Synthesis and properties of a novel family of fluorous triphenylphosphine derivatives

A novel approach to the preparation of perfluorotail-functionalized triarylphosphines using a p-silyl substituent as the branching point has been developed. This approach enabled the attachment of between three and nine perfluorotails per phosphorus atom, resulting in the production of highly fluorous tris[p-(1H,1H,2H, 2H-perfluoroalkylsilyl)aryl]phosphines, P[C(6)H(4)-p-SiMe(3)(-)(n)()(CH(2)CH(2)C(x)()F(2)(x)()(+1))(n)()](3) (n = 1, 2, 3; x = 6, 8), containing between 50 and 67 wt % fluorine. (31)P NMR studies indicate that the phosphorus atoms, and consequently the sigma-donor and pi-acceptor properties of these phosphines, are not influenced by the electron-withdrawing perfluoroalkyltails. The fluorous triarylphosphines are readily soluble in fluorous solvents and display fluorous phase preference in several fluorous biphasic systems. The phase partitioning of these fluorous ligands, as well as their donor properties, is discussed in relation to their potential for fluorous biphasic catalyst separation.     

Light, medium, and heavy fluorous triarylphosphines exhibit comparable reactivities to triphenylphosphine in typical reactions of triarylphosphines

[reaction: see text] The relative reactivities of triphenylphosphine (PPh(3)) and three fluorous triarylphosphines [(p-R(F)(CH(2))(2)C(6)H(4))(n)PPh(3)(-)(n), where n = 1-3] have been compared in internal competition experiments. Product ratios were determined by (31)P NMR spectroscopy. The four phosphines have about the same reactivities in oxidation, alkylation, and Staudinger reactions and give comparable yields in a preparative Mitsunobu reaction. Previously observed rate and yield differences in Staudinger reactions of the fluorous phosphines are attributed to solubility effects, not reactivity differences. A light fluorous phosphine [(p-C(8)F(17)(CH(2))(2)C(6)H(4))PPh(2)] outperforms a commercially available resin-bound phosphine in a competitive benzylation experiment by a factor of about 4.     

Second-generation tags for fluorous chemistry exemplified with a new fluorous Mitsunobu reagent

A new fluorous DEAD reagent bearing two perfluoro-tert-butyloxy groups with propylene spacers shows excellent promise for use in fluorous Mitsunobu reactions. Pure target products were obtained in good yields after removing fluorous byproducts by FSPE. The new reagent serves as a prototype for a greener second generation of fluorous reagents bearing tags that are not expected to degrade in the environment to compounds that are highly persistent or that bioaccumulate in higher organisms.     

Fluorous phase-transfer activation of catalysts: application of a new rate-enhancement strategy to alkene metathesis

Reactions of the bis(pyridine) complex (H2IMes)(Py)2(Cl)2Ru(=CHPh) and fluorous phosphines P(CH2CH2R(fn))3 (n = a, 6; b, 8; c, 10; R(fn) = (CF2)(n-1)CF3) give (H2IMes)(P(CH2CH2R(fn))3)(Cl)2Ru(=CHPh) (2a-c, 64-73%), which are analogs of Grubbs' second generation catalyst and effective alkene metathesis catalysts under organic monophasic and fluorous/organic biphasic conditions. The latter give rate accelerations, which are believed to arise from phase transfer of the dissociated fluorous phosphine.     

Parallel synthesis and study of fluorous biphasic partition coefficients of 1H,1H,2H,2H-perfluoroalkylsilyl derivatives of triphenylphosphine: a statistical approach

