Selective Aerobic Oxidation of Primary Alcohols to Aldehydes

Article abstract of DOI:10.1055/s-0036-1588155

The 2-azaadamantane- N -oxyl (AZADO)- and 9-azanoradamantane- N -oxyl (nor-AZADO)-catalyzed selective oxidation of primary alcohols to the corresponding aldehydes is described. The use of tert -butyl nitrite as the co-catalyst enables efficient aerobic oxidation in MeCN instead of previously reported AcOH; this is important for the selectivity of the reaction. The addition of a solution of saturated aqueous NaHCO ₃ after the completion of the reaction was effective to suppress the overoxidation of the product to the corresponding carboxylic acid during the workup.

Full text of DOI:10.1055/s-0036-1588155

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
cluster
A
M. Shibuya et al.
Cluster
Synlett
Selective Aerobic Oxidation of Primary Alcohols to Aldehydes
Masatoshi Shibuya*
Keisuke Furukawa
N
O
N
O
Yoshihiko Yamamoto
AZADO or Nor-AZADO
(5 mol%)
tBuONO (20 mol%)
O
Department of Basic Medicinal Sciences, Graduate School
of Pharmaceutical Sciences, Nagoya University, Furo-cho,
Chikusa, Nagoya 464-8601, Japan
selective oxidation
to aldehydes
R
OH
R
H
MeCN, r.t.
air balloon
up to 93% yield
11 examples
m-shibu@ps.nagoya-u.ac.jp
Received: 10.01.2017
Accepted after revision: 16.02.2017
Published online: 08.03.2017
because further oxidation of aldehydes is relatively slow.6b
The addition of excess NaOCl and a phase-transfer catalyst
or, more efficiently, a stoichiometric amount of NaClO2 fa-
cilitates further oxidation of aldehydes, affording the corre-
sponding carboxylic acids.6b,7 In anhydrous catalytic sys-
tems using PhI(OAc)2 or trichloroisocyanuric acid (TCCA),
the oxidation of primary alcohols to the corresponding al-
dehydes also proceeds selectively, because the aldehydes
cannot form hydrates in the absence of water.6,8 As aerobic
oxidation is one of the most promising methods with a high
economic efficiency and environmental sustainability,
much effort has been devoted to its development.9 Hu and
Liang developed the first transition-metal-free aerobic oxi-
dation method using TEMPO (1).10a Although several
TEMPO-catalyzed aerobic oxidation methods have been de-
veloped, the substrate scope of these methods is rather lim-
ited.10 We and others recently developed the substantially
improved catalytic systems using highly active nitroxyl rad-
ical catalysts: 5-fluoro-2-azaadamantane N-oxyl (5-F-AZA-
DO, 3), 9-azanoradamantane N-oxyl (nor-AZADO, 4), 9-az-
abicyclo[3.3.1]nonane N-oxyl (ABNO, 5) and keto-ABNO (6,
Figure 1).11–14 Using these catalytic systems, diverse sec-
ondary alcohols were efficiently oxidized to the corre-
sponding ketones with a high compatibility for various
functional groups. On the other hand, the oxidation of ali-
phatic primary alcohols has not been well studied using
these catalytic systems. In our previous studies, the oxida-
tion of primary alcohols afforded the corresponding alde-
hydes in moderate yields (<80% at the maximum) even after
the optimization of the reaction conditions, because of the
overoxidation of aldehydes to the corresponding carboxylic
acids.11a,b Herein, we report the selective oxidation of pri-
mary alcohols to the corresponding aldehydes using AZADO
(2) or nor-AZADO (4) as the catalyst.
DOI: 10.1055/s-0036-1588155; Art ID: st-2017-r0025-c
Abstract The 2-azaadamantane-N-oxyl (AZADO)- and 9-azanorada-
mantane-N-oxyl (nor-AZADO)-catalyzed selective oxidation of primary
alcohols to the corresponding aldehydes is described. The use of tert-
butyl nitrite as the co-catalyst enables efficient aerobic oxidation in
MeCN instead of previously reported AcOH; this is important for the se-
lectivity of the reaction. The addition of a solution of saturated aqueous
NaHCO3 after the completion of the reaction was effective to suppress
the overoxidation of the product to the corresponding carboxylic acid
during the workup.
