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Iodination of Alcohols Under Microwave Irradiation Using KI in the Presence ofa Catalytic Amount of Ionic Liquid Triethylamoniom Hydrogensulfate()Abdol R. Hajipour a; Ghobad Azizi b; Arnold E. Ruoho a

a Department of Pharmacology, University of Wisconsin, Medical School, Madison, Wisconsin, USA b

Department of Chemistry, Isfahan University of Technology, Isfahan, Iran

Online Publication Date: 01 January 2009

To cite this Article Hajipour, Abdol R., Azizi, Ghobad and Ruoho, Arnold E.(2009)'Iodination of Alcohols Under Microwave IrradiationUsing KI in the Presence of a Catalytic Amount of Ionic Liquid Triethylamoniom Hydrogensulfate()',SyntheticCommunications,39:2,242 — 250

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Iodination of Alcohols Under MicrowaveIrradiation Using KI in the Presence of a

Catalytic Amount of Ionic LiquidTriethylamoniom

Hydrogensulfate(½Et3NH�þHSO�4 )

Abdol R. Hajipour,1 Ghobad Azizi,2 and Arnold E. Ruoho1

1Department of Pharmacology, University of Wisconsin, Medical School,Madison, Wisconsin, USA

2Department of Chemistry, Isfahan University of Technology, Isfahan, Iran

Abstract: The iodination of alcohols with KI in the presence of a catalyticamount of triethylamoniom hydrogensulfate (½Et3NH�þHSO�4 ) as a novel andinexpensive ionic liquid under microwave irradiation has been investigated.

Keywords: Acidic ionic liquid, alkyl iodide, iodination of alcohols, KI, triethyla-moniom hydrogensulfate

INTRODUCTION

Alkyl halides are very useful intermediates in organic synthesis. Theyreact with nucleophiles such as amines or alkoxides to give the corre-sponding amines or ethers and can be lithiated to introduce electrophilesvia a halogen–lithium exchange reaction. The most common precursorsfor preparation of alkyl halides are alcohols, and their conversion intohalides is one of the most frequently used functional group transform-ation reactions.[1] Although alkyl iodides are less stable and more expens-ive than other alkyl halides, they are more reactive than the otherhalogens, and in some cases iodides are the only reactive halides. Forconverting alcohols to the corresponding alkyl idodides, several methods

Received February 9, 2008Address correspondence to Abdol R. Hajipour, Department of Chemistry, Isfahan

University of Technology, Isfahan 84156, IR, Iran. E-mail: [email protected]

Synthetic Communications1, 39: 242–250, 2009

Copyright # Taylor & Francis Group, LLC

ISSN: 0039-7911 print/1532-2432 online

DOI: 10.1080/00397910802120916

242

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have been described using a variety of reagent systems such as BF3-Et2O=KI,[2] P4=I2,[3] Cl2SO–DMF=KI,[4] MgI2,[5] ClSiMe3=KI,[6] R3PI2–Et2O,C6H6=HMPA,[7] CeCl3 � 7H2O=KI,[1] PPh3=DDQ=R4NþX�,[8] KI=BF3 �Et2O,[9] and PPh3=DEAD=LiI.[10] Other useful methods includingapplying KI in the presence of phase-transfer catalysts[11] and=or I2=petroleum ether.[12] KI=Amberlyst 15[13] and polymer-supportedtriphenylphosphine=I2=ImH have also been reported for iodination ofbenzylic alcohols.[14] However, some of the reported systems suffer fromdrawbacks such as the danger of explosion (DEAD),[15] low yields,[11,12]

long reaction times,[1,12] harsh reaction conditions, noncommerciallyavailable materials, and tedious workup procedures.[11] Thus newmethods, with higher efficiency higher selectivity, less toxicity, and thatuse commercially available materials, are important.

Recently, room-temperature ionic liquids (RTILs) have receivedmuch attention because of their excellent properties and potential appli-cation in many fields. Ren and Wu[16] have demonstrated that by employ-ing 1,3-dialkylimidazolium halide-based ionic liquids, it is possible toconvert alcohols to alkyl halides in the presence of either an organic orinorganic acid. However, reaction times are very long (24 and 48 h).

