Efficient selective oxidation of alcohols to aldehydes catalyzed by a morpholinone nitroxide

Article abstract of DOI:10.1080/00397911.2019.1666284

Efficient chemoselective oxidation of primary alcohols to the corresponding aldehydes is described. The transformation is promoted by a catalytic morpholinone nitroxide radical catalyst which can be easily synthesized. A broad range of substrates includin

Full text of DOI:10.1080/00397911.2019.1666284

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Efficient selective oxidation of alcohols to
aldehydes catalyzed by a morpholinone nitroxide
Zhenhua Dong, Pengwei Gao & Yongmei Xiao
To cite this article: Zhenhua Dong, Pengwei Gao & Yongmei Xiao (2019): Efficient
selective oxidation of alcohols to aldehydes catalyzed by a morpholinone nitroxide, Synthetic
Communications, DOI: 10.1080/00397911.2019.1666284
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https://doi.org/10.1080/00397911.2019.1666284
Efficient selective oxidation of alcohols to aldehydes
catalyzed by a morpholinone nitroxide
Zhenhua Dong, Pengwei Gao, and Yongmei Xiao
College of Chemistry and Chemical Engineering, Academician Workstation for Natural Medicinal
Chemistry of Henan Province, Henan University of Technology, Zhengzhou, PR China
ABSTRACT
ARTICLE HISTORY
Received 2 August 2019
Efficient chemoselective oxidation of primary alcohols to the corre-
sponding aldehydes is described. The transformation is promoted by
a catalytic morpholinone nitroxide radical catalyst which can be eas-
ily synthesized. A broad range of substrates including aromatic and
aliphatic primary alcohols are converted with excellent yields under
mild conditions. The control experiments reveal that the morpholi-
none nitroxide can be used as a selective oxidant for primary
alcohols in the presence of secondary alcohols.
KEYWORDS
Aaldehyde; nitroxide;
oxidation; primary alcohol;
TEMPO analog
GRAPHICAL ABSTRACT
Introduction
The oxidation of alcohol is one of the most common and crucial transformations in syn-
thetic organic chemistry, especially in the fine chemicals and pharmaceutical industries.[1,2]
Several methods have been developed for the oxidation of alcohols to aldehydes, ketones, or
acids. Traditional methods include the using of chromium reagents, manganese reagents,[3]
[4]
noble metal,
copper reagents,[5] or the periodinane reagents as well as the metal-free
reaction condition.[6] Although such methods can promote the oxidation procedure effi-
ciently, the demand of stoichiometric oxidants or the residual of metal are confronted with
environmental stress. On the other hand, it remains a continuous challenging that chemose-
lective oxidation of primary alcohols to the aldehydes rather than the carboxylic acids.[7]
In the past decades, the oxidation of alcohols catalyzed by stable free radical TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) and its derivations have been used for numerous
CONTACT Zhenhua Dong
hautdong@foxmail.com
College of Chemistry and Chemical Engineering, Henan
University of Technology, Zhengzhou, 450001, PR China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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ZHENHUA DONG ET AL.
Scheme 1. The oxidation of alcohols using different oxidates.
transformation including the pharmaceutical industries and fine chemicals.[8–10]
Comparing with other oxygenant, TEMPO and its derivations can be used in mild reac-
tion condition such as short reaction time, low catalyst loading and green reaction
medium.[11–16] The typically oxidation condition (known by Anelli’s oxidation) by 4-
methoxy-TEMPO with hypochlorite as the primary oxidant in water is showed, and the
alcohols can be oxidized to aldehydes or ketones efficiently (Scheme 1(a)).[17–19] Except
for the oxidation of alcohols, the TEMPO can be used for various transformation.
However, a potential problem is that the expensive of TEMPO would restrict its appli-
cation at an industrial scale. A series of TEMPO derivatives and analogs have been
developed and applied to decrease the cost.[20–22] Such as Iwabuchi reported an azaada-
mantane nitroxyl radical which could be an efficient catalyst for oxidation of alcohols
with shorted reaction time compared with TEMPO (Scheme 1(b)).[23] Nevertheless, the
synthesis of azaadamantane nitroxyl radical (1-Me-AZADO) was difficult.[23] Hence,
there is still significant room for the structural improvement in TEMPO analogs.
Furthermore, mostly of the TMEPO derivatives have the inferior capability for the
selective oxidation of primary alcohols to aldehydes in the presence of secondary alco-
hols. We herein disclose that the morpholinone nitroxide 2, which is served as TEMPO
analog, has an outstanding catalytic capability for the selective oxidation of primary
alcohols to aldehydes (Scheme 1(c)). The morpholinone nitroxide 2 was synthesized by
Rychnovsky in 1998.[24,25] As far as we know, however, its catalytic ability as oxidation
has never been examined.[26–28] Including Rychnovsky’s work in 1999, they didn’t find
its oxidation ability.[28,29
]
Results and discussion
The study was started from the preparing of morpholinone nitroxide 2 as shown in
Scheme 2. The synthesis was concise from cheap material 1 (2-amino-2-methyl-1-

