1,2-Dibromoethane and KI mediated α-acyloxylation of ketones with carboxylic acids

Article abstract of DOI:10.1016/j.cclet.2019.08.052

The 1,2-dibromoethane- and KI-mediated α-acyloxylation of ketones is reported in moderate to good yield without the use of transition metals and strong oxidants. Various acids are well tolerated with wide functional group compatibility. An 1,2-dibromoethane- and KI-catalysed reaction mechanism is proposed based on the results of control experiments.

Full text of DOI:10.1016/j.cclet.2019.08.052

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CCLET 5203 No. of Pages 4
Chinese Chemical Letters xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
1,2-Dibromoethane and KI mediated α-acyloxylation of ketones with
carboxylic acids
*
Xujie Wang, Gangsheng Li, Yanan Yang, Jianshuang Jiang, Ziming Feng, Peicheng Zhang
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking
Union Medical College, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 13 July 2019
Received in revised form 10 August 2019
Accepted 28 August 2019
Available online xxx
The 1,2-dibromoethane- and KI-mediated α-acyloxylation of ketones is reported in moderate to good
yield without the use of transition metals and strong oxidants. Various acids are well tolerated with wide
functional group compatibility. An 1,2-dibromoethane- and KI-catalysed reaction mechanism is
proposed based on the results of control experiments.
© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
1,2-Dibromoethane
KI
α-Acyloxylation
Ketones
Carboxylic acids
α-Acyloxycarbonyl compounds are significant building blocks
in synthetic organic chemistry [1] that can readily transform into
various other functional groups, such as imidazoles, furans and
oxazoles [2]. Traditionally, α-acyloxycarbonyl compounds can be
prepared by the substitution reaction between α-halocarbonyl
compounds [3] and α-diazoketones [4] with alkaline carboxylates
or by the direct oxidative coupling of carbonyl compounds with
toxicheavymetaloxidantssuchasPb(OAc)4,Tl(OAc)3 andMn(OAc)3
[5]. Cu-catalysed oxidative coupling of ketones and carboxylic acids
with oxygen as the sole oxidant have also been developed over the
years [6]. Recently, to overcome the drawback from the use of toxic
reagents or heavy metals, new metal-free oxidative coupling
methods have been investigated. In 2005, Ochiai et al. first reported
the iodobenzene-catalysed α-acyloxylation of ketones with acetic
acid [7]. In 2011, Ishihara and co-workers reported the direct α-
acyloxylation of carbonyl compounds with carboxylic acids under
TBHP and TBAI conditions (Scheme 1a) [8]. Encouraged by this
TBHP/TBAI system, chemists have achieved immense progress in
the α-acyloxylation of ketones by using different substrates and
mild oxidants, such as TBHP, K2S2O8 and H2O2 [9]. While each of
these approaches represents an important advance towards the
objectiveofageneralmethodforthesynthesisofα-acyloxycarbonyl
compounds, each of them still utilizes organic oxidants to complete
the C-O coupling process. Although Tomkinson and co-workers
have reported the α-acyloxylation of carbonyl compounds by
treating ketones with N-methyl-O-benzoylhydroxylamine hydro-
chloride (Scheme 1b) [10], this method still needs a three-step
reaction process to synthesize the substrates. Therefore, the
development of a facile, environmentally benign and efficient
protocol for the preparation of α-acyloxycarbonyl compounds from
simple and readily available starting materials with a broad
substrate scope is still highly desirable.
In this paper, we report the 1,2-dibromoethane (EDB)- and
potassium iodide (KI)-mediated α-acyloxylation of ketones with
carboxylic acids. The most important features of the present
catalytic system include: (1) the direct use of commercially
available materials, (2) transition-metal-free catalytic systems and
(3) milder reaction conditions without the use of strong oxidants,
wide functional group compatibility and a broad substrate scope.
In the investigation of the reaction conditions (Table 1), benzoic
acid 1a (1.0 equiv.) was initially treated with acetone 2a (1 mL) in
the presence of EDB (1.0 equiv.), potassium iodide (KI, 0.2 equiv.),
and potassium carbonate (K2CO3, 1.5 equiv.) at 60 ꢀC for 10 h to
afford 2-oxopropyl benzoate 3a, which was isolated by column
chromatography in 72% yield (entry 1). The yield did not improve
when examining different amounts of KI (entries 2-5). However,
when we tried to replace the KI with NaI, the yield decreased to
64%, and 3a was not detected when EDB was substituted with 1,2-
dichloroethane (entries
6 and 7). Notably, we observed a
satisfactory yield of 86% when the amount of additive EDB was
increased to 1.5 equiv. (entry 10), and a further increase in EDB to
2.0 or 4.0 equiv. did not improve the yield of 3a (entries 11 and 12).
Subsequently, we found that 2 mL of acetone 2a might be the most
suitable equivalent, of which the isolated yield was improved to
* Corresponding author.
E-mail address: pczhang@imm.ac.cn (P. Zhang).
https://doi.org/10.1016/j.cclet.2019.08.052
1001-8417/© 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: X. Wang, et al., 1,2-Dibromoethane and KI mediated α-acyloxylation of ketones with carboxylic acids, Chin.
Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.08.052

