Ruthenium(II) Acetate Catalyzed Synthesis of Silylated Oxazoles via C

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Ruthenium(II) Acetate Catalyzed Synthesis of Silylated Oxazoles via C−H Silylation and Dehalogenation Shun Liu, Shiling Zhang, Qiao Lin, Yiqi Huang, and Bin Li* School of Biotechnology and Health Sciences, Wuyi University, 22 Dongchengcun, Jiangmen 529020, P.R. China

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S Supporting Information *

ABSTRACT: An efficient ruthenium(II)-catalyzed intermolecular selective ortho C−H silylation of 2-aryloxazoles has been described for the first time, which provides a convenient and practical pathway for the synthesis of versatile organosilane compounds with good functional group tolerance and regioselectivity. This catalytic system could be also applied to the dehalogenation of Cl or Br group.

D

halides,17 and alkenes18 (Scheme 1). However, only few reports described the synthesis of silyl-functionalized oxazoles

evelopment of efficient synthetic methods for C−Si bond formation is an important research area in synthetic chemistry because organosilane compounds are not only important structural units existing in advance materials and pharmaceuticals1 but also valuable key synthetic intermediates for chemical transformations of various useful molecules.2 Pioneering classical reactions of halo- or alkoxysilane with aryl Grignard or lithium reagents have been demonstrated as useful synthetic methods for the synthesis of organosilane. However, the formation of waste inorganic salts, low functional group tolerances, and a multistep synthetic sequence still remain elusive and highly challenging.3 Due to the high atom and step economy, transition-metal-catalyzed C−H bond activation has emerged as a competitive alternative strategy for C−Si bond construction to access functional organosilane compounds.4 Although prodigious advances in the C−H silylation of aromatic C−H bonds have been developed using Ir, Rh, or Ru(0) catalysts in recent years,5 the use of easy-to-prepare and more stable ruthenium(II) catalysts for C−H silylation were much less reported, which could facilitate the deprotonation of C−H bonds before any oxidative addition with respect to the ruthenium(0) catalysts.6 Recently, Huang reported a C2selective silylation of O- and S-heteroarenes by using an efficient pincer Ru(II) catalyst.7 Pilarski demonstrated RuH2(CO)(PPh3)3-catalyzed C−H silylation of heteroarenes with Et3SiH using amines as directing groups.8 Murata developed a Ru(cod)(cot) catalytic system for the C−H silylation of amide using (Me3SiO)2MeSiH as the silylated reagent at 200 °C.9 During the past few years, the Ru(II) carboxylate catalytic system has shown efficiency on C−H bond functionalizations, such as arylation,10 alkenylation,11 annulation,12 borylation,13 etc.; however, the application of the Ru(II)-carboxylate catalytic system on selective C−H silylation is still not developed. Oxazole motifs are important structure units in pharmaceutical applications and efficient ligands in coordination chemistry and catalysis.14 Thus, various efficient procedures for oxazole derivatives synthesis have been developed,15 even Ru(II)-catalyzed C−H bond functionalization protocols mainly via reaction with alkenyl halides,16 (hetero)aryl © XXXX American Chemical Society

Scheme 1. Ru(II)-Catalyzed C−H Bond Activation of 2Aryloxazoles

via intermolecular ortho C−H silylation with oxazole as the directing group with Ru(0) catalyst,19 and Murata succeeded in performing aromatic C−H silylation with few oxazoles using (Me3SiO)2MeSiH as a silylating reagent at high temperature (200 °C) using a [RuCl2(p-cymene)]2 catalytic system.20 Herein, we reported the first application of a Ru(II)−OAc catalytic system on selective ortho C−H silylation for the synthesis of silyl-functionalized oxazole derivatives (Scheme 1). Initially, 2-phenyloxazoline (1a) and triethylsilane were chosen as starting materials to optimize the reaction conditions Received: January 8, 2019

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DOI: 10.1021/acs.orglett.9b00085 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

silanes give the low yields and seem not favor this ortho C−H silylation (see the SI). The scope and limitations of this first Ru(II)−OAccatalyzed selective ortho C−H silylation of oxazole derivatives with Et3 SiH were then explored using 5 mol % of [Ru(COD)Cl2]n as catalyst, 50 mol % of KOAc as co-catalyst, and 4 equiv of norbornylene as hydrogen acceptor to produce the silylated oxazole compounds at 120 °C under N2 (Table 1, entry 7). Various 2-aryloxazolines 1 and 2-arylbenzoxazoles 3 were applied to the synthesis the silylated oxazole derivatives. As shown in Scheme 2, silylated oxazoline 2a, which was

(Table 1). No desired product was observed in the presence of 50 mol % of KOAc in toluene at 120 °C under N2 by using 5 Table 1. Optimization of Ru(II)-Catalyzed Ortho C−H Silylation of 2-Phenyloxazolinea

