Catalytic Synthesis of 8-Membered Ring Compounds via Cobalt(III)-Carbene Radicals

The metalloradical activation of o-aryl aldehydes with tosylhydrazide and a cobalt(II) porphyrin catalyst produces cobalt(III)-carbene radical intermediates, providing a new and powerful strategy for the synthesis of medium-sized ring structures. Herein we make use of the intrinsic radical-type reactivity of cobalt(III)-carbene radical intermediates in the [Co^II(TPP)]-catalyzed (TPP=tetraphenylporphyrin) synthesis of two types of 8-membered ring compounds; novel dibenzocyclooctenes and unprecedented monobenzocyclooctadienes. The method was successfully applied to afford a variety of 8-membered ring compounds in good yields and with excellent substituent tolerance. Density functional theory (DFT) calculations and experimental results suggest that the reactions proceed via hydrogen atom transfer from the bis-allylic/benzallylic C−H bond to the carbene radical, followed by two divergent processes for ring-closure to the two different types of 8-membered ring products. While the dibenzocyclooctenes are most likely formed by dissociation of o-quinodimethanes (o-QDMs) which undergo a non-catalyzed 8π-cyclization, DFT calculations suggest that ring-closure to the monobenzocyclooctadienes involves a radical-rebound step in the coordination sphere of cobalt. The latter mechanism implies that unprecedented enantioselective ring-closure reactions to chiral monobenzocyclooctadienes should be possible, as was confirmed for reactions mediated by a chiral cobalt-porphyrin catalyst.     

Synthesis of functionalised azecine and azonine derivatives via an enolate assisted aza Claisen rearrangement

This paper describes the synthesis of functionalised azecine and azonine derivatives incorporating the adrenaline motif. In a key step, an enolate assisted aza Claisen rearrangement was employed to interconvert from 6- and 5-membered heterocycles to their corresponding 10- and 9-membered lactams.     

Conformations of large cycloalkanes: Cyclooctadecane,cyclononadecane and cycloicosane

Summary The conformations of cyclooctadecane, cyclononadecane, and cycloicosane were generated by a stochastic program that works in conjunction with MM2. The shapes of the rings are analyzed in terms of previous work by Dale and others, and in terms of distributions of energies, torsion angle distributions, and torsion angle sequences. A new shape element called the nick has been discovered, and it seems to be increasingly important with 18-membered and larger rings. Previously suggested relationships between ring size and energy distribution were observed, and a geometrical explanation is provided for the relative distributions of stable conformations in 16-, 18-, and 20-membered rings.     

Evidence for an ortho specific loss of OH· in some aromatic aldoximes from examination of metastable peak shapes

The mechanism for loss of an OH radical from the molecular ions of the ortho substituted compounds 2-methyl-, 2-hydroxy-, 2-amino- and 2-methoxybenzaldoxime has been studied. It is inferred from the examination of the first field free region (composite) metastable peak shapes that two distinct mechanisms are operating. Based upon additional deuterium labelling experiments it is proposed that loss of OH involves both participation of the ortho substituent in the formation of a 5-membered heterocyclic ring and the formation of a protonated isocyanide type ion via a 3-membered ring transition state. Loss of OCH3 from the corresponding O-methyl ethers probably occurs by similar mechanisms. The formation of a 5-membered ring is also proposed to be the driving force for the loss of H2NO in the spectrum of 2-methoxybenzaldoxime.     

A Radical Cyclization Approach to Isoindolobenzazepines. Synthesis of Lennoxamine

The alkaloid lennoxamine (1) was synthesized by transannular cyclization of a 10-membered lactam obtained by intramolecular addition of an aryl radical to a (trimethylsilyl)acetylene. The isoindolo[1,2-b][3]benzazepine skeleton present in lennoxamine was also obtained by means of regioselective 7-endo-trig radical cyclization of methylenephthalimidines.     

