有机定制合成网

上海凯康镁科技有限公司 电话:021-51009326 化合物定制询价
专注化合物定制合成服务

双活化底物的烷基化

碳-碳键的构建在有机化合物的合成中占有极其重要的地位,其中一种常用并且有效的构建方式便是在活性基团活化的α碳上的烷基化反应。

所谓的活性基团是因为电负性的差异所导致的,理论上电负性大于碳的原子与碳相连都可以使碳活化,但活化效果各有差别,其中常见的活化基团如下表所示(Acc. Chem. Res. 198821, 456-463):

Table 1 Acidity of α-Hydrogens in Mono- and Di-ActivatedCompounds

其中我们可以简单总结出以下的活化顺序:NO2 > COR > CN ~ CO2R ~ SO2R> Ph ~ SR > H > R。

双活化底物的烷基化

常见的双活化底物有β-酮酸酯、丙二酸酯、丙二腈、氰基乙酸酯、2-硝基乙酸酯、2-磺酰基乙酸酯等,这些双活化底物具有底物的相似性,活性的相近性(活泼氢的PKa低,具有较高的活性),所以它们的烷基化方法也很相似,可以相互借鉴。


常用的方法可以分为以下几种:

i.直接碱作用下的烷基化。

常用的碱可以是无机碱,如K2CO3,Cs2CO3,NaH,NaOEt,KOtBu等,也可以是有机碱,如DBU,TMG等,当底物的酸性足够强时,也可以用Et3N等弱有机碱。

所采用的溶剂多为极性溶剂,如丙酮,THF,DMF,DMSO,EtOH,CH3CN等,其中更以THF和DMF应用最多。

当采用无机碱时,反应体系多为非均相体系,这时,加入TBAI,TBAB等相转移催化剂可以促进反应进行。

因为烷基化试剂中离去基团的离去顺序I > Br > Cl,所以加入催化量的KI可以交换离去基团,提高反应速率。

需要指出的是,烷基化反应是SN2反应,所加入的亲电试剂也会影响反应速率,反应速率大小为allyl-X ~ Bn-X > 1oalkyl-X > 2o alkyl-X。

ii.与共轭底物Michael 加成的方法进行烷基化。

具有共轭结构的底物是很好的亲电受体,因此也被广泛用于烷基化反应中。该类反应具有反应条件更温和,可操控性强的优点,可以采用更弱或者催化量的碱使得反应进行,或者引入手性试剂得到手性产物。

iii.金属催化偶联的方法。

一些具有烯丙基结构的底物可以在金属的作用下生成三中心两电子的缺电过渡态,可以与负离子反应得到烯丙基化产物。


示例1:β-酮酸酯

To a solution of cyclic β-keto ester (1 equiv) and alkyl halide (2 equiv) in acetone was added K2CO3. After refluxing for 12 h, the reaction media was cooled, filtered through Celite, and washed with CH2Cl2. The solvents were removed under reduced pressure, and the crude was purified by flash chromatography on silicagel using a mixture of PE and EtOAc leading to the desired compound.

J. Org. Chem.2012, 77, 6087−6099.



示例2:丙二酸酯

To a 1-dram vial equipped with a magnetic stir bar was added ester (29.2mg, 0.100 mmol, 1.0 equiv), allyl bromide (24.2 mg, 0.200 mmol, 2.0 equiv) and THF (1 mL). DBU (30.4 mg, 0.200 mmol, 2.0 equiv) was added and the reaction was stirred at room temperature for 2 h and then diluted with water and ethyl acetate. The organic was washed with water followed by brine, dried over sodium sulfate and concentrated in vacuo. Flash chromatography provided product (31.2 mg, 0.940 mmol,94% yield) as a white solid.

J. Am. Chem. Soc., 2012134 (17), 7329–7332.



示例3:丙二腈

To a solution of cinnamyl bromide (1.97g, 10.0 mmol) and malononitrile (6.61 g, 100 mmol) in THF (10.0 mL) was added K2CO3(1.38 g, 10.0 mmol) portion-wise at 0 oC, after which the solution was stirred at room temperature overnight. After dilution with CH2Cl2(40 mL) and water (40 mL) the phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed sequentially with 1M aq. NaOH and brine, dried, concentrated and purified on silica (EtOAc/pentane 1:19 to 1:3) to yield product (1.40 g, 77%) as a colorless solid.

Angewandte Chemie, InternationalEdition2011, 50(7),1580-1583.



示例4:硝基乙酸酯

Ethyl 2-nitropropionate (3.4 g, 23 mmol) was dissolved in a mixture of acetonitrile (10 g, 244 mmol) and triethylamine (0.2 g, 2mmol). Methacrolein (2.7 g, 38 mmol) was slowly added at 0 oC. The solution was kept at 10 oC for 1.5 h and then poured into a solution of ice-cold HCl (5 ml of concentrated HCl in 150 ml of water). The solution was extracted 3 times with CH2Cl2 and dried over MgSO4. After filtration, the mixture was distilled under reduced pressure, and the purity of the remaining product was assessed by thin layer chromatography and IR spectroscopy. Average yield: 84% (crude product).

Bioorganic & MedicinalChemistry2009, 17(21),7572-7584.



示例5:腈基乙酸酯


In a dried schlenk reactor, were dissolved the boronate (1eq), Pd(OAc)2 (1 mol %) and PPh3(3 mol %) in 2mL of anhydrous THF. In another schlenk reactor, to a solution of NaH (60% suspension in oil, 1.1 eq) washed with 2 mL dry ether was added freshly distilled dimethyl malonate at 0 °C (1.1 eq). After 1h at room temperature, the malonate salt was added to the palladium-boronate mixture at RT. After 4 h under reflux, the reaction mixture was concentrated, dissolved in CH2Cl2 (20mL/mmol). This organic solution was washed with water (10mL/mmol), brine (2x 10mL/mmol), dried, and concentrated under reduced pressure. The residual oil was purified by silica gel column flash chromatography.

Organic Letters, 2011, 13(15), 4132-4135.


有机定制合成网 » 双活化底物的烷基化

咨询化合物定制合成与纳米材料 提供技术支持和售后服务

咨询定制合成 购买化合物产品
在线营销
live chat
cache
Processed in 0.020371 Second.