Preparation, properties and synthetic potentials of fluorous boronates

A fluorous approach to the chemistry of boronic acids and its application in fluorous-phase techniques are described. Treatment of fluorous bromosilane 2 with allyl Grignard reagent followed by dihydroxylation provided fluorous diol 1. A series of boronic acids were attached to 1 by esterification. The formed fluorous boronates 4 were moisture sensitive and thus their synthetic potentials were limited. Thus a fluorous pinacol, 5, was designed and synthesized by treatment of fluorous bromosilane 2 with excess 2,3-dimethyl-2-butyenylmagnesium bromide 9 to afford fluorous tetramethyl ethene 8, and was dihydroxylated. Compound 5 was successfully used to prepare fluorous boronates in a one-pot process from organic bromides. We have demonstrated that olefin cross-metathesis can be carried out in a fluorous version. It is noteworthy that all of the fluorinated compounds reported in this paper were purified by simple liquid extraction.     

Greener fluorous chemistry: Convenient preparation of new types of ‘CF3-rich’ secondary alkyl mesylates and their use for the synthesis of azides, amines, imidazoles and imidazolium salts

2,2,2-Trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, and nonafluoro-tert-butyl alcohol were used as precursors for the preparation of the appropriate bis(polyfluoroalkoxymethyl)carbinols [(R_FHOCH₂)₂CHOH, 1a-c, R_FH = (a) CF₃CH₂, (b) (CF₃)₂CH, and (c) (CF₃)₃C] and the corresponding mesylates [(R_FHOCH₂)₂CHOSO₂CH₃, 2a-c]. This novel design paradigm is introduced to eliminate the persistence and bioaccumulation problems of fluorous chemistry, which are associated with the use of longer linear perfluoroalkyl groups (e.g. R_fn ≥ n-C₈F₁₇, n-C₇F₁₅). Secondary mesylates 2a,b and the primary tosylate [(CF₃)₃COCH₂CH₂OTs, 2d] displayed acceptable reactivity towards azide and imidazole nucleophiles to allow the syntheses of novel fluorous azides, which on hydrogenolysis with H₂/Pd-C offered fluorous amines [(R_FHOCH₂)₂CHNH₂, 8a,b], and 1-(polyfluoroalkyl)imidazoles (5a,b,d), respectively, while 2c showed no reactivity due to steric hindrance. The reaction of 8a,b with formaline, glyoxal and hydrochloric acid gave symmetrical 1,3-dialkylated imidazolium chlorides (9a,b), while 5a,b,d were effectively alkylated using n-C₈F₁₇(CH₂)₃I, methyl iodide, 2-bromoethanol, and 2d to yield the corresponding 1,3-dialkylimidazolium iodides, bromides, and tosylates (7aa-ec). Some physical properties of new compounds including mp, bp and solubility patterns were also analyzed; and the fluorophilicity values of 1a-c, and 2a-c were experimentally determined by GC and/or ¹⁹F NMR spectroscopy.     

Efficient, recoverable, copper-catalyzed aerobic oxidation of alcohols under FBS and thermomorphic mode

A series of fluorinated bipyridine derivatives, (4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy) {R_f = n-C₈F₁₇ (1a), n-C₉F₁₉ (1b), n-C₁₀F₂₁ (1c), n-C₁₁F₂₃ (1d)} have been successfully synthesized using 4,4′-bis(bromomethylene)-2,2′-bpy and fluorinated alkoxides. Bpy 1a-d have been characterized by multi-nuclei (¹H, ¹⁹F, and ¹³C) NMR, GC/MS and FTIR. The Cu complexes 2a-d could be generated in situ by stirring ligands 1a-d with CuBr·Me₂S at room temperature, respectively. The 3-component systems 3c-d, CuBr·Me₂S/Bpy (1c-d)/2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO), were successfully used to the aerobic oxidation of alcohols under the fluorous biphasic system (FBS). The resulting products from FBS could be easily recovered by two phase separation with high yields up to 8 runs (>90%). In order to avoid using the expensive fluorous solvents, systems 3a-d, CuBr·Me₂S/Bpy (1a-d)/TEMPO, were also successfully shown to catalyze the aerobic alcohol oxidation under the thermomorphic condition (in C₆H₅Cl), and the yields of oxidation of 4-nitrobenzyl alcohol were close to 100% even after 8 runs. In particular, 3a was most effective under the thermomorphic mode in the chemoselectivity of aerobic oxidation of aliphatic primary alcohols to aldehydes without any overoxidized acids.     