A library of fluorous, (1H,1H,2H,2H-perfluoroalkyl)silyl-substituted derivatives of triphenylphosphine, Ph(3-a)P[C(6)H(5-y)[SiMe(3-b)(CH(2)CH(2)C(x)F(2x+1))(b)](y)-pos](a) [a = 1-3; b = 1-3; x = 4, 6, 8, or 10; pos = 3, 4 (y = 1) or 3,5 (y = 2)], was prepared using parallel synthetic techniques. Upon variation of these four parameters, a total of 108 different fluorous phosphines can be synthesized. Using factorial design, 37 phosphines were selected and their partition coefficients in the typical fluorous biphasic solvent system PFMCH/toluene (PFMCH = perfluoromethylcyclohexane) determined. By fitting of the partition coefficient data to linear functions of the parameters a, b, and x, the partition coefficients of the remaining 71 fluorous phosphines, which were not prepared, could be predicted. Using this approach, some unexpected trends in the dependence of the partition coefficient on variations of the four parameters became clear, resulting in a better understanding of the optimum fluorous substitution pattern for obtaining the highest partition coefficient (P). In this way, the partition coefficient was increased by 2 orders of magnitude, i.e., from the initial value P = 7.8 for 1(3, 2, 6, C4) to P > 238 for 1(2, 3, 6, C3C5). Para- and 3,5-substituted phosphines showed irregular behavior in the sense that elongation or increase of the number of perfluoroalkyl tails did not necessarily lead to higher partition coefficients. Particularly high values were found for phosphines containing a total of 72 fluorinated carbon atoms on the meta position(s) of the aryl rings. Linear relationships were found between the predicted log P of 1(a, b, x, C4) and the experimentally determined log P values of fluorous diphosphines [CH(2)P[C(6)H(4)(SiMe(3-b)(CH(2)CH(2)C(6)F(13))(b))-4](2)](2) and monophosphines Ph(3-a)P(C(6)H(4)(CH(2)CH(2)C(6)F(13))-4)(a). One of the most fluorophilic phosphines, i.e., 1(3, 1, 8, C3C5), was applied and efficiently recycled in rhodium-catalyzed, fluorous hydrosilylation of 1-hexene by HSiMe(2)Ph using PFMCH as the fluorous phase and the substrates as the organic phase. It was demonstrated that a higher partition coefficient of the ligand in PFMCH/toluene at 0 degrees C indeed resulted in less leaching of both the catalyst and the free ligand during phase separation.     

Chiral fluorous phosphorus ligands based on the binaphthyl skeleton: synthesis and applications in asymmetric catalysis

Two enantiopure fluorous phosphines have been conveniently synthesized by combining palladium-catalyzed coupling reactions of easily available binaphthyl building-blocks with the introduction of fluorous ponytails onto aromatic compounds via ether bond formation. These new fluorous chiral phosphines have been tested as ligands in metal-catalyzed asymmetric transformations, the best results being obtained in the palladium-catalyzed asymmetric allylic substitution of 1,3-diphenyl-2-propenyl acetate affording the products of up to 87% e.e.     

Preparative fluorous mixture synthesis of diazonium-functionalized oligo(phenylene vinylene)s

[structure: see text] A series of building blocks for the synthesis of oligo(phenylene vinylene)s (OPVs) and hybrid oligomers were prepared, and alternating Heck coupling and Horner-Wadswoth-Emmons (HWE) reactions were used to couple the building blocks. Model studies were carried out to optimize the reaction strategies. The products were made to bear aryl diazonium functionalities that allow them to be used as surface grafting moieties in hybrid silicon/molecule assemblies. A library of OPV and hybrid oligomer tetramers was synthesized using fluorous mixture synthesis (FMS). The fluorous tags, which are secondary amines bearing different numbers of fluorine atoms, were synthesized and used as phase tags in mixture synthesis. The tags and substrates were anchored together by triazene linkages. The mixture synthesis was monitored by analytical HPLC on a fluorous column, and isolation of final OPV and hybrid oligomer tetramers was achieved by preparative HPLC. At the end of the FMS, after demixing, the tagged products were detagged by cleaving the triazene linkage and generating a series of aryl diazonium compounds. The fluorous tags could be recovered and reused. The NMR spectra of the 1-aryl-3,3-dialkyltriazenes are discussed.     

