based imino-pyridyl palladium(II) complexes: Synthesis, molecular structures and Heck coupling reactions

Eight Pd(II) complexes of the general formulae [PdCl 2 (L)] and [PdClMe(L)] have been synthesized and characterized (L = the new pyridyl-imine ligands (5-methyl-2-thiophene-2-pyridyl(R))imine and (5-bromo-2-thiophene-2-pyridyl(R)imine [R = methyl,ethyl]). The complexes showed good activity as catalysts for standard Heck coupling reactions.


Introduction
The palladium-catalyzed olefination of aryl halides (Heck reaction) has emerged as one of the most powerful methods for carbon-carbon bond formation in organic synthesis since its inception in 1971 [1][2][3].It features applications that range from fine chemical synthesis of various hydrocarbons and industrial production of pharmaceuticals, to advanced syntheses of natural products [4][5][6][7].The wide application of the Heck reaction is encouraged by its high tolerance to various functional groups [8] as well as an ability to proceed under mild reaction conditions [9].Palladium complexes containing phosphine ligands have been widely used to catalyze Heck reactions [10][11][12][13][14][15][16].These catalysts have been preferentially used because they provide thermally robust catalysts [15,16].In general, these catalyst precursors contain P-P and P-N ligand moieties, and the substituents on the ligands have been successively optimized by different researchers to increase the catalyst turnover and efficiency.However, the ligands that are normally used to prepare such palladium catalysts are in general expensive, toxic and also sensitive to air and moisture.They generally undergo phosphine degradation by P-C bond cleavage [17].In view of this, much research effort is currently directed at the development of phosphine-free palladium catalysts.For example, many catalytic systems consisting of nitrogen-based heterocyclic compounds [18][19][20] diimine [21][22][23][24][25][26], dipyridine [27][28][29], bisimidazole [30,31], pyrazole [32][33][34][35] and hydrazone [36] derivatives have been reported.These stronger donor ligands have started to receive attention as possible replacements of phosphine-based catalysts because of the ease of synthesis and their resistance to oxidation reactions [27].The substituents on the ligands make their complexes display robust properties.Their nature has been found to exert a strong influence on catalyst activity such that electron-withdrawing substituents tend to enhance activity while, conversely, electron-donating substitutents decrease activity.However, the electronic/steric influence of the ligand also depends on the nature of the metal, ring

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3 substituents in ligands and their position within the ligands.When the ligands in general possess aromatic or hetero-aromatic rings with substituents in their -ortho and -para positions, they will afford highly active catalysts, but one drawback is that they usually require multi-step procedures to prepare, leading to very low yields.Palladium complexes with P-N type ligands have been reported to show pronounced catalytic activity in olefin polymerisation, which was attributed to the discussed electronic influence [37].Recently, we reported new imino-pyridyl nickel(II) thiolate complexes [38a] and phenylene-bridged bis-(imino-quinolyl) binuclear palladium(II) complexes [38b] with high activity in Heck coupling reactions.However, they were non-substituted and there were thus no electronic effects to consider.In the same context, we have successfully synthesized and characterized substituted thiophene based imino-pyridyl palladium(II) complexes.The new compounds have been investigated as Heck coupling catalysts of aryl halides with methyl acrylate.The impact of ligand substituents on catalytic performance has also been investigated.

General
All reactions were carried out under oxygen free atmosphere using a dual vacuum/nitrogen line and standard Schlenk techniques, unless stated otherwise.The solvents were purified by heating under reflux and nitrogen in the presence of a suitable drying agent.The metal precursors [PdCl 2 (COD)] and [PdClMe(COD)] were prepared following literature methods [39].The chemical reagents were of analytical grade or higher.They were purchased from Sigma Aldrich and were used without further purification.

General procedure for the synthesis of ligands L1-L4
An equimolar amount of pyridyl amine was added dropwise to a MeOH solution (15 mL) of substituted thiophene carboxaldehyde.Anhydrous magnesium sulfate was added in excess (ca. 1 g) to remove water formed as a byproduct in the Schiff condensation.The reaction was allowed to proceed at room temperature for 12 h and was monitored by IR spectroscopy.At the end of the reaction, the magnesium sulfate was filtered off and the solvent evaporated under reduced pressure to obtain an orange oil.The oily product was washed with water (10 mL), extracted with CH 2 Cl 2 (2 x 10 mL), and again dried over magnesium sulfate.The solvent was evaporated to obtain the ultimate product which was a light orange oil.

