Mechanistic insight into aerobic alcohol oxidation using NOx-nitroxide catalysis based on catalyst structure-activity relationships

Article abstract of DOI:10.1021/jo501862k

The mechanism of an NO_x-assisted, nitroxide(nitroxyl radical)-catalyzed aerobic oxidation of alcohols was investigated using a set of sterically and electronically modified nitroxides (i.e., TEMPO, AZADO (1), 5-F-AZADO (2), 5,7-DiF-AZADO (3), 5-MeO-AZADO (4), 5,7-DiMeO-AZADO (5), oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8)). The motivation for the present study stemmed from our previous observation that the introduction of an F atom at a remote position from the nitroxyl radical moiety on the azaadamantane nucleus effectively enhanced the catalytic activity under typical NO_x-mediated aerobic-oxidation conditions. The kinetic profiles of the azaadamantane-N-oxyl-[AZADO (1)-, 5-F-AZADO (2)-, and 5,7-DiF-AZADO (3)]-catalyzed aerobic oxidations were closely investigated, revealing that AZADO (1) showed a high initial reaction rate compared to 5-F-AZADO (2) and 5,7-DiF-AZADO (3); however, AZADO-catalyzed oxidation exhibited a marked slowdown, resulting in ～90% conversion, whereas 5-F-AZADO-catalyzed oxidation smoothly reached completion without a marked slowdown. The reasons for the marked slowdown and the role of the fluoro group are discussed. Oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8) were designed and synthesized to confirm their comparable catalytic efficiency to that of 5-F-AZADO (2), providing supporting evidence for the electronic effect on the catalytic efficiency of the heteroatoms under NO_x-assisted aerobic-oxidation conditions.

Full text of DOI:10.1021/jo501862k

Article
pubs.acs.org/joc
Mechanistic Insight into Aerobic Alcohol Oxidation Using NOx−
Nitroxide Catalysis Based on Catalyst Structure−Activity
Relationships
Masatoshi Shibuya,† Shota Nagasawa,‡ Yuji Osada,‡ and Yoshiharu Iwabuchi*,‡
†Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya
464-8601, Japan
‡Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama 6-3, Sendai
980-8578, Japan
S
* Supporting Information
ABSTRACT: The mechanism of an NOx-assisted, nitroxide(nitroxyl
radical)-catalyzed aerobic oxidation of alcohols was investigated using a
set of sterically and electronically modified nitroxides (i.e., TEMPO,
AZADO (1), 5-F-AZADO (2), 5,7-DiF-AZADO (3), 5-MeO-AZADO
(4), 5,7-DiMeO-AZADO (5), oxa-AZADO (6), TsN-AZADO (7), and
DiAZADO (8)). The motivation for the present study stemmed from our
previous observation that the introduction of an F atom at a remote
position from the nitroxyl radical moiety on the azaadamantane nucleus
effectively enhanced the catalytic activity under typical NOx-mediated
aerobic-oxidation conditions. The kinetic profiles of the azaadamantane-
N-oxyl-[AZADO (1)-, 5-F-AZADO (2)-, and 5,7-DiF-AZADO (3)]-
catalyzed aerobic oxidations were closely investigated, revealing that
AZADO (1) showed a high initial reaction rate compared to 5-F-AZADO
(2) and 5,7-DiF-AZADO (3); however, AZADO-catalyzed oxidation exhibited a marked slowdown, resulting in ∼90%
conversion, whereas 5-F-AZADO-catalyzed oxidation smoothly reached completion without a marked slowdown. The reasons
for the marked slowdown and the role of the fluoro group are discussed. Oxa-AZADO (6), TsN-AZADO (7), and DiAZADO
(8) were designed and synthesized to confirm their comparable catalytic efficiency to that of 5-F-AZADO (2), providing
supporting evidence for the electronic effect on the catalytic efficiency of the heteroatoms under NOx-assisted aerobic-oxidation
conditions.
been achieved by Sheldon and co-workers,4 Kumpulainen and
INTRODUCTION
■
Koskinen,5 and Stahl and co-workers,6 resulting in TEMPO/
The oxidation of alcohols to their corresponding carbonyl
Cu-catalyzed aerobic oxidation, a reliable method of choice in
compounds is a fundamental transformation in organic
chemistry, where quests for the realization of an efficient and
practical organic synthesis.7,8 We also developed an AZADO/
Cu system for a highly chemoselective aerobic oxidation of
selective oxidation method have continuously spurred active
amino alcohols.9 In 2004, Hu and Liang et al. developed the
investigations to enrich the repertoire of useful reagents and
methods.1 In addition to such development processes, the
first transition-metal-free aerobic oxidation catalyzed by
TEMPO, which employs Br2 and NOx as cocatalysts.10
recent social demand to evolve sustainable chemistry
encourages the development of a catalytic alcohol-oxidation
Subsequently, both they and Studer’s group achieved
TEMPO-catalyzed aerobic oxidation under a halogen- and
method that uses molecular oxygen (O2) as the terminal
transition-metal-free condition (TEMPO/tert-butyl nitrite,
oxidant, presenting a difficult, but rewarding, challenge:
TEMPO/NH2OH).11,12 Unfortunately, the substrate applic-
designing an aerobic-oxidation method that is the ideal
ability of the previously mentioned TEMPO/NOx-catalyzed
chemical process, using the minimum amount of nontoxic
aerobic-oxidation methods is limited to benzylic alcohols and a
catalyst under mild conditions and yielding H2O as the only
byproduct.2
few simple aliphatic alcohols. Thus, we have recently developed
a highly efficient aerobic-oxidation method using AZADO-type
nitroxides as catalysts. This method can be applied to a broad
range of aliphatic alcohols including alkenyl alcohols,
Throughout the history of the development of aerobic
alcohol oxidation processes, a class of stable nitroxyl radicals
has played salient roles. In 1984, Semmelhack et al. disclosed
the first catalytic aerobic alcohol oxidation using TEMPO with
CuCl in DMF.3 After their seminal report, significant progress
in terms of catalytic efficiency and substrate applicability has
Received: August 18, 2014
© XXXX American Chemical Society
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carbohydrates, and nucleic acid derivatives.13 During our
research on this aerobic-oxidation system, we found that
fluorinated azaadamantane N-oxyl (5-F-AZADO, 2) exhibits a
higher efficiency than nonsubstituted AZADO (1). Although
the F atom of 5-F-AZADO (2) is located at a remote position
from the nitroxyl radical moiety, the introduction of the F atom
significantly affects its catalytic behavior. Herein, we inves-
tigated the kinetic profile of a series of AZADOs to probe the
role of F groups. New nitroxyl radicals oxa-AZADO (6), TsN-
AZADO (7), and DiAZADO (8) have been developed with the
above insight.
Figure 2. Temporal profiles of AZADO (1), 5-F-AZADO (2), 5,7-
DiF-AZADO (3), and TEMPO. Substrate: l-menthol (9a).
Figure 1. Structures of a series of AZADO derivatives.
RESULTS AND DISCUSSION
■
Our investigation commenced with the comparison of the
temporal profiles of AZADO (1), 5-F-AZADO (2), and 5,7-
DiF-AZADO (3),14 using l-menthol (9a) as the substrate under
conditions identical to those in our original report (1 mol %
nitroxyl radical, 10 mol % NaNO2, AcOH solvent, air
balloon).13a The kinetic profile of TEMPO was also
investigated for reference. 5-F-AZADO had completely
oxidized 9a within 6 h, whereas AZADO and 5,7-DiF-
AZADO had not completely oxidized 9a even after 12 h.
Under TEMPO-catalyzed conditions, no oxidized products
were detected after 12 h. The following results were also
observed: (1) AZADO exhibited a higher initial rate than that
of 5-F-AZADO, (2) AZADO-catalyzed oxidation reaction
showed a marked slowdown, resulting in ∼90% conversion,
and (3) the introduction of a second F atom markedly
attenuated the catalytic efficiency. These observations indicated
that the introduction of one F atom into AZADO does not
accelerate the reaction rate but prevents the slowdown (Figure
2). The reproducibility of this result is confirmed by repeated
experiments. Similar profiles were also obtained from the
oxidation of 4-phenyl-2-butanol (10a, Figure 3) and 2-octanol
(11a, Figure 4). The temporal profiles of ABNO using these
three alcohols were examined (Figures S1−S3). The initial rates
were similar to those of AZADO; however, the marked
slowdown of the reaction was observed at slightly lower
conversion than that of AZADO.
