9-azanoradamantane N-Oxyl (Nor-AZADO): A highly active organocatalyst for alcohol oxidation

Article abstract of DOI:10.1248/cpb.59.1570

A highly active organocatalyst for alcohol oxidation has been developed. 9-Azanoradamantane N-oxyl (Nor-AZADO 4), constituting an unhindered, stable nitroxyl radical, exhibits superior catalytic activity to 2,2,6,6- tetramethylpiperidine-1-oxyl (TEMPO) and AZADOs in the oxidation of alcohols to their corresponding carbonyl compounds.

Full text of DOI:10.1248/cpb.59.1570

1570
Communication to the Editor
Chem. Pharm. Bull. 59(12) 1570—1573 (2011)
Vol. 59, No. 12
priority in the pharmaceutical industry as an efficient, mild,
and environmentally acceptable method. However, TEMPO
is often inefficient in the oxidation of structurally hindered
alcohols, posing a problem in the oxidation of secondary al-
cohols.
9-Azanoradamantane N-Oxyl (Nor-
AZADO): A Highly Active
Organocatalyst for Alcohol Oxidation
Masaki HAYASHI,a,b Yusuke SASANO,a Shota NAGASAWA,a
We have recently reported that a less-hindered class of
nitroxyl radicals, namely, 2-azaadamantane N-oxyls [AZA-
DOs; AZADO (2a) and 1-Me-AZADO (2b)] and 9-azabicy-
clo[3.3.1]nonane N-oxyl [ABNO (3)], exhibit significantly
enhanced reactivity compared with TEMPO.20—26) They ex-
hibit extremely high activities toward a wide range of alco-
hols, including structurally hindered secondary alcohols that
a
,a
*
Masatoshi SHIBUYA, and Yoshiharu IWABUCHI
a Department of Organic Chemistry, Graduate School of
Pharmaceutical Sciences, Tohoku University; 6–3 Aobayama,
Sendai 980–8578, Japan: and b Process Technology Research
Laboratories, Daiichi Sankyo Co., Ltd.; 1–12–1 Shinomiya,
Hiratsuka, Kanagawa 254–0014, Japan.
Received August 15, 2011; accepted September 9, 2011; published TEMPO fails to efficiently oxidize.20,21) A structure–activity
online September 12, 2011
comparison indicated that the steric congestion near the ac-
tive center exerts a critical impact on catalytic efficiency.20)
In our continuous interest in nitroxyl-radical-based oxida-
tion, we envisaged that the catalytic activity of nitroxyl radi-
cals can further be enhanced by reducing the steric factors
around their active center. We herein report the advanced cat-
alytic activity of 9-azanoradamantane N-oxyl [Nor-AZADO
(4); Fig. 1]. This new catalyst exhibits superior catalytic effi-
ciency to AZADO, 1-Me-AZADO and ABNO as well as to
TEMPO.
A highly active organocatalyst for alcohol oxidation has been
developed. 9-Azanoradamantane N-oxyl (Nor-AZADO 4), con-
stituting an unhindered, stable nitroxyl radical, exhibits supe-
rior catalytic activity to 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) and AZADOs in the oxidation of alcohols to their
corresponding carbonyl compounds.
Key words organocatalyst; nitroxyl radical; alcohol oxidation; aerobic
oxidation; 2-azaadamantane N-oxyl AZADO
Nor-AZADO (4) was firstly synthesized in 1978 by
The oxidation of alcohols to their corresponding carbonyl Dupeyre and Rassat and reported to be a stable class of ni-
compounds is one of the most fundamental transformations troxyl radicals.27) To the best of our knowledge, however, no
in both laboratory synthesis and industrial manufacturing, study of Nor-AZADO has been reported since then. We were
and numerous methods of such oxidation have been devel- particularly interested in determining whether Nor-AZADO,
oped.1,2) In recent years, a stable class of nitroxyl radicals, as which is a constraint variant of AZADO, produces the
exemplified by TEMPO [2,2,6,6-tetramethyl piperidinyl 1- oxoammonium ions, which are useful for alcohol oxidation.
oxyl (1); Fig. 1], has been extensively used as a catalyst for
Nor-AZADO was prepared in five steps from acetonedi-
the oxidation of alcohols in a wide range of chemistry.3—19) carboxylic acid (5), glutaraldehyde, and benzylamine, by a
In particular, TEMPO-catalyzed alcohol oxidation has high previous method (Chart 1) with slight modification.27,28)
Fig. 1. Design Concept of Nor-AZADO
Chart 1. Preparation of Nor-AZADO
∗ To whom correspondence should be addressed. e-mail: y-iwabuchi@m.tohoku.ac.jp
© 2011 Pharmaceutical Society of Japan

