Novel and efficient route for the synthesis of 4-Aryl-substituted 2(5H)-furanones

Article abstract of DOI:10.1080/00397910802656026

4-Aryl-substituted 2(5H)-furanones were prepared by reaction of diethylphosphono acetic acid and phenacyl bromides, followed by an intramolecular Horner-Emmons-type cyclization. Both the reactions were carried out in situ to give the desired 4-aryl substituted 2(5H)-furanone derivatives.

Full text of DOI:10.1080/00397910802656026

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Novel and Efficient Route
for the Synthesis of 4-Aryl-
Substituted 2(5H)-Furanones
Pravin Thombare a , Jigar Desai a , Anil Argade a
Sanjay Gite a , Kiran Shah a , Laxmikant Pavase a
Pankaj Patel a
,
&
a Medicinal Chemistry Division, Zydus Research
Center, Gujarat, India
Version of record first published: 01 Jun 2009
To cite this article: Pravin Thombare, Jigar Desai, Anil Argade, Sanjay Gite, Kiran
Shah, Laxmikant Pavase & Pankaj Patel (2009): Novel and Efficient Route for the
Synthesis of 4-Aryl-Substituted 2(5H)-Furanones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:13,
2423-2429
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Synthetic Communications1, 39: 2423–2429, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802656026
Novel and Efficient Route for the Synthesis
of 4-Aryl-Substituted 2(5H)-Furanones
Pravin Thombare, Jigar Desai, Anil Argade, Sanjay Gite,
Kiran Shah, Laxmikant Pavase, and Pankaj Patel
Medicinal Chemistry Division, Zydus Research Center, Gujarat, India
Abstract: 4-Aryl-substituted 2(5H)-furanones were prepared by reaction of
diethylphosphono acetic acid and phenacyl bromides, followed by an intramole-
cular Horner–Emmons-type cyclization. Both the reactions were carried out
in situ to give the desired 4-aryl substituted 2(5H)-furanone derivatives.
Keywords: DBU, diethylphosphono acetic acid, furanone, Horner–Emmons
cyclization, phenacyl bromides
a,b-Unsaturated c-butyrolactones [2(5H)-furanones] possess interesting
biological properties such as antiulcer, antibiotic, insecticidal, fungicidal,
antimicrobial, and antitumor activities.[1–4]
The synthesis of 4-substituted 2(5H)-furanone is more challenging
than the corresponding three or five analogs.[3,4] Considering the impor-
tance and challenging synthesis of 2(5H)-furanones, much attention has
been paid to the preparation of 4-substituted 2(5H)-furanones. The
majority of these methods involve transition-metal-catalyzed coupling
leading to the desired 2(5H)-furanones. The most widely used reactions
are Stille,[5] Suzuki,[6] and Suzuki–Miyaura[7] couplings.
The major drawback of the Stille cross-coupling reaction is the annoying
preparation of organotin compounds and difficult removal of the toxic orga-
notin by-products. Development of Suzuki coupling reaction along with the
Received August 22, 2008.
ZRC Communication No. 228.
Address correspondence to Jigar Desai, Medicinal Chemistry Division, Zydus
Research Center, Sarkhej Bavla, NH No. 8A, Moraiya, Ahmedabad 382210,
Gujarat, India. E-mail: jigarndesai@rediffmail.com
2423

