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.     

The effect of fluorine substitution on the structure of oxiranes and on the energetics of the oxiranylcarbinyl radical ring opening

Fluorine substituent effects on the structure of oxirane and on the kinetic behavior of oxiranylcarbinyl radicals, as determined by DFT calculations, have been found to be similar to those observed for the analogous fluorinated cyclopropylcarbinyl radical systems. A structural and energetic analysis showed that a stereoelectronic effect involving preferential interaction of the semi-occupied atomic orbital of the radical with the weaker ring bond is the major factor that contributes to the regiochemistry of the ring opening of fluorinated oxiranylcarbinyl radicals. With low and potentially zero activation barriers, 3,3-difluorooxiranylcarbinyl radical and cation undergo ring opening with CO bond cleavage and CC cleavage, respectively.     

5-endo-dig radical cyclizations: "the poor cousins" of the radical cyclizations family

Kinetics and thermodynamics of 5-endo-dig radical cyclizations were studied using a combination of DFT computations and Marcus theory. When the reactant is stabilized by conjugation of the radical center with the bridge pi-system, the cyclization starts with reorientation of the radical orbital needed to reach the in-plane acetylene pi-orbital in the bond-forming step. This reorientation leads to loss of the above conjugative stabilization, increases the activation energy, and renders such cyclizations less exothermic. As a result, even when the radical needed for the 5-endo cyclization is formed efficiently, it undergoes either H-abstraction or equilibration with an isomeric radical. Only when the bridging moiety is saturated or when intramolecular constraints prevent the overlap of the bridge pi-orbital and the radical center, 5-endo cyclizations may be able to proceed with moderate efficiency under conditions when H-abstraction is slow. The main remaining caveat in designing such geometrically constrained 5-endo-dig cyclizations is their sensitivity to strain effects, especially when polycyclic systems are formed. The strain effects can be counterbalanced by increasing the stabilization of the product (e.g., by introducing heteroatoms into the bridging moiety). Electronic effects of such substitutions can be manifested in various ways, ranging from aromatic stabilization to a hyperconjugative beta-Si effect. The 4-exo-dig cyclization is kinetically competitive with the 5-endo-dig process but less favorable thermodynamically. As a result, by proper design of reaction conditions, 5-endo-dig radical cyclizations should be experimentally feasible.     

Intramolecular 1,8-hydrogen atom transfer reactions in disaccharide systems containing furanose units

A previously developed 1,8-hydrogen atom transfer (HAT) reaction promoted by 6-O-yl alkoxyl radicals between the two pyranose units in Hexp-(1→4)-Hexp disaccharides has been extended to other systems containing at least a furanose ring in their structures. In Penf-(1→3)-Penf (A) and Hexp-(1→3)-Penf (B) disaccharides, the 1,8-HAT reaction and concomitant cyclization to a 1,3,5-trioxocane ring are in competition with radical β-scission of the C4-C5 bond and formation of dehomologated products. The influence of the stereoelectronic β-oxygen effect on the β-scission and consequently on the 1,8-HAT reaction has been studied using the four possible isomeric d-furanoses. d-xylo- and d-lyxo-derivatives afforded preferentially 1,8-HAT products, whereas d-arabino- and d-ribo-derivatives gave exclusively direct β-scission of the alkoxyl radical. When the 6-O-yl radical is on a pyranose ring, as occurs in Penf-(1→4)-Hexp (C), it has been shown to provide the cyclized products exclusively.     

In search of efficient 5-endo-dig cyclization of a carbon-centered radical: 40 years from a prediction to another success for the Baldwin rules

Despite being predicted to be stereoelectronically favorable by the Baldwin rules, efficient formation of a C-C bond through a 5-endo-dig radical cyclization remained unknown for more than 40 years. This work reports a remarkable increase in the efficiency of this process upon beta-Ts substitution, which led to the development of an expedient approach to densely functionalized cyclic 1,3-dienes. Good qualitative agreement between the increased efficiency and stereoselectivity for the 5-endo-dig cyclization of Ts-substituted vinyl radicals and the results of density functional theory analysis further confirms the utility of computational methods in the design of new radical processes. Although reactions of Br atoms generated through photochemical Ts-Br bond homolysis lead to the formation of cyclic dibromide side products, the yields of target bromosulfones in the photochemically induced reactions can be increased by recycling the dibromide byproduct into the target bromosulfones through a sequence of addition/elimination reactions at the exocyclic double bond. Discovery of a relatively efficient radical 5-endo-dig closure, accompanied by a C-C bond formation, provides further support to stereoelectronic considerations at the heart of the Baldwin rules and fills one of the last remaining gaps in the arsenal of radical cyclizations.     

