Next Article in Journal
Regioselective Synthesis of New 2-(E)-Cyano(thiazolidin-2-ylidene)thiazoles
Next Article in Special Issue
Molecular Iodine—An Expedient Reagent for Oxidative Aromatization Reactions of α,β-Unsaturated Cyclic Compounds
Previous Article in Journal
Synthesis and Study of Novel Coumarin Derivatives Potentially Utilizable as Memory Media
Previous Article in Special Issue
New Lipophilic Piceatannol Derivatives Exhibiting Antioxidant Activity Prepared by Aromatic Hydroxylation with 2-Iodoxybenzoic Acid (IBX)
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 14
Issue 12
10.3390/molecules14124814
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

by
Malose Jack Mphahlele
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, P.O. Box 392, Pretoria 0003, South Africa
Molecules 2009, 14(12), 4814-4837; https://doi.org/10.3390/molecules14124814
Submission received: 10 October 2009 / Revised: 9 November 2009 / Accepted: 12 November 2009 / Published: 25 November 2009
(This article belongs to the Special Issue Organic Iodine Chemistry)
Browse Figures
Versions Notes

Abstract

:
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.

Graphical Abstract

1. 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 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].
Molecules 14 04814 g001 550
Figure 1. Structures of naphtha[2,3-b]furan-4,9-diones 1 and naphtha[1,2-b]furan-4,5-diones 2.
Figure 1. Structures of naphtha[2,3-b]furan-4,9-diones 1 and naphtha[1,2-b]furan-4,5-diones 2.
Molecules 14 04814 g001
Molecules 14 04814 g002 550
Figure 2. Structures of benzo[b]thiophene analogues 3a–c.
Figure 2. Structures of benzo[b]thiophene analogues 3a–c.
Molecules 14 04814 g002
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.

2. 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.

2.1. Iodine-promoted cyclization reactions

Halocyclization is a reaction whereby the intramolecular nucleophilic group attacks the carbon–carbon 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 S-containing group as an intramolecular nucleophile.

2.1.1. Iodocyclization of heteroatom-containing alkenyl derivatives

Iodocyclization of 4-penten-1-ol 4 using iodine in chloroform with 1 equivalent of pyridine is reported to afford mixture of products characterized as the tetrahydrofuran 5 and tetrahydropyran 6 (Scheme 1) [24]. Iodine (3 equiv.) in acetonitrile (CH3CN) was found to promote iodocyclization of furyl-substituted pent-4-ene-1,2-diols 7a (XR1=OH; R=H, alkyl) and their sulfonamide derivatives 7b (XR1=NHTs; R=H) to afford iodotetrahydrofurans 8a (X=O; R=H, alkyl) and 5-furylpyrrolidine-2-methanol 8b (X=NTs, R=H), respectively (Scheme 2) [4].
Molecules 14 04814 sch001 550
Scheme 1. Iodocyclization of 5-penten-1-ol in the presence of pyridine.
Scheme 1. Iodocyclization of 5-penten-1-ol in the presence of pyridine.
Molecules 14 04814 sch001
Molecules 14 04814 sch002 550
Scheme 2. Iodocyclization of furyl-substituted pent-4-ene-1,2-diols.
Scheme 2. Iodocyclization of furyl-substituted pent-4-ene-1,2-diols.
Molecules 14 04814 sch002
Tetrahydropyrans 10a and b were prepared in the ratio 2:1 from a diastereomeric mixture of 9a and b using iodine in dry acetonitrile (Scheme 3) [25].
Molecules 14 04814 sch003 550
Scheme 3. Iodocyclization of alkenyl 1,3-diols.
Scheme 3. Iodocyclization of alkenyl 1,3-diols.
Molecules 14 04814 sch003
Iodocylization of γ-alkenyl-β-enaminoesters and α-alkenyl-β-enaminoesters with iodine-NaHCO3 mixture in dichloromethane at room temperature, on the other hand, previously afforded novel 2-, and N-substituted 5-methylene-pyrrolidine benzamides and 2-, 3- and N-substituted 5-methylene-2-pyrroline benzamides, respectively [26]. Substituted proline derivatives 12 and 13 were prepared in excellent yields through 5-endo-iodocylization of the corresponding α-alkenyl-α-amino esters 11 with iodine in the presence and absence of a base (Scheme 4) [27]. The analogous (E)-homoallylic sulfonamides have been found to undergo the normally disfavored 5-endo-trig iodocyclization in the presence of potassium carbonate or sodium carbonate in acetonitrile to afford trans-2,5-disubstituted-3-iodopyrrolidines in high yields [28]. The isomeric cis-2,5-disubstituted-3-iodopyrrolidine isomers were isolated as sole products in the absence of a base. It is believed that in the absence of a base, the initial kinetic trans products undergo rapid isomerization to afford the thermodynamic cis-2,5-disubstituted-3-iodopyrrolidine isomers by a ring opening-ring closure mechanism [28].
Molecules 14 04814 sch004 550
Scheme 4. Base-promoted iodocyclization of α-alkenyl-α-amino esters.
Scheme 4. Base-promoted iodocyclization of α-alkenyl-α-amino esters.
Molecules 14 04814 sch004
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 O-cyclized derivative (Scheme 5).
Molecules 14 04814 sch005 550
Scheme 5. Base-promoted iodocyclization of N-ethoxycarbonyl allylcarbamate.
Scheme 5. Base-promoted iodocyclization of N-ethoxycarbonyl allylcarbamate.
Molecules 14 04814 sch005
Exclusive formation of the O-cyclized derivative 18 was observed when N-ethoxycarbonyl-N’-allylurea 16 was treated with iodine–NaHCO3 mixture in ether (Scheme 6) [29]. The N-cyclized derivatives of N-ethoxycarbonyl N’-allylurea 17 were isolated as sole products only when n-BuLi or Li(Al(Ot-Bu)4 were used as bases. This reverse regioselectivity is presumably the result of the tendency for lithium ion to coordinate strongly with oxygen atoms in a six-membered cyclic transition state. Such interaction would render oxygen less nucleophilic and in turn favour nucleophilic attack by nitrogen to afford the N-cyclized products.
Molecules 14 04814 sch006 550
Scheme 6. Iodine-mediated cyclization of N-ethoxycarbonyl N’-allylurea.
Scheme 6. Iodine-mediated cyclization of N-ethoxycarbonyl N’-allylurea.
Molecules 14 04814 sch006
Ferraz and coworkers previously reported the synthesis of N-substituted pyrrole derivatives from alkenyl 1,3-dicarbonyl compounds via the formation of iodo-1,3-enamino esters followed by dehydroiodination [30,31]. Iodine-promoted cyclization of 19 to afford mixture of cis and trans isomers of 4,5-dihydro-5-iodomethyl-4-phenyl-2(3H)-furanones 20 and 21 has been described before (Scheme 7) [32]. A detailed review describing examples of iodine–mediated cyclization of nonconjugated unsaturated acids, diallyl-hydroxyacetic acids, benzyl carbamates, norbornene derivatives, aryl-allenoic acids, olefinic amides and γ-methallyl malonic acids to afford iodolactones and lactones was published recently [33].
Molecules 14 04814 sch007 550
Scheme 7. Iodine-promoted cyclization of nonconjugated unsaturated acids.
Scheme 7. Iodine-promoted cyclization of nonconjugated unsaturated acids.
Molecules 14 04814 sch007
Variously substituted (E)-(pyridin-2-yl)allyl acetates 22 were previously subjected to iodine in triethyl amine to afford the corresponding indolizines 23 via 5-endo-trig iodocyclization (Scheme 8) [34]. In this one-pot reaction sequence, pyridinyl nitrogen was involved as an internal nucleophile of iodocyclization.
Molecules 14 04814 sch008 550
Scheme 8. Iodocyclization of (E)-(pyridin-2-yl)allyl acetates.
Scheme 8. Iodocyclization of (E)-(pyridin-2-yl)allyl acetates.
Molecules 14 04814 sch008
Stereoselective formation of Z-4-(1-iodo-2-alkyl)ethylene-2-trichloromethyl-4,5-dihydro-1,3-oxazoles 25 was previously achieved via iodocyclization of the trichloroacetimidate derivatives of primary α-allenic alcohol 24 using iodine and potassium carbonate mixture in ether (Scheme 9) [35]. The Z-vinyl iodides 25 (R=alkyl) were isolated in high yields (58 – 80%) as major isomers.
Molecules 14 04814 sch009 550
Scheme 9. Iodocyclization of the trichloroacetimidate derivatives of primary α-allenic alcohol.
Scheme 9. Iodocyclization of the trichloroacetimidate derivatives of primary α-allenic alcohol.
Molecules 14 04814 sch009

