Iodocyclization

The iodocyclization of 1,4-dihydropyridines was used as the key step for the formal total synthesis of Sempervirine (327) as shown in Scheme 102 (99JOC2997). 

The Lewis acid-catalyzed ene reaction of 3-methylene-2,3-dihydrofuran (available by Wolflf-Kishner reduction of 3-furaldehyde <93TL5221>) with aldehydes gives the corre onding alcohols in good to excellent yields <96TL7893>. 5- >ttto-dig iodocyclizations of alk-3-yn-l,2-diols. 

The 4-pentenoyl group is easily removed from amides by I2 and can be used as a protecting group. The mechanism of cleavage involves iodocyclization and hydrolysis of the resulting iminolactone (see Section 4.2.1).239... 

Similar to pyridinium hydrotribromide Selective iodination and iodocyclization. 

Electrophilic iodine reagents are extensively employed in iodocyclization (see Section 4.2.1). Several salts of pyridine complexes with 1+ such as bis-(pyridinium)iodonium tetrafluoroborate and b/.s-(collidine)iodonium hexafluorophos-... 

Several other nucleophilic functional groups can be induced to participate in iodocyclization reactions. t-Butyl carbonate esters cyclize to diol carbonates.79... 

Enhanced stereoselectivity has been found using IBr, which reacts at a lower temperature.81 (Compare Entries 6 and 7 in Scheme 4.4.) Other reagent systems that generate electrophilic iodine, such as KI + KHSOs,82 can be used for iodocyclization. 

Analogous cyclization reactions are induced by brominating reagents but they tend to be less selective than the iodocyclizations.83 The bromonium ion intermediates are much more reactive and less selective. 

The iodocyclization products have a potentially nucleophilic oxygen substituent (3 to the iodide, which makes them useful in stereospecific syntheses of epoxides and diols. 

Positive halogen reagents can cyclize y- and 8-hydroxyalkenes to tetrahydro-furan and tetrahydropyran derivatives, respectively.85 Iodocyclization of homoal-lylic alcohols generates 3-iodotetrahydrofiirans when conducted in anhydrous acetonitrile.86 The reactions are stereospecific, with the /(-alcohols generating the irons and the Z-isomer the cis product. These are endo-5 cyclizations, which are preferred to exo-4 reactions. 

Other nucleophilic functional groups can participate in iodocyclization. Amides usually react at oxygen, generating imino lactones that are hydrolyzed to lactones.88... 

Entries 15 to 18 are examples of use of iodocyclization in multistep syntheses. In Entry 15, iodolactonization was followed by elimination of HI from the bicyclic lactone. In Entry 16, a cyclic peroxide group remained unaffected by the standard iodolactonization and subsequent Bu3SnH reductive deiodination. (See Section 5.5 for... 

Asymmetric Diels-Alder reactions have been carried out to investigate the efficacy of anilide 44 and imide 45 as dienophiles. In the presence of iodine, the asymmetric Diels-Alder reaction of anilide (+)-44 shows a remarkable improvement in both reactivity and stereoselectivity (Table 5-1). Therefore, it is believed that, in the presence of I2, Diels-Alder reactions of A -al I yl ic enamides take place through an activating process involving the formation of a cationic iodocyclization intermediate. 

Other protocols, such as iodocyclization of alkene or alkyne 345 affording 346 (Equation 60) <1996JA9073, 2000BML2015>, cyclization of allyl chloride derivative <1998EJO509>, or of mesylate <1998JOC5680> were used in order to access this class of products. 

The iodocyclization of 2-methallylmercapto benzimidazole 247 proceeded in a regioselective manner by treatment with iodine and aqueous KOH in chloroform to give the dihydro-thiazolo[3,2- ]benzimidazole 248 (Equation 108) <1999RJO730>. 

A novel methodology for cyclization to partially reduced tetrazolo[5,l- ]isoquinolines has been elaborated by Ek et al. <2003T6759> as shown in Scheme 29. The key step is the iodocyclization of an allylphenyltetrazole compound 124 - conveniently synthesized from the appropriate allyl-substituted benzonitrile 123 - under very mild conditions (iodine, acetonitrile solution, 0°C, 3h) to give the iodomethyl-substituted product 125. 