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3
Scheme 2. Synthesis of morpholinone nitroxide 2.
Scheme 3. Optimized oxidation conditions.
propanol), which was commercially available. The routes were concise and easy
to operation.
In the initiatory experiment, we found the morpholinone nitroxide 2 could promote
the oxidation of benzyl alcohol to benzaldehyde efficiently under mild aqueous condi-
tions. To our surprise, the morpholinone nitroxide 2 displayed efficient catalytic activity
using only 1 mol% catalyst loading. The transformation could be completed entirely in
30 min as shown in Scheme 3. During the optimization of the reaction conditions, we
found that other solvents and additives have poor influence for the transformation.
Under the optimized conditions, we tested the scope of this process and a number of
primary alcohols were oxidized with morpholinone nitroxide 2 (Table 1). For diverse
primary alcohols, including electron-withdrawing and electron-donating substitutional
benzyl alcohol 3 b-3f, condensed ring and heterocycle alcohols, 3 g and 3 h, excellent
yields could be achieved. For the saturated alkyl alcohols and aryl alkyl substrates, the
oxidation could also be proceeded smoothly. Unfortunately, when the secondary alco-
hols 3o and 3p were employed, no any products were obtained even though the reac-
tion time was prolonged to 12 h. The results revealed this method could be a selective
oxidation of primary alcohols to aldehydes.
Except for the NaOCl, PhI(OAc)2 was also a common used oxidizing agent in
TEMPO oxidation. In our exploration, the primary alcohols could be oxidized by using
PhI(OAc)2. However, it is obvious that the method using NaOCl was better than using
PhI(OAc)2. Because longer reaction times were needed. And the price of the PhI(OAc)2
was considerably higher than NaOCl. However, the nitroxide-PhI(OAc)2 system was
also a chemoselective oxidant as shown by Table 2. Moreover, the method using
PhI(OAc)2 resulted in a little higher yields than the method using NaOCl. Because the
washing by water was an indispensable operation in method using NaOCl. It was inevit-
ably that the products, aldehydes, may be dissolved in water slightly. Comparing with
the TEMPO- PhI(OAc)2 system, morpholinone nitroxide 2 has a better catalytic activ-
ities under low catalytic loading (1 mol%).[30]

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Table 1. The oxidation of different alcohols.[a].
Entry
Alcohol
Aldehyde
Yield%[b]
1
2
3
4
5
6
7
PhCH2OH, 3a
PhCHO, 4a
86
91
89
86
90
84
88
2-Cl-C6H4CH2OH, 3b
2-Me-C6H4CH2OH, 3c
4-Me-C6H4CH2OH, 3d
4-Cl-C6H4CH2OH, 3e
4-OMe-C6H4CH2OH, 3f
2-Cl-C6H4CHO, 4b
2-Me-C6H4CHO, 4c
4-Me-C6H4CHO, 4d
4-Cl-C6H4CHO, 4e
4-OMe-C6H4CHO, 4f
,3g
,4g
8
91
,3h
,4h
9
1-Octanol, 3i
1-Hexanol, 3j
Octanal, 4i
Hexanal, 4j
86
88
88
10
11
,4k
,4l
,3k
,3l
12
13
14
15
81
82
,3m
,3n
,4m
90
,4n
nr[c]
,3o
,3p
,4o
,4p
16
nr
[a] The reaction was carried out by morpholinone nitroxide 2 (1 mol %)
with NaOCl (150 mol %), KBr (10 mol %), Bu4NBr (5 mol %), aq. NaHCO3
in CH2Cl2 at 0 ꢀC for 30 min. [b] Isolated yield. [c] nr ¼ no reaction.

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Table 2. Comparison experiments under PhI(OAc)2 condition[a].
[a] The reaction was carried out in CH2Cl2 using morpholinone nitroxide 2 (1 mol %) as a catalyst, the yields of products
were isolated yields. [b] Using 1.5 equiv of NaOCl as an oxidation at 0 ꢀC for 30 min. [c] Using 1.1 equiv of PhI(OAc)2
as an oxidation at room temperature for 9 h.
Scheme 4. Selective oxidation experiment.
Scheme 5. A plausible reaction mechanism.
A control experiment was also tested for proving the exceptional chemoselectivity as
shown in Scheme 4. The reaction of a 1:1 mixture of 1-phenethyl alcohol 3o and 2-phe-
nethyl alcohol 3k was carried on under the standard reaction conditions. Only the