2.1.2. Iodocyclization of heteroatom-containing alkynyl and ynone derivatives

Iodine and sodium bicarbonate mixture in dichloromethane at 0 ºC was found to promote a one-pot 5-endo-dig cyclization of 3-alkynyl-1,2-diols and subsequent dehydration to afford β-iodofurans in high yield [1,3]. In a follow up investigation, Knight and coworkers treated a series of 3-alkyne-1,2-diols 27 with iodine (3.3 equiv.) and NaHCO3 (3.3 equiv.) mixture in MeCN at room temperature and isolated the corresponding β-iodofurans 28 (Scheme 10) [36].
Molecules 14 04814 sch010 550
Scheme 10. Iodocyclization of 3-alkyne-1,2-diols.
Scheme 10. Iodocyclization of 3-alkyne-1,2-diols.
Molecules 14 04814 sch010
A representative series of homopropargylic sulfonamides have been found to undergo 5-endo-dig cyclization upon exposure to excess iodine in acetonitrile in the presence of potassium carbonate to afford 4-iodo-2,3-dihydropyrroles and β-iodopyrroles substituted with ester group at the 2-position [4]. A range of 3-hydroxy-2-sulfonylamino-4-alkynes 29 was also treated with iodine–K2CO3 mixture in dichloromethane to afford systems 30, which were in turn dehydrated using methanesulfonyl chloride in dichloromethane in the presence of triethylamine to yield iodopyrroles 31 (Scheme 11) [37].
Molecules 14 04814 sch011 550
Scheme 11. Iodocyclization of homopropargylic sulfonamides.
Scheme 11. Iodocyclization of homopropargylic sulfonamides.
Molecules 14 04814 sch011
A pyridinyl nitrogen was involved as an internal nucleophile during iodine-mediated 5-endo-dig cyclization of series of propargylic acid esters 32 in dichloromethane at room temperature to afford the corresponding highly functionalized indolizines 33 (R2=alkyl, aromatic or heteroaromatic) in high yields (Scheme 12) [38]. Under similar reaction conditions, the analogues 2-pyridin-2-yl-pent-4-ynoic acid ethyl esters 34 afforded the corresponding 3-acylated indolizines 35 (R=alkyl or aryl) via iodine-mediated hydrative cyclization (Scheme 13) [39]. Improved yields were observed when acetonitrile-water mixture (10:1, v/v) was used as solvent. The mechanism of this transformation is believed to involve 5-exo-dig iodocyclization, deprotonation, incorporation of another iodo group, deprotonation and subsequent replacement of the diiodo group by water.
Molecules 14 04814 sch012 550
Scheme 12. Iodocyclization of (E)-(pyridin-2-yl)alkynyl acetates.
Scheme 12. Iodocyclization of (E)-(pyridin-2-yl)alkynyl acetates.
Molecules 14 04814 sch012
Molecules 14 04814 sch013 550
Scheme 13. Iodocyclization of 2-pyridin-2-yl-pent-4-ynoic acid ethyl esters.
Scheme 13. Iodocyclization of 2-pyridin-2-yl-pent-4-ynoic acid ethyl esters.
Molecules 14 04814 sch013
Iodine–promoted cyclization of 2-alkynylaniline 36 (X=CH; R1, R3=H; R2=2-HO-C6H4, 2-MeO-C6H4) afforded iodoindoles 37 (X=CH; R1, R3=H; R2=2-HO-C6H4, 2-MeO-C6H4) in low yields (10–20%) presumably due to the presence of free hydroxyl or amino groups on the substrate (Scheme 14) [40]. Treatment of the analogous N-tosyl-2-alkynylaniline derivatives 36 (X=CH; R1=Ts; R2=Ph, Bu, Si(CH3)3; R3=5-NO2) and 2-(N-tosyl)-3-alkynylpyridines (X=N; R1=Ts; R2=Ph, Si(CH3)3; R3=H) with iodine (3 equiv.) and K2CO3 (3 equiv) in acetonitrile at 0–20 °C afforded the corresponding iodoindoles (82–95%) and azaindoles (75–89%), respectively [9]. Iodocyclization of 2-alkynyldimethylaniline derivatives (R1=Me; R2=alkyl) previously afforded 3-iodoindole (R2=Me) [41]. Electrophilic cyclization of N,N-dialkyl-o-(alkynyl)anilines with iodine in dichloromethane, on the other hand, led to the isolation of N-alkyl-3-iodoindoles in excellent yields [8].
Molecules 14 04814 sch014 550
Scheme 14. Iodine-promoted cyclization of 2-alkynylanilines, N-tosyl-2-alkynylanilines and 2-(N-tosyl)-3-alkynylpyridine derivatives.
Scheme 14. Iodine-promoted cyclization of 2-alkynylanilines, N-tosyl-2-alkynylanilines and 2-(N-tosyl)-3-alkynylpyridine derivatives.
Molecules 14 04814 sch014
The 5-endo-dig-iodocyclization of 2-alkynylphenols with iodine in the presence of NaHCO3 at room temperature produced 2-substituted 3-iodobenzo[b]furans, which are useful synthetic intermediates for the preparation of 2,3-disubstituted benzo[b]furans via Pd-catalyzed reactions [13,14,42]. Iodocyclization of 2-alkynylanisole derivatives 38a and the alkyl(2-alkynylphenyl) sulfides 38b afforded the corresponding iodofuran 39a [40] and 3-iodobenzo[b]thiophenes 39b [41], respectively (Scheme 15). o-(Phenylethynyl)thioanisole and o-(1-alkynyl)thioanisoles have also been treated with iodine (1.5 equiv.) in dichloromethane at room temperature to afford 3-iodo-2-(alkyl/aryl)benzo[b]thiophenes in more than 95% yield [13]. Flynn and coworkers previously employed this strategy in the synthesis of novel tubulin polymerization inhibitors 3 from the corresponding 3-iodobenzo[b]thiophene prepared, in turn, via 5-endo-dig iodocyclization of benzyl o-ethynylphenyl sulfides with iodine in dichloromenthane [12].
