Cu-catalyzed esterification reaction via aerobic oxygenation and C-C bond cleavage: An approach to α-ketoesters

Article abstract of DOI:10.1021/ja4085463

The Cu-catalyzed novel aerobic oxidative esterification reaction of 1,3-diones for the synthesis of α-ketoesters has been developed. This method combines C-C σ-bond cleavage, dioxygen activation and oxidative C-H bond functionalization, as well as provides a practical, neutral, and mild synthetic approach to α-ketoesters which are important units in many biologically active compounds and useful precursors in a variety of functional group transformations. A plausible radical process is proposed on the basis of mechanistic studies.

Full text of DOI:10.1021/ja4085463

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Article
Cu-Catalyzed Esterification Reaction via Aerobic Oxygenation
and C-C Bond Cleavage: An Approach to #-Ketoesters
Chun Zhang, Peng Feng, and Ning Jiao
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4085463 • Publication Date (Web): 13 Sep 2013
Downloaded from http://pubs.acs.org on September 17, 2013
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Cu-Catalyzed Esterification Reaction via Aerobic Oxygenation
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and C-C Bond Cleavage: An Approach to α-Ketoesters
Chun Zhang† Peng Feng† and Ning Jiao*,†,‡
† State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan
Road 38, Beijing 100191 (China);
‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences. Shanghai 200032 (China)
KEYWORDS：α-Ketoesters, Copper, C-C bond cleavage, C-H bond functionalization, Dioxygen activation.
ABSTRACT: The Cu-catalyzed novel aerobic oxidative esterification reaction of 1,3-diones for the synthesis of α-ketoesters has been
developed. This method combines C-C σ-bond cleavage, dioxygen activation and oxidative C-H bond functionalization, as well as
provides a practical, neutral, and mild synthetic approach to α-ketoesters which are important units in many biologically active com-
pounds and useful precursors in a variety of functional group transformations. A plausible radical process is proposed on the basis of
mechanistic studies.
Table 1. The Effect of Different Parameters on the Reaction
of 1a and 2a.a
INTRODUCTION:
The transition-metal-catalyzed unstrained C-C bond activa-
tion has attracted much attention and emerged as a tremendous
challenge in the past years.1,2 This strategy enables the possibility
of the direct transformation of inert starting materials. However,
to make C-C bond cleavage strategy more useful and practical
in organic synthesis, there are at least three big challenges
should be addressed: 1) The selectivity between C-C bond and
C-H bond cleavage of unstrained substrates should be con-
trolled; 2) There should be enough energy to activate C-C sig-
ma-bond under mild conditions; 3) The reaction system should
ensure that other starting materials do not undergo degradation
under the necessary oxidative reaction conditions.
a 1a (0.25 mmol), 2a (0.75 mmol), catalyst (0.025 mmol), to-
luene (1.5 mL), ligand (0.125 mmol), O2 (1 atm), at 90 oC, 18 h.
b Isolated yields. c HPLC yields. d 20 mol% of pyridine was used.
Because of the above challenging issues, the oxidative esteri-
fication reaction via C-C σ-bond cleavage with alcohol as a
partner has not been realized, although it would substantially
broaden the field of cross-coupling and offer more functiona-
lized products. Herein, we demonstrate the first example of
aerobic oxidative esterification reaction of 1,3-dione com-
pounds with alcohols through C-C σ-bond cleavage and oxyge-
nation with molecular oxygen (Eq. 1). This method successfully
combines C-C bond cleavage, dioxygen activation3,4 and oxida-
tive C-H bond functionalization.5 This protocol also provides a
practical, neutral, and mild synthetic approach to α-ketoesters6-9
which are important units in many biologically active com-
pounds10 and useful precursors in a variety of functional group
transformations.11
e 2.0 eq. of pyridine was used. 10 mol% ligand was used. Un-
f
g
h
der air (1 atm) condition. 0.5 mmol H2O2 was employed as
i
oxidant under air (1 atm) condition. 0.5 mmol TBHP was
employed as oxidant under air (1 atm) condition. j 0.5 mmol
k
H2O2 was employed as oxidant under Ar (1 atm) condition.
