Palladium Catalyzed Heck Arylation of 2,3-Dihydrofuran—Effect of the Palladium Precursor

Heck arylation of 2,3-dihydrofuran with iodobenzene was carried out in systems consisting of different palladium precursors (Pd2(dba)3, Pd(acac)2, PdCl2(cod), [PdCl(allyl)]2, PdCl2(PhCN)2, PdCl2(PPh3)2) and ionic liquids (CILs) with L-prolinate or L-lactate anions. All the tested CILs caused remarkable increases of the conversion values and in all of the reactions 2-phenyl-2,3-dihydrofuran (3) was obtained as the main product with a yield of up to 59.2%. The highest conversions of iodobenzene were achieved for the [PdCl(allyl)]2 precursor. Formation of Pd(0) nanoparticles, representing the resting state of the catalyst, was evidenced by TEM.

In order to learn more about the mechanism of DHF arylation we concentrated our efforts on evaluation of different palladium precursors to compare their applicability in place of Pd(OAc) 2 . We selected five phosphine-free palladium complexes, Pd 2 (dba) 3 , Pd(acac) 2 , PdCl 2 (cod), [PdCl(allyl)] 2 , PdCl 2 (PhCN) 2 and PdCl 2 (PPh 3 ) 2 . On the basis of the previous results, four CILs were chosen, three containing L-prolinate anion and one L-lactate.
Despite of chirality of CILs, preliminary catalytic tests shown low enantioselectivity of the studied reactions. Therefore we focused our investigations on the selection of the best palladium precursor facilitating high conversion of substrates. It is well accepted in the literature that under catalytic reaction conditions palladium precursors are transformed to catalytically active forms, monomolecular complexes or palladium nanoparticles [29][30][31][32][33][34][35][36][37][38][39]. In this context it was interesting to study relation between structure of palladium precursor and its reactivity in the Heck reaction. used in 2-10-fold excess to palladium which was applied in amount of 1% mol. In all the cases, the conversion of iodobenzene was higher after addition of two equivalents of CIL than in the reference reaction carried out with palladium complexes only. When the amount of CIL exceeded 2, conversion continued to increase, however, that positive effect was observed only to [CIL]/[Pd] equal 4-6, and then the conversion dropped down. In some systems the reaction was stopped completely at [CIL]/[Pd] = 10. The best results, up to 74.5% of the arylated products, were obtained for dimeric complex [PdCl(allyl)] 2 . Interestingly, relatively low conversions were noted for Pd 2 (dba) 3 , the only Pd(0) species in the studied series. Reactivity of PdCl 2 (PPh 3 ) 2 differs significantly from that of the phosphine-free palladium precursors and already a 2-fold amount of CIL inhibited the reaction totally.

Arylation of DHF at the Presence of [BA][L-PRO]
The influence of [BA][L-PRO] (BA = cation with C 12 H 25 and C 14 H 29 alkyl groups in proportions equal to 60% and 40% respectively) on the Heck arylation of DHF is shown in

Arylation of DHF at the Presence of [NBu 4 ][L-PRO]
The results of testing of the next CIL with the same anion, Similarly as for the previously studied L-prolinate salts, the biggest change of the 3/(2+4) parameter caused by the presence of [NBu 4 ][L-PRO] was observed for PdCl 2 (cod). Interestingly, the selectivity of the Heck coupling with the most efficient complex, [PdCl(allyl)] 2 , was not very sensitive to CIL which caused a change of the 3/(2+4) value from 4.8 to 2.3-2.5.

