Oxidation of propargylic alcohols with a 2-quinoxalinol salen copper(II) complex and tert-butyl hydroperoxide

Article abstract of DOI:10.1002/ejoc.201201394

The copper(II) complex of 2-quinoxalinol salen (salqu) is an efficient catalyst for the selective oxidation of propargylic alcohols to yield the corresponding α,β-acetylenic carbonyl compounds when used in combination with the oxidant tert-butyl hydroperoxide (TBHP). Excellent yields (up to 99 %) are achieved for a variety of propargylic alcohols within 1 h of reaction time. The (salqu)copper(II) complex with TBHP can be used with propargylic alcohols that contain alkyl groups in the α-position, which can be difficult to oxidize selectively with other commonly available methods. By using this catalytic protocol, excellent selectivity was also achieved for the oxidation of propargylic alcohols over that of isolated hydroxy groups, triple bonds, or propargylic methylene groups. The 2-quinoxalinol salen copper(II) complex is an efficient catalyst when used with tert-butyl hydroperoxide for the oxidation of propargylic alcohols to yield the corresponding carbonyl compounds. This catalytic system provides excellent selectivity for the reaction with propargylic alcohols, and high yields (up to 99 %) are achieved within 1 h and with 1 mol-% of catalyst loading. Copyright

Full text of DOI:10.1002/ejoc.201201394

Job/Unit: O21394
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FULL PAPER
DOI: 10.1002/ejoc.201201394
Oxidation of Propargylic Alcohols with a 2-Quinoxalinol Salen Copper(II)
Complex and tert-Butyl Hydroperoxide
Kushan C. Weerasiri[a] and Anne E. V. Gorden*[a]
Keywords: Synthetic methods / Copper / Oxidation / Homogeneous catalysis / Alcohols / Alkynes
The copper(II) complex of 2-quinoxalinol salen (salqu) is an can be used with propargylic alcohols that contain alkyl
efficient catalyst for the selective oxidation of propargylic groups in the α-position, which can be difficult to oxidize se-
alcohols to yield the corresponding α,β-acetylenic carbonyl lectively with other commonly available methods. By using
compounds when used in combination with the oxidant tert- this catalytic protocol, excellent selectivity was also achieved
butyl hydroperoxide (TBHP). Excellent yields (up to 99%) for the oxidation of propargylic alcohols over that of isolated
are achieved for a variety of propargylic alcohols within 1 h hydroxy groups, triple bonds, or propargylic methylene
of reaction time. The (salqu)copper(II) complex with TBHP groups.
dition, the toxicity of the metal involved is a major issue
Introduction
with both of these methodologies.[33,34] There are new re-
The oxidation of propargylic alcohols to yield carbonyl
compounds is of great interest because of their utility as
starting materials for a wide range of organic compounds
ported methods in which copper has also been used as a
catalyst for the oxidation of propargylic alcohol. For in-
stance, ligand-promoted copper nanoparticles with tert-
butyl hydroperoxide (TBHP) or air as the oxidant[35] and
CuCl under aerobic conditions have been described.[36]
These methods indicate the potential for copper as a cata-
lyst in similar oxidations, but each method requires 10–
20 mol-% of catalyst loading. Most of these available meth-
ods require high catalyst loadings (e.g., 5–6 mol-%,[33,37] 10–
[2]
such as heterocycles,[1] aromatic compounds, and other
substances.[3–15] Propargylic alcohols have also been used in
the syntheses of biologically active compounds[16] such as
anticancer agents[17] and nucleosides.[18] In addition to the
oxidation of propargylic alcohols, the direct α-oxidation of
alkynes to the corresponding ketones[19–21] and some other
methods that use a terminal alkyne as a building block[22–30]
have also been reported for the preparation of α,β-acetyl-
enic ketones.
Uemura and co-workers have demonstrated the capa-
bility of both vanadium oxyacetylacetonate[31] and calcium
phosphate vanadate apatite[32] as catalytic systems for the
oxidation of propargylic alcohols under aerobic conditions.
Both of these systems provide good results, but produce
poor to moderate yields with propargylic alcohols that are
derived from alkylalkynes.[31,32] Pedro and co-workers have
described the use of a cobalt(III) complex in the catalyzed
aerobic oxidation of propargylic alcohols that are derived
from arylalkynes.[33] Meanwhile, Hanson and co-workers
have reported isolated examples of the oxidation of prop-
argylic alcohols by using a vanadium 8-quinolinate complex
with air,[34] but this system is not effective with propargylic
alcohols that have aryl groups in the α-position. In ad-
20 mol-%,[35,36] and 30 mol-%[32]
) and long reaction
times.[32–34,36] Furthermore, limitations still remain, as these
systems are incompatible with propargylic alcohols that are
derived from alkylalkynes.[32] Therefore, in the view of green
and sustainable chemistry, the development of a fast, ef-
ficient and less toxic method is desirable.
