Verónica Estévez

Bio: Verónica Estévez is an academic researcher from Complutense University of Madrid. The author has contributed to research in topics: Hantzsch pyrrole synthesis & Pyrrole. The author has an hindex of 8, co-authored 14 publications receiving 1277 citations.

Multicomponent reactions for the synthesis of pyrroles

Abstract: Multicomponent reactions are one of the most interesting concepts in modern synthetic chemistry and, as shown in this critical review, they provide an attractive entry into pyrrole derivatives, which are very important heterocycles from many points of view including medicinal and pharmaceutical chemistry and materials science (97 references).

Recent advances in the synthesis of pyrroles by multicomponent reactions

Abstract: Pyrrole is one of the most important one-ring heterocycles. The ready availability of suitably substituted and functionalized pyrrole derivatives is essential for the progress of many branches of science, including biology and materials science. Access to this key heterocycle by multicomponent routes is particularly attractive in terms of synthetic efficiency, and also from the environmental point of view. We update here our previous review on this topic by describing the progress made in this area in the period between mid-2009 and the end of 2013.

The Hantzsch Pyrrole Synthesis: Non-conventional Variations and Applications of a Neglected Classical Reaction

Abstract: Pyrrole is one of the most important one-ring heterocycles because of its widespread presence in natural products and unnatural bioactive compounds and drugs in clinical use. The preparation of pyrroles by reaction between primary amines, β-dicarbonyl compounds, and α-halo ketones, known as the Hantzsch pyrrole synthesis, is reviewed here for the first time. In spite of its age and its named reaction status, this method has received little attention in the literature. Recent work involving the use of non-conventional conditions has rejuvenated this classical reaction and this is emphasized in this review. Some applications of the Hantzsch reaction in target-oriented synthesis are also discussed. 1 Introduction 2 The Conventional Hantzsch Pyrrole Synthesis 3 Hantzsch Pyrrole Synthesis under Non-conventional Conditions 4 Applications of the Hantzsch Pyrrole Synthesis 5 Conclusions

New types of reactivity of α,β-unsaturated N,N-dimethylhydrazones: chemodivergent diastereoselective synthesis of functionalized tetrahydroquinolines and hexahydropyrrolo[3,2-b]indoles.

Abstract: The indium trichloride-catalyzed reaction between aromatic imines and α,β-unsaturated N,N-dimethylhydrazones in acetonitrile afforded 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C4 through a one-pot diastereoselective domino process that involves the formation of two C-C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β-unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels-Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl 3 with BF 3·Et 2O as catalyst afforded polysubstituted 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles as major products through a fully diastereoselective ABB′C four-component domino process that generates two cycles, three stereocenters, two C-C bonds, and two C-N bonds in a single operation. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Visible-Light Photocatalysis: Does It Make a Difference in Organic Synthesis?

Abstract: Visible-light photocatalysis has evolved over the last decade into a widely used method in organic synthesis. Photocatalytic variants have been reported for many important transformations, such as cross-coupling reactions, α-amino functionalizations, cycloadditions, ATRA reactions, or fluorinations. To help chemists select photocatalytic methods for their synthesis, we compare in this Review classical and photocatalytic procedures for selected classes of reactions and highlight their advantages and limitations. In many cases, the photocatalytic reactions proceed under milder reaction conditions, typically at room temperature, and stoichiometric reagents are replaced by simple oxidants or reductants, such as air, oxygen, or amines. Does visible-light photocatalysis make a difference in organic synthesis? The prospect of shuttling electrons back and forth to substrates and intermediates or to selectively transfer energy through a visible-light-absorbing photocatalyst holds the promise to improve current procedures in radical chemistry and to open up new avenues by accessing reactive species hitherto unknown, especially by merging photocatalysis with organo- or metal catalysis.

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

Abstract: Heterocycles constitute the largest and the most diverse family of organic compounds Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis 2 Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc Reviews devoted to an application of a particular type of starting materials have also been published Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed

