庫林科維奇反應

庫林科維奇反應; Kulinkovich reaction
命名根據	Oleg Kulinkovich
反應類型	成環反應
標識
有機化學網站對應網頁	kulinkovich-reaction
RSC序號	RXNO:0000682

Kulinkovich反應（Kulinkovich reaction），又稱Kulinkovich環丙烷化反應、Kulinkovich環丙化反應（Kulinkovich cyclopropanation），由 O. Kulinkovich 等人在1989年報道。^[1]^[2]^[3]^[4]^[5]^[6]

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在異丙醇鈦(Ⅳ)（Ti(OiPr)₄）催化下，乙基或更高級的格氏試劑（有β-氫）與酯反應生成環丙醇衍生物。

除異丙醇鈦外烷氧基鈦催化劑還可以是 ClTi(OiPr)₃ 、 ClTi(OtBu)₃ 或 Ti(OtBu)₄。常用反應溶劑有乙醚、四氫呋喃和甲苯。反應物可以帶醚、硫醚和亞胺等官能團進行反應。不過醯胺、伯胺、仲胺與氨基甲酸酯則不在可耐受官能團之列。

這一反應最初使用化學計量的烷氧基鈦，逐漸發展到僅使用催化量的烷氧基鈦。後來 Corey 又進一步發展了含有TADDOL配體的手性鈦催化的不對稱反應。^[7]

一般認為，反應機理中，首先為兩分子格氏試劑與烷氧基鈦進行轉金屬作用，產生一個對熱不穩定的二烷基二烷氧基鈦絡合物，後者很快發生β-氫消除、歧化，放出烷烴並產生一分子取代鈦雜環丙烷中間體 (1)。該中間體作為1,2-雙碳負離子等價物，其較弱的 C–Ti 鍵接受酯羰基的插入反應，得到噁鈦雜環戊烷中間體 (2)，並接下來重排為酮 (3)。上述插入過程重複一次，(3) 的羰基分子內插入 C–Ti 鍵中，再進行一次烷基化，得到環丙醇衍生物中間體 (4)。這一步是總反應的限速步驟，被還原的鈦(Ⅱ)亦在此步驟中被重新氧化為鈦(Ⅳ)。此步的產物 (4) 是一種烷氧基鈦化合物，與反應使用的烷氧基鈦催化劑類似， (4) 也可以與格氏試劑發生轉金屬作用，再生烷基鈦，從而完成此反應的催化循環。而且，此一步的另一產物環丙醇鎂鹽 (5)，經過水解，即得游離的環丙醇。

若使用比乙基更為高級的格氏試劑，產物中將會產生兩個新的立體中心，並且，反應底物中不含螯合基團時，反應也有很高的非對映選擇性，這是此反應的一個特點。有認為此非對映選擇性是由於噁鈦雜環戊烷 (3)向環丙醇鈦鹽 (4)轉化一步過渡態中，底物的 C–H 鍵與鈦原子之間形成的抓氫鍵作用而造成的。

雖然2001年吳雲東對此反應的機理進行了系統的理論計算，^[6] 但該反應的具體機理在某些方面仍不很清楚，例如，2007年時 Kulinkovich 曾提出反應可能經過鈦酸根型陰離子配合物（ate complex）中間體。^[8]

使用乙基格氏試劑時，實驗測得反應體系除了會產生歧化一步生成的乙烷外，還有少量的乙烯產生。Kulinkovich 認為反應中亦存在取代鈦雜環丙烷中間體與異丙醇鈦(Ⅳ)發生作用的副反應，兩者作用產生兩分子的異丙醇鈦(Ⅲ)，並放出乙烯。^[9]

從上述機理可以看出，由於反應中存在歧化一步，因此在參與反應的兩分子格氏試劑中，實際上只有一分子能用於構建環丙烷環系，另一分子格氏試劑則會轉變為烷烴副產物。這一點在反應中所用格氏試劑並不易得時成為反應的一個主要缺點。

