Lebedev and Kazarnovskii published the first study on the stable, nonconjugated nitroxyl
radical (2,2,6,6-tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl
(TEMPO) (CAS: 2564-83-2) in 1960.[1] It is made by oxidizing 2,2,6,6-tetramethylpiperidine. This solid, red-orange heterocyclic
molecule is sublime. The four methyl groups provide adequate protection for the reactive
radical, and the radical’s stability is due to its delocalization into a two-center,
three-electron N–O bond. It is used in both chemistry and biochemistry as a stable
aminoxyl radical. TEMPO is employed as an electrode in all-organic radical batteries,
as a reagent in organic synthesis, as a radical marker, as a structural probe for
biological systems in conjunction with electron spin resonance spectroscopy, and as
a mediator in controlled radical polymerization.[2] Furthermore, TEMPO is a common antioxidant in academic research.[3] The price of TEMPO makes it suitable for laboratory use. TEMPO has certain limits
in singlet oxygen detection, despite being a useful reagent in organic synthesis,
particularly in medicinal chemistry and total synthesis. The TEMPO-mediated oxidation
process has excellent outcomes, but it has drawbacks for the environment due to the
usage of halogenated chemicals, challenges with recycling (closed-loop operations),
and high costs. The adaptability of TEMPO in organic synthesis and catalysis is highlighted
in this Spotlight article.
Ethiraj and Pavithra sequentially cyclized cyclohexane-1,3-dicarbonyl compounds to
produce a succession of xanthenediones from benzyl alcohols using TEMPO/CuCl2-catalyzed one-pot aerobic oxidation (Table [1], A).[4] Similar methods were used to produce the acridinediones from different benzyl alcohols.
Iminyl radical cyclizations that were driven by microwaves were revealed by Castle
and colleagues. Microwave-promoted iminyl radical cyclizations can be terminated by
trapping with TEMPO, affording functionalized adducts (Table [1], B).[5] The use of alkynes as radical acceptors furnishes 2-acylpyrroles by a process involving
isomerization and fragmentation. To create 2,5-disubstituted 1,3,4-oxadiazole derivatives,
Ding and colleagues found a quick and effective cationic Fe(III)/TEMPO-catalyzed oxidative
cyclization of aroyl hydrazones (Table [1], C).[6] By using the reactions of ketones, aldehydes, or esters with amidines in the presence
of an in situ produced recyclable iron(II) complex, Ji et al. came up with an effective method
for the modular synthesis of several pyrimidine derivatives (Table [1], D).[7] This research resulted in the synthesis of a novel metal-organocatalytic procedure
that involves a series of TEMPO complexation, enamine addition, transient occupancy,
TEMPO elimination, and cyclization to selectively β-functionalize unactivated ketones,
aldehydes, and esters. Han and his team successfully developed an entirely novel,
effective, and simple method for the synthesis of structurally significant pyrimidines
by employing Cu-catalyzed and 4-HO-TEMPO-mediated [3+3] annulation of commercially
available amidines with saturated ketones (Table [1], E).[8] With the use of direct β-C(sp3)–H functionalization of saturated ketones and annulation with amidines, this procedure
introduces a novel approach for the synthesis of pyrimidines.
