Argonaut Quest Training Workshop 2 (pdf) - Artisan Scientific

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INTRODUCTIONNew methodologies that enable psolution phase synthesis of organic compoundsare becoming an important complement tosolid phase synthesis for the generation ofcompound libraries. The primary benefitsrelative to solid phase synthesis are:reaction conditions* the ability to convepurification must be developed as an- alternative to individud aqueo -- - --extractions, crystallization and flashprovides a simple and very effectiveinvestigation.'*IBACKGROUNDThe resins developed for parallel solution phase synthesisfall into two main categories:Scavenger ResinsBound ReagentsScavenger resins provide a convenient means of effectingchemically-driven separations, allowing work upand p-cation of chemical reactions without the needfor chromatography. A scavenger resin is added afterthe reaction is complete to quench and selectively reactwith excess reactants and/or reaction byproducts. Theresulting resin bound reactants are removed by simplefiltration. The removal of excess reactant is depicted inScheme 1.Solution Phase Reaction Scavenger Resin Product1 Incubate2 F~lterchromto~~h~- The use of polymer- 1.5 R, + R2 - P + 0.5 R1 - - Pbound reagents and scavengersR, and R2 = ReactantsP = Product ckx c&x R1means of purifying multiple solutionphase reactions in parallel and hasrecently been the subject of intense--In response, Argonaut Technologieshas developed a variety of polymer scavengersand reagents to facilitate a wide range ofreactions and workups. Thesused individu- - -- - --Solution Phase Flea~=+ , ProductI Bound Reagent 1 SCHEME 13R1 + R2Filter--- - PA bound reagent is present during the reaction andallows removal of both unreacted and spent reagent byfiltration (Scheme 1). Properly designed boundreagents will often perform in a manner similar to theirsmall molecule equivalents with minimal optimizationfor a given synthetic transformation.--1mation for this methodspecific product information, including scopeof reactivity and detailed procedures for use inBound reagents and/or scavengers may be used individuallyor in concert to simpldy reaction workups andArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

OVERVIEW OF ARGONAUT'S CHEMISTRYPRODUCTS FOR PAWEL SOLUTIONPHASE SYNTHESIS AND PUR~FJCATIONTo meet the growing demand from chemistsseeking to increase their use of parallelchemistry, Argonaut Technologies has introducedthe set of polymer scavengers and reagentsshown in Table 1.These products enable parallelsolution phase reactions in the medicinalchemistry laboratory. Detailed product information,including specitic product descriptions,scope of reactivity and procedures for use areprovided in the following sections. A briefoverview of the products is provided below.1. Chemistry Products for Paralleln Phase Synthesis and PurificationProduct Name1 Structure FunctionPS-Trisamine~ N H - N i ~ ~ zavoid time consuming aqueous extraction and chro-matography. It should be noted that polymer scav-engers and reagents can also be quite useful for thepurification of cleaved products from solid phasereactions. Cleavage strategies which allow for adiverse set of inputs, e.g. arnines, are not restricted tovolatile reagents when scavenging protocols areemployed.TERMINOLOGYScavenge electrophiles: acid chlorides,sulfonyl chlorides, isocyanatesPS-Isocyanate NCO Scavenge nucleophiles: mines, thiols,alkoxides, organometalhcsPS-TSNHNH2PS-ThiophenolPS-TsC1PS-DIEAPS-NMMPS-DMAPMP-CarbonateMP-TsOH9. ,o s. NHNH. Scavenge carbonyl compounds:aldehydes, ketonesQhsn0 0s,,Scavenge alkylating agents: halides,mesylates, tosylates, a,bunsaturatedcarbonylsThe following terminology is used when describingresins in this technical paper.Resin TypeThe product name provides information regardingthe resin type and the comparable small moleculereagent. PS designates lightly crosslinked polystyreneand MP a more highly crosslinked macroporousresin backbone. Lightly crosslinked poly-- -Bound tosyl chloride equivalent:"catch and release" of alcohols,I-PrN\ I-PrTertiary amine base: bound DIEAequivalent--9. 0S ~ N H - N ~ Tertiary amhe base: bound N-methyimorpholineequivalent (non-benzylic)Na-Bound dimethylaminopyridine:Meacylation catalyst, acid and sulfonylhalide "catch and release"NEI,+( CO,~ )General base: quenching reagent,0 5neutralization of amine hydrochlorides,scavenging acids and acidic phenols0~. 0s'tOH1. The produd name des~giates the resin type and the co~nparabk small moteculermgeni (PS: Lghtly croshked poIystyrene, MP: macroporous polystyrene).General acid: quenching reagent, aminescavenger, mine "catch and release"styrenes typically require theuse of solvents that will swellthe resin to allow reagents toaccess the resin-bound functionalgroups. In cases wherethe solvent does not swell the -resin, it may be necessary toadd a cosolvent that is compatiblewith the resin, e.g.THF.Macroporous polystyrenes areporous resins; the resin functionalityis accessed by reactantsthrough the pore networkwhich is typically notdependent on solvent.ScavengersPolymer scavengers are resinswhich are added after chernicalreactions to remove excessreactants and byproducts.Thefunctionality removed by eachscavenger is given in Table 1and the accompanying detailedproduct descriptions. Thecapacity of each resin has beedetermined by measurementof the uptake of a model substrateto better reflect the scav-Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

enging capability as compared to a loading based onelemental analysis. In addition, the effectiveness ofeach scavenger resin was measured for a series ofsubstrates of varying reactivity to provide a guide for- applications involving a range of substrate reactivi-ties.Since the reactive functionality of scavengers is poly-mer bound, mixtures of incompatible scavengersand reagents can be used together in the same vesselwithout limitation^.^ For example, a mixture of DDQand DDQ-H was scavenged with a mixed-bed of abound tetraalkylammonium ascorbate, to reduceunreacted DDQ, and bicarbonate resin, to sequesterDDQ-H.6 MP-Carbonate and MP-TsOH can also beused together as scavengers for acidic and basiccompounds, respectively. The use of MP-TsOH andMP-Carbonate as a rnixed-bed can be an effectivemeans of removing a variety of weak Bronsted acidsalts. The MP-TsOH acid protonates the anion,sequestering the cation, and the newly formed acidis subsequently sequestered on the MP-Carbonateresin. This method is useful for the removal of carboxylateand fluoride salts.- Bound ReagentsBound reagents perform the same function as thesmall molecule analog. The tertiary amine resins, PS-DIEA and PS-NMM, are designed to behave similarlyto diisopropylethylamine (DIEA) and N-methylmorpholine(NMM), respectively. In reactions wherethese serve as tertiary amine bases, they form boundamine hydrochloride salts which are readily removedby filtration. These may be used in conjunction withPS-DMAP where DMAP catalysis is required."Catch and Release" ResinsThese are a subset of the polymer reagents whichallow the "catching" of a small molecule as an activat-ed polymer intermediate, analogous to resincapture.' The resin can be washed to remove solublebyproducts and then subjected to a second transformationto "release" the product. This has beenapplied using PS-TsCI to "catch" alcohols as polymerboundtosylates. After a simple workup involvingresin washing, the resin-bound tosylates can be react-ed with secondary amines to "release" tertiary amineproducts.Bound Acids and BasesMP-TsOH and MP-Carbonate are quite useful in anumber of capacities as a bound acid and base,respectively. These can be used to quench and purifyreactions, analgous to an aqueous acid or baseextraction. MP-Carbonate is quite useful for neutralizingamine hydrochloride and carboxylate salts inreagent preparation, reaction workup or during reactions.In the case of insoluble amine hydrochlorides,a catalytic amount of a soluble base, e.g, DIEA, can beadded as a "transfer base" to assist in the neutralization.References1. Kaldor, S. W.; Siegel, M. G. Curr Opin Chem. Biol.1997,1,101.2. Flynn, D.; Krich, J. Z.; Devraj, R.V.; Hockerman, S.L. ; Parlow, J. J.; South, M. S.; Woodard, S. J Am.Chem. Soc. 1997,119,4874.3. Booth, R. J.; Hodges, J. C. JAm. Chem. Soc. 1997,119,4882.4. Gayo, L. M.; Suto, M. J. Tetrahedron Lett., 1997,38,513.5. Parlow, J. J. Tetrahedron Lett. 1995,1395.6. Deegan,T. L.; Gooding, O.W.; Baudart, S.; Porco, J.A., Jr. Tetrahedron Lett. 1997,38,4973.7. Brown, S. D.;Armstrong, R.W JAm. Chem. Soc.1996,118,6331.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT INFORMATIONProduct: PS-TrisamineChemical Name: Tris-(2-aminoethy1)aminepolystyreneCapacity: 3 - 4 mmoOg (based on benzoylchloride uptake)Resin wpe: 1 % crosslinked Poly(styrene-codivinylbenzene)Application: Scavenging acid chlorides, sulfonylchlorides, isocyanates, and other electrophileswpical Scavenging Conditions: 3 - 6 equivrelative to acid chloride, 1 - 4 h, 20 " C. If an additionalresin-bound base is present: 1.5 - 3 equivCompatible Solvents: CH2C12 ( 7 mL/g),THF (6Wg), DMF (5.2 mug) and other swellingsolventsRecommended Agitation: Gentle magneticstirring, swirling or overhead stirring for largeresin quantities (>5 g)1 part# Quantity 1Representative Procedure:Acid Chloride ScavengingReaction: The applicationamide synthesis was testedchloride (1.5 equiv, 0.60 mol) with benzylarnine(44 yL, 0.40 mmol) in the presence ofpyridine (97 pL, 1.2 mmol) in 2 mL of CH,C12 for1 h at RT.PS-Trisarnine is an arnine functional resin for theremoval of excess electrophilic reagents during thequenching and purification of reaction mixtures.' PS-Trisamine resin has a scavenging capacity of 3.0 - 4.0mrnol/g based on reaction with an excess of benzoy! -chloride. Scavenging of common electrophiles typicallyrequires a 3 - 6 equiv of PS-Trisarnine and occurswith 0.5 - 3 h at room temperature.The scope of PS-Trisamine as a scavenger for electrophilicreagents was investigated using 4-chlorobenzoylchloride, 2-phenylbutyryl chloride and 2,Gdimethoxybenzoyl chloride as a series of acid chlorideswith decreasing reactivity. Acid chlorides werecompletely scavenged in 0.5 h using 3.5 equivalentsPS-Trisamine (Table 2).The presence of a tertiarybase, e.g. PS-DIEA or PS-NMM, reduces the amount ofPS-Trisarnine required in the reaction by removing thehydrogen chloride formed. In addition to acid chlorides,benzenesulfonyl chloride and 4-methoxyphenylisocyanate were effectively scavenged in 0.5 h.TABLE 2. Comparative Scavenging ofElectrophiles in Dichloromethane for 0.5 hElectrophile4-Chlorobenioyl chloride2-Phenylbutyryl chloride2,GDimethoxybenzoyl chloride4-rnethoxyphenyl isocyanateBenzenesulfonyl chloridePS-Trisamine(equivI13.53.53.5241) Relative to electrophile, no additional base presentScavenged I100References1. Booth, R. J.; Hodges J. C. JAm. Chem. Soc, 1997,113,4882.Reaction Workub: 6 equiv of PS-Trisamine, relativeto excess acid chloride, was added to thereaction mixture and agitated for 3 h. The resinwas removed by fdtration and washed 3 x withCH,Cl, .The fdtrate was concentrated to affordthe desired amide. This procedure was used toprepare benzyl2,G.dimethoxybenzamide as thesole product in 97% yield.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

