The Handbook is part of the Handbook of Reagents for Organic Chemistry series, aiming at collecting articles on a particular theme that individual researchers in academia or industry can use on a daily basis. The Handbook starts with a section discussing the most important aspects of heteroarene functionalization. The introduction is followed by the alphabetical listing of the most relevant reagents drawn from the EROS database. The Editor, Andre Charette from the University of Montreal, has selected 120 reagent descriptions, many of them updated with heteroarene-specific reactions for this Handbook. Following the standard format for EROS, each article contains an overview of the synthesis and physical properties of the reagents or catalyst, conditions for its storage, and purification methods. Given the importance of heteroarenes in biology and especially in medicinal chemistry, a Handbook that focuses exclusively on heteroarene functionalization has been long overdue. This Handbook will have a broad appeal to many individuals engaged in the area of medicinal chemistry, fine chemical synthesis and industrial-scale chemistry. Key features: * Builds on the success of the previously published Handbooks ofReagents for Organic Synthesis * Compares the numerous new C-H functionalization reactions that have been developed in the past decade * Heteroarene functionalization is widely used in the development of pharmaceuticals and other bioactive compounds * Contains listings of secondary reagents for which more information is available in the online edition
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Liczba stron: 2111
Other Titles in this Collection
e-EROS Editorial Board
Terminal Oxidants Finder
Oxidation Catalyst Finder
Recent Review Articles and Monographs
Short Note on InChIs and InChIKeys
Benzenecarboperoxoic acid, 1, 1-dimethylethyl Ester
1,2-Benziodoxol-3(1H)-one, 1-Hydroxy, 1-Oxide, IBX
1,2-Benziodoxol-3(1H)-one, 1-Hydroxy, 1-Oxide, stabilized (stabilized IBX)
2,2′-Bipyrrolidines, (2S,2′S) and (2R,2′R)
Bis[[(1 R,1′′R)-3,3′′-[(1 R,2 R)-1,2-cyclohexanediylbis[(nitrilo-κN)-methylidyne]]bis[2′ -phenyl[1,1′-binaphthalen]-2-olato-κO ]](2-)]di-μ-oxodi-titanium and Bis[[(1 S,1′′S)-3,3′′- [(1 S,2 S)-1,2-cyclohexanediylbis[(nitrilo-κN)methylidyne]]bis[2′-phenyl[1,1′-binaphthalen]-2-olato-κO ]](2-)]di-μ-oxodi-titanium
N,N′-Bis(2,4,6-trimethylphenyl)imidazol-2-ylidene Palladium(I) Allyl Chloride
C: Calcium Hypochlorite1
Cobalt, [5,10,15,20-tetraphenyl-21H,23H -porphinato(2−)-κN 21,κN 22,κN 23,κN 24]-
N,N′ -(1R,2R)-1,2-Cyclohexanediylbis-[N -hydroxy-α -phenybenzeneacetamide]
N,N-Dibromobenzenesulfonamide and N,N-Dibromo-p-toluenesulfonamide
(S,S)-2,2′-(Dimethylmethylene)bis(4-tert-butyl-2-oxazoline) and (R,R)-2,2′-(Dimethylmethylene)bis(4-tert-butyl-2-oxazoline)*1
Dispiro[2H-pyran-2,4′-[4H-5,6,8b]triazaacenaphthylene-7′(5′H),2′′-[2H]pyran], 1′,2′,2′a,3,3′,3′′,4,4′′,5,5′′, 6,6′′,8′,8′a-tetradecahydro-1′,2′-dimethoxy-6,6′′-dimethyl-, monohydrochloride, (1′S,2R,2′S,2′′R, 2′aS,6S,6′′S,8′aS)-
H: Hydrogen Peroxide
Iridium, [N -[(1R,2R)-2-(amino-κN)-cyclohexyl]-4-methylbenzenesulfonamidato-κN ]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4,-cyclopentadien-1-yl]-; Iridium, [N -[(1R,2R)-2-(amino-κN)-cyclohexyl]-4-methylbenzenesulfonamidato-κN ]chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4,-cyclopentadien-1-yl]-; Iridium, [N -[(1S,2S)-2-(amino-κN)-cyclohexyl]-4-methylbenzenesulfonamidato-κN ]-chloro[(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4,-cyclopentadien-1-yl]-
