Enantioselective alkylation of β-keto esters promoted by dimeric Cinchona -derived ammonium salts as recoverable organocatalysts

Dimeric anthracenyldimethyl-derived Cinchona ammonium salts are used as chiral organocatalysts in 5 mol% for the phase-transfer enantioselective alkylation reaction of 2-alkoxycarbonyl-1-indanones with activated bromides. The corresponding adducts bearing a new all-carbon quaternary center are obtained usually in high yield and with moderate and opposite enantioselectivity (up to 55%) when using ammonium salts derived from quinidine and its pseudoenantiomer quinine as organocatalysts. These catalysts can be almost quantitatively recovered by precipitation in ether and reused.


Introduction
The enantioselective generation of a quaternary stereogenic center is probably one of the most challenging tasks for a synthetic organic chemist, 1 and results particularly interesting when is carried out on substrates such as β-keto esters which offer ample opportunity for further structural elaboration. 2Among the transformations suitable for this purpose, the enantioselective alkylation of α-substituted β-keto esters has been performed under palladium catalysis, 3 although the development of metal-free alkylation procedures based on the fast forwarding topic of enantioselective organocatalysis 4 is nowadays desirable.
Among the organocatalytic methodologies, phase transfer catalysis (PTC) is one of the most simple and convenient, its use in many enantioselective transformations being profuse and successful. 5The most frequently employed chiral catalysts in enantioselective PTC transformations are ammonium salts derived from Cinchona alkaloids, 6 due to its availability and low price.
Surprisingly, the use of the PTC methodology for the enantioselective alkylation of αsubstituted β-keto esters leading to quaternary stereocenters has been rather limited.Thus, a dimeric mandelamide-derived phosphonium salt was pioneeringly used in the liquid-liquid phase transfer catalyzed alkylation of tert-butyl 2-oxocyclopentanecarboxylate, giving enantioselectivities up to 50%. 7More recently a binaphthyl-derived with C2-symmetry ammonium salt has afforded high ee's in the alkylation of several cyclic β-keto esters. 8However, the use of the popular Cinchona alkaloid-derived ammonium salts as phase-transfer organocatalysts has been limited to the use of cinchonine-, cinchonidine-and quinine-derived ammonium salts in the solid-liquid phase transfer benzylation of tert-butyl 2oxocyclopentanecarboxylate achieving enantioselections in the range 7-46%, the highest value being obtained using the cinchonine-derived salt 1. 9 In addition, very high ee's have been obtained with some electrophiles using the cinchonine-derived salt 2 in the alkylation reaction of different cyclic β-keto esters under solid-liquid phase transfer conditions. 10ur group has been working in the last years on developing recoverable unsupported [11][12][13] and supported 14 Cinchona alkaloid-derived ammonium salts for their use as chiral organocatalysts in enantioselective transformations.The recovery of the organocatalyst is an important problem when scaling up a synthetic procedure, the development of recyclable organocatalyst being therefore attractive for industrial purposes.Particularly interesting has been the preparation of a series of dimeric anthracenyldimethyl-derived ammonium salts from Cinchona alkaloids, which have been employed as recoverable organocatalysts in enantioselective reactions such as asymmetric alkylation 11 and Michael addition 12 reactions of glycinate Schiff bases for the enantioselective synthesis of -amino acids, being also used in enantioselective cyanoformylations. 13Recently, these dimeric ammonium salts have been employed in the conjugate addition of cyclic -keto esters and related substrates achieving enantioselectivities up to 94% ee. 15 Now we report the use of these dimeric ammonium salts in the alkylation of cyclic -keto esters leading to the enantioselective generation of quaternary stereocenters.