1993年 Kulinkovich 等發現鈦雜環丙烷可以與烯烴發生配體交換，生成與烯烴相對應的鈦雜環丙烷中間體，從而所有參與反應的烯烴都得到利用，而且意味著此反應實際上提供了一種活化烯烴進而與酯反應、形成環丙烷環系的手段，使反應的應用範圍得到拓展。^[10] 不過後來發現，儘管苯乙烯可以與鈦中間體形成絡合物，但是其他烯烴，如1-庚烯、α-甲基苯乙烯和乙基乙烯醚卻無法反應。 Cha 等用位阻大的環戊烯或環己基格氏試劑解決這一問題。^[11]

1995年有人將此改進法用於分子內的 Kulinkovich 反應。^[12]

此外 de Meijere 還報道了另一種使所有格氏試劑都得到利用的改進法，即先製得 MeTi(OiPr)₃，並且使其與格氏試劑以 1:1.1 的比例參與反應。只有一分子格氏試劑與上述鈦試劑反應產生交換後生成的異丙醇鎂並生成取代鈦雜環丙烷中間體。反應的另一個產物則為甲烷。

在類似條件下，醯胺可被轉化為環丙胺衍生物，稱為 de Meijere 變體或 Kulinkovich–de Meijere 反應。^[13]^[14]

分子內的 Kulinkovich–de Meijere 反應也有報道。^[15]^[16]^[17]^[18]^[19]^[20]^[21]^[22]^[23]^[24]

以腈作為底物，得到氨基環丙烷產物，稱為 Szymoniak 變體或 Kulinkovich–Szymoniak 反應。^[25]^[26]

