Intramolecular Heck Coupling Research Articles

Cascade Alkynyl Prins Cyclization and Aza-Michael Reaction: En Route to Regioselective Pyrano- and Isochromenoquinoline Scaffolds.

A metal-free, Lewis acid approach for the regioselective synthesis of dihydropyranoquinoline scaffolds has been unveiled. The methodology employs a cascade alkynyl Prins-aza-Michael reaction sequence to deliver the products in good to excellent yields. The strategy features mild reaction conditions, broad substrate scope, and high functional group tolerance. The protocol has been further extended to include isochromenoquinoline derivatives. The utility of the reaction lies in the synthesis of highly fused polycyclic N,O-heterocycles via intramolecular Heck coupling. Additionally, a Rh(III)-catalyzed annulation results in the formation of highly fluorescent pentacyclic ammonium salts in excellent yields. Photophysical studies reveal that these pentacyclic ammonium salts exhibit strong emission in the green region (500-550 nm).

1,4-Pd Migration-Enabled Synthesis of Fused 4-Membered Rings.

1,4-Palladium migration has been widely used for the functionalization of remote C-H bonds. However, this mechanism has been limited to aryl halide precursors. This work reports an unprecedented Pd0-catalyzed cyclobutanation protocol producing valuable fused cyclobutanes starting from cycloalkenyl (pseudo)halides. This reaction takes place via alkenyl-to-alkyl 1,4-Pd migration, followed by intramolecular Heck coupling. The method performs best with cyclohexenyl precursors, giving access to a variety of substituted bicyclo[4,2,0]octenes. Reactants containing an N-methyl or methoxy group give rise to fused azetidines or oxetanes, respectively, via the same mechanism. Kinetic and deuterium-labeling studies point to a rate-limiting C(sp3)-H activation step.

Exploring the Reactivity of Substituted [(Allyloxy)methyl]phosphonates in Cycloaddition and Coupling Reactions

AbstractThis paper describes the versatility of substituted [(allyl­oxy)methyl]phosphonates to open the way to the synthesis of original phosphonated molecules with heterocyclic architectures. In 1,3-dipolar cycloaddition reactions with nitrile oxides, nitrile imines, and nitrones, these [(allyloxy)methyl]phosphonates react as dipolarophiles to give, regioselectively, the corresponding isoxazolines, pyrazolines, and isoxazolidines. Transition-metal-catalyzed reactions, including inter- or intramolecular Heck coupling, provided access to cinnamyl- and indenyl-linked moieties and phosphonated benzo-fused oxacycles, respectively. Additionally, ring-closing metathesis reactions enabled the synthesis of 2,5-dihydrofurans with the phosphonate group at the anomeric position. In this work, 51 novel phosphorylated heterocyclic compounds, which may find significance in the pharmaceutical and agrochemical fields, were prepared.

Bis-benzofulvenes: Synthesis and Studies on Their Optoelectronic Properties.

We report the synthesis of bis-benzofulvenes and the studies on their optical and redox properties. Bis-benzofulvenes were achieved through the Pd-catalyzed intramolecular Heck coupling followed by Ni0-mediated C(sp2)-Br dimerization. Low optical and electrochemical energy gaps of 2.05 and 1.68 eV were achieved by tuning the substituent on the exomethylene unit and the aromatic ring. The observed trends in the energy gaps were compared, and the frontier molecular orbitals were visualized using the density functional theory.

Asymmetric Total Synthesis of (2E)-Macrolactin 3

AbstractAsymmetric total synthesis of (2E)-macrolactin 3 has been accomplished in a highly convergent manner utilizing our earlier developed tandem isomerization followed by C–O and C–C bond-forming reaction, Sharpless asymmetric dihydroxylation, and a late-stage intramolecular Heck coupling reaction. Comparison of the NMR spectra of the coupled product and thorough analysis of the 2D NMR data of the final compound led to the conclusion that the Z-double bond at C2 was isomerized during the coupling reaction.

A Short Synthesis of Ergot Alkaloids and Evaluation of the 5-HT1/2 Receptor Selectivity of Lysergols and Isolysergols.

Key transformations in a four-step synthesis of the ergot alkaloid scaffold include a novel cesium carbonate-mediated hydrogen autotransfer alkylation to generate the C(3)-C(4) bond and an intramolecular Heck reaction that directly establishes the C(9)-C(10) alkene of methyl lysergate. An ester reduction and a streamlined experimental procedure establish a readily scalable, expedient total synthesis of all four stereoisomers of lysergol and isolysergol, including the previously unknown (-)-lysergol, for pharmacological evaluation at 5-HT1A and 5HT2A,B,C receptors. A bicyclic scaffold is also characterized for the first time in the intramolecular Heck coupling.

Pd(0)-Catalyzed Intramolecular Heck reaction of 2/3-Aryl(amino)methyl-3/2-bromoindoles: Syntheses of 3,4-Benzo[c]-β-carbolines, Benzo[4,5]isothiazolo[2,3-a]indole 5,5-Dioxides, and 1,2-Benzo[a]-γ-carbolines.

