Reformatsky reaction promoted by an ionic liquid ([Bmim]Cl) in the synthesis of β-hydroxyl ketone derivatives bearing a coumarin unit

Article abstract of DOI:10.3184/174751912X13371652436057

A number of β-hydroxy-ketone derivatives bearing a coumarin unit have been synthesised by the Reformatsky reaction of formyl coumarin and α-bromoacetophenone in an ionic liquid (1-butyl-3-methylimidazolium chloride, [Bmim]Cl). The recovered ionic liquid c

Full text of DOI:10.3184/174751912X13371652436057

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 393
JULY, 393–395
Reformatsky reaction promoted by an ionic liquid ([Bmim]Cl) in the
synthesis of β-hydroxyl ketone derivatives bearing a coumarin unit
Bing Zhao, Meng-jiao Fan, Zhuo Liu, Li-feng Hu, Bo Song, Li-yan Wang and Qi-gang Deng*
Chemistry and Chemical Engineering Institute, Qiqihar University, Heilongjiang Qiqihar 161006, P. R. China
A number of β-hydroxy-ketone derivatives bearing a coumarin unit have been synthesised by the Reformatsky reac-
tion of formyl coumarin and α-bromoacetophenone in an ionic liquid (1-butyl-3-methylimidazolium chloride,
[Bmim]Cl). The recovered ionic liquid can be reused at least five times without a significant reduction in yield. This
procedure is green, mild and environmentally benign.
Keywords: Reformatsky reaction, β-hydroxyl ketone, coumarin, ionic liquid
Since its discovery in 1887, the Reformatsky reaction has
been one of the important reactions for carbon–carbon bond
formation in organic chemistry.1 With constant improvement,
the Reformatsky reaction has been applied to the reaction
of α-halo-ketones and aldehydes or ketones in which the
corresponding products were β-hydroxy-ketone.2–4 It offers the
advantage of regioselective enolate formation under nearly
neutral conditions.5–7 However, the classic method employing
zinc dust as a reactant can be plagued by extended reaction
times and/or byproduct formation.8Many other approaches
have been developed. to address these concerns, employing
either alternative elemental reactants or low-valent organome-
tallic species.9–11 Unfortunately, several reagents have limita-
tions of cost, availability, toxicity, and/or selectivity. Recently,
many green approaches to Reformatsky reaction using
aqueous media had been reported.12–15
In general, these reactions are carried out in organic
solvents. Most organic solvents are flammable and may cause
contamination of the environment. Accordingly, the use of
green solvent in organic reactions is currently one of the most
important issues in green chemistry, a field where new chemi-
cal methodologies are being developed to reduce the environ-
mental impact of many chemical processes. Ionic liquids as
solvent have been used in many organic reactions.16–18 How-
ever, the Reformatsky reaction in ionic liquid is little known.
In order to establish suitable conditions for the synthesis
of β-hydroxy-ketone derivatives bearing coumarin unit, we
investigated the Reformatsky reaction of formyl coumarin and
α-bromoacetophenone in the ionic liquid of 1-butyl-3-methyl-
imidazolium choloride ([Bmim]Cl) (Scheme 1).
Results and discussion
α-Bromoacetophenone derivatives (1) were prepared by the
reaction of the acetophenones (acetophenone, 4-methyl aceto-
phenone and 4-methoxy acetophenone) with bromine in diethyl
ether in the presence of AlCl3. Three 2-oxo-2H-chromene
carbaldehydes (2) were synthesised by the oxidation of the
corresponding methyl 2-oxo-2H-chromene and their structures
were confirmed on the basis of their spectroscopic data and
elemental analysis. The β-Hydroxy-ketone derivatives bearing
coumarin unit (3a–i) that were synthesised in the ionic liquid
([Bmim]Cl) are shown in Scheme 1. α-Bromoacetophenones
activated by zinc powder reacted with the formyl coumarins
in ionic liquid to give the products. The whole procedure
was very simple: A mixture of α-bromoacetophenone, formyl
coumarin, zinc powder, trace iodine and anhydrous IL was
stirred at 50–60 °C. At the end of the reaction, water was added
to the mixture, and the crude product was extracted from the
reaction medium with ethyl acetate. The pure product was
isolated by the column chromatography.
