Claisen condensation cyclization

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... 

In 1888 Claisen (1888CB1149) first recognized a general synthesis of isoxazoles (283) by the condensation-cyclization of 1,3-diketones (280) with hydroxylamine. It is now generally accepted that the monoxime (281) of the 1,3-diketone and the subsequent 5-hydroxy-isoxazoline (282) are the intermediate products of the reaction. The isolation of the monoxime (281) and 5-hydroxyisoxazoline (282), which were both readily converted into the isoxazole (283) by treatment with acid or base, has been reported (62HC(17)l). 

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 mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /3-keto ester product results. 

Intramolecular Claisen condensation (Dieckmann cyclization Section 23.91... 

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

Based on the three-dimensional structure of CHS, we proposed that the initiation/elongation/cyclization cavity serves as a structural template that selectively stabilizes a particular folded conformation of the linear tetraketide, allowing the Claisen condensation to proceed from C6 to Cl of the reaction intermediate.14 In contrast, CTAL formation can occur either in solution or alternatively while sequestered in the enzyme active site. In either case, enolization of the C5 ketone followed by nucleophilic attack on the Cl ketone with either a hydroxyl group (in solution) or the cysteine thiolate (enzyme bound) as the leaving group results in CTAL. Similar lactones are commonly formed as by-products of in vitro reactions in other PKS systems.36 38... 

To resolve the issue of cyclization specificity, the x-ray crystal structure of the stilbene synthase from pine was determined to atomic resolution. This information allowed the mutagenic conversion of alfalfa CHS to a functional STS, and crystal structures of this engineered STS were solved, in the apo form and with resveratrol bound in the active site (Austin and Noel, unpublished). These experiments support a mechanistic proposal, which prompted further mutagenic and modeling experiments. This work has allowed the elucidation of the structural and mechanistic basis for cyclization specificity (aldol versus Claisen condensation) in the CHS family of type III PKSs. 

Dieckmann Condensation The intramolecular equivalent of a Claisen condensation where dicarboxylic acid ester undergoes base-catalyzed cyclization to form a P-keto ester. 

Other methods of preparing flavone include the action of ethanolic alkali on 2 -acetoxy-a,/3-dibromochalcone 7 Claisen condensation of ethyl o-ethoxybenzoate and acetophenone, and cyclization of the resulting 1,3-diketone with hydriodic acid 8 and treatment of 3-bromoflavanone with potassium hydroxide in ethanol.9 Flavone has also been prepared from ethyl phenyl-propiolate by condensation with sodium phenoxide and subsequent cyclization with phosphorus pentachloride in benzene 10 by fusing o-hydroxyacetophenone with benzoic anhydride and sodium benzoate 11 by the dehydrogenation of 2 -hydroxychal-cone with selenium dioxide 12 and by the action of alkali on flavylium chloride.13... 

The aniline nitrogen is then converted to the para-toluenesulfonamide (4-3). Reaction of this intermediate with ethyl co-chlorobutyrate in the presence of potassium carbonate then gives the alkylation product (4-4). Potassium tert-butoxide-catalyzed Claisen condensation of this diester leads to azepinone (4-5) as a mixture of methyl and ethyl esters resulting from alternate cyclization routes. A strong acid leads to the transient keto-acid, which then decarboxylates the toluensulfonyl group is lost under reaction conditions as well as affording the benzazepinone (4-6). This last intermediate is then acylated with the benzoyl chloride (4-7) to afford amide (4-8). 

Amino groups in compounds of type (23, Z=NH) are frequently derived from nitro groups. In the Reissert indole synthesis, o-nitrotoluene undergoes Claisen condensation with oxalic ester to yield the pyruvic ester (24). When this is reduced with Zn-AcOH the corresponding amino derivative spontaneously cyclizes to the 2-ethoxycarbonylindole (25) (63OS(43)40). 

The condensation of glycine esters with /S-keto esters gives 3-hydroxypyrroIes (equation 115). The cyclization is effected using strong base and is, in effect, an intramolecular Claisen condensation (67AJC935). 

Most of the pigments of flowers arise from a single polyketide precursor. Phenylalanine is converted to trans-cinnamic acid (Eq. 14-45) and then to cinnamoyl-CoA. The latter acts as the starter piece for chain elongation via malonyl-CoA (step a in the accompanying scheme). The resulting (3-polyketone derivative can cyclize in two ways. The aldol condensation (step b) leads to stilbenecar-boxylic acid and to such compounds as pinosylvin of pine trees. The Claisen condensation (step c) produces chalcones, flavonones, and flavones. These, in turn, can be converted to the yellow fla-vonol pigments and to the red, purple, and blue anthocyanidins.3 c... 

The acylation of ketones by ethyl phenylpropynoate is accompanied by cyclization and is a useful route to pyran-4-ones (54JCS1775, 74JHC1101). The base-catalyzed reaction probably proceeds through an alkynic diketone formed by a Claisen condensation. The use of 1-tetralone gives the fused pyran-4-one (413) (59JCS2588). 

Upon treatment with a base, the activated methyl group in 2-hydroxyacetophenone is converted into a carbanion. Claisen condensation with an ester gives rise to a 1,3-diketone, the sodium salt of which may be isolated although this process is usually unnecessary. Cyclization to the chromone occurs readily in acid solution (Scheme 147). 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

The triketo ester (602) undergoes a Claisen condensation in aqueous potassium hydroxide yielding the chalcone (603). On heating, cyclization to the flavanone, pinocembrin (604), occurred (67JA6734). Methanolic potassium hydroxide effects an alternative cyclization to methyl 2,4-dihydroxy-6-styrylbenzoate. 

Fluorinated esters have synthetic utility m Claisen condensations [24, 25] (equation 21) and Dieckmann cyclizations [26]. 

Two sequential thio-Claisen condensations convert dialkyl ketones into thiopyran-4-ones in a rapid, high-yielding process. Initial reaction with an aromatic dithioester produces an a, 3-unsaturated ketone which, after alkylation at sulfur, undergoes reaction with a second dithioester and cyclization to the substituted thiopyranone follows (Scheme 200) <1993JOC3042>. 

Key Mechanism 22-12 The Claisen Ester Condensation 1071 22-13 The Dieckmann Condensation A Claisen Cyclization 1074 22-14 Crossed Claisen Condensations 1074 22-15 Syntheses Using /3-Dicarbonyl Compounds 1077 22-16 The Malonic Ester Synthesis 1079 22-17 The Acetoacetic Ester Synthesis 1082 22-18 Conjugate Additions The Michael Reaction 1085 Mechanism 22-13 1,2-Addition and 1,4-Addition (Conjugate Addition) 1085... 

An internal Claisen condensation of a diester forms a ring. Such an internal Claisen cyclization is called a Dieckmann condensation or a Dieckmann cyclization. Five- and six-membered rings are easily formed by Dieckmann condensations. Rings smaller than five carbons or larger than six carbons are rarely formed by this method. 

The ethoxide ion released in this first reaction will, as usual, form a stable enolate from the 1,3-diketone but this now cyclizes in a second Claisen condensation on to the second ester group,... 

C. Intramolecular Claisen condensations the Dieckmann cyclization (Section 23.9). 

Claisen condensation reaction Dieckmann cyclization Michael reaction Michael acceptor... 

Fluorinated esters have synthetic utility in Claisen condensations, c.g. formation of 26, - and Dieekmann cyclizations. ... 

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