Bis(pyridine)iodonium(I) Tetrafluoroborate1

[15656-28-7]  · C10H10BF4IN2  · Bis(pyridine)iodonium(I) Tetrafluoroborate  · (MW 371.91)

(iodinating agent for the selective functionalization of unsaturated compounds;2-4 can also mediate C-C bond formation5)

Physical Data: mp 149-151 °C (dec).6

Solubility: sol CH2Cl2, DMSO, MeCN, pyridine, DMF; modestly sol CHCl3; insol ether, THF, hexane.

Analysis of Reagent Purity: spectroscopic data: IR,6 NMR (1H, 13C).6

Preparative Method: prepared by the reaction of HgO/HBF4-SiO27 with iodine and pyridine in dry CH2Cl2 at rt.2,6 Solids are filtered off, and the reagent is isolated by precipitation from CH2Cl2 solution by addition of cold ether, repeating the operation several times until a negative test for mercury(II) is obtained (i.e. absence of precipitation of mercury by treatment of an aliquot with NaBH4/NaOH).2

Purification: recrystallization from CH2Cl2-CHCl3 (white solid).

Handling, Storage, and Precautions: can be safely stored under a nitrogen atmosphere (in the dark at 4 °C) for long periods of time (up to 3 months has been observed) without changing either properties or physical appearance.

Reaction with Alkenes.

Ipy2BF4 reacts readily with alkenes in CH2Cl2 to afford 1,2-disubstituted products arising from addition of iodine and pyridine.6 Synthetically more important is the reaction of alkenes with Ipy2BF4 in the presence of nucleophiles, which provides a general method for the vicinal iodofunctionalization of alkenes. In this regard, HBF4 (used as commercially available 54% ethereal soultion) is usually added to the reaction mixture to avoid the competitive formation of products from pyridine acting as nucleophile (eq 1).6 Tetrafluoroboric Acid was selected to neutralize pyridine on the basis of its low nucleophilic character. As an alternative, the use of Boron Trifluoride Etherate has been reported.

A variety of nucleophiles participate in this reaction, and the nature of the nucleophile is important in determining the experimental protocol. Typical inorganic salts (e.g. Br-) behave as efficient nucleophiles in this reaction using dioxane:water (10:1 v/v) as solvent, so that addition of HBF4 is not required. A different and representative procedure can be followed for nucleophiles that can be used as solvents; for instance, MeCN reacts at -30 °C with alkenes and Ipy2BF4-HBF4 (1:2 molar ratio), furnishing 2-iodoamides after hydrolysis. On some occasions, CH2Cl2 can be employed as the solvent, allowing a reduction in the amount of nucleophile. Oxygenated compounds (for instance methanol) and arenes can also be employed as nucleophiles following the latter approach.

Remarkably, reaction of alkenes with Ipy2BF4-HBF4 in CH2Cl2 (-60 °C, 30 min) in the absence of nucleophile produces iodofluorinated compounds in high yield. The regioselectivity of the process is illustrated in the reaction of 1-hexene (eq 2).3 Regarding the stereochemistry of the reaction, it was found that cyclohexene leads exclusively to trans-1-fluoro-2-iodocyclohexane in 89% yield. This mild iodofluorination process is quite general with respect to the structure of the alkene and has been nicely adapted to fluoroiodinate the less reactive esters of acrylic acid. The regio- and stereoselectivity shown together with other features of this process are compatible with an initial electrophilic attack of iodine to the alkene followed by ring opening of the resulting iodonium ion via nucleophilic attack of one fluoride ion liberated by BF4-.8

Carbon-carbon bond formation can also be mediated by the title reagent, providing routes to carbocycles. Reaction of difunctional a,d-arylalkenes with Ipy2BF4-HBF4 results in a diastereoselective and high-yield intramolecular six-membered ring construction (eq 3).9 The regio- and stereochemistry found can be rationalized in terms of a chairlike transition state for the attack of electrophilic iodine to the difunctional compound, in agreement with the Stork-Eschenmoser hypothesis.10 The reaction of 1,5- and 1,6-dienes took place in a related manner. It was found that, besides intramolecular carbon-carbon bond formation, concomitant fluorine incorporation into the cyclized products took place (e.g. 1,5-hexadiene gives 1-fluoro-4-iodocyclohexane as the major reaction product). Interestingly, cyclizations also occur when using Trifluoromethanesulfonic Acid instead of HBF4; thus 1,5-hexadiene furnishes 4-iodocyclohexene in 70% yield.

Reaction with 1,3-Dienes.