One-pot synthesis of 3,4-benzo[c]-β-carbolines was achieved from 2-aryl(tosylamino)methyl-3-bromoindoles via 10 mol % Pd(OAc)2/PPh3-mediated intramolecular Heck coupling using K2CO3 as a base in DMF at 110 °C with concomitant aromatization through an elimination of tosylsulfinic acid. Under identical conditions, the isomeric 3-aryl(tosylamino)methyl-2-bromoindoles upon intramolecular Heck reaction furnished benzo[4,5]isothiazolo[2,3-a]indole 5,5-dioxides instead of the expected γ-carbolines. However, synthesis of the expected γ-carboline framework, 3-tosyl-6,9-dihydro-1,2-benzo[a]-γ-carbolines, could be achieved from 3-aryl(tosylamino)methyl-2-bromoindoles containing a mesitylene sulfonyl unit as a protecting group on the indole nitrogen.

Regioselective synthesis of arylsulfonyl heterocycles from bromoallyl sulfones via intramolecular Heck coupling reaction

Indoles, benzofurans and benzosultams endowed with arylsulfonyl groups were prepared in two steps from 2-bromoallyl sulfones. ortho-Halosulfonamides and ortho-iodophenol reacted with 2-bromoallyl sulfones in the presence of cesium carbonate to furnish products resulting from a formal vinylic substitution reaction. Palladium-catalyzed intramolecular Heck reaction of these adducts furnished sulfonylated indoles, benzosultams and benzofurans. Isomerization of the double bond participating in the Heck reaction under basic conditions led to the formation of two isomeric products in two cases. Conditions for selectively accessing each of the regioisomeric indoles were developed.

Microwave-assisted intramolecular reductive Heck in aqueous medium: Synthesis of 3,3′-Disubstituted heterocyclic compounds

Heterocyclic products have been accomplished using microwave-assisted [Pd]-catalyzed intramolecular reductive Heck coupling. The protocol found suitable in delivering indolines, oxindoles, and dihydrobenzofurans. Notably, the process was successful in sole aqueous medium and furnished the products bearing a quaternary carbon center.

Studies toward the synthesis of macrotermycin C: stereoselective construction of the acyclic skeleton of the aglycon.

The stereoselective construction of the acyclic skeleton of the aglycon of polyene macrolactam macrotermycin C has been achieved for the first time using a convergent strategy. The important features of this synthesis study include Evans methylation, Takai olefination, Sonogashira coupling followed by selective alkyne reduction, intermolecular Heck coupling, and Wittig olefination. Intramolecular Heck coupling has been tested for macrocyclization.

Synthesis of Diversely Functionalized 2 H-Chromenes through Pd-Catalyzed Cascade Reactions of 1,1-Dibromoolefin Derivatives with Arylboronic Acids.

In this work, an unprecedented synthesis of (2 H-chromen-2-ylidene)acetates and (2 H-chromen-2-ylidene)ethanones with controlled stereoselectivity via Pd-catalyzed cascade reactions of 3-(2-(2,2-dibromovinyl)phenoxy)acrylates or 3-(2-(2,2-dibromovinyl)phenoxy)enones with aryl boronic acids has been established. This protocol combines two C-C bond forming reactions (an intermolecular Suzuki coupling followed by an intramolecular Heck coupling) in one pot under the catalysis of the same catalyst. Compared with literature methods for the preparation of 2 H-chromene derivatives, it has advantages such as easily obtainable or commercially available substrates, diverse substitution pattern of products, simple procedure, and excellent stereoselectivity. Interestingly, this cascade reaction could distinguish the subtle difference of the electron-withdrawing capacity and the size of various functional groups and thus resulted in a different chemoselectivity. In addition, the utility of the (2 H-chromen-2-ylidene)acetate thus obtained was showcased by its facile transformation into the synthetically and photophysically significant 3 H-xanthen-3-one derivative.

Facile synthesis of 2-fluoroindenones via a Knoevenagel condensation/palladium-catalyzed annulation

An efficient synthesis of 2-fluoroindenones was developed starting from simple o-bromo-2-fluroethenones and aldehydes. This domino reaction involved Knoevenagel condensation and intramolecular Heck coupling cyclization. A variety of 2-fluoroindenones were generated in good to excellent yields.

Total Synthesis of Biselyngbyolide B and Its C21-C22 Z-Isomer.

Investigations toward the synthesis of the 18-membered macrolactone biselyngbyolide B (2) from a C1-C13 and a C14-C23 fragment are described. As a key reaction in the synthesis of the C1-C13 fragment, we used an asymmetric propargylation of chiral vinylketene silyl N, O-acetal 12. Access to a C14-C23 fragment featuring a skipped diene and a sensitive allyl alcohol function was initially attempted via reductive fragmentation of a pyran template. However, this ring opening on iodide 32 with t-BuLi led to dienynol 33 with a 21 Z double bond. With a silyl protecting group at 3-OH and by implementing an intramolecular Stille coupling for macrolactonization, the 21 Z-isomer of biselyngbyolide B (47) was obtained. For preparation of a C14-C23 fragment with the 21 E-configuration, a cross-coupling of vinylstannane 48 with 4-bromocrotonate (49) set the configuration of the two double bonds. Biselyngbyolide B (2) was then accessed by an intramolecular Heck coupling. In preliminary biological cytotoxicity assays, 2 turned out to be active, whereas the 21 Z-isomer 47 was much less active. The 3-OMEM analogue 40 was devoid of activity. These results support the notion that the side chain with the correct configuration is relevant for binding to the Ca2+-ATPase and the biological activity.

