Intermediate Carbon Radical Research Articles

Nickel‐Catalyzed Cascade Cyclization‐Negishi Coupling of Redox Active Esters for the Synthesis of Pyrrolidines

AbstractWe have developed a Ni‐catalyzed cascade cyclization/Negishi‐coupling reaction for the formation of pyrrolidines and pyrrolidinones starting from N‐protected allylamines and acrylamides which contain a redox active ester group. The reaction provides two C−C bonds in a single operation and takes place with both alkylzinc and arylzinc bromides as nucleophiles. Activation of RAE by low valent Ni complexes involving a radical pathway followed by a fast cyclization of intermediate carbon radicals is proposed.

Nitrogen-Centered Radicals in Functionalization of sp2 Systems: Generation, Reactivity, and Applications in Synthesis

The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp2 moieties without prefunctionalization, allowing for faster and more streamlined synthesis. This Review addresses the generation, reactivity, and application of NCRs, including, but not limited to, iminyl, aminyl, amidyl, and aminium species. Contributions from early discovery up to the most recent examples have been highlighted, covering radical initiation, thermolysis, photolysis, and, more recently, photoredox catalysis. Radical-mediated intermolecular amination of (hetero)arenes can occur with a variety of complex amine precursors, generating aniline derivatives, an important class of structures for drug discovery and development. Functionalization of olefins is achievable in high anti-Markovnikov regioselectivity and allows access to difunctionalized structures when the intermediate carbon radicals are trapped. Additionally, the reactivity of NCRs can be harnessed for the rapid construction of N-heterocycles such as pyrrolidines, phenanthridines, quinoxalines, and quinazolinones.

Molecular probes of the mechanism of cytochrome P450. Oxygen traps a substrate radical intermediate

The diagnostic substrate tetramethylcyclopropane (TMCP) has been reexamined as a substrate with three drug- and xenobiotic-metabolizing cytochrome P450 enzymes, human CYP2E1, CYP3A4 and rat CYP2B1. The major hydroxylation product in all cases was the unrearranged primary alcohol along with smaller amounts of a rearranged tertiary alcohol. Significantly, another ring-opened product, diacetone alcohol, was also observed. With CYP2E1 this product accounted for 20% of the total turnover. Diacetone alcohol also was detected as a product from TMCP with a biomimetic model catalyst, FeTMPyP, but not with a ruthenium porphyrin catalyst. Lifetimes of the intermediate radicals were determined from the ratios of rearranged and unrearranged products to be 120, 13 and 1 ps for CYP2E1, CYP3A4 and CYP2B1, respectively, corresponding to rebound rates of 0.9 × 10 10 s −1, 7.2 × 10 10 s −1 and 1.0 × 10 12 s −1. For the model iron porphyrin, FeTMPyP, a radical lifetime of 81 ps and a rebound rate of 1.2 × 10 10 s −1 were determined. These apparent radical lifetimes are consistent with earlier reports with a variety of CYP enzymes and radical clock substrates, however, the large amounts of diacetone alcohol with CYP2E1 and the iron porphyrin suggest that for these systems a considerable amount of the intermediate carbon radical is trapped by molecular oxygen. These results add to the view that cage escape of the intermediate carbon radical in [Fe IV–OH R] can compete with cage collapse to form a C–O bond. The results could be significant with regard to our understanding of iron-catalyzed C–H hydroxylation, the observation of P450-dependent peroxidation and the development of oxidative stress, especially for CYP2E1.

Theoretical calculations of carbon-oxygen bond dissociation enthalpies of peroxyl radicals formed in the autoxidation of lipids.

