Copper-catalyzed α-C-H acyloxylation of carbonyl compounds with terminal alkynes

Article abstract of DOI:10.1039/c7nj03989a

Herein, a copper/TBHP catalyst system for the α-C-H acyloxylation of carbonyl compounds is developed using terminal alkynes as the acyloxy source. A variety of carbonyl compounds and terminal alkynes are tolerated in this reaction. In addition, its possible mechanism is proposed.

Full text of DOI:10.1039/c7nj03989a

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Copper-catalyzed a-C–H acyloxylation of
carbonyl compounds with terminal alkynes†
Cite this:DOI: 10.1039/c7nj03989a
Jiao Li, Zan Yang, Tao Yang,* Jianmin Yi and Congshan Zhou
*
Received 16th October 2017,
Accepted 21st December 2017
DOI: 10.1039/c7nj03989a
rsc.li/njc
Herein, a copper/TBHP catalyst system for the a-C–H acyloxylation To overcome the limitations of the traditional methods, some
of carbonyl compounds is developed using terminal alkynes as the new synthetic strategies have also been developed.8 For example,
acyloxy source. A variety of carbonyl compounds and terminal a-acyloxylation of carbonyl compounds with N-methyl-O-
alkynes are tolerated in this reaction. In addition, its possible benzoylhydroxylamine was developed by Tomkinson.8a Moreover,
mechanism is proposed.
TBAI/TBHP-catalyzed C–H bond activation for the synthesis of
a-acyloxycarbonyl compounds from carbonyl compounds has
Transition metal-catalyzed C–H bond activation to construct been reported.9
C–C, C–O, C–N, and C-hetero bonds plays an important role in
Terminal alkyne derivatives have found wide application in
modern organic chemistry.1 Among them, the copper/oxidant organic chemistry.10 Among the many transformations, metal-
catalytic system has attracted significant attention due to or metal-free-catalyzed C–C triple bond activation provides a
its lower cost and high efficiency. Some excellent C–C or new strategy for the direct formation of C–C or C-heteroatom
C-heteroatom bond formation reactions have been developed bonds.11 Lei and co-workers reported an efficient silver/base or
in recent years.2 Simultaneously, C–O bond formation via I2/TBHP-mediated C–C bond formation reaction for carbonyl
transition metal-catalyzed C–H bond functionalization has also compounds with terminal alkynes (Scheme 1).11a,b Consequently,
attracted significant attention from organic chemists.3
a copper or TBAI (tetrabutylammonium iodide)-catalyzed C–O
Over the past few years, carbonyl compounds have been bond formation reaction using terminal alkyne derivatives, such
used in transition metal-catalyzed a-C–H functionalization for as acyl carboxy (ArCOO–), was also developed.12 However, only a
the synthesis of bioactive or natural compounds.4 Among them, few examples of C–O bond formation from C–C triple bond
the transition metal-catalyzed selective a-C–H functionalization activation have been reported. Therefore, the formation of C–O
of carbonyl compounds seems to provide a direct and efficient bonds from the C–C triple bond has become a key focus in the
approach.5 For example, Ritter and co-workers reported the modern synthetic chemistry. Based on previous research, herein,
Pd-catalyzed a-hydroxylation of carbonyl compounds with mole- we disclosed that in the presence of Cu(acac)2/TBHP, the reaction
cular oxygen as the oxidant.5c Zhang and co-workers developed between carbonyl compounds and terminal alkynes could afford
the iron-catalyzed arylation of carbonyl compounds.5a The C–O bond formation using terminal alkyne derivatives as the
copper-catalyzed radical coupling of carbonyl compounds with acyloxy source.
alkenes for the synthesis of tetracarbonyl compounds was
As shown in Table 1, we initially investigated propiophenone 1a
developed by Guan and co-workers.5b On the other hand, and phenylacetylene 2a as model substrates for reaction optimization.
a-acyloxylation of carbonyl compounds is an important trans-
formation in organic synthetic chemistry.6 Traditionally,
a-acyloxycarbonyl compounds are prepared using a-halo carbonyl
compounds with carboxylates.7 For example, Srinivasan reported
the efficient esterification of a-halo carbonyl compounds with
sodium carboxylates under DMSO/ionic-liquid conditions.7c
College of Chemistry and Chemical Engineering, Hunan Institute of Science and
Technology, Yueyang 414006, P. R. China. E-mail: zhoucongsh@126.com,
yangtaozcs@126.com
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nj03989a
Scheme 1 Oxidative coupling of carbonyl compounds and terminal alkynes.