RESULTS AND DISCUSSION

In continuation of our effort to develop a mild procedure for organicfunctional group transformation,[17–21] here we report a novel applicationof RTILS for selective iodination of alcohols using KI under solvent-freeconditions with microwave (MW) irradiation in short reaction times andhigh yields (Scheme 1).

Triethylamoniom hydrogensulfate ½Et3NH�þ½HSO4�� is an efficientRTIL that can be used as an alternative for other mineral acids such asH2SO4 and HCl for conversion of benzyl alcohols into the correspondingbenzyl iodides. To optimize the reaction conditions for iodination ofbenzyl alcohol to the corresponding benzyl iodide, we tried different

Scheme 1. Iodination of alcohols with acidic ionic liquid under microwaveirradiation.

Iodination of Alcohols Using Microwaves 243


conditions. Initially we examined a mixture containing 1 mmol of benzylalcohol, 0.05 g of ionic liquid, and 1 mmol of KI in CH3CN at roomtemperature. After 10 h of stirring, no reaction was occurred at all;however, reaction mixture was converted to benzyl in 80% yields after4 h of refluxing. By grinding a mixture of benzyl alcohol and KI in thepresence of catalytic amounts of ½Et3NH�þ½HSO4�� as an acid catalystby a pestle, the reaction time for iodination was reduced to 2 h with90% conversion. Under microwave irradiation, the benzyl alcohol wasconverted to benzyl iodide in quantitative yields after 60 s. Therefore,based on the optimized conditions, several alcohols were iodinated(Table 1).

To optimize the amount of ionic liquid, 1 mmol of benzyl alcohol and1 mmol of KI were treated in the presence of different amounts of ionicliquid using microwave irradiation (200 W). As showing in Fig. 1,20 mmol% ionic liquid as acid catalyst gave the best conversion.

The power for iodination of 4-nitrobenzyl alcohol was reduced to100 W. This may be due to the polar NO2 substituent, which absorbsmicrowave irradiation; at the higher powers, the reaction mixture wasincinerated. On the other hand, in the case of secondary alcohols, theconversion into corresponding iodides needed longer reaction times(entries l, m, and n). The reaction was found to be highly selective onlyfor allylic and benzylic alcohols, and saturated aliphatic alcoholswere not iodinated even after a prolonged reaction time. By this method,secondary allylic or benzylic alcohols also were easily converted to thecorresponding allylic or benzylic iodide in high yields.

The possible mechanism for this transformation is outlined inScheme 2. The acidic ionic liquid (½Et3H�þHSO�4 ) protonated the oxygenof alcohol to form a good leaving group for nucleophilic substitution ofiodide.

To evaluate the chemoselectivity of this method, we studied thecompetitive reactions. As shown in Table 2, entries 1 and 2, when wetreated a mixture of benzylic and saturated alcohols in the presence ofcatalytic amounts of ½Et3H�þHSO�4 , only benzylic alcohols wereiodinated. In competition between the benzyl and 4-nitrobenzyl alcohol,the 4-nitrobenzyl alcohol was intact and only the benzyl alcohol wasiodinated (Table 2, entry 3).

CONCLUSION

In conclusion, the present study shows that this procedure is a valuablealternative for conversion of alcohols into iodo derivatives undersolvent-free conditions with high yield in short reaction times. The

244 A. R. Hajipour, G. Azizi, and A. E. Ruoho


Table 1. Conversion of alcohols to the corresponding iodides using½Et3NH�þ½HSO4�� under microwave irradiation

Entry Substrate Product Time (s) Yielda (%)

a 60 95

b 90 90

c 60 86

d 90 80

e 30 98

f 40 93

g 80 94

h 50 92

i 60 86

j 50 90

k > 120 50b

l 100 91

m 120 70

n 100 93

(Continued)



straightforward procedure, inexpensive reagents, and short reaction timesare advantages of the present method over reported methods.

EXPERIMENTAL

General

All reagents were purchased from Merck and Aldrich and used withoutfurther purification. All yields refer to isolated products afterpurification. Products were characterized by comparison with authenticsamples and by spectroscopic data (IR, 1H NMR, and MS analysis).1H NMR spectra were recorded at 300 MHz in CDCl3, relative toTMS (0.00 ppm). All of the reactions were carried out using a Milestonemicrowave oven (MicroSYNTH).

