Solid-Supported ReagentsSave Time and Achieve Higher Purities

2 Solid-Supported Reagents | © Biotage 2014

Solid-Supported Reagents and Scavengers

Solid-Supported ReagentsSolid-supported reagents, also known as polymer-bound or resin-bound reagents, are functionalized polymers that perform synthetic transformations in the same manner as their non-bound counterparts. They can be used as reactants in solution-phase or as supports for solid-phase organic synthesis (SPOS). In solution-phase chemistry, spent reagents are simply filtered off leaving the desired product in solution. In SPOS, on the other hand, the product is isolated by filtration leaving spent reagents in solution. In either case, product isolation is expedited through simply filtering or decanting, in some cases negating the need to further purify the product.

Biotage offers a wide range of supported reagents including reducing agents, oxidants, acids, bases and even catalysts anchored to solid supports.

ScavengersUnlike solution-phase chemistry, polymer-bound reagents and scavengers can be added together into reactions.Multiple resins can be used together in a single pot as even incompatible functional groups will not interact when bound to a solid support.

Figure 1. Solid-supported reagents simplify product purification, because spent and excess reagents can be removed by filtration.

Figure 2. Example of polymer-assisted organic synthesis. The solid-supported triphenylphosphine is converted to the triphenylphosphine oxide during transformation of the azide to the amine in the Staudinger reaction.

Accelerate a wide range of solution-phase reactions and work-ups with Biotage's scavenger resins and solid-supported reagents. Solid-supported reagents allow chemists to rapidly separate mixture components by simple filtering or decanting, often eliminating the need for liquid-liquid extraction, chromatography, or crystallization. In addition, Biotage's supported reagents provide unique benefits, such as selectivity and immobilization of toxic intermediates.

Figure 3. Classic synthesis and purification of N-substituted pyrazolines using multiple scavenger resins. Following synthesis a purification cocktail containing multiple scavenger resins was used to remove unreacted pyrazoline and electrophile.Reaction conditions: (1) R3COCl, PS-DIEA, (2) R3NCO, (3) R3SO2Cl, PS-DIEA, (4) R3OCOCl, PS-DIEAPurification cocktail: PS-Trisamine and PS-Isocyanate

Bauer, U. et al. Tetrahedron Lett. 2000, 41, 2713-2717

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Solvent Compatibility/Microwave Chemistry

Solvent Compatibility Lightly cross-linked polystyrene resins require the use of solvents that swell the resin to allow reagents to gain access to the resin-bound functional groups. If the reaction solvent does not swell the resin, it may be necessary to add a co-solvent that is compatible with the resin. In this brochure, lightly cross-linked polystyrene resins have a “PS-” prefix.

More highly cross-linked macroporous resins have a permanent pore network and do not require the use of a swelling solvent. These resins are effective in any solvent that is not reactive with the resin open functionality. In addition, macroporous resins do not swell or undergo a significant volume change in contrast to their polystyrene counterparts.In this brochure, the names of macroporous resins have a “MP-” prefix.

Microwave Chemistry and Solid-Supported ReagentsCombining microwave-assisted organic synthesis (MAOS) with solid-supported reagents and scavengers can further impact the discovery process by decreasing reaction times while still taking advantage of an expedited work-up. A variety of transformations can be accelerated using microwave energy including substitutions, additions and organometallic reactions.

In addition to speeding up reactions, microwave heating may also enable the use of solvents that are traditionally considered “non-swelling” solvents in relation to low cross-linked PS-resins.

Synthesized Product Base Solvent or AcidTime (Conventional Heating)

Yield (Conventional Heating)

Time (Microwave Heating)

Yield (Microwave Heating)

Enol ketone 3 NaH, DME 2 h 60% 10 min 95%Pyrazole 5 pTsOH 7 h 95% 5 min 61%Pyrazole 5 Si-TsOH 6 h 84% 5 min 95%

Table 4. Effect of microwave heating on reaction time and yield. Microwave heating was performed at 160 °C and conventional, non-microwave heating was performed at 100 °C.

Figure 4. Synthesis of a 1,5-diarylpyrazole. Reference: Humphries, P.S. and Finefield, J.M. Tetrahedron Lett. 2006, 47, 2443-2446, Biotage® Technical Note TN0016.0406.

4 Solid-Supported Reagents | © Biotage 2014

Scavengers for ElectrophilesWhich Compounds to Scavenge?

