Broad-spectrum radical cyclizations boosted by polarity matching. Carbonylative access to alpha-stannylmethylene lactams from azaenynes and CO

Free-radical mediated stannylcarbonylation of azaenynes provides a general [n + 1]-type annulation approach leading to alpha-stannylmethylene lactams. The cyclization is unusual in its breadth, covering 4-exo, 5-exo, 6-exo, 7-exo, and 8-exo modes.     

Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions

This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a 5-exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations. Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the β position.     

Controlling the regiochemistry of radical cyclizations

This review describes the results of our recent studies on the control of the regiochemistry of radical cyclizations. N-vinylic alpha-chloroacetamides generally cyclized in a 5-endo-trig manner to give five-membered lactams, whereas 4-exo-trig cyclization occurred when the cyclized radical intermediates were highly stabilized by an adjacent phenyl or phenylthio group to afford beta-lactams. The 5-exo or 6-exo cyclization of aryl radicals onto the alkenic bond of enamides could be shifted to the corresponding 6-endo or 7-endo mode of cyclization by a positional change of the carbonyl group of enamides. The 6-endo- and 7-endo-selective aryl radical cyclizations were applied to radical cascades for the synthesis of alkaloids such as phenanthroindolizidine, cephalotaxine skeleton, and lennoxamine. The 5-exo-trig cyclization of an alkyl radical onto the alkenyl bond of enamides could also be shifted to the 6-endo mode by a positional change of the carbonyl group of enamides. The 6-endo- selective cyclization was applied to the radical cascade to afford a cylindricine skeleton. Other examples of controlling the regiochemistry of radical cyclizations and their applications to the synthesis of natural products are also discussed.     

Stereoselective cascade reactions that incorporate a 7-exo acyl radical cyclization

[reaction: see text] Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two stereocenters are created by the reaction, and a single isomeric product was obtained from each of the five substrates examined. The relative configurations of the products are consistent with cyclizations occurring via chairlike or pseudochairlike transition states.     

Iodocyclization reactions for the desymmetrization of cyclohexa-1,4-dienes

Fifteen examples are presented showing that various modes of cyclization (5-endo, 5-exo, 6-endo, 6-exo, and 7-endo) can be used for the desymmetrization of cyclohexa-1,4-dienes. All take place with complete diastereocontrol and good yield.     

A study of aryl radical cyclization in enaminone esters

Aryl radical cyclization in N-phenyl, N-benzyl, and N-phenethyl enaminone esters 1a-f was studied. N-Benzyl and N-phenethyl enaminones afforded 5-exo and 6-exo cyclization products, respectively, but radical cyclization did not occur in N-phenyl enaminones. The rate constants for the 5-exo and 6-exo cyclization processes in secondary enaminones were estimated as being on the order of 10(7) s(-1) at 353 K; since DNMR experiments showed the rate constant for rotation around the enaminone C3-N bond to be on the order of 10(4) s(-1) at this temperature, the initial enaminone configuration is maintained throughout the cyclization process. PM3 calculations suggested that the nonoccurrence of endo and 4-exo cyclizations is due to the corresponding transition structures involving significant distortion of the conjugated enaminone system.     

8-endo versus 7-exo cyclization of alpha-carbamoyl radicals. A combination of experimental and theoretical studies

Atom transfer radical cyclization reactions of N-(4-pentenyl)iodoacetamides were investigated. The reactions were efficiently promoted by BF3.OEt2. For N-alkenyl-substituted iodoamides, excellent regioselectivity in favor of 8-endo cyclization was observed, while both 7-exo and 8-endo cyclization products were formed with the 8-endo cyclization preferred in the cases of N-(2-allylphenyl)-substituted iodoamides. Density functional theory calculations at the B3LYP/6-31G level revealed that both the s-trans and the s-cis conformational transition structures were feasible for the 8-endo cyclization of N-alkenyl-substituted alpha-carbamoyl radicals while 7-exo transition structures were much less stable. For the cyclization of N-(2-allylphenyl)-substituted alpha-carbamoyl radicals, the transition structures for 8-endo and 7-exo cyclizations were of comparable energy. These results were in excellent agreement with the experimental observations.     

Pushing radical cyclization from regioselective to regiospecific: cyclization of amidyl radicals controlled by vinylic halogen substitution

Efficient and regiospecific 6-exo, 7-endo, 7-exo, and even 8-endo amidyl radical cyclizations can be accomplished by the direct reactions of unsaturated N-H amides if they bear a vinylic halogen (Cl, Br, I) substituent. This remarkable halogen-substitution effect could be rationalized in terms of lone pair-lone pair electron repulsion between the N radical and the vinylic halogen atom, in addition to the well-known steric and radical-stabilizing effect. [reaction: see text]     

Generation of 6-(Trifluoromethyl)-4,5-dihydro-2(3H)-pyridone and the Application to Synthesis of Some Fused Nitrogen Heterocycles Carrying a Trifluoromethyl Group on the Bridgehead Position via Radical Cyclization of Dihydropyridones

