An alternative method for the synthesis of γ-lactones by using cesium fluoride-celite/acetonitrile combination

Article abstract of DOI:10.1081/SCC-120024003

A variety of 2-(1-bromoalkyl) benzoic acids 4 undergo intramolecular nucleophilic substitution reaction when treated with a CsF-Celite as solid base in acetonitrile under reflux condition to give the corresponding cyclized phthalides in moderate to very good yield. These 2-(1-bromoalkyl) benzoic acids 4 are formed by the α-bromination of 2-alkylbenzoic acids 3 using N-bromosuccinimide and a catalytic amount of α,α′ -azoisobutyronitrile in carbon tetrachloride under reflux.

Full text of DOI:10.1081/SCC-120024003

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An Alternative Method for the Synthesis of γ-
Lactones by Using Cesium Fluoride-Celite/Acetonitrile
Combination
Khalid Mohammed Khan a , Safdar Hayat a , Zia-Ullah a , Atta-ur-Rahman a , M. Iqbal
Choudhary a , Ghulam Murtaza Maharvi a & Ernst Bayer a
a International Center for Chemical Sciences , H.E.J. Research Institute of Chemistry ,
University of Karachi , Karachi, Pakistan
Published online: 15 Aug 2006.
To cite this article: Khalid Mohammed Khan , Safdar Hayat , Zia-Ullah , Atta-ur-Rahman , M. Iqbal Choudhary , Ghulam
Murtaza Maharvi & Ernst Bayer (2003) An Alternative Method for the Synthesis of γ-Lactones by Using Cesium Fluoride-Celite/
Acetonitrile Combination, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 33:19, 3435-3453
To link to this article: http://dx.doi.org/10.1081/SCC-120024003
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3435–3453, 2003
An Alternative Method for the Synthesis of
g-Lactones by Using Cesium
Fluoride-Celite/Acetonitrile Combination
*
Khalid Mohammed Khan, Safdar Hayat,
Zia-Ullah, Atta-ur-Rahman, M. Iqbal Choudhary,
Ghulam Murtaza Maharvi, and Ernst Bayery
International Center for Chemical Sciences,
H.E.J. Research Institute of Chemistry,
University of Karachi, Karachi, Pakistan
ABSTRACT
A variety of 2-(1-bromoalkyl) benzoic acids 4 undergo intramolecular
nucleophilic substitution reaction when treated with a CsF-Celite as
solid base in acetonitrile under reflux condition to give the correspond-
ing cyclized phthalides in moderate to very good yield. These
*Correspondence: Khalid Mohammed Khan, International Center for Chemical
Sciences, H.E.J. Research Institute of Chemistry, University of Karachi, Karachi
75270, Pakistan; Fax: (92-21) 9243190-91; E-mail: hassaan2@super.net.pk.
yThis communication is the result of a joint research program with Late
Prof. Dr. Ernst Bayer, Institut fur Organische Chemie der Universitat Tubingen,
Tubingen, Germany.
3435
DOI: 10.1081/SCC-120024003
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3436
Khan et al.
2-(1-bromoalkyl) benzoic acids 4 are formed by the a-bromination of
2-alkylbenzoic acids 3 using N-bromosuccinimide and a catalytic
amount of a,a0-azoisobutyronitrile in carbon tetrachloride under
reflux.
Key Words: Cesium fluoride; Celite 521, 2-(1-Bromoalkyl) benzoic
acids; Intramolecular nucleophilic substitution; Phthalide and
derivatives.
INTRODUCTION
Many natural products have g-lactones skeletons[1] most of
which display a wide variety of significant biological activity.[2] They
have also been employed as key intermediates for the synthesis of natural
products.[3] Therefore, the synthesis of g-lactones is a very important
and useful in organic chemistry. Although a number of articles[4–6]
and reviews[7] have been published to achieve this goal, some of these
require expensive reagents and tedious reaction work-up. Other methods
involve the direct preparation of g-lactones from the corresponding
o-alkyl aromatic carboxylic acids and the use of Na2S2O8/AgNO3
ꢀ
and CuX2 a t 80C,[8] [bis(trifluoroacetoxy)iodo]benzene and iodine[9,10]
and organohypervalent iodine compounds in the Suarez system[11]
as reagent. More recently, we have reported the conversion of o-alkyl
benzoic acids into its corresponding g-lactones by using the
NaBrO3/NaHSO3 reagent under a two-phase system.[12] In extension of
our work for the synthesis of these important phthalides, we developed a
new moderate to high yielding methodology. In this article we describe
the conversion of 2-(1-bromoalkyl) aromatic carboxylic acids into its
corresponding g-lactones by using the CsF-Celite as a solid base in
acetonitrile.
The chemistry of the CsF-Celite has been studied because
it can serve as an excellent base for converting carboxylic acid
into their corresponding esters with alkyl halides.[13] Alkylation of
cesium carboxylate salts with alkyl halides is also very useful tool
for the preparation of carboxylic esters.[14,15] In the course of our
study to extend the scope of the CsF-Celite in organic chemistry,
we have found that 2-(1-bromoalkyl) aromatic carboxylic acids are
converted in the presence of CH3CN under reflux conditions to the
corresponding g-lactones. In previous reports, no single example
has appeared for the intramolecular reaction of this type by the same
reagent.