Synthesis and reactions of fluorous carbobenzyloxy (FCbz) derivatives of alpha-amino acids

Fluorous carbobenzyloxy ((F)Cbz) reagents RfCH(2)CH(2)C(6)H(4)CH(2)OC(O)OSu (where Su is succinimidoyl and Rf is C(6)F(13) and C(8)F(17)) have been used to make (F)Cbz derivatives of 18 of the 20 natural amino acids. The potential utility of this new family of reagents in both standard fluorous synthesis with spe separation and fluorous quasiracemic synthesis is illustrated with representative reactions of the (F)Cbz-Phe derivatives.     

Second generation fluorous DEAD reagents have expanded scope in the Mitsunobu reaction and retain convenient separation features

First generation fluorous DEAD reagent bis(perfluorohexylethyl)azo dicarboxylate (C(6)F(13)(CH(2))(2)O(2)CN=NCO(2)(CH(2))(2)C(6)F(13), F-DEAD-1) has been shown to underperform relative to diisopropylazodicarboxylate in difficult Mitsunobu reactions involving hindered alcohols or less acidic pronucleophiles (phenols). Two new second generation fluorous reagents bearing propylene spacers instead of the ethylene spacers show expanded reaction scope while retaining the easy fluorous separation features. Byproducts from "half fluorous" reagent perfluorooctylpropyl tert-butyl azo dicarboxylate (C(8)F(17)(CH(2))(3)O(2)CN=NCO2(t)Bu, F-DEAD-2) can be removed by fluorous flash chromatography, and byproducts from bis(perfluorohexylpropyl)azo dicarboxylate (C(6)F(13)(CH(2))(3)O(2)CN=NCO(2)(CH(2))(3)C(6)F(13), F-DEAD-3) can be removed by fluorous solid-phase extraction. The new reagents promise to provide general and complementary solutions for separation problems in Mitsunobu reactions without restricting reaction scope.     

Palladium-catalyzed synthesis of aqueous, fluorous, and supercritical CO2-soluble phosphines

[reaction: see text]A generic, simple, and economical route has been developed for the synthesis of phosphines soluble in aqueous, fluorous, and supercritical CO2 phases. The methodology is based on the palladium-catalyzed Heck olefination of haloarylphosphine oxides followed by reduction, affording various arylphosphines in high yields.     

Recyclable benzyl-type fluorous tags: Preparation and application in oligosaccharide synthesis

We herein described the design, synthesis and application of two recyclable benzyl-type fluorous tags with double fluorous chains. The benzyl-type fluorous tags were prepared in 3 steps from a commercially available fluorous alcohol. The glycosylation of the benzyl-type tags with imidate donors proceeded smoothly to provide the corresponding fluorous-tagged carbohydrates in good to excellent yields, which were readily purified by fluorous solid-phase extraction(FSPE). Efficient removal of the tags from tagtethered carbohydrates were conducted under the common catalytic hydrogenation condition and the initial benzyl-type fluorous tags could be regenerated [5_TD$IF]via a 2-step simple procedure in 69%–93% yields.The utility of the new benzyl-fluorous tag was demonstrated [7_TD$IF]via the FSPE-assisted synthesis of oligosaccharides Gb3.     

Highly active thermomorphic fluorous palladacycle catalyst precursors for the Heck reaction; evidence for a palladium nanoparticle pathway

[reaction: see text] The fluorous Schiff base p-Rf8(CH2)3C6H4C(=N(CH2)3Rf8)(CH2)2Rf8 (Rf8 = n-C8F17) is prepared in six steps from p-iodobenzaldehyde and then cyclopalladated (Pd(OAc)2) to give highly effective catalyst precursors for Heck reactions, conducted under homogeneous conditions (DMF, 80-140 degrees C, turnover numbers >10(6)) in the absence of fluorous solvents. Rate, recycling, and other data suggest that the palladacycles serve as sources of palladium nanoparticles, which are the dominant active catalysts.     

