A Simple and Efficient Method for the Preparation of α-Halogenated Ketones Using Iron(III) Chloride and Iron(III) Bromide as Halogen Sources with Phenyliodonium Diacetate as Oxidant

Article abstract of DOI:10.1002/adsc.201700833

α-Halogenated ketones are both unique structure moieties existing in biologically natural products and valuable synthetic intermediates for the preparation of functional molecules. An efficient and scalable method for the preparation of α-halogenated ketone using iron (III) chloride and iron (III) bromide as halogen sources with phenyliodonium diacetate as oxidant has been developed, featuring mild reaction conditions, environmentally friendly reagents, and wide substrate scope. Notably, the three-step synthesis of drug prasugrel was achieved using this developed method as a key step with 30% yield on gram-scale. Additionally, the reaction mechanism involving chloride cation was proposed based on some preliminary control experiments. (Figure presented.).

Full text of DOI:10.1002/adsc.201700833

Title: A Simple and Efficient Method for the Preparation of α-
Halogenated Ketones Using Iron(III) Chloride and Iron(III)
Bromide as Halogen Sources with Phenyliodonium Diacetate as
Oxidant
Authors: Shi-Zhong Tang, Wenshuang Zhao, Tao Chen, Yang Liu,
Xioa-Ming Zhang, and Fu-Min Zhang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700833
Link to VoR: http://dx.doi.org/10.1002/adsc.201700833

10.1002/adsc.201700833
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
A Simple and Efficient Method for the Preparation of α-
Halogenated Ketones Using Iron(III) Chloride and Iron(III)
Bromide as Halogen Sources with Phenyliodonium Diacetate as
Oxidant
Shi-Zhong Tang,a Wenshuang Zhao,a Tao Chen,a Yang Liu,a Xiao-Ming Zhang,a and
Fu-Min Zhanga,b,*
a
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou,
730000, P.R. China. Email: zhangfm@lzu.edu.cn. Phone: 86-931-8912293. Fax: 86-931-8912582.
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School
b
of Pharmacy, Sichuan University, Chengdu, 610041, P. R. China.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
approaches. Apart from these methods, the direct
carbonyl
Abstract. α-Halogenated ketones are both unique structure
moieties existing in biologically natural products and halogenation at α-position of
a
valuable synthetic intermediates for the preparation of
functional molecules. An efficient and scalable method for
the preparation of α-halogenated ketone using iron (III)
chloride and iron (III) bromide as halogen sources with
phenyliodonium diacetate as oxidant has been developed,
featuring mild reaction conditions, environmentally
friendly reagents, and wide substrate scope. Notably, the
three-step synthesis of drug prasugrel was achieved using
this developed method as a key step with 30% yield on
gram-scale. Additionally, the reaction mechanism
involving chloride cation was proposed based on some
preliminary control experiments.
compound is still a common and universal
protocol.[5] In this context, the exploitation of new
chloride sources[6] or new reaction procedures[7]
such as in ionic liquid or under microwave
irradiation has attracted the interests of synthetic
chemists. Alternatively, the utilization of the
known
chlorinating
reagents
for
this
transformation has also been an active subject.
Therefore, SOCl2,[3c] Me3SiCl,[8a,8c] NCS (N-
chlorosuccinimide),[8b] MeCOCl,[5c] NH4Cl,[8d]
[8h]
NaCl,[8e] MgCl2,[8f] HCl,[8g] and ICl3 have been
used. However, some disadvantages exist in the
known methods, such as poor yields, narrow
substrate scope, the use of relatively toxic and
expensive chlorinating reagents, and tedious
manipulation procedure. In contrast to the above-
mentioned chloride sources, FeCl3·6H2O has its
inherent advantages in organic synthesis because
it is nontoxic, inexpensive, environmentally
friendly, not sensitive to air and moisture, and
thus easy to handle.[9] In continuation with our
interest in organic synthesis involving iron (III)
and hypervalent iodine (III) reagents,[10] herein,
we report a novel method for the preparation of
α-halogenated ketones, in which FeCl3·6H2O was
used as the chloride source[11] with easily
available phenyliodonium diacetate (PIDA)
served as the oxidant.
Keywords: α-halogenated ketone; iron (III) bromide; iron
(III) chloride; phenyliodonium diacetate; prasugrel.