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Synthesis of g-Lactones
RESULTS AND DISCUSSION
Preparation of Substrate 4 for Phthalides
3437
The 2-(1-bromoalkyl) benzoic acids 4 were prepared by the
a-bromination of 2-alkylbenzoic acids 3. Few of the 2-alkylbenzoic
acid 3 are commercially available. Those not available such as 2-ethyl-
benzoic acid (3e), 2-n-propylbenzoic acid (3f ), and 2-n-butylbenzoic acid
(3g) were prepared by the lithiation-alkylation of o-methyl benzoic
acid[16] whereas substituted 2-benzylbenzoic acids 3i–o were prepared
using the procedures described in Sch. 1. Substituted phenyl 1l–o were
R
R
O
O
anhydrous AlCl3
O
O
+
45 min
OH
O
1l-1o
2i-2o
C
d/
H2, P
12 h
R
OH
O
3i-3o
i:
R =
p
p
p
-OH
l:
R =
R =
R =
R =
p
p
p
-Br
j:
R =
R =
-F
m:
n:
-I
-Cl
-OCH3
k:
o:
m-NO2
Scheme 1.

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3438
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Synthesis of g-Lactones
3439

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3440
Khan et al.
reacted with phthalic anhydride in the presence of anhydrous AlCl3 to
yield the corresponding substituted 2-benzoylbenzoic acids 2l–o,[17]
while 2i, 2j, a nd2k were commercially available. The ketonic group
from 2i–o was reduced by high pressure hydrogenation at 70ꢀC to yield
substituted 2-benzylbenzoic acids 3i–o.[18] The spectroscopic data of the
following compounds were collected in Table 1.
The 2-alkyl benzoic acids 3 were then subjected to 2-(1-bromoalkyl)
benzoic acids 4 by using N-bromosuccinimide and carbon tetrachloride
(CCl4) as a solvent in the presence of a,a0-azoisobutyronitrile under
stirring at reflux for 6 h[19] (Sch. 2). The following compounds were
obtained in 35–65% yields and characterized by spectroscopic data
collected in Table 2.
Synthesis of g-Lactones
The reaction of 4 (1 mmol) with cesium fluoride-celite (1.5 mmol) in
acetonitrile under reflux for 10 h, led to the formation of the corresponding
phthalides 5 in moderate to excellent yields (Sch. 2). The yields of
g-lactones are shown in Table 3. This methodology shows that the
a-bromobenzoic acid undergoes intramolecular nucleophilic substitution
reaction to afford the corresponding g-lactones. The versatility of the
reaction was demonstrated by its application to a wide range of structur-
ally different a-bromobenzoic acids 4a–o. The spectroscopic data of the all
synthesized compounds were collected in Table 4.
CONCLUSION
The convenient, efficient, simple, and moderate to high yielding
phthalides were prepared from the substituted a-brominates benzoic acids
using CsF-Celite as a solid base in acetonitrile, presented in this article,
serves as a useful synthetic entry to valuable 3-alkyl and 3-arylphthalides.
EXPERIMENTAL
Melting points were determined with aBu chi SMP-20 apparatus and
are uncorrected. The ultraviolet spectra were measured in chloroform on
aLambda5 UV/VIS spectrometer (Perkin–Elmer). Infrared spectra(KBr
discs) were recorded on aBruker FT-IR IFS 48 spectrometer. EI mass
spectral data were recorded with Varian MAT 711 (70 eV) spectrometer

