Heterocyclic Trost’s ligands. Synthesis and applications in asymmetric allylic alkylation

Condensation of (1R,2R)- 1,2-diaminocyclohexane with 2-(diphenylphosphino)nicotinic acid and 3-(diphenylphosphino)quinoxaline-2-carboxylic acid afforded the corresponding diphosphines. These ligands were used in the palladium-catalyzed alkylation of various allylic acetates with carbon and nitrogen nucleophiles, giving generally lower enantioselectivities than the analogous non-heterocyclic ligands.


Introduction
2][3][4][5] Although a variety of ligands has been found to achieve high level of enantioselectivity in this coupling reaction, the most important breakthrough was the synthesis and the use of Trost's ligand.Enantioselectivities higher than 95% have been achieved using this ligand in carbon-carbon as well as carbon-nitrogen and carbon-oxygen bond formation. 3][8][9][10] However to our knowledge there is no study concerning the preparation of such ligands containing an aromatic heterocycle instead of a phenyl ring.We present in this paper the preparation of two ligands 4 and 5, bearing an aromatic heterocycle, and give some preliminary results in the use of these ligands in asymmetric alkylation.

Scheme 1. Synthesis of diphenylphosphino acids.
The chiral ligands 4 and 5 were obtained according to Trost's methodology. 6The condensation of (1R,2R)-1,2-diaminocyclohexane (3) with the corresponding phosphinocarboxylic acids 1 and 2 in THF at rt in the presence of DCC and a catalytic amount of DMAP gave the corresponding diphosphines 4 and 5 in 57% and 32% chemical yield, respectively, after purification by flash-chromatography (Scheme 2).
In order to investigate the ability of these new ligands in asymmetric catalysis and particularly in asymmetric alkylation, we performed some palladium-catalyzed reactions shown in Scheme 3. Preliminary results for reactions 1-3 are summarized in Table 1.
The palladium-catalyzed alkylation of allylic acetates was carried out in the presence of a (πallyl)-palladium-ligand complex generated in situ from 2 mol% [Pd(η 3 -C 3 H 5 )Cl] 2 and 8 mol% of the appropriate chiral ligand.Alkylation of rac-1,3-diphenyl-2-propenyl acetate in THF as the solvent with the nucleophile generated from dimethyl malonate and NaH gave a quantitative transformation after 24 h using 4 as the chiral ligand (Table1, entry 1); however the observed enantioselectivity (24%) was low.No improvement of this enantioselectivity was observed when the reaction was performed in CH 2 Cl 2 as the solvent and in the presence of (C 6 H 13 ) 4 NBr 11 in order to increase the solubility of the nucleophile (Table 1, entry 2).When 5 was used as the ligand, the reaction was sluggish (only 37% conversion after 24 h), with no enantioselectivity (Table 1, entry 3).Allylic alkylation of (2E)-1-propyl-2-hexen-1-yl acetate in THF using 4 as the ligand gave higher enantioselectivity (59% ee), but lower conversion (48%) ( The condensation of cyclohexenyl acetate with the sodium salt of dimethyl malonate using 4 as the chiral ligand occured quantitatively in THF, the ee of compound 7 being 18% (Table 1, entry 6).It is to be noted that when 5 was used as the ligand, the reaction was again very sluggish, only 18% conversion being observed after 24 h (Table 1, entry 10).Lower conversion was obtained when the alkylation reaction using 4 as the ligand was performed in THF in the presence of (C 6 H 13 ) 4 NBr, 11 the enantioselectivity being 28% (Table 1, entry 7).However the use of CH 2 Cl 2 as the solvent in the presence of (C 6 H 13 ) 4 NBr gave a quantitative conversion, with an enantioselectivity up to 19% ; when the reaction was performed at 0 °C, the conversion was 63% and the enantioselectivity increased to 53% (Table 1, entries 8-10).
Eq. 2 Eq. 3 Finally we used potassium phthalimide as a nitrogen nucleophile.Surprisingly when the reaction was carried out in CH 2 Cl 2 in the presence of (C 6 H 13 ) 4 NBr using 4 as the ligand, the conversion to the corresponding amine 8 was quantitative, and the enantioselectivity was 94%.(Table 1, entry 11) When 5 was used as the ligand, although the conversion was quantitative, the enantioselectivity of the coupling reaction was very low (only 8%) (Table 1, entry 12).
These two new heterocyclic ligands gave ee lower than those observed using Trost's ligand, except when potassium phthalimide was used as the nucleophile.This lower enantioselectivity may be attributed to competition between the P-P (structure A), and the P-N (structure C), and eventually the P-O (structure B) chelation (Scheme 4).This rationale is also supported by the lower efficiency of ligand 5 vs 4 due to the higher number of possible P,N-chelations involved in.][14] The dynamic isomerisation equilibrium between the P-O and the P-N chelation complexes has already been studied for the η 3 -allyl nickel complex of methyl 2-(diphenylphosphino)benzoate. 15t is obvious that in the P-O chelation, and moreover in the P-N chelation complex, less efficient chiral environnement is effectively expected, since the chiral centers are remote from the π-allyl system.In conclusion the heterocyclic Trost's ligands gave lower enantioselectivities in the palladium-catalyzed alkylation reaction compared to the usual Trost's ligand.One reason of this huge decrease in enantioselectivity is probably the formation of P-N complexes instead of the usual P-P or even P-O π-allyl complexes.