其機理與 Kulinkovich 反應機理類似。

化學反應列表

[1]
Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org. Khim., 25, 2244 (1989).
[2]
Oleg G. Kulinkovich, Sergei V. Sviridov, Dmitry A. Vasilevski. Titanium(IV) Isopropoxide-Catalyzed Formation of 1-Substituted Cyclopropanols in the Reaction of Ethylmagnesium Bromide with Methyl Alkanecarboxylates. Synthesis. 1991, 1991 (03): 234. doi:10.1055/s-1991-26431.
[3]
Oleg G. Kulinkovich and Armin de Meijere. 1,n-Dicarbanionic Titanium Intermediates from Monocarbanionic Organometallics and Their Application in Organic Synthesis. Chem. Rev. 2000, 100 (8): 2789–2834. doi:10.1021/cr980046z.
[4]
Fumie Sato, Hirokazu Urabe, and Sentaro Okamoto. Synthesis of Organotitanium Complexes from Alkenes and Alkynes and Their Synthetic Applications. Chem. Rev. 2000, 100 (8): 2835–2886. doi:10.1021/cr990277l.
[5]
O. G. Kulinkovich. Alkylation of carboxylic acid derivatives with dialkoxytitanacyclopropane reagents. Russ. Chem. Bull. 2005, (5): 1065 [2009-10-26]. （原始內容存檔於2016-03-04）.
[6]
Yun-Dong Wu and Zhi-Xiang Yu. A Theoretical Study on the Mechanism and Diastereoselectivity of the Kulinkovich Hydroxycyclopropanation Reaction. J. Am. Chem. Soc. 2001, 123 (24): 5777–5786. doi:10.1021/ja010114q.
[7]
E. J. Corey, S. Achyutha Rao, Mark C. Noe. Catalytic Diastereoselective Synthesis of Cis-1,2-Disubstituted Cyclopropanols from Esters Using a Vicinal Dicarbanion Equivalent. J. Am. Chem. Soc. 1994, 116 (20): 9345–9346. doi:10.1021/ja00099a068.
[8]
Oleg G. Kulinkovich, Dzmitry G. Kananovich. Advanced Procedure for the Preparation of cis-1,2-Dialkylcyclopropanols - Modified Ate Complex Mechanism for Titanium-Mediated Cyclopropanation of Carboxylic Esters with Grignard Reagents. Eur. J. Org. Chem. 2007, 2007 (13): 2121–2132. doi:10.1002/ejoc.200601035.
[9]
Evgenii A. Matiushenkov, Nikolai A. Sokolov, Oleg G. Kulinkovich. Alkylative Reduction of Titanium(IV) Isopropoxide with EtMgBr: Convenient Method for the Generation of Subvalent Titanium Alkoxide Reagents and their Reactivity in Pinacol Coupling Reactions. Synlett. 2004: 77–80. doi:10.1055/s-2003-43370.
[10]
Oleg G. Kulinkovich, Andrey I. Savchenko, a, Sergey V. Sviridov, a and Dmitry A. Vasilevski. Titanium(IV) Isopropoxide-catalysed Reaction of Ethylmagnesium Bromide with Ethyl Acetate in the Presence of Styrene. Mendeleev Commun. 1993, 3 (6): 230–231. doi:10.1070/MC1993v003n06ABEH000304.
[11]
Jinhwa Lee, Heejin Kim, and Jin Kun Cha. A New Variant of the Kulinkovich Hydroxycyclopropanation. Reductive Coupling of Carboxylic Esters with Terminal Olefins. J. Am. Chem. Soc. 1996, 118 (17): 4198–4199. doi:10.1021/ja954147f.
[12]
Aleksandr Kasatkin and Fumie Sato. Diastereoselective synthesis of trans-1,2-disubstituted cyclopropanols from homoallyl or bis-homoallyl esters via tandem intramolecular nucleophilic acyl substitution and intramolecular carbonyl addition reactions mediated by Ti(OPr-i)₄ / 2 i-PrMgBr reagent. Tetrahedron Lett. 1995, 36 (34): 6079–6082. doi:10.1016/0040-4039(95)01208-Y.
[13]
Dipl.-Chem. Vladimir Chaplinski, Prof. Dr. Armin de Meijere. A Versatile New Preparation of Cyclopropylamines from Acid Dialkylamides. Angew. Chem. Int. Ed. Engl. 1996, 35 (4): 413–414. doi:10.1002/anie.199604131.
[14]
Armin de Meijere, Harald Winsel, and Björn Stecker, "Facile Syntheses of Aminocyclopropanes: N,N-Dibenzyl-N-(2-ethenylcyclopropyl)amine （頁面存檔備份，存於網際網路檔案館）", Organic Syntheses, Vol. 81, p.14 (2005).
[15]
Jinhwa Lee and Jin Kun Cha. Facile Preparation of Cyclopropylamines from Carboxamides. J. Org. Chem. 1997, 62 (6): 1584–1585. doi:10.1021/jo962368d.
[16]
Vladimir Chaplinski, Harald Winsel, Markus Kordes, Armin de Meijere. A New Versatile Reagent for the Synthesis of Cyclopropylamines Including 4-Azaspiro[2.n]alkanes and Bicyclo[n.1.0]alkylamines. Synlett. 1997, 1997 (01): 111–114. doi:10.1055/s-1997-17828.
[17]
Bin Cao, Dong Xiao, and Madeleine M. Joullié. Synthesis of Bicyclic Cyclopropylamines by Intramolecular Cyclopropanation of N-Allylamino Acid Dimethylamides. Org. Lett. 1999, 1 (11): 1799–1801. doi:10.1021/ol9910520.
[18]
Hee Bong Lee, Moo Je Sung, Silas C. Blackstock, and Jin Kun Cha. Radical Cation-Mediated Annulation. Stereoselective Construction of Bicyclo[5.3.0]decan-3-ones by Aerobic Oxidation of Cyclopropylamines. J. Am. Chem. Soc. 2001, 123 (45): 11322–11324. doi:10.1021/ja017043f.
[19]
Martina Gensini, Sergei I. Kozhushkov, Dmitrii S. Yufit, Judith A. K. Howard, Mazen Es-Sayed, Armin de Meijere. 3-Azabicyclo[3.1.0]hex-1-ylamines by Ti-Mediated Intramolecular Reductive Cyclopropanation of α-(N-Allylamino)-Substituted N,N-Dialkylcarboxamides and Carbonitriles. Eur. J. Org. Chem. 2002, 2002 (15): 2499–2507. DOI:<2499::AID-EJOC2499>3.0.CO;2-V 10.1002/1099-0690(200208)2002:15<2499::AID-EJOC2499>3.0.CO;2-V
[20]
Gerd-Dieter Tebben, Karsten Rauch, Christian Stratmann, Craig M. Williams, and Armin de Meijere. Intramolecular Titanium-Mediated Aminocyclopropanation of Terminal Alkenes: Easy Access to Various Substituted Azabicyclo[n.1.0]alkanes. Org. Lett. 2003, 5 (4): 483–485. doi:10.1021/ol027352q.
[21]
Nouara Ouhamou and Yvan Six. Studies on the intramolecular Kulinkovich–de Meijere reaction of disubstituted alkenes bearing carboxylic amide groups. Org. Biomol. Chem. 2003, (1): 3007–3009. doi:10.1039/b306719j.
[22]
Martina Gensini, Dr., Armin de Meijere, Prof. Dr. Cyclopropane-Annelated Azaoligoheterocycles by Ti-Mediated Intramolecular Reductive Cyclopropanation of Cyclic Amino Acid Amides. Chem. Eur. J. 2004, 10 (3): 785–790. doi:10.1002/chem.200305068.
[23]
Laurent Larquetoux, Justyna A. Kowalska, Yvan Six. The Formal [3+2+1] Cyclisation of Cyclopropylamines with Carboxylic Anhydrides: A Quick Access to Polysubstituted 2,3,3a,4-Tetrahydro-6(5H)-indolone Ring Systems. Eur. J. Org. Chem. 2004, 2004 (16): 3517–3525. doi:10.1002/ejoc.200400291.
[24]
Laurent Larquetoux, Nouara Ouhamou, Angèle Chiaroni, Yvan Six. The Intramolecular Aromatic Electrophilic Substitution of Aminocyclopropanes Prepared by the Kulinkovich-de Meijere Reaction. Eur. J. Org. Chem. 2005, 2005 (21): 4654–4662. doi:10.1002/ejoc.200500428.
[25]
Philippe Bertus and Jan Szymoniak. New and easy route to primary cyclopropylamines from nitriles. Chem. Commun. 2001, (18): 1792–1793. doi:10.1039/b105293b.
[26]
Dipl.-Chem. Vladimir Chaplinski, Prof. Dr. Armin de Meijere. A Versatile New Preparation of Cyclopropylamines from Acid Dialkylamides. Angew. Chem. Int. Ed. Engl. 1996, 35 (4): 413–414. doi:10.1002/anie.199604131.