To evaluate the effect of recycling on the efficiency of ionic
liquid [Bmim]Cl, the ethyl acetate used to extract the residual
water system was evaporated under vacuum and the residual
ionic liquid was reused without any treatment for a third, fourth
and fifth time. The recovered IL in mass had a little loss, but
the activity did not decrease. Though the reaction time had
slightly increased after a total of five cycles, the yield was still
close to the first reaction, which indicated that the ionic liquid
can be recycled and the reactivity of [Bmim]Cl was not
decreased. The results of subsequent studies were shown in
Table 1.
Scheme 1 Synthetic method of compounds 3a–i.
* Correspondent. E-mail: zhao_submit@yahoo.com.cn

394 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Reuse of ionic liquid [Bmim]Cl in successive cycles of
compound 3a synthesis
was dried and concentrated to obtain the crude product. Purification
by column chromatography afforded the products in the moderate
yield.
Runa
Time /min
Yield/%b
IL Recovery/%c
4-(1-Hydroxy-3-oxo-3-phenylpropyl)-6-methyl-2H-chromen-2-one
(3a): 93%; m.p. 81–83 °C; IR(KBr) υ: 3433 (OH), 2916 (CH), 2844
(CH), 1715 (C=O), 1635 (C=O), 1167 (C–O) cm−1; 1H NMR(CDCl3,
400 MHz) δ: 8.05 (d, 2H, J = 8.0 Hz, ArH); 7.63 (t, 1H, J = 3.2 Hz,
ArH); 7.54 (t, 2H, J = 7.5 Hz, ArH); 7.27 (d, 1H, J = 7.5 Hz, ArH);
7.25 (d, 1H, J = 7.5 Hz, ArH); 7.23 (s, 1H, ArH); 6.75 (s, 1H, CH=C);
5.72 (brs, 1H, OH); 3.76–3.62 (m, 1H, CH); 3.49 (dd, 1H, J1 = 2.4, J2
= 18.0 Hz, CH2); 3.41 (dd, 1H, J1 = 9.0, J2 = 15.0 Hz, CH2); 2.38 (s,
3H, CH3); Anal. Calcd for C19H16O4: C, 74.01; H, 5.23. Found: C,
74.11; H, 5.39%.
4-(1-Hydroxy-3-oxo-3-p-tolylpropyl)-6-methyl-2H-chromen-2-one
(3b): 91%; m.p. 83–85 °C; IR(KBr) υ: 3402 (OH), 3066 (ArH), 2923
(CH), 1722 (C=O), 1653 (C=O), 1167 (C–O) cm−1; 1H NMR (CDCl3,
400 MHz) δ: 7.87 (d, 2H, J = 8.5 Hz, ArH); 7.34 (d, 2H, J = 8.5 Hz,
ArH); 7.31 (d, 1H, J = 9.0 Hz, ArH); 7.29 (d, 1H, J = 9.0 Hz, ArH);
7.17 (s, 1H, ArH); 6.75 (s, 1H, CH=C); 5.72 (brs, 1H, OH); 3.76–3.73
(m, 1H, CH); 3.50 (dd, 1H, J1 = 3.8, J2 = 18.0 Hz, CH2); 3.36 (dd, 1H,
J1 = 9.0, J2 = 18.0 Hz, CH2); 2.49 (s, 3H, CH3); 2.39 (s, 3H, CH3);
Anal. Calcd for C20H18O4: C, 74.52; H, 5.63. Found: C, 74.32; H,
5.71%.
1
2
3
4
5
200
200
240
240
240
76
74
74
70
70
97
96
96
95
95
a The conditions of all runs were consistent comparable to
those in the experimental.
b Yields is the isolated product.
c Recovery percent of IL in mass is compared to the first
reaction.
In conclusion, a green, solvent-free and environmentally
benign method has been investigated for the synthesis of
β-hydroxy-ketone derivatives bearing coumarin unit in ionic
liquid. This reaction medium can be recycled five times without
significantreductioninyield.Thesesimpleandmildconditions,
moderate yields and multiple recycling of ionic liquid make
this reaction useful and attractive from the environmental point
of view.