α-Chlorinated ketone is a common structural unit
in natural products, such as merochlorin C and
D,[1a] and gomerone C.[1b] Due to the presence of
a chloride adjacent to the carbonyl group, this
unit has been widely used as a valuable
intermediate, especially as an umpolung
synthon,[2] for further chemical transformations to
synthesize natural products, drugs, and other
functional
molecules.[3]
Therefore,
the
preparation of this unit has been a center topic for
synthetic chemistry, and numerous synthetic
methods have been developed,[4] including Au-
catalyzed transformation of terminal alkynes,[4b,c]
electrochemical oxidation of olefin,[4i] oxidative
In our investigation of the chlorination of 2-
]
phenylcyclohexanone,[10a we found that when
phenylacetone (1a) was used as the substrate, the
mono-chlorinated product 2a was isolated in 57%
yield (entry 1, Table 1). Encouraged by this initial
result, we investigated other reaction parameters to
further improve the reaction results. When Dess-
Martin periodinane (DMP) was replaced by PIDA,
the expected chlorination reaction also took place,
hydrolysis of haloalkenes,[4e] photooxidation of
[4k]
vinyl silanes or vinyl sulfides,
direct
conversion of alcohols using trichloroisocyanuric
acid as both a chloride source and an oxidant,[4h]
Fe(III)-catalyzed cascade reaction of α-halo
substituted styrenes,[4g] and various other
1
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10.1002/adsc.201700833
Advanced Synthesis & Catalysis
albeit affording 2a in a decreased yield (entry 2,
Table 1). Pleasingly, when the reaction was
conducted in acetic
acid (AcOH), the product yield increased to 68%
(entry 3, Table 1). Therefore, further screening of
other solvents were carried out, and the results
indicated that AcOH was superior (entries 4-10,
Table 1). Various other oxidants were then examined.
Except for phenyliodonium bis(trifluoroacetate)
(PIFA), which gave a similar reaction result in
comparison to PIDA, no reaction or unsatisfactory
reaction results were generally observed (entries 11-
18, Table 1). Next, the amount of FeCl3·6H2O was
investigated. Lowering
the amount of FeCl3·6H2O dramatically diminished
the yield of this transformation (entries 19-20, Table
1), while increasing the FeCl3·6H2O to 2.5 equivalent
slightly enhanced the yield (entry 21, Table 1).
Considering the marginal difference in product yield,
we selected 2.0 equivalent of FeCl3·6H2O as the
standard amount. Finally, other chloride sources were
also investigated, with inferior result obtained in each
case (entries 22-33, Table 1). Therefore, the reaction
conditions listed in entry 3 (Table 1) was selected as
the optimal reaction conditions.
Table 1. The optimization of reaction conditionsa.
Entry Cl source Oxidant Solvent Coversion Yield
(2.0 equiv) (1.2 equiv)
FeCl3·6H2O DMP
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
FeCl3·6H2O PIDA
(%)b,[12] (%/)c
1d
2e
3
4
5
6
7
8
9
EA/AcOH
EA/AcOH
AcOH
DMF
57
100
43
100
68
100
28
32
91
22
47
94
27
100
92
99
99
50
42
50
28
97
100
100
100
5
trace
trace
26
NRf
trace
43
trace
66
42
THF
CH3CN
DMSO
DCM
hexane
toluene
AcOH
AcOH
10
11g FeCl3·6H2O PIFA
With the optimal reaction conditions in hand, we
investigated the generality of this chlorination
reaction. Various benzyl ketones, aromatic
12
FeCl3·6H2O Na2IO4
13h FeCl3·6H2O mCPBA AcOH
FeCl3·6H2O I2
15i FeCl3·6H2O DDQ
42
15
14
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
ketones, cyclic benzoketones, and
aliphatic
trace
NR
NR
NR
41
50
70
56
trace
trace
NR
trace
trace
NR
ketones were subjected to the optimal conditions,
and the reaction results were shown in Table 2.
Firstly, a series of phenylacetones containing
either F, Cl, Br or NO2 substituents at para-
position or Br at meta- or ortha- position of the
aryl ring were investigated, and all the reactions
performed well, providing the corresponding
16
17
18
FeCl3·6H2O K2S2O8
FeCl3·6H2O O2
FeCl3·6H2O air
19j FeCl3·6H2O PIDA
20k FeCl3·6H2O PIDA
21l FeCl3·6H2O PIDA
22m 1.0 M HCl
PIDA
products 2a-2g in good to excellent yields.
23
24
25
26
27
28
CuCl2·2H2O PIDA
CoCl2·6H2O PIDA
NiCl2·6H2O PIDA
However, the strong electron-donating OMe
group of the aryl ring has a detrimental effect on
the reaction, which gave a complex mixture.
33
5
26
13
27
MgCl2
NaCl
SnCl2
PIDA
PIDA
PIDA
Notably,
1-cyclopropyl-2-(2-fluorophenyl)-
ethanone (1h) was also an amenable substrate,
affording the product 2h in 75% yield.