Staudinger/aza-Wittig reaction of 6,6,6-trifluoro-5-oxohexanoyl azide with PPh(3) or PBu(3) was examined. A reactive intermediate acyl imine 1 was trapped by methanol. Without nucleophile, isomerized enamide form 3 was obtained. N-Iodobenzoylation and N-haloalkylation of 3 and following radical cyclization via the 5-exo or 6-exo mode gave benzoindolizidinone, indolizidinone, and quinolizidinone derivatives 10-14, which have a trifluoromethyl group at the bridgehead position adjacent to nitrogen. Although LiAlH(4) reduction of 10 and 11 gave a mixture of saturated benzoindolizidine 15 and amino alcohol 16, reduction with BH(3)/THF selectively gave the desired 15 and indolizidine 17 from 13.     

Laser flash photolysis kinetic studies of enol ether radical cations. Rate constants for heterolysis of alpha-methoxy-beta-phosphatoxyalkyl radicals and for cyclizations of enol ether radical cations

Two series of enol ether radical cations were studied by laser flash photolysis methods. The radical cations were produced by heterolyses of the phosphate groups from the corresponding alpha-methoxy-beta-diethylphosphatoxy or beta-diphenylphosphatoxy radicals that were produced by 355 nm photolysis of N-hydroxypryidine-2-thione (PTOC) ester radical precursors. Syntheses of the radical precursors are described. Cyclizations of enol ether radical cations 1 gave distonic radical cations containing the diphenylalkyl radical, whereas cyclizations of enol ether radical cations 2 gave distonic radical cation products containing a diphenylcyclopropylcarbinyl radical moiety that rapidly ring-opened to a diphenylalkyl radical product. For 5-exo cyclizations, the heterolysis reactions were rate limiting, whereas for 6-exo and 7-exo cyclizations, the heterolyses were fast and the cyclizations were rate limiting. Rate constants were measured in acetonitrile and in acetonitrile solutions containing 2,2,2-trifluoroethanol, and several Arrhenius functions were determined. The heterolysis reactions showed a strong solvent polarity effect, whereas the cyclization reactions that gave distonic radical cation products did not. Recombination reactions or deprotonations of the radical cation within the first-formed ion pair compete with diffusive escape of the ions, and the yields of distonic radical cation products were a function of solvent polarity and increased in more polar solvent mixtures. The 5-exo cyclizations were fast enough to compete efficiently with other reactions within the ion pair (k approximately 2 x 10(9) s(-1) at 20 degrees C). The 6-exo cyclization reactions of the enol ether radical cations are 100 times faster (radical cations 1) and 10 000 times faster (radical cations 2) than cyclizations of the corresponding radicals (k approximately 4 x 10(7) s(-1) at 20 degrees C). Second-order rate constants were determined for reactions of one enol ether radical cation with water and with methanol; the rate constants at ambient temperature are 1.1 x 10(6) and 1.4 x 10(6) M(-1) s(-1), respectively.     

Asymmetric Synthesis of Octahydrobenzofuran Core Structure with Three Contiguous Stereogenic Centers and Development of the Absolute Configurations

Cyclization of enantiopure (S/R)-1 with halogen-reagent-constructed enantiopure octahydrobenzofuran core structure with contiguous three stereogenic centers of both enantiomers (SRR and RSS). The absolute configurations of all compounds have been established from x-ray analysis of the single crystal of (3aS,7aR,7R)-3. The chiral initiation in diastereoselective mode of 5-exo ring closure across C?C bond of pendant cyclohexene moiety has been proposed.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

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.     

Synthesis and Chemical Transformations of 7-Hydroxybicyclo[3.3.1]nonane-3-carbohydrazide

Russian Journal of Organic Chemistry - The reaction of 4-oxahomoadamantan-5-one with hydrazine gave (3-exo,7-endo)-7-hydroxybicyclo[3.3.1]nonane-3-carbohydrazide. The latter was reacted with...     

Generation of alpha-phosphonovinyl radicals and development of a new route to highly functionalized vinylphosphonates and vinylphosphonate-incorporated carbocyclic or heterocyclic compounds via a radical trapping sequence

The first direct generation of synthetically useful alpha-phosphonovinyl radicals was achieved by treatment of alpha-phosphonovinyl halides with a tributyltin radical. The alpha-phosphonovinyl radicals 2a-d were trapped with electron-rich olefins and an electron-deficient olefin to produce alpha-functionalized vinylphosphonates 3a-f in 16-55% yields. The alpha-phosphonovinyl radicals 7e-g containing the YCH2CH=CH2 (Y = O, CH2, S) substituent at the beta-position afforded mixtures of 5-exo and 6-endo cyclization products, 5e-g and 6e-g, in good yields. The 5-exo/6-endo product ratios increase in the following order of the beta-substituent: OCH2CH=CH2 > CH2CH2CH=CH2 > SCH2CH=CH2. The effects of the beta-substituents upon the cyclization reaction were discussed. Radical cyclization of alpha-phosphonovinyl radicals bearing functional groups such as geranyloxy, geranylthio, and (2-cyclohexen-1-yl)thio groups at the beta-position afforded 5-exo, 5-exo and 6-endo, and cis-fused-5,6-ring cyclization products incorporating an alpha,beta-unsaturated phosphonate unit within the ring, respectively, in good yields. The alpha-phosphonovinyl radical 20 underwent tandem radical cyclization-radical cyclization to produce a mixture of two isomeric bicyclo[4.3.0]nonenes including a vinylphosphonate moiety in high yield.     