4PRODUCT INFORMATIONProduct: PS-IsocyanateChemical Name: Polystyrene methylisocyanateCapacity: 1 .O - 1.7 rnmol/g (based onbenqlamine uptake)Resin Type: 1 % crosslinked Poly(styrene-codivinylbenzene)Application: Scavenging nucleophiles,including amines and alkoxidesTypical Scavenging Conditions: 2 - 3 equivrelative to nucleophde, 1 - 16 h, 20 "CCompatible Solvents: CH,Cl, (9.5 myg),dichloroethane (7.2 mL/g),THF (8.2 Wg),toluene (7.8 mWg), incompatible with water andalcoholsRecommended Agitation. Gentle magneticstirring, swirling or overhead stirring for largeresin quantities (>5 g)Part # Quantity 1PS-Isocyanate is a 1% crosslinked Polystyrene-codivinylbenzenewhich has pendent benzylisocyanatefunctionality. The resin is produced from aminomethylresin by a superior process which gives high conversionwith minimal urea formation as determined by IRspectroscopy (Figure 1, on next page).The resin canreadily scavenge excess nucelophiles from solution,which are often used to drive reactions to completionthereby facilitating workup and purification.'-5 Thereaction of nucleophiles with the isocyanate moietyoccurs without liberation of small molecule byproducts.Removal of nucleophiles from solution generallyrequires a 2 - 3 equiv of PS-Isocyanate depending onsubstrate reactivity. Comparative scavenging of aminesand alcohols (0.2 - 0.05 M) of varying reactivity wastested as a function of time and temperature (Table3).Typical aliphatic amines are completely sequesteredby two equiv of PS-Isocyanate within 1 h.Two equiv ofPS-Isocyanate sequestered 89% and 99% aniline atroom temperature and 60 " C for 16 h, respectively.Complete removal of aniline would likely occur atroom temperature with 3 - 4 equiv of PS-Isocyanate. Aless reactive aromatic amine, 2-aminobenzophenone,was not completely sequestered even at elevated temperatures.Theuse of diisopropylethylamine as a catalystdid not improve the scavenging efficiency of PS-Isocyanate towards aromatic amines. Alcohols werenot reactive towards PS-Isocyanate at room temperature,suggesting that aliphatic amines can be selectivelysequestered in the presence of alcohol functionality.More nucleophilic alcohols may be removed at elevatedtemperatures.Upon completion of the scavenging, the product isTABLE 3. Comparative Scavenging of Nucleophiles inDichloromethaneNucleophileScavengedpiperidinebenzyl amineanilineaniline4methoxyphenyl-1 -butan014methoxyphenyl-1-butanol2-aminobenzophenone1) Dichloroethane solventPS-Isocyanate(equiv)3.02.03.0% Scavengedwashed away from the resin with a suitable solvent.Suitable solvents include those which dissolve the productand swell polystyrene, but are not nucleophilicenough to react with the resin. CH,Cl,, dichloroethane,THF and toluene are all good choices with CH,Cl, beingpreferred.68298 1Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PS-Isocyanate was testedin an amide bond formingapplication where 4-chlorobenzoyl chloridewas allowed to reactwith excess benzylamine in the presenceof PS-DIEA resin as base(Scheme 2, Table 4).Upon completion of the SCHEME 2reaction, the excess ben- 1zylarnine was scavenged using 3 equiv PS-Isocyanateresin.The product was then isolated by washing it freeof the resin followed by concentration.The yields weredetermined gravimetrically and the purities by GC. PS-Isocyanate was also used to sequester excess secondaryarnines in the preparation of tertiary arnines using PS-TsCl (see PS-TsCI product information).1.2 mmol pyridineor PS-DIEA4ml DCM, 20 O CCI /-0.6mmol 0.4mmol /+0.6 mmolPS-DIEAPS-DIEA1-3 h, 20 OCNCOTABLE 4. Amide Bond Formation3 hrsNHaN"P~FIGURE 1. FT-IR Spectra of (a) PS-Isocyanate, 1.2 mmoVg; (b) polystyrene methylisocyanate, 0.9mmol/g, prepared by the procedure described in reference 4.HRepresentative Procedure: Amide FormationReaction: 4-chlorobenzoyl chloride was allowed toreact for one hour with 1.5 equiv of benzylarnine inCHZC1, with 3 equiv of PS-DIEA resin as the base.References1. Rebek, J.; Brown, D.; Zimmerman, S. JAm. Chem.SOC. 1975,97,4407.2. Kaldor, S. W.; Seigel, M. G.; Fritz, J. E. ; Dressman, B. A.;Hahn, PJ Tetrahedron Lett. 1996,37,7193.3. Kaldor, S. W.; Fritz, J. E.;Tang, J.; McKenney, E. R.Reaction Worku~: The excess benzylamine was scavagedby adding PS-Isocyanate resin (3 equiv relative to Bioorg. Med. Chem. Lett. 1996,6,3041.excess amine).The beads were removed by filtration, 4. Booth, J. R.; Hodges, J. C. J Am. Chem. Soc. 1997,washed 2 x with CH,Cl, and the combined filtrate was 119,4882.concentrated to afford the benzyl 4-chlorobenzamide as 5. Creswell, M. W.; Bolton, G. L.; Hodges, J. C.; Meppea,the sole product in 87 % yield. M. Tetrahedron 1998,54,3983.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT ~NFORMAT~ONProduct- PS-TsNHNHaPS-TsNHNH, is a resin-bound equivalent of p-toluene-sulfonyl hydrazide and readily reacts with aldehydesand ketones. In contrast to reported sulfonyl hydrazideresins,' j PS-TsNHNH, is a moderately loaded resin, in-which all sulfonyl hydrazide reaction sites display good0, ,,oaccessibility to carbonyl reactants. Comparison with aS, NHNH2 polymeric benzyl hydrazide showed PS-TsNHNH, was asuperior scavenger for carbonyls and much more stableto storage (the benzyl hydrazide resin decomposed onstorage).Product: Polystyrene sulfonyl hydrazideCapacity: 1.8 - 3.2 mmol/g (based onRemoval of excess carbonyls from solution generallybenzaldehyde uptake)requires a threefold excess of PS-TsNHNH,. Addition ofResin we: 1% crosslinked Poly(styrene-coacatalytic amount of acetic acid (5 - 10 %) may bedivinylbenzene)required for ketones and hindered aldehydes.AceticScavenging aldehydes and ketones acid is also required for sequestering aldehydes in DMETypical Scavenging Conditions: 3 equivComplete removal of common aldehydes occurs in 0.5relative to carbonyl, 1 - 3 h, 20 "C, CH,CI,.to 3 h and removal of a ketone takes from 2 to 16 h.Ketones and hindered aldehydes are accelerated Elevated temperatures were required for hinderedby the addition of acetic acid (-lo%) and/or heat.ketones, e.g. 2,Gdimethylcyclohexanone. Upon comple-Compatible Solvents: CH,C12 (7 mug),tion of the scavenging, the resin is rinsed with a suitdichloroethane(7 mL/g),THF (6.5 Wg), DMF able solvent, i.e. those which swell polystyrene, and the(7.2 mL/g), and other swelling solvents product is isolated by concentration. RepresentativeRecommended Agitation: Gentle magnetic aldehyde and ketone scavenging examples are presentstirring,swirling or overhead stirring for large ed in Table 5. PS-TsNHNH, was successfully used toresin quantities (>5 g)workup the synthesis of alcohols by addition of aGrignard reagent to aldehydes.-Part # QuantityPS-TsNHNH, is also potentially useful as a polymeric800270 10 greagent. Bound sulfonyl hydrazones, formed by conden-800271 25 gsation with carbonyl compounds, can be utilized in fur-800272 100 gther synthetic transformations. The high accessibility oftosyl hydrazide functional groups in PS-TsNHNH,should afford high synthetic fidelity relative to report-Representative Procedure: Alcoholed systems.'Formation by Addition of Butyl Grignardto HexanalReaction: Butylrnagnesium chloride (1 equiv) inTHF was added to excess hexanal (2 equiv).TABLE 5. Comparative Scavenging Timesin DichloromethaneRedction Wo&ub:To the reac- Carbonyl SubstratesAdditivetion was added 1 equiv ofacetic acid, relative to butylmagnesiumchloride, and 3eq~v of BT~N~,,relativeto excess hsranal.The mixturewas agitated for 2 h, filteredand the resin was washed 2 xBenzaldehydeHexanal2,GDimthoxybenzaldeh~deCyclohexanoneAcetophenone2 ,GDimethylcyclohexanone''PS-TsNHNH2(equiv)333333Acetic AcidAcetic AcidAcetic Acid (70 C )'YOScavenged10010010010010085with THE The combined liltrates were concentrat-Referencesed to afford Sdecanol as the sole product in 97%1. Emerson, D. W.; Emerson, R. R.; Joshi, S. C.; Sorensen,.- yield. For less reactive carbonyl compounds, acetic E. M.; Nrek, J. J Org. Chem. 1979,44,4634.acid was added to bring the concentration to 10%2. Kamogawa, H.; Kanzawa,A.; Kodoya, M.; Naito,T.;for scavenging. Excess acetic acid can be removed Nanasawa, M. Bull. Chem. Soc. Jpn., 1983,56,762.in zmo or by the addition of MPCarbonate. 3. Galioglu, 0.; Auar, A. Eur P0lym.J 1989,25,313.Time(h)1111810Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT INFORMATIONProduct: PS-ThiophenolChemical Name: 3-(3-mercaptopheny1)propanamidomethylpolystyreneCapacity: 1.0 - 1.5 mmol/g (based on benzylbromide uptake)Resin Type: 1% crosslinked poly(styrene-codivinylbenzene)Application: Scavenging alkylating agentsDisulfide Reduction: The resin is treated witha 0.7 M tributylphosphine solution (95:5THF/water) for 0.5 - 1 h, followed by washingwith 3 xTI3.F (deoxygenated) to reduce sulfides.Typical Scavenging Conditions: 2 - 3 equivrelative to nucleophile, 20 " C, DMF or THF:EtOH(1:1), 1 - 16 h. Scavenging requires conversion tothe thiophenolate with potassium trimethylsilanolate(TMSOK) or use in conjunction withdiisopropylethylamine (DIEA, 2 equiv) and MP-Carbonate (2 equiv). Scavenging is best performedinTHJ?/ethanol or DME The ethanol isadded for the scavenging process and may providebenefit in solvents other than 'ITECompatible Solvents. DMF (7.0 mug), THF(7.0 rnL/g) , CH,C12 (7.0 mL/g), and otherswelling solventsRecommended Agitation: Gentle magneticstirring, swirling or overhead stirring for largeresin quantities (>5 g)Part #QuantityPS-Thiophenol is based on an aminomethyl resin with atethered thiophenol functionality.The resin wasdesigned for the scavenging of alkylating agents, e.g.alkyl halides. PS-Thiophenol was tested and found effec.tive in scavenging alkylating agents ranging from octylbromide to benzyl brornide.The scavenging effectivenessof PS-Thiophenol was found to be greater than apolymer bound benzyl thiol towards octyl bromide,indicative of the higher nucleophilicity of the thiophenolate.As a precautionary measure, PS-Thiophenol is typicallyprepared for use by reduction with a 0.7 M tributylphospinesolution (95:5,THF/water) to cleave disulfidelinkages that may be present. PS-Thiophenol treatedin this fashion has been found to be unchanged forseveral weeks (longer term stability studies inprogress).Effective scavenging of active halides requires the useof either the potassium thiolate salt (formed withpotassium trimethylsilanolate) or in the presence ofdiisopropylethylamine (DIEA) and MP-CarbonateThesolvent used for the scavenging reaction is critical forgood scavenging rates. Both 1:1 THF/ethanol(THF/EtOH) mixtures and dimethylformamide (Dm)were found to be effective solvents for the scavengingreaction. Low levels of scavenging were observed in -pure THE indicating that removal of alkyl halides from areaction carried out in THF would require the additionof ethanol to accelerate the reaction. It is likely thataddition of ethanol may be necessary to accelerate thescavenging process in other solvents, by analogy toTHEIn the case of potassium trimethylsilanolate (TMSOK),two equivalents of base are incubated with the resinfor 30 min inTHE The resin is then rinsed 3 x withTHF to remove excess base.This can be carried out inbulk or individually and distributed. One equivalent ofbase can be used relative to PS-Thiophenol, which circumventsthe need to post wash the resin, since thehexamethylsiloxane formed is volatile. However, a slightincrease in the equiv of resin used may be required.Alternatively, DIEA (2 equiv) can be added to PS-Thiophenol in the presence of MP-Carbonate (2 equiv).The DIEA acts as a base for the hydrogen halide generatedduring thioether formation and the amine hydrohalideformed is subsequently neutralized by the carbonateresin. Ultimate removal of the DIM is performedby evaporation.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PS-Thiophenolcontinued. ....The scope of scavengingefficiency of PS-- Thiophenol was testedfor a set of electrophilesranging inreactivity from octyl tobenzyl bromide usingboth the TMSOK andDIWMP-Carbonatemethods, and is givenin Table 6.SCHEME 3PS-Thiophenol waseffectively used as a scavenger inWilliamson ether synthesis asshown in Scheme 3. High yieldsand purities were achieved usingeither the TMSOK or DIEA/MP-Carbonate scavenging method.RBr Scavenging1) t-BuOK RTRBr \1.R = Bn 96% (TMSOK Method)65'~84% (DIEA Method)S- K+ SR = Oct 83% (TMSOK Method)R = Bn, 5h75% (DIEA Method)= Oct, 20horAlkylatingAgentBenzyl BrBenzyl BrCinnarnyl C1Cinnamyl C1DIENMP-CarbonateTABLE 6. Scavenging of Alkylating Agentswith PS-ThiophenolRepresentative Procedure:Scavenging Excess Electrophiles ocql Br79 100from W i ~ ~ Ether 0 n Synthesis oc~l Br 1.89 DIEAIMP-Carbonate2 - 86Reaction: To a 0.2 M solution ofI I I1) Conditions affording > 80% scavenging can typically be drivenphenol (57 mg, 0'60 mmol) was addedto completion with additional I - 2 equiv of resin. I ) Two equiv of-- 1.61 M potassium t-butoxide (0.66 mmol). After 0.5 h 110 DIEA and RIP-Carbonate relative to PS-Thio~henol.pL of benzyl bromide (1.5 equiv, 0.90 mmol) was addedand the solution was heated at 65 " C with stirring for 5 h.Reaction Workup: (A)TMSOK Method: PSThiophenol(0.692 mg, 0.87 mrnol/g, 0.60 rnrnol, 2 equiv) was treatedwith 7 rnL of a deoxygenated 0.17 M TMSOK solution(154 mg, 1.20 mrnol, 2 equiv) inTHF:EtOH (1:l) andallowed to react for 30 rnin.The solution was removed byfiltration and the resin was washed 3 x withTHF:EtOH(deoxygenated).The reaction mixture was added to theprepared bed of PSThiophenol, 3 rnL of ethanol wasadded, and the mixture was stirred overnight.The solutionwas fdtered through celite and the beads werewashed 2 X withTHF:EtOH.The phenyl benzyl etherproduct was isolated in 94% yield after concentration. (B)DIWMP-Carbonate Method: The reaction solution wasadded to a mixture of 0.692 g of PS-Thiophenol and 0.4g of MP-Carbonate (2 equiv) and 3 mL of ethanol and 210pL of DIEA was added.After agitation for 16 h the phenylbenzyl ether product was isolated by analogy to methodA in 85% yield (depending on the product structure upto 5 x wash of the resin is employed with MP-- Carbonate). An analogous procedure applied to a synthesisusing octyl bromide as the electrophile required a 20h reaction time and 4 equiv of PS-Thiophenol to affordphenyl octyl ether in 83% and 75% yield by MethodAand B, respectively.PS-Thiophenol(equiv)1.902.342.252.181.87BaseTMSOKDIEA/MP€arbonate2TMSOKDIWMP-Carbonate2TMSOK%Scavengedin DMF1lhl6h- 93-100 -- 100- 92%Scavengedin THF:EtOH11hl6h100 -92 100100 -Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT INFORMATIONProduct: PS-TsCZChemical Name: Polystyrene sulfonyl chlorideCapacity: 1.0 - 2.0 mmol/g (based on sulfuranalysis)Resin me: 1% crosslinked Poly(styrene-codivinylbenzene)Application: Loading of alcohols and nucleophilicdisplacement

PS-TsCIcontinued. ....displacementreaction. This- expeditedapproachI SCHEME 4-R'R*NH (2 equiv) PS-Isocyanateo, ,oROH (10 equiv) S, DlEA (6 equiv) (3 equiv)OR . --- +DCMIPyridine5hCH3CN, 70 OC, 18 h2 rnL THF, 3 hR'R*NRafforded ter- I Itiary amineTABLE 7. Synthesis of Tertiary Atnines from Alcohols using PS-TsClproducts in high yield and puritywhile circumventing extractionsand chromatography in productisolation and purification.Entry2Representative ExperimentalProcedures (entry 1, Table 7):To a reaction vessel containing 75mg of PS-TsCI resin, (1.47 mrnol/g,0.11 mmol) under argon, 3 mL of a34-4-methoxyphenyl-1-butanol(178 pL, 1.05 rnrnol) wasReferencesadded in DCM/~yridine mixture was stirred 1 Rueter, J, K.; Nortey, S 0,; Baner, E.W; Leo, G C,;for 5 h.The resin was then washed with DCM (3 x),Reitz,A. B. Tetrahedron Lett. 1998,39,975.DMF (5 DMFm20 (3:13 (3 DCM (3 2. Baxter, E. W; Ructer, J. K.; Nortcy, S. 0.; Reitz,A B.and dried under vacuum. A solution of l-phenylpiper-Tetrahedron Lett. 1998,37,979.azine (3 1 pL, 0.21 mmol) and N,N-diisopropylethy-3. Zhong, H. M.; Greco, M. N.; Maryanoff, B. E. J. Org.lamine (107 pL, 0.63 mmol) in 3 rnL acetonitrile, wasChem., 1997,62,9326.added and the mixture was heated at 70 O C for h.4. For reviews on the use of polymer-supported aryl-Finally, 255 mg of PS-Isocyanate resin (1.21 mmol/g,sulfonyl chloride resin, see Huang, W.; He, B. Chin.J-- 0.31 mmol) was added, with 2 mL of THE After 3 h,Reactive Polymers (Engl.) 1992,1,61.the solution was into a pre-~eighed (three 5, Hunt,,.*.; Roush,W R. JAm. Chem. Sot. 1996, 118,THF washes to rinse product from the resin).The sol-9998.vent was then concentrated to give 1-phenyl-4-(4-methoxypheny1)butyl-piperazine in 98% yield (GC purity100%). 1H NMR (CDCI,, 300 MHz): 6 7.33-6.81 (m, 9H,Ar-H), 3.79 (s, 3 H, CH,O), 3.27 (m, 4 H), 2.72-2.41(m, 8 H), 1.63 (m, 4 H) ppm; 17C NMR (CDClj, 75 MHz):6 157.69, 150.88, 134.12, 129.12, 129.02,119.90,116.11, 113.61,58.05,55.00,52.66,48.37,34.45,29.11,25.39 ppm.1ROHC H ~ O ~ ( C H ~ ) ~ OHN H A N-P.c ~ 3 0 ~ ~ c ~ * ) + 0P HCf'&cHzbo*R'R*NHc ~ ~ ~ ( c H , r , ~h-z- o ~uAHN N-phuCH~RIR~NRCH-.-(CH~.N~-P~CH@