Interestingly, when the symmetric 1,3-
diphenylpropan-2-one was used, the mono-
chlorinating product 2i was obtained with 79%
yield without the isolation of symmetric
29
30
31
32
ZnCl2
AlCl3
SnCl4
TiCl4
PIDA
PIDA
PIDA
PIDA
PIDA
-
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
trace
55
59
58
NR
0l
22
100
100
100
33
33n NCS
34 FeCl3·6H2O
dichlorinated product. Next,
acetophenone derivatives were studied, which
also provided the expected phenacyl chlorides 2j
a
range of
50
-
a) Reactions were performed using phenylacetone (0.2
mmol), FeCl3·6H2O (0.4 mmol), oxidant (0.24 mmol)
in 1.0 mL solvent at room temperature under an argon
atmosphere; b) determination by using isopropyl-
benzene as interior label;[12] c) isolated yield; d) DMP
2r with good yield. Except for the preparation of
product 2n, an elevated reaction temperature (50
oC) was generally required for achieving the
satisfactory yields. In these reactions, the
substituents at para-position of the aryl ring, the
length of the alkyl group, as well as the chloride
at the alkyl chain have little influence on the
reaction outcomes. However, product 2n bearing
strong electron-donating OMe group at para-
position of the aryl ring was isolated only in a
low yield (30%), along with recovery of 1n
(38%). Remarkably, propiophenone and 1-
=
Dess-Martin
Periodinane;
e)
PIDA
=
phenyliodonium diacetate; f) NR = no reaction; g)
PIFA = phenyliodonium bis(trifluoroacetate); h) m-
CPBA = meta-chloroperbenzoic acid; i) DDQ = 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone; j) 1.0 equiv
FeCl3·6H2O was used; k) 1.5 equiv FeCl3·6H2O was
used; l) 2.5 equiv FeCl3·6H2O was used; m) 6.0 equiv
HCl was used n) NCS = N-chloro-succinimide; l) the
phenylbutan-1-one
were
ideal
substrates,
starting material was partically consumed without 2a
.
2
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10.1002/adsc.201700833
Advanced Synthesis & Catalysis
a) Unless otherwise noted, reactions were performed using
ketone derivatives (0.2 mmol) in 1.0 mL AcOH at room
temperature under an argon atmosphere and the starting
materials were completely conversed; b) the reaction was
performed at 50oC; c) 10 mmol scale; d) the recovery
starting material (38%).
affording the expect products 2o and 2p with
84% and 84% yield, respectively. It is noteworthy
that the substrates bearing a chloride at distal site
of the alkyl chain reacted smoothly, resulting in
the 1,3-dichlorides 2q and 2r with satisfied yields.
Cyclic benzoketones were also proved to be
suitable substrates, which could be easily
transformed to the corresponding five-, six-, and
To verify the synthetic utility of this transformation,
eight representative substrates were carried out on a
gram-scale reaction (10.0 mmol) under the optimal
conditions, and a slightly improved or similar yield
were obtained, respectively, along with some minor
seven-membered ring products 2s-2u with good
to excellent yields, respectively. Moreover,
isochroman-3-one was also tested, giving the
expected product 2v with 49% yield. Finally,
when 7-tridecanone and cyclododecanone were
subjected to the optimal conditions, the expected
products 2w and 2x was isolated with 90% and
79% yields, respectively, while 4-phenylbutan-2-
one was selected as a substrate, products 2y and
2y' were isolated with low regioselectivity.
Similarly, the α-brominated ketone not only is a
key structural scaffold in natural products,[1a] but
also serves as a building block in the design and
exploration of new chemical reaction.[13] In order
to further expand this α-chlorinated reaction to a
corresponding bromination process, FeBr3 was
used in place of FeCl3·6H2O under the optimal
conditions. The reaction proceeded smoothly,
]
byproducts (Table 2).[12 These results indicated that
the present protocol could be applied for the
preparation of α-chlorinated/α-brominated ketones
on gram-scale.
The synthetic application of this protocol was further
demonstrated through the gram-scale synthesis of
prasugrel,[14] a clinically used pharmaceutical for
preventing the formation of blood clots. The product
2h could be achieved in 79% yield when the gram-
scale reaction of the commercially available substrate
1h (2.14 g, 12.0 mmol) was conducted. Condensation
of the chlorinated product 2h (1.0 g) with the
commercially available 5,6,7,7α-tetrahydrothieno
[3,2-c] pyridine-2(4H)-one (3a, 1.10 g) gave
intermediate 3 in 50% yield, and the subsequent
acylation 3 (1.14 g) with acetic anhydride (0.53 g)
afforded the target compound in 75% yield. The
overall yield of the three-step synthesis is 30% from
two commercially available materials 1h and 3a
(Scheme 1).
affording the expected brominated products 2z
-
2ac with good to excellent yields. These results
demonstrate that the present transformation could
be applied for the preparation of α-brominated
ketone, either the linear benzylketone or
phenylketone or the cyclic benzoketone or
aliphatic ketone.
