Evaluation of Electron‐Deficient Phosphine Ligands for Direct Arylation of Heterocycles

Abstract

New electron-deficient biarylphosphine ligands were studied and proved to be efficient for the direct arylation of heteroarenes with aryl iodides. The ability of a more electron-deficient palladium centre to accelerate the arylation of heterocycles that remained unreactive with aryl iodides in the past has been validated and these heteroarenes can now be smoothly reacted in the presence of a new electrophilic catalyst. Experimental evidence suggests a viable concerted metalation-deprotonation pathway for the C À H bond cleavage step with an electron-deficient palladium centre.Keywords: concerted metalation-deprotonation; direct arylation; heterocycles; palladium; phosphine ligands Heterocyclic biaryl compounds are predominant in natural products [1] and medicinal compounds.[2] Although the traditional methods to prepare these valuable motifs necessitate the use of a stoichiometric amount of organometallic coupling partner through transition metal catalysis, [3] more efficient processes in which the organometallic species can be replaced by a simple heteroarene have proven to be a viable alternative for the preparation of heteroatom-containing biaryls. [4,5] However, general conditions that are widely compatible with all classes of heterocyclic coupling partners are only sparsely reported [6] and the use of a different set of conditions for each class of substrate remains the norm. In order to further improve direct arylation and establish more broadly applicable reaction conditions, a better understanding of the reaction mechanism and the development of novel high-performance ligands are essential.As part of a program dedicated to the study of the direct arylation mechanism and the development of broadly applicable reaction conditions, we became interested in investigating the effect of electron-deficient phosphine ligands [7] on the C À H bond cleavage step of this process under Pd(0) catalysis. Whilst most of the focus has traditionally been on the study of electron-rich ligands, few studies on the effect of electron-deficient phosphine ligands are described in the literature.[4] Reports by Baudoin, [8] Gevorgyan [9] as well as our group [10] have validated the efficiency of electron-deficient ligands in intramolecular processes with Pd(0) catalysts. Additionally, new intermolecular reactions using p-accepting phosphite ligands have also been observed by Itami and co-workers under Rh(I) catalysis.[11]Herein, we report the development of a new class of electron-poor fluoroarylphosphine ligands that is compatible with a broad variety of heterocycles. We demonstrate that a more electron-deficient metal centre accelerates the direct arylation reaction and also report evidence that a concerted metalationdeprotonation (CMD) mechanism [12] is operative. These results should encourage further investigation of electron-deficient ligands in new transition metalcatalyzed transformations.In our initial ligand design studies, we focused our efforts toward the synthesis of biaryl-type phosphine ligands bearing elec...

Cu/Pd‐Catalyzed C‐2–H Arylation of ­Quinazolin‐4(3H)‐ones with (Hetero)aryl Halides

“…In addition, direct arylation by a concerted metalation-deprotonation process, which tends to be accelerated by an electron-poor phosphine ligand, [15] was also ruled out. Indeed, phosphines bearing fluoro substituents, such as P(C 6 F 5 ) 3 , did not increase the activity of the palladium catalyst and did not show any ligand acceleration effect (Table 1, Entry 6).…”

“…For chlorobenzene, Pd 0 complexes with PPh 3 or bidentate ligands such as 1,3-bis(diphenylphosphanyl)propane (dppp), 1,3-bis(diisopropylphosphanyl)propane (dippp), 1,2-bis(dicyclohexylphosphanyl)ethane (dCype), 1,1Ј-bis(di-tert-butylphosphanyl)-ferrocene (dbpf), or 4,5-bis(diphenylphosphanyl)-9,9-dimethylxanthene (Xantphos) were all inactive (Table 1, Entries [8][9][10][11][12][13][14][15]. [10] On the basis of the ability of palladium complexes of 4,6-bis(diphenylphosphanyl)phenoxazine (the NiXantphos ligand of Van Leeuwen) to effectively crosscouple organometallics with aryl chlorides, [11] the reaction was examined with 6 mol-% of this ligand.…”

Cross‐Coupling of Heteroarenes by CH Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom

“…of 4-iodotoluene gave compound 77 ( Figure 14) in 46% yield and the C-5 arylation of 72 with methyl 4-iodobenzoate gave compound 78 ( Figure 14) in 43% yield. [51] A year later, after a short ligand optimization, Daugulis and co-workers found that when NMP was used as the solvent, K 3 PO 4 was the base and the catalyst system consisted of a mixture of 5 mol% PdA C H T U N G T R E N N U N G (OAc) 2 and 10 mol% 2-(dicyclohexylphosphino)biphenyl (L4), furan (79) and its 2-substituted derivatives 48 and 49 underwent arylation at position 5 with electron-rich and electron-poor aryl chlorides as well as 2-chloropyridine in good to excellent yields (Scheme 32). [52] Ligands such as dicyclohexylphenyl-, tricyclohexyl-and n-butyl-bis(1-adamantyl)phosphine proved to be not effective.…”

“…of Ag 2 CO 3 as the promoting agent, DMA as the solvent and a catalyst system composed of 5 mol% PdA C H T U N G T R E N N U N G (OAc) 2 , 10 mol% electron-deficient phosphane ligand L3 and 30 mol% pivalic acid. [51] The reaction (Scheme 105) gave 1,2,5-trisubstituted pyrrole 201 in 43% yield. In 2011, El Abed, Doucet and co-workers demonstrated that the PdClA C H T U N G T R E N N U N G (C 3 H 5 )A C H T U N G T R E N N U N G (dppb)-catalyzed reaction between 1.5 equiv.…”

“…[50] In 2010, ligand L3, an electron-deficient variant of the S-Phos ligand ( Figure 13), was employed as a component of the catalyst system developed for the direct arylation of heteroarenes, including 2-substituted furans 7g and 72, 2-substituted thiophene 13a, benzo[b]thiophene (68), 2-isobutylthiazole (73), 1-methyl-2-acetylpyrrole (74), 1-methylimidazole (75), 1-phenylpyrazole (76) and 4-butyl-1-phenyl-1,2,3-triazole (77) (Figure 13) with aryl iodides. [51] The highly selective reactions were carried out in DMA at 100 8C for 16 h in the presence of 5 mol% PdA C H T U N G T R E N N U N G (OAc) 2 , 10 mol% L3, 30 mol% PivOH, 0.5 equiv. of Ag 2 CO 3 and 1.5 equiv.…”