Heck Alkenylation Research Articles

Diastereoselective and Enantioselective Heck Alkenylation of Cyclopent‐3‐en‐1‐ylmethanol with Alkenyl Triflates and Evaluation of Noncovalent Effects

AbstractThis work describes an effective method to obtain chiral vinyl cyclopentenols with a high degree of enantioselectivity and diastereoselectivity through Heck desymmetrization of cyclopent‐3‐en‐1‐ylmethanol using vinyl triflates as coupling agents and chiral N,N ligands. This Heck vinylation protocol allowed the synthesis of several structurally complex cyclopentenols in isolated yields of up to 80 % in enantiomeric ratios of up to 97 : 3 and diastereoselectivities higher than 20 : 1 in most cases. Experiments using (E) or (Z) vinyl triflates, and desymmetrization of protected olefin 1‐(cyclopent‐3‐en‐1‐ylmethoxy)‐4‐nitrobenzene (17) were instrumental in rationalizing the observed diastereoselectivities of Heck products involving the interaction of vinyl triflate carbonyl and the hydroxyl group moiety of the substrate with the cationic Pd(II) complex. The absolute configuration of the vinylated Heck products was determined by Vibrational Circular Dichroism (VCD) spectroscopy.

Rapid plugged flow synthesis of nucleoside analogues via Suzuki-Miyaura coupling and heck Alkenylation of 5-Iodo-2'-deoxyuridine (or cytidine).

The online version contains supplementary material available at 10.1007/s41981-023-00265-1.

Carboxylate‐Directed Palladium‐Catalyzed Regioselective Mizoroki‐Heck Alkenylation of γ,δ‐Unsaturated Carboxylic Acids

AbstractA carboxylate‐directed palladium‐catalyzed Mizoroki–Heck alkenylation of γ,δ‐unsaturated carboxylic acids with alkenyl bromides is reported. This carboxylate group is effective for chelation to a Pd center, enabling the distal alkenylation of electronically unbiased internal alkenes in the formation of conjugated 1,3‐dienes with high stereoselectivity. In addition, the conjugated 1,3‐diene products can be used for synthetic applications through reduction, epoxidation, methylation, amidation, and cycloaddition.magnified image

Suzuki-Miyaura Coupling, Heck Alkenylation, and Amidation of DMTr-Protected 5-Iodo-2'-Deoxyuridine via Palladium-catalyzed Reactions.

Modification of nucleosides via cross-coupling processes has been carried out extensively on unprotected halonucleosides to produce functionalized nucleosides that are often developed for incorporation into oligonucleotides or used as fluorescent probes. This approach requires protection of the 5'-OH with the 4,4'-dimethoxytrityl (DMTr) group, which is complicated and a common cause of reaction failure. Here we report a method for direct functionalization of 5'-O-DMTr-5-iodo-2'-deoxyuridine via Suzuki-Miyaura cross-coupling, Heck alkenylation, and carboamidation. This approach facilitates rapid synthesis of a variety of C5-substituted 5'-O-DMTr-2'-deoxyuridine derivatives. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of the SerrKap palladacycle complex Basic Protocol 2: Suzuki-Miyaura coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine using SerrKap palladacycle Basic Protocol 3: Heck coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine using SerrKap palladacycle Basic Protocol 4: Heck coupling of 5'-O-DMTr-5-iodo-2'-deoxyuridine with Ruth linker using Pd(OAc)2 /PTABS Basic Protocol 5: Carbonylative amidation of 5'-O-DMTr-5-iodo-2'-deoxyuridine using Pd(OAc)2 /PTABS.

Asymmetric Total Syntheses of (+)-5-epi-Schisansphenin B and the Proposed Structure of (+)-15-Hydroxyacora-4(14),8-diene.

The asymmetric total syntheses of (+)-5-epi-schisansphenin B and the proposed structure of (+)-15-hydroxyacora-4(14),8-diene have been accomplished from 1,3-cyclopentadione (10) in eight synthetic steps. The enantioselective palladium-catalyzed redox-relay Heck alkenylation, the intramolecular Stetter reaction, and the regioselective Tiffeneau-Demjanov-type ring expansion were the pivotal steps in these syntheses.

