Practical preparation methods for highly active azaadamantane-nitroxyl- radical-type oxidation catalysts

Article abstract of DOI:10.1055/s-0030-1260257

We have recently disclosed that a less hindered class of nitroxyl radicals, i.e., 2-azaadamantan-N-oxyl (AZADO), 1-Me-AZADO, and 9-azabicyclo[3.3.1]nonan- N-oxyl (ABNO), exhibit marked catalytic activity for the oxidation of alcohols with the aid of environmentally friendly oxidants, offering a green and sustainable option for current alcohol oxidation. Encouraged by their outstanding catalytic performance, we envisioned the development of scalable routes to these radicals that could be extended to the commercialization of these radicals for benchtop use as well as for industrial use as optional reagents that complement TEMPO, the flagship compound of stable nitroxyl radicals. We herein describe short and reproducible preparation methods for AZADO and 1-Me-AZADO, featuring an efficient construction of the 2-azaadamantane skeleton. 1 Introduction 2 1-Me-AZADO and AZADO: First-Generation Syntheses 3 Second-Generation Synthesis of 1-Me-AZADO 4 Synthetic Venture towards 2-Azaadamantane: Second-Generation Synthesis of AZADO 5 Conclusion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260257

3418
FEATURE ARTICLE
Practical Preparation Methods for Highly Active Azaadamantane-Nitroxyl-
Radical-Type Oxidation Catalysts
HighlyActive
A
zaada
m
a
antane-N
i
s
troxyl-Ra
d
a
ical-Type
t
O
xidat
o
ion Catalystsshi Shibuya,a Yusuke Sasano,a Masaki Tomizawa,a Toshimasa Hamada,b Masami Kozawa,c
Noriaki Nagahama,c Yoshiharu Iwabuchi*a
a
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan
Fax +81(22)7956845; E-mail: iwabuchi@mail.pharm.tohoku.ac.jp
Performance Materials Division, Planning & Development Dept., Nissan Chemical Industries, Ltd., 3-7-1 Kanda-Nishiki-cho,
b
Chiyoda-ku, Tokyo 101-0054, Japan
Synthesis Research Dept., Nissan Chemical Industries, Ltd., 2-10-1 Tsuboi-nishi, Funabashi, Chiba 274-8507, Japan
c
Received 3 August 2011; revised 16 September 2011
other distinguishing feature of the TEMPO-based method
Abstract: We have recently disclosed that a less hindered class of
is its capability for the selective oxidation of primary al-
nitroxyl radicals, i.e., 2-azaadamantan-N-oxyl (AZADO), 1-Me-
AZADO, and 9-azabicyclo[3.3.1]nonan-N-oxyl (ABNO), exhibit
marked catalytic activity for the oxidation of alcohols with the aid
cohols in the presence of secondary alcohols.8 The ratio-
nale behind such a feature is its reaction mechanism and
of environmentally friendly oxidants, offering a green and sustain- its structure, in which four methyl groups flanking the
able option for current alcohol oxidation. Encouraged by their out-
standing catalytic performance, we envisioned the development of
scalable routes to these radicals that could be extended to the com-
collapses to a carbonyl compound and the hydroxylamine
mercialization of these radicals for benchtop use as well as for in-
dustrial use as optional reagents that complement TEMPO, the
nearby catalytic center play key roles in preventing bulky
substrates from forming the key intermediate B, which
C (Scheme 1). As a result, TEMPO (1) is inefficient in the
oxidation of structurally hindered secondary alcohols,
posing a problem in the oxidation of alcohols. Such fea-
tures of the TEMPO oxidation led us to envision that the
use of a structurally less hindered nitroxyl radical can
solve this problem and expand the scope of the oxidation
of alcohols.
flagship compound of stable nitroxyl radicals. We herein describe
short and reproducible preparation methods for AZADO and 1-Me-
AZADO, featuring an efficient construction of the 2-azaadaman-
tane skeleton.
1
2
3
4
Introduction
1-Me-AZADO and AZADO: First-Generation Syntheses
Second-Generation Synthesis of 1-Me-AZADO
Synthetic Venture towards 2-Azaadamantane: Second-
Generation Synthesis of AZADO
[O]
R1
X
HO
O
R2
N
O
5
Conclusion
H
oxoammonium salt A
Key words: alcohol oxidation, organocatalyst, nitroxyl radical,
adamantane, hydroamination
R1
R2
O
N
O
N
R1
O
H
TEMPO (1)
R2
B
N
OH
1
Introduction
hydroxylamine C
Scheme 1 Plausible mechanism of TEMPO oxidation
The oxidation of alcohols to their corresponding carbonyl
compounds is a fundamental transformation in organic
chemistry.1 In recent years, oxidation catalyzed by
2,2,6,6-tetramethylpiperidyl-1-oxyl [TEMPO (1), a ni-
troxyl radical]2 has attracted increased attention in many
areas of synthetic organic chemistry for several reasons:
TEMPO (1) is readily available from chemical suppliers
at a reasonable price, and the method allows the use of
various safe bulk oxidants, thereby enabling a safe and ex-
tremely efficient oxidation of alcohols with considerable
operational simplicity.3–6 Catalytic oxidation using
TEMPO (1) and sodium hypochorite consolidated its po-
sition in industrial synthesis due to its safety, eco-friend-
liness, economy, and ease of handling, and this has
accelerated its advancement in research activities.7 An-
A literature survey provided an overview, showing that
chemical studies of less hindered nitroxyl radicals
emerged in the mid-1970s when the major scientific con-
cern was their inherent physical properties as unusually
stable radicals (Figure 1).9–11 Our chemical intuition, as-
sociated with aesthetic interest, promptly centered on
AZADO (4) as the subject of our research. AZADO (4)
was first synthesized in 1975 by Dupeyre and Rassat, but
since then no study has yet been performed to examine its
capability as an oxidation catalyst.11 Thus, it was apparent
that considerable challenges remain to explore and exploit
the catalytic use of AZADO (4) in alcohol oxidation. We,
therefore, started the preparation of AZADO (4) by trac-
ing the described procedures (cf. Scheme 6) to examine
whether 4 gives sufficient oxoammonium ions 4+ to medi-
ate alcohol oxidation.12 To our disappointment, we en-
countered several problems in reproducing the key
SYNTHESIS 2011, No. 21, pp 3418–3425
x
x.
x
x
.
