Ligand-promoted, copper nanoparticles catalyzed oxidation of propargylic alcohols with TBHP or Air as Oxidant

Article abstract of DOI:10.1055/s-0030-1261227

A highly efficient oxidation of propargylic alcohols to ynones was catalyzed by copper nanoparticles (Cu Nps) with TBHP as an oxidant at room temperature. With bipyridine as the ligand, the reaction was accelerated significantly and led in good to excellent yields to a variety of propargylic alcohols. Furthermore, with Cu Nps as the catalyst, molecular oxygen in air could be utilized as oxidant effectively in the presence of bpy ligand. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261227

LETTER
2363
Ligand-Promoted, Copper Nanoparticles Catalyzed Oxidation of Propargylic
Alcohols with TBHP or Air as Oxidant
Highly Efficient
O
xidation of
e
Propargylic
n
Alcohols to
g
Y
nones yan Han, Min Yu, Weijiang Sun, Xiaoquan Yao*
Department of Applied Chemistry, School of Material Science and Engineering, Nanjing University of Aeronautics and Astronautics,
Nanjing 210016, P. R. of China
Fax +86(25)52112626; E-mail: yaoxq@nuaa.edu.cn
Received 30 May 2011
Herein, we hope to report a highly efficient oxidation of
Abstract: A highly efficient oxidation of propargylic alcohols to
propargylic alcohols to ynones catalyzed by copper nano-
particles with TBHP as a clean and mild oxidant at room
temperature. With bipyridine (bpy) as ligand, the reaction
ynones was catalyzed by copper nanoparticles (Cu Nps) with TBHP
as an oxidant at room temperature. With bipyridine as the ligand,
the reaction was accelerated significantly and led in good to excel-
lent yields to a variety of propargylic alcohols. Furthermore, with
Cu Nps as the catalyst, molecular oxygen in air could be utilized as
oxidant effectively in the presence of bpy ligand.
Table 1 Catalytic Oxidation of Propargylic Alcohol 1aa
OH
O
catalyst, ligand, TBHP
solvent, r.t.
Key words: propargylic alcohols, oxidation, ynones, copper nano-
particles, ligand effect
1a
2a
a,b-Acetylenic carbonyl compounds (ynones) are of great
importance for their widespread occurrence in natural
products.1 Ynones are also of considerable interest in or-
ganic synthesis because they are useful precursors for the
synthesis of various heterocyclic derivatives and other
compounds.2 Many synthetic strategies for ynones have
been reported. Among them, the oxidation of propargylic
alcohols, which were easily prepared from the addition of
terminal alkynes to aldehydes, provides a competitive al-
ternative procedure because of its efficiency and avoiding
the usage of expensive palladium catalysts.3 There are
several methodologies reported about the oxidation of
propargylic alcohols since the last decade, including stoi-
Entry Catalyst
Ligand
Time
Conversion Yield
(%)b
>99
>99
ND
75e
(%)c
1
Cu Nps
Cu Nps
free
–
6 h
2 h
94
2
bpy
–
>98
ND
73
3
24 h
24 h
24 h
24 h
3.5h
2 h
4d
5d
6f
7
Cu Nps
Cu Nps
Cu Nps
Cu Nps
Cu Nps
Cu Nps
Cu2O Nps
CuCl
bpy
–
trace
78e
trace
75
bpy
1,10-phen
bpy
bpy
bpy
bpy
bpy
bpy
bpy
–
>99
>99
>99
>99
>99
35e
96
6
chiometric oxidation systems, such as NO,4 IBX,5 MnO2
8g
9h
95
and NaIO4,7 and catalytic aerobic oxidation, such as
Co(III)-8 and VO(acac)2-catalyzed9 reactions. Among
them, VO(acac)2-catalyzed oxidation of propargylic alco-
hols shows the best efficiency and substrate scope. How-
ever, there are still some limitations in these reactions,
such as unsuitability for the propargylic alcohols derived
from alkyl alkynes and sensitivity to water.
24 h
3 h
90
10
88
11
12
13
14
15
16d
3 h
92
CuCl2
24 h
8 h
29
Cu(NO3)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
>99
>99
>99
ND
90
On the other hand, because of easy preparation and being
relative stable in air, the nanoparticles of coinage metals
were widely reported, and there are many excellent exam-
ples on their applications as catalysts,10 in which copper
nanoparticles (Cu Nps)-catalyzed dehydrogenation/oxi-
dation of aliphatic alcohols at higher temperature were
also reported.11 However, propargylic alcohols and allylic
alcohols could not be utilized as substrates in these reac-
tions.