Scale-Up of a Heck Alkenylation Reaction: Application to the Synthesis of an Amino-Modifier Nucleoside ‘Ruth Linker’

AbstractRuth linker is a C5 pyrimidine modified nucleoside analogue widely utilized for the incorporation of a primary amine in a synthetic oligonucleotide. The increasing demand for non-radioactive labeling, detection of biomolecules, and assembly of COVID-19 test kits has triggered a need for scale-up of Ruth linker. Herein, an efficient protocol involving a palladium-catalyzed Heck alkenylation is described. The synthesis has been optimized with a goal of low catalyst concentration, column-free isolation, high product purity, reproducibility, and shorter reaction time. The scalability and utility of the process have been demonstrated successfully on a 100 g scale (starting material). Additionally, for scale-up of the Heck alkenylation protocol, 7-phospha-1,3,5-triaza-adamantanebutane sulfonate (PTABS) as the coordinating caged phosphine ligand was also synthesized on a multigram scale after careful optimization of the conditions.

Enantioselective Synthesis of Alkyl Allyl Ethers via Palladium-Catalyzed Redox-Relay Heck Alkenylation of O-Alkyl Enol Ethers.

Herein we report a transformation that generates an array of enantiomerically enriched, alkyl allyl ethers. Cyclic, acyclic, and heteroatom-bearing alkenyl triflates undergo an enantioselective, palladium-catalyzed C-C bond formation with diverse acyclic O-alkyl enol ethers in good yields and excellent enantioselectivities.

Amido-functionalized N-Heterocyclic carbene ligands and corresponding PalladiumComplexes: Synthesis, characterization and catalytic activity

Thirteen amido functionalized N-heterocyclic carbene ligands were synthesized via a simple synthetic procedure. The synthesized ligands were characterized by NMR, FAB-MS and single crystal X-ray analysis, unanimously confirming the proposed structures. Subsequent complexation with a palladium precursor allowed the synthesis of four new complexes. The molecules structures of all four complexes were confirmed by single crystal X-ray diffraction. The catalytic activity of the synthesized ligands and complexes was tested for the Heck alkenylation of aryl iodide readily allowing the synthesis of cinnamic acids esterin yields ranging from 67 to 93% for ligands and 69–95% for complexes while turn-over-numbers of up to 75000 was observed for the complexes.

Pd/PTABS: Catalyst for Efficient C−H (Hetero)Arylation of 1,3,4‐Oxadiazoles Using Bromo(Hetero)Arenes

AbstractA highly efficient catalytic protocol for the C−H (hetero)arylation of 1,3,4‐oxadiazoles using low catalyst loading of Pd/PTABS system with bromo(hetero)arenes has been disclosed. The developed reaction conditions enable the synthesis of a library of differently (hetero)arylated oxadiazoles along with a commercially available fluorescent organic scintillation material, butyl‐PBD as well as anti‐tubercular agent PHOXPY. The combination of C−H arylation of oxadiazoles with Sonogashira reaction (steroidal substructures bearing alkynes), Heck alkenylation or Suzuki‐Miyaura coupling in a one‐pot tandem procedure was also made possible with an intent for new drug discovery possibilities.

Palladium-catalyzed enantioselective alkenylation of alkenylbenzene derivatives.

A regioselective and enantioselective palladium-catalyzed relay Heck alkenylation of alkenylbenzene derivatives to construct remote stereocenters is disclosed. Various β-substituted styrenes were readily obtained in moderate yields with good to excellent levels of enantioselectivity. This strategy provides rapid access to enantioenriched δ, ε, ζ, and η-alkenyl aryl compounds from simple starting materials. Mechanistic studies suggest that termination of the relay reaction is controlled by affinity of the arene for the Pd complex during migration.

Palladium-Catalyzed Enantioselective Heck Alkenylation of Trisubstituted Allylic Alkenols: A Redox-Relay Strategy to Construct Vicinal Stereocenters.

An enantioselective, redox-relay Heck alkenylation of trisubstituted allylic alkenol substrates has been developed. This process enables the construction of vicinal stereocenters in high diastereo- and enantioselectivity and allows the formation of enolizable α-carbonyl methyl-substituted stereocenters with no observed epimerization under the reported reaction conditions.

Modulation of the Electronic Properties of Non-innocent (E,E)-Dibenzylideneacetone for Palladium(0)-Mediated Heck Alkenylation of 5-Iodo-2′-deoxyuridine and Scale-Up Studies

Subtle modulation of the electronic properties of the dibenzylideneacetone (dba) ligand allows the development of an efficient protocol for the Heck alkenylation of 5-iodo-2′-deoxyuridine. This protocol enables the large-scale synthesis of commercially important nucleoside building blocks. The isolation of one key molecule was accomplished under column-free conditions on a 10-gram scale.