2
0
1
1
Advanced online publication: 07.10.2011
DOI: 10.1055/s-0030-1260257; Art ID: F76611SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Highly Active Azaadamantane-Nitroxyl-Radical-Type Oxidation Catalysts
3419
Dr Masatoshi Shibuya was Ogasawara and his Ph.D. in K. C. Nicolaou’s group.
born in Nagano, Japan, in degree in 2009 under the su- His current research interest
1978. He studied at the De- pervision of Prof. Yoshiharu is the development of selec-
partment of Pharmaceutical Iwabuchi. He is a Research tive oxidation using organo-
Sciences, Tohoku Universi- Instructor and Assistant catalysis as
ty, where he obtained his Professor at Tohoku Uni- methodology.
B.S. degree in 2003 in the versity; he has spent one
a synthetic
laboratory of Prof. Kunio year as a research associate
Yusuke Sasano was born in degree in 2010 under the su- Sciences (DC1), working on
Sagamihara, Japan, in 1986. pervision of Prof. Yoshiharu the development of highly
He studied at the Depart- Iwabuchi. He is currently a efficient aerobic alcohol ox-
ment of Pharmaceutical Sci- Ph.D. candidate in the idation methods using ni-
ences, Tohoku University, Iwabuchi group, and a re- troxyl radical catalysts.
where he obtained his B.S. search fellow of the Japan
degree in 2008 and his M.S. Society for the Promotion of
Dr Masaki Tomizawa was 2009. He was a research fel- catalytic alcohol oxidation
born in 1982 in Japan. He low of the Japan Society for methodology and total syn-
studied at Tohoku Universi- the Promotion of Sciences thesis of natural products.
ty and received his Ph.D. in (DC2) in 2007–2009. His
Pharmaceutical Sciences in research interests are the
Toshimasa Hamada was joined Nissan Chemical In- Tokyo, Japan. His current
born in Hiroshima, Japan, in dustries, Ltd. as a research responsibilities
include
1969. He received his chemist in the Central Re- planning and development
M.Eng. in applied chemistry search Institute. In 2000, he of organic functional mate-
from Kinki University in moved to Nissan Chemi- rials.
1993. In the same year, he cal’s Head Quarters in
Masami Kozawa was born master’s degree in the labo- Development Project in
in Aichi, Japan, in 1970. He ratory of Prof. Kohei Tamao 1998–1999. He has worked
studied at the Department of in 1995. After finishing, he in the field of process chem-
Energy and Hydrocarbon entered Nissan Chemical In- istry.
Chemistry, Kyoto Universi- dustries, Ltd. He joined the
ty, where he obtained his Noyori Molecular Catalyst
Noriaki Nagahama was Tokyo in 2002. In the same Chemical Research Labora-
born in Tokyo, Japan, in year, he joined Nissan tories.
1977. He received his M.S. Chemical Industries, Ltd. as
from the University of a process chemist in the
Dr Yoshiharu Iwabuchi Kunio Ogasawara in 1991. group at Nagasaki Universi-
was born in Yamagata, After a year of postdoctoral ty. In 2002 he returned to
Japan, in 1963. He studied work with Prof. K. C. Tohoku University as a Full
at the Department of Phar- Nicolaou in The Scripps Professor. His research in-
maceutical Sciences, Tohoku Research Institute, he joined terests include the develop-
University, where he ob- the group of Dr Ikuo Fujii at ment of organocatalysts,
tained his B.S. in 1986, and the Protein Research Insti- asymmetric synthesis, and
his Ph.D. in the laboratory tute. In 1997 he was ap- natural product synthesis.
of Prof. Seiichi Takano un- pointed Associate Professor
der the guidance of Dr in Prof. Susumi Hatakeyama’s
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York

3420
M. Shibuya et al.
FEATURE ARTICLE
transformation. The reliable production of the azaada- mantane (16), and (iii) oxidation of 16 under conventional
mantane 9 was hampered by two problems, firstly, an in- conditions (cat. Na2WO4, 30% H2O2).15
tractable physical property of the diketone 6, which is an
OH
equilibrium mixture with the highly polar hydrate form 7,
O
NOH
TsCl
NH2OH
⋅H2O
and secondly, complicated procedures for the sodium cy-
anoborohydride mediated reduction of the in situ generat-
ed half-imine 8. We always obtained the oxa-adamantane
10 as the major product with a trace amount of 9
(Scheme 2). As such, we identified problems in the con-
struction of the 2-azaadamantane skeleton and started
synthetic studies of 2-azaadamantanes.
py/PhH
75 °C
(81%)
py
OH
(100%)
11
12
13
15
NH
NH2
I2
NaBH4, MoO3
MeOH, 0 °C
MeCN
(48% for 2 steps)
I
14
16
O
N
NH
H2O2, Na2WO4
LiAlH4
N
N
N
N
O
O
O
O
H2O, MeCN
(42%)
THF, reflux
(92%)
nortropane-N-oxyl (2)
(K. U. Ingold, 1971)
ABNO (3)
(K. U. Ingold, 1973)
AZADO (4)
(A. Rassat, 1975)
nor-AZADO (5)
(A. Rassat, 1975)
17
Figure 1 Panel of less-hindered nitroxyl radicals
Scheme 3 First-generation synthesis of 1-Me-AZADO
AcONH4
O
O
O
Encouraged by finding the useful oximation and
Ipaktschi’s reduction sequence for the reductive amina-
tion of bulky ketones, we returned to our first goal of syn-
thesizing AZADO with a slight modification to the
original route (Scheme 4). Prior to conducting the reduc-
tive amination, partial protection was achieved by treating
the diketone 6 with ethylene glycol in boiling toluene in
the presence of 4-toluenesulfonic acid to give selectively
the monoketone 18 in 94% yield.