We also investigated the temporal profiles of 5-MeO-
AZADO (4) and 5,7-DiMeO-AZADO (5)15 under identical
conditions to probe the effect of the F atom on robust catalytic
activity. Although 5-MeO-AZADO (4) showed a slightly lower
catalytic activity than did 5-F-AZADO (2), the reaction went to
completion without any marked slowdown. The introduction of
a second MeO group attenuated the reaction rate in a manner
similar to that of fluorinated AZADOs. Moreover, 5-MeO-
AZADO (4) enabled the completion of the oxidation within 10
h without any marked slowdown, and the initial rate decreased
in a manner dependent on the number of introduced MeO
Figure 3. Temporal profiles of AZADO (1), 5-F-AZADO (2), 5,7-
DiF-AZADO (3), and TEMPO. Substrate: 4-phenyl-2-butanol (10a).
groups (Figure 5). These results support the notion that an
inductive effect of the heteroatoms plays an important role in
preventing a marked slowdown of the reaction.
In the course of the development of a 5-F-AZADO-catalyzed
aerobic-oxidation method, it was revealed that the acidity of
AcOH plays an essential role. Therefore, we obtained the
temporal profiles of AZADO (1) and 5-F-AZADO (2) for five
different amounts of AcOH in MeCN to evaluate the effect of
AcOH on the reaction rate. The results are shown in Figure 6.
Under the 5-F-AZADO-catalyzed condition, the larger the
amount of AcOH, the higher the reaction rate. However, two
interesting catalytic behavioral features of AZADO (1) were
also observed: (i) the initial rate increased as the loading
amount of AcOH increased in a way that was similar to the 5-F-
AZADO-catalyzed condition and (ii) a slowdown was evident
when more than 10 equiv of AcOH was loaded. Regarding the
possible reasons for the marked slowdown under the AZADO-
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Figure 4. Temporal profiles of AZADO (1), 5-F-AZADO (2), 5,7-
DiF-AZADO (3), and TEMPO. Substrate: 2-octanol (11a).
Figure 6. Effects of the amount of AcOH on catalytic efficiencies.
Figure 5. Temporal profiles of AZADO (1), 5-MeO-AZADO (4), and
5,7-DiMeO-AZADO (5).
catalyzed condition, we postulated the following: (i) AZADO
(1) deactivation, (ii) the depletion of catalytically active NOx,
and (iii) the concomitant generation of catalytic poisons.
An additional 1 mol % AZADO (1) was added immediately
after the slowdown was observed (Figure 7, 8 h) to examine the
possibility of AZADO (1) deactivation. However, only a slight
increase in the conversion rate was observed, indicating the
presence of deactivating factors. However, the addition of 1 mol
% 5-F-AZADO (2) led to the completion of the reaction
(Figure 7).
Next, an additional 10 mol % NaNO2 was added immediately
after the slowdown was observed to examine the possibility of
the depletion of catalytically active NOx. The result showed
that although a marginal increment in conversion was observed,
the reaction did not reach completion (Figure 8). The
formation of a small amount of menthyl nitrite was detected
instead.16
Figure 7. Effects of the addition of extra AZADO (1) and 5-F-
AZADO (2) on temporal profiles.
were each considered to be candidate catalytic poisons. The
results of the evaluation of the effect of AcOH have already
suggested that AZADO-catalyzed oxidation is more sensitive to
the acidity of the reaction mixture than is 5-F-AZADO-
catalyzed oxidation (Figure 6). First, we postulated that HNO3,
which is generated via NOx autoxidation, quenches the
oxidation.17 AZADO- and 5-F-AZADO-catalyzed aerobic
oxidations in the presence of HNO3 were examined to verify
the possibility. The result showed that the addition of 1 mol %
The third possible cause of the marked slowdown is the
concomitant generation of catalytic poisons; HNO3 and H2O
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However, we observed no detectable pH change in the reaction
mixture using conventional pH-indicator paper. The possibility
of H2O acting as a catalytic poison, which is a byproduct of the
reduction of O2 under aerobic oxidation, was investigated by
determining the temporal profiles of the AZADO- and 5-F-
AZADO-catalyzed oxidation in the presence of H2O (Figure
10).18 The result showed that 1 equiv of H2O to substrate
Figure 8. Effect of the addition of extra NaNO2 on the temporal
profile of AZADO-catalyzed oxidation.
HNO3 decreased the conversion rate of the AZADO-catalyzed
oxidation by about 5% but enabled the completion of the 5-F-
AZADO-catalyzed oxidation with a slight deceleration. A
similar slowdown was observed under the 5-F-AZADO-
catalyzed condition in the presence of more than 10 mol %
HNO3 (Figure 9). These results are in agreement with the
catalytic behavior of AZADO (1) and 5-F-AZADO (2).
Figure 10. Effects of H2O on the temporal profiles of AZADO- and 5-
F-AZADO-catalyzed oxidations.
clearly decreased the conversion rate under the AZADO-
catalyzed condition up to ∼80%, although a slight extension of
the reaction time was observed under the 5-F-AZADO-
catalyzed condition. It was found that AZADO-catalyzed
oxidation is clearly more sensitive to H2O than 5-F-AZADO-
catalyzed oxidation. These results suggest that H2O generated
from O2 inhibits the catalytic cycles of AZADO oxidation.19
Two experiments were conducted to shed light on the
shutdown event. In the first experiment, 9a (0.96 mmol, 1.0
equiv) was subjected to 1 mol % AZADO-catalyzed oxidation,
and an additional 0.5 equiv (0.48 mmol) of 9a was added when
the reaction reached ∼70% conversion (Figure 11, just before
the slowdown was observed). Interestingly, more than 1.0 equiv
of 9a (∼1.2 equiv) was oxidized to menthone (9b), suggesting
that the slowdown begins when the amount of remaining
alcohol is critically decreased.
In the second experiment, 9a (0.96 mmol, 1.0 equiv) was
subjected to 1 mol % AZADO-catalyzed oxidation; after 8 h, an
additional 0.5 equiv (0.48 mmol) of 9a was added (Figure 12,
just after the slowdown). No obvious progression of the
Figure 9. Effects of HNO3 on the temporal profiles of AZADO- and 5-
F-AZADO-catalyzed oxidations.
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reaction mixture was concentrated to give a dark residue, from
which alkoxyamines 12 and 13 were isolated as major AZADO-
derived products.
On the basis of all of the above results, the following are
plausible explanations for the effect of the F atom and the
marked slowdown of AZADO-catalyzed aerobic oxidation
(Scheme 2). The oxoammonium species (III) forms a hydrate
(IV) with H2O in equilibrium, which is promoted by acids. As
the amount of water increases with the advance of oxidation,
the equilibrium between the catalytically active oxoammonium
species (III) and the inactive hydrate (IV) shifts toward
hydrate (IV) formation, thereby decreasing the probability of
forming the alcohol adduct (V).20 In this way, AZADO-
catalyzed oxidation suffers from a slowdown, and AZADO is
deactivated via an irreversible reaction between AZADO+ (III,
X = H) and the carbonyl compound. Because the oxygen atom
of 5-F-AZADO+ is slightly less basic than that of AZADO+
(owing to the strong inductive effect of the F atom), 5-F-
AZADO+ is difficult to protonate and thereby eludes the
hydrate (IV) formation reaction.21 As such, 5-F-AZADO (2)
efficiently catalyzes the aerobic oxidation without causing the
fatal hydrate formation.
Figure 11. Effect of the addition of 0.5 equiv of l-menthol (9a) at
approximately 70% conversion on the temporal profile of AZADO-
catalyzed oxidation.
On the basis of the above kinetic study results, we are now
interested in determining the reactivities of nitroxyl radical
catalysts with a heteroatom in the azaadamantane nucleus. To
examine the effect of the introduction of a heteroatom into the
azaadamantane nucleus, we designed and synthesized three new
catalysts ,i.e., oxa-AZADO (6), TsN-AZADO (7), and
DiAZADO (8)22 (Figure 13). These catalysts have a slightly
Figure 13. Structures of the newly synthesized aerobic-oxidation
catalysts.
more compact nucleus than AZADO (1) and 5-F-AZADO (2),
resulting from the shorter bond lengths of C−O and C−N
compared to that of C−C. We considered that these three
catalysts were synthesized from their common intermediate N-
Ts-9-azabicyclo[3.3.1]nonan-3-one (14), which can be readily
prepared by the three-component condensation of acetonedi-
carboxylic acid, glutaraldehyde, and ammonia23, followed by Ts
protection. Oxa-AZADO (6) can be easily prepared in five
steps from such an intermediate according to Tius’s procedure
(Scheme 3).24 TsN-AZADO (7) and DiAZADO (8) were
Figure 12. Effect of the addition of 0.5 equiv of l-menthol (9a) after 8
h on the temporal profile of AZADO-catalyzed oxidation.
reaction was observed, indicating that the observed slowdown
results from a deactivation of the reaction rather than some
kind of equilibrium being reached.