4-(1-Hydroxy-3-(4-methoxyphenyl)-3-oxopropyl)-6-methyl-2H-
chromen-2-one (3c): 91%; m.p. 166–169 °C; IR(KBr) υ: 3425 (OH),
1
2922 (CH), 1715 (C=O), 1689 (C=O), 1209 (C–O) cm−1; H NMR
(CDCl3, 400 MHz) δ: 7.92 (d, 2H, J = 8.5 Hz, ArH); 7.34 (d, 2H,
J = 8.5 Hz, ArH); 7.26 (d, 1H, J = 9.0 Hz, ArH); 7.24 (d, 1H,
J = 9.0 Hz, ArH); 7.20 (s, 1H, ArH); 6.56 (s, 1H, CH=C); 5.74 (brs,
1H, OH); 3.98 (s, 3H, OCH3); 3.74–3.70 (m, 1H, CH); 3.41 (dd, 1H,
J1 = 2.4, J2 = 18.0 Hz, CH2); 3.36 (dd, 1H, J1 = 9.0, J2 = 18.0 Hz, CH2);
2.40 (s, 3H, CH3); Anal. Calcd for C20H18O5: C, 70.99; H, 5.36. Found:
C, 71.15; H, 5.25%.
4-(1-Hydroxy-3-oxo-3-phenylpropyl)-7-methoxy-2H-chromen-2-
one (3d): 91.%; m.p. 245–246 °C; IR(KBr) υ: 3425 (OH), 2922 (CH),
1715 (C=O), 1674 (C=O), 1209 (C–O) cm−1; 1H NMR (CDCl3,
400 MHz) δ: 7.96 (d, 2H, J = 8.0 Hz, ArH); 7.68 (t, 1H, J = 3.2 Hz,
ArH); 7.60 (t, 2H, J = 3.2 Hz, ArH); 7.40 (d, 1H, J = 9.0 Hz, ArH);
6.95 (d, 1H, J = 9.0 Hz, ArH); 6.88 (s, 1H, ArH); 6.60 (s, 1H, CH=C);
5.73 (brs, 1H, OH); 3.92 (s, 3H, OCH3); 3.64–3.63 (m, 1H, CH); 3.40
(dd, 2H, J1 = 2.4, J2 = 14.0 Hz, CH2); Anal. Calcd for C19H16O5: C,
70.36; H, 4.97. Found: C, 70.15; H, 5.04%.
4-(1-Hydroxy-3-oxo-3-p-tolylpropyl)-7-methoxy-2H-chromen-2-
one (3e): 90.2%; m.p. 166–169 °C; IR(KBr) υ: 3730 (OH), 2958
(CH), 1718 (C=O), 1646 (C=O), 1209 (C–O) cm−1; 1H NMR (CDCl3,
400 MHz) δ: 7.84 (d, 2H, J = 8.5 Hz, ArH); 7.48 (d, 2H, J = 9.0 Hz,
ArH); 7.35 (d, 1H, J = 9.0 Hz, ArH); 6.88 (s, 1H, ArH); 6.84 (d, 1H,
J = 9.0 Hz, ArH); 6.59 (s, 1H, CH=C); 5.72 (brs, 1H, OH); 3.89 (s, 3H,
OCH3); 3.71–3.68 (m, 1H, CH); 3.46 (dd, 1H, J1 = 2.4, J2 = 18.0 Hz,
CH2); 3.38 (dd, 1H, J1 = 9.0, J2 = 18.0 Hz, CH2); 2.40 (s, 3H, CH3);
Anal. Calcd for C20H18O5: C, 70.99; H, 5.36;. Found: C, 70.87; H,
5.29%.
Experimental
All reagents and solvents were of analytical grade and were obtained
from commercial sources and used without further purification.
Melting points were taken on a Stuart scientific melting point apparatus
in open capillary tubes. 1H-NMR spectra were recorded on a 400 MHz
spectrometer in CDCl3 with TMS as the internal standard. IR spectra
were determined as KBr pellets on a Perkin-Elmer PE-683 IR
spectrometer. Elemental analyses were performed on an Elementer
Vario EL III elementary analysis instrument.
