2-Azaadamantane N-oxyl (AZADO)/Cu Catalysis Enables Chemoselective Aerobic Oxidation of Alcohols Containing Electron-Rich Divalent Sulfur Functionalities

Article abstract of DOI:10.1021/acs.orglett.8b02528

The chemoselective oxidation of alcohols containing electron-rich sulfur functionalities (e.g., 1,3-dithianes and sulfides) into their corresponding carbonyl compounds with the sulfur groups can sometimes be a demanding task in modern organic chemistry. A reliable method for this transformation, which features azaadamantane-type nitroxyl radical/copper catalysis using ambient air as the terminal oxidant is reported. The superiority of the developed method was demonstrated by comparing it with various conventional alcohol oxidation methods.

Full text of DOI:10.1021/acs.orglett.8b02528

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
2
‑Azaadamantane N‑oxyl (AZADO)/Cu Catalysis Enables
Chemoselective Aerobic Oxidation of Alcohols Containing Electron-
Rich Divalent Sulfur Functionalities
†
Yusuke Sasano, Naoki Kogure, Shota Nagasawa, Koki Kasabata, and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku,
Sendai 980-8578, Japan
*
S Supporting Information
ABSTRACT: The chemoselective oxidation of alcohols con-
taining electron-rich sulfur functionalities (e.g., 1,3-dithianes
and sulfides) into their corresponding carbonyl compounds
with the sulfur groups can sometimes be a demanding task in
modern organic chemistry. A reliable method for this transformation, which features azaadamantane-type nitroxyl radical/
copper catalysis using ambient air as the terminal oxidant is reported. The superiority of the developed method was
demonstrated by comparing it with various conventional alcohol oxidation methods.
lcohols are ubiquitous functional groups embedded in
A
numerous organic molecules. Therefore, a chemoselective
method for their selective modification will provide chemists
with opportunities to design and synthesize valuable new
molecules. Among the various types of modification methods
for alcohols, the oxidation of the primary and secondary
alcohols to give the corresponding carbonyl compounds plays
indispensable roles in organic synthesis, because of their
versatile uses. Thus, a diverse range of methods to efficiently
Figure 1. Nitroxyl radicals.
alcohols with oxidation-labile sulfur-containing functional
groups if we could identify an appropriate combination of
nitroxyl radical/copper salt/ligand/additives. Although several
combination catalysts of nitroxyl radicals and copper for
1
conduct this particular transformation have been developed.
However, increases in functional group diversity and molecular
complexity pose significant challenges, with regard to the
chemoselectivity issue, which requires the development of
breakthrough methods that enable selective alcohol oxidation
in the presence of oxidation-labile, electron-rich functional
groups. Some sulfur-containing functional groups, such as
dithianes and sulfides, are examples of the oxidation-labile
6
aerobic alcohol oxidation have been reported, their applic-
ability to electron-rich sulfur-containing alcohols has rarely
7
been reported. The main issues that must be overcome in
nitroxyl radical/copper catalysis are as follows: (i) the
oxidatively active species must be orthogonal to the sulfur-
containing moiety, (ii) the active catalytic copper complex
must not be deactivated by coordination to the sulfur group,
2
functional groups. Thus, in the synthesis of organosulfur
and (iii) H O generated in situ after alcohol oxidation must
compounds, sulfur-containing functional groups are often
2
2
3
be dismutated before it reacts with the sulfur moiety. Here, we
report a highly chemoselective aerobic oxidation of oxidation-
labile sulfur-containing alcohols into the corresponding
carbonyl compounds.
introduced at a late stage. Considering the great importance
of organosulfur compounds as pharmaceuticals, agrichemicals,
flavors/fragrances, materials, and synthetic intermediates,
4
among others, it would be highly rewarding to develop a
In this study, we first optimized the reaction conditions
using 1,3-dithiane-containing alcohol 1a as a substrate model
reliable method for the chemoselective oxidation of sulfur-
containing alcohols into the corresponding carbonyl com-
pounds, as this would expand the diversity of the synthetic
strategy for organosulfur compounds.
