Acrylate resin bound

The imidazole ring is a privileged structure in medicinal chemistry since it is found in the core structure of a wide range of pharmaceutically active compounds efficient methods for the preparation of substituted imidazole libraries are therefore of great interest. Recently, a rapid synthetic route to imidazole-4-carboxylic acids using Wang resin was reported by Henkel (Fig. 17) [64]. An excess aliphatic or aromatic amine was added to the commercially available Wang-resin-bound 3-Ar,M-(dimethylamino)isocyano-acrylate, and the mixture was heated in a sealed vial with microwave irradi-... 

Tandem [4+2]/[3+2] cycloadditions of nitrostyrenes 476 with enol ethers 475 and resin-bound acrylate 477, promoted by high pressure, yielded a number of interesting heterocycles including the furoisoxazolooxazine 479 (Scheme 37) <1998TL3613>. 

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]. 

Thioethers have also been prepared on cross-linked polystyrene by radical addition of thiols to support-bound alkenes and by reaction of support-bound carbon radicals (generated by addition of carbon radicals to resin-bound acrylates) with esters of l-hydroxy-l,2-dihydro-2-pyridinethione ( Barton esters Entry 6, Table 8.5). Additional methods include the reaction of metallated supports with symmetric disulfides (Entries 7-9, Table 8.5) and the alkylation of polystyrene-bound, a-lithiated thioani-sole [65],... 

Acrylic acid esterified with cross-linked hydroxymethyl polystyrene or Wang resin reacts smoothly with primary or secondary aliphatic amines at room temperature (Entries 1 and 2, Table 10.6). Only sterically demanding amines or amines of low nucleophilicity (anilines, a-amino acid esters) fail to add to polystyrene-bound acrylate. Support-bound acrylamides are less reactive than acrylic esters, and generally require heating to undergo addition with amines (Entries 4 and 5, Table 10.6). a, 3-Unsaturated esters with substituents in the 3-position (e.g. crotonates, Entry 3, Table 10.6) react significantly more slowly with nucleophiles than do acrylates. The examples in Table 10.6 also show that polystyrene-bound esters are rather stable towards aminolysis, and provide for robust attachment even in the presence of high concentrations of amines. Entry 10 in Table 10.6 is an example of the alkylation of a resin-bound amine with an electron-poor alkene to yield a fluorinated peptide mimetic. 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

Examples of the N-alkylation and N-arylation of pyrazoles on insoluble supports have also been reported. Unsubstituted pyrazole undergoes Michael addition to resin-bound a-acetamido acrylates to yield 1-pyrazolylalanine derivatives (Entry 9, Table... 

The resulting triazoles can be N-alkylated by treatment with alkyl halides (0.25 mol/L, 30 equiv., DMF, NaOH), but mixtures of the 1-alkylated and 2-alkylated triazoles are obtained [255]. 1,2,4-Triazoles have also been prepared from N-amino-amidines (amidohydrazones Entry 4, Table 15.20), which were prepared from resin-bound thioamides by S-alkylation with methyl triflate followed by treatment with hydrazine [256]. 1,2,4-Tri azoles undergo Michael addition to polystyrene-bound a-acetamido acrylates to yield triazole-derived a-amino acids (Entry 7, Table 15.20). Benzotriazoles have been N-arylated on insoluble supports by treatment with aryl-boronic acids in the presence of catalytic amounts of copper salts (Entry 8, Table... 

Binding enzymes to solid supports can be achieved via covalent bonds, ionic interactions, or physical adsorption, although the last two options are prone to leaching. Enzymes are easily bound to several types of synthetic polymers, such as acrylic resins, as well as biopolymers, e.g., starch, cellulose [52], or chitosan [53,54]. Degussa s Eupergit resins, for example, are used as enzyme carriers in the production of semisynthetic antibiotics and chiral pharmaceuticals [55], Typically, these copolymers contain an acrylamide/methacrylate backbone, with epoxide side groups... 

