Intramolecular radical additions to pyridines

Intramolecular 6-exolendo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the alpha-, beta- and gamma-carbons of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether, ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation pathways. All attempts to effect 5-exolendo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane, tris(trimethylsilyl)germane and, in part, samarium(II) iodide can each be employed as mediators of the reaction.     

Microwave-enhanced ruthenium-catalysed atom transfer radical additions

The first monomode microwave-assisted atom transfer radical additions (ATRA) of carbon tetrachloride to various olefins were successfully performed, affording the adducts with almost quantitative yields in less than 10 min at 160 °C.     

Lanthanide Lewis acid-mediated enantioselective conjugate radical additions

[reaction: see text] Lanthanide triflates along with proline-derived ligands have been found to be efficient catalysts for enantioselective conjugate addition of nucleophilic radicals to enoates. N-Acyl oxazolidinones, when used as achiral additives, gave meaningful enhancements in the ees for the product.     

Diastereoselective tin-free tandem radical additions to 3-formylchromones

A tin-free tandem radical addition methodology onto 3-formylchromones is presented. This radical process yields functionalized chromone structures via two carbon-carbon bond-forming steps. These products contain up to three contiguous stereocenters with good to excellent dr's and yields.     

Vinylcyclopropylacyl and polyeneacyl radicals. Intramolecular ketene alkyl radical additions in ring synthesis

Treatment of a variety of substituted vinylcyclopropyl selenyl esters, e.g. 11, with Bu(3)SnH-AIBN in refluxing benzene leads to the corresponding acyl radical intermediates, which undergo rearrangement and intramolecular cyclisations via their ketene alkyl radical equivalents producing cyclohexenones in 50-60% yield. By contrast, treatment of conjugated triene selenyl esters, e.g. 32, with Bu(3)SnH-AIBN produces substituted 2-cyclopentenones via intramolecular cyclisations of their ketene alkyl radical intermediates. Under the same radical-initiating conditions the selenyl esters derived from o-vinylbenzoic acid and o-vinylcinnamic acid undergo intramolecular cyclisations producing 1-indanone and 5,6-dihydrobenzocyclohepten-7-one respectively in 60-70% yields. A tandem radical cyclisation from the alpha,beta,gamma,delta-diene selenyl ester 31 provides an expeditious synthesis of the diquinane 35 in 69% yield.     

Asymmetric radical additions using chiral 1,3-dioxolane-4-ones

Moderate facial selectivities are observed in additions of alkyl radicals to the chiral (c,d) olefin (2S)-2-tert-butyl-5-ethoxycarbonylmethylene-1,3-dioxolane-4-one 1. The following hydrogen abstraction from tributylstannane proceeds with excellent asymmetric stereocontrol, leading to two of four possible diastereoisomers with high diastereomeric excesses. Additions of chiral radicals obtained from (2R,5R)-5-alkyl-5-bromo-1,3-dioxolane-4-ones to ethyl acrylate show high asymmetric 1,3-induction.     

Cycloruthenated complexes as homogeneous catalysts for atom-transfer radical additions

Various cycloruthenated complexes were used as homogeneous catalysts for the atom-transfer radical addition of polyhalogenated compounds to several olefinic substrates. Yields obtained through conventional or microwave heating could reach high values (up to 98% with CBrCl₃ and 88% with CCl₄).     

Asymmetric radical additions of trialkylboranes to 2H-azirine-3-carboxylates

Asymmetric additions of alkyl radicals, generated from R3B, to chiral 2H-azirine-3-carboxylates offer a new entry to enantio-enriched aziridines, and proceed with high diastereoselectivity when using 8-phenylmenthol as chiral auxiliary.     

Pyrones to pyrans: enantioselective radical additions to acyloxy pyrones

This paper describes a highly site-, diastereo-, and enantioselective intermolecular radical addition/hydrogen atom transfer to hydroxypyrone pyromeconic and kojic acids. The methodology can be extended to the formation of chiral quaternary centers. The products obtained are densely functionalized pyran moieties. The products contain structural features amenable for the introduction of additional substituents.     

Differences in reactivity and selectivity between radical additions and cycloadditions

Alkenes and alkynes show one-bone-bond reactivity with radicals and two-bond reactivity with diazomethane.     

Reactions of dispiro[2.0.2.2]oct-7-ene. Electrophilic and free radical additions

Dispiro[2.0.2.2]oct-7-ene 1 was synthesized by debrominatioa of cis- and trans-7,8-dibromodispiro[2.0.2.2]octane 3a with LAH and by dechlorination of cis- and trans-7,8-dichlorodispiro[2.0.2.2]octane 3b with magnesium. Stepwise electrophilic additions to 1 of HBr, HI, Br₂ and Cl₂ were studied. The major products (and yields) from these reactions were: 7-bromodispiro[2.0.2.2]octane 2a (43%), 4-iodo-4,5-ethanospiro[2,3]hexane 4b (ca. 50%); trans-3a (40%); and cis-3b (20%). Free-radical addition of hydrogen bromide to 1 gave an 80% yield of 7-bromodispiro[2.0.2.2]octane 2a. At ?10°, hydroboration-oxidation of 1 was found to give mainly 7-hydroxydispiro[2.0.2.2]octane 2a in ca. 90% yield; at 25°, near equal amounts of 2c and 4-(2-hydroxyethyl) spiro[2.3]hex-4-ene 14 were obtained.     

Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide

In this work, mechanistic studies were performed to understand the SmI2/H2O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing gamma-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the alpha,beta-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J. Am. Chem. Soc. 2005, 127, 6544). Rate measurements support the preferred reduction of an acrylate or acrylamide by SmI2/H2O in the presence of an N-acyl oxazolidinone. In the absence of the N-acyl oxazolidinone, SmI2/H2O promotes dimerization of the acrylates, whereas the C=C bond of the acrylamides is reduced. In addition, coupling of the Pfp ester of Cbz-protected phenylalanine with an acrylamide leads only to reduction of the acrylamide and recovered ester, whereas the same coupling with the N-acyl oxazolidinone derivative provides the gamma-keto amides. These results imply that a pathway involving nucleophilic acyl substitution cannot take place and that a radical mechanism must be invoked to explain the C-C bond formation. We propose that the acrylate/acrylamide is reduced to a conjugated ketyl radical that adds to the exocyclic carbonyl group of the N-acyl oxazolidinone, activated through bidentate coordination to a lanthanide ion.     

Free radical additions to the C=O bond of formaldehyde

The reactions between formaldehyde and n-propyl radicals were studied at 333 and 363 K. Addition to the C=O bond was found to be several times faster than abstraction of the formyl hydrogen atom. With a TST estimate of log(A/dm³ mol^–1 s^–1)=7.9±0.5, 28.0±2.1 kJ mol^–1 was obtained for the activation energy of the addition reaction.

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- 333 363 . C=O . 28.0±2.1 ^–1 , lg(A/ ^{–1 –1})=7.9±0.5 .

     

Quantum mechanical study of regioselectivity of radical additions to substituted olefins

Regiochemical trends in the addition of free radicals to substituted olefins are investigated by different quantum chemical approaches with special reference to oxygen centered radicals. From a methodological point of view, density functional methods provide correct general trends but they do not reach quantitative accuracy, especially for intermediate complexes. More reliable results are obtained by single point post‐Hartree–Fock computations at density functional geometries. A number of test computations show that reoptimization of the geometry and computation of vibrational frequencies by correlated methods can be safely avoided. As a consequence, the overall computational approach has very reasonable computer costs. From a more chemical point of view, a careful analysis of computational results points out the significant role of anomeric and polar effects in tuning the common filicity of carbon centered radicals. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 675–691, 2000     

Stereochemistry of free radical additions of methanol and acetaldehyde to perfluorinated cycloalkenes

γ-Ray and peroxide-initiated additions of methanol and acetaldehyde to perfluorocyclo-butene (3), -pentene (4), and -hexene (5) gave mixtures of stereo-isomers in most cases. Stereospecific $\text{cis}$-addition of acetaldehyde to (5) occurs under γ-initiation. A simple ¹⁹F n.m.r. method is advanced to distinguish the geometric isomers.     

Theoretical study on peroxyl radical additions to methyl‐substituted ethenes

The electrophilic additions of hydroperoxyl (HO$_{2}^{\mbox{\mathversion{bold}$\cdot$}}$) and alkylperoxyl (RO$_{2}^{\mbox{\mathversion{bold}$\cdot$}}$) radicals to substituted ethenes were studied using the AM1 semiempirical molecular orbital (MO) methods at the self‐consistent field/unrestricted Hartree–Fock (SCF/UHF) level. Reactantlike transition states were predicted for the title additions. The reactivity of an alkylperoxyl radical toward ethenes was found to be decreased as the degree of methyl (Me) substitution on the alkyl group of the radical increased. The relative reactivity and regioselectivity in HO$_{2}^{\mbox{\mathversion{bold}$\cdot$}}$ additions to substituted ethenes was suggested to be SOMO (singly occupied)‐HOMO controlled. A good correlation was established between the activation enthalpy $(\Delta H_{f}^{\ast})$ for the studied additions and the Taft polar substituent constants (σ*) of RO$_{2}^{\mbox{\mathversion{bold}$\cdot$}}$. The Evans–Polanyi correlation between $\Delta H^{\mbox{\mathversion{bold}$\cdot$}}_{f}$ and $\Delta H^{\circ}_{r}$ was justified and the validity of the Hammond postulate was indicated. The calculated results were compared with the available experimental data. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 77: 761–771, 2000     

Electrophilic additions involving fluoronium ions. I. Fluoroxy additions to perfluoro-olefinic bonds

The fluoroxy addition of perfluoro-t-butyl hypofluorite to hexafluoro-propene leads predominantly (> 95%) to perfluoro-n-propyl perfluoro-t-butyl ether. The unique structural orientation of this perfluoro-n-propyl product is of interest because the products of fluoride ion addition reactions have previously been reported as perfluoroisopropyl derivatives. The results obtained in this study provide a simple experimental demonstration of electrophilic attack by the O-F group, leading to the addition of the fluoronium ion to the more nucleophilic unsaturated carbon atom.The same mechanism as for a perfluoro-α-olefin applies in fluoroxy addition to a perfluorovinyl ether. The perfluoro-t-butoxy group also adds predominantly (> 95%) to the terminal unsaturated carbon atom.