A large-scale oxidation of 2-octanol (11a, 2.57 g) using 30
mg of AZADO (1) was conducted to probe the deactivation
pathway (Scheme 1). After a slowdown was observed (9 h), the
synthesized using modified Hofmann−Loffler−Freytag reaction
̈
conditions25 in order to construct diazaadamantane skeletons
Scheme 1. Aerobic Oxidation of 2-Octanol (11a) on a Large Scale Using 30 mg of AZADO (1) and the Isolation of Azado-
Derived Products
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Scheme 2. Plausible Overall Mechanism of 5-F-AZADO- and AZADO-Catalyzed Oxidations
Scheme 3. Synthesis of Oxa-AZADO (6)
Scheme 4. Syntheses of TsN-AZADO (7) and DiAZADO (8)
(Scheme 4). DiAZADO (8) was obtained more efficiently by
extension of the reaction time for the deprotection of Ts groups
using sodium bis(2-methoxyethoxy)aluminum hydride (red-Al)
(Scheme 5).
Scheme 5. More Efficient Procedure for the Synthesis of
DiAZADO (8)
We examined the temporal profiles of oxa-AZADO (6),
TsN-AZADO (7), and DiAZADO (8) (Figure 14). We found
that these three catalysts are not markedly superior to 5-F-
AZADO; however, they all enable the completion of the
reaction without a marked slowdown. These catalysts also have
a broad range of substrate applicabilities (Table 1).
F
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mm, basic). The eluents employed are reported as volume/volume
percentages.
Melting points were determined using a melting-point apparatus
and are reported uncorrected. The recrystallization solvents are shown
in parentheses after the melting point. Proton nuclear magnetic
resonance (1H NMR) spectra were recorded using 400 or 700 MHz
spectrometers. Chemical shifts (δ) are reported in parts per million
(ppm) downfield relative to tetramethylsilane (TMS, 0.00 ppm).
Coupling constants (J) are reported in hertz. Multiplicities are
reported using the following abbreviations: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; dd, double doublet; dt, double triplet;
dq, double quartet. Carbon-13 nuclear magnetic resonance (13C
NMR) spectra were recorded using a 100 or 175 MHz spectrometer.
The chemical shift is reported in parts per million (ppm) relative to
the center line of the triplet of CDCl3 (77.0 ppm). Infrared spectra
were obtained at 4.0 cm−1 resolution and are reported in wave-
numbers. Low-resolution mass spectra (MS) and high-resolution mass
spectra (HRMS) were recorded using an electron impact (EI) with
magnetic sector time-of-flight mass analyzer or an electrospray
ionization (ESI) with ion-trap mass analyzer. HPLC was performed
using a UV/vistbl1 detector at 254 nm.
Syntheses of 5-MeO-AZADO (4) and 5,7-DiMeO-AZADO (5)
(Scheme 6).15
Figure 14. Temporal profiles of oxa-AZADO (6), TsN-AZADO (7),
and DiAZADO (8) for the oxidation of l-menthol (9a).
Scheme 6. Syntheses of 5-MeO-AZADO (4) and 5,7-
DiMeO-AZADO (5)
CONCLUSIONS
■
We have investigated the kinetic behavior of AZADO, (Di)F-
AZADO, and (Di)MeO-AZADO under NOx-assisted aerobic
alcohol-oxidation conditions. From the results, it became clear
that AZADO (1) has the highest initial rate among these
catalysts but suffers from a marked slowdown in its catalyzed
reaction, resulting in only ∼90% conversion. Although the
introduction of an F atom and a MeO group decreases the
reaction rate, the introduction of a monoheteroatom prevents
such a marked slowdown. 5-F-AZADO (2) consequently shows
the best performance as an aerobic-oxidation catalyst. Further
kinetic studies suggested that H2O works as a catalytic poison
in NOx-nitroxide aerobic-oxidation systems and that the
deceleration effect of H2O is promoted by acids. 5-F-AZADO
(2) is less susceptible to such an effect than is AZADO (1)
because of the less-basic oxygen atom in its nitroxide moiety.
Newly synthesized oxa-AZADO (6), TsN-AZADO (7), and
DiAZADO (8) all showed catalytic performance comparable to
that of 5-F-AZADO (2).
N-Trifluoroacetyl-5-hydroxy-2-azaadamantane (34) and N-Tri-
fluoroacetyl-5,7-dihydroxy-2-azaadamantane (35). To a solution of
N-trifluoroacetyl-2-azaadamantane (33) (6.00 g, 25.7 mmol) and
RuCl3·nH2O (1.60 g, 7.72 mmol) in a mixture of CCl4−MeCN−H2O
(1.65 M, 15 mL; 1.1 M, 23 mL; 1.1 M, 23 mL) was added NaIO4 (19.3
g, 90.1 mmol) at ambient temperature. The mixture was vigorously
stirred for 41 h at 70 °C. After being cooled to room temperature, sat
NaHCO3 (aq) and 20% Na2S2O3 (aq) were added to the mixture
before filtering it through Celite. The filtrate was extracted with AcOEt
(6×). The organic layer was washed with brine, dried over MgSO4,
and evaporated. The residue was purified with column chromatog-
raphy (AcOEt−hexane = 1:4 to AcOEt) to afford N-trifluoroacetyl-5-
hydroxy-2-azaadamantane (34) (1.98 g, 7.95 mmol, 31%) as a
colorless solid and N-trifluoroacetyl-5,7-dihydroxy-2-azaadamantane
(35) (1.93 g, 7.28 mmol, 28%) as a colorless solid, accompanied by
recovered 33 (276 mg). 34: colorless crystals; mp 95−96 °C (CHCl3−
Et2O); 1H NMR (400 MHz, CDCl3) δ 4.97 (s, 1H), 4.43 (s, 1H), 2.41
(s, 1H), 1.89−1.56 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 154.0
(q, J = 35.2 Hz), 116.5 (q, J = 286.4 Hz), 66.6, 51.5 (q, J = 3.6 Hz),
48.3, 43.6, 43.1, 42.9, 34.9, 34.0, 28.8; IR (neat, cm−1) 3425, 1681; MS
m/z 249 (M+), 249 (100%); HRMS (EI) calcd for C11H14F3NO2,
249.0977; found, 249.0956; Anal. calcd for C11H14F3NO2: C, 53.01; H,
5.66; N, 5.62; found: C, 52.88; H, 5.66; N, 5.62. 35: colorless crystals;
EXPERIMENTAL SECTION
■
General Experimental Procedures. Aerobic oxidations were
carried out under an air atmosphere (balloon). All reactions for the
preparations of oxa-AZADO (6), TsN-AZADO (7), and DiAZADO
(8) were carried out under an atmosphere of argon or N2. Ethereal
solvents and dichloromethane (anhydrous grade) were used without
further purification. All solvents except AcOH were dried and distilled
by standard procedures. Reagents were purchased from commercial
suppliers and used without further purification. AZADO (1) was
generously provided by Nissan Chemical Industries, Ltd. and purified
with flash column chromatography (Et2O−hexane = 1:1). 5-F-
AZADO (2)13a and 5,7-DiF-AZADO (3)14 were synthesized
according to our previous reports.
Reactions were monitored by thin-layer chromatography (TLC)
carried out on 0.25 mm silica gel plates (60F254) using a UV light as
visualizing agent, p-anisaldehyde in ethanol−aqueous H2SO4−AcOH,
phosphomolybdic acid in ethanol, and nynhydrin in AcOH−n-BuOH
for staining. Column chromatography was performed with silica gel
60N (spherical, particle size 0.063−0.210 mm, neutral), silica gel 60N
(spherical, particle size 0.040−0.050 mm, neutral), or CHROMA-
TOREX-NH (spherical, particle size 0.040−0.075 mm or 0.075−0.200
1
mp 167 °C (AcOEt); H NMR (400 MHz, CD3OD) δ 4.97 (s, 1H),
4.52 (s, 1H), 1.87−1.69 (m, 10H); 13C NMR (100 MHz, CD3OD) δ
155.3 (q, J = 35.9 Hz), 118.1 (q, J = 274.2 Hz), 69.4, 53.2 (q, J = 3.8
Hz), 51.5, 50.3, 43.3, 42.5; IR (neat, cm−1) 3335, 3197, 1686; MS m/z
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Table 1. Scope of Oxa-AZADO (6), TsN-AZADO (7), and DiAZADO (8)
a
b
c
d
3 mol % nitroxyl radical was used. AcOH (0.4 M) was used. 5 mol % nitroxyl radical was used. MeCN (1 M), AcOH (2 equiv) were used.
