Diels-Alder reactions resin-bound

To generate molecular libraries, a series of 5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs were prepared via a stereospecific Diels-Alder reaction by reacting Wang-resin-bound diene 35 with a variety of dienophiles [28]. After removing the solid support with a strong acid, adducts 36 were isolated examples of reactions that have furnished the best yields are reported in Scheme 4.6. 

Scheme 44 Diels-Alder reactions of resin-bound pyrazinones...

Another approach towards monocyclic N-unsubstituted 2-pyridones is based on a solid-phase supported Diels-Alder reaction where a resin-bound 2(lH)-pyrazinone 9 is reacted with acetylenic dienophiles (Fig. 4) [43]. The initially formed cycloadduct then undergoes a retro Diels-Alder reaction and depending on the substitution pattern of the starting pyrazinone the reaction... 

A traceless linker for solid-phase homo- and hetero-Diels-Alder reactions was based upon resin bound quinodimethane precursors... 

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

A combination of a multicomponent Ugi transformation and an intramolecular Diels-Alder reaction has been developed by Paulvannan [13]. Hence, condensation of the resin-bound (acid-labile ArgoGel-Rink resin) amine 10-37 with a tenfold... 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

Van der Eycken and coworkers have presented a study describing the microwave-assisted solid-phase Diels-Alder cycloaddition reaction of 2(lH)-pyrazinones with dienophiles [69]. After fragmentation of the resin-bound primary cydoadduct formed by Diels-Alder reaction of the 2(lH)-pyrazinone with an acetylenic dieno-phile, separation of the resulting pyridines from the pyridinone by-products was achieved by applying a traceless linking concept, whereby the pyridinones remained on the solid support with concomitant release of the pyridine products into solution (Scheme 7.58). 

For the development of an appropriate strategy for cleavage from the novel syringaldehyde resin, the authors adapted a previously elaborated solution-phase model study on intramolecular Diels-Alder reactions for the solid-phase procedure (Scheme 7.60). The resulting pyridines could be easily separated from the polymer-bound by-products by employing a simple filtration step and subsequent evaporation of the solvent. The remaining resins were each washed and dried. After drying,... 

As the first multi-component domino reaction on solid phase the above mentioned domino-Knoevenagel-hetero-Diels-Alder reaction was performed using a 1,3-dicarbonyl compound bound to a modified Merrifield resin.171... 

Solid phase chemistry has gained widespread use in recent years. Among the immense number of reactions that can be performed on the resin nowadays, the all-carbon Diels-Alder reaction still takes a minor place. The resin-bound Diels-Alder reactions reported in the literature between 1992 and 1997 have been reviewed recently143. 

Winkler and Kwak144 recently prepared tricyclic ester 221 from 215 by means of three consecutive Diels-Alder reactions with 216, 218 and 91b to give 217, 219 and 220, respectively, followed by cleavage of the triple adduct 221 from the resin (equation 61). The overall yield was almost three times higher than when the same reaction sequence was performed in solution, thereby demonstrating the efficiency of resin-bound reactions in this case. 

On the other hand, Hird and colleagues145 studied the Diels-Alder reactions of resin-bound 2-amino-1,3-butadienes with several iV-substituted maleimides and nitrostyrenes. 

Schlessinger and Bergstrom146 reported some asymmetric Diels-Alder reactions of several polystyrene bound furans to which a chiral auxiliary had been attached with methyl acrylate. The adducts were obtained with de values of more than 99%, as was determined after cleavage of the adducts from the resin. 

Alkenes have also been prepared by retro-Diels-Alder reaction of resin-bound cyclohexenes. Figure 3.40 depicts an interesting example of this strategy, in which the retro-Diels-Alder reaction is induced by conversion of a thermally stable, resin-bound 7-oxanorbornadiene into a thermally unstable 7-oxanorbornene [795]. 

