An assessment of late transition metals as hydroamination catalysts in the cyclization of C-propargyl vinylogous amides into pyrroles

It has been shown that common and inexpensive salts of the late transition metals serve as effective hydroamination catalysts in the conversion of C-propargyl vinylogous amides into pyrroles. The oxide, acetate, nitrate and chloride derivatives of Cu(II), Ag(I), Zn(II), Cd(II) and Hg(II) were utilized as hydroamination catalysts in the oxidation states shown. Although the Zn(II) catalysts with the exception of ZnO afforded the highest yields of product under mild conditions, all of the group 12 metal catalysts provided excellent yields of product under more forcing conditions. The nature of the counterion plays an important role in the efficiency of hydroamination reactions, as well as the Lewis acidity of the metal centre.     

A new entry to the substituted pyrrolo[3,2-c]quinoline derivatives of biological interest by intramolecular heteroannulation of internal imines

New 1,3,4-substituted pyrrolo[3,2-c]quinoline derivatives were synthesised in good yields by oxidative heteroannulation of internal imines starting from easily prepared substituted 5-(2-aminophenyl)pyrroles and commercially available aryl and heteroaryl aldehydes. The reaction occurs as a one-pot process involving an intramolecular acid catalysed reaction.     

Cycloaddition reactions of 1-lithio-1,3-dienes with aromatic nitriles affording multiply substituted pyridines, pyrroles, and linear butadienylimines

Fully or partially substituted 1-iodo- or 1-bromo-1,3-dienes could be readily lithiated using t-BuLi or n-BuLi to afford their corresponding 1-lithio-1,3-diene derivatives in quantitative yields. When these in situ generated lithium reagents were treated with organonitriles, depending on the substitution patterns of the butadienyl skeletons, substituted pyridines, pyrroles, and/or linear butadienyl imines were formed in good to excellent yields via N-lithioketimine intermediates. In the cases of 1,2,3,4-tetrasubstituted and 2,3-disubstituted 1-lithio-1,3-dienes, pyridine derivatives or linear butadienyl imines were generally formed depending on the reaction temperatures. When 1,2,3,4-tetrasubstituted 4-halo-1-lithio-1,3-dienes and 1,2-disubstituted 1-lithio-1,3-dienes were treated with organonitriles, pyrrole derivatives or linear butadienyl imines were obtained. Competition between 5-exo and 6-endo cyclization was found to be responsible for the formation of either pyrroles or pyridines. Selective elimination of RLi from the lithiated cyclic N-containing intermediates was observed. The order of elimination was found to be LiCl > Me3SiLi > LiH.     

Lewis acid promoted imino Diels-Alder reactions of 5-dienyl pyrimidinones with N-aryl/naphthyl imines: synthesis of novel quinoline/benzoquinoline derivatives

The chemo- as well as regioselective imino Diels-Alder reactions of 5-dienyl pyrimidinones with N-aryl as well as N-naphthyl imines in the presence of a different Lewis acid catalysts resulting in novel quinoline and benzoquinoline derivatives are reported.     

Chemoselective Catalysis with Organosoluble Lewis Acidic Polyoxotungstates

The preparation of new organosoluble Lewis acidic polyoxometalates (POMs) is reported. These complexes were prepared by the incorporation of Zr, Sc, and Y atoms into the corresponding monolacunary Dawson [P₂W₁₇O₆₁]^10? and Keggin [PW₁₁O₃₉]^7? polyoxotungstates. The catalytic activity of these compounds was evaluated for C? C bond formation in the Diels–Alder, Mannich, and Mukaiyama‐type reactions. Comparisons with previously described Lewis acidic POMs are reported. Competitive reactions between imines and aldehydes or between various imines demonstrated that fine tuning of the reactivity could be reached by varying the metal atom incorporated into the polyanionic framework. A series of experiments that employed pyridine derivatives allowed us to distinguish between the Lewis and induced Brønsted acidity of the POMs. These catalysts activate imines in a Lewis acidic way, whereas aldehydes are activated by indirect Brønsted catalysis.     

The ruthenium catalyzed formation of chiral dihydropyrrolones from α,β-unsaturated imines: extending the reaction to terminal alkenes and investigating the formation of pyrroles as side-products

The reaction of α,β-unsaturated imines derived from cinnamaldehyde with CO and various alkenes produces chiral 1,3-dihydropyrrolone derivatives. As a byproduct the formation of 2,3-disubstituted pyrroles is observed in every reaction. If the imines are reacted with ethylene only, products with an ethyl group at C-3 of the imine chain are formed. The implications of these findings on the reaction mechanism are discussed.     

