Revisiting Sodium Hypochlorite Pentahydrate (NaOCl·5H 2 O) for the Oxidation of Alcohols in Acetonitrile without Nitroxyl Radicals

Article abstract of DOI:10.1055/s-0037-1609629

Sodium hypochlorite pentahydrate (NaOCl·5H ₂ O) is capable of oxidizing alcohols in acetonitrile at 20 °C without the use of catalysts. The oxidation is selective to allylic, benzylic, and secondary alcohols. Aliphatic primary alcohols are not oxidized.

Full text of DOI:10.1055/s-0037-1609629

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
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Synlett
T. Hirashita et al.
Letter
Revisiting Sodium Hypochlorite Pentahydrate (NaOCl·5H O) for
2
the Oxidation of Alcohols in Acetonitrile without Nitroxyl Radicals
Tsunehisa Hirashita*
Yuto Sugihara
Shota Ishikawa
Yohei Naito
0
0
0
0-0
0
0
1-
7
1
9
6-3
3
3
9
OH
R2
O
NaOCl·5H2O
1
0 examples
R1
CH3CN
R1
R2
up to 97% yield
benzylic and aliphatic secondary alcohols
Yuta Matsukawa
Shuki Araki
NaOCl·5H O
TEMPO, Bu4NHSO4
CH2Cl2
NaOCl (Bleach)
TEMPO, KBr
CH2Cl2
2
NaOCl·5H2O
No Catalyst
CH CN
3
1° > 2°
1° = 2°
1° < 2°
Life Science and Applied Chemistry, Graduate School of
Engineering, Nagoya Institute of Technology, Gokiso-cho,
Showa-ku, Nagoya 466-8555, Japan
hirasita@nitech.ac.jp
Received: 04.07.2018
Accepted after revision: 26.09.2018
Published online: 17.10.2018
was performed in [bmim][PF ] (where bmim = 1-butyl-3-
methylimidazolium), the ionic TEMPO 1 was found to be
6
DOI: 10.1055/s-0037-1609629; Art ID: st-2018-u0413-l
superior to TEMPO (entries 3 and 4), as had been observed
in the aerobic version. Using NaOCl·5H O instead of conven-
2
Abstract Sodium hypochlorite pentahydrate (NaOCl·5H O) is capable
2
tional bleach gave better conversion, and a moderate yield
was attained even after only 3 min (entries 5 and 6). We
were surprised to find a similar level of oxidation when or-
ganic radicals were not present (entry 7). In acetonitrile,
of oxidizing alcohols in acetonitrile at 20 °C without the use of catalysts.
The oxidation is selective to allylic, benzylic, and secondary alcohols.
Aliphatic primary alcohols are not oxidized.
Key words oxidation, alcohol, sodium hypochlorite pentahydrate,
aldehyde, ketone
Table 1 Oxidation of Benzyl Alcohol with NaOCl (bleach) or
a
NaOCl·5H O
The selective oxidation of alcohols to the corresponding
aldehydes and ketones is ranked as one of the pivotal func-
tional transformations in organic synthesis. Selective oxi-
2
R
1
dation of alcohols can be performed with sodium hypochlo-
rite as a terminal oxidizing agent, using 2,2,6,6-tetramethyl-
piperidine 1-oxyl (TEMPO) and its derivatives as
oxidizing agent
catalyst
PhCH OH
2
PhCHO
N
O
2
mediators. Recently, solid sodium hypochlorite penta-
TEMPO: R = H
: R = NBu2Me⋅PF6
1
hydrate (NaOCl·5H O) became commercially available, and
2
3
it has proven to be an attractive oxidizing agent. This ‘solid
Entry Oxidizing agent Solvent (mL)
Catalyst
t (min) Yield (%)b
bleach’ has a higher effective chlorine concentration than
conventional household bleach, and thus lends itself to
more concentrated reaction mixtures. We have recently re-
ported that the aerobic oxidation of alcohols is more suc-
cessful using the TEMPO derivative 1 in an ionic liquid than
that performed using either TEMPO in an ionic liquid or us-
1c
bleach
CH
CH
Cl
Cl
(2)
(2)
TEMPO
1
20
60
60
60
60
3
92 (2)
78 (9)
27 (70)
61 (29)
97 (3)
51 (36)
58 (21)
80 (7)
2 (74)
2
2
2
2
2c
bleach
3d
bleach
bmim·PF
bmim·PF
bmim·PF
bmim·PF
bmim·PF
6
6
6
6
6
(1)
TEMPO
1
4d
bleach
(1)
5
6
7
8
NaOCl·5H
NaOCl·5H
NaOCl·5H
2
2
2
O
O
O
(1.5)
(1.5)
(1.5)
1
4
ing 1 in conventional organic solvents. We envisaged that
1
our oxidation system could be applied using NaOCl·5H O
2
none
none
none
3
instead of conventional bleach as the terminal oxidant.