[a] Department of Chemistry and Biochemistry, College of Science
and Mathematics, Auburn University,
As a part of an ongoing effort to develop new and selec-
tive methods for the oxidation of organic compounds by
using copper(II) complexes, we herein report the use of a 2-
quinoxalinol salen (salqu) copper(II) complex with tert-
butyl hydroperoxide (TBHP) as the oxidant in the catalytic
Auburn, Alabama 36849-5319, USA
Fax: +1-334-844-6959
E-mail: gordeae@auburn.edu
Homepage: www.auburn.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201394.
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K. C. Weerasiri, A. E. V. Gorden
FULL PAPER
oxidation of propargylic alcohols to the corresponding α,β-
acetylenic ketones (see Scheme 1). To our delight, excellent
yields (up to 99%) were achieved for a variety of proparg-
ylic alcohols within 1 h of reaction time and with 1 mol-%
of catalyst loading. Moreover, by using this catalytic proto-
col, excellent selectivities were realized for the oxidation of
propargylic alcohols over isolated hydroxy groups, alkynes,
and propargylic methylene groups.
Figure 1. GC yields and conversions with increasing number of
equivalents of oxidant.
Scheme 1. Oxidation of propargylic alcohols.
The effect of solvent was determined by performing the
reaction in different solvents (see Table 2). In dichlorometh-
ane, the reaction resulted in both low yield and low conver-
sion of 1-phenyl-2-propyn-1-ol (see Table 2, Entry 1). Both
chloroform and 1,2-dichloroethane (DCE) produced mod-
erate yields and good conversion of the starting propargylic
alcohol (see Table 2, Entries 2 and 3). Acetonitrile resulted
in very good yields as well as good conversion, whereas tert-
butyl alcohol and benzonitrile provided low yields and low
conversions of the 1-phenyl-2-propyn-1-ol in comparison to
the other solvents (see Table 2, Entries 5 and 6).
Results and Discussion
For our model system, we began by investigating the oxi-
dation of 1-phenyl-2-propyn-1-ol (0.5 mmol) with TBHP
(1 equiv.) and the copper(II) catalyst (1 mol-%) in CH3CN
(1.5 mL), as the reaction mixture was stirred at 70 °C for
24 h. The yield of 1-phenyl-2-propyn-1-one was low under
these conditions, but it improved significantly when the re-
action time was reduced (see Table 1, Entries 1–3). The
yield had no considerable change when the reaction time
was reduced from 3 to 1 h (see Table 1, Entries 1 and 2),
and therefore, the reaction time was set at 1 h to optimize
the other conditions of the reaction.
Table 2. Effect of solvent.[a]
Entry Solvent
Conversion of 1a [%]
GC yield of 2a [%]
1
2
3
4
5
6
CH2Cl2
CHCl3
DCE
CH3CN
tBuOH
PhCN
72
97
96
98
53
59
44
64
62
83
39
45
Table 1. Oxidation of 1-phenyl-2-propyn-1-ol.
[a] Reagents and conditions: 1a (0.5 mmol), catalyst (1 mol-%),
TBHP (2.5 equiv.), solvent (1.5 mL), 70 °C, 1 h.
Finally, a time profile of the oxidation of 1-phenyl-2-pro-
pyn-1-ol was examined with TBHP (2.5 equiv.) and the cop-
per(II) catalyst (1 mol-%) in CH3CN (1.5 mL), as the reac-
tion mixture was stirred at 70 °C (see Figure 2). The prod-
uct yield gradually increased and then leveled off after 1 h
of reaction time. The conversion of the 1-phenyl-2-propyn-
Entry
TBHP
[equiv.]
Time
[h]
Conversion
of 1a [%]
GC yield
of 2a [%]
1
2
3
1
1
1
1
3
24
88
90
85
56
55
41
Next, the required amount of TBHP was examined (see
Figure 1). When the amount of oxidant was increased from
1 equiv. to 2.5 equiv., a trend of both increasing percent
yield of product and increasing percent conversion of the 1-
phenyl-2-propyn-1-ol was observed. The conversion of the
starting propargylic alcohol remained the same with further
increases, but the yield was reduced when the amount of
TBHP was increased beyond 2.5 equiv. Perhaps, this is due
to the over-oxidation of the 1-phenyl-2-propyn-1-one.
