Nano-to-nano Fe/ppm Pd catalysis of cross-coupling reactions in water

Abstract

In one embodiment, the present application discloses a catalyst composition comprising: a) a reaction solvent or a reaction medium; b) organometallic nanoparticles comprising: i) a nanoparticle (NP) catalyst, prepared by a reduction of an iron salt in an organic solvent, wherein the catalyst comprises at least one other metal selected from the group consisting of Pd, Pt, Au, Ni, Co, Cu, Mn, Rh, Ir, Ru and Os or mixtures thereof; c) a ligand; and d) a surfactant; wherein the metal or mixtures thereof is present in less than or equal to 50,000 ppm relative to the iron salt.

Claims

1. An aqueous micellar composition in a reaction solvent for enabling cross-coupling reactions containing organometallic nanoparticles (NPs) as catalyst, comprising: a) an element selected from the group consisting of Fe, C, H, O, Mg, and a halide, or the entire combination thereof; and b) palladium (Pd), or at least one other metal selected from the group consisting of Pt, Au, Ni, Co, Cu and Mn, or a mixture thereof; wherein the catalyst (NPs) is prepared from a reduction of an iron salt or an iron complex in a solvent and in the presence of a ligand using a reducing agent.

2. The aqueous micellar composition of claim 1, wherein the iron is selected from the group consisting of a Fe(II) or Fe(III) salt, a Fe(II) salt precursor or Fe(III) salt precursor.

3. The aqueous micellar composition of claim 1, wherein the Pd is naturally present in the iron salt or the iron complex in amounts less than or equal to 1 ppm, 10 ppm, 50 ppm, 100 ppm, 200 ppm, 300 ppm, 400 ppm or 500 ppm relative to the iron salt or iron complex.

4. The aqueous micellar composition of claim 3, where the amount of Pd present is controlled by external addition of a palladium salt to an iron salt.

5. The aqueous micellar composition of claim 3, wherein the reducing reagent is a Grignard reagent selected from the group consisting of MeMgCl, MeMgBr, MeMgI, EtMgCl, EtMgBr, EtMgI, i-PrMgCl, i-PrMgBr, i-PrMgI, PhMgCl, PhMgBr, PhMgI, n-hexyl-MgBr, n-hexyl-MgCl, n-hexyl-MgBr, n-hexyl-MgCl, n-hexyl-MgI, NaBH.sub.4, liBH.sub.4, BH.sub.3-THF, BH.sub.3SMe.sub.2, borane, DIBAL-H and LiAlH.sub.4; and mixtures thereof.

6. The aqueous micellar composition of claim 1 further comprising a surfactant, wherein the surfactant is selected from the group consisting of TPGS-500, TPGS-500-M, TPGS-750, TPGS-750-M, TPGS-1000 and TPGS-1000-M, Nok and PTS, or a mixture thereof.

7. The aqueous micellar composition of claim 1, further comprising a ligand selected from the group consisting of PPh.sub.3, (o-Tol).sub.3P, (p-Tol).sub.3P, dppf, dtbpf, BiDime, Tangphos, IMes, IPr, SPhos, t-BuSPhos, XPhos, t-BuXPhos, BrettPhos and t-BuBrettPhos, and HandaPhos or an analog thereof.

8. The aqueous micellar composition of claim 1, wherein the iron metal complex as nanoparticles is heterogeneous and can be isolated from the composition, stored and recycled.

9. The composition of claim 1, wherein the reaction solvent is water, and the reaction solvent further comprising an organic solvent, wherein the organic co-solvent is present in at least 5%, 10%, 20%, 30%, 40%, 50%, 70%, 80% or at least 90% wt/wt.

Description

BRIEF DESCRIPTION OF THE FIGURE

(1) FIG. 1 on page 1 is a graphical representation showing a new approach to the Suzuki-Miyaura coupling reaction.

(2) FIG. 2 is a representation of a Cryo-TEM analysis of Fe/Pd nanorods in aqueous TPGS-750-M (a-c); SEM of solid nanomaterial (d-e); AFM image of solid nanomaterial (f). See SI for details.

(3) FIG. 3 is a representation of a TGA analysis of Fe/Pd nanomaterial.

(4) FIG. 4 is a representative figure showing a process for the recycling of the aqueous reaction mixture.

(5) FIG. 5 shows a representative scheme of results using doped and non-doped iron nanoparticles.

(6) FIG. 6 shows representative results of Sonogashira Coupling Reactions.

