Combinatorial chemistry and automated organic synthesis have proven to be highly effective means for the generation of multiplicities of novel molecules known as libraries. As the size of such a library grows, so does the likelihood that it will contain individual molecules with useful biological activities which may be employed in the treatment of human, animal, and plant diseases. Research organizations that can prepare and screen a large number of diverse compounds efficiently, have an increased likelihood of discovering and optimizing new products. For recent reviews in the use of combinatorial chemistry in pharmaceutical discovery see Gallop M. A., et al., J. Med. Chem., 1994; 37: 1233 and Gordon E. M., et al., ibid., 1994; 37: 1385.

In the practice of organic synthesis, the most time consuming element is typically the purification of the desired product following each synthetic transformation. Traditionally, automated organic synthesis and combinatorial chemistry have relied on a number of methods to reduce the amount of time and effort devoted to purification. Such methods include water soluble reagents, polymer-supported reagents, and polymer-supported synthesis. Water soluble reagents and byproducts derived therefrom have the advantage of being easily removed by partitioning the crude reaction mixture between water (which dissolves the reagent and associated byproducts) and an organic solvent (which dissolves the desired product). Separation of the organic layer gives a purified form of the product relative to the crude reaction mixture. An example of a water soluble reagent is N-ethyl-N'-dimethylaminopropylcarbodiimide (EDC). EDC is a reagent that is used in the coupling of carboxylic acids and amines to form amide bonds. EDC and the corresponding urea produced during the course of the

reaction (N-ethyl-N'-dimethylaminopropylurea) are both soluble in water at low pH and can thus be washed away into an acidic water layer. The use of EDC greatly simplifies purification of the amide product relative to other carbodiimides such as N, N'-dicyclohexylcarbodiimide (DCC) which are not water soluble.

Polymer-supported reagents and byproducts derived therefrom are likewise easily separated by filtration of the polymeric materials from a crude reaction mixture.

An example of a polymer-supported reagent is poly (styrene-divinylbenzene)- supported triphenylphosphine which may be used in Wittig olefination reactions.

The byproduct of this transformation, polymer-supported triphenylphosphine oxide, is easily removed by filtration which simplifies purification greatly compared to the solution phase reagent. The use of triphenylphosphine in solution phase Wittig reactions gives triphenylphosphine oxide as a byproduct which is difficult to completely remove except by time consuming chromatography or repeated crystallization. Polymer-supported synthesis minimizes time spent on purifications by attaching a starting material to a polymer. Subsequent synthetic transformations are carried out in such a manner that desired reactions are driven to completion on the polymer-supported material and excess reagents and byproducts in solution are subsequently removed by filtering the polymer and rinsing with solvent (s). At the end of the synthesis, the desired product is chemically cleaved from the polymer. The resulting product is typically obtained in greater purity than would be possible if all of the steps were carried out in solution with no chromatography or crystallization of synthetic intermediates.

Purification in a multistep synthesis is thus largely reduced to a number of filtrations, although a single purification of the final product by conventional means is often necessary to remove byproducts resulting from the resin cleavage step. Thus, water soluble reagents, polymer-supported reagents, and polymer- supported synthesis each provide increased efficiency reducing purification to mechanically simple liquid-liquid and liquid-solid separation methods which are easy to automate.

The increased simplicity and efficiency which allow automation of organic synthesis using the methods described above comes at the price of increased reagent cost and/or substantial synthesis development time. Water soluble

reagents and polymer-supported reagents must be customized for each type of synthetic transformation. The time necessary to optimize a particular reagent significantly increases its cost. Consequently, EDC is more expensive than DCC and polystyrene-supported triphenylphosphine is more expensive than triphenylphosphine. Polymer-supported syntheses traditionally require longer development time than solution phase due to the limitations imposed by the method. One must choose the optimum polymer, develop a linking strategy which can be reversed at the end of the synthesis and find successful conditions for each reaction without many of the conventional spectral and chromatographic analysis tools that are available to solution phase synthesis. Thus, at the current state of the art, much of the time/cost saved by increasing the efficiency of purifications via the above methods is lost to increased reagent costs and/or synthetic development time.

Polymer-supported reagents have been extensively reviewed in the literature. The following citation is representative of the current state of this art: Sherrington D. C., Chem. Ind., (London) 1991; 1: 15-19.

Solid-supported synthesis has been extensively reviewed in the literature.

The following two citations are representative of the current state of this art: Fruchtel J. S. and Jung G., Angew. Chem. Int. Ed. Engl., 1996; 35: 17-42, Thompson L. A. and Ellman J. A., Chem. Rev., 1996; 96: 555-600.

A purification process known as covalent chromatography has been described in the scientific literature. Using covalent chromatography a desired material is isolated from a complex mixture by selective reaction with a polymeric reagent, followed by filtration, and rinsing. The desired material is then liberated from the polymer by a chemical cleavage. Typically this process is applied to proteins and other macromolecules as a way of isolating them from complex mixtures of cellular components. This technique has also been applied in the separation of low molecular weight allergens from plant oils as described by Cheminat A., et al., in Tetr. Lett., 1990; 617-619. Covalent chromatography differs from the instant invention in that the polymeric materials used must be both capable of covalently reacting with a desired material in a solution containing impurities and capable of subsequent cleavage of said covalent bond during the retrieval of the desired material. Polymer-supported quench methods rely on

chemically robust and ideally irreversible attachment of undesired materials that are found in the crude product of an organic reaction to a polymeric support, leaving the desired product in solution.

Polymeric reagents have been employed during the course of a reaction to enhance yield of the desired product by minimizing side reactions as described by Rubenstein M. and Patchornik A., Tetr. Lett., 1975; 1445-8, but this use of a polymeric reagent does not eliminate the need for conventional purification of the desired product.

Polymeric reagents which selectively remove metal ions from solutions by chelation have been described but this use of a polymeric reagent in purification does not involve formation of covalent bonds. For a review of the current state of this art see Alexandratos S. D. and Crick D. W., Ind. Eng. Chem. Res., 1996; 35: 635-44.

The synthesis of dendritic polyamides on polymeric supports has been described by Ulrich K. E., et al., Polvmer Bul., 1991; 25: 551-8. As synthetic intermediates of the synthesis, polymer-supported dendritic polyamines are described which, by virtue of the fact that they contain an easily cleaved linker, are structurally distinct from those of the present invention which contain chemically robust linkers.

Polymer-supported quench reagents have been used in the generation of compound libraries, e. g., Kaldor S. W., et al., Tetrahedron Lett., 1996; 37: 7193- 7196; Kaldor S. W., et al., Curr. Opin. Chem. Biol., 1997; 1: 101-106; Booth R. J., et al., J. Am. Chem. Soc., 1997; 119: 4882-4886; Flynn D. L., et al., J. Am. Chem.

Soc., 1997; 119: 4874-4881 ; Parlow J. J., et al., Tetrahedron, 1998; 54: 4013-4031; and Ault-Justus S., et al., Biotechnol. Bioeng., 1998; 61: 17-22.

The aforementioned references do not describe or suggest the polyaromatic hydrocarbon (PAH) quench reagents disclosed herein, nor do they teach methods of preparation of PAH quench reagents disclosed herein, nor do they teach the rapid purification utility of PAH quench in the practice of automated organic synthesis and combinatorial chemistry as described in the present invention.

Thus, we have surprisingly and unexpectedly found that one or more PAH reagents can be added at the conclusion of an organic reaction to covalently react

with excess reagents and/or unwanted byproducts. The PAH impurities are then easily removed by addition of charcoal and conventional solid-liquid phase separation techniques leaving a solution of the desired synthetic intermediate or product which is enhanced in purity relative to the crude reaction mixture.

Purification by PAH quench is mechanically simple and rapid compared to conventional means of purification such as column chromatography, distillation or crystallization. This means of purification is readily applied to large variety of organic reactions and is amenable to both manual and automated organic synthesis environments. Hence, it is of tremendous value in the preparation of large libraries of organic molecules by automated parallel synthesis and by automated or manual combinatorial synthesis.

SUMMARY OF THE INVENTION Accordingly, a first aspect of the present invention is a compound of Formula I, P-L-Q I wherein: P is a polyaromatic hydrocarbon of low chemical reactivity which is soluble; Q is one or more quenching reagents, or an acid or base addition salt thereof, that are capable of selective covalent reaction with unwanted byproducts, or excess reagents; and L is one or more chemically robust linkers or dendritic linkers that join P and Q.

A second aspect of the present invention is a method for enhancing the purity of a desired compound which comprises: Step (a) treating a crude reaction product which contains at least one desired compound, unreacted starting materials and/or byproducts with at least one polyaromatic hydrocarbon quenching reagent of Formula I, P-L-Q I

wherein: P is a polyaromatic hydrocarbon of low chemical reactivity which is soluble; Q is one or more quenching reagents, or an acid or base addition salt thereof, that are capable of selective covalent reaction with unwanted byproducts, or excess reagents; and L is one or more chemically robust linkers or dendritic linkers that join P and Q.

Step (b) allowing the polyaromatic hydrocarbon quenching reagent to covalently react with unreacted starting materials and/or byproducts to afford a derivatized reagent of Formula II, P-L-Q-X II wherein: X is unreacted starting material and/or byproduct and P, L, and Q are as defined above.