(5-Methyl-2-thiophene-2-pyridylmethyl)imine (L1)
The ligand was prepared following the above general procedure using The ligand was prepared according to the general procedure using
The structure was solved by the charge flipping method using the SHELXT program.A multiscan absorption correction based on equivalent reflections (SADABS-2012/1 [41]) was applied to the data.Structural refinement was carried out using SHELXL-2014 [42] with the UCSF Chimera [43] and SHELXLE-2014 graphical user interfaces.Hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms with C-H = 0.95-0.99Å and U iso = 1.2-1.5⋅Ueq (parent atom).For complex 8, single-crystal X-ray diffraction data were collected on a Bruker KAPPA APEX II DUO and Nonius Kappa-CCD diffractometer using graphite-monochromated Mo-Kα radiation (χ = 0.71073 Å).Data collection was carried out at 173(2) K. Temperature was controlled by an Oxford Cryostream cooling system (Oxford Cryostat).Cell refinement and data reduction were performed using the program SAINT [44].The data were scaled and absorption correction performed using SADABS [45].The structures were solved by direct methods using SHELXS-97 and refined by full-matrix least-squares methods based on F 2 using SHELXL-97 [42] and using the graphics interface program X-Seed [42].All non-hydrogen atoms were refined anisotropically.All hydrogen atoms were placed in idealized positions and refined with geometrical constraints.

General procedure for Heck reactions
A dry 100 ml capacity Schlenk tube equipped with a magnetic stirrer bar was charged with aryl halide (10 mmol), methyl acrylate (10 mmol) and triethylamine (10 ml).The catalyst

Synthesis and characterization of ligands and complexes
The thiophene-based imino-pyridyl compounds L1-L4 were prepared via Schiff base condensation of the appropriate substituted thiophene carboxaldehyde with an appropriate pyridyl amine in methanol.Their corresponding palladium(II) complexes 1-8 were prepared by equimolar reactions of the potential ligands with either [PdCl 2 (COD)] or [PdClMe(COD)] (Scheme 1).

<Scheme 1>
All new compounds were characterized using IR, 1 H and 13 C NMR spectroscopy, elemental analysis, mass spectrometry and, for 1, 2, 6 and 8, single crystal X-ray diffraction studies.
Elemental analysis and mass spectra were consistent with the proposed formulae of the compounds.In the IR spectra of the ligands, the imine formation was confirmed by the strong absorption bands observed in the region 1630 -1632 cm -1 [46][47][48][49].The other bands observed between 1593 cm -1 and 1568 cm -1 were attributed to the ν(C=N) and ν(C=C) pyridyl vibrations, respectively [48].The evidence of coordination of the ligands to the metal center was observed by the imine absorption bands being shifted to lower frequencies (between 1624 and 1607 cm -1 ) compared to the corresponding free ligands [46][47][48][49].Further evidence of imine formation was derived from the NMR spectra of the compounds.For example, in the