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Synthesis of g-Lactones
3441
R2
Br
O
R2
R3
R3
R1
R1
NBS, CCl4
reflux, 6 h
OH
OH
R4
R4
O
3
4
CsF-Celite
CH3CN
R2
R1
O
R3
O
R4
5
a:
b:
c:
d:
e:
f:
R1 = R2 = R3 = R4 = H
h:
i:
j:
k:
l:
m:
n:
o:
R2 = R3 = R4 = H, R1 = C6H5
R1 = R3 = R4 = H, R2 = NO2
R1 = R2 = R4 = H, R3 = Br
R1 = R2 = R3 = H, R4 = NH2
R2 = R3 = R4 = H, R1 = CH3
R2 = R3 = R4 = H, R1 = C2H5
R2 = R3 = R4 = H, R1 = C3H7
R2 = R3 = R4 = H, R1 = p-OH-C6H5
R2 = R3 = R4 = H, R1 = p-F-C6H5
R2 = R3 = R4 = H, R1 = p-Cl-C6H5
R2 = R3 = R4 = H, R1 = p-Br-C6H5
R2 = R3 = R4 = H, R1 = p-I-C6H5
R2 = R3 = R4 = H, R1 = p-OCH3-C6H5
R2 = R3 = R4 = H, R1 = m-NO2-C6H5
g:
Scheme 2.
and data are tabulated as m/z. 3-Nitrobenzyl alcohol was used in the
1
matrix of mass spectra. H NMR and 13C NMR spectrawere recorded
in CDCl3, MeOH-d6 and acetone-d6 containing ca. 1% tetramethylsilane
as an internal standard with Bruker AC 250 (250 MHz and 62.9 MHz)
spectrometer, respectively. Splitting patterns were as follows: s, singlet; d,
doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet; br, broad.
Chemical shifts are reported in d (ppm) and coupling constants are given
in Hz. The progress of all reactions was monitored by TLC, which was
performed on 2.0 Â 5.0 cm aluminum sheets precoated with silica gel
60F254 to a thickness of 0.25 mm (Merck). The chromatograms were
visualized under ultraviolet light (254–366 nm).
N-Bromosuccinimide, a,a0-azoisobutyronitrile, phthalic anhydride,
and substituted phenyl 1l–o are commercially available (Fluka, Aldrich).
The 2i, 2j, 3a–d, a nd3h were used as obtained from Fluka and
Aldrich chemical companies. All reagents palladium on carbon (5%
Pd), CsF, celite, and anhydrous AlCl3 are also available from Fluka
and Aldrich. The CsF-Celite was adsorbed on Celite 521 using water

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3442
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Synthesis of g-Lactones
3443

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3444
Khan et al.
Table 3. Conversion of 2-(1-bromoalkyl)
benzoic acids 4 into g-lactones using a CsF-
celite/CH3CN system.
Substrate
g-Lactone
Yielda (%)
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
80
60
65
84
68
65
64
70
86
77
80
80
82
85
75
4g
4h
4i
5g
5h
5i
4j
5j
4k
4l
5k
5l
4m
4n
4o
5m
5n
5o
aIsolated yield of pure products.
under stirring at room temperature for 20 min.[13] The carbon tetrachlo-
ride (CCl4) dried with potassium hydroxide and stored over 5 Aꢀ molecular
sieves,[20] while anhydrous acetonitrile and methanol were purchased
from Merck and used without purification.
General Procedure for the Preparation of 2l–o
A mixture of substituted phenyl substrate 1l–o (20 mmol), phthalic
anhydride (2.36 g, 16 mmol), and anhydrous AlCl3 (4.36 g, 32 mmol) was
throughly ground in an agate mortor and pestle for 45 min. The reaction
mixture was mixed with crushed ice and extracted with ether. The
ethereal extract was washed with brine, dried over anhydrous MgSO4,
and filtered. The filtrate was evaporated in vacuo; the residue was purified
by column chromatography on silica gel (hexane/EtOAc, 8:2, v/v) to
afford the corresponding products 2l–o.
2-(40-Bromobenzoyl) benzoic acid (2l). Yield: 3.66 g (60%); colorless
compound. M.p.: 86–89ꢀC. Rf ¼ 0.43 (hexane:ethyl acetate, 5:2). EI MS:
m/z (%) ¼ 305 [Mþ] (51), 260 (17), 225 (100), 149 (22), 121 (44), 104 (15), 76
(79). Anal. calcd. for C14H9BrO3: C 55.11, H 2.97. Found: C 55.19, H 2.89.