Hence, both the maximum yield and the maximum
conversion of 1-phenyl-2-propyn-1-ol were observed with
2.5 equiv. of TBHP.
Figure 2. Time profile for the oxidation of 1-phenyl-2-propyn-1-ol.
2
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Oxidation of Propargylic Alcohols
1-ol increased and then reached a maximum after 1 h. The compounds in high yields (see Table 3, Entries 1, and 3–9).
subsequent extension of the reaction times further reduced When the aryl group was substituted in the 2-, 3-, and 4-
the yields of the desired product, presumably because of the positions by a Cl group, the yields of the corresponding
additional oxidation of the resulting carbonyl compound.
carbonyl compound increased to 39, 71, and 78%, respec-
On the basis of these optimized reaction conditions, a tively (see Table 3, Entries 2–4). The low yield for the 2-
variety of propargylic alcohol substrates were oxidized by chloroaryl-substituted alcohol could be the result of steric
using TBHP (2.5 equiv.) and the CuII catalyst (1 mol-%) in hindrance at the ortho position.
CH3CN (1.5 mL), as the reaction mixture was stirred at
When the aryl group of the propargylic alcohol was sub-
70 °C for 1 h (see Table 3). First, the oxidation of proparg- stituted in the 4-position by Br or I, the yield also increased
ylic alcohols with aryl group substituents in the α-position (see Table 3, Entries 5 and 6). These results reflect the elec-
was examined. Most of these aryl-substituted propargylic tronic effect of the substituent on the aromatic ring. Elec-
alcohols were converted into the corresponding carbonyl tron-donating groups such as methyl and tert-butyl pro-
Table 3. Oxidation of propargylic alcohols under optimized conditions with 1 mol-% of catalyst.
[a] Reaction time was 5 h. [b] GC yield.
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K. C. Weerasiri, A. E. V. Gorden
FULL PAPER
duced good yields under these conditions (see Table 3, En- ate, and thus, the electron-donating substituents help to sta-
tries 7–8), whereas the strong electron-donating methoxy bilize the intermediate, which results in high reaction
group produced a slightly lower yield in comparison to that yields.
of the tert-butyl group. This is possibly a result of the over-
logkX/kH = ρσp
(1)
oxidation of the resulting ketone (see Table 3, Entry 9).
When an electron-withdrawing nitro group was introduced
in the para position, the yield was comparatively low (see
Table 3, Entry 10). Propargylic alcohols that contain the 1-
naphthyl and 2-naphthyl groups also produced good yields
of the corresponding carbonyl compound (see Table 3, En-
tries 11 and 12), but again, the alcohol with the 2-naphthyl
group produced a higher yield in comparison to that with
the 1-naphthyl group, which reflects the importance of the
effect of steric hindrance. Thus, a wide range of functional
groups such as Cl, Br, I, Me, tBu, OMe, and NO2 are toler-
ated under the reaction conditions.
Under the optimized conditions, a propargylic alcohol
that contains aryl groups as both R1 and R2 was oxidized
to produce the product in excellent yield (see Table 3, En-
try 13). When oxidized for 1 h, propargylic alcohols with
alkyl groups in the α-position gave low yields of the ketone.
However, when the reaction time was increased to 5 h, they
afforded the corresponding ketone in good yields (see
Table 3, Entries 14, 15, and 17). Under this change in the
reaction conditions, even a primary propargylic alcohol was
oxidized (H in α-position) to give the α,β-acetylenic alde-
hyde in good yield (see Table 3, Entry 16).
Finally, the reaction was studied by using an alkyne sub-
strate with an isolated hydroxy group (in the β-position,
see Table 3, Entry 18). In this case, no oxidized ketone was
observed after a reaction time of 5 h, but a small percentage
of substrate conversion did occur, which was possibly a re-
sult of the oxidation of the triple bond. As this reaction is
expected to go through a radical pathway, a radical in α-
position to a triple bond should be more stable than that
of an isolated radical. Thus, this could be the reason why
the propargylic alcohols are more reactive than homoprop-
argylic alcohols under these reaction conditions. When an
alkyne substrate was oxidized, no α,β-acetylenic ketones re-
sulted (see Table 3, Entry 19). Again, this demonstrates the
selectivity of this catalyst system for the oxidation of prop-
argylic alcohols, and propargylic methylene groups are re-
sistant to oxidation under this catalytic protocol.
