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TEMPO, 2,2,6,6-Tetramethylpiperidinyloxy

2,2,6,6-Tetramethylpiperidinyloxy is a stable nitroxyl radical, which serves in oxidations as catalyst. By substitution in position 4 (4-hydroxy-TEMPO, 4-acetamido-TEMPO) its reactivity can be steered.

For example, processes with oxygen and 5 mol-% TEMPO permit environmentally benign reactions as alternatives to some oxidations, where so far e.g. chrome reagents were used.

Proposed mechanism for the oxidation of primary alcohols under basic conditions
M. Angelin, M. Hermansson, H. Dong, O. Ramström, Eur. J. Org. Chem., 2006, 4323-4326.

2-Azaadamantane N-Oxyl (AZADO), 9-Azabicyclo[3.3.1]nonane N-Oxyl (ABNO), 9-Azanoradamantane N-oxyl (Nor-AZADO) form a less hindered class of nitroxyl radicals and exhibit an enhanced reactivity compared with TEMPO.

Recent Literature

Sodium hypochlorite pentahydrate crystals with very low NaOH and NaCl contents oxidize primary and secondary alcohols to the corresponding aldehydes and ketones in the presence of TEMPO/Bu4NHSO4 without pH adjustment. This new oxidation method is also applicable to sterically hindered secondary alcohols.
T. Okada, T. Asawa, Y. Sugiyama, M. Kirihara, T. Iwai, Y. Kimura, Synlett, 2014, 25, 596-598.

Oxidation of primary and secondary alcohols, using catalytic amounts of TEMPO and tetra-n-butylammonium bromide in combination with periodic acid and wet alumina in dichloromethane is compatible with a broad range of functional groups and acid-sensitive protecting groups. The system also enables a chemoselective oxidation of secondary alcohols in the presence of primary alcohols.
M. Attoui, J.-M. Vatèle, Synlett, 2014, 25, 2923-2927.

A convenient method enables the preparation of a silica gel supported  TEMPO catalyst. The catalyst prepared from [4-hydroxy-TEMPO + NaCl]/SiO2 was used for an aerobic oxidation of alcohols to carbonyls under mild reaction conditions in the presence of Fe(NO3)3 • 9 H2O. Alcohols were converted to the corresponding carbonyls in good to excellent yields. After a simple filtration, the catalyst can be reused at least six times.
N. Tamura, T. Aoyama, T. Takido, M. Kodomari, Synlett, 2012, 23, 1397-1407.

A rapid oxidation of primary and secondary alcohols using catalytic amounts of TEMPO and Yb(OTf)3 in combination with a stoichiometric amount of iodosylbenzene afforded carbonyl compounds in excellent yields without over-oxidation. Oxidation of primary alcohols in the presence of secondary alcohols proceeded with good selectivity.
J.-M. Vatèle, Synlett, 2006, 2055-2058.

An aerobic oxidation of primary and secondary alcohols to aldehydes and ketones using TEMPO-CuCl as catalyst in the ionic liquid [bmin][PF6] has been developed. The system needs no bubbling of O2 due to its good solubility in the ionic liquid. The resulting aldehydes (with no traces of carboxylic acids) and ketones can be extracted with organic solvents. The ionic liquid can be reused after washing with water and drying under high vacuum (8 runs for the oxidation of benzyl alcohol: yields of 72%, 70, 68, 70, 65, 64, 62, and 60).
I. A. Ansari, R. Gree, Org. Lett., 2001, 1507-1509.

A highly efficient 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO) catalyzed reaction using recyclable 1-chloro-1,2-benziodoxol-3(1H)-one as the terminal oxidant allows the conversion of various alcohols to their corresponding carbonyl compounds in high to excellent yields at room temperature in ethyl acetate, which is an environmentally friendly organic solvent.
X.-Q. Li, C. Zhang, Synthesis, 2009, 1163-1169.

The combination of TEMPO and CAN can be used for the aerobic oxidation of benzylic and allylic alcohols into their corresponding carbonyl compounds. However, steric hindrance has been observed to impede the reaction with some substituted allylic systems. The present method is superior to others currently available due to its relatively short reaction times and excellent yields.
S. S. Kim, H. C. Jung, Synthesis, 2003, 2135-2137.