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12 1 H NMR spectra of the ligands, the signal for the imine proton appeared as singlet peaks between 8.12 and 8.44 ppm [50,51].The other singlet peaks observed upfield at 4.89 and 4.87 ppm were attributed to the CH 2 linker protons in L1 and L3, respectively [50].In the 13 C NMR analysis of the ligands, the signals for the imine carbons appeared at around 159.0 ppm [50,51].
In the 1 H NMR spectra of the complexes, the signals generally shifted downfield with respect to their position in the free ligand due to coordination of the ligand [50,51].As the five-or six-membered Pd-N-(C) n -N rings formed by coordination of the ligands (cf.Scheme 1) are non-planar, the methylene protons of the ligand backbones become diastereotopic.However, if inversion of the methylene carbons is relatively rapid on the NMR time scale, averaged signals will be observed even though the methylene protons remain diastereotopic at all times.This appears to be the case for the complexes in this study.In an attempt to freeze out backbone inversion, variable temperature 1 H NMR spectra of complex 2 were recorded, 13 is cis to the imine nitrogen atom and trans to H 6 of the pyridine ring (Fig. 1).On the other hand, the observed correlation between the methyl ligand protons (0.89 ppm) and the H 6 proton of the pyridine ring (8.50 ppm) established the formation of the isomer in which the methyl ligand is cis to the H 6 of the pyridine ring and trans to the imine nitrogen atom.
Corresponding resonances are seen in the 1 H NMR spectrum of complex 7 (cf.Section 2.3.7), and are assigned to corresponding trans-and cis-isomers of this complex (trans/cis to the imine functionality, Fig. 1).Integration of resonances for the cis-and trans-isomers in the 1 H NMR spectra of complexes 5 and 7 indicates a slight excess of the trans-isomers for each complex (54% and 56%, respectively) at ambient temperature (20 o C).
However, in contrast to the above observations, corresponding sets of signals for cis-/transisomers were not observed for the related complexes 6 and 8. Instead the 1 H NMR spectra indicated the exclusive formation of the isomer where the methyl substituent is cis to the imine nitrogen.This observation may be attributed to the presence of two carbons as a linker between the imine nitrogen atom and a pyridine ring, resulting in the formation of a 6membered chelate ring structure that prevents rotation of the methyl ligand around the palladium atom because of steric hindrance exerted by the pyridyl substituent.The molecular structures 6 and 8 were corroborated by their crystal structures (vide infra). <Fig.1>

Molecular structures of 1 and 2
The molecular structures of complexes 1 and 2 were confirmed by X-ray crystallography.
Crystallographic data and refinement parameters are summarized in Table 1, while selected bond lengths and bond angles are summarized in Table 2.The molecular structures of the complexes are shown in Figs. 2 and 3, respectively.Complex 1 crystallizes in the tetragonal P421c space system while complex 2 has two configurational isomers, 2a and 2b, where 2a crystallizes in the Orthorhombic P 212121 space system while 2b crystallizes in the monoclinic P2 1 /n space system.The ligands form a five-and a six-membered chelating ring with the metal in complexes 1 and 2, respectively.In all three structures, the palladium atom is fourcoordinate via two N atoms of the pyridine ring and an imine, and two chloride anions, generating a distorted square planar coordination geometry around the metal center.The distorted geometries are confirmed by the bond angles around the palladium metal atom, which show significant deviations from 90° [44,45], with the bond angles N(2)-Pd(1)-N(1) and The two configurational isomers 2a and 2b both contain a boat conformation of the above-mentioned six-membered chelate ring.The complexes are chiral, and 2a crystallized in enantiopure form, while 2b crystallized as a racemate; the enantiomers of each configurational isomer may be distinguished by considering the relative orientation of the C6-C7 vector to the N1-N2 vector, i.e. the enantiomers are λ and δ skew isomers.Inversion about carbons C6, C7 and nitrogens N1, N2 will interconvert the boat conformation of one enantiomer of 2a to the boat conformation of one enantiomer of 2b.In addition, inversion about carbons C6 and C7 in either configurational isomer, while maintaining the orientation around the nitrogens (or vice versa), will convert the boat conformation to the corresponding (chiral) chair conformation.As the low temperature NMR investigation shows (vide supra), the barriers to such inversions are relatively low.Furthermore, in the solid state, the two isomers differ in the relative orientation of the furyl moiety; this difference is likely due to crystal packing effects.

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<Figs. 2 and 3>

Molecular structures of 6 and 8
The molecular structures of complexes 6 and 8 were also confirmed by X-ray crystallography.Crystallographic data and refinement parameters are summarized in Table 1, while selected bond lengths and bond angles are summarized in Table 2.

