Mild and efficient α-chlorination of carbonyl compounds using ammonium chloride and oxone (2KHSO5·KHSO4· K2SO4)

Article abstract of DOI:10.1246/cl.2012.432

A simple protocol for the α-monochlorination of ketones and 1,3-dicarbonyl compounds utilizing NH₄Cl as a source of chlorine and Oxone as an oxidant in methanol without catalyst is presented. The reaction proceeds at ambient temperature in yields ranging from moderate to excellent.

Full text of DOI:10.1246/cl.2012.432

doi:10.1246/cl.2012.432
432
Published on the web April 4, 2012
Mild and Efficient ¡-Chlorination of Carbonyl Compounds Using Ammonium Chloride
and Oxone (2KHSO5¢KHSO4¢K2SO4)
Peraka Swamy, Macharla Arun Kumar, Marri Mahender Reddy, and Nama Narender*
Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India 500 007
(Received January 4, 2012; CL-111232; E-mail: nama@iict.res.in)
A simple protocol for the ¡-monochlorination of ketones
Oxone (2KHSO5¢KHSO4¢K2SO4), a potassium triple salt
containing potassium peroxymonosulfate, is an effective oxi-
dant. Owing to its stability, water solubility, ease of transport,
nontoxic (green) nature, and cost-effectiveness, this oxidant has
become an increasingly popular reagent for several oxidative
transformations.26
and 1,3-dicarbonyl compounds utilizing NH4Cl as a source of
chlorine and Oxone as an oxidant in methanol without catalyst
is presented. The reaction proceeds at ambient temperature in
yields ranging from moderate to excellent.
First, acetophenone was chosen as a model substrate for
chlorination in order to find optimal conditions. Several solvents
were investigated and results revealed that reaction was depend-
ent on polarity of solvent and miscibility of reagents in reaction
media (Table 1). The best results were obtained when MeOH
was used as a solvent among others in terms of reaction yields
and time, probably due to its high polarity and solubility of
NH4Cl and acetophenone in reaction media. On the other hand
EtOH, CH3CN, or THF used as solvents afforded lower yields
even after 24 h, possibly due to poor solubility of NH4Cl in these
solvents. This transformation was also attempted in other
solvents such as acetone, ethyl acetate, DCM, CHCl3, or CCl4.
The reaction barely took place and nearly no conversion of
acetophenone was observed, maybe due to the low polarity of
solvents and insolubility of NH4Cl in these solvents. Despite
complete solubility of NH4Cl and Oxone in water (highly polar
solvent), the yield was very low due to poor solubility of
acetophenone in water. 1.1 equivalent of NH4Cl-Oxone afforded
better results than to 1.0 equivalent of NH4Cl-Oxone.
¡-Haloketones are important synthetic intermediates and are
used as precursors for various organic transformations. Among
them, ¡-chloroketones have received considerable attention
because of their versatile applications in organic synthesis and
their high reactivity makes them react with a large number of
nucleophiles to provide a variety of useful compounds.1 They also
serve as metabolically more stable alternatives to hydrogen and
methyl functionality in drugs without loss of therapeutic efficacy.2
Synthesis of ¡-chloroketones has usually been achieved by
indirect routes, which include the reaction of silyl enol ethers
with transition-metal chlorides3 and reaction of aromatic com-
pounds with chloroacetyl chloride.4 Direct conversion of
ketones into ¡-chloroketones is an important synthetic trans-
formation that has received considerable attention. Generally the
direct chlorination can be accompanied by using chlorination
agents such as copper(II) chloride,5 p-toluenesulfonyl chloride,6
sulfuryl chloride,7 tetraethylammonium trichloride,8 and N-
chlorosuccinimide.9
Recently several procedures and reagent combinations have
been reported for the ¡-chlorination of ketones. These include:
(CH3)3SiCl-KNO3,10 DCDMH (1,3-dichloro-5,5-dimethylhy-
dantoin),11 N-halosuccinimide (NCS)-solvent free conditions,12
N-halosuccinamide-DMSO,13 NCS-UHP (urea-hydrogen per-
oxide) in ionic liquid,14 [Hmim][NO3]-HCl,15 AlCl3/Urea-
H2O2 in ionic liquid,16 NCS-Amberlyst-15,17 HTIB ([hydroxy-
(tosyloxy)iodo]benzene)-MgCl2-MW,18 NCS-Lewis acid,19
NCS-thiourea,20 NaClO2-[Mn(acac)3]-alumina,21 (CH3)3SiCl-
DMSO,22 and (CH3)3SiCl-SeO2.23 However, most of these
methods have drawbacks such as use of costly, hazardous or
toxic reagents with potential environmental problems due to the
generation of hazardous waste and require tedious work up
procedures. Therefore, there is still a need to develop more
convenient, efficient, eco-friendly, and selective procedures for
the ¡-monochlorination of carbonyl compounds. From the
green-chemistry point of view, a noncatalytic process is very
significant and alternative for synthetic organic chemistry.
In our on-going efforts to achieve environmentally friendly
halogenation procedures,24 earlier we have reported the aromatic
chlorination using NH4Cl-Oxone without catalyst25 and to the
best of our knowledge, there are no reports of selective ¡-
chlorination of ketones or 1,3-dicarbonyl compounds using
NH4Cl and Oxone. Here we wish to report that the NH4Cl-
Oxone reagent system can be used for the direct ¡-monochlori-
nation of ketones and 1,3-dicarbonyl compounds.
Having optimized the reaction conditions, we continued our
investigation with various structurally different carbonyl com-
