Alan Pettman

pH-Regulated Asymmetric Transfer Hydrogenation of Quinolines in Water†

1,2,3,4-Tetrahydroquinolines exist as key structural elements in many natural products and have found broad commercial application. In particular, optically pure tetrahydroquinolines are commonly present in alkaloids and are required in pharmaceutical and agrochemical synthesis. Representative examples include the bioactive alkaloids (+)-galipinine and ( )-augustureine, 3] and the antibacterial drug (S)-flumequine.

A Versatile Catalyst for Reductive Amination by Transfer Hydrogenation

Reductive amination (RA), the coupling of ketones or aldehydes with amines in the presence of a reducing reagent, is one of the most studied and useful reactions in synthetic chemistry. Applications of the reaction are widespread in the pharmaceutical, agrochemical, and chemical industries, materials science, and biotechnology. In both academic research and commercial-scale preparations, RA is effected mainly with stoichiometric boron hydrides and heterogeneous hydrogenation. Apart from generating copious waste, the use of boron hydrides is associated with other problems, such as the high toxicity of NaBH3CN and the inability to aminate aromatic ketones with NaBH(OAc)3, two most widely used hydrides in RA. RA by heterogeneous hydrogenation has long been practiced, but its application is limited by its relatively poor chemoselectivity, for example, reduction of C= O, C=C, and -NO2 over C=N bonds. [1, 2b] In the past decade or so, a small number of homogeneous catalysts and enzymes have been developed, allowing for enantioselective RA. However, the substrate scope remains to be improved. Herein we disclose a class of air-stable cyclometalated imido Ir complexes that catalyze transfer hydrogenative RA with safe, inexpensive formate, providing high chemoselectivity and activity along with wide substrate scope. Transfer hydrogenation has enjoyed a huge success in the reduction of ketones. However, its application in the reduction of imines, the key intermediate in RA, is less developed; examples of transfer hydrogenative RA are even rarer. In our effort to develop an asymmetric transfer hydrogenation system for RA, we initially examined reaction conditions for the transfer hydrogenation of a model imine prepared from acetophenone and p-anisidine, which was not reduced under asymmetric transfer hydrogenation conditions. With a previously prepared [Cp*IrCl(Tsdpen-H)] catalyst [Cp* = pentamethylcyclopentadienyl; Tsdpen = (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine] (0.5 mol%), 30 % conversion to the corresponding amine in 13 % ee was observed by using an azeotropic mixture of formic acid/triethylamine (F/T) in MeOH at 40 8C in 3 h. Surprisingly, when the catalyst was prepared in situ by treating [{Cp*IrCl2}2] with Tsdpen, the conversion rose to 95%, but the resulting amine was racemic. Of yet further interest is that when [{Cp*IrCl2}2] (0.25 mol %) was used without any added ligand, the reaction proceeded to afford the same result as that obtained with the in situ catalyst. These observations prompted us to ponder what the real catalytic species might be. One possibility is a cyclometalated iridium complex with the substrate ketimine acting as ligand through C H activation. This hypothesis was quickly supported by the fact that by simply stirring [{Cp*IrCl2}2] and the imine substrate in MeOH at 40 8C for 1 h, the iridium dimer was converted into a cyclometalated imido complex in greater than 99% conversion. Encouraged by the results above, we then explored cyclometalated Ir complexes of aromatic ketimines for the reduction of an aliphatic ketimine, which itself is difficult to undergo cyclometalation and indeed showed no activity in the [{Cp*IrCl2}2]-catalyzed reduction (Figure 1). Dramatic accel-

Real-time monitoring of nitrile biotransformations by mid-infrared spectroscopy

In this study mid-infrared spectroscopy was used to follow the enzyme kinetics involved in nitrile biocatalysis using whole cell suspensions of the bacterium Rhodococcus rhodochrous LL100-21. The bacteria were grown on acetonitrile to induce a two-step enzymatic pathway. Acetonitrile was biotransformed to acetamide by a nitrile hydratase enzyme and subsequently to acetic acid (carboxylate ion) by an amidase enzyme. The bacteria were also grown on benzonitrile to induce a one-step enzymatic pathway. Benzonitrile was biotransformed directly to benzoic acid (carboxylate ion) by a nitrilase enzyme. These reactions were followed by React IR using a silicon probe and gave excellent quantitative and qualitative real-time data of both nitrile biocatalytic reactions. This study has shown that this novel technique has potentially useful applications in biocatalysis.

