N-Functionalized Amino Acids Promoted Aerobic Copper-Catalyzed Oxidation of Benzylic Alcohols in Water

Article abstract of DOI:10.1055/s-0034-1380126

Instead of traditional N,N-bidentate ligands, N-functionlized amino acids were used as powerful N,O-bidentate ligands in aerobic copper/TEMPO-catalyzed system for promoting oxidation of benzylic alcohols. Under the optimized reaction conditions, a wide range of primary and secondary benzylic alcohols have been efficiently converted into aldehydes and ketones with good to excellent yields in water.

Full text of DOI:10.1055/s-0034-1380126

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 779–784
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Letter
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N-Functionalized Amino Acids Promoted Aerobic Copper-Cata-
lyzed Oxidation of Benzylic Alcohols in Water
Guofu Zhang
Jie Lei
copper salt, N-functionalized amino acid
TEMPO, base
OH
O
Xingwang Han
Yuxin Luan
R1
R2
H2O, air, reflux
R1
R2
R1 = aryl, thienyl, pyridyl, furyl, allylic
1 = aryl, thienyl, furyl
R2 = H
27 examples
Chengrong Ding*
Shang Shan*
80–92% yields
20 examples
76–91% yields
R
R2 = Me, Et
College of Chemical Engineering, Zhejiang University of Technology,
18 Chaowang Road, Hangzhou 310014, P. R. of China
dingcr@zjut.edu.cn
shans2001@163.com
Received: 18.11.2014
Accepted after revision: 05.01.2015
Published online: 09.02.2015
During the past decades, copper-catalyzed aerobic alco-
hol oxidation have been widely reported.8 Particularly, N,N-
bidentate ligands such as 1,10-phenanthroline (phen), 2,2′-
bipyridine (bipy) and their derivatives were widely used in
these oxidation systems. For instance, Markó et al. first
reported an efficient CuCl/phen catalytic system for the
oxidation of primary and secondary alcohols in toluene.9
Sheldon and co-workers developed a CuBr2/TEMPO/bipy
(TEMPO = 2,2,6,6-tetramethylpiperidine-1-oxyl) system,
which provided aldehydes from primary benzylic alcohols
in mixed solution.10 Later on, Stahl and co-workers investi-
gated Cu(I)/bipy catalytic system, and various alcohols were
oxidized into desired carbonyl compounds in acetonitrile or
acetone.11
DOI: 10.1055/s-0034-1380126; Art ID: st-2014-w0953-l
Abstract Instead of traditional N,N-bidentate ligands, N-functionlized
amino acids were used as powerful N,O-bidentate ligands in aerobic
copper/TEMPO-catalyzed system for promoting oxidation of benzylic
alcohols. Under the optimized reaction conditions, a wide range of pri-
mary and secondary benzylic alcohols have been efficiently converted
into aldehydes and ketones with good to excellent yields in water.
Key words N,O-bidentate ligand, N-functionalized amino acid, cop-
per, alcohol oxidation, benzylic alcohol, water
Transition-metal-catalyzed selective aerobic alcohol ox-
idation is an important chemical transformation in organic
synthesis.1 Traditionally, the alcohol oxidations were per-
formed with stoichiometric oxidants such as CrO3, SeO2,
and KMnO4,2 which were usually hazardous or toxic and
generated large quantities of noxious byproducts. In con-
trast, the oxidation systems, utilizing transition metal as
catalyst and O2 (or air) as terminal oxidant, have significant
benefits from both economic and environmental view-
points. Accordingly, various catalysts derived from precious
metals have been developed, including platinum,3 rutheni-
um,4 palladium,5 gold,6 and iridium.7 However, considering
the rarity and high cost of noble metals, it would be more
desirable to develop non-noble-metal catalysts to promote
alcohol oxidation, such as copper, which is an earth-abun-
dant and commercially available metal. Moreover, com-
pared with precious transition metals, copper catalysts not
only show similar excellent activity for the oxidation of a
broad range of alcohols, but also overcome the deactivation
problems arose from the coordination between metal cata-
lysts and heteroatoms in tested substrates.
