Polymer-bound ester

One widely used method of formation of protected compounds involves polymer-supported reagents, with the advantage of simple workup by filtration and automated syntheses, especially of polypeptides. Polymer-supported reagents are used to protect a terminal — COOH group as a polymer-bound ester (RCOOR —( ) during peptide syntheses, to protect primary alcohols as... 

Tosylate is displaced by weak oxyanions with little elimination in aprotic solvents, providing alternative routes to polymer-bound esters and aryl ethers. Alkoxides, unfortunately, give significant functional yields of (vinyl)polystyrene under the same conditions. Phosphines and sulfides can also be prepared from the appropriate anions (57), the latter lipophilic enough for phase-transfer catalysis free from poisonning by released tosylate. 

As a suitable model reaction, the coupling of various substituted carboxylic acids to polymer resins has been investigated by Stadler and Kappe (Scheme 7.8) [28]. The resulting polymer-bound esters served as useful building blocks in a variety of further solid-phase transformations. In a preliminary experiment, benzoic acid was attached to Merrifield resin under microwave conditions within 5 min (Scheme 7.8 a). This functionalization was additionally used to determine the effect of micro-wave irradiation on the cleavage of substrates from polymer supports (see Section 7.1.10). The benzoic acid was quantitatively coupled within 5 min via its cesium salt utilizing standard glassware under atmospheric reflux conditions at 200 °C. 

In addition to the aforementioned microwave-assisted reactions on solid supports, several publications also describe microwave-assisted resin cleavage. In this context it has been demonstrated that carboxylic acids could be cleaved from conventional Merrifield resin, using the standard TFA-DCM 1 1 mixture, by exposure of the polymer-bound ester and the cleavage reagent to microwave irradiation in a dedicated Teflon autoclave (multimode instrument). After 30 min at 120 °C, complete recovery of the carboxylic acid was achieved (Scheme 12.9) [26]. At room temperature, however, virtually no cleavage was detected after 2 h in 1 1 TFA-DCM. 

As a suitable model reaction, the coupling of various substituted carboxylic acids to polymer supports has been investigated (Scheme 7.7)27. The resulting polymer-bound esters served as useful building blocks in a variety of further solid-phase transformations. In a preliminary experiment, benzoic acid was attached to Merrifield resin under... 

In a more recent study, Westman and Lundin described the solid-phase synthesis of aminopropenones and aminopropenoates, respectively30 as intermediates for heterocyclic synthesis. Two different three-step methods for the preparation of heterocycles have been developed. The first method involved formation of a polymer-bound ester from a IV-protected glycine derivative and Merrifield resin (Scheme 7.10a), while the second method employed an interesting approach utilising simple aqueous methy-lamine solution for functionalisation of the solid support (Scheme 7.10b). In this latter approach, a variety of hetero cycles were readily synthesised from the generated polymer-bound benzylamine using a two-step protocol (see Section 5.3.3). 

The idea that a polymer support could help to isolate polymer-bound reactive species from one another was suggested and illustrated sh y after the flrst solid phase peptide syntheses. Cyclic tetrapeptides were obtained in higher yields from polymer-bound 2-nitrophenyl esters than from analogous micromolecular active esters (Scheme 1) (X). Polymer-bound ester enolates were formed at 0 °C and trapped with alkyl bromides and carboxylic acid chlorides with no competing selfcondensation (Scheme 2) (Z). Soluble analogs gave primarily self-condensation. 

Effect of Degree of Esterification on Yields of p-Nitrobenzoylation of a Polymer-Bound Ester... 

C-Acylation with a polymer-bound ester in the presence of polymer-based trityllithium has been demonstrated as example of efficient multi-polymer reactions A novel degradation of peptides from the carboxyl end through the acid azide is performed on a controlled-pore glass support ... 

The protective group is removed by mildly alkaline conditions that do not cleave methyl or benzyl esters. The group is stable to CF3COOH, HCl-AcOH, and HBr-AcOH. A polymer-bound version of this group has also been developed. ... 

