Synthesis of chlorinated β- and γ-lactones from unsaturated acids with sodium hypochlorite and Lewis acids

Article abstract of DOI:10.1016/j.tetlet.2007.01.043

The direct synthesis of several β- and γ-lactones used as electrophilic sources of chlorine, sodium hypochlorite and a Lewis acid is described. The scope and limitations of the method are discussed.

Full text of DOI:10.1016/j.tetlet.2007.01.043

Tetrahedron Letters 48 (2007) 1749–1752
Synthesis of chlorinated b- and c-lactones from unsaturated
acids with sodium hypochlorite and Lewis acids
Jos e´ A. L o´ pez-L o´ pez, Francisco M. Guerra, F. Javier Moreno-Dorado,
Zacar ´ı as D. Jorge and Guillermo M. Massanet*
Departamento de Qu ı´ mica Org a´ nica, Facultad de Ciencias, Universidad de C a´ diz,
Pol ı´ gono R ı´ o San Pedro S/N, 11510 Puerto Real, C a´ diz, Spain
Received 21 November 2006; revised 8 January 2007; accepted 9 January 2007
Available online 13 January 2007
Abstract—The direct synthesis of several b- and c-lactones used as electrophilic sources of chlorine, sodium hypochlorite and a
Lewis acid is described. The scope and limitations of the method are discussed.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1
. Introduction
O
CeCl ·7H O
3
2
O
O
OH
Cl
n
NaClO
n
Recently, we have reported the allylic chlorination of
terminal double bonds by sodium hypochlorite pro-
moted by cerium trichloride heptahydrate. This system
produces efficiently electrophilic chlorine and constitutes
an easy and safe alternative to the use of chlorine gas,
avoiding the use of harsh conditions, in agreement with
the current concerns of green chemistry.
n = 1, 2
CH Cl :H O
n = 1, 2
2
2
2
1
Scheme 2. Chlorolactonization with CeCl
3
Æ7H
2
O/NaClO.
4
iodolactones has been well documented. The synthesis
of chlorolactones has drawn minor attention and only
a few methods have been reported.
The mechanistic insights of the reaction point to a cer-
ium-promoted formation of a chloronium ion and the
subsequent loss of the adjacent proton (Scheme 1). We
thought that this chloronium ion could be trapped intra-
molecularly by a nucleophilic group present in the mole-
cule so as to give rise to a heterocyclic ring. If such a
group resulted to be a carboxylic acid, the correspond-
Damin et al. discovered that the use of chloramine T in
conjunction with methanesulfonic acid is able to pro-
duce chlorolactones from the corresponding alkenoic
acids. Mellegaard and Tunge proposed the use of
PhSeCl and NCS in b,c-unsaturated acids as a way to
5
prepare butenolides, but the reaction produced mixtures
6
2
of allyl chlorides and chlorolactones. These authors
ing lactone should be formed (Scheme 2).
have also demonstrated the capacity of arylselenides to
enhance the electrophilicity of halogen sources.7
Since the pioneering works by Bougalt at the beginning
3
of the twentieth century, the preparation of bromo and
R1
2. Results and discussion
R1
CeCl
3
R1
Cl
Cl
R2
R2
R2
NaClO
Herein, we report a simple method to transform b,c-
and c,d-unsaturated acids into the corresponding b- or
c-lactones by the action of electrophilic chlorine gener-
ated from sodium hypochlorite and a Lewis acid. The
choice of the Lewis acid is a key point. Given our expe-
rience in the use of cerium trichloride, this metal was our
first option, but as in the case of the allylic chlorination,
we soon discovered that other metallic salts were also
H
Scheme 1. Allylic chlorination with CeCl
3
Æ7H
2
O/NaClO.
Keywords: c-Lactone; b-Lactone; Lactonization; Sodium hypochlorite;
Lewis acid.
*
Corresponding author. Tel.: +34 956 016366; fax: +34 956 016193;
e-mail: g.martinez@uca.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.043

