Fujiwara-Moritani Reaction Research Articles

Synthesis of β‐Aryl‐α,β‐Dehydroaminophosphonates by Pd‐Catalyzed Fujiwara–Moritani C−C Coupling

AbstractThe treatment of diethyl α,β‐dehydroaminophosphonate 1 with various arenes (ArH=toluene 2 a, benzene 2 b, anisole 2 c, bromobenzene 2 d, chlorobenzene 2 e, benzyl alcohol 2 f, p‐xylene 2 g) in acetic acid (AcOH) at 120 °C for 8 h in the presence of Pd(OAc)2 (10 % mol, OAc=acetate) and AgOAc (3.4 equivalents) results in the formation of the corresponding β‐aryl derivatives E‐Ar(H)C=C(NHAc)P(O)(OEt)2 3 a–3 g. The reaction proceeds through double C−H activation (arene and alkene) and subsequent C−C oxidative coupling (Fujiwara–Moritani reaction), processes catalyzed by Pd and assisted by Ag. The obtained products 3 a–3 g are isosteric analogs of phenylalanine and are obtained with high selectivity. Thus, geometrical E‐isomers have been obtained in all studied cases, however mixtures of ortho‐/meta‐/para‐isomers are observed when the activated position in the starting arene 2 is considered.

Iron-Catalyzed C-H Activation for Heterocoupling and Copolymerization of Thiophenes with Enamines.

C-H/C-H coupling via C-H activation provides straightforward synthetic access to the construction of complex π-conjugated organic molecules. The palladium-catalyzed Fujiwara-Moritani (FM) coupling between an arene and an electron-deficient olefin presents an early example but is not applicable to enamines such as N-vinylcarbazoles and N-vinylindoles. We report herein iron-catalyzed C-H/C-H heterocoupling between enamines and thiophenes and its application to copolymerization of bisenamine and bisthiophene using diethyl oxalate as an oxidant and AlMe3 as a base, as a result of our realization that synthetic limitations in oxidative C-H/C-H couplings imposed by the high redox potential of the Pd(II)/Pd(0) catalytic cycle can be circumvented by the use of iron, which has a lower Fe(III)/Fe(I) redox potential. The trisphosphine ligand provides a coordination environment for iron to achieve the reaction's regio-, stereo-, and chemoselectivity. The reaction includes C-H activation of thiophene via σ-bond metathesis and subsequent enamine C-H cleavage triggered by nucleophilic enamine addition to the Fe(III) center, thereby differing from the FM reaction in mechanism and synthetic scope. The copolymers synthesized by the new reaction possess a new type of enamine-incorporated polymer backbone.

Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites.

The Fujiwara-Moritani reaction has had a profound contribution in the emergence of contemporary C-H activation protocols. Despite the applicability of the traditional approach in different fields, the associated reactivity and regioselectivity issues had rendered it redundant. The revival of this exemplary reaction requires the development of a mechanistic paradigm that would have simultaneous control on both the reactivity and regioselectivity. Often, the high thermal energy required to promote olefination leads to multiple site functionalizations. To this aim, we established a photoredox catalytic system constituting a merger of palladium/organo-photocatalyst (PC) that forges oxidative olefination in an explicit regioselective fashion with diverse arenes and heteroarenes. Visible light plays a significant role in executing "regioresolved" Fujiwara-Moritani reactions without the requirement of silver salts and thermal energy. The catalytic system is also amenable toward proximal and distal olefination aided by the respective directing groups (DGs), which entails the versatility of the protocol in engaging the entire spectrum of C(sp2)-H olefination. Furthermore, streamlining the synthesis of natural products, chiral molecules, drugs, and diversification through late-stage functionalizations underscore the importance of this sustainable protocol. The photoinduced attainment of this regioselective transformation is mechanistically established through control reactions and kinetic studies.

Non-directed Pd-catalysed electrooxidative olefination of arenes.

The Fujiwara–Moritani reaction is a powerful tool for the olefination of arenes by Pd-catalysed C–H activation. However, the need for superstoichiometric amounts of toxic chemical oxidants makes the reaction unattractive from an environmental and atom-economical view. Herein, we report the first non-directed and regioselective olefination of simple arenes via an electrooxidative Fujiwara–Moritani reaction. The versatility of this operator-friendly approach was demonstrated by a broad substrate scope which includes arenes, heteroarenes and a variety of olefins. Electroanalytical studies suggest the involvement of a Pd(ii)/Pd(iv) catalytic cycle via a Pd(iii) intermediate.