[1] [1]
Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pritytskaya, T. S. Zh. Org. Khim., 25, 2244 (1989).

[2] [2]
Oleg G. Kulinkovich, Sergei V. Sviridov, Dmitry A. Vasilevski. Titanium(IV) Isopropoxide-Catalyzed Formation of 1-Substituted Cyclopropanols in the Reaction of Ethylmagnesium Bromide with Methyl Alkanecarboxylates. Synthesis. 1991, 1991 (03): 234. doi:10.1055/s-1991-26431.

[3] [3]
Oleg G. Kulinkovich and Armin de Meijere. 1,n-Dicarbanionic Titanium Intermediates from Monocarbanionic Organometallics and Their Application in Organic Synthesis. Chem. Rev. 2000, 100 (8): 2789–2834. doi:10.1021/cr980046z.

[4] [4]
Fumie Sato, Hirokazu Urabe, and Sentaro Okamoto. Synthesis of Organotitanium Complexes from Alkenes and Alkynes and Their Synthetic Applications. Chem. Rev. 2000, 100 (8): 2835–2886. doi:10.1021/cr990277l.

[5] [5]
O. G. Kulinkovich. Alkylation of carboxylic acid derivatives with dialkoxytitanacyclopropane reagents. Russ. Chem. Bull. 2005, (5): 1065 [2009-10-26]. （原始內容存檔於2016-03-04）.

