Intramolecular Addition Reactions Research Articles

Comparative DFT Study of the Spin Trapping of Methyl, Mercapto, Hydroperoxy, Superoxide, and Nitric Oxide Radicals by Various Substituted Cyclic Nitrones

The thermodynamics of the spin trapping of various cyclic nitrones with biologically relevant radicals such as methyl, mercapto, hydroperoxy, superoxide anion, and nitric oxide was investigated using computational methods. A density functional theory (DFT) approach was employed in this study at the B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level. The order of increasing favorability for Delta G(rxn) (kcal/mol) of the radical reaction with various nitrones, in general, follows a trend similar to their respective experimental reduction potentials as well as their experimental second-order rate constants in aqueous solution: NO (14.57) < O2*- (-7.51) < *O2H (-13.92) < *SH (-16.55) < *CH3 (-32.17) < *OH (-43.66). The same qualitative trend is predicted upon considering the effect of solvation using the polarizable continuum model (PCM): i.e., NO (14.12) < O2*- (9.95) < *O2H (-6.95) < *SH (-13.57) < *CH3 (-32.88) < *OH (-38.91). All radical reactions with these nitrones are exoergic, except for NO (and O2*- in the aqueous phase), which is endoergic, and the free energy of activation (Delta G) for the NO additions ranges from 17.7 to 20.3 kcal/mol. This study also predicts the favorable formation of certain adducts that exhibit intramolecular H-bonding interactions, nucleophilic addition, or H-atom transfer reactions. The spin density on the nitronyl N of the superoxide adducts reveals conformational dependences. The failure of nitrones to trap NO at normal conditions was theoretically rationalized due to the endoergic reaction parameters.

Double Cyclometalation: Implications for C—H Oxidative Addition with PCP Pincer Compounds of Iridium

AbstractFor Abstract see ChemInform Abstract in Full Text.

Application of the Palladium(0)-Catalyzed Ullmann Cross-Coupling Reaction in a Total Synthesis of (±)-Aspidospermidine and thus Representing an Approach to the Lower Hemisphere of the Binary Indole - Indoline Alkaloid Vinblastine

As part of ongoing studies directed towards the construction of the anti-cancer agent vinblastine (1), the related but structurally less complex natural product aspidospermidine (3) has been synthesized. Two approaches to target 3 were pursued. In the first, which was unsuccessful, the amine-tethered enone 6 was prepared but this failed to engage in the pivotal intramolecular conjugate addition reaction to give the bicyclic system 5. In contrast, the related compound 46, incorporating tethered enone and azide moieties, engaged in an intramolecular 1,3-dipolar cycloaddition reaction to give, presumably via an intermediate triazoline, the isolable and ring-fused aziridine 47. This was then converted, over two steps, into the previously reported tetrahydrocarbazole 4. Application of established protocols to this last compound allowed for the installation of the E-ring of the title alkaloid 3 and completion of the total synthesis.

Stereoselective synthesis of 2,5-disubstituted-1,4-oxathiane S-oxides

Beta-allyloxy and beta-propargyloxy tert-butyl sulfoxides undergo tandem sulfoxide eliminination-intramolecular sulfenic acid addition reactions to produce 1,4-oxathiane S-oxides.

Intramolecular reactions of 2-indolylacyl radicals: access to 1,2-fused ring indole derivatives.

The generation of 2-indolylacyl radicals from the corresponding phenyl selenoesters under reductive conditions and their behavior in intramolecular addition reactions to carbon-carbon double bonds located at the indole nitrogen have been studied. [reaction: see text]

Variable strategy toward carbasugars and relatives. 5.(1) Focus on preparation of chiral nonracemic medium-sized carbocycles.

