Molecular Iodine—An Expedient Reagent for Oxidative Aromatization Reactions of α,β-Unsaturated Cyclic Compounds

Prompted by the scant attention paid by published literature reviews to the applications of molecular iodine in oxidative aromatization reactions, we decided to review methods developed to-date involving iodine as an oxidant to promote aromatization of α,β-unsaturated cyclic compounds.


Introduction
Aromatization of substituted cyclohexenones to the corresponding phenol or phenyl ether derivatives has attracted a great deal of attention for a long time. Catalytic dehydrogenation of substituted 2-cyclohexen-1-one derivatives using 5% palladium-carbon in high boiling hydrocarbon solvents, for example, previously afforded the corresponding phenolic systems in high yields [1]. Under similar reaction conditions, substituted 2-cyclohexenone derivatives were found to undergo disproportionation leading to reduced yields of the target phenolic or phenyl ether derivatives [2]. In another development, copper(II) bromide/lithium bromide mixture in boiling acetonitrile was applied to 2-cyclohexen-1-ones and their fused derivatives to afford 75-85% of the corresponding phenolic compounds [3]. This reaction, which is believed to proceed by halogenation of the homoannular enol form of the conjugated carbonyl group, was found to occur with conservation of ring junction stereochemistry and without halogenation α to the nonconjugated carbonyl group. Dehydrogenation of 4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid and its methyl ester derivative with copper(II) OPEN ACCESS bromide (CuBr 2 ) in refluxing methanol also afforded the corresponding 4-hydroxy-2,3dihydrobenzofuran-2-carboxylic acid derivatives [4]. Despite the observed trans-esterification or esterification, the application of CuBr 2 was found to be more effective than the use of sulfur at 250 ºC or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in benzene under reflux [4]. Homogenous transition metal complex such as rhodium trichloride trihydrate (RhCl 3· 3H 2 O) was also found to induce oxidative aromatization and remote double bond migration of alkenylcyclohexenones and unsaturated imines to afford substituted phenols and aniline derivatives [5]. Treatment of ω-alkenyl substituted cyclohexenone-1,3-diones with RhCl 3· 3H 2 O in methanol or ethanol afforded substituted resorcinols [6]. Under similar reaction conditions, related enol ethers afforded dienones. Vanadiumcatalyzed oxidative aromatization of α,β-unsaturated cyclohexenones using VO(OR)Cl 2 in refluxing alcohols also afforded aryl ether derivatives [7]. An efficient catalytic oxidative aromatization of 2-cyclohexenones involving a combination of a commercially available ligand-free vanadium catalyst (VOSO 4 ), a bromide source (Bu 4 NBr or HBr), and an acid (trifluoroacetic acid) under atmospheric oxygen or air recently afforded the corresponding phenol derivatives [8] Although heterogenous or homogenous metal-catalyzed aromatization of substituted cyclohexenones to the corresponding phenols or phenol ethers is a well established procedure, it involves severe reaction conditions accompanied by prolonged reaction times.
The oxidative potential of iodine has been exploited over the years in the synthesis of novel aromatic and heteroaromatic compounds that may possess some biological activity or serve as building blocks for the synthesis of derivatives with potential biological applications. The naturally occurring olivetol (1a) and the antifungal antibiotic DB2073 (1b), for example, were synthesized before from substituted resorcinols, prepared in turn from the corresponding 1,3-cyclohexanediones using iodine in refluxing methanol [9]. 4-Methoxy-2-phenylquinoline (2a) and its 4-methoxy-2-(3,4methylenedioxyphenyl)quinoline analogue 2b, which are plant-based [10] are readily accessible in the laboratory via iodine-mediated oxidative aromatization of the corresponding 2-aryl-1,2,3,4tetrahydroquinolin-4-ones [11]. These alkoxyquinoline derivatives, which are reported to exhibit inhibitory activity against Mycobacterium tuberculosis H 37 Rv [12] can also be accessible from 2-aryl-1,2,3,4-tetrahydroquinolin-4-ones using thallium(III) nitrate [13] or [hydroxyl(tosyloxy)iodo]benzene [14] in trimethyl orthoformate in the presence of catalytic amount of perchloric acid or using FeCl 3 .6H 2 O in methanol [15]. The use of potentially explosive perchloric acid and/ or environmentally unfriendly metallic reagents that are not easy to obtain represent some of the drawbacks of these methods.  1a Olivetol (R 1 =H; R 2 = -CH 2 (CH 2 ) 3 CH 3 ); 1b DB2073 (R 1 =-CH 2 (CH 2 ) 4 CH 3 ; R 2 = -CH 2 CH 2 CH 3 ) In recent years, molecular iodine has received considerable attention as an inexpensive, non-toxic, readily available oxidant to promote aromatization of cyclohexenone derivatives and their heterocyclic analogues. Despite the growing applications of iodine as an expedient oxidizing agent to promote oxidative aromatization of α,β-unsaturated cyclic compounds such examples feature less or not at all in literature reviews on the applications of iodine in various chemical transformation as a Lewis acid catalyst, electrophile or oxidant [16][17][18][19]. We address this need in the present review by focusing primarily on the application of molecular iodine as an oxidizing agent to effect aromatization of α,βunsaturated cyclic compounds and their heterocyclic analogues.