Molecules 14 04814 sch015 550
Scheme 15. Iodine-promoted cyclization of 2-alkynylanisoles and alkyl(2-alkynylphenyl) sulfides.
Scheme 15. Iodine-promoted cyclization of 2-alkynylanisoles and alkyl(2-alkynylphenyl) sulfides.
Molecules 14 04814 sch015
Iodine–cerium(IV) ammonium nitrate (CAN) mixture in acetonitrile at room temperature previously induced cyclization of (2-methoxyaryl)-substituted ynones 40 to produce 3-iodochromenones (3-iodo-4H-1-benzopyran-4-ones) 41 in excellent yields (Scheme 16) [43]. In another development, the phenyl derivative 40 (R=Ph) was transformed to 41a using iodine in dichloromethane at room temperature [40]. 1-(2-Alkylthiophenyl)alk-2-yn-1-ones 42 and their 1-(2-alkylthiophenyl)alk-2-yn-1-ol derivatives exhibited strong bias toward the 5-exo-dig pathway to give 43 instead of the 6-endo-dig pathway leading to 3-iodothioflavones 44 (Scheme 17) [14,41].
Molecules 14 04814 sch016 550
Scheme 16. Iodine-CAN mediated cyclizations of (2-methoxyaryl) alk-2-yn-1-ones.
Scheme 16. Iodine-CAN mediated cyclizations of (2-methoxyaryl) alk-2-yn-1-ones.
Molecules 14 04814 sch016
Molecules 14 04814 sch017 550
Scheme 17. Iodine-mediated cyclization of 2-(N,N-dimethylaminophenyl)alk-2-yn-1-ones.
Scheme 17. Iodine-mediated cyclization of 2-(N,N-dimethylaminophenyl)alk-2-yn-1-ones.
Molecules 14 04814 sch017
Highly selective 5-exo- and 6-endo-dig iodocyclization protocols that give direct access to a variety of indoles and quinolines have been described in literature [41]. Iodocyclization of the dimethylamino systems 45 using iodine in dichloromethane or acetonitrile proved highly selective for the 6-endo-digonal pathway to afford 2-substituted 3-iodo-1-methylquinolin-4(1H)-ones in high yield 46 (Scheme 18) [41].
Molecules 14 04814 sch018 550
Scheme 18. Iodine-mediated cyclization of 2-(N,N-dimethylamino) substituted ynones.
Scheme 18. Iodine-mediated cyclization of 2-(N,N-dimethylamino) substituted ynones.
Molecules 14 04814 sch018
When secondary and tertiary alcohols 47 were subjected to iodine in acetonitrile or dichloromethane, the endo product 48 was produced exclusively and then transformed to quinolium salt 50 by direct heating of the reaction mixture (Scheme 19) [41]. The 5-exo-dig products 49 which were isolated as 2-acylindoles 51 were found to form exclusively in protic solvents such as methanol or ethanol. This strategy was previously applied for the synthesis of novel tubulin polymerization inhibitors 3a-c from the corresponding 3-iodobenzo[b]thiophene prepared, in turn, via 5-endo-dig iodocyclization of benzyl o-ethynylphenyl sulfides with iodine in dichloromenthane [6,14].
The reaction of β-(2-aminophenyl)-α,β-ynone 52 with I2 and NaHCO3 in CH3CN afforded the 3,4-diiodo-2-(4-methoxyphenyl)quinoline 53 in 34% yield (Scheme 20) [44]. This observation was found to be remarkably different from the regio-controlled iodoaminocyclization reaction of related derivatives.
Molecular iodine in acetonitrile effected regioselective iodocyclization of o-(1-alkynyl)benzenesulfonamides 54 to yield a variety of 4-iodo-2H-benzo[e][1,2]thiazene-1,1-dioxides 55 (Scheme 21) [45]. The iodocyclization step was found to tolerate a variety of functional groups such as hydroxyl, chloro, cyano, and methoxy substituent to produce a six-membered ring exclusively.
Molecules 14 04814 sch019 550
Scheme 19. Iodine-mediated cyclization of 2-(N,N-dimethylaminophenyl)alk-2-yn-1-ols in polar aprotic (CH3CN) and polar protic (methanol or ethanol) solvents.
Scheme 19. Iodine-mediated cyclization of 2-(N,N-dimethylaminophenyl)alk-2-yn-1-ols in polar aprotic (CH3CN) and polar protic (methanol or ethanol) solvents.
Molecules 14 04814 sch019
Molecules 14 04814 sch020 550
Scheme 20. Iodine-NaHCO3 promoted cyclization of β-(2-aminophenyl)-α,β-ynone.
Scheme 20. Iodine-NaHCO3 promoted cyclization of β-(2-aminophenyl)-α,β-ynone.
Molecules 14 04814 sch020
Molecules 14 04814 sch021 550
Scheme 21. Iodine-K2CO3 mediated cylization of o-(1-alkynyl)benzenesulfonamides.
Scheme 21. Iodine-K2CO3 mediated cylization of o-(1-alkynyl)benzenesulfonamides.
Molecules 14 04814 sch021
A series of o-(1-alkynyl)benzamides 56 were previously treated with iodine in dichloromethane at room temperature to afford the corresponding isoindolin-1-ones 57 and isoquinolin-1(2H)-ones 58 as a mixture (Scheme 22) [46]. Better regioselectivity was observed for iodine compared to other electrophiles (ICl, NBS, PhSeCl and p-NO2C6H4SCl) and this improved in acetonitrile or methanol in the presence of a base.
Molecules 14 04814 sch022 550
Scheme 22. Iodine-NaHCO3 mediated cylization of o-(1-alkynyl)benzamides.
Scheme 22. Iodine-NaHCO3 mediated cylization of o-(1-alkynyl)benzamides.
Molecules 14 04814 sch022

