Cu-catalyzed aerobic oxidative esterification of acetophenones with alcohols to ?±-ketoesters

Article abstract of DOI:10.1021/ol503472x

Copper-catalyzed aerobic oxidative esterification of acetophenones with alcohols using molecular oxygen has been developed to form a broad range of ?±-ketoesters in good yields. In addition to reporting scope and limitations of our new method, mechanism studies are reported that reveal that the carbonyl oxygen in the ester mainly originated from dioxygen.

Full text of DOI:10.1021/ol503472x

Letter
pubs.acs.org/OrgLett
Cu-Catalyzed Aerobic Oxidative Esterification of Acetophenones
with Alcohols to α‑Ketoesters
Xuezhao Xu,† Wen Ding,† Yuanguang Lin,‡ and Qiuling Song*,†
‡
†Institute of Next Generation Matter Transformation, College of Chemical Engineering, and College of Materials Science &
Engineering, at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China
S
* Supporting Information
ABSTRACT: Copper-catalyzed aerobic oxidative esterification of acetophenones with alcohols using molecular oxygen has been
developed to form a broad range of α-ketoesters in good yields. In addition to reporting scope and limitations of our new
method, mechanism studies are reported that reveal that the carbonyl oxygen in the ester mainly originated from dioxygen.
construct α-ketoesters from 1,3-dione compounds or α-
he development of transition-metal-catalyzed aerobic
Toxidative C−C, C−O, C−N, and carbon−heteroatom
bond formation continues to be widely pursued in modern
synthetic chemistry in order to achieve environmentally benign
transformations. Among them, the copper/O2 system has
attracted the most attention because copper is a cheap and low
toxic transition metal and dioxygen is abundant, low cost, and
sustainable. By eliminating the waste inherent in functional
group manipulation, catalytic aerobic C−H bond functionaliza-
tion reactions are emerging as green, efficient, and economical
processes. Because of their low cost and ready availability, aryl
methyl ketones or their derivatives are widely used in these
transformations.
carbonyl aldehydes with alcohols (Scheme 1).15,16
Scheme 1. Copper-Catalyzed Aerobic Oxidative α-Ketoester
Formation
For example, Ji et al. reported one elegant method for the
synthesis of α-ketoamides from aryl methyl ketones and
secondary amines under copper-catalyzed aerobic oxidative
condition.1 Recently, we developed an efficient and chemo-
selective method for construction of 2-acylbenzothiazoles from
aryl methyl ketones and benzothiazoles.2 We also found that α-
ketoamides were readily synthesized from aryl methyl ketones
and DMF under copper-catalyzed oxidative reaction con-
ditions.3 Wu and co-workers developed various I2-mediated
methods which functionalized the sp3 C−H bond in aryl methyl
ketones.4 Despite the advances in this field, there has been no
report on C(sp3)−H bond functionalization of aryl methyl
ketones with alcohols with dioxygen as oxidant.
Based on our own research, we hypothesized that α-
ketoesters should be formed when aryl methyl ketones were
treated with alcohols under aerobic oxidative conditions. α-
Ketoesters are important skeletons in bioactive compounds5−7
and valuable precursors in synthetic organic chemistry.8,9
Consequently, they have elicited many efforts10−14 to stream-
line their synthesis. In addition to the traditional methods, very
recently, two transition-metal-catalyzed aerobic oxidative
methods have been reported by Jiao and co-workers to
Although great progress has been achieved, there are still
some drawbacks for the existing methods, such as low atom
efficiency, expensive starting materials, or solvent. These
weaknesses underscore the need to develop an efficient method
for construction of α-ketoesters that uses cheap and readily
available starting materials and reagents. To address these
limitations, herein we report a copper-catalyzed aerobic
oxidative esterification between aryl methyl ketones and
alcohols to form a broad range of α-ketoesters and esters
using molecular oxygen17 as the terminal oxidant.