(7) ICP analysis was performed on the product resulting from both a coupling under micellar conditions as well as that formed using traditional Pd-catalysis in an organic medium (Scheme 4). Aside from the higher yield, in one aspect of the method, avoidance of organic solvent, and far lower levels of metal used, the amount of residual palladium in the product formed in n-butanol analyzed at 160 ppm, while that found in the product using Fe/ppm Pd micellar technology was only 7 ppm Pd.

(8) ##STR00178##

(9) The potential to apply this chemistry to an array of 1-pot sequential reactions, heteroaryl iodide 1 containing carbamate and trimethylsilyl protecting groups was generated in situ for use in a subsequent cross-coupling reaction with alkenyl tetrafluoroborate salt 2. From the cross-coupling product 3, TMS groups were removed in situ to 4, followed by Boc removal to provide intermediate 5. Final aryl amination to 6 with bromobenzene provided an overall novel one-pot route for the synthesis of this bioactive class of 2,4,5-substituted pyrazol-3-one in 68% overall yield (Scheme 5)..sup.[13]

(10) ##STR00179##

(11) The use of the catalyst system to mediate other important Pd-catalyzed reactions, such as Sonogashira couplings, was carried out employing the coupling partners illustrated in Scheme 6. The technology may accommodate a broad array of functional groups and efficiency of reaction.

(12) ##STR00180##
Synthesis of Active Nanoparticles:

(13) In a flame dried two-neck round-bottomed flask, anhydrous pure FeCl.sub.3 (500 mg, 3.09 mmol), XPhos (1177 mg, 2.47 mmol), and Pd(OAc).sub.2 (6.0 mg, 0.027 mmol) were placed under an atmosphere of dry argon. The flask was closed with a septum, and dry THF (10 mL) was added. The reaction mixture was stirred for 20 min at RT. While maintaining a dry atmosphere at RT, MeMgCl (12.4 ml, 6.18 mmol; 0.5 M solution) in THF was very slowly (1 drop/two sec) added to the reaction mixture. After complete addition of the Grignard reagent, the reaction mixture was stirred for an additional 10 min at RT. An appearance of a dark-brown coloration was indicative of generation of nanomaterial.

(14) After 20 min, the mixture was quenched with a 0.1 mL of degassed water, and THF was evaporated under reduced pressure at RT followed by triturating the mixture with dry pentane to provide a light brown-colored nanopowder (2.82 g, including material bound to THF). The nanomaterial was dried under reduced pressure at RT for 10 min and could be used as such for Sonogashira reactions under micellar conditions.

(15) General Procedure for Sonogashira Reactions:

(16) a) Using In Situ Formation of Catalyst

(17) Fe/ppm Pd nanoparticle formation as well as Sonogashira reactions were air sensitive, all reactions were ran under argon. Pure FeCl.sub.3 (97%, source Sigma-Aldrich) was doped with 320 ppm of palladium using 0.005 M solution of Pd(OAc).sub.2 (source, Oakwood Chemicals) in dry CH.sub.2Cl.sub.2 when nanoparticles were in situ formed.

(18) In a flame dried 4 mL microwave reaction vial, FeCl.sub.3 (4.1 mg, 5 mol %) containing ppm levels of palladium (ca. 350 ppm), XPhos (12 mg, 5 mol %) was added under anhydrous conditions. The reaction vial was closed with a rubber septum and the mixture was evacuated-and-backfilled with argon three times. Dry CH.sub.2Cl.sub.2 (1.0 mL) was added to the vial and the mixture was stirred for 30 min at RT, after which, while maintaining the inert atmosphere, CH.sub.2Cl.sub.2 was evaporated under reduced pressure. MeMgCl in THF (0.2 mL, 10 mol %; 0.1 M) was added to the reaction mixture, which was stirred at RT for one min. A freshly degassed aqueous solution of 2 wt % TPGS-750-M (1.0 mL) was added to the vial followed by sequential addition of aryl bromide or iodide (0.5 mmol), terminal alkyne (0.75 mmol, 1.5 equiv), and triethylamine (139 L, 1.0 mmol, 2.0 equiv). The vial was closed with a rubber septum and evacuated-and-back-filled with argon three times. The mixture was stirred vigorously at 45 C. for the desired time period.

(19) After complete consumption of starting material, as monitored by TLC or GCMS, the reaction mixture was allowed to cool to RT. EtOAc or MTBE (1 mL) or 5% EtOAc/MTBE was added to the reaction mixture, which was stirred gently for 5 min. Stirring was stopped and the magnetic stir bar was removed. The organic layer was separated with the aid of a centrifuge and then dried over anhydrous sodium sulfate. The solvent was then evacuated under reduced pressure to obtain crude material which was purified by flash chromatography over silica gel using EtOAc/hexanes or ether/hexanes as eluent.

