Cascade radical reaction of 2-alkynyl-substituted aryl radicals with aryl isothiocyanates: a novel entry to benzothieno[2,3-b]quinolines through alpha-(Arylsulfanyl)imidoyl radicals

The novel cascade radical reaction of 2-(phenylalkynyl)aryl radicals with 4-Y-phenyl isothiocyanates (Y = H, OMe, Me, Cl, CN) provides a useful one-pot protocol for the production of 8-Y-substituted (12) and/or 9-Y-substituted benzothieno[2,3-b]quinolines (11). The whole process entails primary formation of an alpha-(2-alkynylarylsulfanyl)imidoyl radical that undergoes smooth 5-exo-dig cyclization onto the alkynyl triple bond. The derived 1-phenylvinyl radical then exhibits six-membered cyclization onto the isothiocyanate ring, to give 11, and/or five-membered ipso-cyclization to an azaspiro intermediate, whose eventual rearrangement affords 12. The overall findings clearly showed that the relative proportion of the outcoming isomeric benzothienoquinolines 11 and 12 can be markedly affected by the nature of the original isothiocyanate substituent. Moreover, the findings also furnished the first chemical evidence that enhancing the electrophilic power of the employed radical can properly enhance the reactivity of aryl radicals toward isothiocyanates.     

Construction of fluorinated pyrazole derivatives via a one-pot tandem C–H insertion/electrophilic fluorination reaction

A series of 4-fluoro-pyrazole derivatives were synthesized in moderate to good yields via a one-pot tandem procedure involving an Rh₂(OAc)₄-catalyzed C–H insertion and an electrophilic fluorination with N-fluorobenzenesulfonimide (NFSI).     

Polymeric and polymer-ligated spirobicyclic zwitterionic Janovsky complexes

A novel approach to the synthesis of spirobicyclic Janovsky complexes is described. The complexes were prepared on silica and polystyrene polymeric supports as well as on a solution-borne poly(carbodiimide) polymer with 100% atom economy. A carbon-centered intramolecular de-aromatizing nucleophilic aromatic substitution ipso-cyclization mechanism describes the synthesis of these spirobicyclics. The molecules were characterized by solution and solid-state ¹H and ¹³C NMR, IR, and MS.     

Efficient and Divergent Synthesis of α‐Halogenated Amides and Esters by Double Electrophilic Activation of Ynamides

An efficient and modular entry to α‐halogenated amides and esters is reported. This reaction is based on an underestimated double electrophilic activation of ynamides sequentially involving highly reactive activated keteniminium and iminium ions. Upon simple reaction with HCl and an electrophilic halogenation reagent in the presence of water or an alcohol, a broad range of ynamides can be transformed, in a highly divergent manner, to α‐halo amides and esters with high efficiency and under mild conditions.     

Efficient and Divergent Synthesis of α-Halogenated Amides and Esters by Double Electrophilic Activation of Ynamides

An efficient and modular entry to α-halogenated amides and esters is reported. This reaction is based on an underestimated double electrophilic activation of ynamides sequentially involving highly reactive activated keteniminium and iminium ions. Upon simple reaction with HCl and an electrophilic halogenation reagent in the presence of water or an alcohol, a broad range of ynamides can be transformed, in a highly divergent manner, to α-halo amides and esters with high efficiency and under mild conditions.     

Electrophilic interaction of 2,3-allenoates with PhSeCl. An unexpected highly stereoselective synthesis of 3-phenylseleno-4-oxo-2(E)-alkenoates

We have previously reported an efficient synthesis of beta-phenylselenium-substituted butenolides via electrophilic cyclization of 2,3-allenoates with PhSeCl in aqueous MeCN. However, when 2,3-allenoates were treated with PhSeCl in MeCN, 3-phenylseleno-4-oxo-2(E)-alkenoates were formed unexpectedly. The addition of Li2CO3 improved the yield and the selectivity of the reaction. A possible mechanism involving a decomposition of selenate esters was proposed.     

Intramolecular C→N 1,3-Migration of Alkoxycarbonyl or Acetyl Group—Applications, Limitations and Mechanism

A new type of intramolecular electrophilic rearrangements involving the shift of alkoxycarbonyl or acetyl groups from a carbon atom to an N-anionic center is presented.     

Synthesis of dibenzo[g,p]chrysenes from bis(biaryl)acetylenes via sequential ICl-induced cyclization and Mizoroki-Heck coupling

We report a facile synthesis of functionalized dibenzo[g,p]chrysenes via initial ICl-promoted cyclization of bis(biaryl)acetylenes, followed by the Mizoroki-Heck coupling reaction. This new approach works well for various bis(biaryl)acetylenes to afford dibenzo[g,p]chrysenes bearing various functionalities. With substrates of one special type including 4'-methoxy-2-ethynylbiphenyls, we found that the ICl treatment led to ipso cyclization to give bicyclic spirocyclohexadienones. In the presence of MeOH/H2SO4, these spiroketone products undergo rearrangement to give 9-iodophenanthrenes through a selective 1,2-alkenyl migration. We prepared various 4'-methoxy-2-ethynylbiphenyl compounds to show the generalization of such an ipso cyclization and 1,2-alkenyl shift. This ipso-cyclization approach can be extended to the preparation of dibenzo[g,p]chrysenes.     