Synthesis of monodentate ferrocenylphosphines and their application to the palladium-catalyzed Suzuki reaction of aryl chlorides

Racemic and enantiopure ((p)()S)-1-bromo-2-methylferrocene 6 were synthesized in 4 steps from 2-(4,4-dimethyloxazolinyl)ferrocene and (S)-2-(4-methylethyloxazolinyl)ferrocene, respectively (46 and 81% overall yield). Bromolithium exchange and addition of ClPR(2) gave the corresponding racemic or enantiopure 2-methylferrocenyl phosphine ligands 2-MeFcPR(2) 11 (R = Ph), 12 (R = Cy), and 13 (R = (t)Bu) in 28-93% yield. Use of PCl(3) gave the C(3)-symmetric phosphine (2-MeFc)(3)P 5 from ((p)()S)-6(72% yield) but racemic 6 did not lead to the formation of triferrocenyl phosphines. Combination of 5 and Pd(2)(dba)(3) gave an active catalyst for the Suzuki reaction of aryl chlorides, for example, 4-chlorotoluene and phenylboronic acid reacted at only 60 degrees C in dioxane (86% yield). Other examples are reported together with the use of 12 in this same protocol. From the X-ray crystal structure of 5 the cone angle was determined as 211 degrees. With this, and the electronic character of 11, 12, and other phosphines (derived from nu(CO) of trans-[(R(3)P)(2)Rh(CO)Cl]), an analysis is made of the steric and electronic influences on ligand activity in the Suzuki reaction.     

Hydroformylation in fluorous solvents

Triaryl-phosphines and -phosphites bearing fluorous ponytails give high rates, good linear selectivity and good retention of catalyst in the fluorous phase during hydroformylation of alkenes in fluorous solvents.     

Homogeneous catalysts supported on soluble polymers: biphasic Suzuki-Miyaura coupling of aryl chlorides using phase-tagged palladium-phosphine catalysts

The Suzuki-Miyaura coupling of aryl chlorides and PhB(OH)(2) under biphasic conditions (DMSO/heptane) can be performed in almost quantitative yields over several cycles by means of polymeric Pd catalysts with soluble polyethylene glycol phase tags. Three sterically demanding and electron-rich phosphines 1-CH(2)Br,4-CH(2)P(1-Ad)(2)-C(6)H(4), and 2-PCy(2),2'-OH-biphenyl, and 2-PtBu(2),2'-OH-biphenyl were covalently bonded to 2000 Dalton MeOPEG-OH. The catalysts, which were formed in situ from Na(2)[PdCl(4)], the respective polymeric phosphine, KF/K(3)PO(4), and PhB(OH)(2), efficiently couple aryl chlorides at 80 degrees C at 0.5 mol % loading, resulting in a >90 % yield of the respective biphenyl derivatives. The use of polar phase tags allows the efficient recovery of palladium-phosphine catalysts by simple phase separation of the catalyst-containing DMSO solution and the product-containing n-heptane phase. The high activity (TOF) of the catalyst remains almost constant over more than five reaction cycles, which involve the catalytic reaction, separation of the product phase from the catalyst phase, and addition of new reactants to initiate the next cycle. The Buchwald type biphenyl phosphines form the most active Pd catalysts, which are 1.3-2.8 times more active than catalysts derived from diadamantyl-benzylphosphine, but appear to be less robust in the recycling experiments. There is no apparent leaching of the catalyst into the heptane solution (<0.05 %), as evidenced by spectrophotometric measurements, and contamination of the product with Pd is avoided.     

Fluorous catalysis under homogeneous conditions without fluorous solvents: a "greener" catalyst recycling protocol based upon temperature-dependent solubilities and liquid/solid phase separation

The thermomorphic fluorous phosphines P((CH(2))(m)()(CF(2))(7)CF(3))(3) (m = 2, 1a; m = 3, 1b) exhibit ca. 600-fold solubility increases in n-octane between -20 (1a = 0.104 mM) and 80 degrees C (63.4 mM) and 1500-fold solubility increases between -20 and 100 degrees C (151 mM). They catalyze conjugate additions of alcohols to methyl propiolate under homogeneous conditions in n-octane at 65 degrees C and can be recovered by simple cooling and precipitation and used again. This avoids the use of fluorous solvents during the reaction or workup, which are expensive and can leach in small amounts. Teflon shavings can be used to mechanically facilitate recycling, and (31)P NMR analyses indicate >97% phosphorus recovery (85.2% 1a, 12.2% other). (19)F NMR analyses show that 2.3% of the (CF(2))(7)CF(3) moieties of 1a leach, in some form, into the n-octane (value normalized to phosphorus). 1a similarly catalyzes additions in the absence of solvent. Yield data match or exceed those of reactions conducted under fluorous/organic liquid/liquid biphase conditions. The extra methylene groups render 1b more nucleophilic than 1a and, thus, a more active catalyst. The temperature dependence of the solubility of 1a is measured in additional solvents and compared to that of the nonfluorous phosphine PPh(3).     

