The regiochemistry of cyclization of alpha-sulfenyl-, alpha-sulfinyl-, and alpha-sulfonyl-5-hexenyl radicals: procedures leading to regioselective syntheses of cyclic sulfones and sulfoxides

A study of the cyclization of alpha-sulfenyl-, alpha-sulfinyl-, and alpha-sulfonyl-5-hexenyl and 5-methyl-5-hexenyl radicals reveals a unique contrast in the mode of ring closure of the radicals. In the case of the 5-hexenyl radicals, the sulfinyl-substituted species displays unexpected regioselectivity relative to its analogues. Thus, while the alpha-S- and alpha-SO(2)-5-hexenyl radicals give measurable and increasing quantities of 6-endo product, the alpha-sulfinyl species cyclizes with high selectivity (95.5:4.5) via a 5-exo mode. By contrast, ring closure of the 5-methyl-5-hexenyl radicals is found to give substantially the 6-endo product in all cases. It is the alpha-sulfonyl-5-methyl-5-hexenyl radical that now exhibits high regioselectivity (97.5:2.5) for 6-endo closure: an illustration of the synthetic value of this observation is the independent synthesis of the model cyclohexyl sulfone 61 in high yield. It is found that ring closure under the conditions employed occurs irreversibly in all cases.     

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 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).     

Regioselectivity of ring closure of 2-thia- and 2-sulfonyl-5-methyl-5-hexenyl radicals

Ring closure of the alpha-substituted radicals 4 (X = S, SO(2)) is observed to be irreversible and to lead to significant amounts of the product of 6-endo cyclization. Indeed, reduction of the sulfonyl-based radical 4 (X = SO(2)), in which regioselectivity is believed to be controlled by a combination of both steric and FMO interactions, is found to provide an excellent route to the cyclic sulfone 7 (X = SO(2)) in high yield. [reaction: see text]     

Control of the regioselectivity of sulfonamidyl radical cyclization by vinylic halogen substitution

The radical cyclization reactions of unsaturated sulfonamides were investigated. The photolysis of N-(4-halo-4-pentenyl)sulfonamides (X=I, Br, or Cl) with (diacetoxyiodo)benzene (DIB) and iodine at room temperature afforded exclusively the corresponding piperidines in 73-98% yield via 6-endo radical cyclization. On the other hand, the reactions of N-(5-halo-4-pentenyl)sulfonamides with DIB/I2 led to the only formation of the pyrrolidine products in 84-99% yield via 5-exo radical cyclization. The vinylic halogen substitution not only successfully inhibits the competing ionic iodocyclization process to allow the radical cyclization to proceed smoothly but also shows a remarkable effect in controlling the regioselectivity of cyclization.     

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.     

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.     

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.     

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.     

Regiochemistry in radical cyclization of allenes

The cyclization of allenic radicals was systematically studied for the first time by computational methods. It was found that the theoretical results at the ONIOM(QCISD(T)/6-311+G(2df,2p):UB3LYP/6-311+G(2df,2p)) level were in good agreement with all the available experimental data. For the cyclization of penta-3,4-dien-1-yl radicals the major product was penta-1,2-diene from direct reduction whereas a small amount of vinylcyclopropane may also be produced. For the cyclization of hexa-4,5-dien-1-yl radicals the major product is 1-methyl-cyclopentene. Furthermore, for the cyclization of hepta-5,6-dien-1-yl radicals both vinylcyclopentane and 1-methyl-cyclohexene are produced. Marcus theory analysis indicated that the formation of an olefinic radical product always had a lower intrinsic energy barrier than the formation of an allylic radical product. On the other hand, the formation of an olefinic radical product was always much less favorable than the formation of an allylic radical product in the thermodynamic term. For the cyclization of substituted hexa-4,5-dien-1-yl radicals, substitution at the allene moiety does not affect the regioselectivity where the allylic radical product is always favored. For the cyclization of hepta-5,6-dien-1-yl radicals, substitution at the allene moiety dramatically affects the regioselectivity, where some radical-stabilizing groups such as -CN and -COMe may even completely reserve the regioselectivity.     