265 (M+), 265 (100%); HRMS (EI) calcd for C11H14F3NO3,
265.0926; found, 265.0925.
hexane = 1:4) to afford N-trifluoroacetyl-5-methoxy-2-azaadamantane
(36) (443 mg) containing some amount of Me2SO4. 36 was used
without further purification. To a solution of 36 in EtOH (7.1 mL)
was added NaOH (aq) (10%, 3.5 mL) at ambient temperature. After
the reaction mixture was stirred for 2.5 h at ambient temperature, the
mixture was concentrated under reduced pressure. The residue was
extracted with CHCl3. The organic layer was dried over K2CO3 and
evaporated. The residue was used in the next reaction without further
purification. Na2WO4·2H2O (333 mg, 1.01 mmol) was added to a
solution of the residue in MeCN (0.2 M, 10 mL) at ambient
temperature. The suspension was stirred at the same temperature for
30 min. UHP (760 mg, 8.08 mmol) was added to the reaction mixture
5-Methoxy-2-azaadamantane N-Oxyl (5-MeO-AZADO, 4). To a
suspension of 60% NaH (241 mg, 6.02 mmol) in THF (1.8 mL) was
slowly added via cannula a solution of N-trifluoroacetyl-5-hydroxy-2-
azaadamantane (34) (500 mg, 2.01 mmol) in THF (4.9 mL) at 0 °C.
After the reaction mixture was stirred for 30 min at 0 °C, Me2SO4 (571
μL, 6.02 mmol) was added dropwise to the reaction mixture. The
mixture was stirred for 5 h at ambient temperature. The mixture was
quenched with H2O and extracted with Et2O (3×). The organic layer
was washed with brine, dried over MgSO4, and evaporated. The
residue was purified with flash column chromatography (AcOEt−
H
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at 0 °C. The mixture was stirred for 3 h at room temperature.
Additional UHP (190 mg, 2.02 mmol) at 0 °C was added, and the
mixture was stirred for an additional 1 h at room temperature. The
mixture was diluted with sat NaHCO3 (aq) and extracted with CHCl3
(3×). The organic layer was dried over K2CO3 and evaporated. The
residue was purified with flash column chromatography (AcOEt−
hexane = 1:1) to afford 5-methoxy-2-azaadamantane N-oxyl (4) (5-
MeO-AZADO, 216 mg, 1.19 mmol, 59% for three steps) as a yellow
an air atmosphere (balloon). The conversion of the reaction was
monitored directly by GC analysis.
Conditions for GC Analysis. Sample, 5 μL of the reaction mixture in
1 mL of acetone; column, HP-5 (30 m × 0.32 mm, 0.25 μm); FID
detector, 270 °C; injection, 250 °C; carrier gas, helium (3.0 mL/min);
column temperature, l-menthol (9a): 70 °C for 2 min, raised to 140
°C at a rate of 10 °C/min, then 140 °C for 1 min or 70 °C for 2 min,
raised to 210 °C at a rate of 20 °C/min, then 210 °C for 1 min; 4-
phenyl-2-butanol (10a): 70 °C for 2 min, raised to 280 °C at a rate of
30 °C/min, then 280 °C for 1 min; 2-octanol (11a): 50 °C for 2 min,
raised to 70 °C at a rate of 5 °C/min, then 70 °C for 1 min, raised to
130 °C at a rate of 30 °C/min, then 130 °C for 1 min.
1
solid. 36: H NMR (400 MHz, CDCl3) δ 4.98 (s, 1H), 4.45 (s, 1H),
3.25 (s, 3H), 2.42 (s, 1H), 1.95−1.69 (m, 10H). 5-MeO-AZADO (4):
yellow prisms; mp 64 °C (hexane); IR (neat, cm−1) 1443, 1350, 1115;
MS m/z 182 (M+), 182 (100%); HRMS (EI) calcd for C10H16NO2,
182.1181; found, 182.1165; Anal. calcd for C10H16NO2: C, 65.91; H,
8.85; N, 7.69; found: C, 65.97; H, 9.04 ; N, 7.71.
Large-Scale Aerobic Oxidation for the Isolation of AZADO-
Derived Products (Scheme 1). To a solution of 2-octanol (11a)
(2.57 g, 19.7 mmol) and AZADO (1) (30.0 mg, 0.197 mmol) in
AcOH (20 mL) in a 1 L recovery flask was added NaNO2 (136 mg,
1.97 mmol) at room temperature. The mixture was stirred at the same
temperature under an air atmosphere (balloon) for 9 h. The mixture
was concentrated under reduced pressure to remove AcOH, 2-octanol,
and 2-octanone (50 °C, 100 Pa). The residue was diluted with AcOEt
and sat NaHCO3 (aq) and extracted with AcOEt (3×). The organic
layer was dried over MgSO4 and evaporated. The residue was purified
with column chromatography (AcOEt−hexane = 1:8 to CHCl3−
MeOH = 4:1) to afford a mixture of alkoxyamines 12 and 13 (20.8
mg, 74.4 μmol, 38%, 12−13 = 4:1) and several unidentified products
(total 9.72 mg) as a colorless oil. (In this experiment, AZADO and/or
AZADOL (hydroxylamine form of AZADO) were not recovered.) 3-
N-Trifluoroacetyl-5,7-dimethoxy-2-azaadamantane (37). To a
suspension of 60% NaH (604 mg, 15.1 mmol) in THF (3.5 mL) was
slowly added via cannula a solution of 5,7-dihydroxy-2-azaadamantane
(35) (500 mg, 1.89 mmol) in THF (9.5 mL) at 0 °C. After the
reaction mixture was stirred for 30 min at 0 °C, Me2SO4 (1.43 mL,
15.1 mmol) was added dropwise to the reaction mixture. After the
reaction mixture was stirred for 5 h at ambient temperature, the
mixture was quenched with H2O and extracted with Et2O (3×). The
organic layer was washed with brine, dried over MgSO4, and
evaporated. The residue was purified with flash column chromatog-
raphy (AcOEt−hexane = 1:2) to afford N-trifluoroacetyl-5,7-
dimethoxy-2-azaadamantane (37) (446 mg, 1.52 mmol, 81%) as a
colorless oil. 37: 1H NMR (400 MHz, CDCl3) δ 5.12 (s, 1H), 4.58 (s,
1H), 3.26 (s, 6H), 1.96−1.87 (m, 2H), 1.85−1.79 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 153.7 (q, J = 36.5 Hz), 116.3 (q, J = 289.7 Hz),
77.2, 72.8, 72.7, 50.9, 50.8, 48.3 (q, J = 1.90 Hz), 47.8, 42.7, 38.9, 38.0;
IR (neat, cm−1) 1689, 1458, 1225, 1191, 1124; MS m/z 293 (M+), 138
(100%); HRMS (EI) calcd for C13H18F3NO3, 293.1239; found,
293.1232.
5,7-Dimethoxy-2-azaadamantane N-Oxyl (5,7-DiMeO-AZADO,
5). To a solution of N-trifluoroacetyl-5,7-dimethoxy-2-azaadamantane
(37) (400 mg, 1.36 mmol) in EtOH (4.8 mL) was added NaOH (aq)
(10%, 2.4 mL) at ambient temperature. After the reaction mixture was
stirred for 1 h at ambient temperature, it was concentrated under
reduced pressure. The residue was extracted with CHCl3. The organic
layer was dried over K2CO3 and evaporated. The crude product was
used in the next reaction without further purification. Na2WO4·2H2O
(224 mg, 0.680 mmol) was added to the solution of the residue in
MeCN (0.2 M, 6.8 mL). The suspension was stirred at ambient
temperature for 30 min. UHP (512 mg, 5.44 mmol) at 0 °C was added
to the reaction mixture, and the mixture was stirred at room
temperature for 2 h. Additional UHP (128 mg, 1.36 mmol) at 0 °C
was added, and the mixture was stirred for another 3 h at room
temperature. The mixture was diluted with sat NaHCO3 (aq) and
extracted with CHCl3. The organic layer was dried over K2CO3 and
evaporated. The residue was purified with flash column chromatog-
raphy (AcOEt−hexane = 2:1) to afford 5,7-dimethoxy-2-azaadaman-
tane N-oxyl (5,7-diMeO-AZADO (5), 193 mg, 0.910 mmol, 67% for
two steps) as a yellow solid. 5: yellow prisms; mp 105−106 °C
(Et2O−hexane); IR (neat, cm−1) 1444, 1305, 1119, 1108; MS m/z 212
(M+), 212 (100%); HRMS (EI) calcd for C11H18NO3, 212.1287;
found, 212.1303; Anal. calcd for C11H18NO3: C, 62.24; H, 8.55; N,
6.60; found: C, 62.07; H, 8.55; N, 6.53.