0.5 mmol TBHP (tert-butylhydroperoxide) was employed as
oxidant under Ar (1 atm) condition.
Our study commenced with the reaction of 1,3-
diphenylpropane-1,3-dione (1a) and 2-phenylethanol (2a) cata-
lyzed by copper salts. The screening of different parameters was
summarized in Table 1 and SI. Interestingly, phenethyl 2-oxo-2-
phenylacetate (3aa) was produced in 78% yield when CuBr was
used as the catalyst (entry 1, Table 1). It is noteworthy that phe-
nethyl benzoate (4aa) as a by-product was also obtained in 56%
yield in this case (entry 1, Table 1), which demonstrates that the
RESULTS AND DISCUSSION:
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other part of 1,3-diones execute the coupling process also with
Table 3. Cu-catalyzed Aerobic Oxidative Coupling of 1a with
different alcohol (2).a
alcohol substrates (1) to produce the corresponding esters.12
The reaction in the absence of Cu-catalyst did not work (entry
2). Other copper catalysts including Cu(II) salts showed low
efficiencies (entries 1, and 3, Table 1, and SI). Toluene is the
best choice as solvent for this transformation (see SI). Further
studies indicated that pyridine is crucial to this transformation.
The reaction did not work in the absence of pyridine (entry 5).
50 mol% equivalent of pyridine which may play the key role as
ligand, is the optimal dosage (entries 1, 6 and 7). In contrast,
the reactions with some bidentate ligands did not work (entries
8-9, Table 1). When this reaction was performed under air, 3aa
was obtained in 25% yield (entry 10, Table 1). The addition of
external oxidants such as H2O2 and TBHP under air or argon
condition, could not improve the efficiency of this transforma-
tion (entries 11-14, Table 1).
O
O
O
CuBr (10 mol%)
pyridine (50 mol%)
O
O
+
Ph
C
O
R
R
+
Ph
HO
R
2
Ph
C
Ph
O
toluene (1.5 mL)
2 (1 atm), 90 oC, 18 h
H2
3b
4c
O
1a
10
11
12
13
14
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entry
2
yield of 3 (%)b
yield of 4 (%)c
R'=
1
2
3
H (2a)
78% (3aa)
76% (3ab)
87% (3ac)
56% (4aa)
71% (4ab)
82% (4ac)
OH
R'
4-Br (2b)
4-OMe (2c)
OH
4
(2d)
75% (3ad)
70% (73%)b (4ad)
R'=
5
6
H (2e)
78% (3ae)
76% (3af)
72% (3ag)
77% (3ah)
83% (3ai)
73% (3aj)
77% (3ak)
87% (3al)
92% (3am)
58% (3an)
73% (3ao)
74% (3ap)
36% (4ae)
23% (4af)
4-Me (2f)
2-Me (2g)
3-Me (2h)
4-F (2i)
7
44% (4ag)
8
46% (4ah)
OH
9
35% (4ai)
R'
10
11
12
13
14
15
16
4-Cl (2j)
20% (4aj)
