Molecular Iodine-Mediated Cyclization of Tethered Heteroatom-Containing Alkenyl or Alkynyl Systems

Molecular iodine has established itself as a readily available and easy-to-handle electrophilic and oxidizing reagent used in various organic transformations. In this review attention is focused on the use of molecular iodine in promoting cyclization (iodocyclization and cyclodehydroiodination) of tethered heteroatom-containing alkenyl or alkynyl systems.


Introduction
In recent years, molecular iodine has received considerable attention as an inexpensive, non-toxic, readily available reagent to effect iodocyclization and cyclodehydroiodination reactions of tethered heteroatom-containing alkenyl or alkynyl systems to afford heterocyclic compounds with many synthetic and biological applications. For example, iodine-promoted cyclization of tethered heteroatom (oxygen-, nitrogen-or sulfur-)-containing alkynes has proven to be an effective method for the synthesis of furans [1][2][3], pyrroles [4,5], thiophenes [6,7] indoles [8,9], benzo[b]furans [10,11], and benzo [b]thiophenes [12][13][14]. The pyrrole moiety is widely distributed in a large number of naturally occurring compounds which display a variety of physiological properties [15] including antibacterial [16], antiviral [17], and antioxidant activities and also inhibit cytokine-mediated diseases [18,19]. On the other hand, the furan moiety is also found in naturally occurring compounds or synthetic derivatives such as naphtha[2,3-b]furan-4,9-diones 1 and naphtha[1,2-b]furan-4,5-diones 2 which have OPEN ACCESS been found to exhibit in vitro cyctotoxicity against KB cells [20]. Benzo [b]thiophene analogues 3a-c prepared through a combination of palladium-mediated coupling and iodine-promoted iodocyclization were found to exhibit tubulin binding activities [6]. Although the popularity of molecular iodine-mediated cyclization reactions has been increasing over the years, to our knowledge, there is no comprehensive review in the literature on the use of iodine as an electrophile and/or oxidizing agent in the synthesis of heteroatom-containing compounds with potential synthetic and/ or biological applications. Its applications in the oxidation of alcohols and aldehydes to esters, nitriles and amides as well as the introduction of protecting groups and deprotection have however been reviewed in detail before [21]. In another development, Banerjee et al. reviewed the application of molecular iodine in esterification, cycloaddition, allyllation of aldehydes, acetalization of carbonyl compounds, acylation of alcohols, synthesis of cyclic ethers and aromatization of α,β-unsaturated ketones [22]. In this review, particular attention is focused on methods that employ molecular iodine as an electrophile and/ or oxidizing agent to promote cyclization of tethered alkenyl and alkynyl derivatives bearing a nucleophilic heteroatom-containing group.

Iodine as an Electrophile in Cyclization Reactions
Although halogen molecules on their own are nonpolar, they are easily polarized by the pi electrons of the C=C double bond to become electrophilic. The electrophilic properties of iodine have been exploited over the years to effect cyclization of heteroatom-containing alkenyl and alkynyl derivatives.

Iodine-promoted cyclization reactions
Halocyclization is a reaction whereby the intramolecular nucleophilic group attacks the carboncarbon double or triple bond activated by electrophilic halogenating reagent to give cyclic compounds. The outcome of this cyclization strategy which has been exploited in recent years for the synthesis of furans, pyrroles and quinolinones and their analogues is rationalized in terms of the rules previously developed by Baldwin for predicting the relative ease of organic ring-forming reactions [23]. The physical bases for these three rules are the stereochemistry requirements of the transition states for various tetrahedral, trigonal, and digonal systems in nucleophilic, homolytic, and cationic ring closure processes [23]. Iodocyclization of tethered heteroatom-containing alkenyl or alkynyl derivatives as well as iodocyclization of 2-allyl-1,3-dicarbonyl derivatives take advantage of the electrophilic nature of iodine. We herein focus attention on iodine-mediated cyclization reactions involving O-, N-or Scontaining group as an intramolecular nucleophile.
A general method for iodine-mediated cyclization reactions of unsaturated carbamates, ureas and amides which gives N-cyclized products as single regio-isomers was achieved in the presence of a strong base such as NaH or LiAl(Ot-Bu) 4 [29]. The reaction of N-ethoxycarbonyl allylcarbamate 14 with iodine (3 equiv.) in tetrahydrofuran (THF) or toluene-THF mixture in the presence of NaH, nBuLi or LiAl(Ot-Bu) 4 afforded the N-cyclized product 15 in 58 -85% yield without traces of the Ocyclized derivative (Scheme 5).  4 Toluene-THF 85 Reagents: (i) I 2 , base, THF or THF-toluene.
The 2-iodomethyl-3,5,6,7-tetrahydrobenzofuran-4-ones have also been recently prepared by polymer-supported selenium-induced electrophilic cyclization of allyl substituted 1,3-dicarbonyl compounds followed by cleavage of the selenium linkers using CH 3 I/NaI in DMF [24]. In another development, Ferraz and coworkers applied I 2 -NaHCO 3 mixture in dichloromethane at room temperature to series of α-alkenyl β-keto esters and γ-alkenyl β-keto esters bearing mono or disubstituted double bond to afford variously substituted iodocyclic ethers [54] Among the systems employed as substrates were the 2-allyl-1,3-cyclohexanedione derivatives 70, which afforded 2iodomethyl-3,5,6,7-tetrahydrobenzofuran-4-ones 71 in high yield (Scheme 27) [54]. Ferraz and coworkers also subjected 2-allyl-β-benzylaminodimedone 72 to I 2 -NEt 3 mixture to afford 2-iodomethyl-6,6-dimethyl-1-(phenylmethyl)indol-4-one 73 followed by its dehydrohalogenation with 1,8-diazobicyclo [5.4.0]undec-7-ene (DBU) to form 4-oxo-6,7-dihydroindole 74 in 87% yield (Scheme 28) [30]. However, these authors did not provide the corresponding analytical data and the yield for compound 73, which is implicated in the reaction and the generality of this reaction has not been demonstrated. A series of 2-allyl-3-benzylamino-2-cyclohexenones 75 were recently subjected to iodine-methanol mixture under reflux to afford products characterized by combination of NMR ( 1 H-and 13 C-), IR and mass spectroscopic techniques as the conjugated iodolium betaine derivatives of 2iodomethyltetrahydroindolones 77 (Scheme 29) [55]. The zwitterionic nature of the products in solution and in the solid state was also confirmed by their chemical behavior and the experimental data were corroborated by information from quantum chemical calculations. Several attempts to dehydrohalogenate systems 77 in analogy with strategy previously employed by Ferraz and coworkers [31] on product 73 above led to complicated mixtures of products. Compounds 79a, b and d, however, aromatized on attempted purification on silica gel column to afford the corresponding 4-hydroxy-2iodomethyldihydroindole derivatives 80 in low yields due to decomposition. The observed stability of these conjugated iodolium betaine derivatives is attributed to the increased propensity of nitrogen for electron pair delocalization resulting in a strong C 2P -N 2P pi bond interaction.