We started by examining the oxidation of benzyl alco-
NaOCl·5H O
2
CH CN (5)
3
3
hol using bleach or NaOCl·5H O in various solvents. When
2
9
NaOCl·5H O
CH Cl (5)
60
2
2
2
benzyl alcohol was mixed with bleach in methylene chlo-
ride, the reaction using TEMPO proceeded faster than that
involving the ionic TEMPO 1 (Table 1, entries 1 and 2). This
is the same tendency as observed in aerobic oxidation using
a
All reactions were carried out with benzyl alcohol (0.50 mmol), NaOCl
(bleach) or NaOCl·5H O (125 mol%), and catalyst (1 mol%) in solvent at
2
room temperature unless otherwise noted.
b
GC yield. Values in parentheses show the recovery of benzyl alcohol.
With benzyl alcohol (1.0 mmol).
With benzyl alcohol (0.25 mmol).
c
4
d
sodium nitrite as the oxidizing agent. When the oxidation
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
Synlett
T. Hirashita et al.
Letter
the oxidation proceeded quite fast to provide 2-octanone in
high yield (entry 8). However, almost no reaction proceeded
in methylene chloride (entry 9).
TEMPO (1 mol%)
Bu4NHSO4 (5 mol%)
NaOCl·5H2O
120 mol%)
(
3
CH CN, 5 °C, 1 h
Contrary to the above results, Okada et al. reported that
acetonitrile is not a suitable solvent for the oxidation of
alcohols in the presence of an ammonium salt and TEMPO
as catalysts, because the oxidation reaction of 2-octanol did
not go to completion in acetonitrile.3c We confirmed that
the oxidation of 2-octanol in the presence of catalytic
amounts of TEMPO and tetrabutylammonium hydrogensul-
fate reached a plateau at less than 60% conversion under the
reported conditions (Figure 1, blue line). When the oxida-
tion was performed in the absence of additives, the reaction
proceeded more smoothly, providing 2-octanone in higher
yields (red line). We also found that the amount of aceto-
nitrile has a strong effect on the conversion. Under dilute
conditions, both the reactions with and without additives
proceeded more quickly than those performed under rela-
tively concentrated conditions.
