REM resin

Brown AR, Rees DC, Rankovic Z, Morphy JR. Synthesis of tertiary amines using a polystryerene (REM) resin. J Am Chem Soc 1997 119 3288-3295. 

Nonoligomeric libraries. Peptide and peptoid libraries are examples of oligomeric (polymeric) libraries made up of repeating monomers (a-amino acids, A-substitutcd glycines). Random libraries composed of nonoligomeric compounds have been extensively explored. One illustration comes from the former laboratories at Organon (Fig. 1.6) (16). Thirteen different secondary amino-phenol inputs were attached to solid support by reaction with REM resin yielding resin-bound b-amino propionates. Two-site derivatization was then used to drive library diversity. The free phenolic OH was subjected to O-alkylation,... 

Barn, D., Caulfield, W., Cowley, P, Dick-ins, R, Bakker, W. I., McGuire, R, Morphy, J. R, Rankovic, Z., Thorn, M. (2001) Design and synthesis of a maximally diverse and druglike screening library using REM resin methodology. / Comb Chem 3, 534-541. 

Fig. 1. Comparison of a regular tertiary amine synthesis on REM resin (left) with the planned traceless benzimidazole route.

Typical nucleophilically cleavable linkers are the REM resin linker 86 [75] (polymer-bound benzyl acrylate regenerated Michael acceptor) and the Dde group 87 (ADCC (4-Acetyl-3,5-dioxo-l-methylcyclohexane carboxylic acid) anchor) [76], which are linkers for tertiary and primary amines, respectively (Figure 6.1.7). 

Toy PH, Reger TS, Janda KD, Soluble polymer bound cleavage reagents A multipolymer strategy for the cleavage of tertiary amines from REM resins, Org. Lett., 2 2205-2207, 2000. 

Computational studies concerning theoretical approaches to the intrinsic basicity of neutral nitrogen bases have been reported, including those of phos-phoranimines. The non-ionic phosphazene bases BEMP (112), BTPP (113) and (114, R = Ph) appear to be excellent catalysts for the Michael addition reactions. Thus the yield of the coupling reaction of ethyl isocyanoacetate with l,2-bis(4-bromomethylphenyl)ethane is increased by the addition of the phosphazene base BEMP. Polymer-supported BEMP (P-BEMP) has been applied for the allylation of 2H-benzo[d]l,3-dioxolan-5-ol by allyl bromide. " Cyclodehydration of 1,2 diacylhydrazines by tosyl chloride in the presence of P-BEMP leads to excellent yields of 1,3,4,-oxadiazoles. Addition of P-BEMP also improves the yield of the Hofmann elimination step in the synthesis of tertiary mines using REM resin (polymer-bound acrylate ester). ... 

Sammelson, R. E., Kurth, M. J. Oxidation-Cope elimination a REM-resin cleavage protocol for the solid-phase synthesis of hydroxylamines. Tetrahedron Lett. 2001,42, 3419-3422. 

Cottney J, Rankovic Z, Morphy JR (1999) Synthesis of novel analogues of the delta opioid ligand SNC-80 using REM resin. Bioorg Med Chem Lett 9 1323-1328... 

Heck reactions in SC-CO2 were performed on REM resin. Palladium trifluoroacetate (10 mol%) in conjunction with DIPEA gave the highest yields at only 40 °C. Aryl bromides gave somewhat lower yields than aryl iodides [42]. 

Reactions of this type have been used in the synthesis of indoles on a solid phase [143, 144]. Yamazaki et al. described a combination of palladium-catalyzed amination and Heck reaction in a synthesis of indole [145]. One indole synthesis is performed by a Heck reaction of N-acyl dehydroalanine immobilized on REM resin (24) -with 1-2 halobenzenes (26). In the case of 2-N-acyl-aminocinnamoyl esters, the N-acetyl groups gave higher yields than CBz-groups and 1,2-dibromo-benzene (78%) was more efficient than l-bromo-2-triflyloxybenzene (41%) (Scheme 3). 

A highly regioselective and traceless solid-phase route to N(l)-N(7)-disubstituted purines 73 has been developed. The reaction involves coupling of 6-chloropurine 72 to the REM resin (Michael addition), oxidation, N(l)-alkylation, quatemization and product release through Hoffman elimination <05JCC734>. 