NaBH3CN
O
O
OH
12 M HCl, MeOH
8 d
10
60%
6
6
+
H2O
O
NH3
NH
OH
NH
O
OH
9
OH
trace
( 37%:
Henkel's
report )
7
8
OH
1) TsCl, py/PhH
75 °C (81%)
O
O
O
(HOCH2)2, TsOH
O
Scheme 2 Reduction of diketone 6
PhMe, reflux
(94%)
O
2) OsO4, NaIO4,
THF–H2O (54%)
OH
11
6
18
2
1-Me-AZADO and AZADO: First-Genera-
tion Syntheses
NaBH4, MoO3
MeOH, 0 °C;
NHCbz
O
NOH
O
5% HCl
NH2OH
py
⋅
H2O
MeOH
(100%)
O
CbzCl, Et3N
(75%)
One compromise was made to avoid the difficulty in using
the diketone 6: we considered synthesizing 1-Me-AZADO
(17), which should be the second best catalyst having the
advantage of the ‘one-methyl’ downsize effect over
TEMPO (1). 1-Me-AZADO (17) could be synthesized
from the ketone 12 via reductive amination and subse-
quent halo-amination (Scheme 3). Once again, the reduc-
tive amination of the ketone 1213 to give the amine 14
turned out to be a formidable task, in which most conven-
tional reductive amination procedures via various imines,
oximes, or oxime ethers failed to give 14, presumably ow-
ing to the repulsion between the pyramidalizing C–N moi-
ety and p-electrons of the exomethylene moiety. After
considerable experimentation, we finally learned that
Ipaktschi’s conditions14 provided the desired results; the
treatment of the oxime 13 with sodium borohydride in the
presence of a stoichiometric amount of molybdenum(VI)
oxide in methanol at 0 °C gave 14. The first-generation
synthesis of 1-Me-AZADO (17) was achieved through the
three-step sequence consisting of (i) iodine-mediated ring
closure to 15, (ii) subsequent lithium aluminum hydride
mediated excision of iodine to give 1-methyl-2-azaada-
O
(100%)
19
20
1) H2, Pd/C
MeOH
O
UHP, Na2WO4
NCbz
NH
N
OH
MeOH
2) SOCl2
reflux
(60% for 4 steps)
3) LAH
21
22
4
DME, reflux
Scheme 4 First-generation synthesis of AZADO
Upon exposure to hydrochloric acid, 20 gave N-Cbz-1-hy-
droxy-2-azaadamantane 21. Subsequent deprotection of
the Cbz group afforded the known 1-hydroxy-2-azaada-
mantane (9), from which 2-azaadamantane (22) was pre-
pared in a straightforward manner, as described by Henkel
et al.12a,15 In the final oxidation of 2-azaadamantane (22)
to AZADO (4), the combination of urea hydrogen perox-
ide (UHP) and sodium tungstate gave a slightly better re-
sult than that of hydrogen peroxide and sodium tungstate.
With AZADO (4) and 1-Me-AZADO (17) in hand, we
carried out a comparative evaluation of their catalytic ac-
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Active Azaadamantane-Nitroxyl-Radical-Type Oxidation Catalysts
3421
tivity with that of TEMPO (1) under typical alcohol oxi-
dation conditions.15,16 It was found that AZADO (4) as
well as 1-Me-AZADO (17) exhibited superior catalytic
activities to TEMPO (1); interestingly, 4 and 17 showed
catalytic efficiency under the standard oxidation condi-
tions developed by Anelli et al.3,15 As shown in Tables 1
and 2, both AZADO (4) and 1-Me-AZADO (17) exhibit
surprisingly high catalytic efficiency for the oxidation of
various secondary alcohols with which TEMPO (1) suf-
fers from poor reactivity. Having confirmed their excel-
lent catalytic activity in alcohol oxidation, we sought to
expand their use as standard reagents in chemical labora-
tories. As a first step to this end, we next improved the ef-
ficiency of the synthesis of AZADO (4) and 1-Me-
AZADO (17) so that they could be produced in multigram
quantities.
Table 2 Scope of AZADO-Catalyzed Oxidation
catalyst (1 mol%)
NaOCl (150 mol%), KBr (10 mol%)
O
OH
Bu4NBr (5 mol%)
R1
R2
R1
R2
CH2Cl2, aq NaHCO3, 0 °C, 20 min
Entry Substrate
Yield (%)
TEMPO
1-Me-AZADO AZADO
OH
1
2
83
94
98
0
16
5
94
99
95
93
99
94
OH
OH
3
4
Ph
Table 1 Catalytic Efficiency under Anelli et al.’s Conditions
OH
catalyst
NaOCl (130 mol%), KBr (10 mol%)
Bu4NBr (5 mol%)
Ph
Ph
OH
O
CH2Cl2, aq NaHCO3, 0 °C
OH
5
6
13
15
95
93
91
92
Loading amount Time (min) Yield (%)
(mol%)
Ph
OH
TEMPO 1-Me-AZADO AZADO
0.1
20
30
30
60
88
95
91
81
62
90
89
83
51
O
O
O
0.01
0.003
0.001
23
O
7
8
99
97
n.d.
n.d.
