Direct synthesis of γ-butyrolactones via γ-phenyl substituted butyric acids mediated benzyl radical cyclization

Article abstract of DOI:10.1081/SCC-100104057

Synthesis of several γ-butyrolactones with aromatic substitution at carbon 5 from comparative γ-aryl acids with 25-85% yield are covered. The straight oxidation in the presence of peroxydisulphate-copper(II)chloride system in aqueous medium was applied. The reaction is highly regioselective and leads exclusively to γ-butyrolactone, through stable benzylic radical intermediate.

Full text of DOI:10.1081/SCC-100104057

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DIRECT SYNTHESIS OF γ-
BUTYROLACTONES VIA γ-
PHENYL SUBTITUTED BUTYRIC
ACIDS MEDIATED BENZYL
RADICAL CYCLIZATION
a
a
N. O. Mahmoodi & M. Jazayri
a
University of Guilan, P.O. Box 1914, Rasht, Iran
Version of record first published: 02 Aug 2010.
To cite this article: N. O. Mahmoodi & M. Jazayri (2001): DIRECT SYNTHESIS OF γ-
BUTYROLACTONES VIA γ-PHENYL SUBTITUTED BUTYRIC ACIDS MEDIATED BENZYL
RADICAL CYCLIZATION, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 31:10, 1467-1475
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SYNTHETIC COMMUNICATIONS, 31(10), 1467–1475 (2001)
DIRECT SYNTHESIS OF
g-BUTYROLACTONES VIA g-PHENYL
SUBSTITUTED BUTYRIC ACIDS MEDIATED
BENZYL RADICAL CYCLIZATION
N. O. Mahmoodi* and M. Jazayri
Organic Research Laboratory, Department of Chemistry,
University of Guilan, Rasht, P.O. Box1914, Iran
ABSTRACT
Synthesis of several g-butyrolactones with aromatic
substitution at carbon 5 from comparative g-aryl acids with
2
5–85% yield are covered. The straight oxidation in the pre-
sence of peroxydisulphate-copper(II)chloride system in aqu-
eous medium was applied. The reaction is highly regioselective
and leads exclusively to g-butyrolactone, through stable
benzylic radical intermediate.
Oxidative addition of carboxylic acids and alkenes was used as a
1
–4
mild methodology for formation of g-butyrolactones.
The oxidative
different oxidants’
2
systems such as S2O8 -Ag , S2O -Ag -Cu,
ꢀ
þ
2ꢀ
þ
5–7
8
8
–10
derivatives of Pb(IV), Co(III), Ag(II), other polyvalent metals,
and
1
1
KMnO4 can interact with carboxylic acids, resulting usually in their
decarboxylation and creation of alkyl radicals. Direct oxidative systems
such as oxidative lactonization of carboxylic acids in the presence of
*
Corresponding author.
1
467
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1
468
MAHMOODI AND JAZAYRI
peroxydisulphate-containing systems have been published. However, the
yields of conversion are either very low or the reaction is not selective,
e.g., 3.3–9.5% and 4–10%, respectively, for mixtures that contain 5- and
1
2
6
The objectives of this study are to convert 4-substituted aryl acids in the
-member ring lactones together with some decarboxyllated compounds.
2
8
ꢀ
2þ
presence of an oxidative system such as S O -Cu from mild to high
2
yields, and to monitor the conversion to exclusively 5-member lactone
ring. Recently, we synthesized several mono, and di-substituted g-butyro-
lactones with aryl and aliphatic substitution at carbon 5, 3,5 and 3,4 as an
1
3
14–17
essence, an anti-glaucoma, and an anti-tumor,
oxidation system in the presence of peroxydisulphate-copper chloride, and
respectively. The direct
ꢁ
in the aqueous solution at 90 C was applied. The reaction is regioselective
and leads mainly to g-butyrolactone (Scheme 1).
Scheme 1.

