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Oxygen

  1. A. Brian Jones1,
  2. Jun Wang2,
  3. Ashton T. Hamme II2,
  4. Wooseok Han3

Published Online: 16 SEP 2013

DOI: 10.1002/047084289X.ro028.pub3

e-EROS Encyclopedia of Reagents for Organic Synthesis

e-EROS Encyclopedia of Reagents for Organic Synthesis

How to Cite

Jones, A. B., Wang, J., Hamme, A. T. and Han, W. 2013. Oxygen. e-EROS Encyclopedia of Reagents for Organic Synthesis. .

Author Information

  1. 1

    Merck Research Laboratories, Rahway, NJ, USA

  2. 2

    Jackson State University, Jackson, MS, USA

  3. 3

    Novartis Institutes For BioMedical Research, Emeryville, CA, USA

Publication History

  1. Published Online: 16 SEP 2013

Chemistry Terms

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Abstract

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography
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[7782-44-7] O2 (MW 32.00)

InChI = 1S/O2/c1-2

(oxidizing agent for many organic systems, including, most commonly, organometallic compounds, carbon radicals, and heteroatoms such as sulfur)

Physical Data: mp −218 °C; bp −183 °C; d 1.429 g L−1 (0 °C), 1.149 g L−1 (−183 °C).

Solubility: sol to some extent in most solvents. Selected data, expressed as mL of O2 (at 0 °C/760 mmHg) dissolved in 1 mL of solvent when the partial pressure of the gas is 760 mmHg, are as follows: Me2CO (0.207/18 °C), CHCl3 (0.205/16 °C), Et2O (0.415/20 °C), EtOAc (0.163/20 °C), MeOH (0.175/19 °C), petroleum ether (0.409/19 °C), PhMe (0.168/18 °C), H2O (0.023/20 °C).

Form Supplied in: dry gas; dilutions in Ar, He, or N2; 18O2; 17O2.

Handling, Storage, and Precautions: of itself, oxygen gas is essentially nontoxic. However, it will support and vigorously increase the rate of combustion of most materials. It may ignite combustibles and can cause an explosion on contact with oil and grease. The potential for autoxidative formation of explosive peroxides (e.g. with Et2O) should always be borne in mind.

Original Commentary

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Oxygenation of Carbanions and Organometallic Compounds

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Many organometallic species react with triplet oxygen to form the corresponding hydroperoxides,1, 2 although the products are more usually reduced in situ or during workup to afford alcohols as the isolated products. A number of other sources of electrophilic oxygen have been developed (e.g. Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH), sulfonyloxaziridines) and compete for this niche, but no single reagent is universally preferable. As carbon anion equivalents, Grignard reagents are optimal for simple hydrocarbons,2 but organolithiums are more frequently employed. The potential for radical-mediated oxidative dimerization can constrain utility (particularly for aryl organometallics). Useful oxygenations of alkyl,3 vinylic,4 allylic,5 benzylic,6 and aryl (eq 1)6 organolithium compounds have been reported. 1,1-Diorganometallics give the corresponding carbonyl derivatives (eq 2).7

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Effective oxygenation of enolate anions is generally restricted to tertiary centers where over-oxidation is not possible.8 Nonetheless, ketones (eq 3),9 esters/lactones,8 amides/lactams (eq 4),10 and carboxylic acids8 can all be usefully α-hydroxylated. In most cases the intermediate α-hydroperoxides are reduced in situ (usually with Triethyl Phosphite),11 although they can be isolated if desired.12 The small size of the electrophile and the potential for radical involvement8 do not encourage stereochemical chastity in these processes, but where sufficient bias exists, good discrimination can be observed (see eqs 3 and 4). A slightly different approach uses enolates derived from aqueous base treatment. These species have been usefully hydroxylated where there was little or no ambiguity in the direction of enolization8 and this process forms the basis for a surprisingly effective catalytic, enantioselective oxygenation (eq 5).13