2.1.3. Iodocyclization of ortho-allylphenols

Iodoenolcyclization of ortho-allylphenol 59 using either I2-SnCl4 mixture in dichloromethane [47] or I2 and Ethopropazine, EPZ-10 (a clay-supported ZnCl2 catalyst) mixture or ZnCl2 in methanol is reported to afford the 2-iodomethyl-2,3-dihydrobenzofuran 60 (Scheme 23) [48]. Iodoenolcyclization of 2-(2-butenyl)phenol 61 with I2-SnCl4 mixture in dichloromethane at room temperature, on the other hand, previously afforded 3-iodo-2-methylbenzopyran 62 in excellent yield (Scheme 24) [47]. Muzart et al. [49], reported the reaction of a variety of 2-allylphenols with iodine in water which led to the corresponding 2-iodomethyl-2,3-dihydrobenzofurans in the absence of any additives or organic solvents.
Molecules 14 04814 sch023 550
Scheme 23. Iodine-SnCl4 mediated cylization of 2-allylphenol.
Scheme 23. Iodine-SnCl4 mediated cylization of 2-allylphenol.
Molecules 14 04814 sch023
Molecules 14 04814 sch024 550
Scheme 24. Iodine-SnCl4 mediated cylization of 2-(2-butenyl)phenol.
Scheme 24. Iodine-SnCl4 mediated cylization of 2-(2-butenyl)phenol.
Molecules 14 04814 sch024

2.1.4. Iodocyclization of 2-allyl-1,3-dicarbonyl derivatives

A convenient approach to furan derivatives by iodine-induced cyclization of 2-alkenyl substituted 1,3-dicarbonyl compounds was first reported by Antonioletti and coworkers [50]. These authors subjected a series of 2-alkenyl substituted 1,3-dicarbonyl compounds 63 to I2–NaHCO3 mixture in dichloromethane at room temperature to afford 5-iodoalkyl-4,5-dihydrofurans 64 (Scheme 25). Treatment of the latter with 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) in refluxing benzene afforded 5-alkylidene-4,5-diydrofurans 65, which were in turn isomerized to the corresponding 2,3,5-trisubstituted furans 66 in ether using an acid catalyst. The generality of this reaction was demonstrated in a follow up study involving treatment of 2-alkenyl-1,3-dicarbonyl derivatives under similar reaction conditions to yield series of 2,3,4,5-tetrasubstituted furans [51].
Molecules 14 04814 sch025 550
Scheme 25. I2–NaHCO3 mediated iodoenolcyclization of 2-alkenyl-1,3-dicarbonyl compounds.
Scheme 25. I2–NaHCO3 mediated iodoenolcyclization of 2-alkenyl-1,3-dicarbonyl compounds.
Molecules 14 04814 sch025
Antonioletti’s group also showed that I2–Na2CO3 mixture promotes iodoenolcyclization of 2-allyl-1,3-dicarbonyl derivatives 67 bearing mono and disubstituted double bonds in dichloromethane at room temperature to afford diastereomeric mixtures of 5-iodomethyl-4,5-dihydrofuran derivatives 68 which can be dehydroiodinated using DBU to afford 69 (Scheme 26) [52,53]. Alkyl substituents were found to favour trans 5-iodomethyl-4,5-dihydrofuran isomers, whereas aromatic substituents led to cis isomers.
Molecules 14 04814 sch026 550
Scheme 26. I2–Na2CO3 mediated iodoenolcyclization of 2-allyl-1,3-dicarbonyl derivatives.
Scheme 26. I2–Na2CO3 mediated iodoenolcyclization of 2-allyl-1,3-dicarbonyl derivatives.
Molecules 14 04814 sch026
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 CH3I/NaI in DMF [24]. In another development, Ferraz and coworkers applied I2–NaHCO3 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 2-iodomethyl-3,5,6,7-tetrahydrobenzofuran-4-ones 71 in high yield (Scheme 27) [54].
Molecules 14 04814 sch027 550
Scheme 27. Iodine-mediated cylization of 2-allylcyclohexane-1,3-diones.
Scheme 27. Iodine-mediated cylization of 2-allylcyclohexane-1,3-diones.
Molecules 14 04814 sch027
Ferraz and coworkers also subjected 2-allyl-β-benzylaminodimedone 72 to I2–NEt3 mixture to afford 2-iodomethyl-6,6-dimethyl-1-(phenylmethyl)indol-4-one 73 followed by its dehydro-halogenation 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.
Molecules 14 04814 sch028 550
Scheme 28. Iodocyclization of 2-allyl-3-benzylamino-5,5-dimethyl-2-cyclohexen-1-one.
Scheme 28. Iodocyclization of 2-allyl-3-benzylamino-5,5-dimethyl-2-cyclohexen-1-one.
Molecules 14 04814 sch028
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 (1H- and 13C-), IR and mass spectroscopic techniques as the conjugated iodolium betaine derivatives of 2-iodomethyltetrahydroindolones 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-2-iodomethyldihydroindole 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 C2P–N2P pi bond interaction.
Molecules 14 04814 sch029 550
Scheme 29. Iodine-methanol promoted cyclization of 2-allyl-3-benzylamine-2-cyclohexen-1-ones.
Scheme 29. Iodine-methanol promoted cyclization of 2-allyl-3-benzylamine-2-cyclohexen-1-ones.
Molecules 14 04814 sch029
Lee and Oh previously subjected α-allyl substituted β-keto sulfones 81 to I2–NaHCO3 mixture in acetonitrile and isolated the corresponding 4,5-dihydro-5-iodomethylfurans 82 (Scheme 30) [56]. Dehydroiodination with DBU (1.2 equiv.) in benzene at room temperature afforded 4,5-dihydro-5-methylenefuran 83. Direct one-pot dehydroiodination–isomerization to furan derivatives 84 was achieved through the use of excess DBU (3–5 equiv.) in benzene at room temperature or under reflux.
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.
Molecules 14 04814 sch030 550
Scheme 30. Iodocyclization of β-keto sulfones and subsequent dehydroiodination.
Scheme 30. Iodocyclization of β-keto sulfones and subsequent dehydroiodination.
Molecules 14 04814 sch030
Molecules 14 04814 sch031 550
Scheme 31. Iodine-mediated carbocyclization of active methylene compounds.
Scheme 31. Iodine-mediated carbocyclization of active methylene compounds.
Molecules 14 04814 sch031

3. 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].