Catalytic enantioselective cyclopropanation of allylic alcohols using recyclable fluorous disulfonamide ligand

Cyclopropanation of allylic alcohols with Et₂Zn and CH₂I₂ in the presence of a catalytic amount of fluorous disulfonamide 3 afforded the corresponding cyclopropylmethanols in 69-96% yield with 49-83% ee. The fluorous ligand 3 was readily recovered from the reaction mixture by the fluorous solid-phase extraction (FSPE) and could be reused without a significant loss of the catalytic activity and enantioselectivity.     

The synthesis and application of fluorous boronates without perfluorinated solvents

The synthesis of a fluorous diol 4 bearing a perfluorodecyl chain was described. A series of boronic acid were attached to 4 by esterification. The purification of the products was fulfilled by facile filtration instead of expensive and environmental troublesome fluorous liquid-liquid extraction. The Suzuki cross-coupling reactions of the formed fluorous boronates 5 underwent smoothly and the fluorous diol 4 was recycled in good yields.     

Rapid oligosaccharide synthesis on a fluorous support

The novel fluorous support Hfb (hexakisfluorous chain-type butanoyl) was easily prepared. The Hfb group was readily introduced into the anomeric hydroxyl group of a carbohydrate, and was recyclable after cleavage. The use of the Hfb group was applicable for the rapid oligosaccharide synthesis in which the synthetic intermediates could be purified using fluorous and normal organic solvents. Each synthetic intermediate could be monitored by TLC, NMR and mass spectrometry.     

Convenient syntheses of fluorous phenols of the formula HOC6H5−n((CH2)3(CF2)7CF3)n (n=1, 2) and the corresponding triarylphosphites

The aldehydic benzyl ethers PhCH₂OC₆H₄CHO (2; a/b = para/meta series) are readily available from the corresponding phenols and react with Wittig reagents derived from [Ph₃PCH₂CH₂R_f8]⁺I⁻ (R_f8=(CF₂)₇CF₃) to give PhCH₂OC₆H₄CHCHCH₂R_f8 (86-93%, Z major). Reactions with H₂ over Pd/C give the fluorous phenols HOC₆H₄(CH₂)₃R_f8(4a,b; 87-91%). Condensations with PCl₃ and NEt₃ (3.0:1.0:3.3 mol ratio) give the fluorous phosphites P[OC₆H₄(CH₂)₃R_f8]₃(5a,b; 92-94%), but traces of 4a,b are difficult to remove. The phthalate-based benzyl ethers PhCH₂OC₆H₃(COOR)₂ (7; ,5/3,4 OC₆H₃-3,n-(R)₂ series) are easily accessed and reduced with LiAlH₄ to the diols PhCH₂OC₆H₃(CH₂OH)₂(8c,d; 89-90%). Diol 8c and the Dess-Martin periodinane react to give the dialdehyde PhCH₂OC₆H₃(CHO)₂ (9c; 95%). This is elaborated by a sequence analogous to 2→4→5 to the fluorous phenol HOC₆H₃((CH₂)₃R_f8)₂ (11c; 97%/96%, two steps) and phosphite P[OC₆H₃((CH₂)₃R_f8)₂]₃ (12c, 92%), from which traces of 11c are difficult to remove. Diol 8d can be similarly elaborated to 11d, but the dialdehyde 9d is labile and the combined yield of the Dess-Martin/Wittig steps is 32%. The CF₃C₆F₁₁/toluene partition coefficients of 11c,d, and 12c (two pony tails; 70:30, 72:28, 92:8) are much higher than those of 4a and b (one pony tail; 12:88, 14:86).     

Fluorinated alcohol directed formation of dispiro-1,2,4,5-tetraoxanes by hydrogen peroxide under acid conditions

The oxidative system MTO/30%H₂O₂/HBF₄/fluorous alcohol is promising for the selective synthesis of biologically important antimalarial dispiro-1,2,4,5-tetraoxanes by direct acid-catalysed cyclisation of various 4-substituted cyclohexanones (1, R=Me, Et, tBu, Ph, COOEt, CF₃). The role of the substitutent at the 4-position was important in the selectivity of formation of tetraoxane (2, TO) with respect to hexaoxonane (3, HO). By the use of fluorinated alcohols and under the right reaction conditions, tetraoxanes 2 were selectively formed and synthesised in 46-86% isolated yield from 4-substituted cyclohexanones 1.     

Fluorous glycol derivatives: novel carbonyl protective groups

Fluorous glycol derivatives 5 were prepared and evaluated as reagents for the protection of carbonyl groups for use in fluorous synthesis. The acetals formed from fluorous diol 5b (Rf=n-C₈F₁₇) with carbonyl compounds can be separated and purified by simple fluorous-organic extraction.     