O
OH
OH
NOH
NaBH4, MoO3
NHCbz
1) TsCl, py, 70 °C
MeOH, 0 °C;
3
Second-Generation Synthesis of
1-Me-AZADO
OH
2) NH2OH
⋅
HCl
CbzCl, Et3N
(61%)
(86 %, 2 steps)
11
13
23
Concerned with improving the preparation of 1-Me-AZADO
(17), we considered following two points. One is avoiding
the isolation of the polar amine 14, which requires tedious
handling. The other is the development of transannular
hydroamination instead of iodoamination for ring closure,
which could eliminate extraneous redox sequences.
1) H2, Pd/C
MeOH
O
NCbz
N
2 M aq HCl
2) UHP, Na2WO4
MeCN
(82%, 2 steps)
MeOH, 40 °C
(100%)
24
17
Scheme 5 Second-generation route to 1-Me-AZADO (17)
We commenced with the examination of the in situ pro-
tection of the amine 14 (Scheme 5). Benzyl chloroformate
was directly added to the resulting reaction mixture after
the reduction of the oxime 13 under Ipaktschi’s condi-
tions.14 The protection smoothly proceeded, and Cbz car-
bamate 23 was isolated without difficulty in good yield.
Although the projected transannular hydroamination was
unprecedented, we think that it is possible owing to the fa-
vorable position of nitrogen atoms and exomethylene and
the precedent cyclization of alkenol to form oxaadaman-
tane employing hydroetherification.17 This cyclization
was easily affected by treating 23 with 2 M hydrochloric
acid at 40 °C. In the final oxidation, urea hydrogen perox-
ide instead of hydrogen peroxide gave a better result. In
this way, an improved preparation method has been devel-
oped.
4
Synthetic Venture towards 2-Azaadaman-
tane: Second-Generation Synthesis of
AZADO
Before embarking on the synthetic venture to AZADO
(4), we reviewed reported preparation routes to the 2-
azaadamantane nucleus (Scheme 6).12,18,19 2-Azaadaman-
tane (22) and its derivatives have attracted the attention of
many organic chemists as hetero analogues of adaman-
tane for the investigation of not only their fundamental
chemical properties, but also their potential pharmaco-
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York

3422
M. Shibuya et al.
FEATURE ARTICLE
W. H. Staas (1974)
O
HO
NBz
CO2H
NHBz
NaN3
MCPBA
MsOH
(74%)
CH2Cl2
(82.5 %)
5 steps
26
27
25
28
J. G. Henkel (1981)
Br
OH
O
AcONH4
NaBH3CN
NH
NH
NH
O
MeOH, 8 d
(37%)
Br
2 steps
2 steps
29
6
9
22
T. Sasaki (1982)
OH
H2SO4
(58%)
N3
NOH
30
J. G. Henkel (1990)
31
9
O
R
N
O
MCPBA
HO
RNH2, NaBH3CN
AcOH, MeOH, r.t.
O
O
CH2Cl2
(84%)
25
32
33
34
Scheme 6 Previous reports on 2-azaadamantane and its derivatives
phoric actions.20 Representative routes to 2-azaadaman- produce the N-Cbz carbamate 35. Note that using 26 as a
tanes are shown in Scheme 6.
0.13 M solution in toluene with two equivalents of DPPA
afforded the undesired acyl azide 37 as the sole detectable
product, which indicated the reaction of the generated iso-
cyanate and the azide anion derived from excessive
DPPA. The conditions using the 1 M solution of 26 in tol-
uene was essential for reaching completion of the azida-
tion. (Scheme 9). The next step was crucial intramolecular
hydroamination. Although the hydroamination of 35 did
not proceed to 22 using 2 M hydrochloric acid, similar to
conversion of 23 into 24 in the synthesis of 1-Me-
AZADO (17),15 it was found that anhydrous conditions
using four equivalents of triflic acid achieved the key in-
tramolecular hydroamination, accompanied by the con-
comitant deprotection of the Cbz group. These results are
consistent with the stability of the intermediate carboca-
tion; a secondary carbocation generated from the 1,2-dis-
ubstituted olefin of 35 is less stable than the tertiary
carbocation generated from the 1,1-disubstituted olefin.
Subsequent oxidation of 2-azaadamantane (22) with sodi-
um tungstate and urea hydrogen peroxide afforded
AZADO (4) in 50% yield.
We envisaged that improvements in synthetic routes to
azaadamantane derivatives reported by Staas could lead to
the development of a short-step route (Scheme 7).18
A
possible one-pot Curtius rearrangement employing
Shioiri’s procedure would shorten the five-step transfor-
mation from the bicyclic carboxylic acid 26 to the N-pro-
tected bicyclic amine 35.21 Considering the successful
cyclization of 23 via a tertiary carbocation, we hoped to
realize the desirable transannular hydroamination of the
N-protected bicyclic amine 35, which proceeds through a
less-favored secondary carbocation. To facilitate the re-
moval of the protecting group, we decided to utilize Cbz
protection (35) instead of benzoyl (Bz) protection (27).12a
O
Curtius
rearrangement
Sasaki and Staas'
method
CO2H
NHCbz
25
26
35
O
N
intramolecular
hydroamination
NCbz
1. deprotection
2. oxidation
O
DPPA (1.01 equiv), Et3N
PhMe (1 M);
NHCbz
CO2H
36
4
NaN3, MsOH;
aq KOH
(68%)
BnOH
reflux (87%)
Scheme 7 Plan for improved route to AZADO (4)
25
26
35
According to Sasaki and Staas’ procedure,18 the carboxy-
lic acid 26 was prepared from commercially available
adamantan-2-one (25) in good yield (Scheme 8).22 The
subsequent Curtius rearrangement was successively pro-
moted with 26 in a 1 M toluene solution using 1.01 equiv-
alents of diphenyl phosphoryl azide (DPPA) upon heating
to reflux, with subsequent addition of benzyl alcohol to
O
N
NH
UHP, Na2WO4
TfOH (4 equiv)
MeOH
(50%)
CH2Cl2, 0 °C
(79%)
22
4
Scheme 8 Second-generation route to AZADO (4)
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Active Azaadamantane-Nitroxyl-Radical-Type Oxidation Catalysts
3423
COOH
column chromatography (EtOAc–hexane, 1:4) to afford 13 (17.7 g,
NHCbz
DPPA, Et3N, PhMe, r.t.;
NHCON3
107 mmol, 86%) as a colorless solid.