2 h
>98
93
8 h
bpy
24 h
ND
a Reaction conditions: 1a (0.2 mmol), catalyst (10 mol%), ligand (10
mol%) and TBHP (0.4 mmol; 70% in H2O) were mixed in CH2Cl2
(1.5 mL), stirred at r.t. in air.
b Detected by GC.
c Isolated yield.
d TBHP-free, only stirred under air.
e Based on the recovered starting material.
f TBHP-free, stirred under an oxygen atmosphere.
g The reaction was performed with toluene as solvent.
h The reaction was performed with THF as solvent.
SYNLETT 2011, No. 16, pp 2363–2368
x
x
.x
x
.2
0
1
1
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261227; Art ID: W12811ST
© Georg Thieme Verlag Stuttgart · New York

2364
C. Han et al.
LETTER
Table 2 Copper Nanoparticles Catalyzed Oxidation of Propargylic
was accelerated significantly and gave good to excellent
yields of a variety of propargylic alcohols. Furthermore, a
bpy-triggered catalytic aerobic oxidation was also
achieved with Cu Nps as catalyst. To the best of our
knowledge, there are few examples reported about the
ligand effect on coinage metal nanoparticle catalyzed re-
actions.12
Alcoholsa
O
Cu Nps (10 mol%)
bipyridine (10 mol%)
TBHP (2 equiv)
OH
R1
R1
R2
CH2Cl2, r.t., air
1
R2
2
Entry Substrate 1
Time Convers. 2:Yield
(%)b
(%)c
With 1,3-diphenyl-2-propyn-1-ol (1a) as a prototype, the
catalysts and other conditions were screened, and the re-
sults are summarized in Table 1.
OH
As demonstrated in Table 1, Cu Nps13 showed good activ-
ity at room temperature to catalyze the oxidation of 1a
with two equivalents of TBHP as oxidant (entry 1,
Table 1). With the addition of bpy ligand, the catalytic ac-
tivity was increased significantly: the reaction time was
shortened from six hours to two hours, and an almost
quantitative yield was achieved (entry 1 vs. entry 2). In the
absence of copper catalyst, the reaction did not occur at all
(entry 3). It should be noted that the reaction could also be
carried out with Cu Nps–bpy as catalyst in the absence of
TBHP, which suggested that the catalyst could utilize mo-
lecular oxygen directly under current conditions (entry 4),
and that the reaction was ligand-triggered (entry 5). How-
ever, only a slight improvement was observed when oxy-
gen was used instead of air (entry 6). Changing the ligand
to 1,10-phenanthroline did not make much difference (en-
try 2 vs. entry 7). Some other solvents, such as toluene and
THF, were also used in the reaction (entries 8 and 9). Tol-
uene showed similar results as CH2Cl2, while THF de-
creased the catalytic activity significantly. Other copper
precursors were also scanned (entries 10–16). Cu2O Nps
and some other copper salts, including Cu(I) and Cu(II)
species, also gave good catalytic activities in the presence
of bpy ligand.14 Among them, Cu(OAc)2–bpy showed al-
most same catalytic activity and ligand effect as Cu Nps
with TBHP as oxidant (entries 14 and 15). However,
Cu(OAc)2–bpy could not catalyze the aerobic oxidation of
propargylic alcohols at all (entry 16).
Using the optimum conditions (entry 2, Table 1),15 vari-
ous substrates were investigated. It can be seen from
Table 2 that the substrates derived from aromatic alde-
hydes and aryl alkynes, gave good to excellent yields, and
more than 98% yields were achieved, except for the bro-
mo-substituted compound 1b (entries 1–8). Even for sub-
strates 1i and 1j, in which there is a phenol group on
benzene ring and which are usually sensitive to oxidation
conditions, around 75–80% yields were also obtained (en-
tries 9 and 10). It is noteworthy that excellent yields and
high reactivities were also observed for the oxidation of
1k, 1l and 1m, which were usually not good starting ma-
terials in reported procedures (entries 11–13).4–9 On the
other hand, starting materials 1n, 1o and 1p, derived from
aliphatic aldehydes, showed lower reactivities and gave
the yields around 75%. However, for these substrates, bet-
ter results were observed with Cu(OAc)2–bpy as catalyst,
which gave similar or slightly worse results in most exam-
ples than those obtained in Cu Nps–bpy catalyzed reaction
(entries 14–16).