The reaction of KBrO3 and NH2OH • HCl in situ generates NOx and Br anion, which allows in the presence of 2,2,6,6-tetramethylpiperidine-N-oxide (TEMPO) an activation of dioxygen to oxidize various benzylic alcohols quantitatively to their corresponding carbonyl compounds under mild conditions.
G. Yang, W. Wang, W. Zhu, C. An, X. Gao, M. Song, Synlett, 2010, 437-440.

TEMPO-derived reagents tagged with multiple perfluoroalkyl chains and triazole moieties promote the oxidation of alcohols to aldehydes in organic solvent/water mixtures with reaction rates comparable to homogeneous TEMPO reagents, but can be easily recovered by liquid/emulsion filtration.
A. Gheorghe, T. Chinnusamy, E. Cuevas-Yañez, P. Hilgers, O. Reiser, Org. Lett., 2008, 10, 4171-4174.

A. Gheorghe, T. Chinnusamy, E. Cuevas-Yañez, P. Hilgers, O. Reiser, Org. Lett., 2008, 10, 4171-4174.

A four-component system consisting of acetamido-TEMPO/Cu(ClO4)2/TMDP/DABCO in DMSO allows an efficient room-temperature aerobic alcohol oxidation of various alcohols into their corresponding aldehydes or ketones in good to excellent yields. The catalytic system can be recycled.
N. Jiang, A. J. Ragauskas, J. Org. Chem., 2006, 71, 7087-7090.

The system Cu(ClO4)2/acetamido-TEMPO/DMAP catalyses the room-temperature aerobic oxidation of primary alcohols to aldehydes in the ionic liquid [bmpy]PF6. The catalysts can be recycled and reused.
N. Jiang, A. J. Ragauskas, Org. Lett., 2005, 7, 3689-3692.

A highly efficient and mild procedure for the oxidation of different types of alcohols uses TEMPO as catalyst, iodobenzene dichloride as stoichiometric oxidant, and pyridine as base. Oxidation of 1,2-diols gives α-hydroxy ketones or α-diketones depending on the amount of oxidant used. High yielding procedures for the preparation of iodoarene dichlorides have been developed.
X.-F. Zhao, C. Zhang, Synthesis, 2007, 551-557.

A stable nitroxyl radical class of catalysts, 2-azaadamantane N-oxyl (AZADO) and 1-Me-AZADO, exhibit superior catalytic proficiency to TEMPO, converting various sterically hindered alcohols to the corresponding carbonyl compounds in excellent yields.
M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem. Soc., 2006, 128, 8412-8413.

An eco-friendly and mild aerobic oxidation of allylic alcohols using Fe(NO3)3·9H2O/TEMPO/NaCl as catalysts under atmospheric pressure of oxygen at room temperature provides a convenient pathway to the synthesis of stereodefined α,β-unsaturated enals or enones with the retention of the double-bond configuration.
J. Liu, S. Ma, Org. Lett., 2013, 15, 5150-5153.

A method for generating (E)-α,β-unsaturated aldehydes from Z- or E-allylic alcohols involves a Cu-catalyzed oxidation followed by an organocatalytic Z/E-isomerization with N,N-dimethylaminopyridine (DMAP).
D. Könning, W. Hiller, M. Christmann, Org. Lett., 2012, 14, 5258-5261.

X.-F. Zhao, C. Zhang, Synthesis, 2007, 551-557.

The use of NaClO/TEMPO/Co(OAc)2 enabled a benzylic oxidation of alkyl arenes to yield various aromatic aldehydes and ketones in very good yields. The reaction reactivity, selectivity, and scope of the reaction were investigated.
C. Jin, L. Zhang, W. Su, Synlett, 2011, 1435-1438.

A one-pot two-step sequence involving an oxidation/imine-iminium formation/reduction allowed the N-alkylation of amines by alcohols. Optically active alcohols and amines can be converted without any epimerization.
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy, Org. Lett., 2011, 13, 3478-3481.

A sequential one-pot synthesis for the oxidation of primary and secondary tert-butyldimethylsilyl (TBDMS) ethers, using the presence of PhIO or PhI(OAc)2 and catalytic amounts of metal triflates and TEMPO in THF or acetonitrile tolerates acid-sensitive protecting groups and leaves tert-butyldiphenylsilyl ethers and phenolic TBDMS groups untouched.
B. Barnych, J.-M. Vatèle, Synlett, 2011, 2048-2052.

