Electron-rich Heteroaromatics Research Articles

Formation and Reactions of Brønsted and Lewis Acid Adducts with Electron-Rich Heteroaromatic Compounds.

Electron-rich heteroaromatics, such as furan, thiophene and pyrrole, as well as their benzo-condensed derivatives, are of great interest as components of natural products and as starting substances for various products including high-tech materials. Although their reactions with Brønsted and Lewis acids play important roles, in particular as the primary step of various transformations, they are often disregarded and mechanistically not understood. The present publication gives a first overview about this chemistry focusing on the parent compounds. It comprises reactions with strong Brønsted acids forming adducts that can undergo intramolecular proton and/or substituent transfer reactions, ring openings or ring transformations into other heterocycles, depending on their structure. Interactions with weak Brønsted acids usually initiate oligomerizations/polymerizations. A similar behaviour is observed in reactions of these heteroaromatics with Lewis acids. Special effects are achieved when the Lewis acids are activated through primary protonation. Deuterated Brønsted acids allow straight forward deuteration of electron-rich heteroaromatics. Mercury salts as extremely weak Lewis acids cause direct metalation in a straight forward way replacing ring H-atoms yielding organomercury heterocycles. This review will provide comprehensive information about the chemistry of adducts of such heterocycles with Brønsted and Lewis acids enabling chemists to understand the mechanisms and the potential of this field and to apply the findings in future syntheses.

Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Component Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes.

An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse carbon-centered radical precursors and electron-rich heteroaromatics by a copper(I) and chiral phosphoric acid cooperative catalysis strategy has been developed, providing straightforward access to chiral triarylmethanes bearing quaternary all-carbon stereocenters with high efficiency as well as excellent chemo- and enantioselectivity. The key to success is not only the introduction of a sterically demanding chiral phosphoric acid to favor radical difunctionalization over the otherwise remarkable side reactions but also the in situ generation of carbocation intermediates from benzylic radical to realize asymmetric induction with the aid of a removable hydroxy directing group via cooperative interactions with chiral phosphate. Density functional theory calculations elucidated the critical chiral environment created by the hydrogen-bonding and ion-pair interactions between the chiral phosphoric acid catalyst and substrates, which leads to the enantioselective C-C bond formation.

Phenolic Activation in Chiral Brønsted Acid-Catalyzed Intramolecular α-Amidoalkylation Reactions for the Synthesis of Fused Isoquinolines.

An organolithium addition–intramolecular α-amidoalkylation sequence on N-phenethylimides has been developed for the synthesis of fused tetrahydroisoquinoline systems using 1,1′-bi-2-naphthol (binol)-derived Brønsted acids. This transformation is the first in which activated benzene derivatives are used as internal nucleophiles, instead of electron-rich heteroaromatics, generating a quaternary stereocenter. Phenolic substitution on the aromatic ring of the phenethylamino moiety and the use of binol-derived N-triflylphosphoramides as catalysts are determinants to achieve reasonable levels of enantioselection, that is, up to 75% enantiomeric excess, in the α-amidoalkylation step. The procedure is complementary to the intermolecular α-amidoalkylation process, as opposite enantiomers are formed, and to the Pictet–Spengler cyclization, which allows the formation of tertiary stereocenters.

Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds.

The stereospecific cross-coupling of secondary boronic esters with sp2 electrophiles (Suzuki–Miyaura reaction) is a long-standing problem in synthesis, but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. To address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel–Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C–C bond. Elimination (preceded by further oxidation in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, and ethers). The reaction also worked well with other electron-rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found under which the B(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C(sp2)–C(sp3) and an adjacent C–B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases, the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations.

Stereoselective synthesis of novel C-azanucleoside analogues by microwave-assisted nucleophilic addition of sugar-derived cyclic nitrones

A series of C-azanucleoside analogues were synthesized by microwave-assisted nucleophilic addition of electron-rich hetero-aromatics to sugar-derived cyclic nitrones, and followed by reduction and deprotection. The nucleophilic addition afforded the 2′,3′-trans isomer as the dominant by the favorite exo attack and showed high stereoselectivity in polar solvent.

Reaction Behavior of Cumulene: Diels–Alder, Friedel–Crafts, and Pd-Catalyzed Domino Reactions

Diels―Alder, Friedel―Crafts, and domino reactions mediated by Pd-catalyst of [3]cumulene 1 were investigated. Although the Diels―Alder reaction with cyclopentadiene occurred selectively on the C2, C3 double bond to give tetrasubstituted allenyl products, the Friedel―Crafts type addition of electron-rich heteroaromatics and subsequent protonation cleanly occurred on the C3, C4 double bond to afford tetrasubstituted conjugated dienes. In the Heck reaction with aryl iodide, the arylpalladium species was selectively inserted into the C3, C4 double bond and a subsequent C―H activation reaction with a neighboring phenyl group gave indene derivatives with a tetrasubstituted olefin moiety. Furthermore, Pd-catalyzed domino cyclization―allylation reaction of in situ generated [3]cumulene alkoxide afforded tetrasubstituted furan.

