Sep-Oct 2003
Direct Synthesis of γ-Substituted Phthalides
877
Preparation of 3-(4-Methoxy-phenyl)-3H-isobenzofuran-1-one (13c).
ether and dried over MgSO . The solvent was removed and 2.25
4
g (56%) of 5 mp = 73 °C (lit. 72-74°)[17] was collected as a pure
A Typical Procedure.
center cut from silica gel plate. The solvent system used was 5-
1
13
2-(4-Methoxy-benzyl)-benzoic acid (9c) 1.2 g (5 mmol), 18 ml
distilled water and 0.85 g (5 mmol) copper (II) chloride•2H O
were combined in a 100 ml two-neck round bottom-flask. The
flask was equipped with a reflux condenser and an additional
10% EtOAc:ligroin. The IR, H, CNMR spectra are recorded
(Table2).
2
Synthesis of 2-(4-Methoxy-benzoyl)-benzoic Acid (8c).
funnel. A solution of 1.2 g (5 mmol) Na S O and 10 ml water
2
2 8
A Typical Procedure.
were added to the additional funnel. The reaction mixture was
allowed to reflux by vigorous stirring while the temperature of
solution was adjusted to 85-90 °C. The solution from the addi-
tional funnel was added dropwise to a flask during 40 min. and
the flask was refluxed for 3.5 hrs. After this time the reaction
was stopped. The flask was cooled and extracted with 3 x 10 ml
To a two neck round-buttom flask equipped with a reflux con-
denser and addition funnel was added 4.4 mL (4.32 g, 40 mmol)
anisole, 120 mL nitrobenzene (as a solvent) and 7.4 g (50 mmol)
phthalic anhydride. To the additional funnel was added a solution
of 13.34 g (100 mmol) of powdered anhydrous aluminum chlo-
ride and 30 mL nitrobenzene. This solution, at rt, was dropwise
added to the flask during 40 m. The contents of the flask were
stirred at rt for 5.5 h. After this time the reaction mixture was
added to a solution of 600 mL HCl 20% and 400 g ice and mixed
throughly, extracted with 3 X 20+100mL ether. This phase was
ether and dried with MgSO . The solvent was removed and 1.01g
4
(85%) mp=114 °C of 13c was collected as a pure center cut from
preparative chromatography. The solvent system used was 10 to
1
13
20% EtOAc:ligroin. The IR, H, C NMR spectra and Exact
+
mass (M ) are given in Table 2.
washed with 3 X 30 mL H O, and extracted with 5 X 40+100mL
2
Synthesis of 2-(Naphthalene-1-carbonyl)-benzoic Acid (8d).
saturated NaHCO . This solution was then washed with 3 X 20
3
mL ether. The aqueous solution was transfer to a large beaker and
acidified with HCl. The white percipitate formed and was col-
lected by filtration through to give 10.8 g (85%) crystals mp =
130-132 °C. The IR and NMR were recorded and are given in
(Table 2).
A similar procedure as used for 8c was applied, but instead of
nitrobenzene as a solvent dichloromethane was used.
Acknowledgments.
We appreciate Research Committee of Guilan University for
partial support given to this study.
Preparation of 2-(4-Methoy-benzyl)-benzoic Acid (9c).
A Typical Procedure.
REFERENCES AND NOTES
Zn powder 4.3g (66 mmol), 0.43 g (1.58 mmol) mercury (II)
chloride, 0.2 ml conc. HCl and 5.5 ml distilled water, were com-
bined in a 50 ml flask. The mixture was stirred at room tempera-
ture for several minutes to produce a homogenous solution. After
homogenization was completed, the stirring was stopped and the
liquid was decanted as completely as possible. In a flask
equipped with reflux condenser, 2.7 ml distilled water, 0.65 ml
conc. HCl, 3.6 ml toluene (as solvent) and 2.6 g (10 mmol) 2-(4-
methoy-benzyl)-benzoic acid 8c were combined. The flask was
refluxed vigorously for 40 hrs. During this period 1.8 ml conc.
HCl was added to the flask at approximately 6 hr intervals during
the refluxing period in order to maintain the conc. of HCl. After
cooling, the two layers were separated. Water (7.2 mL) was
added to the aqueous layer, which was extracted with 3x15 ml
ether, the extracted layer was added to toluene, washed with
[1a] J. M. Cassady, M. Suffness, in Anticancer Agents Based on
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[7] N. O. Mahmoodi and S. H. Mirmohammadi, Submitted for
Publication.
water and dried over MgSO . The solvent was evaporated to
4
afford 1.7g (70%) of crystal .The IR and NMR spectra are given
in Table 2.
[8] J. L. Belletire and N.O. Mahmoodi, Tetrahedron Lett., 30,
4363 (1989).
Table 3
[9] J. L. Belletire and N.O. Mahmoodi, Synth. Commun., 19, 3371
(1989).
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MI, USA, 52 (1992).
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(2001).
Reduction Condition for Conversion of 2-Benzoyl-benzoic
Acids to 2-Bezyl-benzoic Acids
2-Benzoyl-
benzoic Acids
Acids
Reagent &
Method [23]
Time of yield
2-Bezyl-
benzoi
Red. hrs
%
8a
8b
8c
8d
amalgamated zinc
amalgamated zinc
amalgamated zinc
amalgamated zinc
30
40
40
20
70
-
70
60
9a
9b
9c
9d
[13] C. J. Li, T.H. Chan, Organic Reactions in Aqueous Media;
John Wiley & Sons, Inc.: New York, (1997), p 198.
[14] C. J. Li, Chem. Rev., 93, 2023 (1993).
[15] P. A. Grieco, Organic Synthesis in Water; Blacky Academic &