Synthesis of novel γ-ketoesters from succinic anhydride

Article abstract of DOI:10.14233/ajchem.2013.15179

Four alkyl g-ketohexanoates (3a-3d) have been prepared from succinic anhydride employing a three step reaction strategy. In the first step using p-toluene sulfonic acid as catalyst, the ring of succinic anhydride was opened with isopropyl, isobutyl, isopentyl and benzyl alcohols, respectively to form alkyl hydrogen succinates (1a-1d). In the 2nd step these alkyl hydrogen succinates on treatment with SOCl2 yielded 4-alkoxy-4-ketobutanoyl chlorides (2a-2d). The acid halides thus obtained, on reaction with diethyl cadmium led to require g-ketoesters. All the synthesised compounds were characterized by recording and analyzing 1H, 13C NMR, IR spectra and mass measurements.

Full text of DOI:10.14233/ajchem.2013.15179

Asian Journal of Chemistry; Vol. 25, No. 17 (2013), 9701-9703
http://dx.doi.org/10.14233/ajchem.2013.15179
Synthesis of Novel γ-Ketoesters from Succinic Anhydride
*
MUHAMMAD IQBAL , IMAM BAKHSH BALOCH and MUSA KALEEM BALOCH
Department of Chemistry, Gomal University, Dera Ismail Khan-29050, Khyber Pakhtunkhwa, Pakistan
*Corresponding author: E-mail: miqbal_44@yahoo.com
(Received: 21 January 2013;
Accepted: 16 October 2013)
AJC-14257
Four alkyl γ-ketohexanoates (3a-3d) have been prepared from succinic anhydride employing a three step reaction strategy. In the first step
using p-toluene sulfonic acid as catalyst, the ring of succinic anhydride was opened with isopropyl, isobutyl, isopentyl and benzyl
alcohols, respectively to form alkyl hydrogen succinates (1a-1d). In the 2nd step these alkyl hydrogen succinates on treatment with SOCl2
yielded 4-alkoxy-4-ketobutanoyl chlorides (2a-2d). The acid halides thus obtained, on reaction with diethyl cadmium led to require
γ-ketoesters.All the synthesised compounds were characterized by recording and analyzing 1H, 13C NMR, IR spectra and mass measurements.
Key Words: γ-Ketoesters, Isopentyl γ-ketohexanoate, Succinic anhydride, Isobutyl alcohol.
rected. The UV spectrum was recorded in absolute methanol
on a IRMECO UV/VIS Model U-2020 spectrophotometer. IR
spectra were obtained on a TENSOR 27 FT-IR spectropho-
INTRODUCTION
γ-Keto-esters are used in the preparation of lactam anti-
biotics1, isoquinolines1, lactonic sex pheromones1,2, furans1,3,
benzotropolones4, alkoxythiophenes5 and other heterocyles6.
They are used as intermediates in the preparation of cyclopen-
tenone3, natural flavor2 and useful building blocks of pharma-
ceutical interest3. Moreover, they are converted to butyro-
lactone, its dimer7,chiral γ-hydroxyester8,9, γ-hydroxycarboxylic
1
tometer supplied by Bruker, Ettlingen, Germany. H and 13C
NMR (1D, 2D, homo/heteronuclear) spectra were acquired in
CDCl3 on a Bruker Biospin, AMX 300 MHz FT NMR (300
1
MHz for H, 75 MHz for 13C) spectrometer. EI-MS were
determined with a direct insertion probe on a double-focusing
Finnigan MAT 112 at 70 eV. HR-EI-MS measurements were
carried out on a JEOL HX 110 spectrometer. Elemental
analyses were obtained by Midwest Microlab, Indianapolis,
IN. Column chromatography was performed using silica gel
(PF254, mesh size 60-70), E. Merck, Darmstadt, Germany and
thin layer chromatography on pre-coated silica gel plates (20
cm × 20 cm, 0.2 mm thickness) with UV fluorescence (PF254),
E. Merck, Darmstadt, Germany; eluting with hexane-EtOAc.
Alkyl hydrogen succinates (1a-1d). General procedure:
To a single-necked round-bottom flask (100 mL), fitted with
a Dean-Stark trap and a reflux condenser and containing a stir
bar, succinic anhydride (3.0 g, 30 mmol), anhydrous
p-toluenesulfonic acid (25 mg) and toluene (15 mL) under
nitrogen were added 30 mmol of the alcohols. After 24 h at
reflux, the solution was left to cool at 25 ºC then poured into a
saturated aqueous NaHCO3 solution (25 mL) and the aqueous
layer was extracted with hexane (3 × 25 mL). The combined
organic (toluene and hexane) layers were washed with brine
(20 mL), dried over anhydrous Na2SO4 and the solvent was
removed under vacuum to give a resinous product, which was
subjected to column chromatography to afford the pure
monoesters.
acids6 and chiral auxiliaries in asymmetric synthesis10,11
.
Although many methods have been developed for γ-ketoesters
synthesis12-24, they often have disadvantages, such as poor
yields, expensive starting materials, sensitivity of the esters to
hydrolysis in acidic or basic medium and use of expensive
23
1
2
catalysts like NaAuCl4 , Co(OAc)2 and Rh2(OAc)4 . Our
objective was thus to develop a new route for the syntheses of
γ-ketoesters (3a-3d) using inexpensive substrates, solvents and
catalysts and to optimize the yield of the products.
EXPERIMENTAL
All the chemicals were of analytical grade, purchased from
E. Merck, Darmstadt, Germany and used as acquired; toluene
was dried and stored over sodium metal before use. The purity
of the alcohols and succinic anhydride was checked by NMR
and IR whereas the purity of thionyl chloride was checked by
IR.All the reactions were carried out in an efficient fume hood
under dry nitrogen. The chemical splash goggles, Nomex
gloves and lab coat were used to minimize the exposure to
diethyl cadmium. Melting points were determined using a
Gallenkamp digital melting point apparatus and are uncor-