Theoretical calculations were carried out to provide a framework for understanding the free radical oxidation of unsaturated lipids. The carbon[bond]hydrogen bond dissociation enthalpies (BDEs) of organic model compounds and oxidizable lipids (R[bond]H) and the carbon[bond]oxygen bond dissociation enthalpies of peroxyl radical intermediates (R[bond]OO*) have been calculated. The carbon[bond]hydrogen BDEs correlate with the rate constant for propagation of free radical autoxidation, and the carbon[bond]oxygen BDEs of peroxyl radicals correlate with rate constants for beta-fragmentation of these intermediates. Oxygen addition to intermediate carbon radicals apparently occurs preferentially at centers having the highest spin density. The calculated spin distribution therefore provides guidance about the partitioning of oxygen to delocalized carbon radicals. Where the C[bond]H BDEs are a function of the extent of conjugation in the parent lipid and the stability of the carbon radical derived therefrom, C[bond]OO* BDEs are also affected by hyperconjugation. This gives way to different rates of beta-fragmentation of peroxyl radicals formed from oxygen addition at different sites along the same delocalized radical. We have also studied by both theory and experiment the propensity for benzylic radicals to undergo oxygen addition at their ortho and para carbons which, combined, possess an equivalent unpaired electron spin density as the benzylic position itself. We find that the intermediate peroxyl radicals in these cases have negative C[bond]OO* BDEs and, thus, have rate constants for beta-fragmentation that exceed the diffusion-controlled limit for the reaction of a carbon-centered radical with oxygen.

Hydroxylation of specifically deuterated limonene enantiomers by cytochrome p450 limonene-6-hydroxylase reveals the mechanism of multiple product formation.

The regiochemistry and facial stereochemistry of the limonene-6-hydroxylase- (CYP71D18-) mediated hydroxylation of the monoterpene olefin limonene are determined by the absolute configuration of the substrate. (-)-(4S)-Limonene is hydroxylated at the C6 allylic position to give (-)-trans-carveol as the only product, whereas (+)-(4R)-limonene yields multiple hydroxylation products with (+)-cis-carveol predominating. Specifically deuterated limonene enantiomers were prepared to investigate the net stereospecificity of hydroxylation at C6 and the mechanism of multiple product formation. The results of isotopically sensitive branching experiments of competitive and noncompetitive design were consistent with a nondissociative kinetic mechanism, indicating that (4R)-limonene has sufficient freedom of motion within the active site of CYP71D18 to allow formation of either the trans-3- or cis-6-hydroxylated product. However, the kinetic isotope effects resulting from deuterium abstraction were significantly smaller than expected for an allylic hydroxylation, and they did not approach the intrinsic isotope effect. (4S)-Limonene is oxygenated with almost complete stereospecificity for hydrogen abstraction from the trans-6-position, demonstrating rigid orientation during hydrogen abstraction and hydroxyl delivery. The oxygenation of (4R)-limonene leading to the formation of (+/-)-trans-carveol is accompanied by considerable allylic rearrangement and stereochemical scrambling, whereas the formation of (+)-cis-carveol proceeds without allylic rearrangement and with nearly complete stereospecificity for hydrogen abstraction from the cis-6-position. These results demonstrate that a single cytochrome P450 enzyme catalyzes the hydroxylation of small antipodal substrates with distinct stereochemistries and reveal that substrate-dependent positional motion of the intermediate carbon radical (and, therefore, hydroxylation stereospecificity) is determined by active-site binding complementarity. Thus, epimerization and allylic rearrangement are not inherent features of these reactions but occur when loss of active-site complementarity allows increased substrate mobility.

Synthesis of New Biotin Derivatives

It is now established that the formation of C–S bonds during the conversion of dethiobiotin into biotin involves intermediate carbon radicals. To examine the behavior of dethiobiotin analogs that could lead to allylic and α-epoxyradicals, we have synthesized 4,5-dehydrodethiobiotins and the corresponding epoxides and 5,6-dehydrodethiobiotins. All these compounds have been labelled with 14C on the carboxyl group.