1
2 h
24 h
3 h
>99
2a: >98
1a
OH
2b: 80
2
85
>99
>99
(65)d
Br
1b
OH
3
2c: >98
2d: >98
2e: 95
Cl
1c
OH
OH
4
1 h
MeO
1d
5
3 h
>99
>99
>99
MeO
1e
HO
24 h
2f: 94
6
(5 h)d
(96)d
1f
OH
7
3 h
2g: 97
2h: 85
1g
OH
O
8
3 h
>99
1h
Synlett 2011, No. 16, 2363–2368 © Thieme Stuttgart · New York

LETTER
Highly Efficient Oxidation of Propargylic Alcohols to Ynones
2365
Table 2 Copper Nanoparticles Catalyzed Oxidation of Propargylic
It should be mentioned here, that Cu(OAc)2–bpy showed
much higher catalytic activity for a-naphthyl substrate 1f
than Cu Nps catalyst (entry 6), but the same phenomenon
was not observed for b-naphthyl substrate 1g (entry 7).
The result suggested that the oxidation might occur on the
surface of Cu Nps, which should be more sensitive than
homogeneous catalysts to sterically more hindered sub-
strate.
Alcoholsa (continued)
O
Cu Nps (10 mol%)
bipyridine (10 mol%)
TBHP (2 equiv)
OH
R1
R1
R2
CH2Cl2, r.t., air
1
R2
2
Entry Substrate 1
Time Convers. 2:Yield
(%)b
(%)c
Primary propargylic alcohols were also examined in the
Cu Nps catalyzed oxidation system (Table 3). Both aro-
matic and aliphatic primary propargylic alcohols could be
oxidized to the corresponding aldehydes in moderate to
good conversions and isolated yields.16 In these reactions,
the formation of carboxylic acids was not observed. Allyl-
ic alcohols and benzyl alcohols were also utilized as sub-
strates in the reaction, and excellent yields were achieved
in both cases (Scheme 1).
OH
9
2 h
>99
2i: 80
OH
1i
OH
Cl
10
2 h
3 h
>99
>99
2j: 75
OH
Table 3 Copper Nanoparticles Catalyzed Oxidation of Primary Pro-
pargylic Alcoholsa
1j
Cu Nps (10 mol%)
O
OH
bipyridine (10 mol%)
TBHP (2 equiv)
OH
11
2k: 96
2l: 97
H
R
CH2Cl2, r.t., air
R
3
4
1k
Entry
1
Substrate 3
Conversion 4: Yield
OH
(%)b
(%)c
12
3.5 h >99
OH
MeO
90
4a: 75
1l
OH
3a
3b
2m:
>98
13
3 h
>99
OH
2
65
4b: 50
1m
OH
80
2n: 72
OH
14
24 h
(87)d
(82)d
3
4
75
55
4c: 58
4d: 45
MeO
1n
3c
OH
OH
80
2o: 75
3d
15
24 h
24 h
(87)d
(83)d
a Reaction conditions: Substrate (0.2 mmol), catalyst (10 mol%),
ligand (10 mol%), TBHP (0.4 mmol), CH2Cl2 (1.5 mL) as solvent,
1o
stirred at r.t.
b Detected by GC.
c Isolated yield.
OH
16
79
2p: 72
In view of green and sustainable chemistry, utilizing a
cleaner oxidant, especially molecular oxygen, is particu-
larly attractive.17 Based on the result observed above (en-
try 4, Table 1), aerobic oxidation conditions were further
optimized in Table 4 with 1d as prototype. There was no
obvious improvement when oxygen was utilized instead
of air (entry 1 vs. entry 2, Table 4). Some solvents and
1p
a Reaction conditions: 1 (0.2 mmol), catalyst (10 mol%), ligand (10
mol%), TBHP (0.4 mmol), CH2Cl2 (1.5 mL), stirred at r.t.
b Detected by GC.
c Isolated yield.
d The reaction was carried out with 10 mol% of Cu(OAc)2–bpy as cat-
alyst.
Synlett 2011, No. 16, 2363–2368 © Thieme Stuttgart · New York

2366
C. Han et al.
LETTER
Table 4 Copper Nanoparticles Catalyzed Aerobic Oxidation of Propargylic Alcohol 1da
OH
O
Cu Nps (10 mol%)
bipyridine (10 mol%)
MeO
MeO
solvent
air
2d
1d
Entry
Conditions
Conversion (%)b
Yield (%)c
1
2
3
4
5
6
CH2Cl2, 40 °C, air
CH2Cl2, 40 °C, O2
DCE, 80 °C, air
88
85
90
88
35
29
DME, 80 °C, air
toluene, 80 °C, air
toluene, 100 °C, air
NDd
NDd
95
>99
>99
90
a Reaction conditions: 1d (0.2 mmol), catalyst (10 mol%), ligand (10 mol%), solvent (1.5 mL), stirred for 8 h.
b Detected by GC.
c Isolated yield.
d Not detected.