Table 1 Recent applications of TEMPO
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(A) Synthesis of xanthenediones and acridinediones:[4]
* simple experimental procedure
* ease of access
* short reaction period
* without the use of any hazardous solvents and expensive chemicals
* one-pot aerobic oxidation
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(B) Synthesis of 2-acylpyrroles:[5]
* organotin-free
* no initiator required
* simple and mild conditions
* without the use of any toxic or hazardous reagents such as azo compounds and peroxides
* tolerates the presence of both acid- and base-sensitive functional groups
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(C) Synthesis of 2,5-disubstituted 1,3,4-oxadiazole:[6]
*broad scope
* good functional group tolerance
* high yields under mild conditions in the presence of O2
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(D) Synthesis of pyrimidines:[7]
* recyclable iron catalyst generated in situ
* β-functionalization of saturated carbonyls
* cleavage of 3 C–H and 3 N–H bonds
(E) Synthesis of pyrimidines:[8]
* first example for the construction of pyrimidine scaffolds through unactivated β-C(sp3)–H functionalization of saturated ketones
* radical pathway
* one-pot strategy
* good functional group tolerance
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(F) Synthesis of pyridines:[9]
* cascade C(sp3)–H functionalization
* broad substrate scope
* simple reaction conditions
* excellent regioselectivity
* atom economy
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(G) Synthesis of benzothiazoles:[10]
* transition-metal-free
* photosensitizer-free
* base-free
* compatible with a wide range of functional groups
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(H) Synthesis of isoxazoles:[11a]
* water as solvent and air as oxidant
* transition-metal-free and base-free
* no toxic byproduct and no need of solvent extraction
* diverse substrate scope
* excellent chemo- and regioselectivity
* heterogeneous version and catalyst recyclability
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(I) Synthesis of 2-aryl-4-quinolones:[12]
* transition-metal-free
* direct C(sp3)–H/C(sp3)–H coupling
* broad substrate scope
* simple and mild conditions
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(J) Di- and trifluoromethoxylation:[13]
* The first application of redoxneutral TEMPO• catalysis to achieve intermolecular di- and trifluoromethoxylation of (hetero)arenes
* use of readily available and inexpensive TEMPO• catalyst
* exhibits high functional group tolerance
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(K) Biomimetic aerobic oxidation of alcohols:[14]
* excellent yields
* excellent functional group compatibility
* mild reaction conditions
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(L) α,β-Dehydrogenation:[15]
* base–metal catalysis
* broad scope: aldehyde, ketone, lactone, lactam, amine and alcohols
* simple one-step reaction
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(M) Oxidation from alcohols (also aldehydes) to carboxylic acids:[16]
* O2 or air as terminal oxidant
* scale-up
* at ambient temperature
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(N) Oxidation of 1,2-diols to α-hydroxy acids:[17]
* chemoselective oxidation
* formation of charge-transfer complex
* synthesis of optically active α-hydroxy acids
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(O) Aldehyde to nitrile:[18]
* wide substrate scope
* oxidative conversion of primary alcohol to nitrile was achieved by a one-pot strategy
* aerobic conditions
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(P) Synthesis of N-sulfinyl and N-sulfonylimines:[19]
* high functional group tolerance
* first example of Fe-catalyzed aerobic oxidative one-pot synthesis of N-sulfinyl and N-sulfonylimines directly from alcohols
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(Q) Dual C(sp3)–H oxidation:[20]
* unprecedented tandem catalytic fashion
* use of environmentally friendly reagents
* selective and catalytic C(sp3)–H oxidation
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(R) Oxidative dearomatization:[21]
* metal-free oxidative dearomatization of indoles with aromatic ketones
* broad substrate scope
* excellent functional group tolerance
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(S) Benzylic oxidation:[22]
* metal-free recyclable catalyst system
* selective aerobic oxidation
* mild reaction conditions
* broad substrate scope
* aerobic conditions
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(T) Oxidative lactonization of diols:[23]
* excellent chemo- and regioselectivity for the oxidation of less hindered unsymmetrical