Nucleophiles react with conjugated dienes in the presence of Ipy2BF4-HBF4, furnishing products derived from 1,2- and/or 1,4-addition.11,12 The structure of the starting diene and, in some cases, the reaction temperature were decisive factors in determining the addition pattern. Terminal dienes (i.e. 1,3-butadiene, isoprene, 2,3-dimethyl-1,3-butadiene) cleanly afford 1,2-addition products (eq 4).11 Exceptions to this trend were found when working with C6H6 and MeCN as nucleophiles, where 1,4-addition products were observed.12

Thus reaction of 1,3-butadiene with Ipy2BF4-HBF4 in MeOH at -40 °C furnished CH2=CH-CH(OMe)CH2I in 86% yield. Similar behavior was noticed for 2,3-dimethyl-1,3-butadiene (78% yield of the 1,2-addition product) without evidence for the formation of the 1,4-regioisomer. Internal dienes, such as 1,3-cyclooctadiene and 2,4-hexadiene, were found to undergo exclusively 1,4-addition irrespective of the nature of the nucleophile (Nu: Cl, OCHO (from DMF), MeCONH (from MeCN); NO2-).11 In fact, 1,3-cyclooctadiene reacted with MeOH, under related conditions to those described for 1,3-butadiene, affording the 1,4-regioisomer in 58% yield. Experimental conditions were also described to isomerize 1,2-addition products (kinetic control) to their 1,4-regioisomers (thermodynamic control).12

Reaction with Alkynes.

This process has been studied in some detail. Alkynes react with Ipy2BF4 and nucleophiles (i.e. RCO2H, Cl-, py, ArH, Br-, I-) to give 1,2-iodofunctionalized alkenes in moderate to good yield.2,13,14 Addition products are generally formed as single regio- and stereoisomers; this fact enhances the synthetic utility of this reaction. The regiochemistry can be predicted by taking into account polar effects exerted by the substituents onto the triple bond; PhC&tbond;CH, n-BuC&tbond;CH, and PhC&tbond;CMe thus incorporated nucleophiles at the underlined carbon atom. With respect to stereoselectivity, the situation is somewhat more complicated but still some helpful generalizations are possible. Thus terminal alkynes furnished products derived from an anti addition of iodine and the nucleophile. For internal acetylenes the outcome was affected by the nature of the nucleophile; syn addition occurs for the strong nucleophile I-, whereas weaker nucleophiles (RCO2H, Cl-, py, ArH) give rise to anti addition products.2,14 Competition between anti and syn addition was noticed for borderline nucleophiles like Br-. The same observation was made for reactions of weaker nucleophiles (RCO2H) with internal alkynes bearing a bulky substituent on the sp carbon (PhC&tbond;C-t-Bu).2 An ionic mechanism that involves participation of a vinyleneiodonium ion was proposed to account for the observed selectivity.

Taking advantage of their reactivity towards the reactive Ipy2BF4-HBF4 in CH2Cl2 solution, alkynes were successfully employed to alkylate aromatic compounds. This type of Friedel-Crafts alkylation reaction had been rarely observed before (eq 5).14 Efficient nucleophiles that take part in this alkylation include C6H6, C6D6, alkylbenzenes, anisole, and naphthalene. Bromobenzene gives only a modest yield (20%) of adduct on reaction with phenylacetylene. The alkyne component can be modified (n-BuC&tbond;CH; PhC&tbond;CMe), maintaining the same regioselectivity pattern in the addition. The intramolecular version of the process is also known.9

The influence of polar effects of the substituents to control the regiochemistry was clearly shown when alkynyl sulfides were used as starting materials (eq 6).15

Based on this special reactivity of Ipy2BF4, a new one-pot procedure to prepare iodinated alkynes from alkynes was reported.16 Room temperature reaction of both components, alkyne and Ipy2BF4, in the presence of MeONa-MeOH affords good yields of products. This process is very clean and is compatible with the presence of several functional groups on the alkyne molecule. The iodoalkynes thus obtained undergo a number of interesting addition reactions; among these the iodofunctionalized product arising from incorporation of isopropanol as nucleophile is of particular interest (eq 7).17

As depicted, treatment of Ph(i-PrO)C=CI2 with excess s-Butyllithium followed by reaction of the metalated intermediate with an electrophile established an easy approach to the stereoselective elaboration of highly functionalized tetrasubstituted alkenes. The nature of the incorporated electrophile can be widely modified (H, D, allyl, MeS, Me, MeCHOH), leading always to the formation of a sole stereoisomer, that showing a trans relationship for the electrophile and the i-PrO group. The intermediate carbenoid species displayed unusual thermal stability in THF up to -20 °C and, remarkably, could be coupled in the presence of Copper(I) Chloride (THF, -60 °C), furnishing 1,4-diisopropoxy-1,4-diphenyl-1,2,3-butatriene in quantitative yield.17 From a synthetic point of view, the second iodine atom can also be replaced. This can be done in a stepwise manner (eq 8)17 or in a one-pot procedure (eq 8).18 The former allows the preparation of functionalized enol ethers with defined stereochemistry.