The feasibility of sequential vinylogous aldol (intermolecular)/silylative aldol (intramolecular) addition reactions involving furan- and pyrrole-based dienoxysilanes, 6 and 12, in the synthesis of carbasugar frameworks is illustrated by the preparation of the scantily investigated carbaseptanose and carbaoctanose representatives of this class of compounds. The target compounds, 1, 2, 3, ent-2, ent-3, and 4, were obtained from readily available carbohydrate precursors (5 and 19) in yields of 21-30% over 8-12 steps. The irreversible silylative ring-closing aldolisation of gamma-substituted dihydro-5H-furan-2-one and pyrrolidin-2-one aldehydes (9, 16, ent-16, and 22) driven by the TBSOTf/Pr(i)(2)EtN Lewis acid-Lewis base couple was shown to be a practical, diastereoselective maneuver to forge the densely functionalized, medium-sized core carbocycles.

Oxidation of FA with alkene of alkyne functionalities studied with chemiluminescence and real‐time IR spectroscopy

AbstractThe oxidation of well‐defined FA derivatives has been studied with real‐time IR (RTIR) and chemiluminescence (CL) techniques. Both methyl esters and model oils based on different FA have been studied to reveal the effect of functionality. The FA used were linoleic and crepenynic acid, the latter with an alkyne functionality. The purpose was to reveal how structural differences affect the oxidation and how this is monitored with CL and RTIR. Both model oils had longer oxidation induction times than the corresponding methyl esters, as seen by both IR and CL. Generally, the induction times measured with IR were shorter than those determined by CL, but the rate of oxidation did not seem to differ much between the model oils and the corresponding methyl esters. The results also imply that the higher functionality of the model oils gives a greater possibility of intramolecular addition reactions instead of chain scission during oxidation, making the model oils emit fewer low‐M.W. volatiles than the methyl esters. There is also a difference between methyl crepenynate and methyl linoleate, in that the alkyne functionality seems to enhance the possibility of chain scission instead of addition reactions. The results presented imply that the CL signal can be used to monitor the oxidation and the formation of volatile compounds from a FA structure. By combining the CL measurements with RTIR data, information about the oxidation reactions can be obtained, giving a greater understanding of what reactions are occurring during oxidation and how they are related to each other.

Spirocyclic and Bicyclic Cyclohexadienyl Complexes from Intramolecular Nucleophilic Addition Reactions in Dicationic Arene Complexes

The dicationic arene complexes [(p-cymene)Ru(PhCH2CH2[CH2]nOH)][OTf]2 and [Cp*Ir(PhCH2CH2[CH2]nOH)][OTf]2 (n = 1−2) react with K2CO3 to cleanly generate spirocyclic cyclohexadienyl complexes through intramolecular nucleophilic addition of the alkoxide at the ipso carbon of the arene ligand. When the internal nucleophile is the bulkier benzenesulfonamide group, cyclohexadienyl complexes derived from both ipso and ortho intramolecular nucleophilic addition are formed.

Palladium(II)‐Catalyzed Coupling of Allenoic Acids and α,β‐Unsaturated Carbonyl Compounds Through Tandem Intramolecular Oxypalladation and Conjugate Addition Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Competing nature of intramolecular [4 + 2] and [3 + 2] cycloaddition reactions: a theoretical study

AbstractComparative study of the intramolecular alkyne triple bond addition reaction to the conjugated ­C≡C—CHX moiety (X = CH2,O,S,NH) revealed that two different pathways are possible in the system, namely [4 + 2] and [3 + 2] cycloaddition reactions. The energetically preferred pathway for enynes (X = CH2) involves [4 + 2] cycloaddition leading to benzene derivatives, whereas heteroatom‐substituted substrates undergo [3 + 2] cycloaddition resulting in an five‐membered aromatic ring in the final product. This paper reports a detailed mechanistic study based on full potential energy surface calculations at the MP2 and B3LYP theory levels, with MP4(SDTQ) energy evaluation. The effect of solvent was included within the PCM approach. Copyright © 2003 John Wiley &amp; Sons, Ltd.

Palladium(II)-catalyzed coupling of allenoic acids and α,β-unsaturated carbonyl compounds through tandem intramolecular oxypalladation and conjugate addition reactions

A regioselective divalent palladium-catalyzed tandem coupling reaction of allenoic acids with α,β-unsaturated carbonyl compounds was developed. The reaction involves intramolecular oxypalladation of an allene, followed by insertion of the α,β-unsaturated carbonyl compound and protonolysis of the CPd bond to regenerate the Pd(II) species in the presence of excess halide ions. Functionalized lactones, tetrahydropyranones and dihydropyranones can be synthesized with high regioselectivity in one step.

