Osmium Tetroxide1

O4sO

[20816-12-0]  · O4Os  · Osmium Tetroxide  · (MW 254.20)

(cis dihydroxylation of alkenes; osmylation; asymmetric and diastereoselective dihydroxylation; oxyamination of alkenes)

Physical Data: mp 39.5-41 °C; bp 130 °C; d 4.906 g cm-3; chlorine- or ozone-like odor.

Solubility: sol water (5.3% at 0 °C, 7.24% at 25 °C); sol many organic solvents (toluene, t-BuOH, CCl4, acetone, methyl t-butyl ether).

Form Supplied in: pale yellow solid in glass ampule, as 4 wt % solution in water, and as 2.5 wt % in t-BuOH.

Handling, Storage, and Precautions: vapor is toxic, causing damage to the eyes, respiratory tract, and skin; may cause temporary blindness; LD50 14 mg/kg for the rat, 162 mg/kg for the mouse. Because of its high toxicity and high vapor pressure, it should be handled with extreme care in a chemical fume hood; chemical-resistant gloves, safety goggles, and other protective clothing should be worn; the solid reagent and its solutions should be stored in a refrigerator.

Dihydroxylation of Alkenes.

The cis dihydroxylation (osmylation) of alkenes by osmium tetroxide to form cis-1,2-diols (vic-glycols) is one of the most reliable synthetic transformations (eq 1).1

The reaction has been proposed to proceed through a [3 + 2] or [2 + 2] pathway to give the common intermediate osmium(VI) monoglycolate ester (osmate ester), which is then hydrolyzed reductively or oxidatively to give the cis-1,2-diol (eq 2). The cis dihydroxylation of alkenes is accelerated by tertiary amines such as Pyridine, quinuclidine, and derivatives of dihydroquinidine (DHQD) or dihydroquinine (DHQ) (eq 3).

Due to the electrophilic nature of osmium tetroxide, electron-withdrawing groups connected to the alkene double bond retard the dihydroxylation.2 This is in contrast to the oxidation of alkenes by Potassium Permanganate, which preferentially attacks electron-deficient double bonds. However, in the presence of a tertiary amine such as pyridine, even the most electron-deficient alkenes can be osmylated by osmium tetroxide (eq 4).3 The more highly substituted double bonds are preferentially oxidized (eq 5).

Under stoichiometric and common catalytic osmylation conditions, alkene double bonds are hydroxylated by osmium tetroxide without affecting other functional groups such as hydroxyl groups, aldehyde and ketone carbonyl groups, acetals, triple bonds, and sulfides (see also Osmium Tetroxide-N-Methylmorpholine N-Oxide).

The cis dihydroxylation can be performed either stoichiometrically, if the alkene is precious, or more economically and conveniently with a catalytic amount of osmium tetroxide (or its precursors such as osmium chloride or potassium osmate) in conjunction with a cooxidant. In the stoichiometric dihydroxylation, the diol product is usually obtained by the reductive hydrolysis of the osmate ester with a reducing agent such as Lithium Aluminum Hydride, Hydrogen Sulfide, K2SO3 or Na2SO3, and KHSO3 or NaHSO3. The reduced osmium species is normally removed by filtration. Osmium can be recovered as osmium tetroxide by oxidation of low-valent osmium compounds with hydrogen peroxide.4 In the catalytic dihydroxylation, the osmate ester is usually hydrolyzed under basic aqueous conditions to produce the diol and osmium(VI) compounds, which are then reoxidized by the cooxidant to osmium tetroxide to continue the catalytic cycle. Normally 0.01% to 2% equiv of osmium tetroxide or precursors are used in the catalytic dihydroxylation. Common cooxidants are metal chlorates, N-Methylmorpholine N-Oxide (NMO), Trimethylamine N-Oxide, Hydrogen Peroxide, t-Butyl Hydroperoxide, and Potassium Ferricyanide. Oxygen has also been used as cooxidant in dihydroxylation of certain alkenes.5 Excess cooxidant and osmium tetroxide are reduced with a reducing agent such as those mentioned above during the workup. The stoichiometric dihydroxylation can be carried out in almost any inert organic solvent, including most commonly MTBE, toluene, and t-BuOH. In the catalytic dihydroxylation, in order to dissolve the inorganic cooxidant and other additives, a mixture of water and an organic solvent are often used. The most common solvent combinations in this case are acetone-water and t-BuOH-water. Because of the high cost and toxicity of osmium tetroxide, the stoichiometric dihydroxylation has been mostly replaced by the catalytic version in preparative organic chemistry (see also Osmium Tetroxide-t-Butyl Hydroperoxide, Osmium Tetroxide-N-Methylmorpholine N-Oxide, and Osmium Tetroxide-Potassium Ferricyanide).