diols
* tolerate diverse functional groups
* ability to perform the reactions at room temperature with ambient air as the oxidant
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(U) Catalytic acceptorless dehydrogenation (CAD):[24]
* TEMPO as the organo-electrocatalyst
* mild and metal-free route via CAD strategy
* broad substrate scope
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(V) Dehydrogenative borylation:[25]
* direct functionalization of both aromatic and aliphatic terminal alkenes
* excellent chemoselectivity, regioselectivity, and stereoselectivity
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Fan and coworkers reported a unique and effective method for synthesizing 3-acylpyridines
and pyridine-3-carboxylates using oxidative one-pot sequential reactions of inactivated
saturated ketones with electron-deficient enamines (Table [1], F).[9]
Lang and colleagues successfully accomplished intramolecular C(sp2)–H thiolation driven by visible light without the need of a photosensitizer, metal
catalyst, or base. Thiobenzanilides undergo cyclization to become benzothiazoles as
a result of this reaction. The substrate absorbs visible light, and when its excited
state interacts with 2,2,6,6-tetramethylpiperidine N-oxyl, a reverse hydrogen-atom transfer (RHAT) occurs, resulting in the formation
of a sulfur radical (Table [1], G).[10] The aryl radical produced by the addition of the sulfur radical to the benzene ring
rearomatizes into benzothiazole via RHAT. The research team of Praveen was able to
successfully synthesize isoxazole/isoxazoline derivatives using the Machetti–De Sarlo
reaction under environmentally friendly circumstances (Table [1], H).[11a] In this process, primary nitroalkanes are cyclocondensed with alkynes or alkenes
using the commonly available catalyst TEMPO to produce a library of isoxazole/isoxazoline
derivatives.
By using homogeneous gold catalysis and 4-MeO-TEMPO as an oxidant, Song et al. established
a quick method for producing 5-oxazole ketones.[11b] Under benign circumstances, the required 5-oxazole ketones were produced in respectable
yields with excellent functional group compatibility. Han and colleagues developed
a brand-new, metal-free, and regioselective method for the synthesis of isoxazoline/cyclic
nitrone featured methylenes by using TEMPO to react with readily available β,γ- and
γ,δ-unsaturated ketoximes via tandem iminoxyl radical promoted cyclization and Cope-like elimination, respectively.[11c] In this approach, the Cope-like elimination was carried out using the commercially
available TEMPO as both the hydrogen acceptor and the iminoxyl radical initiator.
By using readily available N-arylmethyl-2-aminophenylketones as the starting point, Long and coworkers developed
a novel, metal-free oxidative intramolecular Mannich reaction between secondary amines
and unmodified ketones. This reaction uses TEMPO as the oxidant and KOt-Bu as the base to provide a straightforward and direct route to a variety of 2-arylquinolin-4(1H)-ones (Table [1], I).[12] The first TEMPO•-catalyzed, redox-neutral C–H di- and trifluoromethoxylation of (hetero)arenes is
reported by Ngai and his research team (Table [1], J).[13] The oxidation of alcohols to carbonyl compounds with dioxygen was discovered to
be facilitated by a new mixture of FeCl3, l-valine, and TEMPO. The production of aldehydes and ketones from a variety of primary/secondary
benzyl, allylic, and heterocyclic alcohols was accomplished with good to exceptional
isolated yields (Table [1], K).[14]
Kang et al. established an iron-catalyzed α,β-dehydrogenation of carbonyl compounds.
In a straightforward one-step reaction with good yields, a wide range of carbonyls
or analogues, including aldehyde, ketone, lactone, lactam, amine, and alcohol, could
be transformed into their α,β-unsaturated equivalents (Table [1], L).[15] By using a catalytic amount of each of Fe(NO3)3·9H2O/TEMPO/KCl, a series of carboxylic acids were produced from alcohols (also known
as aldehydes) in high yields at room temperature (Table [1], M), demonstrating the effectiveness and applicability of the sustainable oxidation
technology developed by Ma and colleagues.[16] Shibuya and colleagues succeeded in achieving chemoselective catalytic oxidation
of 1,2-diols to α-hydroxy acids in a cat. TEMPO/cat. NaOCl/NaClO2 system. Hydrophobic toluene and water were used to create a two-phase situation,
which reduced the accompanying oxidative cleavage (Table [1], N).[17] For the manufacture of nitrile, the first aldehyde to nitroxyl radical/NOx system
catalyzed aerobic oxidative conversion without the use of transition metals was presented.