[Wu-6] [6]
Yun-Dong Wu and Zhi-Xiang Yu. A Theoretical Study on the Mechanism and Diastereoselectivity of the Kulinkovich Hydroxycyclopropanation Reaction. J. Am. Chem. Soc. 2001, 123 (24): 5777–5786. doi:10.1021/ja010114q.

[7] [7]
E. J. Corey, S. Achyutha Rao, Mark C. Noe. Catalytic Diastereoselective Synthesis of Cis-1,2-Disubstituted Cyclopropanols from Esters Using a Vicinal Dicarbanion Equivalent. J. Am. Chem. Soc. 1994, 116 (20): 9345–9346. doi:10.1021/ja00099a068.

[8] [8]
Oleg G. Kulinkovich, Dzmitry G. Kananovich. Advanced Procedure for the Preparation of cis-1,2-Dialkylcyclopropanols - Modified Ate Complex Mechanism for Titanium-Mediated Cyclopropanation of Carboxylic Esters with Grignard Reagents. Eur. J. Org. Chem. 2007, 2007 (13): 2121–2132. doi:10.1002/ejoc.200601035.

[9] [9]
Evgenii A. Matiushenkov, Nikolai A. Sokolov, Oleg G. Kulinkovich. Alkylative Reduction of Titanium(IV) Isopropoxide with EtMgBr: Convenient Method for the Generation of Subvalent Titanium Alkoxide Reagents and their Reactivity in Pinacol Coupling Reactions. Synlett. 2004: 77–80. doi:10.1055/s-2003-43370.

[10] [10]
Oleg G. Kulinkovich, Andrey I. Savchenko, a, Sergey V. Sviridov, a and Dmitry A. Vasilevski. Titanium(IV) Isopropoxide-catalysed Reaction of Ethylmagnesium Bromide with Ethyl Acetate in the Presence of Styrene. Mendeleev Commun. 1993, 3 (6): 230–231. doi:10.1070/MC1993v003n06ABEH000304.

[11] [11]
Jinhwa Lee, Heejin Kim, and Jin Kun Cha. A New Variant of the Kulinkovich Hydroxycyclopropanation. Reductive Coupling of Carboxylic Esters with Terminal Olefins. J. Am. Chem. Soc. 1996, 118 (17): 4198–4199. doi:10.1021/ja954147f.

[12] [12]
Aleksandr Kasatkin and Fumie Sato. Diastereoselective synthesis of trans-1,2-disubstituted cyclopropanols from homoallyl or bis-homoallyl esters via tandem intramolecular nucleophilic acyl substitution and intramolecular carbonyl addition reactions mediated by Ti(OPr-i)₄ / 2 i-PrMgBr reagent. Tetrahedron Lett. 1995, 36 (34): 6079–6082. doi:10.1016/0040-4039(95)01208-Y.

[13] [13]
Dipl.-Chem. Vladimir Chaplinski, Prof. Dr. Armin de Meijere. A Versatile New Preparation of Cyclopropylamines from Acid Dialkylamides. Angew. Chem. Int. Ed. Engl. 1996, 35 (4): 413–414. doi:10.1002/anie.199604131.

[14] [14]
Armin de Meijere, Harald Winsel, and Björn Stecker, "Facile Syntheses of Aminocyclopropanes: N,N-Dibenzyl-N-(2-ethenylcyclopropyl)amine （頁面存檔備份，存於網際網路檔案館）", Organic Syntheses, Vol. 81, p.14 (2005).

[15] [15]
Jinhwa Lee and Jin Kun Cha. Facile Preparation of Cyclopropylamines from Carboxamides. J. Org. Chem. 1997, 62 (6): 1584–1585. doi:10.1021/jo962368d.

[16] [16]
Vladimir Chaplinski, Harald Winsel, Markus Kordes, Armin de Meijere. A New Versatile Reagent for the Synthesis of Cyclopropylamines Including 4-Azaspiro[2.n]alkanes and Bicyclo[n.1.0]alkylamines. Synlett. 1997, 1997 (01): 111–114. doi:10.1055/s-1997-17828.

