Efficient synthesis of differently substituted triarylpyridines with the Suzuki-Miyaura cross-coupling reaction

A library of differently substituted 3,4,5-triaryl-2,6-dimethylpyridines and 2,3,5-triaryl-4,6-dimethylpyridines were synthesized and characterized using the Suzuki-Miyaura cross-coupling reaction with accordingly selected tribromodimethylpyridines and arylboronic acids. The optimized coupling conditions were found to be general for both isomeric tribromodimethylpyridines and a wide range of arylboronic acids substituted with electro-donating and electro-withdrawing groups


Introduction
8][9] Many aryl-substituted pyridines are essential building blocks of pharmaceutical agents showing anti-inflammatory, 10 antibacterial, 11 and antimalarial 12 activities.The orally administered antimalarial 3,5-diaryl substituted 2-aminopyridines show promising activity against K1 (chloroquine and drug resistant strain) and NF54 (chloroquine-susceptible strain). 13Some polyarylated pyridines were found to be topoisomerase I and II inhibitors exhibiting toxicity toward human tumor cells depending on the nature of the aryl substituents. 14,157][18][19][20] We also studied their interesting atropoisomeric properties and we investigated in detail the process of their formation, creating libraries of their 2-and 4-alkoxy and 2-and 4-amino derivatives. 214][25] This method is routinely applied by us as a "method-of choice" for drugs screening and their "route-specific" markers.Recently, we turned our attention to the presence in the reaction mixtures of several compounds the mass spectra of which were similar to aryl/methylpyridines P3 and P4.More accurate investigation of recorded mass spectra led us to a conclusion that newly discovered compounds may possess general structures of triarylpyridines P5 and P6 (Figure 1).We assumed that the process of their formation may resemble the mechanism of the formation aryl/methylpyridines P3 and P4, with one exception that in the condensation and pyridine ring closure sequence a molecule of an arylaldehyde instead of formaldehyde is involved (Scheme 1).Building blocks in the formation of pyridines P3, P4, P5, and P6 during synthesis of amphetamine analogues by the Leuckart method.Depending on the arrangement of carbonyl partners, the process proceeds through 2-1-2 or 2-2-1 condensations. 26itially, we reported on the preparation of 2,6-dimethyl-3,4,5-triphenylpyridine 1a and 2,4-dimethyl-3,4,6-triphenylpyridine 2a by means of Suzuki-Miyaura cross coupling of 4-bromo-2,6-dimethyl-3,5diphenylpyridine and 2-bromo-4,6-dimethyl-3,5-diphenylpyridine with phenylboronic acid in the presence of Pd[PPh 3 ] 4 as a catalyst and Na 2 CO 3 as a base. 19The major drawback of this method was that it involved de novo preparation of 3,5-diaryldimethylpyridinones from corresponding arylacetones 27 and dibenzylketones. 17,28Both ketones are commercially unavailable and some arylacetones used as precursors of amphetamine analogues remain controlled substances.
Herein, we report detailed results in the application of the Suzuki-Miyaura cross-coupling reaction leading to a library of pyridines P5 and P6.We also present regioselective syntheses of several 3,5-diarylated 4-, and 2-chlorodimethylpyridines 5 and 6.

Results and Discussion
Initially, we prepared the necessary 2,3,5-tribromo-4,6-dimethylpyridine 4 starting from 4,6-dimethylpyridin-2-one (Scheme 2).The 3,4,5-tribromo-2,6-dimethylpyridine 3, 3,5-dibromo-4-chloro-2,6-dimethylpyridine 8, and 3,5-dibromo-2-chloro-4,6-dimethylpyridine 9 were readily prepared from the corresponding pyridones following previously published procedures. 19,29 alysis.The characteristic isotopic pattern of halogen atoms and the presence of abundant peaks corresponding to molecular ions enabled tentative identification of by-products, but unambiguous assignment of isomers within each particular group (A, B, C, D) was not possible.The results of the preliminary reactions are summarized in Table 1.Application of the classical Suzuki catalytic system based on Pd[PPh 3 ] and PdCl 2 [PPh 3 ] 2 in the presence of a medium-strong (Na 2 CO 3 ) or a weak base (K 3 PO 4 ) brought about the formation of 2a in low yield (entries 1-3).The GC-MS analysis indicated significant amounts of chloropyridine 7 and by-products A-C.Interestingly, when more bulky ligand P(o-tol) 3 was used instead of PPh 3 , the arylation occurred predominantly at 3 and 5 positions of 9 leading selectively to compound 7 in 92% yield (entry 4).Similar results were obtained when Pd(dppf)Cl 2 ×CH 2 Cl 2 (4) and a catalytic system consisting of Pd(OAc) 2 / tricyclohexylphosphine was used in the presence of a weak base K 3 PO 4 (entries 9 and 6, respectively).It was also found that using other bases (entries 5 and 7) and palladium source (entry 8) system based on P(Cyc) 3 led again to compound 7 as a main product.The use of ligand system Pd(OAc) 2 /S-Phos in toluene improved the coupling significantly.Appropriate selection of the base led to a better yield of the desired triarylated pyridine 2a (85%, entry 11).A similar result was obtained when another Buchwald ligand X-Phos was applied instead of S-Phos (entry 16).
