Radical Ring Closure Research Articles

The xanthate route to tetralones, tetralins, and naphthalenes. A brief account.

The present account summarises routes to tetralones, tetralines, and naphthalenes based on the chemistry of xanthates developed in the authors' laboratory. The degenerative reversible transfer of xanthates allows radical addition even to unactivated, electronically unbiased alkenes, and tolerates a broad range of functional groups, in particular common polar groups such as esters, ketones, nitriles, amides, carbamates, etc. Xanthates also allow radical ring closures onto aromatic rings. This feature, in combination with the intermolecular addition to alkenes, can be used to construct tetralones and tetralines. With the appropriate appendages, the former can be converted into napthalenes with a variety of substitution patterns. This translates into a convergent approach to a vast array of building blocks of interest to the pharmaceutical and agrochemical industries, and to material sciences.

Visible-light-induced cascade radical ring-closure and pyridylation for the synthesis of tetrahydrofurans

A novel visible-light-enabled alkoxy radical ring-closure and pyridylation from N-alkenyloxypyridinium salts was achieved under metal-free mild conditions, offering a powerful synthetic tool for assembling various pyridine-tethered tetrahydrofurans.

Regioselective Radical Ring Closure of Tertiary Enamides to the Synthesis of Trifluoroethyl‐containing N‐Acyl Isoindoline and N‐Acyl Tetrahydroisoquinoline Derivatives

AbstractThe regioselectivity of radical addition and cyclization reaction of tertiary enamides between 5‐membered benzoyl group and 5/6/7‐membered benzyl group ring closure was investigated, and trifluoroethyl ‐containing N‐Acyl isoindolines, N‐acyl tetrahydro‐isoquinolines, and N‐benzoyl tetrahydro‐1H‐benzo[c]azepine were obtained in moderate to good yields with high atom economy. Possible reaction pathway for the formation of the products was also discussed in this paper.magnified image

Synthesis of the Tetracyclic ABCD Ring Domain of Calyciphylline A-Type Alkaloids via Reductive Radical Cyclizations.

A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

The atmospheric oxidation mechanism and kinetics of 1,3,5-trimethylbenzene initiated by OH radicals – a theoretical study

The atmospheric fate of 1,3,5-trimethylbenzene is determined by OH-radical addition, and subsequent bicyclic peroxy radical ring closure and ring breaking pathways.

Inorganic Cyanide as Protecting Group in the Stereospecific Reconstitution of Vitamin B12 from an Artificial Green Secocorrinoid.

The synthesis of vitamin B12 in four steps from an artificial green secocorrinoid is presented. The stereospecific reconstitution of the B-ring of the cobalamin involves a quantitative and rapid ligand-centered radical ring closure reaction leading first to a new B12 derivative with antivitamin activity that is subsequently converted to the natural product. Chemoselectivity in the one-electron reduction of the macrocycle was achieved by introducing inorganic cyanide as an axially coordinating protecting group of the otherwise reduction-sensitive CoIII-ion. The integrity of structure and function of the reconstituted natural product was unequivocally proven by single crystal structural analysis and a microbiological assay using Lactobacillus leichmannii.

Co(III)-Carbene Radical Approach to Substituted 1H-Indenes.

A new strategy for the catalytic synthesis of substituted 1H-indenes via metalloradical activation of o-cinnamyl N-tosyl hydrazones is presented, taking advantage of the intrinsic reactivity of a Co(III) carbene radical intermediate. The reaction uses readily available starting materials and is operationally simple, thus representing a practical method for the construction of functionalized 1H-indene derivatives. The cheap and easy to prepare low spin cobalt(II) complex [Co(II)(MeTAA)] (MeTAA = tetramethyltetraaza[14]annulene) proved to be the most active catalyst among those investigated, which demonstrates catalytic carbene radical reactivity for a nonporphyrin cobalt(II) complex, and for the first time catalytic activity of [Co(II)(MeTAA)] in general. The methodology has been successfully applied to a broad range of substrates, producing 1H-indenes in good to excellent yields. The metallo-radical catalyzed indene synthesis in this paper represents a unique example of a net (formal) intramolecular carbene insertion reaction into a vinylic C(sp(2))-H bond, made possible by a controlled radical ring-closure process of the carbene radical intermediate involved. The mechanism was investigated computationally, and the results were confirmed by a series of supporting experimental reactions. Density functional theory calculations reveal a stepwise process involving activation of the diazo compound leading to formation of a Co(III)-carbene radical, followed by radical ring-closure to produce an indanyl/benzyl radical intermediate. Subsequent indene product elimination involving a 1,2-hydrogen transfer step regenerates the catalyst. Trapping experiments using 2,2,6,6-tetra-methylpiperidine-1-oxyl (TEMPO) radical or dibenzoylperoxide (DBPO) confirm the involvement of cobalt(III) carbene radical intermediates. Electron paramagnetic resonance spectroscopic spin-trapping experiments using phenyl N-tert-butylnitrone (PBN) reveal the radical nature of the reaction.