RecommendedScavengers

Carbonyls PS-TsNHNH2

PS-TrisamineMP-Trisamine

Si-Tosyl HydrazineSi-Triamine

Si-TrisamineAlkylating agents:Alkyl halides, Mesylates, Tosylates, α-bromoesters, α-bromoketones

PS-ThiophenolPS-Triphenylphosphine

Si-Thiol

Acid chlorides PS-TrisamineMP-Trisamine

PS-NH2

Si-Tosyl HydrazineSi-Triamine

Si-TrisamineSulfonyl chlorides PS-Trisamine

MP-TrisaminePS-DMAP

PS-NH2

PS-TsNHNH2

Si-Tosyl HydrazineSi-Triamine

Si-TrisamineIsocyanates PS-Triamine

MP-TrisaminePS-NH2

Si-Tosyl HydrazineSi-Triamine

Si-TrisamineEpoxides PS-Thiophenol

Si-ThiolOxophilic inorganic, organometallic complexes Lewis acids, e.g., Ti(IV), Sn(IV)

PS-DEAM

Pd(II), Pd(O), Pt, Cu MP-TMTPS-TBDSi-Thiol

Si-TrisamineSi-Triamine

Table 2. Scavengers for electrophiles.

Scavengers for NucleophilesWhich Compounds to Scavenge?

RecommendedScavengers

Alcohols PS-TsCl(HL)Amines:primary/secondary

PS-IsocyanateMP-Isocyanate

MP-TsOH(65)PS-TsCl(HL)

Si-TsOH (SCX-3)Si-Propylsulfonic Acid (SCX-2)

Amines:Selective for primary

PS-Benzaldehyde

Amines:Anilines (Aromatic)

PS-TsCl(HL)MP-TsOH(65)

PS-IsocyanateMP-Isocyanate

Si-Propylsulfonic Acid (SCX-2)Hydrazines PS-Benzaldehyde

PS-TsCl(NH)Enolates PS-BenzaldehydeThiols/Thiolates PS-Isocyanate

MP-IsocyanatePS-Thiophenol

Si-ThiolAlkoxides PS-TsCl(HL)

PS-IsocyanateMP-Isocyanate

Reducing agents PS-BenzaldehydeAcids/Acidic phenols:HOBtPentafluorophenol4-NitrophenolCarboxylic acidPhenolBoronic acid

MP-CarbonatePS-TrisamineMP-TrisaminePS-TsNHNH2

Si-CarbonateSi-Tosyl Hydrazine

Si-TriamineSi-Trisamine

Table 3. Scavengers for nucleophiles.

Figure 5. PS-Trisamine is an example of an electrophilic scavenger that can be used to remove electrophiles such as acid chlorides and isocyanates.

Figure 6. PS-Isocyanate is an example of a nucleophilic scavenger that can be used to remove nucleophiles such as amines and alkoxides.

Scavengers for Electrophiles/Nucleophiles

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Solid-Supported Reagents

Solid-Supported ReagentsWhat Type of Reagent?What Application?

Recommended Solid-Supported Reagent

Acids and BasesBasic Quenching, Neutralize Ammonium Salts

MP-CarbonateSi-Carbonate

Acid Quenching PS-DIEAPS-DMAP

Strong Tertiary Amine Base(e.g. mesylate formation)

PS-DIEA

Tertiary Amine Base(e.g. formation of amides, sulonamides, carbamates)

PS-NMM

Strong Base(e.g. alkylation of phenols, amines, activated methylene compounds, esterification of carboxylic acids)

PS-TBD

Amine purification MP-TsOH(65)Si-Propylsulfonic acid (SCX-2)

Coupling AgentsAmide synthesis PS-Carbodiimide

PS-HOBt(HL)PS-HOBt(HL)/ACTU

PS-DIEAPS-DMAP

Activated ester formation PS-HOBt(HL)/ACTU

Protecting Group CleavageBOC cleavage Si-Propylsulfonic acid (SCX-2)

MP-TsOH(65)BSMOC, FMOC PS-Trisamine

MP-TrisamineSi-TrisamineSi-Triamine

What Type of Reagent?What Application?