In a direct conversion of primary and secondary alcohols into the corresponding α-chloro aldehydes and α-chloro ketones, trichloroisocyanuric acid serves both as stoichiometric oxidant and α-halogenating reagent. For primary alcohols, TEMPO has to be added as an oxidation catalyst, and for the transformation of secondary alcohols MeOH as an additive is essential to promote chlorination of the intermediary ketones.
Y. Jing, C. G. Daniliuc, A. Studer, Org. Lett., 2014, 16, 4932-4935.

In a direct conversion of primary and secondary alcohols into the corresponding α-chloro aldehydes and α-chloro ketones, trichloroisocyanuric acid serves both as stoichiometric oxidant and α-halogenating reagent. For primary alcohols, TEMPO has to be added as an oxidation catalyst, and for the transformation of secondary alcohols MeOH as an additive is essential to promote chlorination of the intermediary ketones.
Y. Jing, C. G. Daniliuc, A. Studer, Org. Lett., 2014, 16, 4932-4935.

An oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent enables a mild and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure of amines with alcohols.
I. A. Khan, A. K. Saxena, J. Org. Chem., 2013, 78, 11656-11669.

A highly regio- and enantioselective hydroxyamination of aldehydes with in situ generated nitrosocarbonyl compounds from hydroxamic acid derivatives was realized by combining TEMPO and BPO as oxidants in the presence of a binaphthyl-modified amine catalyst.
T. Kano, F. Shirozu, K. Maruoka, J. Am. Chem. Soc., 2013, 135, 17735-17738.

Various alcohols were efficiently converted into the corresponding nitriles at room temperature by treatment with tert-butyl hypochlorite, diiodine, or 1,3-diiodo-5,5-dimethylhydantoin (DIH) in the presence of TEMPO, followed by treatment with diiodine and aqueous ammonia. The nitriles were obtained in good yields and high purities by a simple extraction of the reaction mixture with chloroform and subsequent removal of the solvent.
H. Shimojo, K. Moriyama, H. Togo, Synthesis, 2013, 45, 2155-2156.

Iron-catalyzed aerobic oxidative reactions of primary amines, secondary amines, benzylamines with anilines, and alcohols with amines in the presence of air as the economic and safe oxidant, provides several direct, practical, and greener approaches for the preparation of useful imines.
E. Zhang, H. Tian, S. Xu, X. Yu, Q. Xu, Org. Lett., 2013, 15, 2704-2707.

A wide range of olefins with diverse functionalities has been nitrated in synthetically useful yields in a single step under metal-free conditions. This transformation is operationally simple and exhibits excellent E-selectivity. Furthermore, site selective nitration in a complex setup makes this method advantageous.
S. Maity, T. Naveen, U. Sharma, D. Maiti, Org. Lett., 2013, 15, 3384-3387.

Ferric nitrate with catalytic TEMPO is a useful combination of reagents for regio- and stereoselective nitration of various aromatic, aliphatic, and heteroaromatic olefins. This mild and operationally simple reaction provided nitroolefins in preparatively useful yields with excellent E-selectivity.
T. Naveen, S. Maity, U. Sharma, D. Maiti, J. Org. Chem., 2013, 78, 5949-5954.

A Cu-catalyzed oxidative amidation-diketonization reaction of terminal alkynes leads to α-ketoamides. In this copper-catalyzed radical process, O2 not only participates as the ideal oxidant but also undergoes dioxygen activation under ambient conditions.
C. Zhang, N. Jiao, J. Am. Chem. Soc., 2010, 132, 28-29.

Passerini three-component reaction under catalytic aerobic conditions allows the conversion of alcohols instead of aldehydes. The reaction of alcohols, isocyanides, and carboxylic acids in toluene in the presence of a catalytic amount of cupric chloride, NaNO2, and TEMPO afforded, under an oxygen atmosphere, the P-3CR adducts in good yields.
J. Brioche, G. Masson, J. Zhu, Org. Lett., 2010, 12, 1432-1435.

A highly convenient organocatalytic method for the mono-oxidation of unprotected glycosides relies on the chemoselective properties of TEMPO in combination with trichloroisocyanuric acid under very mild, basic conditions. The resulting dialdo-glycosides are efficiently purified with the use of solid-phase imine capture.
M. Angelin, M. Hermansson, H. Dong, O. Ramström, Eur. J. Org. Chem., 2006, 4323-4326.