Dibromomethane as one-carbon source in organic synthesis: a versatile methodology to prepare the cyclic and acyclic α-methylene or α-keto acid derivatives from the corresponding terminal alkenes

Ozonolysis of mono-substituted alkenes A-1 followed by reacting with a preheated mixture of CH₂Br₂-Et₂NH affords α-substituted acroleins A-2 in good yields. Under very mild reaction conditions, these α-substituted acroleins A-2 can be easily converted to α-methylene esters A-4, which could be further converted to the corresponding α-keto esters A-5. This methodology can be also applied to the preparation of α-methylene lactones B-4, α-methylene lactams, and α-keto lactones B-5 with various ring sizes.     

Practical heavy fluorous tag for carbohydrate synthesis with minimal chromatographic purification

A practical heavy fluorous tag 5 bound to a benzylic linker was prepared and applied to carbohydrate synthesis. The fluorous tag 5 was readily introduced to the desired hydroxyl group and carboxyl group by using various methods. Synthesis of the oligosaccharide, which included the terminal structure of class III mucin, was achieved with single-column chromatographic purification. In addition, because of the symmetrical structure of 5, each fluorous synthetic intermediate could be analyzed much easier by NMR spectroscopy than in the case of the fluorous compounds connecting our previous fluorous tags.     

Synthesis,structure and reactivity of novel palladiumdichloride-2,2′-bipyridine with 4,4′-bis(fluorous-ponytail)

With the readily available fluorous alkanols R_fCH₂OH, a series of novel fluorous-ponytailed bpy ligands, 4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy (1a–e), were prepared and treated with [PdCl₂(CH₃CN)₂] to result in the corresponding novel Pd complexes [PdCl₂(4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy)] (2a–e) where R_f = n-C₃F₇ (a), HCF₂(CF₂)₃ (b), HCF₂(CF₂)₇ (c), n-C₈F₁₇ (d), n-C₁₀F₂₁ (e). The new ligands and Pd complexes were spectroscopically characterized by multi-nuclei NMR (¹H, ¹⁹F and ¹³C), FTIR and high resolution mass (FAB). The structure for the Pd complex 2b, the first with fluorinated ponytails on bpy and not on phosphine, was also established by a single crystal X-ray diffraction study. The TGA data of both ligands and Pd complexes indicated that the Pd-complexes were resistant to higher temperatures than the corresponding ligands. The Pd catalysts derived from 2a–c showed an almost quantitative conversion and could be reused for eight runs with Heck reactions, in that the products and unspent reactants were directly removed by distillation. With the highest fluorine content in the series, Pd complex 2e was successfully applied in the Heck reaction using the fluorous biphasic catalysis strategy.     

Synthesis and reactivity of new functionalized Pd(II) cyclometallated complexes with boronic esters

Treatment of the functionalized Schiff base ligands with boronic esters 1a, 1b, 1c and 1d with palladium (II) acetate in toluene gave the polynuclear cyclometallated complexes 2a, 2b, 2c and 2d, respectively, as air-stable solids, with the ligand as a terdentate [C,N,O] moiety after deprotonation of the -OH group. Reaction of 1j with palladium (II) acetate in toluene gave the dinuclear cyclometallated complex 5j. Reaction of the cyclometallated complexes with triphenylphosphine gave the mononuclear species 3a, 3b, 3c, 3d and 6j with cleavage of the polynuclear structure. Treatment of 2c with the diphosphine Ph₂PC₅H₄FeC₅H₄PPh₂ (dppf) in 1:2 molar ratio gave the dinuclear cyclometallated complex 4c as an air-stable solid.Deprotection of the boronic ester can be easily achieved; thus, by stirring the cyclometallated complex 3a in a mixture of acetone/water, 3e is obtained in good yield. Reaction of the tetrameric complex 2a with cis-1,2-cyclopentanediol in chloroform gave complex 2c after a transesterification reaction. Under similar conditions complexes 3a and 3d behaved similarly: with cis-1,2-cyclopentanediol, pinacol or diethanolamine complexes 3c, 3b, 3g and 3f, were obtained. The pinacol derivatives 3b and 3g experiment the Petasis reaction with glyoxylic acid and morpholine in dichloromethane to give complexes 3h, and 3i, respectively.     

