Dichloromethane as a chlorination reagent for α-bromocarbonyl compounds in the presence of a copper catalyst

Article abstract of DOI:10.1246/cl.170062

We found that dichloromethane is a powerful chlorinating reagent for the congested 3° and 2° Csp³Br bond of α-bromocarbonyl amides, esters, and ketones. In the presence of an appropriate copper complex as a catalyst, the desired chlorination occurred within an hour. Control experiments revealed that in situ-generated CuCl₂ is a key chlorinating agent that reacts with the 3° or 2° alkyl radicals generated by the reaction between an α-bromocarbonyl compound and a Cu(I) salt.

Full text of DOI:10.1246/cl.170062

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Dichloromethane as a Chlorination Reagent for α-Bromocarbonyl Compounds in the
Presence of a Copper Catalyst
Kentaro Takeuchi, Syo Ishida, and Takashi Nishikata*
Advance Publication on the web February 16, 2017
doi:10.1246/cl.170062
© 2017 The Chemical Society of Japan
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1
Dichloromethane as a Chlorination Reagent for α-Bromocarbonyl Compounds in the Presence
of a Copper Catalyst
Kentaro Takeuchi, Syo Ishida and Takashi Nishikata*
Graduate School of Science and Engineering, Yamaguchi University 2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan
E-mail: nisikata@yamaguchi-u.ac.jp
We found that dichloromethane is a powerful
chlorination of aromatic hydrocarbons using a
methane–dichloromethane flame11. Herein, we report
an unprecedented methodology for the construction
of 3° Csp3–Cl bonds using CH2Cl2 as the chlorinating
reagent in the presence of a copper catalyst.
chlorinating reagent for the congested 3° and 2°Csp3–Br
bond of α-bromocarbonyl amides, esters, and ketones. In
the presence of a proper copper complex as a catalyst, the
desired chlorination occurred within an hour. Control
experiments revealed that in situ generated CuCl2 is a key
chlorinating reagent that reacts with the 3° or 2° alkyl
radicals generated by the reaction between an α-
bromocarbonyl compound and a Cu(I) salt.
Keywords: chlorination, dichloromethane, copper
The 3° Csp3–Cl bond is a very important fragment
which can be seen in various bioactive compounds
such as napyradiomycin A1, halomon, intricatetraol,
laurencial, and gomerone C (Scheme 1)1. Despite its
importance, the synthetic methodology for the
construction of 3° Csp3–Cl bonds is limited to the
bromochlorination of allylic alcohol with titanium
chloride1b, iridium-catalyzed chlorination of alcohol
with chlorosilanes2, and halogen exchange reaction
Scheme 1. Chlorinated compounds having 3° Csp3–Cl
bonds
For optimization studies,
a
combination of -
3
4
bromocarbonyl compound 1 and a Cl source was
employed in the presence of a Cu salt (10 mol%) and
amine (1 equiv) at 100 °C for 1 h (Table 1). The
effectiveness of the various Cu salts was initially tested,
and Cu salts possessing various counter anions showed
excellent reactivities (Table 1, runs 1–4). According to
our previous works10, we hypothesized that this reaction
involved radical reactions. Therefore, to generate a radical
from 1, Cu(I) (not Cu(II)) must react with 1 via a single-
electron transfer12. However, [Cu(H2O)6](BF4)2 and CuCl2
(Cu(II)) reacted smoothly with 1 to generate the
corresponding chlorinated compound 2 in 90% yield,
which is likely produced by the reduction of Cu(II) to
Cu(I) in the presence of amine (Run 3)13. In this reaction,
amines act as a ligand for copper to generate active
with BiCl3 or SnCl4 . These limitations may be
attributed to the absence of proper chlorinating
reagents. In the synthesis of primary- and secondary-
alkyl chlorides, N-chlorosuccinimide (NCS), 2,2,6,6-
tetrachlorocyclohexanone5, trichloromethanesulfonyl
chloride6, trichloroquinolinone7, alkali chloride8, and
ammonium chloride9 are useful and reliable
chlorination reagents; however, they are not suitable
for the construction of 3° Csp3–Cl bonds. In this
context, further development of new concepts and
reagents for the synthesis of quaternary carbon
centers bearing chlorine atoms would be greatly
desired.
During the course of our research on quaternary
carbon center construction chemistry using
bromocarbonyl compounds10, we discovered that