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Table 1. Comparison of Catalytic Activities toward Secondary Alcohols under Anelli’s Condition
Yield
Loading amount
Entrya)
Substrates
(mol%)
TEMPO
ABNO
1-Me-AZADO
AZADO
Nor-AZADO
1
2
3
4
1
97%
28%
n.d.a)
n.d.a)
100%
94%
91%
24%
99%
97%
76%
67%
99%
99%
96%
74%
99%
99%
96%
92%
0.01
0.005
0.003
5
6
7
8
1
5%
n.d.a)
n.d.a)
n.d.a)
94%
95%
92%
8%
95%
61%
41%
25%
99%
98%
96%
87%
99%
98%
96%
92%
0.01
0.005
0.003
a) Not determined.
Table 2. Comparison of Catalytic Activities toward Primary Alcohols under Anelli’s Condition
Yield
Loading amount
Entrya)
(mol%)
TEMPO
ABNO
1-Me-AZADO
AZADO
Nor-AZADO
1
2
3
1
89%
19%
n.d.a)
91%
83%
59%
91%
89%
79%
91%
88%
82%
92%
89%
82%
0.01
0.003
a) Not determined.
The catalytic activity of Nor-AZADO was compared with test substrates, and their reactions were carried out with
those of TEMPO, AZADO, 1-Me-AZADO, and ABNO 1 mol% catalyst load (Table 3). It was confirmed that Nor-
under Anelli's condition using NaOCl as the bulk oxi- AZADO exhibited superior catalytic efficiency to AZADO
dant12,13) (Tables 1, 2). The catalytic activities toward second- and 1-Me-AZADO particularly in terms of reaction rate. In
ary alcohols are shown in Table 1. Although almost the same all the cases, the reaction completed within several hours
results were obtained for the oxidation of 4-phenyl-butan-2- with Nor-AZADO, of which efficiency is comparable to that
ol (10) when a 1 mol% catalyst load was used, apparent dif- of 5-F-AZADO which exhibit the highest activity for aerobic
ferences in catalytic efficiency were observed, when catalyst oxidation in AZADO derivatives.29) In fact, TEMPO failed to
load was decreased. Nor-AZADO maintained its perfor- serve as an efficient catalyst in all the cases. Although the
mance even with a 0.003 mol% catalyst load, whereas other structural difference between Nor-AZADO and AZADO is
nitroxyl radicals including AZADO showed a decline in per- only one methylene group in their skeletons, they exhibit dif-
formance (Table 1, entry 4). A similar result was obtained in ferent catalytic activities evidently.
the oxidation of L-menthol (11). A 0.003 mol% catalyst load
The substrate applicability of Nor-AZADO-catalyzed aer-
was sufficient to complete the reaction with Nor-AZADO obic oxidation is shown in Table 4. Various alcohols were ox-
(Table 1, entry 8). Note that TEMPO failed to oxidize L-men- idized to their corresponding carbonyl compounds efficiently
thol (11) even with a 1 mol% catalyst load (Table 1, entry 5).
with a 1 mol% catalyst load. The reaction proceeded under
Nor-AZADO also exhibited efficient catalytic activity in air atmosphere, and no significant effect on the catalytic per-
the oxidation of primary alcohol (12) compared with formance was observed with the use of different reaction at-
TEMPO, although AZADO and 1-Me-AZADO also worked mospheres, i.e., O2 and air (data not shown). Aliphatic and
well in this case (Table 2).
benzylic secondary alcohols, including a sugar derivative
We next examined the aerobic oxidation conditions6—8,14—19) (entry 6), a N-protected amine (entry 8), a nucleoside deriva-
using the nitroxyl radical/NaNO2/Air/AcOH system,29) which tive (entry 9) and a pyridine derivative (entry 10), were effec-
we have recently reported as versatile transition-metal-free tively oxidized. An acid-labile isopropylidene protecting
and halogen-free conditions.
group remained in this reaction (entry 6).
The secondary alcohols 10, 11 and 14 were selected as the
The primary alcohols 12 and 23 were also oxidized to their