A mild, aerobic, catalytic synthesis of nitriles directly from alcohols and aqueous ammonia proceeds via a dehydrogenation cascade mediated by catalytic CuI, bpy, and TEMPO in the presence of oxygen. The substrate scope includes various functionalized aromatic and aliphatic alcohols. This protocol also enabled a one-pot synthesis of various biaryl heterocycles directly from commercially available alcohols.
W. Yin, C. Wang, H. Huang, Org. Lett., 2013, 15, 1850-1853.

A direct conversion of a wide range of aliphatic, benzylic, heteroaromatic, allylic, and propargyl alcohols into nitriles with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), iodosobenzene diacetate, and ammonium acetate as a nitrogen source proceeds through an oxidation-imination-aldimine oxidation sequence in situ. Highly chemoselective ammoxidation of primary alcohols in the presence of secondary alcohols was also achieved.
J.-M. Vatèle, Synlett, 2014, 25, 1275-1278.

An efficient and highly selective method for the oxidative conversion of primary amines to the corresponding nitriles using trichloroisocyanuric acid in the presence of catalytic TEMPO provides a new entry to the synthesis of various aliphatic, aromatic and heterocyclic nitriles in excellent yield.
F.-E. Chen, Y.-Y. Kuang, H.-F. Dai, L. Lu, M. Huo, Synthesis, 2003, 2629-2631.

Iodine was compared to other positive halogens as terminal oxidant in chemoselective oxidations of alcohols using catalytic TEMPO and was shown to be superior in cases of electron-rich and heteroaromatic benzylic alcohols.
R. A. Miller, R. S. Hoerrner, Org. Lett., 2003, 5, 285-287.

A novel, metal-free oxidation system for the catalytic synthesis of aldehydes and ketones using TEMPO and a quarternary ammonium salt as catalysts and Oxone as oxidant proved especially successful for the synthesis of ketones. The mild conditions tolerate even sensitive silyl protective groups which can otherwise be cleaved in the presence of Oxone.
C. Bolm, A. S. Magnus, J. P. Hildebrand, Org. Lett., 2000, 2, 1173-1175.

C. Bolm, A. S. Magnus, J. P. Hildebrand, Org. Lett., 2000, 2, 1173-1175.

1 mol-% TEMPO and a catalytic amount of 1,3-dibromo-5,5-dimethylhydantoin and NaNO2 is a highly efficient catalytic system for the aerobic oxidations of benzylic alcohols in water.
R. Liu, C. Dong, X. Liang, X. Wang, X. Hu, J. Org. Chem., 2005, 70, 239-244.

Benzylic ethers are oxidatively cleaved by 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate in wet MeCN at room temperature to give the corresponding aromatic aldehydes and alcohols in high yield. Primary and secondary alkyl alcohols are further oxidized to give carboxylic acids and ketones, respectively.
P. P. Pradhan, J. M. Bobbitt, W. F. Bailey, J. Org. Chem., 2009, 74, 9501-9504.

A smooth, organocatalytic one-pot oxidative cleavage of terminal 1,2-diols to one-carbon-unit-shorter carboxylic acids is catalyzed by 1-Me-AZADO in the presence of a catalytica amount of NaOCl and NaClO2 under mild conditions. A broad range of substrates including carbohydrates and N-protected amino diols were converted without epimerization.
M. Shibuya, R. Doi, T. Shibuta, S.-i. Uesugi, Y. Iwabuchi, Org. Lett., 2012, 14, 5006-5009.

A copper(II)-catalyzed intermolecular three-component oxyarylation of allenes using arylboronic acids as a carbon source and TEMPO as an oxygen source proceeded under mild conditions with high regio- and stereoselectivity and functional group tolerance.
T. Itoh, Y. Shimizu, M. Kanai, Org. Lett., 2014, 16, 2736-2739.

Cu/nitroxyl catalysts promote a highly efficient and selective aerobic oxidative lactonization of diols under mild reaction conditions using ambient air as the oxidant. A Cu/ABNO catalyst system shows excellent reactivity with symmetrical diols and hindered unsymmetrical diols, whereas a Cu/TEMPO catalyst system displays excellent chemo- and regioselectivity for the oxidation of less hindered unsymmetrical diols.
X. Xie, S. S. Stahl, J. Am. Chem. Soc., 2015, 137, 3767-3770.