1
{(2-Azaadamantan-2-yl)-oxy}-octan-2-one (12) (major product): H
NMR (700 MHz, CDCl3) δ 3.99 (s, 1H), 3.36 (s, 1H), 3.29 (s, 1H),
2.41 (d, J = 13.7 Hz, 1H), 2.34 (d, J = 13.7 Hz, 1H), 2.15 (s, 3H), 1.92
(s, 1H), 1.84 (s, 1H), 1.86−1.75 (m, 6H), 1.61−1.26 (m, 8H), 1.38 (t,
J = 13.3 Hz, 2H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (175 MHz,
CDCl3) δ 212.4, 85.5, 55.5, 52.6, 36.6, 31.6, 30.7, 30.2, 26.5, 26.2, 25.3,
22.5, 14.0. 1-{(2-Azaadamantan-2-yl)-oxy}-octan-2-one (13) (minor
product; only assignable signal given): 1H NMR (700 MHz, CDCl3) δ
4.23 (s, 2H), 3.40 (s, 2H), 2.48 (t, J = 7.7 Hz, 2H); 13C NMR (175
MHz, CDCl3) δ 210.4, 76.8, 54.4, 39.2, 29.0, 23.3. 12 + 13: IR (neat,
cm−1) 2853, 1716; MS m/z 279 (M+), 152 (100%); HRMS (EI) calcd
for C17H29NO2, 279.2198; found, 279.2200.
Synthesis of Oxa-AZADO (6) (Scheme 3). N-p-Toluenesulfon-
yl-9-azabicyclo[3.3.1]nonan-3-one (14). To a solution of acetonedi-
carboxylic acid (8.00 g, 54.8 mmol) in H2O (200 mL) was added over
15 min 28% NH3 (H2O solution, 19 mL, 274 mmol) at 0 °C.
Glutaraldehyde (50% H2O solution, 10 mL, 55.3 mmol) was added
slowly (1 drop/4−5 s) to the mixture at the same temperature. After
stirring for 24 h at room temperature, the mixture was freeze-dried to
remove H2O. The resulting orange solid was used in the next reaction
without further purification. To a suspension of the orange solid and
Na2CO3 (19.0 g, 178 mmol) in CH2Cl2 (31 mL)−H2O (62 mL) was
added dropwise a solution of TsCl (12.5 g, 65.8 mmol) in CH2Cl2 (31
mL) at 0 °C. The reaction mixture was stirred for 4 h at room
temperature. The mixture was diluted with H2O (100 mL). After the
separation of the organic layer, the aqueous layer was extracted with
AcOEt (2×). The organic extracts were combined, dried over MgSO4,
and evaporated. The residue was purified with column chromatog-
raphy (AcOEt−hexane = 1:4) to afford N-p-toluenesulfonyl-9-
azabicyclo[3.3.1]nonan-3-one (14) (5.80 g, 19.8 mmol, 36% for two
steps) as a colorless solid. 14: colorless crystals; mp 139 °C (CHCl3−
hexane); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.31
(d, J = 8.0 Hz, 2H), 4.50 (s, 2H), 2.71 (dd, J = 17.2, 6.8 Hz, 2H), 2.43
(s, 3H), 2.35 (d, J = 16.8 Hz, 2H), 1.79−1.46 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 207.9, 143.6, 137.8, 129.8, 126.9, 49.6, 45.4,
30.4, 21.5, 15.8; IR (neat, cm−1) 1707, 1351, 1161, 1090; MS m/z 293
(M+), 138 (100%); HRMS (EI) calcd for C15H19NO3S, 293.1086;
found, 293.1068.
Experimental Procedures for the Aerobic Oxidation of
Alcohols. Experiments for the Temporal Profiles of AZADO
Derivatives (Figures 2−5, 7−12, and 14). To a solution of l-menthol
(9a) (150 mg, 0.961 mmol) and AZADO (1) (1.44 mg, 9.61 μmol) in
AcOH (0.961 mL) was added NaNO2 (6.63 mg, 96.1 μmol) at room
temperature. The mixture was stirred at the same temperature under
an air atmosphere (balloon). The conversion of the reaction was
monitored directly by GC analysis.
N-p-Tolueneulfonyl-9-azabicyclo[3.3.1]nonan-3-ol (15). To a
suspension of LiAlH4 (194 mg, 5.12 mmol) in THF (25 mL) was
slowly added N-p-toluenesulfonyl-9-azabicyclo[3.3.1]nonan-3-one
(14) (1.00 g, 3.41 mmol) at 0 °C. After stirring for 3 h at room
temperature, the mixture was quenched with AcOEt and saturated
Experiments for the Evaluation of the Amount of AcOH (Figure
6). To a solution of l-menthol (9a) (150 mg, 0.961 mmol), AcOH (1,
2, 5, and 10 equiv), and AZADO (1) (1.44 mg, 9.61 μmol) in MeCN
(0.961 mL) was added NaNO2 (6.63 mg, 96.1 μmol) at room
temperature. The mixture was stirred at the same temperature under
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aqueous potassium sodium tartrate was added. The biphasic solution
was stirred vigorously at room temperature for 30 min. The mixture
was extracted with AcOEt (3×). The organic layer was washed with
brine, dried over MgSO4, and evaporated. The residue was purified
with column chromatography (AcOEt−hexane = 1:2) to afford N-p-
tolueneulfonyl-9-azabicyclo[3.3.1]nonan-3-ol (15) (719 mg, 2.44
mmol, 71%) as colorless crystals. 15: mp 99−100 °C (CHCl3−
hexane); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.27
(d, J = 7.6 Hz, 2H), 4.25 (m, 2H), 3.72 (m, 1H), 2.42 (s, 3H), 2.36
(m, 2H), 2.13 (qt, J = 13.6, 4.8 Hz, 1H), 1.62−1.31 (m, 8H); 13C
NMR (100 MHz, CDCl3) δ 142.8, 138.9, 129.6, 126.7, 63.6, 47.1, 34.6,
30.3, 21.4, 13.7; IR (neat, cm−1) 3510, 1335, 1312, 1162; MS m/z 295
(M+), 140 (100%); HRMS (EI) calcd for C15H21NO3S, 295.1242;
found, 295.1233.
N-p-Toluenesulfonyl-6-oxa-2-azaadamantane (16). To a suspen-
sion of N-p-tolueneulfonyl-9-azabicyclo[3.3.1]nonan-3-ol (15) (560
mg, 1.90 mmol) and I2 (723 mg, 2.85 mmol) in cyclohexane (14 mL)
was added PhI(OAc)2 (950 mg, 2.95 mmol) at room temperature.
After stirring with irradiation (light source: 100 V, 100 W filament
lamp) for 1 h at 0 °C, the mixture was quenched with sat NaHCO3
(aq) and 20% Na2S2O3 (aq) and extracted with Et2O (3×). The
organic layer was washed with brine, dried over MgSO4, and
evaporated. The residue was purified with flash column chromatog-
raphy (AcOEt−hexane = 1:4) to afford N-p-toluenesulfonyl-6-oxa-2-
azaadamantane (16) (389 mg, 1.33 mmol, 70%) as colorless crystals
and to recover N-p-toluenesulfonyl-9-azabicyclo[3.3.1]nonan-3-one
(14) (47.5 mg, 160 μmol, 8.5%) as a colorless solid. 16: mp 152−153
°C (AcOEt); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H),
7.29 (d, J = 8.4 Hz, 2H), 4.30 (s, 2H), 4.10 (s, 2H), 2.42 (s, 3H), 1.98
(d, J = 12.6 Hz, 4H), 1.75 (d, J = 12.6 Hz, 4H); 13C NMR (100 MHz,
CDCl3) δ 143.2, 138.3, 129.7, 127.0, 66.3, 47.2, 33.9, 21.5; IR (neat,
cm−1) 1345, 1165; MS m/z 293 (M+), 293 (100%); HRMS (EI) calcd
for C15H19NO3S, 293.1086; found, 293.1083.
