Multicomponent reactions Edited by Thomas J. J. Müller Generated on 24 September 2021, 08:23 Imprint Beilstein Journal of Organic Chemistry www.bjoc.org ISSN 1860-5397 Email: [email protected] The Beilstein Journal of Organic Chemistry is published by the Beilstein-Institut zur Förderung der Chemischen Wissenschaften. This thematic issue, published in the Beilstein Beilstein-Institut zur Förderung der Journal of Organic Chemistry, is copyright the Chemischen Wissenschaften Beilstein-Institut zur Förderung der Chemischen Trakehner Straße 7–9 Wissenschaften. The copyright of the individual 60487 Frankfurt am Main articles in this document is the property of their Germany respective authors, subject to a Creative www.beilstein-institut.de Commons Attribution (CC-BY) license. Multicomponent reactions Thomas J. J. Müller Editorial Open Access Address: Beilstein J. Org. Chem. 2011, 7, 960–961. Heinrich-Heine-Universität Düsseldorf, Institut für Makromolekulare doi:10.3762/bjoc.7.107 Chemie und Organische Chemie, Lehrstuhl für Organische Chemie, Universitätsstr. 1, 40225 Düsseldorf, Germany Received: 11 July 2011 Accepted: 11 July 2011 Email: Published: 13 July 2011 Thomas J. J. Müller - [email protected] This article is part of the Thematic Series "Multicomponent reactions". Guest Editor: T. J. J. Müller © 2011 Müller; licensee Beilstein-Institut. License and terms: see end of document. Chemistry as a central science is facing a steadily increasing Now the major conceptual challenge comprises the engineering demand for new chemical entities (NCE). Innovative solutions, of novel types of MCR. Most advantageously and practically, in all kinds of disciplines that depend on chemistry, require new MCR can often be extended into combinatorial, solid phase or molecules with specific properties, and their societal conse- flow syntheses promising manifold opportunities for devel- quences are fundamental and pioneering. However, NCE not oping novel lead structures of active agents, catalysts and even only demand a realistic structural space but also their feasibility novel molecule-based materials. poses challenges to synthetic chemists. Nowadays the question of how to perform a synthesis has become most crucial. This Thematic Series on multicomponent reactions represents a snapshot of a highly dynamic field and spans a broad range, What is the ideal synthesis [1,2]? Certainly it should be simulta- from recent advances in isonitrile-based MCR to transition neously simple, safe, short, selective, high yielding, environ- metal catalysis in MCR; from peptidic and depsi-peptidic to mentally benign, based on readily available starting materials, heterocyclic structures; from reactivity-based to property-based and highly diverse. Additionally, the criterion of selectivity has concepts. The sympathetic reader, expert or newcomer, will to be matched with increasing significance economical and find a tremendous degree of dynamic and exciting new results ecological aspects. In particular multicomponent reactions in this compilation of multicomponent reaction chemistry. (MCR) [3] are masterpieces of synthetic efficiency and reac- tion design. These one-pot processes consist of concatenations As the guest editor of this Thematic Series I am very grateful to of elementary organic reactions under similar conditions. Most all authors for their excellent contributions and, in particular, to interestingly, multicomponent reactions have accompanied the the staff of the Beilstein-Institut for their support and profes- field of organic chemistry since the early days, particularly sional realization. in heterocyclic chemistry, but have not been recognized as a fundamental principle until Ugi's groundbreaking Thomas J. J. Müller extension of the Passerini reaction and the conclusions he drew from this. Düsseldorf, July 2011 960 Beilstein J. Org. Chem. 2011, 7, 960–961. References 1. Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765, 767–769. 2. Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657–4673. doi:10.1021/jo1006812 3. Zhu, J.; Bienaymé, H., Eds. Multicomponent Reactions; Wiley-VCH: Weinheim, Germany, 2005. License and Terms This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc) The definitive version of this article is the electronic one which can be found at: doi:10.3762/bjoc.7.107 961 A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction Christian Eidamshaus, Roopender Kumar, Mrinal K. Bera and Hans-Ulrich Reissig* Full Research Paper Open Access Address: Beilstein J. Org. Chem. 2011, 7, 962–975. Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, doi:10.3762/bjoc.7.108 D-14195 Berlin, Germany Received: 07 March 2011 Email: Accepted: 06 June 2011 Hans-Ulrich Reissig* - [email protected] Published: 13 July 2011 * Corresponding author This article is part of the Thematic Series "Multicomponent reactions". Keywords: Guest Editor: T. J. J. Müller allenes; enantiopure pyridines; ketoenamides; multicomponent reactions; nonaflates © 2011 Eidamshaus et al; licensee Beilstein-Institut. License and terms: see end of document. Abstract A practical approach to highly functionalized 4-hydroxypyridine derivatives with stereogenic side chains in the 2- and 6-positions is described. The presented two-step process utilizes a multicomponent reaction of alkoxyallenes, nitriles and carboxylic acids to provide β-methoxy-β-ketoenamides which are transformed into 4-hydroxypyridines in a subsequent cyclocondensation. The process shows broad substrate scope and leads to differentially substituted enantiopure pyridines in good to moderate yields. The prepar- ation of diverse substituted lactic acid derived pyrid-4-yl nonaflates is described. Additional evidence for the postulated mechanism of the multicomponent reaction is presented. Introduction The pyridine core is ubiquitous in pharmacologically active tion compounds makes pyridines ideal ligands for transition agents, agrochemicals and natural products [1-5]. The HMG- metal-catalyzed processes and for the construction of supra- CoA reductase inhibitors Glenvastatin and Cerivastatin are molecular architectures [13]. Pyridines with chiral side chains exemplarily mentioned as pharmaceuticals that feature the pyri- are widely employed as ligands in asymmetric transformations, dine nucleus [6-10]. Natural products that contain a pyridine for instance, in the asymmetric hydrogenation of olefins, in ring include the 3-alkylpyridine alkaloid niphatesine C and the enantioselective additions of metal organyls to aldehydes and fuzanin family [11,12]. Moreover, the ability to form coordina- enones, as well as in palladium-catalyzed allylic substitution 962 Beilstein J. Org. Chem. 2011, 7, 962–975. Scheme 1: Preparation of β-ketoenamides and subsequent cyclocondensation to 4-hydroxypyridines. a) Et2O, −40 °C to r.t. 16 h, b) TMSOTf, NEt3, CH2Cl2 or ClCH2CH2Cl reflux. reactions [14-20]. Thus, the synthesis of specifically functional- Results and Discussion ized pyridines is of considerable interest, and many approaches In continuation of our previous work, we addressed the ques- toward this heterocyclic structure have been disclosed in the tion whether chiral starting materials react in the above literature [21]. In addition to classical pyridine syntheses such sequence without loss of enantiopurity [40]. Chiral carboxylic as the Kröhnke reaction, many new approaches have recently acids are readily available and their use would allow for a rapid been developed [22-26]. Despite the wide range of conceptu- access to pyridines with side chains bearing stereogenic centers. ally different syntheses, only few methods for introducing In recent years we studied intensively the multicomponent reac- chirality into pyridine side chains have been described: Enantio- tions of lithiated alkoxyallenes with nitriles and carboxylic selective reduction of pyridine carbonyl compounds, the add- acids and could demonstrate that precursor compounds with ition of lithiated pyridine derivatives to chiral ketones or the alkyl, alkenyl or aryl substituents are smoothly converted into resolution of racemates being the most common approaches. β-ketoenamides and subsequently transformed into the desired The preparation of chiral pyridine derivatives starting from 4-hydroxypyridines. The mechanism of the multicomponent simple enantiopure precursors is less common [27,28]. reaction is depicted in Scheme 2. In the first step, a lithiated Recently, we reported a new synthesis of pyridines based on the trimethylsilyl trifluoromethanesulfonate (TMSOTf) induced cyclocondensation reaction of β-ketoenamides [29-34]. This cyclocondensation step can be rationalized as a 6π-electrocy- clization of the disilylated intermediate 5 to provide dihydropy- ridine 6. Elimination of trimethylsilanol and subsequent O-desi- lylation affords the 4-hydroxypyridine 7 (Scheme 1). The desired β-ketoenamides 4 are either accessible by acylation of enaminoketones or by a multicomponent reaction of lithiated alkoxyallenes, nitriles and carboxylic