Key words oxidation, nitroxyl radical, primary alcohols, aldehydes,
chemoselectivity
Oxidation of primary alcohols initially produces the cor-
responding aldehydes; subsequent oxidation of the alde-
hydes produces the corresponding carboxylic acids, often
via the formation of hydrates (gem-diols).1 Because alde-
hydes and carboxylic acids are not only essential compo-
nents of various biologically active compounds, but also
useful functional groups in organic synthesis, selective oxi-
dation of primary alcohols to aldehydes or carboxylic acids
is a valuable transformation.2,3 Nitroxyl-radical-catalyzed
oxidation has attracted much attention in synthetic organic
chemistry owing to its safety and applicability to large-
scale oxidation.4 The pivotal 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO, 1) catalytically oxidizes alcohols to the cor-
responding carbonyl compounds in the presence of diverse
co-oxidants.5,6 The catalytic system using sodium hypo-
chlorite (NaOCl) as the co-oxidant is widely used in aca-
demic organic synthesis as well as industrial organic syn-
thesis, and primary alcohols are treated with an appropri-
ate amount of NaOCl to afford the corresponding aldehydes,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
M. Shibuya et al.
Cluster
Synlett
product 7c was produced during the workup of the reac-
tion: After the reaction mixture was concentrated using a
rotary evaporator after the completion of the reaction, the
yield of 7c substantially increased. We assumed that the ox-
idation of 7b to 7c was caused by HNO3 generated from NOx
during workup. Because the oxidation did not proceed in
the presence of Et3N (Table 1, entry 5), saturated aqueous
NaHCO3 was added to the reaction mixture after the com-
pletion of the reaction to neutralize the acidity of HNO3 (Ta-
ble 1, entry 6). Thus, the production of 7c was suppressed,
and 7b was isolated in 92% yield. The oxidation efficiently
proceeded under an air atmosphere instead of an O2 atmo-
sphere (Table 1, entry 7). The oxidation also proceeded at
room temperature, affording 7b in 93% yield, even though
the reaction time was extended to ten hours (Table 1, entry
8). TEMPO-catalyzed oxidation was slow, affording 7b in
25% yield even after 24 hours (Table 1, entry 9)
With the optimal conditions in hand, the selective oxi-
dation of a variety of primary alcohols was investigated (Ta-
ble 2).15 Not only simple straight-chain alcohols were selec-
tively oxidized to the corresponding aldehydes in high
yields, but also hindered neopentyl alcohols were selective-
ly oxidized (Table 2, entries 1–7). Because the oxidation of
15a–17a afforded the desired products in low-to-moderate
yields, nor-AZADO (4) was used as the catalyst instead of
AZADO (2).
R1
R2
R
N
O
N
O
N
O
N
O
R1 = R2 = H, ABNO (5)
R1, R2 = O, keto-ABNO (6)
TEMPO (1)
R = H, AZADO (2)
R = F, 5-F-AZADO (3)
nor-AZADO (4)
Figure 1 Structures of nitroxyl radicals
First, primary alcohol 7a was subjected to the previous-
ly reported reaction conditions using easily available AZA-
DO (2, 5 mol%) instead of 5-F-AZADO (3),11 yielding a small
amount of aldehyde 7b and carboxylic acid 7c together
with dimeric ester 7d and unreacted 7a (Table 1, entry 1).
To suppress the overoxidation by controlling the hydrate
formation, the conditions for aerobic oxidation in an anhy-
drous solvent were investigated; the use of tert-butyl nitrite
(TBN) instead of NaNO2 was effective for the oxidation in
MeCN under O2 atmosphere (balloon).10e The production of
7d was suppressed, and 7b was obtained in a good yield.
However, 7c was produced in 21% yield (Table 1, entry 2).