Annulated and bridged tetrahydrofurans from alkenoxyl radical cyclization.

4-Pentenoxyl radicals sharing two or more carbon atoms with a cycloalkane cyclize in a predictable manner stereoselectively and regioselectively to afford in solutions of bromotrichloromethane cycloalkyl-fused or -bridged 2-bromomethyltetrahydrofurans in up to 95% yield. Stereoselectivity in alkenoxyl radical ring closures arises from cumulative steric effects. The substituent positioned the closest to the alkene carbon, which is being attacked by the oxygen radical, exerts the strongest stereodirecting effect. This principal inductor guides 5-exo-cyclization 2,3-trans- or 2,4-cis-selectively. The substituent located further from the attacked π-bond is the secondary inductor. A secondary inductor in the relative trans-configuration enhances stereodifferentiation by the primary inductor; a cis-configured secondary inductor decreases this effect. A secondary inductor is not able to overrule the guiding effect of a similar sized primary inductor. Intramolecular 4-pentenoxyl radical additions to a cyclohexene-bound exo-methylene group or to endocyclic double bonds proceed cis-specifically, as exemplified by synthesis of a diastereomerically pure bromobicyclo[2.2.1]heptyl-annulated tetrahydrofuran from the verbenylethyloxyl radical. According to theory, the experimental 2,3-cis-specificity in alkoxyl radical cyclization to an endocyclic π-bond arises from strain associated with the 2,3-trans-ring closure.

Carbon radical attack on a pyrimidine nitrogen. An unusual entry into polycyclic aminopyrimidones.

Unprecedented examples of a synthetically useful radical ring closure onto a pyrimidine nitrogen leading to novel, highly functionalized bi- and tricyclic pyrimidone structures are reported. An unexpected hydrogen atom translocation prior to the cyclization step was observed in some cases.

The kinetics of carbonyl radical ring closures

Kinetic data for intramolecular homolytic substitution reactions of a series of acyl and oxyacyl radicals are reported.

The kinetics of alkyl radical ring closures at selenium: formation of selenane

Intramolecular homolytic substitution reactions of 5-(alkylseleno)pentyl radicals 4 have been investigated by competition kinetics as well as computational techniques.

ChemInform Abstract: Recent Highlights in Ketenimine Chemistry

AbstractReview: 92 refs.

Total Synthesis of (–)-Lycoposerramine-S

Key words lycoposerramine-S - azomethine ylides - 1,3-dipolar cycloaddition

Reconstitution of the B12Macrocycle by Radical Ring Closure of a Blue Secocorrin

A radical B12 synthesis: A recently described blue 7,8-secocorrinoid, a degradation product of vitamin B12, has a remarkable structural predisposition for ring closure. Reductive reconstitution of the corrin macrocycle by means of a stereospecific radical reaction leads to a 7-epicobalamin. Human B12-binding proteins bind this vitamin B12 analogue significantly less strongly than natural cobalamins.

