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).     

Stereoselective 6-exo cyclization of amidyl radicals. An experimental and theoretical study

Unsaturated primary amidyl radicals of Z-configurations underwent efficient chemo- and stereoselective 6-exo cyclization reactions via chair-conformational transition states, leading to the predominant formations of 3,6-trans, 4,6-cis, or 5,6-trans substituted δ-lactams.     

5-Exo versus 6-endo cyclization of primary aminyl radicals: an experimental and theoretical investigation

The cyclization of neutral primary pent-4-enylaminyl radicals was investigated experimentally and theoretically. Unlike the corresponding secondary aminyl radicals, primary pent-4-enylaminyl radicals underwent efficient cyclization to afford the pyrrolidine and/or piperidine products in good to high yields. While the simple pent-4-enylaminyl radical gave predominately the 5-exo cyclization product, 4-chloropent-4-enylaminyl radicals led to the formation of the corresponding 6-endo cyclization products in excellent regioselectivity. Theoretical calculations revealed that the 5-exo cyclization rate of primary aminyl radicals is about 3-4 orders of magnitude higher than that of secondary aminyl radicals.     

Unprecedented aromatic homolytic substitutions and cyclization of amide-iminyl radicals: experimental and theoretical study

Amide-iminyl radicals are versatile and efficient intermediates in cascade radical cyclizations of N-acylcyanamides. They are easily trapped by alkenes or (hetero-)aromatic rings and cyclize into a series of new heterocyclic compounds which bear a pyrroloquinazoline moiety. As an illustration of the synthetic importance of these compounds, the total synthesis of the natural antitumor compound luotonin A was achieved through a tin-free radical cascade cyclization process. Not only do amide-iminyl radicals lead to new tetracyclic heterocycles but these nitrogen-centered radical species also react in aromatic homolytic substitutions. Indeed, the amide-iminyl radical moiety unprecedentedly displaces methyl, methoxy, and fluorine radicals from an aromatic carbon atom. This seminal reaction in the field of radical chemistry has been developed experimentally and its mechanism has additionally been investigated by a theoretical study.     

A combined theoretical and experimental study of efficient and fast titanocene-catalyzed 3-exo cyclizations

The mechanism of titanocene mediated 3-exo cyclizations was investigated by a combined theoretical and experimental study. A gradient corrected density functional theory (DFT) method has been scaled against titanocene dichloride, the parent butenyl radical, and in bond dissociation energy (BDE) calculations. The BP86 method using density fitting, and a basis set of triple-zeta quality emerged as a highly reliable tool for studying titanocene mediated radical reactions. The computational results revealed important kinetic and thermodynamic features of cyclopropane formation. Surprisingly, the beta-titanoxy radicals, the first intermediates of our investigations, were demonstrated to possess essentially the same thermodynamic stabilization as the corresponding alkyl radicals by comparison of the calculated BDEs. In contrast to suggestions for samarium mediated reactions, the cyclization was shown to be thermodynamically favorable in agreement with earlier kinetic studies. It was established that stereoselectivity of the cyclization is governed by the stability of the intermediates and thus the trans disubstituted products are formed preferentially. The observed ratios of products are in good to excellent agreement with the DFT results. By a combination of computational and experimental results, it was also shown that for the completion of the overall cyclopropane formation the efficiency of the trapping of the cyclopropylcarbinyl radicals is decisive.     

Mechanistic study of 7-endo selective radical cyclization of the aryl radical

Mechanistic studies on the novel 7-endo selective radical cyclization were carried out. The reaction afforded three products, 7-endo product, 6-exo product, and reduced product. The distribution of these products was estimated by GC analyses. The 7-endo/6-exo selectivity was almost constant against variation in the concentration of Bu₃SnH, while the reduction/cyclization ratio was sensitive to the concentration of Bu₃SnH. The reduction/cyclization ratio was mainly affected by the rotational isomeric ratio of the cyclization precursor. Kinetic analyses indicated that the cyclization process should be irreversible, and the rate constant of 7-endo/6-exo radical cyclization was estimated to be about 3.3 × 10⁸ s⁻¹ at 80 °C.     