For example, treatment of acrylate and crotonate ephedrine resins 150 and 151, with cyclohexanecarboxaldehyde 149, employing Sml2 in THF with f-butanol as a proton source, gave 152 and 153 respectively, in moderate yield and good to high enantiomeric excess (Scheme 34). The process can be considered an example of an asymmetric catch-release process, where a substrate immobilized using a chiral support captures a reactive intermediate, in this case a ketyl radical anion, from solution [23]. The chiral support controls the asymmetry of the capture step and leads to a diastereomeric, resin-bound intermediate that breaks down to release a non-racemic product. 

A later report demonstrated similar chemistry under milder conditions. The apparently reduced effectiveness of the PTA in the previous work was noted, as was a further report where Pd/MjCOj/PTA had been demonstrated to catalyze the Heck reaction in water in excellent yield under mild conditions. This chemistry was therefore adapted to the solid phase. After tethering 4-iodobenzoic acid to TentaGel resin, the reaction with ethyl acrylate was examined and found to be successful with the conditions shown in Scheme 2. Initial attempts to run the reaction in neat water failed to convert starting material to product in much more than about 50% yield, but introduction of a DMF-water solvent mixture solved this problem. The chemistry was adapted for the coupling of a number of olefins (generally those with attached electron-withdrawing groups). In contrast to the previous report, where these reactions were shown with reversal of polarity (i.e., the reaction of solution-phase iodides and bromides with resin-bound 4-vinylbenzoic acid), no products were obtained in these reversed cases. 

Table 1 shows the specifications of the concrete, carbon fiber sheet and adhesive resin investigated in the present work. The concrete blocks of 30 x 20 x 90 mm were made of normal grade Portland cement and cured in water for 4 weeks. The carbon fiber sheet (UT70-30, Toray) was a unidirectional cloth bound with a few lateral fibers. The adhesive resin (DK-530, Denka) was a modified acrylic resin of two component system. 

These core structures can be accessed as shown in Scheme 19. Michael addition of primary amines to Wang resin-bound acrylic acid 66 produced 3-aminoesters 67, which were reacted with isocyanates to give precursor ureas 68 for cyclization. Treatment of 68 with TFA/water (19 1) at room temperature cleaved mainly the non-cyclized precursors, whereas cyclized products 69 were formed by treatment under rather harsh conditions (toluene saturated with HCl, sealed vial, 95 °C) and were isolated in yields in the range 13-76% [32]. 

Assembly of Diels-Mder reaction components using a Ugi reaction Furfural and related compounds (293) can serve as diene building blocks in intramolecular and intermolecular cycloadditions, as they can be attached to resin-bound amines by reductive amination [306]. Particularly versatile is the use of furfural derivatives in 4-component Ugi reactions, where the diene and the dienophile component can be present. However, in the reaction set-up the electronic characteristics of the building blocks such as HOMO/LUMO energy or electron demand have to be considered to receive high yields. In the study presented by Schreiber et al., an acrylic acid served as dienophile (Scheme 64) [307]. 

In the solid-phase Baylis-Hillman reaction developed in our group [19] resin-bound acrylic ester reacted with aldehydes to form 3-hydroxy-2-methylidene-propionic acids, or with aldehydes and sulfonamides in a three-component reaction to form 3-aminoaryl-2-methylidene sulfonylpropionic acids [20] (Fig. 6.4). 

Successful polymer supported stereoselective Diels-Alder reaction was performed using immobilized enantiopure 4-(3-hydroxy-4,4-dimethyl-2-oxopyrro-lidin-l-yl)benzoic acid 12 as a chiral auxiliary [15]. The corresponding resin-bound acrylate derivate has been applied as the dienophile 13. Preparation of the precursor started with the combination of pantolactone 10 and the sodium salt of 4-aminobenzoic acid. Conversion into the corresponding benzyl ester followed. The obtained racemate was esterified with (lS)-camphanic acid chloride to a dia-stereomeric mixture to gain the enantiopure compounds by chromatographic separation. After subsequent saponification of the camphanic acid moiety and hydrolysis of the benzyl ester the (R)-enantiomer 11 was coupled to Rink amide resin (Scheme 12.6). 

