Heck Reaction Conditions Research Articles

Palladium-Promoted DNA-Compatible Heck Reaction.

Optimal conditions for palladium-promoted Heck reaction on DNA were developed with good to excellent conversions. Versatility with either DNA-conjugated styrene/acrylamide or aryl iodide and a broad substrate scope of the corresponding coupling partners were established. Furthermore, robustness of the Heck reaction conditions on single-strand DNA and feasibility for DNA-encoded library production were demonstrated.

Crystal structure of 13-(E)-(2-amino-benzyl-idene)parthenolide.

The title compound, C21H25NO3 [systematic name: (1aR,4E,7aS,8E,10aS,10bR)-8-(2-amino-benzyl-idene)-1a,5-dimethyl-2,3,6,7,7a,8,10a,10b-octa-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-9(1aH)-one], was synthesized by the reaction of parthenolide [systematic name (1aR,7aS,10aS,10bS,E)-1a,5-dimethyl-8-methyl-ene-2,3,6,7,7a,8,10a,10b-octa-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-9(1aH)-one] with 2-iodo-aniline via Heck reaction conditions. The mol-ecule is composed of fused ten-, five- (lactone), and three-membered (epoxide) rings. The lactone ring shows a flattened envelope-type conformation (r.m.s. deviation from planarity = 0.0477 Å), and bears a 2-amino-benzyl-idene substituent that is disordered over two conformations [occupancy factors 0.901 (4) and 0.099 (4)]. The ten-membered ring has an approximate chair-chair conformation. The dihedral angle between the 2-amino-benzyl-idine moiety (major component) and the lactone ring (mean plane) is 59.93 (7)°. There are no conventional hydrogen bonds, but there are a number of weaker C-H⋯O-type inter-actions.

Palladium-catalyzed olefin migration and 7-endo-trig cyclization of dehydroalanines

1,4- or 1,5-migration of a double bond of dehydroalanines under palladium catalysis is reported. The process occurred with several highly-substituted dehydroalanines under mild typical Heck reaction conditions. Although this was one of the first reports of a palladium-catalyzed 1,5-olefin migration, the outcome of the reaction was susceptible to the starting material. Mechanistically, the process involved a five- (1,4-migration) or six-membered ring (1,5-migration) organopalladium intermediate, which cleaved a C–N bond in an β-amino elimination process.

From α-Bromomethylbutenolide to Fused Tri(Tetra) Cyclic Dihydrofurandiones through Barbier Reaction-Heck Arylation Sequence.

A Barbier reaction–Heck arylation sequence from α-bromomethylbutenolide to fused tri and tetracyclic lactones has been developed. The first step involving a Barbier reaction enabled installing ortho-bromoaromatics in α-ylidene γ-lactones. The latter substrates were subjected to intramolecular Heck reaction conditions which selectively afforded 6,5,5 or 6,6,5 fused ring systems depending on the nature of the base employed.

Two efficient pathways for the synthesis of aryl ketones catalyzed by phosphorus-free palladium catalysts

Allylic alcohols, 1-buten-3-ol, 1-penten-3-ol and 1-octen-3-ol, reacted with aryl iodides (iodotoluene, 4-iodotoluene, 4-iodophenol and 4-iodanisole) under Heck reaction conditions to form corresponding saturated aryl ketones in one step. The same products were obtained in a two-step tandem reaction consisted of the Heck coupling of allylic alcohols with aryl iodides, followed by hydrogenation. Reactions were catalyzed by phosphorus-free palladium precursors modified with the menthol-substituted imidazolium chlorides. Formation of crystalline palladium nanoparticles, of the diameter up to 65nm, in the reaction mixture was evidenced by TEM.

Diastereoselective Intramolecular Heck Reaction Assisted by an Acetate Group: Synthesis of the Decahydrobenzofluorene Derivative Dasyscyphin E.

The first synthesis of antifungal sesquiterpene quinol dasyscyphin E was achieved starting from trans-communic acid. The process described involves the first diastereoselective synthesis of this type of compound by cyclization of an aryl bicyclosesquiterpene. The acid was efficiently transformed into a sesquiterpene synthon, which was converted into the corresponding bromoaryl sesquiterpene. The key step of synthetic sequence was the cyclization of the latter under Heck reaction conditions, which yielded the tetracyclic skeleton of the target compound with complete diastereoselectivity. The participation of an acetate group is decisive, both for the course of the Heck reaction and for the stereoselectivity of the process.

