A one-pot method synthesis of α-chloroketone dimethyl acetals

Article abstract of DOI:10.3184/174751913X13794472538108

A new one-pot method has been developed for the direct preparation of α-chloroketone dimethyl acetals from ketones using ammonium chloride as the source of chlorine and potassium monoperoxysulfate as the oxidant in the presence of trimethyl orthoformate in methanol at room temperature. Ketones which have electron-withdrawing groups on the aryl rings gave the corresponding a-chloroketone dimethyl acetals in moderate to good yields.

Full text of DOI:10.3184/174751913X13794472538108

JOURNAL OF CHEMICAL RESEARCH 2013
OCTOBER, 633–635
RESEARCH PAPER 633
A one-pot method synthesis of α-chloroketone dimethyl acetals
Zhou Zhong-shia*, Li Lia and He Xue-hanb
aCollege of Biological and Environmental Sciences, Zhejiang Shuren University, Hangzhou 310015, P. R. China
bZhejiang Institute of Geology and Mineral Resource Laboratory, Hangzhou 310007, P. R. China
A new one-pot method has been developed for the direct preparation of α-chloroketone dimethyl acetals from ketones using
ammonium chloride as the source of chlorine and potassium monoperoxysulfate as the oxidant in the presence of trimethyl
orthoformate in methanol at room temperature. Ketones which have electron-withdrawing groups on the aryl rings gave the
corresponding α-chloroketone dimethyl acetals in moderate to good yields.
Keywords: α-chloroketone dimethyl acetal, one-pot synthesis
α-Chloroketones are versatile intermediates in organic
synthesis which react with large number of nucleophiles
to provide a variety of useful compounds.1 The synthesis
of α-chloroketones from ketones has received considerable
attention.2−10 Recently, we have investigated the new procedure
for direct α-chlorination of ketones with ammonium chloride
(NH4Cl) and potassium monoperoxysulfate (Oxone®), and
found that this method was suitable for the aryl ketones which
have electron-donating groups on the benzene ring. It gave
the corresponding α-chloroketones in good yields. However,
those having electron-withdrawing groups on the benzene
ring, gave poor yields for the corresponding α-chloroketones
and were usually accompanied by the α-chloroketone dimethyl
acetals.11 Narender’s group has also reported similar results.12
Although the α-chloroketone dimethyl acetals were by-
products, the one-pot route interested us because methods for
the preparation of α-chloroketone dimethyl acetals are rather
limited and usually need chlorination and acetal formation
in two steps using acid as catalysts.13,14 Recently, Zou’s group
have reported a one-pot preparation of α-chloroketone dimethyl
acetals using 1,3-dichloro-5,5-dimethylhydantoin (DCDMH)
as the chlorinating reagent.15 Since α-haloketone dimethyl
acetals are an interesting class of synthetic intermediates
for the preparation of flavour material and other functional
compounds,16,17 the development of a novel, convenient method
for their synthesis is desirable.
4-Nitroacetophenone (1a) was chosen as the model substrate
to investigate the new method for preparation of α-chloroketone
dimethyl acetals. When 1a was treated with Oxone® and NH4Cl
in MeOH at room temperature, a mixture of α-chloro-4-
nitroacetophenone and α-chloro-4-nitroacetophenone dimethyl
acetal (2a) was formed. There is an equilibrium between the
ketone and its ketal, in which we wished to favour the ketals.
In order achieve this, a series of experiments were performed
to determine suitable reaction conditions. The results are
summarised in Table 1.
When 1.0 equiv. of 1a was treated with 1.2 equiv. of Oxone®
and NH4Cl in MeOH at room temperature for 24 h, the reaction
gave the desired product 2a, but, the yields were rather low
(Table 1, entries 1−3). When silica gel (1.0 g) was added and
2.0 equiv. of NH4Cl were used in the reaction, the yield was
only 26% after 24 h. A similar result was obtained when 1.0 g
4A molecular sieve was used to absorb the water (entries 4
and 5) which was produced. When 2.0 equiv. of trimethyl
orthoformate (HC(OMe)3) was added to the reaction, the yield
rose significantly to 65% and the reaction time was shortened
to 2 h. At that time, there was only a trace of α-chloro-4-
nitroacetophenone in the reaction mixture (entries 6, 8–10).