C−H Oxidative Addition with a (PCP)Ir(III)-Pincer Complex

Treatment of 4-MeO-C6H3-2,6-(CH2PtBu2)2 with IrCl3·nH2O in i-PrOH/H2O gives a cyclometalated pincer chlorohydrido iridium complex. A second intramolecular oxidative addition reaction of one of the tert-butyl C−H bonds to the Ir(III) center followed by the reductive elimination of H2 gives a novel doubly metalated compound that is stable to air and water. X-ray crystallographic analysis revealed a chelated square-pyramidal iridium compound with two cyclometalated five-membered rings in the basal plane and the iridium bound methylene group of the four-membered ring in the apical position. The free coordination site is protected by an agostic C−H bond. While a phosphorus−phosphorus coupling constant of 351.1 Hz establishes the trans position of the phosphorus groups there is no indication of a hydridic or weakly bound hydrogen. Electrochemical studies establish an equilibrium between the pincer chlorohydrido compound and the doubly metalated complex and H2. A square scheme can be used to describe the relatio...

Selectivity in the Chemistry of Oxygen‐Centered Radicals — The Formation of Carbon—Oxygen Bonds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Iodine(III)‐Mediated Generation of Nitrogen‐Tethered Orthoquinol Acetates for the Construction of Oxygenated Indole, Quinoline, and Phenanthridine Alkaloid Motifs.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Iodine(III)-mediated generation of nitrogen-tethered orthoquinol acetates for the construction of oxygenated indole, quinoline, and phenanthridine alkaloid motifs.

Functionalized indole and quinoline derivatives are conveniently prepared from nitrogen-tethered 2-methoxyphenols via phenyliodine(III) diacetate mediated oxidative acetoxylation, followed by a fluoride- or base-induced intramolecular nucleophilic addition reaction. This regioselective Michael-type addition step is further discussed in view of the rearrangement of orthoquinol acetate intermediates into paraquinol acetates that is sometimes observed in situ. Application of this methodology to the synthesis of a functionalized phenanthridine, and its potential for the construction of polyoxygenated lycorine-type alkaloid skeleta are here described.

Selectivity in the Chemistry of Oxygen-Centered Radicals - The Formation of Carbon-Oxygen Bonds

In recent years, powerful new methods for the generation of alkoxyl radicals under mild and neutral conditions have been developed. This progress has led to a thorough investigation of most O-radical elementary reactions.Today, sufficiently reliable thermodynamic and kinetic data are available either from experimental or from theoretical studies in order to predict alkoxyl radical reactivities and selectivities in synthesis. For instance, alkoxyl radicals readily add to carbon-carbon and carbon-nitrogen double bonds. Due to generally low activation barriers and strongly negative reaction enthalpies, inter- and intramolecular addition reactions proceed under kinetic control and are associated with high rate constants. Nevertheless, intramolecular 5-exo-trig additions, i.e. cyclizations, proceed with an astonishing degree of diastereoselectivity and often provide complementary selectivities if compared to commonly used methods such as the bromine cyclization of alkenols. Therefore, several useful applications of O-radical cyclizations in the synthesis of functionalized tetrahydrofurans have been discovered in the last few years. A second major reaction channel of alkoxyl radicals is associated with the homolysis of a β-C-C bond. This fragmentation proceeds under thermodynamic control and affords a carbonyl compound besides an alkyl radical from the starting alkoxyl radical. Regioselectivities for C-C bond homolysis may be predicted by considering strain release (cyclic carbon framework) and the stability of the newly formed carbon radical (cyclic and open chain carbon skeletons). The third major group of alkoxyl radical-based transformations are connected with homolytic substitutions such as intramolecular 1,5-hydrogen shifts which have been applied with considerable success to remote functionalization reactions. In view of the diversity of alkoxyl radical reactions it is the aim of this review to organize basic principles of this type of chemistry and to present its latest useful application in organic synthesis.

