Regioselectively nucleus and/or side-chain fluorinated 2-(Phenanthryl)propionic acids by an effective combination of radical and organometallic chemistry

Regioselectively nucleus and/or side-chain fluorinated 2-(phenanthr-1-yl)- and 2-(phenanthr-2-yl)propionic acids 1-5 were prepared using phenanthren-1(2H)-ones 6a-c as key intermediates. Thus, ethyl 2-(fluorophenanthryl)propionates 11 were obtained in good yields by Reformatsky reaction of 6a-c with ethyl 2-bromopropionate followed by dehydratation and DDQ-promoted aromatization of the resulting beta-hydroxyesters. Side-chain alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 14 were obtained by bromine/lithium permutation of dihydrophenanthryl bromides 12a-c with butyllithium followed by quenching of the lithiated intermediates with methyl pyruvate or ethyl 3,3,3-trifluoropyruvate and subsequent DDQ-promoted aromatization. The alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 25 were prepared by reacting 8-bromo-1,3-difluorophenanthrene 24 with butyllithium for 10 seconds at -110 degrees C and subsequent addition of the suitable pyruvate to the lithiated intermediates. Alkyl 2-hydroxy-2-(phenanthr-2-yl)propionates 26 and 29 were suitably obtained by site-selective metalation of 1,3-difluorophenanthrene 28 and the bromophenanthrene 24, respectively, with LDA followed by quenching of the metalated intermediates with the suitable alkyl pyruvate. Fluorination of the above alpha-hydroxypropionates with DAST, followed by the alkaline hydrolysis, allowed the expected 2-(phenanthryl)propionic acids 1-5 to be obtained in satisfactory overall yields.     

First radical addition onto ketenimines: a novel synthesis of indoles

A novel radical-mediated synthesis of 2-alkyl indoles is described. The method is a nonchain process based on the intramolecular addition of benzylic radicals onto the central carbon atom of a ketenimine function, resulting in a 5-exo-dig cyclization.     

Synthesis of dihydrofurans containing trifluoromethyl ketone and heterocycles by radical cyclization of fluorinated 1,3-dicarbonyl compounds with 2-thienyl and 2-furyl substituted alkenes

Manganese(III) acetate based radical cyclization of various fluorinated 1,3-dicarbonyl compounds with 2-thienyl and 2-furyl substituted alkenes produced 3-trifluoroacetyl and 2-trifluoromethyl-dihydrofurans in good yields. The radical cyclizations of 2-methyl-5-[(E)-2-phenylvinyl]furan 2b and 2-[(E)-2-phenylvinyl]thiophene 2c led to the formations of 5-(5-methyl-2-furyl)-4,5-dihydrofuran and 5-(2-thienyl)-4,5-dihydrofuran, respectively. In the reactions of 1,3-dicarbonyls with alkenes, 2-thienyl substituted alkenes formed 4,5-dihydrofurans in higher yields than 2-furyl substituted alkenes.     

A highly selective Ir-catalyzed borylation of 2-substituted indoles: a new access to 2,7- and 2,4,7-substituted indoles

The selective CH-functionalization of 2-substituted indoles is presented. Using bis(pinacolato)diboron (2) in the presence of iridium complexes, a novel catalytic mono-borylation is observed preferentially at the 7-position of the indole. This allows for an efficient synthesis of various 2,7-di- and 2,4,7-trisubstituted indoles, which are otherwise difficult to access. The scope and limitation of the method is demonstrated.     

Topologically driven tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cages

Tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cage compounds is described. The aryl iodides 1 and N-tosyl propargylated amine 8 lead to oxa- and aza-cages, respectively, after two tandem 5-exo-trig radical cyclizations. The alcohols 11 on reaction with ⁿBu₃SnH and AIBN give rise to the oxa-cages 14 bearing the tributyltin moiety after three tandem 5-exo-trig cyclizations. On the other hand, reaction of the propargyl ether 16 under similar conditions furnishes the oxa-cage 17 by a 5-exo-trig, 4-exo-trig, 5-exo-trig tandem radical cyclization sequence.     