PRODUCT INFORMATIONProduct: PS-DIEAIChemical Name: N,N-(Diisopropyl)aminomethylpolystyrene(1% inorganic antistaticagent)Capacity: 3 - 4 mmol/g (based on nitrogenanalysis)Resin Type: 2% crosslinked Poly(styrene-codivinylbenzene)Application: Tertiary amine baseTypical Application Conditions: 2 - 3 equivrelative to limiting reagentResin Swelling: CH,Cl, (3.0 mL/g),THF (4.2W), DMF (2.5 mL/@Recommended Agitation: Gentle magneticstirring, swirling or overhead stirring for largeresin quantities (>5 g)I part # Quantity 1IPS-DIEA is a high loading tertiary amine base which is aresin-bound equivalent of diisopropylethylarnine. PS-DIEA is useful in applications requiring a tertiary aminebase, where the resin-bound ammonium salt byproductsare readily separated by filtration.' Synthesis ofamides, sulfonamides and carbamates can be effectedusing filtration as the only purification step when PS-DIEA is used in conjunction with PS-Trisamine or PS-Isocyanate as scavenger resins.PS-DIEA is linked to the polystyrene backbone throughthe benzylic position by analogy to other resin-boundamine bases, e.g. morpholinomethyl po1ystyrene.A limitationof the benzylic amine linkage is its susceptibilityto cleavage by electrophiles, to form small moleculeimpurities, e.g. amides or car barn ate^.^,^ Chloroformatesare more reactive than benzoyl chloride in cleavingbenzylic amines.We have found that the increasedsteric hindrance associated with the diisopropyl substitutionaffords a significantly more stable benzylic tertiaryamine base in the presence of reactive electrophileslike chloroformates.The stability of polymeric tertiary amines towards electrophileswas studied as a function of arnine structure.A methylene chloride solution of benzoyl chloride ormethyl chloroformate was allowed to react withdimethylamino, N-morpholino and diisopropylamino -functional methyl polystyrenes for 16 h at room temperatureand the filtrate was concentrated and examinedfor cleavage products (Scheme 5 on next page).The results showed good correlation between sterichindrance and amine stability (Table 8 on next page).Dimethylaminomethyl polystyrene was the least stableand showed some formation of dimethyl benzamidewith benzoyl chloride. Morpholinomethyl polystyrenewas stable to benzoyl chloride but underwent cleavagewith methyl chloroformate to afford methyl morpholinocarbamate in 90 % yield. In contrast, PS-DIEA wasvery stable under these conditions and afforded only a2.5 % yield of carbamate.The higher stability of PS-DIEA towards active electrophiles should allow its usein reaction with either excess electrophile or aminewith little or no cleavage of the benqlic amine cleavage.In those cases where some cleavage is observed,the more stable non-benzylic amine resin PS-NMM canbe employed (see PS-NMM product description).PS-DIEA was applied in the preparation of the mesylateof 3-phenylpropanol according to a literature procedure(Scheme 6 on next page).4 The use of 3 equiv -of PS-DIEA afforded complete conversion to the desiredmesylate in 95 % isolated yield. Reaction workupArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PS-DIEA continued, ....required filtration andrinsing of the resin, followedby removal ofthe solvent and excessmethanesulfonyl chloridein vacuo, andhence, was greatly simplifiedover aqueouscxtractions when triethylaminewas used asthe base.I-NR2 = -NMe2, -morpholine, -N( i-Pr)2SCHEME 5011CH2CI2+ 13'-C, t R' -c, +0I ICI 16h NR2R' = Ph-, MeO-CIRepresentative ProcedureMes-vlate Formation: A 10 mL round bottom flask wascharged with 800 mg of PS-DIEA resin (3.8 mmol/g, 3.0mmol), 2.5 mL of CH,Cl, and 1 mrnole of a primaryalcohol and cooled in an ice bath. 0.12 mL (1.5 mmol)of methanesulfonyl chloride was added, dropwise, tothe stirred solution.The reaction mixture was removedfrom the ice bath and allowed to warm to room temperaturefor 0.5 h.The resin was removed by filtrationand rinsed 3 x with CH,Cl,.The combined filtrate wasconcentrated on a rotary evaporator and the residualmethanesulfonyl chloridewas removed in*Iacuo in the presence- of potassium hydroxidedesiccant to afford thedesired mesylate.Thisprocedure was used toprepare the mesylate of SCHEME 63-phenylpropanol in 95% yield.TABLE 8. Stability of Tertiary Amine Resins toAcid Chlorides and ChloroformatesAmineResin (R)MemorpholinemorpholineI-PrElectrophile(R1)PhPhMe0Me0CleavageProduct (9'0)90902.5References1. Booth, R. J.; Hodges, J. C. JAm. Chern. Soc. 1997,lZ9,4882.2. Conti, l?; Demont, D.; Cals, J.; Ottenheijm, H. C. J.;Leysen, D. Tetrahedron Lett. 1997,38,2915.3. Yang, B.V. ; OiRoarke, D.; Li J. Synlett. 1993, 195.4. Gooding, 0. W.; Bansal, R. l? Synth. Comm. 1995,25,1155.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT INFORMATIONProduct: PS-NMMPS-NMM is a resin-bound equivalent of N-methyl morpholine(NMM) and is useful as a bound tertiary arninebase for a variety of chemical transformations. Synthesisof amides, sulfonamides and carbamates can be effectec'using filtration as the only purification step when PS-NMM is used in conjunction with PS-Trisamine or PS-Isocyanate as scavenger resins.Chemical Name: 3-(Morpholino)propyl polystyrenesulfonamideCapacity: 1.5 - 2.5 mmol/g based on nitrogenanalysis.Resin-Type: 1% crosslinked poly(styrene-codivinylbenzene)Application: Tertiary arnine baseTypical Reaction Conditions: 2 - 3 equiv ofPS-NMM resin relative to electrophileCompatible Solvents: CH2Cl2 (7.8 mL/g),tetrahydrofuran (5.8 mL/g), dimethylformamidePS-NMM is linked to the polystyrene backbone through apropylene sulfonamide moiety, as opposed to otherresin-bound morpholine bases (eg. morpholinomethylpolystyrene), which are linked at the benzylic position.We have found that the non-benzylic tertiary amine basePS-NMM is significantly more stable than benzylic tertiaryamine base variants in the presence of reactiveelectrophiles like chloroformates. No cleavage of PS-NMM was observed in the presence of methyl chloroformate(CH,Cl,, 16 h), whereas treatment of morpholinomethylpolystyrene under similar conditions led to 90 %cleavage.Representative uses of PS-NMM resin in the formation of(8.7 rnL/g), methanol (2.2 mL/g) amides, sulfonamides, and carbamates are provided inRecommended Agitation: Gentle magnetic Table 9. The data shows that the use of PS-NMM as thestirring, rocking, or overhead stirring for large base in the synthesis of methyl carbamates from alkyl orresin quantities (> 5g)aromatic amines affords the desired carbamate as thesole product. In contrast, use of morpholinomethyl pol:Quantitystyrene as the tertiary amine, resulted in the formation OFmethyl morpholine carbamate as a side product due to800282secondary cleavage of the N-benzyl linked secondary800283 25 g arnine."." The level of methyl morpholine carbamate800284 100 gformed was 16.4 % when aniline was the reactant, eventhough the aniline was used in excess to the chloroformate.Thelevel of cleavage of benzyl-linked tertiaryRepresentative procedureAmide Formation: A reaction vessel wascharged with 0.66 g (1.2 mmol, 3 equiv) of PS-NMM resin, followed by 6 mL of CH2C12.Benzylamine (66 yL, 0.6 mmol, 1.5equiv) and 4chlorobenzoyl chloride(51 yL, 0.4 mmol, 1.0 equiv) wereadded sequentially and the reactionwas agitated for 2 at RT- O.3 g (0.4-0192 equiv) of PS-lsoc~anate wasthen added and the reaction mixed fora further 2 h.The product was filtered,the resin washed 2 x CH2C12 and 1 xTHF, and the combined filtrates concentrated toafford to N-benzyl-4chlorophenyl carboxamide(94.2%, 100% purity by GC).Electrophile4-C1 benzoyl chloridetosyl chloridemethyl chloroformatemethyl chloroformatemethyl chloroformatemethyl chloroformatearnines will be more signscant in cases where thechloroformate is used in excess.TABLE 9. Formation of Amides, Sulfonamides,and Carbarnates Using PS-NMM ResinAmine Resin YieldbenzylaminebenzylaminebenzylaminebenzylamineanilineanilinePS-NMMPS-NMMPS-NMMP-morpholine'PS-NMMP-morpholine'(%)94.292.799.376.567.067.0Purity("A GC)100.089.0100.095.8'100.083.6?1) Morpholinornethyl polystyrene, 2) Contams 4 2 area % Methyl rnorpholmecarbamate, 3) Contams 16 4 area ?6 Methyl morpholmr carbamateReferences1. Booth, R. J.; Hodges, J. C. JAm. Chem. Soc. 1997,119,4882. -2. Conti, I?; Demont, D.; Cals, J.; Ottenheijm, H. C. J.;Leysen, D. Tetrahedron Lett. 1997,38,2915.3. Yang, B.V.; OiRoarke, D.; Li J. Synlett 1993, 195.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT INFORMATIONProduct: PS-DMAPChemical Name: N-(Methylpolystyrene)4-(methy1amino)pyridineCapacity: 1.1 - 1.8 mmol/g (based on nitrogenanalysis). Approximately 0.3 5 rnmol/g capacityfor acyVsulfony1 chloride in "Catch and Release"applications.Resin Type: 4% crosslinked Poly(styrene-codivinylbenzene)Application: Catalyst for acylation reactions,"Catch and Release" applicationsTi'ypical Catalysis Conditions: 10 mol % (0.1equiv) relative to alcohol, overnight, 1 10 " C.Resin Swelling: Toluene (1.8 niL/g), CH,Cl, (3.8mL/g), DMF (2.6 mL/g), THF (1.9 mL/g)Recommended Agitation: GentIe magneticstirring, swirling or overhead stirring for large- resin quantities (>5 g)800288QuantityPS-DMAP is a polymer-bound equivalent of dimethylaminopyridine(DMAP) which may be used as a catalystfor acylation and related reactions. Typical catalysis conditionsrequire 10 - 20 mol% relative to the nucleophile.Catalytic PS-DMAP accelerates the acylation of sluggishnucleophiles, e.g. tertiary alcohols.The application PS-DMAP as a catalyst for the esterificationof tertiary alcohols was investigated using 1-methylcyclohexanol.1~2 A 0.5 M solution of cyclohexano1(1 equiv) in toluene was acylated with acetic anhydride(1.64 equiv ) in the presence of triethylamine(1.5 equiv) and PS-DMAP (0.1 equiv). The reaction mixturewas heated at the reflux temperature overnight. 1-Methylcyclohexane acetate was isolated by filtration,followed by an aqueous workup.Alternatively, MP-Carbonate was added at the completion of the reaction,followed by concentration to remove triethy-1amine.The results of this reaction are given in Table10. The results indicate the PS-DMAP reaction was 95%complete relative to the 98% complete with DW.PS-DMAP may also be used for "Catch and Release" ofacid chlorides TABLE 10. Synthesis ofand sulfonyl 1-Methylcyclohexyl Acetatechlorides tosynthesize aCatalyst Product Purityvariety of acyl( O hand sulfonyl I None I 79.1 Iderivatives, PS-DMAP 94.9includingDMAP97.7esters, arnides,and s~lfonanlides.~~~ "Catch and Release" involves thereaction of the electrophillic partner with PS-DW,forming an N-substituted pyridinium salt which is thenreacted with various nucleophiles such as alcohols,amines, and thiols without the addition of a tertiaryamine base5 The "Catch and Release" of an acid chlorideby an amine is shown in Scheme 7. Key to thisapproach is the ability to purify the resin-bound saltwith solvent washes. By using the nucleophile as thelimiting reagent, the product is isolated in high purity- by filtration, with the excess electrophile remainingbound to the resin. PS-DMAP functions with a loadingof approximately 0.35 mmole/g for "Catch and Release"applications.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PS-DMAP continued .....In "Catch and Release" applications,PS-DMAP is typically allowed to reactwith 2 equiv of acyl or sulfonylhalide in dichloromethane for 1 h atroom temperature.The resin is thenwashed with dichloromethane followedby the addition of 0.7 equivalentsof arnine.After 16 h the productis isolated by filtration and concentration.Table 11 gives the results for arange of arnides and sulfonamidesprepared by this procedure.Particularly noteworthy is the highBenzoyl C1Benzoyl C1Benzoyl C1Tosyl C1Tosyl C1Tosyl C1p-Anisoyl C1p-Anisoyl C12-Naphthalene Sulfonyl2-Naphthalene Sulfonylproduct purity afforded by this methodology, with singlepeak gas chromatograms observed in most cases. Incases where low levels of arnine starting materialremained, scavenging may be accomplished with PS-Isocyanate.Representative ProcedureAlcohol Acvlation: One equiv of alcohol (e.g. 3 ' alcohol)was reacted with acetic anhydride (1.64 equiv), triethylarnine(1.5 equiv), and 0.1 equiv PS-DMAP in toluene(17.5 ml/g of resin) and heated at the reflux temperatureovernight. After cooling, MP-Carbonate (6 equiv)was added and the mixture was agitated for 4 h.Theresin was removed by filtration and washed 2 - 3 x withCH,Cl,.The combined filtrate was concentrated to affordthe desired product.This procedure was used to prepare1-methylcyclohexane acetate in 95% yield. For less reactiveanhydrides or acid chlorides a mixture of PSTrisarnine (1.5 equiv) and MP-Carbonate (4 equiv) canbe used to work up the reaction."Catch and Release"Amide/Sufonamide Formation:1 equiv of PS-DMAP (approximately 0.35 mrnol/g capacity)was quaternized with an acid or sulfonyl chloride (2equiv) in (5 mL/g of resin) and mixed at room temperaturefor 1 h. The resin was washed 5 x with CH,C12 toremove excess acid and/or sulfonyl chloride. 0.7 equivof an arnine in CH2Cl, (5 mL/g of resin) was added andthe reaction mixed at room temperature for 16 h. Theproduct was filtered and the resin washed 3 x withCH,C12, and the filtrate concentrated to afford the arnideor sulfonamide product.This procedure was used to preparecyclohexyl benzamide and cyclohexyl toluenesulfonamidein 83% and 82% yield, respectively.TABLE 11. Amide and Sulfonamide Formationby "Catch and Release" Using PS-DMAP1&nine1 ( Product Purity 1 %Yield 1Cyclohexylamine2,2-DiphenylethylarninePiperonylamineCyclohexylamineBenzylaminePiperonylamineBenzylaminePiperonylamineCyclohexylamineBenzylamine(% GC)100100100100100100100100861001) Catch: PSDMAP = 0.35 mmol/g, 2 equiv R-COCl/R-SO,Cl, dichloromethane1 h. Relrase: 0.7 equiv mine, dichloromethane, 16 h, room temperature.References1. Keay, J. G.; Scriven , E. EV. Chem. Ind., 1994,53,339.2. Guendouz, E ; Jacquier, R.;Verducci, J. Tetrahedron,1988,44,7095.3. Tomoi, M.; Akada,Y.; Kakiuchi, H. Makromol. Chem.,Rapid Commun., 1982,3,537.4. Shai,Y.; Jacobson, K. A.; Patchornik,A. JAm.Chem.Soc,, 1985,107,4249.5. Patchornik,A. Chemtech, 1987,58.6. Based upon experimental findings for "Catch andRelease" applications, an average of 25% of the tot;DMAP sites are available for reaction on PS-DMAP -resin.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

