Efficient oxidation of alcohols electrochemically mediated by azabicyclo-N-oxyls

Article abstract of DOI:10.1016/j.tetlet.2007.11.016

Preparation of azabicyclo-N-oxyls and the electrochemical oxidation of alcohols using them as mediators have been exploited. This oxidation was applicable to a transformation of sterically hindered secondary alcohols into the corresponding ketones in high yields.

Full text of DOI:10.1016/j.tetlet.2007.11.016

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 48–52
Efficient oxidation of alcohols electrochemically mediated
by azabicyclo-N-oxyls
Yosuke Demizu,a Hirofumi Shiigi,b Takahisa Oda,a Yoshihiro Matsumuraa
and Osamu Onomuraa,*
aGraduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan
bTsukuba Research Laboratory, Tokuyama Corporation, 40 Wadai, Tsukuba 300-4247, Japan
Received 11 October 2007; revised 31 October 2007; accepted 2 November 2007
Available online 7 November 2007
Abstract—Preparation of azabicyclo-N-oxyls and the electrochemical oxidation of alcohols using them as mediators have been
exploited. This oxidation was applicable to a transformation of sterically hindered secondary alcohols into the corresponding
ketones in high yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The oxidation of primary or secondary alcohols to the
corresponding aldehydes or ketones is an important
transformation in organic synthesis. Recently, from
the environmental and atom-economical point of view,
a lot of catalytic methods using clean oxidants have been
exploited.1 A versatile organocatalyst 2,2,6,6-tetra-
methylpiperidine-N-oxyl (TEMPO) has been utilized in
chemical2 and electrochemical oxidation3 of alcohols
as a mediator. TEMPO is a stable but sterically hindered
radical because of the four methyl groups adjacent to
the nitroxyl group. Therefore, TEMPO is not suitable
for the oxidation of sterically hindered alcohols. In
2006, Iwabuchi and co-workers reported an excellent
oxidation of sterically hindered alcohols using
O
O
N
N
N
O
m
n
Azabicyclo-
N-oxyls
TEMPO
1-Me-AZADO
Figure 1. Structures of some N-oxyls.
to the method reported by us as shown in Eq. 1.
Namely, the electrochemical oxidation of N-methoxy-
carbonyl-pyrrolidine (1) and -piperidine (2) afforded
dimethoxylated compounds 3 and 4,8 which were easily
transformed into azabicyclo compounds 5 and 6, respec-
tively, by TiCl4-catalyzed one-pot cyclization with allyl-
trimethylsilane. Finally, reductive dechlorination of 5
and 6 afforded 7 and 8, respectively.9
1-methyl-2-azaadamantane-N-oxyl
(1-Me-AZADO),
which is one of the sterically less hindered class of
nitroxyl radicals (Fig. 1).4
Several azabicyclo-N-oxyls5 (Fig. 1) have been reported.
They exist as stable radicals because of Bredt’s rule.6
Although their physicochemical properties were exam-
ined, the possibility for them acting as mediators for
the oxidation of alcohols has hardly been known.7 We
wish to report herein an efficient electrochemical oxida-
tion of various alcohols mediated by azabicyclo-N-
oxyls. The azabicyclo skeletons were prepared according
Preparation of 3-chloro-8-azabicyclo[3.2.1]octane-N-oxyl
(9) is shown in Eq. 2. That is, deprotection of 5 by
utilizing Me3SiI followed by Na2WO4-catalyzed
oxidation using urea hydrogen peroxide (UHP) afforded
a mixture of 9 and the corresponding hydroxylamine 10.
Also, a mixture of 8-azabicyclo[3.2.1]octane-N-oxyl
(11)5a and the corresponding hydroxylamine 1210 was
synthesized from 7. In a similar manner, 3-chloro-9-aza-
bicyclo[3.3.1]octane-N-oxyl (13)11,12 and 9-azabicyclo-
[3.3.1]octane-N-oxyl (14)5f without any generation of
the hydroxylamines were synthesized from 6 and 8,
respectively, Eq. 3.
Keywords: Oxidation; Alcohol; Ketone; Aldehyde; Nitroxyl radical.
*
Corresponding author. Tel.: +81 95 819 2429; fax: +81 95 819
2476; e-mail: onomura@nagasaki-u.ac.jp
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.016

