An effective method for the preparation of chlorolactones

Article abstract of DOI:10.1016/j.cclet.2010.11.014

The effective chlorolactonization of alkenoic acids with (diacetoxyiodo)benzene and lithium chloride under mild conditions have been studied. Experiments show that various 4-pentenoic acids react with (diacetoxyiodo)benzene and lithium chloride fluently in CH₃OH at room temperature, obtaining five-membered chlorolactones in good yields in short times. Other alkenoic acids, such as 3-butenoic acid and trans 3-hexenoic acid give some more complicated results, and 4-pentynoic acid provides a chloroenol lactone with Z configuration in 40% of yield.

Full text of DOI:10.1016/j.cclet.2010.11.014

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 431–434
www.elsevier.com/locate/cclet
An effective method for the preparation of chlorolactones
*
Min Zhu , Li Li, Jiang Ying Tong, Hui Zhang
College of Biological and Environmental Sciences, Zhejiang Shuren University, Hangzhou 310015, China
Received 23 August 2010
Available online 17 January 2011
Abstract
The effective chlorolactonization of alkenoic acids with (diacetoxyiodo)benzene and lithium chloride under mild conditions
have been studied. Experiments show that various 4-pentenoic acids react with (diacetoxyiodo)benzene and lithium chloride
fluently in CH3OH at room temperature, obtaining five-membered chlorolactones in good yields in short times. Other alkenoic
acids, such as 3-butenoic acid and trans 3-hexenoic acid give some more complicated results, and 4-pentynoic acid provides a
chloroenol lactone with Z configuration in 40% of yield.
# 2010 Min Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Chlorolactone; (Diacetoxyiodo)benzene; Alkenoic acid; Preparation
Halolactonization have been studied extensively, and this type of transformation serves as an important key reaction
in a variety of syntheses [1–3]. Whereas bromo- and iodolactonization are generally well documented, there are
relatively few examples of the preparation of chlorolactones. The conversion of unsaturated carboxylic acids into
chlorolactones is the classical process by adding of chlorine to the salts of unsaturated acids. However, molecular
chlorine is a highly toxic, difficult to handle gas and dichlorocompounds are generally formed as byproducts [4]. To
improve the chlorolactonization, chloramine Tand sodium hypochlorite with Lewis acids were used to replace Cl2 for
the reaction have been successful [5,6]. Diphenyl diselenide and catalyst (DHQD)2PHAL catalyzed the
chlorolactonization of unsaturated acids with N-chlorosuccinimide under mild conditions provided newer methods
[7,8]. The conversion of alcohols into their corresponding chlolides was another method [9–11], but usually it needed
multi-step reaction sequences. Recently, a convenient method for the bromolactonization of 4-pentenoic acid using
hypervalent iodine reagent (diacetoxyiodo)benzene (DIB) and lithium bromide has been reported [12,13]. In order to
extend the scope and develop a simple, mild and efficient chlorolactonization, we have investigated the cyclization of
alkenoic acids with DIB and LiCl. Herein we report a novel and efficient chlorolactonization of unsaturated acids and a
series of five-membered chlorolactones are obtained in good yields.
At the beginning, we select 4-pentenoic acid (1a) as the representative of alkenoic acids and mix it with equal
equivalent of DIB and three equivalents of LiCl in THF at room temperature, we find that the reaction proceeds
smoothly and only in 1 h it is compeled, a product of 5-(chloromethyl)-g-butyrolactone (2a) is obtained in 56% of
yield. Then, a series of experiments are performed on the reaction of 4-pentenoic acid with DIB and chlorides in 1 h in
* Corresponding author.
E-mail address: hzzm60@163.com (M. Zhu).
1001-8417/$ – see front matter # 2010 Min Zhu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.11.014