Figure 3. Correlation between log(kX/kH) and para position Ham-
met constants. The substituent constants σp were taken from ref.[38]
Conclusions
When used in combination with the oxidant TBHP, the
2-quinoxalinol salen (salqu) copper(II) complex efficiently
catalyzes the oxidation of propargylic alcohols to the corre-
sponding carbonyl compounds. This catalytic system re-
sulted in excellent selectivities for the oxidation of proparg-
ylic alcohols over the oxidation of isolated hydroxy groups,
alkynes, and propargylic methylene groups. Excellent yields
were achieved within 1 h, which is a significantly enhanced
reaction time compared to those of the other available
methods.[32–34,37] Most of the other reported methods did
not successfully oxidize propargylic alcohols that contained
alkyl groups as R1;[32] however, the (salqu)copper(II) cata-
lyst along with TBHP worked well and produced high
yields of the reaction product. Furthermore, use of 1 mol-
% of catalyst for the oxidation of all types of propargylic
alcohols (yields up to 99%) is another advantage of this
method with regard to industrial and environmental chem-
istry. Future studies will focus on an explanation of the role
of the oxidant and the characterization of the mechanism
intermediates.
To characterize the effects of the substituent on this reac-
tion, a correlation to Hammett constants was calculated
and plotted according to Equation (1).[38] The correlation
between log(kX/kH) and the para position Hammet con-
stants show a good fit (see Figure 3). According to these
results, the oxidation of the propargylic alcohol was ac-
celerated by electron-donating substituents and decelerated
by electron-withdrawing substituents. The negative slope (ρ)
indicates that the electron-withdrawing substituents de-
crease the ratio of log(kX/kH), which results in lower oxi-
Experimental Section
Synthesis of the 2-Quinoxalinol Salen Copper(II) Complex: The 2-
quinoxalinol salen ligand was synthesized according to a previously
published procedure by our group.[39] A solution of 2-quinoxalinol
salen ligand (0.5 mmol) in dichloromethane (DCM, 50 mL) was
combined with a solution of Cu(OAc)2·H2O (0.6 mmol) in meth-
anol (50 mL) and triethylamine (3 mmol), and the resulting reac-
dation yields, and that under these reaction conditions, the tion mixture was stirred and heated at reflux for 2 h. After the
solvent was removed, the resulting dark red solid was washed with
water (3ϫ) and cold diethyl ether (3ϫ) to give a solid (86% yield).
oxidation of propargylic alcohol 1 with the copper(II) cata-
lyst is likely to be electrophilic in nature [see Equation (1)].
Because of this, it stands to reason that the reaction
General Procedure for the Oxidation of Propargylic Alcohols: Prop-
mechanism may go through an electron-deficient intermedi- argylic alcohol (0.5 mmol), the CuII catalyst (1 mol-%), and TBHP
4
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[14] N. J. Kim, H. Moon, T. Park, H. Yun, J. W. Jung, D. J. Chang,
D. D. Kim, Y. G. Suh, J. Org. Chem. 2010, 75, 7458.
[15] D. A. Rooke, E. M. Ferreira, J. Am. Chem. Soc. 2010, 132,
11926.
[16] N. G. Kundu, S. K. Dasgupta, J. Chem. Soc. Perkin Trans. 1
1993, 2657.
[17] N. G. Kundu, J. S. Mahanty, C. P. Spears, Bioorg. Med. Chem.
Lett. 1996, 6, 1497.
[18] R. M. Adlington, J. E. Baldwin, G. J. Pritchard, K. Spencer,
Tetrahedron Lett. 2000, 41, 575–578.
(5.0 m in decane, 0.25 mL) were stirred in acetonitrile (1.5 mL) at
70 °C for 1 h. The reaction was monitored by TLC. After 1 h, the
mixture was cooled to room temperature, and the solvent was re-
moved by using a rotary evaporator. The product was purified by
column chromatography (hexane/ethyl acetate). Yields were deter-
mined by isolating the product or by using GC analysis, and the
isolated products were characterized by 1H and 13C NMR spec-
troscopy, IR spectroscopy, and HRMS.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data and copies of the 1H and 13C NMR
spectra.
[19] J. Muzart, O. Piva, Tetrahedron Lett. 1988, 29, 2321.
[20] S. Sakaguchi, T. Takase, T. Iwahama, Y. Ishii, Chem. Commun.
1998, 2037.
[21] P. Li, W. M. Fong, C. F. L. Chao, H. C. S. Fung, I. D. Williams,
J. Org. Chem. 2001, 66, 4087–4090.
[22] Y. Tohda, K. Sonogashira, N. Hagihara, Synthesis 1977, 777.
[23] C. Chowdhury, N. Kundu, Tetrahedron 1999, 55, 7011.
[24] M. S. M. Ahmed, A. Mori, Org. Lett. 2003, 5, 3057.
[25] L. Chen, C. J. Li, Org. Lett. 2004, 6, 3151.