Iridium, Dichlorodi- μ-hydrobis[(1,2,3,4,5- η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]di-
L: Lithium Hydroperoxide
M: Manganese(III) Acetate
Manganese(II), bis(octahydro-1,4,7-trimethyl-1H-1,4,7-triazonine-κN1,κN4, κN7)tri-μ-oxodi-, hexafluorophosphate
Molybdenum Chloride Oxide1
N: Noyori Oxidation (Sodium Tungstate Dihydrate, Hydrogen Peroxide, Methyltri-n-octylammonium Hydrogen Sulfate, Phosphonic Acid)
O: 3,3′,3α,3α′,4,4′,5,5′-Octahydro-3,3,3′,3′-tetraisopropyl-6,6′-spirobi-[6H -cyclopent[c]isoxazole]
P: Palladium (II) Sparteine Dichloride
(8 α,9R)-(8′′α,9′′R)-1,1′′-[1,3-Phenylenebis(methylene)]bis[9-hydroxycinchonanium] Dibromide and (9S)-(9′′S)-1,1′′-[1,3-Phenylenebis(methylene)]bis[9-hydroxycinchonanium] Dibromide
(−)(1S)-1-Phenylethyl Hydroperoxide and (+)(1R)-1-Phenylethyl Hydroperoxide
(8α,9R)-(8′′α,9′′R)-9,9′′-[1,4-Phthalazinediylbis(oxy)]bis[10,11-dihydro-6′-methoxycinchonan] & (9S)-(9′′S)-9,9′′-[1,4-Phthalazinediylbis(oxy)]bis[10,11-dihydro-6′-methoxycinchonan]
Pyrrolidine, 3,4-bis(diphenylphosphino)-1-(phenylmethyl)-,(3R,4R) and Pyrrolidine, 3,4-bis(diphenylphosphino)-1-(phenylmethyl)-, (3S,4S)
2-Pyrrolidinemethanol-α, α-bis(3,5-dimethylphenyl)-(2S); and 2-Pyrrolidinemethanol-α, α-bis(3,5-dimethylphenyl)-(2R)∗
R: Rhenium(VII) Oxide
Ruthenium Complex of N,N′,N′-Trimethyl-1,4,7-triazacyclononane and Ruthenium Complex of cis-Diaquabis (6,6′-Dichloro-2,2′-bipyridine)
Ruthenium Dodecacarbonyltri Triangulo
S: Selenium(IV) Oxide
Sodium Hypochlorite–N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-manganese(III) Chloride1
Spiro[6H-1,3-dioxolo[4,5-c]pyran-6,5′-oxazolidine]-3′-carboxylic acid, tetrahydro-2,2-dimethyl-2′,7-dioxo-,2-methyl-2-propyl ester, (3aR, 5′S, 7aR)-
T: Tetrabutylammonium Bis(pyrazinecarboxylato)-dioxo-vanadium(V)
(S)-2-(5-1H-Tetrazolyl)pyrrolidine and (R)-2-(5-1H-Tetrazolyl)pyrrolidine
V: Vanadium,bis[N -[(1S)-1-(carboxy- κO)ethyl]-N -(hydroxy- κO)-l -alaninato(2-)- κN, κO ]-
List of Contributors
Reagent Formula Index
Other Titles in this Collection
Reagents for Silicon-Mediated Organic Synthesis
Edited by Philip L. Fuchs
ISBN 978 0 470 71023 4
Edited by Leo A. Paquette
ISBN 978 0 470 74872 5
Reagents for Radical and Radical Ion Chemistry
Edited by David Crich
ISBN 978 0 470 06536 5
Catalyst Components for Coupling Reactions
Edited by Gary A. Molander
ISBN 978 0 470 51811 3
Edited by Leo A. Paquette
ISBN 978 0 470 02177 4
Reagents for Direct Functionalization of C–H Bonds
Edited by Philip L. Fuchs
ISBN 0 470 01022 3
Reagents for Glycoside, Nucleotide, and Peptide Synthesis
Edited by David Crich
ISBN 0 470 02304 X
Reagents for High-Throughput Solid-Phase and Solution-Phase Organic Synthesis
Edited by Peter Wipf
ISBN 0 470 86298 X
Chiral Reagents for Asymmetric Synthesis
Edited by Leo A. Paquette
ISBN 0 470 85625 4
Activating Agents and Protecting Groups
Edited by Anthony J. Pearson and William R. Roush
ISBN 0 471 97927 9
Acidic and Basic Reagents
Edited by Hans J. Reich and James H. Rigby
ISBN 0 471 97925 2
Oxidizing and Reducing Agents
Edited by Steven D. Burke and Rick L. Danheiser
ISBN 0 471 97926 0
Reagents, Auxiliaries, and Catalysts for C–C Bond Formation
Edited by Robert M. Coates and Scott E. Denmark
ISBN 0 471 97924 4
This edition first published 2013
©2013 John Wiley & Sons Ltd
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Library of Congress Cataloging-in-Publication Data
Handbook of reagents for organic synthesis.
Includes bibliographical references.
