TheFleming–Tamao oxidation, orTamao–Kumada–Fleming oxidation, converts acarbon–silicon bond to acarbon–oxygen bond with aperoxy acid orhydrogen peroxide. Fleming–Tamao oxidation refers to two slightly different conditions developed concurrently in the early 1980s by the Kohei Tamao andIan Fleming research groups.^[1][2][3]

The reaction isstereospecific withretention of configuration at the carbon–silicon bond.^[2][3] This allows the silicon group to be used as afunctional equivalent of thehydroxyl group. Another key feature of the silicon group is that it is relatively stable due to the presence of the silicon atom, and therefore can tolerate various reaction conditions that the hydroxyl group can not tolerate. Due to the stability of the silicon group,organosilicon compounds are useful in thetotal synthesis of complexnatural products andpharmaceutical drugs. For instance, the Fleming–Tamao oxidation has been used to accomplish the synthesis of subunits oftautomycin,^[4] aninhibitor that is used as a lead cancer compound and as animmunosuppressant.

In 1983, Tamao and co-workers were the first to report the successful transformation of anallylalkoxysilyl to anallyl alcohol without anallylic shift.^[5] In their report, thechemists observed that the hydroxyl group was introduced exclusively onto the carbon atom to which the silicon atom was attached. In the same year, Tamao and group published another paper that showed that the carbon–silicon bond in alkoxyorganosilicon compounds can be cleaved using H₂O₂ orm-CPBA underacidic,basic (chemistry), orneutral conditions, to afford the corresponding alcohols.^[6] A year later, Ian Fleming and group reported that the dimethylphenylsilyl (Me₂PhSi) group can be converted to an hydroxyl group in a two-pot sequence.^[2] Later, in 1987, Fleming reported a one-pot variant to the two-pot sequence in which eitherbromine or mercuric ion acts as theelectrophile. These early findings paved the way for the development of a large number of silicon-basedreagents and the use of various silyl groups as functional equivalents of the hydroxyl group.

Although the mechanism below is for the basic condition, the proposed mechanism^[1][7] for the Tamao oxidation is similar under each condition. The mechanism below contains at least one fluorine atom as the substituent, which is theprototype structure that Tamao studied. Fluoride, provided by a fluoride source or a donor solvent, attacks the fluorosilane in a fast andreversible step to give a pentacoordinated species. This species is more electrophilic than the fluorosilane, thereby promoting attack by thenucleophilic oxidant to yield the negatively charged hexacoordinatedtransition state. This step was determined to be therate determining step based on kinetic studies done by Tamao.^[8] Further studies by Tamao on the steric andelectronic effects of different groups attached to the silicon led him to suggest that attack by the oxidanttrans to theelectronegative fluoride group is energetically favored. The groupcis to the peroxide oxygen in the transition state structure then migrates preferentially, thus explaining the retention of configuration at the carbon center. Finally, the newsilicon–oxygen bond of the hexaco-ordinated species ishydrolyzed by water in the reaction medium. Subsequent workup produced the expected alcohol.

Unlike the Tamao oxidation whose starting material is an activated heteroatom-substituted silyl group, theFleming oxidation utilizes a more robust silyl group which has only carbon atoms attached to the silicon atom. The prototype silyl structure that Fleming used was dimethylphenylsilyl. Thisarylsilane is then converted to the more reactive halo- or heterosilane to initiate the oxidation.^[2][3] The mechanism of the two-pot sequence^[1][7] differs from the Tamao oxidation since thereagents are different. First, an electrophile attacks thephenyl ring in theipso position to give a beta-carbocation that is stabilized by the silicon group. A heteroatom then attacks the silicon group, which allows the phenyl ring to leave, in a key step referred to as protodesilylation of the arylsilane. Thealkyl group undergoes 1,2 migration from the silicon to the oxygen atom. Aqueous acid mediatedhydrolysis and subsequent workup yield the desired alcohol. It is difficult to prevent small resulting silyl-alcohols from dehydrating to form siloxanes.

