1925年，A. Vilsmeier及其团队报道了利用POCl3和N-甲基乙酰苯胺反应得到氯化4-氯-1,2-二甲基喹啉盐的文章。接着他们深入研究发现，N-甲基甲酰苯胺和POCl3反应可以得到一种氯代甲基亚胺盐（即是Vilsmeier试剂），此试剂可以和富电子的芳烃反应得到苯甲醛。利用Vilsmeier试剂在富电子芳香化合物上引入甲酰基的反应被称为Vilsmeier-Haack甲酰化反应。Vilsmeier-Haack反应由于其条件温和，操作简便而被广泛用于加碳甲酰化反应。一、Vilsmeier试剂可以通过任何一种N,N-二取代的酰胺和酰氯(e.g., POCl3, SOCl2, 草酰氯)制得；二、最常用的Vilsmeier试剂制备方法就是利用DMF和POCl3制备得到，通常分离后使用；三、Vilsmeier–Haack试剂是弱亲电试剂，对于大多数的富电子芳烃或杂环芳烃、富电子烯烃和1,3-二烯烃都可以发生此反应；四、五元杂环芳烃的反应活性顺序：吡咯 > 呋喃 >噻吩；五、反应溶剂通常为卤代烃（二氯甲烷，二氯乙烷或二氯苯），DMF或POCl3和溶剂的性质对试剂的亲电性有深刻影响，因此应慎重选择；六、反应温度和反应底物的活性有关0 °C 到80 °C不等；七、反应的后处理前的产物为亚胺盐，可以水解得到相应的醛，H2S处理则生成硫代醛，羟胺处理则得到腈，或者还原则生成胺；八、反应有区域选择性，优先在位阻更小的位点反应（苯环对位），但是电子效应也影响反应位点的选择；九、富电子烯烃可以发生此反应水解后得到α,β-不饱和羰基化合物。十、-OH,-OR,-NR1R2,CH(OR)等基团不影响反应。首先DMF和三氯氧磷反应，生成强亲电子的Vilsmeier中间体，接着芳香族化合物进行亲电取代(SEAr)反应。然后加水分解得到甲酰化产物。【J. Org. Chem. 1995, 60, 2964-2965】【J. Org. Chem. 1997, 62, 1083-1094】【Org. Lett. 2001, 3, 2611-2613】【J. Org. Chem. 1992, 57, 3636-3642】【Tetrahedron: Asymmetry 2000, 11, 3375-3393】【J. Chem. Soc., Perkin Trans. 1， 1981, 2662–2665】【Chem. Pharm. Bull. 1985, 33, 3122–3128】【Eur. J. Med. Chem. 2007, 42, 1128–1136】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.】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)】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 ℃.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.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.
1. Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119–122. German chemists Anton Vilsmeier and Albrecht Haack discovered this recation in 1927.
2. Reddy, M. P.; Rao, G. S. K. J. Chem. Soc., Perkin Trans. 1 1981, 2662–2665.
3. Lancelot, J.-C.; Ladureé, D.; Robba, M. Chem. Pharm. Bull. 1985, 33, 3122–3128.
4. Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994.(Book).
5. Seybold, G. J. Prakt. Chem. 1996, 338, 392-396 (Review).
6. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1–330. (Review).
7. Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355–659. (Review).
8. Tasneem, Synlett 2003, 138–139. (Review of the Vilsmeier–Haack reagent).
9. Nandhakumar, R.; Suresh, T.; Jude, A. L. C.; Kannan, V. R.; Mohan, P. S. Eur. J. Med. Chem. 2007, 42, 1128–1136.
10. Tang, X.-Y.; Shi, M. J. Org. Chem. 2008, 73, 8317–8320.
11. Shamsuzzaman, Hena Khanam, H.; Mashrai, A.; Siddiqui, N. Tetrahedron Lett. 2013,54, 874-877.
一、Strategic Applications of Named Reactions in OrganicSynthesis, László Kürti and Barbara Czakó, Vilsmeier-Haack formylation，page 688-689.二、Name Reactions （A Collection of Detailed Reaction Mechanisms）, Jie Jack Li, Vilsmeier-Haack reaction，page 615-616.