IR (CHCl3): 3590 cm–1.
BnOH, heat
26
35
37
1H NMR (400 MHz, CDCl3): d = 4.73 (s, 2 H), 3.17 (d, J = 15.8 Hz,
1 H), 2.43–2.23 (m, 8 H), 1.96 (dd, J = 16.1, 5.4 Hz, 1 H), 1.76 (s,
2 H).
13C NMR (100 MHz, CDCl3): d = 158.4, 143.0, 111.6, 41.6, 40.6,
37.4, 33.2, 30.3, 29.7, 28.6.
2 equiv DPPA, PhMe (0.13 M):
0
79
trace
1.01 equiv DPPA, PhMe (1 M): 87
Scheme 9 Optimization of Curtius rearrangement conditions
MS: m/z = 165 [M]+, 93 (100%).
HRMS (EI): m/z [M]+ calcd for C10H15NO: 165.1154; found:
5
Conclusion
165.1149.
Prompted by the exceptionally high catalytic perfor-
mance, we have developed practical preparation methods
for azaadamantane-type-nitroxyl radicals. In these stud-
ies, it became clear that a two-step sequence consisting of
oximation and reduction under Ipaktschi’s conditions is
suitable for the reductive amination of the bicyclic ketone.
Transannular hydroamination reactions for the construc-
tion of the azaadamantane nucleus are promoted by
Brønsted acids with unprecedented facility owing to the
ideal arrangement of nitrogen atoms and double bonds. 1-
Me-AZADO (17) was prepared in six steps in 43% overall
yield. The preparation route of AZADO (4) was four steps
in 23% yield. These preparation methods not only accel-
erate the development of the further use of these catalysts,
but also enable a sustainable supply for commercial pur-
chase. The synthesis of several kilogram of AZADO (4)
Anal. Calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48. Found: C,
72.61; H, 9.11; N, 8.48.
Benzyl (7-Methylenebicyclo[3.3.1]nonane-3-yl)carbamate (23)
To a mixture of oxime 13 (17.1 g, 103 mmol) and MoO3 (25.2 g,
175 mmol) in MeOH (515 mL), NaBH4 (19.5 g, 515 mmol) was
added portionwise at 0 °C. (Caution! NaBH4 must be added in
many, small portions to suppress runaway gas emission; do not add
NaBH4 in one or only a few portions.) The mixture was stirred until
the oxime was no longer detectable (TLC), Et3N (71.7 mL, 515
mmol) and CbzCl (44 mL, 309 mmol) were added at 0 °C. The mix-
ture was stirred at 0 °C for an additional 2 h and then it was filtered
through Celite. The filtrate was concentrated under reduced pres-
sure. The residue was diluted with EtOAc and H2O. The layers were
separated and the aqueous layer was extracted with EtOAc. The or-
ganic layers were combined, washed with brine, dried (MgSO4),
and evaporated. The crude carbamate was purified by column chro-
has been achieved by Nissan Chemical Industries, Ltd. for matography (EtOAc–hexane, 1:15) to give 23 (18.0 g, 63.1 mmol,
61%) as a colorless solid.
IR (neat): 3333, 1719 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.26 (m, 5 H), 5.36 (br s, 1
H), 5.07 (s, 2 H), 4.83 (s, 2 H), 3.84 (m, 1 H), 2.31 (br d, J = 13.0
Hz, 2 H), 2.14 (br s, 3 H), 2.12 (br d, J = 13.0 Hz, 1 H), 2.09 (dd,
J = 14.0, 6.5 Hz, 2 H), 1.65 (br d, J = 12.8 Hz, 1 H), 1.42 (br d,
J = 12.8 Hz, 1 H), 1.20 (dd, J = 14.0, 6.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 155.6, 146.5, 137.0, 128.4, 128.0,
127.8, 112.0, 66.1, 42.3, 41.2, 34.7, 30.3, 27.8.
MS: m/z = 285 [M]+, 91 (100%).
HRMS (EI): m/z [M]+ calcd for C18H23NO2: 285.1729; found:
industrial application. Recently, we have obtained evi-
dence of the differences in reactivities between AZADO
(4) and 1-Me-AZADO (17), which will be reported in due
course.
All chemicals and solvents were purchased from commercial sup-
pliers and used without further purification. All reactions were
stirred magnetically, under an argon atmosphere, unless otherwise
noted, and monitored with analytical TLC (Merck Silica Gel 60
F254). Column chromatography was carried out with Silica Gel 60
(spherical, particle size 0.063–0.210 mm, neutral, Kanto Chemical
Co. Inc.) or Silica Gel 60 (spherical, particle size 0.040–0.050 mm,
neutral, Kanto Chemical Co. Inc.). Melting points were taken with
Yazawa BY-2 and are uncorrected. NMR spectra were measured on
285.1720.
Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C,
75.76; H, 8.12; N, 4.91.
1
a JEOL JNM-AL400 (400 MHz) relative to TMS (d = 0 ppm, H,
CDCl3) and residual CHCl3 (d = 7.26 ppm, 1H and 77.00 ppm, 13C).