2424
P. Thombare et al.
ready availability of boronic acids has attracted wide attention for the
synthesis of 4-substituted 2(5H)-furanones. Difficulty in the synthesis of
4-bromo-2(5H)-furanone and stability of b-tetronic acid triflate under nor-
mal reaction conditions are the major drawbacks of the Suzuki coupling
reaction. Recently, Wu et al.[4] used 4-tosyl-2(5H)-furanone instead of
b-tetronic acid triflate in the Suzuki coupling reaction. The ease of synthesis
of 4-tosyl-2(5H)-furanone and its stability toward the standard Suzuki
reaction conditions made this substrate more versatile for the synthesis of
4-aryl-2(5H)-furanones. Zhen-Yu et al.[8] used 4-tosyl-2(5H)-furanone under
Suzuki–Miyaura cross couplings in the presence of nickel (0)=tricyclohexyl-
phosphine [Ni(0)=PCy3] catalyst to get 4-substituted-2(5H)-furanones.
Wu et al.[9] used organozinc compounds instead of organoboronic acid with
4-tosyl-2(5H)-furanone in the presence of Ni(II) catalyst. Synthesis of
4-substituted-2(5H)-furanone in the presence of transition metal has
also been reported.[10,11] Mehta et al.[12] synthesized 4-aryl-substituted 2(5H)-
furanones via Heck reaction of diazonium salts with 2,5-dihydrofuran.
Kagabu et al.[13] synthesized 4-aryl-substitited 2(5H)-furanones by treating
b-arylcrotonic esters with selenium dioxide in acetic acid in the presence of
a catalytic amount of perchloric acid. There are very few reports of the synth-
esis of 2(5H)-furanones without using a transition-metal catalyst.
Considering the earlier literature for the synthesis and importance of
2(5H)-furanones, there is a need for an easy, facile, and environmentally
friendly process. The basic requirements for the desired schemes are
(1) ease of availability of starting materials, (2) avoiding the use of
transition-metal catalyst, (3) reaction conditions compatible with diverse
functional groups, and (4) mild reaction condition. To satisfy all these
conditions, we found that intramolecular Horner–Emmons-type cycliza-
tion is an ideal reaction to get suitably substituted furanone derivatives.
The Horner–Emmons-type reaction is widely used in the preparation of
E-disubstituted a,b-unsaturated olefins.[14,15]
In continuation of our research on the green chemistry, herein we
report an easy and facile synthesis of 4-aryl-substituted 2(5H)-furanones.
The furanone formation is the combination of the phenacyl ester forma-
tion followed by an intramolecular Horner–Emmons-type reaction to get
cyclized product. The reaction can be carried out under mild conditions
using a base such as triethylamine or 1,8-diazabicyclo [5,4,0]undec-7-ene
(DBU), of which DBU is preferred.
The reaction of diethylphosphono acetic acid (3) with phenacyl
bromides (2) under mild basic conditions led to the formation of
phosphonate ester (4) in almost quantitative yield. The phosphonate
ester was converted to 4-aryl-substituted 2(5H)-furanone (1) under an intra-
molecular Horner–Emmons-type cyclization reaction. Because of very high
reactivity of phosphonate ester toward intramolecular Horner–Emmons

4-Aryl-Substituted 2(5H)-Furanones
2425
cyclization, it is very difficult to isolate this intermediate (4), and we observed
the formation of desired 4-aryl-substituted 2(5H)-furanone derivatives.
In conclusion, we report herein a versatile method for the efficient
and facile synthesis of 4-aryl-substituted 2(5H)-furanones using easily
available diethylphosphono acetic acid and phenacyl bromides. The ease
of formation of phenacyl ester and its subsequent Horner–Emmons-type
cyclization make the process very simple and highly efficient, and at the
same time, the entire sequence can be carried out in one pot.
EXPERIMENTAL
All the 2-bromo-1-substituted phenyl ethanone derivatives were synthe-
sized according the literature procedure.[16] Diethylphosphono acetic acid
1
obtained from Aldrich was used directly for the experiments. H NMR
spectra were recorded using CDCl3 or dimethylsulfoxide (DMSO) as
solvent with tetramethylsilane (TMS) as an internal standard on Bruker
300-MHz and 400-MHz instruments.
Preparation of (Diethoxy-phosphoryl)-acetic Acid
2-Benzo[1,3]dioxol-5-yl-2-oxo-ethyl Ester
Diethylphosphono acetic acid (0.520 g, 3.24 mmol) was added to a mix-
ture of 1-benzo[1,3]dioxol-5-yl-ethanone (0.5 g, 2.16 mmol) in dimethyl
formamide (10 mL) under nitrogen. The reaction mixture was cooled to
0–5ꢀC. Triethyl amine (1 mL, 6.48 mmol) was added. The mixture was
stirred at 0–5ꢀC for 0.5 h. Completion of the reaction was monitored
by thin-layer chromatography (TLC). The reaction mixture was
quenched in water (50 mL). The compound was extracted in ethyl acetate
(20 mL ꢁ 3). The organic layer was dried over sodium sulfate (4 g), and
the solvent was removed under reduced pressure to get an oily crude com-
pound, which was purified by flash column chromatography using silica
gel (eluent: ethyl acetate) to afford the title compound (0.75 g, 97.26%).
1H NMR (400 MHz, CDCl3): d 1.36 (t, 6H, J ¼ 6.8 Hz); 3.13 (d, 2H);
4.20 (q, 4H, J ¼ 6.8 Hz ); 5.24 (s, 2H); 6.07 (s, 2H); 6.86 (d, 1H, J ¼ 8 Hz);
7.39 (d, 1H, J ¼ 1.6 Hz); 7.49 (d, 1H, J ¼ 8.4 Hz). ESI-MS (359, M þ H)þ.
General Procedure for the Preparation of 4-Aryl Substituted
2(5H)-Furanones Derivatives
Diethylphosphono acetic acid (1.0 mmol) was added to a mixture of
phenacyl bromide derivative (1.0 mmol) in dimethyl formamide (10 mL).