Five- and six-membered ring formation from the intramolecular reaction of a protonated oxirane and alkene

Computational studies of competing five- and six-membered cyclisation of alkenyloxiranes 1a-d show that intramolecular reaction of a protonated oxirane and alkene is a concerted, single-step, exothermic process. The reactions proceed via reactant-like transition states, but where the oxirane C-O bond is considerably stretched. Two factors are seen to affect the regiochemistry: (1) stabilisation of the transitory positive charge in the transition state favours cyclisation to the more highly substituted oxirane carbon; and (2) there is an inherent stereoelectronic preference for six-membered cyclisation over five-membered cyclisation. The inherent preference for six-membered cyclisation has a parallel in Baldwin's rules for six-membered ring closure of a carbocation with an alkene, rather than Baldwin's rule for intramolecular nucleophilic reaction of three-membered rings, suggesting that the protonated oxirane mimics a carbocation. The electronic and stereoelectronic effects for cyclisation are modified by steric interactions of axial methyl groups. These systems provide a model for the A-ring cyclisation of oxidosqualene.     

Controlling regioselectivity in cyclization of unsaturated amidyl radicals: 5-exo versus 6-endo

Intramolecular cyclization of an amidyl radical onto an olefin provides an appealing method for the synthesis of lactams and other nitrogen-containing heterocycles. Here we conducted the first, systematic theoretical study on the regioselectivity in the cyclization of various types of pent-4-enamidyl radicals that carried synthetically relevant substituents. It was found that the cyclization of most of the substituted pent-4-enamidyl radicals produced the 5-exo products (gamma-lactams) almost exclusively. Marcus theory analysis showed the involvement of both the thermodynamic (stabilization of the starting double bond or the resulting radical center) and intrinsic (mainly steric effects) contributions in determining the 5-exo selectivity. Nonetheless, in two types of systems we found that the delta-lactams became the favored products through the 6-endo cyclization. In one of the systems an aromatic substituent was placed at the C4-position, whereas in the other system an electron-rich aromatic ring was incorporated into the pent-4-enamidyl radical backbone at the C2- and C3-positions. This unprecedented 6-endo mode of amidyl radical cyclization provided an interesting route for the preparation of mono- and bicyclic delta-lactams (pyridinones).     

Mechanistic analysis of oxidative C-H cleavages using inter- and intramolecular kinetic isotope effects

A series of monodeuterated benzylic and allylic ethers were subjected to oxidative carbon-hydrogen bond cleavage to determine the impact of structural variation on intramolecular kinetic isotope effects in DDQ-mediated cyclization reactions. These values are compared to the corresponding intermolecular kinetic isotope effects that were accessed through subjecting mixtures of non-deuterated and dideuterated substrates to the reaction conditions. The results indicate that carbon-hydrogen bond cleavage is rate determining and that a radical cation is most likely a key intermediate in the reaction mechanism.     

Electrophilic-induced cyclization reaction of hexahydroindolinone derivatives and its application toward the synthesis of (+/-)-erysotramidine

A convenient synthesis of variously substituted octahydroindolo[7a,1a]-isoquinolinones has been achieved by an acid-induced cyclization of hexahydroindolinones bearing tethered phenethyl groups. The formation of a single lactam diastereomer is the result of the stereoelectronic preference for axial attack by the aromatic ring onto the initially formed N-acyliminium ion from the least hindered side. Additional experiments showed that a variety of hexahydroindolinones containing tethered pi-bonds undergo a related acid-induced cyclization reaction. Treatment of the 3-methylbut-3-enyl-substituted hexahydroindolinone with acid furnished a 3:1 mixture of isomeric octahydropyrido[2,1-i]indolinones in near-quantitative yield. Interestingly, cyclization of the closely related 1-(3-methoxybut-3-enyl)-substituted hexahydroindolin-one afforded a pyrrolo[3,2,1-ij]quinolinone as the exclusive product. With this system, initial protonation takes place on the more nucleophilic enol ether pi-bond and the resulting carbonium ion undergoes a subsequent cyclization with the enamido pi-bond to give the observed product. The electrophilic promoted cyclizations were extended to include the related hexahydro[1]pyrindinone and 1H-quinolinone systems. An NBS-promoted intramolecular electrophilic aromatic substitution reaction of 1-[2-(3,4-dimethoxyphenyl)ethyl]-1,4,5,6-tetrahydroindolinone was used to assemble the tetracyclic core of the erythrinone skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine in three additional steps.     