Influence and correction of temperature perturbations on NIR spectra during the monitoring of a polymorph conversion process prior to self-modelling mixture analysis

The influence of temperature variations on the rank of a NIR dataset, has been investigated by comparing the results of principal component analysis (PCA) and evolving factor analysis (EFA), applied to two datasets measured at constant temperature and varying temperature. After temperature correction, the concentration profiles and spectra were obtained with PCA, SIMPLISMA and the orthogonal projection approach (OPA). The same resolution methods were used on the dataset measured at constant temperature.

The Remarkable Effect of a Simple Ion: Iodide‐Promoted Transfer Hydrogenation of Heteroaromatics

Among a variety of heteroaromatics, 1,2,3,4-tetrahydroquinolines, -isoquinolines and -quinoxalines are three significant substructures in many bioactive compounds and have attracted a great deal of attention in research concerning pharmaceuticals, agrochemicals, dyes and fragrances, as well as hydrogen-storage materials. They can be directly accessed by hydrogenation from commercially available quinolines, isoquinolines and quinoxalines. Traditionally, stoichiometric metal hydrides and reactive metals are used as reducing reagents. Apart from producing copious waste and using often hazardous reagents, these methods suffer from limited substrate scope, incompatibility with functionality and poor chemoselectivity. A more attractive method is to use catalytic hydrogenation. Over the past several decades, a number of homogeneous and heterogeneous catalysts have been applied to the hydrogenation of heteroaromatics, including the asymmetric version. The need for high H2 pressure, high reaction temperature or high catalyst loading is typical of metal-catalysed hydrogenation. Obviating the need for hydrogen gas, transfer hydrogenation (TH) offers an alternative. However, only a few catalysts have been reported thus far that allow for the TH of heteroaromatics, and in all cases the catalyst loading is relatively high ( 0.5 %). Furthermore, in either hydrogenation or TH, there appears to be no catalyst capable of reducing all three classes of heteroaromatics: quinolines, isoquinolines and quinoxalines. Herein, we disclose a highly effective catalyst system, enabled by a simple ion, I , which shows unprecedented activity in the reduction of these heteroaromtics under mild conditions. We recently reported the first example of asymmetric transfer hydrogenation (ATH) of quinolines in water with formate as the hydrogen source. Excellent enantioselectivities were obtained with a Rh–Ts-dpen catalyst, [Cp*RhCl(Ts-dpen-H)] (Ts-dpen =N-(p-toluenesulfonyl)1,2-diphenylethylenediamine). Following this success, we attempted the ATH of quaternary quinoline salts, aiming to directly obtain chiral N-substituted 1,2,3,4-tetrahydroquinolines. We chose the N-methyl-2-methylquinoline iodide salt as a benchmark substrate and Rh–Ts-dpen as the catalyst (1 mol%). There was little reduction using sodium formate as the reductant in water at 40 8C in 24 h, under which quinolines were readily reduced. Somewhat surprisingly, changing the aqueous formate to the azeotropic HCO2H/ NEt3 mixture led to an excellent isolated yield of 95 % but a very low enantiomeric excess (ee) value of 5 % for the tetrahydro product. Interestingly, similar conversion was also observed under identical conditions with [(Cp*RhCl2)2] as catalyst, without adding the Ts-dpen ligand. Thus, the low ee value might result from the diamine ligand in Rh–Ts-dpen being replaced by the iodide anion in the salt during the reaction. Bearing in mind the unusual effects of iodide documented in catalysis and the scarcity of effective catalysts for TH of heteroaromatics, we thought it would be interesting to explore whether [(Cp*RhCl2)2] in combination with the iodide ion would lead to a simple but active catalyst. Choosing 2-methylquinoline 1 a (pKa 5.4) as a model substrate, which is expected to be protonated when using formic acid (pKa 3.6) as the reductant, the TH was first carried out with 0.05 mol % [(Cp*RhCl2)2] in the azeotropic HCO2H/NEt3 at 40 8C. The reduction was insignificant, with the conversion of 1 a being only 6 % (Table 1, entry 2), indicating that iodide might indeed be necessary. To our delight, in the presence of 1 or even 0.1 equivalent of an iodide salt, tetrabutylammonium iodide (TBAI), full conversion was observed (Table 1, entries 3 and 4). In contrast, the analogous bromide salt TBAB is much less effective (Table 1, entry 5) and the chloride TBAC is ineffective (entry 6). The cheaper KI was equally effective, showing that it is the iodide ion that promotes the catalysis (Table 1, entry 7). Remarkably, in the presence of KI, the metal loading could be decreased to 0.01 mol % without affecting the conversion (Table 1, entry 8). At an even a lower loading of 0.001 mol % of rhodium with 0.5 equivalent of KI added, a moderate conversion of 71 % was still obtained, albeit in a longer reaction [a] J. Wu, Dr. W. Tang, Prof. J. Xiao Department of Chemistry, University of Liverpool Liverpool L69 7ZD (UK) E-mail : j.xiao@liv.ac.uk [b] Dr. C. Wang School of Chemistry & Chemical Engineering Shaanxi Normal University, Xi an 710062 (P.R. China) [c] Dr. A. Pettman Chemical R & D, Global Research & Development, Pfizer Sandwich, Kent CT13 9NJ (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201201517.