Conformational Control of Metallocene Backbone by Cyclopentadienyl Ring Substitution: A New Concept in Polyphosphane Ligands Evidenced by “Through-Space” Nuclear Spin−Spin Coupling. Application in Heteroaromatics Arylation by Direct C−H Activation

The present study deals with the conformational control of the metallocene backbone within ferrocenyl polyphosphane ligands and their performance in the highly topical palladium-catalyzed heteroaromatics arylation by direct C−H activation. New substituted cyclopentadienyl rings were synthesized, which allowed the assembling of original tri- and diphosphanes. The bulky cyclopentadienyl lithium salts diphenylphosphino-3-(triphenyl)methylcyclopentadienyllithium (4) and 1,2-bis(diphenylphosphino)-4-(triphenyl)methylcyclopentadienyllithium (5) were prepared in excellent yield. The assembling of these new hindered cyclopentadienyl salts (Cp) with other Cp fragments was performed in order to prepare ferrocenyl ligands with controlled conformation. A comparison of conformations of 1,1′,2-tris(diphenylphosphino)-3′,4-di-tert-butylferrocene (3) and 1,1′,2-tris(diphenylphosphino)-3′-(triphenyl)methyl-4-tert-butylferrocene (6) allowed us to determine, for the first time, the conditions of an efficient control of the orientation of the phosphino substituents on the ferrocene backbone in the absence of an ansa-bridge. The characterization of these metallo-ligands, by multinuclear NMR in solution and by X-ray diffraction in the solid state, focused on nonbonded JPP spin−spin couplings. These unusual couplings are especially useful for assessing the conformation of the ferrocene backbone in solution. The palladium complexes of the triphosphane ligand 6 and the diphosphane 1,1′-bis(diphenylphosphino)-3,3′-di(triphenyl)methylferrocene (7) were successfully used in the direct C−H activation of electron-rich heteroaromatics for coupling to demanding aryl bromides, whether electron rich and/or sterically congested. Products such as 2-butyl-5-(4-methoxyphenyl)furan (10), 2-butyl-5-o-tolylfuran (11), and thiophene analogues (12 and 13) were obtained in yields higher than 90%. The NMR examination of the reaction of [PdCl(η3-C3H5)]2 with ligands 6 and 7 allowed us to determine the coordination chemistry of the precatalysts. The allylic palladium complexes 8 and 9 confirmed the unusual conformation present in 6. As a consequence, the selective and “genuinely” tridentate bonding of a triphosphane to one palladium center is reported. This seldom observed coordination mode is a direct consequence of the successful ferrocene backbone conformation control.

Direct Palladium-Catalyzed Alkynylation of N-Fused Heterocycles

The first example of direct C−H alkynylation of electron-rich heteroaromatics has been demonstrated. This mild, simple, and general method allows for the efficient synthesis of diverse alkynyl heterocycles. Kinetic isotope effect studies support an electrophilic substitution pathway for this transformation.

Reaction Behavior of Cumulene in Diels–Alder and Friedel–Crafts Reactions

Abstract Diels–Alder and Friedel–Crafts reactions of [3]cumulene 1 were investigated. Although the Diels–Alder reaction with cyclopentadiene selectively occurred on the C2, 3 double bond to give tetrasubstituted allenyl products, the Friedel–Crafts addition of electron-rich heteroaromatics and subsequent protonation cleanly occurred on the C3, 4 double bond to afford tetrasubstituted conjugated dienes.

Nucleophilic addition to electron-rich heteroaromatics: dearomatizing anionic cyclizations of pyrrolecarboxamides.

[reaction: see text] Despite its electron-rich nature, a pyrrole ring is susceptible to intramolecular nucleophilic attack by organolithiums. The resulting dearomatizing anionic cyclization yields new 5- or 7-membered heterocyclic rings. Formation of a new 5-membered ring, by cyclization of an N-benzylpyrrolecarboxamide, is accompanied by ring opening of the original pyrrole to yield 3-aminovinylpyrrolinones. Formation of a new 7-membered ring, by cyclization of an N-allyl pyrrolecarboxamide, yields bicyclic pyrroloazepinones.

A Novel Efficient Synthesis of Heteroaryl Substituted α,β-Unsaturated Trifluoromethyl Ketones

A synthesis of a novel electrophilic reagent 1,1,1-trifluoro-4-(phenylsulfonyl)-but-3-ene-2,2-diol 2 is described. The reaction of 2 with various electron-rich heteroaromatics such as furans, pyrroles, indoles is investigated. The addition-elimination reaction proceeds under mild conditions stereospecifically and permits a novel one-step procedure for the preparation of trifluoroacetylvinyl substituted heterocycles in high yield. In all cases only E-isomers of unsaturated CF3 ketones were obtained.

Electrophilic reactions of trihalogenomethanesulfenyl acetates and trifluoroacetates

The stable trihalogenomethanesulfenyl acetates, AcOSCF nCl 3−n (2) were prepared by the reaction of the corresponding trihalogeno- methanesulfenyl chlorides with sodium acetate. These and fluoro- chloromethanesulfenyl trifluoracetates CF 3COOSCF nCl 3−n ( 1 ) added rapidly in trans manner to cyclohexene to yield β-acetoxy and β-trifluoroacetoxy sulfides ( 3 ). The trifluoroacetates ( 1 ) also reacted with some aromatics containing electron-donating substituents, such as anisole, toluene, p-xylene, mesitylene and pentamethylbenzene, or with electron-rich heteroaromatics, such as thiophene, to give trihalogenomethylmercapto derivatives.