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In cases where the activating group is also a leaving group, oxygenation can provide the corresponding carbonyl compound. Thus oxidative decyanation can be effected under either phase transfer14 or anhydrous conditions (eq 6).15 The latter procedure is more general, although it does require treatment with Tin(II) Chloride and base to reduce and fragment the α-hydroperoxide, and this method is not effective for the primary nitrile to aldehyde conversion. α,β-Unsaturated nitriles generally react at the α-position to give α,β-unsaturated ketones.15

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Oxygenation of sulfone anions and the consequent desulfonylation is frequently effected with the MoOPH reagent. In some cases, however, molecular oxygen has proved effective where MoOPH failed.16 This perhaps illustrates a functional advantage over more bulky reagents and a counterpoint to the stereochemical disadvantages (see above). It should be noted that one such attempt resulted in a minor explosion17 although, of course, any reaction involving peroxides bears this possibility. A similar process, preceded by nickel transmetalation, demonstrated the oxidation of the C[BOND]Ni bond, but the synthetic advantage is not clear.18 However, this report did demonstrate the conjugative oxygenation of an allylic sulfone anion to give a γ-hydroxy sulfone.

Oxygenation of phosphorus-stabilized anions also produces the corresponding carbonyl compounds. The anions derived from phosphonates19 (eq 7)20 (including α-heteroatom substituted phosphonates)19 and phosphine oxides21 react smoothly with oxygen. Similarly, phosphorane ylides are readily oxidized.22 In all these cases, however, the reaction of primary substrates suffers from competing self-condensation, giving alkenes.22 It should be noted that a two-stage procedure involving the reaction of phosphonate anion with chlorodimethyl borate followed by oxidation with m-Chloroperbenzoic Acid has been advocated as a more efficient method23 (and, interestingly, allows isolation of the intermediate hydroxy phosphonate).

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Oxygenation of Carbon Radicals

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Not surprisingly, triplet oxygen reacts rapidly with carbon centered radicals.24 Classical autoxidation is the most obvious example of this behavior. Traditionally, autoxidation refers to hydroperoxide formation from alkanes, aralkanes, alkenes, ethers, alcohols, and carbonyl compounds, where the initiating homolysis is induced thermally or photochemically.25, 26 There is an extensive literature concerning these processes dating back many years. While very important commercially, they are generally too promiscuous to be of wide synthetic value, particularly when dealing with complex molecules. Interestingly, however, a deformylative hydroxylation of an allylic neopentyl aldehyde has been observed that bypasses the classical autoxidative fate of aldehydes (eq 8).27

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Radical oxygenation is most valuable where there is more strict control over the site of radical formation and subsequent oxygenation. Good stereochemical control is, of course, not usually achieved, although exceptions can be found in most cases. The mild and controlled methods of radical generation that have seen much use in synthesis are readily applicable to oxygenation. The thermal or photochemical decarboxylation of the esters of thiohydroxamic acids,28 or their room temperature decomposition in the presence of tris(phenylthio)antimony29 (i.e. Barton's methodology), can be intercepted by triplet oxygen to generate the nor-alcohols. The addition of heteroatom radicals to alkenes can provide the source of carbon centered radicals for trapping. An interesting example of oxygenation initiated by phenylthio or phenylseleno radical addition to vinylcyclopropanes showcases the use of this methodology (eq 9).30 Here, instances of moderately successful stereocontrol in the C[BOND]O bond forming step were noted. This transformation also demonstrates the potential of the initially formed hydroperoxy radical to participate in further steps (where higher levels of stereochemical discrimination are observed as a consequence of the intramolecular nature of the radical trapping). Samarium(II) Iodide induced radical processes have been quenched with oxygen to provide hydroxyl functionalized products.31

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One of the most prevalent uses of molecular oxygen in modern synthesis is for oxidative demercuration.32 Carbon radicals generated by the reduction of organomercurials with borohydride are efficiently trapped by oxygen, most frequently in DMF solution, to give hydroperoxides which are reduced under the reaction conditions to generate the corresponding alcohols directly.33 The alkene oxymercuration–oxidative demercuration sequence is commonly practised (usually through a β-alkoxymercury species, since β-hydroxy fails33), particularly where the oxymercuration is an intramolecular cyclization (eq 10).34 Typically, any stereocontrol observed in the oxymercuration (or other C[BOND]Hg bond forming step) is effaced in the oxygenation (as in eq 10).