5a
(
see Table 1). Considering our previous optimization study,
we first compared the activities of CuOTf in a concentrated
8
solution and CuCl in a diluted solution (entries 1 and 2). As a
We previously demonstrated a highly chemoselective aerobic
oxidation of unprotected amino alcohols into amino carbonyl
compounds, based on combination catalysis of a less-hindered
nitroxyl radical [2-azaadamantane N-oxyl (AZADO)] and a
result, CuCl in a diluted solution showed higher activity to
afford ketone 2a in 43% conversion. No other products were
observed in the gas chromatography (GC), thin-layer
1
5
chromatography (TLC), and H nuclear magnetic resonance
copper salt (see Figure 1). Such combination catalysis can
(
NMR) analysis of crude products. The combination of
impart unprecedented chemoselectivity upon an alcohol
oxidation at room temperature, employing ambient molecular
oxygen as the terminal oxidant. We envisaged that AZADO/
copper catalysis could be applicable to the oxidation of
Received: August 7, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02528
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Table 2. Substrate Scope
a
nitroxyl
radical
Cu salt
(mol %)
MeCN
(M)
time
(h)
conversion
(%)
entry
b
b
1
2
3
AZADO
CuOTf (3)
CuCl (3)
CuOTf (3)
CuCl (6)
CuOTf (6)
CuOTf (6)
1
0.2
1
0.2
0.2
0.2
0.2
0.2
0.2
1
3
1
1
2
3
1
1
1
15
43
38
AZADO
AZADO
AZADO
AZADO
AZADO
Nor-AZADO CuCl (6)
ABNO
1-Me-
AZADO
c
d
4
5
6
100 (94 )
b
b
51
89
c
d
7
8
9
100 (97 )
100 (94 )
100 (96 )
d
CuCl (6)
CuCl (6)
d
1
1
1
0
1
2
TEMPO
ketoABNO
AZADOL
CuCl (6)
CuCl (6)
CuCl (6)
0.2
0.2
0.2
3
1
1
trace
100 (94 )
100 (95 )
d
d
a
Determined by GC. Conversion did not increase after an extended
b
reaction time. (CuOTf) ·benzene was used as the CuOTf source.
2
c
4
,4′-Dimethoxy-2,2′-bipyridyl and N-methylimidazole were used
d
1
instead of bpy and DMAP, respectively. Yield determined by H
NMR spectroscopy using 1,3,5-trimethoxybenzene as the internal
standard.
CuOTf, 4,4′-dimethoxy-2,2′-bipyridyl, and N-methylimidazole,
7a
which is reported by Stahl, resulted in only a 38% conversion
(
%
1
Table 1, entry 3). Increasing the amount of CuCl from 3 mol
to 6 mol % achieved complete conversion of the oxidation in
h (Table 1, entry 4). The same amount (6 mol %) of CuOTf
gave lower conversion (Table 1, entries 5 and 6). Next, we
compared the catalytic activities of nitroxyl radicals (Table 1,
entries 7−11). Nitroxyl radicals of a less-hindered class,
9
10
11
namely, Nor-AZADO, ABNO, and 1-Me-AZADO,
induced complete conversion, although highly hindered
TEMPO did not promote any reactions (Table 1, entries 7−
12
1
0). An electron-deficient nitroxyl radical, ketoABNO, also
showed good reactivity (Table 1, entry 11). AZADOL, the
commercially available hydroxylamine variant of AZADO,
showed the same reactivity as AZADO (Table 1, entry 12).
Considering both reactivity and availability, we chose AZADO
11a
as the nitroxyl radical for evaluation of the substrate scope.
