Chemoselective Oxidation of Benzyl, Amino, and Propargyl Alcohols to Aldehydes and Ketones under Mild Reaction Conditions

Article abstract of DOI:10.1002/open.201402082

Catalytic oxidation reactions often suffer from drawbacks such as low yields and poor selectivity. Particularly, selective oxidation of alcohols becomes more difficult when a compound contains more than one oxidizable functional group. In order to deliver a methodology that addresses these issues, herein we report an efficient, aerobic, chemoselective and simplified approach to oxidize a broad range of benzyl and propargyl alcohols containing diverse functional groups to their corresponding aldehydes and ketones in excellent yields under mild reaction conditions. Optimal yields were obtained at room temperature using 1 mmol substrate, 10 mol% copper(I) iodide, 10 mol% 4-dimethylaminopyridine (DMAP), ands 1 mol% 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in acetonitrile, under an oxygen balloon. The catalytic system can be applied even when sensitive and oxidizable groups such as alkynes, amines, and phenols are present; starting materials and products containing such groups were found to be stable under the developed conditions.

Full text of DOI:10.1002/open.201402082

DOI: 10.1002/open.201402082
Chemoselective Oxidation of Benzyl, Amino, and
Propargyl Alcohols to Aldehydes and Ketones under Mild
Reaction Conditions
C. B. Rajashekar Reddy, Sabbasani Rajasekhara Reddy,* and Shivaji Naidu[a]
This article is dedicated to the fond memory of the late Professor A. Sri Krishna from the Indian Institute of Science, Bangalore.
Catalytic oxidation reactions often suffer from drawbacks such
as low yields and poor selectivity. Particularly, selective oxida-
tion of alcohols becomes more difficult when a compound
contains more than one oxidizable functional group. In order
to deliver a methodology that addresses these issues, herein
we report an efficient, aerobic, chemoselective and simplified
approach to oxidize a broad range of benzyl and propargyl al-
cohols containing diverse functional groups to their corre-
sponding aldehydes and ketones in excellent yields under mild
reaction conditions. Optimal yields were obtained at room
temperature using 1 mmol substrate, 10 mol% copper(I)
iodide, 10 mol% 4-dimethylaminopyridine (DMAP), and
1 mol% 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) in aceto-
nitrile, under an oxygen balloon. The catalytic system can be
applied even when sensitive and oxidizable groups such as al-
kynes, amines, and phenols are present; starting materials and
products containing such groups were found to be stable
under the developed conditions.
alyzed systems have been made.[1a,6,7] Recently, chemoselective
aerobic oxidation of amino alcohols to carbonyl compounds
using 2-azaadamantane-N-oxyl (AZADO)/copper complex was
reported.[8] While the reported methods are synthetically
useful, they do possess some limitations like commercial nona-
vailability of reagents and high operating costs caused by the
reaction conditions required, which make them inconvenient
and undesirable.[9] Synthesizing amino carbonyl derivatives
from their respective amino alcohols remains a big challenge
to the synthetic chemist because protection and deprotection
steps have to be used when other oxidizable groups are pres-
ent within the same molecule.[10] The fact might be that inter-
actions between the electron-rich amino groups and the oxi-
dant lead to formation of the desired product in poor yield.
a,b-Acetylenic carbonyl compounds are highly important
precursors for the construction of various bioactive heterocy-
clic compounds and DNA-cleavage agents, and have a wide
range of applications in medicinal chemistry.[11] Various meth-
ods in literature exist for the oxidation of propargyl alcohols to
carbonyl compounds. These include stoichiometric oxidation
systems, such as 2-iodoxybenzoic acid and sodium period-
ate,[12] transition-metal-catalyzed oxidation reactions, such as
with copper(II), ruthenium(II), iron(III) nitrate nonahydrate,
vanadyl acetylacetonate,[13] copper(II) acetylacetonate–N-hy-
droxyphthalimide (NHPI),[14] and copper nanoparticles,[15] and
TEMPO/calcium hypochlorite.[16a] Although the developed
methods are useful, they do have some limitations such as the
instability of the produced carbonyl compounds in the reac-
tion system, catalyst deactivation by the formation of metallic
polymers, formation of stable complexes between metal salts
and some electron donors on the starting alcohols,[16b] and use
of stoichiometric oxidants.[16a,17a–b] Therefore, it is highly impor-
tant to develop a more desirable reagent for chemoselective
oxidation that works under simple and mild reaction condi-
tions and does not affect other oxidizable functional groups
(e.g., amino, alkyne, hydroxy, etc.).