Step (c) absorb P-L-Q-X to charcoal; and Step (d) separation of the reagents of Formula I and Formula II from the solution and removal of solvent to afford a compound of enhanced purity.

A third aspect of the present invention is a process of preparing a compound of Formula I, P-L-Q I wherein: P is a polyaromatic hydrocarbon of low chemical reactivity which is soluble; Q is one or more quenching reagents, or an acid or base addition salt thereof, that are capable of selective covalent reaction with unwanted byproducts, or excess reagents; and L is one or more chemically robust linkers or dendritic linkers that join P and Q, which comprises: Step (a) reacting P and L to afford a compound of P-L; and Step (b) reacting P-L with Q to afford a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION The following Table 1 provides a list of definitions and abbreviations used in the present invention.

TABLE 1. DEFINITIONS AND ABBREVIATIONS Term Definition Acid addition salt A salt derived from inorganic acids such as, for example, hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorous, and the like, as well as from water soluble organic acids such as, for example, aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic, and aromatic sulfonic acids and the like.

Base addition salt A salt derived from inorganic metals such as, for example, sodium, potassium, magnesium, calcium, and the like as well as from water soluble organic amines such as, for example, N-methylmorpholine, diethanolamine, ethylenediamine, procaine, and the like.

Byproduct An undesirable product of a reaction which comprises at least five mole percent of the crude product. Isomers, enantiomers and diastereomers of the desired product are not considered to be byproducts within the scope of this invention.

Chemically robust Not cleaved by a wide variety of reagents used in the art of organic synthesis.

Crude reaction The result of a chemical reaction before any product purification. Synonymous with crude product and crude reaction mixture.

TABLE 1. DEFINITIONS AND ABBREVIATIONS (cont) Term Definition Dendritic molecule A subset of polyfunctional molecules which have two or more equivalent arm-like structures with functional groups at the ends emanating from a central core structure. For example, tris (2-aminoethyl)-amine, ethylenediaminetetraacetic acid, tris (hydroxymethyl)- aminomethane, and 1,3,5-benzenetricarboxylic acid are dendritic molecules.

Dendritic linkers A subset of polyfunctional linkers which have two or more equivalent arm-like structures with functional groups at the ends emanating from a central core substituent. For example, N'- (3-aminopropyl)- N'- (3- {3- [bis- (3-aminopropyl)-amino]-propylamino}- propyl)-propane-1,3-diamine.

Enhancing purity A) For a single desired compound, enhancing purity means the process of removing excess or unreacted starting reagents to the limit of detection by TLC or by NMR spectroscopy and/or reducing the content of any single byproduct to less than ten molar percent, exclusive of solvents.

B) For a combinatorial mixture of desired compounds: The process of removing excess or unreacted starting reagents and or reducing the content of a byproduct using a procedure that has been validated on crude reaction products of analogous single compounds.

Low chemical Not modified or degraded by a wide variety of reagents reactivity used in the art of organic synthesis.

TABLE 1. DEFINITIONS AND ABBREVIATIONS (cont) Term Definition Polyfunctional A compound which contains two or more functional molecule groups attached to a carbon framework or interspersed with more than one carbon framework. For example 2,6-diamino-hexanoic acid, 1,8-diamino- 3,6-diazaoctane, and 2,6-diisocyanatohexane are polyfunctional molecules.

Quenching reagent A molecule that covalently combines with a reactant to make it less reactive or a molecule that covalently combines with a byproduct.

Polyaromatic Polyaromatic hydrocarbon is defined as a substantially hydrocarbon (PAH) planar ring system. This should consist of three or more rings, of which one or more may not be aromatic, such as, for example, naphthalene, anthracene, pyrene, phenanthrene, 3,4-benzofluoranthrene, tetrabenzo- [a, c, g, i]-fluorene, fluorene, SH-dibenz [b, f] azepine, and the like.

Abbreviation Structural Group Boc tertiary Butyloxycarbonyl Fmoc 9-Fluorenylmethyloxycarbonyl Ph Phenyl Abbreviation Solvents and Reagents AcOH (HOAc) Acetic acid Ac20 Acetic acid anhydride Bu4NOH Tetrabutylammonium hydroxide BuLi (nBuLi) n-Butyllithium CH2Cl2 Dichloromethane CSA Camphorsulfonic acid CS2C°3 Cesium carbonate Abbreviation Solvents and Reagents CDC13 Deuterated Chloroform CDI N, N'-Carbonyldiimidazole CF3SO2H Trifluoromethanesulfonic acid chloride(COCl2)2Oxalyl 18-Cr-6 18-Crown-6 DCE Dichloroethane DBU 1,8-Diazabicyclo [5.4.0] undec-7-ene DCM (CH2Cl2) Dichloromethane DCC N, N'-Dicyclohexylcarbodiimide DCU N, N'-Dicyclohexylurea DIBAL Diisobutylaluminum hydride DIC N, N'-Diisopropylcarbodiimide DIEA (iPr2NEt) N, N-Diisopropylethylamine DMA N, N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DMSO Dimethylsulfoxide DMF N, N-Dimethylformamide DTT Dithiothreitol EDC (EDAC) N-Ethyl-N'-Dimethylamino propylcarbodiimide EtOAc Ethyl acetate Et20 Diethyl ether EtOH Ethanol H2SO4 Sulfuric acid HCl Hydrochloric acid H2 Hydrogen HF Hydrofluoric acid H2OWater HOBT1-Hydroxybenzotriazole iBuOCOCI Isobutyl chloroformate Abbreviation Solvents and Reagent iPrOH iso-Propanol (iPrO)3B Triisopropyl borate KOtBu Potassium tert butoxide KOAc Potassium acetate K2C03 Potassium carbonate LAH Lithium aluminum hydride MCPBA Meta chloroperbenzoic acid <BR> <BR> <BR> <BR> MeCN Acetonitrile<BR> <BR> <BR> <BR> <BR> <BR> MeI Iodomethane MeOH (CH30H) Methanol MgS04 Magnesium sulfate NaAl (OtBu) 3H Sodium tri tert butoxyaluminum hydride NaBH4 Sodium borohydride Na2S04 Sodium sulfate chlorideNaClSodium NaCNBH3 Sodium cyanoborohydride NaIO4 Sodium metaperiodate NaI Sodium iodide NaOEt Sodium ethoxide NaOH Sodium hydroxide Na (OAc) 3BH Sodium triacetoxyborohydride Na2C03 Sodium carbonate N2 Nitrogen NH2NH2 (N2H4) Hydrazine NH2NHtBu tert-Butylhydrazine <BR> <BR> <BR> <BR> <BR> hydroxylaminehydrochlorideNH2OAc#HClO-Acetyl (H2NCH2CH2-S-) 2 Cystamine NH20H Hydroxylamine NH3 Ammonia Abbreviation Solvents and Reagents NMP N-Methylpyrrolidone PBr3 Phosphorus tribromide PhN (S02CF3) 2 N-Phenyltrifluoromethane sulfonamide Pd Palladium P (Ph) 3I2 Diiodotriphenylphosphorane (Ph3P)4Pd Tetrakis (triphenylphosphine)-Palladium (O) PSI Pounds per square inch Pd/C Palladium on carbon PhMe Toluene Pr Protecting group P (Ph) 3I2 Diiodotriphenylphosphorane PCC Pyridinium chlorochromate PDC Pyridinium dichromate TEA (Et3N) Triethylamine TsOH Para toluene sulfonic acid TFA Trifluoroacetic acid THF Tetrahydrofuran TMEDA N, N, N', N'-Tetramethylethylene diamine TMG N, N, N'N'-Tetramethylguanidine Abbreviation Analytical Method HPLC High performance liquid chromatography IR Infrared spectroscopy MS Mass spectroscopy MS (CI) Mass spectroscopy with chemical ionization IHNMR Proton nuclear magnetic resonance spectroscopy TLC Thin layer chromatography GC Gas chromatography

The first aspect of the instant invention is a compound of Formula I, P-L-Q I wherein: P is a polyaromatic hydrocarbon of low chemical reactivity including naphthalene, anthracene, pyrene, phenanthrene, 3,4-benzofluoranthrene, tetrabenzo- [a, c, g, i]-fluorene, fluorene, SH-dibenzo [b, tazepine, and the like ; Q is one or more quenching reagents which contain at least one functional group, or an acid or base addition salts thereof, that is capable of selective covalent reaction with unwanted byproducts, or excess reagents such as, for example, primary amine, secondary amine, tertiary amine, isocyanate, isothiocyanate, carboxylic acid, acid chloride, ketone, aldehyde, cyclic imide, cyclic anhydride, hydroxyl, diol, aminoalcohol, thiol, dithiol, aminothiol, thioether, thiourea, chlorosilane, diene, dienophile, dipole, dipolarophile, enolate, enol ether, alkylsulfonate, alkyl halide, aryl halide, arylsulfonate, arylboronic acid, hydrazine, semicarbazide, acyl hydrazide, hydroxylamine, guanidine, and the like; and L is linker that joins P and Q such as, for example, [CH2] q wherein q = 1-10, CH=CH, CH-N, CH2-N, CH-O, CH2-O, CH-S, CH2-S, C (=O) N, NC (=O), NC (=O) N, N (C=O) O, OC (=O) N, dendritic linker, combinations thereof, and the like. L is chosen so as to be chemically robust to conditions of rapid purification. In other words, it is necessary that the linker functionality is not cleavable during the course of reaction with excess reagents and unwanted byproducts and subsequent removal.