1750
J. A. L o´ pez-L o´ pez et al. / Tetrahedron Letters 48 (2007) 1749–1752
a
Table 1. Chlorolactonization of unsaturated carboxylic acids with Lewis acid/NaClO
Entry
Substrate
Products
Yield (%) c-chlorolactone:b-chlorolactone ratio
CeCl
3
Æ
FeCl
6H
3
Æ
O
CuCl
2H
2
Æ
MgCl
6H
2
Æ
ZnCl
2
SnCl
2
Ce(NO
3 3
) Æ
7
H
2
O
2
2
O
2
O
6H
2
O
O
O
O
1
95
95
96
94
94
100
94
40
95
92
OH
OH
1
Cl
2
O
O
O
O
b
2
100
96
95
37
3
Cl
4
Cl
O
O
c
O
3
100
4:1
80
1:0
100
4:1
100
1:0
100
3:1
61
2:1
100
4:1
OH
O
Cl
Cl
O
O
5
6
9
7
Cl
O
c
O
4
OH
100
80
1:0
100
7:2
100
1:0
100
7:3
35
2:1
100
7:2
O
7
:2
8
10
O
O
H N
2
b
OH
O
5
89
93
92
91
92
100
97
75
100
86
89
NH2
Cl
1
1
1
2
Cl
O
O
d
6
0
95
56
OH
O
1
3
1
4
Cl
7
8
96
80
91
80
88
93
92
85
63
21
95
80
CO H
2
O
O
1
5
16
Cl
Ph
OH
Ph
O
100
100
O
O
1
7
1
8
9
100
100
96
85
97
48
90
COOH
COOH
Cl
1
9
20
a
b
c
All reactions were run at room temperature in a 1:1 CH
The observed ratio syn/anti is in all cases 2:3.
Only a single stereoisomer is observed for compounds 6, 7, 9 and 10.
Only dichlorination of the double bond was observed.
2
Cl
2
/H
2
O mixture, with 3 equiv of MCl
n
ÆmH
2
O (1.5 equiv when FeCl
3 2
Æ6H O is employed).
d
capable of promoting the transformation of pent-4-
enoic acid into the corresponding c-lactone 2 (Table 1,
entry 1). This reaction was run in a biphasic system,
employing a water/dichloromethane mixture as solvent
and 3 equiv of Lewis acid and sodium hypochlorite in
most cases. The results are summarized in Table 1.