Palladium acetate assisted synthesis of five-membered N-polyheterocycles

Abstract

The metal-assisted synthesis of heterocyclic compounds is known to be one of the extremely developing as well as significant concepts of organic chemistry. Because of their expensive, complex working of the instrument and difficult procedures, the methodologies used earlier for the heterocycle synthesis were less amicable to the researchers. The Pd(OAc)₂-mediated cyclic reactions have been recognized to be very effective for both the stereoselective as well as regioselective formation of the 5-membered N-bearing heterocyclic compounds. The different uses of palladium acetate, as a catalyst in the formation of 5-membered N-containing polyheterocycles, are covered in this review article.     

alpha-(Arylthio)imidoyl Radicals: [3 + 2] Radical Annulation of Aryl Isothiocyanates with 2-Cyano-Substituted Aryl Radicals

A novel cascade radical reaction is described involving aryl isothiocyanates and 2-cyanoaryl radicals. The mechanism entails the formation of an alpha-(arylthio)imidoyl radical, a 5-exo-dig cyclization onto a cyano group, and a final 6-membered ring closure of an iminyl radical. The competitive 5-membered spiro-cyclization of the iminyl, leading to an isomeric product, was only observed in the case of a disubstituted aryl isothiocyanate. The whole process involves a rare example of [3 + 2] radical annulation and allows the one-pot synthesis of tetracondensed nitrogen heterocycles in good yields.     

Sodium and potassium benzeneazophosphonate complexes with crown ethers: Solid-state microwave synthesis, characterization and biological activity

The eco-friendly synthesis, spectroscopic (IR, MS, ¹H and ¹³C NMR) study and biological (cytostatic, antiviral) activity of sodium and potassium benzeneazophosphonate complexes, obtained by reaction in the solid state under microwave irradiation of the alkali salts of ethyl [α-(4-benzeneazoanilino)-N-benzyl]phosphonic acid and [α-(4-benzeneazoanilino)-N-4-methoxybenzyl]phosphonic acid with crown ethers containing 18-membered (dibenzo-18-crown-6 and bis(4′-di-tert-butylbenzo)-18-crown-6), 24-membered (dibenzo-24-crown-8) and 30-membered (dibenzo-30-crown-10) macrocyclic rings, have been described. The simple work-up solvent free reaction is an efficient green procedure for the formation of mononuclear crown ether complexes in which the sodium/potassium ion is bound to oxygen atoms of the macrocycle and the phosphonic acid oxygen. The free crown ethers, alkali benzeneazophosphonate salts and their complexes were evaluated for their cytostatic activity in vitro against murine leukemia L1210, murine mammary carcinoma FM3A and human T-lymphocyte CEM and MT-4 cell lines, as well as for their antiviral activity against a wide variety of DNA and RNA viruses. The investigated compounds showed no specific antiviral activity, whereas all the free crown ethers and their complexes demonstrated cytostatic activity, which was especially pronounced in the case of bis(4′-di-tert-butylbenzo)-18-crown-6 and its complexes.     

Formation and decay of the ABTS derived radical cation: A comparison of different preparation procedures

Bleaching of a preformed solution of the blue‐green radical cation 2,2′‐azinobis (3‐ethylbenzothizoline‐6‐sulfonic acid) (ABTS^+·) has been extensively used to evaluate the antioxidant capacity of complex mixtures and individual compounds. The reaction of the preformed radical with free‐radical scavengers can be easily monitored by following the decay of the sample absorbance at 734 nm. The ABTS radical cation can be prepared employing different oxidants. Results obtained using MnO₂ as oxidant show that the presence of manganese ions increases the rate of [ABTS]^+· autobleaching in a concentration‐dependent manner. The radicals can also be obtained by oxidizing ABTS with 2,2^′‐azobis(2‐amidinopropane)hydrochloride (AAPH) or peroxodisulfate (PDS). The oxidation by AAPH takes place with a large activation energy and a low reaction order in ABTS. The data support a mechanism in which the homolysis of AAPH is the rate‐limiting step, followed by the reaction of ABTS with the peroxyl radicals produced after the azocompound thermolysis. On the other hand, the low activation energy measured employing PDS, as well as the kinetic law, are compatible with the occurrence of a bimolecular reaction between the oxidant and ABTS. Regarding the use of ABTS‐based methodologies for the evaluation of free radical scavengers, radical cations obtained employing AAPH as oxidant can be used only at low temperatures, conditions where further decomposition of the remaining AAPH is minimized. The best results are obtained with ABTS derived radicals generated in the reaction of PDS with an ABTS/PDS concentration ratio equal (or higher) to two. However, even with radicals prepared by this procedure, stoichiometric coefficients considerably larger than two are obtained for the consumption of the radical cation employing tryptophane or p‐terbutylphenol as reductants. This casts doubts on the use of ABTS‐based procedures for the estimation of antioxidant capacities. © 2002 Wiley Periodicals, Inc. Int J Chem Kinet 34: 659–665, 2002     

