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fluorous silicagel

MeOH

Scheme 3.18 Fluorous protocols for catalyst recycle. a Biphasic liquid-liquid separation. b Temperature-dependent solubility of fluorous catalysts. c Fluorous solid-phase extraction p organic P solvent

f fluorous

C solvent

Cf f

low isoelectric constants, high thermal stability, exceptional chemical inertness under almost all reaction conditions and considerable hydrophobicity; they are also rather lipophobic but miscibility with organic solvents is highly temperature-dependent [123].

The original idea was the development of an efficient methodology for large scale preparations, based on the use of biphasic fluorous/organic solvents systems, whose mutual miscibility could be switched on/off by changing the temperature within a given range. In practical terms, a reaction can be performed in the homogeneous phase resulting from the warming of fluorous/organic solvent mixture and after its completion the biphasic system is restored by cooling to allow the selective separation of fluorinated compounds from non-fluorinated ones. In this way, properly designed perfluorinated catalysts can be selectively recovered in the fluorous phase and reused after addition of fresh reactants (Scheme 3.18a).

The success of such ''fluorous biphasic catalysis'' obviously requires high partition coefficients of catalysts into the fluorous phase and the catalyst ''fluorophilicity'' is usually engineered by attaching a number of fluorinated alkyl chains (called ''pony tails'') to known catalysts. The most common pony tails have a general formula -(CH2)m(CnF2n+2) but second-generation fluorous tags containing perfuoro-tert-butyloxy groups have been recently reported [124]. In modified ''heavy fluorous'' catalysts high fluorous solvent affinities are generally achieved with the introduction of a large number of fluorine atoms (usually 63 or more) while the spacer methylenic chain allows to modulate the electronic influence of the electron-withdrawing perfluoroalkyl substituents by insulating them from the reactive centre.

Although this approach could be considered ''green'' in that regards recycle of chemicals and decreased solvent waste, perfluohydrocarbons are quite expensive and other drawbacks are associated to their environmental persistence due to exceptionally long half-lives, significant global warming potential and toxicity of some products deriving from their atmospheric oxidation, as perfluorooctanoic and perfluorooctanesulfonic acids that bioaccumulate in higher organisms [125, 126]. Taking into account these concerns, the research in this field has been recently focused on the search for more benign fluorous solvents as hydrofluoroethers, that can be used in biphasic systems by ''tuning'' their partition coefficients with addition of small amounts of water or fluorocarbons [127]. Alternative protocols for the recovery of fluorous catalysts based on their thermomorphic (temperature-dependent solubility) properties in non-fluorous organic solvents have been also investigated (Scheme 3.18b) [128].

Moreover, the advent of fluorous solid-phase extraction (FSPE) has led to the development of ''light fluorous chemistry'' with growing application in small-scale medicinal chemistry, natural product synthesis and asymmetric catalysis [129]. Since ''light fluorous'' compounds are labeled with single perfluorohexyl or per-fluorooctyl groups, they are usually more soluble in most organic solvents than in fluorous ones and their recovery from organic solutions is usually performed exploiting their selective affinity for fluorocarbon-bonded silica gel stationary phases in chromatographic-like separations. The fluorous solvent is no more required and at the end of a given reaction the organic solution is loaded on a fluorous silica gel cartridge, that is then eluted with fluorophobic solvents (pure or aqueous MeOH or CH3CN) to give the organic components in the eluate while the fluorous compounds are adsorbed on the stationary phase. Subsequent elution with more fluorophilic solvents (ether or THF) extracts the fluorous compounds off the column (Scheme 3.18c) [130]. The technique is fast, efficient, general and widely applied in manual or automated parallel purification of fluorous reaction mixtures.

Heavy flourous derivatives of privileged ligands for transition-metal based catalysis have been applied for different asymmetric transformations in biphasic fluorous/organic solvent systems and their efficiency has been tuned by changing the number, the position and the length of ponytails. In most cases the fluorous substituents acted as chemically inert phase-tagging moieties without affecting the stereoselectivity observed with the original catalysts [131, 132]. Liquid-liquid separations has often provided acceptable levels of catalyst recovery and metal leaching(<1%) into the organic phase, but increased tendency to oxidation was evidenced for some perfluoroalkyl-modified BINAP ligands [133].