To probe the feasibility of the reaction between aryl methyl
ketones and alcohol, acetophenone (1a) and n-butanol (2a)
were selected as substrates in model reactions. When these
were treated with 10 mol % of CuBr and 0.5 equiv of pyridine
Received: December 7, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503472x
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
at 120 °C in 1 mL of toluene under O2 in a sealed tube, we
were pleased to find that α-ketoester 3aa was formed in 20%
isolated yield with ester 4aa in 70% yield (Table 1, entry 1).
Scheme 2. Substrate Scope for the Formation of α-
Ketoesters from Aryl Methyl Ketones 1 and nBuOH (2a)
a
,b
a
Table 1. Optimization of the Reaction Conditions
a
Conditions: acetophenone 1 (0.5 mmol), alcohol 2 (1.5 mmol),
CuOTf (10 mol %), pyridine (0.25 mmol), TFA (0.25 mmol) in O2 in
a sealed tube, corresponding temperature, 24 h. Isolated yield based
on 1.
a
b
Conditions: 1a (0.5 mmol), 2a (1.5 mmol), catalyst, solvent (1 mL),
b
additive, T (°C), under O2 in a sealed tube. GC yield, isolated yield
listed in the paretheses. Under N2.
c
The formation of ester 4aa could be maximized to 86% by
increasing the pyridine amount (Table 1, entry 21). During
preparation of this manuscript, Jiao and co-workers reported
esterification of aryl ketones with alcohols leading to esters 4.18
Because of their report, we chose to focus on the formation of
α-ketoester 3aa. Further catalyst screening indicated that
CuOTf is the best one among CuBr, Cu(OAc)2, Cu(TFA)2,
CuCl2, and Cu2O (Table 1, entries 1−6). When temperature
was increased to 130 °C, the yield was dropped to 29%, yet
when the temperature was decreased to 100 °C the yield of
desired product 3aa increased to 53%. Further reduction of the
reaction temperature, however, attenuated the formation of 3aa
(Table 1, entries 7−9). The identity of the ligand also affected
the yield of our reaction: 3-methylpyridine and thiazole led to
9% and 52% yield at 100 °C correspondingly (Table 1, entries
10 and 11). Solvent screening indicated that toluene is the
superior choice to dioxane, MeCN, THF, DMSO, and DMF
(Table 1, entries 8, 13, and 14). If the reaction was conducted
under N2 atmosphere, only a trace amount product was
detected (Table 1, entry 12). Additives were also screened, and
the addition of TFA improved the yield to 83% (Table 1,
entries 15−17). In contrast to our previous results, increasing
the temperature to 130 °C slightly increased the yield of the
desired product to 86% yield, a significantly higher yield than in
the absence of TFA (Table 1, entry 20 vs entry 7).
this esterification reaction. Other aromatic rings, such as 2-
naphthyl and 3-thiophene methyl ketone, were compatible in
this reaction (3qa and 3ra).
The scope of alcohol for this transformation was further
explored by changing the identity of the alcohol reagent. As
shown in Scheme 3, a variety of phenylmethanols and 2-
phenylethanols could be used in our transformation regardless
of their substitution pattern or electronic nature (Scheme 3,
3ab−ak). Significantly, heteroaromatic ethanol, such as 2-
thiophene ethanol, was also tolerated under the standard
conditions to afford the desired product (Scheme 3, 3al). Both
primary and secondary aliphatic alcohols, which are susceptible
to oxidative conditions, could be used to generate the α-
ketoester in good yields (Scheme 3, 3aa, 3am, and 3an). To
demonstrate the potential use of our method in late-stage
target-oriented applications, chloresterol was examined as a
substrate. To our delight, α-ketoester 3an was formed in good
yield.
