A novel β-(oxy)alkyl radical during copper(I)-mediated stereoselective synthesis of (Z)-ene-1,4-diones in a reaction of 2,2,2-trichloro-1-phenylethanone

Article abstract of DOI:10.1016/j.tetlet.2016.04.080

A novel β-(oxy)alkyl radical derived from trichloro methyl compound containing neither a suitably located C-C multiple bond nor a leaving group or a H-atom at the β-position of the radical in a reaction of 2,2,2-trichloro-1-phenyl-ethanone with 2 mol equiv each of CuCl and bpy in refluxing DCE under a N₂ atm underwent intramolecular heterolysis (just like formation of intact radical cation-anion pair) during stereoselective radical dimerization to Z-ene-1,4-dione along with small amount of reductive dechlorination product. The stereochemistry was established by X-ray diffraction spectroscopy of various solid crystalline products.

Full text of DOI:10.1016/j.tetlet.2016.04.080

Tetrahedron Letters 57 (2016) 2437–2440
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel b-(oxy)alkyl radical during copper(I)-mediated
stereoselective synthesis of (Z)-ene-1,4-diones in a reaction
of 2,2,2-trichloro-1-phenylethanone
⇑
Ram N. Ram, Ram K. Tittal
Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel b-(oxy)alkyl radical derived from trichloro methyl compound containing neither a suitably
located C–C multiple bond nor a leaving group or a H-atom at the b-position of the radical in a reaction
of 2,2,2-trichloro-1-phenyl-ethanone with 2 mol equiv each of CuCl and bpy in refluxing DCE under a N2
atm underwent intramolecular heterolysis (just like formation of intact radical cation–anion pair) during
stereoselective radical dimerization to Z-ene-1,4-dione along with small amount of reductive dechlorina-
tion product. The stereochemistry was established by X-ray diffraction spectroscopy of various solid crys-
talline products.
Received 22 March 2016
Revised 12 April 2016
Accepted 20 April 2016
Available online 22 April 2016
Keywords:
b-(Oxy)alkyl radical
Contact ion pair (CIP)
Stereoselective radical dimerization
Z-Ene-1,4-dione
Ó 2016 Elsevier Ltd. All rights reserved.
CuCl/bpy
Trichloromethyl group containing compounds are widely used
as reagents,1 synthetic intermediates,2 and finished products in
organic synthesis and possess biological activities like, Barbamide3
which has molluscicidal activity and Dysamide active against pros-
tate cancer.4 Others like chloroform, chloral, trichloroacetone, tri-
chloroacetic acid, trichloroacetamide, trichloro acetonitrile, etc.
are present in commercially used water as a result of chlorination
with chlorine or other chlorinating agents.5 Otherwise it has uses
in agriculture, industries, disease vector control, pharmacy, medi-
cine and other human welfare activities.
As synthetic intermediates, trichloromethyl group containing
organic compounds easily generate a radical intermediate by reac-
tion with transition metal salts or their complexes such as CuCl or
CuCl-ligand (bidentate or tridentate tertiary amine ligands) com-
plex and bring about Intermolecular or intramolecular radical
addition on to C–C multiple bond6 or act as radical initiators in
chlorine Atom Transfer Radical Addition or Polymerization (ATRA
or ATRP) reactions.7 The radicals generated from the trichloro-
methyl group in compounds containing a suitably located C–C
multiple bond with CuCl/bpy underwent intramolecular radical
cyclization.8 The radical cyclization along with mono- and/or di-
reduction of one or two chlorine atom(s) of the trichloromethyl
group was also observed in one of the cases.9 However, radicals
derived from trichloromethyl group in compounds containing no
suitably located C–C multiple bond but having a weak or relatively
better nucleofugal group at the b-position of radical underwent
predominantly rearrangement10 and/or fragmentation,11 respec-
tively. Further, the work reported by this laboratory showed that
2,2,2-trichloroethyl alkyl ethers and trichloromethyl carbinols con-
taining neither suitably located C–C multiple bond nor a leaving
group at the b-position of radical underwent a 1,2-H shift under
similar conditions through the intermediate formation of a cop-
per-carbenoid species.12 Our interest in the mechanistic study of
b-(acyloxy)alkyl radical generated from corresponding trichloro-
methyl group containing compounds prompted us to further bring
about indepth investigation onto the radicals derived from tri-
chloromethyl compounds which contain neither a suitably located
C–C multiple bond nor a leaving group or a hydrogen atom at the
b-position of the radical. Hence, 2,2,2-trichloro-1-phenyl-
ethanones were prepared with a view to investigate the mecha-
nism under this condition.
Thus, 2,2,2-trichloro-1-phenyl-ethanone 1a (Scheme 1) was
prepared by a two-step procedure involving addition of CHCl3 to
benzaldehyde in the presence of DBU at room temperature (25–
30 °C) for 3 h under N2 atmosphere as per a reported procedure13
followed by oxidation of the trichloromethyl carbinol thus formed,
with sodium dichromate in glacial acetic acid (Na2Cr2O7/AcOH) at
25–30 °C by obeying a reported method.14 The trichloromethyl
ketone 1a was obtained as a colorless liquid in 70% isolated yield.
⇑
Corresponding author at present address: Department of Chemistry, National
Institute of Technology Kurukshetra, Haryana 136119, India. Tel./fax: +91 1744
233542.
E-mail address: rktittaliitd@nitkkr.ac.in (R.K. Tittal).
http://dx.doi.org/10.1016/j.tetlet.2016.04.080
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