Compared with traditional N,N-bidentate ligands, N,O-
bidentate ligands have been seldom developed to promote
the aerobic alcohols oxidation.12 During the past decades,
amino acid as an efficient N,O-bidentate ligand has been
widely applied in many fields because of its facile structure
modification and commercial availability.13–15 Recently, we
reported the discovery that L-proline could be used as an
excellent N,O-bidentate ligands to accelerate selective alco-
hol oxidation under air.16 But these catalytic systems show
low activity for benzylic alcohols in water. From an eco-
nomic and environmental viewpoint, aqueous reaction me-
dia has continued to gain much interest in recent years.17
Because water-medium reaction could be regarded as one
important complement of organic synthesis in volatile sol-
vents. Therefore, in this communication, we wish to devel-
op the application of N-functionalized amino acids as pow-
erful ligands in aerobic copper/TEMPO-catalyzed aqueous
oxidation systems to promote benzylic alcohols, particular-
ly for secondary alcohols. To the best of our knowledge,
aqueous oxidation systems for secondary alcohols are still a
challenge.18
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 779–784

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G. Zhang et al.
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Initially, p-tolylmethanol was selected as the model sub-
strate to obtain the best reaction conditions of benzylic al-
cohol oxidation in neat water. From the results summerized
in Table 1, only 46% conversion of the substrate was ob-
tained when the oxidation was catalyzed by CuCl/TEMPO
with L-proline as the ligand under air (Table 1, entry 1). And
some commercially available mono N-Ac-protected amino
acid ligands showed poorer activity within half an hour (Ta-
ble 1, entries 2–5). But N-phenylglycine exhibited great
prospects by providing the desired aldehyde in 97% conver-
sion (Table 1, entry 6). Whilst employing some other N-
phenylated amino acids as the ligand in the oxidation sys-
tem did not yet provide comparable results with N-phenyl-
glycine (Table 1, entries 7–11). Hence, N-phenylglycine was
selected as the best ligand. And the effect of copper salt on
the transformation was then examined (Table 1, entries 6
and 12–19). It was found that copper(I) salts such as CuBr
and CuI displayed moderate catalytic activity with 82% and
87% conversion of substrate (Table 1, entries 12 and 13).
Gratifyingly, an approximately quantitative conversion was
obtained when the reaction was catalyzed by CuBr2 (Table
1, entry 14),19 but other copper(II) salts could only offer
lower conversions (Table 1, entries 15–19). Subsequently,
the screen of different bases showed that Na2CO3 was the
best base, the others were found to dramatically decrease
the conversion (Table 1, entries 14 and 20–28). Finally, the
control experiments showed that CuBr2, N-phenylglycine,
and TEMPO are essential for the alcohol oxidation system.
When CuBr2, N-phenylglycine, or TEMPO was omitted, only
7%, 10%, and trace p-tolymethanol were transformed into p-
tolualdehyde (Table 1, entries 29–31). Hence, the optimized
reaction conditions were obtained (Table 1, entry 14): alco-
hol (1.0 mmol), CuBr2 (5 mol%), N-phenylglycine (5 mol%),
TEMPO (5 mol%), Na2CO3 (1.0 mmol), H2O (3.0 mL), in air
under reflux.
Table 1 The Optimization of Copper-Catalyzed Primary Benzylic Alcohol Aerobic Oxidationa
OH
O
copper salt, ligand, TEMPO, base
H2O, air, reflux
O
O
O
O
O
O
N
OH
NH
Ac
OH
NH
OH
H
Ac
O
NH
OH
Ac
NH
OH
Ac NH
OH
A
B
D
F
C
E
O
NH
OH
NH
OH
O
O
O
MeO
NH
OH
Cl
NH
OH
G
H
NH
OH
I
J
K
Entry
Copper salt
Ligand
Base
Na2CO3
Conv. (%)b
1
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
A
B
C
D
E
F
46
19
15
17
18
97
89
60
55
48
74
82
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
3
4
5
6
7
G
H
I
8
9
10
11
12
J
K
F
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Table 1 (continued)
Entry
Copper salt
Ligand
Base
Na2CO3
Conv. (%)b
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29c
30d
31e
CuI
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
–
F
87
CuBr2
Cu(OAc)2
CuSO4
Cu(OTf)2
CuCl2
Cu(NO3)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
–
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K3PO4
>99 (90)f
40
53
58
60
57
23
NaOH
15
NaHCO3
KOt-Bu
KOAc
36
15
78
K2CO3
49
CsOAc
69
CF3COONa
NaOAc
Na2CO3
Na2CO3
Na2CO3
55
66
7
CuBr2
CuBr2
10
trace
a Reaction conditions: p-tolymethanol (1.0 mmol), copper salt (5 mol%), ligand (5 mol%), TEMPO (5 mol%), base (1.0 equiv), H2O (3.0 mL), in air under reflux,
0.5 h.
b Determined by GC–MS.
c Copper salt was omitted.
d The reaction was carried out in the absence of ligand.
e No TEMPO was used.
f Isolated yields.
