烏吉反應

烏吉反應（德語：Ugi-Reaktion）是一分子醛或酮、一分子胺、一分子異腈以及一分子羧酸縮合生成α-酰氨基酰胺的多組分反應。^[1]^[2]^[3]

反應由德國化學家伊瓦爾·卡爾·烏吉於1959年首先報道。

反應是放熱反應，通常在加入異腈後數分鐘內即可完成，條件溫和。反應物濃度較高時（0.5M－2.0M）時，產率也較高。在極性非質子溶劑如二甲基甲酰胺中進行時效果一般較好，但也可用甲醇和乙醇作為反應溶劑。

反應具有較高的原子經濟性，總反應只生成一分子水副產物。反應產率也一般較高。最近研究顯示水溶液的使用對反應有加速作用。^[4]

反應綜述：^[5]^[6]^[7]^[8]^[9]^[10]^[11]

反應機理

首先胺與醛／酮失水縮合為亞胺，亞胺被羧酸質子化為亞胺離子，亞胺離子與異腈發生親核加成生成腈鎓離子，然後羧酸負離子進攻異腈的碳原子生成另一個亞胺中間體8，最後8發生Mumm重排反應，發生酰基轉移生成烏吉產物。^[12]

烏吉的前幾步反應都可逆，整個反應的驅動力是最後一步重排，酰基的轉移生成了熱力學上穩定的酰胺化合物。

變體

底物變化

烏吉反應的底物適用性很廣，其中酸組分除了羧酸以外，還可以是無機酸，如氫硫酸、疊氮酸或氰酸等，甚至可以是二級銨鹽。羰基組分可以是醛也可以是酮。胺組分可以是一級胺、二級胺，也可以是肼、羥胺或脲。

當烏吉反應所需的兩種官能團同存在於一個分子內時，利用該雙官能團化合物與另外兩個組分進行該反應可以得到不同類型的含氮雜環化合物。^[13]^[14]

例如，β-氨基酸與對硝基苯甲醛反應，經過分子內酰基轉移成環可得β-內酰胺。^[15]

串聯反應與一鍋反應


烏吉-狄爾斯-阿爾德反應^[16]		烏吉-斯邁爾斯反應^[17]


烏吉-布赫瓦爾德-哈特維希反應^[18]		烏吉-赫克反應^[19]

應用

烏吉反應在化學很多領域都有比較廣泛的應用。通過這個反應可以得到產率高的α-氨基酸、多肽、β-內酰胺、氨基甲酸酯、四唑、乙內酰脲等衍生物。由於烏吉反應的高效性和匯聚性，以及它的四種組分都能很方便地連在樹脂上，它在組合化學和多樣性導向合成中也有比較廣泛的應用前景。^[20]

許多卡因類型的麻醉藥如利多卡因和布比卡因都可以通過該反應製取。針對HIV感染的藥物茚地那韋也可通過該法合成。^[21]

