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. Author manuscript; available in PMC: 2007 Jun 21.
Published in final edited form as: Org Lett. 2003 Apr 3;5(7):1015–1017. doi: 10.1021/ol0274864

FluoMar™, a Fluorous Version of the Marshall Resin for Solution-Phase Library Synthesis

Christine Hiu-Tung Chen 1, Wei Zhang 1
PMCID: PMC1894904  NIHMSID: NIHMS20296  PMID: 12659562

Abstract

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The fluorous counterpart of the Marshall resin, 4-(1H,1H,2H,2H-perfluorodecylsulfanyl)phenol (FluoMar™) is prepared by S-alkylation of 4-mercaptophenol with C8F17CH2CH2I and employed in the synthesis of amide and diamide analogs. The final products are purified by solid-phase extraction (SPE) over FluoroFlash™ silica cartridges.

Resin-based solid-phase organic synthesis (SPOS) is popular in drug discovery.1 Its advantage of easy separation, however, is usually counterbalanced by the time-consuming method development, the limitation of reaction scope, and the difficulty of analysis and purification of attached intermediates. Recently Curran and coworkers developed a fluorous tag strategy to overcome some disadvantages associated with the SPOS.2 Functionalized perfluoroalkyl groups instead of polymer supports are employed as the “phase tags”.2b,3 The separation of fluorous-tagged molecules is carried out over fluorous silica gel based on the strong and selective fluorine-fluorine interaction.4

The Marshall resin 1 has been widely used as a carbonate and carbamate linker in solid-phase syntheses.5 The linker can be cleaved with primary and secondary amines to afford the corresponding amides either directly or after oxidation of the sulfide to the sulfone.6 Described in this paper is the synthesis of fluorous version of Marshall resin, perfluoroalkylsulfanylphenol 2 (FluoMar™). The utility of this compound is illustrated by the solution-phase synthesis of amides and diamides.

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The FluoMar™ 2 was readily prepared by S-alkylation of 4-mercaptophenol with C8F17CH2CH2I and purified by flash column chromatography on normal silica gel (Scheme 1).7,8 The ethylene spacer between the C8F17 tag and the sulfur is expected to minimize the strong electron-withdrawing effect from the perfluoroalkyl group and maintain the nucleophilicity of the hydroxy group. This compound has the general features of organic molecules; it dissolves well in common solvents such as CH2Cl2, THF, and AcOEt, and can be analyzed by traditional chromatographic and spectroscopic methods.

Scheme 1.

Scheme 1

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Preparation of FluoMar™

With compound 2 in hand, we first validated the attachment to carboxylic acids 3 and the tag cleavage by the amine displacement (Scheme 2). The coupling of 2 with indole-5-carboxylic acid 3{1} (2.0 equiv) or 7-methoxy-2-benzofurancarboxylic acid 3{2} was carried out under a standard solution-phase conditions with 2.0 equiv of diisopropylcarbodiimide (DIC) and 1.0 equiv of dimethylaminopyridine (DMAP) in DMF. These intermediates were purified by regular flash column chromatography. Compounds 4{1} and 4{2} were each split to three portions and directly displaced with three primary amines 5{1-3} without oxidation of the sulfur to give the corresponding amides 6{1-2,1-3}. After a quick acidic workup with 1.0 N HCl to remove the unreacted amine,9 the crude product was loaded onto a FluoroFlash™ cartridge and the MeOH/H2O fraction was collected to give analytically pure product. The FluoMar™ tag 2 was recovered in the MeOH fraction in 65–70% yield.

Scheme 2.

Scheme 2

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Synthesis of 2x3 array of amides 6{R1,R2}

Encouraged by the preliminary results, we next explored the use of FluoMar™ 2 in a multi-step parallel synthesis of diamides (Scheme 3). The N-Boc isonipecotic acid 7 was coupled with 2 followed by deprotection with TFA and N-acylation with three different acid halides. The resulting compounds 9{1-3} were each split into three portions and displaced by three amines resulting in a demonstration library of diamides 10{1-3,1-3}.11 The final products were purified by SPE and cleaved FluoMar™ 2 was recovered in an average yield of 65%. Figure 1 shows a typical 1H NMR trace of the products prior and after SPE; the crude mixture containing 10{1,2} and cleaved tag 2 (top trace of Figure 1), the MeOH/H2O fraction containing 10{1,2} (middle trace of Figure 1), and the MeOH fraction containing recovered FluoMar 2 (bottom trace of Figure 1).

Scheme 3.

Scheme 3

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Synthesis of 3x3 array of diamides 10{R1,R2}

Figure 1.

Figure 1

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1H NMR spectra of product 10{1,2} and recovered 2

We also carried out a simple experiment to estimate the reactivity difference between the Marshall resin 1 and FluoMar™ 2 towards a typical carboxylic acid. Equimolar amounts of 112 and 2 (1.0 equiv each) were mixed with 1.0 equiv of benzofuran carboxylic acid under a standard coupling condition used in the synthesis of amide 4 and diamides 8 (Scheme 4). The reaction was stopped after 8 h when all the acid was consumed as indicated by TLC analysis. The resin was filtered off from the reaction mixture and washed with DMF and CH2Cl2. The filtrate was analyzed by the HPLC and the ratio of product 11 to the unreacted 2 was 73:27 with the assumption that the 27% unreacted FluoMar™ 2 was due to a competitive reaction of the acid 3 with the Marshall resin. This result suggested that despite the electron withdrawing effect of the fluorous chain, fluorous tag still reacted as least 2.7 times faster than the resin.

Scheme 4.

Scheme 4

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Competitive tagging of 3 with Marshall resin 1 and FluoMar™ 2

recyclable phase tag in the solution-phase synthesis of amides and diamides. This reagent can be used as an alternative to the Marshall resin in combinatorial and parallel synthesis.

Acknowledgments

We thank Dr. John Hodges and Professor Dennis Curran for important suggestions and helpful discussions.

References

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  • 12. Purchased from Aldrich, loading 1.0–1.5 mmol/g, polystyrene with 1% cross linking with DVB. An average loading of 1.25 mmol/g was used for the calculation.

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