IR spectra were recorded on Jasco FT/IR-410. HRMS were record-
ed on a JMS-AX500 or JMS-700 or JMS-T100GC using electron
impact (EI). LR-MS were recorded on JEOL JMS-DX303 using
electron impact (EI) or Agilent LC/MSD Trap (SL) using electro-
spray ionization (ESI). Elemental analyses were performed using
Yanaco CHN CORDER MT-6.
N-(Benzyloxycarbonyl)-1-methyl-2-azaadamantane (24)
To a soln of carbamate 23 (10.8 g, 37.8 mmol) in MeOH (140 mL),
2 M HCl (19 mL) was added at r.t.; the mixture was stirred for at 40
°C for 6 h. The mixture was evaporated, H2O was added, and the re-
sulting mixture was extracted with EtOAc. The organic layer was
washed with brine, dried (MgSO4), and evaporated. The crude N-
Cbz-2-azaadamantane was purified by column chromatography
(EtOAc–hexane, 1:15) to give 24 (10.8 g, 37.8 mmol, 100%) as a
colorless oil.
Preparation of 1-Me-AZADO (17)
7-Methylenebicyclo[3.3.1]nonan-3-one Oxime (13)
To a soln of commercially available adamantane-1,3-diol (11, 21 g,
125 mmol)13a in pyridine (250 mL), TsCl (47.7 g, 250 mmol) was
added at r.t. and the mixture was stirred at 70 °C for 12 h. H2O was
then added and the mixture was extracted with Et2O. The organic
layer was washed with brine, dried (MgSO4), and evaporated. To
the resultant ketone in pyridine soln, NH2OH·HCl (17.4 g, 250
mmol) was added. The mixture was stirred at r.t. for 4 h and concen-
trated in vacuo, and H2O and EtOAc were added. The mixture was
extracted with EtOAc, and the organic layer was washed with brine,
dried (MgSO4), and evaporated. The crude oxime was purified by
IR (neat): 1703 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.29 (m, 5 H), 5.08 (s, 2 H),
4.54 (br s, 1 H), 2.07 (br s, 2 H), 1.89 (br d, J = 13.3 Hz, 2 H), 1.82–
1.79 (m, 3 H), 1.72 (br d, J = 13.0 Hz, 1 H), 1.65 (br d, J = 13.3 Hz,
2 H), 1.54 (s, 3 H), 1.50 (br d, J = 13.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 155.6, 137.2, 128.3, 127.71,
127.70, 127.6, 66.3, 54.8, 49.6, 44.0, 35.3, 30.4, 27.3.
MS: m/z = 285 [M]+, 91 (100%).
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York

3424
M. Shibuya et al.
FEATURE ARTICLE
HRMS (EI): m/z [M]+ calcd for C18H23NO2: 285.1729; found:
purified by column chromatography (EtOAc–hexane, 1:15) to give
285.1720.
35 (19.8 g, 73.0 mmol, 87%) as a colorless oil.
Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91. Found: C,
75.49; H, 8.09; N, 4.95.
IR (neat): 3434, 1721, 1504 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.25 (m, 5 H), 6.05 (t, J = 7.8
Hz, 1 H), 5.92 (d, J = 8.4 Hz, 1 H), 5.79 (dt, J = 9.9, 3.2 Hz, 1 H),
5.08 (d, J = 12.4 Hz, 1 H), 5.03 (d, J = 12.4 Hz, 1 H), 4.03 (m, 1 H),
2.43 (dd, J = 18.8, 7.2 Hz, 1 H), 2.34 (br s, 1 H), 2.18 (br s, 1 H),
2.06 (br d, J = 18.1 Hz, 1 H), 2.00 (dt, J = 14.7, 5.5 Hz, 1 H), 1.89–
1.66 (m, 4 H), 1.55 (br d, J = 12.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 155.5, 136.9, 134.4, 128.8, 128.4,
128.0, 127.9, 66.2, 44.7, 37.5, 34.2, 32.5, 31.0, 27.7, 25.5.
MS: m/z = 271 [M]+, 91 (100%).
HRMS (EI): m/z [M]+ calcd for C17H21NO2: 271.1572; found:
1-Methyl-2-azaadamantan-N-oxyl (1-Me-AZADO, 17)
To a soln of 10% Pd-C (1.0 g) in MeOH (60 mL), N-Cbz-2-azaada-
mantane (24, 10.1 g, 35.4 mmol) in MeOH (60 mL) was slowly
added under an argon atmosphere. The reaction flask was purged
with H2 (3 ×) and the mixture was stirred at r.t. for 4 h under an at-
mosphere of H2. Then the reaction flask was purged with argon and
the mixture was filtered through Celite. The filtrate was concentrat-
ed under reduced pressure. The residue was diluted with CHCl3 and
the soln was treated with sat. Na2CO3, washed with brine, dried
(K2CO3), and evaporated. The crude product was not further puri-
fied. A soln of amine and Na2WO4·2 H2O (6.43 g, 19.5 mmol) in
MeCN (78 mL) was stirred at r.t. for 30 min. UHP (14.7 g, 156
mmol) was added to the mixture. After 2 h, additional UHP (3.67 g,
39.0 mmol) was added and the mixture was stirred for a further 1 h
and diluted with sat. NaHCO3. The mixture was extracted with
EtOAc and the organic layer was washed with brine, dried (K2CO3),
and evaporated. The crude 1-Me-AZADO was purified by column
chromatography (Et2O–hexane, 1:4) to afford 17 (5.33 g, 32.1
mmol, 82%) as a red solid.
271.1554.