Iodocyclization of the olefinic tetrazole 5-but-3-enyl-l//-tetrazole 79 using Nal ICO ( and I2 in anhydrous acetonitrile at 0 °C under argon atmosphere in the dark affords a 72% isolated yield of a 1 1 mixture of 5-iodomethyl-6,7-dihydro-tetrazolo[l,5-zr] pyrrole 80 and 6-iodo-5,6,7,8-tctrahydro-tetrazolo[1,5-tf]pyridinc 81 (Equation 5) <2003T6759>. 

Iodocyclization to hydroxy tetrahydrofurans. Cyclization of y,8-unsaturated alcohols to tetrahydrofurans (12, 254-256) can be directed by an allylic oxygen substituent, which also can increase the rate of cyclization. Thus derivatives of 4-pentene-l,3-diol undergo iodocyclization mainly to dr-3-hydroxy-2-iodomethylte-trahydrofurans. 

Russo and co-workers98 have reported a high stereoselective method for the preparation of 1,2-czls-C-glycosyl compounds based on the iodocyclization of some hept- and hexenitols obtained by Wittig reaction of sugar... 

Scheme 26 1,2-cis-C-Furanosyl compounds generated by iodocyclization of heptenitols. 

Taguchi and colleagues189 studied the reactions of axially chiral maleimide and anilide derivatives 298 and 300 with cyclopentadiene (equation 83). The reaction of 298 with cyclopentadiene, catalyzed by diethylaluminum chloride, proceeded quantitatively with almost complete endo and diastereofacial selectivities to give 299 and 301, respectively. The reaction of 300 with cyclopentadiene was catalyzed by iodine and proceeded via a cationic iodocyclization intermediate. The reaction afforded a mixture of endo and exo isomers in a ratio of endo/exo = 97/3, the endo isomer being obtained with 97% de. 

The I2 addition to 3 in chlorinated solvents yields a mixture of isomeric 2,6-diiodobicy-clo[3.3.0]octanes (endo.exo-69 and endo,endo-7tt) (equation 71)22. When the reaction was carried out in aqueous acetonitrile under similar conditions, the formation of a mixture of acetamido derivatives 71 and 72, arising from iodocyclization followed by the capture of the iodonium ion by the solvent to give a Ritter reaction intermediate, accompanied the formation of products 69 and 70 (equation 72)22. 

Attempted iodocyclization with iodine in moist acetonitrile of ethyl 2-hydroxypent-4-enoate (59) to give the iodotetrahydrofuran (62) gave instead a 2 1 mixture (80%) of syn- and -lactones (60) and (61). Labelling studies with H2 0 indicated that the probable mechanism of the reaction involved initial attack of the ester group upon the iodonium ion (63) to yield a mixture of epimeric carbocations (64), which upon attack by water would yield the orthoesters (65), elimination of ethanol from which giving the epimeric y-lactones (60, 61). ... 

Diaryl tellurium diiodides afford the iodocyclization of 4-pentenoic acid after 5 and 4 days reflux in CHCI3 in the presence of pyridine. ... 

Diaryltellurium diiodides afford the iodocyclization of 4-pentenol. Diaryltellurium dibromides give only traces of bromotetrahydrofurans with 3-butenol and 4-pentenol. ... 

The sequence depicted in the following scheme is additional evidence that the iodocyclization of bntyltellurobutenine (see preceding Section 5.3.1.4a) occurs by pathway a. 

Examples of iodolactonization and related iodocyclizations can be found in Scheme... 

Electrophilic iodine reagents have also been employed in iodocyclization. Several salts of pyridine complexes with I+ such as bis(pyiidinium)iodonium tetrafluoroborate and bis(collidine)iodonium hexafluorophosphate have proven especially effective.61 y-Hydroxy- and d-hydroxyalkcncs can be cyclized to tetrahydrofuran and tetrahydropyran derivatives, respectively, by positive halogen reagents.62 (see entries 6 and 8 in Scheme... 

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