Efficient α-chlorination of 2-[(1-oxocyclohex-2-en-2-yl)methyl]-1,3- dicarbonyl compounds using sodium hypochlorite

Article abstract of DOI:10.3184/174751913X13587668947648

A rapid and efficient regioselective α-chlorination of a new series of β-dicarbonyl compounds using a commercial solution of sodium hypochlorite in the presence of K₂CO₃ in THF at 0°C, is reported. With prolonged reaction times, α-chloro β-keto esters, bearing an acyl moiety, undergo a tandem chlorination-deacylation reaction, affording the corresponding α-chlorinated esters.

Full text of DOI:10.3184/174751913X13587668947648

122 RESEARCH PAPER
FEBRUARY, 122–124
JOURNAL OF CHEMICAL RESEARCH 2013
Efficient α-chlorination of 2-[(1-oxocyclohex-2-en-2-yl)methyl]-1,3-
dicarbonyl compounds using sodium hypochlorite
Olfa Mhasni and Farhat Rezgui*
Laboratoire de Chimie Organique, Faculté des Sciences Campus Universitaire 2092Tunis, Tunisia
A rapid and efficient regioselective α-chlorination of a new series of β-dicarbonyl compounds using a commercial
solution of sodium hypochlorite in the presence of K2CO3 in THF at 0 °C, is reported. With prolonged reaction times,
α-chloro β-keto esters, bearing an acyl moiety, undergo a tandem chlorination–deacylation reaction, affording the
corresponding α-chlorinated esters.
Keywords: Baylis–Hillman, chlorination, sodium hypochlorite, β-dicarbonyl compounds
1
The α-chlorination of carbonyl compounds is an important
organic transformation as the corresponding α-halo derivatives
are useful intermediates in organic synthesis.1,2 For instance,
they have been employed as useful intermediates for the
synthesis of thiazolidine-2,4-diones,3 thiazoles,4,5 a variety of
heterocyclic compounds6,7 as well as functionalised carbonyl
compounds.8
The most commonly used reagents for α-chlorination of
carbonyl compounds include sulfuryl chloride,9,10 organocata-
lysts,11–18 Lewis acids,19–21 amberlyst22 or ionic liquids,23 tri-
haloisocyanuric acids24 and inorganic reagents.25–27 In terms of
accessibility and ease of handling, sodium hypochlorite is a
superior and inexpensive chlorinating reagent. Previously, it
has been utilised for the chlorination of β-dicarbonyl com-
pounds in a mixture of Na2CO3/CCl425 or acetone/acetic acid.26
Unfortunately, the use of a solvent like CCl4 causes serious
environmental pollution. Therefore, there is a need to find an
alternative solvent that would be environmentally benign and
efficient.
In connection with our studies on the behaviour of Baylis–
Hillman adducts towards various nucleophiles,28,29 we have
reported a direct allylic substitution of alcohol 130 with β-keto
esters and β-diketones, affording β-dicarbonyl derivatives 2
(Scheme 1).27
Starting from β-dicarbonyl derivatives 2 in basic conditions,
we have also described two synthetic routes to a new series
of bicyclic dienones.28,31 We have also reported the PTSA-
promoted Robinson annelation of compounds 2, afforded, in
a one-pot process, a variety of hydroxytetrahydronaphthyl
carbonyl compounds.32 In connection with our study on the
reactivity of the multifunctional derivatives 2, we now report
that the use of sodium hypochlorite in the presence of K2CO3
in a commonly available solvent such as THF, is an efficient
medium for regioselective monochlorination of a new series of
1,3-dicarbonyl derivatives 2.
The H NMR data of compound 3a are in agreement with
the proposed structure. Indeed, contrary to the spectrum of 2a,
that of 3a did not show a signal for the proton at the α-position
of the β-dicarbonyl moiety. In addition, the integration of all
the other signals from 2a and 3a was found to be the same.
Moreover, the exact mass of the parent ion of 3a measured
by EI-HRMS (C18H1935ClO4, m/z 334.0966) confirmed the
proposed structure.
This protocol was successfully extended to the selective
monochlorination of the β-keto esters 2d–f (Table 1, entries
4–6) as well as β-diketones or diethyl malonate derivatives
2b–c (Table 1, entries 2 and 3), affording the α-chlorinated
products 3b–f in good to excellent yields.
