One-pot synthesis of acyloxy carbonyl compounds from ketones using a Pybox-copper(II) catalyst

Article abstract of DOI:10.1039/c6ra02186g

We have described the first efficient one-pot method for the synthesis of acyloxy carbonyl compounds from ketones catalyzed by a Pybox-Cu(ii) complex under mild conditions. A series of α-acyloxy ketone products were obtained in good to excellent yields.

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One-Pot Synthesis of Acyloxycarbonyl compounds
from ketones using Pybox-Copper(II) catalysts
Cite this: DOI: 10.1039/x0xx00000x
WeiꢀGuo Jia,* Hui Zhang, DanꢀDan Li, LiꢀQin Yan*
we have described the first oneꢀpot and efficient method for the synthesis of acyloxycarbonyl
compounds from ketones compounds catalyzed by Pybox Cu(II) complex under mild
conditions. A series of αꢀacyloxylation of ketones products were obtained in good and
excellent yields.
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
αꢀacyloxylation of ketones represent an important organic synthesis of biologically and pharmacologically active
synthetic intermediates in organic synthesis and versatile compounds11, we attempted to extend this nucleophileꢀcatalyzed
building blocks in natural products and pharmaceuticals.1 Thus, aerobic oxidation protocol to the synthesis of aromatic αꢀcyano
many efforts have been devoted to efficient synthetic ketones from ketones and potassium hexacyanoferrate as the
approaches to αꢀacyloxylation of ketones and its derivatives CNꢀ source.12 When propiophenone and potassium
using different synthetic method by many research groups. A hexacyanoferrate were applied to the reaction conditions,
variety of protocols have been reported including transitionꢀ previously, the expected 2ꢀmethylꢀ3ꢀoxoꢀ3ꢀphenylpropanenitrile
metalꢀcatalyzed and organocatalysts methods. In 1998, Ohfune was not observed; instead, an unexpected compound was
and coworker reported the copperꢀcatalyzed insertion of αꢀ obtained as the major product.
diazoketones into carboxylic acids to give αꢀacyloxyketones.2 In With this rather unexpected result in hand, we started our study
2009, the Cadierno group described the addition of carboxylic using the model reaction as shown in Table 1: propiophenone
acids to propargyl alcohols leading to αꢀacyloxyketones (0.5 mmol) and potassium hexacyanoferrate(II) (2.4 equiv.) in
catalyzed by Ru complexes.3 However, in contrast to transition DMF (1 mL). However, no reaction took place after heating the
metal catalyst, the organocatalysts have been further extensively mixture at 110 ºC for 9 h only with or without ligand (Table 1,
explored for catalyzed αꢀacyloxylation of ketones formation entry 1 and entry 2). The αꢀacyloxylation product was obtained
including dimsyl anion4, (hypo)iodite5, Nꢀheterocyclic carbene in 48% yield when using CuBr2 as catalysts (Table 1, entry 3);
(NHC)6, amine7, 2ꢀtritylpyrrolidine8 as well as Bu4NI9. However to our delight, 90% yields of desired product were
Although these organocatalysꢀcatalyzed reactions are robust to observed using 2,6ꢀbis[4’,4’ꢀdimethyloxazolinꢀ2’ꢀyl]pyridine
synthesize a variety of αꢀacyloxylation molecular architectures (DmꢀPybox) as the ligand (Table 1, entry 4). Then, we chose
with a series of functional groups, transition metal catalyzed [(DmꢀPybox)Cu(II)Br2] complex as the catalyst to test the
reaction of propiophenone generate αꢀacyloxylation products is influence of solvents on reaction yield (Table 1, entries 5ꢀ7). To
not reported.
our delight, DMF is the best solvent for this transformation.