Diastereoselective Dihydroxylation.

Dihydroxylation of acyclic alkenes containing an allylic, oxygen-bearing stereocenter proceeds with predictable stereochemistry. In general, regardless of the double-bond substitution pattern and geometry, the relative stereochemistry between the pre-existing hydroxyl or alkoxyl group and the adjacent newly formed hydroxyl group of the major diastereomer will be erythro (i.e. anti if the carbon chain is drawn in the zig-zag convention) (eq 6).6,7

In the osmylation of 1,2-disubstituted allylic alcohols and derivatives, cis-alkenes provide higher diastereoselectivity than the corresponding trans-alkenes (eqs 7 and 8).6 Opposite selectivities have been observed in the osmylation of (Z)-enoate and (E)-enoate esters (eqs 9 and 10).8 High selectivity has also been observed in the osmylation of 1,1-disubstituted9 and (E)-trisubstituted allylic alcohols and derivatives10 and bis-allylic compounds11 (eqs 11-13).

The diastereoselective osmylation has been extended to oxygen-substituted allylic silane systems, and the general rule observed for the allylic alcohol system also applies (eq 14).12 High selectivity is also observed in the osmylation of allylsilanes where the substituent on the chiral center bearing the silyl group is larger than a methyl group (eq 15).13 These diastereoselectivities have been achieved in both stoichiometric and catalytic dihydroxylations. Slightly higher selectivity has been observed in the stoichiometric reaction than in the catalytic reaction; this may be due to less selective bis-osmate ester formation in the catalytic reaction using NMO as the cooxidant. Use of K3Fe(CN)6 may solve this discrepancy. Several rationales have been proposed for the observed selectivity.14 The conclusion appears to be that the osmylation of these systems is controlled by steric bias, rather than by the electronic nature of the allylic system, and osmylation will occur from the sterically more accessible face. The high diastereoselectivity of osmium tetroxide in the dihydroxylation of chiral unsaturated compounds has been applied widely in organic synthesis.8,15

Sulfoxide groups direct the dihydroxylation of a remote double bond in an acyclic system perhaps by prior complexation of the sulfoxide oxygen with osmium tetroxide (eqs 16 and 17).16 Chiral sulfoximine-directed diastereoselective osmylation of cycloalkenes has been used for the synthesis of optically pure dihydroxycycloalkanones (eq 18).17 Nitro groups also direct the osmylation of certain cycloalkenes, resulting in dihydroxylation from the more hindered side of the ring. In contrast, without the nitro group the dihydroxylation proceeds from the less hindered side (eq 19).18

Enantioselective Dihydroxylation.

The acceleration of osmylation by tertiary amines brought about the use of chiral amines as chiral ligands for the asymmetric dihydroxylation (AD).1 The AD can be classified into two types: (a) noncatalytic reaction, where stoichiometric amounts of ligand and osmium tetroxide are used, and (b) catalytic reaction, where catalytic amounts of ligand and osmium tetroxide are employed in conjunction with stoichiometric amounts of cooxidant. Generally, in the stoichiometric AD systems, chiral chelating diamines are used as chiral auxiliaries with osmium tetroxide for the introduction of asymmetry to the diol products.1,19 Although high asymmetric inductions have been achieved in these systems, the stoichiometric ADs have limited use in practical organic synthesis because of the cost of both ligand and osmium tetroxide. The discovery of the ligand-accelerated catalysis in AD made the transition from stoichiometric to catalytic AD possible.1c,1d,20 In the most effective catalytic system, osmium tetroxide or its precursors and chiral ligands derived from cinchona alkaloids, dihydroquinidine (DHQD), or dihydroquinine (DHQ), are used catalytically in the presence of a stoichiometric amount of cooxidant such as NMO or K3Fe(CN)6. Besides alkaloid-derived ligands, other types of ligand have been designed and used in the catalytic AD with moderate success.21 (see also Osmium Tetroxide-N-Methylmorpholine N-Oxide and Osmium Tetroxide-Potassium Ferricyanide).