Arylation of DHF with [PdCl(allyl)] 2 Precursor
The performed studies enabled to select the most efficient catalytic systems for the Heck arylation  Interestingly, [PdCl(allyl)] 2 was also indicated as superior palladium precursor in Heck cross-coupling between 4-nitrochlorobenzene and styrene [29].
In order to get deeper knowledge about transformations of [PdCl(allyl)] 2 under catalytic reaction conditions, spectroscopic studies were undertaken. First, coordination of L-prolinate anion to palladium was considered.
It was expected that eventual coordination of L-prolinate to palladium should be visible in 1 H-NMR. To estimate such effect 1 H-NMR spectra of L-proline and Pd(L-PRO) 2 complex [40] were analyzed (Table 1) Difference of chemical shift of CH protons in free and coordinated proline was equal 0.14 ppm. Moreover, in free L-proline signals CH 2 -3 and CH 2 -4 appeared as two multiplets each while only one signal of CH 2 -3 protons was observed in the spectrum of Pd(L-PRO) 2     During that time palladium was reduced and black powder was formed. Analysis of the solution by 1 H-NMR shown only weak signals of L-prolinate anion while signals of allyl group were not detected. Thus, it was possible that palladium was eliminated from the solution as Pd(0) nanoparticles. To verify that hypothesis, TEM measurements were undertaken. Two analyses were performed, using water or methanol as solvent for the black palladium residue. In both samples Pd(0) nanoparticles were identified, partially agglomerated. Separated nanoparticles shown relatively narrow size distribution with maximum ca. 6 nm (Figure 7). Pd(0) nanoparticles identified in the catalytic system most probably represent a resting state of the catalyst. In contact with reactants, in particular with aryl halide, solubilization of nanoparticles occurs with formation of catalytically active monomolecular species, similarly as it was proposed in other systems [30,31,33,39,41]. To estimate better the role of Pd(0) nanoparticles and underligated palladium species in the reaction course the Hg(0) test was performed using 500-fold excess of mercury to palladium. In the reaction performed in the presence of Hg(0) conversion was 32.6% while without Hg(0) 69.5% of substrate reacted. Thus, an inhibiting effect was observed, however soluble palladium species evidently participated in the reaction course.
TEM analysis of the post-reaction mixture shown agglomeration of nanoparticles ( Figure 8). The size of nanoparticles increased from ca. 6 nm to ca., 13 nm and more regular shapes were observed. This observation confirms the conclusion that soluble forms of palladium participated in the catalytic reaction.  Pd(L-PRO) 2 was obtained according to literature method [41].

Heck Reaction
The Heck arylation of DHF with PhI was carried out under N 2 atmosphere using standard Schlenk techniques. The reagents were introduced to the Schlenk tube (50 mL) in the following order: base (K 2 CO 3 or NaOAc 4.34 mmol), palladium precursor (0.0356 mmol, 1% mol ), CIL (an appropriate weighed amount), solvent DMF (6 mL), PhI (0.4 mL, 3.57 mmol), DHF (0.7 mL, 8.59 mmol), mesitylene (internal standard, 0.15 mL). The reaction was carried out at 70 °C for 2 h. Afterwards, the reaction mixture was quenched with H 2 O (5 mL) and the organic products were separated by extraction with diethyl ether (3 times × 5 mL). The products were analyzed by GC-FID (Hewlett Packard 5890). Products 2, 3, 4 were identified by comparison of the MS spectra and the retention times with the literature data. The enantiomeric excess (ee) values were determined by GC-FID (Perkin Elmer Auto System XL) with a chiral β-cyclodextrin column.

Conclusions
We found an efficient catalytic system for arylation of DHF, composed of [PdCl(allyl)] 2 and L-lactate or L-prolinate CILs. Addition of CIL to palladium precursor resulted in increase of iodobenzene conversion from 11% to 74.5%. When an effect of CIL is concerned, the highest conversion of iodobenzene was obtained with application of [Bu 4 N][L-LAC] for all studied palladium precursors.
It should be mentioned, that all ILs used in these studies were tetrabutylammonium salts which are known as very efficient stabilizing agents of nanoparticles [16,[37][38][39]. Thus, the positive effect of ILs on the yield of the Heck reaction can be related to the stabilization of Pd(0) nanoparticles preventing their aggregation.
In all the reactions product 3 was obtained as the main one. The highest amount of product 3, up to 59.2%, was formed in the reaction with PdCl 2 (PPh 3 ) 2 and [NBu 4 ][L-LAC]. Unfortunately, the enantioselectivity was rather poor in that case, with ee values in the 4.3-5.5 range. Analysis of the enantioselectivity of the studied reactions allowed to indicate the best system, namely that composed of Pd 2 (dba) 3