Polymer-Supported Hydroxide1

(the reagent is used as a base, a source of nucleophilic hydroxide, or a scavenger in a wide array of reactions1)

Alternate Name: quaternary ammonium hydroxide anion exchange resin, Amberlite IRA-400 (OH- form), Amberlite IRA 420 (OH- form), Amberlite IRA 410 (OH- form), Amberlite IRN-150, Amberlite IRA 900 (OH- form), Amberlite IRA 904 (OH- form), Amberlite IRA 910 (OH- form), Amberlite A5836, Amberlyst A26 (OH- form), Ambersep 900, Dowex-1 (OH- form), Dowex-3 (OH- form), Dowex 1-X4 (OH- form), Dowex 1-I 9880, Dowex 1-I0131, Dowex 550 A (OH- form), Amberjet 4400.

Form Supplied in: available on a variety of polystyrene-divinylbenzene cross-linked supports of both macroreticular and gel-type ion exchange resins. The reagent can be obtained with a range of basicities (pH) broadly characterized as weakly basic to strongly basic resins. The standard commercial form comes as large spherical beads (up to 4 mm in diameter) usually supplied with a water content of 30-60% by mass.

Purification: elute and wash with suitable solvents prior to use and dry under vacuum if required.

Handling, Storage, and Precautions: irritant; wear suitable protective clothing. Deactivates upon prolonged exposure to air by absorption of carbon dioxide. Decomposition of the tetraalkyl moiety can occur with strong acids/bases, oxidants and high temperatures.

General

Polymer-supported hydroxide has properties fully comparable to its solution phase counterparts. Some practical advantages of the polymer-supported hydroxide over the solution-phase bases is that no neutralization or separation steps are required other than simple filtration and evaporation of solvent leading to essentially pure products. The spent resin can also be easily regenerated and recycled by a simple base activation and washing sequence.3 The resin also shows a good tolerance of most polar and nonpolar organic solvents although some protic and highly acid solvents can ion exchange with the hydroxide resin (e.g. alcohols, which can form the alkoxides on support).

Hydrolysis

Polymer-supported hydroxide serves as a nucleophile in various hydrolysis reactions. Hydrolysis of esters to the constituent acids and alcohols can be carried out under aqueous or methanolic conditions at ambient temperature.4,5 Amides can also be formed from the corresponding nitriles6 and cyclic iodo carbonates are smoothly converted into epoxy alcohols with retention of stereochemistry (eq 1).7

Elimination Reactions

Dehydrochlorination can be carried out efficiently using a strongly basic polymer supported hydroxide column and this method has been used to form indolium hydroxide (eq 2).8 When an excess of base such as ammonia or triethylamine was used instead of the ion-exchange resin, a significant amount of undesired demethylation of the indolium salt was observed, forming 1-methylindole.

Condensation Reactions

The hydroxide anion-exchange resins have also been shown to be excellent catalysts in cyanohydrin formation,9 aldol,10 nitroaldol,11-14 Knoevenagel, Claisen,15 Dieckmann,16 Cannizzaro,11 and Michael condensations.17-20 Amberlite IRA-420 (OH-) has been employed as a strong polymer-supported base to effect the Henry reaction between various aldehydes and nitroalkanes (eq 3).11-14 This reaction has also been utilized in a clean five-step synthesis of an array of 1,2,3,4-tetra-substituted pyrroles where all subsequent steps used polymer-supported reagents.11 It should be noted that a large excess of the nitro compound (usually used neat) is needed for clean reactions and to prevent the Cannizzaro reaction on electron-poor aldehydes. The corresponding Henry reactions involving ketones proceed more slowly and with lower yields.13

The same Amberlite IRA-420 resin under modified conditions has been used to effect a Cannizzaro reaction of electron-poor benzaldehydes.11 In combination with a solid-supported oxidant to reoxidize the benzylic alcohols to the aldehydes, this method was used to generate quantities of benzoic acids.