Developing chemoselective and sustainable catalytic oxidation
methods is important due to their significance in both aca-
deme and industry (e.g., to make chemical intermediates for
the pharmaceutical, perfume, dye, and agrochemical indus-
tries).[1] In order to achieve this, various stoichiometric and cat-
alytic methods were developed using chromium, manganese,
ruthenium, osmium, palladium, platinum, iron, cobalt, nickel,
copper, activated DMSO,[2] hypervalent iodine reagents,[3]
metal-free systems,[4] and other reagents.[5] Among these re-
agents, copper is an essential metal that can easily associate
with different functional groups via Lewis acid interactions
or p-coordination.[6d] Significant efforts towards the chemo-
selective oxidation of alcohols using various copper-catalyzed
and copper—2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-cat-
[a] C. B. R. Reddy, Dr. S. R. Reddy, S. Naidu
Organic Chemistry Division, Department of Chemistry
VIT University, Vellore-632014 (India)
Our research interest is on oxidation catalysis, where we de-
velop mild and widely applicable selective oxidation meth-
ods.[17] Our recent and ongoing efforts towards the synthesis
of azo compounds and hydrazines use a copper(I) bromide/
azobisisobutyronitrile (AIBN)/4-dimethylaminopyridine (DMAP)
catalytic system via dehyrogenative coupling of aromatic
amines under mild reaction conditions.[17c] During our studies
on the selective oxidation of 2-aminobenzyl alcohol, surprising-
ly, we could notice only 2-amino benzaldehyde in 42% yield
E-mail: sekharareddy@vit.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/open.201402082.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are
made.
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instead of the azo compound [(E)-(diazene-1,2-diylbis(2,1-phen-
ylene) dimethanol] under the reported reaction conditions
(Scheme 1).
along with the desired product. Next, AIBN was replaced with
TEMPO, and varying the amounts of TEMPO and DMAP result-
Table 2. Selective oxidation of benzyl and aminobenzyl alcohols.[a]
Entry
1
Substrate
Time
[h]
Product
Yield[b]
[%]
6
6
86
85
84
84
Scheme 1. Copper(I)-catalyzed oxidation of (2-aminophenyl)methanol.
Reagents and conditions: a) CuBr, AIBN, O2, DMAP, CH3CN, rt, 12 h, 42% (alde-
hyde).
2
3
4
This observation prompted us to further investigate the che-
moselective oxidation of amino, propargyl, and a wide range
of diversely functionalized benzyl alcohols. We herein report
an oxidation reaction that can be performed under very mild
conditions (room temperature) in the presence of commercial-
ly available DMAP as the ligand with a copper(I) iodide/TEMPO
catalyst system, without use of an external base, where molec-
ular oxygen acts as a stoichiometric oxidant, and where water
is the only byproduct.
