Synthesis of Fully Substituted Pyrimidines

A novel approach to the synthesis of fully substituted pyrimidine derivatives armed with an oxy-functionalized acetate chain at the ring is described. The manifold uses amidines as the nitrogen source and activated skipped diynes as the electrophilic reactive partners in a coupled domino strategy. In the first domino reaction, two consecutive aza-Michael additions assemble the six-membered ring heterocycle, while in the second domino process, a [H]-shift and a [3,3]-sigmatropic rearrangement lead to the aromatization of the product.This research was supported by the Spanish Ministerio de Economía y Competitividad (MICINN) and the European Regional Development Fund (CTQ2011- 28417-C02-02). S.L.T. thanks the Spanish MEC for an FPU grant.Peer Reviewe

Diverted domino reactivity in tertiary skipped diynes: A convenient access to polyfunctionalized cyclohexadienones and multivalent aromatic scaffolds

Diverting is the game! A new domino manifold has been implemented for the synthesis of cyclohexadienone-based scaffolds from tertiary skipped diynes and secondary amines. The manifold takes advantage of a new O-enolate-driven reactivity pattern discovered for these diynes. The scaffolds are conveniently transformed into the corresponding multivalent salicylate derivatives (see scheme). © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.This research was supported by the Spanish MICINN and the European RDF (CTQ2008–06806-C02–02), the Spanish MSC ISCIII (RETICS RD06/0020/1046), FUNCIS (PI 43/09). S. L.-T. thanks the Spanish MEC for a FPU grant. The authors thank technician Ms. Anna Jurado Varona for her experimental assistance.Peer Reviewe

Tertiary skipped diynes: A pluripotent building block for the modular and diversity-oriented synthesis of nitrogen heterocycles

Dominos! The multivalent reactivity profile of tertiary skipped diynes has been conveniently exploited in the domino and diversity-oriented synthesis of fully substituted pyrazoles and 1, 4-diazepane derivatives (see scheme). The developed manifold is chemically efficient and simple to operate. In addition, the resulting Ncontaining heterocycles are obtained in a regio- and chemoselective manner. (Chemical Equation Presented) © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.This research was supported by the Spanish Ministerio de Ciencia e Innovación, the European Regional Development Fund (CTQ2008-06806-C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/1046), FUNCIS (REDESFAC PI01/06) and the Fundación Instituto Canario de Investigación del Cancer (FICI-G.I.N808/2007). S.L.-T. thanks the Spanish MEC for an FPU grant. The authors thank technician Anna Jurado Varona for her experimental assistance.Peer Reviewe

From conjugated tertiary skipped diynes to chain-functionalized tetrasubstituted pyrroles

A novel and metal-free method for the synthesis of chain-functionalized tetrasubstituted pyrroles from easily accessible tertiary skipped diynes, was reported. The method involved modular synthesis of chain functionalized tetrasubstituted pyrroles from easily available alkyl porpiolates, acid chlorides, and primary amine. The method used a primary amine for the nitrogen source and utilized the reactivity profile of tertiary 1,4-diyne scaffolds. The synthetic manifold in the method operated in the absence of metals and accelerated by the nucleophilic addition of a primary amine on the alkynoate function. Anti-Michael ring-closing hydroamination and a [3,3]-sigmatropic rearrangement helped to complete the process of producing pyrrole. It was observed during the process that the enamine formation is more faster than the enamine cyclization.Authors thank the Spanish Ministerio de Educación y Ciencia and the European Regional Development Fund (CTQ2005-09074-C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/1046), CSIC (Proyecto Intramural Especial 200719) and Fundación Instituto Canario de Investigación del Cáncer (FICI-G.I. No. 08/2007) for financial support. S.L.-T. Thanks MEC for a FPU grant.Peer Reviewe

Propargyl Vinyl Ethers and Tertiary Skipped Diynes: Two Pluripotent Molecular Platforms for Diversity-Oriented Synthesis

During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4–O–C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB′ three-component reaction for PVEs; A2BB′ four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, β,γ-unsaturated esters and acids, and fused polycycles. They can be transformed into more elaborated molecular skeletons by the use of chemical handles generated in their own domino reactions or by appending different functionalities to the pluripotent molecular platform (secondary reactivity principles).This research was supported by the Spanish Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund (CTQ2011-28417-C02-02).Peer reviewe

Fluoride-Triggered Domino Reactions Involving Ammonium Acetylides and Carbonyl Compounds

5 páginas, 3 esquemas.-- Short Communication.We describe the use of tetrabutylammonium fluoride as a basic trigger for reactions capable of generating structurally diverse products from methyl propiolate and carbonyl derivatives. The processes are based on either chemodifferentiating multicomponent ABB′ three-component reactions or bimolecular domino reactions, and they operate through three different and well-defined autocatalytic cycles. These catalytic cycles share a common property: they are launched by the acid–base reaction of fluoride ions to give catalytic amounts of acetylide or enolate salts, but they are maintained by the autocatalytic generation of these salts.This research was supported by the Spanish Ministerio de Ciencia e Innovación, the European Regional Development Fund (CTQ2005-09074-C02-02 and CTQ2008-06806-C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/1046), CSIC (Proyecto Intramural Especial 200719), FUNCIS (REDESFAC PI01/06 and 35/06), and the Fundación Instituto Canario de Investigación del Cáncer (FICIC-G.I.N808/2007). S. L.-T. and G. M.-A. thank the Ministerio de Educación y Ciencia (MEC) for their FPU grants.Peer reviewe

Reactivity control in the addition of N,N′-dialkylated 1,n-diamines to activated skipped diynes: Synthesis of fused bicyclic 1,4-diazepanes and 1,5-diazocanes

A metal-free domino reaction for the synthesis of a new family of fused bicyclic 1,4-diazepanes and 1,5-diazocanes has been developed. The reaction involves the use of N,N′-dialkylated 1,n-diamines as the nitrogen source, through-space orbital interactions between the two nitrogen atoms as the reactivity director element, and an activated skipped diyne as the reactive platform. A key Morita-Baylis-Hillman-like reaction allows the formation of 1,4-diazepanes and 1,5-diazocanes (medium-sized diazoheterocycles). These structures incorporate a 1,n-diazocycle fused to a Î3-butenolide ring and different functionalities to be used as convenient handles for further complexity generation. The good efficiency of this reaction and its simple experimental protocol make this process an excellent candidate for the fast construction of structure-focused libraries based on this fused bicyclic motif. © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.This research was supported by the Spanish Spanish Ministerio de Ciencia e Innovación (MICINN), the European Regional Development Fund (RDF) (CTQ2008-06806-C02-02), and the Spanish Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (MSC ISCIII) (RETICS RD06/0020/1046) and the Fundación Canaria de Investigación y Salud (FUNCIS) (PI 43/09).Peer Reviewe

Acetylides from alkyl propiolates as building blocks for C3 homologation

Alkyl propiolates are reagents with a versatile reactivity profile that entirely remains in the C3-homologated product for further elaboration. To be effective, this C3 homologation requires suitable methods for the generation of the acetylide anion that are compatible with both the conjugated ester and the electrophilic partner. Recent advances include catalytic procedures for the in situ generation of these acetylides in the presence of suitable electrophiles. Whereas the organometallic methods have brought stereoselectivity to these reactions, the organocatalytic methods laid the ground for new efficient domino processes that generate complexity. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.Peer Reviewe