IODINE MONOBROMIDE 1 Iodine Monobromide O OH t 1. IBr, PhMe O -BuO O –80 to –85 °C (2) BrI 2. K2CO3, MeOH 71% OBn 13.9:1 [7789-33-5] Brl (MW 206.80) OBn InChI = 1S/BrI/c1-2 InChIKey = CBEQRNSPHCCXSH-UHFFFAOYAO (diastereoselective cyclizations of homoallylic carbonates; elec- trophilic addition to alkenes; -bromination of steroidal aldehy- Table 1 Regiochemistry of IBr addition to alkenes des and ketones;, cleavage of carbon–metal bonds) Alkene % Markovnikov % anti-Markovnikov Physical Data: mp 40 ◦ C; bp 116 ◦C (dec); d 4.416 g cm−3. Solubility: sol alcohol, ether, CS2, acetic acid, acetone, CH2Cl2, MeCH=CH2 65 35 MeCN, DME, toluene (but with limited solubility below –80 ErCH=CH2 45 55 ◦ C); soluble in H2O, but hydrolyzes to HBr and IOH. i-PrCH=CH2 15 85 Form Supplied in: brownish-black crystals or very hard, black t-BuCH=CH2 0 100 solid; widely available (usually 97–98% purity). PhCH=CH2 100 0 Handling, Storage, and Precautions: corrosive solid and vapor; readily absorbed through skin and mucous membranes; use in a fume hood and wear gloves and appropriate protective clothing; air-, moisture-, and light-sensitive; should be stored refrigerated (under N ) in a tightly sealed amber bottle. Forms explosive 2 mixtures with potassium and sodium, and reacts extremely -Bromination of Steroidal Aldehydes and Ketones. Io- exothermically with phosphorus and tin. dine monobromide is an effective monobrominating reagent for steroidal aldehydes (eq 3). The ratio of diastereomeric products is in part a function of the reaction site’s proximity to an asymmet- Original Commentary ric center, with -orientation favored for the entering bromine. In an analogous application, methyl 3-oxo-5-cholanate has been Ronald G. Brisbois & Randall A. Wanke monobrominated (IBr/MeCO2H; 50% yield) to produce the 2- Hamline University, St. Paul, MN, USA bromo ketone. Electrophilic Cyclization of Homoallylic Carbonates. Io- dine monobromide provides very good diastereoselectivity in electrophilic cyclizations of homoallylic carbonates (eq 1). Iso- CHO IBr, AcOH lated yields of -iodo cyclic carbonates are excellent, and these 30 °C, overnight products can be easily and efficiently converted into the cor- 100% responding epoxides (eq 2). Optimal diastereoselectivity is ob- ◦ tained from reactions performed in toluene at −80 to −85 C. Use Br Br of Iodine/MeCN or Iodine Monochloride/CH2Cl2 yields much lower diastereoselectivity than iodine monobromide under similar CHO CHO + (3) conditions. Results of an equilibration experiment strongly indi- cate that the diastereoselectivity in iodine monobromide-induced cyclization stems from kinetic control. 4.9:1 Electrophilic Addition to Alkenes. Iodine monobromide addition across alkenes is very facile, yielding vicinal bro- moiodoalkanes. In general, addition occurs with high anti stere- Bond Cleavage Reactions. Cleavage of carbon–metal bonds ospecificity, and mechanistic studies have implicated an iodonium by iodine monobromide typically produces the organic iodide and ion intermediate in the overall reaction sequence. The regiochem- the metal bromide. Cleavage of organotin,– organoarsenic, istry of iodine monobromide addition is very sensitive to the initial organoantimony, organogermanium, and organolead bonds alkene structure, such that anti-Markovnikov products are possi- has been investigated (see also Iodine Monochloride for use in ble (Table 1). cleaving carbon–metal bonds). O O O Other Applications. Iodine monobromide has been used for IBr, PhMe brominating phenol and aryl ether derivatives. Ethers and es- –80 to –85 °C OO OO t-BuO O + (1) ters have been cleaved by catalytic iodine monobromide in the 30 min I I Bromotrimethylsilane Pr 95% Pr Pr presence of . Aryl acetals can be directly 25.8:1 oxidized to the corresponding esters in moderate yield. 2 IODINE MONOBROMIDE First Update donors., It provides excellent 1,2-trans stereoselectivity and it is compatible with most common protecting groups and existing Robert A. Field & Balaram Mukhopadhyay O-glycosides. However, issues can arise from the Lewis acidity University of East Anglia, Norwich, UK of IBr, which can effect acyl migration. In addition, compet- ing glycosyl bromide formation may have an impact on reaction Electrophilic Cyclization. Iodine monobromide continues to outcome. These problems can largely be overcome through the be exploited in stereoselective cyclization reactions en route to use of IBr in conjunction with silver triflate. Studies on inter- natural products, such as calyculin and halichondrin B. It can halogen/silver trifluoromethanesulfonate (IX/AgOTf) promoted also be employed in diastereoselective isothiourea iodocycliza- glycosylations reactions identified differences in the sensitivity of the formed oxocarbenium ions, e.g., from compounds with or tion reactions, which proceed smoothly using IBr at low temper- ature. Advanced intermediates in the synthesis of manzacidin A, without participating groups) toward halide nucleophiles. These amongst