Synthesis of α-bromoacetophenones 1; general procedure
Pure bromine (100 mL) was dropwise into the mixture of acetophenone
(100 mmol) and anhydrous AlCl3 (1.65 mmol) in anhydrous diethyl
ether (20 mL) at 0 °C The crude product was precipitated, filtered and
washed by the mixture of petroleum ether and wáter. It dried and
recrystallised from the methanol to obtain the compounds 1. The
characterisation of compounds 1 were observed in the literature19.
Synthesis of 2-oxo-chromene-4-carbaldehyde (2); general procedure
A mixture of 4-methyl-2H-chromen-2-one (20 mmol) and SeO2
(32 mmol) in toluene (20 mL) was stirred and refluxed for 20 h. The
reaction was monitored by TLC until it was complete. The deposit
was separated by filtration and the filtrate was cooled to room
temperature. A pure solid was formed and collected by filtration.
6-Methyl-2-oxo-2H-chromene-4-carbaldehyde: 72.9%; m.p. 165–
167 °C. IR(KBr) υ: 3067 (ArH), 2923 (CH), 2873 (CH), 1738 (C=O),
1704 (C=O) cm−1; 1H NMR (CDCl3, 400 MHz) δ: 10.12 (s, 1H, CHO);
8.38 (s, 1H, ArH); 7.42 (d, 1H, J = 8.5 Hz, ArH); 7.29 (d, 1H, J =
8.5 Hz, ArH); 6.87 (s, 1H, CH=C); 2.44 (s, 3H, CH3); Anal. Calcd for
C11H8O3: C, 70.21; H, 4.29. Found: C, 70.39; H, 4.10%.
7-Methoxy-2-oxo-2H-chromene-4-carbaldehyde: 59.6%; m.p. 200–
202 °C. IR(KBr) υ: 3045 (ArH), 2972 (CH), 2857 (CH), 1712 (C=O),
1674 (C=O), 1211 (C-O) cm−1; 1H NMR (CDCl3, 400 MHz) δ: 10.07
(s, 1H, CHO); 8.50 (d, 1H, J = 9.0 Hz, ArH); 6.91 (d, 1H, J = 9.0 Hz,
ArH); 6.87 (s, 1H, ArH); 6.71 (s, 1H, CH=C); 3.89 (s, 3H, CH3); Anal.
Calcd for C11H8O4: C, 64.71; H, 3.95. Found: C, 64.59; H, 4.05%.
2-Oxo-2H-benzo[h]chromene-4-carbaldehyde: 65.9%; m.p. 202–
203 °C; IR(KBr) υ: 3060 (ArH), 2928 (CH), 2844 (CH), 1758 (C=O),
1709 (C=O) cm−1; 1H NMR (CDCl3, 400 MHz) δ: 10.22 (s, 1H, CHO);
8.57 (d, 1H, J = 8.0 Hz, ArH); 8.54 (d, 1H, J = 8.0 Hz, ArH); 7.91 (d,
1H, J = 9.0 Hz, ArH); 7.76 (d, 1H, J = 9.0 Hz, ArH); 7.71–7.65 (m,
2H, ArH); 6.98 (s, 1H, CH=C); Anal. Calcd for C14H8O3: C, 75.00; H,
3.60. Found: C, 75.12; H, 3.41%.
4-(1-Hydroxy-3-(4-methoxyphenyl)-3-oxopropyl)-7-methoxy-2H-
chromen-2-one (3f): 92%; m.p. 172–175 °C; IR(KBr) υ: 3431 (OH),
1
2922 (CH), 1718 (C=O), 1682 (C=O), 1193 (C–O) cm−1; H NMR
(CDCl3, 400 MHz) δ: 7.94 (d, 2H, J = 8.0 Hz, ArH); 7.44 (d, 2H,
J = 8.0 Hz, ArH); 7.28 (d, 1H, J = 8.0 Hz, ArH); 6.97 (d, 1H,
J = 8.0 Hz, ArH); 6.89 (s, 1H, ArH); 6.66 (s, 1H, CH=C); 5.74 (brs,
1H, OH); 3.99 (s, 3H, OCH3); 3.96 (s, 3H, OCH3); 3.68–3.65 (m, 1H,
CH); 3.43 (dd, 1H, J1 = 2.4, J2 = 18.0 Hz, CH2), 3.40 (dd, 1H, J1 = 9.0,
J2 = 18.0 Hz, CH2); Anal. Calcd for C20H18O6: C, 67.79; H, 5.12;.
