2-Azaadamantane N-oxyl (AZADO) and 1-Me-AZADO: Highly efficient organocatalysts for oxidation of alcohols

Article abstract of DOI:10.1021/ja0620336

Development of a stable nitroxyl radical class of catalysts, 2-azaadamantane N-oxyl (AZADO) and 1-Me-AZADO, for highly efficient oxidation of alcohols is described. AZADO and 1-Me-AZADO exhibit superior catalytic proficiency to TEMPO, converting various sterically hindered alcohols to the corresponding carbonyl compounds in excellent yields. Copyright

Full text of DOI:10.1021/ja0620336

Published on Web 06/14/2006
2-Azaadamantane N-Oxyl (AZADO) and 1-Me-AZADO: Highly Efficient
Organocatalysts for Oxidation of Alcohols
Masatoshi Shibuya, Masaki Tomizawa, Iwao Suzuki, and Yoshiharu Iwabuchi*
Department of Organic Chemistry and Biophysical Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku UniVersity, Aobayama, Sendai 980-8578, Japan
Received March 24, 2006; E-mail: iwabuchi@mail.pharm.tohoku.ac.jp
Table 1. Comparison of Catalytic Efficiencies of TEMPO and
1-Me-AZADO under Anelli’s Conditions
The oxidation of alcohols to their corresponding carbonyl
compounds is a pivotal transformation in organic chemistry.1 The
recent global demand for attenuating environmental stress has
spurred much effort directed toward the development of green
oxidation processes that fulfill the requirements for practical
applications.2 The 2,2,6,6-tetramethyl-1-piperidinyloxy [TEMPO
(1), a nitroxyl radical]-catalyzed oxidation method has attracted
attention in many areas of synthetic organic chemistry because it
enables the use of various safe bulk oxidants, thereby enabling a
safe and extremely efficient oxidation of alcohols with considerable
operational simplicity.3,4
Of the reported nitroxyl radicals, the readily available TEMPO
and its derivative have the highest potential for expanded use. One
distinguishing feature of the TEMPO-based method is its capability
for the selective oxidation of primary alcohols in the presence of
secondary alcohols.5 The rationale behind such a feature is its
reaction mechanism and the catalyst structure it uses, where four
methyl groups flanking the nearby catalytic center play key roles
in preventing bulky substrates from forming the key intermediate
B, which collapses to a carbonyl compound and the hydroxylamine
C3,5 (Scheme 1). Paradoxically, TEMPO is inefficient in the
oxidation of structurally hindered secondary alcohols, posing a
problem in the oxidation of alcohols.
a The run time was 30 min. b The run time was 60 min.
Table 2. Comparison of Catalytic Efficiencies of TEMPO and
1-Me-AZADO under Margarita’s Conditions
Scheme 1
in constructing the azaadamantane skeleton.7 After considerable
experimentations, we developed a 10-step synthesis route for
AZADO8 and a 6-step synthesis route for 1-Me-AZADO (3),8
starting from 1,3-adamantanediol.
In a preliminary experiment, we found that AZADO as well as
1-Me-AZADO exhibited superior catalytic activities to TEMPO;
interestingly, we found that AZADO and 1-Me-AZADO show
similar catalytic efficiencies under the standard oxidation conditions
developed by Anelli et al.4c,d,9 (data not shown). Considering its
synthetic advantage, 1-Me-AZADO was chosen for further inves-
tigations. As shown in Tables 1 and 2, 1-Me-AZADO has high
catalytic efficiencies under low catalytic loading conditions.
Importantly, 1 mol % of 1-Me-AZADO is sufficient for obtaining
a high productivity in the preparation of ketones from a variety of
secondary alcohols, for which TEMPO results in a low pro-
ductivity4a,9,10 (Table 3, entries 1-10).4e,9-13 Note that 1,2:4,5-di-
O-isopropylidene-â-D-fructopyranose is also efficiently oxidized on
a 20 g scale to give Shi’s catalyst in 90% yield.11,12 Unfortunately,
1-Me-AZADO does not efficiently oxidize a substrate containing
amine functionality (entry 11).
We envisaged that the use of a structurally less hindered class
of nitroxyl radicals can solve this problem to expand the scope of
the oxidation of alcohols. We herein disclose the excellent catalytic
activity of the 2-azaadamantane N-oxyl (AZADO) class of nitroxyl
radicals toward a variety of alcohols; this class has a superior
catalytic proficiency to TEMPO.
AZADO (2) was synthesized in 1978 by Dupeyre and Rassat