2438
R. N. Ram, R. K. Tittal / Tetrahedron Letters 57 (2016) 2437–2440
Cl2
Cl1
C8
C9
C12
C13
C14
C3
C11
C16
C4
C2
C10
C7
O2
C1
O1
Br2
C15
C5
C6
Br1
Figure 1. Thermal ellipsoid view of C24H14Cl2O4 with 50% probability.
Scheme 1. The reaction of 2,2,2-trichloro-1-phenyl-ethanone 1a with 2 equiv of
CuCl/bpy in dry DCE under N2 atmosphere.
ral products.17 The ene-1,4-diones also find application in the syn-
theses of various heterocycles such as furan, thiophenes, pyrroles,
and cyclopentenones which are frequently located in many natural
products as well as pharmaceutically important compounds.18
Generally, ene-1,4-diones are prepared by destructive
approaches using oxidative cleavage of pre-existing heterocycles
such as furan, thiophene, pyrrole etc which in turn synthesized
by very complex routes.19,20 Only some constructive methods such
as conversion of various cyclic and acyclic conjugated enones with
t-BuOOH in the presence of Pearlman’s catalyst, i.e., 20% Pd(OH)2/
C,21 CuO in the presence of iodine in DMSO for the synthesis of
2-methylthio substituted ene-1,4-diones by oxidative coupling of
two molecules of methyl ketones are reported.22 Recently, Ray
et al have proposed stereo and regio selective synthesis of Z-1,2-
diiodo-1,4-diketones by the oxidative iodination of buta-1,3-diy-
nes at 70 °C temp using iodonium reagent N-iodo succinimide
(NIS).23 Most of the methods discussed here suffer from one or
more drawbacks like-use of more complex reaction conditions,
destructive approach, expensive and high boiling solvents which
in turn require more time consuming methods for product purifi-
cation. However, the present method is constructive, mild and effi-
cient, and requires a comparatively cheap reagent CuCl/bpy which
requires an easy purification method.
It was a known compound which displayed satisfactory IR, 1H
NMR, and 13C NMR spectra. The reaction of 2,2,2-trichloro-1-phe-
nyl-ethanone 1a with 2 equiv of CuCl/bpy in dry DCE under N2
atmosphere was completed in 1.5 h at reflux. Simple filtration of
the copper complex through a small band of celite pad followed
by purification of crude product by silica gel (60–120 mesh) col-
umn chromatography using n-hexane and ethyl acetate mixture
(9:1 v/v) as the solvent system eluted two products which were
spectroscopically identified as 2,3-dichloro-1,4-diphenylbut-2-
ene-1,4-dione 2a and
a phenacylchloride 4a. The reaction
condition favored less polar solvents such as DCE and benzene, of
them benzene gave an improved yield of ene-1,4-dione 2a. Further,
the reaction condition was generalized by successively applying it
to other trichloromethyl ketones 1 for the formation of the corre-
sponding ene-1,4-diones 2 in 45–70% isolated yields along with
mono or di dechlorination products 3 or 4, respectively, as shown
in Table 1. The final products were characterized by IR, 1H NMR,
and 13C NMR spectroscopy. However, unknown compounds were
supported by HRMS data and solid crystalline unknown samples
were finally supported by their single crystal X-ray diffraction
spectroscopic data which revealed Z-stereochemistry to all crystals
Z-2b, Z-2c, Z-2e, and Z-2f (Fig. 1).
In the view of earlier experiences, it was thought that the stere-
oselective dimerization of trichloromethyl ketones might also have