By using a one-pot sequential approach, it was also possible to convert a primary
alcohol into an aldehyde via aerobic oxidation (Table [1], O).[18] For the oxidation of alcohols followed by condensation with sulfinamide or sulfonamide
in one pot for the production of N-sulfinyl and N-sulfonylimines compounds under benign circumstances, an effective Fe(III), l-valine, and 4-OH-TEMPO catalytic system was identified (Table [1], P).[19]
A new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)–H oxidation of piperazines and morpholines to 2,3-diketopiperazines (2,3-DKP) and
3-morpholinones (3-MPs), respectively, was developed using inexpensive and safe reagents
like NaClO2, NaOCl, and catalytic amounts of TEMPO (Table [1], Q).[20] Further functionalization at the C-2 position of the morpholine skeleton is possible
by preparing 2-alkoxyamino-3-morpholinone from morpholine derivatives by varying the
quantities of TEMPO. Liu and colleagues (Table [1], R) described a metal-free oxidative dearomatization of indoles with aromatic ketones
through the use of TEMPO oxoammonium salt.[21] In the presence of H2SO4, the dearomatization went without a hitch and demonstrated a broad substrate range
with respect to both indoles and aromatic ketones, producing the matching 2,2-disubstituted
indolin-3-ones in good yields. A completely metal-free catalyst system was created
for the selective aerobic oxidation of structurally varied benzylic C(sp3)–H bonds of ethers and alkylarenes. It consists of a novel, easily manufactured,
recyclable sulfonic salt catalyst formed from TEMPO and mineral acids (NaNO2 and HCl). From easily available alkyl aromatic precursors, the mild reaction conditions
enable the production of physiologically and synthetically valuable isochromanones
and xanthones in good yields (Table [1], S).[22] Cu/nitroxyl catalysts that support mild reaction conditions and extremely efficient
and selective aerobic oxidative lactonization of diols using ambient air as the oxidant
have been found. By altering the nitroxyl cocatalyst’s identity, the chemo- and regioselectivity
of the reaction may be adjusted. While a Cu/TEMPO catalyst system exhibits excellent
chemo- and regioselectivity for the oxidation of less hindered unsymmetrical diols,
a Cu/ABNO catalyst system (ABNO = 9-azabicyclo[3.3.1]-nonan-N-oxyl) exhibits excellent reactivity with symmetrical diols and hindered unsymmetrical
diols (Table [1], T).[23] Using TEMPO as the organo-electrocatalyst, Lei et al. effectively created the first
electrochemical acceptorless dehydrogenation (ECAD) of N-heterocycles. Under an undivided cell system, they were able to catalyze the dehydrogenation
of N-heterocycles in the anode and release H2 from the cathode. In this system, a variety of five- and six-membered nitrogen-heteroarenes
may be synthesized with high yields (Table [1], U).[24] Shen and Lu described an effective method for producing alkenylboronates by copper
catalysis. Starting with cheap and plentiful alkenes and pinacol diboron, the Cu/TEMPO
catalytic system demonstrated high reactivity and selectivity for the production of
alkenylboronates (Table [1], V).[25]
Neutral polysaccharides have been subjected to TEMPO oxidation to produce polyuronides
with enhanced functional characteristics.[26] The redox-active TEMPO fragment is a common element in organic systems due to its
advantages, which include outstanding electrochemical performance and respectable
physical characteristics, which allow it to be employed as an energy source in batteries
or supercapacitors.[27] Lung cancer cells are killed off by the photochemical production of the TEMPO radical
from caged nitroxides by near-infrared two-photon irradiation.[28] In the end, it has been revealed that TEMPO has numerous uses in organic synthesis,
catalysis, material science, and biological applications. In accordance with the most
recent TEMPO research, this reagent’s full synthetic potential has not yet been realized.
