Highly Regioselective Palladium-Catalyzed Direct Arylation of Oxazole at C-2 or C-5 with Aryl Bromides, Chlorides, and Triflates

Abstract

Complementary palladium-catalyzed methods for direct arylation of oxazole with high regioselectivity (>100:1) at both C-5 and C-2 have been developed for a wide range of aryl and heteroaryl bromides, chlorides, iodides, and triflates. C-5 arylation is preferred in polar solvents with phosphines 5 or 6, whereas C-2 arylation is preferred by nonpolar solvents and phosphine 3. This represents the first general method for C-5 selective arylation of oxazole and should see broad applicability in the synthesis of biologically active molecules. Additionally, potential mechanisms for these two competing arylation processes are proposed on the basis of mechanistic observations.

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

“…In 2010, Strotman and Chobanian reported the first highly challenging C2- and C5-selective Pd(0)-catalyzed direct arylation of oxazole with arylbromides, chlorides and triflates (Scheme 15 ) [63]. Interestingly, under the same catalytic conditions, the C2 (versus C5) position was preferred in nonpolar toluene solvent (versus polar DMF solvent) with RuPhos ligand (versus CataCXium ® A or 3,4,5,6-tetramethyl- tert -butyl-XPhos ligands).…”

“…Deuterium-incorporation experiments and DFT calculations highly support this pathway as well as the successful palladium-catalyzed arylation of the O -silylated 2-isonitrilephenolate (Scheme 19). Last year, Strotman and Chobanian retained this cross-coupling-type mechanism for their recently developed protocol for the Pd(0)-catalyzed, highly C2-selective, direct (hetero)arylation of oxazole [63]. …”

Potentiation of the fosmidomycin analogue FR 900098 with substituted 2-oxazolines against Francisella novicida

“…Arylation of oxazole was achieved by reacting 2 equivalents of oxazole with aryl bromides ( 3a and 4a ) using Pd(OAc) 2 , KOH, and RuPhos in refluxing toluene (Scheme 3). 25 Neither of the oxidized derivatives 3b or 4b , showed any activity as compared to the more saturated oxazolines. Other heterocylic heads were heads incorporated into the oxazolines position by standard Suzuki coupling conditions.…”

Cyclopentyl Methyl Ether: An Alternative Solvent for Palladium‐Catalyzed Direct Arylation of Heteroaromatics

“…Since the 2-arylation of benzoxazole and the 5-arylation of thiazoles proceed by different mechanisms, we expected different reactivities for these two heteroarenes. The direct 2-arylation of oxazoles seemed to proceed through a simple deprotonation of the oxazole by the base, [18] whereas the 5-arylation Some ethers, such as cyclopentyl methyl ether and di-n-butyl ether, which can be considered as "greener" solvents than N,Ndimethylacetamide (DMAc) or DMF, can be advantageously employed for the palladium-catalyzed direct arylation of heteroaromatics. In the presence of such ethers and only 0.5-1 mol % of palladium catalysts at 125-150 8C, the direct 5-arylation of thiazoles, thiophenes, or furans by using aryl bromides as coupling partners proceeds in moderate to high yields.…”

“…At a higher temperature (125 8C) using as little as 0.5 mol % Pd(OAc) 2 , product 2 was obtained in 88 % yield ( [14][15][16][17][18]. Therefore, we employed Pd(OAc) 2 as the catalyst for the arylation of 2-n-propylthiazole with other aryl bromides.…”