pounds. A variety of aryl alkyl ketones, aliphatic ketones and
1,3-dicarbonyl compounds were reacted smoothly under the
present reaction conditions to provide the corresponding ¡-
chlorinated products in moderate to excellent yields.27 The
Table 1. ¡-Chlorination of acetophenone: effect of solventa
Entry
Solvent
Time/h
Yield/%b
1
2
3
4
5
6
7
8
9
CH3OH
CH3OHc
EtOH
CH3CN
THF
Acetone
Ethyl Acetate
DCM
CHCl3
CCl4
9
12
24
24
24
24
24
24
24
24
24
97
93
13
30
25
®
®
®
®
®
9
10
11
H2O
aAcetophenone (2 mmol), NH4Cl (2.2 mmol), Oxone (2.2 mmol),
solvent (10 mL), room temperature. bThe products were charac-
c
terized by NMR, mass spectra and quantified by GC. Acetophe-
none (2 mmol), NH4Cl (2 mmol), Oxone (2 mmol), solvent
(10 mL), room temperature.
Chem. Lett. 2012, 41, 432-434
© 2012 The Chemical Society of Japan
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433
Table 2. ¡-Chlorination of aryl ketones using NH4Cl and Oxonea
results are summarized in Tables 2 and 3. The structural identity
of all the products was ascertained on the basis of their spectral
properties (1H, 13C NMR and mass spectra, see Supporting
Information).28
As can be seen from Table 2, acetophenone was converted to
the respective ¡-chlorinated product in high yield (97%) within
9 h at room temperature. In order to determine the influence of
the substituent on an aromatic ring on the reaction path with this
reagent system, we have carried out the chlorination reaction
with acetophenone containing electron-donating or -withdrawing
functional groups at different positions.
Acetophenone containing electron-donating groups were
of higher reactivity than ones containing electron-withdrawing
groups under similar reaction conditions. Activated acetophe-
nones gave exclusively corresponding ¡-chlorinated products in
high yields at room temperature (Table 2, Entries 2-6). Whereas,
deactivated acetophenones furnished the ¡-chlorinated products,
along with substantial amount of ¡-chlorodimethyl ketals at
room temperature and exclusively ¡-chlorinated products at
reflux temperature (Table 2, Entries 7-14). In the case of
methoxy- or hydroxyacetophenone, methoxy or hydroxy groups
did not direct chlorination to the ring position and effectively
chlorinated at the side chain (Table 2, Entries 5 and 6).
1-Tetralone (non-methyl ketone) also reacted smoothly and
yielded the respective ¡-chlorinated product in near quantitative
yield (96%) in 7h under similar conditions (Table 2, Entry 16). In
the case of 5-methoxy-1-tetralone, activation of the aromatic ring
with methoxy substituent did not interfere with the regioselec-
tivity of the chlorination and ¡-chlorination was achieved in
moderate yield (53%) even after 24 h (Table 2, Entry 17).
We next explored the scope of the present method by
treating aliphatic ketones under the present reaction conditions.
As can be seen from Table 3, 4-methyl-2-pentanone was
selectively chlorinated at the 1-position to afford 1-chloro-4-
methyl-2-pentanone in 89% yield (Table 3, Entry 1), whereas,
2-nonanone and 3-octanone produced a regioisomeric mixture of
monochlorinated products (Table 3, Entries 2 and 3).
Entry
1
Substrate Time/h
Product
Yield/%b
O
O
Cl
9
97
1a
O
O
O
Cl
15
2
3
96
85
1b
O
11
Cl
1c
O
O
O
Cl
9
4
5
94
82
1d
O
7
Cl
1e
O
O
O
O
O
Cl
24
6
7
8
9
76
1f
OH
O
OH
20 (40)d
84
22
Cl
5c
Br
O
1g
Br
O
43 (29)d
98
24
Cl
3c
1h
Br
Br
O
65 (10)d
98
O
24
1.4c
Cl
Br
1i
Br
O
O
Cl
33 (39)d
84
48
10
11
12
13
14
15
16
17
1j
Cl
O
10c
Cl
O
Cl
43 (20)d
98
48
6c
1k
Cl
Cl
O
O
46 (31)d
98
Cl
48
5c
F
O
1l
Further, we investigated the efficiency of the method with
1,3-dicarbonyl compounds. In recent years, chlorination at the
2-position of 1,3-dicarbonyl compounds received much attention
because of versatile utilities of 2-chloro-1,3-dicarbonyl com-
pounds in organic synthesis.29 As highlighted in Table 3,
2-unsubstituted and 2-substituted 1,3-keto esters were converted
to their corresponding 2-chloro products in high yields using this
procedure. In some cases dichlorination was also observed.
In a blank experiment, reaction was performed with
acetophenone and NH4Cl in the absence of Oxone under similar
reaction conditions and the reaction did not succeed. Thus, the
role played by the Oxone (oxidant) was justified. We propose a
plausible reaction mechanism for the ¡-chlorination of ketones
F
O
Cl
48
48
24
7
85
F
1m
F
O
O
Cl
19 (29)d
90
1n
NO2
NO2
O
O
Cl
1o
O
O
Cl
1p
96
O
O
Cl
¹
is shown in Scheme 1. It is assumed that Oxone oxidizes the Cl
24
53
1q
(NH4Cl) to Cl+ (HOCl),30 which further reacts with enol form of
ketone to afford the corresponding ¡-chlorinated product.
In summary, we have presented a novel and efficient
approach for the ¡-chlorination of various ketones and 1,3-
dicarbonyl compounds using NH4Cl/Oxone in MeOH. The
present protocol is more attractive than the earlier methods,
offers additional advantages such as commercial availability of
the reagents, high yields, formation of cleaner products, mild
reaction conditions, no evolution of hydrogen chloride, and
O
O
aSubstrate (2 mmol), NH4Cl (2.2 mmol), Oxone (2.2 mmol),
methanol (10 mL), room temperature. bThe products were
c
characterized by NMR, mass spectra and quantified by GC. At
d
reflux temperature. ¡-Chlorodimethyl ketal.
Chem. Lett. 2012, 41, 432-434
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