Generic descriptions of preferred polyaromatic hydrocarbon quenching reagents are shown in Schemes 1-19. The most preferred reagents and are listed in Table 2.

The second aspect of the present invention is a method for the preparation of novel polyaromatic hydrocarbon quenching reagents from known polyaromatic hydrocarbons. Polyaromatic hydrocarbon quenching reagents are made in one to four synthetic steps from readily available starting materials, such as for example, pyrene or derivatives thereof which contain convenient linker functionality, and one or more polyfunctional quenching reagents which bear a compatible

connecting functionality and one or more functionalities used in the quenching process.

Preferred polyaromatic hydrocarbon starting materials are pyrene and tetrabenzo- [a, c, g, i]-fluorene.

Preferred solvents used in the chemical transformations of preferred starting polyaromatic hydrocarbons which lead to novel polyaromatic hydrocarbons quenching reagents include, for example, DMF, DMA, NMP, DCM, dioxane, THF, benzene, and the like.

Preferred methods which afford preferred polyaromatic hydrocarbons quenching reagents are described in Schemes 1-19.

In Scheme 1 a PAH chloro or bromo methyl compound can be treated with a suitably protected amine in toluene, or other non-nucleophilic solvent in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkylamine base provides the protected PAH polyamine. Deprotection with acid (TFA, H2SO4, CSA, etc.) for Boc protected amines, or other suitable deprotection method for various protective groups affords the polyamine PAH.

In Scheme 2, a PAH methyl amine can be treated with phosgene, triphosgene, thiophosgene or synthetic equivalent to prepare the isocynate or thioisocynate. Addition of a suitable protected polyamine followed by deprotection provides the polyamine PAH.

In Scheme 3, a PAH methyl alcohol can be treated with phosgene, triphosgene or synthetic equivalent to prepare the chloroformate. Addition of a suitable protected polyamine followed by deprotection provides the polyamine PAH.

In Scheme 4, reaction of a PAH methyl amine with a suitably protected monoamino isocynate, deprotection of the amine and treatment with phosgene, thiophosgene or equivalent provides a PAH isocynate or thioisocynate quench reagent.

Reaction of a PAH methyl amine with thiophosgene, phosgene, or synthetic equivalent affords a PAH isocynate or thioisocynate quench reagent.

Treatment of a PAH methyl chloride or bromide with a monoprotected diamine in the presence of triethylamine, pyridine, N-methyl morpholine or other

lower alkylamine base, deprotection of the amine and treatment with phosgene, thiophosgene or synthetic equivalent gives the PAH isocynate or thioisocynate quench reagent.

Preparation of a phenolic ether containing a monoprotected amino functionality from a PAH methyl halide, followed by deprotection and treatment of the resulting amine with phosgene, thiophosgene or synthetic equivalent affords the PAH isocynate quench reagent.

In Scheme 5, preparation of a PAH dicarboxylic acid can be accomplished by treatment of a PAH methyl amine with acrylic acid, or by treatment of a PAH aldehyde with malonic acid followed by hydrogenation over a palladium catalyst.

Reaction of these diacids with thionyl or oxalyl chloride provides an acid chloride quenching agent.

Reduction of the diacids with DIBAL at-78°C affords the dialdehyde quench resin. Reduction of the diacid with DIBAL, LAH or other reducing agent to provide the dialcohol, and subsequent oxidation via Swern conditions, PCC, PDC or equivalent oxidant affords the dialdehyde.

In Scheme 6, reaction of a PAH methyl halide with a suitable amino alcohol in toluene, benzene or other non-nucleophilic solvent in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkyl amine base affords PAH aminoalcohol quench reagent.

In Scheme 7, reaction of a suitable aminoalcohol with a dialkylsilyl dichloride in the presence of triethylamine, pyridine, N-methyl morpholine or other lower alkyl amine base provides a PAH chlorosilane quenching reagent.

In Scheme 8, reaction of a PAH methyl halide with a co-sulfhydryl sodium thiolate in THF or with thiomorpholine in DMF provides a quenching thiol reagent. Reaction of a suitable PAH amine with 2,2'-bisthioacetic acid in the presence of a suitable coupling reagent, such as DCC, EDC or CDI, followed by reductive cleavage of the dithiane affords a quenching thiol reagent.

In Scheme 9, PAH quenching aryl boronic acids can be prepared by treatment of a PAH methyl halide with 4-iodophenol or 4-bromophenol in a polar aprotic solvent such as THF or DMF with a base, such as potassium carbonate with 18-crown-6. Lithiation of the aryl halide using an organolithium reagent and

quenching of the resulting anion with triisopropyl borate gives the aryl boronic ester. Hydrolysis of this with aqueous acid provides the aryl boronic acid.

In Scheme 10, PAH quenching thioureas can be prepared by reaction of a suitable PAH amine with any suitable isothiocyanate or thiocarbamyl chloride, or by treatment of a suitable PAH isothiocyanate with any primary or secondary amine.

In Scheme 11, coupling of a suitable PAH amine with 2-imidazole acetic acid in the presence of a coupling agent, such as CDI, DCC, EDC, in THF, DMF or other aprotic polar solvent affords the PAH quenching imidazole.

Reaction of a suitable PAH isocyanate or isothiocyanate and 2-imidazole ethyl amine in DMF or THF provides the imidazole quenching reagent.

In Scheme 12, reaction of a suitable PAH amine with maleic anhydride with removal of water, or a PAH methyl halide with the anion of maleimide provides the dienophile quench agent.

Treatment of a suitable PAH amine with 4'-carbomethoxy-3-phenyl- propynoic acid or other similar aryl propynoic acid with an electron withdrawing group in the 4'-position, such as nitro or cyano groups, in the presence of standard peptide coupling reagents provides PAH dipolarophile quenching groups.

Coupling of a PAH boronic acid with methyl 4'-iodo-phenyl-propionic acid using palladium catalysis (Stille or Suzuki conditions) affords a dipolarophile quenching reagent.

In Scheme 13, reaction of PAH methyl halide with the alkoxide form of 2-hydroxymethyl furan or the thiolate of 2-thiomethyl furan in a polar aprotic solvent such as THF or DMF provides the PAH quenching diene. Similarly, reaction with the anion of methyl vinyl ether of methyl acetoacetate followed by treatment with a trialkyl silyl chloride gives the PAH Danishefsky diene equivalent.

Reaction of the PAH methyl halide with the anion of nitromethane in THF or DMF followed by treatment with phenyl isocyanate in DCM, THF, or dioxane affords the nitrile oxide dipole.

Reaction of a suitable PAH amine with bromoacetate in the presence of a lower alkyl tertiary amine base, such as diisopropylamine or triethylamine,

followed by reaction with a dehydration agent, such as Burgess reagent or acetic anhydride, affords the N-methyl-4-oxazole.

In Scheme 14, PAH guanidines can be prepared either by addition of a suitably substituted guanidine to a PAH methyl halide in a polar aprotic solvent, such as DMF, or by addition of a S-methyl thiourea to a PAH amine. A PAH hydrazine or hydroxylamine can be prepared starting from a PAH aldehyde.

Addition of either a monoprotected hydrazine or a suitable hydroxyl amine and reduction of the resulting imine with a reducing agent, such as NaBH3CN or Na (OAc) 3BH, provides the protected hydrazine or hydroxylamine, respectively.

Deprotection of the hydrazine using standard methods affords the hydrazine.

In Scheme 15, a silylenol ether quenching agent can be prepared from the PAH methyl halide and an enolate prepared from a ketone, such as acetophenone.

Reaction of the resulting homologated ketone with a trialkyl silylchloride in the presence of a trialkylamine base, such as triethylamine, gives the PAH enol silyl ether.

Reaction of a methyl sulfhydryl PAH with an a-haloketone, such as a-bromoacetophenone, in the presence of a trialkylamine, such as triethylamine, diisopropylethylamine, oxidation of the thio group to the sulfoxide with an oxidizing agent, such as NaIO4, mCPBA or hydrogen peroxide and enolate formation with an alkoxide base affords the carbanion reagent.

Reaction of a suitable PAH amine with the acid chloride of ethyl malonate in the presence of a trialkylamine, followed by enolization with an alkoxide base, affords the carbanion PAH reagent.

In Scheme 16, PAH alcohols, iodides, and sulfonates can be prepared from a PAH methyl halide and a suitably protected 4'-co-hydroxyphenol. Ether formation using a base such as potassium carbonate and 18-crown-6 and deprotection using standard conditions provides a PAH alkyl alcohol. Oxidation of this intermediate to the aldehyde with an appropriate oxidant, such as PDC, PCC, Swern condition (oxalyl chloride, DMSO), affords the alcohol. Treatment with an iodination reagent, such as triphenylphosphine diiodide produces the alkyl iodide reagent. Treatment of the intermediate alcohol with an alkyl or aryl

sulfonyl chloride in DCM or THF and a trialkylamine, such as triethylamine, gives the alkyl sulfate reagent.

In Scheme 17, reaction of the monoanion of benzo [1,2-c: 4,5-c'] dipyrrole- 1,3,5,7 (2H, 6H)-tetrone or similar diimide with the PAH methyl halide. Alkylation of the resulting imide using potassium tert butoxide or similar strong base, such as sodium hydride, and addition of a lower alkyl halide affords the desired cyclic imide.