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Synthesis of g-Lactones
3445
2-(40-Iodobenzoyl) benzoic acid (2m). Yield: 3.87 g (55%); colorless
compound. M.p.: 83–85ꢀC (Lit. m.p. 86–96ꢀC).[21] Rf ¼ 0.45 (hexane:
ethyl acetate, 5:2); EI MS: m/z (%) ¼ 352 [Mþ] (39), 324 (831), 307
(14), 225 (49), 149 (100), 127 (7), 121 (17), 104 (23), 77 (63). Anal.
calcd. for C14H9IO3: C 47.75, H 2.58. Found: C 47.81, H 2.49.
2-(40-Methoxybenzoyl) benzoic acid (2n). Yield: 3.69 g (72%); color-
less prisms. M.p.: 120–123ꢀC (Lit. m.p. 122–123ꢀC).[22] Rf ¼ 0.38 (hexane:
ethyl acetate, 5:2). EI MS: m/z (%) ¼ 256 [Mþ] (27), 241 (19), 225 (42),
211 (36), 149 (100), 121 (74), 104 (33), 76 (56). Anal. calcd. for C15H12O4:
C 70.31, H 4.72. Found: C 70.25, H 4.78.
2-(30-Nitrobenzoyl) benzoic acid (2o). Yield: 2.98 g (55%); colorless
plates. M.p.: 79–82ꢀC. Rf ¼ 0.35 (hexane:ethyl acetate, 5:2). EI MS: m/z
(%) ¼ 271 [Mþ] (54), 226 (34), 197 (42), 149 (27), 121 (100), 104 (13), 77
(52), 46 (17). Anal. calcd. for C14H9NO5: C 62.00, H 3.34, N 5.16. Found:
C 62.09, H 3.28, N 5.19.
General Procedure for the Preparation of 3i–o
The above keto-acids 2i–o (10 mmol) was dissolved in 20 mL of
methanol along with 5% palladium on carbon (0.59 g). The solution
was maintained under 20 atm of hydrogen at 70ꢀC for 12 h. The reaction
mixture was filtered through celite. The celite was washed well with
methanol. The combined methanol was evaporated to dryness. The
material was then chromatographed on silica gel using 20–40% ethyl
acetate in hexane to give corresponding products 3i–o.
2-(40-Hydroxybenzyl) benzoic acid (3i). Yield: 1.85 g (81%); colorless
needles. M.p.: 149–151ꢀC (Lit. m.p. 151ꢀC).[23] Rf ¼ 0.56 (hexane:ethyl
acetate, 5:2). EI MS: m/z (%) ¼ 228 [Mþ] (48), 211 (43), 183 (64), 135
(51), 121 (100), 76 (25). Anal. calcd. for C14H12O3: C 73.67, H 5.30.
Found: C 73.59, H 5.37.
2-(40-Fluorobenzyl) benzoic acid (3j). Yield: 1.91 g (83%); colorless
compound. M.p.: 121–123ꢀC (Lit. m.p. 122–124ꢀC).[24] Rf ¼ 0.66
(hexane: ethyl acetate, 5:2). EI MS: m/z (%) ¼ 230 [Mþ] (38), 211 (34),
185 (15), 135 (100), 121 (69), 104 (44), 77 (21). Anal. calcd. for
C14H11FO2: C 73.03, H 4.82. Found: C 72.95, H 4.89.
2-(40-Chlorobenzyl) benzoic acid (3k). Yield: 2.12 g (86%); colorless
needles. M.p.: 123–126ꢀC (Lit. m.p. 125–128ꢀC).[18b] Rf ¼ 0.67 (hexane:
ethyl acetate, 5:2). EI MS: m/z (%) ¼ 246 [Mþ] (46), 229 (17), 211 (37),
201 (24), 135 (100), 121 (58), 104 (33), 76 (43). Anal. calcd. for
C14H11ClO2: C 68.16, H 4.49. Found: C 68.24, H 4.41.

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Synthesis of g-Lactones
3447