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Oxidation of Organoboranes

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Boranes, most frequently accessed by hydroboration of alkenes, can be oxidized by triplet oxygen.35, 36 If the oxidation is carried out in fairly concentrated solution (∼ 0.5 N) at 0 °C, intermolecular redox reaction of the intermediate diperoxyborane is facilitated and workup provides the corresponding alcohol.36 While this is quite efficient, Hydrogen Peroxide is more commonly used in synthetic applications. This is partly for convenience, but also a consequence of stereochemical issues. The oxidation with H2O2 occurs with retention of configuration at the carbon center. The radical characteristics of the dioxygen reaction generally lead to at least partial racemization. That this stereochemical corruption is not always complete is an indication of the uncertainty about the mechanism.35 Interestingly, rhodium(III) porphyrin has been shown to promote stereoselective oxidation in the dioxygen procedure (eq 11).37 In dilute solution (0.01–0.05 N) the intermolecular redox process is suppressed and diperoxyboranes are produced. Oxidation of the third B[BOND]C bond with H2O2 or peroxy acid and workup allows isolation of the corresponding alkyl hydroperoxides.36 Alternatively alkyl hydroperoxide formation is facilitated by the use of alkyldichloroboranes.36 This is one of the most convenient approaches to this functionality. The oxygen mediated approach to alcohols may be more convenient than H2O2 for radiolabeling; 17O (eq 12) and 15O alcohols have been prepared in this way.38, 39

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Heteroatom Oxidation

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Oxidation of nitrogen functionality with oxygen, while well precedented,40 and of continuing interest,41, 42 does not generally represent the method of choice for those processes of synthetic significance. However, a report of a mild procedure for the oxidation of silylamines to carbonyl compounds bears some synthetic potential (eq 13).43 Oxidation of phosphorus functionality by oxygen can be quite facile.44 For example, tertiary phosphines are very readily oxidized to their phosphine oxides, and secondary chlorophosphines can give the phosphinic acids.44 Perhaps the most common heteroatom air oxidations are those of Group 16 RX[BOND]H bonds to their corresponding dimers ((RX)2) and particularly the thiol to disulfide oxidation.45 This, of course, is related to the importance of the disulfide bond to peptide and protein secondary structure. One example that reflects current interest in the control of multiple disulfide bond formation in synthetic peptides is given in eq 14.46 Oxidation may be promoted by heavy metal ions.45 Higher oxidations (for example sulfide to sulfoxide) are best performed with other reagents (oxone, peroxy acid, etc.).

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Other Uses

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

The oxidative dimerization of organometallics, alluded to above, is particularly prevalent for organocuprates,47 although not totally unavoidable.48 In fact it is efficient enough to be regarded as a synthetic strategy and has been used as such (eq 15).49 Baeyer–Villiger oxidations generally employ peroxy acids, but a recent report indicates that 1 atm of oxygen can effect the rearrangement even in the absence of either metal catalysts or light.50 Epoxidation by oxygen is possible51 but, of course, is not usually the method of choice for laboratory synthesis.

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There is a vast literature concerning metal-catalyzed oxidative processes involving molecular oxygen,52 of which only a fraction have seen synthetic use. Many metal catalysts behave as oxygen fixing species, that deliver oxygen to the substrate through a peroxo complex. Reports frequently concern experimental systems, probing substrate reactivity and/or asymmetric induction. The function of oxygen in metal-catalyzed oxidations is not necessarily that of a reagent. Thus, for example, in the Wacker oxidation of terminal alkenes it operates as a re-oxidant for copper(II) chloride which in turn is a re-oxidant for the PdII species. All of these applications are best regarded as functions of the metal component and, for this reason, are not discussed here.