However, when the chlorination reaction of 2a–f was
attempted under acidic conditions using the acetone/acetic
acid mixture at 0 °C,26 previously reported for the α-chlorina-
tion of a variety of β-dicarbonyl compounds, the starting mater-
ial was recovered unchanged even after a 48 h reaction time.
In order to investigate the scope and limitations of this
successful monochlorination method, the behaviour of the β-
ketoester compound 2e was first studied as a function of the
reaction time. We have found that under the above-mentioned
conditions but at longer reaction time (2h), 2e gave a mixture
of 3e and its deacylated derivative 4e, in a 39:61 ratio, respec-
tively.
In order to improve the selectivity of this protocol in favour
of the deacylated derivatives 4, the chlorination reaction was
attempted using a longer reaction time. Therefore, starting
from the β-keto ester compounds 2d–f, bearing an acyl
moiety (R2 = Me), the exclusive formation of the deacylated
compounds 4d–f was observed under the above conditions
(8.0 equiv. of commercial 1.8 M NaClO solution, 4.0 equiv. of
K2CO3, 0 °C, THF) (Scheme 3, Table 2, entries 4–6).
Results and discussion
We have found that on treatment with K2CO3 (4.0 equiv.), the
β-dicarbonyl compound 2a reacted with 8.0 equiv. of commer-
cially available 1.8 M sodium hypochlorite solution in THF at
0 °C for 30 min, to generate exclusively the α-chloro β-dicar-
bonyl derivative 3a in 82% yield (Scheme 2, Table 1, entry 1).
Scheme 2
Table 1 α-Chlorination of 1,3-dicarbonyl compounds 2a–f
Entry Starting material R1
R2
Time/min Yield of 3/%
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
OEt
Ph
OEt OEt
OEt Me
OMe Me
OBn Me
Ph
Ph
30
30
15
20
10
15
82
82
95
74
74
73
Scheme 1
* Correspondent. E-mail: rez_far@yahoo.fr

JOURNAL OF CHEMICAL RESEARCH 2013 123
Scheme 3
HRMS (EI): m/z calcd for C18H1935ClO4 (M+): 334.0972; found:
334.0966.
Accordingly, it is well known that β-dicarbonyl compounds
undergo, under various conditions, a one-pot halogenation-
deacylation, affording the corresponding α-halo esters.33–36
On the other hand, when R2 = Ph or OEt (i.e. 2a–c), the
chlorination reaction proceeds well under the previous
conditions, affording the products 3a–c with no trace of the
deacylated compounds 4a–c, even after a 48 h reaction time
(Scheme 3, Table 2, entries 1–3).
2-Chloro-2-[(1-oxocyclohex-2-en-2-yl)methyl]-1,3-diphenylpro-
pane-1,3-dione (3b): Yield: 82%; White solid, m.p. 115 °C. 1H NMR
(300 MHz, CDCl3): δ 7.89–7.47 (m, 4H); 7.45–7.31 (m, 6H); 7.13
(t, J = 4.0 Hz, 1H); 3.59 (s, 2H); 2.42–2.30 (m, 4H); 1.97–1.93
(m, 2H); 13C NMR (75 MHz, CDCl3): δ 198.4, 191.9, 152.1, 134.1,
133.4, 133.2, 129.8, 128.0, 78.0, 38.1, 36.5, 26.4, 22.6. HRMS (EI):
m/z calcd for C22H1935ClO3 (M+): 366.1023; found: 366.1036.
Diethyl
2-chloro-2-[(1-oxocyclohex-2-en-2-yl)methyl]malonate
(3c): Yield: 95%; yellow oil. IR (CHCl3): 1942, 1744, 1676, 1424,
1271, 1240, 1195, 1090, 1033, 913, 858, 732 cm-1. 1H NMR
(300 MHz, CDCl3): δ 6.99 (t, J = 4.0 Hz, 1H); 4.26 (q, J = 7.3 Hz, 4H);
3.19 (s, 2H); 2.43–2.39 (m, 4H); 2.02–1.97 (m, 2H); 1.30 (t, J =
7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 198.3, 166.5, 151.3, 133.0,
69.5, 63.0, 38.0, 36.1, 26.3, 22.7, 13.8. HRMS (EI): m/z calcd for
C14H1935ClO5 (M+): 302.0921; found: 302.0923.