9702 Iqbal et al.
Asian J. Chem.
TABLE-1
YIELD, MELTING POINTS AND ELEMENTAL ANALYSIS OF COMPOUNDS 1-2
Elemental analysis (%) found (calcd.)
Compound
Yield (%)
m.p. (ºC)
b.p./18 mm (ºC)
C
H
76
77
76
76
78
78
72
71
64-65
–
–
52.49 (52.52)
7.55 (7.56)
1a
1b
1c
1d
2a
2b
2c
2d
69-71
55.16 (55.10)
8.10 (8.11)
75-76
115-116 (Lit.117-119)25
–
57.43 (57.45)
8.57 (8.58)
–
63.45 (63.47)
5.81 (5.75)
–
–
–
–
94-95
101-103
108-109
110-112
–
–
–
–
–
–
–
–
TABLE-2
4-Alkoxy-4-ketobutanoyl Chlorides (2a-2d). Typical
procedure: Compound 1a (3.6 g, 22.5 mmol) was mixed with
thionyl chloride (3.26 mL, 45 mmol) and warmed at 30-40 ºC
for 3 h. Then the excess of thionyl chloride was removed on a
steam bath under reduced pressure to afford a colourless resin
(2a) which was purified by distillation at reduced pressure
and characterized by physical and spectroscopic measurements
(Tables 1 and 3).
YIELD AND BPS OF COMPOUNDS 3a-d FOR COMPARISON
Yield (%)
b.p/18mm
Gilman
reagent
Compound
Diethyl
cadmium
Grignard
reagent
(ºC)
77
74
72
71
29
28
27
23
22
21
18
18
106-107
112-113
118-119
116-117
3a
3b
3c
3d26
Alkyl γ-ketohexanoates (3a-3d). Typical procedure:
Compound 3a was synthesized by addition of 10 mmol of 2a
(1.78 g) over a period of 10 min to a solution of diethyl
cadmium in diethyl ether27-29. The mixture was refluxed for
six hours and allowed to stand overnight stirring. The reaction
mixture was then poured into a beaker (500 mL) containing
crushed ice (150 g) and 10 % aqueous H2SO4 (30 mL). It was
vigorously stirred using a magnetic stirrer for 5 min. The
organic layer was extracted with diethyl ether (3 × 20 mL),
washed with 50 % aqueous NaHCO3 solution (40 mL) and
dried over anhydrous Na2SO4. After removal of the solvent,
the obtained material was subjected to column chromatography
using an ethyl acetate/hexane [(1:9) → (2:8) → (3:7)] as eluent.
The desired product 3a was obtained after elution with ethyl
acetate/hexane (3:7).
RESULTS AND DISCUSSION
Reaction of succinic anhydride with alcohols led to alkyl
hydrogen succinates 1a-1d which upon treatment with thionyl
chloride afforded the corresponding 4-alkoxy-4-ketobutanoyl
chlorides 2a-2d (Scheme-I). Reaction of 2a-2d with diethyl
cadmium, ethylmagnesium bromide or the corresponding
TABLE-3
SPECTROSCOPIC DATA OF COMPOUNDS 1-3
HR-EI-MS (m/z)
Comp.
IR (cm-1)
1H NMR (δ) 13C NMR (DEPT) (δ)
Calcd.
Found
160.15
3417 (OH) 1728 (CO2H), 2.55 (t, 6.7), 2.72 (t, 6.7), 4.45 (septet, 7.5), 173.3 (s), 28.2 (t), 36.6 (t), 180 (s),
160.17
C7H12O4
174.19
1a
1755 (CO2R)
3438 (OH) 1725 (CO2H), 2.55 (t, 6.7), 2.72 (t, 6.7) 4.01 (d, 7.5), 1.18