Microwave assisted domino heck cyclization and alkynylation: synthesis of alkyne substituted dihydrobenzofurans

Microwave assisted domino intramolecular Heck and Sonogashira coupling for the efficient synthesis of alkyne substituted dihydrobenzofurans is presented.

Synthetic Utility of Arylmethylsulfones: Annulative π-Extension of Aromatics and Hetero-aromatics Involving Pd(0)-Catalyzed Heck Coupling Reactions.

A straightforward and general method for the synthesis of annulated thiophene, dibenzothiophene, and carbazoles analogues has been achieved involving alkylation of 2-bromo-1-(phenylsulfonylmethyl)arene/heteroarene with arylmethyl bromides/heteroarylmethyl bromides using t-BuOK as a base in DMF, followed by Pd(0)-mediated intramolecular Heck coupling in the presence of K2CO3 in DMF at 80-140 °C. The attractive feature of this protocol is that a wide variety of π-conjugated heterocycles could be readily accessed by an appropriate choice of arylmethylsulfones and benzylic bromides.

Total Synthesis of Pestalotioprolide G and Putative Structure of Pestalotioprolide H.

A concise and convergent route for the stereoselective total synthesis of cytotoxic macrolides pestalotioprolides G and H has been developed for the first time. Intramolecular Heck coupling has been chosen to cyclize the 14-membered macrocycle. This synthetic study strongly suggests that the proposed structure of pestalotioprolide H may need to be corrected as the spectroscopic data on the synthesized molecule deviate from the values reported for the isolated natural product.

Stereoselective Total Synthesis of Bioactive Marine Natural Product Biselyngbyolide B.

A convergent strategy for the stereoselective total synthesis of biologically active marine natural product biselyngbyolide B has been developed. Key strategies of this synthesis include Jamison protocol of trans-hydroalumination/allylation for installation of C18-C23 olefin moiety and intramolecular Heck coupling for macrocyclization.

Identification of azepinone fused tetracyclic heterocycles as new chemotypes with protein kinase inhibitory activities

The design and synthesis of small tetracyclic heterocycles which bear two new regioisomeric 2-carboxyethyl-1H-pyrrole-annulated indoloazepinone scaffolds is described. An azepinone motif, which is inherent in the structures of many well studied protein kinase inhibitors, serves as prominent structural feature of the new compounds. Concise access to the new regioisomeric tetracyclic derivatives was accomplished through amide coupling of appropriate pyrrole and indole precursors followed by an intramolecular Heck coupling reaction of the intermediate amide conjugates. Preliminary evaluation of newly synthesized tetracyclic molecules against a panel of protein kinases indicated their inhibitory activities and revealed promising selectivity profiles. The new compounds displayed no significant antiproliferative activity against MCF-7 cancer cells. Interestingly, derivative 19a exhibited selective TAK1 kinase inhibitory activity and figures as a promising chemotype for the discovery of new TAK1 inhibitors.

Domino Oxidative [Pd]-Catalysis: One-Pot Synthesis of Fluorenones Starting from Simple Benzylamines and Iodo Arenes.

A domino [Pd]-catalysis for the efficient synthesis of fluorenones is presented. The overall reaction proceeds through the formation of a five membered Pd(II)-cycle via a highly regioselective ortho C(sp(2))-H activation(s) of simple benzylamine that combines with external iodo arenes to give ortho arylated products. Significantly, the reaction further activates the C(sp(3))-H and C(sp(2))-H (intramolecular oxidative Heck coupling) bonds to give tricyclic imine systems. Then the usual water workup affords the fused tricyclic ketones (fluorenones). Remarkably, this one-pot operation enabled the effective construction of two C-C to three C-C bonds.

Synthesis of Pyrazolo[5,1-a]isoquinolines and 8-Methylenepyrazolo[5,1-a]isoindoles via Regioselective C-C Coupling and Alkyne Hydroamination.

An efficient and convenient synthesis of pyrazolo[5,1-a]isoquinolines has been achieved via palladium-catalyzed Sonogashira coupling of terminal alkynes with 5-(2-bromophenyl)-1H-pyrazoles, in situ formed from the condensation of 1-(2-bromophenyl)buta-2,3-dien-1-ones with hydrazine hydrate, followed by 6-endo intramolecular alkyne hydroamination. More interestingly, 8-methylenepyrazolo[5,1-a]isoindoles, the regioisomer of pyrazolo[5,1-a]isoquinolines, could also be selectively synthesized from the same starting materials through an initial intermolecular hydroamination of terminal alkynes with 5-(2-bromophenyl)-1H-pyrazoles followed by a palladium-catalyzed 5-exo intramolecular Heck coupling reaction.