[26] R. J. Cox, D. J. Ritson, T. A. Dane, J. Berge, J. P. H. Charmant,
A. Kantacha, Chem. Commun. 2005, 1037.
Acknowledgments
We thank Dr. Christian Goldsmith and his group for the support
given for the GC analysis. Financial support from Auburn Univer-
sity is also gratefully acknowledged.
[27] B. Wang, M. Bonin, L. Micouin, J. Org. Chem. 2005, 70, 6126.
[28] S. S. Palimkr, P. H. Kumar, N. R. Jogdand, T. Daniel, R. J. La-
hoti, K. V. Srinivasan, Tetrahedron Lett. 2006, 47, 5527.
[29] M. T. Rahman, T. Fukuyama, N. Kamata, M. Sato, I. Ryu,
Chem. Commun. 2006, 2236.
[1] J. C. Tseng, J. H. Chen, T. Y. Luh, Synlett 2006, 1209.
[2] X. Zhang, S. Sarkar, R. C. Larock, J. Org. Chem. 2006, 71,
236.
[3] H. Wei, S. H. Kim, T. D. Caputo, D. W. Purkiss, G. Li, Tetrahe-
dron 2000, 56, 2397.
[4] B. G. V. Hoven, B. E. Ali, H. Alper, J. Org. Chem. 2000, 65,
4131.
[5] A. S. Karpov, T. J. Müller, Synthesis 2003, 2815.
[6] A. S. Karpov, T. J. J. Müller, Org. Lett. 2003, 5, 3451.
[7] A. V. Retaru, I. D. Druta, T. Oeser, T. J. J. Müller, Helv. Chim.
Acta 2005, 88, 1798.
[30] D. M. DЈSouza, T. J. J. Müller, Nat. Protoc. 2008, 3, 1660.
[31] Y. Maeda, N. Kakiuchi, S. Matsumura, T. Nishimura, T. Kawa-
mura, S. Uemura, J. Org. Chem. 2002, 67, 6718.
[32] Y. Maeda, Y. Washitake, T. Nishimura, K. Iwai, T. Yamauchi,
S. Uemura, Tetrahedron 2004, 60, 9031.
[33] G. Blay, L. Cardona, I. Fernandez, J. R. Pedro, Synthesis 2007,
21, 3329.
[34] S. K. Hanson, R. Wu, L. A. Silks, Org. Lett. 2011, 13, 1908.
[35] C. Han, M. Yu, W. Sun, X. Yao, Synlett 2011, 16, 2363.
[36] L. Yu, S. Ma, Chin. J. Chem. 2012, 30, 29.
[37] J. Liu, X. Xie, S. Ma, Synthesis 2012, 44, 1569.
[8] J. P. Waldo, R. C. Larock, Org. Lett. 2005, 7, 5203.
[9] M. C. Bagley, M. C. Lubinu, C. J. Mason, Synlett 2007, 704.
[10] B. Willy, F. Rominger, T. J. J. Müller, Synthesis 2008, 293.
[11] B. Willy, T. Dallos, F. Rominger, J. Schönhaber, T. J. J. Müller, [38] C. D. Ritchie, W. F. V. Sager, Prog. Phys. Org. Chem. 1964, 2,
Eur. J. Org. Chem. 2008, 4796.
323.
[12] B. Willy, T. J. J. Müller, Eur. J. Org. Chem. 2008, 4157.
[13] T. M. Trygstad, Y. Pang, C. J. Forsyth, J. Org. Chem. 2009, 74,
910.
[39] X. Wu, A. E. V. Gorden, J. Comb. Chem. 2007, 9, 601.
Received: October 19, 2012
Published Online: ᭿
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Job/Unit: O21394
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Date: 28-01-13 11:00:39
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K. C. Weerasiri, A. E. V. Gorden
FULL PAPER
Oxidation of Propargylic Alcohols
The 2-quinoxalinol salen copper(II) com-
plex is an efficient catalyst when used with
tert-butyl hydroperoxide for the oxidation
of propargylic alcohols to yield the corre-
sponding carbonyl compounds. This cata-
lytic system provides excellent selectivity
for the reaction with propargylic alcohols,
and high yields (up to 99%) are achieved
within 1 h and with 1 mol-% of catalyst
loading.
K. C. Weerasiri, A. E. V. Gorden* ..... 1–6
Oxidation of Propargylic Alcohols with a
2-Quinoxalinol Salen Copper(II) Complex
and tert-Butyl Hydroperoxide
Keywords: Synthetic methods / Copper /
Oxidation
/
Homogeneous catalysis
/
Alcohols / Alkynes
6
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