Bond Activation and Catalysis by Ruthenium Pincer Complexes

Abstract: ed by an internal site in intramolecular heterolytic splitting, intermolecular activation requires an external base. Such intramolecular heterolytic splitting is also applicable to C−H or other heteroatom−H bond activation as is frequently observed with ruthenium pincer complexes and discussed in this section. 3.1. Activation of the H−H Bond As shown in Scheme 4b, formation of a dihydride complex such as [(PNP)Ru(H)2(H2)] 20 is a result of dihydrogen activation by oxidative addition due to the electron-rich ruthenium center as discussed above. Gunnnoe and co-workers reported a five-coordinate amido complex (PCP)Ru(CO)(NH2) 71, which heterolytically activates H2, as 71 has the required vacant coordination site for H2 coordination and a basic amido ligand, which abstracts intramolecularly a proton from coordinated H2, followed by dissociation of the formed ammonia (BDERu−NH3 = 12.6 kcal/mol), providing the complex (PCP)RuH(CO) 72 (Scheme 23). The dearomatized pincer complexes 3a−5a developed by Milstein react with molecular hydrogen at room temperature, undergoing rearomatization to provide the trans-dihydride complexes of 3b−5b, respectively, upon heterolysis of dihydrogen (Scheme 24). In the H NMR spectra, the magnetically equivalent trans-dihydrides of 3b and 4b resonate as a triplet at δ = −4.96 ppm (JPH = 20.0 Hz) and δ = −4.90 ppm (JPH = 17.0 Hz), respectively, whereas they display a doublet at δ = −4.06 ppm (JPH = 17.0 Hz) for complex 5b. Further, the structure of the trans-dihydride complex 5b was determined by a single-crystal X-ray analysis (Figure 2). The trans-dihydride complexes 3b−5b slowly lose H2 at room temperature to regenerate complexes 3a−5a, respectively, setting the stage for several catalytic processes (see below) including the production of molecular hydrogen from biorenewable sources. As discussed in the MLC section, the acridine pincer complex 9 also heterolytically activates dihydrogen (Scheme 16). The amido ruthenium pincer complex 73 is in equilibrium with complexes 74 and 75. Formation of amino trans-dihydride complex 74 results from the reversible heterolysis of dihydrogen (Scheme 25). The trans-dihydrides of 74, which resonate at δ = −8.00 and δ = −8.52 ppm, are magnetically inequivalent (JPH = 16.7−24.3 Hz), due to the proximity of one of the hydrides to the backbone amino proton. As observed in heterolysis of hydrogen by Ir pincer complexes, DFT studies suggest that proton transfer from ruthenium to the amido nitrogen is facilitated by the presence of water, which forms a hydrogen bond with both amido nitrogen and H2, leading to a six-membered transition state and lowering the barrier for proton transfer. Complex 73 was found to be an active dehydrogenation catalyst for ammoniaborane and hydrogenation reactions as discussed below. The heterolytic activation of dihydrogen by NH/H2 MLC was reported by Fryzuk and co-workers in 1987 with pincer Ir and Rh complexes. Using the pincer complex [RuCl(PPh3)Scheme 22. Oxidative Addition versus Heterolytic Cleavage of H−H and H−X Bonds Scheme 23. Heterolytic Activation of Hydrogen Scheme 24. Heterolytic Activation of Hydrogen by Aromatization−Dearomatization Process Figure 2. X-ray structure of complex 5b (50% probability level). Hydrogen atoms (except hydrides) are omitted for clarity. Reproduced with permission from ref 100. Copyright 2011 Nature Publishing Group. Chemical Reviews Review dx.doi.org/10.1021/cr5002782 | Chem. Rev. XXXX, XXX, XXX−XXX K (N(SiMe2CH2PPh2)2)], they reported in 1991 that reaction with H2 resulted in a mixture of Ru−H complexes, albeit the reversibility of the reaction was not observed. Recently, Koridze and co-workers reported that a metallocene-derived PCP pincer ruthenium complex also activates molecular hydrogen heterolytically. 3.2. Activation of C−H Bonds While many PCP-type ruthenium pincer complexes were formed as a result of C−H activation or even double C−H activation of the ligand, there are only a few examples of intraor intermolecular C−H activations by ruthenium pincer complexes, as discussed in this section. C−H activation of arenes is widespread with Ir-pincer PNP and PCP complexes. However, such sp C−H activation by Rupincer complexes is rarely encountered. An example of intramolecular C−H activation in a Ru pincer complex was reported by Fryzuk and co-workers. Gunnnoe and co-workers reported that the five-coordinate complexes [(PCP)Ru(CO)(NH2)] 71 and [(PCP)Ru(CO)(CH3)] 76 liberate ammonia and methane, respectively, to generate the cyclometalated PCP ruthenium pincer complex 77 as a result of intramolecular sp C−H activation (Scheme 26). The conversion rate of the methyl complex 76 to 77 is approximately 5 times faster (Kobs = 3.2(1) × 10 −4 s−1 at 50 °C) than the analogous conversion with the amido complex 71 (Kobs = 6.0(3) × 10 −5 s−1 at 50 °C). However, attempted intermolecular C−H activation of methane by complex 71 was not successful and led only to intramolecular C−H activation to provide 77. Gusev and co-workers reported a double C−H activation reaction in a pincer complex. Caulton’s square-planar Ru(II) pincer complex 63a reacted with 1 equiv of MeLi at −78 °C to afford the hydrido−carbene complex 79 as a result of double C−H activation of a single methyl group (Scheme 27). Apart from the characteristic spectroscopic features, DFT