Reaction of a suitable PAH amine with 1H, 3H-benzo [1,2-c: 4,5-c'] difuran- 1,3,5,7-tetrone, bis-2,6-morpholinedione or other suitable dianhydride and dehydration with a reagent such as acetic anhydride or Burgess reagent provides the PAH cyclic anhydride.

In Scheme 18, PAH amino thiols can be prepared by either addition of 2,2'-dithiobis-ethanamine in a polar aprotic solvent such as DMF and reduction of the dithiane using DTT, NaBH4 or other reducing agent, or addition of thiazolidine in DMF followed by cleavage with hydroxylamine affords the PAH aminothiol reagent.

Coupling of FMOC protected thiazolidine-2-carboxylic acid with a suitable PAH amine using standard peptide coupling agents, such as DCC, EDC, or CDI, followed by cleavage with hydroxylamine in DMF, or other polar aprotic solvent provides the PAH aminothiol reagent.

In Scheme 19, reductive amination of a PAH aldehyde with an appropriately substituted amine provides tertiary amine base PAH quench reagent.

The following legend applies to structures in Schemes 1-19, Equations 1.0-5.0, Table 2, and the Examples.

Legend = Polyaromatic hydrocarbon R = H or CH3 R1 = Boc or other protective group R2 = Me, Et, iPr, tBu, Ph

R4 = any primary or secondary aliphatic group Me,R5= CF3, 4-MePh,4-NO2Ph,4-BrPh,4-ClPh,$-FPh,Ph, 4-CF3Ph R6 = CH2Ph, Me, Et, nPr, nBu, CH2CH=CH2 (L) = linker, or dendritic linker OorSX= Cl,imidazol-1-yl,1,2,3-triazol-1-ylor2-pyridyloxyY= <BR> <BR> <BR> n=2 to 8<BR> <BR> <BR> <BR> m = 3to9<BR> <BR> <BR> <BR> <BR> p = OtolO<BR> <BR> <BR> <BR> q=1 to 10 (EWG) = electron withdrawing group such as NO2, C02Me, CN, CF3, etc.

M+ = Li+, Na+, K+, MgBr+, Cs+ SCHEME 1 Preparation of PAH Quenching Amines Ri = Boc or other protective group SCHEME 2 Preparation of PAH Quenching Amines From Amino-PAH x x (lez N.-. , (CH2) nNHR L ? N/ \N PAH H N PAH H I I n (CH2) nNHR R 2) nNHR R 14 15 8/ \ I phosgene or triphosgene NH2 or synthetic equivalents PAH \\ C x 10 11 2 X L l 6 (NN PAH H I /n N- (CH2) nNHR (CH2) nNHR 12 f X 0 o "R R LJ R PAH H N'' R R/ O N R 13 SCHEME 3 Preparation of PAH Quenching Amines From Hydroxy-PAH 0 0 (L/ (CH2) nNHRL/\ l 0-rO- (CH2) nNHR R N- (CH2) nNHR R 20 /21 21 8 ! ! O phosgene or triphosgene PAH or synthetic equivalents t ° X 16 17 16 17 O 6 0 6 zon PAH I n R 2) nNHR (CH2) nNHR 18 0 0 o R R (cl o (CH2) nNHR 0"N R 19 SCHEME 4<BR> Preparation of PAH Quenching Isocyanates and Isothiocyanates<BR> (Page 1 of 2) 0 1) X=C=N- (CH2) nNHBoc (L)NN (CH2) ri-N=C=X PAH NH2 2) acid PAH'N N 3) phosgene or thiophosgene or equivalent 22 3,5,7,9,10,12,13, 22 14,15,18,19,20,21 (R=H) phosgene or thiophosgene (L) NH2 or equivalent [3r N=C=X PAH 9,10,12,13,14,15,23 18,19,20,21 (R=H) SCHEME 4<BR> Preparation of PAH quenching Isocyanates and Isothiocyanates<BR> (Page 2 of 2) ci1) RHN- (CH2), i---NHBoc N 2) n PAHPAH 2)acid \/R 3) phosgene or thiophosgene or equivalent 24 1 1) HO (CH2) nNHBoc (CL (CH2) ri N-C=0 K2C03,18-cr-6PAH 1 > 2) acid 3) phosgene or thiophosgene 25 or equivalent SCHEME 5 Preparation of PAH Quenching Acid Chlorides, Carboxylic Acids, and Aldehydes SCHEME 6 Preparation of PAH Quenching Aminoalcohols SCHEME 7 Preparation of PAH Quenching Chlorosilanes SCHEME 8 Preparation of PAH Quenching Thiols and Thioethers SCHEME 9 Preparation of PAH Quenching Aryl Boronic Acids 1) 4-iodophenol, OH K2C 03, 18-cr-6 B \ rT OH (L)2) BuLi, THF Cl 3) (iPrO) 3BL \ <4) 1N H Cl[P A H |1 40 1 40 140 SCHEME 10 Preparation of PAH Quenching Thioureas g Any isothiocyanate or thiocarbamyl chloride Nlk N PAH N PAH DMF, DCM or THF 41 3,5,7,9,10,12,13, 41 14,15,18,19,20,21 S Any 1° or 2° amine PAH p DMF, DCM or THF H H S 11,22,23,24 42 SCHEME 11 Preparation of PAH Quenching Imidazoles SCHEME 12<BR> Preparation of PAH Quenching Dienophiles and Dipolarophiles<BR> (Page 1 of 2) o-0 0 (L) NU2 N PAH 2 p benzene, Dean-Stark trap- O 9,10,12,13, 14,15,18,19,20,21 (R=H) 45 0 N 0 O N O CRI N (L) Cl strong base, DMF, THF or dioxane 1 46 H02CH= = (EWG) ° (L), N, R N PAH H peptide coupling reagent PAH DMF R 47/ 3,5,7,9,10,12,13, 47 14,15,18,19,20,21 (EWG) SCHEME 12<BR> Preparation of PAH Quenching Dienophiles and dipolarophiles<BR> (Page 2 of 2) O Me02c C02H PAH tJ H peptide coupling reagent < R < DMF 48\ 3,5,7,9,10,12,13,CO2Me 14,15,18,19,20,21 2 OHMet C OH PAH Pd° catalyst, base, THF > , 40 49 C02Me SCHEME 13 Preparation of PAH Quenching Dienes and Dipoles M+-CH NO PAH Cl-2 2 pAH THF or dioxane [ir 1 53 SCHEME 14 Preparation of PAH Quenching Guanidine, Hydrazines, and Hydroxylamines SCHEME 15 Preparation of PAH Quenching Carbanions and Enol Ethers 03 () SH BrCH2COPh () Sv pat pu O 3'amine, THF 37 63 0 (Lt ClCOCH2CO2Et, (L) bCO2Et (L) 2 2 (L) JLL LUbt NH2 3'amine, THF 9 NH pat H SCHEME 16 Preparation of PAH Quenching Alcohols, Iodides, and Sulfonates m OPr m OPr ci HO ozrl PAH \C1 HD PAH e pur 1) remove Pr 1) remove Pr 2) Swern 2) P (Ph) 3I2, THF Oxidation 1) remove Pr 2) R5so2cl, CHO 3'amine, m-1 DCM or THF PAH 68/IOS02R5 69 m PAH 69 PAH 70 70 SCHEME 17 Preparation of PAH Quenching Cyclic Imides and Cyclic Anhydrides SCHEME 18 Preparation of PAH Quenching Aminothiols SCHEME 19 Preparation of PAH Quenching Tertiary Amine Bases

The third aspect of the present invention is the use of PAH quenching reagents, including novel PAH quenching reagents of the present invention, for the rapid purification of crude product mixtures of organic reactions. Of particular importance is the use of PAH quench purification as an enabling technology for the preparation of libraries of organic molecules with potential biological activity.

PAH quench has utility in reducing purification time associated with automated parallel organic synthesis, manual combinatorial synthesis and automated combinatorial synthesis. Specific types of chemical transformations that benefit from a PAH quench purification procedure include, but are not limited to, O-and N-acylation, O-and N-sulfonylation, O-and N-phosphonylation, O-and N-phosphorylation, C-, O-, N-and S-alkylation, condensation reactions, coupling reactions, cyclization reactions involving two or more components, and the like.

The scope of applications of PAH quench is exemplified in Items I-VI below.

Representative illustrations of specific cases wherein rapid purification of crude reaction mixtures is achieved with most preferred PAH quenching reagents are described in Examples 1 to 22. Utility of the PAH quenching reagents and methods described herein is not limited to the reactions described in these examples. On the contrary, the PAH quenching reagents and methods described herein are broadly useful in these and many other organic reactions.

I. Direct Quench (Equations 1, and 1.2) Reactant A combines with reactant B to form AB. In order to drive the reaction to completion, B is used in excess (Equation 1.0). The excess reactant is quenched by adding a PAH quenching reagent with A-like properties. Once the excess B is attached to the PAH reagent, it is easily and quickly removed by addition of charcoal and a simple filtration. The solution fraction contains AB which is enhanced in purity relative to the crude product.

Using this method, the chemist has a choice of whether to use A or B in excess and subsequently to quench with a PAH quenching reagent with B-like or A-like properties, respectively. Additionally, the chemist may choose to add both A-like and B-like PAH quenching reagents sequentially to ensure that all starting materials have been removed from the desired product in the event that the reaction did not go to completion, despite using an excess of one starting material.