Heck coupling reactions
The thiophene-based imino-pyridyl palladium(II) complexes were screened as catalysts for Heck coupling reactions of iodobenzene, 4-iodotoluene and 1-iodo-4-nitrobenzene with methyl acrylate to obtain the C-C coupled products (Scheme 2).Complexes 1, 2, 5 and 6 have a peripheral electron-donating methyl substituent on the thiophene ring that decreases the electrophilicity of the Pd(II) ion in the active species [54].Conversely, the electronwithdrawing bromine substituent on the thiophene ring in complexes 3, 4, 7 and 8 causes a strain on the ring because it reduces the donation power of the ring and increases the electrophilicity of the Pd(II) center [52].The electron of the soft sulfur atom contributes to the delocalized bonding in the ring, contributing to this effect.The catalytic activities of the complexes were compared after identical optimization experiments were carried out.A summary of the catalytic results is given in Table 3.For comparison, the corresponding catalytic activities of the known complex chloromethyl-[(2-pyridyl-2thiophenemethyl)imine]palladium(II) (9) [47] were studied and are included in Table 3 (entries 8, 14 and 20); the observed catalytic activities for the reference complex were in all cases lower than those found for the complexes in this study.In general, the complexes were effective towards arylation of methyl acrylate, giving yields of up to 87%, with the exclusive formation of the desired trans-methyl cinnamate as confirmed by 1 H NMR spectroscopy.In particular, complexes 4 and 8 gave quantitative yields in Heck coupling of iodobenzene (Table 3, entries 4 and 7) and electron-deficient 1-iodo-4-nitrobenzene (

4 X
-ray structure determinations of complexes 1, 2, 6 and 8 1 mmol) was dissolved in DMF(10 mL)  and transferred quantitatively into the reaction vessel.The reaction was heated while stirring at 110 °C.Samples were drawn at regular intervals and analyzed by GC.The coupling product was isolated by pouring the reaction mixture in water (50 mL) and extracted with CH 2 Cl 2 to give a pure product which was confirmed by 1 H NMR spectroscopy.
to a temperature of -60 o C (213 K).Surprisingly, the methylene signals were still averaged at the lowest temperature, indicating a low barrier to inversion.On the other hand, two signals for the 6-H proton of the pyridyl moiety of ligand L2 could be detected, indicating the formation of two configurational isomers, a phenomenon that could be confirmed by X-ray crystallography (vide infra).Furthermore, sets of signals were found in the 1 H NMR spectra of complexes 5 and 7 that were attributed to the presence of two isomers where the methyl ligand is coordinated to the palladium atom in a cis and trans conformation to the imine nitrogen atom or H 6 of the pyridine ring.The possibility of cis-trans isomerization was confirmed by1 H-1 H NOESY NMR experiments.The NOESY spectrum (Figure S1, Supplementary Material) for complex 5 shows a correlation between the methyl ligand protons (Pd-Me; 0.80 ppm) with the imine nitrogen proton (8.39 ppm).It indicates the presence of the isomer in which the methyl ligand M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT The molecular structures of the complexes are shown in Figs.4 and 5, respectively.Both molecules crystallize in the monoclinic P2 1 /n space system.The thiophene and pyridine ring appeared distorted for both structures.The ligands form a six-membered chelating ring with the metal in a boat conformation.The palladium atom in both structures is four coordinated via two N atoms of the pyridine ring and an imine, a methyl and a chloride anion, generating a distorted square planar coordination geometry around the metal centre.The distortion in square planar geometry is confirmed by the bond angles of N(2)-Pd(1)-N(1) and Cl(1)-Pd(1)-C(14): 84.93(6)° and 89.66(6)° in 6 and 81.66(6)° and 91.56(6)° in 8, respectively, around the palladium metal atom, showing significant deviations from the idealized angle of 90°[47,48].The Pd(1)-Cl(1) bond lengths of 2.312(5)Å in 6 and 2.3296(5)Å in 8 are in agreement with the average Pd-Cl bond distance of 2.298(15)Å for known palladium complexes[52,53].The Pd(1)-C(14) and Pd(1)-C(19) bond lengths in 6 and 8, respectively, are significantly shorter than their corresponding Pd(1)-Cl(1) bond lengths, thus reflecting the stronger trans-influence of the pyridyl group compared to the secondary amine.Furthermore, the Pd(1)-N(1) bond lengths in 6 and 8 are considerably longer than their corresponding Pd(1)-N(2) bond lengths due to the stronger trans-influence of the Pd-CH 3 moiety.<Figs.

Figure 2 .
Figure 2. Mercury plot of the molecular structure of compound 1, showing the atom

Figure 3 .
Figure 3. Mercury plot of the molecular structures of compound 2a (δ isomer, see text; top)

Figure 4 .
Figure 4. Mercury plot of the molecular structure of compound 6, showing the atom

Table 3
effect of the methyl substituent on the catalytic activity.A similar effect was observed in the Heck coupling of iodobenzene by complex 1 (Table3, entry 1); in this reaction, there was a