Chemistry Corner

Silicon in synthesis

Organosilicon reagents offer many benefits over other commonly used organometallic compounds. Dr Cynthia Challener reports

One of the most common elements in the Earth's crust, silicon is an inexpensive raw material for the preparation of interesting organometallic reagents. Organosilicon compounds also have other advantages over commonly used boron acids and tin derivatives, such as greater stability and functional group tolerance, as well as more attractive toxicity profiles.

Although organosilicon chemistry has been investigated for many years, researchers continue to discover both new reactions and new applications that rely on previously identified chemical transformations. For instance, Professor Scott Denmark at the University of Illinois at Urbana-Champaign has been expanding the scope and utility of silicon-based, palladium catalysed C-C cross-coupling reactions.

His group has shown that siletanes, silanols, silyl hydrides, cyclic silyl ethers, disiloxanes and oligosiloxanes with a wide range of functional groups can participate in efficient and stereospecific cross-coupling reactions under mild conditions. These transformations, however, have always required an excess of a fluoride activator such as tetrabutylammonium fluoride (TBAF), so their use has thus been somewhat limited.

Further investigation of the cross-coupling reaction led Denmark and his research team to discover that in situ-generated alkali metal silanolates undergo cross-coupling with aryl iodides, bromides and even chlorides, without the need for a fluoride activator. The new protocol not only widened the scope and applicability of organosilicon cross-coupling reactions, it also led to an unexpected understanding about the mechanism.

"Cross-coupling reactions with silicon were previously thought to occur via the generation of a pentaco-ordinate siliconate anion - the Hirama-Hatanaka paradigm - prior to transmetallation," Denmark explains. "The fact that silanolates are key participants indicates, however, a mechanism that involves an intramolecular transmetallation from a neutral tetracoordinate species, with the Si-O-Pd linkage a critical component of the pathway."

The group has identified four different cross-coupling procedures for organosilanes that do not require fluoride activators. In the first, treatment of the silanol with a weak Brønsted base, such as KOSiMe3, NaOt-Bu, Cs2CO3 or K3PO4, typically at room temperature, leads to reversible deprotonation. A palladium complex and CuI catalyse the coupling with an aryl halide.

The group used this method to couple a protected glucal silanol that was sensitive to both fluoride and strong bases with a hindered aromatic iodide as the key step in the synthesis of the anti-fungal agent (+)-papulacandin D.

Treatment with a stoichiometric amount of a strong base, such as NaH or KH, results in irreversible deprotonation to form silanolate salts. Because no sources of protons are present, protiodesilylation is prevented. The silanolate salt is prepared in situ and is then allowed to react with an aryl halide.

Denmark - Widening the use of organosilicon cross-coupling reactions

Under the right conditions, less expensive but less reactive aryl chlorides bearing nitrile, ester, nitro and ketone substituents provide the desired coupling products in good yields. Tetra-substituted alkenyl silanolates can also be employed in the reaction.

This approach was used in the total synthesis of polyene macrolide RK-397. A 1,4-diene with differentially functionalised silyl groups (a silanol and a silanol surrogate) was used in two sequential silicon-based cross coupling reactions. The potassium silanolate was formed and reacted, then treated with TBAF to unmask a benzylsilane for the second coupling step.

"The use of such bifunctional reagents makes two-directional synthesis possible," remarks Denmark. The silanolate salts can also be isolated and then charged directly into a reaction mixture. The potassium and sodium salts are generally free-flowing powders that are stable under typical storage conditions.

"The preformed silanolates do not require a base to activate, so they are ideal for use with base-sensitive substrates," Denmark observes. "Furthermore, they have enhanced reactivity over their in situ-generated counterparts, particularly those formed under reversible deprotonation conditions. As solids, they are easier to handle than silanols, which often are viscous liquids."

The fourth class of reactions was developed to make possible the coupling of vinyl silane. Divinyltetramethyldisiloxane (DVDS), when treated with KOSiMe3, produces vinyldimethylisilanolate, which can then react with aryl iodides and bromides. In this reaction, triphenylphosphine oxide or an electron-rich phosphine is used with a palladium catalyst.

Importantly, organosilanols can be prepared from a number of precursors, including alkenes, alkynes, arenes and heteroarenes, via the addition of the corresponding organometallic compounds to silicon electrophiles. In addition, transition metal-catalysed hydrosilylation or silyl insertion allows the formation of silanols in substrates that are not amenable to the formation of organometallic derivatives. Organosilanols are also air- and water-stable and can be purified by silica gel chromatography and/or distillation.

"Silicon coupling can be very useful when the more commonly used boronic acids are unstable to the reaction conditions, such as with aromatic compounds flanked by strong electron-withdrawing groups and electron-rich heteroaromatic compounds," Denmark adds.

