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R. Castanedo et al. / Tetrahedron Letters 47 (2006) 973–976
Note: In the case of methoxy substituted benzoic acids,
Acknowledgement
careful acidification with cold acid and rapid extraction is
crucial to avoid hydrolysis of the acid sensitive methoxy enol
ethers present in the products. For alkyl substituted benzoic
acids, the usual acidification and workup can be followed.
4. Furthermore, values thus obtained were checked in every
case by an alternative method involving the two-step
conversion (acid-catalyzed hydrolysis and ethereal
CH2N2) of the alkylated dihydrobenzoic acid methyl esters
into the corresponding cyclic vinylogous methyl esters 5,
which were separated and purified by preparative TLC. If
present, the more polar 2-unsubstituted vinylogous methyl
ester 5a (from monoalkylated product) was easily identified
by the olefin broad singlet signal at ꢀd 5.20 in its 1H NMR
spectrum. This second method of analysis was especially
useful when important amounts of monoalkylated product
were obtained.
´
We thank Q. Alejandrina Acosta, Q. Angeles Pena, Q.
˜
´
Rocıo Patino, and I. Q. Luis Velasco for running spectra.
˜
References and notes
´
1. Guzman, J. A.; Castanedo, R.; Maldonado, L. A. Synth.
Commun. 1991, 21, 1001–1012.
2. Unpublished results.
3. General procedure: In a two-necked 250 mL round bottom
flask, fitted with a dry ice condenser and a stopper, were
placed 1 g (5–8 mmol) of the appropriate benzoic acid and a
stirring bar. Dry liquid NH3 (125 mL, from Na) was
condensed in the flask, and with stirring, the required molar
equivalent of Na (6.2–10.2) was added in small pieces (10–
15 min depending of the amount of metal). The initial
almost colorless solution gradually turns yellow, orange,
and deep red with the first 2 equiv of metal and beyond this
number, the solution becomes deep blue. After 15 min, the
stopper was replaced by an addition funnel containing cold,
neat alkyl bromide (8.2–10.2 molar equiv) and added drop-
wise in about 10 min (CAUTION! Exothermic reaction).
The sequence of colors in the solution reverses, changing
from deep blue to deep red, orange, and finally pale yellow.
NH3 was left to evaporate overnight, the residue dissolved in
H2O (30 mL) and washed with Et2O to remove any neutral
material. The aqueous layer was covered with fresh Et2O
(20 mL) and carefully acidified (pH 5) with small portions of
cold 5% aqueous HCl, shaking vigorously after each
addition. The aqueous solution was extracted again with
20 mL of fresh Et2O and the combined organic extracts
rapidly washed with H2O (2 · 10 mL) and dried over
anhydrous Na2SO4. Removal of solvent gave the crude
product as a white or yellow crystalline mass in the indicated
yields. About 100 mg of the crude acids were quantitatively
esterified with ethereal CH2N2 and the crude methyl esters
MeO2C
O
R2
MeO2C
MeO
R2
1) H3O
2) CH2N2
OMe
OMe
R1
R1
5a, R1 = H
5b, R1 = R2
5. Piers, E.; Grierson, J. R. J. Org. Chem. 1977, 42, 3755–
3757.
6. Collins, C. J.; Hombach, H. P.; Maxwell, B. E.; Benjamin,
B. M.; McKamey, D. J. Am. Chem. Soc. 1981, 103, 1213–
1214.
7. (a) House, H. O.; Strickland, R. C.; Zaiko, E. J. J. Org.
Chem. 1976, 41, 2401–2408; (b) Birch, A. J.; Slobbe, J. Aust.
J. Chem. 1977, 30, 1045–1049.
8. The reductive methylation of 1-naphthoic acid with Li in
liquid NH3–MeI has been previously reported: (a) Slobbe,
J. Aust. J. Chem. 1978, 31, 1157–1159; (b) Murthy, A. R.;
Sundar, N. S.; Subba Rao, G. S. R. Tetrahedron 1982, 38,
2831–2836.
1
were analyzed by H NMR and/or GC.