Reaction Conditions for the Regiodivergent Direct Arylations at C2‐ or C5‐Positions of Oxazoles using Phosphine‐Free Palladium Catalysts

Abstract

Two sets of reaction conditions for the regiodivergent C2-or C5-direct arylations of oxazole are reported. In both cases, phosphine-free catalysts and inexpensive bases were employed allowing the access to the arylated oxazoles in moderate to high yields. Using Pd(OAc)2/KOAc as catalyst and base, regioselective C5arylations were observed; whereas, using Pd(acac)2/Cs2CO3 system, the arylation occurred at the C2-position of oxazole. The higher reactivity of C5-H bond of oxazole as compared to the C2-H bond in the presence of Pd(OAc)2/KOAc system is consistent with a concerted metalation deprotonation mechanism; whereas the C2-arylation likely occurs via a simple base deprotonation of the oxazole C2-position. Then, from these C2-or C5-arylated oxazoles, a second palladium-catalyzed direct C-H bond arylation affords 2,5diaryloxazoles with two different aryl groups. We also applied these sequential arylations to the straightforward synthesis of 2-arylphenanthro[9,10-d]oxazoles via three C-H bond functionalization steps. The Ru-catalyzed C-H arylation of the aryl unit of 2-aryloxazoles is also described.

Effective Tools for the Metal‐Catalyzed Regiodivergent Direct Arylations of (Hetero)arenes

“…Indeed, in 2019 we reported that the regioselectivity of the direct arylation of oxazole can be controlled using the appropriate base [7] . From phosphine‐free Pd(OAc) 2 catalyst associated to KOAc, regioselective C5‐arylations, which likely proceed via a CMD mechanism, were observed (Scheme 1, a).…”

“…We also studied the reactivity of 2‐aryloxazoles using Pd and Ru catalysts [40] . From 2‐aryloxazoles and a set of electron‐rich or ‐poor aryl bromides, in the presence of Pd(OAc) 2 catalyst, the 2,5‐diaryloxazoles were obtained with complete regioselectivity and high yields (Scheme 22, a).…”

Effective C5‐Arylation of Peptide‐Integrated Oxazoles: Almazole D

“…For highly substituted oxazoles some de novo syntheses have been described that allow for their assembly, [17] but are difficult to apply for late‐stage diversification. Moreover, (catalytic) C–H activation of the oxazole ring has been reported, [18–20] such as C5‐functionalization by imidation, [21] alkylation, [22] acylation, [23] alkenylation, [24] or arylation [25] . Several protocols for regioselective C−H activation have been developed, [19,20,26,27] but typically were applied to structurally simple oxazoles stabilized by a C2‐(hetero)aryl group.…”

“…Moreover, (catalytic) C–H activation of the oxazole ring has been reported, [18–20] such as C5‐functionalization by imidation, [21] alkylation, [22] acylation, [23] alkenylation, [24] or arylation [25] . Several protocols for regioselective C−H activation have been developed, [19,20,26,27] but typically were applied to structurally simple oxazoles stabilized by a C2‐(hetero)aryl group. Alternatively, transition metal‐mediated cross‐couplings of 5‐bromooxazoles [27–29] and oxazolyl‐5‐ethers [30] have been realized, but often suffer from limited substrate scope as well as modest stability of the oxazole ring such activated.…”

The Use of 5-Hydroxymethylfurfural towards Fine Chemicals: Synthesis and Direct Arylation of 5-HMF-Based Oxazoles

“…Among these, aryl halides are a cost-effective option that is commercially available in a wide range from different suppliers. The described methodologies for the C 2arylation of 5-aryl-oxazole and benzoxazole using aryl halides report an activation by palladium catalysts (such as Pd(OAc) 2 , 38 Pd(acac) 2 , 50 PdCl 2 (dppf), Hermann-Beller palladacycle, 51 Pd(phen) 2 (PF 6 ) 2 , 52 and Pd(PPh 3 ) 4 53,54 ), nickel catalysts (such as NiBr 2 , 55 Ni(OAc) 2 56 and Ni(COD) 2 57 ), or by equimolar amounts of copper(I) salts (mainly CuI). 58,59 In these methods, the use of both carbonate or alkoxide bases is reported, which suggests that the reaction might go through S E Ar-or CMD-type mechanisms depending on the conditions.…”