Pd(II)-Catalyzed Fujiwara-Moritani Reactions for the Synthesis and Functionalization of Substituted Coumarins.

Highly substituted coumarins, privileged and versatile scaffolds for bioactive natural products and fluorescence imaging, are obtained via a Pd(II)-catalyzed direct C–H alkenylation reaction (Fujiwara–Moritani reaction), which has emerged as a powerful tool for the construction and functionalization of heterocyclic compounds because of its chemical versatility and its environmental advantages. Thus, a selective 6-endo cyclization led to 4-substituted coumarins in moderate yields. Selected examples have been further functionalized in C3 through a second intermolecular C–H alkenylation reaction to give coumarin-acrylate hybrids, whose fluorescence spectra have been measured.

Palladium-Catalyzed Dehydrogenative C-2 Alkenylation of 5-Arylimidazoles and Related Azoles with Styrenes

The construction of carbon–carbon bonds by direct involvement of two unactivated carbon–hydrogen bonds, without any directing group, ensures a high atom economy of the entire process. Here, we describe a simple protocol for the Pd(II)/Cu(II)-promoted intermolecular cross-dehydrogenative coupling (CDC) of 5-arylimidazoles, benzimidazoles, benzoxazole and 4,5-diphenylimidazole at their C-2 position with functionalized styrenes. This specific CDC, known as the Fujiwara–Moritani reaction or oxidative Heck coupling, also allowed the C-4 alkenylation of the imidazole nucleus when both 2 and 5 positions were occupied.

Late-stage construction of stapled peptides through Fujiwara-Moritani reaction between tryptophan and olefins.

Herein, the first example of a palladium-catalyzed Fujiwara-Moritani reaction for olefination of tryptophan (Trp) residues, free from directing groups, was presented. The developed reaction proceeds efficiently for peptide modification, ligation and peptide stapling.

Synthesis of axially chiral biaryl thioglycosides through thiosugar-directed Pd-catalyzed asymmetric C-H activation.

Herein we report for the first time that the thiosugar moiety can be used both as a directing group enabling the regioselective activation of a C-H bond of biaryl scaffolds and as a chiral source inducing axial chirality. Our approach enables the easy generation of complex thioglycoside atropoisomers, thus paving the way to new products of potential biological interest.

Revisiting the mechanism of the Fujiwara–Moritani reaction

A new perspective of the Fujiwara–Moritani reaction is presented, including its kinetic profile and catalyst deactivation studies.

Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl ligands on the oxidative coupling of electron rich arenes and acrylates

A palladium-catalysed direct alkenation of electron rich arenes in the presence of K2S2O8 with an acetic acid/1,4-dioxane solvent combination has been developed. The 1,4-dioxane co-solvent dramatically influences the rate of reaction, giving selectively disubstituted alkenes, while the addition of acetylacetone ligands was shown to increase site selectivity for the alkenation of monofunctionalized arenes. The participation of these carbonyl ligands has been confirmed by ESI-MS studies, with some key in situ intermediates in the catalytic cycle identified. A variety of electron rich arenes and olefinic substrates can be utilised in the direct oxidative coupling to give disubstituted alkenes in moderate to good yields.

Palladium-Mediated Oxidative Annulation of δ-Indolyl-α,β-Unsaturated Compounds toward the Synthesis of Cyclopenta[ b]indoles and Heterogeneous Hydrogenation To Access Fused Indolines.

The cyclopenta[ b]indole moiety represents a key skeletal unit in several natural and synthetic compounds that exhibit diverse biological properties. We described herein a two-step sequence for synthesizing cyclopenta[ b]indoles with great structural diversity in overall yields up to 37%. The key step was a palladium-catalyzed oxidative annulation of 3-alkylindoles (Fujiwara-Moritani reaction). The obtained cyclopenta[ b]indoles were used as substrates in heterogeneous hydrogenation reactions to afford new fused indolines in moderate yields. An acid-catalyzed intramolecular cyclization of three such indolines gave tetracyclic lactams in 89, 90, and 61% yields.

