Rh(I)-Catalyzed Direct Arylation of Pyridines and Quinolines

Abstract

A Rh(I)-catalyzed direct arylation of pyridine and quinoline heterocycles has been developed. The method provides rapid entry into an important class of bis(hetero)aryl products employing inexpensive and readily available starting materials.The pyridine and quinoline nuclei are privileged scaffolds that occupy a central role in many medicinally relevant compounds. 1 Consequently, methods for their expeditious functionalization are of immediate interest. However, despite the immense importance of transition-metal catalyzed cross-coupling for the functionalization of aromatic scaffolds, general solutions for coupling 2-pyridyl organometallics with aryl halides have only recently been presented. 2 Direct arylation at the ortho position of pyridine would constitute an even more efficient approach because it eliminates the need for the stoichiometric preparation and isolation of 2-pyridyl organometallics. 3,4 Progress towards this goal has been achieved by activation of the pyridine nucleus for arylation via conversion to the corresponding pyridine N-oxide 5 or N-iminopyridinium ylide. 6 However, this approach necessitates two additional steps: activation of the pyridine or quinoline starting material, and then unmasking the arylated product. The use of pyridines directly would clearly represent the ideal situation both in terms of cost and simplicity. We now wish to document our efforts in this vein, culminating in an operationally simple Rh(I)-catalyzed direct arylation of pyridines and quinolines.We recently developed an electron-rich Rh(I) system for catalytic alkylation at the ortho position of pyridines and quinolines with alkenes. 7,8 Therefore, we initially focused our attention on the use of similarly electron-rich Rh(I) catalysts for the proposed direct arylation. After screening an array of electron-rich phosphine ligands and Rh(I) salts, only marginal yields (<20%) of the desired product were obtained. Much more efficient was an electron-poor Rh (I) system with [RhCl(CO) 2 ] 2 as precatalyst (Table 1). 9,10 For the direct arylation of picoline with 3,5-dimethyl-bromobenzene, addition of P(O i Pr) 3 afforded a promising 40% yield of the cross coupled product 1a (entry 1). The exclusion of phosphite additive proved even more effective, with the yield of 1a improving to 61% (entry 2). Further enhancement in yield was not observed upon the inclusion of other additives such as MgO (entry 3), various organic bases (entries 4, 5) and inorganic bases (entry 6), or a protic acid source (entry 7). Absolute concentration proved very important, with the best results being obtained at relatively high jellman@berkeley.edu, rbergman@berkeley.edu. concentrations of the aryl bromide (compare entries 8 and 9). A marginal improvement was observed upon running the reaction with 6 equivalents of 2-methyl pyridine (entry 10). 11,12 NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2009 November 12.The reaction temperature could also be increased to 175 or 190 °C while maintaining rea...

Development of Divergent Synthetic Methods of Pyrimidobenzothiazine and Related Tricyclic Heterocycles

“…This reaction provided compound 20a with 16 O, suggesting that ortho-hydroxyl group was derived from Cu(OAc) 2 [25] Notably, the reaction under an Ar atmosphere gave the product in low yield, suggesting that molecular O 2 participates in the reoxidation of the Cu catalyst.…”

“…In general, C-H functionalization proceeds via metallacycle formation by oxidative addition of transition-metal and subsequent coordination of nucleophile and reductive elimination. Recent research has revealed that nitrogen-containing functional groups such as pyridines [14][15][16], imines [17][18][19], oxazolines [20,21], and amidines [22] effectively act as directing groups for regioselective C-H functionalization.…”

“…This reaction would proceed via a nucleophilic addition of the amidine moiety to heterocumulene followed by an intramolecular S N Ar reaction 16,17 of the resulting adducts such as B (Scheme 2.13). Nonactivated aromatic rings efficiently reacted under relatively mild conditions, so two molecules of the heterocumulene may be involved in the reaction to form the intermediate C in which the amidine moiety can be a more powerful electron-withdrawing group suitable for the S N Artype reaction.…”

Iron‐Catalyzed Direct Arylation of Unactivated Arenes with Aryl Halides

“…[2,3] This strategy efficiently avoids the disposal of stoichiometric amounts of metal waste generated from the organometallic reagent, ArM, in the traditional coupling manner. [2,3] Various transition metals have been reported as efficient catalysts for this transformation, for example, Pd, [4][5][6][7][8][9][10][11] Rh, [12][13][14][15] Ru, [16][17][18] Ir, [19,20] Cu, [21][22][23][24][25][26][27] and other transition metals. [28][29][30] The application of inexpensive, non-toxic, commercially available, and environmentally benign iron complexes as catalysts in chemical syntheses has attracted much attention.…”

“…[*] W. Liu [4][5][6][7][8][9][10][11][12][13][14]. In the presence of DMEDA (40 mol %), the direct arylation of benzene was achieved in 66% yield (Table 1, entry 9), and this result showed that this particular diamine ligand was more efficient than others.…”