Considering that 7c was produced by the oxidation of the
hydrate formed from the reaction of 7b with the H2O pro-
duced from O2, the reaction was repeated in the presence of
dehydrating agents such as MS 3A and MgSO4. From these
trials, no significant positive result was obtained: The addi-
tion of MS 3A was detrimental to the reaction, and that of
MgSO4 slightly improved the yield of the desired product
(Table 1, entries 3 and 4). Here, we noticed that most of the
Nor-AZADO (4) efficiently catalyzed the aerobic oxida-
tion of these alcohols, providing the corresponding alde-
Table 1 Optimization of Reaction Conditions
AZADO (2) (5 mol%)
NOx source (X mol%)
H
OH
OH
Ph
Ph
+
Ph
additive
solvent, temp
O
O
7a
7b
7c
Entry
NOx (mol%)
Additive
Oxidant
Solvent
Temp (°C)
Time (h)
7b (%)a
7c (%)a
1
2
3
4
5
6
7
8
9c
NaNO2 (10)
TBN (20)
TBN (20)
TBN (20)
TBN (20)
TBN (20)
TBN (20)
TBN (20)
TBN (20)
none
air
O2
O2
O2
O2
O2
air
air
air
AcOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
r.t.
50
50
50
50
50
50
r.t.
r.t.
12
2
9
77
10
83
0
22
none
21
MS 3A
MgSO4
Et3N
6
trace
10
2
2
0
noneb
noneb
noneb
noneb
2
92
88
93
25
trace
trace
trace
0
2
10
24
a Isolated yield.
b Saturated aqueous NaHCO3 was added after the reaction.
c 5 mol% TEMPO was used as a catalyst.
O
Ph
Ph
O
7d
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
M. Shibuya et al.
Cluster
Synlett
Table 2 Selective Aerobic Oxidation of Primary Alcohols with Catalytic
Amounts of AZADO (2)/TBN or Nor-AZADO (4)/TBN in MeCN
er with a small amount of unidentified products (Figure 2).
Since 19b and 20b have an activated methylene, they might
react with the catalyst, and lead to a deactivation of the re-
action.11b,c
AZADO (2) (5 mol%)
TBN (20 mol%)
O
R
OH
MeCN, r.t.
air balloon
R
H
OH
OH
4
Time (h) Yield (%)a
F3C
Entry Alcohol
Product
19a
20a
TBDPSO
TBDPSO
CHO
OH
5
Figure 2 Limitation of substrate scope
5
1
2
3
24
12
10
86
89
85
8a
8b
CHO
Br
OH
9
Br
9
In conclusion, we developed a method for the chemose-
lective aerobic oxidation of primary alcohols to the corre-
sponding aldehydes. The use of TBN as the cocatalyst en-
ables the aerobic oxidation in an aprotic solvent such as
MeCN, which is effective for the selective oxidation of pri-
mary alcohols to the corresponding aldehydes. The overoxi-
dation to the corresponding carboxylic acids occurs during
the workup, which was effectively suppressed by the addi-
tion of saturated aqueous NaHCO3 after the completion of
the reaction. In some cases, nor-AZADO catalyzed the oxi-
dation reaction more efficiently than AZADO. These oxida-
tion methods would expand the substrate scope of nitroxyl-
radical-catalyzed aerobic oxidation.
9a
9b
CHO
CbzHN
10a
OH
CbzHN
10b
F
F
F
F
4
9
80
CHO
F
F
OH
F
F
F
F
11a
11b
Ph
Ph
5
6
8
92
91
OH
CHO
12a
13a
12b
13b
10
OH
CHO
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Advanced Molecular Transformations by
Organocatalysts’ from MEXT and JSPS KAKENHI 16K080162, and the
Platform Project for Supporting in Drug Discovery and Life Science
Research from AMED. K.F. expresses his thanks for a JSPS Research
Fellowship for Young Scientists (16J04480).