Iridium‐Catalyzed α‐Selective Arylation of Styrenes by Dual C−H Functionalization

AbstractAn IrI‐system modified with a ferrocene derived bisphosphine ligand promotes α‐selective arylation of styrenes by dual C−H functionalization. These studies offer a regioisomeric alternative to the Pd‐catalyzed Fujiwara–Moritani reaction.

Iridium-Catalyzed α-Selective Arylation of Styrenes by Dual C-H Functionalization.

An IrI‐system modified with a ferrocene derived bisphosphine ligand promotes α‐selective arylation of styrenes by dual C−H functionalization. These studies offer a regioisomeric alternative to the Pd‐catalyzed Fujiwara–Moritani reaction.

Dual Ligand-Enabled Nondirected C-H Olefination of Arenes.

The application of the Pd-catalyzed oxidative C-H olefination of arenes, also known as the Fujiwara-Moritani reaction, has traditionally been limited by the requirement for directing groups on the substrate or the need to use the arene in large excess, typically as a (co)solvent. Herein the development of a catalytic system is described that, through the combined action of two complementary ligands, makes it possible to use directing-group-free arenes as limiting reagents for the first time. The reactions proceed under a combination of both steric and electronic control and enable the application of this powerful reaction to valuable arenes, which cannot be utilized in excess.

Continuous-Flow Palladium/Carbon-Catalyzed Fujiwara–Moritani Reaction

Key words Fujiwara–Moritani reaction - palladium catalysis - alkenylation - continuous-flow reaction - biomass-derived solvents

Heterogeneous C–H alkenylations in continuous-flow: oxidative palladium-catalysis in a biomass-derived reaction medium

Herein we report the unprecedented Fujiwara–Moritani reaction catalysed by the commercially available heterogeneous palladium catalyst Pd/C.

ChemInform Abstract: 1,1,1,3,3,3‐Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide‐Directed Fujiwara—Moritani Reaction with Acrylates and Styrenes.

AbstractAccess to atropo‐enantioenriched chiral biaryl moieties through asymmetric direct C—H activation is achieved using an enantiopure sulfoxide as both the directing group and chiral auxiliary.

1,1,1,3,3,3-Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide-Directed Fujiwara-Moritani Reaction with Acrylates and Styrenes.

Axially chiral biaryls are ubiquitous structural motifs of biologically active molecules and privileged ligands for asymmetric catalysis. Their properties are due to their configurationally stable axis, and therefore, the control of their absolute configuration is essential. Efficient access to atropo-enantioenriched biaryl moieties through asymmetric direct C-H activation, by using enantiopure sulfoxide as both the directing group (DG) and chiral auxiliary, is reported. The stereoselective oxidative Heck reactions are performed in high yields and with excellent atropo-stereoselectivities. The pivotal role of 1,1,1,3,3,3-hexafluoropropanol (HFIP) solvent, which enables a drastic increase in yield and stereoselectivity of this transformation, is evidenced and investigated. Finally, the synthetic usefulness of the herein disclosed transformation is showcased because the traceless character of the sulfoxide DG allows straightforward conversions of the newly accessed, atropopure sulfoxide-biaryls into several differently substituted axially chiral scaffolds.

Palladium-Catalyzed Triple Successive C-H Functionalization: Direct Synthesis of Functionalized Carbazoles from Indoles.

A novel Pd(II)-catalyzed approach for the direct synthesis of differentially substituted carbazoles from free (NH) indoles via regioselective triple successive oxidative Heck (Fujiwara-Moritani reaction) has been achieved. It is demonstrated that both electron-deficient and electron-rich alkenes could be used successively for the incorporation of two different functional groups into the product. The proposed mechanistic pathway was well supported by isolating the first and second successive oxidative Heck intermediates as well as by trapping with styrene-d3.

Fujiwara-Moritani Reaction of Weinreb Amides using a Ruthenium-Catalyzed C-H Functionalization Reaction.

The ruthenium-catalyzed Fujiwara-Moritani reaction (oxidative-Heck reaction) of Weinreb amides is reported herein. The reaction affords exclusively ortho-C-H olefination products, has excellent substrate scope and tolerates halogen functionalities, which increase the synthetic utility of the method. A variety of activated olefins as well as styrenes can be employed as coupling partners.