A convenient method for lactonization of α-allyl esters using iodine in dimethylsulphoxide

Article abstract of DOI:10.4314/bcse.v28i3.16

A simple method for the synthesis of α-γ-disubstituted-γ-butyrolactones by cyclization of α-allyl esters using iodine in dimethylsulphoxide is reported. This method is efficient and operationally simple in comparison to methods using transition metal comp

Full text of DOI:10.4314/bcse.v28i3.16

Bull. Chem. Soc. Ethiop. 2014, 28(3), 469-473.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v28i3.16
ISSN 1011-3924
 2014 Chemical Society of Ethiopia
SHORT COMMUNICATION
A CONVENIENT METHOD FOR LACTONIZATION OF α-ALLYL ESTERS USING
IODINE IN DIMETHYLSULPHOXIDE
Beena R. Nawghare, Sunil V. Gaikwad, Bharati V. Pawar and Pradeep D. Lokhande*
The Centre for Advanced Studies, Department of Chemistry, University of Pune, Pune 411007,
India
(Received April 10, 2013; revised May 13, 2014)
ABSTRACT. A simple method for the synthesis of α-γ-disubstituted-γ-butyrolactones by cyclization of α-allyl
esters using iodine in dimethylsulphoxide is reported. This method is efficient and operationally simple in
comparison to methods using transition metal complexes.
KEY WORDS: γ-Butyrolactones, α-Allyl esters, Iodine, Dimethyl sulphoxide
INTRODUCTION
γ-Butyrolactones are important building blocks in the synthesis of many natural products [1].
Saturated γ-lactones are encountered frequently in large number of natural products especially
flavour components and plant growth regulators [2]. γ-Lactones are also very useful in the
synthesis of nucleosides and related bioactive compounds. In particular, some aryl substituted γ-
lactones have shown cancer preventive and anti-inflammatory properties [3].
Several routes to prepare γ-lactones and lactone derivatives have been reported [4].
Numerous synthetic methods [5] have been developed for the synthesis of chiral α-methylene
butyrolactones, often using transition metals or their [6].
Yamazaki et al. reported the use of the allyl group as a protecting group for the acidic
hydrogen in malonic ester [7]. Iodine is available as a crystalline solid and is easy to handle and
not particularly toxic. The DMSO-I2 reagent has been used in the oxidative cyclization of 2’-
hydroxy chalcones to flavones [8], the oxidation of flavanones to flavones [9], isoxazolines to
isoxazoles [10], and pyrazolines to pyrazoles [11]. It has also been used for the deprotection of
allyl carboxylic esters [12]. Very recently we reported the selective deallylation of allyl ethers
and esters using iodine in polyethylene glycol-400 [13]. Allyl ethers of phenols are selectively
deprotected using iodine in dimethyl sulphoxide [14].
Initial results of the use of iodine in dimethylsulphoxide for oxidative cyclization of 2’-
allyloxy chalcones to flavones encouraged us to use this reagent system for the cyclization of α-
allyl esters. 2’-Allyloxy chalcones with iodine (20%) in dimethylsulphoxide result in attack of
the allyloxy oxygen towards reactive alkene group. This results in the deallylation of 2’-allyloxy
chalcones followed by cyclization to give six membered flavone rings. In α-allylphenyl acetate,
the allyl group is attached to a carbon which is bonded to an aryl ring and a carbonyl group. This
carbon is sufficiently acidic to give the deallylated product. To study C-deallylation, α-allyl
esters were reacted with iodine (20%) in dimethylsulphoxide reagent. But under the initial
conditions, it was observed that the oxygen of the ester group attacks the allyl group to form the
corresponding γ-butyrolactone. We herein report the results of a study involving the reaction of
α-allyl esters with I2-DMSO to yield α-γ-disubstituted-γ-butyrolactones.
__________
*Corresponding author. E-mail: pdlokhande@chem.unipune.ernet.in

