Efficient α-chlorination of carbonyl containing compounds under basic conditions using methyl chlorosulfate

Article abstract of DOI:10.1016/j.tetlet.2018.02.036

An efficient method for the α-chlorination of ketones under basic conditions is described using methyl chlorosulfate. Its applicability for the chlorination of other functional groups has also been studied and it is equally useful for the synthesis of α-chloroesters and amides. Methyl chlorosulfate is described for the first time as a positive chlorine source. Some aldol reactions which occur during the chlorination of some substrates are also reported.

Full text of DOI:10.1016/j.tetlet.2018.02.036

Accepted Manuscript
Efficient α-chlorination of carbonyl containing compounds under basic condi-
tions using methyl chlorosulfate.
Saúl Silva, Christopher Maycock
PII:
S0040-4039(18)30224-7
https://doi.org/10.1016/j.tetlet.2018.02.036
TETL 49721
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 January 2018
12 February 2018
14 February 2018
Please cite this article as: Silva, S., Maycock, C., Efficient α-chlorination of carbonyl containing compounds under
basic conditions using methyl chlorosulfate., Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.02.036
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Efficient α-chlorination of carbonyl containing compounds under basic conditions
using methyl chlorosulfate.
Saúl Silvaa and Christopher Maycocka, b, *
a
– António Xavier, Universidade Nova de Lisboa, Av. da República, 2780-157 Oeiras,
Portugal
b
, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa,
Portugal
 Corresponding author.
e-mail: maycock@itqb.unl.pt
Abstract
An efficient method for the α-chlorination of ketones under basic conditions is
described using methyl chlorosulfate. Its applicability for the chlorination of other functional
groups has also been studied and it is equally useful for the synthesis of α-chloroesters and
amides. Methyl chlorosulfate is described for the first time as a positive chlorine source. Some
aldol reactions which occur during the chlorination of some substrates are also reported.
Keywords:
chlorination; halogenation; methyl chlorosulfate; chloroketone; chloroester; chloroamide.
Introduction
Halogenation at the alpha position of carbonyl containing compounds is a classical
method for the introduction of several functional groups in organic chemistry. It is widely used
in synthesis for transformations both in academia and in industry and is particularly useful in
heterocycle generation.1 New methods for the halogenation of carbonylic compounds are still
being developed,2 as the search for more efficient, selective, economical or greener solutions
is essential for improved industrial processes. While the use of acid catalyzed methods has
been extensively explored, methods under basic conditions have been less studied since
polyhalogenation can be difficult to avoid.
Brummond and Gesenberg3 described the chlorination of the lithium enolates of
ketones using sulfonyl chlorides as chlorinating reagents (Scheme 1). This constitutes a good
alternative for the chlorination of acid sensitive molecules, and has been reported using tosyl,
benzenesulfonyl, mesyl and triflic chlorides as a chlorine source.4 Although this is a very useful
method, there is still space for reaction yield improvement. In our experience, the
chromatographic purification of this type of compound often leads to product loss by
hydrolysis. Hence the development of a cleaner process without the need for chromatography
should lead to improved yields.
Scheme 1. Chlorination of ketone lithium enolates with alkyl and arylsulfonyl chlorides.
In the present work, we report the use of methyl chlorosulfate as an improved α-
chlorinating reagent for ketones under basic conditions; its use for the chlorination of other
1