Table 2. Cu-catalyzed Aerobic Oxidative Coupling of different
1,3-diketone (1) with 2a.a
2k
4-Br (
)
28% (4ak)
3-OMe (2l)
4-CN (2m)
4-CF3 (2n)
(2o)
43% (47%)b (4al)
25% (22%)b (4am)
53% (4an)
O
CuBr (10 mol%)
pyridine (50 mol%)
O
O
O
MeOH
EtOH
40% (4ao)
O
HO
Ar
C
O
Ph
Ph
Ph
Ph
+
Ar
C
Ar
+
Ar
O
(2p)
43% (4ap)
toluene (1.5 mL)
H2
2a
O
2 (1 atm), 90 oC, 18 h
4
3
1
OH
17
(2q)
30% (3aq)
23% (4aq)
yield of 3 (%)b
78% (3aa)
yield of 4 (%)c
56% (4aa)
Me
entry
1
1
O
O
O
Br
18
19
(2r)
(2s)
60% (3ar)
62% (3as)
48% (4ar)
49% (4as)
OH
OH
OH
(1a)
Ph
C
H2
Cl
R1
2
3
4
5
6
4-Me (1b)
=
58% (3ba)
50% (3ca)
41% (3da)
65% (3ea)
55% (4ba)
35% (4ca)
37% (4da)
3,4-Me2 (1c)
2-Me (1d)
O
20
(2t)
45% (3at)
17% (4at)
60% (61%)b (4ea)
61% (4fa)
C
4-OMe (1e)
R1
R1
H2
OH
4-tBu (1f)
64% (3fa)
21
22
(2u)
(2v)
46% (3au)
38% (4au)
Ph
Ph
OH
7
8
4-F (1g)
4-Cl (1h)
4-Br (1i)
4-CF3 (1j)
66% (3ga)
59% (3ha)
66% (3ia)
51% (3ja)
63% (4ga)
56% (4ha)
46% (4ia)
45% (4ja)
trace (3av)d
trace (4av)d
Me
Me
9
10
a
O
O
O
O
O
O
Standard reaction conditions: 1a (0.25 mmol), 2 (0.75
mmol), CuBr (0.025 mmol), toluene (1.5 mL), pyridine (0.125
11
12
(1k)
75% (3ka)
62% (3la)
66% (3ma)
66% (4ka)
51% (4la)
56% (4ma)
C
H2
S
S
o
b
c
mmol), O2 (1 atm), at 90 C, 18 h. Isolated yields. HPLC
yields. d Detected by GC-MS.
(1l)
C
H2
The scope of the copper-catalyzed aerobic oxidative coupling
leading to α-ketoesters was further expanded to a variety of
substituted alcohols (2) (Table 3). The aromatic rings of 2-
phenylethanol and phenylmethanol are of great variety contain-
ing electron-rich groups (3af, 3ag, 3ah, 3ac and 3al), electron-
deficient groups (3am, and 3an), and halo-groups (3ab, 3ai, 3aj
and 3ak). It is noteworthy that alkyl alcohols with low boiling-
point also worked well (3ao and 3ap). Furthermore, alkyl alco-
hols containing alkynyl or halogen also give desired product
smoothly (3aq, 3ar and 3as). In addition, secondary alcohol,
such as 1-hydroxyhydrindene and diphenylmethanol, also works
well in this transformation (3at and 3au). However, non-cyclic
secondary alkyl alcohols (2v) only gave trace amount of desired
products. In the above reactions, the conversions of 1,3-
diphenylpropane-1,3-dione (1a) are nearly 100%.
13
(1m)
C
H2
a
Standard reaction conditions: 1 (0.25 mmol), 2a (0.75
mmol), CuBr (0.025 mmol), toluene (1.5 mL), pyridine (0.125
o
b
c
mmol), O2 (1 atm), at 90 C, 18 h. Isolated yields. HPLC
yields.
