Synthesis of Heteroarylated Pyridines via a Double C−H Bond Functionalization using Palladium‐catalyzed 1,4‐Migration Combined with Direct Arylation

The C−H bond functionalization of pyridyl C3‐position of 4‐arylpyridines using Pd 1,4‐migration has been investigated. Under suitable reaction conditions, oxidative addition of 4‐(2‐bromoaryl)pyridines to palladium followed by a Pd 1,4‐migration activates these pyridyl C3‐positions. Next, the Pd‐catalyzed coupling via C−H bond activation of the heteroarenes affords the C3‐heteroarylated 4‐arylpyridines. The new C−C bond created in this coupling reaction results from the functionalization of two C−H bonds. For this coupling reaction, a bromo‐substituent on the aryl unit of 4‐arylpyridines was employed as a traceless directing group. This heteroarylation method tolerates a range of substituents on the benzene ring as well as several heteroarenes. Moreover, from 3‐arylpyridines, C2‐ or C4‐functionalization of the pyridine ring also proved possible. In addition, this procedure uses an air‐stable catalyst and an inexpensive base.


Introduction
Pyridine derivatives are ubiquitous in pharmaceutical compounds and organic materials. [1]Consequently, the discovery of new effective routes to these compounds, enabling the functionalization of specific positions, is a very important aspect of current research involving pyridine derivatives. [2][5][6][7][8] However, to our knowledge, the synthesis of 4-aryl-3-heteroarylpyridines via activation of the CÀ H bond at the C3-position of pyridines has not been reported to date.
We recently reported that during the Pd-catalyzed direct heteroarylation of 2-(2-bromoaryl)thiophenes, partial Pd 1,4migration [9,10] occurred at the thienyl β-positions, [11] leading to a mixture of 1,2-diheteroarylated benzenes and also to βheteroarylated 2-arylthiophene derivatives such as 2'-aryl-2,3'bithiophenes.This Pd 1,4-migration methodology is an appealing method for functionalizing CÀ H bonds in proximity to 2bromoaryl units.We have therefore tried to extend this methodology to (2-haloaryl)pyridines.To date, little is known about Pd-catalyzed 1,4-migration of these substrates.Gallagher et al. reported that the Heck reaction of 4-(2bromoaryl)pyridines with an acrylate gave a mixture of the classical Heck type product and also the Pd 1,4-migration vinylation product in a ratio of 2 : 1 to 3 : 1 (Scheme 1, a). [12] Activation of the CÀ H bond in the C3 position of the pyridyl ring of 4-arylpyridines using a phosphine or phenol as directing groups has also recently been described (Scheme 1, b and c). [13]owever, in general the current preparation of 4-aryl-3heteroarylpyridine derivatives still requires a multi-step syn-thesis.In many cases, this involves the preparation of 4-halo-3heteroarylpyridines, which is rather difficult, as the last step in their synthesis generally consists of Suzuki coupling between bromopyridines and heteroaryl boronic acids (Scheme 1, d). [14] Consequently, the outcome of Pd-catalyzed direct arylation reaction of 4-(2-bromoaryl)pyridines needed to be explored.Our aim was to find conditions favoring Pd 1,4-migration associated with direct arylation for access to 4-aryl-3-heteroarylpyridines via a double CÀ H bond functionalization.Here, we report i) the conditions for Pd-catalyzed regioselective direct heteroarylations of the pyridyl unit of 4-(2-bromoaryl)pyridines using bromide substituent as a traceless directing group, [15] ii) and on the scope the Pd 1,4-migration associated with direct arylation for the formation of 4-aryl-3-heteroarylpyridines via a double CÀ H bond functionalization, iii) on the reactivity of 3-(2bromoaryl)pyridines (Scheme 1, e).