carbonyl-containing functional groups was also studied. To the best of our knowledge this is
the first report of the use of an alkyl chlorosulfate for this purpose.
Results and Discussion
Methyl chlorosulfate can be readily prepared5 by reacting sulfuryl chloride with one
equivalent of methanol and has been used as sulfating6 and methylating7 reagent. Under
neutral conditions its reaction with camphor has been described8 as producing methyl
camphor-3-sulfonate. Consequently, the reaction of ketones with methyl chlorosulfate under
basic conditions would be expected to form the respective methyl α-sulfonates, however it
was found that the α-chloroketones were formed instead (Scheme 2). Unlike chlorosulfonates,
alkyl chlorosulfates have never been described as electrophilic chlorine sources.
Scheme 2. Reaction of ketones with methyl chlorosulfate under basic conditions and possible sulfated and
methylated products.
A range of ketones was submitted to the chlorination conditions (Table 1) and α-
chlorinated products were normally obtained in quantitative yields with the exception of small
volatile molecules (2a, 2b and 2f; entries 1, 2, 6). This relatively clean reaction typically
required no further purification after a simple aqueous wash as work-up. A preparation of 2f
(Entry 6) under basic conditions has been described by Brummond and Gesenberg3 using tosyl
chloride and is the only reported route to this compound. Other chlorination methods would
probably result in chlorination occurring at other positions on the highly functionalised
cyclohexene ring. The reaction worked very well with an α-disubstituted ketone and
chloroketone 2g (Entry 7), having an α-quaternary carbon was formed. Chlorination of 1-
methylcyclohexanone 1i was regioselective (Entry 9), as expected, and only the product 2i
from reaction of the kinetic enolate was obtained. Chlorination of a protected hydroxy
azabicyclo-[4.1.0]-ketone9 1l (Entry 12) produced 2l in good yield; this result shows the
versatility of this method regarding the presence of other functional groups. Aziridine rings are
very sensitive to acidic conditions and it would probably be difficult to perform this
transformation using classical methods. The stereoselectivity observed for the formation 2l is
also interesting since it was obtained as a single diastereomer while other asymmetric
products (2i-k and 2m, entries 9-11 and 13) were obtained as mixtures. Reaction with camphor
under these conditions resulted in a mixture of endo- and exo- chlorinated products 2m.
2

Table 1. α-Chlorination of ketones.
Entry
1
Substrate
Product
Yield (%)
81%
2
3
75%
Quant.
4
Quant.
5
6
7
8
9
Quant.
91%
Quant.
Quant.
Quant.
(38:62a
cis:trans)
3

Quant.
(77:23a
cis:trans)
10
11
12
Quant.
(78:22a
cis:trans)
Quant.
Quant.
(87:13a
exo:endo)
13
14
82%b
a Diastereomeric ratio calculated by 1H NMR spectroscopy. b Yield after chromatographic purification. c Reagents
and conditions: ketone 1 (1 mmol), LDA (1.1 equiv.), MeOSO2Cl (1.1 equiv.), THF (4 mL), -78 °C, 30 min.
When this method was applied to acetophenone (Table 1, entry 14), aldol product 2n
was obtained in 82% yield. Apparently after initial chlorination to form chloroacetophenone
the aldol addition of acetophenone enolate occurs faster than the chlorination (Scheme 3).
Methyl ketones seem to be a substrate limitation of this method. This limitation was also
observed by Brummond and Gesenberg but only decomposition of starting material was
reported, however, the chlorine atom seems to have an important role in the aldol reaction
(ESI, Table 1). This reactivity is expected since the carbonyl of the chloroacetophenone is more
electrophilic and the alkoxide of 2n more stable.
Scheme 3. Formation of 2n by reaction of the acetophenone lithium enolate with 2-chloroacetophenone.
4

Other substrates have been subjected to the same conditions (Table 2 and Table 3). In
the case of aldehyde 3a (Table 2, entry 1) and nitro compound 3m (Table 3, entry 2) no
reaction occurred and all of the starting material was recovered. Some esters (3b-d, Table 2,
entries 2-4), were also tested; in the case of esters 3b and 3d the reaction took place but it was
not complete and some starting material was recovered. More equivalents of base and
reagent were used during attempts to increase the conversion of 3b but no difference was
observed. For the less hindered ester 3c (Entry 3) chlorinated 4c’ and non-chlorinated 4c’’
Claisen condensation products were formed. Amides were also tested (3e-g, entries 5-7) and
chloroamides 4e and 4g were produced in good yield. In the case of less hindered acetamide 3f
(Entry 6) the chlorinated Claisen condensation product 5k was the main product obtained. The
chlorination of 1,3-dicarbonyl compounds (3h-k, entries 8-11) resulted in low conversions and
in the case of ethyl acetoacetate 3i no reaction occurred. Applying the same conditions to
phenylacetonitrile 3l (Table 3, entry 1), dimer 4l and starting material were obtained as major
products. Using two equivalents of base and methylchlorosulfate lead to the complete
conversion of 3l and a higher yield of 4l. Interestingly, formation of 4l was stereoselective and
only one diastereomer was obtained. The formation of 4l during the reaction of 3l with thionyl
chloride under acidic conditions has already been reported.10
Table 2. α-Chlorination of aldehydes, esters and amides.
Entry
1
Substrate
Product
No reaction (only SM recovered).
2
3
4
5
6
7
5