ChemInform Abstract: Reaction of Highly Methylated 2‐Methylenecycloalkyl Hydroperoxides with FeSO4/CuCl2. Remarkably Efficient 5‐endo‐trig or 6‐endo‐trig Cyclization of the Intermediate Carbon Radicals.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Reaction of Highly Methylated 2-Methylenecycloalkyl Hydroperoxides with FeSO4/CuCl2. Remarkably Efficient 5-endo-trigor 6-endo-trigCyclization of the Intermediate Carbon Radicals

Treatment of 1,3,3,4,4,5,5-heptamethyl-2-methylenecyclopentyl hydroperoxide, derived from a singlet oxygen ene reaction of 1,2,3,3,4,4,5,5-octamethylcyclopentene, with FeSO4/CuCl2 gave 1-chloro-2,2,3,3,4,4-hexamethylcyclopentyl methyl ketone in high yield, suggesting that the consecutive O−O and C−C bond fission is followed by a novel 5-endo-trig cyclization of the intermediate carbon radical to the activated C−C double bond. In the case of 1,3,3,6,6-pentamethyl-2-methylene-1-cyclohexyl hydroperoxide also, an efficient 6-endo-trig cyclization of the corresponding carbon radical was realized giving 1-chloro-2,2,5,5-tetramethylcyclohexyl methyl ketone in high yield.

Radical cyclization on solid support: Synthesis of γ-butyrolactones

Synthesis of γ-butyrolactones using radical cyclization on solid-phase has been achieved. Polymer-supported β-bromoethylacetals were treated with tributyltin hydride in the presence of a catalytic amount of α, α′-azobisisobutyronitrile to generate intermediate carbon radicals which cyclize onto the intramolecular carbon-carbon double bond. The cyclization products were released by Jones oxidation from resin to give γ-butyrolactones in good yields. Radical cyclization of bromoacetals on solid phase gave cyclic acetals which were cleaved from the solid phase by Jones oxidation to release γ-butyrolactones in good yields. [Display omitted]

Byproduct identification and mechanism determination in plasma chemical decomposition of trichloroethylene

Plasma chemical behavior of trichloroethylene (TCE) was investigated with a packed-bed ferroelectric pellet reactor and a pulsed corona reactor. Volatile byproducts were identified by gas chromatography and mass spectrometry (GC-MS), and it was shown that reactor type, TCE concentration, flow rate, background gas, and moisture affected TCE decomposition efficiency and product distribution. Byproduct distributions in nitrogen and the negative effect of oxygen and moisture on TCE decomposition efficiency show that TCE decomposition proceeds via initial elimination of chlorine and hydrogen atoms, the addition of which to TCE accelerates its decomposition. Active oxygen species like OH radical is less likely involved in the initial step of TCE decomposition in plasma. Triplet oxygen molecules (/sup 3/O/sub 2/) scavenge intermediate carbon radicals derived from TCE decomposition to give much lower yields of organic byproducts.

Addition Reaction of Phenylphosphines to Styrenes as the Model of Polyaddition. Study on the Rate-Determining Step and Substituent Effect

The addition reactions of phenylphosphine or diphenylphosphine to styrenes or α-methylstyrene were carried out to know the reaction mechanism and the transition state of the addition reaction. Phenylphosphine having two reactive hydrogens added to two styrenes, and the 1:2 adduct [φCH2CH2P(φ)CH2CH2φ] of the anti-Markownikoff’s structure was obtained in a 94% yield. But, a little amount of the by-product containing styrene-styrene unit was produced as compared with the reaction of thiophenol to styrene. Such a side reaction was suppressed by using α-methylstyrene instead of styrene. The kinetics of the addition reaction of the P-H group to the vinyl group was investigated in detail by the addition reaction of diphenylphosphine to styrene, to give scarcely by-product. The rate-determining step of the reaction was the chain transfer step between the intermediate carbon radical (φĊHCH2Pφ2) and diphenylphosphine. In the para substituent effect of styrenes on the chain transfer step, fairly good linear correlation was obtained with modified Hammett’s equation including the resonance effect. The rate-determining step and the substituent effect on this reaction were found to be similar to those of the addition reaction of thiophenol to styrenes. The results were also compared with the polyaddition of phenylphosphine to 1,4-divinylbenzene or 1,4-diisopropenylbenzene.