Next, the selectivity of the Pd-catalyzed reaction of 4-(2bromophenyl)pyridine 1 a with 2-isopropyl-4-methylthiazole was investigated (Table 1).A high selectivity of 87 % for the desired Pd-catalyzed 1,4-migration product 2 a was obtained using 2 mol% Pd(OAc) 2 catalyst combined with KOAc base in DMA at 150 °C; while the product 2 b resulting from the heteroarylation of the aryl unit was obtained with a selectivity of 13 %.(Table 1, entry 1).However, with this phosphine-free  catalyst, conversion of 1 a was not complete, therefore we used PdCl(C 3 H 5 )(dppb) [16] catalyst which gave a similar 2 a : 2 b selectivity of 87 : 13 and a 2 a yield of 61 % with full conversion of 1 a (Table 1, entry 2).The use of carbonate bases Cs 2 CO 3 and K 2 CO 3 proved ineffective, and the formation of several unidentified products was observed (Table 1, entries 3 and 4).In contrast, NaOAc and CsOAc led to good selectivities in 2 a and KOPiv gave 2 a in 89 % selectivity and 63 % yield (Table 1, entries 5-7).We also determined the influence of solvent, but DMF and NMP led to slightly lower yields in 2 a; while xylene and DEC were ineffective (Table 1, entries 8-13). [17]Using tetrabutylammonium acetate (TBAA) as solvent, 2 a was obtained with a good selectivity of 88 % and a yield of 61 % (Table 1, entry 14). [18]This solvent could therefore replace DMA, which is undesirable from the point of view of sustainable chemistry.A lower reaction temperature of 130 °C instead of 150 °C provided 2 a : 2 b with similar selectivity (91 : 9) but low yield due to partial conversion of 1 a (Table 1, entry 15).Then, the scope of the coupling reaction of 4-(2bromophenyl)pyridine 1 a with a set of heteroarenes was studied (Scheme 3).From 2-isopropylthiazole and 1 a, we obtained an a : b ratio of 92 : 8 with the formation of the Pd 1,4migration product 3 a in 72 % yield.In the presence of 2methylthiophene and 2-chlorothiophene, very high a isomers selectivities were also observed, and products 4 a and 5 a were isolated in 78 % and 54 % yield, respectively.No cleavage of the CÀ Cl bond of the thienyl ring was observed, allowing further transformations.Slightly lower a isomers selectivities were achieved using 2-acetylthiophene, ethyl thiophene-2-carboxylate and cyclopropyl-2-thienylketone affording products 6 a-8 a in yields of 60-64 %.In contrast, in the presence of 2-methyl-2-(thiophen-2-yl)-1,3-dioxolane and 2-(thiophen-2-yl)acetonitrile, only the 9 a and 10 a isomers were detected.3-Methylbenzothiophene gave 11 a with 95 % selectivity and 66 % yield.Furan derivatives were also suitable substrates for this reaction.2-Butylfuran and 1-furan-2-ylbutan-1-one afforded products 12 a and 13 a with 100 % selectivity and in good yields.The natural product menthofuran was also used successfully, affording product 14 a with complete selectivity and 76 % yield.Conversely, quite sluggish reactions were observed with a 2acetylpyrrole and 1,2-dimethylimidazole, with the formation of 15 a and 16 a in only 50 % and 48 % yield, respectively due to the formation of some unidentified side-products.Imidazo We had previously observed that with 2-(2bromoaryl)thiophenes, Pd 1,4-migration was favored by the presence of electron-donating substituents on their aryl moiety, whereas electron-withdrawing substituents led to mixtures of products due to partial Pd 1,4-migration. [11]Therefore, the selectivity of the reaction using a set of 4-(2bromophenyl)pyridine bearing a para-substituent on the aryl unit was investigated (Scheme 4).As expected, the presence of a methyl para-substituent (1 b) using 2-methylthiophene and 2butylfuran as reaction partners had practically no influence, affording the products 20 a and 21 a with 100 % selectivity and 78 % and 76 % yield, respectively.The electron-deficient 4- studied.The heteroarylation was regioselective in favor of the C5-position of the pyridyl ring to give 30 a.
