Cyclization Dieckmann reaction

Dieckmann cyclization reaction (Section 23.9) An intramolecular Claisen condensation reaction to give a cyclic /3-keto ester. 

Claisen rearrangement, 660 conjugate carbonyl addition reaction, 725-726 Curtius rearrangement, 935 cyanohydrin formation, 707 dichlorocarbene formation, 227 Dieckmann cyclization reaction, 892-893... 

The Claisen reaction is a carbonyl condensation that occurs between two ester components and gives a /3-keto ester product. Mixed Claisen condensations between two different esters are successful only when one of the two partners has no acidic a hydrogens (ethyl benzoate and ethyl formate, for instance) and thus can function only as the acceptor partner. Intramolecular Claisen condensations, called Dieckmann cyclization reactions, provide excellent syntheses of five- and six-membered cyclic /3-keto esters starting from 1,6- and 1,7-diesters. 

This reaction is an example of a Dieckmann cyclization The anion formed by proton abstraction at the carbon a to one carbonyl group attacks the other carbonyl to form a five membered ring... 

Dieckmann cyclization (Section 21 2) An intra molecular analog of the Claisen condensation Cy die p keto esters in which the ring is five to seven membered may be formed by using this reaction... 

The mercaptals obtained by the acid catalyzed reaction of J3-ketoesters, e.g., ethyl acetoacetate, with methyl thioglycolate (73) undergo the Dieckmann cyclization with alcoholic potassium hydroxide at lower temperatures to give ethyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (74) in 75% yield. ° Besides ethyl acetoacetate, ethyl a-ethylacetoacetate, ethyl benzoyl acetate, and ethyl cyclopentanonecarboxylate were also used in this reaction/ It is claimed that /8-diketones, hydroxy- or alkoxy-methyleneketones, or /8-ketoaldehyde acetals also can be used in this reaction. From acetylacetone and thioglycolic acid, 3,5-dimethyl-2-thiophenecarboxyl-ic acid is obtained. ... 

The ring-contracted analog of alphaprodine is prepared by a variation of the scheme above. Alkylation of 109 with ethyl bromoacetate affords the lower homolog diester (115). Dieckmann cyclization followed by saponification-decarboxylation yields the pyrrolidine (116). Reaction with phenylmagnesium bromide leads to the condensation product (117) acylation with propionic anhydride gives the analgesic agent prolidine (118)... 

Intramolecular Claisen condensations can be carried out with diesters, just as intramolecular aldol condensations can be carried out with diketones (Section 23.6). Called the Dieckmann cyclization, the reaction works best on 1.6-diesters and 1,7-diesters. Intramolecular Claisen cyclization of a 1,6-diester gives a five-membered cyclic /3-keto ester, and cyclization of a 1,7-diester gives a six-membered cyclic /3-keto ester. 

The cyclic /3-keto ester produced in a Dieckmann cyclization can be further alkylated and decarboxylated by a series of reactions analogous to those used in the acetoacetic ester synthesis (Section 22.7). For example, alkylation and subsequent decarboxylation of ethyl 2-oxocyclohexanecarboxylate yields a 2-alkylcvclohexanone. The overall sequence of (1) Dieckmann cyclization, (2) /3-keto ester alkylation, and (3) decarboxylation is a powerful method for preparing 2-substituted cyclohexanones and cyclopentanones. 

In its present form, intermediate 12 is not a viable substrate for the crucial Dieckmann condensation it must undergo prior epimerization at C-16. When intermediate 12 is treated with sodium methoxide in hot methanol, enolization at C-16 occurs and an equilibrium is established between 12 and a diastereomeric substance, intermediate 11. Once formed, 11 can either revert back to 12 through the planar enolate form, or it can participate in a productive cyclization reaction to give a new six-membered ring. Under these conditions, the desired transformations take place with exceptional facility to give, after acidification of the reaction medium, enol ester 10. 

Condensations Highly atom economical since small molecules of water or alcohol are liberated Atom economy increases as the molecular weights of the combining fragments increases For cyclization reactions such as the Dieckmann condensation and the synthesis of cyclic ethers from straight chain diols the atom economy increases with increasing ring size... 

Reaction sequence E removed an extraneous oxygen by Sml2 reduction and installed an oxygen at C(15) by enolate oxidation. The C(l) and C(15) hydroxy groups were protected as a carbonate in Step E-5. After oxidation of the terminal vinyl group, the C-ring was constructed by a Dieckmann cyclization in Step F-4. After temporary protection of the C(7) hydroxy as the MOP derivative, the (1-ketoestcr was subjected to nucleophilic decarboxylation by phenylthiolate and reprotected as the BOM ether (Steps F-5, F- 6, and F-7). 

Selenolo[3,2-h]selenophene (12) and selenolo[2,3-b]selenophene (13) have been synthesized from lithium derivatives of 2-(3-bromo-2-selienienyl) 1,3-dioxane and 2-(3-selenienyl) 1,3-dioxane, respectively, by reaction with selenium and methyl chloroacetate followed by Dieckmann cyclization.46 Even the third classical selenophthene (11) has been synthesized by two different routes, using 2,3-bischloromethyl-5-carbomethoxyselenophene (14) or preferably 4-methylseleno-3-selenophene aldehyde (IS).46 The fourth selenophthene isomer (16), which has a nonclassical structure, has not yet... 

The Dieckmann cyclization of aminomethylenemalonates (1308) in boiling ethanol for 45 min, by the action of alkoxide, gave pyrrole-2,4-dicar-boxylates (1309) in 24-86% yields (77HI821 78CPB2224). Pyrrole-2,4-dicarboxylate (1309, R = H,R = Et) was also prepared in 71% yield from 1308 (R = H, R1 = Et) by reaction with sodium hydride in boiling benzene for 4 hr (78CPB2224). The 1-phenyl derivative (1309, R = Ph, R1 = Et) was prepared in 52% yield in an exothermic reaction of 1308 (R = Ph,... 

In Yamada s retrosynthetic analysis (Scheme 11), elisabethin C (26) is traced back to lactone 64 which would be converted into 26 by deoxygenation and chain elongations. Key intermediate 64 could be obtained by a stereoselective Dieckmann cyclization. The required ester lactone precursor 65 would be accessible from 66 by a series of oxidation reactions. Further disconnection would lead to commercially available (+)-carvone (67). Stereoselective successive alkylation of 67 and reduction of the enone should deliver 66 [30]. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

The 2,2 -bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsNs) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234). 

In a related type of reaction, the styryl isocyanates, readily available by Curtius rearrangement of cinnamoyl azides, undergo thermal cyclization to l-isoquinolones in good yield (equation 34) the reaction can also be carrried out using Friedel-Crafts catalysts. 2,3-Dihydro-4( 1//)- isoquinolones are obtained by Dieckmann cyclization of N- (o- carbalkoxy-benzyl)glycine ester derivatives (equation 35). The same reaction has been used for the synthesis of a range of non-aromatic heterocycles (equations 36 and 37). 

The two major routes to 3,4-dihydro-2JT-l,5-benzodioxepins (274) from (273) and (275) are applicable to a wide range of substituted derivatives. The 3-oxo derivative, important as a perfume odorant, can be prepared via the reaction of 1,2-dihydroxybenzene with chloroacetonitrile (75CJC2279) or via a Dieckmann cyclization (74USP3799892). 

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