To gain insight into the mechanism of α-ketoester formation,
several control experiments were performed (Scheme 4). We
found that the reaction was inhibited if TEMPO and BHT were
added to suggest that the oxidation proceeds through a radical
pathway (Scheme 4, eq 1). The reactions of 2-oxo-2-
phenylacetaldehyde monohydrate (5), 2-hydroxy-1-phenyl-
ethanonebenzoic acid (6), and 2-oxo-2-phenylacetic acid (7)
with n-BuOH under standard conditions were also investigated,
and the desired products were afforded in 95%, 70%, and 61%
yields respectively (Scheme 4, eqs 2−4). These results
demonstrate that compounds 5−7 might be the intermediates
in the reaction process.
The ketone scope for the formation of α-ketoester 3 was
investigated using the optimized conditions (Scheme 2). A
variety of acetophenones (1) worked well with n-BuOH (2a) to
afford α-ketoesters 3 in good yields. Both electron-donating
groups, like methyl, ethyl, t-Bu, n-Bu, methoxy, and methylthiol,
and electron-withdrawing groups, such as halo and methyl-
sulfonyl, were tolerated (Scheme 2, 3ba−pa). In addition to
monosubstituted aryl methyl ketones, bis-substituted aryl
methyl ketones (3da, 3ea, and 3ja) were also well-behaved in
In order to determine the origin of the oxygen in the new
carbonyl group in the desired product, the reaction was
performed using 18O2. Analysis of the reaction mixture using
GC−MS revealed that only 16O18O-3aa was obtained
B
DOI: 10.1021/ol503472x
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
labeling experiments, it appears likely that the oxygen in the
new carbonyl group of the desired product was mainly from
dioxygen.
Scheme 3. Substrate Scope for the formation of α-Ketoesters
from of Acetophenone (1a) and Alcohols 2
a b
,
Based on the previous literature reports15,16 and the above
results, we propose that our Cu-catalyzed aerobic reaction
proceeds through the mechanism in Scheme 5. First,
Scheme 5. Proposed Mechanism
acetophenone is oxidized into compound 6, which was further
oxidized into α-ketoaldehyde 5′. Then two possible pathways,
which could lead to the desired product, are possible: in path a,
α-ketoaldehyde 5′ reacts with water to form monohydrate 5,
and then reaction with alcohol 2 produces hemiacetal 8.
Alternatively when the concentration of alcohol is significantly
greater than water, α-ketoaldehyde 5′ directly produces
hemiacetal 8, which is oxidized to produce α-ketoester 3
(path b).
a
Conditions: acetophenone (1a) (0.5 mmol), alcohol 2 (1.5 mmol),
CuOTf (10 mol %), pyridine (0.25 mmol), TFA (0.25 mmol) in O2 in
a sealed tube, corresponding temperature. Isolated yield based on 1a.
b
Scheme 4. Control Experiments under Standard Conditions
In conclusion, a Cu-catalyzed aerobic oxidative esterification
of acetophenone with various alcohols has been developed
using dioxygen as the sole terminal oxidant. α-Ketoesters could
be obtained in good yields with a broad range of substrate
scope. Further investigations on reaction scope, synthetic
application, and the mechanism of this reaction are underway in
our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and copies of H and 13C NMR
1
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: qsong@hqu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation of
China (21202049), the Recruitment Program of Global Experts
(1000 Talents Plan), Fujian Hundred Talents Program, and
Program for Innovative Research Team of Huaqiao University
are gratefully acknowledged. We also thank Prof. Tom G.
Driver from UIC for his proofreading.
(Supporting Information, Scheme S1), yet the m/z 107 peak
suggested that part of the carbonyl group which is adjacent to
benzene ring has been labeled. Upon addition of 3 equiv of
H2O under 18O2, no 16O16O-3aa was detected, and all of the
product contained 18O (Scheme 4, eqs 5 and 6). Similarly, the
m/z 107 peak existed. If the oxygen originated from water, the
unlabeled product 16O16O-3aa should be the major one under
the 18O2/H2O (3 equiv) system. From these two isotope-
REFERENCES
■
(1) Du, F.-T.; Ji, J.-X. Chem. Sci. 2012, 3, 460−465.