PhCH2OH
PhCHO
97%
5 °C, 0.5 h
Scheme 1 Oxidation of benzyl alcohol (5 mmol) with NaOCl·5H O
exposed to CH CN (15 mL) that contained catalysts
2
3
The oxidation of alcohols with bleach alone proceeds suffi-
ciently in ethereal solvents, though oxidizable substrates
are strictly limited to primary benzylic alcohols; secondary
alcohols, even benzylic alcohol, remain intact under these
conditions.6
Oxidation of 2-Octanol with Only NaOCl·5H O
We next performed a solvent screening for the oxida-
tion of 2-octanol with NaOCl·5H O at 5 °C; the results are
summarized in Table 2. We tested a series of ethereal sol-
2
2
6
vents that are known to support bleach-oxidation. When
2
-octanol was mixed with NaOCl·5H O in 1,2-dimethoxy-
2
ethane (DME), 2-octanone was obtained in 23% yield after 1
h (entry 1). The reaction in 1,4-dioxane was performed at
20 °C due to the high melting point of the solvent, and re-
sulted in a lower yield than that in DME (entry 2). A poor
conversion was observed in THF (entry 3). Although the
best yield among the ethereal solvents was found in DME,
6
which is in agreement with the bleach oxidation, the con-
version was still much lower than that in acetonitrile. We
next employed aprotic polar solvents. The use of DMF
(entry 4) resulted in a similar level of conversion to that ob-
served in 1,4-dioxane and THF. In ethyl acetate and acetone,
little progress was observed (entries 5 and 6). We therefore
turned our attention back to acetonitrile. When the tem-
perature was increased, the reaction rate was clearly accel-
erated (entries 7–9). When the oxidation was performed
Figure 1 Rate profile for the oxidation of 2-octanol (0.10 or 0.33 M in
with 150 mol% NaOCl·5H O at 20 °C, the conversion was al-
acetonitrile) with NaOCl·5H O (120 mol%) with and without the addi-
2
2
tives TEMPO (1 mol%) and Bu NHSO (5 mol%)
most quantitative, providing 2-octanone in 91% yield after
only 1 h, which was determined to be the optimal condi-
tions (entry 10).7
4
4
The difference was speculated to arise from the undesir-
Substrate Scope and Limitations
able oxidation of acetonitrile with NaOCl·5H O under the
influence of the catalysts. This hypothesis was examined by
A series of alcohols were subjected to oxidation under
the optimal conditions. 2-Undecanol was oxidized to 2-un-
decanone in good yield (Table 3, entry 1). L-Menthol was
easily converted into menthone (entry 2), whereas the
more sterically demanding isoborneol resisted oxidation
(entry 3). Benzylic alcohols, including a heteroaromatic,
gave good yields in short reaction times (entries 4–6). The
oxidation of cinnamyl alcohol prevailed over addition of
hypochlorous acid to the double bond, providing cinnamal-
2
admixing NaOCl·5H O and the catalysts in acetonitrile for 1
2
h prior to the addition of benzyl alcohol (Scheme 1), which
led to an almost quantitative conversion of the alcohol into
benzaldehyde. When 2-octanol instead of benzyl alcohol
was allowed to react for 1 h, the yield of 2-octanone was
5
7%. As NaOCl·5H O does not decompose under the reac-
2
tion conditions, the discrepancy in the oxidations remains
puzzling.
There are other reported examples of bleach-mediated
oxidation of alcohols without the use of organic radicals.
Bleach has proven capable of oxidizing secondary alcohols
selectively in the absence of catalysts in glacial acetic acid.5
dehyde in a better yield than when performed under
Anelli’s conditions (entry 7).2
a,2b
Primary aliphatic alcohols
yielded only a small amount of the corresponding alde-
hydes and were largely recovered (entries 8 and 9).
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T. Hirashita et al.
Letter
Table 2 Solvent Effect on the Oxidation of 2-Octanol with only
(Table 4). Benzyl alcohol was oxidized five times faster than
2-octanol (entry 1). The reaction performed at –20 °C re-
sulted in similar selectivity (data not shown). A larger selec-
tivity was observed for L-menthol (entry 2) than for 2-octa-
nol. As expected from the oxidation of aliphatic primary al-
cohols (Table 3, entries 8 and 9), benzaldehyde was
selectively obtained in the competitive reaction with 1-oc-
tanol (Table 4, entry 3).
a
NaOCl·5H O
2
OH
O
NaOCl⋅5H2O
5
solvent, temp.