Having gained the optimized reaction conditions, we
next evaluated the substrate scope of the catalytic system
and representative results are summarized in Scheme 1.
Generally, various primary alcohols were efficiently oxi-
dized into the corresponding aldehydes. Notably, the for-
mation of overoxidized products was not detected in all
cases. A variety of aromatic primary alcohols bearing elec-
tron-donating groups, such as methyl and methoxy, all par-
ticipated in catalytic oxidations smoothly and yielded the
corresponding aldehydes in good yields under standard re-
action conditions (1–8). Notably, the efficient transforma-
tions of p-methylthiobenzyl alcohol into the desired alde-
hyde were observed without transformation to sulfoxide or
sulfone (9). Moreover, electron-deficient substrates, includ-
ing halogen, nitro, and cyano substrates, exhibited good ac-
tivity with almost quantitative conversions in two or three
hours (10–17). Notably, sterically hindered alcohols bearing
an electron-withdrawing group were also converted into
the desired aldehydes with high yields and selectivities,
demonstrating the broad substrate scope of the oxidation
approach (18–22).
Notably, heteroatoms also seem to be well tolerated, 2-
thienyl, 2-furyl, 5-Me-2-furyl, and 3-pyridyl methanol were
conveniently transformed into the desired carbonyl com-
pounds under the standardized conditions and 91%, 89%,
82%, and 80% yields were obtained, respectively (23–26).
Gratifyingly, when the catalytic oxidation was examined
using aliphatic alcohols as substrates such as cinnamyl al-
cohol, the allylic alcohols were excellent substrates giving
the corresponding aldehydes in 90% isolate yields (27). Un-
fortunately, phenethyl alcohol was essentially unreactive
under these conditions (28).
Subsequently, 1-phenylethyl alcohol, a secondary ben-
zylic alcohol, was applied to the aforementioned oxidation
conditions used for primary alcohols; only 53% conversion
was observed. To our delight, by rescreening different li-
gands, copper salts and bases, the optimal reaction condi-
tions for the secondary alcohol oxidation was obtained:
secondary benzylic alcohol (1.0 mmol), CuBr2 (10 mol%), N-
phenylphenylalanine (10 mol%), TEMPO (10 mol%), NaOAc
(2.0 mmol), H2O (3.0 mL), in air, reflux (Table S1 in Support-
ing Information).20 After the optimized reaction conditions
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CHO
CHO
CHO
CHO
CHO
MeO
4; 1 h, >99% (92%)
1; 1 h, 97% (90%)
2; 2 h, 99% (91%)
5; 1 h, >99% (90%)
3; 0.5 h, >99% (90%)
CHO
MeO
MeO
CHO
CHO
CHO
CHO
O
O
MeO
MeS
F
OMe
OMe
9; 3 h, 99% (90%)
8; 8 h, >99% (91%)
10; 3 h, >99% (92%)
6; 1 h, >99% (89%)
7; 1 h, >99% (90%)
CHO
CHO
CHO
CHO
CHO
Br
O2N
Cl
NO2
Cl
11; 2 h, >99% (90%)
12; 2 h, >99% (93%)
13; 2 h, >99% (91%)
14; 2 h, 99% (90%)
15; 2 h, >99% (90%)
CHO
CHO
CHO
CHO
CHO
NO2
CN
Br
NC
CN
18; 2 h, 99% (89%)
17; 2 h, >99% (88%)
16; 2 h, 98% (88%)
20; 2 h, >99% (91%)
19; 2 h, >99% (90%)
Cl
CHO
CHO
CHO
O
CHO
O
CHO
S
Cl
F
25;a 16 h, 93% (82%)
24;a 16 h, 99% (89%)
21; 2 h, >99% (90%)
23; 5 h, >99% (91%)
22; 8 h, >99% (91%)
CHO
O
O
N
28;b 24 h, 5%
26;b 16 h, 89% (80%)
27;b 5 h, 99%(90%)
Scheme 1 Aerobic alcohol oxidation of primary alcohols to aldehydes. Reagents and conditions: substrate (1.0 mmol), CuBr2 (5 mol%), N-phenylglycine
(5 mol%), TEMPO (5 mol%), Na2CO3 (1.0 mmol), H2O (3.0 mL), in air, under reflux, determined by GC–MS and isolated yields in parentheses. a With 2.0
mmol Na2CO3. b With 10 mol% each of CuBr2, N-phenylglycine, and TEMPO.
