Further insight into the mechanism of Heck oxyarylation in the presence of chiral ligands

The Heck oxyarylation reaction to 3-benzyloxypterocarpan ( 15 ) has been studied in the presence of chiral phosphine ligands, a chiral ionic liquid and (+)- α -pinene. The observed small selectivities suggest that this reaction takes place through parallel pathways and the main pathway involves an achiral intermediate 11 where the chirality introduced by the chiral ligands is lost. Although practical asymmetric Heck oxyarylation to chiral pterocarpans could not be achieved, a convenient Heck-oxyarylation synthesis of rac - 15 with (+)- α -pinene as ligand gave the highest yield reported to this type of reactions.


Introduction
Pterocarpans, carrying a cis-fused benzofuranyl-benzopyran skeleton, form the second largest group of naturally occuring isoflavonoids.Many of their derivatives exhibit remarkable pharmacological activity such as antifungal, antibacterial 1 and anti-HIV effects. 2 Nakanishi and co-workers 3 also demonstrated that two representatives of these natural products, cabenegrin A-(I) (1) and cabenegrin A-(II) (2), showed activity against snake and spider venom but their mode of action is still to be explored.Although we have published 4 the total synthesis of (-)-6aR,11aR-1 via (-)-6aR,11aRmaackiain [(-)-3], the synthesis of (-)-3 suffered from limitations such as (i) the need of equimolar amounts of palladium(II) salt in the Heck-oxyarylation reaction of 7-benzyloxy-2Hchromene (13) and 2-chloromercury-3,4-methylenedioxyphenol resulting in the racemic precursor 4 in 53% yield and (ii) the low yield in the resolution of rac-maackiain (3).Recently, a convenient modification of this Heck-oxyarylation step has also been described 5,6 by the replacement of the toxic chloromercury-phenol derivatives with 2-iodophenols which allowed to considerably decrease the amount of the expensive palladium(II) salt (from 100 mol % to 10 mol %) in the presence of triphenylphosphine and silver carbonate in acetone or in ionic liquids such as 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF 6 ]).
Although intermolecular Heck oxyarylation is widely used in the synthesis of racemic pterocarpans [7][8][9][10] , in contrast to the conventional Heck reaction [11][12][13][14] , its mechanism is not fully understood.It presumably proceeds also via the generation of active Pd(0), oxidative addition of the aryl iodide to Pd(0), followed by regioselective syn-addition of 6 to 7 and palladium displacement by the phenolic oxygen whose details are not known (Figure 1).On the basis of the data published in the literature, 15 the displacement step may take place via (i) cationic (10), (ii) neutral (11) or a palladium containing cyclic intermediate (12) as shown in Figure 2. In order to investigate the mechanism of this step (8→9), we envisaged the study of this process in the presence of chiral ligands.Thus, if this step is carried out through the pathway (i) (8→10→9) or pathway (iii) (8→12→9) an asymmetric Heck-oxyarylation synthesis of pterocarpans 9 will be achieved.

Results and Discussion
Since the Heck oxyarylation reaction of 7-benzyloxy-2H-chromene (13) and 2-iodophenol (14)  has been already performed by two of us using 1,2-bis(diphenylphosphino)ethane (dppe) as ligand and Ag 2 CO 3 as base 5 (Scheme 1) it could be expected that the change of  17
Regarding the stereoselectivity, the syn-addition step is considered to be the key one in the AHRs.This step can follow either a cationic or a neutral pathway and the former one is reported 20 to give better enantiomeric excesses.All the oxyarylation reactions were carried out with 3 equivalents of halophilic Ag 2 CO 3 in order to sequester the iodide from the intermediate 8 and thus promote the favored cationic pathway.The enantiomeric purity of the obtained pterocarpan 15 was determined using chiral HPLC and the configurations of the baseline- separated peaks were assigned on the basis of their elution order using our chiral recognition model. 21n contrast to the acceptable 49% yield of entry 1 (Table 1) when the achiral dppe was used as ligand, the reactions with chiral phosphine ligands gave very low yields (Table 1, entry 2-6) and very small selectivities (5-10%).It was found that the (R)-BINAP slightly favored the formation of (6aR,11aR)-15, while the CHIRAPHOS, NORPHOS and TRIPHOS slightly preferred the formation of the 6aS,11aS isomer.It was surprising that the commercially available chiral palladium complex Pd[(R)-BINAP]Cl 2 showed no selectivity at all and lead to racemic 15.It was found earlier 22,23 that besides being a suitable solvent for Heck reactions, ionic liquids like [bmim][PF 6 ] could form a carbene-palladium complex, which turned out to be an active catalyst.Thus, in the presence of ionic liquids, the Heck oxyarylation could be achieved without phosphine ligands (entry 7).Therefore, it was expected that the use of a chiral ionic liquid may afford selectivity in the Heck oxyarylation.The chiral ionic liquid 21 was prepared from Nmethylimidazole (22) and S(+)-1-bromo-2-methylpropane (23) (Scheme 2) and used as both chiral ligand and solvent in the synthesis of 15.