Contents:  Reagents, auxiliaries and catalysts for C–C bond formation / edited by Robert M. Coates and Scott E. Denmark  Oxidizing and reducing agents / edited by Steven D. Burke and Rick L. Danheiser  Acidic and basic reagents / edited by Hans J. Reich and James H. Rigby  Activating agents and protecting groups / edited by Anthony J. Pearson and William R. Roush  Chiral reagents for asymmetric synthesis / edited by Leo A. Paquette  Reagents for high-throughput solid-phase and solution-phase organic synthesis / edited by Peter Wipf  Reagents for glycoside, nucleotide and peptide synthesis / edited by David Crich  Reagents for direct functionalization of C–H bonds/edited by Philip L. Fuchs  Fluorine-Containing Reagents/edited by Leo A. Paquette  Catalyst Components for Coupling Reactions / edited by Gary A. Molander  Reagents for Radical and Radical Ion Chemistry/edited by David Crich  Sulfur-Containing Reagents / edited by Leo A. Paquette  Reagents for Silicon-Mediated Organic Synthesis / edited by Philip L. Fuchs  Catalytic Oxidation ReagentsISBN 0-471-97924-4 (v. 1)ISBN 0-471-97926-0 (v. 2)ISBN 0-471-97925-2 (v. 3)ISBN 0-471-97927-9 (v. 4)ISBN 0-470-85625-4 (v. 5)ISBN 0-470-86298-X (v. 6)ISBN 0-470-02304-X (v. 7)ISBN 0-470-01022-3 (v. 8)ISBN 978-0-470-02177-4 (v. 9)ISBN 978-0-470-51811-3 (v.10)ISBN 978-0-470-06536-5 (v. 11)ISBN 978-0-470-74872-5 (v.12)ISBN 978-0-470-71023-4 (v. 13)ISBN 978-1-119-95327-2 (v.14)1. Chemical tests and reagents.2. Organic compounds-Synthesis.QD77.H37 199998-53088547'.2 dc 21CIP
A catalogue record for this book is available from the British Library.
e-EROS Editorial Board
Wayne State University, Detroit, MI, USA
André B. Charette
Université de Montréal, Montréal, Québec, Canada
Philip L. Fuchs
Purdue University, West Lafayette, IN, USA
Colorado State University, Fort Collins, CO, USA
Leo A. Paquette
The Ohio State University, Columbus, OH, USA
I dedicate this handbook to our family's matriarch, my wife Diane, our two sons Devin and Sean, their wives Stefanie and Celeste, and their children, Dylan and Sadie, respectively.
The eight-volume Encyclopedia of Reagents for Organic Synthesis (EROS), authored and edited by experts in the field, and published in 1995, had the goal of providing an authoritative multivolume reference work describing the properties and reactions of approximately 3000 reagents. With the coming of the Internet age and the continued introduction of new reagents to the field as well as new uses for old reagents, the electronic sequel, e-EROS, was introduced in 2002 and now contains in excess of 4000 reagents, catalysts, and building blocks making it an extremely valuable reference work. At the request of the community, the second edition of the encyclopedia, EROS-II, was published in March 2009 and contains the entire collection of reagents at the time of publication in a 14-volume set.
While the comprehensive nature of EROS and EROS-II and the continually expanding e-EROS render them invaluable as reference works, their very size limits their practicability in a laboratory environment. For this reason, a series of inexpensive one-volume Handbooks of Reagents for Organic Synthesis (HROS), each focused on a specific subset of reagents, was introduced by the original editors of EROS in 1999:
Reagents, Auxiliaries, and Catalysts for C–C Bond FormationEdited by Robert M. Coates and Scott E. Denmark
Oxidizing and Reducing AgentsEdited by Steven D. Burke and Rick L. Danheiser
Acidic and Basic ReagentsEdited by Hans J. Reich and James H. Rigby
Activating Agents and Protecting GroupsEdited by Anthony J. Pearson and William R. RoushThis series has continued over the last several years with the publication of a further series of HROS volumes, each edited by a current member of the e-EROS editorial board:
Chiral Reagents for Asymmetric SynthesisEdited by Leo A. Paquette
Reagents for High-Throughput Solid-Phase and Solution-Phase Organic SynthesisEdited by Peter Wipf
Reagents for Glycoside, Nucleotide, and Peptide SynthesisEdited by David Crich
Reagents for Direct Functionalization of C–H BondsEdited by Philip L. Fuchs
Fluorine-Containing ReagentsEdited by Leo A. Paquette
Catalyst Components for Coupling ReactionsEdited by Gary A. Molander
Reagents for Radical and Radical Ion ChemistryEdited by David Crich
Sulfur-Containing ReagentsEdited by Leo A. Paquette
Reagents for Silicon-Mediated Organic SynthesisEdited by Philip L. Fuchs
This series now continues with the present volume entitled Catalytic Oxidation Reagents, edited by Philip Fuchs, long-standing member of the online e-EROS Editorial Board. This 14th volume in the HROS series, like its predecessors, is intended to be an affordable, practicable compilation of reagents arranged around a central theme that it is hoped will be found at arm's reach from synthetic chemists worldwide. The reagents have been selected to give broad relevance to the volume, within the limits defined by the subject matter. We have enjoyed putting this volume together and hope that our colleagues will find it just as enjoyable and useful to read and consult.