(20) a) Using in Isolated Catalyst:

(21) Under the argon atmosphere, 30 mg nanoparticles were added in to a flame dried 4 mL reaction vial. Reaction vial was closed with a rubber septum and 1.0 mL freshly degassed aqueous solution of 2 wt % TPGS-750-M was added to it via syringe. Reaction mixture was stirred for a minute at RT followed by sequential addition of aryl bromide or iodide (0.5 mmol), terminal alkyne (0.75 mmol, 1.5 equiv), and triethylamine (139 L, 1.0 mmol, 2.0 equiv). The vial was closed with a rubber septum and evacuated-and-back-filled with argon three times. The mixture was stirred vigorously at 45 C. for the desired time period.

(22) After complete consumption of starting material, as monitored by TLC or GCMS, the reaction mixture was allowed to cool to RT. EtOAc or MTBE (1 mL) or 5% EtOAc/MTBE was added to the reaction mixture, which was stirred gently for 5 min. Stirring was stopped and the magnetic stir bar was removed. The organic layer was separated with the aid of a centrifuge and then dried over anhydrous sodium sulfate. The solvent was then evacuated under reduced pressure to obtain crude material which was purified by flash chromatography over silica gel using EtOAc/hexanes or ether/hexanes as eluent.

(23) Synthesis of Active Nanoparticles:

(24) In a flame dried two-neck round-bottomed flask, anhydrous pure FeCl.sub.3 (500 mg, 3.09 mmol), XPhos (1180 mg, 2.47 mmol), and Pd(OAc).sub.2 (6.0 mg, 0.027 mmol) were placed under an atmosphere of dry argon. The flask was closed with a septum, and dry THF (10 mL) was added. The reaction mixture was stirred for 20 min at RT. While maintaining a dry atmosphere at RT, MeMgCl (12.4 ml, 6.18 mmol; 0.5 M solution) in THF was very slowly (1 drop/two sec) added to the reaction mixture. After complete addition of the Grignard reagent, the reaction mixture was stirred for an additional 10 min at RT. An appearance of a dark-brown coloration was indicative of generation of nanomaterial.

(25) After 20 min, the mixture was quenched with a 0.1 mL of degassed water, and THF was evaporated under reduced pressure at RT followed by triturating the mixture with dry pentane to provide a light brown-colored nanopowder (2.82 g, including material bound to THF). The nanomaterial was dried under reduced pressure at RT for 10 min and could be used as such for Sonogashira reactions under micellar conditions.

(26) General Procedure for Sonogashira Reactions:

(27) ##STR00181##
a) Using In Situ Formation of Catalyst:

(28) Fe/ppm Pd nanoparticle formation as well as Sonogashira reactions were air sensitive; all reactions were ran under argon. Pure FeCl.sub.3 (97%, source Sigma-Aldrich) was doped with 320 ppm of palladium using 0.005 M solution of Pd(OAc).sub.2 (Oakwood Chemicals) in dry CH.sub.2Cl.sub.2 when nanoparticles were in situ formed.

(29) In a flame dried 4 mL microwave reaction vial, FeCl.sub.3 (4.1 mg, 5 mol %) containing ppm levels of palladium (ca. 350 ppm), XPhos (12 mg, 5 mol %) was added under anhydrous conditions. The reaction vial was closed with a rubber septum and the mixture was evacuated-and-backfilled with argon three times. Dry CH.sub.2Cl.sub.2 (1.0 mL) was added to the vial and the mixture was stirred for 30 min at RT, after which, while maintaining the inert atmosphere, CH.sub.2Cl.sub.2 was evaporated under reduced pressure. MeMgCl in THF (0.2 mL, 10 mol %; 0.1 M) was added to the reaction mixture, and stirred at RT for one min. A freshly degassed aqueous solution of 2 wt % TPGS-750-M (1.0 mL) was added to the vial followed by sequential addition of N-(2-iodophenyl)acetamide (138 mg, 0.5 mmol), 1-ethynyl-3,5-bis(trifluoromethyl)benzene (179 mg, 0.75 mmol, 1.5 equiv) and triethylamine (139 L, 1.0 mmol, 2.0 equiv). The vial was closed with a rubber septum and evacuated-and-back-filled with argon 3 times. The mixture was stirred vigorously at 45 C. for the 32 h.