Scheme 2
Although the yield of the transformation did not decrease drastically in entry 8 and 9 compared to entry 7, the selectivities remained very low (see entry 8 and 9).When triphenylphosphine was added (entry 9) the yield increased significantly but the chiral induction was completely lost.This indicated that the chiral inductor 21 was completely exchanged by triphenylphospine in the palladium complex and the solvation of the chiral ionic liquid had no effect on the selectivity.
It was also reported by Hosokawa et al. 24 that the enantioselective ring closure of the phenol derivative 24 could be achieved with high yield when the complex of palladium acetate and (-)α-pinene (25) was used as chiral catalyst.Thus, (+)-α-pinene was also tested as chiral ligand in our asymmetric Heck oxyarylation reaction with both acetone and the achiral ionic liquid [bmim][PF 6 ] as solvent (entry 12 and 13).Although the reactions with (+)-α-pinene led to rac-15, these conditions provided the highest yield (71%) of rac-15 obtained ever for the Heck oxyarylation reactions to pterocarpans.Comparing the yield of entry 12 with that of entry 13 it may be assumed that the (+)-αpinene [(+)-25] and the palladium-acetate formed a π-allyl-palladium complex 27 which has better stability and solubility in the applied condition and proved a suitable catalyst system for the Heck-oxyarylation reaction with high turn-over number.
On the basis of the very small or the lack of selectivity obtained during our asymmetric Heck oxyarylations to levo-or dextrorotatory pterocarpans [(6aR,11aR)-9 or (6aS,11aS)-9] the pathways (8→10→9) and (8→12→9) could be ruled out as main pathways.Therefore, one may suggest that the σ-benzylpalladium intermediate 8 (see Figure 1) is first transformed to the carbocation 8 and then the chirality introduced by the syn-addition step (7+6→8) is lost during its transformation to the π-benzylpalladium complex 11 by the removal of 3-H that results in rac-pterocarpan 9.The formation of a similar compound (31) was already reported 24 in the Heck reaction of 2H-chromene (28) and iodobenzene (29) where the ring closure of the corresponding σ-benzylpalladium intermediate (30) was not possible due to the lack of hydroxy group at C-2'.

Scheme 4
Our results strongly support that the formation of pterocarpan 9 mostly takes place through an achiral intermediate, which may be the intermediate 11, and this is the reason for the unexpected small selectivities.

Experimental Section
General Procedures.All reagents and organic compounds used were purchased from Sigma-Aldrich.7-benzyloxy-2H-chromene ( 13) and 1-butyl-3-methylimidazolium hexafluorophosphate (20) were prepared according to the known procedures. 26,27200 MHz 1 H-NMR spectra were recorded with a Bruker WP 200 SY instrument with TMS as internal standard.Precoated silica gel plates (Kieselgel 60 F 254, 0.25 mm Merck) were applied for analytical and preparative TLC.The yields imply the isolated amount of the product after separation by preparative TLC.The HPLC analysis was performed using a chiralpack OT (+) column and hexane: isopropanol 9:1 as eluent which condition gave baseline separation for the enantiomers of 3-benzyloxypterocarpan (15).The optical rotation (α D ) was determined by a Perkin Elmer 341 polarimeter and the concentrations were given in g /100 mL.

Figure 2 .
Figure 2. Possible pathways of the displacement step.