5-exo Cyclization Research Articles

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.

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.

Rate Constants for Anilidyl Radical Cyclization Reactions

[reaction: see text] N-Aryl-5,5-diphenyl-4-pentenamidyl radicals (3) were produced by 266 nm laser-flash photolysis of the corresponding N-(phenylthio) derivatives, and the rate constants for the cyclizations of these radicals were measured directly. The 5-exo cyclization reactions were fast (k(c) > 2 x 10(5) s(-1)), and radicals 3 generally behaved as electrophilic reactants with a Hammett correlation of rho = 1.9 for five of the six radicals studied. However, the p-methoxyphenyl-substituted radical 3f cyclized much faster than expected from the Hammett analysis. Variable temperature studies of parent radical 3a (aryl = phenyl) gave an Arrhenius function with log k = 9.2 - 4.4/2.3RT (kcal/mol). The rate constant for the reaction of p-ethylphenyl-substituted anilidyl radical 3b with Bu(3)SnH at 65 degrees C was k(T) = 4 x 10(5) M(-1) s(-1).

Bu3SnH‐Mediated 5‐Exo Selective Radical Cyclization of N‐Vinyl‐α,β‐unsaturated Amides Leading to γ‐Lactams.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diphenyl Diselenide as a Useful Reagent for Intermolecular Domino Reactions of Various Unsaturated Compounds under Photoirradiation Conditions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Palladium(II)-Catalyzed Oxidative Transformation of Allylic Alcohols and Vinyl Ethers into 2-Alkoxytetrahydrofurans: Catechol as an Activator of Catalyst

[chemical reaction: see text]. A highly effective synthesis of 2-alkoxytetrahydrofurans from allylic alcohols and vinyl ethers was achieved by using catalytic amounts of Pd(OAc)2, Cu(OAc)2, and catechol (1:1:2) under O2. The use of catechol as an activator of Pd(II)-Cu(II) catalyst has been unprecedented. The 2-alkoxytetrahydrofurans are formed via oxypalladation of allylic alcohols toward vinyl ethers followed by 5-exo cyclization of the resulting oxypalladation intermediate and subsequent beta-Pd-H elimination. No 6-endo cyclization of the oxypalladation intermediate occurs.

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.

Thermodynamic and Strain Effects in the Competition between 5-Exo-dig and 6-Endo-dig Cyclizations of Vinyl and Aryl Radicals

Electronic and structural factors controlling the competition between 5-exo-dig and 6-endo-dig cyclizations of sp2-radicals were analyzed using a combination of available experimental data and computation. Although the stereoelectronically favored 5-exo pathways usually has the lower activation energy, formation of a new aromatic ring not only makes the 6-endo process favorable thermodynamically in conjugated systems but also lowers its activation barrier to the extent where the 5-exo/6-endo selectivity is controlled by subtle factors such as the different sensitivity of the two pathways to strain effects in polycyclic systems. In particular, the stronger sensitivity of the 5-exo pathway to strain leads to a crossover in selectivity. The 6-endo cyclization is kinetically favored in smaller (and strained) cycles, whereas the 5-exo cyclization has lower barriers in the larger rings.

Bu 3SnH-mediated 5-exo selective radical cyclization of N-vinyl-α,β-unsaturated amides leading to γ-lactams

Treatment of N-vinyl-α,β-unsaturated amides 1a– h with Bu 3SnH and a catalytic amount of AIBN in boiling benzene caused 5-exo cyclization of allylic O-stannyl ketyl radicals generated by addition of Bu 3Sn· on the amide-oxygen atoms to provide γ-lactams 2a– h after acidic workup. When enamide 1d was treated with Bu 3SnH in the presence of AIBN followed by aldehydes 3a– d , sequential radical cyclization and aldol reactions occurred to afford anti-adducts 4a– d and syn-adducts 5a, b .

Diphenyl Diselenide as a Useful Reagent for Intermolecular Domino Reactions of Various Unsaturated Compounds under Photoirradiation Conditions

Abstract This paper describes full details of a series of intermolecular domino reactions mediated by diphenyl diselenide (PhSeSePh). Diphenyl diselenide, which has just the right strength of carbon radical capturing ability, can be employed as a useful mediator for intermolecular domino reactions of unsaturated compounds. Upon irradiation through Pyrex with a tungsten lamp (hv > 300 nm), a sequential addition of diphenyl diselenide to alkynes bearing an electron-withdrawing group and alkenes bearing an electron-donating group proceeds successfully to provide the corresponding intermolecular three-component coupling products in high yields. In place of alkenes, the use of isocyanides leads to the formation of the corresponding three-component coupling products of alkynes, isocyanides, and (PhSe)2, selectively. Moreover, when two kinds of alkenes (i.e., electron-rich alkenes and electron-poor alkenes) are used in this photoinduced alkyne-(PhSe)2 reaction system, a novel domino reaction of diphenyl diselenide with an alkyne and two kinds of alkenes, followed by 5-exo radical cyclization, takes place sequentially to provide the corresponding cyclic four-component coupling products in good yields.