-Product: MP-CarbonateProduct: Macroporous triethylammoniummethylpolystyrene carbonate (1% inorganic antistaticagent)Capacity: 2.5 - 3.5 mmol/g (based on nitrogenelemental analysis)Resin Type: Macroporous poly(styrene-co-divinylbenzene)Application: General base, ammonium salt neutralization,scavenging acids and acidic phenols.Theneutralization of insoluble amine hydrochloridesrequires the use of 0.05 - 0.1 equiv of diisopropylamineas a soluble transfer base.Typical Scavenging Conditions: 3 equiv relativeto substrate, 0.5 to 2 h, 20 "CResin Swelling: CH2C1, (3 mL/g), dichloroethane(3 mWg),THF (2.8 Wg) , DMF (2.9mL/g)Recommended Agitation: Strong magnetic stirring,swirling or overhead stirring for large resinquantities (>5 g). Due to the large bead size of thisresin, effective mixing may not be achieved withthe Quest 210. Optimal mixing may be achievedwith MP-Carbonate in cartridges or filter platesusing rotatory or orbital mixing.800267Quantity800269 100 gRepresentative Procedure: Neutralization ofAmine Hydrochloride Salt of Ephedrine.Reaction: Ephedrine hydrochloride salt (1 equiv)was converted to the free amine with MP-Carbonate (4 equiv) in CH,CI, or Methanol for onehour. Since ephedrine hydrochloride is not solublein CH2C12, a catalytic amount of DIEA (0.05 equiv)was added as a transfer base and was removed duringsample concentration.Reaction Workub: The resin was removed byfiltration and washed 2 x with CH2Cl2. The filtrate- was concentrated to give ephedrine in 100% yield(Meow and 82% yield (CH,Cl,) (NMR purity:100%).MP-Carbonate resin is a macroporous polystyreneanion-exchange resin that is a resin bound equivalent oftetraalkylamrnonium carbonate. MP-Carbonate may beused as a general base to quench reactions, neutralizearnine hydrochlorides or to scavenge a variety of acidicmolecules like carboxylic acids or acidic phenols.Removal of excess carboxylic acids or acidic phenols,e.g. phenol or nitrophenol, from solution generallyrequires 3 - 4 equiv of MP-Carbonate. Removal of excesshindered phenol requires larger amounts of resin, typicallyup to 5-fold excess MP-Carbonate. Completeremoval takes from 30 minutes to 2 hours. Upon completionof the scavenging, the resin is rinsed three timeswith a suitable solvent, including CH,CL,,THF, orethanol.Representative acids and phenol scavenging examplesare presented in Table 12.MP-Carbonate is also very useful for neutralizing trialky-SubstratesTABLE 12. Comparative Scavenging Timesin DichloromethaneBenzoic acidHexanoic acidBromo-Benzoic acidPhenolNitrophenol2-allylphenol2 ,GDimethylphenolMP-Carbonate(Equiv)3434267lammonium salts, e.g. hydrochlorides and trifluoroacetates,to generate the free base. Applications includeneutralizing reactants, products and ammonium salts ofvolatile amines, e.g. diisoproylethylamine (DIEA) or triethylamine,produced in a chemical transformation.Thelater case allows for neutralization and amine removalin the concentration step, circumventing an aqueousworkup. In cases where the ammonium salt is insolublea catalytic amount of DIEA (0.05 - 0.1 equiv) can beadded as a soluble transfer base.References1. Parlow, J. J.; Naing, W.; South, M. S.; Flynn, D. L.Tetrahedron Lett 1997 ,38,7959.MP-TsOH resin is a sulfonated macroporous polystyreneresin that is a resin-bound equivalent of p-toluenesulfon-Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Product: MP-TsOHChemical Name: Macroporous polystyrene sulfonicacid (1% inorganic antistatic agent)Capacity: 1.1 - 1.6 mmol/g based on uptake ofbenzylamineResin-me: Macroporous poly(styrene-codivinylbenzene)Application: Scavenging and "Catch andRelease" of aminesTypical Scavenging Conditions: Approx. 2 - 3equiv of resin relative to amine, 0.5 - 1 h, 20 " CResin Swelling: CH2C12 (3.0 mL/g),THF (3.1mL/g), DMF (3.1 mug), MeOH (3 .O5 mL/g)Recommended Agitation: Gentle magneticstirring, rocking, or overhead stirring for largeresin quantities (> 5g)1 part # Quantity Iic acid (TsOH). The resin may be used as an equivalentto the strong cation-exchange resin, Arnberlyst A-15(Rohm and Haa~).'-~>"' However, MP-TsOH has beenoptimized for use as a bound reagent or scavenger resifor the synthesis of small molecules.The sulfonic acidgroups in MP-TsOH are predominately restricted to thesurface of the macroporous framework and are readilyaccessible for removal of basic compounds, e.g. primary,secondary, and tertiary arnines, by quatenary salt formation.In addition, MP-TsOH does not contain dark leachableimpurities derived from overoxidation of the polystyrenebackbone observed in higher loading sulfonicacid re~ins.~ Representative amine scavenging examples(batch mode) as a function of time are provided inTable 13. MP-TsOH is a useful alternative to quenchingreactions with aqueous or soluble organic acids.MP-TsOH may also be used in cartridge applications toAmineTABLE 13. Afnine Removal by MP-TsOH(Batch Mode)diisopropylamineaniline2-aminobenzophenonebenzylamineN-benzyldiethylamineMP-TsOH(equiv)2.01.51.61.91.8Scavenged20 min lh100 10096 99.663 71100 10099 106,O/OReferencesFlynn, D. L.; Crich, J. 2.; Devraj, RV;; Hockerman,S.L.;Parlow,J .J.;South,M.S.;WoodaM1,S.S.J:Am. Chem. Soc. 1997,119,4874.Gayo, L. M.; Suto, M. J. Te~mhedron Lett. 1997.38,513.Siegel, M.G.; Hahn, I?J.; Dressman, B.A.; Fritz,J. E.; Grunwell, J. R.; Kaldor, S. W. TetrahedronLett. 1997,38,3357.Shuker,A. J.; Siegel, M. G.; Matthews, D. l?;Weigel, L. 0. Tetrizhedron Lett. 1997,38,6149.Lawrence, M. R. ; Biller, S.A.; Fryszrnan, 0. M.;Poss, M.A. Synthesis 1997,553.ParlowJ. J.; Flynn, DL. Tetrahedron 1998,54,4013Suto, M. J.; Gayo-Fung, L. M.; Palanki, M. S. S.;Sullivan, R. Tetrahedron 1998,54,4141.StahIbush, J.R.; Strom, R.M.; Byers, R.G.;Henry, J.B. ; Skelly, N.E. "Prediction andIdentification of Leachables from CationExchange Resins;' 48th Annual MeetingInternational Water Conf., Pittsburgh, PA(Nov. 1987), WC-87-10.perform "catch and release" of amine derivatives in analogyto silica-derived SCX column^.'.^ MP-TsOH (1.4mrnol/g) has approximately double the sulfonic acidcapacity of SCX media (approx. 0.7 mmol/g). In addition,MP-TsOH circumvents the contamination of amineproducts with particulates that sometimes occurs withsilica-derived SCX columns.This is presumably due todissolution of silica by methanol used to elute amineproducts from the media. Representative amine scavengingexamples (cartridge mode) as a function of timeare provided in Table 14.TABLE 14. Amine Removal by MP-TsOH(Cartridge Mode)N-benzyldiethylamine 4.67 9 5-Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

CHEMISTRY SOLUTIONS FOR PARALLELSYNTHESIS AND PURIFICATIONc In order to facilitate a wide range of solutionphase reactions and workups, Argonaut offers acomplete Solution Phase Toohox and convenientsolution kits to meet specific application needs.olution Phase Toolbox10 gram quantities of each: PS-Trisamine,PS-Thiophenol, PS-Isocyanate, PS-TsNHNH,,MP-Carbonate, PS-DMAP, PS-DIEA, PS-NMM,PS-TsCl, MP-TsOHProduct information and procedure cardsArgoScoopTM (precalibrated scoop forconvenient resin measuring)of each: MP-Carbonate,Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

ARGON1 4UTTECHNC ILOGIES887 INDUSTRIAL ROAD, SUITE G, SAN CARLOS, CA 94070TELEPHONE 650.598.1350 FAX 650.598 1359ST IAKOBS-STRASSE 148, POSTFACH 43, 41 32 MUTTENZ 2, SWJTZERLANITELEPHONE 41.6 1.465.9898 FAX 4 1.61 465.9899MK KOllMACHl BLDG 4-2-1, KOIIMACk-11 CHIYODA-KU, TOKYO 102 IAPANTELEPHONE 81.3.3234.4321 FAX 81 3 3234.1359WWWARGOTECH .COM05/99 RELArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