involved the formation of copper-carbenoid intermediate via suc-
cessive abstraction of two chlorine atoms by CuCl/bpy through
the formation of copper-associated radical12a 5 as shown in
Scheme 2. However, the reactions of o-tolyl, propyl, and
o-methoxy phenyl trichloromethyl ketones 1g, 1j, and 1k,
(Table 1, S. No. 12, 15 and 16) respectively, did not result in the
formation of corresponding intramolecular carbene insertion
products 7, 8, and 9 (Fig. 2) into their active C–H bonds. In this
context, the reaction of p-nitrophenyl trichloromethyl ketone 1i
with 2 mol equiv each of CuCl and bpy in dry THF was
performed with a view to trap the carbenoid species, if formed,
by its insertion into the more reactive C–H bond of the THF
taken as solvent. In this case also, the expected CH-carbene
insertion product 10 was not formed. Rather, the dichlorovinyl
ester 11 was isolated as a light yellow colored solid, mp 178 °C
in 55% along with the dichloroketone 3i in 15% yield. The
structure of dichlorovinyl ester 11 was determined by IR, 1H
NMR, and 13C NMR spectra and finally supported by single
crystal X-ray diffraction spectroscopy. In another attempt to
discern evidence for the intermediacy of a carbenoid species for
The ene-1,4-dione structural units are present in various kinds
of bioactive natural products such as marine natural products,
sesquiterpenes, steroids, antitumor, and antifungal agents.15 For
example, non-3-ene-2,5-dione presented as an important toxic
component of the fire bee Trigona tataira16 The electrophilicity
and electron affinity of ene-1,4-diones make them excellent sub-
strates for further synthetic modifications. They have been used
for the synthesis of important molecules such as prostaglandins,
rethrolones, perfumes, pheromones, macrocycles, and other natu-
Table 1
Reactions of 2,2,2-trichloro methyl ketone 1 with CuCl/bpya
S. No.
1
R
Time (h)
Solvent
Yieldsb (%)
Z-2
3
4
1
2
3
4
5
6
7
8
a
a
b
b
c
c
d
d
e
e
f
g
h
i
j
k
C6H5
C6H5
1.5
3.0
1.0
2.0
1.0
2.0
1.5
3.0
1.5
3.0
2.0
2.5
2.5
12.0
1.0
12.0
DCE
Benzene
DCE
Benzene
DCE
Benzene
DCE
50
64
60
70
52
60
45
58
55
67
65
60
58
—
—
20
p-MeO-C6H4
p-MeO-C6H4
p-Cl-C6H4
p-Cl-C6H4
o-Cl-C6H4
o-Cl-C6H4
p-Br-C6H4
p-Br-C6H4
p-Me-C6H4
o-Me-C6H4
m-Me-C6H4
p-NO2-C6H4
C3H7
—
10
18
08
20
06
—
—
15
—
18
—
—
—
—
—
15
—
—
—
20
—
—
—
the formation of the ene-1,4-diones in
a reaction of 2,2,2-
Benzene
DCE
trichloro-1-phenyl ethanone 1a was performed with 2 mol equiv
each of CuCl and bpy in DMSO at room temperature (25–30 °C)
with a view to trap the carbene by intermolecular oxidation with
DMSO.24 However, the reaction gave no evidence for the formation
of the expected phenyl glyoxyloyl chloride 12 even after prolonged
reaction time, 8 h. These results suggested that the copper-car-
benoid was probably not formed as an intermediate in the reaction.
To check the involvement of radical coupling mechanism, a
reaction of 1b was performed with 1 mol equiv each of CuCl and
bpy in dry benzene and DCE mixture (9:1 v/v) at room temperature
9
10
11
12
13
14
15
16
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
—
20
—
55
—
o-MeO-C6H4
16
a
All the reactions were performed with 0.004 mol of 1 and 0.008 mol each of
CuCl and bpy in 20 mL DCE or benzene at reflux under a N2 atmosphere.
b
Refer isolated yield after column chromatography (silica gel 60–120 mesh).

