Vilsmeier-Haack反应

维尔斯迈尔－哈克反应（Vilsmeier-Haack reaction）

此方法广泛应用于活性芳环，杂环，不饱和脂肪上（富电子）引入甲醛，-OH,-OR,-NR1R2,CH(OR)不影响反应，可用二氯甲烷，二氯乙烷或二氯苯作溶剂，也可不用反应溶剂。（A. Vilsmeier and A. Haack,Ber. 1937 119)

反应机理

Vilsmeier 反应示例一

In a 1L round-bottomed, three-necked flask fitted with an efficient mechanicalstirrer, a drying tube containing drierite and a 125 mL dropping funnel isplaced 288 mL (274g, 3.74moles) of freshly distilled dimethylformamide. The flask and its contents arecooled in an ice-salt bath for about 0.5 hour, and 86 mL (144g, 0.94 moles) of freshly distilledphosphorous oxychloride is subsequently added with stirring to thedimethylformamide over a period of 0.5 hour. The pinkish color of theformylation complex may be observed during this step. The 125-mL droppingfunnel is replaced with a 200 mL dropping funnel, and a solution of 100g (0.85 mole) of indole in 100 mL ofdimethylformamide is added to the yellow solution over a period of 1 hourduring which time the temperature should not rise above 10 ℃. Once the solution iswell mixed, the dropping funnel is replaced with a thermometer, and thetemperature of the viscous solution is brought to 35 ℃. The syrup is stirred efficiently atthis temperature for 1 hour, or for 15 minutes longer than is necessary for theclear yellow solution to become opaque, canary-yellow paste. At the end of thereaction period, 300 g ofcrushed ice is added to the paste with careful stirring, producing a clear,cherry-red aqueous solution.

This solution is transferred with 100 mL of water to a3-l. three-necked flask containing 200 gof crushed ice and fitted with an efficient mechanical stirrer and a separatoryfunnel containing a solution of 375 g.(9.4 mole) of sodium hydroxide in 1Lof water The aqueous base is added. The remaining two-thirds is added rapidlywith efficient stirring until about one-third of it has been added. Theremaining two thirds is added rapidly with efficient stirring, and theresulting suspension is heated rapidly to the boiling point and allowed to coolto room temperature, after which it is placed in a refrigerator overnight. Theprecipitate is collected on a filter and resuspended in 1L of water. Most of the inorganic materialdissolves, and the product is then collected on a filter, washed with three300-mL portions of water and air-dried, yielding about 120 g (97%) of indole-3-aldehyde, mp 196-197 ℃. The indole-3-aldehyderesulting from this procedure is sufficiently pure for most purposes, but itmay be recrystallized from ethanol if desired.

【Reference: Org.Syn., Vol 4, pp 539-541.】

 Vilsmeier 反应示例二

Pyrophosphoryl chloride (1.889g, 7.5 mmol) was added dropwise to a stirredmixture of cold (ice bath) N,N-dimethylformamide (0.731g, 10.0 mmol) and p-dimethoxybenzene (0.691g, 5.0 mmol). The resulting syrup wasthen heated at 100 ℃for 48 hours. The cold product was basified with an aqueous solution of 2M sodium hydroxide and extracted withdichloromethane and dried (MgSO4) and concentrated. Short-path distillationgave 2,5-dimethoxybenzaldehyde (0.332g40%), mp 50-51 ℃.bp 80 ℃ at0.1 mmHg.

【Reference: Tetrahedron，49(19)， 4015-4034 (1993)】

草酰氯-DMF 体系Vilsmeier 反应示例

A 1-L 3-neck flask equipped with a temperaturethermocouple and an efficient overhead stirrer is charged with DMF (46.37 g, 0.63 mole) and acetonitrile (350mL). The reaction is treated dropwise with a solution of oxalyl chloride (66.12 g, 0.521 mole) in actionitrile dropwiseover 20 min so that the temperature is maintained at 20~26℃ with a water bath. Gasevolution is noted and a thick precipitate forms. The reaction is stirred atambient temperature for 1 h to insure complete conversion to the Vilsmeierreagent. The reaction is cooled in a dry-ice bath to -14?to -17?C and asolution of resorcinol (26.87 g,0.244 mole) in acetonitrile (75 mL) is added over 20 min. The Vilsmeier reagentdissolves as the reaction with resorcinol occurs, and soon afterward theprecipitation of chloride salt 4--Scheme 4 begins. The reaction is stirred at-15?C. for 35 min, then at 28~32 oC.for 2 h. The HPLC of the reaction solution shows <6% of the startingmaterial. After cooling to 3~5℃ for 2 h, the reaction is filteredand washed with cold acetonitrile (70 mL). The solid is washed with hexane(30-40 mL) and the product dried. The Vilsmeier formamidinium chloride is driedat 30~35 oC at 0.05 mmof Hg for 24 h. The recovery is 42.3 g;the yield corrected for purity is 79%; it is a single component by HPLC, mp170~173 ℃.

Hydrolysis:

To water (250 mL) stirred at 40 oC is addedthe above salt (42.3 g, 0.209mole) in three portions. The reaction is heated to 50 oC for 0.5 h,and the reaction is cooled. When the temperature had reached 35 oC,sodium thiosulfate solution (0.09M,1-2 mL) is added to discharge the resulting pink color. The reaction is cooledto 5 oC., and stirred for 2 h. The mixture is filtered, the solid iswashed with cold water, and air dried at <35 oC for 24 h giving2,4-dimethoxybenzaldehyde (24.4 g,wt/wt assay by HPLC 97%; corrected yield: 69% from resorcinol) an off-whitesolid, mp 134~136oC.

【Reference:US5599988】

二氯亚砜用于Vilsmeier 反应示例

To 108 g(0.80 mole) of N-methylformanilide cooled in an ice-water bath, 95.2 g (0.80 mole) of thionyl chloride wasadded drop by drop with stirring. After completion of the addition, the mixturewas allowed to stand at room temperature for 2 hours and then heated at 40~50 ℃ for 1 hour under areduced pressure of 60-80 mmHg. To the resulting yellow mixture, 97.6 g (0.80 mole) of1,2-methylenedioxybenzene was added and kept at 15 ℃. After completion of the addition,the reaction mixture was kept at 90 ℃ for 30 minutes, poured into icewater, and allowed to stand for 1 hour. Then, the resulting mixture wasextracted with toluene. By vacuum distillation, the toluene was removed and thedistillate at 84~85℃/30mmHg was then collected to recover unreacted 1,2-methylenedioxybenzene.Subsequently, the distillate at 131~134℃/10 mmHg was collected to obtainpiperonal. The yield (expressed in terms of mole percentage based on the amountof N-methylformanilide used) and selectivity (expressed in terms of molepercentage based on the amount of 1,2-methylenedioxybenzene having reacted) ofpiperonal were 55.6% and 95.1%, respectively.

【Reference: US4157333】

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