With a set of optimized conditions in hand, the scope of
ketones (1) was investigated (Table 2). Both electron-rich and
electron-deficient aryl substituted 1,3-diketones could be
smoothly transformed into the desired products. Furthermore,
substituents at different positions of the aryl ring (para-, meta-,
and ortho-position) do not affect the efficiency. It is noteworthy
that halo- substituted aryl ketones survived well leading to halo-
substituted products, which could be used for further transfor-
mations (3ga, 3ha and 3ia, table 2). In addition, naphthyl subs-
tituted ketone, 1,3-di(naphthalen-1-yl)propane-1,3-dione and
1,3-di(naphthalen-2-yl)propane-1,3-dione were also tolerant in
this transformation generating 3la and 3ma in 62% and 66%
yield respectively (Table 2). Moreover, a heteroaryl substituted
Theoretically, the corresponding esters 4 as by-products of
this transformation should be produced in similar yield with
that of the desired α-ketoester products 3. However, the yields
of 3 and 4 are different in most cases (Table 2 and 3). For some
results, such as 4ba, 4fa, 4ga, 4ha, 4ab, 4ac, 4ad, and 4an were
produced nearly equal to the yield of the corresponding α-
ketoester product (3). However, most of the other substrates in
Table 2 and 3 afforded the esters (4) with lower yield than that
of the corresponding α-ketoester products (3). These results
indicate that another pathway for the generation of α-ketoester
acetaldehydes,
1,3-di(thiophen-3-yl)propane-1,3-dione
per-
formed well generating 3ka in 75% yield (Table 2). In the above
reactions, the conversions of 1,3-diketone derivates (1) are near-
ly 100%.
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products 3 without the formation of 4 may be involved in the
reaction processes.
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Late-stage modification of drug candidates is valuable for
structure-activity relationship (SAR) studies since the complex
target molecules are otherwise more challenging to obtain. By
the present protocol, androsterone which is a biological active
molecules, performed well to access complex α-ketoester mole-
cules (Eq. 2).
To get more information of reaction mechanism, the reac-
tions of 2-phenylethanol (2a) coupling with asymmetric aryl
ketones 1ae and 1aj were investigated (Eq. 5 and Eq. 6). The
results indicate that the electron density of aryl-group does not
affect the chemoselectivity obviously (Eq. 5 and Eq. 6).
Table 4. Cu-catalyzed Aerobic Oxidative Coupling of different
ketone (1) with 2aa.a
There are some competitive reactions which could affect the
efficiency of the desired transformation. For example, 1,3-
diphenylpropane-1,3-dione (1a) could converted into benzil (6)
under standard conditions (see SI). However, it is noteworthy
that the reactions of 2a with benzil (6) or 2-hydroxy-1,2-
diphenylethanone (7) under the standard conditions did not
afford the desired product 3aa (Eq. 7-8). Although 2-oxo-2-
phenylacetaldehyde (8) and 2-oxo-2-phenylacetic acid (9) could
couple with alcohol to afford the desired product under the
standard conditions, 8 and 9 were not detected in the reaction
of 1a in the absence of alcohol substrate under the standard
conditions, but with the benzil (6) as the main product in 51%
yield (Eq. 9). The control reactions indicate that the 2-oxo-2-
phenylacetaldehyde (8) is relatively more stable than 2-oxo-2-
phenylacetic acid (9) under standard conditions and can be
recovered after 1 hour under standard conditions (Eq S1-2, SI).
However, both of 8 and 9 were not detected by GC-MS in situ
(see Eq. 9). These results might exclude 6, 7, 8 or 9 as the poss-
ible intermediates of this copper-catalyzed aerobic oxidative
transformation.
a
Standard reaction conditions: 1 (0.25 mmol), 2a (0.75
mmol), CuBr (0.025 mmol), toluene (1.5 mL), pyridine (0.125
mmol), O2 (1 atm), at 90 oC, 18 h. b Isolated yields.
To our delight, besides 1,3-diphenylpropane-1,3-dione (1a,
entry 1, Table 4), other kinds of ketone substrates such as 1-
phenylbutane-1,3-dione (1n, entry 2, Table 4) and diethyl 2-oxo-
2-phenylethylphosphonate (1o, entry 3, Table 4) were also tole-
rant under the optimal reaction conditions generating 3aa in
45% and 31% yields, respectively.