Metal-free reduction of tertiary phosphine oxides with Hantzsch ester简

The （COCl）2/Hantzsch ester is found to be an effective system for the metal-free reduction of tertiary phosphine oxides. The reaction proceeds under mild conditions, and is applicable to triarylphosphine oxides and alkyldiarylphosphine oxides to produce the corresponding tertiary phosphines in good to excellent yields. This new finding provides a practical, convenient and metal-free method for the reduction of tertiary phosphine oxides to tertiary phosphines, and shows potential application in organic synthesis.     

Increasing fluorous partition coefficients by solvent tuning

Low partition coefficients of fluorous components have been a persistent problem in liquid-liquid separations using perfluoroalkanes as the fluorous phase. Solvent tuning of both the nonfluorous and the fluorous phase dramatically enhances the partitioning of light or polar fluorous molecules into the fluorous liquid phase, while minimally effecting partition coefficients of nonfluorous molecules. These findings suggest an expanded scope for liquid-based separations in fluorous biphasic catalysis, fluorous-tagged reagents, fluorous-supported oligomer synthesis, and related areas. [reaction: see text]     

Steric and electronic properties of N-heterocyclic carbenes (NHC): a detailed study on their interaction with Ni(CO)4

N-heterocyclic carbene ligands IMes (1), SIMes (2), IPr (3), SIPr (4), and ICy (5) react with Ni(CO)(4) to give the saturated tricarbonyl complexes Ni(CO)(3)(IMes) (8), Ni(CO)(3)(SIMes) (9), Ni(CO)(3)(IPr) (10), Ni(CO)(3)(SIPr) (11), and Ni(CO)(3)(ICy) (12), respectively. The electronic properties of these complexes have been compared to their phosphine analogues of general formula Ni(CO)(3)(PR(3)) by recording their nu(CO) stretching frequencies. While all of these NHCs are better donors than tertiary phosphines, the differences in donor properties between ligands 1-5 are surprisingly small. Novel, unsaturated Ni(CO)(2)(IAd) (13) and Ni(CO)(2)(I(t)()Bu) (14) compounds are obtained from the reaction of Ni(CO)(4) with IAd (6) and I(t)()Bu (7). Complexes 13 and 14 are highly active toward substitution of the NHC as well as the carbonyl ligands. This has allowed the determination of Ni-C(NHC) bond dissociation energies and the synthesis of various unsaturated Ni(0) and Ni(II) complexes. Computational studies on compounds 8-14 are in line with the experimental findings and show that IAd (6) and I(t)()Bu (7) are more bulky than IMes (1), SIMes (2), IPr (3), SIPr (4), and ICy (5). Furthermore, a method based on %V(bur) values has been developed for the direct comparison of steric requirements of NHCs and tertiary phosphines. Complexes 8-14, as well as NiCl(C(3)H(5))(I(t)()Bu) (16) and NiBr(C(3)H(5))(I(t)()Bu) (17), have been characterized by X-ray crystallography.     

Conversion of alcohols to bromides using a fluorous phosphine

Reaction of alcohols with the fluorous phosphinecarbon tetrabromide complex in toluene or in a two-phase toluene-FC-72 system afforded the corresponding bromides in good yields. The fluorous-phosphine oxide is readily separated by liquid-liquid extraction, providing an alternative to the homogeneous triphenylphosphine-carbon tetrachloride conversion, as well as to the polymer-supported phosphine method. The fluorous phosphine oxide could be reduced and the product reused.