Reaction of Some Alkenols with Tetrachloromethane

Summary.  The reaction of some alkenols with tetrachloromethane in the presence of a radical initiator was investigated. Regarding the effects of structural features of the starting alkenol (number and position of methyl substituents at the double bond and at the carbinol carbon atom, constitutional relationship between the double bond and the hydroxyl group) there are two possible competing reactions: addition and cyclization. In the case of the simplest alkenols (without substituents and with a more remote double bond) addition occurs; mono- and disubstituted secondary and tertiary Δ⁴- and Δ⁵-alkenols cyclize in high yields to give the corresponding cyclic ethers. Received March 17, 2000. Accepted (revised) May 31, 2000     

Theoretical investigation of the stereoselective stepwise cope rearrangement of a 3-vinylmethylenecyclobutane

The potential energy surface of the rearrangement of 3-vinylmethylenecyclobutane to 4-methylenecyclohexene has been studied computationally using density functional theory (B3LYP) and complete active space ab initio methods (CASSCF and CASPT2). The parent reaction is nonconcerted and occurs through several parallel diradical pathways. Transition structures and diradical intermediates are highly comparable in energy, with no deep potential energy well on the potential energy surface. In the substituted system, stereoelectronic effects of the trialkylsiloxy group regulate torquoselectivity in the bond-breaking processes and this, combined with low barriers to cyclization, leads to a stepwise Cope rearrangement that is, nevertheless, stereoselective.     

Reaction of Some Alkenols with Tetrachloromethane

 The reaction of some alkenols with tetrachloromethane in the presence of a radical initiator was investigated. Regarding the effects of structural features of the starting alkenol (number and position of methyl substituents at the double bond and at the carbinol carbon atom, constitutional relationship between the double bond and the hydroxyl group) there are two possible competing reactions: addition and cyclization. In the case of the simplest alkenols (without substituents and with a more remote double bond) addition occurs; mono- and disubstituted secondary and tertiary Δ⁴- and Δ⁵-alkenols cyclize in high yields to give the corresponding cyclic ethers.     

Effects of introduction of α‐carboxylate,N‐methyl,and N‐formyl groups on intramolecular cyclization of o‐quinone amines: Density functional theory‐based study

o‐Quinone amines, which are relevant to various biological processes, can undergo spontaneous intramolecular cyclization (ring closure reaction by amino‐terminated hydrocarbon side chain) that deactivates them toward another possible reactions, that is, thiol binding. Density functional theory‐based calculation is employed for obtaining the potential energy curves along the C? N bond formation in the intramolecular cyclization of various o‐quinone amines, viz., dopaminequinone, dopaquinone, N‐methyl‐dopaminequinone, N‐formyl‐dopaminequinone, and the corresponding methylene‐inserted analogues. The activation barrier is decreased by introduction of α‐carboxylate and N‐methyl group whereas increased by introduction of N‐formyl group. A negative correlation between the activation barriers and the level of highest occupied molecular orbital is pointed out. Furthermore, the methylene‐inserted analogues show decreased activation barriers. This is explained by reduction of steric repulsion in the transition state.     

A new reaction manifold for the Barton radical intermediates: synthesis of N-heterocyclic furanosides and pyranosides via the formation of the C(1)-C(2) bond

The first radical intermediate in the thiourethane-mediated deoxygenation of an alcohol (Barton-McCombie reaction) can participate in an exo-hex-5-enyl- or exo-hept-6-enyl-type radical cyclization when a suitable radical acceptor (e.g., alpha,beta-unsaturated ester, oxime ether, or hydrazone) is appropriately placed. Carbohydrate-derived imidazolyl and triazolyl thiourethanes with such acceptors, upon addition to excess of a good hydride donor (reverse addition), undergo efficient cyclization reactions to give N-heterocyclic furanosides, and, surprisingly even N-pyranosides. Depending on the acceptor, glycosides with either a C(2)()-amino or a C(2)()-carbon substituent are formed.     

Synthesis of (+)-juruenolide c: use of sequential 5-exo-digonal radical cyclization, 1,5-intramolecular hydrogen transfer, and 5-endo-trigonal cyclization.

Acetylenic alcohol 10 was converted successively into silane 11 and phenylseleno carbonate 14. On treatment with Ph3SnH, the latter underwent 5-exo-digonal radical cyclization, intramolecular hydrogen transfer, and 5-endo-trigonal cyclization, yielding 15. Conversion of the lactone into the lactol benzyl ether 17, carbon-silicon bond cleavage, and regeneration of the lactone carbonyl gave (+)-juruenolide C (1).     