5
Yield (%)b
Entry
Solvent
Temp. (°C)
Time (h)
1
2
3
4
5
6
7
8
9c
DME
5
20
5
1
1
1
1
1
1
1
4
2
1
23 (67)
8 (68)
7 (83)
11 (87)
3 (95)
0 (98)
44 (48)
79 (9)
82 (11)
91 (2)
1,4-dioxane
THF
Table 4 Competitive Oxidations with NaOCl·5H Oa
2
O
DMF
5
Ph
OH
R2
Ph
H
EtOAc
acetone
5
NaOCl·5H O (50 mol%)
2
+
+
5
CH3CN, 20 °C, 15 min.
OH
O
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
5
R1
R1
R2
5
Entry
1st alcohol
2nd alcohol
Relative rate ratiob
10
20
1
0c
1
2
PhCH
PhCH
2
OH
OH
2-octanol
L-menthol
1-octanol
5:1
a
2
Reaction conditions: 2-octanol (0.50 mmol), NaOCl·5H O (120 mol%) in
2
7.6:1
18.5:1
solvent (5 mL).
b
Determined by GC. Figures in parentheses show the recovery of 2-octa-
nol.
NaOCl·5H O (150 mol%) was used.
2
3
2
PhCH OH
a
c
All reactions were carried out with each alcohol (0.50 mmol) and
O (0.50 mmol) in CH CN (5 mL) at 20 °C for 15 min.
NaOCl·5H
2
3
b
The relative rate ratio was determined by the yields of the corresponding
carbonyl compounds.
Table 3 Oxidation of a Series of Alcohols with NaOCl·5H Oa
2
When a mixture of 1-octanol and L-menthol was sub-
jected to the oxidation conditions, menthone was selective-
ly obtained (Scheme 2).
OH
R2
O
NaOCl⋅5H2O (150 mol%)
R1
R1
R2
3
CH CN, 20 °C
Entry
1
Alcohol
CH (CH
Time (h)
1
Yield (%)b
82 (12)
O
OH
6
H
a
3
2
)
8
CH(OH)CH
3
6
0
.50 mmol
4
% (77%)
NaOCl·5H2O (0.50 mmol)
OH
+
+
OH
O
CH3CN, 20 °C, 1 h
2
3
1
97 (3)
iPr
iPr
iPr
34% (66%)a
0
.50 mmol
a
Recovery of alcohol
OH
1.5
10 (53)
Scheme 2
4
5
PhCH
2
OH
0.25
0.25
96 (0)
95 (0)
PhCH(OH)CH
3
1,5-Hexanediol was allowed to react under the same
conditions to afford the corresponding hydroxyketone
selectively with a similar level of conversion (Scheme 3).
OH
6
0.25
83 (0)
8
N
7
8
(E)-PhCH=CHCH
2
OH
0.25
1
72 (0)
2 (80)
2 (70)
OH
O
NaOCl·5H2O (150 mol%)
CH
3
(CH
(CH
2
)
)
6
9
CH
2
2
OH
OH
3
OH
CH3CN, 20 °C, 1 h
3
OH
31% (49%)a
9
CH
3
2
CH
1
a
a
Recovery of the diol
Reaction conditions: alcohol (0.50 mmol) and NaOCl·5H
CN (5.0 mL).
Determined by GC. Figures in parentheses show the recovery of alcohol.
2
O (0.75 mmol)
in CH
3
b
Scheme 3
To gain insight into the nature of the oxidation, benzyl
alcohol was allowed to react competitively with 2-octanol,
In conclusion, NaOCl·5H O proved to function well as an
oxidizing agent for alcohols in acetonitrile without the use
of additives. Benzylic and aliphatic secondary alcohols are
2
menthol, and 1-octanol for a limited amount of NaOCl·5H O
2
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Synlett
T. Hirashita et al.
Letter
selectively oxidized to the corresponding carbonyl com-
pounds; aliphatic primary alcohols are particularly slow to
oxidize under these conditions.
