Solid-Supported Reagents. Save Time and Achieve Higher Purities

Solid-Supported Reagents Save Time and Achieve Higher Purities

Solid-Supported Reagents and Scavengers 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. Solid-Supported Reagents Solid-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. Figure 1. Solid-supported reagents simplify product purification, because spent and excess reagents can be removed by filtration. Biotage offers a wide range of supported reagents including reducing agents, oxidants, acids, bases and even catalysts anchored to solid supports. Scavengers Unlike 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 2. Example of polymer-assisted organic synthesis. The solidsupported triphenylphosphine is converted to the triphenylphosphine oxide during transformation of the azide to the amine in the Staudinger reaction. 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) R 3 COCl, PS-DIEA, (2) R 3 NCO, (3) R 3 SO 2 Cl, PS-DIEA, (4) R 3 OCOCl, PS-DIEA Purification cocktail: and PS-Isocyanate Bauer, U. et al. Tetrahedron Lett. 2000, 41, 2713-2717 2 Solid-Supported Reagents Biotage 2014

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 crosslinked 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 Reagents Combining 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 crosslinked PS-resins. 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. Synthesized Product Base Solvent or Acid Time (Conventional Heating) Yield (Conventional Heating) Time (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% Yield (Microwave Heating) 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. 3

Scavengers for Electrophiles/Nucleophiles Scavengers for Electrophiles Scavengers for Nucleophiles Which Compounds to Scavenge? Recommended Scavengers Carbonyls PS-TsNHNH 2 Alkylating agents: Alkyl halides, Mesylates, Tosylates, α-bromoesters, α-bromoketones Acid chlorides Sulfonyl chlorides Isocyanates Epoxides Oxophilic inorganic, organometallic complexes Lewis acids, e.g., Ti(IV), Sn(IV) Pd(II), Pd(O), Pt, Cu Table 2. Scavengers for electrophiles. PS-Thiophenol PS-Triphenylphosphine Si-Thiol PS-NH 2 PS-NH 2 PS-TsNHNH 2 PS-Triamine PS-NH 2 PS-Thiophenol Si-Thiol PS-DEAM MP-TMT PS-TBD Si-Thiol Which Compounds to Scavenge? Alcohols Amines: primary/secondary Amines: Selective for primary Amines: Anilines (Aromatic) Hydrazines Enolates Thiols/Thiolates Alkoxides Reducing agents Acids/Acidic phenols: HOBt Pentafluorophenol 4-Nitrophenol Carboxylic acid Phenol Boronic acid Table 3. Scavengers for nucleophiles. Recommended Scavengers PS-TsCl(HL) PS-Isocyanate MP-Isocyanate PS-TsCl(HL) Si-TsOH (SCX-3) Si-Propylsulfonic Acid (SCX-2) PS-Benzaldehyde PS-TsCl(HL) PS-Isocyanate MP-Isocyanate Si-Propylsulfonic Acid (SCX-2) PS-Benzaldehyde PS-TsCl(NH) PS-Benzaldehyde PS-Isocyanate MP-Isocyanate PS-Thiophenol Si-Thiol PS-TsCl(HL) PS-Isocyanate MP-Isocyanate PS-Benzaldehyde MP-Carbonate PS-TsNHNH 2 Si-Carbonate Figure 5. 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. 4 Solid-Supported Reagents Biotage 2014

Solid-Supported Reagents Solid-Supported Reagents What Type of Reagent? What Application? Acids and Bases Basic Quenching, Neutralize Ammonium Salts Acid Quenching Strong Tertiary Amine Base (e.g. mesylate formation) Tertiary Amine Base (e.g. formation of amides, sulonamides, carbamates) Strong Base (e.g. alkylation of phenols, amines, activated methylene compounds, esterification of carboxylic acids) Amine purification Coupling Agents Amide synthesis Activated ester formation Recommended Solid- Supported Reagent MP-Carbonate Si-Carbonate PS-DIEA PS-DIEA PS-NMM PS-TBD Si-Propylsulfonic acid (SCX-2) PS-Carbodiimide PS-HOBt(HL) PS-HOBt(HL)/ACTU PS-DIEA PS-HOBt(HL)/ACTU What Type of Reagent? What Application? Recommended Solid- Supported Reagent Reducing Agents Carbonyl Reduction MP-BH 4 Reductive Amination MP-CNBH 4 MP-BH(OAc) 3 MP-BH 4 (with Ti(O i Pr) 4 ) Oxidizing Agents Alcohols to Aldehydes Electrophilic Activation Halogenation (Chlorination, bromination, iodination) Phenylether Formation (i.e. Mitsunobu reaction) Thioester Active Intermediate Alcohol Activation (tosylation) Acid and Sulfonyl Chloride Activation Nucleophilic Activation Carbon-Carbon Bond (e.g. Wittig reaction) Sulfonyl Hydrazone Formation (e.g. Hurd-Mori thiadiazole synthesis) PS-TEMPO PS-Triphenylphosphine PS-Triphenylphosphine PS-Thiophenol PS-TsCl PS-Triphenylphosphine PS-TSNHNH 2 Si-Tosyl-Hydrazine Protecting Group Cleavage BOC cleavage BSMOC, FMOC Table 4. Solid-supported reagents. Si-Propylsulfonic acid (SCX-2) Catalysts Acids Acyl Transfer C-C Coupling Si-Propylsulfonic acid (SCX-2) PS-PPh3-Pd Figure 7. Examples of synthetic transformations using solid-bound triphenylphosphine. Figure 8. Strong cation exchange resin, Si-supported propylsulfonic acid. 5