Under the same reaction conditions, KCl or NaCl was not
effective as NH4Cl (entries 11 and 12). However, when the
reaction was carried out in just (HC(OMe)3), only a 12% yield
of 2a was obtained (entry 7).
Having established the optimum conditions, the reaction
of a series of ketones (1) with 1.2 equiv. of Oxone®,
2.0 equiv. of NH4Cl and 2.0 equiv. of (HC(OMe)3) in MeOH
at room temperature was investigated. The corresponding
α-chloroketone dimethyl acetals (2) were obtained (Scheme
1) and the results are summarised in Table 2. Ketones which
have electron-withdrawing groups on the aryl rings usually
afforded the corresponding α-chloroketone dimethyl acetals in
moderate to good yields a short time, while other ketones gave
poor yields.
The proposed mechanism for preparation of α-chloroketone
dimethyl acetals from ketones is shown in Scheme 2.11,12 The
Cl− from NH4Cl is first efficiently oxidised into the MeOCl by
Oxone®. The methoxy enol ether of the ketone then reacts with
the MeOCl to afford the corresponding α-chloro compound,
Table 1 Optimisation for preparation of α-chloro-4-nitroacetophenone
dimethyl acetal from 4-nitroacetophenone
O
OMe
Cl
MeO
MeOH
R.T.
Oxone
NH4Cl +
+
O2N
O2N
Entry
Additive/equiv.
NH4Cl/equiv.
Time/h
Yield/%a
1
2
3
4
5
6
7
8
9
–
–
–
1.2
2.0
5.0
2.0
2.0
2.0
2.0
2.0
2.0
24
24
24
24
24
24
24
12
6
13
32
33
26
28
61
12
62
63
65
54
40
Silica gel (1.0 g)
4A molecular sieve (1.0 g)
HC(OMe)3 (2.0)
b
HC(OMe)3
HC(OMe)3 (2.0)
HC(OMe)3 (2.0)
HC(OMe)3 (2.0)
HC(OMe)3 (2.0)
HC(OMe)3 (2.0)
10
11
12
2.0
2
2
2
NH4Cl (2.0 equiv)
O
OMe
Cl
MeO
KCl (2.0)
NaCl (2.0)
Oxone (1.2 equiv)
R
2
R
1
R
1
HC(OMe)3 (2.0 equiv)
MeOH, r.t
aIsolated yield.
b2 mL HC(OMe)3 was used as solvent.
1
R
2
2
Scheme 1
* Correspondent. E-mail: jieyan871@163.com
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634 JOURNAL OF CHEMICAL RESEARCH 2013
MeOH
OMe
-
+
2-
-
-
MeO Cl + SO
+ H O
2
HSO + Cl
4
5
Me
H
+
O
MeO OMe
Cl
-H
O
MeOH
OMe
Cl
MeO
R
Cl
R
R
R
R
-
+
MeO Cl
MeOH
Scheme 2
Table 2 The result for preparation of α-chloroketone dimethyl acetals
from ketones
NMR (125 MHz, CDCl3): δ 148.3, 140.8, 133.4, 129.0, 123.5, 122.7, 101.3,
49.4, 45.9; ESI-MS, m/z: 247 (Cl37M+), 245 (Cl35M+).
α-Chloro-4-trifluoromethylacetophenone dimethyl acetal (2c):15 Light
yellow oil; IR (film), ν/cm–1: 1389, 1123, 1071, 1000; 1H NMR (500 MHz,
CDCl3): δ 7.24 (s, 4H), 3.75 (s, 2H), 3.27 (s, 6H); 13C NMR (125 MHz,
CDCl3): δ 142.5, 130.5, 128.1. 125.1, 125.0, 101.5, 49.3, 46.2; ESI-MS,
m/z: 270 (Cl37M+), 268 (Cl35M+).