Herein, we reported an oneꢀpot and efficient method for the However, lower yield was obtained with lower catalyst loading
synthesis of αꢀacyloxylation of carbonyl compounds in the 5 mol% [(DmꢀPybox)Cu(II)Br2] and required longer reaction
presence of both moisture and air catalyzed by Pybox Cu(II) time of 16 hours (Table 1, entry 8). The yield remains
complex. Treatment of a variety of ketones with [(Dmꢀ unchanged with 15 mol% of [(DmꢀPybox)Cu(II)Br2] and
Pybox)Cu(II)Br2] and K4[Fe(CN)6]·3H2O provides the αꢀ reaction time shorter 6 hours (Table 1, entry 9). To ascertain that
acyloxylation of ketones products in 67ꢀ97% isolated yield. The O2 is necessary (as shown in proposed mechanism later on) for
transformation is regiospecific in the discrimination of electronꢀ the reaction to proceed, a control reaction was carried out in
deficient intermediate in the case of nonsymmetrical substrates.
presence of N2. In absence of O2, only 9% of desired product
Recently, we developed an efficient method for the synthesis of were obtained (Table 1, entry 10), which clearly demonstrates
αꢀamination of ketones and esters under aerobic oxidative the role of O2 in this reaction. Finally, the amount of
conditions using [(DmꢀPybox)CuBr2] complex as catalyst K4[Fe(CN)6]·3H2O was also surveyed, 9% desired product was
through αꢀbromo carbonyl intermediate.10 In the continued obtained in the presence of 10% CNꢀ source (Table 1, entry 11).
effort to develop environmentally benign protocols for the It is proved that equivalent K4[Fe(CN)6]·3H2O was necessary
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DOI: 10.1039/C6RA02186G
for the reaction to proceed. A control experiment with the 20% yields. The configuration of 1a was determined by Xꢀray
TEMPO showed no reaction (Table 1, entry 12). This result crystallographic analysis (Fig. 1). More specifically, the
might support the formation of intermediate
mechanism pathway in Scheme 2.
E
through radical efficient conversion of electronꢀdeficient ketones was achieved
at low temperature (Table 2, entry 5). Notably, 2ꢀbutyrylfuran
and 2ꢀbutyrylthiophene were also tested, and these reactions
Table
1
Initial Studies toward αꢀacyloxylation of
proceeded smoothly to give αꢀheteroaryl heteroaryl ketones (6a
and 7a) in good and moderate yields in the presence of 15 mol%
[(DmꢀPybox)Cu(II)Br2]catalysts.
propiophenone
O
O
10 mol% [Cu]/ligand
O
+
K4[Fe(CN)6]—3H2O
0.2 mmol
O
Air, Solvent, 110 , 9 h
Table 2 [(DmꢀPybox)Cu(II)Br2] catalyzed αꢀ oxyacylation of
ketones.
0.5 mmol
Entr
y
Substrate
Product
Time Yield
(%)a,
O
O
(h)
N
b
N
N
Cu
Br
O
O
Br
O
O
Cu complex
[(DmꢀPybox)Cu( )Br2]
1
2
9
90
97
O
1a
Entry
Cu catalyst
(10 mol %)
Ligand Solvent
(mol%)
Yield (%)a,b
O
O
1
2
3
4
5
6
7
8
9
10
11
12
12
12
DMF
NR
NR
48
90
11
8
O
L
DMF
DMF
DMF
DMSO
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2a
CuBr2
O
O
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
Cu complex
O
3
4
8
8
94
93
O
NR
91
3a
O
OCH3
O
73c
92d
9e
O
O
MeO
H3CO
9f
4a
Cl
NRg
50h
33i
O
O
5
6
7
10
15
15
73c
87d
79d
O
O
Cl
Cl
a Isolated yield; b reaction condition: 1mL DMF as solvent, under air, 110℃; c
5 mol% catalyst, reaction time: 16 h; d 15 mol% catalyst, reaction time: 6 h; e
under N2; f 0.0083 mmol K4[Fe(CN)6]·3H2O; g 20mol% TEMPO was added; h
1.2 mmol CuCN; i 1.2 mmol Zn(CN)2.
5a
O
S
O
O
S
S
O
O
O
O
6a
O
O
O
O
7a
a
b
Isolated yield;
reaction condition: 0.5 mmol carbonyls, 0.2 mmol
K4[Fe(CN)6]·3H2O, 10 mol% [PyboxCu(Ⅱ)Br2], 1mL DMF as solvent, under
air; c 90℃; d 15 mol% [(DmꢀPybox)Cu(II)Br2].