The non-covalent immobilization of Ru-57c complex on fluorous silica gel has been recently described as an efficient method to attain sufficient catalyst stabilization, so allowing its recover and reuse up to four cycles with only about 1.5% ruthenium leaching in the products [134] (Scheme 3.19a). In ligands 61 and 62 the perfluoroheptyl substituents worked not only as fluorous tags but, due to their electron-withdrawing character and the closeness to carbinol centres, also remarkably enhanced (by about a 10,000-factor) the acidity of the hydroxyl groups, that became prone to form more stable metal complexes. Indeed, complexes Ti/61 [135] or Ti/62 [136] gave excellent yields and ee values in the addition of Et2Zn or less reactive Me2Zn to aldehydes in toluene or hexane and were selectively extracted by partitioning the reaction mixtures between CH2Cl2 and perfluorohexane (FC-72). After removal of fluorous solvent by evaporation, the pure ligands were reused in successive runs with constant performances in seven consecutive runs (Scheme 3.19b). Aminophosphine 63 displayed good asymmetric induction in Pd-promoted allylic alkylation of 64 with malonate esters and the active catalyst was recovered by precipitation with cold hexane and reused five times without further addition of metal source [137] (Scheme 3.19c).

The Corey-Bakshi-Shibata (CBS) reduction of ketones [138] is a powerful methodology for the access to chiral secondary alcohols based on the use of chiral oxazaborolidines as catalysts and borane as hydrogen source. Oxazaborolidine 65a-c derived from diphenylprolinol provided high levels of asymmetric induction in the reduction of a large variety of substrates [139] and their preparation by treatment of an aminoalcohol precursor with a boron source (borate esters or BH3 • THF) can sometimes require extended heating and excess of borane. In the fluorous version of CBS-reduction, B-methyl oxazaborolidine of prolinol 66a displayed the same high enantioselectivity of the non-fluorous counterpart, but under the recycling conditions hydrolysis of the boron catalyst occurred and only the ligand was almost quantitatively recovered by FSPE. However, it was demonstrated that the in situ formation of the active catalyst from 66a and BH3 • THF was smoothly facilitated, may be due to the electron-withdrawing nature of perfluoroalkyl tags, so that successive runs could be easily performed by addition of borane reagent to the recovered aminoalcohol [140].

PPh2 PPh2

PPh2 PPh2

OH OH

OH OH

(S)-57a Rf = C6F,3 (S)-57b Rf = (CH2)2C6F,3 (S)-57c Rf = Si(CH2CH2CaF17)3 (R)-58c R = H, Rf = Si(CH2CH2CaF17)3

(R,R)-59a R = Rf = CaF,y (R,R)-59b R = i-Bu, Rf = CaF17

CaFi7'

Rf Me oJ<Oh

XI N

RfN U

(Sax,S,S)-61 Rf = C7F15 (R,R,R)-62 Rf = C4F9 (S)-63 Rf = CnF23

CaFi7'

H OH

H OH

MeO2C^,R H3C 1H

FSG = fluorous silica gel

recover of (S,S)-57/Ru complex by washing FSG 3 recycle runs

Et2Zn

94-97%, 95-96% ee recover of (SaXfS,S)-62 by liq-liq extraction with FC-72, 7 recycle runs

OAc Ph^^Ph

CO2Et

EtO2CyCO2Et P^V^Ph

(3 eqv.) 2 9a%, 91% ee recover of (S)-64/Pd complex by ppt in cold hexane 5 recycle runs

Scheme 3.19 Fluorous ligands for transition-metal catalysis

In an alternative protocol, the reduction of acetophenone with 66a/BH3 • DMS was carried out in hydrofluoroether solvent HFE-7500 to give 2-phenylethanol, selectively separated by extraction with DMSO, in >99% yield and 95% ee. Since the aminoalcohol 66a was tightly immobilized in HFE-7500 the fluorous phase

Ph i

(S )-66a R = H, Rr = C8F17 (s)-66b R = TMS, Rr = C8F17

(S )-66a R = H, Rr = C8F17 (s)-66b R = TMS, Rr = C8F17

PIT CH

HFE-7500, rt

OH Ph^CH3 >99%,95% ee recover of (S)-66a by liq-liq extraction with DMSO 8 recycle runs

recover of (S)-66a by ppt from cold CCI4 3recycle runs

O Ar

R = Me, n-Pr,i-Pr, Ar = Ph, 2-tienyl p-Br-Ph, p-OMe-Ph recover of (S)-66b by FSPE 5 recycle runs

Scheme 3.20 Asymmetric reactions with fluorous prolinols

could be reused after addition of fresh BH3 • DMS and consistent catalytic activity was maintained over five cycles [141] (Scheme 3.20a).