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3448
Khan et al.
2-(40-Bromobenzyl) benzoic acid (3l). Yield: 2.44 g (84ꢀ%); colorless com-
pound. M.p.: 131–134ꢀC (Lit. m.p. 136–137 C).[18b] Rf ¼ 0.68
(hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 291 [Mþ] (62), 274 (21),
246 (74), 211 (44), 135 (100), 121 (51), 104 (42), 77 (31). Anal. calcd. for
C14H11BrO2: C 57.76, H 3.81. Found: C 57.69, H 3.75.
2-(40-Iodobenzyl) benzoic acid (3m). Yield: 2.77 g (82%); colorless
compound. M.p.: 127–130ꢀC. Rf ¼ 0.70 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 338 [Mþ] (27), 321 (16), 293 (42), 211 (53), 135 (71),
127 (9), 121 (100), 103 (28), 77 (36). Anal. calcd. for C14H11IO2: C
49.73, H 3.28. Found: C 49.81, H 3.21.
2-(40-Methoxybenzyl) benzoic acid (3n). Yield: 2.05 g (85%); colorless
compound. M.p.: 114–116ꢀC (Lit. m.p. 117–119ꢀC).[18b,22] Rf ¼ 0.58
(hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 242 [Mþ] (49), 227 (41),
225 (17), 211 (37), 197 (9), 135 (100), 121 (61), 104 (53), 77 (34). Anal.
calcd. for C15H14O3: C 74.36, H 5.82. Found: C 74.29, H 5.89.
2-(30-Nitrobenzyl) benzoic acid (3o). Yield: 2.11 g (82%); colorless
compound. M.p.: 113–116ꢀC. Rf ¼ 0.47 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 257 [Mþ] (64), 240 (48), 212 (36), 211 (19), 135 (62),
121 (100), 104 (56), 77 (32), 47 (15). Anal. calcd. for C14H11NO4: C
65.37, H 4.31, N 5.44. Found: C 65.46, H 4.38, N 5.36.
General Procedure for the Preparation of 4a–o
The substituted o-alkyl benzoic acids 3a–o (8 mmol) was dissolved in
dry CCl4 (20 mL), N-bromosuccinimide (1.42 g, 8 mmol) and a,a0-azoiso-
butyronitrile (0.05 g) were added and the mixture was heated to reflux
temperature for 6 h. The solution was cooled, succinimide was filtered off,
and the solvent was removed in vacuo to leave a crude solid. The solid
was chromatographed on silica gel using 20–40% ethyl acetate in hexane
to give corresponding products 4a–o.
2-(Bromomethyl) benzoic acid (4a). Yield: 1.12 g (65%); colorless
compound. M.p.: 134–137ꢀC. Rf ¼ 0.58 (hexane:ethyl acetate, 5:2).
EI MS: m/z (%) ¼ 215 [Mþ] (37), 170 (32), 135 (78), 121 (100), 80 (21),
76 (16). Anal. calcd. for C8H7BrO2: C 44.68, H 3.28. Found: C 44.59,
H 3.36.
2-Bromomethyl-3-nitro-benzoic acid (4b). Yield: 1.10 g (53%); color-
less compound. M.p.: 209–211ꢀC. Rf ¼ 0.53 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 260 [Mþ] (51), 211 (21), 180 (62), 166 (56), 120 (100), 80
(35), 76 (11), 50 (9). Anal. calcd. for C8H6BrNO4: C 36.95, H 2.33, N
5.39. Found: C 36.87, H 2.41, N 5.48.