First Update

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Oxygenation of Carbanions and Organometallic Compounds

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Some recent oxygenation reactions involving organometallic reagents have involved the synthesis of alcohols and alkyl hydroperoxides. Straight chain, cyclic, and benzyl alcohols were synthesized in good yields through the reaction of organozinc compounds with oxygen in THF in the presence of 1 equiv of HMPA.53 This reaction sequence was also used towards the synthesis of a chiral alcohol as a 1:1 mixture of diastereomers (eq 16).

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An analogous organozinc oxygenation in THF without HMPA was used to synthesize halogen, ester, sulfonamide, and silicon-containing alcohols.54, 55 Oxygenation of a geminal trimethylsilyl organozinc compound afforded the corresponding aldehyde (eq 17). The incorporation of different workup conditions can give rise to the isolation of either alcohols or alkyl hydroperoxides during the oxygenation of organozinc compounds in perfluorohexane (PFH) (eq 18).54-56

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Oxygenation of Carbon Radicals

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Carbon-centered radicals generated from the corresponding alkyl halide and radical initiators can be trapped with molecular oxygen to give rise to alcohols. Radiolabeled 18O and 17O alcohols were prepared through the aerobic oxygenation of carbon radicals formed through a Bu2(t-Bu)SnCl–sodium cyanoborohydride catalytic system (eq 19).57 A similar method was used to oxygenate the carbon radical generated after the carbocyclization of an olefinic alkyl halide (eq 20).57

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Radical oxygenation of 2-deoxy-2-iodo hexopyranosides was achieved through a procedure involving AIBN, Bu3SnH, and O2 in toluene at 60 °C (eq 21).58 Either a higher yield or selectivity was achieved with this method when compared to similar methods at room temperature59 or from the analogous chloromercuric starting material.60 An oxygen quench was used after the Bu3SnCl/AIBN/sodium borohydride-initiated cyclization of iodo allyoxy substituted tetrahydrofuran and pyran compounds to afford the corresponding bicyclic alcohols (eq 22).61

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The aerobic reductive oxygenation of an alkyl halide using Bu2(t-Bu)SnH in air with ultrasound irradiation affords the alkyl hydroperoxides in moderate yield but good selectivity.62 Mild reductive work-up of the peroxy-radical intermediate without overreduction of the oxygen-oxygen bond enabled the isolation of the alkyl hydroperoxide over the alcohol.

Oxidation of Organoboranes

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

A variety of diethylorganoboranes were oxidized with oxygen when bromoperfluooctane (BPFO) was used as a solvent.63 A number of functional groups, including halides, TIPS-ether, sulfonamide, esters, and malonate survived the relatively mild reaction conditions. Secondary diethylorganoboranes were oxidized with retention of configuration. An insertion mechanism rationalizes the stereochemical outcome of the reaction due to the high reactivity of the boron-ethyl bond towards oxygen (eq 23).

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The oxidation of alkylboronic esters to afford alcohols has also been achieved in high yields using triethylamine and molecular oxygen in THF.64, 65 This method of oxidizing alkylboronic esters shows a high degree of regioselectivity for terminally substituted alkylboronic esters (eq 24) and stereoselectivity for secondary alkylboronic esters (eq 25). The oxidation of these alkylboronic esters follows both free radical and polar mechanistic pathways (eq 26).64, 65

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Heteroatom Oxidation

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Although the oxidation of nitrogen or sulfur functionalities is precedented,40 the most recent oxidations of these heteroatoms using molecular oxygen usually involve either a transition metal catalyst66-68 or the conversion of an aldehyde into a peracid.69 In these cases, molecular oxygen is not involved in the direct heteroatom oxidation. Therefore, these and other similar examples will not be discussed here.

Other Uses

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

A number of oxygenative radical cyclizations involve cobalt catalysts in the presence of oxygen. Some methods involve the oxygenolysis of the cobalt-carbon bond70 while other methods use a catalytic amount of a cobalt complex, and the resulting carbon radical is oxygenated.71, 72 Carbafuranose compounds were synthesized from 6-iodo-hex-1-enitols through Co(salen)-catalyzed oxygenative radical cyclization (eq 27).73 Perfluorinated ruthenium and nickel complexes were used to synthesize epoxides, sulfones or sulfoxides, and carboxylic acids from the analogous alkene, sulfide, and aldehyde precursors in high yield using a biphasic organic solvent/perfluorohydrocarbon oxygen saturated system.74