Alternatively, a reaction between equimolar quantities of A and B may yield a major desired product, AB, and a minor undesired product, AB' (Equation 1.1). AB'may be removed with a PAH quenching reagent that selectively reacts with this undesired product.

One may run analogous combinatorial reactions wherein a diversity of reactants A I-X are reacted with excess of a diversity of reactants B1-Y to form all of the possible AB combinations (Equation 1.2). The combinatorial product mixture is separated from the remaining B 1-Y using a single PAH quenching reagent with A-like properties as in the one product case above.

Equation 1.0 excess 1. charcoal 2. filter > Purified AB Equation 1.1 excess 1. charcoal 2. filter > Purified AB Equation1.2 AB, A2B2, A3B3,... AB A2B2,A2B3,...A2BY,A1,A2,A3,...AXA2B1, #A3B1,A3B2,A3B3,...A3BY,+excess B1,B2,B3,...BYAXB1,AXB2,AXB3,...AXBY, B, B, B... B 1. excess Purified PAH A1Bl, A2g2, A3B3 AlBY trAn)--Ao 1 o o o o v A2B1, A2B2, A2B3,... A2BY, 2.charcoal A3B1, A3B2 A3B3 A3BY 3. filterAXBl, AA,... AXBY

II. Derivative Quench (Equations 2.0 and 2.1) C reacts with D to form CD (Equation 2.0). In order to drive the reaction to completion, D is used in excess. The excess reagent is derivatized by adding an excess of a third reactant, E. DE and excess E are quenched by adding a larger excess of a PAH quenching reagent which reacts with both DE and E. The PAH is then removed by filtration after absorption into charcoal. The solution fraction contains CD which is enhanced in purity relative to the crude product.

This process may be likewise applied in cases where one of the reactants decomposes in a competing side reaction to give a byproduct (Equation 2.1). Thus when C reacts with excess D to form CD and the byproduct XD, the desired product is purified by adding a PAH quenching reagent that selectively derivatives XD and removing the PAH by addition of charcoal and filtration.

Derivative quench by a PAH quenching reagent may be similarly applied in a combinatorial synthesis mode.

Equation 2.0 C + D excess > CD+D CD + excess excess E p-A'_DE Pat- CD+DE+E PAH-A'-E (PAH) A \ 1. charcoal 2. filter 1. charcoalPurified CD Equation 2.1 C + D excess > CD + XD CD + excess < excess E ppH-,_XDE PAH-A CD+XDE+E PAH-A'-E (PAH)-A 1.charcoal 2. filter Purified CD

III. Use of PAH Quenching Reagents in Conjunction with PAH Reactants (Equation 3.0) A reaction which employs two soluble reactants F and G and one PAH reactant, J, is run in such a fashion that G and PAH-J are used in excess. The desired product, FG, is rapidly purified by adding a larger excess of a PAH quenching reagent with F-like properties which consumes the remaining G.

Filtration to remove the PAH reactant before adding the PAH quenching reagent is not necessary when insoluble polymers are used but may be required when soluble polymers are employed if a chemical incompatibility exists between the reactant and quench reagent. Filtration of the PAH and addition of charcoal gives a solution of FG which is enhanced in purity relative to the crude product.

The use of PAH quenching reagents in conjunction with PAH reactants may be similarly applied in a combinatorial synthesis mode.

Equation 3.0 F + excess (G + PAH-J) -J 1. excess PAH F' l--FG 2. charcoal 3. filter

IV. Mixed PAH Quench (Equation 4.0) A reaction which employs multiple reactants (K, L, M, etc.) is run in such a fashion that one of the reactants is limiting. The desired product is rapidly purified from unconsumed reagents by adding PAH quenching reagents; one for each excess reactant. PAH quenching reagents must be added and removed sequentially unless they are chemically compatible.

PAH quenching reagents may also be combined with insoluble ion- exchange resins, chelating resins, silica gel, reversed-phase adsorbents, alumina, and the like which make noncovalent interactions with impurities as desired in order to increase the efficiency of the purification step. Upon filtration, a purified solution of N is isolated.

Such use of a mixture of solid quenching reagents is equally effective in a combinatorial synthesis mode.

Equation 4.0 K+excess (L+M+etc) > N+L+M+etc 1. excess sequential PAH-Q + PAH-R + etc purifie N 2. charcoal > Purified N 3. filter

V. Combined PAH Reactant and Quench Reagent (Equation 5.0) A PAH quenching reagent may perform a dual role in purifying the product of one reaction and causing a subsequent synthetic transformation as a PAH reagent. Thus, A reacts with excess B to form C. PAH-D quenches the excess B and also converts product C to product E. This dual role is equally applicable in a combinatorial synthesis mode.

Equation 5.0 excess PAH-D PAH-DB A+excessB > C+B > E+ PAH-D 1. charcoal 2. filter ---- Purified E VI. Multistep Syntheses With PAH Quench Purifications Using methodologies described in Equations 1-5 above and variations thereof, individual synthetic transformations may be sequentially combined to give linear or convergent, multistep syntheses. Similar reactions may be run individually in parallel arrays, manually or with the aid of a liquid handling robot, to give single products or alternatively, they may be run in a combinatorial mode to give product mixtures. PAH quench purification may be applied at each intermediate step or at the conclusion of two or more synthetic steps as is appropriate. An individual who is skilled in the art of organic synthesis will be able to determine whether it is most expedient to purify at each step or to combine PAH quench reagents for the removal of accumulated byproducts and excess reagents from two or more steps in one purification step.

The PAH quench reagents and rapid purification methods of the instant invention have, for example, the following advantages over existing methods for automated organic synthesis and combinatorial chemistry: 1. A single PAH quench reagent can remove many different types of reactants and byproducts; hence, customized reagent development time is

minimized and quench reagents may be produced in bulk at decreased cost.

2. No resin attachment site needed in target molecule.

3. Solution phase synthesis results in minimal synthetic development time since more solution phase reactions are known than solid phase reactions.

4. One can choose the limiting reagent in any particular reaction based on the value of the reagent and/or nature of the reaction.

5. Convergent syntheses are possible.

6. Solutions of synthetic intermediates are easily divided into aliquots for automated parallel and combinatorial syntheses by liquid handling robots.

7. The use of resin swelling solvents is not required.

8. Reaction progress and product may be analyzed by traditional chromatographic and spectrographic methods.

9. Lack of resin cleavage reaction avoids resin-derived impurities in final product.

10. Greater product amounts may be synthesized in a given reactor volume as compared to polymer-supported synthesis.

11. A smaller excess of reagent can be used to drive reactions to completion compared to the excess required by solid-supported synthesis.

12. Reactive, volatile, toxic wastes are neutralized to nonhazardous solids by the PAH reagents and charcoal and thereby waste disposal is facilitated.

