On the mechanism and kinetics of radical reactions of epoxyketones and epoxynitriles induced by titanocene chloride

The reactions of a series of epoxynitriles and epoxyketones induced by titanocene chloride have been studied. The kinetics of the decyanogenation of beta,gamma-epoxynitriles with Ti(III) corresponds to a radical reaction (k25 approximately 106 s-1), as demonstrated by competition experiments with H-transfer from 1,4-cyclohexadiene (1,4-CHD) or PhSH or conjugate addition to acrylonitrile. The 5-exo cyclization onto nitrile induced by Ti(III) is a radical reaction (k25 approximately 107 s-1) as seen in competition experiments with H-transfer from PhSH or the titanocene-water complex. The iminyl or alkoxyl radicals generated by 5-exo cyclization onto nitriles or ketones only undergo a reduction with Ti(III). This reaction overwhelms any alternative process, such as tandem cyclization onto alkenes or beta-scission. Iminyl radicals generated by 4-exo cyclizations onto nitriles undergo reduction with Ti(III) and beta-scission reaction in a ratio of 96:4 when the alpha-substituent is CN. Alkoxyl radicals from 4-exo cyclizations onto ketone carbonyls undergo reduction with Ti(III) and beta-scission in a ratio of 60:40 when the alpha-substituent is COOR. In nearly all the reactions studied, the role of Ti(III) is triple: a radical initiator (homolytic cleavage of oxirane), a Lewis acid (coordination to CN or C=O), and a terminator (reduction of iminyl or alkoxyl radicals).     

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.     

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.     

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).     

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.     

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.     

Stereoselective synthesis of 2,4,5-trisubstituted piperidines via radical cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.     

Theoretical elucidation of kinetic and thermodynamic control of radical addition regioselectivity

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*) calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined. Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the observation of different products from different research groups arises from the difference in experimental conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of 6-endo cyclization through kinetic control.     

Preparation of polycyclic systems by sequential 5-exo-digonal radical cyclization, 1,5-hydrogen transfer from silicon, and 5-endo-trigonal cyclization

Radicals of type 1 undergo 5-exo diagonal cyclization, and the resulting vinyl radical abstracts hydrogen from silicon to afford a silicon-centered radical. This radical closes in a 5-endo trigonal manner to generate radicals of type 4, which are reduced (4 --> 5) by stannane, except when the starting acetylene carries a terminal trimethylstannyl group. In this case, radicals 4 expel trimethylstannyl radical to afford vinyl silanes 6. The stereochemical outcome of the radical cascade 1 --> 5 is controlled by the stereochemistry of the oxygen-bearing carbon in 1 (see starred atom). The sequence can be initiated by carbon-, alpha-substituted carbon-, oxyacyl-, and carbamoyl radicals and generates a silicon-containing ring fused onto a carbocycle or heterocycle. Numerous examples are described, as well as a number of transformations of the final cyclization products, especially their response to n-Bu(4)NF and to BF(3).OEt(2), reagents that cleave the newly formed carbon-silicon bond.     

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.     

Cyclization of aryl acyl radicals generated from S-(4-cyano)phenyl thiolesters by a nickel complex catalyzed electroreduction

Aromatic acyl radicals generated from S-(4-cyano)phenyl 2-alkenylthiobenzoate by a nickel complex catalyzed electroreduction undergo 5- and 6-exo cyclization to give 1-indanone and dihydro-1-naphthalenone derivatives, respectively.     

New Fe(III)-mediated radical cascade reactions of cyclopropyl silyl ethers

[reaction: see text] Fe(III)-mediated ring opening of cyclopropyl ethers bearing a phenyl-substituted butenyl side chain leads to the generation of beta-keto radicals that undergo 5-exo cyclization followed by a novel cascade sequence resulting in the formation of tricyclic ethers.     

Radicals masquerading as electrophiles: a computational study of the intramolecular addition reactions of acyl radicals to imines

Ab initio calculations using 6-311G**, cc-pVDZ, and aug-cc-pVDZ, with (MP2, QCISD, CCSD(T)) and without (UHF) electron correlation, and density functional methods (BHandHLYP and B3LYP) predict that cyclization of the 5-aza-5-hexenoyl and (E)-6-aza-5-hexenoyl radicals proceed to afford the 5-exo products. At the CCSD(T)/cc-pVDZ//BHandHLYP/cc-pVDZ level of theory, energy barriers (deltaE(double dagger)) of 36.1 and 47.0 kJ mol(-1) were calculated for the 5-exo and 6-endo pathways for the cyclization of the 5-aza-5-hexenoyl radical. On the other hand, at the same level of theory, deltaE(double dagger) of 38.9 and 45.4 kJ mol(-1) were obtained for the 5-exo and 6-endo cyclization modes of (E)-6-aza-5-hexenoyl radical, with exothermicities of about 27 and 110 kJ mol(-1) calculated for the exo and endo modes, respectively. Under suitable experimental conditions, the 6-endo cyclization product is likely to dominate. Analysis of the molecular orbitals involved in these ring-closure reactions indicate that both reactions at nitrogen are assisted by dual orbital interactions involving simultaneous SOMO-pi* and LP-pi* overlap in the transitions states. Interestingly, the (Z)-6-aza-5-hexenoyl radical, that cannot benefit from these dual orbital effects is predicted to ring-close exclusively in the 5-exo fashion.     