α-Chloro-2-fluoroacetophenone dimethyl acetal (2d):12 Light yellow
oil; IR (film), ν/cm–1: 1389, 1123, 1071, 1000; 1H NMR (500 MHz,
CDCl3): δ 7.24–7.19 (m, 2H), 7.01–6.92 (m, 2H), 3.77 (s, 2H), 3.24 (s, 6H);
13C NMR (125 MHz, CDCl3): δ 161.1, 133.5, 129.6, 126.2, 121.7, 115.4,
98.5, 50.1, 47.1; ESI-MS, m/z: 220 (Cl37M+), 218 (Cl35M+).
α-Chloro-4-chloroacetophenone dimethyl acetal (2e):14 Light yellow
oil; IR (film), ν/cm–1: 1384, 1285, 1123, 1079, 1051; 1H NMR (500 MHz,
CDCl3): δ 7.46 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=8.4 Hz), 3.72 (s, 2H),
3.24 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 138.4, 133.5, 129.9, 126.2,
100.5, 50.3, 47.2; ESI-MS, m/z: 207 (Cl37M+–OMe), 205 (Cl37Cl35M+–
OMe), 203 (Cl35M+–OMe).
α-Chloro-4-bromoacetophenone dimethyl acetal (2f):15 Light yellow
oil; IR (film), ν/cm–1: 1124, 1070, 1051, 1002; 1H NMR (500 MHz,
CDCl3): δ 7.52 (d, 2H, J=8.6 Hz), 7.39 (d, 2H, J=8.6 Hz), 3.72 (s, 2H),
3.23 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 138.1, 131.5, 128.6, 126.1,
101.2, 49.8, 45.9; ESI-MS, m/z: 249 (Br81Cl35M+–OMe), 247 (Br79Cl35M+–
OMe).
α-Chloroketone
Entry
Ketones (1)
dimethyl acetals Time/h Yield/%a
(2)
1
2
3
4
5
6
7
8
9
R1 =p-NO2C6H4, R2 =H 1a
R1 =m-NO2C6H4, R2 =H 1b
R1 =p-CF3C6H4, R2 =H 1c
R1 =o-FC6H4, R2 =H 1d
R1 =p-ClC6H4, R2 =H 1e
R1 =o-BrC6H4, R2 =H 1f
R1 =o-CO2HC6H4, R2 =H 1g
R1 =C6H5, R2 =H 1h
2a
2b
2c
2d
2e
2f
2g
2h
2i
2
2
65
68
75
78
74
71
55
35
10
36
21
5
4
8
12
12
24
24
24
24
R1 =p-MeC6H4, R2 =H 1i
R1 =C6H5, R2 =Me 1j
10
11
2j
2k
R1 =Me, R2 =H 1k
aIsolated yield.
which is finally attacked by MeOH to provide the corresponding
α-chloroketone dimethyl acetal.
In conclusion, we have achieved a novel one-pot procedure
for the direct preparation of α-chloroketone dimethyl acetals
from ketones which have electron-withdrawing groups on aryl
rings. This method does not need acid catalyst and has some
advantages such as mild reaction conditions, simple procedure
and it affords moderate to good yields. Further investigation of
the novel one-pot preparation of α-chloroketone diethyl acetals
will be reported in due course.
2-(2-Chloro-1,1-dimethoxyethyl)benzoic acid (2g): White solid, m.p.
61–62 °C; IR (KBr), ν/cm–1: 3530, 3051, 1185, 1123, 1058, 1043; 1H NMR
(500 MHz, CDCl3): δ 7.90 (d, 1H, J=7.5 Hz), 7.72–7.75 (m, 1H), 7.59–
7.62 (m, 1H), 7.51 (d, 1H, J=7.6 Hz), 3.91 (s, 2H), 3.24 (s, 6H); 13C NMR
(125 MHz, CDCl3): δ 169.4, 135.5, 133.9, 130.2, 128.6, 127.4, 126.9, 103.2,
50.4, 47.1; ESI-MS, m/z: 246 (Cl37M+), 244 (Cl35M+); HR-MS, m/z: calcd
for C11H13O4Cl, 244.0502; found, 244.0484.