An Efficient Preparation of 2, 3-Disubstituted Indole Derivatives Induced by Low-valent Titanium

An efficient synthesis of 2, 3-disubstituted indole derivatives through low-valent titanium induced reductive cyclization of acylamido carbonyl compounds is described.     

Synthesis of fluoroacylated 4,5-dihydrofurans and fluoroalkylated tetrahydrofurans by the radical cyclization using manganese(III) acetate. Part II

Manganese(III) acetate-based radical cyclizations of various fluorinated 1,3-dicarbonyl compounds with alkenes produced 3-fluoroacylated 4,5-dihydrofurans and 2-acetyloxy-2-fluoroalkylated tetrahydrofurans in good yields. Mechanism was proposed for the formation of all compounds. The radical cyclization of fluorinated 1,3-dicarbonyls showed to form different cyclized products depending on the structure of alkenes and enol forms of 1,3-dicarbonyls.     

Novel synthesis of fused indoles and 2-substituted indoles by the palladium-catalyzed cyclization of N-cycloalkenyl-o-haloanilines

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline.     

Synthesis and characterization of fluorinated PEO-b-PDMS-b-fluorinated PEO by free radical addition

Fluorinated poly(ethylene oxide) propyl-b-polydimethylsiloxane-b-propyl fluorinated poly(ethylene oxide)(FPEO-b-PDMS-b-FPEO) was synthesized by a free radical addition of carbon-hydrogen of polyether segments of poly(ethylene oxide) propyl-b-polydimethylsiloxane -b-propyl poly(ethylene oxide)(PEO-b-PDMS-b-PEO) to hexafluoropropylene(HFP) using tert-butyl peroxypivalate as an initiator.In order to reduce the possibility of side reaction,the protection and deprotection via silylation were used for the end-...     

A novel approach to functionalized (E)-1,4-diaryl-1-butenes by Heck reaction and their applications for the construction of dibenzylbutyrolactone lignan skeletons by radical cyclization

A highly regio- and stereoselective [Pd(allyl)Cl]₂ catalyzed Heck reaction of aryl iodides and electronically neutral terminal olefins generated in situ by fluoride induced protiodesilylation of alkenylsilanol derivatives under mild conditions has been developed. The products, viz. terminally substituted styrenes and (E)-1,4-diaryl-1-butenes were obtained in very good yields. The dibenzylbutyrolactone lignan skeletons have been prepared employing two regio- and stereoselective Bu₃SnH-mediated radical cyclization routes.     

Synthesis and characterization of a new fluorinated polyether glycol prepared by radical grafting of hexafluoropropylene onto polytetramethylene glycol

A new fluorinated polyether glycol (PTMG-g-HFP) was prepared by radical grafting of hexafluoropropylene (HFP) onto polytetramethylene glycol (PTMG) in the presence of different initiators. The structure of PTMG-g-HFP was characterized by means of IR, ¹H NMR and ¹³C NMR. The effects of nature and amount of initiator, reaction time and reaction temperature on grafting HFP onto PTMG were investigated. The results showed di-tert-butyl peroxide (DTBP) was the most efficient in the reaction and the optimal reaction conditions were: [DTBP]₀/[PTMG]₀, 0.12; reaction temperature, 140 °C; reaction time, 6 h.     

Synthesis of cyclopropyl silyl ethers and their facile ring opening by photoinduced electron transfer as key step in radical/radical cationic cascade reactions

Various ring-fused cyclopropyl silyl ethers with an benzylic, olefinic or acetylenic side chain have been synthesized. Upon oxidative photoinduced electron transfer (PET) the cyclopropane ring opens and forms a reactive β-keto radical, which undergoes intramolecular cyclization. In some cases we observed only formation of ring opened non-cyclized products. With olefinic side chain 5-exo-trig mode of cyclization rather than 6-endo-trig mode of cyclization takes place whereas in case of acetylenic side chain we observed 6-endo cyclization.     