Iodine-alcohol-mediated aromatization of cyclohexenone derivatives
The use of molecular iodine as an oxidant to promote aromatization of cyclohexenone derivatives was first reported in 1980 by Tamura and Yoshimoto [20]. These authors subjected series of cyclohexenones to iodine in refluxing methanol to afford variously substituted anisole derivatives. Their methodology was later applied by Kotnis on Hagemann's esters 3 to afford substituted p-methoxybenzoates 4, which are building blocks for several marine natural products (Scheme 1) [21]. Scheme 1. Iodine-promoted oxidative aromatization of Hagemann's esters.

Treatment of benzo[b]indeno[2.1-d]furanone derivatives 26
with iodine (2 equiv.) in refluxing methanol afforded anisole derivatives 27 (minor) and 28 (major), respectively (Scheme 11) [28]. The formation of methyl derivatives 28 was rationalized as a consequence of initial acid-catalyzed dehydration of 27 to form a cyclic oxonium intermediate, which then undergoes addition of methanol [25]. The proposed mechanism was proven in a follow up study involving selective methylation of systems 27 to 28 using iodine-methanol mixture and the methylated derivatives were found to be formed selectively under prolonged heating conditions (13-36 h) [29]. Kim and coworkers also employed iodine in refluxing methanol to effect oxidative aromatization of 4-alkylidene-2-cyclohexen-1-ones 29 to afford the corresponding anisole derivatives (Scheme 12) [30]. The mechanism of this reaction which was also confirmed using iodine (1.1 equiv.) on 29b in deuterated methanol to afford deuterated analogue of 30b (OCD 3 in place of OMe) in 32% yield is believed to involve initial conjugate addition of methanol to the exo-methylene moiety followed by attack of the carbonyl carbon by methanol to generate a hemiketal derivative. Dehydration of the latter then occurs followed by iodine-promoted oxidative aromatization to yield the anisole derivatives. The fully conjugated systems 31f and 31g formed as minor products from substrates 29f and 29g are presumably the consequence of slow expulsion of methanol from the dimethoxy products. Kim's group also subjected 2-methylene-2-cyclohexenones to iodine in alcohol (methanol or ethanol) to afford series of novel anisole derivatives [31].

Iodine-methanol-mediated aromatization of 4-quinolone derivatives
The use of iodine as an effective oxidant to promote oxidative aromatization of α,β-unsaturated cyclic carbonyl compounds is not only limited to cyclohexenone derivatives. Molecular iodine in refluxing methanol has also been shown to effect oxidative aromatization of 2-aryl-1,2,3,4-tetrahydro-4-quinolones 34 to afford analogues of the naturally occurring 4-methoxy-2-phenylquinolines 35 with potential antimalarial and anti-tuberculosis activities (Scheme 14) [11]. The mechanism of this reaction is believed to involve initial attack of the protonated quinolone by methanol to generate a hemiacetal derivative. The latter would then undergo dehydration and subsequent oxidative aromatization by iodine to afford 35.