Ordering Information Ordering Information Part Number Description Size 800509 PS-HOBt (HL) 3 g 800417 PS-HOBt (HL) 10 g 800418 PS-HOBt (HL) 25 g 800419 PS-HOBt (HL) 100 g 800420 PS-HOBt (HL) 1,000 g 800496 PS-NMM 3 g 800282 PS-NMM 10 g 800283 PS-NMM 25 g 800284 PS-NMM 100 g 800318 PS-NMM 1,000 g 800473 PS-PPh 3 -Pd 1 g 800474 PS-PPh 3 -Pd 10 g 800475 PS-PPh 3 -Pd 25 g 800476 PS-PPh 3 -Pd 100 g 800513 PS-TBD 3 g 800421 PS-TBD 10 g 800422 PS-TBD 25 g 800423 PS-TBD 100 g 800424 PS-TBD 1,000 g 800517 MP-Triacetoxyborohydride 3 g 800413 MP-Triacetoxyborohydride 10 g 800414 MP-Triacetoxyborohydride 25 g 800415 MP-Triacetoxyborohydride 100 g 800416 MP-Triacetoxyborohydride 1,000 g 800510 PS-Triphenylphosphine 3 g 800378 PS-Triphenylphosphine 10 g 800379 PS-Triphenylphosphine 25 g 800380 PS-Triphenylphosphine 100 g 800381 PS-Triphenylphosphine 1,000 g 800516 ACTU 3 g 800465 ACTU 10 g 800466 ACTU 25 g 800467 ACTU 100 g 800468 ACTU 1,000 g 800512 MP-Borohydride 3 g 800401 MP-Borohydride 10 g 800402 MP-Borohydride 25 g 800403 MP-Borohydride 100 g 800404 MP-Borohydride 1,000 g 800508 PS-Carbodiimide 3 g 800369 PS-Carbodiimide 10 g 800370 PS-Carbodiimide 25 g 800371 PS-Carbodiimide 100 g 800372 PS-Carbodiimide 1,000 g 800493 MP-Carbonate 3 g 800267 MP-Carbonate 10 g 800268 MP-Carbonate 25 g 800269 MP-Carbonate 100 g 800314 MP-Carbonate 1,000 g 800491 PS-NH 2 3 g 800263 PS-NH 2 10 g 800264 PS-NH 2 25 g 800265 PS-NH 2 100 g 800307 PS-NH 2 1,000 g Part Number Description Size 800511 MP-Cyanoborohydride 3 g 800405 MP-Cyanoborohydride 10 g 800406 MP-Cyanoborohydride 25 g 800407 MP-Cyanoborohydride 100 g 800408 MP-Cyanoborohydride 1,000 g 800494 PS-DIEA 3 g 800279 PS-DIEA 10 g 800280 PS-DIEA 25 g 800281 PS-DIEA 100 g 800312 PS-DIEA 1,000 g 800492 3 g 800288 10 g 800289 25 g 800290 100 g 800313 1,000 g 800228 10 g 800229 25 g 800230 100 g 800309 1,000 g 800495 PS-Isocyanate 3 g 800260 PS-Isocyanate 10 g 800261 PS-Isocyanate 25 g 800262 PS-Isocyanate 100 g 800311 PS-Isocyanate 1,000 g 800270 PS-Ts-NHNH 2 10 g 800271 PS-Ts-NHNH 2 25 g 800272 PS-Ts-NHNH 2 100 g 800317 PS-Ts-NHNH 2 1,000 g 800273 PS-Thiophenol 10 g 800274 PS-Thiophenol 25 g 800360 PS-Benzaldehyde 10 g 800361 PS-Benzaldehyde 25 g 800362 PS-Benzaldehyde 100 g 800363 PS-Benzaldehyde 1,000 g 800364 PS-TsCL(HL) 10 g 800365 PS-TsCL(HL) 25 g 800366 PS-TsCL(HL) 100 g 800367 PS-TsCL(HL) 1,000 g 800430 PS-DEAM 10 g 800431 PS-DEAM 25 g 800432 PS-DEAM 100 g 800461 MP-TsOH 10 g 800462 MP-TsOH 25 g 800463 MP-TsOH 100 g 800464 MP-TsOH 1,000 g 800478 10 g 800479 25 g 800480 100 g 800481 1,000 g 9491-0010 ISOLUTE (EC) 10 g 9491-0025 ISOLUTE (EC) 25 g 9491-0100 ISOLUTE (EC) 100 g 9491-0500 ISOLUTE (EC) 500 g 9491-1000 ISOLUTE (EC) 1,000 g 6 Solid-Supported Reagents Biotage 2014