Ethyl 2-chloro-2-[(1-oxocyclohex-2-en-2-yl)methyl]-3-oxobutanoate
(3d): Yield: 74%; yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.98 (t,
J = 4.0 Hz, 1H); 4.28–4.21 (m, 2H); 3.28−2.90 (AB, J = 15.0 Hz, 2H);
2.45–2.40 (m, 4H); 2.33 (s, 3H); 2.02–1.97 (m, 2H); 1.29 (t, J =
6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 198.5, 197.0; 167.0, 151.4,
133.2, 74.3, 63.2, 38.0, 35.0, 26.3, 25.7, 22.7, 13.8. HRMS (EI): m/z
calcd for C13H1735ClO4 (M+): 272.0815; found: 272.0818.
Conclusions
The present work describes a mild, convenient and inexpen-
sive method for regioselective chlorination or tandem chlorin-
ation–deacylation of a variety of 1,3-dicarbonyl compounds
using a weak base (K2CO3) combined with sodium hypochlo-
rite in THF. This chlorination reaction proceeds rapidly at 0 °C
and provides the corresponding α-chlorinated products in high
yields, as important intermediates for organic transformations.
Interestingly, this procedure is highly chemoselective as the
enone moiety remains unaffected.
Experimental
1
Methyl 2-chloro-2-[(1-oxocyclohex-2-en-2-yl)methyl]-3-oxobutanoate
IR spectra were recorded on a Bruker (IFS 66v/S) spectrometer. H
1
NMR and 13C NMR spectra were recorded on a Bruker AC-300
spectrometer (300 MHz for 1H and 75 MHz for 13C) in CDCl3, using
TMS as an internal standard (chemical shifts in δ values, J in Hz).
High-resolution mass spectra (HRMS) were recorded on an Autospec
Ultima/micromass mass spectrometer.
(3e): Yield: 74%; yellow oil. H NMR (300 MHz, CDCl3): δ 6.98 (t,
J = 4.0 Hz, 1H); 3.80 (s, 3H); 3.30−2.87 (AB, J = 14.3 Hz, 2H); 2.43–
2.38 (m, 4H); 2.32 (s, 3H); 2.03–1.97 (m, 2H); 13C NMR (75 MHz,
CDCl3): δ 198.6, 197.0; 167.5, 151.6, 133.2, 74.1, 53.8, 38.0, 35.2,
26.3, 25.7, 22.7. HRMS (EI): m/z calcd for C12H1535ClO4 (M+):
258.0659; found: 258.0665.
Analytical thin layer chromatography (TLC) was performed using
Fluka Kieselgel 60 F254 precoated silica gel plates. Visualisation was
achieved by UV light (254 nm). Flash chromatography was performed
using silica gel 60 (70–230 mesh) and a gradient solvent system (light
petroleum, b.p. 60–80 °C/diethyl ether).
Benzyl 2-chloro-2-[(1-oxocyclohex-2-en-2-yl)methyl]-3-oxobutanoate
(3f): Yield: 73%; yellow oil. IR (CHCl3): 1937, 1728, 1690, 1672,
1
1455, 1262, 1212, 1174, 1107, 1083, 962, 750, 699 cm-1. H NMR
(300 MHz, CDCl3): δ 7.38–7.34 (m, 5H); 6.91 (t, J = 4.0 Hz, 1H); 5.20
(AB, J = 12.0 Hz, 2H); 3.30−2.92 (AB, J = 14.3 Hz, 2H); 2.39–2.32
(m, 4H); 2.24 (s, 3H); 1.98–1.89 (m, 2H); 13C NMR (75 MHz, CDCl3):
δ 198.5, 196.8, 166.9, 135.1, 134.6, 133.9, 133.1, 128.7, 128.5, 74.2,
68.7, 38.0, 35.1, 26.3, 25.6, 22.6. HRMS (EI): m/z calcd for
C18H1935ClO4 (M+): 334.0972; found: 334.0961.
α-Chlorination of 1,3-dicarbonyl compounds 3; typical procedure
A solution of β-ketoester 2a (0.2 g, 0.66 mmol, 1 equiv.) in THF
(3 mL) was added dropwise to a mixture of sodium hypochlorite
(1.8 M, 2.93 mL, 5.28 mmol, 8 equiv.) and K2CO3 (0.36 g, 2.64 mmol,
4 equiv.) cooled at 0 °C. The reaction mixture was stirred for 30 min
at 0 °C, and extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were washed with brine, dried and concentrated. The residue
was purified by column chromatography (light petroleum/diethyl
ether = 1:9) to give the monochlorinated compound 3a (0.18 g,
82%).