High YieldLow levels ofimpuritiesEnhanced ResinPropertiesArgonaut Technologies has developed ~ r~o~el@ resin -- a family of productsbased on a new polyethylene glycol-polystyrene graft (PEG/PS) co-polymer.These support materials are exceptionally stable under the rigors of solidphase organic synthesis. ArgoGel resins provide a high loading capacity, lowlevels of impurities and exhibit compatibility with a broad range of organicreagents and solvents due to their unique structure and improved purificationprocess.9 High Loading Capacity for High YieldsArgoGel resins provide yields approximately two-fold higher than comparableresins. The copolymer is built on a novel framework consisting of twice thenumber of groups per backbone attachment site. This results in higher loadingcapacity per unit weight without sacrificing the benefits conferred by thepolyethylene glycol graft. ArgoGel-OH and -NH2 have loading values in therange of 0.4-0.5 mmole per gram based on standard analytical techniques.Solvent-swollen ArgoGelbeads provide a solution-likeenvironment for solid-phasesynthesis.2 Low levels of impuritiesJChemical StabilityArgoGel supports enable production of higher purity products. ArgoGelemploys an inert 1,3 diol construct which is linked directly to thepoly(styrene/divinylbenzene) core matrix through a carbon-carbon bond.This chemical linkage minimizes degradation of the PEG chain and loss ofloading by aggressive reagents used during cleavage. The result is more pureproduct per gram of resin.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Low leachable impuritiesPolyethylene-glycol-grafted supports contain impurities that often leach outduring normal solid-phase organic chemistry steps. Of special concern areimpurities which are released during the cleavage of the desired product fromthe support and incorporated into the final product. Argonaut has developedadvanced methods for producing resin with low impurity levels. This leads toadvantages which include the following:Accurate product characterization (e.g., elemental analysis, NMR,mass spectra)Purification is minimized- Purification, if needed (e.g., crystallization), is more readily achieved5Fig. 1IScreening (activitylmg) is easily achieved3~ Enhanced resin propertiesUniform PEG graft chain lengthArgoGel resins have been prepared so that the polyethylene grafts are of uniformlength. This provides greater control and reproducibility over chemicaltransformations on the resin. The DSC (Differential Scanning Calorimetry)endotherm shown in Figure 1 documents the uniformity of the chain graftlength. The endotherm is associated with a phase transition in which polyethyleneglycol graft changes from the solid to the fluid state. The sharpnessof the endotherm reflects the purity and uniformity of the polyethylene graft.Optimum swelling for maximum performanceFig. 2As shown in Figure 2, ArgoGel resin exhibits excellent swelling properties in arange of solvents, from strongly polar protic to moderately polar aprotic.Rapid reaction rates are achieved with ArgoGel because core polystyrenematerial is made to an exacting specification, and through construction ofthe polyethylene glycol graft, the user enjoys solution-like reaction conditions.Particle Size DistributionArgoGel is a white to cream colored crystalline material composed of sphericalbeads approximately 170 pm in diameter. The particle size distribution is120-230 pm (95% within). For particle size distributions outside of these specifications,please contact Argonaut's Marketing Department.ARGONAUT TECHNOLOGIES887 INDUSTRIAL ROAD, SUITE G. SAN CARLOS, CA 94070TELEPHONE 650.598.1350 FAX 650.598.1359ST JAKOBS-STRASSE 148, POSTFACH 43.4132 MUTTENZ 2.SWITZERLANDTELEPHONE 41.61.465.9898 FAX 41.61.465.9899MK KOIIMACHI BLDG 4-2-1. KOJIMACHI CHIYODA-KU. TOKYO 102JAPANTELEPHONE 81.3.3234.4321 FAX 81.3.3234.135905/99 REV WWW.ARGOTECH.COMArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Part Number Description900098 Quest 2 10 Collection Rack for Liquid Scintillation Vials.Collection rack for 20 scintillation vials.9001 10 Quest 2 10 Collection Rack for 20 mm x 125 mm Test TubesCollection rack for twenty 20 mm x 125 mm test tubes.111 Quest 2 10 Collection rack for 13 mm x 100 mm Test TubesCollection rack for twenty 13 mm x 100 mm test tubes.123 Quest 2 1 OD05 Chiller Interface Kit (Quest's with 1/4 in. male pipe fittings).Contains the fittings necessary to interface a Quest 210 or 205 reaction bank to a]ulabo F83-MW Refrigerated Recirculating Chiller.900 1 25 Bubbler Kit.Bubbler allows the visualization of the inert gas flow rate through the Quest 210 or205. Includes 6 if of 1/8 in. ~ eflon~ tubing and 1/8 in. Peek fitting and Tefzel ferrule.900137 Quest 2 10 Chiller Interface Kit (Quest 2 10's with barbed fittings).Contains the fittings necessary to interface a Quest 2 10 with barbed fittings to a-Julabo F83-MW Refrigerated Recirculating Chiller.Septum Luer Plugs (IO/pkg).Septum her Plugs allow the quick andefficient delivery of reagents while maintaininga closed reaction environment.They are used in place of the standardupper manifold luer plugs on the Quest,2 1 O/2O5.Quest 2 10 5 mL Blank ReactionVessels ( 5/pkg).Blank reaction vessels occupy theunused reaction vessels positions andallow syntheses with less than 10 reactionvessels in a reaction bank.Quest 2 10 10 mL Blank ReactionVessels (Vpkg).Blank reaction vessels occupy theunused reaction vessels positions andallow syntheses with less than 10 reactionvessels in a reaction bank.ARGONAUTTECHNOLOGIES Page 1 of 3Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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900158 Microfunnels (20/pkg).Microfunnels facilitate the addition of dry reagents of slurry to the Quest 2 10 reaction vessels.900 1 8 1 Quest 2 1 0 Accessory Bundle.Includes the following Quest 2 10900 182.accessories: 900 125, 900 145, 900 146, 900 147, 900 158 andQuest 2 10 Solid Phase ExtractionRack.Rack that holds up to 20 solid phaseextraction cartridges for on-line purificationdirectly on the Quest 2 10. The rackconveniently fits on the Quest WasteTray simplifying product collection.Quest 2 10 Lower Manifold LuerUpgrade.This kit upgrades a Quest 2 10 with standardTeflon reaction vessel outlet linesto having male luer fittings. This kitallows the direct attachment of SPE cartridgeswith female luer connections foron-line purification. Also enables theuse of bank-to-bank transfer cannulasfor multi-step reactions on the Quest2 10. Kit is user installable and includesten bank-to-bank transfer cannulas. Allparts and tools necessary to perform theupgrade are included.Quest 2 10 Funnel Manifold.This manifold has ten integrated funnelsfor solid reagent addition to a bank ofQuest 2 10 reaction vesselsARCONAWTECHNOLOGIES Page 2 of 3Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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900245 Quest 2 1 0 Transfer Cannulas (1 Olpkg).Cannulas used for bank-to-bank transferof reaction solutions.900248 Quest 2 10 Adjustable Height Scintillation Vial Rack.Scintillation vial rack with adjustable legs for use with SPE cartridges.Holds up to 20 scintillation vials. This rack is included with 900 186 Quest2 10 Lower Luer Manifold Update.Page 3 of 3Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Scientific Resources Page 4 of 10The following literature references are for papers authored by Argonautchemists, customers and affiliates.Glycosidation of Solid-Supported Glycosyl Donors Tethered by aTrialkylsilane LinkerDoi, T., Sugik~, M., Yamada, H.; Takahashi, T ; Porco Jr.,J.A., Tetrahedron Letters, 1999, 40, 2141 -2144.Related Argonaut Products: PS-DESCross-Coupling of Aryl Halides and Allyl Acetates with ArylboronReagents in Water Using an Amphiphilic Resin-SupportedPalladium CatalystUozumi, Y.; Danjo, H.; Hayashi, T J. Org Chem., 1999, 3384-3386Related Argonaut Products: ArgoGel-NH,Polymer-bound N-Hydroxysuccinimide Esters: A Column-FreeFluorescent-Labeling MethodKatoh, M.; Sodeoka, M. Bioorg. & Med. Chem. Letters, 1999,9, 881-884.Related Argonaut Products: PS-ThiophenolA polymer-supported silyl triflate and subsequentfunctionalization: synthesis and solid-phase Diels-Alder reactionsof silyloxydienesSmith, E. M. Tetrahedron Lett., 1999, 40, 3285-3288.Related Argonaut Products: PS-DESEster enolate Claisen rearrangement using a polymer-supportedsilyl triflateHu, Y.; Porco, J. A. Tetrahedron Lett., 1999, 40, 3289-329.Related Argonaut Products: PS-DESSolid-supported reagents in organic synthesisDrewry, D. H.; Coe D.M.; Poon, S.; Med Res. Rev. 1999, l9(2), 97-1 48.The current interest in solid-phase organic synthesis has led to a renewed interest in acomplementary technique in which solid supported reagents are used in solution-phasechemistry. This technique obviates the need for attachment of the substrate to a solidsupport,and enables the chemist to monitor the reactions using familiar analyticaltechniques. The purpose of this review is to increase awareness of the wide range of usefultransformations which can be accomplished using solid-supported reagents.On the Development of New Poly(styrene-oxyethylene) GraftArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Scientific Resources Page 5 of 10Copolymer Resin Supports for Solid-Phase Organic SynthesisGooding, O.W.; Baudart, S.; Deegan, T.L.; Heisler, K.; Labadie, J.W.;Newcomb, W.S.; Porco, J.A.,Jr; van Eikeren, P., Journal ofCombinatorial Chemistry 1999, 1,113.Argonaut Related Product: ArgoGel re-siParallel Synthesis of 1,2,3-Thiadiazoles Employing a "Catch andRelease" StrategyHu, Y.; Baudart, S.; Porco, J. A., Jr., J. Org. Chem., 1999, 64 (3),1049-1 0511,2,3-Thiadiazoles were synthesized in parallel on the Quest 210 using a polymersulfonylhydrazide resin (PS-TsNHNH*) employing a "catch and release" synthesis strategy"Resin capture" of ketones synthesized from Weinreb amides and Grignard reagents(quenched using MP-TsOH resin) afforded resin-bound sulfonylhydrazones. Cyclativecleavage of support-bound sulfonylhydrazones with thionyl chloride afforded 1,2.3-thiadiazoles. Excess thionyl chloride was neutralized using liquid-liquid extraction cartridges.Further functionalization reactions (Stille coupling) on resin-bound sulfonylhydrazones arealso described.Related Argonaut Products' Quest 210, PS-TsNHNH, MP-TsOHParallel Synthesis of 1,2,4-Oxadiazoles Using CDI ActivationDeegan, T. L.; Nitz, T. J.; Cebzanov, D.; Pufko, D. E.; Porco, J. A. ,Bioorganic and Medicinal Chemistry Letters,9 (2) 209-21 2 , 19991,2,4-Oxadiazoles were prepared in parallel on the Quest 210 using 1 ,I '-carbonyldiimidazole(CDI) as a reagent for both formation and cyclodehydration of 0-acyl benzamidoximes. Theuse of CDI facilitates parallel purification of the oxadiazole products by simple liquid-liquidextraction and filtration.Related Argonaut Product: Quest 210Polymer-assisted solution phase (PASP) chemical librarysynthesisFlynn et. al. Med. Chem. Res. 1998, 8:415 219-243.Solution-Phase Library Generation: Methods and Applications inDrug DiscoveryGayo, L.M. Biotechnology and Bioengineering (CombinatorialChemistry), 1998, 61, 2, p. 95.Gel phase MAS I-H NMR as a probe for suprarnolecularinteractions at the solid-liquid interfacede Miguel, R.Y.;Barnpos, N.; Nalin de Silva, K.M.; Richards, S.A.;Sanders, J.K.M., Chem. Commun., 1998,2267.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Scientific ResourcesArgonaut Related Product: ArgoGel resin"Polymeric Supports for Solid Phase Synthesis"Labadie, J., Current Opinion in Chemical Biology 2, 346, 1998Related Argonaut Product: General Resins for Solid PhaseSynthesis"Applications of N-Boc-Diamines for the Solution Phasesynthesis of Ketopiperazine Libraries Utilizing a UgilDe-BoclCyclization (UDC) Strategy"Hulrne, C. , Peng, J. ,Louridas, B., Menard, P., Krolikowski, P., Kurnar,N.V., Tetrahedron Lett., 39, 8047, 1998.Related Argonaut Product: PS-DIEA Resin"Phosgenated p-Nitrophenyl(polystyrene)ketoxime or PhoximeResin. A New Resin for the Solid-Phase Synthesis of Ureas viaThermolytic Cleavage of Oxime-Carbamates"Scialdone, M.A, Shuey, S W., Soper, P., Hamuro, Y., Burns, D.M., J.Org. Chem , 63, 4802-4807, 1998.Related Argonaut Product: Nautilus 2400"Chameleon Catches in Combinatorial Chemistry: TebbeOlefination of Polymer Supported Esters and the Synthesis ofAmines, Cyclohexanones, Enones, Methyl Ketones andThiazoles"Ball, C.P., Barrett, A.G.M., Cornrnercon, A., Compere, D., Kuhn, C.,Roberts, R.S , Smith, M.L., Venier, O., Chem. Commun., 2019-2020,1998."Solid Phase Synthesis of Substituted l-Phenyl-2-aminomethylbenzimidazolesand l-Phenyl-2-thiomethyl-benzimidazoles"Tumelty, D. , Schwarz,M., Needels, M.C., Tetrahedron Letters, 39,7467-7470, 1998.Related Argonaut Product: ArgoGel-Rink-Fmoc"Solid Phase Synthesis of Hydroxamic Acids"Dankwardt, S.M., Synlett, 761, 1998.Related Argonaut Product: ArgoGel-OH"Novel Polymer-Supported Trialkylsilanes and Their Use in Solid-Phase Organic Synthesis"Hu, Y.; Porco, J.A. Jr.; Labadie, J.; Gooding; Trost, B.M., O., J. Org.Chem., 63, 451 8-4521, 1998.Polymer-supported trialkylsilanes were prepared and evaluated as linkers for solid-phaseorganic synthesis. Various silanes were prepared by hydrosilylation of the correspondingpolymer-bound terminal olefin. Loading of substrate molecules was accomplished by eitherdirect reaction with the silane (Si-H) or the more reactive silyl chloride derived fromchlorination of the silane. The loading and cleavage of several alcohols and aromaticderivatives are described.Related Argonaut Product: PS-DESComplimentary reprints available by contacting ArgonautTech n o jog~~.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Scientific Resources Page 7 of 10"Solid-Supported Synthesis of Imidazoles: A Strategy for DirectResin-Attachment to the lmidazole Core"Bilodeau, M.T.; Cunningham, A.M., J. Org. Chem., 63, 2800-2801,1998.Related Argonaut Product: ArgoGel-MB-CHO"Alcoholysis and Carbonyl Hydrosilylation Reactions using aPolymer-Supported Trialkylsilane"Hu, Y.; Porco, J.A., Jr., Tetrahedron Letters, 39, 271 1-2714, 1998Polystyrene-diethylsilane (PS-DES) resin may be reacted with alcohols (alcoholysis) andcarbonyl compounds (hydrosilylation) in I-methyl-2-pyrrolidinone (NMP) using Wilkinson'scatalyst (RhCI(PPh3)3) to afford the corresponding resin-bound silyl ethers. The silyl ethersformed were effectively cleaved using HFIpyridine solution in THF. Methoxytrimethylsilanewas employed to scavenge excess HF from product solutions.Related Argonaut Product: PS-DESComplimentary reprints avadable by contacting ArgonautTechnolog~es."Analysis of 9-Fluorenylmethoxycarbonyl (FMOC) Loading ofSolid-Phase Synthesis Resins by Gas Chromatography"Newcomb, W.S., Deegan T.L , Miller, W. and Porco, J.A. ,Biotechnology and Bioengineering (Combmatorial Chemistry), vol. 61,No. 1, Winter, 1998.This technical article compares several sample manual and automated preparation methodsusing the Nautilus 2400 and finds that the Nautilus can be used to reduce operation time andincrease throughput of sample analysis."Automated Chemical Synthesis: Chemistry Development on theNautilusTM 2400"Porco, J.A. Jr.; Deegan, T.L.; Devonport, W.; Gooding, 0.; Labadie,J.W.; MacDonald, A.A.; Newcomb, W.S.; van Eikeren, P. Drugs of theFuture, 23 (I), pp. 71-78, 1998.The automation of the organic synthesis of small molecules is now a major focus in thepharmaceutical industry. Over the last few years, commercially available instrumentation forautomated organic synthesis has steadily increased, concomittant with the need forincreased throughput for chemistry development and library synthesis. However, it isapparent that further development of robust and inert instrumentation is required to facilitatethe automation of a broad range of synthetic organic chemistries, either on solid-support orusing conventional solution-phase methods. In this chapter, we will describe the Nautilus2400, a chemistry development workstation, and demonstrate examples of its ability 1) tohandle air- and moisture-sensitive reagents 2) to exhibit precise control over reaction time,and 3) to perform individual temperature control in segregated reaction vessels. The result isa useful tool for drug discovery which allows chemists to increase efficiency in chemistrydevelopment, lead optimization, and library synthesis.Related Argonaut Product: Nautilus 2400"Solid-Phase Synthesis of 2-Aminothiazoles"Kearney, P.C.; Fernandez, M.; Flygare, J.A., J. Org. Chem., 63, 196-200,1998.Related Argonaut Product: ArqoGel MB-CHOCombinatorial chemistry using polymer-supported reagentsArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Scientific Resources Page 8 of 10Kaldor, S.W.; Siegel, M.G.,Current Opinion in Chemical Biology, 1997,1:IOl-106."Non-Acidic Cleavage of Wang-Derived Ethers From SolidSupport: Utilization of a Mixed-Bed Scavenger for DDQ"Deegan, T.; Gooding, 0.; Baudart, S.; Porco, J.A. , Jr., TetrahedronLetters, Vol. 38, No. 28, pp. 4973-4976, 1997.Ethers derived from ArgoGel Wang Chloride resin have been prepared and evaluated in bothtrifluoroacetic acid and DDQ-mediated cleavage protocols. DDQ cleavage of resin bound p-alkoxy benzyl ethers has been found to circumvent problems associated withtrifluoroacetylation of alcohol products during TFA treatment. In order to facilitate the removalof excess DDQ and DDQH from cleaved products, a mixed bed ion exchange scavenger hasbeen developed.Related Argonaut Product: ArqoGeI Wang-Cl"Tandem UPS: Sequential Mono- and Dialkylation of Resin-BoundGlycine via Automated Synthesis"Gnffith, D.; O'Donnell, M.; Pottorf, R.; Scott, W.; Porco, J.A.,Jr.,Tetrahedron Letters, Vol. 38, No 51, pp. 8821-882, 1997.A method has been developed for the synthes~s of racemlc a.a-dwbst~tuted ammo ac~ds bya tandem alkylat~on process ("Tandem UPS") on sohd support Consecut~ve alkylat~ons ofWang resm-bound benzophenone mnes of glycme afforded unnatural, dwbst~tuted ammoac~der~vat~ves Automated chem~cal synthes~s was used to effic~ently opt~m~ze cond~t~onsfor both format~on and hydrolys~s of resm bound d~subst~tuted benzophenone lmlnes and togenerate a matr~x of d~subst~tuted ammo ac~der~vat~ves"The Solid Phase Synthesis of Trisubstituted 1,4-Diazabicyclo(4.3.0)nonan-2-one Scaffolds: On Bead Monitoring of HeterocycleForming Reactions Using '=N NMR"Swayze, E., Tetrahedron Letters, Vol. 38, No 50, pp. 8643-8646, 1997.Several representative 3.4,8-trisubstituted 1,4-diazabicyclo(3,4,O)nonan-2-ones have beenprepared employing solid phase smethodologies. Elaboration of a 4-hydroxyproline derivativewith an '5~-amino acid derivative allowed convenient monitoring of the reaction sequence onsolid support by gel-phase I5N NMR. An intramolecular Mitsunobu cyclization provided thedesired heterocycle, which could be further functionalized at the 4-position. This syntheticmethod is facile, general and suitable for the construction of large libraries of compounds forbiological assaysRelated Argonaut Product: ArgoGel-OH"Secondary Amide-based Linkers for Solid Phase OrganicSynthesis"Swayze, E., Tetrahedron Letters, Vol. 38, No. 49, pp. 8465-8468,1997.The electron rich benzaldehyde derivatives 4-hydroxybenzaldehyde and 2-methoxy-4-hydroxybenzaldehyde have been investigated for use as linkers for solid phase organicsynthesis. Reductive amination of these aldehydes attached to ArgoGel resins with a modelprimary amine ggave the corresponding benzylic secondary amines. These compounds werethen converted to the corresponding ureas, sulfonamides, aryl amides, and alkyl amides byderivatization with an appropriate electrophile. The desired secondary amide derivative wasthen cleaved from the support by treatment with trifluoroacetic acid to provide essentiallyquantitative yields of products in high purityRelated Argonaut Product: ArgoGel MB-CHOArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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Scientific Resources Page 9 of 10"Parallel Synthesis of Tamoxifen and Derivatives on SolidSupport via Resin Capture"Brown, S.D.; Armstrong, R. W., J. Org Chem., 62, 7076-7077, 1997.Related Argonaut Product: ArgoGel NH2"Solid-Phase Synthesis of4-Arylazetidin-2-ones via Suzuki andHeck Cross-Coupling Reactions"Ruhland, B.; Bombrun, A,; Gallop, M., J. Org. Chem, 62, 7820-7826,1997Related Argonaut Product: ArgoGeI MB-OH"Synthesis of Benzofuran Derivatives on Solid Support via Sml,-Mediated Radical Cyclization"Du, X.; Armstrong, R.W., J. Org. Chem, 62, 5678-5679, 1997Related Argonaut Product: ArgoGel Rink-NH-FMOC"Solid Phase Synthesis of N-Alkyl Sulfonamides"Dankwardt, S M , Smith, D.B., Porco Jr , J.A ; Nguyen, C H , Synlett,854, 1997.Polymer-supported sulfonamides were alkylated using alkyl halides in the presence of DBUor with alcohols via the Mitsunobu reaction.Related Argonaut Product: ArgoGel WangI996"Automated Chemical Synthesis: From Resins to Instruments"Porco, J.A. Jr., Deegan, T.; Devonport, W., Gooding, 0 ; Heisler, K.;Labadie, J.; Newcomb B.; Nguyen, C.; van Eikeren, P.; Wong, J.;Wright, P., Molecular Diversity, 2, 197-206, 1996.Related Argonaut Product: Nautilus 2400; ArgoGel Resins"Automated Solid Phase Synthesis of Small Organic Molecules: ANew Instrument promises to Automate a Broad Range ofChemical Synthetic Procedures"Hoeprich Jr., P., Nature Biotechnology, Volume 14, October 1996.Related Argonaut Product: Nautilus 2400"Boosting the Productivity of Medicinal Chemistry ThroughAutomation Tools: Novel Technological Developments Enable aWide Range of Automated Synthetic Procedures"Gooding, 0.; Hoeprich Jr., P.; Labadie, J.; Porco Jr., J.; van Eikeren,P.; Wright, P., Molecular Diversity and Combinatorial Chemstry, lrwmM. Chaiken and Kim D. Janda, Editors, 1996.The authors describe novel approaches to automating solid phase organic chemistry throughthe use of an instrument, the Nautilus, and a resin. ArgoGel. The Nautilus synthesizerautomates organic reactions through the use of a computer controlled fluid delivery systemwhich is composed of glass and polytetrafluoroethylene and which is isolated from theoutside atmosphere. ArgoGel resin is a novel polyethylene glycol grafted polystyrenepolymer that provides higher loading and higher acid stability than existing gel phase resins.http://www.argotech.com/sciresources. htm 7/29/99Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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INTRODUCTIONThe ArgoPore family of products is based on ahighly-crosslinked, rigid macroporous polystyreneframework. ArgoPore resin has a high internalsurface area with reaction sites at the surface ofthe internal pore structure. These reaction sitesare accessible without the need for swelling bysolvent as with lightly crosslinked poly(styreneco-divinylbenzene)resins, referred to as gel-typeresins. Therefore,ArgoPore can be used with anysolvent, including water.The unique structure of ArgoPore facilitates the- direct transfer of reaction conditions from knownsolution phase methods to solid phase. Inaddition,ArgoPore is ideally suited for automationwith its unique handling properties: rapidwashing and drying and free-flowing beads whichdo not stick to glass reaction vessels.With ArgoPore, byproducts and impurities may beremoved in fewer washes - with shorter washtimes and using virtually any solvent, evenaqueous acids and bases.BENEFITS OF ARGOPORE AS A SUPPORTFOR SOLID PHASE ORGANIC SYNTHESISThe internal structure of ArgoPore offers numerousadvantages for solid phase organic synthesisincluding:Rapid diffusional access of reagents to thereaction sitesImproved reaction rates at low temperaturesAccess to polymer-supported intermediates thatare soluble only under reaction conditionswhich cause collapse of swollen gel-type resinsExcellent resistance to cracking due to rapidswelling (osmotic shock)Rapid solvent removal in vacuo betweensynthesis stepsLow and predictable swelling in all solvents; idealfor small volume reaction vessels and 96-wellplate applications-ArgoPore resins are available as aminomethyl,hydroxymethyl and chloromethyl base resins.Loading values for these base resins range from0.61.1 mmole per gram. In addition, high loadand low load aminomethyl resins are availablewith capacities of 1.1-1.6 and 0.2-0.6 mmole pergram respectively. ArgoPore linker productsinclude Rink, Wang, arylsulfonamide and 2-methoxy-4-alkoxy benzaldehyde.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