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Synthesis of g-Lactones
3449
2-Bromomethyl-4-nitro-benzoic acid (4c). Yield: 1.20 g (51%); color-
less compound. M.p.: 211–214ꢀC. Rf ¼ 0.53 (hexane:ethyl acetate, 5:2).
EI MS: m/z (%) ¼ 294 [Mþ] (19), 277 (35), 249 (42), 214 (45), 200 (19),
120 (100), 80 (38), 77 (14), 49 (8). Anal. calcd. for C8H6Br2O2: C 32.69, H
2.06. Found: C 32.76, H 2.13.
2-Bromomethyl-6-amino-benzoic acid (4d). Yield: 0.87 g (47%); color-
less compound. M.p.: 156–159ꢀC. Rf ¼ 0.43 (hexane:ethyl acetate, 5:2).
EI MS: m/z (%) ¼ 230 [Mþ] (27), 214 (56), 185 (38), 150 (62), 136 (48),
120 (100), 80 (42), 76 (11), 50 (8). Anal. calcd. for C8H8BrNO2: C 41.77,
H 3.51, N 6.09. Found: C 41.85, H 3.59, N 6.01.
2-(1-Bromoethyl) benzoic acid (4e). Yield: 0.96 g (52%); colorless
compound. M.p.: 179–181ꢀC. Rf ¼ 0.55 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 229 [Mþ] (26), 214 (63), 184 (56), 134 (100), 121 (72),
80 (32), 76 (18), 49 (7). Anal. calcd. for C9H9BrO2: C 47.19, H 3.96.
Found: C 47.26, H 3.88.
2-(1-Bromopropyl) benzoic acid (4f ). Yield: 0.97 g (50%); colorless
compound. M.p.: 163–165ꢀC. Rf ¼ 0.65 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 243 [Mþ] (23), 228 (63), 214 (71), 198 (48), 134 (100),
121 (58), 80 (45), 77 (13), 50 (8). Anal. calcd. for C10H11BrO2: C 49.41,
H 4.56. Found: C 49.49, H 4.49.
2-(1-Bromobutyl) benzoic acid (4g). Yield: 0.98 g (48%); colorless
compound. M.p.: 153–156oC. Rf ¼ 0.72 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 257 [Mþ] (33), 242 (56), 226 (62), 212 (48), 177 (42), 134
(100), 121 (72), 80 (38), 77 (12), 50 (6). Anal. calcd. for C11H13BrO2: C
51.38, H 5.10. Found: C 51.46, H 5.15.
2-(Bromobenzyl) benzoic acid (4h). Yield: 1.28 g (55%); colorless com-
pound. M.p.: 192–194ꢀC. Rf ¼ 0.53 (hexane:ethyl acetate, 5:2). EI MS:
m/z (%) ¼ 291 [Mþ] (36), 246 (32), 214 (48), 211 (66), 134 (58), 121 (100),
80 (44), 76 (15), 50 (7). Anal. calcd. for C14H11BrO2: C 57.76, H 3.81.
Found: C 57.69, H 3.88.
2-[40-Hydroxy(bromobenzyl)] benzoic acid (4i). Yield: 1.03 g (42%);
colorless compound. M.p.: 196–199ꢀC. Rf ¼ 0.51 (hexane:ethyl acetate,
5:2). EI MS: m/z (%) ¼ 307 [Mþ] (25), 290 (71), 262 (32), 227 (48), 214
(62), 134 (58), 121 (100), 80 (28), 76 (15), 50 (11). Anal. calcd. for
C14H11BrO3: C 54.75, H 3.61. Found: C 54.81, H 3.56.
2-[40-Fluoro(bromobenzyl)] benzoic acid (4j). Yield: 0.98 g (40%);
colorless compound. M.p.: 161–163ꢀC. Rf ¼ 0.61 (hexane:ethyl acetate,
5:2). EI MS: m/z (%) ¼ 309 [Mþ] (31), 290 (42), 264 (62), 229 (38), 214
(54), 134 (68), 121 (100), 80 (35), 76 (11), 49 (5). Anal. calcd. for
C14H10BrFO2: C 54.40, H 3.26. Found: C 54.49, H 3.18.
2-[40-Chloro(bromobenzyl)] benzoic acid (4k). Yield: 1.07 g (41%);
colorless compound. M.p.: 168–171ꢀC. Rf ¼ 0.62 (hexane:ethyl acetate,