Ordering Information Part Number Description Size 801505 3 g 801397 10 g 801398 25 g 801399 100 g 801400 1,000 g 9495-0010 ISOLUTE (EC) 10 g 9495-0025 ISOLUTE (EC) 25 g 9495-0100 ISOLUTE (EC) 100 g 9495-0500 ISOLUTE (EC) 500 g 9495-1000 ISOLUTE (EC) 1,000 g Part Number Description Size 9536-0025 Si-Propylsulfonic Acid (SCX-2) 25 g 9536-0100 Si-Propylsulfonic Acid (SCX-2) 100 g 9180-0010 ISOLUTE SI-Thiol 10 g 9180-0025 ISOLUTE SI-Thiol 25 g 9180-0100 ISOLUTE SI-Thiol 100 g 9180-0500 ISOLUTE SI-Thiol 500 g 9180-1000 ISOLUTE SI-Thiol 1,000 g 9180-5000 ISOLUTE SI-Thiol 5,000 g 9180-10000 ISOLUTE SI-Thiol 10,000 g Appendix Solvent Compatibility of Polystyrene Resins Solvent Type Swelling Solvents Non-Swelling Solvents Hydrocarbon Toluene, xylene Hexane Chlorinated DCM, dichloromethane, chlorobenzene Ether Tetrahydrofuran (THF), Ethyl ether dioxane, diglyme Ketone Cyclohexanone Acetone Polar aprotic DMF, dimethylsulfoxide ACN (DMSO), N-methylpyrolidone (NMP) 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 Table Mesh Micron 20 850 25 710 35 500 50 300 60 250 70 212 100 150 140 106 200 75 325 45 400 38 Table 6. A table which converts the mesh sizes for resin beads to their average diameter in microns. Abbreviations ACN DBAD DCE DCM DEAD DES DEAM DIC DIEA DMA DMAP DMF EtOH acetonitrile ditertbutylazodicarboxylate 1,2 dichloroethane dichloromethane diethylazodicarboxylate diethylsilane diethanolamine diisopropylcarbodiimide diisopropylethylamine dimethylacetamide dimethylaminopyridine dimethylformamide ethanol HOAc HOBt MeOH MP NMM Py PS TBD THF TS-Cl Ts-OH acetic acid N-hydroxybenzotriaole methanol macroporous N-methyl morpholine pyridine Polystyrene 1,5,7-triazabicyclo[4.4.0]dec-5-ene tetrahydrofuran toluenesulfonyl chloride toluenesulfonic acid 7

Solid-Supported Reagents Page 8 Your Complete Partner for Effective Chemistry Biotage is a worldwide supplier of instruments and accessories designed to facilitate the work of laboratory chemists. With our deep knowledge of the industry, academic contacts and in-house R&D teams, we can deliver the best solutions to your challenges. We take great pride in our flexibility and ability to meet our customer s individual needs. With strong foundations in both analytical and organic chemistry, we can offer the widest range of solutions available on the market. EUROPE Main Office: +46 18 565900 Toll Free: +800 18 565710 Fax: +46 18 591922 Order Tel: +46 18 565710 Order Fax: +46 18 565705 order@biotage.com Support Tel: +46 18 56 59 11 Support Fax: + 46 18 56 57 11 eu-1-pointsupport@biotage.com NORTH & Latin AMERICA Main Office: +1 704 654 4900 Toll Free: +1 800 446 4752 Fax: +1 704 654 4917 Order Tel: +1 704 654 4900 Order Fax: +1 434 296 8217 ordermailbox@biotage.com Support Tel: +1 800 446 4752 Outside US: +1 704 654 4900 us-1-pointsupport@biotage.com JAPAN Tel: +81 3 5627 3123 Fax: +81 3 5627 3121 jp_order@biotage.com jp-1-pointsupport@biotage.com China Tel: +86 21 2898 6655 Fax: +86 21 2898 6153 cn_order@biotage.com cn-1-pointsupport@biotage.com To locate a distributor, please visit our website at www.biotage.com Part Number: PPS307 2014 Biotage. All rights reserved. No material may be reproduced or published without the written permission of Biotage. Information in this document is subject to change without notice and does not represent any commitment from Biotage. E&OE. Product and company names mentioned herein may be trademarks or registered trademarks and/or service marks of their respective owners, and are used only for explanation and to the owners benefit, without intent to infringe. For more information visit www.biotage.com. Biotage 2014