Table 2. Scope of Substratesa.
Scheme 1. The Concise Synthesis of Prasugrel on Gram-
scale.
To elucidate the possible reaction mechanism,
some designed control experiments were carried
out (Scheme 2). First, the compound 4[15a] was
subjected to the optimal reaction conditions, and
the chlorinated product 4a was isolated without
the ring-opening product 4b being observed (eq.
1, Scheme 2.);12 this result excluded a possible
radical reaction process involving Cl·. Second,
the model reaction was performed under the
standard condition in the presence of 1,1-
diphenylethene (DPE,
5
), the compounds 5a[15b]
and 5b[15c] were isolated along with product 2a
(eq.2, Scheme 2.), these experimental results
3
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10.1002/adsc.201700833
Advanced Synthesis & Catalysis
Scheme 3. The Proposed Reaction Mechanism.
ruled out the possibility of chloride anion
participation in the reaction and suggested that a
chloride cation might be involved in the current
transformation based on the combinition of the
formation of product 5a and radical clock
experiment. Third, when FeCl3·6H2O was
replaced by 1.0 mol/L HCl as both of an acid and
chloride source, the reaction led to the desired
product 2a with 56% yield (entry 22, Table 1).
Finally, various metal chlorides were used to
replace FeCl3·6H2O under the optimal conditions.
The results demonstrated that the Lewis activity
of metal chlorides dramatically effect the
expected transformation (entries 23-32, Table 1)
and proved that the enolized process is a crucial
for the success of the reaction. Because some
metal chlorides with weaker Lewis acidity could
not efficiently promote the enolization of
substrate and the activation of the oxidant PIDA,
In conclusion, a new, efficient and scalable
method for introduction of chloride at α-position
of ketones have been developed under the mild
conditions,
and
environmentally
friendly
FeCl3·6H2O and phenyliodonium diacetate were
applied as the chloride source and the oxidant,
respectively. This methodology has been
extended to α-bromination of ketones. Notably, a
clinically drug prasugrel was concisely
synthesized in three steps with 30% yield on
gram-scale.
Experimental Section
Under an argon atmosphere, to a 15 mL reaction tube were
added sequentially a magnetic stir-bar, ketone substrates
(0.2 mmol), FeCl3·6H2O (0.4 mmol, 108.1 mg), PhI(OAc)2
(0.24 mmol, 77.3 mg) and AcOH (1.0 mL). The reaction
mixture was stirred at room temperature (procedure A) or
at 50oC (procedure B) until the starting material
disappeared (monitored by TLC), and the reaction mixture
was diluted with EtOAc and H2O. The mixture was
extracted with EtOAc (30 mL × 3) and the combined
organic layers were washed successively with water and
brine, dried over Na2SO4, filtered, and concentrated under
vacuum to give the crude product, which was purified by
silica gel column with petroleum ether/EtOAc as the eluent
to afford the desired product.
[16]
the expected chlorination could not occur in
these cases. However, FeCl3·6H2O could acted as
“three birds with one stone” reagent,[10a] i.e. the
acceleration of the enolized transformation, the
activation of the oxidant PIDA,[16] and the
chloride source in the current transformation.
Acknowledgements
We gratefully acknowledge financial support from the NSFC
(Grant Nos. 21772076, 21272097, 21290181, and 21502080.)
and PCSIRT of MOE (No. IRT-15R28).
Scheme 2. Some Control Experiments.
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activation of FeCl3, and the Cl anion was
simultaneously released. Subsequently, the
resulting Cl anion was oxidized by PIDA to
generate the active Cl cation,[17] which was
trapped by the intermediate Int-A to afford the
chlorated product and release a Fe(III) species.
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10.1002/adsc.201700833
Advanced Synthesis & Catalysis
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6
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10.1002/adsc.201700833
Advanced Synthesis & Catalysis
COMMUNICATION
A simple and efficient method for the preparation
of α-halogenated ketones using iron(III) chloride
and iron(III) bromide as halogen sources with
phenyliodonium diacetate as oxidant
Adv. Synth. Catal. Year, Volume, Page – Page
Shi-Zhong Tang, Wenshuang Zhao, Tao Chen,
Yang Liu, Xiao-Ming Zhang, and Fu-Min Zhang*
7
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