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Khan et al.
5:2). EI MS: m/z (%) ¼ 325 [Mþ] (22), 290 (56), 280 (51), 245 (18), 214
(42), 134 (11), 121 (100), 80 (37), 77 (19), 50 (7). Anal. calcd. for
C14H10BrClO2: C 51.65, H 3.10. Found: C 51.71, H 3.17.
2-[40-Bromo(bromobenzyl)] benzoic acid (4l). Yield: 1.11 g (38%); col-
orless compound. M.p.: 193–195ꢀC. Rf ¼ 0.63 (hexane:ethyl acetate, 5:2).
EI MS: m/z (%) ¼ 370 [Mþ] (27), 325 (38), 290 (52), 214 (48), 134 (100),
121 (62), 80 (21), 76 (14), 50 (5). Anal. calcd. for C14H10Br2O2: C 45.44, H
2.72. Found: C 45.52, H 2.64.
2-[40-Iodo(bromobenzyl)] benzoic acid (4m). Yield: 1.17 g (35%);
colorless compound. M.p.: 158–161ꢀC. Rf ¼ 0.65 (hexane:ethyl acetate,
5:2). EI MS: m/z (%) ¼ 417 [Mþ] (18), 372 (36), 337 (46), 290 (51), 214
(62), 134 (100), 127 (26), 121 (58), 80 (31), 76 (11), 50 (5). Anal. calcd. for
C14H10BrIO2: C 40.32, H 2.42. Found: C 40.41, H 2.51.
2-[40-Methoxy(bromobenzyl)] benzoic acid (4n). Yield: 1.36 g (53%);
colorless compound. M.p.: 175–177ꢀC. Rf ¼ 0.53 (hexane:ethyl acetate,
5:2). EI MS: m/z (%) ¼ 321 [Mþ] (28), 306 (65), 290 (55), 276 (42), 241
(32), 214 (62), 134 (72), 121 (100), 80 (45), 76 (13), 50 (9). Anal. calcd. for
C15H13BrO3: C 56.10, H 4.08. Found: C 56.17, H 4.15.
2-[30-Nitro(bromobenzyl)] benzoic acid (4o). Yield: 1.14 g (42%); col-
orless compound. M.p.: 167–170ꢀC. Rf ¼ 0.42 (hexane:ethyl acetate, 5:2).
EI MS: m/z (%) ¼ 336 [Mþ] (36), 319 (19), 290 (53), 256 (47), 214 (61),
134 (72), 121 (100), 80 (43), 76 (16), 49 (9). Anal. calcd. for
C14H10BrNO4: C 50.03, H 3.00, N 4.17. Found: C 50.11, H 3.09, N 4.09.
General Procedure for the Synthesis of g-Lactones
To a suspension of substituted 2-(1-bromoalkyl) benzoic acid 4a–o
(1.0 mmol) and CsF-Celite (0.318 g, 1.5 mmol) in 100 mL of dry acetoni-
trile were stirred. The reaction mixture was heated to reflux temperature
for 10 h. The solution was cooled, solvent was evaporated, and the residue
was dissolved in EtOAc. The precipitates were filtered off, washed with
EtOAc (20 mL), and the filtrate was evaporated. The residue was chro-
matographed on silica gel column using a mixture of hexane and ethyl
acetate (7:3, v/v) as eluent to give corresponding products 5a–o.
Phthalide (5a). Yield: 0.11 g (80%); colorless compound. M.p.:
73–75ꢀC (Lit. m.p. 74–75ꢀC).[9] Rf ¼ 0.43 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 134 [Mþ] (48), 105 (100), 89 (15), 77 (38), 50 (20). Anal.
calcd. for C8H6O2: C 71.64, H 4.51. Found: C 71.72, H 4.44.
4-Nitrophthalide (5b). Yield: 0.11 g (60%); colorless compound. M.p.:
151–154ꢀC. Rf ¼ 0.27 (hexane:ethyl acetate, 5:1). EI MS: m/z (%) ¼ 179
[Mþ] (31), 164 (100), 146 (41), 132 (38), 117 (31), 105 (28), 91 (45), 77 (14),

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Synthesis of g-Lactones
3451
51 (9). Anal. calcd. for C8H5NO4: C 53.64, H 2.81, N 7.82. Found: C
53.71, H 2.72, N 7.91.
5-Bromophthalide (5c). Yield: 0.14 g (65%); colorless compound.
M.p.: 153–155ꢀC. Rf ¼ 0.38 (hexane:ethyl acetate, 5:2). EI MS: m/z
(%) ¼ 214 [Mþ-H] (35), 185 (100), 155 (38), 133 (23), 104 (21), 76 (12),
50 (9). Anal. calcd. for C8H5BrO2: C 45.11, H 2.37. Found: C 45.19,
H 2.28.
7-Aminophthalide (5d). Yield: 0.07 g (48%); yellow compound. M.p.:
97–99ꢀC. Rf ¼ 0.25 (hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 150
[Mþ-H] (65), 132 (56), 121 (100), 104 (43), 88 (6), 74 (34), 56 (12), 42
(8). Anal. calcd. for C8H7NO2: C 64.42, H 4.73, N 9.39. Found: C 64.49,
H 4.67, N 9.47.
3-Methylphthalide (5e). Yield: 0.10 g (68%); oily compound.
Rf ¼ 0.33 (hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 148 [Mþ] (73),
133 (41), 104 (62), 76 (36), 61 (11), 50 (100), 38 (7). Anal. calcd. for
C9H8O2: C 72.96, H 5.44. Found: C 73.06, H 5.35.
3-Ethylphthalide (5f ). Yield: 0.10 g (65%); oily compound. Rf ¼ 0.53
(hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 162 [Mþ] (33), 135 (11), 120
(21), 105 (63), 95 (18), 68 (58), 41 (100). Anal. calcd. for C10H10O2: C
74.06, H 6.21. Found: C 74.14, H 6.15.
3-n-Propylphthalide (5g). Yield: 0.11 g (64%); oily compound.
Rf ¼ 0.58 (hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 177 [Mþ-H]
(31), 160 (7), 147 (100), 130 (11), 104 (48), 90 (5), 76 (62), 50 (43).
Anal. calcd. for C11H12O2: C 74.98, H 6.86. Found: C 75.09, H 6.78.
3-Phenylphthalide (5h). Yield: 0.15 g (70%); colorless compound.
M.p.: 111–113oC (lit. m.p. 113–114ꢀC).[11] Rf ¼ 0.49 (hexane:ethyl
acetate, 5:2). EI MS: m/z (%) ¼ 210 [Mþ] (29), 182 (6), 121 (11), 105
(100), 77 (37), 50 (23). Anal. calcd. for C14H10O2: C 79.98, H 4.79.
Found: C 79.91, H 4.86.
3-(40-Hydroxyphenyl)phthalide (5i). Yield: 0.19 g (86%); colorless
compound. M.p.: 162–165ꢀC. Rf ¼ 0.36 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 225 [Mþ-H] (51), 209 (11), 198 (18), 182 (43), 134 (24),
105 (28), 91 (100), 77 (32), 65 (14). Anal. calcd. for C14H10O3: C 74.33,
H 4.46. Found: C 74.24, H 4.52.
3-(40-Fluorophenyl)phthalide (5j). Yield: 0.17 g (77%); colorless
compound. M.p.: 102–104ꢀC (Lit. m.p. 100–101ꢀC).[24] Rf ¼ 0.49
(hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 228 [Mþ] (35), 181 (11),
167 (10), 149 (24), 133 (21), 125 (9), 105 (56), 91 (100), 76 (41), 57 (14).
Anal. calcd. for C14H9FO2: C 73.68, H 3.97. Found: C 73.75, H 3.89.
3-(40-Chlorophenyl)phthalide (5k). Yield: 0.19 g (80%); colorless
compound. M.p.: 111–113ꢀC. Rf ¼ 0.53 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 244 [Mþ] (29), 209 (16), 181 (28), 162 (23), 134 (100), 121

