A practical synthesis of 3-n-propylphenol, a component of tsetse fly attractant blends

Organic Process Research and Development

Volumn 7, Issue 4, 2003, Pages 585-587

  Ujváry, István ^a   Mikite, Gyula ^b  

^a CHEMICAL RESEARCH CENTER   (Hungary)

^b ERCOM Ltd   (Hungary)

Author keywords

[No Author keywords available]

Indexed keywords

3 HYDROXYBENZALDEHYDE; 3 N PROPYLPHENOL; BROMINE DERIVATIVE; ETHYLMAGNESIUM BROMIDE; PHENOL DERIVATIVE; SOLVENT; UNCLASSIFIED DRUG;

ARTICLE; CATALYSIS; GRIGNARD REACTION; HYDROGENATION; INSECT CONTROL; SYNTHESIS; TEMPERATURE; TSETSE FLY;

EID: 0043246690     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op0340309     Document Type: Article

References (25)

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5. Improved Attractants for Enhancing the Efficiency of Tsetse Fly Suppression Operations and Barrier Systems Used in Tsetse Control/Eradication Campaigns; IAEA-TECDOC, International Atomic Energy Agency; Vienna, 2003. In press.
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10. (a) Cousin, S. G.; Lions, F. J. Proc. R. Soc. N. S. W. 1937, 70, 413; Chem. Abstr. 1937, 31, 6637.
11. (b) Strunz, G. M.; Court, A. S. J. Am. Chem. Soc. 1973, 95, 3000.
12. Carvalho, C. F.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1984, 1621.
13. Hassanali, A.; McDowell, P. G.; Owaga, M. L. A.; Saini, R. K. Insect Sci. Its Appl. 1986, 7, 5.
14. Prelog, V.; Würsch, J.; Königsbacher, K. Helv. Chim. Acta 1951, 34, 258.
15. (a) von Auwers, K. Ann. Chem. 1917, 413, 253. This paper describes the preparation of hydroxyphenol 3 by using essentially the same procedure described herein, but no experimental details are given.
16. (b) Another paper using von Auwers's method for the preparation of 3 gives no experimental details either: Pohl, L. R.; Haddock, R.; Garland, W. A.; Trager, W. F. J. Med. Chem. 1975, 18, 513.
17. (c) A fully documented description of this method reports the use of diethyl ether as solvent and a 3.2-fold excess of the Grignard reagent, giving the target phenol 3 in 58% yield: Bird, T. G. C.; Bruneau, P.; Crawley, G. C.; Edwards, M. P.; Foster, S. J.; Girodeau, J.-M.; Kingston, J. F.; McMillan, R. M. J. Med. Chem. 1991, 34, 2176.
18. As in ref 10c, our initial small-scale preparations of 3 employed diethyl ether in which the starting aldehyde is more soluble than in THF although solutions more dilute than the one described here were needed. However, during the Mg-phenolate formation and subsequent Grignard reaction, stirring became a serious problem. This solubility problem, exacerbated by intensive cooling, should be the main reason for the earlier reported low (58%) yield of 3: the Grignard adduct forms an ethyl ether-insoluble double salt covering the surface of unreacted Mg-phenolate precipitate, thus blocking complete consumption of the starting material. This could also explain why even a large, 3.2-fold excess (see ref 10c) of EtMgBr could not drive the reaction to completion. It is speculated that refluxing the reaction mixture after the completion of the addition breaks up the solid particles that include unreacted aldehyde phenolate.
19. In preliminary experiments performed under various conditions on up to 50-g scales indicated (TLC) that the use of 2.2-2.4-fold excess of EtMgBr led to intermediate 3 that was contaminated with some unreacted starting material, the removal of which was cumbersome even by repeated recrystallization (attempted distillation of the crude product led to degradation of 3). Furthermore, hydrogenation of the impure intermediate gave the target phenol contaminated with m-cresol resulting from the reductive deoxygenation of 2. Acceptable yield (80%) and excellent purity of 3 was achieved when the excess of EtMgBr was increased to 2.6-fold, which is significantly less than the 3.2 equiv used in ref 10c.
20. Because continuous addition of the suspension of 2 to the Grignard reagent presents some difficulties (clogging of the addition funnel), "inverse addition" of EtMgBr solution to the vigorously stirred dispersion of the aldehyde is preferred.
21. Repeated extractions with 4 x 1 L methyl tert-butyl ether are necessaxy. Measuring the volume of each extract indicated substantial amounts of extractives present in the acidic aqueous phase: the volumes of the four subsequent extracts were 2. 5, 2.2, 2.0, and 1.8 L, respectively.
22. TLC analysis indicated that the mother liquor of the second crop contained hydroxyphenol 3, some starting material, and other unidentified contaminants.
23. As a rule, analytical grade methanol (>99.9%) is used at the pilot plant of ERCOM for the various syntheses. No other grades were tried, but ordinary methanol could also work. As mentioned earlier, laboratory-scale preparations of 3 also used 95% ethanol (with added acetic acid) successfully for the reduction. Due to the notoriously higher price of ethanol, its use on a larger scale was abandoned.
24. In preliminary small-scale experiments reductions using 5% Pd/C from one supplier (Aldrich) were rather slow even in the presence of acetic acid. Note, however, that catalysts on various support - and even with the same support hut from different sources - can vary in their efficiency. No other types of 5% Pd/C were tested.
25. Although some references give a melting point of 26°C for 3-propylphenol, our double-distilled product is a thick liquid at ambient temperature and remains as such even at ca. 5°C (refrigerator).