Mapping the Interactions of I₂, I^., I⁻, and I⁺ with Alkynes and Their Roles in Iodocyclizations

Abstract

A combination of experiment and theory has been used to explore the mechanisms by which molecular iodine (I2 ) and iodonium ions (I(+) ) activate alkynes towards iodocyclization. Also included in the analysis are the roles of atomic iodine (I(.) ) and iodide ion (I(-) ) in mediating the competing addition of I2 to the alkyne. These studies show that I2 forms a bridged I2 -alkyne complex, in which both alkyne carbons are activated towards nucleophilic attack, even for quite polarized alkynes. By contrast, I(+) gives unsymmetrical, open iodovinyl cations, in which only one carbon is activated toward nucleophilic attack, especially for polarized alkynes. Addition of I2 to alkynes competes with iodocyclization, but is reversible. This fact, together with the capacity of I2 to activate both alkyne carbons towards nucleophilic attack, makes I2 the reagent of choice (superior to iodonium reagents) for iodocyclizations of resistant substrates. The differences in the nature of the activated intermediate formed with I2 versus I(+) can also be exploited to accomplish reagent-controlled 5-exo/6-endo-divergent iodocyclizations.

Electrophile‐Mediated Reactions of Functionalized Propargylic Substrates

“…Thus, functionalized aryl-substituted propargylic amides 1, carbamates 2, ureas 3, or thioureas 4 in the present reaction formed 5-(isochroman-1-yl)-4H-1,3-oxazines or 5-(isochroman-1-yl)-4H-1,3-thiazines in good yields (Table 3, entries 1-6, 9-13, 16, 18-21, and 23-25). Compounds bearing either a terminal propargylic fragment or an electron-poor aromatic ring were not active towards 3,4-dihydroisochromenylium ion mediated reactions (entries 7,8,14,15,22,26). 1-Benzyl-3-[3-(4-methoxyphenyl)prop-2-ynyl]urea (3c) in reaction with 1-methoxyisochroman formed a mixture of inseparable products (entry 17) and we suppose that this is dictated by the two nucleophilic atoms (carbonyl oxygen and the nitrogen of the benzylamino fragment) presenting in the functional group.…”

“…[6] The carbon-carbon triple bond in charge transfer (CT) complexes between alkyne and halogen remains linear; therefore, nucleophilic sulfur attack occurs through the 5-exo-dig mode. From the results obtained, we hypothesized that during the iodonium-mediated reaction, two possible pathways are possible: 5-exo-dig cyclization reaction occurs after formation of a CT complex and competing 6-endo-dig cyclization takes place after conversion of the CT complex into open iodovinyl (I) or bridged iodirenium [7] (II) ions (Scheme 2).…”

“…Reac- The open-chain vinylic carbocations I can be in equilibrium with haloirenium or selenirenium ions II, which is consistent with recent experimental and theoretical studies. [7,8] Neither open-chain nor cyclic antiaromatic ions are very stable and the subsequent nucleophilic attack of the neigh-boring functional group or halogen counterion takes place readily. We suppose that the dominant process is dictated by the nucleophilicity of the internal functional group and by the stability of cyclic intermediates III.…”

“…Reactions between propargylic amides 1 and acyclic acetals under the optimized conditions (Table S1) led to the formation of predominantly six-membered products 7, with minor amounts of enones 23 and 24 (Table 4, entries [1][2][3][4][5][6][7][8].…”

Synthesis of 3‐Iodobenzofurans by Electrophilic Cyclization under Solventless Conditions in a Ball Mill

“…A representative example is machicendiol, which is used in the treatment of asthma, ulcers, and rheumatism . Common synthetic routes towards benzofurans involve electrophilic cyclizations of o ‐alkynylanisoles with molecular iodine, iodine monochloride, or bis(pyridine)iodonium tetrafluoroborate, among others (Scheme a) . Typically, such iodocyclizations are carried out in organic solvents such as DCM, 1,2‐dichloroethane or toluene .…”