(30) After complete consumption of starting material by TLC or GCMS, the reaction mixture was allowed to cool to RT. 2 mL EtOAc was added to the reaction mixture, which was stirred gently for 5 min. Stirring was stopped and the magnetic stir bar was removed. The organic layer was separated with the aid of a centrifuge. Similar extraction procedure was repeated and combined organic layer was dried over anhydrous sodium sulfate. The solvent was then evacuated under reduced pressure to obtain crude material which was purified by flash chromatography over silica gel using EtOAc/hexanes (1:49) as eluent. R.sub.f 0.35 in EtOAc/hexanes, white solid, yield 91% (175 mg). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.18 (d, J=8.8 Hz, 1H), 7.97 (s, 2H), 7.86 (s, 1H), 7.50 (dd, J=8.4 and 1.2 Hz, 1H), 7.43-7.39 (m, 1H), 7.32 (br. s, 1H), 7.06 (t, J=8.0 Hz, 1H), 3.83 (s, 3H); .sup.19F NMP (376 MHz, CDCl.sub.3) 63.2; .sup.13C NMR (101 MHz, CDCl.sub.3) 153.7, 139.4, 132.4, 132.3 (q, J.sub.(C,F)=34 Hz), 131.6, 131.5, 131.0, 125.0, 123.0, 123 (q, J.sub.(C,F)=274 Hz), 122.2 (septet, J.sub.(C,F)=3.8 Hz), 118.3, 110.3, 93.0, 87.9, and 52.7. ppm.

(31) a) Using in Isolated Catalyst:

(32) Under the argon atmosphere, 30 mg nanoparticles were added in to a flame dried 4 mL reaction vial. Reaction vial was closed with a rubber septum and 1.0 mL freshly degassed aqueous solution of 2 wt % TPGS-750-M was added via syringe. Reaction mixture was stirred for a minute at RT followed by sequential addition of N-(2-iodophenyl)acetamide (131 mg, 0.5 mmol), 1-ethynyl-3,5-bis(trifluoromethyl)benzene (179 mg, 0.75 mmol, 1.5 equiv), and triethylamine (139 L, 1.0 mmol, 2.0 equiv). The vial was closed with a rubber septum and evacuated-and-back-filled with argon three times. The mixture was stirred vigorously at 45 C. for 32 hours.

(33) After complete consumption of starting material by TLC or GCMS, the reaction mixture was allowed to cool to RT. 2 mL EtOAc was added to the mixture and stirred for 5 min. Stirring was stopped and the magnetic stir bar was removed. The organic layer was separated with the aid of a centrifuge. Similar extraction procedure was repeated and combined organic layer was dried over anhydrous sodium sulfate. The solvent was then evacuated under reduced pressure to obtain crude material which was purified by flash chromatography over silica gel using EtOAc/hexanes (1:49) as eluent. R.sub.f0.35 in EtOAc/hexanes, white solid, yield 91% (175 mg). .sup.1H NMR (400 MHz, CDCl.sub.3) 8.18 (d, J=8.8 Hz, 1H), 7.97 (s, 2H), 7.86 (s, 1H), 7.50 (dd, J=8.4 and 1.2 Hz, 1H), 7.43-7.39 (m, 1H), 7.32 (br. s, 1H), 7.06 (t, J=8.0 Hz, 1H), 3.83 (s, 3H); .sup.19F NMP (376 MHz, CDCl.sub.3) 63.2; .sup.13C NMR (101 MHz, CDCl.sub.3) 153.7, 139.4, 132.4, 132.3 (q, J.sub.(C,F)=34 Hz), 131.6, 131.5, 131.0, 125.0, 123.0, 123 (q, J.sub.(C,F)=274 Hz), 122.2 (septet, J.sub.(C,F)=3.8 Hz), 118.3, 110.3, 93.0, 87.9 and 52.7. ppm.

(34) As disclosed herein, a new catalyst system may be employed for valuable cross-couplings or cross-coupling reactions that utilizes iron nanoparticles doped naturally, or externally, with ppm levels of Pd. Coupling reactions, such as the Suzuki-Miyaura reactions studied are enabled by micellar catalysis that provides the nano reactors that house and deliver the reaction partners to the catalyst. The conditions are very mild, while efficiencies are high. Both the catalyst and aqueous medium in which the reactions occur are not only recyclable, but also environmentally responsible based on the very low E Factors associated with this chemistry.

(35) The foregoing examples of the related art and limitations are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings or figures as provided herein. In addition to the exemplary embodiments, aspects and variations described above, further embodiments, aspects and variations will become apparent by reference to the drawings and figures and by examination of the following descriptions.

Definitions

(36) Unless specifically noted otherwise herein, the definitions of the terms used are standard definitions used in the art of organic synthesis and pharmaceutical sciences. Exemplary embodiments, aspects and variations are illustratived in the figures and drawings, and it is intended that the embodiments, aspects and variations, and the figures and drawings disclosed herein are to be considered illustrative and not limiting.