NHBn
In another development involving iodine-mediated cyclization, a series of δ-alkynyl-β-ketoesters 85 were reacted with iodine in dichloromethane at room temperature for several hours (Scheme 31) [57]. This 5-endo-dig mode of carbocyclization of active methylene compounds 85 onto terminal and internal alkynes led to novel iodocyclopentenes 86 in 20-80% yield.

Combined Electrophilic and Oxidative Properties of Iodine in Cyclization Reactions
Although the combined electrophilic and oxidizing properties of iodine have been exploited in the synthesis of heteroatom-containing cyclic compounds, such reactions do not feature at all in the recent reviews on the application of molecular iodine in organic transformation [21,22].

Iodine-mediated cyclization and oxidative aromatization reactions
Progress in modern synthesis is dependent on development of novel methodologies and the combined electrophilic and oxidative properties of iodine were exploited further to synthesize novel iodofunctionalized heterocyclic compounds in a one-pot operation. The strategy involved treatment of 2-allylcyclohexenone derivatives 92 with iodine in refluxing methanol to afford a mixture of 2-iodomethyl-3,5,6,7-tetrahydrobenzofurans 93 (minor) and 2-iodomethyl-4-methoxy-2,3dihydrobenzo-furans 94 (major) (Scheme 34) [62]. Products 93 are the result of the exo-trig type of cyclization which is more favoured than endo-trig type of cyclization according to Baldwin's rule [23]. On the other hand, the formation of products 94 was interpreted as a consequence of an initial 1,2addition of methanol to 93 followed by dehydration and oxidative aromatization. The use of iodinemethanol mixture as an oxidant to effect aromatization of cyclohexenones to anisole derivatives was first reported in 1980 by Tamura and Yoshimoto [63]. The generality of this aromatization reaction was later demonstrated by several researchers who employed this mixture on cyclohexenone derivatives [64][65][66][67][68][69][70][71][72] and their heterocyclic analogues [73] to prepare novel aromatic compounds that would be difficult to synthesize otherwise. Iodine-methanol reaction mixture has established itself to be more effective than metal-catalyzed aromatization of substituted cyclohexenones to the corresponding phenols or phenol ethers [74][75][76][77][78]. This reagent mixture was also found to be superior to the use of DDQ in dioxane, which was previously employed to dehydrogenate 5-acetyl-4-oxo-4,5,6,7-tetrahydrobenzofuran and methyl-4oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate [78].

Conclusions
Iodine has established itself as an efficient, readily available and easy-to-handle electrophilic reagent to effect halocyclization reactions to afford novel iodofunctionalized heterocyclic molecules that serve as versatile intermediates in synthetic organic chemistry [79]. Carbon-heteroatom bondforming reactions constitute the central theme of organic synthesis, and progress in modern synthesis is dependent on development of novel methodologies for the same. Series of 3-iodoindoles prepared via iodocyclization of the corresponding N,N-dialkyl-o-(1-alkynyl)anilines, for example, were recently subjected to palladium-catalyzed Sonogashira and Suzuki cross coupling reactions in solution and on a solid support to afford a 42-member library of 1,2,3,5-tetrasubstituted indoles after cleavage from the support [80]. In summary, molecular iodine has allowed in the last years a great advance in organic chemistry in the synthesis of heterocyclic compounds with many applications. Moreover, the combined electrophilic and oxidative potential of iodine can be exploited to synthesize novel aromatic and heteroaromatic compounds that would be difficult to synthesize otherwise.