other examples, have been obtained using this procedure differences can be explained using the Hard-Soft-Acid-Base the- (eq 4). ory. By applying this theory silylation yields were increased for a model reaction from ∼40% using ICl to 74% using IBr. By O SMe increasing the amount of AgOTf from 1 to 1.5 equiv (with re- N spect to IBr) the yield in the model reaction improved to 89%, tBuO IBr, dichloromethane NH2 with a move from xanthate to thiophenyl glycoside donor further Me –78, 2h 95% yield, >20:1 d.r. increasing the yield of the model reaction to 97% (eq 7). O IBr O SR Br (6) PO PO O P = protecting group Glycosyl bromide NSMe tBuO (4) NH OAc OPMB OBn AcO O OMe Me O I O O O AcO O O BnO AcOBr PMBOBr OMe Br Electrophilic Addition to Alkenes. Trihalide-based ionic liquids, produced by mixing equimolar amounts of IBr and OBn BnO OAc [bmim][Br], prove to be effective reagent-solvents for stereose- O O lective iodination of alkenes and alkynes. Yields of iodobromo BnO AcO AcO Br adducts range from very good to almost quantitative for a range BnOBr NPhth of substrates (eq 5). Me IBr NN Me Br 3:2 MeCN:CH2Cl2 OAc –72 °C, 2 h OAc HO OBz [bmim][Br] CO2Me 97% yield + O AcO SPh AcHN O HO O SiMe AcO N3 3 IBr R Me 2 Br NN Me R = various OAc (5) OAc I CO2Me R N3 SiMe3 AcO O O O (7) AcHN O AcO Formation of Glycosyl Bromides. Iodine monobromide is HO OBz used for the synthesis of glycosyl bromides from various alkyl and aryl thioglycosides (eq 6). The reaction of IBr with thio- glycosides is compatible with many of the common protecting Other Applications. Iodine monobromide has been used groups, such as isopropylidene acetals, cyclohexane 1,2-diacetals, as a mild reagent for selective deprotection of O-tert- 4-methoxybenzyl and benzyl ethers, phthalimido groups, etc. butyldimethylsilyl ethers of simple alcohols, carbohydrates, and Compounds containing intersugar glycosidic linkages form gly- nucleosides. Acid labile functionalities such as acetals, O-p- cosyl bromides at their reducing terminal only, without affecting methoxybenzyl ethers, etc., as well as base labile esters and existing glycosidic linkages. amides, are stable in the presence of iodine monobromide. Among several solvents used for the reaction, methanol gives the best Glycosylation Chemistry. Iodine monobromide is an effi- yields, which may indicate that desilylation is a result of in situ cient reagent for O-glycosylation using “disarmed” thioglycoside generation of HBr. IODINE MONOBROMIDE 3 Radical addition of iodine monobromide to chlorotrifluoroethy- OH OH lene forms a useful intermediate in the synthesis of 4,5,5-trifluoro- Cl3CCN, DBU, MeCN 4-ene-pentanol, a useful monomer for fluoropolymer synthesis. O NH IBr, K2CO3, EtCN Related Reagents. Iodine monochloride; bromine N- O iodosuccinimide; N-bromosuccinimide, N-iodosaccharin; iodo- CCl3 nium dicollidine perchlorate. (10) ON O O 86% Second Update NH I HN CCl3 O Nataliya Korol & Mikhailo Slivka Uzhgorod National University, Uzhgorod, Ukraine Preparation of Polymeric Polyhalide Reagents. In order to prepare a dibromoiodate resin, the bromomethyl polystyrene, The bis(trichloroacetimidate) of cis-alkene was treated with prepared from chloromethyl polystyrene, was quaternized with iodine monobromide to give the trans-iodooxazoline as a single excess triethylamine to afford polymer-bound benzyltriethylam- stereoisomer in 86% yield (eq 11). monium bromide resin. The quaternized resin on reaction with iodine monobromide solution in glacial acetic acid gave the polymer-bound benzyltriethylammonium dibromoiodate reagent (eq 8). The polymeric polyhalide anionic reagents were found to OH OH be effective as selective iodinating reagents and are easy to pre- pare by means of quaternary ammonium salt resins. The bound IBr, K2CO3, EtCN O polyhalide reagents differ from other similar supported reagents O in that they possess moderate capacity values. They exhibited CCl effective selectivity toward amines and phenols with a moderate 3 excess of the reagent vs. substrate. ON O (11) O 86% O I KBr/CH3COCH3 (C2H5)3N HN CCl CH2Cl CH2Br 3 KBr/PTC CCl4 + – IBr/CH3COOH CH2N (C2H5)3Br (8) A method of producing salts of 8-halo-4-oxo-2,3,5,9- + – CH2N (C2H5)3IBr2 substituted-5,7,8,9-tetrahydro-4H-thieno- [3,2:5,6]-pirymido [2,1-b][1,3] thiazyn-10-ium, which includes electrophilic heterocyclization of terminal propenyl thioethers of thieno[2,3- b]pyrimidine under halogen, replaced the starting thioether by 3N-pyrimidine (eq 12). Electrophilic Cyclization. Using 2 equiv of iodine monobro- mide resulted in complete cyclization at 10 ◦C during 16 h. The resulting product was obtained with an enhanced 14:1 ratio in favor of the desired isomer, which was secured in a pure state in O R3 78% yield (eq 9). O R2 3 Br– R2 R + IBr S R1 N+ &1 S S OCO.Ph O OCO.Ph R1 N OCO.Ph &1 OH S &1 R4 &1 &1 R4 I &1 I (9) 2 3 4 HO HO R, R = Alk; R , R = Ar (12) The purified (Z)-isomer was cyclized with iodine monobromide to give the trans-oxazoline in 83% overall yield (eq 10).