4[()TD$FIG] 32
M. Zhu et al. / Chinese Chemical Letters 22 (2011) 431–434
O
O
RT
O
PhI(OAc)2
LiCl
OH
Cl
1a
2a
Scheme 1.
Table 1
Optimization of the chlorolactonization of 4-pentenoic acid.
Entry
DIB (equiv.)
LiCl (equiv.)
Solvent
Yield (%)a
1
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0
3.0
CH2Cl2
THF
21
56
42
22
73
20
8
3.0
3
3.0
CH3CN
DMF
4
3.0
5
3.0
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
6
NaBr (3.0)
KBr (3.0)
NH4Br (3.0)
3.0
7
8
23
33
0
9
10
3.0
a
Isolated yield.
[()TD$FIG]
O
O
CH3OH
RT
O
n
n
PhI(OAc) 2
LiCl
OH
Cl
1
2
Scheme 2.
order to determine the optimum reaction conditions (Scheme 1), the results are summarized in Table 1. It is shown that
CH3OH is the most preferred solvent (entries 1–5). Among chlorides, LiCl is the best chioce and others, such as KCl,
NaCl and NH4Cl are not effective in the reaction (entries 5–8). When the amount of DIB is one equivalent and LiCl is
three equivalents, the yield reaches the highest of 73% (entries 5, 9, 10).
Under the optimum reaction conditions, the reaction of a series of alkenoic acids (1) with lithium chloride and
(diacetoxyiodo)benzene in CH3OH at room temperature is investigated (Scheme 2), and several chlorolactones (2) are
provided in good yields, which are characterized by 1H NMR, 13C NMR, IR, MS, HRMS spectra and melting points,
the good results are summarized in Table 2.
It is shown from Table 2 when a series of 4-pentenoic acids are used in the reaction, the desired products of 5-
(chloromethyl)-g-butyrolactones are obtained in good yields (entries 1–4); while 2-cyclopentene-1-acetic acid (1e) is
used, the reaction provides the corresponding product in middle yield due to the restrictive effect of the ring (entry 5).
Similar treatment of 3-butenoic acid and trans 3-hexenoic acids, the reactions give more complicated results: a four-
membered ring chlorolactone and a five-membered ring chlorolactone are obtained from 3-butenoic acid with a ratio
of 3:2; trans 3-hexenoic acids also provides a four-membered ring chlorolactone and a five-membered ring
chlorolactone with the same ratio, besides both of them, an unsaturated lactone (2j) is found by 1H NMR technique
(entries 6, 7). When 4-pentynoic acid is used in the protocol, a chloroenol lactone with Z configuration is provided in
40% yield (entry 8). Efforts for preparation of the six-membered chlorolactone using 5-hexenoic acid are not
successful, it means that this reaction is in favor of five-membered ring lactones and four-membered ring lactones.
The proposed mechanism for the chlorolactonization of alkenoic acids is similar to the literature procedure [14],
which includes the electrophilic addition of (diacetoxyiodo)benzene on the double bond, then an intramolecular
nucleophilic displacement is happened, following another nucleophilic displacement to give the chlorolactone.
A typical procedure for the chlorolactonization of alkenoic acids is as follows:
4-Pentenoic acid (1a) (0.3 mmol), (diacetoxyiodo)benzene (0.3 mmol) and lithium chloride (0.9 mmol) are added
in CH3OH (2 mL). The mixture is stirred at room temperature for 1 h and then separated on a silica gel plate using (3:2

M. Zhu et al. / Chinese Chemical Letters 22 (2011) 431–434
433
Table 2
The result of the chlorolactonization of alkenoic acids.
Entry
Alkenoic acids (1)
Chlorolactones (2)
Yield (%)a
O
[
CH2=CH(CH2)2CO2H
[DT$LINE]
O
1
73
1a
Cl
O
2a [5]
O
Me
[TD$LINE]
[TD$LINE]Me
CH2=CHCH2CHCO2H
2
3
4
5
81
80
87
55
Cl
1b
2b [15]
O
Me
[TD$LINE]
CH2=CHCHCH2CO2H
[DT$LINE]
O
Cl
1c
Me
2c [6]
O
Me
[D$LINE]
TMe
Me
[TD$LINE]
CH2=CHCH2CCO2H
O
Me
Cl
1d
2d [16]
O
O
O
OH
[TD$LINE]
[DT$LINE]
Cl
1e
2e
O
O
CH =CHCH CO H
[TD$LINE]
2
2
2
O
O
[DT$LINE]
O
6
7
(37 + 23)b
1f
Cl
Cl
2f [6] + 2g [17]
O
O
CH3CH2
(30 + 20 + 20)b
O
[DT$LINE]
O
[TD$LINE]
CH=CH
O
CH2CO2H
Cl
Cl
1g
2h [6] +2i [6] + 2j [18]
O
CH C(CH2)2COOH
[TD$LINE]
O
[DT$LINE]
8
40
1h
Cl
H
2k [19]
a
Isolated yield.
b
Determined by the 1H NMR.
hexane:ethyl acetate) as eluant, giving 5-(chloromethyl)-g-butyrolactone (2a) in 73% of yield. Colorless oil; 1H NMR
(500 MHz, CDCl3): d 4.80–4.76 (m, 1H), 3.76–3.68 (m, 2H), 2.70–2.61 (m, 1H), 2.60–2.54 (m, 1H), 2.46–2.39 (m,
1H), 2.22–2.14 (m, 1H); 13C NMR (125 MHz, CDCl3): d 177.10, 78.72, 46.69, 28.36, 24.86; IR (film, cmÀ1) 1775,
1182; MS (EI, m/z, %): 136 (37Cl M+, 2.3), 134 (35Cl M+, 5.8), 85 (100).

434
M. Zhu et al. / Chinese Chemical Letters 22 (2011) 431–434
In summary, we have successfully developed an effective chlorolactonization of pentenoic acids with
(diacetoxyiodo)benzene and lithium chloride, several 5-(chloromethyl)-g-butyrolactones are obtained in good yields.
This method has some advantages such as mild reaction conditions, simple procedure and good yields. Furthermore,
the scope of hypervalent iodine reagents in organic synthesis could be extended.
Acknowledgment
Financial support from the Zhejiang Province Natural Science Foundation of China (No. Y4080068) is greatly
appreciated.
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