CHO
7
24
93
OH
OH
EtO
14a
EtO
14b
Ph
Ph
CHO
24
9
79
3
3
8
9
87b
15a
15b
CHO
Supporting Information
9
86b
OH
MeO
16b
MeO
16a
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588155.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
OH
24
7
24
CHO
O
10
11
N
N
85b
Cbz
Cbz
References and Notes
17a
17b
OH
(1) (a) Toji, G.; Fernández, M. Oxidation of Alcohols to Aldehydes and
Ketones; Springer: New York, 2006. (b) Toji, G.; Fernández, M.
Oxidation of Primary Alcohols to Carboxylic Acids; Springer: New
York, 2007.
(2) For general reviews for the oxidation of primary alcohols to
aldehydes, see: (a) Tidwell, T. T. Synthesis 1990, 857. (b) Ley, S.
V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639. (c) Luzzio, F. A. Org. React. 1998, 53, 1. (d) Tohma, H.; Kita,
Y. Adv. Synth. Catal. 2004, 346, 111. (e) Silva, L. F.; Olofsson, B.
Nat. Prod. Rep. 2011, 28, 1722.
(3) (a) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399.
(b) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977.
(4) (a) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res.
Dev. 2005, 9, 253. (b) Caron, S.; Dugger, R. W.; Ruggeri, S. G.;
Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943.
6
90
Ph
18a
Ph
18b
a Isolated yield.
b 5 mol% of nor-AZADO (4) was used as the catalyst.
hydes 15b–17b in high yields (Table 2, entries 8–10). It was
also confirmed that the racemization of 17b did not occur
during the reaction. Secondary alcohol 18a was also effi-
ciently oxidized to ketone 18b (Table 2, entry 11). However,
in the oxidation of CF3-susbstituted electron-deficient ho-
mobenzylic alcohol 19a and homoallylic alcohol 20a, a
large amount of the starting material was recovered togeth-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
M. Shibuya et al.
Cluster
Synlett
(5) (a) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis
1996, 1153. (b) Bobbitt, J. M.; Brockner, C.; Merbouh, N. Org.
React. 2009, 74, 103. (c) Tebben, L.; Studer, A. Angew. Chem. Int.
Ed. 2011, 50, 5034.
(6) (a) Cella, J. A.; Kelley, J. A.; Kenehan, E. F. J. Org. Chem. 1975, 40,
1860. (b) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org.
Chem. 1987, 52, 2559. (c) Einhorn, J.; Einhorn, C.; Ratajczak, F.;
Pierre, J. L. J. Org. Chem. 1996, 61, 7452. (d) de Mico, A.;
Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem.
1997, 62, 6974. (e) de Luca, L.; Giacomelli, G.; Porcheddu, A. Org.
Lett. 2001, 3, 3041.
(7) (a) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564. (b) Zanka, A.
Chem. Pharm. Bull. 2003, 51, 888.
(8) (a) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293. (b) De
Luca, L.; Giacomelli, G.; Masala, S.; Porcheddu, A. J. Org. Chem.
2003, 68, 4999.
(13) (a) Lauber, M. B.; Stahl, S. S. ACS Catal. 2013, 3, 2612. (b) Miles,
K. C.; Abrams, M. L.; Landis, C. R.; Stahl, S. S. Org. Lett. 2016, 18,
3590.
(14) (a) Sonobe, T.; Oisaki, K.; Kanai, M. Chem. Sci. 2012, 3, 3249.
(b) Kadoh, Y.; Tashiro, M.; Oisaki, K.; Kanai, M. Adv. Synth. Catal.
2015, 357, 2193.