(2) Feng, Q.; Song, Q. Adv. Synth. Catal. 2014, 356, 2445−2452.
(3) Zhou, M.; Song, Q. Synthesis 2014, 46, 1853−1858.
C
DOI: 10.1021/ol503472x
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(4) Zhu, Y.-P.; Lian, M.; Jia, F.-C.; Liu, M.-C.; Yuan, J.-J.; Gao, Q.-H.;
Wu, A.-X. Chem. Commun. 2012, 48, 9086−9088.
(5) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 71−74.
(6) Elsebai, M. F.; Kehraus, S.; Lindequist, U.; Sasse, F.; Shaaban, S.;
Gutschow, M.; Josten, M.; Sahl, H.-G.; Konig, G. M. Org. Biomol.
Chem. 2011, 9, 802−808.
(7) Nie, Y.; Xiao, R.; Xu, Y.; Montelione, G. T. Org. Biomol. Chem.
2011, 9, 4070−4078.
(8) Sarabu, R.; Bizzarro, F. T.; Corbett, W. L.; Dvorozniak, M. T.;
Geng, W.; Grippo, J. F.; Haynes, N.-E.; Hutchings, S.; Garofalo, L.;
Guertin, K. R.; Hilliard, D. W.; Kabat, M.; Kester, R. F.; Ka, W.; Liang,
Z.; Mahaney, P. E.; Marcus, L.; Matschinsky, F. M.; Moore, D.; Racha,
J.; Radinov, R.; Ren, Y.; Qi, L.; Pignatello, M.; Spence, C. L.; Steele, T.;
Tengi, J.; Grimsby, J. J. Med. Chem. 2012, 55, 7021−7036.
(9) Gravenfors, Y.; Viklund, J.; Blid, J.; Ginman, T.; Karlstrom, S.;
̈
Kihlstrom, J.; Kolmodin, K.; Lindstrom, J.; von Berg, S.; von
̈
̈
Kieseritzky, F.; Slivo, C.; Swahn, B.-M.; Olsson, L.-L.; Johansson, P.;
Eketjall, S.; Falting, J.; Jeppsson, F.; Stromberg, K.; Janson, J.; Rahm, F.
̈
̈
̈
J. Med. Chem. 2012, 55, 9297−9311.
(10) Zhang, Z.; Su, J.; Zha, Z.; Wang, Z. Chem.Eur. J. 2013, 19,
17711−17714.
(11) De Almeida, M. V.; Barton, D. H. R.; Bytheway, I.; Ferreira, J.
A.; Hall, M. B.; Liu, W.; Taylor, D. K.; Thomson, L. J. Am. Chem. Soc.
1995, 117, 4870−4874.
̀
(12) Bacchi, A.; Costa, M.; Della Ca, N.; Gabriele, B.; Salerno, G.;
Cassoni, S. J. Org. Chem. 2005, 70, 4971−4979.
(13) Wipf, P.; Stephenson, C. R. J. Org. Lett. 2003, 5, 2449−2452.
(14) Sakakura, T.; Yamashita, H.; Kobayashi, T.; Hayashi, T.; Tanaka,
M. J. Org. Chem. 1987, 52, 5733−5740.
(15) Zhang, C.; Feng, P.; Jiao, N. J. Am. Chem. Soc. 2013, 135,
15257−15262.
(16) Zhang, C.; Jiao, N. Org. Chem. Front. 2014, 1, 109−112.
(17) Zhang, S.; Zhan, M.; Luo, Q.; Zhang, W.-X.; Xi, Z. Chem.
Commun. 2013, 49, 6146−6148.
(18) Huang, X.; Li, X.; Zou, M.; Song, S.; Tang, C.; Yuan, Y.; Jiao, N.
J. Am. Chem. Soc. 2014, 136, 14858−14865.
D
DOI: 10.1021/ol503472x
Org. Lett. XXXX, XXX, XXX−XXX