-
-
catalysts.
Therefore,
multidentate
N,N,N′,N′,N′′-
pentamethyldiethylenetriamine (PMDETA) was highly
effective compared with Et3N, iPr2NH, and imidazole
(runs 4–7). We also tried to examine various multidentate
ligands such as TPMA (tris(2-pyridylmethyl)amine) and
Phen (1,10-phenanthroline), but they were not effective.
We expected that PMDETA is a ligand for a copper salt.
However, reducing the amount of PMDETA (10 mol%)
decreased the chemical yield of 2. Chlorination occurred
chlorocarbonyl compounds were obtained as side
products when dichloromethane (CH2Cl2) was used
as a solvent. This result indicates that CH2Cl2 can
serve as a good reagent for chlorination of hindered

-carbonyl compounds via a radical reaction.
Although there are many organic chlorination
reagents described above, chlorination with CH2Cl2 is
rare. For instance, the Hites group reported on the

2
with various chlorine sources, including CHCl3, 1,2-
dichloroethane, and 1-chloropropane, although 1-chloro-
2,2-dimethylpropane limited the chlorination activity, and
benzyl chloride, allyl chloride, and chlorobenzene lead to
sluggish chlorination activities (runs 8–14). The amounts
of CH2Cl2 can be reduced under appropriate conditions.
For example, when the reaction was conducted in toluene
with 10 equivalents of CH2Cl2, 80% of 2a was obtained
(run 15). Similarly, 5 equivalents of CH2Cl2 led to 2a with
61% yield.
aliphatic alcohols but our reaction left the alcohol
group intact (2i and 2l
Weinreb amide resulted in the corresponding
chlorinated product in moderate to good yields (2j
)
14. Tertiary amide and
and 2k). Similarly,
possessing various structures provided the desired
products in yields ranging from 49% to 94% (2m 2t).
Although -bromocarbonyl compounds possessing a
2° Csp3–Br bond reacted with CH2Cl2 (2u
2w), the
-bromoesters and ketone
–

–
substrates possessing a 1° Csp3–Br bond were
sluggish (2x and 2y). Overall, our chlorination
approach with CH2Cl2 showed good functional group
tolerances.
Table 1. Optimizationa
Cu
O
O
Table 2. Substrate scopea
Cl source
NHPh
NHPh
Br
Cl
Amine
100 oC, 1 h
1
2
Run
Cu
Amine
Cl source Yield (%)
CuI
PMDETA
PMDETA
PMDETA
83
87
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CuCN
CuCl2
90
3
[Cu(H2O)6](BF4)2 PMDETA
93
4
[Cu(H2O)6](BF4)2
[Cu(H2O)6](BF4)2
Et3N
0
5
iPr2NH
0
6
[Cu(H2O)6](BF4)2 imidazole
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
[Cu(H2O)6](BF4)2 PMDETA
0
7
93
8
Cl
75
9
Cl
Cl
Cl
73
10
11
12
13
14
15b
trace
25
BnCl
trace
trace
80
allylCl
PhCl
aConducted at 100 °C for 1 h with 10 mol% Cu, PMDETA (1 equiv),
CH2Cl2 (as a solvent 0.5 M) and 1 (1 equiv) in a sealed tube. Yields
were isolated. b1.5 equiv of PMDETA was used. c2.0 equiv of PMDETA
was used. d Run for 8 h.
CH2Cl2
aConducted at 100 °C for 1 h with 10 mol% Cu, amine (1 equiv),
Cl source (as a solvent 0.5 M) and (1 equiv) in a sealed tube.
Yields were isolated. b10 equivalents of CH2Cl2 was used in
1
The obtained chlorinated products 2 bearing various
active functional groups were easily converted into a wide
range of derivatives using conventional organic reactions,
including reduction with borane and Horner–Wadsworth–
Emmons reactions (Scheme 2).
toluene.
Under optimized conditions,
-bromoamides, -
esters, and -ketones were chlorinated with CH2Cl2
Next, we conducted the following control experiments
(Equations 1–4 in Scheme 3). Equation 1 is a radical
(Table 2). The chlorination of various
-
bromoamides bearing congested 3° Csp3–Br, Ar–Br,
alkyl–Br, carboxylic acid, alcohol, and amino acid
capture
test
with
2,6-bis(1,1-dimethylethyl)-4-
methylphenol (BHT). This chlorination reaction was
inhibited by the addition of BHT, which indicated that
this reaction involves a radical species. Indeed, we
moieties occurred smoothly (2b–2i). Recently, the
Huy group reported a chlorination approach for