98%) as a colorless solid. 17: colorless crystals; mp 149−150 °C
(AcOEt); 1H NMR (400 MHz, CDCl3) δ 8.75 (br s, 1H), 7.75 (d, J =
8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 4.32 (s, 2H), 3.15 (d, J = 16.6
Hz, 1H), 2.58 (dd, J = 15.6, 6.4 Hz, 1H), 2.41 (s, 3H), 2.35 (d, J = 15.6
Hz, 1H), 2.21 (dd, J = 16.6, 6.4 Hz, 1H), 2.00 (s, 1H), 1.84−1.58 (m,
4H), 1.47−1.44 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 157.2,
143.3, 138.3, 129.8, 126.9, 48.8, 48.0, 35.2, 30.9, 30.0, 28.6, 21.4, 16.4;
IR (neat, cm−1) 3242, 1350, 1162; MS m/z 308 (M+), 291 (100%);
HRMS (EI) calcd for C15H20N2O3S, 308.1195; found: 308.1183.
N-[N′-p-Toluenesulfonyl-9-azabicyclo[3.3.1]non-3-yl]-p-toluene-
sulfonamide (18). To a solution of N-p-toluenesulfonyl-9-azabicyclo-
[3.3.1]nonan-3-one oxime (17) (1.00 g, 3.25 mmol) in MeOH (16
mL) was added MoO3 (792 mg, 4.88 mmol) at room temperature.
The mixture was stirred at room temperature for 30 min. NaBH4 (369
mg, 9.75 mmol) was added portionwise to the mixture at 0 °C. The
mixture was stirred until the oxime was no longer detected (ca. 1 h).
Then, TsCl (3.11 g, 16.3 mmol) was added to the mixture at 0 °C.
After stirring for 1 h at the same temperature, the mixture was filtered
through Celite, and the filtrate was concentrated under reduced
pressure. The residue was diluted with H2O and then extracted with
AcOEt. The organic layer was washed with brine, dried over MgSO4,
and evaporated. The residue was purified with column chromatog-
raphy (AcOEt−hexane = 1:1) to afford N-[N′-p-toluenesulfonyl-9-
azabicyclo[3.3.1]non-3-yl]-p-toluenesulfonamide (18) (1.18 g, 2.63
1
mmol, 81%) as colorless crystals: mp 146 °C (AcOEt−hexane); H
NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0
Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.29 (d, J
= 8.4 Hz, 1H), 4.19 (s, 1H), 4.16 (s, 1H), 3.04 (m, 1H), 2.44 (s, 6H),
2.15 (td, J = 12.0, 6.4 Hz, 2H), 1.82 (m, 1H), 1.51−1.42 (m, 3H), 1.30
(d, J = 14.0 Hz, 2H), 1.15 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
143.4, 143.0, 138.7, 137.9, 129.8, 129.7, 126.9, 126.7, 46.9, 46.0, 33.0,
30.4, 21.53, 21.51, 13.4; IR (neat, cm−1) 3279, 1331, 1162; MS m/z
448 (M+), 293 (100%); HRMS (EI) calcd for C22H28N2O4S2,
448.1490; found, 448.1494.
2-Aza-6-oxaadamantane N-Oxyl (Oxa-AZADO, 6). To a solution
of N-p-toluenesulfonyl-2-aza-6-oxaadamantane (16) (200 mg, 682
μmol) in toluene (1.5 mL) was added dropwise sodium bis(2-
methoxyethoxy)aluminum hydride (red-Al, 70% toluene solution, 950
μL, 3.41 mmol) at 0 °C. The mixture was refluxed for 1.5 h. After
being cooled to room temperature, the mixture was diluted with Et2O
and quenched with H2O. The mixture was filtered through Celite. The
filtrate was acidified with 10% HCl (aq) and washed with Et2O (1×).
The aqueous layer was basified with 10% NaOH (aq) and extracted
with CHCl3. The organic layer was dried over K2CO3 and evaporated.
The residue was used in the next reaction without further purification.
Na2WO4·2H2O (112 mg, 341 μmol) was added to a solution of the
residue in MeCN (3.4 mL) at ambient temperature. The mixture was
stirred at the same temperature for 20 min. UHP (256 mg, 2.73
mmol) was added to the solution at room temperature. After stirring
for 2 h at the same temperature, the mixture was diluted with sat
NaHCO3 (aq) and extracted with CHCl3 (3×). The organic layer was
dried over K2CO3 and evaporated. The residue was purified with flash
column chromatography (AcOEt−hexane = 1:1) to afford 2-aza-6-
oxaadamantane N-oxyl (oxa-AZADO, 6) (52.4 mg, 337 μmol, 50% for
two steps) as a yellow solid. 6: mp 115−116 °C (dec); 70 °C (hexane,
color changed from yellow to red); IR (neat, cm−1) 1442, 1338, 1284,
1057; MS m/z 154 (M+), 154 (100%); HRMS (EI) calcd for
C8H12NO2, 154.0868; found, 154.0858; Anal. calcd for C8H12NO2: C,
62.32; H, 7.84; N, 9.08; found: C, 62.14; H, 7.83; N, 8.96.
Syntheses of TsN-AZADO (7) and DiAZADO (8) (Scheme 4).
N-p-Toluenesulfonyl-9-azabicyclo[3.3.1]nonan-3-one Oxime (17).
To a solution of N-p-toluenesulfonyl-9-azabicyclo[3.3.1]nonan-3-one
(14) (15.0 g, 51.2 mmol) and pyridine (17 mL, 205 mmol) in EtOH
(85 mL) was added NH2OH·HCl (11.0 g, 154 mmol) at ambient
temperature. The mixture was stirred at 60 °C for 10 h. After being
cooled to room temperature, EtOH was removed under reduced
pressure. H2O was added to the residue, and the mixture was extracted
with AcOEt. The organic layer was washed with brine, dried over
MgSO4, and evaporated. The residue was purified with column
chromatography (AcOEt−hexane = 1:1) to afford N-p-toluenesulfon-
yl-9-azabicyclo[3.3.1]nonan-3-one oxime (17) (15.5 g, 50.3 mmol,
N,N′-Di-p-toluenesulfonyl-2,6-diazaadamantane (19). To a
solution of N-[N′-p-toluenesulfonyl-9-azabicyclo[3.3.1]non-3-yl]-p-
toluenesulfonamide (18) (1.00 g, 2.23 mmol) and I2 (284 mg, 1.12
mmol) in 1,2-dichloromethane (15 mL) was added PhI(OAc)2 (1.08
g, 3.35 mmol) at room temperature. After stirring with irradiation
(light source: 100 V, 100 W filament lamp) for 3 min at 0 °C, the
mixture was quenched with sat NaHCO3 (aq) and 20% Na2S2O3 (aq)
and extracted with AcOEt (3×). The organic layer was washed with
brine, dried over MgSO4, and evaporated. The residue was
recrystallized from CH2Cl2-MeOH (1:1) to give N,N′-di-p-toluene-
sulfonyl-2,6-diazaadamantane (19) (630 mg, 1.41 mmol, 63%) as
1
colorless needles. 19: mp 248 °C (CH2Cl2−MeOH); H NMR (400
MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 4H), 7.27 (d, J = 8.4 Hz, 4H),
4.20 (s, 4H), 2.41 (s, 6H), 1.74 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 143.4, 138.0, 129.8, 126.9, 47.0, 33.0, 21.5; IR (neat, cm−1)
1341, 1166; MS m/z 446 (M+), 446 (100%); HRMS (EI) calcd for
C22H26N2O4S2, 446.1334; found, 446.1320.
N-p-Toluenesulfonyl-2,6-diazaadamantane N′-Oxyl (TsN-
AZADO, 7), 2,6-Diazaadamantane N,N′-Dioxyl (DiAZADO, 8). To
a solution of N,N′-di-p-toluenesulfonyl-2,6-diazaadamantane (19)
(2.00 g, 4.48 mmol) in toluene (10 mL) was added sodium bis(2-
methoxyethoxy)aluminum hydride (red-Al, 70% toluene solution, 10
mL, 35.9 mmol) dropwise at 0 °C. The mixture was refluxed for 1 h.