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ZHENHUA DONG ET AL.
phenylacetaldehyde was obtained after 30 mins and no any acetophenone was detected
by TLC. The result revealed that the morpholinone nitroxide 2 could be used as a
selective oxidant for primary alcohols.
Based on the results above, a probable reaction mechanism could be proposed
(Scheme 5). The reaction occurred via the oxoammonium salt A, which was readily
generated by the oxidation of morpholinone nitroxide 2 to provide salt intermediate A.
Then a primary alcohol 3 reacted with oxoammonium salt A to form the intermediate
B, which underwent fragmentation to generate the desired aldehyde 4 and hydroxyl-
amine C. In this step, four methyl groups flanking the intermediate B played a key role
in preventing secondary alcohol from generating the similar key intermediate B. This
was the explanation why selective oxidation of primary alcohols in the presence of sec-
ondary alcohols occurred when morpholinone nitroxide 2 was used. Finally, hydroxyl-
amine C was reoxidized to morpholinone nitroxide 2 in the presence of a
stoichiometric co-oxidant. Then the catalytic cycle was closed.
Conclusion
In conclusion, we have disclosed the outstanding catalytic oxidation capacity of mor-
pholinone nitroxide 2 which was synthesized easily and cheaply. The process could be a
fast, selective, and high-yielding oxidation of the primary alcohols to aldehydes in the
presence of secondary alcohols.
Experimental part
Reactions were carried out using commercial available reagents in over-dried apparatus.
1
CH2Cl2 was commercially available and used directly. H NMR spectra were recorded
on commercial instruments.
Synthesis of morpholinone nitroxide 2
A 500 ml 3-neck-flask was equipped with an argon-inlet tube, a thermometer and a mechan-
ical stirrer. Then 2-amino-2-methyl-1-propanol (26.74g, 300 mmol), chloroform (36 mL,
450 mmol), and ketone (220 mL,3000mmol) were added. The flask was cooled to 0ꢀC by
ice-bath. Then the sodium hydroxide powder (60.0 g, 1500mmol) was added in ten portions
and the reaction temperature was kept below 5 ꢀC. The reaction was stirred at 0 ꢀC overnight
after the addition. The mixture was then filtered, and the solid was washed by ketone. Then
the white solid was stirred twice with 100 mL methanol and the combined filtrates were con-
centrated to afford the sodium carboxylate. Subsequently, the crude sodium carboxylate was
refluxed with 250 mL concentrated HCl for 24h. Then most of the HCl was removed by dis-
tilling. The residue was added 200 mL toluene and the residual water was depleted using a
Dean-Stark trap. Et3N (35.4g, 350 mmol) was then added and the mixture was refluxed for
6 h under argon. After cooling to room temperature, the reaction was filtered and concen-
trated. Then the crude product was purified by flash column chromatography (Petroleum
ether: Ethyl acetate ¼ 5: 1) to give a colorless oil (3,3,5,5-tetramethyl-2-oxomorpholine,
30.6 g, 65% yield).

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To a solution of 3,3,5,5-tetramethyl-2-oxomorpholine (1.571 g, 10 mmol) in 50 mL
CH2Cl2 was added m-CPBA (3.45 g, 20 mmol) under 0 ꢀC. Then the mixture was stirred
at room temperature for 12 h. The reaction was then quenched by aq. NaHCO3. The
aqueous layer was extracted with 50 mL CH2Cl2 three times. The combined organic
phases were washed by water and brine, dried by Na2SO4, filtered, and concentrated by
rotary evaporators. The residue was purified by flash chromatography (Petroleum ether:
Ethyl acetate ¼ 2: 1) to furnish an orange solid (1.54 g, 89% yield).
General procedure for the oxidation using NaOCl
A 50 ml flask was charged with a solution of benzyl alcohol, morpholinone nitroxide 2
in CH2Cl2 and a sat. aqueous solution of NaHCO3 containing KBr and n-Bu4NBr. To
this cooled to 0 ꢀC by water-ice bath and well stirred mixture, a pre-mixed solution of
aqueous NaOCl (6–14% Cl) and sat. aqueous solution of NaHCO3 was added dropwise
during 10 min. The reaction was stirred for 30 min at 0 ꢀC, then quenched with sat.
aqueous solution of Na2S2O3. The aqueous layer was separated and extracted with
CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The crude material was purified by flash column
chromatography to give benzaldehyd as a colorless oil.
Full experimental detail, 1H NMR data of all compounds can be found via
the”Supplementary material” section of this article’s webpage. All the products are
known compounds. Hence the products were identified by comparison of their 1H
NMR data with literature.[31
]
Funding
This work was generously supported by the Colleges and Universities Key Research Program
Foundation of Henan Province [No. 17A150007], Doctor Fund of Henan University of
Technology [No. 2015BS013].
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