Experimental
Melting points were measured with an XT-4 melting point apparatus
and uncorrected. IR spectra were recorded on a Thermo Nicolet 6700
instrument. 1H NMR and 13C NMR spectra were measured on a Bruker
Avance III (500 MHz) spectrometer. Mass spectra were determined
on a Thermo ITQ 1100 mass spectrometer. Ketones. NH4Cl, Oxone®,
(HC(OMe)3) and solvents were commercially available.
1
α-Chloroacetophenone dimethyl acetal (2h):15 Light yellow oil; H
NMR (500 MHz, CDCl3): δ 7.51–7.53 (m, 2H), 7.38–7.41 (m, 3H), 3.76
(s, 2H), 3.26 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 137.4, 128.6, 128.7,
127.9, 127.5, 100.5, 49.4, 45.9; ESI-MS, m/z: 202 (Cl37M+), 200 (Cl35M+).
α-Chloro-4-methylacetophenone dimethyl acetal (2i):15 Light yellow
oil; IR (KBr), ν/cm–1: 1135, 1063, 1009; 1H NMR (500 MHz, CDCl3): δ
7.42 (d, 2H, J=8.4 Hz), 7.24 (d, 2H, J=8.4 Hz), 3.72 (s, 2H), 3.23 (s, 6H),
2.43 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 137.5, 135.5, 129.0, 125.2,
101.6, 49.7, 46.0, 24.1; ESI-MS, m/z: 216 (Cl37M+), 214 (Cl35M+).
α-Chloro-acetone dimethyl acetal (2j):14 Light yellow oil; IR (KBr), ν/
cm–1: 1285, 1123, 1070, 1051; 1H NMR (500 MHz, CDCl3): 3.50 (s, 2H),
3.29 (s, 6H), 1.43 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 103.5, 51.6, 50.1,
20.9; ESI-MS, m/z: 140 (Cl37M+), 138 (Cl35M+).
Synthesis of α-chloroketone dimethyl acetal (2); typical procedure
Ketone 1 (0.5 mmol), Oxone® (0.6 mmol), NH4Cl (1.0 mmol) and
(HC(OMe)3) (1.0 mmol) were added to MeOH (2 mL). The mixture was
stirred at room temperature for 2 h and then the solvent was evaporated
under reduced pressure. H2O (10 mL) were added, the mixture was
extracted with CH2Cl2 (3×5 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified on a silica gel plate using
(4:1 hexane-ethyl acetate) as eluant to give the α-chloroketone dimethyl
acetal 2.
Received 6 July 2013; accepted 6 August 2013
Paper 1302045 doi:10.3184/174751913X13794472538108
Published online: 7 October 2013
α-Chloro-4-nitroacetophenone dimethyl acetal (2a): Light yellow
solid, m.p. 48–50 °C (lit.15 48–49 °C); IR (KBr), ν/cm–1: 1530, 1351, 1285,
1123, 1070, 1051; H NMR (500 MHz, CDCl3): δ 8.26 (dd, 2H, J= 7.0,
1
1.9 Hz), 7.72 (dd, 2H, J=7.0, 1.9 Hz), 3.75 (s, 2H), 3.27 (s, 6H); 13C NMR
(125 MHz, CDCl3): δ 148.1, 145.5, 128.6, 123.2, 101.5, 49.4, 45.9; ESI-
MS, m/z: 247 (Cl37M+), 245 (Cl35M+).
α-Chloro-3-nitroacetophenone dimethyl acetal (2b): Light yellow
solid, m.p. 49–51 °C (lit.15 51–52 °C); IR (KBr), ν/cm–1: 1530, 1351, 1125,
1095, 1053; 1H NMR (500 MHz, CDCl3): δ 8.40 (s, 1H), 8.22–8.25 (m,
1H), 7.86–7.88 (m, 1H), 7.58–7.60 (m, 1H), 3.76 (s, 2H), 3.27 (s, 6H); 13C
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