To enlarge the scope of the reactions of addition to 1-haloalkynes, the corresponding chloro and bromo derivatives were brought to react with Ipy2BF4 in the presence of different nucleophiles to afford stereoselectively the related 1-halo-1-iodo-1-alkenes.19,20

A distinctive feature of the reactivity of 1-iodoalkynes has recently been reported. It was shown that these iodoalkynes react with catalytic amounts of Ipy2BF4-HBF4 to yield head-to-tail dimers through an unprecedented coupling reaction (eq 9).5 The reaction works well either when R is an aryl group or when it contains a conjugated carbon-carbon double bond. Also, it was found that the reaction involving p-substituted arylalkynes is quite sensitive to the nature of substituent, and the observed trend of reactivity suggests an electrophilic mechanism. Under the reported reaction condition, no evidence for further oligomerization was found.

Reaction with Aromatic Compounds.

Ipy2BF4 has proven to be an excellent reagent to achieve the iodination of aromatic compounds.4,21 The structure of the iodinated products can be predicted according to aromatic electrophilic substitution rules. The reaction of Ipy2BF4 with arenes takes place at room temperature in the presence of HBF4 or CF3SO3H in CH2Cl2, furnishing monoiodo derivatives with great regioselectivity and high yield. One of the major merits of the procedure lies in its ability to iodinate a wide range of arenes, from very activated compounds such as 1,3,5-trimethoxybenzene to deactivated systems such as nitrobenzene (almost all previously reported iodinating agents failed to react with nitrobenzene) (eq 10),4 as well as heteroarenes such as indole, for which only catalytic amounts of acid are required. Use of either acid gives comparable results when the starting aromatic compound is activated (eq 11), whereas triflic acid is the acid of choice to iodinate deactivated aromatics.

Benzaldehyde is also efficiently iodinated in 80% yield under similar conditions to those reported for nitrobenzene, without formation of oxidation products. In summary, the reported 21 examples4 demonstrate that this is a general and reliable procedure which overcomes the well documented limited scope of aromatic iodination. Moreover, conditions were optimized to regioselectively prepare polyiodinated compounds at room temperature. In particular, reaction of Ipy2BF4 with C6H6 and CF3SO3H in CH2Cl2 provides an easy synthetic entry into a complete set of rarely accessible benzene derivatives (eq 12).22

Finally, Ipy2BF4 is the reagent of choice to prepare 3,5-diamino-4-iodopyrazole through direct iodination of the corresponding pyrazole.23

1. Varvoglis, A. The Chemistry of Polycoordinated Iodine; VCH: Weinheim, 1992.
2. Barluenga, J.; Rodríguez, M. A.; Campos, P. J. JOC 1990, 55, 3104.
3. Barluenga, J.; Campos, P. J.; González, J. M.; Suárez, J. L.; Asensio, G. JOC 1991, 56, 2234.
4. Barluenga, J.; González, J. M.; García-Martín, M. A.; Campos, P. J.; Asensio, G. JOC 1993, 58, 2058.
5. Barluenga, J.; González, J. M.; Llorente, I.; Campos, P. J. AG(E) 1993, 32, 893.
6. Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. AG(E) 1985, 24, 319.
7. Barluenga, J.; Campos, P. J.; González, J. M.; Asensio, G. JCS(P1) 1984, 2623.
8. Sharp, D. W. A. Adv. Fluorine Chem. 1960, 1, 68.
9. Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. AG(E) 1988, 27, 1546.
10. Bartlett, P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: Orlando, FL, 1984; Vol. 3, Chapter 5, p 341.
11. Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. TL 1986, 27, 1715.
12. Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G. TL 1988, 29, 6497.
13. Barluenga, J.; Rodríguez, M. A.; González, J. M.; Campos, P. J.; Asensio, G. TL 1986, 27, 3303.
14. Barluenga, J.; Rodríguez, M. A.; González, J. M.; Campos, P. J.; TL 1990, 31, 4207.
15. Barluenga, J.; Campos, P. J.; López, F.; Llorente, I.; Rodríguez, M. A. TL 1990, 31, 7375.
16. Barluenga, J.; González, J. M.; Rodríguez, M. A.; Campos, P. J.; Asensio, G. S 1987, 661.
17. Barluenga, J.; Rodríguez, M. A.; Campos, P. J.; Asensio, G. JACS 1988, 110, 5567.
18. Barluenga, J.; Rodríguez, M. A.; Campos, P. J.; SL 1990, 270.
19. Barluenga, J.; Rodríguez, M. A.; Campos, P. J. TL 1990, 31, 2751.
20. Barluenga, J.; Rodríguez, M. A.; Campos, P. J. S 1992, 270.
21. Barluenga, J.; González, J. M.; García-Martín, M. A.; Campos, P. J.; Asensio, G. CC 1992, 1016.
22. Barluenga, J.; González, J. M.; García-Martín, M. A.; Campos, P. J. TL 1993, 34, 3893.
23. Echevarría, A.; Elguero, J.; Yranzo, G. I.; Diez-Barra, E.; de la Hoz, A.; Moreno, A.; García-Martín, M. A. JCS(P1) 1993, 2229.

José Barluenga, Miguel Tomás & José M. González

Universidad de Oviedo, Spain

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