Y. Demizu et al. / Tetrahedron Letters 49 (2008) 48–52
49
CO2Me
N
CO2Me
N
( )n
( )n
allylSiMe3
TiCl4
-4e
OMe
MeO
N
N
MeOH
CO2Me
1: n=1
2: n=2
CO2Me
Cl
Cl
6
3: n=1, 77% yield
4: n=2, 71% yield
5
41% yield
45% yield
ð1Þ
CO2Me
N
CO2Me
N
H2
Raney Ni W-2, KOH
7
8
90% yield
90% yield
CO2Me
N
O
N
OH
N
1) Me3SiI, CH2Cl2, rt, 12 h
+
2) UHP, Na2WO4, MeOH
rt, 4.5 h
X
X
X
ð2Þ
ð3Þ
5: X=Cl
7: X=H
9: X=Cl
11: X=H
10: X=Cl
12: X=H
a mixture of 9 and 10 : 67% yield
a mixture of 11 and 12 : 72% yield
CO2Me
N
O
N
1) Me3SiI CH2Cl2, rt, 12 h
2) UHP, Na2WO4, MeOH
rt, 4.5 h
X
X
6: X=Cl
8: X=H
13: X=Cl (54%)
14: X=H (60%)
Cyclic voltammograms for a mixture of N-oxyl 9 and
hydroxylamine 10 (9 + 10) showed reversible wave pat-
tern similar to that for TEMPO. This strongly suggests
that azabicyclo-N-oxyls could play the role of an oxida-
tion mediator just like TEMPO (Fig. 2).13
afforded 1-phenyl-2-propanone (16) quantitatively
(entry 2). Whereas using NaCl in place of NaBr did
not promote the oxidation (entry 3), use of NaI led to
poor yield compared to that of NaBr (28%, entry 4).
These results mean that Brꢀ ion is the most suitable
halogen mediator for this electrochemical oxidation.
Using 0.02–0.01 equiv of (9 + 10) slightly reduced the
yield of 16 (93%, entries 5 and 6).
The electrochemical oxidation of 1-phenyl-2-propanol
(15) using azabicyclo-N-oxyls as a mediator was carried
out under similar conditions used by Torii and co-work-
ers for TEMPO (Eq. 4).3c That is, the oxidation was
conducted using platinum electrodes in an undivided
beaker-type cell, containing a catalytic amount of
(9 + 10), sodium halides (NaX), and a mixture of
CH2Cl2 and satd aqueous NaHCO3 as solvent, at a con-
stant current (50 mA).14 The results are summarized in
Table 1. Oxidation of 15 did not proceed at all in the
absence of (9 + 10) (entry 1). In the presence of 0.1 equiv
of (9 + 10) together with NaBr, the oxidation of 15
-[e], 3.0
F
/mol, NaX (4.0 equiv)
OH
O
(9+10)
CH2Cl2/sat. aq. NaHCO3, rt
15
16
ð4Þ
Other N-oxyls (11 + 12), 13, 14, and 175d,15 were also
good oxidation catalysts just like TEMPO (Eq. 5).
-[e], 3.0 F/mol, NaBr (4.0 equiv)
15
16
O
N
(11+12), 13, 14, 17 or TEMPO (0.1 equiv)
CH2Cl2/sat. aq. NaHCO3, rt
(11+12) : 99%
13 : 80%
ð5Þ
14 : 99%
17
17 : 99%
TEMPO : 92%

50
Y. Demizu et al. / Tetrahedron Letters 49 (2008) 48–52
+40
30
+28
20
10
0
20
10
0
-10
-14
-10
0
0.2
0.4
Potential, V
CV for a mixture of 9+10
Figure 2. Cyclic voltammograms for 9 + 10 and TEMPO.
0.6
0.8 +1.0
0
0.2
0.4
0.6
0.8 +1.0
Potential, V
CV forTEMPO
-[e], 3.0 F/mol, NaBr (4.0 equiv)
Table 1. Electrochemical oxidation of 1-phenyl-2-propanol (15)
15
16
ð6Þ
N-hydroxylamine 10 (0.1 equiv)
CH2Cl2/sat. aq. NaHCO3, rt
Entry
Equiv of (9 + 10)
Sodium halide
Yield of 16 (%)
93% yield
1
2
3
4
5
6
0
NaBr
NaBr
NaCl
NaI
NaBr
NaBr
0
99
0
28
93
93
0.1
0.1
0.1
0.02
0.01
Table 2 shows the electrochemical oxidation of various
primary and secondary alcohols 18–22 using azabi-
cyclo-N-oxyls (9 + 10), (11 + 12), 13, 14, 17, and
TEMPO as mediators (Eq. 7). All N-oxyls had excellent
catalytic activity just like TEMPO toward primary
alcohols 18 and 19 (entries 1 and 2), and secondary
alcohols 20–22 (entries 3–5) to afford the corresponding
carbonyl compounds 23–27 in high yield, respectively.
Moreover, isolated N-hydroxylamine 10 catalyzed the
electrochemical oxidation of 15 as efficiently as N-oxyl
(9 + 10) (Eq. 6).
Table 2. Electrochemical oxidation of various alcohols 18–22
Entry
Alcohol
Product
Yield of product (%)
(9 + 10)
(11 + 12)
13
14
17
TEMPO
99
H
OH
OH
1
18
99
96
99
90
82
23
O
O
H
O
2
3
19
20
24
25
77
99
90
99
91
99
99
99
99
99
68
72
OH
OH
O
4
5
21
26
99
98
97
99
86
99
90
99
99
99
77
84
OH
O
22
27