David CrichDepartment of ChemistryWayne State UniversityDetroit, MI, USA
Terminal Oxidants Finder
Oxidation Catalyst Finder
Short Note on InChIs and InChIKeys
The IUPAC International Chemical Identifier (InChITM) and its compressed form, the InChIKey, are strings of letters representing organic chemical structures that allow for structure searching with a wide range of online search engines and databases such as Google and PubChem. While they are obviously an important development for online reference works, such as Encyclopedia of Reagents for Organic Synthesis (e-EROS), readers of this volume may be surprised to find printed InChI and InChIKey information for each of the reagents.
We introduced InChI and InChIKey to e-EROS in autumn 2009, including the strings in all HTML and PDF files. While we wanted to make sure that all users of e-EROS, the second print edition of EROS, and all derivative handbooks would find the same information, we appreciate that the strings will be of little use to the readers of the print editions, unless they treat them simply as reminders that e-EROS now offers the convenience of InChIs and InChIKeys, allowing the online users to make best use of their browsers and perform searches in a wide range of media.
If you would like to know more about InChIs and InChIKeys, please go to the e-EROS website: http://onlinelibrary.wiley.com/book/10.1002/047084289X and click on the InChI and InChIKey link.
(reagent and catalyst for selective oxidation of alcohols2)
4-Acetamido-TEMPO is a representative of the nitroxide radicals (1) which have been used as reagents or catalysts for the oxidation of organic compounds.1 Several nitroxide radicals have been converted to the corresponding oxoammonium salts (2) and used as stoichiometric oxidizing reagents.1 Nitroxide radicals have also been used as catalysts in the the presence of a secondary, stoichiometric oxidant (see 2,2,6,6-Tetramethylpiperidin-1-oxyl).1
4-Acetamido-TEMPO (3) is not, itself, a reagent for the oxidation of alcohols. Rather, it serves as a convenient precursor for the in situ preparation of an oxoammonium salt (4), which is the true oxidant. The oxoammonium salt (4) is the product of the acid-catalyzed disproportionation of (3) to (4) and (5) in the presence of p -Toluenesulfonic Acid (eq 1) and is a highly selective reagent for alcohol oxidation (eq 2).1 The reactions are carried out in methylene chloride in which TsOH·H2O is essentially insoluble. The only products of the reaction are the desired carbonyl compound product (7) and the hydroxylamine salt (5), which is completely insoluble in methylene chloride. Product isolation simply involves the filtration of (5) and the evaporation of methylene chloride. Compound (5) can be converted back to the nitroxide radical (3) in quantitative yield.2
The reaction has been used for the oxidation of a variety of alcohols with excellent yields of isolated products.2 Primary alcohols are converted to the corresponding aldehydes, and no over-oxidation is observed. Secondary alcohols react as well as primary alcohols and provide the corresponding ketones. The mildness of this reaction has been demonstrated by the oxidations of nerol (8) and geraniol (9) to the corresponding cis-citral (10) and trans-citral (11).
Oxidation with this reagent does not take place when there is an oxygen or nitrogen in the β-position to the alcohol being oxidized and does not take place with 1,2-diols or sugars. Amines,1,4 thiols,5 phenols,6 indoles,7 benzyl ethers,1 and ketones (very slow)1 react with oxoammonium salts and may interfere with alcohol oxidation. However, sulfides, most ethers, amides, esters, and double bonds do not react with oxoammonium salts and should not interfere.1
A number of other oxoammonium salts have been described in the literature.1 In addition, TEMPO-type nitroxide radicals have been used as specific catalysts for the oxidation of alcohols using one or several secondary, stoichiometric oxidants.1,8 Neither 4-acetamido-TEMPO nor any of its derivatives have been used in this manner, but they should function satisfactorily.
1. Bobbitt, J. M.; Flores, M. C. L., Heterocycles1988, 27, 509 (general review on oxoammonium salts, but they are called nitrosonium salts in the title).