Frustrated Lewis Pairs: Metal‐free Hydrogen Activation and More

Sterically encumbered Lewis acid and Lewis base combinations do not undergo the ubiquitous neutralization reaction to form “classical” Lewis acid/Lewis base adducts. Rather, both the unquenched Lewis acidity and basicity of such sterically “frustrated Lewis pairs (FLPs)” is available to carry out unusual reactions. Typical examples of frustrated Lewis pairs are inter‐ or intramolecular combinations of bulky phosphines or amines with strongly electrophilic RB(C₆F₅)₂ components. Many examples of such frustrated Lewis pairs are able to cleave dihydrogen heterolytically. The resulting H⁺/H^? pairs (stabilized for example, in the form of the respective phosphonium cation/hydridoborate anion salts) serve as active metal‐free catalysts for the hydrogenation of, for example, bulky imines, enamines, or enol ethers. Frustrated Lewis pairs also react with alkenes, aldehydes, and a variety of other small molecules, including carbon dioxide, in cooperative three‐component reactions, offering new strategies for synthetic chemistry.     

Diastereoselective addition of α-substituted α-amino-H-phosphinates to imines using Yb(OTf)3 as an efficient Lewis acid catalyst

Diastereoselective addition of α-substituted α-amino-H-phosphinates to imines is described. Among Lewis acids, Yb(OTf)₃ was found to be the best catalyst. α,α′-Diaminophosphinic derivatives were obtained with de's ranging from 10 to 95% in the presence of Yb(OTf)₃ as an efficient Lewis acid catalyst. The reaction proceeded with retention of configuration at the phosphorus atom.     

Brønsted acid activation strategy in transition-metal catalyzed asymmetric hydrogenation of N-unprotected imines, enamines, and N-heteroaromatic compounds

Asymmetric hydrogenation plays an important role in organic synthesis, but that of the challenging substrates such as N‐unprotected imines, enamines, and N‐heteroaromatic compounds (1H‐indoles, 1H‐pyrroles, pyridines, quinolines, and quinoxalines) has only received increased attention in the past three years. Considering the interaction modes of a Brønsted acid with a Lewis base, Brønsted acids may be used as the ideal activators of C?N bonds. This Minireview summarizes the recent advances in transition‐metal‐catalyzed, Brønsted acid activated asymmetric hydrogenation of these challenging substrates, thus offering a promising substrate activation strategy for transformations involving C?N bonds.     

CuAlOx catalyst for the batch-flow tandem synthesis of amino acid-derived furfurylamines

Various amino acid-based furfurylamine derivatives were synthesized by two-stage procedure, which includes the condensation of 5-hydroxymethylfurfural (or furfural) with amino acid salts in methanol followed by hydrogenation of obtained imines in a flow reactor over CuAlO_x catalyst.     

Mechanistically diverse copper-, silver-, and gold-catalyzed acyloxy and phosphatyloxy migrations: efficient synthesis of heterocycles via cascade migration/cycloisomerization approach

A set of cycloisomerization methodologies of alkynyl ketones and imines with concurrent acyloxy, phosphatyloxy, or sulfonyloxy group migration, which allow for the efficient synthesis of multisubstituted furans and N-fused heterocycles, has been developed. Investigation of the reaction course by way of employing 17O-labeled substrates allowed for elucidation of the mechanisms behind these diverse transformations. It was found that, while the phosphatyloxy migration in conjugated alkynyl imines in their cycloisomerization to N-fused pyrroles proceeded via a [3,3]-sigmatropic rearrangement, the analogous cycloisomerization of skipped alkynyl ketones proceeds through two consecutive 1,2-migrations, resulting in an apparent 1,3-shift, followed by a subsequent 1,2-migration through competitive oxirenium and dioxolenylium pathways. Investigations of the 1,2-acyloxy migration of conjugated alkynyl ketones en route to furans demonstrated the involvement of a dioxolenylium intermediate. The mechanism of cycloisomerization of skipped alkynyl ketones containing an acyloxy group was found to be catalyst dependent; Lewis and Br?nsted acid catalysts caused an ionization/SN1' isomerization to the allene, followed by cycloisomerization to the furan, whereas transition metal catalysts evoked a Rautenstrauch-type mechanistic pathway. Furthermore, control experiments in the cycloisomerization of skipped alkynyl ketones under transition metal catalysis revealed that, indeed, these reactions were catalyzed by transition metal complexes as opposed to Br?nsted acids resulting from hydrolysis of these catalysts with eventual water. Further synthetic utility of the obtained phosphatyloxy-substituted heterocycles was demonstrated through their efficient employment in the Kumada cross-coupling reaction with various Grignard reagents.     