Experimental Section
General Procedures.Melting points were determined with a hot-stage microscope.Solvents were purified by standard methods and dried if necessary.Reactions involving palladium catalysis were carried out in Schlenk tube under an inert atmosphere.Tetrahydrofuran was distilled from sodium/benzophenone. Melting points (uncorrected) were determined with a capillary melting point apparatus Büchi SMP-20.Optical rotations were recorded using a Perkin-Elmer 241 polarimeter.Thin-layer chromatography was performed using Merck silica gel 60 F 254 precoated aluminium plates, 0.2 mm thickness.Column chromatography was performed on silica gel (Merck 60, 70-230 mesh).NMR spectra were recorded on a Bruker 200 MHz (200.13MHz for 1 H, and 81.01 MHz for 31 P) spectrometer.

2-(Diphenylphosphino)nicotinic acid (1).
A 0.5 L three-neck round-bottom flask equipped with a dry ice condenser and a glass-covered magnetic stirbar is charged with anhydrous liquid ammonia (150 mL).Then sodium (1.0 g, 44 mmole) is added to the stirred ammonia solution, followed by the addition of PPh 3 (5.25 g, 0.02 mole) in small portions over 30 min.After 3 h, to the red-orange solution of NaPPh 2 is added 2-chloronicotinic acid (3.15 g, 0.02 mole) in small portions over a 30 min, followed by the addition of of anhydrous Et 2 O (100 mL).The reaction mixture is allowed to warm to room temp.under argon.The residue is dissolved in water (150 mL) and extracted with of Et 2 O (100 mL).The aqueous phase is then filtered and acidified to p H 5-6 with concentrated HCl.Filtration of the precipitate and recrystallization from methanol afforded carboxylic phosphine 1 as a pale yellow solid (3.9 g, 64% yield).Mp 168-171 °C (litt.165 °C); 15
After being stirred until all the phosphinoacid has dissapeared (vizualeted by chromatography), the solution was evaporated to dryness.Flash column chromatography of the residue on silica gel using ethyl acetate/petroleum ether

Table 1 .
Some examples of palladium-catalyzed alkylation reactions a a [Allylic substrate]:[nucleophile]:[Pd]:[ligand] = 25:75:1:2; 25 °C; 24 h.b Determined by GC and HPLC analysis.c Determined by comparison of the rotation or the retention time with literature data.d The carbonate was used instead of the acetate.e Reaction carried out at 0 °C.