It seems therefore that the reactivity of pyridine derivative 9 is not sufficient thus we turned our attention to pyridine 4 as a more promising substrate for the synthesis of pyridines 2. Indeed, the reactions with 4 were completed in approximately one hour when Buchwald ligand-based catalytic systems (entries 20 and 21) and in two hours for other trials (entries 18 and 19) leading to product 2a in excellent yields of 97%/96% and 89%/87%, respectively.and by-products from groups A, B, C, and D. d the yield was estimated by GC-MS by comparison of peak areas of products with the sum of areas of the rest products and unconverted substrate.e in calculation of the yield, the sum of peak areas of compounds A, B, C, and D was taken into consideration.
After establishing the optimum conditions (entry 20), the preparation of a library of triaryldimethylpyridines 1a-m and 2a-n was then examined using variously substituted arylboronic acids (Scheme 4).Generally, the best yields of final products were obtained for phenylboronic acid and arylboronic acids containing small substituents (methyl, ethyl) in the meta and para position at the phenyl ring.The electronwithdrawing fluorine-containing groups (3-, 4-F, 4-CF 3 ) did not affect the yield of the product, with the exception of ortho-fluoro-substituted products (1c and 2c).In the case of 3,4,5-trimethoxyphenyl substituted pyridine (2h) GC-MS analysis indicated the presence of a significant amount of the corresponding biphenyls formed in competing dimerization of the arylboronic acid.Therefore additional portions of boronic reagents were required to complete the coupling.The same procedure was used in the reaction with 4methylthiophenylboronic acid.Prior to final work-up, each of the crude reaction mixtures was examined by GC-MS.In each case two regioisomers (for products 1a-m) and three regioisomers of diaryl-substituted pyridines (for product 2a-n) were observed, however the ratio of products/by-products was different and dependent on the nature of the aryl substituent.All attempts to couple compounds 3 or 4 with 2-nitro-, 2cyano-and 2-formyl-phenylboronic acids failed.Neither longer reaction time, higher temperature, nor an increased amount of catalyst had noticeable influence on the outcome.We also observed that the yield of pyridines 1 was slightly lower than pyridines 2. The higher yields obtained for the coupling of 4 can be attributed to the lower steric hindrance present in transition-state in the palladium complex, compared to bulky tribromopyridine 3.