470
Beena R. Nawghare et al.
EXPERIMENTAL
General procedure for cyclization of α-allyl esters to α-γ-disubstituted-γ-butyrolactones (2a-o).
To a solution of α-allyl ester 1 (1 mmol) in dimethylsulphoxide (3 mL) was added iodine (0.2
mmol). The reaction mixture was heated in an oil bath at 80-90 °C for 2 hours. After cooling,
the reaction mixture was diluted with water and iodine was removed by addition of a saturated
solution of sodium thiosulphate followed by a water wash. The product was extracted into ethyl
acetate, washed with water, dried over anhydrous Na2SO4, and the solvent removed using a
rotary evaporator. The product was purified by column chromatography (hexane/ethyl acetate,
9:1).
1
Compound 2a. Colorless oil, H NMR (300 MHz, CDCl3) δ 1.46 (d, J = 7.5 Hz, 3H), 2.61 (m,
2H), 3.88 (t, 4.42 (t, J = 7.2 Hz, 1H), 4.6 (m, 1H), 7.18 (d, J = 7.2 Hz, 2H), 7.32 (m, 3H); 13C
NMR (75 MHz, CDCl3) δ 174.1, 144.3, 134.5, 134.8, 131.2, 121.3, 77.1, 22.8; IR 1763, 1610,
1511 cm-1; MS(m/z) 176 (M+ ion).
Compound 2c [15]. White crystals, yield 74%, m.p. 103–106 ºC. IR(KBr pellet): 1764, 1611,
158 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.13 (d, J = 6.9 Hz, 2H), 7.43 (d, J = 6.9 Hz, 2H), 4.65
(m, 1H), 3.8 (t, J = 6.9 Hz, 1H), 2.61 (m, 2H), 1.46 (d, J = 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 175.44; 147.12; 143.93; 128.65; 123.93; 75.15; 45.07; 37.21; 20.99. B: 175.16;
147.12; 143.44; 128.97; 123.79; 75.20; 47.28; 39.23; 20.71.
Compound 3c [15]. Yellow crystals, yield 56%, m.p. 130–133 ºC. IR (KBr pellet): 3074, 1743,
1600, 1511, 856 cm-1; 1H NMR (300 MHz, CDCl3): δ 8.20 (d, J = 6.9 Hz, 2H), 8.09 (d, J = 6.9
Hz, 2H), 7.78 (d, J = 1.7 Hz, 1H); 5.23 (m, J = 1.7 Hz, 1H); 1.56 (d, J = 6.9 Hz, 3H), 13C NMR
(75 MHz, CDCl3): δ 170.51; 152.14; 147.86; 135.43; 129.53; 127.82; 123.73; 77.08; 18.99;
calcd for C11H9NO4: C, 60.28; H, 4.14; N 6.39; found: C, 60.28; H, 4.08; N 6.39.
RESULTS AND DISCUSSION
Earlier we reported the use of DMSO-I2 for the synthesis of flavones from 2’-allyloxy chalcones
[16] in which the allyl group is first deprotected and the resulting 2’-allyloxychalcones then
oxidatively cyclized to flavones. We thought this type of cyclization would be possible in α-allyl
esters using the same reagent. To test this hypothesis, α-allyl carboxylic esters (1) were reacted
with iodine (20%) in dimethyl sulphoxide in order to generate the γ-butyrolactone. The reaction
was complete in 3-4 hours at 80-90 °C. It was observed that the reaction resulted in cyclization
to give the product α-γ-disubstituted-γ-butyrolactone (2) (Scheme 1).
CH3
O
CH3
O
DMSO - I2 (20%)
DMSO - I2 (20%)
80-90 °C, 3-4 h
OR1
80-90 °C, H+ 3-4 h
R
R
R
O
O
O
3
1
2
Scheme 1. Cyclization of α-allyl carboxylic esters.
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Short Communication
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Table 1. Cyclization of α-allyl esters to α-γ-disubstituted-γ-butyrolactones by using I2-DMSO.
Entry Substrate R
R1
C2H5
C2H5
Yield % 2(a-o)a,b
1
2
1a
1b
1c
1d
1e
1f
C6H5-
78
71
74
61
63
71
59
70
67
72
60
2-NO2-C6H4-
4-NO2-C6H4-
CH3-
3
C2H5
4
CH3
CH3
5
C2H5-
C4H9-
C10H21-
6
C2H5
CH3
7
1g
1h
1i
8
C6H5-
CH-(CH3)2
CH-(CH3)2
CH3
9
2-NO2-C6H4-
2-NO2-C6H4-
10
11
1j
1k
C2H5
C6H5COCHCOOC2H5
12
13
1l
C2H5
C2H5
58
54
4-(OCH3)C6H4COCHCOOC2H5
3,4-(OCH3)2C6H3COCHCOOC2H5
4-ClC6H4COCHCOOC2H5
1m
14
1o
C2H5
52
aIsolated yields of the product. bProducts are characterized by spectral analysis.
There are different methods reported for allyl cyclization using iodine. In most cases,
iodocyclization gives the desired product [17]. In the synthesis of flavones from 2’-
hydroxychalcones, Silva and co-worker reported that traces of HI were observed [18]. In the
presence of HI, our cyclization method results in generation of γ-methyl-butyrolactones.
Presumably, this reaction is initiated by the HI which is formed in situ [19]. The generation of
HI can be explained by the following reaction (Scheme 2).
O
S
O I
S
O I
S
O
S
I2
I
I
HI
I
H
I
Scheme 2. Formation of HI.
A possible mechanism for cyclization of α-allyl carboxylic esters (1) to α-γ-disubstituted-γ-
butyrolactone (2) is presented below (Scheme 3).
H
H
I
H
CH3
O
I-
DMSO - I2
80-90 °C
OR1
R
OR1
R
R
O
O
O
2
1
Scheme 3. A proposed mechanism for lactonization of α-allyl carboxylic esters.
α-Substituted-γ-methyl-butenolides are very important compounds in the synthesis of natural
products. α-Phenyl-γ-methyl-butenolide has antifungal activity [20] against filamentous fungi.
Bull. Chem. Soc. Ethiop. 2014, 28(3)