[17] [17]
Bin Cao, Dong Xiao, and Madeleine M. Joullié. Synthesis of Bicyclic Cyclopropylamines by Intramolecular Cyclopropanation of N-Allylamino Acid Dimethylamides. Org. Lett. 1999, 1 (11): 1799–1801. doi:10.1021/ol9910520.

[18] [18]
Hee Bong Lee, Moo Je Sung, Silas C. Blackstock, and Jin Kun Cha. Radical Cation-Mediated Annulation. Stereoselective Construction of Bicyclo[5.3.0]decan-3-ones by Aerobic Oxidation of Cyclopropylamines. J. Am. Chem. Soc. 2001, 123 (45): 11322–11324. doi:10.1021/ja017043f.

[19] [19]
Martina Gensini, Sergei I. Kozhushkov, Dmitrii S. Yufit, Judith A. K. Howard, Mazen Es-Sayed, Armin de Meijere. 3-Azabicyclo[3.1.0]hex-1-ylamines by Ti-Mediated Intramolecular Reductive Cyclopropanation of α-(N-Allylamino)-Substituted N,N-Dialkylcarboxamides and Carbonitriles. Eur. J. Org. Chem. 2002, 2002 (15): 2499–2507. DOI:<2499::AID-EJOC2499>3.0.CO;2-V 10.1002/1099-0690(200208)2002:15<2499::AID-EJOC2499>3.0.CO;2-V

[20] [20]
Gerd-Dieter Tebben, Karsten Rauch, Christian Stratmann, Craig M. Williams, and Armin de Meijere. Intramolecular Titanium-Mediated Aminocyclopropanation of Terminal Alkenes: Easy Access to Various Substituted Azabicyclo[n.1.0]alkanes. Org. Lett. 2003, 5 (4): 483–485. doi:10.1021/ol027352q.

[21] [21]
Nouara Ouhamou and Yvan Six. Studies on the intramolecular Kulinkovich–de Meijere reaction of disubstituted alkenes bearing carboxylic amide groups. Org. Biomol. Chem. 2003, (1): 3007–3009. doi:10.1039/b306719j.

[22] [22]
Martina Gensini, Dr., Armin de Meijere, Prof. Dr. Cyclopropane-Annelated Azaoligoheterocycles by Ti-Mediated Intramolecular Reductive Cyclopropanation of Cyclic Amino Acid Amides. Chem. Eur. J. 2004, 10 (3): 785–790. doi:10.1002/chem.200305068.

[23] [23]
Laurent Larquetoux, Justyna A. Kowalska, Yvan Six. The Formal [3+2+1] Cyclisation of Cyclopropylamines with Carboxylic Anhydrides: A Quick Access to Polysubstituted 2,3,3a,4-Tetrahydro-6(5H)-indolone Ring Systems. Eur. J. Org. Chem. 2004, 2004 (16): 3517–3525. doi:10.1002/ejoc.200400291.

[24] [24]
Laurent Larquetoux, Nouara Ouhamou, Angèle Chiaroni, Yvan Six. The Intramolecular Aromatic Electrophilic Substitution of Aminocyclopropanes Prepared by the Kulinkovich-de Meijere Reaction. Eur. J. Org. Chem. 2005, 2005 (21): 4654–4662. doi:10.1002/ejoc.200500428.

[25] [25]
Philippe Bertus and Jan Szymoniak. New and easy route to primary cyclopropylamines from nitriles. Chem. Commun. 2001, (18): 1792–1793. doi:10.1039/b105293b.

[26] [26]
Dipl.-Chem. Vladimir Chaplinski, Prof. Dr. Armin de Meijere. A Versatile New Preparation of Cyclopropylamines from Acid Dialkylamides. Angew. Chem. Int. Ed. Engl. 1996, 35 (4): 413–414. doi:10.1002/anie.199604131.

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庫林科維奇反應

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反應機理

與烯烴的配體交換

de Meijere變體

Szymoniak變體

參見

參考資料