Fig. 1 Molecular structure of 1a with thermal ellipsoids drawn
at the 30% level, all hydrogen atoms are omitted for clarity.
To explore the generality and scope of the present αꢀ
oxyacylation synthetic method, several ketones compounds
were examined as substrates under the optimized reaction
conditions. Propiophenones derivatives, which are substituted
with electronꢀdonating or electronꢀwithdrawing groups, gave the
corresponding αꢀbenzoyloxy ketones 1aꢀ5a in good to excellent
2 | J. Name., 2012, 00, 1-4
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DOI: 10.1039/C6RA02186G
Fig. 2 Molecular structure of 8a with thermal ellipsoids drawn
at the 30% level, all hydrogen atoms are omitted for clarity.
K4[Fe(CN)6]—3H2O
O
O
[(DmꢀPybox)Cu( )Br2]
O
O
1a
DMF, 110 , Under air
Table
3
Studying the reaction selectivity toword αꢀ
CNꢀ
ꢀ H2O
O
oxyacylation of ketonesa, b
.
Oꢀ
CN
O
O
O
O
R2
O
R3
O
R2
OH
Under air
H2O
C
O
OH
K [Fe(CN) ]—3H O
ꢀCO2
0.2 mmol
CN
4
6
2
+
R1
R3
O
10 mol% [(DmꢀPybox)Cu( )Br2]
Air, DMF, 100
R1
B
C
A
D
0.25 mmol
major product
0.25 mmol
+
O
O
[(DmꢀPybox)Cu( )Br2]
Air
O
O
O
O
O
O
H2O
O
O
Br
OH
O
O
Cl
Cl
Cu(
)
E
F
2a, 87%
R1 = H; R2 = Et; R3 = H
8a, 88%
9a, 71%
R1 = Cl; R2 = Me; R3 = Me
R1 = Cl; R2 = Me; R3 = H
O
Scheme
2
Proposed catalytic mechanism toward αꢀ
O
O
O
oxyacylation of ketones.
S
O
O
O
O
O
Cl
Cl
To gain further insights into the reaction mechanisms of the Cuꢀ
catalyzed crossꢀcoupling reactions, several starting materials,
such as benzoic acid or benzoyl cyanide, have been added to
investigate the viability of the intermediate. The desired
products were observed in both conditions indicating that the
benzoic acid and benzoyl cyanide involvement of the
mechanism process (see Supporting Information (SI)). Based on
the documented precedents and experiment results, the reaction
mechanism was proposed as shown in Scheme 2. Initially,
12a, 67%c
10a, 89%
11a, 91%
R1 = Cl; R2 = Et; R3 = H
R1 = H; R2 = Me; R3 = Me
R
1 = Cl; R2 = Et
a: Isolated yield; b: reaction condition: 1 mL DMF as solvent, 0.2 mmol
K4[Fe(CN)6]·3H2O, 9 h, under air, 100℃；c: 20 h
In general, the selectivity of the reaction is determined by
electronic effects, the control experiments were carried out to
test the selectivity of αꢀoxyacylation of ketones reaction. Thus,
equimolar amounts of 1ꢀpꢀtolylpropanꢀ1ꢀone and 1ꢀ(4ꢀ
chlorophenyl)propanꢀ1ꢀone were heated in the presence of 10
mol% [(DmꢀPybox)Cu(II)Br2] catalysts and 2.4 equivalents of
CNꢀ in DMF to give 8a in 88% yield (Table 3). No other side
products were observed in this transformation. The
configuration of 8a was also determined by Xꢀray
crystallographic analysis (Fig. 2). Electronꢀwithdrawing groups
on aromatic ring substrate 1ꢀ(4ꢀchlorophenyl)propanꢀ1ꢀone
more favor form the intermediate, and then obtained the
asymmetry αꢀoxyacylation product. Propiophenone and 1ꢀ
phenylbutanꢀ1ꢀone were also transformed well under the
standard conditions, desire products 1ꢀoxoꢀ1ꢀphenylpropanꢀ2ꢀyl
cyanohydrin intermediate
propiophenone. Then, intermediate
oxidation to yield benzoyl cyanide (
conditions, which is hydrolyzed in situ to give the benzoic acid
) under wet organic solvents.13 and then decarbonylation
formation of ( ), On the other hand, propiophenone would
undergo bromination at the αꢀcarbonyl to generate 2ꢀbromoꢀ1ꢀ
phenylpropanꢀ1ꢀone in the presence of [(Dmꢀ
Pybox)Cu(II)Br2] catalyst.14 Then, intermediate
was further
hydrolyzed to afford 2ꢀhydroxyꢀ1ꢀphenylpropanꢀ1ꢀone ( ),
which could react with intermediate to afford final product.
