Reaction iodoetherification

Oxepanes have been obtained by the iodoetherification of unsaturated alcohols using bis(5 / -collidine)iodine(I) hexafluorophosphate <96JOC5793>. Thus 6-hepten-l-ol affords 2-iodomethyloxepane in 95% yield. A similar reaction with, for example, (3Z,6Z)-3,6-octadien-l-ol affords 2-(iodomethyl)-2-methyl-4-oxepane. 

Haloetherification remains one of the most popular approaches towards tetrahydrofuran skeletons. Yus reported a double iodoetherification reaction promoted by a silver salt, affording l,7-dioxaspiro[4.5]decanes, and an example is shown in the scheme below <06T2264>. Kumar and Singh also reported an iodoetherification pathway to form 2,3-diphenyltetrahydrofurans <06T4018>. A bromoetherification converted 3-butenols into bromotetrahydrofurans <06TL5751>. 

A double iodoetherification of C2-symmetric acetals has been used for the desymmetrization of 1,6-dienes in an asymmetric total synthesis of rubrenolide (Equation 78) <2005AGE734>. Remarkably, four stereogenic centers have been installed in one reaction step. Stereoelectronic effects in the diastereoselective synthesis of 2,3,5-trisubstituted tetrahydrofurans via iodoetherification have been studied in detail, and I(2,4,6-collidine)2C104 proved to be an efficient reagent for highly stereoselective iodoetherifications <20010L429>. 

Iodoetherifications are particularly valuable reactions for tetrahydrofuran syntheses, since they not only occur with high stereoselectivities but under incorporation of a useful iodide functionality. Substrate-controlled reactions that... 

Galatsis group [14] reported a study on an NARC sequence involving (i) aldol reactions of enolates derived from the kinetic deprotonation of unsaturated esters, such as 25 and 28, to ketones (Fig. 9) and aldehydes (Fig. 10) followed by (ii) endo-cyclisation via intramolecular iodoetherification. As the enolates used in the study were racemic and the aldol reactions stereorandom, it would be interesting to repeat this work using a chiral auxiliary (e.g. a chiral amide). This should ensure high levels of enantio- and diastereo-selectivity. 

Another interesting use of TEMPO has been in free-radical substitution of alkyl halides. In this reaction, halides react with tributyltin hydride and TEMPO to yield A-alkoxyamine substitution products [18. This reaction is especially attractive in cases where anionic nucleophiles are sterically prevented from carrying out substitution reactions. An example of this can be seen in Barrett s synthesis of sucrose [18b], in which a stereoselective iodoetherification reaction was used to produce neopentyl alkyl iodide 13 (Scheme 5). Free radical substitution mediated by tributyltin hydride and TEMPO yielded A-alkoxyamine 14. The mechanism [19] involves TEMPO abstraction of hydrogen from tributyltin hydride [20] the stannyl radical then abstracts iodide from the substrate, and a second equivalent of TEMPO traps the resulting carbon radical. 

A more efficient route to 720 involves an intramolecular iodoetherification of 718. If the reaction is carried out in THF, a 4.8 1 mixture of 727 and 728 is obtained, but if the same reaction is run in ether the ratio increases to 8.5 1 (Scheme 105) [159,161]. After silylation, the mixture of isomers can be separated by flash chromatography. Removal of iodine affords... 

The bicyclic analogue 140 was prepared from the previously-described 3 -deoxy-3 -C-allylthymidine (Vol. 23, p. 218) by Cannizzaro reaction to establish a 4 -hydroxymethyl substituent followed by iodoetherification and hydro-genolysis. ... 

In a reaction resembling halohydrin formation (Section 6.17), vicinal haloethers are prepared from alkenes by reaction with an alcohol in the presence of halogens— usually bromine or iodine. This haleotherification proceeds through a cyclic halonium ion, which reacts with the alcohol. 1-Methylcyclohexene undergoes iodoetherification with ethanol in the presence of iodine to give ran -l-ethoxy-2-iodo-l-methylcyclohexane. 

An iodoetherification reaction (selected examples of an iodoetherification reaction [35—41] of a terminally disubstituted olefin bearing a hydroxyl group at the allyUc position) is shown in Fig. 7.19. As illustrated in Fig. 7.19, the reaction of substrate 67 with iodine in the presence of NaHC03 in THF gives compound 68a in 91 % yield [42]. The presence of a hydroxyl group induces aUylic 1,3-strain to favor a tram relative stereochemistry between C3-0 and C4—O bonds of the cyclization product (compound 68a). Furthermore, the antiperiplanar addition of the oxygen to the double bond activated by the iodine (I2) results in a product with a residual Cl bond anti to the newly formed C-O bond as in 68, 69 (Fig. 7.19). 

Labelle M, Guindon Y (1989) Diastereoselective synthesis of 2, 3-disubstituted tetrahydrofuran synthons via the iodoetherification reaction. A transition state model based rationaU-zation of the allylic asymmetric induction. J Am Chem Soc 111 2204—2210... 

Hennecke developed enantioselective haloetherification reactions via desymmetrisation of in situ generated meso-iodonium intermediates (Scheme 2.37). Chiral sodium phosphate 58 was used for the cyclisation of symmetrical ene-diol substrates 59 with l-iodopyrrolidin-2-one (60), and the corresponding iodoetherification products 61 were obtained with up to 71% ee. 

There has also been one report of an enantioselective iodoetherification reaction, which was catalyzed by the Na" " salt of a chiral phosphoric acid organocatalyst (Scheme 13.37) [63]. This transformation was unique in the sense that, in contrast to many other halocyclization reactions, the carbon-Todine bond-forming step was not stereodetermining. Rather, carbon-iodine bond-formation generated meso halonium ions, and it was the ring-opening of these achiral intermediates that was stereodetermining. 

The strategy proposed by Kang for achieving a synthesis of lasonohde A is outlined in Scieme 15. For the introduction of the side chain, Lee s procedure was adopted. Macrocychzation was performed via the Horner-Emmons reaction, and the construction of the C12-C28 triene unit was similar to Lee s protocol using Juha-type olefination and Still s ds-olefination. The A-ring 66 was formed by iodoetherification of the alkenyl alcohol 67, the tertially asymmetric centers of which were formed by asymmetric allylations. The construction of the key quaternary asymmetric carbon was carried out by the imique procedure of the thermodynamically controlled transacetahzation. The B-ring 68... 

We thought that the diol 30 might be available from endo alcohol 31 by a tether-mediated RCDA reaction as in the preparation of the diol 28. A mixture of alcohol 31 and alcohol 32 should be available by the coupling/electrocyclization strategy, and the exo alcohol 32 would be removed by iodoetherification and chromatography (Scheme 13). 

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