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Baeyer-Villiger75, 76 and alkene oxidations76 were performed with molecular oxygen and benzaldehyde. The active oxidant is peroxybenzoic acid, which is generated in situ through the reaction of oxygen with benzaldehyde. The synthesis of functionalized α,β-unsaturated butenolides was achieved through an oxidative rearrangement of 6-methoxypyran-2-one compounds involving the oxidation of a ketene intermediate with molecular oxygen.77

Oxygen has also been used as a secondary oxidant in 2,2,6,6-tetramethyl-piperidyl-1-oxo (TEMPO),78, 79 N-hydroxyphthalimide (NHPI),80 transition metal-mediated oxidations.81, 82 Copper-free palladium-catalyzed asymmetric aerobic Wacker cyclizations were also achieved where oxygen served as the reoxidant of the palladium complex.83 Since molecular oxygen serves as a secondary oxidant and not the primary oxidant for other transition metal-based oxidations, no other examples will be discussed at this juncture.

Second Update

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

In recent years, vast efforts have been made on the development of more efficient and environment-friendly catalytic systems. Especially great progress has been made in transition metal-catalyzed reactions.84 Several transition metals such as palladium and copper have been used with many different catalytic reactions that successfully employed molecular oxygen as a terminal oxidant.85 To accomplish more efficient aerobic oxidative catalytic systems using atmospheric air or oxygen with low catalyst loading, and mild temperature, mechanistic studies have been reported.86 In this update, the use of O2 as a terminal oxidant in metal-catalyzed reactions will be specifically featured.

Metal-catalyzed Oxidation

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography
Wacker Oxidation

Recent progress on Wacker oxidation has yielded new solvents and ligands. The replacement of DMF, a common solvent in Wacker oxidation, with DMA (dimethylacetamide) enabled a highly efficient molecular oxygen-coupled Wacker oxidation of terminal olefins (eq 28), resulting in a cocatalysts free process.87 It was proposed that a more negative redox potential of Pd(0) species in DMA resulted in the acceleration of the reoxidation of Pd(0) species by molecular oxygen. A Wacker oxidation of terminal alkenes was performed with PdCl2 in DMA/water under 6 atm of O2 providing methyl ketones in high yields (66–92%). A chiral catalyst Pd[(−)-sparteine]Cl2 enabled Wacker oxidation to proceed at ambient pressures of oxygen.88 In addition, oxidation with this catalytic system avoided alkene isomerization, a common side reaction. The oxidation of enantiomerically enriched allylic or homoallylic ethers yielded the corresponding methyl ketones without racemization (eq 29).

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Alkyne Oxidation

A direct transformation of alkynes to amides has been achieved with CuBr2/DBU under O2 atmosphere. Various aryl or aliphatic alkynes reacted with aryl or aliphatic amines to afford secondary or tertiary amides in modest to good yields (68–25%).89 Although the mechanism was not completely understood, DBU was proposed to work as a strong base to promote copper(I) acetylide formation as well as a ligand for a copper(I) acetylide intermediate to increase solubility and reactivity. Molecular oxygen was utilized as an oxidant and oxygen source for the amide product, a mechanism supported by a labeling experiment using 18O2 (eq 30).

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Dihydroxylation/Oxidative Cleavage

Sequential cis-dihydroxylation/cleavage of alkenes has usually been performed with high-valent oxometal catalysts such as RuO4 and OsO4, which require expensive and harmful oxidants. A Pd(II)-catalyzed reaction using molecular oxygen as an oxidant underwent oxidative cleavage of alkenes providing carbonyl compounds.90 This tandem cis-dihydroxylation/cleavage process occurred in the presence of acids. Under basic conditions, the reaction was stopped at the dihydroxylation stage to yield 1,2-diols (eq 31). The key catalytic species was proposed to be a dioxopalladium complex of the diol. The cleavage occurred under acidic conditions only in the presence of O2, not with other oxidants such as CuCl2 and benzoquinone. Oxidative cleavage of alkynes was achieved in the presence of a Lewis acid additive ZnCl2·2H2O (eq 32).91 With the exception of aliphatic internal alkynes, symmetrical and unsymmetrical alkynes with aryl or aliphatic groups afforded methyl benzoates in good yields.