R. N. Ram, R. K. Tittal / Tetrahedron Letters 57 (2016) 2437–2440
2439
Scheme 2. The copper-carbenoid intermediate.
dimerization mechanism and not a carbene for the formation of
the ene-1,4-diones 2.
On the basis of the foregoing observations, a mechanism for the
present reaction may be proposed as shown in Scheme 4. The for-
mation of the ene-1,4-diones 2 and the reduction products 3 and 4
could be explained by dimerization of the initially formed radical
13 to 14 and its reduction through hydrogen abstraction from
the medium. However, the radical 14 may be considered to be
highly polarized by analogy with the well documented heterolysis
of the C–L bond of the radicals having a leaving group L (phospha-
Figure 2.
toxy, sulfatoxy, nitroxy etc.) at the b-position.6 In this context a
p
bond of the carbonyl group may be regarded as equivalent to an
extremely powerful leaving group which remained intact by C–O
covalent
r-bond. The highly polar character of this radical also
explains the formation of the enol ester 11 in the reaction of highly
electrophilic p-nitrophenyl ketone 1i in a good H-atom donor sol-
vent THF in which the concentration of the enolate 16 or enol 17
would be sufficient for the intermolecular reaction with the
unreacted 1i.
In benzene, the reaction of 1i gave only the monoreduction pro-
duct 3i in 20% yield and the unconsumed 1i. Probably the concen-
tration of the corresponding enolate 16i or enol 17i produced in
the poorer H-atom donor solvent benzene was considerably lower
for its intermolecular reaction with 1i to occur with any percepti-
ble rate. In this case, proton transfer to the enolate followed by tau-
tomerization competes more effectively to give the dichloro ketone
3i. The enol ester 11 was probably not formed by the reaction of 3i
through its enol form with 1i, as both these were present in the
reaction medium during the reaction of 1i using benzene as solvent
in which the formation of the enol ester 11 was not detected. This
mechanism required one equiv of CuCl/bpy for the formation of 11
as against the observed consumption of two equiv of CuCl/bpy.
Probably the remaining one equiv of complex was consumed for
the formation of the radicals by hydrogen abstraction from solvent.
The Z-selectivity for the formation of ene-1,4-diones might be due
to association of the highly polar radical intermediate 14 with cop-
per complex present in the medium.
Scheme 3. The formation and reaction of tetrachloro-1,4-diketone.
(32 °C), the initial brown color due to Cu(I)-bpy complex faded to
whitish green due to the formation of Cu(II)-bpy complex within
30 min, indicating the full consumption of Cu(I)-complex. At this
stage, the reaction was stopped and worked up by simply filtering
off the inorganic material through a small band of celite pad fol-
lowed by purification of the residual material through column
chromatography. The major reaction product was purified and
characterized as tetrachloro-1,4-diketone 15 (Scheme 3) along
with the dichloroketone 3b and some amount of unreacted starting
material 1b was recovered. The structure of 15 was satisfactorily
supported by IR, 1H NMR, and 13C NMR spectra and by comparison
of its mp 148 °C (lit25 mp 144–146 °C) with the reported value. The
isolation of 15 indicated that this would be the intermediate in the
reaction leading to the formation of the ene-1,4-dione 2b. Thus, the
reaction of 15 was performed with 2 mol equiv each of CuCl and
bpy in dry benzene at reflux under N2 atmosphere for 2 h. Usual
work up of the reaction mixture yielded the expected 2b in 68%
isolated yield. The formation of 15 and its subsequent conversion
to 2b under the usual reaction conditions revealed a radical
In conclusion, the reaction of trichloromethyl ketones with two
mol equiv of CuCl/bpy in dry benzene or DCE furnished
Z-2,3-dichlorobut-2-ene-1,4-diones by stereo selective radical
dimerization. In some cases, dichloro methyl or mono
O
O
O
O
O
O
O
CuCl/bpy
benzene
CCl3
2 CuCl/bpy
benzene
x 2
R
R
R
R
R
CCl2
R
R
CCl2
Cl
Cl
Cl
Cl
(Z)-2
Cl
Cl
14
13
1
15
Cl
Cl
O
O
CCl2O
O
O
Cl
Cl
R
R
R
CCl2
CIP
11
11
13
OMe
MeO
SH (solvent)
O
-CCl3
O
OH
CCl2
17
O
O
CuCl/bpy
CHCl2
O
CCl2
R
R
CCl3
R
R
R
R
CH2Cl
O
R
CCl2
H
R
CCl2
- H+
R= p-NO2C6H4
reflux, THF
O
3
4
Cl3C
16
Scheme 4. Proposed radical mechanism for the formation of Z-ene-1,4-dione from 2,2,2-trichloro-1-phenyl-ethanone.

2440
R. N. Ram, R. K. Tittal / Tetrahedron Letters 57 (2016) 2437–2440
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Acknowledgment
We thank IIT Delhi for providing research facilities and teaching
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Supplementary data
Supplementary (detailed experimental procedures, spectral
data, and NMR spectra of all the new and relevant compounds
and CIF of 2e, 2f and 11) data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2016.04.080.
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