A density functional theory study of the 5-exo cyclization reactions of alpha-substituted 6,6-diphenyl-5-hexenyl radicals

Density functional theory computations were done to study the 5-exo radical cyclization reactions of alpha-substituted 6,6-diphenyl-5-hexenyl radicals. The methoxy electron donor group substitution reduced the barrier to reaction by about 0.5 kcal/mol. On the other hand, the electron acceptor group substitutions (ethoxycarbonyl, carboxylic acid, carboxylate, and cyano) raised the barrier to reaction by varying amounts (0.5-2.1 kcal /mol). The entropic terms of these cyclization reactions are briefly discussed. Solvent effects on these reactions were explored by calculations that included a polarizable continuum model for the solvent. The density functional theory calculated results were found to be in good agreement with the experimental data available in the literature and help to explain some of the observed variation in these types of cyclization reactions with various substitutions. Our results also provide an explanation for why the rate constant for the carboxylate group substituted radical was found to be an order of magnitude smaller than the rate constant for those radicals with carboxylic acid and ethoxycarbonyl substitutions.     

Development of a 5-exo, 6-exo tandem radical cyclization to access bisabosqual A

Substrates were designed to undergo tandem radical cyclizations to afford the cis, cis-fused hexahydrobenzofurobenzopyran ring system of the bisabosquals. Studies with these revealed that different initiating systems gave different yields and somewhat different diastereomeric ratios. A photocatalytic cyclization was also successful with the bisabosqual substrate.     

Selective 6-endo cyclization of the acyl radicals onto the nitrogen of imine and oxazoline C-N bonds

Acyl radicals generated by the addition of alkyl or vinyl radicals to carbon monoxide cyclized onto the C-N bonds of imines and oxazoline with perfect 6-endo selectivity, driven by a preference for attack at nitrogen.     

Synthesis of 1H-indazole: a combination of experimental and theoretical studies

A new practical synthesis of 1H-indazole is presented. A previous mechanism for the cyclization step is proved to be nonfeasible and a hydrogen bond propelled mechanism is proposed. The new mechanism is suitable for similar cyclization, and a new reaction is predicted.     

Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its application to synthesis of the caprazamycin core

The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides were investigated. Substitution of the alkyne with an aryl group gave better results, presumably because it stabilized the transition state. Applying the reaction to a secondary amide, the caprazamycin core was successfully synthesized from commercially available material in eight steps.     

Total synthesis of (+)-isoschizandrin utilizing a samarium(II) iodide-promoted 8-endo ketyl-olefin cyclization

The 13-step synthesis of (+)-isoschizandrin reported herein features a samarium(II) iodide-promoted 8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomitantly with the required functionality and stereochemistry. In constructing (+)-isoschizandrin as a single atropisomer, the synthesis utilizes a kinetic resolution of a seven-membered lactone using a CBS-oxazaborolidine.     

Enantioselective total synthesis of guanacastepene N using an uncommon 7-endo Heck cyclization as a pivotal step

A convergent, enantioselective total synthesis of (+)-guanacastepene N was developed that features a 7-endo Heck cyclization as the key step. In the course of this synthesis, short syntheses of the enantiomerically pure cyclopentenone and cyclohexene building blocks 5 and 6, which constitute A and C ring fragments of guanacastepene N, were developed. These fragments were linked by a challenging conjugate addition reaction that also generated the C11 quaternary carbon stereocenter. Regioselective 7-endo Heck cyclization gave rise to a tricyclic intermediate, which was elaborated to complete the first total synthesis of guanacastepene N and the second enantioselective total synthesis of a guanacastepene natural product.     