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Alcohol Oxidation

Aerobic oxidative kinetic resolutions of secondary alcohols were achieved with a chiral catalyst Pd[(−)-sparteine]Cl2 where molecular oxygen is used as a terminal oxidant to regenerate active Pd(II) species. The use of more reactive catalyst Pd[(−)-sparteine]Br2 allowed the kinetic resolution under milder conditions–at room temperature and under air atmosphere (eq 33).92 The use of a (+)-sparteine mimic or an axially chiral bidentate NHC ligand93 afforded access to the other enantiomer. This aerobic oxidative kinetic resolution was successfully applied to the total synthesis of a naturally occurring alkaloid (−)-amurensinine (eq 34). A cationic palladium catalyst/O2 system was used for selective aerobic oxidation of vicinal diols such as glycerol and 1,2-propanediol, where the secondary alcohol was rapidly oxidized to afford dihydroxyacetone and hydroxyacetone (eq 35).94 The oxidation reactions of secondary alcohols with heterogeneous catalysts successfully employed molecular oxygen as an oxidant in place of stoichiometric inorganic oxidants producing harmful by-products (eq 36).95

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Metal-catalyzed C[BOND]H Functionalization

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

Recently, transition metal-catalyzed C[BOND]H activation methods have been extensively studied, which allow functionalization of a carbon–hydrogen bond. In particular, environmentally benign Pd(II) or Cu(II) catalytic systems using molecular oxygen as a terminal oxidant have been applied to many different organic reactions such as oxidative aryl–aryl cross coupling and alcohol oxidation.86

Dehydrogenation

A palladium(II)-catalyzed aerobic dehydrogenation enabled the synthesis of substituted phenols from substituted cyclohexanones via sequential C[BOND]H activation/β-hydride elimination/tautomerization.96 A new ligand 2-(N,N-dimethylamino)pyridine was identified for the palladium(II) complex. To accomplish catalytic dehydrogenation under O2 atmosphere, an acidic additive was crucial to reduce the electron-donating nature of the aminopyridine ligand in the palladium complex. It was proposed that palladium(0) was reoxidized to Pd(II) by molecular oxygen via a dioxopalladium species. Under the optimized catalytic conditions, the dehydrogenation of cyclohexanones having alkyl, aryl, and ester substituents led to the substituted phenols in high yields (eq 37). This methodology is very effective for meta-substituted phenols that are difficult to obtain through conventional electrophilic substitution reactions due to the ortho- and para-directing effects of a phenol. Varied substituted cyclohexanone derivatives can be readily prepared through many well-known methods such as Diels–Alder reactions, aldol/Robinson annulations, conjugated additions to cyclohexanone, and α-functionalizations of cyclohexanones.

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Biaryl Coupling

Pd(II)-catalyzed coupling reactions of electron-rich heterocycles with aryl boronic acids97 or aryl trifluoroborates98 have been performed using molecular oxygen as a terminal oxidant. Varied substituted boronic acids or trifluoroborates reacted selectively at the 2-position of pyrroles and/or indoles under mild conditions (eq 38). Also, aryl trifluoroborates underwent cross coupling with electron-deficient arenes such as phenylacetic and benzoic acids under high oxygen pressure (eq 39).99

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Copper(II) has been also used as a catalyst for oxidative C[BOND]H activation in combination with molecular oxygen as the stoichiometric oxidant.100 Under analogous conditions, an aromatic Glaser–Hay homocoupling reaction of electron-deficient arenes and heterocycles yielded biaryl products in good yields (eq 40).

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Alkenylation

A mild aerobic oxidative Pd(II)-catalyzed C[BOND]H activation protocol has been applied for regioselective C[BOND]H alkenylation of pyrroles.101 Depending on N-protecting group of pyrroles, a C[BOND]H bond at the C-2 or C-3 positions was activated, followed by reaction with an alkene providing a regioisomeric alkenylated pyrrole (eq 41).