Intramolecular reactions of hydroperoxides and oxetanes: stereoselective synthesis of 1,2-dioxolanes and 1,2-dioxanes

[reactions: see text] The 5-exo openings of oxetanes by hydroperoxides proceed rapidly and stereospecifically to furnish 1,2-dioxolanes. The corresponding 6-exo cyclizations are slower and proceed with moderate stereoselectivity. In the case of hydroperoxy acetals, 5-exo nucleophilic transfer of alkoxide competes effectively with 6-exo attack by the hydroperoxide.     

Radical and anionic response of N-(Bromomethanesulfonyl)-substituted alpha,alpha'-bridged piperidine substrates

The N-(bromomethanesulfonyl) azabicyclic ketones 2a-c and their exo-methylene analogues 1a-c were prepared. Our examination of the radical-induced behavior of the latter triad provided experimental evidence for the propensity of the b and c systems to engage in 7-endo cyclization. For 1a, only reductive debromination was observed. In no instance was ring closure by the 6-exo radical mode seen. As concerns ketones 2a-c, all three showed a remarkable facility for engaging in intramolecular S(N)2 displacement in the presence of KHMDS. Yields at the mid-80% level were realized irrespective of the value of n. Molecular mechanics calculations of the Monte Carlo type were performed on several conformational isomers and product classes in an effort to provide support for the explanatory conclusions offered as rationale for the collective experimental observations.     

An unequivocal1H NMR structural assignment of TOX8 and TOX9, the two most abundant toxaphene congeners in marine mammals

The structure of the two most abundant toxaphene congeners has unequivocally been established by 500 MHz¹H NMR spectroscopy as 2-endo,3-exo,5-endo, 6-exo,8,8,9,10,10-nonachlorobornane (TOX9) and as 2-endo,3-exo,5-endo,6-exo,8,8,10,10-octachlorobornane (TOX8). Semiempirical calculations (AM1 and PM3-MNDO) were carried out for both structures. The distance information found by nuclear Overhauser enhancement (NOE) for the protons is in agreement with the energy minimized AM1 and PM3-MNDO structures. For these definitively established NMR data for TOX8 and TOX9, together with literature data for other toxaphene isolates, a set of rules has been derived for¹H chemical shifts in polychlorinated bornane structures. A set of rules is also proposed for assigning systematical nomenclature to NMR-derived polychloro bornane structures.     

Stereoselective amino-hydroxylation of the double bond in 7-oxabicyclo[2.2.1]hept-5-en-2-yl derivatives. Remote substituent participation in acid-catalyzed decompositions of aziridines and triazolines

An efficient method has been developed for the stereoselective substitution of 7-oxabicyclo[2.2.1]hept-2-yl derivatives by protected amino group at C(5-exo) and hydroxy group at C(6-endo).     

Palladium-catalyzed intramolecular cyanoamidation of alkynyl and alkenyl cyanoformamides

[reaction: see text] The five- to seven-membered alpha-alkylidene lactams were prepared in 45-99% yield by the palladium-catalyzed cyanoamidation of alkynyl cyanoformamides. The reaction proceeded exclusively in a 5-exo mode, giving the corresponding (Z)-alkenes as major products. The reaction was also applied to 1,1-disubstituted alkenes to afford oxindoles bearing a quaternary carbon center.     

An unequivocal1H NMR structural assignment of TOX8 and TOX9, the two most abundant toxaphene congeners in marine mammals

The structure of the two most abundant toxaphene congeners has unequivocally been established by 500 MHz¹H NMR spectroscopy as 2-endo,3-exo,5-endo, 6-exo,8,8,9,10,10-nonachlorobornane (TOX9) and as 2-endo,3-exo,5-endo,6-exo,8,8,10,10-octachlorobornane (TOX8). Semiempirical calculations (AM1 and PM3-MNDO) were carried out for both structures. The distance information found by nuclear Overhauser enhancement (NOE) for the protons is in agreement with the energy minimized AM1 and PM3-MNDO structures. For these definitively established NMR data for TOX8 and TOX9, together with literature data for other toxaphene isolates, a set of rules has been derived for¹H chemical shifts in polychlorinated bornane structures. A set of rules is also proposed for assigning systematical nomenclature to NMR-derived polychloro bornane structures.