Isomerisierung von Methoxy- und Carbomethoxysubstituierten Cycloalkyl- und Alken-radikalkationen

The very complex isomerization patterns of methoxy and carbomethoxy substituted cycloalkanes (3- to 7-membered rings) have been investigated using collisional activation, metastable ion characteristics and field ionization kinetics. The extent of isomerization depends on both the ring size and the substituent. Irrespective of the electronic properties of the substituent, ring opening involves exclusively the C-1? C-2 bond whereby linear alkene radical cations are formed. In the case of OCH₃- and COOCH₃ substituents the position of the resulting double bond (terminal or α,β-unsaturated) is determined more by the ring size of the precursor molecules and less by the electronic properties of the substituents. Contrary to these findings alklyl substituted cycloalkanes (3- to 5-membered rings) rearrange exclusively to terminal alkene radical cations. The barrier for double bond isomerization seems to be substantially influenced by substituents.     

Ring and nitrogen inversion in a flexible highly symmetrical molecule: The conformations of 1,3,7,9,13,15,19,21-octaazapentacyclo[19,3,1,1,3,7,19,13,115,19]

The possible conformations of the title compound and their modes of interconversion via ring and nitrogen inversion processes are delineated. At high temperatures (> +80°) the ¹H NMR spectra are consistent with time averaged D_4th symmetry and rapid ring and nitrogen inversion. At lower temperatures (ca. ?10°) the time-averaged symmetry if D_2d and inversion of the 6-membered rings is frozen out, nitrogen inversion remaining rapid. The free energy of activation for the total inversion of all four 6-membered rings is 13·5 kcal mole ^?1, higher than in similar monocyclic systems. This higher energy is a reflection of the multiple ring inversion pathway required for total inversion of all the 6-membered rings.     

The vibrational group frequency of the N-O* stretching band of nitroxide stable free radicals

The group frequency of the N-O radical stretching vibration has received scant attention in the literature. The few existing treatments of the vibrational spectroscopy of nitroxides are incomplete at best and potentially misleading to workers in the field. To close this gap in the available knowledge, the existing literature on the vibrational spectra of nitroxide stable free radicals is critically reviewed with particular reference to the wavenumber position of the N-O stretching vibration, nu(N-O). Poor evidentiary bases for the assignment nu(N-O) were found in many instances. Ab initio Density Field Theory calculations using a model chemistry of UB3LYP at the 6-311++G(d,p) level were performed to obtain a theoretical band position of nu(N-O) for comparison with the published data. Large discrepancies between the theoretical and experimental values were found for the radical 3-carbamoyl-2,2,5,5-tetramethyl-3-pyrrolin-1-yloxyl, which currently sets the lower limit of the accepted wavenumber range of nu(N-O), as well as for the nitronyl and iminyl nitroxides. The wavenumber position of nu(N-O) was found to occur in the range 1450-1420cm(-1) for 5-membered cyclic nitroxides and 1395-1340cm(-1) for 6-membered cyclic and acyclic nitroxides. In nitronyl nitroxides, the symmetric stretching vibration occurs in the region 1470cm(-1), but coupling to other modes makes specific band assignments problematic for the nitronyl nitroxide group.     

Bausteine für funktionalisierte carbocyclische Grosshohlräume — Methanol-Clathrat eineso-Terphenylophans

The syntheses of the functionalized carbomacrocycles5–11 are reported. The diastereomeric diols10a, b form a stable methanol clathrate. The X-ray analysis of9 gives insight into the dimensions of the cavity. In the course of the preparation of4 the side products22 and23 have been characterized. Aldol condensations are also used for the syntheses of the 30-membered ring15 and of its hydrogenation product16. The diesters12–14 have been prepared to make available functionalized carbomacrocycles with high ring member numbers by acyloin condensation. In this connection, the 28-membered tetra-yne20 and its precursors18 and19 are described.