Counterintuitive kinetics in Tsuji-Trost allylation: ion-pair partitioning and implications for asymmetric catalysis

The kinetics of Pd-catalyzed Tsuji-Trost allylation employing simple phosphine ligands (L = Ar3P, etc.) are consistent with turnover-limiting nucleophilic attack of an electrophilic [L2Pd(allyl)]+ catalytic intermediate. Counter-intuitively, when L is made more electron donating, which renders [L2Pd(allyl)]+ less electrophilic (by up to an order of magnitude), higher rates of turnover are observed. In the presence of catalytic NaBAr'F, large rate differentials arise by attenuation of ion-pair return (via generation of [L2Pd(allyl)]+ [BAr'F]-) a process that also increases the asymmetric induction from 28 to 78% ee in an archetypal asymmetric allylation employing BINAP (L*) as ligand. There is substantial potential for analogous application of [M]n+([BAr'F]-)n cocatalysis in other transition metal catalyzed processes involving an ionic reactant or reagent and an ionogenic catalytic cycle.     

Bifunctionalized allenes. Part XXIV. Competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates leading to 2,5-dihydro-1, 2-oxaphospholes and 5,6-dihydro-2H-pyranes

Abstract

We report herein a study on the competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates involving 5-endo-trig and 6-endo-trig mode cyclizations. Reaction with electrophiles produces mixtures of the 2-(2-oxo-2,5-dihydro-1,2-oxaphosphol-5-yl)-alkanoates and (6-oxo-5,6-dihydro-2H-pyran-2-yl)-phosphonates by competitive electrophilic cyclization due to the participation of the neighboring phosphonate and carboxylate groups.     

Suzuki–Miyaura Coupling of (Hetero)Aryl Sulfones: Complementary Reactivity Enables Iterative Polyaryl Synthesis

Ideal organic syntheses involve the rapid construction of C?C bonds, with minimal use of functional group interconversions. The Suzuki–Miyaura cross‐coupling (SMC) is a powerful way to form biaryl linkages, but the relatively similar reactivity of electrophilic partners makes iterative syntheses involving more than two sequential coupling events difficult to achieve without additional manipulations. Here we introduce (hetero)aryl sulfones as electrophilic coupling partners for the SMC reaction, which display an intermediate reactivity between those of typical aryl (pseudo)halides and nitroarenes. The new complementary reactivity allows for rapid sequential cross‐coupling of arenes bearing chloride, sulfone and nitro leaving groups, affording non‐symmetric ter‐ and quateraryls in only 2 or 3 steps, respectively. The SMC reactivity of (hetero)aryl sulfones is demonstrated in over 30 examples. Mechanistic experiments and DFT calculations are consistent with oxidative addition into the sulfone C?S bond as the turnover‐limiting step. The further development of electrophilic cross‐coupling partners with complementary reactivity may open new possibilities for divergent iterative synthesis starting from small pools of polyfunctionalized arenes.     

Tandem gold(I)-catalyzed cyclization/electrophilic cyclopropanation of vinyl allenes

We have developed an expedient method for the synthesis of polycyclic compounds from propargyl acetates or vinyl allenes involving up to three Au(I)-catalyzed elemental steps: 3,3-rearrangement, metalla-Nazarov reaction, and electrophilic cyclopropanation. The reaction proceeds under very mild conditions and in short times. The mechanism has been studied by DFT computations.     

A DFT Study on the Molecular Mechanism of Additions of Electrophilic and Nucleophilic Carbenes to Non-Enolizable Cycloaliphatic Thioketones

The molecular mechanisms of addition of dihalocarbenes and dimethoxycarbene to thioketones derived from 2,2,4,4-tetrmethylcyclobutane-1,3-dione were examined on the basis of the DFT wb97xd/6-311g(d,p)(PCM) calculations. Obtained results demonstrated that the examined processes exhibit polar nature and in the case of electrophilic dichloro-, and dibromocarbenes are initiated by the attack of carbene species onto the sulfur atom of the C=S group. Remarkably, reactions involving more electrophilic carbenes (dichloro-, and dibromocarbene) proceeds via stepwise mechanism involving thiocarbonyl ylide as a transient intermediate. In contrast, analogous reactions with nucleophilic dimethoxycarbene occur via a single step reaction, which can be considered as the [2 + 1] cycloaddition reaction initiated by the attack onto the C=S bond. A computational study showed that difluorocarbene tends to react as a nucleophilic species and resembles rather dimethoxycarbene and not typical dihalocarbene species. Significantly higher reactivity of the thioketone unit in comparison to the ketone group, both present in 3-thioxo-2,2,4,4-tetramthylcyclobutanone molecule, was rationalized in the light of DFT computational study.     

