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Inorganic chemistry, avinyl iodide (also known as aniodoalkene)functional group is analkene with one or moreiodide substituents (i.e. a carbon-carbondouble bond where one or both of the carbons is bound to aniodine). Vinyl iodides are versatile molecules that serve as important building blocks and precursors in organic synthesis. They are commonly used in transition-metal catalyzed cross-coupling reactions which form carbon-carbon bonds, such as theStille reaction,Heck reaction,Sonogashira coupling, andSuzuki coupling.[1] Synthesis of vinyl iodides with well-defined geometry is important in stereoselective synthesis of natural products and drugs.
Vinyl iodides are generally stable undernucleophilic conditions. In SN2 reactions, back-attack is difficult because of steric clash of R groups on carbon adjacent toelectrophilic center (see figure 1a).[2] In addition, the lone pair on iodide donates into the π* of the alkene, which reduces electrophilic character on the carbon as a result of decreased positive charge. Also, thisstereoelectronic effect strengthens the C-I bond, thus making removal of the iodide difficult (see figure 1b).[3] In SN1 case, dissociation is difficult because of the strengthened C-I bond and loss of the iodide will generate an unstablecarbocation(see figure 1c)[2]
In cross-coupling reactions, typically vinyl iodides react faster and under more mild conditions than vinyl chloride and vinyl bromide. The order of reactivity is based on the strength of carbon-halogen bond. C-I bond is the weakest of the halogens, thebond dissociation energies of C-I is 57.6kcal/mol, while fluoride, chloride and bromide are 115, 83.7, 72.1 kcal/mol respectively.[4] As a result of having weaker bond, vinyl iodide does not polymerize as easily as itsvinyl halide counterparts, but rather decompose and releaseiodide.[5]It is generally believed that vinyl iodide cannot survive commonreduction conditions, which reduces the vinyl iodide to anolefin or unsaturatedalkane.[6] However, there is evidence in literature, in which apropargyl alcohol'salkyne was reduced in presence of a vinyl iodide using hydrogen over Pd/CaCO3 orCrabtree's catalyst.[7]
Besides using vinyl iodides as useful substrates in transition metal cross-coupling reaction, they can also undergoelimination with a strong base to give correspondingalkyne, and they can be converted to suitable vinylGrignard reagents. Vinyl iodides are converted toGrignard reagents by magnesium-halogen exchange (see Scheme 1a).[8] The scope of this synthetic method is limited since it requires higher temperatures and longer reaction time, which affects functional group tolerance. However, vinyl iodide withelectron withdrawing group can enhance rate of exchange(see Scheme 1b).[8] Also addition oflithium chloride helps enhance magnesium-halogen exchange (see Scheme 1c). It is predicted lithium chloride breaks up aggregates in organomagnesium reagents.[9]
Vinyl iodides are synthesized by methods such asiodination andsubstitution reaction. Vinyl iodides with well-defined geometry (regiochemistry andstereochemistry) are important in synthesis since manynatural products anddrugs that have specific structure and dimension. Example ofregiochemistry is whether the iodide is positioned in either alpha or beta position on the olefin.Stereochemistry such asE-Z notation orcis-trans alkene geometry is important since some transition metal cross-coupling reactions, such as theSuzuki coupling, can retain olefin geometry. In synthesis, it is useful to introduce vinyl iodide at various positions to be set up for a coupling reaction at the next synthetic step. Below are various means and methods in introducing and synthesizing vinyl iodides.
The common and simplest approach to make vinyl iodide is addition of one equivalentHI toalkyne. This generally makes 2-iodo-1-alkenes or α-vinyl iodide byMarkovnikov's rule. However, this reaction does not happen at good rates or very highstereoselectively.[10] As a result, most synthetic methods often involve ahydrometalation step before addition of I+ source.
Introducing an α-vinyl iodide from a terminal position of an alkyne is a difficult step. in addition, the vinyl metal intermediate can be mildlynucleophilic, for example vinyl aluminum, can form C-C bonds under catalytic conditions. However, Hoveyda group have demonstrated using nickel-based catalyst (Ni(dppp)Cl2),DIBAL-H withN-iodosuccinimide (NIS), selectively favor α-vinyl iodide with little to no byproducts.[11] Also they observed reverse selectivity for β with Ni(PPh3)2Cl2 in theirhydroalumination reactions under same conditions with little or no byproducts. The advantage of this method is that is inexpensive (and commercially available), scalable and one-pot reaction.
Another method doesn't involvehydrometalation buthydroiodation with I2/hydrophosphine binary system, which was developed by Ogawa's group.[12]
The hydroiodation proceeds by Markovnikov-type adduct, no reaction is observed without addition of hydrophoshine. In a plausible mechanism proposed by Ogawa's group, the hydrophosphine reacts with HI to form an intermediate complex that coordinate HI to do Markovnikov hydroiodation on the alkene. The advantage of this system is the conditions are mild, can tolerate wide range of functional groups.
They are generally more methods in making β-vinyl iodides versus α-vinyl iodides usinghydrometalation (with aluminum withDIBAL-H (hydroalumination), with boron (hydroboration), with HZrCp2Cl (hydrozirconation)).[13] However,hydrometalation with alkyne with various functional groups often react poorly with side products. The Chong groups have demonstrated usinghydrostannation, using Bu3SnH with palladium catalyst with high E stereoselectivity.[13] They observed using sterically bulky ligands gave higher regioselectivity for β-vinyl iodide. The advantage of this technique is this technique can tolerate a wide range of functional groups.