J. A. L o´ pez-L o´ pez et al. / Tetrahedron Letters 48 (2007) 1749–1752
1751
The presence of a methyl group in the main chain of the
carboxylic acid does not influence the outcome of the
reaction. Thus, treatment of 3-methylpent-4-enoic acid
Finally, in order to study the role of the anion chloride,
we decided to run the reactions in the presence of cer-
ium nitrate hexahydrate. The yields were in the same
range as that in the other metallic chlorides, suggesting
that a chloride as a counterion of the metal is not
necessary, and that the sodium hypochlorite is able to
provide the chlorine atoms needed for the reaction to
proceed.
3
(entry 2) under the above described conditions pro-
duced 5-(chloromethyl)-4-methylfuranone 4 in high
yields (except with SnCl , vide infra).
2
In all those cases in which regioselection is an issue, the
formation of the most stable lactone is preferred. Inter-
estingly, treatment of (E)-pent-3-enoic acid 5 (entry 3)
provided b-lactone 7 in moderated yields. When the for-
mation of the b-lactone was the only possibility, the
yields resulted to be almost quantitative. Thus, treat-
ment of but-3-enoic acid 13 with 3 equiv of MgCl Æ6H O
All the reactions were finished after 30 min. The trans-
formation from the carboxylic acid to the lactone
started immediately after the addition of the very first
drop of sodium hypochlorite solution, so at the end of
the addition of NaOCl, the reaction was almost finished.
In order for the reaction to proceed, the carboxylic
group must be located two or three bonds far from the
double bond. The procedure is safe, clean and inexpen-
sive, constituting an alternative to consider for the prep-
aration of this type of valuable synthons.
2
2
produced the corresponding b-lactone 14 in 95% yield
entry 6).
(
It is also noteworthy the transformation of the amino-
acid D,L-allylglycine into 3-amino-3-(chloromethyl)fura-
none 12 as a mixture of epimers. This reaction
transcurred quantitatively when MgCl or SnCl was
2
2
employed (entry 5).
3. General procedure
The presence of an aromatic substituent as in styryl-
acetic acid 17 (entry 8) is also tolerated and the reaction
occurred in yields up to 80% of lactone 18. The presence
of chlorinated products in the aromatic ring was not
observed.
The following procedure can be considered as represen-
tative. The amount of metal should be reduced to
1.5 equiv in the case of FeCl Æ6H O.
3
2
3.1. Synthesis of b- and c-lactones with CeCl Æ7H O/
3
2
NaClO
The influence of the distance of the carboxyl group to
the chloronium ion was also inspected. When the car-
boxyl group is too far apart from the chloronium ion,
the reaction is not possible and other competitive reac-
tions take place. In all those cases in which we attempted
to get a d-lactone, only addition of molecular chlorine to
the double bond was observed. In the case of citronellic
acid 19 (entry 9), only the product from the allylic chlo-
rination was formed.
The unsaturated acid (1 mmol) was dissolved in
CH Cl /H O mixture (1:1, 10 mL) and CeCl Æ7H O
2
2
2
3
2
was added (3 equiv). The mixture was vigorously stirred
and diluted NaClO (10–13% available chlorine, 3 equiv)
aqueous solution was added dropwise for 10 min. After
stirring for 30 min, saturated aqueous Na SO solution
2
3
was added and the mixture was filtered through Celite.
The filtered mixture was extracted with EtOAc
(
3 · 20 mL). The organic layer was dried over anhy-
Regarding the nature of the metal, the best yields were
drous sodium sulfate. The solvent was removed in vacuo
to afford the corresponding chlorolactone.
observed by the employment of MgCl Æ6H O, in high
2
2
to quantitative yields. On the other side, SnCl produced
2
8
the poorest results, although surprisingly, this metal
chloride was able to transform allylglycine quantita-
tively into the corresponding amino chlorinated c-lac-
3.2. Selected spectroscopic data for novel compounds
1
3.2.1. 5-Chloromethyl-4-methylfuranone 4. H NMR
tone 12 (entry 5). The behaviour of FeCl was also
(CDCl , 400 MHz, diasteromers mixture): trans-isomer:
3
3
different. First, when 3 equiv of this reagent was em-
ployed, only the addition of chlorine to the double bond
4.6 (dt, 1H, H-5, J = 6.28 Hz), 3.62 (m, 1H, H-6), 2.73
(dd, 1H, H-3 , J = 13.4, 8.4 Hz), 2.5 (m, 1H, H-4),
a
was observed. When the amount of FeCl was reduced
2.16 (dd, 1H, H-3 , J = 13.0, 9.3, 4.1 Hz), 1.11 (d, 2H,
3
b
to 1.5 equiv, the behaviour was similar to other metals,
and more interestingly, it was able to transform itaconic
acid into the highly functionalized lactone 4-carboxy-4-
H-7, J = 6.87 Hz). Cis-isomer: 4.22 (m, 1H, H-5), 3.68
(d, 2H, H-6, J = 4.68 Hz), 2.68 (dd, 1H, H-3a,
J = 13.0, 9.3 Hz), 2.28 (m, 1H, H-4), 2.15 (dd, 1H, H-
(
chloromethyl) oxetanone 22 (Scheme 3). This transfor-
3 , J = 13.0, 9.3 Hz), 1.06 (d, 2H, H-7, J = 6.87 Hz).
b
1
3
mation failed with the other different metals assayed.
C NMR (CDCl , 100 MHz). Trans-isomer: 175.8,
3
8
4
4.8, 44.5, 36.8, 36.5, 18.3. Cis-isomer: 175.6, 80.9,
1.7, 32.9, 32.1, 13.1.
O
O
FeCl ·7H O
3
2
1
OH
NaClO
3.2.2. 4-Chloro-5-methyl-dihydrofuran-2(3H )-one 6.
NMR (CDCl , 400 MHz): 4.62 (dt, 1H, H-5, J = 8.0,
5.1 Hz), 4.15 (ddd, 1H, H-4, J = 7.9, 7.0, 5.6 Hz), 3.09
H
HO
HO2
C
O
3
O
CH Cl :H O
2
2 2
Cl
21
1
:1
22
(dd, 1H, H-3 , J = 18.2, 7.7 Hz), 2.75 (dd, 1H, H-3 ,
a
b
1
3
Scheme 3. Transformation of itaconic acid into 4-carboxy-4-chloro-
J = 18.3, 6.9 Hz), 1.41 (d, 3H, H-6, J = 7.5 Hz).
C
methyl oxetanone.
NMR: 172.6, 83.64, 56.35, 38.49, 18.48.

