Rink-resin

Combinatorial approaches have been applied to this chemistry. In a method amenable to split and pool, PAL, or Rink resin, 89 is modified with an acetoacetate to generate the solid supported aminocrotonate 90. Either a two- or three-component Hantzsch protocol is followed to produce 91. Treatment with TFA carries out the cleavage from the resin and the cyclization to dihydropyridine 92. 

The first microwave-assisted Suzuki reactions involving heteroaromatic skeletons were reported in 1996 [35]. Hallberg et al. Hnked the substrates 4-iodo and 4-bromobenzoic acid to a TentaGel-Rink resin (Scheme 16). Suzuki reactions on these soUd-phase-Unked substrates were easily performed in less than 4 min using a constant microwave irradiation power (45 W) (no temperature control Standard acidic cleavage with TEA yielded the corresponding biaryls with an excellent yield. 

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... 

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

Scheme 4.68 Solid-phase synthesis on a Rink resin.

The introduction of alkoxy groups onto the benzhydryl system leading to a system cleavable by HE was first reported by Walter in 1976 [25] while one additional alkoxy group leads to the Rink linker (12), introduced in 1987 [26]. As quite mild conditions are sufficient for the release of the library components, the Rink resin has effectively been applied to the synthesis of several small molecule libraries [27]. 

Perfluoro(3-isothiocyanato-2-methyl-2-pentene) reacts with N-nucleophiles to produce a series of fluoroalkyl-substituted 6/f-l,3-thiazines <1997RJO720>. The acid-catalyzed cyclization of thioureas immobilized on Wang (X = O) or Rink resin (X = NH) provides a convenient route to a wide range of 2-amino-4/7-benzothiazine derivatives 212 (Scheme 23) <20000L3667>. The thioureas are obtained in four steps from 2-nitrocinnamic acids. A general synthesis of 2-alkylidene-4-imino-l,4-dihydrobenzo-l,3-thiazines 213-215 involves treatment of 2-isothiocyanato-benzonitrile with acidic methylene compounds under basic conditions <2003SL1503>. The ( )-isomers are the predominant isomers formed. 

Peptide 55 was synthesized using a segmental approach where the phosphine sulfide amino acid 50 was coupled as a dipeptide with Ala 56, and the Aib as either a dipeptide Fmoc-Ala-Aib or a tripeptide Ac-Ala-Aib-Ala. Wang, RapidAmide, or Rink resins can be used depending on the C-terminal group desired. 

The peptide was synthesized on Rink resin (0.2 mmol) using Pfp activated ester of the Fmoc-protected amino acids. All couplings were complete after 2 h. After acetylation, the peptide was cleaved by a 2 min treatment with a 50% TFA soln in CH2C12. After filtration, the TFA soln was concentrated by a stream of N2 to 1-2 mL and the crude peptide was precipitated by adding Et20 (25 mL) and cooling to —78 °C. The Et20 layer was removed and the peptide dried under vacuum. After purification by RP-HPLC pure peptide 53 was obtained yield 101 mg (36%) HRFAB-MS mlz 1408.55180 [M + H]+. 

Fmoc-EALAKA-Rink-resin (1.25 equiv) was allowed to swell in DMF (1.5 mL) for 1 h. The DMF was removed by filtration and the resin washed with additional DMF (1.5 mL). The resin was then treated with 20% piperidine/DMF (2 x 1.5 mL) for 10 min to remove the Fmoc protecting group, filtered, and washed with additional DMF (10 x 1.5 mL). A soln of the carboxylic acid prepared above, EDC (1 equiv), and HOBt (1 equiv) in DMF (1.5 mL) was added to the resin and the slurry was stirred for 1 h. The resin was filtered, washed with DMF (2 x 1.5 mL) followed by CH2Q2 (2 x 1.5 mL), and stored in vacuo overnight. 

Rink resin derived imines have been reported to give cycloaddition reactions with acetyl chlorides (or equivalent) using triethylamine as the base and dichloro-methane as the solvent at temperature ranging from 0°C to room temperature [70], The resin-bound p-lactam could be cleaved by using 50% trifluoroacetic acid (TFA) in dichloromethane, to afford the /V-unsubstituted p-lactam. 

The A -unsubstituted (3-lactams are important building blocks for the synthesis of several biologically active antibiotics. However, solution phase techniques normally include acidic conditions, which are not tolerable with acid-sensitive functionalities. In an elegant approach, Banik et al. [133] developed a solid phase synthetic route to access A -unsubstituted (3-lactams directly using Rink resin as the solid support. The method for construction of (3-lactam ring was based on Staudin-ger reaction and subsequent cleavage from the solid support was done with TFA in dichloromethane (Scheme 30). 

Scheme 30 Synthesis of iV-unsubstituted P-lactam using Rink resin...

Fig. 3. Capturing symmetrically functionalized pyrimidine on Rink resin for subsequent derivatization. (i) DIPEA, nBirjNBr, DMF, 90° ... 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

Extensive use of Pd-catalyzed reactions was included in the synthesis of 2,6,8-trisubstituted purines (Fig. II).33 The synthesis started by anchoring dichloropurine to Rink resin via N9 linkage. Polymer-bound 2,6-dichloropurine (63) was selectively substituted at C6 via acid-catalyzed SNAr substitutions. In the absence of Pd catalysis, the substitution on C2 could be performed only with strongly nucleophilic amines. To expand the scope of C2 substitution, catalytic amounts of Pd were used. Under these reaction conditions arylboronic acids and amines successfully substituted the chloro atom on C2 to afford C2-C and C2-N bonds. Subsequently, the C8 position was brominated with a bromine-lutidine complex33 (66) to give resin 67. 

General Procedure for the Synthesis of Rink Resin-Bound 6-Chloro-2-methane sulfenyl pyrimidine (9) (Fig. 3)12... 

Analogously, the reaction between phenylglyoxal, isobutylamine, n-butyl isocyanide, and benzoic acid afforded 3-oxo-3-phenylpropanoic amide 85 which was cy-clized to diphenylimidazol-5-carboxamide 86 in very high yield (Scheme 2.31) [60], The procedure was extended to solid-phase synthesis by employing resin-bound isocyanides. Wang resin was preferred to Rink resin because of its stability. The reaction of the resin-bound isocyanides 87 with supporting Ugi reagents afforded the... 

This palladium-catalyzed three-component coupling reaction leading to the formation of aryl-substituted allylic amines was recently adapted to solid-phase synthesis (Scheme 8.23). Amines were chosen to attach to a solid support (Rink resin) in this three-component coupling process and were reacted with a variety of aryl halides and linear or cyclic non-conjugated dienes, the reaction being carried out at 100 °C for two days in the presence of palladium acetate and diisopropylethyl-amine. A wide variety of aryl-substituted allylic amines were then obtained after cleavage from the solid support by trifluoroacetic acid [60],... 

Note that in the preparation of the above, Rink resin acts as an immobilized ammonia equivalent (RNH2 = Rink amine) and generally gives higher purity products than its solution-phase ammonia counterpart [58]. The cinnamic acid is originally masked as a t-butyl ester in the condensation, only to be subsequently released after TFA treatment. 

The Rink resin 8, with an electron-rich benzhydryl moiety, is particularly useful for attachment of a variety of functionality, for example primary amines [28] (Scheme 6.1.2). Loading of the amine can be achieved via the corresponding chloride or triflate. 

Scheme 6.1.2. The Rink resin as a linker for primary amines.

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