2426
P. Thombare et al.
The reaction mixture was cooled to 0–5ꢀC, and DBU (3 mmol) was
added. The mixture was stirred at 0–5ꢀC for 0.5 h and allowed to warmed
to 25–35ꢀC, then stirred for another 0.5 h. Completion of reaction was
monitored by TLC. The mixture was quenched in 10% aq. HCl
(30 mL), and the compound was extracted by adding ethyl acetate
(20 mL ꢁ 3). Combined organic layer was washed with water (50 mL).
The organic layer was dried over sodium sulfate (4 g), and the solvent
was removed under reduced pressure to get oily crude compound, which
was purified by flash column chromatography using silica gel (230–400
mesh; eluent: petroleum ether–ethyl acetate) to afford 4-aryl-substituted
2(5H)-furanone derivatives 1a–1i. The products were characterized by
1
IR, H NMR, and ESI-MS spectroscopy.
Data
Compound 1a
4-Phenylfuran-2(5H)-one. Yield ¼ 62%, mp 91ꢀC (lit. 87ꢀC).[13] 1H NMR
(400 MHz, DMSO): d 5.38 (d, 2H, J ¼ 1.6 Hz); 6.73 (d, 1H); 7.53 (m, 3H);
7.68 (m, 2H). IR (KBr): 3058, 1795, 1732, 1616, 1450, 1151, 894 cmꢂ1
ESI-MS: 160.8 (Mþ).
.
Compound 1b
4-(4-Methyl-phenyl)furan-2(5H)-one. Yield 75%, mp 115ꢀC (lit.
117ꢀC).[13] 1H NMR (300 MHz, DMSO): d 2.35 (s, 3H); 5.33 (d, 2H,
J ¼ 1.55 Hz); 6.63 (s, 1H); 7.30 (d, 2H, J ¼ 8.03 Hz); 7.59 (d, 2H,
J ¼ 8.13 Hz). IR (KBr): 1789, 1730, 1618, 1161, 1043 cmꢂ1. ESI-MS
(197, M þ Naþ).
Compound 1c
1
4-(4-Isobutylphenyl)furan-2(5H)-one. Yield 79%, mp 154ꢀC. H NMR
(400 MHz; CDCl3): d 0.92 (d, 6H, J ¼ 6.8 Hz); 1.90 (m, 1H); 2.52 (d,
2H, J ¼ 5.1 Hz); 5.21 (d, 2H, J ¼ 1.6 Hz); 6.33 (t, 1H, J ¼ 1.6 Hz); 7.23
(d, 2H, J ¼ 8.4 Hz); 7.42 (d, 2H, J ¼ 8.4 Hz). IR (KBr): 2950, 1795,
1737, 1622, 1164, 896 cmꢂ1. ESI-MS: 216.9 (M þ H)þ.
Compound 1d
4-(3,4-Dimethylphenyl)furan-2(5H)-one. Yield 78%, mp 120ꢀC. 1H NMR
(400 MHz, DMSO): d 2.26 (s, 6H); 5.33 (d, 2H, J ¼ 0.80 Hz); 6.61 (brs,