3
obtained 60% yield of alkylated BHT in the reaction of 1a
with BHT. The other chlorine sources used are shown in
Equation 2. When NaCl, KCl, or CsCl was used instead
of organic chlorides,
Scheme 2. Utilities of the chlorinated building blocks
2a was obtained. Similarly, ammonium chlorides were
also effective in the chlorination reaction. These results
show that copper chloride may be an active chlorine
source. Therefore, a stoichiometric amount of CuCl2 was
used instead of organic chlorides as the chlorine source in
the chlorination reaction of 1a15. As the result, the product
2a was obtained in 99% yield. In Equation 3, 1-chloro-3-
phenylpropane was used as a chlorine source to
understand the role of organic chloride in this reaction. As
the result, 9% of 2a, PhCH2CH2CH2NMe2, and enamine
(via Hofmann elimination) were detected with GC-MS.
This result indicated that ammonium chloride is formed as
a chlorine source during the reaction. In Equation 4,
CH2Cl2-PMDETA (ammonium salt) was used as the
chlorine source. We expected that ammonium chloride
may generate from the reaction of CH2Cl2 and
PMDETA.16 We obtained a salt after the reaction; but we
failed to identify ammonium chloride with HRMS17.
Although the structure of the resulting salt was unknown,
a chloriantion reaction of 1a was conducted in the
presence of this salt. As the result, 2a was obtained in
86% yield. Based on the results of control experiments,
chlorine atom of CH2Cl2 can be used after the reaction of
PMDETA to generate an ammonium salt.
Scheme 3. Control experiments
Scheme 4. Proposed mechanism
In conclusion, we established a chlorination approach for
3° or 2° Csp3–Br bonds with CH2Cl2 as a chlorinating
reagent in the presence of a copper catalyst within an hour.
This is an unprecedented example in which simple
organic chlorides exhibit chlorination activity by using a
metal catalyst. The chlorination mechanism is not fully
clear in this communication but further investigations,
including mechanistic studies, are currently underway.
One possibility involving a radical pathway is shown in
Scheme 4. The reaction starts with the generation of alkyl
radical species A from the reaction between CuX and 1.
An evidence of this step is the reaction in the presence of
BHT, as shown in Scheme 3. The intermediate A
subsequently reacts with CuClX (generated from the
reaction of CuBrX with ammonium chloride B) to yield
the desired chlorinated product 218. CH2Cl2 was finally
converted to C in the catalytic cycle.
Financial support was provided by the Program to
Disseminate Tenure Tracking System, MEXT, Japan and the
Grant-in-Aid for Scientific Research for Challenging

4
Exploratory Research and Tosoh Award (SOCJ). We also
thank Mr. Ryo Fujimoto for supplying the starting materials.
Supporting
Information
is
available
on
http://dx.doi.org/10.1246/cl.******.
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