It is also worthy of note that in the case of compound 1m we observed the presence of three components formed in 49% total yield and in approx.1:1:1 molar ratio, having the same mass spectra and very similar NMR spectra.We were able to separate them using column chromatography and in two cases we performed an Xray study.Therefore, the stereochemistry of all components was unambiguously established.Thus, the above compounds are atropoisomers which phenomenon arises from the restricted rotation about single C 3,4,5-pyridine -C aryl bonds caused by the steric interaction of the ortho substituents with the neighbouring aryl rings.The first eluting compound during the column chromatography has the structure of 1m anti-syn, the second is 1p antianti atropoisomer, and the third is the complementary stereoisomer 1m syn-syn (Figure 2).We have already described a similar phenomenon in the presence of stable atropoisomers of related oligoaryl pyridines. 22,29In the case of compound 1c two diastereomers were detected in the reaction mixture.After their chromatographic separation we recorded their NMR spectra, but apparently due to fast atropoisomerization we were unable to prepare crystals suitable for X-ray study.The crystallographic studies led to some interesting observations.Although both atropoisomers crystallize in the triclinic system, the crystal packing is different.This manifests itself in differences in unit cell volumes (1350.36(6) and 1374.68(14)Å 3 , respectively) and because of the same unit cell contents results in different calculated crystal densities.The molecular geometries of the compounds are characterized by rotations of rigid fragments (rings) and flexible ethoxy groups.In 1m anti-syn all three phenyl rings are not fully perpendicular to the pyridine ring plane.It is worth noting that they are inclined approximately in the same direction -the respective torsion angles are ca.73°, 72° and 74°.The ethoxy groups are almost co-planar with the respective phenyl rings (torsion angles ca.193°, 178° and 186°) and pointing towards the pyridine ring (respective C-O-C-C torsion angles are ca.172°, 186° and 182°).Similarly in 1m anti-anti all phenyl rings are inclined in one direction to the pyridine ring plane forming torsion angles ca.69°, 86° and 79°.The situation with the ethoxy groups looks a little bit different.Although two of them lie approximately in respective phenyl ring planes the third (on the left in the ORTEPå drawing) is out of plane -the C-O-C-C is ca.75°.Such distortion is a result of packing forces in the crystal.
Recently we have also been interested in the synthesis of series of pyridines P3/P4 through the regioselective 3,5-diarylation of 8 and 9 with subsequent dechlorination of intermediary 4-chloro-and 2chloro-3,5-aryldimethylpyridines 5 and 6. 19 Due to unsatisfactory results there was a need to develop an alternative approach based on the use of the corresponding 3,5-dibrominated 2,4-and 2,6-dimethylpyridines as substrates for the cross-coupling.Our previous results 29 as well as data collected in Table 1 (entries 4, 6, 9, 10) indicated that some catalytic systems with a properly chosen base could be suitable for regioselective diarylation of 8 and 9.In a subsequent study we decided to apply ready to use ferrocenylphosphine-based catalyst Pd(dppf)Cl 2 ×CH 2 Cl 2 , mainly because of its air stability and high activity.The final synthesis of 5 and 6 was preceded by optimization of the base and solvent.The results are presented in Table 2.  Table 2 clearly shows that the yield of the desired pyridine 7 is strongly dependent on the choice of both solvent and base.Various combinations of 1,4-dioxane, DMF and acetonitrile with CsF, KF and Cs 2 CO 3 gave multicomponent product mixtures consistently (GC-MS evidence) and 2a only in moderate yield (entries 1, 4, 5, 6).The best yield of 2a was obtained when the combination of mild base and 1,4-dioxane were applied and therefore these conditions were used subsequently for the preparation of a library of pyridines 5 and 6.Scheme 5.The regioselective arylation of halopyridines 8 and 9.
All reactions proceeded in lower yield compared to the pilot study, probably due to competitive formation of monocoupled and debrominated products, indicated by GC-MS analysis.Moreover, difficult isolation and purification of multicomponent crude mixtures decreased the yield of individual compounds.It is noteworthy that all attempts to couple pyridines 8 and 9 with ortho-substituted arylboronic acids failed completely.Neither diaryl pyridines 8 and 9 nor even monsubstituted by-products could be detected in the reaction mixtures.Our efforts to react compounds 5 and 6 with an increased amount of arylboronic acid at elevated temperature (up to 120 o C) resulted only in fast formation of the corresponding biphenyls and various dehalogenated dimethylpyridines.To further investigate this phenomenon, the same cross-coupling conditions were applied in the reaction of tribromopyridines 3 and 4 with 2-methoxyphenylboronic