Room-Temperature Palladium-Catalyzed Direct 2-Arylation of Benzoxazoles with Aryl and Heteroaryl Bromides

Abstract

An efficient room-temperature palladium-catalyzed direct 2-arylation of benzoxazoles with aryl bromides is presented. The Pd(OAc)₂/NiXantphos-based catalyst enables the introduction of various aryl and heteroaryl groups, via a deprotonative cross-coupling process (DCCP) in good to excellent yields (75–99%).

2-Aryl-substituted benzoxazoles are an important class of heterocyclic compounds that are widely found in bioactive molecules,¹ pharmaceuticals² and natural products.³ As such, several strategies for their construction have been reported.⁴ Starting from benzoxazoles, the most common approach is the transition metal catalyzed direct arylation with aryl halides (Scheme 1A).⁵ 2-Aryl-substitued benzoxazoles can also be prepared by the reaction of benzoxazoles with acyl chlorides or aromatic aldehydes via a ring-opening-ring-closing pathway (Scheme 1B).⁶ These protocols all require high temperatures (>100 °C), which limits the substrate scope with temperature-sensitive heterocyclic aryl halides, such as furan derivatives. Furthermore, in many cases these reactions were performed in high boiling solvents, such as DMSO, DMF, and NMP, which complicate product isolation..

Scheme 1.

Synthesis of 2-arylbenzoxazoles

Our group has been interested in the functionalization of weakly acidic sp³ C–H bonds through deprotonative cross-coupling processes (DCCP), wherein the a weakly acidic C–H of the substrate is deprotonated by a base and functionalized in the presence of a transition metal catalyst. Substrates reported to date include chromium-activated benzylic amines,⁷ diarylmethanes,⁸ allylarenes,⁹ amides,¹⁰ sulfones,¹¹ sulfoxides,¹² imines,¹³ phosphine oxides¹⁴ and benzylic phosphonates.¹⁵ We have found that van Leeuwen’s NiXantphos¹⁶ (See Scheme 1 for structure) enables a number of these transformations, whereas other ligands are significantly less effective or fail to provide even trace products.^{8, 12a, 13} The high reactivity of the NiXantphos-based palladium catalysts may be due to the deprotonation of the ligand N–H under basic reaction conditions.^8a Based on these studies, we decided to examine DCCP of sp² C–H bonds. Given the high temperature for metal-catalyzed direct 2-arylation of benzoxazoles, in combination with the importance of these compounds, we viewed this coupling as an ideal testing ground for NiXantphos-based catalysts. Herein, we report a Pd(OAc)₂/NiXantphos-catalyzed direct 2-arylation of benzoxazoles with aryl bromides at room temperature (Scheme 1C). Unlike most catalyst systems,⁵ this catalyst promotes coupling with heteroaryl bromides.

Our investigations into the direct 2-arylation of benzoxazoles were initiated by testing six bases [LiOtBu, NaOtBu, KOtBu, LiN(SiMe₃)₂, NaN(SiMe₃)₂ and KN(SiMe₃)₂] in THF at 65 °C using benzoxazole 1a (1.0 equiv) and 1-bromo-4-tert-butylbenzene 2a (1.2 equiv, Table 1, entries 1–6). The nature of the base had a significant impact on the yield under these conditions, with NaOtBu affording the coupling product 3a in quantitative assay yield after 12 h (Table 1, entry 2). When the reaction temperature was reduced to room temperature, however, the assay yield dropped to 55% (entry 7). We then screened several solvents [DME (1,2-dimethoxyethane), CPME (cyclopentyl methyl ether), toluene and 1,4-dioxane] at rt and obtained 93% assay yield when the reaction was conducted in DME (entry 8). Under these conditions, trace unconverted benzoxazole 1a was detected. Using a benzoxazole to aryl bromide ratio of 1.2: 1.0 at rt, the coupling product 3a was isolated in 98% yield. When the catalyst/ligand loading was lowered, or the reaction time reduced, the reactions did not go to completion.

Table 1.

Optimization of direct 2-arylation of benzoxazole 1a with 1-bromo-4-tert-butylbenzene 2a^a

entry	base	solvent	T (°C)	yield (%)b
1	LiOtBu	THF	65	56
2	NaOtBu	THF	65	100
3	KOtBu	THF	65	98
4	LiN(SiMe3)2	THF	65	90
5	NaN(SiMe3)2	THF	65	88
6	KN(SiMe3)2	THF	65	60
7	NaOtBu	THF	25	55
8	NaOtBu	DME	25	93
9	NaOtBu	CPME	25	72
10	NaOtBu	toluene	25	trace
11	NaOtBu	1,4-dioxane	25	8
12c	NaOtBu	DME	25	98d

^aReactions performed using 1.0 equiv of 1a, 1.2 equiv of 2a and 2.0 equiv of base on a 0.1 mmol scale in 12 hours.

^bNMR assay yields.