were obtained, a wide range of secondary benzylic alcohols
were subjected to the oxidation system and representative
results are presented in Scheme 2. The transformation of al-
cohols with electron-rich groups at the aromatic rings were
carried out efficiently in almost quantitative conversion in
neat water (29–37). Secondary alcohols with electron-defi-
cient substituents, such as halogen and nitro, were suitable
substrates as well, giving the desired products in excellent
conversions in 12 or 16 hours (38–43). Satisfactory conver-
sions were also gained for substrates with S/O-containing
heterocycle alcohols, as shown in the oxidations of 1-(2-
thienyl)ethanol and 1-(2-furyl)ethanol with air as the ter-
minal oxidant (44 and 45).
As already noted, 1-phenylpropan-1-ol derivatives are
less reactive than primary benzylic substrates. In other
aqueous catalytic systems, oxidation of 1-phenylpropan-1-
ol derivatives to their corresponding ketones is still a chal-
lenge. To our delight, after rescreening the reaction condi-
tions, the derivatives of propiophenone were obtained with
high yields in our oxidation system (46–48)
In summary, an efficient Cu/TEMPO/N-functionalized
amino acid catalyzed aerobic alcohol oxidation system for
primary and secondary benzylic alcohol in neat water has
been developed. Under the optimized reaction conditions, a
wide range of benzylic alcohols were successfully converted
into the corresponding aldehydes or ketones in good to ex-
cellent yields.
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CuBr2 (10 mol%), N-phenylphenylalanine (10 mol%)
OH
O
TEMPO (10 mol%), NaOAc (2.0 equiv)
R1
R2
O
R1
R2
H2O, air, reflux
O
O
O
O
MeO
MeO
OMe
29; 12 h, >99% (90%)
30; 12 h, 98% (88%)
32; 12 h, >99% (89%)
33; 12 h, 99% (89%)
31; 12 h, >99% (91%)
O
O
O
O
O
MeO
MeO
OMe
F
O
35; 12 h, 97% (89%)
36; 12 h, >99% (90%)
37; 12 h, 98% (89%)
38; 16 h, 96% (87%)
34; 12 h, 98% (90%)
O
O
O
O
O
Br
Cl
O2N
CF3
Cl
39; 12 h, >99% (90%)
40; 12 h, 97% (89%)
41; 12 h, 97% (89%)
42; 12 h, 97% (89%)
43; 12 h, 91% (82%)
O
O
O
O
O
S
O
Cl
48;a 24 h, 94% (87%)
47;a 24 h, 99% (89%)
46;a 24 h, 96% (87%)
44; 12 h, 96% (83%)
45; 12 h, 85% (76%)
Scheme 2 Aerobic alcohol oxidation of secondary benzylic alcohols to ketones. Reagents and conditions: substrate (1.0 mmol), CuBr2 (10 mol%), N-
phenylphenylalanine (10 mol%), TEMPO (10 mol%), NaOAc (2.0 mmol), H2O (3.0 mL), in air, under reflux, determined by GC–MS and isolated yields in
parentheses. a With 15 mol% each of CuBr, N-phenylphenylalanine, and TEMPO.
Acknowledgment
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1720.
We acknowledge financial support from the National Natural 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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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380126.
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p
p
ortiInfogrmoaitn
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p
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ortioInfgrmoaitn
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351, 2625. (c) Figiel, P. J.; Kirillov, A. M.; Karabach, Y. Y.;
Kopylovich, M. N.; Pomberio, A. J. L. J. Mol. Catal. A: Chem. 2009,
305, 178. (d) Zhang, G. F.; Han, X. W.; Luan, Y. X.; Wang, Y.; Wen,
X.; Xu, L.; Ding, C. R.; Gao, J. R. RSC Adv. 2013, 3, 19255. (e) Chen,
C.; Liu, B.; Chen, W. Z. Synthesis 2013, 45, 3387. (f) Lipshutz, B.
