L-Proline: An efficient N,O-bidentate ligand for copper-catalyzed aerobic oxidation of primary and secondary benzylic alcohols at room temperature

Article abstract of DOI:10.1039/c3cc44122a

A novel and highly practical copper-catalyzed aerobic alcohol oxidation system with l-proline as the ligand at room temperature has been developed. A wide range of primary and secondary benzylic alcohols tested have been smoothly transformed into corresponding aldehydes and ketones with high yields and selectivities.

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L-Proline: an efficient N,O-bidentate ligand for copper-catalyzed
aerobic oxidation of primary and secondary benzylic alcohols at room
temperature
Guofu Zhang,a Xingwang Han,a Yuxin Luan,a Yong Wang,a Xin Wena and Chengrong Dinga*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Punniyamurthy’s group reported a salen analogue N,Oꢀligand to
achieve the efficient primary alcohol oxidation to corresponding
50 aldehydes under oxygen condition.10 Therefore, the application of
N,Oꢀdentate ligand for secondary alcohols oxidation with air or
oxygen as oxidant under mild conditions is still a challenge. In
this paper, we wish to render a commercially available and
inexpensive N,Oꢀdidentate ligand Lꢀproline11 and its high
55 efficient performance in copperꢀcatalyzed aerobic oxidation of
alcohols under mild conditions, particularly for secondary
alcohols (eq. 1).
A novel and highly practical copper-catalyzed aerobic alcohol
oxidation system with L-proline as the ligand at room
temperature has been developed. A wide range of primary
10 and secondary benzylic alcohols tested have been smoothly
transferred into corresponding aldehydes and ketones with
high yields and selectivities.
The selective alcohol oxidation to aldehyde or ketone with
oxygen as the terminal oxidant is a pivotal reaction in organic
15 synthesis.1 However, the direct utilization of oxygen for oxidative
reactions is always unpromising and should be assisted by
transition metal catalysts.2 During the past decades, such noble
metals as Pd,3 Au,4 etc., or their corresponding metal complexes
have been well applied in aerobic alcohol oxidation subsequently.
20 While, considering their rarity and price, those noble catalysts
turn out to be impractical in largeꢀscale industrial applications.
Compared with these transition metals, copper is an inexpensive,
earthꢀabundant metal and its widespread applications in organic
synthesis have been impressively demonstrated in recent
25 publications.5 In many catalytic systems, copper catalysts not
only show similar excellent activity for the oxidation of a wide
range of alcohols, but can also overcome the deactivation
problems caused by the coordination between metal catalysts and
heteroatoms in tested substrates.6
Initially, 1ꢀphenethyl alcohol was selected as the model
60 substrate to gain the optimal conditions. First, solvent effect on
this oxidative transformation was examined (Table 1, entries 1ꢀ6).
Trace conversion of acetophenone was obtained, when the
reaction was performed in CH3OH or C2H5OH with 5 mol%
t
CuCl, 5 mol% Lꢀproline in the presence of 1.0 equiv. BuOK
65 under air at room temperature (entries 1ꢀ2). While the
employment of CH3CN, CH2Cl2 or toluene led to moderate
conversions of the substrate (entries 3ꢀ5). Intriguingly, when
switching the solvent to DMF, the conversion reached to 94%
(entry 6). Subsequently, different copper salts were further
70 screened (entries 7ꢀ12). It was found that CuI salts exhibited
higher catalytic reactivity than CuII salts in this catalytic system.
As showed in Table 1, CuCl2, CuBr2, CuSO4 and Cu(OAc)2 led to
the oxidative reaction with only 68%, 78%, 73% and 79%
substrate conversions respectively after 5 h (Table 1, entries 7ꢀ8,
75 10ꢀ11). And CuI turned out to be the most effective catalyst
precursor compared with other CuI salts tested, offering almost
quantitative conversion of 1ꢀphenethyl alcohol to acetophenone
was observed in 5 h (entries 6, 9, 12). Furthermore, some other
N,Oꢀbidentate ligands were also tested (entries 13ꢀ16). Compared
80 with other ligands, Lꢀproline is the ideal one. Finally, controlled
experiments showed that the starting material gave low
conversion in the absence of CuI or TEMPO, and a drastic
decrease in conversion was observed when Lꢀproline or base was
omitted (entries 17ꢀ20). Thus, we obtained the optimized reaction
85 conditions (entry 12): alcohol (1.0 mmol), TEMPO (5 mol%),
tBuOK (1.0 equiv) under air at room temperature with CuI (5
mol%) as catalyst and Lꢀproline as ligand (5 mol%).