Br
The benzylation of 2-tert-butoxycarbonyl-1-indanone 5a using different dimeric Cinchonaderived ammonium salts was used as a model reaction in order to optimize the reaction conditions (Table 1).Thus, 2-tert-butoxycarbonyl-1-indanone 5a reacted with benzyl bromide in the presence of dimeric cinchonidine-derived ammonium salt 3a (5 mol%) as a phase transfer catalyst using solid potassium carbonate (5 eq) as base and a mixture of toluene/chloroform 7/3 v/v as solvent at room temperature.This solvent mixture has afforded good results when working with this type of dimeric ammonium salts. 11Under this conditions, the corresponding adduct (S)-6aa, bearing a new quaternary stereocenter, was obtained in 30% ee (Table 1, entry 1), its absolute configuration being assigned according to the HPLC retention time of the corresponding enantiomers in the literature. 8However, when the O-allylated cinchonidine-derived ammonium salt 3b was used as catalyst under these reaction conditions, the enantioselectivity for (S)-6aa dropped dramatically (Table 1, entry 2).When the quinine-derived dimeric ammonium salt 3c was employed as phase-transfer catalyst, the enantioselectivity for (S)-6aa raised up to 31% (Table 1, entry 3), whereas exchanging the chloride counteranion in 3c by a tetrafluoroborate 3d or a hexafluorophosphate 3e, an anion exchange that increases in some cases the efficiency of these type of dimeric catalysts, 11b gave rise to lower enantioselections (Table 2, entries 4 and 5).When the pseudoenantiomer of 3a, the cinchonine-derived ammonium salt 4a was used as phase-transfer catalyst, the expected opposite enantioinduction was observed and the benzylation adduct (R)-6aa was obtained in 27% ee (Table 1, entry 6).However, the use of the pseudoenantiomeric salt of 3c as catalyst, the quinidine-derived salt 4b, afforded the corresponding adduct (R)-6aa in a higher 42% ee (Table 1, entry 7).The change of the potassium carbonate as base by cesium carbonate diminished the obtained enantioselectivity for (R)-6aa.
The use of solid hydroxide-based bases was then explored, observing that lithium hydroxide gave no stereoinduction at all (Table 1, entry 9), whereas the use of solid sodium hydroxide afforded 22% ee for (R)-6aa (Table 1, entry 10).When solid potassium carbonate was used as base, the reaction rate increased notably and the benzylated adduct (R)-6aa was obtained in 55% ee (Table 1, entry 11), lower enantioselectivities being obtained when using monohydrated cesium hydroxide or potassium phosphate as solid bases (Table 1, entries 12 and 13).In addition, liquid-liquid phase-transfer catalyzed conditions were attempted using 50% aqueous potassium hydroxide and the mixture toluene/chloroform as solvent at room temperature, but the enantioselectivity for (R)-6aa resulted in only 30% (Table 1, entry 14).
The use of other solvents such as toluene or dichloromethane under the above mentioned solid-liquid phase-transfer conditions using potassium hydroxide as base, gave slightly lower enantioselectivities for (R)-6aa than when using the mixture toluene/chloroform 7/3 (Table 1, entries 15 and 16).In addition, lowering the reaction temperature to 0 ºC proved ineffective (Table 1, entry 17), whereas an even lower reaction temperature (-40 ºC) showed clearly detrimental (Table 1, entry 18).Moreover, the use of homogeneous reaction conditions achieved using diisopropylethylamine as base and dichloromethane as solvent, a method that has shown effective in the enantioselective Michael addition reaction of cyclic β-keto esters catalyzed by these dimeric ammonium salts, 15 gave rise to much lower enantioinduction for (R)-6aa (Table 1, entry 19).Furthermore, using twice the loading of catalyst 4b (10 eq) did not improve the observed ee for (R)-6aa (Table 1, entry 20).Finally, when the quinine-derived pseudoenantiomeric ammonium salt 3c was employed as catalyst, instead of 4b, under the most appropriate reaction conditions conditions, the corresponding (S)-6aa was obtained in only 9% ee (Table 1, entry 21).
Once the most effective catalyst and reaction conditions were established [4b (5 mol%), KOH(s), PhMe/CHCl3, 25 ºC], we explored the scope of this enantioselective alkylation reaction by changing the β-keto ester pro-nucleophile and the electrophile, the obtained results using 4b as phase-transfer organocatalyst being shown in Table 2. Thus, when the tert-butyl group present in the starting pro-nucleophile 5a was changed by the methyl group present in 5b, the corresponding adduct (R)-6ba was obtained, after reaction with benzyl bromide, in a much lower enantioselectivity (24% ee) (Table 2, compare entries 1 and 2).Therefore, a tert-butyl was set as the group of choice.