The transformation of 1a and 2a in the presence of 18O2 (1
atm) generated 18O labeling product 18O-3aa in 75% yield (Eq. 3,
determined by HRMS, see SI). This result indicates that the
oxygen atom of the α-ketoester originated from molecular
oxygen. Furthermore, we estimated the consumed amount of
O2. The reaction of 1a (0.25 mmol) and 2a consumed 0.58
mmol O2 under optimal condition (Eq. 4 and SI). From the
balance of this chemical equation, it is noted that maximal 0.5
mmol O2 is required for this transformation. Based on the ex-
perimental research, we find that the excess amount of dioxy-
gen may be used to oxidize the toluene to benzaldehyde which
could be detected by GC-MS.
The results in Table 2 and 3 show that the ester products (4)
were produced with the similar or lower yield than that of the
corresponding α-ketoester products (3). The data of Table 5
indicate that the ester products (4) are stable under the stan-
dard conditions, because all the recovered yields of 4 are nearly
100% (Table 5). The above results support that hypothesis that
another pathway for the generation of α-ketoester products 3
without the formation of 4 may be involved in the reaction
processes.
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Table 5. The Control Recovery Experiments of 4 under the
Standard Conditions.a
7
O
O
R
8
9
R
O
O
optimal conditions
R1
R1
4
4
10
11
12
13
14
15
16
17
18
19
20
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entry
4
recovery of 4 (%)b
O
O
1
4ga
4ah
99%
O
O
F
2
99%
The electro paramagnetic resonance (EPR) spectra (X band, 9.7
GHz, RT) of (a) reaction of CuBr with dioxygen; (b) pyridine was
added into the reaction of CuBr with dioxygen.
Me
O
OMe
3
4al
98%
99%
O
To probe the role of pyridine in this transformation, we al-
sodesigned some EPR experiments. The signal of (a) support
that CuBr (0.25 mmol) under O2 (1 atm) in toluene (1.5 mL) at
90℃ hardly generated CuII species (Scheme 2). In contrast, the
EPR signal of CuII catalyst was observed clearly if 1.0 mmol
pyridine was added into the above reaction system ((b), scheme
2).14 The above EPR studies indicate that the presence of pyri-
dine could enable the [CuII] formation from [CuI] under mole-
cular oxygen atmosphere.
O
4
4am
O
CN
a
Standard reaction conditions: 4 (0.25 mmol), CuBr (0.025
mmol), toluene (1.5 mL), pyridine (0.125 mmol), O2 (1 atm), at
90 oC, 18 h. b Isolated yields.
Scheme 1. Electro paramagnetic resonance (EPR) Studies of
This Transformation.
Scheme 3. Proposed Main Mechanism of the alcohol substrate
which without serious steric hindrance.
O
O
O
optimal condition
O
HO
2
[CuII]
R
+
Ar
Ar
R
Ar
1
3
O
O
base
[base+H]+
Ar
R
O
Ar
+
H2
O2/pyridine
4
[CuI]
+
O
C-C bond
cleavage
H2O
[O]
O
R
O
Ar
O
HO
OH
O
R
O
10
Ar
R
Ar
O
13
base
O
2 and [Cu]
HO
R
[base+H]+
2
The electro paramagnetic resonance (EPR) spectra (X band, 9.7
GHz, RT) of a) reaction mixture in the presence of the radical trap
DMPO (2.5 X 10-2 M); b) with the addition of superoxide dismu-
tase (SOD).
Ar
O
H
O
Ar
[CuI]
[CuII]
O
O
O
O
O
O
R
O
R
Ar
Ar
OH
11
12
To get more information about the mechanism of this trans-
formation, we also tried to catch some intermediates by EPR. In
the EPR spectra monitored with the addition of the radical trap
5-,5-dimethyl-1-pyrroline N-oxide (DMPO), the signal corres-
ponding to (DMPO–O(H) has been identified13 ((a), Scheme 1),
which are classical 4 peaks. The calculated hyperfine splittings
are g0 (2.019), αH (14.9 G). Furthermore, the above signal dis-
appeared with the addition of the superoxide dismutase (SOD)
(b, Scheme 1). These EPR results demonstrate that the hydroxyl
radical (Scheme 3) may derived from a superoxide compound
such as 11 (Scheme 3), which also produces the anion interme-
diate 12 by this process.