A New Mode of Operation of Pd-NHC Systems Studied in a Catalytic Mizoroki–Heck Reaction

Metal complexes bearing N-heterocyclic carbene (NHC) ligands are typically considered the system of choice for homogeneous catalysis with well-defined molecular active species due to their stable metal–ligand framework. A detailed study involving 19 different Pd-NHC complexes with imidazolium, benzimidazolium, and triazolium ligands has been carried out in the present work and revealed a new mode of operation of metal-NHC systems. The catalytic activity of the studied Pd-NHC systems is predominantly determined by the cleavage of the metal–NHC bond, while the catalyst performance is strongly affected by the stabilization of in situ formed metal clusters. In the present study, the formation of Pd nanoparticles was observed from a broad range of metal complexes with NHC ligands under standard Mizoroki–Heck reaction conditions. A mechanistic analysis revealed two different pathways to connect Pd-NHC complexes to “cocktail”-type catalysis: (i) reductive elimination from a Pd(II) intermediate and the release of...

Synthesis of a new class of bisheterocycles via the Heck reaction of eudesmane type methylene lactones with 8-bromoxanthines

The eudesmane-type methylene lactones (isoalantolactone, alantolactone, 4,15-epoxyisoalantolactone, 2′,2′-dichloro-4H-spiro[cyclopropane-1′,4-eudesma-11(13)-en-8β,12-olide], and alantolactone) react with 8-bromoxanthines (8-bromocaffeine, 8-bromotheobromine, 8-bromo-3-butyltheobromine, 8-bromotheophylline, 8-bromo-9-butyltheophylline) under Heck reaction conditions to produce the target (E)-13-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)eudesma-4(15),11(13)-dien-8β,12-olides and the subsequent endocyclic isomers - 11-(2,6-dioxo-2,3-dihydro-1H-purin-8-yl)-13-normethyleudecma-4(15)-7(11)-dien-8α,12-olides. It was revealed that the yield and product ratio depends on the reaction conditions and the structure of methylene lactone. The effectiveness of Pd(OAc)2–caffeine catalytic system has been demonstrated in this reaction. The electric eel acetylcholinesterase inhibitory activity of the eudecmanolide-xanthine hybrids was evaluated. Among the new type bisheterocycles compound 27 with butyl and 2-oxodecahydronaphtho[2,3-b]furan-3(2H)-ylidene)methyl substituents at C-7 and C-8 of the xanthine core showed moderate activity with IC50 value of 40 μM.

ChemInform Abstract: Palladium Catalyzed Mizoroki—Heck Reaction of Pyrimidin‐2‐yl Tosylates with Aromatic and Aliphatic Olefins.

Abstract Pyrimidin-2-yl tosylates which are successfully applied as the electrophiles instead of halides coupled with olefins via Pd(PPh3)2Cl2 catalyzed Mizoroki–Heck reaction conditions to give the corresponding C2-alkenyl pyrimidine derivatives with high β-regioselectivity. This protocol proves to be tolerant of various pyrimidin-2-yl tosylates as well as various olefins including styrene derivatives, aliphatic olefins (vinyl cyanide, methyl acrylate, ethyl acrylate, n-butyl acrylate, butyl vinyl ether, 1-hexene and 1-octene).

Dearomatized Alkylidene Dihydropyridines as Substrates for Mizoroki–Heck Cyclizations

4-Substituted pyridines linked to iodoarene groups with alkyl amide tethers can be converted to the corresponding alkylidene dihydropyridines by treatment with ethyl chloroformate and Et3N. Subsequent exposure to Pd-catalyzed Mizoroki–Heck reaction conditions results in efficient intramolecular cyclization at the exocyclic alkene to afford isoindolinone and oxindole derivatives. Asymmetric construction of 3,3-disubstituted oxindoles and isoindolinones has also been achieved. This work demonstrates the ability to utilize reactive pyridine anhydrobases in metal-catalyzed transformations and provides the basis for design of new approaches to important heterocyclic ring systems.