CHO
Table 5 Copper Nanoparticles Catalyzed Aerobic Oxidation of Pro-
pargylic Alcoholsa
OH
OH
Cu Nps (10 mol%)
bipyridine (10 mol%)
TBHP (2 equiv)
O
6
Cu Nps (10 mol%)
5
85% of yield
bipyridine (10 mol%)
R1
R1
toluene, 80 °C, 8 h, air
R2
CH2Cl2, r.t., 8 h
R2
OH
1
2
CHO
Entry
Substrate 1
Conversion (%)b 2: Yield (%)c
Br
7
Br
8
1
2
3
4
5
6
1a
1c
1d
1e
1k
1l
90
96
2a: 80
2c: 90
2d: 95
2e: 95
2k: 93
2l: 91
90% of yield
Scheme 1 Copper nanoparticles catalyzed oxidation of allylic alco-
>99
>99
>99
>99
hol and benzyl alcohol
temperature conditions were examined (entries 3–6), and
up to 95% of yield was achieved in toluene solution at 80
°C after eight hours (entry 5).
Thus, the optimum conditions were used to examine the
scope of this transformation (Table 5).18 To our delight, a
variety of substituted propargylic alcohols derived from
aliphatic or aromatic alkynes were compatible with our re-
action conditions, and good to excellent yields were ob-
tained (entries 1–6). Interestingly, the nonsubstituted
compound 1a gave the lowest conversion and yield.
a Reaction conditions: 1 (0.2 mmol), catalyst (10 mol%), ligand (10
mol%), solvent (1.5 mL), stirred for 8 h.
b Detected by GC.
c Isolated yield.
when Cu Nps catalyst was removed after one hour reac-
tion by a simple filtration. On the other hand, the total con-
version was observed in the control experiment after three
hours. The result indicated that the reaction took place on
the surface of the solid catalysts rather than in the soluble
To investigate the nature of the Cu Nps catalyzed oxida-
tion, a ‘hot separation’ experiment was carried out.19 It
can be seen from Scheme 2, the reaction almost stopped
OH
O
Cu Nps (10 mol%)
bipyridine (10 mol%)
TBHP (2.0 equiv)
CH2Cl2, r.t.
1g
2g
3 h, 63% conversion
after hot seperation:
1 h, 60% conversion
control experiment: 3 h, total conversion
Scheme 2 Hot separation experiment of 1g to 2g
Synlett 2011, No. 16, 2363–2368 © Thieme Stuttgart · New York

LETTER
Highly Efficient Oxidation of Propargylic Alcohols to Ynones
2367
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cies into the filtrate was also detected by ICP analysis, and
only 5.4% of catalyst was leached into the solution.20
A tentative mechanism for bpy ligand accelerating the ox-
idation has been suggested. The formation of copper
alkoxide binding with TPHP is proposed as the key step in
the oxidation,21 and then, the coordination of bpy ligand to
copper(II) ion stabilizes the key intermediate, which re-
sults in the acceleration of the reaction (Figure 1).
(3) Palladium-catalyzed cross-coupling of terminal alkynes and
acyl chloride provides an effective method to synthesize
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Sonogashira, K.; Hagihara, N. Synthesis 1977, 777.
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A. S. Synthesis 2008, 3797.
N
N
Cu OOt-Bu
O
R2
R1
(6) For a recent example, see: Bao, W. L.; Wang, Q.; Zheng,
Y. F. Chin. Chem. Lett. 2004, 15, 1029.
Figure 1 Proposed key intermediate in the bpy-accelerated oxidation
(7) Schmieder-Van De Vondervoort, L.; Bouttemy, S.; Padron,
J. M.; Le Bras, J.; Muzart, J.; Alsters, P. L. Synlett. 2002,
243.
In conclusion, a ligand-promoted, copper-catalyzed oxi-
dation of propargylic alcohols was developed with TBHP
as oxidant at room temperature. Copper nanoparticles can
be used as effective catalysts in the reaction in the pres-
ence of bpy ligand. Various propargylic alcohols were ox-
idized to the corresponding ynones with good to excellent
yield. Furthermore, in the absence of TBHP, Cu Nps–bpy
could catalyze the aerobic oxidation of propargylic alco-
hols effectively, and the reaction is ligand-triggered. The
detailed mechanism, the effects of particle size and parti-
cle support as well as the scope of the reaction are current-
ly under further investigations.