To generate dienophile 13, the auxiliary 12 was esterified with acrylic acid chloride. The reactions of the resin-bound acrylate ester 13 with isoprene, 2,3-dimethylbutadiene, cyclopentadiene and 1,3-cyclohexadiene were carried out in the presence of TiCf and yielded 80-98% of 14 after cleavage from the polymer (Scheme 12.7). Enantiomeric excesses (ee) from 40 to 99% have been reported. 

To increase the low enantiomeric excess of 40% in the stereoselective Diels-Alder reaction with isoprene, the resin-bound auxiliary was modified. After introduction of an aminohexanoic acid spacer to the chiral auxiliary, the corresponding acrylate 15 showed an enhanced ee (70%) on applying the same reaction conditions and yielded 77% (Scheme 12.8). 

A fully automated polymer-assisted synthesis of 1,5-biaryl pyrazoles has been reported <04JCO332>. 1,3-Dipolar cycloaddition of resin-supported acrylic acid 53 with phenylhydrazones under microwave irradiation gave resin-bound adducts 54, which were converted to l-phenyl-3-substituted-2-pyrazolinyl-5-carboxylates 55 <04SC3521>. 

The first high-pressure Diels-Alder reactions on the solid phase were performed in our group with resin bound acrylate 1 [5]. The acryloyl function was coupled to the hydroxybenzyl group of the Wang resin under basic conditions (Scheme 9.1). 

The solid phase synthesis of nitroso acetals via a resin-bound dipolarophile will be described first. It has already been mentioned that nitronates react much faster with electron-poor alkenes than with electron-rich alkenes. The reaction of the nitronate formed in situ with the resin-bound acrylate is therefore expected to be faster than its reaction with the enol ether in solution. An acrylate was selected as dipolarophile and coupled to the resin via an ester linkage, which allows the facile cleavage of the resin-bound nitroso acetals by several methods (hydrolysis, reduc-... 

A solid-phase submonomer approach to A-substituted j8-aminopro-pionic acid oligomers or )8-peptoids has been developed by Hamper et al. [63]. It is based on a simple two-step acylation and Michael addition reaction sequence. Treatment of Wang resin with 2 equiv. of acryloyl chloride in the presence of triethylamine in excess afforded the corresponding acrylate resin 86 (Scheme 23) [63]. Michael addition of a 6- to 10-fold excess of a given primary amine in DMSO afforded polymer-bound A-substituted -alanines (87). Trimeric A-benzyl-j8-aminopropionic acid (88) was prepared in 67% overall yield by repetition of this two-step sequence. 

Employing enolate chemistry. Ley et developed a solid-phase synthesis of bicyclo[2.2.2] octanes of type 316 based on a double Michael addition strategy. As depicted in Scheme 4.6.2, polymer-bound acrylate 313 was treated with cyclohexenone enolates derived from 314 to give 315. After reductive animation, resin-bound bicyclo[2.2.2]octanes 316 were cleaved under a set of different conditions. Aminolysis with different amines and acidolysis using TEA led to the formation of 317 and 318, whereas reduction with DIBAH gave alcohols of type 319. 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

In the presence of 3-HQD or DABCO, the MBH reaction between resin-bound acrylate and various aldehydes with different reactivities yielded allylic alcohols 69 and 70 in moderate to excellent yields by simply varying the base or the reaction time, " which led to a combinatorial synthesis of substituted racemic 3-hydroxypropionamides, amino alcohols " or arylpropanolami-nes " via the treatment with amines and the use of different cleavage methods (Scheme 2.30). 

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