2. Ma, Z.; Bobbitt, J. M., J. Org. Chem.1991, 56, 6110.
3. Rozantsev, E. G.; Kokhanov, Y. V., Bull. Acad. Sci. USSR, Div. Chem. Sci.1966, 8, 1422.
4. Hunter, D. H.; Racok, J. S.; Rey, A. W.; Ponce, Y. Z., J. Org. Chem.1988, 53, 1278.
5. Kashiwagi, Y.; Ohsawa, A.; Osa, T.; Ma, Z.; Bobbitt, J. M., Chem. Lett.1991, 581.
6. Bobbitt, J. M.; Ma, Z., Heterocycles1992, 33, 641.
7. Bobbitt, J. M.; Guttermuth, M. C. F.; Ma, Z.; Tang, H., Heterocycles1990, 30, 1131.
8. (a) Anelli, P. L.; Montanari, F.; Quici, S., Org. Synth.1990, 69, 212. (b) Inokuchi, T.; Matsumoto, S.; Torii, S., J. Org. Chem.1991, 56, 2416. (c) Leanna, M. R.; Sowin, T. J.; Morton, H. E., Tetrahedron1992, 33, 5029.
James M. Bobbitt & Zhenkun Ma
University of Connecticut, Storrs, CT, USA
(reagent used to oxidize alcohols to aldehydes or ketones. Of special interest, allyl alcohols can be oxidized without isomerization and phenolic benzyl alcohols can be oxidized without blocking the phenol group; all of these reagents have been used for the oxidation of primary and secondary alcohols to aldehydes or ketones, respectively. They also have a certain number of additional minor oxidation reactions. Many other salts are known1)
The preparation of 1a and its applications are described in a tested procedure in Organic Syntheses.20 The procedure involves the use of a second oxidant, bleach, to increase the yield of salt.
James M. Bobbitt & Nabyl Merbouh
University of Connecticut, Storrs, CT, USA
The title reagent 1a has some remarkable oxidizing properties, and is commercially available from several sources. It can also be prepared from 4-amino-2,2,6,6-tetramethylpiperidine.3 In this preparation, one caution applies. When the nitroxide was prepared, potassium carbonate was used as a base.3 This should be replaced by sodium carbonate since potassium tetrafluoroborate is quite insoluble in water and causes impurity problems with the oxoammonium salt. The nitroxide has interesting solubility properties. It is only slightly soluble in ether and cold water. It can be extracted from an aqueous layer with several portions of CH2Cl2, or from an ether layer with several portions of water. If necessary, the nitroxide can be recrystallized from ethyl acetate.
Reference 3 describes the synthesis and reactions of two oxoammonium salts, the perchlorate and the tetrafluoroborate, but all of the oxidations described were carried out with perchlorate. Unfortunately, the perchlorate proved to be unsafe, and the tetrafluoroborate is now the salt of choice. The oxidizing properties and solubilities of the two salts are essentially identical.
The reaction shown below is actually carried out in a neutral to slightly acidic medium. Silica gel is a potent catalyst, but is not needed for the oxidation of allyl or benzyl alcohols. The oxoammonium salt 1 is bright yellow and its reduction product, the hydroxyamine salt 2, is white in color. The oxidant is sufficiently soluble in the solvent to allow the reaction to occur, but 2 is almost completely insoluble. Thus, a yellow slurry of the reagent 1 (about 5–10% excess) and the appropriate alcohol is stirred in CH2Cl2 (1–2 mmol in 10 mL), with or without silica gel, until the slurry becomes white (eq 3). Filtration through a ca. 0.5-cm pad of silica gel removes the salt 2 and a small trace of 1. The aldehydes or ketones formed are quite pure and are isolated in good yields.3
The hydroxyamine salt 2 can be converted back to nitroxide in the following manner. The precipitated reagent and silica gel are stirred with a small portion of warm water and filtered to remove silica gel. The filtrate is basified with NaHCO3 and treated with an excess of 30% H2O2. The nitroxide forms in about 24 h and can be extracted with CH2Cl2.
This oxidation method has some advantages as well as disadvantages. Advantages are that the reaction is colorimetric (yellow to white), essentially quantitative, and there is no further oxidation to an acid. If there is a hydroxy group in the product which can form a stable hemiacetal, the product will be a lactone. Since 2 is almost insoluble in CH2Cl2, the reaction work-up requires only a filtration. The reaction is ideal for preparing unstable or volatile aldehydes (or ketones) on an ‘as needed’ basis. Since the products are essentially pure as formed, the oxidation can be combined with various other reactions, such as Wittig or Grignard reactions. Wittig reactions work especially well when the Wittig reagent is added to the solution of aldehyde or ketone, either in CH2Cl2 or in diethyl ether. Isolated yields are as high as 90% for the combined reactions.