The main difference between the one-pot and two-pot sequences is that the former has bromine or mercuric ion as the electrophile that is attacked by thebenzene ring. The bromine electrophile is generated bydiatomic bromine or another source such aspotassium bromide, which can be oxidized to generate brominein situ by theperacetic acid. The source of the mercuric ion ismercuric acetate, and this reagent is mixed with peracetic acid inAcOH to provide the oxidizing conditions. The mechanism for the one-pot and two-pot sequences is the same since the bromine or mercuric ion are attacked by the phenyl ring instead of thehydrogen ion.^[3][9]

The Tamao–Kumada oxidation, or theTamao oxidation, uses a silyl group with ahydrogen atom, aheteroatom or an electron-donating group attached to the silicon atom to make it more reactive. Tamao used eitherfluorine orchlorine atom, or analkoxy (OR) oramine group (NR₂) as the substituent on thesubstrates.^[5] In addition to varying the percent composition ofoxidants and combining differentsolvents, Tamao also usedadditives such asacetic anhydride (Ac₂O),potassium hydrogen fluoride (KHF₂), andpotassium hydrogen carbonate (KHCO₃) orsodium hydrogen carbonate (NaHCO₃) to make the reaction conditions slightly acidic, neutral, and alkaline, respectively. The different conditions were used to observe the effect that pH environment had on the oxidativecleavage of the various alkoxy groups. Below is an example of each reaction condition.

Recently, the Fleming–Tamao oxidation has been used to generatephenol and substituted phenols in very good yield.^[10]

The Tamao oxidation was used to synthesizeacid,aldehyde, andketone under varying reaction conditions.^[11] Whereas the carbon-silicon bond of a substituted alkylsilyl is cleaved to a carbon-oxygensingle bond, a substituted alkenylsilyl group is transformed to acarbonyl under the same Tamao oxidation conditions employed for alkylsilane.^[11]

The silyl group is a non-polar and relatively unreactive species and is therefore tolerant of many reagents and reaction conditions that might be incompatible with free alcohols. Consequently, the silyl group also eliminates the need for introduction of hydroxylprotecting groups. In short, by deferring introduction of an alcohol to a late synthetic stage, opting instead to carry through a silane, a number of potential problems experienced in total syntheses can be mitigated or avoided entirely.^[1]

One of the major pitfalls of either the Fleming or Tamao oxidations issteric hindrance.^[2] Increasing the steric bulk at the silicon center generally slows down reaction, potentially even suppressing reaction entirely when certain substituents are employed. In general, less bulky groups such asmethyl orethyl favor oxidation, while bulkier groups such astert-butyl slow down or stop oxidation. There are special cases in which this pattern in not followed. For example, alkoxy groups tend to enhance oxidation,^[6] while oxidation does not proceed under normal conditions when three alkyl substituents are attached to the silicon atom. The trend below illustrates the order in which oxidation proceeds.

The natural product, (+)− pramanicin, became an interesting target for synthesis because it was observed to be active against afungalpathogen that resulted inmeningitis in AIDS patients. Therefore, its synthesis^[12] which utilized the Fleming–Tamao oxidation as a crucial step has been relevant to chemists as well as to patients afflicted by AIDS. Theantifungal agent has also been shown previously to inducecell death and increasecalcium levels invascularendothelial cells. Furthermore, (+)– pramanicin has a wide range of potential applications againsthuman diseases.

Polyols anddiols are especially useful to thefood industry andpolymer chemistry. Their importance is underscored by the fact that they can be used as sugar replacers fordiabetics or those who choose to have sugar-free or low-calorie diets. The Fleming-Tamao has been applied in the synthesis ofstereoselective diols. Woerpel^[13] used the reaction to synthesizeanti-1,3diols from functionalized silylanion.

Alternatively, Hara, K.; Moralee, and Ojima^[14] achievedsyn-1,3 diols using Tamao oxidation.

• Baeyer-Villiger oxidation

• Tamao-Fleming Oxidation

• Organic oxidation reactions
• Name reactions

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