8
9
No reaction (only SM recovered).
10
11
aYield after purification by chromatography. b Reagents and conditions: 3 (1 mmol), LDA (1.1 equiv.), MeOSO2Cl (1.1
equiv.), THF (4 mL), -78 °C, 30 min.
Table 3. Chlorination of other functional groups.
Entry
1
Substrate
Product
No reaction (only SM
recovered).c
2
aYield after purification by chromatography. b Reagents and conditions: 3l (1 mmol), LDA (2.2 equiv.), MeOSO2Cl (2.2
equiv.), THF (4 mL), -78 °C, 30 min. c Reagents and conditions: 3m (1 mmol), LDA (1.1 equiv.), MeOSO2Cl (1.1 equiv.),
THF (4 mL), -78 °C, 30 min.
In general, it appeared that the more stable enolates reacted poorly with the
chlorinating agent (Table 2, entries 9, 10, 11). There were also indications that the chlorinated
carbonyl compounds could undergo aldol or Claisen condensations selectively by reacting with
unchlorinated enolates (Table 2, entries 3 and 6). The lithium dianions of 3-keto esters (3i-j)
and amide (3k) reacted with methyl chlorosulfate (Table 4); in all cases 4-chlorination occurred
cleanly and products 5i-k were obtained in good yield.
Table 4. 4-chlorination of 1,3-dicarbonyl compounds.
Entry
1
Substrate
Product
6

2
3
a Reagents and conditions: 3 (1 mmol), LDA (2.2 equiv.), MeOSO2Cl (1.2 equiv.), THF (4 mL), -78 °C, 30 min.
Conclusion
A simple and efficient method for the α-chlorination of ketones and other carbonyl
functional groups under basic conditions is described. This method is useful for acid sensitive
substrates (e.g. Table 1, entry 12) or the regioselective chlorination of enolates (e.g. Table 1,
entry 9), since most of the reported methods are acid catalyzed. To the best of our knowledge,
this is the first time an alkyl chlorosulfate has been described as a chlorinating reagent. Methyl
chlorosulfate is an inexpensive and easily preparable reagent and was found to have a better
performance when compared to alkyl and aryl chlorosulfonates. Also, the reaction is very clean
and affords quantitative yields; for these reasons it represents a very practical procedure. This
method works particularly well with ketones but can also be applied to esters and amides. It is
useful in the preparation 4-chloro-1,3-dicarbonyl compounds via chlorination of the lithium
dianion.
Acknowlegements
S. Silva thanks the FCT - Fundação para a Ciência e Tecnologia for the grant
SFRH/BD/84309/2012. This work was financially supported by: Project LISBOA-01-0145-FEDER-
007660 (Microbiologia Molecular, Estrutural e Celular) funded by FEDER funds through
COMPETE2020 - Programa Operacional Competitividade e nternacionali a o and y
na onal funds throu h - unda o para a i ncia e a ecnolo ia. The NMR data was
acquired at CERMAX, ITQB-NOVA, Oeiras, Portugal with equipment funded by FCT - Fundação
para a Ciência e Tecnologia, project AAC 01/SAICT/2016.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
https://doi.org/10.1016/j.tetlet.2018.xx.xxx.
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- A clean and efficient method for the alfa chlorination of carbonyl compounds via the enolate
- First use of readily available methyl chlorosulfate as a chlorinating agent
- Can be used with a wide range of substrates
- Chlorination of acid sensitive substrates
9

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