Y. Demizu et al. / Tetrahedron Letters 49 (2008) 48–52
51
-[e], 3.0 F/mol, NaBr (4.0 equiv)
(9+10), (11+12), 13, 14, 17, or TEMPO (0.1 equiv)
ð7Þ
Aldehydes or ketones
Alcohols
18-22
CH2Cl2/sat. aq. NaHCO3, rt
23-27
Table 3. Electrochemical oxidation of sterically hindered alcohols 28–31
Entry
Alcohol
Product
Yield of product (%)
(9 + 10)
(11 + 12)
13
14
17
TEMPO
OH
O
1
28
32
87
65
90
86
82
61
2
29
30
33
34
99
86
92
82
76
23
OH
O
OH
O
3
4
85
72
74
75
94
97
99
99
99
74
41
56
5
5
OH
COOMe
O
31
35
Ph
Ph
COOMe
Table 3 summarizes the electrochemical oxidation of
sterically hindered secondary alcohols 28–31 (Eq. 8). In
the case of TEMPO, the oxidized products 32–35 were
obtained in low to moderate yield (23–61%), while
N-oxyls (9 + 10), (11 + 12), 13, 14, and 17 played a
better role than TEMPO (entries 1–4). These results
prove that azabicylo-N-oxyls are efficient mediators for
the oxidation of sterically hindered alcohols because
they are less hindered than TEMPO.
In summary, azabicyclo-N-oxyls (9 + 10), (11 + 12),
13, 14, and 17 were applicable to electrochemical
oxidation of various alcohols as mediators. Especially
in the oxidation of sterically hindered secondary alco-
hols to the corresponding ketones, these N-oxyls were
much more effective than TEMPO. Preparation of chi-
ral azabicyclo-N-oxyls and enantiospecific oxidation of
secondary alcohols using them as mediators are now
underway.
-[e], 3.0 F/mol, NaBr (4.0 equiv)
(9+10), (11+12), 13, 14, 17, or TEMPO (0.1 equiv)
Alcohols
28-31
Ketones
32-35
CH2Cl2/sat. aq. NaHCO3, rt
Acknowledgments
ð8Þ
This work was supported in part by a Grant-in-Aid
for Young Scientists (B) (19790017) from the
Ministry of Education, Science, Sports and Culture,
Japan and by the president’s discretion fund and a
Grant-in-Aid for Scientific Research from Nagasaki
University.
Azabicyclo-N-oxyls (9 + 10), (11 + 12), 13, 14, and 17
were also effective in the chemical oxidation (Eq. 9).17–19
That is, l-menthol (29) was almost quantitatively oxi-
dized by using these N-oxyls, while in the case of TEM-
PO the yield of l-menthone (33) was only 22%.
NaIO4 (1.2 equiv), NaBr (0.1 equiv)
(9+10), (11+12), 13, 14, 17, or TEMPO (0.1 equiv)
(9+11): 99%
(11+12): 92%
13 : 99%
CH2Cl2 / H2O, rt, 24 h
OH
O
ð9Þ
14 : 99%
29
33
17 : 99%
TEMPO: 22%