4-Aryl-Substituted 2(5H)-Furanones
2427
1H); 7.28 (d, 1H, J ¼ 7.60 Hz); 7.44 (d, 2H, J ¼ 8.00 Hz); 7.49 (brs, 1H).
IR (KBr): 3093, 2943, 1797, 1728, 1618, 1448, 1325, 1197, 896, 823 cmꢂ1
ESI-MS: 188.8 (M þ H)þ.
.
Compound 1e
4-(Biphenyl-4-yl)furan-2(5H)-one. Yield 68%, mp 176ꢀC. 1H NMR
(400 MHz, DMSO): d 5.41 (d, 2H, J ¼ 1.6); 6.77 (1H, brs); 7.40 (t, 1H,
J ¼ 7.6 Hz); 7.49 (t, 2H, J ¼ 7.6 Hz); 7.75 (d, 2H, J ¼ 5.4 Hz); 7.70–7.83
(4H, m). IR (KBr): 3080, 2962, 1792, 1732, 1612, 1487, 1326, 1173,
894 cmꢂ1. ESI-MS: 236.9 (M þ H)þ.
Compound 1f
4-(4-Methoxyphenyl)furan-2(5H)-one. Yield 80%, mp 120ꢀC (lit.
121ꢀC).[13] 1H NMR (400 MHz, DMSO): d 3.81 (s, 3H); 5.32 (d, 2H,
J ¼ 1.2 Hz); 6.56 (brs, 1H); 7.03 (d, 2H, J ¼ 8.81 Hz); 7.65 (d, 2H,
J ¼ 8.81 Hz). IR (KBr): 3113, 2931, 1792, 1735, 1571, 1427, 1238, 1163,
895 cmꢂ1. ESI-MS: 190.8 (M þ H)þ.
Compound 1g
1
4-(Benzo[d][1,3]dioxol-5-yl)furan-2(5H)-one. Yield 80%, mp > 200ꢀC. H
NMR (400 MHz, DMSO): d 5.29 (d, 2H, J ¼ 0.8 Hz); 6.11 (s, 2H); 6.59
(brs, 1H); 7.03 (d, 1H, J ¼ 8.00 Hz); 7.19 (d, 1H, J ¼ 8.00 Hz); 7.38
(s, 1H). IR (KBr): 3097, 2866, 1807, 1720, 1681, 1606, 1269, 1232,
993 cmꢂ1. ESI-MS: 204.9 (M þ H)þ.
Compound 1h
4-(4-(Methylthio)phenyl)furan-2(5H)-one. Yield 76%, mp 101ꢀC. 1H
NMR (300 MHz, DMSO): d 2.48 (s, 3H); 5.33 (d, 2H, J ¼ 1.8 Hz); 6.67
(t, 1H, J ¼ 1.61 Hz); 7.3 (d, 2H, J ¼ 8.53 Hz); 7.6 (d, 2H, J ¼ 8.57 Hz).
IR (KBr): 3085, 1801, 1716, 1681, 1411, 1172, 898 cmꢂ1. ESI-MS: 206.9
(M þ H)þ.
Compound 1i
4-(4-Fluorophenyl)furan-2(5H)-one. Yield 60%, mp 144ꢀC. 1H NMR
(400 MHz, DMSO): d 5.36 (d, 2H, J ¼ 1.6 Hz); 6.71 (brs, 1H); 7.34

2428
P. Thombare et al.
(m, 2H); 7.79 (m, 2H). IR (KBr): 3114, 3070, 1786, 1737, 1624, 1228,
1161, 991 cmꢂ1. ESI-MS: 178.8 (M þ H)þ.
ACKNOWLEDGMENT
The authors are thankful to the management of Cadila Healthcare
Limited for the support of this research.
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