Synthesis of Tetrasubstituted Pyridines by the Acid-CatalyzedBohlmann-Rahtz Reaction.-An improved methodology for the Bohlmann-Rahtz reaction is presented, which allows the synthesis of pyridine derivatives in one step and at lower temperatures. Thus, enamino esters (I) and (V) react with alkynones in the presence of acetic acid or catalytic amounts of ZnBr 2 or Yb(O-Tf) 3 to furnish directly the poly-substituted pyridines in moderate to good yields. The reaction can additionally be extended to acid-labile educts when Amberlyst 15 is used as the catalyst.
Lewis acids catalyse the Bohlmann-Rahtz heteroannulation reaction to generate highly functionalised pyridines from enamino esters and alkynones in a single synthetic step. Of the catalysts studied, ytterbium(III) trifluoromethanesulfonate and zinc(II) bromide are the two most efficient for the synthesis of pyridines and pyrido[2,3-d]pyrimidines, from ethyl b-aminocrotonate or 2,6-diaminopyrimidin-4-one respectively, in up to 94% yield.The synthesis, reactions and biological properties of pyridine-containing derivatives is an ever-expanding subject in heterocyclic chemistry. This structural motif may be found in a large number of pharmaceutical agents, 1 as a pharmacophore of considerable historical importance, and so new methods for their preparation have received a great deal of attention in the literature. The synthesis of pyridine 4 in two steps by Michael addition-cyclodehydration of ethyl b-aminocrotonate 1 and but-3-yn-2-one 2 was first reported by Bohlmann and Rahtz in 1957 and proceeds via aminoheptadienone intermediate 3, that is isolated and heated to high temperature to facilitate the cyclisation (Scheme 1). 2 Since its discovery, it is noteworthy that very few applications of this reaction have appeared in the literature. A synthesis of the modified core of promothiocin antibiotics has been reported, 3 using the Bohlmann-Rahtz heteroannulation reaction for the preparation of clusters of pyridine-containing heterocycles that were elaborated to the natural product. 4,5 Scheme 1In order to improve the utility of the Bohlmann-Rahtz pyridine synthesis, and facilitate the transfer of this technology to the solid phase, we demonstrated that this method, which traditionally requires high cyclodehydration temperatures, may be affected in a single synthetic step for the synthesis of tetrasubstituted pyridines 5 using either acetic acid or Amberlyst 15 ion exchange resin at 50°C (Scheme 2). 6 These modified conditions were for the most part unsuccessful for the synthesis of pyrido[2,3-d]pyrimidine 7 from 2,6-diaminopyrimidin-4-one 6, although the traditional two-step Bohlmann-Rahtz heteroannulation reaction, 2 that proceeds by Michael addition in DMSO and subsequent cyclodehydration at 180°C, proved to be a highly expedient method for the preparation of these heterocycles (Scheme 3). 7 Scheme 2 Scheme 3In order to establish a new one-step general method for the synthesis of pyridines and pyrido [2,3-d]pyrimidines that avoids the use of high temperatures, we have investigated the use of Lewis acid catalysts in the Bohlmann-Rahtz heteroannulation reaction. To test the validity of this approach, Bohlmann-Rahtz intermediate aminodienone 3 was prepared by standard procedures 2 and treated with a Lewis acid to see if cyclodehydration could be conducted at a lower reaction temperature. The use of BF 3 ×OEt 2 failed to generate even a trace of pyridine 4, whereas zinc(II) bromide (15 mol%) or ferric chloride (10 mol%) in dichloromethane did promote the cyclisation. Full conversion was achieved when a solution of aminodi...
The solution phase combinatorial Bohlmann-Rahtz reaction gives highly functionalized pyridine libraries from enamino esters and alkynones in a single synthetic step. Good product ratios and library purities were obtained in reactions catalyzed by zinc(II) bromide, the acid-catalyzed heteroannulation procedure offering considerable improvements over traditional methodology.
Significant efforts are being made to replace mineral oil by renewable raw materials in technical products such as lubricating oils. Energy-and cost-effective production and refinement routes for such oils, e. g., fatty acid esters, are in progress. In this context, a feasibility study is performed into whether the application of membrane-aided separation procedures is suitable for the hydrophobic matrix of fatty acid methylesters (FAME). It is found that an enrichment of saturated acid esters from 28 to 51% is possible in just three steps for an unsaturated fatty acid ester matrix. The free fatty acids content can also be considerably reduced. This cleanup effect can be enhanced by the inclusion of a basic additive. Background and AimsOne example of today's attempts to substitute technical mineral oil fluids by those based on renewable raw products are cooling lubricants, which are applied for metal-working processes. These fluids are responsible for cooling and lubricating the contact area between the tool and the workpiece and also rinse the resulting chips away. About 1.2 million tons of lubricants are employed in Germany annually. However, these highly additive-amended fluids cause work related physiological and ecological problems during application and disposal.Fatty acid esters as base oils produced from plant oils are already being developed as alternative lubricants. Although offering remarkable advantages, they are rarely applied in practice, because of their comparably high price resulting from raw materials and production costs [1,2]. By considering the cost factor, the production of fatty acid esters was recently initiated from cheap waste edible and animal fats, which are substantially more economical raw materials [3,4]. In this respect, processes must be developed that yield high quality ester products from waste fats without losing the advantage of low-cost raw materials due to particularly high costs for production and refinement [5]. Today, the latter consists of cost and energy intensive production steps, e. g., distillation under reduced pressure, catalytic hydrogenation and fractional crystallization [6].In this context, the approach of producing the fatty acid esters by means of enzymatic alcoholysis is surely a valuable step [7,8]. Furthermore, the question has arisen as to whether the use of membranes for cleanup and separation processes could also contribute to a low-cost and energy saving modern production process for customized technical fatty acid ester oils. Only a few publications are cited in the literature for examining this focused direction and these are mostly applied for edible oil treatment [9 -15]. Therefore, the aim of this feasibility study was to examine the efficiency of membranes in the ester oil production process. Materials and Methods DialysisThe separation efficiencies of membranes were tested by dialysis under ambient pressure. The self-constructed dialysis device is depicted in Fig. 1. The fatty acid methyl esters (FAME) used for these experiments were all indus...
Pyridine derivativesPyridine derivatives R 0380 A Facile Solution Phase Combinatorial Synthesis of Tetrasubstituted Pyridines Using the Bohlmann-Rahtz Heteroannulation Reaction. -Enamino ester (IV) and equimolar mixtures of three different alkynones are transformed into three-or tetrasubstituted pyridines in a single synthetic step by either heating in toluene in the presence of AcOH or by reflux in toluene in the presence of catalytic amounts of ZnBr 2 . The results are compared with those obtained by application of traditional two-step Bohlmann-Rahtz conditions. In all cases, complete pyridine libraries are generated with very low levels of impurities. The Lewis acid catalyzed heteroannulation reaction (conditions C) is successful for problematic alkynones with different reactivities. -(BAGLEY*, M. C.; DALE, J. W.; OHNESORGE, M.; XIONG, X.; BOWER, J.; J. Comb. Chem. 5 (2003) 1, 41-44; Dep. Chem., Cardiff Univ., Cardiff CF1 3TB, UK; Eng.) -Klein 21-127
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