Triflic acid-catalyzed highly stereoselective friedel-crafts aminoalkylation of indoles and pyrroles

A simple and efficient synthesis to both enantiomers of highly enantiomerically enriched alpha-trifluoromethyl-alpha-(heteroaryl)-glycine derivatives via highly stereoselective aminoalkylation of indoles and pyrroles is described. The triflic acid-catalyzed reaction of enantiomeric 3,3,3-trifluoro-pyruvate-alpha-methylbenzyl imines with indoles and pyrroles and the subsequent Pd-catalyzed hydrogenolysis of the methylbenzyl group provided the products in high yields and excellent enantioselectivities.     

1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations,and Maybe Something More: A Review

N-acyliminium-type cations are examples of highly reactive intermediates that are willingly used in organic synthesis in intra- or intermolecular α-amidoalkylation reactions. They are usually generated in situ from their corresponding precursors in the presence of acidic catalysts (Brønsted or Lewis acids). In this context, 1-aminoalkyltriarylphosphonium derivatives deserve particular attention. The positively charged phosphonium moiety located in the immediate vicinity of the N-acyl group significantly facilitates C_α-P⁺ bond breaking, even without the use of catalyst. Moreover, minor structural modifications of 1-aminoalkyltriarylphosphonium derivatives make it possible to modulate their reactivity in a simple way. Therefore, these types of compounds can be considered as smart synthetic equivalents of N-acyliminium-type cations. This review intends to familiarize a wide audience with the unique properties of 1-aminoalkyltriarylphosphonium derivatives and encourage their wider use in organic synthesis. Hence, the most important methods for the preparation of 1-aminoalkyltriarylphosphonium salts, as well as the area of their potential synthetic utilization, are demonstrated. In particular, the structure–reactivity correlations for the phosphonium salts are discussed. It was shown that 1-aminoalkyltriarylphosphonium salts are not only an interesting alternative to other α-amidoalkylating agents but also can be used in such important transformations as the Wittig reaction or heterocyclizations. Finally, the prospects and limitations of their further applications in synthesis and medicinal chemistry were considered.     

Quantitative evaluation of Lewis acidity of metal ions with different ligands and counterions in relation to the promoting effects of Lewis acids on electron transfer reduction of oxygen

The g(zz) values of ESR spectra of superoxide (O(2)(.-) complexes of metal ion salts acting as Lewis acids with different ligands and counterions were determined in acetonitrile at 143 K. The binding energies (DeltaE) of (O(2)(.-)/Lewis acid complexes have been evaluated from deviation of the g(zz) values from the free spin value. The DeltaE value is quite sensitive to the difference in the counterions and ligands of metal ion salts acting as Lewis acids. On the other hand, the fluorescence maxima of the singlet excited states of 10-methylacridone/Lewis acid complexes are red-shifted as compared with that of 10-methylacridone, and the relative emission energies (Deltahnu(f)) vary significantly depending on the Lewis acidity of metal ion salts with different counterions and ligands. The promoting effects of Lewis acids were also examined on electron transfer from cobalt(II) tetraphenylporphyrin to oxygen in acetonitrile at 298 K, which does not occur in the absence of Lewis acids under otherwise the same experimental conditions. Both DeltaE and Deltahnu(f) values are well correlated with the promoting effects of Lewis acids on the electron transfer reduction of oxygen. Such correlations indicate that DeltaE and Deltahnu(f) values can be used as quantitative measures of Lewis acidity of metal ion salts with different ligands and counterions. The Lewis acidity thus determined can also be applied to predict the promoting effects of Lewis acids on organic synthesis.     

Bifunctional‐Thiourea‐Catalyzed Diastereo‐ and Enantioselective Aza‐Henry Reaction

Bifunctional thiourea 1 a catalyzes aza‐Henry reaction of nitroalkanes with N‐Boc‐imines to give syn‐β‐nitroamines with good to high diastereo‐ and enantioselectivity. Apart from the catalyst, the reaction requires no additional reagents such as a Lewis acid or a Lewis base. The N‐protecting groups of the imines have a determining effect on the chirality of the products, that is, the reaction of N‐Boc‐imines gives R adducts as major products, whereas the same reaction of N‐phosphonoylimines furnishes the corresponding S adducts. Various types of nitroalkanes bearing aryl, alcohol, ether, and ester groups can be used as nucleophiles, providing access to a wide range of useful chiral building blocks in good yield and high enantiomeric excess. Synthetic versatility of the addition products is demonstrated by the transformation to chiral piperidine derivatives such as CP‐99,994.     