Larson - Hard work to convince industry

"They are also effective for reactions with alkenes because no isomerisation of the double bond occurs. Silyl groups can also be incorporated early on in a multiple step synthesis because they are resistant to many reactions. At a later stage in the synthesis, the precursor can then be used in a stereoselective organosilicon cross-coupling step."

Gelest recently signed a licensing agreement with the University of Illinois at Urbana-Champaign and is now offering both silanols and silanolates for cross-coupling reactions. Purchasers of the compounds will be granted a royalty-free licence to the technology.

"Gelest is always looking for new products that will broaden the use of speciality organosilanes in synthetic applications," states vice president of R&D and quality Dr Gerald L. Larson. "We believe the chemistry from Professor Denmark complements our organotin reagents and has a lot of advantages compared to other coupling methods. Gelest is also ideally suited for scaling up the preparation of these materials."

Larson admits, though, that it is still a challenge to gain interest in silicon-based cross-coupling reactions for commercial applications. Because boronic acid technology is so widely used and libraries of compounds are readily available to the industrial research chemist, organosilicon approaches are often overlooked. Gelest will continue to spread the word about the economic, environmental and synthetic benefits the new coupling reactions offer, he says.

At Michigan State University, Professor Robert Maleczka Junior is also developing palladium-catalysed reactions of organosilanes as alternatives to the corresponding tin analogues. Reductions with polymethylhydrosiloxane (PMHS), an easily handled, inexpensive, non-toxic and mild reducing agent, proceed via the transfer of hydride to other metal catalysts, such as titanium, zinc, copper and palladium.

With Pd(II) acetate, aqueous potassium fluoride (KF) and PMHS nanoparticles are formed that catalyse the rapid reduction of aromatic nitro groups to amines at room temperature in high yield and with high functional group tolerance. Using triethylsilane instead of PMHS/KF facilitates the reduction of aliphatic nitro groups to hydroxylamines. The reduction of acid chlorides and aldehydes and the dehalogenation of aromatic halides are also possible.

Very recently, the Maleczka group reported that catalytic Pd(OAc)2/PMHS/KF effects the chemo-, regio-, and stereoselective deoxygenation of benzylic oxygenated substrates at room temperature in THF. Curiously, these C-O hydrogenolyses are facilitated by the substoichiometric addition of chloroarenes.

Maleczka's group has also investigated alkyllithium-promoted Wittig rearrangements. When α-alkoxysilanes are reacted with methyllithium, [2,3], [1,2] and [1,4]-Wittig rearrangements are possible, depending on the substrate and reaction conditions. The deprotonation of α-benzyloxyallylsilanes with s-BuLi causes these compounds to undergo [1,4]-Wittig rearrangement with very high selectivity. If followed by addition of an electrophile, the α-benzyloxyallylsilanes are converted to α-substituted acylsilanes.

Maleczka - Palladium-catalysed reactions replacing tin

Currently the Maleczka group is developing entantioselective approaches to the α-silyl ethers employed in such Wittig rearrangements so as to better understand the mechanisms of these processes.

Meanwhile, at New York University Professor Keith Woerpel is investigating the application of silylenes to stereoselective synthesis. Since discovering the first metal-catalysed silylene transfer reaction for the synthesis of silacyclopropanes from chiral alkenes, he has been using these active organosilanes to prepare highly functionalised products.

"Carbene-based chemistry has been widely investigated and there are many known applications for these reactive species in synthetic chemistry. Little research had been conducted on silylenes and their reactivity, however, and we were interested in learning more about their potential application in synthesis," Woerpel notes.

Silver-catalysed silylene transfer occurs under mild conditions, making possible the use of a wide variety of functionalised substrates. For example, α,β-unsaturated esters can be converted into silylketene acetals, which can be further reacted with aldehydes. The reaction of enynes leads to dienes that can then undergo diastereoselective Diels-Alder reactions.

Woerpel has also investigated the reactions of allylic silanes for stereoselective synthesis. His students diastereoselectively converted an allylic silane via a [3+2] annulation to a tetrahydrofuran derivative that was a key intermediate in the synthesis of the antibiotic erythronolide A. Separately, α-oxygenated allylic silanes can be employed to prepare functionalised tetrahydrofurans and lactams with high diastereoselectivity.

Silver-mediated silylene transfer to allenes gives highly reactive strained-ring compounds. The alkylidene silacyclopropanes that react with carbonyl compounds to provide oxasilacyclopentanes with high regio and diastereoselectivity in a two-step, one-flask process.

The external double bond of the oxasilacyclopentanes can be epoxidised or otherwise functionalised, allowing the diastereoselective preparation of triols, homoallylic alcohols and other useful building blocks. For example, an optically active allene prepared from an alcohol of >98% ee was converted into a homoallylic alcohol with 96% ee.