(4) Hirashita, T.; Nakanishi, M.; Uchida, T.; Yamamoto, M.; Araki, S.;
Arends, I. W. C. E.; Sheldon, R. A. ChemCatChem 2016, 8, 2704.
(
5) (a) Stevens, R. V.; Chapman, K. T.; Weller, H. N. J. Org. Chem.
980, 45, 2030. (b) Stevens, R. V.; Chapman, K. T.; Stubbs, C. A.;
1
Tam, W. W.; Albizati, K. F. Tetrahedron Lett. 1982, 23, 4647.
6) Fukuda, N.; Kajiwara, T.; Katou, T.; Majima, K.; Ikemoto, T.
Synlett 2013, 24, 1438.
(
Supporting Information
Supporting information for this article is available online at
(7) Oxidation of 2-Octanol; Typical Procedure (entry 10,
Table 2): To a suspension of NaOCl·5H O crystals (123 mg, 0.75
mmol) in acetonitrile (5.0 mL), was added 2-octanol (65 mg,
.50 mmol), and the resulting mixture was stirred at 20 °C. Ali-
https://doi.org/10.1055/s-0037-1609629.
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References and Notes
quots were analyzed at intervals by GC after passing through a
short SiO2 column (eluting with EtOAc/hexane, 9:1). The reac-
(1) (a) Fernandez, M. I.; Tojo, G. Oxidation of Alcohols to Aldehydes
tion was stopped after 1 h by quenching with Na SO3 (94 mg,
2
and Ketones: A Guide to Current Common Practice; Springer:
New York, 2006. (b) Stahl, S. S.; Alsters, P. L. Liquid Phase Aerobic
Oxidation Catalysis; Wiley-VCH: Weinheim, Germany, 2016.
2) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
0.75 mmol) and the mixture was diluted with CH Cl (10 mL).
2
2
The yield of 2-octanone (t : 2.1 min) and the recovery of 2-
R
octanol (t : 2.8 min) were determined to be 91% and 2%, respec-
R
(
tively, by GC analysis based on a calibration curve using authen-
tic samples.
1987, 52, 2559. (b) Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth.
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A.; Chesa Castellana, J. F.; Jackman, H.; Dunn, P. J.; Sheldon, R. A.
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(8) Oxidation of 1,5-hexanediol (Scheme 3): To a suspension of
NaOCl·5H O crystals (123 mg, 0.75 mmol) in acetonitrile (5.0
2
mL), was added 1,5-hexanediol (59 mg, 0.50 mmol), and the
resulting mixture was stirred at 20 °C. The reaction was stopped
after 1 h by quenching with Na SO (95 mg, 0.75 mmol). The
(
3) (a) Okada, T.; Asawa, T.; Sugiyama, Y.; Kirihara, M.; Iwai, T.;
Kimura, Y. Synlett 2014, 25, 596. (b) Okada, T.; Matsumuro, H.;
Iwai, T.; Kitagawa, S.; Yamazaki, K.; Akiyama, T.; Asawa, T.;
Sugiyama, Y.; Kimura, Y.; Kirihara, M. Chem. Lett. 2015, 44, 185.
2
3
1
product was analyzed by H NMR and found to be 6-hydroxy-
hexane-2-one (31%, δ = 2.49 ppm, 2 H) and 1,5-hexanediol (49%
recovery, δ = 1.20 ppm, 3 H) based on a standard material
(triphenylmethane δ = 5.55 ppm, 1 H).
(c) Okada, T.; Asawa, T.; Sugiyama, Y.; Iwai, T.; Kirihara, M.;
Kimura, Y. Tetrahedron 2016, 72, 2818. (d) Kirihara, M.; Okada,
T.; Sugiyama, Y.; Akiyoshi, M.; Matsunaga, T.; Kimura, Y. Org.
Process Res. Dev. 2017, 21, 1925.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D