DOI: 10.1002/chem.201100382 Synthesis of 5-Acetyloxazoles and 1,2-Diketones from b-Alkoxy-b- ketoenamides and Their Subsequent Transformations Tilman Lechel, [a] Markus Gerhard, [a] Daniel Trawny, [a] Boris Brusilowskij, [a] Luise Schefzig, [a] Reinhold Zimmer, [a] Jürgen P. Rabe, [b] Dieter Lentz, [a] Christoph A. Schalley, [a] and Hans-Ulrich Reissig* [a] Dedicated to the memory of Ilya M. Lyapkalo Introduction The oxazole unit plays a privileged role as a substructure in naturally occurring compounds with potent biological activi- ties and, hence, represents a widely used building block in medicinal chemistry. [1] Furthermore, there are many oxazole derivatives with interesting photophysical properties, which is also of importance in the development of new functional compounds. [2] One of the traditional methods used to pre- pare oxazoles is the cyclodehydration of a-acylamino ke- tones, which can be conducted under conditions developed Robinson and Gabriel. [3a,b] This method often requires harsh dehydrating agents and the available substitution pattern is hence restricted to a fairly small number of functional groups. The development of milder and more flexible syn- thetic approaches is therefore highly desirable. [3] However, only a few reports deal with the synthesis of 2,4,5-trisubsti- tuted oxazoles with a flexible substitution pattern at all posi- tions and a direct introduction of functional groups. [4, 5] In previous studies, we reported on the synthetic use of al- koxyallenes, which have found numerous and versatile ap- plications as C 3 -building blocks in the synthesis of natural products or other interesting compounds. [6] We serendipi- tously discovered a novel access to b-alkoxy-b-ketoenamides 5 by a mechanistically intriguing, three-component reaction using lithiated alkoxyallenes 1, nitriles 2, and carboxylic acids 3 as precursors. [7, 8] Enamides, in general, are interest- ing synthetic building blocks in organic chemistry. [9, 10] We demonstrated that the functionalized enamides 5 represent Abstract: Lithiated alkoxyallenes, ni- triles, and carboxylic acids have been employed as precursors in a three-com- ponent reaction leading to highly sub- stituted b-alkoxy-b-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cy- clized to 5-acetyloxazole derivatives. The synthesis is very flexible with re- spect to the substitution pattern at C-2 and C-4 of the oxazole core. A mecha- nistic suggestion for the oxazole forma- tion is presented on the basis of 18 O-la- beled compounds and their mass spec- trometric analysis. In several cases, 1,2-diketones are formed as side prod- ucts or even as major components. The acetyl moiety at C-5 of the oxazole de- rivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reac- tions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophys- ical properties. Sonogashira couplings were performed with 5-alkynyl-substi- tuted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole deriv- ative. The ability of this multivalent compound to form self-assembled mon- olayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C 3 -symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline deriva- tives. Keywords: allenes · cross-coupling · heterocycles · monolayers · scan- ning probe microscopy · self-assem- bly [a] Dr. T. Lechel, M. Gerhard, Dipl.-Chem. D. Trawny, Dr. B. Brusilowskij, L. Schefzig, Dr. R. Zimmer, Prof. Dr. D. Lentz, Prof. Dr. C. A. Schalley, Prof. Dr. H.-U. Reissig Institut für Chemie und Biochemie Freie Universität Berlin Takustr. 3, 14195 Berlin (Germany) Fax: (+ 49) 30-83855367 E-mail: hans.reissig@chemie.fu-berlin.de [b] Prof. Dr. J. P. Rabe Institut für Physik Humboldt Universität zu Berlin Newtonstraße 15, 12489 Berlin (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201100382. It contains experi- mental procedures and characterization data for all compounds. # 2011 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 7480 – 7491 7480