434
References and Notes
1
Table 3. ¡-Chlorination of aliphatic ketones and 1,3-dicarbonyl
compounds using NH4Cl and Oxonea
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Entry
Substrate
Time/h
Product (Yield/%)b
O
O
Cl
1
2
9.3
3.3
(89) 2a
O
O
C6H13
C6H13
C6H13
Cl
(46) 2b
(37) 2c
O
O
O
O
2
Cl
Cl
O
3
7.4
3
4
5
C4H9
C4H9
C4H9
(61) 2d
(38) 2e
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O
O
8
9
Ph
Ph
O
4
5
6
5
5
6
(95) 2f
(94) 2g
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Ph
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O
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O
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Ph
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(66) 2h
(12) 2i
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27 General procedure for the chlorination of carbonyl compounds:
Oxone (2.2 mmol) was slowly added to a well stirred solution of
NH4Cl (2.2 mmol) and carbonyl compound (2 mmol) in methanol.
Then the reaction mixture was allowed to stir at room temperature,
until carbonyl compound completely disappeared (monitored by TLC)
or an appropriate time. Upon the completion of reaction, the mixture
was filtered, solvent was removed under reduced pressure and ethyl
acetate (20 mL) was added to the residue. The ethyl acetate solution
was washed with water (2 © 30 mL) and organic layer was dried over
Na2SO4. After evaporation of the solvent the residue was purified by
column chromatography using silica gel (230-400 mesh) to give pure
¡-chlorinated products.
Cl
O
O
O
O
O
O
Cl
Cl
O
O
O
EtO
OEt (10) 2j
7
24
EtO
OEt
Cl
O
(45) 2k
(80) 2l
(92) 2m
EtO
OEt
Cl Cl
O
O
O
O
O
O
O
Cl
O
O
8
9
4
O
O
O
Ph
Cl
10
Ph
aSubstrate (2 mmol), NH4Cl (2.2 mmol), Oxone (2.2 mmol),
methanol (10 mL), room temperature. bThe products were
characterized by NMR, mass spectra and quantified by GC.
HSO5- + Cl-
OH
HO-Cl+ + SO4
H
2-
OH-
O+
Cl
R
HO-Cl+
R
- H2O
O
O
Cl
R
R
Scheme 1. Plausible reaction mechanism.
28 Supporting Information is available electronically on the CSJ-Journal
Web site, http://www.csj.jp/journals/chem-lett/index.html.
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65, 6069. c) Y. Hayashi, S. Orikasa, K. Tanaka, K. Kanoh, Y. Kiso,
J. Org. Chem. 2000, 65, 8402.
environmentally friendly nature. Hence it offers useful alter-
native to the existing methods.
P. S. thanks the UGC, India, M. A. K. and M. M. R. thanks
the CSIR, India for the financial support.
30 R. E. Montgomery, J. Am. Chem. Soc. 1974, 96, 7820.
Chem. Lett. 2012, 41, 432-434
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/