g-BUTYROLACTONES
Table 1. Yield of Lactonization from 4-Aryl Acids
1469
1
2
3
Lactone
R
R
R
Yield %
10a
10b
10c
10d
10e
10f
H
H
H
Me
H
OMe
H
H
H
Me
H
OMe
H
Me
OH
H
PH
H
41
51
84
25
35
0
Several 4-aryl carboxylic acids for one-pot direct conversion to the
corresponding butyrolactones were elected. These acids were prepared
from available starting materials by using straightforward procedures. The
lactonization was entirely regioselective and only the g-butyrolactones are
isolated with 25–84% yields (Table 1).
Utilization of this oxidation reagent for intramolecular reaction of aryl
acids of 11 (Scheme 2) to expected 5- and 6-members fused lactones 12
failed, and, in one case, lead to ester 13a. Spectroscopic data for all
compounds are shown in (Table 2).
Scheme 2.
Formation of lactone 10c in high yield (Table 1) with hydroxy sub-
stitution instead of methoxy group of starting aryl acids 4c at the para
position, implies that the reaction has involved some extent of ‘‘through
1
8
conjugaction’’ (Scheme 3).
For the same reason, the 4-(2,5-dimethoxy phenyl) butyric acid 4f was
not converted to the corresponding lactone 10f; instead, that entirely led to
the formation of comparable p-benzoquinone, 4-(2,5-cyclohexadiene-1,4-
dione) butanoic acid 19, probably through stable radical 17 and biradical
1
8 (Scheme 4).

1
470
MAHMOODI AND JAZAYRI
Table 2. Physical Property of All Synthesized Compounds
Yield
(%)
ꢀ1
1
13
ꢁ
Entry
IR cm
H & C NMR d
M.p. C & MS
1
1
9
9
3
a
a
(KBr): 3200(b), (CDCl
690(b) 2H, 7.5(m) 3H, 8(m) 2H
(KBr): 3200(b), (CDCl ): 2.1(m) 2H, 2.5(t) 89
3
): 2.4(t) 2H, 3.4(t)
90
114–116 (lit. 115)
47–48 (lit. 47–48)
1
4
3
1700(s)
2H, 2.7(t) 2H, 7.3(m) 5H,
1.1(s) 1H
): 2.5(m) 4H, 5.4(t) 41
H, 7.3(s) 5H, 13C
CDCl ): 32, 82, 125, 128,
29, 130, 165
): 2.5(s) 3H, 2.9(t)
2H, 3.3(t) 2H, 7.4(m) 2H,
.9(m) 2H, 9.9(s) 1H
(KBr): 3200(b), (CDCl ): 1.9(m) 2H, 2.3(s)
690(s) 3H, 2.4(t) 2H, 2.6(t) 2H,
.1(s) 4H, 11.3(s) 1H
1
þ
1
0a
(neat): 1770(s) (CDCl
3
Exact mass(M ):
calcd. ¼ 162.0681,
1
(
3
found 162.0675
1
3
4
1
b
(KBr): 3200(b), (CDCl
680(sb)
3
83
—
122–125
1
7
2
0
b
3
52–55 (lit. 57–48)
1
7
0b
(CCl ): 3005(m), (CDCl ): 2.3(m) 2H, 2.6(t) 51
3
62–64 Exact
4
þ
1780(s)
3H, 5.5(t) 1H, 7.2(s) 4H
mass(M ):calcd.
176.0837, found
176.0836
1
3C(CDCl
25, 126, 128, 129, 165
(KBr): 3200(b), (CDCl ): 2.7(t) 2H, 3.2(t)
3
): 21, 29, 30, 81,
1
3
4
1
c
82
144–152
(lit. 148–150)
3
2
1
1700(s)
2H, 3.8(s) 3H, 6.9(d) 2H,
.9(d) 2H
): 1.9(t) 2H, 2.3(m) 71
2H, 2.6(m) 2H, 3.8(s) 3H,
.0(m) 4H
): 2.5(m) 4H, 5.4(t) 84
1h, 7.3(m) 4H, 8.7(s) 1H
3C(CDC1 ): 29, 30, 81,
26, 128, 176
(KBr): 3200(b), (CDCl ): 2.3(s) 3H, 2.5(s)
7
2
1
c
(KBr): 3200(b), (CDC1
700(s)
3
56–58 (lit. 56–59)
1
7
þ
0c
(neat): 3010(m), (CDCl
765(s)
3
Exact mass: (M ):
calcd. 178.0630,
found 178.0627
1
1
3
1
3
d
d
85
100–102
3
1680(sb)
3H, 2.7(t) 2H, 3.1(t) 2H,
.0(s) 2H, 7.6(m) 1H,
1.3(s) 1H
(KBr): 3200(b), (CDCl ): 2(m) 2H, 2.5(s)
7
1
4
82
62–66
3
1685(s)
6H, 2.8(t) 2H, 5.8(t) 1H,
.2(m) 3H
7
(continued )