Most recently Woerpel's group has been preparing medium-sized unsaturated strained ring systems using silylene transfer reactions. When the silylene moiety is inserted into vinyl epoxides, it is possible to prepare functionalised trans-dioxasilacyclooctenes diastereoselectively.

Woerpel - Applying silylenes in stereoselective synthesis

"The synthesis of functionalised non-racemic cycloctenes remains a challenge. We have developed a route that provides single isomers of these interesting compounds and are now exploring their unique reactivity," he says.

In the process, metal-catalysed silylene insertion into the C-O bond of a vinyl epoxide occurs stereospecifcally and leads to the formation of a vinyl silaoxetane intermediate. This species undergoes nucleophilic addition of aldehydes to yield trans-dioxasilacyclooctenes as single diastereomers and atropisomers.

The strained silaoxetane is highly reactive, even with unreactive aldehydes. Spiro vinyl epoxides yield bicyclic systems. For one such compound, hydroboration of the anti-Bredt olefin and subsequent deprotection of the silyl group provided a cyclohexanol derivative with four contiguous stereocentres.

"Diastereoselective additions to these strained cyclooctenes allow for efficient transfer of planar chirality to the chirality at the stereogenic carbon atoms," Woerpel explains. "Transformation can be carried out with control of both relative regio- and stereoselectivity, which enables the production of optically active functionalised compounds that are highly useful in synthesis."

He adds that the C=C bond in strained rings is known to be very reactive. "We are taking a new approach and are looking at the double bond in these trans-cyclooctene substrates as a new type of functional group with unknown reactivities and are surveying the interaction of these systems with a wide range of other reactive species, such as organometallic compounds and metal hydrids."

The Woerpel group has also prepared strained nine- and seven-membered rings and is hoping to develop a method for accessing the highly strained trans-cyclohexane system. "There are literature references to such compounds, but they have only been generated photochemically and trapped. We hope to be able to prepare derivatives that can be isolated and further manipulated."

Meanwhile, Dr Stephen Philip Fearnley at York College of the City University of New York is investigating the utility of intramolecular reactions of oxocarbenium ions with tethered vinyl silanes, which provide a concise approach to cis-fused bicyclic ether arrays.

Fearnley - New use for vinyl silane chemistry

"Larry Overman and other researchers first investigated vinyl silane chemistry many years ago," Fearnley says. "The chemistry is not new, but the way we are applying it has not been previously reported, and we believe it provides access to interesting intermediates that can be used for the synthesis of a variety of natural products."

He adds that there are not many strategies for the synthesis of cis-fused bicyclic ethers, even though some natural products, such as kumausallene, dysiherbaine, goniofupyrone and dactomelyne, contain this structure.

In the reaction, the vinyl silane is tethered at the proximal position to the oxocarbenium moiety, which is generated in situ from a cyclic acetal via treatment with BF3:OEt2. Constrained intramolecular delivery provides the cis-ring stereochemistry.

"We believe that this type of cyclisation has not been previously used due to the instability of the resulting allylic ether under the reaction conditions. By constructing a bicylic system, we overcome that instability," observes Fearnley.

The reaction has been used to prepare a number of oxacyclic systems with isolated yields for the cyclisation reaction of typically 75% or better. In the case of simple substituted substrates, the choice of the starting isomer can provide access to either cis-diastereomer and the reaction can be extended to carbohydrate-type systems. The precursors are readily prepared either from enol ethers via oxidation and subsequent coupling with vinylsilane or directly from the corresponding 2-hydroxyacetals.

Currently Fearnley is applying the reaction to the construction of cis-fused polycyclic ether natural products targets. For example, the styryllactone framework can be accessed in a five-step synthesis. Possible natural product targets include 3-deoxyisoaltholactone, halichondrin B and azaspiracid, among others.

In a separate project, Fearnley has developed an aryl silane mediated Friedel Crafts ring closure where the ortho-silyl benzyl moiety on the dihydropyran ring affects the reaction through both electronic and steric effects.

"Without a silane substituent, the reaction is very difficult to control and often does not proceed at all," he comments. When the silyl group is present, however, two products are obtained: the expected product formed from ipso-substitution, due to the increased stability of the intermediate carbocation, and the meta-substituted product, due to a steric buttress effect.

If the cyclisation, which is catalysed by BF3:OEt2, is followed by desilylation of the crude mixture, cis-fused tricyclic ethers can be obtained exclusively in good overall yields. The pyranoisochroman framework is present in a number of natural products. Fearnley is currently applying this chemistry to the synthesis of C-aryl glycosides.


From Online Issue: April 2011