The internal pore structure of ArgoPore has beenspecifically designed for synthesis of organic molecules,and has been characterized by nitrogen adsorptionmeasurements. Pore profile data for ArgoPore-NH,, ArgoPore-CI, and ArgoPore-Wang is given in Table1. The smaller average pore diameter and high totalsurface area distinguish ArgoPore resins from macroporousresins designed for biopolymer synthesis andallows At-goPore to be functionalized to significantlyhigher levels.ResinAverage PureDiameter (A)PoreVolume (Wg)SurfaceArea (m2/g)I 1 I I ITABLE 1. Representative Pore Profile Data ForArgoPore ResinsIt is important to note that the pore data presented inTable 1 is measured on polymer in the dry state andthat further pore expansion occurs with solvent regain.The unique pore profile provides ArgoPore with itsrapid washing, drying and diffusional access to reactivesites that is independent of solvent type.ArgoPore resins do not swell appreciably in the presenceof solvents due to their highly crosslinked nature.The resins undergo an approximately 1X volumeexpansion upon addition of organic solvent due to solventregain into the pore structure. In Figure 1 thevolume per gram of ArgoPore-NH, is compared to a gelaminomethyl polystyrene for a series of solvents.The swelling data shows that the ArgoPore occupies avolume of 4-4.5 mL/g in organic solvents, with a slightlylower value of 3.5 mL/g in water. Solvent uptake isvery uniform as a function of solvent. In contrast, th -gel-type resin swells to 9 mL/g in solvents of mediumpolarity and is not swollen at all in polar, protic solvents.The removal of reaction byproducts from ArgoPore isreadily achieved with solvent washes. Table 2 showsthe comparative retention of an impurity in ArgoPore-Wang and polystyrene-Wang when impregnated with asolution of biphenyl in dichloromethane.' The datashows that the majority of the biphenyl was removedmore rapidly from ArgoPore than gel-type polystyrene,and that the biphenyl was totally removed with fewerwashes for ArgoPore than the gel-type resin. This profilewas repeated with other impurities, such asnitrobenzaldehyde and phenanthrene, with similarresults. Equilibration of impurities between the porephase and the bulk solution occurred more rapidlythan with gel-type resin, after which time the solventwas drained and replenished, resulting in shorter washtimes.BIPHENYL REMOVED (O/o)1I- I I I,ResinWash 1 Wash 2 Wash 3 Wash 1ArgoPore-Wang 91.208.00 0.01 0 -Polystyrene-Wang 81.85 14 98 2.62 0.01TABLE 2. Comparative Impurity Removalof ArgoPore-and Polystyrene-WangDuring the course of synthesis applications onArgoPore, it was observed that removal of coloredimpurities and reactant neutralizations were more rapidthan with gel-type resins and required fewer washes.Protic solvents which do not swell polystyrene, includingwater, aqueous acids and aqueous bases, werefound effective as wash solvents. This demonstrates anadditional advantage offered by ArgoPore for productpurification. It is important to note that ArgoPore mustbe wetted with an organic solvent, e.g. methanol orTHE in order to achieve effective absorption of waterinto the pore structure. Also, it is recommended thatthe final solvent wash after a reaction be methanol, asthis leaves the pores in an open, accessible conditionon drying.DCM THF DMF MeOH WaterSolventFIGURE 1. Swelling of ArgoPore-NH, versus 1%Crosslinked Aminomethyl PolystyreneArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

CHEMISTRY ON ARGOPORE RESINSThe utility of ArgoPore for solid phase organic- synthesis was tested in a number of synthetictransformations. These reactions included examplesthat were known to proceed well on geltypepolystyrene, e.g. Suzuki couplings, to morechallenging organometallic-based alkylations andthose which require protic solvents and aqueouschemistry, hence, do not proceed well on geltypepolystyrene resins.SCHEME 1N,Hla: o-lodolb: /"Od(l6 Eq Boronic Acid. 13 Eq. KOH.0.17 Eq. Pd (11) Catalyst, 90 'C*6 Ea Boron~c Acid. 13 Ea. KOH.N,HSuzuki Biuryl SynthesisThe Suzuki couplings of aryl halides and boronicacids2 ' were evaluated on a Rink amide modifiedArgoPore resin (ArgoPore-Rink-NH-Fmoc) in a comparativestudy with polystyrene-Rink resin, the latter ofwhich was known to be an effective support for thesetransformations. Several sterically hindered biaryl productswere included as target compounds to test theeffect of ArgoPore relative to polystyrene in stericallydemanding couplings. The synthetic approach involvedthe reaction of polymer supported o- and p-iodobenzoicacids (la and lb, respectively) or 2-bromonaphthoicacids (2) wit11 o-toly1,p-methoxypl~enyl and naphthaleneboronic acids, in the presence of a palladium(11) catalyst (Scheme 1, Table 3). In the coupling ofhalides la and lb, the reactions were shown to proceedefficiently to high purity products (entries 1-8,Table 3). ' The results revealed ArgoPore-Rink to performequivalently in most cases. The couplings withpmethoxyphenylboronic acid occurred with significantlyhigher yields on ArgoPore than on the gel-typeanalogs (entries 7 and 8, Table 3). Couplings betweenthe highly hindered 2-bromonaphthoicacid with naphthalene boronic acidshowed low conversion, however, theArgoPore resin gave somewhat higherconversion than the gel-type resin(entries 9 and 10, Table 3). The postreactionresins were quickly and easilywashed and shown to retain negligibleamounts of palladium, boron and phosphorusas determined by elementalanalysis The results demonstrate thatArgoPore is effective in palladium catalyzedcross-coupling reactions.R = o-Tolyl.p-Methoxyphenyl, orNaphthylTABLE3. Suzuki BiarylResinVP~AP-RinkPS-KinkAP-RinkPS-RinkAP-RinkPS-RinkAP-RinkPS-RinkAP-RinkPS-RinkBoronic Acido-Tolyl0-Tolyl0-Tolyl0-Tolylo-Tolyl0-Tolylp-Methoqphenjp-MethoxyphenjNaphthylNaphthylHalidelalalalalblblblb22% Yield(% Purity)76(100)78(100)77(100)X6(100)93(100)89(100)97(100)78(100)77(70)72(76)'%,ConversionI"Lktermined by loading and cleavage of the relecant hdobenzoic acidAlkArgoPore. PS = I Y6 (:rosslinketl poly(styrcnc-co-divi~lylbenzenr)Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Synthesis ofdminoketonesUsing Polymer-SupportedWeinreb AmidesAnother test of establishedchemistryi was performed utilizingArgoPore-Wang in the synthesisof aminoketones by reactionof polymer-supportedWeinreb amides with Grignardreagents (Scheme 2, Table 4)."Various Weinreb amide derivativesof amino acids wereloaded quantitatively on thenitrophenyl carbonate derivativeof ArgoPore-Wang .-Aminoketone formation waseffected by reaction of the resin boundWeinreb amides with a series ofGrignard reagents at 25 -C for 4 h. Itwas found that ArgoPore-Wang performedcomparably with polystyreneresins, however it was necessary toincrease the concentration of Grignardreagent from 0.5 M to 1.OM in order toachieve complete conversion (entries 1and 2, Table 4), which was not the casewith gel-type polystyrene. ArgoPoreshowed higher yield in the case of alkylationof the alanine derivative, and comparableconversion and yield relative topolystyrene for entries 3-6 (Table 4).Phenylalanine derivatives showed conversionsin the 80% range and comparableyields to gel-type polystyrene (entries7-10, Table 4).I-Entry-12345678910R = Leu, Ala, PheTABLE 4. Synthesis of Aminoketones Using Polymer-SupportedWeinreb AmidesIResin Loading' Weinreb Grignardb X Yield %n'pe mmoVg Amide Reagent (X Purity) Conversion-AP-WdngAP-WangAP-WangPS- WangAP-WangPS-WangAP-WangPS-WangW-WangPS-Wang0.730.730.630.9140.630.9140.630.9140.630.914LeuLeuAlaAkaAlaAlaPhePhePhePhem-Tolyl'm-Tolylm-Tolylm-TolylBenzylBenzylnz-Tolylm-TolylBenzylRenzyl~oadings determined by loading and cleavage of nitrophcnylcarbonate, andsubsequent IrV analysishGrignard concentration = 1.0 M in THF'Grignard concrntration = 0.5 M in'l'HFAP = ArgoPore, PS = 1% Crosslinked poly(styrene-co-divinylbenzene)Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Alkylation of AcylsulfonamidesThe rigid nature of ArgoPore offers advantages in chemicalreactions where insoluble intermediates are formedm resin. This is exemplified for alkylation of acylsul-- ionamides using Ellman's variant of Kenner's "safetycatch"linker.x~~llman's work was carried out using amacroporous resin, Rohm and Haas's XE-3051°, and thisstudy sought to repeat the synthesis using ArgoPoremodified with the same arylsulfonamide linker. Thereaction sequence Scheme 3 involved deprotonationof the acylsulfonamide with 3.3 equivalents of base, followedby quenching with an electrophile." l2 Cleavageof the product acylsulfonamide resin was achieved byactivation of the linker with trimethylsilyldiazomethanefollowed by addition of butylamine to afford the alkylatedamide product. When a 1% crosslinked polystyreneresin was utilized in this reaction sequence the resincollapsed (deswelled) during the addition of base, thiswas attributed to aggregationof a polyionic SCHEME 3species. After electrophilequench and cleavage, alow conversion to productswas observed, presumablydue to incompletetrianion formationdue to aggregation (entry+ 1, Table 5). WhenArgoPore modified withthe arylsulfonamidelinker, ArgoPore-AS-SO,NH,, was used, high conversion of the acylsulfonamidewas observed and alkylated amides were recoveredin high purity (Entries 2-8, Table 5). Both lithiumdiisopropylamide (LDA) and lithium hexamethyldisilazide(LiHMDS) were found to be effective bases forthe reaction. Notably, the reaction was effective forArgoPore-AS-SO,NH, when the deprotonation was carriedout at -78 " C, whereas the 1% crosslinked polystyreneresin showed no reaction (Entry 6, Table 5).This result was attributed to the facility to which thebase can reach the reaction sites in ArgoPore by diffusionthrough the pore structure, as compared to thepoor diffusion of base through the polymer gel at lowtemperature in the case of 1% crosslinked polystyrene.This example highlights advantages offered byArgoPore over gel-type polystyrene for certain reactionsinvolving anion chemistry.1) Base0 2) RX0 O- &NHY-/(cH2)mphI I0IEntry123Resin qpe"PS-AS-SO,-NH,AP-AS-SO,-NH, - .AP-AS-SO2-NH2LoadinghmmoVg0.690.570.57BnBrRnBrBnBr76 Yield(X Purity)TABLE 5. Enolate Alkylationof Acylsulfonamides45AP-AS-SO,-NH, - -AP-AS-SO,-NH,0.570.57EtIMe167AP-AS-SO,-NH,AP-AS-SO,-NH; - .0.570.57RnBrRnBr89AP-AS-SO,-NH,PS-AS-SO,-NH,0.490.69BnBrRnBr'AP-AS-SO,NHI = ArgoPore-ArylsulfonamidehDetermined by sulfur elemental analysis'3.3 eq. lh'5 eq, 6-l6h- AP = ArgoPore, PS = 1% Crosslinked poly(styrene-co-divinylbenzene)Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Osmium Tetroxide SCHEME 4Mediated OlefinOxidationsA drawback of solid phaseorganic synthesis on geltypepolystyrene resin hasbeen limitation of reactionsolvent, generally excludingreactions which requireprotic, non-swelling solvents.In contrast, thesereactions are possible onArgoPore and have beendemonstrated for osmiumtetroxide mediated oxidationof olefins to aldehydesin aqueous media (Scheme4). The reaction of vinyl substrateson ArgoPore resin proceededin high efficiency and yield.(Table 6). '' The oxidation of polymer-supportedeugenol (Scheme4) occurred with over-oxidationto the aryl aldehyde. Oxidationreactions did not proceed on geltyperesins, yielding starting materialand unidentified byproducts.SubstrateEugenol (4)Eugenol (A)2-propen!lphenol (R)9-decenoic acid (C)The excellent compatibility of ArgoPore resins with awide variety of reaction conditions facilitates the directtransfer of solution phase synthesis conditions to solidphase. Particularly, reagents and solvents from a solutionphase procedure can be successfully transferreddirectly to solid phase synthesis on Argo130re withoutconcern of swelling properties. In general, higher temperaturesand longer reaction times are often requiredrelative to solution chemistry. Other examples ofwhere solution phase reagent/solvent con~binationsand concentrations were used without modificationinclude, osmium tetroxide mediated olefin oxidation,titanium (111) chloride reduction of nitro groups, andsodium borohydride reduction of aldehydes.li In optimizingthese reactions on ArgoPore, only the reactiontime and temperature were varied relative to the successfulsolution phase conditions.Os04, Na104*-H-0 MeCNResinArgoPore-WangArgoPore-Wng76 Yield (X Purity)89 ( 100)Recovered StartingMaterial79 (100)93 (91)76 ConversionTABLE 6. Osmium-Mediated Olefin Oxidations-Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

LOther Argonaut References for ArgoPore Resins"Consumables for Organic Synthesis," 1998 Catalog"Chemistry Products for Parallel Organic Synthesisand Purification," PL-006 Price List1. Resins were incubated with a solution of biphenyl (mL, 32mF/mL in DCM) forIh. The biphenyl solution was drained and the filtrate collected. DCM (41111)\\as added and the resin agitated for imin. The DCM wash was drained andthe filtrate collected as a separate fraction. This was repeated a fnrther 5 times.Each fraction was analyzed bp capillan gas chromatography using naphthaleneas an internal svandard.2. 111 a typical experiment. Y-iodobenzoic acid (0.4irnmol) was coupled toi\rgoPore-Kink resin (0.58 nimoVg, LOOrng, 0.1 16 mmol) in the presence of 4-li?drox~l~enzoletri:noIe (0.3 mmol), diisopropylcarhodiimide (0.-5 mmol).DMF (2 mL), and agitated at 25 "C for 1% Wiashing IW.S conducted with DMETIIF, DCM and MrOH. Snmki hiql coupling of the resulting bcnzamide to o-tolylhoronic acid (0.9 mmol) was conducted in the presence of I'dCI,(PPhJ2(0.0255 mmol), aq. KOH (1.95 mmol, 2M), DME (1.6 mL) and agitated at 90°Cfor 3h. kshing was conducted with DMI, DMFJH,O. 0.2M HCI, and MeOH.T. Rvanabe, h. Miyaura, A. Suzuki. .Sj~zbtt. 1992. LO'.X Yield determined gra\irnetric;dl!-; % Conversion \\as deternlined h) comparisonof 1IPI.C area%, of the svarting material to that of all other products; 'purity\\.as determined hp comparison of IIPLC area% of the desired product to allnon-starting material products. These determinations \\ere used in allchemistries described in this document.T. Deegan, J. Porco, Jr.,Arfionaut Techrzol~~gies;l~p/icatio~t .\htt?#005.a) J.A. Fcrentz, M. Paris, A. Heit7, J. Velek. C.-E Lui. F. U'internitz, J. Martinez.Tetrc!hedron Lett., 1995,36, 78-1; h) T.Q. Dilin, K.W. Armstrong,TWmhedron Lett.. 1996,37, 1161.In a hpical experiment. 4-nitrophenylchlorofor~i~ate (0,'s mmol) \!as coupledto ArgoPore-Wang resin (0.15 mmol. 0.-5 mmol/g) in the presence of N-meth!-lmorpholinc (1.5 mmol) and 1)CM (2 mL) for at 25 "C for rh. Washingwas conducted with MeOIl. MeOWHJ), THF and MeOIl. To nitrophenylcarhonateresin in SMP (2 niL), was added the TFA ralt of Boc-Leu-Snle(OMe)(1.OM. I .5 mmol), DlEA (2.25 mmol) and agitated at 25 T for 1811. Washing\\.as conducted with KMI', DMF, THE DCM and MeOH. The carbamate functionalizetlresin ws rinsed with dl? THF (2 mL) hefore addition of bennlmagne-siumchloride (3.0 mmol). The solution ms agitated at 25 T for ~ h Washing .was conducted \vith DMF, DMF/H?O, TMF, IPA. DCM and MeOH.B.J. Rackes. J.A. E1lman.J dm. Cheni. Jbc., 1994. 116, 111'1.G.W Kenner. 1.R. McDermott. . Jr.,./. . Am. C1)ent. .Sot.. 1971, h3(1.10. Rohm & Haas's XE-305 resin is a low cross-linked niacroporous resin which isno longer commerciallv available.11. In a t!;ical experimen;, phenylacetic acid has loaded on the arylsulfonaniidensing the symmetric anh!dride as described in reference '. The resulting acplsulfonamideresin (0.13 mniol) in 1.3 ml. of THF at 0 "C \\.as treated with 0.65rnL of LDA (2 M. 1.3 mmol) to afford dark green colored heads (LIIMDSafforded orange colored heads). .2fter 1 h at 0 'C. benzyl bromide (2 mmol)uas added and the reaction was stirred overnight. The rpaction ws quenchedwith 3:l methanol /acetic acid and the resin waslied with DMFhvater. TFMTHF,'I'HF, MeOH. and dried in zwctio. The acplsulfonlmiide was activated for cleav-I2j364; b)Patchornik, it.: Kraus. MA., &I. Chem. Soc. 1970.92, '889.13. K. I'appo, D.S. Allen. Jr.. R.L'. Lemiew, W.S. Johnson. J 0%. Chetn., 1956,21.+'8.Ir. In a typical experiment, eugenol (0.75 mmol) was reacted xith Wang resin(0.75 mrnol/g, 0.15 mmol) in the presence of tribut!lphosphine (0.75 mmol),15age hy adding 1 ml. THF, followed by trimethylsilyldizizo1i1etI~a1ie in hesane (1.6mmol) which resulted in mild gas evolution. After 2 11, the solution wasdrained and the resin nashed THE MeOH. and TIIF To the resin in TIlF wasadded 0.2 mI. of butylaniine and the mixturc was agitated overnight. The contentsof the cartridge were drained into a collection flask and the resin wasrinsed DCM and THE The comhined filtrate nas concentrated to afford themide product.Macroporous resins have been reported to he effective in ester enolate acylationsand alkylations. cf: Y.11. Chang and W. T. Ford, .I. 01;s. Chent. 1981, 46,1.1'-x~obis(N,N-dimetlglfor~~a~nide) (0.75 mmol), DCM (1 ml.) and tolnene(1 mL) at 25 "C for 41. The resin?, \\.ere \xwhed with 1)MF. THF, IICM andMeOH. The olefin functiondized resin \\.as rinsed with acetonitrile. Water (2mL), sodium periodate (O.'j mmol), osmium tetroaide (0.00'5 mmol. 4 wl%in wter) were added and the solution heated at 7O Y; for 1-h. The resins werewashed with DMF. TIIF, IXM and MeOH.Reduction of 3- and 4-nitrohenzoate esters on Argol'ore reductions were car-ried \\.it11 six equivalents ol a L: 1 mixture of LO'): TiCl; and acetonitrile at60 "C for 3 h. i\ldehy& reductions on 3- and 4-formyl benzoate sith file equivdentsof sodium boroh!dride in MeOH at 4 j 'C for I h 11. Methoxide mediatedcleavage afforded high purity amino and hydrosymeth~l substituted methyl henzoatesin 7O-9O'% vield.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