g-BUTYROLACTONES
1471
Table 2. Continued
Yield
(%)
ꢀ
1
1
13
H & C NMR d
ꢁ
Entry
IR cm
(CCl
M.p. C & MS
þ
1
0d
4
): 3000(m), (CDCl
775(s) 1H, 7.3(s) 5H, 13C
CDCl ): 32, 82, 125, 128,
29, 130, 165
): 2.8(t) 2H, 3.3 (t) 62
2H, 7.5(m) 7H, 8(m) 2H
(KBr): 3200(b), (CDCl ): 1.9(m) 2H, 2.3(s) 80
3
): 2.5(m) 4H, 5.4(t) 25
Exact mass(M ):
calcd. 190.0994,
found 190.0992
1
(
3
1
3
e
e
(KBr): 3200(b), (CDCl
680(sb)
3
180–182
115–118
1
4
3
1
680(s)
3H, 2.4(t) 2H, 2.6(t) 2H,
.1(s) 4H, 11.3(s) 1H
): 3005(m), (CDCl ): 2.5(m) 4H, 5.5(t) 35
785(s) 1H, 7.5(m) 9H
7
þ
1
0e
f
(CCl
4
3
Exact mass: (M )
calcd. 238.0996,
found 238.0989
1
2
2
3
(KBr): 3200(b), (CDCl
700(s) 2H, 3.8(s) 3H, 3.9(s) 3H,
.0(m) 2H, 7.3(m) 1H,
.8(s) 1H
): 1.9(m) 2H, 2.4(t) 56
2H, 2.6(t) 2H, 3.8(s) 6H,
.7(s) 2H, 7.2(s) 1H
3
) :2.8(t) 2H, 3.4(t)
88
100–102 (lit. 102)
64–68 (lit. 68–69)
1
7
8
2
2
4
1
1
f
(KBr): 3200(b), (CDCl
700(s)
3
1
6
þ
9
(CCl ): 3000(b), (CDCl ): 2(m) 2H, 2.5(t)
4
—
Exact mass: (M )
calcd. 194.0595,
found, 194.0592
3
1
700(s)
2H, 2.8(t) 2H, 6.8(m) 3H,
(s) 1H
9
þ
3a
(neat): 3010(s), (CDCl ): 3.7(s) 2H, 5.11(s)
2H, 7.3(m) 10H
3
—
Exact mass: (M )
calcd. 226.0994,
found, 226.0989
3015(s), 1736(s)
Scheme 3.

1
472
MAHMOODI AND JAZAYRI
Scheme 4.
EXPERIMENTAL
General
Yields refer to isolated pure center cut from column chromatography
or scratched from preparative TLC. Products were characterized by com-
parison with authentic samples (IR, NMR, GC, TLC, and m.p.). Melting
points are uncorrected and determined by Metller Fp5 melting point
1
13
apparatus. The H and C NMR spectra were recorded on a Bruker
spectrometer, generally with TMS as internal standard. The IR spectra
were recorded with a Shimadzu model 470. The high-resolution mass
spectra were obtained from a Fisons Trio-1000 instrument.
Synthesis of 4-Phenyl-4-oxobutanoic Acids 3a: A Typical Procedure
Twenty mL (17.5 g, 0.225 mol) benzene (Na-dried and free of thio-
phene) and 3.4 g (0.034 mol) succinic anhydride were combined in a
1
00 -mL flask equipped with a refluxcondenser connected through a
Y-junction to a single efficient gas absorption device. The succinic anhydride
dissolved in the benzene, 10 g (0.075 mol) of powdered anhydrous aluminum
chloride was added and stirred in the mixture solution. The reaction started
immediately; HCl evolved and the mixture became hot. The resulting mix-
ture was then allowed to warm up at room temperature and then again
allowed to warm up for 30 m at gentle reflux. The solution was cooled in
cold water. Then 15 mL water and 5 mL conc. HCl were added. Excess
benzene was removed by steam distillation. The residue was cooled and
filtered on a Buchner funnel and washed with 10 mL (1:3) dilute HCl and