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

catalyst [RuCl2(p-cymene)]2 (5) RuCl2(2,2′-bipyridyl)3· 6H2O (5) RuCl2(PPh3)3 (5) RuH2(CO)(PPh3)3 (5) RuHCl(CO)(PPh3)3 (5) RuCl3.(H2O)n (5) [Ru(COD)Cl2]n (5) [Ru(COD)Cl2]n (5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5) [Ru(COD)Cl2]n (2.5)

solvent

GC yield (%)

KOAc KOAc

toluene toluene

0 0

KOAc KOAc KOAc KOAc KOAc KOAc KOAc KOtBu KPF6 C6H5CO2K − KOAc KOAc KOAc

toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene THF CH3CN

18 19 87 67 99 (88c) 28d 54 0 51 8 trace 8b 0b 0b

additive

Scheme 2. Ru(II)−OAc-Catalyzed Ortho C−H Silylation of 2-Aryloxazolinesa

a

Conditions: 2-phenyloxazoline 1a (0.5 mmol), Et3SiH (2.0 mmol), Ru catalyst, additive (0.25 mmol), NBE (2 mmol), solvent (1 mL), at 120 °C for 20 h, under N2. bAt 80 °C. cIsolated yield of 2a. dWithout NBE.

mol % of [RuCl2(p-cymene)]2 or 5 mol % of RuCl2(2,2′bipyridyl)3·6H2O as catalyst (Table 1, entries 1 and 2). By using RuCl2(PPh3)3 as catalyst, 18% yield of silylated oxazoline product 2a was detected (entry 3). When RuHCl(CO)(PPh3)3 was employed as the catalyst, the yield of silylated oxazoline product 2a reached 87% (entry 5). Furthermore, complete conversion of silylated oxazoline product 2a was reached, and 88% yield was successfully isolated in the presence of 5 mol % of [Ru(COD)Cl2]n after 20 h at 120 °C (entry 7). Only 28% yield of silylated oxazoline product 2a was obtained in the absence of norbornene (NBE) (entry 8). However, by decreasing the catalyst loading to 2.5 mol %, 54% yield of silylated oxazoline product 2a was obtained (entry 9). Other additives, such as KOtBu, KPF6, and C6H5COOK, could not give better results under this C−H silylation (entries 10−12). The absence of KOAc also gave low conversion for this C−H silylation, which indicated that KOAc plays an important role in coordination to the ruthenium center for promoting the selective C−H silylation. On the other hand, no conversion of product 2a was detected when this reaction was performed in THF or CH3CN at 80 °C (entries 15 and 16). It is noteworthy that the excess of Et3SiH in this catalytic system is necessary because of the kinetic effect, which plays an important role in promoting this C−H silylation. As compared to other silanes, such as Ph3SiH, (EtO)3SiH, (Me)2PhSiH, (Me)2EtOSiH, and Me(EtO)2SiH, Et3SiH as the most efficient coupling reagent could lead to the desired product in good yield, and other

a

Conditions: 2-aryloxazoline 1 (0.5 mmol), Et3SiH (2.0 mmol), [Ru(COD)Cl2]n (0.025 mmol), KOAc (0.25 mmol), NBE (2 mmol), toluene (1 mL), at 120 °C for 20 h, under N2.

silylated at the ortho position on 2-phenyloxazoline 1a, was isolated in 88% yield. The selective C−H silylation could be carried out with −Me, −OMe, and −F groups at the para or meta positions on the oxazoline R1 aryl and give the corresponding products 2b−g in 55−85% isolated yields. Importantly, the ester group on the oxazoline aryl ring could be tolerated, and the corresponding silylated oxazoline product 2h was directly obtained without the hydrosilane addition of the carbonyl moiety. Additionally, this Ru(II)−OAc-catalyzed ortho C−H silylation also proceeded well with the 2heteroaromatic oxazolines containing thiophene and furan groups and leading to the corresponding silylated oxazoline products 2i−k in 83, 78, and 72% isolated yields, respectively. Additionally, various benzo[d]oxazole derivatives were investigated for the Ru(II)−OAc-catalyzed ortho C−H silylation for the first time (Scheme 3). In general, electrondonating substituents such as Me and MeO at the ortho-, meta-, or para-position on the aryl ring were compatible with B

DOI: 10.1021/acs.orglett.9b00085 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Ru(II)−OAc-Catalyzed Ortho C−H Silylation of 2-Arylbenzo[d]oxazolesa

Scheme 4. Ru(II)−OAc-Catalyzed Ortho C−H Silylation and Dehalogenation of 2-Arylbenzo[d]oxazoles

a

silylation and dehalogenation of the Cl or Br group. Moreover, when the reaction with compound 1l was performed under similar conditions but at lower temperature (80 °C), only 32% yield of 2-phenyloxazoline as dehalogenated product was obtained, and no silylated product was detected. These results indicated two points: (1) the reaction rate of dehalogenation is much faster than C−H silylation and (2) the Ru(II)−OAc/ hydrosilane catalytic system could potentially be useful for application in dehalogenation reactions, as dehalogenation of organic halides has attracted much attention not only as a synthetic method but also from their potential use for detoxification of environmentally hazardous organic halides.21 Furthermore, oxazole derivative 4,4-dimethyl-2-phenyl-4,5dihydrooxazole 1m was also examined for the directed orthosilylation, which successfully led to desired silylated compound 2l in 75% isolated yield (eq 3).