Kinetics of the Addition Reactions of Thiobenzoic Acids to Styrenes or Ethynylbenzenes as the Model of Polyaddition. Study on the Rate-Determining Step and Substituent Effect

The reaction mechanism and substituent effect on the addition reaction of thiobenzoic acid to styrene or ethynylbenzene were investigated in detail. Both addition reactions proceeded by a radical chain mechanism, and the rate-determining step was the chain transfer step between each intermediate carbon radical [φĊHCH2SC(=O)φ or φĊ=CHSC(=O)φ] and thiobenzoic acid. The substituent effect on the chain transfer step between the para-X substituted intermediate carbon radicals and para-Y thiobenzoic acids in the styrene and ethynylbenzene systems was better correlated by the modified Hammett’s equation considering resonance effect than by the simple Hammett’s equation. In both styrene and ethynylbenzene systems, the reaction constant ρ for p-X intermediate carbon radicals was negative, and that for p-Y thiobenzoic acids was positive, suggesting that a perturbation between SOMO of each intermediate carbon radical and LUMO of thiobenzoic acid in the transition state is the important controlling factor for reactivity in the adduct formation of thiobenzoic acid with styrene or ethynylbenzene. That is, the intermediate carbon radicals are nucleophilic. Therefore, the overall reaction rate of the adduct formation increases by introducing a strong electron-donating (+I) group into the para position of styrene or ethynylbenzene and a large −I group into the para position of thiobenzoic acid. The results are compared with those of the addition reaction of thiophenol to styrene or ethynylbenzene. The polyaddition mechanism of 1,4-benzenebiscarbothioic acid to 1,4-divinylbenzene or 1,4-diethynylbenzene is discussed.

Novel Conjugated Polymer Containing Anthracene Backbone: Competitive Addition Polymerization of Dithiol Monomers to Diethynyl Monomers and Relative Reactivity

Competitive addition polymerizations of 9,10-anthracenedithiol, 4,4′-biphenyldithiol, and 1,4-benzenedithiol to 9,10-diethynylanthracene, 4,4′-diethynylbiphenyl, and 1,4-diethynylbenzene were carried out in THF at 50°C by UV irradiation under nitrogen atmosphere, and the relative reactivities of the monomers are discussed on the basis of composition analysis for the obtained polymers. To the dithiol monomers, the relative reactivities of diethynyl monomers are in the order of 9,10-diethynylanthracene>4,4′-diethynylbiphenyl>1,4-diethynylbenzene. The relative reactivities of dithiol monomers to the diethynyl monomers are in the order of 9,10-anthracenedithiol>4,4′-biphenyldithiol>1,4-benzenedithiol. These results indicate that the more the monomer conjugation, the higher is the relative reactivity. The high reactivities of anthracene derivatives would be caused from stabilization of the intermediate carbon radical and thio radical by its high conjugation system.

ChemInform Abstract: Invention of New Reactions Useful in the Chemistry of Natural Products