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Alkynylation

A catalytic transition metal/O2 protocol also enabled the direct coupling of terminal alkynes. The perfluoroarenes102 (eq 42) and azoles (eq 43) reacted with various alkynes under mild conditions by employing nickel and/or copper catalyst103 with molecular oxygen as an oxidant. Cu-catalyzed oxidative coupling of terminal alkynes with various nitrogen nucleophiles such as oxazolidines and indoles provided ynamides in good yields (eq 44).104 Under stoichiometric Cu(II)/O2 conditions, terminal alkynes underwent trifluoromethylation with a nucleophilic TMSCF3 reagent (eq 45).105

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Intramolecular Oxidative Cyclization

Cu(II)-catalyzed aerobic oxidative functionalization of amidines and anilides provided 2-substituted benzimidazoles106 and benzoxazoles.107 Aryl or alkyl amidines can be cyclized to afford 2-aryl or -alkyl benzimidazoles (eq 46). The anilide substrate with meta-methoxycarbonyl group underwent cyclization exclusively at the 2-position of the anilide providing the 7-substituted benzoxazole (eq 47).

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Other Metal-Catalyzed Reaction

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography
Oxidative Heck-type Coupling

A chiral pyridinyl oxazoline palladium catalyst under O2 atmosphere was used for an asymmetric oxidative Heck-type coupling between acyclic alkenes and aryl boronic acids.108 The reaction proceeded under mild conditions affording Heck-type products in good yields with modest enantioselectivities (eq 48). Higher enantioselectivity was achieved by using a preformed chiral palladium complex.

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Reductive Coupling

A reductive coupling of aryl boronic esters with styrene derivatives was performed under a palladium(II) catalytic system.109 A Pd(II) hydride species, generated in situ from initial alcohol oxidation by Pd(II), reacted with alkenes followed by transmetallation with aryl boronic esters and reductive elimination leading to diaryl methine products (eq 49). The resulting Pd(0) species was reoxidized to Pd(II) by molecular oxygen. A N-heterocyclic carbene ligand for palladium(II) was employed with a exogenous base, (−)-sparteine, the role of which was proposed to effect dissociation of the dimeric Pd(II) complex or to stabilize Pd(0) species during catalysis. Among several pinacol-derived boronic esters, the ethane-1,2-diol boronic esters afforded highest yields.

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Oxidative Intramolecular Cyclization

Pd(II)-catalyzed intramolecular amination of alkenes provided saturated five-membered nitrogen containing rings such as indolines and pyrrolidines.110 A seven-membered NHC ligand bound Pd complex with AcOH as a cocatalyst was highly effective for the oxidative cyclization (eq 50). The reaction was even successfully performed under ambient air.

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Metal-free Aerobic Oxidation

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography

A transition metal-free oxidation reaction of alcohols has been achieved by using a recyclable TEMPO-functionalized imidazolium chloride salt with NaNO2/CO2/H2O, where molecular oxygen was used as the terminal oxidant.111 Various primary alcohols underwent selective oxidation in the presence of secondary alcohols (eq 51).

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Molecular oxygen was employed in the tandem photooxidation/rearrangement of β-ketoesters to tartronic esters in the presence of catalytic CaI2 (eq 52).112

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Bibliography

  1. Top of page
  2. Original Commentary
  3. Oxygenation of Carbanions and Organometallic Compounds
  4. Oxygenation of Carbon Radicals
  5. Oxidation of Organoboranes
  6. Heteroatom Oxidation
  7. Other Uses
  8. First Update
  9. Oxygenation of Carbanions and Organometallic Compounds
  10. Oxygenation of Carbon Radicals
  11. Oxidation of Organoboranes
  12. Heteroatom Oxidation
  13. Other Uses
  14. Second Update
  15. Metal-catalyzed Oxidation
  16. Metal-catalyzed C[BOND]H Functionalization
  17. Other Metal-Catalyzed Reaction
  18. Metal-free Aerobic Oxidation
  19. Related Reagents
  20. Bibliography