acid.The GC-MS analysis indicated only traces of the corresponding tri(2-methoxyphenyl)pyridines along with minute amount of its di-and monoaryl/bromo substituted derivatives.0][41][42] The catalytic cycle starts with the oxidative-addition of the aryl halide to a Pd(0) complex to form arylpalladium(II) halide intermediate.After ligand exchange between the complex and the base, transmetallation with the arylboronic acid occurs followed by reductive elimination leading to the final product.We assume that in our case the reaction is stopped at the stage of transmetallation due to the steric interaction between the bulky ferrocenylphosphine moiety with the ortho-substituent of the arylboronic reagent.Similar problems with arylation of 1,3-dichloro-4-iodoisoquinoline with 2-methoxyphenylboronic acid in the presence of Pd(dppf)Cl 2 ×CH 2 Cl 2 were reported by Yang. 43

Experimental Section
General.The preparation of 3,4,5-tribromo-2,6-dimethylpyridine 3, 2,3,5-tribromo-4,6-dimethylpyridine 4, 2chloro-3,5-dibromo-4,6-dimethylpyridine 5, 4-chloro-3,5-dibromo-2,6-dimethylpyridine 6, were carried out by our already reported method. 17,19,29The reagents and solvents were commercially available and were used without further purification.All cross-coupling reactions were carried out in 22 mL vials (Supelco) closed with solid cups sealed with PTFE/silicone septa under argon or nitrogen atmosphere.Thin layer chromatography (TLC) analyses were performed on Merck Kieslgel 60 F-254 plates.The visualization of the plates was done under UV light or with iodine vapor.Evaporation of solvents was performed at reduced pressure, using a Buchi rotary evaporator.Melting points were determined on an Electrothermal, Model IA 9200 apparatus and are uncorrected.NMR spectra were recorded on a Varian Unity Plus spectrometer operating at 200 MHz for 1 H NMR and 50 MHz for 13 C NMR, respectively or on a Bruker AVANCE 300 MHz spectrometer operating at 300 or 500 MHz for 1 H NMR and 75 or 125 MHz for 13 C NMR, respectively.The following abbreviations are used: mmultiplet, s-singlet, d-sublet, t-triplet, q-quartet.Low resolution mass spectra were collected on a Agilent Technologies 7000 Triple Quad mass detector coupled with a Agilent Technologies 7890A gas chromatograph.The column HP-5MS 30 m × 0.25 mm ID, with 0.25 µm film thickness was operated at flow rate of 1.5 mL/min (helium) and the oven temperature was ramped between 110 -340 o C. The mass spectra were recorded in the mass range between 40 and 620 amu.HRMS spectra were collected on Quattro LC Micromass and LCT Micromass TOF HiRes apparatus.Crystallographic studies were performed for crystals of two compounds: 1m anti-syn and 1m anti-anti.Monocrystals suitable for X-ray diffraction studies were obtained from hexane-benzene solutions by slow evaporation of solvents.Good quality crystals were selected and glued to grass capillaries and placed on goniometer heads on the Xcalibur-R single crystal diffractometer from Oxford Diffraction.The diffraction data were collected at room temperature using graphite monochromatized CuKα radiation.The unit cell parameters were obtained by least squares of 8019 and 12857 reflections, respectively.The data were corrected for Lorentz-polarization factor and after solving structures also for absorption.Structures were solved using SHELXS-97 software and refined using SHELXL-97 program. 44rystal data: 1m anti-anti, C 31 H 33 NO 3 , Fwt.: 467.58, colourless parallelepiped, size: 0.42 × 0.37 × 0.07 mm, triclinic, space In all structure refinements the hydrogen atoms were included in structure factor calculations in idealized positions but were not refined.The isotropic displacement parameters of hydrogen atoms were approximated from the U(eq) values of atoms to which they were bonded.The detailed information on data collection, structure solution and refinement of the 1m anti-anti and anti-syn atropoisomers have been deposited with Cambridge Structural Data Centre under the numbers CCDC 1484433 and CCDC 1486652, respectively.

a 4
mol equiv. of base was used.b temperature of reaction: 1,4-dioxane, DMF 80 o C; acetonitrile 75 o C; time of reaction -3 h.c the conversion of substrate was measured by GC-MS.It was calculated as a percent ratio of unreacted 9 and sum of the peak areas of the 2a, 6 and by-products from groups A, B, C, and D. d the yield was estimated by GC-MS by comparison of peak areas of products with the sum of areas of the rest products and unconverted substrate.e in calculation of the yields, the sum of peak areas of compound A, B, C, and D was used.

Table 1 .
Optimization of the triarylation reaction of 9 and 4 (Scheme 3); 4.2 equiv. of phenylboronic acid was used a 6 mol equiv. of base was used.b Temperatures of reaction: toluene, 1,4-dioxane, DMF, toluene/H 2 O 90 o C; solvent system toluene/H 2 O/EtOH, 85 o C. c The conversion of substrate was measured by GC-MS.It was calculated as a percent ratio of unreacted 4 or 9 and sum of the peak areas of the 2a, 7 (only for 9)