After being cooled to room temperature, the mixture was diluted with
Et2O and quenched with H2O. The mixture was filtered through
Celite. The filtrate was acidified with 10% HCl (aq) and washed with
Et2O (1×). The aqueous layer was basified with 10% NaOH (aq) and
extracted with CHCl3. The organic layer was dried over K2CO3 and
evaporated. The residue was used in the next reaction without further
purification. Na2WO4·2H2O (739 mg, 2.24 mmol) was added to a
solution of the residue in MeCN (22 mL) at room temperature. The
suspension was stirred at the same temperature for 30 min. UHP (3.36
g, 35.8 mmol) was added to the suspension at room temperature. The
mixture was stirred for 4 h at the same temperature. Additional UHP
(842 mg, 8.96 mmol) was added to the solution at room temperature.
After stirring for another 1.5 h at the same temperature, the mixture
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was diluted with sat NaHCO3 and extracted with CHCl3. The organic
layer was dried over K2CO3 and evaporated. The residue was purified
with column chromatography (CHROMATOREX-NH, CHCl3−
hexane = 2:3) to afford N-p-toluenesulfonyl-2,6-diazaadamanatne N′-
oxyl (TsN-AZADO (7), 223 mg, 726 μmol, 16% for two steps) as a
pale-yellow solid and 2,6-diazaadamantane-N,N′-dioxyl (DiAZADO,
8) (79 mg, 470 μmol, 10% for two steps) as a yellow solid. TsN-
AZADO (7): pale-yellow crystals; mp 173 °C (CHCl3−hexane); IR
(neat, cm−1) 1343, 1161, 686; MS m/z 307 (M+, 100%); HRMS (EI)
calcd for C15H19N2O3S, 307.1116; found, 307.1098; Anal. calcd for
C15H19N2O3S: C, 58.61; H, 6.23; N, 9.11; found, C, 58.61; H, 6.23; N,
8.91. DiAZADO (8): yellow needles; mp 243−245 °C (dec, CHCl3);
IR (neat, cm−1) 1425, 1143; MS m/z 168 (M+), 168 (100%); HRMS
(EI) calcd for C8H12N2O2, 168.0899; found, 168.0891; Anal. calcd for
C8H12N2O2: C, 57.13; H, 7.19; N, 16.66; found: C, 56.86; H, 7.13; N,
16.52.
More Efficient Procedure for the Synthesis of DiAZADO (8)
(Scheme 5). To a solution of N,N′-di-p-toluenesulfonyl-2,6-diazaada-
mantane (19) (1.00 g, 2.24 mmol) in toluene (5.0 mL) was dropwise
added sodium bis(2-methoxyethoxy)aluminum hydride (red-Al, 70%
toluene solution, 6.2 mL, 22.4 mmol) at 0 °C. The mixture was
refluxed for 18 h. After being cooled to room temperature, the mixture
was diluted with Et2O and quenched with H2O. The mixture was
filtered through Celite. The filtrate was acidified with 10% HCl (aq)
and washed with Et2O (1×). The aqueous layer was basified with 10%
NaOH (aq) and extracted with CHCl3. The organic layer was dried
over K2CO3 and evaporated. The residue was used in the next reaction
without further purification. Na2WO4·2H2O (369 mg, 1.12 mmol) was
added to a solution of the residue in MeCN (11 mL) at room
temperature. The mixture was stirred at the same temperature for 30
min. UHP (1.69 g, 17.9 mmol) was added to the solution at room
temperature. The mixture was stirred for 2 h at the same temperature.
Additional UHP (422 mg, 4.48 mmol) was added to the solution at
room temperature. After stirring for another 1 h at the same
temperature, the mixture was diluted with sat NaHCO3 (aq) and
extracted with CHCl3. The organic layer was dried over K2CO3 and
evaporated. The residue was recrystallized from CHCl3 to give 2,6-
diazaadamantane N,N′-dioxyl (DiAZADO, 8) (146 mg, 869 μmol,
39% for two steps) as a bright-yellow needles. The mother liquor was
purified with column chromatography (CHROMATOREX-NH,
CHCl3−hexane = 2:3) to afford DiAZADO (8) (19 mg, 113 μmol,
5.0% for two steps) as a yellow solid.
μmol) at ambient temperature. After stirring for 2.5 h at the same
temperature under an air atmosphere (balloon), the reaction mixture
was diluted with AcOEt and quenched with sat NaHCO3 (aq) and
20% Na2S2O3 aq. The mixture was extracted with AcOEt (3×). The
organic layer was washed with brine, dried over MgSO4, and
evaporated. The residue was purified with flash column chromatog-
raphy (AcOEt−hexane = 2:3) to afford N-carbobenzoxy-4-amino-
cyclohexanone (28b) (42.0 mg, 170 μmol, 98%) as a colorless solid.
Entry 13: N-Carbobenzoxy-l-prolinol (32a) Using DiAZADO (8).
NaNO2 (6.63 mg, 96.1 μmol) at ambient temperature was added to a
solution of N-carbobenzoxy-l-prolinol (32a) (>99% ee) (226 mg,
0.961 mmol), AcOH (110 μL, 1.92 mmol), and DiAZADO (8) (1.62
mg, 9.61 μmol) in MeCN (961 μL). After stirring for 3.5 h at the same
temperature under an air atmosphere, the mixture was diluted with
AcOEt and quenched with sat NaHCO3 and 20% Na2S2O3. The
mixture was extracted with AcOEt (3×). The organic layer was washed
with brine, dried over MgSO4, and evaporated. The residue was
purified with flash column chromatography (AcOEt−hexane = 1:3) to
afford N-carbobenzoxy-l-prolinal (32b) (>99% ee, 166 mg, 0.712
mmol, 74%) as a colorless oil. Enantiomeric excess was determined by
HPLC with CHIRALPAK AD-H (5% iPrOH in hexane; flow rate, 0.5
mL/min).
1
Entry 1: 4-Methoxybezaldehyde (20b). Yellow oil; H NMR (400
MHz, CDCl3) δ 9.88 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8
Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.7, 164.6,
131.9, 129.9, 114.2, 55.5; IR (neat, cm−1) 1683; MS m/z 136 (M+),
135 (100%); HRMS (EI) calcd for C8H8O2, 136.0524; found,
136.0518.
Entry 2: (−)-Camphor (21b). Colorless solid; 1H NMR (400 MHz,
CDCl3) δ 2.35 (dt, J = 18.4, 3.6 Hz, 1H), 2.09 (t, J = 4.4 Hz, 1H),
1.99−1.92 (m, 1H), 1.84 (d, J = 18.4 Hz, 1H), 1.72−1.65 (m, 1H),
1.44−1.31 (m, 2H), 0.96 (s, 3H), 0.91 (s, 3H), 0.84 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 219.5, 57.7, 46.8, 43.3, 43.1, 29.9, 27.0, 19.8,
19.1, 9.2; IR (neat, cm−1) 1739; MS m/z 152 (M+), 149 (100%);
HRMS (EI) calcd for C10H16O, 152.1201; found, 152.1189.
Entry 3: 2-Phenylcyclohexan-1-one (22b). Colorless solid; 1H
NMR (400 MHz, CDCl3) δ 7.35−7.13 (m, 5H), 3.62 (dd, J = 12.2, 5.4
Hz, 1H), 2.56−2.42 (m, 2H), 2.31−2.25 (m, 1H), 2.18−2.13 (m, 1H),
2.09−1.97 (m, 2H), 1.86−1.80 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 210.2, 138.7, 128.5, 128.3, 126.8, 57.3, 42.1, 35.0, 27.7, 25.2;
IR (neat, cm−1) 1698; MS m/z 174 (M+), 174 (100%); HRMS (EI)
calcd for C12H14O, 174.1045; found, 174.1033.
Entry 4: 2,2-Dimethyl-1-phenylpropan-1-one (23b). Yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 2H), 7.47−7.37 (m,
3H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 209.1, 138.6,
130.7, 128.0, 127.7, 44.1, 27.9; IR (neat, cm−1) 1676; MS m/z 162
(M+), 105 (100%); HRMS (EI) calcd for C11H14O, 162.1045; found,
162.1057.
Selected Examples for the Scope of Oxa-AZADO (6), TsN-
AZADO (7), and DiAZADO (8) (Table 1). Substrates. l-Menthol
(9a), 4-phenyl-2-butanol (10a), 2-octanol (11a), 4-methoxy benzy-
lalcohol (20a), (−)-borneol (21a), 2,2-dimethyl-1-phenyl-1-propanol
(23a), 2,2-dimethyl-3-octanol (24a), 4-phenyl-1-butanol (25a), and
cinnamyl alcohol (26a) were purchased from commercial suppliers. 2-
Phenyl-1-cyclohexanol (22a),26 trans-2-benzoyloxy-1-cyclohexanol
(27a),27 N-carbobenzoxy-4-amino-1-cyclohexanol (28a),28 1,2:3,4-di-
O-isoproliridene-D-fructopyranose (29a),29 5-O-tert-butyldimethylsilyl-
1,2-O-isopropylidene-α-D-xylofuranose (30a),30 2′,5′-bis-O-(tert-butyl-
dimethylsilyl)-β-D-adenosine (31a),31 and N-carbobenzoxy-prolinol
(32a)32 were prepared according to the literature.