Hypervalent iodine(III)-mediated oxidative acetoxylation of 2-methoxyphenols for regiocontrolled nitrogen benzannulation

Nitrogen-tethered 2-methoxyphenols are conveniently dearomatized into synthetically useful orthoquinol acetates by treatment with phenyliodine(III) diacetate in methylene chloride at low temperature. Subsequent fluoride- or base-induced intramolecular nucleophilic addition reactions furnish indole and quinoline derivatives. The potential of this methodology for the synthesis of a functionalized lycorine-type alkaloid skeleton is introduced here.

Stereo- and regioselectivity of cyclization reactions in conformationally restricted epoxy ketones: evaluation of C- versus O-alkylation process

The intramolecular addition reaction of metal enolates of ketones to oxiranes has been applied to a series of epoxy ketones derived from cyclohexene oxide. γ-Hydroxy ketones (γ-HKs, C-alkylation products) or hydroxy enol ethers (HEEs, O-alkylation products) are obtained, depending on the nature of the cyclic transition state in each case involved and the application of the Fürst–Plattner rule. The formation of HEEs by reaction of the same epoxy ketones under acid conditions is also described. In some cases, regioconvergent or chemoselective processes are conveniently obtained.

Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

Whereas carbon radical cyclizations have been applied for many years in the stereoselective synthesis of carbocyclic compounds, intramolecular C−O bond formations using alkoxyl radical reactions are less well understood. Since the discovery of N-alkoxypyridine-2(1H)-thiones 8 as efficient sources of oxygen-centered radicals, and the marked progress in the synthesis of these and related compounds which has been made in the last five years, however, a systematic study of O-radical cyclizations under neutral conditions has become available. Kinetic experiments using the radical clock technique found that the parent 4-penten-1-oxyl radical 1 undergoes an extremely fast 5-exo-trig ring-closure [(4 ± 2) × 108 s−1 (30 °C)] which, after hydrogen trapping, selectively affords 2-methyltetrahydrofuran (50). Tetrahydropyran (56), which originates from the slower 6-endo-trig cyclization, was observed in minor amounts. This observation pointed to a more diverse regioselectivity of O-radicals in intramolecular addition reactions to olefinic double bonds than had been predicted from earlier experiments. A mechanistic study of ring-closure reactions of the substituted 4-penten-1-oxyl radicals 51 led to two major conclusions. Firstly, 1-, 2-, 3-, and 5-substituted radicals cyclize stereoselectively and 5-exo-trig-regioselectively. The degree of stereoselectivity is governed by steric effects. To date, the only exceptions to this rule remain cyclizations of the para-substituted 1-aryl-4-penten-1-oxyl radicals 51e−m. These intermediates cyclize regioselectively, butnot stereoselectively. Secondly, substituents at position 4 of the 4-penten-1-oxyl radical are the key for controlling regioselectivities in O-radical ring-closure reactions. Thus, the 4-phenyl-4-penten-1-oxyl radical 51u cyclizes 6-endo-trig-selectively to afford, after hydrogen trapping, 2-phenyltetrahydropyran (59u) as the major product (5-exo:6-endo = 5:95). Results from mechanistic and theoretical studies have been combined in order to derive a general model for predicting alkoxyl radical selectivities in ring closure reactions. The utility of this predictive device has recently been confirmed in the course of a new stereoselective synthesis of the central ring in muscarine alkaloid 72.

ChemInform Abstract: Vinyl and Alkynyl Pyrimidines as Michael Acceptors: An Approach to a Cylindrospermopsin Substructure.

Vinyl pyrimidine 9 and alkynyl pyrimidine 24 undergo base-mediated intramolecular conjugate addition reactions in which a carbamate and a urea, respectively, behave as nitrogen nucleophiles. The cyclic carbamate derived from 9 was converted to 11 via a metalation-oxidation reaction in which 2-phenylsulfonyl-3-phenyloxaziridine behaves as a hydroxylation reagent. The cyclic urea derived from 24 was converted to cylindrospermopsin substructure 30 using dimethyldioxirane to introduce the C(7) hydroxyl group.