H2O2/HCl system: Oxidation-chlorination of secondary alcohols to α,α′-dichloro ketones

Article abstract of DOI:10.1016/j.tetlet.2020.152154

The one-pot oxidation-chlorination of secondary alcohols to give α,α′-dichloro ketones in 62–80percent yields is reported. The convenient and readily available H₂O₂/HCl system acts on secondary alcohols (C₅-C₁₇) with the formation of α,α′-dichloro ketones. The reaction proceeds with high selectivity under the reported conditions; during this process peroxide formation and the Baeyer-Villiger oxidation reactions are not observed.

Full text of DOI:10.1016/j.tetlet.2020.152154

Journal Pre-proofs
H2O2/HCl system: oxidation-chlorination of secondary alcohols to α,α'-di‐
chloro ketones
Gennady I. Nikishin, Nadezhda I. Kapustina, Lyubov' L. Sokova, Oleg V.
Bityukov, Alexander O. Terent'ev
PII:
S0040-4039(20)30614-6
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152154
TETL 152154
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 April 2020
29 May 2020
16 June 2020
Please cite this article as: Nikishin, G.I., Kapustina, N.I., Sokova, L.L., Bityukov, O.V., Terent'ev, A.O.,
H2O2/HCl system: oxidation-chlorination of secondary alcohols to α,α'-dichloro ketones, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152154
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H2O2/HCl system: oxidation-chlorination of secondary
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alcohols to α,α'-dichloro ketones.
Gennady I. Nikishin, Nadezhda I. Kapustina, Lubov’ L. Sokova, Oleg V. Bityukov, Alexander O. Terent’ev

1
Tetrahedron Letters
H2O2/HCl system: oxidation-chlorination of secondary alcohols to α,α'-dichloro
ketones
Gennady I. Nikishina, Nadezhda I. Kapustinaa, Lyubov’ L. Sokovaa, Oleg V. Bityukova and Alexander O.
Terent’eva,b,
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow, 119991, Russian Federation
b All Russian Research Institute for Phytopathology, B. Vyazyomy, Moscow, 143050, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The one-pot oxidation-chlorination of secondary alcohols to give α,α'-dichloro ketones in 62-
80% yield is reported. The convenient and readily available H2O2/HCl system acts on secondary
alcohols (С5-С17) with the formation of α,α'-dichloro ketones. The reaction proceeds with high
selectivity under the reported conditions; during this process peroxide formation and the
Baeyer-Villiger oxidation reactions are not observed.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
α,α'-Dichloro ketones
Secondary alcohols
Oxidation
Chlorination
Hydrogen peroxide
1. Introduction
α,α'-Dichloro ketones have only been synthesized by the
reaction of chlorination of ketones with chlorine23,24 and sulfuryl
The H2O2-HCl(aq) system is used as a chlorinating reagent in
reactions with olefins,1 ketones,2 arenes,3-6 and oximes7 or as an
oxidizing agent for the formation of anthraquinone from
anthracene8 and imidazoles from aldehydes and diamines.9,10 In
this work, we have combined the unique capabilities of the H2O2-
HCl(aq) system for the one-pot oxidation-chlorination of
secondary alcohols to give α,α'-dichloro ketones. This approach
expands the available range of α,α'-dichloro ketones and makes
them more accessible for subsequent transformations.
chloride25 (Scheme 1). α,α'-Dichloro ketones can be transformed
into the corresponding silyl ethers22,49 and oxabicyclanes50
through their reaction with furan. In contrast to α-chloro ketones,
the synthesis of α,α-dichloro ketones has been demonstrated on
only a few examples.
This paper describes the synthesis of α,α'-dichloro ketones by
the one-pot oxidation-chlorination of secondary alcohols with
H2O2-HCl(aq) (Scheme 1). The process is more experimentally
simple, less expensive, and better complies with green chemistry
standards in comparison with the sole method proposed for the
similar transformation based on the chlorination of ketones with
chlorine and sulfuryl chloride (Scheme 1).
Chloro ketones are versatile reagents, which can be
transformed into unsaturated ketones and ketones containing
various functional groups.11-13 Favorskii rearrangement of α-
chloro ketones leads to the formation of esters.14 Condensation of
α-chloro ketones with thiourea leads to the formation of
aminothiazoles,15 with S4N6 - thiadiazoles,16 with indoles - α-
indol carbonyl compounds.17 α,α-Dichloroalkylaryl ketones can
be converted to α-chloro epoxides,18,19 arylglyoxals,20
benzoxazoles,21 and silyl ethers.22 The syntheses of α-chloro
ketones and α,α-dichloro ketones are mainly based on the
chlorination of ketones with chlorine,23,24 sulfuryl chloride,25
thionyl chloride,26-30 methyl chlorosulphate,31 FeCl3/Ox,32,33
CuCl2,34 AlCl3/O2/Cat,35 AlCl3/H2O,36 NH4Cl/Oxone®,37
NH4Cl/Mn(OAc)3,38
NH4Cl/1,3-dichloro-5,5-
dimethylhidantion,39 NCS/SiCl4,40 trichloroisocyanuric acid
(TCCA),41 and H2O2/HCl.2 α-Chloroalkylaryl ketones have been
prepared from alkylaryl carbinols using m-CPBA/HCl,42 NCS,43-
45 p-TosNCl2,46 and TCCA.47,48
Scheme 1. Approaches to the synthesis of α,α'-dichloro ketones.
———
 Corresponding author. Tel.: +7-916-385-4080; e-mail: terentev@ioc.ac.ru