g-BUTYROLACTONES
1473
1
The filtrate was cooled and acidified by conc. HCl at 0 C, 5.4 g (90%)
mL H O. The crystals were boiled in Na CO (4 g in 25 mL H O) for 15 m.
ꢁ
2
2
3
2
ꢁ
ꢁ
19
ꢁ
crystals m.p. 114 –116 C (lit., 115 C) was separated. The IR and NMR
were recorded and shown in Table 2.
Preparation of 4-Phenyl Butanoic Acids 4a: A Typical Procedure
Zn powder (4.3 g), 0.43 g (1.58 mmol) mercury (II) chloride, 0.2 mL
conc. HCl, and 5.5 mL water, were combined in a 50-mL flask. The mixture
was stirred at room temperature for several minutes to produce a homo-
genous solution. After homogenization was completed, the stirring was
stopped and the liquid was decanted as completely as possible. In a flask
equipped with a refluxcondenser, 2.7 mL water, 0.65 mL conc. HCl, 3.6 mL
toluene(as solvent) and 1.8 g (0.01 mol) 4-phenyl-4-oxobutanoic acid 3a were
combined. The flask was refluxed vigorously for 30 h. During this period,
1
.8 mL conc. HCl was added to the flask at approximately 6-h intervals
during the refluxing period to maintain the conc. of HCl. After cooling,
two layers were seperated water (7.2 mL) was added to the aqueous layer,
and was extracted with 3ꢂ30 mL ether. The extracted layer was added
to toluene, washed with water, and dried over MgSO . The solvent was
4
ꢁ
evaporated and the residue was distilled 185 C
ꢁ
(1.49 g, 89%),
0 mmHg
2
ꢁ
20
ꢁ
ꢁ
(
(
m.p. 47 –48 C, lit. 47 –48 C). The IR and NMR spectra were recorded
Table 2).
Preparation of 5-Phenyl-g-butyrolactone 10a: A Typical Procedure
4-Phenyl butanoic acid 4a (4.92 g, 30 mmol), 27 mL water, and 5.1 g
30 mmol) copper (II) chloride 2H O were combined in a 250-mL, two-neck,
(
round-bottom flask equipped with a refluxcondenser and an additional
2
Table 3. Red. Condition for Conversion of Keto Acids to 4-Aryl Acids
Keto Acids
Reagent & Method
Time of Red. (h)
Yield (%)
Aryl Acid
1
1
1
1
1
6
6
6
6
6
7
3a
3b
3c
3d
3e
3f
amalgamated zinc
amalgamated zinc
amalgamated zinc
amalgamated zinc
amalgamated zinc
30
45
40
42
40
7
89
—
71
82
80
56
4a
4b
4c
4d
4e
4f
1
NH2-NH2, KOH

1
474
MAHMOODI AND JAZAYRI
funnel. A solution of 8.5 g (30 mmol) Na S O and 15 mL water was added
2
2
8
to the additional funnel. The reaction mixture was allowed to reflux by
ꢁ
vigorous stirring while the temperature of solution was adjusted to 85 –
ꢁ
9
0 C. The solution from the additional funnel was added dropwise to a
flask during 40 m, and the flask was refluxed for 3.5 h. After this time, the
reaction was stopped. The flask was cooled and extracted with 3ꢂ30 mL
ether and dried with MgSO . The solvent was removed and 2 g (41%) of 10a
4
was collected as a pure center cut from silica gel column chromatography.
1
The solvent system used was 5–10% EtOAc:ligroin. The IR, H, CNMR
13
þ
spectra and Exact mass (M ) were recorded (Table 2).
Synthesis of 4-(4-Methoxyphenyl)-4-oxobutanoic Acid 3c
Nitrobenzene (60 mL redistilled and dried) as a solvent and 2.5 g
0.025 mol) succinic anhydride were combined in a 250-mL, 2-neck,
(
round-bottom flask equipped with a refluxcondenser connected through a
y-junction to a single efficient gas absorption device and an additional
funnel. Then 6.67 g (0.05 mol) anhydrous AlCl powder and 15 mL nitro-
3
benzene (redistilled) from the additional funnel dropwise was added to the
solution during 45 m. The resulting mixture was then stirred at room
temperature for an additional 6 h. After this time, the reaction mixture
was transferred to the solution of 300 mL HCl (20%) and 200 g ice, stirred
vigorously, and extracted with 4ꢂ30 mL ether. The ether layers were com-
bined and washed with 3ꢂ30 mL water, and extracted with 5ꢂ30 mL conc.
NaHCO . The aqueous layers were washed with 3ꢂ20 mL ether, and acid-
3
ꢁ
ꢁ
ified with HCl. The white precipitate (3.4 g, 82% yield), m.p. 144 –152 C
2
lit. 148 –150 C. The IR, and NMR are recorded (Table 2)
1
ꢁ
ꢁ
Synthesis of 4-(4-Methoxy phenyl)butanoic Acid 4c
A similar procedure as used for 4a was applied, but instead of reflux
for 30 h, the solution was refluxed for a 40-h period and 1.8 mL conc. HCl
was added to the flask at 8-h intervals.
Preparation of 5-(4-Hydroxy phenyl)-g-butyrolactone 10c
A similar procedure for 10a was used. The spectral data were recorded
(
Table 2).

g-BUTYROLACTONES
1475
ACKNOWLEDGMENTS
We appreciate the Research Committee of Guilan University for the
partial support given to this study.
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Received in the UK September 21, 1999