H.; Hageman, M.; Fennewald, J. C.; Linstadt, R.; Slack, E.;
Voigtritter, K. Chem. Commun. 2014, 50, 11378. (g) Miao, C. X.;
Wang, J. Q.; Yu, B.; Cheng, W. G.; Sun, J.; Chanfreau, S.; He, L. N.;
Zhang, S. J. Chem. Commun. 2011, 47, 2697.
(19) General Procedures for the Copper-Catalyzed Primary Ben-
zylic Alcohol Oxidation under Air in Water (p-Methylbenzyl
Alcohol)
A mixture of p-methylbenzyl alcohol (1.0 mmol), N-phenylgly-
cine (0.0076 g, 0.05 mmol), CuBr2 (0.0112 g, 0.05 mmol),
Na2CO3 (0.1060 g, 1.0 mmol), TEMPO (0.0078 g, 0.05 mmol),
H2O (3.0 mL) were added to a 100 mL Schlenk tube, which was
vigorously stirred in air under reflux for 0.5 h. After the reac-
tion, the product was extracted with CH2Cl2 (3 × 2.0 mL). The
combined organic phase was washed with H2O (3.0 mL) and
dried over anhydrous MgSO4. After concentration under
vacuum, the residue was purified by column chromatography to
1
afford p-methylbenzaldehyde.Isolated yield: 0.1080 g (90%). H
NMR (500 MHz, CDCl3): δ = 2.38(s, 3 H), 7.27 (d, J = 4.3 Hz, 2 H),
7.73 (d, J = 4.0 Hz, 2 H), 9.91 (s, 1 H). 13C NMR (125 MHz, CDCl3):
δ = 21.5, 129.4, 129.5, 134.0, 145.2, 191.6.
(14) For selected examples of amino acids as ligands to promote C–H
activation, see: (a) Engle, K. M.; Wang, D. H.; Yu, J. Q. J. Am.
Chem. Soc. 2010, 132, 14137. (b) Engle, K. M.; Thuy-Boun, P. S.;
Dang, M.; Yu, J. Q. J. Am. Chem. Soc. 2011, 133, 18183. (c) Engle,
K. M.; Mei, T. S. M.; Wasa, Yu. J. Q. Acc. Chem. Res. 2012, 45, 788.
(15) For selected examples of amino acids as ligands to promote
copper-catalyzed oxidation, see: (a) Chong, H. S.; Ma, X.; Lee,
H.; Bui, P.; Song, H. A.; Birch, N. In Abstracts of Papers, 235th ACS
National Meeting, New Orleans, LA, April 6–10, 2008; American
Chemical Society: Washington DC, 2008, Abstr. 323. (b) Chong,
H. S.; Song, H. A.; Lee, T.; Cheng, D. F.; Lee, H.; Ma, X. In Abstracts
of Papers 235th ACS National Meeting, New Orleans, LA, April 6–
10, 2008; American Chemical Society: Washington DC, 2008,
Abstr. 33. (c) Södergren, M. J.; Andersson, P. G. Tetrahedron Lett.
1996, 37, 7577. (d) Li, Q.; Hu, Y. H. In Abstracts of Papers, 247th
(20) General Procedures for Copper-Catalyzed Secondary Alcohol
Oxidation under Reflux in Neat Water (1-Phenethyl Alcohol)
A mixture of 1-phenethyl alcohol (1.0 mmol), N-(phenyl)phe-
nylalanine (0.0241 g, 0.1 mmol), CuBr2 (0.0223 g, 0.1 mmol),
NaOAc (0.1640 g, 2.0 mmol), TEMPO (0.0156 g, 0.1 mmol), and
H2O (3.0 mL) were placed into a 100 mL Schlenk tube, which
was vigorously stirred in air under reflux for 12 h. After the
reaction, the product was extracted with CH2Cl2 (3 × 2.0 mL).
The combined organic phase was washed with H2O (3.0 mL) and
dried over anhydrous MgSO4. After concentration under
vacuum, the residue was purified by column chromatography to
afford acetophenone.Isolated yield: 0.1080 g (90%). 1H NMR
(500 MHz, CDCl3): δ = 2.52 (s, 3 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.51
(t, J = 7.0 Hz, 1 H), 7.91 (d, J = 4.3 Hz, 2 H).13C NMR (125 MHz,
CDCl3): δ = 26.5, 128.2, 128.5, 133.0, 137.1, 198.1.
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