Regio- and stereoselective synthesis of methyl 5-methylenetetrahydropyran-3-carboxylates from Baylis-Hillman adducts via allyltributylstannane-mediated radical cyclization

Two types of regioisomeric methyl 5-methylenetetrahydropyran-3-carboxylate derivatives 3a-c and 6a-c were synthesized stereoselectively starting from the Baylis-Hillman adducts via the allyltributylstannane-mediated vinyl radical cyclization as the key step.     

Atom-transfer radical addition (ATRA) and cyclization (ATRC) reactions catalyzed by a mixture of [RuCl(2)Cp*(PPh3)] and Magnesium

A new catalytic procedure for atom-transfer radical addition (ATRA) and cyclization (ATRC) reactions is described. The combination of the ruthenium(III) complex [RuCl(2)Cp*(PPh3)] (Cp*: pentamethylcyclopentadienyl) with magnesium allows these reactions to be performed under mild conditions with high efficiency. In most cases, the catalyst concentrations required are significantly lower than those used in previously reported procedures. It is suggested that magnesium acts as a reducing agent that generates and regenerates the catalytically active ruthenium(II) species. The precatalyst [RuCl(2)Cp*(PPh3)] has been analyzed by X-ray crystallography.     

Facile syntheses of 3-trifluoromethylthio substituted thioflavones and benzothiophenes via the radical cyclization

3-CF3 S substituted thioflavones and benzothiophenes were achieved via the reactions of AgSCF3 with methylthiolated alkynones and alkynylthioanisoles,respectively,promoted by persulfate.This protocol possesses good functional group tolerance and high yields.Mechanistic studies suggested that a classic two-step radical process was involved,which includes addition of CF3 S radical to triple bond and cyclization with SMe moiety.     

Synthesis of trans-perhydroisoquinolines by 6-endo-trig radical cyclization of amino-tethered vinyl bromides and cyclohexenes

Bu₃SnH-promoted cyclization of several N-(2-bromoprop-2-enyl)-N-[(4-oxocyclohex-1-enyl)methyl]alkylamines is reported. It has been found that the generated vinyl radicals evolve through a 6-endo-cyclization pathway giving rise to the corresponding 4,6-functionalized perhydroisoquinolines in a prevalent trans-relative configuration.     

Synthesis of 2-fluorotetralones by oxidative radical cyclization of α-fluoroacetophenones and olefins

The oxidative radical cyclization of α-fluoroacetophenones in the presence of olefins offers an efficient access to 2-fluorotetralones. Fluorinated starting materials can be prepared from α-bromoacetophenones. The reaction was optimized with respect to a future application in the synthesis of 18-fluorine labeled compounds, where reaction times are a critical aspect.     

A coordinatively unsaturated ruthenium methoxide as a highly effective catalyst for the halogen atom-transfer radical cyclization of N-allyl dichloroacetamides and related reactions

Atom-transfer radical cyclization (ATRC) catalyzed by coordinatively unsaturated ruthenium alkoxides 4, [(η⁵-C₅Me₅)Ru(OR)]₂, is investigated, and ruthenium methoxide 4a (R=Me) is found to exhibit excellent catalytic activity for the cyclization of N-allyl-α,α-dichloroacetamides at ambient temperature. Addition of some amounts of two-electron donor ligands such as pyridine and triphenylphosphine improves the catalyst efficiency to afford the corresponding γ-lactams in high yields. The high catalytic activity of this catalyst system enables to control the diastereoselectivity of this 5-exo cyclization kinetically. The present 4a/pyridine system is also effective for the 4-exo cyclization of N-vinylacetamides to afford the corresponding β-lactams in quantitative yields. The 4a/pyridine system is also active towards the ATRP of methyl methacrylate (MMA) at room temperature to afford the poly(MMA) with narrow molecular weight distributions (M_w/M_n=1.2) at the initial stage.