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Scheme 1. Direct α-acyloxylation of ketones.
Table 1
Optimization of the reaction conditions.a
Entry
Additive
(equiv.)
Catalyst
(equiv.)
Acetone
(equiv.)
Yield
(%)b
1
2
3
4
5
6
7
8
EDB (1.0)
EDB (1.0)
EDB (1.0)
EDB (1.0)
EDB (1.0)
EDB (1.0)
DCE (1.0)
EDB (0.2)
EDB (0.5)
EDB (1.5)
EDB (2.0)
EDB (4.0)
EDB (1.5)
EDB (1.5)
EDB (1.5)
EDB (1.5)
/
KI (0.2)
KI (0.1)
KI (0.5)
KI (1.0)
KI (2.0)
NaI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
KI (0.2)
/
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
1.0 mL (26.0)
0.5 mL (13.0)
2.0 mL (52.0)
4.0 mL (104.0)
2.0 mL (52.0)
2.0 mL (52.0)
72c
65
70
67
50
64
N.D.
18
28
86
9
10
11
12
13
14
15
16
17
85
56
42
96 (94c)
92
N.D.
N.D.
KI (0.2)
Abbreviations: EDB = 1,2-dibromoethane, DCE = 1,2-dichloroethane, N.D.
= Not
detected.
a
Reaction conditions: 1a (0.5 mmol), K2CO3, (0.75 mmol), additive, catalyst and
acetone under air at 60 ꢀC for 10 h.
b
1H NMR yield, phloroglucinol as the internal standard.
Isolated yields.
c
94%, after evaluating a variety of different amounts of 2a in the
reaction (entries 13-15). Finally, it is important to mention that
product 3a was not detected in the absence of KI or EDB (entries 16
and 17). After a series of screening experiments, the optimal
reaction conditions were obtained when 1a was treated with an
excess of acetone 2a (2 mL, 52.0 equiv.), EDB (1.5 equiv.) and KI (0.2
equiv.) at 60 ꢀC.
With the optimized reaction conditions in hand, we next
evaluated the scope of the procedure by testing various carboxylic
acids with acetone. First, a series of aromatic carboxylic acids were
examined as shown in Scheme 2. Substrates with both electron-
donating and electron-withdrawing substituents afforded the
products in good to excellent yields under the standard conditions
(3b-3p). Notably, hydroxy (3d and 3j), amino (3e) and aldehyde (3l)
groups on the aromatic ring were well tolerated, thus offering
opportunities for further derivatization. Heterocyclic aromatic
carboxylic acids were also investigated and afforded the desired
products in 53%-91% yield (3m-3p). To test whether this method
Scheme 2. Scope of carboxylic acids. Reaction conditions: carboxylic acid
(2.0 mmol), EDB (3.0 mmol), KI (0.4 mmol), K2CO3 (3.0 mmol), 8 mL acetone under
air at 60 ꢀC. Isolated yields.
could be extended to other carboxylic acids, we examined
the reaction of aliphatic carboxylic acids with acetone. To our
excitement, the desired products were obtained in 65%-94% yield
(4a-4l). Notably, cinnamic acid, crotonic acid and propiolic acid
provided the desired products in high yield (4a-4c).
Further exploration of acyloxylation to aliphatic carboxylic
acids also worked smoothly and afforded the coupling
products in very good yields (4d-4h). Notably, the hydroxy and
N-protected amino groups on the aliphatic chain were well
tolerated (4i and 4j). It should be mentioned that steric hindrance
proximal to the acid group also provided good yield, as exemplified
by the successful synthesis of 4k and 4l (89% and 90% yield,
respectively). We also attempted to use potassium phthalimide
Please cite this article in press as: X. Wang, et al., 1,2-Dibromoethane and KI mediated α-acyloxylation of ketones with carboxylic acids, Chin.
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3
Scheme 3. Scope of ketones. Isolated yields. Reaction conditions: a ketone (5 mL), carboxylic acid (2.0 mmol), EDB (3.0 mmol), KI (0.4 mmol), K2CO3 (3.0 mmol) under air at
b
60 ꢀC; ketone (2.0 mmol), carboxylic acid (3.0 mmol), EDB (3.0 mmol), KI (0.4 mmol), K2CO3 (3.0 mmol), 5 mL DMF under air at 60 ꢀC.
Scheme 4. Control experiments to determine the reaction mechanism.
and 4-hydroxyacetophenone with acetone under the standard
reaction conditions to afford the corresponding products 5a in 47%
and 5b in 50% yield, respectively.
target product in 35% yield (6j). However, it should be noted that
2-methyl-1-phenylpropan-1-one was not suitable for the trans-