The oxidation of allyl alcohols when there is a possibility of double bond isomerization is accomplished without isomerization,3 as in the case of 3.4 Benzyl alcohols containing one phenol group can be cleanly oxidized to aldehydes without phenol oxidation,3 as in the case of 4.5 Two phenol groups give decomposition. Yields of aldehydes or ketones are shown in parentheses.
There are also some disadvantages for this oxidation method. The oxidation does not take place when there is a β-oxygen or a nitrogen group attached to the alcohol being oxidized (but see below). Since the reaction conditions are slightly acidic, acetals are opened. In addition, there are two slow reactions that interfere with slow oxidations, such as those of primary alcohols. Benzyl groups are slowly oxidized and cleaved.6 This causes no problem with benzyl alcohols or allyl alcohols, which are oxidized rapidly. In the second reaction, activated double bonds (containing oxygen, nitrogen, or three alkyl groups) are slowly oxidized.3,7 Again, this is not a problem with allyl or benzyl alcohols.
One more reaction of certain oxoammonium salts is known and may be of major importance. This is the oxidation of ketones to α-diketones,8,9 and the oxidation of 1,3-diketones to 1,2,3-triketones.9
Oxidations can also be carried out in a base, for example pyridine in CH2Cl2, but the reaction takes a different course as shown in eq 4.10 Equal amounts (2 equiv) of salt and the base must be used. The products are the orange-colored nitroxide (5) and the base salt of tetrafluoroboric acid.
Fortunately, compounds 5 and 6 can both be easily removed for product isolation. The orange-colored nitroxide is only slightly soluble in dry ether, but the pyridine salt is completely insoluble in CH2Cl2. Thus, the filtration of the reaction mixture removes 6, and evaporation of CH2Cl2 leaves a residue of product and nitroxide. This residue can be extracted with ether, leaving most, but not all of the nitroxide behind. The last traces of nitroxide can be removed on a short column of silica gel.
The reaction has been successfully applied to several sugar derivatives10 such as 7, 8, and 9. It is noteworthy that only oxidation of the anomeric carbon takes place, but the secondary alcohol groups in the sugar are not touched. The reaction has also been successfully applied to other acetals and β-oxygen alcohols, thus alleviating some of the objections of the simpler reaction in CH2Cl2 alone.
James M. Bobbitt
University of Connecticut, Storrs, CT, USA
Simon Fraser University, Burnaby, Canada
A typical oxidation with 1a is shown eq 5, but it is probably specific for this reagent due to the desirable solubilities of the salt and its reduced product, 2.3 In essence, the substrate is dissolved in methylene chloride and treated with the bright yellow 1a, which is only slightly soluble. The salt is best mixed with an equal weight of chromatographic grade silica gel to give faster reactions. The yellow slurry is stirred until it becomes a white slurry and no starch iodide paper test is observed. The slurry is filtered to recover 2 (insoluble in methylene chloride), and the filtrate contains a high yield of essentially pure carbonyl compound. Compound 2 can be recycled back to nitroxide, 5.
There are some specific advantages to this reaction. First, the reaction is colorometric. Second, product isolation is trivial. Third, the reaction is stereospecific in that a double bond and chiral configurations are maintained even when the oxidation is on adjacent atoms. Finally, the reaction can be carried out in the presence of a phenol group.
There are also disadvantages. Alcohols having a beta oxygen or nitrogen function are not oxidized.3,21 Free amino groups react rapidly (see below). Aliphatic alcohol oxidations (which are slow) can be complicated sometimes by reactions with isolated, activated double bonds (see below) and, in some cases, by benzyl ethers (see below).6 Frequently, these secondary reactions are quite slow in methylene chloride and faster in acetonitrile.
Allylic and benzylic alcohols react in 2–3 h. Aliphatic secondary alcohols and acetylenic alcohols react slightly faster than primary alcohols. All of the reactions are faster in the presence of silica gel. The reaction is quite specific in that no carboxylic acids are formed from primary alcohols and carbon–carbon bond cleavage is almost unknown. The one exception is that for diols in which five-or six-membered hemiacetal rings can be formed, the products are lactones.22
Oxidations with the other salts give comparable reactions, although some salts are not stable or are hygroscopic. The specific anions seem to be important in determining the rates of the various oxidations.18,19 In general, the halide salts react faster than the tetrafluoroborate or perchlorate mediated oxidations. The reaction conditions are similar to those given above, but the solubilities of the products may not be the same.
Since amine groups react readily with oxoammonium salts (see below), only such organic bases as pyridine and its derivatives can be used to influence these reactions. Only one such reaction has been carefully studied, the oxidative dimerization of primary alcohols containing a beta oxygen and those give good yields of dimeric esters as shown in eq 6.23
This reaction is complicated by the fact that the reduced product from the oxoammonium salt, 2, reacts with pyridine to give a free hydroxyamine base, which in turn reacts with more oxoammonium salt 1a to give nitroxide 5 as the final product.