Pd–imidate complexes as recyclable catalysts for the synthesis of C5-alkenylated pyrimidine nucleosides via Heck cross-coupling reaction

Pd–imidate complexes as recyclable catalysts for Heck alkenylation of pyrimidine nucleosides. Pd–imidate complexes have been employed as efficient catalysts for the Heck alkenylation of unprotected 5-iodo-2′-deoxyuridine in acetonitrile.

Synthesis of a D-ring isomer of galanthamine via a radical-based Smiles rearrangement reaction.

The 1,9-ethanoiminomethano-bridged tetrahydrodibenzo[b,d]-furan 2, a non-natural isomer of the alkaloid (-)-galanthamine (1) varying in the manner in which the D-ring is annulated to the ABC-core, has been prepared in racemic form. The synthetic sequence starts with the cyclopropane 3 and involves intramolecular Heck alkenylation and radical-based Smiles rearrangement reactions as key steps. Unlike natural product 1, but as predicted by docking studies, compound 2 is not a potent inhibitor of acetylcholine esterase.

Aerobic Dehydrogenative Heck Reaction of Ferrocene with a Pd(OAc)2/4,5-Diazafluoren-9-one Catalyst

The aerobic dehydrogenative Heck alkenylation of ferrocene with alkenes, catalyzed by a Pd(OAc)2/4,5-diazafluoren-9-one system, is disclosed. Monoalkenylated ferrocenes were obtained in moderate yields and selectivities using various electron-poor alkenes. Oxygen at an atmospheric pressure was the sole oxidant. The reaction can be carried out at room temperature (several days) or at 70 °C (∼3 h).

Highly selective synthesis of conjugated dienoic and trienoic esters via alkyne elementometalation–Pd-catalyzed cross-coupling

All four stereoisomers (7-10) of ethyl undeca-2,4-dienoate were prepared in ≥ 98% isomeric purity by Pd-catalyzed alkenylation (Negishi coupling) using ethyl (E)- and (Z)-β-bromoacrylates. Although the stereoisomeric purity of the 2Z,4E-isomer (8) prepared by Suzuki coupling using conventional alkoxide and carbonate bases was ≤ 95%, as reported earlier, the use of CsF or (n)Bu(4)NF as a promoter base has now been found to give all of 7-10 in ≥ 98% selectivity. Other widely known methods reveal considerable limitations. Heck alkenylation was satisfactory for the syntheses of the 2E,4E and 2E,4Z isomers of ≥ 98% purity, but the purity of the 2Z,4E isomer was ≤ 95%. Mutually complementary Horner-Wadsworth-Emmons and Still-Gennari (SG) olefinations are also of considerably limited scopes. Neither 2E,4Z nor 2Z,4Z isomer is readily prepared in ≥ 90% selectivity. In addition to (2Z,4E)-dienoic esters, some (2Z,4E,6E)- and (2Z,4E,6Z)-trienoic esters have been prepared in ≥ 98% selectivity by a newly devised Pd-catalyzed alkenylation-SG olefination tandem process. As models for conjugated higher oligoenoic esters, all eight stereoisomers for ethyl trideca-2,4,6-trienoate (23-30) have been prepared in ≥ 98% overall selectivity.

Recent Advances in Efficient and Selective Synthesis of Di-, Tri-, and Tetrasubstituted Alkenes via Pd-Catalyzed Alkenylation−Carbonyl Olefination Synergy