(37) An alkyl group is a straight, branched, saturated or unsaturated, aliphatic group having a chain of carbon atoms, optionally with oxygen, nitrogen or sulfur atoms inserted between the carbon atoms in the chain or as indicated. A C.sub.1-C.sub.20alkyl or C.sub.1-20alkyl, for example, includes alkyl groups that have a chain of between 1 and 20 carbon atoms, and include, for example, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl, and the like. An alkyl group may also be represented, for example, as a (CR.sup.1R.sup.2).sub.m group where R.sup.1 and R.sup.2 are independently hydrogen or are independently absent, and for example, m is 1 to 8, and such representation is also intended to cover both saturated and unsaturated alkyl groups.

(38) An alkyl as noted with another group such as an aryl group, represented as arylalkyl for example, is intended to be a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group (as in C.sub.1-C.sub.20alkyl, for example) and/or aryl group (as in C.sub.5-C.sub.14aryl, for example) or when no atoms are indicated means a bond between the aryl and the alkyl group. Nonexclusive examples of such group include benzyl, phenethyl and the like.

(39) An alkylene group is a straight, branched, saturated or unsaturated aliphatic divalent group with the number of atoms indicated in the alkyl group; for example, a C.sub.1-C.sub.3 alkylene- or C.sub.1-C.sub.3alkylenyl-.

(40) The term alkynyl refers to a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

(41) The term aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups as disclosed herein, including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, NH.sub.2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term biaryl is a specific type of aryl group and is included in the definition of aryl. In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

(42) The term cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl and the like. The term heterocycloalkyl is a type of cycloalkyl group and is included within the meaning of the term cycloalkyl, where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

(43) A cyclyl such as a monocyclyl or polycyclyl group includes monocyclic, or linearly fused, angularly fused or bridged polycycloalkyl, or combinations thereof. Such cyclyl group is intended to include the heterocyclyl analogs. A cyclyl group may be saturated, partially saturated or aromatic.

(44) Halogen or halo means fluorine, chlorine, bromine or iodine.

(45) The terms heterocycle or heterocyclyl, as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. The term is inclusive of, but not limited to, heterocycloalkyl, heteroaryl, bicyclic heterocycle and polycyclic heterocycle. Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. A heterocyclyl group can also be a C.sub.2 heterocyclyl, C.sub.2-C.sub.3 heterocyclyl, C.sub.2-C.sub.4 heterocyclyl, C.sub.2-C.sub.5 heterocyclyl, C.sub.2-C.sub.6 heterocyclyl, C.sub.2-C.sub.7 heterocyclyl, C.sub.2-C.sub.8 heterocyclyl, C.sub.2-C.sub.9 heterocyclyl, C.sub.2-C.sub.10 heterocyclyl, C.sub.2-C.sub.11 heterocyclyl, and the like up to and including a C.sub.2-C.sub.18 heterocyclyl. For example, a C.sub.2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.

(46) A heteroaryl, refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur and phosphorus. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl or thiol. Heteroaryl groups can be monocyclic, or fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Other examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl and pyrido[2,3-b]pyrazinyl.

(47) The term pseudohalides, by themselves or as part of another substituent, refers to species resembling halides in their charge and reactivity, and are generally a good leaving group in a reaction, such as a substitution reaction. Examples are azides (NNN), isocyanate (NCO), isocyanide, (CN), triflate (OSO.sub.2SF.sub.3) and mesylate (CH.sub.3SO.sub.2O).

(48) Substituted or unsubstituted or optionally substituted means that a group such as, for example, alkyl, aryl, heterocyclyl, C.sub.1-C.sub.8cycloalkyl, heterocyclyl(C.sub.1-C.sub.8)alkyl, aryl(C.sub.1-C.sub.8)alkyl, heteroaryl, heteroaryl(C.sub.1-C.sub.8)alkyl, and the like, unless specifically noted otherwise, may be unsubstituted or, may substituted by 1, 2 or 3 substituents selected from the group such as halo, nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, NH.sub.2, OH, OMe, SH, NHCH.sub.3, N(CH.sub.3).sub.2, SMe, cyano and the like.

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(50) The entire disclosures of all documents cited throughout this application are incorporated herein by reference. While a number of exemplary embodiments, aspects and variations have been provided herein, those of skill in the art will recognize certain modifications, permutations, additions and combinations and certain sub-combinations of the embodiments, aspects and variations. It is intended that the following claims are interpreted to include all such modifications, permutations, additions and combinations and certain sub-combinations of the embodiments, aspects and variations are within their scope.