Diels-Alder reactions have been conducted on solid phase, with either the dieno-phile or the diene linked to the support [156]. The reaction conditions and the regio-and stereoselectivities observed are similar to those in solution [58,157,158]. Illustrative examples of Diels-Alder reactions leading to support-bound cyclohexenes are listed in Table 5.10. Further examples include the cycloaddition of polystyrene-bound 2-sulfonyl-l,3-butadiene and V-phenylmaIcimidc [51], the high-pressure cycloaddition of 1,3-butadienes to resin-bound 1 -nitroacrylates [95], and the intramolecular Diels-Alder reaction of styrenes with acrylates [159]. 

Pyrrolidines and pyrrolidinones can be synthesized on insoluble supports by intramolecular carbometallation of alkenes (Entry 1, Table 15.4) and by Ugi reaction of support-bound isonitriles with amines and 4-oxo acids (Entry 4, Table 15.4). In Entry 5 in Table 15.4, the pyrrolidinone ring is formed by intramolecular Diels-Alder reaction of a furan with a fumaric acid derivative. 2-Pyrrolidinones have also been prepared by treatment of resin-bound O-mesitylenesulfonyl cyclobutanone oximes with... 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

A library of chiral dihydropyrans (226) [241] was synthesized using asymmetric hetero-Diels-Alder reactions (HAD) on polymer-bound enol ethers (221) and a, 3-unsaturated oxalyl esters (222). A chiral Lewis acidic Cu -bisoxazoline complex was used because of its high efficiency, the high predictability of the reaction outcome, and its broad substrate tolerance [280]. Enol ethers were used as alkene components bearing a hydroxy function for attachment to the resin via a silyl linkage (Scheme 49). The diene components carried allyl-ester groups, which could be readily displaced by amino functions in subsequent steps of the combinatorial synthesis. 

The most common C-X fragments are imines, which can be readily obtained from a polymeric support aldehyde by many high-yielding methods [281, 282, 283]. Dor-wald et al. reported Wang resin-supported 3-enaminoamides [284]. Yamazaki generated enamines from support-bound phosphonoesters [148]. Imines serve as starting materials for [2 -r 2]-cycloadditions, [2 -i- 3]-dipolar cycloadditions, and het-ero Diels-Alder reactions (HD). 

Diels-Alder reaction with Sieher resin-bound 5-hydroocymethylfuifiiral (Scheme 61) [303] ... 

Diels-Alder reaction with support-bound 4-[3-(tert-butyldimethylsilyloocy)buta-l,3-die-nyl] groups (Scheme 65) [310] N-[(Fluoren-9-ylmethoxycarbonyl)ethyl]maleimide (304) (135 mg, 0.375 mmol) was weighed into a screw-cap vial (Reacti-Vial) and toluene (800 pL) was added. The vial was sealed and heated until the dienophile dissolved, and resin bearing a diene (302 or 306) was added and allowed to swell in reagent and solution. The vial was sealed and kept at 110 °C overnight The reaction solution was drained and the resin washed as follows ... 

A keteneacetal, the Brassard diene, has also been bound to polystyrene-based resin (308). This has been achieved by the reaction of diketene with alcohol functions on polystyrene resin. The ketone function of the resulting acet-oacetate could readily be enolized by TMOF (trimethyl orthoformate) and a catalytic amount of H, giving the methyl enolate. The remaining ester function was then deprotonated with LDA and subsequently silylated with TBDMSCl. The resulting diene (311) was used in many hetero-Diels-Alder reactions (HDA) with aldehydes and ketones as dienophiles, giving a library... 

Good yields and purities were obtained for the two examples shown. Ugi reaction using solid-supported benzenesulfonamide, prepared by coupHng 4-carbox-ybenzenesulfonamide onto Rink resin, has also been described. The sulfonamide took the place of the amino component in the classical Ugi MCR. An extension of this Ugi reaction involving a support-bound amine, furfural, and an isonitrile and an acrylic acid was used by Schreiber [307] to generate support-bound dipeptides capable of performing intramolecular Diels-Alder reactions (see Section 4.5.9). 

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