參見

參考資料

[1]
Ugi, I; Meyr, R.; Fetzer, U.; Steinbrückner, C. Versuche mit Isonitrilen. Angew. Chem. 1959, 71: 386. doi:10.1002/ange.19590711110.
[2]
Ugi, I; Steinbrückner, C. Über ein neues Kondensations-Prinzip. Angew. Chem. 1960, 72: 267–268. doi:10.1002/ange.19600720709.
[3]
Ugi, I. The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions. Angewandte Chemie International Edition in English. 1962, 1 (1): 8–21. doi:10.1002/anie.196200081.
[4]
Pirrung, M. C.; Sarma, K. D. Multicomponent Reactions Are Accelerated in Water. Journal of the American Chemical Society. 2004, 126: 444–445. doi:10.1021/ja038583a.
[5]
Ugi, I., Lohberger S., Karl R. The Passerini and Ugi Reactions, Chapter 4.6, Comprehensive Organic Synthesis 1991, 2, 1083–1109. ISBN 0-08-040593-2, Pergamon, Oxford, 10196 pages.（綜述）
[6]
Ugi, I.; Werner, B.; Dömling, A. The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries (PDF). Molecules. 2003, 8: 53–66 [2009-09-21]. doi:10.3390/80100053. （原始內容存檔 (PDF)於2016-03-03）.
[7]
Banfi, L., and Riva, R. (2005). The Passerini Reaction. Organic Reactions, Vol. 65 L. E. Overman Ed. Wiley. (ISBN 0-471-68260-8)
[8]
Tempest P.A. Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction. Current Opinion in Drug Discovery & Development. 2005, 8 (6): 776–788.
[9]
Ugi I., Heck S. The multicomponent reactions and their libraries for natural and preparative chemistry. Combinatorial Chemistry & High Throughput Screening. 2001, 4 (1): 1–34.
[10]
Bienayme H, Hulme C, Oddon G, Schmitt P. Maximizing synthetic efficiency: Multi-component transformations lead the way. Chemistry- a European Journal. 2000, 8 (16): 3321–3329.. doi:10.1002/1521-3765(20000915)6:18<3321::AID-CHEM3321>3.0.CO;2-A.
[11]
Dömling A., Ugi I. Multicomponent Reactions with Isocyanides. Angewandte Chemie International Edition in English. 2000, 39 (18): 3168–3210.. doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U.
[12]
S. E. Denmark and Y. Fan. Catalytic, Enantioselective α-Additions of Isocyanides: Lewis Base Catalyzed Passerini-Type Reactions. Journal of Organic Chemistry. 2005, 70 (24): 9667–9676. doi:10.1021/jo050549m.
[13]
Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid. Journal of Organic Chemistry. 1999, 64: 1074–1076. doi:10.1021/jo982192a.
[14]
Short K. M., Mjalli A. M. M. A solid-phase combinatorial method for the synthesis of novel 5- and 6-membered ring lactams. Tetrahedron Letters. 1997, 38: 359–362. doi:10.1021/ol048791n.
[15]
Gedey, S.; Van der Eycken, J.; Fülöp, F. Liquid-Phase Combinatorial Synthesis of Alicyclic β-Lactams via Ugi Four-Component Reaction. Organic Letters. 2002, 4: 1967–1969. doi:10.1021/ol025986r.
[16]
Alexei Ilyin, Volodymyr Kysil, Mikhail Krasavin, Irina Kurashvili, and Alexandre V. Ivachtchenko. Complexity-Enhancing Acid-Promoted Rearrangement of Tricyclic Products of Tandem Ugi 4CC/Intramolecular Diels-Alder Reaction. J. Org. Chem. 2006, 71 (25): 9544–9547. doi:10.1021/jo061825f.
[17]
Laurent El Kaim, Marie Gizolme, Laurence Grimaud, and Julie Oble. Direct Access to Heterocyclic Scaffolds by New Multicomponent Ugi-Smiles Couplings. Org. Lett. 2006, 8 (18): 4019–4021. doi:10.1021/ol061605o.
[18]
Florence Bonnaterre, Michèle Bois-Choussy, and Jieping Zhu. Rapid Access to Oxindoles by the Combined Use of an Ugi Four-Component Reaction and a Microwave-Assisted Intramolecular Buchwald-Hartwig Amidation Reaction. Org. Lett. 2006, 8 (19): 4351–4354. doi:10.1021/ol061755z.
[19]
Zhibo Ma, Zheng Xiang, Tuoping Luo, Kui Lu, Zhibin Xu, Jiahua Chen, and Zhen Yang. Synthesis of Functionalized Quinolines via Ugi and Pd-Catalyzed Intramolecular Arylation Reactions. J. Comb. Chem. 2006, 8 (5): 696–704. doi:10.1021/cc060066b.
[20]
Xiang, Z.; Luo, T.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. Novel Pd-II-mediated cascade carboxylative annulation to construct benzo[b]furan-3-carboxylic acids. Organic Letters. 2004, 6: 3155–3158. doi:10.1021/ol048791n.
[21]
Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.; Reider, P. J. An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan piperazine intermediate. Tetrahedron Letters. 1998, 39: 6823–6826. doi:10.1016/S0040-4039(98)01484-1.

外部連結

烏吉四組分縮合反應的發展及應用

[1] [1]
Ugi, I; Meyr, R.; Fetzer, U.; Steinbrückner, C. Versuche mit Isonitrilen. Angew. Chem. 1959, 71: 386. doi:10.1002/ange.19590711110.

[2] [2]
Ugi, I; Steinbrückner, C. Über ein neues Kondensations-Prinzip. Angew. Chem. 1960, 72: 267–268. doi:10.1002/ange.19600720709.

[3] [3]
Ugi, I. The α-Addition of Immonium Ions and Anions to Isonitriles Accompanied by Secondary Reactions. Angewandte Chemie International Edition in English. 1962, 1 (1): 8–21. doi:10.1002/anie.196200081.

[4] [4]
Pirrung, M. C.; Sarma, K. D. Multicomponent Reactions Are Accelerated in Water. Journal of the American Chemical Society. 2004, 126: 444–445. doi:10.1021/ja038583a.

[5] [5]
Ugi, I., Lohberger S., Karl R. The Passerini and Ugi Reactions, Chapter 4.6, Comprehensive Organic Synthesis 1991, 2, 1083–1109. ISBN 0-08-040593-2, Pergamon, Oxford, 10196 pages.（綜述）

[6] [6]
Ugi, I.; Werner, B.; Dömling, A. The Chemistry of Isocyanides, their MultiComponent Reactions and their Libraries (PDF). Molecules. 2003, 8: 53–66 [2009-09-21]. doi:10.3390/80100053. （原始內容存檔 (PDF)於2016-03-03）.