calculations indicate that the Ru−C bond length (2.08 Å) in complex 78 decreases to 1.84 Å in 79, in line with formation of a Ru− carbene. The intermediate complex 78 facilitates the C−H agostic interaction and the observed loss of methane. The hydrido−carbene complex 79 reacts with excess of pyridine, immediately forming the diamagnetic η-pyridyl complex 80 as a result of ortho sp C−H activation. Recently, Milstein reported the intramolecular sp C−H activation of expanded PNN ruthenium pincer complexes. Upon deprotonation of the saturated Ru(II) PNN pincer complexes (7 and 8), containing alkyl or cycloalkyl groups on one of the methylene arms, the dearomatized pincer complexes 7a and 8a were formed (Scheme 28). Attempted synthesis of 7a also resulted in intramolecular C−H activation and quantitative formation of the cyclometalated 7b after 4 h. Independent synthesis of 7a was possible using the base KHMDS (potassium hexamethyldisilazide) at −35 °C in toluene-d8, although upon workup only 7b was obtained as a single diastereoisomer, implying that 7a is indeed an intermediate that undergoes cyclometalation and concomitant aromatization to provide 7b. The X-ray structure of 7b exhibits a highly distorted octahedron with the PNC donors coordinated in a pseudomeridional manner (Figure 3). The PNN complex 8a, analogous to 7a, was relatively stable due to steric rigidity, and the conversion to cyclometalated aromatized complex 8b occurred slowly over 5 days. Dearomatized pincer complexes, particularly the bipyridine derived [(PNN)Ru(H)(CO)] 6a and its parent complex 6, are involved in the sp CH activation/exchange of αand βpositions of alcohols with D2O, as will be discussed in section 4.3.1. 3.3. Activation of N−H Bonds As in H2 and C−H activation reactions, MLC of pyridinederived pincer complexes also enables N−H activation of amines and ammonia. As described by Milstein, upon reaction of the dearomatized PNP complex 4a with electron-poor anilines, the unsaturated ligand arm was protonated, and the pyridine ring underwent rearomatization as a result of N−H activation (Scheme 29). The saturated amide complexes 82a Scheme 25. Heterolytic Activation of Hydrogen by Amide−Amine Interconversion Scheme 26. Intramolecular Activation of sp C−H Bonds Scheme 27. Double C−H Activation Leading to the Formation of a Hydrido Carbene Complex Chemical Reviews Review dx.doi.org/10.1021/cr5002782 | Chem. Rev. XXXX, XXX, XXX−XXX L and 82b were obtained in pure form from the reaction of complex 4a with 4-nitroaniline and 2-chloro-4-nitroaniline, respectively, and their symmetrical structures were evident from the P NMR (single signal for each complex) and H NMR spectra. However, the reaction of 2-bromoaniline and 3,4dichloroaniline with complex 4a provided equilibrium mixtures of aromatized N−H activated amide complexes 82c and 82d, and the starting 4a, despite the presence of excess of haloanilines. This observation of reversible N−H bond activation at room temperature was unique, and indicated the low barrier for these reactions. For electron-rich amines and ammonia, the amine-coordinated unsaturated complexes of type 81 are thermodynamically favored. Upon reaction of complex 4a with ND3, formation of the deuterated complex 83 was observed after 5 min at room temperature, showing N−D activation (Scheme 30). The H NMR spectrum of 83 confirmed that deuteration at the methylene arm is stereospecific as only one of the two CH2 arm protons disappeared. No exchange occurred with vinylic protons, and such high selectivity indicated that the activation process on these types of pincer systems occurs only intramolecularly on one face of the ligand with the coordinated ND3 ligand. This observation indicated that other activation processes could also be stereoselective. The trend observed in the experiment was in agreement with DFT studies carried out on the N−H activation reactions (Figure 4). In the reaction of 2-bromoaniline with 4a, the unbound state (I) and the activated state (III) have similar energies with a connecting barrier of 20 kcal/mol. The N−H activated complex of isopropylamine is 16.8 kcal mol−1 above the unbound state, and experimentally it reacted with complex 4a upon warming to 80 °C, whereas in the case of the amines that underwent irreversible N−H activation at room temperature the calculated activated complexes (III) are energetically below the unbound state (I) as expected; barriers for the exchange between amine coordinated (II) and activated (III) states are accessible at room temperature. PNP Rh(I) pincer complexes also activate N−H bonds by similar MLC. N−H bond acti

Recent developments in asymmetric multicomponent reactions.

Abstract: Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs.

Recent advances in the synthesis of pyrroles by multicomponent reactions

Abstract: Pyrrole is one of the most important one-ring heterocycles. The ready availability of suitably substituted and functionalized pyrrole derivatives is essential for the progress of many branches of science, including biology and materials science. Access to this key heterocycle by multicomponent routes is particularly attractive in terms of synthetic efficiency, and also from the environmental point of view. We update here our previous review on this topic by describing the progress made in this area in the period between mid-2009 and the end of 2013.