The intermediate is supported by the isolation and MS spectra.
A
formed by cyanide addition to
could also undergo
) under aerobic oxidation
A
B
(
C
D
(E)
E
F
D
F
4ꢀchlorobenzoate
(
9a
)
and 1ꢀoxoꢀ1ꢀphenylbutanꢀ2ꢀyl 4ꢀ
And Cu(II) catalyst were regenerated in the presence of oxygenꢀ
mediated reoxidation of Cu(I).
chlorobenzoate (10a) were obtained in 71% and 89% yields,
respectively (Table 3). Interestingly, the hetercycle substrate 1ꢀ
(thiophenꢀ2ꢀyl)butanꢀ1ꢀone underwent this transformation to
provide 12a in aceptable yields.
Conclusions
To further evaluate the practical utility of the catalyst system,
the model reaction was carried out on a gram scale under the
optimized conditions, and the desired product was obtained in
94% yield (Scheme 1).
In conclusion, we have described the first oneꢀpot and green
efficient method for the synthesis of αꢀacyloxylation of ketones
compounds catalyzed by Pybox Cu(II) complex under mild
conditions. A series of αꢀacyloxylation of ketones products were
obtained in good and excellent yields. This method provides an
excellent alternative to organocatalysts. And a detailed reaction
mechanism is still under investigation.
O
O
10 mol% [(DmꢀPybox)Cu( )Br2]
+
K4[Fe(CN)6]—3H2O
O
O
Air, Solvent, 110 , 9 h
2a
1.260 g, 94% yield
1.480 g, 10 mmol
Acknowledgment
Scheme 1 Gramꢀscale synthesis of 2a
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This work was supported by the National Nature Science 5 M. Uyanik, D. Suzuki, T. Yasui and K. Ishihara, Angew. Chem. Int. Ed.
Foundation of China (21102004), the NSF of Anhui province 2011, 50, 5331ꢀ5334.
(1208085MB25) and the Projectꢀsponsored by SRF for ROCS 6 R. N. Reddi, P. V. Malekar and A. Sudalai, Org. Biomol. Chem., 2013,
and Special and Excellent Research Fund of Anhui Normal 11, 6477ꢀ6482.
University. We are grateful to Prof. Shaowu Wang and Zhuo 7 (a) C. S. Beshara, A. Hall, R. L. Jenkins, K. L. Jones, T. C. Jones, N. M.
,
Chai for their valuable suggestions.
Killeen, P. H. Taylor, S. P. Thomas and N. C. O. Tomkinson, Org. Lett.
2005, , 5729ꢀ5732; (b) D. A. Smithen, C. J. Mathews and N. C. O.
Tomkinson, Org. Biomol. Chem., 2012, 10, 3756ꢀ3762.
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Technology, The Key Laboratory of Functional Molecular Solids,
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wgjiasy@mail.ahnu.edu.cn
yanliqin@mail.ahnu.edu.cn
Electronic Supplementary Information (ESI) available: Additional
（
W. ꢀG. Jia
）
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（L. ꢀQ. Yan
）
†
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Table of Content
One-pot and efficient method for the synthesis of acyloxycarbonyl compounds from ketones compounds catalyzed
by Pybox Cu(II) complex have been obtained under mild conditions.