Iodine/sodium ethoxide-mediated aromatization of cyclohexenone derivatives
Hedge and coworkers, on the other hand, used iodine and sodium ethoxide to convert 2cyclohexenone-4-carboxylates 36 into 2-iodophenols 37 (Scheme 15) [34]. The reaction was found to be favoured by the presence of electron withdrawing carboxyl group at the 4-position and to fail in the case of simple 2-cyclohexenones (R 1 ,R 3 =H; R 2 =alkyl or phenyl) due to reduced acidity of the 4methine or methylene protons. The secondary enamines 38 (R 2 =H, R 3 =alkyl) with NaOEt (6 equiv.) and I 2 (2 equiv.) in EtOH, -78 ºC, on the other hand, afforded the corresponding iodoanilines 39 (X=I) in 42-61% yield as single regioisomers (Scheme 16). Interestingly, the tertiary enamines 38 (R 2 ,R 3 =alkyl, cycloalkyl) afforded the corresponding non-iodinated aromatic derivatives 39 (X=H) in 74-89% yield. The divergence in behavior of the tertiary enamines from those of 4-carboxy substituted cyclohexenones and their secondary enamine derivatives was attributed to different rates of iodination. It was proposed that the iodination of tertiary enamines is sufficiently slow to allow dehydroiodination of the incipient monoiodo species to successfully compete with diiodination step and result in non-iodinated N,Ndialkylanilines. This proposal was further supported by oxidative aromatization of the tertiary enamine (NR 2 R 3 =morpholine) with iodine (1 equiv.) in the presence of triethylamine (2.5 equiv.) and 1,8diazabicyclo [5.4.0]undec-7-ene (DBU) at room temperature to afford the corresponding N,Ndialkylaniline in 56 and 63% yields, respectively.

Iodine-mediated aromatization of Hantzsch ester 1,4-dihydropyridines
Aromatization of Hantzsch ester 1,4-dihydropyridines using iodine in the presence of an alkali or organic base in methanol has been reported [35]. Iodine in refluxing acetonitrile is also reported to promote aromatization of the Hantzsch ester 1,4-dihydropyridines 40 to afford the corresponding pyridine derivatives 42 in high yields and regioselectivity in the absence or presence of ultrasound irradiation (Scheme 17) [36]. The 1,4-dihydropyridine derivative 40e bearing a secondary alkyl group was found to undergo aromatization accompanied by dealkylation to afford the 4-unsubstituted pyridine derivative 41e in excellent yield. The 4-unsubstituted 41 (f and g) and substituted derivatives 42 (f and g) were isolated as mixtures under both reaction conditions when 1,4-dihydropyridines bearing 2-furyl moiety on the 4-position were used as substrates. Although high yielding, aromatization of Hantzsch ester 1,4-dihydropyridines using iodine in methanol in the presence of a base [35] or under neutral conditions in acetonitrile [36] involve prolonged reaction times than that involving ultrasound (US) irradiation. Reagents: (i) I 2 (2 equiv.), CH 3 CN, heat; a I 2 (2 equiv.), CH 3 CN, heat; b US irradiation.
Aromatization of Hantzsch ester 1,4-dihydropyridines using iodine under conventional and ultrasonic irradiation was found to be superior to other methods that involve the use of strong oxidizing agents and severe conditions that require prolonged reaction times leading to low yields [36].

Conclusions
In summary, molecular iodine has established itself in chemical transformation as an efficient, readily available and easy-to-handle oxidizing agent to effect aromatization of α,β-unsaturated cyclohexenone derivatives and their heterocyclic analogues. The generality and brevity of iodine-mediated oxidative aromatization reactions and the accompanying high yields make this methodology a suitable alternative to metal-catalyzed aromatization of related derivatives. Furthermore, direct formation of phenol ethers using iodine-promoted oxidative aromatization avoids an additional step required to convert the hydroxyl compounds formed through metal-catalyzed or DDQ-mediated aromatization to the corresponding alkoxy derivatives.