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3452
Khan et al.
(42), 105 (63), 83 (56), 76 (43), 55 (32). Anal. calcd. for C14H9ClO2: C
68.73, H 3.71. Found: C 68.81, H 3.64.
3-(40-Bromophenyl)phthalide (5l). Yield: 0.23 g (80%); colorless com-
pound. M.p.: 138–141ꢀC (Lit. m.p. 139–140ꢀC).[18b] Rf ¼ 0.54 (hexane:
ethyl acetate, 5:2). EI MS: m/z (%) ¼ 289 [Mþ] (43), 261 (18), 209 (32),
161 (23), 149 (15), 133 (100), 105 (48), 91 (35), 76 (56), 57 (25). Anal.
calcd. for C14H9BrO2: C 58.16, H 3.14. Found: C 58.22, H 3.07.
3-(40-Iodophenyl)phthalide (5m). Yield: 0.27 g (82%); colorless com-
pound. M.p.: 102–105ꢀC. Rf ¼ 0.56 (hexane:ethyl acetate, 5:2). EI MS:
m/z (%) ¼ 336 [Mþ] (38), 308 (31), 293 (16), 279 (22), 209 (56), 134 (62),
127 (48), 105 (100), 76 (28), 57 (18). Anal. calcd. for C14H9IO2: C 50.03,
H 2.70. Found: C 50.11, H 2.62.
3-(40-Methoxyphenyl)phthalide (5n). Yield: 0.20 g (85%); colorless
compound. M.p.: 117–119ꢀC (Lit. m.p. 118–119ꢀC).[5c] Rf ¼ 0.41
(hexane:ethyl acetate, 5:2). EI MS: m/z (%) ¼ 240 [Mþ] (45), 225 (21),
212 (31), 209 (48), 133 (65), 105 (100), 90 (23), 76 (19), 50 (34). Anal.
calcd. for C15H12O3: C 74.99, H 5.03. Found: C 74.91, H 5.11.
3-(30-Nitrophenyl)phthalide (5o). Yield: 0.19 g (75%); colorless
compound. M.p.: 113–116ꢀC. Rf ¼ 0.28 (hexane:ethyl acetate, 5:2). EI
MS: m/z (%) ¼ 256 [Mþ-H] (41), 228 (42), 209 (38), 179 (28), 162 (16),
133 (58), 119 (31), 105 (100), 91 (24), 77 (45), 50 (21). Anal. calcd. for
C14H9NO4: C 65.88, H 3.55, N 5.49. Found: C 65.79, H 3.61, N 5.42.
ACKNOWLEDGMENT
This work was financially supported by Pakistan Science Foundation
(Grant No. SKU/CHEM/372) and Third World Academy of Sciences
(TWAS), Italy (Grant No. 01–310 RG/CHE/AS).
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Synthesis of g-Lactones
3453
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