Then we proceed to check the influence of different substituents on the aromatic ring of the electrophile.Thus, the presence of a tert-butyl or a methyl group gave rise to lower and similar enantioselectivities for the corresponding adducts (R)-6ab and (R)-6ac, respectively (Table 2, entries 3 and 4), whereas the presence of electron-withdrawing substituents such as cyano or trifluoromethyl groups raised up again slightly the enantioselectivity for the corresponding adducts (R)-6ad and (R)-6ae (Table 2, entries 5 and 6).Moreover, using 2-(bromomethyl)naphthalene as electrophile in the alkylation of 5a, the alkylated adduct (R)-6af was obtained in 50% ee (  In addition, the use of allylic bromides as electrophiles was also attempted, giving rise to the products (R)-6ag and (R)-6ah in 41 and 48% ee when using allyl bromide and (E)-(3bromoprop-1-en-1-yl)benzene, respectively, as allylating reagents (Table 2, entries 8 and 9).Furthermore, the use of propargyl bromide as electrophile afforded the corresponding adduct (R)-6ai in 40% ee (Table 2, entry 10).
We also explored the influence of substituents on the β-keto ester pro-nucleophile on the enantioselectivity of the benzylation reaction.Thus the use of indanone 5c bearing a 5-methoxy group was not beneficial and the adduct (R)-6ca was obtained in 40% ee, a value that was lower when using as pro-nucleophile the 5,6-dimethoxy-containing indanone 5d (Table 2, entries 11 and 12).In addition, the use of 5-chloro-containing indanone 5e gave rise to the corresponding adduct (R)-6ea in 38% ee (Table 2, entry 13).
It is interesting to remark that the ammonium salt 4b can be recovered by filtration in a 95% yield, once the reaction was completed, after separation of the base by filtration, evaporation of the solvent and addition of ethyl ether.The recovered ammonium salt has been reused up to three times in the model reaction (Table 2, entry 1) giving rise to almost identical yields and enantioselectivities.
We conclude that quaternary stereocenters can be created in moderate enantioselectivity and usually high yields by an alkylation reaction between cyclic β-keto esters using Cinchonaderived dimeric ammonium as chiral organocatalysts under solid-liquid phase-transfer conditions.The corresponding quinine-derived ammonium salt gave opposite enantioselectivity that its pseudoenantiomer from quinidine, which afforded higher enantioselection values.These organocatalysts can be separated from the reaction medium by precipitation in ether, and reused without loss of activity.

Experimental Section
General.All the reagents and solvents employed were of the best grade available and were used without further purification.Melting points are uncorrected.IR data were collected on a Nicolet Impact 400D-FT spectrometer.The 1 H and 13 C NMR spectra were recorded at 25 ºC on a Bruker AC-300 or a Bruker Advance 400 at 300 MHz and 75 MHz, and 400 MHz and 100 MHz, respectively, using CDCl3 as solvent and TMS as internal standard.MS (EI, 70 eV) were performed on a HP MS-GC-5973A.HRMS analyses were carried out on a Finnigan MAT 95S.Elemental analysis were performed on a Carlo Erba CHNS-O EA1108 analyzer.Enantioselectivities were determined by chiral HPLC using Chiralcel columns and n-hexane/2propanol mixtures as eluent.Reference racemic samples of adducts 6 were obtained by performing the enantioselective alkylation reaction using n-tetrabutylammonium bromide as catalyst.Ammonium salts 3a, 13b 3b, 11a 3c-e, 15 4a 13b and 4b 15 have been prepared following reported procedures.Compounds 5 were prepared following a literature procedure. 16Absolute © ARKAT-USA, Inc. configuration for adducts 6aa,ag,ah 8 and 6ba 10 was determined according to the described order of elution of their enantiomers in chiral HPLC.The absolute configuration of other adducts was assigned by analogy.
Alkylation reactions under PTC conditions.Typical procedure.To a mixture of 5a (232 mg, 1 mmol) and 4b (46 mg, 0.05 mmol) in toluene/chloroform (7/3) (6 mL) was added benzyl bromide (143 µL, 1.2 mmol) and KOH (281 mg, 5 mmol) at room temperature.The mixture was stirred during 1h until reaction completion (TLC) and filtered to remove the solid base.The solvent was evaporated (15 Torr) and diethyl ether (6 mL) was added to precipitate 4b which was recovered by filtration.The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3 x 5 mL).The combined organics were washed with water and brine, dried (MgSO4), filtered and evaporated in vacuo (15 Torr) to afford (R)-4aa.Analytical and spectroscopical data for compounds 6aa,ag,ah 8 and 6ba 10 have been reported.Data for the other obtained compounds 6 follow.