Enones, polymer-bound

In a dedicated combinatorial approach, Strohmeier and Kappe have reported the rapid parallel synthesis of polymer-bound enones [33]. This approach involved a two-step protocol utilizing initial high-speed acetoacetylation of Wang resin with a selection of common /i-ketoesters (Scheme 7.13) and subsequent microwave-mediated Knoevenagel condensations with a set of 13 different aldehydes (see Section 7.3.6). 

As discussed in Section 7.1.4, polymer-bound acetoacetates can be used as precursors for the solid-phase synthesis of enones [33], For these Knoevenagel condensations, the crucial step is to initiate enolization of the CH acidic component. In general, enolization can be initiated with a variety of catalysts (for example, piperidine, piperidinium acetate, ethylenediamine diacetate), but for the microwave-assisted procedure piperidinium acetate was found to be the catalyst of choice, provided that the temperature was kept below 130 °C. At higher reaction temperatures, there is significant cleavage of material from the resin. 

Scheme 7.39 Parallel synthesis of polymer-bound enones. ...

Scheme 4.15 Polymer-bound Lewis acid in allylation of enones.

Strohmeier, G.A. and Kappe, C.O., Rapid parallel synthesis of polymer-bound enones utilizing microwave-assisted solid phase chemistry, /. Comb. Chem., 2002, 4, 154-161. 

Another example of the resin-capture-release technique which should see widespread applications in the future is the selenium-mediated functionalization of organic compounds. Polymer-supported selenium-derived reagents [34] are very versatile because a rich chemistry around the carbon-selenium bond has been established in solution and the difficulties arising from the odor and the toxicity of low-molecular weight selenium compounds can be avoided. Thus, reagent 26 (X = Cl) was first prepared by Michels, Kato and Heitz [35] and was employed in reactions with carbonyl compounds. This treatment yielded polymer-bound a-seleno intermediates, which were set free back into solution as enones from hydrogen peroxide induced elimination. Recently, new selenium-based functionalized polymers 26 (X = Br)-28 were developed, which have been utilized in syntheses according to Scheme 11 (refer also to Scheme 3) [36],... 

Polymer-bound enones also represent interesting templates for the synthesis of a variety of core structures. Scheme 6.12 illustrates some of the synthetic transformations possible with polymer-bound enones. 

Scheme 6.12. Polymer-bound enones as educts for the synthesis of diverse core structures.

Several strategies for the synthesis of polymer-bound enones have been described. One way is to start from immobilized [f-ketoesters, which can be prepared via transesterfica-tion of Wang resin with alkyl fl-keto carboxylates [31], or by treatment with diketene [16]. Knoevenagel reactions of these polymer-bound [f-ketoesters with aldehydes led to the formation of 2-alkylidene- or arylidene-P-ketoesters (Fig. 6.19 (A)). 

The group of M. J. Kurth [36] used polymer-bound enones for the Michael-type addition of aryl thiolates (Fig. 6.20). In the first step 1,4-butanediol was attached to PS-tritylchloride resin. This was followed by an oxidation to the aldehyde, subsequent Wittig reaction and addition of aryl thiolates. Cleavage was performed with formic acid in THF. 

Three different pyridine syntheses starting from polymer-bound enones have been reported. The first synthesis starts from 2-alkylidene- or 2-arylidene-B-ketoesters immobilized on Wang or Sasrin resin (Fig. 6.21). These substrates reacted with enaminones in a Hantzsch reaction to 1,4-dihydropyridines which could be oxidized to the corresponding pyridines with ceric ammonium nitrate (CAN). Cleavage was performed with TFA/DCM. Sixteen compounds were synthesized, with HPLC purities of between 70% and 99%. 

Grosche et al. [33] established the classic Krohnke pyridine synthesis on the solid phase (Fig. 6.22 (A, B a, c)). The polymer-bound enones used in this reaction were obtained from polymer-bound acetophenones as well as polymer-bound aldehydes, thus providing enones with different substitution patterns (Fig. 6.19 (B and C)). 

Marzinzik and Felder [34] synthesized a 3-cyanopyridine via the reaction of a polymer-bound enone with 3-amino-crotonic acid nitrile derived in a Thorpe reaction from acetonitrile and potassium terf-butoxide (B b, d Fig. 6.22) [26]- The product was obtained in 46 % yield, and with a HPLC purity of 78 %. 

Hollinshead [32] used polymer-bound enones for the synthesis of highly functionalized pyrrolidines. 3-Hydroxyacetophenone was immobilized on chlorinated Wang resin and transformed into polymer-bound enones upon a Knoevenagel reaction with aldehydes. Pyrrolidines were then formed in the addition of azomethinylides, generated from imines, LiBr and DBU (Fig. 6.24). 

Marzinzik and Felder [34] used polymer-bound enones which were generated from 4-carboxybenzaldehyde immobilized on Rink amide resin for the synthesis of pyrimidines and pyrimidones.The enones were then treated with different amidines in DMA for 16 h at 100°C (Fig. 6.25). 

Marzinzik and Felder [34] also performed a pyraz.ole synthesis as a possible transformation of polymer-bound enones. A single enone was treated with 2,3-dimethylphenyl-hydrazine under regioselective formation of the N-phenylpyrazole shown in Figure 6.26 (a, b). The crude product had a purity of 83 %, and the isolated yield was 73 %. 

Polymer-bound enones were also used in a hetero Diels-Alder reaction for the synthesis of dihydropyranes [38,39]. 

In summary, we have shown that squaric acid, 3-hydroxy-2-methylidene propionic acids, 5-(2-bromoacetyl)pyrroles and enones are useful polymer-bound key intermediates for the synthesis of a large number of different core structures. Squaric acid was used as a fluid template, because cores structures with different ring sizes could be synthesized. All other examples started from linear templates and afforded linear core structures as well as cyclic core structures. The examples shown here demonstrate the advantages of polymer-bound templates for this type of synthesis. This strategy also reduces the optimization time needed for developing the synthetic route for a specific structure because the synthesis of the polymer-bound educt has to be evaluated only once for the variety of core structures derived from this educt. 

In another paper, a development of the microwave-assisted parallel solid-phase synthesis of a collection of 21 polymer-bound enones was described. The two-step protocol involves initial high-speed acetoacetylation of polystyrene resins with a selection of seven common P-ketoesters. When microwave irradiation at 170 °C was employed, complete conversions were achieved within 1-10 min, a significant improvement over the conventional thermal method, which takes several hours for completion. Significant rate enhancements were also observed for the subsequent microwave-heated Knoevenagel condensations. Reaction times were reduced to 30-60 min at 125 °C in the microwave protocol compared to 1-2 days using conventional thermal conditions. Kinetic comparative studies indicate that the observed rate enhancements can be attributed to the rapid direct heating of the... 

Conjugate Addition Reactions.—The use of polymer-bound dialkylcuprates gives comparable or higher than normal yields in the conjugate addition to enones the major advantage lies in the ease of work-up. The mechanism of conjugate addition of cuprates and the mechanism and stereochemistry of the addition of lithium dimethylcuprate to jS-cyclopropyl-substituted enones have been reported. 

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