碳-碳鍵的構建在有機化合物的合成中占有極其重要的地位，其中一種常用并且有效的構建方式便是在活性基團活化的α碳上的烷基化反應。

所謂的活性基團是因為電負性的差異所導致的，理論上電負性大于碳的原子與碳相連都可以使碳活化，但活化效果各有差別，其中常見的活化基團如下表所示（Acc. Chem. Res. 1988, 21, 456-463）：

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

其中我們可以簡單總結出以下的活化順序：NO₂ > COR > CN ~ CO₂R ~ SO₂R> Ph ~ SR > H > R。

雙活化底物的烷基化

常見的雙活化底物有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，這些雙活化底物具有底物的相似性，活性的相近性（活潑氫的PKa低，具有較高的活性），所以它們的烷基化方法也很相似，可以相互借鑒。

常用的方法可以分為以下幾種：

i.直接堿作用下的烷基化。

常用的堿可以是無機堿，如K₂CO₃，Cs₂CO₃，NaH，NaOEt，KOtBu等，也可以是有機堿，如DBU，TMG等，當底物的酸性足夠強時，也可以用Et₃N等弱有機堿。

所采用的溶劑多為極性溶劑，如丙酮，THF，DMF，DMSO，EtOH，CH₃CN等，其中更以THF和DMF應用最多。

當采用無機堿時，反應體系多為非均相體系，這時，加入TBAI，TBAB等相轉移催化劑可以促進反應進行。

因為烷基化試劑中離去基團的離去順序I > Br > Cl，所以加入催化量的KI可以交換離去基團，提高反應速率。

需要指出的是，烷基化反應是SN2反應，所加入的親電試劑也會影響反應速率，反應速率大小為allyl-X ~ Bn-X > 1^oalkyl-X > 2^o alkyl-X。

ii.與共軛底物Michael 加成的方法進行烷基化。

具有共軛結構的底物是很好的親電受體，因此也被廣泛用于烷基化反應中。該類反應具有反應條件更溫和，可操控性強的優點，可以采用更弱或者催化量的堿使得反應進行，或者引入手性試劑得到手性產物。

iii.金屬催化偶聯的方法。

一些具有烯丙基結構的底物可以在金屬的作用下生成三中心兩電子的缺電過渡態，可以與負離子反應得到烯丙基化產物。

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., 2012, 134 (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, InternationalEdition, 2011, 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 & MedicinalChemistry, 2009, 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.】