Recommended Solid-Supported Reagent

Reducing AgentsCarbonyl Reduction MP-BH4

Reductive Amination MP-CNBH4

MP-BH(OAc)3

MP-BH4 (with Ti(OiPr)4)

Oxidizing AgentsAlcohols to Aldehydes PS-TEMPO

Electrophilic ActivationHalogenation (Chlorination, bromination, iodination)

PS-Triphenylphosphine

Phenylether Formation (i.e. Mitsunobu reaction)

PS-Triphenylphosphine

Thioester Active Intermediate PS-ThiophenolAlcohol Activation (tosylation) PS-TsClAcid and Sulfonyl Chloride Activation

PS-DMAP

Nucleophilic ActivationCarbon-Carbon Bond(e.g. Wittig reaction)

PS-Triphenylphosphine

Sulfonyl Hydrazone Formation (e.g. Hurd-Mori thiadiazole synthesis)

PS-TSNHNH2

Si-Tosyl-Hydrazine

CatalystsAcids MP-TsOH(65)

Si-Propylsulfonic acid (SCX-2)Acyl Transfer PS-DMAP

C-C Coupling PS-PPh3-Pd

Table 4. Solid-supported reagents.

Figure 7. Examples of synthetic transformations using solid-bound triphenylphosphine. Figure 8. Strong cation exchange resin, Si-supported propylsulfonic acid.

6 Solid-Supported Reagents | © Biotage 2014

Ordering InformationPart Number Description Size800509 PS-HOBt (HL) 3 g800417 PS-HOBt (HL) 10 g800418 PS-HOBt (HL) 25 g800419 PS-HOBt (HL) 100 g800420 PS-HOBt (HL) 1,000 g800496 PS-NMM 3 g800282 PS-NMM 10 g800283 PS-NMM 25 g800284 PS-NMM 100 g800318 PS-NMM 1,000 g800473 PS-PPh3-Pd 1 g800474 PS-PPh3-Pd 10 g800475 PS-PPh3-Pd 25 g800476 PS-PPh3-Pd 100 g800513 PS-TBD 3 g800421 PS-TBD 10 g800422 PS-TBD 25 g800423 PS-TBD 100 g800424 PS-TBD 1,000 g800517 MP-Triacetoxyborohydride 3 g800413 MP-Triacetoxyborohydride 10 g800414 MP-Triacetoxyborohydride 25 g800415 MP-Triacetoxyborohydride 100 g800416 MP-Triacetoxyborohydride 1,000 g800510 PS-Triphenylphosphine 3 g800378 PS-Triphenylphosphine 10 g800379 PS-Triphenylphosphine 25 g800380 PS-Triphenylphosphine 100 g800381 PS-Triphenylphosphine 1,000 g800516 ACTU 3 g800465 ACTU 10 g800466 ACTU 25 g800467 ACTU 100 g800468 ACTU 1,000 g800512 MP-Borohydride 3 g800401 MP-Borohydride 10 g800402 MP-Borohydride 25 g800403 MP-Borohydride 100 g800404 MP-Borohydride 1,000 g800508 PS-Carbodiimide 3 g800369 PS-Carbodiimide 10 g800370 PS-Carbodiimide 25 g800371 PS-Carbodiimide 100 g800372 PS-Carbodiimide 1,000 g800493 MP-Carbonate 3 g800267 MP-Carbonate 10 g800268 MP-Carbonate 25 g800269 MP-Carbonate 100 g800314 MP-Carbonate 1,000 g800491 PS-NH2 3 g800263 PS-NH2 10 g800264 PS-NH2 25 g800265 PS-NH2 100 g800307 PS-NH2 1,000 g