Fluorous prolinol 66a also promoted the organocatalytic epoxidation of a,b-enones in CCl4 with moderate to good enantioselectivities and it could be directly recovered by precipitation from the cooled reaction mixture [142]. The related silyl derivative 66b was employed in Michael addition of aldehydes to nitroolefins and sensible enhancements of diastereoselectivity and reaction rate were observed in trifluoromethylbenzene compared with hexane as in the original procedure; the organocatalyst was recovered by FSPE and reused in successive six cycles maintaining excellent performances [143] (Scheme 3.20b, c).

As other examples of fluorous organocatalysts, bifunctional pyrrolidine-thiourea 67 catalyzed the direct enantioselective a-chlorination of a variety of

H2N NHS°2C8F17

recover of (S)-67 by FSPE 5 recycle runs recover of (S)-68 by FSPE 3 recycle runs

brine, rt

65-90%, 86-91% ee recover of (S)-70 by FSPE 5 recycle runs

recover of (S)-70 by FSPE 5 recycle runs

Scheme 3.21 Reactions promoted by other fluorous organocatalysts aldehydes in CCl4 while valine-derived formamide 68 promoted the asymmetric reduction of imines with trichlorosilane (Scheme 3.21a, b). The catalysts were recycled after their FSPE extraction [144, 145] and quite low loading (1-5%) of 68 was sufficient to achieve the reaction products with high optical purities. Due to their high hydrophobicity, related with ponytails substituents, fluorous organoca-talysts appear very suitable for reactions performed in water and additional gain can stem from fluorous-based recovery protocols. So, the addition of aldehydes and ketones to nitrostyrene [146] and some aldol reactions [147, 148] have been beneficially performed in neat water or brine in the presence of sulphonamides 69 and 70, respectively, and the catalysts easily recovered by FSPE to be reused without significant loss of activity and stereoselectivity (Scheme 3.21c).

At the end of this section it should be mentioned that transition-metal complexes with fluorous ligands have also found application in some hydrogenation and hydroformylation reactions performed in scCO2 under controlled temperatures and pressures as nonconventional solvent and, due to the high dif-fusivity of the gaseous reagents in such supercritical fluid, better reaction rates and

scCO2 (d = 0.58-0.69) H2/CO (40 bar), 40 °C R = Ph, p-Cl-Ph, OCOMe

Me R^CHO

Me"

Ph^Me

Scheme 3.22 Asymmetric reactions in supercritical CO2

selectivities in comparison with liquid organic solvents have been often observed. Although the selective recovery of catalyst from scCO2 is not straightforward [149], this reaction medium offers the advantage that it can be easily removed by simple depressurization and, therefore, no hazardous solvent effluent is produced. Furthermore, scCO2 has rather mild critical properties (Tc = 31 °C and Pc = 74 bar), is non-toxic, non-inflammable, chemically inert, readily available and inexpensive. The use of fluorous ligands, many of which derived from BINAP, or highly lipophilic tetrakis[3,5-bis(trifluoromethyl)phenyl] borate (BARF) as counteranion of cationic complexes has often led to satisfactory solubilisation of transition-metal catalysts in rather apolar scCO2 allowing to perform asymmetric transformations in homogeneous phase [150].

As a representative example, Rh(acac)-complex of fluorous BINAPHOS ligand 71 successfully promoted the hydroformylation of styrenes and indene in scCO2, displaying enantioselectivities and regioselectivities in favour of branched chiral aldehydes significantly higher than those achieved in the original procedure with unsubstituted BINAPHOS 71 in benzene (Scheme 3.22a). However, it was demonstrated that regioselectivity was mainly affected by perfluoroalkyl-substitution of the ligand rather than the reaction medium features. Combination of 71 with [Rh(cod)2]BF4 was also active in scCO2 as hydrogenation catalyst and promoted the quantitative conversion of 2-acetamido methylacrylate into (R)-alanine with excellent enantiocontrol [151] (Scheme 3.22b).

Using fluorinated oxazoline 72, a crucial role of BARF counteranion on the enantioselectivity was found in iridium-catalyzed hydrogenation of imines (Scheme 3.22c) and higher TON and TOF values were obtained performing the reaction in scCO2 in comparison with CH2Cl2 [152]. More recently, non-fluorinated monodentate phosphoramidites 73a-b as sufficiently scCO2-philic ligands have been applied for Rh-promoted olefin hydrogenation in this supercritical fluid to afford some aminoacids in good to excellent optical purities (up to 97% ee) [153].

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