3.1. Iodine-mediated oxidative cyclization reactions

Iodine in refluxing triethylene glycol previously promoted oxidative cyclization of 1,3-diphenyl-prop-2-en-1-ones 87 to afford the A- and B-ring substituted flavones 88 (Scheme 32) [58]. The mechanism of this reaction is believed to involve initial electrophilic addition of iodine to the double bond followed by β-elimination of HI. Conjugate addition of the hydroxyl group then affords the 3-iodo flavanone derivative which in turn undergoes β-elimination of HI to afford the flavone. A one-pot iodine–mediated cyclization and oxidative dehydrogenation of 2-hydroxy-3-(4’-methylsulfonyl-phenyl)prop-2-en-1-ones in refluxing dimethylsulfoxide (DMSO) previously afforded 2-{4’-(methyl-sulfonyl)phenyl}benzopyran-4-one as a precursor for the synthesis of 2,3-diarylbenzopyran derivatives with potential to serve as cyclooxygenase-2(COX-2) inhibitors [60]. Use of iodine in triethylene glycol or DMSO has been found to be superior to cyclodehydrogenation of 2-hydroxychalcones with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) in refluxing dioxane, which leads to mixtures of flavanones (3–13%), flavones (28–42%) and aurones (3–17%) [60].
Molecules 14 04814 sch032 550
Scheme 32. One-pot iodocyclization and oxidative dehydrogenation of 2-hydroxy-3-phenylprop-2-en-1-ones.
Scheme 32. One-pot iodocyclization and oxidative dehydrogenation of 2-hydroxy-3-phenylprop-2-en-1-ones.
Molecules 14 04814 sch032
Iodine-pyridine mixture in THF previously effected one-pot oxidative desulfurization and cyclization of N-2-pyridylmethyl thioamides 89 to afford 2-azaindolizines (imidazo[1,5-a]pyridines 90 (59 – 95%) and sulfur-bridged 2-azaindolizine dimer 91 (ca. 7%) (Scheme 33) [61]. Prolonged reaction time (21 hours) in THF or DMF however led to mixtures of 90 and 91 in comparable yields depending on the nature of substituent on the R group.
Molecules 14 04814 sch033 550
Scheme 33. Iodine-mediated oxidative desulfurization promoted cyclization of thioamides.
Scheme 33. Iodine-mediated oxidative desulfurization promoted cyclization of thioamides.
Molecules 14 04814 sch033

3.2. 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-2,3-dihydrobenzo-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 1,2-addition of methanol to 93 followed by dehydration and oxidative aromatization. The use of iodine-methanol 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.
Molecules 14 04814 sch034 550
Scheme 34. One-pot iodocyclization and oxidative aromatization of 2-allylcyclohexenones.
Scheme 34. One-pot iodocyclization and oxidative aromatization of 2-allylcyclohexenones.
Molecules 14 04814 sch034
Under similar reaction conditions applied to systems 92, diethyl {[2-(2-propenyl)cyclo-hexenone]methyl}phosphonates 95 afforded the corresponding 4-[(diethoxyphosphonyl)methyl]-2-iodomethyl-2,3-dihydrobenzofuran derivatives 96a and b as sole products (Scheme 35) [62]. The observed result was interpreted as a consequence of initial formation of hemiacetal A from 95 followed by cyclization and the loss of methanol to form B. Iodine-assisted dehydrogenation of B would then result in the formation of 96.
Molecules 14 04814 sch035 550
Scheme 35. Iodocyclization and oxidative aromatization of diethyl {[2-(2-propenyl)cyclohexenone]methyl}phosphonates.
Scheme 35. Iodocyclization and oxidative aromatization of diethyl {[2-(2-propenyl)cyclohexenone]methyl}phosphonates.
Molecules 14 04814 sch035
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-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate [78].

4. 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 bond-forming 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.

Acknowledgements

Financial support from the University of South Africa and the National Research Foundation is gratefully acknowledged.