Although generally considered competitive, the alkenylation and carbonyl olefination routes to alkenes are also complementary. In this Account, we focus on these approaches for the synthesis of regio- and stereodefined di- and trisubstituted alkenes and a few examples of tetrasubstituted alkenes. We also discuss the subset of regio- and stereodefined dienes and oligoenes that are conjugated. Pd-catalyzed cross-coupling using alkenyl metals containing Zn, Al, Zr, and B (Negishi coupling and Suzuki coupling) or alkenyl halides and related alkenyl electrophiles provides a method of alkenylation with the widest applicability and predictability, with high stereo- and regioselectivity. The requisite alkenyl metals or alkenyl electrophiles are most commonly prepared through highly selective alkyne addition reactions including (i) conventional polar additions, (ii) hydrometalation, (iii) carbometalation, (iv) halometalation, and (v) other heteroatom-metal additions. Although much more limited in applicability, the Heck alkenylation offers an operationally simpler, viable alternative when it is highly selective and satisfactory. A wide variety of carbonyl olefination reactions, especially the Wittig olefination and its modifications represented by the E-selective HWE olefination and the Z-selective Still-Gennari olefination, collectively offer the major alternative to the Pd-catalyzed alkenylation. However, the carbonyl olefination method fundamentally suffers from more limited stereochemical options and generally lower stereoselectivity levels than the Pd-catalyzed alkenylation. In a number of cases, however, very high (>98%) stereoselectivity levels have been attained in the syntheses of both E and Z isomers. The complementarity of the alkenylation and carbonyl olefination routes provide synthetic chemists with valuable options. While the alkenylation involves formation of a C-C single bond to a CC bond, the carbonyl olefination converts a CO bond to a CC bond. When a precursor to the desired alkene is readily available as an aldehyde, the carbonyl olefination is generally the more convenient of the two. This is a particularly important factor in many cases where the desired alkene contains an allylic asymmetric carbon center, since alpha-chiral aldehydes can be prepared by a variety of known asymmetric methods and readily converted to allylically chiral alkenes via carbonyl olefination. On the other hand, a homoallylically carbon-branched asymmetric center can be readily installed by either Pd-catalyzed isoalkyl-alkenyl coupling or Zr-catalyzed asymmetric carboalumination (ZACA reaction) of 1,4-dienes. In short, it takes all kinds to make alkenes, just as it takes all kinds to make the world.

Synthesis of profluorescent isoindoline nitroxides via palladium-catalysed Heck alkenylation

The synthesis of a new structural class of isoindoline nitroxides (aminoxyls), accessible via the palladium-catalysed Heck reaction, is presented. Reaction of the aryl bromoamine, 5-bromo-1,1,3,3-tetramethylisoindoline (4) or dibromoamine, 5,6-dibromo-1,1,3,3-tetramethylisoindoline (5) or the analogous bromonitroxides 6 and 7 with methyl acrylate gives the acrylate substituted tetramethylisoindoline amines 8 and 10 and nitroxides 12 and 14. Similarly, the reaction of the aryl bromides and dibromides 4-7 with methyl 4-vinylbenzoate gives the carboxystyryl substituted tetramethylisoindoline amines 9 and 11 and the analogous nitroxides 13 and 15. The carboxystyryl tetramethylisoindoline nitroxides demonstrate strongly suppressed fluorescence, which is revealed upon removal of the free radical by reduction or radical coupling.

Pyridazine derivatives. Part 39: Reactivity of 5-iodopyridazin-3(2 H)-ones in palladium-catalysed reactions

In the search for novel antiplatelet agents, convenient and efficient methods for the preparation of 2,5-disubstituted pyridazin-3(2 H)-ones are reported that utilise palladium-catalysed cross-coupling reactions. A post-coupling base-promoted isomerisation has been observed during Sonogashira alkynylation of 5-iodopyridazin-3(2 H)-ones ( 3 ) with 1-phenyl-2-propyn-1-ol. Variable amounts of phthalazinones were isolated as by-products during the Heck alkenylation of 3 . The usefulness of the hydroxymethyl fragment as a protecting group during the synthesis of 5-substituted pyridazin-3(2 H)-ones has been validated.

Synthesis and characterization of carbometallated palladacycles over 3-hydroxypropyltriethoxysilyl-functionalized MCM-41

Heterogeneous carbometallated palladacycle catalysts have been synthesized by treatment of palladation reagents with 3-hydroxypropyltriethoxysilane-incorporated MCM-41 (OH-M) under mild reaction conditions. Palladation over organo-functionalized MCM-41 and organo-functionalized silica has been performed and it was found that the spatial confinement induced by the pore walls of organo-functionalized MCM-41 forces the propyl group to cyclize in the presence of an electrophilic metal center which is found to be much lower in organo-functionalized silica. Optimization studies, including change in Pd concentration in solution, different palladation reagents in palladation reactions such as Li 2PdCl 4, Pd(OAc) 2, effect of base, palladation temperature, and different solvents (methanol, chloroform, and acetone used as reaction medium), have been performed over organo-functionalized MCM-41 for obtaining better results of palladation. A number of characterization techniques have been exploited to support the formation of a palladacycle complex inside the pores of mesoporous materials. The Heck alkenylation reaction, which is universally accepted as a sharpening stone of palladium catalysts, was set as a model reaction to evaluate the catalytic activity of all the catalysts investigated in this study. The heterogeneity of the catalyst has also been studied.