SYNTHETIC TRANSFORMATIONS OF SESQUITERPENE LACTONES. 9. SYNTHESIS OF 13-(PYRIDINYL)EUDESMANOLIDES

The reaction of isoalantolactone, a sesquiterpene α-methylidene-γ-lactone, with bromo(iodo)pyridines under the Heck reaction conditions gave 3-(pyridylmethylidene)-8а-methyldecahydronaphtho[2,3- b ]furan-2(3 Н )-ones and 3-(pyridylmethyl)-8а-methyloctahydronaphtho[2,3- b ]furan-2(4 Н )-ones, products of double bond migration. The yield and product ratio depended on the reaction conditions and the nature of halopyridine. The effectiveness of Pd(OAc) 2 –caffeine catalytic system was demonstrated in this reaction. How to Cite Patrushev, S. S.; Shakirov, M. M.; Shults, E. E. Chem. Heterocycl. Compd. 2016 , 52 , 165. [ Khim. Geterotsikl. Soedin. 2016 , 52 , 165.] For this article in the English edition see DOI 10.1007/s10593-016-1855-1

Palladium catalyzed Mizoroki–Heck reaction of pyrimidin-2-yl tosylates with aromatic and aliphatic olefins

Pyrimidin-2-yl tosylates which are successfully applied as the electrophiles instead of halides coupled with olefins via Pd(PPh3)2Cl2 catalyzed Mizoroki–Heck reaction conditions to give the corresponding C2-alkenyl pyrimidine derivatives with high β-regioselectivity. This protocol proves to be tolerant of various pyrimidin-2-yl tosylates as well as various olefins including styrene derivatives, aliphatic olefins (vinyl cyanide, methyl acrylate, ethyl acrylate, n-butyl acrylate, butyl vinyl ether, 1-hexene and 1-octene).

Synthetic transformations of sesquiterpene lactones 9.* Synthesis of 13-(pyridinyl)eudesmanolides

The reaction of isoalantolactone, a sesquiterpene α-methylidene-γ-lactone, with bromo(iodo)pyridines under the Heck reaction conditions gave 3-(pyridylmethylidene)-8а-methyldecahydronaphtho[2,3-b]furan-2(3Н)-ones and 3-(pyridylmethyl)-8а-methyloctahydronaphtho[2,3-b]-furan-2(4Н)-ones, products of double bond migration. The yield and product ratio depended on the reaction conditions and the nature of halopyridine. The effectiveness of Pd(OAc)2–caffeine catalytic system was demonstrated in this reaction.

Poly(benzyl ether) Dendrimers Functionalized at the Core with Palladium Bis(N-Heterocyclic Carbene) Complexes as Catalysts for the Heck Coupling Reaction.

Bis(imidazolylidene)palladium complexes 9-12 containing a sterically hindered aryl group (mesityl or 2,6-diisopropylphenyl) and a poly(benzyl ether) dendron as N-substituents of the NHC ligand are accessible up to the third generation by transmetalation of the corresponding silver complexes. Complexes 9-12 are soluble, active, and very stable catalysts under Heck reaction conditions. The NHC ligand appears to be stably coordinated to the Pd during catalysis. The catalytic activity increases with generation number, although irregularly. The palladium site is not significantly congested in the reaction solvent by the increasing size of the dendritic substituents, as corroborated by X-ray diffraction, fluorescence and DOSY-NMR spectroscopy, and MD simulation studies. This is a consequence of the conformational semiflexibility of the poly(benzyl ether) dendrons and the benzylic link between these dendrons and the N-heterocyclic ligands.

Crystal structure of (E)-13-(pyrimidin-5-yl)parthenolide.

The title compound, C19H22N2O3, {systematic name (1aR,4E,7aS,8E,10aS,10bR)-1a,5-dimethyl-8-[(pyrimidin-5-yl)-methylid-ene]-2,3,6,7,7a,8,10a,10b-octa-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-9(1aH)-one} was obtained from the reaction of parthenolide [systematic name (1aR,7aS,10aS,10bR,E)-1a,5-dimethyl-8-methyl-ene-2,3,6,7,7a,8,10a,10b-octa-hydro-oxireno[2',3':9,10]cyclodeca-[1,2-b]furan-9(1aH)-one] with 5-bromo-pyrimidine under Heck reaction conditions, and was identified as an E isomer. The mol-ecule possesses ten-, five- (lactone) and three-membered (epoxide) rings with a pyrimidine group as a substituent. The ten-membered ring displays an approximate chair-chair conformation, while the lactone ring shows a flattened envelope-type conformation. The dihedral angle between the pyrimidine moiety and the lactone ring system is 29.43 (7)°.