13. PAH reagent solubility allows simplified robotic delivery of PAH reagents.

Table 2. Purification Using PAH Quenching Reagents Quenching Reagent Removes NH2 Acid Chlorides, Acid Anhydrides, Activated Esters, Imidazolides, Isocyanates, Isothiocyanates, Sulfonyl - Chlorides, Phosphonyl Chlorides, NH Phosphoryl Chlorides, Alkyl Halides, fs) i-i Alkylsulfonates, Meerwein Reagent, 3 (R = H, L = CH2, n= 2) Epoxides, Enones, a, ß-Unsaturated Esters, Pseudothioureas, Aldehydes, Ketones, and the like NH2 Acid Chlorides, Acid Anhydrides, Activated Esters, Imidazolides, i on Isocyanates, Isothiocyanates, Sulfonyl Chlorides, Phosphonyl Chlorides, H Phosphoryl Chlorides, Alkyl Halides, 18 (R = H, L = CH2, n = 2) Alkylsulfonates, Meerwein Reagent, i o i\.-n, JL-<ni, n-Z Epoxides, Enones, a, ß-Unsaturated Esters, Pseudothioureas, Aldehydes, Ketones, and the like HNf 1° and 2° Amines, Alcohols, //NH (CH2) 6N=C=O Carboxylic Acids, Guanidines, (i) Amidines, Hydrazines, Acid O= (HNf Hydrazides, Hydroxylamines, H NH (CH2) 6N=C=O Alkoxyamines, Thiols, and the like (CH2) 6N=c=o 22 (X = 0, n = 6, (L) is derived from 3 wherein n = 2 and R = H) Table 2. Purification Using PAH Quenching Reagents (cont) Quenching Reagent Removes C02H Alkyl Halides, Alkyl sulfonates, Diazoalkanes, oc-Haloketones, Silyl CO2H Chlorides, Silyl Triflates, and the like 2 26 (L = CH2) OH Boronic Acids, Alkyl Halides, t di Alkylsulfonates, Diazoalkanes, pat oc-Haloketones, Meerwein Reagent, Silyl Chlorides, Silyl Triflates, Acid N 0 OH Chlorides, Acid Anhydrides, Activated Esters, Imidazolides, 34A (R3= morpholine, Isocyanates, Isothiocyanates, Sulfonyl p = 3) Chlorides, Phosphonyl Chlorides, Phosphoryl Chlorides, and the like Alkyl Halides, Alkylsulfonates, N p Meerwein Reagent, a-Haloketones, Silyl Chlorides, Silyl Triflates, Acid pu 3 Chlorides, Acid Anhydrides, Activated Esters, Imidazolides, Isocyanates, Isothiocyanates, Sulfonyl Chlorides, Phosphonyl Chlorides, OH Phosphoryl Chlorides, and the like 34F (R3 = morpholine, p=3) Table 2. Purification Using PAH Quenching Reagents (cont) Quenching Reagent Removes Alcohols, Carboxylic Acids, Thiols, Silanols, Phenols, Carbanions, 1 ° and N 0 <3 Amines, and the like t/\\ Ntt 0-Si (iPr) 2Cl Q 36 (R3 = morpholine, p = 3, R2 = iPr) Alkyl Halides, Alkylsulfonates, a-Haloketones, Meerwein Reagent, N SH Silyl Chlorides, Silyl Triflates, ) \ S} s Epoxides, Oxidants, Thiols, HS HN- Dissulfides, and the like 0 39 (derived from 3 wherein n = 2 and Ri = H) Oxidants and the like s PAHNJ 38 (L = CH2) Table 2. Purification Using PAH Quenching Reagents (cont) Quenching Reagent Removes B (OH) 2 Aryl Iodides, Aryl Bromides, Aryl Triflates, Vinyl Iodides, Vinyl Bromides, Vinyl Triflates, and the like N 0 Q 40 (R3 = morpholine) S Alkyl Halides, Alkylsulfonates, oc-Haloketones, Meerwein Reagent, NH (PAH) and the like 41 (R4 = NH2, (L) is CH2) Aldehydes, Ketones, Imines, Alkyl (PAH)--. HN- N- TT i-j An t ir. T Halides, Alkylsulfonates, Isocyanates, o (mN N Isothiocyanates, Chloroformates, ) Phosgene, Thiophosgene, and the like HN HT1 N (N "N N 43 (derived from 3 wherein n = 2) Dienes, Dipoles, Sulfides, 1 ° and 2° Amines, and the like N O 45 (L= CH2) Table 2. Purification Using PAH Quenching Reagents (cont) Quenching Reagent Removes Dienophiles, Dipolarophiles, C12, Br2, (PAH)--\ I2, Oxidants, and the like Hz -/two 50 (X = S, L = CH2) Acid Chlorides, Acid Anhydrides, tpAT-f) Activated Esters, Imidazolides, NH Isocyanates, Isothiocyanates, Sulfonyl Chlorides, Phosphonyl Chlorides, T\JTJ NH Phosphoryl Chlorides, Alkyl Halides, 55 (R = H, L = CH2) Alkylsulfonates, Meerwein Reagent, Epoxides, Enones, a, P-Unsaturated Esters, oc-Diketones, ß-Diketones, ß-Keto Esters, and the like Aldehydes, Ketones, Enones, oc, \ ot, ß-Unsaturated Esters, a-Diketones, NHNH2 ß-Diketones, ß-Keto Esters, Acid 58 ((L) = CH) Chlorides, Acid Anhydrides, Activated Esters, Imidazolides, Isocyanates, Isothiocyanates, Sulfonyl Chlorides, Phosphonyl Chlorides, Phosphoryl Chlorides, Alkyl Halides, Alkylsulfonates, Meerwein Reagent, Epoxides, and the like Carbanions, primary amines, Hydroxylamine, Alkoxyamines, Hydrazines, Glycols, 1,3-Diols, 68 (L = CH2) 1,2-Dithiols, 1,3-Dithiols, 1,2-Aminoalcohols, 1,3-Aminoalcohols, 1,2-Aminothiols, 1,3-Aminothiols, Hydride Reducing Agents, and the like Table 2. Purification Using PAH Quenching Reagents (cont) Quenching Reagent Removes Carbanions, primary amines, Hydroxylamine, Alkoxyamines, G\ O~\CHO Hydrazines, Glycols, 1,3-Diols, 1,2-Dithiols, 1,3-Dithiols, 68 1,2-Aminoalcohols, 1,3-Aminoalcohols, 1,2-Aminothiols, 1,3-Aminothiols, Hydride Reducing Agents, and the like Carbanions, Hydroxides, Alkoxides, fPAT-T)--- Ct 1 ° and 2° Amines, Hydride Reducing Agents, and the like 0 0 o N O -Ph 72 (L = CH2, R6 = CH2Ph) HN Alkyl Halides, Alkylsulfonates, PAH ~ SH : x-Haloketones, Meerwein Reagent, 75 (L = CH2) Silyl Chlorides, Silyl Triflates, Epoxides, Oxidants, Thiols, Dissulfides, Ketones, Aldehydes, and the like EXAMPLE 1 Pyrene-1-carbaldehyde

The oxalyl chloride (4.52 mL, 1.2 eq., 0.0516 mol) was added to 50 mL CH2C12, cooled to-78°C under N2. DMSO (6.71 mL, 2.2 eq., 0.0946 mol) was added and allowed to stir for 10 minutes. Pyrenemethanol (10.0 g, 1.0 eq., 0.043 mol) was added as a CH2Cl2 suspension, stirred at-78°C for 20 minutes, then Et3N (30.03 mL, 5.0 eq., 0.215 mol) was added, and the reaction was allowed to warm to room temperature. One hundred milliliters saturated NaCl solution was added, and the reaction was extracted with 150 mL ethyl acetate. The ethyl acetate solution was dried over MgSO4 and rotovaped down to a yellow solid to get 7.8 g desired product, 78% yield. 1H NMR (1H, s, 10.8 ppm; 9H, 8.10-8.45 ppm).

EXAMPLE 2 3-Pyren-1-vl-acrvlic acid The pyrenealdehyde (1.0 g, 0.0043 mol) and malonic acid (0.95 g, 0.009 mol) were stirred in 5 mL pyridine, then 0.25 mL piperidine was added and the reaction heated to 80°C for 30 minutes, then heated to reflux for 4 hours. The reaction mixture was then poured over 10 g crushed ice containing 10 mL conc. HC1. An off-white solid was filtered and washed with water (4x25 mL), dried under high

vacuum overnight to afford a quantitative yield of the title compound. 1 H NMR, CDCl3 (1H, bs, 12.6 ppm; 1H, d, 8.7 ppm; 9H, m, 8.05-8.55 ppm; 1H, d, 6.8 ppm).

EXAMPLE 3 3-Pyren-1-vl-propionic acid

The pyrene unsaturated acid (1.1 g, 0.004 mol) was taken up in 75 mL THF/DMF 1: 2, and 0.2 g 10% Pd/C was added and the reaction put under H2 at 49 psi for 4 hours. Reaction filtered and solvent removed, 0.97 g, 88%, product isolated. 1H NMR, CDCl3 (9H, m, 7.95-8.15 ppm; 2H, t, 3.65 ppm; 2H, t, 2.97 ppm).

EXAMPLE 4 N, N-Bis- (2-amino-ethyl)-3-pvryl-propionamide

The 3-pyren-1-yl-propionic acid (0.50 g, 0.0018 mol), [2- (2-tert- butoxycarbonylamino-ethylamino)-ethyl]-carbamic acid tert-butyl ester (0.56 g, 0.0018 mol), DCC (0.413 g, 0.002 mol), HOBT (0.271 g, 0.002 mol), Et3N (0.280 mL, 0.002 mol) were taken up in 30 mL dichloromethane and stirred overnight under N2 at room temperature. The reaction mixture was washed with 5% citric acid (2x50 mL), 2N Na2C03 (2x50 mL), and sat. brine (2x50 mL). The organic layer was dried over MgSO4 and solvent removed under vacuum.

Chromatographed on flash silica using 5% MeOH in dichloromethane to afford 0.926 g, 91%, desired product. 1H NMR (9H, m, 7.9-8.3 ppm; 1H, bm, 4.95 ppm; 1H, bm, 4.90 ppm; 2H, t, 3.68 ppm; 2H, t, 3.42 ppm; 4H, m, 3.23 ppm; 2H, m, 3.10 ppm; 2H, t, 2.90 ppm; 9H, s, 1.40 ppm; 9H, s, 1.25 ppm).

To 20 mL of a saturated HCl solution in ethyl acetate was added {2- [ (2-tert- <BR> <BR> <BR> butoxycarbonylamino-ethyl)- (3-pyren-1-yl-propionyl)-amino]-ethyl}-carbamic acid tert-butyl ester (0.25 g, 0.00045 mol) and reaction stirred at room temperature for 2 hours. Solvent removed to obtain a yellow solid. The amine HCl salt was suspended in 10 mL dichloromethane and bubbled in NH3. The yellow solid went into solution, and a white solid falls out of solution. The reaction is filtered and solvent is again removed under vacuum to afford a near quantitative yield of desired amine. 1H NMR (9H, m, 7.90-8.30 ppm; 2H, t, 3.75 ppm; 2H, t, 3.42 ppm; 2H, t, 3.18 ppm; 4H, m, 2.90 ppm, 2H, t, 2.70 ppm).

