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POLYMER-BOUND N-METHYLAZIRIDINES : VERSATILE CORE RESINS FOR SOLID-PHASE SYNTHESIS AND COMBINATORIAL CHEMISTRY
K. Sandhya and B. Ravindranath
Bharavi Laboratories, Bangalore 560062, India
Aziridines are often the reactive intermediates when there is a good leaving group beta to an amino function. The aziridines react with a variety of compounds to yield ring-opened or ring-expanded compounds (see latter). Though aziridines are expected to be formed by reaction of primary amines with 1,2-dihaloethanes, in practice, the aminoethane polymers are the more likely products (Scheme 1). However, when the amine is bound to a polymer (as in aminomethyl polystyrene or aminopolystyrene), N-methyl (N-benzyl) or N-arylaziridines are conveniently obtained. Thus, when aminomethyl polystyrene (cross-linked with 1 or 2% divinylbenzene) was reacted with 1,2-dibromoethane in the presence of 2 equiv. of triethylamine, polymer-bound N-methyl (or N-benzyl) aziridine was formed, as shown by the disappearance of the N-H bands in IR and the absence of any bromine in Volhardt estimation. It, however, formed addition compounds with acids like p-toluenesulfonic acid or perchloric acid.
The polymer-bound N-methylaziridine (or N-benzylaziridine) thus obtained can react with a variety of compounds to give a wide range of products (Scheme 2). For example, its reaction with carbon dioxide and carbon disulfide gives benzyl oxazolidinone and benzyl thiazolidinethione. Azirdinium salts react with carbonyl compounds to give oxazolidinium salts. Reaction of N-substituted azirdines with isocyanates yield imidazolidinones. Reaction with epoxides can lead to N-methylmorpholine derivatives.
Reaction of aminomethyl polymer with appropriately substituted 1,2-dihaloethanes can generate scaffolds of substituted aziridines, which can lead to beta substituted amines, if the alpha carbon atom to the N bears an electron-releasing group (as in Wang, Rink, MBHA, etc.).
As part of our program to develop novel, well-defined PEG-grafted resins for use in combinatorial synthesis, we explored the use of the N-methylaziridine on a polystyrene-divinylbenzene resin. The polymer-bound N-methylaziridine, derived from aminomethyl PS-DVB resin of loading 1-3 mmol/g was reacted with commercially available polyethylene glycol monomethyl ethers of mol. Wt. 350, 550, 750 and 2000 for grafting the PEG of appropriate length to the resin. This reaction not only conveniently grafts the PEG to the resin but also generates a reative secondary amine function that can be acylated by a variety of linkers yielding products of value in solid-phase synthesis. Scheme shows a few of the popular linkers, like HMPA, Rink/Knorr and Bayer/trityl). The choice of the N loading on the aminomethyl resin and the MW of the PEG-monnomethyl ether determine the loading of both the PEG and the linker, allowing modulation of the properties.
While the possibilities are endless, we used aminomethyl PS-DVB of N loading of 2.5 mmol/g to yield the desired high-loaded N-methylaziridine resin which was grafted with MeO-PEG-OH (MW 550). This PEG-grafted resin was then reacted with Fmoc-Rink linker-HOBt anhydride (produced by the use of DCCI as the condensing agent; condensing agents like HBTU can also be used). The product thus obtained (Scheme 4), which we call Bharavi Resin PEG-RK had the specifications shown. The swelling properties of the product are given below along with the published values for Tentagel OH and Tentagel NH2. As can be seen from the Table, the Bharavi resins had swelling properties comparable to those of Tentagel resins.
Swelling Properties (ml/g):
Solvent-TentagelOH*
-TentagelNH2*
-Bharavi PEG
-Bharavi PEG-Rink
DCM-5.8-5.5-6.6-4.4
MeOH-3.8-3.0-6.4-4.0
Water-3.8-3.0-4.0-3.6
THF-4.5-3.9-4.4-3.6
DMF-4.5-4.0-5.2-4.0
*Gooding et al., J. Comb. Chem., 1999, 1, 113
CONCLUSIONS:
1. N-Methylaziridine resins are obtainable by treatment of a polymer-bound amine with CH2Br2.
2. The aziridine resin can be opened by MeO-PEG-OH to yield PEG-grafted resin of predetermined length.
3. The amino function of the PEG-grafted resin can be acylated with a linker to yield SPS resins with desirable swelling properties.
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