fueled by their interest in its physical properties as a stable radical.
To the best of our knowledge, however, no study has been
performed to examine its ability as oxidation catalyst.6 We then
started preparing AZADO as described in the literature, but
encountered a problem in terms of reproducibility in a crucial step
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10.1021/ja0620336 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Comparison of Catalytic Efficiencies of TEMPO and
In summary, we have disclosed the excellent catalytic oxidizing
abilities of AZADO and 1-Me-AZADO for the oxidation of
alcohols, which offer complementary use with TEMPO-type
nitroxyl radicals. Information on the structure-activity correlation
of these compounds should inspire new designs of organocatalysts
with increased catalytic efficiencies.
1-Me-AZADO toward Various Secondary Alcoholsa
Acknowledgment. We thank Prof. Emeritus Kunio Ogasawara
of Tohoku University for his encouragement and helpful discussion.
This work was supported by JST, JSPS, and MEXT, Japan.
Supporting Information Available: Experimental procedures,
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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a Method A: reactions were catalyzed by TEMPO or 1-Me-AZADO (1
mol %) with NaOCl (150 mol %), KBr (10 mol %), Bu4NBr (5 mol %),
aq. NaHCO3 in CH2Cl2 at 0 °C for 20 min. Method B: reactions were
catalyzed by TEMPO or 1-Me-AZADO (1 mol%) with 1.1. equiv of
PhI(OAc)2 in CH2Cl2 for 9 h at room temperature. b Isolated yield.
c Reaction was run using 20 g of substrate. d Not determined. e Reaction
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(9) Representative procedure for oxidation of alcohols under Anelli’s
condition.4c To a stirring mixture of 3-phenylpropanol (200 mg, 1.47
mmol), 1-Me-AZADO (3) (0.244 mg, 1.47 µmol) in CH2Cl2 (3.9 mL)
and aqueous sat. NaHCO3 (2 mL) containing KBr (17.5 mg, 0.074 M)
and Bu4NBr (23.7 mg, 0.037 M) was added dropwise a premixed solution
of aqueous NaOCl (8% Cl) and aqueous sat. NaHCO3 (3.3 mL, 1:1.4
v/v) at 0 °C over 6 min. The mixture was vigorously stirred for 20 min
at 0 °C, then quenched with aqueous sat. Na2S2O3 (4 mL). The aqueous
layer was separated and extracted with Et2O. The combined organic layers
were washed with brine, dried over MgSO4, and concentrated. The residue
was purified by flash column chromatography (SiO2, 1:6 Et2O:hexane)
to give 3-phenylpropanal (177 mg, 1.32 mmol, 90%) as colorless oil.
(10) Representative procedure for oxidation of alcohols under Margarita’s
condition.4e PhI(OAc)2 (720 mg, 2.24 mmol) was added to a solution of
cinnamyl alcohol (200 mg, 1.49 mmol) and 1-Me-AZADO (3) (2.47 mg,
14.9 µmol) in CH2Cl2 (1.5 mL). The reaction mixture was stirred for 40
min, it was then diluted with Et2O and quenched with aqueous sat.
NaHCO3 (4 mL), followed by aqueous sat. Na2S2O3 (4 mL). The layer
was separated, and the aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over MgSO4, and
concentrated. The residue was purified by flash column chromatography
(SiO2, 1:9 Et2O:hexane) to give cinnamaldehyde (183 mg, 1.39 mmol,
93%) as colorless oil.
To gain insight into the origin of the remarkable catalytic
efficiency of AZADO-type nitroxyl radicals, we synthesized 1,3-
dimethyl-AZADO (4)8 and examined its catalytic efficiency. 1,3-
Dimethyl-AZADO exhibits an activity for the oxidation of
3-phenylpropanol comparable to those exhibited by AZADO (2)
and 1-Me-AZADO (3). On the other hand, it does not efficiently
oxidize l-menthol similarly to TEMPO (1), showing a remarkable
difference from 1-Me-AZADO and AZADO. Cyclic voltammetric
measurements revealed that 2, 3, and 4 show well-defined redox
waves, of which the forms were unchanged after more than 100
cycle measurements, demonstrating their high durability as oxidation
catalysts.8 The E°′ values of the nitroxyl radicals are in the order
of 4 (136 mV) < 3 (186 mV) < 2 (236 mV) < 1 (294 mV).8
However, the total efficiencies of the nitroxyl radicals as catalyst
are in the order of 1 ∼ 4 , 3 ∼ 2.14 These observations support
the notion that the aggressive catalytic natures of 2 and 3 are due
to kinetic factors derived from decreased steric hindrance around
the reaction center.
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