     

Trapping rhodium vinylcarbenoids with aminochalcones for the synthesis of medium-sized azacycles

A rhodium carbenoid initiated cascade has been developed for the stereoselective synthesis of medium-sized azacycles. The cascade approach utilizes readily accessible N-benzyl protected aminochalcones and vinyldiazo compounds to access 9-membered azacycles through a carbene- nitrogen insertion/aldol/oxy-Cope sequence. The cascade reaction has proven general with a range of N-benzyl protected aminochalcones and vinyldiazos to provide diverse medium-sized azacycles.     

Divergent synthesis of the tetracyclic ethers of 6-X-7-6 ring systems

Ladder-shaped polyether natural products show diverse biological activities with extreme potency. As the initial phase of detailed SAR studies of bioactive polyethers, we set out to construct structurally simple mimics. This paper details the divergent synthesis of 6-X-7-6 tetracycles (X=7, 8, or 9) starting from a simple 6-membered ether. Key reactions in the synthesis include (i) the direct formation of an O,S-acetal by the coupling of an alcohol with an α-chlorosulfide, (ii) the construction of a 7-membered ring by radical cyclization, and (iii) cyclization to the 7, 8 or 9-membered ring via a ring-closing metathesis reaction. The neutral reaction conditions of our strategy enable the synthesis of a wide variety of substrates. The results of this study can be applied for the rapid construction of artificial polyether compounds with diversified molecular shapes and sizes.     

Polymerization of diethylene glycol bis(allyl carbonate) by means of di-sec-butyl peroxydicarbonate

The initial stages of the free radical polymerization of diethylene glycol bis(allyl carbonate) at temperatures of 35–65°C have been studied. The polymer is unsaturated and cyclization to give a 16-membered ring occurs only to a small extent. The kinetic order with respect to the initiator, di-sec-butyl peroxydicarbonate, has an average value of 0.79; the order increases slightly with peroxydicarbonate concentration over the range 0.018–0.22M. The molecular weight of the polymer isolated after 3% polymerization is close to 19,000. It shows no significant dependence on initiator concentration or on temperature. The dominant feature of the bulk polymerization, as in free radical polymerization of the other allyl and diallyl monomers, is degradative chain transfer in which the growing polymer radical abstracts a hydrogen atom from a monomer unit to give a relatively unreactive allylic radical. The dependence of rate on initiator concentration is rationalized if some of these allylic radicals are able to reinitiate polymerization. The transfer constant to monomer is 0.014 at 50°C, assuming that the main termination step involves mutual termination of allylic radicals. Carbon tetrachloride is an active transfer agent with a transfer constant of 0.20 ± 0.04 at 50°C. Toluene, which is less active, has a transfer constant of 0.0064 at 50°C and also retards the polymerization. Some kinetic studies have been made with other initiators, including di-2-methyl-pentanoyl peroxide which initiates polymerization at temperatures as low as 13°C.     

Synthesis and antioxidant properties of organosulfur and organoselenium compounds derived from 5-substituted-1,3,4-oxadiazole/thiadiazole-2-thiols

Organosulfur and organoselenium compounds were synthesized in good yields through reaction with 5-aryl-1,3,4-oxadiazole/thiadiazole-2-thiols and α-chloromethyl arylselenides or 4-(chloromethyl)-2-methylthiazole/2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole. The obtained compounds were characterized by NMR and mass spectroscopy and screened for in vitro antioxidant activity as reflected by free radical scavenging against 2,2-diphenyl-2-picrylhydrazyl (DPPH) and reduction of molybdenum (VI) to molybdenum (V). The compounds have significant antioxidant properties in both applied methodologies.     

Synthetic studies on the DEF-rings of FR182877 and hexacyclinic acid

A synthesis of model DEF-rings of the polyketide anti tumor natural products FR182877 and hexacyclinic acid has been achieved. The key steps in the synthesis are an intramolecular Pd(0) catalyzed allylic substitution reaction, which was used to generate a 9-membered carbocycle, and a novel transannular iodocyclization reaction which furnished the DF-rings of both natural products.     

Enyne metathesis for the formation of macrocyclic 1,3-dienes

Macrocyclic 1,3-dienes of a variety of ring sizes are formed in good yield via enyne metathesis. Both endo- and exo-products are observed depending on the size of the macrocycle. In general, 10-membered rings and smaller give exo-products, while 12-membered rings and larger give endo-products. The endo/exo selectivity and the E/Z ratio of the diene products can be further controlled by the presence of ethylene in the reaction.