Polymer-Supported Schwesinger Base


(polymer-bound strong base for acylation and alkylation reactions)

Alternate Name: P-BEMP, PS-BEMP (BEMP=2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine).

Physical Data: loading 2.3 mmol g-1 on polymer (batch dependent).

Solubility: the reagent, immobilized on 1-2% cross-linked polystyrene divinylbenzene co-polymer, is insoluble in all common organic and aqueous solvents.

Form Supplied in: brown powder, commercially available.

Analysis of Reagent Purity: the loading of the reagent is best determined by elemental analysis. The functional activity can be determined by the degree of chemical transformation from use of stoichiometric quantities of reagents.

Handling, Storage, and Precautions: harmful if inhaled or ingested; irritant. Stable at room temperature.

Phosphazene bases have been shown to be useful alternatives to ionic bases for a number of chemical transformations.1 Of these, 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) has a basicity (pKB=27.5) comparable to 5 M aqueous potassium hydroxide/Bu4N/acetonitrile and potassium carbonate/18-crown-6/acetonitrile.2 The commercially available3 polymer-supported equivalent, PS-BEMP,2 retains the basicity of the solution phase reagent and has been exploited in the alkylation and acylation of weakly nucleophilic NH-containing compounds.

Alkylation of Heterocycles

In an early paper, Xu and co-workers4 studied the N-alkylation of a number of weakly acidic NH-containing aromatic heterocycles. Indoles, pyrazoles, and phthalazinones were alkylated with a-bromo ketones or esters in the presence of PS-BEMP in acetonitrile at room temperature. Simple filtration and evaporation, after removal of excess alkylating agent with aminomethyl polystyrene, gave the required products in high chemical yield (93-98%) and high purity (93-99%). The use of more weakly basic resins resulted in no alkylation and this enabled the authors to develop a one-pot procedure for the selective dialkylation of a pyrazole (eq 1).

Similar procedures using PS-BEMP for the alkylation of purines5 and pyrroles6 and for SNAr reactions towards fluoroquinolone antibacterial agents7 have been reported.

Alkylation of Sulfonamides

The principle of orchestrated multi-step synthesis using polymer-supported reagents8 has been applied to the preparation of a series of hydroxamic acids as potential matrix metalloproteinase inhibitors.9 Alkylation of the weakly acidic sulfonamide NH with benzylic halides, a key step in the synthesis, was achieved utilizing PS-BEMP in dichloromethane. Scavenging of the excess alkylating agent with aminomethyl polystyrene followed by filtration and evaporation gave the required products in high yield and purity (eq 2).

Alkylation and Acylation of Weakly Nucleophilic Species

In an analogous way to the alkylation of heterocycles, PS-BEMP has been utilized for the derivatization of weakly nucleophilic heterocyclic amines and hydrazones. Having investigated a range of polymer-bound acyl transfer reagents, Kim and Le found PS-BEMP in THF to be a superior reagent for the acylation of amino-pyridines, -pyrazoles, -thiazoles, -benzothiazoles, and -quinolines with acid chlorides.10 Amides were produced in high purity but only in moderate yield using this chemistry. The alkylation of hydrazone 1, a key intermediate towards the polymer-supported synthesis of sildenafil,11 was achieved in excellent yield with the excess, unreacted a-bromoester being sequestered with aminomethyl polystyrene or polymer-supported trisamine (eq 3).

Application of PS-BEMP to Ring Forming Reactions

In a later stage of the same polymer-supported synthesis of sildenafil,11 PS-BEMP was employed to effect the rapid deprotonation and concomitant cyclization of substituted hydrazone 2 to a tetrasubstituted pyrazole (eq 4).

Using an orchestrated sequence of polymer-supported reagents, Ley and co-workers demonstrated the ten-step synthesis of (±)-epibatidine.12 The key step in the formation of the epibatine framework, a transannular cyclization, was mediated by PS-BEMP (eq 5). The authors found that the supported phospazene base allowed the reaction to proceed in higher yield and more rapidly than under the thermal conditions reported in a previous synthesis. Additionally, no by-products arising from intermolecular alkylation were observed. The only impurity, approximately 10% of the unreacted starting material, could be sequestered using aminomethyl polystyrene.

PS-BEMP has also been utilized in the synthesis of the bis(indole) marine alkaloid, rhopaladin D.13 The key step, formation of the central imidazolinone ring, was effected by an aza-Wittig reaction of phosphorane 3 with indolyl-3-glyoxylyl chloride in the presence of PS-BEMP. Intramolecular cyclization of the resulting imidoyl chloride gave the required rhopaladin ring system (eq 6).

1. Schwesinger, R.; Willaredt, J.; Sclemper, H.; Keller, M.; Schmitt, D.; Fritz, H., Chem. Ber. 1994, 127, 2435.
2. Schwesinger, R., Chimia 1985, 39, 269.
3. Commercially available from Fluka.
4. Xu, W.; Mohan, R.; Morrissey, M. M., Biorg. Med. Chem. Lett. 1998, 8, 1089.
5. McComas, W.; Chen, L.; Kim, K., Tetrahedron Lett. 2000, 41, 3573.
6. Caldarelli, M.; Habermann, J.; Ley, S. V., J. Chem. Soc., Perkin Trans. 1. 1999, 107.
7. Hilty, P.; Hubschwerlen, C.; Thomas, A. W., Tetrahedron Lett. 2001, 42, 1645.
8. Hinzen, B.; Ley, S. V., J. Chem. Soc., Perkin Trans. 1. 1998, 1.
9. Caldarelli, M.; Habermann, J.; Ley, S. V., Biorg. Med. Chem. Lett. 1999, 9, 2049.
10. Kim, K.; Le, K., Synlett 1999, 1957.
11. Baxendale, I. R.; Ley, S. V., Biorg. Med. Chem. Lett. 2000, 10, 1983.
12. Habermann, J.; Ley, S. V.; Scott, J. S., J. Chem. Soc., Perkin Trans. 1. 1999, 1253.
13. Fresneda, P. M.; Molina, P.; Sanz, M. A., Synlett 2001, 218.

Steven V. Ley & Jan J. Scicinski

University of Cambridge, Cambridge, UK

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.