ArgoPore i~ a registered trademurk of Argoncut TechnologiesArgoPore contain s re.rin rnunufactured under one or more of U.S. Patents 4,297,220 and 4,382,1240 Cop,vrighr 1998 Argonaut TechnolofiiesARCONATECHNO887 INDUSTRIAL ROAD SUITE G SAN CARLOS CA 94070TELEPHONE 650 598 1350 FAX 650 598 1359ST IAKOBS-STRASSE 148 POSTFACH 43 41 32 MUTTENZ 2 SWITZERLANDTELEPHONE 41 61 465 9898 FAX 4 1 6 1 465 9899MK KOJlMACHl BLDG 4 2 1 KOIIMACHI CHIYODA-KU TOKYO 102 IAPANTFLEPHONE 81 3 3254 4321 FAX 81 3 3234 1359WWW ARGOTECH COM12/98 REV3Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

1% crosslinked poly(styrene-co-divinylbenzene)resin, commonly referred to as simply polystyrene,is a widely used solid support for organicsynthesis.The many references for polystyrene inthe literature provide a rich source of informationfor chemists planning solid phasechemistry. Some aspects of polystyrene resinthat contribute to its wide use are:stabilityhigh loading capacitygood swelling characteristicscompatibility with a variety of non-proticsolventslow costIn order to provide a full line of resins for solidphase organic synthesis,Argonaut Technologiesoffers three resin types: polystyrene, ~rgoPore@and ~rgo~el@ - each with distinctive characteristics.For a wide range of reactions, standardpolystyrene resins provide a cost-effectiveoption. But due to the hydrophobicity ofpolystyrene divinylbenzene, aqueous or otherprotic solvents do not result in the resinswelling necessary to enable reagents to reachthe reaction sites inside the polymer bead. Forchemistry in protic solvents,ArgoPore resin,based on a highly-crosslinked macroporouspolystyrene framework, or ArgoGel resin, basedon a polyethylene glycol (PEG) graftedpolystyrene, are good alternatives.Linkers provide attachment sites for differentfunctional groups and are subject to differentcleavage conditions. It is important to have a varietyof linkers available in order to allow for flexibility inthe selection of reaction conditions and reagents.Argonaut's polystyrene-based resins offer high purityand high loading capacities. Total extractables aretypically less than 0.2%. Chloromethyl andaminomethyl base resins are available with a loadingrange of 1.2-1.7 mmol/g. Linker products includeKink,Wang, arylsulfonamide, 2-methoxy-4-alkoxybenzaldehyde and butyl diethylsilane (DES).Argonaut's resin products based on 1% crosslinked~>oly(styrene-co-divinylbenzene) are denoted by PS inthe product name.Argonaut's novel PS-DES resin is similar to aTES (triethylsilyl)group in terms of chemical stability, and isgenerally useful as a linker for solid phase synthesis,for the attachment of alcohols, carbonyls, acetylenesand aromatics.In addition to the standard quantities listed in thisdocument, Argonaut's polystyrene resins are alsoavailable in larger bulk quantities and pre-weighed inArgo~aps.'"These capsules are a time-saving, convenientway to deliver fixed units of resins to a reactionvessel.ArgoCaps protect resins from moisturebut are constructed of a polymer which is easily dissolvedwith dichloromethane.#3 size ArgoCaps each contain approximately 150mg of polystyrene resin.#5 size ArgoCaps each contain approximately 65mg of polystyrene resin.Custom resin filling of ArgoCaps is available; pleasecontact Argonaut for more information.LArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Product: PS-ClThis chloromethyl polystyrene derivative (commonlyknown as Merrifield' resin) may be used for directloading of carboxylic acids via their cesium-This resin is also useful as a linker for secondaryamines. 'Chemical Name: Chloromethyl polystyreneCapacity: 1.3 - 1.7 mmol/g (determined byVolhard titration)Bead Size: 100 - 200 mesh (75 - 150 microns)Resin Swelling: CH,Cl, (8.7 mL/g),THF (8.3mL/g), DMF (6.0 mL/g)Linker Functionality: Acids, secondary aminesReaction Conditions Tolerated: Acidic, neutral,mildly basicTypical Cleavage Conditions: Alkoxide inalcohol or alcohol/THFProducts: Esters, aminesRecommended Agitation: Gentle magneticstirring, rocking, or overhead stirring for largeresin quantities (> 5g)References1. Merrifield, R.B. JAm. Chem. Soc. 1963,85,2 149.2. Gisin, B.E Helzi Chern.Actu. 1993.56,1476.3. Frenette, R.; Friesen Tetrahedron Lett. 199449,9 177.4. Conti, F! et al. Tetrahedron Lett. 1997,38,2915.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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PRODUCT INFORMATIONProduct: PS- WangRecommended Agitation: Gentle magnetic stirring,rocking, or overhead stirring for large resinquantities (> 5g)Chemical Name: [4-(Hydroxymethy1)phenoxy]methyl polystyreneCapacity: 1.0 - 1.4 mmol/g (determined by Wquantification of Fmoc chromophore after loadingFmoc-glycine)Bead Size: 100 - 200 mesh (75 - 150 microns)Resin Swelling: CH2Cl2 (6.3 mL/g),THF (8.0mL/g), DMF (7.0 mL/g)Linker Functionality: Acids, amines, phenolsReaction Conditions Tolerated: Mildly acidic,neutral, mildly basicvpical Cleavage Conditions: Ester and carbamatelinked products and generally cleaved withtrifluoroacetic acid/dichloromethane mixtures.Carbamate cleavage via amine-mediated cyclizationto hydantoinsl and quinazoline-2,4-diones2has also been effected.Products: Acids, amines, phenolsThis resin is modified with p-hydroxybenzyl alcohol(commonly known as Wang linker). Carboxylic acidderivatives are readily coupled onto PS-Wang usingDMAP-catalyzed esterification conditions (e.g., diisopropylcarbodiimide (DIC)/methylene chloride/cat.DMAP).Amines can also be attached to PS-Wangusing the 4-nitrophenyl carbonate derivative. 'J [A]PS-Wang may also be used as an effective linker forphenols; in this case the Mitsunobu reaction is thepreferred method to load the resh3References1. Dressman, H.A. ; Spangle, L.A.; Kaldor, S.W.Tetrahedron Lett. 1996,j 7,937.2. Gouilleux, L.J.; Fehrentz, J.A.;Winternitz, E; Martinez,J., Tetrahedron Lett. 1996,37,7031.3. elf: (a) Krchnak,V; Flegelova, 2.; Weichse1,A.S.; Lebl,M., Tetrahedron Lett. 1995,.?6,6193. (b) Rano,T.A. ; Chapman, K.T., Tetrahedron Lett. 1995,36,3789.[A] The preparation of the nitrophenyl carbonatederivative of the resin and the subsequent loadingwith amines is performed by analogy to ArgoGel--Wang. (ArgoGel-Wang Data Sheet DS-006,ArgonautTechnologies)Part #Q~Y800351 10 g800295 25 g800296 100 g800319 50 #3 ArgoCaps800320 100 #3 ArgoCaps800321 500 #3 ArgoCaps800322 1000 #3 ArgoCaps800335 50 #5 ArgoCaps800336 100 #5 ArgoCaps800337 500 #5 ArgoCaps800338 1000 #5 ArgoCapsArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

-Product: PS-MB-CHOChemical Name: (4-Formyl-3-methoxyphenoxy)methylpolystyreneCapacity: 1.0 - 1.4 mmol/g (determined bynitrogen analysis of the 2,4-dinitrophenyl hydrazonederivative)Bead Size: 100 - 200 mesh (75 - 150 microns)Resin Swelling: CH,CI, (8.4 mL/g),THF (7.5mL/g), DMF (6.2 mL/g)Linker Functionality: AminesReaction Conditions Tolerated: Mildly acidic,basicTypical Cleavage Conditions: Activation withan isocyanate, sulfonyl chloride or acyl derivativefollowed by tratment with 95:5 trifluoroaceticacid:water or 95:5 trifluoroacetic acid:triethylsilane.Efficiences for cleavage depend on thenature of the amine and electrophile subsituent.Products: Amines, amides, sulfonamides, ureas,heterocyclesRecommended Agitation: Gentle magneticstirring, rocking, or overhead stirring for largeresin quantities (> 5g)This resin is useful for attachment of amines byreductive amination.' The conditions for reductiveamination are similar to those reported for ArgoGel-MB-CHO [A], with the exception that sodium borohydridein THF/ethanol (3: 1) is used as the reducingagent."") Activation with an isocyanate, sulfonylchloride or acyl derivative can be used as a diversitystep allowing the preparation of amides, sulfonamidesand ureas.References1. (a) Fivush, et al., Tetrahedron Lett., l997,38,7 15 1. (b) Sarantakis, D., Tetrahedron Lett., 1997,38,7325.[A] ArgoGel-MB-CHO Data Sheet,ArgonautTechnologies, DS-0 12.General References for MB-CHO LinkerBilodeau, M.T.; Cunningham, A.M., J. Org. Cbem.,1998,63,2800.Kearney, PC.; Fernandez, M.; Flygare, J.A., J. Org.Cbem., 1998,6.?, 196.Swayze, E., Tetrahedron Lett., 1997, 38,8465.-part #Qty800352 10 g800298 25 g800299 100 g800327 50 #3 ArgoCaps800328 100 #3 ArgoCaps800329 500 #3 ArgoCaps800330 1000 a3 ArgoCaps800343 50 #5 ArgoCaps800344 100 #5 ArgoCaps800345 500 #5 ArgoCaps800346 1000 a5 ArgoCapsArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

PRODUCT INFORMATIONProduct: PS-Rink-NH-FrnocRecommended Agitation: Gentle magnetic stirring,rocking, or overhead stirring for large resinquantities (> 5g)This polystyrene resin is fiinctionalized with a modifiedRink linker.' The linker is attached to anaminomethyl functional polystyrene and is stable tostrong protic acids normally used for compoundcleavage. As a result, colored linker-derived by-productsare not formed during cleavage as is the casewith a benzylic-phenoxy linked system.Chemical Name: 4-(2,4-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxyacetamidoaminomethyl polystyreneCapacity: 0.7 - 1.2 mmol/g (determined by UVquantification of Fmoc chromophore)Bead Size: 100 - 200 mesh (75 - 150 microns)Resin Swelling: CH,CI, (7.0 mL/g), THF (6.0mL/g), DMF (5.8 mL/g)Linker Functionality Acids, aldehydes, sulfonylchlorideReaction Conditions Tolerated: Neutral, basicTypical Cleavage Conditions: 95:5 trifluoroaceticacid:water or 5% trifluoroaceticacid:dichloromethaneProducts: Arnides, amines, sulfonamides, ureasThe linker is supplied in Fmoc-protected form andrequires treatment with 20% piperidine/DMF priorto use. The derived resin-bound benzhydrylamine iscommonly used in the solid phase synthesis of carboxamidesand sulfonamides2 and in condensationreaction^.^References1. Rink, H. Tetrahedron Letters, 1987,28,3787.2. Beaver, K.A.; Siegmund,A.C. Tetrahedron Letters,1996,37,1145.3. Sutherlin, DJ?; Stark,T.M.; Hughes, R.;Armstrong,R.WJ Org. Chervz., 1996,61,8350 and references -cited therein.Part #QV800353 10 g800301 25 g800302 100 g800323 50 #3 ArgoCaps800324 100 #3 ArgoCaps800325 500 #3 ArgoCaps800326 1000 #3 ArgoCaps800339 50 #5 ArgoCaps800340 100 #5 ArgoCaps800341 500 #5 ArgoCaps800342 1000 #5 ArgoCapsArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

This is an excellent resin for the production of carboxylicacid derivatives since acylsulfonamides arestable to both strongly basic and acidic conditionsand are only activated for cleavage under a narrowrange of conditions. This linker system has beensuccessf~illy utilized by Ellman and co-workers in theelaboration of a phenylacetic acid core using a tandemSuzuki reaction/enolate alkylation protocol.'Chemical Name: Arylsulfonamide polystyreneCapacity: 0.9 - 1.3 mmol/g (determined by sulfuranalysis)Bead Size: 100 - 200 mesh (75 - 150 microns)Resin Swelling: CH,CI, (3.7 mL/g),THF (7.1mL/g), DMF (7.1 mL/g)Linker Functionality: AcidsReaction Conditions Tolerated: Acidic, basicTypical Cleavage Conditions: Activation/cleavageis effected by alkylation with (trimethylsi-1yl)diazomethane or iodoacetonitrile, followedby treatment with a nucleophile (amine, hydroxide,etc.) to release a carboxylic acid derivative(e.g., amide).l [A]Products: Acids, amides, estersRecommended Agitation. Gentle magneticstirring, rocking, or overhead stirring for largeresin quantities (> 5g)References1. Backes, B.J.; Ellman, J.A.J Am. Chem. Soc. 1994,116,11171.[A] Loaded by analogy to ArgoGel-AS-SO,NH,.(ArgoGel-AS- S02NH2 Data Sheet DS-005,Argonaut Technologies.)Part #Qty800354 10 g800304 25 .!3800305 100 g800331 50 #3 ArgoCaps800332 100 #3 ArgoCaps800333 500 #3 ArgoCaps800334 1000 #3 ArgoCaps800347 50 #5 ArgoCaps800348 100 #5 ArgoCaps800349 500 #5 ArgoCaps800350 1000 #5 ArgoCapsArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