30
During the past years, many copperꢀcatalyzed systems have
been reported and shown efficient catalytic activity for primary
alcohols.7 Yet their ability for secondary alcohol oxidation was
usually unsatisfying to our knowledge. And only a few examples
have been reported to facilitate the aerobic oxidation of secondary
35 alcohols.8 For instance, Markó and coꢀworkers9a employed 1,10ꢀ
phenanthroline as ligand in CuCl/DBADH2/O2ꢀcatalyzed system,
in which second alcohols were smoothly oxidized into desired
ketones in toluene. Another copperꢀcatalyzed secondary alcohol
oxidation was rendered by Knochel and coꢀworkers,8b which
40 contained
CuBrꢁMe2S as catalyst in
a
fluoroalkylꢀsubstituted bipyridyl ligand with
fluorous biphasic condition
a
(C8F17Br/PhCl) at 90 oC. It was found that the rendered ligands in
copperꢀcatalyzed alcohol oxidations by far are confined to N,Nꢀ
bidentate ligands such as bipyridyl, 1,10ꢀphenanthroline, 1,4ꢀ
45 diazabicyclo[2.2.2]octane, etc.9 While the progress in the design
of N,Oꢀdentate ligands for copperꢀcatalyzed alcohol oxidation
under air or oxygen condition is sluggish, although
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Table 1 The optimization of copperꢀcatalyzed alcohol oxidationa
in methanol phase (see SI, Table S1). As shown in Table 3, a
30 wide range of primary alcohols bearing electronꢀdonating or
electronꢀdrawing groups were converted into their corresponding
Table 2 Aerobic alcohol oxidation of secondary alcohols to ketonesa
Entry
1
2
3
4
5
6
7
8
R1
Ph
Ph
Ph
R2
CH3
Ph
COC6H5
CH3
CH3
CH3
T (h)
5
5
5
5
5
5
5
7
8
8
6
8
8
10
6
5
5
Conv. (%)b Yield (%)c
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
93
94
93
94
94
94
93
91
91
93
91
92
90
89
90
90
93
ꢀ
Entry
1
2
3
4
5
6
7
8
Solvent
CH3OH
C2H5OH
CH3CN
CH2Cl2
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Cat.
Ligand
A
A
A
A
A
A
A
A
A
A
A
A
B
C
D
E
A
A
ꢀ
Conv.(%)b
trace
trace
56
69
63
94
68
78
98
73
79
>99
30
36
56
95
12
10
4ꢀMeC6H
4ꢀMeOC6H4
3,4ꢀMeOC6H3
3,4,5ꢀMeOC6H2 CH3
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
2ꢀClC6H4
3ꢀClC6H4
2,4ꢀClC6H3
3ꢀCF3C6H4
4ꢀPhC6H4
3ꢀpyridyl
2ꢀfuryl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl2
CuBr2
CuBr
CuSO4
Cu(OAc)2
CuI
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
9
10
11
12
13
14
15
16
17
18
19d
9
10
11
12
13
14
15
16
17c
18d
19e
20f
96
>99
98
>99
5
CuI
CuI
CuI
CuI
cyclohexyl
cyclohexyl
12
12
H
20
ꢀ
aReaction condition: substrate (1.0 mmol), CuI (5 mol%), Lꢀproline (5
mol%), TEMPO (5 mol%), base (1.0 mmol), DMF (4.0 mL), 900r/min.
bDetermined by GCꢀMS. cIsolated yield, dUnder 60 oC with CuI (10
mol%), Lꢀproline (10 mol%), TEMPO (10 mol%).
ꢀ
CuI
CuI
CuI
8
5
DMF
A
aReaction condition: 1ꢀphenethyl alcohol (1.0 mmol), copper salt (5
mol%), TEMPO (5 mol%), tBuOK (1.0 mmol), Lꢀproline (5 mol%),
Solvent (4.0 mL), 5 h, 900r/min. bDetermined by GCꢀMS. cCopper salt
was omitted. dThe reaction was carried out in the absence of TEMPO. eNo
Lꢀproline was employed. fBase was omitted.
35 aldehydes with high yields and selectivities (Table 3, entries1ꢀ13).
Notably, the efficient transformations of allylic alcohols to the
desired aldehydes were observed without overꢀoxidation (entry
14). Even with heterocyclic alcohols, 2ꢀthienyl, 2ꢀfuryl and 3ꢀ
pyridyl methanol, the products were obtained in 90%, 87% and
40 92% respectively (entries 15ꢀ17). Although, the primary aliphatic
alcohol displayed no acitivity under the optimized conditions
(entry 18).
Considering the above promising results and related published
researches,12 a mechanism for the present Cu/Lꢀproline/TEMPOꢀ
45 catalyzed alcohol oxidation was proposed as shown in Scheme 1.
The initial step of the reaction was involved in the formation of
complex A, which reacted with O2 to afford a CuIIꢀsuperoxide
5
Having obtained the optimized conditions (Table 1, entry 12),
we turned our attention to examine the substrate scope of this
method. As shown in Table 2, various secondary alcohols were
successfully oxidized into corresponding ketones. Aromatic
secondary alcohols bearing electronꢀdonating groups such as
10 methyl or methoxy at the aromatic ring proceeded smoothly and
yielded the corresponding ketones in good to excellent yields
(Table 2, entries 1ꢀ7). Moreover, substrates bearing an electronꢀ
withdrawing group on the aromatic ring such as halogen,
trifluoromethyl afforded the products with yields up to 89ꢀ93%
15 yet with a prolonged time (entries 8ꢀ15). Of particular note was
the effective oxidation of steric hindrance alcohols, which also
provided the products in excellent yields (entries 11, 13).