Discovery and synthesis of a new class of opioid ligand having a 3-azabicyclo[3.1.0]hexane core. An example of a 'magic methyl' giving a 35-fold improvement in binding.

In looking for a novel achiral μ opioid receptor antagonist for the treatment of pruritus, we designed and synthesised azabicyclo[3.1.0]hexane compounds as a new class of opioid ligand. During optimisation, an addition of a single methyl resulted in a 35-fold improvement in binding. An early example from the series had excellent μ opioid receptor antagonist antagonist activity and was very effective in an in vivo pruritus study.

Chemoenzymatic synthesis of a tachykinin NK-2 antagonist

A non-peptide tachykinin antagonist has been synthesized in a short and efficient four step sequence starting from a chiral enol acetate, which was obtained in enantiomerically pure form by resolution using a lipase catalysed transesterification reaction. The biotransformation was optimized in terms of solvent, temperature and immobilization method used. Oxidative cleavage of the (+)-enol acetate to give the key aldehyde ester intermediate could be achieved indirectly by oxidative rearrangement to an enone followed by Baeyer–Villiger oxidation and ring opening, or by epoxidation, rearrangement and oxidative cleavage or most directly by ozonolysis. X-Ray crystallographic analysis of a camphanic ester derivative of an ester alcohol confirmed that the absolute configuration of the enol acetate was (S).

Copper-catalysed reductive amination of nitriles and organic-group reductions using dimethylamine borane

A heterogeneous copper catalyst, formed in situ, has been shown to dehydrocouple commercially available amine boranes whilst transferring hydrogen for the reduction of selected organic functional groups in an aqueous medium. The catalytic system has also been shown to promote the reductive amination of aryl nitriles.

Electron-Deficient Phosphines Accelerate the Heck Reaction of Electronrich Olefins in Ionic Liquid

Using various substrates and ligands, we show that electron-deficient, bidentate phosphines are the ligands of choice for palladium-catalyzed arylation of electron-rich olefins. This is in contrast to the reaction of electron-deficient olefins, which benefit from electron-rich monodentate phosphines. A tentative explanation is offered based on DFT calculations.

Production of cyclohexanone monooxygenase from Acinetobacter calcoaceticus for large scale Baeyer-Villiger monooxygenase reactions

Cyclohexanone monooxygenase was produced from Acinetobacter calcoaceticus grown on a medium containing both glutamate (30 g l−1) and cyclohexanol (1 g l−1). Productivity was increased to 650 U l−1, an order of magnitude greater than previous production methods, thereby enhancing the potential commercial utility of this enzyme.