Oxidations with stoichiometric amounts of oxoammonium salts, although convenient, have not been extensively used, primarily because the salts are not commercially available. The vast majority of oxoammonium oxidations have been catalytic reactions in which a nitroxide is used with a primary oxidant such as NaOCl (or many other similar reagents). In effect, the oxoammonium ion generated from nitroxide in such reactions provides a high degree of specificity for alcohol oxidation, with the convenience of cheaper and more available oxidants. Catalytic reactions have been extensively reviewed1,2,11,12,24 and will not be considered in this paper.
These reactions are not well known. Some reactions, such as those in eqs 7–9,9,25–27 probably take place through enol forms. Others, such as those in eq 1028 do not, and are not easily explained.
These reactions take place slowly in methylene chloride and faster in acetonitrile (eq 11). The alkene must contain three or four alkyl substituents29 or two phenyl groups.7
These reactions are similar to the one discussed above for double bond reactions except that the intermediate is trapped as an ether (eq 12)7 or as a thymine derivative (eq 13).30
Equations 14 and 15.
Reactions with amines are complicated by the fact that the starting amine reacts with any reduced oxidant (such as 2) to give the free hydroxylamine base, which reacts with oxoammonum salt to give nitroxide (reverse of eq 3). The reactions have not been well explored, and yields are low (eqs 16 and 17). The apparent reaction, however, is much like alcohol oxidation in that an imine is formed by the loss of two hydrogens. Amine oxidation has been more successfully explored in nitroxide catalyzed electrochemical oxidations in the presence of 2,6-lutidine.36
These reactions only show up only when alcohol oxidation is very slow. For example, benzyl alcohols can be oxidized in the presence of benzyl ethers as in eq 19.3
Thiols are oxidized to disulfides (eq 20). Otherwise sulfur oxidations are controversial. Sulfides and sulfones are reported to be unreactive.33 Salt 1a reacts almost violently with DMSO if one attempts to measure an NMR spectrum in that solvent, but the products are not known.39
Tsutomu Inokuchi & Li-Jian Ma
Okayama University, Okayama, Japan
Environmentally benign aerobic alcohol oxidations have gained importance recently. TEMPO and its derivatives are used for aerobic oxidation of alcohols in various nonmetallic and transition metal-mediated reactions. A transition metal-free catalytic system consisting of catalytic sodium nitrite42–44 or PEG (polyethylene glycol)–NO245 with air as the terminal oxidant under acidic conditions was recently developed (eq 21).
In place of NaNO2, tert-butyl nitrite (TBN) was identified as an efficient NO equivalent for the activation of molecular oxygen.46,47 Various alcohols including benzylic alcohols substituted with sulfide were converted into their corresponding carbonyl compounds with TEMPO/HBr/TBN as catalyst, which is suitable for the oxidation of solid alcohols with high melting points and/or low solubility using a minimal amount of solvent to form a slurry (eq 22).
The cascade systems of O2–NaNO2–bromine or O2–Bu4NBr–TEMPO48,49 or O2–NaNO2–PhI(OAc)250 have also been developed (eqs 23 and 24).
A novel catalyst system that uses 1–4 mol % of TEMPO in combination with 4–6 mol % of aqueous hydroxylamine as a NO source is also effective (eq 25).51
Aerobic metal-mediated TEMPO oxidations of alcohols have been examined. These processes have been mainly conducted with copper catalysts. This catalyst system is also useful for oxidation of benzylic alcohols and the reaction is explained by the mechanism below (eq 26).
Ionic liquid [bmpy]PF6 was used as a reaction medium,60 and fluorinated bipyridine ligands were successfully used for aerobic oxidation of alcohols under the fluorous biphasic system (FBS).62 The sequential reaction including alcohol oxidation by TEMPO/Cu and the asymmetric aldol reaction by peptide catalysis was realized using resin-supported TEMPO catalysts.63 Simultaneous irradiation with visible light improved the catalytic oxidation with Cu/TEMPO, especially for unprotected alkyl glycosides (eq 27).55
Other effective metals in place of Cu include a vanadyl complex,64 polymer incarcerated ruthenium (PIRu),65 and combined bimetals such as Cu–Mn oxides,66,67 and Mn–Co.68,69
Efficient and clean aerobic oxidation using 1 atm of oxygen or air, producing aldehydes/ketones from the widest spectrum of alcohols, including allenols and propargylic alcohols, at room temperature within a few hours was developed by cascade reaction of O2–NO/NO2–Fe(III)–TEMPO systems (eqs 28 and 29).70 These processes have been mainly conducted with 4-acetamido-TEMPO/ FeCl3/NaNO2 catalysts71 or TEMPO/cobaloxime/Co(NO3)2 catalyst.72
A combination TiO2–dye cascade system was developed.73 Upon irradiation with visible light, excited dye molecules (Alizarin Red) inject electrons into TiO2 and form dye radicals, which can oxidize TEMPO to TEMPO+, which selectively oxidizes alcohols in the presence of O2 to the corresponding aldehydes. The selectivity is improved when the irradiation exploits visible light.