[7] [7]
Banfi, L., and Riva, R. (2005). The Passerini Reaction. Organic Reactions, Vol. 65 L. E. Overman Ed. Wiley. (ISBN 0-471-68260-8)

[8] [8]
Tempest P.A. Recent advances in heterocycle generation using the efficient Ugi multiple-component condensation reaction. Current Opinion in Drug Discovery & Development. 2005, 8 (6): 776–788.

[9] [9]
Ugi I., Heck S. The multicomponent reactions and their libraries for natural and preparative chemistry. Combinatorial Chemistry & High Throughput Screening. 2001, 4 (1): 1–34.

[10] [10]
Bienayme H, Hulme C, Oddon G, Schmitt P. Maximizing synthetic efficiency: Multi-component transformations lead the way. Chemistry- a European Journal. 2000, 8 (16): 3321–3329.. doi:10.1002/1521-3765(20000915)6:18<3321::AID-CHEM3321>3.0.CO;2-A.

[11] [11]
Dömling A., Ugi I. Multicomponent Reactions with Isocyanides. Angewandte Chemie International Edition in English. 2000, 39 (18): 3168–3210.. doi:10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U.

[12] [12]
S. E. Denmark and Y. Fan. Catalytic, Enantioselective α-Additions of Isocyanides: Lewis Base Catalyzed Passerini-Type Reactions. Journal of Organic Chemistry. 2005, 70 (24): 9667–9676. doi:10.1021/jo050549m.

[13] [13]
Zhang, J.; Jacobson, A.; Rusche, J. R.; Herlihy, W. Unique Structures Generated by Ugi 3CC Reactions Using Bifunctional Starting Materials Containing Aldehyde and Carboxylic Acid. Journal of Organic Chemistry. 1999, 64: 1074–1076. doi:10.1021/jo982192a.

[14] [14]
Short K. M., Mjalli A. M. M. A solid-phase combinatorial method for the synthesis of novel 5- and 6-membered ring lactams. Tetrahedron Letters. 1997, 38: 359–362. doi:10.1021/ol048791n.

[15] [15]
Gedey, S.; Van der Eycken, J.; Fülöp, F. Liquid-Phase Combinatorial Synthesis of Alicyclic β-Lactams via Ugi Four-Component Reaction. Organic Letters. 2002, 4: 1967–1969. doi:10.1021/ol025986r.

[16] [16]
Alexei Ilyin, Volodymyr Kysil, Mikhail Krasavin, Irina Kurashvili, and Alexandre V. Ivachtchenko. Complexity-Enhancing Acid-Promoted Rearrangement of Tricyclic Products of Tandem Ugi 4CC/Intramolecular Diels-Alder Reaction. J. Org. Chem. 2006, 71 (25): 9544–9547. doi:10.1021/jo061825f.

[17] [17]
Laurent El Kaim, Marie Gizolme, Laurence Grimaud, and Julie Oble. Direct Access to Heterocyclic Scaffolds by New Multicomponent Ugi-Smiles Couplings. Org. Lett. 2006, 8 (18): 4019–4021. doi:10.1021/ol061605o.

[18] [18]
Florence Bonnaterre, Michèle Bois-Choussy, and Jieping Zhu. Rapid Access to Oxindoles by the Combined Use of an Ugi Four-Component Reaction and a Microwave-Assisted Intramolecular Buchwald-Hartwig Amidation Reaction. Org. Lett. 2006, 8 (19): 4351–4354. doi:10.1021/ol061755z.

[19] [19]
Zhibo Ma, Zheng Xiang, Tuoping Luo, Kui Lu, Zhibin Xu, Jiahua Chen, and Zhen Yang. Synthesis of Functionalized Quinolines via Ugi and Pd-Catalyzed Intramolecular Arylation Reactions. J. Comb. Chem. 2006, 8 (5): 696–704. doi:10.1021/cc060066b.

[20] [20]
Xiang, Z.; Luo, T.; Cui, J.; Shi, X.; Fathi, R.; Chen, J.; Yang, Z. Novel Pd-II-mediated cascade carboxylative annulation to construct benzo[b]furan-3-carboxylic acids. Organic Letters. 2004, 6: 3155–3158. doi:10.1021/ol048791n.

[21] [21]
Rossen, K.; Pye, P. J.; DiMichele, L. M.; Volante, R. P.; Reider, P. J. An efficient asymmetric hydrogenation approach to the synthesis of the Crixivan piperazine intermediate. Tetrahedron Letters. 1998, 39: 6823–6826. doi:10.1016/S0040-4039(98)01484-1.

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