Catalytic asymmetric Mannich reactions of glycine derivatives with imines. A new approach to optically active alpha,beta-diamino acid derivatives

Imines of glycine alkyl esters react with imines in a diastereo- and highly enantioselective Mannich reaction in the presence of chiral copper(I) complexes as the catalyst to give optically active alpha,beta-diamino acid derivatives. A series of imines of glycine esters derived from glycine and aromatic carbonyl compounds has been screened as substrates for the Mannich reaction with different imines in the presence of various combinations of metal salts and chiral ligands. The benzophenone imine of glycine esters was found to react with N-protected imines in a diastereoselective fashion giving functionalized alpha,beta-diamino acid esters with excellent enantioselectivities. The most effective chiral catalysts are chiral copper(I) complexes having phosphino-oxazoline (P,N)-ligands, and among these ligands, those derived from (1R,2S)-dihydroxy-1,2,3,4-tetrahydronaphthalene gave the best results. The scope of this new catalytic asymmetric reaction of the benzophenone imine glycine esters is demonstrated for the reaction with different N-protected-C-aryl and C-alkyl imines giving the Mannich adducts with excellent optical purity. Furthermore, the synthetic aspects of the reaction are presented by converting the Mannich adducts into alpha,beta-diamino acid derivatives. The relative and absolute configuration of the Mannich adduct have been determined and based on the stereochemical outcome of the reaction a tetrahedral chiral-copper(I)-imino glycine alkyl ester intermediate is proposed. In this intermediate the Re-face of the benzophenone imine glycine ester is shielded by the chiral ligand leaving the Si-face available for approach of the Si-face of the imine. A series of semiempirical calculations has been performed to support the structure of the tetrahedral chiral-copper(I) complex and to account for the influence of the substituents in the chiral phosphino-oxazoline ligands.     

Synthesis of nitrogen-containing compounds using chromium Fischer carbene complexes

Synthetic utility of the Fischer-type carbene complexes of chromium for the preparation of nitrogen-containing compounds is demonstrated. Alkoxy carbene complexes reacted with imines to give (optically active) 3-pyrrolines and beta-methoxy allylic amine derivatives in good yields. The amino carbene complexes reacted with alpha,beta-unsaturated aldehydes to give substituted pyrroles in good yields.     

Regioselective synthesis of pyrrolin-3-ones and 2,3,4,5-tetrahydro[1,3]-oxazines from N-vinylic amidines

Achiral and optically active N-vinylic amidines are obtained by simple addition of amidines to acetylenic esters. Thermal intramolecular cyclization of these substrates containing a carboxylate group in position 3 gives pyrrolin-3-ones. The enaminone character of these compounds towards propargyl bromide, diethyl azodicarboxylate, diethyl acetylenedicarboxylate, ethyl propiolate and phenyl isocyanate is studied and functionalized pyrrolin-3-one derivatives are obtained. The reaction of the pyrrolinones prepared with diethyl ketomalonate leads to new 1,3-oxazine derivatives.     

Isoquinoline skeleton synthesis via chelation-assisted C−H activation

Transition-metal-catalyzed isoquinoline synthesis that profits from the strategy of chelation-assisted C−H activation has flourished over the past decade. By virtue of the directed C−H bond cleavage of imines, amines, amidines, oximes, hydroximoyl halides, hydrazones, or azines, diverse isoquinoline derivatives have been accessed from alkynes, conjugated dienes, or diazo compounds under the catalysis of rhodium, ruthenium, palladium, nickel, or manganese. This digest summarizes the annulation reactions via chelation-assisted C−H activation leading to isoquinolines, isoquinolinium salts, or isoquinoline N-oxides.     

Asymmetric Multicomponent Reactions Based on Trapping of Active Intermediates

Metal carbenes derived from transition metal‐catalyzed decomposition of diazo compounds react with nucleophiles with heteroatoms, such as alcohols and amines, to generate highly active oxonium/ammonium ylides intermediates. These intermediates can be trapped by appropriate electrophiles to provide three‐component products. Based on this novel trapping process, we have developed novel multicomponent reactions (MCRs) of diazo compounds, alcohols/anilines, and electrophiles. The nucleophiles were also extended to electron‐rich heterocycles (indoles and pyrroles)/arenes, in which the resulting zwitterionic intermediates were also trapped by electrophiles. By employing efficient catalysis strategy, the reactions were realized with excellent stereocontrol and wide substrate scope. In this personal account, we introduce our breakthroughs in the development of novel asymmetric MCRs via trapping of the active ylides and zwitterionic intermediates with a number of electrophiles, such as imines, aldehyde, and Michael acceptors, under asymmetric catalysis. Transition metal/chiral Lewis acid catalysis, transition metal/Brønsted acid catalysis, and chiral transition‐metal catalysis, enable excellent stereocontrolled outcomes. The methodologies not only provide experimental evidence to support the existence of protic onium ylides intermediates/zwitterionic intermediates and the stepwise pathways of carbene‐induced O?H, N?H and C?H insertions, but also offer a novel approach for the efficient construction of chiral polyfunctional molecules.