On the basis of above results, a possible mechanism is pro-
posed in Scheme 3. Under copper catalyzed aerobic oxidative
conditions, intermediate 10 is initially generated by the dehy-
drogenative coupling of substrates 1 and 2.15 The active inter-
mediate 10 which could not be isolated, is subsequently oxi-
dized to superoxide intermediate (11) via a copper mediated
pathway under O2.16 Then, copper-mediate SET reduction of
superoxide intermediate 11 form anion intermediate 12 and
hydroxyl radical.17 The subsequent reaction of 12 and 2 afford
the hemiacetal intermediate 13.18 Further oxidative fragmenta-
tion of 13 would produce the desired 3 with the formation of 4
as the byproduct.19 In this step, hydroxyl radical or molecular
oxygen could play the role of the oxidant.
Scheme 2. Electro Paramagnetic Resonance (EPR) Studies of
Pyridine and Cu-catalyst.
The results of Table 2, 3 and 5 have supported the hypothe-
sis of that another pathway for the generation of α-ketoester
products 3 without the formation of 4 may be involved in the
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1999, 38, 870. (e) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res.
reaction processes. Furthermore, from the results in Table 3, it
5
2008, 41, 222. (f) Jun. C.-H. Chem. Soc. Rev. 2004, 33, 610. (g) Nájera,
C.; Sansano, J. M. Angew. Chem. Int. Ed. 2009, 48, 2452. (h) Tobisu, M.;
Chatani, N. Chem. Soc. Rev. 2008, 37, 300. (i) Horino, Y. Angew. Chem.
Int. Ed. 2007, 46, 2144. (j) Rubin, M.; Rubina, M.; Gevorgyan, V.
Chem. Rev. 2007, 107, 3117. (k) Houben-Weyl: Carbocyclic Three-
Membered Ring Compounds, Vol. E17a-c (Ed.: A. de Meijere), Thieme,
Stuttgart, 1996. (l) de Meijere, A. Chem. Rev. 2003, 103, 931.
is noted that the alcohol with steric hindrance, such as benzyl
alcohol derivatives, trend to give low yield of 4. In contrast, the
alcohol substrates with less steric hindrance prefer to afford 3
and 4 in similar efficiency. In order to explain these results,
another pathway especially for the alcohol substrate with steric
hindrance is proposed in Scheme 4. After the generation of
intermediate 12 by the same reaction path with Scheme 3, the
interemediate 13 is partly produced from intermediate 12 espe-
cially in the cases of the steric hindrance alcohols. Alternatively,
neutral intermediate 14 is afforded from intermediate 12. Fur-
ther oxidative fragmentation of 14 would produce the desired 3
with the formation of carboxylic acid and some unknown frag-
ment as the byproduct.20 From these reactions we detected the
corresponding acid (15), which could support the rationality of
this concomitant pathway (Scheme 4).
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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Scheme 4. A Concomitant Mechanism for This Transforma-
tion.
CONCLUSION :
In conclusion, a novel and efficient copper catalyzed aerobic
oxidative C-C bond cleavage of ketone with dioxygen activation
has been developed. This method provides a practical, neutral,
and mild synthetic approach to α-ketoesters, which are impor-
tant units in biologically active molecules. The usage of molecu-
lar oxygen (1 atm) as oxidant and reactant makes this transfor-
mation very green and practical. Further studies to clearly un-
derstand the reaction mechanism and the synthetic applications
are ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, analytical data
for products, NMR spectra of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jiaoning@bjmu.edu.cn.
ACKNOWLEDGMENT
Financial support from National Basic Research Program of China
(973 Program) (Grant No. 2009CB825300), National Science
Foundation of China (No. 21172006), and the Ph.D. Programs
Foundation of the Ministry of Education of China (No.
20120001110013) are greatly appreciated. We thank Leilei Shi in
this group for reproducing the results of 3am and 3ea.
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