Found: C, 67.51; H, 4.99%.
4-(1-Hydroxy-3-oxo-3-phenylpropyl)-2H-benzo[h]chromen-2-one
(3g): 93.%; m.p. 158–160 °C; IR(KBr) υ: 3431 (OH), 2921 (CH),
1720 (C=O), 1679 (C=O), 1260 (C–O) cm−1; 1H NMR (CDCl3, 400 MHz)
δ: 8.00 (d, 1H, J = 8.0 Hz, ArH); 7.86 (d, 2H, J = 8.5 Hz, ArH);
7.75 (d, 1H, J = 8.0 Hz, ArH); 7.71–7.65 (m, 2H, ArH); 7.42 (t, 2H,
J = 8.5 Hz, ArH); 7.34 (t, 1H, J = 8.5 Hz, ArH); 7.28 (d, 1H, J =
7.5 Hz, ArH); 7.26 (d, 1H, J = 7.5 Hz, ArH); 6.40 (s, 1H, CH=C);
5.72 (brs, 1H, OH); 3.74–3.72 (m, 1H, CH); 3.53 (dd, 1H, J1 = 2.4,
J2 = 18.0 Hz, CH2), 3.49 (dd, 1H, J1 = 9.0, J2 = 18.0 Hz, CH2); Anal.
Calcd for C22H16O4: C, 76.73; H, 4.68. Found: C, 76.59; H, 6.75%.
4-(1-Hydroxy-3-oxo-3-p-tolylpropyl)-2H-benzo[h]chromen-2-one
(3h): 93%; m.p. 198–200 °C; IR(KBr) υ: 3445 (OH), 2921 (CH), 1710
Synthesis of β-hydroxy-ketones (3); general procedure
The mixture of the 2-oxo-2H-chromene-4-carbaldehyde derivatives
(4 mmol), α-bromoacetophenones (6 mmol), zinc powder (6 mmol)
and a trace of iodine in ionic liquid [Bmim]Cl (3.0 g) were stirred at
55–60 °C for several hours. Water (15 mL) was added and the reaction
mixture was extracted by ethyl acetate (10 mL × 3). The organic layer
1
(C=O), 1676 (C=O), 1263 (C–O) cm−1; H NMR (CDCl3, 400 MHz)
δ: 8.02 (d, 1H, J = 8.0 Hz, ArH); 7.81 (d, 2H, J = 8.5 Hz, ArH);
7.75–7.71 (m, 2H, ArH); 7.68 (d, 1H, J = 8.0 Hz, ArH); 7.48 (d, 2H,
J = 8.0 Hz, ArH); 7.35 (d, 1H, J = 8.0 Hz, ArH); 7.32 (d, 1H,

JOURNAL OF CHEMICAL RESEARCH 2012 395
References
J = 8.0 Hz, ArH); 6.50 (s, 1H, CH=C); 5.73 (brs, 1H, OH); 3.68–3.65
(m, 1H, CH); 3.51 (dd, 1H, J1 = 2.4, J2 = 18.0 Hz, CH2); 3.48 (dd, 1H,
J1 = 9.0, J2 = 18.0 Hz, CH2); 2.42 (s, 3H, CH3); Anal. Calcd for
C23H18O4: C, 77.08; H, 5.06. Found: C, 76.95; H, 5.18%.
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Recycling of IL([Bmin]Cl)
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We thank the Young Scholars of Heilongjiang Province of
China (grants No. QC2009C61) and the Program for Young
Teachers Scientific Research in Qiqihar University (grant No.
2010K-M23) for financial support.
Received 13 April 2012; accepted 16 April 2012
Paper 1201258 doi: 10.3184/174751912X13371652436057
Published online: 26 June 2012

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