With the optimum conditions determined, we evaluated
their substrate scope (see Table 2). 1,3-Dithiane-containing
cyclohexanol 1a, acyclic alcohol 1b, and even highly oxy-
genated alcohol 1c were chemoselectively oxidized to afford
ketones 2a−2c in high yields. We then examined the oxidation
of sulfide-containing alcohols 1d−1k. Both benzylic alcohol 1d
and aliphatic alcohol 1e with phenylsulfide groups were
efficiently oxidized to ketones 2d and 2e, respectively. The
alcohol oxidation smoothly proceeded in the presence of other
functional groups such as a silyl ether (1f), a tertiary amine, a
nitrile (1g), a secondary benzylic amine (1h), and an ester
a
b
Yields are for the isolated product. The reaction was performed at 0
c
d
(
1i). The AZADO/copper-catalyzed oxidation of 1i gave a
°C. 0.1 M MeCN was used. 1-Me-AZADO was used instead of
AZADO (see ref 5a). 0.1 M MeCN/DMF (1:1) was used as the
solvent, and the product was isolated as the corresponding 2,4-
dinitrophenylhydrazone.
e
higher yield (79%) than the previously reported Swern
oxidation (61%). The primary alcohols 1j and 1k (a biotin
derivative) were respectively oxidized into aldehydes 2j and 2k
in good yields. The oxidation of alcohols 1l−1o with
protected/unprotected thiols were also examined. Alcohols
2
a
1
3
any deprotection, although CuCl is known to catalyze the
deprotection of Tr groups on thiols. Application of AZADO/
copper oxidation to alcohol 1o with an unprotected thiol group
14
1
l−1n, which contain thiols protected by PMB, Tr, and Fm
groups, were oxidized into ketones 2l−2n efficiently without
B
DOI: 10.1021/acs.orglett.8b02528
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
promoted not alcohol oxidation, but disulfide formation to give
only dihydroxydisulfide 1p as a detectable product even after
an extended reaction time. In contrast, the alcohol-selective
oxidation of isolated 1p smoothly proceeded to afford diketone
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02528.
2
p in high yield.
To demonstrate the usefulness of the developed method, we
compared its reaction efficiency with those of conventional
Preparation of the substrates, procedure of alcohol
oxidation, characterization data, and copies of spectra
(PDF)
15
16
17
18
methods, namely, PCC, Swern oxidation, DMP, TPAP,
11
and PhI(OAc) with AZADO catalyst, using 1a and 1l as the
2
model substrates (see Table 3). Although Swern, TPAP, and
AUTHOR INFORMATION
Corresponding Author
a
■
Table 3. Comparison of Oxidation Methods
*
E-mail: y-iwabuchi@m.tohoku.ac.jp.
ORCID
Yoshiharu Iwabuchi: 0000-0002-0679-939X
Present Address
†Department of Chemistry, University of California, Berkeley,
CA 94720, USA.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by JSPS KAKENHI Grant
Nos. 16H00998, 18H04232 (Precisely Designed Catalysts with
Customized Scaffolding), 16H05072, and 15K07848, by
Platform Project for Supporting Drug Discovery and Life
Science Research [Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS)] from AMED
under Grant No. JP18am0101100, and by Core to Core
Program “Advanced Research Network for Asian Cutting-Edge
Organic Chemistry” from JSPS.
a
Reaction conditions for PCC: PCC (1.5 equiv), MS4A (500 mg/1
mmol substrate), CH Cl (0.2 M), rt. Reaction conditions for Swern:
2
2
(
COCl) (0.2 equiv), DMSO (4 equiv), Et N (6 equiv), CH Cl (0.2
2
3
2
2
M), − 78 °C to rt. Reaction conditions for DMP: Dess−Martin
periodinane (1.5 equiv), CH Cl (0.2 M), rt. Reaction conditions for
2
2
TPAP: TPAP (5 mol %), NMO (1.5 equiv), MS4A (500 mg/1 mmol
substrate), CH Cl (0.1 M), rt. Reaction conditions for AZADO/
2
2
PhI(OAc) : AZADO (3 mol %), PhI(OAc) (1.5 equiv), CH Cl (1
2
2
2
2
M), rt; AZADO/Cu/air: AZADO (3 mol %), CuCl (6 mol %), bpy (3
mol %), DMAP (6 mol %), MeCN (0.2 M), air (open), rt. Yields in
terms of product/time (remaining substrate) are shown. Yields were
determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene
as the internal standard.
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DOI: 10.1021/acs.orglett.8b02528
Org. Lett. XXXX, XXX, XXX−XXX