Table 1. Continued

Entry Substrate Product Time (s) Yielda (%)

o 40 90

p 120 —

q 120 —

aYields refer to pure isolated products and were characterized by comparison oftheir physical and spectral data (IR, 1H NMR) with authentic samples.

bPower was 100 W.

Figure 1. Optimization of the amount of ionic liquid.



Preparation of ½Et3H�þHSO�4

Triethylamine (2.8 mL, 20 mmol) was dissolved in dichloromethane(10 mL), and 1 mL of concentrated H2SO4 (20 mmol) was added slowlyat 0�C. The reaction mixture was stirred at room temperature for 30 min.min. The resulting ionic liquid was washed by diethyl ether and dried in avacuum at 80�C. Yield 100%, IR (KBr): 3450, 2978, 2944, 2734, 2600,2494, 1650, 1481, 1398, 1171, 1038, 850 cm�1. 1H NMR (300 MHz,CDCl3): d 9.7 (s, 1 H), 9.35 (s, 1 H), 3.3 (q, 2 H), 1.8 (t, 3 H) ppm.13C NMR (D2O, 500 MHz): d 9 (CH3), 470 (CH2) ppm.

Iodination of Benzyl Alcohol (Typical Procedure)

In a mortar, a mixture of benzyl alcohol (1 mmol, 0.11 g), KI (1.0 mmol,0.15 g), and triethylamoniom hydrogensulfate (0.2 mmol, 0.04 g) wasground with a pestle (30 s) to a homogeneous mixture. The mortar wasput in a sealed Teflon1 vessel, and the reaction mixture was irradiatedfor the time specified in Table 1. Thin-layer chromatography (TLC)

Scheme 2. Proposed mechanism for transformation of alcohols into iodocompounds.

Table 2. Competitive reaction for selective iodination of different alcoholsa

aThe progress of the reaction was determined by GC and TLC analysis.



monitored the progress of the reaction. After disappearance of thealcohol (n-hexane–EtOAc, 75:25) the reaction mixture was diluted withdichloromethane (25 mL). The organic layer was washed with an aqueoussolution of Na2S2O3 (10%, 10 mL), and then H2O (2� 10 mL). Theorganic layer was dried over anhydrous Na2SO4. The solvent was evapo-rated under reduced pressure, and the residue was purified by short-column chromatography (n-hexane–EtOAc, 80:20). Benzyl iodide wasobtained in 95% yield (0.209 g). IR (neat) cm�1: 3010, 2930, 1595,1485, 1430, 1070, 835, 750, 660. 1H NMR (300 MHz, CDCl3, TMS) d7.3–7.0 (m, 5H), 3.95 (s, 2H).

Competitive Reaction for Iodination of 4-Nitrobenzyl Alcohol in the

Presence of Benzyl Alcohol (Typical Procedure)

In a mortar, a mixture of 4-nitrobenzyl alcohol (1 mmol, 0. 26 g), benzylalcohol (1 mmol, 0.11 g), and triethylamoniom hydrogensulfate(0.2 mmol, 0.04 g) was ground with a pestle to obtain a homogeneousmixture. The mortar was put in a sealed Teflon1 vessel, and the reactionmixture was irradiated for 60 s by microwave. TLC monitored theprogress of the reaction. Benzyl iodide was obtained in 93% yield, and4- nitrobenzyl alcohol was intact (Table 2, entry 1).

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21. (a) Hajipour, A. R.; Mahboubkhah, N. 1-Benzyl-4-aza-1-azoniabicyclo-[2.2.2]octane periodate: A mild and efficient oxidation for the cleavage ofoxime double bonds under anhydrous conditions. J. Chem. Res., Synop.1998, 122; (b) Hajipour, A. R.; Ruoho, A. E. Solid state deprotection ofthioacetals and thioketals using 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octaneperiodate and aluminum chloride. Org. Prep. Proced. Int. 2005, 37, 298; (c)Hajipour, A. R.; Ruoho, A. E. Methyltriphenylphosphonium peroxydisulfateand iodine as mild reagents for the iodination of activated aromaticcompounds. Org. Prep. Proced. Int. 2005, 37, 279.



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