Highly chemoselective aerobic oxidation of amino alcohols into amino carbonyl compounds

Article abstract of DOI:10.1002/anie.201309634

The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2-azaadamantane N-oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol-selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen-containing compounds. Strong as an ox: The highly chemoselective aerobic oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has been achieved by using 2-azaadamantane N-oxyl (AZADO)/copper catalysis. This catalytic system oxidizes not only alcohols with tertiary amino groups but also those with secondary and primary amines in good to high yield at ambient temperature in air. bpy=2,2-bipyridyl, DMAP=4-(N,N-dimethylamino)pyridine.

Full text of DOI:10.1002/anie.201309634

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Angewandte
Communications
DOI: 10.1002/anie.201309634
Chemoselectivity
Highly Chemoselective Aerobic Oxidation of Amino Alcohols into
Amino Carbonyl Compounds**
Yusuke Sasano, Shota Nagasawa, Mai Yamazaki, Masatoshi Shibuya, Jaiwook Park, and
Yoshiharu Iwabuchi*
Abstract: The direct oxidation of unprotected amino alcohols
to their corresponding amino carbonyl compounds has often
posed serious challenges in organic synthesis and has con-
strained chemists to adopting an indirect route, such as
a protection/deprotection strategy, to attain their goal. De-
scribed herein is a highly chemoselective aerobic oxidation of
unprotected amino alcohols to their amino carbonyl com-
pounds in which 2-azaadamantane N-oxyl (AZADO)/copper
catalysis is used. The catalytic system developed leads to the
alcohol-selective oxidation of various unprotected amino
alcohols, carrying a primary, secondary, or tertiary amino
group, in good to high yield at ambient temperature with
exposure to air, thus offering flexibility in the synthesis of
nitrogen-containing compounds.
alcohols and amines by dehydrogenative condensation using
ruthenium catalysts has been reported, and has achieved the
selective oxidation of alcohols and hemiaminals in the
presence of amines.[4] However, the general procedure for
the selective oxidation of unprotected amino alcohols to their
amino carbonyl compounds has not yet been reported.
We sought to develop mild and widely applicable methods
for alcohol oxidation using nitroxyl radical catalysts, in which
the corresponding oxoammonium ions serve as active species
(Figure 1a).[5] We focused on less sterically hindered oxo-
T
he oxidation of alcohols into their corresponding carbonyl
compounds is one of the most fundamental transformations in
organic chemistry, and thus numerous selective alcohol
oxidation methods have been developed.[1] Nevertheless, the
direct oxidation of alcohols, having unprotected amino
groups, into their corresponding amino carbonyl compounds
often suffers from poor yield owing to either the non-
productive or destructive interaction between an electron-
rich amino group and the oxidant, and reflects weak state-of-
the-art alcohol oxidation:[2] alcohol moieties of amino alco-
hols are typically oxidized after the amino groups are
protected as amides or carbamates, thus reducing synthetic
efficiency.[3] Recently, the direct synthesis of amides from
Figure 1. Simplified reaction mechanisms of nitroxyl-radical-catalyzed
alcohol oxidation.
[*] Y. Sasano, S. Nagasawa, M. Yamazaki, Dr. M. Shibuya,[+]
Prof. Dr. Y. Iwabuchi
ammonium ions, which are generated by the oxidation of 2-
azaadamantane N-oxyl (AZADO) and related nitroxyl
radicals (Figure 2).[6] AZADO and its relatives exhibit high
catalytic activities for alcohol oxidation with a markedly
broad substrate scope by using various mild or environ-
Department of Organic Chemistry, Graduate School of Pharma-
ceutical Sciences, Tohoku University
6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: y-iwabuchi@m.tohoku.ac.jp
Prof. Dr. J. Park
Department of Chemistry, POSTECH (Pohang University of Science
and Technology), Pohang 790-784 (Republic of Korea)
[+] Current address: Department of Basic Medicinal Sciences
Graduate School of Pharmaceutical Sciences, Nagoya University
Furo-cho, Chikusa-ku, Nagoya 464-8601 (Japan)
[**] This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” from MEXT (Japan), by a Grant-in-Aid for
JSPS Asian Core Program on Cutting-Edge Organic Chemistry in
Asia, by a Grant-in-Aid for Scientific Research (B) (No. 24390001)
from JSPS, and by a Grant-in-Aid for Young Scientists (B) (No.
25860001) from JSPS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309634.