1572
Vol. 59, No. 12
Table 3. Comparison of Catalytic Activities under Aerobic Oxidation
Conversion (time)a)
AZADO
Entry
1
Substrates
TEMPO
1-Me-AZADO
5-F-AZADO
Nor-AZADO
10%
(24 h)
79%
(24 h)
97%
(9 h)
100%
(5 h)
100%
(5 h)
0%
(24 h)
46%
(24 h)
92%
(9.5 h)
100%
(6 h)
100%
(9.5 h)
2
3
1%
(24 h)
99%
(24 h)
100%
(6 h)
100%
(7 h)
100%
(5 h)
a) Conversion was determined by GC.
Table 4. Scope of Nor-AZADO Catalyzed Aerobic Oxidation
Entry
Substrates
Methodsa) Yield (time)
Entry
10
Substrates
Methodsa)
A
Yield (time)
98%
A
1
(4 h)
11
12
A
A
96%
A
2
3
4
(6 h)
95%
A
(7 h)
87%
A
(12 h)
13
A
99%
A
5
6
(4 h)
90%
A
(5 h)
92%
B
7
8
14
A
(22 h)
73%
B
(24 h)
15b)
16c)
A
B
80%
(6 h)
9
B
a) Method A: Reactions were carried out with Nor-AZADO (1 mol%), NaNO2 (20 mol%), and AcOH (2 eq) in MeCN (1 M) under air atmosphere (balloon) at room tempera-
ture. Method B: Reactions were carried out with Nor-AZADO (1 mol%), and NaNO2 (20 mol%) in AcOH (0.3 M), under air atmosphere (balloon) at room temperature. b)
5 mol% Nor-AZADO was used. c) 10 mol% Nor-AZADO was used.

December 2011
1573
corresponding aldehyde 13 and 24 in high yield (entries 11, (8 : 1 v/v)] to afford 2-adamantanone (91.8 mg, 0.611 mmol,
12), although the oxidation of p-nitrobenzyl alcohol (25) to 92%) as a colorless solid.
p-nitrobenzylaldehyde (26) resulted in moderate yield be-
Acknowledgments This work was partly supported by a Grant-in-Aid
for Scientific Research (B) (No. 17390002) from the Japan Society for the
Promotion of Science (JSPS) and a Grant-in-Aid for the Research Fellow-
cause of the overoxidation of (26) to the carboxylic acid (27)
(entry 13). Note that the hydrobenzoin (28), which is prone
to form benzaldehyde because of its easy carbon–carbon
bond cleavage in some other oxidation systems,30) was oxi-
dized to benzil (29) in quantitative yield without oxidative
cleavage (entry 14). This system is also effective for the 3-
quinuclidinol (32), which contains an amine functionality, al-
though a 10 mol% catalyst load is needed (entry 16).
In summary, we have disclosed the excellent catalytic oxi-
dizing abilities of Nor-AZADO for alcohol oxidation. It is
interesting to note that a slight difference in structure be-
tween Nor-AZADO and AZADO affects their catalytic abili-
ties. Nor-AZADO can serve as an environmentally benign
catalyst for the oxidation of wide range of alcohols owing to
its superior catalytic activity and ready availability.
ship for Young Scientists (B) (No. 19790005) from the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT) of Japan.
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