Double Diastereoselective Dihydroxylation.

AD of homochiral alkenes gives matched and mismatched diastereoselectivities due to the steric interaction of the chiral osmium tetroxide-ligand complex with the chiral center in the vicinity of the alkene double bond. For example, in the noncatalytic osmylation of the monothioacetal (eq 20),22 the ratio of (2S,3R) to (2R,3S) diastereomers is 2.5:1 with the achiral quinuclidine as ligand, 40:1 with Dihydroquinidine Acetate (DHQD-OAc) as ligand in the matched case, and 1:16 with Dihydroquinine Acetate (DHQ-OAc) as ligand in the mismatched case.

Diastereoselectivities in the catalytic AD with OsO4-NMO of several a,b-unsaturated uronic acid derivatives are significantly enhanced when the alkenes are matched with the chiral ligands DHQ-CLB (dihydroquinine p-chlorobenzoate) and DHQD-CLB (dihydroquinidine p-chlorobenzoate) (eq 21).23 Using the chiral ligands (DHQD)2-PHAL and (DHQ)2-PHAL, the double diastereoselective dihydroxylation of a chiral unsaturated ester has been tested using Osmium Tetroxide-Potassium Ferricyanide (eq 22).1c These results show that enhanced diastereoselectivity in the dihydroxylation can be achieved by matching of alkene diastereoselectivity with catalyst enantioselectivity. Double diastereoselective dihydroxylation with a bidentate ligand has also been reported.24 Kinetic resolutions of racemic alkenes with OsO4 in the presence of a chiral ligand have been demonstrated.25 An elegant example is the kinetic resolution of the enantiomers of C76, the smallest chiral fullerene, by asymmetric osmylation in the presence of DHQD- and DHQ-derived ligands.26

Oxyamination of Alkenes and Oxidation of Other Functional Groups.

Osmium tetroxide catalyzes the vicinal oxyamination of alkenes to give cis-vicinal hydroxyamides with Chloramine-T (eq 23)27 and alkyl N-chloro-N-argentocarbamate, generated in situ by the reaction of alkyl N-chlorosodiocarbamate (such as ethyl or t-butyl N-chlorosodiocarbamate) with Silver(I) Nitrate (eq 24).28

Since chloramine-T is readily available, the former method offers a practical and direct method for introducing a vicinal hydroxyl group and a tolylsulfonamide to a double bond. While the sulfonamide protecting group is difficult to remove (and undesirable in some cases), the N-chloro-N-argentocarbamate system provides an alternative method, since the carbamate group can be easily removed to give free amine. This latter system is also more regioselective and reactive towards electron-deficient alkenes such as Dimethyl Fumarate and (E)-stilbene than the procedures based on chloramine-T. In all of these oxyamination reactions, monosubstituted alkenes react more rapidly than di- or trisubstituted alkenes. In the presence of tetraethylammonium acetate, trisubstituted alkenes can be oxyaminated with catalytic OsO4 and N-chloro-N-metallocarbamates. So far, attempts to effect catalytic asymmetric oxyamination have not been successful.

Osmium tetroxide also catalyzes the oxidation of organic sulfides to sulfones with NMO or trimethylamine N-oxide (see Osmium Tetroxide-N-Methylmorpholine N-Oxide). In contrast, most sulfides are not oxidized with stoichiometric amounts of OsO4. Oxidations of alkynes and alcohols with OsO4 without and in the presence of cooxidants have also been reported.1a,1b However, these reactions have not found wide synthetic applications because of the availability of other methods.

Related Reagents.

Sodium Periodate-Osmium Tetroxide.


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Yun Gao

Sepracor, Marlborough, MA, USA



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