formation, which indicated that steric effects had a strong
influence on the transformation. 2,3-Dihydro-1H-inden-1-one
and 5-fluoro-2,3-dihydro-1H-inden-1-one were also tested to
generate the products in 30% and 34% yield (6l and 6m),
respectively.
To further investigate the utility of the EDB- and KI- mediated α-
acyloxylation of a carboxylic acid with acetone in preparative
organic synthesize, a gram-scale reaction was conducted. A total of
2.44 g of benzoic acid was treated with 40 mL of acetone 2a (26.0
equiv.) to yield 2.98 g of product 3a (84%), which was in accordance
with the optimized reaction conditions (Table 1, entry 10).
After demonstrating a series of acids, we then investigated the
scope of ketones with benzoic acid. Considering the excess use of
acetone under our optimized conditions, we attempted to reduce
the amount of ketone and use DMF as the solvent, as shown in
Scheme 3. We first treated benzoic acid with both an excess and
1.0 equivalent of cyclohexanone, which provided the target
products in 62% and 32% yield respectively (6a). When 3-(3-
chlorophenyl)propanoic acid and cinnamic acid were treated with
excess cyclohexanone, the desired products were isolated in 59%
and 53% yield, respectively (6b and 6c). An excess of 3-pentanone
reacted with benzoic acid to provide the product in 45% yield (6d).
We then turned our sights to the use of 1.0 equiv. of ketones. To our
delight, acetophenone and 4-fluoroacetophenone reacted with
benzoic acid to obtain desired products in 35% and 32% yield (6e
and 6f), respectively. Different substituted substrates of propio-
phenone were examined with benzoic acid to obtain the desired
products in good yield (6g-6i). 1-Phenylbutan-1-one also gave the
The following control experiments were carried out to gain
insight into the mechanism of the reaction. First, target product 3a
was isolated in 88% yield when 2 equiv. of 2,2,6,6-tetramethylpi-
peridinyloxy (TEMPO) as a radical scavenger was added to the
standard reactions, indicating that this transformation may not
proceed via a radical pathway (Scheme 4, Eq. (1)). The generation
of I2 was observed when treating EDB and KI in acetone at 60 ꢀC
while the I2 was not found in the absence of EDB (details in
Supporting information). Besides, bromoethane and 1,3-dibromo-
propane were used to replace EDB under the optimized conditions,
which failed to provide the desired product (Scheme 4, Eqs. (2) and
(3)). The reaction was also carried out under an argon atmosphere,
which afforded product 3a in 85% yield (Scheme 4, Eq. (4)). The
above experiments indicated that the EDB plays an important role
in the generation of I2. In addition, the generation of 1-bromo-2-
iodoethane was detected by GC-MS when reduced the reaction
process to one hour (Scheme 4, Eq. (5)). The product 3a also formed
when we replaced EDB and KI with I2 (Scheme 4, Eq. (6)).
Remarkably, the α-iodoacetone 2b and α-iodoacetopheneone 2c
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Acknowledgments
We are grateful to the Drug Innovation Major Project (No.
2018ZX09711001-001-001) and CAMS Innovation Fund for Medical
Sciences (CIFMS) (No. 2016-I2M-1-010) for financial support.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2019.08.052.
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desired product 3a.
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tolerated with wide functional group compatibility, and a series of
ketones were also investigated. This protocol provides a conve-
nient and environmentally benign method for the synthesis of α-
acyloxycarbonyl compounds without the use of transition metal
and strong oxidants, even on a gram scale. An 1,2-dibromoethane
and KI-catalysed reaction mechanism is proposed based on the
results of control experiments. Further investigation of the
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Chem. Lett. (2019), https://doi.org/10.1016/j.cclet.2019.08.052