(8) Blay, G.; Cardona, L.; Fernández, I.; Pedro, J. R. Synthesis
2007, 3329.
(9) (a) Maeda, Y.; Kakiuchi, N.; Matsumura, S.; Nishimura, T.;
Uemura, S. Tetrahedron Lett. 2001, 42, 8877. (b) Maeda,
Y.; Kakiuchi, N.; Matsumura, S.; Nishimura, T.; Kawamura,
T.; Uemura, S. J. Org. Chem. 2002, 67, 6718.
(10) For recent reviews, see: (a) Astruc, D.; Lu, F.; Aranzaes,
J. M. Angew. Chem. Int. Ed. 2005, 44, 7852. (b) Corma, A.;
Garcia, H. Chem. Soc. Rev. 2008, 37, 2096. (c) Gu, Y.; Li,
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Very recently, we reported a ligand-promoted, silver nano-
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful for the financial support from the Natural Science
Foundation of Jiangsu Province (BK2008386 to X.Y.), the NUAA
Research Funding (No. 2010169 to X.Y.) and the National Natural
Science Foundation of China (20602018 to X.Y.).
(13) The diameter of Cu Nps is ca. 20–30 nm. The detailed
procedure about the synthesis of Cu Nps is described in the
Supporting Information.
(14) The in situ formed Cu2O on the surface of Cu Nps was
proposed as the catalytic active species in the reaction.
However, when pure Cu2O Nps were utilized as catalyst,
similar catalytic activity but lower selectivity was observed.
(15) Typical Procedure for the Cu Nps Catalyzed Oxidation
of Propargylic Alcohols with TBHP as Oxidant (Entry 1,
Table 2): 1,3-Diphenyl-2-propyn-1-ol (1a, 0.2 mmol), Cu
NPs (1.3 mg, 10 mol%), bipyridine (3.2 mg, 10 mol%),
TBHP (55 mL, 2.0 equiv, 70% in H2O), and CH2Cl2 (1.5 mL)
were added into a 20-mL Schlenk tube under air. The
mixture was stirred at r.t. for 2 h. Then, the reaction was
stopped, and the reaction mixture was purified by flash
column chromatography on silica gel (hexanes–EtOAc,
30:1). Compound 2a was obtained in >98% yield.
(16) From crude 1H NMR and TLC, there are no overoxidized by-
products observed.
References and Notes
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Kang, S. I. J. Med. Chem. 1990, 33, 1975. (b) Kundu, N.
G.; Mahanty, J. S.; Spears, C. P. Bioorg. Med. Chem. Lett.
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Biochem. J. 1981, 193, 217. (d) Midland, M. M.; Nguyen,
N. H. J. Org. Chem. 1981, 46, 4107.
(2) For some recent examples, see: (a) Kel’in, A. V.;
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Synlett 2011, No. 16, 2363–2368 © Thieme Stuttgart · New York

2368
C. Han et al.
LETTER
(17) For a recent review about the aerobic oxidation of alcohols,
see: Schultz, M. J.; Sigman, M. S. Tetrahedron 2006, 62,
8227.
(19) Yamaguchi, K.; Mizuno, N. Chem. Eur. J. 2003, 9, 4353.
(20) This result also indicated the possibility of recycling the
catalyst. In fact, the Cu Nps catalyst could be separated and
recovered conveniently by centrifugation, and then, be
reused directly without additional bpy ligand. With 1d as the
substrate, ca. 80% yield was still obtained in the third
reaction with prolonged reaction time. To improve recycle
capability, the effects of particle size and particle support are
currently under investigations.
(18) Typical Procedure for the Cu Nps Catalyzed Aerobic
Oxidation of Propargylic Alcohols (Entry 1, Table 5):
1,3-Diphenyl-2-propyn-1-ol (1a, 0.2 mmol), Cu Nps (1.3
mg, 10 mol%), bipyridine (3.2 mg, 10 mol%) were mixed
with toluene (1.5 mL) in a 20-mL Schlenk tube under air.
The mixture was stirred at 80 °C for 8 h. Then, the reaction
was stopped, and the reaction mixture was purified by flash
column chromatography on silica gel (hexanes–EtOAc,
30:1). Compound 2a was obtained in 80% yield.
(21) For a similar model, see: Chaudhuri, P.; Hess, M.; Müller, H.
K.; Bill, E.; Weyhermüller, T.; Wieghardt, K. J. Am. Chem.
Soc. 1999, 121, 9599.
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