Synthesis and some transformations of 2-(2-thienyl)naphtho[1,2-d]oxazole

Condensation of 1-amino-2-hydroxynaphthalene with thenoyl chloride in 1-methyl-2-pyrrolidinone medium afforded 2-(2-thienyl)naphtho[1,2-d]oxazole. The latter was brought into electrophilic substitution reactions like nitration, bromination, sulfonation, formylation, and acylation. The reactions proceeded via electrophilic attack at the 5-position of the thiophene ring, but the nitration and bromination occurred involving both the thiophene and naphthalene fragments.     

Alkylation of nucleic acids by the antitumor agent COMC

[reaction: see text]. Mass spectral data are presented indicating that the antitumor agent 2-crotonyloxymethyl-2-cyclohexenone (COMC) is capable of alkylating oligonucleotides via a mechanism involving an electrophilic exocyclic enone intermediate. Under physiological conditions, the exocyclic enone is likely the glutathionylated 2-exomethylenecyclohexenone. This supports a recent hypothesis that the antitumor activity of COMC arises from alkylation of nucleic acids and/or proteins critical to cell function and not from competitive inhibition of glyoxalase I by an adduct of COMC and glutathione.     

Asymmetric Michael reaction involving chiral imines/secondary enamines: stereocontrolled synthesis of 2,2-disubstituted tetrahydrothiophen-3-ones

[reaction: see text] The asymmetric Michael reaction involving a chiral imine derived from 2-methyltetrahydrothiophenone-3-one and enantiopure (R)-1-phenylethylamine with a variety of electrophilic alkenes furnished 2,2-disubstituted tetrahydrothiophenone-3-ones with good yields and excellent stereoselectivity.     

Diastereoselectivity of polar and radical couplings in electrophilic substitutions of rigid 2-lithio-N-methylpyrrolidines

N-Methyl trans-fused perhydroisoindolines substituted with a tributylstannyl group in the 2-position have been prepared and used as precursors of the corresponding alpha-aminoorganolithiums. The steric course of the reactions of these and other conformationally rigid organolithiums with various electrophiles is summarized and compared with the steric course of the unsubstituted analogs. A mechanistic rationale for the steric course of electrophilic substitutions of these organolithiums is discussed. Pathways involving both polar electrophilic substitutions and radical couplings were observed with different electrophiles.     

Regioselective synthesis of 1,5-diaryl-1H-imidazoles by palladium-catalyzed direct arylation of 1-aryl-1H-imidazoles

[reaction: see text] A variety of 1,5-diaryl-1H-imidazoles have been regioselectively synthesized by direct coupling of 1-aryl-1H-imidazoles with aryl iodides or bromides in DMF in the presence of CsF as the base and a catalyst precursor consisting of a mixture of Pd(OAc)2 and AsPh3. The data obtained in this synthetic study support a reaction mechanism involving an electrophilic attack of an arylpalladium(II) halide species onto the imidazole ring. Interestingly, some imidazole derivatives synthesized in this study have been found to exhibit significant cytotoxic activity against human tumor cell lines.     

Microwave-assisted regioselective N-alkylation of cyclic amidines

A simple and efficient methodology for regioselective alkylation of exocyclic nitrogen of cyclic amidines was developed by microwave-assisted heating in the presence of amines. Novel N-alkylated 3,4-dihydropyrazino[2,1-b]quinazolin-6-ones were prepared in good yields. The reaction occurred via a transamination (addition-elimination) process involving a first attack of the amine on the electrophilic carbon of the amidine function.     

C8-selective biomimetic transformation of 5,7-dihydroxylated flavonoids by an acid-catalysed phenolic Mannich reaction: Synthesis of flavonoid alkaloids with quercetin and (–)-epicatechin skeletons

We hereby report the biomimetic synthesis of three flavonoid alkaloids, namely 8-(2″-pyrrolidinon-5″-yl)quercetin, 6-(2″-pyrrolidinon-5″-yl)-(–)-epicatechin and 8-(2″-pyrrolidinon-5″-yl)-(–)-epicatechin. These known natural products were prepared via an acid-catalysed regioselective phenolic Mannich reaction involving the electrophilic attack of an N-acyliminium ion on the corresponding flavonoidal precursors. The products were purified by preparative HPLC. The reactions showed high C8-regioselectivity. The major isomers of the synthesized flavonoid alkaloids were further characterized in terms of their medicinal-chemical properties.