The design of new Radical chain reactions useful in the synthesis or modification of Natural Products is discussed. Such reactions can give good yields, and show a selectivity which complements perfectly the ionic reactions in more general use. A flexible system for the production of many kinds of carbon radicals has been invented. It should be applicable for the generation of other kinds of radicals based on elements other than carbon. In the design of these reactions a vital role is played by a disciplinary group (usually the thiocarbonyl group), an idea which is of general application in the invention of radical chain reactions. In a final section a new synthesis of pyrroles is described which is specially designed (by S.Z.Z) for intermediates in the preparation of porphyrins. New reactions useful in synthesis are usually discovered by accident. It is, however, possible to invent reactions by conception (ref. 1). Most of this article is devoted to the invention of new radical chain reactions to give good yields of products. This can be done with the aid of the disciplinary group concept (vide infra). Radical reactions have, of course, an enormous importance in the synthesis of polymers. However, we are concerned here with their use in the chemical synthesis of homogeneous, low molecular weight molecules. In this area of scientific research, radical reactions are not often used, because they are considered to be unselective and to give poor yields of products. It is the purpose of this article to show that well designed radical reactions can give high yields of single products and play an important role in organic synthesis. Radicals react with various functional groups at very different rates which can vary over many powers of ten. By a judicious choice of reagents, solvents etc.. • one can devise a system capable of effecting a highly selective transformation. Radical—radical interactions however (coupling, disproportionation etc...) are extremely fast processes and therefore much more difficult to control. If the sequence of radical reactions is conceived so as to constitute a linear chain process where the propagating steps are so fast that the concentration of radical species remains very small, radical—radical interactions can be largely avoided. Under such controlled conditions, clean high yielding reactions become possible. Moreover radical and radical chain reactions have several advantages over conventional ionic processes : neutral conditions; lower steric effects; lower polar effects; lower tendancy to unwanted elimination reactions; tolerance of many functional groups that have to be protected in ionic chemistry. In ionic reactions s—elimination is a serious problem in the carbohydrate and amino— glycoside antibiotic fields. These important compounds are heavily functionalised and selective deoxygenation or deamimation presented a challenging problem. We shall first consider the problem of deoxygenation. Many years ago, Van der Kerk (ref. 2) discovered accidentally the facile reduction of alkyl halides by stannanes. The mechanism involved is that of a typical radical chain reaction. The stannyl radicals, generated photochemically, thermally or by a chemical initiator (e.g. azoisobutyronitrile — A.I.B.N.) abstract the halogen to give a carbon radical. This latter abstracts a hydrogen atom from the hydride to give the alkane and a stannyl radical, thus propagating the chain (Scheme 1). This reaction has developed 675 676 D. H. R. BARTON AND S. Z. ZARD into a useful synthetic tool, not only for reducing halides but also for making carbon—carbon bonds by interception of the intermediate carbon radical.

Invention of new reactions useful in the chemistry of natural products

Abstract

Rearrangements involving a C-nitroso group: formation of dialkylhydroxylamines and nitroxides

Photoaddition of a nitrosamine to α-pinene and 5-methylenebicyclo[2.2.1]heptene in acidified methanol solution gave the tertiary nitrosoalkanes derived from 1.2-addition across the double bonds in the latter case and from addition involving cyclobutane ring opening in the former case. Under the reaction conditions, these tertiary nitrosoalkanes underwent a rearrangement involving the C-nitroso-group and a labile pair of proximate π or σ electrons to form bridged bicyclic hydroxylamines. These hydroxylamines are easily oxidized by air to the corresponding nitroxide radicals; one of them is stable enough to be purified. Using bromotrichloromethane as solvent, the intermediate carbon radical in the photoaddition to 5-methylenebicyclo[2.2.1]heptene can be trapped to give a good yield of bromotricyclane derivatives.

Photooxidation reaction of naphthaldehyde

Potential sweep method applied on 1-naphthaldehyde and 2-naphthaldehyde suggested formation of intermediate carbon radicals with elimination of hydrogen from the aldehyde bonded to the 1-position and 2-position, respectively, of the naphthalene ring. Measuemtent, however, was not feasible because of the extreme brevity of life-time of the carbon radicals formed in the course of the electrolytic oxidation but the observed carbon cation pointed to the difference existing between the Ep of 1-naphthalene and that of of 2-naphthalene. Photochemical reaction was introduced to elucidate the behavior of naphthaldehyde, and confirmation of the carbon radicals was made by electron spin resonance (ESR) spectroscopy. To further probe into the oxidation mechanism of naphthaldehyde in the photooxidation reaction, its mixture with hydrogen peroxide was exposed to ultraviolet ray, and while the ESR spectra were examination for carlbon radical behavior, the oxidation was examined with reference to their infrared spectra. The results suggested the following to be the most probable oxidation reaction mechanism for 1-naphthaldehyde and 2-naphthaldehyde.[chemical formula]