References

  1. El-Tach, G.M.M.; Evans, A.B.; Knight, D.W.; Jones, S. Practical alternatives for the synthesis of β-iodofurans by 5-endo-dig cyclizations of 3-alkyne-1,2-diols. Tetrahedron Lett. 2001, 42, 5945–5948. [Google Scholar]
  2. Sniady, A.A.; Wheeler, K.A.; Dembismski, R. 5-Endo-dig electrophilic cyclization of 1,4-disubstituted but-3-yn-1-ones: Regiocontrolled synthesis of 2,5-disubstituted 3-bromo- and 3-iodofurans. Org. Lett. 2005, 7, 1769–1772. [Google Scholar] [CrossRef] [PubMed]
  3. Bew, S.P.; Knight, D.W. A brief synthesis of β-iodofurans. J. Chem. Soc. Chem. Commun. 1996, 1007–1008. [Google Scholar] [CrossRef]
  4. Knight, D.W.; Redfern, A.L.; Gilmore, J. The synthesis of 5-substituted proline derivatives and of 5-substituted pyrrole-2-carboxylates by 5-endo cyclisations featuring a method for effectively favouring these with respect to 5-exo cyclisations. J. Chem. Soc. Perkin Trans. I 2001, 2874–2883. [Google Scholar] [CrossRef]
  5. Knight, D.W.; Redfern, A.L.; Gilmore, J. An approach to 2,3-dihydropyrroles and β-iodopyrroles based on 5-endo-dig cyclizations. J. Chem. Soc. Perkin Trans. I 2002, 622–628. [Google Scholar] [CrossRef]
  6. Flynn, B.L.; Flynn, G.P.; Hamel, E.; Jung, M.K. The synthesis and tubulin binding activity of thiophene-based analogues of combretastatin A-4. Bioorg. Med. Chem. Lett. 2001, 11, 2341–2343. [Google Scholar] [CrossRef]
  7. Ren, X.F.; Turos, E.; Lake, C.H.; Churchill, M.R. Regiochemical and stereochemical studies on halocyclization reactions of unsaturated sulfides. J. Org. Chem. 1995, 60, 6468–6483. [Google Scholar] [CrossRef]
  8. Yue, D.; Larock, R.C. Synthesis of 3-iodoindoles by electrophilic cyclization of N,N-dialkyl-2-(1-alkynyl)anilines. Org. Lett. 2004, 6, 1037–1040. [Google Scholar] [CrossRef] [PubMed]
  9. Amjad, M.; Knight, D.W. A simple, two-step synthesis of 3-iodoindoles. Tetrahedron Lett. 2004, 45, 539–541. [Google Scholar] [CrossRef]
  10. Banwell, M.G.; Flynn, B.L.; Wills, A.C.; Hamel, E. Synthesis, X-ray crystal structure and tubulin-binding properties of a benzofuran analog of the potent cytotoxic agent combretastatin A4. Aust. J. Chem. 1999, 52, 767–774. [Google Scholar] [CrossRef]
  11. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. A new approach to 2,3-disubstituted benzo[b]furans from 2-alkynylphenols via 5-endo-dig-iodocyclisation/palladium-catalyzed reactions. Synlett 1999, 1432–1434. [Google Scholar] [CrossRef]
  12. Flynn, B.L.; Verdier-Pinard, P.; Hamel, E. A novel palladium-mediated coupling approach to 2,3-disubstituted benzo[b]thiophenes and its application to the synthesis of tubulin binding agents. Org. Lett. 2001, 3, 651–654. [Google Scholar] [CrossRef] [PubMed]
  13. Yue, D.; Larock, R.C. Synthesis of 2,3-disubstituted benzo[b]thiophenes via palladium-catalyzed coupling and electrophilic cyclization of terminal acetylenes. J. Org. Chem. 2002, 67, 1905–1909. [Google Scholar] [CrossRef] [PubMed]
  14. Hessian, K.O.; Flynn, B.L. Iodine-induced reaction cascades for the rapid construction of variously substituted benzothiophenes. Org. Lett. 2003, 5, 4377–4380. [Google Scholar] [CrossRef] [PubMed]
  15. Hyashi, T.; Smith, F.T.; Lee, K.H. Antitumor agents. 89. Psychorubrin, a new cytotoxic naphthoquinone from Psychotria rubra and its structure-activity relationships. J. Med. Chem. 1987, 30, 2005–2008. [Google Scholar] [CrossRef]
  16. Yates, F.S. Comprehensive Heterocyclic Chemistry; Boulton, A.J., McKillop, A., Eds.; Pergamon: Oxford, UK, 1984; Vol. 2, Part 2A; p. 511. [Google Scholar]
  17. Tanaka, T.; Oba, T.; Okamure, N.; Watanabe, K.; Kurozumi, S.; Naruki, T. A convenient synthesis of 1,2,5-trisubstituted 3-benzoylpyrroles. Synth. Commun. 1980, 10, 773–789. [Google Scholar] [CrossRef]
  18. Daidone, G.; Maggio, B.; Schillari, D. Salicylanilide and its heterocyclic analogs. A comparative study of their antimicrobial activity. Pharmazie 1990, 45, 441–442. [Google Scholar] [PubMed]
  19. Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfond, J.M. Synthesis and antioxidant activity of new tetraarylpyrroles. J. Med. Chem. 1999, 34, 991–996. [Google Scholar] [CrossRef]
  20. Rao, M.M.; Kingston, D.G.I. Plant anticancer agents. XII. Isolation and structure elucidation of new cytotoxic quinones from Tabebuia cassinoides. J. Nat. Prod. 1982, 45, 600–604. [Google Scholar] [CrossRef] [PubMed]
  21. Hideo, T.; Shinpei, I. Synthetic use of molecular iodine for organic synthesis. Synlett 2006, 14, 2159–2175. [Google Scholar]
  22. Banerjee, A.K.; Vera, W.; Mora, H.; Laya, M.S.; Bedoya, L.; Cabrera, E.V. Iodine in organic synthesis. J. Sci. Ind. Res. 2006, 65, 299–308. [Google Scholar] [CrossRef]
  23. Baldwin, J.E. Rules for ring closure. J. Chem. Soc. Chem. Commun. 1976, 734–736. [Google Scholar] [CrossRef]
  24. Leonard, K.A.; Zhou, F.; Detty, M.R. Chalcogen(IV)-chalcogen(II) redox cycles. 1. Halogenation of organic substrates with dihaloselenium(IV) and -tellurium(IV) derivatives. dehalogenation of vicinal dibromides with diaryl tellurides. Organometallics 1996, 15, 4285–4292. [Google Scholar] [CrossRef]
  25. Singh, P.; Bhardwaj, A.; Kaur, S.; Kumar, S. Design, synthesis and evaluation of tetrahydropyran based COX-1/-2 inhibitors. Eur. J. Med. Chem. 2009, 44, 1278–1287. [Google Scholar] [CrossRef] [PubMed]
  26. De Oliveira, E.O.; Brant, C.A.; Da Silverira, M.A.B.; Glennon, R.A. Synthesis of pyrrolidine-substituted benzamides via iodocyclization of β-enaminoesters. Tetrahedron Lett. 2007, 48, 6393–6396. [Google Scholar] [CrossRef]
  27. Amjad, M.; Knight, D.W. On the rapid synthesis of highly substituted proline analogues by 5-endo-trig iodocyclisation. Tetrahedron Lett. 2006, 47, 2825–2828. [Google Scholar] [CrossRef]
  28. Jones, D.A.; Knight, D.W.; Hibs, D.E. A stereochemically flexible approach to pyrrolidines based on 5-endo-trig iodocyclisations of homoallylic sulfonamides. J. Chem. Soc. Perkin Trans. 1 2001, 1182–1203. [Google Scholar] [CrossRef]
  29. Kitagawa, O.; Futjita, M.; Li, H.; Taguchi, T. Regiocontrolled iodoaminocyclization reaction of an ambident nucleophile mediated by LiAl(Ot-Bu)4. Tetrahedron Lett. 1997, 38, 615–618. [Google Scholar] [CrossRef]
