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 1a (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 1a 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 : [email protected] [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.