New axially dissymmetric ligand recoverable with fluorous solvent

Axially dissymmetric ligands with perfluoroalkyl groups, (Ra)-2,2′-bis[(R)-1-hydroxy-1H-perfluorooctyl]biphenyl [(Ra)-(R)₂-1c] and its enantiomer, have been synthesized successfully by the coupling reaction of the corresponding aryl bromide using Ni(COD)₂. These ligands showed much higher asymmetric induction in the reaction of various aldehydes with diethylzinc than the trifluoromethyl (1a) or pentafluoroethyl (1b) analogues. Furthermore, 1c was recovered quantitatively by extraction with a fluorous solvent from the reaction mixture due to its high fluorine content. The recovered ligand 1c was pure enough to be reused without purification. The efficiency of 1c as the chiral ligand was not decreased at all even after seven times recycling.     

Conjugate additions of lithium dialkynylcuprates [(RCC)2CuLi] to activated chromones. Unexpected formation of the 6H-bis[1]benzopyrano[2,3-b:3′,4′-e]pyridine system

Lithium dialkynylcuprates [(RCC)₂CuLi], 1a-d, are easily generated and undergo conjugate additions to activated chromones giving 2-alkynylchroman-4-ones 4a-d, 13, 15c,d and 5, however, 1,4-additions to 3 proceed anomalously to give the eneynonitriles 6a-b and the bisbenzopyranopyridine 7.     

Bimetallic complexes with ruthenium and tantalocene moieties: Synthesis and use in a catalytic cyclopropanation reaction

The reaction of the tantalocene dichloride monophosphines (1-2) with the binuclear complex [(p-cymene)RuCl₂]₂ gives the heterobimetallic compounds (p-cymene)[(η⁵-C₅H₅)(μ-η⁵:η¹-C₅H₄(CH₂)₂PR₂)TaCl₂]RuCl₂ (3-4). The air oxidation of these bimetallic species 3-4, leads to the cationic hydroxo tantalum ruthenium derivatives 5-6. The last ones are easily deprotonated by a base to afford the oxo analogues 7-8. A preliminary assessment in catalytic cyclopropanation of styrene with tantalum ruthenium bimetallic complexes 3-8 as precatalysts revealed a cooperative effect with a subtle role of the early metal fragment.     

Direct asymmetric aldol reactions in brine with recyclable fluorous β-aminosulfonamide organocatalysts

Fluorous organocatalyst 3 promotes direct asymmetric aldol reactions of ketones with aldehydes in brine, leading to the synthesis of the corresponding anti-aldol products in high yields with up to 96% ee. Fluorous organocatalyst 3 is easily recovered by solid-phase extraction using fluorous silica gel and can be reused up to five times without purification.     

Trimethyl borate/magnesium halide complex-induced one-pot homologation reactions of isoquinoline with dialkyl-TMP-zincate

Novel one-pot homologation reactions of isoquinoline with lithium dialkyl-TMP-zincate⋅2MgBrCl/trimethyl borate are described. 1-Alkylisoquinolines (2, 3A, 4A, 5A, 6, and 7) and 1-alkyl-3,4-dihydroisoquinolines (3B, 4B, and 5B) are easily prepared under the presented reaction conditions. The role of the B(OMe)₃/MgBrCl complex is examined in these homologation reactions. The specific reaction mechanisms, including 1,2-migration of the alkyl ligands from 1-isoquinolylzincates, are proposed. The migratory aptitudes of ligands of 1-isoquinolylzincates are also discussed.     

Synthesis of aminoglycoside derivatives on a Cbz-type heavy fluorous tag

Four aminoglycoside derivatives containing a 2,6-diamino-2,6-dideoxy-d-glucopyranose disaccharide structure were successfully prepared by using a Cbz-type heavy fluorous tag in a fluorous synthesis. A Cbz-type heavy fluorous tag was prepared using the hexakis(fluorous chain)-type alcohol 11, and the fluorous alcohol 11 was recovered in good yield after the synthesis of aminoglycoside derivatives.     

Monomeric and dimeric red/NIR-fluorescent dipyrrin–germanium complexes: facile monomer–dimer interconversion driven by acid/base additions

Highly coordinate germanium complexes of the N2O2-type tetradentate dipyrrin ligand have been synthesized. X-ray crystallographic analysis revealed the pentacoordinate structure of dimeric germanium complex 2 (=(Ge)₂O) and the hexacoordinate structure of monomeric complex 3 (=Ge(OMe)(HOMe)). The dimer 2 was easily hydrolyzed in a solution to give monomer 4, though the corresponding siloxane (Si)₂O did not react under the same conditions. The addition of DBU to a solution of 4 gave dimer 5, and neutralization by adding acetic acid regenerated the monomer 4, providing the facile and reversible interconversion between the monomer and dimer. The dipyrrin germanium complexes showed an intense absorption and fluorescence near the NIR region, which is more red-shifted than the silicon complexes.