Oxoammonium salts enable a practical and highly efficient oxidative rearrangement of tertiary allylic alcohols to β-substituted α,β-unsaturated carbonyl compounds. Acyclic substrates as well as medium membered ring substrates and macrocyclic substrates can be oxidized.
M. Shibuya, M. Tomizawa, Y. Iwabuchi, J. Org. Chem., 2008, 73, 4750-4752.

Microwave-promoted iminyl radical cyclizations can be terminated by trapping with TEMPO, affording functionalized adducts without using toxic and hazardous reagents. The use of alkynes as radical acceptors delivers a range of 2-acylpyrroles in good yields.
Y. Cai, A. Jalan, A. R. Kubosumi, S. L. Castle, Org. Lett., 2015, 17, 488-491.

An efficient oxidative protocol enables the synthesis of multisubstituted or fused tetracyclic benzimidazoles via a metal-free oxidative C-N coupling between the sp3 C-H and free N-H of readily available N1-benzyl/alkyl-1,2-phenylenediamines in the presence of oxygen and TEMPO.
D. Xue, Y.-Q. Long, J. Org. Chem., 2014, 79, 4727-4734.

CuCl/DABCO/4-HO-TEMPO as the catalysts and oxygen as the terminal oxidant enabled an efficient aerobic oxidative synthesis of 2-substituted quinazolines and 4H-3,1-benzoxazines from the one-pot reaction of aldehydes with 2-aminobenzylamines and 2-aminobenzyl alcohols, respectively.
B. Han, X.-L. Yang, C. Wang, Y.-W. Bai, T.-C. Pan, X. Chen, W. Yu, J. Org. Chem., 2012, 77, 1136-1142.

An efficient copper-catalyzed cascade reaction of (2-aminophenyl)methanols with aldehydes using the combination of cerium nitrate hexahydrate and ammonium chloride leads to a wide range of 2-substituted quinazolines in good yields. The method tolerates a various functional groups and represents a convenient and practical strategy for synthesis of 2-substituted quinazoline derivatives.
Z. Chen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang, H. Wu, J. Org. Chem., 2013, 78, 11342-11348.

A fast and simple reaction of amidines gave benzimidazoles via iodine(III)-promoted oxidative C(sp3)-C(sp2) bond formation in nonpolar solvents, whereas the use of polar solvents favoured a C(sp2)-N bond formation to yield quinazolines. Further selective synthesis of quinazolines in polar solvent was realized using TEMPO as catalyst and K2S2O8 as the oxidant. No metal, base, or other additives were needed.
J.-P. Lin, F.-H. Zhang, Y.-Q. Long, Org. Lett., 2014, 16, 2822-2825.

A one-pot dehydrogenative Povarov/oxidation tandem reaction of N-alkyl anilines with mono- and 1,2-disubstituted aryl and alkyl olefins enables the synthesis of a various substituted quinolines. The simple protocol uses cheap and benign iron(III)chloride as the Lewis acid catalyst and a TEMPO oxoammonium salt as a nontoxic, mild, efficient oxidant.
H. Richter, O. G. Mancheño, Org. Lett., 2011, 13, 6066-6069.

Using TEMPO as the oxidant and KOtBu as the base enables a metal-free, a simple and direct access to a broad range of 2-arylquinolin-4(1H)-ones from readily available N-arylmethyl-2-aminophenylketones via oxidative intramolecular Mannich reaction.
W. Hu, J.-P. Lin, L.-R. Song, Y.-Q. Long, Org. Lett., 2015, 17, 1268-1271.

Cross coupling of ortho-substituted aryl Grignard reagents with alkynyl Grignard reagents can be performed without adding any transition metal in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant. Importantly, functional groups such as esters, amides, and cyanides are tolerated.
M. S. Maji, S. Murarka, A. Studer, Org. Lett., 2010, 12, 3878-3881.

A method for aliphatic C-H bond oxidation of oximes and hydrazones mediated by 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) enables the concise assembly of substituted isoxazole and pyrazole skeletons.
X. Zu, Y.-F. Wang, W. Ren, F.-L. Zhang, S. Chiba, Org. Lett., 2013, 15, 3214-3214.