Figure 2. Structure of nitroxyl radicals.
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Table 1: Optimization of the reaction conditions for secondary alcohols.
mentally benign terminal oxidants, such as NaOCl, PhI-
(OAc)2, NOx-O2,[7] and diisopropyl azodicarboxylate.[8]
Unfortunately, most of these methods fail to oxidize unpro-
tected amino alcohols efficiently owing to the conceivable
nonproductive interaction between oxoammonium ions and
amines (Figure 3a).
Entry Nitroxyl radical (mol%) [Cu]
Additive t [h] Conv. [%][a]
1[b]
2
3
4
5
6
7
8
9
10
11
12
13
TEMPO (5)
AZADO (1)
AZADO (1)
AZADO (1)
AZADO (1)
AZADO (1)
AZADO (1)
5-F-AZADO (1)
nor-AZADO (1)
1-Me-AZADO (1)
ABNO (1)
keto-ABNO (1)
TEMPO (1)
CuOTf[c] NMI
CuOTf[c] NMI
24
24
4
3
5
12
2
3
2
3
25
80
100
100
100
56
100
98
100
100
93
CuCl
CuBr
CuI
NMI
NMI
NMI
CuBr2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
NMI
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
6
6
3
50
0
Figure 3. Working hypothesis: oxidation of amino alcohols by oxo-
ammonium or nitroxyl radical/copper.
[a] Determined by GC. [b] [Cu] (10 mol%), bpy (5 mol%), additive
(10 mol%). [c] (CuOTf)2·benzene was used as the CuOTf source.
DMAP=4-(N,N-dimethylamino)pyridine, TEMPO=2,2,6,6-tetramethyl-
1-piperidinyloxy, Tf=trifuoromethanesulfonyl.
Herein, we focus on another type of nitroxyl-radical-
catalyzed oxidation method, namely, nitroxyl radical/copper
catalysis with molecular oxygen as the terminal oxidant
(Figure 1b).[9] Since the pioneering work by Semmelhack
et al. published in 1984, in which TEMPO and CuCl catalysts
were used for the aerobic oxidation of benzylic/allylic
alcohols to aldehydes,[10] the scope of nitroxyl radical/copper
catalysis has grown,[11] especially from the contribution of the
groups of Sheldon,[11g] Koskinen,[11c] and Stahl,[11a] thus
enabling the methodology to lead to highly practical alcohol
oxidations by judicious choice in the copper salt, ligand, and
additives. The applicability of this catalysis has expanded to
the synthesis of imines,[12] nitriles,[13] and nitrogen-containing
heterocycles[14] by oxidizing not only alcohols but also amines.
Most recently, Steves and Stahl have disclosed ABNO/copper
catalysis which displays excellent reactivity with functional-
group tolerance for primary and secondary aliphatic alcohols
to give carbonyl compounds.[15] However, the selectivity of
such catalysis toward the oxidation of unprotected amino
alcohols has barely been addressed.[16] We envisaged that
nitroxyl radical/copper catalysis could achieve the selective
oxidation of amino alcohols into amino carbonyl compounds
because a copper alkoxide intermediate would be more
readily generated than a copper amide intermediate (Fig-
ure 3b). We report herein the highly chemoselective aerobic
oxidation of unprotected amino alcohols into amino carbonyl
compounds using AZADO and copper catalysts.
reactivity than CuOTf, and that the reaction proceeded in
quantitative conversion within 5 hours (entries 3–6). After
screening amine-base types of additives, DMAP was found to
accelerate the reaction (entry 7).[11h] Thus, other nitroxyl
radicals were examined (entries 8–13), and 5-F-AZADO and
nor-AZADO, which showed higher reactivity than AZADO
in the NOx-mediated aerobic oxidation of alcohols, showed
the same activity as AZADO or lower in this case (entries 8
and 9).[6c,7] ABNO and keto-ABNO, which were reported as
catalysts for the copper-mediated aerobic oxidation of
alcohols and amines, respectively, worked less efficiently
than AZADO (entries 11 and 12).[12c,15] Although many
ligands and solvents were also examined, bpy and MeCN
gave the best results.[17]
Next, we determined the optimum reaction conditions for
the oxidation of amino primary alcohols using 6-dimethyl-
amino-1-hexanol (1b) as the model substrate (Table 2).
Table 2: Optimization of the reaction conditions for primary alcohols.