Regiochemistry in aryl radical cyclization onto methylenecycloalkanes

Bu(3)SnH-mediated aryl radical cyclization onto methylenecycloalkanes having a phenylthio, an ester, or a nitrile group at the terminus of the alkenic bond provides exclusively exo cyclization products. The results are in sharp contrast to those reported for nonsubstituted methylenecycloalkanes, which give exclusively endo cyclization products. Formation of endo cyclization products has been suggested to be a result of a consecutive 5-exo cyclization of an aryl radical and neophyl rearrangement. The exo-selective aryl radical cyclization offers a new method for synthesizing fused aromatic compounds containing a benzylic quaternary carbon atom.     

Synthesis of heteroarenes using cascade radical cyclisation via iminyl radicals

Cascade radical cyclisation involving homolytic aromatic substitution has been used to synthesise new tetracycles. Treatment of vinyl iodide radical precursors with Me(3)Sn. radicals (from hexamethylditin) yielded intermediate vinyl radicals which undergo 5-exo cyclisation onto suitably placed nitrile groups to yield intermediate iminyl radicals. The iminyl radicals undergo aromatic homolytic substitution via 6-endo cyclisation (or 5-exo cyclisation followed by neophyl rearrangement) with loss of hydrogen (H.) in a H-abstraction step. We propose that this abstraction was facilitated by tert-butoxyl (t-BuO.) radicals from di-tert-butyl peroxide or methyl radicals, generated from breakdown of trimethylstannyl radicals (Me(3)Sn.). The biologically active alkaloids mappicine and luotonin A were synthesised using the new methodology. A novel radical conversion of nitriles to primary amides is proposed.     

Stereoselective synthesis of cyclic ethers using vinylogous sulfonates as radical acceptors: effect of E/Z geometry and temperature on diastereoselectivity

Treatment of the E-vinylogous sulfonates 1a-g with tris(trimethylsilyl)silane and triethylborane, in the presence of air, furnished the cyclic ethers 2/3a-g with good to excellent diastereoselectivity favoring the cis-isomer 2. This study demonstrated the level of stereocontrol in a 6-exo radical cyclization and may be attributed to the type of radical intermediate. Hence, the modest selectivity obtained for the cyclization of 1e may be a function of the acyl radical geometry (sp2) and high inversion barrier (29 kcal/mol) as compared to the alkyl (1 kcal/mol) and vinyl (2.9 kcal/mol) radicals. This is consistent with the acyl radical cyclization having an earlier transition state than the corresponding alkyl and vinyl radicals. The modest diastereoselectivity can be improved dramatically using the Z-vinylogous sulfonate (> or =34:1; R = Ph) to promote kinetic trapping of the s-trans rotamer I and III, respectively (Figure 1). The 5-exo alkyl radical cyclization reaction under nonreductive Keck-allylation conditions was also examined, in which 8 was formed in 91% overall yield. This transformation provides a convenient method for in situ homologation and should be applicable to target directed synthesis.     

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.     

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.     

Titanocene catalyzed 4-exo cyclizations: mechanism, experiment, catalyst design

A method for the preparation of a variety of cyclobutanes via 4-exo cyclization of radicals is presented. Radical generation is carried out by electron transfer from titanocene(III) chlorides to epoxides. The reaction relies on the acceleration of the cyclization through the use of alpha,beta-unsaturated carbonyl compounds as radical traps and the thermodynamic stabilization of the cyclobutylcarbinyl radicals through conjugation. The mechanism of the transformation was investigated by a combined theoretical and experimental study. The computational results provide the crucial energetic and structural features of pertinent intermediates and transition structures. Moreover, the origins of the diastereoselectivity of the 4-exo cyclization are outlined for the first time. Catalysts for those cases where "Cp2TiCl" did not perform in a satisfactory manner have been devised. Through the introduction of tert-butyl or cyclo-hexyl substituted cyclopentadienyl ligands the longevity of the pivotal beta-titanoxy radicals is increased sufficiently enough to enable the slow but often surprisingly diastereoselective formation of the cyclobutylcarbinyl radical. The resulting transformation constitutes the first general approach to cyclobutanes using radical chemistry.     

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.