Comparative experimental optical studies on 7.O5O.7 dimeric liquid crystal compound using theoretical models

In the present study, the optical properties of the 7.O5O.7 dimeric compound are reported. This dimeric compound exhibits typical smectic A to smectic F phase transition, and the main focus of our study is to observe the optical behaviour in SmA phase. In the dimeric compound, the two mesogens are connected by a linkage group or spacer. The presence of the linkage group and the terminal alkyl chains plays a vital role to change the behaviour of this compound as compared to the traditional monomeric compounds. Study of birefringence, refractive indices and normalised polarisation are essential to investigate the optical nature in liquid crystalline compounds. The optical study in our compound is carried out by using the thin prism experimental method with the help of He-Ne laser of wavelength 633 nm. Four-parameter model was used to obtained theoretically measured refractive indices and birefringence data. The theoretical results are then compared with the experimental results. Both the experimentally and theoretically calculated results are properly fitted in our dimeric compound.     

5-Exo versus 6-endo cyclization of nucleoside 2-sila-5-hexenyl radicals: reaction of 6-(bromomethyl)dimethylsilyl 1',2'-unsaturated uridines

The mode of cyclization of 2-sila-5-hexen-1-yl radicals generated from 6-(bromomethyl)dimethylsilyl-1',2'-unsaturated uridines was investigated. In contrast to the case of the 2'-unsubstituted 6-silicon-tethered substrate (4), which undergoes exclusive 6-endo-cyclization, reactions of the 2'-substituted (Me, CO2Me, OBz, and Cl) derivatives (14, 20, 22, and 24) uniformly proceeded in preferential or exclusive 5-exo-mode. The Tamao oxidation of the resulting cyclized products was also carried out to synthesize the corresponding 1'-C-hydroxymethyl derivatives.     

Kinetic and theoretical study of 4-exo ring closures of carbamoyl radicals onto C=C and C=N bonds

Carbamoyl radicals were generated from oxime oxalate amides, and the kinetics of their 4-exo cyclizations onto C=C and C=NO bonds, leading to beta-lactam-containing species, were studied by EPR spectroscopy. DFT computations with model carbamoyl radicals predicted 4-exo ring closures onto C=NO bonds to be facile, especially when tert-butyl substituents were present. The reverse ring-opening reactions were predicted to have much higher activation energies. Experimental evidence also favored slow reverse ring opening.     

Structural and vibrational investigation of para-nitraminopyridine N-oxide. A combined experimental and theoretical studies

The X-ray and vibrational spectroscopic analysis of para-nitraminopyridine N-oxide are reported. The crystals of investigated compound belong to P2(1) of the monoclinic system, Z=4, a=3.735 A, b=11.767 A, c=14.679 A and beta=93.27 degrees . Room temperature powder infrared and Raman spectra of the title compound and its deuterated analogue were measured. The molecular structure of p-nitraminopyridine N-oxide has been calculated with the aid of density functional (B3LYP) method with the extended 6-311++G(d,p) basis set. The calculated geometrical parameters of investigated molecule in gas phase were compared with experimental X-ray data. The harmonic frequencies, potential energy distribution (PED) and IR intensities of p-nitroaminopyridine N-oxide and its deuterated analogue were calculated with B3LYP method. The assignment of the experimental spectra has been made on the basis of the calculated PED. The time depend Hartree-Fock (TDHF) method was used for calculations of hyperpolarizability beta coefficient.     

Novel 7- and 8-endo 2-indolylacyl radical cyclizations: efficient construction of azepino- and azocinoindoles

Regioselective 7- and 8-endo cyclizations of selenoester derived 2-indolylacyl radicals upon amino tethered alkenes have been used to synthesize azepino[3,2-b]- and azocino[4,3-b]indoles, which are tricyclic subunits present in the indole alkaloids mersicarpine and apparicine, respectively.     

Axial and equatorial cyclohexylacyl and tetrahydropyranyl-2-acyl radicals. An experimental and theoretical study

Axial and equatorial cyclohexylacyl and tetrahydropyranyl-2-acyl radicals gave distinct EPR spectra thanks to surprisingly large beta-hydrogen atom hyperfine splittings that enabled them to be characterized and monitored. DFT computations indicated that the axial species (X = CH(2)) had a higher barrier to rotation about the (O)C(alpha)-C(beta) bond. The computed difference Delta H degrees for the axial and equatorial radicals (R = H, X = CH(2)) was 0.8 kcal mol(-)(1).