4Product: PS-DESChemical Name: Butyl diethylsilane polystyreneCapacity: 0.6 - 1.0 mmol/g (determined byreduction of trityl bromide and quantitation ofthe triphenyl methane produced)Bead Size: 100 - 200 mesh (75 - 150 microns)Resin Swelling: CH,Cl, (8.4 mL/g),THF (8.2mL/g), DMF (3.1 mL/g)Linker Functionality: Alcohols, carbonylgroups, acetylenes, aromatic compoundsReaction Conditions Tolerated: Acidic, basicTypical Cleavage Conditions:AcOH/THF/water (6:6: 1,50 - 80 deg. C) for primaryand secondary alcohols.TBAF (THF) orHF/pyridine/THF (25 deg. C) may also be used.Electron-rich and neutral aromatics cleaved usingTFMDCM, electron-poor using TBAE1Products: Alcohols, aromatics, acetylenes, heterocyclesRecommended Agitation: Gentle magnetic stirring,rocking, or overhead stirring for large resinquantities (> 5g)Part #Qty300142 10 g800143 25 g800 144 100 g8001 45 50 #3 ArgoCaps800 146 100 #3 ArgoCaps800147 500 #3 ArgoCaps800 148 1000 #3 ArgoCaps800184 50 #5 ArgoCaps800 185 100 #5 ArgoCaps800 186 500 #5 ArgoCaps800 187 1000 #5 ArgoCapsSilyl-derivatives are widely used to protect variousfunctional groups such as alcohols, phenols,carboxylic acids, amines, acetylenes, and aromaticcompounds." They are inert to a wide range ofsynthetic transformations, but can be easily removedunder selective conditions (e.g. HF/pyridine, fluorideion).Typically, they are produced by the reaction of asilyl chloride and the corresponding functionality(alcohol, carboxylic acid, acetylene, Grignard oralkyllithium derivatives).Polymer-supported silyl chlorides and arylsilanederivatives' have a number of limitations:Polymeric silyl chlorides are reactive and unstableto hydrolysis leading to poor shelf life.Displacement of silyl chlorides is difficult tomonitor using standard spectroscopic techniques.For many traceless applications, aromatic scaffoldsare attached to a silicon-containing handle whichis subsequently attached to the solid support.' "'Argonaut's PS-DES resin has a silane (Si-H) moietywhich offers a number of unique advantages:Stability to moisture for long shelf life.Direct attachment of functional groups (e.g.alcohol," carbonyl," aromatic, or unsaturatedderivatives) without prior transformation to -activated silylating agents (e.g. silyl chloride).Efficient transformation into a reactive silylchloride derivative which can be used immediately,before hydrolysis or degradation can occur.Ability to monitor reactions using IR spectroscopyby examination of the Si-H stretch (2100 cm-').PS-DES resin may be chlorinated to form the silylchloride derivative by treatment with trichloroiso-Figure 120 -PS DES Cl4000 3500 3000 2500 2000 1500Wavenumbers (cm-I)Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

cyanuric acid in DCM, or withl,3-dichloro-5,5-dimethylhydantoinAldrich) in DCM (Scheme l).liThe- latter procedure allows completeremoval of reagent-derived impuritiesprior to treatment with nucleophilesand is recommended for all applicationswhere the silyl chloride is utilized(alcohol loading, alkyl lithium, andGrignard addition).The silyl chloride intermediate is verymoisture sensitive and should behandled under an inert environment,washed with anhydrous solvents, andused in situ immediately after generation.In this case, examination of the Si-H stretch (IR:2100 cm ') may be usedto effectively monitor the progress ofthe chlorination (Figure 1).Primary and secondary alcohols (ROH)may be attached to PS-DESK1 resin bytreatment with a DCM solution ofalcohol (3 equiv.) and imidazole (3.5equiv.) for 4 hrs at 25 " C. Represent-~tivexamples carried out in our- laboratories are provided in Scheme 2.A common procedure for both directattachment of alcohols and hydrosilylationof carbonyl compounds to PS-DESresin in 1-methyl-2-pyrrolidinone (NMP)uses Wilkinson's catalyst to provideresin-bound silyl ether products.li(Scheme 3)Scheme 1Scheme 2Cleavage of silyl ethers attached to PS-DES may be performed using a 0.3 MHF/pyridine solution in THF for 2 hrs. "'Alternatively, excess HF may bescavenged using methoxytrimethylsilane(MeOSiMe,) which forms theneutral byproducts FSiMe, and MeOH and allowsdirect concentration of cleavage mixtures withoutfurther purification. li Alternatively, cleavage of silylethers derived from primary alcohols was effectedby treatment with 6:6: 1 AcOH/THF/H,O (50 " C, 4-8h). Silyl ethers of secondary alcohols may requirelonger treatment (eg. 60-80 " C, 8-12 h).-Aromatic compounds may be loaded to 13-DES resinby chlorination of the resin using 1,3-dichloro-5,5-dimethylhydantoin, washing to remove reagent-based?Ft-SiSi\\Et ROHIimidazole \ 'EtCI 0.DCM, 4hR&HF-pyridineTTHF\'Et0. R orAcOH/THF/H20(6:6:1)ROH(1 or 2O ROH) Yield after cleavage(3 steps)(s)-(-)-l-(2-methoxybenzoyl)-2-pyrrolid1nemethanol 79%1 -naphthaleneethanol 91%N-Fmoc-ethanolamine 72%1 -(4-methoxyphenoxy)-2-propanol 75%trans-2-phenylcyclohexanol 60%epiandrosterone 77%Scheme 3Scheme 4Si\'~tCI6.iAr-Li\'Et, Ar-78OC to rtTH F1) HFIpyridineTH F2) MeOSiMe(HF scavenger)impurities, and addition of aryl lithium reagents inTHF (-78 " C) (Scheme 4; Table 1). '- IX Electronrich,neutral, and electron-poor aromatics wereloaded using this method and cleaved usingTFA/DCM (1 : 1) for electron-rich aromaticderivatives"' and TBAF for electron-poor aromatics.'"Aromatic derivatives attached to the linker thusbehave similarly to the traceless linker systemreported by Ellman in terms of conditions requiredfor cleavage. 'ROHArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Table 1ArReferencesMethodYieldWoolard, F. X.; Paetsch, J.; Ellman, J. A. J 0%. Chem.l997,62,6102.Greene,T.W.;Wuts, P. G. M. in Protecting Groupsin Organic Synthesis, John Wiley and Sons, 1991,68.Kocienski, I? J. in Protecting Groups, Thieme,1994, 28.Farral, M. J.; Frechet, J. M. J. J. Org. Chem. 1976,41,3877.Chan,T.; Huang, WJ. Chem. Soc., Chem. Commun.1995, 909.Randolph, J.T.; McLure, K. E; Danishefsky, S.J.JAm. Chervz. Soc. 1995, 117,5712.Stover, R. D. H.; Lu, I?; Frechet,]. M. J.J. PolymerBulletin 1991, 25,575.Stranix, B. R.; Liu H. Q. ; Darling, G. D. J. Org. Chem.l997,62,6183.Boehm,T. L.; Showalter, H. D. H.J. Org. Chem.1996,61,6498.Newlander, K.A.; Chenera, B.;Veber, D. E;Yim, N.C. E; Moore, M. L.J. Org Chem., 1997,62,6726.For alcoholysis of hydrosilanes with TBAF in solution,see:Tanabe,Y.; Okumura, H.; Maeda,A.;Murakami, M. Tetrahedron Lett. 199435,8413.For rhodium-catalyzed alcoholysis of hydrosilanesin solution, see: Doyle, M. P; High, K. G.; Bagheri,V; Pieters, R.J.; Lewis, I? J.; Pearson, M. M. JI Org.Chem. l990,55,25.For hydrosilylation of carbonyl compounds insolution, see: a). Ojima, I.; Nihonyanagi, M.;Kogure, T.; Kumagai, M. ; Horiuchi, S. ;Nakatsugawa, K. J. Organorvzet. Chem. 1975,94,449. b). Mukaiyama,T.; Izumi, J.; Shiina, I. Chem.Lett. 1997, 187. c). Fujita, M.; Hiyama,T. J Org.Chem. 1988,53,5405.Representative procedure for chlorination of PS-DES resin:To a 5 ml round bottom flask wasadded under argon 100 mg of PS-DES resin (0.75mmol/g, 0.075 mmol), and a small magnetic stirringbar. 44 mg (0.225 mmol) 1,3-dichloro-5,5-dimethylhydantoin in 0.8 mI. DCM was thenadded.The mixture was stirred at room tempera-ture. After 2 h, the mixture was washed withanhydrous DCM (3 x 3 mL) and anhydrousTHF(3 x 3 mL) under argon.The resin was irnmediatelyused for further transformations. -15. Hu,Y; Porco, J.A.,Jr.., Tetrahedron Lett. 1998,39,2711.16. After cleavage, the resin was washed with THF (3x).The filtrate was treated with a saturated solutionof NaHCO,, and an EtOAc solution ofanthracene (internal standard) was added. Afterextraction with EtOAc, the organic layer wasused for GC quantification.17. Loading qf 4-phenoxyphenyl bromide: To 500mg of PS-DES resin (0.75 mmol/g, 0.375 mmol)was added 220 mg of 1,3-dichloro-5,5-dimethylhydantoin(1.125 mmol) in 4 mL DCM underargon.The mixture was stirred for 2 h at st. Theresin was washed with anhydrous DCM (3 x 7mIJ and anhydrous THF (3 x 7 mL) under argon.To the resin was added at -78 " C 5 equiv. of 4-phenoxyphenyllithium (generated by treating 4-phenoxyphenyl bromide with 1 equiv. of nBuLiat -78" C for 1 h) in 5 mL THE The reaction mixturewas allowed to warm up to room temperature(4 h).The resulting mixture was washedwithTHF (3 x 7 mL),THF/H,O (1:l) (3 x 7 mL),THF (3 x 7 mL), DCM (3 x 7 mL) and driedunder vacuum for 12 h to give the 4-phenoxyphenylsilyl resin. IR (cm'): 1239.8 (Ar-0). -18. Loading of 3-bromoyuinoline: To a t-HuLi solutionin pentane (2 equiv.) was added dropwise aTHF solution of 3-bromoquinoline (1 equiv.)under argon at -78 "C.The mixture was stirred atthis temperature for 5 mins before transferringvia cannula to freshly prepared PS-DES-SiCI resin(- 100 mg) at -78 " C.The reaction mixture wasallowed to warm up to room temperature in 4hrs.The resin was washed withTHF (3 x 7 mL),THF/H,O (1:l) (3 x 7 mL),THF (3 x 7 mL), DCM(3 x 7 mL) and dried under vacuum for 12 h.19. To the 4-phenoxyphenyl silyl resin (100 mg) wasadded TFA/DCM (1: l,3 mL).The mixture wasstirred at 25 OC for 3 h.The resin was filteredand washed with DCM (3 x 2 mL).The combinedfiltrate was treated with saturatedNaHCO,.The organic layer was used for GCquantification (anthracene as internal standard).20. Treatment of the silyl quinoline resin with TBAF(1.0 M in THF, S n1L) for 12 h followed byextraction of the product into DCM led to therecovery of quinoline in 58% yield (GC quantificationusing anthracene as internal standard).General Reference for PS-DES -Hu,Y.; Porco,J.A. Jr.; Labadie, J.; Gooding O.;Trost,B.M., J. Org. Chem., 1998, 63,4518.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

L To facilitate a wide range of solid phase reactions,Argonaut offers a complete Solid PhaseToolbox:Solid Phase Toolbox10 gram quantities of each: PS-Wang,PS-MBCHO, PS-Rink, PS-AS-SO,NH,,PS-NH,, PS-C1, PS-DESProduct information cardsArgoScoopTM (calibrated scoop forconvenient resin measuring)Argonaut's three types of resin have distinctivecharacteristics. These convenient linker kits areavailable to meet specific application needs:Wang Linker Kit10 gram quantities of each: PS-Wang, ArgoGel-L Wang , ArgoPore-Wang1 Pan # 800356 1Rink Linker Kit10 gram quantities of each: PS-Rink,ArgoGel-Rink, ArgoPore-RinkMB-CHO Linker Kit10 gram quantities of each: PS-MB-CHO,ArgoGel-MB-CHO, ArgoPore-MB-CHOPart # 800358AS-S02NH2 Linker Kit10 gram quantities of each: PS-AS-SOJH,,ArgoGel-AS-SO,NH,, ArgoPore-AS-S02NH,This family of resins is based on a highly crosslinkedmacroporous polystyrene framework which provideslow and predictable swelling in all solvents.The unique design means:rapid diffusional access of reagents to reactionsites at the pore surfaceremoval of byproducts using virtually any solventsuitable for reactions with low-solubility intermediatesand low temperaturesa wide range of reaction conditions, includingprotic solvents, e.g. waterThis facilitates the direct transfer of reaction conditionsfrom known solution chemistry to solid phase.Yet ArgoPore is well suited for automation with itsunique handling properties: rapid washing/dryingand free-flowing beads which do not stick to glassreaction vessels.ArgoGel resins are based on a novel grafted polyethyleneglycol-polystyrene (PEG/PS) copolymer.Theflexible PEG grafts provide a solution-like environmentfor resin-bound molecules, resulting in highresolution 'H and "C NMR spectra and faster reactionrates. These properties make ArgoGel resinsideal for reaction development when compared toother polystyrene solid supports.ArgoGel's high quality beads have very low leachablePEG impurities, higher loading and greater stabilitydue to the unique bifurcated linkage versusmore labile benzylic ether linkages and are compatiblewith a wide range of solvents, including water.Rt:ferences for ArgoGel and ArgoPore Resins"Consumables for Organic Synthesis," 1998 CatalogArgoPore Data Sheet, Argonaut Technologies, DS-0 13ArgoGel Data Sheets, Argonaut Technologies, DS-005thru DS-0 12Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

ArgoGrl und ArgoPow ([re regi~tered trudemurks ofArgorraut %I:hnologirs.ArgoCap is u trademurk ofArgonaut Tet chnologirs.resm mi~rurfact~rred under one or more of U.S. Patents 4,297,220 (vzd 4,382,124.8 Copyri~Ar IYYX Argorzuut Tcq ,,hnologir,.ARGONAUTTECHNOLOGlES887 INDUSTRIAL ROAD SUITE G bAN CARLOS CA 94070TELEPHONE 650 598 1350 FAX 650 598 1359ST IAKOBS-STRASSE 148 POSTFACH 43 4132 MUTTENZ 2 SM. 'ITZERLANLTELEPHONE 4 1 61 465 9898 FAX 41 61 465 9899MK KOllMACHl BLDG 4-2-1 KOIIMACHI CHIYODA-KU TOKYOTELEPHONE 81 3 3234 4321 FAX 81 3 3234 1359WWWARCOTECH COMI02 IAPAN11/98 RELArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

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LIIBasicAcidic 1 WangCl & Wane-Br*I INucleophilic PS-DESI 1. .Oxidative Wang€lI IArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Scavengers for NucleophilesWhich compounds toscavenge?ReammendedScavengers*A Primary,SecondaryI Amines 1-4 Selective for Primary 1-bActive methylenes(e.g., keto esters)Reducing Agents)SIBwr;lrldehydcAcidslAcidicPentafluorophenol4-NitrophenolCarboxylic AcidPhenol*Recommended choice in rod.Artisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Scavengers for ElectrophilesWhich compounds toscavenge?RecommendedScavengers*Al kylatingMesylates,Tosylates, =-- PS-Triphenylphosphinea-bromoesters, .1 a-bromoketones ISulfonylChlori&s-.?strb.rarhPS-DMAPPS-NH2*Recommended choice in mdArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Polymer ReagentsWhat type of reagent?What application?Recommended PolymerReagent\Basic quenching,neutralize ammonium saltsStrong tertiary mine base(e.g. mesylate fwmetbnjTertiary amino base(e-g. formation of amides,sulfonamides, carbamates)MP-IAcids1 1Acyl Transfer PSID(YAPICoupling AgentsAmide or Ester FormationIPSICmbtn)iim,PS310miActivated Ester FormationProtecting Group TransferArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Polymer ReagentsWhat type of reagent?What application?Recommended PolymerReagentElectmphilic ActivationHalogenation(chlorination, brommatian.iodination)Phenylether formation(i.e. Mitsunobu reaction)Thioester activeintermediateAlcohol activationIAcid and sulfonylchloride activation 1Carbonlccrrbon bondformation(e.g. Wittig reaction)&Sulfonyl hydtazoneformation(e.g. Hurd-Mod tMadiazdesynthesis)IArtisan Technology Group - Quality Instrumentation ... Guaranteed | (888) 88-SOURCE | www.artisantg.com

Artisan Technology Group is your source for qualitynew and certified-used/pre-owned equipment• FAST SHIPPING ANDDELIVERY• TENS OF THOUSANDS OFIN-STOCK ITEMS• EQUIPMENT DEMOS• HUNDREDS OFMANUFACTURERSSUPPORTED• LEASING/MONTHLYRENTALS• ITAR CERTIFIEDSECURE ASSET SOLUTIONSSERVICE CENTER REPAIRSExperienced engineers and technicians on staffat our full-service, in-house repair centerSMInstraView REMOTE INSPECTIONRemotely inspect equipment before purchasing withour interactive website at www.instraview.comContact us: (888) 88-SOURCE | sales@artisantg.com | www.artisantg.comWE BUY USED EQUIPMENTSell your excess, underutilized, and idle used equipmentWe also offer credit for buy-backs and trade-inswww.artisantg.com/WeBuyEquipmentLOOKING FOR MORE INFORMATION?Visit us on the web at www.artisantg.com for moreinformation on price quotations, drivers, technicalspecifications, manuals, and documentation