Entry 1: 4-Methoxybenzyl Alcohol (20a) Using Oxa-AZADO (6).
To a solution of 4-methoxybenzyl alcohol (20a) (181 mg, 1.31 mmol)
and oxa-AZADO (6) (2.02 mg, 13.1 μmol) in AcOH (1.3 mL) was
added NaNO2 (9.04 mg, 0.131 mmol) at ambient temperature. After
stirring for 3 h at the same temperature under an air atmosphere
(balloon), the reaction mixture was diluted with Et2O and quenched
with sat NaHCO3 (aq) and 20% Na2S2O3 aq. The mixture was
extracted with Et2O (3×). The organic layer was washed with brine,
dried over MgSO4, and evaporated. The residue was purified with flash
column chromatography (Et2O−hexane = 1:4) to afford 4-
methoxybenzaldehyde (20b) (169 mg, 1.24 mmol, 93%) as a light-
yellow oil.
Entry 5: 2,2-Dimethyloctan-3-one (24b). Yellow oil; 1H NMR
(400 MHz, CDCl3) δ 2.47 (t, J = 7.2 Hz, 2H), 1.55 (m, 2H), 1.34−
1.21 (m, 4H), 1.13 (s, 9H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 216.1, 44.1, 36.4, 31.5, 26.4, 23.6, 22.5, 13.9; IR (neat,
cm−1) 1706; MS m/z 156 (M+), 99 (100%); HRMS (EI) calcd for
C10H20O, 156.1514; found, 156.1510.
1
Entry 6: 4-Phenylbutanal (25b). Yellow oil; H NMR (400 MHz,
CDCl3) δ 9.76 (d, J = 1.6 Hz, 1H), 7.31−7.16 (m, 2H), 7.22−7.17 (m,
3H), 2.66 (t, J = 7.4 Hz, 2H) 2.45 (t, J = 7.4 Hz, 2H), 1.96 (quint, J =
7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 202.1, 141.2, 128.4,
126.0, 43.0, 34.9, 23.6; IR (neat, cm−1) 1723; MS m/z 148 (M+), 104
(100%); HRMS (EI) calcd for C10H12O, 148.0888; found, 148.0880.
1
Entry 7: trans-Cinnamaldehyde (26b). Yellow oil; H NMR (400
MHz, CDCl3) δ 9.71 (d, J = 8.0 Hz, 1H), 7.58−7.56 (m, 2H), 7.49 (d,
J = 16.4 Hz, 1H), 7.45−7.42 (m, 3H), 6.73 (dd, J = 16.4, 8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 193.5, 152.6, 134.0, 131.2, 129.0,
128.5, 128.4; IR (neat, cm−1) 1675; MS m/z 132 (M+), 131 (100%);
HRMS (EI) calcd for C9H8O, 132.0575; found, 132.0564.
Entry 8: 2-Benzoyloxycyclohexan-1-one (27b). Colorless solid; 1H
NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6
Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.41 (dd, J = 11.8, 6.4 Hz, 1H), 2.57
(d, J = 11.8 Hz, 1H), 2.51−2.43 (m, 2H), 2.14−1.89 (m, 4H), 1.86−
Entry 9: N-Carbobenzoxy-trans-4-aminocyclohexanol (28a)
Using TsN-AZADO (7). To a solution of N-Cbz-trans-4-amino-
cyclohexanol 28a (43.4 mg, 174 μmol) and TsN-AZADO 7 (1.60
mg, 5.21 μmol) in AcOH (435 μL) was added NaNO2 (1.20 mg, 17.4
K
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1.66 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 204.2, 165.5, 133.1,
129.8, 129.7, 128.3, 76.9, 40.7, 33.2, 27.2, 23.7; IR (neat, cm−1) 1731,
1708; MS m/z 218 (M+), 105 (100%); HRMS (EI) calcd for
C13H14O3, 218.0943; found, 218.0949.
Aid for Scientific Research (B) 17390002 and 21390001 from
the Japan Society for the Promotion of Science (JSPS); and
Grant-in-Aid for Young Scientists (A) 23689001 from JSPS .
We thank Nissan Chemical Industries, Ltd. for the generous gift
of AZADO.
Entry 9: N-Carbobenzoxy-4-aminocyclohexan-1-one (28b). Col-
1
orless solid; H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.11 (s,
2H), 4.78 (s, 1H), 4.00 (br s, 1H), 2.42 (s, 4H), 2.24 (s, 2H), 1.75−
1.64 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 209.5, 155.6, 136.3,
128.5, 128.2, 128.1, 66.8, 47.9, 38.8, 32.1; IR (neat, cm−1) 1717, 1685,
1532. HRMS (ESI) calcd for C14H17NO3Na ([M + Na]+), 247.1208;
found, 247.1172.
REFERENCES
■
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Entry 10: 1,2:4,5-Di-O-isopropylidene-β-D-erythro-2,3-hexodiulo-
1
2,6-pyranose (29b). Colorless solid; H NMR (400 MHz, CDCl3) δ
4.73 (d, J = 5.8 Hz, 1H), 4.61 (d, J = 9.2 Hz, 1H), 4.55 (dd, J = 5.8, 2.0
Hz, 1H), 4.40 (dd, J = 13.6, 2.0 Hz, 1H), 4.12 (d, J = 13.6 Hz, 1H),
3.99 (d, J = 9.2 Hz, 1H), 1.55 (s, 3H), 1.46 (s, 3H), 1.40 (s, 6H); 13C
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60.0, 27.1, 26.4, 26.0, 25.9; IR (neat, cm−1) 1749; MS m/z 259 ([M +
H]+), 114 (100%); HRMS (EI) calcd for C12H19O6, 259.1182; found,
259.1195.
Entry 11: 5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-α-D-
erythro-3-pentulofuranose (30b). Colorless oil; 1H NMR (400
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4.4 Hz, 1H), 3.88 (dd, J = 11.2, 2.0 Hz, 1H), 3.81 (dd, J = 11.2, 2.0 Hz,
1H), 1.45 (s, 3H), 1.44 (s, 3H), 0.86 (s, 9H) 0.05 (s, 3H), 0.03 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 210.9, 114.1, 103.8, 81.7, 77.1,
63.9, 27.7, 27.2, 25.8, 18.1, −5.5, −5.7; IR (neat, cm−1) 1776; MS m/z
245 ([M − tBu]+), 245 (100%); HRMS (EI) calcd for C10H17O5Si,
245.0845; found, 245.0849.
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MHz, CDCl3) δ 8.37 (s, 1H), 8.15 (s, 1H), 6.15 (d, J = 8.0 Hz, 1H),
5.84 (s, 2H), 4.95 (d, J = 8.0 Hz, 1H), 4.31 (s, 1H), 3.98 (s, 2H), 0.93
(s, 9H), 0.73 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H), −0.01 (s, 3H), −0.20
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NMR (400 MHz, CDCl3) δ 9.60 (s, 0.5H), 9.49 (d, J = 2.4 Hz, 0.5H),
7.38−7.28 (m, 5H), 5.21−5.13 (m, 2H), 4.30 (t, 0.5 H, J = 5.8 Hz),
4.20 (t, 0.5 H, J = 5.8 Hz), 3.62−3.50 (m, 2H), 2.17−1.99 (m, 2H),
1.95−1.82 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 200.0, 155.4,
154.5, 136.5, 136.3, 128.5, 128.1, 128.0, 67.33, 67.29, 65.3, 64.9, 47.3,
46.7, 27.9, 26.6, 24.5, 23.8; IR (neat, cm−1) 1734, 1699, 1415, 1356;
MS m/z 204 ([M − CHO]+), 91 (100%); HRMS calcd C12H14NO2,
204.1025; found, 204.1033.
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ASSOCIATED CONTENT
* Supporting Information
Kinetic profile of the ABNO-catalyzed oxidation, raw data of
■
S
1
figures, electrochemical measurement results, and copies of H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: y-iwabuchi@m.tohoku.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysis” from the Ministry of Education,
Culture, Sports, Science, and Technology (MEXT); Grants-in-
L
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M
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