^cThis reaction performed using 1.2 equiv of 1a, 1 equiv of 2a and 2.4 equiv of NaOtBu.

^dIsolated yield.

The substrate scope of aryl bromides 2a–s with benzoxazole 1a was investigated (Scheme 2) with the optimized reaction parameters [benzoxazole 1a (1.2 equiv), aryl bromide 2 (1.0 equiv), Pd(OAc)₂ (5 mol %), NiXantphos (7.5 mol %), and NaOtBu (2.4 equiv) in DME at room temperature for 12 h]. In general, aryl bromides possessing electron-donating, electron-withdrawing and sterically hindered substituents afforded products in good to excellent yields (60–99%).

Scheme 2.

Scope of aryl bromides in direct 2-arylation of benzoxazole 1a

Electron neutral 4-tert-butyl bromobenzene and the parent bromobenzene led to the expected products in 98 and 92% yield, respectively. Aryl bromides bearing 4-methoxy and 4-N,N-dimethylamino substituents gave coupling products 3c and 3d in 88 and 86% yield, respectively. Electron withdrawing substituents (4-Cl, 4-F, and 4-CN) on the aryl bromide were well tolerated, providing products in 81–99% yield. The most challenging substrate for this system was N-(4-bromophenyl)acetamide, with an acidic N–H that could also undergo Buchwald-Hartwig coupling with itself.¹⁷ In this case, the Pd(OAc)₂/NiXantphos-based catalyst exhibited good chemoselectivity, generating the 2-aryl benzoxazole product 3h in 60% yield. Both of 3-bromotoluene and 3-bromobenzotrifluoride provided the coupling products 3i and 3k in 85% yield. Sterically hindered 1-bromonaphthylene was a good substrate, furnishing the coupled 2-arylbenzoxazole 3j in 84% yield.

As mentioned earlier, coupling of heteroaryl bromides is particularly important, but more challenging. To evaluate Pd(OAc)₂/NiXantphos-based catalyst, we examined a series of heteroaromatic coupling partners with benzoxazole. The reactions proceeded very well with heteroaryl bromides such as 3-bromopyridine, 2-bromofuran, 2- and 3-bromothiophenes, 4-bromoquinoline, 3-bromobenzothiophene and 5-bromobenzofuran to afford products in 75–98% yield. It should be noted that direct arylation of benzoxazoles with aryl heteroaryl bromides was carried out with excess amounts of heteroaryl bromides due to possible competing Heck-type reactions. Because of high chemoselectivity of the Pd(OAc)₂/NiXantphos-based catalyst, we were able to use heteroaryl bromides as a limiting reagent. To the best of our knowledge, this is the first successful coupling with sensitive 2-bromofuran (2m).

Based on the successful room temperature coupling of benzoxazole with aryl bromides, we briefly explored the scope of substituted benzoxazoles (Scheme 3). In each case, benzoxazoles substituted with neutral, electron-rich or electron-withdrawing groups coupled with heterocyclic aryl bromides to generate diheteroaryl products with an average yield of 90%. Benzoxazoles possessing chlorine, fluorine, methyl, or methoxy groups coupled with 2-bromothiophene to provide 2-(thiophen-2-yl)benzoxazoles 3t and 3w–y in ≥90% yield at room temperature. DCCP of 5-chlorobenzoxazole with 3-bromothiophene or 3-bromopyridine afforded 5-chloro-2-(thiophen-3-yl)benzoxazole 3u and 5-chloro-2-(pyridin-3-yl)benzoxazole 3v in 86–88% yield.

Scheme 3.

Scope of substituted-benzoxazoles in the arylation with heteroaryl bromides

We also evaluated the scalability of the DCCP by performing the coupling of 5-chlorobenzoxazole 1b with 2-bromothiophene 2o on gram scale. The coupling product, 5-chloro-2-(thiophen-2-yl)benzoxazole 3t was isolated in 84% yield. This yield is reasonably high, considering that the Pd(OAc)₂/NiXantphos-based catalyst can activate aryl chlorides in related reactions.^8a Surprisingly, however, aryl chlorides were not successful coupling partners with benzoxazoles under these reaction conditions.

In summary, we have developed the first room-temperature direct arylation of benzoxazoles with aryl bromides and heteroaryl bromides. The coupling reaction shows good substrate scope and proceeds in high yields (average > 85%). Other catalysts that promote this reaction are typically employed at temperatures >100 °C and exhibit only limited substrate scope. The key to success of our reaction is the Pd(OAc)₂/NiXantphos-based catalyst, which operates via a deprotonative cross-coupling process. This work is the first demonstration that the Pd(OAc)₂/NiXantphos-based catalyst is capable of promoting efficient functionalization of sp² hybridized C–H bonds. We expect that this catalyst will be applicable to many of the known arylation reactions that involve deprotonation of substrates possessing weakly acidic sp² hybridized C–H’s.

Scheme 4.

Arylation of 5-chlorobenzoxazole with 2-bromothiophene on gram scale