EXAMPLE 5 N (2-Amino-ethyl)-N1-pvren-1-ylmethvl-ethane-1, 2-diamine

To a round bottom flask equipped with stirring bar, condenser, and N2 inlet tube were added 1-chloromethyl pyrene (1.085 g, 4.3 mmol, 1 eq.), [2- (2-tert- butoxycarbonylamino-ethylamino)-ethyl]-carbamic acid tert-butyl ester (1.6 g, 5.1 mmol, 1.2 eq.) and Et3N (2.628 g, 25 mmol, 6 eq.) in toluene (20 mL). The mixture was refluxed overnight and filtered the next morning to remove the white solid which formed. Hydrogen chloride was bubbled into the reaction mixture until the solution turned deep orange/red and a deep orange solid precipitated. The solid was filtered to afford the title compound; mp 157°C (HCl). lH NMR (CDCl3): 8 8.15 (d, 1H, J=9.1 Hz), 7.97 (m, 8H), 4.2 (s, 2H), 2.67 (t, 2H, J=5.9 Hz), 2.55 (t, 2H, 5.9 Hz). MS (CI) M (+I) 486. EXAMPLE 6 1-Chloromethvl-pvrene cl SOC12 ; pyridine \ \

The title compound was prepared using the procedure in J. Med. Chem., 1990; 33: 2385-2393. CHN theory C, 81.44; H, 4.42; Cl, 14.14. Found: C, 81.66; H, 4.46; Cl, 13.81. 1H NMR (CDCl3) 8 8.17 (m, 9H), 5.34 (s, 2H).

EXAMPLE 7 1-Bromomethyl-pvrene

Pyren-1-yl-methanol (2.34 g, 10 mmol, 1 eq.) suspended in 50 mL of CH2Cl2 in a 100 mL round bottom flask with N2 and a dropping funnel. Phosphorus tribromide (1.89 mL, 2 eq., 20 mmol) was added over a 20-minute period.

Methanol (2 mL) was added dropwise to quench the reaction. More CH2Cl2 was added. In a separating funnel, the reaction mixture was washed with NaHC03 (100 mL), brine (100 mL), and distilled water (100 mL). The organic layer was dried over MgS04, filtered and concentrated to afford after recrystallization, 1.7 g (50%) of the title compound. 1H NMR (CDC13): 8 8.17 (m, 9H), 5.26 (s, 2H). EXAMPLE 8 Diethyl-pvren-1-ylmethyl-amine \ \ wBr (_N Et2NH, Benzene I I/HCl, EtOH I I/ /

The title compound was prepared according to the procedure in J. Med. Chem., 1990; 33 (9): 2385-2393. In that reference, the 1-chloropyrene was used instead of 1-bromopyrene; mp 242°C (reference 252-254°C). lH NMR (CDCl3): 8 8.35 (d, 1 H): 5 8.14 (m, 8H), 4.25 (s, 2H), 2.62 (q, 4H), 1.13 (t, 6H).

EXAMPLE 9 j3-(Pyren-1-ylmethoxy)-phenvll-methanol OH GOY Xl ; 18crown6 W 3-Hydroxy Benzyl Alcohol \ I/ I The title compound was prepared according to the procedure in J. Am. Chem.

Soc., 1996; 118 : 4354-4360. Weight of purified material: 0.22 g (62% weight recovery); mp 112-114°C (reference 117-119°C).

EXAMPLE 10 Urea Synthesis From Amine and Isocvanate m-tolylamide4-Benzo[1,3]dioxol-5-ylmethyl-piperazine-1-carbo xylicacid 1) NCO e cess O \ _ H < NH 2) NH'I N/2 O I W PAH WNH2 0 2 3) Charcoal To a solution of 1-piperonylpiperazine (0.36 mmol) in DCM (2 mL) is added m-tolyl isocyanate (0.4 mmol). The reaction mixture is shaken for 2 hours, and then the PAH quenching reagent (0.4 mmol) is added. After shaking for 3 hours charcoal is added, and the reaction is shaken for 2 hours. Filtration and concentration gives the purified product.

EXAMPLE 11 Amide Synthesis From Amine and Acid Chloride A. Excess Acid Chloride Quenched with PAH Amine N-Benzvl-2-bromo-N-methvl-benzamide

3) Charcoal To a solution of N-benzylmethylamine (0.4 mmol) in DCM were added Et3N (3 mmol) and 2-bromobenzoyl chloride (0.6 mmol). The reaction mixture was shaken for 4 hours, and then the PAH quenching amine was added in 1 mL of

DCM. After 2 hours, charcoal (300 mg) was added and the reaction mixture shaken an additional 2 hours. The reaction was filtered, concentrated and partitioned between aqueous NaOH and EtOAc to afford the purified product.

MS (CI) 306,304 (M+1).

B. Excess Amine Quenched With PAH Isocyanate N-Methylbenzylamine (0.23 mmol) and 2-bromobenzoyl chloride (0.146 mmol) and Et3N is combined in DCM (2 mL). The reaction mixture is shaken for 5 hours. Isocyanate PAH quenching reagent (0.25 mmol) is added followed by DCM (1 mL), and then reaction mixture is shaken for 4 hours. Charcoal is added, and the reaction is shaken for 2 hours. Filtration and concentration gives the purified product.

EXAMPLE 12 Sulfonamide Synthesis From Amine and Sulfonyl Chloride 4-tert-Butyl-N-methyl-N-naphthalen-1-ylmethyl-benzenesulfona mide 1) S02C1/tBu ( NH-excess N" HCl p2 1 \ \ \ / PAHNH2 3) Charcoal To a solution of N-methyl-1-napthalenemethylamine hydrochloride (0.4 mmol) in DCM (1 mL) is added Et3N (3 mmol) and a solution of 4-tert- butylbenzenesulfonyl chloride (0.6 mmol) in DCM (1 mL). The reaction mixture is shaken for 4 hours, and then the PAH quenching reagent (0.4 mmol) is added.

After shaking for 2 hours, charcoal is added, and the reaction is shaken for 2 hours. Filtration, concentration, and partition between aqueous sodium hydroxide and DCM gives the purified product.

EXAMPLE 13 Sulfonamide N-Alkylation and Desulfonvlation (4-Bromo-benzyl)- (4-methyl-benzyl)-amine in I Br CS2co3 N02 Br excess Au \ H I \ 0 PAH Na Br/ oh

3) Charcoal To a solution of the 2-nitrophenylsulfonamide (0.082 mmol) in DMF (0.5 mL) is added cesium carbonate (0.34 mmol) and 4-bromobenzyl bromide (0.1 mmol).

The reaction mixture is shaken for 1 hour, and the PAH quenching reagent (0.1 mmol) and DMF (0.5 mL) is added. The reaction mixture is shaken for 2 hours, charcoal is added, and the reaction is shaken for 2 hours. Filtration, concentration, and partitioning between water and EtOAc gives the purified product. Note that in this instance, the PAH quenching reagent removes both the excess 4-bromobenzyl bromide and cleaves the 2-nitrophenylsulfonyl protecting group.

EXAMPLE 14 Amide Synthesis From Amine and Carboxvlic Acid 5-(3, 5-Dimethvl-phenoxv)-2-phenvl-pentanoic(3, 5-Dimethvl-phenoxv)-2-phenvl-pentanoic acid (1-phenyl-cyclopentvl)-amide 1)iBuOCOCI, PAH ! ! ID "r 2) H2N+/ Ph ( (limiting reagent) A O Oh O NU Ph NNH2 Ph H PAH 2

4) Charcoal A mixture of the carboxylic acid (0.23 mmol), PAH N-methylmorpholine (0.99 mmol), and DCM (2 mL) is treated with isobutyl chloroformate (0.23 mmol) and stirred at room temperature for 30 minutes before adding a solution of the amine (0.20 mmol) in DCM (1 mL). The reaction is stirred 2 hours, then the PAH quenching reagent (0.3 mmol) is added. The resulting slurry is stirred at room temperature for 3 hours, charcoal is added, and the reaction is shaken for 2 hours, then filtered and solids rinsed with DCM. Combined filtrate and washings is evaporated to give amide.

EXAMPLE 15 Hetero-Diels Alder Reaction 2-(4-Methoxv-phenvl)-l-phenvl-23-dihvdro-1 H-pvridin-4-one Ph /1)NH2 Me gS OX N~NH2 + oye- OMe TMSO + OL 2) Charcoal 0 1 (excess) vOMe/\tOMe OMe OMe

A solution of 4-methoxybenzylidene aniline (0.10 mmol), 1-methoxy-3- trimethylsilyloxy-1,3-butadiene (0.12 mmol), and ytterbium (III) trifluoro-methane- sulfonate (0.01 mmol) in acetonitrile (1.2 mL) is stirred at room temperature for 30 minutes. Triethylamine (0.5 mmol) is added, and the resulting slurry is stirred (room temperature, 2 hours). Charcoal is added, and the reaction is shaken for 2 hours. The resulting slurry is filtered and the filtrate concentrated. The residue is partitioned between EtOAc and IN HCI. The organic layer is washed with brine, dried (MgSO4), and concentrated to give the purified dihydropyridone.

EXAMPLE 16 Suzuki Coupling 14,14-Dimethoxy-tetradeca-6,8-dien-1-ol 1) (Ph3P) 4Pd, NaOEt, C6H6 Me 2)-OH N + 9, OH OMe Me OH 3 Charcoal HO \ OMe HO <BsOH A solution of the iodide (0.23 mmol) and the vinylboronic acid (0.28 mmol) in 1.5 mL of freshly distilled benzene is treated under argon atmosphere with freshly prepared, degassed NaOEt (1 M, 0.68 mmol) in EtOH.