1759 (CO2R (septet, 7.5), 1.1 (d, 7.5)
1.1 (d, 7.5)
68.3 (d) 21.2 (q)
173.3 (s), 28.2 (t), 36.6 (t),180 (s),
68.3 (t), 26.7 (d), 21.2 (q)
174.18
188.24
208.19
178.62
192.65
206.66
226. 67
172.21
186.24
200. 26
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
C8H14O4
188.22
3396 (OH), 1722 (CO2H), 2.55 (t, 6.7), 2.72 (t, 6.7) 4.45 (d, 7.5), 1.48 173.3 (s), 28.2 (t), 36.6 (t), 180 (s),
1765 (CO2R) (m), 1.77 (m), 1.1 (d, 7.5) 68.3 (t), 36.7 (t), 23.6 (d), 21.2 (q)
3324 (OH), 3014 (Ar-H), 2.57 (t, 6.7), 2.69 (t, 6.7) 5.2 (s), 7.2-7.3 (Ph) 171.7 (s), 28.3 (t), 35.5 (t), 203.2 (s),
C9H16O4
208.21
1748 (CO2R), 1708 (CO)
79.1 (t), 128-137, (1C, s, 5C, d)
C11H12O4
178.61
1810 (COCl), 1755
(CO2R), 741 (C-Cl)
2.53 (t, 6.7), 2.73 (t, 6.7) 4.5 (septet, 7.5), 171.4 (s), 28.4 (t), 37.5 (t), 172.6 (s),
1.12 (d, 7.5)
66.2 (d), 20.1 (q)
C7H11ClO3
192.64
1802 (COCl) 1740 (CO2R), 2.56 (t, 6.7), 2.70 (t, 6.7) 4.05 (d, 7.5), 1.47 172.2 (s), 27.0 (t), 37.8 (t), 205.2 (s)
734 (C-Cl) (m), 1.16 (d, 7.5) 64.5 (t), 31.7 (d), 22.1 (q)
1807 (COCl) 1739 (CO2R), 2.58 (t, 6.7), 2.74 (t, 6.7) 4.1 (t, 7.5), 1.6 (dt, 171.1 (s), 27.5 (t) 36.9 (t), 172.3 (s),
C8H13ClO3
206.67
739 (C-Cl)
7.5), 1.5 (m), 1.1 (d, 7.5)
59.9 (t), 37.2 (t) 25.5 (d), 22.2 (q)
C11H20O3
226.66
3094 (Ar-H), 1787 (COCl),
1748 (CO2R) 734 (C-Cl)
2.57 (t, 6.7), 2.69 (t, 6.7),
5.2 (s), 7.2-7.3 (Ph)
171.7 (s), 28.3 (t) 35.5 (t), 176.7 (s),
79.1(t), 128-137 (1C, s. 5C, d)
C11H11ClO3
172.22
1745 (CO2R), 1729 (CO), 2.57 (t, 6.7), 2.71 (t, 6.7) 2.49 (t, 7.3), 1.08 (t, 171.2 (s), 27.9 (t), 35.6 (t), 204.5 (s),
1210 (C-O) 7.3), 4.52 (septet,7.5), 1.15 (d, 5) 34.7 (t), 7.9 (q) 63.7 (d), 22.6 (q)
1740 (CO2R), 1722 (C=O), 2.56 (t, 6.7), 2.70 (t, 6.7) 2.47 (t, 7.3), 1.07 (t, 172.3 (s), 27.0 (t), 37.8 (t), 205.2 (s),
C9H16O3
186.23
1220 (C-O)
7.3), 4.05 (d, 7.5), 1.47(m), 1.16 (d, 7.5)
35.2 (t), 8.3 (q), 64.5 (t), 31.7 (d)
C10H18O3
200.27
C11H20O3
1739 (CO2R), 1717 (C=O) 2.58 (t, 6.7), 2.74 (t, 6.7), 2.51 (q, 7.3), 1.09
(t, 7.3), 4.1 (t, 7.5), 1.6 (dt, 7.5), 1.5 (septet,
7.5), 1.1 (d, 7.5)
173.2 (s), 27.5 (t), 36.9 (t), 202.3 (s)
35.9 (t), 7.7 (q), 59.9 (t), 37.2 (t),
25.5 (d), 22.2 (q)
1225 (C-O)
3d26
1736 (CO2R), 1718 (C=O), 1.05 (t, J = 7.3 Hz, 3 H), 2.48 (q, J = 7.3 Hz, 2 171.7 (s), 28.3 (t), 35.5 (t), 208.2 (s),
1230 (C-O)
220.26
C13H16O3
220.24
H), 2.65 (t, J = 6.7 Hz, 2 H), 2.74 (t, J = 6.7
Hz, 2 H), 5.15 (s, 2 H), 7.33–7.35 (m, 5 H)
36.1 (t), 7.9 (q), 66.1 (t), 128-137,
(1C, s, 5C, d)

Vol. 25, No. 17 (2013)
Synthesis of Novel γ-Ketoesters from Succinic Anhydride 9703
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