Conditions: 2-arylbenzo[d]oxazoles 3 (0.5 mmol), Et3SiH (2.0 mmol), [Ru(COD)Cl2]n (0.025 mmol), KOAc (0.25 mmol), NBE (2 mmol), toluene (1 mL), at 120 °C for 20 h, under N2.

this Ru(II)−OAc-catalyzed ortho C−H silylation, affording to the desired silylated products in moderate to excellent yields (4b−g). These results indicated that the steric effect of the donating group did not hamper the reaction. The electronwithdrawing groups such as CO2Me and F at the para-position on the aryl ring also proceeded well for this reaction (4h and 4i), and no reduction of CO2Me group was detected with Et3SiH as reductant. The structure of compound 4h was confirmed by X-ray crystallography. Moreover, thiophenecontaining silylated benzo[d]oxazole products were successfully synthesized in 83% or 85% yields (4j and 4k), while only 57% yield was obtained for 2-(3-(triethylsilyl)furan-2-yl)benzo[d]oxazole (4l). Interestingly, when this reaction was performed with HSiEt3 and compounds 3m−o which bear a −Cl or −Br group at the ortho- or para-position under similar conditions, the silylated product 4a was selectively obtained in 76−83% isolated yields (Scheme 4). Analogously, 65% yield of silylated product 2a was isolated in the presence of 2-(4-chlorophenyl)-4,5dihydrooxazole 1l (eq 1). Compound 4a or 2a in these reactions results formally from a “one-pot” ortho C−H

The ease and reversibility of the ortho C−H bond cleavage were studied by H/D exchange. First, the reaction of 1a in the presence D2O (0.2 mL) was carried out at 120 °C for 12 h. Only 5% of H/D exchange took place at the ortho C−H bond (Scheme 5). However, the same reaction performed with 0.5 equiv of KOAc led to an increased H/D exchange at the ortho Scheme 5. H/D Exchange Experiments in 2Phenyloxazoline 1a

C

DOI: 10.1021/acs.orglett.9b00085 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters position (50%) at 120 °C for only 12 h, which indicated that the KOAc plays an important role in promoting this C−H silylation. To gather more information, we performed competitive experiments under this Ru(II)−KOAc catalytic system. These studies revealed that the electron-rich arenes gave slight higher reactivity in this C−H silylation, which could be explained by an acetate-assisted electrophilic substitution (IES)-type mechanism22d (Scheme 6).

Ru(II)−OAc catalyst could be regenerated for the next catalytic cycle. In summary, we have developed a new Ru(II)−OAc catalytic system and its application in the ortho C−H silylation of 2-aryloxazole derivatives using HSiEt3 as the silylating reagent. Various oxazolines and benzo[d]oxazoles were successfully converted to monosilylated compounds in moderate to excellent yields. Moreover, this catalytic system could be applied to the dehalogenation of a Cl or Br group. A mechanism of Ru(II)−OAc-catalyzed ortho C−H silylation of 2-aryloxazoles was proposed. Further studies on the mechanism of Ru(II)−OAc dehalogenation with hydrosilane are currently underway.

Scheme 6. Competitive C−H Silylation Reaction

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00085. Experimental procedure and product characterization (PDF)

For the Ru(II)−OAc-catalytic C−H bond activation, the use of OAc− as the co-catalyst to the Ru center promoted cleavage of the aryl ortho C−H bond has been well demonstrated.22 On the other hand, for the Ru(II)-catalyzed hydrosilylation, Gunanathan and co-workers demonstrated that ruthenium(IV) can easily formed by the triethylsilane oxidative addition to Ru(II) center.23 On the basis of the previous works, a proposed catalytic cycle for the [Ru(COD)Cl2]n/KOAccatalyzed ortho C−H silylation of 2-aryloxazole derivatives is illustrated in Scheme 7. By salt metathesis with KOAc, the

Accession Codes

CCDC 1862519 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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Scheme 7. Proposed Mechanism

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Bin Li: 0000-0001-5173-1098 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge support from the National Natural Science Foundation of China (No. 21702148) and the Foundation of Department of Education of Guangdong Province.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b00085 Org. Lett. XXXX, XXX, XXX−XXX