Intramolecular cyclization of beta-amino and beta-ammonio radicals: a new synthetic route to the 1-azabicyclo

Treatment of 1-(2-phenylselenoethyl)-1,2,5,6-tetrahydropyridine (15) with tributyltin hydride affords only the product of reduction, demonstrating the reluctance of the 5-hexenyl radical 9 to undergo ring closure. When the nature of the radical is modified, either by introduction of an ester group at C4 or via its quaternary ammonium salt, cyclization occurs readily; while the radical 52 gives an excellent yield of 1-methyl-1-azoniabicyclo[3.2.1.]octyl bromide (55) uncontaminated with the product of reduction, the bicyclic product from 21 is accompanied by some reduced material. Production of the unwanted alkene can be eliminated in the latter by recourse to the quaternary ammonium ester 1-(2-bromoethyl)-4-carbethoxy-1-methyl-1,2,5,6-tetrahydropyridinium bromide (35) which, when exposed to tributyltin hydride, affords a 1:1 endo/exo mixture of 4-carbethoxy-1-methyl-1-azoniabicyclo[3.2.1]octyl bromide (37) exclusively. These results support the demonstration of the powerful polar effect of an ester function when attached to the double bond of a 5-hexenyl system, a property which can be exploited in the case of the radical 58. Treatment of the precursor, 1-(2-bromoethyl)-3-carbethoxy-1-methyl-3-pyrrolinium bromide (60), with tributyltin hydride generates 58 which is found to cyclize with high regioselectivity, affording a convenient high-yielding synthesis of the endo/exo isomers of 3-carbethoxy-1-methyl-1-azoniabicyclo[2.2.1]heptyl bromide 57. The isomeric bicyclo[2.2.1]heptyl ester 63 was not detected. These observations are in accordance with predictions based upon frontier molecular orbital considerations.     

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.     

7-endo selective aryl radical cyclization onto enamides leading to 3-benzazepines: concise construction of a cephalotaxine skeleton

Bu3SnH-mediated radical cyclizations of 2-(2-bromophenyl)-N-ethenylacetamide gave 6-exo cyclization product 15 as the major product, whereas N-[2-(2-bromophenyl)ethyl]-N-ethenylamides gave almost exclusively 7-endo cyclization products. These results indicated that the position of the carbonyl group on enamide played an important role in deciding the course of the cyclization. The 7-endo selective cyclization was applied to concise construction of a cephalotaxine skeleton.     

Synthesis of Nitrogen Bridgehead Bicyclic Heterocycles via Ring-Closure of beta-Ammonio 5-Hexenyl Radicals

The 2-(3-methylenepiperidinyl)ethyl radical (6) displays considerable reluctance to ring-closure under conditions which its carbocyclic analog, the 2-(3-methylenecyclohexyl)ethyl radical (2), cyclizes essentially completely. Molecular mechanics calculations suggest that the increased activation barrier associated with ring-closure of 6 is the result of a higher than expected transition state energy. A study of the behavior of beta-ammonio-substituted 5-hexenyl radicals, such as the 3,3-dimethyl-3-azonia-5-hexenyl radical (22), reveals that cyclization occurs readily. Treatment of 1-methyl-1-(2-(phenylselenyl)ethyl)-3-methylenepiperidinium iodide (20) with tributyltin hydride in tert-amyl alcohol yields the bridgehead nitrogen bicyclic heterocycle, 1,5-dimethyl-1-azoniabicyclo[3.2.1]octane iodide (26), in excellent yield and without contamination, thus providing an attractive synthetic route to this hitherto unknown heterocyclic system.     

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.     