52
Y. Demizu et al. / Tetrahedron Letters 49 (2008) 48–52
pressure. The residue was purified by silica gel column
References and notes
chromatography (n-hexane/AcOEt = 10:1) to afford
N-oxyl 13 (175 mg, 54% yield) as an yellow solid. Mp:
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69–70 ꢁC. IR (neat): 2991, 1441, 1358, 1298 cmꢀ1
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MS[HR-FAB(+)] m/z: [M+H]+ calcd for C8H14ClNO,
175.0764; found, 175.0781.
12. Relative stereoconfiguration of 13 was determined by the
X-ray analysis. Crystallographic data for this structure
have been deposited with the Cambridge Crystallographic
Data Centre as Supplementary Publication Number
CCDC 663222. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge CB21EZ, UK; fax: +44(0) 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk.
13. Cyclic voltammogram for a mixture of 9 + 10 was
measured in 0.1 M Et4NBF4/MeCN solution using
glassy-carbon as a working electrode, platinum as a
counter electrode, and Ag/0.01 M AgNO3 as a reference
electrode. Concentration of (9 + 10): 1.0 mM. Scan rate:
10 mV/s. Other N-oxyls (11 + 12), 13, 14, and 17 were
represented by the similar reversible wave patterns.
14. Representative procedure for the electrochemical oxida-
tion of alcohols: Anodic oxidation of 15 was carried out
using platinum electrodes (1 cm · 2 cm) in an undivided
beaker-type cell. Alcohol 15 (68 mg, 0.5 mmol), a mixture
of 9 + 10 (8.1 mg, 0.05 mmol) and NaBr (206 mg,
2.0 mmol) were added into a mixture of CH2Cl2 (2.5 mL)
and satd aqueous NaHCO3 (2.5 mL). After passing
through 3.0 F/mol of electricity at constant current
(50 mA) at rt, the mixture was poured in water and
extracted with AcOEt (20 mL · 3). The combined organic
layer was dried on MgSO4 and the solvent removed under
reduced pressure. The residue was purified by silica gel
column chromatography (n-hexane/AcOEt = 20:1) to
afford 16 (66 mg, 99% yield) as a colorless oil.
4. Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y.
J. Am. Chem. Soc. 2006, 128, 8412–8413.
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Graetz, B.; Rychnovsky, S.; Leu, W.; Farmer, P.; Lin, R.
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15. Azabicyclo-N-oxyl 175d was prepared from N-Cbz-7-aza-
bicyclo[2.2.1]heptane.16 Since isolated 17 was somewhat
unstable, it gradually changed into the corresponding
N-hydroxylamine even at ꢀ20 ꢁC.
´
´
16. Olivo, H. F.; Peeples, T. L.; Rıos, M.-Y.; Velazquez, F.;
Kim, J.-W.; Narang, S. J. Mol. Catal. B: Enzym. 2003, 21,
97–105.
17. A procedure for the chemical oxidation (Ref. 18) of 29:
Under an aerobic atmosphere, 29 (78 mg, 0.5 mmol), a
mixture of 9 + 10 (8.1 mg, 0.05 mmol), NaIO4 (128 mg,
0.6 mmol), and NaBr (5.1 mg, 0.05 mmol) were added into
a mixture of CH2Cl2 (1.0 mL) and water (1.0 mL). After
stirring for 24 h at rt, the solution was poured in water and
extracted with AcOEt (20 mL · 3). The combined organic
layer was dried on MgSO4 and the solvent removed under
reduced pressure. The residue was purified by silica gel
column chromatography (n-hexane/AcOEt = 20:1) to
afford 33 (77 mg, 99% yield) as a colorless oil.
10. Mendenhall, G. D.; Ingold, K. U. J. Am. Chem. Soc. 1973,
95, 2963–2971.
11. A typical procedure for the preparation of N-oxyl 13: A
solution of 6 (218 mg, 1.0 mmol) and Me3SiI (600 mg,
3.0 mmol) in CH2Cl2 (5.0 mL) was stirred for 12 h at rt.
The solution was added into saturated aqueous NaHCO3
and extracted with CHCl3 (20 mL · 3). The combined
organic layer was dried over K2CO3 and the solvent
removed under reduced pressure to afford a crude amine
that was used for the next reaction without purification. A
solution of amine and Na2WO4Æ2H2O (33 mg, 0.1 mmol)
in MeOH (2.0 mL) was stirred for 30 min at rt. To the
solution was added urea hydrogen peroxide (470 mg,
5.0 mmol). After stirring for 4 h at rt, the solution was
poured in saturated aqueous NaHCO3 and extracted with
CHCl3 (20 mL · 3). The combined organic layer was dried
over K2CO3 and the solvent removed under reduced
18. Lei, M.; Hu, R.-J.; Wang, Y.-G. Tetrahedron 2006, 62,
8928–8932.
19. Recently, some methods for highly efficient chemical
oxidation of sterically hindered secondary alcohols using
TEMPO or its analogs have been reported: (a) Bobbitt, J.
M. J. Org. Chem. 1998, 63, 9367–9374; (b) Zhao, X.-F.;
Zhang, C. Synthesis 2007, 551–557.