(15) 4-Phenylbutanal (7b); Typical Procedure
To a solution of 4-phenylbutan-1-ol (7a, 45.8 mg, 0.305 mmol)
and AZADO (2, 2.36 mg, 15.5 μmol) in MeCN (1.5 mL) was
added TBN (92%, 7.9 μL, 61 μmol). The reaction mixture was
stirred under an air atmosphere at r.t for 10 h. After the addition
of a saturated aqueous NaHCO3 solution (3 mL), the resulting
mixture was extracted with EtOAc (3 × 5 mL). The combined
organic layer was dried over MgSO4, filtered, and the filtrate
was concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (hexane–
EtOAc, 20:1) to give 4-phenylbutanal (7b) as a colorless oil; 42.0
mg (93%). 1H NMR (400 MHz, CDCl3): δ = 9.56 (t, J = 1.6 Hz, 1 H),
7.34–7.25 (m, 2 H), 7.24–7.16 (m, 3 H), 2.66 (t, J = 7.6 Hz, 2 H),
2.45 (dt, J = 7.6, 1.6 Hz, 2 H), 1.97 (quint, J = 7.6 Hz, 2 H). 13C
NMR (100 MHz, CDCl3): δ = 201.3, 140.2, 127.5, 125.1, 42.2,
34.0, 22.7.
(9) (a) Sheldon, R. A.; Arends, I. W. C. E. Adv. Synth. Catal. 2004, 346,
1051. (b) Parmeggiani, C.; Cardona, F. Green Chem. 2012, 14,
547. (c) Cao, Q.; Dornan, L. M.; Rogan, L.; Hughes, N. L.;
Muldoon, M. J. Chem. Commun. 2014, 50, 4524. (d) Ryland, B. L.;
Stahl, S. S. Angew. Chem. Int. Ed. 2014, 53, 2.
(10) (a) Liu, R. H.; Liang, X. M.; Dong, C. Y.; Hu, X. Q. J. Am. Chem. Soc.
2004, 126, 4112. (b) Wang, N.; Liu, R.; Chen, J.; Liang, X. Chem.
Commun. 2005, 5322. (c) Xie, Y.; Mo, W. M.; Xu, D.; Shen, Z. L.;
Sun, N.; Hu, B. X.; Hu, X. Q. J. Org. Chem. 2007, 72, 4288.
(d) Wang, X.; Liu, R.; Jin, Y.; Liang, X. Chem. Eur. J. 2008, 14, 2679.
(e) He, X. J.; Shen, Z. L.; Mo, W. M.; Sun, N.; Hu, B. X.; Hu, X. Q.
Adv. Synth. Catal. 2009, 351, 89.
3-Pentafluorophenylpropanal (11b)
Colorless oil; 66.4 mg (80%). 1H NMR (400 MHz, CDCl3): δ = 9.81
(s, 1 H), 3.03 (t, J = 7.2 Hz, 2 H), 2.80 (t, J = 7.2 Hz, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 199.4, 145.0 (dm, J = 245 Hz), 140.0 (dm,
J = 243 Hz), 137.5 (dm, J = 251 Hz), 113.3 (td, J = 18.1, 3.8 Hz),
42.5, 15.1. HRMS (DART): m/z calcd for C18H14F10NO3·NH4 [2M +
NH4]+: 466.0865; found: 466.0858.
(11) (a) Shibuya, M.; Osada, Y.; Sasano, Y.; Tomizawa, M.; Iwabuchi,
Y. J. Am. Chem. Soc. 2011, 133, 6497. (b) Shibuya, M.; Nagasawa,
S.; Osada, Y.; Iwabuchi, Y. J. Org. Chem. 2014, 79, 10256.
(c) Furukawa, K.; Inada, H.; Shibuya, M.; Yamamoto, Y. Org. Lett.
2016, 18, 4230.
4-Methoxyphenylacetaldehyde (16b)
Pale yellow oil; 56.8 mg (86%). 1H NMR (400 MHz, CDCl3): δ =
9.72 (t, J = 2.0 Hz, 1 H), 7.17–7.09 (m, 2 H), 6.95–6.85 (m, 2 H),
3.80 (s, 3 H), 3.62 (d, J = 2.0 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
δ = 199.6, 158.9, 130.6, 123.7, 114.4, 55.2, 49.7.
(12) Hayashi, M.; Sasano, Y.; Nagasawa, S.; Shibuya, M.; Iwabuchi, Y.
Chem. Pharm. Bull. 2011, 59, 1570.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D