To determine the influence of the position of the nitrogen atom on the pyridine ring on the reactivity and selectivity of the Pd 1,4-migration/direct arylation reaction, the result of the reaction with 3-(2-bromophenyl)pyridine 1 j was examined (Scheme 5).Using 2-methylthiophene as the reaction partner, no formation of coupling products 31 a-c was detected by GC/ MS analysis with Pd(OAc) 2 (2 mol%) or PdCl(C 3 H 5 )(dppb) (5 mol%) catalysts, and 3-(2-bromophenyl)pyridine 1 l was recovered unreacted.A similar result was observed with 2butylfuran as the heteroaryl source.This lack of reactivity could be explained by the formation of a stable Pd complex by reaction with 3-(2-bromophenyl)pyridine 1 l or 31 a, as 2-(thiophen-2-yl)pyridines can give stable palladacycles by CÀ H activation. [19] With 5-(2-bromophenyl)pyrimidine 1 q in the presence of 2-methylthiophene, an identical result was observed.The starting material 1 q was recovered and no coupling product was detected, which is consistent with the formation of a stable palladacycle.
To confirm the poisoning of the Pd catalyst by 3-(2bromophenyl)pyridine 1 l, we performed a reaction using an equimolar mixture of 3-and 4-(2-bromophenyl)pyridines 1 a and 1 l with 2-methylthiophene as the heteroaryl coupling partner (Scheme 6).No coupling product formation was detected and arylpyridines 1 a and 1 l were recovered.
The influence of substituents on the adjacent positions of the nitrogen atom of 3-(2-bromophenyl)pyridines was then examined, as their electronic or blocking properties may result The selectivity and yield of the reaction of 1 a with (5methylthiophen-2-yl)boronic acid instead of 2-methylthiophene using the Pd(OAc) 2 /dppf catalyst and KOPiv base were also determined (Scheme 8).Selective formation of the product 4 a from 1,4-migration reaction with Suzuki coupling [20] was also observed, albeit in very low yield (< 10 %).Consequently, the use of the Pd 1,4-migration reaction in combination with direct arylation seems more attractive than Pd 1,4-migration reaction in combination with Suzuki type coupling for the preparation of such compounds.
A possible mechanism for access to 3-heteroarylated pyridines a is described in Scheme 9.The first step is the oxidative addition of aryl bromide to palladium to form intermediate A. Next, ligand exchange with KOPiv and Pd-1,4migration provides intermediate B. After a concerted metallation deprotonation (CMD) [21] of the 5-membered ring heteroarene coupling partner, intermediate C is produced.Finally, reductive elimination affords 4-aryl-3-heteroarylpyridines a with catalyst regeneration.

Conclusions
In summary, bromo-substituent as a traceless directing group was successfully employed to access heteroarylated pyridine derivatives.From both 3-and 4-(2-bromophenyl)pyridines, Pd 1,4-migration combined with direct arylation enabled the introduction of heteroarenes at positions 2, 3 or 4 on the pyridine rings.The new CÀ C bond created during this coupling reaction, results from the functionalization of two CÀ H bonds.The reaction proceeds nicely with a wide variety of heteroarenes and tolerates several substituents on the phenyl and pyridine rings of (2-bromophenyl)pyridines.In addition, this procedure employs an air stable palladium source combined with an inexpensive base and readily available 3-or 4pyridineboronic acids and dihalobenzenes.Consequently, this methodology constitutes a powerful tool for the heteroarylation of pyridines and could certainly be applied to introduce other functional groups on CÀ H bonds of pyridines.

Experimental section
Procedure for the preparation of arylated arylpyridines 2 a-35 a: As a typical experiment, the reaction of the (2-bromoaryl)pyridine derivative 1 a-1 p (1 mmol), heteroarene (2 mmol) and KOPiv (0.280 g, 2 mmol) at 150 °C during 16 h in DMA (4 mL) in the presence of PdCl(C 3 H 5 )(dppb) (12.2 mg, 0.02 mmol) under argon affords the coupling product after evaporation of the solvent and purification on silica gel using a CombiFlash NextGen 300 with Buchi FlashPure cartridges containing 40 μm irregular silica.The a : b ratios were determined by 1 H NMR and GC/MS analysis of the crude mixtures.