Generation of α‐Phosphonovinyl Radicals and Development of a New Route to Highly Functionalized Vinylphosphonates and Vinylphosphonate‐Incorporated Carbocyclic or Heterocyclic Compounds via a Radical Trapping Sequence.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Total Synthesis of (.+‐.)‐Heliannuol C and E via Aromatic Claisen Rearrangement.

The total synthesis of heliannuol C and E from a common intermediate are described. Key steps in the synthesis include a regioselective aromatic Claisen rearrangement to install the (1-vinyl)-4-methyl-3-pentenyl substituent and regioselective biomimetic 7-endo and 6-exo phenol epoxide cyclizations to form the cyclic ether moieties.

Intramolecular cyanoboration of alkynes via activation of boron–cyanide bonds by transition metal catalysts

Cyano(dialkylamino)boryl ethers of homopropargylic alcohols undergo intramolecular addition of a B–CN bond across their carbon–carbon triple bonds (cyanoboration) in the presence of palladium and nickel catalysts, furnishing five-membered cyclic boryl ethers regioselectively in good yields via 5-exo cyclization. The products were transformed into highly substituted α,β-unsaturated nitriles via Suzuki–Miyaura coupling to aryl iodides, rhodium-catalyzed conjugative addition to methyl vinyl ketone, and rhodium-catalyzed protodeborylation.

Theoretical Investigation on the Mechanisms of the PtCl2-Mediated Cycloisomerization of Polyfunctionalized 1,6-Enynes. 2. Propargylic Carboxylates

The PtCl2-mediated cycloisomerization of hept-1-en-6-ynes functionalized at propargylic positions shows a high versatility and may afford different kinds of products. On the basis of a broad DFT computational study, mechanistic understandings of these processes are provided. The results suggest that these reactions could proceed through cyclopropyl platinum carbenes formed by endo or by exo cyclization routes. The role of the propargylic substituent and the additional alkene chain for dienyne precursors in the course of each type of cycloisomerization is discussed. Thus, although the metathesis process and formation of polycyclic adducts involves an initial 5-exo cyclopropanation path, a propargylic acyl group promotes the formation of bicyclic enol esters by an initial endo cyclopropanation, followed by [1,2]-acyl migration. This bulky propargylic group also inhibits other cycloisomerization reactions due to steric interactions, such as the Alder-ene process, and simultaneously allows an easy [1,2]-acyl migration by anchimeric assistance to yield bicyclic [n.1.0] enol esters.

Microwave Enhanced Tandem 5‐exo Cyclization/Claisen Rearrangement Reactions: A Convenient Route to Cycloheptanoid Ring Systems.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Palladium(II)-Catalyzed Intramolecular Aminobromination and Aminochlorination of Olefins.

The first intramolecular aminobromination and aminochlorination of olefins catalyzed by palladium(II) is reported. These reactions use a stoichiometric amount of copper(II) halide salt to aid in halogen transfer and catalyst oxidation. The yields are generally high and the degree of regioselectivity (endo vs exo cyclization) varies with substrate structure. Control experiments were performed to determine the requirements for a catalytic reaction. Solvent, temperature, and the nature of the copper halide salt all effect the course of the reaction.

NO3×‐Induced Self‐Terminating Radical Oxygenations: Diastereoselective Synthesis of Anellated Pyrrolidines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cyclization or Hydrogen Migration: Theoretical Study and Experimental Evidence on the Reactivities of Unsaturated Amidyl Radicals

[reaction: see text] Theoretical calculations (B3LYP/6-31G) backed up by deuterated experiments reveal that the N-substituents (R) play a crucial role in determining the reaction pathways of unsaturated amidyl radicals. With the increase of the bulkiness of N-alkyl group, the activation energy for 6-exo cyclization increases steadily, while the activation energy for 1,5-H abstraction remains almost unchanged. Therefore, cyclization occurs exclusively when R is H while 1,5-H migration occurs exclusively when R is t-Bu.

A pox on hexavalent chromium: OSHA's proposal to severely reduce emission levels has spurred the search for substitute materials

Important naphthoquinones fused with an O-containing six-, seven- and eight-membered ring along with one tetracyclic compound, which are normally difficult to construct, have been synthesized using intramolecular Heck reaction where 6-exo trig, 7-endo trig and 8-endo trig cyclizations take place, respectively.

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.