Microwave resin cleavage

A protocol for microwave-assisted acid-mediated resin cleavage has been presented by Stadler and Kappe [28]. Several resin-bound carboxylic acids (see Scheme 7.8) were cleaved from traditionally non-acid-sensitive Merrifield resin by... 

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. 

Scheme 12.9 Microwave-assisted cleavage of benzoic acid from Merrifield resin.

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

Figure 7.15 Structural representation of imides obtained by synthesis on solid support in solid state (microwave reaction time for imide formation and isolated yield of imide products after resin cleavage quoted).

In addition to the aforementioned microwave-assisted reactions on solid supports, several publications describe microwave-assisted resin cleavage. A variety of cleavage procedures have been investigated, depending on the nature of the linker used. In this context it was shown that several resin-bound carboxylic acids (Scheme 16.1) were cleaved from traditionally non-acid-sensitive Merrifield resin by using 50% trifluoroacetic acid in dichloromethane (Scheme 16.37). Microwave irradiation enables these cleavages to be conducted at elevated pressure and/or temperature in sealed Teflon vessels [23]. Evaporation of the filtrate to dryness furnished the recovered benzoic acid in quantitative yield and excellent purity. 

In another application of microwave-assisted resin cleavage, N-benzoylated alanine attached to 4-sulfamylbutyryl resin was cleaved (after activation of the linker with bromoacetonitrile by using Kenner s safety catch principle) with a variety of... 

The preparation of purine derivatives substituted at the C-2 position via amine displacement of a halogen is known as a difficult reaction step requiring several days of reaction time. However, Al-Obeidi and coworkers have recently prepared 2,6,9-trisubstituted purines on soUd-phase by employing a synthetic route in which the critical step was performed with microwave irradiation (Fig. 37) [62]. PS resin-bound 2-iodosubstituted purine was treated with diethanolamine or propanolamine in NMP with microwave irradiation at 200 °C for 30 min. Trifluoroacetic acid-mediated cleavage resulted in the 2-amino substituted purines in 45-59% yields and 77-89% purities. 

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 very detailed comparison for every single step of the whole sequence (linking of a pyrazinone to the solid support, Diels-Alder reaction with acetylenic dienophile and cleavage of a formed pyridinone from the resin) was made between microwave irradiation and conventional heating conditions [115]. 

Table 2 Product distribution and microwave cleavage conditions from the three different types of resins...

It has to be noted that the temperatures up to 220 °C involved in the transformations on polystyrene-based support do not affect the resin stabihty. The controlled microwave irradiation appeared to be very effective in speeding up the linking of 2(lH)-pyrazinones to an appropriate resin as well as in accelerating the rate of subsequent solid-phase Diels-Alder reaction and the following cleavage of a resulting pyridinone from the sohd support. 

It was also shown that the commercially available Wang resin is well suited for the reaction, but a tailor-made resin (based on syringealdehyde and Mer-rifield resin) offers milder cleavage conditions. By comparing conventional heating versus MAOS it was found that similar yields for the cycloaddition step were obtained, but the cleavage from the resin can be performed under much milder conditions when microwave irradiation is used, and in some cases the procedure only works using the microwave technique (Table 1). 

Table 1 Comparison between conventional heating and microwave irradiation for the cleavage of resin bound 2-pyridones under acidic conditions...

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. 

Combs and coworkers have presented a study on the solid-phase synthesis of oxa-zolidinone antimicrobials by microwave-mediated Suzuki coupling [38], A valuable oxazolidinone scaffold was coupled to Bal resin (PS-PEG resin with a 4-formyl-3,5-dimethoxyphenoxy linker) to afford the corresponding resin-bound secondary amine (Scheme 7.18). After subsequent acylation, the resulting intermediate was transformed to the corresponding biaryl compound by microwave-assisted Suzuki coupling. Cleavage with trifluoroacetic acid/dichloromethane yielded the desired target structures. 

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... 

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