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Beena R. Nawghare et al.
α-Butyl-γ-methyl-butenolide can be used as a precursor for the synthesis of blastmycinone,
blastmycinolactol.
Previous studies reported the synthesis of flavones from 2’-allyloxy chalcones [16]. In this
reaction, deallylation with oxidative cyclization of 2’-allyloxy chalcones gives flavones at 130
°C in 30 min. The same reaction can be accomplished at 60 °C in presence of a drop of
concentrated sulphuric acid. In order to examine the effect of acid in reducing the temperature of
the cyclization reaction of α-allyl carboxylic esters (1), a drop of concentrated sulfuric acid was
added to the iodine in dimethylsulphoxide (Scheme 2). The reaction was completed in 3 h
giving 40% yield. The plausible mechanism for the formation of α-substituted-γ-methyl-
butenolide from α-allyl carboxylic esters (1) is shown in Scheme 4.
Table 2. Cyclization of α-allyl esters to α-substituted-γ-methyl-butenolide by using I2-DMSO/H+.
Entry
Substrate
R
R1
Yield % 3(a-e)a,b
1
2
3
4
5
1a
1b
1c
1d
1e
C6H5-
CH3
CH3
CH3
CH3
CH3
40
35
30
15
25
2-NO2-C6H4-
4-NO2-C6H4-
CH3-
C4H9-
aIsolated yields of the product. bProducts are characterized by spectral analysis.
Table 3. Effect of Quantity of iodine.
Entry
Compound
Iodine (mmol)
0.10
Yield 2a(%)a,b
1
2
3
4
1a
1a
1a
1a
35
52
78
79
0.15
0.20
0.25
aIsolated yields of the product. bProducts are characterized by spectral analysis.
CH3
O
CH3
O
CH3
O
CH3
O
CH3
H
DMSO - I2
I-I
OR1
O
R
80-90 °C
H+
R
R
R
R
R
O
H
O
I
H+
I
O
I
O
O
O
I
H
H
3
1
2
Scheme 4. The plausible mechanism for the formation of α-substituted-γ-methyl-butenolide.
In conclusion, we report a method for preparing α-γ-disubstituted-γ-butyrolactones by
cyclization of α-allyl esters using iodine in dimethylsulphoxide. The efficiency, ready
availability, and ease of handling encourages using the reagent for lactonization of various α-
allyl- esters. The DMSO-I2 reagent in the presence of a catalytic amount of H+ is useful for the
synthesis of α-substituted-γ-methyl-butenolides.
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