Gratifyingly, the novel system showed promising activity for the
oxidation of heterocyclic secondary alcohols such as 1ꢀ(3ꢀ
20 pyridyl)ethanol and 1ꢀ(2ꢀfurfuryl)ethanol (entries 16ꢀ17). While
aliphatic alcohol like cyclohexyl showed lower activity even
under 60 oC with 10 mol% catalyst loading (entries 18ꢀ19).
Furthermore, the extensive application of Cu/TEMPO/Lꢀ
proline for primary alcohols was also tested. During the reaction
25 conditions optimization, it was found that the CuI salts exhibit
higher activity than CuII salts for primary alcohols as well. And
the model substrate pꢀtolylmethanol could nearly completely
convert to aldehyde with CuBr as copper source, Na2CO3 as base
Table 3 Aerobic alcohol oxidation of primary alcohols to aldehydesa
Entry
1
2
3
4
5
6
7
8
R
C6H5
T (h)
5
5
5
5
5
3
6
6
6
6
7
6
Conv. (%)b
>99
>99
>99
>99
>99
>99
96
97
98
>99
>99
>99
>99
Yield (%)c
94
94
93
94
95
95
90
91
92
92
91
92
92
4ꢀCH3C6H4
4ꢀCH3OC6H4
3,4ꢀCH3C6H3
2ꢀCH3OC6H4
1ꢀnaphthyl
4ꢀNO2C6H4
4ꢀFC6H4
4ꢀClC6H4
4ꢀBrC6H4
2ꢀClC6H3
3ꢀClC6H4
2,4ꢀClC6H3
9
10
11
12
13
6
2
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DOI: 10.1039/C3CC44122A
14
15
16
17
18
C6H5CH=CH
2ꢀthienyl
2ꢀfuryl
3ꢀpyridyl
nꢀC7H15
5
5
5
5
96
96
95
98
NR
92
90
87
92
ꢀ
† Electronic Supplementary Information (ESI) available: Detailed
experimental procedures, the optimization of copperꢀcatalyzed primary
35 alcohol oxidation and NMR data for products. See DOI:
10.1039/b000000x/
10
1
(a) M. Hundlucky, Oxidations in Organic Chemistry, ACS Press,
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aReaction condition: substrate (1.0 mmol), CuBr (5 mol%), Lꢀproline (5
mol%), TEMPO (5 mol%), Na2CO3 (1.0 mmol), CH3OH (4.0 mL),
900r/min. bDetermined by GCꢀMS. cIsolated yield.
40
45
50
55
60
65
70
75
80
85
90
95
100
2
3
L. Boisvert, K. I. Goldberg, Acc. Chem. Res., 2012, 45, 899.
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L. P. Yang, Z. J. Shi, J. Am. Chem. Soc., 2005, 127, 18004; (b) H.
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Scheme 1 A plausible mechanism for the copper/Lꢀproline/TEMPO
catalyzed alcohol oxidation.
species B. Then it resembled the reactions of O2 with biomimetic
Nꢀchelated CuI complexes,13 which abstracted hydrogen radical
from TEMPOH to form C. Subsequent reaction of the CuIIꢀOOH
intermediate with water released H2O2 and afford a CuIIꢀOH
species D. Then, the insertion of an alcohol to afford an alkoxo
copper specie E (CuIIꢀOCH2R). βꢀHydrogen elimination of the
5
8
9
10 alkoxo moiety in E would occur to give a carbonyl product and
TEMPOH, and regenerated A.
Conclusions
In conclusion, a novel and mild copperꢀcatalyzed aerobic
alcohol oxidation system particularly for secondary alcohols was
15 successfully developed. Under the optimized reaction conditions,
various kinds of alcohols such as primary/secondary benzyl and
allylic alcohols were smoothly converted into corresponding
aldehydes or ketones with high yields and selectivities. To the
best of our knowledge, this is the first example of copperꢀ
20 catalyzed aerobic oxidations for efficient secondary alcohol
oxidation using Lꢀproline as ligand. The use of green reagents,
such as air as oxidant and inexpensive Lꢀproline as ligand, made
it a convenient procedure for practical applications.
We acknowledge financial support from the National Natural
25 Science Foundation of China (No. 20702051), the Natural
Science Foundation of Zhejiang Province (LY13B020017) and
the Key Innovation Team of Science and Technology in Zhejiang
Province (No. 2010R50018).
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12 (a) J. M. Hoover, B. L. Ryland, S. S. Stahl, J. Am. Chem. Soc., 2013,
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Notes and references
30 a College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou 310014. People's Republic of China
Fax/Tel: (+86)-571-88320147; E-mail: dingcr@zjut.edu.cn.
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