2-Azaadamantane (22)
To a soln of carbamate 35 (6.51 g, 24.0 mmol) in CH2Cl2 (60 mL),
TfOH (8.49 mL, 95.9 mmol) was added at 0 °C. The mixture was
stirred at 0 °C for 30 min and then Et3N (16 mL) was added. 10%
NaOH (30 mL) was added and the mixture was stirred for 1 h and
extracted with CH2Cl2. 10% HCl was added to the organic layer and
the layers separated. The resultant aqueous layer was basified with
10% NaOH and then extracted with CH2Cl2. The organic layer was
dried (K2CO3) and evaporated to afford 22 (2.59 g, 18.9 mmol,
79%) as a colorless solid.
IR (CHCl3): 3432 cm–1.
MS: m/z = 166 [M]+, 93 (100%).
1H NMR (400 MHz, CDCl3): d = 3.13 (s, 2 H), 2.04 (s, 2 H), 1.94
(d, J = 11.4 Hz, 4 H), 1.87 (s, 2 H), 1.77 (d, J = 11.4 Hz, 4 H).
HRMS (EI): m/z [M]+ calcd for C10H16NO: 166.1232; found:
166.1194.
Anal. Calcd for C10H16NO: C, 72.25; H, 9.70; N, 8.43. Found: C,
72.55; H, 9.60; N, 8.28.
2-Azaadamantan-N-oxyl (AZADO, 4)
A soln of 2-azaadamantane (22, 3.55 g, 25.9 mmol) and Na2WO4·2
H2O (4.27 g, 13.0 mmol) in MeOH (52 mL) was stirred at r.t. for 30
min. UHP (9.75 g, 104 mmol) was added to the mixture. After 3 h,
the mixture was diluted with sat. NaHCO3 and extracted with
CHCl3. The organic layer was dried (K2CO3) and evaporated. The
crude material was purified by column chromatography (EtOAc–
hexane, 1:4) to afford 4 (1.98 g, 13.0 mmol, 50%) as a red solid; mp
145 °C.
Preparation of AZADO (4)
endo-Bicyclo[3.3.1]non-6-ene-3-carboxylic Acid (26)18a
To a soln of adamantan-2-one (25, 48.0 g, 320 mmol) and MsOH
(202 mL) in a 1-L 3-neck flask with a reflux condenser, NaN3 (22.9
g, 353 mmol) was added portionwise, keeping the temperature un-
der 35 °C; the mixture was stirred for 2 h. H2O (100 mL) and then
50% KOH (450 mL) were slowly added without external cooling.
After cooling to r.t., the mixture was washed with Et2O (600 mL)
and concd HCl (120 mL) was added. The precipitated bicyclic acid
was collected by filtration, washed with H2O and dried in vacuo to
give 26 (36.3 g, 218 mmol, 68%) as colorless solid.
IR (neat): 1445, 1281 cm–1.
Anal. Calcd for C9H14NO: C, 9.27; H, 71.02; N, 9.20. Found: H,
9.18; C, 71.06; N, 9.13.
IR (neat): 1680 cm–1.
Acknowledgment
1H NMR (400 MHz, CDCl3): d = 5.65(m, 1 H), 5.58 (dt, J = 9.5, 3.2
Hz, 1 H), 2.57 (t, J = 6.3 Hz, 1 H), 2.39 (d, J = 14.0 Hz, 1 H), 2.36–
2.20 (m, 4 H), 2.06 (br s, 1 H), 1.78–1.66 (m, 3 H), 1.54 (br d,
J = 12.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 182.6, 130.6, 129.5, 35.9, 31.9,
31.4, 31.1, 29.8, 28.5, 26.2.
This work was partially supported by a Grant-in-Aid for Scientific
Research (B) (17390002) from the Japan Society for the Promotion
of Science (JSPS) and a Grant-in-Aid for Young Scientists (B)
(17790005) from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology (MEXT). The second-generation synthesis of
AZADO (4) was financially supported by the Japan Science and
Technology Agency (JST).
MS: m/z = 166 [M]+, 79 (100%).
HRMS (EI): m/z [M]+ calcd for C10H14O2: 166.0994; found:
166.0989.
References
N-(Benzyloxycarbonyl)-endo-bicyclo[3.3.1]non-6-en-3-ylamine
(35)
(1) (a) Bäckvall, J.-E. Modern Oxidation Methods; Wiley-VCH:
Weinheim, 2004. (b) Ley, S. V. In Comprehensive Organic
Synthesis, Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon:
Oxford, 1991, 251–327.
(2) (a) Studer, A.; Tebben, L. Angew. Chem. Int. Ed. 2011, 50,
5034. (b) Ciriminna, R.; Pagliaro, M. Org. Process Res. Dev.
2010, 14, 245. (c) Vogler, T.; Studer, A. Synthesis 2008,
1979. (d) Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth.
Catal. 2004, 346, 1051. (e) Adam, W.; Saha-Moller, C. R.;
To a soln of carboxylic acid 26 (14.0 g, 84.3 mmol) in toluene (84
mL), DPPA (18.3 mL, 85.1 mmol) and Et3N (28.4 mL, 202 mmol)
were added at r.t. The mixture was stirred for at r.t. for 1.5 h, then
BnOH (70 mL, 675 mmol) was added and the resultant mixture was
refluxed for 1.5 h. After cooling to r.t., H2O was added. The mixture
was extracted with EtOAc. The organic layer was washed with
brine, dried (MgSO4), and evaporated. The crude carbamate was
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Active Azaadamantane-Nitroxyl-Radical-Type Oxidation Catalysts
3425
Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499.
(11) (a) Dupeyre, R. M.; Rassat, A. Tetrahedron Lett. 1975, 16,
1839. (b) Dupeyre, R. M.; Rassat, A. Tetrahedron 1978, 34,
1501.
(12) (a) Henkel, J. G.; Faith, W. C. J. Org. Chem. 1981, 46, 4953.
(b) Stetter, H.; Tacke, P.; Gartner, J. Chem. Ber. 1964, 97,
3480.
