Meyers醛合成反应

通过水解四氢恶嗪制备醛的反应。此反应以美国化学家 Albert I. Meyers名字命名。手性恶嗪类化合物可以得到手性醛。此反应以2-烷基-二氢-1,3-恶嗪为底物，恶嗪的α-位的氢有酸性可以被强碱（丁基锂）拔去，接着可以和卤代烃反应进行烷基化，用硼氢化钠还原恶嗪的碳氮双键，得到的四氢恶嗪是胺缩醛，可以用草酸水解得到醛。

【 J. Am. Chem. Soc. 1969; 91(3); 763-764.】

与此反应类似的更出名的反应是Meyers恶唑啉合成法。

Albert I. Meyers在韦恩州立大学任副教授的时候，派德药厂 ( George Moersch 和Harry Crooks博士)就利用他的方法通过手性恶唑啉合成数公斤 (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol（Meyers称其为Parke–Davis二醇）。后来他一直到1972年都在科罗拉多州立大学任教。Meyers2007年去世。

反应实例

A. 2-(1-Phenylcyclopentyl)-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine. A 1-l., three-necked flaskis equipped with a magnetic stirring bar, a 125-ml. pressure-equalizing funnel fitted with a rubberseptum, and a nitrogen inlet tube. The system is flushed with nitrogen, and 500 ml. of drytetrahydrofuran (Note 1) and 21.7 g. (0.100 mole) of 2-benzyl-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine (Note 2) are added to the flask. The stirred solution is cooled to −78° with an acetone–dry iceDOI:10.15227/orgsyn.051.0024bath, and 49 ml. (0.11 mole) of a 2.25 M solution of n-butyllithium in n-hexane (Note 3) is injectedinto the addition funnel. The n-butyllithium solution is added over a period of 15 minutes, and thefunnel is rinsed by injecting 5 ml. of dry tetrahydrofuran. The yellow to orange solution is allowed tostir at −78° for 30 minutes (Note 4).1,4-Dibromobutane (23.8 g., 0.110 mole) (Note 5) is injected into the addition funnel and added tothe solution with stirring over a period of about 15 minutes. The funnel is rinsed by injection of 5 ml. ofdry tetrahydrofuran, and the reaction is stirred at −78° for 45 minutes. n-Butyllithium (55 ml., 0.12mole) in n-hexane is injected into the addition funnel and added to the solution over a period of 15minutes. The reaction is stirred at −78° for 1 hour and stored at −20° overnight (Note 6). The mixture ispoured into about 300 ml. of ice water and acidified to pH 2–3 with 9 N hydrochloric acid. The acidicsolution is shaken with three 200-ml. portions of diethyl ether, and the ether extracts are discarded. Theaqueous layer is made basic by careful addition of 40% sodium hydroxide (Note 7). The resultingmixture is shaken with four 200-ml. portions of ether, and the ether extracts are dried over anhydrouspotassium carbonate. The ether is removed with a rotary evaporator, giving 24.4–25.8 g. (90–95%) ofcrude 2-(1-phenylcyclopentyl)-4,4,6-trimethyl-5,6-dihydro-1,3(4H)-oxazine, which is sufficiently purefor use in the following step.

 B. 2-(1-Phenylcyclopentyl)-4,4,6-trimethyltetrahydro-1,3-oxazine. A 600-ml. beaker containing amagnetic stirring bar is charged with 200 ml. of tetrahydrofuran, 200 ml. of 95% ethanol, and 25.0 g.(0.0922 mole) of the oxazine obtained in Part A. The mixture is stirred and cooled to −35 to −40° withan acetone bath to which dry ice is added as needed. A 9 N hydrochloric acid solution is added dropwiseto the stirred solution until an approximate pH of 7 is obtained as determined by pH paper. A solution ofsodium borohydride is prepared by dissolving 5.0 g. (0.13 mole) in a minimum amount of water (5–8ml.) to which 1 drop of 40% sodium hydroxide is added (Note 8). The sodium borohydride solution and9 N hydrochloric acid solution are alternately added dropwise to the stirred solution so that a pH 6–8 ismaintained (Note 9). During the addition care is taken to maintain a temperature between −35 and −45°.After addition of the borohydride solution is complete, the reaction mixture is stirred at −35° for 1 hour.A pH of 7 is maintained by occasional addition of 9 N hydrochloric acid (Note 10). The reactionmixture is then stored at −20° overnight.The reaction mixture is poured into 300 ml. of water, and the resulting mixture is made basic with40% sodium hydroxide. The mixture is shaken three times with 200-ml. portions of ether, and thecombined ether extracts are washed with 10 ml. of saturated sodium chloride. After drying overpotassium carbonate, the ether is removed with a rotary evaporator, giving 22.9–25.0 g. (91–99%) ofproduct, which is used without purification in the next step (Note 11).

C. 1-Phenylcyclopentanecarboxyaldehyde. The crude tetrahydroöxazine (25.0 g., 0.0916 mole)from Part B is heated at reflux with 300 ml. of water containing 37.8 g. (0.300 mole) of oxalic aciddihydrate for 3 hours. The solution is cooled, and the aldehyde is extracted with four 150-ml. portions ofpetroleum ether (b.p. 40–60°). The organic extracts are combined, washed with 10 ml. of saturatedsodium hydrogen carbonate, and dried with anhydrous powdered magnesium sulfate. The petroleumether is removed with a rotary evaporator, and the product is distilled through a Vigreux column, giving7.8–8.7 g. (50–55%) of 1-phenylcyclopentanecarboxaldehyde, b.p. 70–73° (0.1 mm.) nD 1.5350, IRspectrum (neat) 1720 cm.−1 (C=O) (Note 12).

【 Organic Syntheses, Coll. Vol. 6, p.905 (1988); Vol. 51, p.24 (1971). http://www.orgsynth.org/orgsyn/pdfs/CV6P0905.pdf】

参考文献

一、维基百科：Meyers synthesis