  30. Ferraz, H.M.; Oliveria, E.; Payret-Arrua, M.E.; Brandt, C.A. A new and efficient approach to cyclic β-enamino esters and β-enamino ketones by iodine-promoted cyclization. J. Org. Chem. 1995, 60, 7357–7359. [Google Scholar] [CrossRef]
  31. Ferraz, H.M.; Pereira, F.L.C.; Leite, F.S.; Nunes, M.R.S.; Payret-Arrua, M.E. Synthesis of N-substituted pyrrole and tetrahydroindole derivatives from alkenyl β-dicarbonyl compounds. Tetrahedron 1999, 55, 10915–10924. [Google Scholar] [CrossRef]
  32. Gonzalez, F.B.; Bartlett, P.A. Stereocontrolled iodocyclization of acyclic olefinic acids. The trans and cis isomers of 4,5-dihydro-5-iodomethyl-4-phenyl-2(3-H)-furanone. Org. Synth. 1990, 7, 164. [Google Scholar]
  33. Laya, M.S.; Banerjee, A.K.; Cabrera, E.V. Iodolactonization. Past and present examples. Curr. Org. Chem. 2009, 13, 720–730. [Google Scholar] [CrossRef]
  34. Kim, I.; Won, H.K.; Choi, J.; Lee, G.H. A novel and efficient approach to highly substituted indolizines via 5-endo-trig iodocyclization. Tetrahedron 2007, 63, 12954–12960. [Google Scholar] [CrossRef]
  35. Friesen, R.W.; Giroux, A.; Cook, K.L. Iodocyclization reactions of α-allenic alcohol derivatives. Stereoselective formation of Z-4-(1-iodo-2-alkylethylene)-2-trichloromethyl-4,5-dihydro-1,3-oxazoles. Tetrahedron Lett. 1993, 34, 5983–5986. [Google Scholar] [CrossRef]
  36. Bew, S.P.; El-Taeb, G.M.M.; Jones, S.; Knight, D.W.; Tan, W.F. Expedient syntheses of β-iodofurans by 5-endo-dig cyclisations. Eur. J. Org. Chem. 2007, 5759–5770. [Google Scholar] [CrossRef]
  37. Knight, D.W.; Rost, H.C.; Sharland, C.M.; Singhornrat, J. A general approach to polysubstituted pyrroles. Tetrahedron Lett. 2007, 48, 7906–7910. [Google Scholar] [CrossRef]
  38. Kim, I.K.; Choi, J.; Won, H.K.; Lee, G.H. Expeditious synthesis of indolizine derivatives via iodine mediated 5-endo-dig cyclization. Tetrahedron Lett. 2007, 48, 6863–6867. [Google Scholar] [CrossRef]
  39. Kim, I.K.; Kim, S.G.; Kim, J.Y.; Lee, G.H. A novel approach to 3-acylated indolizine structures via iodine-mediated hydrative cyclization. Tetrahedron Lett. 2007, 48, 8976–8981. [Google Scholar] [CrossRef]
  40. Ahmed, N.; Dubuc, C.; Rousseau, J.; Bénard, F.; van Lier, J.E. Synthesis, characterization, and estrogen receptor binding affinity of flavone-, indole-, and furan-estradiol conjugates. Bioorg. Med. Chem. Lett. 2007, 17, 3212–3216. [Google Scholar] [CrossRef] [PubMed]
  41. Hessian, K.O.; Flynn, B.L. Selective endo and exo iodocyclizations in the synthesis of quinolines and indoles. Org. Lett. 2006, 8, 243–246. [Google Scholar] [CrossRef] [PubMed]
  42. Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. A new approach to 2,3-disubstituted benzo[b]furans from 2-alkynylphenols via 5-endo-dig-iodocyclisation/palladium-catalyzed reactions. Synlett 1999, 1432–1434. [Google Scholar] [CrossRef]
  43. Likhar, P.R.; Subhas, M.S.; Roy, M.; Roy, S.; Kantam, M.L. Copper-free Sonogashira coupling of acid chlorides with terminal alkynes in the presence of a reusable palladium catalyst: An improved synthesis of 3-iodochromenones (= 3-iodo-4H-1-benzopyran-4-ones). Helv. Chim. Acta 2008, 91, 259–264. [Google Scholar] [CrossRef]
  44. Arcadi, A.; Marinelli, F.; Rossi, E. Synthesis of functionalized quinolines through tandem addition/annulation reactions of β-(2-aminophenyl)-α,β-ynones. Tetrahedron 1999, 55, 13233–13250. [Google Scholar] [CrossRef]
  45. Barange, D.K.; Batchu, V.R.; Gorja, D.; Pattabiraman, V.R.; Tatini, L.K.; Babu, J.M.; Pal, M. Regioselective construction of six-membered fused heterocyclic rings via Pd/C-mediated C-C coupling followed by iodocyclization strategy: A new entry to 2H-1,2-benzothiazine-1,1-dioxides. Tetrahedron 2007, 63, 1775–1789. [Google Scholar] [CrossRef]
  46. Yao, T.; Larock, R.C. Regio- and stereoselective synthesis of isoindolin-1-ones via electrophilic cyclization. J. Org. Chem. 2004, 70, 1432–1437. [Google Scholar] [CrossRef] [PubMed]
  47. Orito, K.; Hatakayama, T.; Takeo, M.; Suginome, H.; Tokuda, M. Synthesis of 5-iodobenzofurans and 6-iodobenzopyrans via direct iodination with mercury(II) oxide-iodine reagent. Synthesis 1997, 23–25. [Google Scholar] [CrossRef]
  48. Mahajan, V.A.; Shinde, P.D.; Gajare, A.S.; Karthikeyan, M.; Wakharkar, R.D. EPZ-10 catalyzed regioselective transformation of alkenes into β-iodo ethers, iodohydrins and 2-iodomethyl-2,3-dihydrobenzofurans. Green Chem. 2002, 4, 325–327. [Google Scholar] [CrossRef]
  49. Fousteris, M.; Chevrin, C.; Le Bras, J.; Muzart, J. Water-promoted iodocyclization of 2-allylphenols. Green Chem. 2006, 8, 522–523. [Google Scholar] [CrossRef]
  50. Antonioetti, R.; Bonadies, F.; Scettri, A. A convenient approach to furan derivatives by iodine-induced cyclization of 2-alkenyl substituted 1,3-dicarbonyl compounds. Tetrahedron Lett. 1988, 29, 4987–4990. [Google Scholar] [CrossRef]
  51. Antonioletti, R.; Cecchini, C.; Ciani, B.; Magnabti, S. Iodoenolycyclization. III. A general approach to tetrasubstituted furans from 2-alkenyl-1,3-dicarbonyl compounds. Tetrahedron Lett. 1995, 36, 9019–9022. [Google Scholar] [CrossRef]
  52. Antonioletti, R.; Malancona, S.; Bovicelli, P. Diastereoselective synthesis of 4,5-dihydrofurans by iodoenolcyclization of 2-allyl-1,3-dicarbonyl compounds. Tetrahedron 2002, 58, 8825–8831. [Google Scholar] [CrossRef]
  53. Antonioletti, R.; Malancona, S.; Cattaruzza, F.; Bovicelli, P. Iodoenolcyclization of 2-allyl-substituted β-keto esters under thermodynamic conditions. Tetrahedron 2003, 59, 1673–1678. [Google Scholar] [CrossRef]
  54. Ferraz, H.M.C.; Sano, M.K.; Nunes, M.R.S.; Bianco, G.G. Synthesis of cyclic enol ethers from alkenyl-beta-dicarbonyl compounds. J. Org. Chem. 2002, 67, 4122–4126. [Google Scholar] [CrossRef] [PubMed]
  55. Mphahlele, M.J.; El-Gogary, T.M. Synthesis and chemical transformation of 2-iodomethyl-1-(phenylmethyl)-1,5,6,7-tetrahydroindol-4-ones. J. Chem. Res. 2008, 227–231. [Google Scholar] [CrossRef]
  56. Lee, J.W.; Oh, D.Y. Iodine-induced enoletherification of α-allyl substituted β-keto sulfones; a route to 3-phenylsulfonyl-2,5-disubstituted furans. Heterocycles 1990, 31, 1417–1421. [Google Scholar]