1752
J. A. L o´ pez-L o´ pez et al. / Tetrahedron Letters 48 (2007) 1749–1752
1
3
.2.3. 4-(1-Chloroethyl)oxetan-2-one 7.
H
NMR
References and notes
(
4
1
CDCl , 400 MHz): 5.18 (ddd, 1H, H-4, J = 8.8, 5.6,
3
.1 Hz), 4.43 (td, 1H, H-5, J = 8.9, 3.4 Hz), 3.56 (dd,
H, H-3 , J = 16.7, 5.7 Hz), 2.77 (dd, 1H, H-3 ,
1. Moreno-Dorado, F. J.; Guerra, F. M.; Manzano, F. L.;
Aladro, J.; Jorge, Z. D.; Massanet, G. M. Tetrahedron Lett.
2003, 44, 6691–6693.
a
b
1
3
J = 16.7, 4.2 Hz), 1.55 (d, 3H, H-6, J = 7.4 Hz).
NMR: 166.4, 72.1, 49.4, 41.6, 20.7.
C
2
. Van Tamelen, E. E.; Shamma, M. J. Am. Chem. Soc. 1954,
6, 2315.
7
3
. (a) Bougault, M. J. Ann. Chim. Phys. 1908, 14, 145; (b)
Bougault, M. J. Ann. Chim. Phys. 1908, 15, 296.
1
3
.2.4. 4-Chloro-5-ethyl-dihydrofuran-2(3H )-one 9.
H
NMR (CDCl , 400 MHz): 4.60 (dt, 1H, H-5, J = 8.0,
.1 Hz), 4.19 (ddd, 1H, H-4, J = 7.9, 7.0, 5.6 Hz), 3.20
dd, 1H, H-3 , J = 17.9, 8.0 Hz), 2.92 (dd, 1H, H-3 ,
J = 18.0, 6.9 Hz), 1.86 (m, 1H, H-6 ), 1.71 (m, 1H, H-
3
4. (a) Arnold, R. T.; Campos, M. M.; Lindsay, K. L. J.
Am. Chem. Soc. 1953, 75, 1044; (b) Dowle, M. D.;
Davies, D. I. Chem. Soc. Rev. 1979, 38, 800–802; (c)
Harding, K. E.; Tiner, T. H. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; 1991; pp 363–421; (d)
Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 3099;
5
(
a
b
a
1
3
6b), 1.10 (t, 3H, H-7, J = 7.5 Hz). C NMR: 173.5,
8
9.4, 42.7, 39.7, 26.6, 10.0.
.2.5. 4-(1-Chloropropyl)oxetan-2-one 10. H NMR
CDCl , 400 MHz): 4.54 (ddd, 1H, H-4, J = 8.8, 5.6,
.1 Hz), 3.99 (td, 1H, H-5, J = 8.5, 3.7 Hz), 3.65 (dd,
H, H-3 , J = 16.7, 5.7 Hz), 3.35 (dd, 1H, H-3 ,
(
e) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N.
1
K.; Jayaraman, N. Tetrahedron 2004, 60, 5273–5308; (f)
Drake, M. D.; Bateman, M. A.; Detty, M. R. Organo-
metallics 2003, 22, 4158–4162; (g) Mellegaard-Waetzig, S.
R.; Wang, C.; Tunge, J. A. Tetrahedron 2006, 62, 7191–
7198.
3
(
4
1
3
a
b
J = 16.2, 4.4 Hz), 2.13 (m, 1H, H-6 ), 1.83 (m, 1H, H-
6b), 1.14 (t, 3H, H-7, J = 7.4 Hz). C NMR: 167.2,
5. Damin, B.; Forestiere, A.; Garapon, J.; Sillion, B. J. Org.
Chem. 1981, 46, 3552.
a
1
3
7
1.7, 57.2, 44.2, 28.2, 11.9.
6. Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004, 69,
8
979–8981.
1
7
8
. Wang, C.; Tunge, J. Chem. Commun. 2004, 2694–2695.
. Lactones 2, 6, 7, 9, 10, 12, 14, 16 and 18 have been
previously reported in the following articles. Lactone 2:
see Ref. 5; lactones 6, 7, 9 and 10: Gauthier, P. M. F.;
Le Moult, M. M. P.; Rochelle, J. C.; Senet, J. P. EU
Patent FR2655334, 1991 (No spectroscopic data are
provided in the patent); lactone 12: Witkop, B.; Beiler,
T. J. Am. Chem. Soc. 1956, 78, 2882–2893; lactone 14:
Iida, M.; Araki, T.; Teranishi, K.; Tani, H. Macromole-
cules 1997, 10, 275–284; lactone 16: Hart, H.; Chloupek,
F. J. J. Am. Chem. Soc. 1961, 85, 1155–1160, lactone 18:
see Ref. 6.
3
.2.6. 4-Carboxy-4-(chloromethyl)oxetanone 22.
H
NMR (DMSO-d , 400 MHz): 4.25 (dd, 2H, H-6,
J = 12.3, 11.1 Hz), 3.82 (dd, 2H, H-3, J = 26.9,
1
1
6
1
3
6.9 Hz).
C NMR (100 MHz, DMSO-d ): 175.8,
6
67.9, 94.6, 47.6, 31.9.
Acknowledgement
This investigation was supported by the Consejer ´ı a de
Medio Ambiente de la Junta de Andaluc ´ı a.