Tetrakis (triphenylphosphine) palladium (13 mg, 0.01 mmol) is added, and the reaction is heated at reflux for 3 hours. The black mixture is cooled to room temperature, treated with the aminodiol PAH quench reagent (0.3 mmol), and agitated for 2 hours. Diethyl ether/hexane (1: 1,4 mL) and charcoal is added, and the reaction is shaken for 2 hours. The reaction mixture is filtered, rinsing the solids with Et20/hexane (1: 1,4 mL). The filtrate is evaporated to give the purified diene.

EXAMPLE 17 17H-Cvclopentalt1, 2-1: 3*4-l'ldiphenanthrene-17-ethanol From TBF and 2- (2- Bromoethoxy) tetrahydro-2H-pyra

8bH-tetrabenzo [a, c, g, i] fluorene (TBF) (3.66 g, 0.01 mol) was suspended in anhydrous 1,4-dioxane (130 mL) and heated to reflux under an atmosphere of nitrogen, and a solution of tetrabutylammonium hydroxide (40% in water, 0.01 mol) in degassed 1,4-dioxane (15 mL) added whereby a yellow-green precipitate formed. The solid was separated by filtration under nitrogen, washed with warm dioxane (2x50 mL) and diethyl ether (2x50 mL). The resulting bright yellow solid was resuspended in anhydrous 1,4-dioxane (130 mL) and 2- (2- bromoethoxy) tetrahydro-2H-pyran added. The mixture was refluxed under an atmosphere of nitrogen overnight, all precipitate dissolved, and a deep brown solution formed. MS: 495 (M+1) + and TLC (Hexanes/Ethyl Acetate: 19/1) showed the product (Rf : 0.25). The reaction mixture was concentrated to give a dark oil, which was dissolved in methanol (150 mL), catalytic amount TsOH added, and the mixture stirred for 30 hours. After removal of all volatiles in vacuo, the

residue was directly run on the flash column chromatography with hexanes/ethyl acetate (20/1 then 3/1) to give the product 2.9 g. Yield: 71%.

MS: 411 (M+1) + EXAMPLE 18 17H-Cvclopenta 2-1: 3,4-1'ldiphenanthrene-17-acetaldehvde From 17H- cyclopentarl, 2-1: 3, *4-1'ldiphenanthrene-17-ethanol A 100-mL round bottom flask was charged with dry CH2C12 (15 mL) and cooled to-78°C, and oxalyl chloride (0.445 mL, 5.1 mmol, 1.7 eq.) added. Anhydrous DMSO (0.745 mL, 10.5 mmol, 3.5 eq.) was then added dropwise, and the reaction mixture was allowed to stir for 15 minutes at-78°C. The alcohol (1.23 g, 3 mmol, 1 eq.) was added dropwise slowly as a solution of CH2C12 (20 mL). The reaction mixture was stirred for further 0.5 hour. Triethylamine (0.91 g, 9 mmol, 3 eq.) was then added, and the flask was removed from the cold bath. The mixture was allowed to react at room temperature and was stirred for 0.5 hour before addition of water (20 mL). The aqueous layer was extracted with dichloromethane (3x20 mL). The combined organic layer was washed with Na2CO3 (sat. aqueous solution) and brine, and dried with anhydrous MgS04. The solvent was evaporated under reduced pressure to give the crude product 1.29 g. The crude aldehyde was suitable for use without further purification.

MS: 409 (M+l) + EXAMPLE 19 N-(2-aminoethyl)-N-[2-(17H-cvclopenta [1(2-aminoethyl)-N-[2-(17H-cvclopenta [1 2-1: 3,4-1']diphenanthrene-17-yl)ethyl] 1,2-ethanediamine NHBoc NH2 1) 1) HCI/ethyl acetate N HBoc 2 NaOH/CH2C12 NH2

The aldehyde (0.86 g,-2 mmol) and NH (CH2CH2NHBoc) 2 were dissolved in DCE (35 mL), and NaB (OAc) 3H was added. The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 3 hours. The mixture was concentrated and the residue purified by chromatography with hexanes/ethyl acetate (3/1, then 3/2) to give the product as a white solid. The yield:-45%.

The starting material was added to a HCl-gas-saturated ethyl acetate (50 mL) at 0°C, allowing the ice in the cold bath to melt naturally and an earth-like solid was formed. The solid was filtered and washed with ethyl acetate. Dried in vacuo and 740 mg of an HCl salt was obtained. Yield: 94%. The salt (284 mg, 0.5 mmol) was dissolved in 5 mL water, NaOH (100 mg, 2.5 mmol, 5 eq.) added, some oil-like product formed immediately and 10 mL CH2C12 added. The reaction was stirred overnight and the water layer extracted with CH2C12 (4x10 mL). The combined organic layers were washed with brine (2x15 mL) and dried over

Na2SO4. Concentration afforded the free amine product as a foam-like solid.

201 mg. Yield: 81%.

MS: 496 (M+1) + 1H NMR (CDCl3, 400Hz): 8/ppm 8.82 (4H, d, J=8.2Hz, Ar-H); 8.68 (2H, d, J=8.2Hz, Ar-H); 8.29 (2H, d, J=7.7Hz, Ar-H); 7.62-7.75 (8H, m, Ar-H); 5.11 (lH, t, J=4.6Hz, Cyclopenten-H,); 2.82-2.87 (2H, m, TBF-CH2); 2.06 (4H, t, J=5.8Hz, CH2CH2NH2); 1.94 (4H, t, J=5.7Hz, CH2CH2NH2); 1.83 (4H, NH2); 1.52 (2H, t, J=7.5Hz, TBF-CH2CH2) EXAMPLE 20 N,N''-[[[2-(17H-cyclopenta[1,2-1:3,4-1']diphenanthren-17-yl) ethyl]imino]di-2,1- ethanediyllbis [N- (3-aminopropyl)- 1, 3-Propanediamine and 3, 3',3'',3'''-[[[2- (17H-cyclopenta[1,2-1:3,4-1']diphenanthren-17-yl)ethyl]imino ]bis(2,1- N-(2-amonoethyl)-N-[2-(17H-ethanediylnitrilo)]tetrakis-Propa nenitritrileFrom Cyclopenta[1,2-1:3,4-1']diphenanthrene-17-yl)ethyl]-1,2-Etha nediamine CN NH2 \ \/l \ l N CH2=CHCN reflux NH2 N CN Con CON Co(II)/NaBH4 N CH30H, 12 hours = < NH2 A) NH2

N (2-Amonoethyl)-N [2- (17H-cyclopenta [1, 2-1: 3,4-l gdiphenanthrene-17- yl) ethyl]- 1,2-ethanediamine (200 mg) was suspended in 10 mL acrylonitrile and reflux for 12 hours, concentrated and purified (column chromatography on silica gel with ethyl acetate). The tetranitrile was suspended in 5 mL methanol and cobalt (II) chloride hexahydrate (8 equiv.) added. Sodium borohydride (80 equiv.) was added in portions. The resultant mixture was stirred for 12 hours. The reaction mixture was acidified with concentrated hydrochloric acid and the mixture concentrated. The residue was taken up in concentrated ammonia solution and chloroform. The precipitate was filtered, the aqueous phase extracted with chloroform, and then dried with magnesium sulfate. The crude product was obtained after concentration.

MS: 724.4 (M+1) + EXAMPLE 21 N- [2- (17H-Cyclopentar 1,2-1:3,4-1'] diphenanthrene-17-yl) ethyl]-N-2- (diethvlamino) ethyll-N N-diethyl- 1,2-Ethanediamine

TBFCH2CHO (crude product) (0.86 g,-2 mmol) and N, N, N'N' tetraethyldiethylenetriamine were all dissolved in DCE (35 mL), NaB (OAc) 3H was added. The reaction mixture was stirred under an atmosphere of nitrogen at room temperature for 3 hours. TLC showed the product. (Hexanes/Ethyl Acetate: 2/1, Rf : 0.3) The mixture was concentrated and the residue

chromatographed with CHC13 on Alumina (neutral) to give the product as a brown oil. The yield: 63%.

MS: 608 (M+1) + EXAMPLE 22 Amide Synthesis From Amine and Acid Chloride Br NEZ 1. cI +-N /Cl TBF- N I H \-- /N NU2 vu (Quench reagent) 2. TBF ~ NH2 3. Charcoal

N-[2-(17H-Cyclopenta [1, 2-l [2-(17H-Cyclopenta [1, 2-l 3,4-1 diphenanthrene-17-yl) ethyl]-N-[2- (diethylamino) ethyl]-N, N-diethyl-1,2-ethanediamine (284 mg, 0.47 mmol) was dissolved in 3 mL CH2Cl2, N-benzylmethylamine (48.4 mg, 0.4 mmol) and m-Bromobenzyl chloride (131.7 mg, 0.6 mmol) added, stirred at room temperature overnight, then quench reagent N (2-amonoethyl)-N [2- (17H-cyclopenta [1,2- 1: 3, 4-1 ]diphenanthrene-17-yl)ethyl]-1, 2-ethanediamine (74 mg, 0.15 mmol) was added, stirred at room temperature for 7 hours, 2 mL reaction solution was taken filtered through charcoal column directly, concentration of the filtration gave the purified amide.

MS (CI): 306,304 (M+1).

1H NMR showed quench reagent <0. 5%.