2
Tetrahedron
It is important to note that under our reaction conditions we
Scheme 2. Main stages of the process involving oxidants.
did not detect the formation of traditional Baeyer-Villiger
oxidation products51-53 or the expected peroxides,54,55 which could
form as products of the reaction between the carbonyl group and
hydrogen peroxide (Scheme 1).
Decreasing the reaction temperature to 40 °C reduced the
conversion of alcohol 1a and the yield of α,α'-dichloro ketone 2a
(Entry 6). When using other solvents (THF, MeOH, 1,2-DCE)
the reaction of 1a proceeded with low conversion and less
selectively; α,α'-dichloro ketone 2a and α-chloro ketone 3a were
obtained in comparable amounts (Entries 11-13).
2. Results and Discussion
Initially, the influence of molar ratio of the starting reagents
and solvent type on the yields of α,α'-dichloro ketone 2a and α-
chloro ketone 3a was determined using 3-pentanol 1a as a model
compound. The reaction was carried out by the addition of a 35%
aqueous solution of H2O2 in acetonitrile to a solution of 3-
pentanol 1a and 37% HCl(aq) in acetonitrile, and stirring for 6-
10 hours (Table 1).
Results of the optimization (Table 1) demonstrate that the
reaction direction is mainly influenced by the molar ratio of the
secondary alcohol, hydrogen peroxide, and hydrochloric acid.
From the results of Table 1 we can conclude that 3-pentanone
formed as an intermediate during the oxidation of alcohol 1a, and
that α-chloro ketone 3a generated in the next step reacted with
H2O2-HCl(aq) faster than the starting alcohol 1a. In the cases
with incomplete conversion of 1a in CH3CN only α,α'-dichloro
ketone 2a and α-chloro ketone 3a were formed, and 3-pentanone
formation was not observed.
Table 1. Oxidation-chlorination of 1a with the H2O2-HCl(aq)
system.a
Using the optimized reaction conditions in hand (Entry 10), a
number of α,α'-dichloro ketones 2a-l were prepared (Table 2).
Alcohols 1a-i with unbranched structures were readily converted
into α,α'-dichloro ketones 2a-i with good yields. From the
branched alcohols 1j-l, the corresponding α,α'-dichloro ketones
2j-l were also successfully obtained.
Molar ratio:
Yield (%)
τ
Conv.
of 1a
(%)
Entry
Solvent
mole
HCl/mole
1a
mole
H2O2/mole
1a
(h)
2a
3a
Table 2. Oxidation-chlorination of secondary alcohols 1a-l using
the H2O2-HCl(aq) system to give α,α'-dichloro ketones 2a-l.a
1
2
1.4
10
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
10
10
10
10
6
36
80
75
81
80
47
41
95
95
99
64
32
29
12
61
18
11
2
3
4
4
4
4
6
8
8
6
6
6
10
10
10
10
10
5
3
67 trace
69 trace
4
5
6b
61
29
13
13
6
CH3CN
CH3CN
7
10
10
10
10
10
10
32 trace
80 trace
83 trace
8
10
10
15
10
10
10
CH3CN
CH3CN
CH3CN
THF
2c, 77% (69%)b
dr 1:1
2a, 87% (80%)b
dr > 20:1
2b, 81% (72%)b
dr > 20:1
9
10
11
12
13
a
87
40
11
11
-
21
14
13
MeOH
1,2-DCE 10
2f, 73% (64%)b
dr > 20:1
2d, 75% (68%)b
dr > 20:1
2e, 72% (64%)b
dr 1:3
General procedure: a solution of H2O2 (35% aqueous, 5-15 mmol, 0.43-
1.29 mL) in solvent (1 mL) was added portionwise (0.2-0.3 mL) during 6-10
h to a vigorously stirred solution of alcohol 1a (1 mmol, 88.2 mg) and HCl
(37% aqueous, 1.4-8 mmol, 0.14-0.79 mg) in solvent (1 mL) at 65 °C.
Yields were determined by GC analysis with octan-4-one as the internal
standard. b40 °C.
2g, 74% (66%)b
dr > 20:1
2h, 72% (65%)b
dr > 20:1
2i, 70% (62%)b
dr > 20:1
According to the obtained data, the highest yield of α,α'-
dichloro ketone 2a was achieved using a 15-fold molar excess of
H2O2 and 8 equivalents of HCl (Entry 10). Decreasing the
amount of HCl from 1.4 to 6 equivalents (Entries 1-4, 8) and
H2O2 to 5-10 equivalents (Entries 1-9) reduced the yield of 2a.
2j, 75% (69%)b
dr 1:1.5
2k, 77% (68%)b
dr > 20:1
The formation of positive chlorine species (Cl2, HOCl) is a
complex and multistep process. The main stages of the process
are represented in Scheme 2. Presumably an excess of hydrogen
peroxide is necessary since it is consumed in the side reaction
with chlorine resulting in hydrochloric acid and oxygen
formation.
2l, 75% (67%)b
a General procedure: a solution of H2O2 (35% aqueous, 15 mmol, 1.29 mL)
in CH3CN (1 mL) was added portionwise (0.2-0.3 mL) during 10 h to a
vigorously stirred solution of alcohol 1a-l (1 mmol, 88.2-256.5 mg) and HCl
(37% aqueous, 8 mmol, 0.79 mg) in CH3CN (1 mL) at 65 °C. Yields were
determined by GC analysis with octan-4-one as the internal standard. The
diastereomeric ratio (dr) was determined by 1H NMR spectroscopic analysis.
bIsolated yields.

3
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This work was supported by the Russian Science Foundation
(grant № 18-13-00027).
Supplementary Material
Supplementary data (experimental procedures, spectroscopic
data for all of the synthesized compounds) associated with this
article can be found, in the online version, at http://........
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4
Tetrahedron
Highlights
Synthesis of α,α'-dichloro ketones from secondary
alcohols
The H2O2/HCl system for safe and technological
oxidation-chlorination
Oxidation-chlorination without external free
chlorine