14
6
5
6
12
6
65
81
Preliminary experiments were carried out using 2-aminoben-
zyl alcohol as model substrate. The first set of experiments was
examined using copper(I) bromide as standard catalyst while
changing the amount of AIBN and TEMPO. In the copper(I)
bromide/DMAP/AIBN system, the maximum yield obtained was
42% (Table 1, entries 1 and 2). By increasing the reaction tem-
peratures to 60 and 808C, the reaction was not selective, and
unidentified products were formed in the reaction mixture
7
8
16
3
80
92
90
92
92
91
Table 1. Optimizing conditions for Aerobic oxidation of o-aminobenzyl
alcohol.[a]
9
6
Entry CuX
DMAP
AIBN
TEMPO Temp
Time Yield
10
11
12
1.5
1.5
3
[mol%] [mol%] [mol%]
[h]
[%]
1
2
3
4
5
6
7
8
9
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
CuI
CuI
CuI
CuI
CuI
120
120
120
120
20
20
20
20
10
30
100
–
–
–
–
–
–
–
–
–
10
5
5
5
5
1
1
1
rt
rt
rt
rt
rt
rt
rt
rt
12
12
12
12
12
12
3
3
3
12
3
42
42
78
78
85
76
87
88
88
-
60–658C
rt
rt
10
11
–
10
–
–
[a] Reagents and conditions: substrate (1 mmol), CuI (10 mol%), DMAP
(10 mol%), and TEMPO (1 mol% ) in CH3CN (5 mL) under O2 balloon at rt;
reaction time as mentioned in the table. [b] Isolated yield after column
chromatography.
1
88
a] Reagents and conditions: substrate (1 mmol), Cu catalyst (10 mol%),
CH3CN (3 mL) under O2 balloon.
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ed in an increase in yield to 85% in 12 h (Table 1, entry 5). The
second set of experiments was performed under similar condi-
tions using copper(I) chloride, which resulted in a 76% yield of
desired product (Table 1, entry 6). The third set of experiments
was examined by using copper(I) iodide in place of copper(I)
bromide and copper(I) chloride and varying the amount of
DMAP and TEMPO (Table 1, entries 7–11).
their respective aldehydes in excellent yields (11b, 12b, and
13b, Table 2).
Finally, the scope of this oxidation system was extended to
propargyl alcohols to produce their respective aldehydes and
ketones. Our initial experiments were carried out without any
substituent on the phenyl moiety, that is, 3-phenylprop-2-yn-1-
ol (14a, Table 3), which was successfully converted to the de-
sired aldehyde 14b with excellent yield. Here starting materials
of fluorine and pyridine-containing propargyl alcohols were
synthesized according to reported methods.[18] The synthesized
propargyl alcohols were efficiently converted to their respec-
tive aldehydes in excellent yields. In addition, the developed
protocol was extended to the oxidation of secondary proparg-
yl alcohols (17a–20a, Table 3). Significantly, secondary alcohols
with both electron-donating (hydrogen and methyl) and elec-
tron-withdrawing (nitro, fluoro, and bromo) groups were suc-
cessfully converted to their corresponding ketones at room
Among the copper(I) halides, copper(I) iodide was the most
effective (Table 1). The maximum isolated yield of 88% was ob-
served in the reaction lasting 3 h with copper(I) iodide
(10 mol%,), DMAP (10 mol%), and TEMPO (1 mol%) (Table 1,
Entry 11). Interestingly, in the presence of copper(I) iodide and
TEMPO without using DMAP, no reaction takes place under op-
timized conditions (Table 1, entry 10).
Next, the scope of this oxidation system was extended to
various substituted 2-aminobenzyl alcohols to produce a series
of amino aldehydes under the developed reaction conditions
(Table 2). Next experiments were
carried out with electron rich (2-
Table 3. Selective oxidation of propargyl alcohols.[a]
amino-5-methylphenyl)methanol
(2a, Table 2). The reaction pro-
gressed smoothly and gave the
corresponding aldehyde 2b in
excellent yield (Table 2). Further-
more, aminobenzyl alcohols
bearing a halogen substitution
(3a–8a, Table 2) were converted
into their respective carbonyl de-
rivatives (3b–8b, Table 2) in
good to excellent yields. When
the chloro group was in ortho-
position to the benzyl alcohol,
the resultant aldehyde was ob-
tained in 65% yield due to the
ortho effect of chlorine. Notably,
no overoxidized products, like
carboxylic acids or other N-oxi-
dized byproducts, were ob-
served. In addition to the selec-
tive oxidation of aminobenzyl al-
cohols to aldehydes, the devel-
oped protocol was extended to
various hydroxy-, nitro-, and me-
thoxy-substituted benzyl alco-
hols (9a–13a, Table 2). As antici-
pated, substrates containing
ortho-hydroxy and para-hydroxy
groups, that is, 4-(hydroxyme-
thyl)phenol (9a) and 2-(hydroxy-
methyl)phenol (10a), were selec-
tively converted into their re-
spective aldehydes in excellent
yields (9b and 10b, Table 2). No-
tably, benzyl alcohols with deac-
tivating ortho- and para-nitro
groups or an activating para-me-
thoxy group were converted to
Entry
Substrate
Time
[h]
Product
Yield[b]
[%]
1
2
3
6
6
8
81
86
84
4
5
6
7
3
3
3
3
95
88
86
89
[a] Reagents and conditions: substrate (1 mmol), CuI (10 mol%), DMAP (10 mol%), and TEMPO (1 mol% ) in
CH3CN (5 mL) under O2 balloon at rt; reaction time as mentioned in the table. [b] Isolated yield after column
chromatography.