Synthesis of 4; typical procedure
These deacylated derivatives were prepared and purified as previously
described for compounds 3 but the reaction mixture was left for a
longer time (Table 2).
Ethyl 2-chloro-3-(1-oxocyclohex-2-en-2-yl)propanoate (4d): Yield:
68%; yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.90 (t, J = 4.0 Hz,
1H); 4.51–4.46 (m, 1H); 4.21 (q, J = 6.9 Hz, 2H); 2.97–2.64 (m, 2H);
2.44–2.39 (m, 4H); 2.02–1.98 (m, 2H); 1.29 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3): δ 198.8, 169.4; 150.1, 134.1, 61.9, 55.2,
38.2, 36.0, 26.3, 22.8, 14.0. HRMS (EI): m/z calcd for C11H1535ClO3
(M+): 230.0710; found: 230.0713.
Ethyl 2-chloro-2-[(1-oxocyclohex-2-en-2-yl)methyl]-3-oxo-3-phe-
nylpropanoate (3a): Yield: 82%; yellow oil. IR (CHCl3): 1929, 1755,
1690, 1672, 1448, 1269, 1234, 1201, 1022, 742, 692 cm-1. H NMR
1
(300 MHz, CDCl3): δ 7.97–7.94 (m, 2H); 7.53–7.39 (m, 3H); 7.02
(t, J = 4.0 Hz, 1H); 4.15–4.08 (m, 2H); 3.55−2.98 (AB, J = 13.9 Hz,
2H); 2.45–2.38 (m, 4H); 2.03–1.99 (m, 2H); 1.04 (t, J = 6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): δ 198.5, 188.8, 176.1, 152.0, 133.7,
133.2, 133.0, 129.3, 128.3, 71.4, 63.1, 38.0, 36.3, 26.4, 22.8, 13.4.
Methyl 2-chloro-3-(1-oxocyclohex-2-en-2-yl)propanoate (4e): Yield:
63%; yellow oil. IR (CHCl3): 1953, 1747, 1672, 1434, 1378, 1295,
1
1250, 1196, 1171, 1101, 1021, 909, 711 cm-1. H NMR (300 MHz,
CDCl3): δ 6.90 (t, J = 4.0 Hz, 1H); 4.54−4.49 (m, 1H); 3.77 (s, 3H);
3.00–2.64 (m, 2H); 2.46–2.39 (m, 4H); 2.04–1.98 (m, 2H); 13C NMR
(75 MHz, CDCl3): δ 198.8, 169.9, 150.1, 134.1, 55.1, 52.8, 38.2, 36.0,
26.1, 22.8. HRMS (EI): m/z calcd for C10H1335ClO3 (M+): 216.0553;
found: 216.0542.
Table 2 α-Chlorination or tandem α-chlorination–deacylation
of dicarbonyl compounds 2a–f
Entry Starting
material
R1
R2
Time/h Yield of Yield of
3/%
4/%
Benzyl 2-chloro-3-(1-oxocyclohex-2-en-2-yl)propanoate (4f): Yield:
60%; yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.38–7.26 (m, 5H);
6.78 (t, J = 4.0 Hz, 1H); 5.17 (s, 2H); 4.54 (t, J = 6.9 Hz, 1H); 2.95–
2.68 (m, 2H); 2.40–2.34 (m, 4H); 1.94–1.89 (m, 2H); 13C NMR
(75 MHz, CDCl3): δ 199.0, 169.4, 150.4, 140.9, 135.2, 134.0, 128.7,
128.5, 67.6, 55.2, 38.2, 36.1, 26.1, 22.8. HRMS (EI): m/z calcd for
C16H1735ClO3 (M+): 292.0866; found: 292.0864.
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
OEt
Ph
OEt
OEt
OMe Me
OBn Me
Ph
Ph
OEt
Me
48
48
48
10
11
14
68
66
73
0
0
0
0
68
63
60
0
0

124 JOURNAL OF CHEMICAL RESEARCH 2013
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K.A. Jørgensen, Chem. Eur. J., 2005, 11, 7083.
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We are grateful to the DGRST, Ministry of Higher Education,
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Received 24 June 2012; accepted 19 January 2013
Paper 1100632 doi: 10.3184/174751913X13587668947648
Published online: 13 February 2013
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