Structure,bonding, and spectra of cyclic dithia radical cations: a theoretical study

Ab initio molecular orbital and hybrid density functional theory methods are employed to characterize the structure, bonding and properties of several cyclic dithia radical cation systems, particularly in the context of intra molecular two-center three-electron (2c-3e) bonding between two sulfur atoms. The calculated results are able to interpret the time-resolved transient optical spectra obtained from pulse radiolysis technique for these positively charged dithia systems in aqueous solution. Visualization of the appropriate molecular orbital (MO) in the systems is able to depict the presence of a 2c-3e bond between two sulfur atoms and its sigma character. Geometry optimizations of these doublet systems are carried out at restricted open shell Becke's half-and-half (BHH) nonlocal exchange and Lee-Yang-Parr (LYP) nonlocal correlation functionals (BHHLYP) with 6-311+G(d,p) basis set including solvent effects adopting Onsager's reaction field model. Hessian calculations are done at the same level to check the nature of the equilibrium geometry. Energy data are further improved by performing MP2/6-311+G(d,p) calculations on these radical cation systems. Excited-state calculations are done following configuration interaction with single-electron excitation (CIS) method and the optical transition wavelength from the highest doubly occupied molecular orbital (HDOMO) to the lowest singly occupied molecular orbital (LSOMO) is seen to correspond and match to the position of the absorption maxima (lambda(max)) obtained from the experimental spectra for all these radical cation systems in aqueous solution. These calculations are able to resolve a long-standing ambiguity in the assignment of intra molecular 2c-3e bonding in the case of the 3-methyl-2,4-dithiapentane radical cation system and to provide new insights into bonding features of this odd electron system as well as of other cyclic dithia systems studied.     

Theoretical Studies on the Reaction Mechanism of 1-Chloroethane with Hydroxyl Radical

The reaction mechanism of 1-chloroethane with hydroxyl radical has been inves- tigated by using density functional theory (DFT) B3LYP/6-31G (d, p) method. All bond dissociation enthalpies were computed at the same theoretical level. It was found that hydrogen abstraction pathway is the most favorable. There are two hydrogen abstraction pathways with activation barriers of 0.630 and 4.988 kJ/mol, respectively, while chlorine abstraction pathway was not found. It was observed that activation energies have a more reasonable correlation with the reaction enthalpy changes (△Hr) than with bond dissociation enthalpies (BDE).     

Generation and reactivity toward oxygen of carbon-centered radicals containing indane,indene, and fluorenyl moieties

Resonance-stabilized radicals containing indane, indene, and fluorenyl moieties exhibit attenuated reactivity toward oxygen. Rate constants of approximately 10(5) M(-1) s(-1) were observed for the most stabilized radicals. The dependence of k(OX) (rate constant for radical trapping by oxygen) on the corresponding bond dissociation energies revealed that stereoelectronic effects are more important than steric effects in determining the low radical reactivity with oxygen. Scavenging by the nitroxide TEMPO was also examined, and revealed that in this case steric effects are more important than in the case of oxygen. The rate constants for the hydrogen abstraction by cumyloxyl and tert-butoxyl radicals generated thermally and photochemically have been determined in benzene, and were in the range of ca. (1-13) x 10(6) M(-1) s(-1), showing that benzylic stabilization has a modest effect on substrate reactivity as a hydrogen donor toward alkoxyl radicals.     

Controlling the Scholl reaction

Guidelines for the application of the Scholl reaction were developed. Labeling experiments demonstrate that the Scholl reaction fails in small, unsubstituted oligophenylenes (e.g., o-terphenyl) due to oligomerization of the products (e.g., triphenylene). Incorporation of suitably placed blocking groups (e.g., t-butyl) suppresses oligomerization. The well-established directing group effects in electrophilic aromatic substitution predict the outcome of Scholl reactions of substituted substrates. Activating o,p-directing groups (e.g., MeO) direct bond formation o,p, either intramolecularly or intermolecularly. Deactivating o,p-directing groups (e.g., Br) also direct bond formation o,p but yields are lower. Deactivating m-directors (e.g., NO2) suppress reaction. MoCl5 and PhI(OOCCF3)2/BF3.Et2O are general and effective reagents for the Scholl oxidation. Calculations (B3LYP/6-31G(d)) predict the Scholl reaction in alkoxyarenes to proceed via arenium cations, not radical cations. Suzuki-Miyaura couplings were used to generate 12 substituted o-terphenyl derivatives.     

Metal-directed formation of three-dimensional M(3)L(2) trigonal-bipyramidal cages

[reaction: see text] The simple combination of two angular tritopic pyridine donor linkers (109 degrees bond angle) with three ditopic platinum acceptors (90 degrees bond angle) leads to essentially quantitative formation of self-assembled M(3)L(2) trigonal-bipyramidal (TBP) supramolecular species.