  57. Barluenga, J.; Palomas, D.; Rubio, E.; Gonzalez, J.M. Iodocarbocyclization reaction of β-ketoesters and alkynes. Org. Lett. 2007, 9, 2823–2826. [Google Scholar] [CrossRef] [PubMed]
  58. Miyake, H.; Takizawa, E.; Sasaki, M. Syntheses of flavones via the iodine-mediated oxidative cyclization of 1,3-diphenylprop-2-en-1-ones. Bull. Chem. Soc. Jpn. 2003, 76, 835–836. [Google Scholar] [CrossRef]
  59. Joo, Y.H.; Kim, J.K.; Kang, S.H.; Noh, M.S.; Ha, J.Y.; Choi, J.K.; Lim, K.M.; Lee, C.H.; Chung, S. 2,3-Diarylbenzopyran derivatives as a novel class of selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem. Lett. 2003, 13, 413–417. [Google Scholar] [CrossRef]
  60. Imafuku, K.; Honda, M.; McOmie, J.F.W. Cyclodehydrogenation of 2′-hydroxychalcones with 2,3-dichloro-5,6-dicyano-p-benzoquinone: A simple route for flavones and aurones. Synthesis 1987, 199–201. [Google Scholar] [CrossRef]
  61. Shibahara, F.; Kitagawa, A.; Yamaguchi, E.; Murai, T. Synthesis of 2-azaindolizines by using an iodine-mediated oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides and an investigation of their photophysical properties. Org. Lett. 2006, 8, 5621–5624. [Google Scholar]
  62. Mphahlele, M.J.; Moekwa, T.B. Iodo- and bromo-enolcyclization of 2-(2-propenyl)cyclohexanediones and 2-(2-propenyl)cyclohexenone derivatives using iodine in methanol and pyridinium hydrobromide perbromide in dichloromethane. Org. Biomol. Chem. 2005, 3, 2469–2475. [Google Scholar] [CrossRef] [PubMed]
  63. Tamura, Y.; Yoshimoto, Y. An improved method for the conversion of cyclohexenones into anisoles. Chem. Ind. 1980, 888–389. [Google Scholar]
  64. Kotnis, A.S. A rapid entry to highly functionalized p-methoxybenzoates: Synthesis of the aromatic portion of milbemycin β3. Tetrahedron Lett. 1990, 31, 481–484. [Google Scholar] [CrossRef]
  65. Kotnis, A.S. A convenient, practical synthesis of substituted resorcinols: Synthesis of DB-2073 and olivetol. Tetrahedron Lett. 1991, 32, 3441–344. [Google Scholar] [CrossRef]
  66. Mphahlele, M.J.; Pienaar, A.; Modro, T.A. Reactions of phosphorus-stabilized carbanions with cyclic enones. Aromatization of the substitution and addition products. J. Chem. Soc. Perkin Trans. II 1996, 1455–1460. [Google Scholar] [CrossRef]
  67. Kim, J.M.; Lee, K.Y.; Kim, J.N. Oxidative aromatization of 2-acylcyclohexane-1,3-dione derivatives using iodine in methanol. Bull. Korean. Chem. Soc. 2003, 24, 1057–1058. [Google Scholar] [CrossRef]
  68. Hedge, S.G.; Kassim, A.M.; Ingram, A.I. Aromatization of cyclohexenones with iodine/sodium alkoxide. A regioselective synthesis of 2-iodophenols. Tetrahedron Lett. 1995, 36, 8395–8398. [Google Scholar]
  69. Kim, J.M.; Lee, K.Y.; Kim, T.H.; Kim, J.N. Synthesis of anisole derivatives from 4-alkylidene-2-cyclohexen-1-ones with iodine in methanol. Bull. Korean. Chem. Soc. 2003, 24, 999–1001. [Google Scholar] [CrossRef]
  70. Kim, J.M.; Lee, K.Y.; Kim, J.N. Synthesis of 4-methylene-2-cyclohexenones and their aromatization reaction toward para-methoxylmethyl anisole derivatives. Bull. Korean. Chem. Soc. 2004, 25, 328–330. [Google Scholar] [CrossRef]
  71. Na, J.E.; GowriSankar, S.; Lee, S.; Kim, J.N. Selective methylation of the ninhydrin-phenol adducts with I2 in MeOH. Bull. Korean Chem. Soc. 2004, 54, 569–572. [Google Scholar] [CrossRef]
  72. Na, J.E.; Kim, J.M.; Lee, S.; Kim, J.N. Synthesis of benzo[b]indeno[2,1-d]furanone skeleton from ninhydrin and cyclohexane-1,3-dione derivatives. Bull. Korean. Chem. Soc. 2003, 24, 1725–1726. [Google Scholar] [CrossRef]
  73. Mphahlele, M.J.; Hlatshwayo, S.M.; Mogamisi, F.K.; Tsanwani, M.; Mampa, R. Iodine-Methanol–Promoted Aromatization of 2-Aryl-1,2,3,4-tetrahydro-4-quinolones to 2-Aryl-4-methoxyquinolines. M. J. Chem. Res. (S) 1999, 706–707. [Google Scholar] [CrossRef]
  74. Grieco, P.A.; Marinovic, N. Rhodium-catalyzed migration of double bonds: Preparation of substituted phenols and anilines. Tetrahedron Lett. 1978, 29, 2545–2548. [Google Scholar] [CrossRef]
  75. Blagbrough, I.S.; Pattenden, G.; Raphael, E.F. Isomerization of ω-alkenyl-substituted cyclohexane-1,3-dione enol derivatives using rhodium catalysis. A practical synthesis of substituted resorcinols. Tetrahedron Lett. 1982, 23, 4843–4846. [Google Scholar] [CrossRef]
  76. Yamaguchi, S.; Yamamoto, K.; Ueda, T.; Morikawa, T.; Kawase, Y. A new preparative method of 4-hydroxybenzofuran-2-carboxylic acid derivatives. Bull. Chem. Soc. Jpn. 1989, 62, 4066–4068. [Google Scholar] [CrossRef]
  77. Hirao, T.; Mori, M.; Ohshiro, Y. VO(OR)Cl2-induced oxidative aromatization of α,β-unsaturated cyclohexenones. J. Org. Chem. 1990, 55, 358–360. [Google Scholar] [CrossRef]
  78. Lee, Y.R.; Morehead, A.T., Jr. A new route for the synthesis of furanoflavone and furanochalcone natural products. Tetrahedron 1995, 51, 4909–4922. [Google Scholar] [CrossRef]
  79. For review on the use of iodofunctionalized system in metal-catalyzed C–C formation see: Kirsch, G.; Hesse, S.; Comel, A. Synthesis of five- and six-membered heterocycles through palladium-catalyzed reactions. Curr. Org. Synth. 2004, 1, 47–63. [Google Scholar] [CrossRef]
  80. Worlikar, S.A.; Neuenswander, B.; Lushington, G.H.; Larock, R.C. Highly substituted indole library synthesis by palladium-catalyzed coupling reactions in solution and on a solid support. J. Comb. Chem. 2009, 11, 875–879. [Google Scholar] [CrossRef] [PubMed]
Sample Availability: Not Available.

Share and Cite

MDPI and ACS Style

Mphahlele, M.J. Molecular Iodine-Mediated Cyclization of Tethered Heteroatom-Containing Alkenyl or Alkynyl Systems. Molecules 2009, 14, 4814-4837. https://doi.org/10.3390/molecules14124814

AMA Style

Mphahlele MJ. Molecular Iodine-Mediated Cyclization of Tethered Heteroatom-Containing Alkenyl or Alkynyl Systems. Molecules. 2009; 14(12):4814-4837. https://doi.org/10.3390/molecules14124814

Chicago/Turabian Style

Mphahlele, Malose Jack. 2009. "Molecular Iodine-Mediated Cyclization of Tethered Heteroatom-Containing Alkenyl or Alkynyl Systems" Molecules 14, no. 12: 4814-4837. https://doi.org/10.3390/molecules14124814

Article Metrics

Back to TopTop