One year later, Tietze and co-workers (97BMC1303) presented a general and straightforward method for the synthesis of diverse polymer-bound -keto esters starting from acid chlorides and Meldrum s acid. One such resin-bound y3-keto ester, 43, was treated with hydrazine hydrate in THF to afford resin-ffee N-2-unsubstituted pyrazolone 44 in 84% yield (Scheme 13). In the same paper, the synthesis of a large number of 4,5-disubstituted 2-phenyl-2,4-dihydro-37/-pyrazol-3-ones was reported. 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

The protocol offers a direct and efficient method for the synthesis of the boronic ester in the solid phase, which hitherto met with little success using classical methodology (Scheme 1-42). A solid-phase boronate (113 [155], 114 [156]) is quantitatively obtained by treating a polymer-bound iodoarene with the diboron (82). The subsequent coupling with haloarenes furnishes various biaryls. The robot synthesis or the parallel synthesis on the surface of resin is the topic of further accounts of the research. 

In the context of the synthesis of polymer-bound antiphlogistic drugs, a polymeric carboxylic acid was converted into the polyimidazolide, to which pharmaceutical agents were attached in the form of their amino esters [1571... 

The reaction of a polymer-bound imidazole-iV-carboxylate with a Grignard reagent leads to an ester [93]... 

Ally] esters (R2 = CH2C(R3)=CH2) could be transformed to the corresponding 3-allyltetronic acids by maintaining microwave irradiation at 120 °C for 60 min [59]. However, cleavage of the tetronic acids under the above mentioned conditions remained somewhat troublesome. To obtain satisfactory amounts of product, the polymer-bound intermediates had to be protected at the 04 position so that cleavage could be accomplished with a mixture of trifluoroacetic acid/dichloromethane (1 9) (Scheme 7.44). 

Additionally, the authors chose 3-chloropropionyl chloride as the immobilized building block in order to carry out a ring-expansion approach, which led to the generation of a 14-member library of thioxotetrahydropyrimidinones [85, 86], The initially prepared polymer-bound chloropropionyl ester was efficiently transformed into the corresponding diamines by transamination utilizing several primary amines. These diamine intermediates could also be obtained by treatment of the pure polymeric support with acryloyl chloride and subsequent addition of the appropriate amines (Scheme 7.74). 

Polymer-bound 1-hydroxybenzotriazole 1008 reacts with carboxylic acids in the presence of 1,3-diisopropylcarbo-diimide (1,3-DIC) and DMAP to produce esters 1009. Treated with hydroxylamine, esters 1009 are converted to hydroxamic acids 1010 (Scheme 167) <20030BC850>. Starting 1-hydroxybenzotriazole 1008 is recycled in the process and can be used for other syntheses. This method is well suited for automated synthesis of a library of hydroxamic acids. In similar applications of polymer-supported 1-hydroxybenzotriazole 1008, a wide variety of amides is synthesized <1997JOC2594, 2002JC0576>. 

Additionally, it has been shown that novel benzylidene titanium complexes of type 74 react with polymer-bound carboxylic esters to form the corresponding enol ethers (Scheme 28).79... 

The first published report on the use of this catalyst for the cross-metathesis of functionalised acyclic alkenes was by Blechert and co-workers towards the end of 1996 [37]. This report was also noteworthy for its use of polymer-bound alkenes in the cross-metathesis reaction. Tritylpolystyrene-bound AT-Boc N-al-lylglycinol 18 was successfully cross-metathesised with both unfunctionalised alkenes and unsaturated esters (Eq. 17) (Table 1). 

It is noticeable that cross-metathesis with the unfunctionalised alkenes occurred in significantly higher yields over shorter reaction times and required a smaller excess of the soluble alkene. This was possibly due to the unfunctionalised alkenes, which are more nucleophilic than their ester containing counterparts, complementing the less nucleophilic/more carbon-metal bond stabilising allylglycinol 18. Comparable results were obtained from cross-metathesis reactions of the polymer-bound isomeric N-Boc C-allylglycinol with the same four alkenes. 

Scheme 3. Proposed mechanism for the protodesilylation of the polymer-bound metathesis products formed from allyl ethers or esters...

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