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scope of terminal alkynesa,b
Entry
Catalyst
Oxidant
Solvent
Yieldb
1
2
3
4
5
6
7
8
FeCl3Á6H2O
CuBr2
Cu(OAc)2ÁH2O
CuCl2ÁH2O
Cu(TFA)2
CuONPs
CuNPs/ZY
CuSO4
Cu(NO3)2ÁH2O
Cu(acac)2
CuBr
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
—
TBHPc
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
Tol
N.R.
N.R.
35%
44%
Trace
39%
Trace
N.R.
Trace
70%
N.R.
N.R.
N.R.
N.R.
68%
30%
59%
Trace
N.R.
N.R.
50%
Trace
20%
42%
33%
N.R.
N.R.
9
10
11
12
13
14
15e
16e,f
17e,g
18e
19e
20e
21e
22e
23e
24e,h
25e,i
26
27e
d
H2O2
DTBP
Oxone
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
DCE
CCl4
DMSO
EtOAc
MeCN
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), Cu(acac)2 (5 mol%),
Chlorobenzene
Chlorobenzene
Chlorobenzene
Chlorobenzene
TBHP (4.0 eq.), chlorobenzene (1 mL), in air atmosphere for 12 h at
b
120 1C. Isolated yield of product after silica gel chromatography.
Cu(acac)2
a
Reaction conditions (unless otherwise mentioned): 1a (0.4 mmol), 2a
product 3a was not obtained (Table 1, entries 26 and 27).
Therefore, the use of propiophenone 1a (0.4 mmol), phenyl-
chromatography. tert-Butyl hydroperoxide (aq. 70%). H2O2 (aq. 35%). acetylene 2a (0.2 mmol), Cu(acac)2 (5 mol%), THBP (aq. 70%)
(0.2 mmol), catalyst (20 mol%), oxidant (4.0 eq.), solvent (1 mL), in air
b
atmosphere for 12 h at 120 1C. Yield of product after silica gel
c
d
e
f
g
Catalyst (5 mol%) was used. Oxidant (3.0 eq.) was used. Oxidnat
(4.0 eq.), and chlorobenzene (1 mL) at 120 1C for 12 h was
suitable for this reaction system.
h
i
(5.0 eq.) was used. Conducted at 110 1C. Conducted at 130 1C.
Under the optimized conditions, the scope of terminal alkynes
was investigated, as shown in Table 2. Generally, the reaction was
No product 3a was obtained when FeCl3Á6H2O was used as the tolerant to terminal alkynes since both electron-withdrawing and
catalyst (Table 1, entry 1). Next, various copper(I) (CuBr) and electron-donating groups worked well to provide the a-C–H acyl-
copper(II) (CuBr2, Cu(OAc)2ÁH2O, CuCl2ÁH2O, Cu(TFA)2, CuONPs, oxylation products in moderate to good yields. Initially, different
CuNPs/ZY, CuSO4, Cu(NO3)2ÁH2O, and Cu(acac)2) catalysts were para-substituted terminal alkyne derivatives were investigated,
also investigated (Table 1, entries 2–11), and Cu(acac)2 (Table 1, which gave the desired products 3aa–3af, 3ah in moderate to good
entry 10) was found to be best for this reaction. Other oxidants, yields. Additionally, disubstituted aromatic alkynes, such as
such as H2O2, DTBP, and oxone, were used instead of TBHP, but 4-ethynyl-1,2-dimethoxybenzene 2g, provided the desired a-C–H
product 3a was not generated (Table 1, entries 12–14). In contrast, acyloxylation products in moderate yields. Furthermore, 2-ethynyl-
there was no obvious decrease in product 3a when Cu(acac)2 naphthalene was employed in this transformation, and the desired
(5 mol%) was used (Table 1, entry 15). No further improvement product 3ai was obtained in moderate yields. When ortho-
in the yield of the product 3a was obtained by either increasing substituted or meta-substituted terminal alkynes (2j and 2k) were
the oxidant TBHP (5.0 eq.), or decreasing the oxidant TBHP reacted with 1a, a lower yield of the corresponding products was
(3.0 eq.) (Table 1, entries 16 and 17). Furthermore, different observed. Importantly, the a-C–H acyloxylation transformation was
solvents were screened. The solvents MeCN (20%) and DMSO also suitable for heterocyclic aromatic alkyne derivatives, which
(50%) gave the product 3a, but in a low yield, whereas other gave 3al in a moderate yield. However, the reaction of tert-
solvents, such as toluene, DCE, CCl4, and EtOAc, were ineffec- butylacetylene with 1a failed to give the desired product 3am.
