常見的環丙烷化反應----Kulinkovich反應

1989年，O.G. Kulinkovich報道了在一倍當量的四異丙氧鈦存在下簡單羧酸酯和過量的乙基溴化鎂作用得到1-烷基環丙醇的反應。此反應在催化量的Ti(Oi-Pr)4存在下，兩倍當量的格氏試劑也可進行。

在鈦(II)催化下，羧酸酯或酰胺和格氏試劑反應一鍋法得到相應的1-烷基環丙醇或1-烷基環丙胺的反應被稱為Kulinkovich反應。

反應特點 ：1、此反應的活性中間體是鈦雜環丙烷中間體，其相當于1,2-碳負離子等價物，對羰基進行兩次烷基化。2、復雜的格氏試劑參與反應，則生成1,2-順式二取代環丙醇，并具有很好的非對映選擇性。3、由酰胺制備順式環丙胺的立體選擇不好。4、反應受R1基團的性質影響很大，芳基酯不反應，空間位阻也影響反應，R1 基團的α位取代和體積較大的R2基團，反應產率都很低。5、當反應體系中有端基烯烴時，烯烴會參與反應。6、手性配體催化TADDOL催化下可以進行不對稱 Kulinkovich反應 【 J. Am. Chem. Soc. , 1994 , 116, 9345】

反應機理

首先Ti(Oi-Pr)4先和兩倍當量的乙基溴化鎂反應得到二烷基化產物，二乙基鈦中間體迅速進行β-H消除，得到鈦雜環丙烷中間體，作為1,2-二碳負離子等價物和羰基反應，進行二烷基化。另外的乙基溴化鎂加成到鈦上，引發第一次碳碳鍵形成得到氧鈦在環戊烷絡合物。開始底物酯的烷氧基以鎂鹽的形式離去（酰胺則是氧化鎂鹽消除），第二次碳碳鍵形成得到環丙烷環。生成的環丙氧鈦與格氏試劑反應進行烷基化，則二乙基鈦中間體再生，產物的鎂鹽生成。酸化得到產物。

反應實例

【Org. Lett.2001, 3, 3273-3275】

【Org. Lett.1999, 1, 1799-1801】

【J. Am. Chem. Soc. 2001, 123, 11322-11324】

【J. Am. Chem. Soc.1995, 117, 9919-9920】

A 50-mL round-bottomed flask containing an oversize cylindrical magnetic stirring bar was charged with 678 mg neat methyl thiomethyl ether (1.53 mmol). The flask was evacuated and purged with nitrogen three times to degas the substrate. In a glove bag, a preweighed portion of Ti(O-i-Pr)3Cl (997 mg, 3.83 mmol, 2.5 eq.) was added directly to the flask as a solid. The contents of the flask were then dissolved in 5.5 mL THF, and the resulting colorless solution was cooled to 0?C. Freshly prepared 1.64 M EtMgBr in THF (4.66 mL, 7.64 mmol, 5.0 eq.) was added dropwise to the flask from a syringe over 5 min. The addition initially caused a dark orange and ultimately a brown-black discoloration of the reaction mixture. After gas evolution (ethane) had subsided, the ice bath was removed, and the mixture was warmed to room temperature. The flask was then sealed tightly with a plastic cap, and the thick, dark brown mixture was stirred vigorously at room temperature for 48 h. After diluting with 10 mL Et2O, the contents of the flask were then poured into a separatory funnel containing 125 mL saturated ammonium chloride. The aqueous layer

was then extracted with Et2O (4 × 100 mL). The combined organic washes were dried over MgSO4 and filtered to a colorless solution. Concentration and purification over silica gel (Rf = 0.30 in 4.5:1 hexanes/ EtOAc) afforded 404 mg cyclopropanyl alcohol as a colorless

oil, in a yield of 60%.

【J. Am. Chem. Soc., 2005, 127, 13813】

To a solution of 150 g ethyl 2-{[tert-butyl(diphenyl)silyl]-oxy}acetate (0.46 mol) in 3.0 L THF was added 30 mL Ti(O-i-Pr)4 (0.10 mol) at ?10?C. A solution of 365 mL 3.0 M EtMgBr in THF (1.09 mol) was added to the mixture dropwise within 4 h under nitrogen, while temperature was controlled < 5?C. The mixture was allowed to warm to 25?C and stirred for an additional h. The reaction mixture was quenched by adding 400 mL water dropwise for 1 h below 10?C. After removal of THF, the aqueous layer was extracted with n-hexane (3 × 500 mL), and the combined extracts were washed with 300 mL brine and 300 mL water. The organic layer was concentrated in vacuo, and the residue was diluted with 150 mL n-heptane. The solution was slowly stirred to generate white solids at ?5?C, and the solids were collected to afford 84.0 g 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol. The second crop of

1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol (30 g) was obtained from the mother liquor. A total of 114 g cyclopropanol was obtained, in a yield of 80%.

【J. Med. Chem., 2004, 47, 2864】

參考資料：

一、Strategic Applications of Named Reactions in OrganicSynthesis, László Kürti and Barbara Czakó, Kulinkovich Reaction, page 256-257。

二、Comprehensive Organic Name Reactions and Reagents, by Zerong Wang，P1708。