

A novel chiral amine-phosphine tagged with an amido-napthyridine moiety has been synthesised and found to bind complementary pyridinone additives. These additives were found to have a modest but measurable promotional effect on the catalytic activity and/or enantioselectivity of Ir- and Rh-catalysed reductions. One explanation for the relatively poor results obtained with the Ir and Ru catalysts is the formation of complexes, in which the ligand adopts an anionic tridentate coordination mode. Pt and Rh complexes of this type were isolated and characterised.

On the rate-determining step and the ligand electronic effects in rhodium catalysed hydrogenation of enamines and the hydroaminomethylation of alkenes

In the course of studies on the tandem hydroformylation–reductive amination (hydroaminomethylation), fluorinated mono-phosphines were found to be more active than their more electron-donating counterparts in the enamine hydrogenation step of the reaction; this is in contrast to the widely held view that alkene hydrogenation activity increases with ligand donor strength. DFT calculations comparing the reaction pathways for a simple alkene and a representative enamine show that the rate-determining step changes from the first insertion into a Rh–H bond for but-2-ene to the final reductive elimination step from the Rh–hydride–alkyl species in the enamine hydrogenations.

Rapid Asymmetric Transfer Hydroformylation (ATHF) of Disubstituted Alkenes Using Paraformaldehyde as a Syngas Surrogate

As an alternative to conventional asymmetric hydroformylation (AHF), asymmetric transfer hydroformylation (ATHF) by using formaldehyde as a surrogate for syngas is reported. A catalyst derived from commercially available [Rh(acac)(CO)2] (acac=acetylacetonate) and 1,2-bis[(2S,5S)-2,5-diphenylphospholano]ethane(1,5-cyclooctadiene) (Ph-BPE) stands out in terms of both activity and enantioselectivity. Remarkably, not only are high selectivities achievable, the reactions are very simple to perform, and higher enantioselectivity (up to 96 % ee) and/or turnover frequencies than those achievable by using the same catalyst (or other leading catalysts) can be obtained by using typical conditions for AHF.

On the functional group tolerance of ester hydrogenation and polyester depolymerisation catalysed by ruthenium complexes of tridentate aminophosphine ligands

The synthesis of a range of phosphine-diamine, phosphine-amino-alcohol, and phosphine-amino-amide ligands and their ruthenium(II) complexes are reported. Five of these were characterised by X-ray crystallography. The activities of this collection of catalysts were initially compared for the hydrogenation of two model ester hydrogenations. Catalyst turnover frequencies up to 2400 h(-1) were observed at 85 °C. However, turnover is slow at near ambient temperatures. By using a phosphine-diamine Ru(II) complex, identified as the most active catalyst, a range of aromatic esters were reduced in high yield. The hydrogenation of alkene-, diene-, and alkyne-functionalised esters was also studied. Substrates with a remote, but reactive terminal alkene substituent could be reduced chemoselectively in the presence of 4-dimethylaminopyridine (DMAP) co-catalyst. The chemoselective reduction of the ester function in conjugated dienoate ethyl sorbate could deliver (2E,4E)-hexa-2,4-dien-1-ol, a precursor to leaf alcohol. The monounsaturated alcohol (E)-hex-4-en-1-ol was produced with reasonable selectivity, but complete chemoselectivity of C=O over the diene is elusive. High chemoselectivity for the reduction of an ester over an alkyne group was observed in the hydrogenation of an alkynoate for the first time. The catalysts were also active in the depolymerisation reduction of samples of waste poly(ethylene terephthalate) (PET) to produce benzene dimethanol. These depolymerisations were found to be poisoned by the ethylene glycol side product, although good yields could still be achieved.

A convenient catalyst system for microwave accelerated cross-coupling of a range of aryl boronic acids with aryl chlorides

A convenient microwave accelerated cross-coupling procedure between aryl chlorides with a range of boronic acids has been developed. An explanation for the low reactivity of highly fluorinated boronic acids in Suzuki coupling is provided.