Synthesis of costunolide derivatives by Pd-catalyzed Heck arylation and evaluation of their cytotoxic activities

As part of pharmacological-phytochemical in- tegrated studies of medicinal plants from Indian flora, costunolide (1) was isolated as a major compound from Saussurea lappa, plant traditionally used in different Asian traditional medicine systems. To improve the efficacy of this natural product lead, a series of analogues have been synthesized by the coupling of various aryl iodides using the standard Heck reaction conditions and evaluated for their cytotoxic activities against human cancer cell lines. The results indicated that several of the analogues were effective against the tested cell lines compared to the parent compound costunolide. Among the tested com- pounds, 2c and 2j demonstrated good activity against Hela cell line while compounds 2d showed potent activity against DU-145 and MCF-7 cell lines, respectively. Graphical Abstract A series of costunolide derivatives have been synthesized by Pd(II)-catalyzed Heck reaction and were studied for their cytotoxic properties against the panel of human cancer cell lines (B-16, DU-145, Hela, A549, MCF-7).

Lossen Rearrangements under Heck Reaction Conditions

AbstractThe classical Lossen rearrangement converts activated hydroxamic acids to isocyanates that form numerous products upon their reaction with nucleophiles. We report a simple and highly efficient method of using Heck reaction conditions to initiate Lossen rearrangements of hydroxamic acids. In addition, Lossen rearrangements occur in the presence of palladium(II) acetate or triethylamine, components of the Heck reaction, alone. A potential mechanism is provided to explain this reactivity and these results show that Heck reactions and Lossen rearrangements occur under the same conditions and may provide new methods for facile initiation of Lossen rearrangements.magnified image

Facile and Simple Synthesis of N-Alkyl and N-Aryl 2-Benzazepines by Nucleophilic Heteroannulation

An efficient and practical synthesis of N-alkyl and N-aryl 2-benzazepine has been developed. The key steps involved in the synthesis were palladium-mediated Heck reaction followed by aza heterocyclic ring construction by nucleophilic heteroannulation. This four-step sequence synthetic protocol gave moderate to good yields for a wide range of substrates. Subsequently, functionalization of the synthesized compound was carried out under Heck and Suzuki reaction conditions.

(E)-13-(2-Bromo-phen-yl)micheliolide.

The title compound, C21H23BrO3 [systematic name: (3E,3aS,6Z,9R,9aS,9bS)-3-(2-bromo­benzyl­idene)-9-hy­droxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octa­hydro­azuleno[4,5-b]furan-2(9bH)-one] was prepared by the reaction of 1-bromo-2-iodo­benzene with micheliolide [systematic name: (3aS,R,9aS,9bS,Z)-9-hy­droxy-6,9-dimethyl-3-methyl­ene-3,3a,4,5,7,8,9,9a-octa­hydro­azuleno[4,5-b]furan-2(9bH)-one] under Heck reaction conditions. The title compound exhibits intra­molecular O—H⋯O hydrogen bonding between the hy­droxy group and the lactone ring O atom, forming a ring of graph-set motif S(6). The 2-bromo­phenyl group is trans to the lactone ring, indicating that this is the E isomer (geometry of the exocyclic C=C bond). The dihedral angle between the benzene ring of the 2-bromo­phenyl moiety and the mean plane of the lactone ring is 51.68 (7)°.

(E)-13-(4-Amino-phen-yl)parthenolide.

The title compound, C21H25NO3 [systematic name: (3aS,9aR,10aR,10bS,E)-3-[(E)-4-(4-amino­benzyl­idene)-6,9a-dimethyl-3a,4,5,8,9,9a,10a,10b-octa­hydro­oxireno[2′,3′:9,10]cyclo­deca­[1,2-b]furan-2(3H)-one] was obtained from the reaction of parthenolide [synonym: 4,5-ep­oxy­germacra-1(10),11(13)-dieno-12,6-lactone] with 4-iodo­aniline under Heck reaction conditions. It was identified as the E-isomer (conformation about the exocyclic methyl­idene C=C bond; the conformation about the C=C bond in the ten-membered ring is also E). The mol­ecule is built up from fused ten-, five- (lactone) and three-membered (epoxide) rings with a 4-amino­phenyl group as a substituent. The ten-membered ring displays an approximate chair–chair conformation, while the lactone ring has an envelope conformation with the C atom bonded to the ring O atom as the flap. The dihedral angle between the benzene ring of the 4-amino­phenyl moiety and the lactone ring mean plane is 23.50 (8)°. In the crystal, mol­ecules are linked via N—H⋯O hydrogen bonds, between the amine group and the lactone and epoxide ring O atoms, forming chains propagating along the b-axis direction. Adjacent chains are linked via C—H⋯O inter­actions, forming an undulating two-dimensional network lying parallel to the plane (001). The absolute structure of the mol­ecule in the crystal was confirmed by resonance scattering [Flack parameter = 0.03 (3)].