Amberlite IRA-904 has been used in the dynamic resolution of cyanohydrins formed and racemized in situ by the basic anion exchange resin (eq 4).9 The lipase used in the resolution was stable to the basic resin and enantiomeric excesses of up to 91% were achieved.

Aldol reactions have also been carried out using polymer-supported hydroxide for the synthesis of a variety of heterocyclic ketols and their dehydration products with improved yields over the conventional solution phase preparation.10 The catalyzed reaction of a range of pyridinecarboxaldehydes and substituted acetophenones in ethanol furnished the corresponding aldol or a,b-unsaturated ketones, the propensity for dehydration was shown to be a direct function of the strength of the polymer base used.

In a similar way the polymer-supported hydroxide resin Ambersep 900 (OH-) was used in the formation of a library of oxazoles via deprotonation of p-tolylsulfonylmethyl isocyanide (TosMIC) and subsequent addition to aromatic aldehydes.21 A base-induced elimination of sulfinic acid which is sequestered by the basic resin leaves after filtering a clean solution of the oxazole product (eq 5).

In library generation, purification by removal of impurities can be a tedious process, Beemashakar et al. have shown the advantage of using the hydroxide resin as both a reagent and purification aid in the combinatorial synthesis of 2,4-pyrrolidinediones.22 In this synthesis, the hydroxide resin acts both as a base for the Dieckmann reaction and as product-sequestering agents in a ‘catch-and-release’ purification; the product remains tightly bound to the resin, enabling impurities to be removed by simple filtration and subsequent acidification releases the product into solution (eq 6).

Alkylation Reactions

In the presence of a hydroxide resin, phenols can be converted to the corresponding ethers and acids to ester using alkyl halides or dialkyl sulfates; in this case any unreacted phenol or acid becomes bound to the basic resin aiding purification.23-27 This protocol serves as a very facile method for carrying out O-alkylation of phenoxides with various alkyl halides. In these reactions, primary halides give higher yields than secondary, and bromides consistently give improved yields over chlorides.25,26

Shimo and Wakamatsu3 and Gelbard27 have reported the alkylation of various active methylene group-containing compounds like ethyl malonate, cyanoacetic esters and cyanoacetamides with various alkyl halides in the presence of Amberlite IRA-400 and IRA-900 (OH-).28 Another interesting example is the intramolecular alkylation leading to ring closure and formation of b- and g-lactams as demonstrated by Chatterjee et al. (eq 7).29

In a related process, Domann et al. have recently employed the polymeric resin Amberlyst A26 in the formation of epoxysilanes from vinyl silanes in a one-pot process (eq 8).30 Starting from the vinylsilanes, the polymer-bound haloate(I) reagent generated the 1,2-cohalogenated product which under basic conditions was transformed to the corresponding epoxysilane in good yield and high purity.

Horner-Wittig Reactions

Amberlyst A26 (OH- form) has found use in the activation of stabilized phosphonates bearing a-nitrile or ester functionality for the olefination of carbonyl compounds (eq 9).31 The reactions described gave good yields, although the E/Z ratio was not as high as would be expected under normal solution-phase conditions. It was however noted that the process was independent of the solvent used, with the resin providing a microenvironment making the reaction independent of the external medium (i.e. a greater range of solvents could be employed).

Scavenging

The hydroxide resins have also been employed as purification aids, for example, in the preparation of a library of azo-dyes which were subjected to a ‘catch-and-release’ work-up which involved shaking the colored solution with Dowex(OH).32 This procedure captured only the product leaving a colorless solution after filtration. The isolated resin was subsequently washed with acetic acid to release pure product. Amberlite IRA-420 has also been used as a scavenger to remove unreacted 2-aminothiophenol.33 The polymer-supported hydroxide has also been employed extensively for the removal of acids and phenols and in a more conventional role for liberating the free base from protonated salts.

Related Reagents.

Quaternary tetraalkylammonium hydroxide has also been grafted onto other supports such as silica and MCM-41.2


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Steven V. Ley, Ian R Baxendale & Ai-Lan Lee

University of Cambridge, Cambridge, UK



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