Development of highly regioselective amidyl radical cyclization based on lone pair-lone pair repulsion

The substituent effect on the reactivity and regioselectivity of N-(4-pentenyl)amidyl radical cyclization was investigated. Exclusive 6- endo cyclization was observed for N-(4-pentenyl)amidyl radicals with internal vinylic heteroatom substitution (Cl, Br, I, OMe, SEt). The substituent on the carbonyl group also showed a significant influence on the reactivity of amidyl radicals, which increases in the order of Ph < Me < OEt. As a result, the photostimulated reactions of N-(4-halopent-4-enyl)amides and carbamates (X = Cl, Br, I) with DIB/I 2 or Pb(OAc) 4/I 2 led to the efficient and exclusive formation of the corresponding piperidines while those of N-(5-halopent-4-enyl)amides afforded the pyrrolidine products only. The halogen-substitution effect also allowed the 6- exo and 7- endo amidyl radical cyclization to proceed in a highly regioselective manner. The above experimental results, in combination with theoretical analyses, revealed that the lone pair-lone pair repulsion between the nitrogen radical and the vinylic heteroatom played an important role in controlling the regioselectivity of cyclization.     

Palladium-catalyzed synthesis of 2,3-disubstituted 5-azaindoles via heteroannulation reaction and of 2-substituted 5-azaindoles through domino sila-Sonogashira/5-endo cyclization

A general and efficient procedure for the synthesis of 2,3-disubstituted 5-azaindoles through the palladium-catalyzed heteroannulation of 4-acetamido-3-iodopyridines and diaryl-, dialkyl-, or arylalkylalkynes is described along with a study of the reaction regioselectivity. The preparation of 2-monosubstituted 5-azaindoles via sila-Sonogashira/5-endo cyclization is also reported. These methods allowed us to prepare 36 diversely substituted 5-azaindoles in good yields.     

Regiochemical control in intramolecular cyclization of methylene-interrupted epoxydiols

[reaction: see text] Methylene-interrupted epoxydiols have multiple regiochemical routes for cyclization. The 5-exo process is the most prevalent under acidic conditions. However, the regioselectivity can be controlled by the appropriate choice of acid promoter and pendant groups adjacent to the epoxide. The 5-exo product is obtained exclusively without the presence of a carbocation-stabilizing pendant group. Alkenyl and thiophenyl groups adjacent to the epoxide alter the regioselectivity and enable access to the 5-endo tetrahydrofuran and 6-endo tetrahydropyran products.     

New type of azacyclization: thermal preparation of 4,6-disubstituted 2-piperidinone from N-sulfonyldienamide and its substituent effect

The thermal 6-endo cyclization of N-sulfonyl-2,4-dienamide compounds to produce 4,6-disubstituted 2-piperidinone is described. The observed remarkable substituent effect due to the N-sulfonyl and C3 ethoxycarbonyl groups for acceleration of this 6-endo cyclization strongly suggests that the reaction would proceed via the 6π-azaelectrocyclization of the intermediary imidic acid. On the contrary, the corresponding 5-formyl and 5-acetyl derivatives rapidly cyclized at room temperature to produce the 5-exo cyclized products.     

5-Endo-trig radical cyclizations: disfavored or favored processes?

Relative kinetic data were determined for the 5-endo-trig cyclization of radical 12 compared to hydrogen abstraction from (TMS)(3)SiH in the temperature range of 344-430 K, which allows for the estimation of a rate constant of 2 x 10(4) s(-)(1) at 298 K with an activation energy of ca. 9 kcal/mol for the cyclization process. The 5-endo-trig cyclization of a variety of radicals that afford five-membered nitrogen-containing heterocycles was addressed computationally at the UB3LYP/6-31G level. The 5-endo vs 4-exo mode of cyclication and the effect of delocalization of the unpaired electron in the transition state were investigated. Because the ring formed during cyclization contains five sp(2) centers, electrocyclization via a pentadienyl-like resonance form was also considered. For comparison, similar calculations were performed for 4-penten-1-yl and related radicals. The factors that affect the activation energies of homolytic 5-endo-trig cyclization were determined. In the absence of steric or conformational effects, the endo cyclization to form the five-membered ring was strongly favored over exo cyclization to form the four-membered ring not only on thermodynamic grounds but also kinetically. When a substituent on the double bond was able to delocalize the unpaired electron in the transition state of the 4-exo path, the two modes of cyclization became kinetically comparable. These results have an important bearing on the generalization of the Baldwin-Beckwith rules, which classified the 5-endo-trig radical cyclization as a "disfavored" process.