(13) (a) Muraoka, O.; Wang, Y. L.; Okumura, M.; Nishiura, S.;
Tanabe, G.; Momose, T. Synth. Commun. 1996, 26, 1555.
(b) Shibuya, M.; Taniguchi, T.; Takahashi, M.; Ogasawara,
K. Tetrahedron Lett. 2002, 43, 4145.
(14) Ipaktschi, J. Chem. Ber. 1984, 117, 856.
(15) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am.
Chem. Soc. 2006, 128, 8412.
(16) (a) Tomizawa, M.; Shibuya, M.; Iwabuchi, Y. Org. Lett.
2009, 11, 1829. (b) Shibuya, M.; Sato, T.; Tomizawa, M.;
Iwabuchi, Y. Chem. Commun. 2009, 1739.
(17) Stetter, H.; Gartner, J.; Tacke, P. Chem. Ber. 1966, 99, 1435.
(18) (a) Staas, W. H.; Spurlock, L. A. J. Org. Chem. 1974, 39,
3822. (b) Sasaki, T.; Eguchi, S.; Toru, T. J. Org. Chem.
1970, 35, 4109.
(19) (a) Hane, J. T.; Henkel, J. G. Tetrahedron Lett. 1990, 31,
2949. (b) Sasaki, T.; Eguchi, S.; Okano, T.; Wakata, Y.
J. Org. Chem. 1983, 48, 4067. (c) Sasaki, T.; Eguchi, S.;
Okano, T. Tetrahedron Lett. 1982, 23, 4969.
(20) (a) Tius, M. A.; Dixon, D. D.; Sethumadhavan, D.;
Benneche, T.; Banaag, A. R.; Thakur, G. A.; Bowman, A.;
Wood, J. T.; Makriyannis, A. J. Med. Chem. 2010, 53, 5656.
(b) Tius, M. A.; Le Goanvic, D. J. Org. Chem. 2006, 71,
7800. (c) Nirogi, R.; Mohammed, A. R.; Ahmad, I.;
Jayarajan, P.; Kandikere, N. V.; Shinde, A. K.;
Kambhampati, R. S.; Bhyrapuneni, G.; Ravula, J.; Patanala,
S. M.; Jasti, V. WO 2011,030,349, 2011.
(21) (a) Shioiri, T.; Murata, M.; Hamada, Y. Chem. Pharm. Bull.
1987, 35, 2698. (b) Murato, K.; Shioiri, T.; Yamada, S. I.
Chem. Pharm. Bull. 1975, 23, 1738. (c) Ninomiya, K.;
Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(22) Hamada, T.; Nagahama, N.; Kozawa, M.; Iwabuchi, Y.;
Shibuya, M.; Tomizawa, M.; Sasano, Y. WO 2009,066,735,
2009.
(f) deNooy, A. E. J.; Besemer, A. C.; vanBekkum, H.
Synthesis 1996, 1153. (g) Bobbitt, J. M.; Flores, M. C. L.
Heterocycles 1988, 27, 509.
(3) (a) Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J. Org.
Chem. 1989, 54, 2970. (b) Anelli, P. L.; Biffi, C.;
Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559.
(4) DeMico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
(5) (a) Miller, R. A.; Hoerrner, R. S. Org. Lett. 2003, 5, 285.
(b) De Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A.
J. Org. Chem. 2003, 68, 4999. (c) Bragd, P. L.; Besemer, A.
C.; van Bekkum, H. Carbohydr. Polym. 2002, 49, 397.
(d) De Luca, L.; Giacomelli, G.; Porcheddu, A. Org. Lett.
2001, 3, 3041. (e) Bolm, C.; Magnus, A. S.; Hildebrand, J.
P. Org. Lett. 2000, 2, 1173. (f) Rychnovsky, S. D.;
Vaidyanathan, R. J. Org. Chem. 1999, 64, 310. (g) Cella, J.
A.; Mcgrath, J. P.; Kelley, J. A.; Elsoukkary, O.; Hilpert, L.
J. Org. Chem. 1977, 42, 2077.
(6) (a) Zhao, M. M.; Li, J.; Mano, E.; Song, Z. J.; Tschaen, D.
M. Org. Synth. 2005, 81, 195. (b) Zanka, A. Chem. Pharm.
Bull. 2003, 51, 888. (c) Zhao, M. Z.; Li, J.; Mano, E.; Song,
Z. G.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564. (d) Epp, J. B.; Widlanski,
T. S. J. Org. Chem. 1999, 64, 293.
(7) (a) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.;
Ripin, D. H. B. Chem. Rev. 2006, 106, 2943. (b) Dugger, R.
W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res. Dev.
2005, 9, 253.
(8) (a) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J.
H.; Abrams, J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44,
57. (b) Davis, N. J.; Flitsch, S. L. Tetrahedron Lett. 1993, 34,
1181. (c) Siedlecka, R.; Skarzewski, J.; Mlochowski, J.
Tetrahedron Lett. 1990, 31, 2177. (d) Semmelhack, M. F.;
Chou, C. S.; Cortes, D. A. J. Am. Chem. Soc. 1983, 105,
4492.
(9) (a) Adamic, K.; Bowman, D. F.; Gillan, T.; Ingold, K. U.
J. Am. Chem. Soc. 1971, 93, 902. (b) Mendenha, G. d.;
Ingold, K. U. J. Am. Chem. Soc. 1972, 94, 7166.
(10) (a) Malatest, V.; Ingold, K. U. J. Am. Chem. Soc. 1973, 95,
6404. (b) Mendenha, Gd.; Ingold, K. U. J. Am. Chem. Soc.
1973, 95, 6395. (c) Shibuya, M.; Tomizawa, M.; Sasano, Y.;
Iwabuchi, Y. J. Org. Chem. 2009, 74, 4619.
Synthesis 2011, No. 21, 3418–3425 © Thieme Stuttgart · New York