A combination of IL-supported TEMPO (14) with BAIB (bis(acetoxy)-iodobenzene)74 or IL-supported TEMPO with tetra-n-butyl-ammonium peroxymonosulfate (n-Bu4NHSO5), available from Oxone and n-Bu4NHSO4 in an ionic liquid medium, has been developed.75
Organically modified silica-based SiliaCat TEMPOs (15, 16) are an oxidizing catalyst that can efficiently replace homogeneous stable nitroxyl radicals and effect the oxidation in either organic solvents or water, with or without KBr as cocatalyst.76,77
Oxidation–hydrocyanation of γ,δ-unsaturated alcohols using immobilized TEMPO/PhI(OAc)2 in combination with HbHNL (hydroxynitrile lyase from Hevea brasiliensis) proceeds smoothly, the resulting cyanohydrin derivatives being obtained in good overall yields and with high ees (eq 30).78
Other immobilized TEMPOs shown below include phosphonium-supported TEMPO (17),79 polyurethane-and polystyrene-supported TEMPO (18),80 molecularly imprinted polymeric TEMPO (19),81 a highly active and easily recoverable TEMPO with the attachment of multiple triazole moieties and perfluoroalkyl chains (20),82 readily isolable “fluorous-tagged” TEMPOs,83a and TEMPO-linked metalloporphyrins.83b
Site-isolated encapsulated linear polymeric catalysts bound with TEMPO have 2.5 times faster reaction rates than the analogous resin-supported catalysts, in the oxidation of sec-phenethyl alcohol to acetophenone (eq 31).84
TEMPO–iodobenzene hybrid catalyst was used in the double catalytic reaction of arylmethyl and alkylmethyl alcohols as a substrate in a 9% acetic acid solution of peracetic acid (PAA) as a cooxidant, giving the corresponding carboxylic acids in good to excellent yields (56~99%) (eq 32).85
Sustainability of the TEMPO oxidation finds a variety of industrial applications as highly selective oxidation catalysts for the production of pharmaceuticals, flavors and fragrances, agrochemicals, and a variety of other specialty chemicals, and examples are reviewed.86 In developing the manufacturing route for the cathepsin K inhibitor SB-462795, the TEMPO oxidation of a secondary alcohol for the final chemical stage has been exploited (eq 33).87
Other examples are synthesis of betulinic acid by oxidation with 4-acetamido-TEMPO/NaClO2/NaOCl (86%)88 and unprotected dialdo-glycosides with TEMPO–TCC (trichloroisocyanuric acid) (65~100%) (eq 34).89
In the pilot plant synthesis of (2-chlorophenyl)[2-(phenylsulfonyl)pyridin-3-yl]methanone, reactivities of TEMPO derivatives, such as 4-MeO-TEMPO and 4-AcNH-TEMPO, were compared (eq 35).90
Technical production of aldehydes by continuous bleach oxidation of alcohols was achieved in a tube reactor. This system is essential for the synthesis of activated α-substituted aldehydes and also recommended for nonactivated aldehydes (eq 36).91
An efficient tandem reaction system was developed in which primary alcohols were oxidized to the corresponding aldehydes followed by an asymmetric α-oxyamination with a resin-supported peptide catalyst (eq 37).92 A similar transformation has also been achieved using an anodic oxidation (eq 38).93
A chiral cobalt-catalyzed reaction features enantioselective aerobic oxidative kinetic resolution of (+)-α-hydroxy esters, using molecular oxygen as the sole oxidant (eq 39).94
A convenient oxidation for a variety of electron-rich benzylic alcohols using HIO3 and I2O5 as safer stoichiometric oxidants with catalytic amounts of TEMPO or 4-hydroxy-TEMPO in water was devised.95
This article includes some reactions of 4-methoxy-2,2,-6,6-tetramethyl-1-piperidinyloxy (4-methoxy-TEMPO) [95407-69-5], 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (4-acetylamino-TEMPO) [14691-89-5], and derivatives of 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (4-hydroxy-TEMPO) [2226-96-2] and 1-piperidinyloxy, 2,2,6,6-tetramethyl-4-(2-propyn-1-yloxy)-[147045-24-7].
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