Ordering Information

Part Number Description Size800511 MP-Cyanoborohydride 3 g800405 MP-Cyanoborohydride 10 g800406 MP-Cyanoborohydride 25 g800407 MP-Cyanoborohydride 100 g800408 MP-Cyanoborohydride 1,000 g800494 PS-DIEA 3 g800279 PS-DIEA 10 g800280 PS-DIEA 25 g800281 PS-DIEA 100 g800312 PS-DIEA 1,000 g800492 PS-DMAP 3 g800288 PS-DMAP 10 g800289 PS-DMAP 25 g800290 PS-DMAP 100 g800313 PS-DMAP 1,000 g800228 PS-Trisamine 10 g800229 PS-Trisamine 25 g800230 PS-Trisamine 100 g800309 PS-Trisamine 1,000 g800495 PS-Isocyanate 3 g800260 PS-Isocyanate 10 g800261 PS-Isocyanate 25 g800262 PS-Isocyanate 100 g800311 PS-Isocyanate 1,000 g800270 PS-Ts-NHNH2 10 g800271 PS-Ts-NHNH2 25 g800272 PS-Ts-NHNH2 100 g800317 PS-Ts-NHNH2 1,000 g800273 PS-Thiophenol 10 g800274 PS-Thiophenol 25 g800360 PS-Benzaldehyde 10 g800361 PS-Benzaldehyde 25 g800362 PS-Benzaldehyde 100 g800363 PS-Benzaldehyde 1,000 g800364 PS-TsCL(HL) 10 g800365 PS-TsCL(HL) 25 g800366 PS-TsCL(HL) 100 g800367 PS-TsCL(HL) 1,000 g800430 PS-DEAM 10 g800431 PS-DEAM 25 g800432 PS-DEAM 100 g800461 MP-TsOH 10 g800462 MP-TsOH 25 g800463 MP-TsOH 100 g800464 MP-TsOH 1,000 g800478 MP-TsOH(65) 10 g800479 MP-TsOH(65) 25 g800480 MP-TsOH(65) 100 g800481 MP-TsOH(65) 1,000 g9491-0010 ISOLUTE® Si-Triamine (EC) 10 g9491-0025 ISOLUTE® Si-Triamine (EC) 25 g9491-0100 ISOLUTE® Si-Triamine (EC) 100 g9491-0500 ISOLUTE® Si-Triamine (EC) 500 g9491-1000 ISOLUTE® Si-Triamine (EC) 1,000 g

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Ordering Information

Solvent Compatibility of Polystyrene Resins

Solvent Type Swelling Solvents Non-Swelling Solvents

Hydrocarbon Toluene, xylene HexaneChlorinated DCM, dichloromethane,

chlorobenzeneEther Tetrahydrofuran (THF),

dioxane, diglymeEthyl ether

Ketone Cyclohexanone AcetonePolar aprotic DMF, dimethylsulfoxide

(DMSO), N-methylpyrolidone (NMP)

ACN

Protic Ethoxyethanol MeOH, EtOH, isopropanol, water

Table 5. Solvent compatibility of polystyrene resins. Lightly cross-linked polystyrene (”PS-”) resins need to be used in solvents that swell the resin beads.

Mesh Size to Microns Converter TableMesh Micron20 85025 71035 50050 30060 25070 212100 150140 106200 75325 45400 38

Table 6. A table which converts the mesh sizes for resin beads to their average diameter in microns.

Appendix

AbbreviationsACN acetonitrile

DBAD ditertbutylazodicarboxylateDCE 1,2 dichloroethaneDCM dichloromethaneDEAD diethylazodicarboxylateDES diethylsilaneDEAM diethanolamineDIC diisopropylcarbodiimideDIEA diisopropylethylamineDMA dimethylacetamideDMAP dimethylaminopyridineDMF dimethylformamideEtOH ethanol

HOAc acetic acidHOBt N-hydroxybenzotriaoleMeOH methanolMP macroporousNMM N-methyl morpholinePy pyridinePS PolystyreneTBD 1,5,7-triazabicyclo[4.4.0]dec-5-eneTHF tetrahydrofuranTS-Cl toluenesulfonyl chlorideTs-OH toluenesulfonic acid

Part Number Description Size801505 MP-Trisamine 3 g801397 MP-Trisamine 10 g801398 MP-Trisamine 25 g801399 MP-Trisamine 100 g801400 MP-Trisamine 1,000 g9495-0010 ISOLUTE® Si-Trisamine (EC) 10 g9495-0025 ISOLUTE® Si-Trisamine (EC) 25 g9495-0100 ISOLUTE® Si-Trisamine (EC) 100 g9495-0500 ISOLUTE® Si-Trisamine (EC) 500 g9495-1000 ISOLUTE® Si-Trisamine (EC) 1,000 g

Part Number Description Size9536-0025 Si-Propylsulfonic Acid (SCX-2) 25 g9536-0100 Si-Propylsulfonic Acid (SCX-2) 100 g9180-0010 ISOLUTE® SI-Thiol 10 g9180-0025 ISOLUTE® SI-Thiol 25 g9180-0100 ISOLUTE® SI-Thiol 100 g9180-0500 ISOLUTE® SI-Thiol 500 g9180-1000 ISOLUTE® SI-Thiol 1,000 g9180-5000 ISOLUTE® SI-Thiol 5,000 g9180-10000 ISOLUTE® SI-Thiol 10,000 g

© Biotage 2014

Solid-Supported Reagents | Page 8

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