Hagemann's ester
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| Names | |
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| Preferred IUPAC name
Ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate | |
| Other names
Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate
4-Carbethoxy-3-methyl-2-cyclohexen-1-one | |
| Identifiers | |
3D model (JSmol)
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| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.006.962 |
| EC Number |
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PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties[1] | |
| C10H14O3 | |
| Molar mass | 182.219 g·mol−1 |
| Density | 1.078 g/mL |
| Boiling point | 268 to 272 °C (514 to 522 °F; 541 to 545 K) |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Hagemann's ester, ethyl 2-methyl-4-oxo-2-cyclohexenecarboxylate, is an organic compound that was first prepared and described in 1893 by German chemist Carl Hagemann. The compound is used in organic chemistry as a reagent in the synthesis of many natural products including sterols, trisporic acids, and terpenoids.
Preparation
[edit]Hagemann's approach
[edit]Methylene iodide and two equivalents of ethyl acetoacetate react in the presence of sodium methoxide to form the diethyl ester of 2,4-diacetyl pentane. This precursor is treated with base to induce cyclization. Finally, heat is applied to generate Hagemann's ester.[2][3]
Knoevenagel's approach
[edit]Soon after Hagemann, Emil Knoevenagel described a modified procedure to produce the same intermediate diethyl ester of 2,4-diacetyl pentane using formaldehyde and two equivalents of ethyl acetoacetate which undergo condensation in the presence of a catalytic amount of piperidine.[3]
Newman and Lloyd approach
[edit]2-Methoxy-1,3-butadiene and ethyl-2-butynoate undergo a Diels-Alder reaction to generate a precursor which is hydrolyzed to obtain Hagemann's ester. By varying the substituents on the butynoate starting material, this approach allows for different C2 alkylated Hagemann's ester derivatives to be synthesized.[3]
Mannich and Forneau approach
[edit]Original
[edit]Methyl vinyl ketone, ethyl acetoacetate, and diethyl-methyl-(3-oxo-butyl)-ammonium iodide react to form a cyclic aldol product. Sodium methoxide is added to generate Hagemann's ester.
Variations
[edit]Methyl vinyl ketone and ethyl acetoacetate undergo aldol cyclization in the presence of catalytic pyrrolidinum acetate or Triton B or sodium ethoxide to produce Hagemann's ester.[3] This variant is a type of Robinson annulation.[4]
Uses
[edit]Hagemann's ester has been used as a key building block in many syntheses.[3] For example, a key intermediate for the fungal hormone trisporic acid was made by its alkylation[5] and it has been used to make sterols.[6] Other authors have used it in inverse-electron-demand Diels–Alder reactions leading to sesquiterpene dimers[7] or in reactions forming simple derivatives.[8][9][10]
References
[edit]- ^ 2-methyl-4-oxo-2-cyclohexenecarboxylate at Sigma-Aldrich
- ^ Hagemann, C. Th. L. (1893). "Ueber die Einwirkung von Methylenjodid auf Natracetessigäther". Berichte der Deutschen Chemischen Gesellschaft (in German). 26: 876–890. doi:10.1002/cber.189302601181.
- ^ a b c d e Pollini, Gian Piero; Benetti, Simonetta; De Risi, Carmela; Zanirato, Vinicio (2010). "Hagemann's ester: a timeless building block for natural product synthesis". Tetrahedron. 66 (15): 2775–2802. doi:10.1016/j.tet.2010.01.078.
- ^ Rapson, William Sage; Robinson, Robert (1935). "307. Experiments on the synthesis of substances related to the sterols. Part II. A new general method for the synthesis of substituted cyclohexenones". Journal of the Chemical Society (Resumed): 1285. doi:10.1039/JR9350001285.
- ^ White, James D.; Sung, Wing Lam (1974). "Alkylation of Hagemann's ester. Preparation of an intermediate for trisporic acid synthesis". The Journal of Organic Chemistry. 39 (16): 2323–2328. doi:10.1021/jo00930a001.
- ^ Hogg, John A. (1948). "Synthetic Sterols. I. Model Experiments Employing Hagemann's Ester". Journal of the American Chemical Society. 70 (1): 161–164. doi:10.1021/ja01181a047. PMID 18918810.
- ^ Liu, Bo; Yang, Li; Yue, Guizhou; Yuan, Changchun; Du, Biao; Deng, Heping (2014). "Synthetic Studies toward Lindenane-Type Sesquiterpenoid Dimers". Synlett. 25 (17): 2471–2474. doi:10.1055/s-0034-1379001.
- ^ McAndrew, Bruce A. (1979). "Ethyl 2- methyl-4-oxocyclohex-2-enecarboxylate (Hagemann's ester) as a precursor to alkyl-substituted 3-methylcyclohexenones". Journal of the Chemical Society, Perkin Transactions 1: 1837. doi:10.1039/P19790001837.
- ^ Nasipuri, D.; Mitra, K.; Venkataraman, S. (1972). "Cyclohexenone derivatives. Part VI. C-3 and C-1 alkylation of Hagemann's ester (Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate) with alkyl halides and Michael acceptors". Journal of the Chemical Society, Perkin Transactions 1: 1836. doi:10.1039/P19720001836.
- ^ Begbie, A. L.; Golding, B. T. (1972). "A new synthesis of ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (Hagemann's ester) and its methyl and t-butyl analogues". Journal of the Chemical Society, Perkin Transactions 1: 602. doi:10.1039/P19720000602.