Inside Back Cover: Reconstitution of the B12Macrocycle by Radical Ring Closure of a Blue Secocorrin (Angew. Chem. Int. Ed. 27/2012)

Inside Back Cover: Reconstitution of the B₁₂Macrocycle by Radical Ring Closure of a Blue Secocorrin (Angew. Chem. Int. Ed. 27/2012)

Search for conical intersection points (CI) by Newton trajectories

Recently, valley–ridge inflection points on the potential energy surface for the ring opening of the cyclopropyl radical have been determined using Newton trajectories (NTs) [W. Quapp, J.M. Bofill, A. Aguilar-Mogas, Theor. Chem. Acc. 129 (2011) 803]. This Letter is the report about the utilization of NTs for the search for conical intersection (CI) points. These points play a main role in the understanding of intersections of different electronic surfaces which open the door for photochemical reactions. We explain the reason why Newton trajectories can find CI points, and report a CI seam on the CASSCF (3,3) surface of the allyl radical ring closure.

ChemInform Abstract: Microwave‐Assisted Radical Organic Syntheses.

AbstractReview: ca. 80 refs.

Microwave assisted radical organic syntheses

Applications of microwave (MW)-assistance to radical-mediated organic preparations and procedures are reviewed. Radical additions and cyclisations onto a wide range of acceptors benefited from the technique, as did organic halide reductions by tin hydrides and numerous cascade and sequential processes. Reaction times of chain processes initiated by AIBN were, in several cases, reduced to a few minutes. Regioselectivity in radical additions and ring closures was normally maintained under MW conditions, although stereoselectivities were usually poorer. MW methods have been developed for generation of C-, N-, O-, S- and P-centred radicals. As a result of this a notable number and diversity of heterocycles have been accessed. MW-methods have opened up several new and innocuous alternatives to toxic organotin reagents. Alkoxyamines smoothly release C-centred radicals and oxime ethers provide a variety of iminyl radicals on MW heating. In addition, several types of organo-element and organometallic precursors have yielded novel C-centred and hetero-radicals. To date applications of MW-assistance to homolytic processes are comparatively limited, but it is clear the alliance of the two holds a lot of promise.

Rules for Anionic and Radical Ring Closure of Alkynes

This work reexamined the stereoelectronic basis for the "favored attack trajectories" regarding the nucleophilic and radical cyclizations of alkynes. In contrast to the original Baldwin rules, the acute attack angle of a nucleophile leading to the proposed endo-dig preference for the formation of small cycles is less favorable stereoelectronically than the alternative obtuse trajectory leading to the formation of exo-dig products. For smaller cycles, this intrinsic stereoelectronic preference can be masked by the greater thermodynamic stability of the less strained endo-products. Unbiased comparison of competing cyclization attacks has been accomplished via dissection of the activation barrier into the intrinsic barrier and thermodynamic component via Marcus theory. Intrinsic barriers of thermoneutral reactions strongly favor exo-dig closures, in full accord with the greater magnitude of two-electron bond forming interactions for the obtuse trajectory. This analysis agrees very well with experimental observations of efficient 3-exo-dig and 4-exo-dig cyclizations predicted to be unfavorable by the Baldwin rules and with the calculated 3-exo-/4-endo-, 4-exo-/5-endo-, and 5-exo-/6-endo-dig selectivities in the cyclizations of carbon-, nitrogen-, and oxygen-centered nucleophiles. The generality of these predictions is confirmed by analogous trends for the related radical cyclizations where the stereoelectronically favorable exo-closures are also preferred kinetically, with a few exceptions where a large difference in product stability skews the intrinsic stereoelectronic trends.

ChemInform Abstract: Studies on the Intramolecular Competitive Addition of Carbon Radicals to Aldehydo and Alkenyl Groups.

Cyclizations of ω-formylalkyl radicals can provide an efficient route to the corresponding cycloalkanols. However, if an ω-vinyl group is present an alternative mode of cyclization exists, and there is competition between cycloalkanol and methyl cycloalkane formation (i.e. (C=O) n versus (C=C) m ). Cyclohexanol formation, (C=O) 6 , usually overwhelms any alternative process, but cyclopentanol and methylcyclopentane processes ((C=O) 5 and (C=C) 5 ) can be competitive. The latter process involves the well-studied 5-hexenyl radical ring closure, and hence by choice of a suitable substrate, where both modes of cyclization are optimal, we have obtained rate data for cyclopentanol (C=O) 5 formation in a direct-competition experiment. The value k c=O ≥9.6×10 5 s −1 is consistent with that obtained by Beckwith and Hay. The study has also helped to define some of the requirements for optimizing the formation of cycloalkanols