This study commenced with the comparison of the
catalytic efficiencies of TEMPO and AZADO by using N-
methyl-4-piperidinol (1a) as the model substrate under the
reaction conditions reported by Hoover and Stahl who
employed a nitroxyl radical, CuOTf, 2,2-bipyridyl (bpy), and
N-methylimidazole (NMI) as the catalysts in MeCN at
ambient temperature in open air.[11a] The result shows that
1 mol% AZADO oxidized 1a to its corresponding ketone 2a
in 80% conversion, whereas 5 mol% TEMPO oxidized 1a in
only 25% conversion (Table 1, entries 1 and 2). The screening
of copper salts indicated that halide salts of CuI showed higher
Entry
Nitroxyl radical
[Cu]
Additive
t [h]
Conv. [%][a]
1
2
3
4
5
6
7
8
TEMPO
AZADO
AZADO
5-F-AZADO
nor-AZADO
1-Me-AZADO
ABNO
CuOTf[b]
CuOTf[b]
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
NMI
NMI
1
1
1
1
1
2
1
0.5
10
29
42
36
36
67
39
7
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
TEMPO
[a] Determined by GC. Conversions did not increase after an extended
reaction time. [b] (CuOTf)2·benzene was used as the CuOTf source.
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AZADO showed superior catalytic activity to TEMPO in the
oxidation of 1b to give the aldehyde 2b in 29% conversion
under the standard reaction conditions reported by Hoover
and Stahl (entries 1 and 2). The combination of CuCl and
DMAP gave better conversion than that of CuOTf and NMI
(entry 3). After screening nitroxyl radical catalysts, it was
found that the more bulky 1-Me-AZADO showed higher
activity than AZADO (entries 4–8). Previous structure–
activity relationship studies showed that less sterically hin-
dered nitroxyl radicals exhibited higher reactivity.[6c,d]
With the optimum reaction conditions in hand, we
compared the reactivity of AZADO/copper catalysis with
that of conventional selective alcohol oxidation methods,
namely, PCC oxidation,[18] Swern oxidation,[19] Dess–Martin
oxidation,[20] and TPAP oxidation,[21] by oxidizing secondary
alcohols with tertiary and secondary amines (Table 3). In the
control experiments, it was confirmed that all the methods
efficiently oxidized the N-Cbz-protected piperidinol 1c in
high yield. In contrast, the oxidation of the amino alcohols 1a,
1d, and 1e was ineffective in the cases of the conventional
methods, thereby giving the ketones in low or modest yield.
AZADO/copper catalysis exhibited excellent activities for all
the amino alcohols, including the highly functionalized amino
alcohol 1e, to give the amino ketones in high yields and it
worked well even on a 50 mmol scale. Notably, imino ketones
or imino alcohols were not obtained in the oxidation of the
benzylamino alcohol 1d or 1e even though nitroxyl radical/
copper catalysis can oxidize benzylic amines to imines.[12c,22]
Encouraged by the promising results, we applied the
optimum reaction conditions to examine the substrate scope
(Table 4 and Table 5). Note that the yields of amino carbonyl
products with aliphatic secondary and primary amines were
determined by isolating the Boc-protected products, because
of the difficulty in isolating the highly polar unprotected
products (Table 5). The benzylic alcohol 1 f and the allylic
alcohol 1g were efficiently oxidized with 1 mol% AZADO
(Table 4, entries 1 and 2). The examination of the functional-
group tolerance indicated that AZADO/copper catalysis
tolerated benzylic and allylic amines, an ester, and N-hetero-
cycles (entries 3–9). Furthermore, this catalysis selectively
oxidized not only the sterically bulky secondary alcohols 1o
and 1p but also the primary alcohol 1q in good yields
(entries 10–12). The oxidation of the chiral primary alcohols
1r and 1s proceeded with almost complete retention of their
stereochemistry (entries 13 and 14). Notably, 5-benzylamino-
1-pentanol (1t), which was converted into d-valerolactam by
ruthenium-catalyzed dehydrogenation,[23] was transformed
into the enamine dimer 4 in good yield (entry 15). Unfortu-
nately, the vicinal amino alcohol 1u was not oxidized
(entry 16). Secondary alcohols with aliphatic secondary and
primary amines were efficiently oxidized into the amino
ketones even in the case of the bulky alcohol 1w with a nitrile
group (Table 5, entries 1–4). The more challenging primary
alcohol 1z, having a secondary amine, was also selectively
oxidized to give the aldehyde in moderate yield (entry 5).