The classical Hofmann elimination reaction (which dates back to 1851) has been adapted to the solid phase in combination with the Michael addition. The REM resin, called this way because the resin tinker is REgenerated after product cleavage and functionalized by means of a Michael addition, has been developed to prepare arrays of tertiary amines. The procedure involves acylation of hydroxy-methylpolystyrene with acrylic chloride to furnish the acrylate on resin. Then, a secondary amine, whose substituents offer two potential sites of diversity, is bound by Michael addition. Quaternization of the amine with an alkyl halide (or reductive animation) introduces another site of diversity and activates the tinker to release the amine by a Hofmann elimination with DIEA (Figure 15.14) [127-129]. Additionally, the use of a second basic resin has been described as a source reagent to promote the elimination [130, 131]. 

TRAM linker by Belshaw et al. [45] and the REM resin by Morphy et al. [46] should be mentioned here, as they are built on a quaternization strategy of amines as activation step and subsequent (3-elimination by basic treatment as well. While the REM resin releases tertiary amines from the solid support, the use of the TRAM linker yields Michael acceptors. 

Hydroxyethylene resin HMPA resin Chloromethyl resin Hydroxymethyl resin Tritylchloride resin Rink amide resin Wang resin REM resin Aminomethyl resin Chloromethyl resin Wang resin Rink amide resin PAL amide resin MBHA resin Chloromethyl resin Chlorotrityl resin Wang resin PAM resin Polystyrene resin Chloromethyl resin Chlorotrityl resin Wang resin Rink amide resin Sasrin resin Polystyrene resin Chloromethyl resin Benzoic acid resin Wang resin Trityl resin 2-Chlorotrityl resin PAL resin Rink amide resin MBHA resin REM resin Hydroxymethyl resin Polystyrene Aminomethyl resin Chloromethyl resin 2-Chlorotrityl resin Hydroxyethyl resin Rink amide resin Wang resin MBHA resin Sieber resin... 

Cleavage, nonstandard Aminomethyl resin Chloromethyl resin Benzoic acid resin Hydroxymethyl resin Rink amide resin Wang resin PAL amide resin MBHA resin Kaiser oxime resin REM resin TentaGel S OH TentaGel S PHB Spheron Ara 1000 ... 

Supported catalysts involving palladium on carbon and dendrimer-encapsulated palladium and a polymer-supported phosphine palladium catalyst have facilitated C-C coupling reactions in SCCO2. Polymer-tethered substrates or amine bases have also been successfully used for the Mizoroki-Heck and Suzuki-Miyaura reactions in SCCO2. For example, REM resin underwent a Mizoroki-Heck reaction with iodobenzene to yield, after cleavage, ( )-methyl cinnamate 48 (74%) (Scheme 88). It is assumed that SCCO2 acts as a good solvent that swells the polymers and exposes reactive sites. 

REM resin (a polystyrene resin) (1.0 g, 0.74 mmol) was suspended in a mixture of 927 /xL 1,2,3,4-tetrahydroisoquinoline (7.4 mmol) and 7 mL DMF in a 15-mL polypropylene tube and agitated on a rotator for 2.5 h. The resin was drained and washed using a VacMaster station with DMF (4x2.5 mL) and then briefly dried under reduced pressure. The resin was resuspended in a solution of 326 /xL allyl bromide (3.7 mmol) in 7 mL DMF and agitated on the rotator for 2.5 h. The resin was drained and washed using a VacMaster station with DMF (4 x 2.5 mL) and CH2CI2 (4 x 2.5 mL), then briefly dried under reduced pressure. 

Scheme 6.46. Chemoselective preparation of tertiary amines, (a) Utilization of a REM resin to synthesize multiply substituted tertiary amines. R and R = Me, (CH2)2Ph, tetrahydroisoquinoline, ethyl Isonipecotate, ethyl nipecotate R = allyl, 4-NO2-C6H4. (b) Selective quaternizatlon of diamines to yield tertiary amines. R = CHPh2, CONHPh R = Me, allyl.

S. Lober, P. Gmeiner, Click chemistry on solid support synthesis of a new REM resin and application for the preparation of tertiary amines. Tetrahedron, 2004, 60, 8699-8702. 

Scheme 16 Modified REM resin suitable for reactions involving Grignard reagents...

---