Z selective β-vinyl iodides are slightly more difficult to introduce than E-β-vinyl iodides, often requiring more than one step.Hydroalumination andhydroboration usually proceed by syn fashion, therefore selectively favors E geometry. The Oshima group have demonstrated usinghydroindation with HInCl selectively favors Z geometry.[14] They suggested that the reaction proceeds by a radical mechanism. They predict that HInCl adds to alkyne by radical addition in a Z geometry. It does not isomerized to E geometry because of low reactivity of radical InCl2 with intermediate complex (no second addition). If second addition occurs then isomerization will occur throughdiindium intermediate. They confirm a radical mechanism in a mechanistic study with alkyne and alkene cyclization.
Substitution is perhaps most useful method in introducing vinyl iodide into the molecule. Halogen-exchange can be useful since vinyl iodides are more reactivity than othervinyl halides. Buchwald group demonstrates a halogen-exchange from vinyl bromide to vinyl iodide with copper catalyst under mild conditions.[15] It is possible that this method can tolerate variousfunctional groups since these conditions were testedaryl halides initially. The scope of this exchange forregiochemistry andstereochemistry is currently unexplored.
Halogen-exchange can also be done with zirconium derivatives that retainolefin's geometry[16]
The Marek group have further investigated using zirconium catalyst on E or Zvinyl ethers, which selective for E-vinyl ethers.[16] The zirconium'soxophilic nature allows eliminationalkoxy group at the β position to form intermediate vinyl zirconium complex. The E geometry selectivity is not cause by sterics but rather the reaction itself is not concerted. In a mechanistic study, they observedisomerization, which suggest E geometry product is more favored than Z geometry. The difference of results between halogen exchange and E-vinyl ether reaction is that only when there is a presence of anoxonium intermediate, isisomerization observed.
An interesting substitution reaction is vinyl boronic acid to vinyl iodide done by Brown's group.[17] Depending on order of addition of iodide or base, vinylborate can yield differentstereoisomers of vinyl iodide (see scheme 2a). The Whiting group, however, noticed that Brown's method was not applicable to more sterically hinderedboronic esters (no reaction).[18] They proposed that the iodide source was not electropositive enough. So they decided to useICl which is more polar than I2, in which, they observed similar results (see scheme 2b).
Radical substitution of carboxylic acid to iodide is demonstrated by a modifiedHunsdiecker reaction.[19]Homolytic cleavage of O-I bond generates CO2 and vinyl radical. Vinyl radical recombines with iodide radical to form vinyl iodide.
Iododesilylation is a substitution reaction ofsilyl group for iodide. The advantages of iododesilylation are that it avoids toxic tin reagent and intermediate vinyl silyl are stable, nontoxic and easily handled and stored. Vinyl silyl can be made from terminal alkyne or other methods.
The Kishi's group reported a mild preparation of vinyl iodide from vinyl silyl using NIS in mixture ofacetonitrile andchloroacetonitrile.[20] They observed retention of olefin geometry in some vinyl silyl substrates while inversion in others. They reasoned that the R group's size had an effect on the geometry of the olefin. If the R group is small, the solventacetonitrile can participate in the reaction leading to inversion of the olefin's geometry. If the R group is big, the solvent is unable to participate, leading to retention of olefin's geometry
Zakarian's group then decided to run the reaction inHFIP, which gave high retention of olefin geometry.[21] They reasoned that HFIP is a lownucleophilicity solvent, unlikeacetonitrile. In addition, they observed accelerated reaction rate because HFIP activate NIS byhydrogen bonding.
Unfortunately, iododesilylation under those conditions (above) can potentially yield multiple byproducts in highly functionalized molecules with oxygenfunctional groups. Vilarrasa and Costa's group hypothesized thatradical reactions producingHI and I2 help facilitate cleavage in alcohol'sprotecting group and may add into other alkene bonds.[22] They experimented with the use ofsilver additives such assilver acetate andsilver carbonate in which the silver can react with the excess iodide to formsilver iodide. They achieved better conversions with these conditions.
Some famous vinyl iodide synthesis methods involve conversion ofaldehyde orketone to vinyl iodide. Barton'shydrazone iodination method involves addition ofhydrazines toaldehyde orketone to formhydrazone. Then thehydrazone is converted to vinyl iodide by addition of iodide andDBU.[23][24] This method has been used in natural product synthesis ofTaxol by Danishefsky[25] andCortistatin A by Shair.[26]Another method is theTakai olefination which usesiodoform andchromium(II) chloride to make vinyl iodide from aldehyde with highstereoselectivity for E geometry.[27] For highstereoselectivity for Z geometry, Stork-Zhao olefination proceeds byWittig-like reaction. High yields and Zstereoselectivity occurred at low temperature and at the presence ofHMPA.[28]
Below is example of employing both Takai olefination and Stork-Zhao olefination in total synthesis of (+)-3-(E)- and (+)-3-(Z)-Pinnatifidenyne.[29]
Vinyl iodides are rarely by made an elimination reaction ofvicinaldiiodide because it tends to decompose to alkene and iodide.[30] The Baker group have shown using decarboxylation, elimination can occur.[31]