tive for this reaction (Table 1, entries 18–23). No further
Next, the scope of carbonyl compounds was also investigated in
improvement in the yield of the product 3a was obtained by Table 3. Initially, para-substituted and meta-substituted carbonyl
either increasing (130 1C) or decreasing the reaction tempera- compounds reacted with phenylacetylene and gave the desired
ture (110 1C) (Table 1, entries 24 and 25). However, in the products in moderate yields (3ba–3ga). Furthermore, butyro-
absence of the catalyst Cu(acac)2 or oxidant TBHP, the desired phenone and acetophenone were successfully achieved to obtain
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Table 3 Substrate scope of carbonyl compoundsa,b
Scheme 3 Proposed mechanism for a-C–H acyloxylation.
product 3aa was obtained. Next, benzaldehyde 4 or benzoic acid 5
was also reacted with propiophenone 1a under optimal conditions,
but no desired product 3aa was observed. Surprisingly, 10% yield
of 3aa was obtained when propiophenone 1a reacted with
carboxylic anion 6. Based on the control experiment results
and previous reports, the possible mechanism is proposed in
Scheme 3. At first, Cu(acac)2 reacts with propiophenone to form
the metal enolate complex B.4a,5e Then, Cu(acac) and ketone
radical D are formed by Cu(II)–C bond cleavage of the metal
enolate complex B.4a Ketone radical D undergoes SET (single
electron transfer) to form the ketone cation E. Further, alkyne
in the presence of TBHP leads to the formation of t-butyl
perester F.12 Since t-butyl perester F is formed, ketone radical
D reacts with t-butyl perester E to achieve the product (Path a).
In the other pathway, carboxylic anion G is formed by t-butyl
perester F under the optimized conditions.9c Next, the ketone
cation reacts with the carboxylic anion and generates the
desired product (Path b). Finally, TBHP or O2-mediated oxida-
tion of Cu(acac) regenerates the Cu(acac)2 catalyst.
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), Cu(acac)2 (5 mol%),
TBHP (4.0 eq.), chlorobenzene (1 mL), in air atmosphere for 12 h at
120 1C. Yield of product after silica gel chromatography.
b
the desired products 3Ia and 3ja. A heterocyclic carbonyl com-
pound was also reacted under these reaction conditions. Moreover,
benzoyl acetic ester, dimethylmalonate, and cyclohexanone also
reacted with 2a to afford the desired product (3ka, 3na, and 3oa).
However, 1,2-diphenylethanone failed to give the product 3la.
To further investigate the reaction mechanism, several control
experiments were performed (Scheme 2). At first, TEMPO (2.0 eq.)
was used as a radical scavenger, but no desired a-acyloxylation
In summary, we have developed an efficient approach for the
synthesis of a-acyloxycarbonyl compounds via the copper-catalyzed
direct a-C–H acyloxylation of carbonyl compounds with terminal
alkynes. This acyloxylation oxidant coupling process provides a
useful method for acyloxylation at the carbonyl a-position, which
also shows a range of functional group tolerance. In addition, the
Cu-catalyzed a-C–H acyloxylation mechanism was disclosed by
mechanistic studies. Investigation of the reaction mechanism
and application of the copper/TBHP catalytic system to other
a-C–H functionalization transformations are ongoing.
This work was supported by the National Natural Science
Foundation of China (No. 21476068, 21471053).
Conflicts of interest
Scheme 2 Control experiments.
There are no conflicts to declare.
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