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temperature in excellent yields after 3 h of reaction time (17b–
20b, Table 3).
Kali Kishore Reddy (VIT University) for his valuable suggestions
during the drafting stage of this article.
In conclusion, the developed chemoselective oxidation
method is simple, clean and requires mild reaction conditions
to produce a wide variety of functional-group-containing
amino aldehydes, hydroxy aldehydes, and a,b-acetylenic car-
bonyl compounds. A highlight of the proposed method is the
use of commercially available and cheap reagents. Remarkably,
sensitive groups like alkynes and oxidizable groups such as ac-
tivated benzylic carbons, hydroxy groups of phenols, amino
groups, and heteroatoms (as in pyridine) did not undergo oxi-
dation; rather, these reactions selectively gave the respective
aldehydes and ketones in excellent yields. Furthermore, the
target molecules were obtained without formation of any by-
products in the reaction mixture.
Keywords: aldehydes · benzyl alcohols · copper(I) catalyst ·
ketones · oxidation · propargyl alcohols
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General procedure for oxidation of alcohols: A mixture of 2-ami-
nobenzyl alcohol (123 mg, 1 mmol), CuI (19.2 mg, 0.1 mmol), and
CH3CN (5 mL) in a 25 mL round-bottom flask was stirred for 5–
10 min. DMAP (12.1 mg, 0.1 mmol) and TEMPO (1.56 mg, 1 mol%,)
were added, and the resulting mixture was stirred under an O2 bal-
loon at rt until the reaction reached completion as determined by
TLC. The resulting reaction mixture was filtered and washed with
CH3CN (2ꢁ5 mL), and the solvent was removed in vacuo. The ob-
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100—200 mesh silica gel (n-hexane/EtOAc, 98:2) to provide the de-
sired product.
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Supporting Information is available for detailed experimental pro-
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Acknowledgements
Dr. S. R. Reddy thanks the Department of Science and Technolo-
gy–Science and Engineering Research Board (DST—SERB, India)
Fast Track Scheme (SR/FT/CS-93/2011) for funding this project.
The authors thank SIF-VIT-DST-FIST and VIT University for provid-
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Received: November 17, 2014
Published online on && &&, 0000
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COMMUNICATIONS
Chemoselective alcohol oxidation! Cat-
alytic oxidation reactions often suffer
from low yields and selectivity. Here we
develop a method using copper(I) cata-
lysts to selectively oxidize a wide range
of benzyl and propargyl alcohols to
their corresponding aldehydes and ke-
tones under mild reaction conditions
and with excellent yields. This chemose-
lective catalytic oxidation scheme can
tolerate even sensitive and oxidizable
groups such as alkynes, amines, and
phenols.
C. B. R. Reddy, S. R. Reddy,* S. Naidu
&& – &&
Chemoselective Oxidation of Benzyl,
Amino, and Propargyl Alcohols to
Aldehydes and Ketones under Mild
Reaction Conditions
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemistryOpen 2014, 00, 1 – 4
&
5
&
ÞÞ
These are not the final page numbers!