To demonstrate the utilization of the highly chemo-
selective alcohol oxidation, we applied AZADO/copper
oxidation to the synthesis of nitrogen-containing natural
products. The readily prepared pyridyl amino alcohol 1aa was
efficiently converted into myosmine (6) in 60% yield under
the standard reaction conditions, whereas the TPAP oxidation
of the alcohol 1aa afforded only a trace amount of myosmine
(6; Scheme 1a).[24] AZADO/copper catalysis also oxidized
mesembranol (1ab) to (À)-mesembrine (2ab) in high yield.
The reaction has recently been reported by Geoghegan and
Table 3: Comparison of known methods and AZADO/copper catalysis of
amino alcohol oxidation.[a]
Amino alcohol
PCC[b]
Swern[b] DMP[b]
TPAP[b] AZADO/Cu[c]
92%
/2 h
95%
/0.75 h /2 h
97%
90%
/0.75 h /1.5 h
97%
65%
/1 h
(10%) (17%)
20%
/3 h
32%
96%
/3 h
16%
/1.5 h
/3 h[d]
(29%)
26%
/1 h
(<5%)
0%
32%
68%
92%
/4 h
/2 h
/4 h
/1.2 h
(<29%) (13%)
97%
/2 h
14%
/2 h
(29%) (3%)
10%
Dec.
/2 h
/1 h
<1%
/12 h
(72%)
99%
/3.5 h[e]
[a] Reaction conditions: PCC: PCC (1.5 equiv), 4 ꢀ M.S. (500 mg/
1 mmol substrate), CH2Cl2 (0.2m), RT; Swern: (COCl)2 (2.0 equiv),
DMSO (4.0 equiv), Et3N (6.0 equiv), CH2Cl2 (0.17m), À788C to RT;
DMP: Dess–Martin periodinane (1.5 equiv), CH2Cl2 (0.2m),RT; TPAP:
TPAP (5 mol%), NMO (1.5 equiv), 4 ꢀ M.S. (500 mg/1 mmol substrate),
CH2Cl2 (0.1m), RT; AZADO/Cu: AZADO (3 mol%), CuCl (3 mol%), bpy
(3 mol%), DMAP (6 mol%), MeCN (0.2m), air (open), RT. Yields of
product/time (remaining substrate) are shown. [b] Yield determined by
1H NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal
standard. [c] Yield of isolated product. [d] 1 mol% AZADO was used.
[e] 50 mmol scale. Cbz=benzyloxycarbonyl.
Scheme 1. Application to synthesis of natural alkaloids.
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Table 4: Oxidation of alcohols with tertiary and benzylic secondary
Table 5: Oxidation of alcohols with aliphatic secondary and primary
amines.[a]
amines.[a]
Entry
Amino alcohol
x/y
t
[h]
Yield
[%][a]
Entry
1
Amino alcohol
x/y
t [h]
Yield [%][a]
89
1v
1w
1x
3/3
4
1
2
1/3 2.5
1/3
92
90
2
3
5/5
3/3
2.5
1
74
88
3
3
4
5
6
1h: R=allyl
1i: R=Bn
1j: R=PMB
1/3 2.5
1/3 2.5
1/3 3
97
97
99
87
1k: R=geranyl 3/3 4.8
4[b]
1y
1z
5/5
5/5
2
72
61
7
8
1/3
2
94
96
5[b,c]
1.5
3/3 1.7
5/5 4.5
[a] Yield of isolated product. [b] 0.1m MeCN was used. [c] 1-Me-AZADO
was used instead of AZADO. Boc=tert-butoxycarbonyl.
9
77
In summary, we have developed a highly efficient and
chemoselective aerobic oxidation of amino alcohols to amino
carbonyl compounds. The catalytic system consisting of
AZADO and copper(I) oxidized not only alcohols with
tertiary amino groups but also those with secondary and
primary amines in good to high yield. Moreover, AZADO/
copper catalysis could be utilized for the synthesis of nitrogen-
containing natural products. Studies of the precise mechanism
of this catalysis are under way.
10
3/3
2
88
80
11
5/5 2.5
12[b]
5/5
1
74
Received: November 5, 2013
Revised: December 31, 2013
Published online: February 19, 2014
66[c,d]
13[b]
5/5 2.5
5/5 1.5
Keywords: amino alcohol · chemoselectivity · copper ·
oxidation · radical chemistry
.
64[c,e]
14[b]
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3/3
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